Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:40]([S:48]([CH3:51])(=[O:50])=[O:49])[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[N:4][C:5]([N:30]([CH2:36][CH2:37][O:38][CH3:39])[CH2:31][C@@H:32]2[CH2:34][C@H:33]2[CH3:35])=[CH:6][C:7]=1[C:8]1[O:12][C:11]([C@@:13]([NH:22]C(=O)OC(C)(C)C)([CH3:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C@:13]([C:11]1[O:12][C:8]([C:7]2[CH:6]=[C:5]([N:30]([CH2:36][CH2:37][O:38][CH3:39])[CH2:31][C@@H:32]3[CH2:34][C@H:33]3[CH3:35])[N:4]=[C:3]([N:40]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)[S:48]([CH3:51])(=[O:50])=[O:49])[C:2]=2[Cl:1])=[N:9][N:10]=1)([CH3:21])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COCCN(C[C@@H]1C[C@H]1C)c1cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c(Cl)c(N(Cc2ccccn2)S(C)(=O)=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCN(C[C@@H]1C[C@H]1C)c1cc(-c2nnc([C@](C)(N)Cc3ccccc3)o2)c(Cl)c(N(Cc2ccccn2)S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (1R)-1-(5-{3-chloro-6-((2-methoxyethyl) {[trans-2-methylcyclopropyl]methyl}amino)-2-[(methylsulfonyl)(pyridin-2-ylmethyl)amino]pyridin-4-yl}-1,3,4-oxadiazol-2-yl)-1-methyl-2-phenylethylcarbamate in CH2Cl2 (1 ml) was added TFA (0.5 ml) and stirred for 30 minutes at rt. Evaporation of the solvent afforded 0.008 g of N-[4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3,4-oxadiazol-2-yl}-3-chloro-6-((2-methoxyethyl) {[trans-2-methylcyclopropyl]methyl}amino)pyridin-2-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide. LCMS [M+H]640.2 Exact mass calculated for C31H38ClN7O4S: 640.2468; measured 640.2484
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(F)cc1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(F)cc1OCc1ccccc1
Reaction time: 2 h
Yield: 58.6 %

