Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH2:12][CH3:13])[CH2:7]2.[C:15]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Na+].[Na+].C(O)CO>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+]>[CH2:12]([CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:22]3[CH:23]=[CH:24][C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][CH:21]=3)[CH:3]=[CH:4][C:5]=2[CH3:14])[C:9]1=[O:11])[CH3:13]
Reactant: CCC1Cc2c(C)ccc(Cl)c2C1=O
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: OCCO
Solvent: O
Product: CCC1Cc2c(C)ccc(-c3ccc(C(C)(C)C)cc3)c2C1=O
Yield: 105.7 %

Procedure:
Using a method analogous to Example 1d, 29.0 g (138.96 mmol) of 7-chloro-2-ethyl-4-methyl-1-indanone (1b), 29.7 g (166.8 mmol) of 4-tert-butylphenylboronic acid, 36.8 g (347.3 mmol) of sodium carbonate, 300 ml of ethylene glycol and 40 ml of water were reacted at 80° C. in the presence of a freshly prepared catalyst solution of 156 mg (0.695 mmol) of palladium acetate, 3.5 ml (2.08 mmol) of an aqueous TPPTS solution (0.6 molar) in 19 ml of water. 45.00 g of (2c) were isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]3[CH:23]=[CH:22][CH:21]=[C:20](F)[C:17]=3[C:18]#[N:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(=O)(O)O.[NH2:31][C:32]([NH2:34])=[NH:33]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:17]=3[C:18]([NH2:19])=[N:33][C:32]([NH2:34])=[N:31]4)[CH2:12][CH2:13]2)=[O:7])=[CH:25][CH:26]=1
Reactant: N#Cc1c(F)cccc1OCC1CCN(C(=O)c2ccc(Cl)cc2)CC1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2c(OCC3CCN(C(=O)c4ccc(Cl)cc4)CC3)cccc2n1
Yield: 60.7 %

Procedure:
2-[1-(4-Chlorobenzoyl)piperidin-4-ylmethoxy]-6-fluorobenzonitrile (110 mg, 0.3 mmol) and guanidine carbonate (53 mg; 0.3 mmol) were heated at 140° C. in dimethylacetamide for 4 hours. The mixture was cooled and triturated with water for 45 minutes. Solids were filter off and triturated with 3 mL of ethanol. Solids were collected by filtration and dried to afford 75 mg of title compound (59% yield) 1HNMR (400 MHz, DMSO-d6) δ 7.52 (m, 2H), 7.43 (m, 2H), 7.35 (t, J=8.4 Hz, 1H), 7.17 (br d, J=15.2 Hz, 2H), 6.77 (dd, J=8.4, 0.8 Hz, 1H), 6.54 (d, J=7.2 Hz, 1H), 5.95 (br s, 2H), 4.51 (br s, 1H), 4.03 (d, J=6.4 Hz, 2H), 3.59 (br s, 1H), 3.11 (br s, 1H), 2.84 (br s, 1H), 2.22 (m, 1H), 1.87 (br s, 1H), 1.76 (br s, 1H), 1.3 (br d, J=10.4 Hz, 2H). MS m/z (ESI) 412 (M−H)+.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH2:13]([O:15][C:16](Cl)=[O:17])[CH3:14]>>[CH2:13]([O:15][C:16]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])=[O:17])[CH3:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)Cl
Agent: [K]
Product: CCOC(=O)N1C(=O)c2ccccc2C1=O

