Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:21]2[S:22][CH:23]=[C:24]([C:26](Cl)=[O:27])[N:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26]([C:24]1[N:25]=[C:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[S:22][CH:23]=1)=[O:27]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1csc(-c2ccccc2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1csc(-c2ccccc2)n1
Yield: 65.8 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0441 g, 0.187 mmol), 2-phenylthiazole-4-carbonyl chloride (0.044 g; 0.187 mmol), and triethylamine (0.066 mL; 0.467 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 3 to 30% of ethyl acetate in dichloromethane gave 0.047 g (66%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-phenylthiazole-4-carboxamide as a solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)[C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=2)=[N:6][CH:7]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=1[C:2]1[N:3]=[C:4]([C:16]2[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=2)[C:5]([C:8]2[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(C)cc(-c2ncc(Cl)nc2-c2cc(C)cc(C)c2)c1
Reactant: Cc1cccc(C)c1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C)cc(-c2ncc(-c3c(C)cccc3C)nc2-c2cc(C)cc(C)c2)c1
Yield: 89 %

Procedure:
Next, a mixture of 1.21 g of 5-chloro-2,3-bis(3,5-dimethylphenyl)pyrazine, 1.10 g of 2,6-dimethylphenylboronic acid, 0.78 g of sodium carbonate, 15 mg of PdCl2(PPh3)2, 14 mL of water, and 14 mL of acetonitrile was degassed by bubbling argon for 15 minutes and irradiated with microwaves (2.45 GHz, 100 W) for 3 hours. To the mixture were further added 0.55 g of 2,6-dimethylphenylboronic acid, 0.39 g of sodium carbonate, and 7 mg of PdCl2(PPh3)2, and the mixture was degassed by bubbling argon for 15 minutes and heated again by irradiating with microwaves for 6 hours. The mixture was suction-filtered, and the resulting solid was washed with ethanol. The obtained solid was dissolved in dichloromethane, which was followed by filtration through Celite, alumina, and Celite in this order. The filtrate was concentrated to give 5-(2,6-dimethylphenyl)-2,3-bis(3,5-dimethylphenyl)pyrazine as white powder in 89% yield. Explanation of the following reactions is omitted because they are the same as those in Example 5.
Reaction SMILES: C[O-].[Na+].[N:4]1[N:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]2=[C:6]([C:13]#[N:14])[CH:5]=1.[Cl-:15].[NH4+:16]>CO.C(OCC)(=O)C>[ClH:15].[N:4]1[N:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]2=[C:6]([C:13](=[NH:16])[NH2:14])[CH:5]=1
Reactant: [Cl-]
Reactant: N#Cc1cnn2ccncc12
Reactant: [NH4+]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cl
Product: N=C(N)c1cnn2ccncc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 101.7 %

Procedure:
Freshly prepared sodium methoxide (0.44 g, 8.1 mmol) was added to a suspension of pyrazolo[1,5-a]pyrazine-3-carbonitrile (Preparation 24b, 6.09 g, 42.3 mmol) in anhydrous methanol (350 mL) and the mixture was stirred at ambient temperature. After 20 hours, further sodium methoxide (0.44 g, 8.1 mmol) was added and the reaction mixture was stirred for a further 48 hours. Ammonium chloride (3.91 g, 73.1 mmol) was added and the mixture was stirred and heated to 70° C. in a sealed tube. After 3 days, the mixture was concentrated to dryness to give a solid which was suspended in ethyl acetate and stirred overnight. The precipitate was filtered and dried in vacuo to give the crude title compound (8.50 g, >100%) as a white solid which was used in the next synthetic step without further purification.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:18][N:19]([CH2:21][CH2:22][Cl:23])[CH3:20]>>[ClH:23].[CH3:18][N:19]([CH3:20])[CH:21]([C:14]1[C:13]([CH3:16])=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[N:8][NH:9]2)[CH3:22]
Reactant: CN(C)CCCl
Reactant: Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Agent: Cl
Product: Cc1ccc2[nH]nc(-c3ccccc3)c2c1C(C)N(C)C
Yield: 63.2 %

