Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[Cl:9].C1COCC1.C([Mg]Cl)(C)C.[CH:20]1[CH2:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[Cl:9][C:3]1[CH:2]=[CH:7][CH:6]=[C:5]2[C:4]=1[CH:24]1[CH2:23][CH:22]2[CH:21]=[CH:20]1
Reactant: Clc1cccc(Br)c1Cl
Reactant: C1=CCC=C1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Clc1cccc2c1C1C=CC2C1
Temperature: -10 °C
Reaction time: 1 h
Yield: 117.9 %

Procedure:
115 g of 1-Bromo-2,3-dichlorobenzene was dissolved in 470 g of toluene and the solution was cooled down to −10° C. Then a 20% THF solution of isopropylmagnesium chloride (309 g) was added over 30 min and the reaction mixture was stirred 1 hour at −10° C. Freshly distilled cyclopentadiene (44.5 g, 1.3 eq) was added over 10 min. After one hour stirring at ambient temperature, the mixture was heated to reflux. When the conversion was completed, the reaction mixture was filtered off and washed twice with toluene. The mother liquor was evaporated and 106 g of brown crude oil was obtained (yield: 91.5%. The material can be purified by distillation or by CC (silica gel, eluant: Hept/TBME 19/1).
Reaction SMILES: [N:1]1([C:6]2[N:7]=[C:8]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=3)[C:9]3[CH:14]=[C:13]([CH3:15])[S:12][C:10]=3[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>CO.[Ni]>[N:1]1([C:6]2[N:7]=[C:8]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=3)[C:9]3[CH:14]=[C:13]([CH3:15])[S:12][C:10]=3[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3ccnc3)nc2s1
Agent: [Ni]
Solvent: CO
Product: Cc1cc2c(NCc3cccc(N)c3)nc(-n3ccnc3)nc2s1

Procedure:
A solution of 2-(Imidazol-1-yl)-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine in methanol is hydrogenated in the presence of Raney-nickel. The catalyst is filtered off and the solution is concentrated. Recrystallization yields 2-(imidazol-1-yl)-6-methyl-4-(3-aminobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[C:26]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=S)=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1)#[N:2].C([O-])(=O)C1C=CC=CC=1>>[CH2:31]([NH:30][C:28]1[N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])=[CH:10][CH:11]=2)[C:17]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=[CH:25][C:26]=2[N:27]=1)[CH3:32]
Reactant: CCNC(=S)Nc1cccc(C(=O)OC)c1NCc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])c1ccccc1
Product: CCNc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
The title compound was prepared as colorless crystals (3.2 g, 32%) according to the procedure for Working Example 8 from methyl 2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]-3-(3-ethylthioureido)benzoate (10.5 g), which was synthesized from methyl 3-amino-2-[[2′-cyanobiphenyl-4-yl)methyl]amino]benzoate in substantially the same manner as Reference Example 5.
Reaction SMILES: BrCCO.Cl.C1([CH:12]([CH:16]2[CH2:21][CH2:20][N:19](C3C=CC(NC(C4C=CC=CC=4C4C=CC(C(F)(F)F)=CC=4)=O)=CC=3)[CH2:18][CH2:17]2)[C:13]([OH:15])=[O:14])C=CC=CC=1>CN(C=O)C>[NH:19]1[CH2:20][CH2:21][CH:16]([CH2:12][C:13]([OH:15])=[O:14])[CH2:17][CH2:18]1
Reactant: O=C(Nc1ccc(N2CCC(C(C(=O)O)c3ccccc3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: OCCBr
Solvent: CN(C)C=O
Product: O=C(O)CC1CCNCC1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
2-Bromoethanol (1.2 equiv, 0.00010 mol) was added to a mixture of intermediate (24) (0.000084 mol) in DMF (5 ml) and CsCO3 (0.00018 mol) and the reaction mixture was stirred for 3 hours at 70° C. The solvent was evaporated. The residue was partitioned between water and DCM. The extract's solvent was evaporated. The residue was purified by HPLC (Waters column, with Xterra MS C18; eluent: [(0.5% NH4OAc in H2O)/CH3CN 90/10)]/CH3CN (0 minutes) 85/15, (10 minutes) 10/90, (16 minutes) 0/100, (18.10-20.00 minutes) 85/15). The product fractions were collected and the organic solvent was evaporated. The aqueous concentrates were extracted and the extract's solvent was evaporated, yielding 4-piperidineacetic acid, α-phenyl-1-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-, 2-hydroxyethyl ester (compound 134).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.N1C=CC=CC=1.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>ClCCl>[CH:17]1([C:20]([CH:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])=[O:21])[CH2:19][CH2:18]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(C(=O)C2CC2)C(=O)O1
Temperature: 0 °C
Yield: 82.2 %

