Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]([O:12][C:13](=[O:27])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[NH:17][C:16]=1[CH3:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[H-].[Na+].[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1.CCOCC>CN(C)C=O.O.C(O)(=O)C>[C:1]([O:4][CH:5]([O:12][C:13](=[O:27])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]([C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:31]([Cl:30])=[CH:32][CH:33]=2)[C:16]=1[CH3:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc2[nH]c(C)c(CC(=O)OC(OC(C)=O)c3ccccc3)c2c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)c(CC(=O)OC(OC(C)=O)c1ccccc1)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1.84 g of (5-methoxy-2-methyl-3-indoleacetoxy)-benzyl acetate in 19 ml of dimethylformamide, was added to 0.51 g of a suspension of sodium hydride in 20 ml of dimethylformamide, stirred for 20 minutes at 0°C under nitrogen and then 1.19 mol of p-chlorobenzoyl chloride were introduced. The mixture was stirred for 5 hours under nitrogen at 0° to 5°C and thereafter introduced into 115 ml of ether, 115 ml of glacial acetic acid and 230 ml of iced water. The layers were separated and the aqueous phase was extracted by shaking several times with ether. The combined ethereal phases were washed with water, dried and concentrated by evaporation under vacuum. 1.7 g of a crude product were obtained and this was purified by chromatography from cyclohexane-glacial acetic acid (3:1) on kieselguhr. The yield was 0.3 g which corresponds to 11.9% of the theoretical yield with a melting point of 92-94°C. The [1 -(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetoxy]-benzyl acetate which formed was converted in the manner indicated into the free acid.
Reaction SMILES: [BH4-].[Li+].CO.[C:5]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]([CH3:35])[C:24](=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](OC)=[O:31])[CH2:17][CH2:16]1)=[O:13].[OH-].[Na+]>O1CCCC1>[C:5]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:13])[O:14][CH:15]1[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][N:23]([C:24](=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[CH3:35])[CH2:19][CH2:20]1
Reactant: COC(=O)CCCCCC(=O)N(C)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.2 %

Procedure:
Lithium borohydride (39 mg, 1.80 mmol) was suspended in tetrahydrofuran (6 mL), methanol (73 μL, 1.80 mmol) and a solution of the compound (235 mg, 0.450 mmol) obtained in Example 39a in tetrahydrofuran (7 mL) was added, and the mixture was stirred at room temperature for 2 days. A 1 N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=50:1, v/v) to give the title compound (163 mg; yield, 75%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26](O)=[O:27])#[N:2].C(Cl)(=O)C(Cl)=O.Cl.[CH3:36][O:37][C:38](=[O:42])[C@@H:39]([CH3:41])[NH2:40].C(N(CC)CC)C>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:40][C@@H:39]([C:38]([O:37][CH3:36])=[O:42])[CH3:41])=[O:27])#[N:2]
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H](C)NC(=O)/C=C/c1c(C#N)c2c(C)cc(C)nc2n1[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of D-alanine methyl ester hydrochloride (226 mg, 1.62 mmol), triethylamine (0.676 ml, 4.86 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane and ethyl acetate.
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([C:9]([OH:11])=O)=[CH:5][CH:6]=[CH:7][CH:8]=1.O.[NH2:14][NH2:15]>C(O)C>[C:9]1(=[O:11])[C:4]2[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:2]=[N:15][NH:14]1
Reactant: O=C(O)c1ccccc1C(Br)Br
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1[nH]ncc2ccccc12
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A solution of 29.4 g (0.1 mole) of α,α-dibromo-o-toluic acid and 16 g (0.32 mole) of hydrazine hydrate in 200 ml of ethanol was heated under reflux with stirring for 1 hour. The solvent was evaporated under reduced pressure, and the residue recrystallized from ethanol to give 12.8 g (yield: 88%) of 1-phthalazinone having a melting point of 181°-182° C.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)C.Cl.[CH3:25][O:26][C:27]1[C:28]([NH2:33])=[CH:29][CH:30]=[CH:31][CH:32]=1.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.CO>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH3:25])[CH2:11][CH2:10]2)=[O:20])=[CH:18][CH:17]=1
Reactant: CCOC(CN1CCC(C(=O)c2ccc(F)cc2)CC1)OCC
Reactant: COc1ccccc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1NCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Reaction time: 1 h
Yield: 66.2 %

