Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[O:4]=[CH:5][C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7].[Sn].[CH2:17](Br)[CH:18]=[CH2:19]>O>[CH2:19]([CH:5]([C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7])[OH:4])[CH:18]=[CH2:17]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C=CCBr
Agent: [Sn]
Solvent: CCO
Solvent: O
Product: C=CCC(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C

Procedure:
A 3 L, three-necked round bottom flask, equipped with heating mantle, stirrer, nitrogen inlet, and condenser, was charged with 900 mL of ethanol, 150 mL of water, 180 g (1.00 mole) of D-glucose, 119 g (1.00 mole) of tin powder (−100 mesh), and 121 g (1.00 mole) of allyl bromide. The mixture was stirred and slowly heated to reflux—a significant exotherm and gas evolution was observed at 60° C. The gray suspension was stirred at reflux for two days, in which time the reaction mixture turned an orange/brown color. Heat was removed and the mixture was allowed to cool to room temperature. The reaction was neutralized to pH=7 by adding approximately 200 ml of 5M NaOH aqueous solution. The suspension was filtered to remove solids, and the yellow solution was decolorized with multiple treatments of activated carbon. The activated carbon was removed by filtration, and the solvent was removed by rotary evaporation to isolate a white syrup. Typical yield was 200 g with threo-erythro ratio of 6:1, based on GC-MS. The syrup was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9](=[N:24][O:25][CH2:26][CH3:27])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1>C(#N)C>[Br:1][C:2]1[C:3](/[C:9](=[N:24]\[O:25][CH2:26][CH3:27])/[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:20])[F:22])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CCON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Br)cc1Br
Solvent: CC#N
Product: CCO/N=C(/CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Br)cc1Br
Yield: 64.1 %

Procedure:
195 mg of N-[2-(3,5-dibromopyridin-2-yl)-2-(ethoxyimino)ethyl]-2-(trifluoromethyl)benzamide was dissolved in 3 ml of acetonitrile, and the solution was irradiated with light for 12 hours in a quartz cell (manufactured by Fine, 4 clear windows for spectroscopy) using a 100 W high-pressure mercury lamp (manufactured by USHIO INC., lamp: UM-102, power supply: UM-103B-B). After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 5:5) as the eluent to obtain 125 mg of the desired product as a pale yellow resinous substance.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br-].[CH3:14][O:15][C:16]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:17]=1[CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:44][O:45][C:46](=[O:59])[C:47]1[CH:52]=[C:51]([CH:53]=O)[CH:50]=[CH:49][C:48]=1[NH:55][C:56](=[O:58])[CH3:57].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH3:44][O:45][C:46](=[O:59])[C:47]1[CH:52]=[C:51]([CH:53]=[CH:18][C:17]2[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=[CH:41][C:16]=2[O:15][CH3:14])[CH:50]=[CH:49][C:48]=1[NH:55][C:56](=[O:58])[CH3:57]
Reactant: COc1ccc(OC)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: COC(=O)c1cc(C=O)ccc1NC(C)=O
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1cc(C=Cc2cc(OC)ccc2OC)ccc1NC(C)=O
Reaction time: 0.5 h

Procedure:
4.1 mmol of n-butyllithium (0.4 ml of 1.6 M solution in hexane) are added at -40° to a solution of 412 mg of diisopropylamine in 30 ml of dry tetrahydrofuran. After stirring for 30 minutes 672 mg of 2,5-dimethoxybenzyl-triphenylphosphonium bromide are added at this temperature. The suspension is stirred for another 30 minutes, cooled to -70° and treated with 300 mg of 2-acetylamino-5-formyl-benzoic acid methylester in 8 ml of absolute tetrahydrofuran. The mixture is stirred for one hour at -70° and for two hours at room temperature and then poured onto aqueous ammonium chloride solution. Extraction with ethyl acetate and evaporation yields a crude product, which is subjected to silica gel chromatography (hexane/ethyl acetate =9/1) to obtain the title compound as a mixture of the E- and Z-isomers.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:18]=[C:17]([C:19]([O:21]CC)=[O:20])[N:16]=[CH:15]3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[OH-].[Li+]>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[N:16]=[CH:15]3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1c2ccc(-n3cnc(C(=O)O)c3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
A mixture of ethyl 1-[(cis)1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazole-4-carboxylate (for a preparation see Intermediate 82) (1.8 g, 4.2 mmol), methanol (15 mL), and lithium hydroxide (1M in water, 15 mL) was stirred at room temperature for 6 h then most of the methanol was removed in vacuo. The residue was diluted with water (15 mL) and acidified with glacial acetic acid. The resulting aqueous phase was extracted with AcOEt (3×30 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to give 1-[(cis)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazole-4-carboxylic acid (1.1 g, 2.75 mmol, 65%) as a colourless solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]([F:30])([F:29])[CH2:24][S:25](Cl)(=[O:27])=[O:26]>>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[S:25]([CH2:24][C:23]([F:30])([F:29])[F:22])(=[O:27])=[O:26])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Oc2ccc(NCc3cccnc3)cc2)cc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Product: O=S(=O)(CC(F)(F)F)N(Cc1cccnc1)c1ccc(Oc2ccccc2)cc1

