Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[CH:42]=[CH:41][C:24]([CH2:25][N:26]2[CH:30]=[C:29]([C:31](OCC)=[O:32])[C:28]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)=[N:27]2)=[CH:23][CH:22]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:26]2[CH:30]=[C:29]([CH2:31][OH:32])[C:28]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)=[N:27]2)=[CH:41][CH:42]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1cccs1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CO)c(-c3cccs3)n2)cc1
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Lithium aluminium hydride (1100 mg) was added gradually to a solution of ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate (14.39 g) in tetrahydrofuran (50 ml) at 0° C., which was stirred for 30 minutes. Sodium sulfate decahydrate (12.14 g) was added to the reaction mixture, and the precipitate was removed by filtration. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography to obtain [1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]methanol (12.20 g, yield: 93%) as pale yellow oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH2:1]([C@H:8]([CH2:20][C@@H:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:22]([OH:24])=[O:23])[C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.O.[Rh]>[CH:2]1([CH2:1][C@@H:8]([CH2:20][C@H:21]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:22]([OH:24])=[O:23])[C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)O)C(=O)O
Agent: [Rh]
Solvent: CCO
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@@H](CC1CCCCC1)C[C@H](CC1CCCCC1)C(=O)O)C(=O)O
Reaction time: 36 h

Procedure:
A suspension of 0.5g of N-[(S,S)-2,4-dibenzyl-4-carboxybutyryl]-(L)-leucine and 0.5g of 5% Rh/C in 10 ml of ethanol and 10 ml of water is hydrogenated for 36 hours at 3 atmospheres pressure (50 psi). The mixture is filtered through celite and concentrated. The colorless oil is treated with 1.0 N sodium hydroxide in methanol and concentrated to yield N-[(S,S)-2,4-di-(cyclohexylmethyl)-4-carboxybutyryl]-(L)-leucine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[C:15]1([S:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([S:21][CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]2[CH:3]=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=3[CH:14]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)OC(=O)Nc2ccc(O)cc21
Reactant: BrCCCCSc1ccccc1
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccccc3)cc21

Procedure:
Prepared analogously to Example 5 from 6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-phenylmercaptobutylbromide (B.p. 0.03 mb : 95°-104° C.).
Reaction SMILES: [C:1]([C@@H:9]1[CH2:13][CH:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:11](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:35])(=O)C1C=CC=CC=1.CCN(C(C)C)C(C)C.[O-]S([O-])(=O)=O.[Mg+2].C=O.Cl>O1CCCC1.C1(C)C=CC=CC=1>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:12]2[N:11](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10](=[O:35])[C:9](=[CH2:1])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Agent: C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
(S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (4a, R1=styryl, R4=phenyl) (1.0 g, 2.2 mmol) is dissolved in 5 mL of anhydrous tetrahydrofuran, add iPr2NEt (370 mg, 2.8 mmol) anhydrous Lithium chloride (49 mg, 1.1 mmol) and anhydrous MgSO4 (260 mg, 2.2 mmol), reflux for 30 min under nitrogen atmosphere, then add paraformaldehyde (80 mg, 2.7 mmol), reflux for 2 h under nitrogen atmosphere. The reaction mixture is cooled to room temperature, add 20 mL of toluene and 10 mL of 5% HCl(aq), separate the aqueous phase, wash with saturated sodium hydrogen carbonate aqueous solution and brine, dry over anhydrous sodium sulfate and concentrate under vacuum to obtain (R)-5-Biphenyl-4-ylmethyl-3-methylene-1-((E)-styryl)-pyrrolidin-2-one (1a, R1=styryl).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-:3])=[O:2].[CH:16]([N:18]1[CH:27](C(O)=O)[CH:26]([CH3:31])[CH:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH2:24]2)[CH2:19]1)=O>C(OC(=O)C)(=O)C>[CH3:31][CH:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][N:18]2[CH:16]=[C:7]3[C:8]([C:9](=[O:14])[C:10]4[CH:11]=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=4[C:6]3=[O:15])=[C:27]12
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CC1C2CC=CC=C2CN(C=O)C1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1c2ccccc2Cn2cc3c(c21)C(=O)c1cccc([N+](=O)[O-])c1C3=O
Yield: 138.9 %

