Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28](O)=[O:29])=[CH:20][C:19]=3[CH:31]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[N:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[S:47][CH2:48][C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=1>C1COCC1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:53][C:52]4[CH:54]=[CH:55][C:49]([CH2:48][S:47][C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][N:41]=5)=[CH:50][CH:51]=4)=[O:29])=[CH:20][C:19]=3[CH:31]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(CSc2ccccn2)cc1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCC)cc1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4ccccn4)cc2)CCN3CCC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (1.0 g) was dissolved in THF (20 ml), DMF (2 droplets) was added to the solution, thionyl chloride (0.34 ml) was added to the solution, and the solution was stirred at room temperature for 1 hour. The solution was added dropwise to the solution of 4-[(2-pyridinylsulfanyl)methyl]aniline (0.56 g) and triethylamine (1.97 ml) in THF (20 ml) under ice-cooling at room temperature and the mixture was stirred for 2 hours. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(2-pyridinylsulfanyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 180) (0.56 g).
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]([C:7]1[S:8][C:9]([Br:13])=[CH:10][C:11]=1[Br:12])=[O:6])C.Cl>CC(C)=O>[Br:12][C:11]1[CH:10]=[C:9]([Br:13])[S:8][C:7]=1[C:5](=[O:6])[C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)C(=O)c1sc(Br)cc1Br
Agent: Cl
Solvent: CC(C)=O
Product: O=C(O)C(=O)c1sc(Br)cc1Br
Yield: 99.2 %

Procedure:
(3,5-Dibromothiophen-2-yl)-oxo-acetic acid ethyl ester (513 mg, 1.50 mmol) was dissolved in 25 ml acetone and treated with 15 ml 8 N HCl at reflux for a total of 4 hours. The reaction mixture was concentrated in vacuo, poured into 50 ml water, and extracted into 100 ml of dichloromethane. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield (3,5-dibromothiophen-2-yl)-oxo-acetic acid (467 mg, 99%). MS (M+H)+: 314.84; 1H NMR (300 MHz, DMSO-d6) δ7.64 (1H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:18][C:19](Br)=[CH:20][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.[CH2:24]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[CH:36])=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH3:27].C(NC(C)C)(C)C>CN(C)C=O.O1CCCC1.[Cu]I>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:18][C:19]([C:36]#[C:35][C:32]4[CH:33]=[CH:34][C:29]([O:28][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:30][CH:31]=4)=[CH:20][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: C#Cc1ccc(OCCCC)cc1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Br)o3)cc2)C1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCOc1ccc(C#Cc2ccc(C(=O)Nc3ccc(N4CCC(N(C)C)C4)cc3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolid in-1-yl)phenyl]amide (75 mg) was dissolved together with 1-butoxy-4-ethynylbenzene (35 mg) in N,N-dimethylformamide (1 ml) and, under argon, added dropwise to a suspension of Pd(tBu3P)2Cl2 (4 mg), copper (I) iodide (75 mg) and N,N-diisopropylamine (20 mg) in anhydrous tetrahydrofuran (3 ml). The mixture was stirred at room temperature for 8 hours. The reaction was worked up by filtration through a syringe filter and concentrated, and the crude product was purified by preparative HPLC. This resulted in the product with the molecular weight of 471.6 (C29H33N3O3); MS (ESI): 472 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][C:3]=1[N+:11]([O-])=O>CO.[Pd]>[NH2:11][C:3]1[CH:4]=[C:5]([B:8]([OH:10])[OH:9])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(B(O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(B(O)O)cc1N
Yield: 91 %

