As the field of single-atom skeletal editing has evolved, a key question has emerged: which singleatom transformations would be the most impactful if developed? We have sought to answer this question by employing computational tools to screen virtual chemical space for the novelty and diversity introduced by single-atom transformations. Advances in software and hardware over the last decade have enabled researchers to navigate virtual chemical spaces containing billions of structures that can be made on demand using cheminformatics. Virtual comparative analysis can identify areas of chemical space that are currently inaccessible or underexplored. This may assist in the identification of synthetic challenges and opportunities for reaction development that could provide access to these unique structural motifs. Indeed, the use of computational tools is closely linked to the development of new synthetic methodologies as well as the discovery and optimization of biologically active compounds. To the best of our knowledge, there has been no quantitative analysis of the potential impact that a given skeletal edit may have on accessible chemical space. Powerful methods for skeletal editing of saturated heterocycles and carbocycles have emerged; however, the majority of recently developed skeletal editing reactions focus on aromatic heterocycles (i.e., heteroarenes). Because of the complimentary prevalence of heteroarenes in FDA-approved drugs, we sought to develop a cheminformatic platform to analyze the potential impact of "virtual" skeletal edits by evaluating the number of unknown molecules generated when both single-atom and multi-atom skeletal transformations are applied to the most prevalent heteroaromatic motifs in pharmaceutical compounds. This platform enabled us to identify transformations for converting one heteroaromatic unit to another that would most greatly increase commercially accessible chemical space if developed. Methods. We extracted molecules containing eleven distinct heteroaromatic rings from the Enamine 350/3 lead-like library, a subset of the REAL database containing over 613 million synthetically feasible molecules. In total, over 275 million of the 613 million molecules contain at least one of the eleven heteroaromatic motifs we extracted. We selected these heteroaromatic cores (shown in Figure ) because of their prevalence in FDA-approved drug molecules. Compounds containing fused heteroaromatic rings were also included; for example, quinolines and aza-indoles were classified as pyridines, quinazolines were classified as pyrimidines, indoles were classified as pyrroles, etc. The ring-fusion element of benzo-fused heteroaromatics was maintained throughout each virtual skeletal edit transformation (i.e., the fusing carbon atoms were excluded as viable points of transformation). The same extraction protocol was also applied to the Mcule and ChEMBL databases, which feature purchasable molecules designed for screening against biological targets. Notably, the ChEMBL database of bioactive molecules is manually curated to suit this purpose. The heteroaromatics analyzed, as well as the percentages of the total dataset they represent in each database, are shown in Figure .