Procedure:
A mixture of 5-nitro-1,4-naphthoquinone (4.7 g) and N-formyl-4-methyl-3-tetrahydroisoquinolinecarboxylic acid (2.4 g) suspended in acetic anhydride (15 ml) was stirred and heated at 70°-75° for 21/2 hours. The mixture was cooled and the solid formed was collected by filtration, washed with acetic anhydride, then with ether and finally dried to give the title compound (5.4 g) as a yellow crystalline solid. N.m.r. in DMSOd6 (ppm) δ 1.49(14-CH3);4.88(14-H); 5.37, 5.47(5-CH2); 8.39(10-H). U.v. λmax 246 nm, E11 481; 376 nm, E11 83.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:11][C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:22].[Na+]>O1CCOCC1.O>[NH2:3][C:4]1[C:5]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([OH:22])=[O:1]
Reactant: [OH-]
Reactant: O=C1Cc2cccc(Oc3ccc4ccccc4c3)c2N1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(CC(=O)O)cccc1Oc1ccc2ccccc2c1
Reaction time: 72 h
Yield: 54.4 %

Procedure:
A mixture of 2-oxo-7-(β-naphthoxy)indoline (5 g) and sodium hydroxide (1.6 g) in dioxane (40 ml) and water (80 ml) was refluxed with stirring for 72 hrs. After cooling, the reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue was dissolved in hot ethanol and filtered. The filtrate was evaporated in vacuo, and ethyl acetate was added to the residue. The resultant ethyl acetate solution was heated. The precipitating crystals were collected by filtration and recrystallized from ethanol to give 2-[2-amino-3-(β-naphthoxy)phenyl]acetic acid (2.9 g). This substance was dissolved in an aqueous sodium bicarbonate, and the solution was filtered and lyophilized to give sodium 2-[2-amino-3-(β-naphtoxy)phenyl]acetate (2.8 g).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:10][CH3:11])=[CH:5][C:6]=1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=N[C:31]2[CH:32]=[CH:33][CH:34]=[N:35][C:30]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCCC1>CN(C=O)C.C(#N)C.O>[Cl:1][C:2]1[S:3][C:4]([CH2:10][CH3:11])=[CH:5][C:6]=1[C:7]([N:35]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)=[O:9]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCc1cc(C(=O)O)c(Cl)s1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCc1cc(C(=O)N2CCCCC2)c(Cl)s1
Reaction time: 8 h
Yield: 42.5 %

Procedure:
2-Chloro-5-ethyl-thiophene-3-carboxylic acid (0.04 g, 0.21 mmol) was dissolved in DMF (6 mL). DIPEA (0.63 mmol), HATU (0.21 mmol) and piperidine (2.0 mmol) were added and the reaction stirred overnight. The mixture was diluted with acetonitrile and water and the product purified by HPLC, eluting with 20%-95% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.023 g). LCMS m/z 358.08 [M+H]+RT=10.84 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 6.6 (s, 1H), 3.7 (s, 2H), 3.35 (s, 2H), 2.75 (q, 2H), 1.6 (s, 6H), 1.3 (t, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:21][CH2:20][C:11]2[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[N:14]=[CH:15][C:10]=2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:19][C:16]([F:17])([F:18])[C:13]1[N:14]=[CH:15][C:10]2[CH2:9][NH:8][CH2:21][CH2:20][C:11]=2[N:12]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(C(F)(F)F)ncc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ncc2c(n1)CCNC2

Procedure:
Reaction of the product from Step A above with trifluoroacetic acid in dichloromethane according to the procedure outlined for Intermediate 28, Step C afforded the title compound as a white powder. LC/MS 204.0 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH:5]=[CH:4][C:3]=1B(O)O.[CH2:30]([O:32][C:33](=[O:41])[C:34]1[CH:39]=[CH:38][C:37](Br)=[CH:36][CH:35]=1)[CH3:31].C(=O)([O-])[O-].[Na+].[Na+]>O.C1(C)C=CC=CC=1>[CH2:30]([O:32][C:33]([C:34]1[CH:39]=[CH:38][C:37]([C:3]2[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[C:7]([F:8])[C:2]=2[F:1])=[CH:36][CH:35]=1)=[O:41])[CH3:31]
Reactant: OB(O)c1ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c1F
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)cc1
Temperature: 25 °C

