# Higher-Level Strategies for Computer-Aided Retrosynthesis

## TL;DR

This paper introduces a new framework for computer-aided retrosynthesis that improves the planning of complex molecule syntheses by focusing on higher-level strategies.

## Contribution

A novel higher-level framework for retrosynthesis that reduces search space complexity and improves accuracy for complex molecules.

## Key findings

- The framework achieves higher top-k accuracy in single-step retrosynthesis.
- It identifies multistep routes for more targets than previous methods.
- Case studies show it enables synthesis plans for complex drugs and natural products where prior approaches fail.

## Abstract

Retrosynthesis is
a core technique in organic chemistry
that simplifies
target molecules into more readily available components. Computer-aided
synthesis planning (CASP) automates this process by recursively proposing
immediate precursors to identify multistep synthetic pathways. However,
CASP typically struggles for complex molecules that require longer
synthetic pathways and present a greater number of possible disconnections.
Here, we introduce a new higher-level framework for
computer-aided retrosynthesis. Our approach abstracts detailed substructures
in pathway intermediates not appearing in the target product, allowing
the algorithm to emphasize higher-level strategies while postponing
the consideration of specific functional group choices, thus reducing
the effective width and depth of the search space. This framework
achieves higher top-k accuracy in single-step retrosynthesis
and identifies multistep routes for more targets than the original
approach. Through case studies on complex drugs and natural products,
we demonstrate how routes proposed by our framework provide a powerful
basis for developing full synthesis plans, particularly in challenging
cases where the original approach fails, while enabling chemists to
leverage their expertise to refine the synthesis design. Ultimately,
focusing on higher-level strategies enables an effective and intuitive
approach for challenging targets in computer-aided retrosynthesis.