Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@@H:16]([C:28](=[O:50])[N:29]([C@H:31]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:32]([N:34]1[CH2:38][CH2:37][CH2:36][C@H:35]1[CH2:39][N:40]([CH3:42])[CH3:41])=[O:33])[CH3:30])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)C)(C)(C)C>ClCCl>[CH2:43]([C@@H:31]([N:29]([CH3:30])[C:28](=[O:50])[C@H:16]([NH:14][CH3:13])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[C:32]([N:34]1[CH2:38][CH2:37][CH2:36][C@H:35]1[CH2:39][N:40]([CH3:41])[CH3:42])=[O:33])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CN(C)C[C@@H]1CCCN1C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1CN(C)C
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 60.6 %

Procedure:
At 0° C., trifluoroacetic acid (10 ml) was added to a solution of N-((1R)-1-{N-[(1R)-1-benzyl-2-((2S)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester (1.37 g, 2.28 mmol) in dichloromethane (10 ml). The reaction mixture was stirred for 75 min at 0° C. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (70 ml) and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 692 mg of (2R)—N-[(1R)-1-benzyl-2-((2S)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.
Reaction SMILES: Br[CH:2]([CH3:18])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4].C(=O)(O)[O-].[Na+].[CH3:24][NH2:25]>C(#N)C>[CH3:24][NH:25][CH:2]([CH3:18])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4]
Reactant: CN
Reactant: CCCCCCCCCCCCOC(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCCCCCOC(=O)C(C)NC
Temperature: 27.5 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To a stirred solution of 59 (10 g, 31.2 mmol) in acetonitrile (20 mL) was added sodium bicarbonate (2.62 g, 31.2 mmol) and followed by mono methyl amine (40% in water) (30 mL, 3 vol) at 25-30° C. The reaction mixture was stirred for 3 hour at 25-30° C.; the reaction was monitored by TLC. The solid obtained in the reaction mixture was filtered under vacuum. The solvent was concentrated, diluted with ethyl acetate/water and stirred for 15 minutes at 25-30° C. The aqueous and organic layers were separated, and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine solution, dried over Na2SO4 and concentrated under vacuum to afford crude 60 (7 g, yield: 82.3%) as a liquid
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])[CH:4]=[CH2:5].N1C=CN=C1.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Si:26]([O:1][CH2:2][C@@H:3]([N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])[CH:4]=[CH2:5])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28]
Reactant: C=C[C@@H](CO)N1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)c2ccccc2C1=O
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-2-(1-hydroxybut-3-en-2-yl)isoindoline-1,3-dione (Intermediate 1, 69.4 g, 319.49 mmol) and imidazole (26.1 g, 383.39 mmol) in methylene chloride (160 mL), at ambient temperature under an atmosphere of nitrogen, was added tert-butyldimethylchlorosilane (55.4 g, 367.41 mmol) as a solid. This addition was performed over approximately ten minutes. Warming of the mixture was observed during this addition. After two hours stirring, the solution was poured into a saturated solution of aqueous sodium bicarbonate (approximately 150 mL); this biphasic mixture was shaken, and the organic layer was separated. The aqueous layer was back-extracted three times with 200 mL methylene chloride each time. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The desired product was obtained as a pale yellow solid after drying overnight under high vacuum (107 g, 101%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[OH:11].[Na].[C:13]1([CH:19]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:20]2[CH2:23][CH:22](OS(C)(=O)=O)[CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S([O-])(=O)(=O)C>CC(C)CC(=O)C>[Cl:1][C:2]1[C:3]([O:11][CH:22]2[CH2:23][N:20]([CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:21]2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: Oc1c(Cl)ccc2c1CCC2
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CS(=O)(=O)[O-]
Agent: [Na]
Solvent: CC(=O)CC(C)C
Product: Clc1ccc2c(c1OC1CN(C(c3ccccc3)c3ccccc3)C1)CCC2
Temperature: 120 °C
Reaction time: 64 h
Yield: 91.4 %

