The late-stage functionalization (LSF) of pharmaceutical and agrochemical compounds by the site-selective activation of C-H bonds offers immediate access to diverse structural analogs and expands the accessible chemical space. We report an C-H functionalization LSF strategy that hinges on the use of an alkyne linchpin to assemble conjugates of sp2-rich marketed pharmaceuticals and agrochemicals with sp3-rich 3D-fragments and natural products. This is accomplished through a template-assisted inverse Sonogashira reaction that displays high levels of selectivity for the meta-position. This protocol is also amenable to distal structural modifications of a-amino acids. The transformation of alkyne functionality to other functional groups further highlights the applicative potential. Computational and experimental mechanistic studies shed light on the detailed mechanism. Turnover-limiting 1,2-migratory insertion of the bromoalkyne coupling partner occurs after relatively fast C-H activation. While this insertion occurs unselectively, regioconvergence results from one of the adducts undergoing a 1,2-trialkylsilyl migration to form the alkynylated product. A heterobimetallic Pd–Ag TS, which is essential for product formation, is explicitly implicated in the β-bromide elimination step.