Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.[OH-].[K+]>CCO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)c1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C(=O)O)c1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 85.7 %

Procedure:
A solution of methyl 2-(4-bromophenyl)-2,2-dimethylacetate (3880 μL, 15090 μmol) in EtOH (80 mL) and water (20 mL) was treated with KOH (4233 mg, 75450 μmol). The reaction was heated to 90° C. After 15 hours, the reaction was cooled to 23° C. and concentrated in vacuo. The crude mixture was partitioned between water/diethyl ether (150 mL each). The aqueous layer was separated and extracted with diethyl ether (100 mL). The combined ether layers were then extracted with a 1N NaOH solution (25 mL). The combined aqueous washes were acidified with concentrated HCl to pH=2.0 and extracted with EtOAc (3×100 mL). The combined EtOAc layers were dried over MgSO4, and concentrated in vacuo to afford 3144 mg of 2-(4-bromophenyl)-2-methylpropanoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:21]=[CH:22][C:23]=2[S:24](O)(=[O:26])=[O:25])[C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH3:20])=[O:5])[CH3:2].[F:28][C:29]([F:33])([F:32])[CH2:30][NH2:31]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:11]2[N:10]3[N:21]=[CH:22][C:23]([S:24](=[O:26])(=[O:25])[NH:31][CH2:30][C:29]([F:33])([F:32])[F:28])=[C:9]3[N:8]=[CH:7][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:14]([CH3:20])[CH:15]=1
Reactant: NCC(F)(F)F
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)O)cnn2c1Nc1ccc(F)cc1C
Product: CCOC(=O)c1cnc2c(S(=O)(=O)NCC(F)(F)F)cnn2c1Nc1ccc(F)cc1C
Yield: 87.6 %

Procedure:
Using 6-ethoxycarbonyl-7-(4-fluoro-2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-3-sulfonic acid (0.970 g, 2.460 mmol) obtained in Example 1 step 2 and 2,2,2-trifluoroethylamine (0.975 g, 9.838 mmol) instead of tert-butylamine, and in the same manner as in Example 1 step 3, the title compound (1.024 g, 87%) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:46]=[CH:45][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:31][C:32](=[O:42])[C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=3)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:18][C:17]=2[O:43][CH3:44])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>[Pd]>[CH2:1]([O:8][C:9]1[CH:46]=[CH:45][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:31][C:32](=[O:42])[C:33]3[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=3)[C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[CH:18][C:17]=2[O:43][CH3:44])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CC(NC(=O)c3ccc([N+](=O)[O-])cc3)C(=O)OC(C)(C)C)cc2OC)cc1
Agent: [Pd]
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CC(NC(=O)c3ccc(N)cc3)C(=O)OC(C)(C)C)cc2OC)cc1
Reaction time: 8 h
Yield: 73 %

