Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22](N(OC)C)=[O:23])[CH:17]=[N:18][CH:19]=1>>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22](=[O:23])[C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1])[CH:17]=[N:18][CH:19]=1
Reactant: FC(F)(F)C(F)(F)I
Reactant: CON(C)C(=O)C=Cc1cncc(Br)c1
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: O=C(C=Cc1cncc(Br)c1)C(F)(F)C(F)(F)F
Reaction time: 0.33 h
Yield: 29 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (108.0 mL, 91.0 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (61.0 mL, 91.0 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then a solution of 3-(5-bromo-pyridin-3-yl)-N-methoxy-N-methyl-acrylamide (8.2 g, 30.3 mmol, in diethyl ether/tetrahydrofuran 50.0 mL/150.0 mL) prepared in Step 2 was slowly added thereto at −78° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with distilled water, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 2.9 g of the titled compound as a yellow solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.S=[C:17]1[CH2:21][S:20][C:19](=[O:22])[NH:18]1>C(O)C>[O:22]=[C:19]1[N:18]=[C:17]([NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:21][S:20]1
Reactant: O=C1NC(=S)CS1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
To a solution of ethyl glycinate hydrochloride (5.00 g) and triethylamine (4.99 mL) in ethanol (60 mL) was added 4-thioxo-1,3-thiazolidin-2-one (3.98 g), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.84 g).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=[O:14].C(N(CC)CC)C.[CH:22]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[O:9]=[C:8]1[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3](=[O:14])[CH:2]1[NH:1][C:27]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:28]
Reactant: O=C(Cl)C1CCCC1
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1C(=O)Nc2ccccc2NC1=O)C1CCCC1
Reaction time: 8 h
Yield: 87 %

