Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@:4]1([OH:19])[C@H:9]([OH:10])[C@@H:8]([CH2:11][OH:12])[O:7][C:6](C(=O)C)=[C:5]1C(=O)C)(=O)C.[N-:20]=[N+:21]=[N-:22].[Na+].[CH3:24][C:25]([O-:27])=[O:26].[Na+]>CC#N.CC(O)=O>[N:20]([C@@H:5]1[C@@H:4]([OH:19])[C@H:9]([OH:10])[C@@H:8]([CH2:11][OH:12])[O:7][CH:6]1[O:26][CH2:25][CH3:24])=[N+:21]=[N-:22].[N:20]([C@@H:5]1[C@@H:4]([O:19][C:6](=[O:7])[CH3:5])[C@H:9]([O:10][C:9](=[O:10])[CH3:4])[C@@H:8]([CH2:11][O:12][C:11](=[O:12])[CH3:8])[O:7][CH:6]1[O:26][C:25](=[O:27])[CH3:24])=[N+:21]=[N-:22]
Reactant: CC(=O)C1=C(C(C)=O)[C@](O)(C(C)=O)[C@H](O)[C@@H](CO)O1
Reactant: CC(=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CCOC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N=[N+]=[N-]

Procedure:
The acceptor, ethyl 2-azido-2-deoxy-D-glucopyranoside was prepared as follows: Triacetyl-D-glucal was azidonitrated [Lemieux et al., Can. J. Chem., 57:1244 (1979)][NaN3 and Ce(NH4)2(NO3)6 in CH3CN] and acetolyzed (NaOAc in AcOH) to give 2-azido-1,3,4,6-tetra-O-acetyl-2-deoxy-D-glucopyranose, which was treated with TiBr4 in CH2Cl2 and EtOAc, giving a glycosyl bromide, then glycosylated with EtOH in the presence of AgOTf and MS 4 Å in CH2Cl2 to give after O-deacetylation with NaOMe in MeOH, ethyl 2-azido-2-deoxy-D-glucopyranoside (22 percent overall yield) as a mixture of α and β 1:1.5. 1H NMR (D2O) δ: 1.21 (t, J 7.80 Hz, OCH2CH3 of β anomer), 1.22 (t, J 7.80 Hz, OCH2CH3), 2.99 (dd, J 7.43, 9.83 Hz, H-2 of β anomer), 5.11 (d, J 3.58 Hz, H-1 of a anomer). HRMS calcd for C8H15N3O5Cs (M+Cs+) 366.0066, found 366.0066.
Reaction SMILES: Cl[C:2]1[C:3]([S:9][CH:10]([CH3:12])[CH3:11])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C-:13]#[N:14].[K+]>O.O.[Ni](Cl)Cl.[Mn].CN(C)C=O>[NH2:5][C:4]1[C:3]([S:9][CH:10]([CH3:12])[CH3:11])=[C:2]([CH:8]=[CH:7][CH:6]=1)[C:13]#[N:14]
Reactant: [C-]#N
Reactant: CC(C)Sc1c(N)cccc1Cl
Agent: Cl[Ni]Cl
Agent: [Mn]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Sc1c(N)cccc1C#N
Temperature: 50 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
6 liters of dimethylformamide are added to 50 g of nickel chloride dihydrate, 200 g of BPPFA (1,1'-bisdiphenylphosphine-1-(dimethylaminoethyl)ferrocene) and 49 g of manganese powder, and the mixture is stirred at 50° C. for 2 hours under an inert atmosphere. A brown suspension forms. 1,200 g of 3-chloro-2-isopropylthioaniline and 430 g of KCN are added to the suspension and the mixture is stirred for 16 hours at 50° C. After working up, white crystals of m.p. 82° C. are obtained in a yield of approximately 90%.
Reaction SMILES: C([O:4][C@H:5]([CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]3[CH2:20][CH2:21][N:22]([CH2:23][O:24][CH2:25][CH3:26])[C:15]3=[N:14][C:13]=2[N:12]([CH3:27])[C:11]1=[O:28])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:25]([O:24][CH2:23][N:22]1[C:15]2=[N:14][C:13]3[N:12]([CH3:27])[C:11](=[O:28])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:29])[C:18](=[O:19])[C:17]=3[N:16]2[CH2:20][CH2:21]1)[CH3:26]
Reactant: CCOCN1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOCN1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)O)c(=O)n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