Procedure:
A mixture of 4-methyl-3-nitro-phenyl boronic acid (3.34 g, 18-45 mmol) and 10% Pd/C, (334 mg) in MeOH (30 ml) was hydrogenated (1 atm.) at 23° C. After 22 h the reaction mixture was filtered through celite and concentrated to give 3-amino-4-methyl phenyl boronic acid (2.53 g, 91%). 1H NMR (300 MHz, DMSO-d4) δ 7.21 (s, 1H), 7.08 (d, 1H, J=75 Hz), 6.92 (d, 1H, J=7.46 Hz), 4.81 (bs, 2H), 2.09 (s, 3H). MS (ESI) [M+H]/z Calc'd 152, found 152.
Reaction SMILES: C([O:8][C:9]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:34][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.C(Cl)(Cl)Cl>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)=[CH:34][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1cc(N2CCCCC2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(piperidin-1-yl)benzamido)-4-phenoxybenzoate (0.093 g) in ethyl acetate (1.5 mL) and methanol (1.5 mL), 10% palladium-carbon (0.047 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. Chloroform was added to the reaction mixture. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-70% hexane/ethyl acetate] to obtain 0.067 g of tert-butyl 2-(2-hydroxy-5-(piperidin-1-yl)benzamido)-4-phenoxybenzoate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:14]2[CH:15]=[CH:16][C:11]([C:10]([F:21])([F:20])[F:9])=[CH:12][CH:13]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Temperature: 80 °C

Procedure:
To a 500-mL, round-bottomed flask was added 4,6-dichloropyrimidine (14 g, 95 mmol, Aldrich), 4-(trifluoromethyl)phenylboronic acid (6.0 g, 32 mmol, Aldrich), acetonitrile (95 mL) and 1 M aq sodium carbonate (95 mL). The mixture was deoxygenated by sparging with N2 for 15 min. The catalyst, Pd(PPh3)4 (1.9 g, 1.6 mmol, Strem), was added and the yellow mixture was heated at 80° C. for 15 h. After cooling to 25° C., the solution was concentrated to remove the acetonitrile. The solution was diluted with aq NaHCO3 and extracted with CH2Cl2. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography with gradient from 1.5% to 10% solution of ethyl acetate in hexane afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 259 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C([O:15][CH2:16][C@H:17]1[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]1)(=O)C1C=CC=CC=1>O>[CH3:22][C:19]1([CH3:23])[O:18][C@@H:17]([CH2:16][OH:15])[CH2:21][O:20]1
Reactant: CC1(C)OC[C@H](COC(=O)c2ccccc2)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)OC[C@H](CO)O1
Temperature: 100 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
Then sodium carbonate (39.43 g, 0.372 mol) was added to a mixture of the crude (R)-4-benzoyloxymethyl-2,2-dimethyl-1,3-dioxolane (58.63 g, 0.248 mol) and water (130 ml resulting mixture was stirred for 8 hours at 100° C. After cooling the reaction mixture was extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and condensed in vacuo. The crude product was distilled to give 21.96 g of (S)-2,2-dimethyl-1,3-dioxolane-4-methanol (yield 67%, b.p. 65° C. at 3 mmHg, optical purity 97.3 % e.e., specific rotation [α]D20 +10.84°(c=1,MeOH)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:9](=O)[CH2:10][CH:11](O)[C:12](OCC)=[O:13])=[CH:4][CH:3]=1.O.[NH2:27][NH2:28]>C(O)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:9]2[CH:10]=[CH:11][C:12](=[O:13])[NH:27][N:28]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)C(O)CC(=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CCCCO
Solvent: O
Product: O=c1ccc(C(c2ccc(F)cc2)c2ccc(F)cc2)n[nH]1
Temperature: 130 °C
Reaction time: 12 h
Yield: 50.5 %

