Aiming at advancing protocols for safer, environmentally sensible peptide synthesis we report our findings with regard to the occurrence of hydrogen cyanide (HCN, prussic acid) in amide bond-forming reactions mediated by diisopropylcarbodiimide (DIC) and Et (hydroxyimino)cyanoacetate (Oxyma). We determined that HCN is always formed in amide bond-forming reactions on solid support in N,N-dimethylformamide (DMF) when DIC/Oxyma is employed. In an attempt to minimize the formation of prussic acid by means of preventing the linear DIC/Oxyma adduct 2 from cyclizing to oxadiazole 3 and in turn releasing HCN, we evaluated a series of greener solvents such as N-butylpyrrolidinone (NBP), NBP/ethyl acetate (EtOAc, 1:1), Me 5-(dimethylamino)-2-methyl-5-oxopentanoate (PolarClean, PC), and PC/EtOAc (1:1). We found that the ratio between 2 and 3 greatly depends on the solvent used, and consequently, we further examined DMF, NBP, NBP/EtOAc (1:1), and NBP/EtOAc (1:4) as solvents for DIC/Oxyma-mediated amidations on solid support and in solution We found that using carboxylic acid/Oxyma/DIC in a 1:1:1 ratio the rate of HCN formation decreases in the following order DMF > NBP > NBP/EtOAc (1:1) > NBP/EtOAc (1:4), while the reaction rate increases in the order of DMF ≈ NBP < NBP/EtOAc (1:1) < NBP/EtOAc (1:4). Of the solvents examined, the NBP/EtOAc (1:4) mixture gave the lowest rate of HCN formation and the highest rate of amide bond formation both in solution and on solid support. As altering the solvent for DIC/Oxyma-mediated amidations resulted in suppressing HCN rather than its full elimination we evaluated the concept of in situ scavenging of the HCN formed. We performed DIC/Oxyma-mediated amidation of Fmoc-Gly-OH + (S)-(-)-1-phenylethylamine (Fmoc = 9-fluorenylmethoxycarbonyl) in deuterated DMF with 0, 5, and 10 equiv of di-Me trisulfide (DMTS) as HCN scavenger. The formation of HCN and rate of amidation was monitored by 1H NMR, revealing that DMTS scavenges HCN without inhibiting the rate of amidation. DIC/Oxyma-mediated amidations of Fmoc-Ser(t-Bu)-OH with (S)-(-)-1-phenylethylamine in DMF and NBP/EtOAc (1:4) with and without 10 equiv of DMTS were performed and found to be comparable.