Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH3:12].C[O:14][B:15](OC)[O:16]C>C1COCC1.BrCCBr.O>[CH3:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[B:15]([OH:16])[OH:14]
Reactant: Cc1cc(F)ccc1Br
Reactant: COB(OC)OC
Agent: II
Agent: [Mg]
Solvent: BrCCBr
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1B(O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To dry magnesium (113 g, 46.4 mmol) in 25 mL THF was added a small amount of 1,2-dibromoethane (2 drops) and iodine (2crystals). 1-Bromo-4-fluoro-2-methylbenzene (4.95 mL, 39.15 mmol) was added the resulting solution was refluxed for 4 h. The solution was cooled to RT and transferred by syringe to a solution of trimethylborate (4.5 mL, 40 mmol) in 20 mL THF at −78° C. The solution was warmed to RT and stirred for 2 days. Water (200 mL) was added and the mixture was concentrated (to remove most of the organics). The mixture was then treated with 2N HCl (200 mL) and stirred 2 hrs. The suspension was extracted with ethyl ether, dried over MgSO4, filtered and concentrated to give 2-methyl-4-fluoro-phenylboronic acid. LC1: 1.72 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[CH3:42][O:43][CH2:44][C:45](Cl)=[O:46]>C1COCC1.C(OCC)(=O)C>[F:32][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:45](=[O:46])[CH2:44][O:43][CH3:42])[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1([C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[O:23])[CH2:21][CH2:20]1)=[O:18]
Reactant: COCC(=O)Cl
Reactant: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCC(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
To a solution of N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (130 mg, 0.29 mmol) in 10 mL, of anhydrous tetrahydrofuran was added diisopropylethylamine (75 mg, 0.58 mmol). A solution of methoxyacetyl chloride (34.5 mg, 0.32 mmol) in THF (1 mL) was added drop wise at 0° C. The resultant reaction mixture was stirred at R.T. for 0.5 h. It was diluted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated. The residue was purified by prep-TLC to give N-(2,5-difluoro-4-((2-(2-methoxyacetamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (75 mg, 50% yield). 1H NMR (400 MHz, CDCl3): δ 9.79 (s, 1H), 8.89 (s, 1H), 8.53 (s, 1H), 8.30 (dd, J=12.0, 7.2 Hz, 1H), 8.17 (d, J=5.6 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.49-7.45 (m, 2H), 7.07-6.99 (m, 3H), 6.64 (dd, J=5.6, 2.4 Hz 1H), 3.98 (s, 2H), 3.49 (s, 3H), 1.78-1.66 (m, 4H); MS (ESI): m/z 515.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22](=[O:24])[CH3:23])([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](OC)(=[O:30])[C:26]([O:28]C)=[O:27].[H-].[Na+].Cl>C(COC)OC.C1COCC1>[ClH:21].[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22](=[O:24])[CH2:23][C:25](=[O:30])[C:26]([OH:28])=[O:27])([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C1(Cc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Reactant: COC(=O)C(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=C(O)C(=O)CC(=O)C1(Cc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A solution of N-Benzyl-4-Acetyl-4-(4-Chlorobenzyl)piperidine (600 mg, 1.75 mmol) and dimethyl oxalate (310 mg, 2.63 mmol) in dimethoxyethane (20 mL) was treated with sodium hydride (105 mg of a 60% dispersion in mineral oil, 2.63 mmol) and heated to reflux for 3 hours. The reaction was then cooled to room temperature, poured into 1N aqueous HCl (200 mL) and extracted with ethyl ether (1×50 mL). The ether extract was discarded. The pH of the aqueous phase was adjusted to pH 8 and extracted with ethyl acetate (3×200 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The crude ester thus obtained was dissolved in THF (5 mL) and 3N HCl (20 mL) and heated to reflux for 1 hour. The reaction was then cooled to room temperature, and concentrated at reduced pressure. The residue was triturated with tetrahydrofuran and the solid collected by filtration and crystallized from isopropanol to give 200 mg of the title compound. mp. 189°-181° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[BH4-].[Na+].O.C(O)(=O)C>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)C(=Cc1ccc(Cl)cc1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)C(O)C(=Cc1ccc(Cl)cc1)n1cncn1
Reaction time: 3 h
Yield: 69 %

