Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[CH3:13][NH:14][S:15](Cl)(=[O:17])=[O:16]>ClCCl>[CH3:13][NH:14][S:15]([N:3]([CH3:2])[O:4][CH3:5])(=[O:17])=[O:16]
Reactant: CNOC
Reactant: CNS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNS(=O)(=O)N(C)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
5.75 g (58.9 mmol) of N,O-dimethylhydroxylamine hydrochloride was suspended in 300 ml of dichloromethane, and 11.9 g (118 mmol) of triethylamine was added thereto. Then, the mixture was cooled with ice, and a dichloromethane solution of 7.63 g of methylsulfamoyl chloride was dropwise added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure. To the residue, 200 ml of benzene was added, and insoluble substance was filtered off. Then, the solvent was distilled off again under reduced pressure. By the distillation under reduced pressure, 4.4 g of N,N'-dimethyl-N'-methoxysulfamide was obtained (boiling point: 85°-88° C./1.9 mmHg).
Reaction SMILES: [OH-].[Na+].C[C:4]1[C:5]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=[O:8]>CO>[CH2:16]([C:5]1[CH:4]=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1c([N+](=O)[O-])ccc(C(=O)O)c1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc([N+](=O)[O-])cc1Cc1ccccc1

Procedure:
2N Aqueous sodium hydroxide solution (2.0 mL, 4 mmol) was added to a solution of compound (28) (2.06 mmol) in methanol (10 mL) at ambient temperature. After 2 hrs the reaction mixture was evaporated to remove the methanol and then partitioned between ethyl ether (20 mL) and 2N aqueous sodium hydroxide solution (20 mL). The aqueous phase was acidified to pH⅔ with 2N HCl and extracted with ethyl acetate(3×20 mL). The combined organics were washed with water (20 mL) and brine (20 mL), filtered through phase separating paper and evaporated to yield 2-benzyl-4nitrobenzoic acid (compound 29).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10]>ClCCl.[O-2].[Mn+2]>[F:1][CH:2]([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[O:10]
Reactant: OCc1ccccc1C(F)F
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccccc1C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A mixture of (2-(difluoromethyl)phenyl)methanol (100 mg, 0.632 mmol) and manganese oxide (275 mg, 3.16 mmol) in dichloromethane was stirred at room temperature for twelve hours and then at 45° C. for 1 h. The reaction was filtered through celite and concentrated, to give 2-(difluoromethyl)benzaldehyde as an oil (99 mg). 1H NMR (400 MHz, CDCl3) δ 10.2 (s, 1H), 7.94 (d, 1H), 7.81 (d, 1H), 7.70 (m, 2H), 6.93 (t, 1H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=3)=[N:11]2)=[CH:6][CH:5]=1.[H-].[Li+].[Al+3].[H-].[H-].[H-].O>O1CCCC1>[F:27][C:2]([F:1])([F:26])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][OH:24])[CH:18]=[CH:19][CH:20]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=C(O)CCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
In a 500 mL round bottomed flask 3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoic acid (CA13) (5.68 g, 15.1 mmol) was dissolved in tetrahydrofuran (151 mL). The reaction was cooled in an ice water bath and placed under inert atmosphere. Aluminum(III) lithium hydride (2.0 M in tetrahydrofuran, 15.8 mL, 31.6 mmol) was added dropwise. The reaction was allowed to gradually warm to room temperature and stir overnight. The reaction was cooled in an ice bath and water (1.2 mL) was added dropwise to quench excess aluminum(III) lithium hydride, the reaction mixture was allowed to stir for 1 hour. Then sodium hydroxide (15 wt %, 1.2 mL) was added dropwise. The reaction was allowed to stir for 1 hour. Then water (3.6 mL) was added. The resulting precipitate was removed via filtration. The filtrate was concentrated to give a yellow solid (5.20 g). The solid was purified by flash column chromatography using 0-60% ethyl acetate/hexanes as eluent providing the title compound as a white solid (4.01 g, 72%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.18-8.04 (m, 2H), 7.99-7.89 (m, 2H), 7.68-7.57 (m, 2H), 7.43 (t, J=7.6 Hz, 1H), 7.32 (dt, J=7.7, 1.5 Hz, 1H), 4.51 (t, J=5.2 Hz, 1H), 3.45 (td, J=6.4, 5.1 Hz, 2H), 2.71 (dd, J=8.8, 6.7 Hz, 2H), 1.87-1.70 (m, 2H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 364 ([M+H]+).