Procedure:
A suspension comprisng 25 millimoles of potassium phthalimide and 20 ml ethylchloroformate is refluxed for approximately 31/2 hours. Insolubles are removed by hot acetone treatment in the manner described in preparation B. Upon completion of the acetone treatment and removal of mother liquor the product is combined and recrystallized from ethanol. Further recrystallizaton from a mixture of ethylchloroformate and ether yields a white product having a melting point of 89.5° - 90.5°C.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([C:11](=O)[CH3:12])[CH:9]=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.[NH2:16][OH:17].Cl.CC([O-])=O.[Na+].O>CO>[OH:1][B:2]1[C:6]2[CH:7]=[C:8](/[C:11](=[N:16]/[OH:17])/[CH3:12])[CH:9]=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1
Reactant: NO
Reactant: CC(=O)c1ccc2c(c1)B(O)OC2(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C/C(=N\O)c1ccc2c(c1)B(O)OC2(C)C
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]-oxaborol-6-yl)ethanone (190 mg, 0.93 mmol), NH2OH HCl (77 mg, 1.12 mmol) and NaOAc (114 mg, 1.4 mmol) in MeOH (15 mL) was heated to 65° C. and stirred for 3 h. Water was added and the mixture was extracted with DCM. The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give (E)-1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)ethanone oxime as a white solid. It was used in the next step without further purification. MS: m/z=220.1 (M+1, ESI+).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[NH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:8][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=2)=[CH:2][CH:1]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
At room temperature, p-aminophenol (0.51 g, 4.70 mmol, 1 eq) was dissolved in N,N-dimethylformamide (10 mL). To the resulted solution, potassium tert-butoxide (0.53 g, 4.70 mmol, 1 eq) was added in portions and the resulted mixture was stirred for 0.5 hours. Tert-butyl 4-chloropicolinate (1 g, 4.70 mmol, 1 eq) and potassium carbonate (45 mg, 0.33 mmol, 0.07 eq) were added, and the mixture was heated to 80° C. and stirred for 2 hours. The mixture was cooled to room temperature and ethyl acetate (50 mL) was added. The mixture was filtered to remove the undissolved material and the filtrate was washed with saturated brine (20 mL×2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (dichloromethane:ethyl acetate=30:1) to give the title compound (805 mg, purity 96%, yield 60%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15]Br)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:23][N:24]2[CH3:27])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][N:31]3[CH2:30][CH2:29][CH:28]([C:22]4[C:21]5[C:25](=[CH:26][C:18]([F:17])=[CH:19][CH:20]=5)[N:24]([CH3:27])[N:23]=4)[CH2:33][CH2:32]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(sc(C)c2CCBr)C1
Reactant: Cn1nc(C2CCNCC2)c2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2c(sc(C)c2CCN2CCC(c3nn(C)c4cc(F)ccc34)CC2)C1
Temperature: 90 °C
Reaction time: 22 h
Yield: 60.8 %

Procedure:
A mixture of 590 mg of 6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine, 580 mg of 4-(6-fluoro-1-methyl- 1H-indazol-3-yl) piperidine, 780 mg of potassium carbonate and 415 mg of potassium iodide in 10 ml of dimethylformamide and 10 ml of toluene was stirred at 90° C. for 22 hours and concentrated in vacuo. To the residue were added ethyl acetate and water, and separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a silica gel to give 540 mg of 6-acetyl-3-(2-(4-(6-fluoro-1-methyl-1H-indazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 213°-216° C. as oxalate thereof.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C:13](O)([CH2:18][O:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:14]([F:17])([F:16])[F:15])(=O)=O)=CC=1.C(=O)([O-])[O-]>ClCCl>[CH3:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([O:19][CH2:18][C:13]2([C:14]([F:17])([F:16])[F:15])[CH2:12][O:11]2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(O)(COS(=O)(=O)c2ccc(C)cc2)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C(F)(F)F)CO2)cc1
Yield: 84.4 %

Procedure:
3,3,3-Trifluoro-2-hydroxy-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)propyl 4-methylbenzenesulfonate (14.29 g, 29 mmol) in dichloromethane (75 ml) was pumped through a cartridge containing PS-carbonate resin (not pre-swelled) (3 mmol/g, 25 g, 75 mmol) at 675 microliters/min. The temperature was set to approx. 50° C. by wrapping a Whatman thin film heater around the cartridge. The pressure was regulated at 40 psi. After all the reagent had been aspirated, the column was washed through with dichloromethane—at this point the column started to leak slightly and the back pressure regulator had to be removed to reduce the pressure. The collected solution was concentrated in vacuo to afford the title compound (7.25 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:9]=[C:10]([C:11]([OH:13])=O)[C:4]=2[O:3]1.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:31]([N:33]1[CH2:37][CH2:36][CH2:35][CH:34]1[CH2:38][NH2:39])[CH3:32]>CN(C)C=O.CC(C)=O>[CH2:31]([N:33]1[CH2:37][CH2:36][CH2:35][CH:34]1[CH2:38][NH:39][C:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:9]=1)=[O:13])[CH3:32]
Reactant: CC1Cc2cc(S(N)(=O)=O)cc(C(=O)O)c2O1
Reactant: CCN1CCCC1CN
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Temperature: 15 °C
Reaction time: 8 h

