Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].C1([C:8]([PH3+])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].O=C1CCC([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])CC1.O>O1CCCC1>[CH2:8]=[C:15]1[CH2:16][CH2:17][CH:18]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:19][CH2:20]1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 92.3 %

Procedure:
Triphenylmethylphosphonium bromide (53.7 g, 0.15 mol) was dissolved in 500 mL of tetrahydrofuran, potassium tert-butoxide (16.8 g, 0.15 mol) was added at −20° C., reacted for 0.5 h after the temperature was raised to 0° C. Then, tert-butyl 4-oxo-cyclohexylcarbamate (Compound 7-1) (21.3 g, 0.1 mol) was dissolved in 100 mL of THF and added dropwise into the flask under nitrogen. After 3 hours of reaction at room temperature, a small amount of water was added to dissolve the solids. The mixture was rotary evaporated to remove THF, extracted with anhydrous diethyl ether, and dried, concentrated, the concentrate was dissolved in n-hexane, and filtered by silica gel, then concentrated to give Compound 7-2 as a colorless liquid (19.5 g, 92.3% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[N:12]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=3)[C:11]2=[S:30])[CH:5]=[CH:6][C:7]=1[CH2:8]O.S(Cl)([Cl:33])=O>>[Cl:33][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:10]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[N:12]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=3)[C:11]2=[S:30])=[CH:3][C:2]=1[F:1]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(CO)c(F)c1
Reactant: O=S(Cl)Cl
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(CCl)c(F)c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
The title compound was prepared according to General Method 10. 4-[3-(3-Fluoro-4-hydroxymethyl-phenyl)-4,4-dimethyl-5-oxo-2-thioxo-imidazolidin-1-yl]-2-trifluoromethyl-benzonitrile (0.5 g, 1.14 mmol) was dissolved in thionyl chloride (5 mL) and the solution was stirred at 100° C. for 12 h. The reaction mixture was concentrated under reduced pressure to obtain 300 mg of product.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17](SC)=[N:16][C:15]=2[CH:21]=1>CC(O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([N:4]3[CH:5]4[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]4)[CH2:2][CH2:3]3)=[N:16][C:15]=2[CH:21]=1
Reactant: C1CN2CCC(CC2)N1
Reactant: CSc1nc2cc(Br)ccc2o1
Solvent: CC(C)O
Product: Brc1ccc2oc(N3CCN4CCC3CC4)nc2c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 55.3 %

Procedure:
1,4-Diazabicyclo[3.2.2]nonane (57%, 731 mg, 3.31 mmol) was added to a solution of 5-bromo-2-methylsulfanyl-benzooxazole (538 mg, 2.20 mmol) in iPrOH (4.4 mL). The mixture was placed in an oil bath at 90° C. and the solvent was evaporated. The mixture was allowed to stir neat at 90° C. for 18 h. Upon cooling to RT the mixture was purified by chromatography (Biotage, 25M) eluting with 4% MeOH in CHCl3 with 20 drops of NH4OH per liter of eluent to afford 392 mg (55%) of the title compound as an oil: 1H NMR (CDCl3, 400 MHz) δ 7.40 (t, 1H, J=1.2 Hz), 7.05 (d, 2H, J=1.2 Hz), 4.46-4.43 (m, 1H), 3.87 (t, 2H, J=5.8 Hz), 3.14-2.93 (m, 6H), 2.13-2.06 (m, 2H), 1.81-1.73 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 162.3, 148.0, 145.6, 122.9, 119.0, 116.8, 109.8, 57.2, 50.5, 46.5, 44.4, 27.0; MS (Cl) m/z 322.0 (M+1); HPLC retention time=3.36 min. The hydrochloride salt was prepared by diluting in ethyl acetate and adding a solution of 2.5 N HCl in ethyl acetate: mp>300° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](F)([F:12])[C:7](F)([F:14])[CH:6]=[CH:5]2.O.O.O.O.O.O.[OH-].C[N+](C)(C)C>[Zn].C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([F:12])=[C:7]([F:14])[CH:6]=[CH:5]2
Reactant: FC1(F)C=Cc2cc(Br)ccc2C1(F)F
Agent: C[N+](C)(C)C
Agent: [OH-]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc2cc(Br)ccc2c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Zinc (0.89 g, 14 mmol) was added to a stirred mixture of 2.4 g (8.7 mmol) of 6-bromo-1,1,2,2-tetrafluoro-1,2-dihydronaphthalene, 4 ml of water, 6 ml of THF, and 7.6 g of tetramethylammonium hydroxide pentahydrate that was cooled in an ice bath. The mixture was allowed to warm to room temperature. After 2 hours, the zinc was filtered, and the phases were separated. The aqueous layer was extracted three times with hexanes. The combined organic phase was washed three times with brine, stirred over MgSO4 and activated carbon for 3 hours, and then stored for 15 hours. The MgSO4 and carbon were filtered off, and the solvent was removed under vacuum. A colorless solid (1.9 g, 7.7 mmol, 89%) remained.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][C:29]1[CH:33]=[C:32]([CH2:34][C:35](O)=[O:36])[O:31][N:30]=1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][C:32]5[O:31][N:30]=[C:29]([CH3:28])[CH:33]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: Cc1cc(CC(=O)O)on1
Agent: Cl
Product: Cc1cc(CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4cccc5c4OCO5)CC3)CC2)on1

