Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:29])([CH:26]([F:28])[F:27])[CH2:16][O:17][C:18]1[N:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=1.[OH-].[K+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:25][CH2:24][C:21]2[CH:22]=[N:23][C:18]([O:17][CH2:16][C:15]([F:29])([F:14])[CH:26]([F:28])[F:27])=[CH:19][CH:20]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: OCc1ccc(OCC(F)(F)C(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(OCc2ccc(OCC(F)(F)C(F)F)nc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
In 40 ml of N,N-dimethylformamide were dissolved 2.2 g of 2-t-butyl-4,5-dichloro-3(2H)-pyridazinone and 2.5 g of 6-(2,2,3,3-tetrafluoropropyloxy)-3-pyridine methanol, and thereto was added 0.7 g of powdery potassium hydroxide. The reaction mixture was stirred overnight at room temperature and poured into water. Then, procedures similar to those in Preparation Example 24 were conducted to obtain 3.6 g of 2-t-butyl-4-chloro-5-[{6-(2,2,3,3-tetrafluoropropyloxy)-3-pyridyl}-methyloxy]-3(2H)-pyridazinone, m.p. 112.0°~118.0° C.
Reaction SMILES: [Br:1][CH:2](O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CN=C1.[OH2:38]>CN(C=O)C.C(OCC)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:38][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCCCCCCCCCC(O)Br
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCCCCCCCCCCCBr)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
1-Bromododecanol (2.511 g, 9.47 mmol), tert-butyldiphenylsilylchloride (2.66 mL, 15.15 mmol), and imidazole (1.418 g, 20.83 mmol) were dissolved in dry DMF (20 mL) and the resulting mixture was stirred under nitrogen for 3 h at room temperature. Upon completion of reaction, water (15 mL) and diethyl ether (25 mL) were added, the two layers were separated and the water layer was extracted with diethyl ether (3×25 mL). The combined organic extracts were washed with water, brine, dried over MgSO4, filtered and filtrate evaporated. The crude was purified by silica gel column chromatography using 100% hexane to 5% ethyl acetate/hexane as eluent to afford the title product as a clear thick oil (3.57 g, 75%). 1H NMR (CDCl3): δ7.66 (m, 4H), 7.39 (m, 6H), 3.62 (t, 2H, J=6.5 Hz), 3.40 (t, 2H, J=6.9 Hz), 1.85 (m, 2H), 1.54 (m, 2H), 1.44-1.25 (m, 16H), 1.04 (s, 9H). m/z (APCI) 505.37 (M++1).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:36])([CH3:35])[CH:33]=[CH2:34])[NH:9]1)=[O:7])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:36])[CH:33]=[CH2:34])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: C=CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 91 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 80b (1.0 g, 1.7 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.0 g, 91%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:13]=[C:12]([N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]2[CH2:23][CH2:22][O:21][CH2:20]2)[C:11]([N+:24]([O-])=O)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[Cl-].[NH4+].O1CCCC1.CO>O>[NH2:24][C:11]1[C:12]([N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]2[CH2:23][CH2:22][O:21][CH2:20]2)=[CH:13][C:4]([CH2:3][O:2][CH3:1])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COCc1cc(-n2ccnc2C2CCOC2)c([N+](=O)[O-])cc1C(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCc1cc(-n2ccnc2C2CCOC2)c(N)cc1C(=O)OC
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 86.9 %

Procedure:
To a mixture of 6.65 g of methyl 2-(methoxymethyl)-5-nitro-4-[2-(tetrahydrofuran-3-yl)-1H-imidazol-1-yl]benzoate, 980 mg of ammonium chloride, 33.0 mL of tetrahydrofuran, 66.0 mL of methanol, and 33.0 mL of water was added 4.8 g of reduced iron, followed by stirring at 70° C. for 4.5 hours. The insoluble matter was filtered through celite. The filtrate was concentrated, and water and ethyl acetate were added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 5.30 g of methyl 5-amino-2-(methoxymethyl)-4-[2-(tetrahydrofuran-3-yl)-1H-imidazol-1-yl]benzoate as a brown solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Br:6][C:7]1[CH:8]=[N:9][N:10]([CH2:12][CH2:13]Cl)[CH:11]=1>CS(C)=O.CCOC(C)=O>[Br:6][C:7]1[CH:8]=[N:9][N:10]([CH2:12][CH2:13][NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH:11]=1
Reactant: ClCCn1cc(Br)cn1
Reactant: COCCN
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCCNCCn1cc(Br)cn1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 2-methoxyethanamine (8.9 mL, 102.06 mmol) and chloride 75 (7.13 g, 34.02 mmol) in DMSO (20 mL) was heated at 60° C. 5 h. The mixture was then cooled to room temperature, diluted with EtOAc, washed with aqueous sodium bicarbonate, water and brine. The organic phase was further extracted with 1N HCl and the acid extract was collected and basified with 2N NaOH (pH˜11). The basic aqueous solution was extracted with DCM, the DCM extract was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford title compound 76 (8.44 g, 99%) as brown foam. MS (m/z): 248.04 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.C([O-])([O-])=O.[K+].[K+]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-n2ccc3ccccc32)cc1

