The Cook–Heilbron thiazole synthesis highlights the formation of 5-aminothiazoles through the chemical reaction of α-aminonitriles or aminocynoacetates with dithioacids, carbon disulphide, carbon oxysulfide, or isothiocynates at room temperature and under mild or aqueous conditions. Variation of substituents at the 2nd and 4th position of the thiazole is introduced by selecting different combinations of starting reagents. This reaction was first discovered in 1947 by Alan H. Cook, Sir Ian Heilbron, and A.L Levy, and marks one of the first examples of 5-aminothiazole synthesis with significant yield and diversity in scope. Prior to their discovery, 5-aminothiazoles were a relatively unknown class of compounds, but were of synthetic interest and utility. Their premier publication illustrated the formation of 5-amino-2-benzylthiazole and 5-amino-4-carbethoxy-2-benzylthiazole by reacting dithiophenylacetic acid with aminoacetonitrile and ethyl aminocyanoacetate, respectively. Subsequent experiments by Cook and Heilbron, detailed in their series of publications titled “Studies in the Azole Series” describe early attempts to expand the scope of 5-aminothiazole synthesis, as well as employ 5-aminothiazoles in the formation of purines and pyridines. Mechanism In the first step of the reaction mechanism for the synthesis of a 5-aminothiazole from an α-aminonitrile and carbon disulphide, a lone pair on the nitrogen of the α-aminonitrile performs a nucleophilic attack on the slightly electropositive carbon of carbondisulfide. This addition reaction pushes electrons from the carbon-sulfur double bond onto one of the sulfur atoms. Acting as a Lewis Base, the sulfur atom donates its electrons to the carbon atom of the nitrile, forming a sulfur-carbon sigma bond in an intramolecular 5-exo-dig cyclization. This cyclization forms a 5-imino-2-thione thiazolidine compound that undergoes a tautomerization when a base, such as water, abstracts the hydrogens at positions 3 and 4. The electrons from the carbon-hydrogen sigma bond are pushed back into the thiazole ring, forming two new double bonds with the adjacent carbon atoms, and catalyzing the formation of two new nitrogen-hydrogen, and sulfur-hydrogen sigma bonds. This tautomerization occurs because it is thermodynamically favourable, yielding the aromatic final product: 5-aminothiazole. Applications Few instances of applications of the Cook–Heilbron thiazole synthesis are found in literature. In recent years, modifications of the Hantzsch thiazole synthesis are the most common, partly because of its ease in introducing R- group diversity. However, in 2008 Scott et al. employed a Cook-Heilbron synthesis in their approach to synthesize novel of pyridyl and thiazoyl bisamide CSF-1R inhibitors for use in novel cancer therapeutics. A couple of the compounds that