Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH:9][C:10](=[O:19])[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1N.N([O-])=O.[Na+]>Cl.O.CCO.O>[F:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:11]=1[C:10]([OH:19])=[N:9][N:8]2[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Nc1cccc(F)c1C(=O)NNc1ccccc1F
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Oc1nn(-c2ccccc2F)c2cccc(F)c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Intermediate 44 (2.182 g, 8.289 mmol) was suspended in 1M HCl (20 ml), cooled to 0° C. and treated dropwise with a solution of sodium nitrite (1.144 g, 16.58 mmol) in water (7 ml). The mixture was stirred for 10 minutes at 0° C., diluted with 1:1 EtOH/H2O (30 ml) and heated to reflux for 3 hours, then stirred at room temperature for 18 hours. The solid was filtered, rinsed with water and dried to afford 1.939 g (95%) of 4-fluoro-1-(2-fluoro-phenyl)-1H-indazol-3-ol (Intermediate 45) as a tan solid. MS (APCI): (M+1)=247.1, (M−1)=245.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=3)[CH:12]=2)[C:7]1=[O:27])[CH3:2].[O-][CH2:30][CH2:31]CC.[Na+].C(O)CCC.Cl>>[CH2:1]([O:3][C:4]([C:5]1[NH:6][C:7](=[O:27])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)=[O:28])[CH2:2][CH2:30][CH3:31]
Reactant: CCCC[O-]
Reactant: CCCOc1ccc(Oc2ccc3c(c2)C(=O)N(CC(=O)OCC)C3=O)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CCCCOC(=O)c1[nH]c(=O)c2ccc(Oc3ccc(OCCC)cc3)cc2c1O
Temperature: 25 °C

Procedure:
A mixture of [1,3-dioxo-5-(4-propoxy-phenoxy)-1,3-dihydro-isoindol-2-yl]-acetic acid ethyl ester (2.485 g, 6.48 mmol), sodium butoxide, and butanol (14.3 mmol, 27 mL butanol) was heated at 90° C. to 100° C. for 2 h. Then the reaction mixture was allowed to cool to ambient temperature, acidified with 2 M HCl to pH 3-4, and extracted with EtOAc. The organic phase was then washed with water and saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (722 mg). ESI MS (m/z): 412 (M+H)+.
Reaction SMILES: [C:1]([OH:7])([C:3](F)(F)F)=O.C1N2CN3CN(C2)CN1C3.[CH:18]1([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30]C=2)[N:28]([CH3:32])[C:27](=[O:33])[CH2:26][CH2:25]3)[CH2:20][CH2:19]1>>[CH:18]1([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][C:3]=2[CH:1]=[O:7])[N:28]([CH3:32])[C:27](=[O:33])[CH2:26][CH2:25]3)[CH2:20][CH2:19]1
Reactant: O=C(O)C(F)(F)F
Reactant: CN1C(=O)CCc2cc(OC3CC3)ccc21
Agent: C1N2CN3CN1CN(C2)C3
Product: CN1C(=O)CCc2cc(OC3CC3)c(C=O)cc21
Temperature: 65 °C
Yield: 37 %

