Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:5][C:6](=O)[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[CH2:22]([O:24][C:25]([CH:27]1[CH2:32][CH2:31][N:30]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][NH2:43])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:29][CH2:28]1)=[O:26])[CH3:23].C(N(CC)CC)C>CO>[CH2:22]([O:24][C:25]([CH:27]1[CH2:32][CH2:31][N:30]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][N:43]3[C:4]([C:1](=[O:3])[CH3:2])=[C:13]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([Br:20])[CH:11]=4)[C:6]3=[O:5])=[CH:38][CH:37]=2)(=[O:34])=[O:35])[CH2:29][CH2:28]1)=[O:26])[CH3:23]
Reactant: CC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(CN)cc2)CC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(Cn3c(C(C)=O)c(-c4ccccc4)c4cc(Br)ccc4c3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 14 %

Procedure:
[Step 3] To a solution of 3-acetyl-6-bromo-4-phenylisochromen-1-one (343 mg) in methanol (20 ml) were added 1-(4-aminomethylbenzenesulfonyl)piperidine-4-carboxylic acid ethyl ester (979 mg) and triethylamine (1.4 ml), and the mixture was stirred at room temperature for 72 hrs. The solvent was evaporated under reduced pressure, and partitioned between 1N hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, 4N hydrochloric acid ethyl acetate solution (5 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 10 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate solution and saturated brine and dried by adding sodium sulfate. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=7/3→2/3) to give the title compound (91 mg, 14%). 1H-NMR (CDCl3) δ: 1.21 (3H, t, J=7.0 Hz), 1.37 (3H, s), 1.65-2.01 (4H, m), 2.11 (1H, m), 2.38-2.56 (2H, m), 3.50-3.66 (2H, m), 4.09 (2H, q, J=7.0 Hz), 5.47 (2H, s), 7.24-7.50 (8H, m), 7.67-7.76 (3H, m), 8.41 (1H, d, J=8.4 Hz).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([F:35])([F:34])[S:21](OC1C=CC([N+]([O-])=O)=CC=1)(=[O:23])=[O:22].CCOC(C)=O>CN(C=O)C>[F:19][C:20]([F:35])([F:34])[S:21]([O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[O:10][CH3:11])(=[O:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: COc1cc(C=O)c(C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(C)cc1OS(=O)(=O)C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 4-Hydroxy-5-methoxy-2-methylbenzaldehyde (20.0 g, 122 mmol) in DMF (200 mL) at room temperature was added potassium carbonate (33.3 g, 241 mmol) and 4-nitrophenyl trifluoromethanesulfonate (49.0 g, 181 mmol) and the reaction mixture was stirred for 8 hr. EtOAc (600 mL) was added to the reaction mixture and the organic layer was washed three times with water, dried, filtered, and concentrated. The crude compound was then purified by flash chromatography (ethylacetate/hexanes 1:9→3:7) to provide 4-Formyl-2-methoxy-5-methylphenyl trifluoromethanesulfonate. 1H NMR (CDCl3, 500 MHz) δ 10.34 (s, 1H), 7.53 (s, 1H), 7.16 (s, 1H), 3.99 (s, 3H), 2.67 (s, 3H); LC/MS: (IE, m/z) [M+1]+=298.97; tR=3.44 min.
