Elena Ostanel

Francesco Campagnari

The urban agenda in Canada. Limited room for action in federal-municipal relations

The urban agenda has lived short periods of explicit discussion in Canada. The federal government has tackled urban issues only on limited periods, in particular from 1968 to 1979 and from 2001 to 2006. The chapter argues that, while in these periods the federal government established new agencies, developed programs and aimed to acquire knowledge on urban issues, their impacts have been limited by the provincial jurisdiction over municipal and urban affairs. While federal governments often develop place-based narratives supporting the importance of decisions taken locally about land use, transportation, and any other issue related to urban development, a deep analysis shows that local governments have limited room for action. In order to illustrate the limited effects of past federal measures and the current lack of autonomy of municipal governments, the chapter first explores the two main phases of explicit urban action by the federal government, followed by the analysis of the urban approach of the current government. It then discusses the planning mechanisms in the city of Toronto and the measures adopted by federal and provincial governments to support urban areas during the Covid-19 emergency.

1 Università Iuav di Venezia 2 Università Iuav di Venezia 3 The authors developed and discussed the chapter together. They wrote jointly sections 1, 4 and 5. Elena Ostanel is responsible for section 3 and Francesco Campagnari for section 2. 4 Canada is a Federal parliamentary constitutional monarchy. It is divided in ten provices and three territories: the former have higher degrees of autonomy then the latter. Provinces have responsibility for multiple policy fields such as health care, education, welfare, urban planning, municipal autonomy

Introduction

In order to understand the extent and nature of the Canadian urban agenda, we should locate it in the context of the Canadian Constitution, of the relations between federal and provincial government and of the fiscal and power imbalance they create for municipalities 4 (Stoney and Graham 2009, 393). The jurisdiction over municipalities in Canada is in fact attributed by the Constitution to provincial governments, who have the power to create and legislate on municipal powers and responsibilities. Municipal governments, being "creatures of the provinces", do not have vast powers of autonomy Furthermore, federal-municipal relations have fluctuated over the decades for causes linked to nation-building strategies [START_REF] Wolfe | A national urban policy for Canada? Prospects and challenges[END_REF], the amount of available Federal surplus, the state of relations between federal and provincial levels of government, consensus strategies by federal parties [START_REF] Stoney | Federal-municipal relations in Canada: The changing organizational landscape[END_REF]. Even though federal impacts in urban affairs are unavoidable5 (Berdahl 2004, 27) both by direct policy actions (immigration policies, infrastructure policies) or by the indirect effects of government employment strategies and governmental real estate, the room for a concrete realization of the Federal Urban Agenda in Canada still remains limited.

Starting from these considerations, the chapter argues that the Federal Urban Agenda has been short lived and ineffective even in the few occasions where the federal government explicitly referred to urban problems (often with progressive approaches).

The Chapter highlights that while federal governments often develop placebased narratives supporting the idea that decisions taken locally about land use, transportation, and any other issue related to urban development are crucial to effectively tackle these issues, a deep analysis shows that local governments have limited room for action. The localist agenda of the federal government, aimed at the financial autonomy of municipalities, was often blocked by provincial governments. In this condition, as Lehrer pointed out for Toronto, urban changes are strongly impacted by the global economy more than by the capacity of local policies to govern them [START_REF] Lehrer | Willing the Global City: Berlin's Cultural Strategies of Interurban Competition after 1989[END_REF].

The chapter is organized as follows: the first section illustrates the historical evolution of the approaches of the Canadian federal government to urban issues. Exploring federal programs and policies developed since the beginning of the XX century, the section focuses on two main periods of explicit discussion of a federal urban agenda, linking them with the approach of the current Trudeau government. We argue that the periods of explicit urban intervention did not generate relevant impacts on the level of autonomy of municipalities, and that the approach of the current government to urban issues has not generated different outcomes.

The second section explores the planning mechanisms in the city of Toronto, in order to understand the practical implications of the lack of municipal autonomy; similarly, the third section explores the effects of the Covid-19 emergency on Canadian cities, assessing the measures adopted by federal and provincial govern-ments to support urban areas. The conclusions finally summarize the contribution of the chapter to the current debate, allowing a better understanding of the current tackling of urban issues in Canadian cities.

The federal urban agenda: short lived efforts for explicit urban actions

Over the years, the Federal Canadian Government has adopted different approaches to the issues emerging from Canadian cities. Differently from other cases outlined in this volume, the Canadian government explicitly conceptualized these issues as urban -meaning considering their interconnected and intersectoral nature -only in short periods. And, as we will see, even in these brief phases the Federal Government developed policies and programs with little impact at local level.

This section focuses on the two periods of explicit urban action by the Federal Government -from 1968 to 1979 and from 2001 to 2006 -and on the position of the current government, in charge since 2015. The following table summarizes the three periods. In the two periods of explicit development of urban visions and programs, the federal government showed the will to engage with urban issues. In both periods the government established new agencies, developed programs and aimed to acquire knowledge on urban issues. Through their differences, and in particular in the respective construction of urban problems, we can have a better understanding of their respective failures, of their impacts and and of their influence on today's urban agenda.

-1979: the Federal government as direct urban actor

In the first half of the XX century, as the Canadian population shifted towards cities, the problem of living conditions in urban areas entered the federal agenda. In this period the issue was mostly framed in quantitative terms, in relation to the material and infrastructural equipment of cities, pushing for new housing and sanitary policies [START_REF] Wolfe | A national urban policy for Canada? Prospects and challenges[END_REF]. The understanding of these problems focused on this infrastructural dimension; action to tackle them was straightforward, and structured around federal-provincial collaborations.

At the end of the 1960s urban issues re-emerged in the federal agenda. Rising housing prices, the destruction of inner-city neighborhoods, and increased sensitivity to environmental protection led to protest movements for public housing and against urban renewal plans, mostly carried out by municipalities. In this phase these issues started being understood as multidimensional, thanks to the involvement of multiple problem-setting actors (civil society, technical and political actors).

The Liberal-led federal government, until then mostly focused on housing issues, adopted this integrated approach to urban affairs, influenced by the experiences being developed in that period by the US Department of Housing and Urban Development. The federal Task Force for Housing and Urban Development -appointed in 1968 -recommended a stronger federal role in urban affairs and the establishment of a dedicated Ministry to coordinate comprehensive planning and research activity on urban affairs [START_REF] Stoney | Federal-municipal relations in Canada: The changing organizational landscape[END_REF]. In 1971 the Ministry of State and Urban Affairs (MSUA) was established to influence the process of urbanization, integrating federal policies and establishing cooperative relations with provincial and local stakeholders. The housing issue was now positioned in a broader frame, acknowledging the interconnectedness of the urbanization phenomenon.

