Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCC([O:5][CH2:6][CH3:7])=O.[CH2:8]([NH2:11])[CH2:9][NH2:10].C[O-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.CO>[C:16]1([CH2:15][N:10]2[CH2:9][CH2:8][NH:11][C:6](=[O:5])[CH2:7]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: NCCN
Reactant: CCOC(=O)CCl
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: O=C1CN(Cc2ccccc2)CCN1
Reaction time: 8 h

Procedure:
A solution of ethyl chloroacetate (204 g., 1.67 mole) in ethanol (500 ml.) is added to a stirred solution of ethylenediamine (600 g., 10 mole) in ethanol (3 l.) at 0°. After addition is complete the solution is allowed to warm to 20°-25°. After 5 hours a solution of sodium methoxide (90.0 g., 1.67 mole) in methanol (200 ml.) is added and the solution is stirred overnight, filtered to remove inorganic salts and evaporated to remove solvent and unreacted ethylenediamine. The residual oil (189 g.) is added to a mixture of benzyl chloride (241 g., 1.9 mole) anhydrous sodium carbonate (191 g., 2.28 mole) in ethanol (2.3 l.) and the solution is stirred under reflux for 3 hours. The ethanol is removed under reduced pressure and the residue is partitioned between chloroform and water. Evaporation of the chloroform gave a crystalline product which was recrystallized from ethyl acetate to give the title compound, m.p. 154°- 156°.
Reaction SMILES: [C:1]([N:11]1[CH2:15]C=CC1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C[N+]1([O-])CC[O:20]CC1.OS([O-])=O.[Na+].[CH3:29][C:30]([CH3:32])=[O:31]>O=[Os](=O)(=O)=O>[OH:31][CH:30]1[CH:32]([OH:20])[CH2:15][N:11]([C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:29]1
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Product: O=C(OCc1ccccc1)N1CC(O)C(O)C1
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of N-carbobenzoxy-3-pyrroline (1.00 g, 4.92 mmol, 1.0 eq) in acetone (20 mL) was added NMO (1.0 g, 7.38 mmol, 1.5 eq) followed by OsO4 (cat. 10 mg in 1 mL iPrOH). The mixture was stirred for 3 h. To this, saturated NaHSO3 aqueous solution (5 mL) was added, and the mixture was stirred for another 0.5 h. The organic phase was separated from the mixture, and the water phase was extracted with EtOAc (20 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (EtOAc) to give the compound as colorless oil (1.16 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:17]([CH2:18][C:19]([N:37]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])=[O:21])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:7][CH:8]=1
Reactant: CCCNCCC
Reactant: COc1ccc(-c2nc3cccnc3n2CC(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(OC)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.7 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-methoxyphenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (4.2 g, 0.015mole) and 1,1'-carbonyldiimidazole (2.43 g, 0.015 mole) in 120 ml of tetrahydrofuran was stirred at room temperature for 3 hrs. The dipropylamine (3.04 g, 0.03 mole) was added and the reaction mixture was allowed to stir at room temperature overnight, then heated at reflux for 8 hrs. The reaction mixture was filtered and the filtrate ws evaporated to dryness, then placed under high vacuum over the weekend. The residue was treated with water and the solid was collected by filtration, washed with water, and dried under high vacuum. The solid was dissolved in 100 ml of isopropyl alcohol, filtered, and the filtrate concentrated to 50 ml. The filtrate was diluted with water, seeded, and placed in a freezer overnight. The solid was collected by filtration, washed with water, and dried under high vacuum at 50°-60° C. overnight to give 1.8 g (33%) of title compound, mp 127°-29° C. Analysis: Calculated for C21H26N4O2 : C, 68.83; H, 7.15; N, 14.29; Found : C, 68.74; H, 7.15; N, 15.18.
Reaction SMILES: [CH:1]1([C:7](=[CH2:10])[CH:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:11]([Mg]Br)=[CH:12][CH2:13][CH3:14].BrCCC=C.[Mg]>CCOCC>[CH:1]1([C:7]([CH:8]([OH:9])[CH2:14][CH2:13][CH:12]=[CH2:11])=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC=C[Mg]Br
Reactant: C=C(C=O)C1CCCCC1
Agent: C=CCCBr
Agent: [Mg]
Solvent: CCOCC
Product: C=CCCC(O)C(=C)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
2-Cyclohexylprop-2-en-1-al (69 g, 0.5 mol) in 100 ml of ether was slowly added to but-1-enylmagnesium bromide prepared by slow addition of 4-bromo-but-1-ene (81.0 g, 0.6 mol) in 100 ml of ether at 0° C. to magnesium turnings (13.2 g, 0.55 mol) in 300 ml of ether. After the addition was complete, the reaction mixture was allowed to warm to room temperature (RT) and was stirred for additional 3 hours. After quenching with 2N HCl, the organic phase was separated, washed with H2O until neutral pH was achieved, dried (MgSO4), and the solvent was evaporated in vacuo. The crude product was distilled over a Vigreux column (0.15 Torr, 91° C.) yielding 85 g (88%) of pure product as colorless oil.
Reaction SMILES: S(=O)(O)[O-].[Na+].[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([F:15])[CH:14]=1)[CH:10]=[O:11].[C-:16]#[N:17].[Na+]>O>[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([F:15])[CH:14]=1)[CH:10]([OH:11])[C:16]#[N:17]
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: N#CC(O)c1cc(F)cc(F)c1
Yield: 85.7 %

