Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])=[O:18])[N:14]=2)=[CH:6][C:5]=1[OH:28].[CH2:30]1[CH2:40]CN2C(=NCCC2)C[CH2:31]1.[Br-].O>C(O)C.C(OCC)(=O)C>[CH2:40]([O:28][C:5]1[CH:6]=[C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])=[O:18])[N:14]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH:2]([F:1])[F:29])[CH:30]=[CH2:31]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Agent: [Br-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: C=CCOc1cc(-c2nc(CCC(=O)c3ccccc3OCC)co2)ccc1OC(F)F
Reaction time: 2 h

Procedure:
A 0.15 g quantity of the compound obtained in Example 229 and 0.17 ml of DBU were dissolved in 4 ml of ethanol, 0.14 g of ally bromide was then added to the obtained solution, and heating and refluxing were conducted for 2 hours. After cooling, water was added to the obtained reaction mixture, and ethyl acetate extraction was performed. The organic layer was washed twice with water, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1). The obtained crystals were recrystallized from aqueous 80% ethanol, thereby yielding 90 mg of white powdery 3-[2-(3-allyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6](=[O:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9].Cl>CO>[C:1]([CH2:5][C:6](=[O:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: COC(=O)CC(=O)CBr
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COC(=O)CC(=O)CC#N
Temperature: 25 °C
Yield: 85.3 %

Procedure:
10.0 g of potassium cyanide was dissolved in 400 ml of methanol, to which then 24.8 g of methyl 4-bromo-3-oxobutanoate was added dropwise from a dropping funnel over 20 minutes. Methyl 4-bromo-3-oxobutanoate remaining in the dripping funnel was dissolved further in 10 ml of methanol and added dropwise, and the mixture was stirred with cooling on ice for 1 hour and at room temperature for 2 hours. Subsequently, the reaction mixture was cooled on ice, and treated dropwise with 3 ml of a concentrated hydrochloric acid. The reaction mixture was extracted three times with diethylether (2000 ml of diethylether in total). The organic layers were combined, washed twice with 100 ml of saturated brine, dried over magnesium sulfate, concentrated under reduced pressure to obtain 15.3 g of methyl 4-cyano-3-oxobutanoate (purity: 83%).
Reaction SMILES: C(Cl)CCl.[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25](O)=[O:26])[CH2:20][CH2:19]1)(=[O:7])[NH2:6].[F:28][C:29]([F:45])([F:44])[C:30]1[CH:31]=[C:32]([S:40]([NH2:43])(=[O:42])=[O:41])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:33]=[C:32]([S:40]([NH:43][C:25](=[O:26])[CH2:24][CH:21]2[CH2:20][CH2:19][N:18]([C:9]3[CH:10]=[C:11]([C:14]([F:15])([F:17])[F:16])[CH:12]=[CH:13][C:8]=3[C:5]([NH2:6])=[O:7])[CH2:23][CH2:22]2)(=[O:42])=[O:41])[CH:31]=[C:30]([C:29]([F:45])([F:28])[F:44])[CH:35]=1
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1N1CCC(CC(=O)O)CC1
Reactant: NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(C(F)(F)F)cc1N1CCC(CC(=O)NS(=O)(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
0.46 g of 2-fluoro-4-(trifluoromethyl)benzamide are added to a suspension of 1.8 g K2CO3 and 0.8 g of piperidin-4-yl acetic acid hydrochloride In 12 ml of DMSO, the mixture obtained is stirred for 4 h at 150°, solvent is evaporated, the evaporation residue obtained is suspended in MeOH and filtrated. The filtrate obtained is concentrated and subjected to chromatography on silica gel. [1-(2-Carbamoyl-5-trifluoromethyl-phenyl)-piperidin-4-yl]-acetic acid is obtained. 300 mg of EDC are added to a solution of 260 mg of [1-(2-carbamoyl-5-trifluoromethyl-phenyl)-piperidin-4-yl]-acetic acid, 230 mg of 3,5-bis-trifluoromethyl-benzenesulfonamide, 200 mg of DIEA and 90 mg of DMAP in 4 ml of DMF. The mixture obtained is stirred for 3 days at RT, solvent is evaporated in vacuo and the evaporation residue obtained is treated with EtAc. The mixture obtained is washed with 1 N HCl, saturated aqueous NaHCO3 solution and brine, dried, concentrated in vacuo and subjected to chromatography on silica gel. 2-{4-[2-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-2-oxo-ethyl]-piperidin-1-yl}-4-trifluoromethyl-benzamide is obtained.
Reaction SMILES: [H-].[Na+].[Br-].[CH:4]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>CS(C)=O.O>[C:4]1(=[CH:32][C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[O:29][CH3:28])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COc1ccccc1C=O
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CCCC2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1C=C1CCCC1
Temperature: 60 °C
Yield: 67 %