Procedure:
A mixture of 2-(benzyloxy)-4-fluorobenzyl alcohol (6.54 g) and manganese(IV) oxide (9.04 g) in chloroform (70 ml) was refluxed and stirred for 2 hr. The insoluble material was removed by filtration and washed with chloroform. The filrate was evaporated and the residue (6.7 g) was chromatographed over silica gel (90 g) eluting with a mixture of hexane and dichloromethane (5:1) to dichloromethane to give a colorless oil of 2-(benzyloxy)-4-fluorobenzaldehyde (3.8 g, 59%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[C:12]1[CH2:20][NH2:21].Cl.C1(C2N=NC(CN)=CC=2)C=CC=CC=1>>[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[C:12]1[CH2:20][NH:21][S:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:9])=[O:8]
Reactant: NCc1cc2ccccc2o1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Agent: NCc1ccc(-c2ccccc2)nn1
Product: O=S(=O)(NCc1cc2ccccc2o1)c1cccnc1
Yield: 95.6 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Reference Example 2-(d) except for using 3-pyridylsulfonyl chloride (154 mg, 0.867 mmol), and using (benzofuran-2-ylmethyl)amine (128 mg, 0.870 mmol) obtained in Reference Example 10-(b) in place of (6-phenylpyridazin-3-ylmethyl)amine hydrochloride to afford the title compound (239 mg) as a white solid. (Yield: 96%)
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2N)[CH2:8][CH2:7][CH2:6]1.O>CCOCC>[NH:1]1[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH2:8][CH2:7][CH2:6][N:4]3[C:2]1=[O:3]
Reactant: NC(N)=O
Reactant: Nc1cccc2c1NCCC2
Solvent: O
Solvent: CCOCC
Product: O=c1[nH]c2cccc3c2n1CCC3
Temperature: 180 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
13 g (0.216 mol) of urea are added to 32 g (0.216 mol) of 1,2,3,4-tetrahydroquinolin-8-amine and the mixture is heated for 3 hours at 180° C. Boiling water is added, the reaction mixture is allowed to cool, ether is added and the mixture is stirred for 2 hours. The reaction mixture is then filtered, the precipitate is sucked dry, washed successively with water and ether and dried under vacuum. There are obtained 19 g of product which is recrystallized from isopropanol. The residue is purified by chromatography on a column of silica gel, the eluent being a dichloromethane/methanol (95/5) mixture. There are obtained 7 g of product which is used as is in the following stage.
Reaction SMILES: [O:1]=[C:2]([N:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][O:12][C:11]1=[O:21])[CH2:3]P(=O)(OC)OC.CC(C)([O-])C.[K+].[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>C1COCC1>[Cl:28][C:29]1[CH:36]=[CH:35][C:32](/[CH:33]=[CH:3]/[C:2]([N:10]2[C@H:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:13][O:12][C:11]2=[O:21])=[O:1])=[CH:31][CH:30]=1
Reactant: COP(=O)(CC(=O)N1C(=O)OC[C@H]1c1ccccc1)OC
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(Cl)cc1)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
A solution of (R)-dimethyl 2-oxo-2-(2-oxo-4-phenyloxazolidin-3-yl)ethylphosphonate (60.7 g, 177.8 mmol) in dry THF (275 ml) under an atmosphere of N2 was cooled to 0° C. in an ice-water bath. Potassium tert-butoxide (23.9 g, 213.4 mmol, 1.0 M solution in THF) was added over a period of 45 min in a dropwise manner and the reaction mixture stirred at 0° C. for 30 min. A solution of 4-chlorobenzaldehyde (25.0 g, 177.84 mmol) in dry THF (100 ml) was added over a period of 20 min and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was cooled to 0° C. and quenched with saturated solution of ammonium chloride (250 mL) and diluted with EtOAc (1.5 L). The biphasic system was stirred at ambient temperature for 10 min and the layers were separated. The organic layer was washed with brine (250 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by SiO2 column using a gradient elution of 0-25% EtOAc in hexanes. Fractions containing product were combined and the solvents were removed in vacuo to provide the product (43.0 g, 74%) as a pale yellow solid.
Reaction SMILES: [OH-].[Na+].[I:3][C:4]1[C:12]2[CH:11]=[CH:10][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][C:7]=2[N:6](S(C2C=CC(C)=CC=2)(=O)=O)[N:5]=1.C(OCC)(=O)C>O1CCCC1>[I:3][C:4]1[C:12]2[CH:11]=[CH:10][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][C:7]=2[NH:6][N:5]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(I)c3c2CC(c2ccccc2)(c2ccccc2)C=C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Ic1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Yield: 110 %

Procedure:
3 cm3 of aqueous 1N sodium hydroxide solution are added to a solution of 0.55 g of 3-iodo-6,6-diphenyl-1-(4-toluenesulphonyl)-6,7-dihydro-1H-indazole in 10 cm3 of tetrahydrofuran. After stirring for about 36 hours at a temperature in the region of 20° C., 30 cm3 of ethyl acetate are added. After separation of the phases by settling, the organic phase is washed with three times 15 cm3 of water, 20 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). 0.436 g of 3-iodo-6,6-diphenyl-6,7-dihydro-1H-indazole is obtained in the form of a solid, the characteristics 30′ of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[N:11]1([C:17]([S:19][CH3:20])=[S:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:14]1[CH2:15][CH2:16][N:11]([C:17]([S:19][CH3:20])=[S:18])[CH2:12][CH2:13]1
Reactant: COc1cccc(CCl)c1
Reactant: CSC(=S)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(CN2CCN(C(=S)SC)CC2)c1
Yield: 82.8 %

