A simple and robust method for instant carbon monoxide generation at room temperature using easily accessible standard lab chemicals: formic acid, mesyl chloride and triethylamine.

The first example of an alkyl-aryl Negishi coupling in a practical, sustainable, and high-yielding process using a silica-supported catalyst in flow is described. Excellent conversions and good functional group compatibility were obtained under very mild conditions. Functionalized alkyl groups were also introduced to provide access to synthetically useful molecules and to demonstrate the versatility of the method. The scalability was assessed, and a throughput of 7.5 mmol/h of processed substrate was achieved. All crude products were free from phosphine derivatives and ready for use in subsequent reaction steps.

The first continuous flow carbonylation reaction using aryl formates as CO precursor is reported. The reaction is practical, scalable and high yielding. The use of a flow protocol safely allows expanding the scope to activated chlorides, nitrogen heterocycles and to the selective introduction of an ester group in dihalo-derivatives. Further selective reduction of the ester formed to an aldehyde in flow is also described.

Background:The size and/or protein nature of current von Willebrand factor (VWF)-glycoprotein (GP) Ib␣ inhibitors limits oral bioavailability and clinical development. Results: Through a rational approach, a small molecule was selected that modulates the VWF-GPIb interaction. Conclusion: Further chemical modifications will now allow full characterization and manipulation of the specific activity of the compound. Significance: Rational design allows for the identification of small molecules that interfere with protein-protein interactions.

We performed a systematic investigation of the conditions causing or preventing self-ignition of spent palladium on a carbon catalyst after hydrogenation reactions. The solvent used for hydrogenation plays a major role. We compared the pyrophoricity of a filtered catalyst, produced with 11 commonly used hydrogenation solvents. Self-ignition was only observed with alcoholic solvents. We also show that self-ignition of spent catalyst can be prevented by an efficient water rinse and/or addition of thiophene. A method is also presented to evaluate the risk of spontaneous ignition of the catalyst cake after hydrogenation with palladium on carbon in a systematic way.

The design and synthesis of oligoamide α-helix peptidomimetics is reported. The oligoamide type systems are prepared in a modular fashion by coupling the monomers using palladium-catalyzed carbonylation chemistry. This enabled us to use substrates with a low nucleophilicity, leading to previously unreported pyrazine based oligoamide α-helix mimetics. The proof of principle is given by synthesizing a small set of compounds. Various end-capping groups were introduced and also a mixed multimer was successfully prepared.

An integrated approach comprising STD NMR screening, pharmacophore based analogue selection and a bioassay is presented for the discovery of a stabilizer of the clinically relevant VWF-GPIbα protein-protein interaction.

Anticoagulants play a critical role in the prevention and treatment of thrombotic-driven cardiovascular diseases. Factor XIa (FXIa) inhibitors have the potential to improve the benefit/risk profile of existing anticoagulants through a safer bleeding profile in a variety of conditions where patients are predisposed to a high risk of thrombotic or bleeding events. To support the clinical development program of milvexian (BMS-986177/JNJ-70033093), a FXIa inhibitor that recently completed phase II clinical trials, we improved the discovery route to deliver the suitable quantity of key intermediate 1 for clinical supply. This paper describes our optimization of the Suzuki cross-coupling and how we simplified and improved the isolation of 4-trimethylsilyl-1,2,3-triazole 6 after the azidation–click sequence. On top of streamlining the processes for the chlorination and demethylation steps, we demonstrated that the recrystallization of the penultimate intermediate 7 was key to control the purity and the color of the desired 4-chloro-1,2,3-triazole 1, which could be obtained in a 70% yield over five steps.