Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[F:24][C:25]([F:32])([F:31])[S:26]([O:29]C)(=[O:28])=[O:27]>C(Cl)Cl>[F:24][C:25]([F:32])([F:31])[S:26]([O-:29])(=[O:28])=[O:27].[CH3:25][N+:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13]([C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: O=C(Oc1ccccc1)c1c2ccccc2nc2ccccc12
Solvent: ClCCl
Product: C[n+]1c2ccccc2c(C(=O)Oc2ccccc2)c2ccccc21
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenyl acridine-9-carboxylate (530 mg, 1.7 mmol) was dissolved in methylenechloride (5 mL) under argon and methyl trifluoromethanesulfonate (1 mL, 8.8mmol) was added. The solution was stirred overnight at room temperature to yield a thick yellow precipitate. This precipitate was filtered, washed with ether and dried to obtain the product as yellow crystals. 1H NMR (acetone-d6) δ5.22 (s, 3H), 7.47-7.71 (m, 5H), 8.23-9.07 (m, 8H).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:4]=1[O:15]C>C(O)(=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:4]=1[OH:15]
Reactant: COC(=O)C(C)c1ccc(Cl)c(OC)c1
Agent: Br
Solvent: CC(=O)O
Product: COC(=O)C(C)c1ccc(Cl)c(O)c1
Temperature: 100 °C

Procedure:
48% aqueous HBr (10 ml) was added to the product of step (ii) (0.21 g) in acetic acid (10 ml) and heated at 100° C. for 10 h.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([Br:11])[C:5]([Br:12])=[C:4]([C:13]([OH:15])=[O:14])[C:3]=1[Br:16].[OH-].[K+].[CH2:19](Br)[CH:20]=[CH2:21].[CH:23](O)([CH3:25])[CH3:24]>C(N(CC)CC)C>[Br:1][C:2]1[C:7]([C:8]([O:10][CH2:19][CH:20]=[CH2:21])=[O:9])=[C:6]([Br:11])[C:5]([Br:12])=[C:4]([C:13]([O:15][CH2:25][CH:23]=[CH2:24])=[O:14])[C:3]=1[Br:16]
Reactant: O=C(O)c1c(Br)c(Br)c(C(=O)O)c(Br)c1Br
Reactant: C=CCBr
Reactant: CC(C)O
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: C=CCOC(=O)c1c(Br)c(Br)c(C(=O)OCC=C)c(Br)c1Br

Procedure:
To a liquid mixture consisting of 19.3 parts of tetrabromoterephthalic acid and 40 parts of isopropyl alcohol, were added with stirring 13 parts of a 50% aqueous solution of caustic potash. After continuously mixing the thus-obtained mixture for 30 minutes, 12.6 parts of allyl bromide and 1.0 part of triethylamine were added. The resulting mixture was heated until isopropanol started to reflux. The mixture was maintained at the temperature for 8 hours. After allowing the resulting reaction mixture to cool, the liquid reaction mixture was concentrated under reduced pressures, followed by an addition of 50 parts of chloroform to dissolve the residue. The resultant solution was poured in a separation funnel and then washed with an aqueous solution of sodium bicarbonate and thereafter with water. The organic layer was concentrated and the resultant white solid was recrystallized from ethyl acetate, thereby obtaining 12 parts of diallyl tetrabromoterephthalate (hereinafter called "Compound B") as white irregular crystals (m.p. 125°-127° C.).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]2([C:23]([O:25]CC3C=CC=CC=3)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[H][H]>C(O)C.[C].[Pd]>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)NC2(C(=O)OCc3ccccc3)CCCCC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)NC2(C(=O)O)CCCCC2)CC1
Yield: 94.8 %

Procedure:
Further, 4.3 g (9.65 mmol) of the above phenylmethyl 1-[N-[4-(2-methyl-2-propyloxycarbonyl)piperazine-1-carbonyl]amino]cyclohexanecarboxylate was dissolved in 200 ml of ethanol and 400 mg of 10% palladium carbon was suspended thereinto and under air current of hydrogen stirred for 15 hours. The insoluble components were removed from the reaction mixture by filtration. The filtrate was concentrated under reduced pressure, whereby 3.25 g of the captioned 1-[N-[4-(2-methyl-2-propyloxycarbonyl)piperazine-1-carbonyl]amino]cyclohexanecarboxylic acid was obtained in a yield of 45%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH:6]1[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.Br[CH2:23][CH2:24][O:25][CH3:26]>>[CH3:26][O:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(O)c2)CC1
Reactant: COCCBr
Product: COCCOc1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 96 %

