Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]Cl)[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH2:28][C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-(4-(4-cyanophenyl)phenyl)-N-ethylsulfonylamine (200 mg, 0.7 mmol), 3-picolyl chloride hydrochloride (123 mg, 0.75 mmol), and cesium carbonate (2.3 g, 7.0 mmol) was dissolved in 10 ml DMF and stirred for 18 h at room temperature. The mixture was diluted with 80 ml ethyl acetate, 20 ml water. The organic phase was separated and washed twice with 25 ml of water. The organic phase was then dried over sodium sulfate, filtered, and concentrated in vacuo to an oily residue. The residue was flushed through a 20 g mega bond elut silica column with 0 to 5% methanol/ethyl acetate. The desired fractions were concentrated in vacuo to afford the title compound. 1H NMR: 8.55 (bs,1H), 8.41 (bs,1H), 7.78 (d,1H,J=8 Hz), 7.72 (d,2H,J=12 Hz), 7.6 (d,2H,J=12 Hz), 7.52 (d,2H,J=12 Hz), 7.35 (d,2H,J=12 Hz), 7.29 (m,1H), 4.95 (s,1H), 3.15 (q,2H,J=8 Hz), 1.45 (t,3H,J=8 Hz). MS calcd. 377.5; MS (M+1) 378.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:16]=1)[CH2:7][O:8][Si](C(C)(C)C)(C)C.C([Mg]Cl)(C)C.[CH:23]1[N:24]=[CH:25][N:26]2[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[C:27]=12.Cl>O1CCCC1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]2([OH:32])[CH2:29][CH2:30][CH2:31][N:26]3[CH:25]=[N:24][CH:23]=[C:27]23)=[C:6]([CH2:7][OH:8])[CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1I
Reactant: O=C1CCCn2cncc21
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCc1cc(Br)ccc1C1(O)CCCn2cncc21
Reaction time: 1 h

Procedure:
A solution of 6.55 mmol of (5-bromo-2-iodo-benzyloxy)-tert-butyl-dimethyl-silane in 20 ml of tetrahydrofuran is cooled to −20° C. 6.55 mmol of an isopropymagnesium chloride solution (2M in tetrahydrofuran) is added dropwise and stirring continued for 1 h at −20° C. A solution of 4.37 mmol of 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [426219-51-4] in 40 ml of tetrahydrofuran is added dropwise and the reaction mixture stirred for 40 minutes at −20° C. The reaction mixture is poured into a mixture of 0.1N aqueous HCl and dichloromethane and the layers are separated. The aqueous layer is basified with sodium bicarbonate and extracted with ethyl acetate. The combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound is obtained as a white foam and used for the next step without further purification. Rt=4.61 (gradient II).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[O:36][CH3:37])=[N:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=2[F:25])=[O:16])=[CH:10][CH:9]=1)#[N:2].C([O-])([O-])=[O:39].[K+].[K+]>CS(C)=O.OO.[Cl-].[Na+].O>[CH3:37][O:36][C:29]1[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:28]=1[CH2:27][NH:26][C:4]1[C:3]([C:1]([NH2:2])=[O:39])=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=3[F:25])=[O:16])=[CH:10][CH:9]=2)[S:6][N:5]=1
Reactant: COc1ccc(CNc2nsc(-c3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2C#N)c(OC)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CNc2nsc(-c3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2C(N)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 1-(4-{4-cyano-3-[(2,4-dimethoxybenzyl)amino]isothiazol-5-yl}phenyl)-3-(2-fluoro-5-methylphenyl)urea (26 mg, 0.050 mmol) in 0.8 mL DMSO at rt was added catalytic K2CO3, 5 drops 30% hydrogen peroxide and the reaction stirred at rt for 30 min. The reaction was added into a solution of dilute brine and the precipitant filtered and rinsed with water, then 30% EtOAc/hexane to give the title compound as a pale yellow solid (24 mg, 91%).
Reaction SMILES: C(P(=O)(O)O)=C.[CH:7]([P:9]([Cl:12])([Cl:11])=[O:10])=[CH2:8].[C:13]([Cl:16])(Cl)=O>ClCCCl>[CH:7]([P:9]([Cl:12])([Cl:11])=[O:10])=[CH2:8].[Cl:16][CH2:13][CH2:7][P:9]([Cl:12])([Cl:11])=[O:10]
Reactant: O=C(Cl)Cl
Agent: C=CP(=O)(Cl)Cl
Agent: C=CP(=O)(O)O
Solvent: ClCCCl
Product: O=P(Cl)(Cl)CCCl
Reaction time: 10 h

