Several additives were screened for the stereoselective reduction of a 4-substituted cyclohexanone en route to linrodostat mesylate. It was found that the addition of sub-stoichiometric cerium(III) chloride in conjunction with sodium borohydride provided the desired trans-cyclohexanol (arising out of axial delivery of the hydride onto the carbonyl) in >16:1 selectivity and excellent conversion. The reaction was initially scaled up to 3.5 kg scale and eventually to >100 kg scale.

We report herein an improved synthesis of 6-nitrovanillin, an important building block used in pharmaceuticals and agrochemicals. The key step in this sequence is the nitration of O-Bn vanillin, which was carried out using fuming HNO 3 . Sulfolane emerged as the solvent of choice for this transformation due to its high stability toward strongly acidic and oxidizing conditions. The specific hazards of this reaction were studied, and the nitration was efficiently and safely conducted leveraging flow conditions.

Two approaches to a 1-aryl-4-trifluoromethyltriazole are described. Initially, a late-stage trifluoromethylation of the corresponding 1-aryl-4-iodotriazole using methyl fluorosulfonyldifluoroacetate (MDFA) was employed. However, the reaction was fraught with several safety and operational challenges, primarily due to the evolution of ∼33 equiv of gas per equiv of substrate. While some of these challenges were either addressed or mitigated through operations in plug flow, the process remained low yielding and suboptimal. Subsequently, a more convergent, longer-term route involving a Cu-mediated decarboxylative Click reaction was developed.