Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:6][CH:5]=1.O>C1C=CC=CC=1>[CH3:18][CH:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][CH:6]=1)[CH2:12][CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: COC(=O)c1ccc(OC(C)CCCC(C)C)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)CCCC(C)Oc1ccc(CO)cc1

Procedure:
42 g of p-[(1,5-dimethylhexyl)oxy]benzoic acid methyl ester is dissolved in 250 ml of benzene and, with stirring, treated dropwise with 50 g of 70% bis(2-methoxy-ethoxy)sodium aluminum hydride. The reaction solution is further stirred at 25°C. for 5 hours and thereafter treated with water. The organic phase is separated off, dried under sodium sulfate, carefully filtered (using a filter aid) and evaporated under reduced pressure. There is obtained a residual of p-[(1,5-dimethylhexyl)oxy]benzyl alcohol; B.P. 180°-182°C/1.0 mmHg.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C[C:10]1[CH:11]=[N:12][C:13]2[C:22](C=1C)=[CH:21][CH:20]=[C:19]1[C:14]=2N=CC(C)=C1C.C(=O)([O-])[O-:28].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOC(C)=O.[Cu](I)I>[Cl:8][C:4]1[N:3]=[C:2]([O:28][CH2:10][CH2:11][NH:12][CH:13]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:14]2)[CH:7]=[N:6][CH:5]=1
Reactant: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Reactant: Clc1cncc(Cl)n1
Reactant: O=C([O-])[O-]
Agent: I[Cu]I
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1cncc(OCCNC2CCCCC2)n1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a stirred solution of n-cyclohexylethanolamine (0.48 g, 3.4 mmol) and 2,6-dichloropyrazine (0.50 g, 3.4 mmol) in toluene (17 mL) was added 3,4,7,8-tetramethyl-1,10-phenanthroline (7.9 mg, 0.034 mmol), copper iodide (0.032 g, 0.17 mmol) and cesium carbonate (2.2 g, 6.7 mmol). The reaction mixture was stirred at 100° C. After 18 h, the reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), filtered through celite and concentrated. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford N-{2-[(6-chloropyrazin-2-yl)oxy]ethyl}cyclohexanamine as an orange oil. LRMS (ESI) calculated for C12H18ClN3O [M+H]+, 256.1; found 256.1.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:22])=[CH:17][CH:16]=3)[C:10]2=[O:29])=[N:6][C:5]=1[CH3:30])(=O)[CH3:2].CO[C:33](OC)([N:35](C)C)[CH3:34].O.[NH2:41]N>CN(C)C(=O)C.C(OCC)(=O)C>[CH3:30][C:5]1[N:6]=[C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)=[O:22])=[CH:19][CH:20]=3)[C:10]2=[O:29])[S:8][C:4]=1[C:1]1[NH:41][N:35]=[C:33]([CH3:34])[CH:2]=1
Reactant: COC(C)(OC)N(C)C
Reactant: CC(=O)c1sc(N2CCN(Cc3ccc(C(=O)N4CCCCC4)cc3)C2=O)nc1C
Reactant: NN
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(-c2sc(N3CCN(Cc4ccc(C(=O)N5CCCCC5)cc4)C3=O)nc2C)[nH]n1
Temperature: 110 °C
Yield: 46 %

