Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[F:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[C:31]([F:38])[N:30]=1>>[F:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)[CH:32]=[C:31]([F:38])[N:30]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: OB(O)c1cc(F)nc(F)c1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cc(F)nc(F)c4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-4-morpholino-6-((4-N-methylsulfonylpiperazin-1-yl)methyl)thieno[3,2-d]pyrimidine was reacted with 2,6-difluoropyridine-4-boronic acid in General Procedure A. Purification on silica yielded 2-(2,6-difluoro-pyridin-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH:11](O)[O:10][C:9]1=[O:14])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[NH2:27][C@H:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:29][SH:30].Cl.O>CCO>[CH3:34][O:33][C:31]([CH:28]1[CH2:29][S:30][CH:11]([CH2:12][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])([C:9]([OH:10])=[O:14])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:27]1)=[O:32]
Reactant: COC(=O)[C@@H](N)CS
Reactant: CC(C)(C)OC(=O)NC1(c2ccccc2)CC(O)OC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)C1CSC(CC(NC(=O)OC(C)(C)C)(C(=O)O)c2ccccc2)N1
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a solution of compound 14 (5.6 g, 19.1 mmol) in EtOH (80 mL) was added 1 M aq. NaHCO3 solution (19.1 mL, 19.1 mmol), followed by the addition of L-Cys-OMe.HCl (3.3 g 19.1 mmol). The pH value of the resulting mixture was adjusted to 6.5 with 1 M NaHCO3 solution. After stirring overnight, the mixture was poured into water, extracted with ethyl acetate, and the combined organic phases were dried over Na2SO4 and concentrated to afford product 15 (7 g, 51.1%). MS (M+1): 411. This product was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([CH3:17])[C:9](=[O:18])[CH:8]([NH:19]C(OCC3C=CC=CC=3)=O)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br.C(OCC)C>C(O)(=O)C>[NH2:19][CH:8]1[N:7]=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH3:17])[C:9]1=[O:18]
Reactant: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCC2)c2ccccc21
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CN1C(=O)C(N)N=C(C2CCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To 5-cyclopentyl-1,3-dihydro-1-methyl-3(R,S)-[(benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (475 mg, 1.2 mmol) was added 45% hydrobromic acid in acetic acid (1 ml) and the mixture stirred at room temperature for 2 h. Anhydrous diethyl ether (50 ml) was added and the resultant cream coloured suspension stirred at 0° C. for 1 h. On settling, the solvent was decanted off, and the solid triturated in anhydrous diethyl ether. The resultant solid was collected by filtration and washed with more diethyl ether. The solid was partitioned between 10% Na2CO3 solution (25 ml) and ethyl acetate (20 ml), the aqueous layer was further extracted with ethyl acetate (4×10 ml) and the organic extracts combined, dried (MgSO4), and evaporated to give the title compound (247 mg, 79%) as a colourless off.
