Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:25]C(=O)OC(C)(C)C)([CH3:24])[C:3](=[O:23])[NH:4][C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[C:17]3[C:18]4([CH2:21][O:22][C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH2:20][CH2:19]4)=[CH:9][CH:10]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:24][C:2]([C:3]([NH:4][C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[C:17]3[C:18]4([CH2:21][O:22][C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH2:20][CH2:19]4)=[CH:9][CH:10]=1)=[O:23])([CH3:1])[NH2:25]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a solution of 1,1-dimethylethyl (1,1-dimethyl-2-oxo-2-{[6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinyl]amino}ethyl)carbamate (Reference Intermediate 219, 50 mg) in dry dichloromethane (4 mL) at 0° C. TFA (1 ml, 12.98 mmol) was slowly added and the reaction mixture was stirred for 2 hours at the same temperature. The reaction was diluted with dichloromethane (10 ml) and an aqueous saturated solution of NaHCO3 was added while the pH was allowed to reach ˜8. Two phases were separated and the organic layer was dried over sodium sulphate, filtered and evaporated affording the title compound (35 mg) as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][CH:24]1[C:42](=[O:43])[N:26]2[C:27]([C:39]([OH:41])=[O:40])=[C:28]([CH2:31][S:32][C:33]3[N:37]([CH3:38])[N:36]=[N:35][N:34]=3)[CH2:29][S:30][C@H:25]12>>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=1)[C:12]([NH:23][CH:24]1[C:42](=[O:43])[N:26]2[C:27]([C:39]([OH:41])=[O:40])=[C:28]([CH2:31][S:32][C:33]3[N:37]([CH3:38])[N:36]=[N:35][N:34]=3)[CH2:29][S:30][C@H:25]12)=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1ccc(O)c(Cl)c1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3ccc(O)c(Cl)c3)[C@H]2SC1
Yield: 77.3 %

Procedure:
2-t-Butoxycarbonylmethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (1 g.) and 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1 g.) were reacted according to similar manners to those of Examples 1 and 2 to give powder of 7-[2-t-butoxycarbonylmethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.5 g.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:20]([Cl:21])=[C:19]([O:22][CH2:23][C:24]([OH:26])=[O:25])[CH:18]=[C:17]2[C:9]=1[C:10]1[C:15]([CH2:27][CH3:28])([CH2:16]2)[CH2:14][CH2:13][C:12](=[O:29])[CH:11]=1.Cl[CH2:31][C:32](=[O:34])[CH3:33].O>CN(C)C=O.CCOCC>[Cl:7][C:8]1[C:20]([Cl:21])=[C:19]([O:22][CH2:23][C:24]([O:26][CH2:31][C:32](=[O:34])[CH3:33])=[O:25])[CH:18]=[C:17]2[C:9]=1[C:10]1[C:15]([CH2:27][CH3:28])([CH2:16]2)[CH2:14][CH2:13][C:12](=[O:29])[CH:11]=1
Reactant: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OCC(C)=O)c(Cl)c1Cl)C2

