Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[C:33](=[O:34])[N:32]([C:35]3[CH:46]=[CH:45][C:38]([O:39][CH:40]([CH3:44])[C:41]([NH2:43])=[O:42])=[CH:37][CH:36]=3)[C:31]([CH3:47])=[N:30][C:29]=2[CH2:48][CH2:49][CH3:50])=[CH:23][CH:22]=1)#[N:14]>O.C(OCC)(=O)C>[CH3:47][C:31]1[N:32]([C:35]2[CH:36]=[CH:37][C:38]([O:39][CH:40]([CH3:44])[C:41]([NH2:43])=[O:42])=[CH:45][CH:46]=2)[C:33](=[O:34])[C:28]([CH2:27][C:24]2[CH:23]=[CH:22][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:13]3[NH:3][C:4](=[O:7])[O:5][N:14]=3)=[CH:26][CH:25]=2)=[C:29]([CH2:48][CH2:49][CH3:50])[N:30]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)C(N)=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC(C)C(N)=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
A mixture of hydroxylammonium chloride (1.41 g), sodium hydrogen carbonate (2.05 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 2-{4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}propanamide (1.03 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.39 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.36 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.63 g, 55%).
Reaction SMILES: [H-].[Na+].[CH:3]([C@@H:6]1[C:11](=[O:12])[NH:10][CH2:9][CH2:8][N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:5])[CH3:4].[F:20][C:21]1[CH:30]=[C:29](F)[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24].CCOC(C)=O>CN(C=O)C>[F:20][C:21]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][C:28]([N+:32]([O-:34])=[O:33])=[C:29]([N:10]2[CH2:9][CH2:8][N:7]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C@H:6]([CH:3]([CH3:5])[CH3:4])[C:11]2=[O:12])[CH:30]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: CC(C)[C@@H]1C(=O)NCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])c(N2CCN(C(=O)OC(C)(C)C)[C@H](C(C)C)C2=O)cc1F
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
Under N2 atmosphere, NaH (8.8 g, 0.22 mol, 60% in mineral oil, 1.1 eq.) was added in portions at −10° C. to a 1 L three-neck flask containing (R)-tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate (26.7 g, 0.11 mol) in DMF (300 mL). The mixture was stirred at −10° C. for 30 min. The mixture was added dropwise to a 1 L three-neck flask containing methyl 2,4-difluoro-5-nitrobenzoate (26.3 g, 0.121 mol, 1.1 eq.) in DMF (200 mL) at −20° C. over 10 min. After addition, the resulting mixture was stirred between −20° C. and −30° C. for another 10 min. The reaction was quenched with sat. aq. ammonium chloride (200 mL) and then water (800 mL). The aqueous layer was extracted with EtOAc (3×1 L). The combined organic layers were washed with water (3×1 L) and brine, and then dried over anhydrous Na2SO4. After the mixture was filtered and the filter was evaporated under vacuum, the residue was purified by column chromatography on silica gel eluting with PE:EtOAc 8:1˜4:1 to give (R)-tert-butyl 4-(5-fluoro-4-(methoxycarbonyl)-2-nitrophenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate (32 g, 66.3% yield) as a yellow solid. LC-MS MS (ESI) m/z 384.1 [M-56+H]+, 462.1 [M+Na]+. 1H NMR (CDCl3 300 MHz): δ 8.63 (d, J=6.9 Hz, 1H), 7.16 (d, J=10.2 Hz, 1H), 4.61-4.30 (m, 2H), 3.97-3.89 (m, 4H), 3.62-3.48 (m, 2H), 2.40-2.34 (m, 1H), 1.49 (s, 9H), 1.08 (d, J=6.9 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1.N1C=CC=CC=1.Cl[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15].O>O1CCCC1>[O:4]1[CH:5]=[CH:6][C:2]([NH:1][C:14](=[O:15])[O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[N:3]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccon1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccon1)OCC(Cl)(Cl)Cl
Yield: 94.2 %

Procedure:
To a solution of 3-aminoisoxazole (0.878 ml, 11.9 mmol) and pyridine (1.13 ml, 14.3 mmol) in tetrahydrofuran (30 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.97 ml, 14.3 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give 2.91 g (94.1%) of the desired product as a solid.
