Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:11]([F:14])([F:13])[F:12])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN[C@@H]1CCCC[C@H]1NC>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:11]([F:13])([F:14])[F:12])=[N:8][N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: Ic1ccccc1
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2ccccc2)nc1C(F)(F)F
Temperature: 110 °C
Yield: 82.1 %

Procedure:
A mixture of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.25 g, 6.0 mmol), copper (I) iodide (0.342 g, 1.8 mmol) and potassium carbonate (0.58 g, 4.2 mmol) in toluene (6 mL) in a round bottom flask was purged with argon. To the reaction mixture was then added iodobenzene (0.81 mL, 7.2 mmol) and racemic trans-N,N′-dimethyl-cyclohexane-1,2-diamine (0.58 mL, 3.6 mmol). The slurry was heated under Ar in an oil bath at 110° C. for 24 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through a bed of celite. After washing the celite with ethyl acetate, the filtrates were combined and concentrated to give a crude which was purified by silica gel chromatography (Isco 120 g column, 0 to 30% ethyl acetate/hexanes) to give 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.40 g, 82%) as an off-white solid. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]2[N:9]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[C:10](=[O:12])[NH:11][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].I[CH3:22]>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]2[N:9]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[C:10](=[O:12])[N:11]([CH3:22])[C:7]=2[CH:6]=1)=[O:4]
Reactant: CI
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)n2C1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)n(C)c(=O)n2C1CCC1
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To a solution of 1-cyclobutyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester (17.01 g, 69.1 mmol) in methyl sulfoxide (60 ml) was added sodium hydride (2.76 g as a 60% dispersion in oil, 69 mmol). The reaction mixture was stirred for 30 minutes prior to the dropwise addition of iodomethane (4.3 ml, 69.1 mmol). The reaction was stirred for 1 hour, was diluted with water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated in vacuo to give 17.76 g of 1-Cyclobutyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][CH:7]([CH3:9])[CH3:8])=[C:4]([N+:12]([O-])=O)[CH:3]=1.Cl.N>C(O)C.[Zn]>[NH2:12][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=1[NH:6][CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: N
Agent: [Zn]
Solvent: CCO
Product: CC(C)Nc1ccc(Cl)cc1N
Yield: 61 %

Procedure:
4-Chloro-N-isopropyl-2-nitroaniline (8 g) was dissolved in ethanol (20 ml) and thereto zinc powder (9.8 g) was added, and concentrated hydrochloric acid (20 ml) was added in portions. The mixture was neutralized with aqueous ammonia and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was distilled (bp 90° C./0.4 mmHg) to give 2-amino-4-chloro-N-isopropylaniline (4.2 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]1[O:21][C:20]2[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][C:13]=2[O:12]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(C(C)=O)C>[O:21]1[C:20]2[CH:19]=[CH:18][C:15]([CH2:16][O:10][C:8]3[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=3)=[CH:14][C:13]=2[O:12][CH2:11]1
Reactant: O=Cc1ccc(O)cc1O
Reactant: ClCc1ccc2c(c1)OCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCC(C)=O
Product: O=Cc1ccc(OCc2ccc3c(c2)OCO3)cc1O
Yield: 31.4 %

