Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si](=O)=O.Br[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16].C(=O)([O-])[O-:19].[Na+].[Na+].Cl>CC(C)=O.O.N1C=CC=CC=1>[OH:19][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: O=[Si]=O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(O)c1ccc(CO)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
4-[N-(3-triethoxysilyl)propyl]-carbamoyl-2-nitrobenzyl isonicotinate (TCNI) which binds to silicon dioxide through the ethoxysilyl groups, and has a pyridine metal binding group and a nitrobenzyl radiation sensitive group was prepared according to the synthetic procedure represented in Scheme 2. 4-Bromomethyl-3-nitrobenzoic acid (A) was refluxed overnight with sodium carbonate in acetone/water (1:1). After cooling to room temperature, the reaction mixture was made acidic with 1 N hydrochloric acid and the product was extracted into ethyl acetate, dried over magnesium sulfate and rotary evaporated to yield 4-hydroxymethyl-3-nitrobenzoic acid. The 4-hydroxymethyl-3-nitrobenzoic acid (B) was dissolved in pyridine and reacted with isonicotinoyl chloride hydrochloride at room temperature for 2 days. The resultant solution was poured onto ice, stirred overnight at room temperature and extracted with ethyl acetate. The organics were dried over magnesium sulfate and rotary evaporated to remove the solvents. Residual pyridine was removed by the addition of toluene followed by rotary evaporation. The resultant solid was slurried in ethanol at room temperature and the product, 4-carboxy-2-nitrobenzyl isonicotinate, was isolated by filtration and dried under vacuum.
Reaction SMILES: C[O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)\[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[OH-].[Na+]>CO>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14](/[C:7](/[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:22])=[O:2])=[CH:19][CH:18]=1
Reactant: COC(=O)/C=C/C=C(/c1ccc(OC)cc1)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(=C/C=C/C(=O)O)c2cccnc2)cc1
Reaction time: 1 h
Yield: 98.2 %

Procedure:
In the manner described in Example 99, (2E,4Z)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid methyl ester (6.2 g) was saponified a refluxing mixture of methanol (30 mL) and 1N NaOH (30 mL). After 1 hour, the cooled reaction was neutralized with the addition of 1N HCI (30 mL) and the resulting crystalline solid was filtered off and washed well with water to give 5.8 g of (2E,4Z)-5-(4-methoxyphenyl)-5(3-pyridinyl)-2,4-pentadienoic acid, mp 235°-238° C. A sample was recrystallized from methanol to furnish the analytical specimen, mp 238°-240° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:18])[F:17])=[CH:5][CH:4]=1)=O.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[F:17][C:16]([F:19])([F:18])[O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[C:24]2[S:20][C:21](=[O:26])[NH:22][C:23]2=[O:25])=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(-c2ccccc2OC(F)(F)F)cc1
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(=Cc2ccc(-c3ccccc3OC(F)(F)F)cc2)S1

