Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[C:8](=[O:18])[NH:7]1)C.[OH-].[Na+].Cl.CCOC(C)=O>C1COCC1>[N+:15]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C:4]([OH:19])=[O:3])[NH:7][C:8]2=[O:18])([O-:17])=[O:16]
Reactant: CCOC(=O)Cn1[nH]c(=O)c2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)Cn1[nH]c(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of (5-nitro-3-oxo-2,3-dihydro-indazol-1-yl)-acetic acid ethyl ester (0.24 g) in THF (9 mL), was added 2 N NaOH (aq.) (1.8 mL). The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was acidified with 2 N HCl (aq.) and extricated with EtOAc. Evaporation of the organic phases afforded the desired crude (5-nitro-3-oxo-2,3-dihydro-indazol-1-yl)-acetic acid (0.146 g) which was taken into the next step without further purification.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1.O.[NH2:13][NH2:14]>C(O)C>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:13][NH2:14])=[O:2])=[CH:5][CH:6]=1
Reactant: NN
Reactant: COC(=O)c1ccc(Br)cc1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(Br)cc1
Yield: 67 %

Procedure:
First, 3.0 g (13.9 mmol) of methyl-4-bromobenzoate was put in a 100-mL three-neck flask, 10 mL of ethanol was added therein, and the mixture was stirred. Thereafter, 4.0 mL of hydrazine monohydrate was added therein, and the mixture was heated and stirred at 78° C. for 5 hours. The obtained solid was washed with water and collected by suction filtration; thus, 2.0 g of a white solid of 4-bromobenzohydrazide that was an object was obtained (yield: 67%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].O[CH2:11][CH:12]([CH2:14]O)O.[N+](C1C=CC=CC=1)([O-])=O.[OH-].[Na+]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]2[C:8]=1[CH:11]=[CH:12][CH:14]=[N:7]2
Reactant: Cc1ccc(Br)cc1N
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: Cc1ccc(Br)c2cccnc12
Temperature: 0 °C
Yield: 67.6 %