Procedure:
Prepared using General Procedure 9: A stirred solution of 4-(3-(tert-butoxy)-2-(4-nitrobenzamido)-3-oxopropyl)-2-methoxyphenyl 4-(heptyloxy)benzoate INT-8 (1.70 g, 2.68 mmol) in THF (30 mL) was degassed under N2 flow. Pd/C (10 wt % 0.17 g, 0.16 mmol) was added and the suspension was degassed under N2 flow. The reaction vessel was flushed with hydrogen gas and the reaction was stirred under an atmosphere of hydrogen overnight. The reaction was diluted with THF (10 mL) and filtered over celite. The material was concentrated and purified by chromatography (EA/hexanes) to afford 1.20 g (73%) of 4-(2-(4-aminobenzamido)-3-(tert-butoxy)-3-oxopropyl)-2-methoxyphenyl 4-(heptyloxy)benzoate INT-9. LCMS-ESI (m/z) calculated for C35H44N2O7: 604; found 605 [M+H]+, tR=3.15 min (Method 4). 1H NMR (400 MHz, DMSO) δ 8.24-8.18 (d, J=7.8 Hz, 1H), 8.05-7.94 (m, 2H), 7.61-7.52 (m, 2H), 7.13-7.04 (m, 4H), 6.93-6.85 (m, 1H), 6.57-6.48 (m, 2H), 5.65 (s, 2H), 4.58-4.50 (m, 1H), 4.12-4.03 (t, J=6.5 Hz, 2H), 3.71 (s, 3H), 3.16-3.03 (m, 2H), 1.79-1.69 (m, 2H), 1.47-1.23 (m, 17H), 0.90-0.82 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:21]([O:23]C)=[O:22])[C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:13][CH:14]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH-].[K+].O.[ClH:28]>O1CCCC1.CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:21]([OH:23])=[O:22])[C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:13][CH:14]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[ClH:28]
Reactant: COC(=O)c1cc(-c2cc(C)cc(C)c2)cnc1-c1cccnc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2cnc(-c3cccnc3)c(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-chloro-2,3′-bipyridine-3-carboxylate (1-2, 0.3 g, 1.20 mmol) in dioxane (6 mL) was added 3,5-dimethylphenyl boronic acid (0.452 g, 3.01 mmol), cesium carbonate (1.17 g, 3.61 mmol), tricyclohexylphosphine (0.101 g, 0.362 mmol), and tris(dibenzylideneacetone)-dipalladium (0.166 g, 0.181 mmol), and stirred at 95° C. overnight. The reaction was then cooled to room temperature, and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and filtered, concentrated and purified via normal phase chromatography (0->5% MeOH in DCM) afforded methyl 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylate as a yellow foam. ESI+ MS [MH]+ C20H18N2O2=319.25. To a solution of methyl 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylate (0.385 g, 1.20 mmol) in tetrahydrofuran (3 mL) and methanol (3 mL) was added potassium hydroxide (0.122 g, 2.17 mmol) and water (1.25 mL) and the system was stirred at room temperature overnight. The reaction mixture was then neutralized with 6N HCl to a pH of 2.0 and then concentrated in vacuo to afford 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylic acid as a bone powder in the form of a bis HCl salt. ESI+ MS [MH]+ C19H16N2O2=305.0. To a solution of the bis HCl salt form of 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylic acid (0.390 g, 1.03 mmol) and 3,4-dimethoxybenzylamine (0.173 g, 1.03 mmol) in dimethylformamide (5 mL) was added EDC (0.029 g, 0.191 mmol), HOBt (0.317 g, 2.06 mmol) and triethylamine (0.720 mL, 5.16 mmol) and the system was stirred in the microwave at 100° C. for 15 minutes. The system was cooled to room temperature, extracted with EtOAc, washed with water and dried over magnesium sulfate. The crude reaction mixture was purified using normal phase chromatography (0->10% MeOH in DCM) to afford the title compound (1-3) as a white powder. 1H NMR (500 MHz, CDCl3) δ 8.98-9.00 (m, 2H), 8.65-8.66 (m, 1H), 8.17 (d, J=2 Hz, 1H), 7.98-8.00 (m, 1H), 7.28-7.30 (m, 3H), 7.11 (s, 1H), 6.78 (d, J=8 Hz, 1H), 6.41-6.67 (m, 2H), 5.72 (br s, 1H), 4.42 (d, J=6 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 2.43 (s, 6H). HRMS [M+H] C28H27N3O3 calc'd 454.2125, found 454.2107.
Reaction SMILES: CO[C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:16]([S:17][CH3:18])=[C:15]3[C:10]([N:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:12](=[O:21])[N:13]([CH3:20])[C:14]3=[O:19])=[N:9]2)=[CH:5][CH:4]=1.BrCC1C=CC([N:37]2[CH:41]=[CH:40][CH:39]=[N:38]2)=CC=1>>[N:37]1([C:3]2[CH:4]=[CH:5][C:6]([CH2:7][N:8]3[C:16]([S:17][CH3:18])=[C:15]4[C:10]([N:11]([CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[C:12](=[O:21])[N:13]([CH3:20])[C:14]4=[O:19])=[N:9]3)=[CH:27][CH:28]=2)[CH:41]=[CH:40][CH:39]=[N:38]1
Reactant: COc1ccc(Cn2nc3c(c2SC)c(=O)n(C)c(=O)n3CC(C)(C)C)cc1
Reactant: BrCc1ccc(-n2cccn2)cc1
Product: CSc1c2c(=O)n(C)c(=O)n(CC(C)(C)C)c2nn1Cc1ccc(-n2cccn2)cc1

