Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[N:5]=[C:4](S(C(C)C)(=O)=O)[N:3]=1.[CH2:19]([OH:22])[C:20]#[CH:21].[H-].[Na+].[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>O1CCCC1.O>[N:25]1([C:2]2[C:7]([I:8])=[C:6]([C:9]([F:10])([F:11])[F:12])[N:5]=[C:4]([O:22][CH2:19][C:20]#[CH:21])[N:3]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: CC(C)S(=O)(=O)c1nc(Cl)c(I)c(C(F)(F)F)n1
Reactant: c1c[nH]cn1
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCOc1nc(-n2ccnc2)c(I)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.6 %

Procedure:
4-Chloro-5-iodo-2-isopropylsulfonyl-6-trifluoromethypyrimidine (0.79 g) was dissolved in tetrahydrofuran (5.0 ml) and added propargyl alcohol (0.11 g). The mixture was cooled to ice bath temperature and added sodium hydride (oily 80%, 57 mg). The mixture was stirred at that temperature for 10 minutes, and then added imidazole (0.39 g) at the same temperature. The mixture was stirred at that temperature for 30 minutes, and then it warmed to room temperature. After stirring over night, the mixture was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-THF). The fraction was triturated by hexane to give 4-imidazol-1-yl-5-iodo-2-prop-2-ynyloxy-6-trifluoromethyl-pyrimidine (0.20 g) as colorless crystalline solid, mp 128-129° C.
Reaction SMILES: C([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[N:13]([CH3:23])[C:12]2=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:27].[H][H]>CO.[Pd]>[ClH:27].[CH3:23][N:13]1[C:12](=[O:24])[C:11]2([CH2:10][CH2:9][NH:8][CH2:26][CH2:25]2)[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]1=[O:22]
Reactant: CN1C(=O)N(c2ccccc2)C2(CCN(Cc3ccccc3)CC2)C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN1C(=O)N(c2ccccc2)C2(CCNCC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of 8-benzyl-3-methyl-1-phenyl-1,3,8-triazaspiro[4,5]decane-2,4-dione (470 mg, 1.3 mmol), from Step D, in methanol (100 mL) were added concentrated aqueous hydrochloric acid (0.12 mL, 1.4 mmol) and wet 20% palladium on carbon (0.47 g). The reaction vessel was pressurized with hydrogen (4 atmospheres) and shaken on a Parr apparatus at ambient temperature for 2 hours. The reaction mixture was then filtered sequentially through a paper filter and through a PTFE (polytetrafluoroethylene) filter membrane (0.45μ), rinsing with methanol. The filtrate was concentrated under reduced pressure and then the residue was dried to give 0.34 g (89% yield) of the title compound as a white solid, m.p.>330° C. (dec); MS (DCl/NH3) M/Z: 260 (M+H)+, 277 (M+NH4)+ ; 300 MHz 1H NMR (CDCl3) δ2.02 (td, J=5, 14 Hz, 2H), 2.31 (d, J=15 Hz, 2H), 3.08 (s, 3H), 3.34-3.43 (m, 2H), 3.72 (td, J=3, 12 Hz, 2H), 7.29-7.35 (m, 2H), 7.49-7.58 (m, 3H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[C:10]([C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.C(O)C>O>[CH3:3][O:4][C:5]1[C:10]([CH:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[OH:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: COc1ncccc1C(=O)c1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ncccc1C(O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
303 mg of sodium borohydride was added little by little to a solution containing 1.46 g of 2-methoxy-3-(2-thienylcarbonyl)pyridine and 10 ml of ethanol under ice-cooling. After stirring at room temperature for 2 hours, water was slowly added thereto and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and the solvent was removed, to give 1.47 g of the target compound.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([NH2:11])[N:5]=1.FC(F)(F)S(O[CH2:18][CH3:19])(=O)=O.CO>CN(C=O)C>[CH2:18]([O:10][C:8]1[N:9]=[C:4]([NH2:3])[N:5]=[C:6]([NH2:11])[CH:7]=1)[CH3:19]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: Nc1cc(O)nc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCOc1cc(N)nc(N)n1
Reaction time: 0.5 h

