Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:12])[C:10]#[N:11].O.Cl.[O:15]1CCOCC1>C(OCC)(=O)C>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:12])[C:10]([NH2:11])=[O:15]
Reactant: N#CC(=O)c1ccccc1CCl
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)C(=O)c1ccccc1CCl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Crude 2-(2-chloromethylphenyl)-2-oxoacetonitrile (purity: about 72%)(17.6 g), water (1.76 g) and 5N hydrogen chloride/dioxane solution (200 ml) were added into a round-bottom flask. The flask was stoppered, and then the mixture was stirred at room temperature for 3 days. After the reaction mixture was ice-cooled, water (150 ml) was added, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was diluted with ethyl acetate, and washed successively with a saturated aqueous solution of sodium bicarbonate, water and saturated brine. The ethyl acetate layer obtained was dried over anhydrous sodium sulfate and at the same time decolorized with Norit SX-3. Evaporation of the solvent under reduced pressure gave the crude product (16.6 g). The crude product was crystallized from ethyl acetate-hexane, and the crystallization mother liquor was purified by column chromatography on silica gel to obtain the title compound (11.3 g, total yield in the two steps: 57.3%, pale yellow crystals).
Reaction SMILES: [F:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[C:4]([N+:23]([O-])=O)[CH:3]=1.O.NN>C(O)C.[Ni]>[NH2:23][C:4]1[CH:3]=[C:2]([F:1])[C:7]([Br:8])=[CH:6][C:5]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)c(F)cc2[N+](=O)[O-])CC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)c(F)cc2N)CC1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl 4-[(4-fluoro5-bromo-2-nitrophenyl)amino]-piperidinecarboxylate (D43) (0.91 g, 2.2 mmole) was suspended in ethanol (25 ml) and Raney nickel (50% aqueous suspension, 100 mg) was added at room temperature; the mixture was heated to 45° C. and hydrazine monohydrate (3.0 ml) was added over 10 min. After 1 hr more, the reaction mixture was cooled to room temperature, filtered through Celite and the solvent was evaporated to yield the title compound as an orange brown gum, 0.83 g, 98%. LC/MS—96% m/e 388/390 (M+H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: OB(O)c1cccs1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: c1csc(-c2nccs2)c1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
2-Bromothiazole (15.0 g) and 2-thiopheneboronic acid (14.0 g) were dissolved in dimethoxyethane (150 ml). To the mixture was added bis(triphenyl)phosphine palladium(II)dichloride (3.2 g) and 2M sodium carbonate (137 ml), and the mixture was refluxed under argon atmosphere for 2 hours. The mixture was cooled to room temperature, and the reaction solution was diluted with ethyl acetate, and washed with water. The organic layer was collected, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=96:4) to give 2-(2-thienyl)thiazole (9.87 g) as oil. APCI-Mass m/z 168 (M+H) (2) The above compound (3.17 g) was treated in a manner similar to Reference Example 121 to give 5-fluoro-2-(2-thienyl)thiazole (1.58 g) as oil. APCI-Mass m/z 186 (M+H) (3) The above compound (1.58 g) was dissolved in chloroform (16 ml), cooled to 0° C., and thereto was added dropwise a solution of bromine (1.43 g) in chloroform (15 ml). The mixture was stirred at the same temperature for one hour, warmed, and further stirred at room temperature for one hour. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The extract was washed with 10% aqueous sodium thiosulfate solution, brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3) to give 2-(5-bromo-2-thienyl)-5-fluorothiazole (1.81 g) as a pale yellow solid. (4) The above compound (300 mg) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were used and treated in a manner similar to Reference Example 7 to give the desired 5-bromo-2-chloro-1-(5-(5-fluorothiazol-2-yl)-2-thienylmethyl)benzene (199 mg) as a pale yellow powder.
