Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[C:6]([CH3:30])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[C:9]=1[CH3:10].[OH-].[Na+].O.Cl>O1CCOCC1>[CH3:30][C:6]1[C:5]([CH2:4][C:3]([OH:31])=[O:2])=[C:9]([CH3:10])[N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][S:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)=[CH:16][CH:17]=2)[N:7]=1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(CSc3ccc(C(F)(F)F)cc3)cc2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nn(Cc2ccc(CSc3ccc(C(F)(F)F)cc3)cc2)c(C)c1CC(=O)O
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
{3,5-Dimethyl-1-[4-(4-trifluoromethyl-phenylsulfanylmethyl)-benzyl]-1H-pyrazol-4-yl}-acetic acid methyl ester (intermediate 16.1.3, 80 mg, 0.18 mmol) was dissolved in 2 ml dioxane and aqueous NaOH solution (0.36 ml, 1 M) was added. After stirring for 2.5 h at 60° C. and dilution with water, aqueous HCl solution (0.37 ml, 1 M) was added. The product was isolated by filtration, washed with water and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][N:31]3[C:35](=[O:36])[C:34]4=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]4[C:32]3=[O:41])[CH:24]=2)[C:10]1=[O:42].[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[NH:43]([C:14]1[N:13]=[C:12]2[N:11]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][N:31]4[C:32](=[O:41])[C:33]5=[CH:40][CH:39]=[CH:38][CH:37]=[C:34]5[C:35]4=[O:36])[CH:24]=3)[C:10](=[O:42])[N:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:18][C:17]2=[CH:16][N:15]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: Nc1ccccc1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1cccc(CCN3C(=O)c4ccccc4C3=O)c1)C(=O)N(c1c(Cl)cccc1Cl)C2
Product: O=C1c2ccccc2C(=O)N1CCc1cccc(N2C(=O)N(c3c(Cl)cccc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Temperature: 180 °C
Yield: 29 %

Procedure:
A mixture of 200 mg (0.52 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one and 3 ml of aniline was heated at 180° C. for 40 minutes and then cooled. The mixture was partitioned between 40 ml of dichloromethane and 40 ml of 2M hydrochloric acid. The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was subjected to column chromatography on silica gel using diethyl ether/hexane (1:1) for the elution. The product-containing fractions were combined and evaporated to give 30 mg (29%) of 7-anilino3-(2,6-dichlorophenyl)-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 142° C.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[N:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[CH2:26]([Mg]Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[F:8][C:7]1[C:2]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[N:3][CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[N:6]=1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3cnc(Br)c(F)n3)cc2)CC1
Reactant: CCCCCCCC[Mg]Br
Product: CCCCCCCCc1ncc(-c2ccc([C@H]3CC[C@H](CCCCC)CC3)cc2)nc1F

Procedure:
In an analogous reaction to Example 1d, 2.75 g (6.80 mmol) of 2-bromo-3-fluoro-5-[4-(trans-4-pentylcyclohexyl)phenyl]pyrazine and 10.2 mmol of octylmagnesium bromide give 1.53 g of 2-fluoro-3-octyl-6-[4-(trans-4-pentylcyclohexyl)phenyl]pyrazine. ##STR21## The compound has the following phase sequence:
Reaction SMILES: [C:1]([N:9]1[C:13](=[O:14])[CH:12]=[CH:11][S:10]1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:15][C:12]1[C:13](=[O:14])[N:9]([C:1]([CH2:4][C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:2])[CH3:3])[S:10][CH:11]=1
Reactant: CC(C)(C)CC(C)(C)n1sccc1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC(C)(C)CC(C)(C)n1scc(Br)c1=O
Reaction time: 3 h

Procedure:
To a solution of 10.7 g. (0.05 mole) of 2-t-octyl-3-isothiazolone in 100 ml. of chloroform was added in a single portion 17.8 g. (0.1 mole) of N-bromosuccinimide, and a slight exotherm was observed. After stirring for 3 hours the mixture was filtered, and the solid washed with ether. The chloroform filtrate and ether washings were then evaporated to give a total of 7.8 g. (54%) of 4-bromo-2-t-cetyl-3-isothiazolone, m.p. 133-142.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[Cl:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[NH:17][N:16]([CH3:18])[C:15](=[O:19])[CH:14]=2)=[C:8]([F:20])[CH:7]=1.[OH-].[Na+].O>O1CCOCC1>[Cl:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[CH:14]=[C:15]([O:19][CH:2]([F:4])[F:3])[N:16]([CH3:18])[N:17]=2)=[C:8]([F:20])[CH:7]=1
Reactant: FC(F)Cl
Reactant: Cc1cc(-c2cc(=O)n(C)[nH]2)c(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(OC(F)F)n(C)n2)c(F)cc1Cl

Procedure:
Gaseous chlorodifluoromethane was passed at room temperature for 2 hours into a solution of 133 g (0.55 mol) of 5-(4-chloro-2-fluoro-5-methylphenyl)-1,2-dihydro-2-methyl-3H-pyrazol-3-one and 110 g (2.7 mol) of sodium hydroxide in 1 l of dioxane and 0.5 1 of water. The reaction solution was then poured into 2 l of water, whereupon the aqueous phase was extracted three times using ethyl acetate. The combined organic phases were dried over magnesium sulfate and then filtered and concentrated. The residue was purified by means of column chromatography on silica gel (eluent: cyclohexane/ethyl acetate=9:1), followed by preparative MPLC on silica gel (same eluent). Yield: 43 g.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]1[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=1)[N:26](C(OC(C)(C)C)=O)[CH:25]=[CH:24]3)[C:16](=[O:37])[CH2:15][CH2:14]2.ClCCCN1CCC[C@H]1C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH:26]1[C:27]2[C:23](=[CH:22][C:21]([N:17]3[C:18]4[C:13](=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][C@H:2]5[CH3:1])=[CH:20][CH:19]=4)[CH2:14][CH2:15][C:16]3=[O:37])=[CH:29][CH:28]=2)[CH:24]=[CH:25]1
Reactant: C[C@@H]1CCCN1CCCOc1ccc2c(c1)CCC(=O)N2c1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Agent: C[C@@H]1CCCN1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@@H]1CCCN1CCCOc1ccc2c(c1)CCC(=O)N2c1ccc2[nH]ccc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 2.2 %

Procedure:
To a solution of tert-butyl 5-[6-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}-2-oxo-3,4-dihydroquinolin-1(2H)-yl]-1H-indole-1-carboxylate (Compound No. 41) prepared in the same manner as shown in Example 1 (0.050 g) in methanol (0.19 mL), water (0.3 mL) and potassium carbonate (0.041 g) were added and stirred at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by NH-type preparative TLC (on three plates of 0.25 mm thickness, developing solvent: ethyl acetate) to give the titled compound (0.0090 g, 2.2%) as a colorless amorphous substance.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Cl[CH2:13][CH2:14][CH2:15][O:16][CH3:17]>>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=[C:5]([O:11][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH:6]=1
Reactant: COc1cc(O)cc(CO)c1
Reactant: COCCCCl
Product: COCCCOc1cc(CO)cc(OC)c1

Procedure:
Analogously to Method F, 3.15 g of 3-hydroxymethyl-5-methoxyphenol are reacted with 1-chloro-3-methoxypropane. The title compound is obtained as a slightly yellowish oil. Rf=0.27 (1:1 EtOAc-heptane). Rt=3.23.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:15])[C:4]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:6]=2[CH:5]=1.[C:16](OC(=O)C)(=O)[CH3:17]>>[CH3:14][O:13][C:12]1[C:6]2[CH:5]=[C:4]([C:3]3[N:15]=[C:16]([CH3:17])[O:1][N:2]=3)[O:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc2oc(C(N)=NO)cc12
Reactant: CC(=O)OC(C)=O
Product: COc1cccc2oc(-c3noc(C)n3)cc12

Procedure:
1-(Hydroxyimino)-1-(4-methoxybenzo(b)furan-2-yl)methylamine (3.4 g) was dissolved in acetic anhydride (40 ml) and the mixture was refluxed under heating for 14 hr. The reaction mixture was concentrated under reduced pressure and the obtained residue was recrystallized from acetonitrile to give the title compound (1.1 g) as pale-as brown crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:19][C@H:18]([O:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:17][C@H:13]2[C:14](O)=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(#N)C>[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]([C:14]([C@@H:13]2[CH2:17][C@@H:18]([O:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[CH2:19][N:12]2[C:10]([O:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:26][CH:25]=2)=[O:11])=[O:15])[CH2:32][CH2:31]1
Reactant: C[Si](C)(C)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: OCCN1CCNCC1
Solvent: CC#N
Product: C[Si](C)(C)O[C@@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
674 mg of trans-1-(4-nitrobenzyloxycarbonyl)-4-trimethylsilyloxy-L-proline [prepared as described in step (2) above] were dissolved in 14 ml of anhydrous acetonitrile, and 343 mg of N,N'-carbonyldiimidazole were added to the resulting solution. The resulting mixture was then stirred at room temperature for 1 hour. At the end of this time, a solution of 275 mg of 1-(2-hydroxyethyl)piperazine in 1 ml of anhydrous acetonitrile was added to the reaction mixture, and the resulting mixture was stirred overnight at room temperature. It was then concentrated by evaporation under reduced pressure, and the resulting residue was mixed with an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, to give 574 mg of (2S,4R)-2-(4-(2-hydroxyethyl)-1-piperazinylcarbonyl)-4-trimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine as an oil. The whole of this product was dissolved in 5.7 ml of methylene chloride, and 170 mg of 4-dimethylaminopyridine and 300 mg of 4-nitrobenzyl chloroformate were added to the resulting solution, whilst ice-cooling. The mixture was then stirred at room temperature for 1 hour, after which the solvent was removed by distillation under reduced pressure. The resulting residue was mixed with 15 ml of 1N aqueous hydrochloric acid and then stirred at room temperature for 1 hour. At the end of this time, the mixture was made mildly basic by the addition of an aqueous solution of sodium hydrogen-carbonate; it was then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate; the solvent was then removed by distillation under reduced pressure, and the resulting residue was purified in a similar manner to that described in step (b) above, to afford 348 mg of the title compound. The infra-red absorption spectrum and nuclear magnetic resonance spectrum of the product thus obtained were identical with those of the compound prepared as described in step (a), above.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[C:13]([CH3:26])[CH:12]=2)[CH2:6]1)=O.[CH3:27][NH2:28]>C(O)C>[CH3:27][NH:28][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[C:13]([CH3:26])[CH:12]=2)[CH2:6]1)=[O:2]
Reactant: CN
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)c(C)c2)C1
Solvent: CCO
Product: CNC(=O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)c(C)c2)C1

Procedure:
In analogy to the aminolysis described in Example 1e), the (RS)-1-[(4-(3-fluoro-benzyloxy)-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester is treated in a sealed tube with methylamine in ethanol at 60° C. for 18 h to yield the (RS)-1-[(4-(3-fluoro-benzyloxy)-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl amide as a light yellow solid; MS: m/e=357 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH2:12][CH2:13][CH:14]([OH:16])[CH3:15])=[CH:6][CH:5]=1.[CH2:19]([O:21][C:22](=[O:35])[C:23]([O:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][C:28]=1[CH3:34])([CH3:25])[CH3:24])[CH3:20]>>[CH2:19]([O:21][C:22](=[O:35])[C:23]([CH3:25])([O:26][C:27]1[CH:32]=[CH:31][C:30]([O:16][CH:14]([CH3:15])[CH2:13][CH2:12][C:11]#[C:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:17])([F:18])[F:1])=[CH:9][CH:8]=2)=[CH:29][C:28]=1[CH3:34])[CH3:24])[CH3:20]
Reactant: CC(O)CCC#Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(OC(C)CCC#Cc2ccc(OC(F)(F)F)cc2)cc1C

Procedure:
In analogy to the procedure described in example 24A], rac-6-(4-trifluoromethoxy-phenyl)-hex-5-yn-2-ol (example 31E]) and 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) yielded the title compound as yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[CH2:13][N+:14]([O-:16])=[O:15]>CO>[CH3:2][O:3][N:4]=[C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[OH:5])[CH2:13][N+:14]([O-:16])=[O:15]
Reactant: O=C(C[N+](=O)[O-])c1ccccc1O
Reactant: CON
Agent: Cl
Solvent: CO
Product: CON=C(C[N+](=O)[O-])c1ccccc1O
Temperature: 47.5 °C
Reaction time: 10 h
Yield: 77.9 %

