Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:13]#[N:14])=[CH:4][CH:5]1[CH:7]([C:8]([O-:10])=[O:9])[C:6]1([CH3:12])[CH3:11].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:13]#[N:14])=[CH:4][CH:5]1[CH:7]([C:8]([OH:10])=[O:9])[C:6]1([CH3:11])[CH3:12]
Reactant: COC(C#N)=CC1C(C(=O)[O-])C1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(C#N)=CC1C(C(=O)O)C1(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3 g of tert-butyl (1R,trans ΔZ) 3-(2-methoxy-2-cyanoethenyl)-2,2-dimethyl-cyclopropane carboxylate were dissolved in 60 ml of methylene chloride and 14.6 ml of trifluoroacetic acid were introduced slowly at 0° C. with stirring for 3 hours at 0° C. The mixture was evaporated to dryness by distillation under reduced pressure and cyclohexane was added to the residue. The mixture was again evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a mixture of hexane and ethyl acetate (4/6) yielded 2.05 g of (1R,trans,ΔZ) 3-(2-methoxy-2-cyanoethenyl)-2,2-dimethyl-cyclopropane carboxylic acid melting at 110° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:29]=[CH:28][C:21]([CH2:22][C@@H:23]([C:25]([OH:27])=[O:26])[NH2:24])=[CH:20][CH:19]=1>>[C:25]([C@@H:23]([NH:24][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:22][C:21]1[CH:28]=[CH:29][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)([OH:27])=[O:26]
Reactant: COc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: COc1ccc(C[C@H](Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)cc1
Yield: 60 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 4-methoxy-L-phenylalanine to provide the title compound in 60% yield as yellow needles (recrystallization from EtOH).
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([F:19])[C:9]([O:20][CH:21]([CH3:23])[CH3:22])=[C:8]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([N:31]4[CH2:40][CH2:39][C:38]5[N:37]=[C:36]([CH2:41][CH3:42])[C:35]([C:43]([O:45]C)=[O:44])=[CH:34][C:33]=5[C:32]4=[O:47])[CH2:27][CH2:26]3)[CH:7]=2)[CH2:5][CH2:4]1.Cl.O>CO>[CH:3]1([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([F:19])[C:9]([O:20][CH:21]([CH3:23])[CH3:22])=[C:8]([CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([N:31]4[CH2:40][CH2:39][C:38]5[N:37]=[C:36]([CH2:41][CH3:42])[C:35]([C:43]([OH:45])=[O:44])=[CH:34][C:33]=5[C:32]4=[O:47])[CH2:29][CH2:30]3)[CH:7]=2)[CH2:5][CH2:4]1
Reactant: CCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)c(F)c3OC(C)C)CC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)c(F)c3OC(C)C)CC1)CC2
Reaction time: 2 h
Yield: 92.5 %

Procedure:
2M aqueous sodium hydroxide solution (20 mL) was added to a solution of methyl 6-(1-((6-cyclopropyl-2,4′-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-2-ethyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (8.03 g) in methanol (25 mL) at 70° C. The mixture was stirred at the same temperature under nitrogen atmosphere for 2 hours. The mixture was neutralized with 1M hydrochloric acid at room temperature and added to water (100 mL). The mixture was stirred at 70° C. for 30 minutes and at room temperature for 2 hours to give colorless crystals. After filtration, the crystals were dissolved in ethanol. The solution was filtrated and the filtrate was concentrated in vacuo to give a colorless solid. The solid was recrystallized from ethanol-water (45 mL-130 mL) to give the title compound (7.26 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:21][NH2:22])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:6]
Reactant: COc1ccc(C(CN)N2CCOCC2)cc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: COc1ccc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCOCC2)cc1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-methoxy-phenyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:8]([OH:11])[CH2:9][CH3:10])[CH:7]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:7]=1
Reactant: CCC(O)c1cc(Br)ccc1F