Reaction SMILES: [CH:1]([N:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=O)=[CH:6][C:5]1=[O:13])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:36][CH2:37][C:38]1[C:39]([OH:46])=[N:40][C:41]([CH3:45])=[CH:42][C:43]=1[CH3:44]>ClCCl.C(N(CC)CC)C>[OH:46][C:39]1[C:38]([CH2:37][NH:36][C:10]([C:7]2[CH:8]=[CH:9][N:4]([CH:1]([CH3:2])[CH3:3])[C:5](=[O:13])[CH:6]=2)=[O:12])=[C:43]([CH3:44])[CH:42]=[C:41]([CH3:45])[N:40]=1
Reactant: CC(C)n1ccc(C(=O)O)cc1=O
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccn(C(C)C)c(=O)c2)c(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (50 mg, 0.28 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (95 mg, 0.5 mmol), 1-Hydroxybenzotriazole (67 mg, 0.5 mmol), triethylamine (0.1 mL) in dichloromethane (5 mL) were stirred at 25° C. for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (50 mg, 0.33 mmol) was added to the above mixture. The mixture was stirred at 25° C. overnight and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxamide (31 mg, 35%) as a white solid. LRMS (M+H+) m/z: 315.16. found 315. HPLC Purity (214 nm): 100%. 1H NMR (300 MHz, DMSO): δ 11.48 (d, J=4.2 Hz, 1H), 8.53 (t, J=5.1 Hz, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 6.56-6.53 (m, 1H), 5.85 (s, 1H), 5.03-4.98 (m, 1H), 4.24 (d, J=5.1 Hz, 2H), 2.14-2.09 (m, 6H), 1.28-1.22 (m, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]4[CH:27]=[C:28]([C:30]5[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=5)[S:29][C:22]=34)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1>>[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]4[CH:27]=[C:28]([C:30]5[CH:37]=[CH:36][C:33]([CH2:34][NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:10])[CH3:1])=[CH:32][CH:31]=5)[S:29][C:22]=34)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1
Reactant: O=Cc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: CN(C)CCCCCCN
Product: CN(C)CCCCCCNCc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from N,N-dimethyl-hexane-1,6-diamine and 4-[7-(1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-benzaldehyde by a procedure analogous to example 17. LC-MS: 498 (MH+); HPLC RT: 3.93 minutes.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17](O)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:24])=O.CCOC(C)=O>CN(C=O)C>[Cl:24][C:17]1[CH:18]=[CH:19][N:14]([C:11]2[CH:12]=[CH:13][C:6]3[N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:8]([CH3:9])[C:7]=3[CH:10]=2)[C:15](=[O:21])[CH:16]=1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(Cl)cc3=O)cc21
Temperature: 47.5 °C
Reaction time: 26 h

Procedure:
To a suspension of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (75 g) in DMF (1.3 L) was added phosphorus oxychloride (29.8 ml) at room temperature, and the mixture was stirred at 45-50° C. under Ar atmosphere for 26 h. The mixture was poured into EtOAc (1.5 L), and washed with saturated NaHCO3 solution (1.5 L). The organic layer was separated, and aqueous layer was extracted with EtOAc (2.0 L) two times. The combined organic layer was washed with brine (1.0 L), dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in EtOAc/THF (1/1, 700 ml), and NH silica gel (100 g) was added to the solution. The mixture was filtered through a plug of NH silica gel (500 g) with EtOAc as an eluent to give the title compound (47.0 g) as a pale yellow solid.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.[H-].[Na+].Cl[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1>C1COCC1>[CH:1]1([O:6][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: COc1ccc(CCl)cc1
Reactant: OC1CC=CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COC2CC=CC2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of cyclopent-3-en-1-ol (CAS number 14320-38-8; 15 g, 178 mmol) in dry THF (357 ml) at 0° C. under nitrogen was added sodium hydride (60%, 9.27 g, 232 mmol). After fizzing had ceased, to this was then added drop wise 1-(chloromethyl)-4-methoxybenzene (CAS number 824-94-2; 31.4 ml, 232 mmol). The reaction was allowed to warm to room temperature and stirred for 17 hours then quenched by the addition of methanol and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-50% DCM/petrol) to afford the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:9]1)=O)(C)(C)C.