Procedure:
By the method of Preparation C43, p-bromoanisole (140 g, 0.75 mole), indole (60 g, 0.51 mole), K2CO3 (75 g, 0.54 mole) and Cu2Br2 (28 g, 0.1 mole) were converted to title product, purified by distillation, rather than chromatography, 67.7 g, b.p. 150-160/0.4-0.5 mm, which crystallized on storage in the refrigerator, m.p. 52°-54° C.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:4][C:5]([N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=[O:13])=[O:6])[CH3:3].C[Si]([N:19]([Si](C)(C)C)[C:20]1[CH:21]=[C:22]([Mg]Cl)[CH:23]=[CH:24][CH:25]=1)(C)C>C1COCC1>[CH3:3][C:2]([CH3:14])([O:4][C:5]([N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]([C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:19])[CH:25]=1)[OH:13])=[O:6])[CH3:1]
Reactant: C[Si](C)(C)N(c1cccc([Mg]Cl)c1)[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)n1cccc1C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cccc1C(O)c1cccc(N)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of N-(dimethylethoxycarbonyl)pyrrole-2-carboxaldehyde (10 g, 50 mmol) in THF (500 mL) at −30° C. under nitrogen was added dropwise to 3-[bis(trimethylsilyl)amino]phenylmagnesium chloride (55 mL of a 1M solution in THF, 55 mmol). After addition the reaction mixture was gradually warmed up and stirred at 0° C. for 1 hour, then at ambient temperature for 15 minutes. The reaction mixture was poured into ice water, and stirred for 30 minutes. The reaction mixture was extracted with ethyl ether (1 L). The combined organic layers were dried (Na2SO4) and concentrated. Chromatography on SiO2 (700 g) using 1:1 hexane/ethyl acetate afforded [N-(dimethylethoxycarbonyl)pyrrol-2-yl](3-aminophenyl)methanol (11.2 g).
Reaction SMILES: [CH:1]([C:4]1[C:9]([B:10]([OH:12])[OH:11])=[C:8]([CH3:13])[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>O>[CH:1]([C:4]1[C:9]([B:10]([OH:12])[OH:11])=[C:8]([CH3:13])[C:7]([N+:14]([O-:16])=[O:15])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C(C)C)c1B(O)O
Solvent: O
Product: Cc1c([N+](=O)[O-])ccc(C(C)C)c1B(O)O
Temperature: -35 °C
Reaction time: 0.25 h

Procedure:
6-Isopropyl-2-methylbenzeneboronic acid (8 g) is added portionwise over 1 hour to 90% HNO3 (50 mL) at −40° C., maintaining an internal temperature below −30° C. After addition, the mixture is stirred at −40 to −30° C. for 15 minutes, then poured onto ice, and diluted with water. The solid is collected by filtration, washed with water and dried to give 6-isopropyl-2-methyl-3-nitrobenzeneboronic acid as a white solid. NMR (DMSO-d6) 7.78 (d, 2H), 7.30 (d, 2H), 2.85 (m, 1H), 2.38 (s, 3H), 1.15 (d, 6H).
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[O:8])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)C=CC(=O)c1ccccc1
Product: O=C(O)C=CC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
22g of finely powdered 3-benzoylacrylic acid was added in 1-gram portions to 11 g of stirred fuming (90%) nitric acid at -5° over a 30 minute period, the mixture being allowed to heat to 0°. Then the temperature of the mixture was allowed to rise to 2° and held until a clear solution was obtained. The mixture then was poured on ice, and the solid which formed was filtered, washed with water, dried (MgSO4) and recrystallized from ethanol to give 3-(3-nitrobenzoyl)acrylic acid (8A), m.p.: 199°-201°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[F:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:24]([OH:28])=[CH:23][C:21]=1[NH2:22].C(O)(C)C>CC(O)CCC>[F:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:24]([OH:28])=[CH:23][C:21]=1[NH:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COCCOc1cc2nncc(Cl)c2cc1OC
Solvent: CCCC(C)O
Solvent: CC(C)O
Product: COCCOc1cc2nncc(Nc3cc(O)c(C)cc3F)c2cc1OC

