In order to discover a new medicine, academic and industrial researchers require access to diverse collections of molecules. However, the slow step in medicine discovery is the synthesis of these biologically active molecules from simpler building blocks. In many cases, key molecules are inaccessible with current technologies, which prevents researchers exploring the full range of chemical structures required to understand and develop a new medicine. Around 80% of the molecules used in the drug discovery process contain a nitrogen atom (in the form of amines), and therefore novel methods that generate new amine structures are highly valued in the drug discovery arena. In this project, we will explore the unique reactivity of organoboranes to develop a novel and general catalytic platform for the synthesis of amines. Organoboranes have an unusual ability to abstract hydride from amines, generating a reactive cationic intermediate and a hydride bound to boron. This unique reactivity will allow common and readily available building blocks to be used in novel processes. The methods discovered in the project will be easy to use and not require special training. It will also generate low waste through high atom economy. The project will demonstrate the utility of these new tools to targeted end-users in academia, and pharmaceutical and supporting Contract Research industries, by solving specific challenges in drug discovery. For example, by addressing limitations in the synthesis of nitrogen-containing molecules, we will enable access to new and previously inaccessible structures. This will transform medicinal and biological chemists' abilities by enabling them to develop clear pictures of structure-activity relationships that are critical for studying disease and developing new treatments. The project is divided into three Aims that represent the three reaction classes where we will employ the unique abilities of organoboranes to solve challenges. - Aim 1 will target the first direct and modular synthesis of privileged aryl alkyl amines found in serotonergic/dopaminergic pharmaceuticals that treat a variety of mental illnesses. This Aim will enable efficient access to aryl alkyl amines and allow a full and systematic study of how structure affects activity and therefore lead to more efficacious treatments. - Aim 2 will develop a new approach to the catalytic alpha CH arylation of amines. We will demonstrate utility of this method in the late-stage-functionalisation of a variety of validated medicines so that new or improved bioactivity can be efficiently discovered from known molecular templates. - Aim 3 will develop a new approach to the synthesis of a common class of bioactive N- heterocycles, tetrahydroquinolines. We will address specific limitations of current methods and will enable the rapid exploration of chemical space for structure activity relationships related to treatments for cancer, pain, osteoporosis, parasite infections and allergies for the first time.

The EPSRC CDT in Integrated Catalysis (iCAT) will train students in process-engineering, chemical catalysis, and biological catalysis, connecting these disciplines in a way that will transform the way molecules are made. Traditionally, PhD students are trained in either chemocatalysis (using chemical catalysts such as metal salts) or biocatalysis (using enzymes), but very rarely both, a situation that is no longer tenable given the demands of industry to rapidly produce new products based on chemical synthesis. Graduate engineers and scientists entering the chemical industry now need to have the skills and agility to work across a far broader base of catalysis - iCAT will meet this challenge by training the next generation of interdisciplinary scientists and engineers who are comfortable working in both bio and chemo catalysis regimes, and can exploit their synergies for the discovery and production of molecules essential to society. iCAT features world-leading chemistry and engineering groups advancing the state-of-the-art in bio and chemo catalysis, with an outstanding track record in PhD training. The CDT will be managed by a strong and experienced team with guidance from a distinguished membership of an International Advisory Group. The rich portfolio of interdisciplinary CDT projects will feature blue-sky research blended in with more problem-solving studies across scientific themes such as supramolecular-assisted catalysis using molecular machines, directed evolution and biosynthetic engineering for synthesis, and process integration of chemo and bio-catalysis for sustainable synthesis. The iCAT training structure has been co-developed with industry end-users to create a state-of-the-art training centre at the University of Manchester, equipping PhD students with the skills and industrial experience needed to develop new catalytic processes that meet the stringent standards of a future sustainable chemicals industry in the UK. This chemical industry is world-class and a crucial industrial sector for the UK, providing significant numbers of jobs and creating wealth (currently contributing £15 billion of added value each year to our economy). The industry relies first and foremost on skilled researchers with the ability to design and build, using catalysis, molecules with well-defined properties to produce the drugs, agrochemicals, polymers, speciality chemicals of the future. iCAT will deliver this new breed of scientist / engineer that the UK requires, involving industry in the design and provision of training, and dovetailing with other EPSRC-, University-, and Industry-led initiatives in the research landscape.