Procedure:
To a solution of 4-formyl-(2′-trifluoromethoxy-1,1′-biphenyl) (0.31 g, 1.16 mmol) and 2,4-thiazolidinedione (0.164 g, 1.4 mmol) in toluene (20 mL) were added piperidine (0.015 mL, 0.152 mmol) and benzoic acid (0.021 mg, 0.175 mmol), and the reaction was refluxed for 3 h with continuous removal of water. The solvent was then distilled off and the residue was crystallized from ether-pet ether to yield titled product as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([CH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])[C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)([N:26]1C=CN=C1)=O.O.N.O>O1CCCC1.C(OCC)(=O)C>[NH2:26][C:11](=[O:12])[C@@H:10]([CH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(Cl)cc1C[C@@H](CNC(=O)OC(C)(C)C)C(=O)O
Agent: N
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1C[C@@H](CNC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
(Step 3) To (2S)-3-[(tert-butoxycarbonyl)amino]-2-(5-chloro-2-methoxybenzyl)propanoic acid (30 g) in tetrahydrofuran (150 ml) solution, 1,1′-carbonyldiimidazole (15.6 g) was added under ice cooling and the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled to 0° C., 28% ammonia water (30 ml) was added, and the mixture was stirred at room temperature for 30 minutes. Distilled water and ethyl acetate were added to the reaction solution, the aqueous layer and the organic layer were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was successively washed with saturated potassium hydrogensulfate aqueous solution and saturated saline, dried over with anhydrous sodium sulfate, then concentrated. Hexane and ethyl acetate were added to the precipitated solid and the mixture was stirred in the suspended state at room temperature. The precipitated solid was collected by filtration to obtain the title compound (29.2 g).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:28](OCC)=[O:29])=[CH:16][C:15]([F:33])=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:35][NH2:36]>CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:35][NH:36][C:28](=[O:29])[C:17]=4[CH:16]=[C:15]([F:33])[CH:14]=3)[CH:20]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: NN
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ccccc1)C(c1ccc(CN(C)C)cc1)N2
Solvent: O
Solvent: CO
Product: CN(C)Cc1ccc(C2Nc3cc(F)cc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A mixture of compound ethyl 2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (80 mg, 0.18 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The solvent was removed in vacuum; the crude product was purified by chromatography to obtain the title compound as a yellow solid (22 mg, yield 30%). LC-MS (ESI) m/z: 415 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.14 (s, 6H), 3.36 (s, 2H), 4.18-4.21 (d, J=8.8 Hz, 1H), 4.67-4.69 (d, J=9.2 Hz, 1H), 6.81-6.84 (m, 1H), 6.99-7.01 (m, 2H), 7.08-7.19 (m, 8H).
Reaction SMILES: [C:1]([N:4]1[CH:16]2[CH:5]1[C:6]1([OH:23])[O:17][N:14]([CH2:15]2)[C:13]2[C:8](=[C:9]([OH:20])[CH:10]=[C:11]([CH:18]=[O:19])[CH:12]=2)[CH:7]1[CH2:21][OH:22])(=[O:3])[CH3:2].[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[C:24]1([NH:30][C:31](=[O:32])[O:22][CH2:21][CH:7]2[C:6]3([OH:23])[O:17][N:14]([CH2:15][CH:16]4[CH:5]3[N:4]4[C:1](=[O:3])[CH3:2])[C:13]3[C:8]2=[C:9]([O:20][C:31](=[O:32])[NH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:10]=[C:11]([CH:18]=[O:19])[CH:12]=3)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(=O)N1C2CN3OC(O)(C(CO)c4c(O)cc(C=O)cc43)C21
Solvent: CN(C)C=O
Product: CC(=O)N1C2CN3OC(O)(C(COC(=O)Nc4ccccc4)c4c(OC(=O)Nc5ccccc5)cc(C=O)cc43)C21
Reaction time: 0.5 h

Procedure:
To a solution of 11-acetyl-6,9-dihydroxy-8-hydroxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carbaldehyde (18 mg) in dimethylformamide (1.0 ml) was added a mixture of phenyl isocyanate (12.5 μl) in dimethylformamide (1.25 ml) in an ice-water bath. The mixture was stirred for 30 minutes in an ice-water bath and then stirred for additional 1 hour at ambient temperature. The mixture was evaporated in vacuo and subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (15:1, v/v) to afford 11-acetyl-4-formyl-9-hydroxy-6-(N-phenylcarbamoyloxy)-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl N-phenyl-carbamate (12 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:14][S:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:24]Br>C(O)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:14]([Br:24])[S:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: BrBr
Reactant: COc1ccc(-c2cscc2-c2ccc(S(C)(=O)=O)cc2)cc1
Solvent: CC(=O)O
Product: COc1ccc(-c2c(-c3ccc(S(C)(=O)=O)cc3)csc2Br)cc1
Reaction time: 0.25 h

