Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21](Cl)=[O:22])([O-:17])=[O:16]>C(Cl)Cl.CN(C)C>[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21]([O:14][C@@H:12]([C@@:9]1([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:11][O:10]1)[CH3:13])=[O:22])([O-:17])=[O:16]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: C[C@@H](O)C1(c2ccc(F)cc2F)CO1
Agent: CN(C)C
Solvent: ClCCl
Product: C[C@@H](OC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)[C@@]1(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 46.3 %

Procedure:
(1R)-1-[2-(2,4-Difluorophenyl)-2-oxiranyl]ethanol (31.5 g) and 3,5-dinitrobenzoyl chloride (40 g) were dissolved in methylene chloride (500 ml), to which trimethylamine (24.1 ml) was added dropwise at ice-bath temperature. After the mixture was stirred at room temperature for 3.5 hours, it was washed with water (150 ml) and 5% sodium bicarbonate aqueous solution successively, dried over magnesium sulfate and concentrated under reduced pressure. The precipitated crystals were filtrated and washed with methylene chloride. The mother liquor and the washings were combined and distilled off under reduced pressure. Ethyl acetate (25 ml) and methanol (300 ml) were added to the residue, and the mixture was cooled in an ice bath. The precipitated crystals were collected by filtration and recrystallized from a mixture of ethyl acetate (25 ml) and methanol (250 ml) to give [(1R)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethyl] 3,5-dinitrobenzoate (28.7 g) as colorless needles.
Reaction SMILES: C(OC(NC[C@H]1CC[C@H](C(O)=O)CC1)=O)(C)(C)C.C(OC(Cl)=O)C.C[CH:26]1[CH:31](C)[CH2:30][CH2:29][CH:28]([NH:33][C:34](=[O:69])[C@H:35]([CH2:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:57][CH:56]=2)[NH:36][C:37](=[O:53])[C:38]2[CH:43]=[CH:42][C:41]([CH2:44][NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[CH:40][CH:39]=2)[CH2:27]1>C(N(CC)CC)C>[CH:28]1([NH:33][C:34](=[O:69])[C@H:35]([CH2:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][CH2:62][C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)=[CH:57][CH:56]=2)[NH:36][C:37](=[O:53])[C:38]2[CH:39]=[CH:40][C:41]([CH2:44][NH:45][C:46]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:47])=[CH:42][CH:43]=2)[CH2:29][CH2:30][CH2:31][CH2:26][CH2:27]1
Reactant: CC1CCC(NC(=O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)CC1C
Agent: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)NC2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
Triethylamine (1.5 ml) was added to a solution of N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine (I) (2 g) dissolved in dry tetrahydrofuran (30 ml) and ethyl chlorocarbonate (0.65 g) was added under ice-cooling, followed by stirring for 30 minutes. To this solution was added 4-trifluoromethylaniline (0.65 g) and the mixture was stirred at room temperature for 10 hours. Post-treatment was carried out in the same manner as in Example 1 to obtain 1.3 g of N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine 4-trifluoromethylanilide (II). to the above compound (II) (0.5 g) was added under ice-cooling 4N-hydrogen chloride/dioxane solution (3 ml) and the mixture was stirred at room temperature for 30 minutes. Post-treatment