Procedure:
A mixture of 2,2-dimethyl-1,3-dioxan-4,6-dione (20.0 g) and pyridine (22,0 g) in dichloromethane (200 ml) was stirred and cooled to 0° C. in an ice bath. A solution of cyclopropylcarbonyl chloride (16.0 g) in dichloromethane (50 ml) was added dropwise with stirring in an atmosphere of nitrogen whilst maintaining the temperature below 3° C. by external cooling. The mixture was stirred at 0° C. for 1 hour and at ambient temperature for 2 hours. The resultant orange suspension was washed with hydrochloric acid (2M, 2×50 ml), water (2×50 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was dissolved in ether (150 ml) and the solution was treated with decolourizing charcoal and filtered. The filtrate was evaporated to dryness to give 5-cyclopropylcarbonyl-2,2-dimethyl-1,3-dioxan4,6-dione (24.2 g) as a yellow solid mp 44°-46° C.
Reaction SMILES: Br[C:2]([CH3:16])=[C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1COCC1.C([Li])CCC.Cl[P:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[C:4]1([C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([P:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:16])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(Br)=C(c1ccccc1)c1ccccc1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=C(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Temperature: -70 °C
Reaction time: 13 h
Yield: 57.1 %

Procedure:
Into a reactor were introduced 1.37 g (5.00 mmol) of the 2-bromo-1,1-diphenylpropene and 14 mL of THF under a nitrogen atmosphere. The contents were cooled to −70° C., and 3.4 mL (5.5 mmol; 1.6 M hexane solution) of butyllithium was gradually added dropwise thereto. The resultant mixture was stirred for 30 minutes. Thereafter, 1.1 mL (6.0 mmol) of chlorodiphenylphosphine was added, and this mixture was heated to room temperature and then stirred for 13 hours. Water was added to the reaction mixture. The organic layer was extracted with ethyl acetate, and the extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol to obtain 1.08 g (60%) of the target compound as white crystals.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:18]=[O:19]>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C>[NH:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([CH:18]=[O:19])=[CH:3]1
Reactant: Brc1c[nH]c2ncccc12
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1c[nH]c2ncccc12
Temperature: -60 °C
Reaction time: 4 h
Yield: 82.8 %

Procedure:
To a suspension of 3-bromo-1H-pyrrolo[2,3-b]pyridine (9.85 g, 50.0 mmol) in THF (300 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (42 mL, 105.0 mmol, 2.1 equiv.) at −70° C. The temperature of the reaction mixture was raised to −60° C. during the addition and became a clear solution. The resulting brick red color solution was slowly allowed to warm to −10° C. during a period of 1 h and then stirred for 4 h at this temperature. Again, the mixture was cooled to −70° C. and a solution of dimethylformamide (8.5 mL, 110.0 mmol) in THF (30 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 15 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude brown solid which was dissolved in ethyl acetate (˜70 mL) at hot condition and then stored in the refrigerator overnight. The solids were collected by filtration and washed with ethyl acetate. After drying in air, 6.05 g (83% yield) of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde was isolated as an yellow solid: EI-HRMS m/e calcd for C8H6N2O (M+) 146.0480. found 146.0478.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C12(CS(O)(=O)=O)[C:14](C)(C)[CH:11](CC1)[CH2:10][C:8]2=[O:9]>C(=O)(O)[O-].[Na+]>[C:1]([O:6][CH:14]1[CH2:11][CH2:10][CH2:8][O:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: C=C(C)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: C=C(C)C(=O)OC1CCCO1
Reaction time: 1 h
Yield: 4001.8 %