Procedure:
1-(2,2-Diethoxyethyl)-4-(4-fluorobenzoyl)piperidine (81 mg, 0.25 mmol) was dissolved in THF (3 ml) to which was subsequently added 10% hydrochloric acid (2 ml) at room temperature. After 1 hour of stirring at the same temperature, the solvent was removed by evaporation, and the resulting residue was subjected to azeotropic distillation using benzene (5 ml×4) to obtain an orange glutinous material. The thus obtained residue was dissolved in methanol (2 ml) to which were subsequently added o-anisidine (29 μl, 0.25 mmol) and sodium cyanoborohydride (11 mg, 0.166 mmol) at room temperature. After 2 hours of stirring at the same temperature, the reaction solution was mixed with saturated sodium carbonate aqueous solution (10 ml), extracted with ethyl acetate and then washed with water and saturated brine. The resulting organic layer was dried on anhydrous sodium carbonate, the solvent was removed by evaporation and then the resulting residue was purified by subjecting it to a silica gel column chromatography (ether:hexane=2:1-ether) to obtain 59 mg (66.2%) of the title compound in the form of colorless solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1([C:17]([O:19]C)=O)[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].[H][H]>CO.N.O.[Ni]>[O:19]=[C:17]1[C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH2:3][CH2:1][NH:2]1
Reactant: COC(=O)C1(CC#N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CCNC2=O)CC1

Procedure:
A suspension of 1-tert-butyl 4-methyl 4-(cyanomethyl)piperidine-1,4-dicarboxylate (70.0 g, 247.9 mmol) and Raney Ni (60 g) in MeOH (1500 mL) and NH3.H2O (80 mL) was stirred at 2 MPa of hydrogen pressure at 50° C. for 18 h. The reaction mixture was filtered through a pad of CELITE® and the filtrate was concentrated under vacuum to give a crude product, which was washed with ethyl acetate (200 mL) to give the title compound. 1H-NMR (400 MHz, CDCl3) δ 6.05 (s, 1H), 4.0 (s, 2H), 3.37-3.34 (m, 2H), 3.02-2.96 (m, 2H), 2.08-2.05 (m, 2H), 1.88-1.87 (m, 2H), 1.51-1.41 (m, 11H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31].Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)=[O:10])[CH2:31][CH2:30][C:29]([O:33][CH3:34])=[O:32])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)cn1
Reactant: C=CC(=O)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COC(=O)CCC(C(=O)c1ccc(Cl)cn1)c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 368.5 g (1.39 mol) of 2-(3-chlorophenyl)-1-(5-chloropyridin-2-yl)ethanone (Example 121, Step B) in dioxane (1.5 L) at 80° C. was added DBU (207 mL, 1.39 mole, 1 eq), followed by dropwise addition of methyl acrylate (124.7 mL, 1.39 mol, 1 eq) at 80° C. The reaction was stirred at 80° C. for 1 h 30 min and then allowed to cool to ambient temperature. It was quenched with 2 M aqueous HCl solution (56.5 eq) and then basified to pH 7 with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (2×4 L). The combined organic layers were dried over Na2SO4, filtered and the filtrate was evaporated. Purification by flash chromatography on silica gel (eluent: 40 to 100% DCM/hexanes) provided the title compound as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:25][C:26]([C:28]2[C:29](=[O:41])[N:30]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[N:31]=[CH:32][CH:33]=2)=[O:27])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([CH:18]3[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]3)[S:17][C:10]=12.[CH3:42][NH:43][CH3:44].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:42][N:43]([CH3:44])[CH:21]1[CH2:20][CH2:19][CH:18]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:25][C:26]([C:28]4[C:29](=[O:41])[N:30]([C:34]5[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=5)[N:31]=[CH:32][CH:33]=4)=[O:27])=[CH:3][C:2]=3[F:1])[CH:15]=2)[CH2:23][CH2:22]1
Reactant: O=C1CCC(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C1CCC(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
A round-bottomed flask was charged with N-(3-fluoro-4-(2-(4-oxocyclohexyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 162, Step C, 3.2 mg, 0.0056 mmol), dimethylamine (1.3 mg, 0.028 mmol), NaBH(OAc)3 (3.6 mg, 0.017 mmol) and CH2Cl2 (2 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (30 mL) and H2O (30 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×30 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (2.1 mg, 62%). LRMS (APCI pos): m/e 602 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 8.43 (d, 1H), 8.41 (d, 1H), 8.24 (d, 1H), 7.95 (dd, 1H), 7.60 (m, 2H), 7.38 (m, 1H), 7.21-7.32 (m, 4H), 6.45 (d, 1H), 3.22 (m, 1H), 2.30 (s, 6H), 2.22 (m, 1H), 1.55-1.94 (m, 8H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][CH3:22])=[O:16])=[CH:11][N:10]=1)=[O:8].C1C=C(Cl)C=C(C(OO)=[O:31])C=1>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH+:6]([O-:31])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][CH3:22])=[O:16])=[CH:11][N:10]=1)=[O:8]
Reactant: COCCCNC(=O)c1ccc(C(=O)NCCCOC)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COCCCNC(=O)c1ccc(C(=O)[NH+]([O-])CCCOC)nc1

