Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Li].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]2[CH:12]([O:13]2)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(OCC)C.[Cu]I>[C:3]([O:7][C:8]([N:10]1[CH2:11][C@@H:12]([CH3:1])[C@H:14]([OH:13])[CH2:15]1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: [Li]C
Agent: [Cu]I
Solvent: CCOCC
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1O
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
Cool down a suspension of copper (I) iodide (1 g, 5.5 mmol) in dry diethyl ether (13 mL) under nitrogen to −10° C. with a saturated aqueous sodium chloride/ice bath and add methyllithium (1.6 M in diethyl ether, 6.8 mL, 10.9 mmol) dropwise to maintain the temperature at −10° C. Stir for 20 min at this temperature and add a solution of 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (430 mg, 2.32 mmol) in dry diethyl ether (5 mL). Stir for 1 h at −10° C. then add water (5 mL) dropwise and dichloromethane (5 mL), filter the resulting mixture through a pad of Celite® and wash thoroughly with dichloromethane. Separate the aqueous and organic phases and extract with 30:70 isopropanol:chloroform and wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give trans-3-hydroxy-4-methylpyrrolidine-1-carboxylic acid tert-butyl ester which can be used without further purification (360 mg, 77%). 1H NMR (300 MHz, CDCl3) δ 3.84-3.91 (1H, m), 3.48-3.62 (2H, m), 3.10-3.23 (1H, m), 2.88-3.02 (1H, m), 1.98-2.12 (1H, m), 1.39 (9H, s), 0.95 (3H, d, J=6.97 Hz), MS (ES): m/z=224 [M+Na].
Reaction SMILES: Br[C:2]1[C:17]([F:18])=[CH:16][C:5]([O:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[N:12][CH:13]=2)=[C:4]([O:19][CH3:20])[CH:3]=1.[Cu][C:22]#[N:23]>CN(C)C=O.ClCCl>[F:18][C:17]1[CH:16]=[C:5]([O:6][CH2:7][C:8]2[CH:13]=[N:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:4]([O:19][CH3:20])=[CH:3][C:2]=1[C:22]#[N:23]
Reactant: COc1ccc(COc2cc(F)c(Br)cc2OC)cn1
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(F)c(C#N)cc2OC)cn1
Temperature: 150 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
To a stirred solution of 5-((4-bromo-5-fluoro-2-methoxyphenoxy)methyl)-2-methoxypyridine (4.57 g, 13.36 mmol) in N,N-dimethylformamide (50 mL) was added copper(I) cyanide (3.59 g, 40.07 mmol). The mixture was heated to 150° C. After 16 h, the mixture was allowed to cool to room temperature and was diluted with dichloromethane. The mixture was filtered through Celite. The filtrate was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (Combi-Flash, 80 g SiO2 column, 1-5% methanol/dichloromethane elute) afforded 3.25 g (84%) of 2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzonitrile as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:13]2[CH2:12][CH2:11][N:10]([CH3:14])[CH2:9][CH2:8][N:7](N)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:16]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC.C(OCC)(=O)C>[Cl:1][C:2]1[C:13]2[CH2:12][CH2:11][N:10]([CH3:14])[CH2:9][CH2:8][N:7]3[C:6]=2[C:5]([C:16]2[CH2:20][CH2:19][CH2:18][C:17]=23)=[CH:4][CH:3]=1
Reactant: CN1CCc2c(Cl)cccc2N(N)CC1
Reactant: O=C1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCCO
Solvent: O
Product: CN1CCc2c(Cl)ccc3c4c(n(c23)CC1)CCC4
Temperature: 25 °C
Yield: 13.7 %

Procedure:
To a solution of 7-chloro-4-methyl-3,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-1-ylamine (1.20 g, 5.32 mmole) in 1-propanol (100 mL) was added cyclopentanone (6.66 g, 79.14 mmole) followed by p-toluenesulfonic acid monohydrate (3.2 g, 16.8 mmole) and the resulting reaction mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature and solvent removed in vacuo to produce a brown residue. The residue was diluted with ethyl acetate (300 mL) and washed with saturated sodium bicarbonate (150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 1:1) provided 0.20 g of the title compound as a white solid, mp 138-140° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1([C:14]([OH:16])=[O:15])[CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]1.[CH3:17]O>>[ClH:3].[CH3:17][O:15][C:14]([C:6]1([NH2:5])[CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]1)=[O:16]
Reactant: CON1CCC(N)(C(=O)O)CC1
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)C1(N)CCN(OC)CC1
Product: Cl
Temperature: 60 °C