Procedure:
By the procedure similar to that described in Example 1, 3-phenyl-5-methylindazole (4.17 g) and dimethylaminoethyl chloride hydrochloride (4.32 g) were treated to obtain 4.0 g of 1-dimethylaminoethyl-3-phenyl-5-methylindazole hydrochloride (m.p. 191°-192° C).
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:21][CH2:22][C:23]([CH3:26])([OH:25])[CH3:24])=[C:13]([N+:18]([O-])=O)[CH:14]=[N:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[N:40]=[CH:39][C:38]([N+:44]([O-])=O)=[C:37]2[NH:47][CH2:48][C:49]([CH3:52])([OH:51])[CH3:50])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[NH2:18][C:13]1[CH:14]=[N:15][C:16]2[C:11]([C:12]=1[NH:21][CH2:22][C:23]([CH3:26])([OH:25])[CH3:24])=[CH:10][CH:9]=[C:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:17]=2.[NH2:44][C:38]1[CH:39]=[N:40][C:41]2[C:36]([C:37]=1[NH:47][CH2:48][C:49]([CH3:52])([OH:51])[CH3:50])=[CH:35][C:34]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[CH:43][CH:42]=2
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2ccc(Cc3ccccc3)cc12
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Cc3ccccc3)ccc12
Product: CC(C)(O)CNc1c(N)cnc2cc(Cc3ccccc3)ccc12
Product: CC(C)(O)CNc1c(N)cnc2ccc(Cc3ccccc3)cc12
Reaction time: 48 h

Procedure:
A modification of the method described in Part A of Examples 427-429 was used to reduce 1-(7-benzyl-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol or 1-(6-benzyl-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol. The reaction was shaken for one or two days to provide 1-(3-amino-7-benzylquinolin-4-ylamino)-2-methylpropan-2-ol or 1-(3-amino-6-benzylquinolin-4-ylamino)-2-methylpropan-2-ol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=1)[CH2:21][C:22]1[O:23][CH:24]=[N:25][N:26]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:24]2[O:23][C:22]([CH2:21][C:20]3[CH:27]=[CH:28][CH:29]=[C:18]([C:17]([F:30])([F:31])[F:16])[CH:19]=3)=[N:26][N:25]=2)[OH:15])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: FC(F)(F)c1cccc(Cc2nnco2)c1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(Cc2cccc(C(F)(F)F)c2)o1

Procedure:
Prepared according to the procedure described in Example 30, Step 1, using 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-(3-trifluoromethyl-benzyl)-[1,3,4]oxadiazole.
Reaction SMILES: O.NN.C1(=O)[N:8]([O:9][CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[CH:15][CH:14]=2)C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[NH:20][C:19]2=[O:24])=[CH:25][CH:26]=1
Reactant: O=C1NC(=O)C(Cc2ccc(OCCON3C(=O)c4ccccc4C3=O)cc2)S1
Agent: NN
Solvent: O
Solvent: CCO
Product: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 106.8 %

Procedure:
0.32 ml of hydrazine monohydrate was added to a suspension of 2.64 g of 5-[4-(2-phthalimidooxyethoxy)benzyl]thiazolidine-2,4-dione [prepared as described in step (d) above] in 30 ml of ethanol, and the resulting mixture was stirred at 80° C. for 2 hours. At the end of this time, the reaction mixture was cooled and the precipitated phthalhydrazide was filtered off. The filtrate was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1:20 by volume mixture of methanol and methylene chloride as the eluent, to give 1.93 g of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione as a syrup.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:19][C:20](=[O:33])[NH:21][C:22]2[CH:27]=[C:26]([Cl:28])[C:25]([O:29][CH3:30])=[CH:24][C:23]=2[O:31][CH3:32])[C:9]1=[O:34])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:28][C:26]1[C:25]([O:29][CH3:30])=[CH:24][C:23]([O:31][CH3:32])=[C:22]([NH:21][C:20]([CH2:19][N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[N:15][C:12]=3[C:13](=[O:14])[N:8]([CH2:7][C:6]([OH:35])=[O:5])[C:9]2=[O:34])=[O:33])[CH:27]=1
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)OC(C)(C)C)c(=O)c3ncccc32)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3ncccc32)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirring solution of {1-[(5-chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl}-acetic acid tert-butyl ester (Intermediate R) (22.1 mg, 0.044 mmol) in DCM (1 ml) is treated with TFA (1 ml). The reaction mixture is stirred at RT and monitored by HPLC/LCMS until the starting material is consumed. After 3 hours, the reaction mixture is diluted with a minimal amount of DCM and concentrated in vacuo. The residue is taken up in a minimal amount of MeOH, concentrated in vacuo, the again in a minimal amount of EtOAc and concentrated in vacuo to afford the title compound as an off white solid; [M+H]+ 449
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2Br)=[O:10])=[N:6][CH:7]=1.[CH3:18][C:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[CH:21][N:20]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH:25][C:24]2[C:19]([CH3:18])=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1ncccc1N
Reactant: Cc1nc(C(=O)Nc2ccc(F)cn2)c(Br)s1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1nc(C(=O)Nc2ccc(F)cn2)c(Nc2cccnc2C)s1
Yield: 68.2 %

