Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32]>>[C:13]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Reactant: COc1ccccc1Br
Product: COc1ccccc1C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1

Procedure:
This compound was prepared by method C using compound 12a and 2-bromoanisole. HRMS (ESI+): m/z=355.1459 [M+H]
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C1(SC)C=CC=CC=1.[OH:16][C:17]1[CH:18]=[C:19]([N:24]2[CH2:28][CH2:27][N:26]([S:29]([NH:32][C:33]([N:35]3[CH2:38][C@H:37]([NH:39]C(=O)OCC4C=CC=CC=4)[C:36]3=[O:50])=[O:34])(=[O:31])=[O:30])[C:25]2=[O:51])[CH:20]=[CH:21][C:22]=1[OH:23]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:39][C@H:37]1[CH2:38][N:35]([C:33]([NH:32][S:29]([N:26]2[CH2:27][CH2:28][N:24]([C:19]3[CH:20]=[CH:21][C:22]([OH:23])=[C:17]([OH:16])[CH:18]=3)[C:25]2=[O:51])(=[O:30])=[O:31])=[O:34])[C:36]1=[O:50]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)N2CCN(c3ccc(O)c(O)c3)C2=O)C1=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: N[C@H]1CN(C(=O)NS(=O)(=O)N2CCN(c3ccc(O)c(O)c3)C2=O)C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 16 ml of trifluoroacetic acid and 4 ml of thioanisole was cooled to 0° C., and 4 g (7.7 mmol) of (S)-[1-[[[[3-(3,4-dihydroxyphenyl)-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester was added. The mixture was stirred overnight at room temperature, evaporated in vacuo, and the residue triturated with ether. The precipitate was filtered off by suction, washed with ether, dichlormethane and isopropanol and dried in vacuo; yield: 3.19 g.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[CH:4]1[CH2:10][CH2:9][CH:8]2[CH:6]([CH2:7]2)[CH2:5]1.[CH:12]1([C:15](=O)[CH2:16][C:17]([O:19]C)=[O:18])[CH2:14][CH2:13]1>>[CH:6]12[CH2:7][CH:8]1[CH2:9][CH2:10][CH:4]([C:3]1[C:16]([C:17]([OH:19])=[O:18])=[C:15]([CH:12]3[CH2:14][CH2:13]3)[O:1][N:2]=1)[CH2:5]2
Reactant: COC(=O)CC(=O)C1CC1
Reactant: ON=C(Cl)C1CCC2CC2C1
Product: O=C(O)c1c(C2CCC3CC3C2)noc1C1CC1

Procedure:
3-(Bicyclo[4.1.0]heptan-3-yl)-5-cyclopropylisoxazole-4-carboxylic acid (I-12F) was prepared from N-hydroxybicyclo[4.1.0]heptane-3-carbimidoyl chloride and methyl 3-cyclopropyl-3-oxopropanoate following the same protocol as described for I-6E. MS m/z 248.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]([F:29])([F:28])[O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([F:17])([C:14](=[O:16])[NH:25][C:24]2[CH:26]=[CH:27][C:21]([O:20][C:19]([F:18])([F:28])[F:29])=[CH:22][CH:23]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C(=O)O)CC1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: CC(C)(C)OC(=O)N1CCC(F)(C(=O)Nc2ccc(OC(F)(F)F)cc2)CC1
Yield: 68.9 %

Procedure:
In analogy to example 1 from 4-fluoro-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.565 g), synthesis described in WO2008/98977, and 4-trifluoromethoxy-aniline (0.405 g) there as obtained 4-fluoro-4-(4-trifluoromethoxy-phenylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (0.64 g) as an off white solid. MS (ESI): 405.1 ([M-H]−).
Reaction SMILES: O[N:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:16]([CH3:17])[C:15]4[CH:18]=[CH:19][C:20]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[O:23])=[CH:21][C:14]=4[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[H][H].Cl>[Pd].CO>[NH2:2][CH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:16]([CH3:17])[C:15]4[CH:18]=[CH:19][C:20]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[O:23])=[CH:21][C:14]=4[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc3c(c1)CCC3=NO)n2C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc3c(c1)CCC3N)n2C

