Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.[F:6][C:7]([F:36])([F:35])[C:8]1[CH:9]=[C:10]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:27]=3[CH:28]=[CH:29][NH:30]4)[N:22]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17].[OH-].[Na+].O.CN([CH:43]=[O:44])C>>[F:36][C:7]([F:6])([F:35])[C:8]1[CH:9]=[C:10]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:27]=3[C:28]([CH:43]=[O:44])=[CH:29][NH:30]4)[N:22]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:20])[C:16]([F:17])([F:18])[F:19]
Reactant: CC(Oc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1C(F)(F)F)C(F)(F)F
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(Oc1ccc(-c2nc(-c3cccc4[nH]cc(C=O)c34)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
POCl3 (158.4 μl) was added dropwise to a DMF solution (4 ml) at 0° C. After warming to room temperature, it was stirred for 0.5 hour. Then, a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (500.0 mg) in DMF (1 ml) was added thereto at 0° C., followed by stirring at room temperature for 15 hours. After cooling to 0° C., to the reaction solution was added a 1M aqueous NaOH solution for adjustment of its pH to 9 to 10. This solution was stirred at 100° C. for 1 hour. After being left to be cooled, to the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml). The organic layer was combined, washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, n-hexane, EtOAc=90:10 to 70:30) to obtain 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole-3-carboaldehyde (456.7 mg) as a white solid.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:39]=[CH:38][C:18]([O:19][CH2:20][CH:21]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1.[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>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.C(O)C>[F:40][C:41]1[CH:46]=[C:45]([C:15]2[CH:39]=[CH:38][C:18]([O:19][CH2:20][CH:21]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)[CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCc1cccnc1)COc1ccc(Br)cc1
Reactant: OB(O)c1cccc(F)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: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC(CCc1cccnc1)COc1ccc(-c2cccc(F)c2)cc1
Temperature: 120 °C
Yield: 60.7 %

Procedure:
Prepared according to the method described in Example 33a) from toluene (5 ml), aqueous sodium carbonate (2 M, 2.2 ml), (±)-3-(4(4-bromophenoxy)-3-(tert-butyldimethylsilyloxy)butyl)pyridine (0.79 g), ethanol (1.3 ml), 3-fluorobenzeneboronic acid (0.25 g) and tetrakis(triphenylphosphine)palladium(0) (72 mg) with heating at 120° C. for 6 hours. The residue obtained after work up was purified by column chromatography over silica to give the sub-title compound as an oil (0.49 g).
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH2:2][CH3:3].C(OCC)(OCC)(OCC)C.[CH2:24]([O:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36]([NH:43][CH2:44][CH:45]([CH3:47])[CH3:46])=[C:37]([NH2:42])[CH:38]=[N:39]2)=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32]1[CH:33]=[CH:34][C:35]2[C:36]3[N:43]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:1]([CH2:2][CH3:3])=[N:42][C:37]=3[CH:38]=[N:39][C:40]=2[CH:41]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reactant: CCOC(CC)(OCC)OCC
Agent: CCOC(C)(OCC)OCC
Product: CCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Yield: 34.3 %

Procedure:
The general method described in Part A of Example 9 was followed. Triethyl orthopropionate (7.66 mL, 58.1 mmol) was added in lieu of triethyl orthoacetate to a solution of 7-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine (18.68 g, 58.11 mmol) in xylenes (200 mL). At the end of the reaction, the precipitate was collected in three crops to provide 7.16 g of 7-benzyloxy-2-ethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as a light-brown solid, mp 127° C.
Reaction SMILES: N.C([O:5][C:6]1[C:7]([Cl:31])=[CH:8][C:9]([F:30])=[C:10]([CH:29]=1)[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1)(=O)C>CO.O>[Cl:31][C:7]1[C:6]([OH:5])=[CH:29][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[C:9]([F:30])[CH:8]=1
Reactant: COCCOc1cc2ncnc(Nc3cc(OC(C)=O)c(Cl)cc3F)c2cc1OC
Agent: N
Solvent: O
Solvent: CO
Product: COCCOc1cc2ncnc(Nc3cc(O)c(Cl)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.3 %

