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As part of an ongoing effort at Amgen to develop a disease-modifying therapy for Alzheimer’s disease, we have previously used the aminooxazoline xanthene (AOX) scaffold to generate potent and orally efficacious BACE1 inhibitors. While AOX-BACE1 inhibitors demonstrated acceptable cardiovascular safety margins, a retinal pathological finding in rat toxicological studies demanded further investigation. It has been widely postulated that such retinal toxicity might be related to off-target inhibition of Cathepsin D (CatD), a closely related aspartyl protease. We report the development of AOX-BACE1 inhibitors with improved selectivity against CatD by following a structure- and property-based approach. Our efforts culminated in the discovery of a picolinamide-substituted 3-aza-AOX-BACE1 inhibitor absent of retinal effects in an early screening rat toxicology study.

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Reference:
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]dichloropalladium(II)

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The present invention relates to compounds of the formula (I) wherein R1 and R2 are each independently lower alkyl lower alkenyl, acyl, amino, lower alkoxy, lower cycloalkyloxy, aryl, aryloxy, sulfooxy, mercapto, sulfo, hydrogen, halogen, nitro, cyano or hydroxy, or may form a ring structure; Q1 is N or CH; L is optionally substituted unsaturated 3 to 10-membered heterocyclic group; X is optionally substituted monocyclic arylene or monocyclic heteroarylene; Y is -(A1)m-(A2)n-(A4)k-; Z is directbond, ?CH2-, ?NH? or ?O?; and R is hydrogen or lower alkyl, or a salt thereof The compounds of the present invention inhibit apolipoprotein B (Apo B) secretion and are useful as a medicament for prophylactic and treatment of diseases or conditions resulting from elevated circulating levels of Apo B.

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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 new method of Sonogashira coupling reactions between diorganyl tellurides and terminal alkynes is reported. The coupling reactions are performed using Pd(dppf)Cl2 as a catalyst, CuI as a co-catalyst in the presence of K2CO3 in DMSO. The reactions are carried out at room temperature and completed within 2 h when phenyl acetylene is used as a terminal alkyne. For aliphatic terminal alkynes, such as 1-hexyne and 1-octyne, an elevated temperature and longer reaction time are needed for the completion of the reactions. This process results in good yields of Sonogashira coupling products which is applicable for diaryl, divinyl and dialkynyl tellurides but not applicable for dialkyl tellurides.

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

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9-Hydroxyfluorenes are easily synthesized via a tandem Suzuki/phenolic aldolisation sequence. This process was extended to 9-aminofluorenes by simply adding various amines as third partners. X-ray structures and NMR studies confirmed the presence of intermolecular O?H ? ? ? N hydrogen bonding. (Figure presented.).

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

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The process development for the synthesis of BMS-986020 (1) via a palladium catalyzed tandem borylation/Suzuki reaction is described. Evaluation of conditions culminated in an efficient borylation procedure using tetrahydroxydiboron followed by a tandem Suzuki reaction employing the same commercially available palladium catalyst for both steps. This methodology addressed shortcomings of early synthetic routes and was ultimately used for the multikilogram scale synthesis of the active pharmaceutical ingredient 1. Further evaluation of the borylation reaction showed useful reactivity with a range of substituted aryl bromides and iodides as coupling partners. These findings represent a practical, efficient, mild, and scalable method for borylation.

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

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In heterogeneous catalysis, the catalyst is in a different phase from the reactants. Formula: C42H42P2Pd, At least one of the reactants interacts with the solid surface in a physical process called adsorption in such a way. 69861-71-8, name is Bis(tri-o-tolylphosphine)palladium(0). In an article,Which mentioned a new discovery about 69861-71-8

Catechol diethers that incorporate a 7-cyano-2-naphthyl substituent are reported as non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). Many of the compounds have 1-10 nM potencies toward wild-type HIV-1. An interesting conformational effect allows two unique conformers for the naphthyl group in complexes with HIV-RT. X-ray crystal structures for 4a and 4f illustrate the alternatives.

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

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Condensation of [Mn2(CO)8(mu-PPh2)]- with Pd(II) assisted by Ag(I) leads to cluster disproportionation, viz. Mn2Pd2Ag(mu-Cl)(mu-PPh2)2(mu-d ppm)(CO)8 and MnPd(mu-PPh2)(CO)4(eta2-P-P) (P-P = dppm, dppe, dppf). The former shows a distorted bow-tie structure with two heterometallic triangles {AgPdMn} sharing an Ag center. The unexpected phosphide migration across different metals holds the key to the cleavage and formation of metal-metal bonds. The bimetallic complexes are stabilized by all common diphosphines whereas the polymetallic structure is isolated only when supported by dppm. The latter shows three different types of heterometal-metal bonds Ag-Mn (2.6938(4) A), Ag-Pd (2.7637(1) A) and Mn-Pd (2.8183(9) A) (average values).

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

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The lipid kinase phosphoinositide 3-kinase gamma (PI3Kgamma) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kgamma, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kgamma. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.

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

Awesome Chemistry Experiments For 69861-71-8

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The coupling reaction of 1,1-disubstituted olefins (alpha-methyl-styrene, n-butyl methacrylate) with various aryl bromides (Heck reaction) has been studied as a new concept to synthesize trisubstituted olefins. Surprisingly, the nature of the base dramatically influences the product distribution. Thus, a systematic investigation on the role of base in Heck reactions of 1,1-disubstituted olefins was performed. Less coordinating bases like NaOAc, NaOBz or Na2CO3 yield a statistical distribution of regioisomers with the terminal olefin 10 as the major product. However, by using amines like Bu3N or diisopropylethylamine (DIPEA) as base internal olefins can be synthesized with high selectivities. With phosphapalladacycle 3 as catalyst precursor, we were able to obtain catalyst turnover numbers up to 1000, while Pd(OAc)2/2PPh3 was one order of magnitude less active. Analysis of the reaction profile by kinetic investigations led to the postulation of a reduction and subsequent oxidative addition of the catalyst precursor 3 to form 12 as catalytically active intermediate.

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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 new heterometallic dyad composed of a zinc porphyrin linked by bisethynyl quaterthiophene to a gold porphyrin was synthesized according to a stepwise modular approach. The latter dyad and the parent reference compounds (porphyrin-ethynylquaterthiophene) were characterized by electrochemistry, spectroelectrochemistry, and femtosecond transient absorption spectrocopy. We showed that light excitation of the zinc or the gold porphyrin induces a very fast and quantitative charge separation over a distance of 25 A which occurs through a superexchange mechanism. The lifetime of the charge-separated state is 3.3 ns in toluene and 100 ps in dichloromethane, and it recombines to the ground state in both solvents.

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