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC(=O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.2 %

Procedure:
To 1-(5-bromo-2-fluorophenyl)propan-1-ol (12.1 g, 64.8 mmol) in CH2Cl2 (100 mL) was added pyridinium dichromate (73.2 g, 194 mmol) and powdered molecular sieves. The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through a pad of diatomaceous earth and washed with diethyl ether. The combined ether and CH2Cl2 layers were collected and concentrated under vacuum to afford 1-(5-bromo-2-fluorophenyl)propan-1-one (12.6 g, 98%) as a syrup. 1H NMR (CDCl3): δ 7.9-8.0 (m, 1H), 7.5-7.6 (m, 1H), 7.0 (t, 1H), 3.0-3.1 (m, 2H), 1.2 (t, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12]C)=[O:11])=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(-c2ccncc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of methyl 3-(pyridin-4-yl)benzoate (450 mg, 2.1 mmol) in MeOH (5 mL) was added an aqueous solution of NaOH (1.5 mL, 0.4M). The mixture was stirred at room temperature for 2 h. The reaction solution was then concentrated, the residue was next dissolved in water and adjusted pH to 5-6 with the 2N HCl. After extraction with EtOAc, the organic layers were dried and concentrated to give the product desired (600 mg, Yield 90%). LCMS (m/z): 200.1 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>Cl.CCO>[CH3:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: COc1ccccc1OC(c1ccccc1)C1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1ccccc1OC(c1ccccc1)C1CCNC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-[(2-Methoxyphenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester was dissolved in a solution of HCl in EtOH (1.25M, 8 mL) and stirred at room temperature for 18 hours, and then evaporated to dryness. The residue was purified by reverse phase preparative HPLC to afford the TFA salt of the RS/SR mixture of enantiomers of the title compound as a TFA salt (90 mg, 95% purity). MS m/z: [M+H]+ calcd for C18H21NO2, 284.16. found 284.4. 1H NMR (CD3OD, 400 MHz) δ (ppm): 7.40-7.35 (m, 4H), 7.32-7.28 (m, 1H), 7.00-6.98 (m, 1H), 6.92-6.88 (m, 1H), 6.71-6.65 (m, 2H), 5.32 (d, J=5.2, 1H), 3.90 (s, 3H), 3.62-3.55 (m, 1H), 3.36-3.30 (obscure, 3H, overlap with solvent), 2.97-2.92 (m, 1H), 2.28-2.21 (m, 1H), 2.13-2.07 (m, 1H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[C:17]([C:18]([N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[CH:16][N:15]=[C:14]2[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:29]=[C:30]([CH3:31])[C:13]=12>CN(C)C=O>[CH2:1]([O:8][C:12]1[C:17]([C:18]([N:20]([CH3:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:19])=[CH:16][N:15]=[C:14]2[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:29]=[C:30]([CH3:31])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn(-c2ccccn2)c2ncc(C(=O)N(C)c3ccccc3)c(Cl)c12
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccn2)c2ncc(C(=O)N(C)c3ccccc3)c(OCc3ccccc3)c12
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a solution of benzyl alcohol (0.40 g, 3.7 mmol) in N,N-dimethylformamide (10 mL), sodium hydride (0.16 g, 40 mmol, 60% oil) was added at room temperature, and the resulting mixture was stirred at the same temperature for 30 minutes. To the solution, a solution of 4-chloro-N,3-dimethyl-N-phenyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (1.0 g, 2.8 mmol) in N,N-dimethylformamide (10 mL) solution was added at room temperature, and stirred at 100° C. for 11.5 hours. The mixture was concentrated under reduced pressure, and the residue was poured into water. Organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Purification of the resulting residue by silica gel chromatography (hexane:chloroform:ethyl acetate=2:1:1 to 1:1:1 to 1:2:2) gave the title compound (0.99 g, 80% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][C:13]1[C:14]([C:19]([CH3:23])([CH3:22])[CH:20]=[O:21])=[N:15][CH:16]=[CH:17][CH:18]=1)=[CH:7]2.[CH3:24][Mg]Cl.O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][C:13]1[C:14]([C:19]([CH3:23])([CH3:22])[CH:20]([OH:21])[CH3:24])=[N:15][CH:16]=[CH:17][CH:18]=1)=[CH:7]2
