Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:14][C@H:13]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:27])=[CH:10][C:11]=2[Cl:26])[NH:6]1)=[O:4]>CS(C)=O>[C:3]([C@H:5]1[CH2:14][C@H:13]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:27])=[CH:10][C:11]=2[Cl:26])[NH:6]1)([OH:4])=[O:2]
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)Nc2ccc(I)cc2)c2c(Cl)cc(Cl)cc2N1
Solvent: CS(C)=O
Product: O=C(Nc1ccc(I)cc1)N[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21

Procedure:
This compound was prepared by the method given for Example 38 step b using trans-2-methoxycarbonyl-5,7-dichloro-4(4-iodophenylaminocarbonyl)amino-1,2,3,4-tetrahydroquinoline in place of trans-2-methoxycarbonyl-5,7-dichloro-4(phenylaminocarbonyl)amino-1,2,3,4-tetrahydroquinoline to give the title compound as colourless crystals, m.p. 224°-226° C. δ (DMSO, 360 MHz) 1.62 (1H, ddd, J=13.1, 12.9 and 3.4 Hz, CHACHBHCCHD), 2.31 (1H, dm, J=13.1 Hz, CHACHBHCCHD), 3.87 (1H, dd, J=12.7 and 2.7 Hz, CHACHBHCCHD), 4.92 (1H, m, CHACHBHCCHD), 6.58 (1H, d, J=6.6 Hz, NHCONHAr), 6.68 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.79 (1H, s, ArNHCH), 6.88 (1H, d, J=2.0 Hz, 6-H or 8-H), 7.25 (2H, d, J=8.7 Hz-Ar-H), 7.54 (2H, d, 8.7 Hz, Ar-H), 8.26 (1H, s, NHCONHAr); m/e (FAB+) 506 (M+1) 93 (100%); Found C, 40.14; H, 2.80; N, 8.20; C17H14Cl2N3IO3.O.1H2O requires C, 40.20; H, 2.82; N, 8.24%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[C:28]([NH2:31])(=[O:30])[CH3:29]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:31][C:28](=[O:30])[CH3:29])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: CC(N)=O
Product: CC(=O)Nc1ccc(C(=O)N2CCN(c3ccc(C)cc3C)CC2)c(S(C)(=O)=O)c1
Yield: 10.8 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (526 mg) described in Preparation Example 110 and acetamide (75.7 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (54 mg) was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[C:18]([C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28])=[CH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.O>CN(C)C=O>[CH3:34][O:33][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)[N:13]=[CH:12][CH:11]=[C:10]2[O:16][C:17]1[C:18]([C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28])=[CH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: C1COCCN1
Reactant: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCCl)c(OC)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCN3CCOCC3)c(OC)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Propyl 3-[7-(3-chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-naphthalene-2-carboxylate (compound 325) (110 mg) was dissolved in N,N-dimethylformamide (3 ml) to prepare a solution. Potassium carbonate (317 mg) and morpholine (0.1 ml) were added to the solution, and the mixture was stirred at 60° C. overnight. Water was added to the reaction solution, the mixture was extracted with chloroform, and the chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was pufified by thin layer chromatography using chloroform-methanol to give the title compound (106 mg, yield 87%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([C:12]([O:14]C)=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.Cl>O>[ClH:1].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c(Cl)ccnc2cc1OC
Agent: Cl
Solvent: O
Product: COc1cc2nccc(Cl)c2cc1C(=O)O
Temperature: 90 °C
Yield: 171.4 %