Procedure:
At 20° C., 73.5 g (0.88 mol) of methoxyamine hydrochloride are added to a solution of 80.0 g (0.44 mol) of o-hydroxy-ω-nitroacetophenone in 500 ml of methanol, and the mixture is stirred at 45 to 50° C. for 8 to 12 hours. The solution is cooled to 20° C., poured into 1 l of ice-water and stirred for one hour. The crystalline product is filtered off and washed with 500 ml of water a little at a time and dried at 40° C. in a vacuum drying cabinet. 72 g (74.6% of theory) of 1-(2-hydroxyphenyl)-2-nitro-ethanone O-methyl-oxime are obtained as a mixture of stereoisomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:36])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[C:24]([O:34]C)[CH:23]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.O.C(=O)(O)[O-].[Na+].Cl.C(O)C>ClCCl.B(Br)(Br)Br.O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:36])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[C:24]([OH:34])[CH:23]=3)[CH2:17][CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: COc1cc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)ccc1-c1ccncc1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccncc2)c(O)c1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
In dichloromethane (1 ml), boron tribromide (115 μl) was dissolved, followed by the dropwise addition of a solution of 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[3-methoxy-4-(pyridin-4-yl)benzoyl]piperazine (105 mg), which had been obtained in Example 30, in dichloromethane (dichloromethane: 4 ml) at an external temperature of about −78° C. While heating gradually to room temperature, the resulting mixture was stirred for 23 hours. After dichloromethane and water were added to the reaction mixture and the resulting mixture was stirred for a while, sodium bicarbonate was added to make alkaline the reaction mixture, which was separated into an organic layer and a water layer. From the water layer, another organic layer was extracted with dichloromethane. These organic layers were combined together, washed with saturated saline and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane˜3% methanol-dichloromethane). The crudely purified product so obtained was dissolved in tetrahydrofuran. Ethanol hydrochloride was added to the resulting solution to solidify the same. The resulting solid was collected by filtration and then dissolved in a mixed solvent of water and methanol. After the removal of the insoluble matter by filtration, the filtrate was distilled under reduced pressure, whereby the title compound (36 mg, 30%) was obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH3:19][Si:20]([CH3:29])([CH3:28])[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl[Si:31]([CH3:34])([CH3:33])[CH3:32]>C1COCC1>[CH2:25]([O:24][C:22]([O:23][Si:31]([CH3:34])([CH3:33])[CH3:32])=[C:21]([Si:20]([CH3:28])([CH3:29])[CH3:19])[CH3:27])[CH3:26]
Reactant: CCOC(=O)C(C)[Si](C)(C)C
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(O[Si](C)(C)C)=C(C)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of 21.8 mL (0.156 mole) of diisopropylamine in 100 mL of THF at 0° was added 0.156 mole of butyl lithium/hexane. After 30 minutes, the solution was cooled to -78°, and 27.19 g of ethyl 2-trimethylsilylpropionate (vide supra) was added. After 30 minutes at -78°, 17.38 g (20.3 mL, 0.16 mole) of chlorotrimethylsilane was added. The mixture was allowed to warm to ambient temperature, filtered under argon, and the filtrate was evaporated. The residue was treated with hexane and filtered. The filtrate was concentrated and distilled in a spinning band column to give, in three fractions, 29.6 g of (82% E-) [(1-ethoxy-2-trimethylsilyl-1-propenyl)oxy]-trimethylsilane, b.p 36°/0.8 mm, -43°/0.7 mm. There were no compositional differences in the three fractions. A fraction with b.p. 45°/0.7 mm was analyzed.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[N:5]=[C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([NH2:31])=[N:27][C:28]=1[O:29][CH3:30].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([NH:31][C:2]2[C:3]3[N:4]([CH:18]=[CH:19][N:20]=3)[N:5]=[C:6]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[CH:7]=2)=[N:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(N)nc1OC
Reactant: COC(=O)c1ccc(-c2cc(Br)c3nccn3n2)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cc(Nc3ccc(OC)c(OC)n3)c3nccn3n2)cc1
Temperature: 100 °C
Yield: 141.3 %

