Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[C:13]=1[C:21](OCC)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-])=O.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>[Ti](Cl)(Cl)(Cl)Cl.C1(OC)C=CC=CC=1>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=[C:21]([N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)[C:13]2[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[S:16][C:12]1=2
Reactant: CCOC(=O)c1c(N(C)c2ccccc2[N+](=O)[O-])sc2ccccc12
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3ccccc3N(C)c3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 2-(N-methyl-2-nitroanilino)benzo[b]thiophene-3-carboxylate (3.2 g), 1-methylpiperazine, anisole (80 ml) and titanium tetrachloride (3.5 ml), 6-methyl-12-(4-methylpiperazin-1-yl)[1]benzothieno[2,3-b][1,5]benzodiazepine (166 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:7]([CH2:13][CH3:14])=[N:8][NH:9][C:10]=1[CH2:11][CH3:12].[CH2:19]=[O:20]>O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH2:19][OH:20])[C:7]=1[CH2:13][CH3:14]
Reactant: CCc1n[nH]c(CC)c1Cc1cc(Cl)cc(Cl)c1
Reactant: C=O
Solvent: O
Solvent: CCO
Product: CCc1nn(CO)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.7 %

Procedure:
A solution of the pyrazole of Example 11 (283 mg, 1.00 mmol) in water (1 ml) and ethanol (0.5 ml) was treated with 37% W/w aqueous formaldehyde solution (112 μL, 1.50 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The reaction was then stirred under reflux for 2 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (2:1, by volume) to afford the title compound (231 mg) as a white solid, m.p. 117–118° C.
Reaction SMILES: CO[C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.Cl.CC(C)=[O:21]>>[N:11](=[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]1[CH:4]=[CH:3][C:17]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:21]
Reactant: CC(C)=O
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Agent: Cl
Product: ON=C1C=CC=CC1C=Cc1ccccc1
Temperature: 25 °C
Yield: 97 %

Procedure:
A 2-L, three-necked flask equipped with a mechanical stirrer, thermometer and nitrogen inlet was charged with 10-methoxyiminostilbene I (110.0 g, 0.49 mol) and 330 mL acetone. A 10% solution of hydrochloric acid (28.6 g, 0.08 mol) was then added. The reaction mixture was stirred at ambient temperature for 1–1.5 hours until reaction completion. The product was precipitated by the addition of 660 mL of deionized water, and the resulting suspension was stirred for 3–4 hours. The suspension was filtered and washed with water. After drying, oximinostilbene (99.92 g, 97%) was obtained as a bright yellow solid having a purity of 99% by HPLC.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[CH3:17][C:18]([NH:26][C:27](=[O:31])[CH2:28][CH2:29][NH2:30])([CH3:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[CH3:25][C:18]([NH:26][C:27](=[O:31])[CH2:28][CH2:29][NH:30][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(NC(=O)CCN)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(NC(=O)CCNC(=O)c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 86.4 %

