Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:14])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Cl.O>CN(C)C=O>[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=2)[C:9]([CH3:14])=[CH:10]1
Reactant: COC(=O)c1ccc2c(C)c[nH]c2c1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C)cn(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
6-(Methoxycarbonyl)-3-methylindole (0.57 g) is dissolved in N,N-dimethylformamide (10 ml), to which is added sodium hydride (60% oily, 0.145 g) With cooling with ice. Then, 2,4-dichlorobenzyl chloride (0.707 g) is added thereto, and stirred at room temperature for 1.5 hours. Water is added to the reaction mixture, which is then extracted with ethyl acetate. The organic layer is washed with a saturated saline solution, and dried with anhydrous magnesium sulfate. The drying agent is removed through filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified through silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 1-(2,4-dichlorobenzyl)-6-(methoxycarbonyl)-3-methylindole (72) (0.83 g).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:9][C:8]=2[C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CI.[C:40](OCC)(=O)C>CN(C=O)C>[CH:1]1([O:6][C:7]2[C:8]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[CH:9][C:10]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:11][C:12]=2[N:13]([CH3:40])[C:14](=[O:19])[C:15]([F:17])([F:16])[F:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: COC(=O)CCc1cc(NC(=O)C(F)(F)F)c(OC2CCCC2)c(-c2ccc3ccccc3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCc1cc(-c2ccc3ccccc3c2)c(OC2CCCC2)c(N(C)C(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of Intermediate 54 (208 mg) in DMF (5 ml) was added with 60% sodium hydride (21 mg) under ice cooling, and stirred for 20 minutes. This reaction mixture was added dropwise with methyl iodide (150 μl), stirred for 10 minutes, then warmed to room temperature, and further stirred for 1 hour. The reaction mixture was poured into ice water, and ethyl acetate (100 ml) was added for extraction. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate 5:1) to obtain the title compound (Intermediate 55, 200 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:23][CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:40]>C(Cl)Cl.O1CCOCC1>[ClH:40].[ClH:40].[CH:34]1([C:18]2[N:17]=[N:16][C:15]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:20][C:19]=2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:23][CH:22]=2)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(-c3ccc(OC4CCCCC4)cc3)c(C3CCCCC3)nn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1cc(-c2cc(OC3CCNCC3)nnc2C2CCCCC2)ccc1OC1CCCCC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.40 mmol, 0.08 g) in THF (0.45 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (0.54 mmol, 0.022 g) and continued stirring for 10 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 6-chloro-3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-pyridazine (0.27 mmol, 0.10 g) in THF (0.45 mL). After completion of addition, the reaction mixture was warmed to 65° C. and stirred for 2 hours. After cooling the reaction to room temperature, the reaction was quenched with water (1 mL) and extracted with ethyl acetate (1×2 mL). The ethyl acetate layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 4 g SiO2 cartridge eluting with an ethyl acetate/hexanes gradient to give 4-[6-cyclohexyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 81%). To a solution of 4-[6-cyclohexyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.22 mmol, 0.12 g) in DCM (1.5 mL) was added 4 N HCl in dioxane (0.5 mL) and the reaction was stirred for 30 min. The solvents were removed under reduced pressure and the residue was triturated with anhydrous ethyl ether (50 mL) and filtered to give 3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.095 g).
Reaction SMILES: [O:1]=[C:2]1[CH:18](C(OC)=O)[C:17](=[O:23])[C:5]2([CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:6]2)[CH2:4][NH:3]1>C(#N)C.O>[O:1]=[C:2]1[CH2:18][C:17](=[O:23])[C:5]2([CH2:9][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:7][CH2:6]2)[CH2:4][NH:3]1
Reactant: COC(=O)C1C(=O)NCC2(CCN(C(=O)OC(C)(C)C)C2)C1=O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC2(CNC(=O)CC2=O)C1
Yield: 66.7 %

