Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][C@@H:7]([OH:9])[C@H:6]([CH3:10])[CH2:5][CH2:4]1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([C:19]([NH2:21])=[O:20])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].C1COCC1>O>[Cl:11][C:12]1[N:17]=[C:16]([NH:2][C@@H:3]2[CH2:4][CH2:5][C@@H:6]([CH3:10])[C@H:7]([OH:9])[CH2:8]2)[C:15]([C:19]([NH2:21])=[O:20])=[CH:14][N:13]=1
Reactant: C[C@@H]1CC[C@@H](N)C[C@H]1O
Reactant: NC(=O)c1cnc(Cl)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@H](Nc2nc(Cl)ncc2C(N)=O)C[C@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a reactor was added (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (16.0 kg), 2,4-dichloropyrimidine-5-carboxamide (19.0 kg), K2CO3 (14.9 kg) and THF (160 L) at 25° C. The batch was cooled to 0° C., and water (160 L) was added. The batch was stirred for an additional 1 h at 0° C., warmed to 25° C. and held for 16 h. Water (288 L) was added to the batch while keeping the batch at 25° C., and the batch was cooled to 15° C. and agitated for an additional 4 hs. The batch was filtered, rinsed twice with water (2×80 L), and dried in a vacuum oven at 40° C. with nitrogen bleed for 24 h to give 2-chloro-4-{[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino}pyrimidine-5-carboxamide as white powder (23.3 kg, 86% yield). 1H NMR (DMSO-d6) δ 0.93 (d, J=5.7 Hz, 3H), 0.97-1.29 (m, 4H), 1.63-1.68 (m, 1H), 1.75-1.88 (m, 1H), 2.09-2.13 (m, 1H), 3.00-3.08 (m, 1H), 3.80-3.95 (m, 1H), 4.65 (d, J=5.1 Hz, 1H), 7.69 (br. s., 1H), 8.20 (br. s., 1H), 8.53 (s, 1H), 9.22 (d, J=7.5 Hz, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@H:11]([OH:16])[C:12]([O:14][CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:15][O:14][C:12](=[O:13])[C@@H:11]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Yield: 89.1 %

Procedure:
A solution of 2.48 g (10.00 mmol) of methyl (S)-4-(tert-butyldimethylsilyloxy)-2-hydroxybutanoate (J. Am. Chem. Soc. 2005 127, 1090-1091) in 50 ml of CH2Cl2 was treated with 2.09 ml (15.00 mmol, 1.5 eq) of triethylamine and at 0° C. during 5 min with 0.82 ml (10.50 mmol, 1.051 eq) of methanesulfonyl chloride. After 1 h at 0° C. the reaction was partitioned between 10% aq KH2PO4/Et2O (×3), the organic phases were washed with sat. aq. NaHCO3 solution (freshly prepared) and 10% aq. NaCl solution, dried over Na2SO4 and evaporated to give 2.91 g (89%) of the title compound as yellow oil. MS: 327.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[C:5]([Cl:8])=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]([CH:3]=1)[CH:9]=[O:10]
Reactant: OCc1cc(Br)cnc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.9 %

