Project Abstract This proposal concerns the development of new reagents and strategies for the preparation of basic, aromatic, nitrogenous heterocycles through single-atom insertion reactions. The medicinal importance of such structures (pyridines, pyrimidines, pyridazines) is difficult to overstate – of the thirty new small molecule drugs approved in 2019, ten of them contain one or more of these motifs and their prevalence among medicinally-relevant compounds is a long-standing trend. This privileged status has prompted the development of a variety of synthetic strategies for their preparation, which can largely be subdivided into de novo assembly of the heteroaromatic nucleus (typically condensations), and attachment of preformed heteroarenes via cross-coupling and nucleophilic aromatic substitution approaches. These strategies have enabled the proliferation of such compounds for wide-ranging medicinal applications, but their implementation is nonetheless far from trivial, necessitating the continuing development of novel strategies. A conceptual mid-point exists between de novo synthesis and attachment wherein one heterocyclic structure is converted into another. Such an approach has limited historical precedent but holds substantial promise due to the orthogonal reactivity preferences (e.g. nucleophilic vs. electrophilic) and reaction compatibility of 5- vs. 6- membered heterocycles. We propose herein a set of reagents which will enable such transformations to be realized in a synthetically straightforward manner. Our focus on single-atom changes is calculated: rearrangement reactions, though lauded, are rarely employed in synthesis due to their retrosynthetic complexity. By developing transformations that are easy to recognize in a retrosynthetic sense (e.g. “remove this nitrogen atom”) we hope to provide user-friendly tools for medicinal chemists to employ. Moreover, the ability to transform pyrroles, pyrazoles, and imidazoles into a variety of 6-membered ring heterocycles feeds naturally into late-stage skeletal editing of pharmaceuticals, allowing diversification of bioactive scaffolds for more efficient structure- activity relationship determination and for site-specific isotopic labeling. As such, successful realization of the goals enumerated herein will advance the ability for chemists to interrogate biological function of heteroaromatic compounds by affording a powerful new set of tools for their synthesis.