Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]#[N:8])=[N:4][O:5][N:6]=1.[CH2:9]([NH2:13])[CH:10]([CH3:12])[CH3:11].[Al+3].[Cl-].[Cl-].[Cl-]>ClC(Cl)C>[NH2:1][C:2]1[C:3]([C:7]([NH:13][CH2:9][CH:10]([CH3:12])[CH3:11])=[NH:8])=[N:4][O:5][N:6]=1
Reactant: CC(C)CN
Reactant: N#Cc1nonc1N
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(C)CNC(=N)c1nonc1N
Reaction time: 0.33 h

Procedure:
To a solution of 4-amino-1,2,5-oxadiazole-3-carbonitrile (220 mg, 2 mmol) and isobutylamine (0.2 mL, 2 mmol) in dichloroethane (1 mL) was added AlCl3 (293 mg, 2.2 mmol). The reaction mixture is stirred for 20 min and then quenched with ice cold water (5 mL). The mixture is extracted with diethyl ether (3×20 mL). Combined extracts was dried over anhydrous Na2SO4 and concentrated under vacuum to afford the title compound as a white solid. MS 184 M+1. The crude product was carried to next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH:6]([S:8]([CH:11]=[CH2:12])(=[O:10])=[O:9])=[CH2:7]>>[O:9]=[S:8]1(=[O:10])[CH2:11][CH2:12][N:1]([CH2:2][CH2:3][CH2:4][OH:5])[CH2:7][CH2:6]1
Reactant: C=CS(=O)(=O)C=C
Reactant: NCCCO
Product: O=S1(=O)CCN(CCCO)CC1
Temperature: 110 °C
Yield: 49.3 %

Procedure:
A mixture of 3-amino-1-propanol (650 μl, 8.4 mmol) and vinyl sulphone (1 g, 8.4 mmol) was heated at 110° C. for 45 minutes. The mixture was allowed to cool and was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 3-(1,1-dioxothiomorpholino)-1-propanol (800 mg, 90%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[O:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[N+:10]([C:13]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][C:14]=1[O:15][CH:16]([CH3:20])[C:17](Cl)=[O:18])([O-:12])=[O:11]>C(Cl)Cl>[CH2:1]([N:3]([CH2:4][C:5]1[O:9][CH:8]=[CH:7][CH:6]=1)[C:17](=[O:18])[CH:16]([O:15][C:14]1[CH:21]=[C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:23]=[CH:24][C:13]=1[N+:10]([O-:12])=[O:11])[CH3:20])[CH3:2]
Reactant: CCNCc1ccco1
Reactant: CC(Oc1cc(Oc2ccc(F)cc2)ccc1[N+](=O)[O-])C(=O)Cl
Solvent: ClCCl
Product: CCN(Cc1ccco1)C(=O)C(C)Oc1cc(Oc2ccc(F)cc2)ccc1[N+](=O)[O-]
Temperature: -15 °C

