Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]1[CH:4]=[C:5]([C:10]2[N:11]=[C:12]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:13]([CH2:15][C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[CH3:22])[CH:14]=2)[CH:6]=[CH:7][C:8]=1[F:9].Cl[C:31]1[C:32]2[CH:39]([CH2:40][CH3:41])[C:38](=[O:42])[NH:37][C:33]=2[N:34]=[CH:35][N:36]=1.CCN(C(C)C)C(C)C.CC(O)C>O>[F:29][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([C:10]2[N:11]=[C:12]([CH:23]3[CH2:24][CH2:25][N:26]([C:31]4[C:32]5[CH:39]([CH2:40][CH3:41])[C:38](=[O:42])[NH:37][C:33]=5[N:34]=[CH:35][N:36]=4)[CH2:27][CH2:28]3)[N:13]([CH2:15][C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[CH3:22])[CH:14]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CN1CCCC[C@@H]1Cn1cc(-c2ccc(F)c(C(F)F)c2)nc1C1CCNCC1
Reactant: CCC1C(=O)Nc2ncnc(Cl)c21
Solvent: CC(C)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCC1C(=O)Nc2ncnc(N3CCC(c4nc(-c5ccc(F)c(C(F)F)c5)cn4C[C@H]4CCCCN4C)CC3)c21
Yield: 5.4 %

Procedure:
Combine (R)-2-((4-(3-(difluoromethyl)-4-fluorophenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)methyl)-1-methylpiperidine (0.8 g, 0.0018 mol, 1.0 eq); 4-chloro-5-ethyl-5,7 dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.425 g, 0.00216 mol, 1.2 eq); DIPEA (2.3 mL, 0.0126 mol, 7.0 eq) and IPA (15 mL) in a pressure tube and heat at 120° C. overnight under sealed condition. Cool the reaction mass and dilute with water (25 mL). Extract in EA (2×50 mL) and wash the organic layer with brine (2×50 mL). Dry over anhydrous sodium sulfate and concentrate the crude compound. Filter the crude product through a short silica pad (100-200 mesh) using 0-8% MeOH-DCM). LCMS of concentrated crude product shows 70% of the desired product (m/z=568 [M+H]). Purify through reverse phase preparative HPLC to get 0.055 g of the title compound. MS (ES+): m/z=568 (M+H).
Reaction SMILES: [OH:1][C:2]12[CH2:10][CH:6]([O:7][C:8]1=[O:9])[CH:5]([OH:11])[CH:4]([OH:12])[CH2:3]2.[CH2:13]([NH2:16])[CH2:14][CH3:15].C(O)(=O)C>CO.C(Cl)(Cl)Cl>[CH2:13]([NH:16][C:8]([C:2]1([OH:1])[CH2:10][CH:6]([OH:7])[CH:5]([OH:11])[CH:4]([OH:12])[CH2:3]1)=[O:9])[CH2:14][CH3:15]
Reactant: O=C1OC2CC1(O)CC(O)C2O
Reactant: CCCN
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCNC(=O)C1(O)CC(O)C(O)C(O)C1
Yield: 80 %

