Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)C1C=C[C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1.C(Cl)(=O)C(Cl)=[O:35].CNC(N)=O.N1C=CC=CC=1>ClC1C=CC=CC=1.CN(C=O)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:15]2[C:16](=[O:21])[C:17]([CH3:20])=[C:18]([CH3:19])[CH:14]2[S:13][CH2:12][C:11]([NH:10][C:7]([NH:6][CH3:5])=[O:35])=[O:31])=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Reactant: O=C(Cl)C(=O)Cl
Agent: CNC(N)=O
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Solvent: c1ccncc1
Product: CNC(=O)NC(=O)CSC1C(C)=C(C)C(=O)N1Cc1ccc(OC)cc1
Reaction time: 1 h
Yield: 55 %

Procedure:
The product from Example 1, Part C (200 mg, 0.6 mmol) was dissolved in 3 mL chlorobenzene and 2 drops DMF, then cooled to 0° C. Oxalyl chloride (0.72 mL, 2 M in CH2Cl2) was added and the mixture was stirred for 1 h while the temperature rose to room temperature. Methyl urea (133 mg, 1.2 mmol) was added and the mixture was stirred at 70° C. for 10 min. pyridine (0.12 mL, 1.2 mmol) was added and the mixture was stirred at 70° C. for 0.5 h. The reaction solvent was evaporated and the product was purified by silica gel chromatography. Recrystallization from CH2Cl2/ether provided the title compound as a white solid (130 mg, 55%). 1H NMR (400 MHz, CDCl3) δ 9.98 (br s, 1H), 8.21 (br s, 1H), 7.20 (d, J=8 Hz, 2H), 6.83 (d, J=8 Hz, 2H), 50.8 (d, J=15 Hz, 1H), 4.57 (s, 1H), 4.14 (d, J=15 Hz, 1H), 3.77 (s, 3H), 2.89 (m, 5H), 1.95 (s, 3H), 1.84 (s, 3H). MS: m/z (MH+) 378.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[CH2:8]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[CH3:7][C:4]1[S:5][CH:6]=[C:2]([C:11]#[C:10][CH2:9][CH2:8][C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[N:3]=1
Reactant: Cc1nc(Br)cs1
Reactant: C#CCCc1nc2ccccc2o1
Product: Cc1nc(C#CCCc2nc3ccccc3o2)cs1
Reaction time: 24 h
Yield: 2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 4-bromo-2-methylthiazole (47 mg, 2.7 mmol) and 2-(but-3-ynyl)benzo[d]oxazole (454 mg, 2.65 mmol, Example 8(A)). The reaction mixture was stirred for one day under reflux. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) and trituration with pentane to yield 14 mg (52 μmol, 2%) of 2-(4-(2-methylthiazol-4-yl)but-3-ynyl)benzo[d]oxazole as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[CH:14]1(N)[CH2:18][CH2:17][CH2:16][CH2:15]1>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: NC1CCCC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)cc1NC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A mixture of 20 g of 4-chloro-1,2-dinitrobenzene and 20 g of cyclopentylamine in 50 ml of 95° EtOH is stirred overnight at RT. The precipitate formed is filtered off and washed with 95° EtOH to give 14 g of the expected product. M.p.=75° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)=[N:6][CH:7]=1.CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]2)=[N:6][CH:7]=1
Reactant: O[C@@H]1CCN(c2ccc(Br)cn2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1CCN(c2ccc(Br)cn2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
Dissolve (R)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-ol (6.8 g, 27.64 mmol), (prepare according to Stenkamp, D. et al WO 2005103032) in CH2Cl2 (50 mL), and cool to 0° C. Treat the mixture with Et3N (5.0 mL, 35.93 mmol), followed by MsCl (2.4 mL, 30.4 mmol). Stir the mixture at 0° C. for 30 min and then at RT for 1 h. Dilute with CH2Cl2 (100 mL), and wash with H2O (100 mL), and brine (100 mL). Dry with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 50-70% EtOAc/hexane, to give 8.86 g (97%) of the title compound. MS/ES m/z (79Br) 321.0 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][N:15]=[C:16]([C:20](=[O:22])[CH3:21])[C:17](=[O:19])[CH3:18])([CH3:6])([CH3:5])[CH3:4].[CH2:23]([O:30][CH2:31][C:32](Cl)=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C1COCC1>[CH2:23]([O:30][CH2:31][C:32](=[O:33])[CH2:21][C:20](=[O:22])[C:16](=[N:15][NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][C:3]([CH3:6])([CH3:4])[CH3:5])[C:17](=[O:19])[CH3:18])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CC(=O)C(=NNc1ccccc1OC(C)(C)C)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C(=NNc1ccccc1OC(C)(C)C)C(=O)CC(=O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
NaH (4.28 g) was suspended in THF (30 mL), and a solution of 3-[(2-tert-butoxyphenyl)hydrazono]pentane-2,4-dione (7.47 g) in THF (100 mL) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 40 min, a solution of (benzyloxy)acetylchloride (5.55 mL) in THF (20 mL) was added at 0° C., and the mixture was stirred at 0° C. for 5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (5.58 g).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[F:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])[NH2:20].C1(OC2C=CC=CC=2)C=CC=CC=1>>[F:24][C:23]1[CH:22]=[C:21]2[C:19](=[CH:18][C:17]=1[F:16])[NH:20][CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]2=[O:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(F)c(F)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cc(F)c(F)cc2c1=O
Temperature: 130 °C
Reaction time: 17 h

