Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C(C)=C(C)[SiH](C)[SiH-](C)(C)C=1.[Na+].C(OP([CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])(OCC)=O)C.C(=O)=O.C(#N)C.[CH2:39]([CH:41]1[CH:67]=[C:66]([CH3:68])[CH2:65][CH:64]([CH3:69])[CH2:63][CH:62]([O:70][CH3:71])[CH:61]2[O:72][C:57]([OH:76])([CH:58]([CH3:75])[CH2:59][CH:60]2[O:73][CH3:74])[C:56](=[O:77])[C:55](=[O:78])[N:54]2[CH:49]([CH2:50][CH2:51][CH2:52][CH2:53]2)[C:48](=[O:79])[O:47][CH:46]([C:80]([CH3:91])=[CH:81][CH:82]2[CH2:87][CH2:86][C:85](=O)[CH:84]([O:89][CH3:90])[CH2:83]2)[CH:45]([CH3:92])[CH:44]([O:93][Si:94]([C:97]([CH3:100])([CH3:99])[CH3:98])([CH3:96])[CH3:95])[CH2:43][C:42]1=[O:101])[CH3:40]>C1COCC1>[CH2:39]([CH:41]1[CH:67]=[C:66]([CH3:68])[CH2:65][CH:64]([CH3:69])[CH2:63][CH:62]([O:70][CH3:71])[CH:61]2[O:72][C:57]([OH:76])([CH:58]([CH3:75])[CH2:59][CH:60]2[O:73][CH3:74])[C:56](=[O:77])[C:55](=[O:78])[N:54]2[CH:49]([CH2:50][CH2:51][CH2:52][CH2:53]2)[C:48](=[O:79])[O:47][CH:46]([C:80]([CH3:91])=[CH:81][CH:82]2[CH2:87][CH2:86][C:85](=[CH:22][C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])[CH:84]([O:89][CH3:90])[CH2:83]2)[CH:45]([CH3:92])[CH:44]([O:93][Si:94]([C:97]([CH3:98])([CH3:99])[CH3:100])([CH3:96])[CH3:95])[CH2:43][C:42]1=[O:101])[CH3:40]
Reactant: CCOP(=O)(CC(=O)OCc1ccccc1)OCC
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: CC1=C[SiH-](C)(C)[SiH](C)C(C)=C1C
Agent: O=C=O
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=CC(=O)OCc4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
A solution of 20 mL of a 1.0 M solution of sodium hexamethyldisilamide in THF was cooled to 0° C. in an ice bath under nitrogen. Then a solution of 5.85 g (20 mmole) of benzyl diethylphosphonoacetate in 10 mL of dry THF was added and the solution was stirred at 0° C. under nitrogen. After 15 min., the solution was cooled to -40° C. (dry ice-acetonitrile bath) under nitrogen, and 4.5 g (5 mmole) of 17-ethyl-1-hydroxy-12-[2'-(4"-oxo-3"-methoxycyclohexyl)-1'-methylvinyl]-14-t-butyl-dimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (Example 9) in 10 mL of dry tetrahydrofuran was added dropwise over 5 minutes and the solution was stirred at -40° C. under nitrogen. After 3 hr, the reaction was quenched by addition of 2 mL of glacial acetic acid in 10 mL of dry THF. Et2O was added and the mixture was partitioned between Et2O and water and the aqueous layer was washed with Et2O. The organic extracts were sequentially washed with saturated KHCO3 solution and brine, then the combined extract was dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The oily residue was purified by flash chromatography (silica gel, 6 cm×20 cm) using ethyl acetate-hexane to afford 3.28 g (63%) of the title compound as a colorless foam; NMR (CDCl3) indicated about a 9:1 mixture of E::Z olefin isomers; MS (FAB) 1042 (M+Li).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[N:20]4[N:21]=[C:22]([NH2:24])[N:23]=[C:19]4[C:18]4[CH:17]=[CH:16][C:15](F)=[CH:14][C:13]=4[N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[N:20]4[N:21]=[C:22]([NH2:24])[N:23]=[C:19]4[C:18]4[CH:17]=[CH:16][C:15]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[CH:14][C:13]=4[N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: C1COCCN1
Reactant: Nc1nc2c3ccc(F)cc3nc(Cc3ccc4c(c3)OCO4)n2n1
Product: Nc1nc2c3ccc(N4CCOCC4)cc3nc(Cc3ccc4c(c3)OCO4)n2n1
Temperature: 140 °C
Yield: 50 %

Procedure:
To 5-benzo[1,3]dioxol-5-ylmethyl-8-fluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine (0.05 g, 0.15 mmol), prepared as described in Example 21, morpholine (1 mL) was added and the mixture was heated at 140° C. for 2 h. The reaction was cooled at room temperature, the solid precipitated was filtered and washed with a mixture MeOH/H2O 9:1, to provide the title compound (0.03 g, 50% yield).