Procedure:
In a 50 mL round-bottom flask fitted with a stirring bar, reflux condenser, 0.196 g Lactone 2 (1.125 mmol), and propylamine (0.83 ml, 0.6 g, 10.13 mmol) were combined, then glacial acetic acid (0.19 ml, 0.20 g, 3.36 mmol) was added. The solution was warmed to 85° C. in an oil bath for 30 min, at which time TLC(CHCl3:MeOH:NH3OH=100:10:1) indicated complete consumption of the starting lactone. Reaction mixture was purified by flash column with the same solvent as TLC. Product 3 was collected, yielding 206 mg (80% yield). Mp: 132-133° C., Rf 0.03 (CHCl3:MeOH:NH3OH=100:10:1); MS: [M-H]−=232; 1H NMR (300 MHz, DMSO) δ 0.81 (t, J=6.0 Hz, 3H), 1.41 (ddd, J=13.8, 7.5, 6.9 Hz, 2H) 1.66-1.83 (m, 4H), 3.02 (dd, J=6.9, 6.6 Hz, 2H), 3.22 (t, J=6.0 Hz, 1H), 3.75 (ddd, J=13.8, 9.0, 5.7 Hz, 1H), 3.94 (s, 1H), 4.69 (d, J=4.5 Hz, 1H), 4.90 (d, J=5.4 Hz, 1H), 5.19 (d, J=3.6 Hz, 1H), 5.47 (s, 1H), 7.76 (t, J=5.4 Hz, 1H).
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([O:7]CC)=O)(=O)[CH3:2].[C:17](=[NH:23])([NH2:22])[CH2:18][CH2:19][CH2:20][CH3:21].C[O-].[Na+].CO.C(OCC)(=O)C>CO.O>[CH2:18]([C:17]1[NH:23][C:5](=[O:7])[C:4]([CH2:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:14])[CH3:15])=[C:1]([CH3:2])[N:22]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(=N)N
Reactant: CCOC(=O)C(CC(=O)C(C)(C)C)C(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CCCCc1nc(C)c(CC(=O)C(C)(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 2-acetyl-5,5-dimethyl-4-oxohexanoate (1.04 g) and pentanimidamide (0.89 g) in methanol (10 mL) was added 28% sodium methoxide-methanol solution (3.7 mL), and the mixture was stirred at room temperature for 24 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.34 g, 36%).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]=O.CO[C:7](=[O:21])[CH2:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[N+:11]([O-:13])=[O:12].[Na+].[Cl-]>O1CCOCC1.C(OCC)(=O)C>[Cl:20][C:16]1[CH:15]=[C:14]([C:10]2([N+:11]([O-:13])=[O:12])[CH2:1][N:2]([CH3:3])[C:7](=[O:21])[CH2:8][CH2:9]2)[CH:19]=[CH:18][CH:17]=1
Reactant: C=O
Reactant: CN
Reactant: COC(=O)CCC(c1cccc(Cl)c1)[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN1CC(c2cccc(Cl)c2)([N+](=O)[O-])CCC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.8 %

Procedure:
To a stirred room temperature solution of 164 ul (1.940 mmol) methylamine (41% in water) in 1 ml dioxane was added 141 ul (1.940 mmol) formaldehyde (37% in water) dropwise (exothermic reaction). The mixture was stirred for 5 min and then a solution of 0.5 g (1.940 mmol) rac-4-(3-chloro-phenyl)-4-nitro-butyric acid methyl ester in 1.5 ml dioxane was added at once. The mixture was stirred at 65° C. for 6 h. The mixture was cooled to room temperature, ethyl acetate and a saturated NaCl solution were added. Aqueous phase was extracted 2 times with ethyl acetate. Combined organic phases were washed with a saturated NaCl solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified with flash column chromatography on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 395 mg (76%) of the title compound as a colorless oil. MS (m/e): 269.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.Br[CH:12]([CH3:20])[C:13](=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:10][CH:12]([CH3:20])[C:13](=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(S)cc(Cl)c1
Reactant: COC(=O)CC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)C(C)Sc1cc(Cl)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
A mixture of 3-chloro-5-methoxybenzenethiol (1.90 g), methyl 4-bromo-3-oxopentanoate (2.50 g) and K2CO3 (1.80 g) in DMF (dry) (36.3 mL) was stirred at room temperature overnight. The reaction was quenched with H2O and diluted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (2.09 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[OH:25].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=1[F:17]
Reactant: O=S(=O)(c1ccc(F)c(Br)c1)N1CCCC1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=S(=O)(c1ccc(Oc2ccc(F)cc2F)c(Br)c1)N1CCCC1
Yield: 82 %

