Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=O)[CH:9]=[CH:8]2)([CH3:4])[CH3:3].Cl.Cl.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C@H:27]([NH2:29])[CH3:28])[CH:23]=[N:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([CH:27]([NH:29][C:15]([C:10]2[CH:9]=[CH:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[CH:6]=3)[CH:11]=2)=[O:17])[CH3:28])[CH:23]=[N:22]1
Reactant: CC(C)(O)c1ccc2cc(C(=O)O)ccc2c1
Reactant: Cc1c([C@@H](C)N)cnn1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C(C)NC(=O)c2ccc3cc(C(C)(C)O)ccc3c2)cnn1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.2 %

Procedure:
To a DMF (3 ml) solution of 6-(1-Hydroxy-1-methyl-ethyl)-naphthalene-2-carboxylic acid (U.S. Pat. No. 4,638,087, published 20 Jan. 1987, 95 mg, 0.413 mmol), Amine 9 (1-(5-Methyl-1H-pyrazol-4-yl)ethanamine dihydrochloride, 95 mg, 0.352 mmol), HBTU (188 mg, 0.495 mmol) and triethylamine (0.173 ml, 1.24 mmol) were added and the mixture was stirred for 24 hours at room temperature. The reaction was quenched with sat. NaHCO3 aq and water, and the product extracted with EtOAc 3 times. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (Ethylacetate:Hexane=2:1) to give the title product as a white solid (84.4 mg, 58.2% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.46-1.49 (3H, d), 1.50-1.53 (6H, s) 2.22-2.24 (3H, s) 3.67-3.68 (3H s) 5.13-5.20 (2H, m) 7.38-7.39 (1H, s) 7.69-7.72 (1H, d) 7.81-8.00 (4H, m) 8.39-8.40 (1H, s) 8.68-8.72 (1H, d). MS (ESI) m/z 352 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2[C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:15]1([C:13]([C:6]2[C:7]([CH3:12])=[N:8][C:9]3[C:4]([C:5]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:3][C:2]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:11][CH:10]=3)=[O:14])[CH2:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C1CC1
Product: Cc1nc2ccc(N3CCCCC3)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C1CC1
Yield: 39 %

Procedure:
The title compound was prepared from [6-Bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-cyclopropyl-methanone [example 50] and piperidine according to the procedure of example 51. Yield: 39%; MS: m/z=449 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[N:7]2.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccccc1CNc1ccc2c(Br)cccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1CNc1ccc2c(-c3ccccc3)cccc2n1

Procedure:
(5-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (200 mg, 0.583 mmol) was dissolved in 8 mL 1,2-dimethoxyethane and 4 mL 1M sodium carbonate solution. The reaction mixture was evacuated and backfilled with argon for three times to remove oxygen. Phenylboronic acid (88 mg, 0.699 mmol), palladium(II)acetate (7 mg, 0.029 mmol) and triphenylphosphine (16 mg, 0.058 mmol) were added. The reaction mixture was refluxed overnight. The reaction mixture was poured into 100 mL water and extracted three times with ethyl acetate (100 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The residue purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->80:20 gradient). The title compound was obtained as a white solid (191 mg, 96%), MS: m/e=341.3 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([CH2:6][C@H:7]([CH3:18])[C:8]([O:10]CC1C=CC=CC=1)=[O:9])(=[O:5])=[O:4]>C(O)(=O)C.[Pd]>[CH3:19][N:2]([CH3:1])[S:3]([CH2:6][C@H:7]([CH3:18])[C:8]([OH:10])=[O:9])(=[O:4])=[O:5]
Reactant: C[C@@H](CS(=O)(=O)N(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@@H](CS(=O)(=O)N(C)C)C(=O)O
Reaction time: 24 h
Yield: 94 %

Procedure:
A 100 mL Fisher/Porter vessel was charged with 1.4 g of benzyl 3-[(dimethylamino)sulfonyl]-2(R)-methylpropionate in 30 mL acetic acid with a catalytic amount of 10% Pd—C. The reaction was hydrogenated at 50 psi for 24 hours, filtered through Celite and concentrated in vacuo. The residue was azeotroped with toluene then concentrated in vacuo to afford 900 mg of 3-[(dimethylamino)sulfonyl]-2(R)-methylpropionic acid which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4](S)[N:3]=1>O.[Ni]>[CH2:8]([C:6]1[N:5]=[CH:4][NH:3][C:2](=[O:1])[CH:7]=1)[CH3:9]
Reactant: CCc1cc(O)nc(S)n1
Agent: [Ni]
Solvent: O
Product: CCc1cc(=O)[nH]cn1

