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A practical and mild process to access 2-aminopyridine derivatives using ruthenium-catalyzed [2+2+2] cycloaddition of various 1,6- and 1,7-diynes with cyanamides is described. This straightforward atom-economical catalytic cycloaddition is scalable and showed excellent regioselectivities to approach a wide range of 2-aminopyridines of high synthetic utility. Postfunctionalization reactions of halo-containing adducts, via Pd- and Cu-catalyzed cross-couplings as well as cyanation and amination reactions, delivered substituted 2-aminopyridine derivatives in good to excellent yields.

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A novel series of pyridazinone-based phosphodiesterase 10A (PDE10A) inhibitors were synthesized. Our optimization efforts using structure-based drug design (SBDD) techniques on the basis of the X-ray crystal structure of PDE10A in complex with hit compound 1 (IC50 = 23 nM; 110-fold selectivity over other PDEs) led to the identification of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (27h). Compound 27h has potent inhibitory activity (IC50 = 0.30 nM), excellent selectivity (>15000-fold selectivity over other PDEs), and favorable pharmacokinetics, including high brain penetration, in mice. Oral administration of compound 27h to mice elevated striatal 3,5-cyclic adenosine monophosphate (cAMP) and 3,5-cyclic guanosine monophosphate (cGMP) levels at 0.3 mg/kg and showed potent suppression of phencyclidine (PCP)-induced hyperlocomotion at a minimum effective dose (MED) of 0.3 mg/kg. Compound 27h (TAK-063) is currently being evaluated in clinical trials for the treatment of schizophrenia.

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Dual-curable formulation was used to prepare epoxy prepregs with tailored tack and drape. The obtained formulation had enhanced stability during the storage which eliminates the instability as the main drawback of prepregs. Diethylenetriamine was used as a low-temperature curing agent in the off-stoichiometry ratio for pre-curing and dicyandiamide was used as a latent curing agent for final curing. DSC Tests showed that simultaneous presence of two curing agents with different reactivities results in two different curing reaction without interference. FT-IR and DSC tests showed that the inactivity of latent curing agent in the pre-curing step causes to the loss of thermal history. The FT-IR tests showed only a 7% increase in conversion after 21 days of storage at room temperature. Tack and drape as main parameters of epoxy prepreg were tailored by adjusting the degree of cure based on using different amount of double curing agents.

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Balancing high glass transition temperature (Tg) and crack-propagation resistance is a well-known dilemma in epoxy thermosets used for high-performance composite applications ranging from automotive to aerospace. Thermoset polymers with tightly formed 3D crosslinked structures are characterized by restricted long chain molecular movement, which can delay the onset of glass transition and extend the service temperature. However, when such thermosets are subject to an impact, the plastic deformation is confined at the crack tip by the tightly crosslinked network, resulting in minimal fracture toughness that is not improved significantly even with rubber toughening. In this work, we study the effect of using an isocyanate modified bisphenol A diglycidyl ether epoxy resin comprised of epoxy-terminated oxazolidone ring structure on the Tg and toughenability of bifunctional epoxy resins. Specifically, we will investigate the hypothesis that incorporation of the modified epoxy may enable enhanced toughenability through an increase in chain length between the crosslinks while also providing sufficient molecular rigidity for superior Tg performance due to the oxazolidone ring in the backbone structure. Preliminary results show the toughened thermoset containing the modified epoxy exhibits up to 250% improvement in fracture energy (GIC) with Tg of 200C.

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The origin of virtually complete face diastereoselectivity in the organic base-catalyzed, room temperature Michael addition reactions between Ni(II)-complexes of Schiff bases of glycine and chiral 3-(E-enoyl)-4-substituted-1,3-oxazolidin-2-ones was shown to stem from the unusual mode of steric interactions in determining the corresponding transition state. (C) 2000 Elsevier Science Ltd.

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Oxazolidinones are multifunctional compounds possessing diverse biological and pharmacological activity. Enzymatic synthesis of oxazolidin-2-one was studied using 2-aminoalochol and dimethyl carbonate and synthesis of 3-ethyl-1,3-oxazolidin-2-one was chosen as the model reaction using a variety of immobilized lipases; among which Candida antarctica lipase B (Novozyme 435) was the best catalyst. The reaction leads to the final product oxazolidin-2-one via methyl ethyl (2-hydroxyethyl) carbamate as the intermediate. The parameters affecting rate of reaction and the conversion of both steps were studied systematically and covered effects of agitation speed, solvent, catalyst loading and reaction temperature. A reaction mechanism was proposed wherein the coproduct methanol is generated in the first step leading to the formation of methyl ethyl (2-hydroxyethyl) carbamate as the intermediate which rearranges itself leading to the final products 3-ethyl-1,3-oxazolidin-2-one and methanol. The kinetic constant and activation energy were determined for each step of the reaction. The study was further extended to other 2-aminoalochols under optimized reaction conditions to prepare different oxazolidinones. This is a first report of its kind describing kinetics and mechanism of bimolecular consecutive enzyme catalyzed reactions.

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An unprecedented Pd-catalyzed regioselective activation of gem-difluorinated cyclopropanes induced by C-C bond cleavage is reported. It provides a general and efficient access to a variety of 2-fluoroallylic amines, ethers, esters, and alkylation products in high Z-selectivity, which are important skeletons in many biologically active molecules. In addition, the transformation represents the first general application of gem-difluorinated cyclopropanes as reaction partners in transition-metal-catalyzed cross-coupling reaction. C-C bond cleavage under Pd catalysis induces a regioselective activation of gem-difluorinated cyclopropanes. The reaction provides access to a variety of 2-fluoroallylic scaffolds with high Z-selectivity and represents the first general application of gem-difluorinated cyclopropanes as reaction partners in transition-metal-catalyzed cross-coupling reactions.

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A series of novel carbazole-containing amides and ureas were synthesized. A structure?activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the desired pharmacokinetic/pharmacodynamic parameters and the results of efficacy studies in db/db mice, compound 50 was selected for further profiling.

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The copper(i)-catalyzed hydroboration of alkynamides with B 2pin2 afforded the alkenamide boronates in 66% to nearly quantitative yields with high regio- and stereo-selectivity. It was interesting to note that the regio-selectivity of the reaction is opposite to that observed in the carbometallation reaction of alkynamides, and the resulting alkenyl boronates provided access to alpha,-disubstituted (Z)-alkenamides through further elaboration. This journal is the Partner Organisations 2014.

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A new class of Michael acceptors based on alpha,beta-unsaturated amino acids has been prepared and applied in asymmetric organocatalysis. With the use of thiourea derivatives of cinchona alkaloid-derived catalysts, efficient addition of thiols to the dehydroamino acids occurred with formation of beta-thiol functionalized alpha-amino acids in high yields, moderate diastereoselectivities and ee values up to 95%. Georg Thieme Verlag Stuttgart ? New York.

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