Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH2:30][C:31]4C=CC=CC=4)=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[C:39](OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N)=CN=C3CC2)=O)=CC=1)=N)(C)(C)C.CC(C)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH:30]([CH3:39])[CH3:31])=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:14][CH:15]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NCc4ccccc4)c(=O)n32)cc1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(N)c(=O)n32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)Nc1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Yield: 65 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 1k, intermediate 1j (60 mg, 0.14 mmol), acetone (97.6 mg, 1.68 mmol) and NaBH(OAc)3 (385.7 mg, 1.82 mmol) yielded 43 mg (65%) of intermediate 4a. MS (ESI) 469.1 (M+H+).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C:11]=3[C:12](=[O:32])[CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2].C([O-])(=[O:35])C.[Na+].OO.O>O1CCCC1>[C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C:11]=3[C:12](=[O:32])[CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH:18]([OH:35])[CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CCC3=C4C(=O)C[C@H]([C@H](C)CCC=C(C)C)[C@@]4(C)CC[C@@H]32)C1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CCC3=C4C(=O)C[C@H]([C@H](C)CCC(O)C(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3β-acetoxy-5α-cholesta-8(14),24-dien-15-one (220 mg) in tetrahydrofuran (3 ml) was added boranedimethyl sulfide (0.125 ml) dropwise at 0° C. After standing overnight at -20° C., 3N sodium acetate (0.4 ml) was added followed by 30% aqueous H2O2 (0.4 ml) at room temperature. After stirring for 3 h at room temperature, the reaction mixture was poured into water (10 ml) and extracted 3 times with ether (5-ml portions). The combined ether extracts were washed with water (5 ml), dried over anhydrous sodium sulfate, and evaporated to dryness. The resulting oily residue was subjected to silica gel column (15 cm×0.8 cm) chromatography. Using 16% ethyl acetate in hexane as the eluting solvent, fractions 8 ml in volume were collected. The contents of fractions 64-99 were pooled and, after evaporation of the solvent, gave 3β-acetoxy-24 -hydroxy-5α-cholest-8(14)-en-15-one (66 mg) as an oil to which, after dissolving in methanol (3 ml), potassium carbonate (40 mg) was added. After stirring for 4 h at room tempeature, TLC analyses (solvent systems, 70% ethyl acetate in hexane and 50% acetone in benzene) indicated completion of the reaction with one major product (with Rf values of 0.51 and 0.27 in the 2 solvent systems, respectively). The reaction mixture was poured into water (10 ml), extracted 3 times with ether (5 ml portions), and the combined ether extracts were dried over anhydrous sodium sulfate and evaporated to dryness. The residue (55 mg) was subjected to chromatography on a silica gel (4 g) column (10 cm×0.8 cm). Using 30% ethyl acetate in hexane as the eluting solvent, fractions 8 ml in volume were collected. The contents of fractions 11-17 were combined and, after evaporation of the solvent, gave 3β,24-dihydroxy-5α-cholest-8(14)-en-15-one (21 mg; 10% yield). The structure was confirmed by I.R., N.M.R., and M.S. analyses.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH2:11][CH3:12])=[O:5])C.[OH-].[Na+].C(O)C>C(OCC)C>[CH2:11]([C:7]1[N:8]=[CH:9][O:10][C:6]=1[C:4]([OH:5])=[O:3])[CH3:12]
Reactant: CCOC(=O)c1ocnc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCc1ncoc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
4-Ethyl-oxazole-5-carboxylic acid ethyl ester (4.6 g) was stirred in a solution of 1N NaOH (25 ml) and ethanol (1 ml). The reaction mixture was then stirred at room temperature for 16 hours. Diethyl ether (25 ml) was added, and then the aqueous layer separated and acidified with 1N HCl (26 ml). A yellow solid formed that was collected by filtration, washed with water, then with n-pentane, providing the title compound (2.6 g) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=3[F:26])[C:9](=[O:27])[C:8]=2[C:7](O)=[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=12)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S([O:44][CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O.O>CN(C=O)C>[CH2:1]([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=3[F:26])[C:9](=[O:27])[C:8]=2[C:7]([O:44][CH2:45][C:46]([F:47])([F:48])[F:49])=[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=12)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3O)C2=O)c(F)c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.2 %

