Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:32][C:33]1[CH:41]=[C:40]([N+:42]([O-:44])=[O:43])[CH:39]=[CH:38][C:34]=1[C:35]([OH:37])=O.[CH3:45][NH:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49]>CN(C=O)C>[F:32][C:33]1[CH:41]=[C:40]([N+:42]([O-:44])=[O:43])[CH:39]=[CH:38][C:34]=1[C:35]([N:46]([CH3:45])[NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:37]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CNNC(=O)OC(C)(C)C
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(NC(=O)OC(C)(C)C)C(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under argon and at RT, 17.1 g (53.4 mmol, 1.3 eq.) of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate and 21.4 ml (123.1 mol, 3.0 eq.) of N,N-diisopropylethylamine were added to a solution of 9.1 g (49.3 mmol, 1.2 eq.) of 2-fluoro-4-nitrobenzoic acid in 200 ml of DMF, and the mixture was stirred at RT for 20 min. A solution of 12.5 g (purity 48%, 41 mmol) of tert-butyl 2-methylhydrazinecarboxylate in 50 ml of DMF was added, and the reaction mixture was stirred at RT for 6 h. After removal of the DMF under reduced pressure and addition of water/ethyl acetate and phase separation, the organic phase was washed with 10% aqueous citric acid and with saturated aqueous sodium chloride solution, dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures). Yield: 8.35 g (65% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[N:12][C:11]([OH:22])=[N:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:30][C:31]([F:34])([F:33])[F:32].C(OCC)(=O)C>CS(C)=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=[C:11]([O:22][CH2:30][C:31]([F:34])([F:33])[F:32])[N:12]=2)=[CH:15][N:16]=1
Reactant: COc1ccc(-n2nc(O)nc2-c2ccc(OC)nc2)cc1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(-n2nc(OCC(F)(F)F)nc2-c2ccc(OC)nc2)cc1
Temperature: 100 °C
Yield: 23.5 %

Procedure:
A mixture of 1-(4-methoxyphenyl)-5-(6-methoxypridin-3-yl)-1H-1,2,4-triazol-3-ol (200 mg, 0.67 mmol), potassium carbonate (278 mg, 2.01 mmol), and 2-iodo-1,1,1-trifluoroethane (0.198 mL, 2.01 mmol) in dimethylsulfoxide (1 mL) were heated at 100° C. for 1 hour. After cooling, ice water and ethyl acetate were poured into the mixture and the organic layer was separated, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography (toluene-ethyl acetate 10:1). The desired product was washed with hexane to give 2-methoxy-5-(1-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H-1,2,4-triazole-5-yl)pyridine. (60 mg, 23.5% yield)
Reaction SMILES: [CH3:1][P:2]([C:7]1[CH:12]=[C:11](Cl)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])(=[O:6])[O:3]CC.[CH2:17]([SH:19])[CH3:18].[OH-].[Na+]>CS(C)=O.O>[CH3:1][P:2]([C:7]1[CH:12]=[C:11]([S:19][CH2:17][CH3:18])[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])(=[O:6])[OH:3]
Reactant: CCOP(C)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCS
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCSc1ccc([N+](=O)[O-])c(P(C)(=O)O)c1

Procedure:
To a solution of ethyl P-methyl-2-nitro-5-chlorophenylphosphinate (20.0 mmol) and ethanethiol (60.0 mmol) in dimethylsulfoxide (20 ml) is added a solution of sodium hydroxide (40.0 mmol) in 1 ml of water. The mixture is warmed to 60° overnight, after which it is poured into water and extracted with ether. The aqueous solution is acidified, extracted with methylene chloride, dried and evaporated to give P-methyl-2-nitro-5-ethylthiophenylphosphinic acid, which is then treated with diazomethane in methanol to give methyl P-methyl-2-nitro-5-ethylthiophenylphosphinate.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([S:28][CH3:29])[N:22]=1.Cl>C1COCC1.O>[Cl:20][C:21]1[CH:26]=[C:25]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[C:2]([F:9])([F:8])[F:1])[N:24]=[C:23]([S:28][CH3:29])[N:22]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: FC(F)(F)[C@@H]1CCCN1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1nc(Cl)cc(N2CCC[C@H]2C(F)(F)F)n1
Reaction time: 0.08 h
Yield: 77.3 %