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5]([C@H:7]1[CH2:11][C@@H:10]([N:12]=[N+:13]=[N-:14])[CH2:9][N:8]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O.C(=O)(O)[O-].[Na+]>CCOCC>[C:18]([O:17][C:15]([N:8]1[CH2:9][C@H:10]([N:12]=[N+:13]=[N-:14])[CH2:11][C@@H:7]1[CH2:5][OH:4])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)[C@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])C[C@@H]1CO
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
Add lithium borohydride (8.50 g, 351 mmol) to a solution of (2R,4R)-4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (95 g, 351 mmol) in ether (1 L) at −30° C. under nitrogen. Allow the temperature to rise to 0° C. over 1.5 h and stir for an additional 2 h. Cool to −70° C. and add saturated aqueous sodium bicarbonate (1 L) dropwise. Allow to warm to room temperature, separate the layers and extract the aqueous layer with ether (1 L). Combine the ether layers, dry over sodium sulfate, filter, and concentrate. Dry the resulting material under high vacuum to obtain a yellow oil (82 g, 96%). [α]D20+20.3 (c=1.0 in methanol). 1H NMR (400 MHz, DMSO-d6) δ 1.38 (s, 9H), 1.99 (br s, 1H, OH), 2.20 (m, 1H), 3.34 (m, 1H), 3.50-3.78 (m, 1H), 4.29 (m, 1H), 4.78 (m, 1H).
Reaction SMILES: C([O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][C:8]([CH:9]=[O:10])=[C:7](Br)[C:6]=1[O:16][CH3:17])(=O)C.[C:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)([OH:20])=[O:19]>>[CH:9]([C:8]1[C:7]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C:18]([OH:20])=[O:19])[CH:26]=2)=[C:6]([O:16][CH3:17])[C:5]([OH:4])=[C:12]([O:13][CH3:14])[CH:11]=1)=[O:10]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: COc1cc(C=O)c(Br)c(OC)c1OC(C)=O
Product: COc1cc(C=O)c(-c2cccc(C(=O)O)c2)c(OC)c1O

Procedure:
6′-Formyl-3′-hydroxy-2′,4′-dimethoxy-biphenyl-3-carboxylic acid was prepared from 4-acetoxy-2-bromo-3,5-dimethoxybenzaldehyde (Example 162, step a) and 3-carboxyphenyl boronic acid using the protocol described in Example 145, step a. Mass Spectrum 288 (M+1).
