Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([NH2:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([N+:25]([O-:27])=[O:26])[C:19]=1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.[Cl-].[NH4+]>[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([N+:25]([O-:27])=[O:26])[C:19]=1[S:28]([NH:14][CH:3]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[C:2]([F:1])([F:15])[F:16])(=[O:29])=[O:30]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: Cc1cc(C)c(S(=O)(=O)NC(Cc2c[nH]c3ccccc23)C(F)(F)F)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 53.2 %

Procedure:
To a solution of 150 mg (0.66 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine in 2 mL of pyridine was added 165 mg (0.66 mmol) of 2,4-dimethyl-6-nitrobenzenesulfonyl chloride. The mixture stirred at 80° C. in a sealed tube. After 6 hours, the mixture was diluted with 10 mL of saturated aqueous ammonium chloride solution and extracted with three 10 mL portions of ethyl acetate. The combined ethyl acetate layers were washed with five 10 mL portions of 1 N aqueous HCl, three 10 mL portions of brine, and three 10 mL portions of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was chromatographed on silica gel using dichloromethane-hexanes (50-100% gradient). The material from the column was triturated with ether-hexanes to afford 155 mg (53%) of 2,4-dimethyl-6-nitro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide. MS: m/z 442.43 (M+1).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=1)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Cn1ccc(N)n1
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ccn(C)n2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 3-amino-1-methylpyrazol (40 mg, 0.417 mmol) was added. The resulting mixture was stirred at room temperature during three hours and the final product was collected by filtration and washed with diethylether to yield the title compound (56 mg, 59.6% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
To a solution of 3-hydroxyphenyl acetic acid, (5.0 g, 0.033 mol) in methanol (100 mL) was added concentrated sulfuric acid (1 mL) and the reaction mixture stirred at room temperature for 12 hours. After concentration to remove methanol, the crude oil was dissolved in ethyl acetate (75 mL), washed with water (50 ml), saturated aqueous NaHCO3 (50 mL), and brine (50 ml). The organic layer was dried over Na2SO4, and concentrated to give the methyl ester (1) as an oil (5.28 g) in 96% yield, which was used without further purification. 1H NMR (CDCl3) δ 7.17 (t, 1H), 6.81 (m, 3H), 6.48 (s, 1H), 3.69 (s, 3H), 3.57 (s, 2H). 13C NMR (CDCl3) δ 169.9, 153.3, 132.3, 126.9, 118.4, 111.5, 57.8, 38.4.
Reaction SMILES: [CH3:1][C:2]([NH:14]C(=O)C)([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)[CH3:3].[OH-].[K+].Cl>C(O)CO.CCOCC>[CH3:3][C:2]([NH2:14])([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:11])[F:12])=[CH:6][CH:5]=1)[CH3:1]
Reactant: CC(=O)NC(C)(C)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CCOCC
Product: CC(C)(N)c1ccc(C(F)(F)F)cc1
Temperature: 170 °C
Yield: 72.4 %

Procedure:
To a solution N-{1-methyl-1-[4-(trifluoromethyl)phenyl]ethyl}acetamide (2.0 g, 8.16 mmol) in ethylene glycol (5 mL) was added KOH (3.66 g, 8.16 mmol) and the resulting mixture was heated for 48 h at 170° C. After cooling to rt, the reaction mixture was extracted with Et2O (3×20 mL). The combined organic layers were washed with water (4×), dried over MgSO4, filtered and evaporated to give a colorless oil. This oil was dissolved in Et2O (30 mL) and a saturated solution of HCl in Et2O (10 mL) was added. The white precipitate was collected, washed with Et2O (3×10 mL) and dried under vacuo. This solid was then poured into Et2O (50 mL) and a 1N aqueous solution of NaOH (20 mL) were added. The organic layer was separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed with water (2×20 mL), dried over MgSO4, filtered and evaporated to give the title compound as colorless oil (1.2 g, 72%). 1H NMR (CDCl3, 300 MHz) δ 7.60-7.46 (m, 4H), 1.53 (br s, 2H), 1.43 (s, 6H). HPLC (Condition A), Rt: 1.73 min (HPLC purity: 94.0%).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[C:10](=O)[NH:9][CH:8]=[N:7][C:6]=2[N:12]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:10]1[C:5]2[S:4][C:3]([S:2][CH3:1])=[N:12][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: CSc1nc2nc[nH]c(=O)c2s1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1nc2ncnc(Cl)c2s1
Yield: 86 %