Procedure:
A solution of D5 (1.90 mmol, 0.62 g) in 40 mL acetonitrile/water (1/1) was refluxed for 5 hours. The reaction mixture was evaporated in vacuo. The crude product was purified by flash silicagel chromatography (DCM/MeOH=95/5) yielding 0.34 g of a yellow oil (66%). 1H-NMR (400 MHz, CDCl3, 300K): δ=1.46 (9H, s), 1.88 (1H, m), 2.26 (1H, m), 3.50 (8H, m), 6.70 (1H, br d, 34.8 Hz); MS (ES) C13H20N2O4 requires: 268. found: 269.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:10][C:11]([F:21])([F:20])[C:12](=O)[CH2:13][C:14](OCC)=[O:15].C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[C:3]([N:8]2[C:14]([OH:15])=[CH:13][C:12]([C:11]([F:21])([F:20])[F:10])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1NN
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cccnc1-n1nc(C(F)(F)F)cc1O
Temperature: 60 °C
Yield: 10.1 %

Procedure:
A mixture of 3-methyl-2-pyridylhydrazine (1.0 g, 8.13 mmol), acetic acid (7.0 mL) and ethyl trifluoroacetoacetate (1.2 mL, 8.13 mmol) was heated at 60° C. for 9 hours. The reaction mixture was neutralized with NaHCO3 and then was extracted with EtOAc (3×). The EtOAc extracts were combined, dried over MgSO4, filtered and concentrated to afford crude product which was purified by column chromatography on silica gel to afford 200 mg of 1-(3-methyl-2-pyridyl)-3-trifluoromethyl-5-hydroxypyrazole.
Reaction SMILES: O=[C:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:3][NH:4][C:5]([C:7]1[CH:29]=[N:28][C:10]2[O:11][CH2:12][CH2:13][N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:9]=2[CH:8]=1)=O.C([O-])(=O)C.[NH4+:40].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:30]1([C:2]2[NH:40][C:5]([C:7]3[CH:29]=[N:28][C:10]4[O:11][CH2:12][CH2:13][N:14]([S:15]([C:18]5[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:22][CH:23]=5)(=[O:17])=[O:16])[C:9]=4[CH:8]=3)=[N:4][CH:3]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(CNC(=O)c1cnc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCO2)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCOc2ncc(-c3ncc(-c4ccccc4)[nH]3)cc21
Yield: 860.8 %

Procedure:
To a solution of N-(2-oxo-2-phenylethyl)-1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide (40 mg, 0.079 mmol) in DMF (1 mL) was added ammonium acetate (61 mg, 0.791 mmol). The reaction was subjected to microwave irradiation (150° C., 30 min). The reaction mixture was treated with saturated aqueous NaHCO3 (1 mL) and extracted with EtOAc (2×1 mL). The combined organic layers were dried with sodium sulfate, filtered and evaporated. The residue was purified by flash column chromatography using a gradient elution of hexanes with 25-100% EtOAc Providing 7-(5-phenyl-1H-imidazol-2-yl)-1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (33 mg, 0.68 mmol, 86% yield) as a white/brown solid. LCMS (+ESI) m/z=487.0 [M+H]+; 1H-NMR (CDCl3) δ 8.69-8.67 (m, 2H), 7.82 (d, 2H), 7.75 (d, 2H), 7.72 (d, 2H), 7.42 (s, 1H), 7.36 (t, 2H) 7.26 (m, 2H) 3.95 (m, 2H), 3.84 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][CH:16]([NH:31][C:32](=[O:46])[CH:33]([N:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]1=[O:45])[CH3:34])[C:17](=[O:30])[CH2:18][O:19][C:20](=[O:29])[C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:28])=[O:14])(C)(C)C>ClCCl>[C:13]([CH2:15][CH:16]([NH:31][C:32](=[O:46])[CH:33]([N:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]1=[O:45])[CH3:34])[C:17](=[O:30])[CH2:18][O:19][C:20](=[O:29])[C:21]1[C:22]([Cl:28])=[CH:23][CH:24]=[CH:25][C:26]=1[Cl:27])([OH:14])=[O:12]
Reactant: CC(C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COC(=O)c1c(Cl)cccc1Cl)n1ccc2ccccc2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C(=O)NC(CC(=O)O)C(=O)COC(=O)c1c(Cl)cccc1Cl)n1ccc2ccccc2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.2 %

