Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[S:15]([N:18]=C=O)(=[O:17])=[O:16].[Cl-].[Cl-].[Cl-].[Al+3]>[N+](CC)([O-])=O>[NH2:11][C:10]1[CH:9]=[CH:8][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:13][C:12]=1[S:15]([NH2:18])(=[O:17])=[O:16]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1ccc(C2CCCCC2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Product: Nc1ccc(C2CCCCC2)cc1S(N)(=O)=O
Temperature: 0 °C
Yield: 31 %

Procedure:
A solution of 4-cyclohexylaniline (0.877 g, 5.0 mmol, 1.0 eq) in nitroethane (5 mL) was cooled to −40° C., treated dropwise with chlorosulfonyl isocyanate (0.87 g, (0.523 mL, 6.15 mmol, 1.23 eq), warmed to 0° C., treated with aluminum trichloride (0.85 g, 6.35 mmol, 1.27 eq), heated in a 110° C. oil bath for 30 minutes, cooled to ambient temperature, and poured into 200 mL of ice water. The mixture was filtered and the filter cake was rinsed with cold water, dissolved in 50% H2SO4 (25 mL), heated to reflux for 4 hours, cooled to ambient temperature, poured into 200 mL of ice water, and carefully neutralized to pH 7 with 40% NaOH. The reaction mixture was extracted with ethyl acetate (3×100 mL) and the combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to give 0.40 g of the desired product (31% yield). MS (ESI+) m/z 255.0 (M+H)+, 272.1 (M+H2O)+, 277.0 (M+Na)+; 1H NMR (300 MHz, DMSO-d6) δ 1.32 (m 4H), 1.71 (m, 6H), 2.36 (m, 1H), 5.64 (s, 2H), 6.72 (d, J=8.09 Hz, 1H), 7.11 (dd, J=8.46, 2.21 Hz, 1H), 7.16 (s, 2H), 7.38 (d, J=2.21 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[CH:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29]>O1CCOCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:8]2[C:6]3[N:7]=[C:2]([N:33]4[CH2:34][CH2:35][N:30]([CH:28]=[O:29])[CH2:31][CH2:32]4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:15][CH:16]=1
Reactant: O=CN1CCNCC1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccc(F)cc4)ncnc23)CC1
Solvent: C1COCCO1
Product: O=CN1CCN(c2nc(N3CCS(=O)CC3)c3ncnc(SCc4ccc(F)cc4)c3n2)CC1

Procedure:
This compound was prepared analogous to Example 93 from 2-chloro-8-(4-fluorobenzyl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 192°-194° C.) and N-formyl-piperazine in dioxane.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C/C=C/c1ccc2c(c1)OCCO2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.9 %

Procedure:
To a solution of ethyl (2E,4E)-5-(2,3-dihydro-1,4-benzodioxin-6-yl)penta-2,4-dienoate (5.00 g) in ethanol (100 mL) was added 10% palladium-activated carbon (1.0 g), followed by stirring at room temperature under hydrogen atmosphere (4 atm.) for 5 hours. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=85/15) to obtain ethyl 5-(2,3-dihydro-1,4-benzodioxin-6-yl)pentanoate (2.94 g).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH:13]=[O:14].[Cl-].[NH4+]>CCOCC.O1CCCC1.O>[C:1]1([CH:13]2[O:14][CH:9]([OH:15])[CH2:10][CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCCC=O
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: OC1CCCC(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
136.1 ml of a 3 M solution of phenyl magnesium bromide in ether was added, drop by drop, to a solution of 37.1 g of 4A in 375 ml of tetrahydrofuran at -60°±10° C. The mixture was allowed to warm (over a two-hour period) to room temperature. Then 75 ml of a saturated solution of ammonium chloride in water was added, the temperature of the mixture being held at 0°-5° C. The mixture was stirred for 15 minutes, then the supernatant oil was decanted, dried (MgSO4), and stripped of solvent. The residue was passed through a short column of silica gel using ethyl acetate as eluent. The eluate was stripped of solvent, and the residue was chromatographed (high pressure liquid) over silica gel, using as eluents one liter each, in sequence, of six mixtures of ethyl acetate and hexane, varying in content from 30% to 75% ethyl acetate, followed by two liters of ethyl acetate alone. Fractions 7 through 12 (in order of increasing polarity) were combined and stripped of solvent. The resulting solid was recrystallized from hexane to give tetrahydro-6-phenyl-2H-pyran-2-ol (as a mixture of diastereomers) (4B), as a solid, m.p.: 64.5°-71° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[CH3:17][NH2:18]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:18][CH3:17])[N:3]=1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Reactant: CN
Solvent: CCO
Product: CNc1nc(N)nc(-c2ccco2)c1C#N
Yield: 69.4 %