Reaction SMILES: N.[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[CH:16]=[C:15]4[NH:17][C:18](=[O:20])[CH2:19][C:14]4=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.C(O)C.[CH3:24][C:25]([CH3:27])=O>O>[C:25](=[C:19]1[C:14]2[C:15](=[CH:16][C:10]3[NH:9][C:8]([C:5]4[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=4)=[N:12][C:11]=3[CH:13]=2)[NH:17][C:18]1=[O:20])([CH3:27])[CH3:24]
Reactant: O=C1Cc2cc3nc(-c4ccncc4)[nH]c3cc2N1
Reactant: CC(C)=O
Agent: N
Solvent: O
Solvent: CCO
Product: CC(C)=C1C(=O)Nc2cc3[nH]c(-c4ccncc4)nc3cc21
Reaction time: 4 h

Procedure:
Ammonia is passed up to saturation into a suspension of 0.4 g. (1.6 mmol) 2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one in 20 ml. ethanol and 10 ml. acetone and the reaction mixture then stirred for 2 hours at 60° C. Subsequently, a further 10 ml. acetone are added thereto and stirring continued for 4 hours at 60° C., whereafter the reaction mixture is evaporated, the residue is taken up in ethanol, acidified and suction filtered from the precipitate. The residue obtained is dissolved in water and rendered neutral and the crystals obtained are filtered off with suction and recrystallised from isopropanol/ethyl acetate. Yield: 40 mg. (9% of theory); m.p. >300° C.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O:7][C:8]1[C:17]2[O:16][CH2:15][O:14][CH2:13][C:12]=2[CH:11]=[C:10]([CH:18]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:19]([NH2:21])=[S:20])[CH:9]=1.[C:35](=O)([O-])O.[Na+].C(OCC)(=O)C>C(#N)C>[CH3:35][S:20][C:19](=[NH:21])[CH:18]([C:10]1[CH:9]=[C:8]([O:7][CH3:6])[C:17]2[O:16][CH2:15][O:14][CH2:13][C:12]=2[CH:11]=1)[NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:27][CH:28]=1
Reactant: O=C([O-])O
Reactant: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)cc2c1OCOC2
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc2c1OCOC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After adding 10.6 g of Me3O+BF4− to a solution of 28.2 g of a crude product of 2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetamide in 100 ml of acetonitrile, the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (27.2 g, crude product) as a light yellow solid.
Reaction SMILES: C([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=O)(OCC1C=CC=CC=1)=O.[BH4-].[Na+].[Br:21][C:22]1[CH:23]=C(N2CCC=C2)[CH:25]=[N:26][CH:27]=1>COCCOC.C(Cl)Cl>[Br:21][C:22]1[CH:23]=[C:13]([CH:12]2[CH2:16][CH2:17][CH2:18][NH:11]2)[CH:25]=[N:26][CH:27]=1
Reactant: Brc1cncc(N2C=CCC2)c1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: Brc1cncc(C2CCCN2)c1
Temperature: 0 °C
Yield: 72.2 %

Procedure:
Carbobenzyloxy-L-proline (37.4 g, 150 mmol) was dissolved in DME (100 mL) and cooled to 0° C. with stirring. Sodium borohydride (1.89 g, 50 mmol) was added in portions (gas evolution) and the resulting mixture was stirred for 2 h at 25° C. affording a colorless solution. The solvents were removed in vacuo and the resulting gum dissolved in methylene chloride (50 mL). To this solution was added a mixture of 5-bromo-3-(2-pyrrolin-1-yl)pyridine (5.63 g, 25 mmol) and carbobenzyloxy-L-proline (6.23 g, 25 mmol) in methylene chloride (50 mL) and this was stirred at 25° C. for 36 h. The solvent was removed in vacuo and 6M HCl (200 mL) was added to the residue. The resulting solution was extracted with isopropyl acetate (200 mL) and the phases separated. The acidic aqueous phase was basified with solid NaOH to pH 14 and then extracted with methylene chloride (3×200 mL). The combined methylene chloride extracts were washed with brine (150 mL), dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed on silica gel with ethyl acetate, then methanol:ethyl acetate (1:19 to 1:9) as eluants to afford 5-bromo-3-(2-pyrrolidinyl)pyridine (4.1 g, 72%) obtained as a pale yellow oil. LRMS (EI) m/e 227 (C9H11N281 Br--H+), 225 (C9H11N279Br--H+); 1H NMR (DMSO-d6, 300 MHz) δ 8.53 (d, J=2.2 Hz, 1H), 8.49 (d, J=1.8 Hz, 1H), 7.91 (t, J=2.0 Hz, 1H), 4.17 (t, J=7.7 Hz, 1H), 3.18 (m, 1H), 3.06 (m, 1H), 2.00 (m, 1H), 2.07 (s, 1H), 2.00-1.77 (m, 2H), 1.63 (m, 1H).
