Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][O:36][C:37]1[C:43]([O:44][CH3:45])=[CH:42][CH:41]=[CH:40][C:38]=1[NH2:39].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:35][O:36][C:37]1[C:43]([O:44][CH3:45])=[CH:42][CH:41]=[CH:40][C:38]=1[NH:39][C:24]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:26]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc(N)c1OC
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc(OC)c4OC)cc3)c2cc1OC
Yield: 100 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (74 mg) was added, and the admixture was refluxed with heat for 3 minutes. 2,3-Dimethoxyaniline (0.05 ml) was added to the reaction mixture, and the admixture was refluxed with heat for 11 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 83 mg of the title compound (yield: 100%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+].[CH3:22][C:23](C)=O>>[CH2:22]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([O:1][CH2:12][CH2:13][CH2:14][Cl:15])=[CH:3][CH:4]=1)[CH3:23]
Reactant: O=C([O-])c1ccc(O)cc1
Reactant: CC(C)=O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccc(OCCCCl)cc1

Procedure:
Ethyl, 4-hydroxybenzoate 83.1 g (0.50 mole), 107 ml (1.0 mole) of 1-bromo-3-chloropropane, and potassium carbonate (1.5 mole, 207.3 g) were mechanically stirred in 600 ml of refluxing acetone under nitrogen overnight. The potassium carbonate was removed by filtration, and the filtrate was evaporated under reduced pressure to give 122 g of a liquid. This liquid was dissolved in 250 ml of petroleum ether and with stirring and cooling in an ice/2-propanol bath. A white precipitate formed and was collected by filtration and washed with cold petroleum ether to yield 108 g of a solid. An additional 6 g of the product was obtained from the mother liquor. A small sample of the solid was dissolved in petroleum ether at room temperature. The solution was stirred and cooled in an ice bath. White crystals were collected by filtration, washed with cold petroleum ether and dried under vacuum at room temperature, m.p. 24°-25° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](I)[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CCI
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(Cl)cc1

Procedure:
p-Chlorophenol (10 g., 0.077 mole), ethyl iodide (13.1 g., 0.084 mole) and anhydrous potassium carbonate (10.6 g., 0.077 mole) were combined in 130 ml. of acetone and the stirred mixture heated to reflux for 16 hours. The reaction mixture was filtered and the filtrate evaporated to dryness. The residue was taken up in 300 ml. of chloroform, washed in sequence with two 120 ml. portions of 1 N sodium hydroxide, 50 ml. of brine and 50 ml. of water, dried over anhydrous magnesium sulfate, filtered and evaporated to yield 4-ethoxyphenyl chloride as an oil [10.5 g.; pnmr/CDCl3 /delta 1.4 (t, 3H), 4.0 (q, 2H), 6.6-7.3 (m, 4H)].
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([NH:16][S:17]([CH2:20][CH2:21][CH2:22]CC(O)=O)(=[O:19])=[O:18])=[O:15])=O)(C)(C)C.[ClH:27].C(OCC)(=[O:30])C>CO>[ClH:27].[NH2:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([NH:16][S:17]([CH2:20][CH2:21][CH2:22][OH:30])(=[O:18])=[O:19])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C(=O)NS(=O)(=O)CCCCC(=O)O
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CO
Product: N[C@H]1CCC[C@H]1C(=O)NS(=O)(=O)CCCO
Temperature: 25 °C

