Recent advances have made possible the replacement of individual atoms within a molecular skeleton while preserving the integrity of the surrounding framework. These skeletal editing reactions are emerging as powerful tools for molecular optimization, as they directly mirror tactics central to structure–activity-relationship studies and therefore have the potential to accelerate progress in discovery chemistry settings. This review introduces a comprehensive framework for categorizing atom replacement reactions in aromatic systems, while also delineating strategies that enable these transformations. Important heuristics related to shape-conservation are discussed, including notions of skeletal rotation, introduction of vestigial substituents, and retrosynthetic simplicity. Examples of reactions which obey these principles are analyzed, focusing first on C-to-N replacement in aromatic systems (“benzene to pyridine” and related reactions) before moving to other classes of aromatic and aliphatic replacement reactions.

Pairs of heterocycles differing by a single constitutive ring atom can exhibit stark differences in the retrosynthetic disconnections available for their preparation. Such a synthesis gap is exemplifi...