Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Yield: 62.4 %

Procedure:
Ethyl 4-hydroxybenzoate (4.15 g, 25.0 mmol), tert-butyl 4-hydroxytetrahydro-1(2H)-pyridinecarboxylate (5.0 g, 25.0 mmol) and triphenyl phosphine (7.87 g, 30.0 mmol) were dissolved in tetrahydrofuran (50 mL), and with stirring at 0° C., diisopropyl azodicarboxylate (6.06 g, 30.0 mmol) was added thereto and stirred for 24 hours. The reaction solution was concentrated, and the precipitated white solid was taken out through filtration and washed with ethyl acetate. The mother liquid was washed with aqueous 1 N sodium hydroxide solution and saturated saline water in that order, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain the intended compound (5.45 g, 62%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]2[CH:9]=[C:10]3[C:15](=[C:16]([NH:18][S:19]([C:22]4[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:36])[CH2:30][C:31]([O:33]CC)=[O:32])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[N:17]=2)[N:14]=[CH:13][CH:12]=[CH:11]3)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)(=O)C>[OH-].[Na+].O>[CH3:1][C:2]1[C:3]([C:8]2[CH:9]=[C:10]3[C:15](=[C:16]([NH:18][S:19]([C:22]4[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:36])[CH2:30][C:31]([OH:33])=[O:32])=[CH:26][CH:27]=4)(=[O:21])=[O:20])[N:17]=2)[N:14]=[CH:13][CH:12]=[CH:11]3)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(S(=O)(=O)Nc2nc(-c3ncccc3C)cc3cccnc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccnc1-c1cc2cccnc2c(NS(=O)(=O)c2ccc(NC(=O)CC(=O)O)cc2)n1
Temperature: 25 °C

Procedure:
Heat a stirred suspension of ethyl 3-[[4-[[[6-(3-methyl-2-pyridinyl)-1,7-naphthyridin-8-yl]amino]sulfonyl]-phenyl]amino]-3-oxopropanoate (387 mg, 0.765 mmol) in 0.125 N aqueous sodium hydroxide solution at 60° C. for 2 hours. Allow the reaction solution to cool to room temperature, and adjust the pH of the solution to 4-5 by the dropwise addition of glacial acetic acid. Dilute with water (50 mL) and filter. Triturate the isolate solid with methanol (1.5 mL), dilute with water (50 mL), filter and vacuum dry to obtain the title compound as a monohydrate, C23H19N5O5S.H2O, mp 163-164° C. (dec). FABMS: MH+ 478 (100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.[C:13]([O:17][C:18](=[O:20])O)([CH3:16])([CH3:15])[CH3:14].O1CCCC1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:20])[N:10]([CH2:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[OH:12])[CH3:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CNCC(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(CC(O)c1ccc(F)cc1)C(=O)OC(C)(C)C

Procedure:
A solution of 1-(4-fluorophenyl)-2-methylamino ethanol (the compound of Preparation Example 17) (9.7 g) and t-butylbicarbonate (10.0 g) in a mixed solvent of tetrahydrofuran solution (100 mL) and an aqueous solution of saturated sodium bicarbonate (50 mL) was stirred at room temperature for 1.5 hours. The solution was diluted with ethyl acetate, and washed with water and saturated sodium chloride water. After drying the organic layer with anhydrous sodium sulfate, the residue that was obtained by evaporating the solvent at reduced pressure was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (9.5 g) was obtained as a colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH3:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:4][CH2:3][CH2:2][N:9]1[CH2:10][CH2:11][N:6]([CH3:5])[CH2:7][CH2:8]1
Reactant: CN1CCNCC1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCN(CCO)CC1
Yield: 46.4 %

Procedure:
2-Bromoethanol (2.36 g, 19 mmol) was added dropwise to a mixture of 1-methylpiperazine (1.26 g, 13 mmol) and potassium carbonate (5.0 g, 36 mmol) in absolute ethanol (150 ml) and the mixture heated at reflux for 18 hours. The mixture was allowed to cool and the precipitates were removed by filtration and the solvent volatiles were removed by evaporation. The residue was treated with acetone/methylene chloride, the insolubles were removed by filtration and the solvent was removed from the filtrate by evaporation to give 4-(2-hydroxyethyl)-1-methylpiperazine (870 mg, 48%) as a light brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:5]2[O:6][CH:7]([CH2:9][NH2:10])[CH2:8][C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[CH3:1][C:2]1[C:15]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:5]2[O:6][CH:7]([CH2:9][NH:10][C:26](=[O:27])[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(c3c1CCC3)OC(CN)C2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(c3c1CCC3)OC(CNC(=O)OCc1ccccc1)C2
Yield: 107.2 %