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11]3=[N:18][NH:19][N:20]=[C:10]3[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:21]([O-])([O-:23])=[O:22].[K+].[OH-].[NH4+]>S(=O)(=O)(O)O>[N+:21]([C:5]1[CH:6]=[C:1]([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11]3=[N:18][NH:19][N:20]=[C:10]3[CH2:9][N:8]=2)[CH:2]=[CH:3][CH:4]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])[O-]
Reactant: c1ccc(C2=NCc3n[nH]nc3-c3ccccc32)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: O=[N+]([O-])c1cccc(C2=NCc3n[nH]nc3-c3ccccc32)c1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
A mixture of 1.6 g (4.5 mmole) of the methanesulfonate salt of 6-phenyl-2H,4H-[1,2,3]triazolo[4,5-d][2]benzazepine, 8.6 g of potassium nitrate, and 20 ml of sulfuric acid was stirred at 0° C. for 3.5 hr. The mixture was poured over ice, basified with ammonium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried with anhydrous sodium sulfate and concentrated at reduced pressure. The residue was triturated with ether to give tan crystals (mp 223°-225° C.). Recrystallization from methylene chloride gave cream colored prisms, mp 224°-225° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:16][C@@H:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=2)[CH2:18][N:19]2[C:20](=[O:29])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a 50 mL round-bottomed flask was added 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (226 mg, 0.93 mmol) [prepared according to the procedure of Example 95], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (519 mg, 1.349 mmol) [prepared according to Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (515 mg, 1.1 mmol) in chloroform (10 mL). DIEA (820 μL, 4.70 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (379 mg, 69%): LC-MS (ES) m/z=573 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:22][CH2:21][C:20]3[N:19]4[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]4)=[C:13]([F:23])[C:12]=3[C:11]2=[O:24])[N:5]=[CH:4][CH:3]=1.[CH3:25][N:26]1[C:30]([CH3:31])=[CH:29][C:28]([NH:32][C:33]2[C:34](=[O:49])[N:35]([CH3:48])[CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=2)=[N:27]1.C([O-])([O-])=O.[Cs+].[Cs+].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].O>[CH3:25][N:26]1[C:30]([CH3:31])=[CH:29][C:28]([NH:32][C:33]2[C:34](=[O:49])[N:35]([CH3:48])[CH:36]=[C:37]([C:2]3[CH:3]=[CH:4][N:5]=[C:6]([N:10]4[CH2:22][CH2:21][C:20]5[N:19]6[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]6)=[C:13]([F:23])[C:12]=5[C:11]4=[O:24])[C:7]=3[CH:8]=[O:9])[CH:38]=2)=[N:27]1
Reactant: O=Cc1c(Cl)ccnc1N1CCc2c(c(F)c3n2CCCC3)C1=O
Reactant: Cc1cc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nn1C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(-c3ccnc(N4CCc5c(c(F)c6n5CCCC6)C4=O)c3C=O)cn(C)c2=O)nn1C
Temperature: 110 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 4-chloro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)nicotinaldehyde 134c (97 mg, 0.28 mmol), 3-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]-1-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one 218a (192.6 mg, 0.56 mmol), Pd2(dba)3 (54.9 mg, 0.060 mmol), tri(cyclohexyl)phsphine (50.2 mg, 0.18 mmol), Cs2CO3 (182.6 mg, 0.56 mmol), dioxane (8 mL), and water (0.25 mL). After three cycles of vacuum/argon flush, the mixture was stirred at 110° C. for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 35:1 ethyl acetate/methanol to afford 261a (90 mg, 61%) as a black solid. MS-ESI: [M+H]+ 530.2