Procedure:
Prepared from 2-(1-hydroxyimino-5-indanyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-1-methyl-benzimidazole by reduction with 5 bars of hydrogen in a 50:1 mixture of methanol and methanolic hydrochloric acid at ambient temperature in the presence of 10% palladium/charcoal.
Reaction SMILES: OC[CH2:3][CH2:4][C:5]1[NH:6]C=CN=1.N1C=CC=C(N=C=O)C=1.[C:19]([NH:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][C:29]1[N:30]=[C:31]([F:53])[N:32]([C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=1)=[O:24])(=O)[CH3:20]>>[F:53][C:31]1[N:32]([C:34]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:33]=[C:29]([CH2:28][CH2:27][CH2:26][O:25][C:23](=[O:24])[NH:22][C:19]2[CH:20]=[N:6][CH:5]=[CH:4][CH:3]=2)[N:30]=1
Reactant: OCCCc1ncc[nH]1
Reactant: CC(=O)NC(=O)OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: O=C=Nc1cccnc1
Product: O=C(Nc1cccnc1)OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
A solution of the hydroxypropylimidazole was treated with 3-pyridylisocyanate as for the starting material of Example 12, to give 2-fluoro-4-[3-(pyrid-3-yl)carbamoyloxypropyl]-1-triphenylmethylimidazole having the following n.m.r. spectrum in CDCl3 : 1.97 (m, 2H); 2.5 (t, 2H); 4.16 (t, 2H); 6.25 (s, 1H); 6.9 (br s, 1H); 7.0-7.5 (m, 15H); 7.7-8.6 (m, 4H).
Reaction SMILES: [CH:1](C(OC)(F)F)([C:6]([F:9])([F:8])[F:7])[C:2]([F:5])([F:4])[F:3].CCOCC.C1(C)C=CC=CC=1>[Ni].O>[CH2:1]([C:6]([F:9])([F:8])[F:7])[C:2]([F:5])([F:4])[F:3]
Reactant: COC(F)(F)C(C(F)(F)F)C(F)(F)F
Agent: [Ni]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: FC(F)(F)CC(F)(F)F

Procedure:
A 100 g mixture containing 59.0% (CF3)2CHCF2OCH3 (ether A), 20% (CF3)2C=CFOCH3 (ether B), 15.9% toluene and 150 mL water was heated in a Hastelloy™ nickel alloy tube for 3 hours at 135° C. and 6 hours at 200° C. The volatiles were bubbled through a solution of aqueous NaOH and a CaSO4 drying column, and condensed in a dry ice cooled trap to give 12.9 g HFC-236fa identified by its infrared spectrum. The liquid contents of the tube contained two layers. The upper layer, 14.9 g, was shown by 1H and 19F NMR spectroscopy to contain 16.5 wt. percent HFC-236fa and toluene. The combined HFC-236fa from the volatiles and the toluene corresponded to a yield of 15.4 g, 29.0% based on the starting ethers.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].O>O1CCCC1.CN(C)C=O>[CH2:43]([O:42][C:40](=[O:41])[CH2:39][N:33]1[CH2:34][CH2:35][CH:30]([CH2:29][O:28][C:22]2[CH:21]=[C:20]3[C:25]([CH2:26][CH2:27][N:18]([C:9](=[N:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19]3)=[CH:24][CH:23]=2)[CH2:31][CH2:32]1)[CH3:44]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCNCC3)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CN1CCC(COc2ccc3c(c2)CN(C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N,N′-di-tert-butoxycarbonyl-7-(piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in a mixture of tetrahydrofuran (1 ml) and dimethylformamide (1 ml) were added 9.1N aqueous sodium hydroxide solution (0.027 ml) and ethyl bromoacetate (0.027 ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:acetone=4:1) and dried under reduced pressure to give the title compound (100 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>CCOCC>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: CO
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of 2,6-dichloronicotinic acid (20.2 g, 0.105 mol) in MeOH (500 mL) was cooled to 0 ° C. and neat thionyl chloride (38 mL, 63 g, 0.525 mol) was added over ˜0.5 hours. The reaction mixture was stirred at 0° C. for 1 hour. The cooling bath was removed, the reaction temperature was allowed to warm to 25° C., and the reaction was allowed to stir for an additional 2 days at 25° C. The solvent was removed under reduced pressure to give an off-white residue. The residue was dissolved in Et2O (˜500 mL) and the resulting solution was washed successively with saturated aqueous NaHCO3 solution (˜300 mL), water (˜300 mL), and brine solution (˜300 mL). The organic layer was separated, dried over anhydrous MgSO4, and filtered. Removal of the solvent under reduced pressure yielded methyl 2,6-dichloronicotinate (21.0 g, 97%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1(S(C2ON2C2C=CC=CC=2)(=O)=[O:36])C=CC=CC=1>C1COCC1>[OH:36][CH:5]1[CH2:4][CH2:3][CH2:2][CH:1]1[CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8]
Reactant: COc1ccc(COC(=O)CC2CCCC2)cc1
Reactant: O=S(=O)(c1ccccc1)C1ON1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)CC2CCCC2O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.7 %

