Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:17]2[C:18](F)=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1.[OH:26][C:27]1[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]2[C:28]=1[CH:29]=[CH:30][NH:31][C:32]2=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:17]2[C:18]([O:26][C:27]3[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]4[C:28]=3[CH:29]=[CH:30][NH:31][C:32]4=[O:38])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cnc3c(-c4cccnc4F)ncnc32)cc1
Reactant: Cc1ccc2c(=O)[nH]ccc2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Cn2cnc3c(-c4cccnc4Oc4c(C)ccc5c(=O)[nH]ccc45)ncnc32)cc1
Temperature: 130 °C
Yield: 51 %

Procedure:
A mixture of 9-(4-methoxybenzyl)-6-(2-fluoropyridin-3-yl)-9H-purine (0.48 g, 1.4 mmol), 5-hydroxy-6-methylisoquinolin-1(2H)-one (0.25 g, 1.4 mmol) and cesium carbonate (1.1 g, 3.3 mmol) in NMP (5 mL) was stirred and heated in a Discover® model microwave reactor (CEM, Matthews, N.C.) at 130° C. for 60 min (100 watts, Powermax feature on, ramp time 1 min) The crude reaction mixture was partitioned between 3:1 CHCl3:IPA (100 mL) and water (150 mL). The aqueous phase was extracted with 3:1 CHCl3:IPA (50 mL). The combined organic extracts were washed with 1 N NaOH (2×75 mL), water (2×75 mL), satd NaCl (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a viscous brown oil which was chromatographed through a Redi-Sep® pre-packed silica gel column (80 g), eluting with a gradient of 1% to 7% MeOH in CH2Cl2, to provide 5-(3-(9-(4-methoxybenzyl)-9H-purin-6-yl)pyridin-2-yloxy)-6-methylisoquinolin-1(2H)-one (0.35 g, 51% yield) as a white solid. MS (ESI, pos. ion) m/z: 491.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:19]I.O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]([N:12]([CH3:19])[C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CI
Reactant: COc1ccc(NC(=O)C(F)(F)F)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N(C)C(=O)C(F)(F)F)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.48 g, 12 mmol) was added to a stirred, cooled (0° C.) solution of N-(3-Bromo-4-methoxyphenyl)trifluoroacetamide (Description 43, 2.98 g, 10 mmol) in dimethylformamide (30 ml). The mixture was stirred at 0° C. for 30 min., then methyl iodide (0.75 ml, 1.70 g, 12 mmol) was added. The mixture was stirred at 0° C. for 30 min., then at room temperature for 3 h. Water (50 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic fractions were washed with water (4×50 ml) and brine (50 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/CH2Cl2 (50:50 increasing to 30:70) to give the title compound as a colorless solid (2.72 g, 87%). 1H NMR (250 MHz, CDCl3) δ7.46 (1H, d, J 2.4 Hz), 7.18 (1H, dd, J 8.7, 2.4 Hz), 6.91 (1H, d, J 8.7 Hz), 3.94 (3H, s), and 3.32 (3H, s).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([NH2:21])[CH2:17][CH:18]([CH3:20])[CH3:19]>>[CH2:16]([NH:21][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)CCN
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Product: CC(C)CCNC(=O)c1cccc(-c2ccccc2)c1

Procedure:
Using Preparation Method 1, 3-phenylbenzoic acid was reacted with isoamylamine. The resulting reaction mixture was purified using SiO2 with CH2Cl2 100%. An off-white crystalline solid was obtained (61%). NMR 1H (ppm, CDCl3): 7.96 (s, 1H), 7.69 (d, J3=8.3 Hz, 2H), 7.59 (d, J3=7.2 Hz, 2H), 7.50-7.33 (m, 4H), 6.10 (br. s., 1H), 3.52-3.45 (m, 2H), 1.76-1.64 (m, 1H), 1.52 (quart., 2H), 0.95 (d, J3=6.6 Hz, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH3:10])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][OH:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:19][C:5]1[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH3:10])=[N:7][C:2]([NH:20][C:21]2[CH:22]=[C:23]([CH2:24][OH:25])[CH:26]=[CH:27][CH:28]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CO)c1
Reactant: COc1cccc([C@H](C)Nc2nc(Cl)ncc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc([C@H](C)Nc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 91.5 %

