Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]([CH3:20])[CH3:19])[N:13]=[CH:12]2)(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C>CO>[CH:18]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=2)[CH:12]=[N:13]1)([CH3:20])[CH3:19]
Reactant: CC(C)n1ncc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: F
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)n1ncc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
5-{[tert-Butyl(dimethyl)silyl]oxy}-1-isopropyl-1H-indazole (Preparation 40, 238 mg, 0.819 mmol), triethylamine trishydrofluoride (132 mg, 0.819 mmol) and methanol were combined and stirred at room temperature for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated in vacuo and the residue redissolved with methanolic ammonia and again concentrated in vacuo. The procedure was repeated once more and the residue purified by silica gel chromatography eluting with 0 to 30% EtOAc in heptane to yield the title compound (123 mg, 86%):
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:29]=[C:30]([N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=2)[C:26]([OH:28])=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:38](I)[CH2:39]C>>[C:1]([O:5][C:6]([NH:8][C@:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:29]=[C:30]([N:32]([CH2:37][CH2:38][CH3:39])[S:33]([CH3:36])(=[O:34])=[O:35])[CH:31]=2)[C:26]([OH:28])=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCI
Reactant: CN(c1cc(C(=O)O)cc(-c2nnc(C(C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O
Product: CCCN(c1cc(C(=O)O)cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O

Procedure:
Prepared using a procedure similar to that employed for the synthesis of Intermediate VI, substituting propyl iodide in the place of methyl iodide in Step B of the Intermediate III synthesis.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[CH:7]=1.[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20](F)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:17][C:18]1[CH:19]=[C:20]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[O:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])[N:10]=2)[CH:7]=1
Reactant: O=C(Nc1nc2ccc(O)cn2n1)C1CC1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc2ccc(Oc3cc(F)cc([N+](=O)[O-])c3)cn2n1)C1CC1
Temperature: 140 °C
Reaction time: 6 h
Yield: 485.3 %

Procedure:
A mixture of N-(6-hydroxy[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (200 mg, 0.917 mmol), 1,3-difluoro-5-nitrobenzene (437 mg, 2.75 mmol), potassium carbonate (380 mg, 2.75 mmol) and N,N-dimethylformamide (6 mL) was stirred at 140° C. for 6 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (1.59 g, 89%) as a yellow solid.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=3[N+:28]([O-])=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Ni].CO>[C:31]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[C:19]([NH2:28])=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=3)[CH2:10][CH2:9]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 15 parts of 4-(diphenylmethyl)-N-[2-nitro-4-(trifluoromethyl)phenyl]-1-piperazinepropanamine in 240 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding N1 -{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-4-(trifluoromethyl)-1,2-benzenediamine.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]3[CH2:40][CH2:39][CH:38]([CH2:41][OH:42])[CH2:37][CH2:36]3)=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[N:43]1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C(C)(C)C)(C)C)(=O)=O.[C:66]([O:69]CC)(=[O:68])C>ClCCl>[CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]3[CH2:36][CH2:37][CH:38]([CH2:41][OH:42])[CH2:39][CH2:40]3)=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:43][C:66](=[O:68])[O:69][N:26]=3)=[CH:17][CH:18]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CCOC(C)=O
Reactant: Cc1cccc(C)n1
Reactant: CCCc1nc(CC)n(-c2ccc(OC3CCC(CO)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc(CC)n(-c2ccc(OC3CCC(CO)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-{[4-(hydroxymethyl)cyclohexyl]oxy}phenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.4 g) and 2,6-lutidine (0.25 mL) in dichloromethane (6 mL) was added tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.33 mL) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (6 mL), hydroxylammonium chloride (0.85 g) and sodium hydrogen carbonate (1.2 g) were added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (8 mL). N,N′-carbonyldiimidazole (0.17 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride (1.6 mL, 1.0 M tetrahydrofuran solution) was added, and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.26 g, 77%).
Reaction SMILES: N[S:2]([C:5]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([CH:20]([CH3:22])[CH3:21])[C:6]=1[C:7]([N:9](CC)CC)=[O:8])(=[O:4])=[O:3]>C(O)(=O)C>[CH:20]([C:14]1[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=[C:5]2[C:6]=1[C:7](=[O:8])[NH:9][S:2]2(=[O:4])=[O:3])([CH3:22])[CH3:21]
Reactant: CCN(CC)C(=O)c1c(C(C)C)cc(OC)cc1S(N)(=O)=O
Solvent: CC(=O)O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)NC2=O
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A solution of 2-aminosulfonyl-6-isopropyl-4-methoxy-N,N-diethylbenzamide (429.6 g) in acetic acid (1.5 L) was refluxed for 20 hours, then cooled to room temperature. The solvent was removed under vacuum. The oily residue was dissolved in water (6 L) and the pH was adjusted to 1 with hydrochloric acid (6N). The crude product was collected by filtration, washed with water (2 L), dried at 60° C. under vacuum for 18 hours and recrystallized from ethyl acetate-hexane to give 4-isopropyl-6-methoxysaccharin (303 g, 91% yield, m.p. 188° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12]O)=[CH:10][O:9][N:8]=1.S(Cl)([Cl:16])=O>C(Cl)Cl>[Cl:16][CH2:12][C:11]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][O:9][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1conc1-c1ccccn1
Solvent: ClCCl
Product: ClCc1conc1-c1ccccn1
Reaction time: 1 h
Yield: 102.8 %

