Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[C:2](/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3]\[CH2:4][S:5][C:6]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=1.[CH3:21][C:22]1[C:23]([CH2:31]Cl)=[N:24][CH:25]=[C:26]([CH3:30])[C:27]=1[O:28][CH3:29]>CN(C)C=O.C(Cl)Cl>[CH3:21][C:22]1[C:23]([CH2:31][N:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=[C:6]2[S:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[N:24][CH:25]=[C:26]([CH3:30])[C:27]=1[O:28][CH3:29]
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: CC(C)=CCC/C(C)=C/CSc1nc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C)cnc(Cn2c(SC/C=C(\C)CCC=C(C)C)nc3ccccc32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 126.3 %

Procedure:
To a solution of 2-[(3,7-dimethyl-2,6(E)-octadienyl)thio]-1H-1,3-benzimidazole from Example 1 (1.5 g, 5.2 mmol) and 3,5-dimethyl-4-methoxy-2-pyridylmethyl chloride (0.465 g, 5 2 mmol) in dimethylformamide (7 mL) at 0° C. under nitrogen was added dropwise triton-B (5 mL of a 40% solution). The solution was stirred at ambient temperature for 72 hours, then at 50° C. for 48 hours. Evaporation of the solvent gave a residue which was dissolved in CH2Cl2, washed with water and dried over Na2SO4. Evaporation of the solvent and flash chromatography of the resultant oil (10% Et2O/CH2Cl2, Merck Kieselgel) gave 1.1 g of 1-(3,5-dimethyl-4-methoxy-2-pyridylmethyl)-2-[(3,7-dimethyl-2,6(E)-octadienyl)thio]-1H-1,3-benzimidazole (free base) which was converted to its oxalate salt (1.36 g). m.p. 76°-80° C. NMR (DMSO-d6) δ7.93(s,1H), 7.5(m,1H), 7.1(m,3H), 5.4(s,2H), 5.37(m,1H), 5.07(m,1H), 3.93(m,2H), 3.70(s,3H), 2,27(s,3H), 2.15(s,3H), 2.0(m,4H), 1.6(s,3H), 1.53(s,3H), 1.07(s,3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:12]1[CH:23]=[CH:22][C:15]([C:16]([O:18][CH2:19][CH2:20][CH3:21])=[O:17])=[CH:14][CH:13]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[CH2:19]([O:18][C:16]([CH:15]1[CH2:22][CH2:23][CH:12]([CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:10][OH:11])[CH2:13][CH2:14]1)=[O:17])[CH2:20][CH3:21]
Reactant: CCCOC(=O)c1ccc(C(CO)NC(=O)OC(C)(C)C)cc1
Solvent: CO
Product: CCCOC(=O)C1CCC(C(CO)NC(=O)OC(C)(C)C)CC1
Reaction time: 16 h
Yield: 89.9 %

Procedure:
Propyl 4-(1-tert-Butoxycarbonylamino-2-hydroxy-ethyl)-benzoate (3) (5.35 g, 16.5 mmol) was dissolved in MeOH (150 mL). Argon was bubbled for 20 minutes. 5% Rh/C (1 g) was charged to the solution and argon was bubbled for another 10 minutes. The reaction mixture was stirred at 60 psi hydrogen pressure for 16 hours then at 100 psi for 7 days. Another portion of 10% Rh/C 1% Pd/C (1.2 g) was added. The reaction mixture was stirred at 100 psi hydrogen pressure for another 7 days after which LC/MS analysis indicated complete hydrogenation of the aromatic ring. The reaction mixture was filtered through a celite bed and rinsed with MeOH. The filtrate was concentrated under vacuum to dryness. The residue was filtered through a silica gel bed and eluted with EtOAc/Hexanes (20˜40%) to give 4.9 g (89.9% yield) of the pure 1-4.
Reaction SMILES: [O:1]=[C:2](N1[C@H](C2C=CC=CC=2)COC1=O)[C@@H:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH3:5].C(OCC)C.O.[BH4-].[Li+]>>[OH:1][CH2:2][C@@H:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)[CH3:5]
Reactant: C[C@@H](c1ccc(C(F)(F)F)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@H]1c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: C[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO)NC(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 66.5 %