Procedure:
Concentrated aqueous ammonia (5 ml) was added to a solution of 4-(5-acetoxy-4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methoxyethoxy)quinazoline (180 mg, 0.4 mmol) in methanol (50 ml). The mixture was stirred at ambient temperature for 3 hours, and then diluted with water. Most of the methanol was removed by evaporation and the resulting precipitate collected by filtration, washed with water and dried to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)quinazoline (73 mg, 45%).
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:7]=2[C:8](N(C)OC)=[O:9])[CH2:3][CH2:2]1.[CH2:20]([Mg]Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH:1]1([C:4]#[C:5][C:6]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:7]=2[C:8](=[O:9])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:2][CH2:3]1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COc1ccc(C(=O)N(C)OC)c(C#CC2CC2)c1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2ccccc2)c(C#CC2CC2)c1
Yield: 89 %

Procedure:
2-(Cyclopropylethynyl)-N-methyl-N,4-bis(methyloxy)benzamide (150) (0.47 g, 1.82 mmol) was treated with benzylmagnesium chloride in THF to give 0.47 g (89%) of the title compound (151) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 0.80-0.95 (m, 4H), 1.45-1.55 (m, 1H), 3.82 (s, 3H), 4.41 (s, 2H), 6.80 (dd, J1=8.8 Hz, J2=2.6 Hz, 1H), 6.94 (d, J=2.5 Hz, 1H), 7.20-7.26 (m, 3H), 7.27-7.33 (m, 2H), 7.65 (d, J=8.8 Hz, 1H). LCMS (ESI): m/z 291 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:21])[C:18]([OH:20])=O)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:21])[C:18]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]2)=[O:20])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.1 %

Procedure:
A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoacetic acid (Example 44, 1.50 g, 5.12 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (1.24 g, 6.2 mmol), EDCI (1.24 g, 6.2 mmol) and HOBt (0.95 g, 6.2 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 16 h. The reaction mixture was added to saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution, 1M HCl and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (2.52 g, quant.) as a yellow amorphous.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21](=[O:24])[NH:22][N:23]=3)[CH:15]=2)[CH2:10]1.Br.[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29]>O.C(OCC)(=O)C.O1CCCC1>[C:26]([NH:7][CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21](=[O:24])[NH:22][N:23]=3)[CH:15]=2)[CH2:10]1)(=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reactant: CCCC(=O)Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC(=O)NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reaction time: 3 h
Yield: 81.3 %