A mixture of (R)-3-(5-acetoxyhexyl)-7,8-dihydro-8-ethoxymethyl-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (100 mg, 0.245 mmol) and potassium carbonate (51 mg, 0.368 mmol) in methanol (12 ml) was stirred at room temperature for 16 hours. After concentration under reduced pressure, the residue was treated with 1.0 M aqueous ammonium chloride solution (10 ml) and stirred for 1 hour. The solid was filtered, washed with water, and dried under vacuum to provide (R)-7,8-dihydro-8-ethoxymethyl-3-(5-hydroxyhexyl)-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (60 mg, 67% yield) as a white powder.
Reaction SMILES: [NH2:1][C:2]12[CH2:13][C:6]3([CH3:14])[CH2:7][C:8]([CH2:11][OH:12])([CH2:10][C:4]([CH3:15])([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH2:16]([O:23][C:24](ON1C(=O)CCC1=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([O:23][C:24]([NH:1][C:2]12[CH2:13][C:6]3([CH3:14])[CH2:7][C:8]([CH2:11][OH:12])([CH2:10][C:4]([CH3:15])([CH2:5]3)[CH2:3]1)[CH2:9]2)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC12CC3(C)CC(N)(C1)CC(CO)(C2)C3
Solvent: C1CCOC1
Product: CC12CC3(C)CC(CO)(C1)CC(NC(=O)OCc1ccccc1)(C2)C3
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of 1-amino-3,5-dimethyl-7-hydroxymethyl adamantane (60 mg) in THF (3 mL) was added N-(benzyloxycarbonyloxy)-succinimide (74 mg) and the mixture was stirred at room temperature overnight. THF was removed and the residue was dissolved in ethyl acetate. The solution was washed with water and brine. The product was purified by thin layer chromatography eluting with ethyl acetate and hexane (1:4, v/v) to give a white solid (80 mg). 1H NMR (DMSO-d6, ppm): 7.33 (m, 5 H, C6H5), 6.89 (brs, 1 H, NH), 4.94 (s, 2 H, OCH2), 4.32 (t, 1 H, OH, J=5.7 Hz), 3.04 (d, 2 H, CH2OH, J=5.7 Hz), 1.46 (dd, 6 H), 1.04 (dd, 6 H), 0.84 (s, 6 H, 2×CH3).
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(CC)CC)C>C1C=CC=CC=1.CN(C)C=O>[CH3:18][O:17][N:16]([CH3:15])[C:5]([CH:3]1[CH2:4][CH:2]1[CH3:1])=[O:7]
Reactant: CC1CC1C(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CC1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methylcyclopropanecarboxylic acid (10 g in a mixture of 200 mL benzene and 2 mL N,N-dimethylformamide) at 0° C. was added 10.5 mL of oxalyl chloride and the mixture stirred at 0° C. for 30 minutes then warmed to room temperature for 30 minutes. At this time, 14.6 g of N,O-dimethylhydroxylamine hydrochloride was added followed by 41 mL of triethylamine. The mixture was stirred at room temperature for one hour then quenched by the addition of saturated sodium bicarbonate. The aqueous portion was extracted with ethyl acetate and the combined organics washed with brine, dried over sodium sulfate and concentrated in vacuo. The product was purified by distillation under reduced pressure to give 8.9 g as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[N:9]([O-])=O.[Na+].[Sn](Cl)Cl>Cl.O>[NH:1]([C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1)[NH2:9]
Reactant: Nc1cccc(O)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc(O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.5 %

Procedure:
To a stirred, ice cooled solution of 3-aminophenol (2.00 g, 18.3 mmol) in concentrated HCl (20 mL) was added dropwise a solution of sodium nitrite (1.33 g, 19.24 mmol) in H2O (10 mL), ensuring the internal temperature did not exceed 10° C. After 10 min, a solution of tin (II) chloride (7.645 g, 40.3 mmol) in concentrated HCl (10 mL) was added dropwise, and the ice bath removed. After stirring at RT for 45 min, the reaction was basified to pH 10 with careful addition of 10 M NaOH solution (50 mL), and then extracted with EtOAc (3×). The organic extracts were dried over MgSO4, concentrated in vacuo and triturated with Et2O to afford the title compound as a brown solid (353 mg, 16%). 1H NMR (300 MHz, d6-DMSO): 3.83 (2H, br s), 5.96-6.02 (1H, m), 6.15-6.21 (1H, m), 6.22 (1H, t, J=2.2 Hz), 6.52 (1H, br s), 6.84 (1H, t, J=8.0 Hz), 8.91 (1H, br s).
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C1(=O)OC(=O)C=C1>CC(C)=O.CO>[C:6]([OH:8])(=[O:7])[C:5]1[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: O=C1C=CC(=O)O1
Solvent: CO
Solvent: CC(C)=O
Product: O=C(O)c1ccccc1
Yield: 163.4 %

Procedure:
Solution "A" was prepared by dissolving 42.6 grams of para-aminobenzoic acid in 300 ml acetone plus 50 ml of methyl alcohol. Solution "B" was prepared by dissolving 36.6 g of maleic anhydride in 100 ml acetone. Solution "B" was added to solution "A" in one shot at room temperature with stirring. The mixture was allowed to stir for one to two hours until a yellow precipitate was formed. The precipitate was then washed with fresh acetone and dried to yield approximately 62 grams of maleamidated benzoic acid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)=[CH:6][CH:5]=1.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)=[O:20].N1C=CC=CC=1.Cl>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:16][C:2]([F:1])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[CH:13][N:12]([C:25]3[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=3)[C:19]([O:18][CH3:17])=[O:20])[N:11]=2)=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1ccc(-c2cc[nH]n2)cc1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-n2ccc(-c3ccc(OC(F)(F)F)cc3)n2)c1
Temperature: 60 °C

Procedure:
A solution of 3-(4-trifluoromethoxy-phenyl)-1H-pyrazole (250 mg), 3-methoxycarbonylphenylboronic acid (540 mg) and pyridine (0.18 mL) in dimethylformamide (5 mL) is treated with copper (II) acetate (214 mg) and powdered activated 4 Å molecular sieves (0.5 g). The resulting mixture is heated to 60° C. for 16 h and cooled. The reaction mixture is poured into 1M aq. HCl (300 mL), and the resulting mixture is filtered through a glass microfiber filter pad. The pad is washed with ethyl acetate, and the filtrate is evaporated to afford the product, methyl 3-[3-(4-trifluoromethoxy-phenyl)-pyrazol-1-yl]-benzoate, as a solid (204 mg).
Reaction SMILES: [CH3:1][C:2]([O-:5])([CH3:4])[CH3:3].[Na+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=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]>[OH:5][C:2]1([C:4]2[CH:16]=[CH:17][C:18]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:13][CH:19]=2)[CH2:3][CH2:3][C:2](=[O:5])[CH2:1][CH2:1]1
Reactant: CC(C)(C)[O-]
Reactant: C1COCCN1
Reactant: Cc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na+]
Product: O=C1CCC(O)(c2ccc(N3CCOCC3)cc2)CC1

