Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][C@@H:7]([N:29]2[C:46]3[N:45]=[CH:44][N:43]=[C:33]([NH:34][C:35](=[O:42])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:32]=3[N:31]=[CH:30]2)[C@@H:6]1[OH:47])C=C.[CH3:48][N+]1([O-])CCOCC1.CO.C(OCC)(=O)C.[O:64]1CC[O:67][CH2:66][CH2:65]1>C(Cl)Cl>[Si:12]([O:11][CH2:10][C@H:9]1[O:8][C@@H:7]([N:29]2[C:46]3[N:45]=[CH:44][N:43]=[C:33]([NH:34][C:35](=[O:42])[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:32]=3[N:31]=[CH:30]2)[C@H:6]([O:47][CH2:48][CH:66]([OH:67])[CH2:65][OH:64])[C@@H:5]1[OH:4])([C:25]([CH3:28])([CH3:27])[CH3:26])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C1COCCO1
Reactant: C=CCO[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](OCC(O)CO)[C@@H]1O)(c1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
Compound 111 (5.5 g, 8.46 mmol), 4-methylmorpholine N-oxide (1.43 g, 12.18 mmol) were dissolved in dioxane (45.42 mL). 4% aqueous solution of OSO4 (1.99 mL, 0.31 mmol) was added. The reaction mixture was protected from light and stirred for 3 hrs. Reaction was monitored by TLC (5% MeOH in CH2Cl2). Ethyl acetate (100 mL) was added and the resulting reaction mixture was washed with water (1×50 mL). Ethyl acetate layer was dried over anhydrous Na2SO4 and evaporated to get 112 (5.9 g) and used for next step without purification. Rf 0.17 (5% MeOH in CH2Cl2)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:24])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]1[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]1)[CH2:7]2.CI.[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:24])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]1[CH2:13][CH2:14][N:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:16][CH2:17]1)[CH:7]2[CH3:27]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C1c2c(Br)cc(F)cc2CN1C1CCN(C2CCCCC2)CC1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1c2cc(F)cc(Br)c2C(=O)N1C1CCN(C2CCCCC2)CC1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 7-bromo-2-(1-cyclohexylpiperidin-4-yl)-5-fluoro-2,3-dihydro-1H-isoindol-1-one (70 mg, 0.177 mmol) and methyliodide (1.1 equiv., 0.195 mmol, 0.012 mL) in anhydrous tetrahydrofuran (3.5 mL) under nitrogen at −78° C., 1M sodium bis(trimethylsilyl)amide in tetrahydrofuran (1.2 equiv., 0.212 mL) was slowly added. The reaction mixture was stirred for 90 min and quenched by adding dropwise a 10% ammonium hydroxide solution. Dichloromethane was added, the layers were separated, and the aqueous layer was extracted twice dichloromethane. Organic layers were collected, dried and evaporated. Crude (58 mg) was used without further purification.
Reaction SMILES: [CH2:1](OS(C1C=CC(C)=CC=1)(=O)=O)[C:2]#[C:3][CH3:4].[C:16]1([C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19])[OH:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[C:1]([O:17][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[OH:19])#[C:2][CH2:3][CH3:4]
Reactant: CC#CCOS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC#COc1ccccc1O

Procedure:
A solution of 122 parts of p-toluenesulphonic acid-2-butinyl ester in 150 parts by volume of acetone is dropped into a boiling mixture of 66 parts of pyrocatechol, 75 parts of potassium carbonate, 91 parts of potassium iodide and 360 parts by volume of acetone. The suspension is refluxed for 24 hours, then cooled, filtered and evaporated. The residue is taken up in ether, repeatedly washed with water and while being cooled with ice extracted with 200 parts by volume of sodium hydroxide solution of 10 % strength. The alkaline extract is neutralised with hydrochloric acid and the product taken up with chloroform. The solvent is evaporated and the product distilled at a bath temperature of 120°C under 0.05 mm Hg pressure. The distillate crystallises; it melts at 43° to 46°C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][CH2:7][C:8]1[C:9]([NH2:15])=[N:10][CH:11]=[C:12]([Br:14])[CH:13]=1)C.[H-].[Na+]>CS(C)=O.O>[Br:14][C:12]1[CH:11]=[N:10][C:9]2[NH:15][C:4](=[O:3])[CH2:5][NH:6][CH2:7][C:8]=2[CH:13]=1
Reactant: CCOC(=O)CNCc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CNCc2cc(Br)cnc2N1
Temperature: 25 °C
Reaction time: 27 h
Yield: 72.5 %

Procedure:
