Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[CH2:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:20]([C:25]1[CH:26]=[C:27]([Cl:33])[C:28]([F:32])=[C:29]([Cl:31])[CH:30]=1)[C:21]([F:24])([F:23])[F:22].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[Cl:31][C:29]1[CH:30]=[C:25]([CH:20]([C:21]([F:24])([F:23])[F:22])/[CH:18]=[CH:17]/[C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[CH:26]=[C:27]([Cl:33])[C:28]=1[F:32]
Reactant: Fc1c(Cl)cc(C(Br)C(F)(F)F)cc1Cl
Reactant: C=Cc1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: CC(C)(C)OC(=O)N1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 150 °C
Yield: 11.7 %

Procedure:
To a stirred solution of tert-butyl-5-vinylindoline-1-carboxylate (1.28 g, 5.23 mmol) in 1,2-dichlorobenzene (10.0 mL), was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (3.4 g, 10 mmol), CuCl (103 mg, 1.05 mmol) and 2,2-bipyridyl (0.326 g, 2.092 mmol) and the resultant reaction mixture was degassed with argon for 30 min and heated to 150° C. for 1 h. The reaction mixture was cooled to RT and filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate/petroleum ether) to afford the title compound as a pale yellow gummy solid (0.3 g, 61%): 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=6.0 Hz, 2H), 7.22 (s, 2H), 7.16 (d, J=8.4 Hz, 1H), 6.52 (d, J=16.0 Hz, 1H), 6.21 (dd, J=16.0, 7.6 Hz, 1H), 4.07 (m, 3H), 3.10 (t, J=8.4 Hz, 2H), 1.55 (s, 9H); ESIMS m/z 433.79 ([M−H]−); IR (thin film) 1168, 858 cm−1.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[C:7]([OH:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:14][C:15]([C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1F)=[O:16].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[F:23][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([O:13][C:7]2[CH:8]=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([F:1])[C:11]=3[F:12])[C:17]=1[C:15](=[O:16])[CH3:14]
Reactant: CC(=O)c1c(F)cccc1F
Reactant: Oc1cnc2c(F)c(F)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1c(F)cccc1Oc1cnc2c(F)c(F)ccc2c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 43.4 %

Procedure:
0.5 g of 7,8-difluoro-3-hydroxyquinoline was dissolved in 10 mL of dimethylformamide. 0.52 g of 2,6-difluoroacetophenone and 0.46 g of potassium carbonate were added to the solution, and the mixture was stirred for 2.5 hours at 100° C. The thus obtained reaction solution was poured into ice water and then neutralized with dilute hydrochloric acid, the liquid was separated with ethyl acetate. The organic layer was concentrated and purified by silica gel column chromatography to obtain 0.38 g of 1-[2-fluoro-6-(7,8-difluoroquinolin-3-yloxy)-phenyl]-ethanone (Compound Number 391).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH:34]1([NH:37][CH3:38])[CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH:34]1([N:37]([CH3:38])[S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:15]=2)(=[O:22])=[O:21])[CH2:36][CH2:35]1
Reactant: CNC1CC1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N(C)C4CC4)c3)n2)n1
Yield: 51.4 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available N-cyclopropyl-N-methylamine [CAS-no. 5163-20-2] (0.16 ml, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.110 g, 51%) as a white solid. MS (ISP) 524.3 [(M+H)+]; mp 157° C.
Reaction SMILES: C[O-].[Na+].CN(C)[CH:6]=[O:7].Cl[C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([CH3:17])[CH:11]=1.O>CO>[CH3:6][O:7][C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([CH3:17])[CH:11]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Cl)cc(C)n1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C)nc(C)c1
Yield: 72 %

