Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([O:5][C:6](=[O:12])[O:7][C:8](Cl)(Cl)Cl)(Cl)Cl.[N:13]1[CH:18]=CC=C[CH:14]=1.[O:19]1[CH2:23]C[CH2:21][CH2:20]1>>[ClH:1].[C:6](=[O:12])([O:7][CH2:8][CH2:18][NH:13][CH3:14])[O:5][CH2:2][CH2:21][CH2:20][O:19][CH3:23]
Reactant: c1ccncc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1CCOC1
Product: CNCCOC(=O)OCCCOC
Product: Cl
Reaction time: 0.08 h

Procedure:
To a solution of bis(trichloromethyl)carbonate (0.53 g) in tetrahydrofuran (20 mL) was added dropwise a solution of pyridine (0.44 mL) in tetrahydrofuran (1 mL) under ice-cooling. The reaction solution was stirred for 5 minutes under ice-cooling, and 3-methoxypropyl 2-(methylamino)ethyl carbonate hydrochloride (0.82 g) obtained in Reference Synthetic Example 49 was added thereto. A solution of triethylamine (0.75 mL) in tetrahydrofuran (1 mL) was added dropwise, and stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, and to the residue was added water (50 mL), and then extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2 N hydrochloric acid (20 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 mL). To the solution were added (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.11 g), triethylamine (0.63 mL) and 4-dimethylaminopyridine (0.037 g), and stirred at 60° C. for 6 hrs, and further at room temperature for 6 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (50 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified with basic silica gel column chromatography (eluted with ethyl acetate:hexane=3:7, then ethyl acetate:hexane=7:3). The purified material was crystallized from diethyl ether to give title compound as colorless solid (0.70 g).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH:18]3[CH2:23][CH2:22][CH:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19]3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C1COCC1>[C:24]([C@H:21]1[CH2:22][CH2:23][C@H:18]([O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][CH2:9][CH2:10]3)[CH2:19][CH2:20]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OC3CCC(C(C)(C)C)CC3)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CCN3)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-(4-tert-butyl-cyclohexyloxy)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.92 g, 2.5 mmol) in THF (10 mL) was added 4 M HCl in dioxane (6 mL, 25 mmol). The mixture was stirred at room temperature for 48 hrs to form white precipitate. This mixture was partitioned between dichloromethane and aqueous sodium bicarbonate, and the organic phase was dried over MgSO4, filtered and concentrated. The crude was purified with a silica gel column eluted with methanol in dichloromethane from 0 to 8% to give precipitate (0.67 g, yield: 99%). ESI-MS: 274.2 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH2:6][C:7](OCC)=[O:8])(=[O:3])[CH3:2].[BH4-].[Na+].CO.[OH-].[Na+]>C1COCC1.O>[F:18][C:14]1[CH:13]=[C:12]([C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7][OH:8])[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C[C@H](NC(C)=O)c1cccc(F)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N[C@@H](CCO)c1cccc(F)c1
Temperature: 50 °C
Yield: 99.5 %

Procedure:
A stirred suspension of ethyl (3S)-3-(acetylamino)-3-(3-fluorophenyl)propanoate (2.5 g, 9.9 mmol) and sodium borohydride (0.76 g, 20 mmol) in THF (20 ml) was heated at 50° C. under a nitrogen atmosphere. Methanol (1.8 ml) was then carefully added dropwise and the reaction mixture heated under reflux for one hour. The reaction was allowed to cool to room temperature then water (10 ml) and aqueous sodium hydroxide solution (1.5 g NaOH in 4 ml water) carefully added dropwise. The solution was extracted with ethyl acetate (3×30 ml) and the combined organic extracts dried (MgSO4) and evaporated to give the title compound as a white solid (2.08 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C@:12]12[CH2:17][C@H:16]1[CH2:15][NH:14][CH2:13]2.Br[CH2:19][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].C(N(CC)CC)C.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C1COCC1>[CH3:28][C:26]([Si:23]([CH3:25])([CH3:24])[O:22][CH2:21][CH2:20][CH2:19][N:14]1[CH2:15][C@H:16]2[C@:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[F:1])([CH2:17]2)[CH2:13]1)([CH3:27])[CH3:29]
Reactant: Fc1cc(C(F)(F)F)ccc1[C@@]12CNC[C@@H]1C2
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCCN1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2F)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.8 %