Procedure:
Combine 3-amino-1H-1,5-benzodiazepine-2,4-(3H, 5H)-dione (7.0 g, 36.6 mmol) and triethyl amine (4.07 g, 40.3 mmol) in 120 mL DMF and add dropwise cyclopentanecarbonyl chloride (5.34 g, 40.3 mmol) at RT. After stirring overnight, remove DMF under reduced pressure, suspend the residue in a mixed solvent (CHCl3/i-PrOH=3/1, 400 mL). Collect an off-white solid via suction filtration to give the title compound. Wash the filtrate with NaHCO3 (sat.2×100 mL) and dry with Na2SO4. Concentrate the the solvent to give second crop of title compound, total 9.13 g, yield 87%: 1H NMR (300 MHz, DMSO-d6): 10.70 (s, 2H), 8.11 (d, 1H, J=7.8 Hz), 7.24–7.15 (m, 4H), 4.73 (d, 1H, J=7.5 Hz), 2.96–2.87 (m, 1H), 1.74–1.45 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:21])[NH:13][CH:14]=[CH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][C:30]([N:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[Cl:41])[CH3:33])=[O:31]>CN(C)C=O>[Cl:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][N:32]([CH3:33])[C:30](=[O:31])[CH2:29][N:13]1[CH:14]=[CH:15][C:16]([C:17]([F:18])([F:19])[F:20])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:12]1=[O:21]
Reactant: CN(Cc1ccccc1Cl)C(=O)CCl
Reactant: N#Cc1cc(Cl)cc(Oc2c(C(F)(F)F)cc[nH]c2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1Cl)C(=O)Cn1ccc(C(F)(F)F)c(Oc2cc(Cl)cc(C#N)c2)c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a flask charged with 3-chloro-5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}benzonitrile (3C, 0.020 g, 0.064 mmol) and potassium carbonate (0.0088 g, 0.064 mmol) was added 2-chloro-N-(2-chlorobenzyl)-N-methylacetamide in dimethylformamide (0.75 mL). The reaction mixture was allowed to stir at room temperature. After 1.5 hours, the reaction mixture was filtered and the filtrate was purified by preparative HPLC Phenomenex Luna C18 100A 10μ, eluting with 30-95% MeCN/H2O+0.1% TFA. and lyophilized to yield the title compound. 1H NMR (DMSO-d6) δ 7.90-7.84 (m, 1H), 7.76-7.74 (m, 1H), 7.54-7.43 (m, 3H), 7.42-7.32 (m, 1H), 7.31-7.26 (m, 2H), 7.23-7.19 (m, 1H), 6.68-6.62 (m, 1H), 5.09 (s, 1.35H), 4.80 (s, 0.65H), 4.72 (s, 0.65H), 4.59 (s, 1.35H), 3.06 (s, 2H), 2.82 (s, 1H). HRMS (M+1)=510.0591.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[NH:13][C:12]1([CH3:20])[CH3:19].C(O[Cl:26])(C)(C)C>CO>[Cl:26][N:13]1[C:14]([CH3:18])([CH3:17])[C:15](=[O:16])[N:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]1([CH3:20])[CH3:19]
Reactant: COCCOCCOCCN1C(=O)C(C)(C)NC1(C)C
Reactant: CC(C)(C)OCl
Solvent: CO
Product: COCCOCCOCCN1C(=O)C(C)(C)N(Cl)C1(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
To a 0° C. solution of 3-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2,2,5,5-tetramethylimidazolidin-4-one (15.03 g, 52.1 mmol) in methanol (150 ml) was added tert-butylhypochlorite (8.50 g of 0.91 g/mL, 78.3 mmol), over a 10 minute period. The mixture was stirred for 1 hour at 0° C. The reaction mixture was checked for completion by high pressure liquid chromatography. The reaction mixture was concentrated in vacuo, and crude material was purified by silica gel flash chromatography (0 to 10% methanol in dichloromethane) to give 15.43 g (92%) of the title compound. 1H NMR (D2O, 400 MHz) δ 3.74-3.65 (m, 8H), 3.62-3.60 (m, 2H), 3.55 (t, J=6 Hz, 2H), 3.37 (s, 3H), 1.53 (s, 6H), 1.36 (s, 6H). 13C NMR (D2O, 100 MHz) δ 175.00, 83.68, 70.98, 69.59 (2 peaks), 69.39, 67.65, 66.02, 57.99, 40.16, 24.07, 22.52. LRMS (ESI/APCI) m/z 323 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12]C)[CH:6]=2>C(Cl)(Cl)Cl.CO>[OH:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([CH3:1])[C:3]([C:26]3[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=3)=[C:4]2[O:14][C:15]2[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:19][CH:20]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(-c2c(C)cc3ccc(OC)cc3c2Oc2ccc(/C=C/C(=O)O)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cc2ccc(O)cc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccc(O)cc1

Procedure:
Synthesized in a manner similar to Example 46 (Step 8) using (2E)-3-[4-({3-methyl-7-(methyloxy)-2-[4-(methyloxy)phenyl]-1-naphthalenyl}oxy)phenyl]-2-propenoic acid (266). 1H NMR (CD3OD, 400 MHz) δ 7.71 (d, J=8.6 Hz, 1H), 7.58 (s, 1H), 7.49 (d, J=15.5 Hz, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.04 (dd, J=8.7, 2.0 Hz, 1H), 7.00 (s, 1H), 6.94 (d, J=8.5 Hz, 2H), 6.68 (d, J=8.4 Hz, 2H), 6.58 (d, J=8.4 Hz, 2H), 6.27 (d, J=15.2 Hz, 1H), 2.19 (s, 3H). TLC (90:10; CHCl3/MeOH): Rf=0.19.
Reaction SMILES: Br[C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1.[Cu](C#N)[C:36]#[N:37].CN1CCCC1=O>O>[C:36]([C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1)#[N:37]
Reactant: N#C[Cu]C#N
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1C#N
Temperature: 160 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
A mixture of 0.23 g of 3-{2-bromo-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [present compound 9-7], 75 mg of copper cyanide and 2 ml of N-methyl-2-pyrrolidone was stirred at 160° C. for 2 hours. There action mixture was cooled to room temperature, water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.16 g of 3-{2-cyano-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [present compound 9-27].
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[I:13][CH2:14][C:15](O)=[O:16].C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O>[I:13][CH2:14][C:15]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(O)CI
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(CI)ON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.6 %

