Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:9])([C:7]#[CH:8])[CH2:3][C:4]([OH:6])=[O:5].[CH3:10][CH2:11][CH2:12][CH2:13][SnH:14]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18].B(CC)(CC)CC.[F:30][C:31]1[C:36]([F:37])=[CH:35][C:34]([F:38])=[C:33]([F:39])[C:32]=1O.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:9])([CH:7]=[CH:8][Sn:14]([CH2:13][CH2:12][CH2:11][CH3:10])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][C:32]1[C:31]([F:30])=[C:36]([F:37])[CH:35]=[C:34]([F:38])[C:33]=1[F:39])=[O:5]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: Oc1c(F)c(F)cc(F)c1F
Reactant: C#CC(C)(C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCB(CC)CC
Solvent: Cc1ccccc1
Product: CCCC[Sn](C=CC(C)(C)CC(=O)Oc1c(F)c(F)cc(F)c1F)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
To a solution of 3,3-dimethyl-4-pentynoic acid (20 mg, 0.16 mmol) in toluene (0.30 mL) under N2 was added Bu3SnH (0.10 mL, 0.38 mmol) followed by Et3B (0.03 mL, 1.0M solutions in hexanes, 0.03 mmol). The resulting solution was stirred at room temperature for 21/2 hours after which the solvent was evaporated under reduced pressure. The resulting oil was dissolved in anhydrous THF (0.32 mL) and 2,3,5,6-tetrafluorophenol (60 mg, 0.36 mmol) followed by dicyclohexylcarbodiimide (68 mg, 033 mmol) were added. The resulting solution was stirred at room temperature overnight during which time a white precipitate formed. The THF was evaporated under reduced pressure and the residue was suspended in CH3CN. The insoluble precipitate was filtered off and the filtrate was purified via flash chromatography (silica gel, 10 mm×160 mm, 2% EtOAc/hexanes) to afford 41 mg (45%) of 2,3,5,6-tetrafluorophenyl 3,3-dimethyl-5-(tri-n-butylstannyl)-4 -pentenoate as a mixture of isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]([CH3:13])[C:10](=[O:14])[CH2:9][CH2:8]2.[CH3:15][O:16]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]2[N:11]([CH3:13])[C:10](=[O:14])[CH2:9][CH2:8][C:7]=2[C:6]([CH:15]=[O:16])=[CH:5][CH:4]=1
Reactant: COC(Cl)Cl
Reactant: COc1cccc2c1N(C)C(=O)CC2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C=O)c2c1N(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
8-Methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one (1.5 g) was dissolved in dichloromethane (15 ml), and dichloromethyl methyl ether (0.86 ml) was added at room temperature, followed by cooling with ice water. Titanium tetrachloride (10.5 ml) was added dropwise, and the resulting mixture was stirred at room temperature overnight. Further, dichloromethyl methyl ether (1.29 ml) and titanium tetrachloride (15.8 ml) were added, and stirring was carried out at room temperature for 5 hours. The reaction mixture was poured into ice water, and the aqueous layer was subjected to extraction with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Hexane was added to the residue, and the produced insoluble matter was collected by filtration and dried to thereby obtain 1.37 g (yield: 80%) of 8-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([O:10][CH3:11])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[CH2:19]([Si](C)(C)C)[CH:20]=C.B(F)(F)F.CCOCC>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH:19]=[CH2:20])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4]
Reactant: COC(=O)C1CCC(OC)N1C(=O)OC(C)(C)C
Reactant: C=CC[Si](C)(C)C
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCOC1CCC(C(=O)OC)N1C(=O)OC(C)(C)C
Yield: 61 %

Procedure:
To a solution of 5-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, 3, (9.86 g, 38.0 mmol) and allyltrimethylsilane (13.0 g, 114 mmol) in CH2Cl2 (200 mL) at −78° C. is added dropwise boron trifluoride etherate (4.82 mL, 38.0 mmol). Once consumption of the starting material is complete, water is cautiously added to quench the reaction. The resulting solution is taken up in ethyl acetate (200 mL) washed with water (1×250 mL), brine (1×250 mL), and dried with Na2SO4. The organics are concentrated in vacuo. The resulting residue is purified over silica (hexanes/ethyl acetate 85:15) to afford 6.2 g (61% yield) of the desired product as a light yellow oil. 1H-NMR (300 MHz, CDCl3): δ 5.85–5.70 (m, 1H), 5.09–5.00 (m, 2H), 4.31–4.16 (m, 1H), 3.95–3.76 (br m, 1H), 3.71–3.69 (m, 3H), 2.72–2.57 (br m, 1H), 2.24–1.69 (m, 5H), 1.45–1.38 (m, 9H); MS (ESI): m/e=270.11 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[N:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[H-].[Na+].Cl[CH2:21][O:22][CH3:23].C(=O)(O)[O-].[Na+]>C(N(CC)C(C)C)(C)C>[Br:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][O:22][CH3:23])[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[N:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1
