Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.CC(C)(C)C(=O)CN1C2C=CC=CC=2C(CC(C)C)=NN(CC(O)=O)C1=O.[C:67]([O:71][C:72](=[O:82])[N:73](C1C=CC=C(N)C=1)[CH3:74])([CH3:70])([CH3:69])[CH3:68].C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[C:67]([O:71][C:72](=[O:82])[N:73]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:74])([CH3:70])([CH3:69])[CH3:68]
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CC(C)CC1=NN(CC(=O)O)C(=O)N(CC(=O)C(C)(C)C)c2ccccc21
Agent: COC(=O)c1cccc(N)c1
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that [1-(3,3-dimethyl-2-oxo-butyl)-5-isobutyl-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 11, step a) and (3-amino-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step c) were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. The compound was further characterised as the hydrochloride salt. 1H NMR (DMSO-d6) 10.03 (1H, br s), 7.56-7.46 (3H, m), 7.28-7.20 (3H, m), 7.13 (1H, d), 6.89 (1H, d), 4.73 (2H, br s), 4.10 (2H, br), 3.85 (1H, br m), 2.78 (3H, s), 2.30 (1H, br m), 1.74 (1H, m), 1.15 (9H, s), 0.86 (6H, br m). Found: C, 61.02; H, 7.35; N, 13.18%; C27H35N5O3.H2O.HCl requires C, 60.95, H, 7.20, N, 13.16%.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]([C:13]2[C:14]([F:23])=[CH:15][C:16]3[S:20][C:19](=O)[NH:18][C:17]=3[CH:22]=2)[N:6]=[C:7]2[C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8]2.[CH2:24](Br)[C:25]#[CH:26].[OH2:28]>CN(C)C=O>[Cl:3][C:4]1[N:5]([C:13]2[C:14]([F:23])=[CH:15][C:16]3[S:20](=[O:28])[CH2:19][N:18]([CH2:24][C:25]#[CH:26])[C:17]=3[CH:22]=2)[N:6]=[C:7]2[C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8]2
Reactant: C#CCBr
Reactant: O
Reactant: O=c1[nH]c2cc(-n3nc4c(c3Cl)CCCC4)c(F)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1CS(=O)c2cc(F)c(-n3nc4c(c3Cl)CCCC4)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium hydride (60% oil; 50 mg) in N,N-dimethylformamide (3 ml) was cooled to 0° C., and 3-chloro-2-(6-fluoro-2(3H)-benzothiazolon-5-yl)-4,5,6,7-tetrahydro-2H-indazole (390 mg) was added thereto at 0°, followed by stirring at the same temperature for 30 minutes. To the suspension, propargyl bromide (160 mg) was added, and the resultant mixture was heated to a temperature of 50° to 60° C. and allowed to react at the same temperature for 2 to 3 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel thin layer chromatography using a mixture of ethyl acetate and hexane (1:4) as a developing solvent to give 3-chloro-2-[6-fluoro-3-(2-propynyl)-2H-benzothiazolon-5-yl]-4,5,6,7-tetrahydro-2H-indazole (24.1 gg). m.p., 130°-132° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[CH:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15](Cl)=[O:16])=[CH:9][CH:8]=1.Cl>[OH-].[Na+]>[N:1]1([C:15]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=2)=[O:16])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: C1CSCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(OCc1ccccc1)N1CCSCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of thiomorpholine (2 g) in 1N NaOH (11.6 mL) was added benzyl chloridocarbonate (1.66 mL) under ice water cooling and the mixture was stirred at ambient temperature for 2 hours. The solution was neutralized with 1N HCl and extracted with EtOAc twice. The combined organic layer was washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography to give benzyl 4-thiomorpholinecarboxylate as a colorless solid (4.8 g).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][N:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:14][CH2:15][CH2:16][NH2:17].CN(C=O)C>CCOC(C)=O.O>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:17][CH2:16][CH2:15][CH2:14][N:13]([CH3:12])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: CN(CCCN)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCCNc1ccc2ncc(Br)n2n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To 300 mg (1.389 mmol) of the 3-bromo-6-fluoroimidazo[1,2-b]pyridazine, was added N1-methyl-N1-phenylpropane-1,3-diamine (456 mg, 2.778 mmol) Cs2CO3 (903 mg, 2.778 mmol) and 10 mL DMF. This mixture is stirred overnight at rt. It was diluted with 30 mL EtOAc, and 15 mL of water. The organic layer was washed with brine and dried over MgSO4. It was concentrated and purified using silica gel chromatography (ISCO) eluting with 0-10% MeOH/DCM to obtain 301 mg (60%) of product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][CH2:9][NH2:10])=[N:6][CH:7]=1.C(N(CC)CC)C.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][CH2:9][NH:10][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[C:19]([F:18])([F:29])[F:30])=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: NCCc1ncc(Br)cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCc1ncc(Br)cn1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
To 0.06 g of 2-(5-bromopyrimidin-2-yl)ethanamine (3.0 mmol) and triethylamine (0.03 g, 1.0 equivalent) in THF (5 ml), at room temperature whilst stirring, was added the 2-trifluoromethyl benzoyl chloride (0.062 g, 1.0 equivalent) and the mixture was left to stir at room temperature overnight. The solvent was removed by evaporation in vacuo and saturated sodium bicarbonate (10 mls) was added. The mixture was extracted with dichloromethane and the organic phase was collected, dried over MgSO4, and evaporated in vacuo to give the crude product which was purified by chromatography on silica using 1:1 heptane/ethyl acetate to yield to 0.036 g of N-[2-(5-bromopyrimidin-2-yl)ethyl]-2-(trifluoromethyl)benzamide (Compound A-1) (32%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1.[C:23](Cl)(=[O:25])[CH3:24]>C1C=CC=CC=1>[C:23]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][N:8]2[C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)[CH2:2]1)(=[O:25])[CH3:24]
Reactant: c1ccc2c(c1)CCc1ccccc1N2CC1CNCCO1
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Product: CC(=O)N1CCOC(CN2c3ccccc3CCc3ccccc32)C1
Reaction time: 4 h

