Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[N+:2]([C:5]1[CH:6]=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]3[O:29][CH:30]=[CH:31][CH:32]=3)=[O:27])=[C:21]([N+:33]([O-])=O)[CH:20]=2)[CH:8]=[CH:9][C:10]=1[NH:11][C:12]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)=[O:13])([O-])=O.[Cl-].[NH4+].[In]>C(O)C.CN1CCCC1=O>[NH2:33][C:21]1[CH:20]=[C:19]([C:7]2[CH:8]=[CH:9][C:10]([NH:11][C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)=[O:13])=[C:5]([NH2:2])[CH:6]=2)[CH:24]=[CH:23][C:22]=1[NH:25][C:26]([C:28]1[O:29][CH:30]=[CH:31][CH:32]=1)=[O:27]
Reactant: O=C(Nc1ccc(-c2ccc(NC(=O)c3ccco3)c([N+](=O)[O-])c2)cc1[N+](=O)[O-])c1ccco1
Agent: [Cl-]
Agent: [In]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1cc(-c2ccc(NC(=O)c3ccco3)c(N)c2)ccc1NC(=O)c1ccco1
Temperature: 80 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
Into a separable flask equipped with a stirrer and a reflux condenser cooled with water, 7.4 g of 3,3′-dinitro-4,4′-di-2-furoylaminobiphenyl, 100 ml of N-methyl-2-pyrrolidone and 75 ml of ethyl alcohol were placed. After adding 40 ml of a saturated aqueous solution of ammonium chloride, 25.6 g of powder of indium metal was added to the prepared solution. The obtained mixture was stirred at 80° C. for 1 hour. After the reaction solution was cooled to the room temperature, the solid substance was removed by filtration. The filtrate was concentrated to about one half at a reduced pressure. To the concentrated filtrate, 300 ml of water was added and the formed solid substance was separated by filtration to obtain 2.9 g of a crude product. The crude product was purified in accordance with the silica gel column chromatography to obtain 1.5 g of 3,3′-diamino-4,4′-di-2-furoylaminobiphenyl. The yield of the isolated product was 23%. This product was recrystallized from N-methyl-2-pyrrolidone/ethyl acetate (the volume ratio: 25/75) and needle crystals having a decomposition temperature of 256 to 259° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24](Br)=[CH:23][CH:22]=2)=[O:18].[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][N:42]=1.C(=O)(O)[O-].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([C:44]1[CH:43]=[N:42][C:41]([O:40][CH3:39])=[CH:46][CH:45]=1)=[CH:23][CH:22]=2)=[O:18]
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3cc(Br)ccc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3c(c2)cc(C(=O)c2cnn(-c4ccc5[nH]c(C)nc5c4)c2N)n3S(=O)(=O)c2ccc(C)cc2)cn1

Procedure:
A mixture of dioxane (0.6 ml), [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[5-bromo-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone (60 mg, 0.102 mmol), dichlorobis(triphenylphosphine)palladium (II) (14 mg, 0.020 mmol), 2-methoxy-5-pyridine boronic acid (39 mg, 0.255 mmol), and an aqueous solution of 2 M sodium bicarbonate (0.255 mL, 0.51 mmol) was stirred at 140° C. for six minutes in a microwave reactor. The reaction mixture was filtered through Celite, and washed with ethyl acetate and then with methanol. The filtrate was dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentration was performed. The residue obtained was purified by amino gel chromatography (dichloromethane/methanol=99/1 to 92/8). Thus, [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[5-(6-methoxy-pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone was obtained as a pale yellow solid (54 mg, 85%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][CH3:3].[H-].[Na+].[CH:10](OCC)=[O:11].O>O1CCCC1>[CH3:3][CH:2]([CH:10]=[O:11])[C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CC
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23.5 %

Procedure:
Into a 500-mL 3-neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl propionate (11.3 mL, 97.9 mmol) in tetrahydrofuran (160 mL). The solution was cooled to 0° C., then sodium hydride (4.1 g, 103 mmol, 60% dispersion in mineral oil) was added in portions. The mixture was stirred at 0° C. for 10 min, then ethyl formate (7.92 mL, 98.5 mmol) was added and the resulting mixture was stirred overnight at room temperature. The reaction was carefully quenched water (100 mL) by drop-wise addition and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by distillation under reduced pressure (50 mm Hg) and the fraction between 70-80° C. was collected to obtain the title compound as a colorless liquid (3.0 g, 24%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].[ClH:17]>P(Cl)(Cl)(Cl)=O>[ClH:12].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:17])(=[O:10])=[O:8])[CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cccnc1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 120 °C