Reaction SMILES: C(O[C:4](=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([NH:17][C:18]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[O:19])=[CH:15][C:14]([C:31]([CH3:34])([CH3:33])[CH3:32])=[N:13]2)=[CH:8][CH:7]=1)C.[NH3:36].CO>CO>[C:31]([C:14]1[CH:15]=[C:16]([NH:17][C:18]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[O:19])[N:12]([C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C:4]([NH2:36])=[O:35])=[CH:11][CH:10]=2)[N:13]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cccc3ccccc23)cc1
Reactant: N
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2ccc(CC(N)=O)cc2)n1
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of {4-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)pyrazol-1-yl]phenyl}acetic acid ethyl ester (150 mg, 0.32 mmol, intermediate in Example 559) in MeOH (2 mL) was added NH3/MeOH (10 mL) at RT. The mixture was stirred at that temperature overnight. After removal of the solvent, the crude product was purified by preparative HPLC to afford 2-{4-[3-t-butyl-5-(3-naphthalen-1-ylureido)pyrazol-1-yl]phenyl}acetamide (48 mg, 31% yield). 1H NMR (300 MHz, CD3OD): δ 7.87 (m, 2H), 7.76 (d, J=5.4 Hz, 1H), 7.68 (d, J=6.0 Hz, 1H), 7.53-7.42 (m, 7H), 6.57 (s, 1H), 3.64 (s, 2H), 1.36 (s, 9H); MS (ESI) m/z: 442 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([OH:14])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C(O)Cc2ccccc2)ccc1OCc1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of 20 g (82.64 mmol) of O-benzylvanillin in 200 mL of dry tetrahydrofuran was slowly added to a stirred solution of benzyl magnesium chloride (103.30 mmol) in 150 mL of diethylether at 10° C. over 20 min, and the reaction mixture was then boiled for 10 min, cooled, quenched with a mixture of ice and dilute hydrochloric acid and evaporated at reduced pressure. The residue was dissolved in dichloromethane, the solution washed with brine, dried with sodium sulphate and the solvent was evaporated under reduced pressure leaving a crystalline residue that was recrystallised from diethylether and petroleum ether. 1-(4-Benzyloxy-3-methoxyphenyl)-2-phenyl-1-ethanol was obtained as white crystals, m.p. 97 to 98° C.
Reaction SMILES: C[C:2]1[C:7]([C:8]([O-])=[O:9])=[C:6](C)[C:5]([C:12]([O-])=[O:13])=[C:4](C)[C:3]=1[C:16]([O-])=[O:17].[H-].[H-].[H-].[H-].[Li+].[Al+3].CO.OS([O-])(=O)=O.[K+]>C1COCC1>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH2:12][OH:13])[CH:4]=[C:3]([CH2:16][OH:17])[CH:2]=1
Reactant: Cc1c(C(=O)[O-])c(C)c(C(=O)[O-])c(C)c1C(=O)[O-]
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc(CO)cc(CO)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
Trimethyl-1,3,5-benzenetricarboxylate 14 (1.98 g, 7.83 mmol) in dry THF (30 mL) was added through a pressure-equalized addition funnel into a stirring suspension of LiAlH4 (0.95 g, 24.9 mmol) in dry THF (65 mL) at 0° C. under an argon atmosphere. The mixture was allowed to warm to rt and stirred for 4 hours. 1H NMR (CDCl3) was used to monitor the reaction. After determining a large amount of starting material remained, additional LiAlH4 (0.50 g, 13.1 mmol) was added to the reaction mixture and the reaction was allowed to proceed at RT for an additional 4 hours. 1H NMR (CDCl3) was used to determine if reaction was complete. After the reaction was complete, MeOH (25 mL) was used to quench the reaction. The suspension was filtered using Celite and the Celite was washed with MeOH (100 mL). The filtrate was concentrated under reduced pressure. The residue was stirred in THF (30 mL), KHSO4 (3.53 g, 26 mmol) and Celite (1.53 g, 25.4 mmol) for 30 minutes. The suspension was filtered and washed with MeOH (50 mL). Solvents were removed under reduced pressure. The resulting solid was dissolved in hot ethyl acetate and filtered. The solid that remained at the filter was collected, dried and to yield triol 15 (0.954 g, 5.68 mmol, 73%). 1H NMR (DMSO): δ 7.22 (s, 3H), 5.17 (br s, 3H), 4.48 (s, 6H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]1([CH3:22])[CH:15]=[CH:14][C:13]([S:16]([N:19]=C=O)(=[O:18])=[O:17])=[CH:12][CH:11]=1.CNCCCNC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:22][C:10]1[CH:11]=[CH:12][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Agent: CNCCCNC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(N)(=O)=O)cc1
Reaction time: 1 h
Yield: 176.8 %

Procedure:
Benzyl ester (100 mg, 0.0842 mmol) and Pd/C (en) (10 mg) were suspended in methanol (1 ml), and the obtained suspension was stirred in a hydrogen atmosphere at room temperature for 8 hours. Thereafter, the catalyst was filtrated with a filter, and was then washed with methanol. The filtrate was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1−7:3), so as to obtain carboxylic acid (91.2 mg) in a quantitative manner. The thus obtained carboxylic acid (75.9 mg, 0.070 mg) was dissolved in THF (0.5 ml). Thereafter, diisopropylethylamine (32 μl, 0.184 mmol) and p-toluenesulfonyl isocyanate (39 μl, 0.256 mmol) were added thereto in an argon atmosphere, and the obtained mixture was stirred for 1 hour. Thereafter, N,N′-dimethyl-1,3-propanediamine (0.1 ml) was added dropwise to the reaction solution, and a 10% citric acid aqueous solution was then added thereto. An aqueous layer was extracted with chloroform. An organic layer was washed with a saline solution, and it was then dried over sodium sulfate. The solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1), so as to obtain 77.5 mg (87%) of tosylamide.