Procedure:
Treatment of (±)-1-(5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine (2.28 g, 11.2 mmol) with diisopropylethylamine (2.16 g, 16.7 mmol) followed by benzyl chloroformate (2.19 g, 12.8 mmol) generally according to the procedure described for Intermediate 15 gave 4.05 g (81%) of (±)-benzyl (5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methylcarbamate as a white solid. Rf=0.33 (silica, ethyl acetate:hexanes 1:4); mp 109-113° C.; Anal. calcd. for C21H23NO3: C, 74.75; H, 6.87; N, 4.15. Found: C, 74.42; H, 6.91; N, 4.10. Chiral HPLC separation of (±)-benzyl (5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methylcarbamate (Chiralcel OJ, methanol) provided two fractions. Fraction 1 (Rt=19.001 min, Chiralcel OJ, methanol); Fraction 2 (Rt=23.125 min, Chiralcel OJ, methanol).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2([C:21]([O:23]CC)=[O:22])[CH2:20][CH2:19]2)[CH:13]=1>ClCCl>[C:21]([C:18]1([C:14]2[CH:13]=[N+:12]([O-:6])[CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:19]1)([OH:23])=[O:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C1(c2cccnc2)CC1
Solvent: ClCCl
Product: O=C(O)C1(c2ccc[n+]([O-])c2)CC1
Reaction time: 16 h
Yield: 58.1 %

Procedure:
70% meta-Chloroperoxybenzoic acid (1.2 g, 4.9 mmol) was added to a solution of ethyl 1-(pyridin-3-yl)cyclopropanecarboxylate (400 mg, 2.4 mmol) in dichloromethane (5 mL) at room temperature and stirred for 16 h. The resulting precipitate was filtered and triturated with dichloromethane to afford the title compound (250 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][NH:5][CH:6]=1.C1C(=O)N([Br:19])C(=O)C1>C1COCC1>[Br:19][C:6]1[NH:5][CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]=1[CH3:1]
Reactant: CCOC(=O)c1c[nH]cc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]c(Br)c1C
Temperature: -30 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of ethyl 4-methyl-3-pyrrolecarboxylate (1.57 g, 10 mmol) in anhyd THF (30 mL) cooled to −78° C. was added NBS (1.9 g, 10 mmol). After stirring 1 h at −30° C., the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography, eluting with EtOAc-Hex (0:100 to 30:70), to yield ethyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate (2.0, 86%) as a white solid. 1H-NMR (CDCl3): δ 8.54 (1H, brs), 7.38 (1H, d), 4.27 (2H, q), 2.24 (3H, s), 1.33 (3H, t). To a solution of ethyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate (2.0 g, 8.6 mmol) in anhyd DMF (30 mL) at 0° C. was added portionwise NaH (60% in mineral oil, 705 mg, 17.6 mmol) under nitrogen. After 1 h at ambient temperature, the reaction mixture was charged with iodomethane (1.5 mL, 24 mmol) and then stirred at ambient temperature overnight. The reaction mixture was quenched by cautious addition of water and then extracted with DCM. The combined extracts were washed with water, dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography, eluting with EtOAc-Hex (0:100 to 20:80), to provide the title compound (1.64 g, 78%) as a white solid. 1H-NMR (CDCl3): δ 7.33 (1H, s), 4.25 (2H, q), 3.58 (3H, s), 2.24 (3H, s), 1.33 (3H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][C:17]([O:23][CH3:24])=[CH:18][CH:19]=5)[C:14]=4[C:13]4[C:25](=[O:30])[N:26]([CH3:29])[C:27](=[O:28])[C:12]=4[C:11]=3[C:5]=2[CH:4]=1.[H-].[Na+].[CH3:33]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:10]3[C:22]4[N:21]([CH3:33])[C:20]5[C:15](=[CH:16][C:17]([O:23][CH3:24])=[CH:18][CH:19]=5)[C:14]=4[C:13]4[C:25](=[O:30])[N:26]([CH3:29])[C:27](=[O:28])[C:12]=4[C:11]=3[C:5]=2[CH:4]=1
Reactant: CI
Reactant: COc1ccc2[nH]c3c4[nH]c5ccc(OC)cc5c4c4c(c3c2c1)C(=O)N(C)C4=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c3c(c4c(c5c6cc(OC)ccc6n(C)c35)C(=O)N(C)C4=O)c2c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 1 g (2.5 mmol) 6,7,12,13-tetrahydro-3,9-dimethoxy-6-methyl-5,7-dioxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole in 50 ml dry dimethylformamide is added dropwise at 20° C. to a suspension of 91 mg (3.0 mmol) sodium hydride (80% in paraffin oil) in 5 ml dimethylformamide under an atmosphere of argon. After stirring for 1 hour at 20° C., 0.2 ml (3.2 mmol) methyl iodide are added thereto and the reaction mixture is stirred for 16 hours at 20° C. It is then evaporated in a vacuum and the residue is partitioned between ethyl acetate and water. The ethyl acetate phase is separated off, dried over anhydrous sodium sulphate, filtered and evaporated. The residue is stirred with 30 ml diisopropyl ether/ethyl acetate (2:1 v/v) and the undissolved product is filtered off. 6,7,12,13-Tetrahydro-3,9-dimethoxy-6,12-dimethyl-5,7-dioxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole is obtained in the form of a pale brown amorphous powder.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7](=[O:18])[NH:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7](=[O:18])[NH:8][CH2:9][CH2:10][S:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:27]
Reactant: O=C1CCCN1C(=O)NCCSc1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1CCCN1C(=O)NCCS(=O)c1ccccn1
Reaction time: 1.5 h
Yield: 43.8 %

