Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][CH:12]([C:17]([OH:19])=O)[CH2:13][CH2:14][CH2:15]C)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.[NH2:24][C:25]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])=[O:28].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][CH:12]([C:17](=[O:19])[NH:24][C:25]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:26]=1[C:27](=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])[CH2:13][CH2:14][CH3:15])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCCCC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCC(NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reaction time: 1 h

Procedure:
19.7 g of N-carbobenzoxy-DL-norleucine are dissolved in 200 ml of absolute tetrahydrofuran, the solution is treated dropwise while cooling with ice with 10 g of thionyl chloride and then stirred for 1 hour. To this solution there is rapidly added dropwise a solution of 17 g (0.065 L M) of 2-amino-5-nitro-2'-fluorobenzophenone in 130 ml of absolute tetrahydrofuran and the mixture is then stirred at room temperature for 60 hours. The solution is concentrtated and the residue is treated with ice and 10% sodium bicarbonate solution and extracted with methylene chloride. The organic solution is dried with sodium sulphate, filtered and concentrated. The residue is purified on a 450 g silica gel column using methylene chloride as the eluting agent and crystallised from ethanol. There is obtained benzyl-rac-{1-[[2-(o-fluorobenzoyl)-4-nitrophenyl]carbamoyl]butyl}carbamate which melts at 148°-150° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][N:14]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].C(N(CC)CC)C>C(Cl)Cl.O>[CH:12]([CH:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:16][CH2:15][N:14]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C=O)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of DMSO (1.41 mL, 19.9 mmol) in CH2Cl2 (5 mL) was added to a solution of oxalyl chloride (0.87 mL, 9.9 mmol) in CH2Cl2 (25 mL) at −60° C. After 5 min, a solution of 1-benzyl 4-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (3.16 g, 9.03 mmol) in CH2Cl2 (5 mL) was added. After 15 min., triethylamine (6.3 mL, 45 mmol) was added, and the reaction mixture was allowed to warm to rt. After 1 h, water (100 mL) was added, the organics were separated, and the aqueous layer was extracted with CH2Cl2 (3×100 mL). The combined organics were washed with brine (3×150 mL), 1% HCl (3×150 mL), water (150 mL), and 5% NaHCO3 (3×150 mL). The organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. This gave 3.07 g (98%) of the desired product as a thick oil. Rf=0.10 in 30% EtOAc/Hexane.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([CH:3]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:6][CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(CO)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.3 %

Procedure:
To 1-benzyl 4-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (0.4 g) in CH2Cl2 (10 ml) under argon was added Dess Martin periodinane (533 mg), the mixture stirred at room temperature for 16 hours, evaporated to half volume, saturated aqueous sodium bicarbonate and ethyl acetate added, the organic phase dried (MgSO4), and evaporated to give the title compound (228 mg, 57%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:19]=[CH:18][C:10]([CH:11]=[N:12][C@@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])=[CH:9][CH:8]=1.CO.C(OCC)(=O)C>O>[CH3:17][C@H:13]([NH:12][CH2:11][C:10]1[CH:18]=[CH:19][C:7]([O:6][CH2:5][C:4]2[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1)[C:14]([NH2:16])=[O:15]
Reactant: C[C@H](N=Cc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](NCc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