Procedure:
In a nitrogen atmosphere, 1.57 g (10.0 mmol.) of 3-methoxybenzyl chloride, 2.00 g (10.0 mmol., purity 88.1% of methyl 1-piperazinecarbodithioate, 1.06 g (10.0 mmol.) of anhydrous sodium carbonate and 20 ml of ethanol. The mixtrue was refluxed under heating for 5 hours. The solvent was distilled off under reduced pressure. The residue was mixed with 15 ml of dichloromethane and 10 ml of water. The mixture was allowed to give separated layers. The organic solvent portion was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. Theresidue was purified over a silica gel column to give 2.46 g of methyl 4-(3-methoxybenzyl)-1-piperazinecarbodithioate as a colorless crystalline product, yield 82.8%.
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].[C:9]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C.O.CCOC(C)=O>[N+:5]([NH:4][C:3]([S:2][CH3:1])=[N:8][CH3:9])([O-:7])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: CSC(=N)N[N+](=O)[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN=C(N[N+](=O)[O-])SC
Reaction time: 8 h
Yield: 11.8 %

Procedure:
To a solution of 2-methyl-1-nitro-2-thiopseudourea (430 mg, 3.19 mmol) in DMF (3 ml) was added Cs2CO3 (1.10 g, 3.38 mmol) and MeI (0.30 ml, 4.82 mmol) and the reaction stirred overnight. The mixture was then diluted with water (10 ml) and EtOAc (40 ml) and the organic layer washed with brine (3×15 ml), dried (Na2SO4) and concentrated. The resultant yellow oil was purified by column chromatography on silica gel (EtOAc/Hexanes, 1:1) to afford S-methyl N-nitro-N′-methylcarbamimidothioate (56 mg, 11%) as a white solid. 1H NMR (CDCl3) δ 2.52 (s, 3H), 3.12 (d, 3H, J=6 Hz), 10.05 (br s, 1H).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]([C:16](=[O:18])[CH3:17])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].[ClH:21]>CO>[ClH:21].[C:16]([C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]1)(=[O:18])[CH3:17]
Reactant: CC(=O)N1CCC(C(C)=O)(c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)C1(c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
1 gram of 1,4 diacetyl-4-phenyl piperidine obtained in Example 2 was dissolved in 25 ml of methanol and sodium hydroxide solution (500 mg dissolved in 2.5 m1 water) was added at room temperature. The solution was stirred at ambient temperature for 10 hrs. Thin layer chromatography showed the complete hydrolysis. The pH of the reaction mixture was adjusted to 2 using dilute hydrochloric acid and filtered to remove the salts. The filtrate was concentrated to remove methanol completely. 25 ml of isopropyl alcohol was added to precipitate the target molecule 4-acetyl 4-phenyl piperidine hydrochloride as white crystalline product. The product was dried under vacuum at 60° C.
Reaction SMILES: C1C2CC3C(=CC=CC=3)C=2C=CC=1.Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Cl-].[C:22]([C:31]([NH3+])([C:41](=O)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:32](=O)[CH2:33][CH2:34][CH2:35]CCCC)(=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]CC.[OH-].[Na+]>>[CH2:15]([C:31]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:48][C:47]=2[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Reactant: CCCCCCCl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCC1(CCCCCC)c2ccccc2-c2ccccc21
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A 250 ml flask was equipped with an electric stirrer, thermowell, and nitrogen pad. It was loaded at room temperature with 24.9 g (0.15 moles) fluorene, 39.5 g (0.327 moles) chlorohexane, 2.9 g of tricaprylylmethylammonium chloride (0.007 moles), and 180 g (2.25 moles) 50% NaOH. No exotherm is observed. It was then heated at 50° C. until reaching 99+% conversion. The reaction took approximately 12 hours. While maintaining at 50° C., the liquid phases were separated (the solid NaCl remained suspended in the top organic phase). The organic phase was extracted with 1×50 ml water followed by 1×25 ml 3.5% HCl (acid wash caused color change from dark to orange). The resulting organic phase weighed 55.8 g and had an area percentage GC analysis for dialkylated product in the 90's. The crude product was forwarded directly to the bromination reaction step. Based on the accountability in the bromination, the yield of the PTC alkylation was 92+%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([O:25][CH3:26])=[N:21][C:22]([O:23]C)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O1CCOCC1.Cl>O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[N:19]=[C:20]([O:25][CH3:26])[NH:21][C:22](=[O:23])[C:17]=3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nc(OC)c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1nc2c(cnn2C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)[nH]1
Temperature: 40 °C