Procedure:
25.7 g of thionylchloride are added at a temperature of 0-10° C. within 40 minutes to a suspension of 12.5 g of 4-amino-1-methoxy-piperidine-4-carboxylic acid in 100 ml of methanol. The reaction mixture is then heated up to 60° C. for 48 h. After cooling to 20° C., the solids are filtered and the filtrate is evaporated to give 13.2 g of 4-amino-1-methoxy-piperidine-4-carboxylic acid methyl ester hydrochloride as brown cristalline solid.
Reaction SMILES: C(CO[C:6]1[C:11]2[CH2:12][C:13](=[CH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][C:27]([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)([OH:30])[CH2:26][CH2:25]3)[C:14]3[C:15]([O:20][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[N:16][CH:17]=[CH:18][CH:19]=3)(O)=O.C(CCC1C2C[C:50](=CCCN3CCC(C4C=CC(Cl)=CC=4)(O)CC3)[C:51]3[C:52]([O:57]C=2C=CC=1)=[N:53]C=CC=3)(O)=O>>[C:52]([CH2:51][CH2:50][C:6]1[C:11]2[CH2:12][C:13](=[CH:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][C:27]([C:31]4[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=4)([OH:30])[CH2:28][CH2:29]3)[C:14]3[C:15]([O:20][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[N:16][CH:17]=[CH:18][CH:19]=3)(=[O:57])[NH2:53]
Reactant: O=C(O)CCc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Reactant: O=C(O)COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Product: NC(=O)CCc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2

Procedure:
The titled compound was prepared by following the procedure of example 181, but replacing the product of example 133 with the product of example 123.
Reaction SMILES: [Si:1]([O:8][CH2:9]/[CH:10]=[N:11]/[S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[Li].CO>[NH4+].[Cl-]>[CH3:5][C:4]([CH3:7])([Si:1]([CH3:3])([CH3:2])[O:8][CH2:9][C@H:10]([C:22]1[S:21][CH:25]=[CH:24][CH:23]=1)[NH:11][S+:12]([O-:13])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:6]
Reactant: [Li]c1cccs1
Reactant: CC(C)(C)S(=O)/N=C/CO[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[S+]([O-])N[C@H](CO[Si](C)(C)C(C)(C)C)c1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A three necked round bottom flask fitted with a temperature probe, nitrogen inlet, mechanical stirrer and slow addition funnel was charged with N-[(1E)-2-{[tert-butyl(dimethyl)silyl]oxy}ethylidene]-2-methylpropane-2-sulfinamide (176 g, 0.530 mol) and DCM (2 L). At an internal temperature of −65° C., 2-thienyl lithium (1.0 M in THF) (0.794 L, 0.794 mol) was added dropwise such that the internal temperature was maintained <−65° C. The reaction mixture was stirred for 60 minutes, quenched at −65° C. with methanol (0.214 L, 5.30 mol), diluted with NH4Cl (2 L) and warmed to room temperature. The layers were then separated and the aqueous layer was back extracted with DCM (2 L). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude concentrate was pre-loaded onto silica, divided into 4 batches, and purified by automated flash chromatography (4×1.5 kg SiO2 columns, hexanes:EtOAc; 5% to 50% gradient over to provide the title compound as an amber oil. 1H NMR ((CD3)2CO) δ 7.42 (1H, d, J=4.0 Hz), 7.14 (1H, s), 7.01 (1H, J=4.0, 3.5 Hz), 4.78-4.75 (1H, m), 4.48 (1H, s), 3.95-3.92 (1H, m), 3.86-3.82 (1H, m), 1.23 (9H, s), 0.94 (9H, s), 0.12 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12]C=CC1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:17]CC1.S([O-])([O-])(=O)=S.[Na+].[Na+].[O:28]1[CH2:32][CH2:31][CH2:30]C1>[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:30][C@H:31]([OH:17])[C@H:32]([OH:28])[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@@H](O)C1
Reaction time: 48 h