Procedure:
174 mg of sodium hydride (60% in mineral oil, 4.36 mmol) are added in portions under an argon atmosphere to a vigorously stirred solution of 500 mg (3.96 mmol) of 2,6-diaminopyrimidin-4-ol in 10 ml of DMF. After 30 min, 700 μl (5.15 mmol) of ethyl trifluoromethanesulfonate are added dropwise, and the solution is stirred for a further 20 min. Methanol (1 ml) is then added to the reaction mixture, which is directly purified by preparative HPLC. Combining the product fractions and removing the solvent result in 370 mg (64% of theory) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[NH:7][CH:6]=1)=[O:4].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1)=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(=O)[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(=O)n(-c2ccccc2)c1
Yield: 55.6 %

Procedure:
Methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (6.0 g, 39.22 mmol), phenylboronic acid (5.74 g, 47.06 mmol), copper(II) acetate monohydrate (11.76 g, 58.82 mmol), pyridine (6.32 mL, 78.43 mmol) and molecular sieves (4 Å, 6.0 g) in dichloromethane (100 mL) was stirred at ambient temperature for 12 hours and filtered. Standard extractive work up provided a crude residue which was purified by silica gel column chromatography (100-200 mesh) (1-2% methanol in chloroform) to give the title compound as a brown solid (5.0 g, 56%). m.p. 100-105° C.; 1H NMR (400 MHz, CDCl3) δ 3.86 (s, 3H), 6.63 (d, J=9.5 Hz, 1H), 7.36-7.55 (m, 5H), 7.91 (dd, J=2.5, 9.9 Hz, 1H), 8.23 (d, J=2.5 Hz, 1H); IR (KBr) u 3058, 2924, 2854, 1721, 1675, 1540, 1446, 1313, 1271, 1103 cm−1; MS 230 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][OH:24])=[C:14]([NH:25][C:26]([C:28]2[NH:29][C:30]3[C:35]([CH:36]=2)=[CH:34][C:33]([O:37][CH3:38])=[CH:32][CH:31]=3)=[O:27])[CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C1COCC1.C(Cl)Cl>[CH3:46][S:47]([O:24][CH2:23][CH2:22][C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[CH:13][C:14]=1[NH:25][C:26]([C:28]1[NH:29][C:30]2[C:35]([CH:36]=1)=[CH:34][C:33]([O:37][CH3:38])=[CH:32][CH:31]=2)=[O:27])(=[O:49])=[O:48]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2[nH]c(C(=O)Nc3cc(NC(=O)OCc4ccccc4)c4ccccc4c3CCO)cc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc2[nH]c(C(=O)Nc3cc(NC(=O)OCc4ccccc4)c4ccccc4c3CCOS(C)(=O)=O)cc2c1
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of 2-[4-(N-benzyloxycarbonylamino)-2-(5-methoxyindole-2-carboxamido)naphthalen-1-yl]ethanol (0.4 g, 0.78 mmol) and triethylamine (0.44 mL, 3.14 mmol) in THF (20 mL) was added methanesulfonyl chloride (0.24 mL, 3.14 mmol) with ice bath and stirred for 1 h. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with H2O (10 mL) and saturated aqueous NaCl (20 mL), and then the organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica-gel column (30% AcOEt-Petroleum ether) to yield as a yellow foam 2-[4-(N-benzyloxycarbonylamino)-2-(5-methoxyindole-2-carboxamido)naphthalen-1-yl]ethyl methanesulfonate (0.28 g, 61%): mp 160° C. (decomp.); 1H NMR (CDCl3, 500 MHz) δ 9.09 (brs, 1H), 8.36 (brs, 1H), 7.89 (d, 9.0, 1H), 7.87 (d, 9.0, 1H), 7.57 (t, 8.5, 1H), 7.48 (d, 7.5, 2H), 7.40 (t, 7.5, 2H), 7.34 (m, 2H), 7.17 (s, 1H), 7.13 (s, 1H), 7.00 (d, 8.5, 1H), 7.00 (d, 9.0, 1H), 4.70 (brs, 2H), 4.61 (t, 6.0, 2H), 4.50 (s, 2H), 3.88 (s, 3H), 3.54 (t, 6.0, 2H), 2.84 (s, 3H); ); FABMS (NBA) m/z 543 (M−CO2+), IR (neat) νmax 3400, 1643, 1591, 1530, 1479, 1453, 1351, 1231, 1213, 1173, 1142, 1076, 1031, 974, 947, 841, 805, 761, 734, 699 cm−1.
Reaction SMILES: Cl.N1([CH2:7][C:8](O)=O)C=NC=N1.[N:11]1([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25](OCC3C=CC=CC=3)=O)[CH2:21][C@H:20]2[C:35](=[O:51])[NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)=[CH:39][CH:38]=2)=[O:18])[CH:15]=[N:14][CH:13]=[N:12]1>>[N:11]1([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:8]3[CH:7]=[CH:39][CH:38]=[CH:37][CH:42]=3)[CH2:21][C@H:20]2[C:35]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)=[CH:39][CH:38]=2)=[O:51])=[O:18])[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)Cn1cncn1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CN(Cc2ccccc2)CCN1C(=O)Cn1cncn1
Yield: 19 %

