Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[C:5]([O:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:4]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[C:3]1=[O:29].C(N(CC)CC)C.Cl[C:38]([O:40][CH3:41])=[O:39]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:13][O:12][N:9]1[CH2:10][CH2:11][C:6]2([N:2]([O:1][C:38]([O:40][CH3:41])=[O:39])[C:3](=[O:29])[C:4]([C:20]3[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[C:5]2[O:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])[CH2:7][CH2:8]1
Reactant: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(O)C12CCN(OC)CC2
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(OC(=O)OC)C12CCN(OC)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of carbonic acid ethyl ester 1-hydroxy-8-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (preparation example 13, step 1; compound P1ii.11) (140 mg, 0.33 mmol), triethylamine (93 μl, 68 mg, 0.67 mmol) and 4-dimethylaminopyridine (2 mg) in tetrahydrofuran (3 ml) at 0° C. was added a solution of methyl chloroformate (33 μl, 41 mg, 0.43 mmol) in tetrahydrofuran (2 ml) dropwise. The suspension was stirred at 0° C. for one hour, and at room temperature for one hour. The reaction mixture was evaporated, diluted with ethyl acetate and filtered to remove salts. The filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution (2×15 ml) and brine, dried over sodium sulfate and concentrated. The oily residue was purified by chromatography on silica gel (ethyl acetate/hexane 1:2). Yield: 30 mg of carbonic acid ethyl ester 8-methoxy-1-methoxycarbonyloxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (title compound P1ii.13) as a colorless gum.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]3[CH:21]=[C:20]([Cl:22])[C:19]([NH:23]C(=O)C(F)(F)F)=[CH:18][C:17]=3[O:30][CH3:31])[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[OH-].[Na+]>O>[CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]3[CH:21]=[C:20]([Cl:22])[C:19]([NH2:23])=[CH:18][C:17]=3[O:30][CH3:31])[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(NC(=O)C(F)(F)F)c(Cl)cc1C(=O)NC1CCN(CC2CCCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.4 %