Procedure:
A solution of crude 2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (10.5 g, 62.1 mmol) in tetrahydro-furan (300 ml) was treated sequentially with osmium tetroxide (2.5% in t-butanol, 6 mL) and N-methylmorpholine-N-oxide at 25° C. After 48 hours, aqueous 10% sodium thiosulfate solution was added and the mixture was stirred 30 minutes, partially concentrated to remove tetrahydro-furan, and the resulting aqueous mixture extracted twice with ether. The ether extracts were washed with 10% sodium thiosulfate, 0.1 N HCl, dried and concentrated giving a dark orange oil which was chromatographed on silica eluted with 1%, 2%, 4%, 8% and 10% ethanol-dichloromethane giving an amber syrup (4.09 g).
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O>C(O)C.O>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:1]#[N:2])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1
Reactant: FC(F)(F)c1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(Br)cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
After N-bromosuccinimide (1.49 g, 6.63 mmol) and 2,2′-azobis(isbutyronitrile) (20 mg) were added to a solution of 4-bromo-1-methyl-2-(trifluoromethyl)benzene (2.0 g, 8.4 mmol) in carbon tetrachloride (20 ml), the mixture was heated under reflux for 5 hours. The temperature of the reaction mixture was returned to room temperature and the residue obtained by removing the solvent under reduced pressure was subjected to silica gel column chromatography (eluting solvent: n-hexane) to give crude 4-bromo-1-bromomethyl-2-(trifluoromethyl)benzene. Potassium cyanide (365 mg, 5.6 mmol) was added to a solution of crude 4-bromo-1-bromomethyl-2-(trifluoromethyl)benzene obtained in the above in a mixture of ethanol-water (3:1, 12 ml), and the mixture was stirred at 70° C. for 3 hours. After the reaction mixture was poured into water and extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/1-5/1) to give [4-bromo-2-(trifluoromethyl)phenyl]acetonitrile as a solid (1.14 g, total yield: 52%).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:26]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: CCOC(=NC(=O)c1ccccc1C(F)(F)F)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine6-carboximidate and 2-trifluoromethylbenzoyl chloride, there is obtained ethyl N-(o-trifluoromethylbenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m,p. 122°-125° C.;
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Cl[C:12]([S:14]Cl)=[O:13]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][C:12](=[O:13])[S:14][N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(N)=O)cc1
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nsc(=O)o2)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a toluene (60 mL) suspension of 4-methylbenzamide (20 g), chlorocarbonylsulfenyl chloride (15 mL) was added, and the resultant was stirred at 120° C. for 3 hours. The reaction solution was concentrated under reduced pressure. The obtained solid was washed with hexane to obtain the title compound (24 g) as a colorless solid.
Reaction SMILES: [Cu][C:2]#[N:3].N(OC(C)(C)C)=O.[CH:11]([C:14]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[C:16]([O:26][CH3:27])[C:15]=1N)([CH3:13])[CH3:12].Cl>CS(C)=O>[CH:11]([C:14]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[C:16]([O:26][CH3:27])[C:15]=1[C:2]#[N:3])([CH3:13])[CH3:12]
Reactant: COc1cc(N2CCOCC2)cc(C(C)C)c1N
Reactant: N#C[Cu]
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CS(C)=O
Product: COc1cc(N2CCOCC2)cc(C(C)C)c1C#N
Temperature: 50 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
Copper(I) cyanide (1.07 g, 11.9 mmol) is added to dimethylsulfoxide (15 ml) at 50° C. followed by the addition of tert-Butyl nitrite (3.8 ml, 27.6 mmol) at once. A solution of (2-isopropyl-6-methoxy-4-morpholin-4-yl-phenyl)-amine (2.3 g, 9.2 mmol) in dimethylsulfoxide (15 ml) is added drop wise via an addition funnel to the above mixture. After completion of the addition, the reaction mixture is allowed to stir for 1 h at 50° C. After being cooled to 45° C., the reaction mixture is slowly treated with 5N hydrochloric acid and cooled to ambient temperature. The resulting mixture is extracted with ethyl acetate (3×50 ml). The combined organic layers are washed with water (30 ml), brine (30 ml), dried over sodium sulfate and evaporated to dryness. The crude product is purified by flash column chromatography (silica gel, 20% ethyl acetate/hexane) to afford 2-isopropyl-6-methoxy-4-morpholin-4-yl-benzonitrile (0.4 g, 1.54 mmol, 17%).
Reaction SMILES: [N:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([OH:11])=[O:10])=[N+:2]=[N-:3].Br[CH2:13][CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:13]([O:10][C:9]([C:5]1[S:6][CH:7]=[CH:8][C:4]=1[N:1]=[N+:2]=[N-:3])=[O:11])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CBr
Reactant: [N-]=[N+]=Nc1ccsc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COC(=O)c1sccc1N=[N+]=[N-]
Temperature: 80 °C
Yield: 77 %