Procedure:
To a solution of 1-(5-acetyl-4-methylthiazol-2-yl)-3-(4-(piperidine-1-carbonyl)benzyl)imidazolidin-2-one (0.43 g, 1.00 mmol) in N,N-dimethylacetamide (5 mL) was added N,N-dimethylacetamide dimethyl acetal (0.5 mL, 3.40 mmol). The reaction mixture was heated for 24 hours at 110° C., and hydrazine monohydrate (0.30 mL, 6.18 mmol) was added. The reaction mixture was heated for another 10 minutes at 110° C., then cooled to ambient temperature, diluted with ethyl acetate and washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a colorless solid in 46% yield (0.25 g): mp 182-183° C. (ethyl acetate): 1H NMR (300 MHz, CDCl3) δ 7.38-7.30 (m, 4H), 6.16 (s, 1H), 4.49 (s, 2H), 4.10-4.04 (m, 2H), 3.68 (br s, 2H), 3.46-3.31 (m, 4H), 2.46 (s, 3H), 2.32 (s, 3H), 1.56-1.49 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 169.9, 156.6, 155.8, 143.6, 137.3, 136.1, 128.2, 127.4, 104.2, 48.7, 47.7, 41.8, 26.5, 25.6, 24.5, 21.1, 16.5: MS (ES+) m/z 465.2 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([CH3:29])=[CH:4][CH2:5][CH2:6][C:7]([CH3:28])=[CH:8][CH2:9][CH2:10][C:11]([CH3:27])=[CH:12][CH:13]=[C:14]([CH:24]([CH3:26])[CH3:25])[CH:15]([O:18][CH:19]([O:21][CH2:22][CH3:23])[CH3:20])[C:16]#[N:17].[Cl-].[NH4+]>CCCCCC.C1C=CC=CC=1.C1C=CC=CC=1>[CH2:22]([O:21][CH:19]([O:18][C:15]1([C:16]#[N:17])[CH2:2][C:3]([CH3:29])=[CH:4][CH2:5][CH2:6][C:7]([CH3:28])=[CH:8][CH2:9][CH2:10][C:11]([CH3:27])=[CH:12][CH:13]=[C:14]1[CH:24]([CH3:26])[CH3:25])[CH3:20])[CH3:23]
Reactant: CCOC(C)OC(C#N)C(=CC=C(C)CCC=C(C)CCC=C(C)CCl)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CCOC(C)OC1(C#N)CC(C)=CCCC(C)=CCCC(C)=CC=C1C(C)C
Reaction time: 0.08 h
Yield: 51.5 %

Procedure:
A solution of hexamethyldisilazane lithium amide (205 mg, 1.11 mmol) in dry hexane/benzene (1:4) solution (5 ml) is stirred on an oil bath at 90° C. and thereto is dropwise added a solution of cyanohydrin ethoxyethyl ether which is 15-chloro-2-(1-ethoxyethoxy)-3-(1-methylethyl)-6, 10,14-trimethyl-3,5,9,13-pentadecatetraenenitrile (115 mg, 0.26 mmol) in dry benzene (6 ml) over 20 minutes. After stirring the mixture at this temperature for 5 minutes, a saturated aqueous ammonium chloride solution is added while stirring on an ice-water bath. The organic layer is extracted with ether (20 ml ×2) and the solvent is removed by distillation under reduced pressure to give 1-(1-ethoxyethoxy)-2-(1-methylethyl)-5,9,13-trimethyl-2,4, 8,12-cyclotetradecatetraene-1-carbonitrile (51.6 mg, 50%) as a mixture of diastereomers. This product is subjected to silica gel column chromatography (n-hexane/ether=20:1) to give one isomer of the above formula.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][C:18]=1[C:19]([OH:21])=[O:20])=[C:14]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])[C:13](=[O:30])[CH:12]=[CH:11]2.[CH2:31](Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CCOCC.CCOC(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][C:18]=1[C:19]([O:21][CH3:31])=[O:20])=[C:14]([C:22]1[C:23]([F:29])=[CH:24][CH:25]=[CH:26][C:27]=1[F:28])[C:13](=[O:30])[CH:12]=[CH:11]2
Reactant: O=C(O)c1ccc2c(-c3c(F)cccc3F)c(=O)ccn2c1-c1ccc(F)cc1F
Reactant: ClCCCl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)c1ccc2c(-c3c(F)cccc3F)c(=O)ccn2c1-c1ccc(F)cc1F
Reaction time: 2 h
Yield: 55.3 %

