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(b) 3-(pyrrolidine-1-carbonyl)thiomorpholine Triethylamine (3.1 ml). followed by a solution of pyrrolidine (2.0 ml) in 10 ml of tetrahydrofuran, was added at 0 C. under a stream of nitrogen to a solution of 5.0 g of 4-(t-butoxycarbonyl)thiomorpholine-3-carboxylic acid in 100 ml of tetrahydrofuran. After the mixture had been stirred for I hour, a solution of 3.6 g of ethyl cyanophosphate in 10 ml of tetrahydrofuran was added to the mixture and the mixture was stirred for 5 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to yield 461 g (74%) of 4-(t-butoxycarbonyl)-3-(pyrrolidine-1-carbonyl)thiomorpholine.

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Reference£º
Patent; Sankyo Company Limited; US5021413; (1991); A;,
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To a solution of N-Boc thiomorpholine carboxylic acid (1.36 g, 5.51 mmol) in dichloromethane (13.6 ml) were added under N2, at r.t., TBTU (1.95 g, 6.06 mmol) and DIPEA (1.92 ml, 11.02 mmol) and the solution was stirred for 30 mins. To a suspension of L-serine methyl ester hydrochloride (1.71 g, 11.02 mmol) in dichloromethane (13.6 ml) was added DIPEA (1.92 ml, 11.02 mmol) and the resulting solution was stirred for 30 mins. Then the solution containing the serine free base was added to the reaction mixture and it was left stirring for 16 hrs. Water was added to the reaction mixture and the aqueous layer was extracted with dichloromethane (x3) and the combined organic phases were dried (Na2SO4) and evaporated to dryness. The crude title compound (3.87 g) was used in the next step without further purification. UPLC/MS: m/z= 371 (M+Na); 349 (M+1 ); 293 (M-fBu); 249 (M-BOC+1 ) (at) t=0.59 min

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Reference£º
Patent; SMITHKLINE BEECHAM CORPORATION; WO2007/28654; (2007); A1;,
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Substituted piperidine amide derivatives and their pharmaceutically acceptable preparation method and in the application of the (by machine translation)

The invention relates to a compound of general formula (I) said substituted piperidine amide derivatives or a stereoisomer thereof, a pharmaceutically acceptable salt, and its preparation method, the drug combination of the local anesthesia or analgesia in and to the use of, the general formula (I) each group definition consistent with the specification; (by machine translation)

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Analgesic thiomorpholins their preparation, and pharmaceutical compositions containing them

Analgesic compounds are of the general formula (I): STR1 in which, R1 and R2 each represents hydrogen or C1 -C6 alkyl, or R1 and R2 together with the nitrogen atom to which they are attached form a heterocycle; E represents methylene, sulfur, oxygen or imino group optionally substituted with C1 -C6 alkyl or aralkyl; ring A is aryl or heteroaryl ring, optionally substituted; R3 is hydrogen or C1 -C6 alkyl and R4 is hydrogen or R3 and R4 together represent a group of formula (IV): (wherein Ra and Ra is C1 -C6 alkyl or hydrogen, up to a maximum of 3 alkyl groups, m is 1, 2, or 3, and Y is two hydrogens or oxygen); provided that when E represents a methylene group, then R3 is a C1 -C6 alkyl group or R3 and R4 together represent a group of the formula (IV).

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Chemistry is the science of change. But why do chemical reactions take place? Why do chemicals react with each other? The answer is in thermodynamics and kinetics.In a document type is Article, the author is Ernouf, Guillaume and a compound is mentioned, HPLC of Formula: C10H17NO4S, 4-(tert-Butoxycarbonyl)thiomorpholine-3-carboxylic acid, introducing its new discovery. HPLC of Formula: C10H17NO4S

Photochemical Strain-Release-Driven Cyclobutylation of C(sp3)-Centered Radicals

A new photoredox-catalyzed decarboxylative radical addition approach to functionalized cyclobutanes is described. The reaction involves an unprecedented formal Giese-type addition of C(sp3)-centered radicals to highly strained bicyclo[1.1.0]butanes. The mild photoredox conditions, which make use of a readily available and bench stable phenyl sulfonyl bicyclo[1.1.0]butane, proved to be amenable to a diverse range of alpha-amino and alpha-oxy carboxylic acids, providing a concise route to 1,3-disubstituted cyclobutanes. Furthermore, kinetic studies and DFT calculations unveiled mechanistic details on bicyclo[1.1.0]butane reactivity relative to the corresponding olefin system.