Procedure:
A mixture of Example 299a (250 mg, 0.811 mmol), 2,4-difluorophenol (106 mg, 0.811 mmol) and cesium carbonate (317 mg, 0.973 mmol) in 5 mL dimethylsulfoxide was heated at 110° C. for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water (2×), saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to give the title compound (278 mg, 82% yield), which was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[C:14]1([N:20]2[CH2:25][CH2:24][N:23]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[N:7]=[CH:6]3)[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: ClCCCn1cnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(N2CCN(CCCn3cnc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.5 %

Procedure:
1-(3-chloropropyl)-1H-benzimidazole (6.98 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, phenyl piperazine (4.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 10-15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.1 g compound (I-7) with a yield of 63.2%. ESI-MS [M+H]+: m/z 321.2.
Reaction SMILES: C12[N:8]([C:9]3C=N[C:16]4[C:11](=[CH:12]C=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[CH:19]12[CH2:25][NH:24][CH:23]1[CH2:22][N:21]([C:26]([C:28]1[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]=1[O:38][CH2:39][CH3:40])=[O:27])[CH2:20]2.ClC1N=C(C)C=C(C)N=1>>[CH3:12][C:11]1[CH:16]=[C:15]([CH3:14])[N:8]=[C:9]([N:24]2[CH2:25][CH:19]3[CH:23]2[CH2:22][N:21]([C:26]([C:28]2[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][C:29]=2[O:38][CH2:39][CH3:40])=[O:27])[CH2:20]3)[N:10]=1
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Reactant: CCOc1ccc2ccccc2c1C(=O)N1CC2CNC2C1
Agent: Cc1cc(C)nc(Cl)n1
Product: CCOc1ccc2ccccc2c1C(=O)N1CC2CN(c3nc(C)cc(C)n3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 24 and 2-chloro-4,6-dimethylpyrimidine. MS (ESI) mass calcd. for C24H26N4O2, 402.5; m/z found, 403.2 [M+H]+.
Reaction SMILES: COC1C=C([C@H]2OC(=O)N[C@@H]2C2C=CC=C(C#CC3C=CC=CC=3)C=2)C=CC=1.Br[C:30]1[N:35]=[C:34]([C@@H:36]2[C@@H:40]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)[O:39][C:38](=[O:49])[NH:37]2)[CH:33]=[CH:32][CH:31]=1.[C:50]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[F:58])#[CH:51]>>[F:58][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=1[C:50]#[C:51][C:30]1[N:35]=[C:34]([C@@H:36]2[C@@H:40]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)[O:39][C:38](=[O:49])[NH:37]2)[CH:33]=[CH:32][CH:31]=1
Reactant: C#Cc1ccccc1F
Reactant: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(Br)n2)c1
Agent: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccccc3)c2)c1
Product: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccccc3F)n2)c1

Procedure:
Prepared according to the same procedure as (+)-(4R,5R)-5-(3-methoxyphenyl)-4-(3-(phenylethynyl)phenyl)oxazolidin-2-one, starting with optically-enriched (4R,5R)-4-(6-bromopyridin-2-yl)-5-(3-methoxyphenyl)oxazolidin-2-one and 1-ethynyl-2-fluorobenzene. 1H-NMR (CDCl3, 500 MHz) δ 7.81 (dd, J=7.9, 7.6, 1H), 7.63 (ddd, J=7.6, 7.0, 1.2, 1H), 7.60 (d, J=7.6, 1H), 7.41 (m, 2H), 7.36 (dd, J=7.9, 7.9, 1H), 7.18 (m, 2H), 7.05 (m, 2H), 6.94 (m, 1H), 5.89 (bs, 1H), 5.62 (d, J=5.8, 1H), 4.98 (d, J=6.1, 1H), 3.86 (s, 3H). 13C-NMR (CDCl3, 126 MHz) δ 163.1 (d, J=253), 162.1, 160.2, 158.9, 158.6, 143.6, 139.8, 137.7, 134.0, 131.2 (d, J=7.7), 130.2, 127.4, 124.2 (d, J=3.8), 120.1, 117.9, 115.8 (d, J=21), 114.9, 111.0, 93.1, 83.7, 83.5, 64.9, 55.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([C:24]([NH2:26])=O)=[CH:22][N:23]=4)[CH:20]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C[N:28]([CH:30]=O)C.CC([N:35](C)C)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([C:24]5[NH:26][N:28]=[CH:30][N:35]=5)=[CH:22][N:23]=4)[CH:20]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)C=O
Reactant: CC(=O)N(C)C
Reactant: NC(=O)c1cnc2ccc(-c3cccnc3-c3ccc(F)c(Cl)c3)cn12
Product: Fc1ccc(-c2ncccc2-c2ccc3ncc(-c4ncn[nH]4)n3c2)cc1Cl
Temperature: 25 °C