Procedure:
To a solution of (3-pyridin-2-yl-isoxazol-4-yl)-methanol (3.0 g, 16 mmol) in DCM (30 mL) at 0° C. was added thionyl chloride (3.75 g, 32 mmol) and the resulting mixture stirred for 1 h and then evaporated. After 1 h the reaction mixture was quenched with a solution of sodium hydrogen carbonate (1 N, 15 mL) and extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, filtered and concentrated to give the title compound (3.2 g, 96%) as a grey solid. MS: m/e=195.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]2([S:15][C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13]2)[CH2:11][O:10]1.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([C:12]1([S:15][C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13]1)[CH2:11][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: c1nc[nH]n1
Reactant: Fc1ccc(C2(C3(SC(F)(F)F)CC3)CO2)c(F)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OC(Cn1cncn1)(c1ccc(F)cc1F)C1(SC(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
A solution of 15.9 g (54 mmol) of 2-(2,4-difluoro- phenyl)-2-[1-(trifluoromethylmercapto)-cycloprop-1-yl]oxirane in 20 ml of absolute dimethylformamide is added dropwise with stirring to a mixture of 12 g (174 mmol) of 1,2,4-triazole and 1.4 g (12.5 mmol) of potassium tert.butylate in 30 ml of absolute dimethylformamide under a nitrogen atmosphere The reaction mixture is stirred at 100° C. for 8 hours. The solvent is then stripped off under reduced pressure, the residue is taken up in ethyl acetate, and the solution is washed twice with water and concentrated under reduced pressure after drying over sodium sulphate The residue is chromatographed on a silica gel column using chloroform as eluent. In this manner, 12.5 g (65 % of theory) of 1-(2,4-difluorophenyl)-1-hydroxy-2-(1,2,4-triazol-1-yl)-1-(1-trifluoromethylmercapto-cycloprop-1-yl)ethane of melting point 103° C. are obtained.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(OC(C)C)(C)C>C(O)C>[N:18]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=2)=[CH:2][N:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=12
Reactant: CCOC(=O)C(C)c1ccc(C(=O)CCl)cc1
Reactant: Nc1ccccn1
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CCOC(=O)C(C)c1ccc(-c2cn3ccccc3n2)cc1
Yield: 40.5 %

Procedure:
A mixture of 47 g of ethyl 2-[4-(chloroacetyl)phenyl]propionate, 100 ml of ethanol and 30 g of 2-aminopyridine is heated under reflux for 2 hours. The ethanol is distilled off under reduced pressure, and water is added to the residue. The mixture is extracted with benzene, and the extract is washed with water, dried and concentrated to give a reddish brown oil. To the oil is added isopropyl ether, and the crystalline precipitate is filtered off and recrystallized from isopropyl ether to give 22 g of ethyl 2-[4-(imidazo[1,2-a]pyridin-2-yl)phenyl]propionate as colorless scales melting at 110°-112°C.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[O:16][CH2:17][CH2:18][CH3:19].[Li+].[OH-]>C1COCC1.CO>[CH2:17]([O:16][C:7]1[CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=[CH:11][C:6]=1[CH:5]=[CH:4][C:3]([OH:20])=[O:2])[CH2:18][CH3:19]
Reactant: CCCOc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOc1cc(C(F)(F)F)ccc1C=CC(=O)O
Yield: 72.2 %

