Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:15]([O-])=O)[CH2:2][CH2:3][CH3:4].[H][H]>[Ni].CO>[NH2:15][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:6]=1[NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:10]([OH:12])=[O:11]
Reactant: [H][H]
Reactant: CCCCNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CCCCNc1ccc(C(=O)O)cc1N
Yield: 100 %

Procedure:
A mixture of 50 parts of 4-(butylamino)-3-nitrobenzoic acid and 240 parts of methanol was hydrogenated in a Parr apparatus at 3.105Pa and at room temperature with 40 parts of Raney Nickel catalyst under nitrogen atmosphere. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated to dry, yielding 43.7 parts (100%) of 3-amino-4-(butylamino)benzoic acid; mp. 158° C. (int. 8).
Reaction SMILES: [C:1]1([NH:7][C:8]2[S:12][N:11]=[N:10][C:9]=2[C:13]([NH2:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:17]1([C:22](N)=[NH:23])C=CC=N1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[C:1]1([NH:7][C:8]2[S:12][N:11]=[N:10][C:9]=2[CH2:13][NH:15][C:22]([NH2:23])=[NH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1nnsc1Nc1ccccc1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)NCc1nnsc1Nc1ccccc1
Temperature: 80 °C

Procedure:
To a 2 mL pyridine solution of 5-phenylamino-[1,2,3]thiadiazole-4-carboxylic acid amide (50 mg, 0.24 mmole), was added the powder of 1H-pyrazole-1-carboxamidine hydrochloride (235 mg, 1.59 mmole) and diisopropyl ethylamine (234 mg, 1.8 mmole). Then the mixture was heated to about 80 ° C. The reaction mixture was cooled to room temperature for 4 hours and the solvent was then evaporated. The residue was loaded onto a preparative TLC plate and eluted sequentially with neat CH2Cl2 and CH2Cl2.MeOH (4:1). A 94 mg of crude product was collected, which was further purified by another preparative TLC (silica gel, CH2Cl2.MeOH.H2O=3.6:0.4:0.06). The title compound was obtained in 40 mg (66%). 1H NMR (ppm, CDCl3): 9.33 (br. t, 1 H), 8.01 (br. s, 1 H), 7.63-7.82 (m, 2 H), 7.20-7.40 (m, 3 H), 6.37 (br. s, 2 H), 6.08 (br. s, 1 H), 4.41 (d, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:26][C:27]([C:29]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[O:28])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([O:24]C)=[O:23])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li+].[OH-]>CO>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:26][C:27]([C:29]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[O:28])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([OH:24])=[O:23])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(Cc2ccccc2C(=O)OC)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)N1CCN(C(=O)C(Cc2ccccc2C(=O)O)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(2-methoxycarbonylphenyl)ethyl]aminocarbonyl-4-methoxyquinoline (220 mg, 0.4 mmol) in methanol was added a solution of LiOH (3 mL, 0.25 M) and the resulting reaction mixture was stirred at ambient temperature overnight. The product was purified by preparative HPLC and lyophilization to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(2-carboxyphenyl)ethyl]aminocarbonyl-4-methoxyquinoline as an orange solid, 140 mg (50%); NMR (DMSO-d6), 1.08 (t, 3), 3.40 (m, 10), 4.00 (q, 2), 4.04 (s, 3), 5.28 (m, 1), 7.26 (t, 1), 7.34 (m; 2), 7.42 (s, 1), 7.82 (m, 2), 8.06 (d, 1), 8.14 (d, 1H), 8.88 (d, 1) ppm.
Reaction SMILES: COCN[C:5]([C:7]1[C:12]([F:13])=[CH:11][C:10]([Br:14])=[CH:9][N:8]=1)=[O:6].CC(C[AlH]CC(C)C)C>C1COCC1>[F:13][C:12]1[C:7]([CH:5]=[O:6])=[N:8][CH:9]=[C:10]([Br:14])[CH:11]=1
Reactant: COCNC(=O)c1ncc(Br)cc1F
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: O=Cc1ncc(Br)cc1F
Temperature: -50 °C
Reaction time: 2 h

