SMARTS-RX: A SMARTS-Based Representation of Chemical Functions for reactivity analysis

Chemical functional group annotation provides a mechanistically meaningful framework to interpret model outcomes and guide synthetic strategies. Here, we present SMARTS-RX—a curated, hierarchical ontology of 406 SMARTS-based functional group descriptors—designed to characterize chemically relevant and reactive functionalities in small molecules. SMARTS-RX achieves a balance between granularity and computational efficiency by focusing on functional groups central to pharmaceutical synthesis and medicinal chemistry. We describe the development of SMARTS-RX, including its systematic nomenclature and SMARTS encoding, which enable precise tracking of chemical environments. The utility of SMARTS-RX for mapping chemical reactivity is demonstrated through analyses of functional group distributions across major reaction types, using large-scale datasets from AstraZeneca’s Electronic Lab Notebooks and Reaxys. Finally, we illustrate how this SMARTS library can be applied to guide building-block selection from commercial catalogues. A public GitHub repository has been created aiming for a continuous improvement of the current SMARTS_RX.