Procedure:
A suspension of 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (0.2 g, 0.74 mmol), (prepared as described for the starting material in Example 2), and 2-fluoro-5-hydroxy-4-methylaniline (126 mg 0.89 mmol) in 2-pentanol (2.5 ml) was heated at reflux for 7.5 hours. After cooling, isopropanol was added and the solid was filtered off, washed with isopropanol and ether, and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline as the hydrochloride salt (yellow solid 196 mg, 64%).
Reaction SMILES: COC1C=CC(C(Cl)=O)=CC=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[NH2:16].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:41][CH:42]=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:46]([NH:45][C:43](=[O:44])[C:40]2[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][CH:39]=2)=[S:47])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: COc1ccc(C(=O)Cl)cc1
Agent: COc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
4-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 86%).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:25]([NH:27][CH2:28][CH2:29][OH:30])[CH3:26]>ClCCl>[NH2:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][N:5]2[C:3](=[O:4])[CH2:2][N:27]([CH2:25][CH3:26])[CH2:28][CH2:29][OH:30])=[CH:9][C:10]=1[O:17][CH3:18]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CC2
Reactant: CCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCN(CCO)CC(=O)N1CCc2cc(OC)c(N)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.2 %

Procedure:
The 1-(bromoacetyl)-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (4.0 g, 12.7 mmol) was dissolved in 50 mL of dicholomethane, then K2CO3 (4.4 g, 31.7 mmol) and 2-(ethylamino)ethanol (2.3 g, 25.4 mmol) in 10 mL dichloromethane were added, the reaction was stirred at RT for 3 hours. After filtration, the organic layers were washed with water (2×100 mL)and dried over Na2SO4. The solvent was removed to yield the 2-[{2-[6-amino-5-(methyloxy)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}(ethyl)amino]ethanol as a yellow solid (3.77 g, 92%).1HNMR (400 MHz, DMSO-d6) δ ppm: 0.94 (t, J=7.14 Hz,3 H), 2.45 (s, 2 H), 2.60 (m, 4 H), 3.18 (t, J=8.42 Hz, 2 H), 3.40 (t, J=6.13 Hz,2H), 3.84 (s, 3 H), 4.19 (t, J=8.51 Hz, 2 H), 7.29 (s, 1 H), 8.43 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][N:5]=[C:4]2[O:15][CH:16]=[CH:17][C:3]=12.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C.O>C1COCC1>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:26])=[O:25])=[CH:12][CH:13]=2)[CH2:6][N:5]=[C:4]2[O:15][CH:16]=[CH:17][C:3]=12
Reactant: NC1=c2ccoc2=NCN1c1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: NC1=c2ccoc2=NCN1c1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To compound 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) (24 mg, 0.044 mmol) in THF (1 mL), benzenesulfonyl chloride (6.8 uL, 0.053 mmol), and N,N-diisopropylethylamine (9 uL, 0.053 mmol) were added. After the mixture was stirred at room temperature for 6 h, water was added to quench the reaction. The solution was extracted with EtOAc. The organic layer was separated, dried (MgSO4), and filtered. The solvent was evaporated. The residue was purified by gilson to afford the desired product MS(ES) m/e 367 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:17]=1)[C:10]([CH3:29])([CH3:28])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:28][C:10]1([CH3:29])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCNCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCNCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To a stirred mixture solution of 3,3-dimethyl-2-(3-piperazin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.0 g, 2.5 mmol) in methanol (5.0 mL) and tetrahydrofuran (6.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3,3-dimethyl-2-(3-piperazin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (820 mg, 90%) as a white solid: LC/MS m/e calcd for C22H27N3O2 (M+H)+: 366.48, observed: 366.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)[CH:26]=[CH:27][C:28]=3[O:29][CH3:30])=[O:22])[C:17]([OH:19])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:42][NH:43][O:44][CH3:45]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:31]4[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=4)[CH:26]=[CH:27][C:28]=3[O:29][CH3:30])=[O:22])[C:17](=[O:19])[N:43]([O:44][CH3:45])[CH3:42])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNOC
Reactant: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)C(=O)O
Agent: Cl
Product: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)C(=O)N(C)OC
Yield: 75.5 %