Procedure:
Potassium carbonate (0.2 g) is suspended in a solution of [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid (Example 20, Step D) (0.4 g, 0.0011 mole) in dimethylformamide (3 ml). After warming the suspension on a steam bath for 15 minutes, chloroacetone (0.5 g, 0.005 mole) is added and the mixture heated for an additional 15 minutes. The reaction mixture is cooled, poured into water (50 ml) and the product extracted into ether (three 15 ml portions. The extract is dried over Na2SO4. After filtration, the extract is concentrated to give a yellow oil. Trituration with cold ether causes crystallization to occur. The crystalline product weighs 0.1 g and melts at 153°-155° C.
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH:5]3[CH2:10][CH:8]2[CH2:7][CH:6]3[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=[CH:2]1.C1C2C(C3CC2CC3NC(=O)[O:31]C(C)(C)C)CC=1>C1(C)C=CC=CC=1>[OH:31][CH:2]1[CH2:3][CH:4]2[CH:9]([CH:8]3[CH2:10][CH:5]2[CH:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:7]3)[CH2:1]1
Reactant: CC(C)(C)OC(=O)NC1CC2CC1C1CC=CC21
Reactant: CC(C)(C)OC(=O)NC1CC2CC1C1C=CCC21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1CC2CC1C1CC(O)CC21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4.87 g of a mixture of tert-butyl (3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl)carbamate and tert-butyl (3a,4,5,6,7,7a-hexahydro-3H-4,7-methanoinden-5-yl)carbamate were dissolved in 30 ml of toluene (anhydrous) and, at RT, 20 ml of a 2 M solution of borane/dimethyl sulfide complex in toluene were added using a syringe. The mixture was stirred at RT for 24 hours, a further 10 ml of a 2 M solution of borane/dimethyl sulfide complex in toluene were added using a syringe, and the mixture was stirred at RT for another 6 hours. The volatile components were then removed under reduced pressure, 200 ml of CH2Cl2 and 33 ml of a 3 N aqueous NaOH solution were added, and the mixture was slowly admixed with 7 ml of a 30% strength aqueous H2O2 solution. The mixture was stirred at RT for 10 minutes, and a further 100 ml of a 3 N aqueous NaOH solution and 20 ml of a 30% strength aqueous H2O2 solution were added. The reaction mixture was stirred at RT for another 10 minutes and then extracted three times with, in each case, 200 ml of CH2Cl2. The extracts were dried over MgSO4 and the solvent was removed under reduced pressure. Chromatography over silica gel using MTB gave 2.9 g of an amorphous solid which was still contaminated by regioisomers.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:2]1.[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH:15]=[CH2:16]>CC#N>[C:19]([O:18][C:14](=[O:17])[CH2:15][CH2:16][N:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:2]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Oc1ccc(C2CNCCO2)cc1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(O)cc2)C1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of 4-morpholin-2-yl-phenol (3.95 g; 22.0 mmol), and tert-butyl acrylate (9.60 mL; 66.1 mmol) in CH3CN (100 mL) was heated under reflux overnight. After cooling to RT, the mixture was concentrated and purified by column chromatography (SiO2, Et2O) to afford 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (5.22 g).
Reaction SMILES: [Mg].[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1.BrC(Br)C.[CH2:22]1[O:24][CH2:23]1.O1CCCC1>O1CCCC1.O>[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:22][CH2:23][OH:24])=[CH:13][CH:12]=1
Reactant: C1CO1
Reactant: Brc1ccc(CCOC2CCCCO2)cc1
Agent: CC(Br)Br
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1ccc(CCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
Magnesium (1.31 g, 53.90 mmol) was added to a solution of 4-(2-(tetrahydropyran-2-yloxy)ethyl)bromobenzene (14.00 g, 49.09 mmol) in tetrahydrofuran (20 ml). Then dibromoethane (0.1 ml) was added under an atmosphere of nitrogen gas, and the mixture was stirred under room temperature for 1 hour. After cooling to ice-cooling temperature, 2M-ethylene oxide/tetrahydrofuran solution (49.09 ml, 98.18 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Then, water (40 ml) was added to the reaction mixture. The mixture was extracted with ethyl ether and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired 4-(2-(tetrahydropyran-2-yloxy)ethyl)phenethyl alcohol (6.00 g, 42%).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:5]([OH:7])=O)[CH3:3].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:33][C@H:34]([C:38]([N:40]([CH3:56])[C@H:41]([C:45]([N:47]1[CH2:55][CH2:54][CH2:53][C@H:48]1[C:49]([O:51][CH3:52])=[O:50])=[O:46])[CH:42]([CH3:44])[CH3:43])=[O:39])[CH:35]([CH3:37])[CH3:36]>C(Cl)Cl.O>[NH:8]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:4]([C:5]([NH:33][C@H:34]([C:38]([N:40]([CH3:56])[C@H:41]([C:45]([N:47]1[CH2:55][CH2:54][CH2:53][C@H:48]1[C:49]([O:51][CH3:52])=[O:50])=[O:46])[CH:42]([CH3:44])[CH3:43])=[O:39])[CH:35]([CH3:36])[CH3:37])=[O:7])[CH:2]([CH3:1])[CH3:3]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(C)C
Temperature: 20 °C
Reaction time: 2 h

