Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9](=[O:15])[CH:10]=[CH:11][CH:12]=[CH:13][CH3:14])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(B(CC)CC)C.[BH4-].[Na+].CO>C1COCC1>[OH:1][CH:2]([CH2:8][CH:9]([OH:15])[CH:10]=[CH:11][CH:12]=[CH:13][CH3:14])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CC=CC=CC(=O)CC(O)CC(=O)OC
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC=CC=CC(O)CC(O)CC(=O)OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 42.7 %

Procedure:
To a cold (-15° C.) solution of methyl 3-hydroxy-5-oxo-6,8-decadienoate (18.5 g, 86.9 mmol) in THF (300 mL) was added triethylborane (1M in THF, 113 mL, 113 mmol) and the solution was stirred for 20 minutes. After the mixture was cooled to -78° C., NaBH4 (6 g, 159 mmol) and methanol (37.5 mL) were added. The solution was vigorously stirred for 30 minutes at -78° C. and at ambient temperature for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (diethyl ether:hexane/3:1) to afford 7.95 g (42.7%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[C:10](=[O:14])/[CH:11]=[CH:12]\[CH3:13].C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[C:10](=[O:14])/[CH:11]=[CH:12]/[CH3:13]
Reactant: C/C=C\C(=O)C1=C(C)CCCC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: C/C=C/C(=O)C1=C(C)CCCC1(C)C
Yield: 90 %

Procedure:
Under an atmosphere of nitrogen, a solution containing 1.16 g. of cis-2,6,6-trimethyl-1-crotonyl-1-cyclohexene prepared according to Example 18, 12 ml. of dry benzene and 0.023 g. of p-toluensulfonic acid were stirred 48 hours at room temperature. The solution was diluted with ether, neutralised and washed as usual. The volatile components were removed in vacuo and distillation gave a 90% yield of trans-2,6,6-trimethyl-1-crotonoyl-1-cyclohexene, b.p. 78°-80°/0.001 Torr, the constants of which were found identical with those of the compound described in Example 12.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH3:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH2:19].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:19]([CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([CH3:14])[CH:16]=1)[CH2:11]2
Reactant: Cc1cccc(CN)c1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cccc(CN2Cc3cccc(I)c3C2=O)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.107 g, 0.3 mmol), 3-methyl-benzylamine (0.063 mL, 0.5 mmol), and K2CO3 (0.138 g, 1.0 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(3-methyl-benzyl)-2,3-dihydro-isoindol-1-one (0.037 g, 34%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.35 (s, 3H), 4.08 (s, 2H), 4.82 (s, 2H), 7.12-7.38 (m, 6H), 7.93 (d, 1H). GC-MS: m/z 363 (M)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:23]=[CH:22][C:8]2[N:9]([CH3:21])[C:10]([NH:12][C:13]3[C:18]([Cl:19])=[CH:17][N:16]=[CH:15][C:14]=3[Cl:20])=[N:11][C:7]=2[CH:6]=1)=[O:4].Cl>CO.[OH-].[Na+]>[Cl:19][C:18]1[CH:17]=[N:16][CH:15]=[C:14]([Cl:20])[C:13]=1[NH:12][C:10]1[N:9]([CH3:21])[C:8]2[CH:22]=[CH:23][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=1
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1c(Cl)cncc1Cl)n2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product obtained at (547a) (240 mg, 0.68 mmol) in 10 mL methanol and 5 mL 4M NaOH (aq) was stirred at ambient temperature for 2 h, the another 5 mL 4M NaOH (aq) were added and the mixture stirred for 16 h at ambient temperature. The mixture was acidified by addition of 4M HCl (aq), the precipitate was filtered, washed with water and dried at 70° C.
Reaction SMILES: [F:1][C:2]([F:16])([CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:3](OCC)=[O:4].[BH4-].[Na+]>C(O)C>[F:16][C:2]([F:1])([CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH2:3][OH:4]
Reactant: CCOC(=O)C(F)(F)COC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC(F)(F)COC1CCCCO1
Temperature: 25 °C

Procedure:
A solution of ethyl 2,2-difluoro-3-tetrahydropyranyloxypropionate (3.5 g, 15 mmol) in absolute ethanol (10 ml) was added dropwise to a slurry of sodium borohydride (0.57 g, 15 mmol) at room temperature in absolute ethanol (20 ml). Then the mixture was stirred an additional hour at room temperature. Then the mixture was concentrated in vacuo, hydrolyzed with aqueous ammonium chloride, extracted with ethyl acetate and dried over magnesium sulfate. The product was purified by flash chromatography on silica gel (ethyl acetate:hexane; 25:75) (2.7 g, 90%).
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH:14]=[CH:15][S:16](Cl)(=[O:18])=[O:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH:14]=[CH:15][S:16]([NH:8][C:1](=[NH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:18])=[O:17]
Reactant: N=C(N)c1ccccc1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)c(Cl)c1
Product: N=C(NS(=O)(=O)C=Cc1ccc(Cl)c(Cl)c1)c1ccccc1

Procedure:
Reaction of benzamidine with 3,4-dichlorostyrylsulfonyl chloride according to the above procedure affords N-[(3,4-DICHLOROSTYRYL)SULFONYL]BENZAMIDINE, m.p. 144°-146° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11](Cl)=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:14][C:15]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:16]=1[C:17]([OH:19])=[O:18].N1C=CC=CC=1>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([NH:14][C:15]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:16]=3[C:17]([OH:19])=[O:18])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Nc1cc(F)cc(F)c1C(=O)O
Reactant: O=C(Cl)Cc1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1ccc2c(c1)OCO2)Nc1cc(F)cc(F)c1C(=O)O
Temperature: 120 °C
Yield: 79.7 %

Procedure:
To a solution of commercially available benzo[1,3]dioxol-5-yl-acetyl chloride (3.70 g, 18.70 mmol) in anhydrous dichloromethane (20 mL) was added 2-amino-4,6-difluoro-benzoic acid (2.20 g, 12.5 mmol). After the addition of pyridine (5 mL), the mixture was heated under microwave condition at 120° C. for 5 minutes. The solvent was evaporated and the residue was diluted with 2 N HCl solution to induce the precipitation of a brown solid which was filtered, washed with water and dried under vacuum at 50° C., to afford the title compound (3.34 g, 80% yield).
Reaction SMILES: [OH-].[K+].[CH2:3]([S:5][C:6](=[NH:8])[NH2:7])[CH3:4].C([O:11][CH:12]=[C:13]([C:19]#[N:20])[C:14](OCC)=O)C>CO>[CH2:3]([S:5][C:6]1[N:7]=[C:12]([OH:11])[C:13]([C:19]#[N:20])=[CH:14][N:8]=1)[CH3:4]
Reactant: CCSC(=N)N
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCSc1ncc(C#N)c(O)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.6 %

Procedure:
To a solution of potassium hydroxide (640 mg, 10 mmol) in methanol (6 mL) at 0° C. was added 2-ethyl-2-thiopseudourea (1.85 g, 10 mmol). The mixture was warmed to room temperature, stirred for 5 min, then filtered off potassium bromide under N2. The filtrate was cooled down to 0° C. then ethyl (ethoxymethylene)cyanoacetate (420 mg, 2.5 mmol) was added. The mixture was gradually warmed to room temperature and stirred for 20 h. The solvent was removed under reduced pressure, and the crude material was purified by flash chromatography using 4% 2M NH3 in MeOH/CH2Cl2 system to obtain 288 mg of the title compound. Mass spectrum 181 (EI, M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27](Br)[CH:26]=2)([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].IC.C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C2(c3ccc(O)c(Br)c3)N=C(NC(=O)OC(C)(C)C)c3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(C2(c3ccc(O)cc3)N=C(NC(=O)OC(C)(C)C)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.8 %

Procedure:
To a solution of [3,3-bis-(4-hydroxy-phenyl)-3H-isoindol-1-yl]-carbamic acid tert-butyl ester (Scheme #2, C) (5.0 g, 12.0 mmol) and cesium carbonate (3.9 mL, 12.0 mmol) in N,N-dimethyl formamide (100 mL) was added iodomethane (0.7 mL, 11.4 mmol) in N,N-dimethyl formamide (3 mL) and the mixture stirred at ambient temperature for 18 hours. The N,N-dimethyl formamide was removed under reduced pressure to yield an amber syrup. To this was added ethyl acetate (250 mL) and the mixture stirred vigorously for 0.5 h. The insolubles were filtered and the filtrate concentrated under reduced pressure to yield a tan solid. The crude compound was purified using flash chromatography (silica; 90:10 dichloromethane:ethyl acetate) to give the title compound as a white solid (2.11 g, 34%). 1H NMR (300 MHz, DMSO-d6) δ 7.83 (d, J=7.5 Hz, 1 H), 7.64 (t, J=7.3 Hz, 1 H), 7.55-7.49 (m, 2 H), 7.16 (d, J=8.8 Hz, 2 H), 7.04 (d, J=8.6 Hz, 2 H), 6.89 (d, J=8.8 Hz, 2 H), 6.71 (d, J=8.7 Hz, 2 H), 3.71 (d, J=8.3 Hz, 3 H), 1.46 (s, 9 H); MS (APCI+) m/z 430 [M+1]+; tR=2.20 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13]CC)=[O:12])=[C:4]([CH3:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]Br.[OH-].[K+].Cl>O.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:10]2([C:11]([OH:13])=[O:12])[CH2:26][CH2:25]2)=[O:16])=[C:4]([CH3:17])[CH:3]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(Br)cc1C
Reactant: BrCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)ccc1NC(=O)C1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 80 %

Procedure:
Into a 250 milliliter Erlenmeyer flask equipped with a magnetic stirrer was added 15.0 grams (0.05 mol) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate prepared as in Example A, 16.56 grams (0.12 mol) of potassium carbonate, 150 milliliters of dimethylformamide and 5.16 milliliters (0.06 mol) of 1,2-dibromethane. The resulting mixture was stirred at ambient temperature for a period of 23 hours (liquid chromatographic analysis indicated 87 percent and 95 percent conversions after 2 and 6 hours respectively). Potassium hydroxide (4.0 grams, 0.07 mol) was then added in one gram increments until no ethyl 1-[(4-bromo-2-methylphenylaminocarbonyl)cyclopropanecarboxylate remained. The reaction mixture was diluted to 900 milliliters with water and acidified with concentrated HCl to a pH of 1-2 to afford a yellow percipitate. The yellow precipitate was dried for a period of about 18 hours in an unheated vacuum oven to give 11.88 gram (0.04 mol) of 1-(4-bromo-2-methylpheylaminocarbonyl)cyclopropanecarboxylic acid. The total yield was 80 percent based on a 96.7 weight percent liquid chromatographic assay of the starting ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.[CH:6]([N:9]1[CH2:14][CH2:13][CH:12]([NH:15][S:16]([CH2:19][CH2:20][CH2:21]Cl)(=[O:18])=[O:17])[CH2:11][CH2:10]1)([CH3:8])[CH3:7].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:6]([N:9]1[CH2:14][CH2:13][CH:12]([NH:15][S:16]([CH2:19][CH2:20][CH2:21][N:1]=[N+:2]=[N-:3])(=[O:18])=[O:17])[CH2:11][CH2:10]1)([CH3:8])[CH3:7]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)N1CCC(NS(=O)(=O)CCCCl)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(NS(=O)(=O)CCCN=[N+]=[N-])CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
183 mg (3 equiv.) NaN3 were added to a mixture of 300 mg (0.94 mmol) 3-chloro-propane-1-sulfonic acid (1-isopropyl-piperidin-4-yl)-amide hydrochloride and 519 mg K2CO3 in 10 ml DMF. The resulting mixture was stirred for 24 h at 50° C. The reaction mixture was concentrated under reduced pressure. The resulting residue was taken up in dichloromethane and filtered. The filtrate was concentrated under vacuo to give crude 3-azido-propane-1-sulfonic acid (1-isopropyl-piperidin-4-yl)-amide as a yellow oil, which was pure enough for further transformations.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[B:15]([O:24]C(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>CCCCCC.C1COCC1>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([O:16][B:15]([OH:24])[OH:20])=[CH:3][CH:4]=1)[CH3:9]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1ccc(OB(O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.3 %