Procedure:
Proceeding as in Examples 11 and 12, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (S)-benzyl 4-(2-(1H-1,2,4-triazol-1-yl)acetyl)-3-(4-(4-fluorophenoxy)phenylcarbamoyl)piperazine-1-carboxylate, respectively, gave Compound 261, (S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)piperazine-2-carboxamide (67.9 mg, 19%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.83 (s, 1H), 8.45 (s, 1H), 7.96 (s, 1H), 7.51 (d, 2H), 7.28-7.13 (m, 7H), 7.06-6.98 (m, 4H), 5.49 (d, 1H), 5.28 (d, 1H), 4.91-4.89 (m, 1H), 3.68-3.38 (m, 5H), 2.92-2.85 (m, 1H), 2.25-2.17 (m, 2H). MS (EI) for C28H27FN6O3. found 515.3 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=2)[CH2:9][CH2:8]1)[CH3:6])C.[OH-].[Na+]>O1CCCC1.CO>[CH3:22][C:5]([CH:7]1[CH2:8][CH2:9][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=2)[CH2:11][CH2:12]1)([CH3:6])[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)C(C)(C)C1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)C1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 140 °C
Yield: 71.6 %

Procedure:
To a solution of 2-methyl-2-(5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-propionic acid ethyl ester (321 mg, 1.0 mmol) in tetrahydrofuran (2 mL) and methanol (6 mL) was added sodium hydroxide solution (1N, 2 mL). The mixture was heated in a microwave at 140° C. for 1.5 hr. The mixture was evaporated and the residue was dissolved in hot methanol and water. The clear solution was then acidified with 1N hydrochloric acid (2.5 mL). The resulting pale yellow precipitate was filtered and dried to give 2-methyl-2-(5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-propionic acid (210 mg). LC-MS calcd. for C14H19N3O4 (m/e) 293.1, obsd 294.1
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14](OC)=O.[NH3:21]>>[NH2:21][C:4]1[CH:3]=[CH:14][C:13]2[C:12](=[C:11]([O:10][CH:7]([CH3:6])[CH2:8][CH2:9][CH2:2][O:1][C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=3[C:4]#[N:5])[CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: N#Cc1ccccc1O
Reactant: N
Product: CC(CCCOc1ccccc1C#N)Oc1cccc2ccc(N)nc12

