Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[O:6]=[C:7]1[CH:14]2[CH2:15][C:10]3(O)[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2.[CH:18]([OH:20])=[O:19]>>[O:6]=[C:7]1[CH:14]2[CH2:15][C:10]3([C:18]([OH:20])=[O:19])[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Reactant: O=CO
Agent: O=S(=O)(O)O
Product: O=C1C2CC3CC1CC(C(=O)O)(C3)C2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 60% fuming sulfuric acid (135 ml) stirred under heating at 80° C., a solution of 4-oxoadamantan-1-ol (15.69 g) in formic acid (250 ml) was added dropwise over 2 hours. After completion of the dropwise addition, the reaction mixture was stirred at 80° C. for 3 hours, to which formic acid (100 ml) was then added at room temperature and stirred overnight at room temperature. After addition of additional formic acid (50 ml), the reaction mixture was stirred at 80° C. for 12 hours and then stirred overnight at room temperature. The reaction mixture was poured into ice-cold water, filtered to remove insoluble materials and then extracted three times with toluene. After the combined organic layers were extracted with 4M aqueous sodium hydroxide, the aqueous layer was washed three times with chloroform. The aqueous layer was adjusted to pH 1 to 2 by addition of 12M aqueous hydrochloric acid and then extracted with chloroform. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to give 4-oxoadamantane-1-carboxylic acid (9.84 g) as a colorless powder. To a solution of 4-oxoadamantane-1-carboxylic acid thus obtained (1.50 g) in 8M ammonia/methanol (30 ml), 10% palladium on activated carbon (150 mg) was added and stirred overnight under a hydrogen atmosphere at room temperature. After addition of water (10 ml), the reaction mixture was filtered through celite and washed with methanol, and the filtrate was concentrated under reduced pressure. To the resulting crystal, acetonitrile (30 ml) was added and stirred at room temperature for 3 hours. The crystal was collected by filtration to give 4-aminoadamantane-1-carboxylic acid (1.28 g) as a colorless powder. To a solution of 4-aminoadamantane-1-carboxylic acid thus obtained (1.28 g) in methanol (13 ml), acetyl chloride (2.34 ml) was added under ice cooling and stirred at room temperature for 20 minutes and then at 45° C. for 8 hours. The reaction mixture was stirred overnight at room temperature and then further stirred at 45° C. for 4 hours. After the reaction mixture was cooled to room temperature and then concentrated, the resulting crystal was dissolved in chloroform and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was converted into a powder form by addition of acetonitrile (10 ml). The crystal was collected by filtration and washed sequentially with acetonitrile and n-hexane to give the titled compound, i.e., methyl 4-aminoadamantane-1-carboxylate (1.22 g) as a colorless powder.
Reaction SMILES: ClC1C=[C:10]2[C:5]([C:6](=O)[C:7]([CH2:18][NH:19][C:20](=[O:31])OC3C=CC([N+]([O-])=O)=CC=3)=CN2C2C=CC=CC=2)=CC=1.C1([NH2:38])CCCC1>>[CH:18]1([NH:19][C:20](=[O:31])[NH2:38])[CH2:7][CH2:6][CH2:5][CH2:10]1
Reactant: NC1CCCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Product: NC(=O)NC1CCCC1

Procedure:
7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3-cyclopentyl-urea was prepared starting from intermediate M and cyclopentylamine. MS calcd. for C22H23ClN3O2 [(M+H)+] 396.1, obsd. 396.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11]C)=[O:10])[CH:5]=[N:6][CH:7]=1.[N:13]1(C2C=C(CC(O)=O)C=CN=2)[CH:17]=[N:16][N:15]=[N:14]1>>[N:13]1([C:2]2[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[N:6][CH:7]=2)[CH:17]=[N:16][N:15]=[N:14]1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: O=C(O)Cc1ccnc(-n2cnnn2)c1
Product: O=C(O)Cc1cncc(-n2cnnn2)c1

Procedure:
[5-(1H-Tetrazol-1-yl)pyridin-3-yl]acetic acid was prepared from methyl (5-bromopyridin-3-yl)acetate according to the procedure outlined for the preparation of intermediate [2-(1H-tetrazol-1-yl)pyridin-4-yl]acetic acid, except that in the final step the ester was hydrolyzed under basic conditions rather than acid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[C:12][C:13]#[N:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Cl.[NH2:16][OH:17]>CCO.[OH-].[Na+].CCOC(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:17][N:16]=[C:13]([NH2:14])[CH:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: N#CC#Cc1ccc2cnccc2c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(-c2ccc3cnccc3c2)on1
Reaction time: 3 h
Yield: 97.5 %