Procedure:
A solution of 5-Bromo-2-methylaniline (7.44 g), glycerol (7.4 g), nitrobenzene (4.9 g) in 75% sulfuric acid (20 ml) was heated at 150° C. for 3 hrs. The solution was cooled to 0° C. then carefully neutralized with aqueous sodium hydroxide. The reaction mixture became a dark gum and was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, then dried with sodium sulphate and the solvent removed in vacuo. The crude product was purified by column chromatography (dichloromethane) to afford the title compound as a solid (6 g). 1H-NMR (CDCl3, 400 MHz) 8.91 (m, 1H), 8.51 (m, 1H), 7.7 (m, 1H), 7.50 (m, 1H), 7.4 (m, 1H), 2.72 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[CH2:19]([N:21]1[C:25]([NH2:26])=[CH:24][CH:23]=[N:22]1)[CH3:20].C(O)(=O)C>CN(C=O)C>[CH2:19]([N:21]1[C:25]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]([NH2:18])=[O:17])=[CH:24][CH:23]=[N:22]1)[CH3:20]
Reactant: CCn1nccc1N
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCn1nccc1Nc1c(C(N)=O)cnc2cc(OC)c(OC)cc12
Temperature: 100 °C
Yield: 32.7 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 1-ethyl-5-aminopyrazol (0.030 g, 0.27 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100° C. for 7.5 h. The DMF was evaporated under reduced pressure and the residue was dissolved in a mixture of MeCN and water (1:7) containing 0.1% trifluoroacetic acid. Preparative HPLC using a gradient (containing 0.1% trifluoroacetic acid) of 10→40% MeCN in water as eluent gave, after evaporation, the title compound as the trifluoroacetic acid salt. The product was suspended in saturated aqueous NaHCO3 and absorbed on a short SPE column [ISOLUTE™ C18 (EC)] pre-conditioned subsequently with methanol and water. The column was washed extensively with water until the pH of the eluent was neutral. The product was then eluted with methanol, the solvent evaporated and the residue crystallized from ethanol to give the title compound (19 mg, 32%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[S:11]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17]O)=[CH:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][S:11][CH:12]=1)[C:5]#[N:6]
Reactant: OCCc1ccsc1
Reactant: N#Cc1ccc(O)c(Br)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1ccc(OCCc2ccsc2)c(Br)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 3-bromo-4-hydroxybenzonitrile (15.0 g) in THF (100 mL) was added 2-(3-thienyl)ethanol (7.94 mL) and triphenyl phosphine (19.84 g). The reaction was cooled to 0° C. and diethylazodicarboxylate (11.92 mL) was added dropwise. The reaction was stirred at room temperature for 16 h. The solvent was then reduced in vacuo and the residue redissolved in diethyl ether (100 mL). The mixture was stirred at 0° C. for 10 min and then filtered. The filtrate was washed with aqueous sodium carbonate solution (80 mL), 1 M aqueous hydrochloric acid (80 mL) and brine (80 mL), dried (MgSO4), reduced in vacuo and purified on silica to give 3-bromo-4-(2-thiophen-3-yl-ethoxy)-benzonitrile.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:29]2[CH2:30][CH2:31][CH:26]([C:22]3[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)=[CH:3][CH:2]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4ccccc4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using [1,1′-biphenyl]-4-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 413.2 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])C1C=CC=CC=1>C(O)C.O1CCOCC1.[OH-].[Pd+2].[OH-]>[CH2:23]([O:22][C:20]([C:14]1[C:13]2[C:18](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=2)[N:17]=[C:16]([CH3:19])[CH:15]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)c1cc(C)nc2c(OCc3ccccc3)cccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1cc(C)nc2c(O)cccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
A mixture of 8-benzyloxy-4-ethoxycarbonyl-2-methylquinoline (663 mg) and palladium(II) hydroxide (60 mg) in a mixture of ethanol (6 ml) and dioxane (6 ml) was stirred for 3 hours at ambient temperature under hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated. The residue was pulverized with n-hexane to give 4-ethoxycarbonyl-8-hydroxy-2-methylquinoline (370 mg) as pale yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14](Br)[CH:15]=1>CN(C=O)C>[Br:9][C:10]1[CH:15]=[C:14]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[CH:13]=[N:12][CH:11]=1
Reactant: Brc1cncc(Br)c1
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1cncc(Br)c1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of N,N-dimethylethanolamine(0.5 mL) in DMF (10 mL) at room temperature was treated with sodium hydride (0.2 g, 8.4 mmol), stirred for 30 minutes, and treated with 3,5-dibromopyridine (1.0 g, 4.2 mmol). The mixture was stirred at 90° C. for 8 hours, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum. Purification by flash column chromatography on silica gel with 50% ethyl acetate/hexane provided the desired product (0.8 g, 78%). MS (DCI/NH3) m/e 246 (M+H)+.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[NH2:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH2:13][S:14][CH3:15].C(=O)([O-])[O-].[Na+].[Na+].[BH4-].[Na+]>O>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH2:1][NH:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH2:13][S:14][CH3:15]
Reactant: Nc1ccccc1C=O
Reactant: CSCC[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CSCC[C@H](NCc1ccccc1N)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 0.1 mol of anthranil aldehyde, 0.1 mol of methionine and a solution of 0.1 mol of sodium carbonate in 50 ml of water was stirred for a few hours. After everything had gone into solution, 0.1 mol of sodium borohydride was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was then acidified to pH3, and the precipitate was collected and dried, yielding 85% of theory of N-(2-amino-benzyl)-methionine, m.p. 198° C. The total yield, based on the anthranilic acid starting material, was 68% of theory.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([O:10][CH2:11][CH2:12]O)[CH:8]=[CH2:9].C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:1]([O:6][CH2:12][CH2:11][O:10][CH2:7][CH:8]=[CH2:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: C=CCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOCCOC(=O)C(=C)C
Temperature: 120 °C
Yield: 72.5 %