Procedure:
2 g of 5-chloro-2,3-dihydro-1H-inden-4-ol were stirred in 75 ml of a 2N sodium hydroxyde solution for 1 hour. To the clear solution were added 75 ml of 4-methyl-2-pentanone and 3.76 g of 1-(diphenylmethyl)-3-methanesulfonyloxy-azetidine and the mixture was heated in an oil bath at 120° C. for 3.5 hours. Then another 2 g of mesylate were added and heating was continued for 64 hours. The upper layer was separated and washed with water. Evaporation in vacuo and chromatography with toluene/ethyl acetate (95:5) gave 4.22 g of 3-[(5-chloro-2,3-dihydro-1H-inden-4-yl)oxy]-1-(diphenylmethyl)-azetidine as a clear oil that solidified spontaneous. M.S. (C.I.) (M/Z): 391 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1.O=S(Cl)Cl.[F:37][C:38]([F:42])([F:41])[CH2:39][NH2:40]>>[CH3:32][N:2]([CH3:1])[C:3]1[C:27]([C:28]([F:30])([F:31])[F:29])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][NH:40][CH2:39][C:38]([F:42])([F:41])[F:37])=[CH:21][N:20]=[N:19]4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1
Reactant: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: NCC(F)(F)F
Solvent: O=S(Cl)Cl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CNCC(F)(F)F)c1)=N2

Procedure:
The title compound was prepared from 7-dimethylamino-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 17) (133 mg, 0.3 mmol) by treatment with SOCl2 (3 eq.) and 2,2,2-trifluoroethylamine (10 eq.) as described in Example 45. Obtained as a light yellow solid (19 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)(S)=[S:8])C=CC=CC=1.[NH2:16][C:17]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[CH3:28])=[CH:23][CH:22]=1)=[CH:18][C:19]#[N:20]>CC(O)C.CCOC(C)=O>[NH2:16][C:17]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[CH3:28])=[CH:23][CH:22]=1)=[CH:18][C:19]([NH2:20])=[S:8]
Reactant: S=P(S)(c1ccccc1)c1ccccc1
Reactant: CC(F)(F)c1ccc(C(N)=CC#N)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(F)(F)c1ccc(C(N)=CC(N)=S)cc1
Temperature: 45 °C
Yield: 67.2 %

Procedure:
Add diphenylphosphinodithioic acid (13.2 g, 52.9 mmol) to a solution of 3-amino-3-[4-(1,1-difluoroethyl)phenyl]acrylonitrile (5.50 g, 26.4 mmol) in propan-2-ol (264 mL). Heat to 45° C. for 4 h. Dilute with EtOAc (400 mL), wash with brine 3× (100 mL), and evaporate. Crystallize from EtOAc/hexane to afford 3-amino-3-[4-(1,1-difluoroethyl)-phenyl]thioacrylamide. Yield: 67.2%. ES-MS: m/e 243.0 (m+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].[F:29][C:30]1[CH:37]=[C:36]([Br:38])[CH:35]=[CH:34][C:31]=1[CH2:32]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:29][C:30]1[CH:37]=[C:36]([Br:38])[CH:35]=[CH:34][C:31]=1[CH2:32][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28]
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Reactant: Fc1cc(Br)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2OCc2ccc(Br)cc2F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl and 0.731 ml (5.181 mmol) of 2-fluoro-4-bromobenzyl bromide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and the resulting mixture was agitated for 2 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 15 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 100/1) to obtain 248.1 mg (0.4322 mmol), 83%) of 2-(2-fluoro-4-bromobenzyloxy)-2'-hydroxy-5, 5'-bis(3-methoxycarbonylpropyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 1.7-2.2 (4H, m, 2CH3), 2.35 (4H, t, 2CH2), 2.67 (4H, t, 2CH2), 3.66 (6H, s, 2CH3), 5.03 (2H, s, CH2), 6.87 (1H, s, OH), 6.8-7.3 (9H, m, arom-H), MS (FAB): 573 (M-H)-
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[O:13]1COCO[CH2:14]1.O>CS(C)=O.C[O-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:14][OH:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: C1OCOCO1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(CO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.6 %

Procedure:
To a stirred solution of methyl (4-fluorophenyl)acetate (5.5 g) in DMSO (220 mL) was added 1,3,5-trioxane (3.24 g) and sodium methoxide (88 mg). The mixture was stirred at room temperature for 16 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 3.8 g of the title compound.
Reaction SMILES: [C:1]([C:3]([OH:10])([CH2:8][Cl:9])[CH2:4][C:5]([OH:7])=[O:6])#[N:2].[OH2:11]>>[C:1]([C:3]([OH:10])([CH2:8][Cl:9])[CH2:4][C:5]([OH:7])=[O:6])(=[O:11])[NH2:2]
Reactant: N#CC(O)(CCl)CC(=O)O
Reactant: O
Product: NC(=O)C(O)(CCl)CC(=O)O