Procedure:
Sodium methoxide (2 eq.) was dissolved in methanol (1.5 volumes) and dry dimethylformamide (2 volumes). The solution was heated to (95-100ℑ C.)and while stirring under a stream of nitrogen, 4-chlorolutidine (1 eq.) was added dropwise. At the end of the reaction (about 2 hours), the mixture was cooled in an ice bath and cold water (10 volumes) was added. The product was extracted with dichloromethane (3×2 volumes). The combined organic extracts were dried over sodium sulfate, filtered and the solvent was evaporated under vacuum. Light yellow oil was obtained in 72% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]([CH3:24])=[C:14]([CH2:16][CH:17](C(O)=O)[C:18]([OH:20])=[O:19])[N:15]=2)=[CH:7][CH:6]=1)=[O:4]>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:12][C:13]([CH3:24])=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[N:15]=2)=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2nc(CC(C(=O)O)C(=O)O)c(C)o2)cc1
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-c2nc(CCC(=O)O)c(C)o2)cc1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
A solution of 2-([2-[4-(methoxycarbonyl)phenyl]-5-methyl-1,3-oxazol-4-yl]methyl)propanedioic acid (2.0 g, 6.00 mmol, 1.00 equiv) in dimethylsulfoxide (30 mL) was stirred at 160° C. for 30 min. The reaction mixture was cooled to room temperature and the product was precipitated by the addition of 150 mL ice and water. The solid was collected by filtration, washed with 1×50 mL of water and dried in vacuum to give 1.5 g (86%) of 3-[2-[4-(methoxycarbonyl)phenyl]-5-methyl-1,3-oxazol-4-yl]propanoic acid as a white solid. LC-MS: (ES, m/z): 290 [M+H]+, 272, 146, 120.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(N(CC)CC)C.[CH2:19]([N:22]=[C:23]=[O:24])[CH2:20][CH3:21]>C(Cl)Cl>[CH2:19]([NH:22][C:23]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([O:10][CH3:11])=[O:9])=[O:24])[CH2:20][CH3:21]
Reactant: COC(=O)c1ccccc1N
Reactant: CCCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)Nc1ccccc1C(=O)OC
Yield: 94.9 %

Procedure:
A mixture of 159 g of methyl anthranilate (1.053 mole), 5 ml of triethylamine and 134 g of n-propylisocyanate (1.58 mole) in 700 ml of petroleum ether (60°-80° C.) was refluxed for seventeen hours until TLC (CH2Cl2, silica) indicated that no methyl antranilate remained. The mixture was cooled and the precipitate was filtered off, washed with a little cold petroleum ether and dried under vacuum at room temperature to obtain 236 g (95% yield) of methyl N-(N'-n-propylcarbamoyl)-anthranilate melting at 101.5°-102.5° C.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][C:34]([NH:36][CH3:37])=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:23])([F:25])[F:24])=[C:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][C:34]([NH:36][CH3:37])=[O:35])=[O:4]
Reactant: CNC(=O)CN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 9 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 30 mg, 0.070 mmol), 2-amino-N-methylacetamide (9.19 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (70.4 mg, 0.696 mmol) were added to DMF (1 mL). This was stirred overnight before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=29.0 min) to provide (R/S)-2-hydroxy-N-(2-(methylamino)-2-oxoethyl)-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (3.5 mg, 6.28 μmol, 9.03% yield): LCMS=502.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.55 (1 H, br. s.), 8.17 (2 H, d, J=8.14 Hz), 7.59-7.85 (7 H, m), 5.20 (1 H, s), 3.78-4.01 (2 H, m), 2.75 (3 H, s); HPLC peak RT=8.2 min (Method A).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].FC(F)(F)S(O[CH2:18][C:19]([F:22])([F:21])[F:20])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:20][C:19]([F:22])([F:21])[CH2:18][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1OCC(F)(F)F
Reaction time: 72 h

Procedure:
A mixture of methyl salicylate (6.4 ml., 7.6 g., 0.05 mole), 2,2,2-trifluoroethyl trifluoromethanesulfonate (13.9 g., 0.06 mole), anhydrous potassium carbonate (13.8 g., 0.1 mole) and acetone (150 ml.) is heated under reflux with efficient stirring for three days. The product is filtered and the filtrate is concentrated to a small volume. It is diluted with cold water and the resulting precipitate is collected and washed successively with cold dilute sodium hydroxide solution and water. The desired material is recrystallized then from aqueous ethanol to afford white solid, m.p. 61-62.
Reaction SMILES: CCN=C=N[CH2:6][CH2:7][CH2:8][N:9]([CH3:11])C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:23]2[CH:24]=[CH:25]C=[CH:27][C:22]=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1>[NH:9]1[C:8]2[C:23](=[CH:22][CH:27]=[CH:6][CH:7]=2)[CH2:24][CH:25]=[CH:11]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CCN=C=NCCCN(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C1=CNc2ccccc2C1

