A highly diastereoselective α-arylation of cyclic nitriles has been developed via a Negishi cross-coupling of commercially available aryl, heteroaryl, and alkenyl halides with cyclobutyl nitriles in the presence of tetramethylpiperidinylzinc chloride lithium chloride (TMPZnCl•LiCl) and catalytic XPhos-Pd-G2. A variety of electronically diverse electrophiles were well tolerated, and this chemistry was further advanced with application of both cyclopropyl and cyclopentyl nitriles.

Magnesium ethoxide has been shown to be a mild, safe, and scalable alternative to trimethylaluminum for the direct addition of amines to aryl nitriles to access cyclic amidines. A variety of electronically diverse oxa-, thia-, and diazepine products were successfully synthesized in moderate to high yields. Further elaboration of these compounds to 5,6-dihydroimidazobenzoxazepines, a privileged class of pharmacologically active heterocycles, highlights the utility of this method.

The regioselective functionalization of 7-azaindole by controlled annular isomerism employing ad irected metalation-group migration is reported. The N7 carbamoyl azaindoles undergo regioselective metalation and quenchingwith an electrophile to furnish C6-substituted derivatives which, in the presence of ac atalytic amount of ClCONR 2 promotes ac arbamoyl group shift or dance from N7 to N1. As econd directed metalation/electrophile quench sequence leads to 2,6substituted azaindoles.O ptimization of the metalation conditions for C2 and C6, separately and iteratively,i sp resented. Using the directed metalation group dance strategy,alate-stage deuteration of an antipsychotic drug is described. Overall, the controlled migration of the carbamoyl directing group allows multiple functionalization events of the bioactive azaindole scaffold.Azaindoles occupy ap rominent position in drug discovery research because of their diverse bioactivities,e specially in protein kinase inhibition for the development of anticancer therapies.Among the four isosteres,the 7-azaindole scaffold, also present in arare class of natural products, [1] has emerged as the key heterocycle for structural modification towards new bioactive molecules ( Figure 1A). [2] Among the synthetic routes for 7-azaindoles,metalation-based methodologies have achieved dominance over classical processes because of the advantages of regioselectivity,m ultiple substitution, and ready modification of the prototype nucleus. [3,4] In previous efforts,w ed emonstrated the power of the directed ortho metalation (DoM) reaction in new halogen-dance strategies, [5] anionic ortho-Fries rearrangement processes, [6] latent directed metalation group (DMG) protocols, [7] and, as demonstrated on the 7-azaindole framework, walk-around-the-ringsequences. [4a,b,8] Whilst synthetically powerful, these metalationbased approaches involve several steps:D MG introduction, its use to direct the functionalization event, and its subsequent removal or modification.

GDC-9545 is a selective estrogen receptor degrader that is being developed as a treatment for ER+/HER2– breast cancer. A robust, convergent manufacturing process for GDC-9545 was developed. The process features a Wenker aziridine synthesis to produce the key starting material tryptamine 11, a highly efficient C–N coupling between aminoazetidine 9 and 2,6-difluoro-4-bromobenzaldehyde diethyl acetal (33) to construct key intermediate 10, and a crystallization-driven diastereoselective Pictet–Spengler reaction to furnish the active pharmaceutical ingredient GDC-9545·tartrate.

Herein, the development of a streamlined manufacturing process for the pan-RAF inhibitor belvarafenib (GDC-5573) is reported. The process to belvarafenib features a number of efficient key reactions, including a robust and scalable Pdcatalyzed carbonylation reaction to generate thienopyrimidine 2 and a highly chemoselective Pt/V/C-catalyzed nitro group reduction to access the penultimate intermediate 3. The final amide coupling was accomplished by a mild and safe protocol employing N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate as the coupling reagent, which afforded belvarafenib on a multikilogram production scale after recrystallization.