Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH3:7])=[O:3].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O-:10])=[O:9].C(N(CC)CC)C.O>C1COCC1>[CH2:5]([O:4][C:2]([O:17][C:14]1[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=1)=[O:3])[CH2:6][CH3:7]
Reactant: CCCOC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
A solution of propyl chloroformate (613 mg) in THF (3 ml) was added to a solution of 4-nitrophenol (693 mg) and triethylamine (0.836 ml) in THF (10 ml) at 0° C. After stirred at room temperature for 30 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous sodium carbonate solution, an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried, and concentrated to obtain the title compound (1.11 g) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[S-2].[Na+].[Na+].Cl[CH2:14][CH2:15][CH3:16].O[O:18][S:19]([O-])=[O:20].[K+]>CN(C)C=O>[CH2:14]([S:19]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)(=[O:20])=[O:18])[CH2:15][CH3:16]
Reactant: CCCCl
Reactant: O=S([O-])OO
Reactant: N#Cc1ccc(Cl)cc1
Agent: [K+]
Agent: [Na+]
Agent: [S-2]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)c1ccc(C#N)cc1
Temperature: 130 °C
Reaction time: 12 h

Procedure:
To 4-chlorobenzonitrile (5 g) in dry N,N-dimethylformamide (50 mL), under nitrogen, was added sodium sulphide (3.11 g), and the stirred mixture heated in an oil bath at 130° C. for 48 h. The mixture was cooled to room temperature, 1-chloropropane (4.0 mL) added and stirring continued for 12 h. The mixture was cooled in an ice-water bath and “OXONE” (34 g) added with stirring. The water bath was removed after 2 h, and the mixture stirred at room temperature for 14 h. The reaction mixture was then diluted with an equal volume of ethyl acetate, solids removed by filtration, and solvent stripped at reduced pressure. The residue was chromatographed on silica gel, eluent 15 to 30% ethyl acetate in isohexane, and the title compound crystallised from isohexane as a white solid. 1H NMR (360 MHz, CDCl3) δ 8.05 (2H, d, J=8.1 Hz), 7.88 (2H, d, J=8.3 Hz), 3.10 (2H, m), 1.76 (2H, m), 1.02 (3H, t, J=7.4 Hz).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](O)[CH2:9][C@H:8]1[CH2:13][CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:51]([OH:59])(=[S:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:58][C:51](=[O:59])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:9][C@H:8]1[CH2:13][CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CCn1cncn1
Reactant: OC(=S)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@@H](SC(=O)c2ccccc2)C[C@H]1CCn1cncn1

Procedure:
(2R,4R)-1-Allyloxycarbonyl-4-hydroxy-2-[2-(1,2, 4-triazol-1-yl)ethyl]pyrrolidine (5.82 g) was reacted with triphenylphosphine (8.62 g), diethyl azodicarboxylate (5.17 ml) and thiobenzoic acid (4.64 ml) in tetrahydrofuran (58 ml) in the same manner as Preparation 3-6) to give (2R,4S)-1-allyloxycarbonyl-4-benzoylthio-2-[2-(1,2, 4-triazol-1-yl)ethyl]pyrrolidine (7.92 g) as a yellow paste.
Reaction SMILES: N.[CH:2]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[CH:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])([CH3:4])[CH3:3].[Li].C(O)C>O1CCCC1.O>[CH:2]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH2:15][CH:16]=[C:17]([O:22][CH3:23])[CH2:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])([CH3:4])[CH3:3]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C(C)C)[C@@H](O)CC[C@@H]12
Agent: N
Agent: [Li]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C(C)C)[C@@H](O)CC[C@@H]32)C1
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
Add liquid ammonia (100 cc.) to 13β-isopropyl-3-methoxy-gona-1,3,5(10)-trien-17β-ol (0.5 g.) in tetrahydrofuran (50 cc.) followed by lithium metal (0.5 g.), and stir the solution for 10 minutes. Then add ethanol (6 cc.) dropwise. When the blue color is discharged, add water and extract the product with ether. Evaporate the washed and dried extracts to give crude 13β-isopropyl-3-methoxy-gona-2,5(10)-dien-17β-ol (0.5 g.) as colorless gum.
Reaction SMILES: CI.[CH3:3][O:4][C:5]([C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[C:9]([OH:16])[CH:8]=1)=[O:6].[C:17](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:3][O:4][C:5]([C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[C:9]([O:16][CH3:17])[CH:8]=1)=[O:6]
Reactant: COC(=O)c1cc(O)c2cc[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(OC)c2cc[nH]c2c1
Yield: 49 %

Procedure:
Methyl iodide (0.72 mL, 11.5 mmol, 1.1 equiv.) was added dropwise, over 10 minutes, to a stirred solution of 4-hydroxy-1H-indole-6-carboxylic acid methyl ester (2 g, 10.5 mmol, 1 equiv.) and potassium carbonate (1.3 g, 15.7 mmol, 1.5 equiv.) in acetone (20 mL) at room temperature and the mixture was heated at reflux for 16 hours. The solvent was removed under vacuum, the residue dissolved in ethyl acetate (20 mL) and washed with saturated aqueous solution of NaHCO3 (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and the solvent removed under vacuum to afford 4-methoxy-1H-indole-6-carboxylic acid methyl ester, 1.1 g (49% yield). LC @215 nm; Rt 1.23: 91%, m/z (ES+): 206 (M+H+.); δH (400 MHz; MeOD) 7.74 (1H, s), 7.15 (1H, m), 7.03 (1H, d), 6.46 (1H, m), 3.86 (3H, s), 3.80 (3H, s).
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]2[S:12][C:13](C([O-])=O)=[CH:14][C:7]=12>CN(C=O)C.C(OCC)(=O)C.C(=O)([O-])[O-].[Ag+2]>[Br:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]2[S:12][CH:13]=[CH:14][C:7]=12
Reactant: O=C([O-])c1cc2c(Br)cncc2s1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Brc1cncc2sccc12
Temperature: 120 °C
Reaction time: 24 h

Procedure:
Silver carbonate (28 mg) and acetic acid (0.006 ml) were added to a solution of 4-bromothieno[2,3-c]pyridine-2-carboxylate obtained in the above-described Step 1 (258 mg) in DMF (2.0 ml), and the reaction solution was stirred at 120° C. for 24 hours. The reaction solution was diluted with ethyl acetate and washed successively with an aqueous sodium bicarbonate solution and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane-ethyl acetate) to obtain 4-bromothieno[2,3-c]pyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([Si](C)(C)C)[O:8][CH:7]=1)=[O:5])[CH3:2].S(Cl)([Cl:18])(=O)=O>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([Cl:18])[O:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)c1coc([Si](C)(C)C)c1
Solvent: CC#N
Product: CCOC(=O)c1coc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
5-Trimethylsilyl-3-furancarboxylic acid (4.1 g) (synthesized in accordance with the method described in Tetrahedron Lett., 25, 4451 (1984)) was dissolved in tetrahydrofuran (100 ml), and N,N-dimethylformamide (3 drops) was added. Oxalyl chloride (3.0 g) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Ethanol (100 ml) and triethylamine (4.7 g) were added, and the resulting mixture was stirred at room temperature for 15 hours. The mixture as concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-trimethylsilyl-3-furancarboxylic acid ethyl ester (3.0 g) as oil. 5-Trimethylsilyl-3-furancarboxylic acid ethyl ester (3.0 g) was dissolved in acetonitrile (15 ml), and sulfuryl chloride (2.0 g) in acetonitrile (5 ml) was added dropwise. The mixture was stirred at room temperature for 30 minutes, poured into ice water and extracted with diethyl ether. The extract was washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-chloro-3-furancarboxylic acid ethyl ester (1.9 g) as oil. 5-Chloro-3-furancarboxylic acid ethyl ester (1.9 g) was dissolved in ethanol (15 ml), and 1N aqueous sodium hydroxide (12 ml) was added. The mixture was stirred at room temperature for 1.5 hour and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magensium sulfate and concentrated under reduced pressure. Precipaitated crystals were collected by filtration and washed with hexane to give 5-chloro-3-furancarboxylic acid (1.1 g) as crystals.
Reaction SMILES: [C:1]([C@H:4]1[CH2:7][C@@H:6]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]1([CH3:20])[CH3:19])(=[O:3])[NH2:2].CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>>[CH3:23][N:24](/[CH:26]=[N:2]/[C:1]([C@H:4]1[CH2:7][C@@H:6]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]1([CH3:20])[CH3:19])=[O:3])[CH3:25]
Reactant: COC(OC)N(C)C
Reactant: CC1(C)[C@@H](C(N)=O)C[C@H]1NC(=O)OCc1ccccc1
Product: CN(C)/C=N/C(=O)[C@H]1C[C@@H](NC(=O)OCc2ccccc2)C1(C)C
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of benzyl ((1R,3S)-3-carbamoyl-2,2-dimethylcyclobutyl)carbamate (638 mg, 2.30 mmol) in N,N-dimethylformamide dimethyl acetal (13 mL) was stirred at 120° C. overnight. The reaction mixture was concentrated at 50° C. in vacuo to give the crude product (850 mg) as a yellow oil, which was used directly in the next step without further purification. MS (ESI) m/z 332.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][O:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[F:23])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: Oc1ccccc1F
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Product: CCN1c2ncc(COc3ccccc3F)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 52 %

Procedure:
Using a procedure analogous to that described in Example 98, the title compound, m.p. 109°-110° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 2-fluorophenol. The yield was 52% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(C)ccc4nc3OC)CC2)c1
Yield: 73 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(3-methoxyphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 73%). 1H NMR (300 MHz, CDCl3): δ 2.43-2.48 (m, 3H), 3.23-3.30 (m, 4H), 3.76-3.87 (m, 3H), 4.04-4.13 (m, 4H), 6.45-6.50 (m, 2H), 6.57 (d, J=8.4 Hz, 1H), 7.01-7.12 (m, 1H), 7.17-7.33 (m, 3H), 7.48-7.65 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.Cl[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11](/[CH:10]=[CH:9]/[C:8]([NH:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([CH:20]=[CH:19][CH:18]=2)[O:1][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:17])[CH:12]=1
Reactant: O=C(/C=C/c1cccnc1)NCCc1cccc(O)c1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc(CCNC(=O)/C=C/c2cccnc2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
(E)-N-(3-hydroxyphenethyl)-3-(3-pyridyl)-2-propenoic acid amide (1.07 g, 4.0 mmol) obtained in Example 81 and methyl chloroacetate (0.52 g, 4.8 mmol) were dissolved in dimethylformamide (12 ml) and potassium carbonate (1.66 g, 12 mmol) was added and stirred at 60° C. for 8 hours. After allowing to cool, ethyl acetate was added to the reaction mixture and insoluble materials were filtered out. The filtrate was washed with water and dried over magnesium sulfate. After the solvent was distilled out under reduced pressure, the residue was recrystallized to yield the titled compound (0.83 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:21]=[N:22][N:23]([C@H:25]3[C:38]4[CH:37]=[CH:36][C:35]5[CH2:34][NH:33][CH2:32][CH2:31][C:30]=5[C:29]=4[CH2:28][CH2:27][CH2:26]3)[CH:24]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:39](=O)[CH:40]([CH3:42])[CH3:41].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:21]=[N:22][N:23]([C@H:25]3[C:38]4[CH:37]=[CH:36][C:35]5[CH2:34][N:33]([CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:32][CH2:31][C:30]=5[C:29]=4[CH2:28][CH2:27][CH2:26]3)[CH:24]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)C=O
Reactant: O=C1NC=CN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)[C@@H]1Cc1cn([C@@H]2CCCc3c2ccc2c3CCNC2)nn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)CN1CCc2c(ccc3c2CCC[C@H]3n2cc(C[C@@H]3C(=O)NC=CN3S(=O)(=O)c3ccc(Cl)c(Cl)c3)nn2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ((R)-4-(3,4-dichlorophenylsulfonyl)-3-((1-((R)-1,2,3,4,7,8,9,10-octahydrobenzo[f]isoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)methyl)-3,4-dihydropyrazin-2(1H)-one (220 mg, 0.384 mmol) and isobutyraldehyde (83 mg, 1.15 mmol) in 3 mL of 1,2-dichloroethane was added sodium triacetoxyborohydride (163 mg, 0.768 mmol) and the resulting solution was stirred at RT overnight. The reaction mixture was quenched with sat. NaHCO3, extracted with EtOAc, dried over Na2SO4, filtered and evaporated to dryness. Flash chromatography (SiO2, EtOAc to EtOAc/MeOH=100:7 to 100:12 to 100:14) afforded the title compound as a white solid.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:30]=[CH:29][C:16]2[N:17]([CH2:27][CH3:28])[C:18](=[O:26])[C:19]([CH3:25])([CH3:24])[C:20](=[O:23])[N:21]([CH3:22])[C:15]=2[CH:14]=1.[N+:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40](Cl)(=[O:42])=[O:41])([O-:33])=[O:32]>ClCCl.O>[CH2:27]([N:17]1[C:18](=[O:26])[C:19]([CH3:24])([CH3:25])[C:20](=[O:23])[N:21]([CH3:22])[C:15]2[CH:14]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][NH:8][S:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N+:31]([O-:33])=[O:32])(=[O:41])=[O:42])[CH:30]=[CH:29][C:16]1=2)[CH3:28]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNS(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Triethylamine (0.8 ml, 5.7 mmol) was added to a dichloromethane solution (50 ml) of 7-(3-aminopropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.22 g, 3.8 mmol) and ice-cooled. o-Nitrobenzenesulfonyl chloride (1.03 g, 4.2 mmol) was added to the resulting mixture, and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution, in this order, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1→0:1): The purified product was concentrated to dryness under reduced pressure to thereby obtain 1.86 g (yield: 97%) of N-(3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl)-2-nitrobenzenesulfonamide as a white amorphous solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C@H:6]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:34])[C@H:12]3[CH2:13][C@@H:14]3[O:19][C@@:18]4([O:25][CH2:24][C@H:22]([CH3:23])[CH2:21][CH2:20]4)[C@@H:16]([CH3:17])[C@@H:15]32)[CH2:7]1)[CH3:2].C[OH:36].[OH-].[Na+].OO>O1CCCC1>[CH2:1]([O:3][CH2:4][O:5][C@H:6]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:8]([C@@H:9]([OH:36])[CH2:10][C@@H:11]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:34])[C@H:12]3[CH2:13][C@@H:14]3[O:19][C@@:18]4([O:25][CH2:24][C@H:22]([CH3:23])[CH2:21][CH2:20]4)[C@@H:16]([CH3:17])[C@@H:15]32)[CH2:7]1)[CH3:2]
Reactant: CCOCO[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4C[C@@H]5O[C@]6(CC[C@@H](C)CO6)[C@@H](C)[C@@H]5[C@@]4(C)CC[C@@H]32)C1
Reactant: CO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOCO[C@H]1CC[C@@]2(C)[C@H](C1)[C@@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]3[C@H](C[C@@H]12)O[C@]1(CC[C@@H](C)CO1)[C@H]3C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Borane-tetrahydrofurancomplex (0.68 mL, 0.68 mmol) was added to a solution of (3β,25R)-3-ethoxymethoxy-5-spirostene (0.10 g, 0.21 mmol) in tetrahydrofuran (8 mL). The mixture was stirred under nitrogen atmosphere at ambient temperature for 3.5 hours. The reaction mixture was cooled to 0° C. and methanol (1.5 mL), 15% sodium hydroxide solution (1.5 mL) and 30% hydrogen peroxide (1.5 mL) were added. The reaction mixture was then gradually warmed to ambient temperature and stirred overnight. The reaction was quenched at 0° C. by the addition of saturated sodium bisulfite solution. The mixture was diluted with ethyl acetate and washed with ammonium chloride solution (1×), brine (1×), dried (sodium sulfate), filtered and concentrated in vacuo to give 0.11 g of a mixture of the 6α-alcohol and the 6β-alcohol. The two products were separated by flash chromatography on silica gel (6:4 hexane/ethyl acetate). The major product (Rf=0.40) was identified to be the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:16])[N:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1.[F-:17].[K+].C1OCCOCCOCCOCCOCCOC1>CN1CCCC1=O>[F:17][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:16])[N:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1
Reactant: [F-]
Reactant: Nc1nc2ccccc2c2ccc(Cl)nc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Nc1nc2ccccc2c2ccc(F)nc12
Temperature: 25 °C