[ClH:30].CCOCC>CO>[ClH:30].[ClH:30].[C:24]1([N:21]2[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:14][CH:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[O:17])[CH2:19][CH2:20]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(COC(=O)N2CCN(c3ccccc3)CC2)C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=C(OCC1CNCCO1)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 2-(4-phenylpiperazine-1-carbonyloxymethyl)-morpholine-4-carboxylic acid tert-butyl ester (6.67 g, 16.5 mmol) in MeOH (10 mL) was added 2M HCl in Et2O solution (16.5 mL, 32.9 mmol). The brown solution was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×26 mm (100 g), 30 mL/min, gradient 0% to 15% (over 75 min) MeOH in water with 0.1% TFA). The pure sample was stirred in a 4M aq HCl solution (20 mL) overnight before being concentrated in vacuo. The resulting yellow oil was washed with heptane, concentrated in vacuo and dried in a vacuum oven overnight to give the morpholin-2-ylmethyl 4-phenylpiperazine-1-carboxylate dihydrochloride salt (4.72 g, 76%) as a pale yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[CH2:5][CH2:6][NH:7][C:8]([CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)=[O:9].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][C:32](O)=[O:33])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:2][O:3][C:4](=[O:16])[CH2:5][CH2:6][NH:7][C:8]([CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:32](=[O:33])[CH2:31][CH2:30][CH:27]2[CH2:26][CH2:25][N:24]([C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH2:29][CH2:28]2)[CH2:11]1)=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Reactant: COC(=O)CCNC(=O)C1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCNC(=O)C1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 0 °C
Yield: 77.2 %

Procedure:
To a mixture of N-[(3-piperidyl)carbonyl]-β-alanine methyl ester hydrochloride (1.57 g),3-(1-tert-butoxycarbonyl-4-piperidyl)propionic acid (1.61 g) and 1-hydroxybenztriazole (0.96 g) in N,N-dimethylformamide (16 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.14 ml) under stirring at 0° C. After stirring at ambient temperature for 1 hour, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, brine and dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with (CHCl3:MeOH 100:1) to give N-[1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-β-alanine methyl ester as an oil (2.19 g).
Reaction SMILES: [N+:1]([CH:4]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[CH2:8][CH:7]=[CH:6][CH2:5]1)([O-:3])=[O:2].[H][H]>C(OCC)(=O)C.[Pd]>[N+:1]([CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)([O-:3])=[O:2]
Reactant: [H][H]
Reactant: COc1ccc(C2CC=CCC2[N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(C2CCCCC2[N+](=O)[O-])cc1OC
Yield: 91 %

Procedure:
To 10 mmol of 4-nitro-5-(3,4-dimethoxyphenyl)cyclohexene in 100 mL of ethyl acetate was added 200 mg of 10% palladium on carbon. The resulting suspension was shaken at 50 psi of hydrogen on a Parr Apparatus for one hour. The catalyst was removed by filtration through Celite® diatomaceous earth and the filtrate evaporated to dryness in vacuo to give a 91% yield of the desired product based on 1H NMR.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][C:13]3([CH3:26])[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][C:13]3([CH3:26])[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC1(NCc2ccc3c(c2)OCCO3)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(NCc2ccc3c(c2)OCCO3)CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5 mL of a dichloromethane solution containing 0.66 g of tert-butyl 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-4-methylpiperidine-1-carboxylate, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and thereto were added chloroform, water and 6 mol/L hydrochloric acid. The aqueous layer was separated, and the aqueous layer was washed with chloroform. Chloroform was added to the aqueous layer, and the resultant solution was adjusted to pH 13 with a 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.26 g of a colorless oily substance, N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylpiperidine-4-amine.