Procedure:
Diethyl ethoxymethylenemalonate was added to 3,4-difluoroaniline at ambient temperature and the mixture was stirred at 130° C. for 17 hours. After diphenyl ether was additionally added to the reaction mixture, stirring was done at 260° C. for one hour. A solid obtained by leaving the reaction mixture to stand for cooling to ambient temperature was filtered, to obtain ethyl 6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.
Reaction SMILES: I[CH3:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1>C(Cl)(Cl)Cl.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH2:21][CH2:20][N:19]([CH3:2])[CH2:18][CH:17]=3)=[N:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: CI
Reactant: Clc1ccc(-c2cnc(-c3ccncc3)nc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN1CC=C(c2ncc(-c3ccc(Cl)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 312 h
Yield: 94 %

Procedure:
Iodomethane (0.65 ml) was added to a solution of 5-(4-chlorophenyl)-2-pyridin-4-ylpyrimidine (0.311 g) in a mixture of chloroform (18 ml) and methanol (2 ml), and the reaction stirred at room temperature, in a stoppered flask, for 13 days. The solvents were then removed under reduced pressure, and the residue was re-suspended in a mixture of methanol (10 ml) and water (2 ml), cooled in an ice-bath and treated portionwise with sodium borohydride (0.088 g) (CAUTION-vigorous effervescence). The reaction was stirred in the ice-bath for 1.5 h, at room temperature for a further 1.5 h, then treated with saturated ammonium chloride (30 ml) followed by water (20 ml), and the resultant suspension was extracted with ethyl acetate (50 ml, then 2×25 ml). The combined organic extracts were washed with water (3×25 ml), saturated brine (20 ml), dried (Na2SO4) and evaporated under reduced pressure to furnish the title compound as a cream solid (0.310 g, 94%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[NH:8][N:7]=1.[C:14]([S:17][CH2:18][CH2:19][C:20](Cl)=[O:21])(=[O:16])[CH3:15]>O.C(=O)([O-])[O-].[Na+].[Na+]>[C:14]([S:17][CH2:18][CH2:19][C:20]([N:8]1[CH:9]([C:11]([OH:13])=[O:12])[CH2:10][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:7]1)=[O:21])(=[O:16])[CH3:15]
Reactant: O=C(O)C1CC(c2ccco2)=NN1
Reactant: CC(=O)SCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)SCCC(=O)N1N=C(c2ccco2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
(±)-3-(2-Furanyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid (4.5 g) is dissolved in 200 cc of water containing 1.38 g of sodium carbonate (pH 9.4) at 10° C. 3-(Acetylthio)propionyl chloride (4.15 g) and 20% sodium carbonate solution are added simultaneously maintaining the pH between 8.5 and 9.4 and the temperature at 10° C. The final reaction mixture (pH 9.7) is stirred at room temperature for 2 hours and extracted with ethyl acetate (discarded) and the aqueous layer made strongly acid with 20% HCl. A precipitate forms which is extracted into ethyl acetate immediately. The solvent is dried and removed to yield 4.5 g of crystalline material which cannot be recrystallized.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Cl:12][C:3]1[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(NS(C)(=O)=O)c1Cl

Procedure:
To a solution of methyl 3-amino-2-chlorobenzoate (517 mg, 2.79 mmol) and pyridine (0.25 mL, 3.06 mmol) in 8 mL CH2Cl2 was added methanesulfonylchloride (0.24 mL, 3.06 mmol). After washing with 1M HCl, methyl 2-chloro-3-[(methylsulfonyl)amino]benzoate was isolated as a solid in quantitative yield. 1H NMR (400 MHz, CDCl3), δ 7.77 (dd, 1H, J=8.2, 1.6 Hz), 7.61 (dd, 1H, J=7.9, 1.6 Hz), 7.33 (t, 1H, J=7.9 Hz), 7.16 (s, 1H), 3.91 (s, 3H), 2.99 (5, 3H); ESI-MS 262 (M−H). Methyl 2-chloro-3-[(methylsulfonyl)amino]benzoate was hydrolyzed using aqueous NaOH to provide 2-chloro-3-[(methylsulfonyl)amino]benzoic acid as a solid, which was used without further purification. ESI-MS 248 (M−H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH:12]=[C:13]([OH:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)C>ClCCl>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH2:12][C:13](=[O:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OC1=Cc2ccccc2C=Cc2c(Cl)cccc21
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1Cc2ccccc2C=Cc2c(Cl)cccc21
Yield: 90 %

