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Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-pKa Polar Moiety

Signaling pathways intersecting with the p21-activated kinases (PAKs) play important roles in tumorigenesis and cancer progression. By recognizing that the limitations of FRAX1036 (1) were chiefly associated with the highly basic amine it contained, we devised a mitigation strategy to address several issues such as hERG activity. The 5-amino-1,3-dioxanyl moiety was identified as an effective means of reducing pKa and logP simultaneously. When positioned properly within the scaffold, this group conferred several benefits including potency, pharmacokinetics, and selectivity. Mouse xenograft PK/PD studies were carried out using an advanced compound, G-5555 (12), derived from this approach. These studies concluded that dose-dependent pathway modulation was achievable and paves the way for further in vivo investigations of PAK1 function in cancer and other diseases.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

Final Thoughts on Chemistry for 95464-05-4

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Direct cross-coupling access to diverse aromatic sulfide: Palladium-catalyzed double C-S bond construction using Na2S 2O3 as a sulfurating reagent

The Pd-catalyzed cross-coupling of aryl halides, alkyl halides, and Na 2S2O3¡¤5H2O to deliver aromatic thioethers is described. Pyridine, furan, thiophene, benzofuran, benzoxazole, benzothiophene, benzothiazole, and pyrazine are all amenable to this protocol. The odorless and stable solid Na2S2O 3¡¤5H2O was used as a convenient and environmentally friendly source of sulfur. Pd-catalyzed cross-couplings without thiols or thiophenols to build C-S bonds have not previously been achieved, which renders our observation more striking.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

Discovery of 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex

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A concise and scalable strategy for the total synthesis of dictyodendrin B based on sequential C-H functionalization

A sequential C-H functionalization strategy for the synthesis of the marine alkaloid dictyodendrin B is reported. Our synthesis begins from commercially available 4-bromoindole and involves six direct functionalizations around the heteroarene core as part of a gram-scale strategy towards the natural product.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

Simple exploration of 95464-05-4

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Intramolecular double or triple Suzuki coupling reaction of substituted di- or tribromobenzenes. An easy synthesis of fused tri- or tetracycles with a benzene core

Double or triple intramolecular Suzuki coupling reaction has been developed for the efficient synthesis of tri- or tetracyclic products with a benzene core in good yields. The reaction was realized via a one-pot procedure combining the hydroboration of the CC bond in the starting aryl halides and the intramolecular Suzuki coupling.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

Extended knowledge of 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex

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The Multiple Facets of Iodine(III) Compounds in an Unprecedented Catalytic Auto-amination for Chiral Amine Synthesis

Iodine(III) reagents are used in catalytic one-pot reactions, first as both oxidants and substrates, then as cross-coupling partners, to afford chiral polyfunctionalized amines. The strategy relies on an initial catalytic auto C(sp3)?H amination of the iodine(III) oxidant, which delivers an amine-derived iodine(I) product that is subsequently used in palladium-catalyzed cross-couplings to afford a variety of useful building blocks with high yields and excellent stereoselectivities. This study demonstrates the concept of self-amination of the hypervalent iodine reagents, which increases the value of the aryl moiety.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

Final Thoughts on Chemistry for 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex

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Discovery of Ruzasvir (MK-8408): A Potent, Pan-Genotype HCV NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Polymorphisms

We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a “flat” GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core while maintaining the imidazole-proline-valine Moc motifs of our previous NS5A inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

Brief introduction of 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex

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1-biaryl-1,8-naphthyridin-4-one phosphodiesterase-4 inhibitors

Compounds represented by Formula (I): 1or a pharmaceutically acceptable salt thereof, are phosphodiesterrase 4 inhibitors useful in the treatment of asthma and inflammation.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

Final Thoughts on Chemistry for 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex

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Compositions and methods for inducing cell dedifferentiation

The present invention provides compositions and methods for dedifferentiating lineage committed mammalian cells.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Amino-Indolyl-Substituted Imidazolyl-Pyrimidines and Their Use as Medicaments

The invention relates to new amino-indole-substituted imidazolyl-pyrimidines of formula 1 wherein R1, R2, R3, R4 and R5 are defined as in claim 1 and pharmaceutically acceptable salts thereof and the use of these compounds for the preparation of a medicament for treating a disease selected from asthma, COPD, rheumatoid arthritis, specific lymphomas and specific diseases of the nervous system.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

Discovery of 95464-05-4

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Methyl scanning: Total synthesis of demethylasterriquinone B1 and derivatives for identification of sites of interaction with and isolation of its receptor(s)

The principle of methyl scanning is proposed for determination of the sites of interaction between biologically active small molecules and their macromolecular target(s). It involves the systematic preparation of a family of methylated derivatives of a compound and their biological testing. As a functional assay, the method can identify the regions of a molecule that are important (and unimportant) for biological activity against even unknown targets, and thus provides an excellent complement to structural biology. Methyl scanning was applied to demethylasterriquinone B1, a small-molecule mimetic of insulin. A new, optimal total synthesis of this natural product was developed that enables the family of methyl scan derivatives to be concisely prepared for evaluation in a cellular assay. The results of this experiment were used to design a biotin-demethylasterriquinone conjugate for use as an affinity reagent. This compound was prepared in tens of milligram quantities in a four-step synthesis.

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Reference£º
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method