Reaction SMILES: [Na+].[CH:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([C:14]=2[C:16]([O:18][CH2:19][C:20]([F:26])([F:25])[S:21]([O-:24])(=[O:23])=[O:22])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.[Na].FC(F)(F)S([O-])(=O)=O.[C:36]1([CH:42]([SH+:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:43]1([CH:42]([SH+:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1.[F:26][C:20]([F:25])([S:21]([OH:24])(=[O:23])=[O:22])[CH2:19][O:18][C:16]([C:14]1[C:13]2[C:8]([CH:7]=[C:6]3[C:15]=1[CH:2]=[CH:3][CH:4]=[CH:5]3)=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:17]
Reactant: O=C(OCC(F)(F)S(=O)(=O)[O-])c1c2ccccc2cc2ccccc12
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Agent: [Na]
Product: O=C(OCC(F)(F)S(=O)(=O)O)c1c2ccccc2cc2ccccc12
Yield: 85.6 %

Procedure:
<2> The reaction described in <3> of Synthesis Example 1 was performed under the same conditions, except that the 9-anthracenecarbonyloxymethyl difluoromethanesulfonic acid sodium salt (3.82 g) produced in <1> of Synthesis Example 9 above was used instead of the benzoyloxymethyldifluorosulfonic acid sodium salt in the reaction with diphenylmethylphenylsulfonium trifluoromethanesulfonic acid sodium salt, and thus 3.86 g (yield 85.6%) of 9-anthracenecarboxylic acid 2,2-difluoro-2-sulfoethyl ester diphenylmethylphenylsulfonium salt as shown in the following reaction scheme 19 was obtained. The structure of the product was confirmed by 1H-NMR.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@@H:5]([C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1)=[O:11])[CH2:6][C:7](=[O:9])[NH2:8].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34](O)=[O:35])[CH:32]=2)[CH:27]=[CH:26]1>>[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([NH:4][C@@H:5]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]4)[CH2:14][CH2:13]3)=[O:11])[CH2:6][C:7](=[O:9])[NH2:8])=[O:35])[CH:32]=2)[CH:27]=[CH:26]1
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)CC(N)=O)CC2)CC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](CC(N)=O)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-(D-asparaginyl)-4-(1-methylpiperidin-4-yl)piperazine trihydrochloride and indole-6-carboxylic acid (45%).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:18]([CH2:25][CH2:26][OH:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:27][CH2:26][CH2:25][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OCCOc1ccccc1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: N=C(OCCOc1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and 2-phenoxyethanol, there is obtained 2-phenoxyethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 358 (20), 265 (7), 237 (65), 194 (100);
Reaction SMILES: C(OC(=O)[N:7]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[C:33]3[C:28](=[N:29][CH:30]=[C:31]([Cl:34])[CH:32]=3)[NH:27][CH:26]=2)=[O:24])=[CH:19][N:18]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:34][C:31]1[CH:32]=[C:33]2[C:25]([C:23]([C:20]3[CH:19]=[N:18][C:17]([NH:7][CH2:8][C:9]4[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=4)=[CH:22][CH:21]=3)=[O:24])=[CH:26][NH:27][C:28]2=[N:29][CH:30]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(=O)c3c[nH]c4ncc(Cl)cc34)cn2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CNc2ccc(C(=O)c3c[nH]c4ncc(Cl)cc34)cn2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
To [5-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (587, 0.020 g, 0.040 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.30 mL, 0.0039 mol). The reaction was stirred at room temperature for 2 hours, then poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (P-0405, 5.5 mg, 34%). MS (ESI) [M+H+]+=394.3.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[C:25]([CH2:29][O:30][CH3:31])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:36]=[N+:37]=[N-:38])(C)C.[Na:39].C(C(CCCC)C(O)=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.CO>[Na:39].[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:38][N:37]=[N:36][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[C:25]([CH2:29][O:30][CH3:31])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nc2cccc(COC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCC(CC)C(=O)O
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCc1nc2cccc(COC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 31 %

