Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]([F:38])([F:37])[C:8]1[CH:9]=[C:10]([NH:14][C:15]([N:17]2[C:25]3[C:20](=[C:21]([F:35])[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH2:33]O)[N:28]=4)=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH3:36])=[O:16])[CH:11]=[CH:12][CH:13]=1.CCN(CC)CC.[CH2:46]([CH2:48][NH2:49])[OH:47]>C(Cl)Cl.CO>[F:38][C:7]([F:6])([F:37])[C:8]1[CH:9]=[C:10]([NH:14][C:15]([N:17]2[C:25]3[C:20](=[C:21]([F:35])[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][NH:49][CH2:48][CH2:46][OH:47])[N:28]=4)=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH3:36])=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: NCCO
Reactant: Cc1cc2c(F)c(Oc3ccnc(CO)n3)ccc2n1C(=O)Nc1cccc(C(F)(F)F)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: Cc1cc2c(F)c(Oc3ccnc(CNCCO)n3)ccc2n1C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
Methanesulfonyl chloride (0.046 mL, 0.586 mmol) is added to a solution of 4-fluoro-5-(2-hydroxymethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (180 mg, 0.391 mmol) and Et3N (0.109 mL, 0.782 mmol) in CH2Cl2 (5 mL) at 0° C. After 10 min, ethanolamine (0.236 mL, 3.91 mmol) is added and the resulting mixture is warmed to and stirred at 23° C. for 4 h. MeOH (2 mL) is added and the reaction is stirred for another 15 h. The reaction mixture is partitioned between EtOAc (40 mL) and water (40 mL). The aqueous layer is extracted with EtOAc (2×40 mL). The combined organic layers are washed with brine (30 mL), dried (Na2SO4), and concentrated. The residue is purified by silica gel chromatography (0-10 MeOH/CH2Cl2) to give 4-fluoro-5-{2-[(2-hydroxy-ethylamino)-methyl]-pyrimidin-4-yloxy}-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 504.2 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.60 (d, J=5.81 Hz, 1H) 8.07 (s, 1H) 7.86 (s, 1H) 7.57-7.62 (m, 1H) 7.46-7.51 (m, 2H) 7.09 (dd, J=8.84, 7.33 Hz, 1H) 6.98 (d, J=5.81 Hz, 1H) 6.54 (s, 1H) 3.82 (s, 2H) 3.55-3.58 (m, 2H) 2.65-2.71 (m, 2H) 2.62 (s, 3H).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[O:46]1[CH2:51][CH2:50][CH:49]([CH2:52]O)[CH2:48][CH2:47]1>C1COCC1>[O:46]1[CH2:51][CH2:50][CH:49]([CH2:52][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=3[C:2](=[O:3])[O:4][C:5]2=[O:12])[CH2:48][CH2:47]1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: OCC1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1oc(=O)n(CC2CCOCC2)c2ccccc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred mixture of isatoic anhydride (2.5 g) and triphenylphosphine (4.0 g) in THF (100 ml) at 0° C. was added drop-wise diisopropyl azodicarboxylate (3.0 ml), followed by addition (tetrahydro-pyran-4-yl)-methanol (1.78 g). The reaction mixture was stirred at room temperature for 15 hours, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (EtOAc/petroleum ether, 9/1) affording impure 1-(tetrahydro-pyran-4-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione. This material was treated with 27% sodium hydroxide (20 ml) at 50° C. for 48 hours. The mixture was cooled to room temperature and 37% hydrochloric acid (15 ml) was added. The mixture was extracted several times with EtOAc and the combined organic layers were washed with water, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica (EtOAc/petroleum ether, 2/8) and gave the title compound. 13C-NMR (DMSO-d6) δ 170.0, 151.0, 134.4, 131.6, 113.9, 111.2, 109.7, 66.7, 47.8, 34.1, 30.4.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([O-:4])=[O:3].[N:12]1([C:17](=N)[NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.ClC1C=CC=CC=1>O>[N+:2]([C:5]1[CH:6]=[C:7]([NH:8][C:17]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[NH:18])[CH:9]=[CH:10][CH:11]=1)([O-:4])=[O:3]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: N=C(N)N1CCCC1
Agent: Cl
Solvent: Clc1ccccc1
Solvent: O
Product: N=C(Nc1cccc([N+](=O)[O-])c1)N1CCCC1