Procedure:
An aqueous solution (100 ml) containing 3.30 g of potassium carbonate dissolved in water was added to 100 ml of a suspension containing 3.50 g of 2-aminomethyl-5-[pyridazin-3(2H)-on-6-yl]indane·hydrobromide suspended in ethyl acetate. Then, under ice cooling, 2.30 g of butyryl chloride dissolved in 30 ml of tetrahydrofuran was added to the mixture, and the resulting mixture was stirred for 3 hours. Crystals precipitated were collected by filtration, washed with water, dried and then recrystallized from methanol to obtain 2.75 g of 2-(butyrylamino)methyl-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=3)=[CH:11][C:10]([S:27]([NH:30][CH2:31][CH2:32][C:33]([O:35]C)=[O:34])(=[O:29])=[O:28])=[C:9]2[CH3:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[Li].O>CO.O>[CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:21])([CH3:20])[CH3:22])[CH:16]=[C:15]([C:23]([CH3:25])([CH3:26])[CH3:24])[CH:14]=3)=[CH:11][C:10]([S:27]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])(=[O:28])=[O:29])=[C:9]2[CH3:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCNS(=O)(=O)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n(CC2CCCCC2)c1C
Agent: [Li]O
Solvent: O
Solvent: CO
Product: Cc1c(S(=O)(=O)NCCC(=O)O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
To a solution of compound 38 (400 mg, 0.75 mmol) in a mixture of MeOH (10 mL) and water (3 mL) was added LiOH.H2O (200 mg, 4.60 mmol) and then this mixture was stirred at 60° C. for 4 h, evaporated and acidified to pH˜5 with 3N HCl. The aq. layer was extracted with EA (3×). The combined organic layers were concentrated and purified by CC (PE/EA=2/1) to give compound 39 (345 mg, 79%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz) δ: 0.60-0.66 (2H, m), 0.93-1.02 (3H, m), 1.23-1.38 (3H, m), 1.34 (18H, s), 1.51-1.55 (3H, m), 2.51 (3H, s), 2.64 (2H, t, J=5.4 Hz), 3.23-3.29 (2H, m), 3.70 (2H, d, J=7.2 Hz), 5.45 (1H, m), 6.42 (1H, s), 7.14 (2H, s), 7.40 (1H, s). MS Calcd.: 516; MS Found: 517 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:14]=3[N:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[N:24]1(C(OC(C)(C)C)=O)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[N:24]1([C:21]([C:19]2[CH:18]=[CH:17][C:15]3[NH:16][C:12]([C:11]4[C:2](=[O:1])[NH:3][C:4]5[C:9]([CH:10]=4)=[CH:8][CH:7]=[CH:6][CH:5]=5)=[N:13][C:14]=3[CH:20]=2)=[O:23])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)nc2c1)N1CCNCC1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
A mixture of 2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-benzimidazole-5-carboxylic acid (4-6, 130 mg, 0.43 mmol, 1 equiv, tert-butyl l-piperazinecarboxylate (79 mg, 0.43 mmol, 1.0 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (97 mg, 0.51 mmol, 1.2 equiv), 1-hydroxy-7-azabenzotriazole (70 mg, 0.51 mmol, 1.2 equiv), and triethylamine (0.148 mL, 1.06 mmol, 2.50 equiv) in DMF (5.0 mL) was stirred at 23° C. for 20 h. The reaction mixture was partitioned between water (50 mL) ethyl actate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. A solution of the residue, DMSO (10 uL), and water (10 uL) in a 1:1 mixture of dichloromethane and trifluoroacetic acid (20 mL) was stirred at 23° C. for 45 min. The reaction mixture was concentrated, and the residue was purified by reverse-phase liquid chromotography (H2O/CH3CN gradient w/0.1% TFA present). The desired fractions were partitioned between saturated sodium bicarbonate solution (50 mL) and a 10% solution of methanol in dichloromethane (2×50 mL) to provide 3-[5-(1-piperazinylcarbonyl)-1H-benzimidazol-2-yl]-2(1H)-quinolinone (14-1) as its free base. 1H NMR (500 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.59 (s, 1H), 7.74 (m, 2H), 7.53 (m, 2H), 7.39 (m, 2H), 7.26 (m, 2H), 3.61 (br m, 1H), 3.60 (br m, 1H), 3.32 (br m, 1H), 1.98 (br m, 1H), 1.89 (br m, 1H), 1.62 (br m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[CH2:18][C:19](=[CH2:21])[CH3:20].C(O)(=O)C>CO.[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: C=C(C)Cc1cc(C(C(=O)OC)C2CCCC2)ccc1O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C(c1ccc(O)c(CC(C)C)c1)C1CCCC1

Procedure:
4 g (0.014 mol) of the compound from Example V are dissolved in 30 ml of methanol and 10 ml of acetic acid and hydrogenated at 5.3 bar using Pd/C as a catalyst. Reaction time: 2.5 h. After filtering off the catalyst, the solvent is evaporated in vacuo and a slightly yellowish oil is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH:12]([C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[C:17]([CH:24]([CH3:26])[CH3:25])[CH:16]=1)([CH3:14])[CH3:13].CCN(CC)CC>O.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:20]2[C:15]([CH:12]([CH3:13])[CH3:14])=[CH:16][C:17]([CH:24]([CH3:26])[CH3:25])=[CH:18][C:19]=2[CH:21]([CH3:23])[CH3:22])=[CH:5][CH:4]=1
Reactant: CC(C)c1cc(C(C)C)cc(C(C)C)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)cc1
Yield: 88.3 %