Procedure:
A stirred solution of 200 mg (0.87 mmol) 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and 5.0 ml (129 mmol) methylamine in 15 ml ethanol in a pressure tube was heated at 100° C. for 16 h. The reaction mixture was then concentrated in vacuo and the resulting crystals washed with ether and ether/ethanol to afford 130 mg (75%) 2-amino-4-furan-2-yl-6-methylamino-pyrimidine-5-carbonitrile as a white crystalline solid. EI-MS m/e (%): 215 (M+, 100), 214 ([M—H]+, 76), 186 (40).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:27])[NH:20][C:21]([CH3:26])=[CH:22][C:23]=2[CH2:24][CH3:25])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[Na].[CH3:29][S:30]([OH:32])=[O:31]>>[CH2:24]([C:23]1[CH:22]=[C:21]([CH3:26])[NH:20][C:19](=[O:27])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:3]=1)=[O:15])[CH3:25]
Reactant: CCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Reactant: CS(=O)O
Agent: [Na]
Product: CCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(S(C)(=O)=O)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared from 6-bromo-N-[(4-ethyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (70 mg, 0.162 mmol) and the sodium salt of methanesulfinic acid (33.5 mg, 0.325 mmol), in the same manner as described for example 91. The product was collected as a white solid (21 mg) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.17 (m, 3H), 1.47-1.56 (m, 6H), 2.15 (s, 3H), 2.58 (q, J=7.58 Hz, 2H), 3.03 (s, 3H), 4.33-4.47 (m, 2H), 5.17-5.30 (m, 1H), 5.94 (s, 1H), 8.01 (d, J=1.26 Hz, 1H), 8.45 (m, 1H), 8.53 (s, 1H), 8.78 (t, J=4.93 Hz, 1H); LCMS: (M+H)+=431.1
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[C:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[CH:5][CH:4]=1.C(O)(=O)C.[H][H]>[Pd].O>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]2[CH:16]3[CH2:15][CH2:14][N:13]([CH2:18][CH2:17]3)[CH2:12]2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: Clc1ccc(CC=C2CN3CCC2CC3)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(CCC2CN3CCC2CC3)cc1

Procedure:
Combine 2.0 g (7 mmole) of 3-[2-(4-chlorophenyl)ethylidene]-1-azabicyclo[2.2.2]octane hydrochloride, 40 ml of acetic acid, 0.2 g of 10% Pd/C catalyst and 5 ml of water. Place the mixture in a Parr apparatus and hydrogenate the mixture at ca. 43 p.s.i. Follow the reaction by the uptake of hydrogen. When the theoretical amount of hydrogen has been absorbed stop the reaction. Remove the catalyst by filtration and wash the catalyst with 40 ml of acetic acid. Remove the solvent from the filtrate in vacuo. Recrystallize the residue from 2-propanol to afford the title compound.
Reaction SMILES: [Br:1]Br.[C:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:15])[CH3:14])(=[O:5])[CH3:4]>C(Cl)(Cl)Cl>[C:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:15])[CH2:14][Br:1])(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1ccccc1C(C)=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccccc1C(=O)CBr

Procedure:
45.0 g (0.282 mol) of dry bromine were added dropwise to a boiling solution of 50.0 g (0.282 mol) of 1-[2-(acetylamino)phenyl]ethanone in 400 ml of chloroform at room temperature. The solvent was distilled off, the residue was distributed between dichloromethane and saturated ice-cold sodium hydrogen carbonate solution. The organic phase was dried over sodium sulphate, evaporated down in vacuo, the residue was triturated with diethylether and suction filtered. After drying in vacuo 35.4 g (49% of theory) of colourless crystals were obtained, Rf=0.48 (eluant: petroleum ether/ethyl acetate 2/1 v/v).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:29])=[C:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=O)C.C[Al](C)C>C1(C)C=CC=CC=1>[C:25]([O:24][C:22]([C:8]1[NH:9][C:10]2[CH2:11][CH2:12][CH2:13][N:14]([CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:4](=[O:3])[C:6]=2[C:7]=1[CH3:29])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)c1c(CCCNCCN2CCCC2)[nH]c(C(=O)OC(C)(C)C)c1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)OC(C)(C)C)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 64.9 %