Procedure:
A solution of 450 mg (1.81 mmol) of cyclopentylacetic acid, 4-(methoxy)benzyl ester (from EXAMPLE 15, Step A) in 6 mL of THF was added to 2.15 mL of 1.0 M sodium bis(trimethylsilyl)amide solution in THF at −78° C. and the resulting mixture was stirred cold for 15 min. A solution of 700 mg (2.67 mmol) of (benzenesulfonyl)phenyloxaziridine in 3 mL of THF was the added and the resulting mixture was stirred at −78° C. for 1 h. The reaction was quenched with sat'd NH4Cl and warmed to rt. The mixture was concentrated and the residue was dissolved in 100 mL of ether and washed with 100 mL of sat'd NaCl. The phases were separated and the aqueous layer was extracted with 100 mL of ether. The combined organic layers were dried over MgSO4 and concentrated. Flash chromatography on silica gel using 9:1 v/v hexanes/EtOAc as the eluant afforded 233 mg (48%) of the title compound: RF: 0.37 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 1.36-1.69 (m, 8H), 2.22 (m, 11H), 3.81 (s, 3H), 4.14 (d, J=4.9, 11H), 5.14 (ABq, J=11.8, 2H), 6.89 (d, J=8.8, 2H), 7.29 (d, J=8.8, 2H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19].CCN=C=NCCCN(C)C.Cl.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.C1COCC1>[C:1]1([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:20][CH2:17][CH2:18][CH3:19])=[O:14])=[CH:15][CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(Nc2ccccc2)cc1
Reactant: CCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCNC(=O)c1ccc(Nc2ccccc2)cc1
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a stirred solution of 1.06 g (5.0 mmol, 1 eq.) of 4-phenylaminobenzoic acid (Portnaya, B. S., Turitsyna, N. F., Bobkova, T. P., and Levkeov, I. I., Zhur. Obshchei. Khim., 30, 2693 (1960)), n-propylamine (0.82 mL, 10.0 mmol, 2 eq.), and 0.061 g (0.5 mmol, 0.1 eq.) of DMAP in THF at 0° C. was added 1.05 g (5.5 mmol, 1.1 eq.) of EDCl. The mixture was stirred overnight while the bath melted. The mixture was poured into 150 mL of ethyl acetate and washed with 50 mL each of water, 1N aqueous HCl, water and saturated aqueous NaHCO3. The ethyl acetate layer was then dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (80 g SiO2, 1:1 ethyl acetate-hexanes) to give 0.51 g (40%) of the title compound. 1H NMR (300 MHz, CDCl3) δ10.57 (bs, 2H), 7.21-7.41 (m, 9H), 3.96 (s, 2H), 2.75 (m, 2H), 1.64 (hextet, 2H), 0.92 (t, 3H). MS (DCl) m/e 255 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][N:13]=[CH:12][C:11]=3[CH2:15][CH2:16][C:17](OC)=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][N:13]=[CH:12][C:11]=3[CH2:15][CH2:16][CH2:17][OH:18])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)CCc1cnoc1-c1ccc2c(c1)OCO2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of methyl 3-[5-(1,3-benzodioxol-5-yl)-4-isoxazolyl]propionate (2.70 g) in tetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 25 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(1,3-benzodioxol-5-yl)-4-isoxazolyl]propan-1-ol (2.33 g, yield 96%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2: 1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 45–46° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:36])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10](=[O:29])[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:8]2)=[O:4].[NH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:22]([N:11]1[C:12]2[C:7](=[C:6]([OH:36])[C:5]([C:3]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:10]1=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2ccc(C)nc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(-c2nc(C(=O)NCCC(=O)O)c(O)c3cc(-c4ccccc4)c(=O)n(Cc4ccccc4)c23)cn1
Temperature: 25 °C
Yield: 10.7 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-8-(6-methyl-pyridin-3-yl)-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.084 mmol), β-alanine (600 mg, 6.7 mmol) and NaOMe solution (10 mL, 5.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration. The crude solid was purified by silica gel chromatography (10-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 4.8 mg of the title compound. MS: (+) m/z 535.33 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:8]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.4 %

Procedure:
A solution of 3-cyclopentyl-2-(4-phenoxy-phenyl)-propionic acid (50 mg, 0.16 mmol),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (106 mg, 0.24 mmol), and 2-aminothiazole (21 mg, 0.24 mmol) in methylene chloride (10 mL) at 25° C. was treated with triethylamine (0.067 mL, 0.48 mmol). The reaction mixture was then stirred at 25° C. for 14 h. After this time, the reaction mixture was diluted with water (10 mL) and then extracted with methylene chloride (3×10 mL). The combined organic extracts were then washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), and a 1N aqueous hydrochloric acid solution (1×10 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-phenoxy-phenyl)-N-thiazol-2-yl-propionamide (48 mg, 76%) as an off-white solid: mp 154.9-155.1° C.; EI-HRMS m/e calcd for C23H24O2N2S (M+) 392.1558, found 392.1546.
Reaction SMILES: [CH3:1][C:2]([N:9]([CH3:11])[CH3:10])([CH2:5][CH2:6][CH2:7][CH3:8])[C:3]#[N:4].O>CCOCC>[CH3:1][C:2]([N:9]([CH3:10])[CH3:11])([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][NH2:4]
Reactant: CCCCC(C)(C#N)N(C)C
Solvent: O
Solvent: CCOCC
Product: CCCCC(C)(CN)N(C)C
Temperature: 0 °C