Procedure:
TFA (1.38 ml) solution of hexamethylenetetramine (58 mg, 0.42 mmol) was heated to 70° C. for 1 hour under nitrogen. Another TFA (0.69 ml) solution of 6-Cyclopropoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one (30 mg, 0.138 mmol) was then added to the above at room temperature and the reaction mixture was heated to 65° C. for an overnight. It was then cooled to room temperature, quenched with water and extracted with ethyl acetate (30 ml). The combined fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was chromatographed using 40% ethylacetate/hexane to yield the title compound as a solid (13 mg, 37% yield). 1H NMR (400 MHz, CDCl3) δ 0.84–0.87 (4H, m), 2.64–2.267 (2H, m), 2.94–2.98 (2H, m), 3.35 (3H, s), 3.80–3.85 (1H, m), 7.17 (1H, s), 7.39 (1H, s), 10.33 (1H, s). m/z (APCI+) 246 (M+1). HPLC (aqueous 200 Mm ammonium acetate buffer/acetonitrile gradient, 3.0 ml/min, Hewlett Packard ODS Hypersil 5 μM, 125×4 mm column), 4.454 min.
Reaction SMILES: [CH:1]1([O:6][NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[S:25]([CH3:28])(=[O:27])=[O:26])[C:12]([C:14]1[NH:19][C:18](=[O:20])[C:17]([CH3:21])=[CH:16][CH:15]=1)=O.O>C(O)CCC>[Cl:8][C:9]1[CH:10]=[C:11](/[C:12](=[N:7]\[O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)/[C:14]2[NH:19][C:18](=[O:20])[C:17]([CH3:21])=[CH:16][CH:15]=2)[CH:22]=[CH:23][C:24]=1[S:25]([CH3:28])(=[O:27])=[O:26]
Reactant: Cc1ccc(C(=O)c2ccc(S(C)(=O)=O)c(Cl)c2)[nH]c1=O
Reactant: NOC1CCCC1
Solvent: CCCCO
Solvent: O
Product: Cc1ccc(/C(=N/OC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)[nH]c1=O
Temperature: 200 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
O-cyclopentylhydroxylamine (0.3 mL) was added to a solution of 6-[3-chloro-4-(methylsulfonyl)benzoyl]-3-methylpyridin-2(1H)-one (220 mg) in n-butanol (2 mL) at room temperature, and the mixture was stirred under microwave irradiation at 200° C. for two hours. O-cyclopentylhydroxylamine (0.3 mL) was further added at room temperature, and the mixture was stirred under microwave irradiation at 200° C. for three hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→1:1) and further purified by silica gel column chromatography (chloroform:ethyl acetate=50:1→25:1). The resulting less polar product was powdered with an ethyl acetate/hexane solution, and filtration operation gave (E)-6-{[3-chloro-4-(methylsulfonyl)phenyl](cyclopentyloxyimino)methyl}-3-methylpyridin-2(1H)-one as a white solid (95 mg, 34%). The more polar product was powdered with an ethyl acetate/hexane solution, and filtration operation gave (Z)-6-{[3-chloro-4-(methylsulfonyl)phenyl](cyclopentyloxyimino)methyl}-3-methylpyridin-2(1H)-one as a white solid (36 mg, 13%).
Reaction SMILES: [OH:1][C:2]([C:15]([F:18])([F:17])[F:16])([CH2:5][C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[CH:3]=O.[NH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:30])[NH:25]2>>[OH:1][C:2]([C:15]([F:16])([F:17])[F:18])([CH2:5][C:6]([CH3:7])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:14])[CH:3]=[N:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:30])[NH:25]2
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccccc1
Reactant: Nc1cccc2[nH]c(=O)ccc12
Product: CC(C)(CC(O)(C=Nc1cccc2[nH]c(=O)ccc12)C(F)(F)F)c1ccccc1

Procedure:
Analogously to Example 13, 600 mg of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal and 337 mg of 5-aminoquinolin-2(1H)-one (52313) are converted into 570 mg of product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[K+].[C:25]([C:27]1[N:28]=[C:29]([C:40]([O-])=[O:41])[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=1)#[N:26]>CCOC(C)=O.CCCCCC>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:40]([C:29]3[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[C:27]([C:25]#[N:26])[N:28]=3)=[O:41])=[C:13]([C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=3)[CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: COC(=O)C1(c2ccc(N)c(C3=CCCCC3)c2)CCOCC1
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)CCOCC1
Yield: 78 %

Procedure:
The title compound was prepared by the coupling procedure of Example 1, step (f) using 4-(4-amino-3-cyclohex-1-enyl-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (as prepared in the previous step, 250 mg, 0.793 mmol), and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 266 mg, 0.872 mmol). Silica gel chromatography (20% EtOAc-hexane) afforded the title compound (348 mg, 78%) as a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C30H40N4O5Si, 565.3 (M+H). found 565.0.
Reaction SMILES: CC1(C)CC=C(C2SC=CN=2)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC1=2.[CH3:29][C:30]1([CH3:58])[CH2:39][CH:38]=[C:37]([C:40]2[S:41][CH:42]=[CH:43][CH:44]=2)[C:36]2[CH:35]=[C:34]([C:45]#[C:46][C:47]3[CH:57]=[CH:56][C:50]([C:51]([O:53]CC)=[O:52])=[CH:49][CH:48]=3)[CH:33]=[CH:32][C:31]1=2>>[CH3:29][C:30]1([CH3:58])[CH2:39][CH:38]=[C:37]([C:40]2[S:41][CH:42]=[CH:43][CH:44]=2)[C:36]2[CH:35]=[C:34]([C:45]#[C:46][C:47]3[CH:48]=[CH:49][C:50]([C:51]([OH:53])=[O:52])=[CH:56][CH:57]=3)[CH:33]=[CH:32][C:31]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccs2)=CCC3(C)C)cc1
Agent: CC1(C)CC=C(c2nccs2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Product: CC1(C)CC=C(c2cccs2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(5,6-dihydro-5,5-dimethyl-8-(2- thiazolyl)-2-naphthalenyl)ethynyl]benzoic acid (Compound 30a), 70.0 mg (0.17 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-thienyl)-2-naphthalenyl)ethynyl]benzoate (Compound 33a) was converted into the title compound (colorless solid) using 17.8 mg (0.42 mmol) of LiOH in H2O. PMR (d6 -DMSO): δ 1.27 (6H, s), 2.33 (2H, d, J=4.9 Hz), 6.23 (1H, t, J=4.9 Hz), 7.14 (2H, m), 7.38-7.56 (4H, m), 7.61 (2H, d, J=8.3 Hz), 7.92 (2H, d, J=8.3 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[Br:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.C(Cl)(Cl)Cl>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12]
Reactant: BrCCCBr
Reactant: O=C1CCCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: O=C1CCCc2c(OCCCBr)cccc21
Yield: 57 %