Procedure:
17.84 kg (70.88 mol) of Z-valine and 4.59 kg (74.42 mol) of triethylamine were dissolved in 170 l of methylene chloride in a 400 l vessel. To this solution were added at -5° to -10° C. 8.58 kg (70.88 mol) of pivaloyl chloride. After a reaction time of 2 h at -5° C., a solution of 24.2 kg of Val-MeVal-Pro-OMe in 86 l of methylene chloride was run in at -5° C. After a further 2 h at -5° C., the mixture was heated to 20° C. and stirred at this temperature for 12 h. 50 l of water were added for working up. After removal of the aqueous phase, the organic phase was extracted once with 40 l of 2N hydrochloric acid and twice with 40 l of 2N sodium hydroxide solution each time. The organic phase was washed until neutral and then the methylene chloride solvent was removed by distillation and replaced by 300 l of diisopropyl ether. The product was crystallized by heating the emulsion of the oily product to 60° C., adding seed crystals and keeping at 60° C. for 7 h. To complete the crystallization, the mixture was stirred further at 50° C. for 5 h and then at 40° C. for 5 h and subsequently cooled to 20° C. The suspension of crystals was discharged through a 120 l pressure filter.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[NH2:13][C:14]([NH2:16])=[S:15]>C(O)C>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=1[CH2:2][S:15][C:14](=[NH:13])[NH2:16])=[O:6].[ClH:1]
Reactant: NC(N)=S
Reactant: COC(=O)c1ccccc1CCl
Solvent: CCO
Product: COC(=O)c1ccccc1CSC(=N)N
Product: Cl
Yield: 40.7 %

Procedure:
A solution of 196 g of methyl 2-chloromethylbenzoate and 83.7 g of thiourea in 500 ml of ethanol is refluxed for 4 hours. The reaction solution is concentrated under reduced pressure and to the resulting residue is added 300 ml of isopropylalcohol. The precipitated crystals are collected by filtration and dried to give 112.8 g of the title compound.
Reaction SMILES: [CH:1]1[N:9]2[C:4]([C:5]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[CH:3][CH:2]=1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=1[S:29]([CH3:32])(=[O:31])=[O:30].C(N(CC)CC)C.C(Cl)CCl>ClCCl>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:16]2[CH2:17][CH2:18][C:5]3([C:4]4=[CH:3][CH:2]=[CH:1][N:9]4[C:8]4[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=4[O:6]3)[CH2:14][CH2:15]2)=[O:25])=[CH:22][C:21]=1[S:29]([CH3:32])(=[O:30])=[O:31]
Reactant: CS(=O)(=O)c1cc(C(=O)O)ccc1F
Reactant: c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CS(=O)(=O)c1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)ccc1F
Temperature: 25 °C
Reaction time: 96 h
Yield: 54.3 %

Procedure:
Spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (257 mg, 0.928 mmol), 4-fluoro-3-methylsulfonyl-benzoic acid (203 mg, 0.928 mmol), triethylamine (518 μL, 3.71 mmol), and EDC (196 mg, 1.02 mmol) were combined in dichloromethane (10 mL) and the reaction mixture was stirred at room temperature for 4 d. The reaction mixture was washed three times with a 1M solution of hydrochloric acid, followed by three washes with a saturated aqueous solution of sodium bicarbonate, followed by three washes of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to yield the crude product. The crude material was purified column chromatography utilizing a gradient of 0-75% ethyl acetate in hexanes to yield (4-fluoro-3-methylsulfonyl-phenyl)-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl-methanone (222 mg, 54%) as a colorless oil. ESI-MS m/z calc. 440.1, found 441.1 (M+1)+; Retention time: 1.51 minutes (3 min run).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[C:17]([C:19]4[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=4)[S:18][C:11]=23)[CH:6]=[CH:5][C:4]=1[NH2:25].S1C=CN=C1C1SC2C(=NC=CC=2OC2C=CC(N[C:48]([NH:50][C:51](=[O:59])[CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[S:49])=CC=2F)C=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[C:17]([C:19]4[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=4)[S:18][C:11]=23)[CH:6]=[CH:5][C:4]=1[NH:25][C:48]([NH:50][C:51](=[O:59])[CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)=[S:49]
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Reactant: COc1cc(Oc2ccnc3cc(-c4nccn4C)sc23)ccc1N
Product: COc1cc(Oc2ccnc3cc(-c4nccn4C)sc23)ccc1NC(=S)NC(=O)Cc1ccccc1
Yield: 48 %