Reactant: CC(C)(C=O)c1ncccc1Oc1cnc2c(F)cccc2c1
Reactant: C[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(O)C(C)(C)c1ncccc1Oc1cnc2c(F)cccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.10 g of 2-[3-(8-fluoro-quinolin-3-yloxy)-pyridin-2-yl]-2-methyl-propioaldehyde were dissolved in 3 ml of tetrahydrofuran. 0.2 ml of a 3.0 M tetrahydrofuran solution of methylmagnesium chloride were added thereto followed by stirring for 30 minutes at 0° C. Subsequently, water was added thereto to stop the reaction. The resultant was then extracted with ethyl acetate followed by distilling off the solvent of the organic layer and purifying by silica gel column chromatography to obtain 0.07 g of 3-[3-(8-fluoro-quinolin-3-yloxy)-pyridin-2-yl]-3-methyl-butan-2-ol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[CH3:17][C:18]1[NH:19][C:20]([CH3:44])=[C:21]([C:37]([O:39][CH2:40][CH2:41][CH2:42]Br)=[O:38])[CH:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=2)[C:23]=1[C:24]([O:26][CH3:27])=[O:25].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:17][C:18]1[NH:19][C:20]([CH3:44])=[C:21]([C:37]([O:39][CH2:40][CH2:41][CH2:42][O:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[CH:15][CH:14]=2)=[O:38])[CH:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=2)[C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: Oc1ccc(CCOC2CCCCO2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCBr)C1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCOc2ccc(CCOC3CCCCO3)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
4-(2-Tetrahydropyran-2-yloxyethyl)phenol (9, 72.1 g, 0.32 mol) was added to a solution of 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(3-bromopropoxycarbonyl)-1,4-dihydropyridine (12, 105 g, 0.23 mol) and K2CO3 (48 g, 0.35 mol) in acetone (700 mL), and the mixture heated at reflux overnight. After cooling, the solid was filtered, the solvent removed under reduced pressure, and the residue solubilised in CH2Cl2 (1 L). The organic layer was washed with 10% NaOH (2×100 mL) and water (2×100 mL) and dried over sodium sulfate. The solvent was evaporated under reduced pressure to provide an oil which was purified by flash chromatography (EtOAc: CH2Cl2 --15:85) to yield 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(3-[4-(2-tetrahydropyran-2-yloxyethyl)phenoxy]propoxycarbonyl)-1,4-dihydropyridine (1, mp<50° C.).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:16][C:17]1[C:18]([NH2:24])=[N:19][CH:20]=[C:21]([Br:23])[CH:22]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)C.[H-].[Na+]>CS(C)=O.O>[Br:23][C:21]1[CH:20]=[N:19][C:18]2[NH:24][C:4](=[O:3])[CH2:5][N:6]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)[CH2:16][C:17]=2[CH:22]=1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1)Cc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CN2CC(=O)Nc3ncc(Br)cc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A solution of [(2-amino-5-bromo-pyridin-3-ylmethyl)-(4-methoxy-benzyl)amino]acetic acid ethyl ester (13.0 g, 31.9 mmol) in DMSO (200 mL) was treated with NaH (60% dispersion in mineral oil, 1.30 g, 32.5 mmol). After stirring at room temperature overnight, the mixture was diluted with H2O (500 mL) and a precipitate formed. The solid was isolated by filtration, washed with H2O, and dried under vacuum at 50° C. for 6.5 h to give the title compound (7.16 g, 62%) as a tan powder: MS (ESI) m/e 362 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([CH3:15])[N:9]=1.