The MSUA was set up as a policy department, tasked with policy development, research and coordination among departments and governments [START_REF] Wolfe | A national urban policy for Canada? Prospects and challenges[END_REF]. It had the goal of generating a beneficial federal government influence on the process of urbanization, integrating the federal government's urban and non-urban policies, and fostering cooperative relationships on urban affairs with provinces and municipalities (Stoney and Graham 2009, 378).

The approach of MSUA rested on the idea that effective solutions to urban issues would result only from the development of federal programs intentionally pursuing these problems, and from the establishment of collaborative governance structures including provinces, municipalities and other federal branches. In particular, the federal government started establishing direct links with municipalities, organizing meetings with Federation of Canadian Municipalities (FCM), reducing the distance between municipal representatives and their federal and provincial counterparts. To integrate responses to urban issues, the federal government introduced trilevel meetings between federal, provincial and municipal governments and also briefings with the FCM.

In 1973, MSUA further expanded its mandate from policy to program development, launching programs for urban renewal in collaboration with provincial and local governments [START_REF] Spicer | Institutional policy learning and formal Federal-urban engagement in Canada[END_REF], providing loans and grants for land clearance, relocation, administration and basic infrastructure. Funding for these programs increased during the 1970s, with a first allocation of $300 millions over four years, and since 1978 $250 years annually [START_REF] Carlson | Revitalizing North American Neighborhoods: a comparison of Canadian and US programs for Neighborhood preservation and housing rehabilitation[END_REF].

The MSUA framed urban problems as interconnected issues requiring the collaboration of different levels of government (in particular municipalities) for effective problem-solving. However, this construction of urban problems exposed federal action to provincial criticism. Provinces were initially hesitant in collaborating with the MSUA [START_REF] Spicer | What will Trudeau's urban agenda look like? IRPP Policy Options blog[END_REF], and later became irritated by it. They perceived an invasion of provincial jurisdiction on municipalities by direct funding programmes and federal-municipal briefings; they also saw as a threat the interaction of the federal government with the FCM [START_REF] Stoney | Federal-municipal relations in Canada: The changing organizational landscape[END_REF]. The Ministry was also criticized by other branches of the federal government, as they perceived the MSUA to be trespassing in policy fields under their jurisdiction.

These critiques ultimately led to the disbandment of the Ministry. In order to keep good relations with provincial governments, the MSUA was shut down by the Federal Government in 1979.

The MSUA experience was a first experimentation of institutionalization of explicit comprehensive intervention of the federal government in urban affairs. It expanded the previous single-issue approach with interdependent aspects of urban programs like citizen participation and intergovernmental coordination. It led however to little long-term changes in the treatment of urban issues, as the collaborative institutional architecture it aimed to establish was swiftly removed by the following governments.

-2006: the Federal government as enabler of Municipal autonomy

In the 1980s urban issues entered only indirectly the federal agenda. A heated constitutional debate focusing on the division of power between federal and provincial governments involved municipal autonomy, but it ultimately led to no revisions of jurisdictions (Berdahl, 2004). Instead of pursuing explicit visions, the federal government aimed to create new policy and program instruments moving the center of action from the federal to provincial and municipal levels [START_REF] Stoney | Federal-municipal relations in Canada: The changing organizational landscape[END_REF], and adopting a place-based approach. The most representative instruments developed in this period is the Urban Development Agreement, a tripartite agreement between municipal, provincial, and federal governments. These agreements addressed complex and intersecting social and economic problems like poverty, crime, health, and social exclusion in inner city neighborhoods, with important applications in Western canadian cities [START_REF] Doberstein | Institutional creation and death: Urban development agreements in Canada[END_REF].

Following the inspiration of the New Labour experience in Great Britain, at the end of the 1990s "new localism" became the main discourse around urban issues in Canada. Municipalities and cities were framed as the drivers of the national economy and the setting of the main social problems [START_REF] Friendly | A Team Canada Approach to Fighting COVID-19: Supporting Provinces, Territories, Municipalities and Indigenous Communities[END_REF]. This discourse supported a devolution of power towards the local level, arguing that municipalities should have greater fiscal and financial autonomy to directly tackle issues. This framework was supported by Liberal Party, by the FCM, and the mayors of the main Canadian cities.

In 2001 the Liberal government created a Cities Secretariat and appointed a Prime Minister's Caucus Task Force on Urban Issues. Its final report (Prime Minister's Caucus Task Force on Urban Issues 2002) supported the establishment of a national urban strategy structured around long-term, stable sources of funding to municipalities for affordable housing, transit and infrastructure [START_REF] Spicer | What will Trudeau's urban agenda look like? IRPP Policy Options blog[END_REF].

In 2002 Paul Martin, Minister of Finance from 1993 to 2002 and Prime Minister from 2004 to 2006, outlined his idea for a "New Deal for cities". The Deal aimed at reframing the way governments work together for the social, cultural, economic and environmental sustainability of cities and communities [START_REF] Bradford | Whither the Federal Urban Agenda? A New Deal in Transition[END_REF]. It aimed to develop cooperative and integrated joined-up governance structures between federal, provincial and municipal governments [START_REF] Leo | Deep federalism: Respecting community difference in national policy[END_REF], while recognizing provinces as their main federal interlocutors on urban affairs [START_REF] Friendly | A Team Canada Approach to Fighting COVID-19: Supporting Provinces, Territories, Municipalities and Indigenous Communities[END_REF][START_REF] Spicer | Institutional policy learning and formal Federal-urban engagement in Canada[END_REF].

In 2004 the federal government created the Ministry of State for Infrastructure and Community (MSIC) with the purposes of providing predictable long-term revenue streams for municipalities (Government of Canada 2005, 2), establishing tri-lateral government collaboration for area-based policy-making, and building knowledge on urban policy [START_REF] Bradford | Whither the Federal Urban Agenda? A New Deal in Transition[END_REF]). Long-term revenue streams were pursued with federal investments and transfers to municipalities. Tripartite agreements supported local partnerships and area-based interventions. The knowledgegenerating effort was pursued with investments in National Research Council regional centres and in research on infrastructure and experimental collaborative projects [START_REF] Stoney | Federal-municipal relations in Canada: The changing organizational landscape[END_REF][START_REF] Bradford | Whither the Federal Urban Agenda? A New Deal in Transition[END_REF]. The federal government also launched an External Advisory Committee on Cities and Communities to develop a 30-years vision for communities and cities in Canada. It proposed a double devolution of power, stable funding for municipalities and a federal leadership for tri-level cooperation in partnerships (External Advisory Committee on Cities and Communities 2006).

Considering the constitutional jurisdictions, the New Deal tried to involve provinces and territories more explicitly, recognizing them as key actors in urban policy and program development. Responsibilities were clearly divided through Memoranda of Understanding, occasionally involving municipalities and other stakeholders [START_REF] Rose | Canadian Municipalities and Services for Immigrants: A Toronto Case Study[END_REF]. This approach recognized that a complete double devolution of powers could only be implemented only with the collaboration of provinces.

