Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C@H:16]([O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH:12]=2)=[CH:7][CH:6]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:18]([O:17][C@H:16]1[C:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)=[CH:12][CH2:13][NH:14][CH2:15]1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)[C@H](OC(=O)C(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)O[C@@H]1CNCC=C1c1ccc(F)cc1

Procedure:
To a dichloromethane solution (32 mL) of tert-butyl (S)-4-(4-fluorophenyl)-5-(pivaloyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (1.62 g, 4.29 mmol) synthesized in Reference Synthesis Example 136, trifluoroacetic acid (6.5 mL) was added and the resultant mixture was stirred at room temperature for 20 hours. After completion of the reaction, saturated sodium bicarbonate aqueous solution was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound as a crude product.
Reaction SMILES: [C:1](=[O:46])([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[O:2][C@H:3]1[CH2:7][C@H:6]([N:8]2[CH:13]=[C:12]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=4)[O:16][C:11]3=[N:10][C:9]2=[O:28])[O:5][C@@H:4]1[CH2:29][O:30][Si](C(C)(C)C)(C)C.C1CCC(N=C=NC2CCCCC2)CC1.[NH:62]([C:70]([O:72][CH2:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)=[O:71])[C@H:63]([C:67](O)=[O:68])[CH:64]([CH3:66])[CH3:65]>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:73]([O:72][C:70]([NH:62][C@@H:63]([CH:64]([CH3:66])[CH3:65])[C:67]([O:30][CH2:29][C@@H:4]1[C@@H:3]([O:2][C:1]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:46])[CH2:7][C@H:6]([N:8]2[CH:13]=[C:12]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:21][CH:22]=4)[O:16][C:11]3=[N:10][C:9]2=[O:28])[O:5]1)=[O:68])=[O:71])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1
Reactant: CCCCCc1ccc(-c2cc3cn([C@H]4C[C@H](OC(=O)OCc5ccccc5)[C@@H](CO[Si](C)(C)C(C)(C)C)O4)c(=O)nc3o2)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2cc3cn([C@H]4C[C@H](OC(=O)OCc5ccccc5)[C@@H](COC(=O)[C@@H](NC(=O)OCc5ccccc5)C(C)C)O4)c(=O)nc3o2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 25 mL flask was added 53 mg (0.1 mmol) of (2R,3S,5R)-5-(2-oxo-6-(4-pentylphenyl)furo[2,3-d]pyrimidin-3 (2H)-yl)-2-((tert-butyldimethylsilyloxy)methyl)-tetrahydrofuran-3-yl benzyl carbonate, 12 mg (0.1 mmol) of DMAP, 31 mg (0.15 mmol) of DCC, 30 mg (0.12 mmol) of Cbz-Val-OH, and 5 mL of THF. The mixture was stirred at rt for 2 h.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]O)[CH:4]=[N:3][CH:2]=1.S(Cl)([Cl:16])=O>ClCCl>[N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Cl:16])[CH:4]=[N:3][CH:2]=1
Reactant: OCCCCCCc1cncnc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCCCCCCc1cncnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 20.6 g of 5-pyrimidinehexanol in 80 ml of dichloromethane was cooled in an ice bath as a solution of 12.3 ml of thionyl chloride in 40 ml of dichloromethane was added dropwise. The mixture was stirred at room temperature for 1 hour and at reflux temperature for 1 hour, was concentrated, azeotroped with toluene, diluted with dichloromethane and washed with water, saturated sodium bicarbonate, and brine. Evaporation gave 22.3 g of 6-(5-pyrimidinyl)hexylchloride.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)[N:4]=1.[OH-].[Na+].O>C(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[N:4]=1
Reactant: COC(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Yield: 38.7 %