Procedure:
Methacrylic acid (86 g, 1 mol) was cooled to 15° C., and camphorsulfonic acid (4.6 g, 0.02 mol) was added thereto. 2-Dihydrofuran (71 g, 1 mol, 1.0 equivalents) was added dropwise to this solution. After stirring for 1 hour, saturated sodium bicarbonate (500 mL) was added, and the mixture was extracted with ethyl acetate (500 mL) and dried with magnesium sulfate; following this insoluble material was filtered, concentration under vacuum was then carried out at no greater than 40° C., and a yellow oily residue was distilled under vacuum, thus giving 125 g of tetrahydrofuran-2-yl methacrylate (MATHF) (yield 80%) as a colorless oily material, this being a fraction with a boiling point (bp.) of 54° C. to 56° C./3.5 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.[CH2:18](C([SnH3])=C(CCCC)CCCC)[CH2:19]CC.[Cl-].[Li+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[C:3]([CH:18]=[CH2:19])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Reactant: COc1nc2cc(Cl)c(Cl)c(I)c2nc1OC
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Temperature: 100 °C
Yield: 79.1 %

Procedure:
A mixture of 6,7-dichloro-2,3-dimethoxy-5-iodoquinoxaline (3.0 g, 7.8 mmol), tributylvinylstannane (4.94 g, 15.6 mmol), lithium chloride (991 mg, 23.4 mmol) and bis(triphenylphosphine)palladium (II) chloride (600 mg, 1.56 mmol) in dry dimethylformamide (100 mL) was heated at 100° C. for 1.5 hours. The mixture was cooled, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with toluene) to give 6,7-dichloro-2,3-dimethoxy-5-ethenylquinoxaline (1.76 g, 79%), as a white solid.
Reaction SMILES: [F:1][C:2]([C:7]1[CH:12]=[CH:11][C:10](CC(C)C)=[CH:9][CH:8]=1)([F:6])[C:3]([OH:5])=[O:4]>C(O)(=O)C.[Pt]=O>[CH:7]1([C:2]([F:1])([F:6])[C:3]([OH:5])=[O:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)Cc1ccc(C(F)(F)C(=O)O)cc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: O=C(O)C(F)(F)C1CCCCC1
Reaction time: 24 h
Yield: 115.1 %

Procedure:
a,α-difluoro-4-isobutyl-phenylacetic acid (900 mg, 3.9 mmol) and platinum oxide (50 mg) were suspended in acetic acid (10 ml). The mixture was hydrogenated at 50 psi for 24 hours. The mixture was filtered over celite, washed with methylene chloride, concentrated in vacuo to give 2-cyclohexyl-2,2-difluoro-acetic acid as an oil (800 mg, 88%).
Reaction SMILES: [Cl-].[CH2:2]([N:4]1[C:8](=[O:9])[C:7](=[CH:10][CH:11]=[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[S:13]2)[S:6][C:5]1=[CH:22][C:23]1[S:24][C:25]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:26]=2[N+:27]=1[CH3:28])[CH3:3].[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]\[C:37]([OH:39])=[O:38]>CO>[C:34]([O-:41])(=[O:40])/[CH:35]=[CH:36]\[C:37]([O-:39])=[O:38].[CH2:2]([N:4]1[C:8](=[O:9])[C:7](=[CH:10][CH:11]=[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[S:13]2)[S:6][C:5]1=[CH:22][C:23]1[S:24][C:25]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:26]=2[N+:27]=1[CH3:28])[CH3:3].[CH2:2]([N:4]1[C:8](=[O:9])[C:7](=[CH:10][CH:11]=[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[S:13]2)[S:6][C:5]1=[CH:22][C:23]1[S:24][C:25]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:26]=2[N+:27]=1[CH3:28])[CH3:3]
Reactant: O=C(O)/C=C\C(=O)O
Agent: CCn1c(=Cc2sc3ccc(F)cc3[n+]2C)sc(=CC=C2Sc3ccccc3N2C)c1=O
Agent: [Cl-]
Solvent: CO
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
After dissolving Compound A, which was obtained in Synthesis Example 1, in methanol, the anion thereof was replaced with maleic acid according to an ordinary method to give 2-((3-ethyl-5-(2-(3-methylbenzo[d]thiazol-2(3H)-ylidene)ethylidene)-4-oxothiazolidin-2-ylidene)methyl)-5-fluoro-3-methylbenzo[d]thiazol-3-ium maleate (Compound C) as a dark-green solid. The physical property values and analytical values of this compound are as described below:
Reaction SMILES: NO.C(=O)/C=C/CC.[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(C)(C)C.C([Zn]CC)C.[C:24]([O:27]C(=O)C)(=[O:26])[CH3:25]>CCCCCC.C1(C)C=CC=CC=1>[C:24]([O:27][CH:16](/[CH:17]=[CH:18]/[CH2:13][CH3:9])[CH2:15][CH3:14])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1ccccc1
Agent: CC/C=C/C=O
Agent: CC[Zn]CC
Agent: NO
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC/C=C/C(CC)OC(C)=O
Reaction time: 72 h