Procedure:
A mixture of methyl 4-chloro-7-methoxyquinoline-6-carboxylate (3 g) and concentrated aqueous hydrochloric acid (36%; 75 ml) was stirred and heated to 90° C. for 45 minutes. The mixture was allowed to cool to ambient temperature, poured into water (150 ml) and washed with methylene chloride. Evaporation of the aqueous phase gave 4-chloro-7-methoxyquinoline-6-carboxylic acid hydrochloride (2.8 g); NMR Spectrum: (DMSOd6) 3.98 (s, 3H), 7.6 (s, 1H), 7.7 (d, 1H), 8.4 (s, 1H), 8.86 (d, 1H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[F:10][C:11]([F:15])([F:14])[CH2:12][OH:13].CC(C)([O-])C.[K+]>O>[F:10][C:11]([F:15])([F:14])[CH2:12][O:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: OCC(F)(F)F
Reactant: N#Cc1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 6-chloronicotinonitrile (0.30 g, 2.2 mmol) was a mixture of 2,2,2-trifluoroethanol (0.19 mL, 2.6 mmol) and potassium tert-butoxide (1M solution in THF, 2.5 mL, 2.5 mmol) added at 0-5° C. The resulting mixture was stirred at ambient temperature for 1 hour. Water was added (20 mL) followed by extraction with ethyl acetate (2×20 mL). The organic layer was dried over sodium sulphate and concentrated in vacuum affording 6-(2,2,2-trifluoroethoxy)nicotinonitrile, 0.42 g (96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (d, J=2.26 Hz, 1 H) 8.28 (dd, J=8.53, 2.26 Hz, 1 H) 7.21 (d, J=8.78 Hz, 1 H) 5.09 (q, J=8.95 Hz, 2 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[S:6][CH:5]([C:7]2[O:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=2)[NH:4][C@H:3]1[C:15]([OH:17])=[O:16].[C:19](OC(=O)C)(=[O:21])[CH3:20]>O>[C:19]([N:4]1[C@@H:3]([C:15]([OH:17])=[O:16])[C:2]([CH3:18])([CH3:1])[S:6][C@H:5]1[C:7]1[O:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)SC(c2ccc([N+](=O)[O-])o2)N[C@H]1C(=O)O
Solvent: O
Product: CC(=O)N1[C@@H](C(=O)O)C(C)(C)S[C@H]1c1ccc([N+](=O)[O-])o1
Temperature: 100 °C
Yield: 84.3 %

Procedure:
A solution containing 2.72 g (10 mmoles) of 5,5-dimethyl-2-(5-nitro-2-furyl)-thiazolidine-4(S)-carboxylic acid in 5.6 ml of water is heated to 100° C. on the steam bath. After adding 5.6 ml of acetic anhydride, the mixture is heated for additional 3 minutes. On the addition of water, 2.6 g (84.3%) of the title compound are precipitated, m.p.: 191°14 194° C., [α]D25 =-315.8° (c=0.938, dimethylsulphoxide).
Reaction SMILES: [CH:1](O)=O.C=O.N.C.[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([OH:26])[C:18]=1[N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[N:15]([NH:27][CH3:28])[CH:14]=[C:13]([C:29]([OH:31])=[O:30])[C:12]2=[O:32]>>[F:8][C:9]1[CH:10]=[C:11]2[C:12](=[O:32])[C:13]([C:29]([OH:31])=[O:30])=[CH:14][N:15]3[C:16]2=[C:17]([C:18]=1[N:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]1)[O:26][CH2:28][N:27]3[CH3:1]
Reactant: O=CO
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)CC3)c(O)c21
Agent: C=O
Agent: N
Product: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2OCN4C)CC1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To the dark brown reaction mixture of step 6) containing 12 340 ml of 85% formic acid (ca. 7.5 mol) were added dropwise during 5 minutes without exceeding a temperature of 50° C. In the temperature range of 40°-50° C. 75.0 ml of aqueous 36.5% formaldehyde (ca. 1.0 mol) were added over 5 minutes and the resulting brown suspension was heated to 70° C. for 30 minutes, during which time gas evolution occurred. After cooling to 5°-10° C. 300 ml of 25% aqueous ammonia (ca. 4 mol) were added and the resulting black solution was stirred for 30 minutes. To this solution 9 g of activated charcoal were added and the resulting black suspension was stirred for 15 minutes and filtered through a glass fibre filter. The filtrate was extracted with 5 portions of 1000 ml, in total 5000 ml, of methylene chloride. The combined extracts were filtered through a glass fibre filter to remove small amounts of insoluble by-products, and the dark brown filtrate was evaporated in a rotary evaporator at 50° C./20 torr to dryness to yield 107.6 g of brown crystals. The crystals were taken up in 400 ml of ethanol and the resulting slurry was stirred for 1 hour at 0°-5° C., filtered, and the filter cake was washed with 100 ml of ethanol to yield after drying at 50° C./35 torr overnight 83.7 g of crude 1 as yellow crystals. This crude material was suspended in a mixture of 835 ml of ethanol, 415 ml of toluene and 415 ml of water (deionized) and heated to reflux. From the clear yellow solution formed 835 ml of solvent mixture was distilled off, whereby the temperature rose from 74°-78° C., and a yellow precipitate was formed. The suspension was cooled to room temperature, stirred for 1 hour, filtered, and the filter cake was washed with 3 portions of 60 ml, in total 180 ml, of ethanol to yield after drying at 50° C./35 torr overnight as the product 77.71 g (43% relative, to 6) of 1 as yellow crystals of m.p. 265°-268° C. (dec.).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8](=[O:22])C2C=C(C)C=CC=2C2C=NN(C)C=2)[C@@H:3]1[CH2:23][N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34].[C:35]1(C(O)=O)[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][N:36]=1>>[C:35]1([C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]2[CH2:23][N:24]2[C:25](=[O:34])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]2=[O:33])=[O:22])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][N:36]=1
Reactant: O=C(O)c1nccc2ccccc12
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Product: C[C@@H]1CCCN(C(=O)c2nccc3ccccc23)[C@@H]1CN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared following the same general protocol as described for 2-(((2S,3R)-3-methyl-1-(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoyl)piperidin-2-yl)methyl)isoindoline-1,3-dione in Example A1, using isoquinoline-1-carboxylic acid. ESI-MS (m/z): 414 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[OH:23]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:7]([C:6]2[CH:5]=[C:4]([CH3:10])[S:3][C:2]=2[Br:1])=[O:9])=[C:17]([OH:23])[CH:18]=1
Reactant: Cc1cc(C(=O)O)c(Br)s1
Reactant: Nc1ccc(F)cc1O
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)Nc2ccc(F)cc2O)c(Br)s1