Procedure:
A solution of 3-fluoro-5-bromopyridine carboxylic acid methoxymethylamide (630 mg, 2.4 mmol) in dry THF (12 mL) was cooled to −50° C. and DIBAL (1M in THF; 2.8 mL, 2.8 mmol) was added over 15 min maintaining the temperature below −50° C. The reaction was stirred at −50° C. for 2 h. An additional portion of and DIBAL (1M in THF; 0.25 mL, 0.25 mmol) was added and the reaction mixture was allowed to warm slowly to −10° C. over 2 h. The reaction was quenched by the dropwise addition of water (5 mL) and the THF was removed in vacuo and a dilute solution of Rochelle's salt was added. The aqueous was extracted with EtOAc (×3) and the combined organics dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (gradient: 10%-90% EtOAc in petroleum ether 40-60c) yielded 3-fluoro-5-bromopyridine-2-carbaldehyde as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:3]=1.[CH3:28][S:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:4]2[CH:3]=[C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([S:29][CH3:28])[CH:35]=3)[CH:7]=[CH:6][N:5]=2)[CH2:9][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[N:11]1
Reactant: CSc1cccc(B(O)O)c1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(Br)ccn2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CSc1cccc(-c2ccnc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
5-(4-Bromo-pyridin-2-yl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (50.0 mg, 0.11 mmol) prepared in Step 4 of Preparation 11, 3-(methylthio)phenylboronic acid (28.0 mg, 0.17 mmol), Pd(PPh3)4 (12.8 mg, cat.) and a 2N sodium carbonate solution (550.0 uL) were added to a mixed solvent of ethanol (550.0 uL) and 1,2-dimethoxyethane (1.2 mL). The reaction mixture was stirred at 85° C. for 3 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 35.0 mg of the titled compound as a white liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH3:11])[N:3]=1.CCN(C(C)C)C(C)C.[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH3:11])[N:3]=1)[CH3:22]
Reactant: CCO
Reactant: Cc1cc(C(=O)O)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1nc(C)cc(C(=O)O)n1

Procedure:
A solution of 2-chloro-6-methylpyrimidine-4-carboxylic acid (265 mg, 1.54 mmol) and Hünig's base (0.8 mL) in ethanol (1.79 mL) is stirred at 70° C. for 24 h. Ethanol is evaporated and the aq. phase is acidified with 25% aq. HCl at 0° C., concentrated and purified by prep. HPLC (X-Bridge) to give 2-ethoxy-6-methyl-pyrimidine-4-carboxylic acid (201 mg) as a yellow solid; LC-MS: tR=0.63 min, [M+H]+=183.04.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[O:5][C:6]1[CH:13]=[C:12]([C:14]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)([OH:39])[C:15]2[N:16]=[CH:17][N:18](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:19]=2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[O:5][C:6]1[CH:13]=[C:12]([C:14]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)([OH:39])[C:15]2[NH:16][CH:17]=[N:18][CH:19]=2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(C(O)(c2ccc(Cl)cc2)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1Oc1cccc(Cl)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(C(O)(c2ccc(Cl)cc2)c2cnc[nH]2)cc1Oc1cccc(Cl)c1

Procedure:
2-(3-Chloro-phenoxy)-4-[(4-chloro-phenyl)-hydroxy-(1-trityl-1H-imidazol-4-yl)-methyl]-benzonitrile (0.269 g, 0.396 mmol), trifluoroacetic acid (5 mL), triethylsilane (0.050 mL, 3.17 mmol) was stirred in CH2Cl2 (5 mL) under Ar for 2 hr. The reaction mixture was concentrated in vacuo, diluted with EtOAc, washed with satd. NaHCO3 solution, water, brine, dried (MgSO4), concentrated and purified using SiO2 chromatography (1-1.5% MeOH/CH2Cl2 w NH4OH) to give the title compound. FAB MS (M+1)=436;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH2:12])[C:3]=1[NH:13][CH3:14].C1COCC1.Cl.[CH2:21]([S:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=O)[CH3:22].C(=O)([O-])O.[Na+]>O>[Cl:1][C:2]1[C:3]2[N:13]([CH3:14])[C:26]([C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[S:23][CH2:21][CH3:22])=[N:12][C:4]=2[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CNc1c(N)cc(C(F)(F)F)cc1Cl
Reactant: CCSc1ccccc1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cc(Cl)c2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.3 %

