We have developed a deaminative–decarboxylative protocol to form new carbon(sp3)–carbon(sp3) bonds from activated amines and carboxylic acids. Amines and carboxylic acids are ubiquitous building blocks, available in broad chemical diversity and at lower cost than typical C−C coupling partners. To leverage amines and acids for C−C coupling, we developed a reductive nickel‐catalyzed cross‐coupling utilizing building block activation as pyridinium salts and redox‐active esters, respectively. Miniaturized high‐throughput experimentation studies were critical to our reaction optimization, with subtle experimental changes such as order of reagent addition, composition of a binary solvent system, and ligand identity having a significant impact on reaction performance. The developed protocol is used in the late‐stage diversification of pharmaceuticals while more than one thousand systematically captured and machine‐readable reaction datapoints are reposited.

High-throughput experimentation (HTE) is an increasingly important tool in reaction discovery. While the hardware for running HTE in the chemical laboratory has evolved significantly in recent years, there remains a need for software solutions to navigate data-rich experiments. Here we have developed phactor™, a software that facilitates the performance and analysis of HTE in a chemical laboratory. phactor™ allows experimentalists to rapidly design arrays of chemical reactions or direct-to-biology experiments in 24, 96, 384, or 1,536 wellplates. Users can access online reagent data, such as a chemical inventory, to virtually populate wells with experiments and produce instructions to perform the reaction array manually, or with the assistance of a liquid handling robot. After completion of the reaction array, analytical results can be uploaded for facile evaluation, and to guide the next series of experiments. All chemical data, metadata, and results are stored in machine-readable formats that are readily translatable to various software. We also demonstrate the use of phactor™ in the discovery of several chemistries, including the identification of a low micromolar inhibitor of the SARS-CoV-2 main protease. Furthermore, phactor™ has been made available for free academic use in 24- and 96-well formats via an online interface.

Oxazolidinone-based sodiated enolates (Evans enolates) were generated using sodium diisopropylamide (NaDA) or sodium hexamethyldisilazide (NaHMDS) in the presence of N,N,N ′,N′-tetramethylethylenediamine (TMEDA), (R,R)-trans-N,N,N′,N′tetramethylcyclohexanediamine [(R,R)-TMCDA], or (S,S)-TMCDA. 13 C NMR spectroscopic analysis in conjunction with the method of continuous variations (MCV) and density functional theory (DFT) computations revealed the enolates to be octahedral bis-diamine-chelated monomers. Rate and computational studies of an alkylation with allyl bromide implicate a bis-diaminechelated-monomer-based transition structure. The sodiated Evans enolates form mixed dimers with NaHMDS, NaDA, or sodium 2,6-di-tert-butylphenolate, the reactivities of which are examined. Stereoselective quaternizations, aldol additions, and azaaldol additions of sodiated Evans enolates are described.

The 60-year history of sodium diisopropylamide (NaDA) is described herein. We review various preparations, solvent-dependent stabilities, and solution structures. Synthetic applications of NaDA reported to date are framed by a mechanism-driven approach, emphasizing selectivities when appropriate. We conclude with examples beyond metalation in which NaDA plays a central role and with a few thoughts on where future applications could be focused.1 Introduction2 Preparation and Physical Properties3 Solution Structures4 Reactivity and Mechanism4.1 Solvent Decomposition4.2 Alkene and Diene Metalation4.3 Arene Metalations4.4 Dehydrohalogenations5 Selectivity and Applications in Synthesis5.1 Picoline Metalations5.2 C–H Metalation5.3 Dehydrohalogenations5.4 Triflate Alkylation5.5 Allyl Ether Isomerizations5.6 Cyclic Allene Synthesis5.7 Epoxide Elimination5.8 Enolization5.9 Orthometalation6 Flow7 Catalysis8 Organosodium Salts and Secondary Applications9 Conclusion

The global disruption caused by the 2020 coronavirus pandemic stressed the supply chain of many products, including pharmaceuticals. Multiple drug repurposing studies for COVID-19 are now underway. If a winning therapeutic emerges, it is unlikely that the existing inventory of the medicine, or even the chemical raw materials needed to synthesize it, will be available in the quantities required. Here, we utilize retrosynthetic software to arrive at alternate chemical supply chains for the antiviral drug umifenovir, as well as eleven other antiviral and anti-inflammatory drugs. We have experimentally validated four routes to umifenovir and one route to bromhexine. In one route to umifenovir the software invokes conversion of six C–H bonds into C–C bonds or functional groups. The strategy we apply of excluding known starting materials from search results can be used to identify distinct starting materials, for instance to relieve stress on existing supply chains.