Procedure:
To a solution of 6-(2,4-difluorophenyl)-1-(2,6-difluorophenyl)-2-oxo-2H-quinolizine-7-carboxylic acid (Example 53, 21 mg) in THF/MeOH (1/1) was added EDC (20 mg) and HOBt (10 mg) at room temperature. After stirring for 2 h, the mixture was diluted with ethyl acetate and washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by silica gel (methylene chloride/methanol=20/1) to give the title compound (12 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[N:7][C:6]=2[CH:11]=1
Reactant: CN1CCNCC1
Reactant: Sc1nc2cc(Cl)ccc2o1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN1CCN(c2nc3cc(Cl)ccc3o2)CC1
Reaction time: 12 h

Procedure:
A 300 mg portion of 5-chloro-2-mercaptobenzoxazole was suspended in 50 ml of anhydrous benzene, and the suspension was mixed with 404 mg of phosphorus pentachloride and heated under reflux for 3 hours. The reaction solution was cooled in an ice bath and, with stirring, 1.6 g of 1-methylpiperazine was added thereto. After 30 minutes of stirring, the ice bath was removed to carry out 12 hours of stirring at room temperature, and then the reaction solution was mixed with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate and then the solvent was evaporated under a reduced pressure. Thereafter, the thus obtained mixture was purified by a silica gel column chromatography (ethyl acetate:methanol=20:1) to obtain the title compound (121 mg) in light yellow color.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH:6]([F:9])[CH:5]1[C:10]1[C:15](F)=[CH:14][C:13]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=O)=[C:12]([N+:26]([O-])=O)[CH:11]=1)(=[O:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1>>[C:1]([N:4]1[CH2:8][CH2:7][CH:6]([F:9])[CH:5]1[C:10]1[C:15]([O:42][C:39]2[CH:38]=[CH:37][C:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[F:29])=[CH:41][CH:40]=2)=[CH:14][C:13]2[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[NH:26][C:12]=2[CH:11]=1)(=[O:3])[CH3:2]
Reactant: Oc1ccc(-c2ccccc2F)cc1
Reactant: CC(=O)N1CCC(F)C1c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Product: CC(=O)N1CCC(F)C1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(-c2ccccc2F)cc1

Procedure:
The entitled compound was obtained in the same method as in Example 338 (step 5) or in accordance with the method or by combining it with an ordinary method but using N-(4-(1-acetyl-3-fluoropyrrolidin-2-yl)-5-fluoro-2-nitrophenyl)pyridin-2-carboxamide enantiomer A and 2′-fluorobiphenyl-4-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:26]([O-:28])=[O:27])[CH2:13][CH2:14][C:15](=[O:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:40](O)[CH2:41][OH:42]>C1CCCCC1>[CH2:41]1[O:42][C:15]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([CH2:14][CH2:13][CH:12]([N+:26]([O-:28])=[O:27])[CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[O:25][CH2:40]1
Reactant: COc1ccc(CC(CCC(=O)CCc2ccc(F)cc2)[N+](=O)[O-])cc1OC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: COc1ccc(CC(CCC2(CCc3ccc(F)cc3)OCCO2)[N+](=O)[O-])cc1OC

