In section 1.4, the reactions of enaminonitrile 1.31 with C-electrophiles will be reviewed.

 and subsequently improved by Swiss ones (Scheme 1.15, route 2); 28 those strategies were related to the reduction of β-diketones 1.33. Scheme 1.15. Synthesis of 2-R-(indolin-2-ylidene)ketones / esters 1.34 by the reduction of β-diketone derivatives 1.33. Compounds 1.33 were synthesized by the condensation of 2-(2nitrophenyl)acetyl chloride 1.32 with methylene active compounds 1.35 (Scheme 1.15, route 1), 27 or with methoxy-magnesium derivative of dimethylmalonate 1.36. 28

 The starting compounds were aldehyde, phenylhydroxylamine and cyanoallen. The reaction intermediates N-phenylnitrons were converted to 2-vinylindole derivatives by means of tandem reactions: 1,3dipolar cycloaddition, Cope rearrangement, retro-Michael addition, and indolization (Scheme 1.16). The reaction proceeds at 20-60 °C in ethanol. According to the structure simplicity of the starting materials, as well as the number of steps, the reaction yield can be seen as satisfactory (36-77%).

PREFACE

Volovenko for giving me the opportunity to work within their research groups. I am grateful for all the efforts they being made for successful passing of this study, for their professional guidance and contribution of time that made me grow up professionally.

I am also most indebted to Dr. Olga V. Khilya (UNTS), who helped me to take my first steps in the scientific world and whose guidance and help I have been privileged to enjoy whenever problems got tough.

My sincere thanks are to Dr. Tetyana Ie. Keda (UNTS) for her valuable advices and significant intellectual contribution into this study.

GENERAL INTRODUCTION

Among the different fields of organic chemistry, Heterocyclic Chemistry is one of the most developed both in terms of methods and applications. Indeed, many textbooks are now nicely giving a detailed overlook of the various general methods available for the building up of heterocycles, and their further functionalizations. Yet, if the preparation of the heterocycles is following well established strategies, the preparation of their precursors can be somehow a little bit tedious. This aspect is one of the major topics described in this manuscript. Indeed, we have been investigating short, efficient, in other words user friendly approaches to precursors of small heterocycles, especially pyrazoles and isoxazoles, as well as their downstream transformations. Such precursors are cyclic 2-Azahetaryl-3-enaminonitriles of general formula A. Cyclic 2-Azahetaryl-3-enaminonitriles have been shown to exhibit different configuration around the double bond depending on their substitution. We have thoroughly investigated their behavior in order to assess the potential relationship between their configuration and their reactivities.

These compounds proved not only useful for azoles syntheses, but we found that they could undergo a further clean functionalization at the not highly reactive position 3 of the pyrrolidine ring under very specific circumstances.

Finally, we also explored the potential coordination properties of these derivatives toward boron and metals. This allowed us to characterize a wide range of new derivatives and investigate their photophysical properties.

Figure GI.2. Fate of cyclic 2-Azahetaryl-3-enaminon itriles within this manuscript.

Thus, this manuscript describes all the experiments carried out in these different directions.

In a first chapter there is a general survey of the literature related to 2-(1-Rpyrrolidine-2-ylidene)acetonitriles and their benzo-fused analogues. Details are provided on the various synthetic approaches to these compounds. Their various reactivities depending on their cyclic or acyclic nature and substitutions are then covered with a range of nucleophiles and with dimethylformamide acetals. A final part of this chapter describes the complexation of boron and metals by 2-(pyrrolidin-2-ylidene)acetonitrile and the applications of the complexes isolated are characterized.

A second chapter describes in details the synthesis and characterization of all Within the third chapter we describe the reactivity of 2-azahetaryl-2-(1-Rpyrrolidin-2-ylidene)acetonitrile as 1,3-dielectrophiles toward binucleophilic compounds, and the synthesis of differently substituted pyrazoles and isoxazoles. The downstream transformations on pyrazoles are thoroughly described and showed excellent region-and chemoselectivities.

Alternate paths observed upon modification of the hetaryl substituent are also reported highlighting the control of the reactions path in spite of the different reactive sites.

After developing the electrophilic nature of 2-azahetaryl-2-(1-R-pyrrolidin-2ylidene)acetonitrile, we demonstrate in chapter 4 that these adducts can also behave as nucleophile in the presence of electrophiles such as dimethylformamide acetals. A detailed investigation of the reaction outcome allowed us to propose a mechanistic rational for the very specific reactivity. Further transformation of the "formylated" adducts are then reported. This chapter is concluded by the description of the photophysical properties of a pyrrolopyridinimine obtained from these previous transformations, and more precisely its ability to react with traces amounts of water in dry organic solvents providing a simple fluorometric way to assess solvent dryness.

Finally the fifth chapter is devoted to the formation of (i) boron-difluoride complexes of 2-azahetaryl-2-(1H-pyrrolidin-2-ylidene)acetonitrile and the photophysical properties of a range of isolated adducts; (ii) d-metal (Cu, Zn, Co, Ni) complexes, their isolation and full characterization as well as their implementation in devices to study their potent applications in solar cells and for detection of the Zn an Cu in biological fluids.

After a general conclusion, the last part of this manuscript provides the experimental details of all the products synthesized and the experiments carried out.

ABBREVIATIONS

СHAPTER 1. SYNTHESIS, REACTIONS AND APPLICATION OF 2-(1-R-PYRROLIDIN-2-YLIDENE)ACETONITRILES AND THEIR BENZO ANALOGUES (literature review)

This chapter is devoted to a comprehensive description of the access to 2-(1-Rpyrrolidin-2-ylidene)acetonitriles (section 1.1) and their benzo analogues (section 1.2) as well as their transformations upon treatment with 1,2-binucleophiles (section 1.3) and N,N-dimethylformamide dialkyl acetals (section 1.4). These transformations The starting material, namely methoxybutyrolactam 1.2a, was obtained by the reaction of pyrrolide-2-one with dimethyl sulfate (Me 2 SO 4 , DMS) or via utilization of triethyloxonium tetrafluoroborate (Meerwein's salt). [5][6] S-methylthiobutyrolactam was prepared in two steps, starting with the reaction of pyrrolide-2-one and 2,4-bis(4methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent, LR) followed by methylation with DMS. 7 The structurally related pyrazolone 1. 4 bearing a heterocyclic substituent are known. They were prepared by the condensation reaction of lactim ether 1.2a or thioester 1.2b and hetaryl acetonitriles (Scheme 1.4). [8][9][START_REF] Shvydenko | Ring opening of cyclic thioimidates in reaction with active methylene compounds[END_REF] Scheme 1.4. Synthesis of enaminonitriles 1.6 bearing heterocyclic substituents.

SMe is better nucleofuge, than ОMe; the condensation reaction of thioester proceeds without addition of basic agents. under strongly acidic conditions, i.e. by using TFA (trifluoroacetic acid) (Scheme 1.5). [START_REF] Fritschi | Semicorrin Metal Complexes as Enantioselective Catalysts. Part 1. Synthesis of Chiral Semicorrin Ligands and General Concepts[END_REF][START_REF] Misun | Enantioselective Reduction of Electrophilic C=C Bonds with Sodium Tetrahydroborate and 'Semicorrin' Cobalt Catalysts[END_REF] This approach was used for the synthesis of semicorrins 1 1.7.

2-(1-Alkylpyrrolidin-2-ylidene)acetonitriles were also synthesized by alkylation of their unsubstituted analogues with alkyl halides. Several examples of alkylation of β,β-pyrrolidienamalononitrile were illustrated, [START_REF] Abbas | Novel substituted and fused pyrrolizine derivatives: synthesis, anti-inflammatory and ulcerogenecity studies[END_REF][START_REF] Barsoum | Synthesis and molecular modeling studies of antiinflammatory active 1H-pyrrolizine-5-carboxamides[END_REF][START_REF] Kadushkin | Synthesis and biological activity of condensed pyrrolo[3,2-d]pyrimidines[END_REF][START_REF] Mezentseva | Synthesis and antitumor activity of pyrrolo[3,2-d]pyrimidines[END_REF] in particular, with 1.3b bromoacetic acid ester, methyl phenacyl bromide and chloroacetanilide 1.8 (Scheme 1.6).

Scheme 1.6. Synthesis of 2-(1-alkylpyrrolidin-2-ylidene)acetonitriles and their further modifications into the potentially biologically active compounds.

The purpose of these transformations was obtaining fused systems: pyrrolizines 1.10

(Thorpe-Ziegler condensation) and pyrrolopyrimidines 1.11, that exhibit a range of biological activities, in particular, antitumor, anti-inflammatory, antiviral. In some experiments, compound 1.9 served as an intermediate and used without isolation, but 1 Semicorrins -nitrogen-containing ligands for enantioselective catalysis (details on their using are in section 1.5.2).

Scheme 1.5. Synthesis of chiral 5-(cyano(5-pyrrolidin-2-ylidene)methyl)-3,4-dihydro-2H-pyrroles 1.7.

immediately transformed to the corresponding pyrrolizines 1.10. Biological in vitro and in vivo studies were also provided.

Alkylation proceeds smoothly, when the pyrrolidine's NH proton is only loosely bound. If a hydrogen bond acceptor, e.g. a carbonyl group, is located close to the NH moiety, then the proton become less acidic and deprotonation becomes harder preventing subsequent alkylation (Scheme 1.7, route 1). [START_REF] Mezentseva | Synthesis and antitumor activity of pyrrolo[3,2-d]pyrimidines[END_REF] Scheme 1.7. Approaches to the synthesis of 2-(1-alkylpyrrolidin-2ylidene)acetonitriles.

An alternative approach to the synthesis of 2-(1-alkylpyrolidine-2ylidene)acetonitriles is the condensation of 1-alkylpyrrolidin-2-one dialkyl acetal 1.14a with a malonate equivalent (Scheme 1.7, route 2).

1-Methylpyrrolidin-2-one diethyl acetal 1.14b is in equilibrium with the corresponding ambident cation 1.15 , formed by dissociation of one ethoxy from 1.14b (Scheme 1.8). 17 Another method for the preparation of 2-(1-alkylpyrrolidin-2ylidene)acetonitriles 1.17 is the condensation reaction of 1-methylpyrrolidin-2-thione and the corresponding substituted acetonitrile in the presence of Ag 2 CO 3 . [START_REF] Brillon | A New Preparation of Difunctionalized Enamines from Thioamides Using Silver(I) Carbonate[END_REF] The silver salt has two significant features: first of all, it is thiophilic; secondly, it acts as a base allowing the reaction to proceed under mild conditions such as at rt (Scheme 1.9). Scheme 1.9. Synthesis of bifunctionalized enamines 1.17 at room temperature with addition of Ag 2 CO 3 .

The reaction occurs with nucleophiles bearing two electron withdrawing groups, and at least one of them should be nitrile moiety. It was observed that no reaction occurs if the nitrile group was replaced with ethyl acetoacetate or dimethyl malonate, which have similar electron withdrawing properties. Also, the reaction does not take place with 1H-pyrrolidin-2-thione; this statement confirms the passivity of neutral silver complexes in this transformation. Solvents with coordination ability were used in above-mentioned transformations, i.e. acetonitrile, tetrahydrofuran.

Substituted α-alkylidene 1.19, can be obtained by a [3+2] cycloaddition reaction between activated alkenes and N-(silylmethyl)-substituted ketene N,Sdithioacetals 1.18, which serve as synthetic equivalents of alkyliden azamethine ylides (Scheme 1.10). 19 The reaction takes place by 1,3-elimination of (methylthio)trimethylsilane with subsequent formation of a dipole A, which reacts stereo-and regiospecifically with activated alkenes to form α-alkylidene pyrrolidines 11). [START_REF] Michael | Syntheses of alkyl (E)-(1-aryl-2pyrrolidinylidene)acetates[END_REF] In the first step of the reaction, salts 1.22 were formed.

Due to the conjugation of nitrogen lone pair with an aromatic ring and decreasing of the nucleophilicity of the sulfur moiety, the reaction takes place over several hours (max. 189 h for R = C 6 H 4 OMe), from rt to 50 °C, in the absence of a solvent (neat).

The produced salts 1.22 without isolation were subjected to the next step. Yields of the target products 1. 23 were low (5-65%) due to the formation of by-products such as the starting 1-arylacetate and 3-alkylthiolactam 1.24.

Scheme 1.11. One-pot synthesis of (1-arylpyrrolidin-2-ylidene)acetates 1.23 by alkylation of thiolactams followed by Sulfur displacement.

For the first time, the method for the C-C bond construction via Sulfur displacement was studied by Knott in his work dedicated to sulfur-containing chromophores. [START_REF] Knott | Compounds containing Sulphur Chromophores.* Part I. The Action of Bases on Heterocyclic Sulphide Quaternury Salts[END_REF][START_REF] Shiosaki | Versatile β-Keto Ester and β-Keto Nitrile Synthesis through Sulfide Contraction[END_REF] In attempts to carry out the dihydrobromination reaction of (phenacylthio)benzothiazolium bromide 1.25 using triethylamine, the corresponding unsaturated ketone 1.27 was formed instead of the expected sulfide 1.26. The reaction passes through the episulfide intermediate A followed by sulfur extrusion (Scheme 1.12).

The authors of the above-described method for the synthesis of (1arylpyrrolidin-2-ylidene)acetates 1.23 also have reported a more efficient method providing higher yields (41-80%); it consists in the condensation of 6-chlorohexanoic acid ethyl ester with aniline at 65 о C in the presence of catalytic amounts of iodine, a drying agent (Na 2 SO 4 ) and a base (Na 2 HPO 4 ) used to trap hydrogen chloride (Scheme 1.13). [START_REF] Michael | Syntheses of alkyl (E)-(1-aryl-2pyrrolidinylidene)acetates[END_REF] This method was unfruitful only with p-nitrophenyl substituents (0% yield).

However, due to the known literature procedures, condensation of nitroanilines with ethyl acetate in the presence of iodine does not occur in the desired direction. [START_REF] Coffey | Ethyl Esters of β-Arylaminocrotonic Acids[END_REF] The disadvantage of the method is the formation of acyclic vinylogues of urethanes, as well as condensation products of the parent ester, which significantly complicates the purification of the final product of the reaction. Application of the alkylation method for cyclic amide by utilizing DMS or Meerwein's salt followed by condensation with acidic CH (the approach used for the synthesis of pyrrolidin-2-ylidenacetonitrile 1.3) in this case is not fruitful. Thus, isatins are mainly alkylated at the nitrogen atom; when the indolin-2-one 1.29 is alkylated with Meerwein's salt, an equilibrium mixture of 2-alkoxy-1H-indole 1.30a and 2-alkoxy-3H-indole 1.30b was obtained, which is passive in reactions with most of the C-nucleophiles. [START_REF] Reiter | Attempted synthesis of a Tenidap isomer and formation of an unexpected stable water adduct[END_REF] In the resulting tautomeric system, the equilibrium is shifted to a more thermodynamically stable isomer 1.30b with 10π electronic aromatic system, comparing to the non-conjugated lactam ester 1.30a (Scheme 1.14). According to 1 H NMR data, the ratio of tautomers 1.30a:1.30b in the equilibrium system was 1:10. [START_REF] Reiter | Attempted synthesis of a Tenidap isomer and formation of an unexpected stable water adduct[END_REF] .

In addition, it was observed that the 2-alkoxy-3H-indole 1.30b is unstable due to subsequent oxidation to the correspoding indirubin under air. [START_REF] Plieninger | Formation of Indirubin and 2-Ethoxy-3-(indol-2-yl)indole from 2-Ethoxyindole[END_REF]

Scheme 1.14. Synthesis of 2-(indolin-2-ylidene)malononitrile 1.31 by alkylation of indolin-2-one 1.29.

For the formation of systems with general formula 1.28a via condensation with acidic CH, it is necessary that the equilibrium is shifted towards the lactam ether 1.30a. For this purpose, the methylene moiety of the nucleophile must be sufficiently activated to promote the shift of equilibrium and, consequently, the reaction. [START_REF] Golovko | New synthesis of pyrido[4,3b]indoles (γ-сarbоlines) on the basis of indolin-2-one laсtim ether[END_REF] The target product 1.31 can only be prepared using malononitrile, which methylene group is located between two strong acceptors, i.e. nitrile groups (Scheme 1.14). The This method was applied for the synthesis of 2-vinylindoles with various substituents, i.e. heterocyclic and aromatic, as well as aliphatic ones. The only limitation in scope for this procedure is the availability of nitrones A; some of them are formed very slowly and are unstable. However, this method does not require the stage of nitrons isolation and purification; they are immediately involved into the next step with cyanoallenes, which made this approach successful.

The resulting 2-vinylindoles 1.37 proved to be a powerful source for the construction of linear carbazole cores, which are the key intermediates in the synthesis of some indole alkaloids (ellypticine, olivacine). [START_REF] Blechert | Domino Reactions -New Concepts in the Synthsis of Indole Alkaloids and Other Polycyclic Indole Derivatives[END_REF] The cycloaddition reaction (Diels-Alder) with electron deficient alkenes in dichloromethane takes place at rt in the presence of TFA and ends with the formation of tetrahydrocarbazols 1.38.

The reaction proceeds with high stereo-and regioselectivity and results in the formation of endo-adducts. Tetrahydrocarbazols 1.38 can be further oxidized to carbazole 1.39 using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (Scheme 1.17). As it was mentioned above, isatins are mainly alkylated at the nitrogen atom;

thus, no examples of the application of their 2-alkoxy derivatives in the construction of 2-C-C bond are reported to date.

In general, the C-2 position of isatin is passive in reactions with nucleophiles (without addition of catalysts for this process, as discussed below) in contrast to C-3, which could be functionalized by widely reported various methods.

The only purposeful approach to the synthesis of 1.28b of 2-R 1 -(3-oxoindolin-2ylidene)acetonitrile with general formula 1.28b, in particular, 2-(6-R 1 -3-oxoindolin-2-ylidene)-2-arylacetonitrile 1.42, is the condensation of 1-acetylindoxyl 1.40 and aldehydes followed by a substitution reaction of the vinyl hydrogen atom with a cyano group. (Scheme 1.18). [31][START_REF] Velezheva | Novel Pyridazino[4,3-b]indoles with Dual Inhibitory Activity against Mycobacterium tuberculosis and Monoamine Oxidase[END_REF] The reaction occurring in the first step of the synthesis is accompanied by hydrolysis of the amide bond (NAc) and the formation of the non-substituted indogenide 1.41. In order to avoid hydrolysis, Buzas et al. [START_REF] Buzas | Synthesis and Reactions of 1-Acetyl-2-benzylidene-3-oxo-2,3-dihydroindoles[END_REF] have developed the method for carrying the reaction in the presence of a less strong base, i.e. piperidine, upon boiling in an inert solvent (benzene/toluene)

In the reaction with potassium cyanide, N(1)-substituted analogues of indogenide 1.41 were found to be better substrates; thus, the modification was carried out by the introduction of an alkyl group in the third step of the synthesis, after the incorporation of nitrile moiety.

Cyanoindogenenes 1.42 and 1. 43 were modified in order to obtain new potent antituberculous drugs -analogues of pyridazoindole. It is known that hydrazine derivatives exhibit activity against different strains of bacteria, in particular M. tuberculosis H37Rv and M. Fortuitum, and also inhibit monoamine oxidase, an enzyme involved in the pathogen metabolism. Tricyclic pyridazoindoles 1. 44 were prepared by the reaction with hydrazine hydrate; their primary amino group were modified by diazotisation-hydrolysis reactions to form pyridazinone 1.45, formylation, which gave pyridazoamide 1. 46 and subsequent acylation led to diacylaminopyridazine 1.47. [START_REF] Velezheva | Novel Pyridazino[4,3-b]indoles with Dual Inhibitory Activity against Mycobacterium tuberculosis and Monoamine Oxidase[END_REF] Analogues of 2-R An interesting alternative approach to the synthesis of 2-R 1 -(3-oxoindolin-2ylidene)acetatoacetates 1. 51 was recently published and consists in simultaneous construction of the C-C and C=O bonds using cross-coupling reaction between the indole 1.50 and β-ketoesters with oxygen as a mild oxidant (Scheme 1.20). [START_REF] Bao | Cu(II)-catalyzed highly regio-and stereoselective construction of C-C double bonds: an efficient method for the ketonization-olefination of indoles[END_REF][START_REF] Wu | Co/Mn-mediated oxidative cross-coupling of indoles with beta-keto esters via dioxygen activation: an efficient access to ketonization-olefination of indoles[END_REF] The reaction is tolerant to a wide range of substituents connected to the indole core and takes place both with the electron-withdrawing and the electron-donating groups.

Also, the reaction is not sensitive to air humidity.

R 1 O O R 2 N H R O R 1 O R 2 N H R O R 1 O R 2 OOH N H R O R 1 O R 2 O [O] A B C D .
Scheme 1.20. Oxidative cross-coupling of indoles 1. 50 with β-ketoesters.

The oxidative cross-coupling takes place regioselective with good yields of the product only with β-ketoesters, since the activity of the catalyst that is formed in situ

[(1,3-diketonato) 2 Co(II)] strongly depends on the electronic effect of 1,3-diketones. [START_REF] Wu | Co/Mn-mediated oxidative cross-coupling of indoles with beta-keto esters via dioxygen activation: an efficient access to ketonization-olefination of indoles[END_REF] The possible reaction mechanism involves the formation of the β-ketoester A radical, which adds to the 2-position of the indole to form a stabilized radical B, which, in turn, reacts with the air oxygen and turns into the corresponding peroxide The reaction of isatin with nucleophiles can also occur by activating the C-2 position by introducing a halogen atom. For the first time such approach was used in the Bayer's works devoted to the synthesis of indigo in 1878-1879 years. [START_REF] Cornforth | Isatin chloride: a phantom. Reactions of 2-(2,2-dichloro-2,3-dihydro-3-oxoindol-1-yl)-3H-indol-3-one[END_REF] He made the statement that the reaction of isatin with phosphorus pentachloride upon boiling in benzene led to 2-chloro-3H-indole-3-one 1.54 (Figure 1.1a), which was isolated and characterized (by methods available at that time: elemental analysis, melting point with a decomposition at 180 °C). This compound is unstable under air and hydrolyzes to the starting isatin. In 1996, the "2-chloroisatin approach" was used in 37 articles and 4 patents published by 26 scientific groups. In 1996, Sir John

Cornforth published an article in which he provided evidence, that upon the synthesis conditions proposed by Bayer, no 2-chloroisatin was formed, as it was thougt to be for more than a century, but its dimer, namely 2-2-2-dichloro-2,3-dihydro-3oxoindol-1-yl)3H-indole-3-one 1.55 (Figure 1.1 b). [START_REF] Cornforth | Isatin chloride: a phantom. Reactions of 2-(2,2-dichloro-2,3-dihydro-3-oxoindol-1-yl)-3H-indol-3-one[END_REF] The structure of the compound was confirmed by X-ray diffraction analysis.

Figure 1.1. а). 2-Chloro-3Н- indole-3-on -phantom. Figure 1.1. b) 2-(2,2-Dichloro-2,3-dihydro-3- oxoindol-1-yl)3H-indole-3-one -a confirmed structure.
Using his own assumptions, Sir John Cornforth explained the strange features observed in the reactions of "2-chloroisatin" with nucleophiles, such as the competitive condensation at the C-3 position, which is less active than C-2, according to the proposed structure 1.54. Prior to this, the results of these reactions were mainly explained by the instability of 2-chloroisatin and its degradation to the starting isatin, which is an active component of the reaction. [START_REF] Katritzky | 2-Chloro-3H-indol-3-one and its reactions with nucleophiles[END_REF] On the example of the reaction with aromatic amines, Sir John Cornforth explained why the structure of the formed products may depend on the amount of the starting amine.

Reactions of β-enaminonitriles with 1,2-binucleophiles for the synthesis of pyrazoles (isoxazoles)

Pyrazole is a common moiety found in many medicinal and agrochemical products (derivatives of 1-arylpyrazole are inhibitors of cyclooxygenase-2 and protein kinase, antifungal drugs, 1,5-diarylpyrazoles inhibitors of HIV-1 reverse transcriptase, etc.). [START_REF] Fustero | From 2000 to mid-2010: a fruitful decade for the synthesis of pyrazoles[END_REF][START_REF] Khan | The therapeutic voyage of pyrazole and its analogs: A review[END_REF] Pyrazole derivatives are also used in food and polymer chemistry (catalysts of polymerization reactions). [START_REF] Fustero | From 2000 to mid-2010: a fruitful decade for the synthesis of pyrazoles[END_REF] Considering the wide array of applications for pyrazoles usage, the interest in their synthesis does not fade over time. Several works of interest have recently been published on combinatorial synthesis of pyrazoles, [START_REF] Borisov | Parallel Liquid-Phase Synthesis of 5-(1H-4-Pyrazolyl)-[1,2,4]oxadiazole Libraries[END_REF] as well as cross-coupling reactions for the postfunctionalization of pyrazoles [START_REF] Jedinak | The Suzuki-Miyaura Cross-Coupling Reaction of Halogenated Aminopyrazoles: Method Development, Scope, and Mechanism of Dehalogenation Side Reaction[END_REF] and modified syntheses of 4-trifluoromethyl Scheme 1.23. Functionalization of the C-2 position of isatins via the formation of imidochloride 1.55a.

substituted pyrazoles. [START_REF] Wang | Copper-Mediated Domino Cyclization/Trifluoromethylation/Deprotection with TMSCF3: Synthesis of 4-(Trifluoromethyl)pyrazoles[END_REF] Chemistry of pyrazoles, [START_REF] Fustero | From 2000 to mid-2010: a fruitful decade for the synthesis of pyrazoles[END_REF] their catalytic properties, [START_REF] Ojwach | Pyrazole and (pyrazol-1-yl)metal complexes as carbon-carbon coupling catalysts[END_REF] and therapeutic use [START_REF] Khan | The therapeutic voyage of pyrazole and its analogs: A review[END_REF] have been extensively reviewed.

There are several approaches to access the pyrazole ring. The most common is condensation between 1,3-dielectrophilic synthons and hydrazines. In this section, we focus on the synthesis of pyrazoles with the participation of cyclic or acyclic enaminonitrile having two electrophilic centres: the carbon atom of the nitrile group and the β-atom of the acrylonitrile fragment; therefore, these compounds may act as a 1,3-dielectrophilic agent (Figure 1.2).

Figure 1.2. Electrophilic sites of cyclic and acyclicenaminonitriles.

A search in the SciFinder database revealed about 720 publications devoted to the reactions of acyclic β-enaminonitrile with 1,2-binucleophiles. Focusing on the nearest analogues of the systems, to which our work is devoted, namely on α-hetarylβ-enaminonitrile, the range was managed to narrow down to about 20 publications, which will be discussed in subsection 1.3.1. The use of cyclic β-enaminonitrile derivatives in the synthesis of azoles, which will be discussed in subsection 1.3.2, has been studied scarcely and described in only 6 publications, whereas cyclic α-hetarylβ-enaminonitrile has been used only once.

Reactions of acyclic α-hetaryl-β-enaminonitrile with 1,2-binucleophiles

A series of works devoted to the synthesis of 4-hetaryl-5-aminopyrazoles from acyclic α-hetaryl-β-enaminonitriles has been reported (Figure 1.3). [START_REF] Abdelhamid | Utility of 2-[4-(3-Oxobenzo[f]-2Hchromen-2-yl)-1,3-thiazol-2-yl]ethanenitrile in Heterocyclic Synthesis[END_REF][START_REF] Abdelhamid | 2-(4-Naphtho[1,2-d]furan-2-yl-1,3thiazol-2-yl)-ethanenitrile in Heterocyclic Synthesis[END_REF][START_REF] Abdelhamid | Utilization of Thiazolylacetonitriles in the Synthesis of Thiophene, Thiazole, Pyrazolo[1,5-a pyrimidine and Pyrazolo [5,1-c]triazine Derivatives[END_REF][START_REF] Abdelhamida | Synthesis and reactivity of N-[3-amino-4-(benzoxazol-2-yl)pyrazol-5-yl]phenylamine[END_REF][START_REF] Dawood | Heterocyclic Synthesis via Enaminonitriles: A Convenient Route to Some New Pyrazole, Isoxazole, Pyrimidine, Pyrazolo[1,5-a]pyrimidine, Pyrimido [1,2-a]benzimidazole and Pyrido[1,2-a]benzimidazole Derivatives[END_REF][START_REF] Elgemeie | Synthesis of Benzimidazole Ketene N,S-Acetals and Their Reactions with Nucleophiles[END_REF][START_REF] Fadda | Revised Synthesis of Some New Derivatives of Biological Interest 2-Heterocyclic Benzothiazolyl Derivatives of Biological Interest[END_REF][START_REF] Fadda | Nitriles in Organic Synthesis: Synthesis of Some New 2-Heterocyclic Benzothiazole Derivatives[END_REF]

Figure 1.3. A schematic representation of the synthesis of 4-hetaryl-5-aminopyrazoles from acyclic α-hetaryl-β-enaminonitriles.

Synthesis started with the functionalization of the methylene group of hetarylacetonitrile 1.62. The necessary precursors, i.e. α-hetaryl-β-enaminonitriles, can be synthesized in three ways: 1) the reaction with dimethylformamide dimethylacetal (DMF DMA) leading at 2-hetaryl-3-(dimethylamino)acrylonitrile 1.63 (Scheme 1.24, route 1); 2) the reaction with carbon disulfide followed by alkylation and the substitution of one methylthiol group by arylamine (Scheme 1.24, route 2); or 3) reaction with isothiocyanate followed by alkylation (Scheme 1.24, route 3) for the preparation of 2-hetaryl-3-(methylthio)-3-(phenylamino) acrylonitrile 1.65. The subsequent cyclization with hydrazines (hydroxylamine) results in 4-hetaryl-5amino-pyrazoles (isoxazoles) 1.66.

Scheme 1.24. Strategies for the preparation of 4-hetaryl-5-aminoazoles 1.66.

The obtained azoles have functional groups, that can be converted into various heterocyclic frames by reactions with the appropriate reagents; thereby, this method opens a range of new ways for creating potentially biologically active compounds.

Thus, in the above-mentioned works were described transformations involving the aromatic exo-amino group and the pyrazole nitrogen. The authors state that in the first step aromatic amino group was involved into the reaction, and secondly, the In 2009 report has appeared opening a way to the synthesis of combinatorial libraries of 5-(1H-4-pyrazolyl)- [1,2,4]oxidiazole (Scheme 1.27). [START_REF] Borisov | Parallel Liquid-Phase Synthesis of 5-(1H-4-Pyrazolyl)-[1,2,4]oxadiazole Libraries[END_REF] The authors of the article synthesized more than 1000 compounds using the parallel liquid phase synthesis.

Scheme 1.27. Parallel liquid-phase synthesis of combinatorial libraries of 5-(1H-4-

pyrazolyl)- [1,2,4]oxidiazoles. 3 Using route 2 (Scheme 1.24) precursors of pyrazoles 3-(methylthio)-3-(arylamino)-2-(thiazol-2-yl)acrylonitrile 1.65 were obtained in a reaction of oxadiazolylacetonitrile 1.62 with CS 2 followed by methylation and substitution of one methylthiol group by the amino moiety. Using this approach, it is possible to synthesize pyrazoles with a large variety of 3-NR 1 R 2 substituents in the core and to avoid the use of toxic isothiocyanate. The authors note, that using the excess of hydrazine hydrate in the cyclization reaction leads to the formation of a by-product Thus, acyclic 2-hetaryl-3-enaminonitrile were starting compounds to prepare 4hetaryl-5-aminopyrazoles. Well-studied cyclizations, involving the exo-amino group and the pyrazole nitrogen atom, were used to obtain the compounds with potential biological activity.

Reactions of cyclic β-enaminonitrile with 1,2-binucleophiles

If an acyclic enaminonitrile is used, then methylthiol or dimethylamine acts as the leaving group in the course of the synthesis of pyrazoles; alternatively, in the case of cyclic analogues, the nucleofuge is ω-aminoalkyl (Figure 1.4). Consequently, the reactions of cyclic 3-enaminonitriles with 1,2-binucleophiles lead to the formation of ω-aminoalkylpyrazoles. In the absence of C-2 activation, the reaction takes place under harsh conditions (an excess of 1,2-binucleophile, at high temperatures). Reactions of cyclic 2-hetaryl-3-enaminonitriles are presented in only one publication, where they were subjected to the reactions with 1,2-binucleophiles in the presence of their acyclic analogues in the mixture.

