We devised a modular scheme for the synthesis of cyanoacrylamide-based PROTACs (see methods and SI). Using this route, we synthesized a series of 12 reversible covalent PROTACs targeting Cysteine 481 in BTK (Supp. Table ). These are based on the scaffold of the covalent BTK binder -Ibrutinib -as the protein targeting moiety , and PEG-based linkers with varying length (Fig. ). We used two approaches: in the first, we synthesized an alkynefunctionalized BTK-binding cyanoacrylamide and an amine-functionalized E3 binder, and linked them in one-pot reactions using azide-PEG-NHS esters of varying lengths. In the second approach, we directly functionalized thalidomide with various PEGs and formed the cyanoacrylamide in a final condensation step.