Procedure:
From 1 g of N,N'-di-(3-methoxypropyl)pyridine-2,5-dicarboxamide and 1.2 g of MCPBA.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20](S(C2C=CC(C)=CC=2)(=O)=O)[C:21]2[C:26]([C:27]=1[F:28])=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18].[OH-].[Na+]>CS(O)(=O)=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[NH:20][C:21]2[C:26]([C:27]=1[F:28])=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18]
Reactant: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)c(F)c3ccccc32)cc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2cc(-n3ncc(C(=O)c4[nH]c5ccccc5c4F)c3N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
[5-Amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[3-fluoro-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone (25.0 mg, 0.041 mmol) was dissolved in methane sulfonic acid (0.25 ml), and stirred at room temperature for one hour. The pH of the reaction mixture was adjusted to 6 using an aqueous solution of 1 M sodium hydroxide. After extraction with ethyl acetate, the extract was dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=60/1 to 40/1) to give [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(3-fluoro-1H-indol-2-yl)-methanone was obtained as a pale yellow solid (8.7 g, with a yield of 55%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[CH2:2].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:21])=[C:18]([CH:20]=1)[NH2:19]>N1C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:21])=[C:18]([NH:19][S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH:20]=1
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(Cl)ccc1F
Solvent: c1ccncc1
Product: C=Cc1ccc(S(=O)(=O)Nc2cc(Cl)ccc2F)cc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-vinylbenzene-1-sulfonyl chloride (950 mg, 4.69 mmol) in pyridine (8 mL) at 20° C. was added 5-chloro-2-fluoroaniline (682 mg, 4.69 mmol). The reaction mixture was stirred at 20° C. for 2 hours then evaporated in vacuo and redissolved in ethyl acetate. The organic phase was washed with saturated aqueous sodium carbonate (25 mL), dried using a hydrophobic frit and evaporated in vacuo to give the crude product as a yellow oil. The crude was purified by silica (Si) chromatography using a 0-25% ethyl acetate-cyclohexane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product, 822.7 mg as a white solid. LCMS [LCMS2] Rt 0.86 min, m/z (ES+) 312 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].N>CCO.[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH:9]=1)[CH2:7][NH2:8]
Reactant: N#Cc1cc(Cl)ccc1-n1cncn1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1cc(Cl)ccc1-n1cncn1
Reaction time: 26 h

Procedure:
To a suspension of 5-chloro-2-[1,2,4]triazol-1-yl-benzonitrile (11.87 g, 58 mmol) in EtOH saturated with NH3 (500 ml) was added Raney Nickel (ca. 5 pipets of suspension in water, washed/decanted with EtOH several times). The mixture was hydrogenated at 1 atm for 26 h. The reaction mixture was filtered on celite under a flow of argon and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 5% MeOH containing 10% NH4OH in CH2Cl2 to 10%) to give 5-chloro-2-[1,2,4]triazol-1-yl-benzylamine as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.47 (s, 1H); 8.14 (s, 1H); 7.58 (d, J=2.3 Hz, 1H); 7.38 (dd, J=2.3, 7.9 Hz, 1H); 7.30 (d, J=7.9 Hz, 1H); 3.70 (s, 2H). 8.72 (d, J=4.8 Hz, 1H); 8.42 (s, 1H); 8.18 (s, 1H); 7.70 (d, J=7.6 Hz, 1H); 7.40 (dd, J=4.8, 7.6 Hz, 1H); 5.85 (bs, 1H); 4.43 (d, J=5.4 Hz, 2H); 1.45 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[CH:5]=[CH:4][C:3]1=2.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CC(C)(C)OC(=O)COc1ccc2c(c1)CCCC2(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCCc2cc(OCC(=O)O)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
A mixture of tert-butyl [(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]acetate (2.8 g, 9.6 mmol), trifluoroacetic acid (10.0 ml) and methylene dichloride (20 ml) was stirred for 2 hours at 0° C. After being concentrated under reduced pressure, the crude residue was triturated using hexane and collected by filtration to give 1.45 g of the title compound as a white solid, which was used for further reaction without purification.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](Cl)(=[O:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)(=O)C>[NH:18]([C:2]1[C:10]([S:11](=[O:13])(=[O:12])[NH:15][C:3]2[CH:4]=[CH:5][CH:9]=[CH:10][CH:2]=2)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c(S(=O)(=O)Cl)c1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc([N+](=O)[O-])c(Nc2ccccc2)c(S(=O)(=O)Nc2ccccc2)c1