-pyrrolidin-2-ylidene 1.28a -indolin-2-ylidene

In the case of enaminoamides 1.98, the reaction with DMF DEA or with tetramethylurea diethylacetal is taking place at the amide group of the side chain to form diene diamines 1.99 (Scheme 1.37). publication. [START_REF] Golovko | New synthesis of pyrido[4,3b]indoles (γ-сarbоlines) on the basis of indolin-2-one laсtim ether[END_REF] By the reaction of the latter compound with the DMF DEA, the crude product 1.112 was obtained in 90% yield; but the amount of isolated product after thorough purification is dramatically decreased to 34% yield. To conclude, the reactions with C-electrophiles takes place 1) at the third position of the pyrrolidine ring, followed by cyclization on the nitrile or carbonyl moiety, or 2) at the amide side chain group, followed by the cyclization at C-3 or 1-NH position of pyrrolidine. The resulting pyrolopyridines and pyrolopyrimidines can be subjected to various modifications of their functional groups allowing various decorations to pursue SAR studies.

Complexes based on 2-(pyrrolidin-2-ylidene)acetonitrile and their benzo analogues

2-(Pyrolidine-2-ylidene)acetonitriles can act as bidentate ligand due to the close spatial arrangement of two donor nitrogen atoms connected by a bridge of three сarbon atoms. Such a feature is used to create BF 2 -rigidified complexes that are similar to BODIPY dyes, as well as metal complexes for the asymmetric catalysis and copolymerization reactions.

Synthesis and application of BF 2 -rigidified complexes

Among heterocycles capable of forming boron-containing complexes, the dominant position is taken by dipiromethene derivatives. By the reaction with boron trifluoride diethyl etherate, the latter compounds form boron-dipiromethenes -BODIPY (Figure 1 .5). This structural framework is based on the class of dyes, discovered by Treibs and Kreuzer in 1968. [START_REF] Loudet | BODIPY Dyes and Their Derivatives: Syntheses and Spectroscopic Properties[END_REF] The interest of the unique properties of BODIPY-dyes (high quantum yields, stability in physiological conditions, narrow absorption and emission bands (Figure ) has grown over time; thus, up to 2018, 4995 articles have already been published The class of BODIPY dyes is used for biomolecules labelling and for studying their distribution in cells/tissues in vitro and ex vivo. Such studies have high accuracy, since the fluorescence spectroscopy method has a high sensitivity ( 10) and high spatial resolution (1 μm). On the other hand, the use of fluorescence studies is limited to the depth of penetration of the emitted light 1 cm). The resulting signal is blurred due to the partial scattering and absorption light by body fluids, water and tissues. [START_REF] James | A molecular imaging primer: modalities, imaging agents, and applications[END_REF] There are two ways to resolve the problem:

1) the synthesis of dyes, which emit the light within the optical window in the infrared spectral region (650 nm), or 2) use a method, not fluorescence based, that invol the emission of photons of greater energy, which, accordingly, increases the depth of light penetration.

A such method is the positron emission tomography according to the Web of Science portal

Schematic representation of the mechanism of positron emission

tomography.

) has grown over time; thus, up to 2018, 4995 articles have already been published

Classic spectrum of BODIPY dye Ф =

The class of BODIPY dyes is used for biomolecules labelling and for studying . Such studies have high accuracy, since the fluorescence spectroscopy method has a high sensitivity (10 -9 -10 - m). On the other hand, the use of fluorescence studies is limited to the depth of penetration of the emitted light 1 cm). The resulting signal is blurred due to the partial scattering and absorption of There are two ways to resolve the problem:

1) the synthesis of dyes, which emit the light within the optical window in the infrared spectral region (650 -900 nm), or 2) use a method, not fluorescence based, that involves the emission of photons of greater energy, which, accordingly, increases the depth of light such method is the positron emission tomography (PET) based on the radioactive decay of a positron-emitting nucleus ( 11 C, [START_REF] Brillon | A New Preparation of Difunctionalized Enamines from Thioamides Using Silver(I) Carbonate[END_REF] F etc.).

The positrons formed during decay annihilate with the electron of surrounding tissues and form two photons with 511keV energies directed at an angle of 180° to each other. High-energy particles are detected by a PET scanner (Figure 1.7). The method is characterized by unlimited depth of penetration, high sensitivity (10 -11 -10 -12 М), but lower resolution -1-2 mm, compared with fluorescence spectroscopy of 1 μm.

The combination of PET and fluorescence spectroscopy methods offset the shortcomings of each other and is a basis for the creation of a bimodal probe.

The presence in the structure of BODIPY BF 2 group, which could be a site for introducing an isotope label -[ 18 F], makes dyes attractive bimodal probe precursors.

The idea of preparation of the bimodal probe based on BODIPY was first presented in 2011 by Gabbai et al. [START_REF] Li | Rapid aqueous [18F]-labeling of a bodipy dye for positron emission tomography/fluorescence dual modality imaging[END_REF] The authors proposed an introduction of [ The authors used the synthesized radioactive dye 1.119 to investigate its ex vivo binding using fluorescence spectroscopy and PET methods; consequently, they have obtained satisfactory results on the stability and selectivity of binding, as well as a high correlation between the results of fluorescence spectroscopy and PET analysis (Figure 1.8).

Subsequently, novel methods have been developed, which allow the direct exchange of 19 F- [START_REF] Brillon | A New Preparation of Difunctionalized Enamines from Thioamides Using Silver(I) Carbonate[END_REF] F in BODIPY dyes in the presence of Lewis acids. [START_REF] Hendricks | Synthesis of [18F]BODIPY: bifunctional reporter for hybrid optical/positron emission tomography imaging[END_REF][START_REF] Keliher | Efficient acid-catalyzed (18) F/(19) F fluoride exchange of BODIPY dyes[END_REF][START_REF] Liu | Lewis Acid-Assisted Isotopic 18F-19F Exchange in BODIPY Dyes: Facile Generation of Positron EmissionTomography/Fluorescence Dual Modality Agents for Tumor Imaging[END_REF] Methods, which allow avoiding azeotropic drying of fluoride ion, are developing to date. For example, cartridges containing boranes with cationic structure -fluoride-ion adherent molecules. [START_REF] Perrio | F]-Fluoride capture and release: azeotropic drying free nucleophilic aromatic radiofluorination assisted by a phosphonium borane[END_REF] At present, about 30 articles 6 have been published in which BODIPY-dyes are used as bimodal probes.

Despite the intense fluorescence of BODIPY-dyes in the solution, which allows them to be used for biological objects labelling, they almost do not fluoresce in solid state, which prevents their use in the field of organic electronics and photonics, including liquid crystal displays, OLEDs, solar collectors. Weak fluorescence is caused by self-absorption, which is the result of almost complete overlapping of absorption and fluorescence spectra of the dye (Stokes shift is on average 5-30 nm). [START_REF] Frath | Luminescent materials: locking pi-conjugated and heterocyclic ligands with boron(III)[END_REF] Small Stokes shifts can also be a problem for the correct interpretation of the signals obtained by labelling of biological objects. In vivo studies shows that light scattering may also occur with tissues in addition to the self-absorption; the reason is in a small difference in absorption and radiation maxima, thus, this light can be perceived as emitted one. In order to overcome this disadvantages it would be desirable to access Stokes shift over 80 nm. [START_REF] Araneda | High Stokes Shift Anilido-Pyridine Boron Difluoride Dyes[END_REF] There are two ways to increase the Stokes shift: 1) BODIPY dye binding with a molecule capable of emitting light. In this case, BODIPY serves as the antenna that receives the signal, then excited and transmitted the signal to another fluorophore (through space or by bonds), whose wavelength of emitted light is much different from that absorbed one. Such systems are usually efficient, but they have a complex structure that requires multistage synthesis. 2) Desimetrization of the bidentant ligand in the boron complex in order to increase the distinction between the electronic structure of the main and excited states. This approach is simpler in terms of synthesis. [START_REF] Araneda | High Stokes Shift Anilido-Pyridine Boron Difluoride Dyes[END_REF] There is a large number of publications devoted to the development of desimetrized dyes based on boroaza cycle (С 3 N 2 B). [START_REF] Frath | Luminescent materials: locking pi-conjugated and heterocyclic ligands with boron(III)[END_REF] However, there are only several studies concerning the molecules containing a structural fragment of 2functionalized-2-(pyrrolidin-2-ylidene)acetonitrile -BODIPY analogue (Figure 1.9). trifluoride etherate treatment in the second step (26-47% yield) (Scheme 1.45). This approach opens the route to the rapid creation of a library of such dyes. Apart from the fluorescence in the solution, the complexes also exhibit fluorescence in solid state (Figure 1.12), unlike the classic BODIPY. Moreover, in all cases there is a bathochromic shift in the emission spectrum ~ 40-70 nm. Also, the fragment of pyrrolidin-2-ylidene acetonitrile became a component of BODIPY-like dyes developed by a group of German scientists. [START_REF] Fischer | Pyrrolopyrrole cyanine dyes: a new class of near-infrared dyes and fluorophores[END_REF][START_REF] Fischer | Pyrrolopyrrole Cyanines: Effect of Substituents on Optical Properties[END_REF][START_REF] Fischer | Asymmetric PPCys: strongly fluorescing NIR labels[END_REF] Synthesized dyes emit light (690-805 nm) within the optical window, in the near infrared (NIR) region of the spectrum. As it was noted above, substances that have such characteristics can be used for biovizualization, since biological fluids and tissues of the body do not absorb light in this region, which increases the depth of light penetration. It should be noted, that the Stokes shift for these dyes is small (within 250-500 cm -1 ). [START_REF] Fischer | Pyrrolopyrrole cyanine dyes: a new class of near-infrared dyes and fluorophores[END_REF][START_REF] Fischer | Pyrrolopyrrole Cyanines: Effect of Substituents on Optical Properties[END_REF] The authors attempted to increase the Stokes shift by synthesizing of the asymmetric dyes, [START_REF] Fischer | Asymmetric PPCys: strongly fluorescing NIR labels[END_REF] Ni(II) complexes with pyrrolidin-2-ylidene acetonitriles have been used as polymerization catalysts to access polyketones (Figure 1.18), polymers with a unique combination of physico-chemical properties. [START_REF] Klaeui | Novel Nickel(II) Complexes for the Catalytic Copolymerization of Ethylene and Carbon Monoxide: Polyketone Synthesisin Supercritical Carbon Dioxide[END_REF][START_REF] Beckmann | Modular Routes Towards New N,O-Bidentate Ligands Containing an Electronically Delocalised β-Enaminone Chelating Backbone[END_REF][START_REF] Domhöver | Catalytic Copolymerization of Ethene and Carbon Monoxide on Nickel Complexes[END_REF] In 1996, polyketones were first synthesized on an industrial scale and named as «Carilon». [START_REF] Domhöver | Catalytic Copolymerization of Ethene and Carbon Monoxide on Nickel Complexes[END_REF] The production was relied on the methodology involving palladium complex with a bidentant ligand (Ph 2 P(CH 2 ) 3 PPh 2 ) as a catalyst, which produces polyketone under mild conditions (90 °C, 45 bar) in 106 grams yield of polymer per gram of catalyst. [START_REF] Drent | Efficient palladium catalysts for the copolymerization of carbon monoxide with olefins to produce perfectly alternating polyketones[END_REF][START_REF] Drent | Palladium-Catalyzed Alternating Copolymerization of Alkenes and Carbon Monoxide[END_REF] The impetus for the study of complexes based on Ni(II) as cheaper Pd(II) analogue in the copolymerization of olefins and carbon monoxide (CO), was reducing the cost of the process, since catalysts can not be regenerated in the production process. [START_REF] Domhöver | Catalytic Copolymerization of Ethene and Carbon Monoxide on Nickel Complexes[END_REF] The starting (E/Z)-(pyrrolidin-2-ylidene)acetonitrile 1.6a was synthesized according to Scheme 1.45 and subsequently used for the synthesis of semicorrin. [START_REF] Misun | Enantioselective Reduction of Electrophilic C=C Bonds with Sodium Tetrahydroborate and 'Semicorrin' Cobalt Catalysts[END_REF] Upon treatment with a weak base and acylating agent (anhydride or acyl chloride), the product of acylation of β-enamine carbon atom 1.137 was obtained. In the case of soft acylating agents featuring bulky substituents, the product of (environmentally friendly solvent). These complexes are the most effective of known nickel-containing catalysts. The reaction of copolymerization in their presence takes place under mild conditions: 60 °C, 40 bar, which emphasizes their promising utility From this literature review covering synthesis, subsequent transformation using various electrophilic and nucleophilic agents, complex formation and the practical application of cyclic β-enaminonitrile, it is easy to find out the directions that need to be deeper investigated. Thus, there is only few information about the reactions of cyclic β-enaminonitriles with 1,2-binucleophiles, although they can serve as a convenient access to polyfunctional pyrazoles, which are widely used for therapeutic applications and for catalysis.

Synthesis and application of metal complexes

In general, syntheses and further transformations of cyclic α-hetaryl-βenaminonitriles are scarcely studied to date. However, it is known that the heterocyclic fragment influence on the synthetic path and its presence might provide novel methods for the construction of heterocyclic compounds. Moreover, a wide diversity of the heterocyclic substituents of starting enaminonitrile allows different biological activities of the products.

Another application of componds featuring 2-hetaryl-3-enaminonitrile moiety is the synthesis of BF 2 -complexes for biovisualization purposes. Pyrrolidin-2ylideneacetonitrile-containing structures are described in only a few articles and are characterized by the simplicity of their synthesis, practically better Stokes shifts, compared to the classical BODIPY dyes, as well as their light emission in the near infrared spectral region. Additionally, it has been shown that the nitrile group contributes to the bathochromic shift of the absorption and emission maxima.

Finally, metal complexes based on cyclic β-enaminonitrile are used as catalysts in the copolymerization of olefins and CO for the preparation of new materials, in particular, polyketones with unique combination of characteristics. Pyrolidine-2ylideneacetonitrile with stereogenic centres exhibit high regio-and stereoselectivity in the cyclopropanation reaction as well as in the alkene reduction.

Therefore, the chemistry of cyclic 2-hetaryl-3-enaminonitrile is scarcely studied but is thought to be a promising topic for future developments.

CHAPTER 2. 2-AZAHETARYL-2-(1-R-PYRROLIDIN/3-OXOINDOLIN-2-YLIDENE)ACETONITRILES: SYNTHESIS AND STRUCTURE

EXPLORATION

Given the promising use of derivatives of pyrrolidinylidene acetonitriles in the synthesis of functionalized azaheterocycles, our primary task was to synthesize their analogues with azaheterocyclic substituents in the position 2 of the enaminonitrile fragment (Figure 2.1).

2-Azahetaryl-2-(pyrrolidin-2-ylidene)acetonitriles

Synthesis

For the first time, the synthesis of 2-(pyrrolidin-2-ylidene)acetonitriles bearing heterocyclic substituents was described in 2000. 9 The method consisted in the condensation of hetarylacetonitrile 2. The theoretical analysis of the ratio between Z/E isomers in the solution was carried out by quantum-chemical calculations using the density functional theory (DFT).

The Gibbs free energy (ΔG) was calculated for 2 diastereomers 7

2-Azahetaryl-2-(1-R-pyrrolidin-2-ylidene)acetonitriles

Synthesis

Theoretically, 2-azahetaryl-2-(1-R-pyrrolidin-2-ylidene)acetonitriles can be obtained by alkylation of their N-unsubstituted analogues. Using the standard alkylation conditions (MeI/DMS, K 2 CO 3 , DMF) for model compound 2.1b, it was possible to obtain only a 35% yield of product 2.7a after 36 hours of heating (Scheme

2.2).

Scheme 2.2. Methylation reaction of enaminonitrile 2.1b.

The present approach is not suitable for the regioselective functionalization of NH group of pyrrolidine, in the presence of several reactive NH groups in the starting material.

Thus in the case of benzimidazol-2-yl-2-(1H-pyrrolidin-2-ylidene)acetonitrile 2.1f, the only reaction product is the 1,3-dimethylbenzimidazole salt 2.8 (Scheme

2.3).

No intermediate alkylation products could be isolated.

Scheme 2.3. Methylation reaction of enaminonitrile 2.1f

. 8 The values are given for the gas phase

In the case of the quinozalinone derivative 2.1j, methylation takes place at oxygen and nitrogen atoms leading to -OMe 2.9 and -NMe 2.10 isomers, which were separated by column chromatography (Scheme 2.4). The yield of -OMe product 2.9 is higher that is probably related to aromatization associated with pyrimidine cycle formation. The difficulties of alkylating such secondary enamines are consistent with those described by Mezentseva et al. [START_REF] Mezentseva | Synthesis and antitumor activity of pyrrolo[3,2-d]pyrimidines[END_REF] for a simpler analogue 2.6g. Thus this authors mentioned that any attempts to alkylate of (Z)-3-oxo-3-phenyl-2-(pyrrolidin-2ylidene) propanonitrile 2.6g in the presence of K 2 CO 3 , NaOEt, Na, and other bases did not lead to the desired products. This might be attributed to the presence of a strong intramolecular bond between the NH group and the oxygen of the carbonyl group stabilizes the starting material to such an extent that the deprotonation of 2.6g is substantially hindered.

To overcome the limits of the alkylation method of pyrrolidine presented above we have developed an alternative approach to the synthesis of 2-azhetaryl-2-(1-Rpyrrolidin-2-ylidene)acetonitriles (Scheme 2.5, route 1).

Scheme 2.5. Synthesis of 2-azahetaryl-2-(1-R-pyrrolidin-2-ylidene)acetonitriles 2.7, 2.13-2.18.

1-R-pyrrolidin-2-ones 2.12 were reacted with DMS. Reaction was followed up The alternative method for the synthesis illustrated on Scheme 2.5, route 2 is analogous to the method that was developed for the synthesis of unsubstituted enaminonitriles 2.1 (Scheme 2.1, route 2).

With these results in hands further 2-azahetaryl-2-(1-R-pyrrolidin-2ylidene)acetonitriles were obtained from methyl(benzyl, cyclopropyl)-substituted pyrrolidin-2-ones. The reaction proceeded immediately at room temperature (rt) leading to the desired compounds 2.7, 2.13-2.18 in good to excellent yields (67-91%).

Pyrrolium salts 2.11а-с are viscous oils, which were used directly in the next step without further purification. They could be obtained as solids upon treatment with KPF 6 in water. The model compound 2.11΄a forms after the anion metathesis as a white precipitate that can be isolated by filtration (Scheme 2.5).

Structure exploration: XRD, 1 Н NMR, DFT-calculations, VTP-experiment

As compared to the unsubstituted enaminonitriles 2.1, which theoretically can exist in the form of three tautomers and two diastereomers ( In all compounds the crystalline state revealed an almost planar conformation of the pyrrolidine ring (deviation from the plane within 0.16 Å), which is coplanar with the heterocyclic substituent (dihedral angle below 9°).

The delocalization of the electron density of the enamine moiety toward the nitrile and heterocycle promotes a general trend toward N4-C10 bond shortening and C10-C8 bond elongation, in a similar fashion as for 2.1. A clear correlation between the C8-C9-N3 angle values and the electronwithdrawing abilities of the heterocyclic substituent is observed, which implies that both the nitrile and the heterocycle are involved in electron delocalization. For example, in the row benzoxazole 2.18b -benzothiazole 2.7b -benzimidazole 2.13b, the angle C8-C9-N3 changes 177.1° -176.1° -173.4°, respectively, which reflects the decrease of the electron withdrawing abilities of the heterocyclic substituent and the displacement of the electron density toward the nitrile group (Table 2.

Table 2.3. The bond lengths and C8-C9-N3 angles of selected compounds

3).

In previous publications [103][104][105] the rotation around C=C bond of such conjugated enamines was identified as a "low energy" process with the free energy for activation (ΔG*) 9-20 kcal/mol. It was also argued that energy barrier decreases as the ability of the substituents to delocalize the charge in the transition state increases.

Since azahetarylacetonitrile is a strong electron withdrawing fragment it was assumed that interchange between E/Z isomers occurs via heteropolar transition state A with efficient negative charge delocalization (Figure 2.8).

Figure 2.8. Interchange between E and Z diastereomers 2.7, 2.13-2.18 via transition state A.

Bond length obtained by XRD analysis provides insight into the ability of rotation around the enamine double bond in the 2.7, 2.13-2.18 and the literature data stated low activation energy barrier for the rotation around C=C bond in similar conjugated enamines. Taking into account the above mentioned data the presence of signals from both diastereomers E and Z was expected in the 1 H NMR spectra. Consequently, the absence of steric hindrance in the E isomer makes it predominant in the diastereomeric mixture, regardless of the type of solvent and the substitution at 2-(pyrrolidin-2-ylidene)acetonitrile fragment. This experimental result is consistent with the data of the quantum-chemical calculations performed for compounds 2.7a and 2.13a, whereby the Gibbs free energy of the E isomer was smaller than the ΔG Z isomer in all the cases, indicating a greater stability of the E form. The relation between isomers is calculated according to the Maxwell-Boltzmann distribution and is given in Table 2.4. ) and singlet (2.97 ppm, N-CH 3 ) corresponded to Z isomer (Figure 2.12).

Base on the spectral data the free activation energy (ΔG ≠ ) for exchange between diastereomeric species 2.13a E and 2.13a Z was calculated. The kinetic parameters for unequal populated isomers were identified from modified Bloch equation (1-3). 103 The free activation energy of rotation at C=C double bond was calculated: ΔG ≠ E→Z = 14.4 kcal/mol, ΔG ≠ Z→E = 13.3 kcal/mol. The values found characterize this process as a low-energy one.

[(δ 2 τ 2 -2)/3] 3 = (ΔP) 2 δ 2 τ 2 (1), τ -1 = τ e -1 + τ z -1 (2), p e τ e -1 = p z τ z -1 (3)

Synthesis of 2-(pyrrolidin-2-ylidene)acetonitriles substituted with quaternized benzazoles

It is known [START_REF] Shvidenko | Recyclization reactions of 2-(1-benzoylpyrrolidin-2-ylidene)malononitrile[END_REF] that the introduction of an electron-withdrawing group at the nitrogen atom in the heterocycle increases the electrophilicity of the adjacent carbon atom, and resulting substrates have increased reactivity in the reactions with nucleophiles.

We have also attempted to use the above mentioned method to increase the electrophilicity of C-2 position of pyrrolidines, but the substrates 2.1 proved unreactive in acylation reactions (Figure 2.13).

Therefore we have chosen a different approach to activate the C-2 position, which consist in increasing the charges separation in the molecule by quaternization of the nitrogen of azaheterocycle substituent.

Direct methylation of substrates 2.12 (Scheme 2.6, route 1) with methyliodide or DMS worked only in the case of benzimadazole 2.13a leading to desired 2-(cyano(1-

methylpyrrolidin-2-ylidene)methyl)-1,3-dimethyl-1H-benzo[d]imidazol-3-ium iodide 2.8 (Scheme 2.6
). The structure of the product was identical to the one obtained by the reaction of 2.1f with methyliodide (section 2.2). In the case of enamines substituted with benzoxazolyl 2.18а and benzothiazolyl 2.7а the starting material was quantitatively recovered under the same conditions.

Scheme 2.6. Synthesis of 2-(pyrrolidin-2-ylidene)acetonitriles substituted with quaternized benzazoles 2.8, 2.21, 2.22.

Access to such charged hetarylenamines was achieved using the method described by A. Dobrydnev et al., 106 which consist in methylation of initial azahetarylacetonitriles. Using this method we were able to synthesize the previously This method corresponds to the one we applied for the formation of enaminonitriles 2.1 and 2.7.

Practically, the reaction proceeds through the formation of emulsion of salts that separates into two layers after the stirring is ceased.

In the crystalline structure of 2-(cyano(1-methylpyrrolidin-2-ylidene)methyl)- 1,3-dimethyl-1H-benzo[d]imidazol-3-ium iodide 2.

the dihedral angle between N,N-

dimethylbenzimidazole and pyrrolidine planes is 53.0°. Nitrile group and pyrrolidine are almost coplanar (the deviation from the plane is under 0.20 Å). There is also a shortening of N4-C12 (1.33 Å) and an elongation of C12-C10 (1.39 Å) bonds that [START_REF] Fritschi | Semicorrin Metal Complexes as Enantioselective Catalysts. Part 1. Synthesis of Chiral Semicorrin Ligands and General Concepts[END_REF] Signals that are in the shielding area of heterocycle (N-CH3 Z isomer and 3-СН2 Е isomer) shifted to high field, and those which are deshielded by nitrile group (N-CH3 Е isomer and 3-СН2 Z isomer) to low field. More detailed explanation was described in section 2.2.

Entry Solvent To conclude, enaminonitrile with quaternized azateterocyclic substituents can be obtained in two ways, one of which involves the introduction of the alkyl group to the hetarylacetonitrile at the first stage of synthesis and appears more versatile. The positive charge of the organic part of the molecule contributes to the charge separation and, as a result, increases the electron deficiency of the C-2 atom of the enaminonitrile fragment.

E/Z ratio Chemical shift (ppm) 2.8 E 2.8 Z N-CH 3 3-CH 2 N-CH 3 3-CH 2

Synthesis of 2-azahetaryl-2-(5-R-3-oxoindolin-2-ylidene)acetonitriles

There is only one publication where the functionalization of the position 2 of oxindole occurs through alkylation and further condensation with CH acidic group. [START_REF] Golovko | New synthesis of pyrido[4,3b]indoles (γ-сarbоlines) on the basis of indolin-2-one laсtim ether[END_REF] (Scheme 2.7).

Scheme 2.7. Functionalization of С-2 position of oxindole.

The applicability of this method is hampered by the equilibrium shift in the intermediate product of synthesis from 2-methoxy-3H-indole to 2-methoxy-1H-indole, [START_REF] Reiter | Attempted synthesis of a Tenidap isomer and formation of an unexpected stable water adduct[END_REF] which reduces the electrophilicity of C-2 atom (detailed description in the section 1.2).

The attempt made in this work to create the С-С bond between С-2 position of oxoindole and hetarylacetonitrile was unsucceful (Scheme 2.7).

To overcome the equilibrium issue we have to prevent the formation of 2methoxy-1H-indole. One way to proceed is to substitute oxindole at C-3 position.

The indolin-2,3-dione 2.23 is a suitable candidate as it has a carbonyl group in the position 3 of the cycle. It is known, [START_REF] Cornforth | Isatin chloride: a phantom. Reactions of 2-(2,2-dichloro-2,3-dihydro-3-oxoindol-1-yl)-3H-indol-3-one[END_REF][START_REF] Katritzky | 2-Chloro-3H-indol-3-one and its reactions with nucleophiles[END_REF][40] that its functionalization by nucleophiles possible at the position 2 via formation of intermediate imidochloride. Usually, the later one is isolated and dissolved in a more polar to perform condensation reaction.

Due to the low stability of imidochloride the yield of the reaction is always low. We have thus developed a new one pot approach that includes the formation of imidochloride in situ (~1 h, boiling in benzene) and its further condensation with hetarylacetonitrile (Scheme 2.8).

Scheme 2.8. Synthesis of 2-azahetaryl-2-(5-R-3-oxoindolin-2-ylidene)acetonitriles 2.24-2.26.

The total reaction time is around 1 h, the limiting step being the formation of imidochloride. The products are formed with high yields and purified by filtration through a plug of silica gel (eluent dichloromethane). There is a predictable dependence between the increased electron donating abilities of the substituent at the position 5 of 3-oxindole (Н→Me→OMe) and the bathochromic shift of λ max in the absorption spectra. This occurs because of a decreased HOMO-LUMO gap.

There is the broadened signal of NH group proton (δ = 11.4-12.0 ppm) in

Scheme 2.10. Alkylation of 2-benzo[d]thiazol-2-yl-2-(5-R-3-oxoindolin-2ylidene)acetonitrile 2.24b

To List of samples In this chapter we report the reactions of various enaminonitriles, which exhibit different electron density distributions and the spatial structures (chapter 2) with 1,2binucleophiles, such as hydrazines and hydroxylamine. Our aim was to explore: 1) the influence of alkyl substituent at the nitrogen of pyrrolidine (section 3.1), and 2)

the influence of the nature and the substitution extent of benzazoles (section 3. We have attempted to conduct the reaction of chain. Such an addition of nucleophile-spiro annulation-ring opening (ANSARO) mechanism is thought to be operative in this transformation (Scheme 3.2). Scheme 3.2. Proposed mechanism for the ring conversion.

Regioselective functionalization of 3-(ω-aminopropyl)-4-azahetaryl-5aminopyrazoles

Having this straightforward access to densely functionalized pyrazoles in hand, we further explored their synthetic potential by assessing the ability to selectively introduce structural variations on their reactive centres, namely, the amino groups.

The first approach was to illustrate the possibility of selectively functionalizing the amino groups substituting the pyrazole core. For that purpose, we confirmed that the secondary alkylamine is significantly more nucleophilic than the primary aromatic one. Indeed, alkylation of the secondary amino group could be achieved simply by stirring 3.1a with 1 equiv of the base and 2.2 equiv of alkylating reagent at room temperature, leaving the primary amino group unaffected (Scheme 3.3). The reaction produced a white precipitate, which structure was confirmed to be 3.8 by analysis of the filtrated solid by 1 H, [START_REF] Abbas | Novel substituted and fused pyrrolizine derivatives: synthesis, anti-inflammatory and ulcerogenecity studies[END_REF] C, and 2D NMR as well as high resolution mass spectrometry (HRMS). Expectedly, the symmetry achieved through formation of the ammonium salt significantly lowers the quadrupolar coupling constant of nitrogen, allowing observation in the [START_REF] Abbas | Novel substituted and fused pyrrolizine derivatives: synthesis, anti-inflammatory and ulcerogenecity studies[END_REF] C NMR spectrum of the [START_REF] Barsoum | Synthesis and molecular modeling studies of antiinflammatory active 1H-pyrrolizine-5-carboxamides[END_REF] N-13 C coupling for the methyl (J CN = 4 Hz) and the methylene (J CN = 3 Hz) carbons of the ammonium.

Extensive attempts to perform Hofmann elimination from 3.8 failed to provide the corresponding alkene 3.9, leading to ammonium recovery or degradation when reaction conditions were forced.

Scheme 3.3. Regioselective alkylation of amino groups from 3.1а.

Consequently, the substitution of the primary aromatic amino group was found to require the protection of the secondary amine (Scheme 3.3). This could be achieved in 93% yield by simple treatment of 3.1a with a slight excess of di-tert-butyl dicarbonate (Boc 2 O) in trifluoroethanol 110 for 10 min at room temperature followed by column chromatography.

With this protection in place, we could perform a reductive amination of the primary amino group. It is known that for 5-aminopyrazoles such transformation does not require any acidic catalysis and proceed at 60 °С. 111 In contrast to the reference data, the primary amino group of 3.1а reacts with aldehyde only at elevated temperature, in the presence of an acid. The produced Shiff bases are unstable and easily degrade to the starting material. After intensive efforts we have found the appropriate reaction conditions involving the use of sealed vessel and inert atmosphere to access the Shiff base. Then following reduction with sodium borohydride proceeded quickly in a protic solvent. Compound 3.10 was isolated after column chromatography in 47% yield (44% over three steps from 3.1a). Unreacted starting material was fully recovered (Scheme

3.3).

The pendant amino group on the pyrazole and proximate NH of the benzimidazole allows condensation of 3.3а with electrophiles such as orthoesters. This approach could deliver pyrazolopyrimidine scaffolds of interest for medicinal chemistry purposes, as has been exemplified in the development of inhibitors of glycogen synthase kinase 3, an enzyme involved in numerous diseases such as type II diabetes, Alzheimer's disease, cancer, bipolar disorder, and inflammation. 112 Upon boiling a mixture of 3.3a and 1,1,1-triethoxyethane in the presence of acetic anhydride, we could achieve the synthesis of 3H-benzo [4,5]imidazo [1,2c]pyrazolo [4,3-e]pyrimidine 3.11 (Scheme 3.4, route 1); it is important to note that a dehydrating agent is required to bring the reaction to completion. This illustrates weak stability of the formed pyrimidine ring that only tends to hydrolyze back to the acylated starting material both under strongly acidic and basic conditions. Under these conditions, the diazonium intermediate could indeed be trapped by the imidazole nitrogen to generate the corresponding triazene 3.12, with concomitant protection of the secondary amine as a nitrosoamine. 3.12 was isolated in 85% yield after column chromatography and fully characterized. It exhibits a unique tetracyclic structure that has never been previously described, and as such, expands the chemical space of heterocyclic chemistry.

