Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH3:13]>CN(C=O)C.C(OCC)(=O)C>[CH2:12]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)[CH3:13]
Reactant: CCBr
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1cc([N+](=O)[O-])cn1
Temperature: -25 °C
Yield: 80.2 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (5.0 g, 44.2 mmol) in anhydrous DMF (100 mL) was NaH (60% in oil) (1.94 g, 48.6 mmol) while being stirred at −25° C. under nitrogen. The mixture was stirred for 30 min before bromoethane (5.30 g, 48.6 mmol) was added. The mixture was continued to stir under nitrogen at −25° C. for 6 h. The solution was diluted with ethyl acetate (100 mL), washed with water (2×50 mL) and brine solution (50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford crude 123a (5.0 g, 80%), which was used in next step without further purification. MS-ESI: [M+H]+ 142.0
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=O)=[C:9]([Br:13])[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[N:7]=1)=[O:5])[CH3:2].[CH:21]([NH2:24])([CH3:23])[CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][NH:24][CH:21]([CH3:23])[CH3:22])=[C:9]([Br:13])[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(Br)c1C=O
Reactant: CC(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(Br)c1CNC(C)C
Reaction time: 18 h

Procedure:
To a stirred solution of 5-bromo-1-(2-chloro-phenyl)-4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (2 g), isopropylamine (0.95 ml) and acetic acid (0.4 ml) in 1,2-dichloroethane (16 ml) was added sodium triacetoxyborohydride (1.8 g) and the resulting slurry was stirred for 18 hours. The reaction was diluted into ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated in vacuo to afford the title compound (I-1c) as a golden oil, 2.5 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5]Cl.[N:13]1([C:19]([S:21][CH3:22])=[S:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][N:16]1[CH2:17][CH2:18][N:13]([C:19]([S:21][CH3:22])=[S:20])[CH2:14][CH2:15]1
Reactant: COc1ccc(OC)c(CCl)c1
Reactant: CSC(=S)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(OC)c(CN2CCN(C(=S)SC)CC2)c1
Yield: 31.9 %

Procedure:
In a nitrogen atmosphere, 2.20 g (11.8 mmol.) of 2,5-dimethoxybenzyl chloride, 2.19 g (11.8 mmol.) of methyl 1-piperazinecarbodithioate, 1.25 g(11.8 mmol.) of anhydrous sodium carbonate and 15 ml of ethanol were mixed and refluxed under heating for 18 hours. Insolubles were removed by filtration. The solvent of the filtrate was distilled off under reduced pressure. To the residue were added 15 ml of dichloromethane and 15 ml of water. The organic solvent portion was taken out, washed with 15 ml of 1-Nhydrochloric acid and 18 ml of 1-N aqueous sodium hydroxide solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by column chromatography to give 1.23 g of methyl 4-(2,5-dimethoxybenzyl)-1-piperazinecarbodithioate, yield 31.9%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:12][N:13]([CH3:17])[CH2:14]2)=[CH:9][C:8]=1[F:25])(=O)=O.BrCC(C1C=CC(Cl)=CC=1)=O.[C:39]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)(=[O:41])[NH2:40].C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH:11]2[C:10]3[C:15](=[CH:16][C:7]([C:45]4[CH:46]=[CH:47][C:42]([C:39]([NH2:40])=[O:41])=[CH:43][CH:44]=4)=[C:8]([F:25])[CH:9]=3)[CH2:14][N:13]([CH3:17])[CH2:12]2)=[CH:19][CH:20]=1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: CN1Cc2cc(OS(=O)(=O)C(F)(F)F)c(F)cc2C(c2ccc(Cl)cc2)C1
Agent: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2cc(-c3ccc(C(N)=O)cc3)c(F)cc2C(c2ccc(Cl)cc2)C1
Temperature: 90 °C
Yield: 31.5 %

