Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([N:6]([S:9]([NH:12][C:13](=O)[O:14]C1C=CC=CC=1)(=[O:11])=[O:10])[O:7][CH3:8])(=[O:5])=[O:4].[CH3:23][C:24]1[CH2:28][CH:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:26][N:25]=1>C1C=CC=CC=1>[CH3:22][N:2]([CH3:1])[S:3]([N:6]([S:9]([NH:12][C:13]([N:26]1[CH:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][C:24]([CH3:23])=[N:25]1)=[O:14])(=[O:11])=[O:10])[O:7][CH3:8])(=[O:4])=[O:5]
Reactant: CON(S(=O)(=O)NC(=O)Oc1ccccc1)S(=O)(=O)N(C)C
Reactant: CC1=NNC(c2ccccc2)C1
Solvent: c1ccccc1
Product: CON(S(=O)(=O)NC(=O)N1N=C(C)CC1c1ccccc1)S(=O)(=O)N(C)C
Yield: 23.8 %

Procedure:
4.24 g (12 mmol) of phenyl N-[(N-dimethylsulfamoyl-N-methoxyamino)sulfonyl]carbamate was dissolved in 30 ml of dry benzene, and 1.6 g (10 mmol) of 3-methyl-5-phenyl-2-pyrazoline was added thereto. The mixture was refluxed for 5 minutes. The mixture was left to cool, and the solvent was distilled off under reduced pressure. The residue was purified by reverse phase column chromatography (CH3CN: H2O=7:3) to obtain 1.0 g of the desired 1-[(N-dimethylsulfamoyl-N-methoxyamino)sulfonylcarbamoyl]-3-methyl-5-phenyl-2-pyrazoline.
Reaction SMILES: [CH3:1]C1(C)OC(=O)CC(=O)O1.N1C=CC=CC=1.[C:17]([CH:19]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])[CH3:20])#[N:18]>ClCCl>[C:24]([C:23]1[CH:22]=[C:21]([CH:19]([CH3:20])[C:17]#[N:18])[CH:29]=[CH:28][CH:27]=1)(=[O:25])[CH3:1]
Reactant: CC(C#N)c1cccc(C(=O)Cl)c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1cccc(C(C)C#N)c1
Reaction time: 0.25 h
Yield: 31.9 %

Procedure:
Next, to a solution of Meldrum's acid (408 mg, 2.84 mmol) in dichloromethane (15 mL) at 0° C. was added pyridine (0.457 mL, 5.68 mmol). The resulting mixture was stirred for 15 min and then 3-(1-cyanoethyl)benzoyl chloride (482.5 mg, 2.5 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min and then for 1 h at room temperature. The reaction mixture was diluted with dichloromethane and washed with 1 N HCl. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was dissolved in AcOH—H2O (1:2) and heated at reflux for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with NaHCO3 solution and brine, then dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography using hexane-ethyl acetate (9:1) as eluent to give 13 (138 mg, 28%). 1H NMR (CDCl3, 400 MHz) δ 1.68 (d, J=7.2 Hz 3H), 2.63 (s, 3H), 3.99 (q, J=7.2 Hz, 1H), 6.60 (d, J=7.6 Hz, 1H), 7.53 (d, J=2.8 Hz, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.91 (t, J=2 Hz, 1H), 7.94 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:22]([CH3:28])[CH2:23][N:24]([CH2:26][CH3:27])[CH3:25])[C:10]=2[CH:9]=1)=S.[ClH:30].C(O)(=O)/C=C/C(O)=[O:35]>C(O)C.C(OC(C)C)(C)C>[ClH:30].[CH3:1][CH:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:22]([CH3:28])[CH2:23][N:24]([CH2:26][CH3:27])[CH3:25])[C:10]=2[CH:9]=1)=[O:35]
Reactant: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C(=S)NCCC(C)C)cc21
Reactant: O=C(O)/C=C/C(=O)O
Agent: Cl
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C(=O)NCCC(C)C)cc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
N-(3-Methylbutyl)-10-[(2RS)-1-(N-ethyl-N-methyl-amino)-2-propyl]-2-phenothiazinecarbothioamide (0.3 g) is dissolved in a solution of fumaric acid (81 mg) in absolute ethanol (5 cc) and the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange product of meringue-like consistency is dissolved in acetic acid (5 cc) and mercuric acetate (0.23 g) is added. The orange suspension obtained is stirred for 16 hours at a temperature in the region of 20° C. The reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 60° C. The residue is taken up with distilled water (10 cc) and filtered and the filtrate is alkalinized with caustic soda (d=1.33) to pH 13 and extracted with ethyl acetate (2×10 cc). The combined organic phases are washed with saturated aqueous sodium chloride solution (10 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (0.15 g) is dissolved in ethyl acetate (2 cc), and isopropyl ether (20 cc) is added. The solution obtained is cooled to a temperature in the region of 5° C. and a solution (5.1 cc) of 0.065N hydrochloric acid in isopropyl ether is added dropwise and with stirring. The precipitate formed is drained, washed with isopropyl ether (3×5 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. N-(3-Methylbutyl)-10-[(2RS)-1-(N-ethyl-N-methylamino)-2-propyl]-2-phenothiazinecarboxamide hydrochloride (0.13 g) is thereby obtained in the form of an off-white solid, m.p. 110-120° C. (melts forming a paste).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:18]1[C:27]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:35]([O:37][CH3:38])=[O:36])[CH:24]=2)[N:19]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:27]2[C:18]([N:12]3[CH2:11][CH2:10][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=4)[CH2:14][CH2:13]3)=[N:19][C:20]3[C:25]([N:26]=2)=[CH:24][C:23]([C:35]([O:37][CH3:38])=[O:36])=[CH:22][CH:21]=3)=[CH:33][CH:32]=1
Reactant: FC(F)(F)c1ccc(C2CCNCC2)cc1
Reactant: COC(=O)c1ccc2nc(Cl)c(-c3ccc(F)cc3)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(N3CCC(c4ccc(C(F)(F)F)cc4)CC3)c(-c3ccc(F)cc3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 20-mL sealed tube, was placed a solution of 4-(4-(trifluoromethyl)phenyl)piperidine (420 mg, 1.83 mmol, 3.00 equiv), methyl 2-chloro-3-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.47 mmol, 1.00 equiv), DIEA (305 mg, 2.36 mmol, 5.00 equiv) in N,N-dimethylformamide (10 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 200 mg (83%) of methyl 3-(4-fluorophenyl)-2-(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:21]2[C:16]([C:17]3[CH:33]=[CH:32][O:31][C:18]=3[C:19](=[O:30])[O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[CH2:34]([N:36]([CH2:53][CH3:54])[CH2:37]/[CH:38]=[CH:39]\[Sn](CCCC)(CCCC)CCCC)[CH3:35]>O1CCOCC1>[CH2:34]([N:36]([CH2:53][CH3:54])[CH2:37]/[CH:38]=[CH:39]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:21]2[C:16]([C:17]3[CH:33]=[CH:32][O:31][C:18]=3[C:19](=[O:30])[O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10])[CH3:35]
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1oc(=O)c1occc12
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(oc(=O)c3occc32)c1C(=O)OC(C)(C)C
Temperature: 95 °C
Yield: 61.5 %

Procedure:
A suspension of tert-butyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4-oxo-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 56, 0.330 g) and N,N-diethyl-N-((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 0.493 g) in dioxane was warmed slightly then de-gassed and purged with nitrogen. tris-(Dibenzylideneacetone)dipalladium (0.056 g) and tri-tert-butylphosphonium tetrafluoroborate (0.036 g) were added and the mixture was de-gassed and purged with nitrogen again. The resultant mixture was heated at 95° C., under an atmosphere of nitrogen for 75 minutes. This was cooled and concentrated in vacuo and the residue was partitioned between water and ethyl acetate (2×). The combined organic layers were dried (MgSO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with methanol and DCM, with a gradient of 0-25%. The product was triturated with ether and the resultant product was dried in vacuo at 50° C. overnight to give tert-butyl 7-[2((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4-oxo-4H-furo[2,3-c]chromene-6-carboxylate (0.215 g) as a sand coloured solid.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].O.[C:18](OCC)(=[O:20])[CH3:19]>>[CH3:14][O:13][C:12]1[C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH2:2][C:18](=[O:20])[CH3:19])[O:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(C)=O
Reactant: COc1cccc2oc(C(C)=O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cccc2oc(C(=O)CC(C)=O)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Acetyl-4-methoxybenzo(b)furan (2.4 g) was dissolved in ethyl acetate (50 ml), and sodium hydride (1.5 g) was added under ice-cooling. The mixture was stirred at room temperature for 10 min, and the mixture was refluxed under heating for 1 hr. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and after filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.7 g).
Reaction SMILES: [CH:1]1([CH:7]([NH:18][CH2:19][C:20]2[C:25]([N+:26]([O-])=O)=[CH:24][N:23]=[C:22]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:21]=2)[CH2:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:26][C:25]1[C:20]([CH2:19][NH:18][CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:10])=[CH:21][C:22]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:23][CH:24]=1
Reactant: CC(C)(C)CCNC(=O)CC(NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)CCNC(=O)CC(NCc1cc(Oc2ccccc2)ncc1N)C1CCCCC1
Temperature: -78 °C
Reaction time: 3.5 h

Procedure:
In a Parr bottle 10% Pd/C (0.42 g) was added and cooled to −78° C., then a solution of 3-cyclohexyl-N-(3,3-dimethyl-butyl)-3-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-propionamide (0.42 g, 0.87 mmol) in ethyl acetate (5 mL) and ethanol (20 mL) was added. The resulting mixture was subjected to hydrogen atmosphere and shaken for 3.5 h. The hydrogen was purged with nitrogen, then the reaction mixture was filtered (glass fiber filter paper) and the solvent was evaporated under reduced pressure to yield the title compound as a residue.
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:6][CH2:7][C@H:8]1[O:13][C@H:12]([CH2:14]I)[CH2:11][C@H:9]1[OH:10])([CH3:4])[CH3:3].[N-:28]=[N+:29]=[N-:30].[Li+]>CN(C)C=O.O>[N:28]([CH2:14][C@H:12]1[O:13][C@H:8]([CH2:7][O:6][Si:5]([C:2]([CH3:3])([CH3:1])[CH3:4])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:9]([OH:10])[CH2:11]1)=[N+:29]=[N-:30]
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@H](CI)C[C@H]1O)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@H]1O[C@H](CN=[N+]=[N-])C[C@H]1O)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A solution, under argon, of 5.0 g of product from Example 275 in 10 ml of dry N,N-dimethylformamide is treated with 0.986 g of lithium azide. The minute is stirred at 80° C. for 1 hour followed by room temperature for 18 hours. The reaction is diluted with water, extracted with diethyl ether, concentrated in vacuo, purified by chromatography (silica gel: 5-50% ethyl acetate/hexane) to give 4.0 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([Br:12])[CH:3]=1.[C:13]([N:21]=[C:22]=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCCCCC>O1CCCC1>[C:13]([NH:21][C:22](=[S:23])[NH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([Br:12])[CH:3]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COC(=O)c1cc(Br)cc(N)n1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1cc(Br)cc(NC(=S)NC(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
2.74 g of methyl 6-amino4-bromopyridine-2-carboxylate was dissolved in 15 ml of tetrahydrofuran and 1.63 ml of benzoyl isothiocyanate was added thereto, followed by stirring at room temperature for 13 hours. To the reaction mixture was added 40 ml of hexane. The resulting solid was filtered and washed with hexane. The obtained solid was dried in vacuo to give the title compound.
Reaction SMILES: [OH:1][C:2]1([CH2:17][CH:18]=O)[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:20](=[O:27])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH2:21].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[C:23]([O:22][C:20]([NH:21][CH2:18][CH2:17][C:2]1([OH:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=CCC1(O)CCCC1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(N)=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCC1(O)CCCC1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.2 %

Procedure:
To a solution of benzyl 2-hydroxy-2-(2-oxoethyl)cyclopentanecarboxylate (from step C, 120 mg, 0.457 mmol) in acetonitrile (2 mL) was added tert-butyl carbamate (214 mg, 1.830 mmol), triethylsilane (213 mg, 1.830 mmol) and trifluoroacetic acid (0.070 mL, 0.915 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and subjected to preparative HPLC(Shimadzu VP-ODS 20×100 mm, 8 min. gradient, Solvent A: 10% MeOH, 90% H2O, 0.1% TFA; Solvent B: 90% MeOH, 10% H2O, 0.1% TFA; wavelength: 220 nM). The desired fractions were concentrated and freeze dried to yield benzyl 2-(2-(tert-butoxycarbonylamino)ethyl)-2-hydroxycyclopentanecarboxylate (70 mg, 0.193 mmol, 42.1% yield) as a solid. MS (ESI+)=386 (M+Na)+
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[NH:3]1.[I:16]Cl>C(O)(=O)C>[I:16][C:13]1[CH:14]=[CH:15][C:4]2[NH:3][C:2](=[O:1])[N:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]=2[CH:12]=1
Reactant: CCOC(=O)n1c(=O)[nH]c2ccccc21
Reactant: ClI
Solvent: CC(=O)O
Product: CCOC(=O)n1c(=O)[nH]c2ccc(I)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 9.00 g (43.6 mmol) of ethyl 2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (IV) and 14.2 g (87.3 mmol) of iodine monochloride in acetic acid (100 ml) was stirred at room temperature for 5 min and then at 85° C. for 2.5 h. The cooled reaction mixture was poured into ice-water. The precipitated solid was filtered off, washed with water, dried in vacuo and recrystallized from THF.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[N:10][OH:11])[CH2:2]1.[H-].[Na+].S(OC)(O[CH3:18])(=O)=O.O>CN(C)C=O>[CH3:18][O:11][N:10]=[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][CH2:2]1
Reactant: COS(=O)(=O)OC
Reactant: ON=C1COc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON=C1COc2ccccc21
Yield: 42 %

Procedure:
3.7 g of benzofuran-3-one oxime are dissolved in 15 ml of dimethylformamide. At 20° C., 1 g of sodium hydride (60%) is added and the mixture is stirred until the evolution of gas ceases. 3.15 g of dimethyl sulphate are then added dropwise and the mixture is stirred at 20° C. for 24 hours. The reaction mixture is poured into water, extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue is chromatographed over silica gel using n-hexane/acetone (4:1). 1.7 g (42% of theory) of benzofuran-3-one O-methyl-oxime are obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C@H:11]([C@@H:26]([OH:28])[CH3:27])[C:12]([NH:14][NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C@@H:11]([C:12]2[O:13][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)=[N:15][N:14]=2)[C@@H:26]([OH:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COc1cccc(C(=O)NNC(=O)[C@H](Nc2ccc(C#N)c(Cl)c2C)[C@H](C)O)c1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: COc1cccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)O)o2)c1
Temperature: 25 °C
Yield: 52.9 %

Procedure:
To a 100 mL round bottom flask was added N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-3-methoxybenzohydrazide (Intermediate 6a) (441 mg, 1.1 mmol) was added THF (90 mL) and stirred at room temperature. PS-BEMP (1.45 g, 3.2 mmol base) was added to the solution followed by slow addition of p-TSCl (208 mg, 1.1 mmol). The reaction mixture was stirred for 2 h and the progress of the reaction was monitored by TLC. After the completion of the reaction, the BEMP reagent was filtered off, washed with methanol (100 mL), and the resulting solution was concentrated to obtain the crude material. The crude material was chromatographed on silica gel with hexanes:EtOAc (2:8) to get the purified product (232 mg, 55%). 1H NMR(400 MHz, d6-acetone, δ in ppm) 7.42 (m, 1H), 7.33 (m, 3H), 7.01 (m, 1H), 6.50 (d, J=8.7 Hz, 1H), 5.37 (d, J=8.5 Hz, 1H), 4.72 (m, 1H), 4.62 (m, 1H), 3.94 (br s, 1H), 3.80 (s, 3H), 2.37 (s, 3H), 1.43 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].O[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C@:23]1([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]1)[CH:17]=[CH:16]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH2:1]([C@@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([C@:23]2([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]2)[CH:17]=[CH:16]3)[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CC[C@H](O)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Yield: 88.3 %

Procedure:
A mixture of trans-4-butyl-cyclohexanol (441 mg, 2.82 mmol), ((R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (572.5 mg, 2.353 mmol) and triphenylphosphine (741 mg, 2.82 mmol) in tetrahydrofuran (20 mL, 0.3 mol) was heated to reflux, and diisopropyl azodicarboxylate (0.556 mL, 2.82 mmol) was added dropwise. The reaction was stirred and refluxed for 3 hours. TLC and LCMS monitoring showed the reaction to be incomplete. The mixture was concentrated and taken up into dichloromethane and subjected to chromatography purification with EtOAc/hexane (10:90 to 80:20) to give product (0.793 g, 88% yield). LCMS 2.35 min (382.93, [M+1], 100%).
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:8]=[C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:26])[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[O:6][N:5]=1)[CH3:3].[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[CH:51][C:52]([C:53]([N:30]4[CH2:31][CH2:32][CH:27]([N:12]5[C:13](=[O:26])[C:14]6[S:18][C:17]([C:19]7[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=7)=[CH:16][C:15]=6[N:10]([CH2:9][C:7]6[O:6][N:5]=[C:4]([CH2:2][CH3:3])[N:8]=6)[C:11]5=[O:33])[CH2:28][CH2:29]4)=[O:54])=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4)cc32)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc(F)cc6)cc5n(Cc5nc(CC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-6-(4-fluorophenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (310 mg; compound B87) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (216 mg; compound C10) and HOBt (83 mg) and EDCI (104 mg) in DMF (10 ml) according to the procedure described in example 46 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: DCM/ethanol, 100/0/to 90/10 (v/v)] and by preparative HPLC as a solid.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([O:15][CH3:16])=[N:9][C:8]=1[CH3:17])C.O.[NH2:20]N>C(O)(=O)C>[CH2:13]([C:11]1[C:10]([O:15][CH3:16])=[N:9][C:8]([CH3:17])=[C:7]([C:6]2[N:5]=[CH:4][NH:2][N:20]=2)[CH:12]=1)[CH3:14]
Reactant: CCc1cc(C(=O)N=CN(C)C)c(C)nc1OC
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(-c2nc[nH]n2)c(C)nc1OC
Temperature: 90 °C
Reaction time: 3.75 h
Yield: 51.9 %

Procedure:
In a round bottom flask under a nitrogen atmosphere N-dimethylaminomethylene-5-ethyl-6-methoxy-2-methylnicotinamide (synthesized on 0.309 mmol scale) is treated with glacial acetic acid (1 mL) followed by hydrazine hydrate (16.5 μL, 0.340 mmol). The resulting mixture is stirred at 90° C. for 3.75 hr. The reaction mixture is evaporated, then partitioned between water and dichloromethane and the pH adjusted to 6-7 by treating with solid sodium bicarbonate. The aqueous layer is separated and then further extracted with five portions of dichloromethane. The combined extract is dried over magnesium sulfate, filtered and evaporated to give 3-ethyl-2-methoxy-6-methyl-5-(1H-1,2,4-triazol-3-yl)-pyridine (35 mg, 52% yield, 2 steps) as a white solid. MS: m/e=219 (M+H); 1H NMR (300 MHz, CDCl3, δ, ppm): 11.52 (1H, s), 8.18 (1H, s), 7.78 (1H, s), 3.98 (3H, s), 2.68 (3H, s), 2.57 (2H, q), 1.19 (3H, t).
Reaction SMILES: C1(C[O:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][C:15]2[N:23]=[CH:22][N:21]=[C:20]3[C:16]=2[N:17]=[CH:18][N:19]3[CH:24]2[C@H:28]([OH:29])[C@H:27]([OH:30])[C@@H:26]([CH2:31][Cl:32])[O:25]2)C=CC=CC=1>C(O)C.C1CCCCC1.[OH-].[Pd+2].[OH-]>[OH:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH:24]1[C@H:28]([OH:29])[C@H:27]([OH:30])[C@@H:26]([CH2:31][Cl:32])[O:25]1
Reactant: O[C@@H]1[C@@H](CCl)OC(n2cnc3c(N[C@@H]4CCC[C@H]4OCc4ccccc4)ncnc32)[C@@H]1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: CCO
Product: O[C@@H]1[C@@H](CCl)OC(n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@@H]1O
Reaction time: 6 h

Procedure:
The 2-(6-{[(1R,2R)-2-(phenylmethoxy)cyclopentyl]amino}purin-9-yl)(4S,5S,3R)-5-(chloromethyl)oxolane-3,4-diol obtained in Example 11 (22 g) was dissolved in ethanol (450 mL) and cyclohexane (200 mL). To this solution was added palladium hydroxide (20 mole %, 1 gram added initially, 1 gram after 6 hours, and 1 gram after 14 hours), and the reaction mixture was refluxed for 18 hours. The reaction mixture was filtered thru celite while still hot, and solvent removed from the filtrate under reduced pressure. The product was triturated with ethanol (20 mL), filtered, and washed with ethanol, to afford 2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]purin-9-yl}(4S,5S,3R)-5-(chloromethyl)oxolane-3,4-diol as a white powder).