Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@@H:22]1[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:24]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:23]1[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:2]=[CH2:3].[H-].[Na+].[CH2:56](Br)[CH:57]=[CH2:58]>CN(C)C=O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH3:21])=[CH:17][CH:18]=2)=[CH:7][C:6]=1[C@H:22]1[C@H:23]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:24]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:25]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:26]([CH2:28][O:29][CH2:58][CH:57]=[CH2:56])[O:27]1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC[C@H]1O[C@@H](c2cc(Cc3ccc(OCC)cc3)c(Cl)cc2OCC=C)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To a solution of primary alcohol (21, 1.5 g, 2.04 mmol) from Step 1 in N,N-dimethylformamide (10 mL) at 0° C. under an atmosphere of nitrogen was added sodium hydride (60% dispersion in mineral oil, 123 mg, 3.06 mmol), and the mixture was stirred for 30 min at the same temperature. Then allyl bromide (0.26 mL, 3.06 mmol) was added dropwise, and the mixture was stirred with gradual warming to ambient temperature over 5 h. After re-cooling to 0° C., the reaction mixture was quenched by addition of water (10 mL). The mixture was diluted with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting crude residue was purified on a Biotage® purification apparatus (silica gel, 5 to 20% tetrahydrofuran in hexanes gradient) to yield the title compound (22, 1.12 g, 1.44 mmol, 71%) as a white solid.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:14]([C:16]([CH3:18])=[O:17])=[CH2:15]>C1COCC1>[O:17]=[C:16]([CH3:18])[CH2:14][CH2:15][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=CC(C)=O
Solvent: C1CCOC1
Product: CC(=O)CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87 %

Procedure:
A solution of tert-butyl piperazine-1-carboxylate (6 g, 32.3 mmol) in THF (50 ml) was gradually added dropwise to a solution of methyl vinyl ketone (2.3 g, 32.9 mmol) in THF (25 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to afford tert-butyl 4-(3-oxobutyl)piperazine-1-carboxylate (7.2 g, yield 87%)as a pale yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])(=O)C.[C:28](OCC)(=[O:30])[CH3:29].CCCCCC>>[C:28]([N:4]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])[CH3:1])(=[O:30])[CH3:29]
Reactant: CCOC(=O)n1c(C(=O)C2CCCCC2)c(NC(C)=O)c2ccc(Cl)cc21
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)N(C)c1c(C(=O)C2CCCCC2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared from 3-acetylamino-6-chloro-2-cyclohexylcarbonyl-1-(ethoxycarbonyl)indole (step 1) according to the procedure described in Example 146. m.p.: 162-163° C. (ethyl acetate/hexane)
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[CH:9](O)([OH:14])[C:10]([F:13])([F:12])[F:11]>>[F:11][C:10]([F:13])([F:12])[CH:9]([C:1]1[CH:2]=[C:3]([CH3:8])[CH:4]=[CH:5][C:6]=1[OH:7])[OH:14]
Reactant: Cc1ccc(O)cc1
Reactant: OC(O)C(F)(F)F
Product: Cc1ccc(O)c(C(O)C(F)(F)F)c1
Temperature: 100 °C
Yield: 90 %

Procedure:
11.6 g (100 mmol) of p-cresol and 3.9 g (25 mmol) of 75% fluoral hydrate are introduced into a 100 ml reactor. 5.0 g of MgO are added. The mixture is heated at 100° C. for 6 hours. After treating according to the protocol described in Example 1, a yield of 90% of the expected alcohol is obtained.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[OH-:19].[K+].Cl>O>[N+:16]([C:13]1[CH:14]=[CH:15][C:2]([OH:19])=[C:3]([CH:12]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])([O-:18])=[O:17]
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.3 %

