Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:24])([CH3:23])[O:6][CH2:7][CH2:8][CH:9]1[CH:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][CH:10]1[OH:22])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[CH3:4][C:2]([Si:5]([CH3:23])([CH3:24])[O:6][CH2:7][CH2:8][CH:9]1[CH:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][CH:10]1[O:22][S:33]([CH3:32])(=[O:35])=[O:34])([CH3:1])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCC1C(O)CC1CO[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCC1C(CO[Si](C)(C)C(C)(C)C)CC1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
2-(2-((1,1-Dimethylethyl)dimethylsilyl)oxy)ethyl)-3-(((1,1-dimethylethyl)dimethyl-silyl)oxymethyl)cyclobutanol (160 mg, 0.43 mmol) from Step B was dissolved in 2 mL of methylene chloride and the resultant solution was cooled to 0° C. Triethylamine (120μL) was added, followed by 36 μL of methanesulfonyl chloride. After stirring the reaction mixture for 30 min at 0° C., it was concentrated in vacuo and the residue was purified on a silica gel column eluted with 10% ethyl acetate in hexane to give 180 mg (89% yield) of the title compound.; MS DCI-NH3M/Z: 447 (M+H)+, 464 (M+NH4)+.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[C:4](OC)(=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.O.Cl>CS(C)=O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([CH2:2][C:1]#[N:3])=[O:13])=[CH:6][CH:7]=1
Reactant: CC#N
Reactant: COC(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C(=O)CC#N)cc1
Temperature: 60 °C
Yield: 79.7 %

Procedure:
To a solution of acetonitrile (15 g) in DMSO (25 mL) was added methyl p-anisate (25 g) and the mixture was stirred with heating at 60° C. for 1 hour. The reaction mixture was allowed to cool and cold water (100 mL) was added dropwise. The mixture was acidified with hydrochloric acid and the precipitated crystals were collected by filtration. The obtained crystals were extracted with ethyl acetate and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give 4-methoxybenzoylacetonitrile (21 g) as colorless crystals. To a solution of the obtained crystals in toluene was added hydrazine monohydrate (13 g) and the mixture was heated under reflux for 3 hours. The mixture was cooled and the precipitated crystals were collected by filtration to give 5-amino-3-(4-methoxyphenyl)pyrazole (22 g). Subsequently, the title compound was prepared from methyl butyrate, 2-chlorobenzaldehyde and 5-amino-3-(4-methoxyphenyl)pyrazole in the same manner as in Example 94.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[N:6][C:5]([N+:11]([O-])=O)=[C:4]([NH2:14])[N:3]=1.[H][H]>[Pd].O>[NH2:1][C:2]1[C:7]([NH2:8])=[N:6][C:5]([NH2:11])=[C:4]([NH2:14])[N:3]=1
Reactant: [H][H]
Reactant: Nc1nc(N)c([N+](=O)[O-])nc1[N+](=O)[O-]
Agent: [Pd]
Solvent: O
Product: Nc1nc(N)c(N)nc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2,6-Diamino 3,5-dinitro pyrazine (15.0 g, 75 mmol), 5% palladium on carbon (2.0 g) and deoxygenated water (200 mL) was added to a parr shaker and charged with 50 psi of hydrogen and allowed to shake at room temperature for 24 hours. The reaction mixture was added to deoxygenated boiling water (750 mL) and filtered hot. The filtrate was allowed to cool to room temperature and the resulting solid was recrystallized from concentrated HCl (16.1 g, 80.1%). Crystal exists as a trihydrogen chloride mono hydrate system.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:36])[CH2:10][C:11]2[S:15][C:14]([NH:16]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:13][CH:12]=2)=[CH:4][C:3]=1[Cl:37]>C(O)(C(F)(F)F)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:36])[CH2:10][C:11]2[S:15][C:14]([NH2:16])=[N:13][CH:12]=2)=[CH:4][C:3]=1[Cl:37]
Reactant: O=C(Cc1cnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1)Nc1ccc(F)c(Cl)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(CC(=O)Nc2ccc(F)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
N-(4-fluoro-3-chlorophenyl)-2-(2-tritylamino-1,3-thiazole-5-yl)acetamide (12.28 g, 23 mmol) was dissolved in TFA (100 ml) and water (10 ml). The mixture was stirred at room temperature for 45 minutes. Water (300 ml) was added to the reaction mixture, a solid was recovered by filtration, washed with water and ether. The solid was dissolved in MeOH, and the solution treated with ammonia (pH 8), MeOH was then partially evaporated, water (300 ml) was added and a precipitate of title compound recovered, dried (5.37 g, 81%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8]N(CC)CC)=[CH:6][C:5]([CH3:14])=[CH:4][C:3]=1[N:15]1[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=[N:16]1.[OH:24][C:25]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28].C[O-].[Na+].C1(C)C=CC=CC=1>CO>[N:16]1[N:15]([C:3]2[CH:4]=[C:5]([CH3:14])[CH:6]=[C:7]([CH2:8][C:38]3[C:37]([O:39][CH3:40])=[CH:36][CH:35]=[C:26]([C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]=3[OH:24])[C:2]=2[OH:1])[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=12
Reactant: COc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: CCN(CC)Cc1cc(C)cc(-n2nc3ccccc3n2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(C(=O)c2ccccc2)c(O)c1Cc1cc(C)cc(-n2nc3ccccc3n2)c1O
Temperature: 130 °C
Reaction time: 20 h
Yield: 68.7 %

