Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][CH:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]1([C:12](OCC)=[O:13])[CH2:11][CH2:10]1.C([O-])(O)=O.[Na+].[OH-].[Na+]>CCOCC>[OH:13][CH2:12][C:9]1([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:7])[CH2:11][CH2:10]1
Reactant: CCOC(=O)C1(C(O)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OCC1(C(O)c2ccccc2)CC1
Temperature: -10 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Lithium aluminum hydride (0.39 g, 10.2 mmol) was mixed with ether (12 ml) and the mixture was cooled to −10° C. Thereto was added dropwise a solution of ethyl 1-[hydroxy(phenyl)methyl]cyclopropanecarboxylate (1.5 g, 6.8 mmol) in ether (3 ml) at the same temperature over 15 min, and the mixture was stirred at −10° C. for 1 h and at room temperature for 2 h. Thereafter, the mixture was cooled to −20° C., and 10% NaHCO3 aq. (2 ml) was added dropwise. Then, 20% NaOH aq. (2 ml) was added dropwise, and the mixture was stirred for 30 min. Sludge was removed by decantation and the organic layer was washed with water (50 ml), dried over anhydrous sodium sulfate, concentrated to dryness, and purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound (1.2 g, 98.9%) as a colorless oil.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:12]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)=[N:11][C:8]=3[O:9][CH2:10][C:5]2=[N:4][N:3]=1.Cl.[CH3:40][NH:41][CH3:42].C(N(CC)CC)C>CN1C(=O)CCC1.C(Cl)Cl.O>[C:34]([O:33][C:32](=[O:38])[NH:31][C:27]1([C:24]2[CH:23]=[CH:22][C:21]([C:12]3[C:13]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:14][C:7]4[N:6]5[C:2]([N:41]([CH3:42])[CH3:40])=[N:3][N:4]=[C:5]5[CH2:10][O:9][C:8]=4[N:11]=3)=[CH:26][CH:25]=2)[CH2:28][CH2:29][CH2:30]1)([CH3:36])([CH3:37])[CH3:35]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(Br)nnc3CO4)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: O
Product: CN(C)c1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Yield: 20.9 %

Procedure:
A mixture of tert-butyl 1-(4-(1-bromo-8-phenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutylcarbamate (41 mg, 0.071 mmol), dimethylamine hydrochloride (58.2 mg, 0.714 mmol), and triethylamine (0.099 ml, 0.714 mmol) in NMP (1 ml) was heating at 130 degree for 50 min under microwave condition. The mixture was diluted with DCM (8 ml) and water (8 ml). The organic phase was washed with water (8 mlX3) and brine (5 ml). Concentrated and purified by column eluted with MeOH/DCM (0-4%) to give product (8 mg). 1H NMR (500 MHz, CDCl3) 8.15 (s, 1H), 7.15-7.34 (m, 9H), 5.51 (s, 2H), 5.01 (s, 1H), 2.95 (s, 6H), 2.4-2.5 (m, 4H), 2.0-2.15 (m, 1H), 1.75-1.85 (m, 1H), 1.2-1.35 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:33][C:28]3[CH2:29][NH:30][CH2:31][CH2:32][C:27]=3[N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:34][C:35](OC(C)=O)=[O:36]>CN(C=O)C.C(OCC)(=O)C>[C:35]([N:30]1[CH2:31][CH2:32][C:27]2[N:26]=[C:25]([C:21]3[C:22]([CH3:24])=[CH:23][C:2]([CH3:1])=[C:3]([CH:20]=3)[C:4]([N:6]3[CH2:7][CH2:8][CH:9]([C:12]4[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=4)[CH2:10][CH2:11]3)=[O:5])[NH:33][C:28]=2[CH2:29]1)(=[O:36])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C)c(-c2nc3c([nH]2)CNCC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2nc(-c3cc(C(=O)N4CCC(c5ccc(C#N)cc5)CC4)c(C)cc3C)[nH]c2C1
Temperature: 1.5 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a stirred mixture of 4-(1-(2,4-dimethyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 2.9, 20 mg, 0.02 mmol, 1.00 equiv, 50%) in DMF (2 mL) under nitrogen was added a solution of Ac2O (2.4 mg, 0.02 mmol, 1.00 equiv) in DMF (0.2 mL) dropwise at 0° C. The resulting solution was stirred for 1 h at 0-3° C. in a water/ice bath. The reaction mixture was then diluted with 50 mL of ethyl acetate and washed with 2×20 mL of brine. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The crude residue (50 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, abridge C18; mobile phase, WATER WITH 0.05% NH3.H2O and CH3CN (hold 5% CH3CN in 2 min, up to 20%-46% in 10 min, up to 100% in 12 min, down to 20% in 14 min); Detector, UV 254/220 nm. The fractions containing pure compound were combined and lyophilized to yield 5.5 mg of the title compound as a white solid. m/z (ES+) 482 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.69 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.39-7.28 (m, 2H), 4.90 (m, 1H, partially obscured by the solvent peak), 4.67 and 4.62 (2 singlets, acetamide rotamers, MeCONCH2-imidazole, 2H), 3.92 (m, 2H), 3.66 (m, 1H), 3.23 (m, 1H), 3.00 (m, 2H), 2.85-2.76 (m, 2H), 2.48 (s, 3H), 2.41 and 2.31 (2 singlets, aryl amide rotamers, ArCH3, 3H), 2.25 and 2.22 (2 singlets, acetamide rotamers, CH3CON, 3H), 2.04 (m, 1H), 1.92-1.20 (m, 3H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3[C:14]([C:25]([O:27]CC)=O)=[N:15][N:16]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:10]=3[C:9]2=[O:30])=[CH:4][CH:3]=1.O.[NH3:32]>C(O)CO>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3[C:14]([C:25]([NH2:32])=[O:27])=[N:15][N:16]([C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[C:10]=3[C:9]2=[O:30])=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(I)cc1)C2=O
Solvent: O
Solvent: OCCO
Product: COc1ccc(-n2nc(C(N)=O)c3c2C(=O)N(c2ccc(I)cc2)CC3)cc1
Temperature: 85 °C