Procedure:
Under stirring, 21 ml of a saturated aqueous solution of sodium bisulfite were added little by little to the mixture of 10.0 g of 3,5-difluorobenzaldehyde, 3.6 g of sodium cyanide and 15 ml of water. Upon the gradual addition, ice pieces were added at the same time to maintain the reaction temperature at 20°-30° C. The reaction mixture was stirred for 10 hours and then extracted with benzene. The resulting organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure, whereby 10.2 g of crude 3,5-difluoromandelonitrile were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([OH:12])=[O:11])([O-:3])=[O:2].Br[CH2:14]C(O)=O.[OH-].[Na+]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([CH3:14])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: O=C(O)CBr
Reactant: O=[N+]([O-])c1ccccc1S(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 91 %

Procedure:
This is contradicted by investigations by A. Courtin, H. -R. von Tobel and G. Auerbach, Helv. Chim. Acta 63, 1412 (1980), according to which, on heating of 1 mol of 2-nitrobenzenesulfinic acid, 2 mol of bromoacetic acid and 2 mol of sodium hydroxide solution under reflux conditions for 24 hours, only methyl 2-nitrophenyl sulfone is obtained in 91% yield. Evidently, the carboxymethyl aryl sulfone forming is immediately decarboxylated to the methyl aryl sulfone under the acidic reaction conditions.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([O:14][C:15](=[O:23])[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13].CN(C)C=O.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([C:16]([CH3:22])([C:15]([O:14][CH2:12][CH3:13])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(F)c1

Procedure:
A mixture of 50.0 g (0.31 mol) of 2,4-difluoronitrobenzene II, 56.1 g (0.32 mol) of diethylmethylmalonate and 400 ml of dimethylformamide are vigorously stirred. To the stirring mixture is added 13.1 g (0.33 mol) sodium hydroxide in one portion at 25° C., cooling with ice to keep the temperature of the reaction mixture at 25°-30° C. during the first hour. Thereafter, stirring is maintained for 3.5 hours, then 800 ml of water is added, the organic layers removed, and the aqueous layer extracted with three 180-ml portions of ethyl acetate-water.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[Br:11])=[N+:2]=[N-:3].[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[Br:11][C:5]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=1[N:1]1[CH:17]=[C:16]([Si:13]([CH3:15])([CH3:14])[CH3:12])[N:3]=[N:2]1
Reactant: [N-]=[N+]=Nc1cc(F)ccc1Br
Reactant: C#C[Si](C)(C)C
Solvent: Cc1ccccc1
Product: C[Si](C)(C)c1cn(-c2cc(F)ccc2Br)nn1
Temperature: 110 °C
Yield: 95.2 %