Procedure:
To a solution of (5-bromo-2-chloropyridin-3-yl)methanol (6.8 g, 30.6 mmol) in DCM (200 mL), was added Dess-Martin periodinane (32.4 g, 76.6 mmol) at 0° C. The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (0 to 30% EtOAc in petroleum ether) to afford 5.05 g of 5-bromo-2-chloronicotinaldehyde. LCMS [M+H]+ 221.1.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7](=[O:15])[C:8]2[CH:14]=[CH:13][CH:12]=[N:11][C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:17]1.C[Mg]Br.[Cl-].[NH4+]>O>[C:7]([C:8]1[C:9]([NH:10][C:5](=[O:6])[C:1]([CH3:4])([CH3:3])[CH3:2])=[N:11][CH:12]=[CH:13][CH:14]=1)(=[O:15])[CH3:17]
Reactant: C1CCOC1
Reactant: CC(C)(C)c1nc2ncccc2c(=O)o1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(=O)c1cccnc1NC(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-tert-butyl-4H-pyrido[2,3-d][1,3]oxazin-4-one (10.2 g, 50 mmol) and tetrahydrofuran (50 mL) was added methyl magnesium bromide (0.97 m tetrahydrofuran solution, 100 mL, 97 mmol) dropwise at −78° C., after the dropwise addition was finished, which was stirred at −78° C. for 30 minutes. To the reaction mixture were added a saturated aqueous solution of ammonium chloride and water, which was extracted with ethyl acetate, and the organic layer was washed with an aqueous solution of ammonium chloride. The solvent was evaporated under a reduced pressure and the precipitated solid was filtered to obtain the title compound (9.1 g)
Reaction SMILES: C[Si](I)(C)C.C[O:7][CH2:8][C@H:9]([CH3:38])[O:10][C:11]1[CH:12]=[C:13]([CH:23]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:37]=[CH:36][O:35][N:34]=3)=[CH:29][CH:28]=2)[CH:25]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1)=[O:15]>C(#N)C.C(OCC)(=O)C>[OH:7][CH2:8][C@H:9]([CH3:38])[O:10][C:11]1[CH:12]=[C:13]([CH:23]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:37]=[CH:36][O:35][N:34]=3)=[CH:29][CH:28]=2)[CH:25]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1)=[O:15]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(-c3ncon3)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H](CO)Oc1cc(Oc2ccc(-c3ncon3)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.5 %

Procedure:
Trimethylsilyl iodide (0.062 mL, 0.434 mmol) was added to a solution of 3-[(1S)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(1,2,4-oxadiazol-3-yl)phenoxy]benzamide (78 mg, 0.174 mmol) in acetonitrile (2 mL) and the reaction mixture allowed to stir at RT for 18 hours. The reaction was diluted with ethyl acetate (15 mL) and quenched by the addition of saturated aqueous sodium bicarbonate (20 mL). The organic phase was washed with saturated aqueous thiosulphate solution (20 mL) and dried (MgSO4). The volatiles were removed under reduced pressure and the resulting oil purified by chromatography on silica, eluting with 0-100% ethyl acetate in iso-hexane, to give the title compound as a colourless solid (64 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([Cl:17])[C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>C1C=CC=CC=1>[C:4]([C:3]1[C:2]([Cl:1])=[CH:15][C:14]([CH2:16][Br:36])=[CH:13][C:12]=1[Cl:17])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cc(Cl)c(C(=O)c2ccccc2)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1c(Cl)cc(CBr)cc1Cl
Yield: 57.7 %

Procedure:
A refluxing solution of 2,6-dichloro-4-methylbenzophenone (3.44 g, 13.0 mmol) and dibenzoylperoxide (325 mg, 1.34 mmol) in benzene (130 ml) was treated in portions with N-bromosuccinimide (2.75 g, 15.5 mmol). After 3 hours at reflux, the mixture was cooled and evaporated under vacuum. The residue was triturated with diethyl ether (150 ml), filtered, and evaporated under vacuum. The residue was chromatographed on a column of silica gel (250 g) eluted with 4:1 (v/v) hexane-dichloromethane to provide 2.58 g (58%) 4-benzoyl-3,5-dichlorobenzyl bromide, m.p. 111°-113° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.Cl[CH2:21][CH2:22][CH2:23][O:24][C:25]1[C:26]2[CH:27]=[CH:28][NH:29][C:30]=2[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]3[CH2:13][CH2:14][N:15]([CH2:21][CH2:22][CH2:23][O:24][C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)[CH2:16][CH:17]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: FC(F)(F)c1ccc2c(C3=CCNCC3)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1ccc2c(C3=CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 192 from 6-trifluoromethyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.50 g, 1.9 mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.39 g, 1.9 mmol) and potassium carbonate (0.29 g, 2.1 mmol). The product was isolated as a white foam. Yield 0.53 g (64%). mp 190°-195° C. FDMS m/e=440 (M+ of free base).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1)(=[O:4])=[O:3].S(=O)(=O)(O)O.[CH3:24]O>>[CH3:24][O:16][C:15](=[O:17])[CH2:14][CH2:13][C:12](=[O:18])[C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
4-[(methylsulfonyl)amino]γ-oxobenzenebutanoic acid IIe, (125 g, 0.46 mol) was placed in a flask with 2.5 L of methanol, and 4.6 g of concentrated sulfuric acid (0.047 mol) was added. The slurry was heated to 60° C. for 4 hr, during this period the solids went into solution. After 4 hrs, an aliquot was removed to monitor completion by HPLC. The reaction was determined complete when NMT 2% of the starting material remained. The solution was cooled to 21° C., allowing the product to crystallize. The slurry was cooled to 0° C., and the product was collected by filtration. The filter cake was washed with a mixture of 375 ml of methanol and 12.5 ml of triethylamine (×2), followed by 375 mL of methanol. The title product was obtained in 92% yield (99 area %). Melting point 181-183° C. 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.8 Hz, 2H), 3.58 (s, 3H), 3.2(s, 1H), 3.24 (t, J=6.4 Hz, 2H), 3.1 (s, 3H), 2.63 (t, J=6.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ C 196.8, 172.8, 143.0, 131.0; CH 129.6, 117.5; CH2 32.7, 27.6; CH3 51.3, 39.8; MS m/z calcd for C12H14NO5S 284.31 (M−H)+; found 284.00 (M−H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:19][OH:20])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[K+].C[O:24][C:25](=O)[CH:26]([OH:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[OH:1][CH:2]([CH2:19][OH:20])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:25](=[O:24])[CH:26]([OH:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCNCC(O)CO
Reactant: CCCCCCC(O)C(=O)OC
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCN(CC(O)CO)C(=O)C(O)CCCCCC

Procedure:
N-(2,3-dihydroxypropyl)-N-tetradecylamine (1.0 g, 0.0035 mole) and potassium hydroxide (0.01 g, 0.18 mmole) were heated to 85° C. under vacuum and methyl-2-hydroxyoctanoate (0.667 g, 0.0038 mole) was added dropwise to the reaction. The reaction was heated under vacuum for 5 hours. A waxy off-white solid was obtained (crude yield=1.33 g). The waxy solid was recrystalized from hot hexane (yield=0.4 g).
Reaction SMILES: O[CH2:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14]2.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[Cl:22][CH2:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14]2
Reactant: O=S(Cl)Cl
Reactant: OCC[C@@H]1CCCN1CCc1ccc2c(c1)CCC2
Solvent: ClC(Cl)Cl
Product: ClCC[C@@H]1CCCN1CCc1ccc2c(c1)CCC2
Yield: 91 %

Procedure:
A solution of (2S)-(2-hydroxyethyl)-1-[2-(indan-5-yl)ethyl]pyrrolidine (0.99 g, 3.8 mmol--see Preparation 17) and thionyl chloride (1 ml) in chloroform (15 ml) was heated under reflux for 3 hours and evaporated. The residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate solution and the organic layer was dried over magnesium sulphate and evaporated to give the title compound (956 mg, 91%) as a brown oil which was not characterised before use (Example 24).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12]C(OCC2C=CC=CC=2)=O)[C:7]1=[O:23])[CH3:5]>[Pd].CO>[NH2:12][C:8]1[C:7](=[O:23])[N:6]([CH:4]([CH3:5])[C:3]([O:2][CH3:1])=[O:24])[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C(C)n1cccc(NC(=O)OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)n1cccc(N)c1=O
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
A mixture of 2(S) methyl-2[3-benzyloxycarbonylamino-1,2-dihydro-2-oxo-1-pyridyl)propionate (49a) (2.75 g, 8.33 mmol), methanol (100 ml), and 10% palladium on carbon (300 mg) was stirred under an atmosphere of hydrogen for 30 min. The mixture was filtered and concentrated to afford 1.63 g (100%) of a colorless solid: 1H NMR (d6 -DMSO) δ 8.35 (1H, brs), 7.46 (1H, d), 7.22 (1H,d), 6.29 (1H, t), 5.22 (1H, q), 3.63 (3H, s), 1.55 (3H, d).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](I)[CH3:20]>CN(C)C=O>[CH2:1]([O:3][C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:19][CH3:20])=[O:7])[CH3:2]
Reactant: CCI
Reactant: CCOc1ncccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of the compound prepared in Example 284 (1.3 g) and cesium carbonate (2.53 g) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 2 hours and then treated with ethyl iodide (0.62 mL) at room temperature, and stirring continued for 18 hours. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and saturated aqueous solution of sodium bicarbonate. The combined organic extracts were washed with brine, dried and evaporated in vacuo to a yellow oil and purified by column chromatography on silica gel (10-50% ethyl acetate in hexane) to obtain the title compound (0.904 g) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][Br:13])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Br)cc1CBr
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A mixture of methyl 4-bromo-2-methylbenzoate (0.7 g, 0.003 mol), N-bromosuccinimide (0.65 g, 0.0037 mol) and benzoyl peroxide (0.038 g, 0.00016 mol) in carbon tetrachloride (30 mL) was refluxed under an atmosphere of nitrogen for 2 h. The mixture was cooled to RT, and filtered through silica gel eluting with dichloromethane followed by diethyl ether. The mixture was concentrated and the residue was purified by chromatography on silica gel with 30% EtOAc in hexanes to afford the desired product (0.86 g, 90%).
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:34])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]2([C:27]([O:29]CCCC)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])CCC.O[Li].O>>[C:27]([C:22]1([CH2:21][CH2:20][CH2:19][CH2:18][C:17](=[O:34])[CH2:16][CH2:15][CH2:14][CH2:13][C:8]2([C:6]([OH:7])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:23][CH2:24][CH2:25][CH2:26]1)([OH:29])=[O:28]
Reactant: CCCCOC(=O)C1(CCCCC(=O)CCCCC2(C(=O)OCCCC)CCCC2)CCCC1
Agent: [Li]O
Solvent: O
Product: O=C(CCCCC1(C(=O)O)CCCC1)CCCCC1(C(=O)O)CCCC1
Yield: 99.3 %

Procedure:
Compound 107g was prepared likewise Method D starting from 106g (7.25 g, 15.0 mmol) and LiOH.H2O (3.21 g, 76.4 mmol) to give 107g (5.46 g, 95% pure by 1H NMR, 94%, mp=99-103° C.) as a white solid. An analytical sample was obtained after recrystallization from iPr2O/heptane. mp=104-106° C. 1H NMR: δ 2.39 (t, J=6.9 Hz, 4H), 2.18-2.10 (m, 4H), 1.69-141 (m, 20H), 1.27-1.14 (m, 4H). 13C NMR: δ 211.1, 184.6 (2×), 53.9 (2×), 42.5 (2×), 39.0 (2×), 35.9 (4×), 25.7 (2×), 24.9 (4×), 24.0 (2×). Anal. calcd for C21H34O5: C, 68.82; H, 9.35, found: C, 68.78; H, 9.47.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[C:21]([C:23]4[O:24][C:25]([CH3:28])=[N:26][N:27]=4)[CH:20]=[CH:19][C:18]=3[CH3:29])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.I[CH2:33][CH3:34]>>[CH2:33]([N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[C:21]([C:23]3[O:24][C:25]([CH3:28])=[N:26][N:27]=3)[CH:20]=[CH:19][C:18]=2[CH3:29])=[CH:15][CH:16]=1)=[O:10])[CH3:34]
Reactant: COc1ccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1
Reactant: CCI
Product: CCN(Cc1ccc(OC)cc1)C(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
N-Ethyl-N-(4-methoxybenzyl)-2′-methyl-5′-(5-methyl- 1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(4-methoxybenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodoethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.75,(1H, s), 7.55-7.47,(5H, m), 7.30,(1H, m), 6.92,(2H, d), 4.64-4.45,(2H, m), 3.74,(3H, s), 3.34-3.16,(2H, m), 2.55,(3H, s), 2.31,(3H, s), 1.05,(3H, b). LCMS; retention time 3.54 min, MH+ 442.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[C:4]([CH3:17])[CH:3]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22](I)=[C:21]([CH3:26])[CH:20]=1>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:16]=[CH:15][C:5]([CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[C:4]([CH3:17])[CH:3]=2)=[C:21]([CH3:26])[CH:20]=1
Reactant: Cc1cc(Br)ccc1CO[Si](C)(C)C(C)(C)C
Reactant: Cc1cc(Br)ccc1I
Product: Cc1cc(-c2ccc(Br)cc2C)ccc1CO[Si](C)(C)C(C)(C)C
Yield: 34 %