Reaction SMILES: [I:1]I.[Br:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12]>S([O-])([O-])(=O)=O.[Ag+2].C(O)C>[Br:3][C:4]1[C:5]([C:11]([F:12])([F:13])[F:14])=[CH:6][C:7]([NH2:8])=[C:9]([I:1])[CH:10]=1
Reactant: II
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)c(Br)cc1I
Temperature: 25 °C

Procedure:
Iodine (1.4 g, 5.5 mmol, 1.1 eq.) was gradually added to a mixture solution of 4-bromo-3-trifluoromethyl aniline (1.2 g, 1.0 mmol), silver sulfate (1.72 g, 5.5 mmol, 1.1 eq.), and anhydrous ethanol (35 ml). This was stirred at room temperature for two and half hours. The reaction mixture was filtered through Celite, and washed with ethyl acetate. The wash solution was washed with aqueous solutions of 10% sodium thiosulfate, saturated sodium bicarbonate, and saturated sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and concentration was performed. Crude solid 4-bromo-2-iodo-5-trifluoromethyl-phenylamine was obtained by concentration under reduced pressure. The resulting crude product was used in subsequent reactions without being purified.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([F:12])[CH:5]=1>CO.O>[F:12][C:6]1[CH:5]=[C:4]([CH2:3][CH:2]=[O:1])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(CC(O)CO)cc1F
Solvent: CO
Solvent: O
Product: N#Cc1ccc(CC=O)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-(2,3-dihydroxypropyl)-2-fluorobenzonitrile (500 mg, 2.6 mmol) in 10 mL of methanol and 3 mL of water was cooled to 0° C. by ice bath, then NaIO4 (820 mg, 3.8 mmol) was added and the mixture was stirred at 0° C. for two hours. The reaction was monitored according to TLC. The mixture was filtered and concentrated. The residue was dissolved in DCM, dried over anhydrous sodium sulfate, and then purified by flash column chromatography to give 2-fluoro-4-(2-oxoethyl)benzonitrile. MS m/z: 164 (M+1)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC([CH:27]1[CH2:32][NH:31][CH2:30][CH2:29][N:28]1[CH:33](O)[CH3:34])=O)(C)(C)C.CCOC(/N=N/C(OCC)=O)=O.O1CCCCC1[N:54]1[C:62]2[C:57](=[CH:58][C:59]([C:63]3[N:67]=[CH:66][N:65](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:64]=3)=[CH:60][CH:61]=2)[C:56]([C:87]2[CH:88]=[C:89]([OH:93])[CH:90]=[CH:91][CH:92]=2)=[N:55]1.Cl>O1CCCC1>[NH:64]1[C:63]([C:59]2[CH:58]=[C:57]3[C:62](=[CH:61][CH:60]=2)[NH:54][N:55]=[C:56]3[C:87]2[CH:92]=[CH:91][CH:90]=[C:89]([O:93][CH2:34][CH2:33][N:28]3[CH2:27][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:88]=2)=[N:67][CH:66]=[N:65]1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CC(O)N1CCNCC1C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCN2CCNCC2)cc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 51.2 %

Procedure:
Triphenylphosphine (0.694 g, 2.65 mmol), tetrahydrofuran (2.12 mL), 2-(tert-butyloxycarbonyl)piperazinylethanol (0.610 g, 2.65 mmol) and diethylazodicarboxylate (0.418 mL, 2.65 mmol) were added to 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenol (0.400 g, 0.662 mmol). The mixture was stirred at ambient temperature for 23 h and poured into aqueous 6N hydrochloric acid (25 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ether (3×). The aqueous fraction was added to aqueous 6 N sodium hydroxide (25 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC (5-70% acetonitrile/water). The desired fractions were concentrated, dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (0.132 g, 52% yield) as the bis-trifluoroacetic acid salt. 1H NMR (D2O) δ 8.26 (s, 1H), 8.12 (s, 1H), 7.61 (d, 1H), 7.37 (d, 1H), 7.31 (m, 2H), 7.19 (m, 1H), 6.90 (m, 1H), 4.35 (m, 2H), 3.62 (m, 6H), 3.52 (m, 4H). ES-MS (m/z) 390 [M+1]+.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[C:13]([CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)#[N:14].IC>C1COCC1>[C:13]([C:15]1([CH3:1])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)#[N:14]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C#N)CN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Yield: 32.5 %