Scheme 3.5. Sandmeyer iodination of the aminopyrazole core.

Finally, following this diazotization strategy, we investigated the lability of the 5-amino group. At first, we explored the ability of these heterocyclic-substituted aminopyrazoles to undergo Sandmeyer-type reactions. After extensive investigation, we found that to avoid the formation of numerous byproducts, the reaction had to be carried out at 65 °C with excess tert-butyl nitrite (5 equiv) and I 2 (4.3 equiv) in acetonitrile, 113 furnishing iodopyrazole 3.13 in 38% yield (Scheme 3.5). As stated above for the formation of 3.12, the secondary amine was converted to its nitrosamine derivative. We found that this could be avoided by first adding TsOH to the reaction mixture; under these acidic conditions, the secondary amine is protected as a weakly acidic ammonium salt avoiding nitrosation. Thus, only the primary aromatic ammonium formed under these conditions appears acidic enough to undergo nitrosation and water elimination to form the transient diazonium salt, which finally generates the iodopyrazole 3.14a in 30% yield.

Interestingly, under these acidic conditions, the reaction proceeds with the formation of the reductive deamination byproduct 3.14b (~1:1).

The introduction of iodine is easily monitored by the [START_REF] Abbas | Novel substituted and fused pyrrolizine derivatives: synthesis, anti-inflammatory and ulcerogenecity studies[END_REF] C NMR spectrum of Further, Boc protection of the secondary amine could be achieved in trifluoroethanol yielding 3.15 in 70% yield. This two step iodination-protection proved only moderately efficient (21%) that is almost two times less than one pot reaction of iodination-nitrosation -38%. The efficiency of the latter approach highlighting the nitrosamine as a potentially useful alternate protecting group, although cancerogenic properties might be found.

With these iodinated pyrazoles in hand, we explored potential C-C bond formation by way of Suzuki-Miyaura cross-coupling with a range of boronic acids (Scheme 3.6). A first attempt using 3.14a and 4-methoxyboronic acid under conventional conditions (5% Pd(PPh 3 ) 4 , dioxane-H 2 O, Cs 2 CO 3 ) provided the desired cross-coupling compound 3.16а in 71% yield. Yet the presence of the secondary amine made chromatographic analysis and purification tedious. We therefore turned to 3.15 as the starting pyrazole and were pleased to achieve the cross-coupling to 3.16b isolated in quantitative yield. We could further exemplify this reactivity by isolating 3.17 and 3. 18 Considering the more efficient access to 3.13 (38% vs 21% for 3.14a), we envisaged the unprecedented use of nitrosamine as a protecting group during the Suzuki-Miyaura cross-coupling. This was found to be a successful approach because the cross-coupling leading to 3.16с occurred in quantitative fashion (Scheme 3.6).We could also access the heterocyclic compound 3.20 using N-Boc-indole 2trifluoroborate, albeit with a moderate yield and under harsher conditions (140 °C) that promoted the thermolysis of the Boc group.

According to XRD study Finally, considering the observation of reduced product 3.14b (∼1:1 relative to iodinated product 3.14a) during the Sandmeyer reaction (Scheme 3.4), we investigated the possibility of performing such a reduction more efficiently.

On the basis of former reports, 114 we could achieve radical deamination of benzothiazole substituted pyrazole 3.1a to 3.21 with tert-butyl nitrite in dimethylformamide (Scheme 3.7). Indeed, opposite to the reaction with benzimidazole 3.3а (Scheme 3.4), no intramolecular trapping to the triazene can be From the mechanistic point of view, the nature of the hydrogen source is expected to be the methyl group of DMF. Indeed, it has been stated 114 that acetonitrile could also act as donor of hydrogen yet better conversions are achieved with DMF.

And as tetramethylurea appears almost as efficicent as DMF it is thought that reduction occurs primarily by hydrogen transfer from the N-methyl group. Although nitrosamines are considered as having limited value as protective groups (mainly as they are considered carcinogenic), 115 we believe, through all our observations, that in this specific case, their facile generation and deprotection make them an attractive option, provided cautious experimental procedures are followed.

Moreover, nitrosamines are also known to promote the umpolung reaction of secondary amines through deprotonation, and as such, they represent an interesting functionalization of aminoalkyl chain. 116 Having this reduced adduct in hand, we explored the possibility of further functionalization through the C-H activation reaction, as previously reported on pyrazoles. [117][118] We found that heating 3.13 at 70 °C in the presence of Pd(OAc) 2 , 4bromoanisole, and tetrabutylammonium acetate in dimethylacetamide (DMAc) for 24 h provided straightforward access to 3.16c in quantitative yield (Scheme 3.8).

Scheme 3.8. Functionalization of pyrazole through C-H Activation.

Once again, this illustrates the excellent compatibility of nitrosamine protection with palladium-catalyzed cross-coupling reactions. Moreover, this reaction path provides a highly efficient approach to densely substituted pyrazoles featuring both aryl and hetaryl substituents at the 4 and 5 positions, as 3.16c is isolated in 71% overall yield from benzothiazolylacetonitrile 2.1b and avoids ineffective stage of 5iodopyrazole formation (21-38%).

In summary, we have developed a two-step procedure for the synthesis of fully substituted 4-hetaryl-5-aminoazoles from readily available starting materials in a modified Knorr-type reaction. The reaction was found to be fully selective thanks to an evidenced marked difference between the two centres of the 1,3-dielectrophile.

These highly functionalized azoles have been shown to represent entries to various polyheterocyclic compounds, providing a straightforward route to a wide chemical space. Indeed, further reactivity of the 4-hetaryl-5-aminopyrazoles obtained was investigated, providing highly regioselective transformations and giving access to unknown derivatives with high nitrogen contents. Moreover, transformation of the 5amino substituent allowed the straightforward introduction of aryl and hetaryl moieties at this position providing a four-step route to densely functionalized pyrazoles. This also illustrates the efficient nitrogen protection as a nitrosamine during the Pd-catalyzed cross-coupling reaction. We consider that this approach opens new routes to enlarge the chemical space of pyrazole-containing pharmacophores as it introduces chemical complexity in an unprecedented swift fashion from simple starting materials.

Reactions of 2-azahetaryl-2-(1-R-pyrrolidin-2-ylidene)acetonitriles with 1,2binucleophiles involving С-2 atom of pyrrolidine and С-2 atom of azaheterocycle

To widen the scope of this kind of transformations of cyclic 2-azahetaryl-3enaminonitriles, we turned our attention to benzoxazolyl substituted derivatives and to quaternized benzazoles substituted ones.

The similarity of the selected objects is that the C-2 atom of azaheterocycle is located between two electron-acceptor groups: the oxygen and the nitrogen in the case of benzoxazole and the corresponding heteroatom (S, N, O) and the quaternized nitrogen atom in another, which, accordingly, increases electron deficiency of above mentioned C-2 atom. Consequently, it could be predicted that the presence of one more electron deficient centre has its impact on the reaction path with 1,2binucleophiles (Figure 3.6).

2-Benzo[d]oxazol-2-yl-2-(1-R-pyrrolidin-2-ylidene)acetonitriles in reactions with 1,2-binucleophiles

Regioselectivity in reactions of benzoxazol-2-yl substituted pyrrolidin-2ylidenes 2.18 with 1,2-binucleophiles was primarily explored.

After proceeding the reaction with methyl hydrazine [START_REF] Misun | Enantioselective Reduction of Electrophilic C=C Bonds with Sodium Tetrahydroborate and 'Semicorrin' Cobalt Catalysts[END_REF] two sets of peaks with the same integral intensity were observed in 1 H NMR of crude reaction mixture arising as one spot on TLC. After the appropriate elution system was found (CHCl In 1 H NMR spectrum the signal of Н-6 aromatic proton is shifted to low field (δ = 7.57 ppm). Such a shift occurred as a consequence of deshielding effect of neighbor oxygen. Indeed, according to XRD study of 3.26b the Н16 and О1 are spatially approximated (dihedral angle between benzene and isoxazole planes is 4.81°). The 4-carboximidamide fragment is planar within 0.016 Å and turned on 17.98° toward isoxazole ring. Such orientation might allow formation of another hydrogen bond between H5A … N4 atoms.

Cyclic enaminonitriles substituted with quaternized benzazoles in reactions with 1,2-binucleophiles

When benzoxazole derivatives reacted with 1,2-binucleophiles three active centres were involved in reaction and the mixture of structural isomers were formed.

The presence of quaternized nitrogen increases the electrophilicity of C-2 atom of heterocycle substituent (details are described in section 2.3) and thus the equilibrium of reaction should be shifted toward formation of one regioisomer -the product of the opening of azole cycle. The reaction proceeds smoothly under milder conditions (refluxing ethanol, and has been finished within 2h (TLC control), most probably as a consequence of the increased reactivity associated with introducing of the positive charge.

In the case of benzimidazole 2.8 and benzoxazole 2.21 derivatives there is only one set of signals in 1 An unexpected result was obtained in reaction of the benzothiazole derivative 2.22 with methylhydrazine. Instead of the expected "simple" product of the thiazole ring opening (as observed with benzimidazolyl 2.8 and benzoxazolyl 2.21) in this case the azepine 3.30 was formed (Scheme 3.10). The product was obtained in 78% yield after column chromatography.

The structure of the compound was established by IR and NMR spectroscopy.

Thus there is no characteristic signal of nitrile group vibration band in IR spectrum indicating its transformation during the reaction.

In the 1 H NMR spectra of 3.30 (Figure 3 2). [START_REF] Abbas | Novel substituted and fused pyrrolizine derivatives: synthesis, anti-inflammatory and ulcerogenecity studies[END_REF] Hereafter formylation by DMF DMA stands for incorporation of dimethylaminomethylidene moiety, formyl equivalent. The reaction path appeared to be highly dependent on the nature of the heterocycle of the 1,[START_REF] Ershov | Lactams of acetals and acid amides, 45. Synthesis of condensed 2-pyridones from activated amides, lactams, and lactones[END_REF] The experimental data as well as precedents from the literature 1,[START_REF] Ershov | Lactams of acetals and acid amides, 45. Synthesis of condensed 2-pyridones from activated amides, lactams, and lactones[END_REF] Compound 4.2a was also reacted with propylamine, 4-metoxyaniline and βaminoethylpropanoate but the formed amines were not stable in solution preventing their characterization.

Synthesis of pyrrolo[3,2-c]pyridin-6-imine, physicochemical study and prospects for use

Intramolecular rection between the nitrile and amino groups provides access to a wide range of nitrogen-containing heterocycles, namely, azines, azoles, quinolines, pyridines, pyrimidines, azepines. 125 Such rection is carried out by treatment with acids, bases or thermally and usually proceeds irreversibly. Numerous reports from Granik V.G. are devoted to the synthesis of pyrimidines and pyridines from derivatives of pyrrolidinylidenes creating C-N bond formation with such methods. 1, 68-73, 75, 119-121 Following on these reports we were able to conduct intramolecular condensation of the derivative of 3-((benzylamino)methylene) pyrrolidine-2-ylidene)acetonitrile Cross peaks are also seen between NH-2-CH 2 and NCH 2 -2,6-H Ph .

The structure of 4.9 was also confirmed by XRD analysis (Figure 4.12, а). In contrast to the solution in the solid state there is only the imine form of the molecule 4.9A. This form is stabilized by the intramolecular hydrogen bond between nitrogen of benzothiazole and hydrogen of pyrrolidine (estimated bond length N1···Н2 2.14 Å, angle N2-H2···N1 125.1°, dihedral angle between the benzothiazole and pyrrolopyridine planes is 6.3°). The bond length in the vinamidine systems of 4.9 are

indicative of an open-chain push-pull conjugated π-system rather than of π- delocalization (Figure 4.12, b). [128][129] The electron density from donor to acceptors imino group and benzothiazole seems arising to a greater extent from the nitrogen of pyrrolidine rather than the nitrogen of pyridine. This evidenced by smaller bond length of N2-C19 1.32 Å in contrast to the bonds N3-C14 1.41 Å and N3-C13 1.38 Å. b) The bonds length in pyrrolopyrimidine fragment according to XRD.

c) The bonds length in diazepine according to XRD. 129 These data correlate with ones given for diazepines (Figure 4.12, с). The small difference in the bond length of N2-C9 and C9-C8 from the corresponding bonds in diazepine N1-C2 and C2-C3 might it be due to the electron delocalization in 4.9 toward benzothiazole substituent.

When attempting to convert pyrrolopyridin-6-imine into pyrolopyrid-6-one by acid hydrolysis with a 30% solution of H 2 SO 4 in a water-dioxane mixture, the only reaction product was the salt 4.10a (Scheme 4.9). The protonation promotes the aromatization to the pyridinium thus preventing hydrolysis.

Compound 4.10b, which only differs by the nature of the conteranion, was accessed by HCl bubbling in the solution of 4.9 in dioxane. The 1 H NMR spectra for both compounds were almost identical (supplementary information).

Scheme 4.9. The interaction of pyrrolo [3,2-с]pyridine derivative 4.9 with acids.

In the 1 From Figure 4.16 it can be seen that the absorption spectrum of 4.9 in protic solvent -freshly distilled methanol (curve 4), is similar to the spectra in acetonitrile with acid and water additives (curves 5,6) and has a maxima around 340 nm while in the aprotic solvents of different polarity, namely, СН 3 СN, DMSO, toluene (curves 1 -3 respectively) there are maxima in the range of 310 -440 nm. 130 Spectrophotometric characteristics of 4.9 is presented in the Table 4.1. Taking into account the experimental data and the calculated pKa 4.9 value of 10.9 leads to the conclusion that at concentration required for spectrophotometric measurements, in solvents such as water, methanol and ethanol most of the molecules are in protonated state (estimated value 99% in water and methanol and about 95% in ethanol). Thus, the UV-spectra of pyrrolopyridine in the mentioned solvents and the spectrum on the salt 4.10 are similar.

According to 1 H NMR spectra of 4.9 recorded in DMSO-d 6 and СDСl 3 compound 4.9 exist as a mixture of imine 4.9А and enamine 4.9В forms in solution.

Thus the spectra in aprotic solvents show a broad absorption band within the range of 310-440 nm reflecting the absorption of a mixture of tautomers.

Pyrrolo[3,2-с]pyridine 4.9 has an intense (quantum yield of 61% in СН 3 СN;

standard -quinine sulfate) with λ max of emission 460 nm. The emission intensity increases with the increase of concentration up to 1 µmol/l, the effect of the internal filter in the spectra does not appear (Figure 4.18). compound that exhibits a high fluorescent quantum yield (Ф = 61%) and proved to be very sensitive to protonation. Both characteristics are expected to be useful to develop an unprecedented water detection test for aprotic solvents. We have demonstrated that such a fluorometric method for determining water content in DMSO presents a limit of detection of 0.068%.

List of samples

CHAPTER 5. COMPLEXES ON THE BASE OF 2-AZHETARYL-2-PYRROLIDIN/5-R-3-OXOINDOLIN-2-YLIDENE)ACETONITRILES

We have so far demonstrated numerous synthetic transformations of cyclic 2azahetaryl-3-enaminonitriles. They also may be considered as bidentate ligands due to the presence of two proximate electron donating nitrogen atom allowed to consider their photophysical properties upon binding to boron and their coordination chemistry toward 3d-metals.

BF 2 -rigidified complexes on the base of 2-azahetaryl-2-(pyrrolidin-2ylidene)acetonitriles

The 5.1). For quinoline 5.1e and quinazoline 5.1g,h derivatives the low field shift is larger than for benzazoles; for pyridine 5.1f derivative the 6-Н proton is shielded and shifted up field by 0.05 ppm (Table 5.1). The complexes formation could be also confirmed by [START_REF] Fritschi | Semicorrin Metal Complexes as Enantioselective Catalysts. Part 1. Synthesis of Chiral Semicorrin Ligands and General Concepts[END_REF] В NMR and 19 F NMR spectra where the triplet and quartet arise respectively due to spin-spin interaction between 11 В (the spin is 3 2 ) and 19 F (the spin is 1 2 ) nuclei (J BF = 29-33 Hz).

The stability of the complexes was checked by 1 H, [START_REF] Fritschi | Semicorrin Metal Complexes as Enantioselective Catalysts. Part 1. Synthesis of Chiral Semicorrin Ligands and General Concepts[END_REF] B and 19 F NMR in CDCl 3 , CD 3 CN and for 5.1a and 5.1c in CD 3 OD. The NMR spectra were recorded: directly after preparation the solutions, in 3h, in 1 day and in 1 week. None of the compounds heteroarenes in order pyridin-2-yl→thiazol-2-yl→benzothiazol-2-yl→quinolin-2-yl (455 nm) [START_REF] Cheng | Diversity-oriented facile access to highly fluorescent membrane-permeable benz[c,d]indole N-heteroarene BF2 dyes[END_REF] .

The decrease of energy gap between HOMO-LUMO is reflected in bathochromic shift of the absorption maximum of complexes 5.1 (9-50 nm) as compared to 2.1 (Table 5.2). 5.

2).

The absence of isosbestic points in the normalized absorption spectra (A/Amax) of the same complex at different concentrations indicates that there is no selfassociation in the solution.

When increasing the Polar solvents exhibit a better solvation of the excited state compared to the ground state. This is reflected in the bathochromic shift of the maximum of excitation when switching from toluene to DMSO (∆λ up to 68 nm). Solvatochromism in absorption spectra is negligible, shift of absorption maxima upon changing the solvent polarity being within 7 nm.

5.1g,h (right) (Solvent: CH 3 CN).

The optical properties of the compounds in solution remain constant for at least a month upon storage in unprotected from air and humidity conditions.

In contrast to BODIPY dyes which are not usually fluorescent in the solid state due to small Stokes, [START_REF] Frath | Luminescent materials: locking pi-conjugated and heterocyclic ligands with boron(III)[END_REF][START_REF] Cheng | Diversity-oriented facile access to highly fluorescent membrane-permeable benz[c,d]indole N-heteroarene BF2 dyes[END_REF] complexes 5.1 have a bright fluorescence in the solid state that could be even detected with a naked eye (Figure 5.6).

Solid-state luminescence usually arises from luminescent dyes carrying peripheral bulky groups that prevent close packing and subsequent aggregationinduced fluorescence annihilation. On the other hand, aggregation-induced fluorescence is sometimes observed for dyes due to the restriction of intramolecular rotation in the solid state compared to solution. 134,[136][137] This phemomenon called "aggregation-induced emission" is probably the case for complexes 5.1, which are characterized by numerous intermolecular С-H···F hydrogen bonds and strong packing, governed by π-π interactions with interlayer distances of 3.36-3.99 Å.

In summary, BF 2 -rigidified complexes that are easily accessible by two-steps approach from azahetarylacetonitriles have advantageous over BODIPY dyes: 1)

Stokes shift up to 9000 cm -1 due to the desimetrization of the ligand around boroazacycle; 2) emission at violet-blue range that is not covered by BODIPY-dyes;

3) fluorescence both in solution (Ф up to 90%) and crystalline state. The brightness of these molecules, especially benzothiazole (86400

М -1 •см -1 )
and benzoxazole (70400 М -1 •см -1 ) derivatives, matches the brightness of BODIPY dyes (for example, BODIPY-FL [START_REF] Barsoum | Synthesis and molecular modeling studies of antiinflammatory active 1H-pyrrolizine-5-carboxamides[END_REF] 86 000 М -1 •см -1 ) and is one of the largest at violetblue range among the dyes that are used for biovizualization (quinine -3000 М -1 •см - 1 , Hoechst 33342 (the dye of dibenzimidazole group) -17000 М -1 •см -1 , 7-hydroxy-4methylcumarin -11000 М -1 •см -1 ). 138 The brightness of these dyes is sufficient for in vitro studies, but their emission (400 -460 nm) is out of the optical window (650 -900 nm) required for in vivo studies. Nevertheless, the presence of BF 2 group could be used for incorporation of radioactive label [ 18 F] and would provide these probes a bimodal character.

An important characteristic for biovizualization is neutrality of such probes allowing crossing through the cell membrane.

Complexes of 2-azahetaryl-2-(pyrrolidin/5-R-3-oxoindolin-2ylidene)acetonitriles with 3d-metals: synthesis, structure and prospects for use

One of the tasks of modern coordination chemistry is the search for new ligands that can form thermodynamically and kinetically stable metal complexes. Bidentatechelating ligands are one of the most studied types due to their ability to coordinate both d-and f-metals. 139 The use of complexes of chiral β-enaminonitriles with Co(II), Cu(II), Zn(II), Ni(II) as catalysts for asymmetric synthesis and copolymerization is reported (subsection 1.5.2). We have investigated the prospect for use of metal complexes on the base of β-enaminonitriles in the synthesis of films of polymeric composites (FPC) that exhibit photovoltaic effect (subsection 5.2.1) and optical probes for Zn(II) and Сu(II) determination (subsection 5.2.2).

Complexes on the base of 2-azahetaryl-(2-pyrrolidin-2-ylidene)acetonitriles

On the base of new ligands of enaminonitrile type (HL) 2.1 the method to access complexes ML 2 was established yielding 5.2 with 60-65%. 139

Scheme 5.2. Synthesis of transition metals coordination compounds with heterocyclic enaminonitriles 5.2.

The IR spectra of 5.2 show no absorption band for NH group assessing the coordination of ligands. The absence of significant changes in the vibrations of CN and C=O (in the case of 5.2j) indicates that these groups do not participate in the coordination of metal ions.

Complexes on the base of 2-azahetaryl-2-(5-R-3-oxoindolin-2ylidene)acetonitriles

As 5.3), which indicates the high visibility of these compounds as chromophore reagents (Δλ ≥ 70 nm). 5.4).

Complex formation occurs slowly with other 3d metals under conditions of interaction with Zn(II) and Cu(II), as in the case of Co(II) or does not occur in the case of Ni(II). For the selective determination of Zn(II), the Cu(II) ions can be masked by thiosulphate ions.

Thus at the pH of biological fluids, the spectrophotometric determination of the microquantities of Zn(II) and Cu(II) can be carried out using 2 ylidene)acetonitriles as chromophore reagents, as they has a low limit of detection of metal ions (0.4-1 µmol/l) with large λ max shift (Δλ ≥ Compared with the method of determining Zn(II) and Cu(II) with the use of porphyrin derivatives 143 (prototype), while maintaining the sensitivity our method is less laborious and energy saving (no need to heat up to 100 ° C). Moreover, the optimal pH corresponds to the acidity of biological fluids as opposed to the prototype, where the determination is carried out in an acid or alkaline medium.

These facts indicate the promising use of the developed chromophore reagents for the analysis of biological fluids.

List of samples

GENERAL CONCLUSIONS

The Therefore this work illustrates the wide potential developments that can be achieved based on an efficienty synthetic approach of polyfunctionnal heterocycles. We have shown that synthetic efforts are not only allowing new accesses to densely functionnalized compounds, but also providing straightforward molecular tools for photophysical studies that allow new development in a wide array of fields.

As such this work contributes to the establish the molecule as the centre of any scientific development in chemical sciences.

EXPERIMENTAL PART

Instrumentation. For monitoring reaction progress, analytical thin layer chromatography (TLC) was performed using precoated Merck glass or alumina backed silica gel plates (Silica gel 60 F254).

Preparative chromatography was performed either manually with silica gel (63-200 μm) or with an automated flash chromatography Interchim Puriflash mediumpressure liquid chromatography system using Interchim high-purity grade silica gel (30 or 50 μm) prepacked columns. Fluorescence quantum yield (Ф ) for BF 2 -rigidified complexes was measured in diluted solution in DMSO with absorption maxima of А = 0.05 and calculated using the equation 1.

Ф = Ф × ! " × #$#% & " (( )! ) #$#% & ! (( )! ) × + ! , + " , (1)
F -the integral of the emission spectrum; A -absorption at maximum of excitation wavelenghth; n -refractive index. "r" -standard, "x" -test sample. The standard for complexes is the solution of 7-(diethylamino)-4-methyl-2H-chromen-2-oneу (λ abs max = 330 nm, Ф r = 0.73) in ethanol. 144 Measurements were made on the UV-3100 spectrophotometer and the SM-3500 spectrofluorometer.

Quantum-chemical calculations were performed using DFT at B3LYP/6-31G* level of theory. Conformations of Z and E isomers in stationary points corresponded

to the minima on the potential energy surfaces that was confirmed by vibrational analyses performed at the same level of theory -no negative vibration frequency was found.

General Consideration. Reactions were performed in oven-dried, roundbottom flasks equipped with a reflux condenser and protected from humidity by a CaCl 2 tube unless otherwise noted.

The ratio between compounds in a reaction mixture and the ratio between Z and E stereoisomers were found by comparing the integration sum under the peaks in the

Synthesis of 2-(cyano(1-methylpyrrolidin-2-ylidene)methyl)-1,3-dimethyl-1Hbenzo[d]imidazol-3-ium iodide (2.8).

A suspension of 2 General procedure for 1-R-pyrrolidin-2-ones 2.12 synthesis.

Synthesis of (Z)-2-(4-methoxyquinazolin

New 1-R-pyrrolidin-2-ones 2.12b,c,d,e,g were obtained according to a reported procedure. 102 Their characteristics are listed below.

General procedure for 5-methoxy-1-R-3,4-dihydro-2H-pyrrol-1-ium methylsulfate salt synthesis (2.11).

1-Alkyl-pyrrolidin-2-one (50 mmol) and dimethyl sulfate (4.74 ml, 55 mmol) were stirred for 2 h at 80 °C to give the desired pyrrolium salt as a viscous oil, which was used directly in the next step without further purification. Reaction progress was controlled by 1 H NMR spectroscopy through the disappearance of 1-R-pyrrolidin-2one in the crude reaction mixture.

Alternatively, such pyrrolium salts could be obtained as solids upon treatment with KPF 6 in water.

5-Methoxy-1-methyl-3,4-dihydro-2H-pyrrol-1-ium hexafluorophospate salt

2.11΄а. Yield 135 mg (0.66 mmol, 66 %), white powder (mp 124 °C).

5-Methoxy-1-R-

2.1і (E)-2-(pyridin-2-yl)-2-(pyrrolidin-2ylidene)acetonitrile

KBr 3439 (NH), 2189 (C≡N), 1578 (С=N, C=C).

(400 MHz, СDCl 3 ), δ, ppm (J, Hz): 2.13 (quint, J = 7.5, 2H, 4-СН 2 ), 3.05 (t, J = 7.9, 2H, 3-СН 2 ), 3.75 (t, J = 7.0, 2H, 5-СН 2 ), 6.92 (ddd, J = 7.5, 7.

(

General method of 2-hetaryl-2-(5-R-3-oxoindolin-2-ylidene)acetonitriles synthesis (2.23а-с, 2.25, 2.26).

Phosphorus pentachloride (1.3 mmol) was added to the strongly stirred suspension/solution of 5-R-isatine (1 mmol) in hot benzene (10 ml -15ml) and the resulting mixture was refluxed over 1 hour. At this point, solution of hetarylacetonitrile in benzene was added portionwise (the characteristic changing of color observed in each case) and the mixture was allowed to cool to room temperature upon stirring. The precipitate was then filtrated and washed with ethanol, water and again with ethanol. Dry precipitate was purified by filtration through the plug of silica gel (eluent: CH 2 Cl 2 )

2-(3-methylbenzo[d]thiazol-2(3Н)-ylidene)-2-(3-oxo-3Н-indol-2-yl)acetonitrile

(2.27a) have been synthesiszed according to the procedure described for the synthesis of 2-hetaryl-2-(5-R-3-oxoindolin-2-ylidene)acetonitriles (2.23а-с, 2.25, 2.26).

2-(Benzo[d]thiazol-2-yl)-2-(1,5-dimethyl-3-oxoindolin-2-ylidene)acetonitrile (2.28b).

The mixture of 2-benzo[d]thiazol-2-yl-2-(5-R-3-oxoindolin-2-ylidene)acetonitrile 2.23b (159 mg, 0.5 mmol) and К 2 СО 3 (83 mg, 0.75 mmol) in a minimal quantity of dry DMF was strirred at room temperature over 10 min. In the presence of К 2 СО 3 the color of solution changes from initial purple to dark-blue. СH 3 I (47 µl, d = 2.28 g/cm 3 , 0.75 mmol) was added to reaction mixture and stirring was continued over 1h.

The precipitate was filtrated off and purified by automatic column chromatography (elution system: CHA-CH 2 Cl 2 , 1:1). Yield 141 mg (0.43 mmol, 85%), dark violet powder. Note: 1) the aliquot for TLC was taken from the reaction mixture followed by addition of saturated aq. NaHCO 3 to make pH neutral-slightly basic and extraction with EtOAc.

2) The solution of t-BuONO is acidic when purchased from commercial sources. Its acidity is enough to generate the nitrosonium ion and bring the reaction to completion.

N-(3-(4-(Benzo[d]thiazol-2-yl)-5-iodo-1-methyl-1H-pyrazol-3-yl)propyl

N-(3-(4-(Benzo[d]-thiazol-2-yl)-5-iodo-1-methyl-1H-pyrazol-3-yl)propyl)-N-

methylpropan-1-amine

CONTENU PRINCIPAL (en français)

Dans l'introduction le cadre général et les objectifs de l'étude de 2azahetaryl-3-énaminonitriles A (Figure 1) sont présentés. La sixième chapitre de la thèse est une partie expérimentale, qui décrit les méthodes de synthèse des composés décrits dans le travail, et une description de leurs caractéristiques spectrales et physiques.

Conclusions général

Les travaux menés dans le cadre de cette thèse ont permis de mettre au point des

  This work was done in collaboration betweenUniversity Toulouse III -Paul Sabatier (UPS), France (Laboratory of coordination chemistry, UPR 8241 (LCC)) and Taras Shevchenko National university of Kyiv (UNTS), Ukraine (Faculty of chemistry) between 2014 and 2018. Financial support from the French government, Ukrainian government and University Paul Sabatier are gratefully acknowledged. I am most thankful to my supervisors Dr. Emmanuel Gras and Pr. Yulian M.

I

  am very grateful to Pr. Remi Chauvin (UPS) and Pr. Zoia V.Voitenko (UNTS) for the attentive guidance of all the organizational aspects relating to this joint PhD course. I would like to thank Pr. Oleksandr O. Ischenko (Institute of Organic chemistry of NAS of Ukraine), Pr. Olga A. Zaporozhetz, PhD Demid S. Milokhov (UNTS) and PhD students Omar Sadek and Alexandre Pocinho (team F, LCC) for their valuable advices during scientific discussions. Especially I wish to aknowledge the Mexicans whom I met during my stay in LCC: PhD Sara Ayala Mariscal (team F, LCC), PhD Alejandro Enriquez-Cabrera and MS Margarita Romero-Avila (team R, LCC and National Autonomous University of Mexico) for their friendship, understanding, encouragement, advices and for so many unforgettable moments I experienced with them. I would like to thank former joint PhD student Adrii O. Karpus and former joint MS student Kateryna Bretosh under UPS -UNTS collaboration for sharing their experience regarding all the program formalities and foremost to receive their friendship. The biggest thanks belong to all of my colleagues for creating such a supportive working atmosphere. All members of team F, LCC and PhD student Olexandra I. Bugera, PhD Andrei I. Kisel, PhD Angelina V. Biitseva (UNTS) who makes my day overjoyed despite hard and sometimes frustrating moments, please take credit for it. I wish to acknowledge the contributions several other people have made. Doctor Sonia Mallet-Ladeira (LCC), Dr. Svitlana V. Shishkina, Viktoriya V. Dyakonenko (Institute for Single Crystals, Kharkov, Ukraine) are thanked for crystal structure determinations; Dr. Yanick Coppel and Dr. Christian Bijani (Servicecommun de RMN, LCC) for the NMR experiments on E/Z isomerisation; Dr. Tetyana Ye. Keda, PhD Yuliya P. Bas, PhD student Anatolii M. Makeev and Vladyslav V. Scherban (UNTS) for studying the photophysical and coordination properties of cyclic azahetarylenaminonitriles; Pr. Volodymir M. Amirkhanov, Doctor Mikola O. Davidenko, PhD Nataliya S. Kariaka and Nataliya S. Kovalska (UNTS) for exploration of solid state structure, photophysical and photovoltaic properties of 3dmetal complexes; PhD student Valerii O. Bukhanko (LCC and UNTS) for quantum chemical calculations and their interpretation. I want to thank my parents Alexandr and Lyudmila, my grandmother Lyubov and the other members of my big and friendly family and my husband family for their love, encouraging and supporting me.