Procedure:
reacting 3-cyano-3-hydroxy-4-chlorobutyric acid with water at a pH of from about 1.0 to about 3.0 to form 3-carbamoyl-3-hydroxy-4-chlorobutyric acid,
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:7](=[O:21])[N:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([O:19]C)=[O:18])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:7](=[O:21])[N:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([OH:19])=[O:18])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(Cc2ccccc2C(=O)OC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1nn(Cc2ccccc2C(=O)O)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
To a solution of 20 mg (0.038 mmole) of 5-n-butyl-2-[2-(carbomethoxy)benzyl]-2,4-dihydro-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol- 3-one (from Example 6) in 200 μl of dry THF was added all at once 84 μl (0.084 mmole) of 1N sodium hydroxide in methanol. The mixture was stirred overnight at room temperature and then evaporated to dryness. The residual solid was dissolved in 1.5 ml of methanol and treated with 90 μl of 1N HCl in methanol (final pH 2). The solvent was evaporated, and the residue was leached with CHCl3. After removal of insoluble solid (NaCl) by filtration through glass wool, the filtrate was concentrated in vacuo and then re-concentrated from toluene. The residue was dried overnight in the presence of P2O5 to give 20 mg (95%) of the titled compound as a stiff, white foam, mp>106° C. (gradual), homogeneous by TLC in 90:10:0.1 CH2Cl2 --MeOH--AcOH; mass spectrum (FAB) m/e 510 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[O:11][CH3:12])[CH3:2].C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>>[CH2:1]([O:3][C:4]1[CH:10]=[C:9]2[C:7](=[CH:6][C:5]=1[O:11][CH3:12])[NH:8][CH:23]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2=[O:15])[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCOc1ccc(N)cc1OC
Product: CCOC(=O)c1c[nH]c2cc(OC)c(OCC)cc2c1=O
Yield: 55.2 %

Procedure:
4-Ethoxy-3-methoxyaniline (2.6 g) and diethyl ethoxymethylenemalonate (3.4 g) were reacted in the same manner as in Experimental Example 1 to obtain 6-ethoxy-3-ethoxycarbonyl-7-methoxy-4(1H)-quinolone (2.5 g). The compound (2.3 g) was ethylated with potassium carbonate (3.3 g) and ethyl iodide (6.1 g) in the same manner as in Experimental Example 9 to obtain 6-ethoxy-3-ethoxycarbonyl-1-ethyl-7-methoxy-4(1H)-quinolone (1.8 g). This compound (1.4 g) was hydrolyzed in the same manner as in Experimental Example 9 to obtain a carboxylic acid (1.2 g), which was then decarboxylated in the same manner as in Experimental Example 9 to obtain 6-ethoxy-1-ethyl-7-methoxy-4(1H)-quinolone (compound 49, 210 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[CH:19]=1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2C1
Reactant: Cc1ccccc1B(O)O
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccccc1-c1ccc2c(c1)CN(C(=O)OC(C)(C)C)CCO2
Yield: 96.8 %

Procedure:
A mixture of tert-butyl 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.609 mmol), a solution of 2-methylphenylboronic acid (124 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.2 mg, 0.0729 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (200 mg, 96.6%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.O=[C:22]([CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:23]([OH:25])=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:22]([C:23]([OH:25])=[O:24])[CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: O=C(O)C(=O)CN1CCCC1
Product: O=C(O)C(CN1CCCC1)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 13, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be stirred with 2-oxo-3-pyrrolidinopropionic acid at room temperature to give 7-chloro-2-[(1-carboxy-2-pyrrolidinoethylidene)-hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:18])[CH3:17])=[CH:14][C:15]=2[N+:19]([O-:21])=[O:20])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1ccc(C2CCN(C(C)=O)CC2)cc1
Product: CC(=O)c1ccc(C2CCN(C(C)=O)CC2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3 g of N-acetyl-4-(4-acetyl-phenyl)-piperidine is added at -15°, with stirring, to 20 ml of fuming nitric acid, and the reaction mixture is subsequently stirred for 30 minutes at a temperature of between 0° and 15°. It is then poured onto 100 g of ice; the pH value is adjusted to 14 with concentrated sodium hydroxide solution, and extraction is performed three times with 50 ml of methylene chloride each time. The organic phases are combined, washed until neutral, dried over sodium sulphate and concentrated in vacuo. The residue is dissolved in ether/ethanol and treated with active charcoal. The crude oily N-acetyl-4-(2-nitro-4-acetyl-phenyl)-piperidine, obtained after filtration and concentration by evaporation, can be further reacted without additional purification.
Reaction SMILES: C(=[N:8][CH:9]([P:22]([O:26][CH3:27])([O:24][CH3:25])=[O:23])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:11])C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1CCCCC1>CCOCC>[NH2:8][CH:9]([P:22]([O:26][CH3:27])([O:24][CH3:25])=[O:23])[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)=[O:11]
Reactant: COc1ccc(COC(=O)C(N=Cc2ccccc2)P(=O)(OC)OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: C1CCCCC1
Product: COc1ccc(COC(=O)C(N)P(=O)(OC)OC)cc1