Procedure:
A mixture of (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (150 mg, 0.6 mmol), [(3-bromopropyl)oxy](1,1-dimethylethyl)dimethylsilane (233 mg, 0.92 mmol), triethylamine (185 mg, 1.83 mmol) and Nal (20 mg) in THF (2 mL) was stirred at r.t. for 20 h. The reaction mixture was concentrated under vacuum, water was added and the aqueous phase was extracted with EtOAc. The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum and the crude was purified by column chromatography (eluting with EtOAc/cyclohexane 3/7) to give 245 mg of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[N+:17]([C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1)([O-:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:16][O:15][C:13]([CH:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][C:23]1[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:14]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC(=O)C(CCCCCCO)C(=O)OC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(CCCCCCOc1ccc([N+](=O)[O-])cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.6 %

Procedure:
Compound 16 (1.92 g, 8.3 mmol), 4-nitrophenol (1.39 g, 10.0 mmol) and triphenylphosphine (2.62 g, 10.0 mmol) were dissolved in dry THF (100 mL) and deaerated with argon. Diisopropyl azodicarboxylate (2.0 mL, 10.0 mmol) was added in ten portions under argon and the mixture was stirred for 3 days at r.t. The mixture was evaporated to dryness and purified on silica gel (CH2Cl2), yielding 2.6 g (89%) of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.CC[N:13]([CH2:16]C)[CH2:14][CH3:15].[CH3:18][CH2:19][OH:20]>CC(O)=O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:15]3[CH:14]=[N:13][CH:16]=[N:9][C:6]=3[C:5]([CH:4]3[CH2:3][CH2:8][O:20][CH2:19][CH2:18]3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCN(CC)CC
Reactant: NNc1ccc(Cl)cc1
Reactant: CCO
Agent: Cl
Solvent: CC(=O)O
Product: Clc1ccc(-n2nc(C3CCOCC3)c3ncncc32)cc1
Yield: 20 %

Procedure:
Intermediate 102 (500 mg, 2.21 mmol) and (4-chlorophenyl)hydrazine hydrochloride (434 mg, 2.43 mmol) were dissolved in EtOH (10 mL) and AcOH (2 mL), and stirred for 18 h. The solvents were removed in vacuo and the residue was dissolved in DCM (50 mL) and washed with sat aq Na2CO3 (50 mL). The aqueous layer was extracted with DCM (50 mL) and the combined organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DMF (10 mL) and Et3N (922 μL, 6.62 mmol) was added. The reaction mixture was heated using a microwave at 150° C. for 30 min. The solvents were removed in vacuo and the residue was purified by normal phase column chromatography to give the title compound as a white solid (137 mg, 20%). HRMS (ESI+) calcd for C16H15ClN4O, 315.1007. found 315.1011. HPLC (method B): Rf 4.45 min, 100% purity.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:17][CH3:18])=[O:4].[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C=O)C>[N:19]([CH2:2][C:3]([C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:17][CH3:18])=[O:4])=[N+:20]=[N-:21]
Reactant: COC(=O)c1cc(OC)c(C(=O)CBr)c(OC)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OC)c(C(=O)CN=[N+]=[N-])c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 4-(bromoacetyl)-3,5-dimethoxybenzoate was dissolved in DMF, sodium azide (96 mg) was added to it, and stirred at room temperature for 1 hour. The reaction liquid was poured into water, extracted with ethyl acetate, the organic layer was washed with water and saturated saline water, and dried with sodium sulfate. Sodium sulfate was removed through filtration, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (hexane/ethyl acetate=100/0 to 60/40) to obtain the title compound.
Reaction SMILES: [CH3:1][Mg+].[Br-].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14](C(OCC)=O)[N:13]=[C:12]2[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])([CH3:23])[CH3:22])=[CH:7][CH:6]=1.ClCCl.CC[O:36][CH2:37][CH3:38]>>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:37]([OH:36])([CH3:38])[CH3:1])[N:13]=[C:12]2[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])([CH3:23])[CH3:22])=[CH:7][CH:6]=1
Reactant: C[Mg+]
Reactant: CCOCC
Reactant: CCOC(=O)c1cn(-c2ccc(Br)cc2)c(C(C)(C)c2ccccc2F)n1
Agent: [Br-]
Solvent: ClCCl
Product: CC(C)(O)c1cn(-c2ccc(Br)cc2)c(C(C)(C)c2ccccc2F)n1
Temperature: 0 °C
Yield: 78 %

