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Palladium-catalyzed hydrofunctionalization of vinyl phenol derivatives with heteroaromatics

A hydroheteroarylation reaction of vinyl phenols using an alkyl chloride as the sacrificial hydride source is reported. The method tolerates a wide range of heterocycles as the exogenous nucleophile including indoles and pyrroles. The resulting products are easily processed to biologically relevant scaffolds.

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CHROMENONE COMPOUNDS AS PI 3 -KINASE INHIBITORS FOR THE TREATMENT OF CANCER

The invention concerns chromenone compounds of Formula I; or pharmaceutically-acceptable salts thereof, wherein each of R1, R2, R3, R4, R5, n and R6 has any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the treatment of cell proliferative disorders.

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Exploiting Chemical Toolboxes for the Expedited Generation of Tetracyclic Quinolines as a Novel Class of PXR Agonists

The discovery of lead compounds relies on the iterative generation of structure-activity relationship data resulting from the synthesis and biological evaluation of hit analogues. Using traditional approaches, a significant time delay may occur from compound design to results, leading to slow and expensive hit-to-lead explorations. Herein, we have exploited the use of chemical toolboxes to expedite lead discovery and optimization. In particular, the integration of flow synthesizers, automation, process analytical technologies, and computational chemistry has provided a prototype system enabling the multicomponent flow synthesis, in-line analysis, and characterization of chiral tetracyclic quinolines as a novel class of PXR agonists. Within 29 compounds, a novel template 19b (3aS,11R,11aS) was identified with an EC50 of 1.2 muM (efficacy 119%) at the PXR receptor.

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Catalytic Strategy for Regioselective Arylethylamine Synthesis

A mild, modular, and practical catalytic system for the synthesis of the highly privileged phenethylamine pharmacophore is reported. Using a unique combination of organic catalysts to promote the transfer of electrons and hydrogen atoms, this system performs direct hydroarylation of vinyl amine derivatives with a wide range of aryl halides (including aryl chlorides). This general and highly chemoselective protocol delivers a broad range of arylethylamine products with complete regiocontrol. The utility of this process is highlighted by its scalability and the modular synthesis of an array of bioactive small molecules.

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Enantioselective hydroformylation of N-vinyl carboxamides, allyl carbamates, and allyl ethers using chiral diazaphospholane ligands

Rhodium complexes of diazaphospholane ligands catalyze the asymmetric hydroformylation of N-vinyl carboxamides, allyl ethers, and allyl carbamates; products include 1,2- and 1,3-aminoaldehydes and 1,3-alkoxyaldehydes. Using glass pressure bottles, short reaction times (generally less than 6 h), and low catalyst loading (commonly 0.5 mol %), 20 substrates are successfully converted to chiral aldehydes with useful regioselectivity and high enantioselectivity (up to 99% ee). Chiral Roche aldehyde is obtained with 97% ee from the hydroformylation of allyl silyl ethers. Commonly difficult substrates such as 1,1- and 1,2-disubstituted alkenes undergo effective hydroformylation with 89-97% ee and complete conversion for six examples. Palladium-catalyzed aerobic oxidative amination of allyl benzyl ether followed by enantioselective hydroformylation yields the beta3-aminoaldehyde with 74% ee.

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Dynamic Kinetic Asymmetric Heck Reaction for the Simultaneous Generation of Central and Axial Chirality

A highly diastereo- A nd enantioselective, scalable Pd-catalyzed dynamic kinetic asymmetric Heck reaction of heterobiaryl sulfonates with electron-rich olefins is described. The coupling of 2,3-dihydrofuran or N-boc protected 2,3-dihydropyrrole with a variety of quinoline, quinazoline, phthalazine, and picoline derivatives takes place with simultaneous installation of central and axial chirality, reaching excellent diastereo- A nd enantiomeric excesses when in situ formed [Pd0/DM-BINAP] was used as the catalyst, with loadings reduced down to 2 mol % in large scale reactions. The coupling of acyclic, electron-rich alkenes can also be performed using a [Pd0/Josiphos ligand] to obtain axially chiral heterobiaryl alpha-substituted alkenes in high yields and enantioselectivities. Products from Boc-protected 2,3-dihydropyrrole can be easily transformed into N,N ligands or appealing axially chiral, bifunctional proline-type organocatalysts. Computational studies suggest that a beta-hydride elimination is the stereocontrolling step, in agreement with the observed stereochemical outcome of the reaction.

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Stereoselective [3+2] Carbocyclization of Indole-Derived Imines and Electron-Rich Alkenes: A Divergent Synthesis of Cyclopenta[b]indole or Tetrahydroquinoline Derivatives

An unprecedented stereoselective [3+2] carbocyclization reaction of indole-2-carboxaldehydes, anilines, and electron-rich alkenes to obtain cyclopenta[b]indoles is disclosed. This pathway is different from the well-established Povarov reaction: the formal [4+2] cycloaddition involving the same components, which affords tetrahydroquinolines. Moreover, by simply changing the Br¡ãnsted acid catalyst, this multicomponent coupling process could be divergently directed towards the conventional Povarov pathway to produce tetrahydroquinolines or to the new pathway (anti-Povarov) to generate cyclopenta[b]indoles. Supported by computational studies, a stepwise Mannich/Friedel-Crafts cascade is proposed for the new anti-Povarov reaction, whereas a concerted [4+2] cycloaddition mechanism is proposed for the Povarov reaction.

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Access to cyclic: Gem-difluoroacyl scaffolds via electrochemical and visible light photocatalytic radical tandem cyclization of heteroaryl chlorodifluoromethyl ketones

A variety of unprecedented scaffolds containing a difluoroacyl moiety were obtained in moderate to good yields, with excellent diastereoselectivity, via electrochemical or photochemical activation of difluoroacyl heteroaryles with a series of olefinic substrates.

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NiH-Catalyzed Migratory Defluorinative Olefin Cross-Coupling: Trifluoromethyl-Substituted Alkenes as Acceptor Olefins to Form gem-Difluoroalkenes

We report a NiH-catalyzed migratory defluorinative coupling between two electronically differentiated olefins. A broad range of unactivated donor olefins can be joined directly to acceptor olefins containing an electron-deficient trifluoromethyl substituent in both intra- and intermolecular fashion to form gem-difluoroalkenes. This migratory coupling shows both site- and chemoselectivity under mild conditions, with the formation of a tertiary or quaternary carbon center.

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PROPENOYL HYDRAZIDES

The present disclosure provides compositions for inhibiting proteases, methods for synthesizing the compositions, and methods of using the disclosed protease inhibitors. Aspects of the disclosure include a peptidyl propenoyl hydrazide compositions that inhibit proteases, for example cysteine proteases, either in vivoor in vitro.

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