Procedure:
To a solution of ethyl 5,5-bis(4-fluorophenyl)-2-hydroxy-4-oxopentanoate (796 mg) in 1-butanol (4 mL) was added hydrazine hydrate (137 mg) at ambient temperature. The reaction mixture was stirred at 130° C. for 12 hours. After cooling to ambient temperature, the reaction mixture was evaporated in vacuo. The resulting residue was stirred at 160° C. for 3 hours. After cooling, the reaction mixture was purified by silica gel column chromatography (EtOAc:n-hexane=2:1) and crystallized from solvent (EtOAc:n-hexane=1:2) to give 6-[bis(4-fluorophenyl)methyl]pyridazin-3(2H)-one (344 mg) as a pale brown solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19]([NH:21][C:22]2[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=2)=[O:20])=[CH:5][CH:4]=1.[OH-].[Na+]>CCO>[F:33][C:2]([F:1])([F:34])[C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19]([NH:21][C:22]2[CH:32]=[CH:31][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[O:20])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(NC(=O)N2CCc3ccccc3[C@H]2c2ccc(C(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(NC(=O)N2CCc3ccccc3[C@H]2c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-ethyl 4-(1-(4-(trifluoromethyl)-phenyl)-1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoate (0.210 g, 0.4 mmol) and NaOH (0.4 mL, 2 mmol) in EtOH (5 mL) was stirred at RT in 24 h. The mixture was concentrated, taken up in H2O and neutralized with 10% HCl. The white solid was collected by filtration and dried. MS (ESI, positive ion) m/z: 441 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:20]([CH2:23]Br)=[N:21][S:22][C:10]=2[C:9]=1[O:25]C(=O)C(C)(C)C)=[O:7])[CH2:2][CH2:3][CH3:4].[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33]1.[H-].[Na+].O>CN(C=O)C>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11]2[C:20]([CH2:23][N:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33]3)=[N:21][S:22][C:10]=2[C:9]=1[OH:25])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCCCOC(=O)c1nc(-c2ccccc2)c2c(CBr)nsc2c1OC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)c1nc(-c2ccccc2)c2c(Cn3ccc4ccccc43)nsc2c1O
Temperature: 25 °C
Yield: 14.1 %

Procedure:
To a solution of 3-bromomethyl-7-(2,2-dimethyl-propionyloxy)-4-phenyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester (86.1 mg) in DMF (0.85 mL) at 0° C. was added indole (39.9 mg) and 60% NaH (13.6 mg). The reaction mixture was allowed to warm up to r.t. and stirred for 2 h before water (20 mL) was added. The mixture was extracted with EtOAc (4×20 mL). The combined organic phases were washed with brine and water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel. Eluting with 1-50% EtOAc/hexanes gave the title compound (11 mg) as a white solid: MS (m/z) 458.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[C:17]([CH3:23])=[N:18][O:19][C:20]=2[CH2:21][OH:22])=[O:9])=[CH:4][CH:3]=1.C(Cl)Cl.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>O>[CH3:34][S:35]([O:22][CH2:21][C:20]1[O:19][N:18]=[C:17]([CH3:23])[C:16]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8](=[O:9])[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1noc(CO)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(COS(C)(=O)=O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a round bottomed flask was added crude (4-chlorophenyl)(2-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)phenyl)methanone (24.9 mg, 0.076 mmol), DCM (2 mL), and Et3N (21.18 μl, 0.152 mmol). This solution was cooled to 0° C. before addition of MsCl (7.10 μl, 0.091 mmol) and the reaction stirred at 0° C. for 30 min before diluting with water and extracting with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated to afford crude (4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methyl methanesulfonate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[CH2:27][C:26]([CH3:29])([CH3:28])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:30]([O:32]CC)=[O:31])[CH:24]=2)[NH:19]1)(=[O:10])=[O:9].O.[OH-].[Li+].[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[CH2:27][C:26]([CH3:28])([CH3:29])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:30]([OH:32])=[O:31])[CH:24]=2)[NH:19]1)(=[O:10])=[O:9]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1NS(=O)(=O)c1ccccc1F)N2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccccc2F)Nc2ccc(C(=O)O)cc21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 2-(2-(2-fluorophenylsulfonamido)phenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (crude 0.62 mmol) in ethanol was added a solution of lithium hydroxide monohydrate (129 mg, 3.08 mmol) and sodium hydroxide (50 mg, 1.23 mmol) in water (1.5 mL) at room temperature. The reaction mixture was stirred at 85° C. overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water, adjusted pH=3˜4 by 1M aqueous hydrochloric acid, extracted with ethyl acetate. The combined organic layer was washed by brine, dried over anhydrous Sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give 2-[2-(2-fluoro-benzenesulfonylamino)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid LC/MS m/e obsd. (ESI+) [(M+H)+] 455.20.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([NH:23][C:24]2[CH:34]=[CH:33][CH:32]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:25]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(Br)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)c1cccc(NC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2ccc(Br)cc2)c1

