Recent Synthetic Methodologies in C–H Activation/Functionalization for Drug‐Oriented Molecular Design: From Transition Metals to Metal‐Free Methodologies

Molecular designs of new medicines often depend on building molecules with the active pharmacophores. Among modern methods, C–H activation has become a powerful technique because it allows chemists to directly change carbon–hydrogen bonds into useful functional groups. This strategy avoids the need for pre‐functionalization, shows broad tolerance to different functional groups, and enables late‐stage functionalization of bioactive scaffolds. Such advantages make it highly significant for synthesizing diverse molecules, improving medicinal characteristics, and designing molecules for applications such as fluorescent labeling or metabolite studies in preclinical research. Although C–H functionalization has been widely explored for making heterocycles and employing late‐stage transformations, there has been no comprehensive summary focused on its role in drug discovery and development. In this review, we highlight recent progress in key areas, including annulation cascades, cross‐coupling (sp 2 –sp 2 /sp 2 –sp 3 ), C–H arylation, amination of N ‐heterocycles, fluorination, alkenylation, C–H allylation, peptide modification, and photochemical as well as metal‐free approaches. In the future, these strategies will expand the toolbox for designing and optimizing complex molecules with improved therapeutic potential.