Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:37]=[CH:36][C:8]([C:9]([NH:11][C:12]2[CH:35]=[CH:34][C:15]3[CH2:16][N:17]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:18](=[O:25])[CH:19]([CH2:21]C(O)=O)[NH:20][C:14]=3[CH:13]=2)=[O:10])=[CH:7][CH:6]=1>>[NH2:2][N:3]=[CH:4][C:5]1[CH:37]=[CH:36][C:8]([C:9]([NH:11][C:12]2[CH:35]=[CH:34][C:15]3[CH2:16][N:17]([CH2:26][CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:18](=[O:25])[C:19]([CH3:21])=[N:20][C:14]=3[CH:13]=2)=[O:10])=[CH:7][CH:6]=1
Reactant: NN=Cc1ccc(C(=O)Nc2ccc3c(c2)NC(CC(=O)O)C(=O)N(CCc2ccccc2)C3)cc1
Agent: Cl
Product: CC1=Nc2cc(NC(=O)c3ccc(C=NN)cc3)ccc2CN(CCc2ccccc2)C1=O

Procedure:
Using the procedure of Preparation 26(e), except substituting TFA for hydrochloric acid, yielded a mixture of 8-[[4-(aminoiminomethyl)benzoyl]-amino]-2,3,4,5-tetrahydro-3-oxo-4-(2-phenylethyl)-1H-1,4-benzodiazepine-2-acetic acid and the title compound (80 mg) which were separated by HPLC RT 24.8 min (YMC ODS AQ, 50×250 mm, 85 mL/min, 30% AN/W-TFA, UV detection at 220 nm); 1H NMR (400 MHz, MeOD4) δ8.1(d, 2H), 7.9(d, 2H), 7.75(s, 1H),7.60(d, 1H), 7.35(d, 1H), 7.22-7.12(m, 5H), 4.20(m, 2H), 3.70(m, 2H), 2.85(m, 2H), 2.42(s, 3H); MS(ES) m/e 440 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][C:35]=2[CH3:37])[N:30]=[CH:29][CH:28]=1.S(Cl)(Cl)(=O)=O>C1COCC1>[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:38]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:39])=[O:40])=[CH:34][C:35]=2[CH3:37])[N:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: Cc1cc(S(=O)(=O)Cl)cc2nccc(Cl)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=S(=O)(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc(C)c3c(Cl)ccnc3c2)cc1
Reaction time: 0.25 h

Procedure:
To a flask containing ice cold suspension of N-(4-methoxybenzyl)thiazol-2-amine (25.1 mg, 0.114 mmol) in THF (418 μl) was added lithium bis(trimethylsilyl)amide (1M in THF) (120 μl, 0.120 mmol) dropwise over 10 min. The mixture was stirred for 15 min prior to the drop wise addition of a solution of 4-chloro-5-methylquinoline-7-sulfonyl chloride (30 mg, 0.109 mmol) in THF (0.6 ml). After 30 min LC/MS indicated desired product and methanolysis of the sulfonyl chloride (about 1:1). Additional solid N-(4-methoxybenzyl)thiazol-2-amine (25.1 mg, 0.114 mmol) was added with stirring at room temperature. After 15 min, no further conversion had occurred. Additional LHMDS (0.5 eq) was added after cooling back to 0° C. and stirring continued. After 20 min, LC/MS indicated consumption of sulfonyl chloride (methanolysis) with product visible as a minor species. To the orange/brown solution was added acetic acid (300 μl) and the mixture dried under reduced pressure. The crude material was purified with a 25 g (25 μm spherical) silica column ramping EtOAc in heptane (0-50%, 5% DCM throughout) to provide 4-chloro-N-(4-methoxybenzyl)-5-methyl-N-(thiazol-2-yl)quinoline-7-sulfonamide (6 mg, 0.013 mmol, 12.01% yield) as a white solid. m/z (ESI) 460.3 (M+H)+.
