Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6](=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]#[N:5].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(N(CC)CC)C>[CH3:16][S:17]([O:1][N:2]=[C:3]([C:6](=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]#[N:5])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC(=NO)C(=O)C=Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)ON=C(C#N)C(=O)C=Cc1ccccc1

Procedure:
2-Hydroxyimino-3-oxo-5-phenyl-pent-4-enenitrile (4.0 g; 0.02 mol) is treated with methanesulfonyl chloride and triethylamine as described in example 3.4. The crude brown product is recrystallized from 40 ml of ethanol. 2-Methylsulfonyloxyimino-3-oxo-5-phenyl-pent-4-enenitrile (2.2 g; %) is obtained as a light ochre solid (mp 163-165° C.).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([C:11]([O:13]CC)=[O:12])=[CH:8][C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:6][C:5]=2[N:4]([CH:22]([CH3:24])[CH3:23])[N:3]=1.[OH-].[Na+].Cl>C1COCC1.C(O)C.O>[Br:1][C:2]1[C:10]2[C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:6][C:5]=2[N:4]([CH:22]([CH3:24])[CH3:23])[N:3]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)nc2c1c(Br)nn2C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)n1nc(Br)c2c(C(=O)O)cc(-c3ccccc3)nc21
Temperature: 55 °C
Reaction time: 3 h

Procedure:
Ethyl 3-bromo-1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (112 mg, 0.288 mmol) was suspended in THF (0.5 mL) and ethanol (1.5 mL), followed by addition of 3N NaOH (150 μl, 0.433 mmol). The reaction mixture was stirred at 55° C. for 3 hours, and then allowed to cool to room temperature. The reaction mixture was diluted with water (1.5 mL), cooled in an ice bath, and acidified with 1N HCl in a dropwise manner. The mixture was extracted with EtOAc. The organic layer was separated and concentrated in vacuo to afford a solid that dried on the high vacuum 3 hours. The product was collected as a pale yellow solid (93.6 mg, 90%). LCMS E-S (M+H)=360.0/362.2. 1H NMR (400 MHz, MeOD) δ8.22 (dd, J=1.52, 8.08 Hz, 2H), 8.05 (s, 1H), 7.48-7.59 (m, 3H), 5.47 (quip, J=6.76 Hz, 1H), 1.63 (d, J=6.82 Hz, 6H)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6].[CH:11]1[CH:16]=[CH:15][C:14]([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1.O.CC#N>CC#N>[Br-:1].[CH:8]([O:7][C:5]([CH2:4][CH2:3][CH2:2][P+:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][CH:15]=1)=[O:6])([CH3:10])[CH3:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)OC(=O)CCCBr
Solvent: CC#N
Solvent: O
Product: CC(C)OC(=O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Reaction time: 1 h

Procedure:
A solution of 4-bromobutyric acid (50 g) in 2-propanol (200 mL) containing 1 mL of H2SO4 was refluxed for 3 h, then cooled to ambient temperature, diluted with ether (500 mL), washed with saturated NaHCO3 (3×300 mL), and brine (300 mL). The organic extract was dried (MgSO4), filtered and concentrated in vacuo to give isopropyl 4-bromo-butyrate (52 g) as an oil. This ester was dissolved in MeCN (380 mL). Ph3P (100 g) was added and the solution was heated at reflux for 72 h, after which TLC analysis (20% water/MeCN, C-18 RP TLC plates) showed complete reaction. The mixture was cooled and concentrated and the residue was slurried with toluene (400 mL) for 1 h. The solid was collected by filtration and was washed with toluene (100 mL) and then dried in vacuo at 50° C. to provide (3-(isopropoxycarbonyl)propyl)triphenylphosphonium bromide (100.6 g). 1H NMR (CDCl3): δ 1.19-1.22 (d, 6H), 1.85-1.97 (m, 2H), 2.85 (t, 2H), 3.95-4.10 (m, 2H), 4.89-5.03 (m, 1H), 7.65-7.94 (m, 15H).
Reaction SMILES: C[C:2]([CH3:31])([CH3:30])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2F)=[N:12]1)=[O:10])[C:4]([NH:6]C)=[O:5].F[C:33]1C=C(C2C3CN(C(OC(C)(C)C)=O)CCC=3NN=2)C=CC=1F.N[C@H](C(N)=O)[C@H](CC)C>>[NH2:6][C:4](=[O:5])[C@@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:22]=[CH:23][C:24]([F:28])=[C:25]([F:27])[CH:26]=2)=[N:12]1)=[O:10])[C@@H:2]([CH3:31])[CH2:30][CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(F)c(F)c3)c2C1
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Agent: CC[C@H](C)[C@H](N)C(N)=O
Product: CC[C@H](C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCN(C)C2)C(N)=O