Procedure:
32.43 g (0.2 mol) 5-hydroxy-1-oxotetraline and 120.14 g (0.6 mol) 1,3-dibromopropane were, while stirring, heated to the boil in 200 ml anhydrous isopropanol and thereafter 41.46 g (0.3 mol) pulverized anhydrous potassium carbonate were added thereto over the course of about three hours. Subsequently, the reaction mixture was vigorously stirred for six hours at reflux temperature, then filtered with suction and the filter cake washed out with isopropanol. The filtrate was evaporated in a vacuum and excess 1,3-dibromopropane was substantially stripped off. The oily evaporation residue obtained was taken up in chloroform, the chloroform solution was extracted several times with a dilute aqueous solution of sodium hydroxide, then shaken with water until neutral and dried. After distilling off the chloroform, the oily residue was distilled at oil pump vacuum. Between 145°-155°C/0.05 mm Hg, there were obtained 32.3 g (57.1% of theory) 5-(3-bromopropoxy)-1-oxotetraline, which was then further worked up.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=1[NH2:12].[OH-].[K+].C(O)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=2[NH2:12])=[CH:4][CH:3]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: Fc1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(F)cc1

Procedure:
A mixture of 29.7 g. (0.231 mole) of 4-fluorothiophenol, 41 g. (0.238 mole) of 2-chloro-5-nitroaniline and 14.9 g. (0.266 mole) of potassium hydroxide in 500 ml. of 95 percent aqueous ethanol is heated to its reflux temperature and maintained at reflux for one hour, then cooled with an ice bath. Some crude product is isolated as a solid by filtration, then the filtrate is diluted with water and extracted with four 300 ml. portions of chloroform. The combined extracts are washed with four 300 ml. portions of water and then with saturated sodium chloride solution and dried. Evaporation under vacuum provides a residue which is combined with the previously isolated crude solid product, 2-(4-fluorophenylthio)-5-nitroaniline. The solid is dissolved in 500 ml. of chloroform, then the solution is saturated with hydrogen chloride gas. The white precipitate which forms is separated by filtration, washed with chloroform and diethyl ether and dried to provide 2-(4-fluorophenylthio)-5-nitroaniline hydrochloride.
Reaction SMILES: C([NH:9][C:10]1[CH:25]=[CH:24][N:13]([C@@H:14]2[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:15]2[O:16]C)[C:12](=[O:26])[N:11]=1)(=O)C1C=CC=CC=1.COC1C=CC(C(Cl)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1>N1C=CC=CC=1>[C@@H:14]1([N:13]2[CH:24]=[CH:25][C:10]([NH2:9])=[N:11][C:12]2=[O:26])[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:15]1[OH:16]
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Agent: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N4-Benzoyl-2′-O-methylcytidine (28 g, 0.077 mol) was evaporated under reduced pressure to an oil with pyridine (400 mL). To the residue was added 4,4′-dimethoxytriphenylmethyl chloride (DMT-Cl, 28.8 g, 0.085 mol) and pyridine (400 ml). The mixture was stirred at 25° C. for 2 h and then quenched by the addition of methanol (10 ml) for 30 min. The mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel (500 g, hexanes-ethyl acetate-triethylamine 60:40:1 and then ethyl acetate-triethylamine 99:1). The appropriate fractions were combined, evaporated under reduced pressure and dried at 40° C./0.2 mmHg for 2 h to give 26 g (74%, 16% from cytidine) of foam; TLC homogenous (Rf 0.45, ethyl acetate); PMR (DMSO) δ 11.3 (H−N4), 8.4-6.9 (H−6, H−5, Bz), 5.95 (H−1′), 5.2 (HO−3′), 3.7 (s, 6, CH3O—trit.), 3.5 (s, 3, CH3O—2′)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Br:11]N1C(=O)CCC1=O>C(#N)C.C(O)C>[Br:11][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCO
Solvent: CC#N
Product: O=C1Cc2cc(Br)ccc2N1
Temperature: 7 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
2-Oxindole (53.3 g) was suspended in 640 mL acetonitrile and the mixture cooled to 7° C. in an ice bath with mechanical stirring. Solid N-bromosuccinimide (74.8 g) was added in portions over 20 minutes. After about one-third of the N-bromosuccinimide had been added (over 5 minutes), the temperature had increased to 12° C. The addition was halted until the temperature of the mixture had dropped to 10° C. The addition was resumed keeping the temperature below 12° C. After the addition was complete, the mixture was stirred for 1 hour at 10° C. and then for 1 additional hour during which the mixture was allowed to warm to ambient temperature. The precipitate was collected by vacuum filtration, washed with 80 mL of ethanol and sucked dry for 20 minutes in the filtration funnel to give product containing 6.4% of 2-oxindole by HPLC. The solid was suspended in 1440 mL of denatured ethanol and slurry-washed by stirring and refluxing for 5 minutes at which time most of the solid had dissolved. The mixture was cooled in an ice bath to 13° C. The solid product was collected by vacuum filtration, washed with 80 mL of ethanol and dried under vacuum to give 57.7 g (68.0%) of 5-bromo-2-oxindole containing 1.13% 2-oxindole by HPLC. Slurry-washing with 30% less ethanol gave a better yield (88%) but contained more 2-oxindole (1.76%).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[NH:9][C:10](=[O:18])[C:11]([O:14][C:15](=[O:17])[CH3:16])([CH3:13])[CH3:12])(=[O:3])[NH2:2].C1C(=O)N([Cl:26])C(=O)C1>CC(O)=O.O>[C:1]([C:4]1[CH:8]=[C:7]([Cl:26])[S:6][C:5]=1[NH:9][C:10](=[O:18])[C:11]([O:14][C:15](=[O:17])[CH3:16])([CH3:12])[CH3:13])(=[O:3])[NH2:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)OC(C)(C)C(=O)Nc1sccc1C(N)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC(C)(C)C(=O)Nc1sc(Cl)cc1C(N)=O
Temperature: 25 °C