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([OH:12])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br>CC(CC)=O.O>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][O:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([O:12][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([F:19])[CH:21]=2)=[CH:2][CH:1]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: O=C(C=Cc1ccc(OCc2cccc(F)c2)cc1)OCc1cccc(F)c1
Yield: 55.9 %

Procedure:
A mixture of 5.0 g (30.5 mmol) p-cumaric acid, 8.4 g (61 mmol) potassium carbonate and 11.5 g (61 mmol) 3-fluorobenzylbromide in 500 ml ethyl methyl ketone is hold over night at 80° C. The reaction mixture is cooled, diluted with water and extracted with ethyl acetate. Chromatography (silica gel, n-hexane/ethyl acetate 4:1) gives 6.48 g (56%) of a colorless solid. MS: m/e=380.2 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]([CH2:24][OH:25])([CH2:22][OH:23])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]([CH2:22][OH:23])([CH2:24][OH:25])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:22][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:13]([C:18]([F:20])([F:19])[F:21])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(O)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(OCCCCC2CCCCC2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 211.7 %

Procedure:
Compound 3-6 (360 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (262 mg) and compound 3-7 (250 mg) were added, and the mixture was stirred at 80° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (520 mg) as a colorless oil.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[OH:18])=[O:2].[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.Cl.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[O:18][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][O:19]1)=[O:2]
Reactant: C1=COCCC1
Reactant: COc1cc(CCCC=O)c(O)c2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(CCCC=O)c(OC2CCCCO2)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 76 mg of 2-(3-formylpropyl)-4-methoxy-1-hydroxynaphthalene in 2 ml methylene chloride is treated with 0.5 ml of dihydropyran and then with a few mg of pyridinium hydrochloride. The resulting solution is stirred at room temperature for 24 hrs at which time TLC analysis indicates no remaining starting material The solution is poured into 20 ml of saturated aqueous sodium bicarbonate and extracted two times with ether. The combined organic extracts are washed with water (pH adjusted to 7 with 10% aqueous sodium bisulfate), dried with magnesium sulfate, filtered and concentrated to give 173 mg of crude product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].C([N:20]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C@H:21]([C:30]([OH:32])=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)(C)(C)C>CC(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH2:36]([O:35][C:33]([NH:20][C@@H:21]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:27][CH:28]=1)[C:30]([O:32][C:23]([CH3:28])([CH3:24])[CH3:22])=[O:31])=[O:34])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)N(C(=O)OCc1ccccc1)[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 222.7 %

Procedure:
8.29 ml (57.9 mmol) of ethyl 4-bromobutanoate and 28.21 g (86.58 mmol) of cesium carbonate were added to 21.5 g (57.9 mmol) of tert-butyl N-benzyloxycarbonyltyrosine in 280 ml of acetone and the mixture was heated to reflux with stirring. After 2 h, a further 2 ml of ethyl 4-bromobutanoate and 2 g of cesium carbonate were added, after a further 2 h a further 2 ml of ethyl 4-bromobutanoate and 3 g of cesium carbonate were added and after standing at room temperature overnight 9 ml of ethyl 4-bromobutanoate were added again and the mixture was heated to reflux for a further 6 h. After cooling, it was filtered, the residue was washed with acetone and the filtrate was concentrated. The residue was taken up in diethyl ether and the organic phase was washed successively with 3% strength citric acid solution, 3×H20 and saturated NaCl solution. The ether phase was dried over MgSO4, the drying agent was filtered off and the filtrate was concentrated in vacua. The residue was chromatographed on silica gel using CH2Cl2 and CH2Cl2MeOH (99/1). 31.3 g of a pale yellow oil were obtained, which was employed without further purification for the synthesis of (1.2).
