Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12]N(C=O)C.S(Cl)(Cl)=O>CO>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: CN(C)C=O
Reactant: Cc1cc(C(=O)O)ccc1O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 4-hydroxy-3-methylbenzoic acid (10.00 g, 65.7 mmol) and DMF (100 μL) in MeOH (35 mL) was added dropwise thionyl chloride (4.8 mL, 65.7 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with the addition of aqueous saturated sodium bicarbonate solution (50 mL), and methanol was removed under reduced pressure. The residue was extracted with EtOAc (3×50 mL) and dried over sodium sulfate, filtered and concentrated in vacuo to provide methyl 4-hydroxy-3-methyl-benzoate (10.53 g, 96%) as a light brown solid. ESI-MS m/z calc. 166.0. found 167.1 (M+1)+; Retention time: 1.09 minutes (3 min run).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([Br:28])[N:23]=[C:22]3[O:29][CH2:30][CH2:31][CH3:32])=[CH:16][C:15]=2[F:33])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:35][OH:36].N1C=CC=CC=1>O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:35][OH:36])=[C:24]([Br:28])[N:23]=[C:22]3[O:29][CH2:30][CH2:31][CH3:32])=[CH:16][C:15]=2[F:33])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)c(F)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCOc1nc(Br)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
Compound A (4.7 g, 9.0 mmol), hydroxylamine hydrochloride (943 mg, 13.6 mmol), pyridine (60 mL, 740 mmol), and water (30 mL, 1.7 mol) were combined and stirred at room temperature overnight. Additional water (30 mL) was added, and the solids were filtered, washed with water, and dried to yield compound B (4.4 g) as a white solid, which was used without further purification.
Reaction SMILES: [C@@H:1]1([OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[OH:7].[C:9](=O)(OC)[O:10]C.C[O-].[Na+]>>[O:7]1[CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]2[O:8][C:9]1=[O:10]
Reactant: COC(=O)OC
Reactant: O[C@@H]1CCCC[C@H]1O
Agent: C[O-]
Agent: [Na+]
Product: O=C1OC2CCCCC2O1
Yield: 93 %

Procedure:
Into 10 g (86 mmol) of trans-1,2-cyclohexanediol (CAS No. 1460-57-7) and 87.7 g (86 mmol) of dimethyl carbonate was added 0.5 g (9 mmol) of sodium methoxide. The resulting mixture was refluxed for 1 hour. After methanol was removed from the mixture, rectification was carried out. A purified hexahydro-1,3-benzodioxol-2-one (trans isomer) was recovered with a yield of 93%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([O:7][CH2:8][C:9]([OH:11])=O)[C:3]=1[Br:12].[N+]([O-])(O)=O.[O:17]([CH2:21][CH2:22][NH2:23])[N+:18]([O-:20])=[O:19].C(OC(C)C)(C)C>>[O:17]([CH2:21][CH2:22][NH:23][C:9](=[O:11])[CH2:8][O:7][C:4]1[C:3]([Br:12])=[C:2]([CH3:1])[O:6][N:5]=1)[N+:18]([O-:20])=[O:19]
Reactant: NCCO[N+](=O)[O-]
Reactant: Cc1onc(OCC(=O)O)c1Br
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: Cc1onc(OCC(=O)NCCO[N+](=O)[O-])c1Br
Yield: 40.9 %

Procedure:
Following a similar treatment to that in Example 2 and using 472 mg of 5-methyl-4-bromo-3-isoxazolyloxyacetic acid and 338 mg of nitroxyethylamine nitrate, 265 mg of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br.Br[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: BrCc1ccccn1
Agent: Br
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1ccccn1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(pyridin-2-ylmethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 2-(bromomethyl)pyridine hydrobromide following General Procedure H.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[N:4][C:3]=1[NH2:12].[H-].[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[N:5]=[N:4][C:3]=1[NH:12][CH:25]1[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:23][CH2:24]1
Reactant: Nc1nnc(C(F)(F)F)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nnc(C(F)(F)F)cc2Cl)CC1
Temperature: 85 °C
Yield: 35.7 %