Reactant: COC(=O)c1cc(Br)cc(Nc2nccs2)n1
Reactant: COCCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COCN(c1cc(Br)cc(C(=O)OC)n1)c1nccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 34.3 g of methyl 4-bromo-6-(1,3-thiazol-2-ylamino)pyridine-2-carboxylate and 440 ml of N,N-diisopropylethylamine was added 5.29 g of sodium hydride (60%, in oil) under an ice bath followed by stirring at the ambient temperature for 30 minutes. To the reaction mixture was added 9.9 ml of chloromethylmethyl ether followed by stirring at the ambient temperature for 4 hours. To the reaction mixture was added 4.52 g of sodium hydride (60%, in oil) and 8.3 ml of chloromethylmethyl ether, followed by further stirring for three hours. After warming to room temperature, to the reaction mixture was added saturated aqueous sodium bicarbonate. The precipitate was filtered off and washed with water. The filtrate was extracted with ethyl acetate and then the organic layer was washed with water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=9/1 to 3/1) to give the title compound as a pale yellow solid.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][C:7]([Cl:19])=[CH:6][CH:5]=2.C[Sn](C)(C)[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Cl:19][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[C:10]2[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CCCc1c(Br)[nH]c2ccc(Cl)cc12
Reactant: C[Sn](C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CCCc1c(-c2ccc([N+](=O)[O-])cc2)[nH]c2ccc(Cl)cc12
Temperature: 50 °C
Yield: 31 %

Procedure:
A mixture of 200 mg (0.58.10−3 mol) of ethyl 2-bromo-5-chloro-1H-indole-3-butanoate, 498 mg (1.74.10−3 mol) of trimethyl(4-nitrophenyl)tin, 140 mg (0.46.10−3 mol) of triphenylarsine, 108 mg (0.12.10−3 mol) of tris(dibenzylideneacetone)dipalladium and 12 ml of dioxane is prepared and this reaction medium is heated at 50° C. for 6 days, with stirring. After cooling, 12 ml of water are added and the mixture is then extracted with ethyl ether. The organic phase is subsequently washed with water and then dried and concentrated under reduced pressure. The residue is purified by chromatography on silica gel using a petroleum ether/ethyl acetate mixture (85/15; v/v) as the eluent. The fractions containing the expected compound are purified again by reversed phase chromatography on C18-grafted silica using an acetonitrile/water mixture (7/3; v/v) as the eluent to give 70 mg of the expected compound in the form of a yellow paste (yield=31%).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH3:17]>>[OH:4][CH2:3][CH2:2][N:1]([CH2:17][CH2:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:9]=1)[CH2:5][CH2:6][OH:7]
Reactant: CCOc1ccccc1Cl
Reactant: OCCNCCO
Product: OCCN(CCO)CCOc1ccccc1

Procedure:
2-[(2-Hydroxyethyl)-(2-phenoxy-ethyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (15.0 g, 150). and 2-chloro-phenetol (15.6 g, 100 mmol). Yield 18 g, (80%); Colorless oil; MS: 226 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[CH:23]=[CH2:24].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([C:8](=[C:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:24]=[CH:23]/[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: Oc1ccc(C(=C2CCOCC2)c2ccc(Br)cc2)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCOCC2)c2ccc(O)cc2)cc1
Temperature: 160 °C
Reaction time: 0.08 h
Yield: 58.9 %

Procedure:
4-[(4-Bromophenyl)(tetrahydro-4H-pyran-4-ylidene)methyl]phenol (46) (0.106 g, 0.307 mmole) was dissolved in DMF (1 mL). tert-Butyl acrylate (0.090 mL, 0.614 mmole), P(o-tolyl)3 (0.0099 g, 0.0325 mmole) and Et3N (0.130 mL, 0.933 mmole) were added followed by Pd(OAc)2 (0.0037 g, 0.0165 mmole). The mixture was heated to 160° C. in a microwave synthesizer for 30 min then was cooled to RT. Water (20 mL) was added and the mixture was extracted with Et2O (3×10 mL). The organics were dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (Isco Sg100c, RediSep 12 g cartridge, 15% EtOAc:hexanes for 5 min, 15% to 40% EtOAc:hexanes over 15 min, 40% EtOAc:hexanes for 5 min to yield 0.071 g (59%) of 47 as a white solid. 1H NMR (CDCl3): δ 7.55 (d, J=16.0 Hz, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.10 (d, J=8.1 Hz, 2H), 6.97 (d, J=8.5 Hz, 2H), 6.76 (d, J=8.5 Hz, 2H), 6.32 (d, J=16.0 Hz, 1H), 5.01 (s, 1H), 3.74 (m, 4H), 2.40 (dd, J=11.1, 5.6 Hz, 4H), 1.53 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.CCCCCC.C([Li])CCC.[Cl:23][C:24]1[CH:38]=[CH:37][C:27]([O:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]#N)=[N:33][CH:34]=2)=[CH:26][CH:25]=1.[O:39]1CCCC1>O.CO>[Cl:23][C:24]1[CH:38]=[CH:37][C:27]([O:28][C:29]2[CH:30]=[CH:31][C:32]([C:35](=[O:39])[C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=3)=[N:33][CH:34]=2)=[CH:26][CH:25]=1
Reactant: N#Cc1ccc(Oc2ccc(Cl)cc2)cn1
Reactant: C1CCOC1
Reactant: COc1ccc(Br)cc1OC
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CO
Product: COc1ccc(C(=O)c2ccc(Oc3ccc(Cl)cc3)cn2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In anhydrous tetrahydrofuran (6 ml) was dissolved 4-bromoveratrol (700 mg). To the solution was added dropwise a 15% n-hexane solution of n-butyllithium (2.2 ml), while stirring under cooling at temperatures ranging from -60° C. to -70° C. under an atmosphere of nitrogen gas. The mixture was stirred at the same temperature range for 20 minutes, and there was added dropwise at temperatures of -70° C. or below a solution of 5-(4-chlorophenoxy)-2-cyanopyridine (500 mg) in dry tetrahydrofuran (6 ml). The mixture was stirred at the same temperature for 30 minutes, and there was added methanol (1 ml) (the temperature rose up to -65° C. from -73° C.), then the temperature of the mixture was slowly warmed to room temperature. To the reaction mixture was added silica gel (3 g), and there was then added water (0.5 ml), and the mixture was stirred at room temperature for 2 hours, and left standing overnight. Silica gel was filtered off, and the filtrate was concentrated. The concentrate was purified by means of a silica gel column chromatography [eluted with a mixture solvent of dichloromethane and ethyl acetate (10:1)] to obtain 5-(4-chloro-phenoxy)-2-(3,4-dimethoxybenzoyl)pyridine (240 mg) as colorless crystals, m.p. 145 to 147° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.Br[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[H-].[Na+].Cl>O.C(OCC)(=O)C.CN(C)C=O>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:18][CH2:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: BrCCOC1CCCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)OB(c2ccc(OCCOC3CCCCO3)cc2)OC1(C)C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
Into dimethylformamide (250 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (10.0 g, 45.5 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (10.0 g, 45.5 mmol) were dissolved, to which 60% sodium hydride in oil (2.98 g, 68.3 mmol) was added while cooling with ice, followed by stirring for three hours while cooling with ice, and further for 17 hours at room temperature. Ethyl acetate was then added, and excess hydrated sodium was neutralized with 1M hydrochloric acid. Further, water was added and the resulting solution was separated. The resulting organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-70:30, V/V) to give the desired title compound (13.3 g, yield 84%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])([O-:8])=[O:7]>>[CH3:16][O:15][C:10]1[C:9]([N+:6]([O-:8])=[O:7])=[CH:14][C:13]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:12][CH:11]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccccc1[N+](=O)[O-]
Product: COc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
2.5 mols (165 ml) of chlorosulphonic acid are placed in a one-liter reaction vessel equipped with a stirring system, a thermometer and a dropping funnel and the acid is cooled to about 0° C. with a mixture of ice and salt. 0.8 mol (100 ml) of 2-nitroanisole is added drop by drop and the solution is then allowed to come back to room temperature; after a contact time of 30 minutes, the reaction mixture is poured onto one fifth of its volume of crushed ice. The sulphonyl chloride precipitates in the form of an oil; this is extracted with chloroform. After evaporation of the organic phase, the sulphonyl chloride is crystallized in a benzene/petroleum ether mixture.
