Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[OH:18][CH2:19][CH2:20][N:21]([CH2:32][CH2:33]O)[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:33][CH2:32][N:21]([CH2:20][CH2:19][OH:18])[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])=[O:15])[CH:7]=[CH:6]2
Reactant: Cc1ccc(S(=O)(=O)N(CCO)CCO)cc1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OCCN(CCO)S(=O)(=O)c3ccc(C)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid(naproxen, 5.0 g, 21.7 mmol), N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide (16.89 g, 65.1 mmol) and N,N-dimethylaminopyridine (DMAP, 0.530 g, 4.34 mmol) in CH2Cl2 (250 mL) and DMF (3 mL) at room temperature was added 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC, 4.99 g, 26.05 mmol). The reaction mixture was stirred overnight at room temperature, and then partitioned between CH2Cl2 and HCl (1N). The aqueous layer was washed with CH2Cl2 and the combined organic extracts were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAC/hexane (1:1) to give the title compound as a thick oil (7.15 g, 15.16 mmol, 70% yield): 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=8.6 Hz, 2H), 7.66 (m, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.40 (dd, J=1.7, 8.5 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.18 (dd, J=2.5, 8.8 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 4.28 (m, 2H), 3.95 (s, 3H), 3.88 (q, J=7.2 Hz, 1H), 3.38 (m, 2H), 3.09 (t, J=5.1 Hz, 2H), 2.44 (s, 3H), 2.18 (t, J=6.0 Hz, 1H), 1.61 (d, J=7.2 Hz, 3H). Mass spectrum (API-TIS) m/z 472 (MH+), 489 (M+18+).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C@@H:3]([OH:15])[CH2:4][NH:5][C:6](=[O:14])[O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.Cl[Si:31]([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C@@H:3]([O:15][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH2:4][NH:5][C:6](=[O:14])[O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:11])[CH3:12]
Reactant: C[Si](C)(C)CCOC(=O)NC[C@H](O)[C@@H](N)CC1CCCCC1
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOC(=O)NC[C@H](O[Si](C)(C)C)[C@@H](N)CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 2-(trimethylsilyl)ethyl (2S,3S)-3-amino-4-cyclohexyl-2-hydroxybutylcarbamate (0.18 g, 0.54 mmol) in anhydrous CH2Cl2 (1.5 mL) at 0° C., triethylamine (0.41 mL, 2.70 mmol) was added, followed by chlorotrimethylsilane (176 mg, 1.62 mmol). The resulting white mixture was warmed to rt slowly, and stirred at rt for another 40 min. Solvent was removed under vacuum, and the residue was redissolved in anhydrous CH2Cl2 (1 mL), and evaporated to dryness under vacuum to give 2-(trimethylsilyl)ethyl (2S,3S)-3-amino-4-cyclohexyl-2-(trimethylsilyloxy)butylcarbamate (quant.) as a white solid; MS m/z 403 (M+H+).
Reaction SMILES: CCOCC.[CH2:6]([Mg]Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:30])=[C:20]([CH:29]=1)[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].[Cl-].[NH4+]>C1C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:30])=[C:20]([C:21]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[OH:22])[CH:29]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: Oc1ccc(Cl)cc1C(O)(Cc1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
322 ml of an ether solution titrating 1.12 M/liter of benzyl magnesium chloride were added over one hour to a solution of 34 g of 5-chloro-2-hydroxy-benzophenone in 150 ml of benzene and the mixture was allowed to stand for one hour and was then stirred at 20° C. for 16 hours. The mixture was poured into one liter of aqueous saturated ammonium chloride solution and the mixture was washed with water and was extracted 3 times with 400 ml of ether. The ether phase was dried over magnesium sulfate and was evaporated to dryness under reduced pressure. The residue was taken up in 100 ml of cyclohexane and the mixture stood for 16 hours at 20° C. and was iced and vacuum filtered to obtain 42.9 g of 5-chloro-2-hydroxy-α-benzyl-α-phenyl-benzene methanol melting at 128° C.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]=2[O:6][CH:5]=1.[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][CH2:18][CH:17]=[CH2:16])=[CH:12][C:7]=2[O:6][CH:5]=1
Reactant: CC(C)(C)Cc1coc2cc(O)ccc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(CC(C)(C)C)coc2c1
Reaction time: 2 h