Molecular sciences, such as chemistry, biophysics, molecular biology and protein science, are vital to innovations in medicine and the discovery of new medicines and diagnostics. As well as making a crucial contribution to health and society, industries in this field provide an essential component to the economy and contribute hugely to employment figures, currently generating nearly 500,000 jobs nationally. To enable and facilitate future economic growth in this area, the CDT will provide a cohort of researchers who have training in both aspects of this interface who will be equipped to become the future innovators and leaders in their field. All projects will be based in both molecular and medical sciences and will focus on unmet medical needs, such as understanding of disease biology, identification of new therapeutic targets, and new approaches to discovery and development of novel therapies. Specific problems will be identified by researchers within the CDT, industrial partners, stakeholders and the CDT students. The research will be structured around three theme areas: Biology of Disease, Molecule and Assay Design and Structural Biology and Computation. The CDT brings together leading researchers with a proven track record across these areas and who have pioneered recent advances in the field, such as multiple approved cancer treatments. Their combined expertise will provide supervision and mentorship to the student cohort who will work on projects that span these research themes and bring their contributions to bear on the medical problems in question. The student cohort approach will allow teams of researchers to work together on joint projects with common goals. Projects will be proposed between academics, industrial partners and students with priority given to those with industrial relevance. The programme of research and training across the disciplines will equip graduates of the CDT with an unprecedented background of knowledge and skills across the disciplines. The programme of research and training across the disciplines will be supplemented by training and hands-on experiences of entrepreneurship, responsible innovation and project management. Taken together this will make graduates of the CDT highly desirable to employers, equip them with the skills they need to envisage and implement future innovations in the area and allow them to become the leaders of tomorrow. A structured and highly experienced management group, consisting of a director, co-directors, theme leads and training coordinators will oversee the execution of the CDT with the full involvement of industry partners and students. This will ensure delivery of the cohort training programme and joint events as well as being accountable for the process of selection of projects and student recruitment. The management team has an established track record of delivery of research and training in the field across industry and academia as well as scientific leadership and network training coordination. The CDT will be delivered as a single, fully integrated programme between Newcastle and Durham Universities, bringing together highly complementary skills and backgrounds from the two institutions. The seamless delivery of the programme across the two institutions is enabled by their unique connectivity with efficient transport links and established regional networks. The concept and structure of the CDT has been developed in conjunction with the industrial partners across the pharmaceutical, biotech and contract research industries, who have given vital steer on the desirability and training need for a CDT in this area as well as to the nature of the theme areas and focus of research. EPSRC funding for the CDT will be supplemented by substantial contributions from both Universities with resources and studentship funding and from industry partners who will provide training, in kind contribution and placements as well as additional studentships.