Procedure:
A suspension of sodium hydride (608 mmol, 24.3 g; 60% dispersion in oil) in dry DMSO (3L) was heated to 60° C. for one hour and cooled to an internal temperature of 42° C. Cyclopentyltriphenylphosphonium bromide (608 mmol, 250 g) was added in one portion and to the resulting red solution was added 2-methoxybenzaldehyde (669 mmol, 91.0 g; 80.7 mL) dropwise over a few minutes. The dark reaction mixture was heated to 60° C. for 18 hours and cooled to room temperature. The reaction was diluted with water (4L), extracted with CH2Cl2 (2×3L) and concentrated in vacuo. The residue was partitioned between 15:1 hexane/EtOAc (1.3L) and water (1.6L), the organics washed with water (3×600 mL), dried (Na2SO4) and concentrated in vacuo. Upon concentration, triphenylphosphine oxide crystallized out of solution. The suspension was diluted with hexane, the solids removed by filtration, and the filtrate concentrated in vacuo to afford a dark oil. This material was vacuum distilled to afford the title compound as a light yellow oil (76.7 g, 67%). The desired material comes over at 90°-97° C. at 0.05 mm Hg and is used as such in the subsequent transformation.
Reaction SMILES: [C:1]([CH2:3][C:4](=O)[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])#[N:2].[C:11]([O-])(=O)C.[NH4+:15].C(O)(=O)C>C1(C)C=CC=CC=1>[NH2:15][C:4]([CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])=[C:3]([C:1]#[N:2])[CH3:11]
Reactant: [NH4+]
Reactant: CC(=O)[O-]
Reactant: CCC(CC)C(=O)CC#N
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCC(CC)C(N)=C(C)C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
13.1 g (94 mmol) of 1-Cyano-3-ethyl-2-oxo-pentane were dissolved in toluene and 15 g (194 mmol) ammonium acetate and 1 ml dry acetic acid were added. The mixture was reflured 2 h and then cooled to room temperature. The mixture was washed, dried and concentrated. Perification by customary methods gove 13. 1 g (100% of theory) of the title compound as a oil.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:21])[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[Br:21][C:14]1[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: CC(C)Oc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)Oc1cc2c(cc1Br)C(C)CNCC2
Reaction time: 8 h
Yield: 76.6 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.014 g, 0.035 mmol) in methanol (1 mL) was treated with 15% aqueous NaOH (1 mL), and stirred overnight at 20 C. The product mixture was diluted with water (3 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (3 mL), dried with Na2SO4 and concentrated to give 0.008 g of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.24 (s, 1H), 6.64 (s, 1H), 4.48 (m, 1H), 2.98 (m, 3H), 2.87 (m, 3H), 1.36 (m, 6H), 1.30 (d, J=7 Hz, 3H), MS calculated for C14H20BrNO+H: 298, observed: 298.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]1[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1)[N:20]=[CH:19]2.[ClH:40].C(Cl)[Cl:42]>CO.CCOCC>[ClH:42].[ClH:40].[CH2:8]([C:6]1[CH:5]=[CH:4][N:3]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:20]=[CH:19]3)[C:2](=[O:1])[CH:7]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2ncc3cc(-n4ccc(CCc5ccccc5)cc4=O)ccc32)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=c1cc(CCc2ccccc2)ccn1-c1ccc2c(cnn2CCN2CCNCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution of tert-butyl 4-(2-(5-(2-oxo-4-phenethylpyridin-1(2H)-yl)-1H-indazol-1-yl)ethyl)piperazine-1-carboxylate (247 mg, 0.468 mmol) in MeOH (2 mL) was treated with 2N HCl in ether (7 mL) under a nitrogen atmosphere. The solution was stirred at room temperature for 2 h and then treated with CH2Cl2 (20 mL) to precipitate product. The liquid was decanted off, and the solids were triturated with ether (3×100 mL) and concentrated to yield the title compound (161.7 mg, 69%) as yellow solid: mp 280-290° C.; 1H NMR (500 MHz, CD3OD) δ 8.23 (s, 1H), 7.83 (s, 2H), 7.62 (d, J=6.95 Hz, 1H), 7.46 (d, J=1.4 Hz, 1H), 7.30-7.17 (m, 5H), 6.51 (dd, J=7.0, 1.1 Hz, 1H), 6.48 (s, 1H), 4.95 (t, J=5.85, 2H), 3.57 (m, 2H), 3.61-3.56 (m, 8H), 3.01-2.98 (m, 2H), 2.94-2.91 (m, 2H); ESI MS m/z 428 [M+H]+. HPLC (Method D) 95.4% (AUC), tR=12.9 min.
Reaction SMILES: CS(C)=O.FC(F)(F)S(O[C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1OS(C(F)(F)F)(=O)=O)=[O:14])(=O)=O.[C:35]1([PH:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)[CH:53]([CH3:55])[CH3:54])(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.C(Cl)Cl>[C:35]1([P:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:11]2[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=2[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[P:41]([C:54]2[CH:53]=[CH:55][CH:47]=[CH:42][CH:43]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:48])=[O:14])=[O:48])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(c1ccccc1OS(=O)(=O)C(F)(F)F)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[PH](c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(c1ccccc1P(=O)(c1ccccc1)c1ccccc1)c1ccccc1P(=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 108.1 %