Procedure:
A mixture of 4-(4,6-dimethoxy-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (1 mmol), 2 M aqueous sodium hydroxide (1 mL) and dioxane (10 mL) is heated at 40° C. for 5 h. The mixture is allowed to cool, and is then neutralized to approximately pH 7 by the addition of 1 M aqueous hydrochloric acid. Ethyl acetate and water are added. The organic layer is washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified by flash chromatography on silica gel to give 4-(6-methoxy-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH:6]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])C.[OH-].[Na+]>CO.O>[C:21]([O:20][C:18]([NH:17][C@H:6]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])[CH2:5][C:4]([OH:25])=[O:3])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)CC(Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Temperature: 42.5 °C
Reaction time: 1.25 h
Yield: 99.6 %

Procedure:
Refer to the common known method Tetrahedron Asymmetry, 2006, 17(2), 205-209. 3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1e (10 g, 27.7 mmol) and sodium hydroxide (3.32 g, 83.1 mmol) were dissolved in 150 mL of the mixture of methanol and water (v:v=1:1). The reaction mixture was stirred at 40-45° C. for 1-1.5 hours, then part of the solution was evaporated under reduced pressure. The residues were added with a little of water, then the pH was adjusted to 2-3 with 1 M hydrochloric acid in an ice-water bath. The mixture was extracted with ethyl acetate (200 mL×3), and the combined organic phase was washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then the residues were recrystallized from ethyl acetate/n-hexane to obtain the title compound (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1f (9.2 g) as a white solid, which was directly used in the next step. MS m/z (ESI): 332.3 [M−1].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO.O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: COC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: COC(=O)C1CCN(c2ccc(N)cc2)CC1
Temperature: 65 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a mixture of methyl 1-(4-nitrophenyl)piperidine-4-carboxylate (3.80 g) and iron powder (3.20 g) in methanol/water (40 mL/10 mL) was added conc. hydrochloric acid (2 mL) at room temperature. The reaction mixture was stirred at 65° C. for 3 hr. The reaction mixture was adjusted to pH=9 with saturated sodium carbonate, and the insoluble substance was removed by the filtration. The filtrate was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (3.20 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)c2ccccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ncc(OCc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.7 %

Procedure:
To a mixture of 1-chloroisoquinolin-4-ol (2.33 g, 13 mmol) and potassium carbonate (3 g) in anhydrous DMF (50 mL) is added benyl bromide (1.73 mL, 14.5 mmole) dropwise at room temperature. The resulting solution is stirred at room temperature for 48 hours, and then poured into ice water. The precipitate is collected by filtration and washed with water and hexanes, and dried to give the desired product as a white solid (3.25 g, yield: 93%). m.p. 97-98° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH:14]([F:16])[F:15])[CH:8]=1.[Br:17][C:18]1[CH:19]=[C:20](/[C:24](/[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[C:39]#[N:40])=[N:25]\S(C(C)(C)C)=O)[CH:21]=[CH:22][CH:23]=1.Cl>C1COCC1>[Br:17][C:18]1[CH:19]=[C:20]([C:24]2([C:7]3[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH:14]([F:16])[F:15])[CH:8]=3)[C:32]3[C:33](=[C:34]([F:38])[CH:35]=[CH:36][CH:37]=3)[C:39]([NH2:40])=[N:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cc(Br)cc(C(F)F)n1
Reactant: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cccc(F)c1C#N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc(C(F)F)n1
Reaction time: 1 h
Yield: 12 %

