Accelerated Chemical Reaction Optimization Using Multi-Task Learning

• Connor J. Taylor*^a,b, Kobi C. Felton^c, Daniel Wigh^b,c, Mohammed I. Jeraal^d, Rachel Grainger^a, Gianni Chessari^a, Christopher N. Johnson^a, and Alexei A. Lapkin*^b,c,d

• ^aAstex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom
• ^bInnovation Centre in Digital Molecular Technologies, Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom
• ^cDepartment of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS, United Kingdom
• ^dCambridge Centre for Advanced Research and Education in Singapore Ltd., 1 Create Way, CREATE Tower #05-05, 138602, Singapore

Functionalization of C–H bonds is a key challenge in medicinal chemistry, particularly for fragment-based drug discovery (FBDD) where such transformations require execution in the presence of polar functionality necessary for protein binding. Recent work has shown the effectiveness of Bayesian optimization (BO) for the self-optimization of chemical reactions; however, in all previous cases these algorithmic procedures have started with no prior information about the reaction of interest. In this work, we explore the use of multitask Bayesian optimization (MTBO) in several in silico case studies by leveraging reaction data collected from historical optimization campaigns to accelerate the optimization of new reactions. This methodology was then translated to real-world, medicinal chemistry applications in the yield optimization of several pharmaceutical intermediates using an autonomous flow-based reactor platform. The use of the MTBO algorithm was shown to be successful in determining optimal conditions of unseen experimental C–H activation reactions with differing substrates, demonstrating an efficient optimization strategy with large potential cost reductions when compared to industry-standard process optimization techniques. Our findings highlight the effectiveness of the methodology as an enabling tool in medicinal chemistry workflows, representing a step-change in the utilization of data and machine learning with the goal of accelerated reaction optimization.

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