Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[C:18]1[N:19]([CH3:34])[C:20]2[C:25]([N:26]=1)=[C:24]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[N:23]=[C:22]([Cl:33])[N:21]=2>CN(C=O)C.CCOC(C)=O>[Cl:33][C:22]1[N:21]=[C:20]2[C:25]([N:26]=[C:18]([O:16][CH:13]3[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11][CH2:12]3)[N:19]2[CH3:34])=[C:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:23]=1
Reactant: Cn1c(Br)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(OC2CCN(C(=O)OC(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of sodium hydride (0.327 g, 8.18 mmol) in DMF (31 mL) at 0° C. was added 1-tert-Butoxycarbonyl-4-hydroxypiperidine (1.266 g, 6.29 mmol). After 10 min, 4-(8-bromo-2-chloro-9-methyl-9H-purin-6-yl)morpholine (2.09 g, 6.29 mmol) was added. The mixture was stirred at rt for 3 h. Diluted with EtOAc, the mixture was washed with ½ brine (2×), brine, and dried (Na2SO4). The crude (3.075 g) was used directly for further transformations. LCMS: M+H+=453.4.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[F:27][C:28]([F:40])([F:39])[O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][C:2]1[N:3]([C:33]2[CH:32]=[CH:31][C:30]([O:29][C:28]([F:27])([F:39])[F:40])=[CH:35][CH:34]=2)[C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCc1nc(C)n(-c2ccc(OC(F)(F)F)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), [4-(trifluoromethoxy)phenyl]boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylene chloride (10 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.12 g, 76%).
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7](=[N:28][O:29][CH3:30])[CH2:8][O:9][N:10]=[C:11]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:5])C.[OH-].[Na+].Cl>CO>[C:4]([CH2:6][C:7](=[N:28][O:29][CH3:30])[CH2:8][O:9][N:10]=[C:11]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CC(CON=C(c1ccc(OC)cc1)c1ccc(OC)cc1)=NOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON=C(CON=C(c1ccc(OC)cc1)c1ccc(OC)cc1)CC(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.5 %

Procedure:
4.14 g of the 4,4'-dimethoxybenzophenone O-(3-ethoxycarbonyl-2-methoxyiminopropyl)oxime as obtained in Example 30 was dissolved in 20 ml of methanol and 3 ml of a 5N aqueous solution of caustic soda was added thereto. The obtained mixture was stirred at room temperature for five hours. After the completion of the reaction, the reaction mixture was acidified with diluted hydrochloric acid and extracted with ethyl acetate. Thus 3.8 g of the title compound was obtained in the form of a colorless oily product.
Reaction SMILES: [C:1]([O:14][CH3:15])(=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH3:11][O:10][C:9]1[CH:12]=[C:2]([CH:3]=[C:4]([O:5][CH3:6])[C:7]=1[O:8][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:1]([O:14][CH3:15])=[O:13]
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1cc(OC)c(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)c1cc(OC)c(OCc2ccccc2)c(OC)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
A mixture of 21.2 g. of methyl syringate, 15 g. of potassium carbonate, 1 g. of sodium iodide, 70 ml. of 95% ethanol (5% methanol), and 14 g. of benzyl chloride was heated at reflux with stirring for 4 hours. The alcohol was stripped off, ice water added, and the mixture extracted with ether. The ether exxtract was washed with water and the ether stripped off. Benzene was added and stripped to remove traces of water. The residual oil was dissolved in isopropanol, charcoal added, and the mixture filtered. Hexane was added and the solution cooled. A total of 19 g. (63% yield) of methyl 3,5-dimethoxy-4-benzyloxybenzoate, m.p. 62°-65° C., was obtained.