Procedure:
To a 250 mL round bottom flask, purged with dry N2 and attached with addition funnel, was added a 3.0M MeMgBr (12 mL, 3.7 equiv) solution in Et2O. The flask was cooled to 0° C. prior to dropwise addition of ethyl 1-(4-bromophenyl)-2-(2-(2-fluorophenyl)propan-2-yl)-1H-imidazole-4-carboxylate (4.22 g, 9.78 mmol) in a solution of anhydrous dichloromethane (80 mL). The reaction solution was allowed to stir, warming to room temperature over 1 hr. The reaction solution was quenched by addition of aq NH4Cl. The mixture was poured to a reparatory funnel and the dichloromethane layer was partitioned, dried over Na2SO4, filtered, concentrated and chromatographed through a 40 g SiO2 column using a gradient of 100% Hx to 70% EtOAc to yield the title compound (3.19 g, 78% yield). LCMS (ES): m/z=417.3, 419.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C(N(CC)CC)C.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>CC(C)=O>[CH3:16][CH:15]1[CH2:17][N:3]2[N:4]=[CH:5][N:6]=[C:2]2[NH:1][C:14]1=[O:18]
Reactant: C=C(C)C(=O)Cl
Reactant: Nc1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC1Cn2ncnc2NC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
33.63 g (0.4 mol) 3-amino-1H-1,2,4-triazole was suspended in 300 ml acetone. 44.44 g (0.44 mol) triethyl amine was added and the mixture was cooled to 0° C. 33.63 g (0.44 mol) methacryloyl chloride was added dropwise over 45 minutes, while the temperature was kept at 0° C. The reaction was allowed to continue at 0° C. for one hour. The precipitated salts were removed by filtration and an additional 10 ml triethyl amine was added to the filtrate. The mixture was refluxed for 18 hours. The precipitated compounds were removed by filtration and the solvent was evaporated under reduced pressure. 6-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidin-5-on was isolated by preparative column chromatography on a Prochrom LC 80 system, using Kromasil C18 100 Å 10 μm silica and MeOH and an aqueous solution of 0.2% (v/v) triethyl amine and 0.5% (v/v) acetic acid in a 42/58 ratio as eluent, at a flow rate of 150 ml/min. 770 mg of 6-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidin-5-on was isolated.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:25])([F:24])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:10]=1[C:11](O)=[O:12].[NH2:26][NH2:27]>CN(C)C=O.C(O)C>[F:5][C:6]([F:25])([F:24])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:10]=1[C:11]([NH:26][NH2:27])=[O:12]
Reactant: NN
Reactant: O=C(O)c1c(OCC(F)(F)F)cccc1OCC(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: NNC(=O)c1c(OCC(F)(F)F)cccc1OCC(F)(F)F
Reaction time: 8 h