Procedure:
90 g (0.58 mol) 4-Hydroxy-2-mercapto-6-ethylpyrimidine and 270 g Raney-Nickel are suspended in water (1000 mL) and the suspension is heated and stirred under reflux over night. The reaction mixture is filtered over celite and the filtrate is concentrated under reduced pressure to give crude product. Yield: 70.0 g (98%).
Reaction SMILES: FC(F)(F)C(O)=O.C(Cl)Cl.C(OC([NH:18][C:19]([C:22]1[O:27][C:26](=[O:28])[C:25]2[C:29]([CH3:33])=[CH:30][CH:31]=[CH:32][C:24]=2[N:23]=1)([CH3:21])[CH3:20])=O)(C)(C)C>Cl.O1CCOCC1>[NH2:18][C:19]([C:22]1[O:27][C:26](=[O:28])[C:25]2[C:29]([CH3:33])=[CH:30][CH:31]=[CH:32][C:24]=2[N:23]=1)([CH3:21])[CH3:20]
Reactant: Cc1cccc2nc(C(C)(C)NC(=O)OC(C)(C)C)oc(=O)c12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2nc(C(C)(C)N)oc(=O)c12

Procedure:
250 ml of a 50% trifluoroacetic acid-methylene chloride solution was added dropwise under ice-cooling to 5.63 g of 2-{1-[(tert-butoxycarbonyl)amino]-1-methylethyl}-5-methyl-4H-3,1-benzoxazin-4-one with stirring. The mixture was stirred at 0° C. for 0.58 hour, and concentration of the mixture gave a residue which was dissolved in 80 ml of a 4N hydrochloric acid-1,4-dioxane solution at 0° C. After stirring for 0.58 hour, the reaction mixture was subjected to azeotropic distilation with toluen so as to give the hydrochloride salt of 2-(1-amino-1-methylethyl)-5-methyl-4H-3,1-benzoxazin-4-one. To the salt was added 4.47 g of 9-fluorenyloxyacetic acid, and dissolved in 180 ml of N,N-dimethylformamide. To the mixture were added successively at room temperature 2.2 ml of N-methylmorpholine, 2.98 g of 1-hydroxybenzotriazole and 5.09 g of a water-soluble carbodiimide hydrochloride. After stirring for 18 hours, the reaction mixture was concentrated to give a residue which was purified by a silica gel column chromatography (eluting solution: methylene chloride-ether), followed by recrystallization from methylene chloride-ether to give 6.34 g of 2-{1-[(9-fluorenyloxyacetyl)amino]-1-methylethyl}-5-methyl-4H-3,1-benzoxazin-4-one: mp 162.1°-162.8° C. (see Table 1).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=O.[CH3:17][O:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1.N1CCCCC1.C(O)(=O)C>C(O)C>[CH3:17][O:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23](=[CH:1][C:3]3[NH:4][C:5]4[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=4[C:11]=3[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1
Reactant: COc1ccc2c(c1)NC(=O)C2
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc2c(c1)NC(=O)C2=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A mixture of 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (5.4 g), 3.6 g of 6-methoxy-2-oxindole and 2.7 g of piperidine in 25 mL of ethanol was refluxed for 4 hours. Upon slow addition of acetic acid (8 mL), a precipitate formed. The mixture was refluxed for 5 minutes and cooled to ambient temperature. The precipitate was collected by vacuum filtration and washed with 20 mL of ethanol. The solids were slurry-washed in 30 mL of refluxing ethanol, cooled, collected by vacuum filtration, washed with 30 mL of ethanol and vacuum dried to give 6.4 g (80% yield) of 3-[2-(6-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid as an orange solid, mp 263-266° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.C(=O)(O)[O-].[Na+].C([O:17][C:18]1[CH:45]=[CH:44][C:43](B2OC(C)(C)C(C)(C)O2)=[CH:42][C:19]=1[C:20]([NH:22][C:23]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:32][C:24]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:21])(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O.CO.COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:43]2[CH:44]=[CH:45][C:18]([OH:17])=[C:19]([CH:42]=2)[C:20]([NH:22][C:23]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:33]=[CH:32][C:24]=2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Reactant: Nc1cccc(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2cccc(N)n2)ccc1O
Temperature: 25 °C
Yield: 46.3 %

