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Process for the preparation of secondary amines

N,N-disubstituted amines in which the amino nitrogen atom is bound to the carbon atom of an aromatic ring disubstituted in the positions ortho to the carbon atom, are prepared by allowing a primary amine and a compound in which an ortho, ortho-disubstituted aromatic compound carrying a nucleofuge substituent, to react in a basic environment in the presence of a catalytic palladium(0) complex and a ligand, the ratio of palladium complex to ligand being greater than at least 1:1. A typical embodiment involves the reaction of 2-methyl-6-ethylphenyl-trifluoromethylsulfonate and (S)-1-methoxy-2-aminopropane in the presence of bis(dibenzylideneacetone)palladium, tri-tert.-butylphosphine, and sodium tert.-butoxide to yield (S)-N-(1-methoxyprop-2-yl)-2-methyl-6-ethylphenylamine.

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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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Silver decoration of a palladacycle through “spacer-guest” interaction

[Pd(dppf)(MeCN)2](OTf)2 [dppf = 1,1?-bis(diphenylphosphino)ferrocene, OTf = triflate] reacts with pyridyl acetic acid (PyAcOH) to yield a dipalladium ring structure, [Pd2(dppf)2(mu-PyOAc)2](OTf)2 (1). The doubly-bridging ligands exhibit basicity at the pendant carboxyl oxygen to attract AgX (X = OTf or CF3CO2) to form [Pd2Ag2(dppf)2(PyOAc)2(OTf)4] (2) and [Pd2Ag2(dppf)2(PyOAc)2(OTf)2(CF3CO2)2] (3), respectively. Complexes 1 and 2 have been crystallographically characterized. Similar spacer-guest affinity is not found in the Pt(II) or isonicotinate analogues.

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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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Ligand exchange as the first irreversible step in the nickel-catalyzed cross-coupling reaction of grignard reagents

Mechanistic studies of the Ni-catalyzed cross-coupling reaction of Grignard reagents through analysis of kinetic isotope effects and theoretical calculations indicated that the product-to-substrate ligand exchange process is the first irreversible step and affects the turnover efficiency and selectivity of the reaction. On the other hand, the oxidative addition step is the first irreversible step in Pd catalysis. This finding has useful implications for the development of efficient Ni catalysis and also illustrates the importance of the catalyst turnover step that has so far received less attention than subsequent catalytic steps. Copyright

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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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AGENT FOR TREATMENT OF EYE DISEASES

The present invention provides agents effective to treat eye diseases, pharmaceutical compositions comprising them, methods for preparing pharmaceuticals for treatment of eye diseases comprising using the agents, use of the agents in manufacture of pharmaceuticals for treatment of eye diseases and methods for treating eye diseases comprising administering the agents or the pharmaceutical compositions. The eye diseases treated by the present invention include particularly glaucoma, especially normal tension glaucoma, or retinitis pigmentosa. The present invention provides the compound of formula (I) wherein R is as defined in the description.

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

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Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with Robust Anticancer Efficacy

Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3). Herein we disclose the discovery of a first-in-class potent, selective, and orally bioavailable EED inhibitor compound 43 (EED226). Guided by X-ray crystallography, compound 43 was discovered by fragmentation and regrowth of compound 7, a PRC2 HTS hit that directly binds EED. The ensuing scaffold hopping followed by multiparameter optimization led to the discovery of 43. Compound 43 induces robust and sustained tumor regression in EZH2MUT preclinical DLBCL model. For the first time we demonstrate that specific and direct inhibition of EED can be effective as an anticancer strategy.

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

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N-[4-(1h-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-sulfonamides and their use as pharmaceuticals

wherein Ar, R1, R2 and n have the meanings indicated in the claims. The compounds of the formula I are valuable pharmacologically active compounds which modulate protein kinase activity, specifically the activity of serum and glucocorticoid regulated kinase (SGK), in particular of serum and glucocorticoid regulated kinase isoform 1 (SGK-1, SGK1),and are suitable for the treatment of diseases in which SGK activity is inappropriate, for example degenerative joint disorders or inflammatory processes such as osteoarthritis or rheumatism. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use as pharmaceuticals, and pharmaceutical compositions comprising them

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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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Factors affecting the oxidative addition of aryl electrophiles to 1,1?-bis(diphenylphosphino)ferrocenepalladium(eta2-methyl acrylate), an isolable Pd[0] alkene complex

The title complex 3 has been synthesized and characterized by X-ray crystallography. It undergoes oxidative addition with aryl triflates and iodides by a nondissociative mechanism in THF. The Heck addition product methyl cinnamate was detected at traces from the reaction with phenyl triflate, and from iodobenzene the direct oxidative addition product was characterized. The addition of halides or acetate salts to the system led to modest effects on the rate of oxidative addition of aryl triflates, but resulted in neutral arylpalladium(II) complexes. Addition of lithium or europium salts enhanced the reaction rate, the effect being most pronounced with Eu(OTf)3, possibly through promotion of a competing dissociative pathway.

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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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(Hetero)arylation of 6-halogenoimidazo[1,2-a]pyridines differently substituted at C(2): Influence of the 2-substituent on the Suzuki cross-coupling reaction

We previously reported that reactivity towards the Suzuki cross-coupling reaction of 3-iodoimidazo[1,2-a]pyridines substituted at C(2) is largely influenced by the nature of this 2-substituent. Hence, with the aim to expand the scope of this coupling process to the 6-position of this series, it seemed important to similarly determine the influence of the nature of the 2-substituent (H, alkyl, or aryl) on the rate of coupling. From this work, the Suzuki-type cross-coupling was shown to proceed efficiently on 6-bromo-2-methyl- and 2-(4-fluorophenyl)imidazo[1,2-a]pyridines, whereas the 6-Br derivative unsubstituted at C(2) appeared to be poorly reactive. By modifying the reaction conditions in terms of catalyst and base, and the nature of the halogen, the reactivity of the unsubstituted series was largely enhanced. Finally, this work led us to establish efficient and convenient Suzuki reaction conditions for the 6-(hetero)arylation of 6-halogenoimidazo[1,2-a]pyridines depending on the nature of the 2-substituent and boronic acid.

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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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Multicomponent Reductive Cross-Coupling of an Inorganic Sulfur Dioxide Surrogate: Straightforward Construction of Diversely Functionalized Sulfones

Conventionally, sulfones are prepared by oxidation of sulfides with strong oxidants. Now, a multicomponent reductive cross-coupling involving an inorganic salt (sodium metabisulfite) for the straightforward construction of sulfones is disclosed. Both intramolecular and intermolecular reductive cross-couplings were comprehensively explored, and diverse sulfones were accessible from the corresponding alkyl and aryl halides. Intramolecular cyclic sulfones were systematically obtained from five- to twelve-membered rings. Naturally occurring aliphatic systems, such as steroids, saccharides, and amino acids, were highly compatible with the SO2-insertion reductive cross-coupling. Four clinically applied drug molecules, which include multiple heteroatoms and functional groups with active hydrogens, were successfully prepared via a late-stage SO2 insertion. Mechanistic studies show that alkyl radicals and sulfonyl radicals were both involved as intermediates in this transformation.

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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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Successive substitution of halogen atoms in 4,6-dihaloquinolines in palladium-catalyzed reactions with amines and arylboronic acids

A procedure was developed for the synthesis of 4,6-diamino- and 4,6- or 6,4-arylaminoquinolines by palladium-catalyzed C-N- and/or C-C-cross-coupling of 6-bromo-4-chloroquinoline.

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