Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]=[C:9]1[S:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)OC(C)(C)C)=[CH:16][CH:15]=2)[NH:10]1>ClCCl>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[NH:10][C:9](=[O:8])[S:13][N:12]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2nsc(=O)[nH]2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2nsc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
At 0° C., 0.8 ml of TFA was added to a solution of 129 mg (purity 70%, 0.44 mmol) of tert-butyl [4-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)phenyl]carbamate in 4 ml of dichloromethane, and the mixture was stirred at RT for 40 min Subsequently, the reaction mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 54 mg (purity 90%, 57% of theory)
Reaction SMILES: [Mg].C(O[Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])C.II.Br[C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=1.Br[C:26]1[CH:31]=CC=CC=1Br>O1CCCC1>[CH2:13]([O:12][Si:5]([O:6][CH2:7][CH3:8])([O:9][CH2:10][CH3:11])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Si:5]([O:12][CH2:31][CH3:26])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])[CH:19]=1)[CH3:14]
Reactant: CCO[Si](OCC)(OCC)OCC
Reactant: Brc1cccc(Br)c1
Reactant: Brc1ccccc1Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCO[Si](OCC)(OCC)c1cccc([Si](OCC)(OCC)OCC)c1
Reaction time: 0.21 h

Procedure:
Magnesium chips (28.0 g, 1.15 mol) and freshly distilled tetraethoxysilane (450 mL, 2 mol) in tetrahydrofuran (750 mL) were placed under nitrogen in a 2 L 3-neck flask equipped with a magnetic stir bar, a condenser, and an additional funnel. A small crystal of iodine was added in order to activate the magnesium. A solution of 1,3-dibromobenzene (100.0 g, 0.424 mol) in tetrahydrofuran (250 mL) was added slowly. When ca. 25 mL of the dibromide had been added, the addition was stopped and stirring was continued until a mildly exothermic reaction began (usually within 20-30 minutes). The addition of dibromobenzene was continued and held at such a rate as to maintain the solution at reflux. After the addition was complete, the reaction mixture was stirred for two additional hours. The resulting brown solution was filtered from the remaining magnesium metal, and the tetrahydrofuran was removed by evacuation. The brown residue was extracted with dry hexane (500 mL), and combined extracts were concentrated in vacuo. Unreacted tetraethyl orthosilicate was removed in vacuo (103 torr), leaving a tea-brown oil. Two distillations gave the product as a clear, colorless oil (0.1 mm Hg, 126-128° C., 58.0 g., 34%). Anal. Calcd for C18H34O6Si2 : C, 53.7; H, 8.51. Found: C, 54.1; H, 8.59. IR (Neat, Csl, cm-1): 3060 W, 2970 s, 2920 s, 2880 s, 2730 w, 1577 m, 1478 w, 1439 m, 1390 s, 1365 m, 1290 m, 1160 s, 1090 vs, 958 s, B05 s, 770 s, 715 m, 705 m, 670 m, 485 s. 1H NMR (benzene-d6, 22° C., 300 MHz ): δ 1.15 (t, J=7.1 Hz, 18 H, OCH2CH3), 3.91 (q, J=7.1 Hz, 12 H, OCH2CH3), 7.30 (t, J=7.2 Hz, 1 H, C6H4), 7.89 (d, J=7.2 Hz, 2 H, C6H4), 8.37 (s, 1 H, C6H4). 13C{1H}NMR (benzene-d6, 22° C., 75.5 MHz): δ 18.43 (PHC2CH3), 58.89 (OCH2CH3), 127.59, 131.52, 137.06, 141.70 (C6H4)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([OH:20])C#C.N1C=C[CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:15][CH2:22][C:23]#[CH:24])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccncc1
Reactant: O=C(Cl)CCCCCCCc1ccccc1
Reactant: C#CCO
Solvent: Cc1ccccc1
Product: C#CCOC(=O)CCCCCCCc1ccccc1
Temperature: 0 °C
Yield: 90 %