An autoclave is loaded with (S)-2-[4-(3-fluorobenzyloxy)benzylidene-amino]propanamide (16.0 g; 0.053 mol), prepared as described above, and wet (50% H2O) Pt/C5% (1.7 kg: Engelhard S.r.l., Rome, Italy) and methanol (90 mL) is added thereto. The autoclave is purged from air with nitrogen and then hydrogen is introduced at 5.0 bars. The reaction is kept at 5.0 bar and at 35° C. for 1 hour. After cooling to room temperature and elimination of the catalyst by filtration, the solvent is distilled off under reduced pressure until a residue of approximately 30 g is obtained. To this residue a mixture of ethyl acetate (150 mL) and H2O (110 mL) is added and the heterogeneous mixture is heated to 40° C., until two clear phases are obtained. These two phases are separated and the aqueous layer is extracted with 50 mL of ethyl acetate at 40° C. The organic phases are collected and evaporated to dryness. The procedure is repeated twice by adding every time 90 mL of ethyl acetate to make the product anhydrous. 95 mL of n-heptane are then added slowly and under stirring to the residue. The mixture is then maintained under stirring for 3 hours at 20° C. The solid formed is collected by filtration, washed with n-heptane (15 mL) and dried under reduced pressure to give 15.2 g (94.8% yield) of safinamide with a HPLC purity of 99.8 (area %, see Example 17A) and a content of (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propanamide lower than 0.005% by weight measured by HPLC see Example 17B).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[H+].[B-](F)(F)(F)F.CCOCC.[Br:24]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Br:24])[CH:6]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)c1ccc(O)c(Br)c1
Temperature: -15 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
This procedure is modified from the work of Oberhauser (J. Org. Chem, 1997, 62, 4504). To a solution of 4-hydroxybenzoic acid ethyl ester (57.8 g, 348 mmol) in 480 mL of dry acetonitrile was added HBF4 Et2O (54% in Et2O, 32.9 mL). The solution was cooled to −15° C. with an ice/methanol bath. N-bromosuccinimide (67.2 g, 378 mmol) was added portionwise at a rate where the temperature would not rise above −10° C. After addition was complete, the cooling bath was removed and the reaction mixture was allowed to stir overnight at room temperature. Worked up by pouring the reaction mixture into aqueous sodium bisulfite (38%, 200 mL) and extracting four times with ethyl acetate. The organic layers were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give a white solid. Recrystallization from ethyl acetate/hexane gave 3-bromo-4-hydroxybenzoic acid ethyl ester (70.7 g, 83%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.39 (t, J=6.7 Hz, 3H, —CO2CH2CH3), 4.34 (t, J=6.7 Hz, 2H, —CO2CH2CH3), 7.02 (d, 1H, arom), 7.91 (dd, 1H, arom), 8.19 (d, 1H, arom).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[H+].[B-](F)(F)(F)F.[Br:19]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Br:19])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(O)c(Br)c1
Temperature: -15 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
This procedure is modified from the work of Oberhauser (J. Org. Chem, 1997, 62,4504). To a solution of 4-hydroxybenzoic acid ethyl ester (57.8 g, 348 mmol) in 480 mL of dry acetonitrile was added HBF4.EtO (54% in Et2O, 32.9 mL). The solution was cooled to −15° C. with an ice/methanol bath. N-bromosuccinimide (67.2 g, 378 mmol) was added portionwise at a rate where the temperature would not rise above −10° C. After addition was complete, the cooling bath was removed and the reaction mixture was allowed to stir overnight at room temperature. Worked up by pouring the reaction mixture into aqueous sodium bisulfite (38%, 200 mL) and extracting four times with ethyl acetate. The organic layers were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give a white solid. Recrystallization from ethyl acetate/hexane gave 3-bromo-4-hydroxybenzoic acid ethyl ester (70.7 g, 83%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.39 (t, J=6.7 Hz, 3H, —CO2CH2CH3), 4.34 (t, J=6.7 Hz, 2H, CO2CH2CH3), 7.02 (d, 1H, arom), 7.91 (dd, 1H, arom), 8.19 (d, 1H, arom).
