Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[C:16](=[O:19])[CH2:17][CH2:18][C:14]=3[N:13]=[C:12]2[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][CH:5]=1>ClCCl.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[C:15]3[CH:16]([OH:19])[CH2:17][CH2:18][C:14]=3[N:13]=[C:12]2[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][CH:9]=1
Reactant: CC(C)(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CC2
Reaction time: 16 h
Yield: 95.3 %

Procedure:
Sodium borohydride (158 mg) was added to a stirred solution of Intermediate 33 (421 mg) in dichloromethane (3 ml) and methanol (3.00 ml). The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under vacuum, partitioned between EtOAc (40 ml) and water (40 ml). The two phases were separated and the aqueous phase was extracted again with EtOAc (30 ml). The phases were separated, the organic extracts were combined, dried (hydrophobic frit) and concentrated under vacuum to give the required product (404 mg). LC/MS MH+ 305, Rt 2.59 min (5 minute run).
Reaction SMILES: [CH:1]1([C@@:6]([OH:15])([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[C@H:29]1[CH:34]2[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]2)[CH2:30]1.O>CN(C=O)C>[N:31]12[CH2:36][CH2:35][CH:34]([CH2:33][CH2:32]1)[C@H:29]([O:8][C:7](=[O:9])[C@:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([OH:15])[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH2:30]2
Reactant: O=C(O)[C@](O)(c1cccs1)C1CCCC1
Reactant: O[C@@H]1CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O[C@@H]1CN2CCC1CC2)[C@](O)(c1cccs1)C1CCCC1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
510 mg (0.00225 mol) of (2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid (obtained by hydrolysis of Intermediate I-15a) were dissolved in 7 ml of DMF. This solution was stirred at room temperature and 638 mg (0.00393 mol) of 1,1′-carbonyldiimidazole were added in several portions. After 4.5 h the reaction mixture was cooled to 0° C. and 315 mg (0.00248 mol) of (3S)-3-hydroxy-1-azabicyclo[2.2.2]octane and 83 mg (0.0021 mol) of HNa (60% dispersion in mineral oil) were added thereto. After stirring 112 h at room temperature the reaction mixture was treated with water and extracted three times with diethyl ether. The organic layers were combined, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (eluent CHCl3/MeOH 15:1) to obtain 360 mg (47.6%) of the title product as an oil, structure confirmed by 1H-RMN.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.CN(C=O)C.O[NH:24][C:25](=[NH:27])[CH3:26]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([O:6]/[N:24]=[C:25](\[NH2:27])/[CH3:26])=[O:5]
Reactant: CC(=N)NO
Reactant: O=C(O)c1c(F)cccc1I
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C/C(N)=N/OC(=O)c1c(F)cccc1I
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.1 %

Procedure:
To a heterogeneous mixture of 2-fluoro-6-iodobenzoic acid (1.51 g, 5.66 mmol) at 0° C. in DCM (28 mL) was added oxalyl chloride (0.635 mL, 7.36 mmol) followed by DMF (0.15 mL). Gas evolution commenced immediately and after 5 min the ice bath was removed. When gas evolution had ceased and the mixture was homogeneous an aliquot was removed and quenched with MeOH. Formation of the methyl ester was confirmed by HPLC and the mixture was concentrated in vacuo. The viscous liquid was dissolved in fresh DCM (28 mL) and treated with solid N-hydroxyacetamidine (503 mg, 6.79 mmol) in several portions followed by TEA (1.2 mL, 8.49 mmol) at 0° C. After stirring for 14 h at ambient temperature the mixture was washed with saturated aqueous NaHCO3 solution. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (Hex to 100% EtOAc/Hex) afforded the desired product as a colorless oil (1.57 g, 86%). MS (ESI) mass calculated for C9H8FIN2O2, 321.96; m/z found, 323.0. 1H NMR (500 MHz, CDCl3): 7.70-7.65 (m, 1H), 7.15-7.11 (m, 2H), 4.87 (br s, 2H), 2.06 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9](Cl)=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]3)[CH:5]=[N:6][CH:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[N:6]1[CH:5]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]3)[CH:3]=[C:2]([C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH:7]=1
Reactant: OB(O)c1cccnc1
Reactant: CN1C(=O)Cc2c1ccc(-c1cncc(Br)c1)c2Cl
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: ClCCl
Product: CN1C(=O)Cc2cc(-c3cncc(-c4cccnc4)c3)ccc21
Temperature: 120 °C