Procedure:
In the same manner as in Starting Material Synthesis Example 67 and using 2-bromo-5-methyl-3-thiophenecarboxylic acid, thionyl chloride and 2-amino-5-fluorophenol, N-(4-fluoro-2-hydroxyphenyl)-2-bromo-5-methyl-3-thiophenecarboxamide is obtained.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([C@@H:26]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[C:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:31]=1)[CH2:27]O)[CH2:19]2.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([C@@H:26]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[C:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:31]=1)[CH2:27][N:46]1[C:42](=[O:52])[C:43]3[C:44](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:45]1=[O:47])[CH2:19]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[Si](C)(C)C#Cc1cccc(C[C@@H](CO)N2Cc3cc(Br)ccc3C2=O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cccc(C[C@@H](CN2C(=O)c3ccccc3C2=O)N2Cc3cc(Br)ccc3C2=O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of diisopropyl azodicarboxylate (0.35 mL, 1.8 mmol) in tetrahydrofuran (2.9 mL) was added 5-bromo-2-((1S)-2-hydroxy-1-{3-[(trimethylsilyl)ethynyl]benzyl}ethyl)-isoindolin-1-one (0.58 g, 1.3 mmol), phthalimide (0.21 g, 1.4 mmol), and triphenylphosphine (0.35 g, 1.3 mmol). The mixture was stirred at room temperature for 4 h. Direct purification by combi-flash chromatography eluting with 0-60% EtOAc in hexanes afforded the desired product. LC-MS found: 571.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:15][C:8]2=[N:9][C:10]([CH3:14])=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH3:4].[Br:16][C:17]1[CH:18]=[N:19][C:20]2[CH:21](Cl)[CH2:22][CH2:23][C:24]=2[CH:25]=1.[Na+].[Br-]>O1CCOCC1>[Br:16][C:17]1[CH:18]=[N:19][C:20]2[CH:21]([N:15]3[C:8]4=[N:9][C:10]([CH3:14])=[CH:11][C:12]([CH3:13])=[C:7]4[N:6]=[C:5]3[CH2:3][CH3:4])[CH2:22][CH2:23][C:24]=2[CH:25]=1
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Reactant: ClC1CCc2cc(Br)cnc21
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCc1nc2c(C)cc(C)nc2n1C1CCc2cc(Br)cnc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 13.8 %

Procedure:
To a solution of NaH, 60% in oil, (163 mg) in 3 mL of 1,4-dioxane was added 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (1.1 gm) at room temperature and stirred for 30 minutes. Then 3-bromo-7-chloro-6,7-dihydro-5H-[1]pyrindine (500 mg, 2.15 mM) in 2 mL of 1,4-dioxane and anhydrous NaBr (442 mg) were added to the solution and the reaction was heated to 100° C. for 24 hours. The reaction was then cooled to room temperature, concentrated to dryness, and extracted into ethyl acetate from water. The organic layers were dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by chromatography on silica gel to yield 110 mg of product.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:4][CH:3]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][C:2]([F:1])([F:25])[CH:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1CN(c2ccncc2[N+](=O)[O-])CCC1(F)F
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CN(c2ccncc2N)CCC1(F)F
Yield: 99 %