Procedure:
The II-A isomer (2.9 g, 0.01 mole; m.p. 108°-109° C.) of 1-(4-chlorophenyl)-4,4-dimethyl-2-(1,2,4-triazole-1-yl)-1-pentene-3-one (Compound No. 1') was dissolved in methanol (50 ml). Sodium borohydride (0.38 g, 0.01 mole) was added thereto while keeping the temperature of the reaction solution at 20° C. or less with ice-cooling. The reaction mixture was kept at 20° C. for 3 hours, and then decomposed with addition of water (100 ml) and acetic acid (1 ml). The organic layer was extracted with ethyl acetate (100 ml), and the extract was washed with a 5% aqueous sodium hydrogen carbonate solution (50 ml) and dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure, and the residue obtained was recrystallized from isopropanol to obtain 2.0 g (yield 69%) of the I'-A isomer having a melting point of 153°-155° C. The elementary analysis and NMR spectrum of the compound are shown below.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([Cl:18])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I>[NH2:10][C:8]1[N:7]([C:12]2[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([Cl:18])[CH:17]=2)[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=1
Reactant: Oc1cc(Cl)cc(Br)c1
Reactant: CC(C)(C)c1cc(N)[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Product: CC(C)(C)c1cc(N)n(-c2cc(O)cc(Cl)c2)n1
Temperature: 110 °C
Yield: 58 %

Procedure:
A microwave vial containing 3-tert butyl-1h-pyrazol-5-amine (559 mg, 4.02 mmol), Intermediate 62a (1.00 g, 4.82 mmol), copper(I) iodide (38 mg, 0.20 mmol) and potassium carbonate (1.16 g, 8.44 mmol) was repeatedly purged with argon. Trans-N,N′-dimethylcyclohexane-1,2-diamine (126 μL, 0.80 mmol) was added and the mixture was re-purged with argon. Degassed toluene (4 mL) was added and the resulting suspension was stirred and heated at 110° C. for 24 h. The cooled suspension was passed through Celite pad and diluted with water and extracted with EtOAc. The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-50% EtOAc in cyclohexane, to give the title compound (620 mg, 62%). LCMS (Method 3): Rt 3.13 min, m/z 266 [MH+].
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:33][CH3:34])=[N:28][CH:29]=[C:30](Cl)[CH:31]=4)=[CH:24][N:23]=[C:22]([N:35]4[CH2:38][CH:37]([F:39])[CH2:36]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:43][C:44]1[C:48](B2OC(C)(C)C(C)(C)O2)=[C:47]([CH3:58])[NH:46][N:45]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[Na+].O.C(OCC)(=O)C>[Pd](Cl)Cl.O.C1COCC1>[F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:33][CH3:34])=[N:28][CH:29]=[C:30]([C:48]5[C:44]([CH3:43])=[N:45][NH:46][C:47]=5[CH3:58])[CH:31]=4)=[CH:24][N:23]=[C:22]([N:35]4[CH2:38][CH:37]([F:39])[CH2:36]4)[N:21]=3)[C@H:14]2[CH3:40])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ncc(Cl)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ncc(-c2c(C)n[nH]c2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5-(5-chloro-2-methoxypyridin-3-yl)-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 1, 0.2 g, 0.323 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.0717 g, 0.323 mmol), potassium phosphate (0.103 g, 0.484 mmol), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride (XPHOS Biphenyl Precatalyst) (0.0254 g, 0.032 mmol), THF (2.40 mL), and H2O (0.80 mL) were sealed in a microwave vessel and subject to microwave irradiation at 120 C for 1.5 hours. The resulting reaction mixture was worked up with brine/ethyl acetate. The combined extracts were dried over Na2SO4, filtered and evaporated to afford a dark mixture. This dark mixture was purified by flash chromatography (SiO2, ISCO, RediSep 12 g Cartridge). The column was eluted by an ethyl acetate/hexanes mixture (0% to 50% ethyl acetate). Related fractions were pooled and evaporated under reduced pressure to afford an off-white solid of 113 mg as the titled compound. LCMS (M+H)+: 680.4. 1H NMR (CDCl3, 500 MHz): δ 8.19-8.11 (m, 2H), 7.85 (s, 1H), 7.73 (s, 2H), 7.42-7.36 (m, 1H), 5.72-5.66 (d, J=8.5 Hz, 1H), 5.53 (s, 1H), 5.41 (s, 1H), 4.72-4.66 (m, 1H), 4.54-4.40 (m, 2H), 4.38-4.26 (m, 3H), 4.00 (s, 3H), 2.51 (m, 1H), 2.42 (s, 3H), 2.30-2.10 (m, 4H), 0.52 (d, J=6.5 Hz, 3H). RTA IC50: 5 nM.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:20][CH2:21][CH:22]([OH:24])[CH3:23]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:14]([O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:20]([CH2:21][CH:22]([OH:24])[CH3:23])[C:5]=32)=[CH:10][CH:9]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)COc1ccc2c(c1)C(=O)C(CC=O)C2
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)COc1ccc2c(c1)-c1c(ccn1CC(C)O)C2
Reaction time: 0.75 h
Yield: 57 %

