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Protein α-N-terminal dimethylation (Nme 2 ) is an underexplored posttranslational modification (PTM) despite the increasing implications of α-N-terminal dimethylation in vital physiological and pathological processes across diverse species; thus, it is imperative to identify the sites of α-N-terminal dimethylation in the proteome. So far, only ∼300 α-N-terminal methylation sites have been discovered including mono-, di-, and tri-methylation, due to the lack of a pan-selective method for detecting α-N-terminal dimethylation. Herein, we introduce the three-component coupling reaction, oxidative nitrile thiazolidination (OxNiTha) for chemoselective modification of α-Nme 2 to thiazolidine ring in the presence of selectfluor, sodium cyanide, and 1,2 aminothiols. One of the major challenges in developing a pan-specific method for the selective modification of α-Nme 2 PTM is the competing reaction with dimethyl lysine (Kme 2 ) PTM of a similar structure. We tackle this challenge by trapping nitrile-modified Nme 2 with aminothiols, leading to the conversion of Nme 2 to a five-membered thiazolidine ring. Surprisingly, the 1,2 aminothiol reaction with nitrile-modified Kme 2 led to de-nitrilation along with the de-methylation to generate monomethyl lysine (Kme 1 ). We demonstrated the application of OxNiTha reaction in pan-selective and robust modification of α-Nme 2 in peptides and proteins to thiazolidine functionalized with varying fluorescent and affinity tags under physiological conditions. Further study with cell lysate enabled the enrichment of Nme 2 PTM containing proteins.