Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](=[O:60])[N:41]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:34])[N:15]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])(OC(C)(C)C)=O.[F:61][C:62]([F:67])([F:66])[C:63]([OH:65])=[O:64]>C(Cl)Cl>[OH:65][C:63]([C:62]([F:67])([F:66])[F:61])=[O:64].[CH3:50][O:49][C:47]([CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][N:41]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])[C:40]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:34])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[O:60])=[O:48]
Reactant: COC(=O)CCCCCN(CCCCCC(=O)OC)C(=O)CCCCCN(CCCCCC(=O)N(CCCCCC(=O)OC)CCCCCC(=O)OC)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCCCCN(CCCCCC(=O)OC)C(=O)CCCCCNCCCCCC(=O)N(CCCCCC(=O)OC)CCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 250 mL round bottom flask, charged with 1.50 g (1.75 mmol) of N—BOC—N,N-bis-(N′,N′-bis(5-methoxycarbonylpentyl)-5-carbamyl pentyl)-amine (17) in 15 mL of methylene chloride, was added 15 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 15 minutes and then concentrated. The residue was diluted with 50 mL of methylene chloride and then concentrated via rotary evaporation. The residue was then diluted with 50 mL of methanol and re-concentrated via rotary evaporation. The residue was again re-diluted with 50 mL of methylene chloride and re-concentrated, first via rotary evaporation and then under full vacuum pump pressure (<0.5 mm Hg).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:8]2[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)#[N:2].[N-:35]=[N+:36]=[N-:37].[Na+].[Cl-].[NH4+].O>CS(C)=O>[CH2:15]([C:10]1[C:9]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:8]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:3][C:1]3[N:35]=[N:36][NH:37][N:2]=3)[CH:6]=2)[N:11]=1)[CH:16]([CH3:17])[CH3:18]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCC#N)cc23)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCc4nn[nH]n4)cc23)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 93.5 %

Procedure:
To a solution of tert-butyl {[6-(cyanomethoxy)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.46 g, 1.0 mmol) and sodium azide (0.13 g, 2.0 mmol) in dimethyl sulfoxide (10 ml) was added ammonium chloride (0.22 g, 4.0 mmol), and the mixture was stirred at 70° C. for 24 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give tert-butyl {[2-isobutyl-4-(4-methylphenyl)-6-(2H-tetrazol-5-ylmethoxy)quinolin-3-yl]methyl}carbamate (0.47 g, yield 93%) as pale-yellow crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].Cl[C:29]1[C:38]2[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=2)[N:32]=[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])[C:30]=1[CH3:47]>CCOC(C)=O>[F:39][C:35]1[CH:34]=[C:33]2[C:38]([C:29]([N:13]3[C:11]4[C:10](=[CH:9][CH:8]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:12]=4)[C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:14]3)=[C:30]([CH3:47])[C:31]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[F:46])=[N:32]2)=[CH:37][CH:36]=1
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Reactant: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21
Temperature: 140 °C

