Suzuki-Miyaura cross-coupling of unprotected -bromoanilines with benzyl, alkyl, aryl, alkenyl and heteroaromatic boronic esters.

A Suzuki-Miyaura cross-coupling reaction was developed on unprotected -bromoanilines. This operationally simple reaction was developed for the diversification of glucocorticoid receptor modulators (GRMs), showed compatibility to various boronic esters featuring unique functionalities, and was demonstrated on a gram scale.

Incorporating Synthetic Accessibility in Drug Design: Predicting Reaction Yields of Suzuki Cross-Couplings by Leveraging AbbVie's 15-Year Parallel Library Data Set.

Despite the increased use of computational tools to supplement medicinal chemists' expertise and intuition in drug design, predicting synthetic yields in medicinal chemistry endeavors remains an unsolved challenge. Existing design workflows could profoundly benefit from reaction yield prediction, as precious material waste could be reduced, and a greater number of relevant compounds could be delivered to advance the design, make, test, analyze (DMTA) cycle. In this work, we detail the evaluation of AbbVie's medicinal chemistry library data set to build machine learning models for the prediction of Suzuki coupling reaction yields.

Di(2-picolyl)amines as Modular and Robust Ligands for Nickel-Catalyzed C(sp)-C(sp) Cross-Electrophile Coupling.

Ni-catalyzed aryl-alkyl coupling reactions are reliant on using a limited set of commercially available bidentate nitrogenous ligands to enable the reaction, because noncommercial analogues usually entail challenging syntheses. In this work, di(2-picolyl)amines (DPAs) are explored as an alternative modular ligand class for the nickel-catalyzed aryl-alkyl cross-electrophile coupling. Novel DPA ligands were synthesized directly from inexpensive amine and pyridine building blocks in a single step.

The Chosen Few: Parallel Library Reaction Methodologies for Drug Discovery.

Parallel library synthesis is an important tool for drug discovery because it enables the synthesis of closely related analogues in parallel via robust and general synthetic transformations. In this perspective, we analyzed the synthetic methodologies used in >5000 parallel libraries representing 15 prevalent synthetic transformations. The library data set contains complex substrates and diverse arrays of building blocks used over the last 14 years at AbbVie.

Rearrangement of 3-Hydroxyazetidines into 2-Oxazolines.

A novel rearrangement sequence of 3-hydroxyazetidines via a Ritter initiated cascade provides highly substituted 2-oxazolines in high yields. The reaction conditions and substrate scope of the transformation have been studied demonstrating the generality of the process. The derived products can also be functionalized in order to undergo further intramolecular cyclization leading to a new class of macrocycle.

Expanding the Medicinal Chemist Toolbox: Comparing Seven C(sp)-C(sp) Cross-Coupling Methods by Library Synthesis.

Despite recent advances in the field of C(sp)-C(sp) cross-couplings and the accompanying increase in publications, it can be hard to determine which method is appropriate for a given reaction when using the highly functionalized intermediates prevalent in medicinal chemistry. Thus a study was done comparing the ability of seven methods to directly install a diverse set of alkyl groups on "drug-like" aryl structures via parallel library synthesis. Each method showed substrates that it excelled at coupling compared with the other methods.

High-Throughput Reaction Screening with Nanomoles of Solid Reagents Coated on Glass Beads.

Technologies that enable rapid screening of diverse reaction conditions are of critical importance to methodology development and reaction optimization, especially when molecules of high complexity and scarcity are involved. The lack of a general solid dispensing method for chemical reagents on micro- and nanomole scale prevents the full utilization of reaction screening technologies. We herein report the development of a technology in which glass beads coated with solid chemical reagents (ChemBeads) enable the delivery of nanomole quantities of solid chemical reagents efficiently.

Emerging Trends in Flow Chemistry and Applications to the Pharmaceutical Industry.

The field of flow chemistry has garnered considerable attention over the past 2 decades. This Perspective highlights many recent advances in the field of flow chemistry and discusses applications to the pharmaceutical industry, from discovery to manufacturing. From a synthetic perspective, a number of new enabling technologies are providing more rationale to run reactions in flow over batch techniques.

High-Temperature Boc Deprotection in Flow and Its Application in Multistep Reaction Sequences.

A simplified Boc deprotection using a high-temperature flow reactor is described. The system afforded the qualitative yield of a wide variety of deprotected substrates within minutes using acetonitrile as the solvent and without the use of acidic conditions or additional workups. Highly efficient, multistep reaction sequences in flow are also demonstrated wherein no extraction or isolation was required between steps.

Tissue-Factor Targeted Peptide Amphiphile Nanofibers as an Injectable Therapy To Control Hemorrhage.

Noncompressible torso hemorrhage is a leading cause of mortality in civilian and battlefield trauma. We sought to develop an i.v.