Procedure:
A solution of 5-bromo-2-methyl-thiazole-4-carboxylic acid (5-fluoro-pyridin-2-yl)-amide (0.24 g, 0.76 mmol) and 2-methyl-pyridin-3-ylamine (0.099 g, 0.92 mmol) in dry dioxane (12 ml) was degassed by sonication and argon bubbling. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.149 g, 0.26 mmol) and palladium dibenzylideneacetone chloroform complex (0.081 g, 0.08 mmol) were added and the mixture was stirred until dissolution was complete. Finally, the mixture was treated with cesium carbonate (0.495 g, 1.52 mmol) and irradiated in a microwave oven at 100° C. for 10 min, 130° C. for 10 min and 150° C. for 10 min. The solvent was removed under vacuum and the residue purified by flash chromatography (heptane, ethyl acetate) to yield the title compound (0.178 g, 68%) as a light brown solid, MS (ISP): m/e=344.0 (M+H+).
Reaction SMILES: Cl[C:2]1S[C:5]([C:7]2[C:16]([O:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=4)[N:21]=[CH:20][CH:19]=3)=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][C:3]=1[CH3:32]>C(N(CC)CC)C.CN(C)C=O.[OH-].[Pd+2].[OH-]>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:17][C:16]1[C:7]([CH2:5][CH2:4][CH:3]([CH3:32])[CH3:2])=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3-c3cc(C)c(Cl)s3)c2cc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc4ccccc4nc3CCC(C)C)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
4-[2-(5-Chloro-4-methyl-thiophen-2-yl)-quinolin-3-yloxy]-6,7-dimethoxy-quinoline (compound 290) (7 mg) was dissolved in triethylamine/N,N-dimethylformamide (0.5 ml/1.5 ml) to prepare a solution, 20% palladium hydroxide (68 mg) was added to the solution, and the mixture was stirred under a hydrogen gas atmosphere at room temperature overnight. The reaction solution was filtered, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (3.6 mg, yield 56%).
Reaction SMILES: [Na].[O:2]=[CH:3][C:4]1[CH:12]=[CH:11][C:9](O)=[C:6]([O:7][CH3:8])[CH:5]=1.Cl[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.[OH2:25]>CO>[CH3:8][O:7][C:6]1[C:5]([O:25][CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[C:4]([CH:12]=[CH:11][CH:9]=1)[CH:3]=[O:2]
Reactant: O
Reactant: COc1cc(C=O)ccc1O
Reactant: ClCc1cccc2ccccc12
Agent: [Na]
Solvent: CO
Product: COc1cccc(C=O)c1OCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5 g of sodium are dissolved in 200 ml of methanol. 30.4 g of vanillin are metered into the resulting solution. The reaction mixture is stirred at room temperature for 30 minutes. 36 g of 1-chloromethylnaphthalene in 70 ml of methanol are then added and the reaction mixture is heated at reflux for 6 hours. The mixture is left to stand overnight and then introduced into 1 liter of water. Extraction is carried out twice using 700 ml of ethyl acetate each time. The organic phases are washed twice using 200 ml of ice-cold 2N sodium hydroxide solution each time and once with 200 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, yielding 3-methoxy(naphthalen-1-ylmethoxy)-benzaldehyde, which can be purified by chromatography on silica gel with ethyl acetate/n-hexane 1:2 and recrystallisation from ethyl acetate/n-hexane, m.p. 98-99° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH:10]([C:12](O)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.[CH2:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[CH3:28].CCN=C=NCCCN(C)C.O.[Cl-].[Na+].O>N1C=CC=CC=1>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:29]([CH2:27][CH3:28])[C:12]([C@@H:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]([C:15](=[O:26])[C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=3)[C@@H:2]([CH3:1])[CH2:11]2)=[O:13])=[CH:31][CH:32]=1
Reactant: CCNc1ccc(Cl)cc1
Reactant: CC1CC(C(=O)O)c2ccccc2N1C(=O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CCN(C(=O)[C@H]1C[C@H](C)N(C(=O)c2ccc(C(F)(F)F)cc2)c2ccccc21)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 39 %