Procedure:
To a mixture of 3-{[({(1R,2S)-2-[(tert-butoxycarbonyl)amino]cyclopentyl}carbonyl)amino]sulfonyl}propylacetic acid (1.2 g) and methanol (12 ml) was added a 4 M hydrogen chloride/ethyl acetate solution (6.0 ml) under ice-cooling, followed by stirring at room temperature over one night. The reaction mixture was concentrated under reduced pressure to obtain (1R,2S)-2-amino-N-[(3-hydroxypropyl)sulfonyl]cyclopentane carboxamide hydrochloride (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:15])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.CN.[CH2:25]([N:27](CC)CC)C>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[NH:27][CH3:25])[CH:8]=[C:9]([Cl:15])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1c(Cl)cc(C(=O)O)cc1Cl
Agent: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Cl)c(C(=O)OC)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A solution of 3,5-dichloro-4-(methoxycarbonyl)benzoic acid (400 mg, 1.6 mmol) in dimethylformamide and dichloromethane was treated with oxalyl chloride (0.16 ml, 1.9 mmol) drop wise at room temperature followed by stirring at same temperature for 30 minutes. The reaction mixture was concentrated under vacuum. The residue was dissolved in dichloromethane, cooled to 0° C. and methylamine hydrochloride (118 mg, 1.7 mmol) was added followed by the drop wise addition of triethylamine (0.33 ml, 2.4 mmol) at the same temperature. The reaction mixture was allowed to warm to room temperature, stirred for 1 hour and concentrated under vacuum. The residue was treated with ice-cooled aqueous sodium bicarbonate solution (5%). The precipitated solid was filtered, washed with water, and dried to yield methyl 2,6-dichloro-4-(methylcarbamoyl)benzoate (340 mg, 70%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2](=[S:16])[C:3]([N:6]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[N:7]1)([CH3:5])[CH3:4].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=O>>[CH3:4][C:3]([N:6]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[N:7]1)([C:2]1[S:16][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)[N:1]=1)[CH3:5]
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cnn(C(C)(C)C(N)=S)c1
Product: CCOC(=O)c1cnn(C(C)(C)c2nc(-c3cccc(C(F)(F)F)c3)cs2)c1
Yield: 91.3 %

Procedure:
By a reaction in the same manner as in Example 1c and using the compound (241 mg, 1.00 mmol) obtained in Example 16b and 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (267 mg, 1.00 mmol), the title compound (374 mg, 91%) was obtained as a colorless oil.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:30]=[CH:29][N:13]([C@@H:14]2[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@@H:16]([OH:17])[CH2:15]2)[C:12](=[O:31])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][S:33]([CH3:35])=O.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>CCOC(C)=O.C(O)(=O)C>[C:1]([NH:9][C:10]1[CH:30]=[CH:29][N:13]([C@@H:14]2[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:23])[CH3:22])[C@@H:16]([O:17][CH2:32][S:33][CH3:35])[CH2:15]2)[C:12](=[O:31])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(NC(=O)c3ccccc3)nc2=O)C[C@@H]1O
Reactant: CS(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CSCO[C@H]1C[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
3.5 g N4-benzoyl-5′-O-tert-butyldimethylsilyl-2′-deoxycytidine (5c) (7.65 mmol) was dissolved in a mixture consisting of 14.7 mL DMSO, 6.7 mL acetic acid, and 21.59 mL acetic anhydride and stirred for 48 h at room temperature. During this period of time, a complete conversion to product was observed by TLC (Rf=0.4, EtOAc:hex/10:1). The mixture was then neutralized with a saturated NaHCO3 solution and extracted with CH2Cl2 (3×100 mL). The combined organic extract was then washed with saturated solution of NaHCO3 and dried over Na2SO4, and concentrated under vacuum. The product was then purified by silica gel column chromatography (EtOAc: hex/2:1 to 9:1) to obtain N4-benzoyl-3′-O-(methylthiomethyl)-5′-O-(tert-butyldimethylsilyl)-2′-deoxycytidine (6c) as white powder in 73% yield (2.9 g, Rf=0.6, EtOAc:hex/9:1). HR-MS: obs. m/z 506.2134, cald. for C24H36O5N3SiS [M+H]+. 506.2145. 1H-NMR (CDCl3): δH 8.43 (d, J=7.1 Hz, 1H), 7.93 (m, 2H), 7.64 (m, 1H), 7.54 (m, 3H), 6.30 (m, 1H), 4.62 & 4.70 (2Xd, J=11.59 Hz, 2H), 4.50 (m, 1H), 4.19 (m, 1H), 3.84 & 3.99 (2Xdd, J=11.59 & 2.79 Hz, 2H), 2.72 (m, 1H), 2.21 (m, 1H), 2.14 (s, 3H), 0.99 (s, 9H), and 0.16 (s, 6H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:19]2[C:18](=O)[CH2:17][CH2:16][CH2:15][C:14]=2[NH:13][CH:12]=1)=[O:10].N1C=CC=CC=1.Cl.[O:28]([NH2:30])[CH3:29]>CCO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:19]2[C:18](=[N:30][O:28][CH3:29])[CH2:17][CH2:16][CH2:15][C:14]=2[NH:13][CH:12]=1)=[O:10]
Reactant: O=C(Nc1ccccc1F)c1c[nH]c2c1C(=O)CCC2
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C1CCCc2[nH]cc(C(=O)Nc3ccccc3F)c21
Temperature: 120 °C
Yield: 72.7 %