Procedure:
Trifluoroacetic acid (2 ml) was added to a stirred ice cold solution of 2,6-dichloro-benzoic acid 4-tert-butoxycarbonyl-2-oxo-3-[2-(1-oxo-1H-isoquinolin-2-yl)-propionylamino]-butyl ester (110 mg, 0.19 mmol) in anhydrous dichloromethane (2 ml). The mixture was stirred at 0° C. for 1 h and at room temperature for 0.5 h. The reaction mixture was concentrated under reduced pressure and then the residue was redissolved in dry dichloromethane. This process was repeated several times in order to remove excess trifluoroacetic acid. The residue was then lyophilized twice from HPLC grade water and then purified by reverse phase HPLC using a gradient eluent of 10:90 CH3CN:water to 100:0 CH3CN:water to afford the title compound as white solid (17 mg, 16%): IR (solid) 3295, 1736, 1648, 1618, 1590 cm−1; 1H NMR (400 MHz, DMSO) 1.57 (3H, 2×d), 2.64-2.80 (2H, m), 4.73 (1H, m), 5.14-5.33 (2H, m), 5.44-5.53 (1H, m), 6.67 (1H, m), 7.44-7.74 (7H, m), 8.20 (1H, d), 8.77-8.83 (1H, bd); 13C NMR (100 MHz, DMSO) 16.72, 16.90, 53.77, 105.36, 105.49, 125.48, 126.37, 126.90, 127.49, 128.85, 130.52, 130.67, 131.15, 132.47, 132.82, 132.93, 137.09, 137.12, 161.38, 163.56, 163.64, 171.15, 171.25; MS (FAB+ve, HR) Calculated for C24H20Cl2N2O7 (MH+) 519.0726, found 519.0701.
Reaction SMILES: [C:1]1([C:7]([C:9]2[O:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C>CO>[CH2:18]([NH:25][N:26]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[O:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NNCc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)c2ccccc2)o1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(C(=NNCc2ccccc2)c2ccccc2)o1

Procedure:
5-Methoxycarbonyl-2-furyl phenyl ketone (5.5 g, 0.024 mole) was dissolved in methanol (60 ml), added with benzylhydrazine (9 g, 0.07 mole) and acetic acid (0.5 ml) and then heated under reflux till the reaction was completed. After cooling, the solvent was evaporated. The resultant residue was extracted with chloroform and washed with dilute HCl solution, then water, and then dried over anhydrous magnesium sulfate and filtered. The solvent of the filtrate was removed to give 5-methoxycarbonylfuryl phenyl ketone benzylhydrazone.
Reaction SMILES: [F:1][CH2:2][C@H:3]1[CH2:8][NH:7][CH2:6][C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25]>>[F:1][CH2:2][C@H:3]1[CH2:8][N:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[CH2:6][C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:4]1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](CF)C1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CF)CN(c2ccncc2[N+](=O)[O-])C1

Procedure:
Method 1 of example 1 was followed using cis(+/−)-tert-butyl 5-(fluoromethyl)piperidin-3-ylcarbamate and 4-chloro-3-nitropyridine yielding cis(+/−)-tert-butyl 5-(fluoromethyl)-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate. LCMS (m/z): 355.1 (MH+); LC Rt=2.41 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH3:9])[C:6]=1[CH2:7]O.[Br:10]P(Br)Br>C(Cl)(Cl)Cl>[Br:10][CH2:7][C:6]1[N:5]([CH3:9])[CH:4]=[N:3][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: Cn1cnc(Cl)c1CO
Solvent: ClC(Cl)Cl
Product: Cn1cnc(Cl)c1CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of (1-methyl-1H-imidazol-5-yl)methanol (1.14 g, 10 mmol) in dioxane (50 mL), in a 250 mL round bottom flask, was added 1-chloropyrrolidine-2,5-dione (1.38 g, 10 mmol). The resulting mixture was stirred at room temperature overnight. Dioxane was removed under vacuum to provide (4-chloro-1-methyl-1H-imidazol-5-yl)methanol. The crude (4-chloro-1-methyl-1H-imidazol-5-yl)methanol was dissolved in 40 mL of chloroform, followed by addition of tribromophosphane (1.9 mL, 20 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was evaporated to provide 5-(bromomethyl)-4-chloro-1-methyl-1H-imidazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8](O)[CH:7]=[CH:6]2.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: COc1ccc2nc(O)ccc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2nc(Cl)ccc2c1
Yield: 86 %