Procedure:
To a solution of 2,5-dichloro-N-[(1S)-1-(3-methoxyphenyl)ethyl]pyrimidin-4-amine (0.70 g, 2.3 mmol) and 3-aminobenzyl alcohol (0.39 g, 3.2 mmol) in 1,4-dioxane (20.0 mL) was added p-toluenesulfonic acid monohydrate (0.16 g, 0.85 mmol). The mixture was heated at 100° C. for 16 hours and NaHCO3 (saturated aqueous solution) was added. The organic solvent was removed under vacuum and water/EtOAc was added. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as a light brown powder (0.81 g, 90%). LCMS for C20H22ClN4O2 (M+H)+: m/z=385.1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[C:38][CH2:39]O)=[CH:33][CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:39][C:38]#[C:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C:26]2[NH:27][CH:28]=[CH:29][N:25]=2)=[CH:36][CH:35]=1)=[O:9]
Reactant: OCC#Cc1ccc(Cc2ncc[nH]2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC#Cc2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 212 mg (1 mM) of 3-[4-(1-imidazolylmethyl)phenyl]-2-propyn-1-ol, 248 mg (1.2 mM of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 421 mg (80%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16](=[O:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[C:18]1([CH2:17][C:16]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)Cc2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=C(Cc1ccccc1)OCC1CCNCC1
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-[(phenylacetoxy)methyl]piperidine (318 mg, 0.95 mmol) in MeOH (0.2 mL) was added 2N anhydrous HCl/ether (1.5 mL, 3.0 mmol). The reaction mixture was stirred overnight. After evaporation, the residue was dissolved in deionized water. EtOAc was used to wash the aqueous layer before the pH was altered to approx. 9-10. The aqueous layer was extracted three times with CH2Cl2 and dried over Na2SO4. After evaporation, 4-[(phenylacetoxy)methyl]piperidine (173 mg, 78%) was obtained as a colorless oil.
Reaction SMILES: C([O:5][C:6](=[O:53])[CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:34])[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=3)[CH:22]=[CH:23][CH:24]=2)=[O:18])[CH:12]=[C:11]([C:35]2[C:43]3[C:38](=[N:39][CH:40]=[CH:41][CH:42]=3)[N:37](S(C3C=CC=CC=3)(=O)=O)[CH:36]=2)[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl>>[F:33][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[F:32])[CH2:25][N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]([NH:16][CH2:15][C:13]2[CH:14]=[C:9]([CH:10]=[C:11]([C:35]3[C:43]4[C:38](=[N:39][CH:40]=[CH:41][CH:42]=4)[NH:37][CH:36]=3)[CH:12]=2)[O:8][CH2:7][C:6]([OH:53])=[O:5])=[O:18])[C:20]1=[O:34]
Reactant: CC(C)(C)OC(=O)COc1cc(CNC(=O)c2cccn(Cc3ccc(F)c(F)c3)c2=O)cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1cc(CNC(=O)c2cccn(Cc3ccc(F)c(F)c3)c2=O)cc(-c2c[nH]c3ncccc23)c1
Reaction time: 8 h
Yield: 36.7 %

Procedure:
A mix of [3-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-({[1-(3,4-difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-acetic acid tert-butyl ester (20 mg, 0.00003 mol) and Trifluoroacetic Acid (20 mg, 0.0001 mol;) in Methylene chloride (8 mL, 0.1 mol) was stirred for overnight. LC-MS showed only formation of the des-phSO2 and saponified product C (1.24 min, ES+/545.64). Evaporated off the solvents and dissolved in DMSO and water and purified on Gilson HPLC to give the desired product (6 mg, 40%) MS (ES+) m/z 545.64 (M+1). 1H NMR (DMSO, 400 MHz): δ 8.41 (dd, 1H), 8.26 (d, 2H), 8.24 (dd, 1H), 7.88 (s, 2H), 7.45-7.35 (m, 2H), 7.30 (s, 2H), 7.18 (m, 1H), 7.10-7.07 (m, 2H), 6.77 (s, 2H), 6.60 (t, 1H), 5.22 (s, 2H), 4.75 (s, 2H), 4.55 (d, 2H),
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:43]([O:50][C@H:51]([CH3:55])[C:52](O)=O)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(N(CC)CC)C>ClCCl>[CH2:43]([O:50][C@@H:51]([C:55]1[O:18][C:5]2[C:6]([C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Cc1cccc(F)c1)c1cc(F)ccc1O
Reactant: C[C@@H](OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](OCc1ccccc1)c1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1
Reaction time: 0.17 h
Yield: 62.7 %