Differently from the MSUA period, the New Deal mostly remained a vision, as no policies or funding programs were implemented before the change of government in 2006. Nonetheless, it consolidated a new strong discourse on urban issues, theorizing the need for local solutions to local problems. Urban problems had to be tackled first and foremost by municipalities at the local level: the role of the federal government was therefore not to directly engage in those problems, rather to enable municipal autonomy. In this period "urban" issues for the federal government coincided with "municipal" or "local" issues, as proven by the use of the two terms as synonyms in policy documents, without distinctions between urbanized and non-urbanized local governments.

-today: a Federal vision and multiple sectoral policies

In 2006 the new government merged the MSIC with the Ministry of Transportation, reversing the push for a New Deal for Cities and Communities (Horak and Young 2012; [START_REF] Bradford | Whither the Federal Urban Agenda? A New Deal in Transition[END_REF]. The Conservative government launched a "New Deal for provinces and territories'', stressing the primary role of provincial governments [START_REF] Bradford | Whither the Federal Urban Agenda? A New Deal in Transition[END_REF]. It adopted the least joined-up and indirect policy instruments, reducing spending and giving tax credits instead of investing directly in social or community infrastructure (ibid). The effort aimed at establishing a minimal yet efficient federal presence in urban areas.

In 2015 the Liberal party went back to government, with a platform based on promises of reviving the New Deal for Cities policies (FCM 2015;[START_REF] Spicer | What will Trudeau's urban agenda look like? IRPP Policy Options blog[END_REF] and committing to highly collaborative governance structures [START_REF] Friendly | A Team Canada Approach to Fighting COVID-19: Supporting Provinces, Territories, Municipalities and Indigenous Communities[END_REF]). In the last six years, the Trudeau Government has recognized the importance of Canadian cities, focusing on economic development, growth, and help to disadvantaged Canadians (McGregor 2016). It has not launched an explicit urban programme or policy [START_REF] Bradford | A National Urban Policy for Canada? The Implicit Federal Agenda[END_REF]OECD 2017), acting instead on two separate but interconnected levels: first, the federal government used international agreements, like the 2030 Agenda for sustainable development, the COP21 agreement and the New Urban Agenda [START_REF] Reid | National Urban Policy regional report: western and eastern europe and North America[END_REF], to outline its vision on urban issues and interact with Mayors of the main Canadian Cities out of Constitutional constraints [START_REF] Scruggs | Canada has emerged as one of Habitat III's strongest advocates for vulnerable groups[END_REF]. The Habitat III National Report (Government of Canada 2016) is the most representative among these international documents. Following the "new localism" approach, the government argued that the complexity of global phenomena active today at the local scale require extensive collaboration between governments, as well as involving non-governmental and private-sector stakeholders. The federal government was tasked with an indirect role, aimed at empowering local governments. It proposed closer federal-provincial collaboration on sectors like infrastructure, poverty reduction, climate change, business innovation, and the introduction of federal accessibility legislation. Municipal-federal alignment in policy priorities was also considered. Furthermore, it recognized the FCM as a key stakeholder, to be integrated in the federal-municipal machinery for climate change policy. This document and the other agreements had however a visioning nature, with little effect on provincial policies on municipalities.

The federal government operated then on a second level. The discussions of urban issues and the will to develop an urban strategy in these international agreements did not lead to federal policies or programs explicitly addressing urban issues, avoiding trespassing provincial jurisdiction over municipal affairs. The federal government focused instead on sectoral plans, programs and strategies, systematizing interventions in fields of federal jurisdiction in connection with the vision embedded in international agreement. Among these instruments we can mention the National Housing Strategy, Canadian Poverty Reduction Strategy, National Climate Plan, National Infrastructure Plan, Early Learning and Child care Framework, Federal Strategy on Gender-based violence, Strategy on Innovation. Each strategy was developed through a process of extensive stakeholder involvement in its specific field. None of these sectoral plans, however, explicitly aims to directly generate integrated urban effects.

These strategies reinforced federal-provincial partnerships and multiplestakeholder involvement. Compared with the international documents like the Habitat III National Report, the federal government mentioned municipal actors more cautiously. This caution testifies that despites efforts and implicit actions, provinces still acted as gatekeepers in federal-municipal relations, and that explicit federal action on that regard is still limited by constitutional constraints.

Municipal action in Toronto between desires and concrete realizations

In the context we described in the previous sections, Canadian cities include a diffuse array of policies and programs aimed at realizing the 'local turn' of the Trudeau government. Bradford talks about 'implicit national urban policy' that to be effective requires creative experimentation with multi-level modes of governance to align national goals with local priorities and leverage collaborative opportunities [START_REF] Bradford | A National Urban Policy for Canada? The Implicit Federal Agenda[END_REF] that are difficult to be achieved.

Analyzing the possible concrete realization of the federal urban agenda at the local level is particularly important in a territorial context where the vast majority of Canadians live in cities and the vast majority of economic output and private investments is concentrated in cities. In fact, roughly half of Canada's GDP is produced in its 6 biggest cities alone -Toronto, Montreal, Vancouver, Calgary, Edmonton, and Ottawa-Gatineau.

Instead of explicit urban development strategies, the Canadian government support for cities has emerged over the years largely as the by-product of many "aspatial" policies and sectoral programs for the economy, environment and society [START_REF] Bradford | A National Urban Policy for Canada? The Implicit Federal Agenda[END_REF]. As explained in the previous sections, Canada does not have a national urban policy, as cities and municipalities are a provincial responsibility (OECD 2017).

In order to better understand this dynamic, we can focus on two of the main assets of the urban agenda of the Trudeau Government and assess their concrete realization in the case study of Toronto: the support to sustainable and resilient communities and access to affordable housing.

Toronto's socio-spatial polarization is proceeding at a rate much greater than elsewhere in Canada. Spatially, formerly middle-income neighbourhoods are transforming into either high or low income [START_REF] Walks | Gentrification, social mix, and social polarization: Testing the linkages in large Canadian cities[END_REF]. The city is increasingly segregated, with visible minorities concentrated in low-income neighbourhoods and white residents dominating affluent areas in numbers far higher than their share of the population [START_REF] Hulchanski | The three cities within Toronto. Income Polarization Among Toronto's Neighbourhoods, 1970-2005[END_REF]. In this context, Toronto is experiencing both sustained gentrification and advanced suburban restructuring [START_REF] August | Gentrification, suburban decline, and the financialization of multi-family rental housing: The case of Toronto[END_REF]. As Lehrer pointed out, urban changes in Toronto are more impacted by the global economy than by the capacity of local policies to govern them [START_REF] Lehrer | Willing the Global City: Berlin's Cultural Strategies of Interurban Competition after 1989[END_REF] particularly in a strong neoliberalized governance" at least since the advent of the 'common sense revolution' in 1995, when a Tory government was elected on a platform of neoliberal reform [START_REF] Hackworth | Neoliberalism, Contingency and Urban Policy: The Case of Social Housing in Ontario[END_REF].