Procedure:
542 Milligrams of 8-phenyloctanoyl chloride was added by drops to a mixture of 140 mg of propargyl alcohol, 198 mg of pyridine and 20 ml of dry toluene with stirring and ice-cooling. After dropwise addition, the resultant solution was stirred for additional 12 hours at room temperature. The thus stirred solution was then poured into ice water. The toluene layer was separated from the resulting mixture. The aqueous layer was extracted once with toluene. These toluene layers were combined, washed with water and then with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off from the dried layer under reduced pressure. The resulting residue was subjected to chromatography on silica gel to obtain 530 mg of propargyl 8-phenyloctanoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7](F)[C:6]=1[Cl:14].[C:16](=O)([O-])[O-:17].[K+].[K+]>CO>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]([O:17][CH3:16])[C:6]=1[Cl:14]
Reactant: COC(=O)Cc1ccc(C#N)c(F)c1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)Cc1ccc(C#N)c(OC)c1Cl
Temperature: 130 °C

Procedure:
A solution of methyl(2-chloro-4-cyano-3-fluorophenyl)acetate (1.40 g, 6.15 mmol) in methanol (30 mL) was divided into two 20 mL microwave (MW) vials. Potassium carbonate (2×850 mg) was added to each MW vial. Each was heated in a microwave at 130° C. for 60 minutes at which time HPLC/MS indicated no starting material was left and the product was all hydrolyzed to the acid. Most of the methanol was removed in vacuo and the residue was diluted with water, acidified with 2M HCl and the mixture was extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was taken up in 1:1 methanol:dichloromethane (50 mL) and 2M trimethylsilyldiazomethane in ether was added until the yellow color persisted to re-esterify the acid. The excess diazomethane was quenched with acetic acid and the mixture was concentrated. The residue was purified by flash chromatography (40% DCM/hexanes to 100% DCM) to give the title product. 1H-NMR (400 MHz, CDCl3) δ ppm 3.73 (s, 3H), 3.83 (s, 2H), 4.07 (s, 3H), 7.139 (d, J=8.1 Hz, 1H), 7.468 (d, J=8.0, 1H).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:37]2)=[CH:30][CH:31]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 53.2 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (80 mg, 0.26 mmol) was reacted with tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (170 mg, 0.44 mmol) to afford the desired product (68 mg, 32%) as a yellow solid: ESI MS m/z 492 [C27H29N3O4S+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.[C:10]1([CH3:23])[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[S:18]([O:21][NH2:22])(=[O:20])=[O:19]>C(Cl)Cl>[NH2:22][N:4]1[C:5]([CH3:8])=[CH:6][N:7]=[C:2]([CH3:1])[C:3]1=[NH2+:9].[CH3:17][C:12]1[CH:13]=[C:14]([CH3:16])[CH:15]=[C:10]([CH3:23])[C:11]=1[S:18]([O-:21])(=[O:20])=[O:19]
Reactant: Cc1cnc(C)c(N)n1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Cc1ncc(C)n(N)c1=[NH2+]
Temperature: 0 °C
Yield: 59.1 %

Procedure:
A mixture of 3,6-dimethylpyrazin-2-amine (1.23 g, 10 mmol) in DCM (20 mL) was cooled to 0° C. and a solution of O-(mesitylsulfonyl)hydroxylamine (4.3 g, 20 mmol) was added slowly. The reaction mixture was allowed to warm to room temperature for 3 h and filtered. The solid collected was washed with DCM (50 mL) to give 1-amino-3,6-dimethylpyrazin-2(1H)-iminium-2,4,6-trimethylbenzenesulfonate as a brown solid (2.0 g, yield 59%). ESI MS: m/z 139 [M−199]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][C:42]([CH2:46][N:47]2[CH:51]=[CH:50][C:49]([NH2:52])=[N:48]2)([OH:45])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:32]([O:36][C:37]([N:39]1[CH2:40][CH2:41][C:42]([CH2:46][N:47]2[CH:51]=[CH:50][C:49]([NH:52][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]3)=[O:30])=[N:48]2)([OH:45])[CH2:43][CH2:44]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cn2ccc(N)n2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)n2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (500 mg, 1.0 mmol), 4-(3-amino-pyrazol-1-ylmethyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (592 mg, 2.0 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 593 mg, 1.5 mmol) and iPr2NEt (0.718 mL, 4 mmol) in CH2Cl2 (50 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified flash column chromatography (1-100% ethyl acetate/heptane) to afford rac-4-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazol-1-ylmethyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester as a white powder (480 mg, 64.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:14]([O:16][CH3:17])=[O:15])[C:7]2=[O:12].[Cl:27][C:28]1[CH:29]=[C:30]([CH:35]([CH3:39])[C:36](O)=[O:37])[CH:31]=[CH:32][C:33]=1[Cl:34].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[Si:20]([O:19][CH2:18][C@@H:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:36](=[O:37])[CH:35]([C:30]2[CH:31]=[CH:32][C:33]([Cl:34])=[C:28]([Cl:27])[CH:29]=2)[CH3:39])[C:7]1=[O:12])[C:14]([O:16][CH3:17])=[O:15])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(NC(=O)C(C)c3ccc(Cl)c(Cl)c3)cccc2c1=O
Temperature: 25 °C

