For the 2997 small molecule structures, we find 261 exact hits, and 721 substructure hits in the Enamine REAL space. On our 8 threads test setup, 90 % of the queries finished in less than 0.5 seconds (see Fig. ). There are a few queries that take several seconds. We found two main reasons for longer query times. Structures that contain long alkyl chains are problematic, as they give rise to a large number of decompositions that cannot be rejected by the connector neighborhood heuristic. Simple structures that contain very few functional groups can be problematic, as in certain cases they lead to unspecific synthon substructures, resulting in large number of actual substructure searches due to the fact that fingerprint filtering of synthons is not efficient. However, in these cases it is usually possible to signif- Green highlighted atoms indicate that an additional neighbor is required. Total Hits is the number of synthon sets that create matching structures (non-unique). Time [ms] is the time in milliseconds that this search took on our 8 core test setup. FragFP Bits is the number of bits for the query structure in the OpenChemLib fragment fingerprint. Valid splits is the number of splits that have to be considered. Split/Rxn Pairs is the number of pairs of synthon reactions and cut sets that survive the connector region heuristic. Labeled splits is the total number of labeled splits that survived the largest fragment heuristic. Substructure Searches is the total number of substructure searches (labeled split fragments vs. synthons) that were performed (before fingerprint filtering, usually, the very large majority of these substructure searches will be done by fingerprint filtering).