Procedure:
Ethyl 6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate from Part C (3.0 g, 5.8 mmol) was suspended in 8% NH3 in ethylene glycol (30 mL) in a 100 mL pressure tube. The mixture was heated at 85° C. for 18 hours. Water was added, and the precipitate was filtered and washed with water. The crude product was dried under vacuum to afford 3.2 g of final product. MS (ES+): 489.2 (M+H)+. 1H NMR (DMSO-d6) δ: 7.72-7.68 (m, 3H), 7.49-7.41 (m, 3H), 7.15 (d, 2H), 6.97 (d, 2H), 4.00 (t, 2H), 3.77 (s, 3H), 3.16 (t, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]([NH2:41])=[O:40]>CN(C=O)C>[NH2:41][C:39](=[O:40])[CH2:38][N:15]([S:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[CH:8]=1)(=[O:13])=[O:14])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:17]1=[O:30]
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](N(CC(N)=O)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
A solution of tert-butyl (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (1.31 g) in DMF (22 ml) was treated with potassium carbonate (0.786 g) followed by 2-bromoacetamide (0.48 g) and the resultant mixture stirred at room temperature for 22 h. Additional 2-bromoacetamide (0.4 g) and potassium carbonate (0.4 g) were added and the mixture was stirred at room temperature for 24 h. The reaction mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The separated organic layer was washed with water, dried (over magnesium sulphate) and evaporated under reduced pressure to give the title compound (1.4 g) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=O)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN(C)C=O.S(Cl)([Cl:25])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([Cl:25])(=[O:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4′-chlorobiphenyl-4-sulfonic acid 12a (15.1 g ,78.1 mmol)in thionyl chloride (150 mL) is added a catalytic amount of N,N-dimethylformamide (0.3 mL). The reaction mixture is heated to reflux for 4 hr. The mixture is then cooled to room temperature, and concentrated under reduced pressure. Toluene is then added and the mixture is concentrated under reduced pressure. The solid crude product is then recrystallized with ethyl acetate and hexanes to give the solid desired product.
Reaction SMILES: [Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:22]I.N1C=CN=C1.[C:29]([O:33][C:34](=[O:46])[NH:35][CH:36]([C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)[CH2:37]O)([CH3:32])([CH3:31])[CH3:30]>C(Cl)Cl>[C:29]([O:33][C:34](=[O:46])[NH:35][CH:36]([C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)[CH2:37][I:22])([CH3:32])([CH3:31])[CH3:30]
Reactant: II
Reactant: CC(C)(C)OC(=O)NC(CO)c1ccc(F)cc1
Agent: [Cl-]
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CI)c1ccc(F)cc1
Yield: 57.6 %