Reaction SMILES: C(N(CC)C(Cl)=O)C.[CH2:9]([N:11]([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:12][CH3:13])[CH3:10].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:40][CH3:41])=[C:35]([O:38][CH3:39])[CH:36]=2)[N:31]=[CH:30][CH:29]=1)[NH2:23].C1(C)C=CC=CC=1>C(O)C>[CH2:9]([N:11]([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:12][CH3:13])[CH3:10].[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:17]([NH:16][C:14]([N:11]([CH2:12][CH3:13])[CH2:9][CH3:10])=[O:15])=[S:18])[CH:24]=[CH:25][C:26]=1[O:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:40][CH3:41])=[C:35]([O:38][CH3:39])[CH:36]=2)[N:31]=[CH:30][CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: CCN(CC)C(=O)Cl
Agent: CCN(CC)C(=O)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN(CC)C(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
(Diethylamino)methanoyl isothiocyanate was prepared using commercially available N,N-diethylcarbamic chloride (80 mg) as a starting compound according to the description of the literature. (Diethylamino)methanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were 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 (52 mg, yield 38%).
Reaction SMILES: [OH-].[Na+].CO.[F:5][C:6]1[CH:30]=[CH:29][C:9]([NH:10][C:11]2[CH:20]=[C:19]([CH2:21][S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:12]=2[C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=1>O1CCCC1>[F:5][C:6]1[CH:30]=[CH:29][C:9]([NH:10][C:11]2[CH:20]=[C:19]([CH2:21][S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:12]=2[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(CSc2ccccc2)cc1Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CSc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 86.6 %

Procedure:
2.0 mol/L Sodium hydroxide aqueous solution 2.0 mL was added to a mixed solution of methanol 2.4 mL and tetrahydrofuran 2.4 mL of methyl 2-(4-fluoroanilino)-4-((phenylthio)methyl)benzoate 0.48 g, and it was stirred at room temperature for 17 hours. The solvent was removed under reduced pressure, ethyl acetate and water were added to it, and it was adjusted to pH4.0 with 1.0 mol/L hydrochloric acid. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue, and solid matter was filtrated to give 2-(4-fluoroanilino)-4-((phenylthio)methyl)benzoic acid 0.40 g of pale yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH3:30][O:31][CH2:32][CH2:33][NH:34][CH3:35]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:34]([CH2:33][CH2:32][O:31][CH3:30])[CH3:35])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: CNCCOC
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Product: COCCN(C)CCOc1n[nH]c2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(Cl)c3)c12
Yield: 52 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 16) and (2-methoxyethyl)methylamine to give the title compound in 52% yield; NMR Spectrum: 2.30 (s, 3H), 2.45 (s, 3H), 2.62 (t, 2H), 2.86 (t, 2H), 3.17 (s, 3H), 3.41 (t, 2H), 4.41 (t, 2H), 7.19 (d, 1H), 7.26 (br s, 2H), 7.72 (d, 1H), 8.14 (s, 1H), 8.21 (s, 1H), 8.36 (s, 1H), 8.62 (br s, 1H); Mass Spectrum: 484 (MH+).
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[NH2:7][C:8]1[C:13]([C:14]2[O:15][C:16]3[C:22]([C:23](OC)=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:12][C:11]([C:27]2[CH:28]=[N:29][N:30]([CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:31]=2)=[CH:10][N:9]=1.N>C1COCC1>[NH2:7][C:8]1[N:9]=[CH:10][C:11]([C:27]2[CH:28]=[N:29][N:30]([CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:39])[CH2:34][CH2:33]3)[CH:31]=2)=[CH:12][C:13]=1[C:14]1[O:15][C:16]2[C:22]([CH2:23][OH:24])=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: COC(=O)c1cccc2nc(-c3cc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc3N)oc12
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5cccc(CO)c5o4)c3)cn2)CC1
Yield: 45.5 %

Procedure:
Aluminium(III) lithium hydride (0.251 ml, 1M in THF) was added dropwise to methyl 2-[2-amino-5-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]-3-pyridyl]-1,3-benzoxazole-7-carboxylate (130 mg) dissolved in THF (5 ml). 7N Methanolic ammonia (15 ml) was added to the mixture and the solution was adsorbed on silica gel and the solvent was evaporated. The crude product was purified by flash chromatography on silica gel eluting with 1 to 4% methanol in dichloromethane. The solvent was evaporated to dryness to afford tert-butyl 4-[4-[6-amino-5-[7-(hydroxymethyl)-1,3-benzoxazol-2-yl]-3-pyridyl]pyrazol-1-yl]piperidine-1-carboxylate (56.0 mg) as a clear yellow solid. NMR Spectrum: (CDCl3): 1.49 (s, 9H), 1.96 (dd, 1H), 2.00 (dd, 1H), 2.13-2.24 (m, 2H), 2.84-3.01 (m, 2H), 4.17-4.44 (m, 3H), 5.09 (s, 2H), 6.98 (bs, 2H), 7.37 (dd, 1H), 7.43 (s, 1H), 7.66 (s, 1H), 7.67 (d, 1H), 7.76 (s, 1H), 8.28 (d, 1H), 8.33 (d, 1H); Mass spectrum: M+H+ 491;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]=[N:14][C:13]([NH2:16])=[N:12][C:11]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8]C)[CH:7]=1.B(Br)(Br)Br>O>[NH2:16][C:13]1[N:14]=[N:15][C:10]([C:4]2[CH:5]=[C:6]([OH:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)=[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=1
Reactant: COc1cc(Cl)cc(-c2nnc(N)nc2-c2ccccc2)c1
Agent: BrB(Br)Br
Solvent: O
Product: Nc1nnc(-c2cc(O)cc(Cl)c2)c(-c2ccccc2)n1
Reaction time: 16 h
Yield: 77.6 %

Procedure:
3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenol (890 mg, 85%) was prepared by demethylation of 6-(3-chloro-5-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (1.2 g, 3.84 mmol; vide supra) with BBr3 (5 mL) at −70° C. for 2 hours and then for a further 16 hours at RT. The resulting mixture was then poured into water (25 mL) and extracted with DCM (3×30 mL). The combined organic extracts were then dried over Na2SO4 and concentrated under vacuum. The crude compound was purified by gradient flash chromatography, eluting with 30% ethyl acetate in hexane to afford the target compound.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[CH:26][C:27]([Br:29])=[CH:28][C:4]=2[N:3]=1>N.CO>[Br:29][C:27]1[CH:26]=[CH:25][C:5]2[N:6]([C@@H:7]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]3[OH:9])[C:2]([Cl:1])=[N:3][C:4]=2[CH:28]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Br)ccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Br)ccc32)[C@H](O)[C@@H]1O
Yield: 85 %

Procedure:
A solution of 0.304 g (0.621 mmole) of 86 in 10 mL of NH3 /MeOH was stirred in a pressure bottle at room temperature for 5 h. The reaction mixture was evaporated and coevaporated with MeOH (3×, bath temperature <4° C.). The residue was recrystallized from MeOH to give 0.192 g (85%) of 87 as white crystals. MP 154°-155° C. MS (Cl) m/e 362.9735 (40%, MH+ 362.9747), 1H NMR (DMSO-d6): d 8.01 (d, 1, 7-H, J7-6 =8.5 Hz), 7.87 (d, 1, 4-H, J4-6 =2.0 Hz), 7.41 (dd, 1, 6-H), 5.89 (d, 1, 1'-H, J1'-2' =8.0 Hz), 5.51 (d, 1, 2'-OH, J2'-2'OH 6-5 Hz), 5.28 (d, 1, 3'-OH, J3'-3'OH =4 5 Hz), 5.25 (t, 1, 5'-OH, J5'-5'OH =5.0 Hz), 4.44 (m, 1, 2'-H, J2'-3' =5.5 Hz), 4.13 (m, 1, 3'-H, J3'-4' =2.5 Hz), 3.98 (m, 1, 4'-H, J4'-5' =J4'-5| =3.5 Hz), 3.68 (m, 2, 5'-H and 5"-H, J5'-5" =12.0 Hz). 13C NMR (DMSO-d6): d 142.81 (C3a), 141.23 (C2), 132.20 (C7a), 125.92 (C6), 121.32 (C4), 115.27 (C5), 114.89 (C7), 89.08 (C1'), 86.21 (C4), 71.47 (C2'), 69.73 (C3'), 61.22 (C5').