Procedure:
Compound 13a (5.8 g, 34.3 mmol) was treated with 1-bromo-2-methylpropane (4.47 mL, 1.2 equiv.) and cesium carbonate (7.82 g, 0.7 equiv.) in anhydrous DMF (0.1 M) and heated to 80° C. for 6 h under argon. The mixture was cooled, dissolved in H2O (150 mL), and extracted with 1:1 diethyl ether:ethyl acetate (3×200 mL). The organic layer was washed with distilled H2O (5×100 mL), dried over Na2SO4, and concentrated in vacuo to give 14a as an oil (6.77 g, 77% yield).
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)=[O:8].[NH2:19][C@@H:20]([CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22]>>[CH2:40]([O:39][CH2:38][C@H:20]([NH:19][C:16](=[O:18])[CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:7]([C:3]2[O:2][CH:6]=[CH:5][CH:4]=2)=[O:8])[CH2:14][CH2:13]1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)CN1CCN(C(=O)c2ccco2)CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCN(C(=O)c2ccco2)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 35.4 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(furan-2-carbonyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 223, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(furan-2-carbonyl)piperazin-1-yl)acetamido)propanamide (17 mg, 35.4%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): 10.22 (s, 1H), 8.04 (d, 1H), 7.84 (s, 1H), 7.61 (d, 2H), 7.26-7.31 (m, 5H), 7.19-7.23 (m, 2H), 6.98-7.04 (m, 5H), 6.63 (dd, 1H), 4.71 (m, 1H), 4.53 (s, 2H), 3.73-3.77 (m, 2H), 3.65 (s, 2H), 3.06 (m, 2H), 2.51-2.54 (m, 4H). MS (EI) for C33H33FN4O6. found 601.6 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][CH:54]([O:57][C:58]2[CH:63]=[C:62]([C:64]([F:67])([F:66])[F:65])[CH:61]=[CH:60][C:59]=2[F:68])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[F:68][C:59]1[CH:60]=[CH:61][C:62]([C:64]([F:65])([F:67])[F:66])=[CH:63][C:58]=1[O:57][CH:54]1[CH2:55][CH2:56][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:21]([C:18]2[CH:17]=[C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:20][N:19]=2)=[O:23])[CH2:52][CH2:53]1
Reactant: NCC(=O)N1CCC(Oc2cc(C(F)(F)F)ccc2F)CC1
Reactant: O=C(O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cc(C(F)(F)F)ccc2F)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 80.9 %

Procedure:
DIPEA (110 mg, 0.85 mmol) was added to a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid (50 mg, 0.24 mmol) in DMF (2 mL) followed by HOBt (33 mg, 0.24 mmol) and EDCI.HCl (49 mg, 0.25 mmol). After 2 minutes 2-amino-1-[4-(2-fluoro-5-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford the residue. The residue obtained was purified by recrystallisation using 25% EtOAc in hexane to afford 89 mg (80.9% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-fluoro-5-trifluoromethyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 457, 90.38%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.2 (bs, 1H), 7.9 (t, 1H), 7.1 (m, 7H), 4.61 (m, 1H), 4.4 (d, 2H), 3.7 (m, 2H), 3.3 (m, 2H), 1.9 (m, 2H), 1.5 (m, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9](=[O:23])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[C:12]=2[C:13]=1[CH3:14])(=O)=O.[C:24]1([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:22][O:21][C:15]1[C:12]2[C:13]([CH3:14])=[C:8]([CH2:7][CH2:6][N:33]3[CH2:34][CH2:35][CH:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:31][CH2:32]3)[C:9](=[O:23])[O:10][C:11]=2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=1
Reactant: COc1cc(OC)c2c(C)c(CCOS(C)(=O)=O)c(=O)oc2c1
Reactant: c1ccc(C2CCNCC2)cc1
Product: COc1cc(OC)c2c(C)c(CCN3CCC(c4ccccc4)CC3)c(=O)oc2c1
Yield: 18 %