Procedure:
To a room temperature solution of triphenylphosphine dichloride (1.53 g (5.85 mmol) in methylene chloride was added iodine (1.481 g, 5.85 mmol). The mixture was stirred for fifteen minutes, then imidazole (663 mg, 9.74 mmol) was added. The mixture was stirred another 15 minutes, then [1-(4-fluoro-phenyl)-2-hydroxy-ethyl]carbamic acid tert-butyl ester (1.0 g, 3.9 mmol) was added. The mixture was heated to reflux for two hours, then stirred at room temperature overnight. Solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium thiosulfate. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed through silica (5-10% ethyl acetate/hexanes) to give 820 mg (58%) of [1-(4-fluoro-phenyl)-2-iodo-ethyl]-carbamic acid tert-butyl ester, MP=138-139° C.
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH2:18][NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:7][C:6]=1[CH2:29][NH:30][CH2:31][CH2:32][CH3:33]>C(O)C>[NH2:1][C:2]1[N:30]([CH2:31][CH2:32][CH3:33])[CH2:29][C:6]2[C:5](=[CH:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][CH2:18][NH:19][S:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)(=[O:22])=[O:21])[CH:7]=2)[N:4]=1
Reactant: N#CBr
Reactant: CCCNCc1cc(-c2ccccc2CCNS(=O)(=O)c2ccccc2)ccc1N
Solvent: CCO
Product: CCCN1Cc2cc(-c3ccccc3CCNS(=O)(=O)c3ccccc3)ccc2N=C1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyanogen bromide (0.00034 mol) was added to a mixture of N-[2-(4′-amino-3′-propylaminomethyl-biphenyl-2-yl)-ethyl]-benzenesulfonamide (0.00031 mol) in ethanol (1 mL) in a Fast-tube, and then the reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by high-performance liquid chromatography. The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:4]2[C:13]3[CH:12]=[CH:11][C:10]([O:14][CH2:15][CH2:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:9][C:8]=3[N:7]=[C:6]([NH2:23])[C:5]=2[N:24]=1.[CH:29]1([N:35]=[C:36]=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)(Cl)Cl>[NH2:23][C:6]1[C:5]2[N:24]=[C:2]([CH3:1])[N:3]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:4]=2[C:13]2[CH:12]=[CH:11][C:10]([O:14][CH2:15][CH2:16][CH:17]3[CH2:18][CH2:19][N:20]([C:36]([NH:35][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:37])[CH2:21][CH2:22]3)=[CH:9][C:8]=2[N:7]=1
Reactant: Cc1nc2c(N)nc3cc(OCCC4CCNCC4)ccc3c2n1CC(C)C
Reactant: O=C=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(N)nc3cc(OCCC4CCN(C(=O)NC5CCCCC5)CC4)ccc3c2n1CC(C)C
Reaction time: 0.5 h
Yield: 32.8 %

Procedure:
A solution of 2-methyl-1-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amine (0.300 g, 0.786 mmol) in chloroform was cooled to 0° C. Cyclohexyl isocyanate (0.100 mL, 0.783 mmol) was added dropwise, and the reaction was stirred for 30 minutes. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with dichloromethane:methanol ranging in ratios from 99:1 to 95:5). The resulting product was recrystallized from ethanol to provide 0.130 g of 4-(2-{[4-amino-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)-N-cyclohexylpiperidine-1-carboxamide as a white powder, mp 213.7-215.7° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:16])[S:13][C:14]=2[CH3:15])[CH:5]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:16])[S:13][C:14]=2[CH2:15][Br:18])[CH:5]=1
Reactant: COC(=O)c1cccc(-c2nc(C)sc2C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(-c2nc(C)sc2CBr)c1
Yield: 118.7 %

Procedure:
A mixture of 3-(2,5-dimethyl-thiazol-4-yl)-benzoic acid methyl ester (3.96 g), N-bromosuccinimid (3.13 g) and α,α′-bis(isobutyronitrile) (0.02 g) in CCl4 (60 mL) was heated at reflux for 30 min. The cooled mixture was filtered and the solvent was evaporated to give crude 3-(5-bromomethyl-2-methyl-thiazol-4-yl)-benzoic acid methyl ester (6.2 g) as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:6](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:7]([O:9]C)=O)=[O:5]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]([C:6]1[C:7](=[O:9])[C:18]2[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:5]
Reactant: COCC(=O)C(=CNc1ccccc1OC)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COCC(=O)c1c[nH]c2c(OC)cccc2c1=O
Yield: 80.9 %

Procedure:
Methyl 2-methoxyacetyl-3-(2-methoxyphenylamino)acrylate (55 g, 0.2 mol) was added in portions to boiling diphenyl ether (500 ml) and the mixture was heated under reflux for 45 minutes. The mixture was allowed to cool and diluted with petroleum ether to afford 3-methoxyacetyl-8-methoxy-4(1H)-quinolone (40 g, 82.5%) as light brown crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.5 %