Reaction SMILES: [BH4-].[Na+].[CH:3]([N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:16]([O-])=O)[CH:12]=2)[C:7]1=[O:19])([CH3:5])[CH3:4].O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:19])[N:6]([CH:3]([CH3:4])[CH3:5])[C:14]2=[O:15]
Reactant: CC(C)N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: Cl[Sn]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)N1C(=O)c2ccc(N)cc2C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
A solution of sodium borohydride (193 mg, 5.12 mmol) in ethanol (4 ml) was added dropwise to a stirred solution of 2-isopropyl-5-nitro-isoindole-1,3-dione (1.20 g, 5.12 mmol) and tin (II) dichloride dihydrate (3.47 g, 15.36 mmol) in ethanol (40 ml) at 60° C. The resulting solution was stirred for 2 hrs, after which time the reaction was cooled to 0° C. and basified using 2M sodium hydroxide. The aqueous phase was extracted with dichloromethane (3×20 ml) and the combined organics washed with brine, then dried (MgSO4) and evaporated in vacuo. The crude residue was purified by preparative HPLC (Method D) to afford the title compound as a yellow solid (512 mg, 49%). HPLC retention time 7.2 min. Mass spectrum (ES+) m/z 205 (M+H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[NH2:13]>C1(C)C=CC=CC=1.CCCCCC>[CH3:18][O:17][C:15]1[CH:14]=[C:12]([NH:13][C:1](=[O:3])[CH3:2])[CH:11]=[C:10]([O:9][CH3:8])[CH:16]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1cc(NC(C)=O)cc(OC)c1
Reaction time: 15 h
Yield: 98 %

Procedure:
Acetic anhydride (6.5 mL) was added slowly to a stirred solution of 3,5-dimethoxy aniline (10 g, 65.359 mmol) in toluene (50 mL) under argon atmosphere at room temperature and resulting reaction mixture was stirred for 15 h. After completion of the reaction, reaction was diluted with Hexane and resulted precipitate was collected by filtration and dried under vacuum to afford the title compound (12.5 g, 98% of yield) as a off-white solid. 1HNMR (CDCl3, 300 MHz): δ 7.38 (s, 1H), 6.75 (d, 2H), 6.23 (s, 1H), 3.76 (s, 6H), 2.15 (s, 3H); MS (ESI): 196.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH:23]([O:31]C(=O)[C@H](C3C=CC=CC=3)C)[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:18][CH2:17]2)[CH2:6]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([CH2:22][CH:23]([OH:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:21]2)[CH2:6]1
Reactant: C[C@H](C(=O)OC(Cc1ccccc1)CC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: OC(Cc1ccccc1)CC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1

Procedure:
The title compound was prepared from 1-(2,4-dichlorobenzyl)-3-(S)-(4-(3-phenyl-2-((S)-2-phenylpropionyl)oxypropyl)piperidinylmethyl)-4-(S)-(3-thienyl)pyrrolidine (isomer 2) according to procedures described in Step 2a. Mass Spectrum (ESI) m/e=543 (M+1 35Cl, 35Cl), 545 (M+1 35Cl, 37Cl), and 547 (M+1 37Cl, 37Cl). [α]D=+16.0 (c=2.0, CHCl3).
Reaction SMILES: [OH:1][C@H:2]([C@H:6]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14]C(=O)C)[C:3]([OH:5])=[O:4]>O>[OH:1][C@H:2]([C@H:6]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])[C:3]([OH:5])=[O:4]
Reactant: COc1ccc([C@H](Sc2ccccc2NC(C)=O)[C@@H](O)C(=O)O)cc1
Solvent: O
Product: COc1ccc([C@H](Sc2ccccc2N)[C@@H](O)C(=O)O)cc1

Procedure:
A process for the preparation of 2S-cis-hydroxy-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4-(5H)-one, in which (2S,3S)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-acetylaminophenylthio)propionic acid (I) is subjected to prolonged ebollition with 1 to 5 moles of mineral acid which is diluted with water in 1:25 to 1:50 ratios.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8](=O)([O-])[O-:9].[Na+:12].[Na+]>CO>[C:4]([O:9][CH3:8])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O-:6])=[O:7].[Na+:12]
Reactant: O=C1C=CC(=O)O1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C=C\C(=O)[O-]
Yield: 199.9 %

Procedure:
One mole of maleic anhydride is dissolved in 1000 ml methanol and 0.5 mole of sodium carbonate is added. The solution is filtered and the methanol is distilled off under pressure. After drying the product in a vacuum oven, 152 g of sodium methyl maleate is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11]OS(C)(=O)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(CCN2CCCCC2)c1
Yield: 44 %

Procedure:
Methanesulfonic acid 2-(3-nitro-phenyl)-ethyl ester was dissolved in piperidine (20 eq) and THF and stirred at 60° C. for one hour. The solvent was removed. The crude product was diluted with ethyl acetate, washed three times with water, dried with anhydrous sodium sulfate, filtered and concentrated. The product was clean enough to carry forward without purification. 44% yield. MH+=235.1.
