After reductive amination, the desired intermediate 42t was obtained and, in turn, O-methylated in the presence of cesium carbonate to yield 42u, a second required intermediate. Both RHS fragments were applied to finalize VHL ligands 20 and 21 (Table ). An alternative attempt to prepare 42t from 51 by a formylation-reductive amination-Heck coupling sequence was not successful (Scheme S2). Overall, except for four substitution patterns (Scheme S2), most of the envisaged first-series VHL ligands were successfully synthesized.