Procedure:
A mixture of 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]- 7-methoxymethylbenzimidazole (0.6 g) and trimethyltin azide (1.2 g) in toluene (12 ml) was heated for 3 days under reflux in toluene (12 ml). The solvent was distilled off. To the residue was added 1N-HCl (8 ml) and the mixture was stirred for a while, followed by extraction with ethyl acetate. The organic layer was washed with water and dried, then the solvent was distilled off. The residue was purified by column chromatography on silica gel to give an oil. The product was dissolved in ethyl acetate, to which was added a methanol solution of sodium salt of 2-ethyl hexanoic acid (0.25 g). The mixture was concentrated. Crystals separated out were recrystallized from toluene --ethyl acetate to afford colorless crystals (0.22 g, 31%), m.p.175-178° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](/[C:12](=[N:27]/[O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)/[CH2:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C>[Cl:1][C:2]1[C:3](/[C:12](=[N:27]\[O:28][CH2:29][CH:30]2[CH2:31][CH2:32]2)/[CH2:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:24])([F:25])[F:23])=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=1
Reactant: O=C(NC/C(=N\OCC1CC1)c1ncc(C(F)(F)F)cc1Cl)c1ccccc1C(F)(F)F
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: O=C(NC/C(=N/OCC1CC1)c1ncc(C(F)(F)F)cc1Cl)c1ccccc1C(F)(F)F
Yield: 55.3 %

Procedure:
To 85 mg of (E)-N-[2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(cyclopropylmethoxyimino)ethyl]-2-(trifluoromethyl)benzamide in 3 ml of acetonitrile, 1 mg of benzophenone was added, and the mixture was irradiated with light for 5 hours in a quartz cell (manufactured by Fine, 4 clear windows for spectroscopy) using a 100 W high-pressure mercury lamp (manufactured by USHIO INC., lamp: UM-102, power supply: UM-103B-B). After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 5:5) as the eluent to obtain 47 mg of the desired product as white crystals.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14])=[O:8]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([Cl:3])=[O:14])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(CCl)Nc1cccc(C(=O)O)c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(CCl)Nc1cccc(C(=O)Cl)c1
Yield: 80 %

Procedure:
To a warm (55°-60° C.) solution of 250 ml. of thionyl chloride and 50 ml. of chloroform and 6 drops of pyridine is added 3-(chloroacetylamino)benzoic acid (150 g., 0.702 mole) in 3 equal portions at 0.5 hr. intervals. After the addition is complete, the reaction mixture is warmed to a temperature of 55°-65° C. for 2 hrs., cooled and diluted with 500 ml. of petroleum ether (b.p. 30°-60° C.). The precipitate which forms is collected, washed with petroleum ether (b.p. 30°-60° C.) and dried under vacuum over potassium hydroxide at room temperature to afford 143 g. (80% yield) of 3-(chloroacetylamino)benzoyl chloride, m.p. 106°-108° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]O)[CH3:2].C1(C)C=CC=CC=1.S(Cl)([Cl:21])=O>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][Cl:21])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOc1cccc(CO)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOc1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-ethoxybenzyl alcohol (4.15 g) and toluene (50 ml) were added one drop of pyridine and thionyl chloride (3.0 ml), and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was diluted with ethyl acetate, washed successively with water, an aqueous saturated solution of sodium bicarbonate, water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 3-ethoxybenzyl chloride (5.34 g) as an oil.
Reaction SMILES: C([C:4]1[C:12]([O:13][CH2:14][CH:15]=[CH2:16])=[CH:11][C:10]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:9][C:5]=1[C:6]([O-])=[O:7])=CC.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.Cl>C(OCC)C.O>[CH2:18]([O:17][C:10]1[CH:9]=[C:5]([CH:4]=[C:12]([O:13][CH2:14][CH:15]=[CH2:16])[CH:11]=1)[CH2:6][OH:7])[CH:19]=[CH2:20]
Reactant: C=CCOc1cc(OCC=C)c(C=CC)c(C(=O)[O-])c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: C=CCOc1cc(CO)cc(OCC=C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.2 %

Procedure:
2-Propenyl-3,5-bis-(2-propenyloxy)-benzoate (23.1 g, 84.2 mmol) was dissolved in dry diethyl ether (250 ml) and added dropwise at 0° C. to a suspension of lithium aluminium hydride (3.45 g, 91.0 mmol) in dry diethyl ether (200 ml). The mixture was stirred at room temperature for 16 h and ethyl acetate (5 ml) was added slowly followed by water (10 ml) and diluted aqueous hydrochloric acid (2 M, 4 ml) to bring pH to 4. The phases were separated and the aqueous phase was extracted with diethyl ether (50 ml). The combined organic phases washed with water (50 ml), dried (Na2SO4), and the solvent was evaporated to give 18.4 g (99%) of the product as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([OH:8])[CH2:6][C@H:5]([CH:9]([F:11])[F:10])[C@@H:4]([OH:12])[C@@H:3]1[OH:13].[C:14](N1C=CN=C1)(N1C=CN=C1)=[S:15]>CN(C=O)C>[F:11][CH:9]([F:10])[C@@H:5]1[C@@H:4]([OH:12])[C@H:3]([OH:13])[C@H:2]2[NH:1][C:14](=[S:15])[O:8][C@H:7]2[CH2:6]1
Reactant: N[C@@H]1[C@@H](O)[C@H](O)[C@@H](C(F)F)C[C@@H]1O
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O[C@H]1[C@H](O)[C@@H](C(F)F)C[C@@H]2OC(=S)N[C@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
To a solution of (1R,2R,3S,4S,6S)-3-amino-6-(difluoromethyl)cyclohexane-1,2,4-triol (300 mg, 1.52 mmol) in DMF (3 mL) at room temperature was added thiocarbonyldiimidazole (298 mg, 1.67 mmol). The mixture was stirred at room temperature for 4 h. Solvent was evaporated and the residue was purified by silica gel column chromatography, eluted with 5%-8% MeOH in DCM to give the product (3aR,4R,5R,6S,7aS)-6-(difluoromethyl)-4,5-dihydroxyhexahydrobenzo[d]oxazole-2(3H)-thione (238 mg, 65%) as a white solid. 1H NMR (400 MHz, MeOD) δ 6.20 (t, J=57.4 Hz, 1H), 4.92-4.96 (m, 1H), 3.71 (t, J=7.1 Hz, 1H), 3.26-3.38 (m, 2H), 2.35 (dt, J=15.3 Hz, 3.0 Hz, 1H), 2.03-2.17 (m, 1H), 1.91-1.99 (m, 1H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[I:10]I.[OH-].[K+]>CN(C=O)C>[I:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][N:2]=1
Reactant: II
Reactant: c1cnc2[nH]ncc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Ic1n[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of 1H-pyrazolo[3,4-b]pyridine (500.0 mg, 4.2 mmol, 1 equiv) in DMF (10 mL) at 0° C., was added iodine (2.13 g, 8.4 mmol, 2 equiv) and potassium hydroxide (943 mg, 16.8 mmol, 4 equiv). The resultant mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction solution was slowly quenched with saturated sodium thiosulfate (Na2S2O5) solution (10 mL), and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water (3×50 mL), brined (50 mL), dried over sodium sulfate and concentrated in vacuo to give 3-Iodo-1H-pyrazolo[3,4-b]pyridine (1.02 g) as a yellow powder which was used without further purification: LCMS (ES) M+H 246.2, Rf 2.17 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C., 1 ml/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B; A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile).
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][CH:8]([NH:18][C:19](=[O:21])[CH3:20])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(=[O:5])[CH3:4].[CH2:22](Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[I-].[K+]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C.CCCCCC.O>[C:3]([O:6][CH2:7][CH:8]([NH:18][C:19](=[O:21])[CH3:20])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:15][CH:16]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)NC(CCc1ccc(O)cc1)COC(C)=O
Reactant: CCCCCCCBr
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCOc1ccc(CCC(COC(C)=O)NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 42.9 %

Procedure:
To a suspension of sodium hydride (0.076 g) in dimethylformamide (1 ml) and tetrahydrofuran (1 ml), under a nitrogen atmosphere, a solution of 2-acetamido-4-(4-hydroxyphenyl)butyl acetate (0.51 g) in dimethylformamide (2 ml) was added and the mixture was stirred at room temperature for 50 minutes. Then, to the solution, heptyl bromide (0.35 g) and catalytic amount of potassium iodide were added and the mixture was stirred at 60° C. for 4 hours and 40 minutes. Then, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with a dilute aqueous sodium hydrogencarbonate solution and a saturated brine, dried over sodium sulfate and the solvent was distilled away under reduced pressure. The residue obtained was subjected to silica gel chromatography (eluent; ethyl acetate-hexane=4:1) to give the subject compound (0.30 g).