Procedure:
To a solution of 5-(2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine (0.34 g) in anhydrous benzene was added excess acetyl chloride under ice cooling. After stirring for 4 hours, the reaction mixture was washed with aqueous 2N sodium hydroxide and then with water, dried and evaporated to afford 5-(4-acetyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oily substance.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24](O)=[O:25])[CH2:9]2)=[O:7])[CH2:3]1.[Cl:27][C:28]1[CH:29]=[C:30]([C:34](=[N:36]O)[NH2:35])[CH:31]=[CH:32][CH:33]=1>>[Cl:27][C:28]1[CH:29]=[C:30]([C:34]2[N:36]=[C:24]([CH:10]3[CH2:11][CH:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=4)[CH2:13][N:8]([C:6]([N:4]4[CH2:3][CH:2]([OH:1])[CH2:5]4)=[O:7])[CH2:9]3)[O:25][N:35]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Reactant: NC(=NO)c1cccc(Cl)c1
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(Cl)c3)no2)C1

Procedure:
90.0 mg (0.242 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 45.4 mg (0.266 mmol) of 3-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 34.7 mg (28% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9]Br)[CH:3]=1.[C:11]1([C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][O:13]1)=[O:12].[K].C[N:23](C=O)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][N:23]2[C:11](=[O:12])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:13])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C1OCc2ccccc21
Reactant: Cc1cc(Br)cc(CBr)c1
Agent: [K]
Product: Cc1cc(Br)cc(CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of 1-bromo-3-(bromomethyl)-5-methylbenzene (34.0 g, 128.8 mmol) in DMF (200 mL), was added potassium phthalide (28.9 g, 154.6 mmol), and the mixture was stirred under reflux for 2 h. The reaction was allowed to cool to room temperature. After the solvent was remove under reduced pressure, the residue was dissolved in CH2Cl2 (300 mL), and washed with water (50 mL×3). The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent gave a white solid. The solid was recrystallized from toluene and EtOH to give the product, 2-[(3-bromo-5-methylphenyl)methyl]-1H-isoindole-1,3(2H)-dione (28.5 g, 67%). 1H NMR (400 MHz, CDCl3): δ 7.87-7.72 (m, 4 H), 7.36 (s, 1H), 7.23 (s, 1 H), 7.15 (s, 1 H), 4.77 (s, 2 H), 2.30 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.ClC(Cl)(O[C:30](=[O:36])OC(Cl)(Cl)Cl)Cl.[CH3:38][C:39]1[CH:51]=[CH:50][CH:49]=[CH:48][C:40]=1[CH2:41][N:42]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43]1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30]([NH:47][CH:44]2[CH2:45][CH2:46][N:42]([CH2:41][C:40]3[CH:48]=[CH:49][CH:50]=[CH:51][C:39]=3[CH3:38])[CH2:43]2)=[O:36])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: Cc1ccccc1CN1CCC(N)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NC4CCN(Cc5ccccc5C)C4)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.3 %