Procedure:
A bipsasic solution of 2,3-difluoro-4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-phenylboronic acid (11A) (1 equi.), 4-bromo-benzoic acid-ethyl ester (12), (1 equi.), sodium carbonate (2.7 equi.), and tetrakis(triphenylphoshine)palladium catalyst (0.01 equi.) in water-toluene (1:1) (2 mL/mmole) was stirred at 100 C temperature for 12 h., cooled to room temperature, extracted with ethyl acetate:hexane(1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. The purification by chromatography on silica gel (5% EtOAc/hexanes) and recrystallization from acetonitrile afforded 2′,3′-difluoro-4′-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-biphenyl-4-carboxylic acid ethyl ester (13A), as a white solid (88%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[OH-].[K+]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl.O.C(O)C>[C:38]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCOC(=O)CCCCCOc1cc(-c2ccc(N)cc2)cc(-c2ccccc2)n1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)CCCCCOc1cc(-c2ccc(NC(=O)c3ccccc3)cc2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of ethyl 6-{[4-(4-aminophenyl)-6-phenyl-2-pyridyl]oxy}hexanoate (4 g), triethylamine (1.7 cc) and a spatula-tip-full of 4dimethylaminopyridine (DMAP) in chloroform (40 cc), is slowly added, at room temperature, benzoyl chloride (1.38 cc) in solution in chloroform (20 cc). The temperature rises up to 33° C. The reaction mixture is then stirred at room temperature for 21 hours and then hydrolysed with distilled water (50 cc). The organic phase is decanted. The aqueous phase is extracted with dichloromethane (2×50 cc). The combined organic phases are washed with distilled water until neutrality, dried over sodium sulphate and concentrated to dryness at 40° C. under reduced pressure. The product is used directly in the next reaction after purification by recrystallization in an n-hexane-ethyl acetate (1-1) mixture (100 cc). The procedure in Example 3 is then followed but using the ethyl 6-{[4-(4-benzamidophenyl)-6-phenyl-2-pyridyl]oxy}hexanoate previously obtained, potassium hydroxide pellets (0.7 g) dissolved in distilled water (15 cc) and ethanol (150 cc). The reaction mixture is refluxed for 2 hours. The product is purified by recrystallization in ethyl acetate (50 cc), whitish crystals (m.p.=167°-169° C.)
Reaction SMILES: CO[C:3](=O)[C@@H:4]1[CH2:8][C:7](=[CH:9][CH2:10][CH3:11])[CH2:6][N:5]1[C:12](OCC1C=CC=CC=1)=O.C[O:24][C:25](=O)[C@@H:26]1CC(=C)CN1C(OCC1C=CC=CC=1)=O>>[CH2:9]([C@@H:7]1[CH2:6][N:5]2[C@H:4]([CH2:3][C:25](=[O:24])[CH2:26][CH2:12]2)[CH2:8]1)[CH2:10][CH3:11]
Reactant: CCC=C1C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Reactant: C=C1C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Product: CCC[C@H]1C[C@H]2CC(=O)CCN2C1
Yield: 24 %