Procedure:
(2S)-2-(Trifluoromethyl)pyrrolidine (858 mg, 6.17 mmol) was dissolved in THF (10 mL) in a 250 mL RB flask. The mixture was cooled in an ice bath. Then molecular sieves were added and let stir for 5 minutes. LiHMDS (6.78 mL, 6.78 mmol) was added slowly followed by addition of 4,6-dichloro-2-(methylthio)pyrimidine (1.444 g, 7.40 mmol), and the reaction was stirred at 0° C. for an additional 10 minutes. Then water (10 mL) was added followed by dropwise addition of 6N HCl until pH was acidic. The mixture was then extracted with EtOAc (3×30 mL) and the organic was combined, washed with saturated NaCl, filtered and concentrated. The crude oil was purified on Biotage 25 g SNAP column with a gradient of 0 to 35% EtOAc in Hexane over 25 minutes to afford the title compound (1.42 g) as a clear oil. LC-MS (ES) m/z=298 [M+H]+.
Reaction SMILES: [SH:1][CH2:2][C:3]([NH2:5])=[O:4].O1CCOCC1.[Cl:12][C:13](=[CH2:18])[C:14]([O:16][CH3:17])=[O:15]>N1C=CC=CC=1>[Cl:12][CH:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:18][S:1][CH2:2][C:3]([NH2:5])=[O:4]
Reactant: C=C(Cl)C(=O)OC
Reactant: NC(=O)CS
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COC(=O)C(Cl)CSCC(N)=O
Reaction time: 1 h

Procedure:
2-Mercaptoacetamide (18.79 g) was stirred in a mixture of dry 1,4-dioxan (200 ml) and dry pyridine (33.5 ml)) whilst methyl 2-chloroacrylate (24.88 g) was added dropwise over 15 minutes. The mixture was stirred for 1 hour then stood overnight. The resultant mixture contained the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[NH:1]([CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)[C:12]([CH3:13])=[O:14]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc2[nH]ccc2c1
Product: CC(=O)NCc1ccc2[nH]ccc2c1
Reaction time: 3 h
Yield: 89 %