Procedure:
A mixture of 2-azido-1-bromo-4-fluorobenzene (1.047 g, 4.85 mmol) and trimethylsilylacetylene (2.01 mL, 14.54 mmol) in toluene (5 mL) was heated in a pressure vessel at 110° C. for 21.5 h. The reaction mixture was concentrated in vacuo and the residue was purified with a Biotage system on silica gel with hexanes:ethyl acetate (9:1) gradient as the eluent to afford the title compound as a colorless oil (1.451 g, 95% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 7.97 (1H, s), 7.74 (1H, dd, J=9.0, 5.4 Hz), 7.37 (1H, dd, J=8.5, 2.9 Hz), 7.16 (1H, ddd, J=8.8, 7.6, 3.0 Hz), 0.40 (9H, s), LCMS (+ESI, M+H+) m/z 314/316.
Reaction SMILES: [CH2:1]([N:4]1[CH:13]2[C:8]3=[C:9]([C:22]([OH:27])=[C:23]([O:25][CH3:26])[CH:24]=[C:7]3[CH2:6][CH2:5]1)[C:10]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:11]=1[CH2:12]2)[CH:2]=[CH2:3].[C:28]1(C)C=CC=CC=1.CN(C)C=O.[OH-].C1([N+](C)(C)C)C=CC=CC=1>CO>[CH2:1]([N:4]1[CH:13]2[C:8]3=[C:9]([C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=[C:7]3[CH2:6][CH2:5]1)[C:10]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:11]=1[CH2:12]2)[CH:2]=[CH2:3]
Reactant: Cc1ccccc1
Reactant: C=CCN1CCc2cc(OC)c(O)c3c2C1Cc1cc(OC)c(OC)cc1-3
Agent: C[N+](C)(C)c1ccccc1
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: C=CCN1CCc2cc(OC)c(OC)c3c2C1Cc1cc(OC)c(OC)cc1-3

Procedure:
4.5 g. (12.2 mmol) (+)-6-Allyl-5,6,6a,7-tetrahydro-1-hydroxy-2,9,10-trimethoxy-4H-dibenzo(de,g)quinoline are reacted in 230 ml. of a mixture of toluene and dimethylformamide (9:1 v/v) with 20 ml. of a 1N solution of phenyltrimethylammonium hydroxide in methanol as described in Variant 1. After appropriate working up, there is obtained (+)-6-allyl-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-4H-dibenzo(de,g)quinoline, which is identical in every respect to the product obtained according to Variant 1. [α]DRT (hydrochloride): +117.7° (c=0.5, methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[CH3:25])=[C:9]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)C=O)=[C:4]([CH3:26])[CH:3]=1.C1(P(=[CH:46][CH:47]=[O:48])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:49]1C=CC=CC=1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[CH3:26])=[C:9]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)[CH:49]=[CH:46][CH:47]=[O:48])=[C:19]([CH3:25])[CH:20]=1
Reactant: c1ccccc1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(F)ccc1C(=C(C=O)c1nnnn1C)c1ccc(F)cc1C
Product: Cc1cc(F)ccc1C(=C(C=CC=O)c1nnnn1C)c1ccc(F)cc1C

Procedure:
A solution of 3,3-bis(4-fluoro-2-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal (0.88 g, 2.5 mmoles) and triphenylphosphoranylidene acetaldehyde (0.75 g, 2.5 mmoles) in benzene (50 mL) was heated at reflux for 3 hours. The solvent was removed by evaporation and the crude residue purified by column chromatography on silica gel eluting with 1% (v/v) methanol in methylene chloride. The fractions containing material having Rf =0.9 [1:20 (v/v) methanolmethylene chloride] were combined and concentrated to give 0.8 g of the title compound; m.p.=75°-95° C. MS: M+ =380;
Reaction SMILES: [OH2:1].O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:19]=1[OH:27])([CH3:17])([CH3:16])[CH3:15]>S(=O)(=O)(O)O.O.C(OCC)C>[C:14]([C:18]1[C:19](=[O:27])[C:20]([CH:24]([CH3:25])[CH3:26])=[CH:21][C:22](=[O:1])[CH:23]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)c1cccc(C(C)(C)C)c1O
Reactant: O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Reaction time: 2.5 h

Procedure:
A 160 g quantity of sodium dichromate dihydrate was dissolved in a mixture of 100 ml of 97% sulfuric acid and 230 ml of water, and the solution was added to a solution of 45.0 g of 2-tert-butyl-6-isopropylphenol in 350 ml of diethyl ether with stirring at a temperature of 5°-10° C. over a period of 2.5 hours. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed serially with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent: diethyl ether-hexane=1:10), giving 12.7 g of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)[N:3]=1
Reactant: [H][H]
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cnc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N

Procedure:
To a stirred solution of (R)-(1-(4-amino-5-nitropyrimidin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (300 mg, 0.937 mmol) in ethanol (15 mL) was added under a nitrogen atmosphere a suspension of 10% palladium-on-carbon (300 mg) in ethanol. The reaction mixture was hydrogenated using a balloon filled with hydrogen gas for 2 h at room temperature. The suspension was filtered through Celite and the filtrate was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[S:16].N12CCN(CC1)CC2.C(OCC)(=O)C>CN(C=O)C.O>[CH3:13][N:14]([CH3:18])[C:15]([O:12][C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[S:16]
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(F)cc1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 81.1 %

