Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[Br:66][C:67]1[CH:68]=[C:69]([CH2:74][NH2:75])[CH:70]=[CH:71][C:72]=1[CH3:73]>ClCCl>[Br:66][C:67]1[CH:68]=[C:69]([CH2:74][NH:75][C:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[N:28]=2)=[O:30])[CH:70]=[CH:71][C:72]=1[CH3:73]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Reactant: Cc1ccc(CN)cc1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(Br)c2)n1
Temperature: 25 °C
Yield: 134.4 %

Procedure:
To a suspension of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (50.8 g, 112 mmol) in a 2 L 3-neck flask was added dichloromethane (DCM) (600 mL) followed by DIPEA (98 ml, 561 mmol), giving a solution. To it was added TBTU (39.7 g, 123 mmol) and the mixture was then stirred at room temperature for 2 min whereupon 1-(3-bromo-4-methylphenyl)methanamine hydrochloride (29.2 g, 123 mmol) was added. The mixture was stirred under nitrogen at room temperature. After 2.5 h the mixture was partitioned between dichloromethane and water and the aqueous layer extracted well with dichloromethane. The combined organics were washed with water, saturated sodium bicarbonate, brine, dried (MgSO4), filtered and evaporated to give 95.5 g of a pale golden foam that was purified on a 750 g Companion XL silica cartridge, eluting with 0-100% ethyl acetate in dichloromethane over 8 column volumes. However, halfway through loading, the material started to crystallise on the column, blocking the loading so this material already on the column was eluted as above to give 30.01 gm, (26%) of a white solid (combined theoretical yield of the two preparations was 116.6 g). The lab HPLC showed 99.4% purity (retention time 2.22 min). LC-MS m/z 634, 636 (M+H)+, 1.06 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Cl[CH2:10][C:11](=O)[CH3:12].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:3]2[S:8][CH:10]=[C:11]([CH3:12])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1ccccc1Cl
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1csc2c(Cl)cccc12
Yield: 63.9 %

Procedure:
A mixture of 2-chlorothiophenol (750 μL, 6.6 mmol), chloroacetone (1.1 mL, 13.8 mmol) and K2CO3 (1.8 g, 13 mmol) in acetone (15 mL) was refluxed for 2 h. The mixture was filtered and the solvent evaporated. The crude product was dissolved in chlorobenzene (30 mL) and polyphosphoric acid (PPA, 0.5 g) was added. The resulting mixture was refluxed over night (Plé et al., (1988) J. Heterocyclic Chem. 25, 1271-1272). Additional PPA (0.5 g) was added and the reaction mixture was refluxed for another 7 h. The solvent was decanted from the PPA-residue, the residue was treated with CH2Cl2 and the combined organic extracts were washed with water and dried, and then the solvents were removed by evaporation. The crude product was purified on silica using heptane as eluent, to give the title compound (770 mg, 64% over two steps). 1H NMR (400 MHz, CDCl3) δ ppm 2.44 (d, J=1.20 Hz, 3 H) 7.14 (q, J=1.20 Hz, 1 H) 7.32-7.38 (m, 2 H) 7.60-7.65 (m, 1 H)
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=O.NN.C1C=CC2N(O)[N:18]=[N:17]C=2C=1.CCN=C=NCCCN(C)C>ClCCl>[O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([NH:17][NH2:18])=[O:8]
Reactant: O=C(O)[C@@H]1CCCO1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: ClCCl
Product: NNC(=O)[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a round-bottom flask was added a solution of (S)-tetrahydrofuran-2-carboxylic acid (3.00 g, 23.3 mmol, 1.00 equiv, 90%) in dichloromethane (40 mL). NH2NH2 (2 mL, 2.00 equiv), HOBt (5.20 g, 38.5 mmol, 1.50 equiv), and EDCI (7.50 g, 39.1 mmol, 1.50 equiv) were added and the resulting mixture was stirred overnight at 25° C. The solids were removed by filtration, and the filtrate was concentrated in vacuo to furnish 2.50 g (74%) of (S)-tetrahydrofuran-2-carbohydrazide as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:20].CO>O1CCCC1>[ClH:20].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cccc(C#N)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc([N+](=O)[O-])cc1-c1cccc(CN)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 47.9 %

Procedure:
