AbstractThe solid‐phase synthesis of cyclic lipopeptidotriazoles derived from the cyclic decapeptide c(Lys‐Lys2‐Leu‐Lys‐Lys5‐Phe‐Lys‐Lys‐Leu‐Gln) (BPC194), incorporating a triazolyl ring at Lys2 and a hexanoyl group at Lys5, was studied. Four different strategies that required the use of five orthogonal protecting groups (Fmoc, tBu, All, pNZ, ivDde) were explored. The influence of the side‐chain protection of Lys2 and Lys5 with the ivDde and pNZ groups was evaluated by incorporating Lys2(ivDde)/Lys5(pNZ) or Lys2(pNZ)/Lys5(ivDde). The order of removal of these protecting groups and of the introduction of the hexanoyl and triazolyl moieties was also studied. The best strategy included: (i) synthesis of a cyclic peptidyl resin bearing Lys2(ivDde) and Lys5(pNZ); (ii) pNZ group removal; (iii) acylation with hexanoic acid; (iv) ivDde group removal; and (v) acylation with propiolic acid followed by an azide–alkyne 1,3‐dipolar cycloaddition. By using this protocol, a set of cyclic lipopeptidotriazoles was prepared in high purities.