Procedure:
A solution of 6-methoxyquinolin-2-ol (400 mg, 2.29 mmol) in POCl3 (5.0 mL) was refluxed for 2 hours. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (50 mL), the organic layer was washed with saturated NaHCO3 (30 mL×2), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column (PE/EtOAc=10/1) to give 2-chloro-6-methoxyquinoline (380 mg, yield 86%) as a solid. 1H NMR (CDCl3 400 MHz): δ 7.92 (d, J=8.4 Hz, 1H), 7.85 (d, J=9.2 Hz, 1H), 7.32-7.25 (m, 2H), 7.00 (d, J=2.4 Hz, 1H), 3.86 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:17][C:18]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]>C(Cl)Cl>[C:8]([NH:17][C:18]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccc(OC)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.1 mL of triethylamine and 1.3 mL of benzoyl chloride were added to 19 mL of methylene chloride solution containing 1.9 g of methyl 2-amino-4-methoxybenzoate while ice-cooled sequentially and stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure and chloroform and 1.0 mol/L hydrochloric acid were added to the obtained residue. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 2.6 g of methyl 2-(benzamido)-4-methoxybenzoate as white solid.
Reaction SMILES: [OH:1][C@@H:2]([C:7]1[C:8]([I:18])=[C:9]2[CH:16]=[CH:15][N:14]([CH3:17])[C:10]2=[N:11][C:12]=1[CH3:13])[C:3]([O:5][CH3:6])=[O:4].C(O[C:23]([CH3:26])([CH3:25])[CH3:24])(=O)C.C([O-])([O-])=O.[Na+].[Na+]>>[C:23]([O:1][C@@H:2]([C:7]1[C:8]([I:18])=[C:9]2[CH:16]=[CH:15][N:14]([CH3:17])[C:10]2=[N:11][C:12]=1[CH3:13])[C:3]([O:5][CH3:6])=[O:4])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](O)c1c(C)nc2c(ccn2C)c1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(ccn2C)c1I
Reaction time: 1 h
Yield: 72 %

Procedure:
A solution of (S)-methyl 2-hydroxy-2-(4-iodo-1,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (9.6 g, 26.7 mmol) in tert-butyl acetate (349 ml, 2583 mmol) was treated dropwise with HClO4 (12.37 ml, 144 mmol). After 1 h, the reaction mixture was poured into 2M Na2CO3 and the layers partitioned. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by ISCO (0-60% EtOAc-hexanes) to afford the title compound as a white foam (8.0 g, 71%). 1H NMR (CHLOROFORM-d) δ 7.13 (d, J=3.3 Hz, 1H), 6.30 (d, J=3.3 Hz, 1H), 5.75 (s, 1H), 3.84 (s, 3H), 3.67 (s, 3H), 2.73 (s, 3H), 1.25 (s, 9H). LC/MS (m/z) ES+=416.9 (M+1)+
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][O:33][C:34]([C:36]1[S:37][CH:38]=[CH:39][C:40]=1[S:41](Cl)(=[O:43])=[O:42])=[O:35].N1C=CC=CC=1>ClCCl>[CH3:32][O:33][C:34]([C:36]1[S:37][CH:38]=[CH:39][C:40]=1[S:41](=[O:43])(=[O:42])[NH:8][C:7]1[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)[C:2]=1[F:1])=[O:35]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. methyl-3-(chlorosulfonyl)thiophene-2-carboxylate (17 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 25 mg of the target compound, methyl-3-(N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)sulfamoyl)thiophene-2-carboxylate (percentage yield: 86%), was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([N:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:23])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([OH:16])=O)=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:17].C(N1C=CN=C1)(N1C=CN=C1)=O.[Na].[CH:42]([S:47]([NH2:50])(=[O:49])=[O:48])=[CH:43][CH2:44][CH2:45][CH3:46].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:21]=[C:20]([N:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:23])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14](=[O:16])[NH:50][S:47](/[CH:42]=[CH:43]/[CH2:44][CH2:45][CH3:46])(=[O:49])=[O:48])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:17]
Reactant: CCOC(=O)N(C)c1ccc(Cn2c(C)nc3ccc(C(=O)O)nc32)c(Cl)c1
Reactant: CCCC=CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCC/C=C/S(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(N(C)C(=O)OCC)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
3-(2-Chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-3H-imidazo[4, 5-b]pyridine-5-carboxylic acid (150 mg) was dissolved in dry N,N-dimethylformamide (1.5 ml), and carbonyldiimidazole (91 mg) was added, which was followed by stirring at room temperature for 1.5 hr. To the reaction mixture was added 1-penten-1-ylsulfonamide sodium salt (96 mg) and the mixture was stirred at room temperature for 7 hr. 1N Hydrochloric acid was added dropwise under ice-cooling to adjust to pH 4. Water (1.5 ml) was added and the mixture was applied to ultrasonic washer for 15 min and then stirred for 15 min. The precipitate was collected by filtration, washed with water, suspended in ethanol (0.5 ml), heated in a boiling bath and stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with ethanol, and recrystallized from N,N-dimethylformamide and water to give 3-(2-chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (165 mg) as colorless crystals. m.p.: 165-166° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.Cl[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1>CN(C)C1C=CN=CC=1.CN(C)C=O>[N+:26]([C:25]1[C:20]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[CH:12]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]3)=[CH:4][CH:3]=2)=[N:21][CH:22]=[CH:23][CH:24]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CN1CCC(c2cccc3ccc(N)cc23)CC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CN1CCC(c2cccc3ccc(Nc4ncccc4[N+](=O)[O-])cc23)CC1
Yield: 33.5 %