Procedure:
Thionyl cloride (11.9 g., 100 mmole), 2,6-di(2,2,2-trifluoroethoxy)benzoic acid (2.0 g., 6.3 mmole) and two drops of dimethyl formamide are heated to reflux temperature and maintained at reflux for 4 hours. Unreacted thionyl chloride is removed by distillation on a steam bath at water aspirator pressure. The residue is dissolved in dry tetrahydrofuran and added dropwise to a solution of 95 per cent hydrazine (3.2 g., 100 mmole) in ethanol (15 ml.). The mixture is allowed to sit overnight and evaporate to dryness. The residue is diluted with water and a white solid collected and purified by sublimation (138°-140°/0.2 to 0.5 mm. Hg.) followed by recrystallization from benzene to give 2,6-di-(2,2,2-trifluoroethoxy)benzoic acid hydrazide, m.p. 153°-154° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CO>[Br:20][C:16]1[N:15]=[C:14]([C:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Br)n2)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(Br)n2)CC1
Temperature: 128 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
As shown in FIG. 7—step ii, compound 1031 (2.0 g) was mixed with TFA (25 mL) in a sealed tube and heated at 128° C. for 2 days. Removal of the TFA gave a residue, which was dissolved in methanol (30 mL) and treated with triethylamine (2 mL) and di-tert-butyl dicarbonate (1.4 mL). After 1 hour, the volatiles were removed in vacuo and water (100 mL) was added. Extraction with dichloromethane (3×), concentration, and purification by chromatography (SiO2, 20% ethyl acetate/hexane) gave 6-bromo-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid, tert-butyl ester (compound 1032) (0.96 g).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C@H:15]([N:19]2[CH2:22][C:21]4([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH2:20]2)[CH2:14][CH2:13]3)[CH:5]=1.[CH3:28][C:29]1[S:33][C:32]2=[N:34][C:35]([CH2:37][C:38](O)=[O:39])=[CH:36][N:31]2[N:30]=1.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl.O>[CH3:28][C:29]1[S:33][C:32]2=[N:34][C:35]([CH2:37][C:38]([N:25]3[CH2:26][CH2:27][C:21]4([CH2:22][N:19]([C@H:15]5[C:16]6[C:12](=[CH:11][C:10]([C:6]7[CH:5]=[C:4]([CH3:3])[N:9]=[CH:8][N:7]=7)=[CH:18][CH:17]=6)[CH2:13][CH2:14]5)[CH2:20]4)[CH2:23][CH2:24]3)=[O:39])=[CH:36][N:31]2[N:30]=1
Reactant: Cc1cc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)ncn1
Reactant: Cc1nn2cc(CC(=O)O)nc2s1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCN(C(=O)Cc4cn5nc(C)sc5n4)CC3)C2)ncn1
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a mixture of 2-[(R)-5-(6-methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane dihydrochloride (3-1g, 800 g, 1.87 mol), (2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)acetic acid (SM-1ae, 406.4 g, 2.06 mol), and triethylamine (1.31 L, 9.37 mol) in dichloromethane (8 L) was added T3P (2150 g, 3.37 mol) dropwise over 45 min and stirred for 1 h maintaining a temperature between 20 and 30° C. Water was added dropwise (4 L) and the reaction was stirred at 30° C. for 15 min. The layers were separated and the aqueous layer was concentrated to remove residual solvent under partial vacuum at 20° C. The aqueous layer was treated with activated charcoal (20 wt %), stirred for 30 min and filtered through Celite® washing with water. The filtrate was adjusted to pH 7.5-8.0 with 1N NaOH. The resulting slurry was extracted with dichloromethane (12 L) and stirred for 10 min at room temperature. The layers were separated and the organic layer was concentrated under reduced pressure to approximately 4 L. Isopropyl acetate (12 L) was added and the solution was concentrated under reduced pressure at 78° C. to 8 L. The solution was cooled slowly over 4 hours to 20° C. The resulting slurry was stirred for 1 h, filtered and washed with isopropyl acetate (2.4 L). The resulting solid was further dried under vacuum at 45° C. for 8 hours to give the title compound 3Z as a white crystalline solid (883 g, 92%). MS (ES+) 514.0 (M+H)+. 1H NMR (CDCl3) δ 1.69-1.72 (m, 4H), 1.88-1.96 (m, 1H), 2.11-2.22 (m, 1H), 2.57 (s, 3H), 2.66 (s, 3H), 2.82-2.88 (m, 1H), 3.03-3.20 (m, 5H), 3.49-3.55 (m, 4H), 3.77 (s, 2H), 3.93-3.97 (m, 1H), 7.36 (d, 1H), 7.53 (s, 1H), 7.61 (s, 1H), 7.84 (d, 1H), 7.93 (s, 1H), 9.10 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([F:23])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:35]([C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25]([F:24])=[CH:26][CH:27]=2)=[O:36])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[C:15]([F:23])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)c(F)c1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)c(F)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-fluoro-4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.21 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (230 mg, 1.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (347 mg, 1.81 mmol) and 1-hydroxy-1H-benzotriazole (185 mg, 1.21 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (525 mg, 86%).
Reaction SMILES: [NH:1]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@@H:2]([C:14]([N:16]([CH3:42])[C@H:17]([C:35]([NH:37][CH2:38][C:39]([OH:41])=[O:40])=[O:36])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:34])[NH:23][S:24]([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].O[N:51]1[C:56](=[O:57])[CH2:55][CH2:54][C:52]1=[O:53].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@@H:2]([C:14]([N:16]([CH3:42])[C@H:17]([C:35]([NH:37][CH2:38][C:39]([O:41][N:51]1[C:56](=[O:57])[CH2:55][CH2:54][C:52]1=[O:53])=[O:40])=[O:36])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:34])[NH:23][S:24]([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:25])=[O:26])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:10]([F:11])([F:13])[F:12])=[O:9]
Reactant: O=C1CCC(=O)N1O
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](C(=O)NCC(=O)O)N(C)C(=O)[C@@H](CCCCNC(=O)C(F)(F)F)NC(=O)OC(C)(C)C)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](C(=O)NCC(=O)ON2C(=O)CCC2=O)N(C)C(=O)[C@@H](CCCCNC(=O)C(F)(F)F)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.3 %