These contradictions are particularly evident if we assess access to affordable housing in a context that relies almost completely on market mechanisms to supply, allocate, and maintain its housing stock [START_REF] Scanlon | International trends in housing tenure and mortgage finance[END_REF]. In fact about 95% of Canadian households obtain their housing through the market [START_REF] Hulchanski | Canada's Dual Housing Policy Assisting Owners, Neglecting Renters[END_REF]; the situation is particularly severe in a period of housing crisis [START_REF] August | Gentrification, suburban decline, and the financialization of multi-family rental housing: The case of Toronto[END_REF]. In this context the concrete realization of the National Housing Strategy is weak. Trends in the federal role in the secondary part (i.e. affordable housing) of the housing system depend on the particular nature of the federal-provincial relations and disputes of the day, the constitutional and social policy philosophy of the federal political party in power, and the effectiveness of national housing and social welfare organizations in mobilizing popular support for specific housing and urban policies and programs' (Hulchanski 2007, 7). Again, Municipalities have limited room for action in the joint-funding formulaan offer of federal money that must be matched by provincial governments (ibidem, 2007).

Even though the Municipal government could use instruments like Section 37 (see below) to provide affordable housing, the reality shows many constraints mainly due to the municipal-provincial relationship.

Rules and regulations that define the development-planning context in Toronto are established in the Province of Ontario's Planning Act. The legislation provides local municipalities with the planning tools that are necessary to regulate growth and development activity. The Provincial level has complete jurisdiction over municipal government activities. The province exercises its oversight on municipal planning and zoning decisions.

In Toronto, when a development requires a Zoning By-law amendment (i.e. city-wide regulations on land use, that could be useful to build affordable housing) the city has an urban planning tool, known as Section 37, which allows for the possibility of requesting benefits to construct or improve facilities in the city. The density for benefit agreements are defined by the Ontario Planning Act (Planning Act, R.S. O. 1990, c. P.13.; Section 37) and establish a form of "density bonusing", which refers to municipal governments' ability to secure 'benefits' from develop-ers in return for allowing development that exceeds existing height and density restrictions [START_REF] Moore | Decentralized decision-making and urban planning: A case study of density for benefit agreements in Toronto and Vancouver[END_REF].

Under Toronto's Official Plan, developments that exceed a threshold of 10,000 square metres of gross floor area, and where the application increases the permitted density by at least 1,500 square metres, and/or significantly increases the permitted height, are typically subject to this tool (City of Toronto 2019, 1).

The power to apply and negotiate the conditions of benefits are held by city councillors, with no involvement of the urban planning city team [START_REF] Moore | Decentralized decision-making and urban planning: A case study of density for benefit agreements in Toronto and Vancouver[END_REF]). As a consequence, benefits are not inserted in a city-wide planning strategy but jeopardized according to the willingness and capacity of local councillors. Section 37 does not give directions about what type of benefits municipalities should secure [START_REF] Moore | Decentralized decision-making and urban planning: A case study of density for benefit agreements in Toronto and Vancouver[END_REF]. Moreover, benefits are in close proximity to the development and do not necessarily impact the root causes of neighborhood inequalities (ibidem, 2016). From 2007 to 2011, Toronto parks, roads and streetscapes account for forty percent of all benefits secured, while heritage preservation and affordable housing account for only eleven percent [START_REF] Moore | Decentralized decision-making and urban planning: A case study of density for benefit agreements in Toronto and Vancouver[END_REF].

Section 37 has been criticized because it can be used strategically by developers to raise density in neighborhoods. Once a density agreement has been approved by the City, other developers can appeal to that change as a condition to redefine the Zoning By-Law amendment. In addition, they can refuse the density agreement proposed by the City by appealing to the Ontario Local Planning Appeal Tribunal (LPAT).

The LPAT is a judicial conflict resolution approach used by the province of Ontario to resolve urban disputes. The LPAT's board is appointed by the Province and it is empowered to adjudicate disputes. It has the option of upholding, striking-down or changing regional and local municipal planning decisions. As Krushelnicki has pointed out, LPAT decisions are final and not subject to appeal based on the planning arguments and evidence presented [START_REF] Krushelnicki | A practical guide to the Ontario Municipal Board[END_REF].

Over its 85 years of existence, the history of the LPAT in urban planning resolutions has been controversial. Some authors have stated that the effect of its resolutions, instead of resolving conflicts, ended up creating planning policies (Webber and Hernandez 2016). [START_REF] Moore | Planning Politics in Toronto: The Ontario Municipal Board and Urban Development[END_REF], who has focused the analysis on the politics around the LPAT, stated that the tribunal act was a way of distancing councilors from the urban planning decision within the City; rather than viewing the Tribunal as an impediment, municipal politicians are complicit in a process that allows them to defer contentious decisions. Supporters, including those associated with the real estate development industry, welcome the apolitical but professional hearing process of the tribunal, particularly when a decision has to be taken in urban contexts where resolutions have to be given without many resources [START_REF] Webber | Big box battles: the Ontario Municipal Board and largeformat retail land-use planning conflicts in the Greater Toronto Area[END_REF].

Beyond the controversy around the LPAT or the Section 37 urban planning tool, it is clear that the Municipal level has limited chances to mitigate negative effects of neighborhood change and promote access to affordable housing. On the one hand, the LPAT is a provincial institution with no representation on the city level, and on the other, the use of Section 37 does not offer guarantees that citizens' demands are accomplished.

Beside the above mentioned specific planning tools, during the last years the City of Toronto has released specific policies directed to address neighborhood inequalities. In 2005 a neighborhood strategy (called 'A strong neighborhood: a call for action') was developed to improve neighborhood wellbeing based on an evaluation of the neighborhood's access to services and safety. Based on this previous assessment, in 2012 the Toronto Strong Neighborhoods Strategy 2020 (TSNT) was designed. The TSNT was aimed at providing "an equitable set of social, economic and cultural opportunities for all residents, leading to equitable outcomes across all neighborhoods" (City of Toronto 2014, 2). The TSNT's definition has been based on a neighborhood wellbeing assessment inspired by the World Health Organization, known as Urban Health Equity Assessment and Response Tool (World Health Organization 2010). This tool has been designed for measuring health inequities in the developing world [START_REF] Prasad | Prioritizing action on health inequities in cities: An evaluation of Urban Health Equity Assessment and Response Tool (Urban HEART) in 15 cities from Asia and Africa[END_REF] and applied and adapted to the specific context of the city Toronto (City of Toronto 2014). The TSNT assessment identifies 31 out of 140 neighborhoods 'below the benchmark' and asks them to define place-based action plans. In order to support the action plans, the TSNT creates three types of funding streams: the first one is a direct investment from the City (called Partnership Opportunities Fund) to build or enhance community infrastructure in City-owned and City-leased locations (City of Toronto 2012); the second is a micro-grant (called Neighborhood Grants) that offers grants to resident-led groups to help them animate their neighborhoods with events or activities (City of Toronto 2012); the last one is called Neighborhood Funders Network and is an indirect funding stream, based on the coordination of Foundations, Private and Public entities around the selected neighborhoods (City of Toronto 2012).

