Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.C(Cl)(Cl)Cl>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CN1CCN(c2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(4-methylpiperazin-1-yl)benzamido)-4-phenylbenzoate (0.26 g) in methanol (2.6 mL) and ethyl acetate (1.3 mL), 10% palladium-carbon (0.26 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. Chloroform was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0.13 g of tert-butyl 2-(2-hydroxy-5-(4-methylpiperazin-1-yl)benzamido)-4-phenylbenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]#[N:17])=[C:7]([C:12]([F:15])([F:14])[F:13])[N:8]2[CH3:11])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Na].[CH2:23]([OH:25])[CH3:24]>C(Cl)(Cl)(Cl)Cl.C(OCC)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]#[N:17])=[C:7]([C:12]([F:13])([F:14])[F:15])[N:8]2[CH2:11][O:25][CH2:23][CH3:24])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Cn1c(C(F)(F)F)c(C#N)c2ccc(Cl)cc21
Agent: [Na]
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOCn1c(C(F)(F)F)c(C#N)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A mixture of 6-chloro-3-cyano-1-methyl-2-(trifluoromethyl)indole (1.08 g, 4.2 mmole) and thionyl chloride (0.68 mL, 8.4 mmole) in carbon tetrachloride is heated at reflux temperature for 18 hours, cooled to room temperature and concentrated in vacuo for 18 hours to remove all volatiles. The residue is dissolved in ethanol and treated with a solution of sodium metal (0.38 g, 16 mmole) in ethanol, stirred or 0.5 hour at room temperature and diluted with diethyl ether. The diluted reaction mixture is washed with water, dried over Na2SO4 and concentrated in vacuo to give a residue. The residue is chromatographed (silica gel/4:1 hexanes: ethyl acetate) to afford the title product as an off-white solid, 0.66 g (52% yield) mp 83°-86° C., identified by IR, 1HNMR, 13CNMR, 19FNMR and mass spectral analyses.
Reaction SMILES: [CH:1]([C:3]1[C:18]([O:19]C)=[C:17]([O:21][CH2:22][CH2:23][CH3:24])[CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])=[O:2].Cl>O1CCCC1>[CH:1]([C:3]1[C:18]([OH:19])=[C:17]([O:21][CH2:22][CH2:23][CH3:24])[CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2]
Reactant: CCCOc1ccc(OCCCCC(=O)OCC)c(C=O)c1OC
Agent: Cl
Solvent: C1CCOC1
Product: CCCOc1ccc(OCCCCC(=O)O)c(C=O)c1O
Reaction time: 5.5 h

Procedure:
2.5 ml of a solution of iodine (6.64 g, 0.026 M) in anhydrous ether (80 ml) was added to a stirred mixture of magnesium metal (2.53 g, 0.105 g. atom) and ether (12.5 ml). When the reaction had commenced the remainder of the iodine solution was added dropwise at such a rate as to cause gentle refluxing. After the addition was complete the reaction mixture was heated to reflux until a colourless solution was obtained (15 mins). The cooled reaction mixture was filtered and the unreacted magnesium metal was washed with ether. The colourless solution of magnesium iodide thus obtained was added dropwise to a stirred solution of ethyl 5-(2-formyl-3-methoxy-4-n-propoxyphenoxy)pentanoate (5.95 g, 0.0176 M) in anhydrous tetrahydrofuran (50 ml). The mixture was brought to reflux with stirring for 5.5 hr. The cooled reaction mixture was poured into 2 N hydrochloric acid (75 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water, dried (sodium sulphate) and evaporated. The residue was dissolved in 95% ethanol (50 ml). 2 N sodium hydroxide solution (50 ml) added and the mixture stirred at room temperature (4 hr). After evaporation of the ethanol the residue was diluted with water, washed with ether and acidified with concentrated hydrochloric acid. The oily product was extracted with ether, the combined extracts washed with water and extracted with 5% sodium bicarbonate solution. The combined extracts were acidified with concentrated hydrochloric acid to pH3 with ice cooling, and the gummy solid produced was filtered off and washed with water. This was chromatographed on kieselgel G (200 g) eluting with chloroform-methanol (9:1), the combined fractions evaporated and the residue recrystallised from benzene-petrol to give 5-(2-formyl-3-hydroxy-4-n-propoxyphenoxy)pentanoic acid, m.p. 78°-79° C. (Found: C, 60.65; H, 6.96, C15H20O6 requires C, 60.80; H, 6.80%).
Reaction SMILES: [CH:1]([Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[NH:14][C:13](=[O:16])[CH:12]=[N:11]2)([CH3:3])[CH3:2].[CH2:23](N(CC)CC)C.C[Si](C=[N+]=[N-])(C)C.CCCCCC>ClCCl.CO.C(#N)C>[CH3:23][O:16][C:13]1[CH:12]=[N:11][C:10]2[C:15](=[C:6]([O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:17]([CH3:19])[CH3:18])[CH:20]([CH3:22])[CH3:21])[CH:7]=[CH:8][CH:9]=2)[N:14]=1
Reactant: CCN(CC)CC
Reactant: CC(C)[Si](Oc1cccc2ncc(=O)[nH]c12)(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CCCCCC
Solvent: CO
Product: COc1cnc2cccc(O[Si](C(C)C)(C(C)C)C(C)C)c2n1
Reaction time: 8 h