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: CCN(CC)CC
Solvent: ClCCl
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: [O-][CH2:2][CH3:3].[Na+].C(O)(=O)C[C:7]([CH2:12]C(O)=O)([C:9]([OH:11])=[O:10])[OH:8].[C:18]1([CH3:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:24]([O:8][CH:7]([CH3:12])[C:9]([O:11][CH2:2][CH3:3])=[O:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC[O-]
Reactant: Cc1ccccc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Product: CCOC(=O)C(C)OCc1ccccc1

Procedure:
The water layer at the time of the extraction with ethyl acetate in Example 3 was collected in its entirety, and was then adjusted to pH 2 with 10% hydrochloric acid. The water layer was then extracted twice with ethyl acetate (100 mL). After the organic layers were combined and dried, the solvent was distilled off to obtain (S)-benzyloxypropionic acid [0.83 g (48.0%), 96% ee]. An aliquot (0.8 g, 4.4 mmol) of the (S)-benzyloxypropionic acid was dissolved in ethanol (10 mL), followed by the addition of concentrated sulfuric acid (0.01 mL). The thus-prepared mixture was then heated under reflux. Eight hours later, the solvent was distilled off, and the residue was extracted with ethyl acetate (20 mL). The extract was washed with a 5% aqueous solution of sodium hydrogencarbonate (10 mL) and water (10 mL), the organic layer was dried, and the solvent was distilled off to obtain (S)-ethyl benzyloxypropionate. It was dissolved in toluene (10 mL), and under ice-cooled stirring, sodium ethoxide (0.33 g, 1.1 eq) was added, followed by stirring at room temperature for 14 hours. By gas chromatography making use of an optically active column, completion of the racemization was confirmed. Thereafter, the reaction mixture was added dropwise into a 10% aqueous solution of citric acid (10 mL). After the organic layer was washed with water (10 mL) and then dried, the solvent was distilled off to afford the title compound (0.74 g). 1H-NMR spectrum data of the compound were in conformity with those of the compound in Example 1. This racemate can be used as a feed for such asymmetric ester hydrolysis as in Examples 1 to 4.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH:7]([NH:16]C(=O)C(F)(F)F)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH2:1]([O:4][CH2:5][CH2:6][CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[NH2:16])[CH:2]=[CH2:3]
Reactant: C=CCOCCC(NC(=O)C(F)(F)F)c1cccc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C=CCOCCC(N)c1cccc(OC)c1
Yield: 91.8 %

Procedure:
Step R (3): N-(3-(Allyloxy)-1-(3-methoxyphenyl)propyl)-2,2,2-trifluoroacetamide from step R (2) (610 mg, 1.92 mmol), potassium carbonate (1.33 g, 9.26 mmol), methanol (50 mL) and H2O (4 mL) were heated to reflux for 16 h. The mixture was concentrated in vacuo. H2O was added, and the aqueous layer was extracted several times with EtOAc. The combined organics were washed with brine, dried over Na2SO4, and concentrated in vacuo to afford 390 mg (92% yield) of 3-(allyloxy)-1-(3-methoxyphenyl)propan-1-amine as a pale-yellow oil. The crude mixture was used without further purification. LC-MS (M+H)+=222.95; 1H NMR (300 MHz, CDCl3) δ ppm 1.82-2.18 (m, 2H) 3.23-3.54 (m, 3H) 3.72-3.82 (m, 3H) 3.83-4.00 (m, 2H) 4.14 (t, J=6.95 Hz, 1H) 5.08-5.31 (m, 2H) 5.76-5.95 (m, 1H) 6.71-6.86 (m, 1H) 6.86-6.97 (m, 1H) 7.14-7.29 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][C@@H:11]([NH:20][CH3:21])[C@H:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C@@H:4]1[N:20]([CH3:21])[C@H:11]([CH3:10])[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:5]1
Reactant: O=Cc1ccccc1Br
Reactant: CN[C@H](C)[C@H](O)c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@@H]1[C@@H](c2ccccc2)O[C@H](c2ccccc2Br)N1C

Procedure:
To a solution of 2-bromobenzaldehyde (18.78 g, 101.50 mmole, 1.0 eq) in toluene (100 mL) was added (-)-pseudoephedrine (16.73 g, 101.24 mmole, 1.0 eq). The mixture was refluxed for 16 h under an argon atmosphere using a Dean-Stark trap to remove the generated ,water. Concentration in vacuo gave 33.53 g (100%, corrected for 2 wt % toluene by 1H NMR) of a 40:1 mixture of title compound and a minor diastereomer as a light yellow oil.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.N1CCCCC1.[C:14]12([C:24]3[CH:25]=[C:26]([C:32]4[CH:33]=[C:34]5[C:39](=[CH:40][CH:41]=4)[CH:38]=[C:37](C=O)[CH:36]=[CH:35]5)[CH:27]=[CH:28][C:29]=3[O:30][CH3:31])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.[S:44]1[CH2:48][C:47](=[O:49])[NH:46][C:45]1=[O:50]>C(O)(=O)C>[C:14]12([C:24]3[CH:25]=[C:26]([C:32]4[CH:33]=[C:34]5[C:39](=[CH:40][CH:41]=4)[CH:38]=[C:37]([N:46]4[C:47](=[O:49])[C:48](=[CH2:1])[S:44][C:45]4=[O:50])[CH:36]=[CH:35]5)[CH:27]=[CH:28][C:29]=3[O:30][CH3:31])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2
Reactant: Cc1ccccc1
Reactant: COc1ccc(-c2ccc3cc(C=O)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: C=C1SC(=O)N(c2ccc3cc(-c4ccc(OC)c(C56CC7CC(CC(C7)C5)C6)c4)ccc3c2)C1=O
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of toluene (150 mL), piperidine (0.48 mL), acetic acid (0.51 mL), 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthaldehyde (5.84 g, 14.75 mmol) and 2,4-thiazolidinedione (1.73 g, 14.75 mmol) was heated at reflux for 18 hours under an argon atmosphere. The resulting suspension was filtered and the solid was stirred at room temperature in 30 mL of EtOH. After 30 minutes the solid was filtered and dried under high vacuum to afford 5.3 g (71%) of 6-[3-(1-adamantyl)-4-methoxyphenyl]-naphthalen-2-yl-methylene-2,4-thiazolidinedione, mp 286–287° C. 1H NMR (300 MHz; DMSO-d6): 1.76 (brs, 6H), 2.07–2.14 (m, 9H), 3.87 (s, 3H), 7.11 (d, J=8.4 Hz, 1H), 7.58 (s, 1H), 7.66 (t, J=9.3 Hz, 2H), 7.88–7.93 (m, 2H), 8.09 (t, J=8.7 Hz, 2H), 8.18 (d, J=5.7 Hz, 2H), 12.63 (brs, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.Cl[C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:23][C:22](=O)[O:21][C:19](=[O:20])[CH2:18]2)=[CH:13][CH:12]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:19](=[O:20])[CH2:18][CH:17]([C:14]4[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=4)[CH2:23][C:22]3=[N:9][C:4]=2[CH:3]=1.[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:22]3[CH2:23][CH:17]([C:14]4[CH:13]=[CH:12][CH:11]=[CH:16][CH:15]=4)[CH2:18][C:19](=[O:21])[N:9]3[C:4]=2[CH:3]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Product: Cc1ccc2c(c1)nc1n2C(=O)CC(c2ccccc2)C1
Product: Cc1ccc2nc3n(c2c1)C(=O)CC(c1ccccc1)C3

Procedure:
By a procedure similar to that of example 1.22.1, starting from commercial 4-methyl-1,2-phenylenediamine and 3-(4-chlorophenyl)glutaric anhydride, a 1:1-mixture of the regioisomers 7-methyl-3-phenyl-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one and 8-methyl-3-phenyl-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one was obtained.