The challenge of balancing model sensitivity and robustness in predicting yields: a benchmarking study of amide coupling reactions

Abstract

Accurate prediction of reaction yield is the holy grail for computer-assisted synthesis prediction, but current models have failed to generalize to large literature datasets. To understand the causes and inspire future design, we systematically benchmarked the yield prediction task. We carefully curated and augmented a literature dataset of 41 239 amide coupling reactions, each with information on reactants, products, intermediates, yields, and reaction contexts, and provided 3D structures for the molecules. We calculated molecular features related to 2D and 3D structure information, as well as physical and electronic properties. These descriptors were paired with 4 categories of machine learning methods (linear, kernel, ensemble, and neural network), yielding valuable benchmarks about feature and model performance. Despite the excellent performance on a high-throughput experiment (HTE) dataset (R² around 0.9), no method gave satisfactory results on the literature data. The best performance was an R² of 0.395 ± 0.020 using the stack technique. Error analysis revealed that reactivity cliff and yield uncertainty are among the main reasons for incorrect predictions. Removing reactivity cliffs and uncertain reactions boosted the R² to 0.457 ± 0.006. These results highlight that yield prediction models must be sensitive to the reactivity change due to the subtle structure variance, as well as be robust to the uncertainty associated with yield measurements.