Procedure:
A round bottom flask with magnetic stirrer was charged with 2-methyl-1-(4-trifluoromethyl-benzoyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (886 mg, 2.44 mmol) in anhydrous pyridine (25.0 mL). To the reaction was added N-ethyl-p-chloroaniline (0.410 mL, 2.95 mmol), followed by EDCI (833 mg, 4.34 mmol). The reaction was stirred at room temperature under an argon atmosphere for 18-20 hours. The reaction was poured into a 1:1 mixture of water/brine (50 mL) and extracted with ethyl acetate (3×35 mL). The combined extractions were washed with brine (1×50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford a brown residue. The residue was purified via silica gel chromatography (hexanes/ethyl acetate) to yield (±)-trans-2-methyl-1-(4-trifluoromethyl-benzoyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (39%). 1H-NMR (CDCl3) δ: 1.02 (d, 3H), 1.12 (t, 3H), 1.64-1.74 (m, 1H), 2.49-2.58 (m, 1H), 3.59-3.72 (m, 1H), 3.77-3.90 (m, 2H), 5.03-5.14 (m, 1H), 6.35-6.41 (m, 1H), 6.74-6.84 (m, 2H), 6.89-6.95 (m, 1H), 7.17-7.25 (m, 2H), 7.44-7.52 (m, 2H), 7.63-7.69 (m, 2H). MS m/z: 501 (M+1).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[C:11]([OH:23])(=[O:22])[CH2:12][C:13]([CH2:18][C:19]([OH:21])=[O:20])([C:15]([OH:17])=[O:16])[OH:14]>C(O)C>[C:1]([O-:10])(=[O:9])[CH:2]([CH:4]([C:6]([O-:8])=[O:7])[OH:5])[OH:3].[C:11]([O-:23])(=[O:22])[CH2:12][C:13]([CH2:18][C:19]([O-:21])=[O:20])([C:15]([O-:17])=[O:16])[OH:14]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=C(O)C(O)C(O)C(=O)O
Solvent: CCO
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
When tartaric acid or citric acid saturated in ethanol was added to the alcoholic solution of the aforesaid syrupy residue with cooling, there was obtained tartarate (mp. 236° C.) or citrate (mp. 218° C.).
Reaction SMILES: [CH2:1]([NH:7][C:8](=[O:29])[C@H:9]([CH:26]([CH3:28])C)[NH:10][C:11](=[O:25])[C@H:12]([CH2:21][CH:22]([CH3:24])[CH3:23])[NH:13]C(OC(C)(C)C)=O)CCCCC.ON1C2C=CC=CC=2N=N1.Cl.CNC(=O)[C@H](CC1[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH2:55][CH3:56])=[CH:49][CH:48]=1)N.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C=O>[CH3:1][NH:7][C:8](=[O:29])[C@H:9]([CH2:26][C:28]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH2:55][CH3:56])=[CH:49][CH:48]=1)[NH:10][C:11](=[O:25])[C@H:12]([CH2:21][CH:22]([CH3:23])[CH3:24])[NH2:13]
Reactant: CCCOc1ccc(C[C@H](N)C(=O)NC)cc1
Reactant: CCCCCCNC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCOc1ccc(C[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)NC)cc1
Temperature: 20 °C