Procedure:
A mixture of methyl 4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoate (600 mg, 1.85 mmol), sodium hydroxide (81 mg, 2.0 mmol), in ethanol (4 ml) and water (4 ml) was stirred at reflux for 1 hour. The reaction mix was allowed to cool and the ethanol was removed under reduced pressure and the residue was partitioned between diethyl ether (10 ml) and water (10 ml). The aqueous layer was separated and made acidic with 2N HCl, then extracted with dichloromethane. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a beige solid (222 mg, 39%)
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=3)=[C:20]([OH:22])[CH:21]=1)=[N:5][CH:6]=[N:7]2.I[CH2:35][CH2:36][CH3:37].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][N:25]=3)=[C:20]([O:22][CH2:35][CH2:36][CH3:37])[CH:21]=1)=[N:5][CH:6]=[N:7]2
Reactant: CCCI
Reactant: Oc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1Oc1cc(C(F)(F)F)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCOc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1Oc1cc(C(F)(F)F)ccn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To a solution of 5-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-(4-trifluoromethylpyridin-2-yloxy)-phenol (0.462 g, 0.5 mmol) in DMSO (5 mL) was added 1-iodopropane (0.204 g, 1.2 mmol) and K2CO3 (0.207 g, 1.5 mmol). The reaction mixture was stirred at 50° C. overnight and then at 70° C. for another 24 h. After cooling to room temperature, the mixture was poured into water and the gum-like material was separated via suction filtration and washed with water. The gum-like product then was partitioned between CH2Cl2 and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo, and the product was purified by preparative reverse phase HPLC to give 0.161 g (32%) of (5,8-difluoroquinazolin-4-yl)-{2-[3-propoxy-4-(4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-amine as a brown gum; MS m/z 504. 1H NMR (CDCl3): δ 8.68 (s, 1H), 8.26 (d, J=4.8 Hz, 1H), 7.33 (m, 1H), 7.08-7.15 (m, 3H), 6.87-7.03 (m, 3H), 6.70-6.83 (br, 1H), 3.89-3.97 (m, 2H), 3.80-3.86 (m, 2H), 3.02 (t, J=6.9 Hz, 2H), 1.51 (m, 2H), 0.66 (t, J=7.2 Hz, 3H). LC/MS: 506.10 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].I[C:29]1[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:21][C:17]1[CH:16]=[C:15]([C:13]2[CH:12]=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:5])=[C:2]([NH:1][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=3)[CH:14]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1N
Reactant: Oc1cccc(I)c1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1Nc1cccc(O)c1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To toluene 3.0 mL suspension of tert-butyl 2-amino-4-(3-chlorophenyl)benzoate 0.12 g and cesium carbonate 0.32 g were added 3-iodophenol 0.17 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.4 mg, tris(dibenzylideneacetone)dipalladium(0) 3.6 mg and palladium acetate 1.8 mg at room temperature, and it was stirred at 110° C. for 24 hours. 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.4 mg, tris(dibenzylideneacetone)dipalladium(0) 3.6 mg and palladium acetate 1.8 mg were added to it, and it was stirred at 110° C. for 21 hours. Cesium carbonate 64 mg, 3-iodophenol 43 mg, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.4 mg, tris(dibenzylideneacetone)dipalladium(0) 3.6 mg and palladium acetate 1.8 mg were added to it, and it was stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=5:1] to give tert-butyl 4-(3-chlorophenyl)-2-((3-hydroxyphenyl)amino)benzoate.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=2)[O:3]1.Br[C:18]1[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=1>>[CH3:23][N:19]1[CH:20]=[CH:21][N:22]=[C:18]1[NH:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)[CH:10]=1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: Cn1ccnc1Br
Product: Cn1ccnc1Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1

Procedure:
A solution of 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (0.5 g, 2.28 mmol) in 2-Bromo-1-methyl-1H-imidazole (0.367 g, 2.28 mmol) was heated in a CEM discover microwave synthesizer (50 W) at 125° C. until the reaction was complete. The reaction mixture was cooled and used directly in the next procedure. MS: [M+H]+ 300
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].[CH3:11][O:12][C:13](=[O:27])[C:14]1[C:15](=[CH:20][C:21]([N+]([O-])=O)=[CH:22][CH:23]=1)[C:16]([O:18][CH3:19])=[O:17]>CN(C=O)C>[CH3:19][O:18][C:16](=[O:17])[C:15]1[C:14](=[CH:23][C:22]([S:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:3])=[CH:21][CH:20]=1)[C:13]([O:12][CH3:11])=[O:27]
Reactant: Nc1ccccc1S
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Sc2ccccc2N)cc1C(=O)OC
Temperature: -25 °C
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
Sodium hydride, 60% dispersion in mineral oil, (0.18 g, 4.5 mmol) was added to a solution of 2-aminothiophenol (0.59 ml, 4.0 mmol) in dry DMF (5 ml) at −20° C. The mixture was stirred at −20 to −30° C. for 10 minutes. A solution of 4-nitrophthalic acid dimethyl ester (0.83 g, 3.5 mmol) in dry DMF (5 ml) was added dropwise. The reaction mixture was stirred at −30° C.±5° C. for 1 hour and then at room temperature for 20 hours, poured into icewater (20 ml) and finally extracted with ethyl acetate (3×25 ml). The combined organic phase was washed with water (25 ml), dried over magnesium sulphate, and evaporated to dryness in vacuo. The crude product was purified on silica gel (eluent: methylene chloride) to give 4-(2-aminophenylsulfenyl)phthalic acid dimethyl ester (yield: 0.56 g (51%)) as a golden oil. 1H—NMR (CDCl3) in ppm: δ 3.85 (3H,s); 3.87 (3H,s); 4.29 (2H,broad s); 6.72-685 (2H,m); 7.07 (1H,d.d.); 7.23-7.34 (2H,m); 7.43 (1H,d.d.): 7.63 (1H,d).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][O:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.Cl.[CH2:20]([NH2:22])[CH3:21]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH2:20][CH3:21])[C:5]2[CH2:10][O:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CCN
Reactant: Fc1ccc(C2OCc3c(Cl)nc(Cl)nc32)cc1
Agent: Cl
Product: CCNc1nc(Cl)nc2c1COC2c1ccc(F)cc1
Yield: 29.7 %

