Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]([O:12]C)=[O:11])[C:6]=1[C:14]([F:17])([F:16])[F:15])[CH:2]([CH3:4])[CH3:3].O.[OH-].[Li+]>CO.O>[CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[C:6]=1[C:14]([F:17])([F:16])[F:15])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1noc(CC(C)C)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)Cc1onc(C(=O)O)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
A mixture of methyl 5-isobutyl-4-(trifluoromethyl)isoxazole-3-carboxylate (0.816 g, 3.25 mmol) and lithium hydroxide hydrate (0.136 g, 3.25 mmol) in methanol (18 mL) and water (9.00 mL) was stirred at room temperature overnight. HPLC and LCMS analysis indicated that the hydrolysis was complete. The reaction mixture was concentrated under reduced pressure, and the residue dissolved in 1N aqueous hydrochloric acid and extracted with ether. The organic layer was collected and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 5-isobutyl-4-(trifluoromethyl)isoxazole-3-carboxylic acid (0.746 g, 3.15 mmol, 97% yield) as an off-white solid. The product had an HPLC ret. time=2.00 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (s, 3H), 0.93 (s, 3H), 1.97-2.09 (m, 1H), and 2.89 (d, J=7.28 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[C:13]([F:20])=[C:14]([OH:19])[CH:15]=[C:16]([F:18])[CH:17]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:25]=O.C(O)(=O)C>CCO>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[C:17]3[C:16]([F:18])=[CH:15][C:14]([OH:19])=[C:13]([F:20])[C:12]=3[C:3]3[C:4]([CH3:11])=[N:5][N:6]([C:7]([CH3:9])([CH3:10])[CH3:8])[C:2]=3[N:1]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1nn(C(C)(C)C)c(N)c1-c1cc(F)cc(O)c1F
Reactant: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nn(C(C)(C)C)c2nc(-c3ccc(OCc4ccccc4)c(Cl)c3)c3c(F)cc(O)c(F)c3c12
Temperature: 120 °C
Reaction time: 4.5 h
Yield: 46.6 %

Procedure:
To 3-[5-amino-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-4-yl]-2,5-difluorophenol (0.050 g, 0.178 mmol) and 3-chloro-4-[(phenylmethyl)oxy]benzaldehyde (0.044 g, 0.178 mmol) was added acetic acid (1 mL). The mixture was stirred at 120° C. for 4.5 h and then concentrated in vacuo to afford a residue which was co-evaporated with EtOH (2×) to afford a film which was purified by column chromatography (ether-dichloromethane 1:20) to afford 5-{3-chloro-4-[(phenylmethyl)oxy]phenyl}-3-(1,1-dimethylethyl)-6,9-difluoro-1-methyl-3H-pyrazolo[3,4-c]isoquinolin-8-ol as a light brown foam (0.042 g, 0.083 mmol, 47% yield). 1H NMR (400 MHz, CDCl3): 7.63 (t, 1H), 7.55-7.51 (m, 2H), 7.46-7.34 (m, 5H), 7.06 (d, 1H), 6.86 (dd, 1H), 5.25 (s, 2H), 2.81 (d, 3H), 1.84 (s, 9H); MS (EI) for C28H24ClF2N3O2: 508 (MH+).
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH2:10][CH2:9][CH2:8][C@H:4]1[C:5]([OH:7])=[O:6].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1.Cl>O.CC(C)=O>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([N:3]2[CH2:10][CH2:9][CH2:8][C@H:4]2[C:5]([OH:7])=[O:6])=[O:21])=[CH:15][CH:14]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(CC(=O)N2CCC[C@H]2C(=O)O)cc1
Temperature: 0 °C
Yield: 68 %