Procedure:
The synthetic procedure of this compound is analogous to EXAMPLE 5 wherein 2-(4-methoxybenzyl)-5-methyl-3-(methylthio)-7-neopentyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione is used instead of 2-(4-methoxybenzyl)-5-methyl-7-neopentyl-3-(phenylthio)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione, and 1-(4-(bromomethyl)phenyl)-1H-pyrazole is used instead of 1-(4-(bromomethyl)phenyl)-1H-1,2,4-triazole. MS (ESI) m/z 439.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][O:32][CH:33]3[CH2:38]CC[CH2:35][O:34]3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18].Cl[C:41]1C=C(NC2C=CC(F)=CC=2F)C=CC=1C(C1C=C(C#C)C=CC=1C)=O.N(CC1COC(C)(C)O1)=[N+]=[N-]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH:31]3[CH2:35][O:34][C:33]([CH3:41])([CH3:38])[O:32]3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18]
Reactant: C#Cc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: CC1(C)OCC(CN=[N+]=[N-])O1
Product: Cc1ccc(-c2cn(CC3COC(C)(C)O3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 407 (1.37 mmol) and compound 410 (1.62 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 20:80 to 35:65 as the eluent to afford the title compound as yellow foam. 13C NMR (DMSO-d6) δ 194.9, 158.7 (dd), 155.7 (dd), 149.4, 145.2, 139.8, 135.9, 133.7, 133.7, 131.7, 128.2, 127.1, 126.5, 126.5 (dd), 125.0, 124.2 (dd), 122.3, 114.8, 111.9 (dd), 111.8, 109.0, 105.0 (dd), 73.7, 65.8, 52.0, 26.4, 25.1, 19.4
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([OH:13])[C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:15](OCC)=[O:16].Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:10](=[O:11])[NH:12][C:15](=[O:16])[O:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)Cl
Reactant: NC(=O)N(O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c(=O)n(-c2ccc(Cl)c(Cl)c2)o1
Reaction time: 0.5 h

Procedure:
1-(3,4-Dichlorophenyl)-1-hydroxyurea (6.0 grams) dissolved in aqueous sodium hydroxide (13 ml; 2.0 M) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of 10° to 15°C and ethyl chloroformate (2.5 ml) is slowly added with stirring resulting in the formation of a white precipitate. After the addition is completed stirring is continued for a period of about 1/2 hour. After this time the reaction mixture is poured into a water-ice mixture and is treated with 6 N hydrochloric acid until the mixture is acidic. The solid product is then recovered by filtration and is dissolved in methylene chloride. The resulting solution is dried over anhydrous magnesium sulfate and is stripped of solvent. The remaining solid residue is then recrystallized from toluene to yield the desired product 2-(3,4-dichlorophenyl)-1,2,4-oxadiazolidin-3,5-dione having a melting point of 126° to 127.5°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:10](=[O:12])(=[O:11])[NH2:13])=[CH:4][CH:3]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccc(F)cc1