Procedure:
The title compound was prepared in 96% yield (355 mg, colorless syrup) from tert-butyl 4-(3-hydroxyphenoxy)piperidine-1-carboxylate (300 mg, 1.02 mmol) and 1-bromo-2-methoxyethane (171 mg, 1.23 mmol) at a reaction temperature of 60° C. by the similar manner in Step-1 of Intermediate-2.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N:12]2[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[N:13]2)=[C:10]([Cl:19])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5]>O1CCOCC1.[OH-].[Na+].O>[Cl:1][C:2]1[C:11]([N:12]2[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[N:13]2)=[C:10]([Cl:19])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(Cl)c(-n2nnn(C)c2=O)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nnn(-c2c(Cl)ccc(C(=O)O)c2Cl)c1=O
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 87.5 %

Procedure:
To a solution of methyl 2,4-dichloro-3-(4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-1-yl)benzoate (4.10 g) in dioxane (70 ml), 10N sodium hydroxide (2.0 ml) and water (4 ml) were added and the mixture was stirred at 60° C. for 1.5 hours. After concentrating under reduced pressure and the addition of water (50 ml), an aqueous solution of sodium hydroxide was added and washed with ethyl acetate (150 ml). The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated salt water and dried with anhydrous magnesium sulfate. By distilling off of ethyl acetate, the objective 2,4-dichloro-3-(4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-1-yl)benzoic acid (3.42 g, yield 87%) was obtained. mp: 221-225° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([NH2:28])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:29])[CH2:10][CH2:9]1)[CH3:7].C(N(CC)CC)C.[C:38](Cl)(=[O:58])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([NH:28][C:38](=[O:58])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:29])[CH2:10][CH2:9]1)[CH3:7]
Reactant: CCCCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](N)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCC(=O)N[C@H]1CC[C@@]2(C)[C@@H](C1)C[C@@H](O)[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]12
Reaction time: 8 h
Yield: 35.3 %

Procedure:
1.0 g of 3β-amino-7α,12α-dihydroxy-5β-cholan-24-oic methylester (FIG. 5A-1) [see Example I] was dissolved in 30 ml dry dimethylformamide and treated with 15 ml triethyl amine under stirring. 1.0 g of arachidoyl chloride in 10 ml dimethylformamide was added dropwise to the resulting solution, and the stirring was continued overnight. The reaction mixture was poured into water, extracted with methylene chloride, the organic fraction was then dried over sodium sulfate, evaporated to dryness and chromatographed over silica gel with a mixture of ethyl acetate and hexane (6:4 and 8:2), to give 0.6 g 3β-arachidylamido-7α,12α-dihydroxy-5β-cholan-24-oic methylester (FIG. 5A-4).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:36][C@H:37]([C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1)[CH3:38]>ClCCl>[CH3:46][O:45][C:43]([C:42]1[CH:47]=[CH:48][C:39]([C@@H:37]([NH:36][C:18]([C@H:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:19])[CH3:38])=[CH:40][CH:41]=1)=[O:44]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.8 %

Procedure:
To a 0° C. mixture of (3R)-2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinoline-3-carboxylic acid (40.0 g, 141.4 mmol) and dichloromethane (784 mL), add triethylamine (21.7 mL, 155.5 mmol). Then add isobutyl chloroformate (20.3 mL, 155.5 mmol) in a dropwise fashion. After the end of the addition, stir the mixture at 0° C. for 20 minutes. Then, add methyl (S)-4-(1-aminoethyl)benzoate (27.9 g, 155.5 mmol), and stir the mixture at room temperature for 1 hour. Add water (400 mL), separate the layers, and wash the organic layer with 1 M aqueous KHSO4 (500 mL), followed by saturated aqueous NaHCO3 (500 mL). Dry the organic phase over MgSO4, filter to remove the solids, and concentrate the filtrate under reduced pressure to furnish the title compound as a white solid (60 g, 97% yield). Mass spectrum (m/z): 339 ([M+H−Boc]+), 383 ([M+H−t-Bu]+), 439 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[CH3:13])=[CH:5][CH:4]=1.[N+:16]([O-])([O-:18])=[O:17].[K+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[CH3:13])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc2[nH]c(=O)c(=O)n(C)c2c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1cc2c(cc1[N+](=O)[O-])[nH]c(=O)c(=O)n2C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of 0.5 g (2.4 mmol) 7-methoxy-1-methylquinox-aline-2,3(1H,4H)-dione in 20 ml concentrated sulfuric acid was added at 0° C. 0.25 g (2.48 mmol) potassium nitrate. Stirring was continued at 0° C. for 30 min, and then at 25° C. for 90 min. The reaction mixture was poured into 100 ml icewater to give 0.51 g (84%) of 7-methoxy-1-methyl-6-nitroquinoxaline- 2,3(1H,4H)-dione as a precipitate. M.p. 343° C. NMR (DMSO-d6): 11.9 (1H, broad s), 7.67 (1H, s), 7.0 (1H, s), 3.97 (3H, s), 3.53 (3H, s).
Reaction SMILES: C([Li])CCC.[CH:6]1[CH:7]=[CH:8][C:9]2[S:14][CH:13]=[CH:12][C:10]=2[CH:11]=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:22]=[O:23])[O:19][C:20]=1[CH3:21]>C1COCC1>[S:14]1[C:13]([CH:22]([C:18]2[O:19][C:20]([CH3:21])=[C:16]([CH3:15])[CH:17]=2)[OH:23])=[CH:12][C:10]2[CH:11]=[CH:6][CH:7]=[CH:8][C:9]1=2
Reactant: Cc1cc(C=O)oc1C
Reactant: c1ccc2sccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(O)c2cc3ccccc3s2)oc1C
Reaction time: 0.25 h
Yield: 102.2 %

