Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:23][O:24][CH:25]1[CH2:28][N:27]([CH2:29][CH2:30][CH2:31][NH2:32])[CH2:26]1>COCCOC>[CH3:23][O:24][CH:25]1[CH2:28][N:27]([CH2:29][CH2:30][CH2:31][NH:32][C:2]2[N:3]=[N+:4]([O-:15])[C:5]3[CH:14]=[C:13]4[C:9]([CH2:10][CH2:11][CH2:12]4)=[CH:8][C:6]=3[N:7]=2)[CH2:26]1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: COC1CN(CCCN)C1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COC1CN(CCCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Yield: 66.8 %

Procedure:
A solution of chloride 21 (1.33 g, 6.0 mmol), Et3N (1.7 mL, 12 mmol) and 3-(3-methoxy-1-azetidinyl)propylamine (299) (1.2 g, 8.4 mmol) in DME (30 mL) was heated at reflux temperature for 18 h. The solution was cooled, the solvent evaporated and the residue partitioned between dilute aqueous NH3 solution (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (2×25 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give 1-oxide 54 (1.32 g, 66%) as a yellow solid: mp 101-102° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.39 (s, 1H, H-5), 6.18 (br s, 1H, NH), 4.07 (p, J=5.9 Hz, 1H, CHO), 3.65-3.71 (m, 2H, CH2N), 3.54 (dt, J=6.2, 5.8 Hz, 2H, CH2N), 3.26 (s, 3H, OCH3), 2.94-3.04 (m, 4H, H-6, H-8), 2.82-2.88 (m, 2H, CH2N), 2.63 (t, J=6.4 Hz, 2H, CH2N), 2.14 (p, J=7.1 Hz, 2H, H-7), 1.70 (p, J=6.4 Hz, 2H, CH2); 13C NMR δ 158.8, 154.5, 148.8, 143.1, 129.8, 120.6, 114.7, 69.7, 61.5 (2), 58.6, 56.0, 40.8, 33.1, 32.3, 26.6, 25.8; MS (APCI) m/z 330 (MH+, 100%). Anal. calcd for C17H23N5O2: C, 62.0; H, 7.0; N, 21.3. Found: C, 61.7; H, 7.2; N, 21.2%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][CH:18](I)[CH3:19]>CC(C)=O>[CH3:17][CH:18]([O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1)[CH3:19]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1cccc(OC(C)C)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
1-(3-Hydroxyphenyl)ethanone (1.36 g, 10 mmol) was dissolved in acetone (50 mL) and potassium carbonate (2.76 g, 20 mmol) and 1-methylethyl iodide (1.5 mL, 15 mmol) were added sequentially, and the mixture was stirred at 70° C. overnight. The reaction solution was filtered, washed with acetone and concentrated in vacuo. The obtained residue was added water and ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with 1N aqueous solution of sodium hydroxide and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. 1-(3-(1-methylethoxy)-phenyl)ethanone (1.67 g (yield 94%)) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21]>>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([CH3:12])=[C:14]([C:20]([F:21])([F:22])[F:23])[CH:15]=1)=[O:9]
Reactant: Cc1ccc(N)cc1C(F)(F)F
Reactant: Cc1ccc(O)c(C(=O)O)c1
Product: Cc1ccc(O)c(C(=O)Nc2ccc(C)c(C(F)(F)F)c2)c1
Yield: 63.7 %