Procedure:
To 1-(5-fluoro-2-hydroxyphenyl)-2-(3-fluorophenyl) ethanone (11 g, 44.31 mmol), in Dichloromethane (110 ml), HATU (33.7 g, 88.63 mmol) and (R)-Benzyloxypropionic acid (9.58 g, 53.17 mmol) were added and stirred for ˜10 min. Triethylamine (67 ml, 478 mmol) was added dropwise and stirred at room temperature (RT) for 24 h. The reaction mixture was quenched with water and extracted with Dichloromethane (2×250 ml). The organic layer was dried with sodium sulphate and concentrated under vacuum. The crude product was purified by column chromatography with ethyl acetate:Petroleum ether to afford the title compound as a off-white solid (10.9 g, 63%). 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.85 (dd, J=8.1, 3.0 Hz, 1H), 7.58 (dd, J=9.1, 4.1 Hz, 1H), 7.47-7.39 (m, 1H), 7.39-7.34 (m, 1H), 7.28-7.20 (m, 3H), 7.20-7.14 (m, 2H), 7.16-7.14 (m, 1H), 6.99-7.89 (m, 2H), 4.50-4.31 (m, 3H), 1.56 (d, J=6.4 Hz, 3H). Mass: 392.9 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:15][C:16]1([CH3:19])[CH2:18][O:17]1>CN(C)C=O.O>[CH3:15][C:16]([OH:17])([CH3:19])[CH2:18][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: CC1(C)CO1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)Cn1ccc([N+](=O)[O-])n1
Temperature: 100 °C
Yield: 53.4 %

Procedure:
A solution of 3-nitro-1H-pyrazole (prepared in Example 3, 200 mg, 1.77 mmol) in N,N-dimethylformamide (5 mL) was treated with solid potassium carbonate (352 mg, 2.55 mmol) and 2,2-dimethyl-oxirane (314 mL, 3.54 mmol) and placed in a sealed tube and heated to 100° C. for 1 h in an oil bath. After this time the reaction was cooled to 25° C. and diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were then combined and dried over sodium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix Intelliflash system (12 g column, 50% ethyl acetate/hexanes to 60% ethyl acetate/hexanes) afforded 2-methyl-1-(3-nitro-pyrazol-1-yl)-propan-2-ol (175 mg, 54%) as a clear colorless oil: ES-HRMS m/e calcd for C7H11N3O3 (M+H)+ 186.0873, observed 186.0873; 1H NMR (300 MHz, CDCl3) δ ppm 1.25 (s, 6H, 2×CH3), 2.11 (br. s., 1H, OH), 4.18 (s, 2H, NCH2), 6.92 (d, J=2.4 Hz, 1H, Ar), 7.60 (d, J=2.4 Hz, 1H, Ar).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:15]=[CH:16][C:17]=3[CH3:18])[N:7]=[CH:8][C:9]=2[N:10]=1.[C:27](Cl)(=[O:29])[CH3:28].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:22]([O:21][C:20](=[O:26])[NH:19][C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([NH:11][C:6]2[N:7]=[CH:8][C:9]3[N:10]=[C:2]([NH:1][C:27](=[O:29])[CH3:28])[S:3][C:4]=3[N:5]=2)[CH:13]=1)([CH3:23])([CH3:25])[CH3:24]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Nc1ncc2nc(N)sc2n1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(Nc3cc(NC(=O)OC(C)(C)C)ccc3C)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of tert-butyl {3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)amino]-4-methylphenyl)carbamate (1.20 g, 3.22 mmol) in pyridine (20 mL) was added acetyl chloride (575 μL, 8.06 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted with ethyl acetate (50 mL, 10 mL). The combined organic layer was washed with saturated brine (10 mL), filtered through a basic silica gel pad, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (1.31 g, 98%) as a pale-purple solid.
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[NH:14][C:12](=[O:13])[C:11]2=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[C:22]([O:28]C)[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[NH:1]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[NH:14][C:12](=[O:13])[C:11]2=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([OH:28])[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2cc3c(cc2Nc2ccccc2)C(=O)NC3=O)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1NC(=O)c2cc(Nc3ccc(O)c(O)c3)c(Nc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 219 mg (0.56 mmol) of 4-anilino-5-(3,4-dimethoxy-anilino)-phthalimide in 5 ml of dichloromethane, a solution of 270 μl (2.8 mmol) boron tribromide in 3 ml of dichloromethane is added dropwise at RT. The reaction mixture is stirred for 5 hours at RT and then quenched with 5 ml of water, and the phases are separated. The water phase is extracted three times with ethyl acetate. The organic phases are combined and washed twice with water, dried over magnesium sulfate and concentrated by evaporation. Excluding light, the evaporation residue is chromatographed with ethylacetate/hexane 2:1 on a silica gel column (precoated with 0.1 g of sodium ascorbate per g silica gel) that is cooled with ice-water (double jacket), and the product fractions are combined and concentrated by evaporation. Recrystallization from ethyl acetate/dichloromethane/hexane yields the title compound in the form of orange crystals, FAB-MS: 362 [M+ +H].
Reaction SMILES: Cl[CH:2]([CH3:12])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7].[Cl:13]C(CCC)CC(OC(C)C)=O>CO>[Cl:13][CH2:12][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7]
Reactant: CC(Cl)CCCC(=O)OC(C)C
Reactant: CCCC(Cl)CC(=O)OC(C)C
Solvent: CO
Product: CC(C)OC(=O)CCCCCCl
Reaction time: 90 h