Reaction SMILES: O.[Na].[SH:3][C:4]1[N:8]([CH3:9])[N:7]=[N:6][N:5]=1.Cl[CH2:11][C:12](=[O:14])[CH3:13]>C(O)C>[CH3:9][N:8]1[C:4]([S:3][CH2:11][C:12]([CH3:13])=[O:14])=[N:5][N:6]=[N:7]1
Reactant: Cn1nnnc1S
Reactant: CC(=O)CCl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC(=O)CSc1nnnn1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3.12 g (0.02 mol) of 5-mercapto-1-methyltetrazole sodium salt hydrate in 60 ml of absolute ethanol was added dropwise, 2.06 g (0.2 mol) of chloroacetone. After stirring for 20 hours at room temperature, the ethanol was evaporated in vacuo. The residue was dissolved in methylene chloride and was washed with water and then brine prior to drying over Na2SO4. Evaporation of the methylene chloride solution gave 1-methyl-5-acetonylthiotetrazole that was purified by flash chromatography on silica gel to yield 0.94 g of the 5-acetonylthio-1-methyltetrazole product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:20]=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C(OP([CH2:29][C:30]#[N:31])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:20]=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)=[CH:29][C:30]#[N:31])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC=C(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Yield: 80.7 %

Procedure:
Bis-benzo[1,3]dioxol-5-yl-methanone (2.41 g, 8.92 mmol), cyanomethylphosphonic acid diethyl ester (2.81 ml, 17.84 mmol) in anhydrous THF (10 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 17.84 ml, 17.84 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 50% EtOAc in hexane in about 40 min.) to give 3,3-bis-benzo[1,3]dioxol-5-yl-acrylonitrile as an off-white solid (2.11 g, 81%): mp, 126-128° C.; 1HNMR (DMSO-d6) δ 7.07-7.03 (2 ds, J=1.84 and J=8 Hz, 2H, Ar), 6.94 (d, J=8 Hz, 1H, Ar), 6.90 (d, J=1 Hz, 1H, Ar), 6.86 (dd, J=1.76 and J =7 Hz, 1H, Ar), 6.74 (dd, J=1.82 and J=8 Hz, 1H, Ar), 6.13 (s, 1H, double bond proton), 6.12 (s, 2H, CH2), 6.10 (s, 2H, CH2); 13C NMR (DMSO-d6) δ 160.8, 149.4, 148.4, 147.8, 147.3, 132.2, 130.9, 123.8, 123.6, 118.5, 109.4, 108.4, 108.2, 107.7, 101.8, 101.6, 93.8. Anal. Calcd. For C17H11NO4: C, 69.62; H, 3.78; N, 4.78. Found: C, 68.43; H, 3.97; N, 4.37.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:16]=4[N:15]=[C:14]3[C:25](=[O:36])[NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:44][C:45]([OH:47])=[O:46]>CN(C=O)C>[C:45]([CH2:44][O:23][C:22]([C:21]1[C:16]2[N:15]=[C:14]([C:25](=[O:36])[NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:34])[CH3:35])[CH2:29][CH2:28]3)[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:17]=2[CH:18]=[CH:19][CH:20]=1)=[O:24])([OH:47])=[O:46]
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Reactant: O=C(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)OCC(=O)O)cccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
50 mg (0.08 mmol) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid were dissolved in 6 mL DMF. Subsequently 27.6 mg KI, 126.5 mg (0.88 mmol) K2CO3 and 62.8 mg (0.64 mmol) chloro-acetic acid were added. The resulting mixture was stirred for 8 h at 60° C. Further 92 mg K2CO3 and 62.8 mg (0.64 mmol) chloro-acetic acid were added. After further 8 h at 60° C. the reaction mixture was concentrated under removed pressure. The remaining residue was purified by preparative HPLC (CH3CN/H2O gradient+0.05% formic acid) to give pure 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid carboxymethyl ester as a white amorphous solid. The corresponding dihydrochloride was obtained by treatment with a 0.1 M HCl-solution and following lyophilization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]([O:15][CH3:16])=[O:14].[H-].[Na+].