Procedure:
Intermediate 10 (78.5 g, 291 mmol) is dissolved in AcOH (850 mL). To the resulting suspension, NCS (42.9 g, 320 mmol) is added. The mixture is stirred at room temperature, after which it is evaporated to give a slurry. This slurry is taken up in water to give a suspension that is filtered. Resulting precipitate is dried in the vacuum oven and used as such.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:7]=1[C:8]([NH:10][C:11]1[C:19]2[O:18][C:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C:16]=3[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:9].O>C(O)(=O)C>[Cl:5][C:6]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:7]=1[C:8]([NH:10][C:11]1[C:19]2[O:18][C:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C:16]=3[C:15]=2[CH:14]=[CH:13][C:12]=1[N+:1]([O-:4])=[O:2])=[O:9]
Reactant: O=C(Nc1cccc2c3c(oc12)CCCC3)c1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1c([N+](=O)[O-])ccc2c3c(oc12)CCCC3)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Nitric acid (d; 1.5, 0.033 ml) was added to a solution of 6-(2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran (200 mg) in acetic acid at 4° C. The mixture was stirred at ambient temperature for 5 hours and poured into cold water. The separated solid was collected and washed with isopropyl alcohol to give 6-(2,6-dichlorobenzoylamino)-7-nitro-1,2,3,4-tetrahydrodibenzofuran (17 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH:24]4[CH2:26][CH2:25]4)=[CH:22][C:21]([CH:27]4[CH2:29][CH2:28]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[S:30]1(=[O:36])(=[O:35])[CH2:34][CH2:33][CH2:32][NH:31]1>>[CH:24]1([C:23]2[C:18]([N:15]3[CH2:16][CH2:17][N:12]([C:10]([C:5]4[CH:4]=[CH:3][C:2]([N:31]5[CH2:32][CH2:33][CH2:34][S:30]5(=[O:36])=[O:35])=[CH:9][C:6]=4[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]3)=[N:19][CH:20]=[C:21]([CH:27]3[CH2:29][CH2:28]3)[CH:22]=2)[CH2:26][CH2:25]1
Reactant: O=S1(=O)CCCN1
Reactant: N#Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: N#Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 90.2 %