Procedure:
2-(2-Hydroxy-3-diethylaminomethyl-5-methylphenyl)-2H-benzotriazole (20.0 g, 0.064 tool), 2-hydroxy-4-methoxybenzophenone (14.7 g, 0,064 mol), and sodium methoxide (1.0 g, 25% in methanol) are charged to a reaction flask. The mixture is heated to 130° C. and held at this temperature for 20 hours with agitation under a nitrogen flow. At that time, the product is identified using thin layer chromatography, with toluene as the mobile phase. To the brown-yellow solid is added hot methanol. The yellow solids are vacuum filtered and triturated twice using methanol, yielding 20.6 g product. To remove the yellow color, the solids are dissolved in hot toluene, and silica gel is introduced. The silica gel is gravity filtered hot. The toluene is removed by vacuum distillation, yielding 12.1 g of the title compound as a pale yellow solid, m.p. 206°-209° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].Cl.[CH:15](N)=N.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][CH:15]=[N:13][S:10](=[O:11])(=[O:12])[C:3]=2[CH:4]=1
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Reactant: N=CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)S(=O)(=O)N=CN2
Temperature: 80 °C

Procedure:
There is stirred for 1 night at 80° C. a suspension of 3.0 g of 2-amino-5-methoxybenzene-sulphonamide in the presence of 1.31 g of formamidine hydrochloride and 2.27 ml of triethylamine in 50 ml of toluene. The toluene is evaporated off in vacuo. The residue is taken up in water and the precipitate is filtered off.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1.[F:10][C:11]([F:21])([F:20])[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].[NH4+].[Cl-]>C1COCC1>[O:6]1[CH2:7][CH2:8][O:9][CH:5]1[CH2:4][CH2:3][CH:14]([C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[C:11]([F:10])([F:20])[F:21])[OH:15]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: BrCCC1OCCO1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CCC1OCCO1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 118.7 %