Procedure:
Under a N2 atmosphere, 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (0.19 g, 0.69 mmol) was dissolved in DMF (2.00 mL, 26 mmol) and sodium hydride (0.018 g, 0.76 mmol) was added and the reaction was treated with 4-chloro-7-fluoro-2-(2-fluorophenyl)-3-methylquinoline (0.100 g, 0.35 mmol) and heated to 140° C. for 6 h. The reaction was then diluted with EtOAc and washed with 2% sodium bicarbonate then brine. The layers were separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The reaction was then purified by flash column chromatography eluting with 40% to 60% EtOAc in hexane and then purified by preparative reverse phase HPLC to afford 1-(7-fluoro-2-(2-fluorophenyl)-3-methyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran]. Mass Spectrum (ESI) m/e=528.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.99 (1H, m), 7.83 (1H, dd, J=10.2, 2.3 Hz), 7.50-7.62 (3H, m), 7.35-7.42 (2H, m), 7.10 (1H, d, J=8.2 Hz), 6.29 (1H, dd, J=8.2, 2.3 Hz), 5.56 (1H, d, J=2.3 Hz), 4.07 (1H, d, J=9.8 Hz), 3.80-3.91 (3H, m), 3.56-3.63 (4H, m), 3.41-3.54 (2H, m), 2.82-2.89 (4H, m), 2.05 (3H, d, J=1.2 Hz), 1.90-2.02 (2H, m), 1.81-1.88 (1H, m), 1.62-1.72 (1H, m)
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[NH2:19][C:20]1[C:25]([NH2:26])=[C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[C:30]([F:41])[CH:29]=2)[CH:23]=[CH:22][N:21]=1>C1COCC1>[O:4]=[C:2]1[NH:19][C:20]2=[N:21][CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:40])[C:36]([F:37])([F:38])[F:39])=[C:30]([F:41])[CH:29]=3)=[C:25]2[NH:26]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1nccc(Oc2ccc(NC(=O)C(F)(F)F)c(F)c2)c1N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)cc1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 48 h
Yield: 49 %

Procedure:
Method E3 (with triphosgene and Pyridine). N-(4-(2,3-Diaminopyridin-4-yl-oxy)-2-fluorophenyl)-2,2,2-trifluoroacetamide (500 mg, 1.5 mmol) was dissolved in dry THF (20 mL), pyridine (1 mL) was added and the solution was cooled at 0° C. Triphosgene (445 mg, 1.5 mmol) in dry THF (10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 48 hours. The solvent was evaporated and the residue washed with water. The precipitate was recovered by filtration to afford the title compound (260 mg, 49%). 1H-NMR (δ, ppm, DMSO-d6): 6.57 (d, 1H, HPy,5), 6.98 (d, 1H, Harom,Ph), 7.36 (d, 1H, Harom,Ph), 7.50 (d, 1H, Harom,Ph), 7.75 (d, 1H, HPy,6), 11.26 (s, 1H, NHPy3), 11.30 (s, 1H, NHCOCF3), 11.48 (s, 1H, NHPy2). LC-MS (m/z): 356 (M, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH:16]([F:18])[F:17])[O:11][C:10]=1[CH:19](O)[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.CCOC(C)=O.Cl>CC#N.[Zn]>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH:16]([F:18])[F:17])[O:11][C:10]=1[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)c1oc(C(F)F)cc(=O)c1OCc1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: CC#N
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCc1oc(C(F)F)cc(=O)c1OCc1ccccc1
Reaction time: 9 h
Yield: 50.5 %