[OH:16][C:17]1[CH:26]=[C:25]([CH3:27])[C:20]2[NH:21][C:22](=[O:24])[O:23][C:19]=2[CH:18]=1.O>CN(C=O)C>[Cl:14][C:12]1[N:11]=[C:10]([CH3:15])[N:9]=[C:8]([O:16][C:17]2[CH:26]=[C:25]([CH3:27])[C:20]3[NH:21][C:22](=[O:24])[O:23][C:19]=3[CH:18]=2)[CH:13]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: Cc1cc(O)cc2oc(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg (0.724 mmol) potassium carbonate and 110 mg (0.655 mmol) 4,6-dichloro-2-methyl-pyrimidine were added to 100 mg (0.575 mmol) 6-hydroxy-4-methyl-3H-benzoxazol-2-one in 1.5 mL DMF and the mixture was stirred for 2 h at RT. Then 15 mL water were added and the mixture was stirred overnight at RT. The precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH2:23])=[O:22])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:47]>>[NH2:47][C:8]1[C:7]2[N:16]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH2:23])=[O:22])[C:6]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCC(N)=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCC(N)=O

Procedure:
5-(2-Propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanamide (4.4 g, 14 mmol) was treated with mCPBA (4.28 g, 24.8 mmol), ammonium hydroxide (40 mL), and p-toluenesulfonyl chloride (5.24 g, 27.4 mmol) according to a modification of the method described in Part F of Example 34. At the completion of the amination reaction, a precipitate was present and was isolated by filtration. The precipitate was triturated and sonicated with acetone, isolated by filtration, and dried in a vacuum oven at 80° C. to provide 1.28 g of 5-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanamide as a tan powder, mp 202-203° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:14])[F:13])[C:3]=1[C:18]([N:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19]>C(O)=O.O>[CH2:32]([O:31][C:29]([N:20]([C:18]([C:3]1[C:4]2[C:9](=[C:8]([C:12]([F:13])([F:15])[F:14])[C:7]([O:16][CH3:17])=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[F:1])=[O:19])[CH2:21][C:22]([OH:24])=[O:23])=[O:30])[CH3:33]
Reactant: CCOC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(F)ccc2c(C(F)(F)F)c(OC)ccc12
Solvent: O=CO
Solvent: O
Product: CCOC(=O)N(CC(=O)O)C(=O)c1c(F)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
A suspension of N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(ethoxycarbonyl)glycine, 1,1-dimethylethyl ester (2.40 g, 5.07 mmol) in formic acid (90 mL) was stirred at room temperature under a dry nitrogen atmosphere. After 10 minutes, dissolution occurred. After 11/2 hours, the reaction solution was diluted with water (1 L). The resultant suspension was stirred rapidly for 45 minutes, then filtered. The solid was washed with water (3×20 mL), air dried, and recrystallized from benzene:petroleum ether to provide the title compound as white needles (1.21 g, 57%), m.p. 135.5°-138° C.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[N:38]=[C:37]([NH:39][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])[CH:36]=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>>[CH3:42][CH:41]([CH3:43])[C:40]([NH:39][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][CH2:24][NH:23][C:8](=[O:9])[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:28][CH2:29]2)[N:38]=1)=[O:44]
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)n1

Procedure:
Example 82 was prepared from triphenylacetic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.05 (d, 1H, J=8.0 Hz), 7.81 (s, 1H), 7.63 (t, 1H, J=7.6 Hz), 7.30–7.24 (m, 15H), 6.84 (d, 1H, J=7.2 Hz), 6.33 (br s, 1H), 3.44 (dd, 2H, J=6.4, 12.4 Hz), 2.89 (d, 2H, J=11.6 Hz), 2.57–2.49 (m, 2H), 2.31 (t, 2H, J=6.8 Hz), 1.95 (t, 2H, J=12.0 Hz), 1.79–1.58 (m, 6H), 1.27 (d, 6H, J=6.8 Hz); ESMS m/e: 575.3 (M+H)+.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:32][C:33]1[C:34](=[O:48])[N:35]([CH2:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[C:36]([CH3:40])=[CH:37][C:38]=1[OH:39].[F:49][C:50]1[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:51]=1[CH2:52]O>CN(C=O)C>[Cl:32][C:33]1[C:34](=[O:48])[N:35]([CH2:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[C:36]([CH3:40])=[CH:37][C:38]=1[O:39][CH2:52][C:51]1[CH:54]=[CH:55][C:56]([F:58])=[CH:57][C:50]=1[F:49]