Procedure:
6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide (290 mg) and DMF.DMA (5 mL) were heated at 95° C. and stirred in a screw capped vial overnight. The pale yellow homogeneous reaction mixture was cooled to room temperature and concentrated the heterogeneous slurry by rotary evaporator under vacuum. The off-white solid residue was transferred to a screw capped vial, treated with AcOH (3 mL) dropwise for 3 min followed by N2H4.H2O (0.05 mL) and heated for 1 h at 90° C. The homogeneous reaction mixture was concentrated, diluted with ice/water and allowed the resulting suspension warm to room temperature. Upon filtration, the collected solid was neutralized with aq. NaHCO3 and filtered again to obtain 6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)-3-(1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyridine as an off-white solid (220 mg). 1H NMR (300 MHz, DMSO-d6): δ 14.03 (br s, 1H), 9.46 (dd, J=1.9, 1.0 Hz, 1H), 8.79-8.70 (m, 1H), 8.70-8.52 (m, 1H), 8.18 (s, 1H), 8.02 (dd, J=7.8, 1.6 Hz, 1H), 7.67 (dd, J=6.2, 1.4 Hz, 1H), 7.61 (dd, J=9.3, 1.0 Hz, 1H), 7.56 (dd, J=7.8, 4.7 Hz, 1H), 7.28 (d, J=0.7 Hz, 1H), 7.27-7.20 (m, 1H), 7.04 (dd, J=9.3, 1.8 Hz, 1H). 19F NMR (282 MHz, DMSO-d6): δ −114.49-−119.56 (m). LCMS: rt 4.70 min (A), purity 99%, MS (m/e) 391 MH+.
Reaction SMILES: [C:1]([CH:4]([C:9]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:5]([O:7]C)=O)(=O)[CH3:2].[CH2:18]([N:20]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[S:21]([C:24]1[CH:25]=[N:26][C:27]([NH:30][NH2:31])=[CH:28][CH:29]=1)(=[O:23])=[O:22])[CH3:19]>CCO.CC(O)=O.CCCCC>[CH2:18]([N:20]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[S:21]([C:24]1[CH:25]=[N:26][C:27]([N:30]2[C:5](=[O:7])[C:4]([C:9]([CH3:17])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])=[C:1]([CH3:2])[NH:31]2)=[CH:28][CH:29]=1)(=[O:23])=[O:22])[CH3:19]
Reactant: CCN(c1ccccc1)S(=O)(=O)c1ccc(NN)nc1
Reactant: COC(=O)C(C(C)=O)C(C)(C)c1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCCCC
Product: CCN(c1ccccc1)S(=O)(=O)c1ccc(-n2[nH]c(C)c(C(C)(C)c3ccccc3)c2=O)nc1
Temperature: 90 °C
Yield: 43.9 %