Procedure:
A mixture of 4-(4-chlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (695 mg, 1.64 mmol) which was prepared using similar methods described in Step A to Step E of Example 26 starting from 2-bromo-1-(4-chlorophenyl)ethanone, 4-carbamoylphenylboronic acid (406 mg, 2.46 mmol) and cesium carbonate (1.6 mg, 4.92 mmol) in water (5 mL) and N,N-dimethylformamide (20 mL) was degassed with argon and then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (59 mg, 0.08 mmol) was added. The mixture was degassed again and then heated to 90° C. for 2 hours. The mixture was partitioned between water and ethyl acetate (3×) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC followed by preparative thin-layer chromatography (90:10:1 diethyl ether/methanol/concentrated ammonium hydroxide) to give 4-(4-(4-chlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide (204 mg, 32%) as an off-white solid: ESI MS m/z 395 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6](OC)=[CH:7][CH:8]=2)[N:3]=1.N1CCCC1.CCN(C(C)C)C(C)C.[O:29]1CCOC[CH2:30]1>O>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:29][CH3:30])[N:3]=1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1
Reactant: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Product: COc1cccc2nc(Cl)cc(Cl)c12
Temperature: 140 °C
Yield: 43.4 %

Procedure:
To a solution of 2,4-dichloro-7-methoxyquinoline (0.1 g, 0.43 mmol) in 1,4-Dioxane (10 ml) was added pyrrolidine (0.3 g, 0.43 mmol) followed by DIPEA (0.11 g, 0.87 mmol) at room temperature. The reaction mass was heated at 140° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (50 mg, 43.4%) as white solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.86-7.83 (d, J=12 Hz, 1H), 7.06 (s, 1H), 6.88-6.85 (d, J=12 Hz, 1H), 6.67 (s, 1H), 3.91 (s, 3H), 3.58 (t, J=8 Hz, 4H), 2.03 (t, J=6 Hz, 1H); MS: MS m/z 263.1 (M++1).
Reaction SMILES: CON(C)[C:4](=[O:30])[CH:5]=[C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:16][CH2:15]2)[CH2:8][CH2:7]1.[CH3:32][Mg]Cl.O>O1CCCC1>[F:29][C:26]([F:28])([F:27])[C:22]1[CH:21]=[C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH:9]3[CH2:10][CH2:11][C:6](=[CH:5][C:4](=[O:30])[CH3:32])[CH2:7][CH2:8]3)[CH2:19][CH2:18]2)[CH:25]=[CH:24][CH:23]=1
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)C=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
To a solution of 114 mg (0.25 mmol) of N-methoxy-N-methyl-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}-cyclohexylidene)acetamide in 5 mL of dry tetrahydrofuran cooled to 0° C. is added 0.2 mL (0.50 mmol) of a 22% methylmagnesium chloride solution in tetrahydrofuran. The mixture is warmed up to 5° C. and stirred for 90 minutes. Hydrolysis is performed by slow addition of 3 mL of water. The product is extracted 3 times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue is purified over 5 g of silica gel (eluant dichloromethane/methanol 95/5) to give 43 mg (44%) of 1-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)propan-2-one as an oil.
Reaction SMILES: [Al]([NH2:4])(C)C.C1C=CC=CC=1.C(O[C:14](=[O:41])[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]([S:35][CH3:36])=[C:22]2[CH2:37][C:38]([NH2:40])=[O:39])C.Cl>C1C=CC=CC=1>[NH2:4][C:20]1[C:19]([O:18][CH2:17][CH2:16][CH2:15][CH:14]=[O:41])=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22]([CH2:37][C:38]([NH2:40])=[O:39])=[C:23]([S:35][CH3:36])[N:24]2[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C[Al](C)N
Reactant: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)c(SC)n2Cc1ccccc1
Agent: Cl
Solvent: c1ccccc1
Product: CSc1c(CC(N)=O)c2c(N)c(OCCCC=O)ccc2n1Cc1ccccc1
Temperature: 50 °C
Yield: 84 %

Procedure:
Ten mL of 0.6M (CH3)2AlNH2 /benzene was added to 200 mg (0.45 mmol) of 4-[[3-(2-amino-2-oxoethyl)-2-methylthio-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid ethyl ester (Example 46) in 25 mL of benzene and the mixture heated at 50° C. for 1.75 hours. After cooling the mixture was decomposed with ice and 1N HCl added. The mixture was extracted with EtOAc, the EtOAc solution washed with saturated NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was crystallized from EtOH/CH2Cl2 to give 155 mg (84% yield) of 5-(4-amino-4-oxobutoxyl-2-(methylthio)-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 185° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>C(Cl)Cl.[Cl-].[Na+].O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2ccc3ccccc32)cc1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(-n2ccc3ccccc32)cc1
Temperature: 25 °C
Yield: 26.8 %

