Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[C:12]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)#[CH:13].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[NH2:18][C:17]1[CH:19]=[CH:20][C:14]([C:12]#[C:13][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=3)[N:7]=2)=[CH:15][CH:16]=1
Reactant: C#Cc1ccc(N)cc1
Reactant: Nc1cn2nc(I)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(C#Cc2ccc3nc(N)cn3n2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To the mixture of 6-iodo-imidazo[1,2-b]pyridazin-2-ylamine (780 mg, 3.0 mmol, 1 eq) and 4-ethynylaniline (543 mg, 1.5 eq) in anhydrous DMF (10 mL) under nitrogen atmosphere was added triethylamine (1.67 mL, 4 eq), bis(triphenylphosphine)palladium(II) dichloride (210 mg, 0.1 eq) and copper(I) iodide (114 mg, 0.2 eq). After the reaction mixture was stirred at 50° C. for 30 minutes, it was partitioned between saturated aqueous sodium bicarbonate and chloroform (containing 3% v/v of MeOH). The organic layer was separated and washed with aqueous ammonium chloride, brine, and lastly dried with anhydrous sodium sulfate. The upper suspension mixture was decanted, concentrated, and the solid residue was subject to a gradient column chromatography (from CHCl3 to MeOH—CHCl3 1:30) to give 6-[(4-aminophenyl)ethynyl]imidazo[1,2-b]pyridazin-2-amine as a yellow solid in amount of 166 mg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][NH:27][CH2:28]3)=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[CH3:2].C(N(C(C)C)CC)(C)C.[ClH:41].[N:42]1([C:47](N)=[NH:48])C=CC=N1>CN(C)C=O>[ClH:41].[ClH:41].[CH2:1]([O:3][C:4](=[O:31])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][N:27]([C:47](=[NH:42])[NH2:48])[CH2:28]3)=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cnccc1N1CCC(COc2ccc3c(c2)CNCC3)CC1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C=Cc1cnccc1N1CCC(COc2ccc3c(c2)CN(C(=N)N)CC3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 101.2 %

Procedure:
To a solution of 3-[4-[4-(1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]-2-propenoic acid ethyl ester (70 mg) in dimethylformamide (1 ml) were added diisopropylethylamine (0.032 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (27 mg), and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated and to the obtained residue was added diethyl ether and the supernatant was removed. This procedure was repeated twice and hydrogen chloride-ethanol solution was added to the obtained residue and insoluble material was removed. The solution was concentrated and dried under reduced pressure to give the title compound (50 mg).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH3:18][N:19]([CH3:28])[C:20]1[CH:21]=[C:22]([CH2:26]O)[CH:23]=[CH:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:18][N:19]([CH3:28])[C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[CH2:26][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:16][CH:15]=1
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Reactant: CN(C)c1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(OCC)c1ccc(OCc2cccc(N(C)C)c2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 76.3 %

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and [3-(dimethylamino)phenyl]methanol (95 mg, 0.630 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a white solid (119 mg, yield: 76%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13][C:14](=[O:41])[N:15]([C:17]1[CH:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]3)=[CH:26][C:25]=2[N+:38]([O-])=O)[N:20]=[CH:19][N:18]=1)[CH3:16]>C1COCC1.CO.[Ni]>[NH2:38][C:25]1[CH:26]=[C:27]([N:30]2[CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH2:35]2)[CH:28]=[CH:29][C:24]=1[NH:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]([N:15]([CH3:16])[C:14]([NH:13][C:3]2[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=2[Cl:1])=[O:41])[CH:22]=1
Reactant: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4c(Cl)c(OC)cc(OC)c4Cl)ncn3)c([N+](=O)[O-])c2)CC1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4c(Cl)c(OC)cc(OC)c4Cl)ncn3)c(N)c2)CC1
Reaction time: 3 h
Yield: 89.1 %

Procedure:
To a solution of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-(4-(4-ethylpiperazin-1-yl)-2-nitrophenylamino)pyrimidin-4-yl)-1-methylurea (330 g, 0.546 mmol) in THF (20 mL) and MeOH (20 mL) was added Raney-Ni (suspension in water) at room temperature, the resulting mixture was stirred for 3 hours under hydrogen atmosphere (1 atm). The reaction was filtered and concentrated. The residue was washed twice with MeOH to obtain the title compound (280 mg, purity: 90%), which was used directly in the next step. MS (ESI): 575 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=O)[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C.[C:40](Cl)(Cl)([Cl:42])[Cl:41]>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[C:40]([Cl:42])[Cl:41])[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(C(F)(F)F)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)C(=C(Cl)Cl)c1ccc(C(F)(F)F)cc1

