Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:5]=[CH:4][NH:3][C:2]=1/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9].[O-]P(OP([O-])([O-])=O)(=O)[O-].[NH2:20][C@@H](CCC(N[C@H](C(NCC(O)=O)=O)CS)=O)C(O)=O>N[C@H](C(O)=O)CC1N=CNC=1>[NH3:3].[NH2:20][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][C:2]1[N:3]=[CH:4][NH:5][CH:1]=1
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: O=C(O)/C=C/c1cnc[nH]1
Agent: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: O=P([O-])([O-])OP(=O)([O-])[O-]
Product: N
Reaction time: 0.08 h

Procedure:
HAL enzyme activity can be determined as described in Baedeker & Schulz (Eur. J. Biochem 2002, 269, 1790-1797), wherein enzyme activity was determined as the rate of urocanate formation, measured spectrophotometrically at 277 nm. For a standard assay, the enzyme was preincubated at 25° C. for 5 min in 2.5 mL buffer containing 0.1 M pyrophosphate (pH 9.3), 10 μM ZnC12 and 2 mM glutathione. The reaction was started by adding 200 μL of 0.5 M histidine solution and then monitored for approximately 5 minutes.
Reaction SMILES: [CH3:1][C:2]([CH3:46])=[CH:3][CH2:4][CH2:5][C@@:6]1([CH3:45])[O:15][C:14]2[C:13]([CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[C:12]3[O:21][C@@:22]45[C@@:32]6([CH2:37]/[CH:38]=[C:39](\[C:41]([OH:43])=[O:42])/[CH3:40])[O:33][C:34]([CH3:36])([CH3:35])[C@@H:23]4[CH2:24][C@H:25]([C:30]6=[O:31])[CH:26]=[C:27]5[C:28](=[O:29])[C:11]3=[C:10]([OH:44])[C:9]=2[CH:8]=[CH:7]1.[CH2:47](Cl)CCl.CO.O>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:1][C:2]([CH3:46])=[CH:3][CH2:4][CH2:5][C@@:6]1([CH3:45])[O:15][C:14]2[C:9](=[C:10]([OH:44])[C:11]3[C:28](=[O:29])[C:27]4[C@@:22]5([C@@:32]6([CH2:37]/[CH:38]=[C:39](\[C:41]([O:43][CH3:47])=[O:42])/[CH3:40])[O:33][C:34]([CH3:35])([CH3:36])[C@@H:23]5[CH2:24][C@H:25]([C:30]6=[O:31])[CH:26]=4)[O:21][C:12]=3[C:13]=2[CH2:16][CH:17]=[C:18]([CH3:19])[CH3:20])[CH:8]=[CH:7]1
Reactant: ClCCCl
Reactant: CC(C)=CCC[C@]1(C)C=Cc2c(O)c3c(c(CC=C(C)C)c2O1)O[C@]12C(=C[C@@H]4C[C@H]1C(C)(C)O[C@@]2(C/C=C(/C)C(=O)O)C4=O)C3=O
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)/C(C)=C\C[C@@]12OC(C)(C)[C@@H]3C[C@@H](C=C4C(=O)c5c(O)c6c(c(CC=C(C)C)c5O[C@]431)O[C@](C)(CCC=C(C)C)C=C6)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
A mixture of gambogic acid (200 mg, 0.32 mmol), DMAP (78 mg, 0.64 mmol), EDC (123 mg, 0.64 mmol) and methanol (102 mg, 3.2 mmol) in THF (5 mL) was stirred at room temperature for 3 h. The solution was poured into water (10 mL) and was extracted with ethyl acetate (3×10 mL). The combined organic layer was dried and concentrated to give the crude product, which was purified by chromatography (SiO2, EtOAc/Hexane 1:5) to give the title compound (196 mg, 95%). 1H NMR (CDCl3): 12.85 (s, 1H), 7.54 (d, J=6.9 Hz, 1H), 6.67 (d, J=10.5 Hz, 1H), 5.94 (t, J=6 Hz, 1H), 5.43 (d, J=10.2 Hz, 1H), 5.05 (m, 2H), 3.49 (m, 1H), 3.43 (s, 3H), 3.35-3.10 (s, 2H), 3.00 (t, J=7.2 Hz, 1H), 2.52 (d, J=10.2 Hz, 1H), 2.32 (quar, J1=4.8 Hz, 1H), 2.02 (m, 1H), 1.74 (s, 3H), 1.69 (s, 3H), 1.67-1.64 (m, 9H), 1.55 (s, 3H), 1.44 (s, 3H), 1.29 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH:3]1([C@@H:6]2[O:16][CH2:15][C:9]3=[N:10][O:11][C@@H:12]([CH2:13][OH:14])[C@@H:8]3[CH2:7]2)[CH2:5][CH2:4]1.I[CH3:18].O>CN(C)C=O>[CH:3]1([C@@H:6]2[O:16][CH2:15][C:9]3=[N:10][O:11][C@@H:12]([CH2:13][O:14][CH3:18])[C@@H:8]3[CH2:7]2)[CH2:4][CH2:5]1
