Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.C(NC(C1CCC(O)C1O)=O)C.Cl[C:28]1[CH:33]=[CH:32][NH:31][C:30](=[O:34])[C:29]=1[N+:35]([O-:37])=[O:36].[Cl:38][C:39]1[CH:43]=[CH:42][S:41][C:40]=1[CH2:44][C@@H:45]([CH2:47][CH3:48])[NH2:46]>>[Cl:38][C:39]1[CH:43]=[CH:42][S:41][C:40]=1[CH2:44][C@H:45]([NH:46][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([OH:34])[C:29]=1[N+:35]([O-:37])=[O:36])[CH2:47][CH3:48]
Reactant: CC[C@@H](N)Cc1sccc1Cl
Reactant: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Agent: CCNC(=O)C1CCC(O)C1O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC[C@H](Cc1sccc1Cl)Nc1ccnc(O)c1[N+](=O)[O-]

Procedure:
A method for preparing the dihydrochloride salt of [1S-[1a,2b,3b,4a(S*)]]-4-[7-[[1-(3-chloro-2-thienyl) methyl]propyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide comprising the steps of reacting 4-chloro-3-nitropyridin-2(1H)-one with (R)-3-chloro-α-ethyl-2-thiopheneethanamine to form (R)-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-2-hydroxy-3-nitro-4-pyridinamine, followed by replacing the hydroxy moiety of (R)-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-2-hydroxy-3-nitro-4-pyridinamine with a chloro group to form (R)-2-chloro-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-3-nitro-4-pyridinamine, followed by reacting (R)-2-chloro-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-3-nitro-4-pyridinamine wit 2R,3S-isopropylidenedioxy-4R-amino-1S-ethylaminocarbonylcyclopentane to form [3aR-[3aa,4a,6a(R*),6aa]]-6-[[4-[[1-[(3-chloro-2-thienyl)methyl]propyl]amino]-3-nitro-2-pyridinyl]amino, followed by reducing [3aR-[3aa,4a,6a(R*),6aa]]-6-[[4-[[1-[(1-chloro-2-thienyl)methyl]propyl]amino]-3-nitro-2-pyridinyl]amino to [3aR-[3aa,4a,6a(R*),6aa]]-6-[[3-amino-4-[[1-[(3-chloro-2-thienyl)methyl]propyl]amino]-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide, followed by hydrolyzing [3aR-[3aa,4a,6a(R*),6aa]]-6-[[3-amino-4-[[1-[(3-chloro-2-thienyl)methyl]propyl]amino]-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide, in the presence of hydrochloric acid, said steps being effected in a concatenated manner, without a necessity for interim isolation and purification of intermediate compounds [3aR-[3aa,4a,6a(R*),6aa]]-6-[[3-amino-4-[[1-[(3-chloro-2-thienyl)methyl]propyl]amino]-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide, [3aR-[3aa,4a,6a(R*)6aa]]-6-[[4-[[1-[(3-chloro-2-thienyl)methyl]propyl]amino]-3-nitro-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide,(R)-2-chloro-N-[1-[(3-chloro-2-thienyl) methyl]propyl]-3-nitro-4-pyridinamine or (R)-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-2-hydroxy-3-nitro-4-pyridinamine.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH2:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1.Cl.NC(N)=O>C(OCCCC)(=O)C.O>[Br:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:11][C:20](=[O:21])[N:19]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)[C:7]2=[O:9]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: NC(N)=O
Solvent: CCCCOC(C)=O
Solvent: O
Product: O=c1[nH]c2ccc(Br)cc2c(=O)n1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
21.6 g of 5-bromoanthranilic acid and 15.4 g of 4-chlorophenyl isocyanate were reacted in a similar procedure as described in Example 1 in 200 ml of butyl acetate at 100° C. and with a further stirring time of 4 hours. 18 g of hydrogen chloride gas were then introduced into the suspension of the urea formed in the course of 30 minutes and the mixture was then further stirred at 100° C. for 3 hours. For the work-up of the reaction mixture, sufficient butyl acetate was first distilled off at atmospheric pressure until a thick suspension had resulted, then 200 ml of water were added and the product precipitated out was filtered off. After drying, 31.5 g (90% of theory) of 6-bromo-3-(4-chlorophenyl)-quinazoline-2,4-dione were obtained having a melting point of 212-214° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][SiH:3]([O:6][CH3:7])[O:4][CH3:5].[CH2:8]([Cl:11])[CH:9]=[CH2:10]>>[Cl:11][CH2:8][CH2:9][CH2:10][Si:3]([O:6][CH3:7])([O:4][CH3:5])[O:2][CH3:1]
Reactant: C=CCCl
Reactant: CO[SiH](OC)OC
Product: CO[Si](CCCCl)(OC)OC
Yield: 73.6 %