Procedure:
A mixture of the product from Example 57 (0.338 g, 1.4 mmol), 2-chloro-3-nitropyridine (0.446 g, 2.81 mmol), and 4-dimethylaminopyridine (0.172 g, 1.4 mmol) in dimethylformamide (6 mL) was refluxed 5 hours. The solvent was removed at reduced pressure and the residue was taken up in methylene chloride. The organic phase was washed with 1N sodium hydroxide and brine, then it was concentrated onto silica gel and flash chromatographed (1×4 inches silica gel). The elution proceeded as follows: 75% methylene chloride/hexane (175 mL) nil; methylene chloride (250 mL) unweighed excess 2-chloro-3-nitropyridine; 2% methanol/methylene chloride (200 mL) nil, (550 mL) 0.373 g of crude product contaminated with 4-dimethylamino-pyridine. This material was triturated with ether and filtered to give 0.17 g of title product as orange crystals. 1H NMR δ 10.34 (br s, 1 H), 8.59 (dd, J=2, 8.5 Hz, 1 H), 8.54-8.50 (m, 2 H), 7.88 (d, J=9 Hz, 1 H), 7.72-7.70 (m, 1 H), 7.66 (dd, J=2, 9 Hz, 1H), 7.45-7.41 (m, 2 H), 6.89 (dd, J=4.5, 8.5 Hz, 1 H), 3.27 (tt, J=4, 11.5 Hz, 1 H), 3.11 (long range coupled d, J=11.5 Hz, 1 H), 2.41 (s, 3 H), 2.27 (dt, J=2.5, 11.5 Hz, 2 H), 2.09-1.89 (m, 4 H).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:12]=2[C:13]([O:15]C)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C1COCC1.CO>[C:1]1([S:7]([NH:10][C:11]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:12]=2[C:13]([OH:15])=[O:14])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reaction time: 48 h
Yield: 100.1 %

Procedure:
To a solution of methyl 2-phenylsulfonylamino-5-chlorobenzoate (600 mg; prepared in Reference Example 2.) in the mixture of THF-MeOH (6 ml+3 ml), 2N NaOH solution (2 ml) was added. The mixture was stirred for 2 days. To the reaction mixture, 1N HCl (4.5 ml) was added. The mixture was extracted with ethyl acetate. The organic layer was washed and dried over to give the title compound (575 mg) having the following physical data.