Procedure:
Method 6 General Experimental: Magnesium (230.0 mmol, 5.6 g) in THF (200 ml), under an argon atmosphere, was treated with 2-(2-bromoethyl)-1,3-dioxolane (200.0 mmol, 23.5 ml), slowly, keeping the internal temperature below 35° C. with the aid of an ice bath. After completion of the addition, the mixture was held at room temperature for an additional 1 h. 2-Trifluoromethyl benzaldehyde (100 mmol, 13.2 ml) in THF (100 ml) was cooled to −78° C. under an argon atmosphere, then treated with the freshly formed Grignard reagent prepared above. After completion of the addition, the solution was allowed to warm to room temperature, then held at room temperature overnight. The reaction mixture was then poured into saturated aqueous NH4Cl (200 ml), and extracted with ethyl acetate (2×150 ml). The combined organics were washed with brine (2×75 ml), then concentrated under reduced pressure to give 32.8 g of 3-[1,3]dioxolan-2-yl-1-(2-trifluoromethyl-phenyl)-propan-1-ol, which may be used without further purification. 1H NMR (CDCl3) δ 7.78 (1H, d, J=7.7), 7.62-7.52 (2H, m), 7.34 (1H, t, J=7.6), 4.92 (1H, t, J=4.0), 4.00-3.81 (5H, m), 1.90-1.80 (4H, m).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([C@H:22]1[O:30][C@H:29]2[C@H:25]([N:26]=[C:27]([N:31]([CH2:39][CH:40]=[CH2:41])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[S:28]2)[C@@H:24]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:23]1[O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)(=[O:21])[CH3:20].[C:58]([Si](C)(C)C)([F:61])([F:60])[F:59]>C1COCC1>[CH2:51]([O:50][C@@H:23]1[C@@H:22]([C:19]([OH:21])([CH3:20])[C:58]([F:61])([F:60])[F:59])[O:30][C@H:29]2[C@H:25]([N:26]=[C:27]([N:31]([CH2:39][CH:40]=[CH2:41])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[S:28]2)[C@H:24]1[O:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: C=CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C(C)=O)O[C@@H]2S1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C(C)(O)C(F)(F)F)O[C@@H]2S1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
A mixture of TBAF (1.1, 4.2 mmol) and 4 Å molecular sieves (4 g) in THF (40 mL) was stirred for 30 minutes at 0° C., followed by addition of a mixture of 144 (4.6 g, 8.3 mmol) and CF3TMS (5.9 g, 42 mmol) in THF (40 mL). The mixture was stirred for 3 hours at room temperature, followed by addition of additional TBAF (6 g, 22 mmol). After 1 hour, the reaction was then quenched by addition of water (80 mL). A filtration was performed and the filtrate was extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (2×30 mL), dried over magnesium sulfate, and concentrated. The residue was purified by flash column chromatography with 6%-12% ethyl acetate in petroleum ether to afford the title compound as a brown syrup (3.5 g, 68%, two isomers, ratio is 1:1 determined by 1H NMR). (ES, m/z): [M+H]+ 623.0; 1H NMR (300 MHz, CDCl3): 7.37-7.23 (m, 10H), 6.13-6.07 (m, 1H), 5.76-5.74 (m, 1H), 5.05-4.92 (m, 2H), 4.74-4.67 (m, 2H), 4.47-4.25 (m, 7H), 3.93-3.88 (m, 1H), 1.50 (s, 9H), 1.28-1.23 (m, 3H).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[Cl:9][C:10]1[N:11]=[C:12]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[CH3:29])[C:13]2[CH2:18][S:17](=[O:20])(=[O:19])[C:16]([CH3:22])([CH3:21])[C:14]=2[N:15]=1.CI>C1COCC1>[Cl:9][C:10]1[N:11]=[C:12]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[CH3:29])[C:13]2[CH:18]([CH3:2])[S:17](=[O:19])(=[O:20])[C:16]([CH3:21])([CH3:22])[C:14]=2[N:15]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CS(=O)(=O)C2(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1c2c(N3CCOC[C@@H]3C)nc(Cl)nc2C(C)(C)S1(=O)=O
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
LDA (2.5 mL, 5 mmol) was added dropwise to a solution of (S)-2-chloro-7,7-dimethyl-4-(3-methylmorpholino)-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (Step vi, 1.5 g, 4.5 mmol) in THF (30 mL) at −78° C. The mixture was stirred at this temperature for 0.5 h, MeI (0.7 g, 5 mmol) in THF (5 mL) was added dropwise to the above mixture. The resulted mixture was stirred at room temperature for 2 h. Then the mixture was poured into sat.NH4Cl, extracted with EtOAc (3×30 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography to give 2-chloro-5,7,7-trimethyl-4-((S)-3-methylmorpholino)-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (1.2 g, yield 77%) as a yellow solid. 1H NMR (400 MHz, CDCl3) 1.38-4.31 (m, 1H), 4.29-4.21 (m, 1H), 3.99-3.96 (m, 1H), 3.78-3.43 (m, 5H), 1.65-1.25 (m, 12H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH:8]1[C:20]2[CH:19]([CH2:21][O:22][C:23]([NH:25][C@@H:26]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=3)[C:27]([O:29][CH3:30])=[O:28])=[O:24])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1>>[CH:8]1[C:20]2[CH:19]([CH2:21][O:22][C:23]([NH:25][C@H:26]([C:27]([O:29][CH3:30])=[O:28])[CH2:31][C:32]3[CH:33]=[CH:34][C:35]([NH:38][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[CH:36][CH:37]=3)=[O:24])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)O1
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: COC(=O)[C@H](Cc1ccc(NC(=O)CCC(=O)O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
Succinic anhydride (6.72 g, 67.2 mmol) was added to the solution of (S)-methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-aminophenyl)propanoate 3C from step 2. The reaction mixture was stirred at room temperature overnight. The solvent was removed, and the residual solid was washed with 30% ethyl acetate/petroleum ether (200 mL) and recrystallized in THF and 30% ethyl acetate/petroleum ether to give (S)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid 3D as a white solid (19 g, 66% yield). 1HNMR (DMSO-d6, 300 MHz) δ: 10-9.9 (s, 1H), 8.0-7.9 (m, 3H), 7.8-7.6 (m, 2H), 7.6-7.5(m, 2H), 7.5-7.4(m, 2H), 7.4-7.3(m, 2H), 7.3-7.1(d, 2H), 4.4-4.2 (m, 4H), 3.8-3.6 (s, 3H), 3.1-2.8 (m, 2H), 2.7-2.5 (m, 4H); ESI-MS: m/z 517.3 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].[H-].[Na+].[CH2:14](I)[CH3:15]>CN1CCCC1=O>[CH2:1]([N:4]([CH2:14][CH3:15])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3]
Reactant: CCI
Reactant: C=CCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C=CCN(CC)C(=O)OC(C)(C)C