Procedure:
A solution of 2-methyl-2-dimethylamino-hexanenitrile (7.70 g.,) in dry ether (100 ml.) was added dropwise to a stirred solution of sodium dihydro-bis(2-methoxyethoxy)aluminate (45.3 g., 70% solution in benzene, 25% excess) in dry ether (100 ml.) under nitrogen with ice water cooling. The solution was refluxed overnight under nitrogen and allowed to cool. Ether (200 ml.) was added, followed by dropwise addition of excess water with ice-water cooling to destroy excess reducing reagent. The mixture was filtered on hyflo and the filtrates extracted with ether (4 × 100 ml.). The combined ether extracts were washed with water (4 × 200 ml.), dried (Na2SO4) and evaporated leaving a colourless oil. Distillation of the oil afforded 2-methyl-2-dimethylamino-hexylamine as a colourless liquid (4.808 g., 61%) b.p. 86-88/12 mm.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([F:18])[CH:7]=1.[C:19]([CH2:23][CH2:24][C:25](Cl)=[O:26])([O:21][CH3:22])=[O:20]>ClCCl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:25](=[O:26])[CH2:24][CH2:23][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=2)=[C:8]([F:18])[CH:7]=1
Reactant: Fc1cc(Cl)ccc1-c1ccccc1
Reactant: COC(=O)CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(Cl)cc2F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.9 %

Procedure:
To a stirred suspension of anhydrous aluminum chloride (1.451 g, 0.0109 mol) in dichloromethane (20 mL) under nitrogen at 5° C. was added dropwise a solution of 4-chloro-2-fluorobiphenyl (0.858 g, 0.00415 mol) in dichloromethane (13 mL) over 10 minutes followed by the dropwise addition of 3-carbomethoxypropionyl chloride (0.57 mL, 0.0046 mol) in dichloromethane (13 mL) over 25 minutes. The resulting mixture was stirred for 2.5 hours then allowed to warm slowly to room temperature. Stirred for 3 days, for convenience. Then the mixture was recooled and quenched with the dropwise addition of water (145 mL). The organic layer was washed with water, aqueous sodium bicarbonate, brine, and dried (MgSO4). The mixture was rotary evaporated to give 1.25 g of 4-(4′-chloro-2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a pale yellow solid; mp 90.5-92.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[N+:10]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH2:1][Br:13])([O-:12])=[O:11]
Reactant: COc1ccc(C)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)cc1[N+](=O)[O-]
Yield: 70 %

Procedure:
A solution of 4-methyl-2-nitroanisole (25 mmol), N-bromosuccinimide (25 mmol) and benzoyl peroxide (2.5 mmol) in carbon tetrachloride (100 mL) was heated at reflux for 18 h. The reaction mixture was then poured into water and solid separated was filtered. The aqueous layer was extracted with carbon tetrachloride (3×50 mL) and organic phase was separated and evaporated to give a solid product. The solid products were combined and recrystallized from ethyl acetate-hexane to give a crystalline product of 3-nitro-4-methoxy benzyl bromide. m.p. 110-112° C., yield 70-75%.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([OH:30])=[CH:25][C:24]=3[Cl:31])=[O:15])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:35][CH2:36][OH:37]>CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH2:35][CH2:36][OH:37])=[CH:25][C:24]=3[Cl:31])=[O:15])[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: OCCBr
Reactant: O=C(c1cnccc1Oc1cc(Cl)c(O)cc1Cl)N1CCN(C2CC2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1cnccc1Oc1cc(Cl)c(OCCO)cc1Cl)N1CCN(C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
To a solution of 0.15 g (0.33 mmol) (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)[4-(2,5-dichloro-4-hydroxy-phenoxy)-pyridin-3-yl]-methanone (Example 57) in 2 mL N,N-dimethylformamide was added 0.016 g (0.37 mmol) sodium hydride (60% dispersion in mineral oil, Aldrich). The reaction mixture was stirred for 15 min. at room temperature before 0.03 mL (0.36 mmol) 2-bromoethanol (commercially available, CAS RN 540-51-2) were added. After stirring for 3 hours at room temperature another 0.03 mL (0.36 mmol) 2-bromoethanole were added. After 72 hours the reaction mixture was poured on water and was extracted three times with ethyl acetate. The organic layers were washed with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 25:75) to give 0.075 g (46%) of the title compound as a light brown foam. MS (ESI): m/z=500.113 [M+H]+.