Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1)([O-])=O.[NH2:20]C1C(=O)NC(=O)N(C=1)[C@@H]1O[C@H](CO)[C@@H](O)C1.N([O-])=O.[Na+]>[Zn]>[N+:1](=[C:4]1[CH2:17][N:8]([C@@H:9]2[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]2)[C:7](=[O:18])[NH:6][C:5]1=[O:19])=[N-:20]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1[N+](=O)[O-]
Reactant: Nc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Product: [N-]=[N+]=C1CN([C@H]2C[C@H](O)[C@@H](CO)O2)C(=O)NC1=O

Procedure:
5-azido-2-'-deoxyuridine nucleoside and nucleotide compounds and a method of producing them. The method involves reacting a 5'-deoxyuridine compound with nitrosonium tetrafluoroborate to produce a 5-nitro-deoxyuridine compound. The 5-nitro-deoxyuridine compound is reduced to a 5-amino-deoxyuridine compound in the presence of metallic zinc. The 5-amino-deoxyuridine compound is acidified and reacted with sodium nitrite to produce a 5-diazo-deoxyuridine compound. The diazo-deoxyuridine compound is then reacted with sodium azide to produce a 5-azido-deoxyuridine compound. The latter, in the monophosphate form, is further reacted with diphenylchlorophosphate to produce the photoactive triphosphate, 5-azido-2'-deoxyuridine-5'-triphosphate or 5-azido-dUTP. The photoactive compound, when added to DNA in an in vitro synthesis reaction, produces photoactive DNA.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:9][N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]=2)[N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[C:27]([C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)=[N:28][C:29]2[N:30]([CH:32]=[CH:33][N:34]=2)[CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[C:27]([C:35]2[CH:36]=[CH:37][C:38]([CH2:39][N:16]3[CH2:17][CH2:18][CH:13]([C:11]4[N:12]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=5)[NH:9][N:10]=4)[CH2:14][CH2:15]3)=[CH:41][CH:42]=2)=[N:28][C:29]2[N:30]([CH:32]=[CH:33][N:34]=2)[CH:31]=1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2F)cc1
Reactant: Cc1cccc(-c2nc(C3CCNCC3)n[nH]2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2nc(C3CCN(Cc4ccc(-c5nc6nccn6cc5-c5ccccc5F)cc4)CC3)n[nH]2)n1
Reaction time: 1 h
Yield: 20.3 %

Procedure:
398.6 mg (1.26 mmol) 2-Methyl-6-(5-piperidine-4-yl-2H-[1,2,4]triazole-3-yl)pyridine×2HCl are dissolved in 10.9 mL NMP. After addition of 0.42 mL triethylamine the reaction mixture is stirred for one hour. 400 mg (1.26 mmol) 4-[6-(2-Fluorophenyl)-imidazo[1,2-a]pyrimidin-7-yl]-benzaldehyde and 0.13 mL acetic acid are added. The reaction mixture is stirred over night at room temperature. 293.9 mg (1.39 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 22 hours. The reaction mixture is treated with saturated NaHCO3 and stirred for 60 minutes. The precipitate is filtered off, washed with water, dried and purified by HPLC yielding 139.1 mg (19.3%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:5]=[C:6]([CH3:20])[C:7]=1[CH:8]1[C:16](=[O:17])[CH:15]2[CH:10]([CH:11]3[O:18][CH:14]2[CH2:13][CH2:12]3)[C:9]1=[O:19].C(N(CC)CC)C.[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>ClCCl>[CH3:36][C:35]([CH3:38])([CH3:37])[C:34]([O:19][C:9]1[CH:10]2[CH:15]([C:16](=[O:17])[C:8]=1[C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:5][C:6]=1[CH3:20])[CH:14]1[O:18][CH:11]2[CH2:12][CH2:13]1)=[O:39]
Reactant: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)C2C3CCC(O3)C2C1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2)cc(C)c1C1=C(OC(=O)C(C)(C)C)C2C3CCC(O3)C2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR,6RS,7SR)-4-(3,5-dimethylbiphenyl-4-yl)-10-oxa-tricyclo-[5.2.1.02,6]decane-3,5-dione (80 mg, 0.23 mmol) in dichloromethane (5 ml) and triethylamine (140 μl, 1 mmol) is added pivaloyl chloride (124 μl, 1 mmol) at room temperature. The reaction mixture is stirred overnight at room temperature. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(3,5-dimethylbiphenyl-4-yl)-5-oxo-10-oxa-tricyclo[5.2.1.02,6]dec-3-en-3-yl 2,2-dimethylpropionate.