Procedure:
A mixture of pyridine-3-sulfonic acid (15.0 g), phosphorous pentachloride (24.0 g) and phosphorous oxychloride (30 mL) was heated to 120° C. for 16 h. The reaction was cooled to room temperature, and the resulting suspension was saturated with HCl (g). A white precipitate was collected, washed with CHCl3, and dried in vacuo to afford the title compound (15.6 g). 1H NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 8.85 (d, 1H), 8.66 (d, 1H), 8.02 (t, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:10]([O:18][C@@H:19]([C:34](OC)=[O:35])[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:10]([O:18][C@H:19]([C:20]1[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:21]=1)[CH2:34][OH:35])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](O[C@@H]1CC[C@H]2[C@H](C#N)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O[C@@H](CO)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]-(methoxycarbonyl)methoxy}-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane (Example 155; 2.408 g, 4 mmol) in methanol (25 ml) was treated with sodium borohydride (2.2698 g, 0.60 mmol) potionwise at 5-10° C. The reaction was quenched with acetone and concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the organics separated and dried (MgSO4) and concentrated in vacuo to afford the title compound as a white foam in quantitative yield.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([OH:15])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](Cl)=[O:27].Cl>ClCCl>[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26]([O:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1)=[O:27]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COc1ccc(O)cc1OC1CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(OC(=O)c2c(Cl)cccc2Cl)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
A stirred solution of 3-cyclopentyloxy-4-methoxyphenol (0.2 g) and triethylamine (1.35 mL) in dichloromethane (5 mL) is treated portionwise at 0°-5° C. with 2,6-dichlorobenzoyl chloride (0.28 g), and the solution is warmed to room temperature and stirred for a further 2 hours. The reaction mixture is poured into hydrochloric acid (50 ml; 2N) and is extracted with diethyl ether (3×50 mL). The combined organic extracts are then washed with water (100 mL), and brine (100 mL), dried over magnesium sulfate and concentrated. The residual oil is subjected to flash chromatography on silica gel, eluting with a mixture of pentane and ethyl acetate (4:1 v/v), to give (3-cyclopentyloxy-4-methoxyphenyl) 2,6-dichlorobenzoate (0.28 g), m.p. 100°-101° C. [Elemental analysis: C,59.7; H,4.7%; calculated: C,59.9; H,4.8%].
Reaction SMILES: [NH2:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[N:12]=[N:13][NH:14][CH:15]=3)[CH2:7][S:8][C@H:3]12.Cl.C(O[CH:25](OCC)[CH2:26][NH:27][C:28]#[N:29])C>COCCOC.O>[NH:29]1[CH:25]=[CH:26][N:27]=[C:28]1[NH:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[N:12]=[N:13][NH:14][CH:15]=3)[CH2:7][S:8][C@H:3]12
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3c[nH]nn3)CS[C@H]12
Reactant: CCOC(CNC#N)OCC
Agent: Cl
Solvent: COCCOC
Solvent: O
Product: O=C(O)C1=C(CSc2c[nH]nn2)CS[C@@H]2C(Nc3ncc[nH]3)C(=O)N12
Temperature: 51 °C
Yield: 10 %

Procedure:
To a suspension of 7-amino-3-(1H-1,2,3-triazol-4-yl)thiomethylceph-3-em-4-carboxylic acid (31.3 g., 0.1 moles) in a mixture of 1,2-dimethyoxyethane (250 ml.) and concentrated HCl (12 ml., 0.138 moles) in water (50 ml.) was added 2,2-diethoxyethylcyanamide (52.05 g., 0.3 moles). The mixture was stirred and heated at 51° C. for 4 hours and the resulting solution was evaporated under reduced pressure to remove the 1,2-dimethoxyethane. The residual oil was diluted with water (250 ml.), the pH of the resulting suspension was adjusted to 4.8 using sodium bicarbonate and then filtered. The filtrate was applied to a column of "Amberlite" XAD-2 (500 ml.) ("Amberlite" is a Trade Mark). The resin was first washed with water (2000 ml.) and then eluted with 40% v/v aqueous methanol. The required fractions were combined and evaporated to dryness to give 7-(imidazol-2-yl)amino-3-(1H-1,2,3-triazol-4-yl)thiomethylceph-3-em-4-carboxylic acid (3.79 g., 10%) having an n.m.r. spectrum identical to the product of Example 5.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(O)(=O)C>[CH3:12][C:11]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])=[O:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccccc1O
Solvent: CC(=O)O
Product: CC(=O)Oc1ccccc1C(=O)O

