Amines, solution-phase combinatorial libraries

The earliest report of a solution-phase combinatorial library of small drug-like molecules was by Smith et al. [2], The reaction of 40 individual acid chlorides with an equimolar mixture of 40 nucleophiles (alcohols or amines) and of the individual nucleophiles with an equimolar mixture of the acid chlorides produced a library of 1600 amides and esters as pools of 40 compounds. The orthogonal design strategy determined that each possible product should appear in a unique pair of samples to allow the rapid identification of lead compounds after screening. 

The reaction of an a-haloketone with thiourea gives rise to the 2-aminothiazole. This reaction has been used in a combinatorial approach for the synthesis of libraries of 2-aminothiazoles in excellent yields and purities first in the solution phase <1996BML1409> and then on a solid support using Rink amide MBHA, glycyl-Rink amide MBHA, and reductively aminated ArgoGel MB-CHO resins (Scheme 55) <1998JOG196>. 

---