Procedure:
A round bottom flask was charged with (R)-methyl 2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-3-(tert-butyldimethylsilyloxy)propanoate (300 mg, 0.0008 mol), 2-(3,4-dichlorophenyl)propanoic acid (200 mg, 0.00092 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (600 mg, 0.002 mol), N,N-diisopropylethylamine (0.3 mL, 0.002 mol) and N,N-dimethylformamide (2 mL, 0.03 mol) and the reaction stirred at room temperature over night. The reaction did not go to completion. The solvent was removed and the residue was purified flash chromatography to obtain the product as a solid. MS m/z=578.3 (M+H).
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][Cl:7].[C:9]([NH2:12])(=[S:11])[CH3:10]>CO.C(OCC)C>[BrH:1].[Cl:7][CH2:6][CH2:5][CH2:4][C:3]1[N:12]=[C:9]([CH3:10])[S:11][CH:2]=1
Reactant: O=C(CBr)CCCCl
Reactant: CC(N)=S
Solvent: CCOCC
Solvent: CO
Product: Br
Product: Cc1nc(CCCCl)cs1
Reaction time: 240 h
Yield: 85.5 %

Procedure:
A solution of 1-bromo-5-chloro-2-pentanone (6.7 g) and thioacetamide (2.5 g) in methanol (10 ml) was stirred at 50° C. for 5 hours. After concentration of the reaction mixture, the residue was allowed to stand for 10 days. The crystalline residue was suspended in a mixture of methanol and diethyl ether and the remained solid was collected by filtration to give brown powder (7.3 g) of 4-(3-chloropropyl)-2-methylthiazole monohydrobromide.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:32])[O:29][CH2:30][CH3:31])[CH2:23][CH2:22]2)[C:10]=1[CH3:33])C1C=CC=CC=1>C(O)C.C1COCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:33][C:10]1[C:9](=[O:8])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[CH2:19][O:20][C@H:21]1[CH2:22][CH2:23][C@H:24]([NH:27][C:28](=[O:32])[O:29][CH2:30][CH3:31])[CH2:25][CH2:26]1
Reactant: CCOC(=O)N[C@H]1CC[C@H](OCc2nc3ccccc3c(OCc3ccccc3)c2C)CC1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)N[C@H]1CC[C@H](OCc2[nH]c3ccccc3c(=O)c2C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl (trans-4-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}cyclohexyl)carbamate (153 mg) in ethanol-THF (1:1, 6 mL) was added 5% Pd—BaSO4 (70 mg) under nitrogen atmosphere, followed by stirring at room temperature under hydrogen atmosphere for 1 hour. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5). The resulting solid was washed with ethyl acetate and dried to obtain ethyl {trans-4-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl]methoxy]cyclohexyl}carbamate (88 mg) as a crystal.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:23](O[Na])(C)=[O:24].O>CN(C=O)C>[CH2:6]([O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=[O:24])=[CH:15][CH:14]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CC(=O)O[Na]
Reactant: CCCCCCOc1cccc2ccccc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(C=O)c2ccccc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
POCl3 (3.22 g, 21 mmol) was dropwise added to a solution of compound 2 (4 g, 17.5 mmol) in anh. DMF (5 ml) at room temperature and under N2. The resulting dark red solution was heated to 100° C. for 3 hours. Concentrated AcONa solution (5 ml) was then added and heating was continued for 2 hours more. After being cooled to room temperature, water (100 ml) was added. The mixture was extracted with Et2O (2×150 ml), the ethereal combined fractions were washed with 10% HCl solution (100 ml), water (100 ml), dried over MgSO4, filtered and evaporated to dryness. Recrystallisation of the brown solid from EtOH afford 2.1 g (47%) of compound 3 as brownish crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].[C:17]([O:20][CH2:21][CH2:22]Br)(=[O:19])[CH3:18]>CC(C)=O.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:22][CH2:21][O:20][C:17](=[O:19])[CH3:18])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(=O)OCCOc1ccc(C=O)cc1Cl
Yield: 41.5 %

