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Heteroaromatics are the basis for many pharmaceuticals. The ability to modify these structures through selective core-atom transformations, or “skeletal edits”, can dramatically expand the landscape for drug discovery and development. However, despite the importance of core-atom modifications, the quantitative impact of such transformations on accessible chemical space remains undefined. Here, we report a cheminformatic platform to analyze which skeletal edits would most increase access to novel chemical space. This study underscores the significance of emerging single and multiple core-atom transformations of heteroaromatics in enhancing chemical diversity, for example, at a late-stage of a drug discovery campaign. Our findings provide a quantitative framework for prioritizing core-atom modifications in heteroaromatic structural motifs, calling for the development of new methods to achieve these types of transformations.