Procedure:
5M Aqueous sodium hydroxide solution (26 ml) was added to a solution of (S)-proline (582 g) in water (3.5 L) and acetone (3.5 L). The mixture was treated with ice (3.5 kg), cooled in an ice/acetone bath, treated over a one hour period with a solution of 4-methoxyphenylacetyl chloride (944 g) in acetone (1.75 L) with vigorous stirring and the simultaneous addition of sufficient 5M aqueous sodium hydroxide solution in order to keep the pH within the range 9.5-9.7. The reaction was stirred for 30 minutes, treated with concentrated hydrochloric acid (6 ml) and partially evaporated under reduced pressure to remove the majority of the acetone. The residue was treated with ice (2 kg), concentrated hydrochloric acid (750 ml) and the mixture stirred at room temperature for one hour. The resulting precipitate was collected, washed with water and recrystallised from toluene/ethanol to give the desired product as a colourless solid (905 g, 75%), m.p. 138°-139° C.
Reaction SMILES: [Br:1][C:2]1[C:12]2[C:13]3[C:5]([CH2:6][CH:7]([OH:14])[C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.Cl[Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CN=C1>C1COCC1.C(OCC)C>[Br:1][C:2]1[C:12]2[C:13]3[C:5]([CH2:6][CH:7]([O:14][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: OC1Cc2ccc(Br)c3cccc1c23
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](OC1Cc2ccc(Br)c3cccc1c23)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 5-bromo-1,2-dihydro-1-acenaphthylenol (0.25 g, 1 mmol) in dry THF (30 mL) was added chloro(tert-butyl)diphenylsilane (0.275 g, 1 mmol) and imidazole (0.34 g, 5 mmol), and the reaction stirred at room temperature under nitrogen for 18 h. The mixture was diluted with diethyl ether, filtered through a pad of silica, and evaporated in vacuo. Purification by flash chromatography on silica, eluting with ethyl acetate/hexane (1:9 to 1:1), yielded the title compound as a colourless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[CH2:11][S:10][N:9]=[C:8]([N:13](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:7]3=[N:28][N:29]([CH2:31][C:32]4[C:37]([CH3:38])=[C:36]([O:39][CH3:40])[C:35]([CH3:41])=[CH:34][N:33]=4)[N:30]=[C:5]([C:6]=23)[CH:4]=1.N1C=CC=CC=1.[C:48](OC(=O)C)(=[O:50])[CH3:49]>ClCCl>[NH2:13][C:8]1[C:7]2[C:6]3[C:5](=[N:30][N:29]([CH2:31][C:32]4[C:37]([CH3:38])=[C:36]([O:39][CH3:40])[C:35]([CH3:41])=[CH:34][N:33]=4)[N:28]=2)[CH:4]=[C:3]([CH2:2][NH:1][C:48](=[O:50])[CH3:49])[C:12]=3[CH2:11][S:10][N:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(C)cnc(Cn2nc3cc(CN)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(C)cnc(Cn2nc3cc(CNC(C)=O)c4c-3c(n2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture composed of di-tert-butyl {8-(aminomethyl)-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 112 (20 mg), pyridine (8.3 μl), acetic anhydride (5 μl) and dichloromethane (0.5 ml) was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure. Dichloromethane (2 ml) and trifluoroacetic acid (0.5 ml) were added to the resulting residue, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate solution was placed into the resulting residue, followed by extraction with chloroform. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (chloroform-methanol) to obtain the title compound (3.7 mg) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)[C:34]2[CH:35]=[CH:36][CH:37]=CC=2N=N1.C(N(CC)C(C)C)(C)C.C1(CN)CC1>CN(C=O)C>[CH:35]1([CH2:34][NH:30][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[N:16][CH:17]=2)[CH2:37][CH2:36]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NCC2CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (60 mg, 0.2 mmol) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and cyclopropanemethylamine (0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (45 mg, 65%) which was obtained as a white solid. MS: m/e=382.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.F[B-](F)(F)F.[CH3:19][O+](C)C>CC(C)=O>[CH3:19][N:3]1[C:2]([CH3:1])=[C:10]2[C:5]([CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:9]2)=[N:4]1
Reactant: C[O+](C)C
Reactant: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Agent: F[B-](F)(F)F
Solvent: CC(C)=O
Product: Cc1c2ccc([N+](=O)[O-])cc2nn1C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro-1H-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetraflouroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHCO3 (600 ml) and a 4:1 mixture of chloroform-isopropanol (200 ml), and the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4×200 ml) and the combined organic phase was dried (Na2SO4). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 ml) to afford 2,3-dimethyl-6-nitro-2H-indazole as a yellow solid (15.85 g, 73%). 1H NMR (300 MHz, d6DMSO) δ 8.51 (s, 1H), 7.94 (d, J=9.1 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([CH:17](OS(C(F)(F)F)(=O)=O)[CH3:18])[CH2:16][CH2:15][CH2:14][O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2>ClCCl>[CH2:1]([O:8][C:9]([C:11]1([CH:17]=[CH2:18])[CH2:16][CH2:15][CH2:14][O:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(OS(=O)(=O)C(F)(F)F)C1(C(=O)OCc2ccccc2)CCCOC1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=CC1(C(=O)OCc2ccccc2)CCCOC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 39.3 %

Procedure:
A solution of 3-(1-trifluoromethanesulfonyloxy-ethyl)-tetrahydro-pyran-3-carboxylic acid benzyl ester (8.368 mmol) in dichloromethane (100 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (5.0 mL, 33.472 mmol). After stirring at room temperature for 2.5 h, the volatiles were removed in vacuo and the residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (809.5 mg, 39% over two steps) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.58-1.80 (m, 3H), 2.29-2.40 (m, 1H), 3.42-3.54 (m, 2H), 3.81 (app dt, J=10.5, 4.2 Hz, 1H), 4.27 (dd, J=11.4, 1.8 Hz, 1H), 5.13-5.27 (m, 4H), 5.77 (dd, J=17.4, 10.9 Hz, 1H), 7.31-7.42 (m, 5H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[CH2:44][CH2:45][C:46]1[N:47]=[C:48](/[CH:51]=[CH:52]/[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[O:49][CH:50]=1>O1CCCC1>[CH:51](/[C:48]1[O:49][CH:50]=[C:46]([CH2:45][CH2:44][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[N:47]=1)=[CH:52]\[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCc1coc(/C=C/c2ccccc2)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCc1coc(/C=C/c2ccccc2)n1
Reaction time: 4 h
Yield: 95.7 %

Procedure:
Phthalimide (200 mg), triphenylphosphine (357 mg) and diethyl azodicarboxylate (0.214 ml) were added to a solution of 4-(2-hydroxyethyl)-2-(trans-styryl)oxazole (292 mg) in tetrahydrofuran (15 ml) at room temperature, and the mixture was stirred for 4 hours. The solvent of the reaction mixture was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the title compound (447 mg) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([NH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[S:20][C:19]([C:21](O)=[O:22])=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([NH:14][C:21]([C:19]2[S:20][C:16]([Cl:15])=[CH:17][CH:18]=2)=[O:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)[C@@H](O)C1
Reactant: O=C(O)c1ccc(Cl)s1
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1

Procedure:
22.4 Using general procedure C (3S,4S)-3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester was reacted with 5-chlorothiophene-2-carboxylic acid to give (3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester. Off-white solid. MS 347.3 ([M+H]+)
Reaction SMILES: [CH3:1][Li].Cl[C:4]1[C:14]2[C:13]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=3[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:10][CH2:9][C:8]=2[N:7]=[C:6]([CH3:26])[N:5]=1>CCOCC.O.S>[Cl:19][C:17]1[CH:16]=[CH:15][C:13]2[C:14]3[C:4]([CH3:1])=[N:5][C:6]([CH3:26])=[N:7][C:8]=3[CH2:9][N:10]=[C:11]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:12]=2[CH:18]=1
Reactant: Cc1nc(Cl)c2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Reactant: [Li]C
Agent: S
Solvent: CCOCC
Solvent: O
Product: Cc1nc(C)c2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dropwise 13.2 ml (18.5 mmol) of a 1.4M ether solution of methyl lithium was added to a suspension of 1.7 g (8.9 mmol) of cuprous iodide in 50 mL of ether which was cooled to 0°. A solution of 0.8 g (2.2 mmol) of 1,9-dichloro-3-methyl-7-phenyl-5H-pyrimido[4,5-d][2]benzazepine in 30 mL of ether was added dropwise to the ether solution of lithium dimethylcuprate which was further cooled to -25°. The mixture was stirred at -25° for 1 hr, warmed to room temperature, diluted with water and saturated with hydrogen sulfide. The resulting precipitate was removed by filtration over celite and the filtrate was concentrated at reduced pressure. Purification of the residue by column chromatography (silica gel, 10 g; eluent, 20% ether in methylene chloride) gave an oil which was crystallized from a mixture of ether and petroleum ether to give off-white needles, mp 121°-124°.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C@H:10]([C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)[OH:11])([CH3:4])[CH3:3].[Cl:18][C:19]1[C:26]([F:27])=[CH:25][C:22]([C:23]#[N:24])=[C:21](F)[CH:20]=1.[H-].[Na+]>CN(C)C=O>[CH3:4][C:2]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C@@H:10]([O:11][C:21]1[CH:20]=[C:19]([Cl:18])[C:26]([F:27])=[CH:25][C:22]=1[C:23]#[N:24])[C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1ccoc1
Reactant: N#Cc1cc(F)c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC[C@@H](Oc1cc(Cl)c(F)cc1C#N)c1ccoc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
The product of step (b) (277 mg, 1.15 mmol) and 4-chloro-2,5-difluorobenzonitrile (199 mg, 1.15 mmol) were dissolved in dimethylformamide (10 ml) and sodium hydride (60%, 48 mg, 1.2 mmol) added in one portion. The reaction was stirred for 2 h at room temperature then quenched with aqueous saturated ammonium chloride solution (30 ml) and extracted with ethyl acetate (3×60 ml). The combined organic extracts were washed with water (3×20 ml), dried (sodium sulphate) and evaporated iii vacuo. The residue was chromatographed on flash silica, eluting with hexane:ethyl acetate (3:1), to give the title compound as a white crystalline solid (330 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[C:16]([C:31]([NH2:33])=[O:32])=[N:17][CH:18]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[N:20]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH2:34](O)C.N1(CO)C2C=CC=CC=2N=N1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[C:16]([C:31]([NH2:33])=[O:32])=[N:17][CH:18]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[N:20]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:34])[CH2:10][CH2:9]1
Reactant: CCO
Reactant: NC(=O)c1ncc(Oc2cccc([N+](=O)[O-])c2)nc1Nc1ccc(N2CCNCC2)c(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: OCn1nnc2ccccc21
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2Br)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 3-{[3-bromo-4-(piperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (523 mg) and ethanol (5 mL)-tetrahydrofuran (15 mL) were added 1H-benzotriazole-1-methanol (159 mg) and sodium triacetoxyborohydride (323 mg), followed by stirring at room temperature for 6 hours, then diluting with chloroform, and washing with a saturated aqueous sodium hydrogen carbonate solution. After the organic phase was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-50:1:0.1) to obtain 3-{[3-bromo-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (447 mg) as a pale yellow solid.
Reaction SMILES: [O:1]([CH2:8][C@H:9]([NH2:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:15][C@@H:16]1[C@H:20]([O:21]C(=O)C)[C@@H:19]([CH2:25][O:26]C(=O)C)[O:18][C@H:17]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([CH3:40])=[N:34][C:35]=2Cl)(=O)C.C(N(CC)CC)C>O1CCOCC1>[CH3:40][C:33]1[N:34]=[C:35]([NH:11][C@H:9]([CH3:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:36]2[N:37]=[CH:38][N:30]([C:31]=2[N:32]=1)[C@@H:17]1[O:18][C@H:19]([CH2:25][OH:26])[C@@H:20]([OH:21])[C@H:16]1[OH:15]
Reactant: C[C@@H](N)COc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1nc(N[C@H](C)COc2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 50 °C
Yield: 50.5 %

Procedure:
(R)-1-phenoxy-2-propylamine (0.56 g, 3 mmol) was reacted with 9-(2,3,5-tri- O-acetyl-β-D-ribofuranosyl)-6-chloro-2-methyl-9H-Purine (0.43 g, 1 mmol) [prepared from 2-methylinosine (Journal of Organic Chemistry, 1967, 32, 3258-3260) by standard acylation and chlorination steps] in dioxan (20 ml) in the presence of triethylamine (0.41 g, 4 mmol). The reaction mixture was heated at 50° C. for 70 h, and at 90° C. for 3 h. before being filtered and evaporated. The product (after purification by flash chromatography) was debenzoylated with methanolic ammonia to provide the title 2-methyl- N-[(R)-1-phenoxy-2-propyl]adenosine (after column chromatography) as a foam (0.21 g, 50%), 1H NMR (DMSO-d6)δ 1.30 (3H, d, --CH3), 2.43 (3H, s, --CH3), 3.53-3.60 (1H, m, H-5'a), 3.66-3.73 (1H, m, H-5'b), 3.94 (1H, dd, --C--H), 3.99 (1H, q, H-4'), 4.12-4.22 (2H, m, H-3' and --C--H), 4.54 (1H, dd, H-2'), 4.76 (1H, m, --CH3C H--), 5.20, 5.52 (2H, 2d, 2' and 3'-OH), 5.73 (1H, t, 5'-OH), 5.87 (1H, d, H-1'), 6.90-7.31 (5H, t, m, t, Ar--H), 7.74 (1H, br d, N--H), 8.28 (1H, s, H-8).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22](Cl)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28]>>[C:27]([N:30]1[CH2:35][CH2:34][N:33]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([NH:17][C:12]3[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:11]=3)=[O:26])=[CH:20][N:21]=2)[CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(Cl)nc1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccccc4)c3)cn2)CC1

Procedure:
N-(3-benzamido-4-chlorophenyl)-6-chloronicotinamide (0.15 mmol) was used in general procedure 3 with 1-acetylpiperazine (0.77 mmol). The product was purified by RP-HPLC to give 6-(4-acetylpiperazin-1-yl)-N-(3-benzamido-4-chlorophenyl)nicotinamide. MS (Q1) 478.0 (M)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:24]1([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)[CH:28]=[N:27][N:26]=[N:25]1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:35][C:32]4[CH:33]=[CH:34][C:29]([N:24]5[CH:28]=[N:27][N:26]=[N:25]5)=[CH:30][CH:31]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(-n2cnnn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(-n5cnnn5)cc4)ncnc32)CC1
Yield: 7.2 %

Procedure:
4-[4-(4-Tetrazol-1-yl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (6 mg, 7%) was prepared using the procedure described for the preparation of Example 41 by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tertbutyl ester (Intermediate 19; 60 mg, 0.18 mmol) with 4-tetrazol-1-yl-phenol (Enamine Ltd., Kiev, Ukraine; 29 mg, 0.18 mmol) in the presence of potassium carbonate (54 mg, 0.39 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@H:4]1[CH2:8][C:7](=[O:9])[CH2:6][N:5]1[C:10](=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.COC(=O)[C@@H]1CC(=O)CN1C(=O)CC1C=CC=CC=1.CCCCCCCCCCCCCCCC>C([O-])(=O)C.[Na+].ClCCl>[CH3:1][O:2][C:3](=[O:19])[CH:4]1[CH2:8][C:7](=[O:9])[CH2:6][N:5]1[C:10](=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@H]1CC(=O)CN1C(=O)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: COC(=O)[C@@H]1CC(=O)CN1C(=O)Cc1ccccc1
Agent: [Na+]
Solvent: CCCCCCCCCCCCCCCC
Solvent: ClCCl
Product: COC(=O)C1CC(=O)CN1C(=O)Cc1ccccc1
Reaction time: 28 h

Procedure:
An aqueous solution (1.0 mL) containing 19 mM of N-(2-phenylacetyl)-4-keto-D-proline methyl ester and 19 mM of N-(2-phenylacetyl)-4-keto-L-proline methyl ester in 0.200M sodium acetate (pH 5.0) and 25 mg/mL of Candida antartica lipase fraction B was mixed at 25° C. The reaction mixture was analyzed by mixing with an equivalent volume of 20 mM hexadecane in dichloromethane for 3 minutes, which resulted in the complete extraction of the unreacted D- and L-isomers. The dichloromethane extract was then analyzed by chiral gas chromatography on a Chiraldex G-TA column (Advanced Separation Technologies, Inc., 50 m×0.32 mm ID) to determine the relative amounts of the unreacted D- and L-isomers. After 28 h, 97% of the D-isomer and 28% of the L-isomer remained, yielding a 55% enantiomeric excess of the D-isomer at 38% conversion of the racemic mixture (E=28).