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2-Aroylquinoxalines (5,6), 1-aroylphthalazines (10,11), and 4-aroylcinnolines (13) were synthesized by using arenecarbaldehydes (2) in the presence of an azolium salt (1) in moderate to good yields. 1,3-Dimethylimidazolium iodide (1a) and sodium sulfinate (7) were also effective catalysts in this aroylation.

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A mild and efficient alpha-heteroarylation of simple esters and amides was developed via nucleophilic aromatic substitution. The choice of NaHMDS in toluene gave the best results. A tandem alpha-heteroarylation and hydroxylation protocol using air as the oxidant afforded tertiary alcohols in good yields.

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The present invention is directed to compounds of Formula I: wherein ring A is phenyl, naphihalenyl, pyridyl, quinolinyl, isoquinolinyl, imidazopyridyl, furanyi, tlisazolyl, isoxazolvl, pyrazolyl, imidazothiazolyi, benzimidazolyl, or indazolyi; R1 is H, alky], aikoxy, hydroxyalkylene, OH, halo, phenyl, triazolyl, oxazolyl, isoxazofyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazmyl, piperazinyl, pyrazolyl, oxadiazolvl, pyrrolidinyl, thiophenyi, morpholinyl, or dialkyiamino; R2 is H, alkyl, aikoxy, hydroxyalkylene, or halo; Z is NH, N-alkyl, or O; R5 is pyridyl, pyrimidinyl, pyrazinyl, pyridazmyl, qumazolinyi, quinoxalinyl, pyrazolyl, benzoxazolyl, imidazopyrazinyl, triazolopyrazinyl, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, aikoxy, or halo; and n is 0 or 1, Methods of making the compounds of Formula 1 are also described. The invention also relates to pharmaceutical compositions comprising compounds of Formula I. Methods of using the compounds of the invention are also within the scope of the invention.

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The first syntheses of 4-chloro-2-(2-quinoxalinyl)-pyridazin-3(2H)-one derivatives are reported.They could be synthesized from 2-hydrazinoquinoxaline derivatives as starting materials.

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A method for the Pd-catalyzed arylation of ammonia with a wide range of aryl and heteroaryl halides, including challenging five-membered heterocyclic substrates, is described. Excellent selectivity for monoarylation of ammonia to primary arylamines was achieved under mild conditions or at rt by the use of bulky biarylphosphine ligands (L6, L7, and L4) as well as their corresponding aminobiphenyl palladacycle precatalysts (3a, 3b, and 3c). As this process requires neither the use of a glovebox nor high pressures of ammonia, it should be widely applicable.

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A general and efficient protocol for direct C-H alkylation and acylation of N-heterocycles, using readily accessible carboxylic acids as radical precursors under visible-light irradiation without a photocatalyst and an additional acid additive, has been developed. This protocol provides expedient access to substituted N-heterocycles under mild and metal-free conditions. Mechanistic experiments indicate that this reaction proceeds through a visible-light-initiated radical chain propagation mechanism.

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Until recently, discriminating between homomeric 5-HT3A and heteromeric 5-HT3AB receptors was only possible with ligands that bind in the receptor pore. This study describes the first series of ligands that can discriminate between these receptor types at the level of the orthosteric binding site. During a recent fragment screen, 2-chloro-3-(4-methylpiperazin-1-yl)quinoxaline (VUF10166) was identified as a ligand that displays an 83-fold difference in [3H]granisetron binding affinity between 5-HT3A and 5-HT3AB receptors. Fragment hit exploration, initiated from VUF10166 and 3-(4-methylpiperazin-1-yl)quinoxalin-2-ol, resulted in a series of compounds with higher affinity at either 5-HT3A or 5-HT3AB receptors. These ligands reveal that a single atom is sufficient to change the selectivity profile of a compound. At the extremes of the new compounds were 2-amino-3-(4-methylpiperazin-1-yl)quinoxaline, which showed 11-fold selectivity for the 5-HT3A receptor, and 2-(4-methylpiperazin-1-yl)quinoxaline, which showed an 8.3-fold selectivity for the 5-HT3AB receptor. These compounds represent novel molecular tools for studying 5-HT3 receptor subtypes and could help elucidate their physiological roles.

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Synthesis of 2(1H)-quinoxalinone O-(2′-quinoxalinyl)oxime (3) results in two easily distinguishable crystal forms with different colours, providing a rare example of colour polymorphism. The crystal structures of the two forms have been determined and compared. Intermolecular interactions and light- absorption characteristics of the polymorphs have been analysed by a mixed quantum chemical/molecular mechanical method. In one of the polymorphic forms the crystal field stabilises relatively high energy conformations by enhanced electrostatic interactions. The difference in the light absorption is found to be caused partly by a conformational difference of the molecules. The crystal field increases the difference in the absorption wavelengths and shift them towards higher values.

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The present disclosure relates to novel compounds including formula (X) and pharmaceutical compositions thereof, and methods for inhibiting the activity of SHP2 phosphatase with the compounds and compositions of the disclosure. The present disclosure further relates to, but is not limited to, methods for treating disorders associated with SHP2 deregulation with the compounds and compositions of the disclosure.

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Quinoxaline – Wikipedia,
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Inter- and intramolecular transition metal-catalyzed amination of 2-chloro-3-iodopyridine and 2,3-dibromopyridine, respectively, with benzodiazinamines yielded six hitherto unknown tetracyclic azaheteroaromatic cores. C-N bond formation was achieved via auto-tandem (Pd-catalyst) as well as one-pot (sequential use of a Pd- and Cu-catalyst) catalysis.

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