Reaction SMILES: [I:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:12]([O:14]C)=[O:13])[C:3]=1[O:16][CH3:17].[OH-].[Na+].CO>C1COCC1.O>[I:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]=1[O:16][CH3:17]
Reactant: COC(=O)c1cc2c(c(I)c1OC)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C(=O)O)cc2c(c1I)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a stirred solution of methyl 4-iodo-3-methoxy-5,6,7,8-tetrahydro-2-naphthalenecarboxylate (3.0 g, 8.67 mmol) in THF (12 mL) and H2O (4 mL) was added 10N NaOH (9 mL). Methanol was added dropwise until the cloudy solution became clear. After stirring overnight at room temperature, the THF was removed in vacuo. The aqueous solution was acidified to pH 2 with 1N HCl and resulting white precipitate was extracted with DCM (3×25 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford a light brown solid (2.8 g, 100%). 1H NMR (CDCl3) δ 7.83 (s, 1H), 3.92 (s, 3H), 2.77 (m, 4H), 1.78 (m, 4H). MS m/z 331 (M−H).
Reaction SMILES: Cl.[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18]C4C(C(NC5C=CC(F)=CC=5F)=O)=CN=CC=4)=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1.F[C:38]1[N:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40]([OH:42])=[O:41].Cl>CN1C(=O)CCC1>[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:38]4[N:46]=[CH:45][CH:44]=[CH:43][C:39]=4[C:40]([OH:42])=[O:41])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1
Reactant: O=C(O)c1cccnc1F
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(O)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
To a homogeneous mixture of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.10 g, 0.42 mmol, Compound C of Example 1) and 2-fluoronicotinic acid (Aldrich, 0.084 g, 0.59 mmol), in anhydrous NMP (0.50 mL), was added HCl (4N in 1,4-dioxane, 0.42 mL, 1.7 mmol). The mixture was microwaved in a CEM Explorer PLS microwave system (300 W). The temperature was measured with an IR temperature sensor and maintained at 120° C. for two hours followed by 140° C. for six hours. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were concentrated in vacuo. The resultant residue was purified by preparative (RP) HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 50% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and concentrated in vacuo to afford the desired compound (0.13 g, 82%) as an off-white solid. 1H NMR (DMSO-d6) δ 13.75 (br s, 1H), 12.11 (s, 1H), 10.60 (s, 1H), 8.40 (dd, 1H, J=4.7, 1.9 Hz), 8.24 (dd, 1H, J=7.7, 1.9 Hz), 8.10-8.20 (m, 2H), 7.30-7.49 (m, 3H), 6.90 (dd, 1H, J=7.7, 4.8 Hz), 6.48 (d, 1H, J=5.8 Hz), 6.31-6.40 (m, 1H); HRMS(ESI+), 365.1050 (M+H)+ calc, 365.1038 (M+H)+ found.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[CH3:20]O>>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH3:20])=[O:13]
Reactant: CO
Reactant: COc1cc(CC(=O)O)c(Br)cc1O
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(OC)c(O)cc1Br

Procedure:
2-Bromo-4-hydroxy-5-methoxyphenylacetic acid is refluxed in methanol in the presence of sulfuric acid, to give methyl 2-(2-bromo-4-hydroxy-5-methoxyphenyl)acetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.Cl[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][O:31]C1=O.[OH-].[Na+].Cl>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH2:27][CH2:28][NH:29][CH2:33][CH2:32][OH:31])[CH2:23][CH2:24]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=C1OCCN1CCCl
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCNCC4)n3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCN(CCNCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 100 mg (0.28 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperazine and 50 mg (0.34 mmol) of 3-(2-chloroethyl)oxazolidin-2-one. The protecting group was cleaved off using a 1N sodium hydroxide solution. The product is in the form of the hydrochloride.