Reaction SMILES: B#B.[CH3:3][S:4]([O:7][CH2:8][CH2:9][CH2:10][C:11]1([CH3:21])[CH:17]2[O:18][C:14]([CH:19]=[CH2:20])([CH2:15][CH2:16]2)[CH2:13][O:12]1)(=[O:6])=[O:5].[OH-:22].[Na+].OO>O1CCCC1.O>[CH3:3][S:4]([O:7][CH2:8][CH2:9][CH2:10][C:11]1([CH3:21])[CH:17]2[O:18][C:14]([CH2:19][CH2:20][OH:22])([CH2:15][CH2:16]2)[CH2:13][O:12]1)(=[O:5])=[O:6]
Reactant: [OH-]
Reactant: C=CC12CCC(O1)C(C)(CCCOS(C)(=O)=O)OC2
Agent: B#B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(CCCOS(C)(=O)=O)OCC2(CCO)CCC1O2
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of diborane in tetrahydrofuran (1 ml, 1 mM) is added slowly to a mixture of (1RS,4SR,5RS)-4-(3-methanesulfonyloxypropyl)-4-methyl-1-vinyl-3,8-dioxabicyclo[3.2.1]octane (350 mg, 1.2 mM) and tetrahydrofuran (5 ml) at 0° C. under nitrogen and stirred for thirty minutes. The resulting mixture is allowed to warm to room temperature and stirred for an additional two hours. The mixture is cooled to 0° C. and 3 N sodium hydroxide (0.3 ml) is added followed by the addition of 30% hydrogen peroxide (0.3 ml). The resulting mixture is allowed to warm to room temperature and stirred for 2.5 hours. The mixture is then treated with water (10 ml) and extracted with ether (5×20 ml). The combined organic phases are dried (Na2SO4) and the solvent is removed in vacuo. The residue is purified by column chromatography on silica gel (30 g) with ether to give (1RS,4SR,5RS)-4-(3-methanesulfonyloxypropyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-ethanol (275 mg, 80%) as a colorless oil.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-].C([Si](C)(C)[O:27][C@@H:28]1[CH2:33][C:32](=[CH:34]/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][C:40]([CH3:59])([CH3:58])[CH2:41]/[CH:42]=[CH:43]/[C:44]([C:54]([F:57])([F:56])[F:55])([O:49][Si](C)(C)C)[C:45]([F:48])([F:47])[F:46])[CH2:31][C@@H:30]([O:60][Si](C(C)(C)C)(C)C)[CH2:29]1)(C)(C)C>O1CCCC1>[F:46][C:45]([F:47])([F:48])[C:44]([C:54]([F:55])([F:56])[F:57])([OH:49])/[CH:43]=[CH:42]/[CH2:41][C:40]([CH3:59])([CH3:58])[CH2:39][CH2:38][CH2:37]/[CH:36]=[CH:35]/[CH:34]=[C:32]1[CH2:33][C@@H:28]([OH:27])[CH2:29][C@H:30]([OH:60])[CH2:31]1
Reactant: CC(C)(C/C=C/C(O[Si](C)(C)C)(C(F)(F)F)C(F)(F)F)CCC/C=C/C=C1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C/C=C/C(O)(C(F)(F)F)C(F)(F)F)CCC/C=C/C=C1C[C@@H](O)C[C@H](O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
1.40 g of tetrabutylammoniumfluoride trihydrate (4.45 mmol) in 6 ml of tetrahydrofuran was carefully dried by stirring during 2 h at room temperature over 1.78 g of 3 Å molecular sieve. This solution was then added to the above prepared 270 mg of (1R,3R)-1,3-bis-(tert-butyl-dimethyl-silanyloxy)-5-((2E,9E)-12,12,12-trifluoro-7,7-dimethyl-11-trifluoromethyl-11-trimethylsilanyloxy-dodeca-2,9-dienylidene)-cyclohexane (0.371 mmol) and kept for 1.5 h at 40°. The reaction mixture was then poured onto crushed ice/NH4Cl, extracted twice with ether, washed with water, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/ethylacetate=25/75) yielded 165 mg of the title compound as colourless oil. Typically, this product is contaminated with small amounts of 2Z-isomer which can be removed by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[NH:10][C:11]2[S:19][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:13]=3[C:12]=2[C:20]([NH2:22])=[O:21])=[CH:4][CH:3]=1.[CH:24]1[CH:25]=[CH:26][C:27]2[N:32](O)[N:31]=[N:30][C:28]=2[CH:29]=1.CCN=C=NCCCN(C)C.CN([CH:48]=[O:49])C>>[NH:30]1[C:28]2[CH:29]=[CH:24][C:25]([C:48]([N:16]3[CH2:17][CH2:18][C:13]4[C:12]([C:20]([NH2:22])=[O:21])=[C:11]([NH:10][C:9]([NH:8][C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)=[O:23])[S:19][C:14]=4[CH2:15]3)=[O:49])=[CH:26][C:27]=2[N:32]=[N:31]1
Reactant: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCNC2
Reactant: On1nnc2ccccc21
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCN(C(=O)c1ccc3[nH]nnc3c1)C2
Temperature: 25 °C
Yield: 28 %