Procedure:
A solution of 3-chlorobenzo[f][1,7]naphthyridin-5-amine (Example 20) (1.0 eq.), potassium fluoride (3.0 eq.), and 18-crown-6 (0.2 eq.) in N-methylpyrrolidone (NMP) (0.4 M) was heated in a microwave reactor at 210° C. for 80 minutes. After cooling to room temperature, the crude reaction mixture was purified by HPLC using 10-50% acetonitrile in water to give 3-fluorobenzo[f][1,7]naphthyridin-5-amine. 1H NMR (acetone d-6): δ 11.40 (br, 2H), 9.38-9.42 (dd, 1H), 8.60 (d, 1H), 7.89-7.92 (dd, 1H), 7.81-7.83 (m, 2H), 7.59-7.66 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]([O:16][CH2:17][CH2:18]Br)(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[C:13]([O:16][CH2:17][CH2:18][O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)(=[O:15])[CH3:14]
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OCCOc1cccc2ccc(C)nc12
Temperature: 70 °C
Yield: 62.2 %

Procedure:
A mixture of 2-methylquinolin-8-ol (0.30 g, 1.9 mmol), 2-bromoethyl acetate (0.8.2 mL, 7.6 mmol) and potassium carbonate (1.6 g, 12 mmol) in acetone (7.5 mL, 1.9 mmol) was heated at 70° C. for 12 hours. The cooled reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on a C18 column (0-100% acetonitrile/water) to provide the title compound (0.29 g, 63%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:18]O>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:18])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1n[nH]c2cc(Br)ccc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1n[nH]c2cc(Br)ccc12
Temperature: 60 °C

Procedure:
To a solution of 6-bromo-1H-indazole-3-carboxylic acid (1.5 g, 6.22 mmol) in methanol (25 mL) was added thionyl chloride (2.26 ml, 31.12 mmol). The mixture was heated at 60° C. for 1 hr. The reaction mixture was cooled and concentrated in vacuo. The crude residue was dissolved in EtOAc (30 mL) and washed with saturated aqueous NaHCO3 (10 mL), water (10 mL) and dried (Na2SO4), filtered and concentrated in vacuo to give the title intermediate: 1H NMR (500 MHz, CDCl3) delta 4.08 (3H, s), 7.44 (1H, d, J=8.6 Hz), 7.89 (1H, s), 8.09 (1H, d, J=8.7 Hz), 11.70 (1H, s); LC-MS: m/z=+254.85/256.75 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20]CC4C=CC=CC=4)=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10](C(OC)=O)[C:9]=2[C:32]([O:34][CH3:35])=[O:33])[CH:5]=[CH:4][N:3]=1>C(O)(=O)C.O1CCOCC1.[C].[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:20])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[CH:10][C:9]2([C:32]([O:34][CH3:35])=[O:33])[C:32]([O:34][CH3:35])=[O:33])[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1cc2cc(OCc3ccccc3)c(OC)cc2c(-c2ccnc(Cl)c2)c1C(=O)OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)C1(C(=O)OC)C=Cc2cc(O)c(OC)cc2C1c1ccnc(Cl)c1
Reaction time: 8 h
Yield: 123.7 %

Procedure:
To a suspension of 1-(2-chloro-4-pyridyl)-2,3-bis(methoxycarbonyl)-6-benzyloxy-7-methoxynaphthalene (6.6 g) in a mixture of acetic acid and dioxane (1:1, 1000 ml) is added 10% palladium-carbon (2 g), and the mixture is subjected to medium-pressure catalytic hydrogenation at room temperature overnight with using a Parr-reduction apparatus. To the reaction solution is added a mixture of acetic acid and dioxane (1000 ml), and thereto is added 10% palladium-carbon (2 g). The mixture is subjected to medium-pressure catalytic hydrogenation at room temperature for 18 hours with using a Parr-reduction apparatus. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is crystallized from ethanol to give 1-(2-chloro-4-pyridyl)-2,2-bis(methoxycarbonyl)-6-hydroxy-7-methoxynaphthalene (3.35 g, yield; 62%).