Procedure:
Into an autoclave, were charged 30 g of 2-chloro-5-nitrobenzophenone, 300 ml of water, and 9.70 g of potassium hydroxide. The mixture was allowed to react at 150° to 160° C. with stirring for 5 hours. Upon cooling to room temperature, there was obtained a clear liquid, reddish orange in color. The liquid was further cooled below 0° C. and strongly acidified with cold concentrated hydrochloric acid. The precipitated solids were collected by filtration, washed with water, and recrystallized from ethanol to yield 15.7 g (56.1%) of 5-nitro-2-hydroxy-benzophenone having a melting point of 122°-123° C. To 150 ml of 40-% aqueous potassium hydroxide solution, was added 25.0 g of 5-nitro-2-hydroxybenzophenone followed by 50 g of hydroxylamine hydrochloride. After 5 hours, the resulting clear liquid was cooled and acidified with concentrated hydrochloric acid to form a precipitate. The precipitate was washed with water and a small volume of 50-% aqueous methanol, then dried in air, and recrystallized from benzene and petroleum ether to yield 5-nitro-2-hydroxybenzophenone oxime.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[C:3]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][N:17]([C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:16][CH2:15]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)(C)c1cc(Cl)ccc1N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)N1CCN(c2ccc(Cl)cc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a mixture of 1-(2-tert-butyl-4-chlorophenyl)piperazine dihydrochloride (Reference Example 20, 0.50 g, 1.54 mmol) and triethylamine (0.48 g, 4.77 mmol) in THF (30 mL) was added ethyl chloro(oxo)acetate (0.23 g, 1.69 mmol). The mixture was stirred at room temperature for 1 h, filtered and concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, died over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, 9:1-3:7, hexane/ethyl acetate) to give the title compound (0.49 g) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][NH:6][C:7]([CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:8].CS[C:16]1[S:17][CH2:18][C:19](=[O:21])[N:20]=1>>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][NH:6][C:7]([CH:9]1[CH2:10][N:11]([C:16]2[S:17][CH2:18][C:19](=[O:21])[N:20]=2)[CH2:12]1)=[O:8]
Reactant: CSC1=NC(=O)CS1
Reactant: COC(=O)CCNC(=O)C1CNC1
Product: COC(=O)CCNC(=O)C1CN(C2=NC(=O)CS2)C1

Procedure:
3-{[1-(4-Oxo-4,5-dihydro-thiazol-2-yl)-azetidine-3-carbonyl]-amino}-propionic acid methyl ester was prepared from 3-[(Azetidine-3-carbonyl)-amino]-propionic acid methyl ester and 2-Methylsulfanyl-thiazol-4-one following General Procedure D.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14](=[O:17])[NH:15][CH:16]=1.[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:18][N:15]1[CH:16]=[C:11]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[CH3:1])[CH:12]=[CH:13][C:14]1=[O:17]
Reactant: Cc1c(-c2ccc(=O)[nH]c2)cccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1c(-c2ccc(=O)n(C)c2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 5-(2-methyl-3-nitrophenyl)pyridin-2-one (9) (0.92 g, 4.0 mmol), DMF (40 mL), potassium carbonate (1.21 g, 8.80 mmol) and iodomethane (625 mg, 4.40 mmol) and purged with nitrogen. The reaction mixture was stirred at room temperature for 2 h. After this time the reaction was cooled to room temperature and partitioned between ethyl acetate (150 mL) and water (75 mL). The organic layer was separated and washed with water (2×50 mL) followed by brine (100 mL) and dried over magnesium sulfate. The drying agent was then removed by filtration and the filtrate concentrated under reduced pressure to afford 0.92 g (94%) of 1-methyl-5-(2-methyl-3-nitrophenyl)pyridin-2-one (10) as a white solid: mp 157-159° C.; 1H NMR (300 MHz, CDCl3) 7.81 (dd, 1H, J=7.8, 1.8 Hz), 7.41 (dd, 1H, J=7.8, 1.8 Hz), 7.38 (d, 1H, J=7.5 Hz), 7.53 (d, 1H, J=9.3 Hz), 7.32 (dd, 1H, J=9.3, 2.7 Hz), 7.27 (d, 1H, J=1.5 Hz), 6.68 (d, 1H, J=9.3 Hz), 3.62 (s, 3H), 2.37 (s, 3H); MS (ESI+) m/z 245 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[CH2:10]1.[C:25](=O)([O:34]N1C(=O)CCC1=O)[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:26][C:25]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=2)[CH2:10]1)=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: COC(=O)c1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3N)C2)cc1
Product: COC(=O)c1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)OCc3ccccc3)C2)cc1