Procedure:
In Step A, a substituted benzaldehyde is condensed with a substituted acetophenone or 1-pyridin-3-yl-ethanone (V), in the presence of an inorganic base such as NaOH, in a polar protic solvent such as MeOH, to give the corresponding α,β-unsaturated ketone of formula (VI). This product can be reduced to the corresponding saturated ketone by hydrogenation in presence of a catalyst, such as platinum (IV) oxide, in a mixture of polar solvents, such as ethanol and EtOAc, as described in Step B. When R1 or R2 are chloro, this moiety can simultaneously be reduced using palladium on carbon as a catalyst instead of platinum (IV) oxide. In step C, the aniline (VII) can be acylated by heating at reflux in the presence of an acyl chloride such as methyl oxalyl chloride in an apolar solvent such as toluene. The amide (VIII) can cyclize by heating at reflux in a polar protic solvent, such as methanol, in the presence of an inorganic base, such as potassium carbonate, as described in Step D to afford the corresponding 1,4-dihydroquinoline. When R1 is a carboxylic ester moiety in the coupling Step A, both the ester and corresponding carboxylic acid can be formed by hydrolysis; the acid can then be coupled with an amine NHR9R10 in the presence of coupling agents such as EDCI and BOP and an organic base such as diisopropylethylamine in a polar solvent such as tetrahydrofuran. The amide of generic formula (IX) can undergo the same Steps described above from B to D to give the corresponding 1,4-dihydroquinoline.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:13]2[CH2:14][CH2:15][N:16]([CH2:19][C:20](=O)[CH2:21][CH2:22][N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)[CH2:17][CH:18]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[C:7]1([C:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)[CH2:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CCn1cccn1)CN1CC=C(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1=C(c2ccccc2)CCN(CCCCn2cccn2)C1
Yield: 82 %

Procedure:
2.0 g of LiAlH4 are added to a solution of 3.3 g (10 mmol) of 1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)-3-oxobutyl]-1H-pyrazole in 25 ml of THF. The resulting mixture is refluxed for 2 hours. The excess LiAlH4 is destroyed by addition of concentrated NaOH and water. The inorganic salts are filtered off and the THF is evaporated under vacuum, giving 2.6 g (8.2 mmol) of 1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-1H-pyrazole.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:31])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C>[N:32]([CH2:12][C@H:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])[CH:17]=[C:18]([F:23])[CH:19]=2)[O:14]1)=[N+:33]=[N-:34]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1C=Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Reaction time: 0.08 h
Yield: 88.5 %

Procedure:
A solution of (R)-(8-(2,6-dichlorophenyl)-6-fluoro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate prepared in Example 57, step 7 (500 mg, 1.0 mmol) and sodium azide (340 mg, 5.2 mmol) in anhydrous DMF (20 mL) was heated at 90° C. under nitrogen for 20 hours. The cooled reaction mixture was quenched by the addition of water (20 mL) and the resulting suspension stirred vigorously for 5 minutes. The mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL), the organic phase separated, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Column chromatography on silica gel with 10–25% ethyl acetate in hexanes afforded 310 mg (85%) of (R)-2-azidomethyl-8-(2,6-dichloro-phenyl)-6-fluoro-2H-chromene as a yellow oil. [α]D25=+282.1° (c=2.7 mg/0.7 MeOH); MS (EI) m/z 349. (M+).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([NH2:16])[CH:15]=1.O.Cl>N1C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([NH:16][C:1](=[O:3])[CH3:2])[CH:15]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C)c(N)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C)c(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
Acetic anhydride (5.6 g, 54.66 mmol) was added to a solution of 5-methoxy-2-methyl-phenylamine (5.0 g, 36.44 mmol) in pyridine (30 mL) and the resulting mixture was stirred at room temperature overnight. Water was added and the pH was adjusted to 5 by addition of an aqueous solution of hydrochloric acid (3 M). The resulting mixture was extracted with dichloromethane; the organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate and with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford 5.93 g of N-(5-methoxy-2-methyl-phenyl)-acetamide as a white solid without further purifications.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:22])[C:15]=1[C:16]([NH:18][CH2:19][CH2:20]Br)=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2.[I-].[K+].[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:22])[C:15]=1[C:16]([NH:18][CH2:19][CH2:20][N:41]1[CH2:42][CH2:43][N:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)[CH2:39][CH2:40]1)=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)NCCBr)cc(OC)c1OC
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)NCCN2CCN(c3ccccn3)CC2)cc(OC)c1OC