Reaction SMILES: S1[CH2:5][CH2:4][N:3]([C:6]([O:8][C@@H:9]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[O:7])[CH2:2]1.ClC1C=CC=C(C(OO)=O)C=1.[S:38]([O-:41])([O-])=[O:39].[Na+].[Na+]>C(Cl)Cl>[O:39]=[S:38]1(=[O:41])[CH2:5][CH2:4][N:3]([C:6]([O:8][C@@H:9]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[O:7])[CH2:2]1
Reactant: O=S([O-])[O-]
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)OC(=O)N1CCSC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)OC(=O)N1CCS(=O)(=O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of benzyl 2(S)-(3-thiazolidine-carbonyloxy)-3-phenylpropionate (371 mg) in methylene chloride (7 ml) was added 80% m-chloroperbenzoic acid (431 mg). The mixture was stirred at ambient temperature for 2 days. Then 10% sodium sulfite aqueous solution and methylene chloride were added thereto, and the mixture was separated. The aqueous layer was extracted with methylene chloride. The combined extract was washed with saturated sodium hydrogen carbonate solution 2 times and saturated sodium chloride solution successively, dried over magnesium sulfate, and concentrated under reduced pressure to give benzyl 2(S)-(1,1-dioxothiazolidine-3-carbonyloxy)-3-phenylpropionate (330 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])=[N:4][C:5]([NH:8][C:9]2[CH:25]=[CH:24][C:12]3[CH2:13][CH2:14][N:15](C(=O)C(F)(F)F)[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])=[N:4][C:5]([NH:8][C:9]2[CH:25]=[CH:24][C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(C(=O)C(F)(F)F)CC3)ncc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCNCC3)ncc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{5-Chloro-2-[3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide (350 mg/0.67 mmol) was dissolved in methanol (5 mL) and treated with solid potassium carbonate (500 mg/3.2 mmol). The suspension was allowed to stir at room temperature overnight. The resulting opaque solution was concentrated and taken up in 10% methanol/methylene chloride. This mixture was filtered and concentrated to afford 2-[5-Chloro-2-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a yellow solid (200 mg/70%). 1H NMR (400 MHz, DMSO-d6) δ 11.52 (br s, 1H), 9.31 (s, 1H), 8.82-8.61 (m, 2H), 8.20 (s, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.49-7.41 (m, 2H), 7.31 (d, J=8.0 Hz, 1H), 7.12 (m, 1H), 6.97 (d, J=8.0 Hz, 1H), 2.82-2.68 (m, 11H). LC/MS found 423 (M+H). mp 162-190° C. (dec.).
Reaction SMILES: C[O:2][CH:3]([O:31]C)[CH2:4][N:5]([C:10](=[O:30])[CH2:11][CH2:12][CH:13]([P:22]([CH2:27][CH:28]=[CH2:29])([CH2:24][CH:25]=[CH2:26])=[O:23])[P:14]([CH2:19][CH:20]=[CH2:21])([CH2:16][CH:17]=[CH2:18])=[O:15])[CH2:6][C:7](O)=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:8]=[CH:7][CH2:6][N:5]([C:10](=[O:30])[CH2:11][CH2:12][CH:13]([P:22]([CH2:27][CH:28]=[CH2:29])([CH2:24][CH:25]=[CH2:26])=[O:23])[P:14]([CH2:16][CH:17]=[CH2:18])([CH2:19][CH:20]=[CH2:21])=[O:15])[CH2:4][C:3]([OH:31])=[O:2]
Reactant: C=CCP(=O)(CC=C)C(CCC(=O)N(CC(=O)O)CC(OC)OC)P(=O)(CC=C)CC=C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCP(=O)(CC=C)C(CCC(=O)N(CC=O)CC(=O)O)P(=O)(CC=C)CC=C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 39 (120 mg, 0.217 mmol) was dissolved in 5 mL of CH2Cl2 and 2.5 mL of TFA (containing 6% H2O) was added. The mixture was stirred for 30 min at room temperature and was then concentrated in vacuo to give the product 40 that was used as such in the next step. 1H NMR (400 MHz, CDCl3) δ 2.29 (m, 2H), 2.64 (m, 2H), 2.86 (m, 1H), 4.04 (bs, 2H), 4.16 (d, J=5.3 Hz, 2H), 4.60 (m, 8H), 4.74 (s, 2H), 5.23-5.27 (m, 4H), 5.35-5.40 (m, 4H), 5.90-6.00 (m, 4H), 9.58 (s, 1H).