Procedure:
To a solution of 2.0 g (7.54 mmol) of 2-oxo-1-[[2-(pyridin-2-ylthio)ethyl]carbamoyl]pyrrolidine in 35 ml of CH2Cl2 was added 1.63 g (7.54 mmol) of m-CPBA (content 80%) under ice-cooling. Then the mixture was stirred for 1.5 hr. at room temperature. The reaction solution was washed with aqueous NaHCO3 and water. After drying, the solvent was removed by evaporration. The residue was refined by silica gel column chromatography, then the crystalline objective compound was obtained from the eluate with benzene/ethyl acetate (3/1-1/1 v/v). The compound was washed with Et2O and collected by filtration, whereby 0.93 g of the crystalline compound (Ib-3) melting at 119.5°-120.5° C. was obtained. Yield: 43.9%.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([C:15]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([OH:14])=[O:13].[OH-].[Na+].O.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>CC(C)=O>[CH2:34]([O:33][C:31]([N:18]1[CH2:17][CH2:16][C:15]([C:12]([OH:14])=[O:13])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19]1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(C(=O)O)(c2ccccc2)CC1
Temperature: 5 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
A mixture of 37.7 g of 4-carboxy-4-phenylpiperidine p-toluenesulphonate, 53.3 g of 30% aqueous NaOH solution and 250 ml of water is cooled to 5° C. A solution of 18 g of benzyl chloroformate in 60 ml of acetone is added rapidly at 5° C., and the mixture is left stirring overnight while allowing the temperature to rise to RT. The reaction mixture is washed twice with ether and, after settling has taken place, the aqueous phase is separated and acidified to pH 1 by adding concentrated HCl and then 2N HCl. The precipitate formed is drained, dried, taken up in ether and drained again. 30.6 g of the expected product are obtained, m.p.=142°-144° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH:25]([CH3:27])[CH3:26])[C:20]([O:22][CH2:23]Cl)=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:28]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH:25]([CH3:27])[CH3:26])[C:20]([O:22][CH2:23][I:28])=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O[C@H](C(=O)OCCl)C(C)C
Reactant: [I-]
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O[C@H](C(=O)OCI)C(C)C

Procedure:
Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyrate was converted to iodide by the method described in Example A-I-1, step e to give the title compound (3.64 g) practically pure. Rf (2% MeOH/CHCl3) 0.85.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[S:26]([O:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:4]1)([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: COC(=O)C1(CO)CN(C(=O)OC(C)(C)C)CCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)C1(COS(=O)(=O)c2ccc(C)cc2)CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.2 %