Procedure:
Potassium Carbonate (678 g, 4.91 mol) was added to a solution of 4-hydroxybenzaldehyde (200 g, 1.63 mol) in DMF (2 L) followed to the addition of benzyl bromide (214 mL, 1.80 mol) at 0° C. and stirred for 18 h at RT. After completion, the reaction mixture was poured into ice water (3 L), filtered the solid and dried to get 4-(benzyloxy)benzaldehyde (230 g, 66%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:24][CH2:25][CH3:26])[N:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[C:18]1([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:12]=2[N:11]([CH2:24][CH2:25][CH3:26])[N:10]=[C:9]3[C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCn1nc(-c2ccc(OC)cc2)c2cccc(-c3ccccc3)c21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCn1nc(-c2ccc(O)cc2)c2cccc(-c3ccccc3)c21
Reaction time: 0.25 h
Yield: 41.3 %

Procedure:
To a solution of 3-(4-methoxyphenyl)-7-phenyl-1-propyl-1H-indazole (0.375 g, 1.09 mmol) in CH2Cl2 (15 mL) was added BBr3 (0.207 mL, 2.19 mmol) at −78° C. The solution was stirred for 15 minutes and allowed to stand overnight in the refrigerator. The reaction was quenched with NH4OH (20 mL) and extracted with CH2Cl2. The organic layer was washed with water and dried (MgSO4). The reaction was purified by flash chromatography (5/1 hexane/ethyl acetate) to give the title compound as a white solid (0.147 g, 0.45 mmol, 41%).
Reaction SMILES: C([O:4][CH:5]([C:7]1[CH:8]=[N:9][C:10]([C:17]2[NH:18][C:19](=[O:26])[C:20]([CH:23]([CH3:25])[CH3:24])([CH3:22])[N:21]=2)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])[CH3:6])(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[OH:4][CH:5]([C:7]1[CH:8]=[N:9][C:10]([C:17]2[NH:18][C:19](=[O:26])[C:20]([CH:23]([CH3:25])[CH3:24])([CH3:22])[N:21]=2)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])[CH3:6]
Reactant: COC(=O)c1cc(C(C)OC(C)=O)cnc1C1=NC(C)(C(C)C)C(=O)N1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(C)O)cnc1C1=NC(C)(C(C)C)C(=O)N1