Procedure:
4-Methoxyphenylboronic acid (152 mg, 1.00 mmol), and Pd(dtbpf)Cl2 (6 mg, 0.01 mmol) were added to a reaction tube equipped with a magnetic stir bar. Under a positive flow of argon while stirring, surfactant solution (1.0 mL, 2 wt % TPGS-M-PEG-750 in water), 2,4,6-triisopropylbenzene (126 μL, 0.50 mmol), and Et3N (0.21 mL, 1.5 mmol) were added by syringe and stirred vigorously for 24 h. The reaction mixture was then diluted with brine and extracted with EtOAc. The solution obtained was dried over MgSO4 and concentrated by rotary evaporation. The residue was purified by flash column chromatography eluting with 5% CH2Cl2/hexanes to afford the product (137 mg, 88%) as a white solid.
Reaction SMILES: [CH:1]1([CH:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C@@H:11]2[C@H:18]3[C@H:14]([CH2:15][NH:16][CH2:17]3)[CH2:13][CH2:12]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O.C(O)(=O)C.C([BH3-])#N>ClCCl>[CH:19]1([CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C@@H:11]2[C@H:18]3[C@H:14]([CH2:15][N:16]([CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[C:27]([C:26]([F:25])([F:35])[F:36])[CH:28]=4)[CH2:17]3)[CH2:13][CH2:12]2)=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)C(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2,2-Dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide (154 mg, 0.463 mmol) from Example 53 and 3-(trifluoromethyl)benzaldehyde (0.062 mL, 0.463 mmol) were combined in dichloromethane (5 mL), and then 2 mL of acetic acid was added. The reaction was stirred at room temperature for 20 minutes, and then PS-cyanoborohydride (396 mg, 0.926 mmol) was added. The reaction was stirred at room temperature overnight, then filtered and the resin was washed with dichloromethane. The solvent was removed in vacuo, and the crude material was purified using a silica gel cartridge (Analogix®, Burlington, Wis., RS-25) eluting with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.73 (s, 1H), 7.66 (d, J=7.7, 1H), 7.56 (s, 1H), 7.50 (t, J=7.7, 1H), 4.51-4.43 (m, 1H), 3.55 (d, J=12.9, 1H), 3.46 (d, J=12.9, 1H), 2.75 (d, J=8.6, 2H), 2.52-2.41 (m, J=8.5, 19.1, 2H), 2.34-2.29 (m, 1H), 2.20 (dd, J=7.7, 9.8, 1H), 2.14 (s, 3H, OAc), 1.96-1.54 (m, 15H), 1.49-1.05 (m, 12H), 1.03-0.93 (m, J=11.7, 21.1, 1H); MS (ESI+) m/z 491 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[CH:12][CH:11]=1
Reactant: COc1ccc(CBr)cc1
Reactant: OC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCC(O)CC2)cc1
Reaction time: 18 h
Yield: 80.1 %

Procedure:
0.97 g (0.00959 mol) of 4-hydroxypiperidine was dissolved in 20 ml of dimethylformamide and cooled to 0°. 1.93 g (0.0096 mol) of 4-methoxybenzyl bromide and 3.0 ml (0.0215 mol) of triethylamine were added under argon and the mixture was left to come to room temperature. It was stirred for 18 hrs., the solvent was distilled off and the residue was taken up in ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated and the residue was chromatographed on silica gel with dicloromethane/methanol (19:1) as the eluent. 1.7 g (80%) of 1-(4-methoxy-benzyl)-piperidin-4-ol were obtained as a brown oil. MS: me/e=222 (C13H20NO2+).
Reaction SMILES: [Cl:1][C:2]([Cl:16])([Cl:15])[CH2:3][O:4][C:5](=[O:14])[NH:6][C@H:7]1[C@@H:11]([O:12][NH2:13])[CH2:10][CH:9]=[CH:8]1.[C:17]([O:21][C:22](ON=C(C1C=CC=CC=1)C#N)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[Cl:1][C:2]([Cl:15])([Cl:16])[CH2:3][O:4][C:5](=[O:14])[NH:6][C@H:7]1[C@@H:11]([O:12][NH:13][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:10][CH:9]=[CH:8]1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NO[C@H]1CC=C[C@H]1NC(=O)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NO[C@H]1CC=C[C@H]1NC(=O)OCC(Cl)(Cl)Cl