Procedure:
(+)-2-Methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylic acid [[α]D =+16.67° (dimethylformamide, c=1)], 6 g, is dissolved in a mixed solvent of 55 ml of dimethylformamide and 55 ml of acetone and 5.9 g of triethylamine is added, and the whole is stirred. Under cooling at 15° C. 2.7 g of ethyl chlorocarbonate is added dropwise for 10 minutes and the solution is stirred at room temperature for 40-45 minutes. Then, (-)-1-ethyl-2-aminomethylpyrrolidine, 7.5 g, is added and the reactant is stirred at room temperature for 20 minutes and allowed to stand overnight. Excess triethylamine and acetone are distilled off under reduced pressure and the resulting residue is poured while stirring into 500-600 ml of water. Precipitated cystals are separated by suction filtration, washed with water and dried. The filtrate, aqueous layer is extracted with ethyl acetate three times. The extract layer is washed with water and dried, and ethyl acetate is distilled off under reduced pressure to give crude crystals. Both the crude crystals are put together and recrystallized from ethyl acetate to afford crystals of N-(1-ethyl-2-pyrrolidinylmethyl)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide, m.p. 164°-165° C., [α]D =-50.867° (dimethylformamide, c=1), which is an optically active compound.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][N:9]=[C:8]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1C=CC=CC=1.[O-2].[O-2].[O-2].[Ni+3].[Ni+3]>[C:1]1([N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2=NCCN2c2ccccc2)CC1
Agent: [Ni+3]
Agent: [O-2]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2nccn2-c2ccccc2)CC1

Procedure:
To a stirred solution of tert-butyl 4-(1-phenyl-4,5-dihydro-1H-imidazol-2-yl)piperidine-1-carboxylate (100 mg) in dry benzene (5 ml), nickel peroxide (350 mg) dissolved in dry benzene (20 ml) was added. The reaction mixture was refluxed for over-night and filtered through a celite pad using CHCl3 as eluent. The combined organic layer was removed under reduced pressure. The resulting oil was purified by column chromatography using ethyl acetate\hexane (3:7) to afford tert-butyl 4-(1-phenyl-1H-imidazol-2-yl)piperidine-1-carboxylate as pure product
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.Cl.[CH3:24][N:25]([CH3:33])[C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29]>>[CH3:24][N:25]([CH3:33])[C:26]1[CH:27]=[C:28]([NH:29][C:9](=[O:10])[C:8]([C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])=[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:21])[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cc(C)c(C(C(=O)O)=C2C(=O)Nc3ccccc32)[nH]1
Reactant: CN(C)c1cccc(N)c1
Agent: Cl
Product: Cc1cc(C)c(C(C(=O)Nc2cccc(N(C)C)c2)=C2C(=O)Nc3ccccc32)[nH]1
Yield: 25.1 %

Procedure:
(3,5-Dimethyl-1H-pyrrol-2-yl)-(2-oxo-1,2-dihydroindol-3-ylidene)-acetic acid (90 mg) was reacted with 3-dimethylaminoaniline dihydrochloride (85 mg) using method B to give 32 mg (25%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=O)=[O:4].[CH3:23][O:24][C:25](=[O:36])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=1>CO>[CH3:1][O:2][C:3]([C:5]1[N:35]([CH2:34][C:31]2[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][C:25]([O:24][CH3:23])=[O:36])=[CH:29][CH:30]=2)[C:7](=[O:6])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:4]
Reactant: COC(=O)CCc1ccc(CN)cc1
Reactant: COC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Solvent: CO
Product: COC(=O)CCc1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.6 %

