Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CO[C:7]1[C:8]([N+:36]([O-:38])=[O:37])=[C:9]([C:19]2[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:22]([N+:28]([O-:30])=[O:29])=[C:21]([O:31][CH3:32])[C:20]=2[N+:33]([O-:35])=[O:34])[C:10]([N+:16]([O-:18])=[O:17])=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]>>[CH3:32][O:31][C:21]1[C:20]([N+:33]([O-:35])=[O:34])=[C:19]([C:9]2[C:10]([N+:16]([O-:18])=[O:17])=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:7]([NH:4][CH2:3][CH2:1][OH:2])[C:8]=2[N+:36]([O-:38])=[O:37])[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]
Reactant: COc1c([N+](=O)[O-])cc([N+](=O)[O-])c(-c2c([N+](=O)[O-])cc([N+](=O)[O-])c(OC)c2[N+](=O)[O-])c1[N+](=O)[O-]
Reactant: NCCO
Product: COc1c([N+](=O)[O-])cc([N+](=O)[O-])c(-c2c([N+](=O)[O-])cc([N+](=O)[O-])c(NCCO)c2[N+](=O)[O-])c1[N+](=O)[O-]

Procedure:
First, one mole of ethanolamine is reacted with each mole of 3,3'-dimethoxy-2,2',4,4',6,6'-hexanitrobiphenyl under the conditions given in example 6 to give 3-methoxy-3'-(2-hydroxyethylamino)-2,2',4,4',6,6'-hexanitrobiphenyl (compound X). Compound X is then reacted with ammonia under the conditions of example 7 to produce 3-amino-3'-(2-hydroxyethylamino)-2,2',4,4',6,6'-hexanitrobiphenyl (compound XI). Compound XI is then nitrated under the conditions of example 8 to produce the product 3-amino-3'-(hydroxyethylaminonitrate)-2,2',4,4',6,6'-hexanitrobiphenyl.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C@@H:15]([CH3:23])[CH2:14]2)[C:9](=[O:12])[CH2:10][OH:11])=[CH:4][CH:3]=1.C(Cl)CCl.[C:28](O)(=[O:30])[CH3:29]>C(Cl)Cl>[C:28]([O:11][CH2:10][C:9]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C@@H:15]([CH3:23])[CH2:14]1)=[O:12])(=[O:30])[CH3:29]
Reactant: C[C@H]1C[C@@H](N(C(=O)CO)c2ccc(Cl)cc2)c2ccccc2N1
Reactant: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)OCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)Nc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.7 %

Procedure:
N-(4-Chlorophenyl)-2-hydroxy-N-[(2S,4R)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (300 mg, 0.91 mmol, 1 equ.) was dissolved in methylene chloride (3 mL). To this solution was added EDC (464 mg, 2.7 mmol, 3 equ.) and acetic acid (164 mg, 2.7 mmol, 3 equ.) and the reaction mixture was stirred at room temperature for 20 h. Reaction mixture was concentrated and the residue dissolved in ethyl acetate and washed with water, brine, and then dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (methylene chloride/methanol: 99/1 to 98/2 gradient) to afford 2-{(4-chlorophenyl)[(2S,4R)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}-2-oxoethyl acetate (240 mg, 84%).
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)(=O)C.C(O)C.[Pd]>[C:22]1([C:17]2[C:18]3[C:19]4[CH2:20][CH2:21][NH:8][CH2:9][CH2:10][C:11]=4[NH:12][C:13]=3[CH:14]=[CH:15][CH:16]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CN2CCc3[nH]c4cccc(-c5ccccc5)c4c3CC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc(-c2cccc3[nH]c4c(c23)CCNCC4)cc1
Yield: 121.7 %