Procedure:
The title compound was prepared according to the procedure described in Example 92 substituting 2-hydroxybenzonitrile for methyl 3-hydroxybenzoate. 1H NMR (500 MHz, CDCl3) δ ppm 7.94 (d, 1H), 7.46 (m, 2H), 7.33 (t, 1H), 7.20 (m, 2H), 6.96 (m, 2H), 6.91 (m, 1H), 4.78 (m, 1H), 4.22 (m, 1H), 4.12 (m, 1H), 2.23 (m, 1H), 1.96–2.18 (m, 3H), 1.47 (d, 3H); MS (DCI/NH3) m/z 348 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.N1C=CC=CC=1.ClC(Cl)(Cl)[C:19](Cl)=[O:20].[O:24]1CCOC[CH2:25]1>>[CH3:25][O:24][C:19]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1)=[O:20]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)c1c[nH]c2ccc(F)cc12
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
To a solution of 5-fluoroindole (2.5 g, 18.5 mmol) in dioxane (75 mL) was added pyridine (14.9 mL, 185 mmol) and trichloroacetyl chloride (10.3 mL, 92.5 mmol). The resulting mixture was stirred at 80° C. for 2.5 hours, poured into ice water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried and evaporated. The residue was dissolved in dry methanol (100 mL), sodium hydroxide (0.25 g) was added and the mixture heated at 80° C. for 30 min. Most of the solvent was evaporated and the residue was partitioned between water and ethyl acetate. The organic phase was washed with brine. dried and concentrated. Purification by silica gel chromatography (heptane-ethyl acetate, 3:1/1:1) gave 3.32 g (93%) of the sub-title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9](=[O:11])[NH2:10])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]([O:18][CH3:19])=[O:17])=[S:14].[C:20](Cl)(=[O:22])[CH3:21]>>[C:20]([NH:1][C:2]1[CH:7]=[C:6]([S:8][C:9](=[O:11])[NH2:10])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]([O:18][CH3:19])=[O:17])=[S:14])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: COC(=O)NC(=S)Nc1ccc(SC(N)=O)cc1N
Product: COC(=O)NC(=S)Nc1ccc(SC(N)=O)cc1NC(C)=O
Reaction time: 2 h

Procedure:
0.7 G. of 2-amino-4-carbamoylthio-1-(3-methoxycarbonyl-2-thioureido)benzene is treated with 1.5 ml. of acetyl chloride. The mixture is stripped after two hours and the residue recrystallized to afford 2-acetamido-4-carbamoylthio-1-(3-methoxycarbonyl-2-thioureido)benzene.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.N1C=CC=CC=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH2:26][C:27](=O)[CH2:28][CH2:29][CH2:30][OH:31])=[CH:21][CH:20]=1>CO>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=[C:27]([CH2:28][CH2:29][CH2:30][OH:31])[CH:26]=2)=[CH:23][CH:24]=1
Reactant: O=C(CCCO)CC(=O)c1ccc(Cl)cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(-n2nc(CCCO)cc2-c2ccc(Cl)cc2)cc1
Reaction time: 1.5 h
Yield: 72 %

Procedure:
4-Methoxyphenylhydrazine hydrochloride [35.0 grams (g), 0.20 moles] was added to CH3OH [50 milliliters (ml)] containing pyridine (20 ml). An additional amount of CH3OH (25 ml) was added to the thick resulting slurry. 1-(4-Chlorophenyl)-6-hydroxyhexan-1,3-dione (48.2 g, 0.20 moles), was added neat, followed by more CH3OH (25 ml). The slurry was stirred at room-temperature for 1.5 hours, after which time the mixture was concentrated and taken up in CHCl3 (300 ml). The CHCl3 solution was washed with 1N HCl (300 ml), dried (Na2SO4), filtered, and concentrated. The oil was decolorized (Norit) in hot diethyl ether (Et2O) (300 ml). The Et2O solution was cooled, and crystallization from Et2O (300 ml) afforded 2 (49.4 g). From the filtrate was obtained additional 2 (9.28 g), total yield 91%, mp 87.5°-88°. NMR (CDCl3) 1.7-2.3 (m, 2H, CH2CH2CH2), 2.55 (brs, 1H, OH), 2.80 (t, 2H, J=7 Hz, CH2), 3.75 (t, 2H, J=6 Hz, CH2O), 3.77 (s, 3H, OCH3), 6.28 (s, 1H, C4 -H), 6.93 (ABq, 4 H, J=12, 9, 4-OMe-C6H4), 6.9-7.3 (m, 4H, 4-Cl--C6H4); IR (KBr) 3320, 2920, 1495; MS, m/e 342 (M+), 312, 298 (100%);
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([F:10])([F:9])[F:8])=[C:4]([C:11]([OH:13])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][CH:42]=1)[O:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([CH:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=2)[N:30]=1.C(N(CC)CC)C>CN(C)C=O.O1CCCC1>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:22]=[C:21]([NH:20][C:11]([C:4]5[CH:3]=[C:2]([CH3:1])[O:6][C:5]=5[C:7]([F:8])([F:9])[F:10])=[O:13])[CH:42]=[CH:41][CH:40]=4)=[N:30][N:29]3[CH:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Cc1cc(C(=O)O)c(C(F)(F)F)o1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c(C(F)(F)F)o1
Yield: 58.1 %