Figure GI. 1 .

 1 Figure GI.1. General structure of cyclic 2-Azahetaryl-3-enaminon itriles investigated in this PhD work.

the 2 -

 2 azahetaryl-2-(1-R-pyrrolidin-2-ylidene)acetonitrile and 2-azahetaryl-2-(3oxoindolin-2-ylidene)acetonitrile obtained in the course of our studies. Thorough investigation of the configuration by different analytical methods, such as X-Ray diffraction, NMR including variable temperature experiments as well as computation is then described.

  provide a fast access to range of heterocyclic scaffolds due to the rich synthetic potential of starting material A featuring two electrophilic sites (the nitrile carbon atom and sp 2 -hybridized C-2 carbon atom of the pyrrolidine moiety) and two nucleophilic sites (N-1 nitrogen atom in the case of R = H and the pyrrolidine C-3 atom) as illustrated in Figure I.1.

Figure I. 1 . 1 . 1 .Scheme 1 . 1 .

 11111 Figure I.1. Graphical representation of the literature review.

4 DMFScheme 1 . 2 . 4 . 4 ( 8 Scheme 1 . 3 .

 41244813 Scheme 1.2. The cyclization of 1.3а into the corresponding pyrazolone 1.4.

2-( 3 , 4 -

 34 Dihydro-2H-pyrrol-5-yl)-2-(pyrrolidin-2-ylidene)acetenonitrile 1.7 featuring a stereogenic centre in the position 5 of the pyrrolidine core was obtained by condensation of substituted O-ethoxybutyrolactame 1.2c and enaminonitrile 1.6

Scheme 1 . 8 . 1 . 15 .

 18115 Scheme 1.8. Diethyl acetal exists as an equilibrium mixture of three forms.

1. 19 .Scheme 1 . 10 .

 19110 Scheme 1.10. Synthesis of α-alkylidene-substituted [3+2] cycloadducts 1.19.

Scheme 1 . 12 . 21 Scheme 1 . 13 . 1 . 2 .

 1122111312 Scheme 1.12. The first application of the C-C bond forming reaction via the Sulfur displacement (1955).[START_REF] Knott | Compounds containing Sulphur Chromophores.* Part I. The Action of Bases on Heterocyclic Sulphide Quaternury Salts[END_REF]

Scheme 1 . 16 .

 116 Scheme 1.16. Synthesis of 2-vinylindoles 1.37 by the tandem reactions.

Scheme 1 . 17 .

 117 Scheme 1.17. Synthesis of tetrahydrocarbazols 1.38 with 2-vinylindoles 1.37 by the Diels-Alder reaction. Oxidation of saturated compounds 1.38 into the corresponding carbazoles 1.39.

C. 51 . 37 Scheme 1 . 21 .

 5137121 Scheme 1.21. The coupling reaction of isatin and alkynoates, which is accompaniedby the migration of oxygen atom.

Imidochloride 1 . 57 . 1 . 22 .

 157122 Scheme 1.22. Reaction of 1.55a imidocloride with aromatic amines.

Scheme 1 . 26 .

 126 Scheme 1.26. Modifications of pyrazoles 1.66.

1 .

 1 Scheme 1.28. 3-(Dimethylamino)-2-(pyridin-2-yl)acrylonitrile 1.63a the keyintermediate in an industrial method for a synthesis of an antibiotic 1.76.

Figure 1 . 4 . 62 Scheme 1 . 29 .Scheme 1 . 30 . 1 . 82 .Scheme 1 . 31 .. 81 .

 146212913018213181 Figure 1.4. Schematic representation of the synthesis of 3-ω-aminoalkyl-5aminopyrazoles from cyclic β-enaminonitriles.

Figure 1 . 5 .

 15 Figure 1.5. а) Biologically active substances of glutamate receptors.

Figure 1 . 5 .Scheme 1 . 32 .

 15132 Figure 1.5. b) Potential glutamate receptor antagonists.

1. 4 . 1 . 1 .Scheme 1 . 36 .

 411136 Scheme 1.36. Synthesis of pyrrolo[3,2-c]pyridines 1.97 via the formation of aderivative with the masked aldehyde group 1.96.

Scheme 1 . 38 . 73 Scheme 1 . 39 .

 13873139 Scheme 1.38. The reaction of 2-cyano-2-(pyrrolidin-2-ylidene)acetate 1.102 with DMF DEA

Scheme 1 . 43 .

 143 Scheme 1.43. Modifications of 2-(3-ethoxymethylene) 1.113 / 2-(3 -((dimethylamino)methylene)indolin-2-ylidene)malononitrile 1.112.

Figure 1 6 )

 16 Figure 1.5. BODIPY core

Figure 1 . 6 .

 16 Figure 1.6. (λabs = 503 nm,

Figure 1 . 7 .

 17 Figure 1.7. Schematic representation of the mechanism of positron emission tomography.

Figure 1 . 6 .

 16 Figure 1.6. Classic spectrum of BODIPY dye λabs = 503 nm, λem = 509 nm, ε = 80000, Ф 90%) 5

Figure 1 . 9 .Figure 1 . 10 .

 19110 Figure 1.9. Structural core of BODIPY (on the left) and its analogue -2-functionalized-2-(pyrrolidin-2ylidene)acetonitrile (right).

Scheme 1 . 45 .

 145 Scheme 1.45. Synthesis of BODIPY-dyes analogues 1.120 and 1.121.

Figure 1 .

 1 Figure 1.11. a) X-ray structural analysis of 1.120.

1 . 4 . 1 . 46 . 1 . 13 .

 14146113 Scheme 1.46. Synthesis of symmetric 1.126a and asymmetric 1.126b BF 2 -PCC.

) 2 SО*

 2 ΔG -Gibbs free energy, J; k -Boltzmann's constant, J/К; Т -temperature, К; N -the total number of particles in the system; N і -the number of particles with the energy ΔG i Quantum-chemical calculations show that the amount of E isomer in a diastereomeric mixture does not exceed 0.1%, which is in agreement with the experimental data we have obtained: the sensitivity of the NMR spectrometer does not allow to register the signals of E isomer, therefore, only one set of signals corresponding to the energetically favorable Z isomer is obserbed. The theoretical data obtained by us are in agreement with the experimental observations presented in the work of Solovea et al. 2 for analogues with compact acceptor groups 2.6c-f and reinforce the conclusions made by them. Soloveva et al. point out that nor prolonged heating of solutions 2.6c-f at 70 ° C neither change of solvent provoke the rise of signals of the E isomer. Also, in the 1 H NMR spectra, recorded in the temperature range from -60 ° C to +60 ° C, the chemical shift of NH proton remains almost unchanged, indicating the presence of a strong intramolecular hydrogen bond. The authors conclude that the presence of hydrogen bonding in secondary amines 2.6c-f accounts for the lower energy of the Z isomer and consequently the absence of E form. Indeed, the calculations we made for the model enaminonitrile 2.1b show that the Gibbs free energy is lower for the configuration Z:ΔG Z isomer = -4.6400118•10 -15 J, ΔG E isomer = -4.6399794•10 -15 J.8

Scheme 2 . 4 . 2 . 10 . 9 .

 242109 Scheme 2.4. Methylation reaction of enaminonitrile 2.1j.

Figure 2 . 6 .

 26 Figure 2.6. Molecular structure of 2.10 according to X-ray diffraction.

by 1 H

 1 NMR spectroscopy through the disappearance of 1-R-pyrrolidin-2-one 2.12 signals in the crude reaction mixture. Pyrrolium salts 2.11 were directly subjected into reaction with the model compound: benzothiazol-2-ylacetonitrile 2.2. Reactions with 1-methyl/benzyl/cyclopropylpyrrolidine-2-ones proceed with the best conversion and yield. 5-Methoxy-1-phenylethyl/tert-butyl-3,4-dihydro-2H-pyrrol-1ium salts 2.11 react with benzothiazol-2-ylacetonitrile 2.2 only with partial conversion to the desired product most probably as a consequence of steric bulk at nitrogen. 1-Phenylpyrrolidin-2-one does not react with DMS even at elevated temperature and excess of the reagent. The reason could be a decrease of the oxygen nucleophilicity resulting from the delocalization of the nitrogen lone pair on the benzene ring. 1-Furan-2-ylmethylpyrrolidine-2-one only yielded a mixture of inseparable products.

  Figure 2.1), N-substituted analogues can only be in the form of Z/E isomers. Analogously to unsubstituted enaminonitriles 2.1, configuration and conformation of the molecules were examined using XRD, NMR and dynamic NMR, and also confirmed by the DFT. Single crystals suitable for XRD study were obtained by solvent diffusion. The structures in the solid state of enamininitriles 2.7, 2.13-2.16, 2.18 revealed, as illustrated in Figure 2.7 for 2.13b, that the diastereomer featuring lower steric strain (N-alkyl and CN in the cis position) is preferentially formed, as expected.

Figure 2 . 7 .

 27 Figure 2.7. а) Molecular structure of 2.13b according to X-ray diffraction (E isomer). b) π-Diastereomerism of 2.13b.

The 1 H

 1 NMR spectrum for the model compound 2.7a recorded in CDCl 3 , where the latter was completely soluble, showed only one set of signals. Nevertheless, the signals of N-CH 3 at 3.46 ppm and 3-CH 2 at 3.54 ppm adjacent to enamine double bond were broadened, that could be due to the fast exchange between isomers in the solution (Figure 2.9). in E, with N-Alk cis to linear nitrile group, as compared to Z with cis orientation of N-Alk and heterocycle substituent leads to constant prevalence of E isomer over Z. This conclusion is also substantiated by multiplets position in 1 H NMR spectra. Protons of N-Alk substituent in E isomer are deshielded by a neighbour-anisotropy effect of cis nitrile group and shifted to low field as compared to N-Alk protons of Z isomer that are located in the shielding area of heterocyclyc moiety (Δδ within 1 ppm). Finally, assignment of the peaks either to E or Z form was made using the 2D NOESY technique (Figure 2.10). The model compound 2.13a was taken in DMSO-d 6 at 298 K. -CH 3 (δ = 2.78, 3.37 ppm) and -NH-(δ = 11.75, 12.24 ppm) protons resonance for E configuration gave a distinguishing positive cross peaks correlating them to the corresponding resonance of Z configuration. There was also a positive cross peak correlating the -NH-protons of benzimidazole to the residual water in the DMSO-d 6 solvent (δ = 3.33, 11.75, 12.24 ppm). Finally, the negative cross-peaks observed in the spectrum due to NOE between 4-CH and 3-CH 2 groups (δ = 7.40 and 3.34 ppm) belonging to isomer with higher integration value has confirmed predominance of E isomer (Figure 2.11).

Figure 2 . 9 .

 29 Figure 2.9. A fragment of the 1 H NMR spectrum of compound 2.7a with the highlighted shift of broadened signals of the protons of NСH 3 and 3-СН 2 moieties (CDCl 3 , 300 MHz).

Figure 2 . 10 .

 210 Figure 2.10. NOESY spectrum of 2.13а. Exchange processes marked with blue and NOE with red (DMSO-d 6, 500 MHz; 298 K).

Figure 2 . 11 .

 211 Figure 2.11. Cross peak іn NOESY spectrum which reflects the correlation between the 4-H and 3-CH 2 protons of the predominant isomer in 2.13a.

  , where δ -maximum chemical shift separation in radians, ΔP = p e -p z , when p e and p z are the molar fractions of the two exchanging diastereomers, τ e and τ z are the life time of E and Z. Rate constants are k e = 1/τ e, k z = 1/τ z. . Inserting the resulting rate constant into Eyring activation function, taking transmission coefficient (t) as unity, provides the ΔG ≠ values: ΔG ≠ E→Z = 14.4 kcal/mol, ΔG ≠ Z→E = 13.3 kcal/mol. = Т к (4), where k -rate constant, t -transmission coefficient, k B -Boltzmann constant, h -Planck constant, Т c -coalescence temperature. Coalescence temperature (T c ) was found as the average value of two consecutive temperatures surrounding the splitting of the signal (T c = 285 K). Found ΔG ≠ values are in agreement with previous ones stated for such conjugated enamines 103-105 and characterize the isomerization process as low-energy one.

Figure 2 . 12 .

 212 Figure 2.12. Exploration of dynamic effects in enaminonitrile 2.13а under cooling its solution in CDCl 3 . Temperature imnterval 298÷213 K.

described 2 -

 2 (3-methylbenzo[d]thiazol-2(3H)-ylidene)acetonitrile 2.20 106 , as well as 2-(3-methylbenzo[d]oxazol-2(3H)-ylidene)acetonitrile 2.19 (Scheme 2.6, route 2).

Figure 2 . 13 .

 213 Figure 2.13. Inactvity of compounds 2.1 in acylation reactions

  conclude, the preparative methods of 2-azahetaryl-2-(pyrrolidin-2ylidene)acetonitriles and 2-azahetaryl-2-(5-R-3-oxoindolin-2-ylidene)acetonitriles synthesis we have developed allowed to study the functionalization of their reactive centres. A thorough structure investigation gives the access to prediction of their behaviour in the reactions with nucleophiles and electrophiles. The closely spaced location of the donor nitrogen atoms in N-unsubstituted pyrrolidines and 3-oxoindolines enables them to coordinate atoms with vacant orbitals. The results of the corresponding studies are presented in chapter 5.

СHAPTER 3 . 2 -

 32 AZAHETARYL-2-(1-R-PYRROLIDIN-2-YLIDENE)ACETONITRILES AS 1,3-DIELECTROPHILES. SYNTHESIS OF PYRAZOLES/ISOXAZOLES AND THEIR CHEMICAL MODIFICATIONThe delocalization of electron density of enamine moiety in 2-azahetaryl-2-(pyrrolidin-2-ylidene)acetonitriles is driving their reactivities toward nucleophiles.We have seen in chapter 2 that both nitrile and heterocycle act as electron withdrawing groups. Such delocalization promotes a shift in the enamine-imminium equilibrium, enhancing the electrophilicity of the C-2 atom of enaminonitrile fragment and simultaneously lowering that of the nitrile group. These observations suggest that 1,3-dielectrophiles can be expected to react with binucleophiles in a very regioselective fashion. This could therefore allow an overall atom-and step-economical generation of 3-(ω-aminoalkyl)-4-hetaryl-5aminoazoles 3.1-3.7, that have only scarcely described 10 (Figure3.1).

Figure 3 . 1 . 2 -

 312 Figure 3.1. 2-Azahetaryl-2-(pyrrolidin-2-ylidene)acetonitriles as 1,3-dielectrophiles.

3 . 1 .

 31 2) on the reaction's path with 1,2-binucleophiles. Synthesized polyaminoazoles were subjected into reactions of regioselective derivatization, transformation into tetracyclic azaheterocycles, Suzuki-Miyaura crosscoupling and reductive deamination with further C-H activation (subsection 3.1.1). Reactions of 2-azahetaryl-2-(1-R-pyrrolidin-2-ylidene)acetonitriles with 1,2binucleophiles involving С-2 atom of pyrrolidine and carbon of nitrile group There are very few references dealing with the reactions of 2-(pyrrolidin-2ylidene)acetonitriles with 1,2-binucleophiles. The reason for this is the lack of reactivity of the latter (subsection 1.3.2). Without activation of С-2 centre of pyrrolidine the transformation requires harsh conditions (the excess of 1,2binucleophile, elevated temperature).

Figure 3 . 2 . 1 Н

 321 Figure 3.2. 1 Н NMR spectrum of pyrazole 3.1а (400 MHz, DMSO-d 6 ).

( 3 .

 3 6a, 8.04 ppm; 3.5b, 8.20 ppm). In both cases, addition of D 2 O promotes the disappearance of these singlets, evidencing the exchangeable nature of the corresponding protons. The 13 C NMR spectra of 3.1-3.7 show three signals corresponding to the carbons of the pyrazoles (isoxazoles). The first one, found at a chemical shift in the 147.1-149.0 ppm range, was assigned to the C5 atom of the pyrazole ring, and again, this signal was shifted up-field for isoxazoles (at around 169.2-170.5 ppm). The signals within the range 90.3-100.8 and 148.6-161.3 ppm correspond to C4 connected with a heterocyclic substituent and to C3 bonded with the ω-aminoalkyl chain, respectively. Pleasingly, 4-hetarylaminopyrazoles 3.1a, 3.1с and 3.2а formed crystals suitable for XRD study, allowing careful analysis of their structure. The benzothiazolyl substituent is almost coplanar with the pyrazole ring, with a dihedral angle of 6.48° and 1.16° for 3.1a and 3.1с, respectively, indicating a significant overlap of the π systems. The flattened orientation of the planar fragments is further stabilized by an intramolecular hydrogen bond between one of the protons of the amino group and the nitrogen of the benzothiazole. In the crystal lattice molecules of 3.2а aligned antiparallel to each other and are complementary paired. Such packing stabilized by intermolecular hydrogen bonds (estimated bond length H4А … N5 2.00 Å, N4-H4A … N5 164.8°) (Figure 3.3).

Figure 3 . 3 .

 33 Figure 3.3. Molecular structure of compound 3.2а according to X-Ray diffraction.Hydrogen bonds formation in the complementary pair.

For 3 .Figure 3 . 4 .

 334 Figure 3.4.Molecular structure of compound 3.6а according to X-Ray diffraction.

Scheme 3 . 4 .

 34 Scheme 3.4. Straightforward access to fused tetracyclic structures 3.11, 3.12.

3 .

 3 14a characterized by considerable shielding of C5 by the adjacent I atom (3.1a, 147.1 ppm; 3.14a, 86.5 ppm).

Scheme 3 . 6 .

 36 Scheme 3.6. Suzuki-Miyaura cross coupling of iodinated pyrazoles 3.13-3.15.

  in 5-indol-2-ylpyrazole 3.20 the indole and pyrazole planes are orthogonal to each other (89.7°); benzothiazole and pyrazole are almost coplanar, the dihedral angle is equal to 3.9° (Figure 3.5). Such a relative position of fragments stabilize by intermolecular hydrogen bonds in complementary pair, that consist of molecules of 5-indole-2-ylpyrazole aligned antiparallel to each other (H2A … O1 2.02 Å, N2-H2A … O1 171.3°).

Figure 3 . 5 .

 35 Figure 3.5. Molecular structure of compound 3.20 according to X-Ray diffraction.

The 1 H

 1 NMR spectrum of 3.21 shows two sets of peaks corresponding to two unequally populated rotamers, and the characteristic singlet of the newly introduced proton arises at 7.88 ppm (in CDCl 3 ). Deprotection of the nitrosamine to the corresponding ammonium salt could be easily achieved by bubbling HCl gas in a methanol solution of 3.21. This two-step procedure gave 3-(4-(benzo[d]thiazol-2-yl)-1-methyl-1H-pyrazol-3-yl)-Nmethylpropan-1-aminium chloride 3.22 in 89% overall yield. The 1 H NMR spectrum of 3.22 recorded in DMSO-d 6 features a broad singlet for the two protons of the ammonium at 8.94 ppm that disappeared upon D 2 O addition.

Figure 3 . 6 .

 36 Figure 3.6. Influence of increased electron deficiency of C-2 atom of azaheterocycle on regioselectivity of reactions with 1,2-binucleophiles.

3 -

 3 CH 3 OH-Et 3 N, 20:2:1) we have separated the products and thoroughly analyze them by 1 H,[START_REF] Abbas | Novel substituted and fused pyrrolizine derivatives: synthesis, anti-inflammatory and ulcerogenecity studies[END_REF] C and 2D NMR techniques as well as HRMS. The characteristic range for benzazoles aromatic protons is 7.1-7.7 ppm. Arising of aromatic protons in the 6.6-7.0 ppm range of one of the products might be influenced by benzoxazole ring opening (Figure3.7). M + H + equal to 286.17 obtained by mass analysis is indicative for the presence of two isomers. Moreover, the stretching vibrations at 2218 cm -1 found by IR analysis unambiguously indicated that one of the isomers has still a nitrile group, thus no nucleophile attack was occurring on this centre. Considering these evidences we have suggested the structure of two isomers 3.23a and 3.24a and the mechanism of their formation (Scheme 3.9).

Figure 3 . 7 .Scheme 3 . 9 .Scheme 3 . 10 .

 3739310 Figure 3.7. A fragment of the 1 H NMR spectrum of 3.23а and 3.24а (Solvent: DMSO-d 6 ).

Figure 3 . 8 .

 38 Figure 3.8. Molecular structure of compound 3.24b according to X-Ray diffraction. Hydrogen bonds formation in the complementary pair.

Figure 3 . 9 .

 39 Figure 3.9. The most indicative correlations found in HMBC spectrum of 3.26b.

Figure 3 . 10 .

 310 Figure 3.10. Molecular structure of compound 3.26b according to X-Ray diffraction.

3 . 28 )

 328 H NMR spectrum indicating a full regioselectivity of the reaction. After purification (recrystallization for 3.27 and column chromatography for the compounds were analyzed by NMR and IR spectroscopy techniques. Indicative vibration band of nitrile group absorption was found at 2214 cm -1 for 3.27 and at 2220 cm -1 for 3.28 in IR spectra; in 1 H NMR spectrum signals of aromatic part were shifted down field and were split into 4 signals in the case of 3.27 as a consequence of the benzimidazole moiety symmetry disruption. The combination of these facts suggests the opening of the imidazole and oxazole cycles.

Figure 3 . 11 .Figure 3 . 12 .

 311312 Figure 3.11. The most indicative correlations found in HMBC, COSY spectra of 3.27.

. 13 )

 13 there is down field shift of aromatic protons (δ = 7.1-7.3 ppm) indicating the opening of the thiazole ring. Doublet at 2.74 ppm (J = 5.0 Hz) and quadruplet at 5.31 ppm (J = 5.1 Hz) matching to СН 3 NH protons of substituent at benzene ring. Two low field singlets at 8.97 and 8.80 ppm belong to the protons of NH groups. The intensity of these signals diminishes upon addition of D 2 O. 31 Р and 19 F NMR spectra are indicative for the presence of PF 6 -counterion. The molecular ion of PF 6 -group was also found by HRMS (calculated 144.9642, found 144.9649).

Figure 3 . 13 .Scheme 3 . 12 .

 313312 Figure 3.13. A fragment of 1 Н NMR spectra of 3.30 (Solvent: DMSO-d 6 ).

Figure 3 . 14 .

 314 Figure 3.14. The most indicative correlations found in HMBC, COSY spectra of 3.30.

75 indoline

 75 : SYNTHESIS AND PROSPECTS FOR USECyclic enaminoamides derivatives are the key compounds in the synthesis of condensed pyridine systems. С-Н activation at С-3 centre of pyrrolidine,1, 69-70, 72, 74-]azepine, 121 featuring electron withdrawing groups (cyanoacetamide, malononitrile, ethylcyanoacetate) at the C-2 position was allowed for the synthesis of 5-azaindolines, condensed pyrimidinecarbolines (pyridoindoles), pyrido[4,3- b]benzo[f]azepines (Figure4.1). These scaffolds are found to be useful for the treatment of cancer, neurodegenerative diseases, as inhibitors of serotonin receptors, antihistaminics.119,[122][123] The common intermediates on the route to condensed pyridine systems are the derivatives of 3-dimethylaminomethylidenes A, obtaining by formylation reaction of C-3 centre of pyrrolidine ring by acetals (Figure4.1).[START_REF] Granik | Acetals of lactams and acid amides, 35. Synthesis of condensed two-and three-ring pyridine systems on the basis of enamino amides[END_REF][START_REF] Ershov | Lactams of acetals and acid amides, 45. Synthesis of condensed 2-pyridones from activated amides, lactams, and lactones[END_REF][START_REF] Granik | Acetals of lactams and acid amides, 39. Synthesis of three-ring derivatives of pyrido[1,2-a]pyrimidines on the basis of the dimethylformamide acetal with dicyanomethylenecycloalkanes[END_REF]

Figure 4 . 1 .

 41 Figure 4.1. Straightforward access to condensed pyridine systems.

Figure 4 . 2 . 2 . 1 , 2 . 7 , 2 . 13 - 2 . 4 . 1 . 2 - 1 .

 42212721324121 Figure 4.2. The reactive centre (С-3) of 2-azahetaryl-2-(pyrrolidin-2ylidene)acetonitriles under reactions with DMF DMA

Figure 4 . 3 .

 43 Figure 4.3. Aza-oxo-stabilized methylene iminium salt 4.1А -the reactive form of acetal.

Figure 4 . 4 .Scheme 4 . 1 .Figure 4 . 5 .

 444145 Figure 4.4. Alternative routes to reactions of 2.1 with DMF DMA.

Scheme 4 . 4 .

 44 Scheme 4.4. Proposed mechanism for reaction of 2-azahetaryl-2-(pyrrolidin-2ylidene)acetonitriles 2.1 with DMF DMA.

Figure 4 . 6 .Scheme 4 . 4 .Scheme 4 . 5 .Scheme 4 . 6 . 6 ). 4 . 4 . 2 . 6 , 4 . 7 Scheme 4 . 7 .

 46444546644264747 Figure 4.6. рКа of conjugate acids of relevant azaheterocycles.

Figure 4 . 7 .

 47 Figure 4.7. A fragment of 1 H NMR spectrum of 4.6 (400 MHz, DMSO-d 6 -CCl 4 ).

Figure 4 . 8 .

 48 Figure 4.8.Molecular structure of 4.6 according to X-ray diffraction.

4. 6 Scheme 4 . 8 . 9 .

 6489 Scheme 4.8. Synthesis of pyrrolo[3,2-c]pyrimidine 4.9. It is known, 120, 126-127 that for the structures of 4.9 type the imine-enamine tautomerism is characteristic (Figure 4.9). Thus, in the 1 Н NMR spectrum of 4.9 recorded in CDCl 3 there is broadened NH protons signals in the region 5.69-10.34 ppm, which may indicate a fast proton transfer on the NMR time scale. When changing the solvent to DMSO-d 6 , the transition between the tautomers is slowing down and signals are observed in the spectrum both for the imine 4.9A and the enamine 4.9B tautomeric forms (Figure 4.10).

Figure 4 . 9 .

 49 Figure 4.9. Imine-enamine tautomerism of 4.9.

Figure 4 . 6 Hz) in 1 Н

 461 Figure 4.10. 1 H NMR spectrum of 4.9 in DMSO-d 6 .

Figure 4 . 11 .

 411 Figure 4.11. The compound 4.9 structure according to 2D NMR (400 MHz, CDCl 3 ) (the arbitrary tautomer is depicted).

Figure 4 .

 4 Figure 4.12. a) Molecular structure of 4.9 according to X-ray diffraction.

H NMR spectrum of compounds 4 . 10 , 4 . 9 ,

 41049 the singlets of amino groups protons are clearly distinguished. The NH proton of pyrrolidine comes out at 8.57 ppm for 4.10a and at 8.61 ppm for 4.10b (s, 1Н) and signal of NH 2 protons at 8.68 and 8.76 ppm (s, 2H), respectively. The significant low field shift of СН 2 protons of benzyl substituent (∆δ ~ 0.4 ppm) and almost constant position of 2-СН 2 signal (∆δ = 0.02 ppm), as compare to initial pyrrolopyridine are indicative of localization of a positive charge on the nitrogen of pyridine ring rather than on the nitrogen of pyrrolidine. These confirm the structure proposed for 4.10b as do further 2D-NMR: COSY, HMQC, HMBC (Figure 4.13). Pyrrolo[3,2-с]pyridine-6-imine 4.9 alkylation with the excess of МеІ and in the presence of K 2 CO 3 leads to the permethylated product 4.11 (Scheme 4.10). It is known 127 , that the formation of permethylated derivatives for similar compounds -2imino-β-carbolines occurs via formation of a dimethylated product at endo-and exocyclic nitrogen atoms. Taking into account precedents from the literature we propose the mechanism for the formation of 4.11. The mechanism involves the deprotonation of 4.9 leading to intermediate А↔В, followed by its methylation leading to С. Finally the methylation at methylamino group occurs yielding 4.11.

Figure 4 . 13 .Scheme 4 . 10 . 9 . 6 in 1 H 11 -

 41341096111 Figure 4.13. The compound 4.10b structure according to 2D NMR (400 MHz, DMSO-d 6 ).

Figure 4 .

 4 Figure 4.16 it is seen that the shape of absorption band of 4.10b in acetonitrile (curve 7) is similar to those obtained by titration of 4.9 by HCl at stoichiometric point (curve 6).

Figure 4 . 14 .

 414 Figure 4.14. Evolution of the absorption spectra of 4.9 upon titration with НСl solution (starting solution of 4.9 (0) with HCl additives (1-13)). C 4.9 = 1.5•10 -5 mol/l. C HCl = 1.4•10 -6 -2.4•10 -5 mol/l. φ H2O = 2.5% (in total).

Figure 4 . 15 . 3 • 10 - 5

 4153105 Figure 4.15. Evolution of the absorption spectra of 4.9 upon titration with Н 2 O (starting solution of 4.9 (0) with Н 2 O additives (1-19)). C 4.9 = 1.5•10 -5 -1.3 •10 -5 mol/l. φ H2O = 11.8% (in total).

Figure 4 . 16 .

 416 Figure 4.16. Normalized absorption spectra of pyrrolo[3,2-c]pyridin-6-imine 4.9 in the solvents of different polarity and proton donating abilities. The absorption spectrum of 4.10b in CH 3 CN (7).

Figure 4 . 4 . 9 Figure 4 . 2 .9 and formylated ones 4 .2a, 4 . 3 , 4 . 4 .

 4494244344 Figure 4.18. а) The spectra of excitation and emission of 9.3•10 -8 -5.6•10 -7 mol/l (λ compound 4.9 solutions of different concentrations in DMSO under irradiation with

  BF 2 complexes of 2azahetaryl-2-(pyrrolidin-2ylidene)acetonitriles 5.1 feature structural analogues with BODIPYdyes, namely, the boroazacycle. This similarity allows us to consider newly synthesized complexes 5.1 as desimetrized analogues of BODIPYdyes (Figure 5.1). BF 2 complexes 5.1 were obtained from 2-azahetaryl-2-(pyrrolidin-2ylidene)acetonitriles 2.1 (Scheme 5.1). As these compounds are easily accessible starting material (section 2.1) it can be expected that a large structural versatility of dyes might be accessed from these precursors. Indeed, complexes are obtained in excellent yields 73-93% by treatment of the mixture of enaminonitrile 2.1, 2.9, 2.10 and N,N-diisopropylethylamine (DIPEA) with BF 3 •OEt 2 in refluxing dichloromethane. Complexes 5.1 are stable to hydrolysis in slightly acidic or basic media and could be purified by aqueous work up followed by column chromatography on silica gel.

Figure 5 . 1 .Scheme 5 . 1 . 1 . 2 . 1 .The 1 Н

 51511211 Figure 5.1. a) Central core of BODIPY-dyes b) Desimetrized analogues of BODIPY-dyes.

Figure 5 . 2 . 1 H

 521 Figure 5.2. 1 H NMR spectra of ligand 2.1b (bottom) and complexe 5.1а (top).

2 .

 2 conditions. Addition of a drop of water to the solutions in CD 3 CN and CD 3 OD and another set of NMR spectra was recorded immediately and after 1 day. No degradation of complexes occurred. The stability of complexes was also checked in electron donating solvents: deuterated pyridine and tetrahydrofuran for compounds 5.1a and 5.1c. The graduate formation of another set of signals was observed only in aliphatic region in pyridine solution for compound 5.1a. The 11 B and 19 F NMR spectra showed no variation with time. Such change could be due to competitive coordination of pyridine to boron atom. The compound 5.1c stayed unaffected in pyridine solution. Tetrahydrofuran does not influence anyhow on the structure of complexes. Crystals suitable for X-ray analysis were obtained by slow diffusion of hexane into their dichloromethane solutions at room temperature. XRD shows a dihedral angle between azaheterocycle and pyrrolidine is within the range of 2.5-13.9°. The boron atom has distorted tetrahedral geometry [N 2 F 2 ] (angles around B vary from 105.8° to 112.0°). The dyes are well ordered and packed densely due to С-H···F and π-π interactions. The same packing is observed for other BF 2 -carrying compounds [N 2 F 2 ] 86 and [NОF 2 ] 134 reported in the literature. The structure of complexes (Figure 5.2а), orthogonal projection (Figure 5.2b) and packing (Figure 5.2c,d) for the representative complex 5.1d are shown at Figure 5.Absorption spectra are represented at Figure 5.3. 135 In the near UV and visible range there are bands resulting from transitions within aromatic fragments that are conjugated with heteroatoms lone pairs (n→π*, π→π* transitions). Most absorption maxima are located within the range of 320 -400 nm (

4 -

 4 Metoxyquinazoline derivative 5.1g has a batochromic shift of long wavelength maximum (λ abs max ) relative to its structural isomer, namely, the derivative of 3methyl-4-oxo-3,4-dihydroquinazoline 5.1h (СН 3 СN). This arise from the elongation of p,π-conjugation chain (Figure 5.3, Table

Figure5. 4 .