Reactant: OCc1ccc(F)cc1F
Reactant: Cc1cc(O)c(Cl)c(=O)n1Cc1cccnc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1cccnc1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
To a degassed cold solution of DMF (10 mL) and PPh3 (resin, 2.2 g, 6.6 mmol) was added DEAD (1.038 mL, 6.6 mmol). The reaction mixture stirred at −10° C. for 20 minutes under nitrogen. A solution of 3-chloro-4-hydroxy-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one (1.00 g, 4.0 mmol) and 2,4-difluorobenzylalcohol (0.66 mL, 6.0 mmol) in DMF (10 mL) was added to the resin suspension. The reaction mixture stirred at −10° C. for 30 minutes and then allowed to stir at room temperature for 1 hour. The resin was filtered and rinsed with fresh MeOH and the filtrate concentrated. The residue was dissolved in ethyl acetate and purified by flash column chromatography (5% methanol in ethyl acetate). The appropriate fractions were concentrated. 1H-NMR (CD3OD, 400 MHz) δ 8.45 (ddd, 2H, J=1.6 Hz, 1.6 Hz, 1.6 Hz), 7.61 (m, 2H), 7.41 (dd, 1H, J=4.4 Hz, 4.8 Hz), 7.02 (m, 2H), 6.55 (s, 1H), 5.43 (s, 2H), 5.29 (s, 2H), 2.41 (s, 3H); ES-HRMS m/z 377.0882/379.0840 (M+H calculated for C19H16N2O2F2Cl requires 377.0863/379.0840).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[CH2:17][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([OH:16])[C:10]=3[C:8](=[O:9])[C:4]2=[C:5]([OH:7])[CH:6]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>C1(C)C=CC=CC=1>[OH:16][C:15]1[C:10]2[C:8](=[O:9])[C:4]3[C:3](=[CH:2][CH:1]=[CH:6][C:5]=3[OH:7])[CH:17]([C:24](=[O:27])[CH2:25][CH3:26])[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CCC(=O)Cl
Reactant: O=C1c2c(O)cccc2Cc2cccc(O)c21
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCC(=O)C1c2cccc(O)c2C(=O)c2c(O)cccc21
Temperature: 85 °C

Procedure:
To a suspension of 56.6 g (0.25 mol) of purified anthralin in 1750 m3 of anhydrous toluene at room temperature, 27.3 cm3 (0.34 mol) of anhydrous pyridine was added first and then 26.2 cm3 (0.3 mol) of propionyl chloride was added dropwise in around 20 minutes. The mixture was then heated to around 85° C. for 1 hour. The mixture was recooled to room temperature, 27.3 cm3 of pyridine and 26.2 cm3 of propionyl chloride were again added and the mixture was heated for 1 hour to a temperature of around 85° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Reaction time: 4 h
Yield: 90.1 %

Procedure:
To a solution of the 4-fluoro-3-nitrobenzoic acid (0.12 mol, 22.2 g) in 100 mL of anhydrous DCM was added 10 drops of anhydrous DMF. To this solution was added drop wise over 60 min, oxalyl chloride (0.144 mol, 12.6 mL). During the addition, the solid slowly dissolved to give rise to a yellow solution. The mixture was stirred for an additional 4 h and the solvent was stripped down to give a yellow oil. This oil was distilled under vacuum (110° C., 1.5 mm Hg) to give 4-fluoro-3-nitrobenzoyl chloride as a light yellow liquid (22.0 g, 90% yield).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[CH2:32][NH2:33])=[CH:27][CH:26]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:33][CH2:32][CH:31]([C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=3)[C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)=[O:18])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: NCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: O=C(NCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid was coupled with 2,2-bis-(4-chloro-phenyl)-ethylamine as in EXAMPLE 1, Part C. HPLC: RT=11.40 min. MS (ESI−): mass calcd. for C27H19Cl3N4O3S2, 616.00; m/z found, 615/617 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.49 (s, 1H), 8.36 (dd, J=7.1, 1.0, 1H), 8.23 (dd, J=8.8, 1.0, 1H), 7.72 (dd, J=8.8, 7.0, 1H), 7.68 (d, J=1.8, 1H), 7.34-7.30 (m, 4H), 7.18-7.13 (m, 4H), 6.89 (d, J=8.4, 1H), 6.86 (dd, J=8.4, 1.8, 1H), 5.87 (br t, J=5.6, 1H), 4.24 (t, J=8.0, 1H), 3.95 (dd, J=7.9, 5.9, 2H).