Procedure:
3-(2-Propoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (198 mg) was reacted with 1N LiOH (5 ml) in THF (10 ml) and CH3OH (5 ml) for 1 hr. The reaction mixture was concentrated in vacuo. Water (30 ml) was added to the resulting residue, which was neutralized with 1N HCl solution. The mixture was extracted with ethyl acetate (30 ml×3). The combined organic layer was dried over MgSO4. The filterate was concentrated in vacuo to yield title compound (136 mg, 72%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:7]1([N:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[C:19]([O:22][C:23]4[N:24]=[CH:25][C:26]([C:29](Cl)=[O:30])=[N:27][CH:28]=4)[CH:20]=[CH:21][C:14]=3[CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8]1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1>ClCCl>[CH:7]1([N:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[C:19]([O:22][C:23]4[N:24]=[CH:25][C:26]([C:29]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[O:30])=[N:27][CH:28]=4)[CH:20]=[CH:21][C:14]=3[CH2:13][CH2:12]2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=C(Cl)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Reactant: C1COCCN1
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: O=C(c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Morpholine (0.17 ml, 2.0 mmol) was added to a stirred solution of the product of step 1 (394 mg, 1 mmol) and diethylaminomethyl polystyrene (1.88 g, 3.2 mmol/g, 6 mmol) in dichloromethane (10 ml). The resulting mixture was allowed to stir at room temperature for 24 hours and the filtered. The filtrate was concentrated in vacuo and the resulting crude residue was purified column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (E123). MS (ES+) m/e 409 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[C:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH:22]([CH3:24])[CH3:23])[CH:15]=1)(O)[CH3:12].CC(O)=O.[H][H]>CCO>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[CH:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH:22]([CH3:24])[CH3:23])[CH:15]=1)[CH3:12]
Reactant: COc1cc(C)c(C(C)(O)c2ccc(OC)c(C(C)C)c2)c(C)c1
Reactant: [H][H]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(C)c(C(C)c2ccc(OC)c(C(C)C)c2)c(C)c1
Yield: 78.8 %

Procedure:
A solution of 1-(2,6-dimethyl-4-methoxyphenyl)-1-(3-isopropyl-4-methoxyphenyl) ethanol (400 mg, 1.218 mmol) in 4.4 mL of 9% (v/v) AcOH in EtOH containing 10% Pd/C (40 mg) was hydrogenated at 1 atm at room temperature. When hydrogen uptake was complete (12 hours), the catalyst was filtered off and the filtrate was diluted with 50 mL of ether, washed with sat. NaHCO3 solution (3×10 mL), water (30 mL) and brine (3×10 mL). The solvent was evaporated to yield 300 mg (0.96 mmol, 79%) of 1-(2,6-dimethyl-4-methoxyphenyl)-1-(3-isopropyl-4-methoxyphenyl) ethane as an oil. This material was used in the next step without further purification; 1HNMR (CDCl3) & 1.16 (dd, 6H), 1.63 (d, 3H), 2.12 (s, 6H), 3.27 (heptet, 1H), 3.81 (s, 6H), 4.54 (q, 1H), 6.54 (s, 2H), 6.75 (d, 1H), 6.88 (d, 1H), 7.04 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH3:20])[N:8]=[C:9]2[C:18]=1[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:11]=[C:10]2[NH2:19].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].[I-].[Na+].CN(C=O)C>O>[NH2:19][C:10]1[C:9]2=[N:8][N:7]([CH3:20])[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:25]3[C:21](=[O:31])[C:22]4[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:24]3=[O:26])=[C:18]2[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cn1nc2c(N)nc3c(c2c1CCCCCl)CCCC3
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc2c(N)nc3c(c2c1CCCCN1C(=O)c2ccccc2C1=O)CCCC3
Temperature: 90 °C

Procedure:
A mixture of 1-(4-chlorobutyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinoline-4-amine (385 mg, 1.31 mmol), potassium phthalimide (362 mg, 1.96 mmol), sodium iodide (50 mg, 0.327 mmol), and DMF (2 mL) was heated at 90° C. for 4 hours. The reaction mixture was cooled to ambient temperature and then diluted with water (30 mL) while stirring in an ice bath. A precipitate was isolated by filtration to obtain 2-[4-(4-amino-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]-1H-isoindole-1,3(2H)-dione as a yellow solid.
Reaction SMILES: O[CH:2]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=1)[CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].CCN(CC)CC.CC(C)=O.[C:37]([OH:40])(=[S:39])[CH3:38]>C1(C)C=CC=CC=1>[C:37]([S:39][CH:2]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=1)[CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:40])[CH3:38]
Reactant: CC(O)=S
Reactant: CCCCCc1ccc(OCC(O)CC#CCCCC(=O)OC)cc1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(OCC(CC#CCCCC(=O)OC)SC(C)=O)cc1