Procedure:
Methyl 4-((S)-3-((1R,2R)-2-(benzyloxycarbonylamino)cyclohexylamino) piperidin-1-yl)benzoate was synthesized using methyl 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzoate (98 mg, 0.296 mmol) and benzyl 2,5-dioxopyrrolidin-1-yl carbonate (73.7 mg, 0.296 mmol) according to General Procedure H to give 38 mg (20% yield) of yellow solid. Anal. Calcd. for C27H35N3O4 m/z 465.5, found: 466.1 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.88 (d, J=9.0 Hz, 2H), 7.30-7.18 (m, 3H), 7.16-7.09 (m, 2H), 7.05 (d, J=8.9 Hz, 2H), 4.93 (s, 2H), 3.84 (s, 3H), 3.72-3.47 (m, 3H), 3.47-3.11 (m, 4H), 2.29 (d, J=13.4 Hz, 1H), 2.12-1.99 (m, 2H), 1.96-1.77 (m, 5H), 1.61-1.29 (m, 4H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH2:13][CH3:14])[C:7]=2[C:6](=[O:15])[NH:5][C:4]1=[O:16])[CH3:2].Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23]>>[CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH2:13][CH3:14])[C:7]=2[C:6](=[O:15])[N:5]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])[C:4]1=[O:16])[CH3:2]
Reactant: CC(=O)CCCCCl
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2CC
Product: CCCn1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2CC

Procedure:
3-Ethyl-1-(5-oxohexyl)-7-propylxanthine (melting point 81-82° C.) is prepared from 3-ethyl-7-propylxanthine and 1-chlorohexan-5-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([NH:20][CH3:21])=[CH:18][C:17]([O:22][C:23]([F:38])([F:37])[C:24]([F:36])([F:35])[C:25]([F:34])([F:33])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[N:16]1.ClC1C=CC=C(C(OO)=[O:47])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:10][C:11]([F:14])([F:13])[F:12])=[O:47])=[CH:4][C:3]=1[N:15]1[C:19]([NH:20][CH3:21])=[CH:18][C:17]([O:22][C:23]([F:38])([F:37])[C:24]([F:35])([F:36])[C:25]([F:33])([F:34])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[N:16]1
Reactant: CNc1cc(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CNc1cc(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
0.25 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-methylamino-3-(1,1,2,2,3,3,4,4,5,5,5-undecafluoropentyloxy)pyrazole was dissolved in 10 mL of chloroform, and 95 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous potassium carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:1) to obtain 0.23 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-5-methylamino-3-(1,1,2,2,3,3,4,4,5,5,5-undecafluoropentyloxy)pyrazole.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4][CH:3]1C(OCC)=O.[ClH:21]>>[ClH:21].[NH:6]1[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH2:8][CH2:7]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: Cl
Product: O=C1CCCNCC1

Procedure:
A solution of 1-tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (0.9 g, 3.16 mmol, 1 equiv) in aq. HCl (30 mL, 4N) was stirred at reflux for 7 h. The reaction mixture was then concentrated to give the desired product, which was directly used for the next step without further purification. MS (ESI): 114 (MH+).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH:22]3[CH2:27][CH2:26][N:25](C(O)=O)[CH2:24][CH2:23]3)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[ClH:31].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:31].[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(-c2nc(C3CCN(C(=O)O)CC3)cs2)c1-c1ccc(F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)n1ncc(-c2nc(C3CCNCC3)cs2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 99.7 %

Procedure:
To a solution of 4-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)piperidine-1-carboxylic acid (338 mg, 0.70 mmol) in ethyl acetate (1 mL) was added 4N hydrogen chloride/ethyl acetate (1 mL, 4.00 mmol), and the mixture was stirred at room temperature for 14 hr. The precipitate was collected by filtration, and washed with ethyl acetate to give the title compound (294 mg, 0.698 mmol, 100%) as a pale-yellow powder.
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:10]([OH:13])[CH:11]=[CH2:12])=O)(C)(C)C.[H-].[Na+].CCCCCC>CN(C)C=O>[CH:15]1([CH2:14][C@H:9]2[CH:10]([CH:11]=[CH2:12])[O:13][C:6](=[O:5])[NH:8]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C=CC(O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=CC1OC(=O)N[C@H]1CC1CCCCC1
Reaction time: 3 h