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[P:24]([O-:28])([OH:27])([OH:26])=[O:25].[K+].P([O-])([O-])(O)=O.[K+].[K+].NC1C=CC(C(O)=O)=CC=1.P([O-])([O-])([O-])=O.[Na+:52].[Na+].[Na+].Cl.[CH3:56][NH:57][CH:58]([CH3:67])[C:59]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:60].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[P:24]([O-:28])([O-:27])([O-:26])=[O:25].[Na+:52].[Na+:52].[Na+:52].[CH3:67][C@H:58]([NH:57][CH3:56])[C@@H:59]([OH:60])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: CNC(C)C(=O)c1ccccc1
Reactant: O=P([O-])(O)O
Agent: Cl
Agent: Nc1ccc(C(=O)O)cc1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CN[C@@H](C)[C@@H](O)c1ccccc1
Temperature: 30 °C
Reaction time: 48 h

Procedure:
Rhodococcus erythropolis MAK-34 strain was planted in 5 ml of a medium at pH 7.0 containing 1.0% of saccharose, 0.5% of corn steep liquor, 0.1% of potassium dihydrogenphosphate, 0.3% of dipotassium hydrogenphosphate, 0.01% of p-aminobenzoic acid, and 0.1% of various kinds of inducers, and was shaking-cultured at 30° C. for 48 hours. The culture medium was centrifuged, so as to yield the cells, which were then put into a test tube, and were suspended with 1.0 ml of 0.2-M sodium phosphate buffer solution (pH 7.0) added thereto. With 10 mg of dl-2-methylaminopropiophenone hydrochloride and 20 mg of glucose added thereto, the suspension was shaken at 30° C. for 16 hours, so as to effect a reaction. After the reaction was completed, the reaction mixture was centrifuged, so as to remove the cells, whereas the supernatant was subjected to HPLC (μBondapakphenyl, manufactured by Waters Corporation, with a diameter of 4 mm, a length of 300 mm, an eluent of 0.05 M sodium phosphate buffer solution (containing 7% of acetonitrile, at pH 6.5), a flow rate of 0.8 mL/min, and a detection wavelength of 220 nm), whereby an optically active pseudoephedrine was obtained. The amount of production thereof was remarkably greater than that in the case with no inducer addition as shown in Table 7.
Reaction SMILES: [N:1]1([C:6]2[CH:30]=[CH:29][CH:28]=[CH:27][C:7]=2[C:8]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:16][C:17]2[CH:22]=[N:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)=[O:9])[CH:5]=[CH:4]C=[N:2]1.Cl.FC(F)(F)C1[N:35]=CC(N[C@H]2CCC[C@@H]2N)=NC=1.N1(C2C=CC=CC=2C(O)=O)C=CN=N1>>[N:1]1([C:6]2[CH:30]=[CH:29][CH:28]=[CH:27][C:7]=2[C:8]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:16][C:17]2[CH:22]=[N:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][N:18]=2)=[O:9])[CH:5]=[CH:4][N:35]=[N:2]1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1-n1cccn1
Agent: Cl
Agent: O=C(O)c1ccccc1-n1ccnn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1-n1ccnn1

Procedure:
Prepared according to the procedure for 2-(1H-pyrazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 31) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 213 mg, 0.75 mmol) and 2-(1H-1,2,3-triazol-1-yl)benzoic acid (CAS number 1085458-53-2; 157 mg, 0.83 mmol) except this was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[N+](=[CH2:16])=[N-]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:16][C@@H:9]2[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: COC(=O)/C=C/c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H]1c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of compound 66c (1.50 g, 6.22 mmol) and Pd(OAc)2 (90 mg, 0.40 mmol) in DCM (20 mL) was added an ethereal solution of compound 66b (200 mL). After stirring for 10 min at 0° C., the reaction mixture was concentrated under reduced pressure to yield a residue, which was subjected to flash column chromatography on silica gel (10% EtOAc/petroleum ether) to afford compound 66d as colorless oil. Mass Spectrum (GCMS, ESI pos.): Calcd. for C11H11BrO2: 254.0 (M). found: 254.0.
