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Herein, we report a mild protocol for metal-, photocatalyst-, and light-free Minisci C-H alkylation reactions of N-heteroarenes with alkyl oxalates derived from primary, secondary, and tertiary alcohols. The protocol uses environmentally benign persulfate as a stoichiometric oxidant and does not require high temperatures or large excesses of either of the substrates, making the procedure suitable for late-stage C-H alkylation of complex molecules. Notably, several pharmaceuticals and natural products could be functionalized or prepared with this protocol, thus demonstrating its utility.

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2-Alkynyl-3-chloroquinoxalines are prepared from 2,3-dichloroqionoxaline and alk-1-ynes: use of 2-methylbut-3-yn-2-ol, and the removal of acetone with base, yields 2-chloro-3-ethynylqionoxaline.The chloroalkynes are readily converted into pyrrolo- and thieno<2,3-b>qionoxalines. 2-Chloro-3-phenylethynylquinoxaline with potassium hydroxide gives 2-phenylfurano<2,3-b>quinoxaline but other furano-compounds could not be prepared. 2-Chloro-3-(3-hydroxy-3-methylbut-2-ynyl)quinoxaline with ethanolic sodium ethoxide yields 2H-2,2-dimethyl-3-ethoxypyrano<2,3-b>quinoxaline.When 2-ethynyl- or 2-chloro-3-ethynylqionoxaline is heated with morpholine and sulphur, 2-morpholinothieno<2,3-b>quinoxaline is obtained.The structures of these compounds are established by spectroscopic methods.

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A series of benzoquinolin-3-ones are pharmaceuticals effective in treating conditions consequent on both Type I and Type II 5alpha-reductase and their preparation is disclosed.

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(Chemical Equation Presented) Unprecedented activity: Catalysts derived from Pd and bulky dialkylphosphinobiaryl ligands are shown to be highly stable and active in Suzuki-Miyaura reactions of heteroaryl halides and heteroaryl boronic acids/esters (e.g., 3-or 4-pyridine, indole, and N-protected pyrrole derivatives). Furthermore, this catalyst system is not inhibited by the presence of highly basic aminopyridines or aminopyrimidines.

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A series of N-arylpiperazines were prepared in a parallel fashion using palladium-catalyzed cross-coupling, or nucleophilic aromatic displacement chemistries, and polymer-assisted sequestration and purification techniques as key steps.

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A practical synthesis of 2-benzenesulfonylpyridine, 1, is described which is a key starting material for the manufacture of an investigational new drug candidate at Eli Lilly and Company. An optimized green chemical process was developed which features a novel tandem SNAr/oxidation under mild conditions to produce the target sulfone, 1, in 86% yield and>99% purity. In addition, this novel, environmentally friendly methodology was found to be general for the synthesis of substituted aromatic pyridyl sulfides and sulfones.

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The present invention is directed to diazaspirodecane compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

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Abstract We synthesized several biaryl derivatives as PDE10A inhibitors to prevent phototoxicity of 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1) and found that the energy difference between the energy-minimized conformation and the coplanar conformation of the biaryl moiety helped facilitate prediction of the phototoxic potential of biaryl compounds. Replacement of the quinoline ring of 1 with N-methyl benzimidazole increased this energy difference and prevented phototoxicity in the 3T3 NRU test. Further optimization identified 1-methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one (38b). Compound 38b exhibited good selectivity against other PDEs, and oral administration of 38b improved visual-recognition memory deficit in mice at doses of 0.001 and 0.003 mg/kg in the novel object recognition test. ASP9436 (sesquiphosphate of 38b) may therefore be used for the treatment of schizophrenia with a low risk of phototoxicity.

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The rate constant of the reaction of 2-chloroquinoxaline with piperidine was measured spectrophotometrically using different aqueous solutions containing DMSO or DMF. Whatever the experimental conditions used, this reaction follows pseudo first order kinetics and is not amine catalyzed. Furthermore, the second order rate constant, kA, increases with increasing percentage of DMSO in the solution, in contrast to DMF. The kA values were then correlated with solvent parameters alpha, beta, pi*, ETN and Y. Plots of log10kA against the reciprocal of the dielectric constant at 25 C were found to be nonlinear in DMSO, while a linear relationship with a negative slope was found in the case of DMF. This difference between the solvents is presumably due to different solvation pathways between their initial and transition states. Thus, activation parameters DeltaHNo., DeltaSNo. and DeltaGNo. were evaluated and discussed to support this hypothesis. Finally, DFT calculations were performed, using the B3LYP functional and 6-311G(d,p) basis set, to determine optimum molecular geometry. IR, NMR spectra for both reactant and product and were then compared with experimental values.

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An extension of the Beirut reaction for the preparation of the first members of the 2-phosphonylated quinoxaline 1,4-dioxide series is described. Contrary to their carboxylated equivalents, preparation of these new compounds could not be achieved under basic conditions but required the use of powdered molecular sieves. Good and reproducible yields were obtained only when the initial suspension in THF was transformed into a pasty film by slow evaporation of ca. 90% of the initial solvent volume.

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