Herein, we discover the new reactivity of the 1,3,5-triazine moiety reacting with a phenol group and report the development of biocompatible and catalyst-free triazine-pyridine chemistry (TPC) for tyrosine labelling under physiological conditions and profiling in the whole proteome. TPC exhibited high tyrosine chemoselectivity in biological systems after cysteine blocking, displayed potential in tyrosine-guided protein labelling, and had bio-compatibility in live cells.