Reaction SMILES: [C:1]([Si:5]([C:8]#[CH:9])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].Br[C:11]1[C:16]([F:17])=[CH:15][C:14]([Br:18])=[CH:13][N:12]=1.C(N(CC)CC)C>C1COCC1.[Cu]I>[Br:18][C:14]1[CH:15]=[C:16]([F:17])[C:11]([C:9]#[C:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[N:12][CH:13]=1
Reactant: Fc1cc(Br)cnc1Br
Reactant: C#C[Si](C)(C)C(C)(C)C
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)C#Cc1ncc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere, 2.62 mL (13.811 mmol) of tert-butylethynyldimethylsilane was added to a solution of 3.20 g (12.56 mmol) of 2,5-dibromo-3-fluoropyridine, 5.22 mL of triethylamine (37.67 mmol), 59.8 mg (0.31 mmol) of CuI, and 220.3 mg (0.31 mmol) of bis(triphenylphosphane)palladium (II) chloride in 30 mL of absolute THF at 15° C. and the mixture was stirred for 2 hours at RT. 1 mL of tert-butylethynyldimethylsilane was added and the mixture was again stirred for 1 hour at RT. The reaction mixture was evaporated down in vacuo and the residue was taken up in EtOAc. The organic phase was washed with semisaturated aqueous sodium bicarbonate solution, 5% aqueous ammonia, and water, dried over magnesium sulfate, and evaporated down in vacuo. The crude product was purified by column chromatography (silica gel, PE/DCM 9:1). Yield: 1.62 g (41% of theoretical); C13H17BrFNSi (M=314.269); calc.: molpeak (M+H)+: 314/316 (Br); found: molpeak (M+H)+: 314/316 (Br); HPLC-MS: 7.85 minutes (method B).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[C:25](O)[CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[N+:29]([C:28]1[CH:23]=[CH:24][C:25]([O:21][C:20](=[O:22])[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[CH:26][CH:27]=1)([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-Benzyloxycarbonyl-L-phenylalanine (2.99 g) and p-nitrophenol (1.39 g) are dissolved in tetrahydrofuran (30 ml), and dicyclohexylcarbodiimide (2.1 g) is added thereto under ice-cooling. The mixture is stirred at room temperature for four hours and insoluble materials are filtered off. Ethyl acetate is added to the filtrate and the mixture is washed with an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution, dried, and then concentrated to remove solvent. Hexane is added to the residue to give N-benzyloxycarbonyl-L-phenylalanine-p-nitrophenyl ester as crystals. The product is dissolved in tetrahydrofuran (20 ml), and a solution(15 ml) of L-histidine methyl ester dihydrochloride (2.4 g) and triethylamine (2.8 ml) in water is added thereto under ice-cooling, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure to remove solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=15:1) and crystallized with ethyl acetate to give N-benzyloxycarbonyl-L-phenylalanyl-L-histidine methyl ester (2.8 g) as colorless crystals. Yield ; 64.1%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:14]2([OH:24])[CH:21]3[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)[N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:5]=[CH:6][CH:7]=1.[C:25]([OH:34])(=[O:33])[C@H:26]([C@@H:28]([C:30]([OH:32])=[O:31])[OH:29])[OH:27]>CO.C(#N)C>[C:30]([CH:28]([CH:26]([C:25]([OH:34])=[O:33])[OH:27])[OH:29])([OH:32])=[O:31].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:14]2([OH:24])[CH:15]3[CH2:23][CH:19]4[CH2:18][CH:17]([CH2:22][CH:21]2[CH2:20]4)[CH2:16]3)[N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: OC1(C(c2cccc(Cl)c2)n2ccnc2)C2CC3CC(C2)CC1C3
Solvent: CC#N
Solvent: CO
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