A solution of [(2-amino-5-bromo-pyridin-3-ylmethyl)amino]acetic acid ethyl ester (1.79 g, 6.21 mmol) in DMSO (70 mL) was treated with NaH (60% dispersion in mineral oil, 0.25 g, 6.2 mmol). After stirring at room temperature for 27 h, the mixture was diluted with H2O (300 mL), and extracted then with EtOAc (4×150 mL). The combined organic layers were washed with H2O (3×50 mL) and brine (50 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo to give the title compound (1.09 g, 72%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 8.26 (d, J=2.1 Hz, 1H), 8.17 (s, 1H), 7.54 (d, J=1.9 Hz, 1H), 4.03 (s, 2H), 3.93 (s, 2H), 1.85 (br s, 1H); MS (ESI) m/e 242 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:24])[CH2:15][CH2:16][C@H:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C[C@@H](CCCCC)CCC(O)=O>>[CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:24])[CH2:15][CH2:16][C@@H:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC[C@@H](C)CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Agent: CCCCC[C@H](C)CCC(=O)O
Product: CCCCC[C@H](C)CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Yield: 100 %

Procedure:
A procedure similar to that used to prepare compound 155 was used except that (S)-4-methylnonanoic acid 163 (5.56 g, 32.27 mmol) was used as a reactant to give 164 as an oil (10.70 g 100%). 1H NMR (400 MHz, CDCl3) δ 7.42–7.34 (m, 3H), 7.28 (d, J=6.59 Hz, 2H), 5.64 (d, J=7.33 Hz, 1H), 4.74 (quint, J=6.78 Hz, 1H), 2.94–2.85 (m, 2H), 1.73–1.67 (m, 1H), 1.47–1.43 (m, 1H), 1.39–1.22 0.90–0.84 (m, 8H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=C(SSC2N=CC=CC=2)N=CC=1>C(Cl)Cl>[CH2:16]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: ClCCl
Product: O=C(CNC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 1.05 g. of N-benzyloxycarbonylglycine, 0.54 g. of benzylalcohol and 50 ml. of methylene chloride is added dropwise a solution of 1.31 g. of triphenyl phosphine and 1.10 g. of 2,2'-dipyridyl disulfide in 20 ml. of methylene chloride while stirring at room temperature. After completion of the addition, the mixture is stirred at room temperature for an additional 6 hours. The reaction mixture is treated with the same procedure as described above to give 1.36 g. of the desired product melting at 71° - 72°C.
Reaction SMILES: [CH:1]1([NH:11][C:12]([NH:14][NH:15]C(OC)=O)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[K+].[ClH:22]>>[ClH:22].[CH:1]1([NH:11][C:12](=[O:13])[NH:14][NH2:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)NNC(=O)NC1CCCc2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: NNC(=O)NC1CCCc2ccccc21
Reaction time: 0.5 h

Procedure:
8.13 Grams (0.031 mole) of methyl 3-[(1,2,3,4-tetrahydro-1-naphthyl)carbamoyl]carbazate is added in portions to 31 ml. of stirred 4N potassium hydroxide maintained at 75° C. to 80° C. The mixture is stirred at this temperature for 30 minutes, then cooled in an ice bath and acidified with 12N hydrochloric acid. The precipitate is filtered, washed with cold water and then 2-propanol. The dried product weighs 1.88 grams and has melting point 189° to 191° C. The filtrate is evaporated under reduced pressure and the residue boiled in ethanol and filtered hot. The filtrate is evaporated at reduced pressure. The residue is crystallized from ethanol to give an additional 1.30 grams of product, melting point 191° to 193° C. Recrystallization from water gives the analytical sample, melting point 196° to 198° C. Analysis calculated for C11H16N3OCl: C, 54.66; H, 6.67; N, 17.30. Found: C, 54.57; H, 6.69; N, 17.46.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[Br:27][C:28]1[CH2:32][O:31][C:30](=O)[CH:29]=1>C1COCC1>[Br:27][C:28]1[CH2:32][O:31][C:30](=[C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH:29]=1
Reactant: O=C1C=C(Br)CO1
Reactant: O=C1Cc2ccc(F)cc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2cc(F)ccc2C1=C1C=C(Br)CO1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. stirred solution of 6-fluorooxindole (370 mg, 2.45 mmol) in anhydrous THF (10 mL) was added 1M LiHMDS/THF solution (4.9 mL, 4.9 mmol). The mixture was stirred at 0° C. for 10 minutes. 4-Bromo-5H-furan-2-one (200 mg, 1.23) was added as a solution in 2 mL of THF. The resulting mixture was stirred at 0° C. for 30 minutes, then at room temperature for 1 hour and quenched with 10 mL of 2M HCl. Methanol (5 mL) was added and the mixture was stirred at 50° C. for 0.5 hour. The mixture was poured into 150 mL of water and then stirred for 30 minutes. The precipitates were filtered, washed with water, and dried in vacuum to give 3-(4-bromo-5H-furan-2-ylidene)-6-fluoro-1,3-dihydro-indol-2-one as a yellow solid. Yield: 228 mg, 63%.