Procedure:
3-(4-methylsulphonylphenyl)-4-(4-methoxyphenyl)thiophene from Example 6 (9.3 mg) was dissolved in acetic acid (10 ml) and heated to 90° C. at which time Br2 in acetic acid (1.0 M, 27 μl) was added in one portion. The reaction was stirred for 15 minutes at which time the solvent was removed at reduced pressure. The residue was dissolved in a minimum of ethyl acetate and chromatographed on silica, eluting with 2.5% isopropanol in hexane, yielding 3-(4-methylsulfonylphenyl)-4-(4-methoxyphenyl)-5-bromothiophene. CI MS (M+H): 423/425.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16](Br)[C:11]=2[N:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[C:37]4=[N:38][CH:39]=[CH:40][CH:41]=[C:36]4[N:35]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:34]3=[O:50])=[CH:29][CH:28]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([C:27]3[CH:32]=[CH:31][C:30]([N:33]4[C:37]5=[N:38][CH:39]=[CH:40][CH:41]=[C:36]5[N:35]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:48])([CH3:47])[CH3:49])[C:34]4=[O:50])=[CH:29][CH:28]=3)[C:11]=2[N:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2c(Br)cccc2n1Cc1ccccc1
Reactant: CC1(C)OB(c2ccc(-n3c(=O)n(COCC[Si](C)(C)C)c4cccnc43)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c(-c3ccc(-n4c(=O)n(COCC[Si](C)(C)C)c5cccnc54)cc3)cccc2n1Cc1ccccc1
Temperature: 100 °C
Yield: 53.5 %

Procedure:
Benzyl chloride (1.527 mL) was added to a solution of 4-bromo-2-methyl-1H-benzimidazole (1.40 g) and sodium hydride (0.531 g) in DMF (10 ml) at 0° C. The mixture was stirred at room temperature under a dry atmosphere for 1 h. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 5%-50% EtOAc in hexane) to give 1-benzyl-4-bromo-2-methyl-1H-benzo[d]imidazole (1.88 g) as tan oil. The mixture of 1-benzyl-4-bromo-2-methyl-1H-benzo[d]imidazole (496 mg), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (700 mg), Pd(Ph3P)4 (87 mg), sodium carbonate (476 mg) and THF (18 mL)-water (0.90 mL) was heated at 100° C. for 1 h under microwave irradiation. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10%-50% EtOAc in hexane) to give 3-[4-(1-benzyl-2-methyl-1H-benzimidazol-4-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (450 mg) as white crystals.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[C:10]([NH:12][C@@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]([C@@:16]1([CH3:19])[CH2:18][O:17]1)=[O:15])=[O:11].[C:36]([O:40][C:41]([NH:43][C@@H:44]([CH3:48])[C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][C@H:9]([NH:8][C:45](=[O:46])[C@@H:44]([NH:43][C:41](=[O:42])[O:40][C:36]([CH3:38])([CH3:37])[CH3:39])[CH3:48])[C:10]([NH:12][C@@H:13]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([C@@:16]2([CH3:19])[CH2:18][O:17]2)=[O:15])=[O:11])=[CH:33][CH:32]=1
Reactant: COc1ccc(C[C@H](N)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To (S)-2-amino-3-(4-methoxyphenyl)-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)propanamide TFA salt (2.07 mmol) was added (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (782 mg, 4.14 mmol), HATU (1.82 g, 4.77 mmol), and DMF (7 mL). The mixture was cooled to 0° C. and DIEA (3.54 mL, 20.7 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-80% ethyl acetate/heptane) provided tert-butyl ((S)-1-(((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (897 mg, 89%) as a colorless solid. MS (EI) for C26H37N3O6, found 488.4 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:26]=[CH:25][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18](C(N)=O)[CH:17]=3)=[CH:13][C:12]=2[F:27])=[O:9])[C:4](=[O:28])[N:3]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC#[N:37].O.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C>CCOC(C)=O>[NH2:37][C:18]1[CH:17]=[C:16]([O:15][C:14]2[CH:25]=[CH:26][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:28])[N:3]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[C:12]([F:27])[CH:13]=2)[CH:21]=[CH:20][N:19]=1
Reactant: CC#N
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cc2F)c(=O)n(-c2ccccc2)n1C
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.3 %

