Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1(N)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]([N:11](C(C)C)CC)(C)[CH3:9].C(Cl)(=[O:19])C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:1]1([CH2:9][C:8]([NH2:11])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: NN1CCCCC1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)CN1CCCCC1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of the piperidine amine obtained above (676 mg, 1.59 mmol) in methylene chloride (25 mL) was added diisopropylethylamine (616 mg, 849 uL, 4.77 mmol), followed by acetyl chloride (162 mg, 156 uL, 2.06 mmol). The mixture was stirred at room temperature over night. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with additional methylene chloride. The extracts were combined, washed with brine, dried over sodium sulfate, filtered, dried and concentrated to afford the piperidine acetamide (844 mg, >100%).
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].[CH3:14][C:15]1[O:21]C(C)(C)O[C:17](=[O:18])[CH:16]=1>C1(C)C=CC=CC=1>[C:17]([O:1][CH2:2][N:3]1[C:4](=[O:13])[C:5]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:6]2[C:7]1=[O:8])(=[O:18])[CH2:16][C:15]([CH3:14])=[O:21]
Reactant: O=C1c2ccccc2C(=O)N1CO
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCN1C(=O)c2ccccc2C1=O
Yield: 97.8 %

Procedure:
A solution of 10.0 g (0.056 mol) of N-(hydroxymethyl)phthalimide and 8.02 g (0.056 mol) of 2,2,6-trimethyl-1,3-dioxen-4-one in 100 ml of toluene was refluxed for 24 hours under nitrogen. Recrystallization in ethyl acetate gives 14.3 g (97%) of an off-white solid: mp 106°-109° C.; NMR (CDCl3) 7.6 (4H,m), 5.6 (2H,s), 3.4 (2H,s), 2.18 (3H,s);
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].CO.O>C(OC)(C)(C)C>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CO
Solvent: O
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 1 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in methyl t-butyl ether (0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in methyl t-butyl ether was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 1 hour. Then water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 176 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.
Reaction SMILES: IC1C2C(=NC=NC=2N)N([C@H]2CC[C@@H](N3CCN(C)CC3)CC2)N=1.C([NH:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][C:36]=1[O:44][CH3:45])=[O:34])C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:45][O:44][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:33]([NH2:32])=[O:34]
Reactant: COc1cc(B(O)O)ccc1C(=O)NCc1ccccc1
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1C(N)=O
Yield: 237.5 %

Procedure:
cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (141 mg, 0.319 mmol), 4-[(benzylamino)carbonyl]-3-methoxyphenylboronic acid (100 mg, 0.351 mmol), palladium tetrakistriphenyphosphine (22 mg, 0.019 mmol) and sodium carbonate (81 mg, 0.765 mmol) were mixed with ethylene glycol dimethyl ether (4 mL) and water (2 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile phase to give cis-N1-benzyl-4-44-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide (126 mg, 71%). 1H NMR (CDCl3) δ 1.83 (m, 6H), 2.34 (s, 3H), 2.45 (m, 11H), 4.02 (s, 3H), 4.43 (d, J=5.66 Hz, 2H), 4.95 (m, 1H), 5.52 (bs, 2H), 7.37 (m, 7H), 8.18 (m, 1H), 8.41 (m, 1H); LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.(B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+=555.5, Rt=2.65 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[OH:27][C:28]1[CH:36]=[CH:35][C:31]([CH2:32][CH2:33]O)=[CH:30][CH:29]=1.I.N1C=CN=C1>O.ClCCl>[I:25][CH2:33][CH2:32][C:31]1[CH:35]=[CH:36][C:28]([OH:27])=[CH:29][CH:30]=1
Reactant: II
Reactant: OCCc1ccc(O)cc1
Agent: I
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(CCI)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triphenylphosphine (1.57 g, 0.006 mol) and imidazole (0.41 g, 0.006 mol) were added to dry dichloromethane (20 ml). When the imidazole was in solution iodine (1.52 g, 0.006 mol) was added. After precipitation of the imidazole hydroiodide (4-hydroxyphenethyl) alcohol (0.69 g, 0.005 mol) was added. The mixture was stirred at room temperature for 4 h. Then water was added and the mixture was extracted with dichloromethane. The extracts were washed with water, dried and concentrated in vacuo to give a raw product. Purification by flash chromatography (heptane/ethyl acetate as a gradient eluent 9:1-6:4) gave a pure product. 1H NMR (400 MHz, DMSO-d6): 2.99 (2H, t, 3J=7.6 Hz), 3.38 (2H, t, 3J=7.6 Hz), 6.68 (2H, d, 3J=8.5 Hz), 7.03 (2H, d, 3J=8.5 Hz), 9.24 (1H, s, —OH).
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[CH:9]([CH3:15])[CH2:10][CH2:11][C:12]#[C:13][CH3:14])(=O)OC.[CH:17]([C@H:19]1[C@H:26]([O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][C@H:24]2[C@@H:20]1[CH2:21][C:22](=[O:36])[O:23]2)=O>>[C:28]([O:27][C@@H:26]1[CH2:25][C@H:24]2[C@H:20]([CH2:21][C:22](=[O:36])[O:23]2)[C@H:19]1/[CH:17]=[CH:7]/[C:8](=[O:16])[CH:9]([CH3:15])[CH2:10][CH2:11][C:12]#[C:13][CH3:14])(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Reactant: CC#CCCC(C)C(=O)CP(=O)(OC)OC
Product: CC#CCCC(C)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Yield: 85.8 %

Procedure:
Analogously to Example 1(g), 7.4 g of the title compound was synthesized from 5.4 g of 3-methyl-2-oxooct-6-inylphosphonic acid dimethyl ester and 6 g of (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3,3,0]-octan-3-one [E. J. Corey et al., J. Amer. Chem. Soc. 91: 5675 (1969)].
Reaction SMILES: [NH:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.[OH-].[Na+].Cl[CH2:17][C:18](Cl)=[O:19]>O>[C:2]1([N:1]2[CH2:8][CH2:9][O:10][CH2:17][C:18]2=[O:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: OCCNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1COCCN1c1ccccc1
Temperature: 41 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A 250-mL flask was charged with 2-anilinoethanol (9.17 ml, 73.2 mmol), 9 mL dry EtOH, an overhead stirrer, a calibrated pH probe, and 27 mL water. An addition funnel was charged with 10 N sodium hydroxide solution (45.4 ml, 454 mmol). The solution was heated to 41° C., and treated with chloracetyl chloride (17.5 ml, 220 mmol) via a syringe pump over 1 h. The sodium hydroxide solution was simultaneously added to the stirring solution so that the pH was maintained between 12 and 12.5. After the addition was complete, the solution was cooled to 0° C. and stirred for 1 h. The solids were collected and washed with water (2×60 mL cold water). The solids were dried at 50° C. at 0.2 mm Hg for 36 h to afford 4-phenylmorpholin-3-one (8.10 g, 62.5% yield). 1H NMR (400 MHz, CHLOROFORM-d) 3.75-3.80 (m, 2H) 4.02-4.06 (m, 2H) 4.35 (s, 2H) 7.27-7.36 (m, 3H) 7.39-7.46 (m, 2H). 13C NMR (101 MHz, CHLOROFORM-d) 49.69 (s, 1 C) 64.14 (s, 1 C) 68.57 (s, 1 C) 125.48 (s, 2 C) 127.15 (s, 1 C) 129.30 (s, 2 C) 141.31 (s, 1 C) 166.59 (s, 1 C).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].CO.[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13](F)=[CH:12][C:11]=1[F:20].O>CN(C=O)C>[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([O:4][CH3:2])=[CH:12][C:11]=1[F:20]
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COc1cc(F)c(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.5 %

Procedure:
To a mixture of potassium tert-butoxide (3.0 g, 26.9 mmol) in DMF (20 mL), methanol (0.79 g, 24.8 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes then a solution of 1-chloro-2,4-difluoro-5-nitrobenzene (4.0 g, 20.7 mmol) in DMF (20 mL) was added at 0° C. and the reaction mass stirred for 3 hours at room temperature. Water (200 mL) was added to the reaction mixture and reaction mass was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water (80 mL), brine (80 mL), dried (Na2SO4) and concentrated under reduced pressure. The product was purified by column chromatography on neutral silica gel using 20-25% EtOAc in hexane to give the desired product (3 g, 71%) as a solid.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N12CCN(CC1)CC2.C([Li:21])CCC.CCCCCC>O1CCCC1>[C:1]1([S:7][CH2:8][Li:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccccc1
Reactant: [Li]CCCC
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]CSc1ccccc1
Temperature: 0 °C

Procedure:
A solution of 5.4 g (44 mmol) of thioanisole and 4.89 g (43.6 mmol) of 1,4-diazabicyclo[2,2,2]octane in 44 ml of tetrahydrofuran was placed in an oven-dried flask and cooled to 0° C. A 2.5M solution of butyl lithium in hexane (17.4 ml, 43.6 mmol) was added with stirring and the mixture allowed to warm to room temperature and react for about 1 hour to form phenylthiomethyl lithium. A solution of 3.14 g (8.71 mmol) of 1-(2-methoxymethoxyphenyl)-1-(3,4-dimethoxy-2-methoxymethoxyphenyl)ethene in tetrahydrofuran was added and the mixture heated to reflux with stirring under an argon atmosphere. After 10 hours another 21 8 mmol of phenylthiomethyl lithium was prepared and added to the mixture and refluxing was continued overnight. The mixture was then cooled and poured into 200 ml of 5 percent aqueous sodium hypochlorite solution and 200 g of ice and 150 ml of ether added. The organic phase was separated, dried over magnesium sulfate and concentrated by evaporation under reduced pressure to obtain 6.61 g of an oil. This was purified by silica gel chromatography (80 mm×3" filter funnel), eluting with hexane containing ever increasing amounts of ether to obtain 1.16 g of the title compound as an oil. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:20])[C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)C1CCCCC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(C(=O)C1CCCCC1)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.9 %

Procedure:
To a solution of cyclohexanecarboxylic acid (4-fluoro-3-nitro-phenyl)amide (see Example 1) (0.75 g, 2.82 mmol) in DMSO (15 mL) was added a 1M solution of sodium bistrimethylsilylamide (3.36 mL, 3.36 mmol), with stirring at room temperature. After 15 min, iodomethane (0.53 mL, 8.5 mmol) was added. After 1 h, the mixture was diluted with ethyl acetate, washed twice with water, dried over magnesium sulfate, and evaporated. The residue was purified by flash chromatography, eluting with hexane/ethyl acetate (7:3) to give cyclohexanecarboxylic acid (4-fluoro-3-nitro-phenyl)-methyl-amide (402 mg, 51%) as the first eluted component.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[O:24]>C1COCC1>[Cl:19][C:20]1[CH:21]=[C:22]([CH:23]([OH:24])[CH2:14][C:13]([O:16][CH2:17][CH3:18])=[O:15])[CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(C)=O
Reactant: O=Cc1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of diisopropyl amine (12.4 mL, 88.2 mmol) in THF (50 mL) at −78° C. was added n-butyllithium (35.3 mL, 88.2 mmol). The reaction mixture was stirred at −78° C. for 30 min, at which time ethyl acetate was added (16.1 mL, 163.2 mmol). After 1 h, 3-chlorobenzaldehyde was added and the reaction mixture was allowed to warm to room temperature over 2 h. The reaction mixture was quenched with aqueous saturated NH4Cl (20 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was rinsed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford yellow oil. The crude product was purified by column chromatography on silica gel, eluted with ethyl acetate-hexanes (1:4) to afford ethyl 3-(3-chloro-phenyl)-3-hydroxy-propionate as a yellow oil (10.0 g, 99.0%). 1H NMR (400 MHz, d-DMSO): δ 7.43-7.30 (m, 4H), 5.66 (d, 1H), 5.01-4.95 (q, 1H), 4.14-4.04 (m, 2H), 2.71-2.58 (m, 2H), 1.24-1.17 (t, 3H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:3); Rf=0.50.
Reaction SMILES: C([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:38])[CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:26][CH:25]=2)=[O:22])[CH2:5][CH2:4]1)=O.Cl.C(=O)([O-])O.[Na+].O>C(OCC)(=O)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[CH:10][C:9]3[NH:3][CH2:4][CH2:5][C:6]([C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:38])[CH:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)=[CH:26][CH:25]=4)=[O:22])=[CH:7][C:8]=3[CH:13]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To 1-formyl-7-(4-methylphenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (1177 mg) was added 1N hydrochloric acid (20 ml), and the mixture was stirred at 100° C. for 1 hour. The mixture was dilute with ethyl acetate(50 ml) and made weakly basic with saturated sodium hydrogen carbonate solution (45 ml). To the mixture were added ethyl acetate (250 ml) and water (100 ml),and separated. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (75 g, ethyl acetate/ethanol=9:1) to give 7-(4-methylphenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 318)—(804 mg, 72%) as amorphous.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[N+:19]([O-:31])[CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1cccc(Nc2nccc(-c3cccnc3)n2)c1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(Nc2nccc(-c3ccc[n+]([O-])c3)n2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
200 mg (0.68 mmol) of N-(3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine are suspended in 5 ml of methylene chloride, and 225 mg (0.71 mmol) of 3-chloroperbenzoic acid are added. After 2 hours a further 10 ml of methylene chloride are added. The suspension is stirred for a further 20 hours at room temperature. Filtration and flash chromatography of the residue (methylene chloride:methanol:25% aqueous ammonia solution=90:10:1) yield N-(3-nitro-phenyl)-4-(N-oxido-3-pyridyl)-2-pyrimidine-amine; Rf =0.4 (methylene chloride:methanol:25% aqueous ammonia solution=90: 10:1), m.p. 252°-258°.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH2:8]([O:15][C:16]1[C:17]([C:34]([OH:36])=O)=[N:18][N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:21](=[O:33])[C:20]=12)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[CH2:8]([O:15][C:16]1[C:17]([C:34]([NH:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[O:36])=[N:18][N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:21](=[O:33])[C:20]=12)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)c1nn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)CC2
Reactant: NCCN1CCOCC1
Agent: O=C([O-])C(F)(F)F
Product: O=C(NCCN1CCOCC1)c1nn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)CC2

Procedure:
The title compound was prepared as the trifluoroacetate salt from 3-benzyloxy-5-(4-fluorobenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid using a procedure similar to that found in Example 15, Step 1, except that 4-(2-aminoethyl)morpholine was used in place of 1,2,3,4-tetrahydroisoquinoline. 1H NMR (400 MHz, CDCl3) δ 7.70-7.67 (t, 1H), 7.48-7.46 (m, 2H), 7.36-7.27 (m, 5H), 7.08-7.04 (m, 2H), 5.46 (s, 2H), 5.30 (s, 2H), 4.74 (s, 2H), 4.28-4.25 (t, 2H), 3.96 (br s, 4H), 3.78-3.68 (m, 4H), 3.61-3.58 (t, 2H), 3.30-3.26 (t, 2H); ES MS (M+1)=508.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[C:8]2[C:12]=1[N:11]([CH3:13])[C@H:10]1[N:14]([CH3:17])[CH2:15][CH2:16][C@@:9]21[CH3:18])([O-])=O.[C:20](OC(=O)C)(=[O:22])[CH3:21].[H][H]>[Pt].O1CCCC1>[C:20]([NH:1][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[C:8]2[C:12]=1[N:11]([CH3:13])[C@H:10]1[N:14]([CH3:17])[CH2:15][CH2:16][C@@:9]21[CH3:18])(=[O:22])[CH3:21]
Reactant: [H][H]
Reactant: CN1CC[C@@]2(C)c3cc(O)cc([N+](=O)[O-])c3N(C)[C@@H]12
Reactant: CC(=O)OC(C)=O
Agent: [Pt]
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(O)cc2c1N(C)[C@H]1N(C)CC[C@@]21C

Procedure:
A Parr hydrogenation bottle is charged with 3.20 g of (3aS-cis)-1,2,3,3a,8,8a-hexahydro-7-nitro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-ol, methyl carbamate ester, 0.3 g of 1% platinum-on-carbon catalyst, 1.53 g of acetic anhydride and 50 ml of degassed tetrahydrofuran. The mixture is shaken at room temperature under an initial hydrogen pressure of 40 psi (pounds per square inch) until uptake of hydrogen ceases. The catalyst is removed by filtration and the filtrate is concentrated in vacuo to afford 7-acetylamino-(3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-ol, methyl carbamate ester.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].ClCCl.[CH3:10][O:11][C:12]1[C:17](B(O)O)=[CH:16][CH:15]=[CH:14][N:13]=1.[C:21]([O:24][C@@H:25]1[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:37]([O:43][C:44](=[O:46])[CH3:45])[CH2:36][S:35][C@H:26]1[O:27][C:28]1[CH:29]=[N:30][C:31](Br)=[CH:32][CH:33]=1)(=[O:23])[CH3:22]>O.COCCOC>[C:21]([O:24][C@@H:25]1[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:37]([O:43][C:44](=[O:46])[CH3:45])[CH2:36][S:35][C@H:26]1[O:27][C:28]1[CH:29]=[N:30][C:31]([C:17]2[C:12]([O:11][CH3:10])=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:32][CH:33]=1)(=[O:23])[CH3:22]
Reactant: COc1ncccc1B(O)O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: COc1ncccc1-c1ccc(O[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cn1
Yield: 70 %

Procedure:
A solution of 0.354 g (3.34 mM) of sodium carbonate in 3 ml of water, 0.18 g (0.223 mM) of the [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and 0.68 g (4.46 mM) of 2-methoxy-3-pyridineboronic acid are added to a solution of 1 g (2.23 mM) of 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, in 10 ml of DME. The reaction mixture is heated using microwave radiation at 120° C. for 20 minutes and cooled, water is added and extraction is carried out with ethyl acetate. The organic phase is washed with a 1M sodium carbonate solution and then with water to neutral pH, dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by chromatography on a silica column (eluent: toluene/acctone 90/10; v/v) in order to obtain the expected product in the form of a white solid with a yield of 70%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[C:5]#N.[OH-:17].[Na+].Cl.[OH2:20]>C(O)CO>[CH3:1][S:2][C:3]1[CH:10]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[C:5]([OH:20])=[O:17]
Reactant: O
Reactant: [OH-]
Reactant: CSc1cc(S(F)(F)(F)(F)F)ccc1C#N
Agent: Cl
Agent: [Na+]
Solvent: OCCO
Product: CSc1cc(S(F)(F)(F)(F)F)ccc1C(=O)O

Procedure:
A mixture of 2-methylthio-4-pentafluorosulphanylbenzonitrile (0.47 g) and sodium hydroxide (0.2 g) in a mixture of water and ethylene glycol (1:5) was heated at reflux for 5 hours. The cooled mixture was diluted (water), acidified (hydrochloric acid) and the solid filtered, washed (water) and dried to give 2-methylthio-4-pentafluorosulphanylbenzoic acid (0.38g), m.p.150-152° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[C:12]([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ncccc1O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ncccc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.1 %

Procedure:
In a 50 mL round-bottom flask fitted with magnetic stirrer were placed 3-hydroxypyridine-2-carboxylic acid methyl ester (3.5 g, 22.80 mmol), K2CO3 (3.46 g, 25.0 mmol), Mel (4.87 g, 34.3 mmol) and DMF (20 mL). The reaction mixture was stirred for 18 h at rt under nitrogen. The reaction mixture was diluted with EtOAc (30 mL) and water (10 mL). The organic layer was separated and aqueous layer was extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by column chromatography using 30% EtOAc in hexane to give 2.1 g of 3-methoxypyridine-2-carboxylic acid methyl ester (54%).