Procedure:
A solution of 16 g of methyl 5-(1-acetoxyethyl)-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate and 0.5 g sodium methoxide in 150 mL methanol is stirred at room temperature under nitrogen for 5 days. The reaction is acidified to pH 5 with acetic acid and concentrated in vacuo. The residue is partitioned between methylene chloride and water, the aqueous layer is further extracted with methylene chloride, and the combined organic phases are dried over sodium sulfate and concentrated in vacuo to an orange oil. Column chromatography of this oil using ether-hexane as eluent affords the desired product as a white foam.
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[C:11]([CH2:36][CH2:37][CH3:38])[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:39])=[O:3])=[CH:10][C:11]=3[CH2:36][CH2:37][CH3:38])[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCCc1cc(OC(C)(C)C(=O)OCC)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1cc(OC(C)(C)C(=O)O)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-propylphenoxy}-2-methylpropionic acid ethyl ester, (0.57 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (1.1 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (40 mL) and water (20 mL) and acidified to pH=1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 2-{4-[2-(2-Biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-propylphenoxy}-2-methylpropionic acid 1H NMR (400 MHz, CDCl3), δ 8.04 (dd, J=6.6, 1.7 Hz, 2H), 7.68-7.62 (m, 4H), 7.47-7.44 (m, 2H), 7.39-7.35 (m, 11H), 6.78 (d, J=8.8 Hz, 11H), 6.72 (d, J=2.9 Hz, 1H), 6.61 (dd, J=8.8, 2.9 Hz, 1H), 4.18 (t, J=6.6 Hz, 2H), 2.99 (t, J=6.6 Hz, 2H), 2.53 (t, J=7.8 Hz, 2H), 2.39 (s, 3H), 1.59 (quintet, J=7.5 Hz, 2H), 1.55 (s, 6H), 0.94 (t, J=7.3 Hz, 3H), MS (ES) m/e 500 M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[C:13](N[C@@H](C2C=CC=CC=2)C)=[CH:12][C@H:11]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=2)[N:10]1[C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1.O=C1C(=O)C[C@H](C2C=CC=C(OC(F)(F)F)C=2)N1C1C=CC(C#N)=CC=1.[CH3:68][C:69]([NH2:81])([C:71]1[CH:76]=[CH:75][CH:74]=[C:73]([C:77]([F:80])([F:79])[F:78])[N:72]=1)[CH3:70]>ClCCl.O>[CH3:70][C:69]([NH:81][C:13]1[C:9](=[O:8])[N:10]([C:34]2[CH:35]=[CH:36][C:37]([C:38]#[N:39])=[CH:40][CH:41]=2)[C@@H:11]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:31])([F:33])[F:32])[CH:24]=2)[CH:12]=1)([C:71]1[CH:76]=[CH:75][CH:74]=[C:73]([C:77]([F:79])([F:80])[F:78])[N:72]=1)[CH3:68]
Reactant: CC(C)(N)c1cccc(C(F)(F)F)n1
Reactant: C[C@@H](NC1=C[C@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(C#N)cc2)C1=O)c1ccccc1
Agent: N#Cc1ccc(N2C(=O)C(=O)C[C@@H]2c2cccc(OC(F)(F)F)c2)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(NC1=C[C@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(C#N)cc2)C1=O)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
Add trifluoroacetic acid (2.00 mL, 26.43 mmol) to a biphasic mixture of 4-[(R)-2-oxo-3-((R)-1-phenyl-ethylamino)-5-(3-trifluoromethoxy-phenyl)-2,5-dihydro-pyrrol-1-yl]-benzonitrile) in dichloromethane (12 mL) and water (4.9 mL). Stir at ambient temperature for 2 hours. Observe significant formation of 4-[(R)-2,3-dioxo-5-(3-trifluoromethoxy-phenyl)-pyrrolidin-1-yl]-benzonitrile (LC-MS ESI m/z: 361 (M+H)+, Tr=2.34 min., method 2. Wash the reaction mixture with water. Filter the organic phase through sodium sulfate and add 1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamine (1.30 g, 6.35 mmol). Heat to reflux temperature for 18 hours. Partially concentrate reaction mixture and place on a silica gel chromatography column. Purify by silica gel chromatography (25% ethyl acetate-hexane) to obtain 4-[(R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-2-oxo-5-(3-trifluoromethoxy-phenyl)-2,5-dihydro-pyrrol-1-yl]-benzonitrile (1.06 g, 37%). 1H NMR (400 MHz, CDCl3) δ 7.71 (t, J=7.9 Hz, 1H), 7.64-7.61 (m, 2H), 7.59 (d, J=7.9 Hz, 1H), 7.53-7.44 (m, 4H), 7.26-7.24 (m, 1H), 7.04-6.96 (m, 2H), 6.80 (s, 1H), 5.38 (d, J=2.6 Hz, 1H), 4.99-4.97 (m, 1H), 4.69 (d, J=2.6 Hz, 1H), 1.65 (d, J=7.5 Hz, 6H).
Reaction SMILES: [OH:1][C:2]12[CH2:17][CH:16]([CH3:18])[CH2:15][C:14](=[O:19])[CH:13]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2.[CH:20]([O:22][CH2:23][CH3:24])=[CH2:21].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CCCCC.C(OCC)C>[CH2:20]([O:22][CH2:23][CH2:24][O:1][C:2]12[CH2:17][CH:16]([CH3:18])[CH2:15][C:14](=[O:19])[CH:13]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH3:21]
Reactant: CC1CC(=O)C2CCCCCCCCCCC2(O)C1
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCCCC
Product: CCOCCOC12CCCCCCCCCCC1C(=O)CC(C)C2
Yield: 24.8 %

Procedure:
A mixture of 133 mg (0.5 mmol) of (34) and 67 μl (0.7 mmol) ethyl vinyl ether in 0.4 ml CH2Cl2 was stirred at 40° C. in the presence of 63 mg (0.25 mmol) pyridinium p-toluenesulfonate (PPTS) for 3 hours (57% conversion). Flash chromatography of the reaction mixture, using SiO2 (14 g) and n-pentane/diethyl ether=9:1 as eluent, afforded 42 mg (25%) of (35) as a ˜1:1 mixture of diastereomers and 72 mg (0.27 mmol) of the starting material (34).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH2:22][CH2:23][C@H:24]1[C@@H:28]([CH3:29])[CH2:27][NH:26][CH2:25]1>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][C@H:28]([CH3:29])[C@H:24]([CH2:23][NH2:22])[CH2:25]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: C[C@H]1CNC[C@H]1CN
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CC#N
Product: C[C@H]1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H]1CN
Yield: 81 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.22 g), cis-3-aminomethyl-4-methylpyrrolidine (1.68 g), and acetonitrile (30 ml) was refluxed for 4.5 hours. The reaction mixture was concentrated to dryness under reduced pressure. The resulting crude crystals were recrystallized from ethanol to give 5-amino-7-(cis-3-aminomethyl-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.3 g), recrystallized from ethanol-chloroform, m.p. 221°-223° C.