Procedure:
The resultant product of Example 118 (2.80 g, 9.88 mmol) in dry dimethylformamide (DMF) (50 ml) was added to a stirred suspension of NaH (593 mg of a 60% dispersion in oil, 14.8 mmol, hexane washed) in dry DMF (50 ml). After 3 h, the mixture was quenched (750 ml water+100 m brine) and extracted with ether (5×100 ml). The combined organic phase was washed with brine (3×50 ml), dried (MgSO4), filtered and evaporated to an oil (2.33 g). The NMR spectrum of the crude product revealed an 82:18 mixture of 5S:5R diastereomers. Silica gel chromatography gave 80% recovery of pure diastereomers. 5S:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCNCC
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Product: CCN(CC)S(=O)(=O)c1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 100 g. of sodium 4-acetylbenzenesulfonate is added to a stirred solution of 500 ml. of 50% aqueous diethylamine. The mixture is stirred at room temperature for 4 hours, cooled, and the precipitated 4-acetyl-N,N-diethylbenzenesulfonamide removed fy filtration, washed with water and dried; m.p. 78°-79° C. after crystallization from 2-propanol.
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12](=[O:29])[C@@H:13]([NH:19][C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[CH2:14][CH2:15][C:16](O)=[O:17])([CH3:10])([CH3:9])[CH3:8].CN1CCOCC1.[BH4-].[Na+]>C1COCC1.O>[OH:17][CH2:16][CH2:15][CH2:14][C@@H:13]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:29])[NH:19][C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])=[O:21]
Reactant: CC(C)(C)OC(=O)[C@H](CCC(=O)O)NC(=O)OCC[Si](C)(C)C
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)OC(=O)[C@H](CCCO)NC(=O)OCC[Si](C)(C)C
Temperature: 0 °C
Yield: 97.1 %

Procedure:
Ethyl chloroformate (0.441 ml, 4.59 mmol) was added slowly to a stirred solution of (4S)-5-tert-butoxy-5-oxo-4-({[2-(trimethylsilyl)ethoxy]carbonyl}amino) pentanoic acid (1.33 g, 3.83 mmol) and N-methylmorpholine (0.547 ml, 4.98 mmol) in THF (10 ml) at −20° C. A thick white solid precipitated from the solution and hindered stirring. THF (ca. 4 ml) was added to mobilise the suspension. The resulting mixture was stirred at −20° C. for 30 min, then allowed to warm slowly to 0° C. over the course of 2 h. The mixture was therefore stirred at 0° C. for a further 1 h. The slurry was filtered and the filtrate added portion wise over 30 min to a stirred solution of sodium borohydride (0.434 g, 11.48 mmol) in THF (4 ml) and water (1 ml) at 0° C. The mixture was quenched with NH4Cl solution, diluted with Et2O (50 ml) and the phases separated. The aqueous phase was extracted with Et2O (25 ml) and the combined organic phases were washed with NaHCO3 solution (25 ml) and brine (25 ml), dried (MgSO4) and evaporated to give tert-Butyl 5-hydroxy-N-{[2-(trimethylsilyl)ethoxy]carbonyl}-L-norvalinate (1.24 g) as a clear colourless oil.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[F:17])[CH2:7][CH3:8].[CH2:18]([C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][CH2:28][C@H:29]2[CH2:34][CH2:33][C@H:32]([CH2:35][CH2:36]I)[CH2:31][CH2:30]2)[CH2:23][CH2:22]1)[CH2:19][CH3:20].CC1N(C(N(C)C)=O)C1>CCCCCC.O1CCCC1>[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:36][CH2:35][C@H:32]2[CH2:33][CH2:34][C@H:29]([CH2:28][CH2:27][C@H:24]3[CH2:23][CH2:22][C@H:21]([CH2:18][CH2:19][CH3:20])[CH2:26][CH2:25]3)[CH2:30][CH2:31]2)=[C:12]([F:16])[C:11]=1[F:17])[CH2:7][CH3:8]
Reactant: CCCOc1cccc(F)c1F
Reactant: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](CCI)CC2)CC1
Agent: CC1CN1C(=O)N(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCOc1ccc(CC[C@H]2CC[C@H](CC[C@H]3CC[C@H](CCC)CC3)CC2)c(F)c1F
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
65 ml of a solution of 0.1 mol of n-butyllithium in hexane is added at -100° C. to a mixture of 0.1 mol of 4- propoxy-2,3-difluorobenzene, 0.09 mol of potassium tert.butylate and 250 ml of tetrahydrofuran. After stirring for 10 minutes a mixture of 0.1 mole of trans-4-(trans-4-propylcyclohexylethyl)-cyclohexylethyl iodide, 0.1 mol of N,N-dimethylpropyleneurea and 100 ml of tetrahydrofuran is added to the mixture. Stirring for 1 hour at -85° C., warming up to -40° C. and working up in the customary manner gives trans-4-(2-(4-propoxy-2,3-difluorophenyl)-ethyl)-1-(2-(trans-4-propylcyclohexyl)ethyl)-cyclohexane.
Reaction SMILES: CON1CCN(C2C=CC=CC=2)CC1.C1(CC(O)=O)C2C=CC=CC=2CCCO1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:44](=O)[CH2:45][CH:46]3[C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=4[CH2:50][CH2:49][CH2:48][O:47]3)[CH2:40][CH2:39]2)=[CH:34][CH:33]=1.[ClH:58]>CCOCC.CO>[ClH:58].[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([N:38]2[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][CH:46]3[C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=4[CH2:50][CH2:49][CH2:48][O:47]3)[CH2:40][CH2:39]2)=[CH:36][CH:37]=1
Reactant: COc1ccc(N2CCN(C(=O)CC3OCCCc4ccccc43)CC2)cc1
Agent: CON1CCN(c2ccccc2)CC1
Agent: Cl
Agent: O=C(O)CC1OCCCc2ccccc21
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(N2CCN(CCC3OCCCc4ccccc43)CC2)cc1