conducted in the same manner as in Example 1 gave quantitatively 4-benzyloxy-L-phenylalanine 4-trifluoromethylanilide (III). On the other hand, trans-4-(t-butyloxycarbonyl)aminomethylcyclohexylcarboxylic acid (0.25 g) and triethylamine (0.2 ml) were added, and ethylchlorocarbonate (0.1 g) was added under ice-cooling, followed by stirring for 30 minutes. To this solution were added the above compound (III) (0.42 g) and triethylamine (1 ml), and the mixture was stirred at room temperature for 3 hours. After extraction with chloroform, according to the same post-treatment as in Example 1, 0.28 g of N-[trans-4-(t-butyloxycarbonyl)aminomethylcyclohexylcarbonyl]-4-benzyloxy-L-phenylalanine 4-trifluoromethylanilide (IV) was obtained. To the above compound (IV) (0.28 g) was added 4N-hydrogen chloride/dioxane solution (2 ml) and, after stirring at room temperature for 30 minutes, following the same procedure as in Example 1, 0.15 g of N-(trans-4-aminomethylcyclohexylcarbonyl)-4-benzyloxy-L-phenylalanine 4-trifluoromethylanilide hydrochloride was obtained.
Reaction SMILES: O=[C:2]([CH2:16][CH2:17][C:18]([O-:20])=[O:19])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:4].ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:46]([O:53][C:54]([NH:56][C@@H:57]1[CH2:61][O:60][NH:59][C:58]1=[O:62])=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[CH2:46]([O:53][C:54]([NH:56][C@@H:57]1[CH2:61][O:60][N:59]([C:2]2([C:3]([O:5][CH2:6][C:7]3[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=3)=[O:4])[CH2:16][CH2:17][C:18](=[O:19])[O:20]2)[C:58]1=[O:62])=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C([O-])CCC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(N[C@@H]1CONC1=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C1CCC(C(=O)OCc2ccc([N+](=O)[O-])cc2)(N2OC[C@@H](NC(=O)OCc3ccccc3)C2=O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
In 3 ml of dichloromethane were dissolved 85 mg of the Compound (1) obtained in Example 1 and 41 mg of 1-hydroxybenzotriazole (HOBT). To the solution was added 62 mg of DCC, and the mixture was stirred at room temperature for 30 minutes, to which was added 60 mg of (4R)-4-benzyloxycarbonylamino-3-isoxazolidinone, prepared by the method described in Journal of Medicinal Chemistry, 13 1013 (1970), followed by stirring at room temperature for 30 minutes. The insolubles which separated out were filtered off and washed with dichloromethane. The filtrate and the washing were combined and concentrated. The concentrate was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogen carbonate and a saturated saline, successively, which was then dried (Na2SO4). The solvent was evaporated off under reduced pressure, and the residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (1:1) to give 96 mg of the subject compound (8) as colorless foamy substance.
Reaction SMILES: C[Si]([PH:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])([O-:9])[O:6][CH2:7][CH3:8])(C)C.[CH:17]([C:19]([CH3:21])=[O:20])=[CH2:18]>O>[O:20]=[C:19]([CH3:21])[CH2:17][CH2:18][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: C=CC(C)=O
Reactant: CCOC(OCC)[PH]([O-])(OCC)[Si](C)(C)C
Solvent: O
Product: CCOC(OCC)P(=O)(CCC(C)=O)OCC
Reaction time: 0.5 h