Procedure:
4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (2-fluoro-phenyl)-amide (0.73 mmol), pyridine (2.2 mmol), EtOH (10 ml) and methoxylamine hydrochloride (2.2 mmol) are combined in a sealed tube and heated at 120° C. for 16 hours. The reaction mixture is cooled to room temperature, the solvent is removed in vacuo and the residue is treated with 10 ml of H2O for 5 minutes. The resulting solid is collected by vacuum filtration to yield 160 mg (72%) of 4-methoxyimino-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (2-fluoro-phenyl)-amide as a white solid. 1H NMR (DMSO-d6) δ 1.80-1.86 (m, 2H), 2.62-2.73 (m, 4H), 3.81 (s, 3H), 7.10-7.29 (m, 3H), 7.48 (d, 1H), 8.01 (t, 1H), 11.70 (s, 1H), 11.81 (s, 1H).
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH3:19])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]([CH3:18])[CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1.[Cl:21][C:22]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:23]=1[O:24][CH2:25][CH:26]1[O:28][CH2:27]1>C(O)(C)(C)C>[Cl:21][C:22]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:23]=1[O:24][CH2:25][CH:26]([OH:28])[CH2:27][NH:1][C:2]([CH3:19])([CH3:20])[CH2:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]([CH3:18])[CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(Cl)c(OCC2CO2)c1
Reactant: CC1CC(=O)NN=C1c1ccc(NCC(C)(C)N)cc1
Solvent: CC(C)(C)O
Product: CC1CC(=O)NN=C1c1ccc(NCC(C)(C)NCC(O)COc2cc(Cl)ccc2Cl)cc1
Reaction time: 24 h
Yield: 88.4 %

Procedure:
A mixture of 6-[4-(2-amino-2-methylpropylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (3 g), 1-(2,5-dichlorophenoxy)-2,3-epoxypropane (2.4 g) and t-butanol (100 ml) was stirred at 65° to 70° C. for 24 hours. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, 120 g). From the chloroform/methanol (=50/1) eluted portion, 6-[4-[2-[3-(2,5-dichlorophenoxy)-2-hydroxypropylamino]-2-methylpropylamino]phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (4.77 g) was obtained.
Reaction SMILES: [C:1]([C:9]1[NH:10][CH:11]=[CH:12][C:13]=1[CH2:14][CH2:15][CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[H-].[Na+].[Br:34]N1C(=O)CCC1=O>O>[C:1]([C:9]1[NH:10][CH:11]=[CH:12][C:13]=1[CH2:14][CH2:15][C:16]([Br:34])([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(CCc1cc[nH]c1C(=O)c1ccccc1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Br)(CCc1cc[nH]c1C(=O)c1ccccc1)C(=O)OCC
Reaction time: 0.5 h

Procedure:
To a cold solution of a compound of formula IV, preferably 2-benzoyl-[3,3-di(ethoxycarbonyl)propyl]pyrrole, in an aprotic polar solvent, such as tetrahydrofuran, is added a slight excess of a strong base, preferably sodium hydride. The reaction mixture is allowed to stir for about 30 minutes. To the reaction mixture is then added a halogenating agent, preferably N-bromosuccinimide. The reaction mixture is allowed to stir until complete The mixture is poured into water and extracted with an aprotic polar solvent, such as diethyl ether. The organic layers are combined, washed with water and brine, dried, and concentrated under reduced pressure. The residue may be purified by conventional means to produce a compound of formula VII, preferably 2-benzoyl-[3-bromo-3,3-di(ethoxycarbonyl)propyl]pyrrole.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[F:32]C1C=CC(CCC(O)=O)=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[F:32][C:7]1[CH:6]=[CH:5][C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)CCc1ccc(F)cc1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCc2ccc(F)cc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(4-fluoro-phenyl)-propanoic-acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CC#N>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: C1COCCN1
Reactant: COc1ccc(Nc2nccc(-c3sc(NC(=O)CCBr)nc3C)n2)cc1
Solvent: CC#N
Product: COc1ccc(Nc2nccc(-c3sc(NC(=O)CCN4CCOCC4)nc3C)n2)cc1

