The constant search for new chemical entities to address unmet medical needs compels the continued invention of new molecular editing approaches to derivatize complex small molecules. Single atom changes in a molecule alter the electronic properties of the molecule without extensive accompanying structural changes and are known to dramatically alter its biological activity. However, methods that enable substitutions of atoms embedded in the carbon framework of a molecule remain sparse. Substitution of a single atom – “atom swapping” – in the core structure of a molecule, rather than on the periphery, is challenging to execute because it involves multiple bond- breaking and bond-forming events. The conventional approach for introducing single atom changes in a molecule is thus to re-design synthesis routes to access atom-swapped derivatives. We challenge this long-standing practice by presenting a general strategy for atom swapping that proceeds in two stages – oxidation and transition metal-catalyzed carbon-extrusion reactions. The proposed research encompasses carbon-to-oxygen and carbon-to-nitrogen substitutions, and the conversion of lactones to lactams or cycloalkenes. The key step in all the proposed transformations is a transition metal-catalyzed decarbonylation or decarboxylation reaction. We will focus our efforts on the discovery and development of catalysts that promote decarbonylation and decarboxylation reactions on core motifs native to natural products and pharmaceuticals. These proposed reactions require that the catalyst be able to: 1) activate inert amide or ester bonds yet promote challenging carbon-heteroatom reductive eliminations; and 2) undergo site-selective oxidative addition. To identify catalysts that fulfil both criteria, we will examine ligand effects in each step of the catalytic cycle to enable rational ligand design and optimization. We will then interface the newly developed catalytic systems with well-documented C- H oxidation and rearrangement reactions to directly modify the carbon framework of cyclic natural products and pharmaceuticals. Realization of the goals of this proposal will circumvent tedious de novo synthesis for a single atom change and bring to fruition a highly desired transformation in the pharmaceutical industry.