Procedure:
Compound 50 was prepared according to the procedure described for the synthesis of compound 37 by replacing intermediate 19 with intermediate 15, and replacing tert-leucine methylamide with L-isoleucine amide. 1H NMR (CDCl3) δ 7.67 (d, J=8.8 Hz, 1H), 7.49-7.55 (m, 1H), 7.37-7.41 (m, 1H), 7.19-7.24 (m, 1H), 5.95 (s, 1H), 5.63 (s, 1H), 4.30-4.33 (m, 1H), 3.59 (s, 2H), 3.20 (s, 2H), 2.75-2.78 (m, 2H), 2.54 (s, 3H), 2.07-2.10 (m, 1H), 1.60-1.67 (m, 1H), 1.22-1.30 (m, 1H), 1.03 (d, J=6.8 Hz, 3H), 0.98 (t, J=7.4 Hz, 3H). LCMS (+ESI) m/z=406.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[N:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)(Cl)Cl>[N:25]1([C:31]([NH:1][C:2]2([C:8]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)N1CCOCC1
Temperature: 60 °C
Yield: 87.2 %

Procedure:
After neutralizing 203 g (500 mmol) of phenylmethyl 1-aminocyclohexanecarboxylate.p-toluenesulfonate with a 10% sodium carbonate solution, the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. The solid material was filtered off, and after adding 56 g (550 mmol) of triethylamine to the chloroform layer, 75 g (500 mmol) of 4-morpholinecarbonyl chloride was added dropwise, and the mixture was heated in an oil bath (60° C.) for 3 days. After completion of the reaction, the reaction mixture was washed successively in the order of water, a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated NaCl solution, and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the resulting crystals were washed with ether to obtain 151 g (Yield: 87%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[O:7][CH:8]=1)([OH:3])=O.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[CH3:41][NH:42][C@H:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH2:45][CH2:44]1>ClCCl>[CH3:41][N:42]([C@H:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH2:45][CH2:44]1)[C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[O:7][CH:8]=1)=[O:3]
Reactant: CN[C@@H]1CCCc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)co2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN(C(=O)c1coc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.5 %

Procedure:
A mixture of 1-(1,1-dimethylethyl) 4-(4-carboxy-2-oxazolyl)-1-piperidinecarboxylate (600 mg, 2.02 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (425.57 mg, 2.22 mmol) and N-methylmorpholine (224.55 mg, 2.22 mmol) in 4 mL dichloromethane was stirred for 15 minutes at room temperature. To the reaction mixture was added 424 mg (2.63 mmol) of (1R)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine was added and the reaction mixture was stirred for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using 25-75% of ethyl acetate in hexanes as eluant to give 360 mg of the title compound as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][CH2:16]1)[C:6]([O:8]C)=[O:7])#[N:2].[OH-].[Li+]>O1CCCC1.CO.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:16][CH2:17]1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(OCC2CC2)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(C(=O)O)ccc1OCC1CC1
Yield: 73.4 %