Procedure:
In accordance with Example 19-(2), but using [(4-bromo-2-methylbenzyl)oxy](tert-butyl)dimethylsilane instead of tert-butyl 5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylate, and 4-bromo-1-iodo-2-methylbenzene instead of tert-butyl[(4-iodobenzyl)oxy]dimethylsilane, the title compound (yield 34%) was afforded as a yellow oil.
Reaction SMILES: [C:1]([N:8]1[CH2:25][CH2:24][C@@:15]23[C:16]4[CH:17]=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[C:1]([N:8]1[CH2:25][CH2:24][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OC(=O)C(C)(C)C)cc13
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of N-Boc-3-hydroxymorphinan 2 (20 mg, 0.058 mmol) and triethylamine (9 μL, 0.064 mmol) in dry CH2Cl2 (1 mL) was slowly added pivaloyl chloride (8 μL, 0.064 mmol) at 0° C. and the mixture stirred for 1 h. Solvent was removed under reduced pressure. The crude product was purified on a silica gel column chromatography (5:1 n-Hexane/EtOAc) to give a colorless oil (23 mg, 92% yield): 1H NMR (300 MHz, CDCl3) 0.9˜1.7 (m, 29H); 2.34 (d, J=9.9 Hz, 1H); 2.52˜2.73 (m, 2H); 3.09˜3.17 (m, 1H); 3.73˜3.84 (m, 1H); 6.83˜6.87 (m, 1H); 6.95 (s, 1H); 7.09˜7.12 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]=[C:7]2[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2=[O:14])=[CH:4][CH:3]=1.[H][H]>C(O)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2=[O:14])=[CH:15][CH:16]=1
Reactant: CC1(C)CCC(=Cc2ccc(Cl)cc2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CCC(Cc2ccc(Cl)cc2)C1=O

Procedure:
5 g of 2-(4-chlorobenzylidene)-5,5-dimethylcylopentanone (prepared in Example 5) was dissolved in 40 ml of ethanol, and 60 mg palladium-carbon (10%) was added to the mixture. The hydrogenation reaction was carried out under normal pressure until theoretical amount of hydrogen was absorbed.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22](Br)=[CH:21][C:20]=1[O:27][CH3:28])[C:14](=[O:29])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:20]([O:27][CH3:28])=[CH:21][C:22]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([F:30])[CH:36]=3)=[C:23]([Cl:25])[CH:24]=1)[C:14](=[O:29])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1cc(Br)c(Cl)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Temperature: 90 °C
Yield: 81 %

Procedure:
A screw cap vial was charged with 6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinolin-2(1H)-one (1.22 g, 2.506 mmol), (3-fluorophenyl)boronic acid (0.526 g, 3.76 mmol), potassium carbonate (1.039 g, 7.52 mmol) and Pd(Ph3P)4 (0.290 g, 0.251 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (9.4 ml) and water (3.1 ml) were added in sequence. The reaction was heated to 90° C. for 1 hour. The mixture was diluted with NH4Cl and extracted with EtOAc (3×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Ultra SNAP column, 25-g silica gel loading column, 0-50% EtOAc/Heptane) to give 6-(benzylthio)-1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)quinolin-2(1H)-one (1.02 g, 2.03 mmol, 81% yield) as a cream-colored solid. m/z (ESI) 502.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]([C:13](Cl)=[N:14][OH:15])=[C:11]([I:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:23](C)C=O.N.C(OCC)(=O)C>O>[CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]([C:13]([NH:14][OH:15])=[NH:23])=[C:11]([I:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(Cl)=NO)c(I)cc1OCc1ccccc1
Reactant: CN(C)C=O
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C(=N)NO)c(I)cc1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a mixture of 4-benzyloxy-N-hydroxy-2-iodo-5-methoxy-benzimidoylchloride and N,N-dimethylformamide (110 mL) was added a 28% ammonia in water (12 mL) under ice-bath cooling. After stirring for 3 hours under ice-bath cooling, water and ethyl acetate were added to the mixture. The separated organic layer was washed with water and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with hexane:diethyl ether=1:4 to give the title compound (9.3 g).