Procedure:
680 mg of oxo-(4-trifluoromethyl-phenyl)-acetic acid ethyl ester and 2.2 g of triphenylphosphine are introduced into 8 ml of acetonitrile. 0.8 ml of carbon tetrachloride is then added and the mixture is heated at reflux for 4 hours. The reaction mixture is concentrated completely and the crude product is purified over silica gel. 3,3-Dichloro-2-(4-trifluoromethyl-phenyl)-acrylic acid ethyl ester is obtained. 1H-NMR (CDCl3) 300 MHz: 1.30 (t, 3H), 4.30 (q, 2H), 7.52 (d, 2H), 7.68 (d, 2H).
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6]=1[CH3:25])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([Li])[CH2:27][CH2:28]C.IC(C)C>O1CCCC1>[C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N:16]([CH:27]([CH3:28])[CH3:26])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6]=1[CH3:25])([CH3:2])([CH3:3])[CH3:4]
Reactant: [Li]CCCC
Reactant: COc1ccc(Nc2cc3c(c(C(C)(C)C)c2C)OCC3(C)C)cc1
Solvent: CC(C)I
Solvent: C1CCOC1
Product: COc1ccc(N(c2cc3c(c(C(C)(C)C)c2C)OCC3(C)C)C(C)C)cc1
Yield: 8.9 %

Procedure:
Following general procedure L and using 7-t-butyl-5-[(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 53, 0.13 g, 0.38 mmol), 1.6M solution of n-butyllithium in hexanes (0.5 mL, 0.8 mmol) and 2-iodopropane (0.5 mL, 5 mmol) in 2 mL of anhydrous tetrahydrofuran, the title compound (0.013 g, 8.9%) was obtained as a brown oil after separation from recovered 7-t-butyl-5-[(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 53, 0.07 g) by preparative normal phase HPLC using 4% ethyl acetate in hexanes as the mobile phase. 1H NMR (300 MHz, C6D6): δ 6.82 (d, 2H, J=9.1 Hz), 6.75 (s, 1H), 6.56 (d, 2H, J=9.1 Hz), 4.09(heptet, 1H, J=6.5 Hz), 3.89 (s, 2H), 3.40(s, 3H), 2.40 (s, 3H), 1.68 (s, 9H), 1.10-1.25(m, 3H), 0.99-1.10(m, 3H), 0.99 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH2:6][CH2:5]1.C(Cl)Cl.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C>[F:26][C:23]([F:24])([F:25])[C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=1)[C:12]([NH:11][CH2:10][CH:7]1[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][NH:1][C:32](=[O:33])[O:34][CH2:35][CH3:36])[CH2:9][CH2:8]1)=[O:27]
Reactant: CCOC(=O)Cl
Reactant: NCCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)NCCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reaction time: 8 h

Procedure:
A solution of N-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide (66 mg, 0.17 mmol) in a 2:1 mixture of CH2Cl2:DMF (3 mL) and TEA (69 μL, 0.50 mmol) was treated with ethyl chloroformate (27 mg, 0.25 mmol). The reaction mixture was allowed to stir overnight, then the solvent was removed in vacuo and the residue was purified by HiTOPs.
Reaction SMILES: O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.I[C:18]1[C:23]([F:24])=[CH:22][C:21]([N:25]2[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]2=[O:35])=[CH:20][C:19]=1[F:36].C[Sn](C)(C)[C:39]1[CH:45]=[CH:44][C:43](=[O:46])[C:42]([O:47][CH3:48])=[CH:41][CH:40]=1>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.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH3:48][O:47][C:42]1[C:43](=[O:46])[CH:44]=[CH:45][C:39]([C:18]2[C:23]([F:24])=[CH:22][C:21]([N:25]3[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]3=[O:35])=[CH:20][C:19]=2[F:36])=[CH:40][CH:41]=1
Reactant: COc1ccc([Sn](C)(C)C)ccc1=O
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(I)c(F)c2)C(=O)O1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2c(F)cc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)ccc1=O
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 68.4 %