Reactant: OC[C@@H]1ON=C2CO[C@@H](C3CC3)C[C@H]21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@@H]1ON=C2CO[C@@H](C3CC3)C[C@H]21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in oil, 395 mg, 9.88 mmol) was slurried in N,N-dimethylformamide (30 mL) and cooled in an ice bath. A solution of rel-[(3R,3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazol-3-yl]methanol (C37) (1.30 g, 6.59 mmol) in minimal N,N-dimethylformamide was added drop-wise, and the reaction mixture was stirred at 0° C. for 30 minutes. Iodomethane (0.45 mL, 7.2 mmol) was then added in a drop-wise manner, and the reaction was allowed to proceed for an additional 30 minutes at 0° C. Water was added, and the mixture was warmed to room temperature and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 60% ethyl acetate in heptane) provided the product as an oil. Yield: 1.0 g, 4.7 mmol, 71%. LCMS m/z 212.1 [M+H+].
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.Br.[NH2:28][C:29]1[S:30][C:31]([Br:34])=[CH:32][N:33]=1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[Br:34][C:31]1[S:30][C:29]([NH:28][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:33][CH:32]=1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1ncc(Br)s1
Agent: Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ncc(Br)s2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid (prepared in Example 130, 300 mg, 1.01 mmol) and dry N,N-dimethylformamide (2 drops) in methylene chloride (3 mL) was cooled to 0° C. and then treated dropwise with oxalyl chloride (115 μL, 1.32 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo. The resulting yellow oil was dissolved in a small amount of methylene chloride and then slowly added to a solution of 2-amino-5-bromothiazole monohydrobromide (395 mg, 1.52 mmol) and triethylamine (424 μL, 3.04 mmol) in N,N-dimethylformamide (3 mL). The resulting reaction mixture was then stirred at 25° C. for 15 h. The resulting reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL), and the layers were separated. The aqueous layer was further extracted with ethyl acetate (50 mL). The combined organic layers were then dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 hexanes/ethyl acetate) afforded the N-(5-bromo-thiazol-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide (160 mg, 35%) as a tan foam: mp 73–75° C. (foam to gel); EI-HRMS m/e calcd for C18H21BrN2O3S2 (M+) 456.0177, found 456.0176.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=1.C(O)C#C.C1C2C(=CC=CC=2)C=CC=1O>>[CH3:18][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:16])=[CH:11][CH:10]=1
Reactant: COc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: C#CCO
Agent: Oc1ccc2ccccc2c1
Product: COc1ccc(C(=O)c2ccc(C)cc2)cc1

Procedure:
4-methyl-4'methoxybenzophenone was prepared from anisole and p-toluoyl chloride using the procedure described in Comparative Example 2. The resulting ketone was converted to the propargyl alcohol and then reacted with 2-naphthol as in Comparative Example 2 to produce 2.1 grams of light yellow crystals having a melting range of 146-147° C. NMR analysis confirmed the product to be 3(4-methylphenyl)-3-(4-methoxyphenyl)-3H-naphtho[2,1-b]pyran.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:32]1[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[N:33]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:24]([N:15]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:16][CH2:17][CH:18]1[CH2:19][CH2:20][N:21]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[N:33]=2)[CH2:22][CH2:23]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(CN(CCC2CCNCC2)Cc2ccccc2)cc1
Reactant: Cc1cc(Cl)nc(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: Cc1cc(N2CCC(CCN(Cc3ccccc3)Cc3ccccc3)CC2)nc(C)n1
Reaction time: 16 h
Yield: 49 %

Procedure:
A mixture of N,N-dibenzyl-2-(piperidin-4-yl)ethanamine trifluoroacetate (see stage 6 AMN-01) (6.372 mmol, 1.0 eq), 4-chloro-2,6-dimethylpyrimidine (1.17 g, 8.283 mmol, 1.3 eq) and K2CO3 (2.64 g, 19.116 mmol, 3.0 eq) in acetone (50 ml) was stirred for 16 hours at boiling temperature. After monitoring by TLC, the mixture was concentrated, diluted with DCM (100 ml) and washed with water (50 ml) and sat. NaCl solution (50 ml). The org. phase was dried over sodium sulfate and concentrated under reduced pressure, and the crude product so obtained was purified by column chromatography (silica gel, 2% MeOH in DCM). Yield: 49% (1.3 g, 3.14 mmol)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1>C(O)C.[Pd]>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: CN(C)CCCc1ccc(C(=O)/C=C/c2ccc(Cl)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCCc1ccc(C(=O)CCc2ccc(Cl)cc2)cc1
Product: Cl
Yield: 85.9 %

Procedure:
3 g of (E)-3-(4-chlorophenyl)-4'-[3-(dimethylamino)propyl]acrylophenone were dissolved in 100 ml of ethanol and, after the addition of 300 mg of 5 percent palladium on carbon, hydrogenated. After the uptake of the theoretical amount of hydrogen the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in ethanol and converted using 10M ethanolic hydrochloric acid solution into the hydrochloride which was precipitated by the addition of hexane. After recrystallization from ethyl acetate/ethanol 5:1 there were obtained 1.44 g (43%) of 3-(4-chlorophenyl)-4'-[3-(dimethylamino)propyl]propiophenone hydrochloride; m.p. 161°-164°.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[CH2:22][CH:21]3[N:17]([CH2:18][CH2:19][CH2:20]3)[C:16]3[N:23]=[C:24]([NH:27][CH2:28][CH3:29])[N:25]=[CH:26][C:15]=3[C:14]2=[O:30])[CH:8]=1)(=[O:3])[CH3:2].ClC(Cl)(Cl)C#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[CH2:28]([NH:27][C:24]1[N:25]=[CH:26][C:15]2[C:14](=[O:30])[N:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:6]4[O:3][C:1]([CH3:2])=[N:4][N:5]=4)[CH:8]=3)[CH2:22][CH:21]3[N:17]([CH2:18][CH2:19][CH2:20]3)[C:16]=2[N:23]=1)[CH3:29]
Reactant: CCNc1ncc2c(n1)N1CCCC1CN(c1cccc(C(=O)NNC(C)=O)c1)C2=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: N#CC(Cl)(Cl)Cl
Product: CCNc1ncc2c(n1)N1CCCC1CN(c1cccc(-c3nnc(C)o3)c1)C2=O
Temperature: 150 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
Compound 19 (136 mg, 0.320 mmol) obtained in Example 19 was dissolved in acetonitrile (2.1 mL), and the mixture was stirred for 1 hour under microwave (CEM; Discover, 300 watts, 150° C.) irradiation after adding trichloroacetonitrile (0.0646 mL, 0.640 mmol) and triphenylphosphine-supported resin (Triphenylphosphine, polymer-supported; 3.08 mmol P/G, 320 mg, 0.960 mmol). The resin was separated by filtration, and the filtrate was collected, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (Compound 20) (108 mg, 83%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[CH2:11][CH:12]([CH3:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:5][CH:4]=1)#[N:2].Br[CH2:21][CH2:22][CH2:23][O:24][CH3:25]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:21][CH2:22][CH2:23][O:24][CH3:25])[C:10](=[O:19])[CH2:11][CH:12]([CH3:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)CC(C)CC(=O)Nc1ccc(C#N)cc1
Reactant: COCCCBr
Product: COCCCN(C(=O)CC(C)CC(=O)OC)c1ccc(C#N)cc1

Procedure:
Using methyl 5-(4-cyanophenylamino)-3-methyl-5-oxopentanoate and 1-bromo-3-methoxypropane, and by the reaction and purification in the same manner as in the method described in Step 2 of Example 8, methyl 5-((4-cyanophenyl)(3-methoxypropyl)amino)-3-methyl-5-oxopentanoate was obtained.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1.C([O-])(=O)C.[Na+].[Br:19]Br.O>C(O)(=O)C>[Br:19][C:8]1[CH:9]=[C:4]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2][NH:1][C:5]2=[N:6][CH:7]=1