Procedure:
Using 5-methylsalicylic acid and 4-methyl-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[CH2:6]([NH:13][CH2:14][CH:15]([CH:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=1)[OH:21])[C:16](OC)=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[OH-].[Na+]>C1COCC1.C(O)C>[CH2:6]([NH:13][CH2:14][CH:15]([CH2:16][OH:17])[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=1)[OH:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(CNCc1ccccc1)C(O)c1ccc(F)c(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CCO
Product: OCC(CNCc1ccccc1)C(O)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of calcium chloride (5.66 g) in THF (80 ml) and ethanol (50 mL) was added sodium borohydride (2.57 g), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added a solution of methyl (2RS,3RS)-2-[(benzylamino)methyl]-3-(3-chloro-4-fluorophenyl)-3-hydroxypropanoate (12.0 g) in THF (20 mL) and ethanol (20 ml) under ice-cooling, and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added aqueous 1 N hydrochloric acid (15 mL) solution, the mixture was stirred for 1 hr, and neutralized with 1 N aqueous sodium hydroxide solution (15 ml), and the mixture was filtered through celite. The obtained oil was diluted with ethyl acetate, and the mixture was washed with distilled water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound as a crude product.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:19]=[N:18][C:17]2[C:8](=[CH:9][CH:10]=[C:11]3[C:16]=2[N:15]=[CH:14][CH:13]([N+:20]([O-:22])=[O:21])[C:12]3=[O:23])[CH:7]=1)=[O:5])C.[OH-].[Na+].C(O)(=O)C>O>[C:4]([C:6]1[CH:19]=[N:18][C:17]2[C:8](=[CH:9][CH:10]=[C:11]3[C:16]=2[N:15]=[CH:14][CH:13]([N+:20]([O-:22])=[O:21])[C:12]3=[O:23])[CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc2c3c(ccc2c1)C(=O)C([N+](=O)[O-])C=N3
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cnc2c3c(ccc2c1)C(=O)C([N+](=O)[O-])C=N3
Yield: 98 %

Procedure:
A mixture of 8-ethoxycarbonyl-3-nitro-4-oxo-3,4-dihydro-1,10-phenanthroline (0.55 g) and 2M sodium hydroxide solution (5 ml) was stirred at reflux for 2 hours. The hot suspension was neutralised with glacial acetic acid, cooled and diluted with water. The mixture was filtered and washed with water to give 8-carboxy-3-nitro-4-oxo-3,4-dihydro-1,10-phenanthroline in 98% yield.
Reaction SMILES: [N:1]1([C:10]2[C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:12][C:13]3[C:18]([N:19]=2)=[CH:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=3)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.CS(C)=O>O>[N:1]1([C:10]2[C:11]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[N:12][C:13]3[C:18]([N:19]=2)=[CH:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=3)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCc4ccccc43)nc2c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(-n3ccc4ccccc43)nc2c1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 3-(indolin-1-yl)-2-phenylquinoxaline-6-carboxylate (150 mg, 0.39 mmol, 1.00 equiv), DDQ (447 mg, 1.97 mmol, 4.00 equiv), DMSO (3 mL). The resulting solution was stirred for overnight at 30° C. in an oil bath. The resulting solution was diluted with 20 mL of H2O. The resulting solids were collected by filtration and applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 30 mg (20%) of methyl 3-(1H-indol-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]#[N:10])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15]([O:17][CH3:18])=[O:16])=[S:13].Cl.[CH3:20][N:21]([CH3:26])[CH2:22][C:23]([Cl:25])=[O:24]>ClCCl>[ClH:25].[CH3:18][O:17][C:15]([NH:14][C:12](=[S:13])[NH:11][C:3]1[CH:4]=[CH:5][C:6]([S:8][C:9]#[N:10])=[CH:7][C:2]=1[NH:1][C:23](=[O:24])[CH2:22][N:21]([CH3:26])[CH3:20])=[O:16]
Reactant: CN(C)CC(=O)Cl
Reactant: COC(=O)NC(=S)Nc1ccc(SC#N)cc1N
Agent: Cl
Solvent: ClCCl
Product: COC(=O)NC(=S)Nc1ccc(SC#N)cc1NC(=O)CN(C)C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
A stirred suspension of 2-amino-1-(3-methoxycarbonyl-2-thioureido)-4-thiocyanatobenzene (5.6 g.) in dichloromethane (190 ml.) was treated in one portion at room temperature with N,N-dimethylglycyl chloride hydrochloride (3.82 g.). The stirring was continued for one hour and the mixture was allowed to stand overnight. The solid was filtered off and recrystallised from methanol to give 1-(3-methoxycarbonyl-2-thioureido)-2-(2-dimethylaminoacetamido)-4-thiocyanatobenzene hydrochloride (4.35 g.), m.p. 192°-193° C. (with decomposition).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[CH3:2].[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[CH2:14][CH2:15]Br>>[Cl:10][C:11]1[CH:12]=[C:13]([CH2:14][CH2:15][CH2:9][C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:17]=[CH:18][CH:19]=1
Reactant: CCc1cnccc1C
Reactant: Clc1cccc(CCBr)c1
Product: CCc1cnccc1CCCc1cccc(Cl)c1
Yield: 50.6 %

Procedure:
1.13 g (9.35 mmol) of 3-ethyl-4-methylpyridine and 2.05 g (9.35 mmol) of m-chlorophenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.23 g of the desired compound (yield: 50.7%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:40][OH:41].C([O-])(O)=O.[Na+]>>[OH:41][N:40]=[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)[CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccc(-c3ccc(C(=O)NCCC(=O)O)cc3)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2ccc(-c3ccc(C(=O)NCCC(=O)O)cc3)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 3-({4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carbonyl}-amino)-propionic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (4:1) as a colorless oil, MS (ESI+): m/z=522.2376 ([M+H]+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:22]>C(Cl)Cl.C(OCC)C>[ClH:22].[ClH:22].[CH3:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)[CH:19]=1
Reactant: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)ncn1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(N2CCC(N)CC2)ncn1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of [1-(6-methyl-pyrimidin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (686 mg, 2.3 mmol) in CH2Cl2 (12 mL) was added at room temperature under stirring a 2 M HCl solution in diethyl ether (6 mL) and was stirred at room temperature over night. The precipitate was filtered off, washed with CH2Cl2 and diethyl ether and dried to yield the title compound as a light yellow solid (610 mg, 98%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]([CH3:25])[CH3:24])=[C:16]([NH:26][C:27]2[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=2)[N:15]=1.O>CN(C=O)C>[CH:23]([N:20]1[CH:19]=[N:18][C:17]2[C:21]1=[N:22][C:14]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[N:15][C:16]=2[NH:26][C:27]1[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=1)([CH3:25])[CH3:24]
Reactant: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(Cl)nc21
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(Oc3cccc([N+](=O)[O-])c3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.4 %

Procedure:
To a solution of 3-nitro-phenol (143 mg, 1.03 mmol) in DMF (15 mL) was added sodium hydride (56 mg, 1.4 mmol) slowly and the mixture was stirred at rt for 30 min. 2-chloro-9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine (200 mg, 0.69 mmol), as prepared in step 1 of Example 2, was added slowly. After the addition, the mixture was stirred at 110° C. overnight. The cooled reaction mixture was poured into water (100 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried over Na2SO4, concentrated and the residue was purified by flash column chromatography (MeOH:EtOAc=1:10) to give the title compound (50 mg, 18% yield) as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[Br:11]Br>CC(O)=O.CCOC(C)=O>[Br:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[Cl:1]
Reactant: Clc1n[nH]c2ccccc12
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Clc1n[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a room temperature solution of 3-chloro-1H-indazole (10.0 g, 65.5 mmol) in AcOH (250 ml) was added Br2 (3.54 ml, 68.8 mmol) dropwise. The reaction mixture was stirred at room temperature for 18 hours, then diluted with EtOAc (500 ml), washed with aqueous NaOH solution (10%), saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered, concentrated, and the residue was recrystallized from toluene. The solid was washed with hexanes and dried in vacuo affording 5-Bromo-3-chloro-1H-indazole CCXIV as a white solid (54% yield).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=2)=[C:4]([F:15])[CH:3]=1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]2)=[C:4]([F:15])[CH:3]=1
Reactant: O=C1C=C(c2cc(F)c(Br)cc2F)CC1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCC(c2cc(F)c(Br)cc2F)C1
Yield: 91.8 %

Procedure:
A solution of 16.4 g (60.2 mmol) of 3-(4-bromo-2,5-difluorophenyl)-2-cyclopentenone in 400 ml of THF was hydrogenated over 2.0 g of Wilkinson's catalyst at 25° C. for 18 hours. The solution was concentrated to a brown oil which was chromatographed on silica gel (E. Merck-230-400 Mesh) to remove the catalyst. The residue obtained was triturated with hexane, and the solids were filtered, washed with hexane, and dried to give 15.2 g (93%) of the title compound; mp 63°-65° C.
Reaction SMILES: C[Mg]Br.[CH:4]([C:6]1[N:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][CH:7]=1)=[O:5].O.[C:16](OCC)(=O)C>O1CCCC1>[OH:5][CH:4]([C:6]1[N:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][CH:7]=1)[CH3:16]
Reactant: CCOC(C)=O
Reactant: NC(=O)c1cccc(C=O)n1
Agent: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1cccc(C(N)=O)n1

Procedure:
An ethereal solution of methyl magnesium bromide (3 mol/l) (546 ml) was added dropwise to a solution of 6-formyl-2-pyridinecarboxamide (61.5 g) in tetrahydrofuran (900 ml) at 0°-13° C. with stirring. After the mixture was stirred at the same temperature for 2 hours and cold water was dropped to the reaction mixture under ice-cooling. To the mixture was added ethyl acetate and adjusted to pH 7 with N-hydrochloric acid. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 6-(1-hydroxyethyl)-2-pyridinecarboxamide (63.2 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[OH:30][CH2:31][CH2:32][N:33]([CH:37]([CH3:39])[CH3:38])[CH2:34][CH2:35]O>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:35][CH2:34][N:33]([CH2:32][CH2:31][OH:30])[CH:37]([CH3:39])[CH3:38])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(C)N(CCO)CCO
Product: CC(C)N(CCO)CCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{2-[(2-hydroxyethyl)(1-methylethyl)amino]ethyl}-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and N,N-bis(2-hydroxyethyl)isopropyl amine following General Procedure J.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5](=O)[CH2:6][CH2:7][O:8][CH3:9].CO.[BH3-]C#[N:16].[Na+].C(Cl)Cl>Cl>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH:5]([NH2:16])[CH2:6][CH2:7][O:8][CH3:9]
Reactant: [BH3-]C#N
Reactant: COCCC(=O)CC(=O)OC
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COCCC(N)CC(=O)OC
Yield: 101.1 %

Procedure:
Methyl-5-methoxy-3-oxovalerate (10 g, 62.5 mmol) was added to methanol (200 ml) followed by ammonium formats (39.4 g, 620 mmol) and NaBH3CN (3.9 g, 46 mmol) at 25° C. After 24 h the methanol was removed in vacuo to leave a white mass. Methylene chloride was added and the mixture filtered. The methylene chloride was evaporated resulting in an oil which was dissolved in 1N HCl (200 ml) and extracted with ether (100 ml). The ether layer was discarded and the aqueous layer was made basic using solid K2CO3. The product was extracted into methylene chloride dried over Na2SO4 and evaporated to give methyl-5-methoxy-3-aminovalerate (7.5 g). 1H NMR (d6-DMSO) δ 1.25 (m, 3H) 1.66 (m, 2H), 1.86 (bs, 2H), 2.9 (M, 2H), 3.33 (s, 3H), 3.49 (M, 2H), 3.7 (s, 3H); MS (FAB) m/z 161.2 (MH+).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:5]1[CH:32]=[CH:31][C:8]2[N:9]([CH2:13][CH2:14][O:15][C:16]3[CH:30]=[CH:29][C:19]([O:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24]CC)=[O:23])=[CH:18][CH:17]=3)[C:10](=[O:12])[S:11][C:7]=2[CH:6]=1.[OH-].[K+].Cl>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:5]1[CH:32]=[CH:31][C:8]2[N:9]([CH2:13][CH2:14][O:15][C:16]3[CH:30]=[CH:29][C:19]([O:20][C:21]([CH3:28])([CH3:27])[C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)[C:10](=[O:12])[S:11][C:7]=2[CH:6]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=NOC)c4ccccc4)ccc32)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C