Procedure:
The tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (450 mg, 0.492 mmol) and the trifurylphosphine (460 mg, 1.969 mmol) were stirred together for 5 min in 1,4-dioxane (25 mL), followed by the addition of (S)-N-[[3-(4-iodo-3,5-difluorophenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide (1.3 g, 3.28 mmol). After degassing the solution three times with N2, the trimethyl(4-methoxy-5-oxo-1,3,6-cycloheptatrien-1-yl)tin (1.47 g, 4.92 mmol) was added. The solution was degassed again (3×) and then the solution was heated to reflux (110 ° C.) for 12 h under N2. Upon cooling, the reaction was determined to be complete by TLC (10% MeOH/CHCl3, UV short wave). The reaction was concentrated under reduced pressure and then redissolved in CH2Cl2 (100 mL). This solution was stirred over aqueous KF (100 mL) for 45 min and then separated. The organic portion was washed with brine (100 mL) and then dried over anhydrous Na2SO4. After drying, it was filtered and concentrated under reduced pressure to yield a brown solid. The crude product was chromatographed on silica gel (175 g of silica gel, packed with 10% CH3CN/CHCl3, eluting with a gradient of 1-5% MeOH in 10% CH3CN/CHCl3) to give a pale yellow solid. This solid was recrystalized by dissolving it in CH2Cl2 /MeOH and triturating with ether to yield 907 mg (68%) of the title compound as an off-white solid with mp 129 ° C (dec) and a HRMS (M+) calculated for C20H18N2O5F2 404.1184, found 404.1183.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40]([OH:42])=O)=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.Cl.[NH2:47][CH2:48][C:49]([NH2:51])=[O:50].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[C:49]([CH2:48][NH:47][C:40]([CH2:39]/[CH:38]=[CH:37]/[C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:44])[CH3:45])=[CH:32][CH:33]=1)=[O:42])(=[O:50])[NH2:51]
Reactant: NCC(N)=O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(/C=C/CC(=O)NCC(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole (0.34 g) in N,N-dimethylformamide (1 mL) were added glycinamide hydrochloride (0.12 g), 1-hydroxybenzotriazole (0.09 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g) and triethylamine (0.27 g), and the mixture was stirred at room temperature overnight. The insoluble material was removed by filtration. To the filtrate was added 5 mol/L aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration, and the filtrate was purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μm, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient, water/acetonitrile=90/10-10/90) to give 4-({4-[(1E)-3-(carbamoylmethylcarbamoyl)prop-1-enyl]phenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (0.03 g). This material was dissolved in methanol (1 mL). To the solution was added 10% palladium-carbon powder (0.01 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (0.02 g).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][NH:18][CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][N:18]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH3:31])[CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccccc1B(O)O
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CNCC3)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1N1CCc2ncnc(Nc3ccc(C(F)(F)F)cc3)c2C1
Reaction time: 6 h
Yield: 4.6 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added o-tolylboronic acid (92 mg, 0.68 mmol), Cu(OAc)2 (124 mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under a vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (6.0 mg, 5%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([O:23][CH3:24])=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([O:23][CH3:24])=[C:18]([NH:19][S:39]([C:33]3[C:34]([F:38])=[CH:35][CH:36]=[CH:37][C:32]=3[F:31])(=[O:41])=[O:40])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: COc1c(N)cccc1-c1nc(C(C)C)sc1-c1ccnc(Cl)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(NS(=O)(=O)c2c(F)cccc2F)cccc1-c1nc(C(C)C)sc1-c1ccnc(Cl)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 58.1 %

Procedure:
To a solution of 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-(methyloxy)aniline (10 g, 28 mmol), in DCM (100 mL) was added pyridine (6.6 g, 83.7 mmol) and the mixture was cooled to 0° C. 2,6-Difluorobenzene-1-sulfonyl chloride (5.9 g, 27.9 mmol) in DCM (100 mL) was added dropwise to the mixture. The reaction was stirred at rt for 4 h. Then the reaction was washed with water (200 mL), and extracted with DCM (2×200 mL). The organic layer was washed with brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:DCM 1:1) to afford the title compound of Step H (8.7 g, 58.2% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.21 (d, J=5.6 Hz, 1H), 7.70-7.75 (m, 1H), 7.63-7.67 (br, 1H), 7.46-7.55 (m, 1H), 7.15-7.19 (m, 2H), 6.95-7.03 (m, 2H), 6.58 (d, J=5.6 Hz, 1H), 3.35-3.40 (m, 4H), 1.44 (d, J=6.4 Hz, 6H). m/z (ES+): 537 [M+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[C:10]([F:18])[CH:9]=1.[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:30][CH2:31][N:32]([C:12]([C:11]4[CH:16]=[CH:17][C:8]([CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:19])=[CH:9][C:10]=4[F:18])=[O:14])[CH2:33][CH2:34]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1
Reactant: COC(=O)c1ccc(CN2CCCS2(=O)=O)cc1F
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(CN3CCCS3(=O)=O)cc2F)CC1
Yield: 83 %