Procedure:
To a stirred solution of D7 (1.6 g, 8.1 mmol) in dimethylformamide (50 ml) at 0° C., under nitrogen, was added NaH (60% in oil; 390 mg, 8.1 mmol) portionwise. The reaction mixture was stirred for 1 h, before 4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid tert-butyl ester (2.9 g, 8.1 mmol), dissolved in dimethylformamide (10 ml), was added dropwise. The reaction mixture was then heated between 80-90° C. for 6 hours. After cooling to room temperature, the solvents were evaporated in vacuo. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried (MgSO4), filtered and the solvents were evaporated in vacuo. The crude product was purified by column chromatography (silica gel; 3% methanol in dichloromethane) to give D8 (1.1 g, 37%). C15H20ClF3N4O2 requires 380; Found 381 (MH+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=5)=[C:36]([C:48]([F:51])([F:50])[F:49])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:61])C=1.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:28])([F:29])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:61])=[C:36]([C:48]([F:51])([F:49])[F:50])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)c(C(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(C(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(2-pyridyl)methyl]-3-trifluoromethylphenyl]-1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (355 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (205 mg), and the mixture was stirred overnight under nitrogen atmosphere. To the mixture was added water, and the mixture was extracted with ethyl acetate, washed with an aqueous solution of saturated sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (176 mg) as colorless amorphous.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([OH:17])=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:18][CH2:19][CH3:20].I[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>O>[CH3:1][CH:2]([CH3:21])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([O:17][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:18][CH2:19][CH3:20]
Reactant: CC(C)(C)OC(=O)NCCCI
Reactant: CCCc1nc2cnc3cc(O)ccc3c2n1CC(C)C
Solvent: O
Product: CCCc1nc2cnc3cc(OCCCNC(=O)OC(C)(C)C)ccc3c2n1CC(C)C

Procedure:
A modification of the general method described in Part L of Example 2 was used to treat 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol with tert-butyl 3-iodopropylcarbamate. The reaction mixture was diluted with water; a precipitate formed. The precipitate was isolated by filtration, washed with water and then with diethyl ether until the filtrate was clear, and dried overnight in a vacuum oven at 60° C. to yield tert-butyl 3-{[1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propylcarbamate as a tan powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:27])[C@H:11]([OH:26])[C@H:12]2[O:17][CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=3)[C:13]2=[O:25])=[CH:5][CH:4]=1)#[N:2].[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:27])[C@H:11]([OH:26])[C@H:12]2[O:17][CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:29]4[S:28][CH:32]=[CH:31][CH:30]=4)=[CH:20][CH:19]=3)[C:13]2=[O:25])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(I)cc3)C2=O)cc1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(-c4cccs4)cc3)C2=O)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a suspension of compound 14-4 (80 mg) in THF—H2O (2 mL-0.67 mL), were added 2-thiopheneboronic acid (43 mgl), Cs2CO3 (0.44 g), and Pd(Ph3P)4 (19.4 mg). The mixture was stirred at 80° C. for 15 hours. The reaction mixture was filtered with Celite® pad and rinsed with the mixed solvent (EtOAc-MeOH=1-1). The filtrate was concentrated in vacuo and the resulting residue was washed with H2O and Et2O. The precipitate was collected by filtration to obtain compound 22-1 (35 mg) as a pale brown amorphous solid.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].[OH:11][CH2:12][CH2:13][NH:14][NH2:15].Cl.N>O.CO>[NH2:6][C:5]1[N:14]([CH2:13][CH2:12][OH:11])[N:15]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: COC(OC)C(C#N)=NO
Reactant: NNCCO
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Product: Nc1c(N=O)cnn1CCO
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a flask having an inner volume of 50 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 4.59 g (30 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 94.3% by weight synthesized in the same manner as in Example 1, 2.98 g (31.5 mmol) of 2-hydroxyethylhydrazine with a purity of 80.5% by weight, 7.8 ml of methanol and 4.5 ml (54 mmol) of conc. hydrochloric acid, and the mixture was reacted at 50 to 52° C. for 3 hours. After completion of the reaction, 7 ml of water was added to the mixture and the resulting mixture was cooled up to 10° C. Then, 3.5 ml (58 mmol) of 28% by weight aqueous ammonia was gradually added dropwise to the mixture, and the mixture was stirred for 30 minutes while maintaining the liquid temperature to 5° C. or lower. The precipitated crystals were collected by filtration, and then, the crystals were washed with 2.5 ml of cold water and 2.5 ml of cold methanol, and dried under reduced pressure to obtain 3.40 g of 5-amino-1-(2-hydroxyethyl)-4-nitrosopyrazole (Isolation yield: 69.7%) as reddish orange crystals with a purity of 96.0% by weight (absolute calibration curve method by high performance liquid chromatography).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([N+:18]([O-:20])=[O:19])=[C:7]([O:21][C:22]2[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:23]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:6]=1)(=O)=O.[CH3:38][N:39]([CH3:49])[C:40]([C:42]1[CH:43]=[C:44]([OH:48])[CH:45]=[CH:46][CH:47]=1)=[O:41]>>[CH3:38][N:39]([CH3:49])[C:40]([C:42]1[CH:43]=[C:44]([CH:45]=[CH:46][CH:47]=1)[O:48][C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([N+:18]([O-:20])=[O:19])=[C:7]([O:21][C:22]2[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:23]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:6]=1)=[O:41]
Reactant: CN(C)C(=O)c1cccc(O)c1
Reactant: CCOC(=O)CNc1nc(S(C)(=O)=O)nc(Oc2cc(C#N)ccc2OCc2ccccc2)c1[N+](=O)[O-]
Product: CCOC(=O)CNc1nc(Oc2cccc(C(=O)N(C)C)c2)nc(Oc2cc(C#N)ccc2OCc2ccccc2)c1[N+](=O)[O-]