Reaction SMILES: Cl.[NH2:2][OH:3].O=[C:5]([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=2)[N:33]=[CH:32][C:31]=1[F:42])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:10][CH:9]1[CH2:25][C:26]([O:28][CH3:29])=[O:27]>N1C=CC=CC=1>[OH:3][N:2]=[C:5]([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=2)[N:33]=[CH:32][C:31]=1[F:42])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:10][CH:9]1[CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)CC1CN(CCSc2cc(F)ccc2F)CCC1CCC(=O)c1c(F)cnc2ccc(OC)cc12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)CC1CN(CCSc2cc(F)ccc2F)CCC1CCC(=NO)c1c(F)cnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 20 h
Yield: 79.2 %

Procedure:
0.347 g of hydroxylamine hydrochloride were added, in several portions, to a mixture of 1 g of methyl (3RS,4RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl)-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate in 10-cm3 of pyridine, with stirring and under an inert atmosphere, and the resulting mixture was stirred in the region of 20° C. for 24 hours and then for 20 hours in the region of 50° C. and for 1.25 hours in the region of 62° C. After cooling in the region of 20° C., the reaction mixture was concentrated to dryness under reduced pressure (1.5 kPa) at a temperature in the region of 50° C. The evaporation residue was taken up in 70-cm3 of ethyl acetate and 40-cm3 of distilled water. The organic phase was separated after settling out, washed 3 times with 40-cm3 of distilled water and 40-cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The evaporation residue was purified by chromatrography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a successive mixture of cyclohexane-ethyl acetate (60/40 by volume) and then dichloromethane-methanol (90/10 by volume) and collecting 10-cm3 fractions. Fractions 1 to 21 were combined and then concentrated to dryness according to the conditions described above. 0.813 g of methyl (3RS,4RS)-4-[3-hydroxyimino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate were obtained in the form of a whitish viscous oil.
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:17][CH2:16][CH2:15]1)[C:5](=[O:14])[NH:6]2.[H-].[Na+].[CH3:20]I.[Cl-].[NH4+]>CN(C=O)C>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:17][CH2:16][CH2:15]1)[C:5](=[O:14])[N:6]2[CH3:20]
Reactant: O=C1Nc2ccc([N+](=O)[O-])c(F)c2C12CCC2
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN1C(=O)C2(CCC2)c2c1ccc([N+](=O)[O-])c2F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4′-fluoro-5′-nitrospiro[cyclobutane-1,3′-indol]-2′ (1′H)-one (300 mg) and sodium hydride (36.6 mg) in DMF (10 mL) was added methyl iodide (0.395 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr under a nitrogen atmosphere. To the reaction mixture was added saturated aqueous ammonium chloride solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (282 mg).
Reaction SMILES: N1([O:10][C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:38]=3[N:39]=[CH:40][N:41]=2)[C@@H:16]2[O:37][C@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:17]2)C2C=CC=CC=2N=N1.C([O-])([O-])=O.[Cs+].[Cs+].[C:48]1(O)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C1(C)C=CC=CC=1>[Si:30]([O:29][C@@H:28]1[C@@H:27]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[O:37][C@@H:16]([N:15]2[C:38]3[N:39]=[CH:40][N:41]=[C:11]([O:10][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:12]=3[N:13]=[CH:14]2)[CH2:17]1)([C:33]([CH3:35])([CH3:36])[CH3:34])([CH3:32])[CH3:31]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(Oc4ccccc4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 105 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
In a clean, dry reaction vial equipped with a stirring bar were placed O6-(benzotriazol-1-yl)-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (63.2 mg, 0.106 mmol), Cs2CO3 (68.9 mg, 0.211 mmol) and phenol (19.9 mg, 0.211 mmol). Dry toluene (1.0 mL) was added and the reaction mixture was flushed with N2 and the mixture was allowed to stir at 105° C. for 2 h. The reaction mixture was filtered through Celite, the residue washed with Et2O and the filtrate evaporated to dryness. Chromatographic purification (SiO2, elution with 20% EtOAc in hexanes) afforded 50.5 mg (86% yield) of the title compound as a clear gum. Rf (20% EtOAc in hexanes)=0.21. 