Procedure:
A mixture of 2-(methylthio)thiazolo[4,5-d]pyrimdin-7-(6H)-one (800 mg) and phosphorous oxychloride (8 mL) was refluxed for 2 h. Solvents were removed under vacuum and the mixture was diluted with chloroform. Again the solvents were removed under vacuum and this procedure repeated twice (yellow color solid). The residue was diluted with ice cold water and basified with 10% aqueous sodium bicarbonate. The solution was extracted with chloroform (3×100 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-ethyl acetate (95:5) as eluents to give the product as a white color solid (750 mg, 86%), mp 148-150° C. 1H NMR (400 MHz, CDCl3): δ 8.95 (1H, s), 2.90 (3H, s); LC-MS (positive ion mode): m/z 218, 220 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Br:25][CH2:26][CH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C(Cl)Cl>[Br:25][CH2:26][CH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([O:17][C:14]2[CH:13]=[CH:12][C:11]([S:8](=[O:9])(=[O:10])[NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:16][CH:15]=2)=[O:33])=[CH:30][CH:29]=1
Reactant: O=S(=O)(Nc1ccccc1)c1ccc(O)cc1
Reactant: O=C(Cl)c1ccc(CCBr)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc(S(=O)(=O)Nc2ccccc2)cc1)c1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
To a mixture of 24.93 g (0.10 mol) of N-phenyl-4-hydroxybenzenesulfonamide, 10.12 g (0.10 mol) of triethylamine and 150 ml of methylene chloride was added, dropwise, a solution of 24.75 g (0.10 mol) of 4-(2-bromoethyl)benzoyl chloride in 150 ml of methylene chloride over a period of 12 minutes. The reaction mixture was stirred at room temperature for 3 hours, after which 500 ml of methylene chloride were added. The solution was washed once with 2% HCl and twice with water, dried over magnesium sulfate and concentrated to a white solid. Recrystallization from ethanol gave 39.7 g (86.1% of theory) of 4-(N-phenylsulfamoyl)phenyl 4-(2-bromoethyl)benzoate, mp=156°-7° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[Cl:18])[NH2:14]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:11]([Cl:10])[CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: Fc1cnc(Cl)nc1Nc1ccc(Cl)c(Cl)c1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3,4-dichloroaniline gave 2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine. LCMS: purity: 95%; MS (m/e): 294 (M+2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[CH3:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[CH3:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCC(C)(F)F)c(Cl)c1
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC(C)(F)F)c(Cl)c1
Yield: 62 %

Procedure:
The title compound is prepared in 62% yield (3.5 g, yellows oil) from 1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethanone (4.0 g, 10.1 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (2.91 g, 24.0 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:5]=[CH:6][C:7]([OH:9])=O.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:31][N:32]([CH3:43])[CH2:33][CH2:34][NH:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([CH3:42])[CH2:38][CH2:37]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:31][N:32]([CH3:43])[CH2:33][CH2:34][N:35]([C@H:36]1[CH2:37][CH2:38][C@H:39]([CH3:42])[CH2:40][CH2:41]1)[C:7](=[O:9])[CH:6]=[CH:5][C:4]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:2]([F:1])[CH:3]=1
Reactant: COc1ccc(C=CC(=O)O)cc1F
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C=CC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)cc1F

Procedure:
Using 2.0 g of 3-fluoro-4-methoxycinnamic acid (Example 99), 2.8 ml of diethyl chlorophosphate, 2.7 ml of triethylamine, 100 ml of methylene chloride, 3 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.5 g of 4-dimethylaminopyridine, a reaction similar to that performed in Example 81 was carried out. As a result, 2.21 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3-fluoro-4-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:20]([O:22][CH3:23])=[O:21])=[CH:12][C:13]([C:16]([O:18]C)=[O:17])=[CH:14][CH:15]=1.C1COCC1.CO.[OH-].[K+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:11]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(C(=O)O)ccc1-c1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a stirred solution of 66.13C (36.50 g, 115 mmol) in THF (70.0 mL, 854 mmol) and MeOH (70.0 mL, 1730 mmol) at 0° C. was added potassium hydroxide (63 mL, 126 mmol) slowly to maintain the temperature below 6° C. The reaction mixture was allowed to warm to room temperature and stirring was continued for 15 hours. The reaction mixture was concentrated in vacuo. 1N HCl was added to the aqueous phase and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4, and concentrated in vacuo to give 2′-fluoro-5′-(methyloxy)-2-((methyloxy)carbonyl)-1,1′-biphenyl-4-carboxylic acid 66.13D as a white solid (35.00 g, 100% yield). MS ESI (pos.) m/e: 322.1 (M+H2O)+, 305.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1.[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](F)[C:19]=1[C:20]#[N:21].CC(C)([O-])C.[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([CH2:11][O:12][C:22]2[CH:23]=[CH:24][CH:25]=[C:18]([F:17])[C:19]=2[C:20]#[N:21])[CH2:9][CH2:10]1
Reactant: OCC1CCC(Cc2ccccc2Cl)CC1
Reactant: N#Cc1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCC1CCC(Cc2ccccc2Cl)CC1
Yield: 99.8 %

