On average, transformations which convert any of the other heteroaromatics to pyridazines generate the greatest percentage of unknown compounds. This result underscores the fact that pyridazines are generally difficult to access and are only sparsely represented in pharmaceutical libraries. The difficulty associated with the synthesis of pyridazines is reflected in the relatively low number of commercially available pyridazine-containing molecules, leading to the high number of new compounds generated in these transformations. Since pyridazines are poorly represented in FDA-approved drugs (see the low prevalence of pyridazines in Figure ), the high degree to which transformations that generate uncharacterized pyridazine heterocycles should be considered in this context. In general, skeletal edits of pyridine give rise to the greatest percentages of uncharacterized compounds. In contrast, transformations that convert other heteroaromatics into pyridines give the lowest percentage of uncharacterized compounds. Additionally, both ring-expansions (e.g., pyrrole-to-pyrimidine) and ring-contractions (e.g., pyridine-to-pyrrole) of nitrogen heteroaromatics lead to high percentages (>80%) of previously uncharacterized structures. However, the percentage of the generated products that are uncharacterized is generally higher for ring-contracting transformations than for ring-expanding variants. Overall, this trend is consistent for each of the datasets; however, the Mcule and ChEMBL databases are much smaller than the Enamine database. Therefore, when using the Mcule or ChEMBL databases, transformations that generate heteroaromatics that are less represented are likely to be skewed toward a higher percentage of new compounds because there are fewer compounds represented in these databases.