Procedure:
A mixture of N-(1-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-trifluoroacetamido-5-chlorobenzamide (8.1 g; 0.017 moles), ethanol (25 ml), water (15 ml) and 8 N sodium hydroxide aqueous solution (25 ml) was stirred for 12 hours at room temperature. After dilution with water, the mixture was extracted with chloroform and the chloroformic solution dried (Na2SO4) and evaporated in vacuo. N-(1-Cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide (5 g) was obtained. It was converted into its hydrochloride by treatment with a saturated solution of ethanolic hydrogen chloride; the hydrochloride melted at 225°-227° C. (dec).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]([CH:5]=[N:6][O:7][CH2:8][CH:9]([CH3:11])[CH3:10])[C@H:3]1[C:12]([OH:14])=[O:13].[O:16]([C:23]1[N:28]=[C:27]([CH2:29]O)[CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CCCCCC>[CH3:15][C:2]1([CH3:1])[CH:4]([CH:5]=[N:6][O:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH:3]1[C:12]([O:14][CH2:29][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:28]=1)=[O:13]
Reactant: OCc1cccc(Oc2ccccc2)n1
Reactant: CC(C)CON=C[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)CON=CC1C(C(=O)OCc2cccc(Oc3ccccc3)n2)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a stirred solution of 0.75 g of (1R,cis)-2,2-dimethyl-3-((isobutoxyimino)methyl)cyclopropanecarboxylic acid, 0.71 g of 6-phenoxy-2-pyridinemethanol and a catalytic amount of 4-dimethylaminopyridine in 40 ml of methylene chloride under argon was added as one portion 1.19 g of N,N-dicyclohexylcarbodiimide. The reaction mixture was stirred at ambient temperature overnight, then diluted with an equal volume of hexane, filtered and stripped. The resulting oil was dissolved in hexane, filtered, washed with dilute potassium carbonate solution, dried and stripped. The crude product was chromatographed using 20% diethyl ether in hexane as eluent to yield 1.0 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2/[CH:16]=[CH:17]/[C@@H:18]2[O:23][C:22](=[O:24])[CH2:21][C@@H:20]([OH:25])[CH2:19]2)=[CH:4][C:3]=1[CH2:26][O:27][Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2/[CH:16]=[CH:17]/[C@@H:18]2[O:23][C:22](=[O:24])[CH2:21][C@@H:20]([OH:25])[CH2:19]2)=[CH:4][C:3]=1[CH2:26][OH:27]
Reactant: Cc1cc(C)c(/C=C/[C@H]2C[C@H](O)CC(=O)O2)c(-c2ccc(F)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(C)c(/C=C/[C@H]2C[C@H](O)CC(=O)O2)c(-c2ccc(F)c(CO)c2)c1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
A solution of the compound (1i) (420 mg, 0.087 mmol) in THF (5 mL) was treated with tetrabutylammonium fluoride (1 M in THF, 2.5 mL, 2.5 mmol). After stirring at 20° C. for 5 minutes, 1 N HCl (100 mL) was added and the product was extracted into Et2O (125 mL). The organic layer was washed with H2O (2×100 mL), dried, filtered and evaporated to provide the desired compound as a faint yellow gum; homogeneous on TLC [Rf 0.20 vs 0.42 for the silyl ether (silica, CHCl3 -MeOH (19:1))] and HPLC [time of elution was 5.36 minutes with a flow rate of 4 mL/min using 20% isopropanol/hexane on a Whatman Partisil PXS 10/25 PAC column]. An analytical sample was crystallized from nBuCl: mp 137°-138° C.; NMR 1.7-1.95 (2 H, m), 2.33 (6 H, s), 2.45-2.75 (2 H, m), 4.05-4.1 (H, m), 4.7-4.85 (2 H, m), 5.12-5.18 (H, m), 5.4 (H, dd, J=7 and 15 Hz), 6.53 (H, d, J=15 Hz), 6.95-7.35 (6 H, m).
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([OH:24])[CH:6]=1)(=[O:3])[CH3:2].[CH3:25]C(C)=O>>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(=O)Oc1cc(O)cc2c1[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Product: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2

Procedure:
1-Acetoxy-3-hydroxyestra-1,3,5(10)-trien-17-one (7.6 g, 23 mM) is added to 600 ml of anhydrous acetone in a 3-neck, 1 liter round bottom flask equipped with condenser, magnetic stirring bar, drying tube and pressure-compensated addition funnel. Dimethyl sulfate (3.2 g, 25 mM) is added and the resulting suspension is refluxed for 16 hrs, and then filtered while still warm. The filter cake is washed repeatedly with anhydrous acetone, and the combined filtrates are evaporated in vacuo. The residue is recrystallized from acetone-water to obtain 1-acetoxy-3-methoxyestra-1,3,5(10)-trien-17-one, yield 6.2 g (80%), m.p. 144°-145°. Further recrystallization from CH2Cl2 -hexane gives material of m.p. 150°-151°.
Reaction SMILES: C(O[CH:5]1[O:28][CH2:27][C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:15]([O:16][CH3:17])[C@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[Si]([C:33]#[N:34])(C)(C)C.B(F)(F)F.CCOCC>[N+](C)([O-])=O>[CH2:8]([O:7][C@@H:6]1[C@@H:15]([O:16][CH3:17])[C@H:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:27][O:28][CH:5]1[C:33]#[N:34])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CO[C@H]1[C@H](OCc2ccccc2)COC(OC(C)=O)[C@@H]1OCc1ccccc1
Reactant: C[Si](C)(C)C#N
Agent: FB(F)F
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: CO[C@H]1[C@H](OCc2ccccc2)COC(C#N)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
To a stirred solution of 2,4-di-O-benzyl-3-O-methyl-a,b-D-xylopyranosyl acetate (20 g, 0.052 mole) and Me3SiCN (20 ml, 0.16 mole) in anhydrous nitromethane (300 ml) was added boron trifluoride etherate (1.0 g, 0.007 mole) at room temperature. After the mixture was stirred at room temperature for 30 min, the mixture was evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel using CH2C12 /AcOEt (99:1) as an eluent to give 2,4-di-O-benzyl-3-O-methyl-a,b-D-xylopyranosyl cyanide as colorless oil (13.0 g, 71% yield); EI-MS: m/z 353 (M+), 262 (M+ -Bn); 1 H-NMR of b-cyano-isomer (CDCl3)d; 3.15 (1H,dd,J=10, 11 Hz), 3.23 (1H,t,J=10 Hz), 3.49 (1H,m), 3.59 (1H,t,J=10 Hz), 3.66 (3H,s), 3.96 (1H,dd,J=5 & 11 Hz), 3.97 (1H,d,J=10 Hz), 4.61 (1H,d,J=12 Hz), 4.73 (1H,d,J=12 Hz), 4.84 (1H,d,J=11 Hz), 4.88 (1H,d,J=11 Hz), 7.29-7.42 (10H,m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][C:19]=1[CH2:42]OS(C)(=O)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:42][C:19]2[CH:20]=[C:21]([O:24][Si:25]([C:38]([CH3:40])([CH3:39])[CH3:41])([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]=[CH:23][C:18]=2[Br:17])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](Oc1ccc(Br)c(COS(C)(=O)=O)c1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2Br)C(=O)C1
Reaction time: 1 h