Procedure:
Using methyl 4-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)-2-fluorobenzoate (115 mg) described in Preparation Example 200 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (104 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (157 mg) was obtained.
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1/[CH:32]=[CH:33]/[CH:34]=[O:35]>>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:10]1[NH:11][C:12]2[O:13][C:34](=[O:35])[CH:33]([CH2:32][C:23]3[CH:24]=[CH:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)[CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[N:9]=1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Reactant: O=C/C=C/c1ccc2ccccc2c1
Product: O=C1Oc2[nH]c(-c3cc(F)ccc3F)nc2C(c2ccccc2)C1Cc1ccc2ccccc2c1
Yield: 71 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(naphthalen-2-yl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 15 as an off-white solid (99 mg, 71%). Analytical data for 15: 1H NMR (500 MHz, CDCl3) δ 9.35 (d, J=8.3 Hz, 1H), 7.89 (ddd, J=9.2, 6.1, 3.3 Hz, 1H), 7.86-7.80 (m, 2H), 7.78-7.74 (m, 1H), 7.53-7.45 (m, 3H), 7.38-7.32 (m, 3H), 7.24 (dd, J=8.5, 1.8 Hz, 1H), 7.07-6.92 (m, 4H), 4.08 (d, J=6.8 Hz, 1H), 3.74 (ddd, J=10.4, 6.8, 4.5 Hz, 1H), 3.54 (dd, J=14.8, 4.5 Hz, 1H), 2.60 (dd, J=14.9, 10.3 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 168.9, 159.1 (d, JCF=243.3 Hz), 155.3 (d, JCF=241.8 Hz), 148.9, 137.1, 136.4, 135.2, 133.4, 132.3, 129.2, 128.4, 128.4, 128.1, 127.8, 127.7, 127.4, 127.0, 126.3, 125.7, 118.4 (dd, JCF=12.5, 8.9 Hz), 117.1 (dd, JCF=25.6, 8.7 Hz), 116.6 (dd, JCF=24.9, 9.9 Hz), 114.5 (dd, JCF=26.8, 3.9 Hz), 111.0 (d, JCF=3.7 Hz), 47.1, 38.4, 32.9; IR (film) cm−1 3057, 3030, 1770, 1635, 1619, 1530, 1481, 1411, 1172, 1116, 1104, 1032, 814, 766, 738, 701; LRMS (ESI): Mass calcd for [M+H]+ C29H21F2N2O2: 467.2. found 467.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel AD-H; 7% IPA/hexanes 1.0 mL/min, 230 nm), Rt1 (major)=37.8, Rt2 (minor)=48.3 min; er=96:4.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[N:34]2[CH2:39][CH2:38][N:37](CCC3C=C(C=CC=3)N)[CH2:36][CH2:35]2)[N:25]=1.[N:49]1([C:54]2[CH:55]=[C:56]([CH2:60][C:61]([OH:63])=O)[CH:57]=[CH:58][CH:59]=2)[CH:53]=[CH:52][CH:51]=[N:50]1>CN(C)C=O>[CH3:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[N:34]2[CH2:39][CH2:38][N:37]([C:61](=[O:63])[CH2:60][C:56]3[CH:57]=[CH:58][CH:59]=[C:54]([N:49]4[CH:53]=[CH:52][CH:51]=[N:50]4)[CH:55]=3)[CH2:36][CH2:35]2)[N:25]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C(O)Cc1cccc(-n2cccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(C(=O)Cc4cccc(-n5cccn5)c4)CC3)cccc2n1

Procedure:
EDC.HCl (1.5 eq), HOBt (2 eq) and 2-methyl-5-(1-piperazinyl)quinoline (D3) (1 eq) were added sequentially to a stirred solution of [3-(1H-pyrazol-1-yl)phenyl]acetic acid (D19) (1.1 eq) in dimethylformamide at room temperature under an inert atmosphere.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:23]([C:25]1[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=1)[CH3:24])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13]C(=O)C2C=CC=CC=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CO>[OH:1][C@@H:2]([C@@H:23]([C:25]1[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=1)[CH3:24])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([OH:13])[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2
Reactant: Cc1cccc([C@@H](C)[C@H](O)/C=C/[C@@H]2[C@H]3CC(=O)O[C@H]3C[C@H]2OC(=O)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cccc([C@@H](C)[C@H](O)/C=C/[C@@H]2[C@H]3CC(=O)O[C@H]3C[C@H]2O)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The crude alcohol, {(1S,5R,6R,7R)-6-[(1E,3R,4R)-3-hydroxy-4-(m-tolyl)-1-pentenyl]-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one} (649.9 g) synthesized in Example 4 was dissolved in methanol (740 mL), potassium carbonate (116.3 g) was added, and the mixture was stirred at room temperature for 17 hr. Acetic acid was added to adjust to pH 7, methanol was evaporated, water was added, and the mixture was extracted with ethyl acetate. The extract was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-0/1) to give the title compound (22.3 g). The structural property was as described below.
Reaction SMILES: [C:1]1([C:7]([NH2:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C:13]2[N:17](C)[C:16]([CH:19]=[O:20])=[CH:15]N=2)CC1>>[CH3:13][N:17]1[C:16]([CH:19]=[O:20])=[CH:15][N:9]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1ccccc1
Reactant: Cn1c(C=O)cnc1C1CC1
Product: Cn1c(C=O)cnc1-c1ccccc1

Procedure:
3-Methyl-2-phenyl-3H-imidazole-4-carbaldehyde was prepared from benzene carboxamide in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).