To a stirring solution of 2-(3-cyanophenyl)-4-nitroanisole from Example 111 (4.0 g, 16 mmol) in tetrahydrofuran (100 mL) was added borane-tetrahydrofuran complex dropwise (48 mL of a 1.0 M solution in tetrahydrofuran, 3 equiv, 48 mmol). The solution was heated to reflux for 3 hours. The solution was allowed to cool to room temperature and hydrochloride acid (24 mL of 4.0 M solution in dioxane, 96 mmol) was added slowly. Methanol (100 mL) was added slowly and the solution was evaporated to dryness. The residue was diluted with methanol (100 mL) and evaporated to dryness. The residue was dissolved in dichloromethane (100 mL). A clear solution was achieved, from which a precipitate began to form (<1 min). The solution was stirred at room temperature for 14 hours and the solid was collected on a Büchner funnel, washed with dichloromethane (10 mL), and dried under high vacuum to afford 2-(3-aminomethylphenyl)-4-nitroanisole hydrochloride (2.26 g, 55% yield).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1([C:14](O)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[OH-].[Na+].O>C1COCC1>[CH3:7][C:8]1([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC1(C(=O)O)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(CO)CCCCC1
Temperature: 4 °C
Yield: 82 %

Procedure:
To a stirring solution of LiAlH4 (20 mmol) in anhydrous THF (10 mL) at 4° C. was added 1-methyl-cyclohexanecarboxylic acid (i, 7.0 mmol) in 50 mL of THF dropwise over a period of 1 hour. The solution was stirred at refluxing temperature under N2 for 6 hours. The solution was cooled to 4° C. by ice bath, and 1 mL of 1 N NaOH (1 mL) followed by H2O (2 mL) was slowly added to the solution to quench the reaction. The solution was stirred at 23° C. for 1 hour and then filtered to remove solid material. The solution was concentrated. Purification by flash silica gel chromatography (ethyl acetate/hexanes, 1:2) gave the product, (1-methyl-cyclohexyl)-methanol (ii), in 82% yield.
Reaction SMILES: Cl.[Cl-].[Ca+2].[Cl-].[S:5]([OH:9])(=[O:8])(=[O:7])[CH3:6].[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]2[N:24]([CH3:25])[C:23]3[CH:26]=[CH:27][C:28]([C:30]([N:32]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[O:31])=[CH:29][C:22]=3[N:21]=2)=[CH:14][CH:13]=1)#[N:11].C(=O)([O-])[O-].[NH4+:50].[NH4+].N>C(O)C>[S:5]([OH:9])(=[O:8])(=[O:7])[CH3:6].[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]2[N:24]([CH3:25])[C:23]3[CH:26]=[CH:27][C:28]([C:30]([N:32]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[O:31])=[CH:29][C:22]=3[N:21]=2)=[CH:14][CH:13]=1)(=[NH:50])[NH2:11]
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccn1
Agent: CS(=O)(=O)O
Agent: Cl
Agent: N
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
Hydrogen chloride gas was passed into a mixture of calcium chloride (125 g) and ethanol (1500 ml) at a temperature below 20° C. for a period of 30 minutes. The reaction mixture was cooled to −15 to −5° C. and stirred for 15 minutes. Ethyl 3-(2-((4-cyanophenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-10 (500 g) was added to the reaction mixture. Hydrogen chloride gas was slowly purged into the reaction mixture for a period of 3 hours. The temperature of the reaction mixture was raised to 25-35° C. and stirred for 10 hours. After completion of the reaction, expell the hydrogen chloride gas present in the reaction mixture under nitrogen atmosphere. Ethanol (2500 ml), followed by ammonium carbonate (2000 g) were added to the reaction mixture and stirred for 40 minutes at −30±5° C. The reaction mixture was cooled to 0-5° C. and ammonia gas was passed into the reaction mixture for 3 hours. The temperature of the reaction mixture was raised to 20-30° C. and stirred for 20 hours. After completion of the reaction, filtered the reaction mixture and the filtrate was concentrated to get title compound. Purity by HPLC: 80.61%;
Reaction SMILES: [OH-].[K+].[CH:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]#[N:20])[CH:15]=[CH:16][CH:17]=1.[BH4-].[Na+]>C(O)C.O.CO>[Br:11][C:12]1[CH:13]=[C:14]([CH:18]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:19]#[N:20])[CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: N#CCc1cccc(Br)c1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: N#CC(Cc1ccccc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
