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A systematic study for optimizing yield and purity of so-called difficult sequences using oxyma/DIC as first choice cheap coupling agent.Morpholine/DBU are identified as preferred deprotection agents over other reagents commonly used in solid phase peptide synthesis.Collidine is identified as preferred base over other organic bases commonly used in solid phase synthesis of strongly aggregating peptides.Persisted vortexing during the coupling steps has a role in improving yield and purity of difficult peptides.Solid-Phase Peptide Synthesis (SPPS) is a rapid and efficient methodology for the chemical synthesis of peptides and small proteins. However, the assembly of peptide sequences classified as “difficult” poses severe synthetic problems in SPPS for the occurrence of extensive aggregation of growing peptide chains which often leads to synthesis failure. In this framework, we have investigated the impact of different synthetic procedures on the yield and final purity of three well-known “difficult peptides” prepared using oxyma as additive for the coupling steps. In particular, we have comparatively investigated the use of piperidine and morpholine/DBU as deprotection reagents, the addition of DIPEA, collidine and N-methylmorpholine as bases to the coupling reagent. Moreover, the effect of different agitation modalities during the acylation reactions has been investigated. Data obtained represent a step forward in optimizing strategies for the synthesis of “difficult peptides”.