Reaction SMILES: [N:1]1[N:5]2[C:6]3[C:11]([N:12]=[CH:13][C:4]2=[N:3][N:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C.[H][H]>C(O)C>[N:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C:4]2=[N:3][N:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: c1ccc2c(c1)ncc1nnnn12
Reactant: [H][H]
Solvent: CCO
Product: c1ccc2c(c1)NCc1nnnn1-2
Reaction time: 2 h
Yield: 45 %

Procedure:
A 1 g. portion of tetrazolo[1,5-a]quinoxaline was dissolved in 200 ml. of ethanol. The solution was placed in a Parr hydrogenator on a shaking apparatus and 100 mg. of 5 percent palladized charcoal was added. The bomb was pressurized to about 2 atmospheres with hydrogen and was shaken for 2 hours. The reaction mixture was then removed and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from ethanol-water to obtain the product, 4,5-dihydrotetrazolo[1,5-a]quinoxaline, m.p. 149°-51°C., in 45 percent yield. The product was identified by nuclear magnetic resonance analysis and by elemental microanalysis, with the following results.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].F[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2c(F)cccc2F)cc1
Temperature: 25 °C

Procedure:
A slurry of 2,6-difluorophenol (1.0 g, 8 mmol), potassium carbonate (3.29 g, 24.2 mmol) and 4-fluoro benzaldehyde (1.36 g 10.4 mmol) in dry DMF (50 mL) was stirred at 100° C. overnight under nitrogen atmosphere. After the reaction is completed it was cooled to room temperature and poured in to ice cold water. The mixture was extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with water (50 mL×2), brine, then dried over anhydrous sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 3% ethyl acetate in hexane to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.C1C=CC=CC=1.[CH3:24][CH:25]([N:27]1[C:31]([NH2:32])=[CH:30][CH:29]=[N:28]1)[CH3:26]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:30]3[CH:29]=[N:28][N:27]([CH:25]([CH3:26])[CH3:24])[C:31]=3[N:32]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(Br)cc1
Reactant: CC(C)n1nccc1N
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccc(Br)cc2)nc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 61 using ethyl 4-(4-bromophenyl)-2,4-dioxobutanoate (956 mg, 3.20 mmol), benzene (10 mL), 1-(1-methylethyl)-1H-pyrazol-5-amine (400 mg, 3.20 mmol), and acetic acid (4 mL). The crude product was purified using column chromatography (Silica gel, eluent: 0 to 100% EtOAc/hexanes) to give 1.1 g (89%) of product. LCMS E-S (M+H)=388.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49-1.57 (t, J=67.2 Hz, 3H), 1.63-1.74 (d, J=6.8 Hz 6H), 4.56 (q, J=7.2 Hz, 2H), 5.46 (spt, J=6.7 Hz, 1H), 7.65-7.71 (m, 2H), 8.04-8.15 (m, 2H), 8.21 (s, 1H), 8.42 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7](=[O:19])[CH2:6]1)[CH2:3][CH3:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:30](OCC)(=[O:36])[C:31](OCC)=[O:32]>C1COCC1>[CH2:3]([CH:2]1[NH:1][C:31](=[O:32])[C:30]([OH:36])=[C:6]2[CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:7]2=[O:19])[CH3:4]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(N)C1CCN(Cc2ccc(F)cc2)C(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1NC(=O)C(O)=C2C(=O)N(Cc3ccc(F)cc3)CCC21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a cooled (−78° C.) solution of 4-(1-aminopropyl)-1-(4-fluorobenzyl)piperidin-2-one (2.0 g, 8 mmol) in anhydrous THF (20 mL) was added LiHMDS (1M in THF, 18.9 mL, 18.9 mmol) under an atmosphere of nitrogen. After stirring at −78° C. for 5 min, diethyl oxalate (3.32 g, 22.7 mmol) was added to the reaction mixture. After stirring for 2 hours at −78° C., then for 0.5 hour