Procedure:
To a solution piperazin-3-one-1-carboxylic acid tert-butyl ester (2.11 g, 10.5 mmol) in dry DMEF (20 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 632 mg, 15.8 mmol). The reaction mixture was stirred for 1 hour, and then a solution of the mesylate from Step C (5.47 g, 10.5 mmol) in DMF (10 mL) was added. The reaction mixture was stirred for 16 hours. The solvent was removed in vacuo and the residue partitioned between methylene chloride (100 mL) and saturated aqueous sodium bicarbonate (100 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (20→50% ethyl acetate/hexane) to provide the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=O)=[O:4].[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1>CO>[CH3:1][O:2][C:3]([C:5]1[N:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C:25]([O:24][CH3:23])=[O:34])=[CH:27][CH:28]=2)[C:7](=[O:6])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:4]
Reactant: COC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: COC(=O)c1ccc(CN)cc1
Solvent: CO
Product: COC(=O)c1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of 6-bromo-4-phenyl-3-isocoumarincarboxylic acid methyl ester (3.60 g) in methanol (50 ml) was added 4-aminomethylbenzoic acid methyl ester (3.16 ml) and the mixture was stirred at room temperature for 18 hrs. The solvent was evaporated under reduced pressure and 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in methanol (100 ml). Conc. sulfuric acid (10 ml) was added, and the mixture was heated under reflux for 3 hr. The solvent was evaporated under reduced pressure, water was added under ice-cooling and the mixture was neutralized with potassium carbonate. The solution was extracted with ethyl acetate and the extract was washed with saturated brine. Sodium sulfate was added to dry the mixture. The obtained residue was recrystallized from methanol to give the title compound (3.39 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.BrC1C=C(N2CCCN([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])CC2)C=NC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: Clc1cncc(N2CCCNCC2)c1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cncc(Br)c2)CC1
Product: CC(C)(C)OC(=O)N1CCCN(c2cncc(Cl)c2)CC1

Procedure:
Was prepared from 1-(5-Chloro-3-pyridyl)-homopiperazine according to 1-(5-Bromo-3-pyridyl)-4-tert-butoxycarbonylhomopiperazine.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:19][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)=[N+]=[N-].[H][H]>CN(C)C=O.[Pd]>[NH2:1][CH2:4][CH:5]1[O:19][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN=[N+]=[N-])C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2
Yield: 102.6 %