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=O)[NH:9][N:8]=2)[S:5][CH:6]=1.P(Cl)(Cl)([Cl:20])=O.[OH-].[Na+]>>[Cl:20][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1csc(-c2n[nH]c(=O)c3ccccc23)n1
Agent: [Na+]
Agent: [OH-]
Product: Cc1csc(-c2nnc(Cl)c3ccccc23)n1

Procedure:
A dry 50 mL RBF set up with stirring bar and reflux condenser was charged with 4-(4-methylthiazol-2-yl)phthalazin-1(2H)-one (1.6 g, 6.6 mmol) and phosphorus oxychloride (7.4 ml, 78.9 mmol). The mixture was stirred under reflux for 18 hrs, then poured onto ice while stirring vigorously. To the iced mixture was added 6N NaOH until pH=9. Stirring was continued vigorously until solids formed. The solids were filtered, washed with water and dried in oven to afford 1-chloro-4-(4-methylthiazol-2-yl)phthalazine. MS m/z=262 [M+H]+. Calc'd for C12H8ClN3S: 261.7.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[N+:9]([O-])([OH:11])=[O:10].[OH-].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(N)nc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cnc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 25.1 %

Procedure:
2-Amino-5-methylpyridine (2.16 g, 20.0 mmol) was added into 10 mL of conc H2SO4 in portions at room temperature with stirring. To the resulting solution was added 70% (HNO3 2.0 mL, 31.5 mmol) at room temperature dropwise with stirring. The mixture was then stirred at 55° C. (bath) for 2 h, cooled to room temperature and poured into crushed ice (about 100 g). The mixture was basified to pH 9 in ice-water bath by the addition of 40% aq. NaOH dropwise and the mixture was extracted with CHCl3 (5×25 mL). The CHCl3 extracts were combined, washed with brine (20 mL), dried (MgSO4), and rota-evaporated to dryness to give 770 mg (25% ) of 38 as a bright yellow powder, mp 175°-6° C. 1H NMR (CDCl3) δ2.291 (s, 3H), 6.556 (bs, 2H), 8.219 (s, 1H), 8.237 (s, 1H).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:26][C:27]1[CH:28]=[C:29]([CH:48]=[CH:49][C:50]=1[F:51])[O:30][C:31]1[CH:45]=[CH:44][C:34]2[N:35]=[C:36]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[S:37][C:33]=2[C:32]=1[C:46]#[N:47]>O1CCCC1.C(OCC)(=O)C>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH:26][C:27]2[CH:28]=[C:29]([O:30][C:31]3[CH:45]=[CH:44][C:34]4[N:35]=[C:36]([NH:38][C:39]([CH:41]5[CH2:43][CH2:42]5)=[O:40])[S:37][C:33]=4[C:32]=3[C:46]#[N:47])[CH:48]=[CH:49][C:50]=2[F:51])=[O:11])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#Cc1c(Oc2ccc(F)c(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1c(Oc2ccc(F)c(NC(=O)c3cccc(C4(C#N)CC4)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)benzoic acid (51 mg, 0.272 mmol) in tetrahydrofuran (1.5 ml) were added oxalyl chloride (29 μL, 0.340 mmol) and N,N-dimethylformamide (15 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(3-Amino-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (84 mg, 0.227 mmol) produced in Example 30(vi) was added to the solution, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (50 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (25 mL) and saturated brine (25 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (105 mg, 86%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:26])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:10]([CH3:17])[NH:11]2.IC.[CH3:30]N(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:26][CH3:30])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:10]([CH3:17])=[N:11]2
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(Cl)cc3)c(=O)c12
