We next sought to explore the scope of scaffold chemical space that is suitable for covalent inhibition of classical tyrosine phosphatases. We selected chloroacetamide as our electrophilic warhead given its precedent in fragment electrophile screens and because the phenyl species showed sufficiently detectable phosphatase inhibition to build upon without the significant multi-site labeling seen for aryl vinyl sulfonates at physiological pH (Figure ). We constructed a small library containing 65 chloroacetamide-functionalized fragments bearing diverse aryl and alkyl substituents (Figure and Table ). These molecules were tested in the same pNPP dephosphorylation assay described above against seven classical human tyrosine phosphatases. Inhibition was assessed over a range of concentrations and time points to obtain timedependent IC50 values (Figure , Figure , and Table ,4). For select compounds, the presence of active site labeling in the phosphatase HePTP was corroborated by LC/MS/MS (Figure ).