Reaction SMILES: C([C:5](C(C)(C)C)([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:30])[CH2:17][N:18]([C:20]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]#[N:29])[CH2:24][CH2:23]2)=[O:21])[CH3:19])=[CH:12][C:11]=1[O:31][CH2:32][C:33]([O-:35])=[O:34])[C:6]([O-:8])=[O:7])(C)(C)C.N1C=CC=CC=1.C(N(CC)CC)C.[SH2:53]>C(OCC)(=O)C>[C:28]([C@H:25]1[CH2:24][CH2:23][C@H:22]([C:20]([N:18]([CH2:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:5][C:6]([OH:8])=[O:7])=[C:11]([O:31][CH2:32][C:33]([OH:35])=[O:34])[CH:12]=2)=[O:30])[CH3:19])=[O:21])[CH2:27][CH2:26]1)(=[S:53])[NH2:29]
Reactant: CN(CC(=O)c1ccc(OC(C(=O)[O-])(C(C)(C)C)C(C)(C)C)c(OCC(=O)[O-])c1)C(=O)[C@H]1CC[C@H](C#N)CC1
Reactant: S
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CN(CC(=O)c1ccc(OCC(=O)O)c(OCC(=O)O)c1)C(=O)[C@H]1CC[C@H](C(N)=S)CC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Into the solution of the compound prepared in (a) (655 mg, 1.2 mmole) in the mixture of pyridine (15 ml) and triethylamine (1 ml) was streamed a hydrogen sulfide gas for 1 hour, and the mixture was stirred in a sealed tube at 50° C. for 5 hours. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate, and washed twice with each of a 5% aqueous sodium hydrogen carbonate and a 1M potassium hydrogen sulfate solution. After the organic layer was dried over anhydrous magnesium sulfate, the inorganic salt was removed by filtration. The filtrate was concentrated under reduced pressure, and the oily product thus obtained was purified by column chromatography on silica gel with an eluent system of chloroform:methanol=50:1 to give 71 mg of the thioamide derivative as a yellow oily product (yield, 10%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=3[N:17]=2)=[CH:12][CH:11]=1.[Cl:28][C:29]1[CH:30]=C(C=C[C:36]=1[Cl:37])C=O.[C:38]1(C)[CH:43]=CC(C=O)=C[CH:39]=1>>[Cl:28][C:29]1[CH:30]=[C:5]([CH:4]=[CH:3][C:36]=1[Cl:37])[CH2:6][N:1]1[CH2:43][CH2:38][CH2:39][CH:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=4[N:17]=3)=[CH:14][CH:15]=2)[CH2:2]1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCCCN4)cc3)nc2c1
Reactant: Cc1ccc(C=O)cc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Product: NC(=O)c1ccc2[nH]c(-c3ccc(OCC4CCCN(Cc5ccc(Cl)c(Cl)c5)C4)cc3)nc2c1

Procedure:
This compound was prepared using the methods outlined in Example 27, substituting 2-[4-(piperidin-3-ylmethoxy)-phenyl]-1H benzoimidazole-5-carboxylic acid amide for 2-[4-(2-piperidin-2-yl-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide and 3,4-dichlorobenzaldehyde for p-tolualdehyde. HPLC (Method C): Rt=4.79. MS (ESI+): mass calcd. for C27H26Cl2N4O2, 508.14; m/z found, 509.3 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.17 (s, 1H), 8.02 (d, J=9.1 Hz, 2H), 7.92 (dd, J=1.5, 8.7 Hz, 1H), 7.67 (m, 2H), 7.58 (d, J=8.3 Hz, 1H), 7.28 (dd, J=2.0, 8.4 Hz, 1H), 7.13 (d, J=9.1 Hz, 2H), 4.32-4.25 (m, 2H), 4.08-4.05 (m, 1H), 3.98-3.94 (m, 1H), 3.61-3.58 (m, 1H), 3.45-3.41 (m, 1H), 2.92-2.87 (m, 2H), 2.36-2.25 (m, 1H), 2.00-1.90 (m, 2H), 1.81-1.71 (m, 1H), 1.46-1.36 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH2:9]O)=[CH:5][CH:4]=1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH2:9][C:17]23[CH:21]=[CH:22][CH:23]=[CH:24][CH:16]2[C:15]([NH:19][C:18]3=[O:20])=[O:25])=[CH:5][CH:4]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCC=Cc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1NC(=O)C2(CC=Cc3ccc(C(F)(F)F)cc3)C=CC=CC12