Procedure:
The title compound, white solid (17 mg, 54%), MS (ISP) m/z=455.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 2-(3-methyl-isoxazol-5-yl)acetic acid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[O:6][CH2:7][CH:8]1[O:10][CH2:9]1.[C:17]1(=[O:23])[NH:21][C:20](=[O:22])[CH2:19][CH2:18]1>N1C=CC=CC=1>[CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[O:6][CH2:7][CH:8]([OH:10])[CH2:9][N:21]1[C:17](=[O:23])[CH2:18][CH2:19][C:20]1=[O:22]
Reactant: O=C1CCC(=O)N1
Reactant: CNc1cc(OCC2CO2)ccc1[N+](=O)[O-]
Solvent: c1ccncc1
Product: CNc1cc(OCC(O)CN2C(=O)CCC2=O)ccc1[N+](=O)[O-]

Procedure:
0.087 mol (19.5 g) of 1-(3'-methylamino-4'-nitrophenoxy)-2,3-epoxypropane is dissolved in 75 ml of absolute alcohol to which 6 drops of pyridine have been added. 0.10 mol (10.1 g) of succinimide is added and the mixture is then heated under reflux for 4 hours. The reaction mixture is filtered at the boil. On cooling of the filtrate, the expected product crystallises. After recrystallisation from alcohol and drying in vacuo, it melts at 152° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.F[C:13]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:14]=1[C:15]#[N:16].O.[OH-].[Li+]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:13]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][C:14]=2[C:15]#[N:16])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(C(F)(F)F)ccc1Nc1ccc(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
Combine 4-fluoro-2-nitro-phenylamine (5.0 g, 32.03 mmol), 2-fluoro-5-trifluoromethyl-benzonitrile (6.07 g, 32.03 mmol) and lithium hydroxide monohydrate (4.03 g, 96.08 mmol) in methyl sulfoxide (DMSO, 60 ml). Heat the resulting mixture to 70° C. for 16 hours. Cool the reaction mixture to ambient temperature, then pour into approximately 400 ml of ice water and stir for one hour. Filter the resulting mixture and collect the precipitate to obtain 9.995 g of the title compound (30.73 mmol, 96% yield) as an orange amorphous solid. Product used as is with no further purification: Mass Spectrum (m/e): 326(M+1).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:18])[N:9]=[C:8]1[CH2:19]Cl.[N:27]1[C:35]([NH2:36])=[C:34]2[C:30]([N:31]=[CH:32][NH:33]2)=[N:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:36][C:35]1[N:27]=[CH:28][N:29]=[C:30]2[C:34]=1[N:33]=[CH:32][N:31]2[CH2:19][C:8]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:18])[N:9]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2cccc(Cl)c2c(=O)n1-c1ccccc1-c1ccccc1
Yield: 68.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2i (400 mg, 1.05 mmol), adenine (155 mg, 1.15 mmol), K2CO3 (159 mg, 1.15 mmol), and DMF (5 mL). The crude product was recrystallized from EtOH to provide 344 mg of a white solid (68%), mp 299.9-300.1° C. (discolors). 1H NMR (DMSO-d6) δ: 8.08 (s, 1H); 7.89 (s, 1H); 7.58-7.73 (m, 5H); 7.51 (d, J=7.9 Hz, 1H); 7.46 (d, J=7.5 Hz, 2H); 7.27-7.41 (m, 3H); 7.14-7.27 (m, 3H); 5.14 (d, J=17 Hz, 1H); 4.82 (d, J=17 Hz, 1H). 13C NMR (DMSO-d6) ppm: 159.6, 156.2, 152.8, 152.5, 150.0, 149.0, 141.7, 140.2, 137.7, 135.0, 133.3, 133.2, 131.8, 130.7, 130.1, 129.8, 129.5, 128.8, 128.6, 128.4, 127.1, 118.4, 117.6, 45.3. MS (ES): m/z 480.1 (M+). Anal. calcd. for C26H18ClN7O: C, 65.07; H, 3.78; Cl, 7.39; N, 20.43. Found: C, 64.77; H, 3.75; Cl, 7.43; N, 20.35.