Procedure:
In a similar manner to the procedures described in Preparative Examples 8(ii)′, 8(iii)′, 8(iv)′, 8(v)′ and 8(vi)′ above, reactions were conducted in turn, using (S)-1-benzyloxycarbonyl-4-propylideneproline methyl ester [prepared as described in Preparative Example 25′ above] instead of (S)-1-benzyloxycarbonyl-4methylideneproline methyl ester, to give the title compound as a brown oil (yield: 24%).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)[N:3]=1.[H-].[Na+].Cl[C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=1.O>CN(C)C=O>[CH3:28][C:27]1[O:26][C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:24][C:23]=1[CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:4]2[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:2]([O:1][C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=3)=[N:3]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(Oc3ccc(C(F)(F)F)cn3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1.00 g) in N,N-dimethylformamide (80 ml), sodium hydride (60%, oily, 100 mg) was added at 0° C., and the solution was stirred at room temperature for 30 minutes. 2-Chloro-5-trifluoromethylpyridine (0.45 g) was added to the reaction mixture, which was stirred at 90° C. for two hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). A mixture of the obtained oily substance, 1 N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml), and ethanol (10 ml) was stirred at room temperature overnight, diluted with 1 N hydrochloric acid (5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(5-trifluoromethyl-2-pyridyloxy)-1H-pyrazol-4-yl]propionic acid was obtained (960 mg, yield: 76%). This was recrystallized from ethyl acetate-hexane. Melting point: 107–108° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N:16]([O-])=O.[Na+]>O.Cl.CC#N>[ClH:1].[NH:2]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1)[NH2:16]
Reactant: O=N[O-]
Reactant: Nc1ccc(C(=O)O)c2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NNc1ccc(C(=O)O)c2ccccc12
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
2.4 g of 4-amino-1-naphthalenecarboxylic acid hydrochloride are mixed at 0° C. with 80 ml of concentrated HCl. A solution of 0.89 g of sodium nitrite in 19 ml of water is added and the mixture is left stirring for 2 hours at 2-3° C. It is cooled to -10° C., and a solution of 9.7 g of stannous chloride dihydrate in 90 ml of concentrated HCl is added slowly. The temperature is allowed to rise to RT and the mixture is kept stirring for 30 minutes. 200 ml of water are added, the mixture is left stirring for 30 minutes and the solid formed is drained. The solid is taken up in MeCN, drained, washed with ether and dried. 2.2 g of the expected product are obtained, m.p.=190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9]O)[CH:5]=[C:4]([Cl:11])[C:3]=1[NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39]>ClCCl>[Br:39][CH2:9][CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([Cl:11])[CH:5]=1
Reactant: CCOC(=O)CNc1c(Cl)cc(CCO)cc1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CNc1c(Cl)cc(CCBr)cc1Cl
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a stirred solution of ethyl N-[2,6-dichloro-4-(2-hydroxyethyl)phenyl]aminoacetate (650 mg) and triphenylphosphine (700 mg) in dichloromethane (10ml) was added carbon tetrabromide (886 mg) under ice-cooling, and the mixture was stirred for 1 hour. Rough purification of the reaction mixture by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) and further purification of the fraction by medium pressure liquid column chromatography on silica gel (eluent: hexane/dichloromethane=1/1) gave ethyl N-[4-(2-bromoethyl)-2,6-dichlorophenyl]-aminoacetate (708 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH:15]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:28][CH:29]=2)=[O:23])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:31][CH2:32][N:33]([C:7](=[O:8])[C:6]4[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:11]([F:14])([F:13])[F:12])[CH2:34][CH2:35]3)=[CH:28][CH:29]=2)=[O:23])[CH2:17][CH2:16]1
Reactant: O=C(Cl)c1cc(Cl)ccc1C(F)(F)F
Reactant: O=C(NCCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCCC1CC1)c1ccc(N2CCN(C(=O)c3cc(Cl)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 5-chloro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-cyclopropylpropyl)amide, the title compound was obtained as a white solid (73% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.86, 7.68-7.65, 7.53-7.5, 7.35, 6.99, 4.05-3.99, 3.89-3.67, 3.52-3.46, 3.37-3.34, 1.75-1.6, 1.31-1.24, 0.71-0.62, 0.43-0.37, 0.02-0.03. 13C NMR (75 MHz, CDCl3) δ 165.9, 162.9, 159.9, 145.4, 138.8, 135.93, 135.9, 129.7, 128.6, 128.4, 121.4, 112.6, 46.3, 44.5, 44.3, 41.3, 39.2, 31.9, 29.5, 10.5, 4.4. MS (ES+) m/z 496.3 (M+1).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[CH3:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:25]([C:24]2[CH:23]=[CH:22][C:21]([S:18]([CH3:17])(=[O:20])=[O:19])=[CH:29][CH:28]=2)[OH:26])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc(S(C)(=O)=O)cc1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 4-methylsulphonyl-benzoic acid
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([OH:9])=O)=[CH:4][S:5][CH:6]=1.[CH2:10]([NH2:12])[CH3:11]>O>[CH2:10]([NH:12][C:7]([C:3]1[C:2]([Br:1])=[CH:6][S:5][CH:4]=1)=[O:9])[CH3:11]
Reactant: CCN
Reactant: O=C(O)c1cscc1Br
Solvent: O
Product: CCNC(=O)c1cscc1Br
Yield: 64.5 %