Procedure:
To a 250 mL round-bottomed flask was added tert-butyl (2S,3S)-1-oxo-1-((R)-2-oxo-4-phenyloxazolidin-3-yl)-3-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (4.80 g, 9.7 mmol), diethyl ether (50.00 mL, 481 mmol), and water (0.19 mL, 11 mmol). The resulting solution was cooled in an ice bath. Lithium borohydride (0.23 g, 11 mmol) was added in one portion and gas evolution was observed. The ice bath was removed, and the solution was stirred for about 12 hours. The reaction was followed by LCMS and once completed, was quenched by the addition of brine. The aqueous layer was extracted with EtOAc (×3), and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 20% to 60% EtOAc in hexane, to provide tert-butyl (2S,3S)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (2.15 g, 66% yield).
Reaction SMILES: Cl[C:2]([O:4][C:5]([C:8]#[N:9])([CH3:7])[CH3:6])=[O:3].[CH:10]12[CH2:18][CH:14]([CH2:15][NH:16][CH2:17]1)[CH2:13][N:12]([CH2:19][CH:20]([OH:31])[CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)[CH2:11]2.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:27]([C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH:20]([OH:31])[CH2:19][N:12]2[CH2:11][CH:10]3[CH2:18][CH:14]([CH2:15][N:16]([C:2]([O:4][C:5]([C:8]#[N:9])([CH3:7])[CH3:6])=[O:3])[CH2:17]3)[CH2:13]2)=[CH:30][CH:29]=1)#[N:28]
Reactant: N#Cc1ccc(OCC(O)CN2CC3CNCC(C3)C2)cc1
Reactant: CC(C)(C#N)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C#N)OC(=O)N1CC2CC(CN(CC(O)COc3ccc(C#N)cc3)C2)C1
Temperature: 40 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
1-Cyano-1-methylethyl chloroformate (0.4 g; 1.65 mmol; from step (a) above) was added to a stirred solution of 4-[3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropoxy]benzonitrile (0.5 g; 1.65 mmol; see Example G above) and K2CO3 (0.7 g) in MeCN (25 mL). The reaction mixture was stirred at 40° C. for 2 h. The salts were filtered off and the filtrate was concentrated and subjected to column chromatography (DCM:MeOH; 19:1) to give the title compound in a 59% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([F:16])=[C:11]([F:17])[CH:10]=2)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:21])=O>O>[Cl:21][C:7]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:15][C:14]2[C:9](=[CH:10][C:11]([F:17])=[C:12]([F:16])[CH:13]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc2cc(F)c(F)cc2[nH]c1=O
Solvent: O
Product: CCOC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Temperature: 70 °C

Procedure:
50 g of 3-ethoxycarbonyl-6,7-difluorocarbostyril are added in the course of 10 minutes with stirring at 20° C. to 200 cm3 of phosphoryl chloride. The suspension is heated to a temperature in the region of 70° C. and maintained at this temperature for 3 hours After cooling to approximately 10° C., the solution obtained is poured with stirring into a mixture of 1,000 cm3 of water and 1,000 g of crushed ice. The temperature is allowed to rise to approximately 20° C. and the mixture is extracted with twice 500 cm3 of dichloromethane. The combined organic extracts are washed with 1,000 cm3 of water, and 1,000 cm3 of water to which sodium bicarbonate has been added to pH 7, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (20 kPa) at approximately 40° C. 45.6 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline are obtained in the form of a beige solid, melting point 108° C., which is used without further purification for the subsequent steps. 2-Chloro-3-ethoxycarbonyl-6,7-difluoroquinoline is converted to 2-chloro-6,7-difluoro-3-quinolinecarboxylic acid according to the customary methods, and can thus lead to the benzo[b][1,8]naphthyridine derivatives described in U.S. Pat. No. 4,970,213.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14].N12CCCN=C1CCCCC2>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[O:7])=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)CCl
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: CCN(CC)C(=O)COC(=O)c1ccc(N)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 4-aminobenzoic acid (1.37 g. 0.01 mole), 2-chloro-N,N-diethylacetamide 2.0 ml, 0.015 mole) and 1.8-diazabicyclo[5.4.0]-undec-7-ene (1.52 g, 0.01 mole) in benzene (20 ml) was stirred at 80° C. for 4 h and then evaporated in vacuo. The residue was taken up in ethyl acetate. After washing with 5% sodium bicarbonate and water the ethyl acetate extract was dried and evaporated in vacuo leaving crude title compound. Recrystallization from ethanol-water gave 1.5 g (60%). Mp 135°-136° C.
Reaction SMILES: [Na].[NH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:4]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[C:21](OCC)(=[O:28])[CH2:22][C:23](OCC)=[O:24].Cl>C(O)C.O>[OH:24][C:23]1[CH:22]=[C:21]([OH:28])[N:7]2[N:6]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[C:4]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:3]2[N:2]=1
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Oc1cc(O)n2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2n1
Yield: 65.2 %

Procedure:
To a solution of sodium (51 mg) in dry ethanol (3 ml) was added 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (254 mg) and diethyl malonate (176 mg). The mixture was refluxed for 5 hours and cooled. To the reaction mixture were added 1N-hydrochloric acid (4 ml) and water (6 ml). The separated solid was collected, washed with water and dried to give 5,7-dihydroxy-2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine (210 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[C:21](=[O:29])[NH:22][CH2:23][CH:24](OC)[O:25]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[C:21](=[O:29])[NH:22][CH2:23][CH:24]=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CNC(=O)[C@@H]1C[C@@H](OC(C)(C)C)CN1C(=O)OCc1ccccc1)OC
Agent: Cl
Solvent: CC(C)=O
Product: CC(C)(C)O[C@@H]1C[C@@H](C(=O)NCC=O)N(C(=O)OCc2ccccc2)C1
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A mixture of (2S,4R)-4-tert-butoxy-2-(2,2-dimethoxy-ethylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (1.8 g, 4.41 mmol) and HCl (1M, 30 mL) in acetone (30 mL) was stirred at room temp. for 8 h. The reaction mixture was then extracted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give (2S,4R)-4-tert-butoxy-2-(2-oxo-ethylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (1.4 g, crude) as a sticky liquid. The compound was used in the next step without further purification. MS calcd. for Cl9H27N2O5 [(M+H)+] 363.0, obsd. 363.2.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=O.Cl.[C:18]([NH:22][NH2:23])([CH3:21])([CH3:20])[CH3:19].C(O)C>>[C:18]([N:22]1[C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][C:3]([C:2]([F:16])([F:15])[F:1])=[N:23]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)NN
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(O)cc1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)n1nc(C(F)(F)F)cc1-c1ccc(O)cc1
Temperature: 150 °C
Yield: 63.3 %

Procedure:
A mixture of 4,4,4-trifluoro-1-(4-hydroxyphenyl)butane-1,3-dione (500 mg, 0.002 mol) and tert-butylhydrazine hydrochloride (270 mg, 0.0022 mol) in ethanol (12 mL, 0.21 mol) was heated at 150° C. in microwave for 1 h. Solvent was removed and the residue was purified via automated flash chromatography (silica gel, 0% to 30% ethyl acetate in hexanes) to give the product as an off-white solid (0.36 g, 60%). LCMS Rt=1.75 minutes
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(O)C>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:15][CH:2]([OH:1])[CH2:3][O:4][C:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=[CH:7][CH:6]=3)[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Reactant: COc1ccc(N2CCNCC2)cc1
Solvent: CCO
Product: COc1ccc(N2CCN(CC(O)COc3cccc4ccccc34)CC2)cc1
Reaction time: 8 h
Yield: 76 %

Procedure:
20.0 g. (0.1 mol) 2,3-epoxy-1-(1-naphthyloxy)-propane were mixed with 30 ml. ethanol and 19.2 g. (0.1 mol) 1-(4-methoxyphenyl)-piperazine, whereafter the reaction mixture was heated to 60° C. and maintained at this temperature for 6 hours. The reaction mixture was then left to stand overnight and the ethanol subsequently evaporated off. The oily residue was dissolved in chloroform, hydrogen chloride was passed through the chloroform solution and then ether was added, the dihydrochloride thereby precipitating out. This was filtered off with suction and recrystallized from methanol/ethanol (1:3). There was obtained 1-(4-methoxy-phenyl)-4-[3-(naphth-1-yloxy)-2-hydroxypropyl]-piperazine in a yield of 76% of theory. The product had a melting point of 237° - 238° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]=C)[CH:12]=[CH:11][C:10]=1[N:17]1[S:21](=[O:23])(=[O:22])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:19](=[O:30])[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:34]CC1.CC(O)(C)C.O.C([O-])(O)=O.[Na+]>CC(O)(C)C.O.O=[Os](=O)(=O)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=1[N:17]1[CH2:18][C:19](=[O:30])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[S:21]1(=[O:23])=[O:22])[CH:15]=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C=O)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-(2-benzyloxy-4-vinylphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (1.9 g, 4.3 mmol) in 1:1:1 THF/t-BuOH/H2O (60 mL) is added 1-methylmorpholine-N-oxide (551 mg, 4.74 mmol) and OsO4 (2 mL of a 2.5 wt % solution in t-BuOH, 0.17 mmol). The reaction is stirred for 4 h at RT, then diluted with water (15 mL) and treated with NalO4 (4.5 g, 21.5 mmol) and NaHCO3 (3.6 g, 43 mmol). The mixture is stirred vigorously for 1 h, then filtered through Celite. The solution is extracted with EtOAc. The organic phase is washed with sat. NaCl. The solution is dried over MgSO4 and the solvent removed under reduced pressure. The residue is purified by column chromatography using a gradient of 0-40% EtOAc/hexane to afford the title compound as a white solid: (M+NH4)+=464.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16](=[O:37])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:19][C:18]=1[NH:30][CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.Cl[C:43]([O:45][CH2:46][CH3:47])=[O:44]>O1CCCC1.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:10]=[C:9]2[NH:15][C:16]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:19][C:18]=1[NH:30][CH:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)=[O:37]
Reactant: CCOC(=O)Cl
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCN(C)CC3)cc2NC2CCOCC2)c2cc(Cc3cc(F)cc(F)c3)ccc21
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To a solution of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide (200 mg, 0.356 mmol) in anhydrous tetrahydrofurane (9 mL) maintained at −50° C. under nitrogen atmosphere a 1M solution of LiHMSD in anhydrous tetrahydrofurane (0.374 mL) was added. After stirring at that temperature for 5 minutes ethyl chloroformate (0.036 mL, 0.374 mmol) was added. After 1 hour at −50° C. the reaction was completed. Reaction mixture was diluted with water/EtOAc, washed with brine, dried over sodium sulphate and evaporated to dryness. The crude was purified by flash chromatography on silica gel eluting with DCM/ethanol 100:5, affording 140 mg (62% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:36][O:37][CH3:38])[C:4]([CH3:35])=[C:5]([C:26]([O:28][CH2:29][O:30][C:31](=[O:34])[CH2:32][CH3:33])=[O:27])[CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:7]=1[C:8]([O:10]COC(=O)CC)=[O:9]>C(OC(C)C)(C)C.O>[CH3:1][C:2]1[N:3]([CH2:36][O:37][CH3:38])[C:4]([CH3:35])=[C:5]([C:26]([O:28][CH2:29][O:30][C:31](=[O:34])[CH2:32][CH3:33])=[O:27])[C@H:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCC(=O)OCOC(=O)C1=C(C)N(COC)C(C)=C(C(=O)OCOC(=O)CC)C1c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: CC(C)OC(C)C
Product: CCC(=O)OCOC(=O)C1=C(C)N(COC)C(C)=C(C(=O)O)[C@H]1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.5 %

