The synthesis of complex molecules by palladium-catalyzed cross-coupling has been pivotal in all stages of drug discovery research. However, this approach has been generally restricted to classical aryl halide electrophiles, requiring the use of a limited pool of precursors. Herein, we report the first highly chemoselective approach to the cross-coupling of bench-stable C–O electrophiles in which abundant phenols can be systematically used as electrophilic cross-coupling partners. Using this approach, we have achieved late-stage functionalization of >20 pharmaceuticals covering various architectures and drug targets. Wingtip-flexible N-heterocyclic carbenes as ancillary ligands enable us to address the major challenges to this mode of catalysis, such as fast oxidative addition to prevent the hydrolysis of C–O electrophiles and facile reductive elimination to establish C–C bond formation in complex settings. The design of wingtip-flexible N-heterocyclic carbene ligands will enable the cross-coupling of a broad range of electrophiles for the development of important medicines.