Procedure:
Step 5--Following the general procedure of EXAMPLE 50 and making non-critical variations p-methoxyphenylpiperazine is acylated with (1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)acetic acid (CXXIII, 619 mg) and the resulting amide, 1-(4-methoxyphenyl)-4-(1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)acetyl piperazine (CXXIV, 1.07 g) is reduced according to the general procedure described in EXAMPLE 50 (making non-critical variations) to give crude product. This crude material is dissolved in ether (30 ml) and methanol (3 ml) and treated with gaseous hydrochloric acid resulting in the formation of a salt. This crude salt is recrystallized from methanol/ethyl acetate to give the title compound, mp 217.0-219.0° (uncorrected, decomp).
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([NH:18][C:19]([C:21]1[N:22]([CH3:32])[C:23]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C.Cl>C(Cl)(Cl)Cl.CO.O1CCOCC1>[NH2:5][CH2:9][CH:10]([NH:18][C:19]([C:21]1[N:22]([CH3:32])[C:23]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cn1nccc1-c1ccc(C(=O)NC(Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)n1C
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cn1nccc1-c1ccc(C(=O)NC(CN)Cc2ccccc2)n1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,1-dimethylethyl[2-({[1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrol-2-yl]carbonyl}amino)-3-phenylpropyl]carbamate (20 mg, 0.05 mmol) [prepared in Example 48] in CHCl3 (4 mL) and MeOH (1 mL) was treated with 4 M HCl in dioxane (2 mL). After stirring for 18 h at RT, the reaction solution was adsorbed onto silica and purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[OH:20][C:21]1[CH:22]=[CH:23][C:24]2[O:29][CH2:28][CH:27]([C:30](O)=[O:31])[O:26][C:25]=2[CH:33]=1>>[OH:20][C:21]1[CH:22]=[CH:23][C:24]2[O:29][CH2:28][CH:27]([C:30]([N:9]3[CH2:10][CH2:11][N:6]([CH2:5][C:4]4[CH:12]=[CH:13][C:14]([O:18][CH3:19])=[C:15]([O:16][CH3:17])[C:3]=4[O:2][CH3:1])[CH2:7][CH2:8]3)=[O:31])[O:26][C:25]=2[CH:33]=1
Reactant: O=C(O)C1COc2ccc(O)cc2O1
Reactant: COc1ccc(CN2CCNCC2)c(OC)c1OC
Product: COc1ccc(CN2CCN(C(=O)C3COc4ccc(O)cc4O3)CC2)c(OC)c1OC
Yield: 65 %

Procedure:
That compound is obtained in a yield of 65% starting from 1-(2,3,4-trimethoxy benzyl)piperazine and 7-hydroxy-2,3-dihydro-1,4-benzodioxin-2-carboxylic acid.