Procedure:
Following Method 2 of Example 49, (+/−)-tert-butyl 4,4-difluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate and triethylamine in ethanol and ethyl acetate (1:1, 0.1 M solution) was reduced yielding (+/−)-tert-butyl 1-(3-aminopyridin-4-yl)-4,4-difluoropiperidin-3-ylcarbamate, (>99%). LCMS (m/z): 329.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[C:18]4[CH:19]=[CH:20][C:21]([C:23]5[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=5)=[CH:22][C:17]=4[N:16]=[CH:15]3)[CH:11]=[C:10]([NH:29]C(=O)C)[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[C:18]4[CH:19]=[CH:20][C:21]([C:23]5[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=5)=[CH:22][C:17]=4[N:16]=[CH:15]3)[CH:11]=[C:10]([NH2:29])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(N)cc(-c3ccc(F)cc3)c2)cn1
Temperature: 85 °C
Yield: 44 %

Procedure:
To a solution of the compound of Example 53 (0.6 g, 1.41 mmol) in ethanol (20 ml) was added aqueous solution of NaOH (451 mg, 11.3 mmol, 8.0 eq.) and the mixture was heated at 85° C. for 4 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the product in 44% yield (0.24 g). LC-MS (ESI): Calculated mass: 383.42; Observed mass: 384.1 [M+H]+ (rt: 1.004 min).
Reaction SMILES: [CH2:1]([C:3]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:32]([OH:42])=[CH:31][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](N(C)C)=[O:22])[C:11]=1[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH3:2].C(C1C=C(C2C=CC(F)=CC=2)C(O)=CC=1[O:47]CCCOC1C=CC=CC=1CCC(O)=O)C>>[CH2:1]([C:3]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:32]([OH:42])=[CH:31][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:47])=[O:22])[C:11]=1[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH3:2]
Reactant: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCOc1ccccc1CCC(=O)O
Reactant: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCOc1cccc(OCCCCC(=O)N(C)C)c1CCC(=O)O
Product: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCOc1cccc(OCCCCC(=O)O)c1CCC(=O)O
Yield: 42 %

Procedure:
3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)propoxy)-6-(4-dimethylaminocarbonylbutyloxy)phenyl)propionic acid, 42% yield, NMR. ##STR21## 4. 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)propoxy)phenyl)propionic acid, 15% yield, NMR, MS. ##STR22## 5. 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)propoxy)-6-(4-carboxybutyloxy)phenyl)propionic acid, yield, NMR, MS.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:20]([N:19]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCNCCCCCC
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N(CCCCCC)CCCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and dihexylamine as starting materials to give the aimed compound.
Reaction SMILES: [CH:1]1([N:4]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)(=[O:26])=[O:25])[C:5]2[CH:6]=[C:7]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:8]=[C:9]3[C:13]=2[NH:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10]3)[CH2:3][CH2:2]1>[O-2].[Mn+4].[O-2].C1(C)C=CC=CC=1>[CH:1]1([N:4]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)(=[O:26])=[O:25])[C:5]2[CH:6]=[C:7]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:8]=[C:9]3[C:13]=2[NH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10]3)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1Cc2cc(OCCOC)cc(N(C3CC3)S(=O)(=O)c3ccccn3)c2N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(OCCOC)cc(N(C3CC3)S(=O)(=O)c3ccccn3)c2[nH]1
Yield: 94.3 %

Procedure:
To a mixture of ethyl 7-[cyclopropyl(pyridin-2-ylsulfonyl)amino]-5-(2-methoxyethoxy)indoline-2-carboxylate (1.31 g) and toluene (30 mL) was added manganese (IV) oxide (0.99 g) at room temperature, and the mixture was refluxed for 3 hr. The catalyst was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give the title compound (1.23 g, yield 94%) as a colorless solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][N:1]2[CH2:5][CH2:4][NH:3][C:2]2=[O:6])=[CH:29][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: O=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1NCCN1Cc1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Yield: 32 %