Procedure:
To a solution ethyl {4-[4-(ethyloxy)-9-hydroxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-fluorophenyl}acetate (0.2 g, 0.458 mmol) in DMF (3 ml), was added sodium carbonate (0.097 g, 0.915 mmol) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.159 g, 0.687 mmol). This was stirred at room temperature for 24 hours. Water was added to the reaction mixture with rapid stirring. The resulting yellow coloured solid was collected by filtration, washed with water and dried in the vacuum oven to give the title compound (0.119 g, 0.23 mmol). LC/MS: Rt=3.82, [MH]+ 520.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([F:12])([F:11])[F:10])=[N:7][CH:8]=1.[C-:13]#[N:14].[K+]>C(O)C.O>[F:10][C:9]([F:12])([F:11])[C:6]1[N:7]=[CH:8][C:3]([CH2:2][C:13]#[N:14])=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(C(F)(F)F)nc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 52.8 %

Procedure:
5-Chloromethyl-2-trifluoromethylpyridine (19.5 g, 99.7 mmol) in ethanol (160 mL) was added to a solution of potassium cyanide (9.74 g, 150 mmol) in water (80 mL) at 90° C. over 30 minutes. The mixture was stirred at 90° C. for 3 hours. Most of the ethanol was removed under reduced pressure and the aqueous layer was extracted with AcOEt (3×100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% AcOEt in hexanes) to afford (6-trifluoromethylpyridin-3-yl)-acetonitrile as a brown oil (9.79 g, 75%). 1H NMR (400 MHz, CDCl3) δ ppm 8.63 (s, 1 H), 7.90 (d, J=8.0 Hz, 1 H), 7.70 (d, J=8.0 Hz 1 H), 3.88 (s, 2 H). 19F NMR (400 MHz, CDCl3):168 cm−1. MS m/z 187.14
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[CH:21][N:22]3[CH3:27])[C:12]([C:15]#[N:16])=[N:13][CH:14]=1.[OH-].[Na+].OO.CC(O)=[O:34]>CCO.CS(C)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[CH:21][N:22]3[CH3:27])[C:12]([C:15]([NH2:16])=[O:34])=[N:13][CH:14]=1
Reactant: Cn1ccc2c(Nc3nc(N[C@@H]4CCCC[C@@H]4N)cnc3C#N)cccc21
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cn1ccc2c(Nc3nc(N[C@@H]4CCCC[C@@H]4N)cnc3C(N)=O)cccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The compound 5-((1R,2S)-2-aminocyclohexylamino)-3-(1-methyl-1H-indol-4-ylamino)pyrazine-2-carbonitrile (18 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (9 mg). MS 380.5 (M+H); UV 221.2, 273.8, 322.5 nm; t 0.518 min.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[N:16][OH:17])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[CH2:19]([O:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31]Br)[CH2:25]1)=[O:23])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:19]([O:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31][O:17][N:16]=[C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8]2)[CH2:25]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Reactant: ON=C1CC(c2ccccc2)c2ccccc21
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1CCCN(CCON=C2CC(c3ccccc3)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 264 h
Yield: 54.1 %

