Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.O[CH2:20][CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([CH2:21][CH2:20][O:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=2)=[CH:23][CH:24]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Reactant: N#Cc1ccc(CCO)cc1
Product: N#Cc1ccc(CCOc2ccc(C(=O)NCC(=O)O)cc2)cc1
Yield: 18.2 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (582 mg, 3.83 mmol) prepared in Example 1 (1a) and 4-(2-hydroxyethyl)benzonitrile (592 mg, 4.02 mmol) to give 226 mg of the title compound (white powder, yield: 46%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:15]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH2:21])[N:7]=1.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.C(O[K])(C)(C)C>CS(C)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:15]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:21][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[N:7]=1
Reactant: Nc1cccc2nc(-c3cccs3)c(-c3cccs3)nc12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)O[K]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Nc2cccc3nc(-c4cccs4)c(-c4cccs4)nc23)cc1
Reaction time: 14 h

Procedure:
While agitating 3.1 g (9.9 mmol) of 2,3-di(2-thienyl)-5-aminoquinoxaline, 1.4 g (9.9 mmol) of 4-fluoronitrobenzene and 15 g of dimethylsulfoxide, 3.3 g (29.6 mmol) of t-butoxy potassium was gently added. After completion of the addition, the reaction container was purged with nitrogen, followed by agitation at room temperature for 14 hours. After completion of the reaction, 100 ml of water was added while cooling, and the resulting compound was filtered and dried, followed by purification with a silica gel column.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][N:11]=1.O.NN>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:10]1[N:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1
Reactant: Cc1ccc(C)c(Oc2ccc([N+](=O)[O-])cn2)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc(C)c(Oc2ccc(N)cn2)c1
Yield: 88.2 %

Procedure:
2-[(2,5-dimethylphenyl)oxy]-5-nitropyridine (Intermediate 33, 140 mg, 0.450 mmol) was dissolved in ethanol (3 mL). Hydrazine hydrate (83 μL, 0.884 mmol) and palladium on carbon (47 mg, 0.044 mmol) were added. The reaction mixture was heated at reflux under argon. After overnight heating, the reaction was cooled down. The reaction mixture was filtered. The organic phase was evaporated under vacuum. The residue was purified by SCX (wash with MeOH, desorbed with 2N methanolic ammonia). Evaporation afforded the title compound (85 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.CO>[Pd].CCOC(C)=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reaction time: 2 h

Procedure:
Pd on C 10% (0.3% p/p) was added to a solution of tert-butyl 4-(4-nitrophenyl)piperazine-1-carboxylate (1 eq) in a mixture (1:1 ratio) MeOH:EtOAc (0.03 M). The atmosphere in the reaction vessel was charged with H2 (1 atm.) and the reaction stirred vigorously for 2 h. At this time, the reaction mixture was filtered through a pad of celite and concentrated in vacuo to afford the title compound (quant); MS (ES+) m/z 278 (M+H)+
Reaction SMILES: N[C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:6]2[CH3:19].C([OH:30])C=C.[OH-].[Na+]>C1COCC1>[F:26][C:22]1[CH:21]=[C:20]([C:5]2[N:6]([CH3:19])[C:7]3[C:3]([N:4]=2)=[C:2]([OH:30])[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=3)[CH:25]=[CH:24][CH:23]=1
Reactant: Cn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC3(O)CCCC3)nc21
Reactant: C=CCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(F)c2)nc2c(O)nc(C#CC3(O)CCCC3)nc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
To 50 mg of 1-{2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol were added 3.0 ml of allyl alcohol and 1.0 ml of 5M NaOH, the mixture was stirred at room temperature for 10 minutes, 1.0 ml of THF was added thereto and the mixture was stirred again at room temperature for 15 hours and 40 minutes. The solvent was evaporated and then 200 ml of ethyl acetate and water (1:1) were added and an extraction was carried out. The aqueous layer was extracted with 100 ml of ethyl acetate again and the all organic layers were combined and washed with water and with brine once each. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The resulting residue was purified by a p-TLC (CH2Cl2:MeOH=10:1), the resulting yellowish white crystals were suspended in diethyl ether and the suspension was filtered to give 217 mg of the title compound as white crystals. The yield was 36%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:48]([CH3:50])([CH3:49])[CH:47]2[OH:51])=[O:20])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=Cc2cccc(Br)c2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a mixture of 4-{[1-(3-bromo-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (6.7 g, 20.1 mmol) and ytterbium(III) triflate hydrate (1.25 g, 2.01 mmol) in dry tetrahydrofuran (15 mL) at 25° C. was added isobutyraldehyde (1.45 g, 20.1 mmol) and water (0.36 mL, 20.1 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (8.12 g, 100%) as a light yellow oil: LC/MS m/e calcd for C20H22BrNO3 M+: 404.3, observed: 404.0, 406.0.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.[H-].[Na+].Br[CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>>[Si:25]([O:24][CH2:23][CH2:22][O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:5][CH2:4]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=C(OCc1ccccc1)N1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OCCOCC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 2.9 %