Procedure:
Samples of 3-nitroaniline hydrochloride, 15.5 g, and 1-pyrrolidinecarboximidamide, 9.6 g, were combined with 12 ml of chlorobenzene, and the mixture was warmed to reflux for three hours, and then allowed to cool. The resulting solid mass was taken up in 200 ml of hot water, and the chlorobenzene layer was separated. The aqueous layer was washed with 30 ml of chloroform and the combined organic layers were washed with 50 ml of water. The aqueous layers were combined, warmed, treated with charcoal and filtered hot. The filtrate was allowed to cool, and made strongly basic with 50% sodium hydroxide. This basic mixture was extracted with 200 ml of chloroform. The chloroform extract was concentrated on a steam bath to 150 ml, then diluted with hexanes to 300 ml, and stirred until yellow solids formed, giving 17 g of the N-(3-nitrophenyl)-1-pyrrolidinecarboximidamide, m.p. 117°-118° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]1[N:24]=[C:23](S(C)(=O)=O)[N:22]3[N:29]=[CH:30][CH:31]=[C:21]3[CH:20]=1)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:36][C:37](=[O:46])[NH:38][C:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37](=[O:46])[NH:38][C:39]1[CH:40]=[CH:41][C:42]([NH:45][C:23]2[N:22]3[N:29]=[CH:30][CH:31]=[C:21]3[CH:20]=[C:19]([C:14]3[CH:13]=[CH:12][C:11]4[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:10]=4)[CH:15]=3)[N:24]=2)=[CH:43][CH:44]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CS(=O)(=O)c1nc(-c2ccc3cc(OCc4ccccc4)ccc3c2)cc2ccnn12
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2nc(-c3ccc4cc(OCc5ccccc5)ccc4c3)cc3ccnn23)cc1
Temperature: 135 °C
Yield: 45.1 %

Procedure:
A mixture of 5-(6-benzyloxy-naphthalen-2-yl)-7-methanesulfonyl-pyrazolo[1,5-c]pyrimidine (compound D2)(87 mg) and 4-amino-phenyl-carbamic acid tert-butyl ester (208 mg) is heated neat at 130 to 140° C. bath temperature for 20 min. After cooling, the crude product is purified by silica gel flash chromatography. A nearly colorless solid (51 mg, 46%) with melting temperature of 189° C. is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccc(C(C)(C)C)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-tert-butyl-phenylboronic acid to give [1-(4-tert-butyl-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 387(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:15])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.CN.[CH2:25]([N:27](CC)CC)C>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[NH:27][CH3:25])[CH:8]=[C:9]([Cl:15])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c(Cl)cc(C(=O)O)cc1Cl
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Cl)c(C(=O)OC)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A solution of 3,5-dichloro-4-(methoxycarbonyl)benzoic acid (400 mg, 1.6 mmol) in dimethylformamide and dichloromethane was treated with oxalyl chloride (0.16 ml, 1.9 mmol) drop wise at room temperature followed by stirring at same temperature for 30 minutes. The reaction mixture was concentrated under vacuum. The residue was dissolved in dichloromethane, cooled to 0° C. and methylamine hydrochloride (118 mg, 1.7 mmol) was added followed by the drop wise addition of triethylamine (0.33 ml, 2.4 mmol) at the same temperature. The reaction mixture was allowed to warm to room temperature, stirred for 1 hour and concentrated under vacuum. The residue was treated with ice-cooled aqueous sodium bicarbonate solution (5%). The precipitated solid was filtered, washed with water, and dried to yield methyl 2,6-dichloro-4-(methylcarbamoyl)benzoate (340 mg, 70%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:8]=[CH:7]2.[C:22](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[CH3:22][O:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:8]=[CH:7]2
Reactant: CCOC(=O)c1cc(O)c2c(cnn2C2CCCCO2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc(OC)c2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.5 %