The switch from traditional organic solvents, many of which are hazardous, volatile or non-sustainable, to modern green solvents is one of the key sustainability objectives in High Value Chemical Manufacture. Currently, the use of green solvents is often explored at process development stage, instead of discovery stage. This necessitates re-optimisation of processes, due to changes in yield, selectivity, impurity profile and purification. These lead to longer development time, cost, and additional uncertainty. On the other hand, selecting the right solvent early may enhance chemoselectivity, avoid additional reaction steps, and simplify purification of the products. Predicting these changes is an important underpinning capability for wider adaptation of green solvents in manufacturing. Unfortunately, the scarcity of reaction data in green solvents is a key obstacle in developing this capability. Thus, there is an urgent need for ML models which predict reactivity in green solvents based on available data in traditional solvents. In addition to addressing the short time-scale of early-stage process development, these will increase the confidence in utilising green solvents at discovery stage, support sophisticated synthetic routes planning tools which takes into account side products, impurity and purification methods, and act as valuable regulatory tools for assessing hazardous impurities. This project will address these challenges through the following objectives: O1 Addressing the scarcity of reactivity data in the literature through curation of reaction data with reliable reaction time and inclusion of rate laws. O2 Developing solvent-dependent reactivity and reaction selectivity prediction models for green solvents. O3 Producing a set of standard substrates based on cheminformatics analysis of industrially relevant reactions and collecting their reactivity data in green solvents. These outputs will have transformative impacts in the chemical manufacture industry, delivering rapid, more sustainable and better quality-controlled processes through shorter development time, and confidence in predicting reaction outcomes in green solvents. The project will be carried out with support from industrial partners working in the field of cheminformatics and AI/Machine learning, e.g. Lhasa Ltd. and Molecule One. Its outputs will be guided and exploited by partners who are end-users in the High Value Chemical Manufacturing sectors: AstraZeneca, CatSci, and Concept Life Science.

Synthesis, the science of making molecules, is central to human wellbeing through its ability to produce new molecules for use as medicines and materials. Every new drug, whether an antibiotic or a cancer treatment, is based on a molecular structure designed and built using the techniques of synthesis. Synthesis is a complex activity, in which bonds between atoms are formed in a carefully choreographed way, and training to a doctoral level is needed to produce scientists with this expertise. Our proposed CDT is tailored towards training the highly creative, technologically skilled scientists essential to the pharmaceutical, biotech, agrochemical and materials sectors, and to many related areas of science which depend on novel molecules. Irrespective of the ingenuity of the synthetic chemist, synthesis is often the limiting step in the development of a new product or the advance of new molecular science. This hurdle has been overcome in some areas by automation (e.g. peptides and DNA), but the operational complexity of a typical synthetic route in, say, medicinal chemistry has hampered the wider use of the technology. Recent developments in the fields of automation, machine learning (ML), virtual reality (VR) and artificial intelligence (AI) now make possible a fundamental change in the way molecules are designed and made, and we propose in this CDT to engineer a revolution in the way that newly trained researchers approach synthetic chemistry, creating a new generation of pioneering innovators. Making use of Bristol's extensive array of automated synthetic equipment, flow reactors, peptide synthesisers, and ML Retrosynthesis Tool, students will learn and appreciate this cutting-edge technology-driven program, its potential and its limitations. Bristol has outstanding facilities, equipment and expertise to deliver this training. At its core will be a state-of-the-art research experience in our world-leading research groups, which will form the majority of the 4-year CDT training period. For the 8 months prior to choosing their project, students with complete a unique, multifaceted Technology & Automation Training Experience (TATE). They will gain hands-on experience in advanced techniques in synthesis, automation, modelling and virtual reality. In conjunction with our Dynamic Laboratory Manual (DLM), the students will also expand their experience and confidence with interactive, virtual versions of essential experimental techniques, using simulations, videos, tutorials and quizzes to allow them to learn from mistakes quickly, effectively and safely before entering the lab. In parallel, they will develop their teamworking, leadership and thinking skills through brainstorming and problemsolving sessions, some of them led by our industrial partners. Brainstorming involves the students generating ideas on outline proposals which they then present to the project leaders in a lively and engaging interactive feedback session, which invariably sees new and student-driven ideas emerge. By allowing students to become fully engaged with the projects and staff, brainstorming ensures that students take ownership of a PhD proposal from the start and develop early on a creative and collaborative atmosphere towards problem solving. TATE also provides a formal assessment mechanism, allow the students to make a fully informed choice of PhD project, and engages them in the use of the key innovative techniques of automation, machine learning and virtual reality that they will build on during their projects. We will integrate into our CDT direct interaction and training from entrepreneurs who themselves have taken scientific ideas from the lab into the market. By combining our expertise in synthesis training with new training platforms in automation, ML/AI/VR and entrepreneurship this new CDT will produce graduates better able to navigate the fast-changing chemical landscape.