Procedure:
The sub-titled compound was prepared from tert-butyl allylcarbamate (1.0 g), 60% sodium hydride (0.254 g), ethyl iodide (1.55 ml) and anhydrous N-methyl-2-pyrrolidinone (4 ml) by the method of Example 2(ii). The crude product was purified by chromatography on silica gel eluting with iso-hexane:ethyl acetate (19:1) to afford (0.53 g) of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:44])[C@H:25]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[NH:26]C(OCC2C=CC=CC=2)=O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[BrH:45].C(OCC)C>C(O)(=O)C>[BrH:45].[BrH:45].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:44])[C@H:25]([CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH2:26])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: Cc1nnc(CNC(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1nnc(CNC(=O)[C@@H](N)Cc2ccccc2)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 79 %

Procedure:
0.50 g of 5-chloro-2-[[(N-benzyloxycarbonyl-L-phenylalanyl)aminomethyl]-5-methyl-4H-1,2,4-triazol-4-yl] benzophenone was treated with a 35% solution of hydrogen bromide in glacial acetic acid for 1 hour. Dry diethyl ether was then added and the separated solid was filtered off, washed with ether and dried in vacuo. The crude product was purified by precipitation from methanol/ethyl acetate. There was obtained 0.36 g (79%) of 5-chloro-2-[3-(L-phenylalanylaminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl] benzophenone dihydrobromide of melting point 164°-171° C (slow decomposition).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:32]=[CH:31][C:8]2[N:9]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:10]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N:15]([CH:22]([CH3:24])[CH3:23])[C:14]3=[O:25])=[N:11][C:7]=2[CH:6]=1)=[NH:4].B(F)(F)F.[CH3:37]COCC>C(OC)(OC)OC>[CH:22]([N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:13]([CH2:12][C:10]2[N:9]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:8]3[CH:31]=[CH:32][C:5]([C:3]4[N:4]=[CH:37][O:1][N:2]=4)=[CH:6][C:7]=3[N:11]=2)[C:14]1=[O:25])([CH3:23])[CH3:24]
Reactant: CCOCC
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C(=N)NO)ccc21
Agent: FB(F)F
Solvent: COC(OC)OC
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(-c3ncon3)ccc21
Temperature: 80 °C
Yield: 53 %

Procedure:
A solution of N-hydroxy-2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxamidine (65 mg, 0.15 mmol) in trimethyl orthoformate (4 mL) in the presence of BF3.OEt2 (5 μL) in a sealed tube was placed in a microwave oven (Smith Creator, Personal Chemistry) and heated at 80° C. for 5 min while stirring. The solvent was removed in vacuo and purified by flash chromatography (eluent hexane-acetone 3:1) to give 1-isopropyl-3-[1-(3-methyl-butyl)-5-[1,2,4]oxadiazol-3-yl-1H-benzoimidazol-2-ylmethyl]-1,3-dihydro-benzoimidazol-2-one (35 mg, 53%) as a white solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([CH2:13][CH2:14]O)[NH:8][CH2:7][CH2:6]2.[F:16][C:17]([F:22])([F:21])[C:18]([NH2:20])=[O:19].C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([CH2:13][CH2:14][Br:24])[NH:8][CH2:7][CH2:6]2.[F:16][C:17]([F:22])([F:21])[C:18]([NH2:20])=[O:19]
Reactant: COc1ccc2c(c1)CCN[C@@H]2CCO
Reactant: BrC(Br)(Br)Br
Agent: NC(=O)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN[C@@H]2CCBr
Yield: 93.4 %

