Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].C1(C)C=CC=CC=1.[CH3:11][O:12][C:13]1[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=[C:28]([CH3:36])[C:14]=1[C:15]([C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[CH:19][C:18]=1Cl)=[O:16].CN(C)P(N(C)C)N(C)C>O>[CH3:11][O:12][C:13]1[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=[C:28]([CH3:36])[C:14]=1[C:15]([C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[CH:19][C:18]=1[O:2][CH3:1])=[O:16]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cncc2C(F)(F)F)c(OC)c1OC
Reactant: C[O-]
Agent: CN(C)P(N(C)C)N(C)C
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(OC)cncc2C(F)(F)F)c(OC)c1OC
Yield: 63.9 %

Procedure:
16.4 g (304 mmol) of sodium methoxide was added to a toluene 150 ml solution of 18.5 g (47.5 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-chloro-5-trifluoromethylpyridine obtained in Step (c) and 16.6 ml (95.4 mmol) of hexamethylphosphorous triamide, followed by stirring under reflux with heating for 30 minutes. Water was added to terminate the reaction, and the aqueous layer was extracted with ethyl acetate. Then, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 11.7 g (yield: 64%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-methoxy-5-trifluoromethylpyridine (melting point: 103 to 106° C.).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][NH:11]2)=O)(C)(C)C.[F:15][C:16]1[CH:17]=C(Br)[CH:19]=[CH:20][CH:21]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[F:15][C:16]1[CH:17]=[C:6]([N:8]2[CH2:13][CH:12]3[CH2:14][CH:9]2[CH2:10][NH:11]3)[CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Reactant: Fc1cccc(Br)c1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(N2CC3CC2CN3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a mixture containing 2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (100 mg, 0.5 mmol), 3-fluoro-phenylbromide (103.8 mg, 0.6 mmol), Pd(AcO) (8 mg, 0.03 mmol), 2-(di-t-butylphosphino)biphenyl (20 mg, 0.07 mmol) and sodium t-butoxide (100 mg, 1 mmol) in toluene (3 mL) was degassed with Ar. The reaction mixture was heated at 50 C for overnight. At the end of reaction, ethyl acetate was added and the mixture was filter through celite. After removal of solvent, TFA was added to the residue. The reaction mixture was stirred at ambient temperature for 1 hour. The excess TFA was removed under vacuum and the residue was purified using prep-HPLC to give desired product (60 mg, 41% yield for two steps) as TFA salt.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[CH3:27]CN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][O:14][C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1

Procedure:
The product (0.867 g) obtained in the above (2) is dissolved in dichloromethane (15 ml), and thereto are added methanol (1.5 ml), 4-dimethylaminopyridine (34 mg) and WSC.HCl (0.633 g) under ice-cooling. The mixture is stirred under ice-cooling for two hours, and then stirred at room temperature for 12 hours. The mixture is concentrated under reduced pressure to the volume of about 5 ml, and the residue is poured into water.
Reaction SMILES: [C:1]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[S:11][C:10]=1[N:16]1[C:20]([CH2:21]Cl)=[N:19][C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:17]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N2CN3CN(C2)C[N:29]1C3>C(O)C>[CH3:14][C:13]1[C:9]2[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:29][CH2:21][C:20]3[N:16]([N:17]=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]=3)[C:10]=2[S:11][C:12]=1[CH3:15]
Reactant: CCOC(=O)c1nc(CCl)n(-c2sc(C)c(C)c2C(=O)c2ccccc2)n1
Reactant: C1N2CN3CN1CN(C2)C3
Solvent: CCO
Product: CCOC(=O)c1nc2n(n1)-c1sc(C)c(C)c1C(c1ccccc1)=NC2

Procedure:
A mixture of ethyl 1-(3-benzoyl-4,5-dimethyl-2-thienyl)-5-chloromethyl-1H-1,2,4-triazole-3-carboxylate, hexamethylenetetramine and ethanol is refluxed for 4 hours in the same manner as in a) to give ethyl 7,8-dimethyl-6-phenyl-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]diazepine-2-carboxylate as colorless plates melting at 173° to 174° C.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH3:9])=[O:5].[C:15](=S)=[S:16].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[I:14][C:11]1[CH:10]=[C:3]2[C:2](=[CH:13][CH:12]=1)[NH:1][C:15](=[S:16])[N:6]([CH2:7][CH2:8][CH3:9])[C:4]2=[O:5]
Reactant: S=C=S
Reactant: CCCNC(=O)c1cc(I)ccc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1c(=S)[nH]c2ccc(I)cc2c1=O
Temperature: 25 °C

Procedure:
To a solution of 2-amino-5-iodo-N-propylbenzamide (1.0 g, 3.1 mmol) and carbon disulfide (0.59 g, 9.38 mmol) in dimethylformamide (3.1 mL) was added potassium carbonate (0.43g, 3.1 mmol). The reaction mixture was heated to reflux for 2 h, cooled to room temperature, and added dropwise to 1N hydrochloric acid (25 mL). The resulting precipitate was filtered, washed with water (2×10 mL), methanol (2×10 mL) and diethyl ether (10 mL), and dried to deliver 1.04 g of the title compound, m.p. 267-269° C.; 1H NMR (300 MHz, Me2SO-d6): δ0.90 (t,3H); 1.68 (m,2H); 4.33 (t,2H); 7.18 (d,1H); 8.04 (dd,1H); 8.19 (d, 1H); 12.98 (s, 1H).
Reaction SMILES: [OH-:1].[K+].[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][N:12]1[C:16]2[CH:17]=[C:18]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:19]=[C:20]([C:21]#[N:22])[C:15]=2[N:14]=[C:13]1[CH3:29].OO>O.C1COCC1>[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][N:12]1[C:16]2[CH:17]=[C:18]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:19]=[C:20]([C:21]([NH2:22])=[O:1])[C:15]=2[N:14]=[C:13]1[CH3:29]
Reactant: Cc1nc2c(C#N)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c(C(N)=O)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Temperature: 50 °C
Yield: 51.1 %

Procedure:
A solution of KOH (78 mg, 1.4 mmol) in water (10 mL) was added dropwise to solution of 1-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole-4-carbonitrile (280 mg, 0.7 mmol) and 30% H2O2 (3 mL) in THF (10 mL) at rt. The mixture was heated at 50° C. for 2 h. When TLC showed no starting material left, the pH of the mixture was acidified to pH ca. 5 and extracted with EtOAc (50 mL×3). The organic layer was washed with brine, dried over MgSO4, concentrated. The resulting residue was purified by silica gel chromatography eluted with EtOAc to give the product (150 mg, 51%), as a white solid. 1H NMR (300 Mhz, DMSO-d6) δ ppm 2.44 (s, 3H), 3.11 (t, 4H, J=4.8 Hz), 3.71 (t, 4H, J=4.8 Hz), 5.60 (s, 2H), 6.31 (d, 1H, J=8.1 Hz), 7.16 (br s, 2H), 7.25 (t, 1H, J=8.1 Hz), 7.35 (d, 1H, J=1.8 Hz), 7.41 (d, 1H, J=1.8 Hz), 7.60 (d, 1H, J=8.1 Hz); LC-MS: m/e=419 [M+1]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: Cc1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)c(Br)c1

Procedure:
A mixture of 18.9 g (100 mmol) of 2-bromo-4-fluorotoluene, 17.8 g (100 mmol) of N-bromosuccinimide, 400 mg of benzoyl peroxide, and 200 ml of CCl4 were refluxed for 2 h. The reaction mixture was filtered through a glass frit (G2), and the precipitate was additionally washed with 3×50 ml of CCl4. The combined filtrate was evaporated to dryness. Fractional distillation of the residue (bp 92-96° C./4 mm Hg) gave the title product as colorless oil. Yield 20.4 g (76%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>C1COCC1>[C:12]([CH:11]([C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=1)[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)#[N:13]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.6 %

Procedure:
Sodium hydride (57.4 g, 60% dispersion in oil, 1.43 mol) was added to a 3 L, 3-necked flask (fitted with mechanical stirrer, exit needle and condenser) and suspended in THF (900 ml). A solution of 3,4-dichlorophenylacetonitrile (257 g, 1.38 mol) in THF (400 ml) was added to the ice-cooled flask via cannula over a period of 1 hour. The mixture was then stirred at room temperature for 1.5 hours during which time there was vigorous gas evolution. The reaction mixture was then ice-cooled and 2-(2-bromoethyl)oxytetrahydropyran (288.5 g, 1.38 mol) was added via teflon cannula under nitrogen pressure over a period of 30 mins. After 40 hours the reaction mixture was quenched with ammonium chloride (10 ml), concentrated (to remove the THF) and water was added. The mixture was extracted with DCM and the organic extracts dried (Na2SO4), concentrated and distilled under reduced pressure (174° C., 100 mtorr) to give an oil. This residue was purified by flash column chromatography (hexane to 1:1, hexane: DCM) to give 2-(3-cyano-3-[3,4-dichlorophenyl]propyl)oxytetrahydropyran as an oil (210 g, 0.67 mol).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[C:1]1([CH2:7][C:8]([N:13]=[C:12]=[S:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N#C[S-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(Cc1ccccc1)N=C=S
Reaction time: 2 h