Procedure:
4-Fluorosalicylic acid (10.0 g, 64 mmol) was dissolved in methanol (300 ml), and concentrated sulfuric acid (6.3 g, 64 mmol) was added thereto. The reaction mixture was refluxed for 48 hrs. The solvent was evaporated, and the residue was neutralized with 2 N aqueous sodium hydroxide solution. Ethyl acetate was added to the mixture. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give methyl 4-fluorosalicylate (10.0 g, 92%) as white crystals. Methyl 4-fluorosalicylate (10.0 g, 58 mmol) and N,N-dimethylthiocarbamoyl chloride (9.6 g, 77 mmol) were dissolved in DMF (100 ml), and 1,4-diazabicyclo[2.2.2]octane (8.5 g, 75 mmol) was added thereto. The reaction mixture was stirred at room temperature for 7 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:5, v/v) were collected, concentrated and recrystallized from ethyl acetate-hexane to give the titled compound (12.1 g, 80%) as white crystals.
Reaction SMILES: C([Li])CCC.[O:6]1CCCC1.Cl[C:12]1[N:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:15]=[CH:14][N:13]=1>C(OCC)(=O)C.O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:18][C:16]2[CH:15]=[CH:14][NH:13][C:12](=[O:6])[N:17]=2)=[CH:21][CH:22]=1
Reactant: C1CCOC1
Reactant: Fc1ccc(COc2ccnc(Cl)n2)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1nc(OCc2ccc(F)cc2)cc[nH]1
Reaction time: 0.5 h
Yield: 24 %

Procedure:
n-Butyl lithium (2.6 M n-hexane solution, 7.2 mL) was added to tetrahydrofuran solution (10 mL) of 2-popenyl alcohol (1.8 mL) at −78° C., and stirred at the same temperature for 30 minutes. This reaction liquid was gradually added to tetrahydrofuran solution (20 mL) of 2-chloro-4-(4-fluorobenzyloxy)pyrimidine (4.36 g) and stirred at 60° C. for 4 hours, followed by 24 hours' reflux. Cooling the reaction liquid to room temperature, ethyl acetate was added thereto, followed by washing with water and saturated brine and drying over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was dissolved in tetrahydrofiaan (20 mL). To the solution piperidine (2 mL) and tetrakis(triphenylphosphine)palladium (780 mg) were added and stirred at room temperature for 4 hours. The reaction liquid was added to water (100 mL)-ethyl acetate (50 mL) mixture, and the insoluble matter was recovered by filtration to provide the title compound (0.96 g, 24%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[CH:12]([O:30]2)[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Product: COc1cccc(C23CCN(C(=O)OC(C)(C)C)CC2O3)c1
Yield: 94.9 %