Procedure:
Boc-D-Lys(Tfa)-NMeArg(Tos)-Gly (8.00 g, 11.0 mmol), HOSu (1.25 g, 10.8 mmol) and DCC (2.22 g, 10.8 mmol) were dissolved in DMF (75 ml) and stirred at room temperature for 2 days. The solids were removed by filtration and washed with DMF (2×15 ml). The filtrate was concentrated under reduced pressure and the resulting syrup dried under reduced pressure at 40° C. to give a tan solid (6.50 g, 72%). MP=66°-69° C.; FAB-MS: [M+H]=821.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH2:7]([O:9][C:10](=[O:27])[CH2:11][N:12]1[CH2:16][C:15](=O)[C@@H:14]([NH:18][C:19]([C:21]2[S:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[O:20])[CH2:13]1)[CH3:8]>C1COCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[CH2:7]([O:9][C:10](=[O:27])[CH2:11][N:12]1[CH2:16][C:15](=[CH2:1])[C@@H:14]([NH:18][C:19]([C:21]2[S:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[O:20])[CH2:13]1)[CH3:8]
Reactant: CCOC(=O)CN1CC(=O)[C@@H](NC(=O)c2ccc(Cl)s2)C1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1CN(CC(=O)OCC)C[C@@H]1NC(=O)c1ccc(Cl)s1
Temperature: 0 °C
Yield: 76.5 %

Procedure:
39.3 To a cooled (0° C.), stirred suspension of 44 mg potassium tert-butylate in 3 ml THF under an argon atmosphere were added 149 mg methyltriphenylphosphonium bromide. The yellow slurry was then stirred for 1 h 30, slowly warming up to room temperature. A solution of 100 mg {(S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-oxo-pyrrolidin-1-yl}-acetic acid ethyl ester in 2 ml THF was then added. The mixture was heated to reflux and stirred for 2 hrs. The mixture (dark brown slurry) was cooled to r.t., diluted with EtOAc, washed with sat. aq. NH4C1, H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel, gradient: CH2Cl2->CH2Cl2/MeOH 95:5) to give 76 mg {(R)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methylene-pyrrolidin-1-yl}-acetic acid ethyl ester (contaminated with 43 w % triphenylphosphin oxide). Amorphous gum. MS 329.0 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7](=[O:17])[NH:8][C@@H:9]([CH:14]([CH3:16])[CH3:15])[C:10](OC)=[O:11].CCN(CC)CC>CO>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[C@H:9]([CH:14]([CH3:16])[CH3:15])[NH:8][C:7]1=[O:17]
Reactant: COC(=O)[C@@H](NC(=O)NCc1ccc(OC)cc1OC)C(C)C
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C(=O)N[C@@H](C(C)C)C2=O)c(OC)c1
Temperature: 100 °C
Yield: 70.6 %

Procedure:
A solution of (S)-methyl 2-(3-(2,4-dimethoxybenzyl)ureido)-3-methylbutanoate (1.00 g, 3.10 mmol) in MeOH (7.5 mL) and NEt3 (0.430 mL, 3.10 mmol) in a sealed vessel was placed in preheated sand bath (at 100° C.) and heated for 18 hours. The cooled reaction mixture was concentrated and the residue was taken up in ether, washed with water, dried over sodium sulfate and filtered. Purification of the crude material by column chromatography, eluting with 1-3% MeOH/dichloromethane, afforded (S)-3-(2,4-dimethoxybenzyl)-5-isopropylimidazolidine-2,4-dione as an ivory colored solid (0.640 g, 71%). LCMS (APCI+) m/z 293 [M+H]+.