Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[C:7]([C:9]1[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=2)=[O:14])=[C:11](F)[CH:10]=1)#[N:8].[F:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([O:34][CH3:35])[CH:28]=1>CN(C=O)C>[C:7]([C:9]1[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=2)=[O:14])=[C:11]([O:33][C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][C:29]=2[O:34][CH3:35])[CH:10]=1)#[N:8]
Reactant: N#Cc1ccc(C(=O)Nc2cc[nH]c(=O)c2)c(F)c1
Reactant: COc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1Oc1cc(C#N)ccc1C(=O)Nc1cc[nH]c(=O)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
Cs2CO3 (651.4 mg, 2.0 mmol) was added to a solution of 4-cyano-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (51.4 mg, 0.2 mmol) and 4-fluoro-2-methoxyphenol (244 μL, 2.0 mmol) in DMF (1 mL) and the reaction was stirred at 100° C. for 1 hour. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield 4-cyano-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (22) (26.8 mg, 35%). ESI-MS m/z calc. 379.10. found 380.17 (M+1)+; Retention time: 1.30 minutes (3 minutes run).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([O:23][C:24]3[C:25]([F:34])=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28]([CH3:33])=[CH:27]4)=[CH:18][N:19]=[N:20]2)=[CH:15][C:14]=1[O:35][CH3:36]>CN(C=O)C>[F:34][C:25]1[C:24]([O:23][C:17]2[C:16]3[C:21](=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[C:14]([O:35][CH3:36])[CH:15]=3)[N:20]=[N:19][CH:18]=2)=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[C:28]([CH3:33])[NH:29]2
Reactant: OC1CCNCC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCCBr
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCCN1CCC(O)CC1
Yield: 8 %

Procedure:
A solution of 4-hydroxypiperidine (0.5 g, 4.95 mmol) and 7-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline (0.3 g, 0.65 mmol) in DMF (4 ml) was stirred at 60° C. for 30 minutes. The volatiles were removed under vacuum and the residue was purified by column chromatography eluting with ethyl acetate/methylene chloride (1/1) followed by ethyl acetate/methanol/methylene chloride (4/1/5) followed by methylene chloride/methanol saturated with ammonia (9/1). The fractions containing the expected product were combined and evaporated to give 4-(4-fluoro-2-methylindol-5-yloxy)-7-(3-(4-hydroxypiperidin-1-yl)propoxy)-6-methoxycinnoline (25 mg, 8%).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[CH3:9][N+:10]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]([N:26]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[O:25])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[CH:15]2.[Cl-].[NH4+]>C(O)C.C(Cl)Cl.[Zn]>[CH3:9][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]([C:24]([N:26]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[NH:27][S:28]([C:31]2[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=2)(=[O:30])=[O:29])=[O:25])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]1=2
Reactant: Cc1ccc(S(=O)(=O)NN(C(=O)c2c3ccccc3[n+](C)c3ccccc23)c2ccccc2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NN(C(=O)C2c3ccccc3N(C)c3ccccc32)c2ccccc2)cc1
Reaction time: 2 h

Procedure:
10-Methyl-N-(phenyl)-N-(p-toluenesulfonamido)acridinium-9-carboxamide trifluoromethanesulfonate (10 mg, 0.0016 mmol) was suspended in absolute ethanol (10 mL) and solution was refluxed for 15 min to obtain a clear solution. Ammonium chloride (88 mg, 1.6 mmol) was added by portions to thesolution followed by zinc (108 mg, 1.6 mmol). The yellow color of solution disappeared immediately after the addition of zinc. Colorless solution wasrefluxed for 2 h. TLC of reaction mixture showed complete conversion to a non-polar material. Solution was filtered and precipitate was washed with ethanol (3×20 mL). Solution was concentrated to obtain an off-white solid which was redissolved in methylene chloride and washed with water (2×15 mL). Organic layer was dried over Na2SO4 and concentrated to yield the crude product which was purified by preparative TLC using (30% ethyl acetate:hexane) Pure product was obtained as an off-white solid. 1HNMR (CDCl3) δ2.40 (s, 3H), 3.18 (s, 3H) 5.00 (s, 1H), 6.76-7.77 (m, 12H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2.C(Cl)(Cl)Cl>O>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH2:16][CH2:15]2
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Clc1ccc2c(c1)CCN2
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccccc1N1CCc2cc(Cl)ccc21
Reaction time: 8 h

Procedure:
A solution of 32.3 g of 1-fluoro-2-nitrobenzene and 92.2 g of 5-chloroindoline are stirred at 120° C. under N2 overnight (20 hours). The mixture is cooled, and stirred vigorously in a two phase chloroform and water system. The undissolved material is filtered off and the organic phase is then separated, washed with 3 N--HCl, water, dried over Na2SO4, and concentrated to an oil which is dried further in vacuo at 90° C. This is taken up in isopropyl ether and refrigerated overnight to provide 5-chloro-1-(2-nitrophenyl)indoline, m.p. 85°-89° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH2:27]([NH2:31])[CH2:28][CH2:29][CH3:30]>C(#N)C>[CH3:26][S:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][CH:13]([CH2:12][NH:31][CH2:27][CH2:28][CH2:29][CH3:30])[O:14]2)=[CH:19][CH:18]=1)(=[O:24])=[O:25]
Reactant: CCCCN
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCCCNCC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), butan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 297 (M+, 6), 254 (9), 131 (8), 87 (7), 86 (bp), 77 (7).
Reaction SMILES: [CH:1](CC[Si](Cl)(Cl)Cl)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[SiH](C)C.[CH3:19][CH2:20]CCCC>[Pt]>[CH:19]([C:6]1[CH:5]=[CH:4][C:3]([CH:2]=[CH2:1])=[CH:8][CH:7]=1)=[CH2:20]
Reactant: CCCCCC
Reactant: Cl[Si](Cl)(Cl)CCC=Cc1ccccc1
Agent: [Pt]
Agent: C[SiH](C)Cl
Product: C=Cc1ccc(C=C)cc1

Procedure:
(Styrylethyl)-trichlorosilane is first synthesized by a platinum-catalyzed mono-hydrosilylation of p-DVB with chlorodimethylsilane in hexane. Kim, I-J.; Faust, R. Polym. Prepr., (Am. Chem. Soc. Div. Polym. Chem) 2000, 41(2), 1309. A styryl-POSS macromer is then prepared by corner capping reaction of incompletely condensed trisilanol (c-C5H9)7Si7O9(OH)3 with (styrylethyl)-trichlorosilane, according to the procedure reported in Haddad, T. S.; Lichtenhan, J. D. Macromolecules 1996, 29, 7302.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:14][CH2:15][CH3:16])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:17])[CH:5]=1.Cl.[N:19]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][N:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[ClH:1].[NH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]([N:19]2[CH2:20][CH2:21][N:22]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([N:10]([CH2:14][CH2:15][CH3:16])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:17])[CH:5]=3)[CH2:23][CH2:24]2)=[N:26]1
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: CCCN(C(C)=O)c1ccc(CCCl)cc1C
Agent: Cl
Product: CCCN(C(C)=O)c1ccc(CCN2CCN(c3n[nH]c4ccccc34)CC2)cc1C
Yield: 20 %

Procedure:
N-[4-(2-Chloro-ethyl)-2-methyl-phenyl]-N-propyl-acetamide (0.090 g, 0.355 mmole) was reacted with 3-piperazin-1-yl-1H-indazole hydrochloride (0.127 g, 0.532 mmol) according to the method outlined in Example 501. The titled product was precipitated as its hydrochloride salt from dioxane/HCl(gas) treatment (0.030 g, 0.071 mmol). Yield=20%. 100% purity at 254 nm; LCMS (APCI): 437.3 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 10.50 (s, 1H), 7.79 (d, J=8.55 Hz, 1H), 7.37 (d, J=8.55 Hz, 1H), 7.32–7.26 (m, 2H), 7.21–7.12 (m, 2H), 6.99 (t, J=7.48 Hz, 1H), 3.97 (bd, J=8.70 Hz, 2H), 3.87–3.77 (m, 1H), 3.65 (bd, J=7.25 Hz, 2H), 3.39 (bs, DMSO-H2O), 3.31–3.21 (m, 6H), 3.10–2.92 (m, 3H), 2.14 (s, 3H), 1.58 (s, 3H), 1.39 (sextet, J=7.38 Hz, 2H), 0.79 (t, 7.38 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][CH2:8][C:9]1(C(OCC)=O)[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])=[N:11][C:10]1=[O:25])([CH3:4])([CH3:3])[CH3:2].C1COCC1.O[Li].O.Cl>O.CO>[O:25]=[C:10]1[CH:9]([CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:31])[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:22])[F:23])=[N:11]1
Reactant: CCOC(=O)C1(CCC(=O)OC(C)(C)C)SC(Nc2ccccc2C(F)(F)F)=NC1=O
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)CCC1SC(Nc2ccccc2C(F)(F)F)=NC1=O
Reaction time: 3 h

Procedure:
To a mixture of ethyl 5-(3-tert-butoxy-3-oxopropyl)-4-oxo-2-(2-(trifluoromethyl)phenylamino)-4,5-dihydrothiazole-5-carboxylate (88.7 mg, 0.19 mmol), THF (1 mL), MeOH (0.3 mL), and water (0.3 mL) was added LiOH.H2O (Aldrich, 20 mg, 0.47 mmol) at room temperature. After 3 h, 1N HCl (0.7 mL) was added to the reaction mixture at 0° C. The mixture was extracted with EtOAc, and the organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography. MS: 389 (M+1).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][NH:9][CH2:8][CH:7]2[CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19].C(N(CC)CC)C>CO.C1(C)C=CC=CC=1.[Pd]>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[C:7]2[CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19]
Reactant: CCC(=O)NCCC1CNCc2ccc(OC)cc21
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: Cc1ccccc1
Product: CCC(=O)NCCc1cncc2ccc(OC)cc12

Procedure:
The compound of Example 5 is dissolved in a minimum of methanol with the application of heat and then diluted with toluene. 1.5 equivalents of triethylamine are then added to the solution, and the reaction mixture is subsequently heated at reflux in the presence of palladium-on-carbon (10% by weight) for 3 hours. After removal of the catalyst by filtration, the solution is evaporated under reduced pressure. The oil obtained is purified by chromatography on silica gel (eluant dichlormethane/methanol 9/1). The purified oil is taken up in ether saturated with HCl(g) and stirred until a precipitate is obtained. The precipitate so formed is suction-filtered off and placed under vacuum in a dessicator. The title product is obtained in the form of a white solid.
Reaction SMILES: [OH:1][CH:2]([CH:10]1[CH2:14][CH2:13][CH:12]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH:11]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:31]([O:1][CH:2]([CH:10]1[CH2:14][CH2:13][CH:12]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH:11]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:33])[CH3:32]
Reactant: CCCCCC#CC(O)C1CCC(OC2CCCCO2)C1CCCCCCC(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCC#CC(OC(C)=O)C1CCC(OC2CCCCO2)C1CCCCCCC(=O)O
Reaction time: 8 h

Procedure:
To a solution of 2-(1-hydroxy-2-octynyl)-5-(tetrahydropyran-2-yloxy)-cyclopentaneheptanoic acid (11.5 g), described in Example 2, in dry pyridine (50 ml), acetic anhydride (35.6 ml) is added. The mixture is stirred overnight. The solvent is removed under reduced pressure. The residue is dissolved in ether and the solution is washed with ether, dried and concentrated to yield 2-(1-acetoxy-2-octynyl)-5-(tetrahydropyran-2-yloxy)-cyclopentaneheptanoic acid, (3; R1 = H, R2 = tetrahydropyran-2-yl and R3 = CH3CO), νmaxfilm 1700, 1735 cm-1.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][N:32]=1>>[Cl:30][C:31]1[N:32]=[CH:33][C:34]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]4)=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]2)=[O:9])=[CH:35][CH:36]=1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1ccc(Cl)nc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(Cl)nc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 2-chloropyridine-5-boronic acid. The title compound was obtained in 36% yield as orange foam. MS (m/e): 517.3 (MH+, 100%).
Reaction SMILES: F[C:2](F)(F)[C:3](OC(=O)C(F)(F)F)=[O:4].[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[O:24][CH:25]=[CH:26][CH:27]=1)(=[O:16])[CH3:15].O>C(O)(=O)C>[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[O:24][C:25]([C:3](=[O:4])[CH3:2])=[CH:26][CH:27]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OCCCCCc1ccco1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCCCCCc1ccc(C(C)=O)o1
Reaction time: 16 h

Procedure:
To a mixture of 100 ml of trifluoroacetic anhydride and 100 ml of glacial acetic acid was added 89 g of 5-(2-furanyl)pentanol acetate in 100 ml of acetic acid. The reaction mixture was allowed to stand at room temperature for about 16 hours, then poured into water and extracted with methylene dichloride. The extracts were concentrated and the residue distilled to give 60.6 g of 5-(5-acetyl-2-furanyl)pentanol acetate, b.p. 120°-123° C. (0.05 mm).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH:11]=[O:12].[CH:13]1([Mg]Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl-].[NH4+].C[N+]1([O-])CCOCC1>O1CCCC1.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(#N)C>[CH:13]1([C:11]([C:3]2[S:4][C:5]3=[CH:6][N:7]=[CH:8][CH:9]=[C:10]3[C:2]=2[CH3:1])=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1c(C=O)sc2cnccc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1c(C(=O)C2CCCCC2)sc2cnccc12
Reaction time: 1.5 h
Yield: 31 %

Procedure:
To a solution (30 mL) of 3-methylthieno[2,3-c]pyridine-2-carbaldehyde (1.39 g) synthesized above in tetrahydrofuran was added a 1.0M solution (15.7 mL) of cyclohexylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred for 1.5 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, tetrahydrofuran was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give a pale-yellow solid. To a mixture of the obtained solid, 4-methylmorpholine N-oxide (680 mg) and acetonitrile (20 mL) was added tetrapropylammonium perruthenate (113 mg), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-40% ethyl acetate/hexane) to give the title object compound (628 mg, 31%) as a colorless oil.
Reaction SMILES: [CH3:1][Li].[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5].[Cl-].[NH4+]>O1CCCC1>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([OH:5])([CH3:1])[CH3:3])=[CH:7][CH:8]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
Methyllithium (1.10 mol/l solution in diethyl ether, 502 mL, 0.552 mol) was added to a solution of 4-bromoacetophenone (100 g, 0.502 mol) in tetrahydrofuran (500 mL) in a nitrogen atmosphere at −78° C., and the mixture was stirred at the same temperature for one hour. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give crude 2-(4-bromo-phenyl)-propan-2-ol.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2=[C:6]3[N:17]=[C:16]([C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:25])[NH:15][C:7]3=[C:8]3[C:13]([C:12](=[O:14])[NH:11][CH:10]=[CH:9]3)=[C:4]2[CH:3]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[C:31]([F:38])[N:30]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>[Cl-].[Na+].O>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[C:16]1[NH:15][C:7]2=[C:8]3[C:13](=[C:4]4[CH:3]=[C:2]([C:34]5[C:29]([F:28])=[N:30][C:31]([F:38])=[CH:32][CH:33]=5)[CH:27]=[CH:26][C:5]4=[C:6]2[N:17]=1)[C:12](=[O:14])[NH:11][CH:10]=[CH:9]3
Reactant: OB(O)c1ccc(F)nc1F
Reactant: O=c1[nH]ccc2c3[nH]c(-c4c(F)cccc4Cl)nc3c3ccc(Br)cc3c12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1[nH]ccc2c3[nH]c(-c4c(F)cccc4Cl)nc3c3ccc(-c4ccc(F)nc4F)cc3c12
Reaction time: 3 h

Procedure:
A sealed tube was charged with the intermediate from Example 1 Step E (230 mg, 0.52 mmol), (2,6-difluoropyridin-3-yl)boronic acid (580 mg, 3.6 mmol), and bis(triphenylphosphine)palladium(n) chloride (73 mg, 0.1 mmol). The tube was evacuated and backfilled with argon three times. Fully degassed toluene (3.0 mL) and ethanol (3.0 mL) were added, followed by the addition of 2.0M aqueous sodium carbonate solution (2.6 mL, 5.2 mmol). The tube was sealed, placed in an oil bath at 90° C., and stirred for 3 hours. The reaction mixture was then cooled and poured into a mixture of ethyl acetate and brine. The aqueous layer was extracted twice with ethyl acetate and the combined organics were dried over magnesium sulfate, filtered, concentrated in vacuo. Purification via flash chromatography (silica, 0-20% methanol/dichloromethane) was followed by purification via preparative chiral HPLC (AD column, 25% ethanol/heptane isocratic) to afford the title compound. 1H NMR (600 MHz, d6-DMSO) δ 11.75 (s, 1H), 10.57 (s, 1H), 8.49 (broad s, 1H), 8.43 (q, 1H), 7.92 (d, 1H), 7.72-7.69 (m, 1H), 7.62-7.61 (m, 2H), 7.58-7.52 (m, 1H), 7.37 (dd, 1H), 7.27 (broad s, 1H). Imidazole proton was not observed [M+H]+ 476. τR: 9.44 min (analytical chiral HPLC, AD column, 0.46 cm×25 cm, 25% ethanol/heptane, isocratic, flow rate=0.75 mL/min).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:10]=[C:9]([CH2:20][CH2:21][CH3:22])[C:8]=2/[CH:23]=[N:24]/[OH:25])=[C:5]([CH3:26])[O:4][N:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[N:10]=[C:9]([CH2:20][CH2:21][CH3:22])[C:8]=2[CH:23]=[N:24][OH:25])=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: CCCc1nn(-c2ccc(OC)cc2)c(-c2c(C)noc2C)c1/C=N/O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCc1nn(-c2ccc(OC)cc2)c(-c2c(C)noc2C)c1C=NO
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
10% of the crude (E)-5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-propyl-1H-pyrazole-4-carbaldehyde oxime (1.2 mg, 0.003 mmol) from step (e) was dissolved in CH2Cl2 (4 mL) and BBr3 (1 M solution in DCM, 0.4 mL, 0.37 mmol) was added. The mixture was stirred at room temperature for 4 h. Water and DCM were added and the phases were separated. The organic phase was purified on preparative HPLC to give E4 5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-propyl-1H-pyrazole-4-carbaldehyde oxime (0.58 mg, 3% over three steps). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 341.16 (M+II), 339.25 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.84 s 1H, 7.14 m 2H, 6.85 m 2H; (missing m 2H under H2O); 2.18 s 3H, 1.85 s 3H, 1.75 m 2H, 0.99 t (7.6 Hz) 3H.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=O)[NH:5][CH2:4][C:3]1=[O:14].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:14])[CH2:4][N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1C(=O)CNC(=O)c2ccccc21
Product: CN1C(=O)CN=C(Cl)c2ccccc21