Procedure:
Water (0.3 mL), 2-amino-6-bromopyridine (0.037 g), sodium bicarbonate (0.036 g), and bis(triphenylphosphine)palladium(II) dichloride (5.0 mg) were added to an ethylene glycol dimethyl ether (1 mL) suspension of tert-butyl 2-(2-acetoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-4-phenylbenzoate (0.080 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then bis(triphenylphosphine)palladium(II) dichloride (5.0 mg) was added thereto, followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and methanol (0.3 mL) and sodium carbonate (0.046 g) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 20 minutes. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-60% hexane/ethyl acetate] to obtain 0.032 g of tert-butyl 2-(5-(6-aminopyridin-2-yl)-2-hydroxybenzamido)-4-phenylbenzoate.
Reaction SMILES: [CH2:1]1CCN2C(=NCCC2)CC1.[C:12]1([C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH3:22])[C:19]([OH:21])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CI>C(#N)C>[C:12]1([C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH3:22])[C:19]([O:21][CH3:1])=[O:20])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CI
Product: COC(=O)C(C)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
37.60 g (0.247 mol) of DBU are added dropwise to a suspension of 50.8 g (0.225 mol) of 2,2-diphenylpropionic acid and 200 ml of acetonitrile at 20° C. 70.10 g (0.494 mol) of methyliodide are added dropwise to the resulting solution within 30 min. Then the mixture is stirred overnight at 20° C. The solvent is evaporated down, the residue is extracted with diethylether/water, the organic phase is washed with water, dried over Na2SO4 and evaporated to dryness. Yield: 48.29 g of viscous residue 32 (=89% of theory).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:6]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[C:28]1([C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[C:1]([C:4]1[CH:5]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:6]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:38]2[CH2:39][CH2:40][C:35](=[C:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:36][CH2:37]2)=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)NC(C)=C(C(=O)CCCCCl)C1c1cccc([N+](=O)[O-])c1
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)CCCCN2CCC(=C(c3ccccc3)c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1

Procedure:
4.7 g (12 mmol) 5-acetyl-1,4-dihydro-2,6-dimethyl-3-(5-chloropentanoyl)-4-(3-nitrophenyl)-pyridine and 3 g (14 mmol) 4-diphenylmethylenepiperidine are boiled under reflux with 1.9 g (12 mmol) sodium iodide and 5 g (48 mmol) sodium carbonate in 200 ml acetone for 5 days. The mixture is filtered and concentrated, and the residue is taken up in 100 ml ethyl acetate. This solution is extracted by shaking with 40 ml sodium thiosulphate solution (5%). The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is chromatographed with toluene/acetone=6/4, The title compound is obtained as a yellow oil. Yield: 2.2 g (32%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].O>CN(C=O)C>[N+:21]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To phenol (6.5 g) in 20 ml DMF at room temperature was added K2CO3 (20 g) and this mixture stirred for 15 minutes at room temperature. Then 4-chloro-3-nitropyridine (10.0 g) in 60 ml DMF was added dropwise and the mixture stirred for two hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, anhy. MgSO4).
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6][N:7](C)C)C.[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)N.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:16]1[C:4](=[O:15])[C:5]([N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)=[CH:6][NH:7]1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Reactant: NNc1ccccn1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: O=c1c(-n2ccnn2)c[nH]n1-c1ccccn1

Procedure:
250 mg (1.19 mmol) of the compound from Example 3A, 108 mg (0.99 mmol) 2-hydrazinopyridine and 23 mg (99 mmol) camphor-10-sulfonic acid are dissolved in 5 ml anhydrous ethanol and the mixture is heated under reflux overnight. In each case 108 mg (0.99 mmol) 2-hydrazinopyridine are added again a total of four times and the mixture is heated further under reflux until the conversion of the compound from Example 3A is complete. After cooling, the reaction mixture is purified by preparative HPLC several times (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid) and 6 mg (2% of th.) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:13]([CH2:14][NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][C:5]([C:6]([O:8][CH2:9][CH2:10]Cl)=[O:7])=[CH:4][C:3]=1[Br:20].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([O-:39])=[O:38].[Na+]>>[NH2:1][C:2]1[C:13]([CH2:14][NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][C:5]([C:6]([O:8][CH2:9][CH2:10][O:39][C:37](=[O:38])[CH2:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[NH:29][C:23]2[C:22]([Cl:21])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:28])=[O:7])=[CH:4][C:3]=1[Br:20]
Reactant: CC(C)(C)NCc1cc(C(=O)OCCCl)cc(Br)c1N
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Product: CC(C)(C)NCc1cc(C(=O)OCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc(Br)c1N