Procedure:
The same researchers also report the results of directly hydrosilating allyl chloride with trimethoxysilane in the presence of several ruthenium complexes. A maximum yield of 73.6% of chloropropyltrimethoxysilane is reported in Table 2 for the reaction between trimethoxysilane and allyl chloride at a 4/l molar ratio. Assuming the use of the "typical reaction procedure," the process may have employed a ruthenium carbonyl catalyst in an amount to provide at least about 155 parts per million by weight of ruthenium metal in the reaction mixture. Apparently, the reaction also was conducted in a sealed reactor under autogenous pressure in the presence of at least 13.3% by weight of toluene solvent for 16 hours at 80° C. The conversion of limiting allyl chloride was complete, and thus the yields of by-products such as propyltrimethoxysilane, tetramethoxysilane and hydrogen, were not insignificant. The same reaction, at a 2/1 molar ratio of trimethoxysilane to allyl chloride, in the presence of the same absolute weights of ruthenium catalyst and toluene solvent, provided a 72.2% yield of chloropropyltrimethoxysilane on a molar basis, with similar by-product yields at complete conversion of limiting allyl chloride. At a 1/1 molar ratio, the conversion of allyl chloride was not complete. At this mole ratio, a maximum yield of only 52.4% was obtained after 16 hours at 50° C., while at 80° C. the yield was only 26.4%. (Table 2).
Reaction SMILES: O[C:2]1([CH2:13][CH2:14][CH2:15][OH:16])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.CC([O-])(C)C.[K+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C1COCC1>[C:9]([O:8][C:6]([N:4]1[CH2:3][C:2]2([O:16][CH2:15][CH2:14][CH2:13]2)[CH2:5]1)=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC(O)(CCCO)C1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2(CCCO2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 3-hydroxy-3-(3-hydroxypropyl)azetidine-1-carboxylate (27 mg, 0.13 mmol) in THF (2 ml) was added in rapid succession, KOtBu (31 mg, 0.27 mmol) and p-toluenesulfonylchloride (25 mg, 0.13 mmol) and the solution stirred at room temperature for 90 mins. Water (10 ml) was added and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to give an oil. The oil was used crude in the next step.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2)[CH3:6])=[O:4].C(N(CC)CC)C.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([O:47][CH3:48])=[O:46])=[CH:41][CH:40]=1)=[O:37]>O1CCCC1>[Cl:27][C:8]1[C:7]([N:5]([C:3](=[O:4])[CH2:2][NH:1][C:36]([O:38][C:39]2[CH:40]=[CH:41][C:42]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:44]=2)=[O:37])[CH3:6])=[CH:25][CH:24]=[C:23]([Cl:26])[C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1
Reaction time: 1 h
Yield: 27.8 %

Procedure:
To a suspension of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (100 mg) in tetrahydrofuran were added triethylamine (18.8 mg) and 4-methoxycarbonylphenyl chloroformate (39.8 mg) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 1 hour at the same temperature. The solvent was removed, and ethyl acetate and water were added to the residue. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by preparative thin-layer chromatography (ethyl acetate:n-hexane=2:1, V/V) to give 8-[2,6-dichloro-3-[N-[(4-methoxycarbonylphenoxycarbonyl)glycyl]-N-methylamino]benzyloxy]-2-methylquinoline (30 mg) as an amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:4]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17](Cl)(=[O:19])=[O:18])=[CH:9][CH:8]=1)=[O:5].[N:29]([CH:32]([CH3:34])C)=[C:30]=[O:31]>C(N(CC)CC)C>[C:30]([N:29]1[CH2:32][CH2:34][CH:4]([NH:6][S:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=[CH:24][C:2]=3[F:1])=[CH:8][CH:9]=2)(=[O:19])=[O:18])[CH2:3][CH2:2]1)(=[O:31])[CH2:8][CH2:7][CH3:16]
Reactant: CC(C)N=C=O
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1c(F)cccc1C(F)(F)F
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3c(F)cccc3C(F)(F)F)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general procedure in Scheme 5, beginning with 4-(2-fluoro-6-trifluoromethyl-benzoylamino)-naphthalene-1-sulfonyl chloride and substituting butyric chloride and triethylamine for 2-isocyanato-propane. 1H NMR (300 MHz, DMSO) δ 11.12 (s, 1H), 8.71 (m, 1H), 8.26 (m, 2H), 8.13 (m, 1H), 7.98 (d, 1H), 7.79 (m, 6H), 4.01 (d, 1H), 3.60 (d, 1H), 2.93 (t, 1H), 2.59 (m, 2H), 2.15 (t, 2H), 1.45 (m, 2H), 1.43 (q, 2H), 1.17 (m, 2H), 0.81 (t, 3H). LC/MS m/z 514 (M−H)−, 516 (M+H)+
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=C/N(C)C.O.CC[O:18]C(C)=O>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]=[O:18]
Reactant: CN(C)/C=C/c1nc2ccccc2o1
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1nc2ccccc2o1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To (E)-2-(benzo[d]oxazol-2-yl)-N,N-dimethylethenamine (1 g, 5.32 mmol) in THF (15 mL) at 0° C. was added water (15 mL) and NaIO4 (3.4 g, 16 mmol). The resulting mixture was stirred at 0° C. for 10 min, then at room temperature for 2 h. To the solution was added H2O and EtOAc and then the mixture was filtered. The clear solution was extracted with EtOAc and the organic phase was washed with aqueous NaHCO3 solution. The organic phase was concentrated and the residue was purified by column chromatography to give the title compound (120 mg). MS (ESI) m/z 148 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=[C:7]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:6]=2.Cl.N1C=C[CH:37]=[CH:36][CH:35]=1.C(OC)(OC)(OC)CC>C1(C)C=CC=CC=1>[CH2:26]([O:25][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:35]([CH2:36][CH3:37])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reactant: c1ccncc1
Agent: CCC(OC)(OC)OC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 206.3 %

Procedure:
tert-Butyl [4-(3-amino-7-benzyloxyquinolin-4-ylamino)butyl]carbamate (20.7 g, 43.6 mmol) was dissolved in toluene (225 mL). Pyridine hydrochloride (2.03 g) and trimethyl orthopropionate (6.2 mL, 43.6 mmol) were added, and the mixture was heated at reflux for 3.25 hours. The reaction was allowed to cool to room temperature; a fine precipitate formed. The precipitate was isolated by filtration and washed with toluene. The off-white solid was allowed to dry for 2 hours under vacuum. The filtrate was evaporated, and the residue was dissolved in dichloromethane. The resulting solution was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a brown amorphous solid. The solids were combined to provide 17.2 g of tert-butyl [4-(7-benzyloxy-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:18]([N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[C:17]([CH3:33])=[C:16]([Cl:34])[CH:15]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:34][C:16]1[CH:15]=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:18]([N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[C:17]=1[CH3:33]
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1N1CCOC1=O
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c1N1CCOC1=O
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (6.3 mg, 0.032 mmol), 3-[6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl]-1,3-oxazolidin-2-one (10 mg, 0.03 mmol), and N,N-diisopropylethylamine (0.010 mL, 0.057 mmol) in isopropyl alcohol (0.1 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min, to give the desired. LCMS calculated for C23H21ClFN6O2 (M+H)+: m/z=467.1. found: 467.1.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([C:4](=O)[CH2:5][CH2:6][C:7](=O)[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:3].[CH:15]1[CH2:19][CH:18]=[CH:17][CH:16]=1.C[O-].[Na+]>CO>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[C:15]2[C:16]=1[CH:17]=[CH:18][CH2:19]2)([CH3:14])([CH3:3])[CH3:1]
Reactant: C1=CCC=C1
Reactant: CC(C)(C)C(=O)CCC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(C(C)(C)C)c2c1C=CC2
Temperature: 25 °C
Reaction time: 30 h
Yield: 10.3 %

