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PERFLUORINATED 5,6-DIHYDRO-4H-1,3-OXAZIN-2-AMINE COMPOUNDS AS BETA-SECRETASE INHIBITORS AND METHODS OF USE

The present invention provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula I: wherein variables A4, A5, A6, A8, each of R1 and R2, R3 and R7 of Formula I, independently, are defined herein. The invention also provides pharmaceutical compositions comprising the compounds, and corresponding uses of the compounds and compositions for treatment of disorders and/or conditions related to A-beta plaque formation and deposition, resulting from the biological activity of BACE. Such BACE mediated disorders include, for example, Alzheimer’s Disease, cognitive deficits, cognitive impairments, schizophrenia and other central nervous system conditions. The invention further provides compounds of Formulas II and III, and sub-formula embodiments thereof, intermediates and processes and methods useful for the preparation of compounds of Formulas I-III.

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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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The Enantioselective Synthesis of Chiral Carbocyclic Nucleosides via Palladium-Catalyzed Asymmetric Allylic Amination of Alicyclic MBH Adducts with Purines

The enantioselective synthesis of carbocyclic nucleosides through the palladium-catalyzed asymmetric allylic amination of alicyclic Morita-Baylis-Hillman (MBH) adducts with purines was successfully developed. With a combination of Pd2(dba)3/L7 as catalyst, various optically active carbocyclic nucleosides featuring a C=C double bond in the carbocycle moiety were obtained in high yields (up to 97%) with excellent N9/N7-selectivities (>95/5) and enantioselectivities (up to >99.6%). In addition, these nucleoside analogs allowed for rapid transformation to a variety of other interesting structurally diverse chiral carbocyclic nucleosides. (Figure presented.).

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

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3-Substituted tetrahydropyridopyrimidinone derivatives, method for producing the same, and their use

3-substituted tetrahydropyridopyrimidinone derivatives of the formula (I) wherein the radicals have the meanings given in the Description, to a method for producing said derivatives and, to their use for producing active ingredients for drugs.

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

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Palladium-Catalyzed 2,2,2-Trifluoroethoxylation of Aromatic and Heteroaromatic Chlorides Utilizing Borate Salt and the Synthesis of a Trifluoro Analogue of Sildenafil

A simple and convenient method was developed for the introduction of a 2,2,2-trifluoroethoxy group to various aromatic and heteroaromatic systems. The novel process utilizes aromatic chlorides as substrates, and tetrakis(2,2,2-trifluoroethoxy) borate salt as an inexpensive and readily available fluoroalkoxy source in a palladium-catalyzed cross-coupling reaction. The power of the developed methodology was demonstrated in the synthesis of a fluorous derivative of Sildenafil.

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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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Benzimidazolyl Palladium Complexes as Highly Active and General Bifunctional Catalysts in Sustainable Cross-Coupling Reactions

A family of air- A nd moisture-stable dinuclear palladium complexes bearing 2-benzimidazolyl ligands is reported and shown to be a highly effective and general catalytic platform in diverse cross-coupling reactions. The rigidity and conformation of the ligand scaffold was readily modified via tethering of the 2-benzimidazolyl moiety to diamine ligands, resulting in significant changes in catalytic activity. Under optimal conditions, Suzuki, Heck, and Sonogashira-type couplings of aryl bromides can all be performed efficiently with good functional group compatibility using only 0.1 mola?% of catalyst, in aqueous or alcohol solvents. Experimental evidence highlights the importance of the bifunctional character of the ligand for catalytic activity, where the basic N-functionality in the ligand framework is proposed to accelerate (trans)metalation steps via intramolecular assistance.

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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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Derivatives of DANPY (Dialkylaminonaphthylpyridinium), a DNA-Binding Fluorophore: Practical Synthesis of Tricyclic 2-Amino-6-bromonaphthalenes by Bucherer Reaction

A simple and convergent way to synthesize 2-amino-6-bromonaphthalenes involves condensation of free secondary amines with the corresponding 2-naphthol under Bucherer conditions. The amination protocol relies on common Teflon-capped pressure flasks and has been used to modify the tertiary aminonaphthalene core of DANPY, a biocompatible chromophore shown to be safe and effective for staining a variety of cellular targets. Following a Suzuki reaction with pyridine 4-boronic acid, additional diversity is introduced upon N-alkylation to install the pyridinium cation. New DANPY derivatives and intermediates reported herein reflect the modularity of the dye nucleus, including the addition of groups useful for applications in membrane staining and DNA-based biophotonics.

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

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INDANYLOXYPHENYLCYCLOPROPANECARBOXYLIC ACIDS

The present invention relates to compounds of general formula I, wherein the groups R1, R2, R3, m and n are defined as in claim 1, which have valuable pharmacological properties, in particular bind to the GPR40 receptor and modulate its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2. Furthermore, the invention relates to novel intermediates, useful for the synthesis of compounds of formula I.

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

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Highly Stereospecific Cross-Coupling Reactions of Anomeric Stannanes for the Synthesis of C-Aryl Glycosides

We demonstrate that configurationally stable anomeric stannanes undergo a stereospecific cross-coupling reaction with aromatic halides in the presence of a palladium catalyst with exceptionally high levels of stereocontrol. In addition to a broad substrate scope (>40 examples), this reaction eliminates critical problems inherent to nucleophilic displacement methods and is applicable to (hetero)aromatics, peptides, pharmaceuticals, common monosaccharides, and saccharides containing free hydroxyl groups.

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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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Activator-free palladium-catalyzed silylation of aryl chlorides with silylsilatranes

The palladium-catalyzed silylation of aryl chlorides with silylsilatranes proceeds under activator-free conditions; hence, wide functional group compatibility is displayed and boryl and siloxy groups are able to survive. Experimental and computational studies revealed that smooth transmetalation from the silylsilatrane to the arylpalladium chloride is facilitated by strong interaction between the Lewis acidic silicon and the chloride.

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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 cross-coupling of benzyl chlorides with cyclopropanol-derived ketone homoenolates

The palladium-catalyzed cross-coupling reaction of cyclopropanol-derived ketone homoenolates with benzyl chlorides is reported. This reaction proceeds in high yields with electron-neutral and electron-rich benzyl chlorides; however, yields are low with electron-poor benzyl chlorides. In addition, a range of cyclopropanols can be coupled in good yields. The reaction can be conducted with a low catalyst loading (1% Pd) and on a gram scale without reduction in yield.

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