Procedure:
A mixture of 2.7 g of ethyl trimethylsilyldiethoxymethylphosphonite and 0.7 g of methyl vinyl ketone is warmed to 50° for 1 hour under an atmosphere of nitrogen. Then 10 ml of water are added and the mixture is stirred for additional 30 minutes. The residue is extracted thrice with 50 ml of chloroform, the organic phases are combined, dried over magnesium sulphate, filtered and evaporated to dryness. The residue is then distilled to yield ethyl 3-oxobutyl(diethoxymethyl)phosphinate, b.p. 130°-5° (13.6 mbar).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]1([CH3:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC1(c2ccccc2Cl)CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CC1(c2ccccc2Cl)CCNCC1
Reaction time: 12 h
Yield: 73.4 %

Procedure:
A solution of 1-benzyl-4-(2-chloro-phenyl)-4-methyl-piperidine (0.59 g, 1.95 mmol) in 1,2-dichloroethane (10 mL) was treated with 1-chloroethyl chloroformate (0.28 mL, 2.6 mmol). This mixture was stirred for 12 hr at reflux, then evaporated in vacuo. The residue was redissolved in methanol (10 mL) and heated to reflux for 1 hr, then evaporated in vacuo. The resulting brown solid (the hydrochlorie salt) was washed with ethyl acetate, then freebased with ethyl acetate/sodium hydroxide to yield 0.30 g (72%) of the title compound, ESI-MS m/z: 246 [M+1].
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:16][C:17]1[N:18]=[CH:19][N:20]=[C:21]([N:12]2[CH2:13][CH2:14][N:10]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[CH:1]3[CH2:3][CH2:2]3)[C:11]2=[O:15])[CH:22]=1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: Clc1cc(Cl)ncn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1N(c2cc(Cl)ncn2)CCN1c1cnccc1C1CC1
Yield: 18 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 11 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 500 mg, 2.46 mmol) was reacted with 4,6-dichloro-pyrimidine (403 mg, 2.70 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (117 mg, 0.246 mmol), Pd2(dba)3 (112 mg, 0.123 mmol), cesium carbonate (2.009 g, 6.15 mmol) and toluene (10 mL) in seal tube at 110° C. for 14 hours. Purification by column chromatography on silica gel (1.5% methanol in chloroform) afforded 140 mg of the product (18.18% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:30]=[CH:29][C:11]([O:12][CH2:13][O:14][C:15]([C:25]([F:28])([F:27])[F:26])([C:21]([F:24])([F:23])[F:22])[C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].CO>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][O:14][C:15]([C:21]([F:22])([F:23])[F:24])([C:25]([F:26])([F:27])[F:28])[C:16]([OH:18])=[O:17])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(OCOc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(OCOc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 22 h
Yield: 43.3 %

Procedure:
A mixture of ethyl 2-[4-(4-chlorophenyl)phenoxymethoxy]-3,3,3-trifluoro-2-trifluoromethylpropionate (502 mg.) postassium hydroxide (88 mg.), methanol (4 ml.) and water (1 ml.) is stirred at 20° C. for 22 hours, then evaporated in vacuo. The residue is dissolved in water, and the solution is acidified with 3 N-hydrochloric acid. The solid which separates is filtered off. Crystallisation from a mixture of cyclohexane and light petroleum (b.p. 40°-60° C.) gives prisms (204 mg.) of 2-[4-(4-chlorophenyl)phenoxymethoxy]-3,3,3-trifluoro-2-trifluoromethylpropionic acid, m.p. 134°-135° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](N)=[CH:5][CH:4]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].N(O)=O.[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24]>C(O)(=O)C.[Pd].C(N)(C)(C)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:24]=[CH:23][C:22]([O:26][CH3:27])=[O:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: C=CC(=O)OC
Agent: [Pd]
Agent: O=NO
Agent: O=N[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)(C)N
Product: COC(=O)C=Cc1ccc(OC)cc1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
p-Anisidine (12.3 g) was dissolved in 55 ml acetic acid and 15 ml water and cooled to 10° C. 98% Sulfuric acid (15 g) was added slowly with agitation while cooling the reaction vessel, a 500 ml three necked round bottom flask equipped with stirrer, thermometer, dropping funnel and cooling bath. Sodium nitrite (6.9 g dissolved in 20 ml water) was then added at 0°-2° C. over one hour while stirring. Excess nitrous acid was then neutralized by the addition of 0.05 g t-butylamine. After 10 minutes, palladium (O) dibenzylidene acetone (Pd(dba)2, 0.15 g) was added followed by methyl acrylate (12.9 g) and butylated hydroxytoluene (0.03 g). The cooling bath was then removed and the temperature allowed to slowly reach ambient conditions (25° C.). After 22 hours of stirring, the acid was neutralized with excess 10% sodium hydroxide solution (aqueous) and the mixture allowed to separate. The aqueous layer was separated and extracted twice with 20 ml portions of ethyl ether. The ether layers were combined with the organic phase, concentrated on a rotary evaporator to remove the ether and distilled to give 19.0 g of methyl p-methoxycinnamate (99% yield, purity 95% by GC).
Reaction SMILES: C(O)C.O.[CH3:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[N+:14]([O-])=O)[C:9]#[N:10]>C(O)(=O)C>[NH2:14][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH3:5]
Reactant: Cc1cc(C#N)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(C#N)ccc1N
Temperature: 85 °C
Yield: 93 %

Procedure:
To an ethanol (500 ml)-water (60 ml)-acetic acid (30 ml) mixed solvent were added 3-methyl-4-nitrobenzonitrile (8.40 g, 51.8 mmol) and reduced iron (18 g, 322 mmol), and the mixture was stirred with heating at 85° C. for 3 hr. The reaction mixture was cooled, filtered through celite, and the solution was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed with diluted aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (6.37 g, yield 93%) as a pale-yellow solid.
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13]([NH2:15])=[O:14])[CH2:11][S:10][CH2:9]1)=O)(C)(C)C.[ClH:16].O1CCOCC1>>[ClH:16].[S:10]1[CH2:11][C@@H:12]([C:13]([NH2:15])=[O:14])[NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)[C@@H]1CSCN1
Yield: 99 %