43.0 g (125.4 mmol) of (3-chlorophenyl)-(2-hydroxy-2-adamantyl)-(1-imidazolyl)-methane and 18.83 g (125.4 mmol) of D(-)-tartaric acid were dissolved in a mixture of 67 ml of methanol and 440 ml of acetonitrile at the boiling point. When the solution was slowly cooled to room temperature, crystallization occurred. After 2 days, the crystals were filtered off under suction and washed with acetonitrile and ether and dried for 3 hours at 98° C./3-6 mbar. 23.50 g of (3-chlorophenyl)-(2-hydroxy-2-adamant-yl)-(1-imidazolyl)-methane hydrogen tartrate ([α]D : (+) 4.26° (c=1.0, CH3OH)) were obtained. This product was dissolved in a boiling mixture of 33 ml of methanol and 193 ml of acetonitrile and allowed to crystallize out at room temperature. After isolation as described above, 18.00 g of product [α]D22 : (+) 5.30° (c=1.0, CH3OH)) were obtained. These 18.00 g were recrystallized in an analogous manner from 26 ml of methanol and 151 ml of acetonitrile. 14.2 g of product [α]D22 : (+) 5.53° (c=1.0, CH3OH)) were obtained. A further recrystallization from 20 ml of methanol and 116 ml of acetonitrile gave 11.7 g of product ([α]D22 : (+) 5.90° (c=1.0, CH3OH)). Further recrystallization of this substance from 16 ml of methanol and 95 ml of acetonitrile in 9.60 g of (3-chlorophenyl)-(2-hydroxy-2-adamantyl)-(1-imidazolyl)-methane hydrogen tartrate ([α]D22 : (+) 6.18° (c=1.0, CH 3 OH)) as a pure diastereomeric salt of melting point 112°-113° C. (decomposition).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a stirred solution of 4-fluoronitrobenzene (7 g, 50 mmol), N,N-dimethylethylenediamine (5.2 g, 60 mmol) and potassium carbonate (7 g, 50 mmol) in 25 ml of dimethysulfoxide was added 0.2 g of tris(3,6-dioxaheptyl) amine(TDA-1). The heterogenous mixture was heated at 90° for 2 h. After cooling to room temperature, 100 g of crushed ice was added to precipitate out the yellow product in 90% yield (9.4 g, 45 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][CH:9]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(N)cn1
Reaction time: 2.5 h
Yield: 98 %

Procedure:
A mixture of tert-butyl 5-nitropyridin-2-ylcarbamate (3.76 g, 15.7 mmol) and Pd/C (Aldrich) (0.588 g, 5.52 mmol) in EtOH (100 mL) was evacuated under vacuum and refilled with hydrogen (6 times). The mixture was hydrogenated under balloon pressure of hydrogen at rt for 2.5 h. The reaction mixture was filtered through a pad of Celite® (diatomaceous earth) (eluent:EtOH) and concentrated to give tert-butyl 5-aminopyridin-2-ylcarbamate (3.22 g, 98% yield) as a cream color solid. 1H NMR (300 MHz, d6-DMSO) δ 9.06 (s, 1H); 7.62 (d, J=1.75 Hz, 1H); 7.40 (d, J=8.62 Hz, 1H); 6.94 (dd, J=8.70, 2.27 Hz, 1H); 4.93 (s, 2H); 1.44 (s, 9H). m/z (ESI, +ve ion) 210.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=O>CC(O)C.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][CH:14]([CH3:16])[C:13]([OH:18])=[O:17]
Reactant: CC(=O)C(=O)O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [Pd]
Solvent: CC(C)O
Product: CC(Nc1ccc(F)c(F)c1F)C(=O)O
Temperature: 40 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
2,3,4-Trifluoronitrobenzene (5.03 g) and pyruvic acid (2.75 g) were dissolved in IPA (40 ml). After adding 10% Pd-C (0.21 g), the mixture was stirred at 40° C. under a hydrogen gas pressure of 2.94 MPa for 3 hours. After filtering off Pd-C, the obtained filtrate was concentrated under reduced pressure. Thus the title compound (6.09 g) was obtained as colorless crystals. Various spectral data of this product was identical with those of a specimen synthesized separately.