Procedure:
The reaction was carried out in the similar procedure to Example 75a using 5.00 g (20.1 mmol) of benzyl 4-(hydroxymethyl)piperidine-1-carboxylate, 0.88 g (20.1 mmol) of sodium hydride (55% or more, oily) and 5.28 g (22.1 mmol) of (2-bromoethoxy)-tert-butyldimethylsilane to obtain 237 mg (yield: 3%) of the title compound as a brown oil.
Reaction SMILES: N1C=CC=CC=1.[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:18])[NH:13][CH:14]=[N:15]2)=[C:10]([O:19][CH:20]([CH3:22])[CH3:21])[CH:9]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>O>[C:23]([O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:18])[NH:13][CH:14]=[N:15]2)=[C:10]([O:19][CH:20]([CH3:22])[CH3:21])[CH:9]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Oc1cc(O)cc2nc[nH]c(=O)c12
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1cc(OC(C)C)c2c(=O)[nH]cnc2c1
Temperature: 75 °C
Reaction time: 0.75 h
Yield: 66.1 %

Procedure:
Pyridine (0.18 ml, 1.5 mmol) was added to a suspension of 7-hydroxy-5-isopropoxyquinazolin-4(3H)-one (3.3 g, 15 mmol) in acetic anhydride (10 ml, 75 mmol) and the mixture was stirred at 75° C. for 45 minutes. The mixture was evaporated under reduced pressure and the residue obtained was stirred in water (50 ml) at 75° C. for 1 hour and then cooled to ambient temperature and filtered to afford 5-isopropoxy-4-oxo-3,4-dihydroquinazolin-7-yl acetate (2.6 g, 65% yield) as a white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][C:40]([C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[N:31]([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:19]4[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:29][CH:28]=2)[C:32]([CH3:44])=[C:33]3[CH3:43])=[O:41])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](N)c1cccc(Cl)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3cccc(Cl)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(3-chlorophenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 537/538/539 [M+H]+.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[C:24]12([C:34]3[S:38][C:37]([NH2:39])=[N:36][N:35]=3)[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>>[C:24]12([C:34]3[S:38][C:37]([NH:39][C:1]([C:4]45[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]6[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]6[C:22]#[N:23])=[O:15])([CH2:6][CH2:5]4)[CH2:8][CH2:9]5)=[O:3])=[N:36][N:35]=3)[CH2:25][CH:26]3[CH2:27][CH:28]([CH2:29][CH:30]([CH2:32]3)[CH2:31]1)[CH2:33]2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1nnc(C23CC4CC(CC(C4)C2)C3)s1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3nnc(C45CC6CC(CC(C6)C4)C5)s3)(CC1)CC2
Yield: 67.8 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 5-adamantyl-2-amino-1,3,4-thiadiazole (80.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(5-adamantyl-1,3,4-thiadiazol-2-yl)amino]carbonylbicyclo[2.2.2)oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (56.7 mg).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[O:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[CH2:15][CH2:14]1>CCOCC>[F:9][C:2]([F:1])([F:8])[C:3]([CH:15]1[C:16](=[O:23])[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:13][CH2:14]1)=[O:5]
Reactant: CCOC(=O)C(F)(F)F
Reactant: O=C1CCOc2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C1c2ccccc2OCC1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18.3 h
Yield: 64.6 %