Procedure:
To a mixture of 3-chloro-N2-methyl-5-trifluoromethylbenzene-1,2-diamine (1.12 g) and THF (5 ml), 2-ethylsulfanylbenzoic acid hydrochloride (1.00 g) was added under ice-cooling, heated to room temperature, and stirred for 1 hour. Sodium hydrogen carbonate (0.46 g) was added thereto, and then the reaction mixture was allowed to stand overnight. The reaction mixture was heated to 66° C., and stirred under reflux for 1.5 hours. After the mixture was cooled to room temperature, 2-ethylsulfanylbenzoic acid hydrochloride (0.5 g) was added at room temperature. After the reaction mixture was allowed to stand at room temperature overnight, sodium hydrogen carbonate (1.00 g) was added, and stirred. The reaction mixture was ice-cooled, and then water was added under ice-cooling, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.48 g of 7-chloro-2-(2-ethylsulfanylphenyl)-1-methyl-5-trifluoromethyl-1H-benzimidazole (hereinafter referred to as Present Compound 71).
Reaction SMILES: [H-].[Na+].IC.C(O[C:10](=O)[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH2:14][CH2:13]1)(C)(C)C>CC#N>[CH3:10][NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nccs2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CC#N
Product: CNC1CCN(c2nccs2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
384 mg (8.0 mmol, 60% in mineral oil) sodium hydride and 500 μl (8.0 mmol) iodomethane were added in turn to a solution of 1.13 g (4.0 mmol) (1-thiazol-2-yl-piperidin-4-yl)-carbamic acid-tert-butyl ester (see example 5a) for synthesis) in MeCN (40 ml). The reaction solution was stirred for 1 h at RT. Subsequently, a further 192 mg (4.0 mmol, 60% in mineral oil) sodium hydride and 250 μl (4.0 mmol) iodomethane were added and stirring took place for a further hour. Subsequently, 25% aq. ammoniac solution (2 ml) were added and concentration took place in vacuo. The residue was extracted with chloroform. The organic solution was washed with water and brine in turn, dried over MgSO4, filtered, and concentrated in vacuo. This residue was dissolved in EtOH (10 ml) and a sat. ethereal HCl soln (20 ml) was added. After 1 h stirring at RT, concentration took place in vacuo. The residue was taken up by ether (20 ml) and water (30 ml) was added. After separation of the organic phase, the aqueous phase was made basic (pH>11) with a 20% NaOH soln. Extraction subsequently took place with chloroform. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. 786 mg (3.99 mmol, 99%) N-methyl-1-(thiazol-2-yl)piperidine-4-amine were thus obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13].Cl.Cl[CH2:16][CH2:17][N:18]([CH2:20][CH2:21]Cl)[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:19][N:18]1[CH2:20][CH2:21][N:2]([C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[OH:13])[CH2:16][CH2:17]1
Reactant: CN(CCCl)CCCl
Reactant: Nc1c(O)ccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CN1CCN(c2c(O)ccc3ccccc23)CC1
Reaction time: 48 h

Procedure:
1-Aminonaphthalen-2-ol hydrochloride (5 g, 25.6 mmol) is brought to the reflux point of 1-butanol (100 ml) in the presence of 2-chloro-N-(chloroethyl)-N-methylethanamine hydrochloride (4.9 g, 25.6 mmol) and sodium carbonate (5.4 g, 51 mmol). After 48 h, the reaction mixture is concentrated and impregnated onto silica and then purified by flash chromatography with a mixture (93/7/1) of dichloromethane/methanol/aqueous ammonia.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO[C:15](OC)(OC)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[Cl:12][C:8]1[CH:9]=[C:10]2[O:11][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:1][C:2]2=[C:3]([C:4]([OH:6])=[O:5])[CH:7]=1
Reactant: Nc1c(O)cc(Cl)cc1C(=O)O
Reactant: COC(OC)(OC)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: O=C(O)c1cc(Cl)cc2oc(-c3ccccc3)nc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
A 25-mL, round bottomed flask equipped with a magnetic stirrer was charged with 2-amino-5-chloro-3-hydroxybenzoic acid (0.931 g, 4.96 mmol), trimethyl orthobenzoate (7.23 g, 39.7 mmol), and pyridinium p-toluenesulfonate (0.062 g, 0.248 mmol). After stirring at 90° C. for 1 h, the reaction was diluted with hexanes (30 mL) filtered, and the filter cake dried in a vacuum oven at 40° C. to afford 0.455 g (33% yield) of 6-chloro-2-phenyl-benzoxazole-4-carboxylic acid as a brown solid: 1H NMR (500 MHz, DMSO-d6) δ 8.24 (m, 3H), 7.84 (s, 1H), 7.65 (m, 3H); MS (ESI) m/z 272 (M−H).
Reaction SMILES: [CH3:1][N:2]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:6]=2[N:7]=1.Br[CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:1][N:2]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:18][CH:17]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:15])[F:14])=[CH:8][C:6]=2[N:7]=1
Reactant: CN(c1ccc(O)cc1)c1nc2cc(C(F)(F)F)ccc2o1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2nc3cc(C(F)(F)F)ccc3o2)cc1
Reaction time: 7 h
Yield: 32.7 %