Procedure:
N-Ethyl-N-furfurylamine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-nitro-5-(4-fluorophenoxy)phenoxy]propionyl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature with continued stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. This residue is then purified by subjecting it to elution chromatography using mixtures of ethyl acetate and hexane with increasing concentrations of ethyl acetate as the eluant. The desired fractions determined by IR spectroscopy are then stripped of solvent to yield the desired product N-ethyl-N-furfuryl-2-[2-nitro-5-(4-fluorophenoxy)phenoxy]propionamide.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[S:16][CH2:17][C@@H:18]2[CH2:23][C@@H:22]([O:24][CH3:25])[CH2:21][C@:19]2([C:26]2[CH:31]=[C:30]([NH:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:28][C:27]=2[F:43])[N:20]=1)(C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:14][C:15]1[S:16][CH2:17][C@@H:18]2[CH2:23][C@@H:22]([O:24][CH3:25])[CH2:21][C@:19]2([C:26]2[CH:31]=[C:30]([NH:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:28][C:27]=2[F:43])[N:20]=1
Reactant: CO[C@@H]1C[C@H]2CSC(NC(=O)OC(C)(C)C)=N[C@@]2(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H]1C[C@H]2CSC(N)=N[C@@]2(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl((4aR*,6R*,7aS*)-7a-{5-[(5-cyanopyridine-2-carbonyl)amino]-2-fluorophenyl}-6-methoxy-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl)carbamate (29 mg) in dichloromethane (2 mL), and the reaction solution was stirred at room temperature for one hour. The reaction solution was poured into a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by NH-silica gel column chromatography to obtain the title compound (12 mg).
Reaction SMILES: [C:1](=[O:53])([O:22][C:23]1[C:24]([CH3:52])=[C:25]2[C:30](=[C:31]([CH3:34])[C:32]=1[CH3:33])[O:29][C:28]([CH3:51])([CH2:35][CH2:36][CH2:37][CH:38]([CH3:50])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:49])[CH2:43][CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:27][CH2:26]2)[O:2][CH2:3][CH2:4][CH:5]([CH2:14][O:15]C1CCCCO1)[CH2:6][O:7]C1CCCCO1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[C:1](=[O:53])([O:22][C:23]1[C:24]([CH3:52])=[C:25]2[C:30](=[C:31]([CH3:34])[C:32]=1[CH3:33])[O:29][C:28]([CH3:51])([CH2:35][CH2:36][CH2:37][CH:38]([CH3:50])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:49])[CH2:43][CH2:44][CH2:45][CH:46]([CH3:47])[CH3:48])[CH2:27][CH2:26]2)[O:2][CH2:3][CH2:4][CH:5]([CH2:14][OH:15])[CH2:6][OH:7]
Reactant: Cc1c(C)c2c(c(C)c1OC(=O)OCCC(COC1CCCCO1)COC1CCCCO1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Cc1c(C)c2c(c(C)c1OC(=O)OCCC(CO)CO)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
27.5 g (0.037 mol) of the 4-(2-tetrahydro-pyranyloxy)-3-(2-tetrahydropyranyloxymethyl)butyl 2,5,7,8-tetramethyl-2-(4',8', 12'-trimethyltridecyl)-6-chromanyl carbonate prepared in the above step was dissolved in 300 ml of methanol. To the obtained solution was added 5 g of p-toluenesulfonic acid followed by stirring at room temperature for 1 hour. 1 l of water was added to the reaction mixture and the oily matter thus separated out was extracted with ether. The extract was washed with water and dried. After distilling off the solvent, the obtained oily residue was purified by column chromatography (silica gel, hexane : ethyl acetate=3:1). Thus 16.5 g of the title compound was obtained as a colorless viscous liquid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[CH2:3][C:2]1=O.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:4]1[N:9]=[CH:8][CH:7]=[C:6]2[CH:3]=[CH:2][O:1][C:5]=12
Reactant: O=C1Cc2ncccc2O1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccc2ccoc12

Procedure:
Alternatively, furan-3-aldehyde is converted to furan-3-acrylic acid with acetic anhydride and potassium carbonate and the acid converted to the acid azide by first reacting the acid with ethoxycarbonyl chloride and triethylamine to form the acid chloride and then reacting the mixed anhydride with sodium azide in water. The furan-3-acrylic acid azide is then heated in diphenylmethane with tributylamine to a temperature of about 190° C. to about 210° C. to form the furopyridone represented by the formula ##STR11## The furopyridone is allowed to react with phosphorus oxychloride to form 7-chlorofuro[2,3-c]pyridine and the latter is reductively dechlorinated with zinc in acetic acid to provide furo[2,3-c]pyridine.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:3]([N:10]([CH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CNCCCSc2ccncc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N(CCCSc1ccncc1)Cc1ccccc1
Yield: 50.2 %

Procedure:
To a solution of 400 mg (1.21 mmol) of 4-[3-(N-benzylamino)propylthio] pyridine dihydrochloride and 0.55 ml (4.00 mmol) of triethylamine in 5 ml of methylene chloride, 0.17 ml (1.45 mmol) of benzoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 0.22 g of the desired compound (yield: 50.4%, yellow oil).
Reaction SMILES: CO.[C:3]1([CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:11]=[CH:12][CH2:13][OH:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[H][H].[Pd]>[C:15]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OCC=CCC(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: OCCCCC(c1ccccc1)c1ccccc1

Procedure:
10 ml of methanol was added to a mixture of 320 mg (1.34 mmol) of 5,5-diphenyl-2-pentene-1-ol and a catalytic amount of 10% palladium/carbon, and they were stirred in hydrogen atmosphere at room temperature under ambient pressure for 12 hours. The catalyst was filtered out and the obtained filtrate was concentrated under reduced pressure to obtain the unpurified title compound.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.[H-].[Na+].Cl[CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:18][C:19]=1[CH3:20].O>CN(C)C=O>[CH3:20][C:19]1[S:18][C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:16][C:15]=1[CH2:14][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: COC(=O)c1cc(O)no1
Reactant: Cc1sc(-c2ccccc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCc2nc(-c3ccccc3)sc2C)no1
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To a solution of methyl 3-hydroxyisoxazole-5-carboxylate (3.51 g) in N,N-dimethylformamide (100 mL) was added sodium hydride (60%, oil, 1.07 g) at 0° C. After stirring for 30 min., 4-chloromethyl-5-methyl-2-phenylthiazole (5.00 g) was added. After stirring at 60° C. for 2 hrs, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give methyl 3-(5-methyl-2-phenyl-4-thiazolylmethoxy)-5-isoxazolecarboxylate (5.42 g, 74%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 89-90° C.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:8][C:9]=1[NH:10]2.[CH3:29][C:30]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=[CH:33][C:31]=1[NH2:32]>>[NH2:32][C:31]1[C:30]([CH3:29])=[C:36]([C:2]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]3[C:3]=2[C:4]2[CH2:5][CH2:6][CH:7]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:8][C:9]=2[NH:10]3)[CH:35]=[CH:34][CH:33]=1
Reactant: NC(=O)c1ccc(Br)c2c3c([nH]c12)CC(NC(=O)OCc1ccccc1)CC3
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Product: Cc1c(N)cccc1-c1ccc(C(N)=O)c2[nH]c3c(c12)CCC(NC(=O)OCc1ccccc1)C3