Procedure:
In a dry flask equipped with a condenser was placed 4 g of methyl 8-hydroxy-9-(4-pentylphenoxy)-5-nonynoate, the product of Example 8, 1.69 ml of Et3N, 20 ml of toluene and 20 ml of acetone. To the mixture was added 3.43 g of N-methyl-2-fluoropyridimium tosylate stirring at RT for 1 hr. A solution of 0.87 ml of thioacetic acid and 1.69 ml of Et3N in 5 ml of toluene was added. The resulting solution was refluxed for 2 hr. Solvent was removed and the residue was dissolved in Et2O and then was washed with NaHCO3 solution and dried over MgSO4. The crude product, after solvent removal, was purified on a Waters Prep 500 HPLC (EtOAc-hexane 1:16) to obtain the title compound.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[CH:8]=[C:7]([CH3:11])[O:6][C:5]=1[CH3:12])([OH:3])=[O:2].[C:13](Cl)(=O)C.CO.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:1]([C:4]1[C:9](=[O:10])[CH:8]=[C:7]([CH3:11])[O:6][C:5]=1[CH3:12])([O:3][CH3:13])=[O:2]
Reactant: Cc1cc(=O)c(C(=O)O)c(C)o1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1c(C)oc(C)cc1=O

Procedure:
42 g of 3-carboxy-2,6-dimethylpyr-4-one is dissolved in 250 ml of methylene chloride. In a second flask, 20 ml of acetyl chloride is cautiously added to 400 ml of methanol. The two solutions are mixed and refluxed for five hours. Solid sodium carbonate is added and the solvent removed after a water wash. The residue is distilled (115°-125° at 0.1 mm) to give 40 g of 3-carbomethoxy-2,6-dimethylpyr-4-one as a waxy solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:9]=1)[NH2:6])[CH3:2].N1C(C)=CC=CC=1C.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].Cl>C1COCC1.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:6][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=[C:8]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:9]=1)[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCc1cc(N)cc(-c2nnnn2C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Reaction time: 1 h
Yield: 97.7 %

Procedure:
3-Ethyl-5-(1-methyl-1H-tetraazol-5-yl)aniline (3.83 g, 19 mmol, 1 equiv.), was dissolved in THF at 25° C. under nitrogen then 2,6-lutidine (Aldrich, 2.17 ml, 19 mmol, 1 equiv.) was added. Cooled the reaction to 0° C. Added a THF solution of phenyl chloroformate (2.36 ml, 19 mmol, 1 equiv.) dropwise via an addition funnel. Worked up after 1 hour by adding ethyl acetate and 0.1 N HCl. Separated the layers and rinsed the organic layer twice more with 0.1 N HCl and once with brine. The organic layer was dried over MgSO4 then stripped in vacuo to give 6.00 g of tan solids as product. NMR (300 MHz, CDCl3) δ 7.86 (s, 1H), 7.50-7.30 (m, 5H), 7.30-7.10 (m, 3H), 4.17 (s, 3H), 2.71 (q, 2H, J=7 Hz), 1.27 (t, 3H, J=7 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:19][CH:20]([S:23](Cl)(=[O:25])=[O:24])[CH2:21][CH3:22]>>[CH3:19][CH:20]([S:23]([NH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:25])=[O:24])[CH2:21][CH3:22]
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(N)c1
Reactant: CCC(C)S(=O)(=O)Cl
Product: CCC(C)S(=O)(=O)Nc1cccc(OCCNC(=O)OC(C)(C)C)c1

Procedure:
Sulfonation of tert-butyl 2-(3-aminophenoxy)ethylcarbamate (3) using butane-2-sulfonyl chloride following the method described in Example 1 gave tert-butyl 2-(3-(1-methylpropylsulfonamido)phenoxy)ethylcarbamate (6) as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.97 (t, J=6.0 Hz, 1H), 6.76-6.78 (m, 2H), 6.59-6.62 (m, 1H), 3.87 (t, J=5.6 Hz, 2H), 3.24 (q, J=6.4 Hz, 2H), 2.93-3.02 (m, 1H), 1.80-1.91 (m, 1H), 1.40-1.48 (m, 1H), 1.35 (s, 9H), 1.19 (d, J=6.8 Hz, 3H), 0.88 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:25][CH:26]1[CH:31]2[CH:27]1[CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30]2.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:25][CH:26]3[CH:31]4[CH:27]3[CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30]4)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CC(C)(C)OC(=O)N1CC2C(N)C2C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2C(C1)C2NC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.250 g, 1.0 eq.) was dissolved in DCM (12 mL). tert-butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.17 g, 1.2 eq.) was added and the reaction mixture was cooled to −60° C. T3P (0.51 mL, 1.2 eq.), followed by DIPEA (0.24 mL, 2.0 eq.) was then added at the same temperature. The reaction mixture was stirred for 30 min. and transferred into water (50 mL) and extracted with DCM (2×50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure (25° C., 20 mmHg) to afford crude product, which was purified by chromatography (0-5% MeOH in DCM) to give (Z)-tert-butyl 6-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylamido)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.28 g; 66.1% yield).