Preparation of the database was performed using MOE (2022.2). Washing, desalting, neutralising charges, and calculating the dominant protonation state were done using the builtin functions. Filtering unwanted substructures was performed with RDKit's Filter catalogue module using the PAINS, BRENK, NIH, and ZINC parameters. Enamine kindly provided the REAL Space S subset in annotated files. All molecules with a logP lower or equal to 3.5 and less than 26 heavy atoms (442 000 626 compounds) were transformed into a substructuresearchable database with OpenEye's OEChem toolkit, optimised for using SMARTS as queries. All putative fragments' number of substructure matches and the respective heavy atom counts were calculated by querying the databases using the OEChem toolkit again.