Procedure:
Using 5-methyl-2-(trifluoromethyl)-3-furancarboxylic acid (133.6 mg, 0.668 mmol), N,N-dimethylformamide (1 drop), oxalyl chloride (75 μL, 0.868 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (159 mg, 0.514 mmol), triethylamine (156 mg, 1.54 mmol) and tetrahydrofuran (15 mL) as starting materials and in the same manner as in Example 109, the title compound (145 mg, 58%) was obtained as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][C:6]2[C:7]([OH:21])=[CH:8][C:9]3[C:10]([CH3:20])([CH3:19])[C:11]4[CH:12]=[C:13](Br)[CH:14]=[CH:15][C:16]=4[C:17]=3[C:5]=2[CH:4]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].COC>O>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][C:6]2[C:7]([OH:21])=[CH:8][C:9]3[C:10]([CH3:20])([CH3:19])[C:11]4[CH:12]=[C:13]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[O:27][CH3:26])[CH:14]=[CH:15][C:16]=4[C:17]=3[C:5]=2[CH:4]=1
Reactant: COc1cc2c(O)cc3c(c2cc1OC)-c1ccc(Br)cc1C3(C)C
Reactant: COc1ccccc1B(O)O
Agent: COC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc2c(O)cc3c(c2cc1OC)-c1ccc(-c2ccccc2OC)cc1C3(C)C
Temperature: 25 °C
Yield: 93.6 %

Procedure:
To a 500 mL single-neck flask was added 2,3-dimethoxy-7,7-dimethyl-9-bromo-7H-benzo[C]fluoren-5-ol (10 g) prepared according to the first five steps of example 1 in US 2006/0226402 which is included herein as reference, 2-methoxyphenylboronic acid (4.3 g), sodium carbonate (5.9 g), dimethyl ether (120 mL) and water (24 mL). The mixture was purged with N2 for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.6 g) was added to the mixture. The reaction mixture was heated to reflux for 18 hours. The mixture was cooled to room temperature and poured into water (180 mL). The resulting mixture was extracted with ethyl acetate (100 mL). The top layer was dried over sodium sulfate and then condensed to lesser volume. Solid 2,3-dimethoxy-7,7-dimethyl-9-(2-methoxyphenyl)-7H-benzo[C]fluoren-5-ol (10 g) was obtained by recrystallization from solution in t-butyl methyl ether/hexanes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH2:16]Cl)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH2:16][N:21]2[CH2:26][CH2:25][N:24]([CH2:16][C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:14]=3)[CH2:23][CH2:22]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: C1CNCCN1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cccc(CN3CCN(Cc4cccc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)c2)cc(OC)c1OC

Procedure:
3-(3,4,5-Trimethoxyphenyl)benzyl chloride (120 mg) and piperazine (17 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.O>CN(C1C=CC=CN=1)C.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][N:8]([S:18]([C:15]3[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=3)(=[O:20])=[O:19])[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.7 %

