Figure depicts examples of cyclizations with small molecules, natural products, and commercial drugs under the optimized conditions with catalyst 2h and azeotropic removal of water. Simple 5-and 6membered heterocycles 5-9 were formed in excellent yields (68%-98%, Figure ). Similarly, substituted serine (10-12, 14), threonine (4, 13, 15) and cysteine (19) substrates were readily converted into their corresponding oxazoline and thiazoline heterocycles. Even azolines prone to facile epimerization such as conjugate (16) and di-phenyl (17) oxazolines could be formed with no loss of stereochemical integrity under the optimized conditions. The transformation of D-glucosamine hemiacetal represents a direct synthesis of a valuable glycosyl donor 18 that can be incorporated into chemoenzymatic synthesis of N-linked glycans. In some cases, more polar co-solvents such as 1,4-dioxane or PhCl were added to ensure full solubility of the substrates, but the inhibitory effects of potentially coordinating solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) on the reaction rates were significant, and these solvents were not pursued further. Taken together, the direct method offers an entry into a valuable class of heterocycles that can be converted into aromatic thia-or oxazoles, a structural motif that is relevant towards modification of bioactive natural products and commercial drugs. Several complex substrates for site-selective cyclodehydration are noteworthy of a detailed analysis (Figure ). Commercial amides such as bactericidal antibiotic florfenicol (20) and a gap-junction modulator tonabersat (21) represent a subset of substrates with one available site for amide activation. In the case of a small-molecule inhibitor of MEK1/2, pirmasertib, only the conjugated oxazoline 22 was formed. On the other hand, the reaction with chloramphenicol 41 represents a unique example demonstrating the control of regioselectivity in competing cyclodehydrations between alcohols in different steric arrangements resulting in a 2.3:1 ratio of 23 with the preference toward a more substituted oxazoline 23b derived from the secondary alcohol. We also note that compound 23b did not equilibrate under the reaction conditions in the absence of catalyst, but a 93:7 mixture of 23a:23b was formed upon heating 23a under the reaction conditions for 48 h. This suggests that isomerization is catalyzed by 2h and supports the notion that the cyclodehydration proceeds under the kinetic control. Other substrates with basic sites that may render the cyclization prohibitively slow such as aminonucleoside antibiotic puromycin (24) or HIV protease inhibitors indinavir (25) and lopinavir (26) underwent cyclodehydrations in consistently high yields. The reaction with paclitaxel (27), a potent anti-cancer agent, represents another extreme example of high regioselectivity and functional group compatibility in a substrate containing a number of potentially reactive functionalities prone to elimination such as esters, alcohols, and a strained oxetane ring that might react with Lewis acids. Indeed, attempted cyclodehydration of paclitaxel with a highly electrophilic phosphonium salt (the Hendrickson reagent) or Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride) afforded <5% of 27 (based on LC analysis) along with several unidentified products showing loss of water. Cyclization of a narrow-spectrum antibiotic lincomycin demonstrates also that the resultant oxazoline can undergo intramolecular opening with a neighboring alcohol to form an ether as shown in 28.