Procedure:
Using the procedure of Example 3-2, benzyl 5-bromo-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazol-2-ylcarbamate (Intermediate 50-4(a), 300 mg, 0.678 mmol) and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Intermediate 50-1, 237 mg, 1.017 mmol) were converted into benzyl 5-(3-amino-2-methylphenyl)-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazol-2-ylcarbamate, TFA salt, isolated as a white solid after preparative HPLC purification (60 mg, 15%). 1H NMR (400 MHz, methanol-d4) δ 7.63 (1H, dd, J=7.7, 2.9 Hz), 7.18-7.46 (8H, m), 6.82 (1H, dd, J=7.5, 2.8 Hz), 5.10 (2H, s), 3.90 (1H, br. s.), 3.14 (1H, d, J=4.8 Hz), 2.72 (1H, br. s.), 1.77-2.19 (6H, m), 1.51-1.68 (1H, m). Mass spectrum m/z 469.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+].Cl>O1CCCC1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH2:7][OH:8]
Reactant: COc1cc(Br)cc(C=O)c1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(Br)cc(CO)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
10.67 g of 5-bromo-2,3-dimethoxybenzaldehyde was dissolved in 100 ml of tetrahydrofuran and 100 ml of ethanol, and 1 g of sodium borohydride was added, and then the solution was stirred overnight at room temperature. 1 N hydrochloric acid was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with water and an aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 10.27 g of 5-bromo-2,3-dimethoxybenzyl alcohol. 5.326 g of this crude product was dissolved in 50 ml of N,N-dimethylformamide, and 1.8 g of imidazole and 5.9 g of t-butylchlorodiphenylsilane were added thereto, and the solution was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 10.72 g of [(5-bromo-2,3-dimethoxybenzyl)oxy](t-butyl)diphenylsilane.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:35])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](OC2C=CC([N+]([O-])=O)=CC=2)=[O:24])=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].[NH2:36][CH2:37][CH2:38][CH:39]([N:43]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH3:44])[C:40]([OH:42])=[O:41]>ClCCl>[CH2:1]([O:4][C:5](=[O:35])[C@@H:6]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([NH:36][CH2:37][CH2:38][CH:39]([N:43]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH3:44])[C:40]([OH:42])=[O:41])=[O:24])=[CH:18][CH:17]=1)[CH:2]=[CH2:3]
Reactant: CN(C(=O)OC(C)(C)C)C(CCN)C(=O)O
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCCC(C(=O)O)N(C)C(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
0.931 g (1.92 mmol) of the compound from example 1A was dissolved in 30 ml dichloromethane. 0.455 g (1.92 mmol) of the compound from example 6A was added. The reaction mixture was split into 2 portions. The portions were heated for 30 min in a sealed tube at 80° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed under reduced pressure. The raw product was purified by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 0.523 g (0.85 mmol, 44% of theory) of the desired product as a mixture of 2 diastereomers.
Reaction SMILES: O1CCOCC1.CO.C([NH:11][CH:12]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>>[NH2:11][CH:12]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(CCC(NC=O)c2cccnc2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CCC(N)c2cccnc2)cc1
Temperature: 60 °C
Yield: 87.4 %

Procedure:
To 10 ml of the solution of 0.62 g of methyl 4-[3-formamido-3-(3-pyridyl)propyl]benzoate methanol-1,4 dioxane (1:1) was added 5 ml of 4% sulfuric acid, and stirred under heating at 60° C. overnight, which was then poured into saturated aqueous sodium hydrogencarbonate solution to be extracted with ethyl acetate. The obtained ethyl acetate phase was washed in saturated aqueous sodium chloride and dried over magnesium sulfate, to distill off the solvent, so that 0.35 g of methyl 4-[3-amino-3-(3-pyridyl)propyl]benzoate was yielded.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][C@H:23]([C:32]([O:34][CH3:35])=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.O1CCCC1.C(N(CC)CC)C>[C:1]([NH:9][C@H:10]([C:18]([NH:22][C@H:23]([C:32]([O:34][CH3:35])=[O:33])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1)=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Reaction time: 3 h
Yield: 73.9 %