 4 Figure5.4. Diagram of distribution of complexes 5.1 depending on quantum yield and λ fl max .

Figure 5 . 5 .

 55 Figure 5.5. Normalized spectra of fluorescence of complexes substituted with azole 5.1с and benzazoles 5.1а,b,d (left) and quinoline 5.1е, pyridine 5.1а and azines 5.1g,h (right) (Solvent: CH 3 CN).

Figure 5 . 6 .

 56 Figure 5.6. Photographs of borate complexes as amorphous powders 5.1a,c,e;powders and solutions under bench UV lamp (irradiation λ ex =365 nm).

Figure 5 . 7 .

 57 Figure 5.7. Molecular structure of compound 5.2b with Co(ІІ) (left) and 5.2g with Ni(II) (right) according to X-Ray diffraction.

Figure 5 . 8 .

 58 Figure 5.8. Films composites of a copolymer of styrene with octyl methacrylate and additions of the 5.2d with Сo(II), Cu(II), Ni(II).

  photophysical properties in the presence of 3d-metal ions. 141 Two model compounds that characterized by the highest extinction coefficient and λ max of absorption (section 2.4) were selected, namely benzothiazole derivative 2.24b and benzoxazole derivative 2.25a. A spectrophotometric study showed that with a gradual addition to the solutions of compounds 2.24b and 2.25a in DMSO:H 2 O Cu(II) and Zn(II) acetates in a buffer solution (Tris, pH = 7.2), a significant bathochromic shift of the absorption maxima occurs (Figure 5.8 , Table 5.3), which indicates the high visibility of these

Figure 5 . 8 .

 58 Figure 5.8. а) The absorption spectra of 2.24b with and without Zn(II). φ(DMSO) = 83 %, С 2.24b = 38 µmol/l.

  work carried out within this PhD project has allowed the development of preparative methods of 2-azahetaryl-2-(1-R-pyrrolidine-2-ylidene)acetonitriles featuring azaheterocyclic substituents of neutral and cationic nature and 2azahetaryl-2-(5-R-3-oxoindolin-2-ylidene)acetonitriles. The method to access 2azahetaryl-2-(1H-pyrrolidine-2-ylidene)acetonitriles has been optimized, allowing a significant broadening of the scope of the reaction to numerous azaheterocyclic substituents (up to 12, starting from 2). We have established that 2-azahetaryl-2-(1H-pyrrolidine-2-ylidene)acetonitriles exist both in the solution and the solid state as Z isomers in contrast to 2-azahetaryl-2-(1-alkylpyrrolidin-2-ylidene)acetonitriles that exists as Z isomers in the solid state and as a mixture of Z/E diastereomers in the solution. The free activation energy of rotation at C=C double bond has been calculated: ΔG ≠ E→Z = 14.4 kcal/mol, ΔG ≠ Z→E = 13.3 kcal/mol, a value that is characteristic of low-energy processes. In our investigation on the reaction of 2-azahetaryl-2-(1-R-pyrrolidine-2ylidene)acetonitriles with binucleophilic moieties, such as hydrazines and hydroxylamine we obseved a complete regioselectivity. Indeed it was established that the first nucleophilic attack is directed at C-2 atom of pyrrolidine. The orientation of the following attack is determined by the nature of azaheterocylic substituent: -in the case of neutral azaheterocyclic substituents (beside benzoxazole) the attack is directed at the carbon of nitrile group leading to 3-(ω-aminopropyl)-4azahetaryl-5-aminopyrazoles; -in the case of benzoxazole derivatives the attack occurs both at nitrile group and with the same probability at the C-2 atom of azaheterocycle leading to the structural isomers: 4-benzo[d]oxazol-2-yl-3-(ω-aminopropyl)-1H-azol-5-amines and 5-((2-hydroxyphenyl)amino)-3-(3-(R-amino)propyl)-1H-pyrazol-4carbonitriles (4-carboxydiimide in the case of hydroxylamine); -in the case of quaternized benzoxazole and benzimidazole the attack is directed at С-2 atom of azaheterocycle leading to protonated 3-(4-cyano-5-((2-Rphenyl)methyamino)-1-R 1 -1H-pyrazol-3-yl)-N-methylpropan-1-amines. With quaternized benzothiazole the first attack is directed at carbon of nitrile group followed by next nitrogen of ω-aminopropyl chain attack at C-2 atom of Nmethylbenzothiazole leading to an original azepine derivative. Starting from 3-(ω-aminopropyl)-4-azahetaryl-5-aminopyrazoles, we investigated methods for regioselective functionalization of their amino groups, condensation in tetracyclic compounds, namely, benzo[4,5]imidazo[1,2-c]pyrazolo[4,3e]pyrimidine and [1,2,3]triazine derivatives with up to 87% overall yield; and deamination via diazotization step followed by Suzuki-Miyaura arylation and C-H activation leading to 5-aryl(styryl, indol-2-yl)-substituted pyrazoles with up to 92% overall yield were developed. We also explored the properties of 2-azahetaryl-2-(1-R-pyrrolidine-2ylidene)acetonitriles in reaction with DMF DMA. It was established that the presence of easily accessible NH group is essential in "formylation" of the C-3 centre of pyrrolidine. The method of the synthesis of pyrrolo[3,2-c]pyridine-6imine (PP) with 59% over 3 steps was developed. The prospect use of PP for water content determination in aprotic organic solvents by fluorometric assay was developed for DMSO presenting a limit of detection of 0.068%. Finally, we studied the structure and photophysical properties of complexes of 2azahetaryl-2-(pyrrolidin/3-oxoindolin-2-ylidene)acetonitriles with 3d-metals and boron. This allowed us to establish their potent usefulness since: -The key characteristics of BF 2 complexes based on 2-azahetaryl-2-(pyrrolidin-2ylidene)acetonitriles are the big Stokes shifts (up to 9000 cm -1 ), high brightness (up to 86400 l•mol -1 •cm -1 ), positive solvatofluorochromy, fluorescence in the solid state and water stability. -Films of polymeric composites with additions of metal complexes of 2azahetaryl-2-(pyrrolidin-2-ylidene)acetonitriles with Сo(II), Cu(II), Ni(II) (ML 2 ) exhibite photovoltaic effect. Electric potential of the surface attain the biggest value of 180 mV in the case of СоL 2 . -2-Azahetaryl-2-(5-R-3-oxoindolin-2-ylidene)acetonitriles have demonstrated the high visibility when chelating Zn(II) and Cu(II): Δλ ≥ 70 nm, λligand max = 515-530 nm (red-purple), λcomplex max = 590-605 nm (blue), at the рH of biological fluids. Limit of ions detection is 0.4-1.0 µmol/l.

  Coupling constants (J), are reported in Hz, chemical shift (δ) in ppm. The multiplicity of signals is indicated using the following abbreviations: s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, quint = quintet, dd = doublet of doublets, ddd = doublet of doublets of doublets, dt = doublet of triplets, and m = multiplet.IR spectra recorded on FT-IR spectrometries Perkin Elmer in KBr plates and neat films.High resolution mass spectra (HRМS) were recorded on GCT Premier spectrometer upon electron spray ionization (ESI) or chemical ionization (DCI, CH 4 ).Elemental analysis was performed on "CHNOS elementar vario MICRO Cube" analizator.The melting points Melting points were determined on a Boetius micro hot stage apparatus with VEB Analytik 1399RNMK 05 observation lens or on Stuart melting point apparatus SMP10. X-Ray diffraction was performed on on single crystal diffractometers: Agilent Gemini, Bruker Nonius, Bruker Kappa Apex II, and Xcalibur 3. All crystals were grown by the gas diffusion method or slow crystallization from solution.The absorption spectra recorded on UV-Vis spectrometer UV-240IPC (Shimadzu). The excitation and emission spectra recorded on fluorescent spectrometer Perkin Elmer ls55. Weighing of samples was carried out on analytical scales VPK, VLR-200.

1 HRoute 1 (

 11 NMR spectrum of the reaction mixture.The distance between layers in the crystal lattice of BF 2 -complexes was calculated as the distance between the molecule plain from the layer n and centroid of the molecule from the layer n+1. for 2.1a-f). 5-Methoxy-3,4-dihydro-2H-pyrrole (0.15 г, 1.5 mmol) was added to a hot stirred solution of hetarylacetonitrile 2.2 (1 mmol) and triethylamine (0.21 ml, d = 0.726 g/ml, 1.5 mmol) in toluene. The reaction mixture was refluxed for 3-20 h (TLC control, elution system: CH 2 Cl 2 -CH 3 OH 95:5) and after the reaction ceased was cooled down to room temperature and concentrated under reduced pressure.Compounds were purified by column chromatography (for enaminionitriles 2.1а,і), or recrystallization from ethanol (for enaminonitriles 2.1b,d,е,h) or mixture i-PrOH-dioxane (for enaminonitriles 2.1с,f,j), or СHCl 3 (2.1g) in the presence of activated charcoal.Route 2 (for 2.1a-d).A vigorously stirred solution of hetarylacetonitrile 2 (2 mmol) and pyrrolidinone 4 (3 mmol) in dioxane (8 ml) was treated by dropwise addition of POCl 3 (0.28 ml, d=1.64 g/mlл, 3 mmol) and then refluxed for 1 h. The mixture was then cooled, treated with H 2 O, and stirred for 30 min at 10° C. The obtained precipitate was filtered off and recrystallized from EtOH (in the case of pyrrolidines 2.1а,b,d) or from i-PrOH-dioxane mixture (for pyrrolidine 2.1c) in the presence of activated charcoal.

  -2-(4-oxo-3,4-dihydroquinazolin-2-yl)-2-(pyrrolidin-2ylidene)acetonitrile 1g (505 mg, 2 mmol), iodomethane (0.3 ml, d = 2.28 g/cm 3 ,5 mmol) and potassium carbonate (690 mg, 5mmol) in anhydrous DMF (5 ml) was heated to 80 °C over a 1 h period (TLC elution system: EtOAc-CH 2 Cl 2 , 1:10. The reaction mixture was then concentrated under reduced pressure ant triturated with CH 2 Cl 2 . The solid was filtered off and the filtrate was concentrated. Products were separated by manual column chromatography (elution system: EtOAc-CH 2 Cl 2 ,1:10, R f 2.9 = 0.58, R f 2.10 = 0.18).

( 1 .

 1 71 ml, d = 1.33g/cm 3 , 18 mmol) was stirred for 40 min at 70°C. Then the reaction mixture was poured into water (10 ml) and a solution of NaOH (5% solution in water) was added with stirring. a) The solution was neutralized with 2M HCl to pH = 7 and extracted with EtOAc (3 times). The combined extracts were evaporated under reduced pressure and the solid residual was purified by column chromatography (elution system: CHA-EtOAc, 3:1) to give 2.21 as a yellow solid (MS (ESI) m/z: [M + H] + Found for C 10 H 9 N 2 O 173.11); b) The precipitate formed was filtered off, washed with cold water and recrystallized from ethanol to give 2.22 as a yellow solid.

( 1 H

 1 NMR (400 MHz, CDCl 3 ), δ, ppm (J, Hz): 3.36 (br.s, 3H, СН 3 ), 6.95 (d, J = 8.1, 1H, Н-4), 7.07-7.13 (m, 1H, Н-6), 7.28-7.33 (m, 1H, Н-5), 7.42 (d, J = 7.8, 1H, Н-7). The obtained compounds were used in the next step without any further characterization. A solution of 2-(3-methylbenzo[d]oxazol/thiazol-2(3H)ylidene)acetonitrile 2.21 or 2.22 and N-methylpyrrolidin-2-one 2.12а (1.2 equiv) in dioxane (5 ml) was heated up to reflux and POCl 3 (1.2 equiv) was added to the reaction mixture dropwise. In 5 min the stirring was ceased and emulsion of the formed salts in dioxane separated into 2 layers. The viscous oil of the bottom layer was gathered with Pasteur pipette and dropped into solution of KPF 6 (2 equiv) in water (5 ml) with stirring. The formed precipitate was filtrated off, dried and characterized.

  137 ml, d = 2.28 g/ml, 2.2 mmol) was added dropwise to a stirred solution of4-(benzo[d]thiazol-2-yl)-1-methyl-3-(3-(methylamino)propyl)-1H-pyrazol-5-amine 3.1a (301 mg, 1 mmol) and MeONa (54 mg, 1 mmol) in MeOH(6 ml). Stirring was pursued for 3 h. The resulting white precipitate (mp 249-250 °C) was filtered off and analyzed without additional purification steps. We observed complete conversion of the starting material to the desired product but we suspected the presence of NaI.tert-Butyl (3-(4-(benzo[d]thiazol-2-yl)-5-(benzylamino)-1-methyl-1H-pyrazol-3yl)propyl)(methyl)carbamate (3.10).Di-tert-butyl dicarbonate (120 mg, 0.55 mmol) was added to a stirred solution of 4-(benzo[d]thiazol-2-yl)-1-methyl-3-(3-(methylamino)propyl)-1H-pyrazol-5-amine3.1a (151 mg, 0.5 mmol) in trifluoroethanol (TFE) (3 ml) at rt. The reaction was completed in 10 min. After evaporation of volatiles under reduced pressure, the crude product was purified by automated flash chromatography (elution system: gradient of CH 2 Cl 2 -acetone, 9:1 to CH 2 Cl 2 -acetone, 2:3) to yield 187 mg (0.47 mmol, 93%) of white solid (mp 129-130 °C).A suspension of tert-butyl(3-(5-amino-4-(benzo[d]thiazol-2-yl)-1-methyl-1Hpyrazol-3-yl)propyl)(methyl)carbamate (187 mg, 0.47 mmol), AcOH (0.05 ml, 0.94 mmol), benzaldehyde (0.06 ml, 0.56 mmol), and activated molecular sieves in toluene (5 ml) was stirred in a sealed vessel overnight at 120 °C. At this point, two spots were detected by TLC (CH 2 Cl 2 -acetone, 9:1) corresponding to the reactant (R f = 0.27) and the desired imine (R f = 0.67 (bright yellow spot)). The reaction was broken off at that point, filtrated through a plug of celite, and the liquid was concentrated under reduced pressure. The obtained solid was redissolved in dry ethanol (5 ml) and 3 equiv of NaBH 4 (53 mg, 1.4 mmol) was subsequently added.The reaction was stirred for 30 min at rt (during this time, the color of the reaction mixture changed from yellow to white due to reduction of the imine to amine) under Ar. Dilution of the reaction mixture with ethanol, filtration through a plug of Celite, and concentration under reduced pressure gave a mixture of 3.1a and 3.10 in 100% yield. After compound separation by automated flash chromatography (elution system:gradient of CH 2 Cl 2 -acetone, 19:1 to CH 2 Cl 2 -acetone, 9:1), secondary amine 3.10 was obtained as a colorless oil (108 mg, 0.22 mmol, 47%).4-(1H-benzo[d]imidazol-2-yl)-1-methyl-3-(3-(methylamino)propyl)-1H-pyrazol-5-amine 3.3a (142 mg, 0.5 mmol) in 1,1,1-triethoxyethane (10 ml) was refluxed for 20 min, and Ac 2 O (0.47 ml, d= 1.087 g/ml, 5 mmol) was added to the reaction mixture at this point. After another 5 min of stirring, the reaction ceased (TLC elution system: CHCl 3 -acetone, 2:1) and the mixture was concentrated under reduced pressure. The crude product was purified by automated flash chromatography (elution system: gradient of CHCl 3 -acetone, 2:1) to yield 152 mg (0.43 mmol, 87%) of white solid (mp 97-98 °C). triazin-1-yl)propyl)nitrous amide (3.12) t-BuONO (0.12 ml, d = 0.867 g/ml, 1 mmol) was added dropwise to a strongly stirred solution of 4-(1H-benzo[d]-imidazol-2-yl)-1-methyl-3-(3-(methylamino)propyl)-1H-pyrazol-5-amine 3.3a (142 mg, 0.5 mmol) in DMF (5 ml, 65 °C), and the gas evolution was observed by bubble counter. After 10 min of stirring, TLC control (CH 2 Cl 2 -acetone, 9:1) indicated the presence of two spots corresponding to the starting material and new product. The pH of the reaction mixture was slightly basic. Another portion of t-BuONO (0.24 ml, 2 mmol) was added dropwise, and the pH of the reaction mixture turned to acidic (pH ∼ 3). After 10 min of stirring, another TLC control was made to ensure the conversion of starting material and formation of one main product. The reaction mixture was allowed to cool to rt, and pH was brought to neutral-slightly basic by addition of saturated aq. NaHCO 3 . This aqueous phase was extracted with EtOAc (three times), and collected organic extracts were washed with brine and dried over MgSO 4 . The solution was concentrated under reduced pressure and the residue was purified by automated flash chromatography (elution system: CH 2 Cl 2 -acetone, 19:1) to yield 137 mg (0.42 mmol, 85%) of 3.12 as a bright yellow solid (mp 163-164 °C).

  (0.6 ml, d = 0.876 g/ml, 5 mmol) was added dropwise to a stirring suspension of 3.1a (301 mg, 1 mmol) and I 2(1.1 g, 4.3 mmol) in acetonitrile (10 ml) at 65 °C. After stirring for 20 min, the mixture was cooled to room temperature, and saturated aq. Na 2 S 2 O 3 was added. The mixture was extracted three times with ethyl acetate, and the combined organic extracts were washed with saturated aq. NaCl and dried over MgSO 4 . Evaporation of volatiles under reduced pressure and further purification by automated flash chromatography (elution system: CH 2 Cl 2 -acetone, 19:1) yielded 168 mg of 3.13 (0.38 mmol, 38%) as a light orange solid (mp 104-105 °C). The reaction was directly scaled up to 1.8 g (6 mmol) of starting material, affording 0.83 g (32% yield) of the desired product. (3.14a). p-TsOH monohydrate (1.52 g, 8 mmol) was added portionwise to a strongly stirred solution of 4-(benzo[d]thiazol-2-yl)-1-methyl-3-(3-(methylamino)propyl)-1H-pyrazol-5-amine 3.1a (0.602 g, 2 mmol) in MeCN 10 (ml), and the reaction mixture was stirred over a 5 min period. The flask was then cooled to 0 °C in an ice-water bath and KI (0.83 g, 5 mmol), CuI (1 mg, 0.005 mmol), and t-BuONO (0.302 ml, d = 1.368 g/ml, 4 mmol) were added subsequently to the reaction mixture. The solution was stirred at 0 °C for 20 min then allowed to warm to rt, and stirring was continued for a further 2 h. Then, the reaction mixture was quenched with water (30 ml), 5% aq. Na 2 S 2 O 3 solution (30 ml), and saturated aq. NaHCO 3 solution to reach pH 8-9. This mixture was transferred to a separatory funnel, and the aqueous phase was extracted with EtOAc (3 × 50 ml). The combined organic extracts were dried over anhydrous MgSO 4 , filtered, and then concentrated under reduced pressure. The crude mixture was purified by automated flash chromatography (elution system: gradient of CHCl 3 -Et 3 N,10:1 to CHCl 3 -Et 3 N-CH 3 OH, 10:1:0.2) to give 0.247 g (0.6 mmol, 30%) of 3.14a as a white solid (mp 189 °C) after trituration of the residues with MeCN. The reaction was directly scaled up to 1.8 g (6 mmol) of starting material, affording 0.74 g (30% yield) of the desired product. tert-Butyl (3-(4-(Benzo[d]thiazol-2-yl)-5-iodo-1-methyl-1H-pyrazol-3yl)propyl)(methyl)carbamate (3.15). Ditert-butyl dicarbonate (120 mg, 0.55 mmol) was added to a stirred solution of 22 (206 mg, 0.5 mmol) in TFE (3 ml) at rt followed by the addition of NaOMe (30 mg, 0.55 mmol). The reaction was completed in 30 min. After evaporation of volatiles under reduced pressure, the crude product was purified by automated flash chromatography (elution system: gradient of CH 2 Cl 2 -acetone, 19:1 to CH 2 Cl 2 -acetone, 9:1) to yield 179 mg (0.35 mmol, 70%) of 3.15 as a white solid (mp 122 °C). General Procedure for the Synthesis of R-(3-(4-(Benzo[d]thiazol-2-yl)-5aryl/hetaryl/styryl-1-methyl-1Hpyrazol-3-yl))propyl-1-amine (3.16-3.20).

( 8 Pyrazoles 3 . 23 - 3 . 28 , 3 . 3 . 1 - 3 . 7 .General procedure for the synthesis of 5 -

 8323328331375 ml) was degassed beforehand by the Freeze-Pump-Thaw method and transferred to the reaction vessel under a positive pressure of argon. The resulting mixture was stirred under argon at 110 °C overnight. After cooling to room temperature, the reaction mixture was diluted with H2O, transferred to the separatory funnel, and extracted three times with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by automated flash chromatography. Reaction conditions for 3.20: teflon reactor, 140 °C, 24 h. Note: indole was implemented into the reaction in the form of trifluoroboronate salt with nitrogen protected with tert-(0.24 ml, d = 0.867 g/ml, 2 mmol) was added dropwise to a strongly stirred solution of 4-(benzo[d]thiazol-2-yl)-1-methyl-3-(3-(methylamino)propyl)-1Hpyrazol-5-amine 3.1a (0.301 g, 1 mmol) in DMF (5 ml, 65 °C), and the gas evolution was observed by bubble counter. After 10 min of stirring, the TLC control (CH 2 Cl 2acetone, 9:1) indicated the presence of two spots corresponding to the starting material and new product. The pH of the reaction mixture was slightly basic. Another portion of t-BuONO (0.48 ml, 4 mmol) was added dropwise, and the pH of the reaction mixture turned to acidic (pH ∼ 3). After 10 min of stirring, another TLC control was made to ensure the conversion of starting material and formation of one main product. The reaction mixture was allowed to cool to rt, and pH was brought to neutral-slightly basic by addition of saturated aq. NaHCO 3 . This aqueous phase was extracted with EtOAc (three times), and collected organic extracts were washed with brine and dried over MgSO 4 . The solution was concentrated under reduced pressure, and the residue was purified by automated flash chromatography (system: gradient of EtOAc-CHA, 7:3 to EtOAc, 100%) to yield 290 mg (0.92 mmol, 92%) of white solid (mp 72-73 °C). HCl gas (generated by dropwise addition of H 2 SO 4 on solid NaCl) was bubbled vigorously through an ice-cold solution of N-(3-(4-(benzo[d]thiazol-2-yl)-1-methyl-1H-pyrazol-3-yl)propyl)-N-methylnitrous amide 3.21 (158 mg, 0.5 mmol) in dry methanol (8 ml) for 20 min. The resultant precipitate was filtered off and washed with ether to yield 157 mg (0.485 mmol, 97%) of white solid (mp 152-153 °C). 3-(4-(Benzo[d]thiazol-2-yl)-1-methyl-1H-pyrazol-3-yl)propyl)-N-methylnitrous amide 3.21 (95 mg, 0.3 mmol), Pd(OAc) 2 (3.4 mg, 0.015 mmol), and Bu 4 NOAc (181 mg, 0.6 mmol) were placed in a flame-dried two-necked flask fitted with a water condenser and rubber septum. The system was evacuated and back-filled with argon. This sequence was repeated three times. DMA (3 ml) and 4-bromoanisole (0.06 ml, d = 1.494 g/ml, 0.45 mmol) were sequentially added under a stream of argon at room temperature. The resulting mixture was stirred at 70 °C for 24 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered through a plug of Celite, and eluted with additional EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified using automated flash chromatography (system: gradient of CH 2 Cl 2 -acetone, 19:1 to CH 2 Cl 2 -acetone, 9:1) to yield 126 mg (0.3 mmol, 100%) of 3.16c as a light orange solid (mp 140 °C). 30 and amide 3.31a were obtained according to the general procedure described for 3-(ω-aminopropyl)-4-hetaryl-5-aminopyrazoles (isoxazoles) Note: for pyrazoles 3.27, 3.28, 3.30 that were synthesized from pyrrolidinacetonitriles substituted with quaternized azaheterocycles the solvent for reaction is EtOH. The reaction continues during 2-3 h. The strongly stirred mixture of 2-(cyano(1-methylpyrrolidin-2-ylidene)methyl)-1,3dimethyl-1H-benzo[d]imidazol-3-ium iodide 2.8 (0.3 mmol, 118 mg) and 20 equiv of 2.5 M NaOH in ethanol (3 ml) was refluxed over 3 h period. At this point the reaction was cooled down and treated with 1M HCl to slightly acidic pH (pH around 6). The reaction mixture was concentrated under reduced pressure and the solid precipitate was triturated with dry ethanol. The precipitate was filtered off and the mother liquid was collected, concentrated under reduced presure and triturated with minimal quantity of ethanol. After another filtration-mother liquid collection-concentration 3.31b was obtained as a beige solid (71 mg, 0.22 mmol,73%).

4 ) 2 -

 42 DМF DМА (0.16 ml, 0.6 mmol) was added to a solution of 2benzo[d]imidazol-2-yl-2-(1-methylpyrrolidin-2-ylidene)acetonitrile 2.13а (119 mg, 0.5 mmol) in anhydrouys toluene (8 ml) and the resultant mixture was left to reflux until complete convertion of starting material, approimately 30 min (TLC control, CHCl 3 -CH 3 OH, 9:1). Product was purified by tritutation with hot propan-2-ol. Yield 111 mg (0.45 mmol, 90%), white powder (mp > 300 °С). General procedure for the synthesis of 2-(benzo[d]thiazol-2-yl)--amine (1.5 mmol) was added to a solution of (Z)-2-(benzo[d]thiazol-2-yl)-2-((E)-3-((dimethylamino)methylene)pyrrolidin-2-ylidene)acetonitrile 4.2a (592 mg, 2 mmol) in dioxane-ethanol mixture (16 ml, 1:1) and the resultant mixture was left to reflux over 3 h. At this point another portion of 1-R-amine (1.5 mmol) was added and the refluxing was continued until complete convertion of starting material (TLC control, CHCl 3 -CH 3 OH, 19:1).

Сomparison 3 .

 3 23a and 3.24a (Z)-3-(3-(benzylamino)propyl)-N'-hydroxy-5-((2-hydroxyphenyl)amino)isoxazole-4carboximidamide (3.26b). cycle de l'azépine. Dans le cas des énaminonitriles substitués par un benzoxazolyle dans les mêmes conditions, les deux régioisomères sont formés. La réaction de formylation du 2-(benzo[d]thiazol-2-yl)-2-(pyrrolidin-2-ylidène) acétonitrile avec le N,N-diméthylformamide diméthylacétal (DMF DMA), suivie d'une amination et d'une cyclisation dans des conditions basiques a engendré à la pyrrolo[3,2-c]pyridine-6-imine, un composé qui présente un rendement quantique fluorescent élevé (Ф = 61%) et s'est révélé très sensible à la protonation. Les deux caractéristiques devraient être utiles pour développer un test de détection d'eau originaux pour les solvants aprotiques. Nous avons démontré qu'une telle méthode fluorométrique pour déterminer la teneur en eau dans le DMSO présente une limite de détection de 0,068%. A partir d'autres réactions d'énaminonitriles avec du DMF DMA un mélange de produits méthylés et formylés est obtenu, soit seulement des produits méthylés (peu d'adduits ont également montré une non-réactivité). Ces observations nous ont amenés à supposer que la présence de groupe NH facilement accessible est essentielle dans la formylation du centre C-3 de la pyrrolidine permettant de proposer un mécanisme pour cette réaction peu commune. Les 2-azahetaryl-2-(pyrrolidin-2-ylidène)acétonitriles et leurs 3-oxo-benzoanalogues ont également été utilisés pour créer: a) des sondes spectrophotométriques pour Zn(II); b) des complexes BF 2 -rigidifiés stables à l'eau qui dépassent les limitations des BODIPY et ont des décalages de Stokes jusqu'à 9000 cm -1 , émission en bleu violet, fluorescence à la fois en solution (Ф jusqu'à 90%) et à l'état cristallin; c) des films de composites polymériques présentant un effet photovoltaïque.

Figure 1 .

 1 Figure 1. Structure générale des 2-azahéaryl-3-énaminonitriles cycliques étudiés dans cette thèse.

Figure 2 .Schéma 1 . 1 .Schéma 2 . 2 -Schéma 5 .Schéma 9 .Le metal 3d central dans le complexe 47 comportant les ligands enaminonitrile 1

 2112259471 Figure 2. Représentation graphique de la revue de littérature.

Figure 3 .

 3 Figure 3. Structure moléculaire du composé 47b avec Co (ІІ).

  photophysiques permettant de nouveaux développements dans un large éventail de domaines. À ce titre, ces travaux contribuent à faire de la molécule le centre de tout développement scientifique en sciences chimiques.

  Due to the low yield of the target product an AlCl 3 catalysis was used[START_REF] Granik | Acetals of lactams and acid amides, 39. Synthesis of three-ring derivatives of pyrido[1,2-a]pyrimidines on the basis of the dimethylformamide acetal with dicyanomethylenecycloalkanes[END_REF] , notably, the It is assumed that in this case, AlCl 3 catalyses the cleavage of the dimethylamino group from DMF DEA, in contrast to the previously described catalytic sequence

	Scheme 1.41. Reactions 2-(indolin-2-ylidene)malononitrile 1.31 with C-
	nucleophiles.

reaction took place in a different way. In particular the formation of 3ethoxymethylene 1.113 (26% yield) instead of 3-dimethylaminomethylene 1.112 was observed. The same product 1.113 was obtained by condensation reaction 1.31 with triethylorthoformiate (87% yield); Scheme 1.41. (Scheme 1.42). 75 Scheme 1.42. The mechanism of AlCl 3 catalysis.

According to the known literature procedures,

[START_REF] Granik | Transamination with enamidines and a new method for the synthesis of oxolinic acid[END_REF]

ethoxymethylene derivatives are more active in the reactions with nucleophiles, than enamines. Thus, ethoxymethylene nitrile 1.113 reacts with primary and secondary amines in mild conditions with good yields (62-79%) providing compounds 1.114, while dimethylmethylene derivatives are reacting only with privary amines (52%). Upon

Figure 1.14 Figure 1.13 20µм

	macrocycle that is part of the cobalamin (vitamin B 12 ). The systematic name of the
	ligand: 5-(cyano(5-pyrrolidin-2-ylidene)methyl)-3,4-dihydro-2H-pyrrole. 11
	One of the advantages of semicorrins is their simple synthesis and modification
	of substituents at stereogenic centres. Enantiomerically pure ligands can be
	synthesized on multigram scale starting with commercially available L-or D-
	pyroglutaminic acid 1.131 with 30-40% total yield (Scheme 1.47).
	Many steps have already been done to create enantioselective catalysts; the
	necessity of developing new asymmetric catalysts is increasing with the enlargement
	in the number of new pharmaceutical, agro-pharmaceuticals, flavor and odor
	regulators, that are effective only in an enantiomerically pure form.
			Typically, asymmetric catalysts are
			molecules consisting of metal and chiral
			ligand.
	Corrin -a macrocycle	Semicorrin -Semicorrin -	One class of ligands for asymmetric
	that is part of the structure of cobalamin	the name of the class of ligands, which was	catalysis, well-studied in the 80s-90s is
	(vitamin B 12 )	proposed by American scientist Stevens in the 70s	semicorrins (Figure 1.14). This name of
			compounds was proposed by Stevens in
	the 70s. The name is associated with the corrin (eng, "core" -"base") -a natural

11 Scheme. 1.47. Semicorrins synthesis.

	The synthesis includes the following steps: the esterification of L-pyroglutamic
	acid 1.131, which is catalyzed by an ion-exchange resin, followed by alkylation with
	a Meerwein salt;

condensation of 1.2c with tert-butyl 2-cyanoacetate, which gave the enamine 1.132; hydrolysis of tert-butyl ester and subsequent decarboxylation were applied for the preparation of cyanogenamine 1.6 as

	Semicorrins ester groups can be easily modified by various methods (Scheme
	1.48).
	Scheme 1.48. Structural modifications of semicorrins.
	The reaction with an excess of Grignard's reagent gave diols 1.135. The
	reduction with sodium borohydride resulted in the formation of
	bis(hydroxymethyl)semicorrins 1.133. Hydroxy groups can be modified with silyl or
	triphenylmethyl groups 1
	a mixture of Z/E-isomers. The
	last step was the hardest to implement, in particular, methods that worked on similar
	systems previously did not lead to the target product. Thus, an attempt to connect two
	monocyclic bilding blocks 1.2c and 1.6 by carboximidate-enamine condensation was
	unsuccessful. In neutral or weakly basic conditions, condensation did not occur at all.
	Strong basic conditions could not be applied due to the potential racemization of the
	product. Semicorrin 1.7 can by synthesized only in the presence of TFA in 70%
	yield. Catalysis by other acids (AcOH, TsOH, BF 3 •Et 2 O) gave a less satisfactory
	results.