Procedure:
Using the procedure of Example 75, a mixture of 11.2 g (0.1 mole) of 4-flurophenol and 9.1 ml (0.105 mole) of chlorosulfonyl isocyanate in 50 ml of toluene gave, after recrystallization from benzene, 15.0 g (79%) of the title compound as a white solid, mp 82.5°-85.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10](I)=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:8][N:7]=1)=[O:5])[CH3:2].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.Cl.[F:32][C:33]([F:37])([F:36])[CH2:34][OH:35]>C(O)C.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[C:10]([O:35][CH2:34][C:33]([F:37])([F:36])[F:32])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]c(C(=O)OCC)c1I
Reactant: OCC(F)(F)F
Agent: [Cu]I
Agent: Cl
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCO
Product: CCOC(=O)c1n[nH]c(C(=O)OCC)c1OCC(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 1 g 4-Iodo-1H-pyrazole-3,5-dicarboxylic acid diethyl ester in 5 ml 2,2,2-trifluoro-ethanol 1.4 g Cs2CO3, 56 mg CuI and 106 mg 1,10-Phenanthroline were added. The reaction mixture heated for 4 h to 100° C. under microwave irradiation (100 W, CEM Discover™ apparatus). Then 10 HCl in ethanol (8M) was added and the solution was stirred at RT. After 16 h the solvents were removed under reduced pressure and the residue taken up in DCM and water. The organic phase was separated and the aqueous layer was extracted with DCM (2×50 ml). The combined organic layers were dried over MgSO4, filtered and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 359 mg.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([O:13]CC)=[O:12])[NH:8][C:7]=12.[OH-].[K+]>O1CCCC1.CO>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[NH:8][C:7]=12
Reactant: CCOC(=O)c1cc2ccnc(Cl)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2ccnc(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 94.6 %

Procedure:
Ethyl 7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (0.64 g, 2.85 mmol) was dissolved in tetrahydrofuran (5.7 mL) and methanol (6.8 mL). To the mixture was added 3 N KOH (2.85 mL). After stirring overnight (15.5 h) at room temperature, the reaction mixture was concentrated to dryness. The residue was dissolved in water. This aqueous solution was made acidic (pH 3) using 6 N HCl. The precipitate was collected by filtration. The precipitate was dissolved in methanol and concentrated to dryness to afford 7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (0.53 g, 2.7=mmol, 94%) as a yellow powder: mp 210-214° C.; 1H NMR (300 MHz, CD3OD) δ7.25 (1H, s), 7.65 (1H, d, J=5.4 Hz), 7.94 (1H, d, J=5.4 Hz); ESI MS m/z 195 [C8H5ClN2O2—H]−; HPLC (Method A) >99% (AUC), tR=12.2 min.
Reaction SMILES: [N:1]1([C:6]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]3[NH:12][C:11](=[O:19])[N:10]4[NH:20][C:21](=[O:23])[N:22]=[C:9]4[C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>CN(C=O)C>[N:1]1([C:6]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]3[NH:12][C:11](=[O:19])[N:22]4[C:21](=[O:23])[NH:20][N:10]=[C:9]4[C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=c1nc2c3cc(-n4ccnc4)c([N+](=O)[O-])cc3[nH]c(=O)n2[nH]1
Solvent: CN(C)C=O
Product: O=c1[nH]nc2c3cc(-n4ccnc4)c([N+](=O)[O-])cc3[nH]c(=O)n12
Yield: 83.8 %

Procedure:
A solution of 100 mg (0.32 mmol) of 9-imidazol-1-yl-8-nitro-2,3,5,6-tetrahydro-[1,2,4]triazolo[1,5-c]quinazoline-2,5-dione and 10 ml of DMF was heated to 80° C. for 30 min. and subsequently concentrated to dryness. After trituration with acetone the residue was filtered off under suction. There were obtained 84 mg (84%) of 9-imidazol-1-yl-8-nitro-2,3,5,6-tetrahydro-[1,2,4]triazolo[4,3-c]quinazoline-3,5-dione.
Reaction SMILES: C([SiH](CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][CH:21]=2)O)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH3:17].CO.O>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[C:11]([CH2:18][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][CH:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH3:17]
Reactant: CCOc1ccc(C(O)c2ccc(CC)cc2)cc1Br
Agent: CC[SiH](CC)CC
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCOc1ccc(Cc2ccc(CC)cc2)cc1Br
Reaction time: 3 h
Yield: 99.8 %