Procedure:
To a solution of 1-chloro-5-hydroxy-dibenzo[a,e]cyclooctene (1.5 g) in dry dichloromethane (60 ml) was added pyridinium dichromate (5.0 g) and crushed 4A molecular sieves (2.5 g). After stirring at room temperature for 3h. diethyl ether (150 ml) was added and the reaction mixture was filtered through a plug of celite. The solvent was removed in vacuo and the residue purified by chromatography on flash silica with 10% ethyl acetate in hexane as eluent to give the title compound (1.35 g) m.p. 151°-153° C. δ(360 MHz, CDCl3) 4.09 (2H, s, CH2 --C=O). 7.06 (1H, d, J=11.9 Hz, ArCHA =CHBAr), 7.18 (1H, d, J=11.9 Hz, ArCHA =CHBAr), 7.20-7.30 (5H, m, aromatics), 7.50 (1H, dd, J=7.8 and 1.4 Hz, CH=CCl) and 7.86 (1H, dd, J=8.0 and 1.3 Hz, CH=C--C=O). m/e 254 (M+). i.r. (νmax, nujol) 1670 cm-1 (CO). Found: C, 75.1; H, 4.6. C16H11C10 requires: C, 75.4; H, 4.4%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([F:50])[CH:39]=2)/[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][N:53]=1>C(Cl)Cl>[Br:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:35](=[O:37])/[C:34](/[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([F:50])[CH:39]=2)=[CH:33]/[CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[N:53][CH:54]=1
Reactant: Nc1ccc(Br)cn1
Reactant: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A solution of triphenylphosphine (262 mg, 1 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (178 mg, 1 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with (E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid (158 mg, 0.5 mmol). The reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-amino-5-bromopyridine (260 mg, 1.5 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (20 mL) and water (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×15 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/1 hexanes/ethyl acetate) afforded (E)-N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylamide (66 mg, 28%) as an amorphous white solid: EI-HRMS m/e calcd for C21H20BrFN6OS (M+) 470.0866, found 470.0864.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1([C:29](Cl)=[O:30])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:29]([C:16]2([CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:22]3[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:30])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1

Procedure:
Prepared analogously to Example 1 from 4-methoxybenzylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([S:39]([C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)(=[O:41])=[O:40])[CH2:17][CH2:18]1)=[N:7]2
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(S(=O)(=O)c3cccnc3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure M using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50 mg, 0.11 mmol) and pyridine-3-sulfonyl chloride to give 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(4-(pyridin-3-ylsulfonyl)piperazin-1-yl)quinolin-4-amine. 1H NMR (DMSO-d6) δ ppm 1.98 (d, J=6.0 Hz, 3H), 3.04 (t, J=4.8 Hz, 4H), 3.18 (br s, 4H), 3.33-3.37 (m, 4H), 3.69 (t, J=4.4 Hz, 4H), 6.48 (s, 1H), 7.13-7.19 (m, 1H), 7.25-7.28 (m, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.70-7.77 (m, 1H), 7.77 (d, J=2.0 Hz, 1H,), 8.19-8.22 (m, 1H), 8.34 (s, 1H), 8.90-8.91 (m, 1H), 8.95 (d, J=2.4 Hz, 1H). Mass Spectrum (ESI) m/e=582.4 (M+1).
Reaction SMILES: O.[N:2]#[C:3]Br.[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl>[C:5]1([O:11][C:3]#[N:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CBr
Reactant: Oc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: N#COc1ccccc1
Reaction time: 0.08 h
Yield: 81.9 %

