2-Alkoxy/thioalkoxy benzo-[d]-imidazole and 2-thione benzo-[d]-imidazole libraries were constructed in solution phase and on solid phase, respectively. The key step in this work is the phase-based chemoselective reaction of the 2-mercaptobenzo-[d]-imidazole intermediate with benzyl chloride (solution phase) and Merrifield resin (solid phase). In the solution-phase case, benzyl chloride reacted with the thiol group of 2-mercaptobenzo-[d]-imidazole, whereas in the solid-phase case, Merrifield resin was introduced at an internal amine group of benzo-[d]-imidazole. To afford the desired 2-alkoxy/thioalkoxy benzo-[d]-imidazole analogues, we used various alkyl halides, alcohols, and thiols in solution phase, and to obtain 2-thione benzo-[d]-imidazole derivatives on solid phase, we used diverse alkyl halides and boronic acids. Finally, to measure the drug potential to be orally active and the molecular diversity in three-dimensional (3D) space, we calculated physicochemical properties and displayed energy-minimized 3D structures. As a result, the libraries from solution phase and solid phase show distinct features in physicochemical properties and skeletal diversities in 3D space.

An efficient solid‐phase methodology has been developed for the synthesis of N‐acyl and N‐sulfonyl substituted 2‐aminobenzo[d][1,3]thiazine derivatives. The key step in this methodology is the preparation of backbone amide linker‐bound 2‐aminobenzo[d][1,3]thiazine resin through cyclization reaction between isothiocyanates and BOMBA resin under microwave irradiation. This 2‐aminobenzo[d][1,3]thiazine core skeleton resin undergoes substitution reactions with various electrophiles, such as acid halides and sulfonyl halides, to generate N‐acyl and N‐sulfonyl substituted 2‐aminobenzo[d][1,3]thiazine resins, respectively. Finally, N‐acyl and N‐sulfonyl‐substituted 2‐aminobenzo[d][1,3]thiazine derivatives are prepared in good yields and purities by cleavage of the respective resins under trifluoroacetic acid (TFA) in dichloromethane (DCM).