Procedure:
Into 5 ml of dimethylsulfoxide were dissolved 191.3 mg (0.4 mmol) of 2,2′-bis(trifluoromethanesulfonyloxy)benzophenone, 9.0 mg (0.04 mmol) of palladium acetate, 17.0 mg (0.04 mmol) of 1,4-bis(diphenylphosphino)butane, and 310 mg (1.2 mmol) of diphenylphosphine oxide, and further thereto was added 191.3 mg (0.4 mmol) of N,N-diisopropylethylamine. The resultant solution was stirred at 100° C. for 18 hours. The reaction mixture was cooled to room temperature, and 10 ml of methylene chloride was added thereto. This solution was washed with 1 N hydrochloric acid, water and brine in sequence, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the resultant was purified by column chromatography on silica gel (ethyl acetate-methylene chloride:methanol=10:1 to give 252 mg (yield: 90%) of the title compound in the form of a brownish-red solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:49])(=O)=O.[CH:52]1(B(O)O)[CH2:54][CH2:53]1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[CH:52]1([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[C:18]4[C:23]([CH:24]=3)=[CH:22][C:21]([CH2:25][N:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:40])([CH3:39])[CH3:41])([CH3:36])[CH3:37])[CH2:30][CH2:31]3)=[CH:20][CH:19]=4)=[C:12]3[C:8]=2[CH2:9][NH:10][C:11]3=[O:49])[CH2:54][CH2:53]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(C3CC3)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc21
Yield: 67.9 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-{1-(tert-butoxycarbonyl)-5-[4-(2-tert-butyldimethylsilyloxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (81.7 mg, 0.109 mmol) was dissolved in dimethoxyethane (4.1 mL), and the solution was treated with cyclopropylboronic acid (28.0 mg, 0.327 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (7.1 mg, 0.0087 mmol), potassium carbonate (75.0 mg, 0.545 mmol) and water (0.058 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=12/1) to obtain 4-cyclopropyl-7-{1-(tert-butoxycarbonyl)-5-[4-(2-tert-butyldimethylsilyloxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (47.7 mg, yield 68%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].S([O-])([O-])(=O)=[O:7].[Na+].[Na+].[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][C:26]#[N:27])[CH:20]=[CH:19]2)([O-:15])=[O:14]>C(Cl)Cl>[C:26]([CH2:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=2)[C:19]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:20]1)(=[O:7])[NH2:27]
Reactant: N#CCn1ccc2cc([N+](=O)[O-])ccc21
Reactant: O=S(=O)([O-])[O-]
Reactant: O=S(=O)(O)Cl
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)Cn1cc(S(=O)(=O)Cl)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 51 %