Procedure:
To an oven-dried flask was charged with Pd2(dba)3 (4.6 mg, 0.005 mmol), (o-biphenyl)P(t-Bu)2 (6.0 mg, 0.02 mmol, 2 mol %), and NaOt-Bu (135 mg, 1.4 mmol). The flask was evacuated and backfilled with nitrogen and then capped with a rubber septum. Toluene (0.5 mL), the aryl iodide (360 mg, 1.0 mmol), morpholine (102 mg, 1.2 mmol), and additional toluene (0.5 mL) were added. The mixture was stirred at room temperature until the starting aryl iodide had been completely consumed as judged by TLC analysis. The mixture was diluted with ether (20 mL), filtered through Celite, and concentrated in vacuo. The crude residue was dissolve in THF (1 mL) and was treated with 5% HCl (9 mL) at rt for 14 h. The mixture was neutralized with 1 N NaOH to pH 7, concentrated on rotovap, and then extracted with EtOAc (2×50 mL). The organic extracts were combined, washed with saline solution (2×50 mL), dried over sodium sulfate, concentrated in vacuo. The resulting residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (100/0 to 0/100), to provide the desired compound (100 mg, 36% for the two steps). LCMS: 276.2 (M+H+, 100%). 1H NMR: (CDCl3) δ 7.42 (d, 2H), 6.88 (d, 2H), 3.99-3.94 (m, 4H), 3.86-3.84 (m, 4H), 3.16-3.13 (m, 4H).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([OH:16])(=[O:15])[C:12]([CH3:14])=[O:13].[OH-].[K+:18]>CO>[O:13]=[C:12]([CH:14]=[CH:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:11]([O-:16])=[O:15].[K+:18]
Reactant: O=C/C=C/c1ccccc1
Reactant: CC(=O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C(=O)C=CC=Cc1ccccc1
Temperature: 2.5 °C
Yield: 61 %

Procedure:
A solution of trans-cinnamaldehyde (26.43 g) and pyruvic acid (11.9 mL) in 10 mL of methanol was stirred and chilled to 0-5° C. in an ice bath. To the chilled solution was added 35 mL of potassium hydroxide (16.83 g in 50 mL of methanol) over a period of 20 minutes. The remaining methanolic potassium hydroxide was added rapidly and the ice bath was removed. The solution changed from a yellow to a dark orange and the precipitate was formed. The reaction mixture was chilled in the refrigerator overnight and the solid was collected by filtration, washed with 50 mL of methanol three times, 50 mL of ether and then air dried to afford 29.3 g of the desired 2-oxo-6-phenyl-3,5-hexadienoate as a yellow solid (61.0%). 1H NMR (DMSO-d6/D2O, 300 MHz), δ(ppm) 7.48 (d, 2H), 7.28 (m, 4H), 7.12 (d, 2H), 6.27 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[CH2:22][CH:21](O)[C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[S:18]3(=[O:29])=[O:28])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[CH:22]=[CH:21][C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[S:18]3(=[O:28])=[O:29])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)c2ccccc2C(O)CC1CCCN1CCN(c2ccc(F)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=S1(=O)c2ccccc2C=CC1CCCN1CCN(c2ccc(F)cc2)CC1
Yield: 59.9 %

Procedure:
A suspension of 41.9 mg (0.1 mmol) of the Compound 23 in 10 ml of 3 N hydrochloric acid aqueous solution was refluxed for 24 hours. The reaction mixture was cooled with ice, adjusted to pH 10 with a 5 N aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by silica gel column chromatography (eluent:methanol:chloroform=1:99) to obtain 24 mg (yield: 60%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[C:19](#[N:21])[CH3:20]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:21]1[CH2:4][CH2:3][C:2](=[CH2:7])[CH2:20][CH2:19]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC#N
Product: C=C1CCN([C@H](C)[C@](O)(Cn2cncn2)c2ccc(F)cc2F)CC1
Temperature: 100 °C

