Robust out-of-distribution prediction of Buchwald–Hartwig reactions

Abstract

Abstract The Buchwald–Hartwig cross-coupling is a cornerstone of modern pharmaceutical synthesis, yet predictive modeling of its outcomes remains constrained by data quality and chemical space coverage. Electronic laboratory notebooks contain heterogeneous, noisy records, while open-source high-throughput experimentation (HTE) datasets are fragmented and narrow in scope, leading to poor model performance on unseen substrates and conditions. Here we introduce a framework that systematically standardizes and integrates multiple reaction datasets into a high-quality, unique-structure-per-entity dataset, coupled with active learning to strategically expand chemical space. By merging published Buchwald–Hartwig HTE data with new experimental results, we achieve a model with predictive power across novel substrates and conditions, delivering improved out-of-distribution predictions compared with previous approaches. Crucially, model-guided reagent recommendations were validated experimentally, confirming the framework’s utility to uncover unexplored reactivity. This work establishes a blueprint for robust machine learning in synthetic chemistry and enables preemptive in silico reagent screening to accelerate pharmaceutical discovery.