Procedure:
A mixture of 2,4-dihydroxybenzaldehyde (22.94 g), 3,4-methylenedioxybenzyl chloride (34 g), potassium carbonate (34.43 g), potassium iodide (41.33 g) and tetra-n-butylammonium bromide (6 g) in methyl ethyl ketone was heated at reflux for 3 hours. The reaction mixture was filtered and evaporated. The residue was partitioned between ethyl acetate (400 ml) and water (400 ml) and the aqueous phase extracted twice with ethyl acetate (200 ml). The combined organic phases were dried over magnesium sulphate and evaporated. The residual beige coloured solid was purified by flash chromatography on silica eluting initially with a mixture of pentane and ethyl acetate (95:5, v/v) then with a mixture of pentane and ethyl acetate (9:1, v/v) and finally with a mixture of pentane and ethyl acetate (85:15, v/v). Fractions homogenous in the required product were combined and evaporated to give the title compound (14.2 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([C:18]([OH:21])([CH3:20])[CH3:19])([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)C.[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[CH2:28].S(=O)(=O)(O)O>N1C=CC=CC=1>[C:1]([O:5][C:6]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([C:18]([O:21][C:26](=[O:30])[C:27]([CH3:29])=[CH2:28])([CH3:20])[CH3:19])([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C12CC3CC(C1)CC(C(C)(C)O)(C3)C2
Reactant: C=C(C)C(=O)Cl
Agent: O=S(=O)(O)O
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: C=C(C)C(=O)OC(C)(C)C12CC3CC(CC(C(=O)OC(C)(C)C)(C3)C1)C2
Temperature: 60 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
In a flask equipped with a stirrer, a thermometer, a dropping funnel, and a Dimroth condenser, 50 g of 3-(1-hydroxy-1-methylethyl)adamantane-1-carboxylic acid t-butyl ester, 200 mL of dichloroethane, and 80 g of pyridine were put, and 71.7 g of methacrylic acid chloride was dropped thereto at 60° C. over 2 hours. After the dropping was completed, the resultant substance was stirred at 60° C. for another 8 hours. Then, the resultant substance was neutralized with 320 g of 10% aqueous solution of sulfuric acid while the flask was ice-cooled. The reaction solution was separated into an organic layer and a water layer. The organic layer was washed twice with 500 mL of ion exchanged water, and then was concentrated. The obtained raw product was purified by silica gel column chromatography. As a result, 25 g of 3-(1-methacryloyloxy-1-methylethyl)adamantane-1-carboxylic acid t-butyl ester was obtained as a white solid. White solid 2, which was obtained, was identified with 1H-NMR, 13C-NMR and IR (see FIGS. 2, 3 and 4).
Reaction SMILES: C[Mg]Br.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]2[CH:22]3[C:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)=[N+:16]([O-:23])[CH2:15]2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[C:24](=O)([O-])[O-].[K+].[K+]>CCOCC.O1CCCC1>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]2[CH:22]3[C:17]([CH3:24])([CH2:18][CH2:19][CH2:20][CH2:21]3)[N:16]([OH:23])[CH2:15]2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C2C[N+]([O-])=C3CCCCC32)cc1OC
Agent: C[Mg]Br
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C2CN(O)C3(C)CCCCC23)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A volume of 10 ml of 3M methyl magnesium bromide in ether was added over a period of two minutes to a stirred solution of 4.12 g (0.015 mole) of 3,3a,4,5,6,7-hexahydro-3-(3,4-dimethoxyphenyl)-2H-indole 1-oxide in 25 ml of tetrahydrofuran. The warm solution was stirred for 1/2 hour at room temperature and then added cautiously to 50 ml of ice water. The mixture was stirred for 5 minutes and solid potassium carbonate was added to saturate. The mixture was extracted into 200 ml of ether and the extract was decanted, dried over K2CO3, filtered and concentrated to ca 50 ml volume. The separated crystals were filtered and washed with ether; wt. 2.5 g, mp 147°-149° C. A second crop weighing 0.6 g was obtained for a total weight of 3.1 g (71% yield). The product was recrystallized from ethyl acetate to give pure white crystals melting at 147°-149° C.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:9][N:8]=[C:7]([NH:19][CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])[N:6]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>C(Cl)Cl>[CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:18])=[O:33])[N:12]=3)=[CH:9][N:8]=[C:7]([NH:19][CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])[N:6]=2)[CH2:2][CH2:3]1
Reactant: CSc1nccc(-c2cnc(NCC(C)(C)O)nc2CC2CC2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2cnc(NCC(C)(C)O)nc2CC2CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To a solution of 1-(4′-(Cyclopropylmethyl)-2-(methylthio)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol (90 mg, 0.261 mmol) in DCM (521 μl), mCPBA (70.6 mg, 0.287 mmol) was added in portions, and the reaction mixture was stirred at rt for 1 h. The crude product was purified by a Biotage silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product as a yellow solid (38 mg, 40% yield). MS (ES+): m/z=362.2 (100) [MH+]. HPLC: tR=0.90 min over 3 min. Purity: 100% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[NH2:27][C@@H](C(O)=O)C.CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH2:27])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(C)=O)cc1OC
Reactant: C[C@@H](N)C(=O)O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: COc1ccc(CC(C)N)cc1OC