Procedure:
n-Butyl lithium (2.5 N in hexanes, 32.2 mL, 80.5 mmol) was added to a stirred solution of thianaphthene (10.6 g, 78.9 mmol) in THF (290 mL) at −78° C. After 15 min., a solution of 4,5-dimethyl-2-furaldehyde (9.79 g, 78.9 mmol) in THF (10 mL) was added. After additional 1 hour, the reaction mixture was quenched with 10% aqueous ammonium chloride (150 mL) and further diluted with water (150 mL). Aqueous mixture was extracted with dichloromethane. The combined dichloromethane extracts were washed with water, dried with brine and anhydrous Na2SO4, and concentrated to provide the title compound as an yellow oil (20.84 g, 100%): NMR (DMSO-d6); δ 7.89 (d, J=8 Hz, 1H), 7.76 (d, J=8, Hz, 1H), 7.35-7.26 (m, 2H), 7.25 (s, 1H), 6.36 (s, 1H), 6.08 (s, 1H), 5.92 (s, 1H), 2.13 (s, 3H), 1.86 (s, 3H); MS (EI): [M+], 258.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:35]=[CH:36][CH:37]=1)[CH2:14][N:15]1[CH2:34][CH2:33][C:18]2([O:23][C:22]([CH3:25])([CH3:24])[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]2)[CH2:17][CH2:16]1.C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:24][C:22]1([CH3:25])[CH2:21][NH:20][CH2:19][C:18]2([CH2:33][CH2:34][N:15]([CH2:14][C:13]3[CH:12]=[C:11]([CH2:10][CH2:9][OH:8])[CH:37]=[CH:36][CH:35]=3)[CH2:16][CH2:17]2)[O:23]1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)OC2(CCN(Cc3cccc(CCO)c3)CC2)C1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCC2(CCN(Cc3cccc(CCO)c3)CC2)O1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl 9-(3-(2-hydroxyethyl)benzyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (Example 271, step d) (0.78 g) in DCM (20 mL) and the reaction mixture allowed to stand for 30 minutes at 20° C. Toluene (40 mL) was added and the solvents evaporated under reduced pressure, the residue was azeotroped with acetonitrile (×2). The residue was dissolved in water (30 mL) and washed with ethyl acetate, the aqueous layer was basified by addition of solid sodium carbonate and stirred for 30 minutes at 20° C. The aqueous mixture was then extracted with DCM (×6), the combined DCM layers were dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.4 g.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#C.[CH3:6][S:7][CH2:8][CH2:9][C:10](=[O:12])[CH3:11].[CH3:13]COCC>>[OH:12][C:10]([CH3:13])([CH2:9][CH2:8][S:7][CH3:6])[CH2:11][C:2]#[CH:3]
Reactant: CCOCC
Reactant: C#CCBr
Reactant: CSCCC(C)=O
Agent: [Mg]
Product: C#CCC(C)(O)CCSC
Reaction time: 0.58 h

