Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[K].[OH:9][N:10]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[CH3:29])[C:12]#[N:13]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:5][O:9][N:10]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[CH3:29])[C:12]#[N:13]
Reactant: Cc1ccc(C)c(OCc2ccccc2C(C#N)=NO)c1
Reactant: COS(=O)(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K]
Solvent: Cc1ccccc1
Product: CON=C(C#N)c1ccccc1COc1cc(C)ccc1C
Reaction time: 1.5 h
Yield: 4.7 %

Procedure:
To a mixture of 924 g of toluene and 13.6 g (0.042 mol) of tetra-n-butylammonium bromide were simultaneously added dropwise 127 g (1.01 mol) of dimethyl sulfate and 1460 g of an aqueous solution containing 268 g (0.84 mol, E/Z=19/81) of the potassium salt of α-hydroxyimino-2-(2,5-dimethylphenoxymethyl)phenylacetonitrile produced in accordance with Example 3-(2) over 5 hours while keeping at 20°-25° C., and the reaction was subsequently allowed to proceed at the same temperature for 1.5 hours. The aqueous layer was removed from the reaction mixture by phase separation, and the organic layer was washed with 1000 g of 5% aqueous sodium hydroxide solution and then washed twice with 250 g of 10% saline solution. The organic layer was concentrated under reduced pressure and dried, which afforded 245 g of α-methoxyimino-2-(2,5-dimethylphenoxymethyl)phenylacetonitrile. The analysis by high performance liquid chromatography revealed that the content and yield of α-methoxyimino-2-(2,5-dimethylphenoxymethyl)phenylacetonitrile was 89.6% and 88.6% (E/Z=17/83), respectively, and the content and yield of the nitron compound as a by-product was 4.8% and 4.7% yield (E/Z=91/9), respectively.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16](=[O:26])[NH:15][C:14]1=[O:27])=[O:6])[CH3:3].[CH2:28](Br)[CH2:29][CH2:30][CH3:31]>C(O)C>[CH2:28]([N:15]1[C:14](=[O:27])[CH:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16]1=[O:26])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCN1C(=O)NC(=O)C1CCCCCCC(=O)OCC
Reactant: CCCCBr
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCN1C(=O)N(CCCC)C(=O)C1CCCCCCC(=O)OCC

Procedure:
To a solution of sodium (308 mg) in ethanol (40 ml) was added 5-(6-ethoxycarbonylhexyl)-1-octylhydantoin, followed by butyl bromide (1.8 g), and the solution was refluxed for 24 hours. The solvent was evaporated, water was added and the insoluble oil was extracted with ether. The washed and dried extract was evaporated to give 3-butyl-5-(6-ethoxycarbonylhexyl)-1-octyl hydantoin.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:28]([O:29][CH3:30])=[CH:27][C:12]([C:13]([N:15]2[CH:19]=[C:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:17][C@H:16]2[CH2:25][OH:26])=[O:14])=[C:11]([N+:31]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl.C(Cl)(Cl)Cl.CO>CO>[NH2:31][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:28]([O:29][CH3:30])=[CH:27][C:12]=1[C:13]([N:15]1[CH:19]=[C:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:17][C@H:16]1[CH2:25][OH:26])=[O:14]
Reactant: COC(=O)CC1=CN(C(=O)c2cc(OC)c(OCc3ccccc3)cc2[N+](=O)[O-])[C@H](CO)C1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)CC1=CN(C(=O)c2cc(OC)c(OCc3ccccc3)cc2N)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.3 %

