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.

A new series with the tetrahydroisoquinoline-fused benzodiazepine (TBD) ring system combined with the surrogates of (1-methyl-1H-pyrrol-3-yl)­benzene (“MPB”) payloads were designed and executed for conjugation with a monoclonal antibody for anticancer therapeutics. DNA models helped in rationally identifying modifications of the “MPB” binding component and guided structure–activity relationship generation. This hybrid series of payloads exhibited excellent in vitro activity when tested against a panel of various cancer cell lines. One of the payloads was appended with a lysosome-cleavable peptide linker and conjugated with an anti-mesothelin antibody via a site-specific conjugation method mediated by the enzyme bacterial transglutaminase (BTGase). Antibody–drug conjugate (ADC) 50 demonstrated good plasma stability and lysosomal cleavage. A single intravenous dose of ADC 50 (5 or 10 nmol/kg) showed robust efficacy in an N87 gastric cancer xenograft model.