Procedure:
To a solution of 3-benzyloxy-6-difluoromethyl-2-(1-hydroxy-ethyl)-pyran-4-one (1.30 g, 4.38 mmol), described in step 2 of Example 10, in CH3CN (14 mL) cooled in an ice-salt bath was added a solution of SOCl2 (0.45 mL, 5.44 mmol) in CH3CN (0.5 mL). The reaction mixture was stirred at ice-cold temperature for 9 hrs. The progress of the reaction was monitored by TLC using a mixture of hexanes and EtOAc (1/1, v/v) as eluant. Volatile materials were removed in vacuo, and ice-cold i-PrOH (15 mL) was added, and the mixture was cooled in an ice-salt bath. Then Zn dust (600 mg, 9 mmol) was added followed by concentrated HCl (1.1 mL). After 20 min, the reaction mixture was filtered through a CELITE™ bed, and the filtrate was evaporated to dryness. The residue was taken up in CH2Cl2 (100 mL), and the organic layer was washed with brine (2×30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residual oil was purified by column chromatography on silica gel using a mixture of hexanes and EtOAc (10/3, v/v) as eluant. Fractions rich in product were combined together, and concentrated to give 3-benzyloxy-6-difluoromethyl-2-ethyl-pyran-4-one (0.62 g) as a yellow oil. HPLC purity (peak area percent) of this material is 99.0% at λ=280 nm using HPLC Method 1 as described above. 1H NMR (400 MHz, DMSO-D6) δ(ppm): 7.30-7.40 (m, 5H), 7.06 (t, J=52.7 Hz, 1H, CF2H), 6.76 (s, 1H), 5.07 (s, 2H), 2.56 (q, J=7.4 Hz, 1H, CH2CH3), 0.97 (t, J=7.5 Hz, 3H, CH2CH3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Cl)[CH:17]=1>CC(C)=O.ClCCl>[Br:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][N:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1
Reactant: ClCc1cccc(Br)c1
Reactant: O=S1(=O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=S1(=O)CCN(Cc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of thiomorpholine 1,1-dioxide (0.72 g, 5.4 mmol) and potassium carbonate (0.74 g, 5.4 mmol) in acetone (10 mL) was added bromo-3-chloromethyl-benzene (0.62 mL, 4.9 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (50 mL), filtered through a plug of diatomaceous earth and evaporated to a waxy solid. The material was purified via chromatography utilizing an ISCO automated purification apparatus (24 g silica gel column 10%→100% ethyl acetate in hexane). 4-(3-Bromo-benzyl)-thiomorpholine 1,1-dioxide was isolated as a clear viscous oil that solidified to a white solid (1.0 g, 67%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.49 (s, 1H), 7.41 (ddd, J=6.9, 1.9, 1.9 Hz, 1H), 7.25-7.19 (m, 2H), 3.62 (s, 2H), 3.10-2.96 (m, 8H). MS=304, 306 (MH)+.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]([NH2:15])=[CH:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=1)[CH2:2][CH3:3].[CH3:16][N:17]([CH3:20])C=O>O>[CH2:1]([N:4]1[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:13])([F:14])[F:12])=[CH:7][C:6]=2[N:15]=[C:11]1[C:8]1[CH:9]=[CH:20][N:17]=[CH:16][CH:7]=1)[CH2:2][CH3:3]
Reactant: CCCNc1ccc(C(F)(F)F)cc1N
Reactant: CN(C)C=O
Solvent: O
Product: CCCn1c(-c2ccncc2)nc2cc(C(F)(F)F)ccc21
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A mixture of 0.44 g of N1-propyl-4-trifluoromethylbenzene-1,2-diamine, 0.51 g of isonicotinealdehyde-bisulfite adduct and 4 ml of N,N-dimethylformamide was stirred for 1 hour at 150° C. The reaction mixture was allowed to cool to room temperature, and water was poured into this, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, then, concentrated under reduced pressure to obtain a solid residue. The residue was washed with hexane, to obtain 0.55 g of 1-propyl-2-(pyridin-4-yl-)-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 218).
Reaction SMILES: P(OCC)(OCC)(O[C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=3)[N:12]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:11]=2)[C:7]([C:33]#[N:34])=[CH:6][N:5]=1)=O.[NH2:41][C@@H:42]([CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1)[CH3:43].C(N(C(C)C)CC)(C)C>C1COCC1.C(OCC)(=O)C>[C:33]([C:7]1[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=3)[N:12]([S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=3)(=[O:24])=[O:25])[CH:11]=2)=[N:9][C:4]([NH:41][C@@H:42]([CH:44]2[CH2:45][CH2:46][N:47]([C:50]([O:52][C:53]([CH3:54])([CH3:56])[CH3:55])=[O:51])[CH2:48][CH2:49]2)[CH3:43])=[N:5][CH:6]=1)#[N:34]
Reactant: CCOP(=O)(OCC)Oc1ncc(C#N)c(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(C(F)(F)F)cc23)n1
Reactant: C[C@@H](N)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCN(C(=O)OC(C)(C)C)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.6 %