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
4-(Trifluoromethyl)cinnamyl alcohol (3 g, 14.84 mmol) was dissolved in THF (60 ml), and phthalimide (2.84 g, 19.29 mmol) and triphenylphosphine (5.84 g, 22.26 mmol) were added to the solution, to which a solution of diethyl azodicarboxylate (3.87 g, 22.26 mmol) in THF (20 ml) was gradually added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/methylene chloride=1/1) to afford 2-[3-(4-trifluoromethylphenyl)-2-propenyl]phthalimide (4.57 g, yield 93%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][C:16]2=[O:24])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].IC.[C:27]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([CH3:27])[C:16]2=[O:24])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(/C=C/C(=O)n2c(=O)[nH]c3ccccc32)cc1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(/C=C/C(=O)n2c(=O)n(C)c3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A mixture of (E)-1-(3-(3,4-dimethoxyphenyl)acryloyl)-1H-benzo[d]imidazol-2(3H)-one (240 mg, 0.75 mmol), iodomethane (68 uL, 1.1 mmol) and K2CO3 (204 mg, 1.5 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction was quenched with water and extracted with DCM. The combined organic phases were washed with brine, dried over sodium sulfate and the solvent removed under reduced pressure. The residue was purified by recrystallisation from EtOH to afford (E)-1-(3-(3,4-dimethoxyphenyl)acryloyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (200 mg, 79%). 1H-NMR (400 MHz, CDCl3) δ 3.46 (s, 3H), 3.96 (s, 3H), 3.98 (s, 3H), 6.91 (d, J=8.4 Hz, 1H), 7.01 (dd, J=7.6, 0.8 Hz, 1H), 7.19-7.28 (m, 4H), 7.98 (d, J=15.6 Hz, 1H), 8.15 (d, J=15.6 Hz, 1H) 8.32 (dd, J=8.0, 0.8 Hz, 1H); LC-MS (ES-API); rt 9.05 min; m/z calculated for C19H18N2O4 [M+H]+ 339.1, found 339.0 and 361.0 ([M+Na]+).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[CH:11]=[C:10]([N:12]2[C:17](=[O:18])[NH:16][C:15](=[O:19])[CH:14]=[N:13]2)[CH:9]=[C:8]([Cl:20])[C:7]=1[CH:21]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:22](Cl)=[O:23].Cl>C1C=CC=CC=1>[Cl:20][C:8]1[CH:9]=[C:10]([N:12]2[C:17](=[O:18])[NH:16][C:15](=[O:19])[CH:14]=[N:13]2)[CH:11]=[C:6]([Cl:5])[C:7]=1[CH:21]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:22](=[O:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(c1ccccc1)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 10 °C
Reaction time: 20 h
Yield: 13 %

Procedure:
A mixture of 4.7 parts of aluminum trichloride and 67.5 parts of benzene was stirred in an ice bath till a temperature of ±10° C. A solution of 4.9 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetylchloride in 22.5 parts of benzene was added dropwise during a period of 15 minutes at this low temperature (exothermic reaction). Upon complete addition, stirring was continued for 20 hours at room temperature. The reaction mixture was poured into 500 parts of ice water and the whole was acidified with concentrated hydrochloric acid. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified three times by column chromatography over silica gel using first a mixture of trichloromethane and methanol (97:3 by volume) and then a mixture of trichloromethane and methanol (99:1 by volume) and finally a mixture of trichloromethane and ethyl acetate (92.5:7.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated in vacuo. The residue was crystallized from 8 parts of ethanol. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 0.7 parts (13.0%) of 2-[3,5-dichloro-4-[1-(4-chlorophenyl)-2-oxo-2-phenylethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione; mp. 143.0° C. (intermediate 41).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:23]#[N:24])[CH:30]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: N#Cc1cccc(B(O)O)c1