Procedure:
To 2.90 g (13 mmol) 1-(4-methoxyphenyl)-1H-indole in 80 ml anhydrous DCM at −78° C. was added 2.27 ml (24 mmol) BBr3. The solution was allowed to gradually warm to room temperature overnight. The solution was poured into a slurry of ice and water. Brine was added and the product was extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated. The crude product was chromatographed on SiO2 to afford 0.73 g 1-(4-hydroxyphenyl)-1H-indole as an oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH3:3].[CH3:14][I:15]>C(Cl)Cl>[I-:15].[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:4][N+:2]([CH3:14])([CH3:1])[CH3:3])=[CH:6]1
Reactant: CI
Reactant: CN(C)Cc1c[nH]c2ccccc12
Solvent: ClCCl
Product: C[N+](C)(C)Cc1c[nH]c2ccccc12
Product: [I-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of indole (5.6 g, 47.8 mmol) in acetonitrile (130 ml) is added Eschenmoser's salt (10 g, 54 mmol) under nitrogen atmosphere and the mixture is stirred for 30 min. The mixture is concentrated in vacuo and the residue is diluted with 1M sodium hydroxide solution and extracted with methylene chloride. The organic layer is dried over sodium carbonate and concentrated in vacuo to give 3-(dimethylaminomethyl)indole as a brown oil. To a solution of 3-(dimethylaminomethyl)indole in methylene chloride (200 ml) is dropped methyl iodide (5 ml, 80 mmol). The mixture is stirred at r.t. for 6 hrs. and concentrated in vacuo to give (3-indolylmethyl)trimethylammonium iodide as a brown foam. To a cooled (0° C.) suspension of sodium hydroxide (1.5 g, 37 mmol) in DMF (100 ml) is added trimethyl phosphonoacetate (6.7 ml, 41 mmol) and the mixture is stirred at 0° C. for 30 min. To the mixture is added (3-indolylmethyl)trimethylammonium iodide and the whole is stirred at r.t. overnight. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with ethyl acetate to give methyl 3-(3-indolyl)-2-(dimethylphosphono)propionate a a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].Br[CH2:19][C:20]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[O:24][CH2:23][CH2:22][O:21]1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:19][C:20]3([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:21][CH2:22][CH2:23][O:24]3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Fc1ccc(C2(CBr)OCCO2)cc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC2(c3ccc(F)cc3)OCCO2)C1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.2 mmol) was dissolved in 5 mL of NMP. KOH (896 mg, 15 mmol) was added at RT under nitrogen atmosphere and the reaction mixture was stirred for 5 min. 2-Bromomethyl-2-(4-fluorophenyl)-1,3-dioxolane (886 mg, 3.4 mmol) was added and the reaction mixture was heated at 100° C. overnight. Water was added and the product was extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-2% MeOH:DCM.
Reaction SMILES: [CH2:1]([S:7][CH2:8][CH:9]1[CH:14]2[O:15][CH:11]([CH2:12][CH2:13]2)[CH:10]1[CH2:16][CH:17]=[CH:18][CH2:19][CH2:20][C:21]([CH3:34])([CH3:33])[C:22](=[N:31]O)[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].I([O-])(=O)(=O)=[O:36].[Na+].O1CCCC1>CO>[CH2:1]([S:7]([CH2:8][CH:9]1[CH:14]2[O:15][CH:11]([CH2:12][CH2:13]2)[CH:10]1[CH2:16][CH:17]=[CH:18][CH2:19][CH2:20][C:21]([CH3:34])([CH3:33])[C:22](=[NH:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCSCC1C2CCC(O2)C1CC=CCCC(C)(C)C(=NO)OCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCS(=O)CC1C2CCC(O2)C1CC=CCCC(C)(C)C(=N)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 634 mg (1.72 mmol) of [1α,2β(5Z),3β,4α]-7-[3-([hexylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-2,2-dimethyl-5-heptenimidic acid, phenylmethyl ester (prepared as described in Example 17) in 6.78 ml of methanol at 0° C. is added dropwise over 4 minutes 4.8 ml of 0.5M aqueous sodium periodate solution. Tetrahydrofuran (2 ml) is then added and the resulting reaction mixture is stirred at room temperature for 15 hours. A precipitate is removed by filtration and washed with ether (3×50 ml). The filtrate is washed with 60 ml of saturated aqueous NaHCO3 solution and dried over anhydrous magnesium sulfate. Concentration in vacuo affords an oily crude product. This is chromatographed on silica gel 60 using 0.5-1.0% CH3OH in CH2Cl2 as eluant. This gives [1α,2β(5Z),3β,4α]- 7-[3-[(hexylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-2,2-dimethyl-5-heptenimidic acid, phenylmethyl ester and [1α,2β(5Z),3β,4α]-7-[3-[(hexylsulfonyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-2,2-dimethyl-5-heptenimidic acid, phenylmethyl ester.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH:10]=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:15]([O:17][C:18](=[O:21])[CH2:19]Br)[CH3:16].II>[Zn].C1C=CC=CC=1>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH:9]1[CH:10]([OH:11])[CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:21])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: CCOC(=O)CBr
Agent: II
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC(O)C1CCCN1C(=O)OC(C)(C)C
Yield: 41 %