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C@@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8]1)([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[N:22]([C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28])=[N+:23]=[N-:24]>C1COCC1>[C:1]([O:5][C:6]([C@@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=1[N:22]=[N+:23]=[N-:24])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Reactant: [N-]=[N+]=Nc1ccccc1C(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)c1ccccc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
A stirred solution of (2S)-5-oxo-proline tert-butyl ester (T. Kolasa and M. J. Miller, J. Org. Chem., 1990, 55, 1711-1721) (1.13 g, 6.13 mmol) in anhydrous THF (15 mL) was treated at −78° C. with LDA (9.19 mmol) and the reaction was stirred for 15min. A solution of 2-azidobenzoyl chloride (T. Okawa, T. Sugimori, S. Eguchi and A. Kakehi, Heterocycles, 1998, 47, 1, 375-382) (6.13 mmol) in anhydrous THF (5 mL) was then added dropwise and the reaction mixture was stirred at −78° C. for 1 h before being quenched with saturated aq.NH4Cl. The reaction was allowed to warm to room temperature and the organic layer was washed with saturated aq.NH4Cl, dried (MgSO4), filtered and evaporated to give an oil which was purified by flash chromatography (20% ethyl acetate in hexane) to afford the title compound as a pale yellow oil (1.67 g, 82%): 1H NMR (400 MHz, CDCl3) δ 1.53 (9H, s), 2.14 (1H, m), 2.43 (1H, m), 2.55 (1H, m), 2.69 (1H, m), 4.79 (1H, dd, J 9.2, 3.2 Hz), 7.19-7.22 (2H, m), 7.36 (1H, m), 7.49 (1H, m). 13C NMR (100 MHz, CDCl3) δ 22.1 (CH2), 28.3 (CH3), 31.9 (CH2), 59.3 (CH), 83.0 (C), 118.7 (CH), 125.0 (CH), 127.9 (C), 129.1 (CH), 131.9 (CH), 137.9 (C), 167.5 (C), 170.2 (C), 173.6 (C).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[S:16]1[C:20]([C:21]2[O:22][CH:23]=[C:24]([CH2:26]Cl)[N:25]=2)=[CH:19][C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]1=2>>[S:16]1[C:20]([C:21]2[O:22][CH:23]=[C:24]([CH2:26][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:25]=2)=[CH:19][C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]1=2
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2cc3ccccc3s2)n1
Product: c1ccc2sc(-c3nc(COc4ccc(CCCn5ccnc5)cc4)co3)cc2c1
Yield: 68 %

Procedure:
In substantially the same manner as in Working Example 48, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-(2-benzo[b]thienyl)-4-chloromethyloxazole to give 2-(2-benzo[b]thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 68%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 149-150° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([CH:13]3[CH2:18][CH2:17][N:16](C(OCC4C=CC=CC=4)=O)[CH2:15][CH2:14]3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[H][H]>CO.[Pd]>[NH:16]1[CH2:17][CH2:18][CH:13]([C:10]2[O:11][C:12]3[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=[CH:7][C:8]=3[N:9]=2)[CH2:14][CH2:15]1
Reactant: [H][H]
Reactant: NC(=O)c1cccc2nc(C3CCN(C(=O)OCc4ccccc4)CC3)oc12
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cccc2nc(C3CCNCC3)oc12
Yield: 32.9 %