Procedure:
A solution of 4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-3-fluorophenoxy)picolinamide (370 mg (a little wet), 0.746 mmol) in EtOAc (4.5 mL), CH3CN (4.5 mL) and H2O (2.5 mL) was cooled and stirred at 0° C. for 30 minutes and then PhI(OAc)2 (288 mg, 0.895 mmol) was added. The resulted mixture was stirred at 0° C. for another 30 minutes, then warmed up to rt and stirred for 7 hours. The mixture was filtered and the filter cake was washed with EtOAc (5 mL). The filtrate was concentrated in vacuo and the residue was purified by a silica column gel chromatography (CH2Cl2/MeOH (v/v)=250/9), followed by purifying again by silica gel column chromatography (CH2Cl2/MeOH (v/v)=50/1) to give the title compound as a beige white solid (46 mg, 17.3%).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:17])[CH2:15][CH3:16].C(N(CC)CC)C.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.C(=O)=O.CC(C)=O.[C:49]([O:53][C:54]([N:56]1[CH2:62][CH2:61][CH2:60][C@H:57]1[CH:58]=[O:59])=[O:55])([CH3:52])([CH3:51])[CH3:50]>ClCCl>[OH:59][C@@H:58]([C@@H:57]1[CH2:60][CH2:61][CH2:62][N:56]1[C:54]([O:53][C:49]([CH3:52])([CH3:50])[CH3:51])=[O:55])[C@@H:15]([CH3:16])[C:14]([N:3]1[C@H:2]([CH3:1])[C@H:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:5][C:4]1=[O:13])=[O:17]
Reactant: CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: CCCC[B+]CCCC
Agent: O=C=O
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)[C@H](C)[C@@H](O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 66.5 %

Procedure:
In following the procedure of Shioiri et al. (Shioiri, T.; Hayashi, K.; Hamada, Y. Tetrahedron. 49(9), 1993, 1913-1924), to a 0° C. (ice-water bath) solution of (4R,5S)-4-methyl-5-phenyl-3-propionyl-2-oxazolidinone (6.4 g, 27 mmol, Fluka) in dichloromethane (110 mL) is added triethylamine (4.3 mL, 31 mmol). Di-n-butylboron triflate (1.0 M solution in dichloromethane, 29 mL, Aldrich) is added dropwise and the resulting mixture is allowed to stir for 45 minutes at 0° C., then cooled to −78° C. (dry ice/acetone bath). N-(tert-butoxycarbonyl)-L-prolinal (3.1 g, 16 mmol, Omega) is added dropwise as a solution in dichloromethane (16 mL) and the reaction mixture is allowed to stir for 2 hours at −78° C. The reaction vessel is then stored in a 0° C. freezer overnight. The next morning, the reaction mixture is warmed to room temperature over 15 minutes and then quenched by the addition of pH 7 phosphate buffer (55 mL) followed by methanol (80 mL). The mixture is then cooled to 0° C. (ice-water bath) and 30% hydrogen peroxide-methanol (1:2, 96 mL) is added dropwise to keep the internal temperature less than 10° C. After stirring for 1 hour in an ice-water bath, to the reaction mixture is added water (55 mL). Volatiles are removed under reduced pressure and the aqueous residue is extracted thrice with diethyl ether. The combined extracts are washed with 1 M potassium bisulfate solution, water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude viscous pale yellow oil (9.5 g) is purified by flash chromatography (hexanes/ethyl acetate) to give 4.6 g (67%) of a white foam. MS (ES+): (M+H)=433.3
Reaction SMILES: C[O-].[Na+].C1(C)C=CC=CC=1.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:14]=[C:15]([CH2:19][C:20]([O:22]C)=O)[CH:16]=[CH:17][CH:18]=1.[C:26]1([CH2:32][C:33]#[N:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[C:33]([CH:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20](=[O:22])[CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:25])[F:24])[CH:14]=1)#[N:34]
Reactant: COC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: N#CCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#CC(C(=O)Cc1cccc(C(F)(F)F)c1)c1ccccc1

