Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH2:17])=[N:13][NH:14]2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH:17][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[N:13][NH:14]2)=[CH:10][CH:9]=1
Reactant: CCCC(=O)Cl
Reactant: Nc1n[nH]c2cc(Br)ccc12
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2cc(Br)ccc12
Temperature: 5 °C
Reaction time: 50 h

Procedure:
0.24 cm3 of butyryl chloride is added to 500 mg of 6-bromo-1H-indazole-3-amine described previously in Example 12, in 15 cm3 of pyridine, and cooled to about 5° C. The reaction medium is allowed to return to about 19° C. over 50 hours. The reaction medium is evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 15 cm3 of ethyl acetate and 15 cm3 of distilled water. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 15 cm3 of dichloromethane and filtered to give after drying (90 Pa; 50° C.), 356 mg of N-[6-bromo-1H-indazol-3-yl]butanamide in the form of an off-white solid melting at 202° C.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([CH3:29])([CH3:28])[CH2:5][CH2:6][N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([S:17](=[O:27])(=[O:26])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:12][CH:13]=2)[CH2:8]1.O=C(N1CCC2C(=CC(S(=O)(=O)NC3C=CC=C(Cl)C=3)=CC=2)C1)C(C)(C)CCN1CCC2C(=CC(S(=O)(=O)NC3C=CC=C(Cl)C=3)=CC=2)C1>>[CH3:28][C:4]([CH3:29])([CH2:5][CH2:6][N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([S:17](=[O:27])(=[O:26])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:12][CH:13]=2)[CH2:8]1)[C:3]([OH:30])=[O:2]
Reactant: COC(=O)C(C)(C)CCN1CCc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1
Agent: CC(C)(CCN1CCc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1)C(=O)N1CCc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1
Product: CC(C)(CCN1CCc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1)C(=O)O

Procedure:
Following the method of Example 2(a), substituting methyl-2,2-dimethyl-4-bromobutanoate (J. L. Bass et al, Tetrahedron, 1966, 22, 285) gave a mixture of methyl-2,2-dimethyl-4-[7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]butanoate and 1-oxo-2,2-dimethyl-1,4-bis-[7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]butane, which were separated by chromatography (silica gel, ether). The former compound was hydrolysed by the method of Example 2(b), substituting methanol for ethanol and carrying out the reaction for 24 hours, to give, after recrystallisation from ethanol, 2,2-dimethyl-4-[7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]butanoic acid, 1.1 C2H5OH, 0.8 H2O, m.p. ca. 120° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[N:12]1[C:16]([CH2:17][NH2:18])=[CH:15][N:14]=[CH:13]1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>ClC(Cl)Cl>[CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[N:12]1[C:16]([CH2:17][NH:18][C:20](=[O:22])[CH3:21])=[CH:15][N:14]=[CH:13]1
Reactant: CC1(C)CCc2ccccc2C1n1cncc1CN
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)NCc1cncn1C1c2ccccc2CCC1(C)C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a stirred mixture of 5.1 parts of 1-(1,2,3,4-tetrahydro-2,2-dimethyl-1-naphthalenyl)-1H-imidazole-5-methanamine and 75 parts of trichloromethane was added dropwise a solution of 2.0 parts of acetic acid anhydride in 150 parts of trichloromethane. Upon complete addition, stirring was continued for 1 hour at room temperature. The reaction mixture was washed with a sodium carbonate solution 10% and water, dried, filtered and evaporated. The residue was crystallized from 2-propanone. The product was filtered off and dried, yielding 3.61 parts (60.6%) of N-[[1-(1,2,3,4-tetrahydro-2,2-dimethyl-1-naphthalenyl)-1H-imidazol-5-yl]methyl]acetamide; mp. 166.3° C. (compound 2.47).
Reaction SMILES: [OH:1][C@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[CH:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:17]([CH3:25])([CH2:18][CH2:19][C:20]=32)[C@@H:11]([C@@H:12]([CH3:16])[CH2:13][CH:14]=O)[CH2:10][CH:9]=4)[C:3]1([CH3:27])[CH3:26].[C:28]1([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:28]1([N:34]2[CH2:39][CH2:38][N:37]([CH2:14][CH2:13][C@@H:12]([C@@H:11]3[C@:17]4([CH3:25])[C:8]([C:7]5[CH2:6][CH2:5][C@@H:4]6[C@:21]([C:20]=5[CH2:19][CH2:18]4)([CH3:24])[CH2:22][CH2:23][C@H:2]([OH:1])[C:3]6([CH3:27])[CH3:26])=[CH:9][CH2:10]3)[CH3:16])[CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: C[C@@H](CC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[C@@H](CCN1CCN(c2ccccc2)CC1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
(20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-carbaldehyde was treated with N-phenylpiperazin and sodium tris(acetoxy)borohydride as described in Example 9d). (20S)-20-[(4-phenylpiperazin-1-yl)ethyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol was isolated as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(CNCCCSc2ccncc2)nc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N(CCCSc1ccncc1)Cc1ccccn1
Yield: 58.9 %