Procedure:
Using the method of Example 343 using N-(4-phenoxypheny)pyridin-3-ylmethylamine and 2,2,2-trifluoroethanesulfonyl chloride (Aldrich) and purifying via preparative HPLC eluting with 90:10 to 70:30 DCM/ethyl acetate gave the title compound. Anal Calcd for C20H17F3N2O3S: C, 56.87; H, 4.06; N, 6.63. Found: C, 56.76; H, 4.09; N, 6.69. MS found 423.1 [M+H]+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:16])[CH2:14][CH3:15].[C:17]([O:21][C:22](=[O:37])[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][N:31]=2)[CH2:25]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22](=[O:37])[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=4)[N:5]=[CH:4][C:3]=3[C:13](=[O:16])[CH2:14][CH3:15])=[CH:32][N:31]=2)[CH2:25]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(N)cn2)C1
Reactant: CCC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CCC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 84.9 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)propan-1-one (500 mg, 1.96 mmol) was reacted with (R)-tert-butyl(1-(5-aminopyridin-2-yl)piperidin-3-yl)carbamate (860 mg, 2.94 mmol) to afford the desired product (850 mg, 84%) as a light brown solid: ESI MS m/z 511 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:15])[CH:10]=[N:9]2)=[C:5]([CH3:25])[O:4][N:3]=1.[C:26](=[O:31])=[N:27][C:28](Cl)=[O:29]>C1COCC1>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:28](=[O:29])[NH:27][C:26](=[O:31])[N:16]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:14]3=[O:15])[CH:10]=[N:9]2)=[C:5]([CH3:25])[O:4][N:3]=1
Reactant: O=C=NC(=O)Cl
Reactant: Cc1noc(C)c1Cn1cc(NC(=O)NCCc2ccccc2)cn1
Solvent: C1CCOC1
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]c(=O)n(CCc3ccccc3)c2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-3-phenethylurea (example 9-7a) (100 mg, 0.29 mmol) in THF (2 mL) was cooled to 0° C. and n-chlorocarbonyl isocyanate (93 mg, 0.88 mmol) was slowly added. After addition, the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was concentrated and the residue was purified by silica column chromotography (100% to 90% dichloromethane in methanol: 30 minute gradient) to afford (1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-3-phenethyl-1,3,5-triazinane-2,4,6-trione (100 mg, 83%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.13 (s, 3H), 2.39(s, 3H), 2.82 (t, J=5.8 Hz, 2H), 3.88 (t, J=8.0 Hz, 2H), 5.17 (s, 2H), 7.19-7.31 (m, 5H), 7.44 (s, 1H), 7.89 (s, 1H), 11.84 (s, 1H). LC/MS; [M+H] calculated for C20H20N6O4; expected 409.15; found 409.20. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 3.03 μM.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[N+:13]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[NH:10][N:9]=[CH:8]2)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc2cn[nH]c2cc1[N+](=O)[O-]
Yield: 28.2 %

Procedure:
By referring to the Step 1 of Example 7, 6-nitroindazole (5 g, 30.7 mmol), 35 mL of acetic acid, concentrated HNO3 (3.6 mL, 181.6 mmol), were used to obtain a product (1.8 g, 28.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](OCC)=[O:15])=[C:12]([CH3:19])[N:11]=[C:10]([CH3:20])[N:9]=2)=[CH:4][CH:3]=1.[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:14][OH:15])=[C:12]([CH3:19])[N:11]=[C:10]([CH3:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)nc(C)nc1-c1ccc(F)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(C)c(CO)c(-c2ccc(F)cc2)n1
Temperature: -78 °C
Yield: 79.3 %

