With an increased emphasis on macrocyclic peptides for drug discovery, we have focused on addressing common synthetic challenges in the preparation of these complex, BRo5 molecules. With a focus on excellence in chemistry, we have been developing 96- and 384-wellplate based, on-resin HTE workflows that enable reaction screening and library synthesis. These approaches deliver crude compounds of high product purity that are suitable for biological screening in DtB format. We have also extended these workflows to enable chemical modification of sidechain residues directly in the growing peptide chain, greatly expanding diversity and avoiding the need for custom building block synthesis.