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A synthetic methodology for a protecting-group-free formation of 3-aryl-substituted 4-aminopyrazoles from acetophenones via a telescoped oximation and hydrazine condensation of 1,3-ketoaldehydes to generate nitrosopyrazoles, and copper-catalyzed NaBH4 reduction of the nitroso group, was demonstrated. The synthesis tolerates a broad scope of substrates with a variety of substituents on the phenyl ring to afford the desired products.

The concise early development route to the Nav1.7 inhibitor GDC-0310 is described. The active pharmaceutical ingredient (API) contains one stereocenter, which was obtained with high enantiomeric excess (>99:1) by using an SN2 displacement approach to connect two intermediates: a chiral benzyl alcohol and a piperidine. The synthesis of the piperidine building block proceeded via a regioselective SNAr reaction on 1-chloro-2,4-difluorobenzene by N-Boc-4-piperidinemethanol, followed by installation of the methyl ester group by electrophilic aromatic bromination and a palladium-catalyzed alkoxycarbonylation. A subsequent Suzuki–Miyaura cross-coupling reaction was then telescoped directly into cleavage of the Boc group to provide the advanced piperidine intermediate. The key feature of the synthesis is the highly selective SN2 displacement of the chiral mesylate of (R)-1-(3,5-dichlorophenyl)ethan-1-ol with the piperidine intermediate, followed by a chiral purity upgrade via the corresponding (1S)-(+)-camphorsulfonic acid salt. After standard hydrolysis of the methyl ester and CDI mediated amidation to couple the resulting acid with methanesulfonamide, enantiomerically pure GDC-0310 was obtained in high overall yield (37%) on a 6.5 kilogram scale.

Hexafluorophosphoric acid promotes 1,3,4-oxadiazolium hexafluorophosphate formation from N′-acyl-N-aroyl-N-arylhydrazides or N′-acyl-N-acyl-N-arylhydrazides under mild conditions. These 1,3,4-oxadiazolium hexafluorophosphates can be treated with cyanamide in propan-2-ol in the presence of triethylamine to generate 1,5-disubstituted 3-amino-1H-1,2,4-triazoles in good yields. This safe and scalable protocol displays a broad scope with respect to N-substitutions and N′-acyl protecting groups.