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH2:11])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].C1(C)C=CC=CC=1.C[O:20][C:21](=O)[CH:22]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:24][CH3:25]>C1COCC1>[C:30]([O:29][C:27](=[O:28])[NH:26][CH:22]([C:21](=[O:20])[NH:11][C:8]1[CH:7]=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[O:10][N:9]=1)[CH2:23][CH2:24][CH3:25])([CH3:31])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CCCC(NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(C(C)(C)C)on1
Reaction time: 1 h
Yield: 141.2 %

Procedure:
To a solution of 5-tert-butyl-isoxazol-3-ylamine hydrochloride (1.22 g, 8.69 mmol) in THF was added 2 M AIMe3 in toluene (4.3 ml, 8.6 mmol) at room temperature and stirred for 1 hr. A solution of 2-tert-butoxycarbonylamino-pentanoic acid methyl ester (1.005 g, 4.34 mmol) in THF was added and the resulting mixture was stirred at room temperature over the weekend. The mixture was quenched with Rochelle salt and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give 2.08 g of the title compound as a crude oil. The oil was purified by silica gel column chromatography using 1% methanl in methylenechloride as eluent to give the title compound as a white solid (0.554 g). 1H NMR (CDCl3) □ 8.8 (brs, 1H), 6.7 (s, 1H), 4.85 (brs, 1H), 4.22 (m, 1H), 1.9 (m, 1H), 1.4-1.7 (m, 3H), 1.45 (s, 9H), 1.44 (s, 9H), 0.97 (t, 3H) ppm. LC-MS M+1=340.3.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[C:20]([NH:22][O:23]C3CCCCO3)=[O:21])[C:13](=[O:35])[CH:12]=2)=[CH:7][CH:6]=1.Cl>O1CCOCC1.CO>[OH:23][NH:22][C:20](=[O:21])[C:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:18][CH2:17][N:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=2)=[CH:12][C:13]1=[O:35]
Reactant: CC(CCn1ccc(-c2ccc(CCCO)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(CCn1ccc(-c2ccc(CCCO)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To 4-{4-[4-(3-hydroxypropyl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (213 mg, 0.420 mmol) was added 4 N hydrogen chloride in dioxane (5.0 mL) and methanol (0.50 mL). The reaction was stirred for 30 minutes and then evaporated to dryness. The residue was dissolved in minimal dichloromethane (2.0 mL) and diluted with ether to produce a precipitate. The suspension was stirred overnight at room temperature. The resulting solid was allowed to settle and the liquid was decanted off. The solid was rinsed twice with ether and dried on a vacuum pump to give the title compound as a white solid (164 mg, 92.4%). 1H NMR (400 MHz, CD3OD, 5 ppm 1.72 (s, 3H), 1.83-1.91 (m, 2H), 2.41 (ddd, J=13.4, 10.9, 5.4 Hz, 1H), 2.66 (ddd, J=13.6, 10.8, 5.4 Hz, 1H), 2.76 (m, 2H), 3.10 (s, 3H), 3.59 (t, J=6.4 Hz, 2H), 4.05 (ddd, J=12.5, 10.5, 5.2 Hz, 1H), 4.38 (ddd, J=12.9, 10.7, 5.0 Hz, 1H), 6.95 (d, J=1.8 Hz, 1H), 7.00 (m, 1H), 7.38 (br d, J=8.3 Hz, 2H), 7.66 (br d, J=8.3 Hz, 2H), 7.87 (d, J=7.1 Hz, 1H). LCMS: 423.3 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[C:27]4[O:26][CH2:25][CH2:24][O:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[CH:14][C:13]2=[O:28])[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:50][C:51]1[CH:55]=[CH:54][N:53]([CH2:56][C:57]([CH3:60])([OH:59])[CH3:58])[N:52]=1>ClCCl>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[C:27]4[O:26][CH2:25][CH2:24][O:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[CH:14][C:13]2=[O:28])[C:9]([NH:50][C:51]2[CH:55]=[CH:54][N:53]([CH2:56][C:57]([OH:59])([CH3:58])[CH3:60])[N:52]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cccc3c2OCCO3)=CC1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3cccc4c3OCCO4)=CC2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
A solution of (S)-3-cyclohexyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (200 mg, 0.52 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (81 mg, 0.52 mmol) and 1-hydroxybenzotriazole (75 mg, 0.54 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 88 mg, 0.57 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (117 mg, 43%) as a white solid: LR-ES-MS m/z calculated for C28H36N4O6 [M]+ 524, observed [M+H]+ 525; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.74-1.33 (m, 6H) 1.04 (s, 3H) 1.06 (s, 3H) 1.49-1.89 (m, 7H) 3.89 (s, 2H) 4.11 (d, J=18.4 Hz, 1H) 4.28 (s, 4H) 4.52 (d, J=18.4 Hz, 1H) 4.68 (s, 1H) 4.84 (s, 1H) 4.89 (dd, J=10.6, 4.8 Hz, 1H) 6.44 (d, J=2.1 Hz, 1H) 6.72-6.95 (m, 3H) 7.53 (d, J=2.1 Hz, 1H) 10.77 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1F.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[Br:16]
Reactant: Oc1ccccc1Br
Reactant: COC(=O)c1ccc(C(=O)OC)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)OC)c(Oc2ccccc2Br)c1
Temperature: 100 °C

Procedure:
A mixture of 2-fluoro-terephthalic acid dimethyl ester 2j (10 g, 47.1 mmol), 2-bromophenol 1j (6.0 mL, 51.8 mmol) and potassium carbonate (7.16 g, 51.8 mmol) in N,N-dimethylformamide (100 mL) was heated at 100° C. for 36 h. The mixture was allowed to cool to rt, then poured into cold dilute hydrochloric acid (0.5 N, 350 mL). The product was extracted into EtOAc, washed with water (4×) and brine (1×) and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was purified by flash chromatography on silica gel using dichloromethane as the eluant. The crude product was isolated (10.5 g) and used without further purification in the subsequent reaction. MS: m/z 365 (MH+).