Procedure:
Triethylsilane (2.7 mL, 16.9 mmol) and a boron trifluoride-diethyl ether complex (1.2 mL, 9.47 mmol) were added to a solution of (3-bromo-4-ethoxyphenyl)-(4-ethylphenyl)methanol (2.83 g, 8.44 mmol) in methylene chloride (20 mL) at 0° C. and the mixture was stirred for three hours. Methanol (50%)-water (4 mL) was added to the reaction mixture and the resulting mixture was extracted with methylene chloride. The extract was washed with a saturated sodium chloride aqueous solution, and then dried over magnesium sulfate. The residue obtained by distilling the solvent under reduced pressure was purified by silica gel column chromatography {developing solution=n-hexane to n-hexane-ethyl acetate [4% (v/v)]} to obtain the title compound (2.69 g, 100%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.O.[OH-].[Na+]>C(Cl)Cl>[CH3:26][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=2)[CH:25]=[CH:24][N:23]=1
Reactant: Cc1cc(-c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C3CCNCC3)nc2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
2″-Methyl-3,4,5,6-tetrahydro-2H-[4,2′;5′,4″]terpyridine-1-carboxylic acid tert-butyl ester (0.54 g, 1.528 mmol) was dissolved in DCM (12 mL), TFA (4mL) was added the reaction mixture was stirred at RT for 2 hours. The reaction mixture was added water and 1N NaOH until pH=12. The organic phase was washed dried with Na2CO3 filtered and evaporation gave 310 mg (80%) yellow crystals.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:41]=[CH:40][C:10]([C:11]([C:13]3[CH:33]=[CH:32][C:16]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([O:29]CC)=[O:28])=[CH:21][CH:20]=4)=[C:15]([CH2:34][CH2:35][C:36]([O:38]C)=[O:37])[CH:14]=3)=[O:12])=[C:9]([OH:42])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.O1CCCC1.[OH-].[Na+]>[CH:1]1([O:6][C:7]2[CH:41]=[CH:40][C:10]([C:11]([C:13]3[CH:33]=[CH:32][C:16]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=4)=[C:15]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH:14]=3)=[O:12])=[C:9]([OH:42])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)/C=C/c1ccc(COc2ccc(C(=O)c3ccc(OC4CCCC4)cc3O)cc2CCC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)/C=C/c1ccc(COc2ccc(C(=O)c3ccc(OC4CCCC4)cc3O)cc2CCC(=O)O)cc1
Reaction time: 1 h
Yield: 75.6 %

Procedure:
1.20 g of ethyl (E)-3-(4-{[4-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-methoxy-3-oxopropyl)phenoxy]methyl}phenyl)-2-propenoate was dissolved in a mixed solvent of 12 mL of methanol and 12 mL of tetrahydrofuran, to which 2.4 mL of a 20% aqueous solution of sodium hydroxide was added at room temperature, and then this mixture was stirred for one hour at the same temperature. The reaction mixture was concentrated under reduced pressure, to which water was added, and then adjusted to pH 2 with 6M hydrochloric acid. The resultant precipitate was filtered out and washed with water to yield 0.841 g of (E)-3-(4-{[4-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-hydroxy-3-oxopropyl)phenoxy]methyl}phenyl)-2-propenoic acid as light yellow solid.
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:8])(=O)=O.[Br:17][C:18]1[CH:19]=[C:20]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29](O)[N:28]=2)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[Br:17][C:18]1[CH:19]=[C:20]([NH:26][C:27]2[N:28]=[C:29]([O:5][CH2:6][C@@H:7]([NH:9][C:10](=[O:11])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:8])[CH:30]=[CH:31][CH:32]=2)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=1
Reactant: Cn1cc(Br)cc(Nc2cccc(O)n2)c1=O
Reactant: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](COc1cccc(Nc2cc(Br)cn(C)c2=O)n1)NC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 16 h
Yield: 22.1 %