Procedure:
3-Methyl-5-[3-(2-pyrrolidin-1-yl-ethylamino)-propyl]-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 28a (6.754 g, 16.6 mmol) was dissolved in 150 ml of toluene under stirring, and added slowly with a solution of trimethyl aluminum in toluene (16.6 ml, 2 mol/L, 33.2 mmol) to the solution under an argon atmosphere. The reaction mixture was stirred for 20 minutes at room temperature until no white smoke was released, and refluxed for another 3.5 hours in an oil bath. After thin lay chromatography showed the disappearance of starting materials, the oil bath was removed. The reaction mixture was quenched with little ethanol (95%), added with ethyl acetate (100 ml), filtered through a pad of Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carboxylic acid tert-butyl ester 28b (3.894 g, yield 65%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH:27]([C:31](O)=[O:32])[CH2:26]3)[N:22]=1)=[CH:5]2.[CH3:34][NH:35][CH3:36].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:34][N:35]([CH3:36])[C:31]([CH:27]1[CH2:28][CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C@@H:21]2[CH2:20][S:19][C:18]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=4[NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:22]2)[CH2:26]1)=[O:32]
Reactant: O=C(O)C1CCCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)C1
Reactant: CNC
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1CCCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
The compound (84 mg, 0.18 mmol) prepared in Example 112 was dissolved in N,N-dimethylformamide (4 ml). Dimethylamine (0.13 ml, 2M in THF, 0.27 mmol), EDC (58 mg, 0.30 mmol) and HOBT (48 mg, 0.35 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (18 mg, Yield 20%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[CH:28]=1.C(N(CC)CC)C>CN1C(=O)CCC1.CN(C1C=CN=CC=1)C>[NH2:33][C:29]1[CH:28]=[C:27]([O:8][C:7]2[CH:6]=[CH:5][C:4]([NH:9][C:10]3[N:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:11]=3[C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:13])=[CH:3][C:2]=2[F:1])[CH:32]=[CH:31][N:30]=1
Reactant: Cc1cnc(Nc2ccc(O)c(F)c2)c(C(=O)Nc2ccccc2)c1
Reactant: Nc1cc(Cl)ccn1
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1cnc(Nc2ccc(Oc3ccnc(N)c3)c(F)c2)c(C(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
365 mg of a mixture of 2-(3-fluoro-4-hydroxyphenylamino)-5-methyl-N-phenylnicotinamide and the des-methyl analog and 4-chloropyridin-2-amine (264 mg, 2054 μmol) were dissolved in NMP (5.0 ml) and triethylamine (0.75 ml, 5381 μmol) was added. The flask was fitted with a reflux condenser, placed in a preheated oil bath (185° C.-190° C.), and stirred under argon. After about 22 hours, more 4-chloropyridin-2-amine (250 mg, 1.95 mmol), DMAP (171 mg, 1.40 mmol), triethylamine (0.30 ml, 4.1 mmol), and NMP (1 ml) were added, and stirring was continued at 190 C for another day. The reaction was then cooled to room temperature and quenched with water (20 ml). The water was decanted, and the residual solid was collected with DCM and MeOH, concentrated, and purified on silica gel (50:1→25:1 DCM/MeOH→15:1 DCM/2 N ammonia in MeOH) to afford the desired 2-(4-(2-aminopyridine-4-yloxy)-3-fluorophenylamino)-5-methyl-N-phenylnicotinamide along with the des-methyl analog. This mixture was taken to the last step.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[NH:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][NH:17][CH2:16][C:15]1=[O:25]>C(O)CCC>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=[C:2]([N:17]2[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:14][C:15](=[O:25])[CH2:16]2)[CH:11]=1
Reactant: O=C1CNCc2ccccc2N1
Reactant: Cc1ccc2nc(Cl)cc(Cl)c2c1
Solvent: CCCCO
Product: Cc1ccc2nc(N3CC(=O)Nc4ccccc4C3)cc(Cl)c2c1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
The mixture of 2,4-dichloro-6-methyl-quinoline (422 mg, 2 mmol), 1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one (298 mg, 2 mmol) and n-butyl alcohol (15 mL) was heated with stirring in a 20 mL microwave process vial for 3 hours at 160° C. under microwave irradiation. After cooling, the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (methanol/dichloromethane, 1:20) to give the product. MS obsd. (ESI+) [(M+H)+] 338.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])C.C(O)=O>C1COCC1.C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH:4]1[C:5]([NH:6][CH:9]=[O:11])=[CH:7][CH:8]=[C:2]([I:1])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(I)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=CNc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of 4-iodoaniline (30.0 g, 137 mmol) in 100 mL THF and 100 mL toluene, a solution of acetic anhydride (16.0 g, 157 mmol) and formic acid (10.8 g, 235 mmol) was slowly added from an addition funnel under argon atmosphere. The reaction mixture temperature was maintained below 15° C. during the addition. After the addition was finished, the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with water (300 mL) and ethyl acetate (200 mL). The organic layer was separated, washed with water (2×200 mL), and 200 mL saturated aqueous sodium bicarbonate solution. After drying over sodium sulfate, the mixture was concentrated under reduced pressure to afford 4-iodoformanilide as an off-white solid (33.5 g, >98%). 1H NMR (DMSO-d6) δ 10.27 (s, 1H), 8.26 (d, J=2 Hz, 1H), 7.64 (d, J=12 Hz, 2H), 7.40 (d, J=11.7 Hz, 2H) and 30% tautomer; ESI-MS m/z 248.0 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:7](C(O)=O)=[CH:6][N:5]=[C:4]2[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:12]=[CH:13][C:3]=12.O.C(OCC)(=O)C.C1COCC1.O>CN1CCN(C)C1=O.C(=O)([O-])[O-].[Cu+2]>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[C:4]3[N:5]=[CH:6][CH:7]=[C:2]([OH:1])[C:3]=3[CH:13]=[N:12]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(Cn2ncc3c(O)c(C(=O)O)cnc32)cc1
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Solvent: CN1CCN(C)C1=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2ncc3c(O)ccnc32)cc1
Temperature: 180 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
4-Hydroxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (2.54 g) was dissolved in dimethylimidazolidinone (24 mL), and basic copper carbonate (204 mg, 0.1 equivalents) was added thereto. The resulting mixture was stirred at 180° C. for 3 hours and then allowed to cool. After dilution with water (about 50 mL), ethyl acetate/THF/water (400/100/500 mL) were added thereto. Insoluble substance was removed by filtration, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (about 200 mL). The combined organic layer was washed with saturated brine and dried. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica-gel column chromatography (dichloromethane/methanol=100/0 to 5/1) to give 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (759 mg, 35%) as a yellow amorphous material.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[O:12]=[C:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CS(C)=O>[CH:7]1[C:8]2[C:3](=[C:2]([N:18]3[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:14][C:13]3=[O:12])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Brc1cccc2cnccc12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3cnccc23)C(=O)C1
Temperature: 130 °C
Reaction time: 24 h
Yield: 33.3 %