Notwithstanding the investment of the Partnership Opportunities Fund ($12 million capital investment fund), the investment deals with infrastructure owned or leased by the City, excluding action on private properties and other public infrastructure not owned by the city. Micro-grants, as the TSNT Neighborhood Grants, have demonstrated to be a cost-effective approach for mobilizing social and health improvement action projects [START_REF] Schmidt | Micro grants as a stimulus for community action in residential health programmes: A case study[END_REF]). In addition, microgrants work as an incentive to stimulate community action and progress [START_REF] Owens | Social Innovation Microgrants as Catalysts to Community Development in Economically Marginalized Urban Communities[END_REF]. Lastly, the Toronto Neighborhood Funders Network funding stream is a good approach for coordination, especially with funders that can overlap objectives and visions, in a situation where a big number of nonprofits, not necessarily connected with the neighborhood and with different levels of organization, are competing for funding.

The TSNS confirms what the OECD described in the assessment of the stateof-the-art of the national urban policy in Canada: the national level contributes indirectly to urban development by serving as a key infrastructure funding partner, working with provinces, territories, municipalities, the private sector and nonprofit organisations, as well as other federal departments (OECD 2017). But in a context where multi-level governance is difficult to be implemented, while prov-inces act as gatekeepers in federal-municipal relations and private investments are difficult to be planned by the municipal level, ambitious federal policies (like the National Housing Strategy) are intended to remain on paper.

The impact of the Covid-19 emergency on Canadian cities

As described in the previous sections, international agreements and documents helped develop a vision for urban areas for the current Federal government. Sectoral plans and programs may have helped approach monothematic aspects of urban issues. However, the Federal government still lacks a way to support Canadian municipalitiesas envisioned by the current federal discourses on urban areas and municipalities -in autonomously tackling urban issues.

This limited municipal autonomy has been visible in particular during the Covid-19 crisis. Canadian Municipalities have been at the frontline in emergency management. They have often clashed with provincial governments (which override municipal ones) about the level of toughness of restrictions [START_REF] Moore | Municipal responses to the Covid-19 pandemic in Canada. Local Government Information Unit[END_REF]. The Federal government has provided additional financial support for municipalities through existing funding redistribution schemes like the Federal Gas Tax Fund (Government of Canada 2020a). The Safe Restart Agreement between Federal and Provincial governments, focused on providing subnational governments with increasing testing and contact tracing capacities, personal protective equipment procurement, and to fund enhanced sanitation measures to protect the elderly and most vulnerable, also included a dedicated funding stream for municipalities for Covid-19 and public transit costs (Government of Canada 2020b). Provinces like Ontario also provided additional funding to address increases in operating costs (Province of Ontario 2020).

These measures provided additional temporary funding through existing institutional relations but without proposing intervention on the root issue of lack of municipal autonomy.

As a consequence, the pandemic triggered a series of unprecedented situations at a local level particularly delineating long-term effects on rental housing and urban neighbourhoods. From 2014 to 2017 almost 40,000 rental units were constructed in Toronto and only 2.5% of them were considered to be affordable [START_REF] Monsebraaten | Mayor's affordable housing plan 'missing the mark[END_REF]. During the initial months of COVID-19, it is estimated that over 1 million jobs were lost in Canada [START_REF] Evans | Canada has already lost more than a million jobs To COVID-19 and the worst is yet to come[END_REF]. Due to job loss, affording basic necessities such as food and shelter became very difficult for many individuals. During the first state of emergency in the City of Toronto (March 2020), many individuals were provided with rent relief from their landlords and subsidies from the Federal government. This was for a limited period of time. Although, it may be assumed that rental prices would decrease given the COVID-19 pandemic, that is not the case [START_REF] Sunny | Affordable Rental Housing: Exploring the Impacts of COVID-19 on Rental Housing in the City of Toronto[END_REF]. CMHC notes that the increase in rental pricing may be related to the high vacancy rate within the City throughout 2020. The vacancy rate went from 1.5% in 2019 to 3.4% in 2020, which is the highest vacancy rate in the past 14-years. Since there have been less renters in the City, landlords are increasing the cost of rent to offset the balance of not having enough tenants (ibidem 2021).

In the wake of the pandemic, the Federation of Canadian Municipalities still advocates for greater municipal autonomy, proposing the formalization of federalmunicipal collaborations (FCM 2021). Similarly, Canadian urban scholars have renewed their call for an explicit urban policy [START_REF] Eidelman | The Case for a Canadian Urban Policy Observatory[END_REF].

Conclusions

The Chapter has highlighted how the Federal Urban Agenda in Canada has limited room for action due to diverse and often interrelated factors. First of all, there is a question of competencies: the constitutional jurisdiction of Provinces over Municipalities has blocked any federal initiative directed to support the realization of the Urban Agenda at local level. This must be inserted in a political realm where calls for provincial sovereignty are rooted in discourses of protection of cultural differences (in particular from the french-speaking province of Quebec), and in the support of provincial predominance over federal government on municipal issues by conservative parties at federal level. Municipal governments, being "creatures of the provinces", do not have vast powers of autonomy so they have organized lobbying structures such as the Federation of Canadian Municipalities (FCM) to influence policies at the provincial and federal level, thus not directly impacting on the Federal Agenda's implementation.

Even if federal impacts in urban affairs are unavoidable both by direct policy actions (immigration policies, infrastructure policies) or by the indirect effects of government employment strategies and governmental real estate (Berdahl 2004, 27), the consistency of the Urban Agenda at local level has been short lived and ineffective.

As the Chapter has highlighted, this situation leads to a paradox: while federal governments often develop place-based narratives supporting the idea that decisions taken locally about land use, transportation, and any other issue related to urban development are crucial, a deep analysis shows how -even with a Federal government active in the definition of a National Housing Strategy -local governments have limited room for action. The case study of Toronto shows how urban changes are strongly impacted by the global economy more than by the capacity of local policies to govern them [START_REF] Lehrer | Willing the Global City: Berlin's Cultural Strategies of Interurban Competition after 1989[END_REF]).

Table 1 .

 1 Periods of explicit urban action by the Canadian Federal Government

	Period Government	Conceptualization of the federal urban	International references
		party	agenda
	1968-	Liberal party The Federal Government (FG) is a direct	United States HUD programs
	1979		actor on urban issues	and policies
	2001-	Liberal party The FG enables municipal autonomy on	UK's New Localism approach
	2006		urban issues	to local autonomy
	2015-	Liberal party The FG develops comprehensive urban	COP21, UN Habitat III, 2030
	today		visions but disjointed sectoral policies	SDGs.