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine (Preparation M) (125 mg, 0.438 mmol) and ethylamine hydrochloride (53.6 mg, 0.658 mmol) were combined and purified as per Preparation Ha to give 2-chloro-N-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine (38.17 mg, 0.130 mmol, 29.6% yield). LC-MS (M+H)+=294.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.24-7.38 (2H, m), 6.92-7.08 (2H, m), 5.73-5.98 (1H, m), 4.83-5.21 (2H, m), 3.36-3.63 (2H, m), 1.13-1.28 (3H, m).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:30][CH2:31][CH3:32]
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Reactant: CCCCBr
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc(CCC(=O)OCC)cc1-c1cc(CCC(=O)OCC)ccc1O
Yield: 87 %

Procedure:
To 3 ml of a DMF solution containing 100 mg (0.2591 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 281.1 μl (2.591 mmol) of butyl bromide, there were added 42.9 mg (0.3109 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 23 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 10 g of WAKO-gel C-200 eluent: hexane and toluene/ethyl acetate of 100/1 and 50/1) to obtain 99.6 mg (0.2253 mmol, 87%) of 2-butoxy-2'-hydroxy-5,5'-bis (2ethoxycarbonylethyl) biphenyl as an oily product.
Reaction SMILES: [F:1][C:2]([F:23])([CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[CH2:3][O:4]C1CCCCO1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[F:23][C:2]([F:1])([CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[CH2:3][OH:4]
Reactant: O=C1c2ccccc2C(=O)N1CC(F)(F)COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CC(F)(F)CO

Procedure:
A solution of 2,2-difluoro-3-phthalimido-1-tetrahydropyranyloxypropane (2 g, 6.15 mmol), paratoluene sulfonic acid (0.1 g) in absolute ethanol was stirred overnight at room temperature. Then the mixture was concentrated in vacuo, diluted with ethyl acetate and washed with brine. The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo. The crude alcohol 2,2-difluoro-3-phthalimido-1-propanol (1.4 g) was used for the next step without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3[C:25](/[CH:26]=[CH:27]\[S:28]([CH3:30])=[O:29])=[CH:24][N:23]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:22]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.ClC1C=CC=C(C(OO)=[O:48])C=1.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3[C:25](/[CH:26]=[CH:27]\[S:28]([CH3:30])(=[O:48])=[O:29])=[CH:24][N:23]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:22]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C\S(C)=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C\S(C)(=O)=O)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a mixture of 2-(2-furyl)-4-({2-methoxy-4-[({4-[(Z)-2-(methylsulfinyl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole (0.20 g) and tetrahydrofuran (20 mL) was added m-chloroperbenzoic acid (0.08 g) at room temperature, and the mixture was stirred at the same temperature for 1 hr. Saturated aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was stirred at room temperature for 10 min, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give 2-(2-furyl)-4-({2-methoxy-4-[({4-[(Z)-2-(methylsulfonyl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.15 g, yield 71%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 158-159° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][C:22](=[O:41])[NH:23][C:24]1[S:25][C:26]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:31]=2)=[C:27]([CH3:29])[N:28]=1)(C)(C)C.Cl>ClCCl>[ClH:36].[NH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][C:22]([NH:23][C:24]1[S:25][C:26]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([S:37]([CH3:40])(=[O:38])=[O:39])[CH:31]=2)=[C:27]([CH3:29])[N:28]=1)=[O:41]
Reactant: Cc1nc(NC(=O)CCOCCOCCOCCOCCNC(=O)OC(C)(C)C)sc1-c1ccc(Cl)c(S(C)(=O)=O)c1
Agent: Cl
Solvent: ClCCl
Product: Cc1nc(NC(=O)CCOCCOCCOCCOCCN)sc1-c1ccc(Cl)c(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2-{2-[2-(2-{2[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylcarbamoyl]-ethoxy}-ethoxy)-ethoxy]-ethoxy}-ethyl)-carbamic acid tert-butyl ester (1.0 g 1.5 mmol) was dissolved in dichloromethane (10 ml) and treated with HCl (4 ml 4M solution in dioxane). The reaction was stirred at room temperature for 3 hours. The solvent was evaporated and the residue dried under vacuum to yield 3-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-N-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2yl]-propionamide hydrochloride as a yellow viscous oil (830 mg residual solvent present) 1H NMR (400 MHz CDCl3) 8.4 (br s, 3H), 8.2 (s, 1H), 7.7 (br d, 1H), 7.6 (br d, 1H) 3.9 (br m, 4H), 3.8-3.6 (br m, 12H), 3.3 (s, 3H), 3.3 (br m, 2H), 3.1 (br m, 2H), 2.6 (s, 3H). NMR spectra were obtained on a Bruker dpx400.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[Cl:31])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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:31][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][C:14]1[CH:32]=[CH:33][C:11]([C:9](=[O:10])[NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([C:38]4[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=4)[N:7]=3)=[CH:12][CH:13]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(Br)n4)cc3)c(Cl)cc21
Reactant: OB(O)c1ccc(Cl)cc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(Cl)cc5)n4)cc3)c(Cl)cc21
Temperature: 100 °C
Reaction time: 12 h
Yield: 94.7 %