Procedure:
Chlorosulfonic acid (3.05 ml, 45.9 mmole) from the above Step was added to a suspension of anhydrous sodium sulfate (0.71 g) in methylene chloride (30 ml). After stirring for 25 minutes at room temperature, (5-nitro-indol-1-yl)-acetonitrile (1.00 g) dissolved in methylene chloride was added via syringe. After stirring for 2 h, the reaction mixture was worked up by the cautious addition of ice. When the ice had melted, the mixture was filtered to afford an off-white powder which was washed well with water to afford 0.806 g of 1-carbamoylmethyl-5-nitro-1H-indole-3-sulfonyl chloride (51% yield).
Reaction SMILES: [OH-:1].[Na+].C[O:4][C:5](=[O:43])[C@@H:6](NC(OC(C)(C)C)=O)[CH2:7][S:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:27]4[O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:26]=4[CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.Cl.[CH3:45][OH:46]>O1CCCC1.O>[C:10]([O:1][C:45]([C@H:6]([CH2:7][S:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:27]4[O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:26]=4[CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[C:5]([OH:4])=[O:43])=[O:46])([CH3:15])([CH3:11])[CH3:9]
Reactant: COC(=O)[C@H](CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)NC(=O)OC(C)(C)C
Reactant: CO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Temperature: 25 °C

Procedure:
2N Sodium hydroxide solution (1.32 mL, 2.64 mmol) was added dropwise to a stirred solution of (2R)-methyl-2-tert-butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)propionate (500 mg, 0.88 mmol) in tetrahydrofuran (15 mL) and methanol (3 mL). The clear reaction mixture was stirred at room temperature until the reaction was complete (TLC control), and then diluted with water (10 mL), and acidified to pH 3 with 2N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (2×20 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 5-10% methanol in methylene chloride as eluent, afforded the title compound has a white solid (420 mg, 87%), m.pt. 205-206° C.; Rf: 0.40 (10% methanol in dichloromethane); 1H NMR (MeOH-d4): δ 7.90 (4H, m, Ar—H), 7.67 (2H, d, J=9 Hz, Ar—H), 7.56 (2H, d, J=9 Hz, Ar—H), 7.53 (2H, d, J=8 Hz, Ar—H), 7.29-7.41 (5H, m, Ar—H), 4.34 (1H, m, CHN), 3.87 (2H, s, PhCH2S), 2.95 (1H, dd, J=15, 5 Hz, CHHCHN), 2.86 (1H, dd, J=15, 7 Hz, CHHCHN), 1.42 (9H, s, CMe3); ESI-LCMS e/z calcd for C33H31NO5S 553.676, found 554 (M+H)+, 576 (M+Na)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[C:17]3[O:16][CH2:15][C:14](=[O:18])[NH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.Br[CH2:20][CH2:21][O:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:33])=[N:28]2>>[CH3:33][C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][CH:31]=[CH:32][C:23]=2[O:22][CH2:21][CH2:20][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][C:8]3[C:17]4[O:16][CH2:15][C:14](=[O:18])[NH:13][C:12]=4[CH:11]=[CH:10][CH:9]=3)[CH2:3][CH2:2]2)[N:28]=1
Reactant: Cc1ccc2c(OCCBr)cccc2n1
Reactant: O=C1COc2c(CC3CCNCC3)cccc2N1
Product: Cc1ccc2c(OCCN3CCC(Cc4cccc5c4OCC(=O)N5)CC3)cccc2n1

Procedure:
The title compound was prepared from 8-(piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one and 5-(2-bromoethoxy)-2-methylquinoline in a similar manner to Example 1.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[OH:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:14]1([C:12]([NH:11][C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([O:17][C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=4)[C:21]([O:23][CH3:24])=[O:22])=[N:7][N:6]3[CH:8]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Temperature: 110 °C
Reaction time: 48 h
Yield: 40.4 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (518 mg, 1.58 mmol), methyl 3-hydroxybenzoate (360 mg, 2.37 mmol), potassium carbonate (654 mg, 4.73 mmol) and N,N-dimethylformamide (4.0 mL) was stirred at 110° C. for 2 days. The solvent was evaporated under reduced pressure, ethyl acetate, tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted three times with ethyl acetate/tetrahydrofuran. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→85/15) to give methyl 3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoate (225 mg, 41%) as a white powder.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O>>[CH:17]1[C:13]2[C:14](=[O:16])[NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:11][C:12]=2[CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccccc1C(=O)O
Product: O=C1Nc2ccccc2Nc2ccccc21
Yield: 30.9 %