Procedure:
To 5-(5-bromo-pyridin-3-yl)-4-chloro-1-methyl-1,3-dihydro-indol-2-one prepared as described in Example 28, (100 mg, 0.30 mmol) was added 3-pyridine boronic acid (CAS#1692-25-7, 47.3 mg, 0.385 mmol), 1,2-dimethoxyethane (3 mL), and 2 M aqueous sodium carbonate (0.385 mL, 0.770 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (135 mg, 0.015 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 2.5 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 1 to 8%) to furnish 5-[3,3′]bipyridinyl-5-yl-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 336.0905 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.18 (s, 3H), 3.68 (s, 2H), 7.15 (d, J=8.1 Hz, 1H), 7.50-7.60 (m, 2H), 8.20 (t, J=2.1 Hz, 1H), 8.21-8.27 (m, 1H), 8.65 (dd, J=4.7, 1.6 Hz, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.97 (d, J=2.1 Hz, 1H), 9.03 (d, J=2.4 Hz, 1H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1.OS(O)(=O)=O>O>[CH2:18]([O:17][C:15]([CH:12]1[CH2:13][CH2:14][C:9]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)[CH2:10][CH2:11]1)=[O:16])[CH3:19]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C1CCC(c2ccc(O)cc2)(c2ccc(O)cc2)CC1
Temperature: 0 °C
Yield: 50.5 %

Procedure:
Phenol (1.1 g, 11.8 mmol) was diluted with water (0.53 mL) and cooled to 0° C. with stirring. Ethyl 4-oxocyclohexanecarboxylate (0.94 mL, 5.87 mmol) was added followed by dropwise addition of concentrated H2SO4 (2.11 g). After 10 min the mixture was warmed to room temperature and allowed to stir for 4 hr. The mixture was then diluted with water and the product extracted with EtOAc (2×). The organic layer was washed with water, brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, 2:1 Hexane/EtOAc) to give 1.01 g (51%) of 4,4-bis(4-hydroxyphenyl)cyclohexane carboxylic acid ethyl ester.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]2)[CH:9]=[CH:8][CH:7]=1.C(O)=O>O>[CH:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10]2[N:11]=[C:6]([CH:2]=[O:1])[CH:7]=[CH:8][CH:9]=2)[CH2:17][CH2:16]1)([CH3:20])[CH3:19]
Reactant: CC(C)N1CCN(c2cccc(C3OCCO3)n2)CC1
Solvent: O=CO
Solvent: O
Product: CC(C)N1CCN(c2cccc(C=O)n2)CC1
Temperature: 60 °C
Yield: 81.8 %

Procedure:
A mixture of 1-[6-(1,3-dioxolan-2-yl)pyridin-2-yl]-4-isopropylpiperazine (8, 0.31 g, 1.1 mmol), formic acid (2.50 g, 50 mmol) and water (0.5 mL) was heated at 60° C. for 5 h. After this time, the mixture was concentrated and the residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to afford the title compound (0.21 g, 82%) as a yellow oil; ESI MS m/z 234 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:15]1)=[O:4].Cl[C:31]1[N:39]=[CH:38][N:37]=[C:36]2[C:32]=1[N:33]=[CH:34][N:35]2[CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1.CCN(C(C)C)C(C)C>C(O)CCC>[F:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:31]2[N:39]=[CH:38][N:37]=[C:36]3[C:32]=2[N:33]=[CH:34][N:35]3[CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[CH3:29])=[C:7]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:15]2)[CH:8]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)C(=O)Nc1ccc(F)cc1N[C@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)C(=O)Nc1ccc(F)cc1N[C@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 90 °C
Reaction time: 16 h
Yield: 65.8 %

Procedure:
A mixture of 2,2-dimethylpropionic acid 2-{(S)-3-[2-((S)-2-aminopropionylamino)-5-fluorophenylamino]piperidin-1-yl}ethyl ester, (0.591 g, 1.45 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.346 g, 1.45 mmol), and DIPEA (0.74 mL, 4.32 mmol) in n-butanol (7 mL) was stirred in a sealed vial at 90° C. for 16 h. After cooling to RT the volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 2-8% 2M NH3/MeOH in DCM) affording the title compound as a colourless gum (0.583 g, 66%). LCMS (Method J): RT 2.39 min [M+H]+ 611.
Reaction SMILES: [CH3:1][CH:2]([C:8](=O)[CH2:9][O:10][CH3:11])[C:3](OCC)=[O:4].C[O-].[Na+].[NH2:16][C:17]([NH2:19])=[NH:18].S(=O)(=O)(O)O>CN(C)C=O.C(O)C>[NH2:19][C:17]1[N:18]=[C:3]([OH:4])[C:2]([CH3:1])=[C:8]([CH2:9][O:10][CH3:11])[N:16]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(C)C(=O)COC
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COCc1nc(N)nc(O)c1C
Temperature: 20 °C
Yield: 26.6 %

