Searching the Enamine REAL space -A small molecule queries benchmark For testing and benchmarking internally we use a set of 2977 small molecule structures collected from DrugCentral. We consider only compounds containing in between 12 and 32 non-H atoms, because this seems to cover most realistic substructure searches (smaller substructures may lead to excessive amounts of results, for larger compounds it becomes increasingly unlikely to find hits). We further exclude structures containing alkylic chains of more than ten unsubstituted carbon atoms as this for certain molecules leads to rather long runtimes and because we do not consider these searches as very relevant. We ran all tests on a 6 core (12 threads) Intel Core i7-7800X at 3.5 GHz with 64 GB of RAM, and we run the queries parallelized using 8 threads. For each structure we consider two different searches: