Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH2:19][CH3:20])=[CH:16][CH:15]=[C:14](Cl)[C:13]=3[F:22])=[CH:6][C:5]=1[OH:23].[CH2:25]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[CH2:26][CH2:27][CH3:28].[F-].[Cs+].[Li+].[OH-]>O1CCOCC1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Pd]>[CH2:25]([C:29]1[CH:34]=[CH:33][C:32]([C:14]2[C:13]([F:22])=[C:12]3[C:17]([C:18]([CH2:19][CH3:20])=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:24])=[C:5]([OH:23])[CH:6]=4)[NH:11]3)=[CH:16][CH:15]=2)=[CH:31][CH:30]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCc1ccc(B(O)O)cc1
Reactant: CCc1c(-c2ccc(C(=O)OC)c(O)c2)[nH]c2c(F)c(Cl)ccc12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCCCc1ccc(-c2ccc3c(CC)c(-c4ccc(C(=O)O)c(O)c4)[nH]c3c2F)cc1
Temperature: 120 °C

Procedure:
Steps 8 and 9: To a mixture of 4-(6-chloro-3-ethyl-7-fluoro-1H-indol-2-yl)-2-hydroxy-benzoic acid methyl ester (50 mg, 0.14 mmol), 4-n-butyl-phenylboronic acid (50 mg, 0.28 mmol), and cesium fluoride (78 mg, 0.52 mmol) in dioxane (3 mL, anhydrous) is added palladium bis(tri-tert-butyl-phosphine) (6 mg, 10 mol %). This mixture is purged with N2 for 3 minutes and then heated in a sealed tube at 120° C. for 4 hours. The mixture is cooled to room temperature, filtered, and the filtrate is concentrated. The resulting residue is dissolved in ethanol/H2O (1 mL/0.1 mL) and transferred to a microwave tube. LiOH (12 mg, 0.54 mmol) is added and the mixture is heated at 120° C. for 6 minutes under microwave irradiation. The crude product mixture is filtered. After concentration of the filtrate, the crude product is purified by preparative RP LC-MS to give 4-[6-(4-butyl-phenyl)-3-ethyl-7-fluoro-1H-indol-2-yl]-2-hydroxy-benzoic acid as a yellow solid: 1H NMR (400 MHz, CD3OD) δ 7.96 (d, 1H, J=8.8 Hz), 7.50 (d, 2H, J=8 Hz), 7.42 (d, 1H, J=8.4 Hz), 7.24 (d, 2H, J=8 Hz), 7.21-7.20 (m, 2H), 7.10 (dd, 1H, J=8, 8 Hz), 2.95 (q, 2H, J=7.6 Hz), 2.66 (t, 2H, J=8 Hz), 1.65 (m, 2H), 1.40 (m, 2H), 1.34 (t, 3H, J=7.6 Hz), 0.97 (t, 3H, J=7.6 Hz); ESMS m/z 432.2 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1C(O)=O.C1C=CC(P([N:35]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(CC)CC.[OH-].[Na+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[NH2:35][C:3]1[C:2](=[O:1])[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=1
Reactant: O=C(O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
A mixture of 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylic acid (5.00 g, 17.6 mmol), DPPA (5.67 mL, 26.4 mmol) and Et3N (3.65 mL, 26.4 mmol) in toluene (35 mL) was heated to 100° C. for 2 h. To the mixture was added 8 M NaOH aqueous solution (22 mL) at 0° C. The mixture was stirred at room temperature for 2 h, diluted with brine, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was washed with EtOAc/i-Pr2O and filtered. The filtrate was concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/EtOAc=50/50 to 0/100) and washed with EtOAc/hexane to yield the title compound (2.50 g, 56% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.17 (1H, d, J=7.5 Hz), 6.52 (2H, brs), 7.67-7.81 (2H, m), 8.04 (1H, d, J=7.5 Hz), 8.10 (1H, s), 8.75 (1H, d, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:22]=[CH:21][C:16]([O:17][CH2:18][C:19]#[N:20])=[C:15]([CH:23]=O)[CH:14]=1.N1CCCC1>CO>[Cl:12][C:13]1[CH:22]=[CH:21][C:16]([O:17][CH2:18][C:19]#[N:20])=[C:15](/[CH:23]=[C:6]2\[C:7](=[O:11])[NH:8][C:9]3[C:5]\2=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH:14]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: N#CCOc1ccc(Cl)cc1C=O
Solvent: CO
Solvent: C1CCNC1
Product: N#CCOc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 22.4 %

Procedure:
To the mixture of 6-chlorooxindole (18.4 g, 0.110 mol) and (4-chloro-2-formyl-phenoxy)-acetonitrile (21.5 g, 0.110 mol) in methanol (200 mL) was added pyrrolidine (8.60 g, 0.121 mol) dropwise. Then the mixture was heated at 70° C. for 2 h. After cooled to room temperature, the mixture was filtered. The precipitate was collected and dried to give the title compound as a yellow solid (8.5 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.FC(F)(F)S(O[C:49]1[N:50]=[C:51]([CH2:68][CH2:69][C:70]([F:73])([F:72])[F:71])[N:52]([C:56]2[CH:61]=[CH:60][C:59]([O:62][CH2:63][C:64]([F:67])([F:66])[F:65])=[CH:58][CH:57]=2)[C:53](=[O:55])[CH:54]=1)(=O)=O.C1(C(C2C=CC=CC=2)=[NH:83])C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:83][C:49]1[N:50]=[C:51]([CH2:68][CH2:69][C:70]([F:72])([F:73])[F:71])[N:52]([C:56]2[CH:61]=[CH:60][C:59]([O:62][CH2:63][C:64]([F:65])([F:67])[F:66])=[CH:58][CH:57]=2)[C:53](=[O:55])[CH:54]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)nc(CCC(F)(F)F)n1-c1ccc(OCC(F)(F)F)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Nc1cc(=O)n(-c2ccc(OCC(F)(F)F)cc2)c(CCC(F)(F)F)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of tris(dibenzylideneacetone)dipalladium(0) (537 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (679 mg) in toluene (50 mL) were added 6-oxo-1-[4-(2,2,2-trifluoroethoxy)phenyl]-2-(3,3,3-trifluoropropyl)-1,6-dihydropyrimidin-4-yl trifluoromethanesulfonate (5.03 g), 1,1-diphenylmethanimine (1.97 mL) and cesium carbonate (7.97 g) at room temperature, and the mixture was stirred overnight at 100° C. The reaction mixture was concentrated under reduced pressure. To the residue was added THF, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure. To a solution of the obtained residue in THF (100 mL) was added 1N hydrochloric acid (100 mL) at 0° C., and the mixture was stirred for 2 hr. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to aminopropylsilane-bonded silica gel column chromatography (ethyl acetate/hexane) and then silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.64 g) as a solid.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH:16]([CH2:18][CH:19]=[O:20])[C:15](=[O:21])[C:14]([CH3:22])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:23])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>CC(O)C>[CH2:1]([C:5]12[CH2:17][CH:16]([CH2:18][CH2:19][OH:20])[C:15](=[O:21])[C:14]([CH3:22])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:23])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12Cc3cc(O)ccc3C1=C(C)C(=O)C(CC=O)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCCCC12Cc3cc(O)ccc3C1=C(C)C(=O)C(CCO)C2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of (2RS,9aSR)-9a-butyl-7-hydroxy-4-methyl-2-(2-oxo-ethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (17 mg, 0.05 mmol) in 2-propanol (2 mL) was treated with NaBH4 (1.9 mg, 0.05 mmol) and the mixture was stirred at room temperature for 40 minutes. The solvent was evaporated under vacuum. The residue was taken up in EtOAc (60 mL), washed with 0.2N HCl (30 mL), 5% NaHCO3, and brine, dried over MgSO4, filtered, and concentrated under vacuum to a gum (24 mg). This material was purified by PLC on a 0.1×20×20 cm silica gel GF plate using 2:1 hexanes-EtOAc as developing solvent. The UV visible band at Rf 0.06-0.11 afforded (2RS,9aSR)-9a-butyl-7-hydroxy-2-(2-hydroxyethyl)-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an oil.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3ccc(OC)cc3)nc2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (200 mg, 0.58 mmol, 1.00 equiv) in 1,4-dioxane (3 mL). To this was added 4-methoxyphenylboronic acid (133 mg, 0.88 mmol, 1.50 equiv). Addition of Pd2(dba)3 (32 mg, 0.03 mmol, 0.06 equiv) was next. This was followed by the addition of PCy3 (22 mg, 0.08 mmol, 0.14 equiv). To the mixture was added K3PO4 (330 mg, 1.56 mmol, 3.00 equiv). The resulting solution was allowed to react, with stifling, overnight while the temperature was maintained at 110° 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 (1:50). This resulted in 160 mg (74%) of methyl 3-(4-methoxyphenyl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([CH3:20])[CH:14]=2)[N:10]=[C:9]1[CH2:21]O)[CH3:7].[CH2:23]([N:25](CC)CC)C.[C-]#N.[K+]>O1CCCC1>[CH2:6]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([CH3:20])[CH:14]=2)[N:10]=[C:9]1[CH2:21][C:23]#[N:25])[CH3:7]
Reactant: CCn1cc(-c2ccc(F)c(C)c2)nc1CO
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Product: CCn1cc(-c2ccc(F)c(C)c2)nc1CC#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
870 μL methanesulfonyl chloride was added to 2.5 g (1-ethyl-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl)-methanol and 1.85 mL triethylamine in 50 mL tetrahydrofuran. The reaction was stirred 1 h at RT and 1.4 g potassium cyanide was added and stiffing was continued for 3 h. Then 1.4 g potassium cyanide and 500 mg dibenzo-18-crone-6 was added and the reaction was stirred over night at RT. The mixture was filtered and evaporated. Dichlormethane was added to the residue and extracted with aqueous potassium carbonate solution. The organic layer was dried and evaporated. The residue was purified by chromatographie on silica gel (cyclohexane/ethyl acetate 3:2) to yield 533 mg of the desired product. Rt: 1.29 min (method K), (M+H)+: 244
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH3:12])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>CO.[H][H].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH3:12])=[CH:25][CH:26]=1
Reactant: COc1ccc(CCN(C)CCOc2ccc([N+](=O)[O-])cc2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(CCN(C)CCOc2ccc(N)cc2)cc1OC

Procedure:
The 1-(4-nitrophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane prepared in (2) above in an amount of 5.5 g (0.015 mol) was dissolved in methanol (200 ml) and ethyl acetate (200 ml) and, thereafter, 10% Pd/C (2 g) was added to the resulting reaction solution and the reaction mixture was stirred in hydrogen gas for 8 h, followed by filtration and concentration under vacuum to yield the end compound 1-(4-aminophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane (5 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.[BH4-].[Na+].[F:10][C:11]1[CH:12]=[C:13]([CH:17](O)[C:18]2[CH:19]=[C:20]3[C:26]4([CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)[CH2:25][N:24]([C:39]4[C:40]5[C@H:47]([CH3:48])[CH2:46][CH2:45][C:41]=5[N:42]=[CH:43][N:44]=4)[C:21]3=[CH:22][CH:23]=2)[CH:14]=[CH:15][CH:16]=1.[OH-].[Na+].[ClH:52]>C(Cl)Cl.O.CCOCC>[ClH:52].[ClH:52].[F:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[CH2:17][C:18]1[CH:19]=[C:20]2[C:26]3([CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)[CH2:25][N:24]([C:39]3[C:40]4[C@H:47]([CH3:48])[CH2:46][CH2:45][C:41]=4[N:42]=[CH:43][N:44]=3)[C:21]2=[CH:22][CH:23]=1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(C(O)c5cccc(F)c5)ccc43)c21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4cc(Cc5cccc(F)c5)ccc43)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 6 %

Procedure:
A flask charged with TFA (0.294 ml, 3.82 mmol) was cooled to about 0° C. and treated with NaBH4 (0.0133 g, 0.353 mmol) in small portions. The mixture was stirred for 1 hour. A solution of tert-butyl 5-((3-fluorophenyl)(hydroxy)methyl)-1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.032 g, 0.0588 mmol) in DCM (0.18 mL) was added slowly over about 15 minutes. The mixture was allowed to warm to about room temperature and stirred overnight. An additional 3 equivalents of NaBH4 was added the reaction was stirred at about room temperature overnight. The reaction was diluted with water, basified with 2N NaOH, and extracted with EtOAc. The combined organics were washed with water, dried over MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography (4% 7 N ammonia in MeOH/DCM) to yield the free base, which was taken up in DCM and acidified with 2N HCl in Et2O. Removal of the solvents afforded ((R)-5-(3-fluorobenzyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]dihydrochloride (0.001 g, 6%). LCMS (APCI+) m/z 429.4 [M+H]+; Rt=3.15 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(O)(=O)C.C(O)(=O)C.[I:19]C1C=CC=CC=1.II>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCCl.C(O[Pd]OC(=O)C)(=O)C>[I:19][C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Ic1ccccc1
Reactant: Cc1cccc(C(=O)O)c1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: II
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(I)c(C(=O)O)c1
Temperature: 85 °C

Procedure:
3-Methylbenzoic acid (6.12 g; 45 mmol), iodobenzene diacetate (14.49 g; 45 mmol), tetrabutylammonium iodide (16.62 g, 45 mmol), iodine (11.43 g; 45 mmol) and diacetoxypalladium (0.5 g; 2.2 mmol) are dissolved in 1,2-dichloroethane, and then the mixture is heated in a sealed tube at 85° C. for 1 hour and 45 minutes. The cooled solution is purified by chromatography over silica gel using dichloromethane and methanol as eluants to yield the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:35][S:36]([N:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1)(=[O:38])=[O:37]>>[F:34][C:20]1[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:45][CH:42]3[CH2:43][CH2:44][N:39]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:40][CH2:41]3)[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[O:30][CH:31]=[CH:32][CH:33]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccco1
Product: CS(=O)(=O)N1CCC(Nc2nccc(-c3sc(N4CCOCC4)nc3-c3cccc(NS(=O)(=O)c4ccco4)c3F)n2)CC1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-furansulfonamide (91.2 mg, 0.175 mmol) and 1-(methylsulfonyl)-4-piperidinamine (249 mg, 1.398 mmol) the title compound was obtained as a yellow solid (55 mg, 48% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1H), 7.82-8.02 (m, 2H), 7.34 (td, J=7.3, 1.8 Hz, 1H), 7.17-7.29 (m, 2H), 6.95-7.15 (m, 2H), 6.54 (dd, J=3.2, 1.7 Hz, 1H), 5.71 (s, 2H), 3.67 (t, J=4.6 Hz, 4H), 3.36-3.55 (m, 6H), 2.64-2.95 (m, 5H), 1.86 (d, J=10.3 Hz, 2H), 1.48 (d, J=10.4 Hz 2H). MS (ESI): 664.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.O>ClCCCl>[CH3:1][C:2]1[CH:3]=[C:4]([C:5]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)=[O:7])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: Cc1cc(C(=O)N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Methyl-4-nitrobenzoic acid (5.525 mmol, 1.0 gram) was taken in a 25 mL two necked round bottom flask attached with a condenser, provided with a guard tube. To this, thionyl chloride (6.07 mmol, 0.735 gram) and 1,2-dichloroethane (5 mL) were added and the solution was refluxed for a period of 3 hours. This reaction mixture was added to another 100 mL flask, containing a solution of N-methylpiperazine (16.57 mmol, 1.66 grams) in 10 mL 1,2-dichloroethane, which is maintained at temperature below 5° C. The reaction mixture was then stirred for 0.5 hour at 25° C. After the completion of reaction, the reaction mixture was poured onto 50 mL water. 1,2-dichloroethane layer was separated, washed with water (2×10 mL), brine (10 mL) and dried over anhydrous sodium sulfate. The volatiles were removed under the reduced pressure to obtain thick syrupy mass. This thick syrupy mass was used for next step of reaction without purification.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:16][O:15][CH2:14][C@H:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12](=[O:25])[O:11][C@@H:10]([CH3:26])[C@@H:9]1[O:27]/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[CH2:1]([C@H:8]1[CH2:16][O:15][CH2:14][C@H:13]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C:12](=[O:25])[O:11][C@@H:10]([CH3:26])[C@@H:9]1[O:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/O[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Reaction time: 17 h
Yield: 96.7 %

Procedure:
To a solution of (E)-methyl 3-((3S,6S,7R,8S)-8-benzyl-3-(tert-butoxycarbonylamino)-6-methyl-4-oxo-1,5-dioxonan-7-yloxy)acrylate (168 mg, 0.362 mmol, 1.00 equiv) in EtOAc (3.6 mL, 0.1 M) was added 10% Pd/C (19 mg, 0.018 mmol, 0.050 equiv). The flask was equipped with a rubber septum and the atmosphere was replaced with H2 via needle-equipped balloon. After 17 h at room temperature, the catalyst was removed by filtration through Celite® and the pad was flushed with EtOAc. The filtrate was concentrated to provide methyl 3-((3S,6S,7R,8S)-8-benzyl-3-(tert-butoxycarbonylamino)-6-methyl-4-oxo-1,5-dioxonan-7-yloxy)propanoate (163 mg, 97%) as a clear, colorless film: IR (neat film) 3357, 3026, 2978, 2880, 1741, 1711, 1497, 1367, 1294, 1198, 1163, 1070, 1023, 911, 731 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.34-7.27 (m, 2H), 7.24-7.10 (m, 3H), 5.18-5.03 (d, J=8.3 Hz, 1H), 5.01-4.81 (dq, J=9.2, 6.4 Hz, 1H), 4.69-4.47 (q, J=7.3 Hz, 1H), 4.07-3.76 (m, 3H), 3.75-3.61 (s, 3H), 3.53-3.31 (m, 2H), 3.31-3.03 (m, 3H), 2.71-2.52 (t, J=6.2 Hz, 2H), 2.41-2.22 (t, J=12.6 Hz, 1H), 1.98-1.75 (s, 1H), 1.53-1.46 (d, J=6.4 Hz, 3H), 1.46-1.36 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.23, 171.73, 139.78, 129.15, 128.44, 126.14, 85.23, 80.11, 75.32, 72.86, 72.28, 67.67, 52.91, 51.82, 47.16, 35.24, 35.05, 28.26, 18.68; HRMS-ESI (m/z) [M+Na]+ calc'd for C24H35NO8Na, 488.2255. found, 488.2260.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.P([O:15][C@H:16]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]1[OH:18])(O)(O)=O>>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@:16]1([O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]1[OH:18])[OH:15]
Reactant: O=P(O)(O)O[C@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Clc1ncnc2nc[nH]c12
Product: OC[C@H]1O[C@](O)(n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O

Procedure:
One mL of a reaction solution consisting of 10 mM 6-chloropurine (Aldrich), 50 mM D-ribose-1-phosphate (22) prepared in Example 10, 0.1 mL of the ultrasonic enzyme homogenate from a purinenucleoside-phosphorylase producing strain prepared in Example 25 and 100 mM Tris-hydrochloride buffer (pH 7.5) was reacted at 50° C. for 20 hours. After completion of the reaction, HPLC analysis for the reaction solution under the conditions described below showed a peak of the title compound. A reaction inversion rate was calculated to be 62.4% after determining the concentration of 6-chloro-9-(β-D-ribofuranos-1-yl)purine in the post-reaction solution.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[N+:6]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])([O-:8])=[O:7].N1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:2][C:3]([NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[N+:6]([O-:8])=[O:7])=[O:4]
Reactant: O=C(Br)CBr
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CBr)Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91.9 %

Procedure:
2-Bromoacetyl bromide (173 μL, 1.99 mmol) was added dropwise to a solution of 2-nitroaniline (250 mg, 1.81 mmol) and pyridine (293 μL) in CH2Cl2 (9 mL). The reaction mixture was stirred at room temperature for 45 min. The mixture was then diluted with CH2Cl2 (10 mL), washed with aqueous 1 N HCl solution (10 mL), water (10 ml) and brine (10 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to yield the title compound (431 mg, 92% yield) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[C:7](=[O:15])[C:6]1=[O:16].[N+:21]([CH3:24])([O-:23])=[O:22]>O>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=1[Cl:1])[C:6](=[O:16])[C:7]2([OH:15])[CH2:24][N+:21]([O-:23])=[O:22]
Reactant: C[N+](=O)[O-]
Reactant: O=C1C(=O)N(Cc2ccccc2Cl)c2ccc(Cl)cc21
Solvent: O
Product: O=C1N(Cc2ccccc2Cl)c2ccc(Cl)cc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 18 h

Procedure:
1-(2-chlorobenzyl)-5-chloroindoline-2,3-dione (0.153 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 18 hours. The formed solid product was filtered and recrystallized with MeOH to afford pure product.