Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:23])=[C:11]([C:16]2[N:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=2)[CH:12]=[CH:13][C:14]=1[CH3:15])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[NH2:22][C:19]1[N:20]=[CH:21][C:16]([C:11]2[C:10]([F:23])=[C:9]([OH:8])[C:14]([CH3:15])=[CH:13][CH:12]=2)=[N:17][CH:18]=1
Reactant: Cc1ccc(-c2cnc(N)cn2)c(F)c1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cnc(N)cn2)c(F)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(3-((tert-Butyldimethylsilyl)oxy)-2-fluoro-4-methylphenyl)pyrazin-2-amine (342 mg, 1.03 mmol) was dissolved in THF (1.2 mL) at rt and then treated with tetrabutylammonium fluoride (1.2 mL, 1 M in THF). The reaction was stirred for 1 hour at rt, before diluting with water (10 mL) and extracting with EtOAc (10 mL×4). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by FCC to provide the title compound. 1H NMR (500 MHz, CD3OD) δ 8.26 (dd, J=2.3, 1.5, 1H), 8.01 (d, J=1.5, 1H), 7.09 (m, 1H), 6.94 (m, 1H), 2.25 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[CH:15]=[CH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[C:19]1([CH2:18][CH2:17][CH:16]=[CH:15][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[CH:14][C:5]=2[C:3]([OH:4])=[O:2])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc2ccccc2c1C=CCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2ccccc2c1C=CCCc1ccccc1
Yield: 98.7 %

Procedure:
175 mg 1-(4-phenyl-but-1-enyl)-naphthalene-2-carboxylic acid methyl ester were reacted with 1 ml of 2 M aqueous sodium hydroxide in 1.5 ml methanol and 4 ml THF for 1 h at 60° C. The organic solvents were removed in vacuo, the mixture was acidified with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated to yield 165 mg of a mixture of the (E)- and (Z)-isomers of 1-(4-phenyl-but-1-enyl)-naphthalene-2-carboxylic acid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)([CH3:3])=[CH2:2].[Cl:14]N1C(=O)CCC1=O.C1C=CC=CC=1>CCCCCC>[Cl:14][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:11])[F:12])[N:5]=1)=[CH2:3]
Reactant: C=C(C)c1cccc(C(F)(F)F)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccccc1
Solvent: CCCCCC
Product: C=C(CCl)c1cccc(C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 7 h
Yield: 42.2 %

Procedure:
A mixture of 11.0 g of 2-isopropenyl-6-trifluoromethylpyridine, 8.7 g of N-chlorosuccinimide and 25 ml of benzene was stirred at 80° C. for 7 hours. After the reaction mixture was cooled to room temperature, 50 ml of n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane then n-hexane-ethyl acetate 20:1) to obtain 5.5 g of the objective compound.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl.Cl[CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C)C=O.O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Reactant: ClCCCN1CCOCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(=O)c1cnc2c(OCCCN3CCOCC3)cccc2c1Nc1ccccc1C
Reaction time: 2.5 h
Yield: 58.1 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) and potassium t-butoxide (5.0 g, 40 mmol) were stirred in dry dimethylformamide (100 ml) at 100° , then 4-(3-chloropropyl)morpholine hydrochloride (5 0 g, 14 mmol) was added. Heating was continued for 2.5 hours, then the mixture was diluted with water and extracted with ether. The combined extracts were dried and evaporated to an oily residue. Chromatography (silica gel, 3% methanolic ammonia in chloroform) and crystallisation from petroleum ether gave 3-butyryl-4-(2-methylphenylamino)-8-(3-morpholinopropoxy)quinoline (2.6 g, 58 %), m.p. 111°-113°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:26]=[C:25]([C:27]([NH2:29])=[O:28])[CH:24]=[CH:23][N:22]=1>>[C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][NH:19][C:21]3[N:26]=[C:25]([C:27]([NH2:29])=[O:28])[CH:24]=[CH:23][N:22]=3)[CH2:16][CH2:17]2)(=[O:10])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Reactant: NC(=O)c1ccnc(Cl)n1
Product: NC(=O)c1ccnc(NCC2CCN(S(=O)(=O)CCc3ccccc3)CC2)n1

Procedure:
EXAMPLE 83 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2-chloro-pyrimidine-4-carboxylic acid amide (2-chloro-pyrimidine-4-carboxylic acid amide was prepared according to G. D. Davies, D. E. O'Brien, L. R. Lewis, C. C. Cheng, J. Heterocyclic Chem., 1:130–131(1964):
Reaction SMILES: [H-].[Na+].C1[O:28][C:6]([O:25][CH2:26][CH3:27])([CH2:7][CH2:8][C:9](=[O:24])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])OC1.[CH:29](OCC)=[O:30]>>[O:24]=[C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:8][CH:7]([CH:29]=[O:30])[C:6]([O:25][CH2:26][CH3:27])=[O:28]
Reactant: CCOC=O
Reactant: CCCCCCCCCCCCCCC(=O)CCC1(OCC)OCCO1
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCC(=O)CC(C=O)C(=O)OCC
Temperature: 25 °C
Yield: 51.2 %

Procedure:
To 20 ml of an ethereal suspension of 1.20 g (30 mmol) of 60% sodium hydride was added dropwise 20 ml of an ethereal solution of 7.42 g (20 mmol) of ethyl γ-ketooctadecanoate ethylene ketal prepared in Synthetic Example 3 and 1.93 g (26 mmol) of ethyl formate under stirring at room temperature. The mixture was stirred at room temperature for 18 hours. Then, 0.70 g (17 mmol) of 60% sodium hydride and 1.00 g (13 mmol) of ethyl formate were further added to the mixture and the whole was stirred at the room temperature for 50 hours. The reaction was terminated by adding diluted hydrochloric acid and the resulting mixture was extracted with ether. A residue obtained by removing the solvent from the extract under reduced pressure was treated with 30 ml of concentrated hydrochloric acid under vigorous stirring for 1.5 hours. The resulting mixture was extracted with ether, washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removing the solvent under a reduced pressure, the residue was purified by subjecting it to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/10) to obtain 3.63 g (51% yield) of ethyl γ-keto-α-formyloctadecanoate.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH-].[Na+:9].C(O)(=[O:13])C=C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].OO>>[C:1]([O-:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:13])=[O:5].[Na+:9].[Na+:9]
Reactant: O=C1C=CC(=O)O1
Reactant: C=CC(=O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: OO
Agent: [NH4+]
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
An aqueous sodium maleate solution was prepared by neutralizing maleic anhydride with an aqueous sodium hydroxide solution in a four-necked flask. The aqueous solution polymerization of this solution and an aqueous acrylic acid solution was effected in the presence of ammonium persulfate, hydrogen peroxide and sodium hydroxide at 100° C. for 6 h.
Reaction SMILES: C([O:8][C@H:9](C)[C:10]([NH:12][C@H:13]1[CH2:17][C@@H:16]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([N:42]2C[CH2:45][C@@H:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[CH2:43]2)=[N:22][C:23]=3[NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:15]([OH:57])[C@@H:14]1[OH:58])=[O:11])C1C=CC=CC=1.[NH2:60][C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)[C@H](OCC4C=CC=CC=4)C)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1>>[C:36]1([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][NH:27][C:23]2[N:22]=[C:21]([N:42]3[CH:43]=[C:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[CH:45]=[N:60]3)[N:20]=[C:19]3[C:24]=2[N:25]=[CH:26][N:18]3[C@@H:16]2[CH2:17][C@H:13]([NH:12][C:10](=[O:11])[CH2:9][OH:8])[C@@H:14]([OH:58])[C@H:15]2[OH:57])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(NC(=O)Nc5cccnc5)cn4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to (R)-2-benzyloxy-N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (Example 181, step 5), by substituting N-{(1S,2R,3S,4R)-4-[2-(4-amino-pyrazol-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZP) for (R)—N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (Example 181, step 4).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15]O)=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][Cl:3])=[CH:8][CH:7]=1
Reactant: OCc1ccccc1Sc1ccc(F)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: Fc1ccc(Sc2ccccc2CCl)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
8.5 g of thionyl chloride are added dropwise over a 10 minute span to a stirring mixture of 13.0 g of 2-(4-fluorophenylthio)benzyl alcohol in 80 ml of benzene at ambient temperature. After total addition, the reaction mixture is stirred for 16 hours before being carefully poured onto 350 ml of crushed ice containing 8 g of sodium bicarbonate. The mixture is stirred until the ice melts. The layers separate and the benzene layer is successively washed twice with 40 ml portions of a half saturated sodium bicarbonate solution, washed twice with 40 ml portions of water, washed once with 25 ml of saturated sodium chloride solution, dried and rotary evaporated to provide 2-(4-fluorophenylthio)benzyl chloride.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14](=[O:23])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)=[CH:13][C:8]=2[O:7][CH2:6]1>CC(O)=O.C1COCC1.O>[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14](=[O:23])[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)=[N:1][OH:3])=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: O=N[O-]
Reactant: Cc1cccc(CC(=O)c2ccc3c(c2)OCO3)n1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(C(=NO)C(=O)c2ccc3c(c2)OCO3)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
Sodium nitrite (0.405 g, 5.88 mmol) was added to a solution of 1-benzo[1,3]dioxol-5-yl-2-(6-methyl-pyridin-2-yl)-ethanone (1.0 g, 3.92 mmol; see Example 3B above) in a mixture of HOAc/THF/H2O (6:4:1, 22 mL). The mixture was stirred at 0° C. for 1 hour and then at room temperature for 1 hour. Solvent was removed under reduced pressure. Residue was dissolved in water and NaOH (3N) was added until the pH value was more than 8. The aqueous solution was then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give 0.90 g (81%) of 1-Benzo[1,3]dioxol-5-yl-2-(6-methyl-pyridin-2-yl)ethane-1,2-dione 2-oxime as a yellow foam. MS (ESP+) m/z 285.1 (M+1). 1H NMR (300 MHz, CDCl3) δ 7.49 (m, 4H), 7.09 (d, 1H, J=7.5 Hz), 6.81 (d, 1H, J=7.8 Hz), 6.04 (s, 2H), 2.43 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([CH:12]1[CH2:17][CH2:16][CH2:15][O:14][CH2:13]1)[CH2:6][C:5]2=O.C[Si]([N:23]=[C:24]=[N:25][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([CH:12]1[CH2:17][CH2:16][CH2:15][O:14][CH2:13]1)[CH2:6]/[C:5]/2=[N:25]\[C:24]#[N:23]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1CC(C2CCCOC2)Oc2ccc(Br)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC(C2CCCOC2)Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of 6-bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-one (300 mg, 0.98 mmol) in anhydrous DCM (8 mL) was added TiCl4 (1 M solution in DCM, 1.96 mL, 1.96 mmol) dropwise within 15 min at room temperature. It was stirred for 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (400.7 mg, 2.15 mmol) dropwise. The resulting mixture was stirred for 18 h after the addition. The reaction mixture was poured into ice-water (100 g) and extracted with DCM (3×50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give (E)-N-(6-bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-ylidene)cyanamide (300 mg, 100%), which was used in next step without further purification.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]3[N:18]=[N:17][NH:16][N:15]=3)=[CH:12][C:11]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:10]([Cl:23])[CH:9]=2)[S:4][CH:5]=1.C=O.CN([CH:29]=[O:30])C>C(Cl)Cl.C(Cl)Cl.CN(C=O)C>[Cl:23][C:10]1[CH:9]=[C:8]([NH:7][CH2:6][C:3]2[S:4][CH:5]=[CH:1][CH:2]=2)[C:13]([C:14]2[N:15]([CH2:29][OH:30])[N:16]=[N:17][N:18]=2)=[CH:12][C:11]=1[S:19]([NH2:22])(=[O:21])=[O:20]
Reactant: CN(C)C=O
Reactant: NS(=O)(=O)c1cc(-c2nn[nH]n2)c(NCc2cccs2)cc1Cl
Agent: C=O
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(-c2nnnn2CO)c(NCc2cccs2)cc1Cl

Procedure:
Azosemide can be reacted with formaldehyde in methylene chloride, methylene chloride-DMF mixtures or DMF to yield 2-chloro-5-[1-(hydroxymethyl)-1H-tetrazol-5-yl]-4-[(2-thienylmethyl)amino]benzenesulfonamide.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10](Br)=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([C:16]#[N:17])[C:3]=1[S:18][C:19]([F:22])([F:21])[F:20].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+].COCCOCCOC>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O>[Cl:15][C:8]1[CH:9]=[C:10]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=2)[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([NH2:1])=[C:3]([S:18][C:19]([F:22])([F:21])[F:20])[C:4]([C:16]#[N:17])=[N:5]1
Reactant: N#Cc1nn(-c2c(Cl)cc(Br)cc2Cl)c(N)c1SC(F)(F)F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOCCOC
Product: N#Cc1nn(-c2c(Cl)cc(-c3ccc(C(F)(F)F)cc3)cc2Cl)c(N)c1SC(F)(F)F
Temperature: 20 °C
Yield: 56.5 %

Procedure:
A mixture of 6 g of 5-amino-3-cyano-1-(2,6-dichloro-4-bromophenyl)-4-trifluoromethylthiopyrazole (prepared according to procedures reported in U.S. Pat. No. 5,232,940), 4-trifluoromethylphenylboronic acid (5.3 g), K2CO3 (5.8 g), tris-(dibenzylidene acetone) dipalladium (0.6 g) and diglyme was heated at 130° C. for 25 hours. After cooling to 20° C., the mixture was poured into water and extracted with diethyl ether. The ether solutions were combined, dried, filtered and the filtrate concentrated and purified by chromatography. The desired product as a solid (3.9 g, mp 181-184° C.) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[C:9]([I:23])[CH:8]=2)=[C:5]([CH3:24])[O:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.I[CH2:37][CH3:38]>CCOC(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([N:16]([CH2:37][CH3:38])[C:17](=[O:22])[C:18]([F:20])([F:21])[F:19])=[C:9]([I:23])[CH:8]=2)=[C:5]([CH3:24])[O:4][N:3]=1
Reactant: CCI
Reactant: Cc1noc(C)c1-c1cc(I)c(NC(=O)C(F)(F)F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(C(=O)C(F)(F)F)c1c(I)cc(-c2c(C)noc2C)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of N-(4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitrophenyl)-2,2,2-trifluoroacetamide (2.2 g, 4.83 mmol), cesium carbonate (3.94 g, 12.08 mmol) and N,N-Dimethylformamide (100 ml) was stirred at room temperature under argon. To the mixture was added iodoethane (3.77 g, 24.17 mmol) and reaction was heated to 45° C. overnight. Crude mixture was diluted in EtOAc and water and extracted 3 times with EtOAc. Organics were washed with water, aq LiCl, then brine, dried over sodium sulfate and evaporated to dryness under reduced pressure to afford crude N-(4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitrophenyl)-N-ethyl-2,2,2-trifluoroacetamide as a dark oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.F[C:17]1[CH:18]=[CH:19][C:20]([N+:25]([O-:27])=[O:26])=[C:21]([CH:24]=1)[NH:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:23][NH:22][C:21]1[CH:24]=[C:17]([CH:18]=[CH:19][C:20]=1[N+:25]([O-:27])=[O:26])[O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CNc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNc1cc(Oc2cccc(NC(=O)OC(C)(C)C)c2)ccc1[N+](=O)[O-]
Yield: 120.4 %

Procedure:
Using tert-butyl (3-hydroxyphenyl)carbamate (11.0 g, 52.3 mmol) produced in Example C1(i), 5-fluoro-N-methyl-2-nitroaniline (8.58 g, 50.4 mmol), N,N-dimethylformamide (200 ml) and potassium carbonate (28.6 g, 207 mmol) as starting materials, and in the same manner as in Example C1(ii) except that the reaction temperature was set to 80° C., the title compound (21.8 g) was obtained as an orange syrup.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:43][O:44][C:45]1[CH:46]=[C:47]2[C:52](=[CH:53][CH:54]=1)[CH:51]=[N:50][C:49]([NH2:55])=[CH:48]2.Cl[C:57]1[CH:62]=[C:61]([CH2:63][N:64]2[CH2:68][CH2:67][CH2:66][CH2:65]2)[CH:60]=[CH:59][N:58]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[CH3:43][O:44][C:45]1[CH:46]=[C:47]2[C:52](=[CH:53][CH:54]=1)[CH:51]=[N:50][C:49]([NH:55][C:59]1[CH:60]=[C:61]([CH2:63][N:64]3[CH2:65][CH2:66][CH2:67][CH2:68]3)[CH:62]=[CH:57][N:58]=1)=[CH:48]2
Reactant: COc1ccc2cnc(N)cc2c1
Reactant: Clc1cc(CN2CCCC2)ccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc2cnc(Nc3cc(CN4CCCC4)ccn3)cc2c1
Yield: 40 %

