To synthesise linkers which would enable orthogonal trifunctionality, we adapted the approach seen in Scheme 1 and previously reported to make the linker for SIM1. 11 The linker design consisted of the following functionalities: a carboxylic acid, to allow for facile amide coupling to VHL ligands; an amine masked as an azide, to enable future SNAr attachment to thalidomide; an alcohol protected by an acid labile acetal, to allow for esterification to JQ1, and also to allow for mesylation and subsequent nucleophilic substitution of piperazine substituted derivatives of thalidomide (Scheme 2). To make linkers which would ultimately result in a primary alcohol required for later esterification to JQ1, acetal protecting groups, methoxyethoxymethyl (MEM) and methoxymethyl (MOM), were selected to mask the alcohol functionality. Firstly, triethylene and diethylene To build the trifunctional scaffold, diol 5 was carefully deprotonated using 1.2 eq. of sodium hydride at 0°C in DMF, before addition of azido mesylates 6 and 7 with heating at 60°C to yield mono-alkylated products 41 and 42, respectively. This alkylation step was repeated by deprotonation of the alcohols of 41 and 42, using 1.5 eq. of sodium hydride at 0°C, before heating to 60°C with acetal-protected mesylates 40 and 39