Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]=C(C3C=CC=CC=3)C3C=CC=CC=3)=[C:16]([F:34])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:34])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N=C(c3ccccc3)c3ccccc3)c(F)c2)C1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(F)c2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a stirred solution of (RS)-2-[4-(benzhydrylidene-amino)-3-fluoro-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (2.21 g) in methanol (40 ml) was added ammonium formate (4.54 g). The reaction mixture was degassed by bubbling argon into the mixture for several minutes. 10% Palladium on activated charcoal (255 mg) was then added and the reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was then filtered through celite and the filtrate was poured into 1 M aq. NaOH and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes) to afford (RS)-2-(4-amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (1.42 g, 74%) as a white solid. MS (ISP): 319.2 ([M+Na]+), 297.3 ([M+H]+), 241.2 ([M+H—C4H8]+), 197.2 ([M+H—C4H8—CO2]+).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[SH-:17].[Na+]>O>[CH2:15]([O:14][C:12]([C:4]1[CH:3]=[C:2]([SH:17])[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1cc(Cl)n2nc(C)nc2n1
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(S)n2nc(C)nc2n1
Yield: 74.1 %

Procedure:
The product obtained in Step 2 (15 g) was added all at once at room temperature to a solution of sodium hydrosulfide (15 g) in 300 ml of water with stirring under a nitrogen stream, and the reaction mixture was worked up in the same manner as Step 3 of Example 37, affording 11 g of the objective compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[I:13])[C:5](OCC)=[O:6].C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[I:13]
Reactant: CCOC(=O)c1cc(Cl)c(I)c(OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(CO)cc(Cl)c1I
Temperature: -78 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a mixture of ethyl 3-chloro-4-iodo-5-methoxybenzoate (15.6 g, 45.8 mmol) and toluene (150 mL) was added diisobutylaluminum hydride (1.01 M solution in toluene: 95.2 mL, 96.2 mmol) while stirring at −78° C., and stirring was continued for 3 hours while raising the temperature to −30° C. After then adding a solution of Rochelle salt (sodium potassium (+)-tartrate tetrahydrate) (77.6 g, 275 mmol) in water (400 mL) to the mixture, stirring was continued for 5 hours at room temperature and ethyl acetate was added. After thoroughly shaking the mixture, the organic layer was separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was then filtered, and the solvent in the filtrate was distilled off under reduced pressure to obtain the title compound (13.7 g, 45.8 mmol).
Reaction SMILES: C([C:3](Br)(CC)[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)C.[P:21]([O:28]CC)([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24]>>[C:12]1([CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3][P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCC(Br)(CC)CC(c1ccccc1)c1ccccc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCC(c1ccccc1)c1ccccc1)OCC
Reaction time: 3 h

Procedure:
Diethyl 3,3-diphenylpropylbromide (43.0 g, 0.156 mol) and triethyl phosphite (51.9 g, 0.31 mol) was heated to 150° C. for 20 hours in a flask equipped with nitrogen flow through and an air condenser. Extra triethyl phosphite (20 ml) was added and heating continued to 160° C. for 3 hours. The yellow reaction solution was distilled, collecting several fractions to give the title product as a pale yellow liquid (b.p. 162-176° C. at 0.08 mbar) that crystallised on standing.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[C:37]=2[CH3:43])[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[C:37]=2[CH3:43])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c1C
Product: Cc1nccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)c1C