Procedure:
0.3 g of benzoyl chloride was slowly dropped onto 10 ml of a toluene solution containing 0.4 g of N-(α,α-dimethylbenzyl)-3-aminopropionamide (prepared as described in Preparation 3) and 0.22 g of triethylamine. The reaction solution was then stirred for 2 hours, and, after dilution with 20 ml of diethyl ether, was washed with water and dried over anhydrous sodium sulfate. The reaction solution was then concentrated by evaporation under reduced pressure, and purified by silica gel chromatography, to give 0.52 g (yield 87%) of the title compound melting at 147°-148° C.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH:23]1[C:36]2[NH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:28][C:27]=2[CH:26]=[CH:25][CH:24]=1.Br[C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][CH2:46][CH3:47])=[CH:40][CH:39]=1.CC(C)([O-])C.[Na+].Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:44]([C:41]1[CH:42]=[CH:43][C:38]([N:35]2[C:36]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[O:28][C:29]3[C:34]2=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:39][CH:40]=1)[CH2:45][CH2:46][CH3:47]
Reactant: CCCCc1ccc(Br)cc1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCCCc1ccc(N2c3ccccc3Oc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Palladium acetate, tri-o-tolylphosphine and toluene were charged in a three-necked round-bottomed flask, and stirred for 20 minutes at room temperature. Phenoxazine, 1-bromo-4-butylbenzene, sodium t-butoxide and toluene were added, and the mixture was heated in an oil bath and refluxed for 15 hours. After cooling, concentrated hydrochloric acid was added and the mixture was stirred for 1 hour, then, the solution was passed through a neutral alumina column. The column was washed with toluene, and the solvent was removed using a rotary evaporator, to obtain yellow solid. The solid was re-crystallized from toluene/methanol, to obtain N-(4-n-butylphenyl)phenoxazine.
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:24][CH2:23][C@@H:18]([O:19]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]=[C:26]([CH3:30])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1.[Li+].[OH-].BrC1N([C@@H]2OC[C@@H](O)[C@@H](O)[C@H]2O)C2C=C(Cl)C(Cl)=CC=2N=1>O1CCOCC1>[Br:1][C:2]1[N:6]([C@@H:7]2[O:24][CH2:23][C@@H:18]([OH:19])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[C:26]([CH3:30])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2cc(Cl)c(C)cc21
Agent: O[C@@H]1[C@H](O)[C@H](O)CO[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc2c(cc1Cl)nc(Br)n2[C@@H]1OC[C@@H](O)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-5-chloro-6-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.097 g ) was deprotected as outlined in General Procedure V by being dissolved in 5 ml dioxane and the resultant solution cooled in an ice bath between 0 and 5° C. To this solution was added all at once, 0.78 ml (0.78 mmol) of 1M aq. LiOH. The mixture was removed from the ice bath and allowed to stir at ambient temperature for 0.5 h. The mixture was diluted with 50 ml of pH 7 phosphate buffer and extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate (anhyd.), filtered and solvents evaporated. The residue was triturated in dichloromethane and 0.028 g (0.074 mmol) of 2-bromo-5,6-dichloro-1-beta-D-ribopyranosyl-1H-benzimidazole was collected by vacuum filtration. The product was dried in a vacuum oven at 50° C. overnight; m.p. 150° C. (foams); MS (AP+): m/z (rel. intensity) 400 (1.0, M+23 (Na)); 1H NMR (DMSO-d6) δ7.67 (s,1H), 7.65 (s, 1H), 5.62-5.60 (d, J=8.9 Hz), 5.13 (bs, 2H), 4.88-4.87 (m, 1H), 4.13 (bs, 1H), 4.00 (bs, 2H), 3.93 (m, 1H), 2.40 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:31][CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[F:27]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccccc1F
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccccc3F)c2CC1)C(F)(F)F

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-fluorobenzyl amine. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 and 4:1) to give 7-chloro-6-(2-fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow solid. MS (ES+) m/z: 401 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([F:30])[CH:24]=3)[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:40][CH2:41][C:42]([CH3:48])([CH3:47])[C:43]([O:45][CH3:46])=[O:44]>CN(C=O)C>[C:9]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:40][CH2:41][C:42]([CH3:48])([CH3:47])[C:43]([O:45][CH3:46])=[O:44])=[C:25]([F:30])[CH:24]=2)=[O:31])[C@@H:14]([CH3:32])[CH2:13]1)(=[O:11])[CH3:10]
Reactant: COC(=O)C(C)(C)CCBr
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)c(F)c2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
N-(4-chlorophenyl)-N-[(2S,4R)-1-(3-fluoro-4-hydroxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (317 mg, 0.70 mmol) was dissolved in DMF at room temperature and Cs2CO3 (567 mg, 1.75 mmol) was added. Methyl 4-bromo-2,2-dimethylbutanoate (465 mg, 1.05 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (hexanes/ethyl acetate system) to afford the product (176 mg, 43%).
Reaction SMILES: CO[CH:3]1[C:12]([CH3:14])([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:15])[NH:4]1.P(Cl)(Cl)(Cl)(Cl)Cl>C(OCC)C>[CH3:13][C:12]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:15])[NH:4][CH2:3]1
Reactant: COC1NC(=O)c2ccccc2C1(C)C
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: CC1(C)CNC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 162.2 %

Procedure:
The compound (1.3 g) obtained in step (d) just above was dissolved in diethyl ether (15 ml). Phosphorus pentachloride (1.1 g) was added to the solution. The mixture was stirred at room temperature for 30 min. The solvent was then removed by distillation under the reduced pressure. Glyme (20 ml) and sodium boron hydride (1.1 g) were added to the residue. The mixture was stirred at room temperature for one hr. Water was added to the reaction solution, followed by stirring. The mixture was then extracted with ethyl acetate. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=30:1) to give 4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (1.8 g).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:25])=[O:24])=[CH:18]2.[CH3:38][O:39][C:40]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:41]=1[CH2:42][NH:43][C:44]1[S:48][N:47]=[CH:46][N:45]=1.C1COCC1.CC(C)([O-])C.[Li+]>[Cl-].[NH4+]>[CH3:38][O:39][C:40]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:41]=1[CH2:42][N:43]([C:44]1[S:48][N:47]=[CH:46][N:45]=1)[S:23]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[CH:22][C:13]=2[CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[CH:18]=1)(=[O:24])=[O:25]
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3)cccc2c1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(C4CCCN4)cccc3c2)c(OC)c1
Reaction time: 0.58 h
Yield: 63.8 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 5-(pyrrolidin-2-yl)naphthalene-2-sulfonate 2,2,2-trifluoroacetate (104.73 mg, 0.188 mmol), N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (56.7 mg, 0.225 mmol), and THF (1879 μl) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 10 min, then lithium tert-butoxide (Sigma-Aldrich, St. Louis, Mo., 1M in hexane) (413 μl, 0.413 mmol) was added dropwise. After 35 min, the flask was submerged in an ice-bath for 2 h. The mixture was diluted with saturated aq ammonium chloride, then extracted with EtOAC (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g, 0 to 10% MeOH/DCM) to give N-(2,4-dimethoxybenzyl)-5-(pyrrolidin-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (61.5 mg, 0.120 mmol, 64.1% yield) as a white foam: 1H NMR (400 MHz, DMSO-d6) δ ppm=8.55 (d, J=2.2 Hz, 1H), 8.41-8.33 (m, 2H), 8.01 (dd, J=7.7, 19.2 Hz, 2H), 7.78 (dd, J=2.2, 9.1 Hz, 1H), 7.68-7.61 (m, 1H), 7.03-6.95 (m, 1H), 6.36 (qd, J=2.3, 4.5 Hz, 2H), 5.18 (s, 2H), 4.77 (t, J=7.4 Hz, 1H), 3.67 (s, 3H), 3.63 (s, 3H), 3.12-2.95 (m, 2H), 2.40-2.30 (m, 1H), 1.83-1.72 (m, 2H), 1.51-1.40 (m, 1H); m/z (ESI) 511.4 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:15]I.O>CN(C)C=O.C(OCC)(=O)C>[CH3:15][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc2ccc([N+](=O)[O-])cc21
Reaction time: 0.17 h

Procedure:
4 g 6-nitro-1H-indole are added batchwise at 0° C. to 800 mg sodium hydride (60% in mineral oil) in 20 mg dimethylformamide. The mixture is stirred for 10 minutes, then 1.86 ml methyl iodide are added dropwise and the mixture is left overnight to come up to ambient temperature. Then it is divided between water and ethyl acetate, the aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][N:17]=[C:16]([NH:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=3[CH:25]=2)[CH:6]=1)C.[Li+].[OH-]>CO>[CH2:20]([NH:19][C:16]1[C:15]2[CH:25]=[C:11]([C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[C:4]([OH:26])=[O:3])[CH:12]=[CH:13][C:14]=2[O:18][N:17]=1)[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1cccc(-c2ccc3onc(NCC(C)(C)C)c3c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)CNc1noc2ccc(-c3cccc(C(=O)O)c3)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.1 %

