Alkylating agents for nucleic acids have been widely used in cancer chemotherapy, as well as in chemical biology for strong inhibitors and tagging methods. We provide a series of reactive OFF–ON type alkylating agents which enable the reactivity modulation toward G-quadruplex (G4) DNA and RNA. Due to the protonation-accelerated process and equilibrium elimination method, the amine leaving groups show highly reactive and storable properties in an extensive investigation of vinyl quinazolinone (VQ) precursors with different leaving groups.