Procedure:
After ten hours in reaction, 1.5 g of a substrate 1-(3,4-dimethoxyphenyl)-2-propanone, 4.17 g of D-glucose, 4.13 g of D-alanine, and 3.3 mg of pyridoxal phosphate were added. During the reaction, the reaction liquid was sampled. From the sample, 1-(3,4-dimethoxyphenyl)-2-aminopropane was extracted by the addition of ethyl acetate after basifying the sample with 6 N aqueous solution of sodium hydroxide. The amount of 1-(3,4-dimethoxyphenyl)-2-aminopropane produced was measured by analyzing 1-(3,4-dimethoxyphenyl)-2-aminopropane under the following HPLC conditions. Further, by the law of the art, 1-(3,4-dimethoxyphenyl)-2-aminopropane thus obtained was acted on by 3,5-dinitrobenzyl chloride to form a dinitrobenzyl derivative. After that, the dinitrobenzyl derivative was analyzed under the following HPLC conditions, whereby the optical purity thereof was measured. In the result, the amount of 1-(3,4-dimethoxyphenyl)-2-aminopropane produced after 27 hours in reaction was 2.42 g. The absolute configuration of 1-(3,4-dimethoxyphenyl)-2-aminopropane was (R), and the optical purity was not less than 99.9% e.e.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)=[O:8])([O-])=O.[H][H]>[Pd].O1CCOCC1>[NH2:1][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)=[O:8]
Reactant: [H][H]
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)c2cccc(N)c2)c1

Procedure:
A solution of 14.3 g of 3,3'-dinitrobenzanilide in 150 ml. of dioxane is hydrogenated at three atmospheres of hydrogen using 1 g. of 10% palladium-on-charcoal catalyst. The catalyst is removed by filtration and the filtrate evaporated to dryness. The residue is recrystallized from ethanol. There is obtained 8.72 g. of material melting at 123°-4°.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]#[N:10])=[C:7]([OH:11])[N:6]=[C:5]([CH3:12])[CH:4]=1)[CH3:2].N>CO.[Ni]>[NH2:10][CH2:9][C:8]1[C:7]([OH:11])=[N:6][C:5]([CH3:12])=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc(C)nc(O)c1C#N
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCc1cc(C)nc(O)c1CN
Reaction time: 3 h
Yield: 87.9 %

Procedure:
To a solution of 4-ethyl-2-hydroxy-6-methylnicotinonitrile (0.5 g, 3.08 mmol) in methanol (10 mL), Raney Ni and ammonia (1 mL) were added and reaction stirred under hydrogen balloon pressure for 3 h. On completion, reaction mass was filtered through celite bed and filtrate concentrated to obtain the desired product (0.45 g, 87.9%).
Reaction SMILES: N[C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].N(OCCC(C)C)=O.C(I)[I:19]>>[I:19][C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: ICI
Reactant: Cc1ccnc(C)c1N
Agent: CC(C)CCON=O
Product: Cc1ccnc(C)c1I

Procedure:
In a manner similar to that described in Example 5 (Step 1), commercially available 3-amino-2,4-dimethylpyridine was treated with isoamyl nitrite and CH2I2 to provide 3-iodo-2,4-dimethylpyridine (16A).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[C:14]2[C:13]([C:15]3[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=3)[NH2:18])=[N:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:39][C:40](=[CH2:44])[C:41](Cl)=[O:42]>C1COCC1>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[C:14]2[C:13]([C:15]3[CH:16]=[C:17]([NH:18][C:41](=[O:42])[C:40]([CH3:44])=[CH2:39])[CH:19]=[CH:20][CH:21]=3)=[N:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(C2CCCO2)c2c(-c3cccc(N)c3)ncnc21
Reactant: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2c(C2CCCO2)cn3COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 0° C. solution of crude 3-(5-(tetrahydrofuran-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)aniline (410 mg, 1.00 mmol) in THF (10 mL), was added DIPEA (258 mg, 2.00 mmol) followed by dropwise addition of 2-methylprop-2-enoyl chloride (125 mg, 1.20 mmol). The resulting solution was stirred for 4 hours at room temperature prior to being quenched by addition of water. The resulting solution was extracted with ethyl acetate (×3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was purified by chromatography using silica gel, eluting with 0-100% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford N-(3-(5-(tetrahydrofuran-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide as a off-white solid. LRMS (ESI) calc'd for C26H35N4O3Si [M+H]+: 479, found 479.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[C:6]([OH:13])[C:5]([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[C:4]([OH:19])[C:3]=1[C:20](=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[Cl:39])[C:33](Cl)=O>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C1(C)C=CC=CC=1>[F:29][C:30]1[CH:31]=[C:32]([C:33]2[O:1][C:2]3[C:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[C:6]([OH:13])[C:5]([CH2:14][CH:15]=[C:16]([CH3:17])[CH3:18])=[C:4]([OH:19])[C:3]=3[C:20](=[O:22])[CH:21]=2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: O=C(Cl)c1ccc(Cl)c(F)c1
Reactant: CC(=O)c1c(O)c(CC=C(C)C)c(O)c(CC=C(C)C)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)=CCc1c(O)c(CC=C(C)C)c2oc(-c3ccc(Cl)c(F)c3)cc(=O)c2c1O
Temperature: 25 °C
Yield: 3.4 %