Procedure:
A mixture of 3-chloro-4-hydroxybenzaldehyde (10 g, 63.9 mmol), K2CO3 (26.5 g, 191.6 mmol) and 2-bromoethyl acetate (26.7 g, 159.7 mmol) in acetone (250 mL) is refluxed for 18 h before it is diluted with diethyl ether (200 mL) and washed with water (3×200 mL). The washings are extracted with diethyl ether (200 mL). The combined organic extracts are dried over MgSO4 and concentrated. The remaining residue is purified by column chromatography on silica gel eluting with heptane/EA 1:1 to afford the title compound (6.44 g) as colourless solid. 1H NMR (CDCl3): δ 9.85 (s, 1H9, 7.91 (d, J=1.8 Hz, 1H), 7.75 (dd, J=1.8, 8.2 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 4.53-4.49 (m, 2H), 4.35-4.31 (m, 2H), 2.12 (s, 3H).
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[K+]>C1(C)C(C)=CC=CC=1.CO>[C:7]1([CH:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCCCC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CO
Product: CCCCC(O)c1ccccc1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
Tris(triphenylphosphine)ruthenium (II) chloride (1.9 mg, 2 μmol, 0.5 mol %) and a chiral ligand (M=Ru, R=i-Pr, Ar=C6H5—, 1.3 μmol, 0.33 mol %) were dissolved in xylene (3 mL) under nitrogen atmosphere, and then heated and stirred for 1 h at 140° C. After the mixture was cooled to room temperature, pentanophenone (0.4 mmol), xylene (2 mL) and a solution of potassium hydroxide in methanol (0.4 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 12 h under H2 (10 atm) at 25° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent:ethyl acetate/petroleum ether=1/8). Accordingly, pure 1-phenylpentanol was obtained and the ee value (ee=99.6%) was measured by GC analysis.
Reaction SMILES: [Mg].I[CH2:3][CH3:4].[CH3:5][C:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=O)[CH2:8][CH:7]=1.[CH2:15](OCC)[CH3:16]>>[CH2:15]([C:12]([CH2:3][CH3:4])([CH:9]1[CH2:10][CH2:11][C:6]([CH3:5])=[CH:7][CH2:8]1)[OH:14])[CH3:16]
Reactant: CCI
Reactant: CCOCC
Reactant: CC1=CCC(C(=O)O)CC1
Agent: [Mg]
Product: CCC(O)(CC)C1CC=C(C)CC1

