Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20](O)=[O:21])=[N:18][CH:19]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:20](=[O:21])[C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][N:18]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
TEA (0.61 mL, 4.35 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.87 mmol, Example 1, Step H), 5-chloropicolinic acid (160 mg, 1.04 mmol) and BOP-Cl (332 mg, 1.30 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 1 hour, and then a LiOH solution (2 N, 3 mL) was added. The mixture was stirred for 30 minutes, and water (10 mL) was added. The solid formed was collected by filtration, washed with DCM (10 mL) and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-chloropicolinamide (240 mg, 73% yield) as a solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)=[O:3].[Se](=O)=[O:16]>>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[O:16])=[CH:5][C:6]=1[C:11]([F:14])([F:12])[F:13]
Reactant: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: O=[Se]=O
Product: O=CC(=O)c1ccc(F)c(C(F)(F)F)c1

Procedure:
4-Fluoro-3-(trifluoromethyl)acetophenone (2 g, 9.70 mmol) was reacted with selenium dioxide (1.6 g, 14.6 mmol) using the method described in Example 1 to give crude (4-fluoro-3-trifluoromethylphenyl)-oxoacetaldehyde as a yellow oil: m/z (ES+) 221.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)#[N:28]>>[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:26][C@H:23]2[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][CH:12]([C:11]4[C:6]5[CH2:5][CH2:4][O:3][C:7]=5[CH:8]=[CH:9][CH:10]=4)[CH2:13][CH2:14]3)[CH2:25][CH2:24]2)=[O:34])=[CH:31][CH:30]=1)#[N:28]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: N#Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4CCO5)CC3)CC2)cc1

Procedure:
The title compound, off-white solid (90 mg, 79%), MS (ISP) m/z=458.3 [(M+H)+], mp 230° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-cyano-benzoic acid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[NH:14][CH2:13][CH2:12]2.CCN(C(C)C)C(C)C>CO.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[N:14]1[CH:15]2[CH2:18][CH2:19][N:11]([CH2:17][CH2:16]2)[CH2:12][CH2:13]1
Reactant: Clc1nc2ccccc2o1
Reactant: C1CN2CCC(CC2)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: c1ccc2oc(N3CCN4CCC3CC4)nc2c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 34.9 %

Procedure:
2-Chlorobenzoxazole (Aldrich, 99 μL, 0.87 mmol) was added to a solution of 1,4-diazabicyclo[3.2.2]nonane (100 mg, 0.79 mmol) in methanol (2.65 mL) at 0° C. The reaction mixture was allowed to slowly warm to RT. After a period of 16 h iPr2NEt (138 μL, 0.79 mmol) was added and the mixture was stirred at RT for 4.5 h at which time it was diluted with CHCl3 and NaHCO3. The layers were partitioned and the aqueous layer was extracted with CHCl3 (×3). The combined organic layers were washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by chromatography (Biotage, 12L) eluting with 4% MeOH in CHCl3 containing 20 drops of NH4OH per liter of eluent to afford 67 mg (35%) of the title compound as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 7.30 (d, 1H, J=7.5 Hz), 7.19 (d, 1H, J=7.9 Hz), 7.10 (t, 1H, J=7.5 Hz), 6.94 (t, 1H, J=7.9 Hz), 4.46 (s, 1H), 3.87, (t, 2H, J=5.8 Hz), 3.12-2.92 (m, 6H), 2.15-2.05 (m, 2H), 1.79-1.70 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 161.8, 148.9, 143.7, 124.1, 120.3, 116.1, 108.7, 57.3, 50.3, 46.5, 44.4, 27.1; MS (Cl) m/z 244.3 (M+1). The hydrochloride salt was prepared by dissolving the title compound in iPrOH and adding 0.1 mL of 6 M hydrochloric acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1/[CH:10]=[N:11]/[N:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:19]=2)[CH:14]=[CH:13]1.[BH4-].[Na+]>CO.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][NH:11][N:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:19]=2)[CH:14]=[CH:13]1
Reactant: Fc1ccc(Cl)c(/C=N/n2ccc3ncc(-c4cnn(C5CCNCC5)c4)cc32)c1Cl
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(Cl)c(CNn2ccc3ncc(-c4cnn(C5CCNCC5)c4)cc32)c1Cl