Procedure:
In a similar manner, 2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (M), prepared as described below in Preparation 4, is treated with 3-(dimethylaminocarbonyl)phenol, a compound of formula (B) to afford 2-(3-dimethylaminocarbonylphenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (N).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9]C(C)(O)C)[CH:5]=[CH:4][C:3]=1[CH3:14].[OH-].[Na+].C1C=CC=CC=1>O>[F:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[CH:4][C:3]=1[CH3:14]
Reactant: Cc1ccc(C#CC(C)(C)O)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: C#Cc1ccc(C)c(F)c1
Yield: 40 %

Procedure:
The mixture of 2-fluoro-4-(3-methyl-3-hydroxy-1-butynyl)toluene (0.035 mol), sodium hydroxide (0.07 mol), and benzene 40 ml was refluxed for 3 hours. After cooling, water 40 ml was added and the mixture was thoroughly stirred. Insoluble materials were filtered away with Celite (trade name of Johns-Manville Company), and the residue was dried over anhydrous magnesium sulfate. The drying agent was separated away, the solvent was carefully distilled away from the solution under reduced pressure, the residue was purified by silica gel chromatography (elution liquid: hexane) and then distilled away the solvent under reduced pressure (boiling point: 100° C., 20 mmHg) to obtain cororless oily 2-fluoro-4-ethynyltoluene (0.014 mol).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:11]([CH3:12])=[CH:10][C:9]([CH:13]=O)=[C:8]1[CH3:15])(=[O:3])[CH3:2].Cl.NO.[N:19]1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]#[N:19])=[C:8]1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCn1c(C)cc(C=O)c1C
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: Cc1ccccc1
Product: CC(=O)NCCn1c(C)cc(C#N)c1C

Procedure:
5.2 g (0.025 mol) of 1-(2-acetylaminoethyl)-2,5-dimethylpyrrole-3-aldehyde, 1.75 g (0.025 mol) of hydroxylamine hydrochloride and 2 ml (0.025 mol) of pyridine are heated under reflux in 25 ml of toluene for 1.5 hours. After the mixture has been concentrated, the residue is taken up in water, the mixture is extracted with methylene chloride and the product is recrystallized from toluene.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][C:9]=2[CH:13]=O)=[CH:4][CH:3]=1.Cl.[NH2:16]O.C([O-])(=O)C.[Na+]>C(O)C.C(OC(=O)C)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][C:9]=2[C:13]#[N:16])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccc(-c2ccoc2C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: Cc1ccc(-c2ccoc2C#N)cc1
Temperature: 65 °C
Yield: 89.8 %

Procedure:
A mixture of 3-(4-methylphenyl)furane-2-carbaldehyde (1.0 g), hydroxylamine hydrochloride (560 mg), and sodium acetate (660 mg) in 60% aqueous ethanol (10 ml) was stirred for one and half hours at 65° C. The mixture was concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried, and concentrated in vacuo to give a yellow solid. A mixture of the solid and sodium acetate (56 mg) in acetic anhydride (10.5 ml) was refluxed for 5 hours and then evaporated in vacuo. The residue was purified by column chromatography on silica gel (elution by n-hexane/ethyl acetate=15/1) to yield 3-(4-methylphenyl)furane-2-carbonitrile (884 mg) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N([CH2:33][C:34](C)([OH:36])[CH3:35])N>>[CH3:33][C:34]([OH:36])([CH3:35])[CH2:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1
Reactant: CC(C)(O)CNN
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Product: CC(C)(O)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-Hydrazino-2-methyl-propan-2-ol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=6.2 Hz, 2H), 8.19 (d, J=8.7 Hz, 1H), 8.07 (d, J=8.7 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.74 (t, J=8.3 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.62 (s, 1H), 7.55 (t, J=7.1 Hz, 1H), 7.39 (d, J=8.7 Hz, 2H), 7.17 (m, 2H), 7.01 (d, J=8.7 Hz, 2H), 5.39 (s, 2H) 4.09 (s, 2H), 1.23 (s, 2H); MS: (M+H m/z=451.2).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(P(N(C)C)(N(C)C)=O)C.[P:26](Cl)([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27].Cl>CN(C1C=CN=CC=1)C.CCOCC>[CH2:13]([O:12][C:10](=[O:11])/[CH:9]=[C:1](/[O:8][P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:14]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)/C=C(/OP(=O)(OCC)OCC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of ethyl benzoylacetate (10 g, 52.03 mmol) was added DMAP (699.2 mg, 5.72 mmol), HMPA (9.96 mL, 57.23 mmol), TEA (7.98 mL, 57.23 mmol). The resulting yellow solution was stirred at 0° C. for 30 minutes and then coiled to −20° C. Diethyl chlorophosphate was added dropwise to the cooled solution and a heavy precipitate began to form immediately. The yellow-orange paste was warmed to room temperature and stirred for another 4 hours. The reaction mixture was diluted with ether and acidified with 1N HCl. The ethereal extracts were washed with saturated aqueous CuSO4 to remove HMPA, dried over MgSO4, and concentrated. The residue was purified through flash column chromatography on silica gel (EtOAc:hexanes=2:3) to give 11.6 g in 68% yield.
Reaction SMILES: [C:1]1([C:7]2([CH2:16][C:17]([OH:19])=O)[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:32]>CCOCC>[C:1]1([C:7]2([CH2:16][C:17]([NH2:32])=[O:19])[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=C(O)CC1(c2ccccc2)Oc2ccccc2O1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: c1ccccc1
Product: NC(=O)CC1(c2ccccc2)Oc2ccccc2O1
Reaction time: 12 h