Procedure:
Ethyl trifluoroacetate (9.78 g, 68 mmol) was placed in a 250 mL round bottom flask, and dissolved in ether (50 mL). To the stirred solution was added 25% sodium methoxide (15.11 g, 70 mmol), followed by 4-chromanone (10.07 g, 68 mmol) dissolved in ether (25 mL). The reaction was stirred at room temperature overnight (18.3 hours), poured into a separatory funnel and washed with 3N hydrochloric acid (20 mL) and with brine (20 mL), dried over MgSO4, concentrated in vacuo, and recrystallized from ether/hexane to give a yellow solid (10.72 g, 65%): mp 81°-83° C.; 1H NMR (CDCl3) 300 MHz 16.04 (br s, 1H) 7.84 (d, J=7.9 Hz, 1H) 7.51 (m, 1H) 7.09 (m, 1H) 6.98 (d, J=8.5 Hz, 1H) 5.08 (s, 2H); 19F NMR (CDCl3) 300 MHz: -72.56 (s). Mass spectrum: M+=244.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=3)=[CH:11][C:10]([NH2:28])=[N:9]2)=[CH:4][CH:3]=1.[O:29]=[C:30]1[NH:34][CH2:33][C@@H:32]([C:35](O)=[O:36])[CH2:31]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:24])([F:25])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=3)=[CH:11][C:10]([NH:28][C:35]([C@H:32]3[CH2:31][C:30](=[O:29])[NH:34][CH2:33]3)=[O:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1cc(F)cc(-c2cc(N)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: O=C1C[C@H](C(=O)O)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](OCc1cc(F)cc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Reaction time: 3 h

Procedure:
To a solution of 1-(4-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine prepared in the previous step (about 0.125 mmol) in dimethylformamide (0.5 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (18 mg) prepared according to the same procedures as Preparation 14 and WSC.HCl (29 mg) at room temperature, and the mixture was stirred for 3 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (31 mg).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[NH:16][NH2:17]>>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:17][NH:16][C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)NN
Product: CC(C)(C)OC(=O)NN=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a three-neck flask equipped with a mechanical stirrer and a condenser was loaded 1-Boc-4-piperidone (10.0 g, 50.2 mmol), tert-butyl carbazate (7.30 g, 55.2 mmol) and hexanes (20 mL). The mixture was heated to reflux for 3 h, then cooled to room temperature and filtered. The solid was washed with hexanes and dried at room temperature to give 4-(tert-butoxycarbonyl-hydrazono)piperidine-1-carboxylic acid tert-butyl ester (14.84 g, 94%) as a white powder. 1H NMR (CDCl3) δ 1.46 (s, 9H), 1.50 (s, 9H), 2.32 (m, 2H), 2.52 (m, 2H), 3.55 (m, 4H), 7.48 (br, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[N:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[N:21]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[N:25][C:20]2=[N:19][CH:18]=1)CCC>>[CH:9]([O:8][C:4]1[N:3]=[C:2]([C:17]2[N:21]3[CH:22]=[CH:23][C:24]([C:26]([F:27])([F:28])[F:29])=[N:25][C:20]3=[N:19][CH:18]=2)[CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH3:10]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: CC(C)Oc1cccc(Br)n1
Product: CC(C)Oc1cccc(-c2cnc3nc(C(F)(F)F)ccn23)n1
Yield: 35.7 %