Procedure:
To a solution of 200 mg (0.85 mmol) of methyl 2-acetyl-3-methyl-3-phenylbutanoate in 2 mL of EtOH/AcOH mixture (1:1) are added 249 mg (0.85 mmol) of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide and the reaction mixture is then heated for 2 hours at 90° C. After concentrating under reduced pressure, the residue is taken up in 100 mL of DCM, washed with 2×30 mL of saturated NaHCO3 solution, dried over Na2SO4, filtered, concentrated under reduced pressure and then purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 20% EtOAc. After concentrating under reduced pressure, 312 mg of a yellow oil are obtained, and are solidified in 20 mL of pentane. The solid obtained is filtered off, and then dried under vacuum. 178 mg of N-ethyl-6-[3-methyl-4-(1-methyl-1-phenylethyl)-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-phenylpyridine-3-sulfonamide are obtained in the form of a white powder.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=2)=[CH:12]/[CH2:13][OH:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[CH:33]=[C:32](OC/C=C(/C2C=CC(C#CCN3CCOCC3)=CC=2)\C2C=CC=CC=2)[CH:31]=[CH:30][C:24]=1[O:25][CH2:26][C:27]([OH:29])=[O:28].[C:59]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=2)=[CH:12]/[CH2:13][O:14][C:32]2[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([O:29][CH3:59])=[O:28])=[C:23]([CH3:22])[CH:33]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(/C(=C/CO)c2ccc(I)cc2)cc1
Reactant: Cc1cc(OC/C=C(\c2ccccc2)c2ccc(C#CCN3CCOCC3)cc2)ccc1OCC(=O)O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(C)(C)C)cc2)cc1C
Temperature: 0 °C

Procedure:
The above allyl alcohol (2.46 g, 6.27 mmol), methyl (4-hydroxy-2-methylphenoxy)-acetate (1.35 g, 6.88 mmol; example 2) and triphenylphosphine (1.97 g, 7.51 mmol) were dissolved in a mixture of anhydrous toluene (135 mL) and tetrahydrofuran (45 mL). The mixture was cooled to 0° C., kept under nitrogen and a degassed solution of diisopropyl azodicarboxylate (1.5 mL, 7.57 mmol) in anhydrous tetrahydrofuran (15 mL) was added dropwise during 30 min. The reaction mixture was allowed to warm up the ambient temperature with the bath and then stirred over night. The solvents were evaporated in vacuo and the residue was submitted to flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 12:1-10:1) affording methyl (Z)-[4-[3-(4-tert-butylphenyl)-3-(4-iodophenyl)allyloxy]-2-methyl-phenoxy]acetate as yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:9]([O:10][CH:11]2[CH2:14][CH2:13][CH2:12]2)=[C:8](OC)[C:7]([O:17][CH3:18])=[CH:6][C:4]=1[NH2:5])#[N:2].[C:19]([N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:23]1)(=O)[CH3:20].[CH2:37]([O:39]CC)C>>[CH:11]1([O:10][C:9]2[C:3]([C:1]#[N:2])=[C:4]([N:5]=[C:19]([N:22]3[CH2:31][CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][C:28]=4[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:23]3)[CH3:20])[C:6]([O:39][CH3:37])=[C:7]([O:17][CH3:18])[CH:8]=2)[CH2:12][CH2:13][CH2:14]1
Reactant: CCOCC
Reactant: CC(=O)N1CCc2c(cccc2NS(C)(=O)=O)C1
Reactant: COc1cc(N)c(C#N)c(OC2CCC2)c1OC
Product: COc1cc(OC2CCC2)c(C#N)c(N=C(C)N2CCc3c(cccc3NS(C)(=O)=O)C2)c1OC
Yield: 85 %

Procedure:
The subtitle compound was prepared from 2-cyano-3-cyclobutyloxy-4,5-dimethoxyaniline and 2-acetyl-5-methanesulfonamido-1,2,3,4-tetrahydroisoquinoline following the procedure described in Example 10(g). Trituration with diethyl ether afforded the subtitle compound as a colourless solid (85%). Rf 0.14 (ethyl acetate:hexane 1: 1, v/v).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH3:4].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(O)(=O)C>CN(C=O)C>[CH2:3]([O:5][C:6](=[O:16])[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])=[CH:10][CH:9]=1)[CH3:4]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)C(=O)OCC)cc1
Temperature: 25 °C
Yield: 84 %