Procedure:
To a solution of 4-chloro-3-nitro-5-chlorosulphonyl-benzoic acid (6 g) in ethyl acetate (50 ml), aniline (7.5 g) was added, while stirring. The reaction mixture was stirred for a further 8 hours and filtered. The filtrate was evaporated, and the residue was dissolved in a mixture of aqueous sodium hydrogen carbonate and diethyl ether. The aqueous layer was separated, and the 4-anilino-3-nitro-5-phenylsulphamyl-benzoic acid was precipitated by addition of 4N hydrochloric acid. After recrystallization from aqueous ethanol (25% ethanol in water), the melting point was 249°-250°C.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[C:21]([CH2:23][C:24]1[CH:29]=[C:28](O)[CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][C:33]([O:35]C)=[O:34])#[N:22]>>[C:21]([CH2:23][C:24]1[CH:29]=[C:28]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)[CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][C:33]([OH:35])=[O:34])#[N:22]
Reactant: COC(=O)CCc1ccc(O)cc1CC#N
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)c(CC#N)c2)cc1)c1ccccc1
Yield: 71 %

Procedure:
Compound 44 was synthesized from (1Z)-2-[4-(hydroxymethyl)-phenoxy]-1-phenylethanone O-methyloxime (0.3 g, 1.28 mmol) and methyl 3-[2-(cyanomethyl)-4-hydroxyphenyl]propanoate (0.348 g, 1.28 mmol) by following the procedure described in scheme 18 (0.1 g, yield: 71.00%); Purity: 92.72%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:22]([CH2:23][CH3:24])[CH2:20][CH3:21])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: CCNCC
Solvent: CS(C)=O
Product: CCN(CC)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) (3.0 g, 9.77 mmol) and diethyl-amine (3.57 g, 48.8 mmol) in DMSO (35 mL) at 60° C. according to the general procedure C. Obtained as a yellow solid (2.63 g).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[CH:7][C:6]=1[C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:3])[CH3:2].C1N2CN3CN(C2)CN1C3.Cl.[C:30](OC1C(C(C)(C)C)=CC(O)=C(C=1C(C)C)C=O)(=[O:32])C>FC(F)(F)C(O)=O.O>[C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[C:7]([C:6]=1[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:30]=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)C)cc(O)cc1C(C)(C)C
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C=O)c1C(C)C
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)Oc1c(C(C)C)cc(O)c(C=O)c1C(C)(C)C
Temperature: 0 °C
Yield: 48 %

Procedure:
0.75 g of 4-acetoxy-3-t-butyl-5-isopropylphenol and hexamethylenetetramine dissolved in 2.6 ml of trifluoroacetic acid and the solution was heated under reflux for 15 minutes. After cooling to 0° C., 2 ml of 3N hydrochloric acid was added and the solution was heated under reflux for 1.5 hours. Additional 2 ml of 3N hydrochloric acid was added and the solution was heated under reflux for 5 hours. After cooling to room temperature, the reaction solution was combined with water and extracted with ethyl acetate. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 5%ethyl acetate) to give 0.40 g of a mixture of 5-acetoxy-4-t-butyl-2-hydroxy-6-isopropylbenzaldehyde and 5-acetoxy-6-t-butyl-2-hydroxy-4-isopropylbenzaldehyde as a pale yellow oil (yield 48%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:13][CH:14]([OH:16])[CH3:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:3])[CH3:2].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)([O-:19])=[O:18]>Cl.O1CCOCC1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[CH:24]([C:23]1[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=1)[O:16][CH:14]([CH3:15])[CH2:13]2)(=[O:3])[CH3:2]
Reactant: COc1ccc(CC(C)O)cc1NC(C)=O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(cc1NC(C)=O)CC(C)OC2c1ccc([N+](=O)[O-])cc1
Yield: 57.2 %

Procedure:
To a solution of compound 13 (0.23 g, 1.03 mmol) in 15 ml of HCl solution in 1,4-dioxane was added 4-nitrobenzaldehyde (0.16 g, 1.06 mmol) in one portion. After refluxing for 5 hours, the solvent was removed under reduced pressure. The residue was washed with cold ethanol three times, and dried to give the product 14 (0.21 g, 66%).