Procedure:
To a solution of 6-bromo-4-phenyl-3-isocoumarincarboxylic acid methyl ester (359 mg) in methanol (20 ml) was added 3-(4-aminomethylphenyl)propionic acid methyl ester (387 mg) and the mixture was stirred at room temperature for 18 hr. The solvent was evaporated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in methanol (30 ml) and conc. sulfuric acid (3 ml) was added. The mixture was heated under reflux for 3 hrs. The solvent was evaporated under reduced pressure, water was added under ice-cooling and the mixture was neutralized with potassium carbonate. The solution was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=19/1→3/1) to give the title compound (425 mg, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: Oc1cccc(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
3-Bromophenol (100 g, 580 mmol) and triethylamine (104 mL, 750 mmol) were dissolved in dichloromethane (500 mL), and the solution was cooled in an ice bath. Acetyl chloride (49.7 g, 630 mmol) was added dropwise. After 1 h the cooling bath was removed and the mixture was stirred overnight (approx 16 h) at room temperature. The mixture was washed with hydrochloric acid (1N, 250 mL), water (250 mL), 5% NaHCO3 (250 mL), and brine (250 mL). The organic layer was dried and evaporated to provide 124 g (99%) of 3-bromophenyl acetate as a light brown liquid; 1H NMR (CDCl3) δ 7.36 (d, 1H), 7.32-7.20 (m, 2H), 7.05 (d, 1H), 2.28 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:26]=1[C:27](O)=[O:28]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:27](=[O:28])[C:26]5[C:25]([F:24])=[CH:33][CH:32]=[CH:31][C:30]=5[F:34])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(O)c1c(F)cccc1F
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4c(F)cccc4F)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2,6-difluoro-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.48 mmol) and 2,6-difluorobenzoic acid. The title compound was obtained as off-white powder (24 mg).
Reaction SMILES: C([O:8][N:9]1[CH2:13][C@@H:12]([CH3:14])[C@@H:11]([NH:15][C@@H](C2C=CC=CC=2)C)[C:10]1=[O:24])C1C=CC=CC=1>CO.C(O)(=O)C>[NH2:15][C@@H:11]1[C@H:12]([CH3:14])[CH2:13][N:9]([OH:8])[C:10]1=[O:24]
Reactant: C[C@@H]1CN(OCc2ccccc2)C(=O)[C@@H]1N[C@H](C)c1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1CN(O)C(=O)[C@@H]1N
Yield: 89.7 %

Procedure:
(3R,4R)-1-Benzyloxy-4-methyl-3-[(R)-1-phenylethylamino]pyrrolidin-2-one (6.4 g. 19.7 mmol) was hydrogenolysed on Pearlman's catalyst (1.6 g) in methanol (100 ml) and acetic acid (2 ml) for 2 h at 50 psi. After filtration and evaporation, the residue was dissolved in water and applied to a column containing DOWEX 50W-X8 (100-200 mesh, 4×4 cm, H+ form). After washing the resin with water (150 ml) the product was eluted with dilute aqueous ammonia. The fractions containing the product were freeze dried to give (3R,4R)-3-amino-1-hydroxy-4-methylpyrrolidin-2-one (2.3 g, 90%) as a white foam. [α]D =+16.3° (c=0.48, MeOH). The 1H NMR of this product was identical to that of the racemate. To the foam was added D-(-)-tartaric acid (1.33 g), the solids dissolved in water, and freeze dried to give (3R,4R)-3-amino-1-hydroxy-4-methylpyrrolidin-2-one, (-)tartrate salt (3.91 g). 1H NMR (360 MHz, D2O) 4.36 (1 H, s, CHOH), 4.24 (1 H, d, J=8.4 Hz, CHN), 3.90 H(1H, dd, J=6.6 and 9.5 Hz, NCHAHB), 3.34 (1 H, dd, J=2.2 and 9.5 Hz, NCHAHB), 2.8-3.0 (1 H, m, CHCH3), 1.74 (3 H, d, J=7.1 Hz, CH3), m/z (CI, NH3) 131 (M+ +H) (Found: C, 38.09; H, 6.65; N, 12.65. C7H13N2O5 +0.9 H2O requires C, 37.97; H, 6.73, N, 12.65). Analysis by HPLC on a chiral stationary phase found enantiomeric purity of 99.66%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:12]([CH3:21])[C:11]([C:22](O)=O)=[N:10]1.[CH3:25][C:26]([NH:31][CH3:32])([CH3:30])[C:27]([NH2:29])=[O:28]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[C:12]([CH3:21])[C:11]([C:22]2[N:31]([CH3:32])[C:26]([CH3:30])([CH3:25])[C:27](=[O:28])[N:29]=2)=[N:10]1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(F)cc1
Reactant: CNC(C)(C)C(N)=O
Product: Cc1c(C2=NC(=O)C(C)(C)N2C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(F)cc1

