Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:17])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[NH:18]1[CH2:23][CH2:22][CH:21]([NH:24][S:25]([C:28]2[CH:37]=[CH:36][C:31]3[O:32][CH2:33][CH2:34][O:35][C:30]=3[CH:29]=2)(=[O:27])=[O:26])[CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:17])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:18]2[CH2:19][CH2:20][CH:21]([NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:31]4[O:32][CH2:33][CH2:34][O:35][C:30]=4[CH:29]=3)(=[O:27])=[O:26])[CH2:22][CH2:23]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C)cc(=O)n(CC=O)c2c1
Reactant: O=S(=O)(NC1CCNCC1)c1ccc2c(c1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(C)cc(=O)n(CCN3CCC(NS(=O)(=O)c4ccc5c(c4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To 2 mL of dichloromethane solution containing 30 mg of (7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde, 39 mg of N-(piperidin-4-yl)-2,3-dihydro-1,4-benzodioxin-6-sulfonamide and 7.4 μl of acetic acid were added and stirred at room temperature for 2 hours. To the reaction mixture, 41 mg of sodium triacetoxyborohydride was added and stirred at the same temperature for 2 hours. Chloroform and water were added, and adjusted to pH 7.8 with aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=10:1] to give 55 mg of N-(1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)-2,3-dihydro-1,4-benzodioxin-6-sulfonamide as a light brown foam.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([CH2:18][OH:19])[CH:8]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.Cl>C(O)C>[OH:19][CH2:18][C:7]1[CH:6]=[C:5]([OH:4])[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=1
Reactant: COCOc1cc(CO)cc(Oc2ccccc2)c1
Agent: Cl
Solvent: CCO
Product: OCc1cc(O)cc(Oc2ccccc2)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of [3-(methoxymethoxy)-5-phenoxyphenyl]methanol (0.75 g, 2.86 mmol) in ethanol (10 mL) was added concentrated hydrochloric acid (1 mL), and the mixture was stirred at 40° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=5:5) to give the title compound (0.60 g, yield 96%) as an oily matter.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O-:21])=[O:20])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[C:25]([O:28][CH2:29]Br)(=[O:27])[CH3:26]>CN(C=O)C>[OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O:21][CH2:29][O:28][C:25](=[O:27])[CH3:26])=[O:20])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cncc4s3)[C@H](C)[C@H]12
Reactant: CC(=O)OCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCOC(=O)C1=C(c2cn3cncc3s2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: -10 °C
Reaction time: 3 h
Yield: 19.7 %

Procedure:
To a solution of 49 mg of sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 1 ml of DMF was added 32 mg of acetoxymethyl bromide under the atmosphere of argon at −20° C., and the mixture was stirred for 3 hours during which the temperature was raised up to −10° C. The reaction mixture was extracted twice with 20 ml of ethyl acetate, and the organic layer was washed twice with 10 ml of semi-saturated aqueous saline, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to a volume of 2 ml. The residue thus obtained was purified by column chromatography on silica gel (chloroform:methanol=9:1) and on Sephadex LH-20 (dichloromethane:methanol=1:1) in this sequence to give 11 mg of the title compound.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][N:19]([CH3:24])[S:20](Cl)(=[O:22])=[O:21]>CN(C)C=O.O>[CH3:18][N:19]([CH3:24])[S:20]([N:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]=[CH:10]1)(=[O:22])=[O:21]
Reactant: c1ccc(-c2cnc[nH]2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)n1cnc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.3 %

Procedure:
To a solution of 5-phenyl-1H-imidazole (5 g, 34.7 mmol) and K2CO3 (6 g, 41.6 mmol) in N,N-dimethylformamide (DMF) (20 mL) was added dimethylsulfamoyl chloride (4.11 mL, 38.2 mmol) drop wise at room temperature. The resulting mixture was stirred at room temperature for 4 h and then diluted with water (500 mL). The resulting solid was collected by vacuum filtration and dried to give the desired product (7 g). LC-MS: m/z 252 (M+H+).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([O:29]CC)=[O:28])[CH2:23][CH2:22]2)[CH:14]=[CH:13]3)[CH2:5][CH2:4]1)[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([C@@H:3]1[CH2:4][CH2:5][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]2)[CH:14]=[CH:13]3)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@@H](CC)CC4)ccc3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC[C@H]1CC[C@@H](Oc2ccc3cc(CN4CCC(C(=O)O)CC4)ccc3c2)CC1
Yield: 69.5 %