Procedure:
3-(Isoquinolin-6-yl)propiolonitrile (0.060 g, 0.34 mmol) was suspended in 3.0 mL of EtOH. Hydroxylamine hydrochloride (0.070 g, 1.0 mmol) was added to the mixture in 1.5 mL of 10% aq. NaOH. The solution turned a clear, light yellow color immediately. After 3 hours, the reaction mixture was diluted with 20 mL of EtOAc and transferred to a separatory funnel. The mixture was washed with 3 mL of water and 5 mL of brine. The organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure, affording 5-(isoquinolin-6-yl)isoxazol-3-amine (0.070 g, 98% yield) as a yellow solid. MS m/z: 212 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 9.36 (s, 1H), 8.56 (d, J=5.7 Hz, 1H), 8.40 (s, 1H), 8.23 (d, J=8.6 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.93 (d, J=5.9 Hz, 1H), 6.57 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[C:9](O)=O)[CH:5]=[CH:6][CH:7]=1.[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([NH2:21])=[C:16]([NH2:22])[CH:15]=1.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]2[NH:21][C:17]3[CH:18]=[C:19]([F:20])[C:14]([F:13])=[CH:15][C:16]=3[N:22]=2)[OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(O)c1cccc(Br)c1
Reactant: Nc1cc(F)c(F)cc1N
Agent: [Na+]
Agent: [OH-]
Product: OC(c1cccc(Br)c1)c1nc2cc(F)c(F)cc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of (3-bromophenyl)hydroxyacetic acid (809 mg) and 4,5-difluoro-ortho-phenylenediamine (500 mg) in 5N aqueous hydrochloric solution (2 mL) is heated under reflux for 15 h and cooled back to room temperature. The mixture is basified with concentrated sodium hydroxide and extracted with ethyl acetate. The organic phase is then dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by trituration in dichloromethane to afford the pure 3-bromophenyl(5,6-difluoro-1H-benzimidazol-2-yl)methanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:14](=[O:34])[N:13]1[CH:9]([CH2:10][CH:11]([OH:35])[CH2:12]1)[C:8](=[O:36])[NH:7]2)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.[CH2:46]([O:48][CH2:49]Cl)[CH3:47]>ClCCl>[CH2:1]([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:14](=[O:34])[N:13]1[CH:9]([CH2:10][CH:11]([O:35][CH2:49][O:48][CH2:46][CH3:47])[CH2:12]1)[C:8](=[O:36])[NH:7]2)=[O:5])[CH3:2]
Reactant: CCOCCl
Reactant: CCOC(=O)C12CC1C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(O)CC1C(=O)N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCOC1CC2C(=O)NC3(C(=O)OCC)CC3C=CCCCCCN(Cc3ccc(OC)cc3)C(=O)N2C1
Temperature: 25 °C

Procedure:
To a stirred solution of the alcohol 21f (1.35 g, 2.70 mmol, 75% purity) and N-ethyldiisopropylamine (1.42 ml, 8.1 mmol) in dichloromethane (15 ml) at 0° C. was added chloromethyl ethyl ether (0.5 ml, 5.4 mmol). After stirring at rt on the reaction mixture was cooled to 0° C. and more N-ethyldiisopropylamine (1 ml, 5.7 mmol) and chloromethyl ethyl ether (0.3 ml, 3.2 mmol) was added, then stirred additional 16 h at rt. The reaction mixture was then directly applied on a silicagel column and eluted using stepwise gradient elution (ethyl acetate in hexane 50-80%). Concentration of the appropriate fractions gave the title compound as a slight brown syrup which crystallized upon standing (0.8 g, 53%). LR-MS: Calcd for C30H44N3O7: 558. Found: 558 [M+H].
Reaction SMILES: [CH3:1][NH2:2].Br[CH:4]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:7]=2[NH:6][C:5]1=[O:23]>C1COCC1.CCOC(C)=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:7]2[NH:6][C:5](=[O:23])[CH:4]([NH:2][CH3:1])[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:8]=2[CH:18]=1
Reactant: CN
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2Cl)=CC1Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC1C=C(c2ccccc2Cl)c2cc(Cl)ccc2NC1=O
Reaction time: 0.17 h