Procedure:
Methyl 3-cyano-4-[(cyclopropylmethyl)oxy]benzoate (D23; 74 mg, 0.320 mmol) was stirred at room temperature under nitrogen with lithium hydroxide (15.33 mg, 0.640 mmol) in tetrahydrofuran (THF) (2 ml), methanol (2 ml) and water (1 ml) for 20 h. The mixture was partitioned between water (20 ml), 2N hydrochloric acid (5 ml) and ethyl acetate (3×20 ml), and the organic layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and evaporated in vacuo to give the title compound as a white solid (51 mg)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:43]=[CH:42][C:34]3[NH:35][C:36]([C:38]([O:40]C)=[O:39])=[N:37][C:33]=3[CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:43]=[CH:42][C:34]3[NH:35][C:36]([C:38]([OH:40])=[O:39])=[N:37][C:33]=3[CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc3[nH]c(C(=O)O)nc3c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
A solution of chiral methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-1H-benzo[d]imidazole-2-carboxylate (84.4 mg, mmol) in THF (6 ml) was reacted with LITHIUM HYDROXIDE MONOHYDRATE (22.9 mg, 0.545 mmol) in water (3 ml) and stirred at rt overnight. The reaction mixture was treated with 1 N HCl (0.37 ml, pH 3-4) and extracted with ethyl acetate. The organic extract was washed with water and brine, dried with sodium sulfate, filtered and lyophilized to give chiral-5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-1H-benzo[d]imidazole-2-carboxylic acid (36 mg, 43.6%) a white solid, MS (ES+) m/z Calcd: [(M+H)+]: 626.15. found: 626.0.
Reaction SMILES: [F:1][CH2:2][C:3]([O:8][CH3:9])([O:6][CH3:7])[C:4]#[CH:5].[C:10](=[O:17])(OCC)[O:11][CH2:12][CH3:13].[O-:18][CH2:19][CH3:20].[K+].[NH4+].[Cl-]>CN(C=O)C.O>[CH2:19]([O:18][C:4]([C:3]([O:8][CH3:9])([O:6][CH3:7])[CH2:2][F:1])=[CH:5][C:10]([O:11][CH2:12][CH3:13])=[O:17])[CH3:20]
Reactant: CC[O-]
Reactant: C#CC(CF)(OC)OC
Reactant: CCOC(=O)OCC
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(OCC)C(CF)(OC)OC
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
A mixture of 4-fluoro-3,3-dimethoxy-but-1-yne (4, R2=methyl, 20.0 g, 152 mmol) and diethyl carbonate (20.1 mL, 167 mmol) in DMF (150 mL) was cooled to 0° C., and treated with potassium ethoxide (3.8 g, 45.2 mmol). After stirring at 0° C. for 4 h, the solution was charged with a 1:1 mixture of saturated aqueous NH4Cl and water (200 mL) and extracted with t-butylmethylether (200 mL×2). The combined organic phase was washed with water (100 mL) and dried over anhydrous MgSO4 to give a crude the title compound (9, R1 and R3=ethyl, R2=methyl, 37.8 g, 99.7%, Z:E=6.5:1). (Z)-isomer: 1H NMR (400 MHz, CDCl3) δ 5.84 (s, 1H), 4.48 (d, J=46.8 Hz, 2H), 4.27 (q, J=7.2 Hz, 2H), 4.17 (q, J=7.2 Hz, 2H), 3.26 (s, 6H), 1.32 (t, J=7.2 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 164.9, 162.5, 100.7, 99.2 (d, J=30 Hz), 78.5 (d, J=180 Hz), 70.7, 59.7, 48.9, 15.3, 14.0. (E)-isomer: 1H NMR (400 MHz, CDCl3) δ 5.21 (s, 1H), 4.59 (d, J=46.8 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H), 3.82 (q, J=7.2 Hz, 2H), 3.29 (s, 6H), 1.35 (t, J=7.2 Hz, 3H), 1.29 (t, J=7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.2, 157.3, 99.8 (d, J=20 Hz), 97.6, 80.6 (d, J=180 Hz), 64.0, 60.2, 49.4, 14.0.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([OH:4])[CH3:3]>C(O)(C(F)(F)F)C(F)(F)F>[C:1]1(=[O:5])[O:5][CH2:1][CH2:2][CH2:3][CH2:3][CH2:2]1.[CH3:3][C@@H:2]1[O:4][C:1](=[O:5])[C@H:2]([CH3:3])[O:4][C:1]1=[O:5]
Reactant: CC(O)CO
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: C[C@@H]1OC(=O)[C@H](C)OC1=O
Product: O=C1CCCCCO1

Procedure:
The procedure in Example 3 was substantially repeated, except that 4.4 mL (60 mmol) propylene glycol (USP grade) was used instead of 5.6 mL of 1-dodecanol. The copolymer had an inherent viscosity of 0.17 dL/g in HFIP at 25° C.
Reaction SMILES: C[O:2][C:3]1[N:4]=[CH:5][C:6]2[C:11]([CH:12]=1)=[C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]1=[C:8]1[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=21.Cl.N1C=CC=CC=1>O>[CH:5]1[C:6]2[C:11](=[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[C:8]3[CH:17]=[CH:18][CH:19]=[CH:20][C:7]3=2)[CH:12]=[C:3]([OH:2])[N:4]=1
Reactant: COc1cc2c3ccccc3c3ccccc3c2cn1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1cc2c3ccccc3c3ccccc3c2cn1
Yield: 95.1 %