Procedure:
The title compound was prepared by a modification of the procedure described in Organic Syntheses, 61, 35 (1983). A 3-necked, 2 L R.B. flask, equipped with a 500 mL pressure equalized dropping funnel, a mechanical stirrer and a thermometer, was charged with water and cooled in an ice-salt bath. Cyanogen bromide (189.1 g, 1.78 mol) was added and the mixture was stirred for 5 min. Phenol (160.0 g., 1.7 mol) in carbon tetrachloride (535 mL) was added in one portion. The mixture was stirred vigorously while triethylamine (236.9 mL, 172.0 g, 1.7 mol) was added dropwise at a rate such that the reaction temperature did not exceed 5° C. (total addition time=45 min.). The mixture was stirred for a further 15 min. then transferred to a 2 L separatory funnel. The organic layer was separated and the aqueous layer was extracted with carbon tetrachloride (2×90 mL). The combined organic layers were washed with water (3×90 mL) then dried by stirring with phosphorus pentoxide (10 g) for 15 min. The mixture was filtered and the solvent was evaporated under reduced pressure (water aspirator) at 20° C. to give a yellow oil. Polyphosphate ester [Y. Kanaoka, et al., Chem. Pharm. Bull., 13, 1065-1072 (1965)](0.2 mL) was added and the mixture was distilled under reduced pressure through a 15 cm Vigreux column to give phenyl cyanate (165.8 g, 82%) as a colorless oil, b.p. 79-82° C. (16 mmHg). The product was stored under nitrogen at -10° C. (freezes).
Reaction SMILES: O[CH:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][C:4]1[C:9]([CH2:10][CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.S(Cl)([Cl:30])=O>>[Cl:30][CH:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][C:4]1[C:9]([CH2:10][CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(CCc2cccnc2CC(O)c2ccccc2)cc1
Product: COC(=O)c1ccc(CCc2cccnc2CC(Cl)c2ccccc2)cc1
Reaction time: 1 h

Procedure:
Methyl 4-[2-(2-(2-hydroxy-2-(phenyl)ethyl)-3-pyridyl)ethyl]benzoate (0.47 g), 1.29 mmol) was cooled in an ice bath. Thionyl chloride (15 ml) was added and the reaction held at 0° C. for 1 hour. The reaction mixture was evaporated and azeotroped with toluene to give methyl 4-[2-(2-(2-chloro-2-(phenyl)ethyl)-3-pyridyl)ethyl]benzoate (0.549 g) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]2[C:5]([C:6](=[O:24])[CH:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[O:9]2)=[CH:4][CH:3]=1.[H][H].[ClH:27]>CO.[Pd]>[ClH:27].[NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6](=[O:24])[CH:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([N:21]([CH3:22])[CH3:23])=[CH:17][CH:16]=3)[O:9]2)=[CH:4][CH:3]=1
Reactant: CN(C)c1ccc(-c2cc(=O)c3ccc(N)c([N+](=O)[O-])c3o2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)c1ccc(-c2cc(=O)c3ccc(N)c(N)c3o2)cc1
Yield: 88 %

Procedure:
A solution of 7-amino-2-(4-(dimethylamino)phenyl)-8-nitro-4H-chromen-4-one (4, 900 mg, 2.77 mmol) and 10% Pd/C (450 mg) in methanol (9 mL) and concentrated hydrochloride (aq., 9 mL) was stirred at the atmosphere of hydrogen overnight. The solid was filtered and the filtrate was evaporated in reduced pressure to afford 7,8-diamino-2-(4-(dimethylamino)phenyl)-4H-chromen-4-one hydrochloride (5) as a light yellow solid (810 mg, yield: 88%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[O:10][CH:11]=[CH:12][C:5]=2[CH2:4]1)[CH3:2].[C:13]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](F)=[CH:17][CH:16]=1)#[N:14]>>[C:13]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([O:9][CH:7]2[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[CH:12]=[CH:11][O:10][C:6]2=3)=[CH:17][CH:16]=1)#[N:14]
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: CCN1Cc2ccoc2C(O)C1
Product: CCN1Cc2ccoc2C(Oc2ccc(C#N)c3ccccc23)C1

Procedure:
The same method as in Example 1 was conducted using 5-ethyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridin-7-ol (Reference Example 34) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-cyano-1-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([CH3:13])[C:6]=2[C:14]=1[O:15][CH3:16].C(Cl)(=O)C(Cl)=O.[CH3:23][O:24][C:25](=[O:47])[C@@H:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH:27]([CH3:29])[CH3:28].N1C=CC=CC=1>ClCCl>[CH3:23][O:24][C:25](=[O:47])[C@@H:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:41]=[CH:42][C:43]([NH:46][C:10]([C:8]3[O:9][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[C:14]([O:15][CH3:16])[C:6]=4[C:7]=3[CH3:13])=[O:12])=[CH:44][CH:45]=2)=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH:27]([CH3:29])[CH3:28]
Reactant: COc1c(Cl)ccc2oc(C(=O)O)c(C)c12
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4ccc(Cl)c(OC)c4c3C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To 80 mg (0.33 mmol) of 5-chloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 2 mL of oxalyl chloride and the mixture refluxed for 2 h, then stirred room temperature overnight. The excess oxalyl chloride was removed under vacuum. The residue was dissolved in 2 mL of dichloromethane and was added to a mixture of 181 mg (0.5 mmol) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester and 1 mL of pyridine in an ice/water bath. The mixture was stirred at 0° C. overnight. The reaction mixture was diluted with dichloromethane and was washed with 2N HCl, and water. Removal of the solvent in vacuo gave the crude product which was purified by column chromatography to give 168 mg (86% yield) of (S)-2-{4′-[(5-chloro-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester as a white solid.