Procedure:
(4R)-3-(tert-Butyloxycarbonyl)thiazolidine-4-carboxamide (8.6 g, 37.1 mmol) was dissolved in 4M HCl/dioxan (50 ml). After 1 h at room temperature the solvent was evaporated in vacuo to give a white solid identified as the title compound (6.2 g, 36.8 mmol, 99%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=O.Cl.[NH2:14]O.C([O-])(=O)C.[Na+]>C(O)C>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:14]
Reactant: NO
Reactant: O=Cc1ccc2ccccc2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc2ccccc2c1

Procedure:
2-Cyanonaphthalene is prepared by refluxing 2-formylnaphthalene with hydroxylamine hydrochloride and sodium acetate in ethanol to furnish the corresponding oxime which is refluxed with acetic anhydride in the presence of an acid catalyst to furnish 2-cyanonaphthalene.
Reaction SMILES: [BH4-].[Na+].O.[F:4][C:5]1([F:23])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C:6]1([F:22])[F:21]>C(O)(C)C>[F:4][C:5]1([F:23])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]([OH:16])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C:6]1([F:21])[F:22]
Reactant: O=C1c2ccccc2C(F)(F)C(F)(F)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: OC1c2ccccc2C(F)(F)C(F)(F)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 190 mg. (0.0005 mole) of sodium borohydride in 1 ml. of water is added dropwise to a stirred solution of 830 mg. (0.00296 mole) of 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-one in 10 ml. of isopropyl alcohol. After stirring the mixture for 3 hours at room temperature and 30 minutes at reflux, the isopropyl alcohol is evaporated under reduced pressure. The residue is partitioned between benzene and water and the benzene extract is separated, washed, and dried. Evaporation under reduced pressure leaves the product as the residual pale yellow oil. A sample for analysis is evaporatively distilled at 80°C. and 0.1 mm.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.Cl.[OH-].[Na+]>[Fe].C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(Br)cnc1N
Temperature: 80 °C
Reaction time: 0.83 h
Yield: 87.2 %

Procedure:
A suspension of 2-amino-5-bromo-3-nitropyridine (21.0 g), iron filings (26.9 g) and ethanol (150 ml) was cooled with ice, and to the suspension was added dropwise concentrated hydrochloric acid (20 ml). After the dropwise addition, the mixture was stirred at room temperature for 10 minutes and at 80° C. for 50 minutes. The reaction mixture was poured onto ice, neutralized with 8 N sodium hydroxide, and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v) (at that time, insolubles were filtered off by using celite). The organic layer was dried over MgSO4, the solvent was distilled off under reduced pressure, and crystals were collected by filtration to obtain 2,3-diamino-5-bromopyridine (15.8 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.O.O.[Sn](Cl)Cl.[BH4-].[Na+].C(OCC)(=O)C>CC(O)(C)C>[Br:11][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: Nc1cc(Br)cnc1N

Procedure:
A procedure similar to that described in Preparation 42 was repeated, except that 12.0 g of 2-amino-5-bromo-3-nitropyridine (prepared as described in preparation 56), 62.1 g of tin(II) chloride dihydrate, 1.04 g of sodium borohydride and 300 ml of a 9:1 by volume mixture of ethyl acetate and 2-methyl-2-propanol were used, to give the title compound as a crude product. This crude product was crystallized by trituration with a mixture of ethyl acetate and hexane, to give 7.46 g of the title compound, melting at 135°-137° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].C[O:12]B(OC)OC.Cl.OO>CCCCCC>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[OH:12]
Reactant: COc1ccc(F)c(F)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: OO
Solvent: CCCCCC
Product: COc1ccc(F)c(F)c1O

