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Palladium-catalyzed decarboxylative coupling of alpha,beta-unsaturated carboxylic acids with aryl tosylates

We report a general method for selective cross-coupling of alpha,beta-unsaturated carboxylic acids with aryl tosylates enabled by versatile Pd(II) complexes. This method features the general cross-coupling of ubiquitous alpha,beta-unsaturated carboxylic acids by decarboxylation. The transformation is characterized by its operational simplicity, the use of inexpensive, air-stable Pd(II) catalysts, scalability and wide substrate scope. The reaction proceeds with high trans selectivity to furnish valuable (E)-1,2-diarylethenes.

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

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Selectivity Controlled Palladium-Catalyzed Carbonylative Synthesis of Propiolates and Chromenones from Phenols and Alkynes

An interesting selectivity-controlled palladium-catalyzed oxidative carbonylation procedure for the synthesis of propiolates and chromenones has been developed. Starting from phenols and alkynes, under slightly different conditions, various propiolates and chromenones can be isolated in moderate to good yields. Additionally, this also presents the first example of direct carbonylative annulation of nonpreactivated phenols and terminal alkynes to produce chromenones.

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

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Discovery of GSK2656157: An optimized PERK inhibitor selected for preclinical development

We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.

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

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A practical, ligand-free, palladium-catalyzed isocyanide insertion reaction for the construction of novel ring-fused quinazolinones

A high-yielding, ligand-free, palladium-catalyzed isocyanide insertion reaction for the synthesis of phthalazino[1,2-b]quinazolinones from the readily obtainable quinazolinones has been developed. Easily handled and relatively low-cost palladium(II) acetate was used as the catalyst, without an additional ligand. Preparation of the quinazolinones involved the cascade reaction of isatoic anhydrides, phenylhydrazines and 2-bromobenzaldehyde catalyzed by p-toluenesulfonic acid in one pot. This novel protocol may be applicable for the synthesis of other important ring-fused heterocyclic compounds. Georg Thieme Verlag Stuttgart. New York.

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

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Total synthesis of an atropdiastereomer of RP-66453 and determination of its absolute configuration

The absolute configuration (aR, S, S, S, S, S) was assigned to the natural product RP-66453 (1) after the total synthesis of its atropdiastereomer and spectroscopic studies on the two compounds. A sequence of SNAr-based cyclo-etherification and an intramolecular atropdiastereoselective Suzuki-Miyaura coupling were used for the construction of the elusive A-B-O-C bicyclic skeleton of RP-66453.

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

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TRICYCLIC PI3K INHIBITOR COMPOUNDS AND METHODS OF USE

Described herein are tricyclic compounds with phosphoinositide-3 kinase (PI3K) modulation activity or function having the Formula I structure: or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I compounds, as well as methods of using such PI3K modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon PI3K dysregulation.

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

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Self-assembly of a copper(II)-based metallosupramolecular hexagon

The self-assembly of a 1:1 mixture of copper(II) ions and a rigid heteroditopic ligand L containing phen and terpy binding units gives rise in the solid state to green crystals of a hexanuclear metallamacrocycle 1. X-ray crystallography reveals that 1 consists of molecular hexagons of the grid-type family in which each metal ion is bound to two different ligands through the phen and terpy units, plus a weakly coordinated PF6- anion in a highly distorted octahedral geometry. ES-MS studies of acetonitrile solutions of L and copper(II) in a 1:1 ratio show mixtures of polynuclear complexes in which trinuclear L3Cu3 species are predominant.

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

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Peptide Ligation via the Suzuki-Miyaura Cross-Coupling Reaction

Chemoselective ligation of two 28-mer peptides has been accomplished using the Suzuki-Miyaura cross-coupling reaction at or near physiological temperature in an aqueous solution containing sodium dodecyl sulfate in 83% yield. The effects of Pd source, solvent, base, and temperature were investigated, and the optimized reaction conditions were studied for compatibility with naturally present and artificially introduced functional groups in peptides including S-protected thiol and azide. The peptide conjugations were carried out in high yield (90%) with their functional groups intact. This method also allowed for facile introduction of an affinity tag or fluorescent probe into 20-mer peptides in >80% yield. These results suggest that the Suzuki-Miyaura cross-coupling is useful for multiple conjugations of peptides in conjunction with conventional conjugation reactions performed in sequence.

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

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Synthesis and reactivity of phosphanido bridged 1,1?-bis(diphenylphosphino)ferrocene complexes [(RF)2Pt(mu-PPh2)2M(dppf)] [M = Pt, Pd]

Hetero-trinuclear complexes of formula [(C6F5)2Pt(mu-PPh2)2M(dppf)] [dppf = 1,1?-bis(diphenylphosphino)ferrocene, M = Pt (1), M = Pd (2)] were prepared by coupling between cis-[(C6F5)2Pt(PPh2)2]Li2and cis-MCl2(dppf). Reaction of the Pt/Pt/Fe species 1 with [Ag(OClO3)(PPh3)] or I2resulted in the formation of the complexes [(C6F5)(PPh3)Pt(mu-PPh2)2Pt(dppf)] (3) and [(C6F5)(I)Pt(mu-PPh2)2Pt(dppf)] (4), respectively, in which one of the pentafluorophenyl ligands has been replaced by PPh3or I. Reaction of the Pt/Pd/Fe species 2 with Ag(ClO4) afforded the tetranuclear complex [(C6F5)2Pt(mu-PPh2)2Pd(dppf)Ag] (5) where the silver atom is bonded to Pd, to one of the bridging P and to one of the dppf P atoms. With [Ag(OClO3)(PPh3)], complex 5 is also formed, although mixed with [Ag(PPh3)2][ClO4]. A dynamic process in solution, in which the silver atom passes from one Pd?muPPh2bond to the other, has been observed at room temperature for complex 5. The crystal structures of 3, 4 and 5 are reported.

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

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Methods for treating an inflammatory condition or inhibiting JNK

This invention is generally directed to Indazole Derivatives having the following structure: 1 or pharmaceutically acceptable salt thereof, wherein R1, R2 and A are as defined herein. Such compounds have utility in the treatment of a wide range of diseases and disorders that are responsive to JNK inhibition, such as an inflammatory disease or disorder. Thus, methods of treating such diseases and disorders are also disclosed, as are pharmaceutical compositions containing one or more compounds of the above compounds.

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