Procedure:
To a mixture of ethyl 7-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (WO2009144554) (100 mg, 0.34 mmol) and potassium carbonate (95.1 mg, 0.68 mmol) in N,N-dimethylformamide (1 mL) was added methyl iodide (32 μL, 0.51 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate (4×). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give the title compound (105 mg, 100%) as a yellow oil. +ESI (M+1-THP) 221.2; 1H NMR (400 MHz, CDCl3, δ): 8.07-8.10 (m, 2H), 7.43 (d, J=0.98 Hz, 1H), 6.24 (dd, J=10.24, 2.44 Hz, 1H), 4.38 (q, J=7.15 Hz, 2H), 4.08 (dt, J=11.56, 2.02 Hz, 1H), 4.04 (s, 3H), 3.70-3.78 (m, 1H), 2.54-2.66 (m, 1H), 2.09-2.19 (m, 1H), 2.01-2.08 (m, 1H), 1.71-1.83 (m, 2H), 1.55-1.64 (m, 1H), 1.41 (t, J=7.12 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:20])[N:7]([CH3:21])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: CCCc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CCCc1ccc(N(C)C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.6 %

Procedure:
To a solution of (3-nitro-4-propyl-phenyl)-carbamic acid tert-butyl ester (200 mg, 0.71 mmol) in DMF (5 mL) was added Ag2O (1.0 g, 6.0 mmol) followed by methyl iodide (0.20 mL, 3.2 mmol). The resulting suspension was stirred at room temperature for 18 h and filtered through a pad of Celite. The filter cake was washed with CH2Cl2 (10 mL). The filtrate was concentrated in vacuo. The crude oil was purified by column chromatography (0-10% CH2Cl2-MeOH) to afford methyl-(3-nitro-4-propyl-phenyl)-carbamic acid tert-butyl ester as a yellow oil (110 mg, 52%). 1H NMR (CDCl3, 300 MHz) δ 7.78 (d, J=2.2 Hz, 1H), 7.42 (dd, J=8.2, 2.2 Hz, 1H), 7.26 (d, J=8.2 Hz, 1H), 3.27 (s, 3H), 2.81 (t, J=7.7 Hz, 2H), 1.66 (m, 2H), 1.61 (s, 9H), 0.97 (t, J=7.4 Hz, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:24])[NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][CH:10]=1>C(N(CC)CC)C.CN(C=O)C>[CH3:5][O:4][C:2]([NH:6][N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:24])[NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][CH:10]=1)=[O:3]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)CNC(=O)Nc1ccc(C=NN)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)Nc1ccc(C=NNC(=O)OC)cc1
Reaction time: 168 h

Procedure:
1.74 g (22.7 mmol) of methyl chloroformate are added dropwise to a solution of 5 g (18.92 mmol) of ethyl (3-(4-(aminoiminomethyl)phenyl)ureido)acetate in 53 ml of triethylamine and 100 ml of DMF. After 7 d at room temperature, solid is filtered off and the filtrate is concentrated in vacuo. The residue is chromatographed on silica gel (ethyl acetate/methanol 95:5).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1C(C)O.[C:14]1(C)C(S(O)(=O)=O)=CC=C[CH:19]=1>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:14]=[CH2:19])=[CH:9][CH:10]=1
Reactant: CC(O)c1ccccc1CCCBr
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: C=Cc1ccc(CCCBr)cc1

Procedure:
The product from Example 2 is used as a stating material in this procedure. The resulting product from Example 2 was diluted in 200 mL of toluene. Next, 0.125 g of toluensulfonic acid was added to the reaction mixture. The reaction mixture was refluxed under argon atmosphere for 44 hours. The mixture was then washed with 50 mL of water and the solvent was removed under vacuum. The resulting product was then purified by silica gel chromatography with the use of 90% hexane and 10% ethyl acetate. The resulting product was recovered as the solvent was removed under vacuum.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:21][C:22](=O)[O:23]CC(Cl)(Cl)Cl)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>CCCCCC.C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:21][C:22]([NH:35][CH2:34][CH2:33][O:32][CH3:31])=[O:23])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Reactant: COCCN
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COCCNC(=O)Nc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Yield: 58 %