Procedure:
The title compound 467 (1.54 g, 8.10 mmol) was heated in phosphorus oxychloride (15 mL) at 95° C. for 2 hours. The reaction mixture was then cooled to room temperature and excess of phosphorus oxychloride was removed under reduced pressure. The black oil was dissolved in ethyl acetate and the organic phase was washed with sodium bicarbonate (saturated solution) and brine, dried over sodium sulfate, filtered and concentrated to afford crude title compound 468 that was used as such for the next step. MS (ESI): 209.12 (MH)+.
Reaction SMILES: [C:1]([S:5]([OH:8])(=[O:7])=[O:6])([F:4])([F:3])[F:2].[OH-].[Na+:10].FF.ClCl.C(=O)([O-])[O-]>>[C:1]([S:5]([O:8][Na:10])(=[O:7])=[O:6])([F:4])([F:3])[F:2]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: [Na+]
Agent: ClCl
Agent: FF
Agent: O=C([O-])[O-]
Product: O=S(=O)(O[Na])C(F)(F)F

Procedure:
A teflon vessel was charged with 75% aqueous solution of CF3SO3H used in Example 1, and 50% aqueous solution of NaOH (free fluorine 33 ppm, free chlorine ppm, carbonate radical 1.1%) was poured into the solution such that the reaction between the acid and the alkali proceeded under acidic conditions and terminated while pH of the reaction liquid was 2. Then the reaction liquid was dried in the same manner as in Example 1 to thereby obtain a powder of CF3SO3Na.
Reaction SMILES: C[Al]1[CH2:7][CH2:6][CH2:5][CH2:4]O1.[C:8]1(C)[CH:13]=[CH:12]C=[CH:10][CH:9]=1>C([Ti](CC1C=CC=CC=1)(CC1C=CC=CC=1)CC1C=CC=CC=1)C1C=CC=CC=1>[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([CH:13]=[CH2:12])=[CH:7][CH:6]=1
Reactant: Cc1ccccc1
Reactant: C[Al]1CCCCO1
Agent: c1ccc(C[Ti](Cc2ccccc2)(Cc2ccccc2)Cc2ccccc2)cc1
Product: C=Cc1ccc(C)cc1

Procedure:
A syndiotactic poly-p-methyl-styrene in powder form is prepared according to the method described in Macromolecules, 1989, 22, 104. p-Methyl-styrene (0.5 mmoles) is polymerized in toluene (59 ml) at 50° C. for 24 hours, in the presence of tetrabenzyltitanium (5·10 moles) and methylalumoxane (0.3 g); 8.5 g of s-PpMS are obtained. A film about 100 microns thick is produced by compression molding at a pressure of 2 Kg/cm2 and at a temperature of 230° C. An amorphous film is thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9]O)=[C:6]([F:8])[CH:7]=1.[BrH:12].O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9][Br:12])=[C:6]([F:8])[CH:7]=1
Reactant: OCc1c(F)cc(Br)cc1F
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Product: Fc1cc(Br)cc(F)c1CBr
Yield: 98 %

Procedure:
A solution of 5-Bromo-2-hydroxymethyl-1,3-difluoro-benzene (0.89 g, 4.0 mmol) and 30 wt % of hydrogen bromide in acetic acid was stirred at room temperature for 90 minutes before it was poured into 80 ml of water. The mixture was extracted with pentane (3×50 ml) and the combined organic layers were washed with water (3×20 ml), dried over MgSO4 and concentrated at low pressure to afford the desired product (10.0 g, 98% yield). 1H NMR (CDCl3) δ: 4.47 (s, 2H), 7.09–7.10 (m, 1H), 7.12–7.13 (m, 1H).