Procedure:
A mixture of the above oxime (1.1 g, 5 mmol), (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (1.7 g, 5 mmol, EP 374801), potassium carbonate (1.7 g, 13 mmol) and acetone (25 ml) was stirred at ambient temperature for 11 days. The mixture was filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography on silica gel (100 g, heptane/ethyl acetate=1/1) to give 1.1 g of (R)-1-(2-(((3-phenyl-1-indanylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]([C:14]2[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:19]=2)=[C:4]([F:26])[CH:3]=1.O.[C:28]1(C)C=CC(S(O)(=O)=O)=C[CH:29]=1>C(O)CC>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:28][CH3:29])=[O:11])=[CH:6][C:5]([C:14]2[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:19]=2)=[C:4]([F:26])[CH:3]=1
Reactant: COC(=O)COc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCO
Solvent: O
Product: CCCOC(=O)COc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 342 %

Procedure:
To a solution of 100 mg of 3-{4-chloro-2-fluoro-5-[(methoxycarbonyl)methoxy]phenyl}-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-165) in 1.0 ml of propanol was added 10 mg of p-toluenesulfonic acid monohydrate, and the mixture was heated under reflux for 5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the excess propanol was distilled out under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 76 mg (yield, 71%) of 3-{4-chloro-2-fluoro-5-[(propoxycarbonyl)methoxy]phenyl}-1-methyl-6-trifluoromethyl-2-oxo -1,2-dihydropyrazine (present compound 1-167).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][C:18](=[O:20])[C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH:13]=[CH:12][CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[O:30]1[C@H:12]2[CH2:11][C@H:10]3[C@:15]([CH3:16])([CH2:14][C@@H:13]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@@:2]([CH2:19][C:18]1=[O:20])([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]2)[CH2:8][CH2:9]3
Reactant: C[C@]12CC=CC[C@@H]1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A mixture of 5α-androst-2-ene-11,17-dione (37.2 g), m-chloroperbenzoic acid (30 g) and chloroform (600 ml) was allowed to stand for 0.5 hour at room temperature before partitioning between chloroform and saturated aqueous NaHCO3 solution. The organic phase was isolated and washed with water, dried and evaporated to a low volume. Addition of petroleum ether (b.p. 60°-80° C.) followed by refrigeration overnight afforded crystalline material (27.5 g). Recrystallisation from ethyl acetate-petroleum ether (b.p. 60°-80° C.) afforded the title compound, m.p. 166°-167°, [α]D +126°.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:24]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:25]=1)=[O:11])([OH:6])=[O:5]
Reactant: CCCCCCCCCCOc1ccccc1CC(=O)OCC
Reactant: O=C1OC(=O)c2ccccc21
Product: CCCCCCCCCCOc1ccc(C(=O)c2ccccc2C(=O)O)cc1CC(=O)OCC
Yield: 8 %

Procedure:
Following the procedure of Examples 30 and 31, phthalic anhydride and ethyl 2-decyloxybenzene acetate were reacted to provide the title product in 8% yield. The product was an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]([CH2:11][C:12]([OH:14])=[O:13])[N:9]=[N:8][N:7]=2)=[CH:2]1.S(=O)(=O)(O)O.[CH3:20][O:21][CH2:22][CH2:23]O>>[CH3:20][O:21][CH2:22][CH2:23][O:13][C:12](=[O:14])[CH2:11][N:10]1[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][N:8]=[N:9]1
Reactant: O=C(O)Cn1nnnc1-c1ccsc1
Reactant: COCCO
Agent: O=S(=O)(O)O
Product: COCCOC(=O)Cn1nnnc1-c1ccsc1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 82.3 %