Procedure:
To 5-bromoisoquinoline (0.3 g, 1.442 mmol) and tert-butyl 3-oxopiperazine-1-carboxylate (0.289 g, 1.442 mmol) was added DMSO (4 mL), 1,10-phenanthroline (0.026 g, 0.144 mmol) and K2CO3 (0.498 g, 3.60 mmol). The mixture was degassed for 10 min and then was added CuI (0.055 g, 0.288 mmol). The reaction was heated in a sealed tube in oil bath at 130° C. After 24 h, the reaction was incomplete. After cooling and degassing with argon, more CuI was added and heating was repeated. After 24 h, the reaction was quenched with dilute NH4OH (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (15 mL) and dried (MgSO4). The crude product was purified by normal phase chromatography followed by HPLC. After partitioning with saturated NaHCO3 (15 mL) and EtOAc (50 mL), organic layer was washed with brine and dried (MgSO4) to afford 0.157 g (54%) of Intermediate 21A as a white solid. MS (ESI) m/z: 328 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][N:10]3[CH2:19][CH2:20][CH2:21][C:9]=23)[CH:5]=[CH:4][N:3]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[C:13]1([C:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:25][CH:22]([CH3:24])[CH3:23])[CH:7]=3)=[C:9]3[CH2:21][CH2:20][CH2:19][N:10]3[N:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)N
Reactant: Fc1cc(-c2c(-c3ccccc3)nn3c2CCC3)ccn1
Product: CC(C)Nc1cc(-c2c(-c3ccccc3)nn3c2CCC3)ccn1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
In an autoclave, a mixture of 1.10 g (0.39 mmol) of 3-(2-fluoropyridin-4-yl)-2-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole and 1.5 ml of isopropylamine is heated at 140° C. After 16 h, the reaction mixture is concentrated under reduced pressure. After purification by column chromatography on silica gel (cyclohexane/ethyl acetate), 50 mg (35%) of the desired product are obtained; log P(HCOOH): 1.21; 1H-NMR (DMSO-d6): 7.81 (d, 1H), 7.36 (m, 5H), 6.28 (s, 1H), 6.21 (m, 2H), 4.15 (dd, 2H), 3.84 (m, 1H), 2.98 (dd, 2H), 2.59 (m, 2H), 1.08 (d, 6H).
Reaction SMILES: CN(C)/C=C/C(C1SC(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)=NC=1C)=O.C[N:32](C)/[C:33](/[CH3:60])=[CH:34]/[C:35]([C:37]1[S:41][C:40]([N:42]2[CH2:46][CH2:45][N:44]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)[C:43]2=[O:58])=[N:39][C:38]=1[CH3:59])=[O:36].Cl.NO>>[CH3:59][C:38]1[N:39]=[C:40]([N:42]2[CH2:46][CH2:45][N:44]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)[C:43]2=[O:58])[S:41][C:37]=1[C:35]1[O:36][N:32]=[C:33]([CH3:60])[CH:34]=1
Reactant: C/C(=C\C(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C)N(C)C
Agent: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)/C=C/N(C)C
Agent: Cl
Agent: NO
Product: Cc1cc(-c2sc(N3CCN(Cc4ccc(C(F)(F)F)cc4)C3=O)nc2C)on1
Yield: 53 %