Procedure:
By treatment of 3-bromo-N-{5-[2-(4-methoxy-phenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide with morpholine. Anal. RP-HPLC: tR=12.7 min (0-60% MeCN, purity>90%). 1H-NMR (CDCl3) δ: 1.20 (m, 2H, CH2), 2.54-2.63 (m, 7H, CH3 and CH2), 3.34 (m, 2H, CH2), 3.80 (m, 5H, CH3 and CH2), 4.03 (m, 2H, CH2), 6.87-6.92 (m, 3H, pyrimidinyl-H and Ph-H), 7.17 (brs, 1H, NH), 7.53 (m, 2H, Ph-H), 8.35 (m, 1H, pyrimidinyl-H), 10.33 (brs, 1H, NH).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][C:5]1([CH3:39])[C@@H:35](O)[CH2:34][CH2:33][C@@:32]2([CH3:37])[CH:6]1[CH2:7][CH2:8][C:9]1[C:10]3[C@:28]([CH3:38])([CH2:29][CH2:30][C:31]=12)[C@@H:13]([C@H:14]([CH3:27])[CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:12][CH:11]=3.[OH2:40]>CS(C)=O>[OH:40][C@H:35]1[CH2:34][CH2:33][C@@:32]2([CH3:37])[CH:6]([CH2:7][CH2:8][C:9]3[C:10]4[C@:28]([CH3:38])([CH2:29][CH2:30][C:31]=32)[C@@H:13]([C@@H:14]([CH3:27])[CH2:15][C:1]#[N:2])[CH2:12][CH:11]=4)[C:5]1([CH3:39])[CH3:4]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)[C@H]2CC=C3C4=C(CC[C@@]32C)[C@@]2(C)CC[C@H](O)C(C)(C)C2CC4)cc1
Reactant: O
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](CC#N)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Temperature: 90 °C
Reaction time: 2 h

Procedure:
1.7 g potassium cyanide were added to a solution of 4.7 g (20S)-4,4,20-trimethyl-21-tosyloxy-pregna-8,14-dien-3β-ol in 90 ml DMSO at room temperature. The mixture was stirred for 2 h at 90° C., poured into water, extracted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2.8 g (20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-carbonitril as a white solid which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]3[C:14](=[C:15]([O:20][CH:21]([F:23])[F:22])[CH:16]=[CH:17][CH:18]=3)[C:13](=[O:24])[C:12]([C:25]([O:27]CC)=[O:26])=[N:11]2)=[CH:6][CH:5]=1.[OH-].[Na+].C(O)C>O>[F:31][C:2]([F:1])([F:30])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:19]3[C:14](=[C:15]([O:20][CH:21]([F:23])[F:22])[CH:16]=[CH:17][CH:18]=3)[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[N:11]2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)c2cccc(OC(F)F)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1nn(-c2ccc(OC(F)(F)F)cc2)c2cccc(OC(F)F)c2c1=O
Temperature: 25 °C
Yield: 64 %

Procedure:
Ethyl 1-(4-trifluoromethoxyphenyl)-1,4-dihydro-4-oxo-5-difluoromethoxycinnoline-3-carboxylate (200 mg) and a 1N aqueous solution of sodium hydroxide (0.93 ml) were added to a mixed solvent of ethanol (5.5 ml) and water (1.5 ml), and the resultant mixture was stirred at 70° to 80° C. for 3 hours. After being allowed to cool to room temperature, the mixture was diluted with water (50 ml), and washed with ethyl acetate (20 ml). The pH of the water layer was adjusted to pH 2 with concentrated hydrochloric acid to precipitate crystals. The precipitated crystals were collected by filtration, washed with water (5 ml) two times, and dried under reduced pressure to give 120 mg of desired 1-(4-trifluoromethoxyphenyl)-1,4-dihydro-4-oxo-5-difluoromethoxycinnoline-3-carboxylic acid (yield: 64.2%). m.p., 236.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:34][CH3:35])[CH:10]=1.C(O)C(F)(F)F>>[NH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]([C:23]2[CH:22]=[CH:21][N:20]=[C:19]([NH:18][C:12]3[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:9]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:10][C:11]=3[O:34][CH3:35])[N:24]=2)=[CH:26]1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Reactant: CN1CCNCC1
Solvent: OCC(F)(F)F
Product: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 120 °C
Yield: 32.8 %