Procedure:
5-Aminomethylindole (5.3 g, 0.036 mol) was mixed with acetic anhydride (13 ml) and kept at room temperature for 3 h. The solvent was removed under reduced pressure and the residue was stirred with toluene. The precipitated solid was collected by filtration to yield 6.1 g (89%) of 5-acetaminomethylindole.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:27][CH3:28])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([CH2:24][OH:25])[CH:17]=4)=[N:14][N:13]([CH3:26])[C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1.[CH3:29]I.[H-].[Na+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([O:27][CH3:28])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([CH2:24][O:25][CH3:29])[CH:17]=4)=[N:14][N:13]([CH3:26])[C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1
Reactant: CI
Reactant: COc1cc2ncc3c(c(-c4ccc(C#N)c(CO)c4)nn3C)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1cc(-c2nn(C)c3cnc4cc(OC)c(OC)cc4c23)ccc1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
4-(7,8-Dimethoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)-2-hydroxymethylbenzonitrile (17 mg, 44 μmol) is dissolved in N,N-dimethylformamide (2.1 ml) under argon, and methyl iodide (8.2 μl, 131 μmol) and sodium hydride (95%, 2.4 mg, 96 μmol) are subsequently added. The reaction solution is stirred at 0° C. for 2 h. After addition of a little water, the mixture is extracted with ethyl acetate and semi-saturated sodium chloride solution for work-up. The organic phase is dried over Na2SO4, filtered with suction and evaporated to dryness at 40° C. in vacuo. The residue is purified by chromatography (pHPLC, solvent gradient water/1-30% by vol. of acetonitrile, 0.1% by vol. of formic acid), and the product fractions are freeze-dried, giving 4-(7,8-dimethoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)-2-methoxymethylbenzonitrile (4 mg, 10.3 μmol) as a colourless solid. MS: 389.2 (M+H+), TLC (HPTLC): Rf=0.41 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[F:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50]Br)=[CH:48][CH:47]=1>CN(C)C=O.O>[F:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50][O:38][C:35]2[CH:36]=[CH:37][C:32]([CH:2]([OH:1])[CH:3]([NH:18][C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=34)=[O:20])[CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=3)=[CH:33][CH:34]=2)=[CH:48][CH:47]=1
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(OCc2ccc(F)cc2)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (313 mg, 2.27 mmol) and 4-fluorobenzyl bromide (428 mg, 2.27 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the objective substance (381 mg, 79%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12].[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:2][C:3]2[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=2[O:5][CH2:6][C:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:11]=2[CH3:12])=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH3:24]
Reactant: CCOC(=O)CCc1cc(O)ccc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(OCc2ccccc2OCc2nc(-c3ccccc3)oc2C)cc1CCC(=O)O
Temperature: 80 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
A mixture of 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.65 g), ethyl 3-(2-ethoxy-5-hydroxyphenyl)propionate (0.46 g), anhydrous potassium carbonate (0.30 g) and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 5 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give an oil from a fraction eluted with ethyl acetate-hexane (1:4, v/v). To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to acidify the residue. The precipitated solid was collected by filtration and dried with air to give crystals (0.89 g, 95%) of 3-[2-ethoxy-5-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 146-147° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([F:22])([C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].S(=O)(=O)(O)O.[I:30]N1C(=O)CCC1=O.[OH-].[Na+]>C(OCC)(=O)C.C(O)C>[I:30][C:16]1[CH:17]=[C:11]([C:3]([F:22])([C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6])[C:2]([F:23])([F:24])[F:1])[CH:12]=[C:13]([C:18]([F:19])([F:20])[F:21])[C:14]=1[NH2:15]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1C(F)(F)F
Temperature: 40 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
To 100 mL of ethanol was added 17.0 g (44.8 mmol) of 4-(perfluorobutan-2-yl)-2-(trifluoromethyl)aniline, and 5.28 g (53.8 mmol) of concentrated sulfuric acid and 12.6 g (55.8 mmol) of N-iodosuccinimide were added thereto under ice-cooling, followed by stirring at room temperature for 1 hour and 30 minutes and at 40° C. for 4 hours. To the reaction solution was added a 4 M aqueous sodium hydroxide solution to neutralize the reaction solution, and then ethyl acetate was added thereto to extract the organic phase. The organic phase was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=10:1) to prepare 14.6 g (yield 65%) of a target compound.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[C:17]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([NH:16][S:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[O:40])=[O:39])=[CH:15][C:9]=3[O:8]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Nc1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 6 %

Procedure:
2,2-Diphenyl-1,3-benzodioxol-5-amine was dissolved in dichloromethane (5 ml). N-ethyldiisopropyl amine (0.1 ml. 0.6 mmol) and benzenesulfonyl chloride (88 mg, 0.5 mmol) were added. The reaction was stirred for 5 hours at room temperature. The reaction was washed with cold 1N aqueous HCl, with 1N aqueous NaOH and with saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography using dichloromethane as the eluant. The product was crystallized from hexane to yield the product as white crystals (12 mg, 6%).
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([O:7]CC)=O)(=O)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:28]1([CH3:43])[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[C:29]=1[C:36]1[C:37]([CH3:42])=[N:38][NH:39][C:40]=1[NH2:41]>C1(C)C(C)=CC=CC=1>[C:28]1([CH3:43])[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[C:29]=1[C:36]1[C:37]([CH3:42])=[N:38][N:39]2[C:5](=[O:7])[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:1]([CH3:2])[NH:41][C:40]=12
Reactant: Cc1cc(C)c(-c2c(C)n[nH]c2N)c(C)c1
Reactant: CCOC(=O)CC(C(C)=O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)Cc1c(C)[nH]c2c(-c3c(C)cc(C)cc3C)c(C)nn2c1=O
Reaction time: 3 h