Procedure:
Commercially, aspirin is synthesized using a two-step process. Phenol, generally extracted from coal tar, is treated with sodium base to generate sodium phenoxide. Sodium phenoxide is then reacted with carbon dioxide under high temperature and pressure to yield salicylate, which is acidified to obtain salicylic acid. This process is known as the Kolbe-Schmitt reaction. Salicylic acid is acetylated with acetic anhydride to produce aspirin and acetic acid as byproduct.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[C@H:13]([NH2:14])[CH2:12][CH2:11][O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26]Br>C(#N)C>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[C@H:13]([N:14]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:12][CH2:11][O:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCCBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1COCC[C@H]1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1COCC[C@H]1N1CCCC1
Yield: 83.9 %

Procedure:
trans-(4-Amino-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester (intermediate G, 330 mg, 1.53 mmol) was dissolved in 8 mL acetonitrile. Potassium carbonate (1.05 g, 7.6 mmol) and 1,4-dibromobutane (672 mg, 3.11 mmol) were added and the reaction mixture was refluxed overnight. The solvent was evaporated off. The residue was taken up in water and extracted three times with diethylether. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 1:0:0→140:10:1) yielded the title compound as a yellow oil (347 mg, 84%), MS: m/e=271.3 [(M+H)+].
Reaction SMILES: C([C:3](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([N+:18]([O-])=O)[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])C.[O:21]1CCC[CH2:22]1>[Pd].C(O)C>[NH2:18][C:12]1[CH:11]=[C:10]([CH2:9][CH:3]([O:21][CH3:22])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: CCOC(=O)C(=Cc1ccc(OC)c([N+](=O)[O-])c1)CC
Reactant: C1CCOC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(OC)c(N)c1)OC
Yield: 95 %

Procedure:
Next, ethyl 2-ethyl-3-(4-methoxy-3-nitrophenyl)acrylate (4.50 g, 16.0 mmol), 10% palladium on carbon (1.50 g) and a 1:1 mixed solvent (150 mL) of tetrahydrofuran with ethanol were mixed and hydrogenation was carried out at an initial pressure of 294.3 kPa at room temperature. After completion of the reaction, the catalyst was removed by filtration and the filtrate was concentrated to afford 3.84 g (95%) of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=1.Cl[CH2:13][C:14]([OH:16])=[O:15]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][O:9][CH2:13][C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCO)cc1
Reactant: O=C(O)CCl
Solvent: Cc1ccccc1
Product: COc1ccc(CCOCC(=O)O)cc1
Yield: 79.1 %

Procedure:
6.08 g of 4-methoxyphenethyl alcohol were reacted with 3.8 g of chloroacetic acid in a manner analogous to that described in Example 4(a) to give 6.64 g (79%) of 2-(4-methoxyphenyl)ethoxyacetic acid of melting point 82°-84° C. (from toluene).
Reaction SMILES: [H-].[Na+].CS(C)=O.Cl.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:16])[C:10]=1[CH3:17].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1>O>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH2:8])=[C:10]([CH3:17])[C:11]=1[CH3:16]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1c(N)ccc(O)c1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
Sodium hydride (60 wt %, 0.72 g) was added to dimethyl sulfoxide (10 ml). The mixture was stirred at 50° C. for 30 min and was then cooled to room temperature. 4-Amino-2,3-dimethylphenol hydrochloride (1.55 g) was added to the cooled mixture, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue. The precipitated crystal was collected by suction filtration to give 0.94 g (yield 65%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH3:14]>O1CCCC1>[Cl:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:14])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: N
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(Cl)cc(Cl)c1O
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A solution of 26.1 gm (0.1 mole) 3,5-dichloro-2-hydroxybenzenesulfonyl chloride in 400 ml dry tetrahydrofuran was cooled to 0° with an ice bath, and 11 ml (0.5 mole) anhydrous ammonia was added dropwise, with stirring. The rate of addition was sufficiently slow so as to keep the temperature of the reaction medium less than 10°. The mixture was stirred for 1.5 hours at 0° then slowly warmed to room temperature. The solvent was removed in vacuo and the residue was treated with 100 ml H2O. A small amount of insoluble by-product was filtered off and then the aqueous solution was acidified to pH=2.0 with 1 N HCl solution. Filtration of the resulting white precipitate and drying of the precipitate at 50° under vacuum gave 23.6 gm (97%) white solid, m.p. >225°. The infrared spectrum showed strong absorption at 3300, 1540, 1450 and 1320 cm-1, and the nuclear magnetic resonance spectrum showed a broad singlet at 7.2δ, 3 protons, and a doublet of doublets at 7.8δ, 2 protons. These data are consistent with the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=4)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Product: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccc(C)cc3)ccc2o1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and 4-methylphenylboronic acid (234 mg, 1.71 mmol) the subtitle compound was obtained (273 mg, 53%). The product was used directly in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](N)=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.N(OCCCC)=O.[H+].[F:24][P-](F)(F)(F)(F)F>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:24])=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: Nc1ccc(Cl)nc1Oc1ccccc1
Reactant: F[P-](F)(F)(F)(F)F
Agent: CCCCON=O
Agent: [H+]
Product: Fc1ccc(Cl)nc1Oc1ccccc1