Procedure:
Compound 19 was synthesized from 4g (248 mg, 0.68 mmol) and 5a (130 mg, 1.08 mmol) as a white solid (121 mg, 39%) in a manner similar to that described in Example 36. 1H NMR (400 MHz, CDCl3) δ 7.39 (d, 1H), 7.20 (dd, 1H), 7.13 (d, 1H), 7.06 (dd, 2H), 6.97 (dd, 2H), 3.43 (s, 3H), 2.33 (s, 3H), 1.36 (s, 6H); ESMS m/z: 445.0 (M+1).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].Cl[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1>O.O1CCCC1.CCCCCC>[N:28]1[CH:29]=[CH:30][CH:31]=[N:32][C:27]=1[Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: Clc1ncccn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3.2 ml of a hexane solution containing 1.57 mol of n-butyllithium was slowly added dropwise into a solution of 20 ml of tetrahydrofuran containing 707 μl of diisopropylamine under ice-cooling. After stirring at 0° C. for 30 minutes, 1.4 ml of tri-n-butyltin hydride was slowly added dropwise thereinto. After stirring at 0° C. for 30 minutes, the mixture cooled to −78° C. and a suspension of 30 ml of tetrahydrofuran containing 2-chloropyrimidine was slowly added drowise thereinto. After stirring at −78° C. for one hour as it was and then at 0° C. for 2 hours, water was added to the reaction solution. The mixture was extracted with ethyl acetate, and the organic phase was washed with brine and the solvent was removed. Then, the residue was subjected to silica gel column chromatography and eluted with hexane/ethyl acetate (10:1) and then with hexane/ethyl acetate (7:1), to give 654 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[CH:10]=[N:9]2)=[C:4]([F:17])[CH:3]=1.[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:18]([O-:20])=[O:19])=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[CH:10]=[N:9]2)=[C:4]([F:17])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cn1c(=O)cnn(-c2ccc(Cl)cc2F)c1=O
Agent: O=S(=O)(O)O
Product: Cn1c(=O)cnn(-c2cc([N+](=O)[O-])c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 24.7 g (0.097 mole) of 2-(4-chloro-2-fluorophenyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione in 30 mL of concentrated sulfuric acid was added dropwise a mixture of 70 mL of concentrated sulfuric acid and 100 mL of fuming nitric acid. The reaction mixture temperature was kept below 40° C. during the addition. Upon completion of addition the reaction mixture was stirred at ambient temperature for four hours. The reaction mixture was poured into ice-water and the mixture extracted with ethyl acetate. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield a solid. The solid was triturated with diethyl ether and collected by filtration to yield 20.6 g of 2-(4-chloro-2-fluoro-5-nitrophenyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:8][C:7]=1[N+:28]([O-])=O)=[O:4].[H][H]>CN(C)C=O.[Pt](=O)=O>[NH2:28][C:7]1[CH:8]=[C:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:31])([CH3:1])[CH3:32]
Reactant: [H][H]
Reactant: CC(C)(C)C(=O)Nc1cc(OCc2ccccc2)c(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1cc(OCc2ccccc2)c(OCc2ccccc2)cc1N
Temperature: 60 °C

Procedure:
Under nitrogen, the title compound of Example 28A (15.77 g, 35.0 mmol) was dissolved in 350 ml dimethylformamide. 500 mg platinum (IV) oxide were added, the mixture was heated to 60° C. and hydrogenated by monitoring with thin layer chromatography until the end of the reaction (1-5 days). The hydrogen was replaced with nitrogen, the catalyst was filtered off and the filtrate evaporated (all operations under nitrogen, otherwise the product has a deep blue color). The residue was triturated with degassed water to remove residual dimethylformamide.