Procedure:
N-Hydroxyphthalimide (1.4 g, 8.7 mmol), iodoacetic acid (1.6 g, 8.7 mmol) and DCC (1.7 g, 8.7 mmol) were added to dry EtOAc (250 mL), and the mixture was stirred for 5 hours at room temperature. The reaction mixture was then filtered, the filtrate was dried, and the residue was crystallized from ethanol to give a white solid (2.15 g, 75%), m.p. 120° C.
Reaction SMILES: Br[CH:2]=[CH:3]Br.[Li]CCCC.[CH3:10][O:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:28]([CH2:29][CH2:30][C@:13]12[CH3:14])[C@:26]1([CH3:27])[C@@H:21]([CH2:22][C:23](=[O:31])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3>C1COCC1.C(Cl)Cl>[C:2]([C@@:23]1([OH:31])[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:21]([CH2:20][CH2:19][C@@H:18]3[C@@H:28]2[CH2:29][CH2:30][C@@:13]2([CH3:14])[C@H:15]3[CH2:16][CH2:17][C@@H:12]2[O:11][CH3:10])[CH2:22]1)#[CH:3]
Reactant: BrC=CBr
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#C[C@@]1(O)CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC)CC[C@@H]32)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
A solution of 1,2-dibromoethylene (1.6 mL, 3.7 g, 19.71 mmol) in dry THF (10 mL) was treated with n-BuLi (16.4 mL, 2.4M in THF, 39.4 mmol) at −75° C. After stirring the mixture at −78° C. for 0.25 hr, a solution of 17β-methoxy-5β-androstan-3-one (2 g, 6.57 mmol) in THF (20 mL) was added and the mixture was stirred at −78° C. for 15 min. The cooling bath was then removed and the mixture was quenched with NH4Cl solution (3 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (95:5) gave 3β-ethynyl-3α-hydroxy-17β-methoxy-5β-androstane (1.70 g) as a colorless solid; mp 62-65° C.; TLC Rf (toluene:acetone 95:5)=0.23.
Reaction SMILES: O[CH:2]([C:18]1[N:19]=[CH:20][N:21](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:22]=1[CH3:23])[CH:3]1[C:16](=[O:17])[N:7]2[C:8]3[C:13]([C:14]([CH3:15])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C([O-])=O.[NH4+]>C(O)(=O)C.[Pd]>[CH3:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]2[C:16](=[O:17])[CH:3]([CH2:2][C:18]3[N:19]=[CH:20][NH:21][C:22]=3[CH3:23])[CH2:4][CH2:5][C:6]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)C(C(O)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1[nH]cnc1CC1CCc2c(C)c3ccccc3n2C1=O
Yield: 76.4 %