Procedure:
A solution of N-[(E)-(2,6-dichloro-3-fluorophenyl)methylidene]-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridin-1-amine (35 mg, 0.063 mmol) in MeOH (5 mL) was treated with excess amount of NaBH4 under reflux. HPLC check indicated disappearance of the starting material. The mixture was diluted with aqueous NaHCO3, and extracted with ethyl acetate. The organic solution was dried and evaporated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[C:5]([Cl:18])=[CH:4][C:3]=1[O:19]C.Cl>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH3:17])=[CH:13][CH:14]=2)[C:5]([Cl:18])=[CH:4][C:3]=1[OH:19]
Reactant: CCOc1ccc(Cc2cc(Br)c(OC)cc2Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOc1ccc(Cc2cc(Br)c(O)cc2Cl)cc1
Temperature: 90 °C

Procedure:
To a solution of 1-Bromo-4-chloro-5-(4-ethoxybenzyl)-2-methoxybenzene (6, 11.3 mmol) in N,N-dimethylformamide (50 mL) was added sodium ethane thiolate (3.17 g, 34 mmol) and heated at 90° C. for 3 h. The reaction mixture was cooled to 0° C., neutralized with 1N HCl, and the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to yield the title compound as yellow oil which was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([OH:23])=O.[C:24]1([CH:30]2[O:35][CH2:34][CH2:33][NH:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>ClCCl>[O:23]=[C:21]([N:32]1[CH2:33][CH2:34][O:35][CH:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:31]1)[CH2:20][N:3]1[CH2:4][CH2:5][CH2:6][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]1=[O:1]
Reactant: c1ccc(C2CNCCO2)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCOC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
To 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.103 g, 0.334 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.155 g, 0.408 mmol) and 2-phenylmorpholine (0.074 g, 0.371 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.097 mL, 0.556 mmol), and the reaction mixture was stirred at room temperature. After stirring overnight, the reaction was directly loaded onto a silica gel column (Analogix®, SF15-12), and the product was eluted with a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes with a flow rate of 30 mL/minute. The product eluted with a more polar impurity. The product was rechromatographed over silica gel (Analogix®, SF15-12), and the title compound was eluted with a gradient of 0.4% to 7.5% methanol/dichloromethane over 20 minutes with a flow rate of 30 mL/minute. 1H NMR (300 MHz, CDCl3) δ ppm 7.18-7.40 (m, 15H), 4.37-4.68 (m, 3H), 3.98-4.17 (m, 2H), 3.32-3.85 (m, 6H), 2.64-2.70 (m, 2H), 1.82-1.88 (m, 2H); MS (ESI+) m/z 455 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[CH3:10][C:11]([O:14][C:15]([NH:17][C@@H:18]1[C:21](=[O:22])[O:20][CH2:19]1)=[O:16])([CH3:13])[CH3:12]>C1COCC1>[OH:22][CH2:21][CH:18]([NH:17][C:15](=[O:16])[O:14][C:11]([CH3:12])([CH3:10])[CH3:13])[C:19]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:20]
Reactant: COc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1COC1=O
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)C(CO)NC(=O)OC(C)(C)C)c1

Procedure:
To a solution of m-anisidine (171 mg, 1.38 mmol) in THF (30 ml), N-(tert-butoxycarbonyl)-L-serine β-lactone (200 mg, 1.06 mmol) was added, and the mixture was refluxed overnight under argon. The reaction mixture was concentrated on a rotary evaporator. The residue was subjected to flash column chromatography, eluting with EtOAc/hexanes of various compositions.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[N:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)=[N+:11]=[N-:12]>C([O-])(O)=O.[Na+].O>[N:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:21])=[O:20])=[CH:17][CH:18]=1)=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccc(S(=O)(=O)NCCCCCC(=O)O)cc1
Reaction time: 8 h
Yield: 41.9 %

Procedure:
4.57 g of ε-aminocaproic acid were dissolved in a solution of 8.8 g of NaHCO3 in 100 ml water. 7.6 g of p-azidobenzenesulfonic acid chloride were suspended therein and the mixture was stirred overnight. The product was precipitated from the resulting solution with HCl, filtered off and washed with water. 4.56 g of ε-(p-azidobenzenesulfonylamino)caproic acid were obtained after drying in a high vacuum at room temperature. The IR showed the expected bands at 2907 (azide), 1715 (acid carbonyl), 1585+1400 (aromatic), 1282 (COOH), 1319+1153 (aryl sulfonyl), 834 (p- disubst. benzene); TLC (silica gel: EtOAc)/EtOH=3) Rf=0.55; m.p.=126-127° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:23][N:24]4[CH2:27][CH:26]([C:28]([O:30]C)=[O:29])[CH2:25]4)=[N:20][C:21]=3[CH3:22])[N:12]=2)=[CH:7][C:6]=1[CH3:32])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(O)(=O)C.C(O)(=O)C(O)=O>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:23][N:24]4[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]4)=[N:20][C:21]=3[CH3:22])[N:12]=2)=[CH:7][C:6]=1[CH3:32])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)C1CN(Cc2ccc(-c3noc(-c4ccc(CC(C)C)c(C)c4)n3)c(C)n2)C1
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc(-c2nc(-c3ccc(CN4CC(C(=O)O)C4)nc3C)no2)ccc1CC(C)C
Yield: 84.9 %