Procedure:
A stirred solution of the product from Step E (2.880 grams) in dry DMF (30 mL) was treated with allyl bromide (1.282 mL) followed by cesium carbonate (4.828 grams). After 2 hours, the mixture was partitioned between isopropyl acetate and pH4 pthalate buffer. The organic was washed twice with water, dried over magnesium sulfate and filtered. Concentration gave the title compound in such purity that further processing was not required.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([CH3:12])=[N:5][CH:6]=[C:7]([CH:11]=1)[C:8](Cl)=[O:9].[H-].[Na+].[CH2:15]([O:17][C:18](=[O:28])[CH:19]=[CH:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:16].O>O1CCCC1>[CH2:15]([O:17][C:18](=[O:28])[C:19]([C:8]([C:7]1[CH:6]=[N:5][C:4]([CH3:12])=[C:3]([CH3:2])[CH:11]=1)=[O:9])=[CH:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:16]
Reactant: CCOC(=O)C=CNc1ccccc1
Reactant: Cc1cc(C(=O)Cl)cnc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=CNc1ccccc1)C(=O)c1cnc(C)c(C)c1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 7.7 %

Procedure:
3.31 g (16.0 mmol) of 5,6-dimethyl-nicotinoyl chloride hydrochloride 6a (prepared as described by Paine, J. B.; J. Het. Chem. 1987, 351) was dissolved in 35 mL of dry tetrahydrofuran and cooled down to −10° C. under nitrogen atmosphere. To the resultant solution was added 1.60 g (40.0 mmol) of 60% sodium hydride and the mixture was stirred for 15 minutes, followed by the addition of 3.06 g (16.0 mmol) of 3-phenylamino-acrylic acid ethyl ester 5a. The mixture was stirred at −10° C. for 2 hours, followed by the addition of 100 mL of water to the reaction mixture. The product was extracted twice with 100 mL dichloromethane. The combined organic extracts were dried with MgSO4 and concentrated in vacuo. Purification of the crude product using flash chromatography (10-75% ethyl acetate in hexane) yielded 400 mg of 2-(5,6-dimethyl-pyridine-3-carbonyl)-3-phenylamino-acrylic acid ethyl ester 2d as a yellow solid.
Reaction SMILES: [CH2:1]([OH:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:14]([O:16][CH2:17]Cl)[CH3:15].C(OCC)(=O)C>CN(C)C=O>[CH2:14]([O:16][CH2:17][O:11][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)[CH3:15]
Reactant: CCOCCl
Reactant: OCc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCOCc1ccc2c(c1)OCO2
Reaction time: 0.5 h

Procedure:
4.56 g of piperonyl alcohol and 1.20 g of 60% sodium hydride were suspended in 30 ml of N,N-dimethylformamide. After stirring for 30 minutes under ice-cooling, 2.28 ml of chloromethyl ethyl ether was added thereto, and the mixture was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution. The mixture was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:20), to give 4.98 g of the title compound as a colorless oil.
Reaction SMILES: [CH:1]([N:14]=[C:15]=[S:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][NH2:18]>CCOCC>[CH:1]([NH:14][C:15]([NH:18][CH3:17])=[S:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=NC(c1ccccc1)c1ccccc1
Reactant: CN
Solvent: CCOCC
Product: CNC(=S)NC(c1ccccc1)c1ccccc1

