However, the generic Murcko scaffolds and SCINS (Table ) are a lot less diverse. While keeping the reaction type the same, a change in atom types in the building blocks with the same topological connectivity leads to a different Murcko scaffold, but the same generic Murcko scaffold and SCINS (Supplementary Figure ). Changing the size of a ring and/or the connectivity pattern between rings and chains further changes the generic Murcko scaffold, but the SCINS remains in most cases unchanged because it neglects topology and ring size (Supplementary Figure ). Therefore, the combinatorial element in the building strategy that On the other hand, ChEMBL is not restricted by a defined set of reactions and building blocks, but rather covers literature-reported usually biologically active compounds. In contrast to Enamine REAL, this results in a much larger SCINS space covered. However, this is sparsely populated as indicated by the lower average number of compounds, Murcko and generic Murcko scaffolds per SCINS class. This is further supported by Supplementary Figure and Supplementary Figure , which show that the population of SCINS classes is highly skewed towards sparsely populated classes, unlike in the case of Enamine Diverse, where this distribution is relatively more even. For example, a small number of macrocyclic compounds (25,070) corresponds to a substantial number of SCINS classes (1,609), whereas Enamine REAL Diverse contains no macrocycles. Hence, a significant portion of ChEMBL SCINS space is sparsely populated when considering the number of distinct structures per SCINS.