Procedure:
The title compound (0.10 g) was synthesized in a yield of 78% as a white crystalline solid by conducting the similar reaction to that mentioned in Example 21 (21d) using methyl 1-({5-[5-(4-isobutyl-3-methylphenyl)-1,2,4-oxadiazol-3-yl]-6-methylpyridin-2-yl}methyl)azetidine-3-carboxylate (0.12 g, 0.28 mmol) that was obtained in Example 27 (27f), a 1N aqueous solution of sodium hydroxide (0.84 ml, 0.84 mmol), acetic acid (48 μl, 0.84 mmol), and oxalic acid (13 mg, 0.14 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:16])[N:12]([CH2:14][CH3:15])[CH:13]=2)=[CH:4][CH:3]=1.[NH2:17][NH2:18].CO>CC(O)C.O>[NH:17]([C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:16])[N:12]([CH2:14][CH3:15])[CH:13]=2)=[CH:4][CH:3]=1)[NH2:18]
Reactant: NN
Reactant: CCn1cc(-c2ccc(Cl)nc2)ccc1=O
Solvent: CO
Solvent: CC(C)O
Solvent: O
Product: CCn1cc(-c2ccc(NN)nc2)ccc1=O
Temperature: 140 °C
Yield: 95.8 %

Procedure:
A mixture of 5-(6-chloropyridin-3-yl)-1-ethylpyridin-2(1 H)-one (1.2 g, 5.44 mmol) and hydrazine (820 mg, 25.62 mmol) in 2-propanol (5 ml) was heated in a microwave at 140° C. for 4 hrs. The mixture was co-evaporated with MeOH (3×) and then suspended in water (50 ml). The resulting solid was collected by filtration and dried under high vacuum for one day to give crude title compound, 5-(6-hydrazinylpyridin-3-yl)-1-ethylpyridin-2(1 H)-one (1.2 g, 95.9% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:8](=[O:22])[CH2:7]2.Cl[CH2:32][C:33]1[N:34]=[CH:35][N:36]([C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37]=1[CH3:38]>>[CH3:1][C:2]1[C:3]([C:23]2[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:8](=[O:22])[C:7]2([CH2:32][C:33]1[N:34]=[CH:35][N:36]([C:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:37]=1[CH3:38])[CH2:32][C:33]1[N:34]=[CH:35][N:36]([C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37]=1[CH3:38]
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c(-c2ccc(C#N)cc2)ccc2c1N(Cc1cccc3ccccc13)C(=O)C2
Product: Cc1c(-c2ccc(C#N)cc2)ccc2c1N(Cc1cccc3ccccc13)C(=O)C2(Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C)Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C

Procedure:
Following the same procedure as described in example 14A, the reaction of the title compound of 13A (0.191 g, 0.49 mmol) and 4-chloromethyl-5-methyl-1-trityl-1H-imidazole (0.55 g, 1.48 mmol) yielded the title compound of 15A (282.2 mg, 71% yield).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH:12](=O)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:11][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: CCCC=O
Product: CCCCNc1ccc2c(c1)OCCO2
Yield: 90.4 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 1,4-benzodioxan-6-amine (410 μL, 3.31 mmol) and butyraldehyde (300 μL, 3.31 mmol) were converted to the title compound (620 mg, 83%). 1H NMR (CDCl3) δ 6.77-6.58 (m, 1H), 6.28-5.96 (m, 2H), 4.30-4.12 (m, 4H), 3.04 (t, J=7.2 Hz, 2H), 1.65-1.49 (m, 2H), 1.49-1.37 (m, 2H), 0.95 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 208.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][S:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:7]=1)[CH3:2].Cl[C:31]([O:33][CH2:34][CH2:35][Cl:36])=[O:32]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:31]([O:33][CH2:34][CH2:35][Cl:36])=[O:32])=[CH:17][C:16]=2[CH2:22][S:23][CH2:24][C:25]([F:26])([F:27])[F:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CSCC(F)(F)F)c1
Reactant: O=C(Cl)OCCCl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)OCCCl)cc2CSCC(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 6, using the following starting materials: {3-[4-amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and 2-chloroethyl chloroformate.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[N:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.ClCCl>[C:11]1([CH:9]([O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:3]=2)[CH3:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(Oc1cncc(Cl)n1)c1ccccc1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(Oc1cncc(N2CCNCC2)n1)c1ccccc1
Temperature: 90 °C