Procedure:
A diazonium salt is formed by reacting 2-chloro-5-amino- 6-phenoxypyridine with butyl nitrite in the presence of HPF6 and is decomposed by heating (Baltz-Schiemann reaction) to obtain 2-chloro-5-fluoro-6-phenoxypyridine. The obtained product is reacted with magnesium and then with a formylating agent such as dimethylformamide to obtain 5-fluoro-6-phenoxy picolinic aldehyde. In the case where cyano(5-fluoro-6-phenoxy-2-pyridyl) methyl alcohol is required, it is prepared by reacting the aldehyde with sodiumbisulfite and then with a cyanide compound such as sodium cyanide.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][CH2:19][C:20]2[C:21]([C:27]([O:29][CH3:30])=[O:28])=[N:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[CH:16][CH:15]=1.[CH3:33][N:34]1[C:38]([CH2:39][CH:40]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)O)=[CH:37][N:36]=[CH:35]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH2:19][C:20]2[C:21]([C:27]([O:29][CH3:30])=[O:28])=[N:22][C:23]([O:26][CH:40]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)[CH2:39][C:38]3[N:34]([CH3:33])[CH:35]=[N:36][CH:37]=3)=[CH:24][CH:25]=2)=[CH:31][CH:32]=1
Reactant: Cn1cncc1CC(O)c1ccc(F)cc1
Reactant: COC(=O)c1nc(O)ccc1CCc1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1nc(OC(Cc2cncn2C)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Reaction time: 16 h
Yield: 89.9 %

Procedure:
DEAD (0.85 ml) was added dropwise over 2 minutes to a stirred suspension of methyl 3-(4-fluorophenethyl)-6-hydroxypyridin-2-carboxylate (1.0 g), 2-(1-methylimidazol-5-yl)-1-(4-fluorophenyl)ethanol (0.80 g) and triphenylphosphine (1.43 g) in THF (70 ml) under an inert atmosphere at ambient temperature. After stirring for 16 hours the solution was concentrated under reduced pressure and loaded directly onto a silica flash column eluting with methanol/dichloromethane (1:20) to give methyl 3-(4-fluorophenethyl)-6-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]pyridin-2-carboxylate as a colourless oil (1.56 g).
Reaction SMILES: FC(F)(F)C1C=C(C(Cl)=O)C=CC=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=1[F:36].[F:37][C:38]([F:51])([F:50])[C:39]1[CH:40]=[C:41]([C:45]([N:47]=[C:48]=[S:49])=[O:46])[CH:42]=[CH:43][CH:44]=1>C1(C)C=CC=CC=1.C(O)C>[F:50][C:38]([F:37])([F:51])[C:39]1[CH:40]=[C:41]([C:45]([N:47]=[C:48]=[S:49])=[O:46])[CH:42]=[CH:43][CH:44]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:48]([NH:47][C:45](=[O:46])[C:41]2[CH:42]=[CH:43][CH:44]=[C:39]([C:38]([F:37])([F:51])[F:50])[CH:40]=2)=[S:49])=[CH:31][C:30]=1[F:36]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C(N=C=S)c1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C(F)(F)F)c4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
3-(Trifluoromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-(trifluoromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-(trifluoromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 89%).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.ClCCl.P(Br)(Br)[Br:17].N>O>[Br:17][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: BrP(Br)Br
Agent: N
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
11.5 g (70 mmol) of methyl 4-hydroxymethylbenzoate are added to 120 ml of dichloromethane and 47.3 ml of phosphorus tribromide are added thereto. The mixture is stirred for one hour at ambient temperature and a semi-concentrated solution of ammonia in water is carefully added, whilst cooling with ice, until a pH of 8 to 9 is achieved. The organic phase is separated off and dried and the solvent is distilled off. 13.4 g (84% of theory) of the methyl 4-bromomethylbenzoate are obtained (analogously to Compound 6).