Procedure:
A solution of 13.50 g (0.06 Mole) of benzhydrylisothiocyanate in ether is saturated with anhydrous methylamine in an ice bath. The crystals are filtered to yield the product, N-benzhydryl-N'-methylthiourea; mp 152°-154° C, which is sufficiently pure for the next step.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][CH:8]([NH3+:14])[C:7]2=[O:15].C(N(C(C)C)CC)(C)C.[C:25]([O:28][CH2:29][CH3:30])(=[O:27])C>O1CCCC1>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][CH:8]([NH:14][C:25](=[O:27])[O:28][CH2:29][CH3:30])[C:7]2=[O:15]
Reactant: COc1ccc2c(c1)C(=O)C([NH3+])CO2
Reactant: CCOC(C)=O
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)NC1COc2ccc(OC)cc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.82 g (12.3 mmol) of 6-methoxy-4-oxochroman-3-aminium chloride were dissolved in tetrahydrofuran under nitrogen atmosphere and cooled to 0° C. with an ice bath. Diisopropylethylamine and ethyl carbononochloridate were added. The mixture was allowed to warm to room temperature and stirred for 30 min. The mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution (2×) and water (1×). The organic phase was washed dried over MgSO4, and concentrated in vacuo to give 3.5 g (13.2 mmol, quant.) of crude material.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.O>[F:20][C:16]1[CH:15]=[C:14]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Fc1cccc(Br)c1
Reactant: CCCc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2cccc(F)c2)cc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
Into a reaction vessel under an atmosphere of nitrogen, 4-propyl phenylboronic acid (T16; 200.0 g), 1-bromo-3-fluorobenzene (T8; 177.8 g), potassium carbonate (281.9 g), Pd(Ph3P)2Cl2 (7.2 g), toluene (600 ml), and Solmix A-11 (600 ml) were put and heated under reflux for 2 hours. After the reaction mixture had been cooled to 25° C., the solution was poured into water (2,000 ml) and toluene (1,000 ml), and mixed. The mixture was then allowed to stand to be separated into two layers of an organic layer and an aqueous layer. Extraction into an organic layer was carried out and the resulting organic layer was fractionated. The extracts were washed with water, and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure, and the residue was purified by means of fraction-collecting column chromatography using heptane as the eluent and silica gel as the stationary phase powder. The solution was further purified by recrystallization from Solmix A-11 and then dried, whereby 175.5 g of 3-fluoro-4′-propylbiphenyl (T17) was obtained. The yield based on the compound (T8) was 80.3%.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH2:5]1.[CH:12](OCC)=[O:13].C(O)C>C(OCC)C.C(O)C>[OH:13]/[CH:12]=[C:7]1\[C:6](=[O:10])[CH2:5][C:4]([CH3:11])([CH3:3])[CH2:9][CH2:8]\1
Reactant: CCOC=O
Reactant: CC1(C)CCCC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CC1(C)CC/C(=C/O)C(=O)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.4 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 475 mg, 11.9 mmol) in diethyl ether (25 mL) at 0° C. was added ethanol (0.06 ml, 1.03 mmol) dropwise. The grey suspension was stirred at 0° C. for 20 min. A solution of 3,3-dimethylcyclohexanone (1.50 g, 11.9 mmol) and ethyl formate (1.45 ml, 17.8 mmol) in diethyl ether (3 mL) was added dropwise over 10 min. The yellow heterogeneous reaction mixture was stirred at 0° C. for 1 h then warmed to room temperature and stirred for 2 h. Ethanol (1 mL) was added and the mixture was stirred at room temperature for 1 h then quenched with water (25 mL). The layers were separated and the aqueous phase was washed with diethyl ether. The aqueous layer was acidified with 1M HCl until pH=2 and then extracted with diethyl ether (2×). The combined organic layers were dried over MgSO4 and concentrated to afford 1.64 g (90%) of 2-[1-hydroxy-meth-(Z)-ylidene]-5,5-dimethyl-cyclohexanone as a light yellow oil. 1H NMR (CDCl3, 400 MHz): δ (ppm) 14.38 (br. s., 1H), 8.79 (s, 1H), 2.34-2.47 (m, 2H), 2.16 (s, 2H), 1.42-1.53 (m, 2H), 1.00 (s, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:10]=[C:11]([O:16][CH3:17])[CH:12]=[CH:13][C:14]=1[CH3:15].[N:18]([O-:20])=[O:19].[Na+]>O>[CH3:15][C:14]1[C:9]([CH3:8])=[CH:10][C:11]([O:16][CH3:17])=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: COc1ccc(C)c(C)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 55 %