Procedure:
To a three-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a Dean-Stark apparatus were added methacrylic acid (137.7 g, 1.6 moles), ethyleneglycol monoallylether (80.7 g, 0.8 moles), p-toluenesulfonic acid (0.76 g, 4.0 mmole) and toluene (650 mL). The mixture was heated to 120° C. for 5 hours with exclusion of water. Another portion of p-toluenesulfonic acid (0.12 g) and the mixture was heated to 120° C. for 6 hours. The other portion of p-toluenesulfonic acid (0.1 g) was added and the mixture was heated to 120° C. for 9 hours. During the reaction, the consumption of methacrylic acid and ethyleneglycol monoallylether were monitored by liquid chromatography and the conversion reached 98%. The mixture was neutralized by addition of aq. NaHCO3 and the layers were separated. The aqueous layer was extracted with toluene and the combined organic layers were dried over CaCl2 and concentrated under reduced pressure. Distillation of the crude material (60° C. at 2 mmHg) yielded 2-allyloxyethyl methacrylate (98.7 g, 73%) shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=1
Reactant: COC(=O)CCc1nc(-c2cc(Cl)cc(C(F)(F)F)c2)co1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1nc(-c2cc(Cl)cc(C(F)(F)F)c2)co1
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a stirred solution of methyl 3-(4-(3-chloro-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 36, 0.386 g, 1.16 mmol) in methanol (10.0 mL) was added sodium hydroxide (1.50 mL, 1.0 M in water, 1.50 mmol) at room temperature. After 16 h, the reaction was quenched with 1.0 M hydrochloric acid (1.70 mL), diluted with ethyl acetate, washed with water, and saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was triturated with methylene chloride and hexanes to provide 3-(4-(3-chloro-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoic acid (0.316 g, 85%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([C:14]2([CH3:17])[CH2:16][O:15]2)=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.Cl([O-])(=O)(=O)=O.[Na+]>C(#N)C>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][CH2:16][C:14]([OH:15])([CH3:17])[C:12]([NH:11][C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=2)=[O:13])=[CH:21][CH:20]=1
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Reactant: Nc1ccc(F)cc1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: Cc1cc(NC(=O)C(C)(O)CNc2ccc(F)cc2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide (0.2 g, 0.85 mmol), 4-fluoroaniline (0.18 g, 1.7 mmol) and sodium perchlorate (0.21 g, 1.7 mmol) in 2 ml of acetonitrile was boiled under reflux for 6 hours. After a workup of the reaction mixture, the crude product was purified by flash chromatography (dichloromethane-1% methanol). 1H NMR (400 MHz, DMSO-d6): 1.41 (3H, s), 2.51 (3H, s), 3.10 (1H, dd, J=12.7 Hz, J=4.6 Hz), 3.41 (1H, dd, J=12.7 Hz, J=7.7 Hz), 5.26 (1H, m), 6.02 (1H, s), 6.62-6.66 (2H, m), 6.84-6.89 (2H, m), 7.79-7.83 (2H, m), 8.02 (1H, d, J=8.9 Hz), 9.99 (1H, s).
Reaction SMILES: [O:1]=[C:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Br:9]Br>C(Cl)Cl.CCOC(C)=O>[Br:9][CH:7]([CH3:8])[C:2](=[O:1])[C:3]([O:5][CH3:6])=[O:4]
Reactant: BrBr
Reactant: CCC(=O)C(=O)OC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(=O)C(C)Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a solution of methyl 2-oxobutanoate (6.92 g, 59.6 mmol) in DCM (60 mL) at 0° C. was added bromine (3.10 mL, 60.3 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h, diluted with EtOAc, washed with saturated NaHCO3 (2×), water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. The product, methyl 3-bromo-2-oxobutanoate, (8.26 g, 42.4 mmol, 71% yield) was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:10]([C:20]([OH:22])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[CH2:59]([CH:66]1[CH2:70][CH2:69][CH2:68][NH:67]1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:10]([C:20]([N:67]2[CH2:68][CH2:69][CH2:70][CH:66]2[CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C1CN(Cc2ccccc2)CC1C(=O)O
Reactant: c1ccc(CC2CCCN2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1C1CN(Cc2ccccc2)CC1C(=O)N1CCCC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 1-Benzyl-4-(2-methylphenyl)pyrrolidine-3-carboxylic acid (0.088 g, 0.298 mmol) in CH2Cl2 (1.490 ml) was added BOP (0.138 g, 0.313 mmol), DIPEA (0.208 ml, 1.192 mmol), and 2-benzylpyrrolidine (0.050 g, 0.313 mmol). The solution was stirred at room temperature for 4 hours. Concentrate, filter, and purify on reverse phase HPLC. HRMS (M+H)=439.2739
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:20][C:21]([CH3:25])=[CH:22][CH2:23]Br.[H-].[Na+]>C1COCC1>[CH3:20][C:21]([CH3:25])=[CH:22][CH2:23][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COc1cccc2nc(-c3c(F)cccc3F)[nH]c12
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2c1nc(-c1c(F)cccc1F)n2CC=C(C)C
Reaction time: 4 h
Yield: 350 %

Procedure:
To 2-(2,6-difluorophenyl)-4-methoxylbenzimidazole (5005, Example 46) (0.28 g, 1.08 mmol) and 3,3-dimethylallyl bromide (0.20 mL, 0.26 mmol, 160 M %) dissolved in THF (3 mL) was added NaH (60% dispersion in mineral oil) (0.15 g, 3.75 mmol, 350 M %). After 4 h, the reaction was quenched with MeOH and concentrated. The residue was redissolved in dichloromethane, washed with water and NaCl (sat. aq.), dried (Na2SO4), filtered and concentrated. The product was purified by flash chromatography eluting with 2% MeOH/CH2Cl2 and recrystallized from hexane to give white powders of 1-(3,3-dimethylallyl)-2-(2,6-difluorophenyl)-4-methoxyl-benzimidazole (0.30 g, 0.91 mmol, 84% yield). M.p. 101-103° C. 1H-NMR (200 MHz, CD2Cl2): 7.52 (m, 1H, H4″), 7.24 (dd, J=7.9, 8.2 Hz, 1H, H6), 7.08 (m, 2H, H3″,5″), 7.02 (dd, J=0.9, 8.2 Hz, 1H, H5), 6.73 (dd, J=0.9, 7.9 Hz, 1H, H7), 5.19 (t, J=7.0 Hz, 1H, H2′), 4.02 (s, 3H, OCH3), 4.62 (d, J=7.0 Hz, 2H, H1′), 1.64 (s, 3H, CH3), 1.58 (s, 3H, CH3).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=[O:7])=[O:2].I[C:14]1C(C)=CC(C)=C(C=1)C(O)=O>>[CH:1]([C:3]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:14])=[C:5]([CH:4]=1)[C:6]([OH:8])=[O:7])=[O:2]
Reactant: Cc1ccc(C(=O)O)cc1C=O
Reactant: Cc1cc(C)c(C(=O)O)cc1I
Product: Cc1cc(C)c(C(=O)O)cc1C=O