Procedure:
Freshly activated zinc powder (0.79 g, 12 mmol, Aldrich) and benzene (50 mL) were placed into a 250-mL two neck round bottom flask under N2. This flask was attached to a Dean-Stark apparatus and 25 mL of benzene was distilled into the trap. Under reflux, a solution of Boc- D-Prolinal (1.90 g, 9.5 mmol) and ethylbromoacetate (2.0 g, 12 mmol, Aldrich) was added dropwise. A crystal of iodine was added to initiate the reaction after half of the dropping solution was added. After complete addition, the mixture was refluxed for 3 hours, cooled, and carefully washed with 0.5 n HCl. The aqueous solution was extracted with ether (25 mL) and the combined organic solution was washed successively with water (30 mL) and saturated NaHCO3 (30 mL), then dried with anhydrous Na2SO4 and concentrated under vacuum. A yellow oil was chromatographed on silica (with hexane/ethyl acetate) to isolate a colourless oil (1.12 g, 41%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21](OC)=[O:22])[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:26])([CH3:25])[C:8]1=[O:27].[CH:28]([NH:31][C@H:32]1[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]1)([CH3:30])[CH3:29]>>[CH:28]([N:31]([C:21]([C:14]1[C:15]([C:17]([F:20])([F:18])[F:19])=[CH:16][C:11]2[O:10][C:9]([CH3:26])([CH3:25])[C:8](=[O:27])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]=2[CH:13]=1)=[O:22])[C@H:32]1[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:33]1)([CH3:30])[CH3:29]
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)OC)cc21
Reactant: CC(C)N[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Product: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21

Procedure:
Using methyl 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate and tert-butyl (3S)-3-(isopropylamino)piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 5.
Reaction SMILES: C=[C:2]([CH2:7][CH:8]([N+:22]([O-:24])=[O:23])[CH:9]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21])[CH2:10][CH:11]=C)[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.CS(C)=O>ClCCCl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[N+:22]([C@@H:8]1[CH2:7][C:2]([C:3]([O:5][CH3:6])=[O:4])=[CH:11][CH2:10][C@H:9]1[C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21])([O-:24])=[O:23]
Reactant: C=CCC(c1cc(F)c(F)cc1F)C(CC(=C)C(=O)OC)[N+](=O)[O-]
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)C1=CC[C@@H](c2cc(F)c(F)cc2F)[C@H]([N+](=O)[O-])C1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A stream of dinitrogen gas was bubbled through a mechanically-stirred solution of methyl 2-methylene-4-nitro-5-(2,4,5-trifluorophenyl)oct-7-enoate (98 g, 285.7 mmol, 1:1 mixture of erythro and threo isomers) in DCE (1.43 L) at 70° C. A solution of Grubbs' 2nd generation catalyst (9.7 g, 11.4 mmol) in DCE (61 mL) was added via syringe pump over about twelve hours. The reaction was then cooled to 55° C., and triethylamine (3.98 mL, 28.6 mmol) was added. After eight hours, the heating bath was removed, and DMSO (64 mL, 912 mmol) was added to the reaction. After stirring for twelve hours, the reaction was concentrated under reduced pressure, and the crude residue was purified by MPLC on SiO2 gel (15% EtOAc in Hx) to give the title compound as a dark waxy solid (63 g, 72%). 1H NMR (300 MHz, CDCl3) δ ppm 7.06-6.90 (m, 3H), 5.03 (ddd, J=5.8, 10.5 and 10.5 Hz, 1H), 3.79 (s, 3H), 3.64 (ddd, J=6.1, 10.5, and 10.5 Hz, 1H), 3.20-3.12 (m, 1H), 3.01-2.89 (m, 1H), 2.80-2.70 (m, 1H), 2.63-2.51 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1.[Cl:28]N1C(=O)CCC1=O>ClC(Cl)C>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH2:5][C:6]1[CH:15]=[C:14]([Cl:28])[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1.[CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH2:5][C:6]1[C:15]([Cl:28])=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)[C@@H](Cc1ccc2[nH]c(=O)oc2c1)NC(=O)OCc1ccccc1
Solvent: CC(Cl)Cl
Product: COC(=O)C(Cc1cc2oc(=O)[nH]c2cc1Cl)NC(=O)OCc1ccccc1
Product: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]c(=O)oc2c1)NC(=O)OCc1ccccc1
Temperature: 90 °C
Yield: 9.8 %
Yield: 19 %