Procedure:
5-cyano-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl diethyl phosphate (200 mg, 0.3359 mmol) was treated with a solution of (R)-tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate (76.70 mg, 0.3359 mmol) in THF (2 mL), and diisopropylethylamine (70.22 μL, 0.4031 mmol). The reaction mixture was stirred at room temperature for 24 hours. The crude mixture was diluted with ethyl acetate and washed with aqueous NaHCO3. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified on silica gel by flash column chromatography to afford the title compound as a colourless glass (188 mg, 84% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:21]2)=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:22]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[N:21]2)=[CH:17][CH:16]=1
Reactant: COC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A mixture of methyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (640 mg), lithium hydroxide monohydrate (363 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours, and 1N hydrochloric acid (9 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (592 mg, yield: 97%). This was recrystallized from ethyl acetate-hexane. Melting point: 179–180° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[CH:13]=[CH:12][C:11](OC)=[C:10](OC)[CH:9]=1)=[O:7].[C:23]1(OC)[C:24](=CC=[CH:29][CH:30]=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].C1(C(Cl)=O)C2C(=CC=CC=2)C=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[C:9]2[C:10](=[CH:24][CH:23]=[CH:30][CH:29]=2)[CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Reactant: COc1ccccc1OC
Agent: O=C(Cl)c1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2cccc3ccccc23)cc1OC

Procedure:
1-(3,4-Dimethoxybenzoyl)naphthalene was prepared analogously to 3,4,3′,4′-tetramethoxybenzophenone using veratrole (1.3 mL, 10 mmol), aluminum chloride (1.5 g, 11 mmol) and 1-naphthoyl chloride (1.5 mL, 10 mmol) with a reaction time of 24 hours at room temperature. The crude product was purified by flash column chromatography (silica gel, 2.5% ethyl acetate/methylene chloride) to afford 1.85 g (63%) of the product as a white solid: mp 92.5-94.5° C.; 1H NMR (CDCl3) δ8.06-7.84 (m, 3 H), 7.80-7.39 (m, 5 H), 7.31-7.21 (m, 1 H), 6.84-6.74 (m, 1 H), 3.94 (s, 3 H), 3.91 (s, 3 H); 13C NMR (CDCl3) δ196.6, 153.5, 149.0, 136.8, 133.6, 131.1, 130.9, 130.5, 128.2, 126.9, 126.7, 126.3, 126.3, 125.6, 124.3, 111.3, 109.7, 56.0, 55.9; Anal. Calcd for C19H16O3. Theoretical: C, 78.06; H, 5.52. Found: C, 77.97; H, 5.66.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:16])[C:8](=[O:15])[NH:9]2.[CH2:17]([O:19][C:20](=[O:26])/[CH:21]=[CH:22]/[C:23](O)=[O:24])[CH3:18].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl>CN(C)C=O.O.C(N(CC)CC)C>[CH2:17]([O:19][C:20](=[O:26])[CH:21]=[CH:22][C:23](=[O:24])[NH:2][CH2:3][C:4]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:16])[C:8](=[O:15])[NH:9]2)[CH3:18]
Reactant: NCc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12
Reactant: CCOC(=O)/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=CC(=O)NCc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12
Reaction time: 0.25 h

Procedure:
351 mg (1 mmol) of 5-aminomethyl-7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline hydrochloride, (Example 2) 217 mg (1.5 equiv.) of fumaric acid monoethyl ester, 0.210 ml of triethylamine, 383 mg (2 equiv.) of N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride and 270 mg (2 equiv.) of 1-hydroxy-benzotriazole are stirred at 20° C. in dried dimethylformamide for 18 hours. The mixture is poured into 700 ml of water and 3 ml of 1 N hydrochloric acid and stirred for 15 minutes. The solid is filtered off, washed with water and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.Cl[CH2:11][CH2:12][O:13][CH2:14][CH2:15]Cl.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: ClCCOCCCl
Reactant: COc1cccc(N)c1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(N2CCOCC2)c1
Yield: 77.1 %