1H NMR (500 MHz, CDCl3): δ 8.49 (s, 1H, Ar—H), 8.40 (s, 1H, Ar—H), 7.45 (app t, 2H, Ar—H, Japp˜7.8), 7.29-7.26 (m, 3H, Ar—H), 6.53 (t, 1H, H-1′, J=6.3), 4.64 (m, 1H, H-3′), 4.04 (q, 1H, H-4′, J=3.4), 3.90 (dd, 1H, H-5′, J=11.2, 3.9), 3.70 (dd, 1H, H-5′, J=11.2, 2.7), 2.65 (app quint, 1H, H-2′, Japp˜6.3), 2.48 (ddd, 1H, H-2′, J=13.2, 6.1, 4.1), 0.92, 0.91 (2 s, 18H, tert-Bu), 0.10 (s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 160.2, 152.5, 152.4, 152.0, 141.6, 129.6, 125.7, 122.1, 121.9, 88.0, 84.6, 71.8, 62.7, 41.5, 26.0, 25.7, 18.4, 18.0, −4.7, −4.8, −5.4, −5.5. FAB HRMS calcd for C28H45N4O4Si2 (M++H) 557.2979. found 557.2978.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH:15]=[N:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+]>CO>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH2:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(OCCCN(C)C)c(C=NCCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(OCCCN(C)C)c(CNCCc2ccccc2)c1
Yield: 74.7 %

Procedure:
N-[[2-[3-(Dimethylamino)propoxy]-5-methoxyphenyl]-methylene]benzeneethanamine (39.5 g) is reduced with 13.0 g of sodium borohydride in 200 ml of methanol following the procedure described in Example 1C yielding 29.7 g of the title compound, boiling point 205°-210° C. at 0.4-0.5 mm of Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8](=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:21])[C:9](O)=[O:10].[Cl:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>>[Cl:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C:9](=[O:10])[C:8]([C:3]1[NH:4][C:5]([CH3:7])=[CH:6][C:2]=1[CH3:1])=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:21]
Reactant: Cc1cc(C)c(C(C(=O)O)=C2C(=O)Nc3ccccc32)[nH]1
Reactant: Nc1ccccc1Cl
Product: Cc1cc(C)c(C(C(=O)Nc2ccccc2Cl)=C2C(=O)Nc3ccccc32)[nH]1
Yield: 22.4 %

Procedure:
(3,5-Dimethyl-1H-pyrrol-2-yl)-(2-oxo-1,2-dihydro-indol-3-ylidene)-acetic acid (90 mg) was reacted with 2-chloroaniline (80 mg) using method B to give 28 mg (22%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.Br[CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18].[I-].[Na+].C(N(CC)CC)C.[OH-].[Na+].Cl>O.CS(C)=O>[CH3:18][C:17]([CH3:19])=[CH:16][CH2:15][C:11]1[C:10](=[O:12])[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3](=[O:13])[C:2]=1[OH:1]
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: CC(C)=CCBr
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)=CCC1=C(O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a dried 2,000 ml round bottomed flask was added 2-hydroxy-1,4-napthoquinone (69.7 g, 0.40 mol), 1-bromo-3-methyl-2-butene (66 g, 0.44 mol), sodium iodide (60 g, 0.4 mol), triethylamine (58.55 ml, 0.42 mol) and dimethylsulfoxide (DMSO), 500 ml. The mixture was stirred vigorously at room temperature under Argon atmosphere for 1 hour, then heated with a heating mantle to 45° C. After 3-6 hours, at 45° C. with vigorous stirring, the mixture was cooled down in an ice bath, and 800 ml of water was added to stop the reaction. The mixture is then transferred into a 2,000 ml separatory funnel and extracted three times with methylene chloride (500 ml, 300 ml and 200 ml). The organic phases were pooled and washed successively with water (800 ml), 5% aqueous sodium bicarbonate (2×800 ml)* and 1% aqueous sodium chloride (800 ml), then dried with sodium sulfate (50 g). After filtration, the filtrate was evaporated to dryness by Rotovap. The residue was dissolved in toluene (1,000 ml) with heating in a 50° C. water bath, and any insoluble material existing was filtered off. The warm toluene solution was extracted three times with freshly prepared, warm 2N sodium hydroxide (800 ml, 300 ml and 200 ml). The aqueous phases were pooled and neutralized by addition of hydrochloric acid (220 ml) with vigorous manual stirring, then extracted three times with toluene (500 ml, 300 ml and 300 ml). The organic phase were pooled and any black solid existing in the organic phases was removed by filtration. The combined organic phase was washed successively with 1% aqueous sodium chloride (800 ml), 5% aqueous sodium bicarbonate (500 ml) and 1% aqueous sodium chloride (800 ml), and then dried with sodium sulfate (50 g). After filtration, the filtrate was evaporated to dryness by Rotovap, then isopropanol (300 ml) was added for co-evaporation to completely remove residual toluene. The residue was dissolved in isopropanol (300 ml) with heating in an 80° C. water bath and then was cooled to 4° C. slowly. Pure lapachol was obtained after filtering, washing with cold isopropanol (4° C., 50-100 ml) and drying under vacuum.