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J19) (233 mg, 0.75 mmol) and 3-[3-(2,3-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K18) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow oil (340 mg, 81%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[C:21]([OH:22])=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[C:14]([Br:23])[N:13]=1)=[O:11].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]([C:12]1[C:21]([O:22][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[C:14]([Br:23])[N:13]=1)=[O:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1nc(Br)c2cccnc2c1O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1nc(Br)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 35 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
Triethylamine (0.759 g, 7.50 mmol) was added to a suspension of 5-bromo-8-hydroxy-1,6-naphthyridine-7-carboxylic acid methyl ester (6, 1.415 g, 5.000 mmol) in chloroform (5 mL) over 5 min maintaining the temperature at 20-50° C. to give a yellow suspension. p-Toluenesulfonyl chloride (1.15 g, 6.00 mmol) was added over 5 min maintaining the temperature at 20-40° C. to give a yellow solution. The mixture was aged at 40° C. for 2 h during which a crystalline solid precipitated out of the mixture and the color faded (HPLC analysis indicated <0.5% starting material remaining). The mixture was cooled to 20° C. over 15 min. MeOH (10 mL) was added over 30 min then a 1:1 mixture of MeOH:water (10 mL) was added over 30 min. The mixture was cooled to −40° C. over 30 min and aged at −40° C. for 30 min. The cold mixture was filtered and the solid was washed with 1:1 MeOH:water (10 mL), MeOH (5 mL), MTBE (10 mL) and hexanes (10 mL) all at 10-20° C. The off-white crystalline solid was dried under a stream of nitrogen to provide 2.112 g (97% yield) of 5-bromo-8-(p-toluenesulfonyloxy)-1,6-naphthyridine-7-carboxylic acid methyl ester (7)
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:8]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH3:31]>O1CCCC1>[CH:1]1([N:6]([CH3:31])[C:7]2[C:8]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCCC3)nc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C3CCCC3)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(cyclopentylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (200 mg, 0.55 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (96 mg, 4.00 mmol) at 0° C. After stirring for 1 h at room temperature, iodomethane (141.94 mg, 1.00 mmol) was added at 0° C. and the reaction mixture was stirred overnight. The reaction was then quenched by the addition of water (3 mL), extracted with dichloromethane (3×15 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give methyl 3-(cyclopentyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow oil (120 mg, crude).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[CH:49][CH:48]=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:50]([Cl:51])=[CH:49][CH:48]=[CH:47][C:46]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Clc1cccc(Cl)c1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3c(Cl)cccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,3-dichlorobenzene and isolated as white solid (5.2 mg, 29%). MS(m/e): 441.3 (MH+).
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O.C(OCC)(=O)C>C(O)C>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:1]#[N:2])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1
Reactant: FC(F)(F)c1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(Br)cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
Potassium cyanide (630 mg) was added to an emulsion of 4-bromo-1-bromomethyl-2-trifluoromethylbenzene (3.86 g) in ethanol (15 mL)-water (5 mL), and the mixture was stirred at 70° C. for three hours and 15 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Wakogel C-200; elution solvent:heptane:ethyl acetate=9:1) to obtain 2.28 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]([NH2:19])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15]([F:18])([F:17])[F:16]>FC(F)(F)C(O)=O.Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[C:15]([F:17])([F:18])[F:16])=[CH:6][C:5]2[NH:19][C:9]([C:15]([F:18])([F:17])[F:16])=[N:20][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(-c2ccc(Cl)cc2C(F)(F)F)cc1N
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1nc2cc(Cl)c(-c3ccc(Cl)cc3C(F)(F)F)cc2[nH]1
Yield: 164.4 %

Procedure:
To a solution of 5-chloro-4-iodo-2-nitroaniline (2 g, 6.70 mmol) in dioxane (100 ml) and water (10 ml) which maintained with an inert atmosphere of nitrogen was added [4-chloro-2-(trifluoromethyl)phenyl]boronic acid (1.8 g, 8.02 mmol), K3PO4 (2.6 g, 12.24 mmol), Pd(PPH3)4 (0.78 g, 335.77 mmol) with stirring overnight at 95° C. in an oil bath. The resulting mixture was concentrated under vacuum to give a residue which was purified by a silica gel column, eluting with 2% to 3% acetate in petroleum ether to produce 5-chloro-4-[4-chloro-2-(trifluoromethyl)phenyl]-2-nitroaniline as a yellow solid (800 mg, 34%). Next, to a solution of 5-chloro-4-[4-chloro-2-(trifluoromethyl)phenyl]-2-nitroaniline (1.6 g, 4.56 mmol) in ethanol (50 ml) was added Zn powder (1.8 g, 27.69 mmol), hydrogen chloride (2 ml) with stirring for 2 h at 85° C. in an oil bath. The solution was poured into water (300 ml), adjusted to pH 8 with saturated aqueous sodium carbonate and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluting with 5% to 20% ethyl acetate in petroleum to produce 4-chloro-5-[4-chloro-2-(trifluoromethyl)phenyl]benzene-1,2-diamine as a crude red solid (560 mg, 76%). Finally, the solution of 4-chloro-5-[4-chloro-2-(trifluoromethyl)phenyl]benzene-1,2-diamine (100 mg, 0.31 mmol) in trifluoroacetic acid (5 m 1) and hydrogen chloride (1 ml) was stirred overnight at 80° C. in an oil bath. The mixture was quenched with water (100 ml), adjusted to pH 8 with saturated aqueous sodium carbonate solution and extracted with ethyl acetate (50 ml×3). The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to afford 5-chloro-6-[4-chloro-2-(trifluoromethyl)phenyl]-2-(trifluoro methyl)-1H-1,3-benzodiazole as a white solid (101.7 mg, 82%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Mg]Cl)(C)C.[Br:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19](=[O:32])[C:20](=[O:31])[N:21]2[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>O1CCCC1.ClCCl>[Br:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19]([OH:32])([C:7]1[C:8]([OH:10])=[CH:9][C:4]3[O:3][CH2:2][O:1][C:5]=3[CH:6]=1)[C:20](=[O:31])[N:21]2[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Reactant: Oc1ccc2c(c1)OCO2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
To a solution of 1,3-benzodioxol-5-ol (12.8 g, 92.9 mmol) in tetrahydrofuran (200 mL) was added isopropylmagnesium chloride solution (50.7 mL, 101 mmol, 2.0 M in ether) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h, upon which time the colorless precipitate was formed. After the solvent was removed under reduced pressure, the residue was dissolved in methylene chloride (100 mL) and added to a solution of 4-bromo-1-pentyl-1H-indole-2,3-dione (25.0 g, 84.5 mmol) in dichloromethane (100 mL) via a canula over 10 min at 0° C. The reaction mixture was stirred at ambient temperature for 16 h, quenched with saturated ammonium chloride solution (100 mL) and the organic layer was separated. The aqueous layer was extracted with dichloromethane (100 mL). The combined organic layers was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate-hexane to give the title compound (34.9 g, 97%) as a brown gummy material: 1H NMR (300 MHz, DMSO-d6) δ 8.95 (s, 1H), 7.29-7.21 (m, 2H), 6.88-6.81 (m, 1H), 6.55, (s, 1H), 6.14 (s, 1H), 5.86 (dd, 2H), 4.24 (s, 1H), 3.70-3.52 (m, 2H), 1.69-1.55 (m, 2H), 1.31-1.24 (m, 4H), 0.83 (t, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.6, 152.6, 149.1, 144.8, 141.2, 131.7, 127.7, 127.6, 121.0, 113.8, 108.3, 106.7, 101.7, 101.4, 80.5 40.5, 28.8, 26.7 22.2, 13.9.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH2:5]([NH2:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:5]([NH:16][C:1]([NH:16][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[S:2])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: S=C(Cl)Cl
Reactant: CCCCCCCCCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCCCCCCCCNC(=S)NCCCCCCCCCCC
Reaction time: 0.75 h
Yield: 60.7 %