Procedure:
Starting from compound 216 and following the procedure described above for the synthesis of compound 13a (scheme 2, step 5, example 12), title compound 217 was obtained in 48% yield. 1H NMR (400 MHz, DMSO-d6 δ pp 12.07 (1H, s), 11.59 (1H, s), 8.45 (1H, d, J=5.48 Hz), 7.91 (1H, d, J=8.80 Hz), 7.85 (1H, s), 7.41 (1H, s), 7.24-6.98 (8H, m), 6.66 (1H, d, J=5.67 Hz), 3.99 (3H, s), 3.78 (3H, s), 3.59 (2H, s). MS (m/z) 530.2 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:17]=[CH:16][C:6]2[NH:7][C:8]3[S:9][CH:10]=[CH:11][C:12]=3[C:13]([NH2:15])=[N:14][C:5]=2[CH:4]=1.[CH3:18][O:19][CH2:20][CH2:21][CH2:22][C@H:23]1[CH2:28]N[CH2:26][CH2:25][NH:24]1.CS(C)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:2][C:3]1[CH:17]=[CH:16][C:6]2[NH:7][C:8]3[S:9][CH:10]=[CH:11][C:12]=3[C:13]([N:15]3[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:22][CH2:21][CH2:20][O:19][CH3:18])[CH2:28]3)=[N:14][C:5]=2[CH:4]=1
Reactant: NC1=Nc2cc(Cl)ccc2Nc2sccc21
Reactant: COCCC[C@H]1CNCCN1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCCC[C@H]1CN(C2=Nc3cc(Cl)ccc3Nc3sccc32)CCN1
Temperature: 105 °C
Reaction time: 48 h
Yield: 26.1 %

Procedure:
Combine 7-chloro-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (786.7 mg, 2.75 mmol), (S)-2-(3-methoxy-propyl)-piperazine (870.0 mg, 5.50 mmol), DMSO (2.0 ml), and toluene (8.0 ml). Stir and heat the mixture at 105° C. After 48 hours, cool the mixture to ambient temperature. Dilute the mixture with ethyl acetate and wash the organic layer with 0.1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using a gradient of dichloromethane to dichloromethane/methanol (90:10) to give 280.3 mg (26%) of the title compound: mass spectrum (ion spray): m/z=391.1 (M+1).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14]/[CH:15]=[C:16](\[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:34]CCl>C(O)C>[ClH:34].[F:30][C:26]1[CH:25]=[C:24](/[C:16](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:15]\[O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/C=C(\c2cccc(F)c2)c2ccccc2C)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1/C(=C/OCCN1CCC[C@@H](C(=O)O)C1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 20 %

Procedure:
Z or E-(R)-1-[2-[[2-(3-Fluorophenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (0.50 g, 0.22123 mol) (prepared as described in Method A) (opposite geometric isomer of example 9) was dissolved in ethanol (5 ml) and 12 N sodium hydroxide solution (0.3 ml) was introduced. After stirring the solution at room temperature for 5 h, 37% hydrochloric acid solution was added until the pH was measured as ca. 1. Dichloromethane (250 ml) was introduced, and the resultant precipitate was dissolved by addition of ice with vigorous stirring. The organic phase was separated, dried (Na2SO4) and evaporated to a residue, which was co-evaporated with acetone. Recrystallization from acetone provided the title compound (0.10 g, 20%) as a white solid, m.p. 193°-195°
Reaction SMILES: [C:1](CP(=O)(OCC)OCC)#[N:2].[CH3:12]N1C(=O)N(C)CCC1.[H-].[Na+].[Cl:23][C:24]1[CH:25]=[C:26]([C@@H:30]2[C@@H:35]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[N:34]([C@@H:43]([CH2:46][CH3:47])[CH:44]=O)[C:33](=[O:48])[C@@H:32]([CH2:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:31]2)[CH:27]=[CH:28][CH:29]=1>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([C@@H:30]2[C@@H:35]([C:36]3[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=3)[N:34]([C@@H:43]([CH2:44][CH3:12])[CH:46]=[CH:47][C:1]#[N:2])[C:33](=[O:48])[C@@H:32]([CH2:49][C:50]([O:52][C:53]([CH3:56])([CH3:54])[CH3:55])=[O:51])[CH2:31]2)[CH:27]=[CH:28][CH:29]=1
Reactant: CC[C@@H](C=O)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CN1CCCN(C)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](C=CC#N)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a solution of diethyl cyanomethylphosphonate (62.4 μL, 0.396 mmol) and DMPU (239 μL, 1.98 mmol) in THF (661 μL) was added 60% sodium hydride as a suspension in mineral oil (11.89 mg, 0.297 mmol) at 0° C. The mixture was stirred for 30 min, and then treated with a solution of 100 mg (0.2 mmol) of tert-butyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((R)-1-oxobutan-2-yl)piperidin-3-yl)acetate (Example 21, Step C) in THF (661 μL). After being stirred for 12 h, the reaction was quenched with water, extracted (2×EtOAc) and the combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (10 to 20% EtOAc/Hex, a gradient elution) provided the of the title compound as a mixture of E- and Z-isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([O:16]O)([CH3:15])[CH3:14])[CH:9]=2)[CH:4]=1.COC1C=CC2C(=CC=C(C(C)=C)C=2)C=1>>[CH2:15]1[O:16][CH:13]1[CH3:14].[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([OH:16])([CH3:14])[CH3:15])[CH:9]=2)[CH:4]=1
Reactant: COc1ccc2cc(C(C)(C)OO)ccc2c1
Agent: C=C(C)c1ccc2cc(OC)ccc2c1
Product: CC1CO1
Product: COc1ccc2cc(C(C)(C)O)ccc2c1