Procedure:
2-Azidomethyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (759 mg) was dissolved in dimethylformamide (20 ml). To the solution, 10% palladium-on-carbon (455 mg) was added, and the solution was hydrogenated in the atmosphere of hydrogen at ambient temperature and under atmospheric pressure. After completion of the reaction, the catalyst was filtered off. When the solvent was evaporated, 0.7 g of the title compound was obtained as a crude product. This product was purified by silica gel column chromatography to obtain 409 mg of a free base (60.0%). The obtained free base was converted into a hydrochloric acid salt, followed by recrystallizing from a solvent mixture of methanol-diethylether, obtaining yellow powdery crystals having a melting point over 300° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:10])[CH2:8][CH2:7][CH2:6][CH:5]([NH2:9])[CH2:4]1.C(N(CC)C(C)C)(C)C.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(#N)C>[CH3:2][C:3]1([CH3:10])[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:21](=[O:22])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C)CCCC(N)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1(C)CCCC(NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3,3-dimethylcyclohexyl)amine hydrochloride (10.0 g, 0.060 mol) and N,N-diisopropylethylamine (15.8 g, 0.12 mol) in acetonitrile (125 mL) at ice bath temperature was added a solution of benzyl chloroformate (11.4 g, 0.067 mol) in acetonitrile (25 mL), dropwise. The mixture was stirred overnight, gradually warming to ambient temperature, and concentrated in vacuo. The residue was partitioned between ethyl acetate/5% citric acid solution and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, adsorbed onto silica gel and purified by flash chromatography (CH2Cl2/hexanes) affording the title compound as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm: 0.85 (s, 6H), 0.92-1.02 (m, 3 H), 1.25 (d, 1 H), 1.36-1.52 (m, 3 H), 1.76 (br. d, 1 H), 3.36-3.44 (m, 1 H), 4.96 (s, 2H), 7.10 (d, 1 H), 7.27-7.36 (m, 5H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:32][CH3:33].[N:34]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:42]4[CH2:43][CH2:44][CH:39]([N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:40][CH2:41]4)=[C:7]([O:32][CH3:33])[CH:8]=3)[N:13]=[CH:12][CH:11]=2)=[C:18]([C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:25])[CH:19]=1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCl
Reactant: C1CCN(C2CCNCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCN1CCC(N2CCCC2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (112 mg), 4-(1-pyrrolidinyl)piperidine (111 mg), and potassium carbonate (166 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (47 mg, yield 35%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.Cl[C:21]1[N:29]=[C:28]([NH2:30])[N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(CC)CC>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH:19][C:21]3[N:29]=[C:28]([NH2:30])[N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:18])=[C:8]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[CH:9]=2)[CH:4]=[CH:3]1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCOCC1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nc(N)nc2[nH]cnc12)c1nc2ccn(C)c2cc1N1CCOCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
To a 10 mL vial were added (S)-1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (100 mg, 0.384 mmol), 6-chloro-9H-purin-2-amine (65.1 mg, 0.384 mmol) and Et3N (0.11 mL, 0.77 mmol) in DMF (3 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The reaction mixture was purified by preparative HPLC eluting with 20-40% ACN in water (with 0.05% ammonium formate). The fractions containing the desired product were combined and lyophilized to give the title compound as a white solid (38 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.52 (m, 4 H), 2.68-2.86 (m, 3 H), 3.01-3.18 (m, 3 H), 3.69-3.95 (m, 9 H), 5.62-5.82 (m, 2 H), 5.88-6.08 (m, 1 H), 6.46-6.59 (m, 2 H), 6.74-6.92 (m, 1 H), 7.52-7.59 (m, 1 H), 7.59-7.74 (m, 1 H), 7.76-7.90 (m, 1 H), 12.00-12.22 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H23N9O, 394. found 394.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([OH:13])[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O>[CH2:1]([N:8]1[CH2:11][CH:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(CCl)CNCc1ccccc1
Solvent: O
Product: OC1CN(Cc2ccccc2)C1
Reaction time: 24 h
Yield: 27 %