Procedure:
A solution of the nitro-alcohol 20 (0.35 g, 0.77 mmol) and SnCl2/2H2O (0.87 g, 3.86 mmol) in methanol (16 mL) was heated to reflux and monitored by TLC (90% CHCl3/MeOH). After 1 hour the MeOH was evaporated in vacuo and the resulting residue cooled (ice), and treated carefully with saturated NaHCO3 (65 mL). The mixture was diluted with EtOAc (65 mL), and after 16 hours stirring at room temperature the inorganic precipitate was removed by filtration through celite. The organic layer was separated, washed with brine (100 mL), dried (MgSO4), filtered and evaporated in vacuo to give the crude amine 21 as a pale orange glass (0.29 g, 88%) which was carried through to the next step without further purification or analysis due to the instability of the amine.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:12]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:28]=[C:29]=[O:30])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.ClCC(OCC)=O.Cl>O1CCCC1>[O:12]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:28]2[C:9](=[O:11])[CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:29]2=[O:30])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)CNc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(=O)CCl
Solvent: C1CCOC1
Product: O=C1CN(c2ccccc2)C(=O)N1S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 9.2 %

Procedure:
To a solution of 1.25 g (8.29 mmol) of N-phenylaminoacetic acid in 100 ml of tetrahydrofuran, 2.0 g (8.29 mmol) of 4-phenoxybenzenesulfonyl isocyanate were added at room temperature, and the resultant mixture was stirred for 16 hours. After completion of the reaction, the liquid reaction mixture was cooled to 0° C. and added with 2.09 g (20.7 mmol) of triethylamine and 900 mg (8.29 mmol) of ethyl chloroacetate, followed by stirring at 0° C. for 1 hour. After completion of the reaction, the liquid reaction mixture was added with 40 ml of 1N hydrochloric acid and 60 ml of saturated saline and subjected to extraction with ethyl acetate. After washing the resultant extract with water, it was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The thus-obtained crude product was purified by column chromatography on silica gel (hexane/ethyl acetate=3:1) and subjected to crystallization from hexane/ethyl acetate, thereby obtaining 310 mg (yield: 9.2%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16].S(=O)(=O)([OH:19])N.[O-]Cl=O.[Na+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]([OH:19])=[O:8])=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: NS(=O)(=O)O
Reactant: COCCCCc1cc(C=O)ccc1OC
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(=O)O
Solvent: O
Product: COCCCCc1cc(C(=O)O)ccc1OC
Reaction time: 3 h

Procedure:
To a stirred suspension of 4-methoxy-3-(4-methoxy-butyl)-benzaldehyde (300 mg, 1.35 mmol) and sulfamic acid (176 mg, 1.81 mmol) in 80% acetic acid (2.3 mL) is added dropwise a solution of 80% NaClO2 (127 mg, 1.40 mmol; dissolved in 170 μL of H2O) in water (0.65 mL) over 5 min and by keeping the temperature at 18-20° C. Stirring of the yellow slurry is continued over 3 hrs at 20° C. before adding another aliquot of 80% NaClO2 (151 mg, 1.67 mmol; dissolved in 205 μL of H2O), dissolved in water (0.8 mL), and sulfamic acid (130 mg, 1.34 mmol) in 80% aqueous acetic acid. After stirring overnight, the reaction mixture is diluted by adding water (2.3 mL), the resulting suspension is stirred for 30 min and filtered. The precipitate is dried to give the title product as white solid. TLC, Rf (CH2Cl2/MeOH 98:2)=0.5. MS: 239.0 [M+H]+. 1H-NMR (CD3OD): δ 1.55-1.7 (m, 4H), 2.65 (t, 2H), 3.31 (s, 3H), 3.41 (t, 2H), 3.89 (s, 3H), 4.87 (s, 1H+D2O), 6.98 (m, 1H), 7.78 (s, 1H), 7.87 (m, 1H) ppm.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(NCC(C)C)C(C)C.S(Cl)([Cl:26])(=O)=O>C1(C)C=CC=CC=1>[Cl:26][C:9]1[CH:8]=[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:12]=[CH:11][C:10]=1[OH:13]
Reactant: Oc1ccc(C2CCOCC2)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: CC(C)CNCC(C)C
Solvent: Cc1ccccc1
Product: Oc1ccc(C2CCOCC2)cc1Cl
Temperature: 70 °C
Yield: 78.9 %

Procedure:
To a 30 ml Toluene solution of 4-(4-tetrahydropyranyl)phenol 1 g (5.61 mmol) and diisobutylamine 0.08 ml (0.46 mmol) was added sulfuryl chloride 0.51 ml (6.35 mmol) over 3 hr period upon heating at 70° C. Stirring was continued at that temp. for 2 hr after the addition of sulfuryl chloride was complete. The solvent was removed under reduced pressure, diluted with ethyl acetate and washed with 2N aqueous HCl, saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, concentrated, chromatographed on silica gel (hexanes: ethyl acetate) to give 0.941 g of the title compound as while solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:20](=[CH:21][CH:22]=1)[O:19][C:7]1([CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:23].[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:23]=[C:5]1[C:4]2[C:20](=[CH:21][CH:22]=[C:2]([C:30]3[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=3)[C:24]#[N:25])[CH:3]=2)[O:19][C:7]2([CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:6]1
Reactant: O=C1CC2(CCC(c3ccccc3)CC2)Oc2ccc(Br)cc21
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC2(CCC(c4ccccc4)CC2)O3)c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
In a 50 mL round bottom flask was placed 6-bromo-4′-phenylspiro[chroman-2,1′-cyclohexan]-4-one (300 mg, 0.811 mmol), 3-cyanobenzeneboronic acid (155 mg, 1.06 mmol), PdCl2(PPh3)2 (57 mg, 0.08 mmol) and cesium carbonate (661 mg, 2.03 mmol). This solid mixture was dissolved in a Dioxane/water mixture (8 mL, 6:1 ratio, respectively). The solution was purged with a N2 stream for 30 seconds. A condenser was attached to the flask and the reaction was allowed to stir at 95° C. for 1 hour. At this time, the mixture was filtered through a Celite plug. The plug was rinsed with dichloromethane (20 mL) and water (20 mL). The phases in the filtrate were separated. The aqueous phase was back-extracted with dichloromethane twice (5 mL/each). The combined organic phases were dried over MgSO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 12 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding 3-(4-oxo-4′-phenylspiro[chroman-2,1′-cyclohexane]-6-yl)benzonitrile (173 mg, 0.440 mmol, 58% yield) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[F:17])[C:3]=1[C:18]#[N:19].O.O.[Sn](Cl)Cl>O1CCCC1.C(O)C>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([F:17])=[C:8]([C:4]2[C:3]([C:18]#[N:19])=[C:2]([F:1])[CH:7]=[CH:6][CH:5]=2)[CH:13]=1
Reactant: N#Cc1c(F)cccc1-c1cc([N+](=O)[O-])ccc1F
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(F)cccc1-c1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
A suspension of 2-bromo-6-fluorobenzonitrile (2.50 g, 12.5 mmol), potassium fluoride (2.40 g, 41.3 mmol) and 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (4.67 g, 17.5 mmol) in tetrahydrofuran (50 ml) was degassed with nitrogen for 30 min. Tris(dibenzylideneacetone)dipalladium(0) and tri-tert-butylphosphine (0.2M solution in 1,4-dioxane, 3.7 ml) were added and the mixture stirred at ambient temperature for 15 min then at 50° C. for 18 h. After cooling to ambient temperature, the resulting dark suspension was poured onto 0.5M sodium hydroxide solution (500 ml) and stirred vigorously for 2 h. The dark solid was collected by filtration, washed with water (100 ml) and isohexane (50 ml) and left to air dry which gave 3,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile as a brown/black solid (3.25 g, 100%): δH (360 MHz, CDCl3) 7.32-7.44 (3H, m), 7.71-7.77 (1H, m), 8.35-8.41 (2H, m). 3,2′-Difluoro-5′-nitrobiphenyl-2-carbonitrile (3.25 g, 12.5 mmol) in tetrahydrofuran (20 ml) and ethanol (20 ml) was treated with tin(II) chloride dihydrate (9.86 g, 43.8 mmol) and the mixture left to stir at ambient temperature for 18 h. The solvent was evaporated and the residue stirred with 2N sodium hydroxide solution (40 ml) for 2 h. The resulting suspension was diluted with water (100 ml) and extracted with dichloromethane (3×200 ml). The combined organics were washed with water (200 ml), brine (200 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give 5′-amino-3,2′-difluorobiphenyl-2-carbonitrile as a brown solid (2.87 g, 100%): δH (360 MHz, CDCl3) 3.74 (2H, s), 6.66-6.75 (2H, m), 7.01 (1H, dd, J 9 and 9), 7.19-7.30 (2H, m), 7.59-7.65 (1H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[F:34][C:35]([F:39])([F:38])[CH2:36]I.O>CN(C)C=O>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:3][C:2]=1[O:1][CH2:36][C:35]([F:39])([F:38])[F:34]
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(O)c2)n1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(OCC(F)(F)F)c2)n1
Temperature: 50 °C

Procedure:
A 0.3 g quantity of the N-[2-(3-hydroxy-4-methoxy phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide obtained in Example 2 and 0.22 g of potassium carbonate were dissolved in 10 ml of dimethylformamide, and 0.34 g of 1,1,1-trifluoro-2-iodoethane was added thereto. The mixture was stirred with heating at 50° C. overnight. The reaction mixture was allowed to cool, water was then added thereto, and extraction was performed with ethyl acetate. After washing with water twice, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give 0.14 g of white powdery N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-2-ethoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10](C=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1.[CH3:51][N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.[C:58](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CS(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:51][N:52]3[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(Cl)c(-c3cccc(C=O)c3)c2)c1
Reactant: CN1CCNCC1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(Cl)c(-c3cccc(CN4CCN(C)CC4)c3)c2)c1
Yield: 53.7 %

Procedure:
N-[(6-Chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (30.36 mg, 0.044 mmol), 1-methylpiperazine (43.9 mg, 0.44 mmol, 10 eq) and acetic acid (2.51 μL, 0.044 mmol, 1 eq) were dissolved in DMSO (1.5 mL). The mixture was stirred in VX-2500 Multi-Tube Vortexer for overnight at room temperature. MP-triacetoxyborohydride (133 mg, 0.310 mmol, 7 eq) was then added and the mixture was stirred again in VX-2500 Multi-Tube Vortexer for overnight at room temperature. The reaction mixture was filtered through a polypropylene cartridge (10 mL tube) on Bohdan Miniblock in a reaction tube and concentrated in a Glas-Col evaporator. The reaction mixture was then purified using a Gilson HPLC with a water-acetonitrile with 0.1% TFA buffer. The desired product fractions were combined, filtered through amine cartouche (500 mg) on Bohdan Miniblock and concentrated in a Glas-Col evaporator, giving 18.38 mg (48.6%) of the title compound. LC-MS m/z 777 (M+H)+, 1.41 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Cl[CH2:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:10](=[O:13])[N:11]([CH2:23][C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=3)=[O:25])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)NCc1cccc(C(F)(F)F)c1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1Cc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(Cc2cccc(F)c2)c1=O)NCc1cccc(C(F)(F)F)c1

Procedure:
200 mg (0.66 mmol) of 5-(4-chlorophenyl)-4-(3-fluorophenylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one from Example 41A, 193 mg (0.69 mmol) of 2-chloro-N-[3-(trifluoromethyl)phenylmethyl]-acetamide [preparable according to EP 0 163 607, Example 28] and 182 mg (1.32 mmol) of potassium carbonate are suspended in 2.5 ml of acetonitrile and heated under reflux overnight. After cooling, this is diluted with water, and purified by preparative HPLC [Method 9] and 219 mg (64% of theory) of the target compound are thus obtained.
Reaction SMILES: [C:1]([N:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)O)(=[O:3])[CH3:2].Cl[C:13]1[CH:18]=[N:17][CH:16]=[CH:15][N:14]=1.[H-].[Na+].CN(C)C=[O:24]>O>[C:1]([NH:4][C:6]1[CH:11]=[CH:10][C:9]([C:16]2[N:17]=[CH:18][C:13](=[O:24])[NH:14][CH:15]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: Clc1cnccn1
Reactant: CN(C)C=O
Reactant: CC(=O)N(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Reaction time: 0.5 h

Procedure:
N-Acetylphenylhydroxylamine (100 g) and 2-chloropyrazine (79 g) were dissolved in anhydrous dimethylformamide (500 ml). Sodium hydride (50% oil; 46 g) was added in portions over 11/2 hours, ensuring that the temperature was maintained between 20°-40° C. The reaction mixture was cooled, diluted with water (2500 ml), washed with dichloromethane (4 times) and filtered through diatomaceous earth. Acetic acid was slowly added with stirring to take the pH of the filtrate to 5-6. During this addition crystalline solid formed. After 30 minutes, this was collected by filtration, washed with very dilute acetic acid and dried at 60° C. to yield 5-(4-acetamidophenyl)-2-(1H)-pyrazinone (94.6 g).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][NH:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)C(C)C)(C)C.Cl[C:30]1[C:35]([CH3:36])=[C:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[N:33]=[CH:32][N:31]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][N:16]([C:30]2[C:35]([CH3:36])=[C:34]([C:37]3[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=3)[N:33]=[CH:32][N:31]=2)[CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCCNCc1ccc(OCC(=O)OCC)c(C)c1
Reactant: Cc1c(Cl)ncnc1-c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(C(F)(F)F)cc2)c1C
Temperature: 100 °C
Yield: 45.3 %

Procedure:
A mixture of ethyl {2-methyl-4-[(propylamino)methyl]phenoxy}acetate (0.279 g, 1.05 mmol), N,N-diisopropylethylamine (0.24 mL, 1.4 mmol) and 4-chloro-5-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (0.191 g, 0.7 mmol) were heated at 100° C. in a sealed reactivial for 18 h. After this time the reactivial was allowed to cool to room temperature and the residue dissolved in CH2Cl2 (50 mL) and washed with water (20 mL). The organic extract was separated by hydrophobic frit and evaporated. Purification by Biotage™ chromatography (Si, 40 g) eluting 9:1 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (159 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.[CH2:35]([SH:38])[CH:36]=[CH2:37]>>[CH2:35]([S:38][CH2:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([F:34])([F:33])[F:22])[CH:8]=2)[NH:3][C:2]([CH3:1])([CH3:21])[CH:11]=1)[CH:36]=[CH2:37]
Reactant: C=CCS
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: C=CCSCC1=CC(C)(C)Nc2ccc(-c3ccccc3C(F)(F)F)cc21

Procedure:
Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester was coupled with 2-trifluoromethylphenylboronic acid. Bromination and coupling reaction with allyl mercaptan gave 23 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([CH2:5][CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4].[H-].[Na+].I[CH3:22].O>O1CCCC1>[CH3:18][N:2]([CH3:1])[C:3]([CH2:5][CH2:6][N:7]([CH3:22])[C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4]
Reactant: CI
Reactant: CN(C)C(=O)CCNC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)CCN(C)C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 86 %

Procedure:
Benzyl [2-(dimethylcarbamoyl)ethyl]carbamate (I-139) (0.69 g, 2.76 mmol) was dissolved in tetrahydrofuran (10 ml), and with cooling with ice, sodium hydride (oily, about 55%, 0.15 g, 3.44 mmol) was added, followed by stirring for 10 minutes. Iodomethane (0.26 ml, 4.18 mmol) was added, followed by stirring at room temperature for 18 hours, and water was added. After extraction with ethyl acetate and drying over anhydrous sodium sulfate, the solvent was evaporated away, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=40:1) to obtain a colorless oil (0.63 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=2[C:16]#[N:17])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: N#Cc1ccccc1CBr
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: N#Cc1ccccc1COc1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 2-Bromomethyl-benzonitrile using the conditions described in Example 10C to provide 2-(4-Chloro-3-nitro-phenoxymethyl)-benzonitrile which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.