N-Aryl pyrazoles were prepared from anilines in a three step telescoped approach. An aniline was diazotized to give the diazonium fluoroborate, followed by reduction with tin(II) chloride to give the corresponding hydrazine, which in turn reacted with a ketoenamine to give the N-aryl pyrazole. The deprotection of the methyl ether was accomplished with PhBCl 2 to give the final product. The continuous flow methodology was used to minimize accumulation of the highly energetic and potentially explosive diazonium salt and hydrazine intermediates to enable the safe scale-up of N-aryl pyrazoles. The heterogeneous reaction mixture was successfully handled in both lab scale and production scale. A continuous extraction was employed to remove organic impurities from the diazotization step, which eliminated the need for chromatography in the purification of the final N-aryl pyrazole.

The synthesis and properties of the bridged piperidine (oxaazabicyclo) compounds 8, 9, and 11 are described. A conformational analysis of these structures is compared with the representative GPR119 ligand 1. These results and the differences in agonist pharmacology are used to formulate a conformation-based hypothesis to understand activation of the GPR119 receptor. We also show for these structures that the agonist pharmacology in rat masks the important differences in human pharmacology.

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We herein report the development of ac onformationally defined, electron-rich, C 2 -symmetric, P-chiral bisphosphorus ligand, ArcPhos,b yt aking advantage of stereoelectronic effects in ligand design. With the Rh-ArcPhos catalyst, excellent enantioselectivities and unprecedentedly high turnovers (TON up to 10 000) were achieved in the asymmetric hydrogenation of aliphatic carbocyclic and heterocyclic tetrasubstituted enamides,t og enerate as eries of chiral cis-2-alkylsubstituted carbocyclic and heterocyclic amine derivatives in excellent enantiomeric ratios.T his method also enabled an efficient and practical synthesis of the Janus kinase inhibitor (R)-tofacitinib.

Pyrido[4,3-d]pyrimidin-4(3H)-one (1) was prepared by reacting 2-trifluoromethyl-4-iodo-nicotinic acid (2) with amidine 9a catalyzed by Pd(2)(dba)(3) and Xantphos, followed by cyclization effected with HBTU and subsequent demethylation using PhBCl(2). The amidine arylation method was found applicable for the syntheses of quinazolin-4(3H)-ones. Thus, reaction of 2-bromo or 2-iodo benzoate esters with amdidines afforded substituted quinazolin-4(3H)-ones in 44-89% yields.