Procedure:
To 0.325 g (8.1 mmol) of a 60% oil dispersion of NaH suspended in 15 ml of anhydrous DMF and stirred under an argon atmosphere at room temperature was added 1.5 g (7.73 mmol) of 4-hydroxyalpha-oxobenzeneacetic acid ethyl ester. The reaction mixture was stirred at room temperature for 20 minutes and a solution of 3.2 g (9.66 mmol) of 1-bromooctadecane in 20 ml of anhydrous DMF was added dropwise over 15 minutes. After stirring at reflux for 16 hours, 5 ml of acetic acid was added and the solvent was removed at reduced pressure. Water was added to the residue and the product was extracted with methylene chloride. The dried extract was concentrated at reduced pressure and the solid residue was purified by HPLC using 50% methylene chloride-hexane to give 2.9 g (84% yield, mp 46°-48°) of 4-(octadecyloxy)-alpha-oxobenzeneacetic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[C:4]([F:13])[C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[Br:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[CH:18][C:17]=1[S:25](Cl)(=[O:27])=[O:26].COC1C=CC(N)=CC=1.[OH:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[NH2:42]>>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([NH:42][C:41]2[CH:43]=[CH:44][C:45]([O:46][CH3:47])=[C:39]([OH:38])[CH:40]=2)(=[O:10])=[O:9])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14].[Br:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[CH:18][C:17]=1[S:25]([NH:42][C:41]1[CH:43]=[CH:44][C:45]([O:46][CH3:47])=[C:39]([OH:38])[CH:40]=1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1cc(Br)c(F)c(F)c1F
Reactant: COc1ccc(N)cc1O
Reactant: O=S(=O)(Cl)c1cc(F)c(F)c(F)c1Br
Solvent: COc1ccc(N)cc1
Product: COc1ccc(NS(=O)(=O)c2cc(Br)c(F)c(F)c2F)cc1O
Product: COc1ccc(NS(=O)(=O)c2cc(F)c(F)c(F)c2Br)cc1O

Procedure:
1-Bromo-2,3,4-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene (Example 12) and 1-Bromo-4,5,6-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene (Example 13) were prepared in a manner similar to that described in Example 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with a mixture of 5-bromo-2,3,4-trifluorophenylsulfonyl chloride (Example D) and 2-bromo-3,4,5-trifluorophenylsulfonyl chloride (Example E) and replacing p anisidine with 3-hydroxy-4-methoxyaniline. The two isomeric compounds were separated by column chromatography (silica gel; ethyl acetate:hexanes, 1:4). 1H-NMR (CDCl3): δ 7.79 (1H, m), 6.72-6.62 (4H, m), 5.65 (1H, s), 3.85 (3H, s).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[F:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[F:42])[C:36](Cl)=[O:37]>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][C:41]([F:42])=[C:33]([F:32])[CH:34]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc(F)c(F)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 3,4-difluorobenzoyl chloride (0.5 g, 2.8 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was quenched with MeOH (1 mL) and was filtered. The solid was rinsed with CH2Cl2 (5 mL) and then dissolved in acetone (4 mL). Ether (10 mL) and hexane (10 mL) were added to the solution and the resulting suspension was filtered to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3,4-difluoro-benzamide as a white solid (0.7 g, 75%): mp, 218-220° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.1 min. (99%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.51-2.64 (m, 2H), 2.87-2.93 (m, 1H), 4.95 (d, J=5.8 Hz, 2H), 5.15-5.21 (dd, J=5, 12 Hz, 1H), 7.55-8.01 (m, 6H), 9.26 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.96, 30.92, 39.20, 48.86, 116.77, 116.65, 116.89, 117.51, 117.74, 121.95, 124.75, 124.80, 124.85, 124.89, 127.18, 131.28, 131.32, 131.39, 131.53, 133.15, 134.82, 138.86, 147.42, 147.59, 149.70, 149.87, 150.68, 150.85, 153.02, 153.19, 164.45, 166.93, 167.49, 169.81, 172.74. Anal Calcd for C21H15F2N3O5: C, 59.02; H, 3.54; N, 9.83; F, 8.89. Found: C, 59.12; H, 3.60; N, 9.68; F, 8.86.