Procedure:
A mixture of ethyl 1-((6-(cis-4-ethylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylate (1.6 g, 0.004 mol, 1.0 eq) and NaOH (0.48 g, 0.012 mol, 3.0 eq) in ethanol (10 mL) and water (2 mL) was refluxed for 2 h. After the solvent was removed in vacuo, the residue was dissolved in water (20 mL) and acidified with 1 N HCl to pH=7. The mixture was extracted with dichloromethane (50 mL*3) and the combined organic layers were washed with brine (30 mL), dried over sodium sulfate, concentrated and recrystallized in ethyl acetate to give 1-((6-(cis-4-ethylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid (1.1 g, yield: 71%) as a white solid. ESI-MS (M+H)+: 396.3. HPLC: 100%. 1H NMR (400 MHz, DMSO-d6) δ: 7.77 (d, J=9.2 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H) 7.63 (s, 1H), 7.39 (dd, J=8.4, 1.2 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.15 (dd, J=8.8, 2.4 Hz, 1H), 4.71-4.69 (m, 1H), 3.54 (s, 2H), 2.78-2.74 (m, 2H), 2.16-2.15 (m, 1H), 2.01-1.93 (m, 4H), 1.77-1.75 (m, 2H), 1.63-1.50 (m, 6H), 1.34-1.24 (m, 5H), 0.87 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(O[C:4](=[O:20])[C:5]1[CH:15]=[C:14]([CH:16]=[C:17]([CH3:19])[CH3:18])[CH:13]=[C:7]([C:8]([O:10]CC)=[O:9])[CH:6]=1)C.[OH-].[Na+].Cl.[CH3:24][N:25](C)[CH2:26][CH2:27][CH2:28]N=C=NCC.ON1C2C=CC=CC=2N=N1.CNCCC.C(N(CC)CC)C.[OH-].[Li+].Cl>CC(C)=O.CO.CN(C=O)C.C(OCC)(=O)C>[CH3:24][N:25]([CH2:26][CH2:27][CH3:28])[C:4](=[O:20])[C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([CH:16]=[C:17]([CH3:18])[CH3:19])[CH:15]=1)[C:8]([OH:10])=[O:9]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)c1cc(C=C(C)C)cc(C(=O)OCC)c1
Agent: CCCNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCN(C)C(=O)c1cc(C=C(C)C)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.2 %

Procedure:
Dissolve 5-(2-methylpropenyl)-isophthalic acid diethyl ester (535 mg, 1.94 mmol) in acetone (10 mL) and add a solution of NaOH (77 mg, 1.94 mmol) in methanol (2 mL). Stir at room temperature 2 days and concentrate. Dissolve in water and wash with diethyl ether. Acidify the water layer to about pH=1 with 1 N HCl and extract with dichloromethane. Dry the dichloromethane layer over magnesium sulfate, filter and concentrate. Dissolve the residue in DMF (10 mL) and add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (409 mg, 2.13 mmol) and 1-hydroxybenzotriazole (288 mg, 2.13 mmol). After 30 min, add methyl-propyl-amine (283 mg, 3.87 mmol) and triethylamine (665 mg, 6.58 mmol) in DMF (2 mL). Stir at room temperature 1 h and dilute with ethyl acetate. Wash with 10% aqueous potassium carbonate, 0.1 N citric acid, 1 N lithium chloride and saturated aqueous sodium chloride and concentrate. Dissolve the residue in THF (20 mL) and add 1 N lithium hydroxide (10 mL, 10 mmol). Stir at room temperature for 4 h and acidify to about pH=1 with 1 N HCl. Extract with dichloromethane, dry (magnesium sulfate), filter and concentrate to give the title compound as a solid (220 mg, 41%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH:13]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1)[OH:14])[CH3:2]>C(O)C.[C].[Pd]>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]([CH:13]([C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)[OH:14])=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=1
Reactant: CCOc1cc([N+](=O)[O-])ccc1C(O)c1cc(C)ccn1
Agent: [Pd]
Solvent: CCO
Product: CCOc1cc(N)ccc1C(O)c1cc(C)ccn1
Yield: 99.9 %

Procedure:
(2-ethoxy-4-nitrophenyl)(4-methylpyridin-2-yl)methanol (1.9 g) was dissolved in ethanol (100 ml), and the solution was reduced by catalytic hydrogenation with 10% palladium-carbon (0.2 g) of 50% hydration overnight. The catalyst was removed, and the solvent of the filtrate was evaporated to give (4-amino-2-ethoxyphenyl)(4-methylpyridin-2-yl)methanol (1.7 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:12][C@H:11]([NH:13][C:14]2[C:15]([NH2:21])=[CH:16][CH:17]=[C:18]([F:20])[CH:19]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH3:34])[C:31](O)=O)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:22]([O:26][C:27](=[O:28])[NH:29][C@H:30]([C:31]1[N:13]([C@H:11]2[CH2:12][C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:10]2)[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[N:21]=1)[CH3:34])([CH3:25])([CH3:24])[CH3:23]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1N[C@H]1C[C@H](OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of N2-(trans-3-benzyloxycyclobutyl)-4-fluoro-benzene-1,2-diamine (1.73 g, 2.55 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.54 g, 2.81 mmol) and HOAt (0.38 g, 2.81 mmol) in DCM (20 mL) were cooled to 0° C. under nitrogen atmosphere. To this mixture N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.54 g, 2.81 mmol) was added portion wise and the reaction mixture was stirred at RT for 1 h. The reaction mixture allowed to warm to RT then partitioned between DCM (30 mL) and 10% aqueous citric acid (20 mL). The organic layer was washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) to afford the title compound as a off-white gum, which solidified on standing (0.88 g, 75%). NMR: 328289. LCMS (Method B): RT 3.85 min [M+H]+ 458.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C=O)C>[CH2:17]([C:14]1[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:4][CH:5]=2)[C:12](=[O:25])[CH:13]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C1CCNC1
Reactant: O=c1cc(CCc2ccccc2)ccn1CCc1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: O=c1cc(CCc2ccccc2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 85 mg (0.21 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-phenethyl-1H-pyridin-2-one (example 18.1b) in 1.0 mL DMF is added 36 μL (0.43 mmol) pyrrolidine at RT. The reaction mixture is stirred overnight at RT, filtered and directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][C@H:33]1[CH2:38][NH:37][C@@H:36]([CH3:39])[CH2:35][NH:34]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:34]5[CH2:35][CH:36]([CH3:39])[NH:37][CH2:38][CH:33]5[CH3:32])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: C[C@H]1CN[C@@H](C)CN1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C(C)CN1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2,5-dimethyl-piperazin-1-yl)-thiazol-4-one one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-(S),5-(S)-Dimethyl-piperazine following General Procedure C.
Reaction SMILES: [NH2:1][CH:2](/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[C:3]([OH:5])=[O:4].Cl.[CH2:14](O)[CH3:15]>>[CH2:14]([O:4][C:3](=[O:5])[CH:2]([NH2:1])[CH:6]=[CH:7][CH2:8][P:9]([OH:12])([OH:11])=[O:10])[CH3:15]
Reactant: NC(/C=C/CP(=O)(O)O)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(N)C=CCP(=O)(O)O

Procedure:
2.0 g of E-2-amino-5-phosphono-3-pentenoic acid are placed in 50 ml of ethanol and the whole is saturated with hydrogen chloride gas for 21/2 hours at 50°. After concentration, the residue is dissolved in 18 ml of ethanol, 18 ml of propylene oxide are added and the precipitate is filtered off. Recrystallisation from water/ethanol 1:3 yields 2-amino-5-phosphono-3-pentenoic acid ethyl ester, m.p. 167°-168°.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[C:15]([CH3:18])([CH3:17])[S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:29]O.O>C(O)(=O)C.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:19]([O:21][CH2:22][C:23]([Cl:24])([Cl:25])[Cl:26])=[O:20])[C:15]([CH3:18])([CH3:17])[S:16](=[O:29])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: OO
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1=O
Reaction time: 1.5 h

Procedure:
Sodium tungstate dihydrate (500 mg.) was added to a solution of 2,2,2-trichloroethyl 6-(2-phenylacetamido)-2,2-dimethylpenam-3-carboxylate (31.5 g.) in acetic acid (150 cc.), and to the mixture was added, dropwise, 30% hydrogen peroxide (9.1 cc) while cooling in an ice bath. The mixture was stirred for 1.5 hours, and then water was added thereto. The precipitate was collected by filtration, washed with water and dried to yield crystals (33.2 g.) of 2,2,2-trichloroethyl 6-(2-phenylacetamido)-2,2-dimethylpenam-3-carboxylate-1-oxide, m.p. 165.5°-168.5° C.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]2=[N:4][CH:3]=1.CN([CH:14]=[O:15])C.O>C1COCC1.C([Li])CCC>[CH:14]([C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]2=[N:4][CH:3]=1)=[O:15]
Reactant: CN(C)C=O
Reactant: Brc1cnc2n1CCCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cnc2n1CCCC2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (2.84 g) in THF (50 ml), n-butyllithium (1.6M hexane solution, 28 ml) was added dropwise at −78° C. The mixture was stirred for 1 hour at −78° C., DMF (5 ml) was added to the mixture, and the mixture was stirred for 0.5 hour at room temperature. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→ethyl acetate), to give 3-formyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (1.48 g) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14](=O)[CH2:13][CH2:12][N:11]([CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.C(O)(=O)C([O-])=O.N1CCCCC1=O.[NH2:30][OH:31]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14](=[N:30][OH:31])[CH2:13][CH2:12][N:11]([CH3:16])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2CN(C)CCC2=O)cc1
Reactant: NO
Agent: O=C([O-])C(=O)O
Agent: O=C1CCCCN1
Product: COc1ccc(C2CN(C)CCC2=NO)cc1

Procedure:
Cis-8-methoxy-2-methyl-6-phenyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine is obtained by addition of 3-amino-2-p-methoxyphenylpropionic acid ethyl ester to acrylic acid ethyl ester, reductive methylation of 2-p-methoxyphenyl-3,3'-iminodipropionic acid diethyl ester (M.P. of the hydrogen oxalate 152°) with formaldehyde to obtain 2-p-methoxymethyl-N-methyl-3,3'-iminodipropionic acid diethyl ester, reaction of the latter compound to obtain 3-carbethoxy-5-(p-methoxyphenyl)-1-methyl-4-piperidone (M.P. of the hydrochloride 180°-182°), which is converted by hydrolysis and subsequent decarboxylation into 3-p-methoxyphenyl-1-methyl-4-piperidone (M.P. of the hydrogen oxalate 137°-138°). The resulting piperidone is reacted with hydroxylamine to obtain 3-p-methoxyphenyl-1-methyl-4-piperidone oxime (M.P. 121°-122°), the oxime is hydrogenated with Raney nickel to obtain 4-amino-3-p-methoxyphenyl-1-methyl-piperidine (mixture of the two diastereoisomers), the amino compound is treated with benzoyl chloride, cis-4-benzoylamino-3-p-methoxyphenyl-1-methylpiperidine (M.P. 164°-165°) is isolated from the reaction mixture, and the latter amide is cyclized with phosphorus oxychloride to obtain the desired benzonaphthyridine.
Reaction SMILES: CO.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:13])[F:12])=[C:6]([O:14][CH:15]([CH:22]2[CH2:24][CH2:23]2)[C:16]#[C:17][Si](C)(C)C)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:13])[F:12])=[C:6]([O:14][CH:15]([CH:22]2[CH2:24][CH2:23]2)[C:16]#[CH:17])[CH:5]=1
Reactant: C[Si](C)(C)C#CC(Oc1cc(Br)ccc1OC(F)F)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#CC(Oc1cc(Br)ccc1OC(F)F)C1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.1 %