Procedure:
In 20 ml of isopropyl ether saturated with water was dissolved 120 mg of bis(propionyloxymethyl) 1,4-dihydro -2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate obtained in Example 12, and 50 mg of Lipase PS was added thereto, followed by stirring at room temperature for 72 hours. Any insoluble matter was removed by filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to obtain 77 mg (yield: 78%) of (R)-1,4-dihydro-2,6-dimethyl-1-methoxymethyl -4-(3-nitrophenyl)-5-propionyloxymethoxycarbonyl -3-pyridinecarbox-ylic acid as a pale yellow crystal.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]([CH3:27])[CH2:15]2)[C:3]=1[CH3:28].[O:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[C:37]([NH2:41])[CH:38]=[N:39][CH:40]=2)[CH2:31][CH2:30]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:41][C:37]1[CH:38]=[N:39][CH:40]=[C:35]([N:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)[CH:36]=1)=[C:3]([CH3:28])[C:4]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[C@@H:16]([CH3:27])[CH2:15]1)=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using (S)-tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-2-methylpiperazine-1-carboxylate (350 mg, 0.85 mmol) and 5-morpholinopyridin-3-amine in toluene to give (S)-tert-butyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-2-methylpiperazine-1-carboxylate. 1H NMR (CDCl3) δ ppm 7.93 (1H, d, J=2.3 Hz), 7.69 (1H, d, J=2.2 Hz), 7.29 (1H, ddd, J=10.0, 2.5, 1.4 Hz), 6.89 (1H, d, J=13.1 Hz), 6.80 (1H, ddd, J=13.9, 8.6, 2.5 Hz), 6.57 (1H, t, J=2.4 Hz), 4.38 (1H, br. s.), 3.98 (1H, d, J=13.3 Hz), 3.79-3.91 (4H, m), 3.64-3.75 (1H, m), 3.49-3.61 (1H, m), 3.32 (1H, td, J=12.7, 3.1 Hz), 3.16 (4H, dd, J=5.7, 3.9 Hz), 3.10 (1H, dd, J=12.8, 3.8 Hz), 2.92 (1H, td, J=12.5, 3.3 Hz), 2.09 (3H, s), 1.50 (9H, s), 1.29 (3H, d, J=6.7 Hz). Mass Spectrum (ESI) m/e=555.3 (M+1).
Reaction SMILES: [F-].C([N+:6](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][N:26]2COCC[Si](C)(C)C)=[CH:22][C:21]=1[C:43]1[CH:48]=[CH:47]C([N+]([O-])=O)=[CH:45][CH:44]=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][NH:26]2)=[CH:22][C:21]=1[C:43]1[CH:44]=[CH:45][N:6]=[CH:47][CH:48]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccc([N+](=O)[O-])cc3)cc12
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(Cl)c(-c3ccncc3)cc12

Procedure:
36.8 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 3 g of N-[6-chloro-5-(4-nitrophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 135 cm3 of tetrahydrofuran. The medium is then refluxed for 18 hours and is then allowed to return to room temperature to add 100 cm3 of ethyl acetate and 75 cm3 of saturated aqueous sodium hydrogen carbonate solution. The organic phase is separated out after settling of the phases has taken place, washed with 100 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 100 cm3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa; 50° C.); the residue is taken up in 35 cm3 of diisopropyl ether, filtered off on a sinter funnel and then washed with 2×20 cm3 of diisopropyl ether. After drying (90 Pa; 50° C.), 88 mg of N-[6-chloro-5-(4-nitrophenyl)-1H-indazol-3-yl]butanamide are obtained in the form of yellow crystals melting at 260° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N+:9]([O-:20])=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:6]=[CH:7][CH:8]=1>CS(C)=O.[Mn]>[CH:2]([C:3]1[CH:4]=[C:5]([N+:9]([O-:20])=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:6]=[CH:7][CH:8]=1)=[O:1]
Reactant: O=[N+]([O-])c1cccc(C=[N+]([O-])c2cccc(CO)c2)c1
Agent: [Mn]
Solvent: CS(C)=O
Product: O=Cc1cccc([N+]([O-])=Cc2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
To a solution of N-(3-hydroxymethylphenyl)-α-(3-nitrophenyl)nitrone (92) (1.38 g, 5.1 mmol) in dimethyl sulfoxide (50 mL) was added active manganese dioxide82 (15 g). The resulting mixture was stirred at room temperature for 21/2 h. The mixture was filtered and the solvent was slowly poured into water (200 mL), and the precipitate product was collected. The crude product was dissolved in dichloromethane, and the solution was washed with water (50 mL). The solution was then dried (MgSO4), and the solvent was removed with a rotary evaporator. Recrystallization from dichloromethane/petroleum ether afforded 0.95 g (3.5 mmol, 69%) of 89 as a yellow crystalline solid: mp 195°-197° C.; IR (Nujol) 1690, 1525, 1340, 1150, 1060, 790 cm-1 ; 1H NMR (Me2SO-d6) δ 7.77-8.74 (m, 7H), 8.93 (s, 1H), 9.53 (s, 1H), 10.10 (s, 1H); 13C NMR (Me2SO-d6) δ 122.44, 123.26, 125.58, 127.64, 130.67, 130.85, 131.76, 132.73, 133.15, 135.48, 137.54, 148.34, 149.15, 192.78; mass spectrum, m/e (relative intensity) 270 (M+, 13.1), 254 (19.8), 119 (100), 91 (72.6), 77 (146.4); high resolution mass spectrum, m/e 270.0644 (calcd for C14H10N2O4, 270.0640).