Procedure:
Into a 1 l. r.b. flask equpped with a Dean-Stark trap was placed 79 g (0.2 mole) of 1-(3',4'-dimethoxyphenyl)-7-(4'-fluorophenyl)-2-nitro-5-heptanone, 38 g p-toluenesulfonic acid, 120 ml ethylene glycol and 400 ml cyclohexane. The mixture was allowed to reflux overnight, then concentrated in vacuo. Dil NaHCO3 solution was added to the residue and extracted with methylene chloride. The organic layer was backwashed with water, dried over anh MgSO4, filtered and concentrated under reduced pressure to obtain 84.8 g of oily product.
Reaction SMILES: [CH2:1]([PH:5](=[O:9])[O:6][CH2:7][CH3:8])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.C[Si](C)(C)Cl.[C:22]([O:26][C:27]([NH:29][CH:30]1[O:33][C:31]1([CH3:34])[CH3:32])=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCCC1.ClCCl.[Cl-].[Zn+2].[Cl-]>[C:22]([O:26][C:27]([NH:29][CH2:30][C:31]([OH:33])([CH3:34])[CH2:32][P:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:9])[O:6][CH2:7][CH3:8])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCCC[PH](=O)OCC
Reactant: CC(C)(C)OC(=O)NC1OC1(C)C
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCP(=O)(CC(C)(O)CNC(=O)OC(C)(C)C)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 15.0 g of ethyl n-butylphosphinate in anhydrous tetrahydrofuran containing 11.11 g of triethylamine is treated under an inert gas with an anhydrous tetrahydrofuran solution of 11.95 g of trimethylchlorosilane. A white precipitate forms immediately and the resulting suspension is stirred for 24 hours at room temperature under an inert gas. The reaction mixture is then filtered under an inert gas and the filtrate concentrated in vacuo to afford a cloudy oil which is then treated with 3.76 g of 3-(N-tert.-butoxycarbonylamino)-2-methyl-2,3-epoxypropane and 1 g of anhydrous zinc chloride. An exothermic reaction results. After the exotherm has subsided the clear solution is heated slowly to 70° and stirred at this temperature for 4 hours, after which time chromatographic analysis indicates the reaction to be complete. The reaction mixture is cooled to room temperature, diluted with dichloromethane and washed with water. Drying of the solvent and removal in vacuo affords an oil. The excess starting material is removed by Kugelrohr-distillation in high vacuum and the pale yellow residue chromatographed on silica-gel to give ethyl 3 -(N-tert.-butoxycarbonylamino)-2-hydroxy-2-methyl-propyl-(n-butyl)phosphinate as a colourless oil; 1H-NMR (CDCl3): δ (ppm)=5.17+4.68 (1H, Exch. D2O, NH), 4.07 (2H, m, CH2OP), 3.18 (2H, m, CH2N), 1.93-1.22 (24H, m, becomes 23H on D2O exchange), 0.92 (3H, t,CH3). 31P-NMR (CDCl3); 59.6, 59.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[C:13](=[O:16])([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:16][CH3:13])=[CH:7][CH:6]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccccc2OC)cc1
Temperature: 100 °C
Yield: 179.7 %

Procedure:
A mixture of 4-bromo benzoic acid ethyl ester (2.7 mL, 16.5 mmol), 2-methoxy boronic acid (2.5 g, 16.5 mmol) and sodium carbonate (7.7 g, 72.6 mmol) in toluene:ethanol:water (75 mL:37 mL:37 mL), was flushed with nitrogen for 1 hour. After addition of the tetrakis (triphenylphosphine)palladium (0) catalyst (0.96 g, 0.83 mmol), the reaction mixture was heated at 100° C. overnight. After cooling, the mixture was filtered through Celite which was then rinsed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification of the residue by flash chromatography with a solvent gradient from 25% to 50% dichloromethane in hexane provided the title compound (3.8 g, 89.9%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([CH2:33][NH:34][CH3:35])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:56][S:57](Cl)(=[O:59])=[O:58].C(=O)([O-])O.[Na+]>ClCCl>[F:48][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([CH2:33][N:34]([CH3:35])[S:57]([CH3:56])(=[O:59])=[O:58])=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:44])[F:46])=[CH:41][CH:42]=2)[CH2:6][CH2:7]1
Reactant: CNCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a solution of 65 mg (95 μmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-(1-{5-[(methylamino)methyl]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 58, in 0.2 ml of dichloromethane, 30 μl (0.19 mmol) of triethylamine and 8 μl (0.1 mmol) of methanesulfonyl chloride were added, and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, saturated sodium hydrogencarbonate aqueous solution was poured into the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=100/0-40/60 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 37 mg of the title compound as a white solid (yield: 52%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:10](N1C=CC=CC1=O)([N:12]1C=CC=CC1=O)=[S:11].N.CO>C(Cl)Cl>[NH:1]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:10]([NH2:12])=[S:11]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)CNC(N)=S
Reaction time: 18 h