Procedure:
To a solution of 46.5 g (0.169 mol) of ethyl 4-(4-fluorophenyl)-2,6-dimethyl-5-pyrimidinecarboxylate in 500 mL of dichloromethane at -78° C. under nitrogen was added 340 mL of a 1M solution of diisobutylauminum hydride (0.339 mol) in dichloromethane. The resulting mixture was stirred at -78° C. for one-half hour and then the reaction was quenched by the addition of a saturated aqueous solution of sodium sulfate (48.15 g, 0.34 mol). The cooling bath was removed and the mixture was vigorously stirred for twenty minutes and then filtered through Celite®. The filter cake was thoroughly washed with chloroform and the combined filtrate and washings were dried over anhydrous magnesium sulfate and evaporated to yield 31.14 g of 4-(4-fluorophenyl)-2,6-dimethyl-5-pyrimidinemethanol, mp 174°-176° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([CH:16]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:17](OC)=[O:18])(=O)[CH3:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH3:25][O:24][C:22](=[O:23])[CH2:21][C:16]1[CH:17]([OH:18])[N:10]2[N:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:11]2[NH:12][C:13]=1[CH3:14]
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Reactant: Nc1[nH]ncc1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)CC1=C(C)Nc2c(-c3ccccc3)cnn2C1O
Yield: 79.8 %

Procedure:
To a solution of 4-phenyl-1H-pyrazol-5-amine (0.5 g, 3.14 mmol) and dimethyl 2-acetylsuccinate (1.77 g, 9.4 mmol) in xylene (100 mL) was added p-toluenesulfonic acid monohydrate (5 mg, 0.263 mmol). The reaction mixture was heated at reflux under a Dean-Stark trap for 20 hrs. The solid was filtered and washed by hexanes to afford (0.75 g, 80%) of the title compound. 1H-NMR (500 MHz, DMSO-d6) δ ppm 2.38 (3H, s), 3.39 (2H, s), 3.59 (3H, s), 7.33 (1H, S), 7.47 (2H, m), 7.57 (2H, m) 8.13 (1H, S), 11.87 (1H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH:17]([F:19])[F:18])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH2:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)=[O:56])[CH2:51][CH2:52][CH3:53]>C(OCC)(=O)C>[CH2:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][N:60]([C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH:17]([F:19])[F:18])[CH2:59][CH2:58]1)=[O:56])[CH2:51][CH2:52][CH3:53]
Reactant: CCCCOC(=O)N1CCNCC1
Reactant: O=C(N[C@@H](CC(F)F)C(=O)O)OCc1ccccc1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CC(F)F)NC(=O)OCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 114 mg (S)-2-Benzyloxycarbonylamino-4,4-difluoro-butyric acid were added 0.11 ml N-ethylmorpholine, 138 mg TOTU and 78 mg 1-butoxycarbonylpiperazine. After stirring for 12 h the reaction mixture was diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl, saturated aqueous NaHCO3 and brine. The crude product obtained was used without further purification. Yield: 150 mg
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20](O)=[O:21])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:40][C:41]1[NH:45][N:44]=[N:43][N:42]=1>CN(C)C=O.C(Cl)Cl>[NH:42]1[C:41]([NH:40][C:20](=[O:21])[CH2:19][O:18][C:17]2[CH:23]=[CH:24][C:14]([CH2:13][CH2:12][NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])=[CH:15][CH:16]=2)=[N:45][N:44]=[N:43]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)COc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(COc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1)Nc1nnn[nH]1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 7.30 g. (20 mMol) 4-[2-(4-chlorobenzenesulphonamido)-ethyl]-phenoxyacetic acid (preparation see European Patent Specification No. 0,239,907) and 2.20 ml. 4-methylmorpholine in 60 ml. dry methylene chloride is added dropwise at -10° C. 2.76 g. (20 mMol) isobutyl chloroformate, dissolved in 40 ml. dry methylene chloride, within the course of 15 minutes. After a further 15 minutes, a solution of 3.06 g. (20 mMol) 5-amino-1,2,3,4-tetrazole and 20 ml. dimethylformamide are added dropwise thereto within the course of 15 minutes. After stirring for 1 hour at -10° C., the reaction mixture is allowed to come to ambient temperature overnight, the solvent is distilled off, the oily residue is taken up in ethyl acetate and shaken out with 2N aqueous sodium hydroxide solution. The aqueous alkaline phases are acidified with 2N sulphuric acid and the resultant precipitate is filtered off with suction and thoroughly washed with water. After crystallisation from ethanol, there are obtained 4.20 g. (48% of theory) of colourless crystals; m.p. 227.5°-229.5° C.
Reaction SMILES: C([O-])=O.[NH4+].[CH2:5]([C:7]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[C:34]([CH2:38][C:39]([OH:41])=[O:40])[CH:35]=[N:36][CH:37]=2)=[C:28]([CH3:42])[CH:27]=1)([C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2([OH:24])[CH2:23][CH2:22][S:21][CH2:20][CH2:19]2)=[C:12]([CH3:25])[CH:11]=1)[CH2:8][CH3:9])[CH3:6]>C(O)C.[Pd]>[CH2:5]([C:7]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[C:34]([CH2:38][C:39]([OH:41])=[O:40])[CH:35]=[N:36][CH:37]=2)=[C:28]([CH3:42])[CH:27]=1)([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2([OH:24])[CH2:19][CH2:20][S:21][CH2:22][CH2:23]2)=[C:12]([CH3:25])[CH:11]=1)[CH2:8][CH3:9])[CH3:6]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCSCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCC(CC)(c1ccc(CCC2(O)CCSCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Temperature: 130 °C
Yield: 65.8 %

