Skeletal Editing from Pyridine to Aniline via <i>C</i> ‐Insertion and <i>N‐</i> Isomerization

Pyridine is a prevalent structural motif in drug molecules, and modifying the pyridine core is a widely utilized strategy for lead optimization in drug discovery. Nitrogen scanning systematically evaluates the effects of varying the nitrogen position within pyridyl isomers, including the extension of the nitrogen atom one or two bonds outside the ring, often resulting in anilines or benzonitriles. This strategy aims to bring the hydrogen‐bonding site closer to the target protein, which can lead to substantial improvements in binding activity. In this study, a synthetic strategy is presented that transforms pyridines into anilines, with the original pyridine nitrogen atom externalized at either the ipso or ortho position. The approach employs a carbene insertion step prior to nitrogen isomerization, preserving the ring size and structural integrity throughout the transformation. This method demonstrates broad applicability, enabling the late‐stage functionalization of a variety of natural products and pharmaceutical agents, and underscores its versatility and potential in drug discovery applications.