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BRIDGED PIPERIDINE DERIVATIVES

The present invention relates to a compound of formula (I), wherein Het Ar is a five or six membered hetaryl group, containing one, two or three heteroatoms, selected from N, O or S; R1 is hydrogen, lower alkyl, lower alkyl substituted by halogen, halogen, or lower alkoxy; R2 is lower alkyl substituted by halogen, -CH2-C3-6-cycloalkyl, substituted by one or two substituents, selected from lower alkyl substituted by halogen or halogen, or is lower alkenyl substituted by halogen; R3 is hydrogen, lower alkyl substituted by halogen, lower alkyl, halogen, C3-6-cycloalkyl or lower alkyl substituted by hydroxy; n is 1 or 2; for n = 2, R1 can be independent to each other; Y is CH or N; or to a pharmaceutically active acid addition salt thereof, to a racemic mixture or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof. The compounds may be used for the treatment of Alzheimer’s disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica or Down syndrome.

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

Can You Really Do Chemisty Experiments About Pd2(DBA)3

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Torsional Bias as a Strategy to Tune Singlet-Triplet Gaps in Organic Diradicals

Quinoidal compounds with proaromatic structures possess differing degrees of diradical character, where the open-shell diradical resonance form has restored aromaticity throughout the compound. Methods to tune the diradical character of these compounds have traditionally focused on altering the length and the molecular composition of the pi-conjugated backbones. However, other molecular design strategies to tune the singlet-triplet gap of pi-conjugated quinoidal molecules have not been extensively explored. We previously reported a strikingly small energy gap between the quinoidal and diradical states of a quinoidal small molecule containing methano[10]annulene (TMTQ) that was dictated in large part by the unusual aromaticity of the central annulene ring. Here, we report on two alkylated derivatives of TMTQ that present substantially different torsional biases to the planarity of the TMTQ pi-system. Using a combination of electronic and vibrational spectroscopies, magnetic measurements, and quantum chemical calculations, we demonstrate here how a steric effect rather than pi-electron compositional molecular engineering can dramatically narrow the singlet-triplet gap of a quinoidal compound to as small as -0.52 kcal/mol, determined experimentally. This study offers important insight for the continued development of open-shell diradical molecules that need not rely exclusively on the design of synthesis of new and complex pi-conjugated systems.

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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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Competing reactions of hydrophenylation and phenylation in tetraphenylantimony chloride methyl acrylate palladium chloride system

A new catalytic reaction of the competing phenylation and hydrophenylation in air of methyl acrylate with tetraphenylantimony chloride in the presence of PdCl2 (0.04 mol per 1 mol of organometallic compound) in acetonitrile at 50C for 6 h was studied. The yields of methyl cynnamate and methyl hydrocynnamate were 0.73 and 0.27 mol mol-1 respectively. The products ratio obtained depends slightly on the process duration, the Ph 4SbCl and methyl acrylate ratio, and the structure of Pd salt [PdCl2, Pd(OAc)2, Li2PdCl4], but significantly on the nature of a solvent (MeCN > DMF > THF). The use of Ph4SbCl instead of Ph4SbBr leads to decrease in the yield of methyl hydrocynnamate to 0.04 mol mol-1. In the reactions of Ph4SbX (X = F, I, OAc, O2CEt) the product is not formed at all. Pleiades Publishing, Inc., 2006.

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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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HETEROCYCLIC NUCLEAR HORMONE RECEPTOR MODULATORS

Provided are fused bicyclic compounds of Formula (I) effective to modulate the glucocorticoid receptor, wherein X, Y, Z, M, Q, L, J, G, E, A, Ring 1 and 2 are defined as in the description. Also provided herein are a pharmaceutical composition thereof, and uses in the manufacture of a medicament for treating corresponding disease thereof.

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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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Development of a Synthesis of Kinase Inhibitor AKN028

The novel tyrosine kinase inhibitor AKN028 has demonstrated promising results in preclinical trials. An expedient protocol for the synthesis of the compound at kilogram scale is described, including an SNAr reaction with high regioselectivity and a Suzuki coupling. Furthermore, an efficient method for purification and removal of residual palladium is described.

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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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Highly stereoselective synthesis of (1E)-2-melethyl-1,3-dienes by palladium-catalyzed trans-selective cross-coupling of 1,1-dibromo-1-alkenes with alkenylzine reagents

Ligand control: The use of Pd complexes containing tBu3P or nitrogen-heterocyclic carbene (NHC) ligands almost completely prevents stereoisomerization, thereby permitting an efficient and selective methylation and higher alkylation of (Z)-2-bromo-1,3-dienes (see scheme, dba = trans,trans-dibenzylideneacetone).