Procedure:
Using the procedure of Example 39, 125 g of 3,4-difluoroanisole (commercial) and 500 ml of a 1.6 M solution of N-butyl-lithium in hexane were reacted at −72° C., and then 92.4 ml of trimethylborate, 500 ml of hydrochloric acid and 120 g of intermediate compound were reacted and the product was reacted with 440 ml of 30% hydrogen peroxide to obtain 82.4 g of the expected product melting at 46.6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Clc1cnc2[nH]cc(I)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
5-Chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (150, 31.2 g, 0.112 mol) was dissolved in N-methylpyrrolidinone (800 mL) and NaH (60% dispersion, 4.93 g, 0.123 mol) was added at room temperature. The resulting mixture was stirred for 30 minutes. To this mixture was then added triisopropylsilylchloride (24.0 mL, 0.112 mol) and the resulting mixture was stirred for 2 hours. The reaction was quenched with water and extracted with ethyl acetate three times, washed by brine, dried, filtered, and concentrated in vacuo. The residue was subjected to silica gel flash chromatography (eluted by heptane to 5% ethyl acetate/heptane) to afford the desired compound (43 g 88%) as a pale-yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-:3])=[O:2].[CH2:16]=[CH:17][CH:18]=[CH2:19].[N+](C1C2C(=CC=CC=2)C=CC=1)([O-])=O>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]1[CH:8]([C:9]2=[O:14])[CH2:19][CH:18]=[CH:17][CH2:16]1)([O-:3])=[O:2]
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: C=CC=C
Agent: O=[N+]([O-])c1cccc2ccccc12
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)C2CC=CCC12

Procedure:
The 5-nitro-1,4-naphthoquinone introduced into the reactor 8 for the Diels-Alder reaction is subjected to Diels-Alder reaction with 1,3-butadiene introduced from the tank 9 via a line 26 at a suitable temperature under a suitable pressure in the presence of a suitable solvent introduced from the tank 7 via a line 27. Since the unreacted 1-nitronaphthalene present in the reaction solution does not react with 1,3-butadiene, no side reaction occurs. The reaction mixture is filtered in the filter 10. The crystals of 5-nitro-1,4,4a,9a-tetrahydroanthraquinone formed by the Diels-Alder reaction are sent to the reactor 12 for the reducing reaction via a line 30, and reduced with a suitable reducing agent introduced from the tank 13 via a line 33 to form 1-aminoanthraquinone. Meanwhile, the filtrate is sent to the separation tower 11 via a line 29 and separated into the solvent and 1-nitronaphthalene by, for example, distillation. The solvent is sent to the tank 7 via a line 32, and 1-nitronaphthalene is recycled to the tank 4 via line 31 for re-use.
Reaction SMILES: CN(C=O)C.Br[CH2:7][CH2:8][Cl:9].C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([Br:24])[C:18]=1[OH:25]>C(OCC)(=O)C>[Br:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([Br:24])[C:18]=1[O:25][CH2:7][CH2:8][Cl:9]
Reactant: Oc1c(Br)cc(F)cc1Br
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cc(Br)c(OCCCl)c(Br)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
DMF (50 mL), 1-bromo-2-chloroethane (1.0 mL, 12 mmol), and potassium carbonate (1.7 g, 12 mmol) were added to 2,6-dibromo-4-fluorophenol (3.0 g, 11 mmol), and stirred at 50° C. overnight. Ethyl acetate was used as an extraction solvent, and after washing with water and saturated brine, and the resultant was dried over magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel column chromatography to thus obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](Cl)=[N:8][CH:9]=1)([O-:3])=[O:2].[F-:11].[K+].C1CS(=O)(=O)CC1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([F:11])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5-nitro-2-chloropyridine (2.0 g, 12.6 mmol) and anhydrous potassium fluoride (2.2 g, 38 mmol) in a combination of sulfalone (6 mL) and benzene (4 mL) was stirred at RT for 20 min. The benzene was then removed by distillation. The resulting mixture was heated at 150° C. for 12h. The mixture was cooled to RT whereupon water (60 mL) was added. The desired product was separated from the solution via steam distillation. Extraction of the distillate with diethyl ether (2×10 mL) followed by drying (Na2SO4) and concentration gave 5-nitro-2-fluoropyridine as a water white oil (1.3 g, 73%).