Procedure:
3-methoxydibenzo[f,h]isoquinoline (1.0 g, 3.9 mmol) and pyridine hydrochloride (4.5 g, 39 mmol) were heated at ca. 220° C. for 1.5 h. The reaction was cooled and water was added. The resulting solids were filtered, wash with water and dried in vacuum to give dibenzo[f,h]isoquinolin-3-ol (0.91 g, 95%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([C:22]3[CH2:27][CH2:26][C:25](=[O:28])[NH:24][N:23]=3)=[CH:17][C:16]=2[F:29])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:21][C:20]1[CH:19]=[C:18]([C:22]2[CH2:27][CH2:26][C:25](=[O:28])[NH:24][N:23]=2)[CH:17]=[C:16]([F:29])[C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(F)cc(C3=NNC(=O)CC3)cc2F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(c2cc(F)c(OC3CCNCC3)c(F)c2)=NN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 113.2 %

Procedure:
A solution of 4-[2,6-difluoro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (0.42 g, 1 mmol) in methylene chloride (5 mL) was treated with trifluoro acetic acid (10 mL). The mixture was stirred at RT for 3 h and TFA was concentrated at reduced pressure to give 6-[3,5-difluoro-4-(piperidin-4-yloxy)-phenyl]-4,5-dihydro-2H-pyridazin-3-one (0.35 g, quantitative yield), MS m/z 310 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[C:6]([NH:8][NH2:9])=[O:7].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O>>[F:17][C:18]([F:27])([F:28])[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[N:9][NH:8][C:6](=[O:7])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=1
Reactant: COc1cc(C(=O)NN)cc(OC)c1OC
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: COc1cc(C(=O)NN=Cc2cccc(C(F)(F)F)c2)cc(OC)c1OC

Procedure:
The title compound was prepared from 3,4,5-trimethoxy-benzoic acid hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (DMSO-d6): 11.93 (s, 1H), 8.57 (s, 1H), 8.08 (s, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.26 (s, 2H), 3.89 (s, 6H), 3.75 (s, 3H). MS (MH+, MH−): 451, 453.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:19])[C:15]=1[C:16](O)=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2.S(Cl)(C)(=O)=O.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])[CH2:40][CH2:39]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:26][O:25][C:21]1[CH:20]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:22]=1[O:23][CH3:24])[C:6]1[O:7][C:8]2[C:9]([C:14](=[O:19])[C:15]=1[C:16]([NH:48][CH2:47][CH2:46][CH2:45][CH2:44][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:10][CH:11]=[CH:12][CH:13]=2
Reactant: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)O)cc(OC)c1OC
Reactant: NCCCCN1CCN(c2ccccn2)CC1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)NCCCCN2CCN(c3ccccn3)CC2)cc(OC)c1OC

Procedure:
Under the conditions described in Example 1 (a) 3.6 g 3',4',5'-trimethoxyflavone-3-carboxylic acid were converted with 2.1 g 4-dimethylaminopyridine and 0.72 ml mesyl chloride in 100 ml absolute dichloromethane into the mixed anhydride, and this was then reacted under the conditions described in Example 4 (d) with 2.2 g of 4-[4-(2-pyridyl)-piperazin-1-yl]-butylamine. The reaction mixture was then worked up analogously to Example 4 (d). 3.4 g of 3',4',5'-trimethoxy-3-{4-[4-(2-pyridyl)-piperazin-1-yl]-butylaminocarbonyl}flavone were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([O:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([Mg]Br)[CH3:33].O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([OH:14])[CH2:32][CH3:33])=[C:11]([O:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Mg]Br
Reactant: COc1cc2nccc(Oc3cc(OCc4ccccc4)ccc3C=O)c2cc1OC
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)c1ccc(OCc2ccccc2)cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(Benzyloxy)-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde was dissolved in anhydrous tetrahydrofuran (1 ml). A 1 M tetrahydrofuran solution (0.5 ml) of ethylmagnesium bromide was added thereto at 0° C., and the mixture was stirred at 0° C. for one hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give 1-{4-(benzyloxy)-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-propanol.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([C:16]=2C2C=C(O)C=CC=2)=[CH:14][CH:13]=[CH:12][C:11]=3[C:24]([F:27])([F:26])[F:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28](=[O:31])([O-])[O-].[K+].[K+].[CH2:34]([O:36][C:37](=[O:47])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][CH:40]=1)[CH3:35].Cl>CN(C=O)C>[CH2:34]([O:36][C:37](=[O:47])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][O:31][C:28]2[CH:5]=[CH:6][CH:1]=[C:2]([C:8]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:16][C:15]4[C:10](=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:12]=[CH:13][CH:14]=4)[N:9]=3)[CH:3]=2)=[CH:41][CH:40]=1)[CH3:35]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(-c2c(-c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOC(=O)Cc1ccc(CBr)cc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(COc2cccc(-c3nc4c(C(F)(F)F)cccc4cc3-c3ccccc3)c2)cc1
Reaction time: 2 h
Yield: 38.7 %