Procedure:
To a stirred mixture of 6.6 g. (0.275 moles) of magnesium and 116 mg. of mercuric chloride in 35 ml. of ether is added, dropwise under argon atmosphere, 35.2 g. of propargyl bromide (80% solution in toluene) and 25 g. (0.21 moles) of methylmercaptobutane-3-one [D. B. Reisner, J. Am. Chem. Soc., 78, 2132 (1956) in 100 ml. of ether at a rate to maintain gentle refluxing. After stirring at the reflux temperature for 35 minutes, the cooled mixture is quenched by dropwise addition of 140 ml. of saturated ammonium chloride solution. The ether phase is separated, washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation of the residual oil provides 27.4 g. (82%) of product as a colorless oil; b.p 114°-115° C. (7-8 mm.).
Reaction SMILES: [F:1][CH2:2][C:3]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:5]([SH:8])=[N:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](=[O:40])(=[O:39])[NH2:38])=[CH:33][C:32]=1[Cl:41])=[O:29].O>CN(C=O)C>[Cl:41][C:32]1[CH:33]=[C:34]([S:37](=[O:40])(=[O:39])[NH2:38])[CH:35]=[CH:36][C:31]=1[NH:30][C:28](=[O:29])[CH2:27][S:8][C:5]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:3]([CH2:2][F:1])=[N:7][N:6]=1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CCl)c(Cl)c1
Reactant: Cc1ccc(-n2c(S)nnc2CF)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-n2c(CF)nnc2SCC(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
In a solution of 5-fluoromethyl-4-(4-methyl-naphthalen-1-yl)-4H-[1,2,4]triazole-3-thiol (89 mg, 0.33 mmol), K2CO3 (50.0 mg, 0.36 mmol) in DMF (2.0 mL) was added 2-chloro-N-(2-chloro-4-sulfamoyl-phenyl)-acetamide (93 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 16 h. Upon the completion of the reaction, H2O (2.0 mL) was added to the reaction and stirred till precipitation occurred and filtered to give solid (126.8 mg, 74% yield). 1H NMR (DMSO, 300 MHz) δ 10.12 (broad s, 1H), 8.18 (d, J=8.7 Hz, 1H), 8.04 (dd, J=4.8, 8.7 Hz), 7.87 (s, 1H), 7.76-7.52 (m, 5H), 7.46 (s, 2H), 7.11 (d, J=8.7 Hz, 1H), 5.35 (dd, J=12.3, 26.7 Hz, 1H), 5.19 (dd, J=11.7, 25.8 Hz, 1H); 4.26 (s, 2H), 2.75 (s, 3H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li:10]CCCC>>[CH:1]1([Li:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: [Li]CCCC
Reactant: C1=Cc2ccccc2C1
Product: [Li]C1C=Cc2ccccc21