Procedure:
Starting material 5 (847 mg, 2.4 mmol) was suspended in DMF (8 ml) and 1H-1,2,3-benzothiazole-5-carboxyllic acid (473 mg, 2.9 mmol), dry HOBt (427 mg, 2.9 mmol) and EDCI (606 mg, 2.9 mmol) were added. The brown suspension was stirred at ambient temperature over the weekend. As the reaction was not complete yet, the reaction was further stirred at 80° for 4 h. Thereby a brown solution was formed. The solvent was evaporated in vacuo and the crude product was further purified by prep. HPLC (Method 1). The product fractions were merged, the solvent was evaporated and the product lyophilized. Thereby 310 mg of the desired product 6 (0.635 mmol, 28%) were isolated as a light brown solid and additional 58 mg of the same product with 76% content which could have been purified further.
Reaction SMILES: [N:1]1[N:2]=[C:3]([NH:6][CH:7]2[CH2:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8]2)[NH:4][CH:5]=1.[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][CH:31]([C:37](=O)[CH2:38][CH2:39][CH3:40])[C:32](OCC)=[O:33])=[C:26]([F:42])[CH:25]=1)#[N:17].Cl>C(N(CC)C1C=CC=CC=1)C>[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][C:31]2[C:32](=[O:33])[N:6]([C@H:7]3[CH2:8][C@H:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10]3)[C:3]3[N:2]([N:1]=[CH:5][N:4]=3)[C:37]=2[CH2:38][CH2:39][CH3:40])=[C:26]([F:42])[CH:25]=1)#[N:17]
Reactant: CCOC(=O)C1CC(Nc2nnc[nH]2)C1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](C(=O)OCC)C2)c2ncnn12
Temperature: 180 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 3-(4H-1,2,4-triazol-3-ylamino)cyclobutanecarboxylate (2.5 g), ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (7.9 g) and N,N-diethylaniline (10 mL) was stirred at 180° C. for 18 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.86 g, 14%).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)([CH3:5])[C:3]#[CH:4].[O:16]1C2C=CC=CC=2[O:18][BH:17]1>>[CH3:5][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:14])([F:13])[F:15])=[CH:8][CH:7]=1)([CH3:1])/[CH:3]=[CH:4]/[B:17]([OH:18])[OH:16]
Reactant: B1Oc2ccccc2O1
Reactant: C#CC(C)(C)c1ccc(C(F)(F)F)cc1
Product: CC(C)(/C=C/B(O)O)c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.1 %

Procedure:
Under a nitrogen atmosphere, a stirred mixture of 25.2 grams (0.12 mole) of 3-methyl-3-(4-trifluoromethylphenyl)-1-butyne and 12.7 mL (0.12 mole) of 1,3,2-benzodioxaborole was warmed to 70° C. where it stirred for six hours. The reaction mixture was then cooled and poured slowly into 500 mL of ice-water while flushing with nitrogen. The mixture was then allowed to warm to ambient temperature where it stirred for about 18 hours. The mixture was cooled in an ice-bath, and the resultant solid was collected by filtration. The solid was washed with water and then dissolved in diethyl ether. The solution was washed with 100 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a residual solid. The solid was added under vacuum without heat, yielding 27.6 grams of trans-3-methyl-3-(4-trifluoromethylphenyl)-1-butenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH:13]=O)[CH:3]=1.[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][NH:19][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:3]=1
Reactant: O=Cc1cc(Cl)c2c(c1)OCCCO2
Reactant: CC(C)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)CNCc1cc(Cl)c2c(c1)OCCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cold mixture of 9-chloro-3,4-dihydro-2H-1,5-benzodioxepine-7-carbaldehyde (2.07 g) and of isobutylamine (7.5 ml 8 eq.) were combined in 1,2-dichloroethane (75 ml) and cooled in ice water bath. Acetic acid (5.68 ml) was then added and followed by sodium triacetoxyborohydride (2.75 g, 1.4 eq.). The mixture was allowed to stir at room temperature overnight. It was partitioned with aqueous K2CO3 (75 mL, 1.5M). The aqueous layer was extracted with of dichloromethane (75 ml×2). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography (10-100% ethyl acetate in hexanes) gave the desired amine as a light yellow oil: MS (m+1)=270.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13].[C:20](#[N:23])[CH:21]=[CH2:22].C[O-].[Na+]>CO.ClCCl>[C:20]([CH2:21][CH2:22][C:11]([C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1])([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])#[N:23]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Reactant: C=CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(CCC#N)(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Reaction time: 40 h