Procedure:
Chloroform (13 ml) and triethylamine (2 ml) were added to 4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) to prepare a solution. Triphosgene (96 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. 1-(2-Methylbenzyl)-3-pyrrolidinamine (83 mg) was then added thereto, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/acetone for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (38 mg, yield 23%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.BrN1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:43][CH:42]=1.N1C=CC=CC=1>ClCCl.CN(C)C=O>[C:44]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:43]=[CH:42][C:41]([NH:40][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([OH:1])[CH:3]=2)=[CH:46][CH:45]=1
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: COc1ccc(C(=O)O)cc1O
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(-c3ccccc3)cc2)cc1O
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-hydroxy-4-methoxybenzoic acid (0.5 g, 3 mmol) in dichloromethane and dimethylformamide was cooled to −20° C., and N-bromosuccinimide (0.57 g, 3.2 mmol) and triphenylphosphine (0.8 g, 3.1 mmol) were added in one portion. The mixture was stirred at −20° C. for 10 min, and treated with a solution of 4-aminobiphenyl (0.5 g, 3 mmol) and dry pyridine (0.3 g, 3.8 mmol) in dichloromethane (5 mL). The mixture was allowed to warm to RT, stirred 20 h, concentrated in vacuo, and the residue was stirred in 5% methanol/dichloromethane (40 mL) and filtered. The filtrate was concentrated in vacuo, chromatographed (silica gel, 5% methanol/dichloromethane), and fractions containing the product were pooled, concentrated in vacuo, and dissolved in dichloromethane from which the title compound precipitated (0.11 g): MS(ES) m/e 320 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:19][CH2:20]C=O)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[CH3:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH:29]1[CH2:33][CH2:32][C@H:31]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:30]1>>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:40]([C:37]3[CH:38]=[CH:39][C:34]([CH:31]4[CH2:32][CH2:33][CH:29]([N:25]5[CH2:26][CH2:27][CH2:28][CH:24]5[CH3:23])[CH2:30]4)=[CH:35][CH:36]=3)[CH2:20][CH2:19]2)[CH2:11][CH2:10]1)=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C1(CCC=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Product: CC1CCCN1C1CCC(c2ccc(N3CCC4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)cc2)C1

Procedure:
The title compound was synthesized in the manner essentially the same as the Example 1 by condensing 4-(3-oxo-propyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (Intermediate 4) with 4-[(S)-3-(2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 15), and subsequently cyclization.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:35]([O:36][CH3:37])=[CH:34][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[CH:6]=1)[N:14]=[CH:13][C:12]([C:17]#[N:18])=[C:11]3[NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]2[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=2)=[C:22]([Cl:33])[CH:21]=1.[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.[I-].[Na+]>>[Cl:33][C:22]1[CH:21]=[C:20]([NH:19][C:11]2[C:10]3[C:15](=[CH:16][C:7]4[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:42]5[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]5)[C:35]([O:36][CH3:37])=[CH:34][C:8]=4[CH:9]=3)[N:14]=[CH:13][C:12]=2[C:17]#[N:18])[CH:25]=[CH:24][C:23]=1[S:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1
Reactant: CN1CCNCC1
Reactant: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCCl
Agent: [I-]
Agent: [Na+]
Product: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCN1CCN(C)CC1

Procedure:
Following procedure 1 of Example 149, a mixture of 0.15 g (0.3 mmol) of 8-(2-chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.5 mL of 1-methylpiperazine and 0.02 g of sodium iodide is heated under reflux for 16 hours. Purification of the material is carried out by silica gel flash chromatography, utilizing a 90:10 to 85:15 gradient of methylene chloride/methanol to give 0.052 g of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-[2-(4-methylpiperazin-1-yl)ethoxy]-benzo[g]quinoline-3-carbonitrile as a yellow solid, mp 184–186° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al:8]>CC1C=CC(C)=CC=1>[C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3:8].[C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: [Al]
Solvent: Cc1ccc(C)cc1
Product: [Al+3]
Product: [O-]c1ccccc1

