Similarity based functionalization for enumeration of synthetically plausible chemical libraries surrounding a target

Abstract

Functionalization of lead compounds to create analogs is a challenging step in discovering new molecules with desired properties and it is conducted throughout the chemical industry, including pharmaceuticals and agrochemicals. The process can be time-consuming and expensive, requiring expert intuition and experience. To help address synthesis planning challenges in late-stage functionalization, we have developed a molecular similarity approach that proposes single-step functionalization reactions based on analogy to precedent reactions. The developed approach mimics reaction strategies and suggests co-reactants defined implicitly by a corpus of known reactions. Using ca. 348 k reactions from the patent literature as a knowledge base, the recorded products or close analogs are among the top 20 proposed products in 74% of ∼44 k test reactions. The combinatorial growth inherent in recursive applications of the tool allows the enumeration of chemical libraries surrounding a target compound of interest. Moreover, each step of the resulting library synthesis leverages common chemical transformations reported in the literature accessible to most chemists.