Procedure:
To a solution of the compound obtained in Step B of Example 31 (0.8 g) in 5 ml of ethanol 95° there is added potassium hydroxide (100 mg) dissolved in 1 ml of ethanol 95° The reaction mixture is heated at reflux overnight. After cooling to ambient temperature, the solution is acidified using 1N HCl. The precipitate obtained is then filtered and purified on a reverse phase, RP18, eluant MeOH/H2O 6/4, to yield the title compound in the form of a white powder.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][P:11]([O-:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30]Cl)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30][P:11](=[O:20])([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: ClCCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=P(CCCCc1ccccc1)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride 50% oil dispersion (1.01 g., 20.8 mmole) is added to a solution of dibenzylphosphite (5.25 g., 20.0 mmole) in dry dimethylformamide (30 ml.) under argon. The resulting mixture is stirred at room temperature for one hour and at 40° (bath temperature) for 30 minutes. The resulting clear, yellow solution is allowed to cool to room temperature and treated with a solution of 4-phenylbutyl chloride (4.0 g., 23.7 mmole) in dimethylformamide (3 ml.). The resulting mixture is stirred at room temperature for 18 hours and at 40° for 2 hours. The mixture is partitioned between ethyl acetate-1% potassium bisulfate. The organic phase is washed successively with water (twice), saturated sodium bicarbonate (twice), and saturated sodium chloride (twice), dried over sodium sulfate, and evaporated. The residue is purified by flash chromatography (silica gel, 100 g. of LPS-1) eluting with ethyl acetate:hexane (3:7) to give (4-phenylbutyl)phosphonic acid, dibenzyl ester as a colorless, somewhat viscous oil.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]=O)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.[Br-].[CH:44]1([CH2:47][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:46][CH2:45]1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:38])[CH3:39])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]=[CH:47][CH:44]3[CH2:46][CH2:45]3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:2][CH2:3]1
Reactant: c1ccc([P+](CC2CC2)(c2ccccc2)c2ccccc2)cc1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(C=O)c(-c3ccc(OC(F)F)c(OC4CC4)c3)n2COCC[Si](C)(C)C)c1=O
Agent: [Br-]
Product: C[Si](C)(C)CCOCn1ncc2c(c(C=CC3CC3)c(-c3ccc(OC(F)F)c(OC4CC4)c3)n2COCC[Si](C)(C)C)c1=O
Yield: 71.2 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 68-(a) except for using 0.62 g (1.00 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-formyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the same manner as in Example 15-(a), and using 1.19 g (3.00 mmol) of cyclopropylmethyltriphenylphosphonium bromide in place of butyltriphenylphosphonium bromide, whereby 0.47 g of the title compound was obtained as a colorless oil. (Yield: 71%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([N:7]([CH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)=[O:6])[CH3:2]>CCOC(C)=O.CCO.CCOC(C)=O.O=[Pt]=O>[CH2:1]([O:3][C:4](=[O:27])[C:5]([N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1)[CH2:18][C:19]1[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)N(Cc1ccc([N+](=O)[O-])cc1)Cc1cc(Cl)cc(Cl)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)N(Cc1ccc(N)cc1)Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
A suspension of PtO2 (250 mg) in EtOAc (5 mL) was added to a solution of ethyl[(3,5-dichlorobenzyl) (4-nitrobenzyl)amino](oxo)acetate (2.00 g, 4.86 mmol) in EtOH/EtOAc (2/1, 90 mL) under H2 (1 atm). The reaction mixture was stirred vigorously at rt for 30 min. The reaction mixture was filtered over a pad of Celite and silica gel to remove the catalyst. The solvents were removed under reduced pressure. The residue was purified by flash chromatography over silica gel (c-Hex/EtOAc 2/1) to give the title compound as a pale yellow oil (1.21 g, 61%). 1H NMR (CDCl3, 300 MHz) δ 7.31-7.05 (m, 5H), 6.71 (m, 2H), 4.39 (m, 4H), 4.25 (br s, 2H), 1.36 (m, 3H). HPLC (Condition A), Rt: 3.4 min (HPLC purity: 94.1%).