Procedure:
To a mixture of 1-bromo-4-ethylbenzene (743 mmol) and 500 ml of THF, was added dropwise 500 ml of a solution of n-butyl lithium (corresponding to 780 mmol) in hexane at −78° C. in 1.6 hours, and stirred at the same temperature for 1.5 hours. To this solution was added dropwise 200 ml of a solution of triisopropyl borate (1,486 mmol) in THF, the solution was gradually warmed up to room temperature, and then the solution was stirred overnight. After 750 ml of 7.3% hydrochloric acid was added and stirred for 30 min, the reaction solution was extracted twice with diethyl ether, washed thrice with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was recrystallized from about 1,000 ml of toluene to give a white solid of 4-ethylphenyl boric acid (515 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[CH:23]=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][C:14]2[CH:23]=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCc1cnc2ccccc2n1
Product: FCc1cccc(C#CCCc2cnc3ccccc3n2)n1
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (104 mg, 0.55 mmol) and 2-but-3-ynyl-quinoxaline (100 mg, 0.55 mmol). Microwave conditions: 120° C. for 15 minutes. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 116 mg (0.40 mmol, 72%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline as an orange solid (M.P.: 136° C. dec.).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]#[N:9])=[CH:5][C:4]=1[C:10]1[S:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1.O.[NH2:22][NH2:23]>CCO>[NH:22]([C:8]([C:6]1[S:7][C:3]([S:2][CH3:1])=[C:4]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:5]=1)=[NH:9])[NH2:23]
Reactant: NN
Reactant: CSc1sc(C#N)cc1-c1nc(-c2ccccc2)cs1
Solvent: O
Solvent: CCO
Product: CSc1sc(C(=N)NN)cc1-c1nc(-c2ccccc2)cs1
Yield: 45 %

Procedure:
5-Methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carbonitrile (100 mg, 0.32 mmol) as prepared in previous step was dissolved in EtOH (10 mL). To this solution hydrazine monohydrate (10 eq) was added and the mixture was heated at reflux for 3 h. The EtOH solution was concentrated down to 1 mL and water (2 mL) was added to this solution. This resulted in the formation of a white solid. The solid was collected by filtration washed with a small amount of water and dried under vacuum to give 50 mg (45%) of hydrazino[5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))(2-thienyl)]methanimine. 1H-NMR (CD3OD/CDCl3; 300 MHz) δ2.69 (s, 3H), 7.35-7.43 (m, 1H), 7.44-7.49 (m, 2H), 7.52 (s, 1H), 7.96-7.99 (m, 2), 8.10 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for C15H14N4S3, 347.04 (M+H), found 347.1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:20]>[OH-].[Na+]>[ClH:20].[C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCN(CCc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CCN(CCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A suspension of 1-(2-phenylethyl)-4-carbetoxypiperidine (12.2 g, 0.047 mol) obtained as described in J. Med. Chem. 1996 (39), 749-756, in 1N NaOH (100 ml) was heated under reflux for 4 h. After cooling to room temperature, the solution was made acid with 6N HCl to pH 2, concentrated by evaporation at reduced pressure, and the solid thus obtained was filtered and dried in a stove under vacuum to give the desired product (12.1 g),
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22].[CH2:23]([NH:25][C:26](=[O:46])[NH:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[C:30]([C:37]2[S:38][CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:41]=2)[CH:29]=1)[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][N:14]([CH3:16])[CH2:13][CH2:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([C:31]3[CH:32]=[N:33][C:28]([NH:27][C:26](=[O:46])[NH:25][CH2:23][CH3:24])=[CH:29][C:30]=3[C:37]3[S:38][CH:39]=[C:40]([C:42]([F:45])([F:43])[F:44])[N:41]=3)=[CH:11][N:10]=2)[C:5](=[O:22])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7]1
Reactant: CCOC(=O)c1cn(CCN(C)C)c2ncc(Br)cc2c1=O
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCC)cn3CCN(C)C)cn1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
In a round bottomed flask ethyl 6-bromo-1-[2-(dimethylamino)ethyl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 21, 200 mg, 0.54 mmol), 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 9, 288 mg, 0.65 mmol) and sodium carbonate (115 mg, 1.08 mmol) were combined and suspended in dimethylformamide (10 mL) and purged with argon gas for 10 min. Tetrakis (triphenylphosphine) palladium (62 mg, 0.05 mmol) was added under argon atmosphere and the reaction mixture was heated to 90° C. for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was poured into water and was stirred for 20 min. The obtained solid was filtered and washed with water then dried to afford 110 mg (33%) of ethyl 1-[2-(dimethylamino)ethyl]-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:10](=[O:20])[C:9]2[C:4](=[CH:5][C:6]3[CH2:23][CH2:22][CH:21]([NH:24][C:25]4[CH:46]=[CH:45][C:28]([C:29]([NH:31][C@H:32]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:30])=[CH:27][CH:26]=4)[C:7]=3[CH:8]=2)[N:3]=1.[CH2:47](Br)[C:48]#[CH:49].C(=O)([O-])[O-].[Ca+2]>CC(N(C)C)=O>[CH3:1][C:2]1[N:11]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[C:10](=[O:20])[C:9]2[C:4](=[CH:5][C:6]3[CH2:23][CH2:22][CH:21]([N:24]([C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH:31][C@H:32]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:30])=[CH:45][CH:46]=4)[CH2:49][C:48]#[CH:47])[C:7]=3[CH:8]=2)[N:3]=1
Reactant: C#CCBr
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NC2CCc3cc4nc(C)n(COC(=O)C(C)(C)C)c(=O)c4cc32)cc1)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)N(C)C
Product: C#CCN(c1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc1)C1CCc2cc3nc(C)n(COC(=O)C(C)(C)C)c(=O)c3cc21
Temperature: 110 °C

Procedure:
A mixture of diethyl N-{p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzoyl}-L-glutamate (13.5 g), propargyl bromide (32 g), calcium carbonate (10.7 g) and DMA (250 ml) was stirred and heated to 110° C. for 5 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluant. There was thus obtained diethyl -{p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)--amino]benzoyl }-L-glutamate as a foam (9 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:16][C:17]2[CH:38]=[CH:37][C:20]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[C:25]([F:36])[CH:24]=3)=[CH:19][CH:18]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O1CCCC1.O>[C:1]([C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:7]([CH2:16][C:17]2[CH:38]=[CH:37][C:20]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[C:25]([F:36])[CH:24]=3)=[CH:19][CH:18]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(Cn3nc(C(C)(C)C)cc3-c3ccccc3)cc2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(-c2ccccc2)n(Cc2ccc(COc3ccc(CCC(=O)O)c(F)c3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
The oil obtained in Example 140 was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), and 2 N aqueous sodium hydroxide solution (3 mL) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water, and neutralized with 1 N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (Manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-1:4) to give the title compound (90 mg, yield 18%, 2 steps) as colorless crystals. 1H NMR (CDCl3) δ: 1.37 (9H, s), 2.64 (2H, t, J=7.6 Hz), 2.91 (2H, t, J=7.6 Hz), 4.97 (2H, s), 5.32 (2H, s), 6.20 (1H, s), 6.67 (2H, s), 7.01 (2H, d, J=8.3 Hz), 7.09 (1H, t, J=8.8 Hz), 7.25-7.40 (7H, m).
Reaction SMILES: Br.Br[CH:3]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[C:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=O.C(N(CC)CC)C.[NH2:24][C:25]([NH2:27])=[S:26].C(=O)([O-])O.[Na+]>C(O)C>[NH2:27][C:25]1[S:26][C:3]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:4]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)[N:24]=1
Reactant: O=C(c1ccco1)C(Br)c1ccncc1
Reactant: NC(N)=S
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(-c2ccco2)c(-c2ccncc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-1-(2-furyl)-2-(4-pyridyl)ethanone hydrobromide (7.59 g, 21.9 mmol) was suspended in ethanol (110 mL), and triethylamine (3.35 mL, 24.1 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. Thiourea (1.83 g, 24.1 mmol) was added to the reaction mixture, followed by stirring under heating and reflux for 30 minutes. The reaction mixture was allowed to cool down to room temperature, and then a saturated aqueous solution of sodium hydrogencarbonate was added thereto, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=10:1) to afford the entitled Compound a (5.10 g, 96%) as pale yellow crystals.