Procedure:
A mixture of 14.8 g (74.6 mmol) of 2,2,7,7-tetramethyl-3,6-octanedione and 6.7 ml (82.1 mmol) of cyclopentadiene was added to 34.3 ml of a 30 percent strength solution of sodium methanolate (186 mmol) in methanol at 0° C. in the course of 10 minutes. After the mixture had been stirred at room temperature for 30 hours, it was hydrolyzed and extracted with methylene chloride. After drying over MgSO4, the product was evaporated to dryness. Column chromatography on silica gel with hexane as the mobile phase gave 1.75 g (10 %) of the indene 10. For the NMR data, see Table 1.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].O>CN(C=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCn1ccc([N+](=O)[O-])n1
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
A solution of 3-nitropyrazole (22.6 g.) in dry DMF (25 ml.) was added dropwise over 30 minutes to a suspension of sodium hydride (5.28 g.) in dry DMF (50 ml.) at 0°. The mixture was stirred for 30 minutes, ethyl 3-bromopropionate (36.8 g.) was added over 10 minutes, the mixture was kept at -15° for 17 hours and then allowed to warm to 20°. Water (550 ml.) was added, the solution was extracted with EtOAc (4×100 ml.) and the combined extracts were dried (MgSO4) and evaporated in vacuo to an oil. Fractionation on a silica medium pressure liquid chromatography column eluted with EtOAc/petrol (b.p.60°-80°) 1:1 v/v gave ethyl 3-(3-nitropyrazol-1-yl)propionate (19.2 g.) as a low melting solid. The n.m.r. spectrum in CDCl3 included the following resonances: 7 6 (d, 1H); 6.85 (d, 1H); 4.5 (t, 2H); 4.1 (q, 2H); 2.95 (t, 2H); 1.2 (t, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([C:27]([CH3:31])([CH3:30])[C:28]#[N:29])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-:33].[K+].[K+].OO.O>CS(C)=O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([C:27]([CH3:31])([CH3:30])[C:28]([NH2:29])=[O:33])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(C)(C)C#N)C3)ccc1-2
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(C)(C)C(N)=O)C3)ccc1-2
Temperature: 45 °C
Yield: 49.7 %

Procedure:
A solution of 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionitrile (0.26 g, 0.6 mmol) in DMSO (5 mL) was treated with potassium carbonate (16 mg, 0.12 mmol) followed by hydrogen peroxide (30% aq., 0.33 mL) and the mixture was heated at 45° C. for 18 hours then at 50° C. for a few more hours. Further hydrogen peroxide (33 mL, 30% aq.) was added and the mixture heated at 50° C. for 18 hours. After cooling, water was added and the mixture was extracted with EtOAc (×5). The combined organic extracts were dried (Na2SO4), and concentrated in vacuo and the residue purified by flash chromatography (SiO2, first time with 0-10% MeOH in EtOAc then second time with 0-5% MeOH in DCM). Further purification was by reverse-phase preparative HPLC (Gemini C18 column, gradient 30-40% MeOH in H2O+0.1% HCO2H). A solution of the product in a mixture of chloroform and DCM was treated with 0.2M HCl in ether (0.32 mL) and then concentrated in vacuo to give 446 (27 mg, 9%). LCMS: RT=7.41 min, [M+H]+=453. 1H NMR δ (ppm) (DMSO-d6): 10.79 (1 H, s), 8.34-8.28 (1 H, m), 8.06 (1 H, s), 7.82 (1 H, d, J=17.45 Hz), 7.65 (1 H, d, J=4.94 Hz), 7.27-7.16 (1 H, m), 7.07 (1 H, d, J=1.80 Hz), 5.80-5.72 (1 H, m), 4.47 (1 H, td, J=10.76, 4.67 Hz), 4.37-4.26 (3 H, m), 4.20-3.94 (3 H, m), 3.41 (2 H, q, J=4.96 Hz), 1.55-1.45 (12 H, m)
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O-:13])(=[O:12])[CH2:10][CH3:11].[K+]>C(O)(=O)CC.[Mn+3]>[CH3:11][CH:10]1[CH2:1][CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:13][C:9]1=[O:12]
Reactant: C=Cc1ccccc1
Reactant: CCC(=O)[O-]
Agent: [Mn+3]
Agent: [K+]
Solvent: CCC(=O)O
Product: CC1CC(c2ccccc2)OC1=O
Yield: 50 %