Procedure:
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-3-phenylpropanoic acid (2 g) and ethyl 3-aminobenzoate were condensed in dichloromethane (100 ml) in the presence of N,N'-dicyclohexylcarbodiimide (1.29 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-phenylpropanamide (812 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]3[O:20][CH2:21][O:22][C:15]=13)=[CH:10][C:9]([O:23][CH3:24])=[C:8]([O:25][CH2:26][C@@H:27]1[O:29][CH2:28]1)[CH:7]=2)#[N:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(O)CC>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]3[O:20][CH2:21][O:22][C:15]=13)=[CH:10][C:9]([O:23][CH3:24])=[C:8]([O:25][CH2:26][C@H:27]([OH:29])[CH2:28][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[CH:7]=2)#[N:2]
Reactant: COc1cc2c(Nc3cccc4c3OCO4)c(C#N)cnc2cc1OC[C@H]1CO1
Reactant: C1COCCN1
Solvent: CCCO
Product: COc1cc2c(Nc3cccc4c3OCO4)c(C#N)cnc2cc1OC[C@H](O)CN1CCOCC1
Temperature: 80 °C
Yield: 32.7 %

Procedure:
A mixture of 3-cyano-7-[(2R)-2,3-epoxypropoxy]-6-methoxy-4-(2,3-methylenedioxyanilino)quinoline (0.1 g), morpholine (0.11 g) and propanol (5 ml) was stirred and heated to 80° C. for 3 hours. The resultant mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. The material so obtained was triturated under diethyl ether to give the title compound (0.04 g); NMR Spectrum: (DMSOd6) 2.35-2.52 (m, 6H), 3.56 (m, 4H), 3.93 (s, 3H), 4.04.1 (m, 2H), 4.17 (m, 1H), 4.9 (d, 1H), 5.98 (s, 2), 6.9-6.92 (m, 3H), 7.33 (s, 1H), 7.86 (s, 1H), 8.4 (s, 1H), 9.48 (br s, 1H); Mass Spectrum: M−H− 477.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11]>O>[OH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11]
Reactant: Oc1ccc2ccccc2c1
Solvent: O
Product: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Temperature: 65 °C

Procedure:
Add 2 g 2-naphthol, 11.4 g FeCl3.6H2O and 100 ml water into a 200 ml beaker and agitate them at 65° C. by water bath; conduct TLC (thin-layer chromatography) track and maintain the reaction for 3 h; filter the solution to get solid 2,2′-dihydroxyl-1,1′-binaphthyl; scrub 2,2′-dihydroxyl-1,1′-binaphthyl with 50 ml water and add the cleaning solution into the filtrate; add 7.5 ml 30% H2O2 dropwise slowly into the filtrate while agitation and agitate the solution continuously for 10 min; add 2 g 2-naphthol and maintain the reaction at 65° C. while agitation; conduct TLC track until the reaction finishes; filter the solution to obtain 2,2′-dihydroxyl-1,1′-binaphthyl. Repeat these steps and obtain results as shown in Table 6. The HPLC analysis results of the reaction product obtained in the 11th time of cycle are: the conversion of 2-naphthol ≧98%, and the yield of 2,2′-dihydroxyl-1,1′-binaphthyl ≦99%.
Reaction SMILES: O.O.O.O.O.[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[O-:21].[Na+].[C:26]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1)#[N:27].O.CCOCC>CN(C=O)C>[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[O:21][CH2:32][C:31]1[CH:34]=[CH:35][C:28]([C:26]#[N:27])=[CH:29][CH:30]=1
Reactant: [O-]c1cccc(OCc2ccc3ccccc3n2)c1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#Cc1ccc(COc2cccc(OCc3ccc4ccccc4n3)c2)cc1
Temperature: 25 °C