Procedure:
A mixture of (R)-2-benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester (373 mg, 1.01 mmol), N-chlorosuccinimide (168 mg, 1.26 mmol), silica gel (EM Scientific, 230-400 mesh, 3.73 g) in dichloroethane (20 mL) was heated at 90° C. for 16 h. After cooling down to room temperature, the solvents were removed in vacuo. The residue was subjected to silica gel chromatography using ethyl acetate/hexanes (1:2) as eluent to afford the title compound (40 mg, 9.8%), also 2-benzyloxycarbonylamino-3-(5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester (78 mg, 19%). The structure was confirmed by 2D NMR and by comparison with that of 2-benzyloxycarbonylamino-3-(5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester prepared by the reaction shown below. 1H-NMR (CD3COCD3, 500 MHz) δ 7.37-7.27 (m, 5H), 7.18 (d, J=1.0 Hz, 1H), 7.16 (s, 1H), 6.76 (d, J=8.5 Hz, 1H), 5.06 (d, J=12.5 Hz, 1H), 5.02 (d, J=12.5 Hz, 1H), 4.55-4.51 (m, 1H), 3.72 (s, 3H), 3.26 (dd, J=14.0, 5.0 Hz, 1H), 3.04 (dd, J=14.0, 9.5 Hz, 1H); 13C-NMR (CD3COCD3, 125 MHz) δ 172.2, 156.4, 154.0, 144.8, 137.6, 133.3, 128.7, 128.2, 128.0, 127.9, 125.0, 66.3, 55.9, 52.0, 37.3; Mass spec. 405 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]2[N:13]=[C:14]([C:17]([OH:19])=[O:18])[NH:15][CH:16]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]2[N:13]=[C:14]([C:17]([OH:19])=[O:18])[NH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCc2c[nH]c(C(=O)O)n2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1nc(CCCc2ccc(O)cc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
A solution of the ethyl ester of 13e (1.15 g, 4.0 mmol) in dry dichloromethane (50 ml) was treated with boron tribromide (16 ml, 1.0M solution in CH2 Cl2, 16.0 mmol) at 0° C. After 15 min at 0° C., the mixture was warmed to 25° C. and stirred for 16 h. The reaction mixture was cooled in an ice bath and quenched with a dropwise addition of water (20 ml). The resulting mixture was briefly stirred at 25° C. then filtered. The filtrate was carefully neutralised by the addition of solid NaHCO3 to afford 13f (700 mg, 71%) as a white solid: m.p. 186°-187° C. (decomp.) (recrystallised from MeOH); IR (KBr) 3500-2400, 2935, 1640, 1516, 1396, 1232; 1H NMR(d6 -DMSO) δ 9.83 (3H, bs), 7.16 (1H, s), 6.98 (2H, d, J=8.2), 6.66 (2H, d, J=8.2), 2.60-2.40 (4H, m), 1.84 (2H, m). Anal. Calcd for C13H14N2O3 : C, 63.40; H, 5.73; N, 11.38. Found: C, 62.96; H, 5.70; N, 11.27.