Expanding the Synthome: Generating and integrating novel reactions into retrosynthesis tools.

Abstract

Synthesising compounds is a major component of the time and cost of drug discovery. Retrosynthesis approaches have grown in prominence in efficiently predicting synthetic routes. For such tools to be truly impactful they should be able to effectively incorporate rarely seen chemical reactions and synthesise unknown molecules. We show that whilst existing tools can often effectively replicate known routes in familiar chemical spaces, they tend to fail in less explored regions. To overcome this challenge, we present a novel approach that integrates under-utilised reactions, resulting in improved performance in nearly 70% of tested cases. We introduce a tool that identifies, prioritises, and incorporates entirely new chemical transformations, demonstrating an average reduction in predicted synthesis costs of [~] 20%. Importantly, our tool can highlight new chemical reactions that should be prioritised for development to improve synthesis efficiency. Our findings lay the groundwork for next generation retrosynthesis tools, which will be capable of driving the discovery of novel chemical transformations and more efficient exploration of chemical space.