Procedure:
An 7.8 g. quantity of crude (IR,5S)-2,2,2-trichloroethyl-5-(aminooxy)-2cyclopentene-1-carbamate is dissolved in 25 ml. of tetrahydrofuran and 6.15 g (25 mm) of 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile and the mixture stirred for 22 hours at room temperature, 20 hours at 50° C., 72 hours at room temperature and then evaporated in vacuo. The residue is chromatographed over 900 g. of silica gel eluted with (15-85) ethylacetate-toluene. Three hundred ml. fractions are collected. The product is found in fractions 10-12. Evaporation and recrystallization of the residue from Skellysolve B yields (IR,5S)-2,2,2-trichloroethyl-5-[[[(t-butyloxy)carbonyl]amino]oxy]-2-cyclopentene-1-carbamate m.p. 83°-84° C. as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([N+:15]([O-])=O)=[C:13]([O:18][CH3:19])[CH:12]=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[N:23]#[C:24]Br>CO.[Pt]=O>[NH2:23][C:24]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2[C:10]([O:20][CH3:21])=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[C:14]=2[N:15]=1
Reactant: N#CBr
Reactant: COc1ccc(OC)c([N+](=O)[O-])c1NCc1ccccc1
Agent: O=[Pt]
Solvent: CO
Solvent: O
Product: COc1ccc(OC)c2c1nc(N)n2Cc1ccccc1

Procedure:
2-Benzylamino-3-nitro-1,4-dimethoxybenzene (10.0 g, 0.03 mole) is suspended in methanol and hydrogenated in the presence of platinum oxide catalyst at 50 psi for about twelve hours. After this time the solution changes color from red to colorless. The methanol is then removed in vacuo. To the residue is added approximately 250 ml water and 3.50 g (0.03 mole) of cyanogen bromide. The flask containing this mixture is stoppered, shaken, and stirred overnight at room temperature. After treatment with activated charcoal, the solution is filtered into excess 1N NaOH, causing the precipitation of the product. The amorphous white powder melts at 191°-193° C.
Reaction SMILES: [OH:1][CH:2]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:23])[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=3)=[CH:11][O:12]2)=[CH:7][CH:6]=1.B(Br)(Br)Br>>[OH:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[C:9](=[O:23])[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:6][CH:7]=3)[O:12][CH:11]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(-c2coc3cc(OCC(O)Cc4ccccc4)ccc3c2=O)cc1
Agent: BrB(Br)Br
Product: O=c1c(-c2ccc(O)cc2)coc2cc(OCC(O)Cc3ccccc3)ccc12

Procedure:
The product of step 1 was then reacted with boron tribromide as shown in Example 16, step 3, to provide 3-(4-hydroxyphenyl)-7-(2-hydroxy-3-phenylpropoxy)chromen-4-one.
Reaction SMILES: BrC1C=C(C([N:16]2C[CH2:20][NH:19][C:18](=[O:22])[CH2:17]2)=O)OC=1C1C=CC=C(Cl)C=1.[Br:23][C:24]1[O:28][C:27]([C:29]([OH:31])=O)=[CH:26][C:25]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1.C(N(CC)C(C)C)(C)C>>[Br:23][C:24]1[O:28][C:27]([C:29]([N:16]2[CH2:17][C:18](=[O:22])[NH:19][CH2:20]2)=[O:31])=[CH:26][C:25]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)c(Br)o1
Reactant: O=C1CN(C(=O)c2cc(Br)c(-c3cccc(Cl)c3)o2)CCN1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(Br)o2)CN1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 27A starting with the compound from Example 22A and the compound from Example 35A. 3.5 equivalents of N,N-diisopropylethylamine are used. During the reaction, the product precipitates. The precipitate is collected by suction filtration, washed with tetrahydrofuran and dried under high vacuum. 1.17 g (100% of theory) of the title compound are obtained.