Procedure:
Using 2,2,2-trichloroethyl (3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and 2-methoxyethylamine, the title compound was synthesized in the same manner as in Example 143. Yield: 58%. Melting point: 172-173° C. (hexane-ethyl acetate).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1.[CH3:25][O:26][C:27](OC)(OC)OC.C(O)(=O)CC>>[CH3:25][O:26][C:27]1[N:17]([CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:2]3[NH:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)[CH2:12][CH2:13]2)[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:23]2[N:24]=1
Reactant: Nc1cccnc1NC1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: COC(OC)(OC)OC
Solvent: CCC(=O)O
Product: COc1nc2cccnc2n1C1CCC(Nc2nc3ccccc3[nH]2)CC1
Temperature: 90 °C
Yield: 14.4 %

Procedure:
N2-[4-((1H-Benzo[d]imidazol-2-yl)amino)cyclohexyl)pyridine-2,3-diamine (320 mg, 0.99 mmol) was combined with tetramethylorthocarbonate (2 mL) and propionic acid (8 mg), the mixture was heated at 90° C. for 2 hours. After that, the reaction solution was concentrated under reduced pressure and the residue was purified by silica chromatography to give N-(4-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)cyclohexyl)-1H-benzo[d]imidazol-2-amine (50 mg, 0.14 mmol, 14.4% yield). M+1: 380.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]4[CH2:27][CH:26]([C:28]([O:30]C)=[O:29])[CH2:25]4)=[N:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]4[CH2:25][CH:26]([C:28]([OH:30])=[O:29])[CH2:27]4)=[N:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: COC(=O)C1CN(Cc2ccc(-c3noc(-c4ccc(CC(C)C)c(F)c4)n3)cn2)C1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(CN4CC(C(=O)O)C4)nc3)no2)cc1F
Yield: 81.2 %

Procedure:
The title compound (90 mg) was synthesized in a yield of 81% as a white crystalline solid using methyl 1-({5-[5-(3-fluoro-4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}methyl)azetidine-3-carboxylate (0.12 g, 0.27 mmol) that was obtained in Example 23 (23g) and a 1 N aqueous solution of sodium hydroxide (0.81 mL, 0.81 mmol) by conducting the reaction similar to that mentioned in Example 3 (3e).
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][C:12](OC)=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.O>C1COCC1>[OH:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][CH2:12][OH:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1coc2c(O)cccc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1coc2c(O)cccc12
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 86.4 %

Procedure:
Methyl (7-hydroxybenzofuran-3-yl)acetate (1.46 g) was dissolved in THF (30 ml) and the solution was cooled to 0° C. To this solution, lithium aluminum hydride (269 mg) was added and the solution was stirred for 3.5 hours. After making the pH of the reaction solution not more than 2 by adding 1N hydrochloric acid, the reaction solution was poured into water layer (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). After combining the organic layers, the resultant was washed with saturated brine and dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=1/1) using silica gel to obtain the desired compound (1.09 g, yield: 86%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][O-:15].[Na+]>>[CH3:14][O:15][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: C[O-]
Agent: [Na+]
Product: COc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
2-Chloro-5-nitro-benzoic acid (3 g, 14 mmol) was added to a solution of freshly prepared sodium methoxide (from sodium (1.36 g, 56 mmol) in dry methanol (15 ml)) and the reaction was heated to reflux for 12 hr. Methanol was evaporated and the reaction mass diluted with water (25 ml). Conc hydrochloric acid was added until the pH was ˜2. The reaction mixture was stirred at room temperature for 30 min, then the precipitate was filtered and washed with water. Drying at 60-70° C. yielded 2-methoxy-5-nitro benzoic acid (2.4 g, 81%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[O:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([NH:21]C(=O)C(F)(F)F)=[CH:16][C:15]=2[F:28])[NH:6][CH:5]=1>C(O)C>[Cl:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[O:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([NH2:21])=[CH:16][C:15]=2[F:28])[NH:6][CH:5]=1
Reactant: O=C(Nc1cc(F)c(Oc2ccnc3[nH]cc(Cl)c23)c(F)c1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(F)c(Oc2ccnc3[nH]cc(Cl)c23)c(F)c1
Reaction time: 8 h