Procedure:
N-Tertiary butyloxycarbonyl-O-propyl-L-tyrosine N-methyl amide (370 mg, 1.1 mM) in dichloromethane (8 ml) was treated with trifluoroacetic acid (2 ml) at 20° C. for 2 h. The solvent was removed in vacuo and the residue redissolved in ether saturated with hydrogen chloride and this procedure repeated twice more to afford O-propyl-L-tyrosine-N-methyl amide hydrochloride (1.1 mM) which was used directly in the next step. N-(3-N-(Benzyloxycarbonyl)amino-1-(R)-methoxycarbonylpropyl)-L-leucine hydrochloride (prepared as described in Example 1) (416 mg, 1 mM) in dichloromethane (10 ml) and dimethyl formamide (2 ml) was treated with 1-hydroxybenzotriazole (159 mg, 1.04 mM), O-propyl-L-tyrosine-N-methyl amide hydrochloride (1.1 mM), N-methyl morpholine (315 mg, 3.3 mM) and N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (200 mg, 1.04 mM) at 0° C. The reaction mixture was stirred continuously as it was allowed to warm to 20° C. over 16 h. The reaction was diluted with dichloromethane (30 ml) and washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous citric acid (1M) dried over anhydrous sodium sulphate and concentrated in vacuo to afford N-(3-N-Benzyloxycarbonyl)amino-1-(R)-methoxycarbonylpropyl)-L-leucyl-O-propyl-L-tyrosine-N-methyl amide (0.22 g, 0.36 mM) which crystallised from ethyl acetate/hexane as needles m.p. 135°-140° C. (Found: C,62.8; H,7.8; N,9.2. C32H46N4O7 +0.5 H2O requires: C,63.2; H,7.8; N,9.2%); δ(CDCl3) 0.86 (6H,d,d,J=4 Hz J=4 Hz (CH3)2C); 1.02 (3H,t,J=7 Hz CH3CH2); 1.1-1.98 (9H,m,CH,CH2,CH2,CH2CH2); 2.74 (3H,d,J=4 Hz CH3NH); 2.86-3.48, (5H,m,CH2CH2,CH); 3.64 (3H,s,OCH3); 3.86 (2H,t,J=6 Hz,CH2O); 4.58 (1H,m,NHCHCO); 5.06 (2H,s,CH2C6H5); 5.14 (1H,m,NH) 6.54 (1H,m,NH); 6.76, and 7.06 (4 H,each d, each J=8 Hz,C6H4); 7.32 (5H,m,C6H5); 7.42 (1H,m,NH).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C@H:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[CH:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH:15]3OCC[O:26][CH:16]32)[CH2:8]1)C.C(O)(=O)C(C(C(O)=O)O)O.O>O1CCOCC1>[CH:4]([CH2:5][O:6][C@H:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[CH:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C:16]2=[O:26])[CH2:8]1)=[O:3]
Reactant: CCOC(CO[C@H]1CC[C@@]2(C)C(CC[C@@H]3[C@@H]2CC[C@]2(C)C4OCCOC4C[C@@H]32)C1)OCC
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: C1COCCO1
Solvent: O
Product: C[C@]12CC[C@H](OCC=O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 84.7 %

Procedure:
A solution of 7.2 g of 3β-(2,2-diethoxyethoxy)-17-ethylenedioxy-androstane, in 250 ml of dioxane and 250 ml of a saturated solution of tartaric acid was heated at 70° C. for 2 hrs in a nitrogen atmosphere, 100 ml of water were then added and the residue was extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using as eluant n-hexane/ethyl acetate 70/30 to give 4.5 g of 3β-formylmethoxy-androstan-17-one as a white solid.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[Na+].[C:19](=[S:21])=[S:20].[C:22]1([CH2:27]Cl)[S:26][CH:25]=[CH:24][CH:23]=1>CS(C)=O>[C:22]1([CH2:27][S:20][C:19]([N:2]2[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)=[S:21])[S:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Reactant: S=C=S
Reactant: ClCc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)C1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1cccs1

Procedure:
In the same manner as descsribed in Example 32, (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (4.32 g), 20N NaOH (2.2 ml), carbon disulfide (1.45 ml), dimethylsulfoxide (13 ml) and 2-thenyl chloride (3.18 g) are reacted and treated. The product is crystallized from ethanol to give the title compound (4.1 g) as pale yellow crystals, m.p. 172° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](CC(N)=O)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.C(O[CH2:32][CH3:33])(=O)C.C(=O)([O-])O.[Na+].C[N:40](C)C=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:10])[C:33]([C:32]#[N:40])=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: CN(C)C=O
Reactant: NC(=O)Cc1[nH]c(-c2ccc(Cl)cc2)nc1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(-c2ccc(Cl)cc2)nc(-c2ccccc2)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-chlorophenyl)-4-phenylimidazol-5-yl acetamide (10.00 g) in N,N-dimethylformamide (50 ml) was added dropwise 8.9 ml of phosphorus oxychloride (8.9 ml) below 20° C., and the mixture was stirred at room temperature for one hour. To the reaction mixture were added ice-water and ethyl acetate, and the mixture was neutralized by sodium hydrogen carbonate. The organic layer was collected, washed with brine, and dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was crystallized from diisopropyl ether to obtain 2-(4-chlorophenyl)-5-cyano-methyl-4-phenylimidazole (6.85 g).