The pyridine-enabled cross dehydrogenative coupling of sp² C–H bonds of polyfluoroarenes and unactivated sp³ C–H bonds of amides was achieved via a copper-promoted process with good functional group compatibility. This reaction showed great site-selectivity by favoring the sp² C–H bonds ortho to two fluoro atoms of arenes and the sp³ C–H bonds of α-methyl groups over those of the α-methylene, β- or γ-methyl groups of the aliphatic amides. Mechanistic studies revealed that sp³ C–H bond cleavage is an irreversible but not the rate-determining step, and the sp² C–H functionalization of arenes appears precedent to the sp³ C–H functionalization of amides in this process.