Procedure:
Ethyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (50 mg, 0.094 mmol), 4-chlorophenylboronic acid (59 mg, 0.38 mmol), Na2CO3 (30 mg, 0.28 mmol) and Pd(PPh3)4 (11 mg, 0.0094 mmol) were place in a 1 mL vial and diluted with toluene (800 μL) and water (80 μL). The vial was purged with argon, sealed and heated to 100° C. After stirring for 12 hours, the reaction was cooled and loaded directly onto a biotage 25 cartridge eluting with 5% ethyl acetate/hexanes to 60% ethyl acetate/hexanes to yield ethyl 6-chloro-7-(4-(6-(4-chlorophenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (50 mg, 0.089 mmol, 94% yield).
Reaction SMILES: FC(F)(F)C=CC[O:6]C1C=CC(F)=CC=1Br.[F:17][C:18]([F:32])([F:31])[CH:19]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Br:29])[C:23]=1[OH:30])[CH:20]=C.O=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[OH:6][CH:20]1[CH:19]([C:18]([F:32])([F:31])[F:17])[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Br:29])[C:23]=2[O:30]1
Reactant: Fc1ccc(OCC=CC(F)(F)F)c(Br)c1
Reactant: C=CC(c1cc(F)cc(Br)c1O)C(F)(F)F
Agent: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: OC1Oc2c(Br)cc(F)cc2C1C(F)(F)F
Temperature: -78 °C
Reaction time: 64 h

Procedure:
1.0 gm (3.34 mmol) 1-(1-trifluoromethylprop-1-en-3-yloxy)-2-bromo-4-fluorobenzene was heated at 250° C. for 3 hours. The reaction mixture, containing primarily 2-(3-trifluoromethylprop-1-en-3-yl)-4-fluoro-6-bromophenol, was diluted with dichloromethane and the solution cooled to −78° C. This solution was then treated with excess ozone and was stirred at −78° C. until the 2-(3-trifluoromethylprop-1-en-3-yl)-4-fluoro-6-bromophenol was consumed as measured by thin layer chromatography. At this point the ozone was purged from the reaction with oxygen and then 0.88 gm (3.34 mMol) triphenylphosphine were added. The mixture was stored at −20° C. for about 64 hours. The reaction mixture was then concentrated under reduced pressure and the residue subjected to flash silica gel chromatography, eluting with hexane containing 10% ethyl acetate. Fractions containing the desired compound were combined and concentrated under reduced pressure to provide 2-hydroxy-3-trifluoromethyl-5-fluoro-7-bromo-2,3-dihydrobenzofuran. A solution of this dihydrobenzofuran in 10 mL toluene was treated with 4 drops of sulfuric acid and was stirred at reflux for 10 minutes. The reaction mixture was cooled to room temperature and was then washed with saturated aqueous sodium bicarbonate. The organic phase was separated and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with hexane. Fractions containing product were combined and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:38]3[C:33](=[CH:34][C:35]([F:40])=[C:36](F)[CH:37]=3)[C:32](=[O:41])[N:31]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:30]2=[O:50])=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[C:38]3[C:33](=[CH:34][C:35]([F:40])=[C:36]([N:11]4[CH2:12][CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]4)[CH:37]=3)[C:32](=[O:41])[N:31]([O:42][CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:30]2=[O:50])=[CH:27][CH:28]=1
Reactant: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(F)cc32)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Product: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCC(NC(=O)OC(C)(C)C)C4)cc32)cc1
Yield: 86.7 %

Procedure:
Using General Method 4, the reaction of 3-t-butoxycarbonylamino-pyrrolidine (0.28 g, 1.5 mmol), triethylamine (0.2 mL, 1.5 mmol), and 1-(4-methoxyphenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example C-1, 0.2 g, 0.5 mmol) provided 0.25 g of the title compound as a solid.