Procedure:
Trifluoroacetic acid(250 ml) was added into 3,4-dimethylanisole(17.1 g, 0.13 mol), successively sodium nitrite(16.6 g, 0.24 mol) was added slowly in water bath, and stirred at room temperature for 14 hrs. After trifluoroacetic acid was removed and water was added thereto, the resulting mixture was extracted with ether, and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH:11]=[C:10]([CH3:14])[NH:9]2)=[CH:4][CH:3]=1.[F:15][C:16]([F:24])([F:23])[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19]>C(Cl)(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])[C:17]([OH:22])([C:16]([F:24])([F:23])[F:15])[C:11]1[C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[NH:9][C:10]=1[CH3:14]
Reactant: COC(=O)C(=O)C(F)(F)F
Reactant: Cc1cc(=O)n(-c2ccc(Cl)cc2)[nH]1
Solvent: ClC(Cl)Cl
Product: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(Cl)cc2)c1=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a chloroform solution (5 ml) of 1-(4-chlorophenyl)-3-methyl-5-pyrazolone (104 mg, 0.5 mmol), methyl trifluoropyruvate (78 mg, 0.5 mmol) was added at room temperature and the mixture was stirred at 80° C. for 2 hours. After removing the solvent under reduced pressure, the title compound was obtained as a colorless solid (182 mg).
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=2)=[CH:27][CH:26]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccc(F)cc3)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 4-fluorophenylboronic acid (140 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (64 mg, yield 82%).
Reaction SMILES: [OH-].[Li+].CC1(C)[O:9][C:8](=[O:10])[C:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:6](=[O:31])[O:5]1.O1CCCC1.O.Cl>O>[N+:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][C:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)([C:6]([OH:31])=[O:5])[C:8]([OH:10])=[O:9])=[CH:17][CH:16]=1)([O-:20])=[O:19]
Reactant: CC1(C)OC(=O)C(Cc2ccc([N+](=O)[O-])cc2)(Cc2ccc([N+](=O)[O-])cc2)C(=O)O1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)O

Procedure:
2.185 g (52.07 mmol) of lithium hydroxide are added to a suspension of 10.79 g (26.04 mmol) of 2,2-dimethyl-5,5-bis(4-nitrobenzyl)-1,3-dioxane-4,6-dione and 110 ml mixture of tetrahydrofurane:water 9:1. The mixture is subsequently allowed to react for 21.5 hours at 25° C., added to 500 ml water and acidified to pH=1 with 20 ml hydrochloric acid 3N. The mixture is partitioned between water and ethyl acetate; the organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue 9.54 g (98%) of 2,2-bis(4-nitrobenzyl)malonic acid as white powder is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Cl.[NH2:12][C:13]([CH3:40])([CH3:39])[C:14]([NH:16][C@H:17]([B:26]1[O:30][C@@H:29]2[CH2:31][C@@H:32]3[CH2:35][C@H:34]([C@:28]2([CH3:38])[O:27]1)[C:33]3([CH3:37])[CH3:36])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)=[O:15].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:12][C:13]([CH3:40])([CH3:39])[C:14]([NH:16][C@H:17]([B:26]2[O:30][C@@H:29]3[CH2:31][C@@H:32]4[CH2:35][C@H:34]([C@:28]3([CH3:38])[O:27]2)[C:33]4([CH3:37])[CH3:36])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)=[O:15])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: Cc1cccc(C[C@H](NC(=O)C(C)(C)N)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cccc(C[C@H](NC(=O)C(C)(C)NC(=O)c2ccc(Cl)cc2)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)c1
Temperature: 22 °C
Reaction time: 12 h
Yield: 77.8 %