Procedure:
A mixture of benzyl 4-(7-carbamoylbenzo[d]oxazol-2-yl)piperidine-1-carboxylate (98 mg, 0.26 mmol), 10% Pd/C (20 mg) in methanol (30 ml) was stirred at room temperature over 1 atm hydrogen for 2 hr. The mixture was filtered, and evaporated under reduced pressure. The residue was purified by pre-HPLC. 21 mg of 2-(piperidin-4-yl)benzo[d]oxazole-7-carboxamide as a solid was obtained, yield 33%. LCMS (ESI) m/z: 246 (M+1)+. 1H-NMR (400 MHz, DMSO-d6): δ 1.24 (brs, 1H), 1.71-1.74 (m, 2H), 2.03-2.06 (d, J=12 Hz, 2H), 2.64 (t, 2H), 3.01-3.04 (t, 2H), 3.14 (t, 1H), 7.41 (t, J=7.2 Hz, 1H), 7.72 (d, J=7.2 Hz, 1H), 7.72 (brs, 1H), 7.78 (brs, 1H), 7.85 (d, J=7.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH2:14][NH:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:33][CH2:34][C@H:35]([OH:45])[CH2:36][O:37][C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3)=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)=[O:17])[O:5][CH2:6][C:7]([O:9]C)=[O:8].[Li+].[OH-]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH2:14][NH:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:33][CH2:34][C@H:35]([OH:45])[CH2:36][O:37][C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3)=[CH:27][CH:26]=2)[CH2:22][CH2:23]1)=[O:17])[O:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: COC(=O)COc1ccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 50 %

Procedure:
Methyl 2-(3-fluoro-4-{[({4-[4-(2-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino)ethyl)anilino]-1-piperidinyl}carbonyl)amino]methyl}phenoxy)acetate (0.107 g, 0.2 mmol) was dissolved in tetrahydrofuran. To this solution was added 1N LiOH (2 mL, 0.2 mmol) and stirred at ambient temperature for four days. The solvent was removed in vacuo and the resulting solid lyophilized to yield the title compound (0.075 g, 0.1 mmol).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:1][CH:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:7]([OH:9])=[O:8])=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)[C@H](N)C(=O)O
Product: CC(C)(C)C(NC(=O)c1ccc(Cl)cc1)C(=O)O

Procedure:
Racemic tert-butylglycine and 4-chlorobenzoyl chloride were processed as described in Example 26A to provide the desired product.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1.FC(F)(F)C(O)=O>>[CH3:1][CH:2]([CH3:33])[CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1
Reactant: CC(C)Cc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(2-methylpropyl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[O:19][CH:20]=[C:21]([C:23]([O:25]C)=[O:24])[N:22]=2)[CH2:14][CH2:13]1)=[O:11].O.[OH-].[Na+]>O1CCCC1.[Cl-].[Na+]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[O:19][CH:20]=[C:21]([C:23]([OH:25])=[O:24])[N:22]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: COC(=O)c1coc(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)n1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C)c(CC(=O)N2CCC(c3nc(C(=O)O)co3)CC2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl 2-[1-[(2,5-dimethylphenyl)acetyl]-4-piperidinyl]-4-oxazolecarboxylate (i.e. the product of Example 9, Step E) (665 mg, 1.87 mmol) was dissolved in 5 mL tetrahydrofuran, and 3.3 mL of water was added. The reaction mixture was cooled to 0° C. with vigorous stirring. A 1 N aqueous sodium hydroxide solution (3.7 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with saturated sodium chloride solution (4 mL), washed with diethyl ether, and the aqueous phase was acidified to pH 3-4 by dropwise addition of 20% citric acid solution. The precipitated solid was filtered and dried to give 490 mg of the title compound. 1H NMR (DMSO-d6) δ 1.55 (m, 2H), 2.0 m, 2H), 2.14 (s, 3H), 2.23 (s, 3H), 2.85 (m, 1H), 3.1-3.3 (m, 2H), 3.65 (m, 2H), 3.9 (m, 1H), 4.35 (m, 1H), 6.8-7.1 (m, 3H), 8.66 (s, 1H), 13.0 (s, 1H).
Reaction SMILES: [C:1]([CH:3]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)[CH2:4]O)#[N:2].N1C=CC=CC=1.P(Br)(Br)[Br:20]>C(Cl)Cl>[C:1]([CH:3]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)[CH2:4][Br:20])#[N:2]
Reactant: BrP(Br)Br
Reactant: N#CC(CO)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#CC(CBr)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 24 g (0.11 mol) 2-cyano-2-(4-bromophenyl)-ethanol and 4.5 g (0.055 mol) pyridine in 100 ml CH2Cl2 are slowly added, at -5° to 0°, 12 g (0.044 mol) PBr3. The mixture is stirred for 3 hours at room temperature, thereafter for 2 hours at 40°, allowed to cool off, then poured into 500 ml ice water and extracted with CH2Cl2. The extract is washed with water, dried and evaporated. The resulting residue is chromatographed over a silica gel column with hexane/diethylether 6:4. The glassy residue obtained after evaporation is worked up in toluene and thereafter ether to give the title compound in the form of a yellow powder, m.p. 171° (decomposing).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([CH2:44][CH2:45][OH:46])[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:36]([CH2:44][CH2:45][OH:46])[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO)n1
Reactant: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A mixture of Intermediate 139c (125 mg, 0.33 mmol), Intermediate 110b (115 mg, 0.33 mmol) and DIPEA (115 μL, 0.66 mmol) in dioxane (3 mL) was stirred at 80° C. overnight. After cooling, the reaction mixture was partitioned between water and DCM. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC, using a gradient of 0-10% MeOH in DCM, to afford the title compound (94 mg, 48%). A sample of this (40.0 mg) was further purified by MDAP (Method 7) purification to afford the title compound (20 mg) as a white solid. LCMS (Method 5): Rt 3.64 min, m/z 589 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.83 (3H, d, J=5.6 Hz), 1.16 (9H, s), 1.83-1.96 (2H, m), 1.97-2.07 (1H, m), 2.08-2.17 (1H, m), 2.95 (114, ddd, J=12.0, 7.2, 4.9 Hz), 3.17 (1H, dt, J=12.2, 3.3 Hz), 3.36-3.44 (2H, m), 3.62 (2H, q, J=5.5 Hz), 3.72-3.80 (2H, m), 3.81-3.88 (1H, m), 3.88-3.92 (2H, t, J=6.0 Hz), 4.81 (114, td, J=8.5, 6.1 Hz), 4.96 (1H, t, J=5.0 Hz), 5.52 (1H, t, J=4.2 Hz), 6.02 (1H, s), 7.05 (1H, d, J=8.6 Hz), 7.18 (1H, dd, J=9.9, 2.1 Hz), 7.22-7.27 (1H, m), 7.30-7.37 (3H, m), 7.62 (1H, d, J=9.9 Hz), 7.79 (1H, d, J=1.9 Hz), 8.16 (1H, s).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:12][CH2:13][C:14]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)([F:16])[F:15].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[F:16][C:14]([F:15])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:13][CH2:12][S:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1S
Reactant: Fc1ccc(C(F)(F)CCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccccc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 36.9 %

