Overall, transformations involving multi-atom changes to the heteroaromatic core give, on average, the lowest percentages of characterized products (Figure ) and larger percentages of novel compounds (Figure ). Therefore, these multi-atom transformations would be characterized as highly impactful on commercially accessible chemical space. However, single-atom changes to the heteroaromatic core are logical from a retrosynthetic standpoint, and the precision associated with single-atom skeletal edits make them highly valuable in the context of drug discovery. A modified heatmap containing only single-atom changes is shown in Figure . If we only analyze transformations involving single-atom changes to the starting heteroaromatic unit, the pyrimidineto-imidazole conversion (a single carbon deletion) emerges as the leading transformation for accessing novel chemical space (only 11.8% known). Interestingly, the opposite of this transformation -the imidazole-to-pyrimidine ring expansion -follows closely, with only 18% of the products having been previously characterized. The analogous pyrimidine-to-pyrrole transformation (a nitrogen deletion from the pyrimidine core) gives similarly few known products (17%). As such, the development of new methodologies for these deceptively simple transformations would most meaningfully impact late-stage access to novel chemical space. The result of this analysis, taken together with the large percentage of new compounds generated through these transformations (shown in Figure ) highlights the importance of continued development of skeletal editing methods focused on the pyridine and pyrimidine heterocycles. Finally, atom transmutations of the thiazole heterocycle to give pyrroles or imidazoles by either sulfur-to-carbon or sulfur-to-nitrogen exchanges also give low percentages (13% and 14%, respectively) of characterized products and would therefore be impactful. More generally, both ring contracting and ring expanding transformations for simple nitrogen-containing heteroaromatics lead to relatively few characterized compounds (9-34%). As mentioned previously, ring contracting and expanding transformations of these types of heteroaromatics give products with the highest percentages of uncharacterized compounds (Figure ).