Canada is today a highly urban country, with 81% of its population living in urban areas. The situation was highly different at the end of the XIX century, when its institutional architecture was designed: in 1861 84% of the population lived in rural areas (Statistics Canada, 2015). The main Canadian cities are Toronto (5,5 million inhabitants), Montreal (3,5 million inhabitants), Vancouver (2,3 million inhabitants), Calgary (1,2 million inhabitants), Edmonton (1 million inhabitants)


Matthieu Lavayssiere

Frédéric Lamaty
email: frederic.lamaty@umontpellier.fr

Amidation by Reactive Extrusion for the Synthesis of Active Pharmaceutical Ingredients Teriflunomide and Moclobemide

The amidation reaction is a key step for the preparation of a large number of organic molecules, including active pharmaceutical ingredients (APIs), but still challenging from the point of view of its efficiency and sustainability. In this context, the solventless synthesis of an amide, starting from a carboxylic acid and an amine, was performed in a twin-screw extruder (TSE) in the presence of a coupling agent, providing a high yielding and productive method. Reaction conditions were evaluated and successfully used to prepare two APIs, teriflunomide and moclobemide. This complements the synthetic tool box of twin-screw extrusion to prepare organic molecules and opens the way to broader applications, including in an industrial perspective.

Introduction

The amide bond is ubiquitous in nature, structuring biomacromolecules such as proteins and playing a major role in their biological activities. It is involved in numerous interactions (e.g., hydrogen bonding or electrostatic interactions) related to biological processes. Amide bonds are also present in a large number of manufactured molecules such as materials and pharmacologically active compounds. This includes marketed drugs, 25 % of their active pharmaceutical ingredients (APIs) are owning an amide bond, 1 as depicted in Figure 1, with the examples of major drugs.

Figure 1 Selected examples of amides as APIs

While alternative methods to prepare amides are under development, 2 the amide bond is typically synthesized from a carboxylic acid and an amine. 3 However, the synthesis of these compounds, including at the industrial level, 4 often requires reaction conditions involving hazardous and toxic reagents (coupling agents, bases…) in stoichiometric quantities, source of pollution, including the use of large amounts of solvent to solubilize the reaction medium and purify the synthesized product. To counteract the ecological and economic issues in relation with the use of solvents in the fine chemical industries, research teams have developed solvent-free or solventless methods by ball-milling for the preparation of organic molecules 5 including APIs. 13,14 In 2012, our team reported the first example of solvent-free amide bond synthesis starting from a carboxylic acid and an amine, in a ball-mill, with CDI (1,1'-carbonyl diimidazole) 15 as a coupling agent. 16 This method was applied to the organic-solvent free synthesis of the API teriflunomide. 16,17 Nearly concomitantly, the group of Štrukil and Margetić reported amidation reaction including EDC.HCl (N-Ethyl-N'-(3dimethylaminopropyl)carbodiimide hydrochloride) as an efficient coupling agent. 18 Recently, further developments were reported with the use of various coupling agents in a ball-mill to prepare an amide. [19][20][21] Furthermore, the mechanochemical approach to the synthesis of peptides has pioneered and complemented the evaluation of coupling systems in the absence of solvent. 11,13,[22][23][24] Nevertheless, the ball-milling approach corresponds to a discontinuous batch process and the scaling-up of the corresponding reaction with larger mills, currently employed in the mineral industry, raises problems of safety for organic synthesis. While flow chemistry is currently revolutionizing the processing of chemicals, this approach necessitates large amount of solvent and is not well-adapted to the use of solids or of concentrated mixtures. Recently, it has been demonstrated, including work from our team involving peptide formation, 25 that extruders, another mechanochemistry tool, could provide a continuous approach for solventfree or solvent less organic reactions, involving solids or viscous mixtures, 26,27 with few reports regarding the preparation of APIs. [28][29][30] This approach was also recognized by IUPAC as one of the ten most important chemical innovations that could change our world, 31 including at the industrial level. In order to fill in the gap of the number of reactions developed by reactive extrusion, further developments are needed to provide chemists with practical tools to synthesize efficiently organic molecules, including the widespread amidation. We now disclose a first report on the continuous synthesis of amides by reactive extrusion including the preparation of two important APIs, teriflunomide and moclobemide.

Results and discussion

Capitalizing on previous results obtained in the synthesis of peptides, 25,32 the amidation reaction was studied and optimized using a corotating twin-screw extruder (Pharma Melt Extruder (PME) Xplore). This extruder can be used in a continuous mode when reaction time is short, or with a recirculation to increase the residence time in the barrel, corresponding to a longer length of the screw. The previously reported model reaction, used for studying the reaction conditions in a ball-mill, 16 namely the coupling of 3-phenylpropionic acid 1 and benzyl amine 2 was investigated in various conditions including coupling agents and bases/additives if needed. Two important parameters, belonging to the extruder and which could be optimized, if necessary, are the temperature of the barrel and the rotation speed of the screws. Many coupling agents and conditions are available and reported in literature to carry out efficiently an amidation reaction. Among them, a limited number has been effectively used in the pharmaceutical industry for large scale applications. 4 Selection criteria for choosing a coupling system (including coupling agent, base, additives, solvent) are efficiency, availability, practical handling and ease of purification of the final product, as well as safety, toxicity and environmental impact. We evaluated the toolbox for amidation using an extruder focusing on three coupling agents: CDI, EDC.HCl, and 1-[(1-(Cyano-2-ethoxy-2oxoethylideneaminooxy) dimethylaminomorpholino)] uronium hexafluorophosphate (COMU).