Procedure:
A solution of methyl amine (16.0 mL of a 1.1N THF solution, 17.6 mmole) in 50 mL of dry THF was cooled to 0°-5° C. in an ice-water bath. To this solution was added, over a ten minute period, a solution of crude rac-3-bromo-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2-H1-benzazepin-2-one (3.36 g estimated to be 85% pure, 7.36 mmole), dissolved in 55 mL of THF. After 10 minutes, the reaction solution was diluted with 300 mL of EtOAc, washed with water and brine, and dried (sodium sulfate). Concentration and drying under high vacuum yielded 2.98 g of crude material, which was used as is in the next step.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[S:8])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[CH:3]=1.[CH3:16][O-].[Na+].CI>CO>[NH2:1][C:2]1[CH:3]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:5]([C:9]#[N:10])=[C:6]([S:8][CH3:16])[N:7]=1
Reactant: C[O-]
Reactant: N#Cc1c(-c2ccco2)cc(N)[nH]c1=S
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSc1nc(N)cc(-c2ccco2)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
To a stirred solution of 150 mg (0.69 mmol) 6-amino-4-furan-2-yl-2-thioxo-1,2-dihydro-pyridine-3-carbonitrile in 3 ml methanol were added 0.13 ml (0.69 mmol) sodium methylate solution (5.4M in ethanol) and 0.04 ml (0.69 mmol) methyl iodide and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was then concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ether to afford 113 mg (71%) 6-amino-4-furan-2-yl-2-methylsulfanyl-nicotinonitrile as a brown crystalline solid. ES-MS m/e (%): 232 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[CH:6]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=1.Br[CH2:28][C:29]([N:31]([CH3:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>CN(C=O)C>[CH3:3][C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:28][C:29]([N:31]([CH3:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:30])[C:7](=[O:15])[CH:6]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=1
Reactant: CN(C(=O)CBr)c1ccccc1
Reactant: CC1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=NC(NC(=O)OCc2ccccc2)C(=O)N(CC(=O)N(C)c2ccccc2)c2ccccc21
Reaction time: 0.5 h
Yield: 39 %

Procedure:
80% Sodium hydride in oil (102 mg) was added to a solution of phenylmethyl [2,3-dihydro-5-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]carbamate (1.00 g) in dry DMF (10 ml) under nitrogen. The mixture was stirred for 0.5 h at 23° and was treated with a solution of 2-bromo-N-methyl-N-phenylacetamide (707 mg) in dry DMF (1 ml). The mixture was stirred at 23° for 1 h, partitioned between phosphate buffer solution (pH6.5) and EA, the organic phase was washed with water and dried. The solvent was evaporated in vacuo and the residue was purified by chromatography on alumina. Elution with MeOH-DCM (1:50) gave the title compound (568 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[C:3]=1N.COCCO.S(=O)(=O)(O)O.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[CH:3]=1
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COCCO
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cc(Cl)c1
Yield: 92 %

Procedure:
207 parts of 2,6-dichloro-4-nitro-aniline are introduced into 500 parts of glycol monomethyl ether and 1,000 parts of 50 percent strength by weight sulfuric acid are then added to the mixture. 90 parts of NaNO2 in 150 parts of water are added slowly at 70° C. The mixture is cooled and the product is filtered off. 179 parts (92% of theory) of 3,5-dichloro-nitro-benzene, of melting point 56°-59° C., are obtained.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[Cl:9][C:10]1[CH:11]=[C:12]([N+:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=[CH:14][C:15]=1[C:16]([O:18]C)=[O:17].FC(F)(F)C(O)=O>O>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[C:16]([C:15]1[CH:14]=[CH:13][C:12]([N+:20]([CH3:22])([CH3:21])[CH3:23])=[CH:11][C:10]=1[Cl:9])([OH:18])=[O:17]
Reactant: COC(=O)c1ccc([N+](C)(C)C)cc1Cl
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[N+](C)(C)c1ccc(C(=O)O)c(Cl)c1

Procedure:
A solution of 0.5 g (1.32 mmol) 1b, 12 ml dest. water and 12 ml trifluoroacetic acid was refluxed for 2 days. The reaction mixture was evaporated, dried by use of oil pump vacuum over night and treated with diethyl ether. The resulting solid was filtered, washed extensively with diethyl ether and dried by oil pump vacuum. The solid crude 1c was obtained in 98% yield (471 mg, 1.3 mmol) and crude compound 1c was used for the next step without purification.
Reaction SMILES: [CH:1]1([CH:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:8][C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[CH:1]1([CH:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:8][C:9]([Cl:21])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CC(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CC(C1CCCCC1)C1CCCCC1
Reaction time: 1 h
Yield: 98 %