Procedure:
To a solution of 3-[3-phenyl-8-(trifluoromethyl)quinolin-4-yl]phenol (0.178 g, 0.487 mmol), and potassium carbonate (0.134 g, 0.974 mmol), in DMF at 120° C. is added 4-bromomethylphenylacetic acid ethyl ester (0.334 g, 1.46 mmol), drop wise over 2 h. After an additional 2 h, the cooled reaction is poured into 2N aq HCl and extracted with ethyl acetate. The combined extracts are washed with sat aq NaHCO3, water, brine, and dried with magnesium sulfate. The extracts are concentrated and the residue is chromatographed with 1:9 ethyl acetate:hexanes to afford the title compound as a syrup (0.051 g, 37%). MS m/z 542; HRMS: calcd for C33H26NF3O3+H, 542.19430; found (ESI, [M+H]+), 542.194.
Reaction SMILES: [C:1](=[O:3])=[O:2].[K].[CH3:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[C:8]([CH3:20])[C:7]=1[CH2:21][CH:22]1[C:26](=O)O[CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:23]1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].CI>C1(C)C=CC=CC=1.C1COCC1>[CH3:20][C:8]1[CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:11]=[C:6]([CH3:5])[C:7]=1[CH2:21][C:22]1([CH3:26])[C:1](=[O:3])[O:2][CH:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:23]1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1CC1C(=O)OC(c2ccccc2)N1C(=O)OCc1ccccc1
Reactant: O=C=O
Agent: [K]
Solvent: C1CCOC1
Solvent: CI
Solvent: Cc1ccccc1
Product: Cc1cc(OCc2ccccc2)cc(C)c1CC1(C)C(=O)OC(c2ccccc2)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 500 ml round bottom flask fitted with a magnetic stirrer, thermometer, dropping funnel, and y-tube (connected to an N2 inlet and a drying tube outlet) was charged with dry THF (150 ml), which was cooled (dry ice bath) to -60°. A solution of potassium hexamethyldislazane in toluene (0.653M, 21.0 ml, Callery Chemical Company, Callery, Pa.) was added all at once. The solution was cooled back to -70°, and a solution of the title compound of Example 53 (5.5 g, 10.6 mmol) in THF (100 ml) was added dropwise rapidly, keeping the reaction temperature at or below -62°. The mixture was then stirred in the cold bath for 30 min, and the cold bath was then removed. Stirring at room temperature for another 30 min elevated the reaction tempature to -12°. The reaction mixture was then re-immersed in the cold bath, and the temperature returned to -70°. Methyl iodide (1.05 ml, 2.40 g, 16.9 mmol) was added al at once, and after another 10 min the cold bath was removed. The reaction mixture was permitted to warm to room temperature, and 3 hr after removal of the cold bath the mixture was partitioned between a mixture of H2 0 (200 ml), 0.5N KHSO4 (50 ml), saturated brine (200 ml) and ether (200 ml). The aqueous phase was washed with ether, the organic fractions were combined, dried (MgSO4), filtered, and stripped to an oil. The oil was applied to silica gel column chromatography on using ethyl acetate-hexane eluent, giving the title compound. NMR: α methyl group at ∫2.71 A, 3 protons.