Procedure:
4-(2-Chlorobenzyl)cyclohexylmethanol (68 mg; 0.28 mmol) and 2,6-difluorobenzonitrile (40 mg; 0.28 mmol) were carried out using Method I with potassium t-butoxide (35 mg; 0.31 mmol) in 1.5 mL of dimethylformamide. Material was purified by flash chromatography to give 100 mgs of title compound as a colorless oil. (100% yield).
Reaction SMILES: C[O:2][C:3](=[O:30])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](O)=[O:37])([O-:33])=[O:32]>>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:8]2([C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:30])[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([NH:29][C:36]([C:35]4[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=4[N+:31]([O-:33])=[O:32])=[O:37])=[CH:27][CH:28]=3)=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccc(OC)cc2)CCCC1
Product: COc1ccc(CC2(C(=O)N[C@@H](Cc3ccc(NC(=O)c4ccccc4[N+](=O)[O-])cc3)C(=O)O)CCCC2)cc1
Yield: 51 %

Procedure:
4-Amino-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester (32.3 mg, 0.079 mmol) and 2-nitrobenzoic acid (17 mg, 0.10 mmol) were reacted as described in example 40 to give 22 mg of N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-4-[[(2-nitrophenyl)carbonyl]amino]-L-phenylalanine, HR-FAB-MS: obs. mass 546.2235. Calcd. mass 546.2240 (M+H).
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.Br[CH:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12].O>CS(C)=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:10](=[O:5])[C:11]([O:13][CH3:14])=[O:12])=[CH:16][CH:17]=1
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Reactant: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(=O)c1ccc(Cl)cc1
Temperature: 22.5 °C
Reaction time: 24 h

Procedure:
97.2 g of a 75% strength aqueous N-methylmorpholine N-oxide solution were added with ice-cooling to a solution of 100 g (0.38 mol) of the compound of Example 1 in 400 ml of dimethyl sulfoxide (DMSO). After the mixture had been stirred for 24 hours at 20 to 25° C., it was poured into water and extracted with methyl tert-butyl ether (MtBE). After the organic phases had been dried, stripped from the solvent and chromatographed on silica gel (cyclohexane/MtBE [3:1]), 69 g of the title compound was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[O:6][CH:7]=1.[CH3:31][NH:32][CH3:33].O>CCO>[CH3:31][N:32]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[O:6][CH:7]=1)[CH3:33]
Reactant: CNC
Reactant: O=C1CC(c2cccc(-c3nc(CCl)co3)c2)=Nc2ccc(-n3cccc3)cc2N1
Solvent: CCO
Solvent: O
Product: CN(C)Cc1coc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 4-[3-(4-chloromethyl-oxazol-2-yl)-phenyl]-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 78a) (125 mg) and KI (5 mg) in a 5.6M solution of dimethylamine in EtOH (1.5 mL) was stirred at 20° C. for 16 h. H2O (20 mL) was added and the precipitate was collected by filtration and purified by chromatography on silica gel using MeOH as eluent. The product was stirred with 20% aqueous MeOH (10 mL) the pH of the mixture being set to 11 by addition of 1N NaOH solution, and the solid was isolated by filtration to give the title compound (50 mg) as yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[C:21]([F:22])=[C:20]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])OC(C)(C)C)[CH3:26])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:8][C:7]=2[F:35])[CH2:3][CH2:2]1.Cl.[C:37](OCC)(=O)C>>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[C:21]([F:22])=[C:20]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])[CH3:37])[CH3:26])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:8][C:7]=2[F:35])[CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COc1ccc2nc(-c3cc(F)c(OCC4CC4)c(F)c3)oc2c1F)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cc(F)c(OCC4CC4)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-3,5-difluorophenyl)-7-fluoro-1,3-benzoxazol-6-yl)oxy)propan-2-yl)carbamate (1.28 g) was added 4 M hydrogen chloride/ethyl acetate (10 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate/methanol, and the solution was subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained solid was recrystallized (hexane/ethyl acetate) to give the title compound as white crystals (477 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10]N=C2CCCCCC2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH:20](O)([CH3:22])[CH3:21]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:10][C:20]3[CH2:22][CH2:6][CH2:5][CH2:4][CH2:9][C:21]=3[C:8]=2[CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(ON=C2CCCCCC2)cc1
Reactant: CC(C)O
Agent: Cl
Product: O=[N+]([O-])c1ccc2oc3c(c2c1)CCCCC3