Procedure:
p-Methoxybenzyl N-benzylidene-α-amino-dimethylphosphonoacetate (9.78 g) in ether (50 ml) is added over 20 minutes to a stirring solution of p-toluenesulfonic acid monohydrate (4.76 g) in ether (150 ml). Cyclohexane (100 ml) is added and the solvents are decanted off. The residue is washed with more 2:1 ether-cyclohexane, which is again decanted off. The residue is partitioned between methylene chloride and 1 M dipotassium hydrogen phosphate (50 ml). The organic portion is separated, washed with water, dried, and evaporated in vacuo to give p-methoxybenzyl α-aminodimethylphosphonoacetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.IC.[C:14](=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:14][O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
3 g of 5-fluoro-2-nitrophenol are dissolved in DMF and, after addition of 1.1 equivalent each of iodomethane and cesium carbonate, stirred at room temperature. After the reaction is complete, the reaction mixture is poured into water, extracted with diethyl ether, washed and concentrated. 3.2 g of 2-methoxy-4-fluoronitro-benzene are produced. Starting from this, 4.2 g of 2-methoxy-4-pyrrolidinylnitrobenzene are prepared by reaction with pyrrolidine by general reaction method A. The crude product is hydrogenated by general method B. 3.6 g of 2-methoxy-4-pyrrolidinylaminobenzene are obtained. Starting from 150 mg of the crude product and by reaction with 2-thiophenesulfonyl chloride, 154 mg of thiophene-2-sulfonic acid 2-methoxy-4-pyrrolidin-1-ylphenylamide are prepared by general method C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>COCCOC>[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: OB(O)c1ccccc1F
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1-c1ccccc1F
Yield: 24.7 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 2-fluoro-phenylboronic acid (27 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (13 mg, 25%). LC-MS m/e 405.28 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH:9]([C:17]#[N:18])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6]([Cl:19])=[CH:5][C:3]=1[NH2:4].[F:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:22]=1[C:23]([N:25]=[C:26]=[O:27])=[O:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([CH:9]([C:17]#[N:18])[C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[C:6]([Cl:19])=[CH:5][C:3]=1[NH:4][C:26]([NH:25][C:23](=[O:24])[C:22]1[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:21]=1[F:20])=[O:27]
Reactant: N#CC(c1ccc(F)cc1)c1cc(Cl)c(N)cc1Cl
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: N#CC(c1ccc(F)cc1)c1cc(Cl)c(NC(=O)NC(=O)c2c(F)cccc2F)cc1Cl
Temperature: 25 °C

Procedure:
Into a 100 milliliter round bottom flask equipped with a thermometer, magnetic stirrer and condenser was added 30 milliliters of toluene, 1.2 grams (0.004 moles) of 2,5-dichloro-4-(alpha-cyano-4-fluorobenzyl)aniline prepared in Part B and 1.0 grams (0.005 moles) of 2,6-difluorobenzoyl isocyanate under a nitrogen atmosphere at ambient temperature. The reaction mixture was then heated in an oil bath for a period of 2 hours. After cooling to ambient temperature, the reaction mixture was filtered and dried overnight in a vacuum oven at 50° C. This afforded 1.3 grams of a white solid having a melting point of 216° C.-218° C. Elemental analysis of the white solid indicated the following:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[OH-].[NH4+:13]>>[Cl:1][C:2]1[N:7]=[C:6]([NH2:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: [OH-]
Product: Nc1nc(Cl)ncc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a rapidly stirred solution of saturated aqueous ammonium hydroxide (50 mL) and ice in a 0 deg. C. bath was added 2,4-dichloro-5-nitropyrimidine (6.0 g, 31 mmol) in portions. The resulting yellow foamy mixture was allowed to stir for 30 min, at which point the precipitate was isolated by filtration. The solid was rinsed several times with ice-cold water and once with ice cold ethanol to give a peach-colored solid. The crude solid was purified by adsorption onto 18 g silica gel, followed by silica gel chromatography, eluting with 0-20% MeOH/dichloromethane to give 2-chloro-5-nitropyrimidin-4-amine as an off-white solid. MS (ES+): 175 (M+H)+; Calc. for C4H3ClN4O2=174.55.