Procedure:
A stirred solution of 3,3-dicyclohexylpropionic acid (15.2 g, 0.064 mol) in 225 ml of dichloromethane was cooled to 5° C. and treated with 6.8 ml (0.078 mol) of oxalyl chloride, followed by 10 drops of dimethylformamide. The cooling bath was removed and stirring was continued at room temperature. Gas evolution, which was vigorous initially, essentially ceased after 1 hour. After 3 hours, dichloromethane and excess oxalyl chloride were removed on a rotary evaporator. The residue was taken up in dichloromethane and the evaporation was repeated to give 16.1 g of a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5].[H-].[Na+].[I-].[Na+].Cl[CH2:29][C:30]([NH2:32])=[O:31]>CN(C)C=O.O>[C:30]([CH2:29][O:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5])(=[O:31])[NH2:32]
Reactant: NC(=O)CCl
Reactant: O=C(NCc1ccccn1)c1cc(OCC(F)(F)F)ccc1O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)COc1ccc(OCC(F)(F)F)cc1C(=O)NCc1ccccn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of 6.5 g (0.02 mole) of 2-hydroxy-N-(2-pyridylmethyl)-5-(2,2,2-trifluoroethoxy)benzamide in 20 ml of dimethylformamide was added dropwise to a suspension of 0.021 mole of sodium hydride in 10 ml dimethylformamide. The resulting mixture was stirred at about 25° C. for 30 minutes, at 60° C. for 30 minutes, and then 0.3 g of sodium iodide was added followed by the addition of a solution of 1.7 g (0.018 mole) of 2-chloroacetamide in 15 ml dry dimethylformamide. The reaction mixture was stirred for about 16 hours at 60° C. and then poured into 500 ml cold water. The resulting precipitate was collected and dried, then dissolved in a minimum of 5% methanol in chloroform and washed through a column of basic alumina. The eluent was evaporated to give a white solid which was recrystallized from about 300 ml of 3:4 water:ethanol to give 4.9 g of white crystalline 2-carbamoylmethoxy-N-(2-pyridylmethyl)-5-(2,2,2-trifluoroethoxy)benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[N:9][C:8]2=[O:26])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:9][C:8]2=[O:26])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncn(Cc3ccc(Cl)cc3)c(=O)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1nc(N2CCNCC2)ncn1Cc1ccc(Cl)cc1
Yield: 45.8 %

Procedure:
To a dichloromethane solution (92 mL) of tert-butyl 4-[5-(4-chlorobenzyl)-4-oxo-4,5-dihydro-1,3,5-triazin-2-yl]piperazine-1-carboxylate (9.20 g, 22.7 mmol) synthesized in Reference Synthesis Example 8, trifluoroacetic acid (40 mL) was added and the resultant solution was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and pH was adjusted to 7 by adding water and saturated sodium bicarbonate aqueous solution. Extraction with ethyl acetate from the resultant liquid was performed three times, and the organic layer was washed with brine. A deposited solid was collected by filtration, washed with water and ethyl acetate, and dried under reduced pressure to obtain the title compound (3.18 g, yield 46%).
Reaction SMILES: [CH:1]1([OH:13])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[Br:14]N1C(=O)CCC1=O>CN(C=O)C>[Br:14][C:6]1[C:7]2[C:12]3[C:3]([CH2:2][CH:1]([OH:13])[C:11]=3[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:5]=1
Reactant: OC1Cc2cccc3cccc1c23
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: OC1Cc2ccc(Br)c3cccc1c23
Reaction time: 3 h

Procedure:
To 1,2-dihydro-1-acenaphthylenol (0.34 g, 2 mmol) in dry DMF (10 mL) was added recrystallised N-bromosuccinimide (0.39 g, 2.2 mmol), and the mixture stirred for 3 h under nitrogen. The solution was poured onto water (500 mL) and the precipitate filtered off. The resultant solid was redissolved in methanol, filtered and evaporated in vacuo to yield the title compound as a brown solid.
Reaction SMILES: [NH2:1][O:2][CH2:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1.[CH3:22][C:23]([CH3:25])=O>CO.C(#N)C>[NH2:16][C:8]1[C:7]2[N:17]=[C:4]([CH2:3][O:2][N:1]=[C:23]([CH3:25])[CH3:22])[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]=2[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[N:9]=1
Reactant: CC(C)Cn1c(CON)nc2c(N)nc3c(c21)CCCC3
Reactant: CC(C)=O
Solvent: CO
Solvent: CC#N
Product: CC(C)=NOCc1nc2c(N)nc3c(c2n1CC(C)C)CCCC3