.134. Figure 1.15. Crystal structure, numbering and stereoscopic view of the semicorrin complex with Cu(II). 11

	of the stereochemistry of the reaction occurring in the coordination sphere of the
	complex (Figure 1.16).
	Figure 1.16. Spatial view of the complex: 3D structure (left) and orthogonal
	projection (right). 11
	Semicorrin complexes generated in situ or
	synthesized in advance with Cu(II) 1.136a and Co (II)
	1.136b (Figure 1.17) were used as catalysts for
	enantioselective cyclopropanation of olefins by diazo
	compounds 90 and for reduction of α,β-unsaturated esters
	as well as amides (Scheme 1.49 and 1.50). 12, 91-93
	Semicorrins form stable complexes with a number of metal ions: Co(II), Rh(I),
	Ni(II), Pd(II), or Cu(II). Structures of some complexes were studied by X-ray
	diffraction analysis (Figure 1.15). It was observed that, depending on the metal ion,
	the structure of the ligand and the reaction conditions, mono-or bis(semicorrins) can
	be prepared.
	In metal complexes with semicorrins as ligands, two substituents at the
	stereogenic centres of pyrrolidine are close to the coordination centre. They surround
	the atom of metal from two opposite sides, which should noticeably induce a control

Scheme 1.49. Asymmetric synthesis of cyclopropanes.

	Scheme 1.50. Reduction of α,β-unsaturated esters and amides.
	Notably, isolated double bond are inert in these conditions, a high
	chemoselectivity is achieved only with electrophilic C=C bonds conjugated with
	electron-withdrawing groups.
	Figure 1.17. Semicorrin
	complex with Cu(ІІ)
	(1.136а) and Cо(ІІ)
	(1.136b).
	The best enantiomeric excess (95-97%) was achieved in the case of R 1 = Ph or
	CH 2 =CH 2 ; R 2 = D-menthyl; R = СMe 2 OH (Scheme 1.49).
	Reduction reactions with the Co(II) complex 1.136a were carried out in
	quantitative 90-99% yield with enantiomeric excess (up to 99.9%, in the case R 1 =
	Ph(CH 2 ) 2 , R 2 =CONHMe) (Scheme 1.48). The solvent plays the key role in the
	reaction. In particular, changing the reaction media from DMF/ethanol to the
	diglyme/ethanol solution dramatically increased the reaction rate. According to the
	authors, such effect is associated with better solubility of sodium borohydride in
	diglyme. 91

compounds 2.1b-h,j depicted on the Scheme 2.1, route 1. We have also developed a new method for the synthesis of enaminonitriles 2.1

	compounds such as (Z)-2-(1,3-benzoxazol-2-yl)-2-(pyrrolidin-2-ylidene)acetonitrile
	2.1с, (Z)-2-(4-methylthiazol-2-yl)-2-(pyrrolidin-2-ylidene)acetonitrile 2.1d.
	The yields of known enaminonitriles are comparable or higher to those
	described in the literature: 2.1а -58% route 1, 67% route 2 and 73% according to the
	literature; 2.1j -70% route 1, 57% according to the literature; 9 2.1b -85% route 1,
	86% route 2 and 56% according to the literature.
	Figure 2.1. Target
	molecule.
	2 (CH-acid) with O-methylbutyrolactam 2.3 in
	the presence of Et 3 N in boiling toluene. This method has been described for quinolin-
	2-yl 2.1a and pyridin-2-yl 2.1i as heterocyclic substituents.
	The adjustment of the synthetic scheme allowed us to expand the number of
	heterocyclic substituent in 2-(pyrrolidin-2-ylidene)acetonitriles and obtain 8 new
	by using a three-component condensation of hetarylacetonitrile 2.2, phosphorus
	oxychloride, and pyrrolidin-2-one 2.4. In contrast to the previously described method
	(Scheme 2.1, route 1) which requires the initial preparation of 5-methoxy-3,4-
	dihydro-2H-pyrroles 2.3 the proposed method is streamlined enabling in situ
	generation of 5-chloro-3,4-dihydro-2H-pyrrolinium cation 2.5 and preparation of the
	desired 2-hetaryl-2-(pyrrolidin-2-ylidene)acetonitrile 2.1 within 1 h (Scheme 2.1.
	route 2). Our method allowed us to obtain both the previously known (E)-2-
	(pyrrolidin-2-ylidene)-2-(quinolin-2-yl)acetonitrile 2.1а 9 and (Z)-2-(1,3-benzothiazol-
	2-yl)-2-(pyrrolidin-2-ylidene)acetonitrile 2.1b, 10 as well as good yields of new

10 Scheme 2.1. The routes to the synthesis of 2-azahetaryl-2-(pyrrolidin-2- ylidene)acetonitriles 2.1. 2.1.2. Structure exploration: XRD, 1 H NMR, DFT-calculations

	spectra in the 10-12 ppm range assigned to the chelated proton. There are also no
	multiplets that would appear for the spin-spin coupling of 1-H and 6-H protons for
	2.1i in tautomeric form B.
			Our results are in
			agreement with these
			statements. Thus we
			observe	the	same
			stretching vibrations in
			IR and broad signal of
			chelated proton in the
			1 H NMR spectra for
			enaminonitriles	2.1.
	Figure 2.3. A fragment of the 1 H NMR spectrum of		(Figure 2.3).
	compound 2.1b with the highlighted shift of NH proton	Beside	three
	(CDCl 3 , 400 MHz).		tautomeric	forms
	(Figure 2.1) compounds 2.1 can also exist as 2 diastereomers (E and Z). (Figure 2.4).
	The explorations carried out indicate the
	existence of compounds 2.1 as Z isomer both in
	solid state and in solution with the heterocyclic
	substituent and the NH group of pyrrolidine in the
	cis position.
	The XRD study of the compounds 2.1b and
	2.1d has shown that molecules exist exclusively as	Theoretically, enaminonitriles
	2.1 can exist in three tautomeric Z-isomers in a crystalline state (Figure 2.5). XRD seems to indicate that Н1 atom has
	forms A-C (Figure 2.1). It was a covalent bond with N1 atom of pyrrolidine (Н1-N1 0.86 Å) and form the hydrogen
	previously mentioned that the only bond with N2 (H1···N2 2.13 Å, N1-H1···N2 127.6°). The enaminonitrile 2.1b
	form for compounds 2.1a and 2.1i is framework is almost planar, (deviation of the pyrrolidine ring from the plane below Figure 2.2. Tautomeric forms of enaminonitriles 2.1.
	the enamine C. 9 This conclusion was 0.096 Å, the angle between the planes of pyrrolidine and benzothiazole is 4.91°,
	made on the basis of IR spectra analysis, in which there is a stretching vibration in the which is indicative of the delocalization of the enamine moiety electron density both
	region ~ 3100-3400 cm -1 corresponding to a NH bond and a broad signal in 1 H NMR toward the nitrile and benzothiazole. The shift promotes N1-C10 bond shortening

Figure 2.4. Diastereomers of tautomer C.

	(1.32 Å) and C10-C8 bond elongation 1.39 Å (as compared to standard bond length
	values 99 ) and also the deviation of the С8-С9-N3 angle (177.8°) from sp
	hybridization.
	Figure 2.5. а) Molecular structure of 2.1b according to X-ray diffraction.	b) Orthogonal projection 2.1b.
	The low field shift of proton of NH group is observed in the 1 H NMR spectra
	(table 2.1) due to its intramolecular hydrogen bond with the nitrogen atom of the
	heterocycle. This bond stabilizes the Z isomer in the solution.

Table 2 .1. The shift of NH proton in the 1 H NMR spectra of enaminonitriles 2.1.

 2

	Entry	1	2	3	4	5	6	7	8	9	10
	Compound	2.1a	2.1b	2.1c	2.1d	2.1e	2.1f	2.1g	2.1h	2.1i	2.1j
	Shift NH,	11.35 10.27	9.65	9.83	9.60 10.10 10.64	8.70 10.46 10.69
	ppm
	Solvent	CDCl 3	CDCl 3	CDCl 3	CDCl 3	CDCl 3	dmso-	CDCl 3	dmso-	CDCl 3	dmso-
							d 6		d 6		d 6
					According to the literature data the shift of NH
				proton in 2-(pyrrolidin-2-ylidene)malononitrile 2.6a
				is 7.52 ppm (solvent СDCl 3 ). In the latter one there is
				not possible to form the intramolecular hydrogen
				bond. By contrast the NH proton shift in 3-
				(pyrrolidin-2-ylidene)pentan-2,4-dione 2.6b, where
				the intramolecular hydrogen bond exists (С=О … Н),
	is 11.45 ppm (solvent СDCl 3 ). 2

Table 2 .2. The

 2

	of 2.1b in the

Maxwell-Boltzmann distribution: N

i /N = exp(-ΔG i /kT)/∑ j exp(-ΔG j /kT)*

	Compound		2.1b
	Ratio Z/E	1903	1667	1642	1630
	Solvent	CНCl 3	(СН 3 ) 2 СО	CH 3 OH	(СН 3

  R = Me, Bn, cyclopropyl, CH(Me)Ph, CH 2 Fur, t-Bu, Ph

									r oute 2
				Het	CN
				R = Me 2.2	dioxane , 1 h POCl 3		route 1
	Cl	O	Cl	1) R-NH 2 2) KOt-Bu	O		DMS	O	Het	2.2	CN	Het	CN
						N R	80 o C, 2h	N R SO 4 Me	NaH, DMF rt, 1 h	N R
		R = a: Me, b: Bn; c: cyclopropyl 0.32 M KPF 6 30 min, rt 2.11a 2.12: 2.12	N	O PF 6 2.19a	NaOMe 2.11a-c	N R Acetal method O O Het	2.7, 2.13-2.18, 57-91% CN 2.2
				2.7: benzothiazol-2-yl			Route 1:
				2.13: benzimidazol-2-yl 2.14: quinolin-2-yl 2.15: 3,4-dihydro-4-oxoquinazolin-2-yl 2.16: 4-methylthiazol-2-yl 2.17: 1-methyl-1H-benzimidazol-2-yl	2.Route 2:
				2.18: benzoxazol-2-yl			2.7a: 88%

101, 9

Such derivatives can be accessed through the condensation of the anion of 2-azahetarylacetonitriles 2.2 (obtained via deprotonation by NaH) and 5-methoxy-1-R-3,4-dihydro-2H-pyrrol-1ium salt 2.11 in DMF. The starting 1-R-pyrrolidin-2-ones 2.12 have been synthesized in two steps by reaction between chloroanhydride of chlorobutiric acid and corresponding amines, and further cyclization is promoted in the presence of potassium tert-butoxide.

102

This approach allows us to obtain a large set of substituents on the nitrogen atom. We have managed to obtain derivatives featuring a benzyl 2.12b, cyclopropyl 2.12c, 1-phenylethyl 2.12d, furan-2-ylmethyl 2.12e, tertbutyl 2.12f, phenyl 2.12g substituent. 10 7a: 91%; 2.7b: 80%; 2.7c: 74% 2.13a: 80%; 2.13b: 77%; 2.13c: 60% 2.14b: 67%; 2.15a: 75%; 2.16b: 72%; 2.17a: 57%; 2.18a: 88%; 2.18b: 79%

Table 2 . 4

 24

	Compound		2.7a
	E/Z ratio	46	30	29	28
	Solvent	CНCl 3	(СН 3 ) 2 СО	CH 3 OH	(СН 3 ) 2 SО
	Compound		2.13а
	E/Z ratio	64	22	20	19
	Solvent	CНCl 3	(СН 3 ) 2 СО	CH 3 OH	(СН 3 ) 2 SО

. Ratio between E/Z isomers of 2-benzo[d]thiazol-2-yl-2-(1methylpyrrolidin-2-ylidene)acetonitrile 2.7 a and 2-benzo[d]imidazol-2-yl-2-(1methylpurrolidin-2-ylidene)acetonitrile 2.13а.

To study the dynamic behavior of those compounds in the solution VTP experiment has been conducted for compound 2.13a. Upon cooling the solution of 2.13а in CDCl 3 down to 213 K the peaks of Z isomer arise. (table

2.

5). Two broad singlets of 3-CH 2 (3.57 ppm) and N-CH 3 (3.46 ppm) signals splitted into four independent peaks upon cooling: triplet (3.48 ppm, J = 7.7 Hz, 3-СН 2 ) and singlet (3.45 ppm, N-CH 3 ) corresponded to E isomer and triplet (3.08 ppm, J = 7.5 Hz, 3-СН 2 '

Table 2 .

 2

	Entry Solvent	Temp.	E/Z ratio			Chemical shift (ppm)
			(K)
					N-CH 3 3-CH 2	NH	N-CH 3	3-CH 2	NH
	1	CDCl 3	298	mixture	3.46	3.57	-	-	-	-
	2					2.13a E			2.13a Z
		CDCl 3	213	7:1	3.45	3.48	9.89 3.08	2.97	10.88

5. Selected chemical shifts data and ratio of isomers at different temperature observed for 2.13a in 1 H NMR spectra (Solvent: CDCl 3 )

Table 2 .6. Comparison

 2 The bottom layercompounds 2.19 and 2.20 were separated and solidified by anion metathesis from Cl -

	to PF 6	-.

The 1 H NMR spectra of 2.

21

and 2.22 are indicative of a single diastereomer. Considering the structure analysis results obtained for N-substituted enaminonitriles 2.7, 2.13-2.18 (section 2.2) these signals are thought to correspond to the less steric hindered E isomer (all the multiplets are well resolved). Comprehensive assignment of signals of 2.21 was made by homonuclear (COSY) and hetereronuclear (HMQC, HMBC) and NOESY 2D NMR techniques. The negative cross-peaks observed in the spectrum due to NOE between CH 3 and 3-CH 2 groups (δ = 3.22, 4.05 ppm) again confirmed the E configuration (Figure 2.14). The similarity of the chemical shifts of the corresponding protons in the 1 H NMR spectrum of benzoxazole derivative 2.22 also indicates E configuration. For such cationic structures the existence of two resonance forms with localization of a positive charge on the nitrogen of azaheterocycle A or on the nitrogen atom of pyrrolidine B can be envisaged (Figure 2.15). The signal of one of -CH 3 groups is shifted to low field (δ = 4.02 ppm vs 3.50 ppm for 2.21; δ = 4.05 ppm vs 3.27 ppm for 2.22) as a potential consequence of its positioning at the nitrogen bearing more positive charge. From the

Figure 2.14. The most indicative correlations found in NOESY and HMBC spectra of 2.21.

Figure 2.15. Resonance forms of enaminonitriles 2.8, 2.21, 2.22. other hand there is only minor changes in the location of -CH 3 group of pyrrolidine in cationic structure as compare to neutral one (δ = 3.38 ppm for 2.7a vs 3.27 ppm for 2.22; δ = 3.52 ppm for 2.18a vs 3.50 ppm for 2.21). Moreover, HMBC correlations with C-2 and the node carbon of benzothiazole situated next to the nitrogen (Figure 2.14) are providing further evidence that this CH 3 group is placed at nitrogen of benzothiazole and the predominant resonance structure is A (Figure 2.15). In the case of 2.8, with 1,3-dimethyl-1H-benzo[d]imidazol-3-ium (Х = NMe) substituent, heterocycle is symmetric about C-2 axis and the signals of both CH 3 groups arise as one singlet (6H) in 1 H NMR spectrum. It has a low field shift versus N-CH 3 group of pyrrolidine (δ = 4.20 ppm vs 3.60 ppm), but there is also a significant low field shift of -CH 3 group of pyrrolidine as compared to the neutral analogue (δ = 2.42 ppm for 2.17a vs 3.60 ppm for 2.8). These evidences cannot be indicative for predominance of one resonance form over the other.

PF

6

-is evidenced by a septet in the

31

Р NMR spectra and doublet in 19 F NMR spectra of compounds 2.21 and 2.22. As illustrated in table 2.6 the 13 С NMR spectrum of compound 2.8, 2.21 and 2.22 exhibit a low field shift of С-2 atom of enaminonitrile fragment in comparison with neutral analogues. This indicates the extra deshielding related to the displacement of the electron density to the electron deficient nitrogen. of the chemical shift of С-2 atom of enaminonitrile fragment in N-substituted uncharged enaminonitriles 2.13а, 2.7а,2.18а and their analogues with quaternized azaheterocycles 2.8, 2.21,2.22. The 1 H NMR spectra of compounds 2.8 (in which the azaheterocyclic substituent is 1,3-dimethyl-1H-benzo[d]imidazole-3-ium) is indicative of the presence of the 2 diastereomers, 2 sets of signals being observed . An analysis of their chemical shifts leads to conclusion that the compound exists as a mixture of E and Z isomers. 11 Interestingly the diastereomeric ratio varies with the solvent indicating equilibrium (Table 2.7)

Table 2 . 7 .

 27 Chemical shifts of N-CH 3 and 3-СН 2 groups of compound 2.8, that indicate the belonging of the set of signals to E or Z isomer.

  charge is + 0.372. This result is in agreement with the conclusion on the increased electron deficiency of the C-2 atom, made from experimental data (low field shift of the signal of C-2 atoms in the[START_REF] Abbas | Novel substituted and fused pyrrolizine derivatives: synthesis, anti-inflammatory and ulcerogenecity studies[END_REF] C NMR spectrum).

	1	CDCl 3	1.4:1	3.60	2.94	2.76	3.36
	2	CD 3 CN	1:1.2	3.51	2.51	2.46	3.25

а) b) Figure 2.16. а) Molecular structure of 2.8 according to X-ray diffraction . b) Orthogonal projection. are indicative of the electron density distribution. Taking into consideration the value of dihedral angle it can be assumed that delocalization on azaheterocycle is limited by the lack of planarity with the enamine moiety. Thus delocalization toward the nitrile group is mainly occurring (Figure 2.16). DFT calculation of partial charges in molecule 2.8 which has a quaternized heterocyclic substituent and its neutral analog 2.13a indicate a partial positive charge on С-2 atom of pyrrolidine in 2.8 is equal to +0.435 whereas in 2.13а in the same position, the

Table 2 .8. Spectrophotometric characteristics of compounds 2.24а-с, 2.25 solutions.

 2

	2-Azahetaryl-2-(5-R-3-oxoindoline-2-ylidene)acetonitriles are brightly colored
	compounds varying from red to violet. They exhibit low solubility in common
	organic solvents and water, as usually observed for the isatin's derivatives. 107-108 The
	compounds 2.24a-c, 2.25a give a long wave-length absorption band in the 515-
	550 nm range (Figure 2.17, table 2.8).
	a)	b)
	Entry Compound	λ max , nm	ε λmax , l•mol -1 •cm -1 , 10 4
	1	2.24а	520	1,48±0,05
	2	2.24b	530	1,38±0,05
	3	2.24c	550	1,03±0,05
	4	2.25а	515	1,66±0,10

c) Absorption spectra of 2.24a-c, 2.25а in DMSO. С = 10 µmol/l.

Figure 2.17. Photo of 2.24b (a) and 2.24с (b) in the solution (DMSO) and a solid state.

  While increasing the basicity of the medium the batochromic shift of absorption λ max is occurring, 150 nm for 2.24b (λ abs max = 680 nm) and 130 nm for 2.25а (λ abs max = 665 nm). Visually it is the change from purple to blue color.

	In the case of 2-(3-methylbenzo			ylidene)acetonitrile 2.19 the
	reaction product is the base				, which is analogue to the one
	obtained in the reaction with				ones (section 2.3). The imine-
	enamine equilibrium shift The conditional dissociation constants (pKa) were calculated for 2.24b and charge on the nitrogen of
	azaheterocycle (Scheme 2.9 2.25a on the basis of the obtained data: pKa 2.24b = 10.09±0.05; pKa 2.25a = 10.96±0.25.
	Considering	the	ease	of	S	CN 2-azahetaryl-2-(5-R-3-oxoindolin-2-S CN
	O ylidene)acetonitriles deprotonation we have tried to alkylate them. As it was 1) PCl 5, benz zene, ∆, 1 h N O N O
	N H mentioned earlier in the text (section 2.1) 2-azahetaryl-2-(pyrrolidin-2-O S 2) S CN HN Cl N
	Figure 2.18. а) Molecular structure of 2.24b according to X-ray diffraction. N 2.23a Scheme 2.9. The reaction of isatin Conclusions regarding the structure of the synthesized molecule were made on b) Orthogonal projection. the basis of IR spectrum group, as well as 1 H NMR spectr The particularity of when changing the acidity of the medium. Absorption of function of pH (from 3.8 A 2.19 The reaction of isatin 2.23a with N-methylbenzothiazolylacetonitrile 2.27a ylidene)acetonitriles 2.1 require harsh reaction conditions and even in this case the alkylation proceed only partly. In contrast methylation of 2.24b proceed already at 2.20) and DMSO:Н N 2.19. room temperature with stochiometric amount of K 2 CO
	which indicates an effective delocalization
	of charge in the molecule.
	The 2D NMR techniques (COSY, HMQC, HMBC) were used to provide a		Figure 2.19. The chemical shifts of protons and carbons in 2.25а found by
	comprehensive attribution of the 1 Н and		2D NMR spectroscopy.
	13 С NMR signals (Figure 2.19). absorption spectra of		Figure 2.21. The absorption
		О (5:1) at different		2.25a in DMSO:Н 2 О
		2.24b = 40 µmol/l		acidity of the medium
						85

1 H NMR spectra of 2.24-2.26 as it was observed for 2-(pyrrolidin-2-ylidene)acetonitrile derivatives 2.1. Such low field shift caused by intramolecular hydrogen bond between nitrogen of azaheterocycle and hydrogen of pyrrolidine (NH). According to XRD estimated length of H3А···N1 hydrogen bond is 2.15 Å, the angle N3-H3А···N1 123.3° (Figure 2.18). The low field shift is additionally enhanced due to the deshielding effect of conjugated carbonyl group. The dihedral angle between the 3oxindole and benzothiazole planes in 2.24b is equal to 8.8° (Figure 2.18, b)), 2 О 3:2

Figure 2.20. The absorption 2.24b in DMSO:Н 2 О (5:1) acidity of the medium.С 2.24 methylbenzo[d]thiazolyl-2(3H)-ylidene reaction product is the base 2.27а, but not the salt А, which is analogue to the one obtained in the reaction with N-methylpyrrolidin-2-ones (section 2.3) shift is promoted by the positive charge Scheme 2.9) . Conclusions regarding the structure of the synthesized molecule were made on um, in which there is no characteristic H NMR spectra, in which the signal of NH group of 2-functionalized-3-oxindoles 2.24-2.26 when changing the acidity of the medium. Absorption of 2.24 to 11.2) were studied in DMSO:Н 2 О 5:1 О 3:2 for 2.25а (Figure 2.21). methylbenzothiazolylacetonitrile Conclusions regarding the structure of the synthesized molecule were made on , in which there is no characteristic vibration of the NH NH group proton is absent. 2.26 is their behavior 2.24b and 2.25а as a О 5:1 for 2.24b (Figure absorption spectra of О (3:2) at different medium. С 2.25a = 40 µmol/l 3 (Scheme 2.10).

  N-unsubstituted pyrrolidines 2.1 with 1,2-binucleophiles. Neither the excess of binucleophile nor the high temperature lead to the expected product. The starting material remained unchanged or the product of degradation was observed (hetarylacetonitrile was isolated).

	The involvement
	of the nitrile group,
	initially present in 2.7,
	2.13-2.15,	in	the
	reaction is highlighted
	by the disappearance
	of its characteristic
	stretching	vibration
	absorptions in the although benzothiazole substitution systematically provided better efficiencies, all 2198-2178 cm -1 range things being otherwise equivalent. of the IR spectra. 3-(ω-Aminoalkyl)-4-hetaryl-5-aminopyrazoles 3.1-3.4, 3.6 and isoxazoles 3.5, Thorough 3.7 were isolated with good analytical quality after a simple solvent evaporation and structural analysis of the compounds was carried out using 1 H NMR, 13 C MNR, 2D trituration in acetone or acetonitrile, or column chromatography. NMR techniques and IR. Particularly, in DMSO-d 6 , a characteristic singlet of NH 2 in
	the

In contrast, N-alkylpyrrolidines 2.7, 2.13-2.15 that has no intramolecular hydrogen bond react with 1,2-binucleophiles successfully. The reaction proceeded smoothly in refluxing dioxane with 10-20 equiv excess of the binucleophile reagent and provided the pyrazoles and isoxazoles in moderate to good yields (scheme3.1).

101, 109

The nature of the alkyl substituent on the pyrrolidine nitrogen was shown to only moderately affect the efficiency of the reaction (3.1а-с). Moving from methylhydrazine to hydrazine hydrate was found to promote a decrease in reaction yields (3.1c vs. 3.2c), whereas no discernable effect was observed upon switching from methylhydrazine to hydroxylamine (3.4b vs. 3.5b). Finally, variations in the nature of the heterocyclic moiety did not significantly affect the overall efficiency, . Scheme 3.1. Reactions of 2-azahetaryl-2-(1-R-pyrrolidin-2-ylidene)acetonitriles 2.7, 2.13-2.15 with 1,2-binucleophiles. 1 H NMR spectrum is observed at 6.25-6.94 ppm. Interestingly, this signal is shifted up-field for isoxazoles, probably as a consequence of oxygen electronegativity

  quantitatively, and 3.19 in 72% yield. Yet,

	moving	to	ortho-substituted	2-nitrophenylboronic	acid	and	2,6-bis-
	(trifluoromethyl)phenylboronic acid fully inhibited the coupling reactivity due to the
	steric bulk around the reactive site of the iodopyrazole derivative.

Table 4 . 1 .

 41 Spectrophotometric characteristics of 4.9.

	Solvent λ max of	ε max , 10 4	Solvent	λ max of	ε max , 10 4	Solvent	λ max of	ε max , 10 4
		absorp tion,	•		absorp tion,	•		absorp tion,	•
		nm			nm			nm
		324	0.46±0,02		323	1.05±0,01		320	0.42±0,02
		339	0.54±0,02		335	1.31±0,02		335	0.56±0,02
	DMSO	366	0.59±0,02	CH 3 CN	360	1.25±0,04	Toluene	372	0.71±0,05
		390	0.72±0,09		384	1.46±0,19		391	1.15±0,07
		409	0.69±0,09		404	1.33±0,18		414	0.99±0,07
	СН 3 СN	325	2.15±0,07		326	0.92±0,07		328	1.35
	:HCl СН 3 СN :H 2 O	340 357	2.47±0,06 1.95±0,02	CH 3 OH	341 358	1.11±0,08 0.90±0,06	Ethanol *	342 359	1.69 1.41
		332	0.79		319	0.55		397	0.14
	Propan -2-ol*	342 361 379	0.79 1.00 1.00	tert-Buthano l*	332 363 382	0.70 0.87 1.08	* The molar absorption coefficient is calculated for the solution with C 4.9 =1.5•10 -5 mol/l
		397	0.91		400	0.97
	With a decrease of рKа of the solvents 131 and their ability to act as donors of
	hydrogen bond, characterized by alpha coefficient, 132 moving from methanol to
	ethanol, propan-2-ol and tert-buthanol induced a significant decrease of the donor
	solvent effect and the spectra in tert-butanol and propan-2-ol being close to the ones
	in aprotic solvents (Figure 4.17).

Table 5 .

 5

	Com	δ of aromatic	δ of 5-CH 2 -	Com	δ of	δ corresponding
	poun	proton, ppm	protons, ppm	poun	corresponding	CH 2 -protons
	d			d	aromatic proton,
					ppm
	5.1а	8.05	4.07	2.1b	7.81	3.85
	5.1b	7.71	4.06	2.1c	7.52	3.85
	5.1c	2.51 (CH 3 )	3.98	2.1d	2.37 (CH 3 )	3.76
	5.1d	7.82	4.03	2.1g	7.57	3.82
	5.1e	8.61	4.10	2.1a	7.84	3.85
	5.1f	8.31	3.98	2.1i	8.36	3.75
	5.1g	8.38	4.05	2.9	7.67	3.85
	5.1h	8.28	4.10	2.10	7.47	3.86

1.

1

H NMR chemical shifts of protons modified by complex formation and corresponding protons in initial hetarylenaminonitriles 2.1(Solvent: СDCl 3 ).

Table 5

 5

	.2), except for
	quinoline derivative 5.1е, which
	exhibits a λ max = 420 nm,
	(Solvent: CH 3 CN); this is in
	agreement with the data reported in the literature for BF 2 -rigidified pyrrolopyrrole

cyanines for which λ max increase in order benzoxazol-2-yl→pyridin-2-yl→benzothiazol-2-yl→quinolin-2-yl (754 nm)

[START_REF] Fischer | Pyrrolopyrrole cyanine dyes: a new class of near-infrared dyes and fluorophores[END_REF]

, and for BF 2 -benzo[c,d]indole N-

Table 5 . 2

 52

	Compound Solvent	λ abs (nm)	ε abs max (M -1 •cm -1 )	λ fl (nm)	∆ʋ, (cm -1 )	Ф, DMSO,	ε× Ф (M -
							%	1 •cm	-1 )
	2.1b	CHCl 3	336	20 000
		DMSO	360	96 000	398	2652	90	86 400
		CH 3 CN	358	52 700	398	2807
	5.1a	CHCl 3	361	43 300	393	2256
		Толуен	364	42 100	392	1361
		Solid state			406, 423
	2.1с	DMSO	323	43 000
		DMSO	322	84 800	450	8 834	83	70 400
		CH 3 CN	320	40 600	447	8 879
	5.1b	CHCl 3	323	31 900	406	6 329
		Toluene	325	31 300	382	4 591
	2.1d	DMSO	327	33 900
		DMSO	349	28 000	400	3653	10	2 800
		CH 3 CN	349	30 900	430	5397
	5.1с	CHCl 3	349	13 900	395	3337
		Toluene	355	34 100	386	2262
		Solid state			434
	2.1g	DMSO	338 325,	26 900
		DMSO	339	46 000	370, 382 3321	17	7800
		CH 3 CN	337	63 800	431	6472
	5.1d	CHCl 3	339	14 900	453	7423
		Toluene	342	36 700	366	1917
		Solid state			376, 396
	2.1а	DMSO	380	24 100
		DMSO	398, 417	38 100 35 900	462	3 481	87	33 100
		CH 3 CN	396,	35 000	459	3 466
			416	33 700
	5.1е	CHCl 3	397,	22 400
			420	22 200
		Toluene	400,	19 200	441	9 092
			424	19 600
		Solid state			496
	2.1і	DMSO	334 295,	18 600

. Photophysical characteristics of complexes 5.1а-h and the ligands 2.1ad,g,i; 2.9, 2.10 in various solvents.

Table 5 .3. The

 5

	Entry	Compound	λ max of absorption of reagent, nm	λ max , nm	The influence of metal ion Zn(II) Cu(II) Δλ, nm λ max , nm	Δλ, nm
	1	2.24b	530	600	70	605	75
	2	2.25a	515	590	75	590

influence of Zn(II) and Cu(II) on spectrophotometric characteristics of 2.24b (DMSO 83%) and 2.25a (DMSO 70%) in solution DMSO-H 2 O.