Procedure:
2-Phenylacetyl chloride (0.180 ml) was dissolved in acetonitrile (20 ml) under a nitrogen atmosphere, and then potassium thiocyanate (197 mg) was added thereto at 50° C., followed by stirring at the same temperature for 2 hrs. The reaction mixture was concentrated under a reduced pressure to give a residue, to which ethyl acetate (20 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml) were then added, followed by stirring for 30 min. The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to provide 2-phenylacetyl isothiocyanate, which was used to prepare a solution in toluene (5 ml)-ethanol (5 ml). To the solution was added 4-(4-amino-2-fluorophenoxy)-2-[(4-hydroxypiperidin-1-yl)carbonylamino]pyridine (168 mg), followed by stirring overnight. The reaction mixture was concentrated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (20 ml) was added to suspend. The resultant solid was filtered off and dried under aeration to provide the titled compound (106 mg, 42%) as white powder.
Reaction SMILES: Br[C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:35])[C@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:13][CH2:12]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C@@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:17](=[O:35])[N:14]2[CH2:15][CH2:16][N:11]([C:3]3[C:2]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:7][N:6]=[C:5]4[NH:8][CH:9]=[CH:10][C:4]=34)[CH2:12][CH2:13]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1
Temperature: 80 °C
Yield: 10 %

Procedure:
(R)-tert-Butyl 1-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-(4-chlorophenyl)-1-oxopropan-2-ylcarbamate (0.180 g, 0.320 mmol, see Example 1), phenylboronic acid (0.0468 g, 0.384 mmol), Pd(PPh3)4 (0.0185 g, 0.0160 mmol) and 10% K2CO3 (aq., 0.66 mL, 0.47 mmol) were added to an Ar degassed solution of 2:1 toluene:EtOH (3 mL). The reaction was then heated to 80° C. overnight. The reaction was then cooled to room temperature, diluted with water, and extracted with DCM. The organic fractions were dried, filtered, concentrated, and purified (500:10-500:15) to give (R)-tert-butyl 3-(4-chlorophenyl)-1-oxo-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propan-2-ylcarbamate (0.018 g, 10.0% yield).
Reaction SMILES: [N:1]([CH:4]([C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])=[CH:49][CH:48]=1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[NH2:1][CH:4]([C:47]1[CH:48]=[CH:49][C:50]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])=[CH:51][CH:52]=1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:7][CH:6]=1
Reactant: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCOc1ccc(C(N=[N+]=[N-])c2ccc(OCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCOc1ccc(C(N)c2ccc(OCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 62.2 %

Procedure:
To azido-bis[4-(12-docosoxydodecyloxy)phenyl]methane (72.0 mg, 58.7 μmol) were added toluene (2 ml), purified water (2 ml), and triphenylphosphine (29 mg, 110 μmol), and the mixture was vigorously stirred at 45° C. for 3 hours and 60° C. for 3.5 hours. The reaction mixture was cooled to room temperature, and 10% aqueous sodium hydrogen carbonate (2 ml) was added. After stirring for a while, toluene (8 ml) was added and the aqueous layer was discarded. The organic layer was washed with purified water (10 ml)×2. The organic layer was evaporated under reduced pressure, and the residue was crystallized from acetonitrile, and the obtained crystals were washed with purified water to give amino-bis[4-(12-docosoxydodecyloxy)phenyl]methane (44 mg, 36.5 μmol, 62%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[CH3:13].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:12][CH3:13])=[O:5]
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Cl)cnc1Cl
Temperature: 130 °C