Procedure:
A solution of 10.5 gm(0.03 mol) of diamine 15, 6.2 gm(0.03 mol) of isopropyl 5-chlorohexanoate, and 10.0 gm of MeOH was charged to the flask and heated to reflux. After 90 hours, 1.0 gm(5 mmol) of isopropyl 3-chlorohexanoate was added to the mixture. At least 5% amine was present after refluxing 6 hours and the heating was stopped. The crude product was removed of volatiles by rotary evaporation and washed until all of the residue was removed leaving 15 gm(94%) of Quat 7.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1.C([N-]C(C)C)(C)C.[Li+:20].[S:21](=[O:23])=[O:22]>C(OCC)C>[Cl:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([S:21]([O-:23])=[O:22])[N:4]([CH3:12])[N:3]=1.[Li+:20]
Reactant: O=S=O
Reactant: CCOC(=O)c1cn(C)nc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CCOC(=O)c1c(Cl)nn(C)c1S(=O)[O-]
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
5.0 g of ethyl 3-chloro-1-methylpyrazole-4-carboxylate was dispersed in dry diethyl ether under cooling at -60° C. or lower. Into this solution there was added lithium diisopropylamide (1.2 molar equivalent) and after stirring for an hour sulfur dioxide gas was passed into this solution for 30 minutes. After stirring at -60° C. for 2 hours the reaction mixture was stirred at room temperature for 2 hours. Filtration and drying of the precipitate gave 6.0 g of lithium 3-chloro-4-ethoxycarbonyl-1-methylpyrazole-5-sulfinate. This product was added into a solution of 100 ml of ice-water and 100 ml of dichloromethane and 6.0 g of N-chloro succinimide was added thereinto at 0°-5° C. After stirring for 45 minutes at room temperature the dichloromethane layer was separated and water layer was extracted with 100 ml of dichloromethane. The combined dichloromethane solution of 3-chloro-4-ethoxycarbonyl-1-methylpyrazole-5-sulfonyl chloride (b.p.: 133° C./ 0.25 mmHg.) was added dropwise into 80 ml of aqueous ammonia (28%) under cooling at 10° C. After stirring for an hour, evaporation of the solvent gave 3.6 g of 3-chloro-4-ethoxycarbonyl-1-methylpyrazole-5-sulfonamide. m.p.: 121°-123° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([CH3:25])[CH2:20]1)=[O:18]>CCCCCC.C(OCC)(=O)C>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([CH3:25])[CH2:20]1)=[O:18]
Reactant: CCOC(=O)n1c(C(=O)C2CCCC(C)C2)c(N)c2ccc(Cl)cc21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1CCCC(C(=O)c2[nH]c3cc(Cl)ccc3c2N)C1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 3-amino-6-chloro-1-ethoxycarbonyl-2-(3-methylcyclohexylcarbonyl)indole (step 2). m.p.: 140-142° C. (hexane/ethyl acetate)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[CH:23]1([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([O:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:5]=[C:4]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Reactant: OC1CCCC1
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC3CCCC3)c2cc1OC