Procedure:
Ammonium formate (100 mg, 1.6 mmol) and Pd/C (30 mg) were added to a solution of [5-(4-{1-ethyl-1-[4-(4-hydroxy-tetrahydrothiopyran-4-ylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid (Example 137-(3); 5 mg, 0.01 mmol) in ethanol, and the mixture was stirred with microwave heating at 130° C. for 10 minutes. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (dichloromethane/methanol=10/1) to give the title compound (3.5 mg, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO.O1CCOCC1.[C:22]([O:26][C:27](=O)[O:28]C(C)(C)C)([CH3:25])([CH3:24])[CH3:23]>C1COCC1.ClCCl.C(OCC)(=O)C>[C:22]([O:26][C:27](=[O:28])[NH:13][CH2:12][CH2:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])([CH3:25])([CH3:24])[CH3:23]
Reactant: N#CCS(=O)(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCS(=O)(=O)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 28.8 %

Procedure:
Suspend (4-Bromobenzenesulfonyl)-acetonitrile (10.41 g, 40.02 mmol) in THF and cooled to 0° C., and add borane-dimethylsulfide complex (10 M, 12 mL, 120 mmol) to the suspension which is allowed to slowly warm to ambient temperature. The next day, quench the reaction with a slow addition of methanol until off-gassing ceases. Concentrate the reaction to dryness and add more methanol and bring to reflux for 3 hours. Concentrate the reaction to dryness, then dissolve in dichloromethane and extract with 1 N HCl (2×150 mL). Make the acidic aqueous extracts basic using 50% NaOH and Na2CO3. Treat the aqueous solution with dioxane (500 mL) and di-tertbutylcarbonate (10.91 g, 50.00 mmol) for 3 days. Dilute the reaction with dichloromethane, separate the layers and re-extract the aqueous with dichloromethane. Wash the organic extracts with aqueous saturated sodium chloride, dry over MgSO4, filter and concentrate to yield a crude oil. Chromatograph on silica utilizing (0→5→8%) ethyl acetate in dichloromethane to afford the title compound (4.20 g, 11.53 mmol). MS(ES), m/z 307/309 (M+1 minus t-butyl).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C@@H:11]1[CH2:17][CH2:16][C@@H:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[F:25])[CH2:14][N:13](CC2C=CC(OC)=CC=2OC)[C:12]1=[O:37])[CH:9]=[CH2:10].C([C@H]1CC[C@H](C2C=CC=C(F)C=2F)CN(CC2C=CC(OC)=CC=2OC)C1=O)C=C>ClCCl>[CH2:8]([CH:11]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[F:25])[CH2:14][NH:13][C:12]1=[O:37])[CH:9]=[CH2:10]
Reactant: C=CC[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(Cc2ccc(OC)cc2OC)C1=O
Agent: C=CC[C@H]1CC[C@H](c2cccc(F)c2F)CN(Cc2ccc(OC)cc2OC)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCC1CCC(c2cccc(F)c2F)CNC1=O
Reaction time: 2.5 h