Reactant: BrBr
Reactant: COC(=O)c1n[nH]c2ncccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1n[nH]c2ncc(Br)cc12
Temperature: 120 °C
Yield: 31 %

Procedure:
A mixture of methyl 1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XVI) (0.177 g, 1 mmol), sodium acetate (0.492 g, 6 mmol) and bromine (0.308 mL, 6 mmol) in glacial acetic acid (5 mL) was heated overnight at 120° C. in a sealed tube. The solution was cooled and poured into water. The solids formed were filtered, washed with water and dried at room temperature under vacuum. The crude product was purified on a flash silica gel column (100% DCM→2:98 MeOH:DCM) to produce methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XVII) as a white solid (78 mg, 0.31 mmol, 30% yield). 1H NMR (CDCl3) δ ppm 3.95 (s, 3H), 8.62 (d, J=3.01 Hz, 1H), 8.73 (d, J=3.01 Hz, 1H); ESIMS found for C8H6BrN3O2 m/z 256.3 (M+H).
Reaction SMILES: FC(F)(F)C1C=C(NC2C(=O)C(=O)C=2N[C@@H](C2C3C(=CC=C(OC)C=3)N=CC=2)[C@H]2CC3CCN2CC3C=C)C=C(C(F)(F)F)C=1.[C:46]([O:50][C:51](=[O:75])[C:52]1[CH:57]=[CH:56][C:55]([C:58](=[O:73])/[CH:59]=[C:60](\[C:65]2[CH:70]=[C:69]([Cl:71])[CH:68]=[C:67]([Cl:72])[CH:66]=2)/[C:61]([F:64])([F:63])[F:62])=[CH:54][C:53]=1[CH3:74])([CH3:49])([CH3:48])[CH3:47].[N+:76]([CH3:79])([O-:78])=[O:77].O>ClCCCl>[C:46]([O:50][C:51](=[O:75])[C:52]1[CH:57]=[CH:56][C:55]([C:58](=[O:73])[CH2:59][C@:60]([C:65]2[CH:70]=[C:69]([Cl:71])[CH:68]=[C:67]([Cl:72])[CH:66]=2)([CH2:79][N+:76]([O-:78])=[O:77])[C:61]([F:62])([F:64])[F:63])=[CH:54][C:53]=1[CH3:74])([CH3:49])([CH3:48])[CH3:47]
Reactant: C[N+](=O)[O-]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Agent: C=CC1CN2CCC1C[C@@H]2[C@@H](Nc1c(Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(=O)c1=O)c1ccnc2ccc(OC)cc12
Solvent: ClCCCl
Solvent: O
Product: Cc1cc(C(=O)C[C@@](C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 3-(3,5-Bis-trifluoromethyl-phenylamino)-4-{[(S)-(6-methoxy-quinolin-4-yl)-((R)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methyl]-amino}-cyclobut-3-ene-1,2-dione (20 mg, prepared according to the literature: Org. Lett., 2010, 12 (23), 5450-5453) in 1,2-dichloroethane (1.5 mL) under argon, was added 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (300 mg) and nitromethane (0.35 ml). The solution was refluxed for 24 hours then more 3-(3,5-Bis-trifluoromethyl-phenylamino)-4-{[(S)-(6-methoxy-quinolin-4-yl)-((R)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methyl]-amino}-cyclobut-3-ene-1,2-dione (20 mg) was added. The solution was refluxed for 48 hours then more nitromethane (0.35 mL) and 3-(3,5-Bis-trifluoromethyl-phenylamino)-4-{[(S)-(6-methoxy-quinolin-4-yl)-((R)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methyl]-amino}-cyclobut-3-ene-1,2-dione (25 mg) were added. The solution was refluxed for another 16 hours and then the heating was stopped. The reaction mixture was cooled to room temperature and water was added. The resulting mixture was extracted with dichloromethane and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane) to afford 4-[(S)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester (127 mg). Chiral HPLC analysis (Chiralpack IA, Heptane:2-propanol:diethylamine=90:10:0.1, 1 ml/min, retention time 7.52 minutes (major enantiomer), 6.30 minutes (minor enantiomer) indicated that the reaction proceeded with 93% enantioselectivity in favor of the S enantiomer.