A solution of 40% KOH (2.83 g in 5.0 ml of H2O) in ethanol (13 ml) was added to a solution of benzaldehyde (2.85 ml, 28.05 mmol) and 3-bromophenylacetonitrile (5 g, 25.50 mmol) in ethanol (9 ml). The reaction mixture was then stirred at room temperature for 2 hours and the precipitate was collected by suction filtration and washed with cold ethanol (6.68 g, 92%). The crude product (3.45 g, 12.14 mmol) was then dissolved methanol (35 ml) and heated to 65° C. Sodium borohydride (459 mg, 12.14 mmol) was added in portions and the reaction mixture was maintained at this temperature for a further 2 hours. Upon cooling, water (10 ml) was added and the solvent was removed under reduced pressure. The residue was partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to afford the desired product (1.80 g, 52%), which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc([N+](=O)[O-])cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Temperature: 25 °C

Procedure:
A suspension of 2-chloro-4-nitrotoluene (10.0 g, 58.3 mmol), N-bromosuccinimide (NBS, 10.9 g, 61.2 mmol), and 2,2′-azobis(2-methylpropionitrile) (AIBN, 0.29 g, 1.75 mmol) in 120 mL of CCl4 was heated at reflux under an atmosphere of N2 for 12 h. The reaction mixture was cooled to ambient temperature, and the solid was filtered and washed with EtOAc. The combined filtrate was washed with aq. NaHCO3, dried over Na2SO4, filtered, concentrated on rotovap, and further dried under vacuum. 1H NMR indicated the ratio of desired product to unreacted 2-chloro-4-nitrotoluene to be 50:50. This material was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Na+].[Na+].B(O)(O)[C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1>C(COC)OC.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>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)#[N:5]
Reactant: N#Cc1ccccc1Br
Reactant: Cc1ccc(B(O)O)cc1
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: COCCOC
Product: Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
Nitrogen was bubbled through a solution of 2-bromobenzonitrile (309.4 g, 1.70 mol) in dimethoxyethane (4.2 L) for 30 minutes then the following reagents added in succession: tetrakis(triphenylphosphine)palladium(0), (95 g, 0.082 mol); 2M aqueous sodium carbonate solution (1785 mL, 3.57 mol); and p-tolylboronic acid (239.1 g, 1.76 mol). The reaction mixture was heated under an atmosphere of nitrogen at 70° to 78° C. for 19 hours. The two-phase mixture was cooled to room temperature and the layers separated. The organic layer was evaporated to dryness under reduced pressure. The aqueous layer was extracted with ether (3×1.2 L) and the extracts added to the organic residue. The insoluble material was filtered off and washed with ether. The filtrate was dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The oily residue was filtered to remove the solids and the filtrate distilled under high vacuum (0.1-0.2 torr) collecting the fraction boiling between 135° to 140° C. to afford 325 g of 2-cyano-4'-methylbiphenyl. MS (DEI) 193 (M+).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[OH:27].O[CH:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Cl:15][C:16]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[O:27][CH:33]1[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: N#Cc1cc(O)c(Cl)c([N+](=O)[O-])c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C#N)cc([N+](=O)[O-])c2Cl)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
DIAD (0.309 mL, 1.495 mmol) was added to a solution of 4-chloro-3-hydroxy-5-nitrobenzonitrile (Example 425B) (223 mg, 1.122 mmol), (+/−)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (200 mg, 1.068 mmol) and triphenylphosphine resin (3 mmol/g loading, 560 mg, 2.136 mmol) in THF (5 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 0-20% ethyl acetate/dichloromethane). (+/−)-tert-butyl 3-(2-chloro-5-cyano-3-nitrophenoxy)pyrrolidine-1-carboxylate (272 mg) was obtained as a yellow solid.