Reaction SMILES: [C:1]([O:20][CH2:21][C@@H:22]([OH:26])[CH2:23][CH2:24][OH:25])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C=O)C>[Si:32]([O:25][CH2:24][CH2:23][C@H:22]([OH:26])[CH2:21][O:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 270.2 %

Procedure:
(S)-1-Trityloxy-2,4-butanediol (1.64 g, 4.7 mmol) and imidazole (0.321 g, 4.715 mmol) were dissolved in DMF (20 ml) and the solution was cooled to 0° C. To the solution was dropped tert-butyldimethylsilyl chloride (0.5 ml, 1.44 mmol, 50% in toluene). After stirring for 1 hour, again to the solution was dropped tert-butyldimethylsilyl chloride (0.5 ml, 1.44 mmol) and the solution was stirred for 1 hour. Further tert-butyldimethylsilyl chloride (0.6 ml, 1.73 mmol) was added to the solution and the solution was stirred over night at room temperature. After dilution with toluene (100 ml), the solution was washed with water (100 ml) twice and saturated brine once, dried on magnesium sulfate, filtered and condensed in vacuo. The residue was subjected to silica gel chromatography to give (S)-4-tert-butyldimethylsilyloxy-1-trityloxy-2-butanol (1.80 g, yield 82.6%).
Reaction SMILES: [CH3:1][N:2]1[C:20](=[O:21])[N:5]2[N:6]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=3)[C:8]([CH3:10])=[CH:9][C:4]2=[N:3]1.FC(F)(F)C(O)=O.[H][H]>[Pd]>[NH2:17][C:13]1[CH:12]=[C:11]([C:7]2[C:8]([CH3:10])=[CH:9][C:4]3[N:5]([C:20](=[O:21])[N:2]([CH3:1])[N:3]=3)[N:6]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc2nn(C)c(=O)n2nc1-c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2nn(C)c(=O)n2nc1-c1cccc(N)c1

Procedure:
A mixture of 5.0 g of 2,7-dimethyl-6-(m-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazin-3(2H)-one, 50 ml. of trifluoroacetic acid and a catalytic amount of 10% palladium on carbon are shaken in a Parr bottle under 40 lb. pressure of hydrogen for 2 hours and then filtered. The filtrate is concentrated in vacuo to an oil which is dissolved in 50 ml. of water and adjusted to pH 4.7 with 5N sodium hydroxide. The resulting solid is collected by filtration and air dried, giving 3.6 g. of the desired product as a green solid, m.p. 192°-195° C.