Procedure:
In 100 ml of a mixture of chloroform-tetrahydrofuran (2:1), were dissolved 5.39 g of N-benzoylphenylalanine, 4.64 g of methyl tyrosinate hydrochloride, 2.02 g of triethylamine and 2.30 g of N-hydroxysuccinimide and the solution was cooled with ice. To the cold solution, 4.12 g of N,N'-dicyclohexylcarbodiimide was added. The mixture was stirred for three hours, then allowed to stand at room temperature overnight. The precipitates were removed by filtration and the filtrate was concentrated. The residue was extracted with ethyl acetate and the extract was washed with 2% hydrochloric acid, 4% sodium bicarbonate and water, then dried and concentrated to dryness. The residue was crystallized from ethyl acetate-petroleum ether to give 6.6 g of methyl N-benzoylphenylalanyltyrosinate with a mp. 188°-190° C in a yield of 74%. Analysis, calculated for C26H26O5N2C 69.94, H 5.87, N 6.27, found C 69.56, H 6.01, N 6.39.
Reaction SMILES: Br.[CH:2]1([O:7][C:8]2[CH:9]=[CH:10][C:11](/[C:16](/[C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=3)=[CH:17]/[C@@H:18]3[N:22](CC4C=CC(OC)=CC=4OC)[C:21](=[O:34])[CH2:20][CH2:19]3)=[N:12][C:13]=2[O:14]C)[CH2:6][CH2:5][CH2:4][CH2:3]1.O>O1CCOCC1>[CH:2]1([O:7][C:8]2[C:13](=[O:14])[NH:12][C:11](/[C:16](/[C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][CH:36]=3)=[CH:17]/[C@H:18]3[CH2:19][CH2:20][C:21](=[O:34])[NH:22]3)=[CH:10][CH:9]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(F)(F)F)cc2)c2ccc(OC3CCCC3)c(OC)n2)c(OC)c1
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: O=C1CC[C@H](/C=C(\c2ccc(C(F)(F)F)cc2)c2ccc(OC3CCCC3)c(=O)[nH]2)N1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
48% hydrobromic acid (3 mL) was added to a solution of (5R)-5-{(E)-2-[5-(cyclopentyloxy)-6-methoxypyridin-2-yl]-2-[4-(trifluoromethyl)phenyl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (184 mg) in 1,4-dioxane (2 mL), and the mixture was stirred at 65° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A solution of the residue in trifluoroacetic acid (4 mL) and anisole (2 mL) was stirred at 80° C. for six hours. The solvent was evaporated from the reaction solution under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1→4:1) and powdered with ethyl acetate-diethyl ether-hexane to give the title compound as a colorless amorphous (59 mg, 47%).
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8](I)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: C#C[Si](C)(C)C
Reactant: CCCN(CCC)C1CCc2cccc(I)c2C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(C#C[Si](C)(C)C)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(Di-n-propylamino)-8-iodo-1,2,3,4-tetrahydronaphthalene (4.3 g, 12.1 mmol), as prepared in co-pending U.S. application Ser. No. 07/653,583 triethylamine (100 ml) was added copper(I) iodide (228 mg), bis(triphenylphosphine)-palladium(II) chloride (841 mg) and trimethylsilylacetylene (1.7 ml). This mixture was stirred at room temperature overnight. The reaction was poured into water and extracted with ether. The extract was washed with brine, dried (Na2SO4), and concentrated to give 5 g of crude product. Purification by flash chromatography using 20:1 methylene chloride:methanol as solvent gave 4.33 g of 2-(di-n-propylamino)-8-(2-trimethylsilylethynyl)-1,2,3,4-tetrahydronaphthalene which was used in the next reaction.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24](Br)[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[CH3:37][CH2:38]OC(C)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24]([CH:37]=[CH2:38])[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1C=O
Temperature: 90 °C

Procedure:
Intermediate (17a) (5.6 g, 11.5 mmol), tetrakis(triphenylphosphine)palladium(0) (2.1 g, 1.8 mmol), and (2-ethenyl)tri-n-butyltin (13.5 mL, 46.2 mmol) were dissolved in DMF (70 mL, 900 mmol), and heated at 90° C. for 1.5 hours. The mixture was cooled to room temperature and 300 mL of EtOAc was added. The organic layer was washed using a 20% potassium fluoride solution (2×100 mL) and saturated aqueous NaCl. The resulting material was purified by silica gel chromatography (0-60% EtOAc:hexanes) to yield intermediate (17b) (4.3 g). MS m/z: [M+H+] calcd for C26H28N2O4, 433.2; found 433.4.