Procedure:
To a solution of 2,5-dichloronicotinic acid (30 g, 0.16 mol) in toluene (100 ml) was added ethanol (50 ml) and conc. sulfuric acid (1 ml). The reaction mixture was heated at 130° C. for 3 days with stirring. Then the reaction mixture was cooled and poured into sat. sodium bicarbonate solution. The whole mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (sodium sulfate), and concentrated to afford 34 g (quant.) of title compound:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=1)[O:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=[N:5]2.[H-].[Na+].CI.[CH3:31]N(C)C=O>O>[CH3:31][N:12]([C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=1)[O:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]1[CH:6]=[N:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(C)Oc1cccc(Nc2cnc3cc(Cl)ccc3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOC(=O)C(C)Oc1cccc(N(C)c2cnc3cc(Cl)ccc3n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-{3-[N-(6-chloroquinoxalin-2-yl)amino]phenoxy}propionate (10 mmole), sodium hydride (10 mmole), methyl iodide (50 mmole) and dimethylformamide (50 ml) was stirred at room temperature for a period of 3 hours. Water was added to the reaction mixture and the precipitated product was collected by filtration. The product was purified by chromatography over alumina (eluent dichloromethane) to give ethyl 2-{3-[N-methyl-N-(6-chloroquinoxalin-2-yl)amino]phenoxy}propionate as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][N:24]2[C:25](=[O:34])[C:26]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]3[C:28]2=[O:29])=[CH:4][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.8 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (5.00 g), N-hydroxyphthalimide (2.59 g), potassium carbonate (4.40 g) and N,N-dimethylformamide (50 ml) was stirred at room temperature for 20 hours, and water (500 ml) was added. The resultant crystals were filtered, and washed with water to obtain N-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]phthalimide (6.49 g, yield 93%) as colorless crystals. m.p. 155-156° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]=[C:29]=[O:30])[C:23]=1[CH3:31].Cl>C(#N)C>[Cl:21][C:22]1[C:23]([CH3:31])=[C:24]([NH:28][C:29]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[N:7]([CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]2=[O:20])[CH2:6]3)=[O:30])[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1c(Cl)cccc1N=C=O
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Product: Cc1c(Cl)cccc1NC(=O)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 1-chloro-3-isocyanato-2-methyl-benzene (0.13 ml, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding 1-(3-chloro-2-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (400 mg, 91%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4 in H2O: tR=3.23 min (97%); mp. 252-254° C. 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 5H, CHH), 2.25 (s, 3H, CH3), 2.33-2.47 (m, 1H, CHH), 2.61-2.64 (m, 1H, CHH), 2.82-3.01 (m, 1H, CHH), 4.25-4.55 (m, 4H, CH2+CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NC h, 6.98-7.20 (m, 3H, Ar), 7.46 (d, J=7.9 Hz, 1H, Ar), 7.53 (s, 1H, NH), 7.67-7.83 (m, 2H, Ar), 8.02 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.62, 22.49, 31.20, 42.90, 47.12, 51.58, 120.32, 121.96, 123.01, 125.74, 126.78, 126.95, 130.35, 133.39, 139.61, 142.42, 144.61, 155.31, 167.93, 170.99, 172.86. LCMS MH=441. Anal Calcd for: C22H21ClN4O3+0.05HCl: C, 59.69; H, 4.79; N, 12.66; Cl, 8.41. found: C, 59.44; H, 4.57; N, 12.51; Cl, 8.43.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]Br)[C:10]=1/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:44]([Si:48]([CH3:57])([CH3:56])[O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH:54]=O)([CH3:47])([CH3:46])[CH3:45]>C(#N)C.O1C(CC)C1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH:54][CH2:53][CH2:52][CH2:51][CH2:50][O:49][Si:48]([C:44]([CH3:45])([CH3:47])[CH3:46])([CH3:57])[CH3:56])[C:10]=1/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:2]
Reactant: CCOC(=O)/C=C/c1c(CBr)cccc1OCCCC(=O)OCC
Reactant: CC(C)(C)[Si](C)(C)OCCCCC=O
Agent: CCC1CO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)/C=C/c1c(C=CCCCCO[Si](C)(C)C(C)(C)C)cccc1OCCCC(=O)OCC
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A solution of 4-[3-bromomethyl-2-((E)-2-ethoxycarbonyl-vinyl)-phenoxy]-butyric acid ethyl ester (2.0 mmol, 798 mg) and triphenylphosphine (2.2 mmol, 577 mg) in acetonitrile (12 mL) was heated to reflux for 1 h under nitrogen atmosphere. Then, it was cooled to room temperature and a solution of 5-(tert-butyl-dimethyl-silanyloxy)-pentanal (2.8 mmol, 606 mg) in 1,2-epoxybutane (22 mL) was added at room temperature and the mixture was again heated to reflux for 15 h. During this period, the mixture first turned to a brick red color and at the end of the reaction it had become a pale yellow solution. Then, the reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was dissolved in a solution of ethyl acetate and hexanes (1:3, 150 mL) and the resulting cloudy solution was washed with a mixture of methanol and water (2:1, 225 mL). The aqueous layer was extracted one more time with ethyl acetate and hexanes (1:3, 50 mL). The combined organic extracts were washed with brine solution (150 mL) and the organic solution was dried over anhydrous magnesium sulfate. Filtration of the drying agent and the removal of the solvent gave light brown oil. The crude mixture was purified by using a Biotage™ (40 L) column chromatograph eluting with 5 and 15% ethyl acetate in hexanes to obtain the desired 4-[3-[6-(tert-butyl-dimethyl-silanyloxy)-hex-1-enyl]-2-((E)-2-ethoxycarbonyl-vinyl)-phenoxy]-butyric acid ethyl ester (760 mg, 74%) as a colorless oil: ES(+)-HRMS m/e calculated for C29H46O6Si (M+Na)+ 541.2956, found 541.2953.