Procedure:
A mixture of 1-methylpiperazine (148 mg, 1.48 mmol), N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 68, 224 mg, 0.59 mmol) and trifluoroethanol (5 mL) was sealed into a microwave tube and heated to 120° C. for 1 h in a microwave reactor and then cooled to r.t. The mixture was then concentrated in vacuo. Trituration of the resulting brown gum with ethanol and then diethyl ether gave a solid that was collected by filtration and dried under vacuum to give the title compound (89 mg, 33%) as a pale brown solid; 1H NMR: 3.02-3.13 (4H, m), 4.00 (3H, s), 6.86 (1H, s), 7.08 (1H, t), 7.18 (1H, t), 7.31 (1H, d), 7.45 (1H, d), 8.08 (1H, s), 8.33 (2H, dd), 8.82 (1H, d), 11.81 (1H, s); m/z: ES+ MH+ 460.5.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:12]([O-])=O)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]>CCO.CC(O)=O.[Fe]>[NH2:12][C:3]1[C:2]([Cl:1])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1cccc(Cl)c1N
Temperature: 25 °C
Yield: 79 %

Procedure:
Iron powder (1.94 g, 34.8 mmol) was added to the solution of methyl 3-chloro-2-nitrobenzoate (2.5 g, 11.6 mmol) in EtOH/HOAc (100 mL/100 mL) at room temperature, and then the suspension was refluxed under N2 for 2 hrs. After cooling down to room temperature, partial of the solvents was removed on rotary vacuum, the resulting residue was partitioned between H2O/EtOAc (200 mL/300 mL). The separated organic phase was washed with aqueous NaOH (1N, 50 mL), brine (50 mL), dried over MgSO4, and concentrated on rotary vacuum to afford the expected product as a tan oil (1.7 g, 79% yield) which became wax type solid standing on bench. The crude product was pure enough to be used in next step without further purification; 1H NMR (400 MHz, CDCl3) δppm 3.86 (s, 3H), 6.25 (s, 2H), 6.57 (t, J=7.93 Hz, 1H), 7.39 (dd, J=7.81, 1.51 Hz, 1H), 7.79 (dd, J=8.06, 1.51 Hz, 1H); Mass spec. 185.95 (MH+), Calc. for C8H8ClNO2 185.02.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8](=O)[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11].[CH3:17]OC.C(CN)O>O>[CH3:17][O:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[CH:8]=[C:7]1[NH:1][C:2](=[O:3])[NH:4][C:5]1=[O:6]
Reactant: O=Cc1ccccc1O
Reactant: O=C1CNC(=O)N1
Reactant: COC
Solvent: NCCO
Solvent: O
Product: COc1ccccc1C=C1NC(=O)NC1=O
Yield: 83 %

Procedure:
50 g (0.5 mole) of hydantoin, 68.07 l g (0.5 mole) of salicylaldehyde-methyl-ether and 46 g (0.7 mole) of ethanol amine are admixed in 500 ml of water at 70° C. The reaction mixture is worked up as described in Example 2. Thus 90.6 g of the desired compound are obtained, yield 83%, mp.: 178° C.
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[CH2:20][NH2:21].C(O)CCC>O>[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([NH:21][CH2:20][C:19]1[C:18]([F:17])=[CH:25][CH:24]=[CH:23][C:22]=1[F:26])=[NH:11]
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Reactant: NCc1c(F)cccc1F
Agent: I
Solvent: O
Solvent: CCCCO
Product: N=C(NCc1c(F)cccc1F)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 7.80 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydroiodide (U.S. Pat. No. 3,657,337) and 2.86 g. of 2,6-difluorobenzylamine (prepared from 2,6-difluorobenzylamine hydrochloride) in 100 ml. of n-butanol and 20 ml. of water is heated at reflux for 66 hours. The solvent is removed under reduced pressure and the residual yellow oil is dissolved in aqueous ethanol and made basic with 10N NaOH. The resultant mixture is extracted with chloroform and the chloroform extract is evaporated under reduced pressure to give a yellow gum. This gum in ethyl acetate is purified by silica gel column chromatography, giving a colorless solid. This solid is recrystallized from aqueous ethanol, giving the desired product as colorless crystals, m.p. 168.5°-169.5° C.