Procedure:
To an oven-dried 25 mL round bottom flask equipped for stirring was added diisopropylamine (1.318 mL, 9.33 mmol) under nitrogen. THF (10 mL) was added and the colorless solution was cooled to 0° C. n-BuLi in hexanes (1.6N, 5.83 mL, 9.33 mmol) was added dropwise and the solution was stirred at 0° C. for 30 min. The solution was cooled to −78° C. and a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (1 g, 5.49 mmol) in THF (3 mL) was added and the solution was stirred at −78° C. for 30 min. Iodomethane (0.445 mL, 7.13 mmol) was added dropwise at −78° C. The reaction mixture was stirred for 30 min; it was then allowed to slowly warm up to 25° C. and was stirred for 16 h. The reaction mixture was quenched at 0° C. with aqueous ammonium chloride (5 mL) and was extracted with DCM (3 times). The extracts were dried over Na2SO4. Purification by silica column chromatography (MeOH/DCM, 0-5%) afforded the title compound as a yellow oil (0.35 g, 32%). 1H NMR (500 MHz, CDCl3) δ 1.45 (s, 9 H) 1.67 (s, 3 H) 3.80 (d, J=8.30 Hz, 2 H) 4.29 (d, J=8.79 Hz, 2 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:18]2[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=2[O:25][CH2:26][CH3:27])[N:3]=1.[N:28]1([OH:37])C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.NO.C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:28][OH:37])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:18]2[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=2[O:25][CH2:26][CH3:27])[N:3]=1
Reactant: On1nnc2ccccc21
Reactant: CCOc1ccc(Br)cc1-c1cc(Nc2ccc(C(=O)O)cc2)nc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1ccc(Br)cc1-c1cc(Nc2ccc(C(=O)NO)cc2)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a stirred solution of 4-[2-amino-6-(5-bromo-2-ethoxy-phenyl)-pyrimidin-4-ylamino]-benzoic acid (0.086 g, 0.20 mmol) in dimethylformamide (3.0 ml) was added benzotriazol-1-ol (0.054 g, 0.40 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.086 g, 0.44 mmol). After stirring at room temperature for 1 hour, hydroxylamine hydrochloride (0.070 g, 1.0 mmol) was added followed by triethylamine (0.1 g, 1.0 mmol). After stirring for 16 hours, the solvent was evaporated under reduced pressure and the residue was treated with 1 M aqueous sodium carbonate solution (10 ml). Filtration provided the title compound (0.065 g, 73% yield) as a light brown solid. 1H NMR (DMSO-d6) δ 1.38 (t, 3H, J=6.9 Hz, CH3), 4.12 (q, 2H, J=6.9 Hz, CH2), 6.32 (s, 2H, NH2), 6.79 (s, 1H, Ar), 7.08 (d, 1H, J=8.9 Hz, Ar), 7.52 (dd, 1H, J=8.9 Hz, J=2.6 Hz, Ar), 7.66 (b, 4H, Ar), 8.04 (d, 1H, J=2.6 Hz, Ar), 9.24 (s, 1H, NH).
Reaction SMILES: [C:1]([O:4]C1C=C(Cl)C(OC2C=CC(NC(=O)C)=C(Br)C=2)=C(Cl)C=1C)(=[O:3])[CH3:2].C(O[C:30]1[CH:35]=[C:34]([Cl:36])[C:33]([O:37][C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:45](=[O:47])[CH3:46])=[C:40]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:39]=2)=[C:32]([Cl:54])[C:31]=1C)(=O)C>>[Cl:36][C:34]1[CH:35]=[C:30]([CH2:2][C:1]([OH:4])=[O:3])[CH:31]=[C:32]([Cl:54])[C:33]=1[O:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45](=[O:47])[CH3:46])=[C:40]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:39]=1
Reactant: CC(=O)Nc1ccc(Oc2c(Cl)cc(OC(C)=O)c(C)c2Cl)cc1-c1ccccc1
Reactant: CC(=O)Nc1ccc(Oc2c(Cl)cc(OC(C)=O)c(C)c2Cl)cc1Br
Product: CC(=O)Nc1ccc(Oc2c(Cl)cc(CC(=O)O)cc2Cl)cc1-c1ccccc1
Yield: 66.4 %

Procedure:
Methyl[3,5-dichloro-4-(4-acetamido-3-bromophenoxy)phenyl] acetate (100 mg) was coupled with n-tributylphenyltin (140 mg, 0.38 mmol), using the same procedure as described in Example 3(a). This gave 70 mg (70%) of methyl(3,5-dichloro-4-[4-acetamido-3-phenylphenoxy]phenyl) acetate. A part of the obtained ester (50 mg) was hydrolysed using the method described in Example 1(i), to give 45 mg (95%) of 3,5-dichloro-4-(4-acetamido-3-phenylphenoxy)phenylacetic acid, m/z 430.