Procedure:
A solution of (c) (2.0 g, 6.2 mmol) in dichloromethane/methanol/acetonitrile (40 ml/4 ml/40 ml) was treated with triethylamine (1.1 ml, 8 mmol) then a solution of (trimethylsilyl)diazomethane in hexane (2M; 4 ml, 8 mmol). The mixture was stirred overnight then evaporated. The residue was chromatographed on silica eluting with dichloromethane affording an oil (1.0 g, 48%).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH:30]([CH3:32])[CH3:31])[C:12](=[O:29])[C:13]3[C:18]([C:19]=2/[CH:20]=[CH:21]/[CH:22]([OH:28])[CH2:23][C:24]([O:26]C)=[O:25])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:6]([O:33][CH3:34])[CH:5]=1>CO>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH:30]([CH3:31])[CH3:32])[C:12](=[O:29])[C:13]3[C:18]([C:19]=2/[CH:20]=[CH:21]/[CH:22]([OH:28])[CH2:23][C:24]([OH:26])=[O:25])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:6]([O:33][CH3:34])[CH:5]=1
Reactant: COC(=O)CC(O)/C=C/c1c(-c2ccc(F)cc2OC)n(C(C)C)c(=O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(F)ccc1-c1c(/C=C/C(O)CC(=O)O)c2ccccc2c(=O)n1C(C)C
Yield: 84.7 %

Procedure:
1N-Sodium hydroxide (3 ml) was added to a solution of the compound (500 mg) obtained by Step 6 in methanol (25 ml) at room temperature under stirring. The mixture was stirred at room temperature for 1.5 hours and then the solvent was distilled off. The residue to which water was added was washed with ethyl acetate. The aqueous layer was acidified with aqueous potassium hydrogen sulfate solution and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and distilled to give the title compound (410 mg) as colorless crystals. mp 207°-209° C. (from methanol-diethyl ether).
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:12]([F:13])=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=2[F:15])[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[C:21](=[O:28])([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])N>C1COCC1.O>[CH2:24]([O:23][C:21](=[O:28])[NH:14][C:10]1[CH:9]=[C:8]([F:15])[C:7]([C:4]2[CH2:5][CH2:6][S:1][CH2:2][CH:3]=2)=[C:12]([F:13])[CH:11]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)COC(N)=O
Reactant: Nc1cc(F)c(C2=CCSCC2)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)COC(=O)Nc1cc(F)c(C2=CCSCC2)c(F)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a stirred, biphasic mixture of 4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorobenzenamine (Step 4, 3.90 g, 17.2 mmol) in THF/water (2:1, 103 mL) is added sodium bicarbonate (2.88 g, 34.3 mmol) followed by isobutyl carbamate (2.45 mL, 18.9 mmol) dropwise. The reaction mixture is stirred at ambient temperature for 7 h and is then concentrated under reduced pressure, diluted with EtOAc (100 mL) and H2O (50 mL), and the layers are separated. The organic phase is washed with H2O (25 mL) and saline (25 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by chromatography on a Biotage Flash 40M 90 g silica gel cartridge, eluting with 5–10% EtOAc/Hexanes, affords the title compound, mp 136–137° C.; MS (ESI−) for C16H19F2NO2S m/z 326 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:24])[C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][CH2:18]OS(C)(=O)=O)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH3:25][NH:26][CH3:27]>CO>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][CH2:18][N:26]([CH3:27])[CH3:25])[CH2:11][CH2:10]2)[CH3:24])=[N:6][CH:7]=1
Reactant: CNC
Reactant: CN(c1ncc(Br)cn1)[C@H]1CC[C@H](C#CCCOS(C)(=O)=O)CC1
Solvent: CO
Product: CN(C)CCC#C[C@H]1CC[C@H](N(C)c2ncc(Br)cn2)CC1
Temperature: 65 °C

