Advancing chemical reaction prediction in data-scarce drug discovery with active and geometric deep learning.

Abstract

The success of generative molecular design depends on the synthetic accessibility of the molecules it creates. While computational models can help predict chemical reactions, their current effectiveness is limited by a lack of reference data and the difficulty of accurately predicting reaction regioselectivity. Here, to address this, we present an integrated closed-loop workflow that combines efficient reaction data acquisition with high-accuracy deep learning. We developed an active learning strategy, driven by a tree-based ensemble, to guide the acquisition of the most informative laboratory experiments. This experimental campaign yielded a diverse benchmark for C-H borylation. The bespoke dataset allowed us to train and evaluate geometric graph neural networks. We demonstrate that augmenting these symmetry-aware models with self-supervised auxiliary tasks consistently improves performance for both reaction outcome prediction and regioselectivity prediction. Prospective tests on unseen substrates, featuring challenging N-heteroaryl motifs, pinpointed the correct borylation positions in all cases, illustrating the practical utility of our workflow for efficient drug optimization.