Procedure:
Trifluoroacetic acid (35 mL) was added to a solution of (3S,6S)-3-allyl-6-(2,3-difluorophenyl)-1-(2,4-dimethoxybenzyl)azepan-2-one and (3R,6R)-3-allyl-6-(2,3-difluorophenyl)-1-(2,4-dimethoxybenzyl)azepan-2-one (3.39 g, 8.15 mol) in dichloromethane (25 mL). After 2.5 h, the reaction mixture was concentrated. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate (3×). The organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. Purification by silica gel chromatography (98.5% dichloromethane/methanol→97% dichloromethane/methanol) gave the mixture of racemic trans compounds (3S,6S)-3-allyl-6-(2,3-difluorophenyl)azepan-2-one and (3R,6R)-3-allyl-6-(2,3-difluorophenyl)azepan-2-one and racemic cis compounds (3S,6R)-3-allyl-6-(2,3-difluorophenyl)azepan-2-one and (3R,6S)-3-allyl-6-(2,3-difluorophenyl)azepan-2-one. MS 266.1 (M+1).
Reaction SMILES: C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH:22]([C:44]([O:46][CH2:47][CH:48]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]2[C:49]1=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:45])[C@H:23]([C:41]([OH:43])=[O:42])[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:22]([C:44]([O:46][CH2:47][CH:48]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]2[C:49]1=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:45])[C@H:23]([C:41]([OH:43])=[O:42])[CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28]
Reactant: CC(C)(C)OC(=O)N(CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)C(=O)OC(C)(C)C
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O

Procedure:
To 3 g of 2-chlorotrityl chloride resin with 1.3 mmol/g substitution (Novabiochem, 01-64-0114) in 30 ml of dry DCM in 30 ml reaction vessel for solid phase synthesis, 2.577 g (5.85 mmol, 1.5 eq) of Fmoc-Dab(diBoc)-OH (MW=440.5, (Fmoc-(N-γ-Boc)-L-α,β-diaminobutyric acid, AnaSpec, 28246) and 2.23 ml (12.87 mmol, 3.3 eq) of DIPEA (Aldrich, MW=129.2, d=0.74) were added.
Reaction SMILES: Cl.C(O[CH:5](OCC)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Br:17])[CH:10]=1)C.[C:21]([S-:23])#[N:22].[K+].C(O)C.Cl>O>[Br:17][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH2:8][N:7]1[CH:6]=[CH:5][N:22]=[C:21]1[SH:23]
Reactant: N#C[S-]
Reactant: CCOC(CNCc1ccc(OC)c(Br)c1)OCC
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cn2ccnc2S)cc1Br

Procedure:
A solution of 10.74 g (.029 mole) of N-(3-bromo4-methoxybenzyl)aminoacetaldehyde diethyl acetal hydrochloride and 3.37 g (0.35 mole) of KSCN in 50 ml of H20, 50 ml of ethanol and 5 ml of 3N HCl was refluxed for 4.5 hours. One hundred ml of H2O was added and the mixture was cooled. A solid was filtered, washed with H2O and dried. Recrystallization from ethanol gave 1-(3-bromo-4-methoxybenzyl)-2-mercaptoimidazole, 6.3 g (72%), mp 188°.
Reaction SMILES: [BH4-].[Na+].[CH:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>CO>[CH:3]1([C:9]2[CH:10]=[CH:11][C:12]([CH:15]([OH:17])[CH3:16])=[CH:13][CH:14]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CC(=O)c1ccc(C2CCCCC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(C2CCCCC2)cc1
Yield: 102.1 %

Procedure:
11.4 gm (0.3 mol) of sodium borohydride were added in small portions at 20°-25° C to 60.7 gm (0.3 mol) of 4'-cyclohexyl-acetophenone (m.p. 66°-67° C) in 300 ml of methanol while stirring vigorously and cooling on ice. The resulting mixture was then stirred for another hour at room temperature, and the reaction product was precipitated with acidified ice water. After suction filtering, washing and drying, 62.6 gm of crystalline material were obtained. A sample, recrystallized from petroleum ether, melted at 81.5°-82.5° C.