Residue-specific reactions that enable the site-selective incorporation of artificial units into peptides/proteins have advanced research relevant to a variety of biological and biomedical disciplines that involve peptide/protein molecules. Such reactions include bioconjugations specific to cysteine (Cys) and tryptophan (Trp), which are both low in relative abundance in proteins. Typically, general bioconjugation reactions on Cys utilize alkylation of the nucleophilic thiol or metal-catalyzed coupling of the thiol with aryl halides. Umpolung strategies of the nucleophilic thiol have also become an alternative coupling format. In terms of Trp-modification, a variety of indole-selective reactions have been utilized that include transition metal-, metal carbenoid-, or radical-mediated reaction. The C-H sulfenylation of indole with electrophilic sulfenyl chlorides, such as S-chlorocysteine or its congener, represents an inter-residue selective conjugation between Trp and Cys residues, that requires the oxidative umpolung to the S-chlorocysteine using harmful chlorination agents such as sulfuryl chloride (SO2Cl2). Accordingly, these reactions are not compatible with the presence of Trp. Recently, we have developed inter-residue selective reactions between Cys and Trp residues. In these reactions, the S-p-methoxybenzyl or S-acetamidomethyl cysteine sulfoxide (Cys(MBzl)(O) or Cys(Acm)(O)) moieties are converted to the corresponding S-chlorocysteine under acidic conditions using trifluoroacetic acid (TFA) as solvent in the presence of guanidine hydrochloride (Gn•HCl) or diisopropylamine hydrochloride (DA•HCl). The resulting electrophilic species participate in aromatic electrophilic substitution (SEAr) reactions with indole to achieve the C-H sulfenylation of the Trp (Figure ). conversion to the S-chlorocysteine without affecting the indole ring of Trp. Consequently, this format allows intramolecular or intermolecular Cys-Trp linking in peptides. However, the use of TFA as a protein denaturant prevents the method from being applied to proteins. In our current work, we have achieved an alternative sulfoxide-mediated Cys-Trp conjugating condition that is applicable to a wide variety of proteins. Our investigation began by examining whether S-MBzl or S-Acm groups allow formation of S-chlorocysteine from the corresponding sulfoxide under less acidic conditions than TFA.