Procedure:
A mixture of 107a (964 mg, 5.5 mmol), 5-Bromo-3-(6-hydroxypyridin-2-ylamino)-1-methylpyridin-2(1H)-one 101a (4 g crude, 16.5 mmol), Cs2CO3 (5.38 g, 11 mmol) in DMF (20 mL) was stirred at 95° C. for 16 h. The reaction mixture was diluted with DCM, washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to give 107b (550 mg, 22%) as a brown solid. MS-ESI: [M+H]+ 453.1
Reaction SMILES: Cl.[C:2](=[NH:10])(OCC)[CH2:3][CH2:4][CH2:5][CH3:6].[NH2:11]/[C:12](/[C:17]#[N:18])=[C:13](\N)/[C:14]#[N:15]>N1C=CC=CC=1>[CH2:3]([C:2]1[NH:10][C:13]([C:14]#[N:15])=[C:12]([C:17]#[N:18])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: N#C/C(N)=C(/N)C#N
Reactant: CCCCC(=N)OCC
Agent: Cl
Solvent: c1ccncc1
Product: CCCCc1nc(C#N)c(C#N)[nH]1

Procedure:
Ethyl pentanimidate hydrochloride (42.66 g, 257.8 mmol, 1 eq), diaminomaleonitrile (27.90 g, 258.1 mmol, 1 eq) and pyridine (400 mL) were mixed and refluxed for 48 hours under N2. The solvent was removed by rotary evaporation.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17]([I:18])=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1.Cl[CH2:20][C:21]1[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[C:24]([CH3:30])=[CH:23][N+:22]=1[O-:31].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:3]2[C:17]([I:18])=[CH:16][N:15]([CH2:20][C:21]3[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[C:24]([CH3:30])=[CH:23][N+:22]=3[O-:31])[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])[N:7]=1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2c(I)c[nH]c2n1
Reactant: COc1c(C)c[n+]([O-])c(CCl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C)c[n+]([O-])c(Cn2cc(I)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.7 %

Procedure:
A mixture of N-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)pivalamide (235 mg), 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 1-oxide (129 mg), and K2CO3 (413 mg) in DMF (6.0 mL) was stirred at rt for 3 days, and diluted with water. The precipitate was collected by filtration and washed with IPA to give 2-((4-chloro-5-iodo-2-pivalamido-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-methoxy-3,5-dimethylpyridine 1-oxide (124 mg).
Reaction SMILES: [N+:1]([C:4]1[C:12]([NH:13]C(=O)C)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2]>OS(O)(=O)=O>[N+:1]([C:4]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccc2[nH]ncc2c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Nc1ccc2[nH]ncc2c1[N+](=O)[O-]
Yield: 71.3 %

Procedure:
By referring to the Step 5 of Example 1, 4-nitro-5-acetylaminoindazole (6.9 g, 31.5 mmol), 2 mol/L H2SO4 solution (200 mL), were used to obtain a product (4.0 g, 73.6%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH:9]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][C:12]([CH:9]([CH3:11])[CH3:10])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)c1ccc(-c2cncc(Br)c2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 51.7 %

Procedure:
Part A. A solution of 3,5-dibromopyridine (1.0 g, 4.2 mmol) and 4-isopropylbenzeneboronic acid (346 mg, 2.1 mmol) in a mixture of ethanol-toluene-water (10 mL/5 mL/3 mL) is treated with sodium carbonate (450 mg). The mixture is degassed twice, treated with a catalytic amount of tetrakis(triphenylphosphine)palladium, and heated with stirring to 80° C. for 12 h. The mixture is cooled, filtered and evaporated. The residue is partitioned between water and ethyl acetate, and the organic phase is washed with brine, dried over sodium sulfate, filtered and evaporated. The residue is separated by column chromatography to afford 3-bromo-5-(4-isopropyl-phenyl)-pyridine (300 mg, 55%).