Procedure:
4-(3-Methoxy-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2 g, 6.9 mmol) was further purified by flash chromatography (100 DCM on Silicagel) to remove baseline impurities (likely waste palladium from Suzuki reaction), then was dissolved in methylene chloride (28.9 mL, 451 mmol) and treated with m-CPBA 70-75% (70:30, m-chloroperbenzoic acid: 3-chlorobenzoic acid, 2.4 g, 9.7 mmol) at room temperature overnight. The reaction was quenched by treatment with a Na2S2O3 aq solution, followed by sat. NaHCO3 aq. solution, and further extracted twice with dichloromethane. The combined organic extracts were dried (MgSO4) and filtered, and the solvent was evaporated under reduce pressure. The product was used without further purification in the next step: (±)-6-(3-methoxy-phenyl)-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (2 g, 95% yield). 1H NMR (CDCl3): δ ppm 7.26 (m, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.90 (br. s., 1H), 6.84 (d, J=8.1 Hz, 1H), 3.93-4.19 (m, 1H), 3.81 (s, 3H), 3.53-3.79 (m, 2H), 3.10-3.24 (m, 2H), 2.38-2.51 (m, 1H), 2.17 (br. s., 1H), 1.48 (s, 9H).
Reaction SMILES: O=O.[CH3:3][O:4]/[C:5](=[CH:9]\[C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)/[C:6]([OH:8])=[O:7].C1([C@@H](N)C)C=CC=CC=1.[H][H]>C1COCC1.ClCCl>[CH3:3][O:4][C@@H:5]([CH2:9][C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Reactant: [H][H]
Agent: C[C@H](N)c1ccccc1
Agent: O=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a glove box (O2 content≦2 ppm), a 50-ml stainless steel autoclave was charged with 2.26 mg of [Ru(η5-2,4-DMP)((S)—(R)-(3,5-Me2-4-MeOPh)2PF—PtBu2)(NCMe)]BF4 (0.0023 mmol, S/C 1,000) and 6 ml of dichloromethane. The resulting violet solution was stirred for 2 h at r.t. Then, 1.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (2.30 mmol), 4 ml of dichloromethane, 10 ml of THF and 0.06 ml of (S)-1-phenylethylamine (0.47 mmol) were added. The autoclave was sealed and the hydrogenation was run under stirring at 40° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford the crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.5% (>99.9% conversion) and an enantiomeric purity of 87%.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][C:11]1[CH:12]=[C:13]([C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=2)=[CH:20][C:21]#[N:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>C(Cl)Cl>[C:21]([CH:20]=[C:19]([C:13]1[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([NH:10][C:36](=[O:37])[N:35]([CH3:39])[CH3:34])[CH:12]=1)[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)#[N:22]
Reactant: CN(C)C(=O)Cl
Reactant: CCOc1cc(C(=CC#N)c2ccc(OC)c(N)c2)ccc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc(C(=CC#N)c2ccc(OC)c(NC(=O)N(C)C)c2)ccc1OC
Temperature: 85 °C
Yield: 67.8 %

Procedure:
N,N-diisopropylethylamine (1.5 mL, 8.6 mmol) was added to a mixture of (E/Z) 3-(3-amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile (0.70 g, 2.2 mmol) and dimethylcarbamyl chloride (1.6 mL, 17.3 mmol). The reaction mixture was heated at 85° C. for 3 h. CH2Cl2 (100 ml) was added and the mixture was extracted with water (2×50 mL), 4 N HCl (2×50 mL), water (2×50 mL), saturated NaHCO3 (2×50 mL), brine (50 mL) and dried (MgSO4). Removal of solvent and chromatography (Silica Gel) gave a mixture of (E/Z) 3-{5-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-1,1-dimethyl-urea as a solid (0.59 g, 69% yield): mp, 143-145° C.; 1H NMR (CDCl3) δ 1.40-1.47 (m, 6H, 2CH3), 3.02-3.05 (2s, 12H, 4CH3), 3.88-3.94 (3s, 12H, 4OCH3), 3.99-4.12 (m, 4H, 2CH2), 5.55-5.61 (2s, 2H, 2CH), 6.79-7.18 (m, 12H, Ar), 8.18-8.36 (m, 2H, 2NH); 13C NMR (CDCl3) δ 14.71, 36.33, 55.93, 56.00, 64.46, 92.06, 92.33, 109.21, 109.30, 110.93, 110.99, 112.74, 114.22, 118.56, 118.69, 118.79, 120.27, 122.25, 123.06, 123.41, 123.74, 128.97, 129.24, 129.73, 130.11, 131.68, 132.25, 147.83, 148.14, 148.81, 149.27, 150.68, 151.37, 155.22, 155.31, 162.66, 163.11; Anal. Calcd for C22H25N3O4: C, 66.82; H, 6.37; N, 10.63. Found: C, 66.84; H, 6.48; N, 10.43.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[C:5]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[NH:7][N:6]=1.Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].O>CN(C=O)C>[C:21]([O:20][C:18](=[O:19])[CH2:17][N:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:5]([C:4]([F:3])([F:14])[F:15])=[N:6]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Cn1nc(C(F)(F)F)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% [w/w] dispersion in mineral oil, 632 mg, 15.8 mmol) was added portionwise to a stirred solution of 4,5,6,7-tetrahydro-3-(trifluoromethyl)-indazole (3.00 g, 15.8 mmol) in DMF (60 mL), and the mixture stirred at RT for 30 min. Tert-butyl bromoacetate (2.33 mL, 15.8 mmol) was added and the reaction mixture stirred at 80° C. for 2 h, and allowed to cool to RT. Water (50 mL) was added and the resulting solution extracted with EtOAc (3×200 mL), washed with water (200 mL), brine (200 mL), dried over sodium sulfate, and concentrated in vacuo to afford (3-Trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid tert-butyl ester.