Procedure:
Indene was reacted with BuLi to form indenyl lithium, which compound was reacted with methyl iodide to form 1-methylindene. Use was made of: 18.2 grams of indene, 100 ml of n-Buli solution, 22.0 grams of methyl iodide.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:20])[C:14]=2[C:13]2[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:12]1=2.FC(F)(F)C(O)=O.C(Cl)[Cl:41]>>[ClH:41].[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:20])[C:14]=2[C:13]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:12]1=2
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(Cc3nc4ccccc4[nH]3)c3cccc(Br)c23)CC1
Solvent: O=C(O)C(F)(F)F
Product: Brc1cccc2c1c1c(n2Cc2nc3ccccc3[nH]2)CCNCC1
Product: Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
tert-Butyl 6-(1H-benzirnidazol-2-ylmethyl)-10-bromo-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.105 g, 0.212 mmol) was dissolved in CH2Cl2 (5 mL) and trifluoroacetic acid (2.0 mL, 2.96 g, 26.0 mmol, 122 equiv.) was added. This mixture was stirred at rt in a capped vessel for 2.5 h. The reaction mixture was concentrated to dryness. The residue was taken up in EtOAc (2 mL), and 1M HCl in Et2O was added. The hydrochloride salt was collected by filtration and dried under vacuum. 6-(1H-benzimidazol-2-ylmethyl)-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride (0.943 g) was produced in quantitative yield. 1H NMR (300 MHz, DMF) δ 3.61-3.70, 3.83-3.86, 6.12, 7.06, 7.31, 7.36-7.42, 7.66-7.74, 7.74; 1H NMR (300 MHz, CD3OD) δ 3.33-3.36, 3.54-3.59, 3.83-3.86, 6.04, 7.09, 7.35, 7.41, 7.54-7.57, 7.71-7.74; MS (ESI+) for C20H19BrN4 m/z 395, 396.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18].[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](Cl)=[O:26]>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]([C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:22]([C:21]([F:20])([F:35])[F:36])[CH:23]=1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: COC(=O)CNc1cnccc1-c1ccccc1Cl
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Yellow solid (26%). MS (ESI): m/z=517.075 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:14]=[CH:13]2)[CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: OCC[C@H](c1cccc(Br)c1)N1CCc2cccc(OCc3ccccc3)c21
Agent: C[Si](C)(C)Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCC[C@H](c1cccc(Br)c1)n1ccc2cccc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
A stirred solution of (3R)-(−)-3-(3-bromophenyl)-3-(7-benzyloxyindolin-1-yl)propan-1-ol (1.0 g, 2.28 mmol) in dry dichloromethane (30.0 ml) under nitrogen at 5° C. was treated with triethylamine (0.52 ml, 3.77 mmol) followed by chlorotrimethylsilane (0.32 ml, 2.52 mmol) dropwise. The resulting suspension was stirred at room temperature for 20 min, treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.57 g, 2.52 mmol) and stirred at room temperature until the reaction was judged to be complete from TLC inspection (˜30 min). The solvent was removed by evaporation, the residue was taken up in ethyl acetate (200 ml), washed with 2M aqueous sodium hydroxide (3×100 ml), brine (100 ml) and 2M aqueous hydrochloric acid (2×100 ml). Evaporation of the dried organic extracts (Na2SO4) gave a yellow/brown oil. Column chromatography (ethyl acetate-light petroleum (b.p. 40-60° C.), 1:4) gave the title compound as a yellow oil (0.80 g, 80%). [α]D26 −157 (c=0.014 gml−1, CHCl3); νmax (thin film)/cm−1 3418.5 (br. OH), 3064.5, 3033.5, 2935.5, 2879.0, 1593.5, 1570.5; δH (270 MHz) 2.35 (2H, m, 2×2-H); 3.50 (2H, m, 2×1-H); 5.13 (2H, q, CH2Ph, 2J=11.1 Hz); 6.6 (m, 2H, 3-H, indole 3-H); 6.72 (1H, dd, indole 6-H, Jo=7.6 Hz, Jm=0.7 Hz); 6.90 (1H, dd, indole 4-H, Jo=8.3 Hz, Jm=0.8 Hz); 7.00 (2H, m, indole 5-H, 5′-H); 7.15 (1H, d, indole 2-H, 3J2,3=3.0 Hz); 7.19-7.40 (8H, m, 8ArH). δC (67.8 MHz) 38.4 (2-C); 56.4 (3-C); 59.3 (1-C); 70.7 (PhCH2); 103.2 (indole 3-C); 104.3 (indole 6-C); 114.3 (indole 4-C); 120.1 (indole 5-C); 122.5 (3′-C); 125.0 (indole 2-C); 131.8 (1′-C); 136.4 (benzyl ipso-C); 144.9 (indole 7a-C); 146.5(indole 7-C). The remaining signals lie between 126.5-130.7 ppm and cannot be assigned with any certainty.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)C=CC=[CH:3][CH:2]=1.C(O)(=O)C.[C-]#[N:22].[K+]>C(OCCO)C.O>[CH3:3][CH2:2][CH2:1][CH2:7][CH2:8][CH2:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:22]
Reactant: [C-]#N
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CCOCCO
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCC#N
Temperature: 105 °C
Reaction time: 0.25 h

Procedure:
To the chalcone, 157, (17.95 g, 54.7) mmol) in 2-ethoxyethanol (150 mL) at 55° C. was added acetic acid (4 mL) followed by slow addition of potassium cyanide (5.3 g, 81 mmol) in water. The solution was stirred at 105° C. for 0.25 hour. The solution was cooled and treated with water (25 mL). The mixture was filtered to collect the solid. The solid was washed repeatedly with 70% ethanol (50 mL), air dried, and then dried in vacuo to give the nitrile 12.7 g (68%) as a yellow solid. The nitrile was identified by 1H NMR, IR, MS, and microanalysis.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7]2)([O-:3])=[O:2].[OH-].[Na+]>Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7]2)([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]c1=O
Yield: 94.1 %

Procedure:
A mixture of 9.7 g (37 mmol) of the above ester and 200 ml of 1 N sodium hydroxide is heated on the steam bath for 11/4 hours. The resulting suspension is poured over ice and acidified with 250 ml of 1 N hydrochloric acid. The solid is collected by filtration and washed with water and ethanol to give 8.15 g of the title acid, mp>310° C.