Procedure:
2-Bromo-6-isopropoxypyridine (0.32 g, 1.58 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.13 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (20-40%) and trituration with isohexane gave 3-(6-isopropoxypyridin-2-yl)-7-(trifluoromethyl)imidazo[1,2-α]pyrimidine (130 mg) as a pale yellow solid: δH (400 MHz, CDCl3) 1.45 (6H, d, J 6), 5.29 (1H, quin, J 6), 6.69 (1H, d, J 8), 7.34 (1H, d, J 7), 7.39 (1H, d, J 7), 7.70 (1H, dd, J 8 and 7), 8.46 (1H, s), 10.26 (1H, d, J 7); m/z (ES+) 323 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:23]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24]1>ClCCl>[C:27]([CH2:26][CH2:25][CH2:24][C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1)=[O:30])([OH:29])=[O:28]
Reactant: O=C1CCCC(=O)O1
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Solvent: ClCCl
Product: CC1=NN=C(c2ccc(NC(=O)CCCC(=O)O)cc2)c2cc3c(cc2C1)OCO3

Procedure:
A solution of 0.50 g (1.7 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 30 ml of anhydrous dichloromethane was stirred with 0.18 g (1.87 mmol) of glutaric acid anhydride at 20°-25° C. for 6 hours. Next day he crystals formed were filtered at 0°-5° C., washed with 3×2 ml of dichloromethane and dried at 60°-80° C. to give 0.60 g (87.0%) or the pure aimed product, m.p. 225°-227° C. (decomp.).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH2:19]([CH:21]([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[NH2:22])[CH3:20].CO>CCCCCCC>[CH3:28][C:26]1[O:25][N:24]=[C:23]([CH:21]([NH:22][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH2:19][CH3:20])[N:27]=1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CCC(N)c1noc(C)n1
Agent: Cl
Solvent: CCCCCCC
Solvent: CO
Product: CCC(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1noc(C)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α-ethyl-5-methyl-1,2,4-oxadiazole-3-methanamine hydrochloride (1:1) (CAN 111997-68-3) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/8% ethanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 98.5%, 357.1925 (M+H)+, αD20 (MeOH)=+36.7°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][Cl:39]>CN(C)C=O>[Cl:39][CH2:38][CH2:37][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:14][C:15]3[C:16]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=4)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
6-Methoxy-4-(5,6,5′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol (compound 453) (30 mg) was suspended in N,N-dimethylformamide (2 ml). Potassium carbonate (107 mg) and 1-bromo-2-chloroethane (0.03 ml) were added to the suspension, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (36 mg, yield 100%).
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8]CC)=[O:7]>CO.O>[CH3:3][CH:4]([C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1)[CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)CC(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(CC(=O)O)c1ccncc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium hydroxide (0.19 g, 4.8 mmol) was added to a solution of ethyl 3-methyl-3-pyridin-4-ylpropanoate (Method 8; 0.501 g, 2.6 mmol) in MeOH (10 ml) and water (5 ml). The mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue shaken with 1 M hydrochloric acid (4.8 ml). The solvent was removed in vacuo to leave a colourless solid. M/z 164 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([CH3:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:16]1([Mg]Br)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[CH:16]1([CH:13]([C:11]2[C:10]([CH3:15])=[N:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:12]=2)[OH:14])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1nn(-c2cccc(Cl)c2)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: Cc1nn(-c2cccc(Cl)c2)cc1C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a solution (5 mL) of 1-(3-chlorophenyl)-3-methyl-1H-pyrazole-4-carbaldehyde (0.35 g) synthesized in the above-mentioned (2) in tetrahydrofuran under ice-cooling was added dropwise cyclohexylmagnesium bromide (2.4 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.25 g, 51%) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2/[CH:11]=[C:12]1\[O:13][C:14]2[C:21]([CH2:22][N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[C:20]([OH:36])[CH:19]=[CH:18][C:15]=2[C:16]\1=[O:17].[ClH:37]>C(Cl)Cl.O1CCOCC1>[ClH:37].[ClH:37].[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2/[CH:11]=[C:12]1\[O:13][C:14]2[C:21]([CH2:22][N:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)=[C:20]([OH:36])[CH:19]=[CH:18][C:15]=2[C:16]\1=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccc(Br)cc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2c[nH]c3ccc(Br)cc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(5-bromo-1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.015 g, 0.027 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in methylene chloride and thereby washed to obtain (Z)-2-[(5-bromo-1H-indol-3-yl)methylene]-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.012 g, 91%).