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Discovery and synthesis of HIV integrase inhibitors: Development of potent and orally bioavailable N-methyl pyrimidones

The human immunodeficiency virus type-1 (HIV-1) encodes three enzymes essential for viral replication: a reverse transcriptase, a protease, and an integrase. The latter is responsible for the integration of the viral genome into the human genome and, therefore, represents an attractive target for chemotherapeutic intervention against AIDS. A drug based on this mechanism has not yet been approved. Benzyl-dihydroxypyrimidine-carboxamides were discovered in our laboratories as a novel and metabolically stable class of agents that exhibits potent inhibition of the HIV integrase strand transfer step. Further efforts led to very potent compounds based on the structurally related N-Me pyrimidone scaffold. One of the more interesting compounds in this series is the 2-N-Me-morpholino derivative 27a, which shows a CIC95 of 65 nM in the cell in the presence of serum. The compound has favorable pharmacokinetic properties in three preclinical species and shows no liabilities in several counterscreening assays.

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PYRIDINE DERIVATIVES AND THEIR USE IN THE TREATMENT OF PSYCHOTIC DISORDERS

There are provided according to the invention novel compounds of formula (I) or a pharmaceutically acceptable salt thereof: (I) wherein: X represents a nitrogen atom; Y represents-C(H2)-, (-C(H2)-)2,-S(O2)-or-C(=O)-; Z represents-C(H2)-,-S(O2)-,-N(Rz)-, or an oxygen or sulphur atom; A represents hydrogen or-CH2OH; Rz represents hydrogen, C1-6 alkyl, C1-6 alkoxy,-COR7 or-SO2R7; R1 represents halogen, C1-6 alkyl, C1-6 alkoxy, =O, haloC1-6 alkyl, haloC1-6 alkoxy, hydroxyl or-CH2OH; m represents an integer from 0 to 3; R2 represents halogen, =O, C1-6alkyl (optionally substituted by one or more hydroxyl groups),-COOR7,-CONR7R8, C1-6 alkoxy, haloC1-6 alkyl, haloC1-6alkoxy or C1-6 alkyloC1-6 alkyl; n represents an integer from 0 to 3; p and q independently represent an integer from 0 to 2; R3 represents an-aryl,-heteroaryl,-heterocyclyl,-aryl-aryl,-aryl-heteroaryl,-aryl-heterocyclyl,-heteroaryl-aryl,-heteroaryl-heteroaryl,-heteroaryl-heterocyclyl,-heterocyclyl-aryl,-heterocyclyl-heteroaryl or-heterocyclyl-heterocyclyl group, all of which may be optionally substituted by one or more (e.g. 1, 2 or 3) halogen, C1-6 alkyl (optionally substituted by one or more hydroxyl groups), C3-8cycloalkyl, C1-6 alkoxy, hydroxyl, haloC1-6alkyl, haloC1-6 alkoxy, cyano,-S-C1-6 alkyl,-SO-C1-6 alkyl,-SO2-C1-6 alkyl,-COR7,-CONR7R8,-NR7R8,-NR7COC1-6 alkyl,-NR7SO2-C1-6alkyl, C1-6 alkyl-NR7R8,-OCONR7R8 ,-NR7CO2R8 or-SO2NR7R8 groups; R4 and R5 independently represent C1-6 alkyl, or R4 and R5 together with the carbon atom to which they are attached may together form a C3-8cycloalkyl group; R6 represents halogen, C1-6 alkyl, C3-8cycloalkyl, C1-6 alkoxy, haloC1-6 alkyl or haloC1-6 alkoxy; s represents an integer from 0 to 4; R7 and R8 independently represent hydrogen, C1-6 alkyl or C3-8cycloalkyl; or solvates thereof.

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Thiomorpholine – Wikipedia,
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INHIBITORS OF HEPATITIS C VIRUS

The present application includes novel inhibitors of HCV, compositions containing such compounds, therapeutic methods that include the administration of such compounds.

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Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1- tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective K v7.1 (KCNQ1) potassium channel activator

A high-throughput screen utilizing a depolarization-triggered thallium influx through KCNQ1 channels was developed and used to screen the MLSMR collection of over 300,000 compounds. An iterative medicinal chemistry approach was initiated and from this effort, ML277 was identified as a potent activator of KCNQ1 channels (EC50 = 260 nM). ML277 was shown to be highly selective against other KCNQ channels (>100-fold selectivity versus KCNQ2 and KCNQ4) as well as against the distantly related hERG potassium channel.

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Thiomorpholine – Wikipedia,
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Compounds, compositions, and methods for stimulating neuronal growth and elongation

The present invention concerns methods, pharmaceutical compounds, and compositions for stimulating neuroite outgrowth in nerve cells leading to nerve regeneration. These methods, compounds and compositions inhibit rotamase enzyme activity associated with binding proteins.

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