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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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Palladium-catalyzed cyanomethylation of aryl halides through domino Suzuki coupling-isoxazole fragmentation

A one-pot protocol for the cyanomethylation of aryl halides through a palladium-catalyzed reaction with isoxazole-4-boronic acid pinacol ester was developed. Mechanistically, the reaction proceeds through (1) Suzuki coupling, (2) base-induced fragmentation, and (3) deformylation as shown by characterization of all postulated intermediates. Under optimized conditions (PdCl2dppf, KF, DMSO/H2O, 130 C) a broad spectrum of aryl bromides could be converted into arylacetonitriles with up to 88% yield.

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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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Pure and complex nanostructures using poly[bis(triiso-propylsilylethynyl) benzodithiophene-bis(decyltetradecyl-thien) naphthobisthiadiazole], carbon nanotubes and reduced graphene oxide for high-performance polymer solar cells

Crystallization of poly[bis(triiso-propylsilylethynyl) benzodithiophene-bis(decyltetradecyl-thien) naphthobisthiadiazole] (PBDT-TIPS-DTNT-DT) was investigated in supramolecules based on carbon nanotubes (CNTs) and reduced graphene oxide (rGO) and their grafted derivatives. The principal peaks of PBDT-TIPS-DTNT-DT crystals were in the range 3.50?3.75. By grafting the surface of the carbonic materials, the assembling of polymer chains decreased because of hindrance of poly(3-dodecylthiophene) (PDDT) grafts against pi-stacking. The diameters of CNT/polymer and CNT-g-PDDT/polymer supramolecules were 160 and 100 nm. The rGO/polymer supramolecules had the highest melting point (Tm = 282 C) and fusion enthalpy (DeltaHm = 25.98 J g?1), reflecting the largest crystallites and the most ordered constituents. Nano-hybrids based on grafted rGO (276 C and 28.26 J g?1), CNT (275 C and 27.32 J g?1) and grafted CNT (268 C and 22.17 J g?1) were also analyzed. Tm and DeltaHm values were significantly less in corresponding melt-grown systems. The nanostructures were incorporated in active layers of PBDT-TIPS-DTNT-DT:phenyl-C71-butyric acid methyl ester (PC71BM) solar cells to improve the photovoltaic features. The best results were detected for PBDT-TIPS-DTNT-DT:PC71BM:rGO/polymer systems having Jsc = 13.11 mA cm?2, fill factor 60% and Voc = 0.71 V with an efficacy of 5.58%. On grafting the rGO and CNT, efficiency reductions were 12.01% (5.58%?4.91%) and 9.34% (4.07%?3.69%), respectively.

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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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Palladium-catalyzed, sequential, three-component cross-coupling of aryl halides, alkynes, and arynes

(Chemical Equation Presented) Three’s a crowd? Polycyclic aromatic hydrocarbons can be synthesized efficiently and in high yield using the first palladium-catalyzed, sequential, three-component coupling of alkynes and arynes with aryl halides (see scheme). This process appears to involve the catalytic, stepwise carbopalladation of an alkyne and an aryne to generate the three-component products.

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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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Aromatic amine N-oxide organometallic compounds: Searching for prospective agents against infectious diseases

In search of prospective agents against infectious diseases, 1,1?-bis(diphenylphosphino)ferrocene pyridine-2-thiolato-1-oxide M(II) hexafluorophosphate compounds [M(mpo)(dppf)](PF6), where M = palladium or platinum, were synthesized and fully characterized in the solid state and in solution using experimental and DFT computational techniques. The compounds are isomorphous and the M(II) transition metal ions are in a nearly planar trapezoidal cis-coordination bound to the pyridine-2-thiolato-1-oxide (mpo) and to the 1,1?-bis(diphenylphosphino)ferrocene molecules, both acting as bidentate ligands. Both compounds showed high cytotoxic activity on Trypanosoma cruzi and Mycobacterium tuberculosis (MTB) and acceptable selectivities towards MTB, but good to excellent selectivity index values as anti-T. cruzi compounds. The inclusion of the ferrocene moiety (dppf ligand) improved the selectivity towards the parasite when compared to the previously reported [M(mpo)2] complexes. Related to the probable mechanism of action of the complexes, molecular docking studies on modelled T. cruzi NADH-fumarate reductase (TcFR) predicted that both be very good inhibitors of the enzyme. The effect of the compounds on the enzyme activity was experimentally confirmed using T. cruzi protein extracts. According to all obtained results, both [M(mpo)(dppf)](PF6) compounds could be considered prospective anti-trypanosomal agents that deserve further research.

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