Procedure:
A solution of 2.3 g of (RS)-2-(2-oxoethyl)-6-isobutoxy-1-indanone and 70 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.93 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 1:4). 1.52 g (57%) of (RS)-1-(7-isobutoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a red oil.
Reaction SMILES: C([O:3][C:4](=[O:32])/[CH:5]=[C:6](\[CH3:31])/[CH:7]=[CH:8]/[C@@H:9]1[CH2:11][C@@:10]1([C:13]1[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:16]2[O:20][CH2:19][C:18]([CH3:22])([CH3:21])[C:17]=2[CH:23]=1)[CH3:12])C.C(O)C.[OH-].[Na+].O>C(#N)C>[CH3:21][C:18]1([CH3:22])[C:17]2[CH:23]=[C:13]([C@@:10]3([CH3:12])[CH2:11][C@H:9]3/[CH:8]=[CH:7]/[C:6](/[CH3:31])=[CH:5]/[C:4]([OH:32])=[O:3])[CH:14]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[C:16]=2[O:20][CH2:19]1
Reactant: CCOC(=O)/C=C(C)/C=C/[C@@H]1C[C@]1(C)c1cc(-c2ccccc2C)c2c(c1)C(C)(C)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC#N
Product: CC(/C=C/[C@@H]1C[C@]1(C)c1cc(-c2ccccc2C)c2c(c1)C(C)(C)CO2)=C\C(=O)O

Procedure:
Following General Procedure H and using 5-[(1S, 2S)-2-(3,3-dimethyl-7-o-tolyl-2,3-dihydro-benzofuran-5-yl)-2-methyl-cyclopropyl]-3-methyl-penta-2E,4E-dienoic acid ethyl ester (Compound 25, 0.096 g, 0.22 mmol), ethanol (20 mL), and 5M aqueous sodium hydroxide (5 mL) followed by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained (0.044 g, 45%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(OP([CH2:33][C:34]#[N:35])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].COC1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)C=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[CH:33][C:34]#[N:35])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OC
Agent: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(=CC#N)c2cc(OC)c(OC)c(OC)c2)cc1OC
Yield: 76 %