Procedure:
Ethyl 2-methyl-3-oxo4-methoxybutyrate(10.5 g, 60 mmol) was added slowly to a suspension of sodium methoxide (6.5 g, 120 mmol) in dimethylformamide(10 ml) while maintaining the reaction temperature under 20° C. A solution of guanidine(5.7 g, 60 mmol) in ethanol was added to a reaction mixture, which was then refluxed for 5 hours, cooled to a room temperature, and neutralized with conc. sulfuric acid. The resulting solid was filtered and dried to give 2.7 g of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:19][N:20]1[C:24]([Cl:25])=[C:23]([Cl:26])[N:22]=[CH:21]1>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:19][N:20]3[C:24]([Cl:25])=[C:23]([Cl:26])[N:22]=[CH:21]3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: ClCn1cnc(Cl)c1Cl
Reactant: Oc1ccc(Oc2cccc(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(Oc2ccc(OCn3cnc(Cl)c3Cl)cc2)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
At room temperature (about 20° C.), 4.9 g of 4-(6-chloro-2-pyridinyloxy)-phenol in 40 ml of anhydrous dimethylformamide is dripped into 0.6 g of 100% strength sodium hydride in 20 ml of anhydrous dimethylformamide. The mixture is subsequently stirred for 30 minutes at 50° C., and then 4.2 g of 1-chloromethyl-4,5-dichloroimidazole in 20 ml of anhydrous dimethylformamide is dripped in at room temperature. This mixture is stirred for 2 hours at 60° C. and overnight at room temperature. It is then stirred into 200 ml of ice water and the solution is extracted three times with methyl tert-butyl ether. The organic phase is washed with 5% strength sodium hydroxide solution and water, and dried, and the solvent is evaporated off under reduced pressure. The crude product obtained is recrystallized from toluene. There is obtained 6.6 g of 1-[4-(6-chloro-2-pyridinyloxy)-phenoxymethyl]-4,5-dichloroimidazole: m.p.: 94°-98° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](N)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11].C1C=C2C3=C(C(NC(=O)C3=CC=C2)=O)C=1.N>C(OCCCC)(=O)C>[CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][C:17](=[O:18])[C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: N
Agent: O=C1NC(=O)c2cccc3cccc1c23
Solvent: CCCCOC(C)=O
Product: C[Si](C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
4.5 ml of hexamethyldisilazane (22 mmoles) were added to a refluxing mixture of 5.0 g (30.1 mmoles) of 4-nitrobenzamide, 100 mg (0.5 mmole) of 1.8-naphthalimide and 20 ml of butyl acetate and the calculated amount of ammonia was evolved after refluxing for 35 minutes. The same experiment without catalyst was carried out and only 16% of the theoretical amount of ammonia was evolved after refluxing for 15 minutes. After refluxing for 1 hour, 83% of that amount of evolved.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C.[C:21]1([C:26](Cl)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:21]1([C:26]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCCSc1cccnc1
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCSc1cccnc1)c1cccs1
Yield: 85.4 %

Procedure:
To a solution of 2.00 g (8.29 mmol) of 3-(3-aminopropylthio)pyridine dihydrochloride and 4.16 ml (29.9 mmol) of triethylamine in 80 ml of methylene chloride, 1.06 ml (9.95 mmol) of 2-thenoyl chloride was-added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of-sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder was washed with ether and dried to obtain 1.97 g of the desired compound (yield: 85.3%, yellow powder).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[S:44]1[CH:48]=[CH:47][C:46]([CH2:49][C:50](O)=[O:51])=[CH:45]1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:50](=[O:51])[CH2:49][C:46]3[CH:47]=[CH:48][S:44][CH:45]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1ccsc1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 77.3 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3-thiopheneacetic acid (0.3 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-thiophen-3-yl-acetamide (0.7 g, 80%) as a white solid: mp 163-165° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.39 min. (99%); 1H NMR (DMSO-d6) δ 2.02-2.09 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.55 (s, 2H), 4.71 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.04-7.06 (m, 1H), 7.28-7.29 (m, 1H), 7.45-7.48 (m, 1H), 7.61-7.67 (m, 1H), 7.76-7.83 (m, 2H), 8.60 (t, J=5.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ21.95, 30.90, 36.88, 37.83, 48.83, 121.87, 122.35, 125.76, 127.11, 128.67, 131.51, 133.18, 134.67, 135.82, 139.17, 166.91, 167.44, 169.78, 170.23, 172.73; Anal. Calcd. for C20H17N3O5S: C, 58.39; H, 4.16; N, 10.21; S, 7.79. Found: C, 58.37; H, 3.98; N, 10.05; S, 7.83.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](CC3C=CC(OC)=CC=3)[N:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12.IC1C=CN=C2NN=C(C(C)C)C=12.COC1C=CC(CCl)=CC=1.Cl.[CH3:47][N:48]1[CH:52]=[C:51]([C:53]2[N:54]=[CH:55][NH:56][CH:57]=2)[CH:50]=[N:49]1>>[CH:11]([C:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[N:56]2[CH:57]=[C:53]([C:51]3[CH:50]=[N:49][N:48]([CH3:47])[CH:52]=3)[N:54]=[CH:55]2)[NH:8][N:9]=1)([CH3:12])[CH3:13]
Reactant: COc1ccc(Cn2nc(C(C)C)c3c(I)ccnc32)cc1
Reactant: Cn1cc(-c2c[nH]cn2)cn1
Agent: CC(C)c1n[nH]c2nccc(I)c12
Agent: COc1ccc(CCl)cc1
Agent: Cl
Product: CC(C)c1n[nH]c2nccc(-n3cnc(-c4cnn(C)c4)c3)c12
Yield: 63 %