Procedure:
To a magnetically stirred suspension of tert-butyl 2-aminoacetate (11.2 g, 85 mmol) in CH2Cl2 (200 mL) under nitrogen is added 1,1′-thiocarbonyldipyridin-2(1H)-one (21 g, 90 mmol) and the resulting mixture is stirred at room temp. for 18 h. The solvent is removed in vacuo, the residue treated with 2M ammonia in methanol (600 mL, 1200 mmol) and stirred at room temperature for 45 min. The solvent is removed in vacuo and dried under high vacuum to give the title compound as a reddish oil that is used “as is” without further purification in the next step. LC/MS (Condition A): ret. T=2.19 min, (M+H)+ 191—actually see (M−55) 134.95 (this is characteristic of BOC fragmentation pattern).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](Cl)=[O:7])[N:3]=[N:2]1.[CH3:9][O:10][C:11](=[O:26])[C@H:12]([CH3:25])[NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH3:24].Cl.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:9][O:10][C:11](=[O:26])[C@H:12]([CH3:25])[N:13]([C:6]([C:4]1[N:3]=[N:2][S:1][CH:5]=1)=[O:7])[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH3:24]
Reactant: O=C(Cl)c1csnn1
Reactant: COC(=O)[C@H](C)Nc1c(C)ccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)[C@H](C)N(C(=O)c1csnn1)c1c(C)ccc2ccccc12
Yield: 95.3 %

Procedure:
14 g (0.095 mole) of 1,2,3-thiadiazole-4-carbonyl chloride in 30 ml of toluene were added dropwise to a solution of 22.9 g (0.0945 mole) of N-(2-methyl-1-naphthyl)-alanine methyl ester in 100 ml of dry toluene at from +15° C. to +30° C. The mixture was stirred at 80° C. for 8 hours, during which the hydrogen chloride formed was continuously expelled in a weak stream of nitrogen. The mixture was cooled and stirred with a solution of 5 g of sodium bicarbonate in 100 ml of water. The organic phase was separated off, dried over sodium sulfate, decolorized with charcoal and evaporated under reduced pressure. The oily residue which remained was dried at 50° C. and under 0.1 mbar for 3 hours to give 32 g (95.2% of theory) of N-(1,2,3-thiadiazol-4-yl-carbonyl)-N-(2-methyl-1-naphthyl)-alanine methyl ester as a light-brown resin.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH3:9])[CH2:4][CH2:3]1.[Br:10][CH2:11][C:12](Br)=[O:13]>CN(C)C=O.C(Cl)(Cl)Cl>[BrH:10].[CH3:9][N:8]([CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[C:12](=[O:13])[CH2:11][Br:10]
Reactant: CNC1CCN(C)CC1
Reactant: O=C(Br)CBr
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Br
Product: CN1CCC(N(C)C(=O)CBr)CC1
Temperature: 5 °C
Reaction time: 18 h
Yield: 412 %