Procedure:
0.2 g of 3',4',5'-trimethoxy-3-(2-bromoethylamino-carbonyl) flavone were dissolved in 10 ml dichloromethane, and the solution was reacted with a spatula tip full of potassium iodide and 0.5 ml 1-(2-pyridyl)-piperazine. The reaction mixture was heated at reflux temperature for one hour. After cooling, the reaction mixture was worked up by adding further dichloromethane and shaking with saturated sodium carbonate solution and water. Then the organic phase was dried over sodium sulfate, concentrated, and the residue was purified by column chromatography on silica gel under slightly elevated pressure (flash chromatography) using tetrahydrofuran/ethylacetate 1:1 as the eluent. In this way 3',4',5'-trimethoxy-3-{2-[4-(2-pyridyl)-piperazin-1-yl]-ethylamino-carbonyl) flavone was obtained in pure amorphous form.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].Cl.[CH3:16]O>>[C:1]([NH:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:16])=[O:11])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1ccc(C(=O)O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(CNC(C)=O)cc1
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
4-Acetamidomethylbenzoic acid(4.0 g) was dissolved in 0.5% hydrochloric acid—methanol solution (100 ml). The mixture was stirred at 40° C. for 3.5 hr, and poured into ice water (300 ml) and extracted with ethyl acetate (100 ml×4). The extract was washed with saturated sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-yellow solid (4.3 g). The obtained solid was crystallized from ethyl acetate (50 ml) to give the title compound (3.2 g) as pale-yellow white crystals, m.p.=110-111° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][CH:8]=[C:7]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:6]=2.C(N(CC)CC)C.[CH2:36]([O:38][CH2:39][C:40](Cl)=O)[CH3:37]>ClCCCl.C(O)CCC.C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:22]([O:21][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:37]([CH2:36][O:38][CH2:39][CH3:40])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1NC(=O)OC(C)(C)C
Temperature: 135 °C
Reaction time: 2 h
Yield: 41.3 %

Procedure:
A suspension of tert-butyl N′-(3-amino-7-benzyloxyquinolin-4-yl)hydrazinecarboxylate (29.6 g, 77.8 mmol) in 250 mL of 1,2-dichloroethane was placed under an atmosphere of nitrogen. The mixture was treated with triethylamine (30.9 mL, 233 mmol). The mixture was then treated dropwise with ethoxyacetyl chloride (10.5 g, 85.6 mmol). After 2 h, the reaction was concentrated under reduced pressure to give a brown oil. The oil was dissolved in 200 mL of 1-butanol and treated with pyridinium p-toluenesulfonate (0.25 g, 1.0 mmol). The mixture was heated to 135° C. under an atmosphere of nitrogen. After 20 h, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to give a brown oil. The oil was dissolved in 250 mL of CHCl3 and washed with saturated NaHCO3 solution (75 mL), water (75 mL) and brine (75 mL). The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure to give an orange/brown oil. The oil was purified by chromatography (SiO2, 9:1 CHCl3:MeOH) to yield 14.4 g of tert-butyl (7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)carbamate as an orange/brown foam.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][CH3:12])[C:6]([C:13]2[O:17][C:16](=[O:18])[NH:15][N:14]=2)=[CH:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Br:50][CH2:51][CH2:52]O>O.C1COCC1>[Br:50][CH2:51][CH2:52][N:15]1[N:14]=[C:13]([C:6]2[C:7]([NH:9][CH2:10][CH2:11][CH3:12])=[N:8][C:3]([S:2][CH3:1])=[N:4][CH:5]=2)[O:17][C:16]1=[O:18]
Reactant: OCCBr
Reactant: CCCNc1nc(SC)ncc1-c1n[nH]c(=O)o1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCNc1nc(SC)ncc1-c1nn(CCBr)c(=O)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To 5.0 mL of THF, 5-(2-methylthio-4-propylaminopyrimidin-5-yl)-3H-[1,3,4]oxadiazol-2-one (200 mg) obtained in Step 1 of Example 17 was dissolved, then triphenylphosphine (588 mg), DEAD (40% toluene solution, 1.02 mL, 2.34 mmol) and 2-bromoethanol (280 mg) were added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction was confirmed by thin-layer chromatography, the reaction mixture was added with water and was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to give 3-bromoethyl-5-(2-methylthio-4-propylaminopyrimidin-5-yl)-3H-[1,3,4]oxadiazol-2-one [Compound (P) in which R1 represents n-propylamino, R8A represents 2-bromoethyl] (210 mg, yield 75%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH:24]=[O:25])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][OH:25])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CO)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.844 g, 2.30 mmol) in MeOH was added sodium borohydride (0.096 g, 2.53 mmol), and the reaction was stirred at room temperature for 15 minutes. The mixture was concentrated, and the residue was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[NH:4][CH2:3][CH2:2]1.[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]2[O:1][CH2:2][CH2:3][NH:4][C:5](=[O:12])[C:6]=2[CH:11]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1NCCOc2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1NCCOc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 22.2 %

Procedure:
To 2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one (30.34 g, 190 mmol) in conc. sulfuric acid (600 ml) at 0° C. was added potassium nitrate (20.82 g, 206 mmol) portionwise. The mixture was stirred for 20 minutes at 0° C. and then for 4 h at room temperature. The mixture was poured onto ice (21) and the solids were collected by filtration. The solids were taken up in hot ethyl acetate and then cooled to yield the title compound (8.79 g, 22%), MS m/z 209 [M+H]+.