High-throughput experimentation (HTE) has revolutionized the pharmaceutical industry, most notably allowing for rapid screening of compound libraries against therapeutic targets. The past decade has also witnessed the extension of HTE principles toward the realm of small-molecule process chemistry. Today, most major pharmaceutical companies have created dedicated HTE groups within their process development teams, invested in automation technology to accelerate screening, or both. The industry's commitment to accelerating process development has led to rapid innovations in the HTE space. This review will deliver an overview of the latest best practices currently taking place within our teams in process chemistry by sharing frequently studied transformations, our perspective for the next several years in the field, and manual and automated tools to enable experimentation. A series of case studies are presented to exemplify state-of-the-art workflows developed within our laboratories.

Photocatalytic hydrogen atom transfer is a very powerful strategy for the regioselective C(sp 3 )-H functionalization of organic molecules. Herein, we report on the unprecedented combination of decatungstate hydrogen atom transfer photocatalysis with the oxidative radical-polar crossover concept to access the direct net-oxidative C(sp 3 )-H heteroarylation. The present methodology demonstrates a high functional group tolerance (40 examples) and is scalable when using continuous-flow reactor technology. The developed protocol is also amenable to the late-stage functionalization of biologically relevant molecules such as stanozolol, (À)ambroxide, podophyllotoxin, and dideoxyribose.Photocatalytic hydrogen atom transfer (HAT) is witnessing an ever-growing interest from the synthetic community as a versatile strategy for the late-stage functionalization of C(sp 3 )ÀH bonds. [1][2][3] In this activation mode, the excited state of a photocatalyst can be conveniently exploited to cleave C(sp 3 ) À H bonds to obtain carbon-centered radicals. By exploiting inherent electronic and steric properties of the parent molecule and by tuning the reaction conditions, these nucleophilic radicals can be obtained with high regioselectiv-ity, thus obviating the need to use any directing or activating groups (Scheme 1 a).Amongst the different HAT photocatalysts, the decatungstate anion (W; [W 10 O 32 ] 4À ) has proven to be an ideal candidate owing to its unique selectivity, robustness and ease of preparation. [4,5] The excited state of W (W*) can be readily obtained upon exposure to UV-A light (l > 365 nm) and has been used for the activation of C(sp 3 )ÀH bonds within a wide variety of hydrogen donors such as ethers, aldehydes, amides and even alkanes. In most cases, the fleeting radical intermediates were used to forge CÀC, [6] CÀF, [7] and CÀO [8] bonds. In contrast, only a handful of examples demonstrate the formation of C À N bonds. [9] These examples mainly rely on the trapping of the radical with a suitable Michael acceptor, e.g., diisopropyl azodicarboxylate (DIAD), delivering the corresponding hydrazides. Despite its synthetic utility to Scheme 1. a) Photocatalytic hydrogen atom transfer (HAT) enables the conversion of CÀH bonds in complex biologically active molecules. b) Established mechanism for the formation of CÀN bonds via TBADT-mediated HAT. c) Proposed approach to realize the regioselective CÀH bond heteroarylation through combination of decatungstateenabled HAT and Radical-Polar Crossover (RPC).

Carbon–nitrogen bonds are ubiquitous in biologically active compounds, prompting synthetic chemists to design various methodologies for their preparation. Arguably, the ideal synthetic approach is to be able to directly convert omnipresent C–H bonds in organic molecules, enabling even late-stage functionalization of complex organic scaffolds. While this approach has been thoroughly investigated for C(sp 2 )–H bonds, only few examples have been reported for the direct amination of aliphatic C(sp 3 )–H bonds. Herein, we report the use of a newly developed flow photoreactor equipped with high intensity chip-on-board LED technology (144 W optical power) to trigger the regioselective and scalable C(sp 3 )–H amination via decatungstate photocatalysis. This high-intensity reactor platform enables simultaneously fast results gathering and scalability in a single device, thus bridging the gap between academic discovery (mmol scale) and industrial production (>2 kg/day productivity). The photocatalytic transformation is amenable to the conversion of both activated and nonactivated hydrocarbons, leading to protected hydrazine products by reaction with azodicarboxylates. We further validated the robustness of our manifold by designing telescoped flow approaches for the synthesis of pyrazoles, phthalazinones and free amines.

A strategy for both cross-electrophile coupling and 1,2-dicarbofunctionalization of olefins has been developed. Carbon-centered radicals are generated from alkyl bromides by merging benzophenone hydrogen atom transfer (HAT) photocatalysis and silyl radical-induced halogen atom transfer (XAT) and are subsequently intercepted by a nickel catalyst to forge the targeted C(sp 3 )–C(sp 2 ) and C(sp 3 )–C(sp 3 ) bonds. The mild protocol is fast and scalable using flow technology, displays broad functional group tolerance, and is amenable to a wide variety of medicinally relevant moieties. Mechanistic investigations reveal that the ketone catalyst, upon photoexcitation, is responsible for the direct activation of the silicon-based XAT reagent (HAT-mediated XAT) that furnishes the targeted alkyl radical and is ultimately involved in the turnover of the nickel catalytic cycle.

We have identified a non-steroidal selective androgen receptor modulator (SARM), termed LY305, that is bioavailable through a transdermal route of administration while highly cleared via hepatic metabolism to limit parent compound exposure in the liver. Selection of this compound and its transdermal formulation was based on the optimization of skin absorption properties using both in vitro and in vivo skin models that supported PBPK modeling for human PK predictions. This molecule is an agonist in perineal muscle while being a weak partial agonist in the androgenic tissues such as prostate. When LY305 was tested in animal models of skeletal atrophy it restored the skeletal muscle mass through accelerated repair. In a bone fracture model, LY305 remained osteoprotective in the regenerating tissue and void of deleterious effects. Finally, in a small cohort of healthy volunteers, we assessed the safety and tolerability of LY305 when administered transdermally. LY305 showed a dose-dependent increase in serum exposure and was well tolerated with minimal adverse effects. Notably, there were no statistically significant changes to hematocrit or HDL after 4-week treatment period. Collectively, LY305 represents a first of its kind de novo development of a non-steroidal transdermal SARM with unique properties which could find clinical utility in hypogonadal men.