Procedure:
To a flame-dried flask was added 8.1 g. of sodium methoxide, 125 ml. of toluene and 21 ml. of methanol. The mixture was brought to reflux at 85°-87°, and to it was added dropwise a mixture of 22.8 g. of methyl (3-trifluoromethylphenyl)acetate and 12.9 g. of phenylacetonitrile. The apparatus was then set up for distillation, and the mixture was heated to 110°, removing about 46 ml. of distillate. The mixture was then cooled to about 12°, and to it was added 50 ml. of ice-water. The aqueous layer was removed and washed with 20 ml. of cold toluene. The organics were combined and washed with cold water. The aqueous layers were combined, and the pH was adjusted to 3.5 with cold hydrochloric acid. The oily product was collected by extracting the aqueous portion with three 40 ml. portions of dichloromethane, drying the organic layer over sodium sulfate and evaporating it under vacuum to obtain 30.5 g. of oil, which was 89% pure product by vapor phase chromatography.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[N+:7]([O-])([OH:9])=[O:8].S(=O)(=O)(O)O>O>[CH3:1][C:2]1[NH:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ncc([N+](=O)[O-])[nH]1
Reaction time: 0.17 h

Procedure:
In a nitrator made of acid-resistant stainless steel of 75 liters capacity, provided with a reflux condenser, a mixer and a thermometer as well as a cooling mantle, there were dissolved 8 kg of 2-methylimidazole into a solution already nitrated as in example IV, and then 24 liters of nitric acid of 1.40 density were added in such a manner, that the temperature was maintained at 70°. Thereafter sulphuric acid of 1.84 density was added such that, by simultaneous stirring and cooling, a constant temperature was maintained. After addition of 10 liters of sulphuric acid, the introduction was interrupted and after 10 minutes the sulphuric acid was gradually introduced until a total quantity of 24 liters was used. The reaction proceeded progressively more intensively and the flow of cooling water was correspondingly increased. A supplementary reservoir in the form of a tank with a conduit enabled the introduction of 10 liters of already reacted nitrated solution to the nitrator--a similar device was used in all reactions which have begun at a low temperature. During and after addition of the entire quantity of sulphuric acid, the solution was continually stirred and cooled for 15 minutes, and then, after a clear diminution of the reaction and diminishing of the exothermic effect, a slow increase of temperature, degree by degree in one minute, was allowed until a temperature of 110° has been reached. The mixture was maintained at this temperature for 15 minutes more. Then the reflux condenser was disengaged, while simultaneously leading the liberated vapors and gases directly to the absorption device, and the flow of the cooling water was terminated. The temperature of the reacting mixture raised by itself, reaching at the end a temperature of 138°. At this temperature the reaction was completed in 20 minutes, whereby the solution was condensed by distilling off about 3 liters, mainly water and nitric acid (i.e. diluted nitric acid), whereby after this treatment the cooling of the mixture was reinstituted. In the nitrator, 20% of the volume of the solution was retained for the treatment of the following charge, and from the remaining quantity there was obtained in known manner 8.700 kg of 2-methyl-5-nitroimidazole corresponding to 70% of theoretical.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].CN(C)C=O.N1C(Cl)=NC(Cl)=NC=1Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:16]([O:15][C:13]([NH:12][C@H:3]([C:2]#[N:1])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[O:14])([CH3:17])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C[C@@H](C#N)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the compound obtained from Example 11 was added dimethylformamide (1019.5 g) followed by addition of cyanuric chloride (112.0 g) dropwise for 1.5 hours at temperature below 25° C. The reaction solution was stirred for one hour at room temperature, and then 0.1 N aqueous sodium hydroxide solution (1850.0 g) and toluene (1860 ml) were added thereto to separate the layers. The organic layer thus obtained was washed once again with water (700 ml) and then distilled under reduced pressure to obtain 318.3 g of the title compound.