Procedure:
Thiophosgene (10.9 mls, 0.14 moles) is added dropwise to a well stirred mixture of undecylamine (49.9 g, 0.29 moles) and water (400 mls). The mixture is heated to reflux following the addition. After 45 minutes the mixture is allowed to cool while potassium carbonate (20.0 g, 0.14 moles) is added in portions, and is then reheated to reflux. After three hours the mixture is cooled and the product is filtered off, triturated in 2N HCl, refiltered, rinsed with water, and dried. Recrystallization from ethylacetate gave the product (32.7 g) mp 70°-72° C.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:6][CH:5]=1.P(Br)(Br)[Br:24]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:24][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(CCO)cc1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(CCBr)cc1
Temperature: 25 °C

Procedure:
A solution of 2-{2-[4-(2-Hydroxy-ethyl)-phenyl]-ethyl}-isoindole-1,3-dione (Preparation 10, 22.37 g) and phosphorus tribromide (8.20 g) in toluene (500 mL) was refluxed for 4 hours. The mixture was allowed to cool to room temperature, diluted with ethyl acetate (300 mL) and carefully quenched with sodium bisulphite/sodium bicarbonate (1:1) in water (100 mL). The organic layer was separated and washed with further sodium bisulphite/sodium bicarbonate (1:1) in water (100 mL), dried over sodium sulphate and concentrated in vacuo. The resulting solid (24.26 g) was triturated with heptane:tert-butyl methyl ether (100 mL; 9:1, by volume) to give the title compound as a pale green solid, 17.94 g.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:31]=[O:32])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[N:13]2[C:28](=[O:30])[CH3:29])(=O)C.C(=O)(O)[O-].[Na+].C(O)(=O)C>CO>[C:25]([O:24][C:15]12[O:23][N:10]([CH2:11][CH:12]3[CH:14]1[N:13]3[C:28](=[O:30])[CH3:29])[C:9]1[C:17](=[C:5]([OH:4])[CH:6]=[C:7]([CH:31]=[O:32])[CH:8]=1)[CH:16]2[CH2:18][O:19][C:20](=[O:22])[NH2:21])(=[O:27])[CH3:26]
Reactant: CC(=O)Oc1cc(C=O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2C1N2C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)OC12ON(CC3C1N3C(C)=O)c1cc(C=O)cc(O)c1C2COC(N)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55.2 %

Procedure:
To a solution of 11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (52 mg) in methanol (5 ml) was added sodium bicarbonate (10 mg) in an ice-water bath. The mixture was stirred for 30 minutes in an ice-water bath and for additional 2.5 hours at ambient temperature. To the reaction mixture was added acetic acid to adjust the pH value to about 6 in an ice-water bath and the mixture was evaporated in vacuo. The residue was extracted with a mixture of chloroform and methanol (5:1, v/v) (5 ml×3). The extracts were combined and evaporated in vacuo. The residue was subjected to silica gel column chromatography and elution was carried out with a mixture of chloroform and methanol (50:1, v/v) to afford 11-acetyl-8-carbamoyloxymethyl-4-formyl-6-hydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-9-yl acetate (26 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[N:11]([C:12](=[O:15])[CH2:13]Cl)[CH2:10][CH2:9][NH:8][C:7]1=[O:16].N.[NH:18]1CCOCC1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[N:11]([C:12](=[O:15])[CH2:13][NH2:18])[CH2:10][CH2:9][NH:8][C:7]1=[O:16]
Reactant: C1COCCN1
Reactant: O=C1NCCN(C(=O)CCl)C1c1cccs1
Agent: N
Product: NCC(=O)N1CCNC(=O)C1c1cccs1

Procedure:
Reacting the compound obtained in Example 21 with ammonia or morpholine, as described in Example 7, gives 3-(2-thienyl)-4-aminoacetylpiperazin-2-one: melting point: 130° C. (decomposition), or 3-(2-thienyl)-4-(morpholinomethylcarbonyl)-piperazin-2-one: melting point: 144°-146° C., respectively.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5](C#N)=[N:6][CH:7]=1.[CH2:10]1[CH2:14][O:13]CC1.C[Mg+].[Br-]>CCOCC>[F:1][C:2]1[CH:3]=[N:4][C:5]([C:14](=[O:13])[CH3:10])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(F)cn1
Reactant: C1CCOC1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CC(=O)c1ncc(F)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A round-bottom-flask containing 5-fluoropyrimidine-2-carbonitrile (Method 59, 1.50 g, 12.19 mmol) was charged with anhydrous THF (30 ml) under N2. The solution was cooled to 0° C., and a solution of MeMgBr (4.90 ml of a 3.0 M solution in ether, 14.62 mmol) was added dropwise. After 2 hours at 0° C., the reaction mixture was quenched with ice water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, and evaporated to dryness to give the title compound as an oil (0.778 g, yield 46%). GC-MS, 140 (M); 1H NMR (CDCl3) δ 8.65 (s, 2H), 2.65 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:43])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[C:23]([CH2:38][CH2:39][C:40]([OH:42])=[O:41])[CH:22]=1>>[O:10]=[C:6]1[C:5]2[CH:11]=[CH:12][C:2]([O:1][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:24]3[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][C:18]([OH:43])=[O:17])=[CH:22][C:23]=3[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[C:3]([CH2:13][CH2:14][CH3:15])[C:4]=2[O:9][CH2:8][CH2:7]1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCc1ccc(OCCCCCOS(C)(=O)=O)c(CCC(=O)O)c1
Product: CCCc1c(OCCCCCOc2ccc(CCC(=O)O)cc2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 126, 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one was converted into the title compound by alkylation with 4-[5-(methylsulfonyl)oxypentyloxy]-1,3-benzenedipropanoic acid methyl ester from the preceding example, followed by saponification, in 8% overall yield. The product was a colorless solid, mp 108°-109° C., recrystallized from hexane-ethyl acetate.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12]
Reactant: O=Cc1cccc(O)c1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(Oc2nccs2)c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
In a sealed tube, combine 2-bromo-thiazole (2.0 ml, 22.2 mmol), 3-hydroxy-benzaldehyde (1.8 g, 15.0 mmol) and potassium carbonate (2.1 g, 15.0 mmol) in dimethylformamide (20 ml). Heat to 100° C. After 48 hours, cool, pour into water (150 ml), and extract with ether. Combine the organic layers and wash sequentially with distilled water and brine and then dry (Na2SO4), filter, and concentrate to give a residue. Chromatograph the residue eluting with 9:1 hexane:EtOAc to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[NH:9][CH:8]=[C:7](C(O)=O)[C:6]2=[O:17].CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[NH:9][CH:8]=[CH:7][C:6]2=[O:17]
Reactant: COc1cc2c(=O)c(C(=O)O)c[nH]c2cc1C
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: COc1cc2c(=O)cc[nH]c2cc1C
Temperature: 25 °C
Yield: 93 %

Procedure:
6-Methoxy-7-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (22 g) was suspended in diphenyl ether (200 ml), and the suspension was heated under reflux overnight. The reaction solution was cooled to room temperature, hexane was then added to the reaction solution, and the precipitated crystal was collected by filtration to give 6-methoxy-7-methyl-1H-quinolin-4-one (16.6 g, yield 93%).