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 4.1, except 5-iodo-2,4-dimethylbenzoic acid (compound 1.3) was used in place of 3-bromo-4-methylbenzoic acid.
Reaction SMILES: CI.[ClH:3].[CH3:4][NH:5][CH2:6][CH2:7][S:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[C:25](=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:3].[CH3:4][N:5]([CH3:25])[CH2:6][CH2:7][S:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: CNCCSc1nc2ccccc2cc1-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CCO
Product: CN(C)CCSc1nc2ccccc2cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl iodide (0.85 g.) was added to a mixture of 2-(2-methylaminoethylthio)-3-phenylquinoline hydrochloride (1.65 g.) and potassium carbonate (1.65 g.) in dry ethanol (50 ml.) at ambient temperature. The mixture was stirred at ambient temperature for 3 hr. and the solvent was then evaporated. The residue was dissolved in water (50 ml.) and extracted with diethyl ether (3×25 ml.). The diethyl ether extract was washed with brine (25 ml.), dried (MgSO4), and the solvent evaporated. The residual oil was chromatographed on basic alumina (75 g., Brockmann Grade III), eluted with increasing concentrations of methylene dichloride in petroleum ether. The eluate with 50% v/v methylene dichloride in petroleum ether was evaporated. The residue was dissolved in diethyl ether (25 ml.) and ethereal hydrogen chloride added until precipitation was complete. The mixture was filtered and the solid residue was crystallised from methanol-ethyl acetate to give 2-(2-dimethylaminoethylthio)-3-phenylquinoline hydrochloride, m.p. 196°-8°.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[C:32]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1>>[C:32]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:33]=[CH:34][C:35]([NH:38][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]4[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=4)[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])=[CH:36][CH:37]=1
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(COc1ccc(Cl)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Product: O=C(Nc1ccc(-c2ccccc2)cc1)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2

Procedure:
The title compound was synthesized from 2,2,2-trichloro-1-{10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 67 (0.3 mmol) and biphenyl-4-ylamine (2.2 eq.) in the manner of Example 68, m.p. 201-202° C. MS [(+)ESI, m/z]: 548 [M+H]+
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][C:8]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=O)=O.[C:24]([O-:27])(=[S:26])[CH3:25].[K+]>CN(C)C=O>[C:24]([S:26][C:7]1[CH2:16][CH2:15][C:10]2([O:11][CH2:12][CH2:13][O:14]2)[CH2:9][C:8]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:27])[CH3:25]
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCC2(C1)OCCO2
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(SC(C)=O)CCC2(C1)OCCO2
Temperature: 0 °C
Yield: 45.1 %

Procedure:
19.97 g (55.4 mmol) of ethyl 8-trifluoromethanesulfonyloxy-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate [compound described as compound 6 in Tetrahedron Letter, Vol. 39, pp. 6139-6142 (1998)] was dissolved in 200 ml of dimethylformamide, and 9.50 g (83.1 mmol) of potassium thioacetate was added thereto with stirring under ice-cooling, followed by stirring at room temperature for 91 hours. To the reaction solution was added ice water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=17:3) to give 7.15 g of the title compound as a pale brown oil (yield: 45%).
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=[CH:6][C:5]=1[O:41][CH3:42].[OH-].[Na+]>CO.O1CCCC1>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C@:15]3([C@@H:14]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=4[F:40])[C@H:13]([C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[C:5]([O:41][CH3:42])[CH:6]=4)=[O:12])[NH:17][C@H:16]3[CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)O

Procedure:
In a manner similar to the method described in Example 6, rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-2-methoxy-benzoic acid methyl ester prepared in Example 15 (0.1 g, 0.16 mmol), was heated with aqueous NaOH in methanol and tetrahydrofuran at 78° C. to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-2-methoxy-benzoic acid as a off white solid (Yield 0.075 g, 77%).