Procedure:
A solution of 7.24 g (19.92 mmol) of sodium 3-(2quinolinylmethyloxy)phenoxide pentahydrate and 4.68 g (23.90 mmol) of p-cyanobenzyl bromide in 34 ml of dry DMF is stirred at 75° C. under nitrogen for 2 days. The reaction mixture is cooled to room temperature, then poured into 400 ml of 3:1 H2O/Et2O, shaken; and the phases separated. The aqueous layer is extracted and washed with 1:1 brine/H2O and brine. The ether solution is dried over 1:1 Na2SO4MgSO4, filtered and concentrated. The crude product is recrystallized from 70% EtOAc/hexane to obtain 4-(3-(2quinolinylmethyloxy)phenoxy-methyl)benzonitrile. (M.P. 112.5° C.)
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[C:5]2[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[S:9][C:6]=2[NH:7][CH:8]=1)#[N:2].P(Cl)(Cl)([Cl:22])=O>CN(C)C=O>[CH3:18][O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:10]1[S:9][C:6]2=[N:7][CH:8]=[C:3]([C:1]#[N:2])[C:4]([Cl:22])=[C:5]2[CH:11]=1
Reactant: COC(=O)CCCc1cc2c(=O)c(C#N)c[nH]c2s1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)CCCc1cc2c(Cl)c(C#N)cnc2s1

Procedure:
A mixture of methyl 4-(5-cyano-4-oxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl)butanoate (136 mg) and 2 drops of N,N-dimethylformamide in 5 mL of phosphorous oxychloride is heated at reflux for 10 minutes and concentrated. To the residue is added dichloromethane and the solution is washed with 1% aqueous sodium bicarbonate solution. The organic layer is dried and concentrated. The residue is purified by flash column chromatography eluting with dichloromethane to provide 126 mg of 4-(4-chloro-5-cyano-thieno[2,3-b]pyridin-2-yl)-butyric acid methyl ester as a tan solid, mp 55–57° C.; 1H NMR (DMSO-d6) δ 1.98 (quintet, J=7 Hz, 2H), 2.42 (t, J=7 Hz, 2H), 3.04 (t, J=7 Hz, 2H), 3.59 (s, 3H), 7.42 (s, 1H), 8.94 (s, 1H); MS 295.1 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=C[C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:23])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=2)=[O:13])=[CH:4][CH:3]=1.[Br:24]C1C=CC(CCNC)=CC=1.N(C1C=C(C=CC=1)C#N)=C=O>>[Br:24][C:3]1[CH:2]=[CH:7][C:8]([CH2:9][CH2:10][N:11]([CH3:23])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=2)=[O:13])=[CH:5][CH:4]=1
Reactant: CNCCc1ccc(Br)cc1
Reactant: CN(CCCc1ccc(Br)cc1)C(=O)Nc1cccc(C#N)c1
Agent: N#Cc1cccc(N=C=O)c1
Product: CN(CCc1ccc(Br)cc1)C(=O)Nc1cccc(C#N)c1
Yield: 81 %

Procedure:
Using a procedure analogous to that used to prepare 22C, 23B (300 mg, 1.4 mmol) was reacted with 3-isocyanatobenzonitrile to yield 23C (406 g, 81%) as a clear oil. MS (ESI) m/z 358.31/360.29 (M+H)+.