Procedure:
298 g of the vinylphosphonic acid derivatives thus prepared are metered into 300 g of vinylphosphonic acid dichloride at 145° C. during the course of 4 hours, whilst stirring, during which time phosgene gas is continuously introduced into the reaction mixture. The reaction mixture is then further phosgenated for 10 hours at this temperature. 1,2-Dichloroethane which is formed distils off during the phosgenation. After the phosgenation has ended, the excess phosgene is stripped off at room temperature in the vacuum from a water jet. The mixture is then distilled at 2 mm Hg with the aid of a column. 430 g of vinylphosphonic acid dichloride and 140 g of 2-chloroethanephosphonic acid dichloride are obtained. The distillation residue is 39 g. 130 g of vinylphosphonic acid dichloride and 140 g of 2-chloroethanephosphonic acid dichloride were thus prepared from 298 g of vinylphosphonic acid derivatives. The 2-chloroethanephosphonic acid dichloride can again be employed as the reaction medium in a second mixture, instead of the vinylphosphonic acid dichloride.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([OH:11])=[O:10])[N:4]=1.[CH3:14][Si](C=[N+]=[N-])(C)C.O>C1COCC1.CO.CC(O)=O>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11][CH3:14])=[O:10])[N:4]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1nccc(C(F)(F)F)n1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1nccc(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-(trifluoromethyl)pyrimidine-2-carboxylic acid (500 mg, 2.6 mmol) was dissolved in a mixture of 1 mL of THF and 300 μL of MeOH and cooled to 0° C. Trimethylsilyldiazomethane (2M in ether, 2.6 mL, 5.2 mmol) was added dropwise. The solution was stirred for 2 hours at 0° C., then 1 hour at rt. A few drops of AcOH were added, followed by water. The aqueous solution was extracted three times with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated to give an oil which was used without further purification. MS (ESI): mass calcd. for C7H5F3N2O2, 206.0; m/z found, 207.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.24 (d, J=5.0 Hz, 1H), 7.87 (d, J=5.0 Hz, 1H), 4.10 (s, 3H).
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([F:28])[CH:17]=2)[CH3:15])[N:13]=1)([C:3]([O:5]CC)=O)=[O:2].O.[NH3:30]>C(O)C>[C:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([F:28])[CH:17]=2)[CH3:15])[N:13]=1)(=[O:2])[C:3]([NH2:30])=[O:5]
Reactant: N
Reactant: CCOC(=O)C(=O)Nc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)cs1
Solvent: CCO
Solvent: O
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(NC(=O)C(N)=O)n1
Yield: 26 %

Procedure:
To 2-ethoxalylamino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (0.50 g, 1.29 mmol) in ethanol (10 ml) was added ammonia water (2ml). After the addition, the mixture was refluxed for 2 h, evaporated under reduced pressure to a residue, which was extracted with chloroform. The extracts were dried over and evaporated under reduced pressure to residue, which was chromatographed to afford 2-oxamoylamino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (0.121 g, 26% yield) as crystalline material: mp 179.0°-180.0° C.
Reaction SMILES: C([Li])CCC.[I-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])C=CC=CC=1.[CH2:32]([O:34][C:35]([CH:37]1[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1)=[O:36])[CH3:33].[Cl-].[NH4+]>C1COCC1>[F:17][C:16]([F:19])([F:18])[CH2:15][CH:14]=[C:40]1[CH2:41][CH2:42][CH:37]([C:35]([O:34][CH2:32][CH3:33])=[O:36])[CH2:38][CH2:39]1
Reactant: FC(F)(F)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: [Cl-]
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(=CCC(F)(F)F)CC1
Reaction time: 0.33 h
Yield: 95.9 %

Procedure:
n-Butyllithium (1.6 M solution in hexane, 26 ml, 41.6 mmol) was added to a solution of triphenyl-(3,3,3-trifluoro-propyl)-phosphonium iodide (20.25 g, 41.64 mmol) in THF (141 ml) at −78° C. over 13 minutes, and the mixture was stirred at the same temperature for 20 minutes. A solution of 4-oxo-cyclohexanecarboxylic acid ethyl ester (6.56 g, 38.54 mmol) in THF (22 ml) was added to the reaction solution at −78° C. over 17 minutes, and the mixture was stirred at the same temperature for one hour. A 50% saturated aqueous ammonium chloride solution was added, followed by extraction with dichloromethane. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give ethyl 4-(3,3,3-trifluoro-propylidene)-cyclohexanecarboxylate (9.25 g, 96%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][N:18]4[N:21]=[CH:22][C:23]([CH:24]=O)=[C:17]4[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.[NH:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[O:28].N1CCCCC1>CCO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][N:18]4[N:21]=[CH:22][C:23]([CH:24]=[C:32]5[NH:26][C:27](=[O:28])[NH:29][C:30]5=[O:31])=[C:17]4[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: O=C1CNC(=O)N1
Reactant: CN1CCN(c2cccc(Nc3ccn4ncc(C=O)c4n3)c2)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN1CCN(c2cccc(Nc3ccn4ncc(C=C5NC(=O)NC5=O)c4n3)c2)CC1
Temperature: 70 °C

Procedure:
To 5-(3-(4-methylpiperazin-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (74 mg, 0.221 mmol) in EtOH was added hydantoin (22 mg, 0.221 mmol) and piperidine (22 μL, 0.221 mmol). The mixture was heated at 70° C. The solid formed was filtered off and the filtrate was prepared by HPLC to yield 5-((5-(3-(4-methylpiperazin-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=419)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20]C(=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[H-].[Na+].Br[C@@H:31]([C:33]1[CH:38]=[CH:37][C:36]([C:39](=[O:45])[CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:35][CH:34]=1)[CH3:32].O[C@H](C1C=CC(C(=O)CC(C)(C)C)=CC=1)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N(Br)C(=O)C1>CO.[NH4+].[Cl-].CCOC(C)=O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C@H:31]([C:33]3[CH:38]=[CH:37][C:36]([C:39](=[O:45])[CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:35][CH:34]=3)[CH3:32])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: C[C@@H](Br)c1ccc(C(=O)CC(C)(C)C)cc1
Agent: C[C@H](O)c1ccc(C(=O)CC(C)(C)C)cc1
Agent: O=C1CCC(=O)N1Br
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2)c1ccc(C(=O)CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Heat the mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (310 mg, 0.807 mmol) and potassium hydroxide (1.45 g, 25.83 mmol) in methanol (5 mL) at 50° C. for 3 h. Cool the reaction mixture to room temperature and dilute with saturated aqueous NH4Cl and EtOAc. Separate the layers and extract the aqueous layer three times with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine in anhydrous DMF (2 mL) and cool at 0° C. Add sodium hydride (21 mg, 0.888 mmol) and a solution of (R)-1-[4-(1-bromoethyl)-phenyl]-3,3-dimethylbutan-1-one {prepared by the mixture of (S)-1-[4-(1-hydroxyethyl)-phenyl]-3,3-dimethylbutan-1-one (213 mg, 0.969 mmol), triphenylphosphine (296 mg, 1.130 mmol) and NBS (201 mg, 1.13 mmol) in anhydrous THF (5 mL) at 0° C. and then room temperature}. Stir the mixture at 0° C. for 30 min and quench with water. Dilute with EtOAc and extract the aqueous layer three times with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (85:15) to give (S)-3-tert-butoxycarbonyl-7-chloro-6-{1-[4-(3,3-dimethylbutyryl)-phenyl]-ethylthio}-2,3,4,5-tetrahydro-1H-benzo[d]azepine as yellow oil (197 mg, 47%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[S:14](=[O:18])(=[O:17])[CH2:15][CH2:16][C:12]=3[N:11](C(OC(C)(C)C)=O)[C:10]3[CH2:26][O:27][CH2:28][C:29](=[O:30])[C:9]2=3)=[CH:4][C:3]=1[Sn](C)(C)C.ClN1C(=O)CCC1=O.[I-:43].[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[S:14](=[O:18])(=[O:17])[CH2:15][CH2:16][C:12]=3[NH:11][C:10]3[CH2:26][O:27][CH2:28][C:29](=[O:30])[C:9]2=3)=[CH:4][C:3]=1[I:43]
Reactant: CC(C)(C)OC(=O)N1C2=C(C(=O)COC2)C(c2ccc(F)c([Sn](C)(C)C)c2)C2=C1CCS2(=O)=O
Reactant: [I-]
Agent: O=C1CCC(=O)N1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C1COCC2=C1C(c1ccc(F)c(I)c1)C1=C(CCS1(=O)=O)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
The product from Example 1I (0.023 g, 0.038 mmol) in 1% acetic acid in methanol (25 mL) was treated with N-chlorosuccinimide (0.010 g, 0.077 mmol) and sodium iodide (0.011 g, 0.077 mmol), stirred for 10 minutes, treated with pulverized sodium thiosulfate pentahydrate (0.020 g, 0.080 mmol), stirred for 10 minutes and concentrated to dryness. The residue was treated with trifluoroacetic acid (3 mL), stirred at ambient temperature for 15 minutes and concentrated to dryness. The residue was retreated with trifluoroacetic acid (3 mL), heated gently on a steam bath for 1 minute, allowed to cool to ambient temperature and concentrated to dryness. The residue was purified by chromatography on silica gel (2% methanol and then 5% methanol in methylene chloride) to provide the title compound (0.0156 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.O1CCC[CH2:13]1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[CH2:13])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=C1CCc2ccc(Br)cc21
Product: C=C1CCc2ccc(Br)cc21
Yield: 93.4 %