Procedure:
Pd2(dba)3(102 mmg, 0.11 mmol) and xantphos (92 mg, 0.16 mmol) were added to a solution of 6-methoxyisoquinolin-3-amine (195 mg, 1.12 mmol) (Preparation C-10), 2-chloro-4-pyrrolidin-1-ylmethyl-pyridine (220 mg, 1.12 mmol) (Preparation B-11) and Cs2CO3 (500 mg, 1.53 mmol) in toluene (50 mL). The suspension was heated under reflux overnight, and THF (50 mL) was added in to dilute the mixture. After filtration, the filtrate was concentrated. The crude material was further purified by silica gel chromatography (EtOAc/Hexane=1/1) and afforded the title compound (150 mg, 40% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): 8.84 (s, 1H), 8.27˜8.29 (m, 2H), 7.73 (d, J=8.7 Hz, 1 H), 7.60 (bs, 1H), 6.99˜7.08 (m, 3H), 7.02 (s, 1H), 6.86 (d, J=5.1 Hz, 1H), 3.94 (s, 3H), 3.62 (s, 2H), 2.58 (m, 4H), 1.83 (m, 4H); MS: m/z 335.2 (M+H+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[F:7][B-:8]([F:11])([F:10])[F:9].[H+]>O>[F:7][B-:8]([F:11])([F:10])[F:9].[NH2+:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: O=C1CCCN1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Product: O=C1CCC[NH2+]1

Procedure:
To a 100 ml flask containing 8.51 g of 2-pyrrolidone (0.1 mol), 30 ml water was added and stirred for dissolution. Then 21.95 g 40% aqueous solution of tetrafluoroboric acid (0.1 mol) was added dropwise into the flask over 20 min at room temperature. Then the reaction was stirred for another 1 hour. Desired product was formed after water was removed under reduced pressure and then dried at 110° C. under 1–5 mmHg for 1 hour. The brown viscous, moisture- and water-stable liquid of 2-pyrrolidonium tetrafluoroborate was obtained with a yield of 97.2%, which has a glass transition temperature of −73° C., density of 1.46 g/ml, viscosity of 350 cP, an electrochemical window of 2.2 V, an ionic conductivity of 8.39×10−4 S/cm, and a Hammett acidic scale H0 of 0.91 using 2,4-dinitroaniline as indicator. No melting point was observed.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[C:9]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH2:21])[N:15]=2)[CH:11]=[CH:12][CH:13]=1.[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O.O1CCOCC1.C(OCC)(=O)C.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>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:28][C:9]2[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH2:21])[N:15]=3)=[CH:11][CH:12]=[CH:13][C:8]=2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:31][CH:32]=1
Reactant: C=C(c1ccccc1)c1cccc(-c2cccc(Br)c2OCc2ccc(F)cc2)n1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=C(c1ccccc1)c1cccc(-c2cccc(-c3ccccc3)c2OCc2ccc(F)cc2)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
Potassium carbonate (1.44 g, 10.5 mmol, 3.0 equiv) was dissolved in water (15 mL) and added to compound 9 (1.6 g, 3.5 mmol, 1.0 equiv) and phenylboronic acid (0.57 g, 4.2 mmol, 1.2 equiv) in dioxane (30 mL). A stream of nitrogen was bubbled through the solution for 15 min and tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.02 mmol, 0.005 equiv) was added to the reaction. The reaction was refluxed for 2 hr at which point LC/MS and TLC indicated the reaction to be complete. The reaction was allowed to cool to room temperature, diluted with ethyl acetate (50 mL), the organic layer was separated and washed with saturated brine (50 mL). The organic layer was dried over sodium sulfate and absorbed onto silica gel (5 g) by concentration under reduced pressure. This material was purified on a silica gel column (30 g) by eluting with ethyl acetate (1%) in heptanes (200 mL), ethyl acetate (2%) in heptanes (200 mL), ethyl acetate (3%) in heptanes (200 mL) and ethyl acetate (4%) in heptanes (200 mL). The desired product was isolated pure in 94% yield (1.5 g).