NGT efficiently balances exploration and exploitation of ultra-large chemical spaces owing to the mass-covering design of its normalizing flow. For CDK5, NGT found 222,576 compounds satisfying the bioactivity and potency constraints compared to 191,551 compounds for HE (Table ). For the more challenging target ASAH1, NGT found 135,272 compounds, compared to just 24,951 for HE. The NGT constraint-satisfying compounds represent significantly more unique reactions and synthons at each position than those found by HE, with the exception of synthons unique to the 4-component reaction, suggesting HE takes a greedier approach (Figure ). To compare the extent of chemical space covered by both methods, we compared Tanimoto distances for compounds from both methods, visualized with a 2D Uniform Manifold Approximation and Projection (UMAP Fig ). The 2D distributions of compounds suggest that NGT compounds were widely distributed throughout chemical space whereas HE compounds tended to cluster. We attribute mild enrichment of the stratified random selection to the fact that a stratified sample is diverse and that caps of the MEL likely fail to form favorable interactions with the receptor.