Procedure:
To a solution of 2 g (9.51 mM) of [5-(3-thienyl)tetrazol-1-yl]acetic acid in 10 ml of 2-methoxyethanol was added 1 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/ethyl alcohol=30/1) for separation and purification, to give 2.1 g (yield 82.3%) of [5-(3-thienyl)tetrazol-1-yl]acetic acid 2-methoxyethyl ester.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]3[N:28]=[CH:27][CH:26]=[CH:25][C:19]=3[N:20]3[C:24]=2[CH2:23][CH2:22][CH2:21]3)=[CH:13][CH:12]=1.[C:29]([O-])([O-])=O.[K+].[K+].CI.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:29][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]3[N:28]=[CH:27][CH:26]=[CH:25][C:19]=3[N:20]3[C:24]=2[CH2:23][CH2:22][CH2:21]3)=[CH:13][CH:12]=1
Reactant: c1ccc2[nH]c(Oc3ccc(-c4c5n(c6cccnc46)CCC5)cc3)nc2c1
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(Oc2ccc(-c3c4n(c5cccnc35)CCC4)cc2)nc2ccccc21
Temperature: 40 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a mixture of 9-[4-(1H-benzimidazol-2-yloxy)phenyl]-7,8-dihydro-6H-pyrido[2,3-b]pyrrolizine (70 mg) and K2CO3 (79 mg) in DMF (1 mL) was added MeI (0.024 mL). The mixture was stirred at 40° C. overnight. The mixture was poured into saturated NaHCO3 aqueous solution and extracted with AcOEt. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (38.1 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8][CH2:9][C:10]=1OS(C(F)(F)F)(=O)=O)=[O:4].[Cl:26][C:27]1[C:32]([F:33])=[CH:31][CH:30]=[C:29]([F:34])[C:28]=1[C:35]1[CH:39]=[C:38]([CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][N:43]=2)[O:37][N:36]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.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>[CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:8][CH2:9][C:10]=1[C:45]1[CH:44]=[N:43][C:42]([O:41][CH2:40][C:38]2[O:37][N:36]=[C:35]([C:28]3[C:29]([F:34])=[CH:30][CH:31]=[C:32]([F:33])[C:27]=3[Cl:26])[CH:39]=2)=[CH:47][CH:46]=1)=[O:4]
Reactant: CC1(C)OB(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)nc2)OC1(C)C
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)nc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
A mixture of 4-trifluoromethanesulfonyloxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (WO 2004/002957; 6.04 g, 15.5 mmol), 2-[3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (9.28 g, 20.7 mmol) and aq. 2M Na2CO3 (93.1 mL, 186 mmol) in DME (150 mL) was prepared, and Pd(PPh3)4 (1.00 g, 0.866 mmol) was added in portions. The mixture was heated to 80° C., and stirred at this temperature for 1 h. The mixture was allowed to cool to rt, and was diluted with EtOAc. The resulting mixture was washed with water and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:2→2:1) yielded the title compound (4.64 g, 40%). LC-MS: tR=1.34 min; ES+: 562.34.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[F:5][C:6]([F:17])([F:16])[C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[S:15])=[CH:9][CH:8]=1>C(O)C>[C:2]([NH:3][C:14]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]([F:5])([F:16])[F:17])=[CH:12][CH:11]=1)=[S:15])#[N:1]
Reactant: N#CN
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
The suspension of monosodium cyanamide (0.63 g, 9.8 mmol) in absolute ethanol (50 mL) was slowly treated with 4-trifluoromethylphenylisothiocyanate (2.0 g, 9.8 mmol). The reaction was allowed to stir at room temperature for 1 hour and then heated at 75° C. for 4 hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title compound (2.0 g) as a colorless solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][N:19]=1>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ncnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a stirred suspension of NaH (60%, 0.146 g, 3.65 mmol) in DMF (15 mL) was added dropwise a solution of 4-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.611 g, 3.04 mmol) in DMF (5 mL) at 0° C. The reaction was stirred for 1 hour and then 4-chloroquinazoline (0.500 g, 3.04 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was partitioned between H2O and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexanes:EtOAc, 2:1) to give 4-(Quinazolin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (0.76 g, 76%) as a colorless oil. Removal of the Boc group by the procedures described in Example 34, Step 3 afforded 4-(Piperidin-4-yloxy)-quinazoline dihydrochloride as a white solid. 1H NMR (CD3OD, 400 MHz) δ 9.35 (s, 1H), 8.59 (d, J=8.4 Hz, 1H), 8.31 (td, J=7.2 Hz, J=1.2 Hz 1H), 8.11 (d, J=8.4 Hz, 1H), 8.04 (t, J=7.2 Hz, 1H), 6.00 (m, 1H), 3.55 (m, 2H), 3.40 (m, 2H), 2.42 (m, 4H). LCMS (APCI+) m/z 230 [M+H]+; Rt=1.67 min.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][C@H:15]1[CH2:23][N:22]2[C@H:17]([CH2:18][C:19](=[O:24])[CH2:20][CH2:21]2)[CH2:16]1.O>ClCCl>[Si:6]([O:14][C@H:15]1[CH2:23][N:22]2[C@H:17]([CH2:18][C:19](=[O:24])[CH2:20][CH2:21]2)[CH2:16]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: O=C1CCN2C[C@H](O)C[C@H]2C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2CC(=O)CCN2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.7 %