Yield: 52.4 %

Procedure:
To a solution of the nitro diester, Dimethyl 2-(2-fluoro-4-nitrophenyl)malonate (86) (0.4 g, 1.47 mmol) and acrylonitrile (0.11 mL, 1.62 mmol) in absolute methanol (5 mL) was added a catalytic amount of sodium methoxide at 21° C. under argon. The reaction mixture was stirred for 40 h at the same temperature and then diluted with dichloromethane (50 mL). The resulting mixture was washed with water, brine and dried. The residue obtained upon evaporation of the solvents was purified on a silica gel (hexane:ethyl acetate, 8:1) to give Dimethyl 2-(2-cyanoethyl)-2-(2-fluoro-4-nitrophenyl)malonate (73) (0.25 g, 52%): 1H NMR δ 8.07 (dd, 1H, J=8.7, 2.3 Hz), 7.99 (dd, 1H, J=10.9, 2.3 Hz), 7.47 (dd, 1H, J=8.7, 7.3 Hz), 3.85 (s, 6H), 2.65-2.70 (m, 2H), 2.47-2.51 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[C:2]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:3]=1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(Br)c2)c(F)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(-c3ccccc3)c2)c(F)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 966 %

Procedure:
5-(3-Bromo-phenyl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (500.0 mg, 0.10 mmol) prepared in Step 2 of Preparation 5, phenylboronic acid (201.0 mg, 1.65 mmol), Pd(PPh3)4 (64.0 mg, cat.) and a 2N sodium carbonate solution (3.3 mL) were added to N,N-dimethylformamide (5.0 mL). The reaction mixture was stirred at 80° C. for 18 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/60) to give 437.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]=NO)[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)[OH:16]>>[F:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[F:1])[NH:9][C:10](=[O:14])[C:11]2=[O:16]
Reactant: O=C(C=NO)Nc1ccc(F)c(F)c1
Reactant: O=S(=O)(O)O
Product: O=C1Nc2cc(F)c(F)cc2C1=O
Temperature: 80 °C

Procedure:
A 24.5 g portion of N-(3,4-difluorophenyl)-2-(hydroxyimino)acetamide was added portionwise with stirring to 95 ml of concentrated sulfuric acid with the temperature kept between 60° and 70° C. The temperature of the reaction mixture was then raised to 80° C. for 20 minutes followed by cooling to room temperature. The mixture was then poured onto crushed ice and the resulting solid collected, giving 21.3 g of the desired compound as brick red crystals, mp 218°-220° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:37].C(N(CC)C(C)C)(C)C.C(N(CC)CC)C>C(#N)C>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Agent: I
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCn1c(N2CCCN(CCC3(c4ccc(F)c(F)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 12 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.37 g, 1.6 mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.43 g, 0.8 mmol), and N,N-diisopropylethylamine (0.41 g, 3.2 mmol) in acetonitrile (10 mL). Heat to reflux. After 12 hours, cool and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 2% triethylamine/10% methanol/ethyl acetate to give the title compound: Rf=0.36 (silica gel, 2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([N:35]=[C:36]=[S:37])=[O:34]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:35][C:33](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH3:26])=[S:37])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1ccccc1C(=O)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (72 mg, yield 90%).