Procedure:
(3,4-Dimethoxy-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone (3.3 g, 10 mmol), cyanomethylphosphonic acid diethyl ester (2.4 ml, 15 mmol) in anhydrous THF (50 ml), and potassium bis(trimethylsilyl)amide (3.0 g, 15 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude was purified by flash column chromatography to give 3-(3,4-dimethoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile as a solid (2.7 g, 77%): mp, 119-121° C.; 1H NMR (DMSO-d6) 7.14-7.07 (m, 1H), 7.00-6.77 (m, 2H), 6.66 (d, J=3 Hz, 2H), 6.25 (s, 0.5H), 6.19 (s, 0.5H), 3.84-3.71 (m, 15H); 13C NMR (DMSO-d6) □ 161.38, 161.31, 152.65, 150.99, 150.14, 148.64, 148.18, 139.44, 138.44, 133.69, 132.47, 130.01, 128.88, 122.66, 122.43, 118.66, 118.62, 112.75, 111.31, 111.22, 110.94, 106.88, 106.27, 94.23, 93.53, 60.08, 56.02, 55.98, 55.60, 55.55, 55.48; Anal. Calcd. For C20H21NO5: C, 67.59; H, 5.96; N, 3.94. Found: C, 67.66; H, 5.98; N, 3.88.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[CH3:43][O:42][C:39]1[CH:40]=[CH:41][C:36](/[C:34](/[CH3:35])=[CH:33]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:37][CH:38]=1
Reactant: COc1ccc(C(C)=CBr)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(/C(C)=C/n2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (36.7 mg, 0.184 mmol) was dissolved in DMF (6 mL). Copper (I) iodide (4 mg, 0.0184 mmol), L-proline (4.2 mg, 0.037 mmol) and potassium phosphate (78 mg, 0.37 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-4-methoxybenzene (50 mg, 0.22 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 80° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 45 mg. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.60 (d, 2H), 7.25 (s, 1H), 7.10 (d, 1H), 7.0 (m, 4H), 4.30 (m, 2H), 3.80 (s, 3H), 3.50 (m, 2H), 2.98 (m, 2H), 2.85 (s, 3H), 2.38 (s, 3H), 1.80 (s, 3H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])[CH3:10]>>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[C:9](=[O:11])[CH:10]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc2ccccc2c1
Product: O=C(C=Cc1ccccc1)c1ccc2ccccc2c1

Procedure:
By a procedure similar to that of example 1.59.1, starting from benzaldehyde and 2-acetylnaphthalene, 1-(2-naphthalenyl)-3-phenylprop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[BrH:19]>O.[Cu](Br)Br>[Br:19][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Br
Reactant: Nc1cc(C(=O)O)cc(C(F)(F)F)c1
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
To a stirred suspension of 3-amino-5-(trifluoromethyl)benzoic acid (7.90 gm, 38.5 mmol) in a mixture of hydrobromic acid (43% w/v, 100 mL) and water (100 mL) at 0° C. was slowly added a solution of sodium nitrite (7.97 gm, 0.116 mol) in water (50 mL). After 1 hour the inhomogeneous yellow liquid was added to a solution of copper (II) bromide (16.44 gm, 0.115 mol) in water (100 mL) and the mixture was stirred at room temperature for 16 hours. The mixture was extracted with diethyl ether (250 mL), the aqueous layer was separated and extracted with diethyl ether (3×75 mL). The combined organic layers were dried with anhydrous sodium sulfate and the solvent removed under vacuum to give the title compound as a yellow solid (9.0 gm, 87%) which was used in the following reaction without further purification.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH:9]([C:22]1[CH:26]=[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])[O:24][CH:23]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>ClCCl>[C:1]([NH:8][CH:9]([C:22]1[CH:26]=[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])[O:24][CH:23]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCC(N)c1coc([Si](C)(C)C)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCC(NC(C)=O)c1coc([Si](C)(C)C)c1
Reaction time: 8 h