Procedure:
A vial was charged with aminoalcohol A (0.0063 g, 0.026 mmol). To the vial was added 1.68 mL of a stock solution containing trans-2-pentenal (0.34 g), t-butylbenzene internal standard (0.25 g), 1 M diethylzinc in hexane (8.0 mL), and toluene (4.0 mL). After 48 h acetic anhydride (0.200 mL) was added. After an additional 72 h a sample of the solution was analyzed by gas chromatography at 80° C. on a Cyclodex B stationary phase. The product trans-4-hepten-3-yl acetate was formed 87% enantiomeric excess.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[C:60]([C:65]([F:68])([F:67])[F:66])[CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[C:60]([C:65]([F:67])([F:68])[F:66])[CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)c(C(F)(F)F)c2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.4 %

Procedure:
To a solution of 107 mg (0.5 mmol) of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 161 mg of TBTU (0.5 mmol) in 6 ml DMF, were added 0.43 ml (2.51 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 200 mg (0.54 mmol) of (4-tert-butyl-benzyl)-[2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 22 h at rt, the reaction mixture was diluted with 80 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; DCM/heptane 9:1) to give 182 mg off-white solid (54%). MS (EI) 564.2 (M)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3=[CH:11][C:12](=[O:15])[CH2:13][CH2:14][C:8]3([CH2:16][CH2:17][CH3:18])[O:7][C:6]=2[CH:5]=[C:4](O)[C:3]=1[Cl:20].Br[CH2:22][C:23]([O:25]CC)=[O:24]>CN(C)C=O>[Cl:1][C:2]1[C:10]2[C:9]3=[CH:11][C:12](=[O:15])[CH2:13][CH2:14][C:8]3([CH2:16][CH2:17][CH3:18])[O:7][C:6]=2[CH:5]=[C:4]([CH2:22][C:23]([OH:25])=[O:24])[C:3]=1[Cl:20]
Reactant: CCOC(=O)CBr
Reactant: CCCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)O2
Solvent: CN(C)C=O
Product: CCCC12CCC(=O)C=C1c1c(cc(CC(=O)O)c(Cl)c1Cl)O2
Temperature: 65 °C

Procedure:
A stirred mixture of 1,2-dichloro-3-hydroxy-8-oxo-5a-propyl-5a,6,7,8-tetrahydrodibenzofuran (0.4 g) potassium carbonate (0.2 g) and ethyl bromoacetate (200 μl) in N,N-dimethylformamide (7 ml) was heated at 65° C. for 1 1/4 hours. The reaction mixture was poured into ice water and the solid ester which precipitated was removed by filtration then dissolved in methanol (15 ml) containing water (1 ml) and 10N sodium hydroxide (1 ml). After 1/2 hour the methanol solution was poured into dilute aqueous hydrochloric acid, extracted with ether which was washed with water, brine, dried over MgSO4 and evaporated in vacuo. Trituration of the residue with methylene chloride gave 0.35 g of (1,2-dichloro-8-oxo-5a-propyl-5a,6,7,8-tetrahydrodibenzofuran-3-yl)acetic acid which melted at 248°-250° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:4][N:3]=1.S(=O)(=O)(O)O.C([O-])(O)=O.[Na+].[C:22](OCC)(=O)[CH3:23]>C(O)C>[CH2:22]([O:10][C:9](=[O:11])[CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Br:1])[CH:7]=1)[CH3:23]
Reactant: CCOC(C)=O
Reactant: O=C(O)Cc1ccnc(Br)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1ccnc(Br)c1
Temperature: 90 °C