Procedure:
To a solution of 4-chlorobenzoic acid (0.087 g, 0.553 mmol) in CH2Cl2 were added 2-amino-2-methyl-N-{(1R)-2-(3-methylphenyl)-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}propanamide hydrochloride (0.20 g, 0.503 mmol), HOBt (0.075 g, 0.553 mmol), 4-methylmorpholine (0.204 g, 2.42 mmol) and EDCI (0.106 g, 0.553 mmol). The reaction mixture was allowed to stir at 22° C. After 12 h, the reaction mixture was quenched with a saturated solution of sodium bicarbonate and the product partitioned into DCM. The organic layer was dried over MgSO4, filtered and concentrated to give the title compound (0.210 g, 77%). LC/MS: Rt=2.29 min, ES+537 (Formic Acid method).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>C(O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9]
Reactant: OCc1ccc(O)cc1Cl
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: OCc1ccc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-chloro-4-(hydroxymethyl)phenol (for a preparation see Intermediate 16)(3 g, 18.9 mmol) in ethanol (80 ml) was added benzyl bromide (2.25 ml, 18.9 mmol, Aldrich) and then 2 M aqueous sodium hydroxide (10.4 ml, 20.8 mmol). The mixture was stirred at ambient temperature overnight under nitrogen. The solvent was removed in vacuo to leave an aqueous suspension. The residue was partitioned between dichloromethane (100 ml) and water (100 ml). The phases were separated and the aqueous phase extracted with dichloromethane (50 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave an oil. The residue was loaded in dichloromethane and purified on silica (100 g×2) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give {2-chloro-4-[(phenylmethyl)oxy]phenyl}methanol as a white solid (2.18 g).
Reaction SMILES: [NH:1]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:2]([C:7]([NH:9][C@H:10]([C:17]([NH:19][C@H:20]([C:25]([NH:27][C@H:28]([C:33]([NH:35][CH2:36][C:37]([O:39]CC1C=CC=CC=1)=[O:38])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:26])[CH2:21][C:22](=[O:24])[NH2:23])=[O:18])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].[H][H]>C(O)C.[Pd]>[NH:1]([C:47]([O:49][C:50]([CH3:53])([CH3:51])[CH3:52])=[O:48])[C@H:2]([C:7]([NH:9][C@H:10]([C:17]([NH:19][C@H:20]([C:25]([NH:27][C@H:28]([C:33]([NH:35][CH2:36][C:37]([OH:39])=[O:38])=[O:34])[CH2:29][CH:30]([CH3:31])[CH3:32])=[O:26])[CH2:21][C:22](=[O:24])[NH2:23])=[O:18])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [H][H]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O
Reaction time: 3 h
Yield: 71.1 %

Procedure:
10% Pd/C (300 mg) was added to the compound [31] (2.8 g, 3.8 mM) dissolved in ethanol (100 ml) and hydrogen gas was passed therethrough at room temperature for 3 hours. Insoluble materials precipitated in the reaction mixture were filtered and washed with DMF. The filtrate was concentrated in vacuo. Ethanol-ether was added to the residue, and the precipitate was collected by filtration and dried to obtain the product [32].
Reaction SMILES: Cl[CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>O.C(O)C>[OH:5][C:3]([CH3:6])([CH3:4])[CH2:2][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(C)(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(O)COc1ccc(C#N)cc1
Temperature: 80 °C
Yield: 94 %

Procedure:
A mixture of 1-chloro-2-methyl-propan-2-ol (10 mL), 4-hydroxybenzonitrile (2 g, 16.8 mmol), K2CO3 (9.3 g, 67.3 mmol) in water (6 mL) and ethanol (60 mL) was heated at 80° C. for 16 hours. The reaction mixture was cooled and the solvent was concentrated in vacuo. The residue was diluted with ether (200 mL) and filtered and the filtrate was washed sequentially with water (50 mL) and brine solution (50 mL). The organics were separated and dried over MgSO4 and solvent was removed in vacuo to give a residue which was purified by silica gel column chromatography using (0-100%) EtOAc/DCM as eluent to give 4-(2-hydroxy-2-methyl-propoxy)benzonitrile (3.0 g, 94%) as a yellow solid. ESI-MS m/z calc. 191.1. Found 192.3 (M+1)+; Retention time: 1.05 minutes (3 min run).