Procedure:
E3 (3.2 g, 11.62 mmol) was dissolved in pyridine (75 mL), p-toluenesulfonyl chloride (2.66 g, 13.95 mmol) was added in 4 portions in ca. 10 minutes and the solution was stirred for 15 h at RT. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layer was washed with 1 N HCl and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by flash column chromatography (heptane:EtOAc 100:0 to 40:60) yielding the title compound (4.0 g, 80%). MS (ES) C19H27NO8S requires: 429. found: 452.1 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Al](Cl)(C)C.[CH3:13][N:14]([CH3:39])[C:15]([C:17]1[N:22]=[CH:21][C:20]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34](OCC)=[O:35])[CH:25]=2)=[CH:19][CH:18]=1)=[O:16]>ClCCCl.C(Cl)Cl>[CH3:39][N:14]([CH3:13])[C:15]([C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)=[O:35])[CH:25]=2)=[CH:21][N:22]=1)=[O:16]
Reactant: CCOC(=O)c1cc(Oc2ccc(C(=O)N(C)C)nc2)c2cc(C)oc2c1
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N(C)C)nc3)c3cc(C)oc3c2)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 45.2 %

Procedure:
To a solution of 5-methylpyridin-2-amine (191 mg, 1.76 mmol) in DCE at 0° C. was added Al(CH3)2Cl drop-wise. After stirring the mixture at room temperature for 20 minutes ethyl 4-({6-[(dimethylamino)carbonyl]pyridin-3-yl}oxy)-2-methyl-1-benzofuran-6-carboxylate (65 mg, 0.18 mmol) was added. The reaction was stirred at room temperature for 14 hours. The sample was diluted with CH2Cl2 and quenched with potassium sodium tartrate tetrahydrate (20% w/w) (1 mL). Caution, addition was done slowly. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude sample was introduced into a silica gel column and eluted with MeOH/CHCl3 (3/97) to provide the product (35 mg, 85% yield) as white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.32 (s, 3 H) 2.48 (s, 3 H) 3.16 (d, J=7.54 Hz, 6 H) 6.26 (s, 1 H) 7.31 (dd, J=8.67, 2.83 Hz, 1 H) 7.48 (d, J=1.13 Hz, 1 H) 7.58 (d, J=6.78 Hz, 1 H) 7.69 (d, J=8.67 Hz, 1 H) 7.87 (s, 1 H) 8.12 (s, 1 H) 8.26 (d, J=8.48 Hz, 1 H) 8.38 (e, J=2.64 Hz, 1H) 8.53 (s, 1 H); MS (ESI, pos): 431.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[N:7]=[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CS(C)=O>[C:17]1([C:8]2[O:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]([CH2:5][C:1]#[N:2])[N:7]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [C-]#N
Reactant: ClCc1nc(-c2ccccc2)oc1-c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1nc(-c2ccccc2)oc1-c1ccccc1
Temperature: 45 °C
Reaction time: 3 h
Yield: 103.7 %

Procedure:
To a suspension of potassium cyanide (67.1 mg, 0.999 mmol) in DMSO (2 mL) was added dropwise at RT a solution of 4-(chloromethyl)-2,5-diphenyloxazole (245 mg, 908 μmol) in DMSO (3 mL) over a period of 5 min. The reaction mixture was stirred at RT for 2 h and at 45° C. for another 3 h. The reaction mixture was cooled to RT, poured into water (25 mL) and extracted with ethyl acetate (2×75 mL). The organic phases were washed with water (2×20 mL) and brine (1×20 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give 245 mg crude product. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light yellow solid (189 mg, 726 μmol, 79.9%).
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Mg].Br[CH2:28][C@H:29]1[CH2:34][CH2:33][Si@H:32]([CH2:35][CH2:36][CH3:37])[CH2:31][CH2:30]1>[Cu]I.P(OCC)(OCC)(OCC)=O.C1COCC1>[CH2:35]([Si@H:32]1[CH2:33][CH2:34][C@H:29]([CH2:28][CH2:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH2:30][CH2:31]1)[CH2:36][CH3:37]
Reactant: FC(F)(F)Oc1ccc(-c2ccc([C@H]3CC[C@H](CBr)CC3)cc2)cc1
Reactant: CCC[Si@H]1CC[C@H](CBr)CC1
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(OC(F)(F)F)cc4)cc3)CC2)CC1