Procedure:
Under nitrogen atmosphere, 1-[2,4,6-trihydroxy-3,5-di(3-methyl-2-buten-1-yl)phenyl]ethanone (300 mg, 0.986 mmol), anhydrous potassium carbonate powder (817 mg, 5.91 mmol), TBAB (tetrabutyl ammonium bromide, 477 mg, 1.47 mmol) and 3-fluoro-4-chlorobenzoyl chloride (380 mg, 1.97 mmol) were dissolved in toluene (30 mL), and refluxed for 6 hours. After cooling, toluene was removed, and then water (20 mL) was added. The aqueous solution was extracted with ethyl acetate. The combined organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. A brown residue was obtained after removal of solvent. The residue was dissolved in a 5% potassium carbonate aqueous solution and heated to reflux for 2 hr. After cooling to ambient temperature, the mixture was acidified to pH 6 with 1N HCl solution, and extracted with dichloromethane three times. The combined organic phase was dried over anhydrous sodium sulfate, and the solvent was removed. The crude product was purified by silica gel column chromatography (eluent:ethyl acetate/petroleum ether, 1:50) to give the desired compound (15 mg, yield 3.5%). 1H NMR (400 MHz, CDCl3): δ=12.90 (s, 1H), 7.67-7.55 (m, 3H), 6.62 (s, 1H), 6.43 (s, 1H), 5.27-5.24 (m, 2H), 3.54 (d, 2H, J=6.8 Hz), 3.47 (d, 2H, J=6.8 Hz), 1.85 (s, 3H), 1.81 (s, 3H), 1.78 (s, 3H), 1.76 (s, 3H); LC-MS (ESI) m/z 473.6 [M+H]+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([C:25]3[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=3)[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)[C:22]=12
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1ccc(C=O)cc1
Temperature: 86 °C
Yield: 91.6 %

Procedure:
3-(4-Phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.0 g, 6.59 mmol) was mixed with 4-fluorobenzaldehyde (1.06 mL, 9.89 mmol), cesium carbonate (4.30 g, 13.19 mmol) in DMF (6 mL). The reaction mixture was heated at 86° C. overnight. After cooling to room temperature, the reaction mixture was poured onto ice water. The solid was collected by filtration to give 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]benzaldehyde (2.46 g, 92%). 1H NMR (CDCl3) δ 7.19 (m, 5H), 7.46 (m, 2H), 7.78 (d, J=8.64 Hz, 2H), 8.10 (d, J=8.70 Hz, 2H), 8.44 (s, 1H), 8.59 (d, J=8.70 Hz, 2H), 10.03 (s, 1H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2([C:43]3=[CH:44][C:45]4[O:49][CH2:48][O:47][C:46]=4[CH:50]=[C:42]3[O:41][CH2:40]2)[C:32]1=[O:51].CC1(C)COC2=CC3OCC4(C=3C=C12)C1C(=CC=CC=1)NC4=O>>[CH3:19][C:16]1[N:15]=[CH:14][C:13]([CH2:12][N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]3([C:43]4=[CH:44][C:45]5[O:49][CH2:48][O:47][C:46]=5[CH:50]=[C:42]4[O:41][CH2:40]3)[C:32]2=[O:51])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)OCc2ccc(C)nc2)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: Cc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)cn1