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
Solvent: O
Product: N#Cc1cccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)c1
Yield: 49.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 3-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.035 g (49%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-3-carboxamide compound as a white solid.
Reaction SMILES: [OH-].[K+].C1O[CH2:19][CH2:18]OCCOCCOCCOCCOC1.[CH2:21]([C:23]1[CH2:27][CH:26]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:24]=1)[CH3:22].C([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=O)C.Cl>C1COCC1>[C:28]([C:25]1[CH:26]=[C:27]([CH2:18][CH3:19])[C:23](=[C:21]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH3:22])[CH:24]=1)([CH3:30])([CH3:29])[CH3:31]
Reactant: CCC1=CC(C(C)(C)C)=CC1
Reactant: CC(=O)c1ccccc1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC1=CC(C(C)(C)C)=CC1=C(C)c1ccccc1
Reaction time: 4 h
Yield: 25 %

Procedure:
To a 200 ml three-neck flask equipped with a magnetic stirrer chip and a three-way cock, 2.10 g (36.1 mmol) of potassium hydroxide pulverized in mortar, 1.15 g (4.35 mmol) of 18-crown-6 and 50 ml of dehydrated THF were charged under a nitrogen atmosphere. Thereto in a water bath, 3.35 g (22.3 mmol) of 1-ethyl-3-tert-butylcyclopentadiene was added dropwise over 10 minutes, and stirred for 4 hours. The solution was added with 12.5 ml of acetophenone dropwise over 8 minutes, and stirred for 20 hours at room temperature and for 6 hours under reflux. The reaction solution was poured into 100 ml of 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with 150 ml of ether. The obtained organic layers were combined, washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated aqueous solution of sodium chloride. After the solution was dried over magnesium sulfate, the solvent was distilled away, and purified by column chromatography to obtain 1.38 g of a red orange liquid. The yield was 25%. Identification was done by 1H-NMR spectrum. The measurement results are shown as follows.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Cl:8]C1C=C(C=CC=1)C(OO)=[O:13]>C(Cl)Cl>[ClH:8].[NH2:7][C:3]1[CH:2]=[N+:1]([O-:13])[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1cccnc1
Solvent: ClCCl
Product: Cl
Product: Nc1ccc[n+]([O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of pyridin-3-amine (C-1) (10.0 g, 106.3 mmol, 1.0 eq) in DCM (100 mL) at 0° C., m-chloroperoxybenzoic acid (22.0 g, 128 mmol, 1.2 eq) is added in portions (over 15 min). The resulting mixture is allowed to warm to RT and then stirred at RT for 2 h. The reaction is quenched with water (100 mL). The organic phase is separated and the aqueous layer is extracted with DCM (2×100 mL). The resulting aqueous phase is neutralized with concentrated HCl to adjust the pH to 2-3. To this mixture, 1,4-dioxane (100 mL) is added and the resulting mixture is concentrated in vacuo to afford the product, 3-aminopyridine-1-oxide hydrochloride (D-1).
