Here we describe ageneral method for the synthesis of 2,5-diaminoimidazoles,w hichi nvolves at hermal reaction between a-aminoketones and substituted guanylhydrazines without the need for additives.Asone of the few knownwaysto access the 2,5-diaminoimidazole motif,o ur method greatly expands the number of reported diaminoimidazoles and further supports our previous observations that these compounds spontaneously adopt the non-aromatic 4(H) tautomer. The reaction works successfully on both cyclic and acyclic amino ketone starting materials,a sw ell as ar ange of substituted guanylhydrazines.F ollowing optimization, the method was applied to the efficient synthesis of the advanced glycation end product (AGE) methylglyoxal-derived imidazolium crosslink (MODIC). We expect that this method will enable rapid access to av ariety of biologically important 2,5diaminoimidazole-containing products.