Procedure:
A mixture of 4-[N-methyl-N-(5-trifluoromethyl-2-benzoxazolyl)amino]phenol (1.8 g, 0.006 mole), ethyl 2-bromopropionate (1.2 g, 0.006 mole), ethyl 2-bromopropionate (1.2 g, 0.006 mole), anhydrous potassium carbonate (0.9 g, 0.006 mole) and methyl ethyl ketone (25 ml) was heated under reflux, with stirring, for a period of 7 hours and then allowed to stand at room temperature for a period of 48 hours. The solvent was removed by distillation under reduced pressure and the residue was triturated with a mixture of water and diethyl ether. The combined ethereal extracts (200 ml) were washed with brine, dried over anhydrous magnesium sulfate and the ether evaporated to give a yellow oil. The oil was chromatographed over silica gel (eluant diethyl ether) to give the title compound as a yellow oil (0.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[C:19](=[O:24])[NH:20][CH:21]=[CH:22][CH:23]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.Br[CH2:26][CH2:27][CH2:28][C:29]#[N:30].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][CH2:17][C:18]3[C:19]([O:24][CH2:26][CH2:27][CH2:28][C:29]#[N:30])=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CN1CCC(CCc2ccc[nH]c2=O)CC1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ncccc1CN1CCC(CCc2cccnc2OCCCC#N)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 60.2 %

Procedure:
200 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-oxo-1,2-dihydro-3-pyridinyl)ethyl]piperidine obtained in Example 47,95 mg of γ-bromobutyronitrile and 169 mg of potassium carbonate were suspended in 5 ml of N,N-dimethylformamide, and the mixture was stirred at 60° C. for 4 hours. Ethyl acetate was added thereto, the resulting salt was filtered off, and the solvent was evaporated. The crude product was purified by NH form silica gel column chromatography (ethyl acetate:hexane=1:4), to give 77 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8]CS([O-])(=O)=O.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: c1c[nH]cn1
Reactant: Cn1cccc1CCCS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1cccc1CCn1ccnc1
Reaction time: 72 h
Yield: 60.3 %

Procedure:
A mixture of 17.8 g of [2-(1-methyl-1H-pyrrol-2-yl)ethyl]methanesulfonate (ester), 11.7 g of 1H-imidazole, 14 g of potassium carbonate and 410 ml of tetrahydrofuran was stirred for 3 days at reflux temperature. After cooling, the reaction mixture was evaporated and the residue was taken up in water. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2C12 /CH3OH 95:5). The eluent of the desired fraction was evaporated and the residue was co-evaporated with methylbenzene (3×). The product was filtered off and dried, yielding 9.3 g (61.7%) of 1-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1H-imidazole (interm. 1);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([C:19]#[C:20][Si](C)(C)C)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:25]#[N:26])[CH:5]=[CH:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([C:19]#[CH:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:25]#[N:26])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#Cc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cn1
Reaction time: 1 h
Yield: 45.3 %

