Herein, we present an unprecedented azine-limited C5-H polyfluoroarylation of 2-aminopyridines enabled by a transient and electron-deficient perfluoroaryl-Pd species via C-H/C-H coupling. The protocol further allows C3(5)-H polyfluoroarylation of 2-alkoxypyridines guided by sterics and electronics for the first time. The late-stage C-H functionalization of drugs, drug derivatives, and natural product derivatives and synthesis of C5-aryl drug derivatives further demonstrated the method's utility. The preliminary mechanistic studies reveal that the synergistic combination of the bulky yet electrophilic perfluoroaryl-Pd species and the partial nucleophilicity of the C5-position of 2-amino/alkoxy-pyridines is the origin of reactivity and selectivity. Importantly, the first experimental evidence for the role of diisopropyl sulfide is provided.