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and cyclopentanol to give (1-Cyclopentyloxy-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 369(MH+).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][N:29]1[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][C:31]([O:39][Si](C(C)(C)C)(C)C)=[N:30]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1.O>[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][N:29]1[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][C:31]([OH:39])=[N:30]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1cc(O[Si](C)(C)C(C)(C)C)nn1CCNC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(O)nn1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
A 1 M solution of tetrabutylammonium fluoride in THF (20.1 mL, 20.1 mmol) was added to a stirred solution of ethyl 1-{2-[(tert-butoxycarbonyl)amino]ethyl}-3-{[tert-butyl(dimethyl)silyl]oxy}-1H-pyrazole-5-carboxylate (5.54 g, 13.4 mmol) in THF (45 mL). The mixture was stirred at room temperature for 16 hours, diluted with water and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield ethyl 1-{2-[(tert-butoxycarbonyl)amino]ethyl}-3-hydroxy-1H-pyrazole-5-carboxylate (3.32 g, 83% yield) as a white solid, that was used in the next step without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C([N:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH:16]([CH3:21])[CH2:15]1)C1C=CC=CC=1>C1C=CC=CC=1>[C:2]([N:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH:16]([CH3:21])[CH2:15]1)([O:4][CH2:5][CH3:6])=[O:3]
Reactant: CCOC(=O)Cl
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC(=O)C(C)C1
Reaction time: 6 h

Procedure:
Ethyl chloroformate (3.0 g, 26.7 mmol) was added to a stirred solution of 1-benzyl-3-methyl-4-piperidinone (2.0 g, 9.85 mmol) in benzene (30 ml) at ambient temperature. The obtained reaction mixture was refluxed with stirring for 6 hr and concentrated to dryness to give 1-carbethoxy-3-methyl-4-piperidone as oil. Yield 1.4 g (77%), C9H15NO3, m/z 186 (M+1).
Reaction SMILES: [CH2:1]([C:3]1([CH2:12][CH:13]=[CH2:14])[C:8](=[O:9])[NH:7][C:6](=[O:10])[NH:5][C:4]1=[O:11])[CH3:2].[BrH:15]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH2:12][CH2:13][CH2:14][Br:15])[C:4](=[O:11])[NH:5][C:6](=[O:10])[NH:7][C:8]1=[O:9])[CH3:2]
Reactant: C=CCC1(CC)C(=O)NC(=O)NC1=O
Reactant: Br
Solvent: Cc1ccccc1
Product: CCC1(CCCBr)C(=O)NC(=O)NC1=O
Reaction time: 8 h

Procedure:
A suspension of 40 g of 5-ethyl-5-allylbarbituric acid and 800 ml of toluene was stirred and irradiated with a GE sunlamp (275 watts, 110-125 volts) for approximately 90 min. Thereafter, gaseous HBr was passed for 45 min. with further irradiation and stirred for another 45 minutes. The reaction flask was then opened to allow the excess HBr to evaporate. The solution was cooled and filtered. The resulting precipitate was washed with toluene, dried, and then dissolved in a minimal amount of hot acetone. Petroleum ether (60°-68° C.) was added until a small amount of precipitate appeared; the flask was left overnight at 23° C. The crystals were filtered, washed with petroleum ether, and air dried. The melting point was 138°-140° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.Cl[CH2:23][CH2:24][CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>O>[CH2:27]([O:26][CH:25]([O:29][CH2:30][CH3:31])[CH2:24][CH2:23][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1)[CH3:28]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: CCOC(CCCl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CCOc1ccc(C(N)=O)cc1)OCC
Temperature: 100 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
500 mg of 4-hydroxybenzamide, 1.51 g of potassium carbonate, 10 mL of DMF and 730 mg of 3-chloro-1,1-diethoxypropane are added to a flask. The reaction mixture is stirred at 100° C. for 18 hours and then 5 mL of water are added. The aqueous phase is extracted with ethyl acetate, and then the organic phases are collected, washed with water and concentrated under reduced pressure. The product is obtained in the form of a powder in a yield of 89% and with a chemical purity of 95%.