Reaction SMILES: [CH2:1]([CH:9]([C:18]#[N:19])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[CH2:26]=[O:27].[OH-].C([N+](CC)(CC)CC)C1C=CC=CC=1>O>[C:18]([C:9]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:26][OH:27])#[N:19]
Reactant: C=O
Reactant: CCCCCCCCC(C#N)c1ccc(Cl)cc1Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCC(C#N)(CO)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To an ice cold stirred solution of α-n-octyl-2,4-dichlorobenzyl cyanide (40 g., 0.14 mole) in 250 ml. of pyridine containing a suspension of paraformaldehyde (21 g., 0.7 mole) is added 1 ml. of benzyl triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 72 hours. The reaction mixture is poured into 2 liters of water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 40 g. of a thick oil.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[CH:18]OC)[CH2:15]1)([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.[C:21](=O)(O)[O-:22].[Na+]>O1CCCC1.Cl>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][CH:21]=[O:22])[CH2:15]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])O
Reactant: COC=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CCC1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
A solution of 1-benzhydryl-3-methoxymethylene-azetidine (0.19 g, 0.88 mmol) in tetrahydrofuran (20 mL) and 1N hydrogen chloride (10 mL) was refluxed overnight. The mixture was neutralized with saturated sodium bicarbonate and extracted with methylene chloride (3×50 mL). The combined organic extracts were washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford 0.17 g of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][C@H:2]([C@H:17]([CH3:20])[CH2:18][CH3:19])[C:3](N1[C@@H](C2C=CC=CC=2)COC1=O)=[O:4].O[Li].O.OO.[OH:26]S([O-])=O.[Na+]>CCCCCC.O.O1CCCC1>[CH3:1][C@H:2]([C@H:17]([CH3:20])[CH2:18][CH3:19])[C:3]([OH:4])=[O:26]
Reactant: O=S([O-])O
Reactant: CC[C@@H](C)[C@@H](C)C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC[C@@H](C)[C@@H](C)C(=O)O
Temperature: 15 °C

Procedure:
A 20 L jacketed flask was fit with a gas inlet. A nitrogen purge was begun over the reactor and maintained throughout the process. To the flask was charged 450 g (1.634 mol) of (2R,3R,4S)-3-(2,3-dimethyl-pentanoyl)-4-phenyl-oxazolidin-2-one and 3.375 L tetrahydrofuran. The contents of the reactor were stirred at 15° C. In a separate 3 L round bottom flask, placed in an ice bath, was charged 500 mL of water, 137 g (3.269 mol) of LiOH—H2O and 942 mL (9.81 mol) of 30% wt/wt H2O2. The contents of the 3 L round bottom flask were stirred for 3 minutes and then poured into the 20 L jacketed reactor at a rate such that the temperature did not exceed 25° C. The reaction was stirred at 15° C. for 2 hours and then raised to 25° C. and stirred for an additional 2 hours. The jacket temperature of the reactor was set to −20° C. To the reaction was added 1.66 L of saturated NaHSO3 at a rate such that the temperature of the reaction did not exceed 25° C. The layers were separated. The aqueous layer was extracted 2× with 1 L aliquots of MTBE. The organic phases were combined and concentrated to give a solid/oil mixture. The solid/oil mixture was slurried in 1.7 L of hexane. The