Reaction SMILES: ClC[C:3]1([CH3:13])[CH:7]([CH3:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4]1.[C-:14]#[N:15].[Na+].Cl[CH2:18]Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:13][C:3]1[O:4][C:5]2[CH:12]=[C:11]([CH2:18][C:14]#[N:15])[CH:10]=[CH:9][C:6]=2[C:7]=1[CH3:8]
Reactant: ClCCl
Reactant: CC1c2ccccc2OC1(C)CCl
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: Cc1oc2cc(CC#N)ccc2c1C
Reaction time: 18 h
Yield: 52.6 %

Procedure:
A mixture of 2-chloromethyl-2,3-dimethylbenzofuran (7.2 g, 0.037 mol), sodium cyanide (3.57 g, 0.073 mol), tetrabutylammonium bromide (0.74 g, 2.3×10-3 mol), water (19 cm3) and dichloromethane (19 cm3) was vigorously stirred for 18 hr. The mixture was poured into water and extracted with dichloromethane. The extract was washed with water, dried (Na2SO4), filtered and the solvent was removed to give 2,3-dimethylbenzofuran-6-acetonitrile (3.6 g, 0.0194 mol; 52.6%). (Found: C, 77.59; H, 6.11; N, 7.40. C2H11NO requires C, 77.81; H, 5.99; N, 7.56%) t.l.c./silica/toluene RF 0.45.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:31]([NH2:32])=[CH:30][C:29]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:28][N:27]=2)[CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[N:23]1([C:26]2[C:31]([NH:32][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[CH:3]=3)=[CH:30][C:29]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:28][N:27]=2)[CH2:22][CH2:21][O:20][CH2:25][CH2:24]1
Reactant: Fc1cc(F)c2c(Cl)cc(-c3ccccn3)nc2c1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Solvent: Cc1ccccc1
Product: Fc1cc(F)c2c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)cc(-c3ccccn3)nc2c1

Procedure:
Prepared according to Procedure H using 4-chloro-5,7-difluoro-2-(pyridin-2-yl)-quinoline (40.0 mg, 0.145 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give N-(2,5-di-4-morpholinyl-3-pyridinyl)-5,7-difluoro-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (CDCl3) δ ppm 8.65 (1H, d, J=7.2 Hz), 8.62 (1H, dt, J=4.8, 0.8 Hz), 8.54 (1H, s), 8.46 (1H, d, J=17.8 Hz), 7.87 (1H, td, J=7.7, 2.0 Hz), 7.83 (1H, d, J=2.7 Hz), 7.69 (1H, d, J=2.7 Hz), 7.66 (1H, br. s.), 7.36 (1H, ddd, J=7.5, 4.7, 1.1 Hz), 7.02 (1H, ddd, J=14.1, 8.4, 2.5 Hz), 3.89 (4H, dd, J=5.7, 3.9 Hz), 3.80-3.87 (4H, m), 3.24 (4H, dd, J=5.7, 3.9 Hz), 3.03-3.17 (4H, m). Mass Spectrum (ESI) m/e=505.1 (M+1).