Procedure:
A solution of m-anisidine (11.2 mL, 0.1 mol), chloroethyl ether (11.7 mL, 0.1 mol), and diisopropylethylamine (35 mL, 0.2 mol) in toluene (100 mL) was stirred at reflux for 72 h. The precipitate was removed by filtration and washed with toluene (100 mL). The combined toluene solutions were concentrated in vacuo and purified by distillation (120-130° C., 0.2 Torr) to afford the intermediate 4-(3-methoxyphenyl)-morpholine (14.9 g, 77%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].I[C:8]1[NH:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1.C(O)CO>CCOC(C)=O.[Cu]I.CC(O)C>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34][C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:30][CH:29]=1
Reactant: N#Cc1ccc(-c2nc(-c3ccccc3)[nH]c2I)cc1
Reactant: Sc1ccc(Cl)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: OCCO
Product: N#Cc1ccc(-c2nc(-c3ccccc3)[nH]c2Sc2ccc(Cl)cc2)cc1
Temperature: 80 °C

Procedure:
CuI (20 mg, 0.104 mmol), K2CO3 (573 mg, 4.15 mmol), the product of Step 2 (770 mg, 2.0 mmol), and 4-chlorobenzenethiol (330 mg, 2.2 mmol) were added to a flask, which was flushed with N2. 2-Propanol (8 mL) and ethylene glycol (0.23 mL, 4.15 mmol) were added. The reaction mixture was heated at 80° C. for 24 h. Then the reaction was diluted with EtOAc, filtered, concentrated, and the residue was subject to silica column chromatography (5-25% EtOAc in hexanes) to give the title compound. 1H NMR (500 MHz, (CD3OD): 8.08 (m, 1H), 8.01 (d, 2H), 7.78 (d, 2H), 7.47 (m, 4H), 7.24 (d, 2H), 7.17 (d, 2H). LCMS: m/z 388.0 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:24][CH2:25][CH2:26][CH2:27][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)([CH3:23])[CH3:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd]>[N:28]1([CH2:27][CH2:26][CH2:25][NH:24][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)([CH3:23])[CH3:22])[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Product: CC(C)(NCCCn1ccnc1)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
N-[1-(4'-Benzyloxybiphenyl-4-yl)-1-methylethyl]-3-(imidazol-1-yl)propylamine was hydrogenated, using palladium on charcoal as catalyst, in IMS at atmospheric pressure to give 4'-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}biphenyl-4-ol, m.p. 178-180° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=O)[C:3]=1[C:16]([O:18]CC)=[O:17].C1COCC1.[Li+].[OH-]>CO.C(O)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)c1c(O)c2cccc([N+](=O)[O-])c2[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc2c([N+](=O)[O-])cccc2c1O
Temperature: 40 °C
Yield: 63.3 %

Procedure:
A mixture of 2-nitroaniline (6.907 g) and diethyl ethoxymethylenemalonate (10.812 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The mixture is cooled to 80° C. Diphenyl ether (60 mL) is added and the mixture is heated to 250° C. for 2 h. The solution is cooled to room temperature. The resulting solid is collected, washed with hexanes and dried to yield 3.447 g of ethyl 4-hydroxy-8-nitroquinolone-3-carboxylate as a gold solid. To a mixture of this ester (1.2 g) in 66 mL of 1:1 MeOH:THF is added 18 mL of 1M LiOH. The reaction is maintained at 40° C. overnight. The reaction mixture is cooled to room temperature, then diluted with 35 mL glacial acetic acid. The resulting precipitate is collected, washed with H2 0 and hot isopropanol, and dried to yield 0.639 g of 4-hydroxy-8-nitroquinoline-3-carboxylic acid as a yellow solid. A mixture of this acid (0.20 g) and p-chlorobenzylamine (0.10 mL) are dissolved in 25 mL xylenes and heated to reflux. PCl3 (0.037 mL) is added dropwise and the mixture is refluxed for 4 hours. The reaction mixture is cooled to room temperature and H2O is added to quench excess PCl3. An orange solid precipitates, which is collected, washed with ether, and dried. The crude product is recrystallized with hot MeOH to yield 0.0367 g of the desired product as a yellow solid.