Procedure:
3 ml of a 1N sodium hydroxide solution are added to a solution of 90 mg (0.23 mmol) of N-{4-[(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-2,2,2-trifluoroacetamide in ethanol (5 ml). The reaction is stirred overnight. The solution is extracted with tert-butyl methyl ether (two times 10 ml). The combined organic phases are washed with a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. This gives a solid which is not purified any further.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[C:7]([C:14]2[NH:15][C:16]3[C:21]([N:22]=2)=[C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@H:24]2[CH3:29])[N:19]=[C:18]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@H:31]2[CH3:36])[N:17]=3)[CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:36][C@@H:31]1[CH2:32][O:33][CH2:34][CH2:35][N:30]1[C:18]1[N:17]=[C:16]2[C:21]([N:22]=[C:14]([C:7]3[CH:6]=[C:5]([CH2:3][OH:2])[CH:13]=[C:12]4[C:8]=3[CH:9]=[CH:10][NH:11]4)[NH:15]2)=[C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@H:24]2[CH3:29])[N:19]=1
Reactant: COC(=O)c1cc(-c2nc3c(N4CCOC[C@H]4C)nc(N4CCOC[C@H]4C)nc3[nH]2)c2cc[nH]c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc(-c3cc(CO)cc4[nH]ccc34)[nH]c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
4-[2,6-Bis-((R)-3-methyl-morpholin-4-yl)-9H-purin-8-yl]-1H-indole-6-carboxylic acid methyl ester (example 32, 72 mg, 146 μmol) was dissolved in 10 ml THF under argon. 1N LiAlH4 in THF (0.22 mL, 0.22 mmol) was added at 5° C., and the reaction was stirred for 2 hours at room temperature. The reaction was quenched by addition of aqueous saturated Na2SO4 (1 mL). The mixture was diluted with 30 mL of CH2Cl2 and 3 mL of isopropanol. The organic phases were separated, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (12 g SiO2, CH2Cl2/EtOH in a gradient from 100/0 to 88/12) to give the product as a solid (58 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Br[C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:33][CH2:32][N:31]2[C:34](=[O:36])[CH3:35])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:34]([N:31]1[CH2:32][CH2:33][CH:30]1[C:27]1[CH:28]=[CH:29][C:24]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[Cl:1])[NH:8][CH:7]=[C:6]3[C:11]([O:13][CH3:14])=[O:12])=[CH:25][CH:26]=1)(=[O:36])[CH3:35]
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Reactant: CC(=O)N1CCC1c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCN4C(C)=O)cc3)cc12
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 33.6 %

Procedure:
A mixture of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (100 mg, 0.311 mmol), 1-[2-(4-bromophenyl)azetidin-1-yl]ethanone (100 mg, 0.373 mmol), 2.0 M aqueous potassium carbonate (0.50 mL, 1.0 mmol), and Pd(dppf)Cl2 (30 mg, 0.03 mmol) in toluene/ethanol (1.44 mL/0.48 mL) was stirred at 110° C. for 2.5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated to give a residue. This was purified by preparative TLC to give the title compound (40 mg, 51% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[N+]([O-])([O-])=O.[Ag+:13].N>CO.O>[Ag:13].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1
Reactant: [Ag+]
Agent: N
Agent: O=[N+]([O-])[O-]
Agent: Oc1ccc(Br)cn1
Solvent: CO
Solvent: O
Product: [Ag]

Procedure:
5-Bromo-2-hydroxypyridine (1.795 g) was dissolved in methanol (60 mL), a solution of silver nitrate (1.752 g) in water (40 mL) was added and the mixture was stirred. Aqueous ammonia was added, and the precipitate was collected by filtration to give 5-bromo-2-hydroxypyridine silver salt (2.68 g). The salt (2.37 g) and 2-{[4-(chloroacetyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (2.364 g) obtained in Example 1 were dissolved in ethanol (50 mL), and the mixture was stirred for 46 hr with heating under reflux. The reaction mixture was filtered through celite and the solvent was evaporated. The residue was dissolved again in ethyl acetate (100 mL), and the mixture was washed successively with 0.5 mol/L aqueous hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by column chromatography (Yamazen HI-FLASH™ COLUMN size 3 L, elution solvent: hexane/ethyl acetate=9/1-6/4) to give the title compound (247 mg).