Procedure:
n-Butyllithium (0.359 mL, 0.90 mmol) was added to 4-bromo-2-(difluoromethyl)-6-methylpyridine (166 mg, 0.75 mmol) in THF (5 mL) at −78° C. under nitrogen atmosphere. The reaction mixture was stirred for 30 min before (E)-N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (335 mg, 0.82 mmol) in THF (2 mL) was added. The reaction was kept at −78° C. for 1 hour and then allowed to reach room temperature. The reaction was quenched with water and extracted with ethyl acetate (×3). The combined organic layers were washed with brine and concentrated in vacuo. The residue was dissolved in methanol (2.0 mL) and then hydrochloric acid (2.0 M in diethyl ether, 0.393 mL, 0.79 mmol) was added at room temperature. The mixture was stirred over night and then concentrated in vacuo. The residue was partitioned between aqueous sodium bicarbonate (saturated) and ethyl acetate (×3). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by silica gel chromatography using a gradient of 0 to 10% (3.5 M ammonia in methanol) in dichloromethane gave the title compound 40 mg (12%). MS (ES+) m/z 446, 448 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]([CH3:30])[C:23]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:34]2[CH2:35][CH2:36][N:31]([C:23]3[C:24]([CH3:30])=[C:25]([CH3:29])[CH:26]=[C:27]([CH3:28])[C:22]=3[CH3:21])[CH2:32][CH2:33]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Reactant: Cc1cc(C)c(C)c(N2CCNCC2)c1C
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2c(C)c(C)cc(C)c2C)CC1
Yield: 65.5 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(2,3,5,6,-tetramethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.Br[CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1>>[O:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]1[O:21][CH2:20][CH2:19][O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: BrCCOC1CCCCO1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Product: O=C(OCc1ccccc1)N1CCC(OCCOC2CCCCO2)CC1
Yield: 52 %

Procedure:
Using benzyl 4-hydroxy-1-piperidinecarboxylate (1.50 g, 6.35 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (1.92 mL, 12.7 mmol), the desired title compound (1.2 g, yield 52%) was obtained by the same method as in Reference Example 2 (2a).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]>[H][H].[OH-].[OH-].[Pd+2]>[NH:1]1[CH2:6][CH2:5][NH:4][CH:3]=[C:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cnccn1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Product: CCOC(=O)C1=CNCCN1
Yield: 102 %

Procedure:
A solution of ethyl pyrazine-2-carboxylate (60 g) in ETOH (500 ml) was subjected to catalytic reduction using palladium hydroxide on carbon (5.0 g), in hydrogen at 3 atm for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 62.8 g of ethyl 1,4,5,6-tetrahydropyrazine-2-carboxylate as an oil.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[C:7]1[C:16]([C:17]([C:19](=[CH:25]N(C)C)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:18])=[CH:15][C:14]2[C:9](=[C:10]([F:31])[C:11]([F:30])=[C:12]([F:29])[CH:13]=2)[N:8]=1.C1CCN2C(=NCCC2)CC1>ClC(Cl)Cl.C(O)C>[CH2:23]([O:22][C:20]([C:19]1[C:17](=[O:18])[C:16]2[CH:15]=[C:14]3[CH:13]=[C:12]([F:29])[C:11]([F:30])=[C:10]([F:31])[C:9]3=[N:8][C:7]=2[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:25]=1)=[O:21])[CH3:24]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
9.5 g of tert.-butylamine are added at a temperature of about 20° C., in the course of 5 minutes, to a stirred solution of 11.7 g of ethyl 2-(2-chloro-6,7,8-trifluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate in 150 cm3 of trichloromethane at the same temperature. After stirring for 4 hours at about 20° C., the solution is concentrated to dryness under reduced pressure (20 kPa) at about 50° C. The residue obtained is taken up in 100 cm3 of ethanol. 5 g of DBU are added to the solution obtained and the mixture is heated at a temperature close to 75° C. for 3 hours. After cooling to about 20° C., the precipitate obtained is drained and washed with twice 50 cm3 of ethanol and twice 50 cm3 of diisopropyl ether. 9.5 g of 3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a colourless solid melting at 229° C., which can be used for the subsequent steps without further purification.