Procedure:
Diethyl acetylsuccinate (0.3 mL) and a catalytic amount of 4-toluenesulfonic acid monohydrate were added to a solution of 4-mesityl-3-methyl-1H-5-pyrazoleamine (100 mg) of Reference Example 1 in xylene (5 mL). Under heating under reflux, the mixture was stirred for three hours while distilling water off with Dean-Stark. The reaction solution was cooled, water was added thereto. the mixture was extracted twice with ethyl acetate, and washed twice with an aqeous saturated solution of sodium bicarbonate. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography, to give the title compound (200 mg) as a yellow amorphous material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@:10]2([CH2:27][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)[O:14][C@H:13]([CH2:15]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][O:11]2)=[CH:4][CH:3]=1.[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O.O>[N:33]([CH2:15][CH:13]1[CH2:12][O:11][C:10]([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:14]1)=[N+:34]=[N-:35]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO[C@@](CCc3ccc(Cl)cc3)(Cn3ccnc3)O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1COC(CCc2ccc(Cl)cc2)(Cn2ccnc2)O1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a mixture of QC-16 (201 mg, 0.42 mmol) in N,N-dimethylformamide (3 mL) was added sodium azide (546 mg, 8.40 mmol, 20 equiv). The mixture was heated at 110° C. with stirring for 2 h. The reaction mixture was cooled to room temperature, diluted with H2O, extracted with EtOAc (3×), and the combined organic extracts were washed sequentially with a saturated aqueous solution of Na2CO3, and 1120, and then dried (Na2SO4). The solution was concentrated and the golden oily residue purified by flash column chromatography on silica gel (EtOAc) to give the free base as an oil (Rf=0.29, EtOAc). High-vacuum drying left 121 mg (0.35 mmol, 83%) of QC-112 as a colorless oil: [α]D24=+6.6° (c=0.7, CDCl3); 1H NMR (400 MHz, CDCl3): δ 1.90-2.05 (m, 2H), 2.66-2.81 (m, 2), 3.20 (dd, J=13.2, 5.2 Hz, 1H), 3.39 (dd, J=13.2, 4.0 Hz, 1H), 3.44-3.51 (m, 1H), 3.64 (t, J=8.0 Hz, 1H), 3.78 (dd, J=8.0, 6.4 Hz, 1H), 4.02 (s, 2H), 6.98 (br s, 1H), 7.05 (br s, 1H), 7.12 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 7.49 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 29.0, 38.7, 51.8, 53.0, 67.9, 76.1, 109.9, 120.9, 128.8, 129.3, 129.8, 132.1, 138.7, 139.6; HRMS (EI) [M+H]+ Calcd. for C16H19ClN5O2: 348.1227. Found: 348.1234.
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH:31]C(=O)OC(C)(C)C)([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][CH:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl.[CH:40]1([S:43](Cl)(=[O:45])=[O:44])[CH2:42][CH2:41]1>CN(C=O)C>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:28][CH2:27][C:26]([NH:31][S:43]([CH:40]6[CH2:42][CH2:41]6)(=[O:45])=[O:44])([CH2:29][CH2:30]4)[CH2:25][CH2:24]5)=[N:21][CH:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(C45CCC(NC(=O)OC(C)(C)C)(CC4)CC5)n23)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(C45CCC(NS(=O)(=O)C6CC6)(CC4)CC5)n23)cc1
Reaction time: 2 h
Yield: 14.2 %