Procedure:
A solution of ethyl-3-(3-(neopentylamino)benzo[d]isoxazol-5-yl)benzoate (0.38 g, 1.08 mmol, 1 equiv.) in methanol (4 mL) was cooled to 0° C. and an aqueous solution LiOH*H2O (0.16 g, 2.16 mmol, 2 equiv./in H2O (1.5 mL)) added slowly. The reaction mixture was stirred for 15 h at RT and subsequently concentrated in a vacuum. The residue was absorbed in EtOAc (100 mL), washed with 10% aq. citric acid sol. (2×20 mL), dried (MgSO4) and the solvent removed in a vacuum. The desired product (0.34 g, 97%) is obtained in this manner.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:8])[CH2:6]Cl)([CH3:3])[CH3:2].[OH-:9].[Na+]>C(O)(C)C>[CH:1]([O:4][C:5](=[O:8])[CH2:6][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)CCl
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)OC(=O)CC(=O)OC(C)C
Yield: 92 %

Procedure:
20 g of Co2 (CO)8 in 2.5 liters of isopropanol and 546 g (4 moles) of chloroacetic acid isopropyl ester are placed in a pressure vessel of a capacity of 18 liters, as in Example 1. At 55° C., and a pressure of 5 bars of CO, a 2.93% solution of sodium hydroxide in isopropanol is pumped into the vessel over a period of 3 hours, maintaining a pH of 7.0. At a transformation of 82%, 615 g of malonic acid diisopropyl ester (92% yield) is obtained after the usual processing. 98 g of chloroacetic acid isopropyl ester is recovered.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=O.I.CS[C:15](=[NH:28])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=1>N1C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:15]2[NH:28][C:5]([C:4]3[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10][CH:9]=3)=[N:7][N:8]=2)=[CH:18][C:19]=1[C:24]([F:25])([F:26])[F:27]
Reactant: NNC(=O)c1cccc(O)c1
Reactant: CSC(=N)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: I
Solvent: c1ccncc1
Product: Oc1cccc(-c2nnc(Nc3ccc(Cl)c(C(F)(F)F)c3)[nH]2)c1
Temperature: 25 °C
Yield: 31.3 %

