Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:15]([NH:22][C:23](=[O:43])[CH2:24][NH:25][C:26](=[O:42])[C:27]2[CH:32]=[C:31]([NH:33][C:34]3[NH:35][CH2:36][CH:37]([OH:40])[CH2:38][N:39]=3)[CH:30]=[C:29]([OH:41])[CH:28]=2)[CH2:16][C:17]([O:19]CC)=[O:18])[CH:5]=[C:6]([C:8]([OH:14])([CH3:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1.O.[OH-].[Li+].ClCCl>C(#N)C.O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:15]([NH:22][C:23](=[O:43])[CH2:24][NH:25][C:26](=[O:42])[C:27]2[CH:32]=[C:31]([NH:33][C:34]3[NH:39][CH2:38][CH:37]([OH:40])[CH2:36][N:35]=3)[CH:30]=[C:29]([OH:41])[CH:28]=2)[CH2:16][C:17]([OH:19])=[O:18])[CH:5]=[C:6]([C:8]([OH:14])([CH3:13])[C:9]([F:12])([F:10])[F:11])[CH:7]=1
Reactant: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(Cl)cc(C(C)(O)C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CC(O)(c1cc(Cl)cc([C@H](CC(=O)O)NC(=O)CNC(=O)c2cc(O)cc(NC3=NCC(O)CN3)c2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of (3S)-ethyl 3-(3-chloro-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoate (from step 2 above) (0.968 mmol, crude residue) in a mixture of acetonitrile/water (1:1) (8 mL) was added lithium hydroxide monohydrate (203.1 mg, 4.84 mmol) and the reaction mixture was stirred at room temperature overnight (15 h). The solvent was evaporated in vacuo to afford a yellow-orange viscous residue. The residue was dissolved in water (25 mL) and stirred with dichloromethane (50 mL). The DCM layer was removed and discarded after analyzed by LC-MS. The aqueous layer was neutralized with TFA (1 mL in 3 mL ACN) and evaporated in vacuo to afford a pale viscous residue. The crude residue was purified by reverse-phase preparative HPLC on a Biotage 40+M (100 g) C18HS column and a gradient 10-60% acetonitrile in water containing 0.05% TFA to afford the desired product, after lyophilization, as a colorless lyophilized powder (439.2 mg). LC-MS analysis of the solid shows the desired product: (3S)-3-(3-chloro-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoic acid's mass: m/z 602 (35ClM+H) and m/z 604 (37ClM+H); Calcd for C25H27ClF3N5O7: 601.96. 1H NMR (400 MHz, DMSO-d6): δ 1.69 (s, 3H), 2.72 (d, J=7.0 Hz, 2H), 3.16 (d, J=12.8 Hz, 2H), 3.33 (d, J=12.7 Hz, 2H), 3.87 (d, J=5.3 Hz, 2H), 4.08 (s, 1H), 5.21 (appq, 1H), 5.45 (brs, 1H), 6.74 (brs, 1H), 6.79 (brs, 1H), 7.12 (dt/m, 2H), 7.41 (s, 1H), 7.49 (brs, 2H), 8.14 (brs, 2H), 8.58 (dd/m, 1H), 8.63 (brt, 1H), 9.67 (brs, 1H), 10.03 (brs, 1H), 12.40 (brs, 1H). 1H NMR spectrum of the sample was consistent with the structure of the desired titled product.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7](F)=[N:8][CH:9]=1.[OH:11][CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15]>O1CCCC1.CN1CCCN(C)C1=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[N:8][CH:9]=1
Reactant: COC(=O)C(C)(C)CO
Reactant: Fc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
Sodium hydride (60% disp. in oil, 908.0 mg, 22.72 mmol) was added portionwise at room temperature to a solution of 5-bromo-2-fluoropyridine A-5 (1.16 mL, 11.36 mmol) and methyl 3-hydroxy-2,2-dimethylpropanoate (1.88 mL, 14.77 mmol) in anhydrous tetrahydrofuran (32.9 mL) and anhydrous 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (5.0 mL) under an atmosphere of argon and in the presence of 4 Å molecular sieves. After 2 h of stirring at room temperature, the reaction mixture was heated at 50° C. for 10 h and then at 70° C. for 3 h. The suspension was cooled to room temperature, filtered over a thin celite pad, and the pad was rinsed with diethyl ether (150 mL). The filtrate was concentrated to a volume of ca. 5 mL, then diluted with diethyl ether (150 mL), quenched with water (90 mL) and decanted. The aqueous layer was extracted with diethyl ether (2×100 mL); the combined extracts were successively washed with water (3×70 mL), brine (70 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (100:0 to 80:20 hexanes:ethyl acetate gradient) to give methyl 3-(5-bromopyridin-2-yloxy)-2,2-dimethylpropanoate A-6 (1.796 g, Yield=55%). MS (ESI), [M+1]+ 288, 290.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(C(C)(C)C)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 1-(4-tert-butylphenyl)-4-chloro-1-butanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 435.2 (M+H)+.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH:25][CH2:26][CH:27]([CH2:29]O)[OH:28]>>[CH3:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:24][CH2:29][CH:27]([OH:28])[CH2:26][OH:25])=[O:23]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: OCC(O)CO
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO

Procedure:
The preferred source of monoglycerides for use in the esterification process of the present invention is at least about 90%, and is preferably at least about 95%, pure monobehenin. This preferred monoglyceride can be obtained by hydrolysis of substantially completely hydrogenated (i.e., I.V. about 10 or less) high erucic acid rapeseed oil, solventless fractionation of the resulting fatty acid mixture to provide a behenic fatty acid-enriched fraction, and then esterification of glycerol with this behenic acid-enriched fraction to provide a crude mixture of monoglycerides. This synthesis route minimizes the formation of base catalyzed by-products such as difatty ketones or diglycerols. This crude monoglyceride mixture can be subsequently purified by molecular distillation, solvent (e.g., ethyl alcohol) crystallization, liquid/liquid extraction or adsorption on a weak acid ion exchange resin to yield a source of monoglycerides having the desired purity of monobehenin.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](B(O)O)=[CH:7][CH:6]=[C:5]([O:12][CH3:13])[N:4]=1.Br[C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:39])[CH2:23][O:24][CH2:25][C:26]([NH:28][C:29]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:30]=2[C:31]([OH:33])=[O:32])=[O:27])[CH:18]=[CH:19][CH:20]=1>>[Cl:38][C:35]1[CH:36]=[CH:37][C:29]([NH:28][C:26](=[O:27])[CH2:25][O:24][CH2:23][C:22]([NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:8]3[C:3]([O:2][CH3:1])=[N:4][C:5]([O:12][CH3:13])=[CH:6][CH:7]=3)[CH:16]=2)=[O:39])=[C:30]([CH:34]=1)[C:31]([OH:33])=[O:32]
Reactant: COc1ccc(B(O)O)c(OC)n1
Reactant: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(Br)c1
Product: COc1ccc(-c2cccc(NC(=O)COCC(=O)Nc3ccc(Cl)cc3C(=O)O)c2)c(OC)n1

Procedure:
Using the same method as in Example 19-(ii), 2,6-dimethoxy-3-pyridine boronic acid was reacted with the 2-[((2-[(3-bromophenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester obtained in Example 19-(i) to give 5-chloro-2-([(2-([3-(2,6-dimethoxypyridin-3-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 51%).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:10]([N:12]1[CH2:41][CH2:40][CH2:39][C@H:13]1[C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[NH2:1][C@@H:2]([C:10]([N:12]1[CH2:41][CH2:40][CH2:39][C@H:13]1[C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Br
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](N)Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
450 mg (0.44 mmole) of Boc-D-Phe-Pro-Arg-Phe-pNa.HBr are dissolved in 4 ml of trifluoroacetic acid, with the addition of 0.1 ml of anisole, and the solution is stirred at room temperature for 45 minutes. The product is precipitated with ether, centrifuged off and triturated with ether and centrifuged off again several times. The dried substance is triturated with NaHCO3 solution, the mixture is extracted with n-butanol, the organic phase is dried with K2CO3 and filtered and the filtrate is evaporated to dryness. The solid residue is triturated with ether and centrifuged off.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([S:8]([OH:11])(=[O:10])=[O:9])[CH:7]=1.[Na].[OH-].[Na+].[CH2:16]1[O:24][CH:17]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][OH:24])=[C:6]([S:8]([OH:11])(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(O)c1cc(Cl)ccc1O
Reactant: c1ccc(C2CO2)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(O)c1cc(Cl)ccc1OC(CO)c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 5-chloro-2-hydroxybenzenesulfonic acid, sodium salt (7.9 g), NaOH (1.37 g) and water (25 ml) was heated on a boiling water bath until the mixture became homogeneous. Styreneoxide (2.4 g) was added dropwise over a period of 10 minutes and the mixture was heated with stirring on a boiling water bath for 1 hr. It was extracted with ether and the aqueous solution was evaporated to dryness. The residue was treated with water and the insoluble white precipitate was collected by filtration and washed with 5 mL water to obtain 2-(4-chloro-2-sulfophenoxy)-2-phenylethanol (4.1 g).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[N:17]1([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:20]2[CH2:21][CH2:22][N:17]([C:23](=[O:24])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:32])[F:33])[CH2:18][CH2:19]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)(C)CCNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: CC(C)(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3,3-dimethylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (17% yield). 1H NMR (400 MHz, CDCl3) δ 8.05, 7.83-7.72, 7.64, 7.57, 7.38, 6.98, 4.09-3.66, 3.50-3.45, 3.37-3.34, 1.57-1.52, 0.96. MS (ES+) m/z 464.6 (M+1).
Reaction SMILES: [Br:1]CCC1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:18][CH:17]=2)=O)[CH:7]=[CH:8][CH:9]=1.[CH3:37][C:38]1[S:42][CH:41]=[N:40][CH:39]=1.[CH3:43][CH2:44][O:45]CC>C1(C)C=CC=CC=1>[Br-:1].[C:44]([N:13]([CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:20][CH:21]=1)[C:11]1[CH:10]=[C:6]([CH2:5][N+:40]2[CH:39]=[C:38]([CH3:37])[S:42][CH:41]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:45])[CH3:43]
Reactant: Cc1cncs1
Reactant: CCCCCCCCCCCCCCOc1ccc(CCNC(=O)Cc2cccc(CCBr)c2)cc1
Reactant: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOc1ccc(CCN(C(C)=O)c2cccc(C[n+]3csc(C)c3)c2)cc1
Product: [Br-]