Table 5 .

 5

		The absorption spectra of 2.25a with
	logarithmic method for the investigation of complexes 142
	we have established that the complexes of the simplest composition 1:1 exist in the
			Zn(II) = 7.88±0.02, lgK
		4. Limit of detection of
		Cu(II) by
	Entry	Compound	Ion Ion	∆A λmax	LD (3S), (µmol/l)
	1 2	2.24b	Zn(II) Zn(II) ∆A 600 Cu(II) Cu(II) ∆A 605	0.54 0.97
	3 4	2.25a	Zn(II) Zn(II) ∆A 590 Cu(II) Cu(II) ∆A 590	0.94 0.40
	Complex formation occurs slowly with other 3d metals under conditions of
		I) or does not occur in the
	case of Ni(II). For the selective determination of Zn(II), the Cu(II) ions can be
	Thus at the pH of biological fluids, the spectrophotometric determination of the
	) can be carried out using 2-azahetaryl-2-(5-R-3-
					147

ylidene)acetonitriles as chromophore reagents, as they has a low limit Δλ ≥ 70 nm).

Limit of detection of Zn(II) and

Cu(II) by 2.24b and 2.25a.

  potassium carbonate (690 mg, 5mmol) in anhydrous DMF (5 ml) was heated to 80 °C over a 1 h period (TLC elution system: CHCl 3 -CH 3 OH, 95:5) The reaction mixture was then concentrated under reduced pressure ant triturated with CH 2 Cl 2 . The solid was filtered off and the filtrate was concentrated. Purification was

	made by triturating of solid residual with a minimal quantity of CH 3 CN and further
	filtration. Yield 630 mg (1.6 mmol, 79 %) in the case of 2.1f; Yield 654 mg (1.66
	mmol, 83 %) in the case of 2.13а. Light brown powder (mp 197 °C).
	449 mg,	2 mmol)	or	або	2-benzoimidazolyl-2-(1-methylpyrrolidin-2-

-(benzoimidazol-2-yl)-2-(pyrrolidin-2-ylidene)acetonitrile 2.1f ylidene)acetonitrile 2.13а (450 mg, 2 mmol), iodomethane (0.3 ml, d = 2.28 g/cm 3 , 5 mmol) and

  The suspension was allowed to stir for 30 min. The white precipitate was filtrated off to yield 0.65 g of the title compound (2.5 mmol, 56%) as

	Route 2. General procedure for 2-azahetaryl-2-(pyrrolidin-2-ylidene)acetonitriles
	2.1a-f synthesis, route 2 was used to access 2-benzothiazole-2-(1-methyl-2-
	a white solid. pyrrolidin-2-ylidene)acetonitrile 2.7а. Yield 900 mg (88%), white powder, mp
	1 H NMR (300 MHz, acetone-d 6 ), δ, ppm (J, Hz): 2.33-2.55 (m, 2H, 4-СН 2 ), 3.24 (s, 186 °С.
	3H, NCH 3 ), 3.35-3.44 (m, 2H, 3-CH 2 ), 4.02-4.10 (m, 2H, 5-CH 2 ), 4.43 (s, 3H,
	OCH 3 ). 31 P NMR (121 MHz, acetone-d 6 ), δ, ppm (J, Hz): -144.37 (sept, J = 707.5). General procedure for the synthesis of 2-(cyano(1-methylpyrrolidin-2-
	ylidene)methyl)-3-methylbenzo[d]oxazol/thiazol-3-ium hexafluorophosphate
	General procedure for 2-hetaryl-N-R-pyrrolidin-2-ylideneacetonitrile synthesis (2.21, 2.22).
	2.7, 2.13-2.18. A mixture of appropriate hetarylacetonitrile (1.5 mmol) and dimethyl sulfate
	stereoisomers.
	Note: 1) the aliquot for TLC was taken from the crude reaction mixture followed by
	addition of water and extraction with EtOAc. 2) for 2.13а-с, 2.15а NaH (2.1 equiv,
	0.336 g, 8.4 mmol) were used to deprotonate the methylene group in the presence of
	the benzimidazole or 4-oxodihydroquinazolone substituent.

3,4-dihydro-2H-pyrrol-1-ium methylsulfate salt 2.11a (1g, 4.4 mmol) was added dropwise to a strongly stirred solution of KPF 6 (1.47 g, 8 mmol) in water (25 ml) at rt. Route 1. A solution of hetarylacetonitrile (4 mmol) in DMF (10 ml) was added dropwise to a strongly stirred suspension of NaH (107 mg, 4 mmol) in DMF (5 mL), and the reaction mixture was stirred for 10 min until complete evolution of gas had occurred. A solution of 5-methoxy-1-R-3,4-dihydro-2H-pyrrol-1-ium salt

(6 mmol)

in DMF (3 mL) was subsequently added to the reaction mixture, and stirring was pursued until complete conversion of the starting material had occurred (TLC control). Water was then added to the mixture, promoting precipitation. The suspension was additionally stirred for 30 min, and the precipitate was then filtered and washed with cyclohexane. Further precipitation was achieved by concentration of the initial mother liquid (water, DMF) and trituration of the residues at 0 °C with water, filtration, and subsequent washing with cyclohexane. Substances do not require additional purification (2.7с, 2.18а) or purified by column chromatography (2.7b, 2.14b, 2.16b, 2.17а) or by recrystallization from EtOH (2.7a, 2.15а), і-PrOH (2.13a,b), EtOH-dioxane (2.18b). The products are obtained as a mixture of Z and E

Table 6 . 1 .

 61 Physico-chemical characteristics of 2-azahetaryl-2-(1-R-pyrrolidin-2-ylidene)acetonitriles 2.

1a-f, 2.7-2.10, 2.13-2.18, 2.21, 2.22

	Route 1: yield 167 mg (0.74 mmol, 74 %), white powder. Route 2: yield 225 mg (1 mmol, 50%), white powder (mp 230 °С). (m, 1H, Ar H), 10.64 (s, 1H, NH). 170.3 (C).	C, 70.57; H,
	2.1d	(Z)-2-(4-	KBr	(400 MHz, CDCl 3 ), δ, ppm (J, Hz):	(101 MHz, CDCl 3 ), δ, ppm: 17.2	Found, %: С 5.92; N, 23.51.
		methylthiazol-2-yl)-	3475 (NH), 2179	2.08-2.25 (м, 2H, 4-СН 2 ); 2.37 (d, J =	(СН 3 ); 21.9 (CH 2 ); 32.6 (CH 2 ); 48.7	58.33; Н 5.33; N C 14 H 14 N 4 .
	Com	ІUPAC name 2-(pyrrolidin-2-ylidene)acetonitrile	IR, ν, cm -1 (C≡N), 1603 (С=N, C=C).	1 H NMR 1.0, 3H, СН 3 ); 2.99 (t, J = 7.8, 2H, 3-СН 2 ); 3.70-3.81 (м, 2H, 5-СН 2 ); 6.56	(CH 2 ); 70.3 (C); 108.4 (CH); 120.7 13 C NMR (CN); 151.4 (С); 165.8 (2С).	20.12; S 15.15. Found, %: C, HRMS/MS, C 10 H 11 N 3 S. 70.76; H, 6.14;
	poun			(q, J = 1.0, 1H, Н-5); 9.83 (s, 1H,		elemental Calculated, %: N, 24.06.
	d Yield 207 mg (0.87 mmol, 87 %), white powder (mp 184-185 °C). NH).		analysis С 58.51; Н 5.40;
	2.1а 2.1h	(E)-2-(pyrrolidin-2-(E)-2-(2-	KBr KBr	(400 MHz, DMSO-d 6 -ССl 4 ), δ, ppm (400 MHz, DMSO-d 6 -CCl 4 ), δ, ppm	(101 MHz, DMSO-d 6 -ССl 4 ), δ, ppm: (101 MHz, DMSO-d 6 -CCl 4 ), δ, ppm:	Found, %: С N 20.47; S Calculated, %:
		ylidene)-2-(quinolin-methylthiazol-4-yl)-	3468 (NH), 2182 3449 (NH), 2180	(J, Hz): 2.08-2.22 (м, 2H, 4-СН 2 ); (J, Hz): 2.10 (quint, J = 7.2, 2H, 4-	21.2 (CH 2 ); 33.9 (CH 2 ); 49.4 (CH 2 ); 19.3 (CH 3 ), 22.1 (CH 2 ), 32.7 (CH 2 ),	76.59; Н 5.68; N 15.62. C, 58.51; H,
	2-yl)acetonitrile Route 1: yield 138 mg (0.67 mmol, 67 %), white powder. Route 2: yield 316 mg (1.54 mmol, 77%), white powder (mp 150-151 °С). (C≡N), 1588 3.03 (t, J = 7.8, 2H, 3-СН 2 ); 3.84 (t, J 72.5 (С); 118.0 (CH); 121.4 (CN); 2-(pyrrolidin-2-(C≡N), 1602, CH 2 ), 2.72 (s, 3H, CH 3 ), 2.89 (t, J = 48.4 (CH 2 ), 68.3 (C), 105.8 (CH),	17.88. C 15 H 13 N 3 . 5.40; N, 20.47.
	2.1e	(Z)-2-(6-ylidene)acetonitrile	(С=N, C=C). Neat film 1511 (C=C,	= 7.1, 2H, 5-СН 2 ); 7.34-7.40 (м, 1H, (400 MHz, CDCl 3 ), δ, ppm (J, Hz): δ 7.7, 2H, 3-CH 2 ), 3.66 (t, J = 6.8, 2H,	124.4 (CH); 124.7 (С); 127.4 (CH); (101 MHz, CDCl 3 ), δ, ppm: 21.7 121.2 (C), 151.8 (C), 162.7 (C), 165.0	Calculated, %: HRMS (ESI) C 10 H 11 N 3 S.
		methylbenzo[d]oxaz	3224 (NH), 2210 C=N).	Н-6); 7.42 (d, J = 8.8, 1H, Н-3); 7.57-2.25 (quint, J = 7.6, 2H, 4-CH 2 ), 2.48 5-CH 2 ), 6.71 (s, 1H, 5-H), 8.70 (s, 1H,	127.6 (CH); 129.4 (CH); 136.3 (CH); (СH 3 ), 21.8 (СH 2 ), 32.9 (СH 2 ), 49.1 (C).	С 76.57; Н 5.57; Calculated for Found, %: C,
		ol-2-yl)-2-(pyrrolidin-2-	(C≡N), 1613, 1559 (C=N,	7.63 (м, 1H, Н-7); 7.75 (d, J = 8.0, 1H, Н-8); 7.97 (d, J = 8.4, 1H, Н-5); (s, 3H, CH 3 ) 3.10 (t, J = 7.9, 2H, 3-CH 2 ), 3.84 (t, J = 7.1, 2H, 5-CH 2 ), NH).	146.8 (С); 156.3 (С); 168.1 (С). (СH 2 ), 63.3 (C), 110.6 (CH), 116.8 (CH), 118.4 (C), 125.2 (CH), 133.8	N 17.86. 58.33; H, 5.33; C 14 H 14 N 3 O (M + H + ) 240.1137, N, 20.12.
		ylidene)acetonitrile	C=C,), 1255 (C-	8.12 (d, J = 8.8, 1H, Н-4); 11.14 (c, 7.07 -7.11 (м, 2H, 4-H), 7.31 (d d, J	(C), 139.4 (C), 149.3 (C), 162.2 (C),	Found 240.1143.
			O).	1H, NH). = 1.5, 0.7, 1H, 7-H), 7.39 (d, J = 8.0,	169.5 (C).
				1H, 5-H), 9.60 (s, 1H, NH).
	2.1b Yield 134 mg (0.56 mmol, 56 %), white powder. (Z)-2-(benzo[d]thiazol-2-KBr 3450 (NH), 2189	(400 MHz, CDCl 3 ), δ, ppm (J, Hz): 2.18-2.30 (м, 2H, 4-СН 2 ); 3.08 (t, J =	(101 MHz, CDCl 3 ), δ, ppm: 21.7 (CH 2 ); 33.0 (CH 2 ); 49.1 (CH 2 ); 70.6	Found, %: С 64.98; Н 4.87; N
	2.1f	yl)-2-(pyrrolidin-2-(Z)-2-	(C≡N), 1595 K Br	7.9, 2H, 3-СН 2 ); 3.85 (t, J = 7.1, 2H, (400 MHz, DMSO-d 6 ), δ, ppm (J, Hz):	(C); 120.3 (CN); 120.4 (CH); 121.4 (101 MHz, DMSO-d 6 ), δ, ppm: δ 21.7	17.23; S 13.73. Found, %: C,
		ylidene)acetonitrile (benzo[d]imidazol-2-	(С=N, C=C). 3226 (NH), 2197	5-СН 2 ); 7.28 (ddd, J = 7.9, 7.3, 1.3, 2.08 (p, J = 7.6, 2H, 4-CH 2 ), 2.96 (t, J	(CH); 123.6 (CH); 125.9 (CH); 132.7 (CH 2 ), 33.2 (CH 2 ), 49.4 (CH 2 ), 62.6	C 13 H 11 N 3 S. 69.85; H, 6.08;
		yl)-2-(pyrrolidin-2-	(C≡N), 1608	1H, Н-6); 7.41 (ddd, J = 8.0, 7.3, 1.2, = 7.8, 1H, 3-CH 2 ), 3.73 (t, J = 7.1, 1H,	(C); 153.4 (С); 166.4 (С); 167.9 (С). (C), 111.1 (CH), 117.0 (CH), 120.6	Calculated, %: N, 25.08.
		ylidene)acetonitrile	(С=N, C=C).	1H, Н-5); 7.78 (ddd, J = 8.0, 1.3, 0.5, 5-CH 2 ), 7.05-7.12 (м, 2H, 5,6-H),	(C), 121.5 (2CH), 134.1 (C), 143.6	С 64.71; Н 4.59; C 13 H 12 N 4 .
				1H, Н-7); 7.81 (ddd, J = 7.9, 1.2, 0.5, 7.33-7.39 (м, 1H, Ar H), 7.43-7.49	(C), 151.7 (C), 168.5 (C).	N 17.41; S Calculated, %:
				1H, Н-4); 10.27 (s, 1H, NH). (м, 1H, Ar H), 10.10 (s, 1H, NH),		13.29. C, 69.62; H,
	Route 1: yield 205 mg (0.85 mmol, 85 %), white powder. Route 2: yield 415 mg (1.72 mmol, 86%), white powder (mp 226 °С, 223-224 °С10 ). 12.00 (s, 1H, NH Het ). 5.39; N, 24.98.
	2.1с Yield 200 mg (0.89 mmol, 89 %), white powder (mp 292-293 °C). (Z)-2-(benzo[d]oxazol-2-yl)-2-(pyrrolidin-2-ylidene)acetonitrile KBr 3437 (NH), 2203 (C≡N), 1602, 1547 (С=N, C=C). (400 MHz, DMSO-d 6 -ССl 4 ), δ, ppm (J, Hz): 2.19 (quint, J = 7.3, 2H, 4-CH 2 ); 3.06 (t, J = 7.5, 2H, 3-CH 2 ); 3.83 (t, J = 7.1, 2H, 5-CH 2 ); 7.16-7.30 (м, 2H, Н-5,6); 7.50 (d, J = 7.6, 1H, H-7); 7.54 (d, J = 7.5, 1H, H-4); 9.60 (s,1H, NH). 2.1g (Z)-2-(1-methyl-1H-KBr (300 MHz, CDCl 3 ), δ, ppm (J, Hz): benzo[d]imidazol-2-3448 (NH), 2187 2.13-2.30 (м, 2H, 4-CH 2 ), 3.10 (t, J = yl)-2-(pyrrolidin-2-(C≡N), 1609 7.9, 2H, 3-CH 2 ), 3.76 -3.88 (t, J = ylidene) (С=N, C=C). 7.9, 2H, 5-CH 2 ), 4.02 (s, 3H, CH 3 ), 7.34-7.15 (м, 3H, Ar H), 7.64-7.51	(101 MHz, DMSO-d 6 -ССl 4 ), δ, ppm: 21.4 (CH 2 ); 33.5 (CH 2 ); 49.8 (CH 2 ); 61.9 (C); 110.0 (СН); 117.5 (CH); 118.0 (CN); 123.3 (СН); 124.2 (СН); 141.8 (С); 148.7 (С); 162.6 (С); 169.7 (С). (75 MHz, CDCl 3 ), δ, ppm: CH 2 : 21.9 (CH 2 ), 31.1 (CH 3 ), 33.3 (CH 2 ), 49.0 (CH 2 ), 62.4 (C), 108.7 (CH), 117.2 (CH), 121.4 (C), 121.6 (CH), 121.8 (CH), 135.3 (C), 141.8 (C), 150.8 (C),	Found, %: С 69.33; Н 4.25; N MS (ESI) m/z: 18.53. [M + H]+ Found C 13 H 11 N 3 О. for C 14 H 15 N 4 : Calculated, %: 239.1. С 69.32; Н 4.92; N 18.66. Calculated, %:

Route 1: yield 136 mg (0.58 mmol, 58%), yellow powder (elution system for column chromatography: gradient CHCl 3 100% to CHCl 3 -CH 3 OH, 49:1). Route 2: yield 315 mg (1.34 mmol, 67%), yellow powder (mp 207-208 °С, 207 °С9 ).

Table 6 . 2 .

 62 Physico-chemical characteristics of 2-azahetaryl-2-(5-R-3-oxoindolin-2-ylidene)acetonitriles 2.

23, 2.25, 2.26-2.28

				11.42 (s, 1H, NH). 1H, H Bt -5), 7.64 (ddd, J = 8.5, 7.5, 1.2,		318.0699.
				1H, H Bt -6), 7.83 (d, J = 8.4, 1H, H Bt -
				7), 8.14 (d d, J = 8.0, 0.6, 1H, H Bt -4).
	Com	ІUPAC name	IR, ν, cm -1	1 H NMR	13 C NMR	HRMS/MS,
	poun d Yield 225 mg (0.84 mmol, 71%), dark violet powder (mp 270-271 °С). Yield mg (0.87 mmol, 87%), dark violet powder (mp 297-298 °С). 2.28b 2-(Benzo[d]thiazol-Neat film (400 MHz, CD 2 Cl 2 ), δ, ppm (J, Hz):	(101 MHz, CD 2 Cl 2 ), δ, ppm: 20.3	elemental analysis HRMS (ESI)
	2.24а (Z)-2-(Benzo[d]thiazol-2-yl)-2-(3-oxoindolin-2-ylidene)acetonitrile 2.25а (Z)-2-2-yl)-2-(1,5-(Benzo[d]oxazol-2-yl)-2-(3-oxoindolin-2-dimethyl-3-oxoindolin-2-ylidene)acetonitrile ylidene)acetonitrile	KBr 3408 (NH), 2205 (C≡N), 1712(C=O), 1589 (C=C, C=N). KBr 2204 (C≡N), 3435 (NH), 2214 (C≡N), 1719 (C=O). 1596 1713 (C=O), 1574 (C=C, C=N). (C=C, C=N).	(400 MHz, DMSO-d 6 ), δ, ppm (J, Hz): 7.16 (td, J = 7.5, 0.8, 1H, H Is -5), 7.50-7.56 (m, 2H, H Bt -5, H Is -7), 7.66 (ddd, J = 8.2, 7.8, 1.1, 1H, H Bt -6), 7.66-7.71 7), 8.21 (d, J = 8.0, 1.3, 0.6, 1H, H-4), H Is ), 8.20 (d, J = 8.1, 1.0, 0.6, 1H, H-(m, 2H, H Bzo -4,7), 11.37 (s, 1H, NH). 0.6, 1H, Н Bt -4). (m, 1H, H Is -6), 7.73 (d, J = 7.6, 1H, 4-(400 MHz, DMSO-d 6 ), δ, ppm (J, Hz): 2.42 (s, 3H, CH 3 ), 3.34 (s, 3H, CH 3 ), 7.16 (td, J = 7.4, 0.8, 1H, H Is -5), 7.47-7.51 (m, 2H, H Bzo -5,6), 7.52-7.55 (m, 1H), 7.67 (td, J = 7.8, 1.3, 1H, H Is -6), 7.01 (d, J = 8.2, 1H, H Is -7), 7.47-7.53 (m, 1H, H Is -6, H Bt -6), 7.56-7.62 (m, 1H, H Is -7,), 8.01 (ddd, J = 8.0, 1.2, 7.72 (d, J = 7.5, 1H, H Is -4), 7.83-7.90 0.6, 1H, H Bt -7), 8.11 (ddd, J = 8.2, 1.2,	(C). 184.6 (C). 151.9 (C), 154.0 (C), 163.4 (C), 185.1 (C), 149.9 (C), 151.7 (C), 159.5 (C), 153.4 (С), 160.8 (С), 184.4 (С). (101 MHz, DMSO-d 6 ), δ, ppm: 80.2 (C), 114.5 (CH), 116.9 (C), 119.9 (C), 123.0 (CH), 123.2 (CH), 123.6 (CH), 125.7 (CH), 126.4 (CH), 127.6 (CH), 134.3 (C), 138.2 (CH), 143.7 (C), (101 MHz, DMSO-d 6 ), δ, ppm: 74.0 (СН 3 ), 35.3 (СН 3 ), 82.0 (С), 110.4 (C), 111.6 (CH), 114.5 (C), 114.6 (CH), 119.97 (C), 120.01 (CH), 123.8 (CH), 125.7 (CH), 126.0 (CH), 126.6 (СН), 117.6 (С), 119.9 (С), 121.7 (СН), 123.4 (СН), 125.5 (СН), 126.0 (СН), 126.7 (СН), 133.5 (С), 136.0 (CH), 138.3 (CH), 141.7 (C), 145.9 (С), 138.2 (СН), 146.1 (С), 151.9 (С),	304.0545. 288.0773. HRMS (ESI) Calculated for HRMS (ESI) Calculated for C 17 H 10 N 3 OS (M Calculated for C 17 H 10 N 3 O 2 (M C 19 H 14 N 3 OS (M + H + ): 332.0858, + H + ): 288.0773, Found: + H + ): 304.0545, Found: Found: 332.0858.
				11.55 (s, 1H, NH).
	Elution system for column chromatography: CHA-CH 2 Cl 2, 1:1. Yield 141 mg (0.43 mmol, 85%), dark violet powder.
	Yield 236 mg (0.78 mmol, 78%), dark red powder (mp > 300 °С). Yield mg (0.77 mmol, 77%), dark red powder (mp > 300 °С).
	2.24b (Z)-2-(Benzo[d]thiazol-2-yl)-2-(5-methyl-3-oxoindolin-2-ylidene)acetonitrile 2.26а (E)-2-(3-Oxoindolin-2-ylidene)-2-(quinolin-2-yl)acetonitrile	KBr 3433 (NH), 2204 (C≡N), 1718 (C=O). 1596 (C=C, C=N). KBr 3423 (NH), 2203 (C≡N), 1712 (C=O), 1586 (C=C, C=N).	(400 MHz, DMSO-d 6 ), δ, ppm (J, Hz): 2.33 (s, 3H, CH 3 ), 7.40 (d, J = 8.2, 1H, H Is -7), 7.47-7.53 (m, 2H, H Is -6, , H Bt -5), 7.54 (s, 1H, H Is -4), 7.65 (ddd, J = 8.2, 7.6, 1.1, 1H, H Bt -6), 8.18 (d, J = 7.8, 1H, H Bt -4), 8.20 (d, J = 7.7, 1H, H Bt -7), 11.48 (s, 1H, NH). H Q -5), 11.98 (s, 1H, NH). = 8.8, 1H, H Q -3), 8.59 (d, J = 8.5, 1H, (400 MHz, DMSO-d 6 ), δ, ppm (J, Hz): 7.14 (td, J = 7.4, 0.7, 1H, H Is -5), 7.57 (d, J = 8.0 Hz, 1H, H Q -8), 7.66 -7.72 (m, 2H, H Is -6-, H Q -7 ), 7.73 (d, J = 7.5, 1H, 4-H Is ), 7.90 (ddd, J = 8.3, 6.9, 1.4, 8.04 (d, J = 8.3, 1H, H Is -7), 8.56 (d, J 1H, H Q -6), 7.96 (d, J = 8.7, 1H, H Q -3),	(101 MHz, DMSO-d 6 ), δ, ppm (J, Hz): 20.6 (СH 3 ), 79.7 (C), 114.3 (CH), 116.9 (C), 120.0 (C), 122.9 (CH), 123.1 (CH), 125.6 (CH), 126.3 (CH), 127.6 (CH), 133.1 (C), 134.3(C), 138.8 (CH), 143.9 (C), (C). 150.0 (C), 154.0 (C), 163.5 (C), 185.1 (101 MHz, DMSO-d 6 ), δ, ppm: 85.2 (C), 114.3 (CH), 117.3 (C), 119.7 (C), 120.3 (CH), 123.1 (CH), 125.5 (CH), 126.6 (C), 127.9 (CH), 128.3 (CH), 129.5 (CH), 130.9 (CH), 138.0 (CH), 152.0 (C), 153.2 (C), 185.6 (C). 138.4 (CH), 144.5 (C), 147.4 (C),	HRMS (ESI) HRMS (ESI) Calculated for Calculated for C 18 H 12 N 3 OS (M C 19 H 12 N 3 O (M + H + ): 298.0980, + H + ): 318.0701, Found: Found: 318.0704. 298.0984.
	Yield 222 mg (0.7 mmol, 70%), dark red powder (mp 300-301 °С). Yield mg (0.84 mmol, 84%), bright red powder (mp > 300 °С).
	2.24с (Z)-2-2.27a 2-(3-	KBr Neat film	(400 MHz, DMSO-d 6 ), δ, ppm (J, Hz): (400 MHz, DMSO-d 6 ), δ, ppm (J, Hz):	(101 MHz, DMSO-d 6 ), δ, ppm (J,	HRMS (ESI) HRMS (ESI)
		(Benzo[d]thiazol-2-methylbenzo[d]thiaz	3428 (NH), 2201 2197 (C≡N),	3.81 (s, 1H, OCH3), 7.25 (d, J = 2.2, 4.26 (s, 3H, СH 3 ), 7.07-7.14 (m, 1H,	Hz): 56.3 (CH 3 ), 79.6 (C), 108.9	Calculated for Calculated for
		yl)-2-(5-methoxy-3-oxoindolin-2-ol-2(3Н)-ylidene)-2-(3-oxo-3Н-indol-2-	(C≡N), 1702 (C=O), 1591 1725 (C=O), 1511, 1478	1H, H Is -4), 7.28 (d d, J = 8.6, 2.5, 1H, H Is -6), 7.44 (d, J = 8.6, 1H, H Is -7), H Is -5), 7.23 (d, J = 7.7 Hz, 1H, H Is -7), 7.44-7.49 (m, 1H, H Is -6), 7.49-7.52	(CH), 115.5 (C), 117.0 (C), 120.4 (C), 122.9 (CH), 123.1 (CH), 125.2 (CH),	C 18 H 12 N 3 O 2 S (M + H + ): 334.0650, C 18 H 12 N 3 OS (M + H + ): 318.0701,
		ylidene)acetonitrile yl)acetonitrile	(C=C, C=N), (C=C, C=N).	(m, 1H, H Is -4), 7.55 (td, J = 7.5, 1.2,	126.2 (CH), 127.6 (CH), 134.2 (CH),	Found: Found:
			1213 (C-O).		144.1 (C), 146.2 (C), 154.1 (C), 156.2	334.0647.
					(C), 163.5 (C), 185.1 (C).

7.52 (t, J = 7.5, 1H, H Bt -6), 7.65 (t, J = 7.7, 1H, H Bt -5), 8.20 (d, J = 8.0, 1H, H Bt -4), 8.18 (d, J = 8.2, 1H, H Bt -7),

Table 6 . 3 .

 63 Physico-chemical characteristics of 3-(ω-aminopropyl)-4-hetaryl-5-aminopyrazole (or isoxazole) 3.1-3.7.

	Com	ІUPAC name	IR, ν, cm -1	1 H NMR	13 C NMR	HRMS/MS,
	poun					elemental
	d					analysis
	3.1a	4-(Benzo[d]thiazol-	Neat film	(400 MHz, CDCl 3 ), δ, ppm (J, Hz):	(101 MHz, CDCl 3 ), δ, ppm: 26.2	HRMS (ESI)
		2-yl ) -1-methyl -3-	3376, 3292 (NH,	1.98 (quint, J = 7.4 Hz, 2H, 2-СН 2 ),	(CH 2 ), 28.8 (CH 2 ), 33.8 (CH 3 ), 36.5	Calculated for
		(3-(methylamino)propyl	NH 2 ν), 1623 (NH 2 δ), 1564,	2.48 (s, 3H, NHCH 3 ), 2.76 (t, J = 7.1 Hz, 2H, 1-СН 2 ), 2.85-2.97 (m, 2H, 3-	(CH 3 ), 51.9 (CH 2 ), 97.9 (C), 121.08 (CH), 121.09 (CH), 123.5 (CH), 125.9	C 15 H 20 N 5 S (M + H + ): 302.1451,
		)-1H-pyrazol-5-	1536 (C=C,	СН 2 ), 3.66 (s, 3H, NCH 3 ), 5.77 (s, 2H,	(CH), 132.4 (C), 147.1 (C), 149.5 (C),	Found:
		amine	C=N).	NH 2 ), 7.28 (dd, J = 7.1, 1.3, 1H, Н-6),	152.7 (C), 162.2 (C).	302.1446.
				7.43 (dd, J = 7.2, 1.3, H-5), 7.84 (d, J
				= 7.7, 1H, Н-7), 7.88 (d, J = 8.0, 1H,
				Н-4).
	Yield 187 mg (0.62 mmol, 62%), white powder (mp 158-159 °C). The reaction was directly scaled up to 12.61 g of starting material affording 10.3 g
	(85% yield) of the desired product.
	3.1b	4-(Benzo[d]thiazol-	Neat film	(300 MHz, DMSO-d 6 ), δ, ppm (J, Hz):	(75 MHz, CD 3 OD), δ, ppm: 25.4	HRMS (ESI)
		2-yl)-3-(3-	3391, 3298 (NH,	2.05 (quint, 7.4, 2H, 2-СН 2 ), 2.82 (t, J	(CH 2 ), 26.1 (CH 2 ), 33.9 (CH 3 ), 47.9	Calculated for
		(benzylamino)propyl )-	NH 2 ν), 1622 (NH 2 δ), 1539	= 7.4, 2H, 1-СН 2 ), 2.95 (t, 7.8, 2H, 3-СН 2 ), 3.58 (s, 3H, СН 3 ), 4.04 (s, 2H,	(CH 2 ), 52.1 (CH 2 ), 97.8 (C), 121.9 (2CH), 124.6 (CH), 127.0 (CH), 130.0	C 21 H 24 N 5 S (M + H + ): 378.1752,
		1-methyl-1H-	(C=C, C=N).	NCH 2 ), 6.86 (s, 2H, NH 2 ), 7.31 (ddd, J	(2CH), 130.3 (CH), 130.6 (2CH),	Found:
		pyrazol-5-amine		= 8.4, 7.5, 0.9, 1H, Ar H), 7.52-7.35	132.7 (C), 133.2 (C), 148.7 (C), 149.6	378.1747.
				(m, 6H, Ar H), 7. 89 (d, J = 7.9, 1H,	(C), 153.8 (C), 162.6 (C).
				Н-7), 8.00 (d, J = 7.5, 1H, Н-4).
	Yield 264 mg (0.70 mmol, 70%), white powder (mp 192-193 °C).
	3.1c	4-(Benzo[d]thiazol-	Neat film	(300 MHz, CDCl 3 ), δ, ppm (J, Hz):	(101 MHz, CDCl 3 ), δ, ppm: 6.3	HRMS (ESI)

Table 6 . 4 .

 64 Physico-chemical characteristics of 3-(ω-aminopropyl)-4-hetaryl-5-aminopyrazole derivatives 3.8-3.30 and amide 3.31.Elution system for column chromatography: gradient CH 2 Cl 2 -acetone, 19:1 to CH 2 Cl 2 -acetone, 23:2. Yield 53 mg (0.11 mmol, 72%), orange powder (mp 105-106 °C).Products were purified by automatic column chromatography (elution system: gradient CH 3 OH-CH 2 Cl 2 , 1:19 to CH 3 OH-CH 2 Cl 2 , 1:9). Yield 392 mg (0.88 mmol, 88%), white powder (mp 165-166 °C).Products were purified by automatic column chromatography (elution system: gradient CH 3 CN-CH 2 Cl 2 , 19:1 to CH 3 CN-CH 2 Cl 2 , 22:3). Yield 360 mg (0.78 mmol, 78%), white powder (mp 177-178 °C).

