Abstract
<title>Abstract</title> <p>Skeletal editing has emerged as a powerful strategy for atom-precise molecular remodeling, yet pyridine-to-benzene editing remains largely limited to single-atom exchange, restricting structural diversification. Here, we report a programmable deconstruction–reconstruction strategy that converts pyridines into structurally diverse multisubstituted benzenes through single-atom and atom-pair skeletal editing. Controlled pyridine deconstruction followed by programmable reconstruction enables a formal (5 + 1) annulation to access nitrobenzenes, anilines, and nitroanilines, with product identity dictated by the nitroalkane coupling partner. In a complementary pathway, interception of a pyridine-derived diene intermediate enables atom-pair skeletal editing to furnish multi-substituted benzaldehydes and naphthaldehydes. Both transformations proceed under operationally simple conditions, exhibit broad substrate scope, and enable the direct installation of synthetically versatile nitro, amino, and aldehyde functionalities in substitution patterns difficult to access by conventional aromatic functionalization. The strategy is further demonstrated by the late-stage skeletal editing of pyridine-containing pharmaceuticals and bioactive amines, providing a general platform for the programmable synthesis of multisubstituted benzenes from abundant pyridines.</p>