Procedure:
To a mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.67 g, 8.88 mmol), p-toluenesulfonyl chloride (1.72 g, 9.02 mmol) and triethylamine (2.50 mL, 18.0 mmol) in CH2C2 (15 mL), dimethylaminopyridine (30 mg, 0.24 mmol) was added. It was stirred at room temperature for 20 h. Water and CH2Cl2 were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine as a solid (3.03 g).
Reaction SMILES: [K].[CH:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.C(S)CC.[Br:14][C:15](Br)([F:17])[F:16]>CN(C)C=O>[Br:14][C:15]([F:17])([F:16])[O:8][C:7]1[CH:6]=[CH:5][C:4]([CH3:9])=[CH:3][CH:2]=1
Reactant: FC(F)(Br)Br
Reactant: Cc1ccc(O)cc1
Agent: CCCS
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1ccc(OC(F)(F)Br)cc1
Yield: 21 %

Procedure:
According to the process, 0.1 mole of potassium salt of p-cresol is dissolved in dimethylformamide, a catalytic amount of propanethiol is added, dibromodifluoromethane is further added, and reacted at 20° to 30° C. for 4 hours to obtain p-(bromodifluoromethoxy) toluene in a 21% yield.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=[C:9]2[CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[O:17][CH2:18][CH3:19].C([Sn](CCCC)(CCCC)[C:25]([O:27]CC)=[CH2:26])CCC>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:15][C:6]1([CH3:16])[C:5]2[C:10](=[CH:11][C:2]([C:25](=[O:27])[CH3:26])=[C:3]([O:17][CH2:18][CH3:19])[CH:4]=2)[C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH2:7]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCOc1cc2c(cc1Br)C(C(C)C)=CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc2c(cc1C(C)=O)C(C(C)C)=CCC2(C)C
Temperature: 25 °C

Procedure:
To a solution 7-bromo-4,4-dimethyl-6-ethoxy-1-isopropyl-3,4-dihydronaphthalene (Compound A-32, 284 mg, 0.879 mmol) in THF (5 mL) was tributyl(1-ethoxyvinyl) tin (0.445 mL, 1.32 mmol), and the resulting solution was purged with dry argon for 15 min. Dichlorobis(triphenylphosphine)palladium(II) (0.031 g, 0.044 mmol) was added and the solution was refluxed until the reaction was complete by TLC analysis. The reaction was cooled to room temperature. The mixture was diluted with water, extracted with ethyl ether, washed with brine, dried over MgSO4, and filtered. The solvent was removed under reduce pressure, and the residue was purified by flash column chromatography (silica gel, 95:5 hexane/ethyl acetate) to produce the title compound as a colorless solid.
Reaction SMILES: [C:1]([S:7][CH2:8]/[C:9](=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:10]([OH:12])=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>>[O:12]=[C:10]([NH:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])/[C:9](/[CH2:8][S:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])=[CH:13]\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)C(=O)SC/C(=C/c1ccccc1)C(=O)O
Reactant: NCCC(=O)OCc1ccccc1
Product: CC(C)(C)C(=O)SC/C(=C/c1ccccc1)C(=O)NCCC(=O)OCc1ccccc1
Yield: 63 %

Procedure:
The (E)-2-pivaloylthiomethyl-3-phenylpropenoic acid above is coupled with benzyl β-alaninate according to the experimental procedure described in Example 1 (step D). Yield: 63% (after flash chromatography, eluent: ether/petroleum ether 55/45) oil IR: 3320, 1725, 1650, 1620 cm-1 1H NMR (CDCl3): 7.30 (s, 5H); 7.20 (s, 5H); 6.75 (s, 1H); 4.90 (s, 2H); 3.80 (s, 2H); 3.45 (q app; 2H, J=6.0 Hz); 2.40 (t, 2H, J=6.5 Hz); 1.20 (s, 9H). Microanalysis: C25H29NO4S Calc. % C=68.31 H=6.65 N=3.19 Found. % C=68.02 H=6.73 N=3.01