Procedure:
A mixture of methyl 4-(8-bromoimidazo[1,2-b]pyridazin-6-yl)benzoate (0.3 g, 0.904 mmol), 5,6-dimethoxypyridin-2-amine (0.167 g, 1.084 mmol), Pd2(dba)3 (52 mg, 0.09 mmol), BINAP (225 mg, 0.362 mmol) and Cs2CO3 (0.884 g, 2.712 mmol) in dioxane (20 mL) was heated to 100° C. for 16 h in a sealed tube under N2 atmosphere. The mixture was cooled and concentrated in vacuo. The residue was purified by chromatography (silica, 10 g, 200-300 mesh, ethyl acetate:petroleum ether=1:3) to afford methyl 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (0.518 g) as a yellow solid containing unidentified impurities. LC-MS: [M+H]+=406, tR=1.766 min.
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[C:12]([C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(COC)OC.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[O:1]([CH2:8][C:9]1[N:14]=[C:13]2[C:15]([O:20][C:18](=[O:19])[C:12]2=[CH:11][CH:10]=1)=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(COc2ccccc2)nc1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: COCCOC
Product: O=C1OC(=O)c2nc(COc3ccccc3)ccc21

Procedure:
30 g of 6-phenoxymethylpyridine-2,3-dicarboxylic acid are added to a mixture of 100 ml of dimethoxyethane, 28 ml of acetic anhydride and 15 ml of pyridine while stirring and the reaction mixture is further stirred for one hour at room temperature. The whole is then concentrated by evaporation under a high vacuum. The above anhydride remains in the form of a light-coloured oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2[F:19])=[C:5]([O:20][CH3:21])[CH:4]=1)[CH3:2].O1CC[CH2:24][CH2:23]1>C(O)C>[CH2:23]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[O:20][CH3:21])=[C:11]([F:19])[CH:12]=1)[CH3:24]
Reactant: CCc1ccc(Oc2ccc([N+](=O)[O-])cc2F)c(OC)c1
Reactant: C1CCOC1
Solvent: CCO
Product: CCNc1ccc(Oc2ccc(CC)cc2OC)c(F)c1

Procedure:
According to the procedure of example 20(b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for 4-ethyl-1-(2-fluoro-4-nitrophenoxy)-2-methoxybenzene (1.16 g; 4.0 mmol) and tetrahydrofurane for ethanol (16 mL), two compounds were obtained after purification on silica gel (gradient cyclohexane/dichloromethane) 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (466 mg; 45%)
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:38]([C:40]([C:59]1[CH:64]=[CH:63][C:62](/[CH:65]=[CH:66]/[C:67]([C:73]([F:76])([F:75])[F:74])([OH:72])[C:68]([F:71])([F:70])[F:69])=[C:61]([CH3:77])[CH:60]=1)([C:43]1[CH:48]=[CH:47][C:46](B2OC(C)(C)C(C)(C)O2)=[C:45]([CH3:58])[CH:44]=1)[CH2:41][CH3:42])[CH3:39].[CH3:78][O:79][C:80](=[O:89])[CH2:81][C:82]1[CH:87]=[CH:86][CH:85]=[C:84](Br)[CH:83]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:78][O:79][C:80](=[O:89])[CH2:81][C:82]1[CH:83]=[C:84]([C:46]2[CH:47]=[CH:48][C:43]([C:40]([CH2:41][CH3:42])([C:59]3[CH:64]=[CH:63][C:62](/[CH:65]=[CH:66]/[C:67]([OH:72])([C:73]([F:75])([F:76])[F:74])[C:68]([F:71])([F:70])[F:69])=[C:61]([CH3:77])[CH:60]=3)[CH2:38][CH3:39])=[CH:44][C:45]=2[CH3:58])[CH:85]=[CH:86][CH:87]=1
Reactant: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cccc(CC(=O)OC)c2)c(C)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 30.9 %

Procedure:
Palladium acetate (3.6 mg, 0.016 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (13.1 mg, 0.032 mmol), potassium phosphate (51 mg, 0.24 mmol) and water (0.04 mL) were added to a solution of (E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-buten-2-ol (Example 26-(5); 40 mg, 0.070 mmol) and (3-bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44 (2003) 331-334; 28 mg, 0.122 mmol) in toluene (0.4 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. Thereafter, the solution was filtered through amino silica gel, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the target compound as a colorless oil (12.8 mg, 31%).