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(OC)c12
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of [8-chloro-3-(4-chlorobenzyl)-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.13 g), iodomethane (0.20 mL), N,N-dimethylformamide (1.0 mL) and potassium carbonate (0.14 g) were stirred at room temperature for 22 hours. The mixture was diluted with water and extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (1:19 to 19:1 by volume) gave title compound as a gum, 0.059 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>C(#N)C>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:7])=[O:6])=[CH:20][CH:19]=1
Reactant: NC(=O)c1cccc(O)c1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cccc(OCc2ccc(Br)cc2)c1

Procedure:
To 3-hydroxybenzamide (2.0 mM) under nitrogen was added anhydrous acetonitrile (20 ml), potassium carbonate (2.0 mM), and p-bromobenzyl bromide (2.0 mM). The mixture was refluxed for 3 hours, and the progress of the reaction monitored by TLC. The excess solvent was removed under vacuum, until dry, and the title compound was recrystallised from hot dichloromethane (minimum amount). A white crystalline solid was isolated and dried. Melting point: 160-161° C.; Infrared data: cm-1 : KBr disc: 3323; 3146; 1670; 1622. 1H NMR: d6DMSO: δ=5.26 (s; 2H; CH2); 7.3 (dd; 1H: H4); 7.49-7.75 (m, 9H; PhBr; NH2 ; PhO); 13C NMR: d6DMSO: δ=114.031; 118.123; 120.402; 121.295; 129.704; 130.107; 131.690; 136.094; 136.723; 158.371; 167.843. Mass spectra: m/z: EI: 307 (M+1); 262; 212; 169 (100%) 101;90. Elemental analysis: Expect C: 55.26%; H: 3.29%; N: 4.61%; Found C: 54.61%; H: 3.66%; N: 4.47%.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:6][C:7]([F:10])([CH3:9])[CH3:8])C.[OH-].[Na+].ClC1C=CC(S([NH:35]C(CC(F)(C)C)C(O)=O)(=O)=O)=CC=1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+].Cl.CN(C)CCCN=C=NCC>CO.O.CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:5]([CH2:6][C:7]([F:10])([CH3:9])[CH3:8])[C:4]([NH2:35])=[O:3])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: CC(C)(F)CC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Reactant: CCOC(=O)C(CC(C)(C)F)NS(=O)(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(F)CC(NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A solution of 2-(4-chlorobenzenesulfonylamino)-4-fluoro-4-methyl-pentanoic acid ethyl ester (457 mg, 1.30 mmol) in MeOH (20 mL) was treated with 10 N NaOH (780 μL, 7.8 mmol) at rt for 18 h. The crude reaction mixture was concentrated in vacuo. The residue was treated with water (50 mL) and 1 N HCl (20 mL). The aqueous solution was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo to afford a white solid containing 2-(4-chlorobenzenesulfonylamino)-4-fluoro-4-methyl-pentanoic acid. A mixture of the crude solid, 1-hydroxybenzotriazole (263 mg, 1.95 mmol), diisopropylethylamine (670 mg, 5.2 mmol), ammonium chloride (140 mg, 2.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (373 mg, 1.95 mmol), and DMF (20 mL) was stirred at rt for 24 h. The crude mixture was poured into water (500 mL). The aqueous solution was extracted with EtOAc/hexane (90:10, 3×150 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude concentrate was purified using silica gel column chromatography (95:5, chloroform/MeOH) to afford 0.426 g (100% yield) of the title compound: LCMS (M+Na)+ 345.3; 1H NMR (400 MHz, DMSO-d6) δ 8.0 (0 (d, 1H, J=9.2), 7.77 (d, 2H, J=8.5), 7.62 (d, 2H, J=8.9), 7.34 (s, 1H), 6.92 (s, 1H). 3.85 (m, 1H), 1.89 (m, 1H), 1.74 (m, 1H), 1.31 (d, 3H, J=21.7), 1.29 (d, 3H, J=21.9).