Procedure:
1.70 g (24.9 mmol) of imidazole and 1.88 g (12.5 mmol) of t-butyldimethylsilyl chloride were added to a solution of 1.30 g (8.1 mmol) of (2R,8aS)-2-hydroxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one [obtained as described in Preparative Example 2(i)′ above] in 30 ml of dichloromethane and the resulting mixture was stirred for 20 hours at room temperature. At the end of this time, water was added and the reaction mixture was extracted with dichloromethane. The organic extract was washed with water and concentrated by evaporation under reduced pressure, and the resulting residue was then purified by chromatography on an alumina column using a 9:1 by volume mixture of hexane and ethyl acetate as the elaunt to afford 1.98 g (yield: 88%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:19][C:20]([F:27])([F:26])[C:21](OCC)=[O:22]>CO>[C:4]1([CH:7]([C:8]([OH:10])=[O:9])[NH:11][C:21](=[O:22])[C:20]([F:27])([F:26])[F:19])[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: NC(C(=O)O)c1ccccc1
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)C(NC(=O)C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42 %

Procedure:
A mixture of DL-phenylglycine (15.1 g, 0.10 mol) in methanol is treated with triethylamine (10.1 g, 0.10 mol) and ethyl trifluoroacetate (17.8 g, 0.125 mol), stirred at room temperature for 72 hours, diluted with methanol and treated with Dowex 50×8 acidic resin. The reaction mixture is stirred for 10 minutes and filtered. The filtrate is concentrated in vacuo to give a pale yellow solid which is recrystallized from 1,2-dichloroethane to give the title product as white needles, 10.5 g (42% yield), mp 155°-157° C.
Reaction SMILES: NC1C=C(C([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)=CC#N)C=CC=1OC.[Mg].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[N+:35]([O-:37])=[O:36])[CH:30]=[O:31]>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:30]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[OH:31])[CH:32]=[CH:33][C:34]=1[N+:35]([O-:37])=[O:36]
Reactant: COc1cc(C=O)ccc1[N+](=O)[O-]
Reactant: COc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1N
Agent: [Mg]
Product: COc1ccc(C(O)c2ccc([N+](=O)[O-])c(OC)c2)cc1OC
Yield: 72 %

Procedure:
(3-Methoxy-4-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol was prepared analogously to 3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile using 3,4-bromoveratrole (2.5 g, 11.5 mmol), magnesium turning (0.3 g, 11.5 mmol) and 3-methoxy-4-nitro-benzaldehyde (1.5 g, 8.2 mmol). The crude product was purified by flash chromatography (silica gel, CH2Cl2:EtOAc 9:1) to afford (3-methoxy-4-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol (1.9 g, 72%): 1H NMR (CDCl3) δ 7.80 (d, J=8 Hz, 1H), 7.22 (s, 1H), 6.98-6.85 (m, 4H), 5.79 (d, J=2 Hz, 1H), 3.97 (s, 3H), 3.87 (s, 6H).