Procedure:
1.45 g of 1-methyl-4-methylaminopiperidine in 30 cm3 of dry dimethylformamide are placed in a three-necked flask maintained under nitrogen at 5° C. and then 0.95 g of bromoacetyl bromide dissolved in 10 cm3 of chloroform is added over 1 hour. After 18 hours at room temperature, the reaction mixture is concentrated, the residue taken up in 30 cm3 of ether and then stirred for 3 hours. The resulting solid is filtered, washed with ether and then dried under reduced pressure (2.7 kPa) to give 3.2 g of N-methyl-N-(1-methylpiperid-4-yl)-bromoacetamide hydrobromide in the form of a pale-yellow solid which is used as it is.
Reaction SMILES: COC1C=C2C(=CC=1)CC(C1C=CC(C(F)(F)F)=CC=1N)CC2.Cl.[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[C:29](O)=O.FC1C=[C:47](C=CC=1OCCN1CCCCC1)[CH2:48][NH:49][C:50]1[CH:55]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:53]=[CH:52][C:51]=1[CH:60]1[CH2:69][CH2:68][C:67]2[C:62](=[CH:63][CH:64]=[C:65]([O:70][CH3:71])[CH:66]=2)[CH2:61]1>>[CH2:48]([N:49]([CH2:29][C:28]1[CH:32]=[CH:33][C:34]([O:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:26]([F:25])[CH:27]=1)[C:50]1[CH:55]=[C:54]([C:56]([F:57])([F:58])[F:59])[CH:53]=[CH:52][C:51]=1[CH:60]1[CH2:69][CH2:68][C:67]2[C:62](=[CH:63][CH:64]=[C:65]([O:70][CH3:71])[CH:66]=2)[CH2:61]1)[CH3:47]
Reactant: COc1ccc2c(c1)CCC(c1ccc(C(F)(F)F)cc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Agent: COc1ccc2c(c1)CCC(c1ccc(C(F)(F)F)cc1N)C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(C(F)(F)F)ccc1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-trifluoromethylphenylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 282, [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-trifluoromethylphenyl]amine (407 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-trifluoromethylphenyl]amine (343 mg). This compound (341 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (29 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].[CH2:12]([NH2:14])[CH3:13].O.[OH-].[Na+]>O1CCCC1>[CH2:12]([NH:14][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:13]
Reactant: CCN
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCNCc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
2-Nitrobenzylbromide (0.23 mol) in tetrahydrofuran (500 ml) was added to a stirred mixture (4.35M) of 70% aqueous ethylamine (350 ml) and water (350 ml) over a 20 minutes. The reaction stood at ambient temperature for 1 hour, was reduced to low volume, treated with ice/water to 800 ml and basified with an aqueous solution of sodium hydroxide (ION, 23 ml). It was extracted with ether (2×) and the combined extracts dried (MgSO4) and evaporated to give N-ethyl-2-nitrobenzylamine as a yellow oil (44 g, 100%).
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[CH:9]=1)([CH3:5])[C:3]#C.[Cl:17]Cl.N1C=CC=CC=1.[CH2:25]([Cl:27])[Cl:26]>CCOCC>[Cl:15][C:10]1[CH:9]=[C:8]([C:7]2[O:16][C:1]([Cl:17])([CH:25]([Cl:27])[Cl:26])[C:2]([CH3:5])([CH3:3])[N:6]=2)[CH:13]=[C:12]([Cl:14])[CH:11]=1
Reactant: C#CC(C)(C)NC(=O)c1cc(Cl)cc(Cl)c1
Reactant: ClCCl
Reactant: ClCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC1(C)N=C(c2cc(Cl)cc(Cl)c2)OC1(Cl)C(Cl)Cl
Reaction time: 1 h

Procedure:
N-(1',1'-dimethylpropynyl)-3,5-dichlorobenzamide (25 gm, 0.096 m) was dissolved in methylene chloride (300 ml) and excess chlorine (2.5-3 equivalents) was bubbled through this solution at room temperature. After the starting material had disappeared (as indicated by thin layer chromatography, TLC), this solution was washed with aqueous sodium sulfite and the solvent was removed. The white solid obtained was slurried in ether (250 ml) and pyridine (8.0 gm) was added. The mixture was stirred for about 1 hour and then filtered to remove solids. The mother liquor was washed sequentially with cold 1% hydrochloric acid (25 ml), sodium bicarbonate (50 ml), water and brine. The solvent was removed after drying over magnesium sulfate and 28 gm of 2-(3',5'-dichlorophenyl)-4,4-dimethyl-5-chloro-5-dichloromethyloxazoline was obtained.