Firstly CDI, one of the most employed coupling agents, efficient, cheap and considered nontoxic was explored. CDI generates carbon dioxide and imidazole as a by-product, which can serve as a base when the coupled amine is provided as a salt. The reaction was carried out in two steps, first an activation step of carboxylic acid 1, for a given mixing time t1 with CDI, followed by the addition of benzyl amine 2 (Table 1). The reaction mixture was mixed for a further time (t2). The loading of the experiment was fixed at about 2 g, filling completely the available volume of the barrel equipped with screws (2 mL). A slight excess of acid compared to the amine was used. The temperature of the barrel was set to 30°C and the rotation speed to 200 rpm. Premixing 25 or not the starting materials, with a spatula in a beaker, before introduction in the barrel did not change the final result. At the end of the transformation, the output valve was adjusted to recover the crude mixture. In a first experiment (entry 1), when reactants were mixed neat, recirculation did not happen and no conversion was observed. In the next experiment (entry 2), EtOAc was used in a small amount (1.2 mL, η = 0.6 mL.g -1 ) § as liquid additive (LA) to facilitate the fluidity and the homogeneity of the reaction mixture. 33 The conversion sharply increased to completion towards the expected product. Optimization of quantities of LA and reaction time was realized. Decreasing the amount of EtOAc (η = 0.15 mL.g -1 ), conversion was still excellent but introduction of reagents was not facilitated and recovery of the extrudate was difficult (entry 3). Increasing to η = 0.3 mL.g -1 solved this problem (entry 4). When the three reaction components were mixed together (entry 5) avoiding a pre-activation time, high conversion was obtained albeit with the formation of about 4% of urea arising from the reaction of CDI with benzyl amine 2 only. Gratifyingly, reducing both activation and reaction time to 1 minute each (entry 6) afforded almost complete conversion. In this case, the extrudate was solubilized in EtOAc, followed by acidic then basic aqueous washings to afford pure expected N-Benzyl-3-phenylpropanamide 3 in 81% yield. The efficient use of CDI required a two-step procedure since mixing all reagents together provided urea as side product. To develop a potentially more efficient process, other coupling agents were considered. EDC.HCl is another much employed coupling agent and does not require the use of an additional base unless the amine is used as its salt form. EDC.HCl may be preferred over other carbodiimide type coupling agent because the urea by product thus obtained can be removed by a simple aqueous work up. To improve the kinetics of the amidation and reduce the potential epimerization of a chiral center present in the starting material, additives have been used to enhance the reactivity of the coupling agent. One of the mostly used additive is 1-hydroxybenzotriazole (HOBt), but its sensitivity to explosion represents some concerns. Recently, other additives were explored more specifically for peptide synthesis, including oximes. One of the mostly used is ethyl cyano(hydroxyimino)acetate (Oxyma), which was investigated in this study. 34 Finally, carbodiimides being sensitizing molecules, a carbodiimide-free oxyma-based coupling agent 1-[(1-(Cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholino)] uronium hexafluorophosphate (COMU) was also tested. EDC.HCl, widely used together with DMAP as a base, in a catalytic amount, in solution or in solvent-free conditions, 4,18,36 was investigated. 10 minutes of mixing 1 and 2 in the extruder together with EDC.HCl and DMAP yielded an incomplete conversion towards the expected product (entry 1). Adding EtOAc (η = 0.6 mL.g -1 ) did not improve the conversion (entry 2). In the absence of base, conversion was improved but not complete (entry 3). Various less toxic inorganic and organic bases were investigated. Ca(OH)2 , CaO, KHCO3 did not yield satisfactory conversions (entries 4-6). K2CO3 (entry 7) was more effective when the amount of EtOAc was increased to η =0.75 mL.g -1 and the temperature raised to 50°C. Triethylamine (entry 8) was more efficient than DMAP, without reaching full conversion. On the other end, diisopropylethyl amine (DIPEA) gave excellent conversion (entry 9). To avoid the need for recirculation in the extruder, the possibility to reduce further the reaction time was explored, adding Oxyma, known to increase the kinetics of amide bond formation. Surprisingly, in a first experiment (entry 10), the conversion decreased, but switching to CH3CN as liquid additive improved radically the outcome of the reaction, most probably because it provides a more homogeneous reaction mixture in the presence of Oxyma and facilitates the recovery of the extrudate (entry 11). Reaction time could be decreased to 1 min (entry 12), still providing excellent conversion with an isolated yield of 86 % with the same recovery procedure as described above. Noteworthy, in this case, recirculation was not needed and molecule 3 was produced in a continuous mode. With these results in hands the Oxyma-based coupling agent COMU was also tested. Reaction in the presence of DIPEA and EtOAc (entry 13) yielded full conversion in 10 minutes. Switching from DIPEA to less toxic K2CO3 did not impact the conversion (entry 14). CH3CN, for the reasons mentioned above was also used (entry 15) to give a similar result with an isolated yield of 80%. Scaling up the reaction by running the same reaction three times successively in the extruder (entry 16) yielded 99% conversion and an excellent isolated yield of 93% to provide 1.71 g of 3. Attempt to reduce the reaction time to 1 min (entry 17) was not satisfactory, resulting in a lower conversion. The optimal conditions for amidation reported in literature 21 in the case of ball-milling, including COMU and K2HPO4 as a base, were tested (entry 18) but resulted in a lower conversion, most probably because reaction time was not long enough. Finally, combination of COMU, K2CO3 and CH3CN as liquid assistant (entry 19) was not the best combination regarding conversion but the reaction could be carried out in a continuous mode on a larger scale, providing 1.29 g of 3 (77% isolated yield, 85 % conversion). This optimization study of the reaction conditions on a reactive system with various coupling systems demonstrated that it possible to perform efficiently an amidation reaction in a twinscrew extruder (TSE) on a simple model reaction. The use of CDI does not require the presence of base and is a stepwise activation and coupling reaction. This is not the case of EDC.HCl which efficiency could be enhanced by adding Oxyma to reach shorter reaction time, necessary for a continuous process. Finally, COMU is also well-adapted even if reaction times are longer. With these tools in hands, the methods were adapted and applied to the preparation of APIs owning an amide bond. Two molecules were chosen, according to their therapeutic and economical value in the pharmaceutical industry, moclobemide and teriflunomide (Figure 1 and Scheme 1). Teriflunomide is an oral disease-modifying therapy for relapsing forms of multiple sclerosis. 37 Moclobemide is used to treat depression and social anxiety disorder. 38 In the case of teriflunomide, a similar scheme as the one developed in our original work 16 was considered, with the first step (amidation) performed herein in the extruder. Then opening of the isoxazole ring in solution in acidic conditions gave teriflunomide. The isolated yields are reported for the final product recovered by filtration followed by a recrystallization. For moclobemide, [START_REF] Nicholson | For a synthesis of moclobemide in a ball-mill by amidation of esters[END_REF] after the one-step amidation in the extruder, the product was recovered by an extraction and a recrystallization.