Procedure:
Following the procedure as described in Example 38, making variations as required to replace (E)-1-(5-(3-(dimethylamino)acryloyl)-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)imidazolidin-2-one with (E)-1-(5-(3-(dimethylamino)but-2-enoyl)-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)imidazolidin-2-one to react with hydroxylamine hydrochloride, the title compound was obtained as a colorless solid in 53% yield: mp 201-203° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 6.07 (s, 1H), 4.54 (s, 2H), 4.12-4.06 (m, 2H), 3.50-3.44 (m, 2H), 2.51 (s, 3H), 2.24 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.4, 160.8, 158.2, 155.5, 147.8, 139.8, 130.5, 128.5, 125.9, 122.1, 112.0, 101.0, 47.6, 42.0, 41.9, 17.0, 11.4; MS (ES+) m/z 423.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]([C:13]([F:37])([F:36])[C@@:14](O[Si](C(C)(C)C)(C)C)([C@@H:16]([CH:18](O[Si](C(C)(C)C)(C)C)[OH:19])[OH:17])[OH:15])=[O:12].Br>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]([C:13]([F:37])([F:36])[C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])=[O:12]
Reactant: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)n1cnc2c(N)ncnc21
Agent: Br
Solvent: ClCCl
Product: Nc1ncnc2c1ncn2C(=O)C(F)(F)[C@H](O)[C@H](O)CO
Temperature: 0 °C
Reaction time: 4 h
Yield: 187 %

Procedure:
A solution of 100 mg (0.194 mmol) of 1-(6-amino-9H-purin-9-yl)-3,5-bis(t-butyldimethylsiloxy)-2-desoxy-2,2-difluororibose dissolved in 25 ml of methylene chloride cooled to about 0° C. with an external ice bath was saturated with anhydrous hydrogen bromide gas. The mixture was stirred at about 0° C. for about 4 hours, and nitrogen was bubbled through the reaction mixture. The mixture was filtered and the collected solid was washed with methanol to provide 110 mg of solid. The solid was purified by HPLC to provide 12.1 mg of β-1-(6-amino-9H-purin-9-yl)-2-desoxy-2,2-difluororibose and 6.3 mg of α-1-(6-amino-9H-purin-9-yl)-2-desoxy-2,2-difluororibose.