Procedure:
Acetic anhydride (0.1 ml) was added to a solution of 3-(1-aminotridecyl)-5-trimethylsilylfuran (89.8 mg, 0.27 mmol) and triethylamine (0.1 ml) in dichloromethane (1 ml) at room temperature. Stirring was continued overnight (14 hours) while the cooling bath attained room temperature. The residue, after solvent removal, was purified by preparative TLC 20×20 cm, 1000u; developed with 60% ethyl ether/hexane). The title amide was obtained as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:25]=[C:24]2[C:20](/[C:21](=[CH:27]/[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=3)/[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[NH:8][CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:21]2([C:20]3[C:24](=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=3)[NH:23][C:22]2=[O:26])[CH:27]1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(F)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2ccc(F)c(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (6 g, 28 mmol) prepared in Example 1 and E/Z-6-chloro-3-(3-chloro-4-fluoro-benzylidene)-1,3-dihydro-indol-2-one (5 g, 16 mmol) prepared in Example 80 in dichloromethane (100 mL) were added triethyl amine (15 mL, 109 mmol) and AgF (2.7 g, 218 mmol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The organic layer was separated, washed with water, dried over MgSO4, and concentrated. The residue was dissolved into t-butanol (30 mL), and DBU (33 g, 130 mmol) was added. The reaction mixture was heated at 120° C. for 2 h. The mixture was then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (silica gel 120 g, 10-40% EtOAc in hexanes) to give as rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-4-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester as a off white solid (2.4 g, 28%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][C@@H:8]([C:20](N1[C@H](C)[C@@H](C2C=CC=CC=2)OC1=O)=[O:21])[CH2:9][C@H:10]([CH3:19])[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].OO.S([O-])([O-])=[O:42].[Na+].[Na+]>O.C1COCC1>[C:1]([O:5][C:6](=[O:35])[CH2:7][C@H:8]([CH2:9][C@H:10]([CH3:19])[CH2:11][CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[C:20]([OH:21])=[O:42])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](CCC1CCCCC1)C[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@H]1C
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CCC1CCCCC1)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 78.9 %

Procedure:
A flask was charged with 4.13 g (8.50 mmol) of (5R,3S)-7-cyclohexyl-5-methyl-3-((4R,5R)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-heptanoic acid tert-butyl ester, 100 mL of THF, 25 mL of water, and the resulting mixture was cooled in a 0° C. bath. To this solution was added 0.57 g (13.6 mmol) of lithium hydroxide monohydrate and 3.48 mL (34 mmol) of 30% hydrogen peroxide. The mixture was stirred for 2.5 hours. The reaction was quenched by the addition of 4.29 g (34 mmol) of sodium sulfite in 26 mL water. The mixture was allowed to warm to room temperature and stirred overnight. The THF was removed under reduced pressure and the remaining material was further diluted with water. The water layer was made acidic by the slow addition of conc. HCl aq. The aqueous layer was extracted with dichloromethane. The organic layers were dried with magnesium sulfate. The resulting oil was purified by column chromatography (eluent 3:1 hexanes:ethyl acetate). This gave 2.19 g (79% yield) of a clear oil: 1H NMR (400 MHz, CDCl3) δ ppm 0.88 (m, 5H) 1.17 (m, 10H) 1.43 (s, 10H) 1.68 (m, 7H) 2.35 (dd, J=16.35, 5.37 Hz, 1H) 2.60 (m, 1H) 2.87 (m, J=9.09, 9.09, 5.61, 5.49 Hz, 1H). MS (APCI) m+1/z is inconclusive.
Reaction SMILES: C1O[C:9]2C=CC(N)=[CH:4][C:3]=2O1.C(OC)(=O)C(C)=O.[CH3:18][O:19][C:20](=[O:33])[C@H:21]([CH3:32])[NH:22][C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1>C(O)C(C)C>[CH2:18]([O:19][C:20](=[O:33])[C@H:21]([CH3:32])[NH:22][C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1)[CH:3]([CH3:4])[CH3:9]
Reactant: COC(=O)[C@H](C)Nc1ccc2c(c1)OCO2
Reactant: Nc1ccc2c(c1)OCO2
Agent: COC(=O)C(C)=O
Solvent: CC(C)CO
Product: CC(C)COC(=O)[C@H](C)Nc1ccc2c(c1)OCO2

Procedure:
Following reductive amination General Procedure AA above and using 3,4-methylenedioxyaniline (Aldrich) and methyl pyruvate (Aldrich), N-(3,4-methylenedioxyphenyl)alanine methyl ester was prepared. The methyl ester was then transesterified following General Procedure AQ above and using iso-butanol to provide the title compound as an oil. The reaction was monitored by silica gel tlc (Rf=0.61 in 25% EtOAc/hexanes). Purification was by preparative plate chromatography with silica gel using 25% EtOAc/hexanes as the eluant.