Procedure:
21.26 g (119.4 mmol) of the 4-methylenepiperidine hydrobromide (4-MP.HBr) obtained in Production 1 and 2.859 g (119.4 mmol) of lithium hydroxide were added to 80 mL of acetonitrile and stirred for a while. Thereafter, 20 g (79.6 mmol) of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane was added and the mixture was heated under reflux in an oil bath (external temperature: 100° C.) for 14 hours. After the reaction completed, ethanol and distilled water were added to the reaction mixture, whereupon a crystal was precipitated. Thereafter, the crystal was filtered off, washed with 40 mL of an ethanol/water mixture, dried with air at room temperature and further dried under reduced pressure at 40° C. for 12 hours to give a pale yellow crystal of KP-103 in an amount of 24.2 g (yield, 87.3%; purity on HPLC, 95.3%).
Reaction SMILES: [S:1]([O:5][C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8])([OH:4])(=[O:3])=O.[CH:13]1([NH2:17])[CH2:16][CH2:15][CH2:14]1>C(Cl)Cl.CN(C=O)C>[OH:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[O:5][S:1](=[O:3])(=[O:4])[NH:17][CH:13]1[CH2:16][CH2:15][CH2:14]1
Reactant: O=S(=O)(O)Oc1ccccc1O
Reactant: NC1CCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=S(=O)(NC1CCC1)Oc1ccccc1O
Reaction time: 3 h

Procedure:
Cyclobutyl-sulfamic acid 2-hydroxy-phenyl ester was prepared by adding a solution of catechol sulphate (1.32 g, 7.7 mmol) in DCM (2 ml) to a stirred solution of cyclobutylamine (600 μl, 7.0 mmol) and TEA (1.07 ml, 7.7 mmol) in DMF at 0° C., and stirring for 3 hours at this temperature. The mixture was quenched with 1M HCl (50 ml) and extracted with diethyl ether. The organic extract was washed with water, brine, dried and concentrated to dryness. Quantitative yield.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:31]=[CH:30][C:29](OC(F)(F)F)=[CH:28][CH:27]=1.[OH2:38].[NH2:39][NH2:40].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:20][C:19]([F:22])([F:21])[O:38][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][C:24]2[C:3]3[C:4](=[O:23])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:40][N:39]=2)=[CH:31][CH:30]=1
Reactant: NN
Reactant: O
Reactant: O=C(Cc1ccc(OC(F)(F)F)cc1)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccc(OC(F)(F)F)cc3)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a suspension of 4-hydroxy-1-(3-trifluoromethoxyphenyl)-3-(4-trifluoromethoxyphenylacetyl)-1,8-naphthyridin-2(1H)-one (524 mg, 1.0 mmol) produced in Synthesis Example 25 in DMF (5 mL) was added hydrazine monohydrate (purity of 80%, 194 μL), and the mixture was stirred at 100 to 110° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 3-(4-trifluoromethoxybenzyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one (301 mg, yield 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][CH:8]([C:12](=O)[CH3:13])[C:9](=O)[CH3:10])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19].O>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][C:8]2[C:12]([CH3:13])=[N:18][NH:19][C:9]=2[CH3:10])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(=O)C(SCc1ccc(Cl)cc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c(C)c1SCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.6 %