Procedure:
6-Bromo-indan-1-one 38b (898 mg, 4.25 mmol) was dissolved in 5 mL of tetrahydrofuran under stirring followed by addition of above mentioned mixture. The reaction mixture was stirred at room temperature for 1 hour prior to quenching by addition of 25 mL of water. The mixture was extracted with dichloromethane (25 mL×4). The combined organic extracts were washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 6-bromo-1-methylene-indan 38c (830 mg, yield 93.4%) as a yellow oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.CC(OC([NH:15][C@@H:16]([C:27]([OH:29])=O)[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)=O)(C)C.[C:30]([C@H:35]1[CH2:39][CH2:38][C@H:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[NH:36]1)([O:32][CH2:33][CH3:34])=[O:31].C1(OC)C=CC=CC=1.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(Cl)(Cl)Cl.CO>[NH2:15][C@@H:16]([C:27]([N:36]1[C@@H:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:38][CH2:39][C@@H:35]1[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:29])[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)OCC)N1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H]1CC[C@H](C(=O)OCC)N1C(=O)[C@H](N)Cc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 115.4 %

Procedure:
A 25% solution of TFA in CH2Cl2 (25 ml) was added at 0° C. to an isomeric mixture 0.94 g (1.9 mmol) of the tryptophan pyrrolidine diester (2) and 0.41 (3.8 mmol) anisole. The reaction mixture was stirred at 0° C. for 15 min and then at room temperature for 2. hr. TLC analysis (93:7, CHCl3 /MeOH) using a ninhydrin indicator showed the complete disappearance of the starting material and the appearance of a new spot near the baseline. Without isolation of this material, the TFA was neutralized by the addition of 12.12 ml of diisopropylethylamine and the mixture turned from dark red to yellow. After stirring at room temperature for approximately six hours, TLC analysis of the reaction mixture (95:5;CHCl3 /MeOH) showed the presence of two major isomers in approximately a 2:1 ratio. After removal of the CH2Cl2 in vacuo, the suspension was extracted into ethyl acetate and washed and dried over anhydrous MgSO4. Concentration in vacuo resulted in 0.88 g of a dark brown oil. Column chromatography over silica gel (CHCl3) produced 0.30g (44%) of the trans isomer that yielded the following 1H NMR (CDCl3, 360 MHz) data:
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][N:6]([CH:9]2[O:13][CH:12]([CH2:14][O:15][C:16](=[O:22])[CH:17]([NH2:21])[CH:18]([CH3:20])C)[CH:11]([OH:23])[CH:10]2[OH:24])[C:5](=[O:25])[N:4]=1.Cl.NC1C=CN([CH:34]2O[CH:37]([CH2:39]OC(=O)C(N)C)[CH:36](O)[CH:35]2O)C(=O)N=1>>[ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][N:6]([CH:9]2[O:13][CH:12]([CH2:14][O:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][C:20]3[CH:39]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:11]([OH:23])[CH:10]2[OH:24])[C:5](=[O:25])[N:4]=1
Reactant: CC(C)C(N)C(=O)OCC1OC(n2ccc(N)nc2=O)C(O)C1O
Reactant: CC(N)C(=O)OCC1OC(n2ccc(N)nc2=O)C(O)C1O
Agent: Cl
Product: Nc1ccn(C2OC(COC(=O)C(N)Cc3ccccc3)C(O)C2O)c(=O)n1