Procedure:
2-Fluoronitrobenzene (847 g, 6 mmol) and 2-aminobenzoic acid (274 mg, 2.0 mmol) were reacted according to GP7 to give 130 mg of the title compound (160FE15A).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([CH3:23])(Br)[C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1.Cl>C(Cl)Cl>[C:1]([C:9]1[CH:10]=[C:11]([CH2:15][CH:16]=[C:17]([CH3:23])[C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(Br)CCc1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccc2ncccc2c1
Product: COC(=O)C(C)=CCc1cccc(C(=O)c2ccccc2)c1
Temperature: 160 °C
Yield: 53.7 %

Procedure:
A mixture of 1.46 g of methyl 4-(m-benzoyl-phenyl)-2-methyl-2-bromo-butanoate and 7.3 ml of quinoline was heated at 160°C for 3 hours and after cooling to room temperature, 73 ml of 2N hydrochloric acid were added thereto. The mixture was extrated with methylene chloride and the organic phase was washed with 2N hydrochloric acid, with aqueous saturated sodium bicarbonate solution and then with water. The solution was dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure. The residue was chromatographed over magnesium silicate and eluted with methylene chloride to obtain 615 mg of methyl 4-(m-benzoylphenyl)-2-methyl-2-butenoate in the form of an oil.
Reaction SMILES: [C:1]([CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30]C)=[C:26]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:33]=4)[CH:25]=3)[CH:15]=[CH:16][C:17]=2[O:18]C)[CH:9]=[CH:10][CH:11]=1)([O:3][CH3:4])=[O:2].B(Br)(Br)Br>ClCCl>[C:39]([CH2:38][C:34]1[CH:33]=[C:32]([C:26]2[CH:25]=[C:24]([CH2:23][CH2:22][CH2:21][CH2:20][C:14]3[CH:15]=[CH:16][C:17]([OH:18])=[C:12]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([CH2:5][C:1]([O:3][CH3:4])=[O:2])[CH:7]=4)[CH:13]=3)[CH:29]=[CH:28][C:27]=2[OH:30])[CH:37]=[CH:36][CH:35]=1)([O:41][CH3:42])=[O:40]
Reactant: COC(=O)Cc1cccc(-c2cc(CCCCc3ccc(OC)c(-c4cccc(CC(=O)OC)c4)c3)ccc2OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)Cc1cccc(-c2cc(CCCCc3ccc(O)c(-c4cccc(CC(=O)OC)c4)c3)ccc2O)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
1,4-Bis-[3-(3-carbomethoxymethylphenyl)-(4-methoxy)phenyl]butane (0.9 g, 1.6 mmol) was dissolved in dichloromethane (3.0 mL), cooled in a dry ice bath, and treated with boron tribromide (1.2 mL, 12.8 mmol). The mixture was stirred at -78° C. for three hours then placed in a freezer at -10° C overnight. The reaction was quenched with ice water (10 mL) and extracted with dichloromethane (3×5 mL). The organic materials were combined, washed with water (25 mL), saturated sodium chloride (25 mL), dried (MgSO4) then concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 5:1 hexane/ethyl acetate) to give 1,4-bis-[3-(3-carbomethoxymethylphenyl)-4-hydroxyphenyl]butane (0.4 g, 47%). 1H NMR (400 MHz, CDCl3): 7.42 (d, J=7.4 Hz, 2H), 7.35-7.38 (m, 4H), 7.27-7.32 (m, 2H), 7.02-7.05 (m, 4H), 6.87 (d, J=8.0 Hz, 2H), 5.12 (s, 2H), 3.70 (s, 6H), 3.68 (s, 4H), 2.59 (m, 4H), 1.65 (m, 4H) ppm. IR (NaCl): 3439, 1732, 1606, 1263 cm-1.