Procedure:
N-Ethyl-4-bromo-3-thiophenecarboxamide was prepared from 4-bromo-3-thiophenecarboxylic acid (7 g, 34 mmol) and 70% ethylamine in water according to steps a and b of Example 248 in 64.5% yield.
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[C:7](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)\[CH2:8][O:9][Si](C(C)(C)C)(C)C)(=[O:3])[CH3:2]>CC#N.C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5]/[C:6](/[C:23]1[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=1)=[C:7](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)\[CH2:8][OH:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C(=C(\CO[Si](C)(C)C(C)(C)C)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(=O)OC/C(=C(\CO)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
To a solution of 50.5 g of (2Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-enyl acetate in 125 mL of MeCN, 10 mL of PyHF was added and the resulted mixture was stirred at rt for 1.5 hr. The reaction mixture was diluted with 600 mL of toluene and then loaded on silica gel column and eluted with EtOAc. The solvent was evaporated to afford 38.3 g of the titled compound. 1H NMR (acetone-d6, 500 M Hz): δ 7.68 (d, 2H), 7.32 (d, 2H), 7.15–7.00 (m, 5H), 5.20 (s, 2H), 4.62 (d, 2H), 4.09 (t, 1H, OH), 3.02 (s, 3H), 1.92 (s, 3 H),
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([OH:20])[C:14]=3[Cl:21])[C:8]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[NH4+].[I:25]I.Cl>[I-].[K+]>[Cl:21][C:14]1[C:15]([OH:20])=[C:16]([I:25])[CH:17]=[C:18]([Cl:19])[C:13]=1[CH2:12][CH:9]1[CH2:10][CH2:11][N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]1=[O:22]
Reactant: O=C1C(Cc2c(Cl)ccc(O)c2Cl)CCN1C1CCCCC1
Reactant: II
Agent: Cl
Agent: [I-]
Agent: [K+]
Product: O=C1C(Cc2c(Cl)cc(I)c(O)c2Cl)CCN1C1CCCCC1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
Slowly add a solution of 1-cyclohexyl-3-(2,6-dichloro-3-hydroxy-benzyl)-pyrrolidin-2-one (1.0 g, 2.9 mmol) in a minimal amount of ammonium hydroxide (with N,N-dimethylformamide added to aid in dissolution) to a stirred solution of iodine (74 mg, 2.9 mmol) in aqueous potassium iodide at 0° C. Stir over night warming to room temperature. Acidify with conc. HCl to pH less than 2, collect the precipitate, wash with water and ether, and dry under vacuum to yield the title compound 1.2 g (88%) Mass Spectrum (apci) 468 (M+H).
Reaction SMILES: Cl.CCOC(C)=O.C(OC([NH:15][CH:16]([C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:22])[C:17]([O:19][CH3:20])=[O:18])=O)(C)(C)C>CCOC(C)=O>[NH2:15][CH:16]([C:21]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)=[O:22])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)C(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)C(N)C(=O)c1ccc(OC)cc1
Yield: 102.6 %

Procedure:
HCl-EtOAc (6N solution, 200 mL) was added to a solution of methyl 2-(tert-butoxycarbonylamino)-3-(4-methoxyphenyl)-3-oxopropanoate (50.0 g, 155 mmol) in EtOAc (300 mL) at ambient temperature with stirring. The reaction mixture was stirred for 30 min and then concentrated to dryness. The residue was washed with petroleum ether (200 mL×3) and dried to afford methyl 2-amino-3-(4-methoxyphenyl)-3-oxopropanoate (HCl salt, 35.5 g, 88% yield).