Procedure:
To a flask containing tert-butyl 4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-ylcarbamate (0.175 g, 0.327 mmol) was added a solution of HCl (4 N in 1,4-dioxane, 5 mL). After about 2 h at ambient temperature, the reaction mixture was concentrated under reduced pressure. The crude amine hydrochloride was dissolved in DCM (10 mL) and TEA (0.36 mL, 2.6 mmol) was added to the reaction mixture followed by cyclopropanesulfonyl chloride (0.18 g, 1.3 mmol). After about 2 h at ambient temperature, DMF (3 mL) was added and the reaction mixture was concentrated under reduced pressure to remove DCM. After a further about 4 h at ambient temperature, EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL) was added to the reaction mixture. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by chromatography on silica gel using 20-80% EtOAc in DCM to provide N-(4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide as a tan solid (0.025 g, 14%). LC/MS (Table 2, Method a) Rt=2.34 min; MS m/z: 540 (M+H)+.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].CO[CH:8]([O:14]C)[CH2:9][CH2:10][CH2:11][CH:12]=O>CCOC(C)=O.CCCCCC>[N+:1](/[C:4](/[CH3:5])=[CH:12]/[CH2:11][CH2:10][CH2:9][CH:8]=[O:14])([O-:3])=[O:2]
Reactant: CC[N+](=O)[O-]
Reactant: COC(CCCC=O)OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C/C(=C\CCCC=O)[N+](=O)[O-]
Yield: 62.8 %

Procedure:
Prepared according to the general procedure A from nitroethane 112b (80 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (1.58 g, 63% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: [Br-:1].[CH3:2][N+:3]1([CH3:25])[C:12]2[C:7](=[C:8]([N:17]=NC3C=CC=CC=3)[CH:9]=[C:10]([CH2:14][CH2:15][CH3:16])[C:11]=2[OH:13])[CH2:6][CH2:5][CH2:4]1.O.[H][H]>[Pd].CO>[Br-:1].[CH3:25][N+:3]1([CH3:2])[C:12]2[C:7](=[C:8]([NH2:17])[CH:9]=[C:10]([CH2:14][CH2:15][CH3:16])[C:11]=2[OH:13])[CH2:6][CH2:5][CH2:4]1
Reactant: CCCc1cc(N=Nc2ccccc2)c2c(c1O)[N+](C)(C)CCC2
Reactant: [H][H]
Agent: [Pd]
Agent: [Br-]
Solvent: CO
Solvent: O
Product: CCCc1cc(N)c2c(c1O)[N+](C)(C)CCC2

Procedure:
One introduces into a stainless steel autoclave 15.75 g of N,N-dimethyl-1,2,3,4-tetrahydro-5-phenylazo-7-propyl-8-hydroxyquinolinium bromide (i.e. 0.05 mole) with 170 ml of water and 17 ml of methanol, and one adds 3 g of 5% palladium on charcoal. One hydrogenates under a 3 kg/cm2 to 5 kg/cm2 hydrogen pressure. After cooling, one filters off the catalyst, evaporates the filtrate, and redissolves the residue in ether so as to remove the aniline. One recrystallizes in acetonitrile and one washes again with ether.
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=1)[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[B:26](OC)([O:29][CH3:30])[O:27][CH3:28]>C1COCC1>[C:11]1([N:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[CH:8]=[C:7]([B:26]3[O:29][CH2:30][CH2:28][O:27]3)[CH:25]=[CH:24][CH:23]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COB(OC)OC
Reactant: Brc1cccc(N(c2ccccc2)c2ccccc2)c1
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: c1ccc(N(c2ccccc2)c2cccc(B3OCCO3)c2)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
First, 0.45 g of magnesium and 5 ml of THF were suspended, and a tiny amount of 1,2-dibromoethane was added to the obtained suspension. A mixed solution of 3.0 g of 3-bromo-N,N-diphenylaniline and 30 mL of THF was dripped to this suspension, and the mixture was stirred while being heated under reflux for 1.5 hours to cause a reaction. After the reaction, the solution which was naturally cooled to room temperature was cooled to −78° C., and 1.95 g of trimethyl borate was added thereto. The mixture was stirred while the temperature was increased to room temperature to cause a reaction. After the reaction, the solution was concentrated, and 4.8 mL of ethylene glycol and 30 mL of toluene were added to the obtained residue. The mixture was stirred while being heated under reflux for 12 hours to cause a reaction. After the reaction, the solution was filtered and the obtained filtrate was concentrated, so that a while solid was obtained (88% yield). The synthesis scheme of Step 1 is shown by (a-1).