Procedure:
A mixture of 3-benzyl-10-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.22 g, 0.62 mmol), glacial acetic acid (2 drops) and Pd/C (10%, 0.11 g) in ethanol (50.0 mL) was reacted in a manner similar to Example 8 to give 0.198 g (90%) of a brown foam. Crystallization from ethyl acetate gave 0.030 g of the title compound as a beige solid: mp>250° C.; 1H NMR (300 MHz, CDCl3) δ 7.97, 7.48-7.36, 7.16, 6.94, 3.12-3.08, 3.02-2.98, 2.87-2.83, 2.47-2.43; IR (drift) 3053, 3025, 2927, 2895, 2833, 1458, 1428, 1415, 1335, 1292, 1262, 790, 760, 751, 703 cm−1; MS (EI) m/z 262 (M+); HRMS (FAB) calcd for C18H18N2+H: 263.1548, found 263.1550.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10](F)=[C:11]([F:27])[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+].O>CN(C=O)C>[N:29]([C:10]1[C:9]([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[C:11]=1[F:27])=[N+:30]=[N-:31]
Reactant: COC(=O)c1cc(SCc2ccccc2)c(F)c(F)c1Nc1ccccc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(SCc2ccccc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To a solution of methyl 5-(benzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (12.64 g, 31.36 mmol) in DMF (30 mL) was added NaN3 (2.45 g, 37.63 mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h. Then water (150 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL×3) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product (white solid, 10.38 g, 78% yield). 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 7.66 (s, 1H), 7.27-7.12 (m, 3H), 7.10-6.80 (m, 6H), 3.98 (s, 2H), 3.80 (s, 3H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](N[C:23]1[NH:28][C:27](=[O:29])[C:26]([O:30][CH2:31][CH3:32])=[CH:25][N:24]=1)([O-])=O>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:23]2[NH:28][C:27](=[O:29])[C:26]([O:30][CH2:31][CH3:32])=[CH:25][N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CCOc1cnc(N[N+](=O)[O-])[nH]c1=O
Solvent: c1ccncc1
Product: CCOc1cnc(NCCCOc2cccc(CN3CCCCC3)c2)[nH]c1=O

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (1.64 g), 2-nitroamino-5-ethoxypyrimidin-4-one (1.2 g) and pyridine (15 ml) were stirred under reflux conditions for 18 hours. Pyridine was evaporated under reduced pressure and water (25 ml) and chloroform (25 ml) added. The mixture was shaken, the chloroform layer extracted; the aqueous layer was further extracted with chloroform (2×25 ml), and the combined chloroform extracts were washed with water, dried (MgS04) and evaporated under reduced pressure. The resultant residue was subjected to column chromatography on silica gel using chloroform: methanol (95:5) as eluant. The desired fractions were evaporated to give the title product as a residue. This residue was washed with diethyl ether and dissolved in isopropanol. This solution was treated with maleic acid (0.77 g) in isopropanol to give a solid maleate salt which on crystallisation from ethanol gave 2-[3-[3-(piperidinomethyl)phenoxy]propylamino ]-5-ethoxypyrimidin-4-one dimaleate (1.11 g), m.p. 68°-71° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[C@H:12]2[O:13][CH2:14][C@@H:15]([OH:16])[C@H:11]2[O:10][CH2:9]1.[N+:17]([O:20][C@H:21]([CH2:28][O:29][N+:30]([O-:32])=[O:31])[CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])([O-:19])=[O:18].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N+:17]([O:20][C@H:21]([CH2:28][O:29][N+:30]([O-:32])=[O:31])[CH2:22][CH2:23][CH2:24][C:25]([O:16][C@@H:15]1[CH2:14][O:13][C@@H:12]2[C@H:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH2:9][O:10][C@H:11]12)=[O:26])([O-:19])=[O:18]
Reactant: O=C(O)CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2OC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2OC1CCCCO1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
To a solution of (3R,3aR,6R,6aR)-6-(tetrahydro-2H-pyran-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol (2.96 g, 12.9 mmol) in DCM (40.8 mL) a solution of the crude (S)-5,6-di(nitrooxy)hexanoic acid (3.06 g, 12.85 mmol) (Step D) in DCM (9.15 mL) was added followed by EDAC (3.69 g, 19.28 mmol) and 4-dimethylaminopyridine (175 mg, 1.28 mmol). The reaction mixture was stirred at rt for 16.5 hrs. The solvent was removed under reduced pressure. The crude residue was purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 10 to 60%), affording the title product as pale yellow oil.
Reaction SMILES: [S:1](Cl)([N:4]=C=O)(=[O:3])=[O:2].CC(O)(C)C.[NH2:13][C@@H:14]([CH2:25][C:26]1[O:27][C:28]([CH2:31][C:32]2[S:33][C:34]3[CH:40]=[C:39]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:38]=[CH:37][C:35]=3[N:36]=2)=[N:29][N:30]=1)[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)Cl>[C:41]1([C:39]2[CH:38]=[CH:37][C:35]3[N:36]=[C:32]([CH2:31][C:28]4[O:27][C:26]([CH2:25][C@H:14]([NH:13][S:1](=[O:3])(=[O:2])[NH2:4])[C:15]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[O:16])=[N:30][N:29]=4)[S:33][C:34]=3[CH:40]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: N[C@@H](Cc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1)C(=O)OCc1ccccc1
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: NS(=O)(=O)N[C@@H](Cc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1)C(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 85.4 %