Procedure:
A mixture of the product from step 1 above (1.53 g, 6.5 mmol), piperazine (1.62 g, 18.9 mmol) and K2CO3 (0.90 g, 6.5 mmol) in acetonitrile (6 mL) was heated in a sealed pyrex flask at 90° C. for 3.5 h. The reaction mixture was diluted with dichloromethane, filtered and concentrated in vacuo. The semi-solid residue was purified by silica gel chromatography (13×4 cm) using CHCl3/MeOH (9:1) as eluent. Solvents were evaporated off and the remaining oil was redissolved in CHCl3, filtered through a short plug of alumina and concentrated in vacuo. This gave 1.34 g (72%) of the title compound as an oil that solidified when refrigerated. HRMS m/z calcd for C16H20N4O (M)+ 284.1637, found 284.1650. Anal. (C16H20N4O.C4H4O4) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([NH:13][C:14]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24]OCCOC)=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH2:31](OCCOCCO)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]CC.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3](=[O:30])[CH:4]([NH:13][C:14]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:15])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1
Reactant: COCCOCCOCCOCCOC(=O)NC(Cc1ccc(O)cc1)C(=O)OC
Reactant: CCCCCCCCCCCCOCCOCCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOCCOCCOC(=O)NC(Cc1ccc(O)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oligomer XXIV was prepared in an analogous manner to that described above for Oligomer XXII. Diethylene glycol monododecyl ether (2.712 g, 9.88 mmol) was dissolved in 100 mL dry acetonitrile. Triethylamine (2.06 mL, 14.8 mmol) and DSC (3.80 g, 14.8 mmol) were added. After stirring for 18 hours at room temperature under an inert atmosphere, the reaction mixture was concentrated in vacuo. The residual oil was taken up in concentrated sodium bicarbonate solution and extracted with EtOAc (2×200 mL). The combined EtOAc layers were washed with water (2×100 mL) and brine (2×100 mL). The organics were dried over Na2SO4, filtered and evaporated to dryness to give 3.58 g (87%) of XXIII.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:26][CH:25]=3)=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH2:38](O)[CH:39]=[CH2:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.C(Cl)Cl>[CH2:40]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:26][CH:25]=3)=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)[CH:39]=[CH2:38]
Reactant: O=c1oc2cc(O)ccc2c(Cc2ccc(OCCN3CCCC3)cc2)c1-c1ccc(C(F)(F)F)cc1
Reactant: C=CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCOc1ccc2c(Cc3ccc(OCCN4CCCC4)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc2c1
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution containing 7-hydroxy-4-{(4-(2-pyrrolidinylethoxy)phenyl)methyl}-3-(4-(trifluoromethyl)phenyl)-2H-chromen-2-one (0.550 g.) in tetrahydrofuran (6 mL) and methylene chloride (6 mL) was added allyl alcohol (0.226 mL) and triphenylphosphine (0.641 g.). Diisopropylazodicarboxylate (0.437 mL) was then added dropwise to the solution. The resultant mixture was allowed to stir for about one hour (or until the starting material was consumed). The solution was concentrated under reduced pressure and extracted with methylene chloride (3×) and water. The organic layers were dried over magnesium sulfate, the magnesium sulfate was filtered and the solvent was concentrated under reduced pressure to provide an orange oil. The oil was purified via silica gel chromatography (6–10% methanol/methylene chloride) to afford 7-prop-2-enyloxy-4-{(4-(2-pyrrolidinylethoxy)phenyl)methyl}-3-(4-(trifluoromethyl) Phenyl)-2H-chromen-2-one (0.245 g., 40% yield). MS (m/z) 550 (M+1)+.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[F:30][C:31]1[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[F:30][C:31]1[CH:36]=[CH:35][C:34]([NH:8][C:9]2[CH:21]=[C:20]([CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:19]=[CH:18][C:10]=2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:33][CH:32]=1
Reactant: Fc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To toluene 10 mL solution of tert-butyl 2-amino-4-phenethylbenzoate 1.0 g were added 1-fluoro-4-iodobenzene 0.98 mL, cesium carbonate 2.2 g, palladium acetate 8 mg and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 21 mg at room temperature, and it was heated and refluxed under nitrogen atmosphere for 6 hours. After the reaction mixture was cooled to room temperature, palladium acetate 8 mg and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 21 mg were added, and it was heated and refluxed under nitrogen atmosphere for 10 hours. After the reaction mixture was cooled to room temperature, water was added to it, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=5:1] to give tert-butyl 2-(4-fluoroanilino)-4-phenethylbenzoate 0.80 g of pale yellow oil.