Collectively, these results demonstrate that SF reactive fragment screening offers an efficient approach for the discovery of 'beyond-cysteine' covalent ligands. The HTC-D2B approach enables rapid iterative design-maketest cycles to drive toward more potent and selective chemical tools. This HTC-D2B workflow facilitates the exploration of alternative SF groups as the reactive moiety, which can be exploited to reduce the intrinsic reactivity, and thus promiscuity, of the fragments, while simultaneously optimising kinact and KI for the target of interest. This will support the development of covalent chemical probes to expand the liganded proteome, and ultimately, further our understanding of disease biology.