at −20° C., LiHMDS (1M in THF, 22 mL, 22 mmol) was added. After stirring at room temperature for 24 hours, the reaction mixture was quenched with 1N HCl. The mixture was partitioned between EtOAc and water. The organic extract was dried with Na2SO4, filtered, concentrated under vacuum, then filtered through a plug of silica gel and eluting with 1% methanol in CH2Cl2. The diastereomers were separated using reverse phase HPLC on a C18 stationary phase eluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to afford the title compounds. Diastereomer 1, the hydrogens at positions 4a and 5 have a cis relationship to one another: 1H NMR (400 MHz, CDCl3) δ 13.67 (br, 1H), 7.26 (m, 2H), 7.04 (t, J=8.6 Hz, 2H), 4.68 (d, J=14.7 Hz, 1H), 4.52 (d, J=14.7 Hz, 1H), 3.35 (m, 4H), 1.79 (m, 3H), 1.48 (m, 1H), 0.97 (t, J=7.3 Hz, 3H) ppm. ES MS M+1=319. Diastereomer 2, the hydrogens at positions 4a and 5 have a trans relationship to one another: 1H NMR (400 MHz, CDCl3) δ 7.26 (m, 2H), 7.04 (t, J=8.6 Hz, 2H), 6.54 (br, 1H), 4.72 (d, J=14.7 Hz, 1H), 4.49 (d, J=14.7 Hz, 1H), 3.34 (m, 3H), 2.73 (dt, J=4, 13 Hz, 1H), 1.99 (m, 1H), 1.78 (m, 1H), 1.57 (m, 2H), 1.01 (t, J=7.5 Hz, 3H) ppm. ES MS M+1=319.
Reaction SMILES: [CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](OS(C(F)(F)F)(=O)=O)=[N:7][C:6]3[C:23]([CH3:27])=[CH:24][CH:25]=[N:26][C:5]2=3)[CH2:3][CH2:2]1.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>O1CCOCC1>[CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8]([N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)=[N:7][C:6]3[C:23]([CH3:27])=[CH:24][CH:25]=[N:26][C:5]2=3)[CH2:3][CH2:2]1
Reactant: Cc1ccnc2c1N=C(OS(=O)(=O)C(F)(F)F)c1cccnc1N2C1CC1
Reactant: c1c[nH]cn1
Solvent: C1COCCO1
Product: Cc1ccnc2c1N=C(n1ccnc1)c1cccnc1N2C1CC1
Temperature: 100 °C
Yield: 40 %

Procedure:
To a solution of 11-cyclopropyl-4-methyl-6-trifluoromethanesulfonyloxy-11H-dipyrido[3,2-b:2',3'-e][1,4]diazepine (0.12 g, 0.3 mmol) in dioxan (1 mL) was added imidazole (0.06 g, 0.88 mmol). The mixture was heated at 100° C. for 10 min. After cooling to room temperature, the reaction mixture was diluted with ethyl adetate, washed with water, dried over sodium sulfate, filtered and concentrated. The residue was fractionated by preparative layer chromatography (silica gel, eluted with 67% ethyl acetate/hexane) to give the title compound (0.04 g, 0.12 mmol, 42%) which crystallized from di-isopropyl ether, m.p. 198°-200° C.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14]CC)=[O:13])[CH:9]=[C:8]([O:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:6]=2[CH:7]=1)[CH3:2].[OH-].[K+]>CO.O>[CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[C:8]([O:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:6]=2[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CC)oc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)O)cc2o1
Yield: 92.5 %

Procedure:
A mixture of ethyl 2-ethyl-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylate (0.80 g, 2.1 mmol) and KOH (0.35 g, 6.3 mmol) in MeOH (40 mL) and water (4 mL) was heated to reflux overnight. The reaction was monitored by TLC (petroleum ether/EtOAc 4:1). The reaction mixture was concentrated to dryness and poured into water (50 mL). The aqueous layer was acidified to pH˜2 with concentrated HCl (4 mL) and extracted with EtOAc (50 mL×3). The organic layer was washed with brine (50 mL×2), dried over Na2SO4 and concentrated to afford the desired compound (0.70 g, 94%) as an off-white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]=[C:10]3[CH:27]=[C:26](/[CH:28]=[CH:29]/[C:30]4[S:31][CH:32]=[C:33]([CH:35]([CH3:37])[CH3:36])[N:34]=4)[CH:25]=[CH:24][N:11]3[C:12](=[O:23])[C:13]=2/[CH:14]=[CH:15]/[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.ClC(Cl)(Cl)[C:40]([N:42]=C=O)=[O:41].C([O-])=O.