Procedure:
Potassium t-butoxide (19 g, 1600 mmol) was added in portions to a cooled (2° C.) solution of cycloheptanone oxime (19 g, 150 mmol) in DMF (150 mL). The cooled reaction mixture was stirred for 40 minutes and then 1-chloro-4-nitrobenzene (25 g, 160 mmol) in DMF (50 mL) was added over 5 minutes. The reaction mixture was stirred at ˜10° C. for 30 minutes and then allowed to warm to room temperature and stirred for an additional 2 hours, and then stood at ambient temperature for 16 hours. The reaction mixture poured into water (1600 mL) with stirring. The mixture was stirred for an additional 20 minutes and then allowed to stand at room temperature for 5 hours. The precipitate was collected by filtration and washed with water. Recrystallization of the crude material from hexane provided cycloheptanone O-(4-nitro-phenyl)-oxime (30 g). Cycloheptanone O-(4-nitro-phenyl)-oxime (12 g, 50 mmol) was dissolved in warm isopropanol (120 mL) and 12 N hydrochloric acid (17 mL) was added. The reaction mixture was heated to reflux for 4 hours and then cooled in an ice bath. The solid was collected by filtration, washed with water and cold isopropanol, and dried in an oven to give 2-nitro-7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan (7.8 g, 34 mmol). A mixture of 2-nitro-7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan (5.8 g, 25 mmol) and Raney nickel (-5.6 g wet weight) in ethanol (270 mL) was hydrogenated at 50 PSI on a Parr shaker overnight. The mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was purified by flash column chromatography (gradient elution with 15-25% ethyl acetate-hexanes) to give 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (4.6 g). Mp 98-99° C.
Reaction SMILES: COC(=O)CCCN1CCC[C@H]1COC1C=CC(CC2C=CC=CC=2)=CC=1.[CH2:28]([C:35]1[CH:56]=[CH:55][C:38]([O:39][CH2:40][C@H:41]2[CH2:45][CH2:44][CH2:43][N:42]2[CH2:46][CH2:47][CH2:48][C:49]2[O:53][NH:52][N:51]([CH3:54])[CH:50]=2)=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([C:35]1[CH:56]=[CH:55][C:38]([O:39][CH2:40][C@@H:41]2[CH2:45][CH2:44][CH2:43][N:42]2[CH2:46][CH2:47][CH2:48][C:49]2[O:53][NH:52][N:51]([CH3:54])[CH:50]=2)=[CH:37][CH:36]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CN1C=C(CCCN2CCC[C@@H]2COc2ccc(Cc3ccccc3)cc2)ON1
Agent: COC(=O)CCCN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Product: CN1C=C(CCCN2CCC[C@H]2COc2ccc(Cc3ccccc3)cc2)ON1
Yield: 40 %

Procedure:
The title compound (0.210 mg, 40%) was prepared from 4-[(S)-2-(4-benzyl-phenoxymethyl)-pyrrolidin-1-yl]-butyric acid methyl ester (337 mg, 1 mmol) by a similar procedure as that described for the synthesis of 5-{3-[(R)-2-(4-benzyl-phenoxymethyl)-pyrrolidin-1-yl]-propyl}-3-methyl-[1,2,3]oxadiazole: MS; m/z 392 (M+1). 1H NMR (400 HMz, CDCl3) δ 1.62-1.79 (m, 3H), 1.92-2.03 (m, 3H), 2.23 (m, 1H), 2.33 (s, 3H), 2.49 (m, 1H), 2.81-2.99 (m, 4H), 3.14 (m, 1H), 3.73 (dd, J1=6.4 Hz, J2=9.2 Hz, 1H), 3.86 (dd, J1=4.8 Hz, J2=9.6 Hz, 1H), 3.92 (s, 2H), 6.81 (dd, J1=2.0 Hz, J2=6.8 Hz, 2H), 7.08 (d, J=8.0 Hz, 2H), 7.16-7.29 (m, 5H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:13][O-].[Na+].O>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[Cl:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(C=O)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
To a solution of 6.43 g (0.039 mole) 4-acetamidobenzaldehyde (14) (Aldrich, A180-0) in 55 mL of glacial acetic acid, was added 100 mL of 5.25% solution of sodium hypochlorite (Clorox, Pathmark brand) and the reaction mixture was stirred at room temperature for 48 hours. A white precipitate developed in the reaction mixture when a sample of the reaction mixture was taken off for TLC. The mixture was poured into 100 mL water and filtered to give 2.5 g (32%) of 24 as white powder, mp 110-113°. Infrared (IR) and NMR analysis gave the following results:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2].[H-].[Na+].Cl[C:24]1[N:28]([CH3:29])[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]=1.O>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:24]3[N:28]([CH3:29])[C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[N:25]=3)=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(F)cc21
Reactant: Cn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3C)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a stirred solution of 1-ethyl-6-fluoro-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) in DMF (4 mL) was added 60% sodium hydride (13.2 mg) at room temperature. The mixture was stirred at room temperature for 30 min, and then 2-chloro-1-methyl-1H-benzimidazole (67.1 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on NH-silica gel eluting with AcOEt/Hexane. Crystallization from AcOEt/Hexane gave the title compound (104 mg).