Scheme 1 Synthesis of teriflunomide and moclobemide by reactive extrusion

For each of these molecules, the previously evaluated coupling agents were used. The main adjustments consisted in selecting the liquid additive (EtOAc or CH3CN), the base (DIPEA or K2CO3), the temperature of the barrel and the reaction time (Table 3). For teriflunomide, the use of CDI (entry 1) gave a very good result (full conversion for the amidation and 77 % isolated overall yield), provided that CH3CN was used as liquid additive at a temperature of 50°C. These results compare favorably in term of reaction time to the ones previously obtained by ballmilling (5h). 16 Reaction with EDC.HCl/DIPEA was much slower and increasing the reaction temperature resulted in a mixture of products (entry 2). Adding Oxyma (entry 3) reduced the reaction time and provided a good yield of the expected product. COMU gave similar results but was not as fast (entry 4). Noteworthy, the recovery of teriflunomide from the reaction with CDI is facilitated (simple precipitation in water) because of the absence of a base or additives. In the case of a reaction where Oxyma is present, more careful recrystallization was needed to remove the by-products. In contrast to these results, CDI was not adapted to the preparation of moclobemide. Either with EtOAc or CH3CN as liquid additive, recirculation was difficult and resulted in lower conversion and yield than in the case of teriflunomide (entry 5). Again, increasing the temperature to accelerate the reaction with EDC.HCl/DIPEA resulted in a mixture of products (entry 6). The presence of Oxyma dramatically improved the results with a complete conversion obtained within 5 min (entry 7). Switching to K2CO3 as a base (entry 8) proved to be more practical and faster, and the transformation could be carried out in 1 min in a continuous mode to furnish 87 % yield of moclobemide. Conversion and yields with COMU were excellent but the process needed recirculation (entry 9). As expected, the optimal conditions for the synthesis of the two APIs, teriflunomide and moclobemide, in the TSE are different. They depend on the chemical reactivity of the starting materials (the aniline involved in the reaction of teriflunomide is less reactive than the primary amine in the case of moclobemide) but also on the physico-chemical properties of the reaction medium since in the TSE, it is necessary to obtain a homogeneous mixture which can be extruded at the end of the process. Nevertheless, considering the coupling systems reported herein, and the possibility to adjust various parameters, optimal conditions should be obtained for any coupling reaction. In the case of moclobemide, one reaction could be performed in continuous mode (entry 8) because reaction time was short. In the other cases, longer reaction time required recirculation. With the objective of developing a continuous process, this would require in further studies to switch to a TSE which could accommodate longer length of screws. 27

Conclusions

Owing to the importance of the presence of amide bonds in various families of molecules including active pharmaceutical ingredients (APIs), we developed a general amidation method for making these molecules in a twin-screw extruder, in some cases in a continuous mode, starting from a carboxylic acid and an amine. This method was applied to the efficient synthesis of teriflunomide and moclobemide and will complement the toolbox developed for the preparation of APIs by reactive extrusion. It could be also employed for the synthesis of other families of molecules of interest. Furthermore, as it was recently demonstrated, 30 drastically decreasing the amount of solvent used, combined with an improved efficiency of the amidation reaction by engaging quasi stoichiometric amount of starting material results in a more sustainable and cost saving approach. This paves the way for the dissemination of the technology of reactive extrusion for organic synthesis in industry.

Table 1

 1 CDI-promoted amidation Determined by HPLC. b In this case, recovery of the extrudate was incomplete.

	Entry	η (mL.g -1 )	Activation	Reaction	Conv. into
		of EtOAC	step t1 (min)	time t2 (min)	3 (%) a
	1	0	5	10	0
	2	0.6	5	10	>99
	3 b	0.15	5	10	>99
	4	0.3	5	10	>99
	5	0.3	0	5	94 c
	6	0.3	1	1	98 (81) d
	a

c 4% of urea was obtained. d Isolated yield.

Table 2

 2 Amidation with EDC.HCl or COMU

	Entry Coupling	Base (equiv.)	Liquid additive (η	Reacti	Conv.into 3 (%) a
		agent		mL.g -1 )/additive	on
					(min)
	1	EDC.HCl DMAP (0.3)		10	78
	2	EDC.HCl DMAP (0.3)	EtOAc (0.6)	10	79
	3	EDC.HCl		EtOAc (0.6)	10	85
	4	EDC.HCl Ca(OH)2 (0.3)	EtOAc (0.6)	10	72
	5	EDC.HCl CaO (0.3)	EtOAc (0.6)	10	87
	6	EDC.HCl KHCO3 (0.3)	EtOAc (0.75)	10	90
	7 b	EDC.HCl K2CO3 (0.15)	EtOAc (0.75)	10	97
	8	EDC.HCl NEt3 (0.3)	EtOAc (0.6)	10	93
	9	EDC.HCl DIPEA (0.3)	EtOAc (0.6)	10	98
	10	EDC.HCl DIPEA (0.3)	EtOAc (0.75)/Oxyma 10	81
	11	EDC.HCl DIPEA (0.3)	CH3CN (0.6)/ Oxyma 10	>99
	12	EDC.HCl DIPEA (0.3)	CH3CN (0.3)/ Oxyma 1	96 (86) c
	13	COMU	DIPEA (1)	EtOAc (0.75)	10	>99
	14	COMU	K2CO3 (0.5)	EtOAc (0.75)	10	>99 (75) c
	15	COMU	DIPEA (1)	CH3CN (0.6)	10	>99 (80) c
	16	COMU	DIPEA (1)	CH3CN (0.6)	3X10	>99 (93) c
	17	COMU	DIPEA (1)	CH3CN (0.6)	1	94
	18	COMU	K2HPO4 (1)	EtOAc (0.6)	1	52
	19	COMU	K2CO3 (0.5)	CH3CN (0.6)	3X1	85(77) c

a Determined by HPLC. b Extruder barrel temperature set at 50°C. c Isolated yield.

Table 3

 3 Reactive extrusion conditions for the synthesis of teriflunomide and moclobemide

	Entry Coupling	Base (equiv.)	Liquid additive (η mL.g -1 )	T (°C), t	Conv. % b
		agent		/additive (equiv.)	(min)	(Isolated
						Yield, %) c
	Teriflunomide 1	CDI	-	CH3CN (0.6)	50 (10+20) a >99 (77)
	Teriflunomide 2	EDC.HCl	DIPEA (0.33)	CH3CN (0.6)	80 (120)	67 d
	Teriflunomide 3	EDC.HCl	DIPEA (0.3)	CH3CN (0.6)/Oxyma (1)	50 (60)	99 (75%)
	Teriflunomide 4	COMU	DIPEA (1.1)	CH3CN (0.6)	30 (120)	85 (80)
	Moclobemide 5	CDI	-	EtOAc (0.6)	30 (1+2) a	88 (68)
	Moclobemide 6	EDC.HCl	DIPEA (0.33)	CH3CN (0.6)	80 (10)	85 d
	Moclobemide 7	EDC.HCl	DIPEA (0.33)	CH3CN (0.6)/Oxyma (1)	30 (5)	>99
	Moclobemide 8	EDC.HCl	K2CO3 (0.3)	CH3CN (0.6)/Oxyma (1)	30 (1)	95 (87)
	Moclobemide 9	COMU	DIPEA (1.1)	CH3CN (0.6)	30 (10)	99 (95)

a In the case of CDI, activation + reaction time. b Determined by HPLC. c In the case of teriflunomide, isolated yield was calculated on the final product after acidic treatment. d A mixture was obtained.

Acknowledgments:

The Centre National de la Recherche Scientifique (CNRS), University of Montpellier, and Chimie Balard Cirimat Carnot Institute (through the ANR programme N°16 CARN 0008-01) are acknowledged for financial support.

uronium hexafluorophosphate HOBt 1-Hydroxybenzotriazole Oxyma Ethyl hydroxyiminocyanoacetate Notes § η is defined as the ratio between the volume of liquid (in mL) divided by the total mass of solids (in gram)