Reaction SMILES: [CH:1]1([N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH:27]([CH3:29])[CH3:28])[CH2:5][CH3:6])[CH2:3][CH2:2]1.[OH-].[Na+].C(OC(=O)C1C=CC(C#CC2C=CC3C(NC4CC4)CCC(C)(C)C=3C=2)=CC=1)C>C(O)C.O1CCCC1>[CH:1]1([N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH:27]([CH3:28])[CH3:29])[CH2:5][CH3:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(CN(CC)C3CC3)c(C(C)C)c2)cc1
Agent: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3NC2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCN(Cc1ccc(C#Cc2ccc(C(=O)O)cc2)cc1C(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
Using General Procedure I; a solution of ethyl 4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-isopropyl-phenylethynyl}-benzoate (Compound 133, 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (600.0 mg,1 5.0 mmols, 3.0 mL of a 5N aqueous solution) and stirred overnight at room temperature and then at 55° C. for 9 hours. Work-up followed by crystallization of the solid residue from hot CH3CN afforded 45.0 mg (72%) of the title compound as a pale-yellow solid.
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][CH3:6])[CH3:3].[S:7](Cl)([Cl:10])(=[O:9])=[O:8]>>[CH2:2]([N:4]([CH2:5][CH3:6])[S:7]([Cl:10])(=[O:9])=[O:8])[CH3:3]
Reactant: CCNCC
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Product: CCN(CC)S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
A solution of diethylamine hydrochloride (1 g) in sulfuryl chloride (10 ml) was heated at 50° C. for 4 hours. The solution was allowed to cool to ambient temperature and sulfuryl cloride was evaporated in vacuo. To the residue were added ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give diethylsulfamoyl chloride (720 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@@H:14]([OH:15])[CH2:13][C@H:12]([O:16][C@H:17]3[C@@H:22]([OH:23])[CH2:21][C@H:20]([O:24][C@@H:25]4[CH2:30][C@H:29]5[CH2:31][CH2:32][C@H:33]6[C@@:38]7([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]8[CH2:47][O:46][C:44](=[O:45])[CH:43]=8)[C@@:37]7([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]6[C@@:28]5([CH3:51])[CH2:27][CH2:26]4)[O:19][C@@H:18]3[CH3:52])[O:11][C@@H:10]2[CH3:53])[CH2:5][C@H:4]([OH:54])[C@@H:3]1[OH:55].I([O-])(=O)(=O)=O.[Na+]>CN(C=O)C.CO.O>[CH3:52][C@H:18]1[O:19][C@@H:20]([O:24][C@@H:25]2[CH2:30][C@H:29]3[CH2:31][CH2:32][C@H:33]4[C@@:38]5([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]6[CH2:47][O:46][C:44](=[O:45])[CH:43]=6)[C@@:37]5([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]4[C@@:28]3([CH3:51])[CH2:27][CH2:26]2)[CH2:21][C@H:22]([OH:23])[C@@H:17]1[O:16][C@@H:12]1[O:11][C@H:10]([CH3:53])[C@@H:9]([O:8][CH:6]([O:7][CH:2]([CH:3]=[O:55])[CH3:1])[CH2:5][CH:4]=[O:54])[C@@H:14]([OH:15])[CH2:13]1
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H](O[C@H]4CC[C@@]5(C)[C@H](CC[C@@H]6[C@@H]5C[C@@H](O)[C@]5(C)[C@@H](C7=CC(=O)OC7)CC[C@]65O)C4)O[C@@H]3C)O[C@@H]2C)C[C@H](O)[C@@H]1O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C=O)OC(CC=O)O[C@H]1[C@@H](O)C[C@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3CC[C@@]4(C)[C@H](CC[C@@H]5[C@@H]4C[C@@H](O)[C@]4(C)[C@@H](C6=CC(=O)OC6)CC[C@]54O)C3)O[C@@H]2C)O[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
Digoxin (2 g) was dissolved in a mixture of DMF (20 ml), methanol (14 ml) and water (14 ml) and treated dropwise with a solution of sodium periodate (1.434 g) in a mixture of water (10 ml) and methanol (10 ml). The solution was stirred for 3 hours at room temperature, then for 2 days at 4° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried, and evaporated to yield the digoxin dialdehyde as an oily white solid (2 g).