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.O>CN(C=O)C>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7]2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)Cc1c[nH]c2ccc(OC)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-(5-methoxy-1H-indol-3-yl)acetate (60 mg, 0.27 mmol) and NaH (8 mg, 0.33 mmol) were stirred in anhydrous DMF (1 mL) at 0° C. under argon for 30 min, at which time 4-chlorobenzoyl chloride (57 mg, 0.33 mmol) was added. The reaction mixture was stirred overnight at room temperature and was then poured into cold water (2 mL). The organic compound was immediately extracted with dichloromethane (2×2 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified on silica (ethyl acetate/hexane gradient) and recrystallized from hexane. Yield: 18 mg (18%). C19H16ClNO4, Mr=357.79; 1H NMR (400 MHz, DMSO-d6) d: 3.61 (s, 3H), 3.78 (s, 2H), 3.81 (s, 3H), 7.00 (dd, J=2.4/9.0 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.35 (s, 1H), 7.65-7.77 (m, 4H), 8.17 (d, J=8.8 Hz, 1H); LCMS (ESI) tR: 2.81 min (>99%, ELSD), m/z: 358.0 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[Cl:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:19][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2ccc(Cl)c(Cl)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 3,4-dichlorophenol.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:19])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.[C-:20]#[N:21].[Na+].O>CS(C)=O>[CH3:19][C:4]1[C:3]([CH2:2][C:20]#[N:21])=[CH:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:5]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CC#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
27.2 g of 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (95.2 mmol) were dissolved in 100 ml of dimethyl sulfoxide; 5.9 g of sodium cyanide (120 mmol) were added and the mixture was stirred at room temperature for 18 hours. Then, the reaction mixture was poured into a mixture of ice and water and was subsequently extracted with 3 portions of 400 ml of tert-butyl methyl ether. The combined organic phases were washed with water, then with brine and dried with anhydrous sodium sulfate. After evaporation of the solvent, 25.2 g (95.8% of theory) of [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetonitrile were obtained as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C1(S(O[CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH:37][C:38](=[O:40])[CH3:39])(=O)=O)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:27][CH2:28][CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[NH:37][C:38](=[O:40])[CH3:39])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)Nc1ccccc1OCCCOS(=O)(=O)c1ccccc1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1ccccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 45.6 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.4 g, 16 mmol), N-[2-(3-phenylsulfonyloxypropoxy)phenyl]acetamide (5.3 g, 16 mmol), K2CO3 (2.2 g), and acetonitrile (50 ml) was stirred and refluxed for 5 hours. The reaction was poured into water, and the aqueous suspension was extracted with ethyl acetate. The ethyl acetate was washed (water and brine), dried (MgSO) and the solvent was concentrated to afford 6.0 g of a thick, brown oil. The oil was chromatographed on a Waters Prep 500 LC on silica gel. Concentration of the appropriate fractions afforded 3.0 g of a beige solid. This was recrystallized from ethyl acetate to yield (with concentration of the mother liquors) 2.2 g (33%) of N-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)l-piperidinyllpropoxy]phenyl]acetamide as a beige solid, m.p.=118-120° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][O:13][N:14]=[CH:15][C:16]1[N:17]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1.[OH-].[NH4+:34].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[CH3:12][O:13][N:14]=[CH:15][C:16]1[N:17]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:34])[C:19]=2[N:28]=1
Reactant: CON=Cc1nc2cnc3ccccc3c2n1CC(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CON=Cc1nc2c(N)nc3ccccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