Procedure:
To a solution of Compound 45a (460 mg, 0.81 mmol) in DCM (5 mL) was added TFA (5 mL) and the reaction mixture stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was co-evaporated with toluene (3×) and DCM, then dried under high vacuum to give (S)-benzyl 2-amino-3-(5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)propanoate (500 mg, 100% yield) as a yellow solid. LCMS=1.90 min using analytical method (B), 471.0 (M+H). In a separate flask, to a solution of sulfurisocyanatidic chloride (170 mg, 1.2 mmol) in DCM (2 mL) was added 2-methylpropan-2-ol (90 mg, 1.2 mmol) in DCM (2 mL) and the reaction mixture stirred for 20 min. The resulting solution was then added to a mixture of (S)-benzyl 2-amino-3-(5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)propanoate (500 mg, 0.81 mmol) and TEA (0.56 mL, 4.0 mmol) in DCM (5 mL) and the reaction mixture stirred for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc, washed with 1 N HCl solution and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in DCM (6 mL) and treated with TFA (3 mL) then stirred for 1 h. The mixture was concentrated under reduced pressure, co-evaporated under reduced pressure with toluene and DCM, and the residue purified by silica gel chromatography eluting with 0-10% MeOH/DCM to give Compound 45b (380 mg, 86% yield) as a yellow solid. LCMS=2.00 min using analytical method (B), 550.2 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.15-8.08 (m, 1H), 8.06-8.00 (m, 1H), 7.76-7.70 (m, 1H), 7.66-7.58 (m, 2H), 7.50-7.44 (m, 2H), 7.42-7.27 (m, 7H), 5.65-5.58 (m, 1H), 5.23-5.19 (m, 1H), 5.16-5.09 (m, 2H), 4.73-4.61 (m, 3H), 3.53-3.30 (m, 2H).
Reaction SMILES: [F:1][CH:2]([F:35])[C:3]1[N:7]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[N:15]=[CH:16][C:11]3=[C:10]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl.O>[F:35][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:22][CH2:21][N:20]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:19][CH2:18]4)[N:15]=[CH:16][C:11]3=[C:10]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2cnn(C3CCNCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2cnn(C3CCN(S(C)(=O)=O)CC3)c2n1
Temperature: 0 °C
Yield: 0.1 %

Procedure:
A mixture of 75 mg (155 mmol) of 6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1-(4-piperidinyl)-1H-pyrazolo[3,4-d]pyrimidine and 65 mg (465 mmol) of powdered K2CO3 in CH2Cl2 was cooled to 0° C., and 27 mg (233 mmol) of methanesulfonyl chloride was added. The mixture was allowed to warm to room temperature, and after 2 hrs it was diluted with water and washed with aq. NH3. The organic layer was dried (Na2SO4) and concentrated under vacuum to give 80 mg (92% yield) of 6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-1-[1-(methylsulfonyl)-4-piperidinyl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidine: mp (MeOH) 273-276° C.; 1H NMR (CDCl3) δ 8.01 (s, 1H), 7.82 (dd, J=8.4, 0.6 Hz, 1H), 7.46 (t, J=53.6 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 4.85 (tt, J=11.1, 4.1 Hz, 1H), 4.07 (s, 3H), 4.06 (m, 4H), 4.02 (m, 1H), 3.99 (m, 1H), 3.92 (m, 4H), 3.02 (dt, J=12.2, 2.5 Hz, 2H), 2.88 (s, 3H), 2.44 (dq, J=11.6, 4.2 Hz, 2H), 2.17 (m, 2H); Anal. Calcd. for C24H28F2N8O4S: C, 51.2; H, 5.0; N, 19.9. Found: C, 50.85; H, 5.0; N, 19.7%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](Cl)(=[O:12])=[O:11])=[O:4].Cl.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:12])(=[O:11])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:23][CH2:24][C:25](=[O:28])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1)=[O:4]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 2-(methoxycarbonyl)thiophene-3-sulphonyl chloride and 1-(4-amino-phenyl)-piperidin-4-one hydrochloride (which was obtained in Example 224) according to the procedure B of Example 225 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 2.37 (t, J=6.0 Hz, 4 H), 3.50 (t, J=6.0 Hz, 4 H), 3.89 (s, 3 H), 6.90 (d, J=9.1 Hz, 2 H), 6.96 (d, J=9.1 Hz, 2 H), 7.33 (d, J=6.9 Hz, 1 H), 7.90 (d, J=6.9 Hz, 1 H), 9.50 (s, 1 H); MS (ES) m/z: 395.0 (MH+); HRMS Calcd. for C17H19N2O5S2(MH+): 395.0736. Found: 395.0721.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([I:15])=[N:6]1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>CN(C)C=O>[I:15][C:7]1[C:8]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH2:14])[N:5]([CH2:4][CH2:3][CH2:2][N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[N:6]=1
Reactant: Nc1ncnc2c1c(I)nn2CCCBr
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(CCCn2nc(I)c3c(N)ncnc32)CC1
Temperature: 70 °C
Reaction time: 66.25 h
Yield: 45.3 %