Procedure:
39.7 g (0.1 mol) of 4-(trans-4-bromomethylcyclohexyl)-4'-trifluoromethoxybiphenyl was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 23.5 g (0.1 mol) of trans-1-bromomethyl-4-n-propyl-4-silacyclohexane. After a conventional after treatment, purification was conducted by means of chromatography to obtain 43.0 g (yield 88.0%) of 4-(trans-4-(2-(trans-4-n-propyl-4-silacyclohexyl)ethyl)cyclohexyl)-4'-trifluoromethoxybiphenyl was obtained.
Reaction SMILES: C([BH3-])#N.[Na+].[O:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.Cl.[C:13]([C:17]1[O:21][N:20]=[C:19]([NH:22][C:23]([C@@H:25]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][NH:26]2)=[O:24])[CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.CCOC(C)=O>[C:13]([C:17]1[O:21][N:20]=[C:19]([NH:22][C:23]([C@@H:25]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][N:26]2[CH:8]2[CH2:9][CH2:10][O:5][CH2:6][CH2:7]2)=[O:24])[CH:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C1CCOCC1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2)no1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2C2CCOCC2)no1
Reaction time: 4 h

Procedure:
Sodium cyanoborohydride (71 mg, 1.13 mmol) and tetrahydro-pyran-4-one (75 mg, 0.75 mmol) are added to a solution of (S)-perhydro-azepine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide hydrochloride (prepared according to Method T, step 6) (0.2 g, 0.75 mmol) in DCM (8.0 mL). After stirring for four hours, the reaction mixture is diluted with EtOAc and washed twice with water. The organic phase is dried over anhydrous Na2SO4 and after removal of the solvent under reduced pressure, the crude is purified by prep TLC to afford the title compound; m/z 350 [M+H].
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([O:15]C(=O)C)[CH:12]=[CH:11][C:10]=2[O:19]C(=O)C)=[CH:5][CH:4]=1.O.O.O.C([O-])(=[O:29])C.[Na+].CO.Cl>O>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=2[OH:19])=[CH:5][CH:4]=1)=[O:29]
Reactant: CC(=O)[O-]
Reactant: CC(=O)Oc1ccc(OC(C)=O)c(-c2ccc(C(Br)Br)cc2)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=Cc1ccc(-c2cc(O)ccc2O)cc1

Procedure:
A mixture of about 4.4 g. (0.01 mole) of 4'-dibromomethyl-2,5-diacetoxy-1,1'-biphenyl, prepared as described in Example 2, and about 4.4 g. (0.03 mole) of sodium acetate trihydrate in a mixture of 50 ml. of methanol and 25 ml. of water was heated at reflux under nitrogen for about 4 hours. 5 ml. of concentrated hydrochloric acid were added and refluxing continued for an additional 11/2 hours. Most of the methanol was removed by evaporation on a steam bath under nitrogen resulting in precipitation of a light cream colored solid. The mixture was diluted with 50 ml. of water, cooled in an ice bath, and the resultant solid filtered, washed with water, and dried in a vacuum oven. Yield of about 2.0 g. of 4'-formyl-2,5-dihydroxy-1,1'-biphenyl, m.p. 203°-205° C. Thin layer chromatography indicated one component. Proton nuclear magnetic resonance and infrared spectra confirmed the structure and were essentially identical to the spectra obtained from the product of Example 3. The product gave a positive test with 2,4-dinitrophenylhydrazine spray reagent.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16].O>O1CCOCC1>[CH:30]1[C:31]2[CH:19]([CH2:18][O:17][C:15]([N:1]3[CH2:4][CH2:3][C@H:2]3[C:5]([OH:7])=[O:6])=[O:16])[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]=2[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)[C@@H]1CCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 0.50 g of (S)-(-)-2-azetidine carboxylic acid in 15 ml of 10 aqueous sodium carbonate solution was added 1.3 g of 9-fluorenylmethyl chloroformate in 10 ml of dioxane, dropwise, while maintaining the temperature of the reaction mixture at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours, then poured into water and the aqueous solution was washed with ether. The aqueous layer was cooled to 0° C. and adjusted to a pH of 2 with 3N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, filtered, and evaporated in vacuo to give (S)-N-(9-fluorenylmethoxycarbonyl) azetidine-2-carboxylic acid.