Procedure:
Styrene in an amount of 2.1 grams and 11.65 grams of manganic acetate, Mn(C2H3O2)3.2H2O, comprising two equivalents of Mn+3 based on titration value, were refluxed under nitrogen in 200 milliliters of propionic acid containing 20 grams of potassium propionate. In less than an hour, a 50% yield of alpha-methyl-gamma-phenyl butyrolactone was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([O:15][C:16](=[O:19])[NH:17][NH2:18])([CH3:14])([CH3:13])[CH3:12].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:11]([O:15][C:16]([NH:17][NH:18][CH2:7][C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:10])=[O:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)NN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NNCc1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-chloro-2-hydroxybenzaldehyde (1.5 g 9.3 mmol), tert-butylcarbazate (1.25 g, 9.3 mmol) and acetic acid (0.54 mL, 9.3 mmol) in CH2Cl2 (50 mL) was stirred under a nitrogen atmosphere for 30 min at RT. Then sodium triacetoxyborohydride (6.20 g, 27.9 mmol) was added portion wise and the resulting mixture was stirred at RT overnight. The reaction was thoroughly quenched with 2 M HCl (15 mL) and stirred at RT for 1 h. The reaction mixture was partitioned between water (50 mL) and CH2Cl2 (25 mL). The aqueous layer was extracted with CH2Cl2 (25 mL). The combined organic layers were washed with water (2×75 mL), dried (Na2SO4) and evaporated to dryness to give hydrazine 1 as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C@H:20]1[O:41][C@@H:21]1[C@@H:22]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].FC(F)(F)C(O)=O>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C@@H:20]([OH:41])[CH2:21][C@@H:22]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1O[C@@H]1[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 58.1 %

Procedure:
A mixture of 39.2 g (71.2 mmol) of (2S,3R,4R,5S)-2,5-bis-(N-(((benzyl)oxy)carbonyl)amino)-3,4-epoxy-1,6-diphenylhexane in 600 ml of THF was treated under N2 atmosphere with 13 g (0.36 mol) of sodium borohydride. The resulting mixture was treated dropwise with 27.7 ml (0.36 mol) of trifluoroacetic acid. After being stirred for 3.5 h at ambient temperature, the resulting mixture was quenched with 1 N aqueous HCl, diluted with water, and stirred for 16 h. The resulting mixture was filtered, washed with water, and dried to provide 22.85 g (58%) of the desired compound as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][C:6]=1[N+:28]([O-:30])=[O:29])C.[OH-].[K+].Cl>C(O)C.O>[Cl:27][C:22]1[CH:21]=[C:20]([C:14]2([C:16]([F:18])([F:17])[F:19])[O:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:31])=[O:3])=[C:6]([N+:28]([O-:30])=[O:29])[CH:7]=3)[CH2:15]2)[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 118.1 %

Procedure:
In a solution of 0.36 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-nitrobenzoic acid ethyl ester in 8 ml of ethanol, a solution of 0.40 g of potassium hydroxide in 2 ml of water was added, and stirred at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was poured in 15 ml of water, adjusted to pH 4 with concentrated hydrochloric acid, then extracted with ethyl acetate (20 ml×2), the organic phase was washed with water, and then dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain 0.40 g of crude 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-nitro benzoic acid as pale yellow oily substance. The substance was dissolved in 10 ml of chloroform, and 0.24 g of 2-picolylamine, 0.01 g of 4-(N,N-dimethylamino)pyridine and 0.35 g of 1-[3-(diethylamino)propyl]-3-ethylcarbodiimide hydrochloride were added, and stirred at room temperature for 18 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure. The residue was subjected to purification with medium-pressure preparative liquid chromatography (Yamazen Corporation, medium pressure preparative system; YFLC-Wprep) that was eluted with ethyl acetate-hexane (1:1 to 1:0 gradient), and 0.14 g of the aimed product was obtained as colorless resinous substance.