Procedure:
A mixture of 2.5 g of N-[3-(bromoethyl)phenyl-N-[2-[4-(tetradecyloxy)phenyl]ethyl]acetamide and 2.28 g of 5-methylthiazole in 50 ml of toluene is refluxed for 5 hours, cooled and ether added. The solid is collected by centrifugation and washed several times with ether then vacuum dried to give 1.8 g of the desired product as a white solid, m.p. 136°-140° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[O:19][C:18](=[O:23])[C:17]([C:24]([OH:26])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:53]1[C:54]([C:62]2[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=2)=[CH:55][N:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=12>CN(C=O)C>[N:53]1[C:54]([C:62]2[CH:63]=[C:64]([NH:68][C:24]([C:17]3[C:18](=[O:23])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][C:13]([O:12][C:11]([F:10])([F:28])[F:27])=[CH:22][CH:21]=4)=[O:26])[CH:65]=[CH:66][CH:67]=2)=[CH:55][N:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=12
Reactant: O=C(O)c1cc2cc(OC(F)(F)F)ccc2oc1=O
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cc(OC(F)(F)F)ccc2oc1=O
Temperature: 25 °C
Yield: 36.4 %

Procedure:
DIEA (34.9 μL, 0.20 mmol) was added to 6-trifluoromethoxy-3-carboxy-coumarin (50.0 mg, 0.18 mmol) and HATU (76.3 g, 0.20 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (38.2 mg, 0.18 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 30.5 mg of product in 36% yield: LCMS (ESI) m/z 466 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:8]2)=[CH:4][CH:3]=1.Cl.Cl[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:19]1([C:9]2[C:10]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:11][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)=[CH:26][CH:25]=3)[N:8]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccc4ccccc4n3)cc2)nc1-c1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 83.2 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (600 mg), 2-chloromethylquinoline hydrochloride (380 mg), potassium carbonate (360 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). After a mixture of the resulting colorless oily substance, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-phenyl-1-[4-(2-quinolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (660 mg, yield: 83%). This was recrystallized from acetone-hexane. Melting point: 147–148° C.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:23](/B(O)O)=[CH:24]\[CH2:25][CH2:26][CH2:27][CH3:28].C(Cl)Cl.CO.[NH4+].[OH-]>>[CH:23](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:24]\[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CC(C)(C)OC(=O)NCCCNc1ccc2ncc(Br)n2n1
Reactant: CCCC/C=C/B(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCC/C=C/c1cnc2ccc(NCCCNC(=O)OC(C)(C)C)nn12