Procedure:
To 9.4 g of magnesium stirred in 350 ml of diethyl ether was added 60.4 g of iodoethane over 30 minutes to produce a mildly refluxing reaction mixture. The reaction mixture was refluxed for an additional hour, and then 23 g of the methyl ester of 4-methyl-3-cyclohexene-1-carboxylic acid in 20 ml of diethyl ether was added dropwise while maintaining gentle reflux. The reaction mixture was refluxed for an additional 1/2 hour, quenched with water, and extracted with diethyl ether; the ether extract was washed with saturated NaCl solution, dried (MgSO4), and stripped to yield an oil, which upon distillation gave 23.2 g of product, b.p. 90° C. (1 mm).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C@@H:10]2[CH2:12][C@@H:11]2[CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[N:6][CH:7]=1.[Li+].[CH3:27]CC[CH2-].[CH3:31][S:32]SC>C1COCC1>[CH3:31][S:32][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][CH2:10][C@@H:12]2[CH2:27][C@@H:11]2[CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]2)=[N:6][CH:7]=1
Reactant: [CH2-]CCC
Reactant: CSSC
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2OCc2ccc(Br)cn2)CC1
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ccc(COC[C@@H]2C[C@@H]2C2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of the aryl bromide from step B (680 mg, 1.60 mmol) dissolved in THF (10.7 mL) cooled at −78° C. was added N-butyllithium in hexanes (1.5 M, 1.12 mL, 1.68 mmol). After 10 min, dimethyldisulfide (0.16 mL, 1.76 mmol) was added. At 45 min, the reaction was quenched at −78° C. with saturated aqueous NH4Cl (2 mL). The mixture was warmed to room temperature, diluted with EtOAc and washed with H2O (1×) and saturated aqueous NaCl (1×). The aqueous was back-extracted with EtOAc (3×), and the combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to yield a crude oil that was purified by silica gel column chromatography (10-70%, EtOAc-hexanes) to yield the title compound. 1H NMR (500 MHz, CDCl3) δ 8.47 (d, J 2.0 Hz, 1H), 7.62 (dd, J 8.0 & 2.0 Hz, 1H), 7.39 (d, J 8.0 Hz, 1H), 4.68 (d, J 13.5 Hz, 1H), 4.59 (d, J 13.5 Hz, 1H), 4.18-3.98 (br m, 2H), 3.66-3.60 (m, 1H), 3.57-3.51 (m, 1H), 2.75-2.58 (m, 2H), 2.53 (s, 3H), 1.88-1.82 (m, 1H), 1.77-1.69 (m, 1H), 1.47 (s, 9H), 1.37-1.21 (m, 3H), 0.98-0.90 (m, 1H), 0.79-0.68 (m, 2H), 0.07-0.03 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[CH:10]([O:18][N:19]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CCO.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:30])[CH:10]([O:18][NH2:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C(Cc1ccccc1)ON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: NOC(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a solution of the compound from Step 6b (10.00 g, 24.94 mmol) in EtOH (150 mL) was added hydrazine monohydrate (2.50 mL, 49.88 mmol) at room temperature. The resulting mixture was stirred for 1 hour at room temperature, diluted with EtOAc (450 mL), washed with saturated NaHCO3, water (300 mL×2) and brine, dried (Na2SO4), filtered and concentrated to afford 6.73 g of crude product, which was purified by flash chromatography (silica gel, CH2Cl2/Hexane=15/1) to provide 5.37 g (80%) of the title compound. 13C NMR (CDCl3): δ171.9, 136.6, 135.4, 129.3, 129.2, 129.1, 128.4, 128.3, 128.2, 128.1, 128.0, 126.6, 83.8, 66.4, 37.3. Step 6d. Preparation of: N-Boc-2-Aminooxy-3-phenyl-propionic acid benzyl ester
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[N:12]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[CH:11]3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[C:5]2=[CH:4][CH:3]=1.COC([Si](C)(C)C)C.FC(F)(F)C(O)=O.CCN(C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[N:12]([CH2:25][C:26]([OH:28])=[O:27])[CH:11]3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1CC(=O)N(CC(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: COC(C)[Si](C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)cc1C1CC(=O)N(CC(=O)O)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.1 %

Procedure:
To a solution of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.85 g, 1.19 mmol) prepared in example 146d in dichloromethane (10 mL) was added trifluoroacetic acid (20 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated. The residue was redissolved in methanol (10 mL). To the resulting solution was added N,N′-diisopropylethylamine (1.57 mL, 8.70 mmol) and the crude was refluxed for 1 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and HCl aqueous solution (1N). The organic layer was separated, dried over MgSO4 and concentrated. The residue was triturated with ethyl acetate and hexane to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-1′-hydroxycarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 440 mg, 70%).