Procedure:
3-hydroxybenzoic acid hydrazide (2.98 g, 19.58 mmol) and S-methyl N-[4-chloro-3-(trifluoromethyl)phenyl]isothiourea hydroiodide (7.78 g, 19.63 mmol) were suspended in 40 mL of anhydrous pyridine. The reaction mixture was refluxed for 18 hours, during which time it changed color from yellow into dark-red. Then it was cooled down to ambient temperature and poured with stirring into 250 mL of ice-water. The aqueous solution was decanted and the oily residue was purified by silica gel chromatography on Isco column using 0=>50% gradient of ethyl acetate in hexane. Solvent was removed in vacuo to give the title product as a white solid (2.176 g). 31.3% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([S:22][C:23]3C=CC([N+]([O-])=O)=CC=3[N+]([O-])=O)=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.CI.[OH-].[K+].Cl>N#N.O.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([S:22][CH3:23])=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Sc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])sc2-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: N#N
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CI
Product: COc1ccc(-c2cc(SC)sc2-c2ccc(OC)cc2)cc1
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
A suspension of 2,3-bis(4-methoxyphenyl)-5-(2,4-dinitrophenylthio)thiophene (4.8 g, 9.7 mmoles) in 20 ml N2 -purged methanol was cooled to 0° and treated with methyl iodide (1 ml, 14.6 mmoles) and a N2 -purged solution of potassium hydroxide (1.3 g, 19.4 mmoles) in a mixture of 5 ml water and 5 ml methanol. N2 -purged tetrahydrofuran (25 ml) was added and the reaction heated at reflux for 0.5 hour. An additional portion of methyl iodide (1 ml, 14.6 mmoles) was added and heating continued for 0.5 hour. The reaction mixture was cooled, poured into ≃50 ml 1 N HCl and extracted three times with ether and three times with ethyl acetate. The combined organic extracts were washed once with water, once with brine, dried and concentrated to a dark oil. Chromatography on silica gel and recrystallization from methanol gave the title compound (1.39 g), m.p. 106°-8°. Infrared and H-NMR spectra were consistent with the assigned structure. MS 342 (M+)
Reaction SMILES: [CH2:1]([N:4]([CH2:48][CH2:49][CH3:50])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:47]=[CH:46][C:14]([C:15]([N:17]([CH2:32][C:33]2[N:34](COCC[Si](C)(C)C)[CH:35]=[CH:36][N:37]=2)[CH2:18][C:19]2[N:20](COCC[Si](C)(C)C)[CH:21]=[CH:22][N:23]=2)=[O:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].[OH-].[Na+]>CO.Cl>[CH2:48]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:17]([CH2:32][C:33]2[NH:34][CH:35]=[CH:36][N:37]=2)[CH2:18][C:19]2[NH:23][CH:22]=[CH:21][N:20]=2)=[O:16])=[CH:46][CH:47]=1)[CH2:49][CH3:50]
Reactant: CCCN(CCC)CCCCNCc1ccc(C(=O)N(Cc2nccn2COCC[Si](C)(C)C)Cc2nccn2COCC[Si](C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN(CCC)CCCCNCc1ccc(C(=O)N(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of the compound 9 in methanol (2 mL), concentrated hydrochloric acid (2 mL) was added. The reaction mixture was stirred at 80° C. for 5 hours. The reaction mixture was added by an aqueous 5N sodium hydroxide solution and then extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol:28% ammonia water=80:10:1→80:20:4) to obtain the title compound (21 mg) having the following physical properties.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([CH:20]([OH:30])[CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.[CH3:31][O:32][C:33](=[O:42])[CH:34]([P:36]([O:40][CH3:41])([O:38][CH3:39])=[O:37])[NH2:35].COC(=O)C(P(OC)(OC)=O)NC(OCC1C=CC=CC=1)=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.CO.C(OCC)(=O)C>[CH3:31][O:32][C:33](=[O:42])[CH:34]([P:36]([O:38][CH3:39])([O:40][CH3:41])=[O:37])[NH:35][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([CH:20]([OH:30])[CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:19][C:11]=1[Cl:10]
Reactant: COC(=O)C(N)P(=O)(OC)OC
Reactant: O=C(O)c1ccc(C(O)C=Cc2cccc(O)c2)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(NC(=O)c1ccc(C(O)C=Cc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 72 %

Procedure:
Diisopropylethylamine (0.48 mL, 2.8 mmol) was added to a solution of rac.-2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoic acid (Example 93; 225 mg, 0.69 mmol), rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (331 mg, 1 mmol), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (284 mg, 0.75 mmol) and 1-hydroxybenzotriazole (102 mg, 0.76 mmol) in N,N-dimethylformamide (5 mL). The solution was stirred at room temperature for 17 h and then it was concentrated under high vacuum to remove N,N-dimethylformamide. Ethyl acetate (25 mL) was added and the resulting solution was washed in turn with 0.5N hydrochloric acid solution (10 mL), brine (10 mL), saturated sodium bicarbonate solution (10 mL) and brine (10 mL). Each of the aqueous layers was back-extracted in turn with ethyl acetate (10 mL). The combined organic layers were dried (MgSO4), filtered, evaporated and chromatographed over silica gel (50-100% ethyl acetate/hexanes, then 5% methanol/ethyl acetate) to furnish rac.-N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (240 mg, 72% yield) as an oil.