Procedure:
Imidazolidin-2-one (2.0 g; 23.23 mmol) was dissolved in dimethyl sulfoxide (DMSO; 30 ml). Potassium carbonate (3.10 g; 23.23 mmol), potassium iodide (0.95 g; 5.80 mmol) and 4-benzyloxybenzyl chloride (5.4 g; 23.23 mmol) were added thereto. The mixture was heated at 100° C. for 3 hours (h). Cooling to RT was followed by partition between water (100 ml) and ethyl acetate (EtOAc, 100 ml). The phases were separated and the aqueous phase was extracted with EtOAc (3×; 30 ml). The combined organic phases were washed with saturated NaCl solution (80 ml) and dried over MgSO4. The solvent was removed under reduced pressure in a rotary evaporator. Trituration of the residue with EtOAc (10 ml) triturated resulted in 1-(4-benzyloxybenzyl)-imidazolidin-2-one (2.10 g; 7.43 mmol). MS: 283.15 (M+H); Rt: 1.38 min (method: gradient 0 min 90% H2O (0.05% TFA) 1.9 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 10% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:9]([Zn]CC)C.ClCI>ClCCCl.CCCCCC.CCOC(C)=O.Cl>[C:1]12([CH2:7][OH:8])[CH2:9][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: OCC1=CCCCC1
Reactant: CC[Zn]CC
Agent: Cl
Agent: ClCI
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCCl
Product: OCC12CCCCC1C2
Reaction time: 0.17 h

Procedure:
To a solution of cyclohex-1-en-1-ylmethanol (0.6 g, 5.35 mmol) in DCE (5 mL) at 0° C., was added 1 N diethylzinc in hexane (8.56 mL), the reaction mixture was stirred for 10 min, then chloroiodomethane (1.242 ml, 17.12 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h, and then stirred at rt for 16 hr. The reaction was diluted with EtOAc and 1 N HCl, the organic phase was washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield an oil. The crude product was charged to a 25 g silica gel cartridge which was eluted with a 20 min gradient of 0-40% EtOAc in hexane to afford bicyclo[4.1.0]heptan-1-ylmethanol (0.12 g). 1H NMR (400 MHz, CDCl3) ppm 3.27-3.38 (2H, m), 1.81-1.92 (2H, m), 1.54-1.78 (2H, m), 1.11-1.37 (4H, m), 0.81 (1H, dddd, J=9.16, 7.22, 5.46, 1.51 Hz), 0.46 (1H, dd, J=9.29, 4.52 Hz), 0.24 (1H, t, J=5.02 Hz).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[CH2:28]([O:30][C:31]([C:33]1[CH:37]=[C:36]([Sn](CCCC)(CCCC)CCCC)[O:35][N:34]=1)=[O:32])[CH3:29].[F-].[K+]>CN(C=O)C.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].[Cu]I.C(OCC)C>[CH2:28]([O:30][C:31]([C:33]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][OH:11])[CH:3]=2)[O:35][N:34]=1)=[O:32])[CH3:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OCC)no1
Reactant: OCCCc1cccc(I)c1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2cccc(CCCO)c2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To 3-(3-iodophenyl)-1-propanol (1.55 g, 5.60 mmol), tri-2-furylphosphine (130 mg, 0.56 mmol), tris(dibenzylideneacetone)dipalladium (256 mg, 0.23 mmol), and CuI (107 mg, 0.56 mmol) was added DMF (10 mL). To this mixture was added a solution of 5-tributylstannanyl-isoxazole-3-carboxylic acid ethyl ester (2.41 g, 5.60 mmol) as a solution in DMF (10 mL). The reaction was stirred under N2 at ambient temperature for 1 hour, then 5% (w/v) KF(aq) (100 mL) and diethyl ether (50 mL)were added. The biphasic mixture was stirred vigorously for 10 minutes, then filtered through diatomaceous earth to remove the solid precipitates. The precipitate was washed with diethyl ether to recover any organic material from the filter pad, then the combined filtrate and washings were separated. The aqueous layer was extracted with additional ether (2×25 ML), the combined ether layers were washed with water (1×25 mL), and brine (1×25 mL), dried over MgSO4, filtered, and concentrated to an oil. The product was purified via silica gel chromatography, eluting with 40% ethyl acetate/hexanes to provide the titled compound (950 mg, 2%). 1H NMR (500 MHz, d6-DMSO) δ 7.81 (s, 1H), 7.77 (d, 1H, J=7.5 Hz), 7.47 (t, 1H, J=7.6 Hz), 7.47 (s, 1H), 7.39 (d, 1H, J=7.4 Hz), 4.49 (t, 1H, J=5.2 Hz), 4.41 (q, 2H, J=7.2 Hz), 3.44 (q, 2H, J=5.9 Hz), 2.71 (t, 2H, J=7.8 Hz), 1.78 (m, 2H), 1.36 (t, 3H, J=7.2 Hz); MS (ESI) m/z 276 (M+H)+, 293 (M+NH4)+, 298 (M+Na)+.