Procedure:
Prepared from the product from step A and (E)-1-hexeneboronic acid according to general procedure 2 providing the crude Boc-protected olefin (122 mg, 96%) as a brown oil: Rf=0.71 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.78 (d, J=9.7 Hz, 1H), 7.54 (s, 1H), 6.64-6.40 (m, 3H), 3.47 (q, J=6.3 Hz, 2H), 3.29-3.23 (m, 2H), 2.36-2.30 (m, 2H), 1.84-1.81 (m, 2H), 1.50-1.42 (m, 11H), 1.40-1.48 (m, 2H), 0.93 (t, J=7.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:6]([F:7])=[CH:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12]([OH:14])[CH:13]=2)[CH:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:18]([O:14][C:12]1[CH:13]=[C:8]([N:4]2[CH:3]=[C:2]([F:1])[C:6]([F:7])=[CH:5]2)[CH:9]=[CH:10][C:11]=1[N+:15]([O-:17])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(-n2cc(F)c(F)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2cc(F)c(F)c2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 5-(3,4-difluoro-1H-pyrrol-1-yl)-2-nitrophenol (6.39 g), benzyl bromide (3.48 mL) and potassium carbonate (5.51 g) in DMF (60 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (8.57 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21](O)=[O:22])[C:12]3=[O:24])[CH:9]=[CH:10][C:2]1=2.CN(C)C=O.C(Cl)(=O)C([Cl:33])=O>ClCCl>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]([Cl:33])=[O:22])[C:12]3=[O:24])[CH:9]=[CH:10][C:2]1=2
Reactant: O=C(O)c1nc2ccccc2n(-c2ccc3c(c2)OCCO3)c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1nc2ccccc2n(-c2ccc3c(c2)OCCO3)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.9 g (31 mmol) of 1-(2,3-dihydrobenzo[b]1,4-dioxin-6-yl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid was dissolved in dichloromethane (100 mL), and to this solution, N,N-dimethylformamide (0.5 mL) and 4.7 g (37 mmol) of oxalyl chloride were added sequentially. The mixture was stirred for one hour at room temperature. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure to obtain 1-(2,3-dihydrobenzo[b]1,4-dioxin-6-yl)-2-oxo-1,2-dihydroquinoxaline-3-carbonyl chloride as yellow crystals (Compound No. of Production Intermediate: IX-75).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[CH3:9])=[N:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:21]1[CH:25]=[CH:24][C:23]([C:26](Cl)=O)=[N:22]1.Cl.Cl.[F:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[CH2:34][NH:35][NH2:36]>C1(C)C=CC=CC=1.C(O)C>[F:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[CH2:34][N:35]1[C:26]([C:23]2[CH:24]=[CH:25][O:21][N:22]=2)=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)=[N:36]1.[F:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[CH2:34][N:35]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)=[CH:9][C:26]([C:23]2[CH:24]=[CH:25][O:21][N:22]=2)=[N:36]1
Reactant: O=C(Cl)c1ccon1
Reactant: CC(=O)c1ccc(F)cn1
Reactant: NNCc1ccccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)nc1
Product: Fc1ccc(-c2cc(-c3ccon3)nn2Cc2ccccc2F)nc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 13 %
Yield: 14 %

Procedure:
To a cold solution of 1-(5-fluoropyridin-2-yl)ethanone (1 equiv.) in toluene (9.6 ml) at 0° C., was added 1M LiHMDS in toluene (1 equiv.). The mixture was stirred at 0° C. for 5 min. To this mixture, was added a solution of isoxazole-3-carbonyl chloride (1 equiv.) in toluene (4.8 ml). The mixture was removed from the ice bath and stirred at 25° C. for 5 min. To this mixture, were added 6 N HCl (1 equiv.), followed by (2-fluorobenzyl)hydrazine hydrochloride (1 equiv.) and ethanol (5 ml). The mixture was heated to 100° C. for 2 h. The mixture was cooled to 25° C. and concentrated under vacuum to give a thick red oil. The oil was purified by column chromatography (0 to 35% ethyl acetate in hexanes) to give 3-(1-(2-fluorobenzyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-5-yl)isoxazole (13% yield) as a clear film and its regioisomer 3-(1-(2-fluorobenzyl)-5-(5-fluoropyridin-2-yl)-1H-pyrazol-3-yl)isoxazole (14% yield) as a white solid.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:19]([O:21][CH2:22][C:23](Cl)=[O:24])[CH3:20].O>O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:23](=[O:24])[CH2:22][O:21][CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of (S)-4-benzyloxazolidin-2-one (4.4 g, 25 mmol) in dry tetrahydrofuran (20 ml), cooled to -78° C., was added n-butyllithium (2.5M solution in hexane, 10 ml, 25 mmol) dropwise. Another 20 ml of tetrahydrofuran was added to facilitate stirring. A solution of ethoxyacetyl chloride (3.0 g, 25 mmol) in tetrahydrofuran (5 ml) was added and the mixture was stirred at -78° C. for 30 minutes, then warmed to room temperature, poured into water and extracted with ethyl acetate (3×). The combined extracts were washed with water and brine, dried over sodium sulfate and concentrated to a yellow oil (4.3 g, [α]D =56.7°).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[C@H:10]([O:28][CH2:29][CH2:30][O:31][CH3:32])[CH2:9]1)=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[O:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][C@@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]2[O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:20][CH:19]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1Oc1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCO[C@@H]1CNCC[C@H]1Oc1ccc(Oc2ccccc2)cc1

Procedure:
To a solution of (±)-trans-N-tert-butoxycarbonyl-4-(4-phenoxyphenoxy)-3-(2-methoxy-1-ethoxy)piperidine (2.1 g, 4.7 mmol) in dry dichloromethane (20 ml) and trifluoroacetic acid (1.5 ml) was added. After 2 h the volatiles were evaporated. The residue was triturated with petroleum ether to leave the title compound as an oil. Yield 2.2 g 100%.