Procedure:
To 34 ml of methanol solution containing 4.05 g (10.5 mmol) of 4-bromo-2-(1-cyclopropyl-3-trimethylsilyl-2-propynyloxy)-1-difluoromethoxybenzene obtained in Reference example 14-(a) was added 0.48 g (3.5 mmol) of potassium carbonate, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, 50 ml of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 2.8 g of the title compound as colorless liquid. (Yield: 84%)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=[CH:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O.[F:35][C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[CH:44]=1)[C:39]([OH:41])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl.O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[F:35][C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[CH:44]=1)[C:39]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=[CH:19][CH2:20][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:10][CH:9]=1)=[O:41]
Reactant: O=C(O)c1cc(F)cc(N2CCOCC2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=CCN2CCOCC2)c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C=CCN2CCOCC2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1
Yield: 11.8 %

Procedure:
[4-(3-Morpholin-4-yl-propenyl)-naphthalen-1-yl]-carbamic acid tert-butyl ester (367 mg, 1.0 mmol) is stirred at room temperature in dichloromethane (10 ml) and trifluoroacetic acid (5 ml) for 2 hours. The mixture is then evaporated to dryness. The residue, 3-fluoro-5-morpholinyl benzoic acid (337 mg, 1.5 mmol), HBTU (758 mg, 2.0 mmol) and diisopropylethylamine (0.87 ml, 5.0 mmol) are stirred at room temperature in a mixture of tetrahydrofuran (5 ml) and dimethylformamide (1 ml) for 16 hours. The mixture is then poured into ethyl acetate (100 ml) and washed with water (100 ml). The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluted with 50% ethyl acetate in hexanes followed by 2.5% methanol in ethyl acetate to give 3-fluoro-5-morpholin-4-yl-N-[4-(3-morpholin-4-yl-propenyl)-naphthalen-1-yl]-benzamide as a pale yellow oil (56 mg).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:22]=[C:21]([CH3:23])[C:20]([O:24]C(OC)=O)=[CH:19][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[CH:32]=1>>[ClH:1].[F:38][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][C:34]=1[F:37])[CH2:30][O:18][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([NH:5][C:4]3[CH:19]=[C:20]([OH:24])[C:21]([CH3:23])=[CH:22][C:3]=3[F:2])=[N:7][CH:8]=[N:9]2)=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: Fc1ccc(CBr)cc1F
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Agent: Cl
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCc1ccc(F)c(F)c1
Yield: 31.4 %

Procedure:
Using an analogous procedure to that described in Example 36, 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (224 mg, 0.6 mmol), (prepared as described for the starting material in Example 22), was treated with 4-bromomethyl-1,2-difluorobenzene (149 mg, 0.72 mmol) to give 7-(3,4-difluorobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (90 mg, 31%).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]=2[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH:22]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23]1>ClCCl>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][NH:14][C:26]([CH:22]3[CH2:25][CH2:24][CH2:23]3)=[O:27])[C:5]=2[CH2:4][CH2:3]1
Reactant: O=C(Cl)C1CCC1
Reactant: NCCCc1cccc2c1CCO2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCc1cccc2c1CCO2)C1CCC1
Reaction time: 3 h

Procedure:
3-(2,3-Dihydro-benzofuran-4-yl)-propylamine hydrochloride (100 mg) was suspended in dichloromethane (3 ml) containing triethylamine (0.33 ml) and cooled in ice. A solution of cyclobutanecarbonyl chloride (0.054 ml) in dichloromethane (1 ml) was added and the mixture stirred in ice for 3 h. The mixture was purified by elution through a solid phase extraction cartridge to give the title compound as a white solid (110 mg).