Procedure:
To 800 mg of 4-(3-bromo-phenylamino)-6-trimethylsilanylethynyl-[1,7]naphthyridine-3-carbonitrile in 20 mL of tetrahydrofuran at 0° C. under an inert atmosphere was added 2.5 mL of 1 M tetrabutylammonium fluoride/tetrahydrofuran. After 1 hour at ambient temperature, the reaction was diluted with ethyl acetate and washed with brine. The organic layer was dried with sodium sulfate and evaporated. The product was purified by flash chromatography on silica gel to give 300 mg of 4-(3-bromo-phenylamino)-6-ethynyl-[1,7]naphthyridine-3-carbonitrile: melting point 224° C. (decomposed); mass spectrum (m/e): M+H 349.1, 351.1.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.CN(C)CCCN=C=NCC.C(O)(C)(C)C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=1[S:44]([NH2:47])(=[O:46])=[O:45]>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([NH:47][S:44]([C:37]3[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=[CH:41][C:36]=3[Cl:35])(=[O:46])=[O:45])=[O:17])[N:14]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)c1cn2cc(C(F)(F)F)cc(Br)c2n1
Reactant: COc1ccc(Cl)c(S(N)(=O)=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: COc1ccc(Cl)c(S(=O)(=O)NC(=O)c2cn3cc(C(F)(F)F)cc(Br)c3n2)c1
Reaction time: 0.25 h
Yield: 78.4 %

Procedure:
To the product of Step A (200 mg, 0.647 mmol) was added a solution of 4-(dimethylamino)pyridine (237 mg, 1.94 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (309 mg, 1.62 mmol) in a 1:1 mixture of t-butanol (5 mL) and dichloromethane (5 mL). The reaction mixture was stirred for 15 min, 2-chloro-5-methoxybenzenesulfonamide (129 mg, 0.582 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Dichloromethane (200 mL) was then added, the mixture was extracted with 1 N hydrochloric acid (3×100 mL), and the separated organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure to afford a solid. The solid was rinsed with diethyl ether to afford 234 mg of the title compound, a compound of the present invention, as a white solid, m.p. 191-192° C. 1H NMR (CDCl3) δ 10.1 (br s, 1H), 8.51 (s, 1H), 8.30 (s, 1H), 7.87 (d, 1H), 7.72 (s, 1H), 7.38 (d, 1H), 7.08 (dd, 1H) 3.91 (s, 3H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C(=O)(O)[O-].[Na+].[Br:17][C@@H:18]1[C:27]([CH3:29])([CH3:28])[O:26][C:25]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[C@H:19]1[OH:30]>C(Cl)(Cl)Cl>[Br:17][C@@H:18]1[C:27]([CH3:28])([CH3:29])[O:26][C:25]2[CH:24]=[CH:23][N+:22]([O-:9])=[CH:21][C:20]=2[C@H:19]1[OH:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)Oc2ccncc2[C@@H](O)[C@@H]1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1(C)Oc2cc[n+]([O-])cc2[C@@H](O)[C@@H]1Br

Procedure:
To a white suspension of 7,9 mg of m-chloroperbenzoic acid and 4,4 g of dry sodiumbicarbonate in 90 ml of abs. chloroform a solution of 6,7 g of trans-3-bromo-3,4-dihydro-4-hydroxy-2,2-dimethyl-2H-pyrano[3,2-c]pyridin in 70 ml of chloroform is dropwise added under argon. After 2 hours the suspension is concentrated to dryness, the residue taken up in dichloromethane/methanol and filtrated to a clean filtrate. Concentration of the filtrate and purification by chromatography (silica gel, dichloromethan/methanol) of the residue yields solid trans-3-bromo-3,4-dihydro-4-hydroxy-2,2-dimethyl-6-oxido-2H-pyrano-[3,2-c]pyridine.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.Br[C:12]([CH3:21])([CH3:20])[C:13]([O:15]C(C)(C)C)=[O:14]>>[CH2:9]([O:8][C:6]([C:4]1[CH:5]=[N:1][N:2]([C:12]([CH3:21])([CH3:20])[C:13]([OH:15])=[O:14])[CH:3]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Product: CCOC(=O)c1cnn(C(C)(C)C(=O)O)c1
Yield: 83.1 %

Procedure:
By a reaction in the same manner as in Example 10a and using ethyl 1H-pyrazole-4-carboxylate (1.40 g, 10.0 mmol) and tert-butyl 2-bromo-2-methylpropanate (6.70 g, 30.0 mmol), the title compound (1.88 g, 83%) was obtained as a colorless oil.