Procedure:
A solution of 211 mg (0.51 mmol) of crude trans-Methanesulfonic acid 4-{4-[(5-bromo-pyrimidin-2-yl)-methyl-amino]-cyclohexyl}-but-3-ynyl ester in 5 ml of methanol was treated with 0.91 ml (5.1 mmol) Dimethylamine (33% in EtOH, 5.6M) and heated at 65° C. for 4 h. After cooling and evaporation, the residue was extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried (Na2SO4), filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 99:1 to 95:5) gave 141 mg (76%) of trans-(5-Bromo-pyrimidin-2-yl)-[4-(4-dimethylamino-but-1-ynyl)-cyclohexyl]-methyl-amine, MS: 365 (MH+, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:13].[Br:15]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][Br:15]
Reactant: NC(=O)CCC(=O)NBr
Reactant: COC(=O)c1c(C)cccc1[N+](=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Yield: 70 %

Procedure:
Into a stirring solution of methyl-2-methyl-6-nitrobenzoate (3.9 g, 20 mmols) in 50 mL CCl4 anhydrous, N-bromosuccinamide (3.56 g, 20 mmols), and benzoylperoxide (25 mg, 0.10 mmols), was added. The reaction mixture was heated under reflux for about 24 hours. TLC developed in EtOAc/Hex 1:9 mixture showed formation of new product. The CCl4 was evaporated and on leaving a viscous product at RT, light yellow crystals of product were separated. The product was purified by flash silica gel column eluted with Hex/EtOAc. 9:1 mixture to give 3.0 g light yellow crystals (70%). A small portion of dibrominated product was also separated. 1H NMR in CDCl3 confirmed the product as methyl-2-bromomethyl-6-nitrobenzoate.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(N(CC)CC)C.[CH2:14]([O:16][CH2:17]Cl)[CH3:15]>ClCCl>[C:1]([O:6][CH2:17][O:16][CH2:14][CH3:15])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: CCOCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCOCC
Yield: 90.5 %

Procedure:
To a 500-mL, 3-necked round bottomed flask equipped with a thermocouple temperature monitor, 250-mL addition funnel, nitrogen inlet and a magnetic stirrer was added 150 mL of dichloromethane, and 18.9 g (0.22 mol) of methacrylic acid. The addition funnel was charged with a mixture of 22.3 g (0.23 mol) of triethylamine and 25 mL of dichloromethane which was then added in a thin stream to the flask with stirring in an ice-bath. Upon completion of the addition, the addition funnel was recharged with a mixture of 18.9 g (0.2 mol) of chloromethyl ethyl ether and 25 mL of dichloromethane which was subsequently added dropwise to the reaction mixture with cooling over about 15 minutes. The ice bath was removed and the mixture stirred at room temperature overnight. The resulting suspension was filtered and the filtrate washed several times with saturated bicarbonate, water and brine and dried over anhydrous magnesium sulfate. Filtration and removal of the solvent by evaporation on a rotary evaporator provided 26.1 g of a yellowish oil which was distilled at reduced pressure to provide 20.3 g (70%) of the title compound as a clear, colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:13])[CH:9]=2)[N:4]=1)#[N:2].[CH3:14][CH2:15][O:16][P:17](Cl)([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C>C(Cl)Cl>[P:17]([O:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([C:1]#[N:2])[CH:12]=[CH:11]2)([O:19][CH2:20][CH3:21])([O:16][CH2:15][CH3:14])=[O:18]
Reactant: CCOP(=O)(Cl)OCC
Reactant: N#Cc1ccc2cc(O)ccc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)Oc1ccc2nc(C#N)ccc2c1
Yield: 91 %

Procedure:
To the mixture of 2-cyano-6-hydroxyquinoline (0.50 g, 2.94 mmol) and diethyl phosphorochloride (0.67 g, 3.53 mmol) in 15 ml of anhydrous methylene chloride was added triethylamine (0.59 g, 5.88 mmol). The resultant mixture was stirred for 5 hours at room temperature. After removal of the solvent, the product was purified by flash chromatography using heptane/ethyl acetate as eluent in a yield of 91%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12]([NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Reactant: CC(C)(N)CO
Product: Cc1cc(F)ccc1-c1nc(NC(C)(C)CO)nc2c1ccc(=O)n2-c1ccccc1C
Yield: 11.1 %

Procedure:
Following the general procedure outlined in Example 126, the product of Example 121 (222 mg, 0.52 mmol) and 2-amino-2-methyl-1-propanol (0.25 mL, 2.62 mmol) were reacted to give the crude material. Purification by Flash chromatography eluting with dichloromethane/ethanol/triethylamine (100/1/2, v/v/v), followed by preparative HPLC, eluting with acetonitrile/H2O (10/90, v/v to 90/10, v/v, over 10 min), gave the desired product 25 mg (11%). LC-MS: 433.4 (MH+, m/z), 2.10 (Rt, min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:5]2.[C:16]1([C:22]2[CH:23]=[C:24]([NH2:28])[CH:25]=[N:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[CH2:12]([N:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:28][C:24]3[CH:25]=[N:26][CH:27]=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:23]=3)[CH:3]=2)[C:7]1=[O:11])[CH2:13][CH2:14][CH3:15]
Reactant: Nc1cncc(-c2ccccc2)c1
Reactant: CCCCN1Cc2cc(Br)ccc2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCN1Cc2cc(Nc3cncc(-c4ccccc4)c3)ccc2C1=O
Temperature: 120 °C
Yield: 55.5 %

Procedure:
5-Bromo-2-butylisoindolin-1-one (71.6 mg, 0.267 mmol), 5-phenylpyridin-3-amine (50.0 mg, 0.294 mmol) and Cs2CO3 (217.0 mg, 0.668 mmol) were added to suspension of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos) (12.7 mg, 0.027 mmol) and palladium acetate (PdOAc2) (8.0 mg, 0.040 mmol) in toluene (2 mL). The mixture was stirred and heated in the microwave (120° C., 300 W, 60 min). Water and ethyl acetate were added. The organic layer was separated, the aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4. Purification by flash chromatography (dichloromethane/methanol, gradient 1-5% methanol) provided 2-butyl-5-(5-phenylpyridin-3-ylamino)isoindolin-1-one (53 mg, 54%). ESI-MS [M+H]+=358.1.
Reaction SMILES: COCCOC.[H-].[Na+].[O:9]=[C:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11]P(=O)(OC)OC.[CH:23](=O)[C:24]1[CH:33]=[CH:32][C:29]([O:30][CH3:31])=[C:26]([O:27][CH3:28])[CH:25]=1>O>[CH3:28][O:27][C:26]1[CH:25]=[C:24]([CH:23]=[CH:11][C:10](=[O:9])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:33]=[CH:32][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCCCCC(=O)C=Cc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under cooling with ice, to 70 ml of dry 1,2-dimethoxyethane containing 0.87 g of sodium hydride (50% mineral oil) was added dropwise 30 ml of dry 1,2-dimethoxyethane containing 4.0 g of dimethyl 2-oxoheptylphosphonate. Then, the mixture was stirred at room temperature for 1 hour and, after that, cooled at -30° C. Then, 3 ml of dry 1,2-dimethoxyethane containing 3.0 g of veratraldehyde was added dropwise. After dropping, the temperature was restored slowly to room temperature. Then, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried with magnesium sulfate. The solvent was removed by distillation to obtain crude product. After purification of the crude product by means of column chromatography (silica gel/hexane:ethyl acetate=3:1), 1.3 g of the above caption compound was obtained.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)([OH:16])[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[CH:29]1([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([CH2:40]Cl)=[CH:36][CH:35]=2)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH:29]1([CH2:32][O:33][C:34]2[CH:35]=[CH:36][C:37]([CH2:40][N:13]3[CH2:12][CH2:11][CH:10]([C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:27])[F:28])=[CH:8][CH:7]=4)([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=4)[OH:16])[CH2:15][CH2:14]3)=[CH:38][CH:39]=2)[CH2:30][CH2:31]1
Reactant: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCNCC1
Reactant: ClCc1ccc(OCC2CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCN(Cc2ccc(OCC3CC3)cc2)CC1
Yield: 76.5 %

Procedure:
A solution of 20.5 grams (0.051 mole) of 4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine, 10.0 grams (0.051 mole) of 4-(cyclopropylmeth-oxy)phenylmethyl chloride (prepared as in Step A of Example 1), and 35.4 mL (0.203 mole) of N,N'-diisopropylethylamine in 200 mL of dimethyl sulfoxide was stirred at ambient temperature for about 18 hours. The reaction mixture was then poured into an aqueous solution saturated with sodium bicarbonate. The mixture was extracted with two portions of ethyl acetate, and the extracts combined. The combination was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel with 50% heptane in methylene chloride to 50% acetone in methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 22.0 grams of N-[4-(cyclopropylmethoxy)phenylmethyl]-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([CH3:32])[CH:25]=1)[C:9](N1[C@H](CC2C=CC=CC=2)COC1=O)=[O:10])([CH3:4])([CH3:3])[CH3:2].[OH:34]O.O.[OH-].[Li+]>O>[C:1]([O:5][C:6]([NH:7][C@H:8]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([CH3:32])[CH:25]=1)[C:9]([OH:10])=[O:34])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1C
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1C
Temperature: -10 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
To a solution of [(R)-2-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-1-(4-methoxy-3-methyl-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (6.05 g, 13.3 mmol) in 4:1 tetrahdydrofuran/water (200 mL) at −10° C. was added sequentially 30% aqueous hydrogen peroxide (15 mL, 133 mmol) and a solution of lithium hydroxide monohydrate (1.63 g, 40 mmol) in water (20 mL). The reaction mixture was stirred at −10° C., and the progress of the reaction was monitored by thin layer chromatography. After 4 hours, thin layer chromatography indicated almost complete consumption of starting material. Saturated aqueous sodium sulfite solution (100 mL) was added. The mixture was concentrated to half of its original volume under reduced pressure to remove tetrahydrofuran, then extracted with dichloromethane (2×100 mL). The aqueous layer was separated and acidified to pH=4 with aqueous citric acid solution, extracted with ethyl acetate (2×250 mL). The organic layers were separated, combined, dried over sodium sulfate, concentrated under reduced pressure and dried in vacuo to give (R)-tert-butoxycarbonylamino-(4-methoxy-3-methyl-phenyl)-acetic acid as a white foam (2.2 g, 58%).
Reaction SMILES: C1N2CN3CN(C2)CN1C3.N12CCCN=C1CCCCC2.[C:22]([O:26][C:27](=[O:49])[CH2:28][C@H:29]([C:39]1[O:40][CH2:41][C@@H:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:43]=1)[CH2:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)([CH3:25])([CH3:24])[CH3:23]>ClCCl.[Cu](Br)Br>[C:22]([O:26][C:27](=[O:49])[CH2:28][C@H:29]([C:39]1[O:40][CH:41]=[C:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:43]=1)[CH2:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)[C@@H]1COC([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)=N1
Agent: Br[Cu]Br
Agent: C1N2CN3CN1CN(C2)C3
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reaction time: 0.08 h
Yield: 64.3 %

Procedure:
A suspension of copper (II) bromide (2.08 g, 9.31 mmol) and hexamethylenetetramine (1.30 g, 9.31 mmol) In degassed dichloromethane (25 ml) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.39 ml, 9.31 mmol) and then cooled in a cold water bath and stirred for 5 minutes. This suspension was then treated dropwise with a solution of ethyl (4S)-2-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-4,5-dihydro-1,3-oxazole-4-carboxylate (Preparation 31) (0.92 g, 2.33 mmol) in dichloromethane (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and a solution of 0.88 ammonia: saturated aqueous solution of ammonium chloride (1:1, 100 mls). The layers were separated and the aqueous layer was extracted with ethyl acetate (x2). The organic layers were combined, washed sequentially with hydrochloric acid (2M), saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate: pentane (10:90) to afford the title compound as a pale yellow oil (0.59 g).