Procedure:
To a solution of (2-bromo-pyridin-4-yl)-acetic acid (60.0 g, 277.7 mmol) in ethanol (600 ml), conc: sulfuric acid (5.0 ml) was added at rt and the reaction mixture was heated at 90° C. for 9 h. Reaction mixture was cooled to rt and concentrated under reduced pressure to remove solvent completely. The residue obtained was cooled to 0° C. and pH was adjusted to 8 using 10% aqueous NaHCO3 solution. The resultant contents were worked up with ethyl acetate by washing with water, brine and dried over anhy. Na2SO4. Organic layer was concentrated under reduced pressure to obtain crude compound. Column chromtography purification of the crude compound using 15% ethyl acetate in hexane as eluent furnished title compound as a brown oil. Yield: 65.0 g (88.5%). TLC (30% ethyl acetate in hexane) Rf=0.39; LCMS: RtH7=0.824 [M+1]+=243.8 and 245.8; HPLC RtH9=3.759 min (69%); 1H NMR (300 MHz, CDCl3): δ 8.32 (t, 1H), 7.43 (s, 1H), 7.21-7.15 (M, 1H), 4.18 (q, 2H), 1.27 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19](=[O:42])[CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[O:33][N:32]=[C:31]([C:34]3[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:41])[CH:30]=2)[CH:24]=1)[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:50][CH:51]([Cl:55])[C:52](Cl)=[O:53]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19](=[O:42])[CH2:20][CH2:21][N:22]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[O:33][N:32]=[C:31]([C:34]3[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:41])[CH:30]=2)[CH:24]=1)[C:52](=[O:53])[CH:51]([Cl:55])[Cl:50])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(=O)CCNc1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(=O)CCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
(R)-tert-butyl 4-(tert-butoxycarbonylamino)-7-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-ylamino)-5-oxoheptanoate (280 mg, 0.45 mmol) was dissolved in anhydrous dichloromethane with triethylamine (126 μL, 0.90 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (66 μL, 0.68 mmol) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and then washed successively with water, 10% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with 99:1 dichloromethane:methanol to yield (R)-tert-butyl 4-(tert-butoxycarbonylamino)-7-(2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)acetamido)-5-oxoheptanoate (165 mg) as a white foam. 1H NMR (CDCl3): 8.77 (m, 1H), 7.89 (m, 1H), 7.42 (m, 2H), 7.40-7.31 (m, 2H), 7.07 (s, 1H), 6.00 (s, 1H), 5.20 (m, 1H), 4.20 (m, 1H), 4.00 (m, 2H), 2.97 (m, 2H), 2.27 (m, 2H), 2.10 (m, 1H), 1.78 (m, 1H), 1.41 ppm (m, 18H). MW=730 confirmed by LC-MS, tr=13.34 min (Method A) MH+=728-732.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:28])[CH:9]([CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:3][CH2:2]1.[O:29]1[CH2:31][C@@H:30]1[CH2:32][O:33][C:34]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:35]=1[CH:36]=[CH:37][CH:38]=[N:39]2>C(O)(C)C>[OH:29][CH:30]([CH2:32][O:33][C:34]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:35]=1[CH:36]=[CH:37][CH:38]=[N:39]2)[CH2:31][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:28])[CH:9]([CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:3][CH2:2]1
Reactant: O=C(NC1CCNCC1)C(CCCc1ccccc1)CCCc1ccccc1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Solvent: CC(C)O
Product: O=C(NC1CCN(CC(O)COc2cccc3ncccc23)CC1)C(CCCc1ccccc1)CCCc1ccccc1
Temperature: 70 °C
Yield: 76.4 %

Procedure:
5-Phenyl-2-(3-phenyl-propyl)-pentanoic acid piperidin-4-ylamide (24) (100 mg; 0.264 mmol) is dissolved in isopropanol (10 mL) at ambient temperature. (R)-5-Oxiranylmethoxyquinoline (2) (53.2 mg; 0.264 mmol) is added, then the mixture is heated to 70° C. and maintained for 18 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (0%→25% methanol in methylene chloride) affording the desired product (117 mg) as a solid. ESMS: MH+ 580.4 (base).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Rh]>[C:1]([O:5][C:6]([N:8]([CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccccc1
Reactant: [H][H]
Agent: [Rh]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CC(=O)O)C1CCCCC1

Procedure:
Under a nitrogen atmosphere, 5% rhodium/alumina (3.00 g) is added to a solution of DL-N-tert-butoxycarbonylphenylglycine in ethanol (80 ml). The atmosphere is replaced with pressurized hydrogen (4.0 kgf/cm2) and stirred for ten days. The 5% rhodium/alumina is filtered out. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the titled reference compound (25.0 g).