Procedure:
A suspension of 1-(3-bromopropyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.500 g, 1.31 mmol) in dimethylformamide (10 mL) was treated with 1-methylpiperazine (0.157 g, 1.572 mmol) and triethylamine (0.133 g, 1.31 mmol). The reaction mixture was stirred at 70° C. for 66.25 h. Solvent was removed under reduced pressure. Dichloromethane (15 mL) and 1 N hydrochloric acid (20 mL) were added. The layers were partitioned and the aqueous layer was washed with dichloromethane (100 mL). The aqueous layer was neutralized to pH 13 and then extracted with dichloromethane (250 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a step-wise gradient; 20% methanol in dichloromethane to 50% methanol in dichloromethane over 55 minutes on a 35 g ISCO column. The column afforded 0.238 g (45%) of pure 3-iodo-1-[3-(4-methylpiperazino)propyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 8.191 (s, 1H), 4.308-4.273 (t, 2H), 2.262-2.228 (m, 10H), 1.944-1.877(m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 0.75 min (100%), MH+ 402.1.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH:12]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][CH2:18][C:13]21[O:17][CH2:16][CH2:15][O:14]2.C(N(CC)CC)C>ClCCl>[C:1]([NH:10][CH2:11][CH:12]1[C:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:20][CH2:19][CH2:18][C:13]21[O:14][CH2:15][CH2:16][O:17]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1C2(CCCC1(c1ccccc1)c1ccccc1)OCCO2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1C2(CCCC1(c1ccccc1)c1ccccc1)OCCO2)c1ccccc1
Reaction time: 4 h
Yield: 74.7 %

Procedure:
A solution of benzoyl chloride (7.7 g) in anhydrous dichloromethane (10 cc) is added dropwise, in the course of 40 minutes and while the temperature of the reaction mixture is maintained at +5° C., to a solution, cooled to +5° C., of (RS)-6-aminomethyl-7,7-diphenyl-1,4-dioxaspiro[4.5]decane (16.2 g) and triethylamine (5.6 g) in anhydrous dichloromethane (150 cc). The reaction mixture is then stirred for 4 hours at +25° C., thereafter washed with distilled water (125 cc) cooled to +5° C., dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized in a mixture (50 cc) of acetonitrile and isopropyl ether (50:50 by volume). The crystals are drained and dried. (RS)-6-Benzamidomethyl-7,7-diphenyl-1,4-dioxaspiro[4.5]decane (16 g) is obtained in the form of white crystals. M.p. 162° C.
Reaction SMILES: C1COCC1.C[O:7][C:8](=[O:31])[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[C:23]2[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH2:24]2)[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.[OH-].[Na+]>C(O)C>[CH3:29][C:26]1([CH3:30])[CH2:25][CH2:24][C:23](=[C:15]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:12]2[CH:13]=[CH:14][C:9]([C:8]([OH:31])=[O:7])=[CH:10][CH:11]=2)[CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc(C(=C2CCC(C)(C)CC2)c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CCC(=C(c2ccc(O)cc2)c2ccc(C(=O)O)cc2)CC1
Temperature: 65 °C
Yield: 85.9 %

Procedure:
To a solution of THF (2 mL) and ethanol (2 mL) containing 4-[(4,4-dimethyl-cyclohexylidene)-(4-hydroxy-phenyl)-methyl]-benzoic acid methyl ester (171) (0.16 g, 0.457 mmol) was added 1 N NaOH (4 mL). The reaction mixture was heated at 65° C. for 4 h. The reaction mixture was partially concentrated to remove the EtOH and THF. To the basic aqueous mixture was added 1 N HCl to pH ˜1 (according to litmus paper). The acidic aqueous solution was extracted with dichloromethane and the organic extract was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was triturated with dichloromethane, filtered, and dried to give 0.132 g (85%) of the title compound 172 as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 0.93 (s, 6H), 1.32 (s, 4H), 2.12-2.19 (m, 4H), 6.66 (d, J=8.3 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.1 Hz, 2H), 7.83 (d, J=8 Hz, 2H), 9.33 (s, 1H), 12.74 (s, 1H). HRMS (ESI) Calcd for C22H23O3: 335.1647 (M−H)−. Found: 335.1640.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=3)[NH:12][C:11]=2[C:20]([OH:22])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][N:24]1[C:28]([CH2:29][CH2:30][NH2:31])=[CH:27][N:26]=[CH:25]1>>[CH3:23][N:24]1[C:28]([CH2:29][CH2:30][NH:31][C:20]([C:11]2[NH:12][C:13]3[C:18]([C:10]=2[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[O:22])=[CH:27][N:26]=[CH:25]1
Reactant: O=C(O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Reactant: Cn1cncc1CCN
Product: Cn1cncc1CCNC(=O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1

Procedure:
Reaction of 3-phenylsulfonyl-5-chloroindole-2-carboxylic acid with 3-methylhistamine under the conditions of Example 37 gave the title compound, mp 257°-258.5° C.
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[CH:7][C:6]=1[Cl:14])=O.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[C:24]1([C:27](=[S:29])[NH2:28])[CH2:26][CH2:25]1>CN(C)C=O.C(OCC)(=O)C>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[C:24]1([C:27]2[S:29][C:2]([CH3:15])=[C:3]([C:5]3[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[CH:7][C:6]=3[Cl:14])[N:28]=2)[CH2:26][CH2:25]1
Reactant: NC(=S)C1(c2c(F)cccc2Cl)CC1
Reactant: COc1cc(Cl)c(C(=O)C(C)Br)cc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Cl)c(-c2nc(C3(c4c(F)cccc4Cl)CC3)sc2C)cc1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Bromo-1-(2-chloro-4-methoxy-5-methly-phenyl)-propan-1-one (254 mg, 0.87 mmol) and 1-(2-Chloro-6-fluoro-phenyl) cyclopropane carbothioic acid amide (200 mg, 0.87) mmol) were dissolved in dimethlyformamide (DMF) (2.9 mL). The reaction was heated with stirring to 80° C. overnight. The mixture was then cooled, diluted with ethyl acetate and washed three times with water and once with brine. The organic layer was separated, dried with sodium sulfate and concentrated in vacuo. The crude product was then chromatographed on silica using an ethyl acetate/hexane gradient resulting in a pale green-yellow solid. Yield: 110 mg (18%). [MH]+422.0. 1H NMR (300 MHz, CDCl3) •1.54 (m, cyclopropyl, 2H), 2.11 (m, cyclopropyl, 2H), 2.27 (s, CH3, 3H), 2.28 (s, CH3, 3H), 3.93 (s, —OCH3, 3H), 6.97 (s, Ar, 1H), 7.15 (m, Ar, 1H), 7.35 (s, Ar, 1H), 7.37 (m, Ar, 2H).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][C:12]=2[O:19][CH3:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]1([S:7]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=2[O:19][CH3:20])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(CO)ccc1NS(=O)(=O)c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C=O)ccc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To a solution of 4-phenylsulfonylamino-3-methoxybenzyl alcohol (522 mg; prepared in Reference Example 43.) in methylene chloride (15 ml), manganese dioxide (3 g) was added in a stream of argon. The solution was stirred for 1 hour at room temperature. After the termination of reaction, the reaction mixture was filtered. The filtrate was concentrated to give the title compound (404 mg) having the following physical data.
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.CS(O[C@H:29]1[CH2:32][C@@H:31]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:30]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:35]([O:34][CH2:33][C@H:31]1[CH2:32][C@H:29]([N:16]2[C:17]3=[N:18][CH:19]=[N:20][C:21]([NH2:23])=[C:22]3[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)=[N:15]2)[CH2:30]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: CS(=O)(=O)O[C@H]1C[C@@H](COCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@H]1C[C@H](COCc2ccccc2)C1

Procedure:
A solution of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.452 g, 0.00149 mol) in N,N-dimethylformamide (10 mL) was reacted with cis 3-[(benzyloxy)methyl]cyclobutyl methanesulfonate (0.483 g, 0.00179 mol) and cesium carbonate (0.582 g, 0.00179 mol) at 70° C. for two days. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (2×20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica using dichloromethane/methanol (98:2). The solvent was removed in vacuo to give trans 1-{3-[(benzyloxy)methyl]cyclobutyl}-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.325 g, 0.000681 mol) as a tan solid.