Procedure:
In similar fashion substituting boc-L-valine and boc-L-alanine there was obtained respectively, 2-amino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethyl ester hydrochloride (compound 18; MH+=384; MNa+=406) and 2-amino-propionic acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethyl ester hydrochloride (compound 20; MH+=356; MNa+=378).
Reaction SMILES: [H-].[Na+].[N:3]([CH2:6][C@@H:7]1[NH:11][C:10](=[O:12])[CH2:9][CH2:8]1)=[N+:4]=[N-:5].Br[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[N:3]([CH2:6][C@H:7]1[CH2:8][CH2:9][C:10](=[O:12])[N:11]1[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N+:4]=[N-:5]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: [N-]=[N+]=NC[C@H]1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCN1C(=O)CC[C@@H]1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To NaH (128 mg, 3.21 mmol) in DMF (5.0 mL) was added (R)-5-(azidomethyl)pyrrolidin-2-one (300 mg, 2.14 mmol) in DMF (5.0 mL) and stirred at rt for 30 min followed by addition of tert-butyl 3-bromopropylcarbamate. The mixture was heated to 60° C. for 2 h and quenched with sat. NH4Cl solution. The aqueous layer was extracted with EtOAc (50 mL×2) and the combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (R)-tert-butyl 3-(2-(azidomethyl)-5-oxopyrrolidin-1-yl)propylcarbamate (358 mg of crude), which was used for next step without purification. LRMS (M+H+-Boc) m/z 198.1.
Reaction SMILES: [F:1][C:2]([F:5])([F:4])I.[CH2:6]([N:13]([CH3:27])[C:14]([CH2:16][CH2:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH:25]=[O:26])=[O:19])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>[Zn].CN(C=O)C>[CH2:6]([N:13]([CH3:27])[C:14]([CH2:16][CH2:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH:25]([OH:26])[C:2]([F:5])([F:4])[F:1])=[O:19])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C=O
Reactant: FC(F)(F)I
Agent: Cl
Agent: [Zn]
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(O)C(F)(F)F
Yield: 24.8 %

Procedure:
Trifluoroiodomethane (2.3 g) was cooled to -78° C. with a trap. DMF (7 ml), (2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-al (710 mg) and zinc (1.0 g) were added there to. And the mixture was treated with ultrasonic waves for 2 hrs. at room temperature. 1N hydrochloric acid was added to the reaction solution. The mixture was extracted with EtOAc. The extract was washed, dried, and evaporated. The residue was purified by column chromatography on silica gel (hexane-EtOAc) to give the title compound (217 mg) having the following physical data:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[CH2:12]([NH:15][CH2:16][CH:17]=[CH2:18])[CH:13]=[CH2:14].O>C(#N)C>[CH2:12]([N:15]([CH2:16][CH:17]=[CH2:18])[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4])[CH:13]=[CH2:14]
Reactant: C=CCNCC=C
Reactant: O=C(CCl)c1ccc(F)cc1
Solvent: O
Solvent: CC#N
Product: C=CCN(CC=C)CC(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 118.3 %

Procedure:
2-Chloro-1-(4-fluorophenyl)ethanone (10 g, 57.4 mmol) is dissolved in acetonitrile (400 mL). The solution is cooled to 0° C. and diallylamine (15.6 mL, 126.2 mmol) is added. After 1 hour, the mixture is poured into water (500 mL) and extracted twice with ethyl acetate (400 mL). The organic extracts are combined, washed with brine (1×200 mL), dried over sodium sulfate, filtered, and concentrated to give the crude title compound (15.84 g, 118%). ES/MS (m/e): 234 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[S:25][C:24]([CH2:26][N:27]5[CH2:30][CH:29]([C:31]([O:33]CC)=[O:32])[CH2:28]5)=[CH:23][CH:22]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[S:25][C:24]([CH2:26][N:27]5[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]5)=[CH:23][CH:22]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:13])([F:14])[F:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CN(Cc2ccc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)s2)C1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CN(Cc2ccc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)s2)C1
Yield: 53.1 %

Procedure:
The title compound (60 mg) was synthesized in a yield of 53% as a white crystalline solid by conducting the similar reaction to that mentioned in Example 3 (3e) using ethyl 1-[(5-{5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methyl]azetidine-3-carboxylate (0.12 g, 0.23 mmol) that was obtained in Example 4 (4d) and a 1N aqueous solution of sodium hydroxide (0.69 ml, 0.69 mmol).