Procedure:
Following the procedure as described in EXAMPLE 10.21, and making non-critical variations using (6-methylpyridin-3-yl)methyl 4-methylbenzenesulfonate to replace 2-bromomethyl-5-(trifloromethyl)furan, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-[(6-methylpyridin-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (56%), which was treated with 2.0 M HCl in diethyl ether to give the title compound: 1H NMR (300 MHz, CD3OD) δ 8.77 (s, 1H), 8.46 (dd, 1H), 7.91 (d, 1H), 7.33 (t, 1H), 7.24-7.09 (m, 3H), 6.52 (s, 1H), 6.14 (s, 1H), 5.86 (s, 2H), 5.18 (s, 2H), 4.93-4.85 (m, 1H), 4.71 (d, 1H), 2.77 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 180.0, 157.6, 155.1, 150.6, 146.6, 143.8, 142.7, 141.2, 135.7, 133.5, 130.3, 129.5, 125.3, 125.2, 120.5, 110.3, 103.8, 103.0, 94.3, 81.5, 59.7, 41.5, 19.5; MS (ES+) m/z 387.4 (M+1).
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([I:12])[CH:7]=2)[CH2:3][CH2:2]1.[C:13](=O)([O-])[O-].[K+].[K+].CI.C(OCC)C>CC(C)=O>[CH:1]1([N:4]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([I:12])[CH:7]=2)[CH3:13])[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: Ic1cccc(CNC2CC2)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: CCOCC
Product: CN(Cc1cccc(I)c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A solution of cyclopropyl-(3-iodo-benzyl)-amine (Intermediate 88, 4.1 g, 15 mmol) in acetone (20 mL) was treated with potassium carbonate (2.07 g, 15 mmol) and methyl iodide (1.4 mL, 22.5 mmol) and the resulting reaction mixture was stirred at ambient temperature for 1 h. Diethyl ether was added, the solids were filtered off and filtrate was evaporated to a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title compound (3.3 g, 77%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([C:12]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[CH3:19][O:18][C:16](=[O:17])[CH2:15][NH:14][C:12](=[O:13])[C:11]1[CH:20]=[CH:21][C:8]([N:5]2[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][C@H:24]([OH:25])[C:26]3[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=3)[CH2:3][CH2:4]2)=[CH:9][CH:10]=1
Reactant: COC(=O)CNC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: COC(=O)CNC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from methyl {[4-(4-oxo-1-piperidineyl)benzoyl]amino}acetate (which was obtained in Example 162) and N-[5-((1R)-2-amino-1-hydroxy- ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as a white solid; mp >75° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.35 (m, 2H), 1.75-1.90 (m, 2H), 2.50-2.90 (m, 5H), 2.91 (s, 3H), 3.63 (s, 3H), 3.70-3.85 (m, 2H), 3.95 (d, J=5.7 Hz, 2H), 4.49 (dd, J=8.0, 4.3 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.96 (d, J=8.9 Hz, 2H), 7.00 (dd, J=8.2, 2.0 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.71 (d, J=8.9 Hz, 2H), 8.60 (t, J=5.8 Hz, 1H); MS (ES) m/z: 521.3 (MH+); HRMS Calcd. for C25H37N4O7S(M+): 520.2064. Found: 520.2054.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[C:12]1([O-:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+].Cl>O>[O:18]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:10]=1[C:8]([OH:7])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [O-]c1ccccc1
Reactant: Cc1ccc2c(c1)C(=O)OC2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(COc2ccccc2)c(C(=O)O)c1

Procedure:
Stir a mixture of 1.0 gm of 6-methylphthalide and 0.64 gm of sodium phenolate at a temperature of 200°-210° C. for 1 hour. Cool and dissolve the reaction mixture in water. Acidify with 5% hydrochloric acid and extract with ether. Evaporate to dryness and chromatograph the residue over silica gel eluting with chloroform/methanol (50:1). Evaporate the eluate to dryness and crystallize the residue from ethyl acetate/benzene to obtain the title product.