Procedure:
To a solution of 8,9-dihydro-7-[(hydroxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (4.6 g) in acetic acid (92 ml) were added 10% palladium on carbon (2.3 g) and ammonium formate (7.89 g), and the mixture was refluxed gently for 3 hours. After being cooled, the catalyst was filtered off. The filtrate was evaporated, and diluted with water (50 ml) and diisopropyl ether (50 ml). Aqueous sodium hydroxide was added to neutralized the solution. Resulted precipitates were collected, and washed with water and diisopropyl ether successively, to give 8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (1.87 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[N:19](Cl)[S:18][NH:17][CH:16]=1>CN(C)C=O.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:16]2[C:15]([Cl:14])=[N:19][S:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClC1=CNSN1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2nsnc2Cl)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Piperazine-1-carboxylic acid tert-butyl ester (10 g, 0.054 m) was dissolved in anhydrous dimethylformamide (DMF, 50 mL) under nitrogen in a single-necked round bottomed flask. The clear solution was placed in a preheated oil bath (50 C-60 C). 4,5-Dichloro-[1,2,5]thiadiazole (5.0 mL, 0.054 m) was added and the reaction mixture was allowed to stir for 24 h. A yellow solution containing a white solid was observed. After cooling to room temperature, the mixture was diluted with an equal volume of anhydrous ethyl ether and stirred for 5 minutes. The solid was removed by filtration and the yellow filtrate was concentrated under aspirator vacuum to remove ether and then evaporated under oil pump vacuum to remove DMF. The yellow residue was dried at oil pump vacuum overnight to give 9.91 g of 4-(4-chloro-[1,2,5]thiadiazol-3-yl)piperazine-1-carboxylic acid tert-butyl ester. Two recrystallizations of crude product from hexane gave white crystals: mp 83-86° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32].O.[NH2:35][NH2:36].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][C:23]1[C:3]2[C:4](=[O:22])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:36][N:35]=1
Reactant: COc1ccccc1CC(=O)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1Cc1n[nH]c2c1c(=O)n(-c1cccc(C(F)(F)F)c1)c1ncccc21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-methoxyphenylacetyl)-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (493 mg, 1.1 mmol) produced in Synthesis Example 33 in DMF (4.5 mL) was added hydrazine monohydrate (purity of 80%, 175 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-methoxybenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (418 mg, yield 86%).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[F:6][C:7]1[CH:8]=[C:9]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH:21]=3)[C:16](O)=[N:15][C:14]=2[C:30]#[N:31])[CH:10]=[CH:11][CH:12]=1.C([O-])(O)=O.[Na+]>O>[Cl:3][C:16]1[C:17]2[C:22](=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[CH:8]=2)=[C:14]([C:30]#[N:31])[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1nc(O)c2ccc(-c3ccccn3)cc2c1-c1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N#Cc1nc(Cl)c2ccc(-c3ccccn3)cc2c1-c1cccc(F)c1
Temperature: 90 °C

Procedure:
POCl3 (22 mg, 0.15 mmol) was added to 4-(3-fluorophenyl)-1-hydroxy-6-pyridin-2-ylisoquinoline-3-carbonitrile (50 mg, 0.15 mmol) neat. The resulting mixture was heated to 90° C. for 18 h. The reaction was cooled to room temperature and diluted with H2O (10 mL). This was brought to a pH of 9 with NaHCO3. The aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a brown oil.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[CH2:13][C:14](=[O:26])[CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Cl>C1COCC1>[CH:3]1([CH2:9][CH2:10][O:11][CH2:13][C:14](=[O:26])[CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OCCC1CCCCC1
Reactant: O=C(CCl)CC(=O)OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(COCCC1CCCCC1)CC(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
0.68 g (17.0 mmol) of sodium hydride (60% oily) was suspended in 7 ml of THF. 1.36 g (10.6 mmol) of 2-cyclohexylethanol was added to the obtained suspension at 0° C., and they were stirred at 40° C. for 30 minutes. 2.00 g (8.82 mmol) of benzyl 4-chloroacetoacetate was added to the obtained mixture at room temperature, and they were refluxed at 100° C. for 3 hours. 1 N hydrochloric acid was added to the reaction mixture. After the extraction with ethyl acetate, the organic layer was washed with 10% aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=4/1) to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[NH:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:11][N:8]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[C:7]1[C:9]#[N:10]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc([N+](=O)[O-])[nH]1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1c(C#N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
To a solution of 300 mg of 5-nitropyrrole-2carbonitrile (2.14 mol) in 15 mL of acetone, 360 mg of potassium carbonate (2.6 mmol) and 0.65 mL of iodomethane (1.6 mmol, 372 mg) are added. The mixture is then stirred at room temperature for 24 hours. The reaction mixture is poured into ice-water (100 mL) and the precipitate which forms is collected to yield (200 mg), 62% mp 86°-87° C. of 1-methyl-5-nitropyrrole-2-carbonitrile.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:33]=[CH:34][CH:35]=1>CS(C)=O.C(=O)(O)[O-].[Na+]>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([N:36]2[CH2:41][CH2:40][N:39]([CH2:12][C@@H:13]3[O:27][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]5)[CH2:38][CH2:37]2)[CH:33]=[CH:34][CH:35]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: COc1cccc(N2CCNCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(N2CCN(C[C@H]3COc4ccc5nc(C)ccc5c4O3)CC2)c1
Temperature: 65 °C
Yield: 88.5 %

Procedure:
A mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (702 mg, 1.56 mmol) and 3-methoxyphenyl piperazine (890 mg, 4.63 mmol) in anhydrous DMSO (10 mL) were heated at 65° C. overnight. The cooled reaction mixture was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography on silica gel (50% EtOAc/hexanes) afforded 560 mg (88%) of the desired product as a white solid: mp 90–91° C.; MS (ESI) m/z 406 [M+H]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:11][CH2:12][OH:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:13][CH2:12][CH2:11][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: OCCBr
Reactant: c1ccc2c(c1)CNC2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: OCCN1Cc2ccccc2C1
Yield: 62.7 %

Procedure:
A solution of 2.85 g (0.0252 mol) of isoindoline, 2.99 g (0.0252 mol) of 2-bromoethanol and 5.09 g (0.05 mol) of triethylamine in 100 ml of dry toluene was refluxed for 12 hours. After cooling the mixture was filtered, concentrated in vacuo, dissolved in ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate and concentrated in vacuo to yield 2.58 g (63%) of a dark red oil. NMR (CDCl3) δ 2.78 (2H, t), 3.52 (2H, t), 3.82 (4H, s), 7.0 (4H, s)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][C:10]1([CH3:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13][CH2:12][CH2:11]1.Cl>C(=S)=S>[C:5]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[O:13][CH2:12][CH2:11][C:10]2([CH3:20])[CH3:9])(=[O:7])[CH3:6]
Reactant: CC1(C)CCOc2ccccc21
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCO2
Temperature: 0 °C
Reaction time: 4 h
Yield: 319.8 %

Procedure:
To a mixture of 16.3 g (122 mmol) of aluminum chloride, 11.77 g (10.7 mmol) of acetyl chloride and 110 ml of carbon disulfide was added, slowly, with stirring, 18.0 g (111 mmol) of 4,4-dimethylchroman, at 0 to 5° C. After the addition was complete, stirring was continued for 4 hours at 0° C. The mixture was then poured onto 200 ml of 6N hydrochloric acid and 200 g of ice. The resulting mixture was extracted with 500 ml of diethyl ether. The ether extract was dried (MgSO4) and evaporated in vacuo to give an oil, which was fractionally distilled, under reduced pressure, to give 6.99 g (31% yield) of the title compound, bp 110°-113° C. (0.03 mm Hg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([CH:31]([CH3:33])[CH3:32])[N:8]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22]C(=O)C)[CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[C:1]([O:5][C:6](=[O:34])[C@@H:7]([CH:31]([CH3:33])[CH3:32])[N:8]([CH2:26][CH2:27][CH:28]([CH3:29])[CH3:30])[S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)Oc1ccc2cc(S(=O)(=O)N(CCC(C)C)[C@@H](C(=O)OC(C)(C)C)C(C)C)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)CCN([C@@H](C(=O)OC(C)(C)C)C(C)C)S(=O)(=O)c1ccc2cc(O)ccc2c1
Yield: 84.3 %

Procedure:
To a solution of N-isoamyl-N-(6-acetoxy naphthalene-2-sulfonyl)-D-valine tert-butyl ester (0.75 g, 1.53 mmol) in ethanol-water (35 mL-15 mL) is added potassium carbonate (0.422 g, 3.05 mmol), and the reaction is heated to reflux for 16 h. The solvents are removed in vacuo, and the residue is redissolved in water and extracted three times with dichloromethane. The combined organic extracts are washed with sodium bicarbonate and brine, dried over sodium sulfate, and concentrated in vacuo. The crude product is purified by column chromatography (10% hexanes-ethyl acetate) to afford the title compound as a yellow oil (0.58 g, 85% yield).