Procedure:
To a solution of crude 3-(4-chloro-benzylsulfanyl)-pentane-2,4-dione [prepared as described above from 3-chloro-pentan-2,3-dione (1.03 g, 7.63 mmol) and 4-chlorobenzyl mercaptan (1.21 g, 7.63 mmol)] in ethanol (60 mL) was added hydrazine hydrate (0.713 mL, 22.9 mmol) and p-toluenesulfonic acid monohydrate (ca. 25 mg). The solution was heated to reflux and stirred for 15 hours. The reaction mixture was allowed to cool to room temperature, and water (300 mL) was added. The precipitate that formed was removed by filtration, washed with water, and dried to provide 1.38 g (72%) of the product as a white solid: 1H NMR (CDCl3) δ 7.17 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 3.57 (s, 2H), and 2.02 (s, 6H) ppm. 13C NMR (CDCl3) δ 137.2, 132.7, 130.3, 128.3, 105.2, 39.9, 10.7 ppm.
Reaction SMILES: C([NH:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH2:12][CH2:13][C:14]([C:16]2[S:17][C:18]([CH2:27][CH3:28])=[C:19]3[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][C:20]=23)=[O:15])=[CH:7][C:6]=1[CH3:29])C=C.C[N+]1([O-])CC[O:34]CC1.[CH3:38][C:39]([CH3:41])=[O:40]>O.O=[Os](=O)(=O)=O.C(O)(C)(C)C>[NH3:4].[OH:40][CH:39]([CH2:41][OH:34])[CH2:38][NH:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH2:12][CH2:13][C:14]([C:16]2[S:17][C:18]([CH2:27][CH3:28])=[C:19]3[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][C:20]=23)=[O:15])=[CH:7][C:6]=1[CH3:29]
Reactant: C=CCNc1c(C)cc(CCC(=O)c2sc(CC)c3c2CCC(C)(C)C3)cc1C
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC(C)(C)O
Product: CCc1sc(C(=O)CCc2cc(C)c(NCC(O)CO)c(C)c2)c2c1CC(C)(C)CC2
Product: N
Temperature: 25 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
To a solution of 3-(4-allylamino-3,5-dimethyl-phenyl)-1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (80 mg, 0.195 mmol) and NMO (69 mg, 0.507 mmol) in acetone (11.5 mL) and water (1.65 mL), a 2.5 M solution of OsO4 in tert.butanol (88 μL, 7 μmol) is added. The mixture is stirred at rt for 18 h and then separated by prep. HPLC (Waters Symmetry C18 19×50 mm 5 μm, 10-95% acetonitrile in water containing 0.5% of 25% aq. NH3) to afford 3-[4-(2,3-dihydroxy-propylamino)-3,5-dimethyl-phenyl]-1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (52 mg) as a pyle yellow solid; LC-MS: tR=0.90 min, [M+1]+=444.41; 1H NMR (CDCl3): δ 6.98 (s, 2H), 3.92-3.84 (m, 1H), 3.80 (dd, J=3.5, 11.1 Hz, 1H), 3.72 (dd, J=4.7, 11.1 Hz, 1H), 3.14-2.88 (m, 7H), 2.72 (q, J=7.6 Hz, 2H), 2.30 (s, 2H), 2.29 (s, 6H), 1.54 (t, J=6.4 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H), 0.96 (s, 6H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])[CH3:2].S(Cl)([Cl:14])=O>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:14])=[O:7])[CH3:2]
Reactant: CCc1cccc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1cccc(C(=O)Cl)c1

Procedure:
3-ethylbenzoic acid (9.40 g, 62.6 mmol) was added slowly to thionyl chloride (45 mL), and N,N-dimethylformamide (3 drops) was added dropwise. The resulting reaction mixture was heated under reflux for 2 hours under the same condition. The reaction mixture was concentrated, and used in the subsequent reaction without further purification.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH3:22][S:23]([O:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](COS(C)(=O)=O)C1
Temperature: 0 °C
Yield: 100.4 %

Procedure:
A mixture of (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (21.5 g, 107 mmol) and triethylamine (30 mL, 214 mmol) in dichloromethane (250 mL) was cooled to 0° C. Methanesulfonyl chloride (12.5 mL, 160.5 mmol) was added dropwise via an addition funnel and the resulting mixture was stirred at 0° C. then gradually warmed to room temperature over 3 h. A 10% aqueous citric acid solution was added and the two layers were separated. The organic layer was washed with 10% aqueous citric acid, sat'd aqueous NaHCO3, and brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed on a rotary evaporator to afford 30 g of (R)-tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate as an orange oil that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 4.17 (m, 2H), 3.33 (m, 2H), 3.20 (m, 1H), 3.18 (s, 3H), 3.00 (m, 1H), 2.55 (m, 1H), 2.01 (m, 1H), 1.53 (m, 1H), 1.40 (s, 9H).