Procedure:
10 g of 1A was heated under reflux in 150 ml of water with stirring for 24 hours. The reaction mixture was cooled, the aqueous solution was decanted from insoluble material and made alkaline by the addition of solid sodium hydroxide. The oil which separated was extracted with dichloromethane and the extracts were washed with water and dried. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel using acetone as eluent, followed by recrystallization from toluene to give 1, as a crystalline solid, m.p.: 64.5°-65.5° C., in 27% yield.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:12](O)[CH3:13]>>[NH2:2][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: NC1(C(=O)O)CCCCC1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C1(N)CCCCC1
Reaction time: 72 h

Procedure:
Ethanol (4 l) was saturated at 0°-5° C. over 4 hours with hydrogen chloride. 1-Aminocyclohexanecarboxylic acid (600 g) was added in one portion and the mixture was stirred and heated under reflux for 8 hours, then allowed to stand at ambient temperature for 72 hours. The solvent was removed in vacuo and the residue was dissolved in ice-water (1 l) and basified to pH 8-9 at 0°-5° C. by the addition of 2M aqueous sodium hydroxide solution. The product was extracted into dichloromethane (4×300 ml) and the extracts were combined and dried over sodium sulphate. The aqueous residues were basified to pH 10 by the addition of more 2M aqueous sodium hydroxide solution and further product was extracted into dichloromethane (4×200 ml). The extracts were combined and dried over sodium sulphate. The dried dichloromethane extracts were combined and the solvent was removed in vacuo to leave ethyl 1-aminocyclohexanecarboxylate as a pale yellow oil. Yield 669 g.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[N:7]2[CH2:8][CH2:9][N:10]([CH3:24])[C:11]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:6]2=[CH:5][CH:4]=1>ClCCl>[ClH:2].[ClH:1].[Cl:2][C:3]1[N:7]2[CH2:8][CH2:9][N:10]([CH3:24])[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:6]2=[CH:5][CH:4]=1
Reactant: CN1CCn2c(Cl)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Product: CN1CCn2c(Cl)ccc2C12CCNCC2
Temperature: 40 °C
Reaction time: 1 h

Procedure:
HCl (1.84 mL of 4 M in dioxanes, 7.34 mmol) was added to a solution of tert-butyl 6-chloro-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (624 mg, 1.84 mmol) in dichloromethane (2 mL) and was stirred at 40° C. for 1 hour. The reaction was evaporated to dryness to yield 6′-chloro-2′-methyl-3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]dihydrochloride (quantitative) that was used without further purification. ESI-MS m/z calc. 239.1, found 240.3 (M+1)+; Retention time: 0.22 minutes (3 min run).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C@H:16]3[CH2:18][C@H:17]3[CH2:19]O)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([CH3:3])[CH3:2].[I-:21]>>[I:21][CH2:19][C@@H:17]1[CH2:18][C@@H:16]1[CH:13]1[CH2:14][CH2:15][N:10]([C:7]2[N:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][N:8]=2)[CH2:11][CH2:12]1
Reactant: [I-]
Reactant: CC(C)c1cnc(N2CCC([C@H]3C[C@H]3CO)CC2)nc1
Product: CC(C)c1cnc(N2CCC([C@H]3C[C@H]3CI)CC2)nc1

Procedure:
The product of step B was converted to the iodide using the conditions outlined for intermediate 8, step A.
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.CS(O)(=O)=O.CS(O)(=O)=O.[CH3:32][C:33]1([NH:37][CH3:38])[CH2:36][NH:35][CH2:34]1>>[F:1][C:2]1[C:20]([N:35]2[CH2:36][C:33]([CH3:32])([NH:37][CH3:38])[CH2:34]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: CNC1(C)CNC1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Agent: CS(=O)(=O)O
Product: CNC1(C)CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)C1

Procedure:
7-Fluoro-1-methyl-8-(3-methyl-3-methylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid was prepared under the conditions of Example 15, but starting with 1.45 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b]-[1,8]naphthyridine-3-carboxylic acid and 2.34 g of 3-methyl-3-(methylamino)azetidine dimethanesulphonate. The reaction mixture is heated for 1 and a half hours to approximately 90° C. 1.12 g of 7-fluoro-1-methyl-8-(3-methyl-3-methylamino-1-azetidinyl)-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at approximately 336° C.