PROTAC hit identification remains predominantly empirical and every project requires a bespoke screening library at the outset. Recently, high-throughput "Direct-to-Biology" (D2B) approaches have made progress in addressing this challenge . In the main this has been approached by constructing pre-conjugated E3 ligase ligand-linker building blocks and then enabling a single, plate-based, high conversion reaction to attach a protein of interest ligand, with testing of crude mixtures directly in cellular degradation assays. Whilst these platforms significantly accelerate PROTAC discovery and structure-activity-relationship (SAR) exploration, early efforts relied predominantly on amide coupling 6,8,9 , resulting in an inevitable influence on the property space of the resulting libraries, for example by often introducing redundant hydrogen bond donors (HBDs) that can limit cellular or tissue permeability. Recently, towards addressing this gap, Stevens et al. introduced a broader set of medicinal chemistry transformations for D2B PROTAC generation, including reductive amination, SNAr, palladium-mediated cross-coupling, and alkylation 11 . In addition, Roberts et al. had previously used formation of acyl hydrazones to generate a library of nearly 100 Estrogen Receptor PROTACs 5 . Despite significant progress, the requirement for the synthesis and purification of significant numbers of pre-conjugated intermediates reduces agility when wishing to vary all three components of E3 ligand, linker or POI ligand in a given library set-up.