slurry was filtered and the collected solids were washed with 1.7 L of hexane. The hexane filtrates were extracted 2× with 1.35 L aliquots of 1N NaOH. The aqueous extracts were combined and extracted with 800 mL of dichloromethane. The aqueous layer was then acidified with 240 mL of concentrated hydrochloric acid. The aqueous solution was extracted 2× with 1 L aliquots of dichloromethane. The organic extracts were combined, dried over MgSO4 and concentrated to give 201 g of the titled compound: 1H-NMR (DMSO) 11.925 (bs, 1H), 2.204-2.135 (m, 1H), 1.556-1.490 (m, 1H), 1.382-1.300 (m, 1H), 1.111-1.000 (m, 1H), 0.952-0.934 (d, 3H, J=7.018), 0.809-0.767 (m, 6H); Gas Chromatogram 9.308 minutes, 98.91% area; Anal Calc'd for C7H14O2: C, 64.58; H, 10.84; N, 0. Found: C, 64.39; H, 10.77; N, 0.18; MS (Ion Mode: APCI) m/z=131 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[CH:20]([O:19][CH:13]([CH2:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([CH2:3][CH2:2][O:1][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([CH3:32])=[CH:24][CH:25]=2)=[O:31])[CH:5]=1)[C:14]([OH:16])=[O:15])([CH3:21])[CH3:22]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccc(C)cc1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:18])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([CH3:17])=[N:7]2.Br[C:20]1C(F)=CC=C2C=1NC(=O)C(C)=N2.C(N)(CC)(C)C>CS(C)=O>[Br:1][C:2]1[C:3]([F:18])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH2:14][CH3:20])([CH3:15])[CH3:16])[C:8]([CH3:17])=[N:7]2
Reactant: Cc1nc2ccc(F)c(Br)c2[nH]c1=O
Reactant: Cc1nc2ccc(F)c(Br)c2nc1NC(C)(C)C
Agent: CCC(C)(C)N
Solvent: CS(C)=O
Product: CCC(C)(C)Nc1nc2c(Br)c(F)ccc2nc1C
Yield: 81 %

Procedure:
This compound (580 mg, 1.78 mmol, 81% yield) as an orange amorphous solid was prepared according to the procedure described for Intermediate 605a, using 5-bromo-3-chloro-6-fluoro-2-methylquinoxaline (600) (607 mg, 2.20 mmol) and tert-amylamine (Aldrich Chemical Company) (1.29 mL, 11.02 mmol) in DMSO (5.0 mL) as the starting materials. 1H NMR (400 MHz, CDCl3) δ ppm 7.75 (1H, dd, J=9.0, 5.7 Hz), 7.15 (1H, t, J=8.7 Hz), 4.74 (1H, br. s.), 2.54 (3H, s), 2.09 (2H, q, J=7.4 Hz), 1.58 (6H, s), 0.88 (3H, t, J=7.5 Hz). 19F NMR (376 MHz, CDCl3) δ ppm −103.39 (1F, s). m/z (ESI, +ve ion) 326.0/328.0.
Reaction SMILES: C1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[CH:10][O:9][CH:8]=2)=[CH:3][CH:2]=1.Cl.BrC1C=C[N:23]=CC=1.O1C=CC(B(O)O)=C1>>[O:9]1[CH:10]=[CH:11][C:7]([C:4]2[CH:5]=[CH:6][N:23]=[CH:2][CH:3]=2)=[CH:8]1
Reactant: Brc1ccncc1
Reactant: c1ccc(-c2ccc(-c3ccoc3)cc2)cc1
Agent: Cl
Agent: OB(O)c1ccoc1
Product: c1cc(-c2ccoc2)ccn1
Yield: 100 %

Procedure:
According to the procedure described in Example 1(a) for the preparation of 3-biphenyl-4-yl-furan, 4-bromopyridine hydrochloride (500 mg, 2.57 mmol) was coupled to fresh 3-furanboronic acid (see Thompson, W. J.; Gaudino, G. J. Org. Chem. 1984, 49, 5237-5243) to furnish 373 mg(100%) of crude 4-furan-3-yl-pyridine as an unstable solid that was used immediately. NMR and IR matched that of literature (see Ribereau, P.; Queguiner, G. Can. J. Chem. 1983, 61, 334-342 and Ishikura, M.; Ohta, T.; Terashima, M. Chem. Pharm. Bull. 1985, 33, 4755-4763).