Procedure:
To a solution of 6-methoxy-1-(R)-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide (330 mg, 1.09 mmol) obtained in step (b) of Example 190 and carbon tetrabromide (542 mg, 1.63 mmol) in dichloromethane (5 ml) was added gradually triphenyl phosphine (343 mg, 1.31 mmol) with stirring under cooling in a water bath. The resulting mixture was further stirred at room temperature, and after confirming the disappearance of the starting material by thin layer chromatography, the reaction mixture was evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (80:20) as the eluent to afford the title compound (390 mg, yield: 98%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][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:25]([CH:28]([CH3:30])C)=[C:26]=[O:27]>C(N(CC)CC)C>[C:26]([N:25]1[CH2:28][CH2:30][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[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=3[Cl:1])=[CH:8][CH:9]=2)(=[O:19])=[O:18])[CH2:3][CH2:2]1)(=[O:27])[CH2:8][CH2:7][CH3:16]
Reactant: CC(C)N=C=O
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1ccccc1Cl
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3Cl)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general procedure in Scheme 5, beginning with 4-(2-chloro-benzoylamino)-naphthalene-1-sulfonyl chloride, and substituting butyryl chloride and triethylamine for 2-isocyanato-propane. 1H NMR (300 MHz, DMSO) δ 10.86 (s, 1H), 8.68 (d, 1H), 8.35 (d, 1H), {tilde over (□)}□□(d, 1H), 8.13 (d, 1H), 8.0 (m, 1H), 7.74 (m, 3H), 7.64 (m, 3H), 4.00 (d, 1H), 3.60 (d, 1H), 3.26 (m, 1H), 2.93 (t, 1H), 2.59 (m, 2H), 2.17 (t, 2H), 1.46 (m, 2H), 1.43 (q, 2H), 1.17 (m, 1H), 0.82 (t, 3H); LC/MS m/z 512 (M−H)−, 514 (M+H)+.
Reaction SMILES: [NH:1]1C2(CCCCC2)[NH:4][CH2:3][C:2]1=[O:11].CC(C)CO[C:16](=[O:21])[CH2:17][CH:18]1[O:20][CH2:19]1>O.CC(C)=O>[CH2:17]1[C:16](=[O:21])[N:4]([CH2:3][C:2]([NH2:1])=[O:11])[CH2:19][CH:18]1[OH:20]
Reactant: O=C1CNC2(CCCCC2)N1
Reactant: CC(C)COC(=O)CC1CO1
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)CN1CC(O)CC1=O
Temperature: 70 °C
Reaction time: 48 h

Procedure:
19 g 2-(1-Methylethyl)imidazolidinone ((5); R4 =H, R5 =isopropyl) (0.15 moles) are dissolved in 100 ml water and 150 ml acetone. 2-Methylpropyl-3,4-epoxybutanoate (0.15 moles) are added and the mixture is heated and stirred for 48 h at 70° C. The acetone is evaporated in vacuo and 100 ml DMF are added, followed by boiling for 21 h. The mixture is reduced to a small volume in vacuo, the residue is taken up with 40 ml water and washed with 2×40 ml methylene chloride. The aqueous phase is evaporated to dryness and redissolved in 15 ml methanol. This is left to stand for 3 h at 0° C., filtered and dried to give oxiracetam as a white crystalline powder, m.p. 167°-70° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:22]O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:22])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
4′-Hydroxy[1,1′-biphenyl]-4-carboxylic acid (5.0 g, 23.34 mmol, purchased from Aldrich Chemical Co.) and sulfuric acid (0.5 mL) in methanol (100 mL) were heated at reflux temperature for 24 hours. The mixture was allowed to cool to ambient temperature and then filtered. The filter cake was washed with cold methanol (2×25 mL) and dried under reduced pressure to provide the title compound (95% yield).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH:3]([CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH2:11]1)[CH2:4]/[C:5](=[N:7]/[OH:8])/[NH2:6].CCN(C(C)C)C(C)C.[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1>C(Cl)Cl>[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([NH:6]/[C:5](=[N:7]\[OH:8])/[CH2:4][CH:3]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=3)[CH2:11]2)[C:2]([F:1])([F:26])[F:27])=[O:43])=[CH:40][CH:39]=1
Reactant: N/C(CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F)=N\O
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N/C(CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F)=N\O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
In a 10 mL round-bottomed flask, (Z)-4,4,4-trifluoro-N′-hydroxy-3-((3-(3-(trifluoromethyl)phenyl)-piperidin-1-yl)methyl)butanimidamide (120 mg, 302 μmol) and DIEA (117 mg, 158 μl, 906 μmol) were combined with CH2Cl2 (2.00 ml) to give a colorless solution. 4-Fluorobenzoyl chloride (47.9 mg, 302 μmol) in CH2Cl2 (1 ml) was added drop-wise and the resulting mixture was stirred at room temperature overnight. The crude reaction mixture was concentrated in vacuo to afford 120 mg (38%) of (Z)-4-fluoro-N-(4,4,4-trifluoro-1-(hydroxyimino)-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butyl)benzamide and used as is. MH+=520.