Procedure:
In Step E, the 2-methoxy-6-(1-hydroperoxy-1-methylethyl)naphthalene product of Step D (Formula V) is reacted with the 2-methoxy-6-isopropenylnaphthalene of Formula VI in the presence of a solvent and a catalyst at reflux temperatures to form the epoxide derivative 2- 6-methoxy-2-naphthyl)propylene oxide of Formula VII and 2-methoxy-6-(1-hydroxy-1-methylethyl)naphthalene of Formula VIII.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15].N12CCN(CC1)CC2>ClCCl>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][C:14](=[O:15])[N:13]([CH3:12])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc2ncccc2c1)c1ccccc1
Yield: 69.4 %

Procedure:
A solution of 6-hydroxyquinoline (1.00 g, 6.89 mmol), N-methyl-N-phenylcarbamoyl chloride (1.17 g, 6.89 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.77 g, 6.89 mmol) in dichloromethane (20 mL) was stirred at room temperature for 1.25 hours. More dichloromethane was added and the solution was extracted with water. The organic layer was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50). Evaporation of the solvent and recrystallised from ethylacetate/heptane yielded the title compound (1.33 g, 69% yield) as a white solid.
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13][O:14][CH2:15][C:16]1[CH:23]=[C:22]([O:24]C2CCCCO2)[CH:21]=[C:20]([B:31]2[O:35][C:34](C)(C)C(C)(C)[O:32]2)[C:17]=1C=O.Cl>C1COCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH:34]1[O:35][B:31]([OH:32])[C:20]2[CH:21]=[C:22]([OH:24])[CH:23]=[C:16]([CH2:15][O:14][CH3:13])[C:17]1=2)[CH3:12]
Reactant: COCc1cc(OC2CCCCO2)cc(B2OC(C)(C)C(C)(C)O2)c1C=O
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(O)cc(COC)c21
Temperature: 55 °C
Reaction time: 0.75 h
Yield: 67.5 %

Procedure:
To a suspension of zinc dust (5.35 g, 82.3 mmol) in THF (10 mL) was added trimethylsilyl chloride (1.1 g, 10.15 mmol) at 40° C. The mixture was heated to 55° C. and stirred for 45 minutes. After cooling down to 37° C., ethyl bromoacetate (7.58 mL, 74.87 mmol) was slowly added to the reaction mixture at 37-40° C. After addition, the resulting mixture was allowed to cool to room temperature over 30 minutes. This solution was added to a solution of 2-methoxymethyl-4-(tetrahydro-pyran-2-yloxy)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (1.99 g, 5.29 mmol) in THF (6 mL) at 0° C. The mixture was stirred for 10 minutes before treating with 3 N HCl and extracting with EtOAc (2×25 mL). The organic extracts were washed with brine, dried and concentrated in vacuo. The residue was purified by silica gel flash column chromatography and lyophilized to give (1,6-dihydroxy-4-methoxymethyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (1.0 g, 68%). 1H NMR (400 MHz, Acetone-d4) δ 8.40 (s, 1H), 8.00 (s, 1H), 7.10 (s, 1H), 6.90 (s, 1H), 5.60 (m, 1H), 4.47 (m, 2H), 4.08 (m, 2H), 3.37 (s, 3H), 3.10 9m, 1H), 2.25 (m, 1H), 1.20 (m, 3H).