Procedure:
Using 5-bromo-2-[4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (451 mg) described in Preparation Example 245 and isothiazolidine 1,1-dioxide (158 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (443 mg) was obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[N:12]=[N:11]2)=[CH:6][CH:5]=1.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1>C1COCC1>[Cl:18][C:19]1[N:20]=[N:21][C:22]([O:16][CH2:15][C:14]2[N:10]([C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=3)[N:11]=[N:12][C:13]=2[CH3:17])=[CH:23][CH:24]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a suspension of sodium hydride (55%, 106 mg, 2.41 mmol) in THF (4 mL) a solution of [3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-yl]-methanol (500 mg, 2.41 mmol) in THF (6 mL) was added under ice cooling. After the addition was complete the mixture was allowed to warm up to room temperature and stirred for 30 min. Again under ice cooling a solution of 3,6-dichloropyridazine (358 mg, 2.41 mmol) in THF (6 mL) was added and the reaction mixture stirred at room temperature for 16 h. The mixture was then poured into ice water and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) afforded the title compound (735 mg, 95%) as a colourless gun. MS: m/e=3020.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH2:14][CH3:15])[CH2:4][NH:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][CH2:9][O:8]1.C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:28][CH2:29][C:30](Cl)=[O:31]>O>[CH3:1][O:2][CH:3]([O:13][CH2:14][CH3:15])[CH2:4][N:5]([CH2:6][CH:7]1[O:8][CH2:9][CH2:10][CH2:11][O:12]1)[C:30](=[O:31])[CH2:29][Cl:28]
Reactant: O=C(Cl)CCl
Reactant: CCOC(CNCC1OCCCO1)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(CN(CC1OCCCO1)C(=O)CCl)OC

Procedure:
N-(2-Methoxy-2-ethoxyethyl)-N-(1,3-dioxan-2-ylmethyl)-amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel eqiuipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and chloroacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2-methoxy-2-ethoxyethyl)-N-(1,3-dioxan-2-ylmethyl)-α-chloroacetamide as the residue.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:13][C:12]([F:15])([F:14])[C:11]([F:17])([F:16])[CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[ClH:1].[F:16][C:11]1([F:17])[C:12]([F:15])([F:14])[CH2:13][NH:9][CH2:10]1
Reactant: FC1(F)CN(Cc2ccccc2)CC1(F)F
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: FC1(F)CNCC1(F)F

Procedure:
A solution of 1-benzyl-3,3,4,4-tetrafluoro-pyrrolidine hydrochloride (23.8 g, 88 mmol) in ethanol (300 mL) containing 10% palladium on carbon was treated with hydrogen in a Parr shaker at 45 psi for 3 hours. The mixture was filtered through Celite®, the filtrate was concentrated to dryness. The residue was triturated with ether and the solid was collected and dried (13.4 g, 85%, (mp 193-196° C.).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22].N1C=CC=CC=1>C1COCC1>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21]([N:6]([C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:22]
Reactant: COc1ccc(C(=O)Cl)cc1F
Reactant: COc1ccc(Nc2ccc(F)cc2)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)c2ccc(OC)c(F)c2)c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
4-Fluoro-N-(4-methoxyphenyl)aniline (1c) (90.78 g, 0.418 mol) and 3-fluoro-4-methoxybenzoyl chloride (94.55 g, 0.501 mol) were mixed together and dissolved in anhydrous THF (200 mL) in a dry 1 L three-necked round-bottomed flask fitted with a stifling bar, a reflux condenser and an argon inlet. Anhydrous pyridine (132.22 g, 1.672 mol) was added via a syringe at room temperature under argon. The reaction mixture was stirred and heated to reflux overnight. Then, the reaction mixture was cooled to room temperature and filtered to remove pyridine salt. The solution was concentrated to remove THF solvent. The residue oil was washed with 200 mL of 2N HCl solution and extracted with ethyl acetate (2×200 mL). The combined organic layer was washed with a saturated aqueous Na2CO3 solution (150 mL) to remove excess benzoyl chloride and acid, dried over MgSO4 (50 g), filtered, and concentrated under reduced pressure to give an oil. The residue was purified by flash column chromatography using silica-gel with CH2Cl2/acetone (50/1 v/v) to afford the pure corresponding benzamide compound as a yellow solid. M.p. 54-56° C. MS (ESI) m/z 370.1 [M+H]+, 1H NMR (CDCl3/TMS) δ 7.24-7.11 (m, 4H), 7.05-6.97 (m, 4H), 6.85-6.78 (m, 3H), 3.86 (s, 3H), 3.79 (s, 3H).