Reaction SMILES: [N+:1]([CH:4]([C:27]([O:29][CH3:30])=[O:28])[CH:5]([C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=1[O:25][CH3:26])[CH:6]([C:11]([O:13][CH3:14])=[O:12])[C:7](OC)=[O:8])([O-])=O>[Ni].O1CCCC1>[O:8]=[C:7]1[NH:1][CH:4]([C:27]([O:29][CH3:30])=[O:28])[CH:5]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=2[O:25][CH3:26])[CH:6]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(C(=O)OC)C(c1c(OC)cc(OC)cc1OC)C(C(=O)OC)[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)C1NC(=O)C(C(=O)OC)C1c1c(OC)cc(OC)cc1OC

Procedure:
To a 1 L pressure reactor, tetrahydrofuran (100 mL) and Raney nickel (20 g) was added followed by the addition of a solution of (+)-trimethyl 3-nitro-2-(2,4,6-trimethoxyphenyl)propane-1,1,3-tricarboxylate (32 g, 0.074 mol) in tetrahydrofuran (300 mL). Under stirring, the reactor was purged three times with nitrogen followed by hydrogen. The reaction mixture was stirred overnight under a hydrogen pressure of 80 psi. At the end of the reaction, Raney nickel was filtered off and washed with tetrahydrofuran (150 mL) under nitrogen. The organic layer was concentrated under reduced pressure to yield a white solid. 1H NMR revealed the presence of a mixture of isomers. The mixture of cis and trans isomers was obtained in a yield of 25 g (91.32%). A small portion of reaction mixture was purified by column chromatography using 5% methanol in chloroform as eluting agent to separate the isomers and one of the separated isomers was found to be identical to the isomer obtained by reduction using stannous chloride, confirmed by 1H NMR, mass spectra and HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:24])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=[C:12]([C:14](OC)=[O:15])[CH:13]=1.BrC1C(=O)N(C2C=CC=CC=2)C=C(C(OC)=O)C=1.ClC1C=CC=CC=1B(O)O.[H-].C([Al+]CC(C)C)C(C)C.Cl.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:24])[N:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:11]=[C:12]([CH2:14][OH:15])[CH:13]=1
Reactant: COC(=O)c1cc(-c2ccccc2Cl)c(=O)n(-c2ccccc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: COC(=O)c1cc(Br)c(=O)n(-c2ccccc2)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=c1c(-c2ccccc2Cl)cc(CO)cn1-c1ccccc1
Temperature: -78 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
36 mg of 3-(2-chlorophenyl)-5-methoxycarbonyl-1-phenyl-1,2-dihydropyridin-2-one synthesized by the method of Referential Example 3 from 3-bromo-5-methoxycarbonyl-1-phenyl-1,2-dihydropyridin-2-one and 2-chlorophenylboronic acid, was dissolved in 20 ml of toluene. After cooling to −78° C., 0.1 ml diisobutyl aluminum hydride (1.5 M tetrahydrofuran solution) was added dropwise thereinto. While heating from −78° C. to room temperature, the mixture was stirred overnight. Then, 1N hydrochloric acid was added thereto, followed by stirring. The mixture was neutralized with an aqueous solution of sodium hydrogen carbonate; and then extracted with ethyl acetate. Then, the extract was successively washed with water and brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 12 mg of the titles compound.
Reaction SMILES: C([C:3]([CH2:10][CH3:11])([C:7]([O-:9])=[O:8])[C:4]([O-:6])=[O:5])C.BrCCBr>[OH-].[Na+].[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[C:3]1([C:7]([OH:9])=[O:8])([C:4]([OH:6])=[O:5])[CH2:10][CH2:11]1
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: BrCCBr
Product: O=C(O)C1(C(=O)O)CC1
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
In 50% NaOH 187 ml was dissolved 15 g of diethylmalonate at room temperature. Benzyltriethylammoniumchloride (21.3 g) was added and the resulting mixture was stirred for 10 minutes. 1,2-Dibromoethane (12.3 g) was added to the reaction solution and the resulting mixture was stirred for more than 18 hours at room temperature. The reaction mixture was neutralized by adding dropwise conc, sulfuric acid and then extracted with ethyl acetate. The extract was distilled under reduced pressure to give 6.2 g of the title compound as a white solid.