Procedure:
According to Example 97(1), 4-iodo-3-isopropyl-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine was prepared using (100a) (15.5 g) instead of compound (40d) and using 4-methoxybenzyl chloride instead of {2-(chloromethoxy)ethyl}silane and was used in the subsequent reaction without being purified. According to Example 97(2), 3-isopropyl-1-(4-methoxybenzyl)-4-{4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl}-1H-pyrazolo[3,4-b]pyridine was prepared using 4-iodo-3-isopropyl-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine instead of compound (97a) and using 4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole hydrochloride instead of 4-phenyl-1H-imidazole and was used in the subsequent reaction without being purified. This 3-isopropyl-1-(4-methoxybenzyl)-4-{4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl}-1H-pyrazolo[3,4-b]pyridine was dissolved in trifluoroacetic acid (60 mL) and anisole (19 mL), followed by reflux for 5 hr. The reaction solution was concentrated and then diluted with acetonitrile, and saturated sodium bicarbonate water was added thereto. The precipitate was collected by filtration and was dried under reduced pressure to obtain compound (100b) (12.3 g, the third stage yield: 63%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH2:16][O:17][CH3:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]2[N:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([CH2:30][OH:31])=[N:28][CH:29]=3)[O:21][N:20]=2)[N:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH2:16][O:17][CH3:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]2[N:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([CH2:30][O:31][S:33]([CH3:32])(=[O:35])=[O:34])=[N:28][CH:29]=3)[O:21][N:20]=2)[N:3]=1
Reactant: COCCN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(CO)nc3)n2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(COS(C)(=O)=O)nc3)n2)n1
Reaction time: 3 h

Procedure:
To a solution of [5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-yl]-methanol (Intermediate 130, 185 mg, 0.44 mmol) in DCM (40 mL) was added methanesulfonyl chloride (48 μL, 0.61 mmol) drop-wise, followed by triethylamine (92 μL, 0.66 mmol). The resulting solution was stirred for 3 h under an inert atmosphere. Incomplete reaction was observed so additional methanesulfonyl chloride (9 μL, 0.10 mmol) and triethylamine (16 μL, 0.11 mmol) were added and stirring was continued for 1 h. The reaction mixture was washed with water (2×50 mL) and the organic phase dried over magnesium sulfate and evaporated to dryness to afford the methanesulfonic acid 5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-ylmethyl ester intermediate. In a separate flask 2,2,2-trifluoro-ethanol (190 μL, 2.64 mmol) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 97 mg, 2.42 mmol) in anhydrous THF (30 mL) at 0 C under nitrogen. The resulting solution was stirred at 0 C for 30 min and then transferred via cannula to a solution of the methanesulfonic acid 5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-ylmethyl ester intermediate (220 mg, 0.44 mmol) in anhydrous THF (30 mL) at 0 C drop wise. The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with a saturated ammonium chloride aq. solution (5 mL) and extracted with EtOAc (3×50 mL). Combined organics were washed with brine (25 mL), dried over magnesium sulfate and evaporated to dryness. The crude product was purified by silica chromatography (2% MeOH in DCM) and then further by preparative HPLC-MS (Method C) to afford the title compound as an off-white solid (21 mg, 10%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)=[CH:32][CH:33]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(F)cc2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 1-(bromomethyl)-4-fluorobenzene (0.2 mL), potassium carbonate (0.38 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.58 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].N1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)Cl>[CH2:29]([O:28][C:26]([N:11]1[CH2:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:15]([F:18])([F:16])[F:17])[CH:4]=2)([OH:14])[CH2:13][CH2:12]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)Cl
Reactant: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCNCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1CCC(O)(c2ccc(Cl)c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
4-[4-Chloro-3-(trifluoromethyl)phenyl]-4-hydroxypiperidine (ACROS Co., 2.0 g) was dissolved in methylene chloride (10 ml), and pyridine (0.6 ml) and ethyl chloroformate (0.8 ml) were added thereto. The mixture was stirred at room temperature for 5 hr. After completion of the reaction, the reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (1:2)) to give 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinecarboxylic acid ethyl ester (2.03 g, yield 81%).