mCPBA (1.75 g of 77% pure material, 7.79 mmol) was added in portions over a period of five minutes to a solution of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-carbaldehyde O-methyloxime (1.1 g, 3.9 mmol) in chloroform (40 mL), and the reaction was stirred at room temperature for one hour. Ammonium hydroxide (20 mL) was added, and the resulting mixture was stirred for five minutes before the addition of p-toluenesulfonyl chloride (0.891 g, 4.68 mmol) in portions. The reaction mixture was stirred at room temperature for 1.5 hours. The aqueous layer was then separated and extracted with dichloromethane (3×30 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 2.2 g of crude product as a brown foamy solid. The crude product was dissolved in dichloromethane (15 mL) and purified by chromatography using a HORIZON HPFC system (FLASH 40M silica cartridge available from Biotage, Inc., eluting with 2% to 7% methanol in ethyl acetate). The resulting product (580 mg) was recrystallized from acetonitrile (10 mL), and the crystals were isolated by filtration, washed with diethyl ether, and dried overnight in a vacuum oven at 65° C. to provide 236 mg of 4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-carbaldehyde O-methyloxime as a brown solid, mp 181-183° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:21]=1[C:22](O)=[O:23].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:22](=[O:23])[C:21]2[CH:25]=[C:26]([C:29]([F:31])([F:32])[F:30])[CH:27]=[CH:28][C:20]=2[O:19][CH3:18])[N:7]([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: CC(C)(C)c1cc(N)n(CC2CCCCO2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(F)(F)F)cc1C(=O)Nc1cc(C(C)(C)C)nn1CC1CCCCO1
Temperature: 60 °C
Reaction time: 16 h
Yield: 14.7 %

Procedure:
To a solution of Example 63C (0.73 g, 3.1 mmol) in tetrahydrofuran (20 mL) were added 2-methoxy-5-(trifluoromethyl)benzoic acid (0.68 g, 3.1 mmol, JRD Fluorochemicals), 1-hydroxybenzotriazole (0.47 g, 3.1 mmol, Aldrich), N-(3-dimethylaminopropyl)-N-ethylcarbodimide hydrochloride (0.59 g, 3.1 mmol) and triethylamine (1.3 mL, 9.2 mmol). After stirring at 60° C. for 16 h, the reaction mixture was cooled and quenched with saturated NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to provide 0.2 g of the title compound. MS (ESI+) m/z 440 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[N:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1Br)=[O:5])[CH3:2].[C:17]([Cu])#[N:18].C(Cl)Cl>CN1C(=O)CCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[N:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[C:17]#[N:18])=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1c(Br)c(C(C)(C)C)nn1C
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1c(C#N)c(C(C)(C)C)nn1C
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A mixture of 4-bromo-5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.00 g, 3.46 mmol) and CuCN (372 mg, 4.15 mmol) in NMP (10 mL) was stirred at 200° C. under microwave irradiation for 1 h. After cooling to room temperature, the mixture was treated with DCM (100 mL) and filtered through diatomaceous earth. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (0:100-10:90 EtOAc-hexanes) to yield the title compound as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 4.45 (q, J=7.2 Hz, 2H), 4.14 (s, 3H), 1.45 (t, J=7.2 Hz, 3H), 1.43 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C12H17N3O2: 236.1 (M+H). Measured: 236.1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N:22]1[CH2:23][CH2:24][N:25]([C:4]([C:3]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=2[CH3:1])=[O:6])[CH2:26][CH2:27]1
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN(C(=O)c3ccc([N+](=O)[O-])cc3C)CC2)c(C)c1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
2-Methyl-4-nitrobenzoic acid (500 mg), 1-(2,4-dimethylphenyl)piperazine (523 mg) and 1-hydroxybenzotriazole 1 hydrate (373 mg) were dissolved in N,N-dimethylformamide (13 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (531 mg) was added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give [4-(2,4-dimethylphenyl)piperazin-1-yl](2-methyl-4-nitrophenyl)methanone (771 mg). Then, to a mixed solution of ethanol (11 mL) and water (3 mL) were added ammonium chloride (660 mg) and iron (480 mg), and the obtained [4-(2,4-dimethylphenyl)piperazin-1-yl](2-methyl-4-nitrophenyl)methanone (771 mg) was added while stirring at 60° C.-70° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (833 mg).