Procedure:
To a solution of 1.60 g (6.17 mmol) of 4-[3-(N-2-pyridylmethylamino)propylthio)pyridine and 1.05 ml (7.40 mmol) of triethylamine in 10 ml of methylene chloride, 0.86 ml (7.40 mmol) of benzoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate/methanol=10:1) to obtain 1.32 g of the desired compound (yield: 58.9%, yellow oil).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[NH:18][C:19]1[NH:20][CH2:21][CH2:22][N:23]=1>O1CCCC1>[C:1]([N:23]1[CH2:22][CH2:21][N:20]=[C:19]1[NH:18][C:12]1[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:11]=1[Cl:10])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Solvent: C1CCOC1
Product: O=C(c1cccnc1)N1CCN=C1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 48.1 %

Procedure:
5.5 g (44.7 millimoles) of nicotinic acid are dissolved in 800 ml of absolute tetrahydrofuran, 7.3 g (45 millimoles) of N,N'-carbonyldiimidazole are added and the mixture is stirred for 45 minutes at room temperature. A solution of 10.3 g (44.7 millimoles) of 2-(2',6'-dichlorophenylamino)-2-imidazoline in 200 ml of absolute tetrahydrofuran is then added dropwise, with continued stirring, and the mixture is left to stand overnight at room temperature. Thereafter, the reaction solution is freed from solvent on a rotary evaporator, 200 ml of an 0.5% strength sodium bicarbonate solution are added to the residue, and the product which precipitates is filtered off and washed with water. After drying, the crude product is recrystallized from isopropanol. 7.2 g of 1-nicotinoyl-2-(2',6'-dichlorophenylamino)-2-imidazoline, melting point 173°-174° C., are obtained.
Reaction SMILES: COC1C=CC=CC=1C1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:25]=O>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:25]2[NH:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(C=O)cc1OC
Reactant: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1ccc(-c2nc3ccccc3c(=O)[nH]2)cc1OC
Yield: 89 %

Procedure:
According to the preparation of 42, 3,4-dimethoxybenzaldehyde (39) (1.2 g, 7.3 mmol) was used to afford 48 (1.8 g, 89.0%) as pale yellow prism crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[C:13]([C:16]1[NH:17][CH:18]=[CH:19][CH:20]=1)(=O)[CH3:14].N1CCCCC1>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[C:13]([C:16]1[NH:17][CH:18]=[CH:19][CH:20]=1)[CH3:14])#[N:2]
Reactant: CC(=O)c1ccc[nH]1
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(=C1C(=O)Nc2ccc(C#N)cc21)c1ccc[nH]1

Procedure:
To a suspension of 5-cyanoindolin-2-one (158 mg, 1 mmol) in ethanol (15 mL) was added 2-acetylpyrrole (95 mg, 1 mmol) and piperidine (0.1 mL). The reaction mixture was refluxed for 2 hours. A golden-colored product precipitated from the reaction mixture, which was filtered and washed with ethanol to afford 5-cyano-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one; (160 mg) 1H NMR (400 MHz, DMSO-d6) δ 2.80 (s, 3H), 6.40. (m, 1H), 7.04 (d, 1H), 7.20 (m, 1H), 7.42 (m, 1H), 7.60 (dd, 1H), 8.04 (s, 1H), 11.40 (s, 1H) ppm.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1COCC1.[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24].[OH-].[Na+]>O>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH3:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCOCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 1.5 h
Yield: 101.7 %

Procedure:
Under ice cooling, a mixture of 515 g of p-toluenesulfonyl chloride and 500 ml of THF was added dropwise to a mixture of 295 g of 2-(2-methoxyethoxy)ethanol, 589 g of 25 wt % NaOH aqueous solution, and 2,500 ml of THF. The reaction solution was aged for 1.5 hours, after which 1,500 ml of water was added to quench the reaction. The organic layer was separated and concentrated in vacuum. The concentrate was dissolved in a mixture of 660 ml toluene and 330 ml hexane, and washed with water. The organic layer was concentrated in vacuum, obtaining 684.74 g of the target compound, 2-(2-methoxyethoxy)ethyl p-toluenesulfonate as oily matter. Yield 97%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[C:12](=[O:14])[CH2:11][CH2:10]2
Reactant: COc1ccc(CCC(=O)O)cc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: COc1cc2c(cc1Br)CCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
3-(3-Bromo-4-methoxyphenyl)propionic acid (5.0 g, 19.3 mmol) and thionyl chloride (10 ml) were refluxed for 1 hour. This reaction mixture was concentrated under reduced pressure to remove the excess thionyl chloride and the residue was dissolved in 1,2-dichloroethane (50 ml). To this solution was added aluminum chloride (2.8 g, 20.8 mmol) over 10 minutes on an ice bath and the mixture was further stirred at room temperature for 1 hour. This reaction mixture was poured in iced water and extracted with ethyl acetate. The extract was washed serially with saturated saline and water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane to provide the title compound (yield 4.3 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:19])[C:6]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][N:8]=1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:20][CH2:13][C:11]1[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][N:8]=[C:7]([C:6]2[N:5]([CH3:19])[N:4]=[CH:3][C:2]=2[Cl:1])[N:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cnc(-c2c(Cl)cnn2C)nc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc(-c2c(Cl)cnn2C)nc1CBr
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a solution of ethyl 2-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-methylpyrimidine-5-carboxylate (1 g, 3.56 mmol) in carbon tetrachloride (20.0 mL) was added N-bromosuccinimide (697 mg, 3.92 mmol) and 2,2′-azo-bis-isobutyronitrile (30 mg, 0.2 mmol), and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by combi-flash chromatography to afford 0.78 g (61% yield) of the desired product. LC-MS found: 361.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N+:3]=1[O-:10].[CH3:11][N:12]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N+:3]([O-:10])=[CH:4][C:5]([CH2:8][N:15]2[CH2:16][CH2:17][CH2:18][N:12]([CH3:11])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: [O-][n+]1cc(CCl)ccc1Cl
Reactant: CN1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCCN(Cc2ccc(Cl)[n+]([O-])c2)CC1
Temperature: 25 °C
Reaction time: 84 h
Yield: 63.7 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine 1-oxide (940 mg, 5.28 mmol; described in: Tilley, J. W. et al, J. Heterocyclic Chem. 1979, 16, 333) in acetonitrile (30 mL) were added N-methylhomopiperazine (1.21 g, 10.6 mmol), and K2CO3 (730 mg, 5.28 mmol). The reaction mixture was stirred at room temperature for 3.5 days. The solvent was removed in vacuo, and the residue was partitioned between brine and ethyl acetate. The aqueous layer was extracted with another two portions of ethyl acetate and one portion of tetrahydrofuran. The combined organic layers were dried (Na2SO4), and evaporated to give 0.86 g (64% yield) of the title compound as an orange oil: 1H NMR (aceton-d6, 400 MHz) δ 8.30 (dd, J=2 Hz, 1 H), 7.60 (d, J=8 Hz, 1 H), 7.29 (dd, J=8, 2 Hz, 1 H), 3.65 (s, 2 H), 2.74-2.69 (m, 4 H), 2.62-2.54 (m, 4 H), 2.29 (s, 3 H), 1.81-1.75 (m, 2 H); MS (ES) m/z 256 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[C-:13]([N+:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH2:23][CH3:24])[CH:17]=2)[C:12]([NH:25][C:26](=[O:54])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:53])[CH2:35][O:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([CH2:46][CH3:47])([CH3:45])[CH3:44])=[CH:39][C:38]=3[C:48]([CH2:51][CH3:52])([CH3:50])[CH3:49])[CH:28]=2)=[N:11]1.[H][H]>C(O)C.[Ni]>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([N:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH:18]([CH2:23][CH3:24])[CH2:17]2)[C:12]([NH:25][C:26](=[O:54])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:53])[CH2:35][O:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([CH2:46][CH3:47])([CH3:45])[CH3:44])=[CH:39][C:38]=3[C:48]([CH2:51][CH3:52])([CH3:50])[CH3:49])[CH:28]=2)=[N:11]1
Reactant: [H][H]
Reactant: CCc1c[n+](-[c-]2c(NC(=O)c3cccc(NC(=O)COc4ccc(C(C)(C)CC)cc4C(C)(C)CC)c3)nn(-c3c(Cl)cc(Cl)cc3Cl)c2=O)ccc1C
Agent: [Ni]
Solvent: CCO
Product: CCC1CN(C2C(=O)N(c3c(Cl)cc(Cl)cc3Cl)N=C2NC(=O)c2cccc(NC(=O)COc3ccc(C(C)(C)CC)cc3C(C)(C)CC)c2)CCC1C

Procedure:
7.9 grams of 1-(2,4,6-trichlorophenyl)-3-[3-{(2,4 -di-tert-amylphenoxy)acetamido}benzamido]-4-(3-ethyl-4-methyl-1-pyridinio)-5-oxo-2-pyrazolin-4-ide (Compound 1-3; m.p.; 162° - 165° C.) was dissolved in 500 ml of ethanol, and about 10 g of Raney nickel catalyst was added thereto. Then, reaction was conducted in an autoclave at 80° C. for 20 hours with an initial hydrogen pressure of 60 atmospheres. After the reaction, the catalyst was removed, followed by distilling off the solvent. Upon crystallizing the resulting residue from acetonitrile-ethyl acetate (10:1 by volume) 4.2 g of Compound 2-3 having a melting point of 145° - 155° C. was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[C:13](Cl)(=[O:15])[CH3:14].[Sn](Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[C:13]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][CH:8]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)c1c[nH]c2ccc([N+](=O)[O-])cc12
Reaction time: 6 h
Yield: 99 %

Procedure:
A solution of 5-nitroindole (10 g, 61.6 mmol) and acetyl chloride (5.8 g, 74 mmol) in methylene chloride at 0° C. is treated with tin tetrachloride (1M in CH2Cl2, 68 mL), stirred under N2 for 6 h, treated with saturated NaHCO3 to pH 9 and filtered. The filtrate is concentrated in vacuo to give a residue. The residue is dissolved in DMF and filtered. This filtrate is concentrated in vacuo to give the title product, 12.6 g (99% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29](O)=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2([CH3:49])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:21]=[C:22]([CH3:28])[C:23]([OH:27])=[C:24]([CH3:26])[CH:25]=3)[C:29]([N:46]3[CH2:45][CH2:44][C:43]([CH3:49])([N:40]4[CH2:39][CH2:38][N:37]([CH3:36])[CH2:42][CH2:41]4)[CH2:48][CH2:47]3)=[O:30])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1
Reactant: CN1CCN(C2(C)CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C)(N3CCN(C)CC3)CC2)cc(C)c1O

Procedure:
Prepared analogously to Example 1i from 80 mg (0.17 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1h) and 36 mg (0.18 mmol) 1-methyl-4-(4-methyl-piperidin-4-yl)-piperazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].[OH:10][C:11]([CH3:19])([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][SH:13].N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:9])[CH2:4][CH:5]([C:6]([OH:8])=[O:7])[S:13][CH2:12][C:11]([OH:10])([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: COC(=O)/C=C\C(=O)O
Reactant: CCCCCC(C)(O)CS
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCC(C)(O)CSC(CC(=O)OC)C(=O)O
Reaction time: 3 h

Procedure:
A mixture of 2.6 g of maleic acid monomethyl ester, 3.2 g of 2-hydroxy-2-methylheptane-1-thiol, 0.5 ml of pyridine and 120 ml of methylene chloride is stirred for 3 hours at 30°. After the usual working up, 6-hydroxy-3-hydroxycarbonyl-6-methyl-4-thiaundecanoic acid methyl ester is obtained.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[O:11][CH3:12].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[Cl-]>O1CCCC1>[CH3:12][O:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Brc1ccccn1
Reactant: COc1ccc(Br)c(OC)c1
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccn2)c(OC)c1

Procedure:
A stirred suspension of magnesium (8.11 g) in dry tetrahydrofuran (100 mL) is heated, and then treated with a solution of 1-bromo-2,4-dimethoxybenzene (48 mL) in tetrahydrofuran (100 mL) at such a rate as to maintain reflux. The resulting solution is then cooled and added, dropwise, to a solution of 2-bromopyridine (50.3 g) and bis-triphenylphosphinepalladium(II) chloride (3.5 g) in tetrahydrofuran (100 mL) at reflux, and the mixture is maintained at reflux for 6 hours. The solution is then evaporated and the residue is dissolved in ethyl acetate, washed with water, dried and evaporated to give a dark oil. This is subjected to flash chromatography on silica gel, eluting with a mixture of pentane and ethyl acetate (2:1 v/v) to give 2-(2,4-dimethoxyphenyl)pyridine (28 g) in the form of an oil. [NMR(CDCl3):- 3.84(3H,s),3.86(3H,s), 6.55(1H,s),6.6(1H,d),7.2(1H,m),7.7(1H,t),7.77 (1H,d),7.8(1H,d),8.7(1H,d)].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:3][C:2]([N:27]1[CH2:28][CH2:29][CH2:30][CH:26]1[CH3:25])=[CH:11][CH:10]=2)=[O:18]
Reactant: CC1CCCN1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Product: Cc1nc2ccc(N3CCCC3C)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 21 %

Procedure:
The title compound was prepared from 1-(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-2,2,2-trifluoro-ethanone [example 3] and 2-methylpyrrolidine according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 21%; MS: m/z=399. (M+H).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[OH:4].[C:23]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (320 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (528 mg, 83%).