Procedure:
Phenol (6.048 g, 64.4 mmoles), p-xylene (1 ml), and aluminum metal (0.099 g, 0.57 mmoles) were heated at 140° C for 4 hours to form aluminum phenolate. The mixture was cooled to room temperature and 10.7 g of t-butylhydroquinone (64.4 mmoles), 20.5 g of 75% pure divinylbenzene (123 mmoles) and 24 ml of p-xylene were then added and the mixture heated to reflux (151°-153° C) and there maintained for 12 hours. It was cooled to room temperature to yield a viscous reaction mixture. This material was divided into two portions. One (product IIIa) was analyzed, the other (product IIIb) was heated for 6 hours at reflux. The products were worked up by extraction, drying, and precipitation according to the general method set out in Example II. The two materials exhibited properties, upon analysis, consistent with the structure shown in Formula IX ##STR14## These analyses and molecular weight determinations indicated that for peak components of product IIIa, n + m equals 20 while for peak components of product IIIb, n + m equals 24. Based on feed ratios, it is expected that n is about equal to m.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5]C(S(O)(=O)=O)=CC=1.[NH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15].C(N(CC)CC)C.C(OC)(OC)(OC)CCC.[CH2:35]([NH2:39])[CH:36]([CH3:38])[CH3:37].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[NH2:15][C:14]1[N:39]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:5]([CH2:6][CH2:1][CH3:11])=[N:12][C:13]=1[C:16]#[N:17]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)CN
Reactant: N#CC(N)C#N
Agent: CCCC(OC)(OC)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCc1nc(C#N)c(N)n1CC(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
Aminomalononitrile p-toluenesulfonate (25.33 g, 0.100 mol), triethylamine (10.12 g, 0.100 mol), and trimethyl orthobutyrate (14.82 g, 0.11 mol) were combined in toluene (250 mL) and the solution was heated at 60° C. for 1.75 hours. Additional trimethyl orthobutyrate (1.0 mL) was added, and the reaction was allowed to cool over a period of 1.5 hours to 22° C. and further cooled to about 3° C. Triethylamine (10.12 g, 0.100 mol) and isobutylamine (7.32 g, 0.100 mol) were sequentially added, and the reaction was warmed to room temperature slowly and stirred overnight. The reaction mixture was shaken with 10% w/w aqueous sodium carbonate (250 mL), and the mixture was allowed to stand for two hours. A precipitate was present and was isolated by filtration, washed sequentially with toluene and water, air-dried, and further dried under vacuum at 75° C. for 22 hours to provide 14.5 g (70%) of 5-amino-1-(2-methylpropyl)-2-propyl-1H-imidazole-4-carbonitrile as a beige solid, mp 135.0-136.0° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)=[C:11]2[CH2:25][CH2:26][NH2:27])=[O:7])[CH:2]([CH3:4])[CH3:3].[Cl:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37]([CH2:43][CH2:44][CH2:45][CH:46]=O)=[CH:38][CH:39]=[N:40]2)=[CH:35][CH:34]=1.C(O[BH-](O[C:58](=O)[CH3:59])OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:5]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=1)=[C:11]2[CH2:25][CH2:26][N:27]([CH2:46][CH2:45][CH2:44][CH2:43][C:37]1[C:58]2[C:59](=[CH:42][C:33]([Cl:32])=[CH:34][CH:35]=2)[N:40]=[CH:39][CH:38]=1)[CH2:46][CH2:45][CH2:44][CH2:43][C:37]1[C:36]2[C:41](=[CH:42][C:33]([Cl:32])=[CH:34][CH:35]=2)[N:40]=[CH:39][CH:38]=1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=CCCCc1ccnc2cc(Cl)ccc12
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N(CC(C)C)CC(C)C)cc3c2CCN)c1
Agent: [Na+]
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N(CC(C)C)CC(C)C)cc3c2CCN(CCCCc2ccnc3cc(Cl)ccc23)CCCCc2ccnc3cc(Cl)ccc23)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.8 %

Procedure:
To a solution of 3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid diisobutylamide (89 mg in 3.0 mL dry tetrahydrofuran) at 0° C. was added 50 mg 4-(7-chloroquinolin-4-yl)butyraldehyde and the mixture stirred for 10 minutes. At this time, 67.4 mg sodium triacetoxyborohydride were added and the mixture allowed to warm slowly to room temperature. After 5 hours, the reaction was quenched by the addition of brine and the mixture extracted with methylene chloride. The combined organics were dried over sodium sulfate and the concentrate purified by preparative tlc on silica gel (methylene chloride:methanol, 95:5) to give the title compound (21.8 mg).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22]([OH:24])=O)[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35])(C(C)(C)C)(C)C.[C:37]([NH2:41])([CH3:40])([CH3:39])[CH3:38].Cl.C(O)C>>[C:37]([NH:41][C:22](=[O:24])[CH2:21][CH2:20][C@H:19]([C@@H:18]1[C@:26]2([CH3:34])[C:15]([C:14]3[CH2:13][CH2:12][C@@H:11]4[C@:30]([C:29]=3[CH2:28][CH2:27]2)([CH3:33])[CH2:31][CH2:32][C@H:9]([OH:8])[C:10]4([CH3:35])[CH3:36])=[CH:16][CH2:17]1)[CH3:25])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)N
Reactant: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Agent: Cl
Solvent: CCO
Product: C[C@H](CCC(=O)NC(C)(C)C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid (0.50 g) is reacted with tert-butylamine and hydrolysed with HCl/ethanol following the procedure outlined in example 39 to give the title compound (204 mg). Melting point: 171-176° C.