Procedure:
4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(methoxy-methyl-carbamoyl)-ethyl]-amide (0.13 g) was prepared from the 3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-2-(R)-[(4-methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid (0.16 g, 0.28 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.027, 0.28 mmol) according to the general procedure A.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O.O>[CH2:11]([O:18][C:19]([NH:1][CH2:2][CH2:3][OH:4])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NCCO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
2-Aminoethanol (20 g.) and sodium carbonate (84.8 g.) is dissolved in acetone-water (1:1) (500 ml.) and benzylchloroformate (83.9 g.) is added dropwise to the stirred solution at 0° C. over a period of 0.5 hours. The mixture is stirred at 0° C. for a further 2.5 hours. The solids are filtered off and washed with acetone and the filtrate is evaporated to dryness. The resulting gum is taken up in chloroform and filtered. The filtrate is evaporated to dryness. The residue is chromatographed on a silica gel column (140×5 cm.) using chloroform and then 10% methanol in chloroform as the eluant to give 2-benzyloxycarbonylaminoethanol, which crystallizes from hexane as colorless needles; m.p. 53°-55° C.; γ max (CCl4) 3450, 3325, 1720, 1510, 1245 cm-1 ; δ (CDCl3) 3.29 (2H, m HOCH2CH2NH--), 3.57 (2H, m, HOCH2CH2NH--), 5.07 (2H, s, --CH2C6H5) and 7.31 ppm (5H, s, --CH2C6H5).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])=[CH:7][C:6]=1[S:16]([OH:19])(=[O:18])=[O:17].[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([N:40]=[C:41]=[O:42])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1>N1C=CC=CC=1>[NH4+:1].[F:28][C:29]([F:43])([F:44])[C:30]1[CH:31]=[C:32]([NH:40][C:41](=[O:42])[NH:1][C:2]2[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][C:3]=2[O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:15])[CH2:12][CH3:13])=[CH:7][C:6]=2[S:16]([O-:19])(=[O:18])=[O:17])[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=1
Reactant: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2N)c(S(=O)(=O)O)c1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2NC(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(S(=O)(=O)[O-])c1
Product: [NH4+]

Procedure:
2-(2-Amino-4-trifluoromethylphenoxy)-5-(1,1-dimethylpropyl)benzenesulfonic acid (260 mg, 0.0006 mol) and 3,5-bis(trifluoromethyl)phenyl isocyanate (130.9 ml, 0.0005 mol) were mixed in pyridine (5 ml), under argon, for sixteen hours at room temperature. The solvent was evaporated and the residue flash chromatographed (silica gel, methylene chloride/isopropanol/ammonium hydroxide), dried and evaporated to give the title compound. 1H NMR (250 MHz, DMSO) ∂9.20 (s, 1H), 8.90 (s, 1H), 7.90 (s, 1H), 7.50 (s, 2H), 7.25 (d, 1H), 7.05 (s, 1H), 6.80-6.30 (m, 4H), 1.0 (q, 3H), 0.065 (s, 6H), 0.045 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][N:7]1[CH2:12][NH:11][C:10](=[S:13])[NH:9][CH2:8]1.[Br:17][CH:18]([C:23](=O)[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH2:19][C:20]([OH:22])=[O:21].N1C=CC(=S)NN=1>CO>[C:20]([CH2:19][C:18]1[S:13][C:10]2=[N:11][CH2:12][N:7]([CH2:6][C:5]3[CH:14]=[CH:15][CH:16]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:8][N:9]2[C:23]=1[C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)([OH:22])=[O:21].[BrH:17]
Reactant: COc1cccc(CN2CNC(=S)NC2)c1
Reactant: O=C(O)CC(Br)C(=O)c1ccc(Cl)cc1
Agent: S=c1ccnn[nH]1
Solvent: CO
Product: Br
Product: COc1cccc(CN2CN=C3SC(CC(=O)O)=C(c4ccc(Cl)cc4)N3C2)c1
Reaction time: 3 h
Yield: 296.6 %

Procedure:
5-(m-Methoxybenzyl)-3,4,5,6-tetrahydro-s-triazin-2(1H) thione (2.37 g, 0.01 mole) was partly dissolved in methanol (100 ml) at 45° C. and 3-bromo-3-(p-chlorobenzoyl) propionic acid (2.92 g, 0.01 mole) dissolved in the same solvent (50 ml) was added. The temperature was held at about 45° C. until all the triazinthione dissolved, and the mixture was then allowed to stand for 3 hours. The solvent was evaporated to give a pale yellow foam, which was triturated with isopropanol to give the title compound hydrobromide hemipropanolate (2.4 g, 44%) m.p. 123°-125° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[I:13]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[I:13][C:11]1[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[CH3:1]
Reactant: Cc1cc(=O)c2ccccc2s1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: Cc1sc2ccccc2c(=O)c1I
Temperature: 60 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
2-Methyl-4H-thiochromen-4-one (1.0 mmol, 176 mg), iodine (1.2 mmol, 305 mg) and ceric ammonium nitrate (1.1 mmol, 603 mg) were dissolved in acetonitrile (4.0 mL), and the solution was stirred under a nitrogen atmosphere at 60° C. for 4 hours. After the disappearance of the starting materials was confirmed by thin-layer chromatography, the reaction solution was poured into a solution of a 10% saturated aqueous sodium thiosulfate solution under ice-cooling to terminate the reaction. The organic substances were extracted with methylene chloride, the obtained organic layer was dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and the title compound (0.79 mmol, 238 mg) was obtained in a 79% yield.