Procedure:
Process B; starting materials: 3-[2-(methanesulphonyloxy)ethyl]-5,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 35) and 4-phenylpiperidine; yield 18% of crude crystalline product.
Reaction SMILES: O=C1CNCCN1.[CH2:8]([N:10]([CH2:26][CH3:27])[CH:11]([N:13]1[CH2:18][CH2:17][NH:16][C:15](=O)[CH:14]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:12])[CH3:9].O1CCOCC1.[OH-].[Na+]>O.CCOCC>[CH2:26]([N:10]([CH2:8][CH3:9])[CH:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH:14]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:12])[CH3:27]
Reactant: CCN(CC)C(C)N1CCNC(=O)C1c1ccccc1
Agent: O=C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCN(CC)C(C)N1CCNCC1c1ccccc1
Yield: 77 %

Procedure:
89 g. of the keto piperazine prepared as described hereinabove under (a), are dissolved in 200 cc. of absolute dioxane. The solution is added to a suspension of 20 g. of lithium aluminum hydride LiAlH4 in 800 cc. of absolute ether while exposing the mixture to vibration. After addition of the keto piperazine solution is completed, the reaction mixture is boiled under reflux for 6 hours. Thereafter it is decomposed by successive treatment with 21 cc. of 15 % sodium hydroxide solution, 21 cc. of water, 63 cc. of 15 % sodium hydroxide solution, and 42 cc. of water. The decomposed reaction mixture is filtered, the solvent is removed by distillation, and the residue is distilled in a vacuum. 65 g. of a light yellow oil of the boiling point 114°-117° C./0.05 mm. Hg are obtained. This oil corresponds to the above given compound. The yield is 77 % of the theoretical yield.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]([CH3:34])[S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])(=[O:23])=[O:22])=[N:8][CH2:7]1)C.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO>[CH3:34][N:20]([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31])(=[O:23])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11]([C:9]1[S:10][CH:6]([CH2:5][C:4]([OH:35])=[O:3])[CH2:7][N:8]=1)=[CH:19]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4ccccc4C(F)(F)F)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.5 %

Procedure:
Ethyl{2-[7-(methyl{[2-(trifluoromethyl)phenyl]sulfonyl}amino)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (0.55 g) was dissolved in a mixed solvent of tetrahydrofuran (6 mL)-methanol (6 mL). Aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (0.30 g) in water (5 mL)) was added to this solution, and the mixture was stirred at room temperature for 6 hr. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (372 mg, yield: 72%) as pale-yellow crystals. MS:498(MH+). melting point 170-172° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][CH:10]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]2=[O:18].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>ClCCl>[CH3:26][S:27]([O:18][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[N:4]=[CH:5][CH:6]=2)[N:11]=[CH:10][C:9]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:29])=[O:28]
Reactant: CCOC(=O)c1c[nH]c2c(OC)nccc2c1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cnc2c(OC)nccc2c1OS(C)(=O)=O
Reaction time: 1 h
Yield: 67 %

Procedure:
4.96 g of ethyl 8-methoxy-1,7-naphthyridin-4(1H)-one-3-carboxylate and 4.2 ml of triethylamine were dissolved into 70 ml of dichloromethane, and a solution of methanesulfonyl chloride (1.85 ml) in dichloromethane (10 ml) was added dropwise at a temperature of 0° C. to 5° C. The resulting mixture was stirred for 1 hour at the same temperature. Water was added, and the resulting mixture was extracted with dichloromethane three times, and the organic phase was washed with water and then brine, dried over magnesium sulfate and distilled under reduced pressure. Ether was added to the residue to give 4.4 g (67%) of the titled compound as yellow crystals.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([Cl:15])[C:8]([SH:14])=[CH:9][CH:10]=2)[CH2:5]1)(=O)[CH3:2].B#B.O>O1CCCC1>[ClH:15].[Cl:15][C:7]1[C:8]([SH:14])=[CH:9][CH:10]=[C:11]2[C:6]=1[CH2:5][N:4]([CH2:1][CH3:2])[CH2:13][CH2:12]2
Reactant: CC(=O)N1CCc2ccc(S)c(Cl)c2C1
Agent: B#B
Solvent: C1CCOC1
Solvent: O
Product: CCN1CCc2ccc(S)c(Cl)c2C1
Product: Cl

Procedure:
N-Acetyl-8-chloro-7-mercapto-1,2,3,4-tetrahydroisoquinoline (24 g., 0.1 m.) is dissolved in tetrahydrofuran and treated with 300 ml. of 1 M diborane (0.3 m.). The mixture is refluxed, cooled, treated with water and then aqueous hydrochloric acid and evaporated to yield 8-chloro-N-ethyl-7-mercapto-1,2,3,4-tetrahydroisoquinoline hydrochloride.