[Na+].C(Cl)(Cl)Cl>C(OCC)(=O)C.O>[NH2:42][C:40]([O:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]=[C:10]3[CH:27]=[C:26](/[CH:28]=[CH:29]/[C:30]4[S:31][CH:32]=[C:33]([CH:35]([CH3:37])[CH3:36])[N:34]=4)[CH:25]=[CH:24][N:11]3[C:12](=[O:23])[C:13]=2/[CH:14]=[CH:15]/[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:3]1)=[O:41]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCCC(O)C4)nc3c2)n1
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCCC(OC(N)=O)C4)nc3c2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
tert-Butyl (E)-3-{2-(3-hydroxypiperidino)-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (138 mg, 0.264 mmol) was dissolved in ethyl acetate (2.6 ml), added with trichloroacetyl isocyanate (62.6 μl, 0.528 mmol) under ice cooling, and then the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated, dissolved in methanol (5.0 ml) and water (0.5 ml), and then added with sodium formate (71.8 mg, 1.06 mmol), and stirred overnight at room temperature. The reaction mixture was further added with chloroform (3.0 ml) and sodium formate (71.8 mg, 1.06 mmol) and stirred overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0→100:1→100:2, v/v) to obtain the title compound (150 mg, 100%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37]Br)=[CH:26][C:25]=2[O:24]1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:37][CH2:36][CH2:35][CH2:34][O:33][CH2:32][C:27]3[CH:28]=[CH:29][C:30]4[O:31][CH2:23][O:24][C:25]=4[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: BrCCCCOCc1ccc2c(c1)OCO2
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCOCc2ccc3c(c2)OCO3)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 4-((3,4-methylenedioxyphenyl)methoxy)butyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(4-((3,4-methylenedioxyphenyl)methoxy)butyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[CH:15]=[C:16]([C:31]([OH:33])=O)[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH:5]=[C:6]([F:8])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[CH:15]=[C:16]([C:31]([N:47]3[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]3)=[O:33])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc([C@H]2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(C(=O)c2cc([C@H]3CCCN3c3cc(F)cc(F)c3)c3oc(N4CCOCC4)cc(=O)c3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-morpholino-4-oxo-chromene-6-carboxylic acid (see Example 1.03b for preparation, 97 mg, 0.21 mmol), DIPEA (0.185 mL, 1.06 mmol) and 1-methylpiperazine (0.047 mL, 0.43 mmol) were mixed at room temperature in DCM (3 mL). N-propylphosphonic acid anhydride, cyclic trimer (50 wt % solution in EtAc) (0.633 mL, 1.08 mmol) was then added and the reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was purified by preparative HPLC to afford 8-[(2R)-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)]-6-(4-methylpiperazine-1-carbonyl)-2-morpholino-4H-chromen-4-one (67 mg, 59%) as a white foam.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.C(N(CC)CC)C.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1.O>ClCCl>[C:27]1([C:18]2[CH:19]=[CH:20][C:21]([C:24]([N:8]3[CH2:9][CH2:10][C:5]4[CH:4]=[CH:3][O:2][C:6]=4[CH2:7]3)=[O:25])=[CH:22][CH:23]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1cc2c(o1)CNCC2
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.26 g (1.2 mmol) of 4-biphenylcarbonyl chloride was added under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to yield the desired product.