Procedure:
A solution of 2-[(aminooxy)methyl]-1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (700 mg, 2.42 mmol) in methanol (12 mL) and acetone (12 mL) was stirred at room temperature for 1 day, then was concentrated under reduced pressure to yield an oil. The oil was diluted with acetonitrile and concentrated under reduced pressure to yield a solid that was recrystallized from acetonitrile. The crystals were isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to yield 379 mg of acetone O-{[4-amino-1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-2-yl]methyl}oxime as white crystals, mp 176-177° C.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[CH2:8][C:7](=O)[N:6]([C:12]3[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=3[F:19])[C:5]2=[O:20])[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:23])=O.CN(C)C1C=CC=CC=1>O>[Cl:23][C:7]1[N:6]([C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[C:5](=[O:20])[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:9](=[O:10])[CH:8]=1
Reactant: O=C1CC(=O)N(C2CC2)C(=O)N1c1ccc(I)cc1F
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)c1ccccc1
Product: O=c1cc(Cl)n(-c2ccc(I)cc2F)c(=O)n1C1CC1
Temperature: 110 °C

Procedure:
To 1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-pyrimidine-2,4,6-trione 49 (59.0 g) obtained in Step 2 were added phosphorus oxychloride (85.0 ml) and dimethylaniline (29.0 ml), and water (8.3 ml) was added dropwise to the mixture at room temperature with stirring. After the completion of the dropwise addition, the mixture was stirred with heating at 110° C. for 1 hr. After allowing to cool to room temperature, the reaction mixture was added dropwise to ice water-toluene [2:1 (volume ratio), 900 ml] with stirring. The mixture was stirred at room temperature for 1 hr. The organic layer was separated, and washed successively with water (300 ml) and brine (300 ml). Anhydrous magnesium sulfate and activated carbon were added and the mixture was stirred. Anhydrous magnesium sulfate and activated carbon were filtered off, and the filtrate was concentrated under reduced pressure to give a 1:2 mixture (62.9 g) of 6-chloro-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione 50 and 6-chloro-1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione 51 as a yellow foamy oil, which was used for the next step without purification.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:12])[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2)[CH3:2].[CH2:13]([Li])[CH2:14]CC.CN(C)CCN(C)C.ICC.[NH4+].[Cl-]>C1COCC1>[CH2:1]([C:3]1([CH2:13][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:2]
Reactant: [Li]CCCC
Reactant: CCC1=c2ccccc2=NC1=O
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1(CC)C(=O)Nc2ccccc21
Temperature: 25 °C
Yield: 47.6 %

Procedure:
A solution of 3-ethyl-indol-2-one (16 g, 0.1 mol) in dry THF (200 ml) under N2 was cooled to −25° C. and treated drop wise with n-butyllithium (2.5M in hexanes, 80 ml, 0.2 mol). To the resulting solution was added N,N,N′,N′-tetramethylethylenediamine (30 ml, 0.2 mol). After 30 min. iodoethane (8 ml, 0.1 mol) was added and the reaction mixture was allowed to warm to RT and stirred over night. The reaction mixture was poured into an aqueous NH4Cl solution, extracted with EtOAc (2×) and the combined organic layers were washed with dil. HCl, water, brine, dried (MgSO4) and concentrated. The residual oil was triturated with hexane to afford 3,3-diethylindol-2-one (9 g, 45%), mp. 156-159° C.; 1H NMR (DMSO-d6) δ 10.44 (s, 1H), 7.70-7.69 (t, 1H), 7.62-7.59 (m, 1H), 7.58 (d, 1H J=1.7 Hz), 7.53-7.50 (m, 1H), 7.45-7.41 (t, 1H), 7.36-7.35 (m, 1H), 7.34-7.33 (m, 1H), 6.91-6.89 (d, 1H J=8.2 Hz), 1.87-1.80 (m, 2H), 1.77-1.70 (m, 2H), 0.54-0.50 (t, 6H); MS (+ESI) m/z 190 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[C:9][Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:6][CH:5]=[CH:4][N:3]=1>C1COCC1.CCCCCC>[F:1][C:2]1[C:7](/[CH:8]=[CH:9]\[Sn:10]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCCC[Sn](C#Cc1cccnc1F)(CCCC)CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](/C=C\c1cccnc1F)(CCCC)CCCC
Yield: 83.5 %

Procedure:
To a suspension of Cp2ZrHCl (2.58 g) in dry THF (50 mL) was added 2-fluoro-3-(tributylstannylethynyl)pyridine (2.05 g). After 2 hours the mixture was diluted with hexane and filtered through a short silica gel column. Evaporation of the solvents gave Z-2-fluoro-3-(2-tributylstannylethenyl)pyridine as an oil (1.72 g).