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH3:11])[C:6]=2[CH:5]=[C:4]([C:12]([O:14]C)=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24].[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH3:11])[C:6]=2[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24]
Reactant: COC(=O)c1cc2c(C)noc2c(F)c1Nc1ccc(I)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc2c(F)c(Nc3ccc(I)cc3F)c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To a solution of methyl 7-fluoro-6-(2-fluoro-4-iodophenylamino)-3-methylbenzo[d]isoxazole-5-carboxylate (3.77 g, 8.49 mmol) in a mixture of THF (200 ml) and H2O (100 ml) was added a solution of LiOH (1.20 g, 50 mmol) in H2O (50 ml). After stirring at room temperature for 3 h, the reaction was concentrated, acidified with 1 M HCl solution, and extracted with EtOAc (2×100 ml). The organic solution was dried over Na2SO4 and concentrated to give 3.09 g (95%) of 7-fluoro-6-(2-fluoro-4-iodophenylamino)-3-methylbenzo[d]isoxazole-5-carboxylic acid as a light yellow solid.
Reaction SMILES: C(S[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14]1[NH:26][C:17]2=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=[C:16]2[N:15]=1)C.Cl[C:28]1C=CC=C(C(OO)=O)[CH:29]=1.C(=O)([O-])O.[Na+].[S:43]([O-:47])([O-])(=[O:45])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:28]([S:43]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[C:14]1[NH:26][C:17]2=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:21]=[C:16]2[N:15]=1)(=[O:47])=[O:45])[CH3:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cc(C(F)(F)F)ccc1-c1nc2cc(C(F)(F)F)cnc2[nH]1
Reactant: O=S([O-])([O-])=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cc(C(F)(F)F)ccc1-c1nc2cc(C(F)(F)F)cnc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(2-ethylsulfanyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (12 g) and chloroform (111 mL), 69-75% of 3-chloroperbenzoic acid (8.0 g) was added under ice-cooling. The mixture was heated to room temperature, and stirred for 0.5 hours. Into the mixture, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were poured, and extracted with chloroform. The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 9.1 g of 2-(2-ethylsulfonyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, Present Compound 345).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][C:65]=1[O:72][CH3:73]>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:65]([O:72][CH3:73])[CH:66]=1)#[N:69]
Reactant: COc1cc(C#N)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Br)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Br)ccc32)C1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 92 (0.4 g, 0.66 mmol), was reacted with diisopropylethylamine (0.77 g, 5.9 mmol), diphenylphosphinic chloride (0.62 g, 2.6 mmol), then reacted with 4-amino-3-methoxy-benzonitrile prepared in Example 57 (0.29 g, 2.0 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide as a off white solid (Yield 0.15 g, 36%).
Reaction SMILES: [Mg].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][CH2:11][CH2:12]Br)=[CH:5][CH:4]=1.[CH2:21]([N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C:29]1=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH4+].[Cl-].[O:37]1CCCC1>>[CH2:21]([N:28]1[CH2:33][CH2:32][C:31]([CH2:12][CH2:11][CH2:10][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)([OH:37])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Fc1ccc(C(CCCBr)c2ccc(F)cc2)cc1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: OC1(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A Grignard solution was prepared from 3.17 g (0.132 mol) of magnesium filings and 42.8 g (0.132 mol) of 4,4-bis(4-fluorophenyl)butyl bromide in 85 ml of absolute tetrahydrofuran. A solution of 25 g (0.132 mol) of distilled N-benzylpiperidone in 130 ml of absolute tetrahydrofuran was then added dropwise in the course of 30 minutes and the mixture was subsequently stirred at room temperature for 1.5 hours. The reaction mixture was poured onto 800 ml of ice, 400 ml of saturated NH4Cl solution were added and the mixture was extracted several times with ether. The extracts were dried and concentrated.