	Com	IUPAC name	IR, ν, cm -1	1 H NMR	13 C NMR	HRMS/MS,
	poun						elemental
	d						analysis
	3.8	3-(5-Amino-4-	Neat film	(400 MHz, methanol-d 4 ), δ, ppm (J,	(101 MHz, methahol-d 4 ), δ, ppm (J,	HRMS (ESI)
		(benzo[d]thiazol-2-yl)-1-methyl-1Hpyrazol-	3393 (NH 2 ν), 1614 (NH 2 δ), 1563, 1535	Hz): 2.21-2.36 (m, 2H, 2-СН 2 ), 2.96 (t, J = 7.3, 2H, 3-СН 2 ), 3.17 (s, 9H, 3-СН 3 ), 3.48-3.59 (m, 2H, 1-СН 2 ), 3.65	Hz): 21.3 (CH 2 ), 24.3 (CH 2 ), 32.8 (CH 3 ), 52.2 (t, 1 J С-N = 4.0, 3CH 3 ), 65.9 (t, 1 J С-N = 3.0, 2-CH 2 ), 96.7 (C),	Calculated for C 17 H 24 N 5 S (M + H + ): 330.1752,
		3-yl)-N,N,N-	(C=C, C=N).	(s, 3H, NCH 3 ), 7.30 (ddd, J = 8.2, 7.6,	120.79 (CH), 120.84 (CH), 123.5	Found:
		trimethylpropan-1-		1.2, 1H, H-6), 7.45 (ddd, J = 8.2, 7.3,	(CH), 125.9 (CH), 132.0 (C), 147.0	330.1758.
		aminium iodide		1.3, 1H, H-5), 7.86-7.93 (m, 2H, H-	(C), 148.5 (C), 152.8 (C), 161.4 (C).
		N	I		4,7).
		S	N
		N	N
			H 2 N
	Yield 100%, white powder (mp 249-250 °C).
	3.10	tert-Butyl (3-(4-	Neat film	(400 MHz, CDCl 3 ), δ, ppm (J, Hz):	(101 MHz, CDCl 3 ), δ, ppm: 25.8	HRMS	(ESI)
		(benzo[d]thiazol-2-	3271 (NH), 1690	1.47 (s, 9H, 3СH 3 ), 1.95-2.07 (m, 2H,	(CH 2 ), 27.1 (CH 2 ), 28.5 (3CH 3 ), 34.3	Calculated for
		yl)-5-(benzylamino)-1-methyl-1H-	(C=O), 1560 (C=C, C=N),	2-СН 2 ), 2.82-2.94 (m, 5H, 3-СН 2 , NBocCH 3 ), 3.28-3.50 (m, 2H, 1-	(CH 3 ), 36.8 (CH 3 ), 48.9 (CH 2 ), 50.3 (CH 2 ), 79.2 (C), 100.6 (C), 121.0	C 27 H 34 N 5 O 2 S (M + H + ): 492.2433,
		pyrazol-3-		1249 (C-O),	СН 2 ), 3.81 (s, 3H, N Pyr CH 3 ), 4.55 (s,	(CH), 121.2 (CH), 123.7 (CH), 126.0	Found:
		yl)propyl)(methyl)ca	1164 (C-N).	2H, NCH 2 Ph), 7.28-7.38 (m, 4H, H Ph -	(CH), 127.1 (2CH), 127.5 (CH), 128.7	492.2433.
		rbamate			2,4,6, H Bt -6), 7.39-7.47 (m, 3H, H Bt -	(2CH), 132.5 (C), 138.9 (C), 149.3
					5), 7.80-7.88 (m, 2H, H Bt -4,7), 7.79	(C), 149.5 (C), 152.5 (C), 155.8 (C),
					(br. s, NH).	162.0 (C).

Elution system for column chromatography: gradient CH 2 Cl 2 -acetone, 19:1 to CH 2 Cl 2 -acetone, 23:2.Yield 81 mg (0.14 mmol, 90%), white powder

Table 6 . 5 .

 65 (TLC control, CH 2 Cl 2 -CH 3 OH-Et 3 N, 9:1:0.1) the realultant precipitate was filtrated off; filtrate was condensed under reduced pressure and the residue was triturated with CH 2 Cl 2 . Yield 80%, (118 mg, 0.22 mmol), yellowish powder. Physico-chemical characteristics of 2-azahetaryl-2-(pyrrolidin-2-ylidene)acetonitrile derivatives functionalized at С-3 centre of pyrrolidine fragment 4.

The raction mixture was cooled down; the precipitate was filtered off and recrystallized from ethanol. ceased

2a, 4.4, 4.6-4.11

  400 MHz, DMSO-d 6 ), δ, ppm (J, Hz): 3.03 (t, J = 7.9, 2H, 3-СН 2 ), 3.32 (s, 3H, СН 3 ), 3.80 (t, J = 7.8, 2H, 2-СН 2 ), 7.18 (t, J = 7.3, 1H, Ar H), 7.30 (t, J = 7.7, 1H, Ar H), 7.58 (d, J = 7.9, 1H, Н-7), 7.89 (d, J = 7.6, 1H, Н-4). DMSO-d 6 ), δ, ppm (J, Hz): 2.58-2.67 (m, 2H, CH 2 ), 2.76 (t, J = 7.1, 2H, CH 2 ), 3.27-3.43 (m, 2H, CH 2 ), 3.65-3.80 (m, 8H, 2СН 3, CH 2 ), 6.69-6.80 (m, 1H, H-6 3,4-(OMe)2Ar , CHNHCH 2 ), 6.84 (d, J = 1.9, 1H, Н-2 3,4-(OMe)2Ar ), 6.87 (d, J = 8.2, 1H, Н-5 3,4-(OMe)2Ar ), 7.15-7.22 (m, 1H, Н-6), 7.32-7.40 (m, 1H, Н-5), 7.64-7.69 (m, 1H, Ar H), 7.80 (dt, J = 13.2, 1.6, 1H, CHNHCH 2 ), 7.84-7.89 (m, 1H, Ar H), 10.08 (s, 1H, NH). (101 MHz, DMSO-d 6 ), δ, ppm: 26.0 (СН 2 ), 37.0 (СН 2 ), 45.6 (СН 2 ), 50.1 (СН 2 ), 55.8 (СН 3 ), 56.0 (СН 3 ), 61.7, 100.1 (С), 112.5 (СН), 113.1 (СН), 119.8 (СН), 121.1 (СН), 121.7 (СН), 123.1 (СН), 123.3 (С), 126.3 (СН), 131.6 (С), 131.7 (С), 142.3 (С), 147.8 (С), 149.1 (С), 154.0 (С), 162.4 (С), 168.6 (С). 400 MHz, DMSO-d 6 ), δ, ppm (J, Hz): 1.83-1.89 (m, 4H, CHN(CH 2 ) 2 (CH 2 ) 2 ), 3.10 (t, J = 7.7, 2H, 4-CH 2 ), 3.49-3.60 (m, 4H, CHN(CH 2 ) 2 (CH 2 ) 2 ), 3.66 (t, J = 7.9, 2H, 5-CH 2 ), 7.19 (t, J = 7.6, 1H, Н-6), 7.36 (t, J = 7.8, 1H, H-5), 7.68 (d, J = 7.9, 1H, H-7), 7.87 (d, J = 7.8, 1H, H-4), 8.01 (s, 1H, CHN(CH 2 ) 2 (CH 2 ) 2 ), 10.25 (s, 1H, NH). 400 MHz, DMSO-d 6 ), δ, ppm (J, Hz): 3.07-3.13 (m, 2H, 3-СН 2 ), 3.85 (t, J = 8.3, 2H, 2-СН 2 ), 5.45 (s, 2H, СHNCH 2 ), 7.30-7.34 (m, 2H, Н Ph -2,6), 7.34-7.38 (m, 1H, Н Ph -4), 7.39-7.45 (m, 2H, Н Ph -3,5), 7.52 (ddd, J = 8.2, 7.6, 1.2, 1H, Н-6), 7.60 (ddd, J = 8.3, 7.8, 1.3, 1H, Н-5), 7.83 (br.s, 1H, СHNCH 2 ), 8.08 -8.13 (m, 1H, Н-4), 8.18-8.21 (m, 1H, Н-7), 8.61 (s, 1H, NH), 8.76 (c, 2H, NH 2 ). The integral intensity of the signals corresponds to NH protons dimish upon D 2 O addition. (101 MHz, DMSO-d 6 ), δ, ppm: 24.3 (CH 2 ), 48.3 (CH 2 ), 54.8 (CH 2 ), 91.6 (C), 120.8 (C), 122.4 (CH), 122.9 (CH), 126.2 (CH), 127.2 (CH), 127.5 400 MHz, DMSO-d 6 ), δ, ppm (J, Hz): 2.34 (c, 6H, NCH), 3.01-3.10 (m, 2H, 3-СН 2 ), 3.91 (t, J = 8.8, 2H, 2-СН 2 ), 5.27 (s, 2H, СHNCH 2 ), 7.22-7.26 (m, 2H, Н Ph -2,6), 7.32-7.37 (m, 1H, Н Ph -4), 7.39-7.44 (m, 2H, Н Ph -3,5), 7.57 (td, J = 7.6, 1.4, 1H, Н-6), 7.62 (td, J = 7.7, 1.5, 1H, Н-5), 8.00-8.07 (m, 1H, СHNCH 2 ), 8.1 -8.15 (m, 1H, Н-4), 8.22-8.26 (m, 1H, Н-7). (101 MHz, DMSO-d 6 ), δ, ppm: 23.5 (CH 2 ), 35.4 (CH 3 ), 42.4 (CH 3 ), 57.4 (CH 2 ), 57.6 (CH 2 ), 104.8 (C), 123.2 (CH), 123.9 (CH), 126.9 (CH), 127.1

	4.10b 6-Amino-7-	KBr	= 12.9, 1H, CHNHCH 2 ), 10.22 (s, 1H,		HRMS (ESI)
		(benzo[d]thiazol-2-	3400, 3283 (NH),	NH).		Calculated for
		yl)-5-benzyl-2,3-	1677, 1655,			C 21 H 19 N 4 S +
	Com poun d Yield mg (1.84 mmol, 92%), yellow powder (mp 190 °C). IUPAC name IR, ν, cm -1 1 H NMR dihydro-1H-1617, 1596, 1578 4.2a (Z)-2-(benzo[d]thiazol-2-Neat film 3201 (NH), 2172 (400 MHz, DMSO-d 6 ), δ, ppm (J, Hz): 3.02-3.11 (m, 2H, 2СН 3 , 4-СН 2 ), 3.67 amino)methylene)pyr (C=C, C=N). 4.7 (Z)-2-(benzo[d]thiazol-2-yl)-2-((E)-3-(((3,4-dimethoxyphenethyl) KBr 3319 (NH), 2176 (C≡N), 1654, 1648, 1561 chloride c]pyridin-5-ium (400 MHz, Calculated, %: 359.1329, Found 13 C NMR HRMS/MS, elemental analysis (101 MHz, DMSO-d 6 ), δ, ppm: 26.8 (СН 2 ), 42.6 (2СН 3 ), 46.3 (СН 2 ), 61.8 HRMS (ESI) Found, %: C, Calculated for C 24 H 24 N 4 O 2 S. (C). 5.29; N, 12.95. 151.6 (C), 152.2 (C), 158.8 (C), 161.4 C, 66.64; H, 133.4 (C), 134.1 (CH), 135.2 (C), pyrrolo[3,2-(C=C, C=N). (2CH), 128.5 (CH), 129.3 (2CH), 359.1328.
		yl)-2-((E)-3-((dimethylamino)met rolidin-2-ylidene)acetonitrile	(C≡N), 1636, 1553 (C=C,	(t, J = 7.9, 2H, 5-СН 2 ), 7.16-7.22 (m, 1H, Н-6), 7.33-7.39 (m, 1H, Н-5),	(С), 99.0 (С), 119.8 (СН), 121.7 (СН), 123.1 (СН), 123.7 (С), 126.4	C 16 H 17 N 4 S (M + 64.76; H, 5.20; H + ): 297.1174, N, 12.61.
		hylen)pyrrolidin-2-	C=N).	7.68 (d, J = 7.8, 1H, Ar H), 7.76 (s,	(СН), 131.7 (С), 144.5 (СН), 154.0	Found:
		yledene)acetonitrile		1H, CHN(CH 3 ) 2 ), 7.85-7.90 (m, 1H,	(С), 164.7 (С), 168.8 (С).	297.1173.
				Ar H), 10.24 (s, 1H, NH).
	Yield 198 mg (0.49 mmol, 98%), white powder.
	4.11	7-(Benzo[d]thiazol-	Neat film 1660,			HRMS (ESI)
	Yield 840 mg (2.84 mmol, 71%), yellow-green powder (mp 194-195 °С). 4.4 1-Methyl-2,3-dihydro-1Н-benzo[4,5]imidazo[1 ,2-a]pyrrolo [2,3-d]pyridine-11-carbonitrile KBr 2198 (C≡N), 1674, 1590, 1514 (C=C, C=N). 2-yl)-5-benzyl-6-1576, 1527 Yield mg (1.72 mmol, 86%), yellow powder (mp 170 °С). 4.8 (Z)-2-(benzo[d]thiazol-2-yl)-2-((E)-3-(pyrrolidin-1-ylmethylene)pyrrolid in-2-Neat film 3206 (NH), 2171 (C≡N), 1629, 1555 (C=N, C=C). (dimethylamino)-1-(C=C, C=N). methyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-5-ium iodide	(101 MHz, DMSO-d 6 ), δ, ppm: 23.2 (CH 2 ), 34.2 (CH 3 ), 56.4 (CH 2 ), 67.1 (C), 110.8 (CH), 116.8 (C), 117.6 (CH), 120.9 (CH), 121.5 (C), 123.1 (CH), 124.8 (CH), 130.1 (C), 143.5 (C), 149.3 (C), 156.1 (C). (101 MHz, DMSO-d 6 ), δ, ppm: 25.4 (2CH 2 ), 26.6 (CH 2 ), 46.1 (CH 2 ), 51.1 (2CH 2 ), 61.7 (C), 99.8 (C), 119.8 (CH), 121.7 (CH), 123.1 (CH), 123.7 (C), 126.4 (CH), 131.7 (C), 140.9 (CH), 154.0 (C), 164.0 (C), 168.8 (C). (C), 127.2 (2CH), 127.4 (CH), 128.6 (CH), 129.4 (2CH), 135.9 (CH), 136.4 (C), 136.6 (C), 152.5 (C), 158.1 (C), 159.1 (C), 159.6 (C).	Calculated, %: C, 72.56; H, 4.87; N, 22.57. C 15 H 12 N 4 . Found, %: C, 72.58; H, 4.43; Calculated for C 25 H 25 N 4 S + HRMS (ESI) 401.1800, Found Calculated for 401.1800. C 18 H 19 N 4 S (M + Calculated for І -H + ) 323.1330, 126.9045, Found Found 323.1331. 126.9047.
		ylidene)acetonitrile				N, 21.60.
	Yield 111 mg (0.45 mmol, 90%), white powder (mp > 300 °С). Yield mg (1.7 mmol, 85%), yellow powder (mp 221-222 o C). Yield 118 mg (0.22 mmol, 80%), yellowish powder.
	4.6 4.9	(Z)-2-7-(Benzo[d]thiazol-	KBr KBr	(400 MHz, DMSO-d 6 -CCl 4 ), δ, ppm (400 MHz, CDCl 3 ), δ, ppm (J, Hz):	(101 MHz, DMSO-d 6 ), δ, ppm: 26.0 (101 MHz, CDCl 3 ), δ, ppm (J, Hz):	Calculated, %: Calculated, %:
		(benzo[d]thiazol-2-2-yl)-5-benzyl-2,3-	3289, 3258 3315 (NH), 1678,	(J, Hz): 2.75 (t, J = 7.4, 2H, 4-СН 2 ), 2.98 (td, J = 7.8, 1.6, 2H, 3-СН 2 ), 3.96	(СН 2 ), 45.8 (СН 2 ), 51.8 (СН 2 ), 61.9 24.7 (CH 2 ), 47.5 (CH 2 ), 54.3 (CH 2 ),	C, 70.36; H, C, 70.36; H,
		yl)-2-((E)-3-dihydro-1H-	(NH), 2186 1579, 1563	3.78 (t, J = 7.7, 2H, 5-СН 2 ), 4.38 (d, J (t, J = 7.9, 2H, 2-СН 2 ), 4.93 (s, 2H,	(С), 101.2 (С), 120.0 (СН), 121.8 94.4 (C), 112.6 (C), 120.3 (CH), 121.1	5.06; N, 15.63. 5.06; N, 15.63.
		((benzylamino)methy pyrrolo[3,2-	(C≡N), 1645, (C=C, C=N).	= 5.5, 2H, CHNHCH 2 ), 7.04 (d.t, J = СНNCH 2 ), 6.83 (t, J = 1.6, 1Н,	(СН), 123.2 (СН), 123.4 (С), 126.5 (CH), 122.8 (CH), 125.2 (CH), 126.6	C 21 H 18 N 4 S. C 24 H 24 N 4 O 2 S.
		lene)pyrrolidin-2-c]pyridin-6(5H)-	1557 (C=C,	12.3, 5.6, 2H, CHNHCH 2 ), 7.14 (t, J = СНNCH 2 ), 7.24-7.34 (m, 6H, Н-6,	(СН), 127.7 (2СН), 127.8 (CH), 129.1 (2CH), 127.9 (CH), 129.1 (2CH),	Found, %: C, Found, %: C,
		ylidene)acetonitrile imine	C=N).	H Ph -2,4,6), 7.35 -7.39 (m, 2H, H Ph -	130.9 (CH), 134.2 (C), 135.7 (C),	70.40; H, 5.26; 70.56; H, 5.11;
						N, 15.87.

(7.1, 1H, H-6), 7.24-7.40 (m, 6H, Ph H, H-5), 7.61 (d, J = 8.0, 1H, Ar H), 7.76 (d, J = 7.8, 1H, Ar H), 7.95 (d, J (2СН), 131.8 (С), 140.3 (С), 142.4 (СН), 154.1 (С), 162.5 (С), 168.6 (С).

(((

Table 6 . 6 .

 66 Physico-chemical characteristics of BF 2 -complexes 5.1а-h CDCl 3 ), δ, ppm (J, Hz): 2.24-2.36 (m, 2H, 4-СH 2 ), 3.19 (t, J = 8.0, 2H, 3-CH 2 ), 4.04-4.10 (m, 2H, 5-CH 2 ), 7.41 (ddd, J = 8.4, 7.4, 1.1, 1H, H-6), 7.54 (ddd, J = 8.4, 7.4, 1.3, 1H, H-5), 7.75 (ddd, J = 8.0, 1.2, 0.5, 1H, H-7), 8.02 -8.07 (m, 1H, H-4). 19 F NMR (282 MHz, CDCl 3 ), δ, ppm (J, Hz): -139.07 (q, J = 29.0). 11 B NMR (96 MHz, CDCl 3 ), δ, ppm (J, Hz): 1.48 (t, J = 29.3). (75 MHz, CDCl 3 ), δ, ppm (J, Hz): 21.3 (CH 2 ), 34.3 (CH 2 ), 51.6 (CH 2 ), 70.3 (С), 116.6 (C), 118.1 (t, 2 J CN = 3.2, 4-CH), 121.9 (CH), 125.4 (CH), 127.4 (C), 127.8 (CH), 142.9 (C), 166.9 (C), 170.1 (C). Elution system for column chromatography: CH 2 Cl 2 -CHA, 7:3. Yield 133 mg (0.46 mmol, 92%), white powder (mp 233 °C) CDCl 3 ), δ, ppm (J, Hz): 2.24-2.39 (m, 2H, 4-CH 2 ), 3.22 (t, J = 8.0, 2H, 3-CH 2 ), 4.03-4.10 (m, 2H, 5-CH 2 ), 7.40 (ddd, J = 7.9, 7.6, 1.6, 1H, Het H), 7.46 (ddd, J = 7.9, 7.7, 1.5, 1H, Het H), 7.53-7.61 (m, 1H, 7-H, Het H), 7.67-7.75 (m, 1H, 5-H). 19 F NMR (282 MHz, CDCl 3 ), δ, ppm (J, Hz): -140.41 (q, J = 26.0). 11 B NMR (96 MHz, CDCl 3 ), δ, ppm (J, Hz): 1.17 (t, J = 26.2). Elution system for column chromatography: CH 2 Cl 2 -CHA, 7:3. Yield 123 mg (0.45 mmol, 89%), white powder (mp 226-227 °C). CDCl 3 ), δ, ppm (J, Hz): 2.20-2.29 (m, 2H, 4-CH 2 ), 2.51 (td, 3 J HN = 1.6, 3 J HH = 1.2, 3H, CH 3 ), 3.12 (t, J = 8.0, 2H, 3-CH 2 ), 3.95-4.01 (m, 2H, 5-CH 2 ), 6.60 (d, J = 1.2, 1H, H-5). 19 F NMR (282 MHz, CDCl 3 ), δ, ppm (101 MHz, CDCl 3 ), δ, ppm (J, Hz): 14.63 (t, 2 J CN = 4.0, CH 3 ), 21.7 (CH 2 ), 34.0 (CH 2 ), 51.2 (CH 2 ), 69.2 (C), 107.9 (CH), 117.2 (C), 145.1 (C), 167.1 (C), 168.5 (C). J = 6.2, 1H, H-6). 19 F NMR (376 MHz, CDCl 3 ), δ, ppm (J, Hz): -137.84 (q, J = 29.3). 11 B NMR (128 MHz, CDCl 3 ), δ, ppm (J, Hz): 1.24 (t, J = 29.7). 234.1012. Elution system for column chromatography: CH 2 Cl 2 -CHA, 3:2. Yield 105 mg (0.45 mmol, 90%), yellowish powder (mp 158-159 °C). CDCl 3 ), δ, ppm (J, Hz): 2.18-2.33 (m, 2H, 4-СH 2 ), 3.21 (t, J = 8.0, 2H, 3-СH 2 ), 4.02-4.07 (m, 2H, 5-СH 2 ), 4.31 (s, 3H, CH 3 , ОСН 3 ) 7.49 (ddd, J = 8.3, 7.1, 0.8, 1H, H-6), 7.83 (ddd, J = 8.8, 7.1, 1.6, 1H, H-7), 8.10 (dd, J = 8.1, 1.4, 1H, H-5), 8.38 (d.t, 2 J HH = 8.9, 3 J HN = 2.6, 1H, H-8). 19 F NMR (376 MHz, CDCl 3 ), δ, ppm (J, Hz): -134.37 (q, J = 32.1). 11 B NMR (128 MHz, CDCl 3 ), δ, ppm (J, Hz): 2.21 (t, J = 32.6). (101 MHz, CDCl 3 ), δ, ppm (J, Hz): 21.0 (CH 2 ), 34.8 (CH 2 ), 51.8 (CH 2 ), 55.7 (CH 3 ), 73.7 (C), 113.4 (C), 117.9 (C), 121.5 (t, 2 J CN = 7.6, 8-CH), 124.4 (CH), 126.0 (CH), 135.4 (CH), 143.0 (t, 1 J CN = 2.7, (CH) 4 CN), 158.4 (C), 166.7 (C), 171.4 (C). Elution system for column chromatography: CH 2 Cl 2 -CHA, 7:3. Yield 127 mg (0.41 mmol, 81%), greenish powder (mp 232-233 °C). CDCl 3 ), δ, ppm (J, Hz): 2.22-2.34 (m, 2H, 4-CH 2 ), 3.26 (t, J = 8.0, 1H, 3-CH 2 ), 3.98 (s, 3H, NCH 3 ), 4.07-4.13 (m, 2H, 5-CH 2 ), 7.42-7.48 (m, 1H, H-6), 7.76 (ddd, J = 8.9, 7.2, 1.8, 1H, H-7), 8.27 (dd, J = 7.9, 1.7, 1H, H-5), 8.28 (dt, 2 J HH = 8.9, 2 J HN = 3.0, 1H, 8-H). 19 F NMR (376 MHz, CDCl 3 ), δ, ppm (J, Hz): -134.82 (q, J = 30.8). 11 B NMR (128 MHz, CDCl 3 ), δ, ppm (J, Hz): 1.60 (t, J = 31.4). (101 MHz, CDCl 3 ), δ, ppm (J, Hz): 20.4 (CH 2 ), 36.38 (CH 2 ), 36.44 (CH 3 ), 52.7 (CH 2 ), 66.3 (C), 117.7 (C), 118.0 (C), 121.8 (t, 2 J CN = 9.3, 8-CH), 126.4 (CH), 127.7 (CH), 135.4 (CH), 139.8 (t, 1 J CN = 2.4, (CH) 4 CN), 154.7 (C), 160.1 (C), 173.5 (C). Elution system for column chromatography: CH 2 Cl 2 -CHA, 7:3. Yield 118 mg (0.38 mmol, 75%), white powder (mp degradate when heating).

	Com	IUPAC name	IR, ν, cm -1	1 H NMR	13 C NMR	HRMS/MS,
	poun					elemental
	d					analysis
	5.1а	BF 2 -rigidified (Z)-2-	Neat film	(300 MHz, HRMS (DCI-
		(benzo[d]thiazol-2-	2204 (C≡N),			CH 4 ) Calculated
		yl)-2-(pyrrolidin-2-	1598, 1584			for
		ylidene)acetonitrile	(C=N, C=C).			C 13 H 11 BF 2 N 3 S (M + H + )
						290.0735, Found
						290.0741.
	5.1b	BF 2 -rigidified (Z)-2-	Neat film	(300 MHz, (75 MHz, CDCl 3 ), δ, ppm (J, Hz):	HRMS (DCI-
		(benzo[d]oxazol-2-	2214 (C≡N),		21.4 (CH 2 ), 34.8 (CH 2 ), 51.7 (CH 2 ),	CH 4 ) Calculated
		yl)-2-(pyrrolidin-2-	1636, 1616, 1532		61.2 (C), 111.2 (CH), 114.2 (C), 114.9	for
		ylidene)acetonitrile	(C=N, C=C).		(CH), 125.6 (CH), 126.4 (CH), 130.9 (C), 148.1 (C), 162.7 (C), 173.1 (C).	C 13 H 11 BF 2 N 3 O (M + H + )
						274.0963,
						Found:
						274.0969.
	5.1с BF 2 -rigidified (Z)-2-	Neat film	(400 MHz, HRMS (DCI-
		(4-methylthiazol-2-	2202 (C≡N),			CH 4 ) Calculated
		yl)-2-(pyrrolidin-2-	1592, 1567			for:
		ylidene)acetonitrile	(C=N, C=C).			C 10 H 11 BF 2 N 3 S (M + H + )
						254.0735,

authors have not described the structure of the intermediate product and depict it in the form of imidoyl chloride 1.[START_REF] Dawood | Heterocyclic Synthesis via Enaminonitriles: A Convenient Route to Some New Pyrazole, Isoxazole, Pyrimidine, Pyrazolo[1,5-a]pyrimidine, Pyrimido [1,2-a]benzimidazole and Pyrido[1,2-a]benzimidazole Derivatives[END_REF]

The decryption of the substituents R 2 -R 3 , Ar 1 is not given, since the article is devoted to combinatorial synthesis with large number of variants. For more information, please refer to the article

according to the Web of Science portal

only isomers with S in cis position to CN group were taken into account regarding the bigger size of sulfur as compared to nitrogen

The acetal method used to synthesize simpler analogues[START_REF] Zhidkova | Lactam acetals. 11. Reactions of N-methyl-2pyrrolidone diethylacetal with some nucleophilic and electrophilic reagents[END_REF] , in this case, was inefficient.

1-methylpyrrolidin-2-one is cheap and commercially available substance.

General procedure for the synthesis of 3-(ω-aminopropyl)-4-hetaryl-5aminopyrazole (or isoxazole) 3.1-3.7.

10-20 equiv of binucleophile (NH 2 NH 2 •Н 2 О or NH 2 OH (50% water solution) or NH 2 NHMe) were added to a strongly stirred solution of 2-hetaryl-(N-R-pyrrolidin-2ylidene)acetonitrile (1 mmol) in dioxane (10 ml). The reaction mixture was then heated to reflux for 3-8 h (TLC control, elution system: CHCl 3 -CH 3 OH, 20:1 unless otherwise noted), cooled down, and concentrated under reduced pressure. Purification by column chromatography (for 3.4b, 3.5b) or by trituration with a minimal quantity of acetone (for 3.1а, 3.1b, 3.2а, 3.7а) or acetonitrile (for 3.1с, 3.2с) or water-acetone (for 3.6а) yielded the desired product.

Yield 224 mg (0.75 mmol, 75%), light orange powder (mp 171-172 °C).

General procedure for the synthesis of BF 2 -rigidified complexes 5.1а-h.

(Z)-2-hetaryl-2-(pyrrolidin-2-ylidene)acetonitriles 2.1а-d, g, i, 2.9, 2.10 (0.5 mmol) and N,N-diisopropylethylamine (0.25 ml, d = 0.782 g/ml, 1.5 mmol) were heated to reflux in dichloromethane (8 ml) for 15 min. BF 3 •OEt 2 (0.5 ml, d = 1.130 g/ml, 4 mmol) was added and the mixture was refluxed another 30 min. After the reaction was cooled down, it was diluted with additional amount of dichloromethane and washed with water 3 times and brine 1 time. The organic fraction was dried over Na 2 SO 4 , filtrated off and evaporated under reduced pressure. The crude products were purified by automated flash chromatography.

Preparation of the samples of Films of polymeric composites (FPC).

The samples for the investigation were prepared with a free FPC surface, (glass substrate)/ITO/FPC, where ITO is an electroconducting layer of SnO 2 : In 2 O 3 . To prepare the samples filtered solutions of CuL 2 , NiL 2 , CoL 2 complexes, and SOM in methylene chloride were deposited on a glass substrate with a layer of ITO and dried at room temperature for 24 h and then in a drying cabinet at 80 °C for 48 h. The content of HL and metal complexes in the SOM amounted to between 1 and 50 wt.%.

Increase of the concentration of the additives in the SOM to more than 50 wt.% leads to nonuniformity in the morphology of the films, which cannot be permitted for use in photoelectric converters. The thickness of the FPC was ~1.5 µm

SUPPLEMENTARY INFORMATION (Z)-2-(Benzo[d]thiazol-2-yl)-2-(pyrrolidin-2-ylidene)acetonitrile (2.1b

).

2-(Benzo[d]thiazol-2-yl)-2-(1-methylpyrrolidin-2-ylidene)acetonitrile (2.7b).

Thesis summary

The research carried out in the course of this PhD work is centered on cyclic 2azahetaryl-3-enaminonitrile derivatives which represent an attractive scaffold due to its high number of potential reactive sites. Regioselective functionalization of each site may give access to various structurally different Nitrogen-containing moieties featuring an azaheterocycle substituent.

One first application in heterocyclic synthesis of 2-azahetaryl-2-(1-R-pyrrolidin-2-ylidene)acetonitriles, readily accessed from available and cheap starting materials, is their involvement in Knorr-type synthesis of pyrazoles (isoxazoles) where they play the role of the 1,3-dielectrophiles. Thus 4-azahetaryl-3-(ω-aminopropyl)-1Hpyrazole(isoxazole)-5-amines are formed with complete regioselectivity in good yields 50-85%. This establishes an efficient and easily reproducible two-step approach to heterocycle-substituted amino-pyrazoles from heterocyclic acetonitriles.

Unprecedented subsequent transformations were carried out providing an access to regioselectively derivatized polyamino azoles, tetracyclic compounds in up to 45% overall yield and arylated pyrazoles in up to 71% yield through diazotization, followed by arylation through Suzuki-Miyaura cross-coupling or C-H activation.

We illustrated the unprecedented but efficient nitrogen protection as a nitrosamine during the Pd-catalyzed cross-coupling. Also the possibility of pyrazoles C-H activation in order to get densely substituted pyrazoles was shown for the first time.

We also performed the quaternarization of the nitrogen of the heterocycle to investigate the effect of a cationic moiety on the regioselectivity of the reaction of