Procedure:
To a solution of 2-mercapto-benzoic acid (0.10 g, 0.65 mmol) in acetone (30 ml) are added 1-(3-bromo-1,1-difluoro-propyl)-4-fluoro-benzene (0.16 g, 0.65 mmol) and potassium carbonate (0.27 g, 1.95 mmol) at RT. The reaction mixture is stirred at 70° C. for 2.5 h. The reaction mixture is diluted with water (20 ml), acidified with 2M hydrochloric acid and the aqueous layer is extracted with EtOAc (3×20 ml). The combined organic layers are washed with water (15 ml), brine (15 ml), dried over sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography (silica gel, 80% EtOAc/hexane) to yield 2-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-benzoic acid (0.08 g, 0.24 mmol, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:21]([O-])=O)[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1>[Pt].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:18])[CH3:19])[CH:10]=1)[NH2:21]
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1C(C)C
Agent: [Pt]
Solvent: CCO
Product: COc1ccc(Oc2c(Cl)cc(N)cc2Cl)cc1C(C)C

Procedure:
3,5-Dicloro-4-(3'-isopropyl-4'-methoxyphenoxy)-nitrobenzene (2.0 g) and 200 mg. of 10% platinum on carbon in 100 ml. of ethanol are hydrogenated on a Parr shaker. Catalyst is then removed by filtration through Celite and the filtrate is stripped to afford 3,5-dicloro-4-(3'-isopropyl-4'-methoxyphenoxy)-aniline. To this is added 30 g of dimethyl oxalate and this is stirred at 120° for 4 hours. Excess oxalate is removed under high vacuum from a hot water bath and the residue is chromatographed on silica gel with 9:1 toluene:ethyl acetate affording methyl N-[3,5-dichloro-4-(4'-methoxy-3'-isopropylphenoxy)-phenyl]-oxamate; NMR(CDCl3): δ 1.2 (6H,d), 3.3 (1H,m), 3.8 (3H,s), 4.0 (3H,s), 6.5 (1H,d of d), 6.7 (1H,d), 6.8 (1H,d), 7.7 (2H,s).