Procedure:
To 22 g. of (2-phenyl-1,3-benzodioxol-2-yl)-acetic acid in 300 cc. of anhydrous benzene, in the cold, 18.1 g. of PCl5 are added. After leaving the mixture for 2 hours to allow the reaction to be completed a cold solution of NH3 in anhydrous ether is added to the mixture, in drops and with shaking. After 12 hours, the mixture is poured onto ice. The organic phase is separated, washed with H2O until neutral, and finally dried with Na2SO4. The solvent is removed under vacuum and the residue is recrystallised from benzene, m.p. 114°-15°C.
Reaction SMILES: C([C@H]1COC(C2C=CC=C(C3OC[C@H](C(C)C)N=3)N=2)=N1)(C)C.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[O:32][CH2:33][C@H:34]2[O:38][C@@H:37]([N:39]3[CH:46]=[CH:45][C:43](=[O:44])[NH:42][C:40]3=[O:41])[C@H:36]([OH:47])[C@@H:35]2[OH:48])=[CH:27][CH:26]=1.[C:63]1([N:69]=[C:70]=[O:71])[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)OC[C@H]2O[C@@H](N3C=CC(=O)NC3=O)[C@H](OC(=O)NC3C=CC=CC=3)[C@@H]2O)=CC=1>[Cu](Cl)Cl.C1COCC1>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([C:55]2[CH:56]=[CH:57][C:58]([O:61][CH3:62])=[CH:59][CH:60]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[O:32][CH2:33][C@H:34]2[O:38][C@@H:37]([N:39]3[CH:46]=[CH:45][C:43](=[O:44])[NH:42][C:40]3=[O:41])[C@H:36]([OH:47])[C@@H:35]2[O:48][C:70](=[O:71])[NH:69][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C=Nc1ccccc1
Agent: Cl[Cu]Cl
Agent: CC(C)[C@H]1COC(c2cccc(C3=N[C@@H](C(C)C)CO3)n2)=N1
Agent: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OC(=O)Nc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2OC(=O)Nc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
The THF solution (2 ml) including 2,6-bis[(4S)-isopropyl-2-oxazoline-2-yl]pyridine (0.05 mmol, 15.2 mg) and copper chloride (II) (0.05 mmol, 6.9 mg) was stirred for a day at room temperature. After the reaction mixture was cooled to 0° C., the THF solution (2 ml) of 5′-O-[bis(4-methoxyphenyl)phenylmethyl]uridine (0.5 mmol, 274 mg) and the THF solution (2 ml) of phenyl isocyanate (0.5 mmol, 59.6 mg) are added thereto. After the mixture was continuously stirred for two hours at 0° C., the mixture was analyzed with high-performance liquid chromatography. As a result, it was found that 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-2′-O-phenylcarbamoyl-uridine and 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-3′-O-phenylcarbamoyl-uridine were produced at the ratio of 94:6, and the transformation ratio of the reaction was not less than 99%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][CH:9]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CCN)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCNS(C)(=O)=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 72.2 %

Procedure:
Methanesulfonyl chloride (0.082 mL, 1.05 mmol) was added dropwise to tert-butyl 3-amino-1-(4-chlorophenyl)propylcarbamate (Intermediate 25) (300 mg, 1.05 mmol) and N,N-diisopropylethylamine (0.367 mL, 2.11 mmol) in DCM (4 mL) at 20° C. The resulting solution was stirred at 20° C. for 18 hours. The reaction mixture was concentrated and diluted with Et2O (25 mL) and washed with water (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 1-(4-chlorophenyl)-3-(methylsulfonamido)propylcarbamate (275 mg, 71.9%) as a white solid.