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]1[C:28]([Cl:29])=[CH:27][C:26]([O:30][CH3:31])=[CH:25][C:24]=1[Cl:32]>>[C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH:7]1[CH2:8][CH2:9][CH:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:22][C:23]3[C:24]([Cl:32])=[CH:25][C:26]([O:30][CH3:31])=[CH:27][C:28]=3[Cl:29])[C:14]2=[O:18])[CH2:11][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(Cl)c(CBr)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCCC2=O)CC1
Product: COc1cc(Cl)c(CC2CCN(C3CCC(O[Si](C)(C)C(C)(C)C)CC3)C2=O)c(Cl)c1
Yield: 49 %

Procedure:
Using the procedure to synthesize Example 202 and using the reagents of cis-1-[4-(tert-butyl-dimethyl-silanoxy)-cyclohexyl]-pyrrolidin-2-one (Preparation 17) and 2-Bromomethyl-1,3-dichloro-5-methoxy-benzene (Preparation 62). Warm reaction to room temperature, quench with NH4Cl (sat), dilute with diethyl ether, wash with brine, dry over sodium sulfate, filter and evaporate to an oil. Chromatography (silica, 100% hexanes to 75:25 hexanes/EtoAc) yields 1-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-3-(2,6-dichloro-4-methoxy-benzyl)-pyrrolidin-2-one in 49% yield. The silylether is dissolved in THF, treated with 10.0 equivalents of HCl (conc) and allowed to stir at room temperature for 3 h, quench reaction with water, dilute with EtOAc, adjust pH to 7.0, separate, dry over sodium sulfate, filter and evaporate provides the titled compound in 84% yield: Mass spectrum (API-ES positive) m/z=372 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15](=[O:29])[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15](=[O:29])[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(OC(=O)Nc2ccccc2C2CCCCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1C1CCCCC1)OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of the product of step (b) (3.22 g, 8.00 mmol) in 4 M hydrochloric acid in dioxane (40 mL) was heated at 50° C. After 8 h, the reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure to give the title compound. MS m/z: [M+H+] calcd for C18H26N2O2 303.20; found 303.5. 1H NMR (CD3OD, δ): 7.2 (m, 4H), 4.95 (m, 1H), 4.85 (s, 1H), 3.3 (br m, 3H), 2.8 (br m, 1H), 2.2 (br m, 2H), 2.0 (br m, 2H), 1.8 (br m, 5H), 1.4 (br m, 5H).
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[CH:25]=[C:26]([C:28](=[O:30])[CH3:29])[CH:27]=2)[C:10]=1[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])C>[OH-].[Na+]>[C:28]([C:26]1[CH:27]=[C:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]2[C:10]([CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:45])=[O:3])[CH:23]=[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)[CH:25]=1)(=[O:30])[CH3:29]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(C)=O)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2cccc(F)c2)c1
Yield: 66.4 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[3-[6-(5-acetyl-3′-fluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (275 mg, 0.44 mmol) and 1.0 N aqueous sodium hydroxide (10 mL) to afford 4-[3-[6-(5-acetyl-3′-fluoro-biphenyl-3-yloxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (165 mg, 66%) as a white solid: ES(+)-HRMS m/e calcd for C33H37FO7 (M+Na)+ 587.2415. found 587.2415.