In detail, the Enamine REAL database of 4.5 B compounds was searched for similarity to designed molecules through the public interface to SmallWorld , using a graph-edit-distance space search. At each cycle, 100 new, top-scoring compounds were searched, and up to 100 of the most similar compounds from the REAL database were extracted per search query (using a maximum distance of 5 steps). This 10 K compound set was filtered for substructure match with the core using RDKit, and those compounds that passed were added to the active learning search space. Active learning then selects compounds for scoring following Enamine enrichment, as usual, but there is no explicit bias to select compounds from the on-demand catalogue.