Procedure:
This compound was prepared from 2-(4-amino-3-bromo-5-tert.butylaminomethyl-benzoyloxy)-ethyl chloride and sodium 2-[(2,6-dichlorophenyl)-amino]-phenylacetate analogous to Example 8.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[O:4][N:3]1[CH2:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:22]=3[CH3:30])[CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].C(Cl)(Cl)Cl>C1COCC1.CO>[CH3:30][C:22]1[CH:23]=[C:24]([C:27]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:28])[CH:25]=[CH:26][C:21]=1[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][O:13][C:12]2[CH:31]=[CH:32][C:9]([CH2:8][N:3]3[C:2](=[O:1])[NH:6][C:5](=[O:7])[O:4]3)=[CH:10][CH:11]=2)[CH:16]=1
Reactant: Cc1cc(C(=O)O)ccc1-c1cccc(COc2ccc(Cn3oc(=O)[nH]c3=O)cc2)c1
Reactant: C1CCNC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)N2CCCC2)ccc1-c1cccc(COc2ccc(Cn3oc(=O)[nH]c3=O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
3′-({4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}methyl)-2-methylbiphenyl-4-carboxylic acid (10.8 mg) was dissolved in a THF-methanol [1 ml, 4:1 (v/v)] mixed solution, and the solution was added to pyrrolidine (3.2 mg). DMT-MM (12 mg) was added, followed by overnight stirring at room temperature. Thereafter, chloroform was added to the reaction liquid, and the organic layer was washed with 1 M hydrochloric acid. The organic layer was concentrated, and the residue was purified by a fractional HPLC (Waters, product name: Waters SunFire™ Prep C18OBD™ (19×100 mm, 5 μm)) to obtain 2-(4-{[2′-methyl-4′-(pyrrolidin-1-ylcarbonyl)biphenyl-3-yl]methoxy}benzyl)-1,2,4-oxadiazolidine-3,5-dione (8.2 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:23][C:12]1[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)=[CH:3][CH:4]=2)[C:14](=[O:15])[C:13]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nn(Cc2ccc(-c3ccncc3)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 27.7 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(4-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 61, 40 mg, 0.094 mmol), 4-pyridinylboronic acid (14 mg, 0.10 mmol), potassium carbonate (40 mg, 0.290 mmol), and tetrakis(triphenylphosphine)palladium (0) (6 mg, 5 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes, diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was washed with brine, dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 15-95% acetonitrile/water (0.1% TFA)) to afford the title compound (11.0 mg, 0.026 mmol, 28% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.91 (s, 1H), 13.01 (s, 1H), 10.17 (t, J=5.56 Hz, 1H), 8.80 (d, J=6.32 Hz, 2H), 8.04 (d, J=6.32 Hz, 2H), 7.91 (d, J=8.34 Hz, 2H), 7.49 (d, J=8.34 Hz, 2H), 5.35 (s, 2H), 4.10 (d, J=5.56 Hz, 2H), 3.20 (m, 1H), 1.22 (d, J=6.82 Hz, 6 H). MS (ES+) m/e 423 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[F:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1>>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:15][C:12]1[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=1
Reactant: Oc1ccc(F)cc1
Reactant: OC(CCl)CCCl
Product: OC(CCCl)COc1ccc(F)cc1
Yield: 30 %

Procedure:
Utilizing the procedure of Preparation 21, 1,4-dichloro-2-butanol was reacted with 4-fluorophenol to give white title compound, m.p. 53°-55° C. in 30% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:23])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH2:5].[Cl:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[C:27]([N:29]=[C:30]=[O:31])=[O:28]>C1(C)C=CC=CC=1>[Cl:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[C:27]([NH:29][C:30]([NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:7]([Cl:23])[CH:6]=1)=[O:31])=[O:28]
Reactant: Nc1cc(Cl)c(OCc2ccccc2-c2ccccc2)c(Cl)c1
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1ccccc1Cl)Nc1cc(Cl)c(OCc2ccccc2-c2ccccc2)c(Cl)c1
Temperature: 60 °C

Procedure:
To a solution containing 1.55 grams (0.004 moles) of 3,5-dichloro-4-(2-phenylphenylmethoxy) aniline prepared in Part B and 5 milliliters of toluene, which solution was heated to a temperature of 60° C. and placed under an atmosphere of nitrogen, was added 0.98 grams (0.005 moles) of 2-chlorobenzoyl isocyanate. The resulting mixture was maintained at a temperature of 60° C. for a period of 0.5-1.0 hours. After cooling to ambient temperature, the reaction mixture was diluted with 1 milliliter of toluene. This mixture was then filtered to give a solid material. The solid material was washed once with toluene, once with a toluene-hexane mixture (1:1 volume ratio) and finally once with hexane and then dried overnight in a vacuum oven at 50° C. This afforded a white powder material having a melting point of 188.5° C.-192.0° C. Elemental analysis of the white powder indicated the following: