In 1963, Merrifield introduced Cto N-solid-phase peptide synthesis (C-N-SPPS, Scheme 1). After nitration of cross-linked polystyrene 1, tetrapeptide 10 was prepared using sequential carbodiimide couplings and deprotections of N-benzyloxycarbonyl-(Cbz-)protected amino acids with strong acid. Saponification was finally used to cleave the resin. Scheme 1. Merrifield Cto N-direction solid phase peptide synthesis