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[I-].[K+].[OH-].[Na+]>O.CN(C)P(N(C)C)(N(C)C)=O>[C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([O:15][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCOC(=O)C(C)c1ccc(C(=O)c2cccs2)cc1
Reaction time: 1.5 h

Procedure:
To a stirred mixture of 5.2 parts of p-(2-thenoyl)hydratropic acid in 50 parts of dry hexamethylphosphoramide are added 0.86 parts of sodium hydride dispersion 55.3% and the whole is stirred for 1.5 hours. Then there are added 3.86 parts of octyl bromide and 0.01 parts of potassium iodide. Upon completion, stirring is continued for 18 hours at room temperature. The reaction mixture is poured onto benzene and the whole is shaken successively twice with water, twice with sodium hydroxide solution and again twice with water. The organic phase is dried, filtered and evaporated. The residue is taken up in ether and stirred with activated charcoal. The latter is filtered off and the filtrate is evaporated again. The residue is purified by column-chromatography with chloroform. The pure fractions are collected and the solvent is evaporated, yielding octyl p-(2-thenoyl)-hydratropate as a residue.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.Cl.[O-:24][C:25]#[N:26].[Na+]>>[NH:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1)[C:25]([NH2:26])=[O:24]
Reactant: N#C[O-]
Reactant: Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Agent: Cl
Agent: [Na+]
Product: NC(=O)Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Temperature: 0 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a mixture of 5-amino-3-(quinol-4-ylmethylene)-2-oxindole (2.873 g, 10 mmol) in ice water (20 ml) was added 5N HCl (2 ml, 10 mmol) under stirring. Then the mixture was heated to 70°-80° C., sodium cyanate (0.715 g, 11 mmol) was added portionwise and the stirring was continued for further 4 h at this temperature. After cooling, the raw product was extracted with CHCl3, the organic layer washed to neutrality with saline solution, dried and evaporated in vacuo. The residue was chromatographed on silica gel, using CHCl3 --MeOH mixtures as eluant to give pure title compound in about 50% yield.
Reaction SMILES: OS(O)(=O)=O.[F:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].[CH:14]([C:16]([CH3:18])=O)=[CH2:15]>O1CCOCC1>[F:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:8]=1[N:9]=[CH:15][CH:14]=[C:16]2[CH3:18]
Reactant: Nc1ccccc1F
Reactant: C=CC(C)=O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccnc2c(F)cccc12
Yield: 41.4 %

Procedure:
Add H2SO4 (14.4 mL, 270 mmol) to a solution of 2-fluoroaniline (20.0 g, 180 mmol) in 1,4-dioxane (1 L) at room temperature. Heat the mixture to reflux and add methyl vinyl ketone (19.5 mL, 270 mmol) in 1,4-dioxane (50 mL) dropwise over 3 hours. Continue to heat for 1 hour after the addition, then remove the solvent under vacuum. Dissolve the residue in water (100 mL), neutralize with Na2CO3 and extract with CH2Cl2. Wash the combined organic extracts with water and brine, dry with anhydrous Na2SO4 and filter the mixture. Concentrate the filtrate; chromatograph the residue with silica gel (elute with 20% EtOAc in hexanes) to give the title compound 12 g (41%) as a yellowish solid.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[P:20]([O:32][CH2:33][C@H:34]1[O:38][C@@H:37]([N:39]2[C:48]3[N:47]=[CH:46][N:45]=[C:43](N)[C:42]=3[N:41]=[CH:40]2)[C@H:36]([OH:49])[C@@H:35]1[OH:50])([O:23]P(OP(O)(O)=O)(O)=O)(=[O:22])[OH:21].[OH-].[Na+].P(O)(O)([O-])=[O:54].[K+]>>[C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[CH:46]1[NH:47][C:48]2[N:39]([C@@H:37]3[O:38][C@H:34]([CH2:33][O:32][P:20]([OH:21])([OH:23])=[O:22])[C@@H:35]([OH:50])[C@H:36]3[OH:49])[CH:40]=[N:41][C:42]=2[C:43](=[O:54])[N:45]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: O=P([O-])(O)O
Agent: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Agent: [K+]
Agent: [Na+]
Product: O=c1nc[nH]c2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
After completion of fermentation, about 30 g/l of inosine was accumulated in the medium obained in (8) above. As indicated in Table 9, 20 ml of a reaction mixture containing this medium was prepared. In a manner similar to (9), while keeping at 32° C. with vigorously stirring and also keeping pH at 7.2 with 4N NaOH, a reaction was carried out for 13 hours. During the course of reaction, monopotassium phosphate was added as in (9). From 23.5 g/l of initial inosine, 46 g/l of 5'-IMP was produced and accumulated. Also in this case, its molar conversion rate was 90% or more, as in (9).
Reaction SMILES: O=C1CCC2C(=CC(OCCCC[N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:38]=[CH:37][CH:36]=[CH:35][C:24]=4[O:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH:32](C)[CH3:33])=[O:30])[CH2:19][CH2:18]3)=CC=2)N1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:20]1([C:23]2[CH:38]=[CH:37][CH:36]=[CH:35][C:24]=2[O:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:19][CH2:18][NH:17][CH2:22][CH2:21]1
Reactant: CC(C)OC(=O)CCCOc1ccccc1N1CCN(CCCCOc2ccc3c(c2)NC(=O)CC3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCCOc1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(2-(4-ethoxy-4-oxobutoxy)phenyl)piperazine-1-carboxylate 13c (0.5 g) in 1 mL DCM was added 1 mL trifluoroacetic acid. The resulting mixture was stirred at rt for 1 h. The color of the reaction mixture darkened and a gas was evolved. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was concentrated on rotavapor and the residue was poured onto a mixture of crushed ice and sodium bicarbonate (NaHCO3). The aqueous layer was extracted with DCM, dried over magnesium sulfate and evaporated the solvent to give ethyl 4-(2-(piperazin-1-yl)phenoxy)butanoate 25. The compound 25 was carried to next step without any further purification. Brown oil, 0.37 g (99%). 1H NMR (400 MHz, CDCl3): δ 1.22 (t, J=7.2 Hz, 3H); 2.13 (quintet, J=6.8 Hz, 2H); 2.51 (t, J=7.2 Hz, 2H); 3.08 (broad s, 8H); 4.02 (t, J=6.0 Hz, 2H); 4.11 (q, J=7.2 Hz, 2H); 6.82-6.97 (m, 4H). MS (ESI): m/z=293.50 (M+H+).
Reaction SMILES: C[O:2][C:3](OC)([CH3:32])[C:4]([C:6]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[N:9]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:29]=[CH:28][O:27][N:26]=3)=[CH:21][CH:20]=2)[C:8](=[O:30])[C:7]=1[OH:31])=[O:5].C(O)(=O)C>O>[O:5]=[C:4]([C:6]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[N:9]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:29]=[CH:28][O:27][N:26]=3)=[CH:21][CH:20]=2)[C:8](=[O:30])[C:7]=1[OH:31])[C:3](=[O:2])[CH3:32]
Reactant: COc1ccccc1C1C(C(=O)C(C)(OC)OC)=C(O)C(=O)N1c1ccc(-c2ccon2)cc1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccccc1C1C(C(=O)C(C)=O)=C(O)C(=O)N1c1ccc(-c2ccon2)cc1
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 70.3 %

Procedure:
4-(2,2-dimethoxypropionoyl)-3-hydroxy-1-(4-isoxazol-3-ylphenyl)-5-(2-methoxyphenyl)-1,5-dihydropyrrol-2-one (0.08 g, 0.17 mmol) was added with acetic acid (0.1 mL) and water (0.9 mL). The mixture was stirred at 95° C. for 15 min. Then, water was added, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from dichloromethane and ether to give 4-(1,2-dioxopropyl)-3-hydroxy-1-(4-isoxazol-3-ylphenyl)-5-(2-methoxyphenyl)-1,5-dihydropyrrol-2-one (0.05 g, 70%) as yellow crystals.