Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][C:13]2([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][O:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.B(F)(F)F.CC[O:27]CC.[C:30](#[N:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O)(=O)C(O)=O>C(Cl)Cl>[OH:14][C:13]([CH2:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH2:15][NH:37][C:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C1(CS(=O)(=O)c2ccc(OC)cc2)CO1
Reactant: CCOCC
Reactant: N#Cc1ccccc1
Agent: FB(F)F
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Product: CCOC(=O)C(O)(CNC(=O)c1ccccc1)CS(=O)(=O)c1ccc(OC)cc1
Temperature: 65 °C

Procedure:
2-Methoxybenzenesulfonyl)methyl-oxiranecarboxylic acid, ethyl ester (from EXAMPLE 1, Step 2, 0.3 g, 1 mmol), boron trifluoride etherate (0.495 mL, 4.0 mmol), and benzonitrile (0.36 mL, 4.0 mmol) are dissolved in 40 mL of methylene chloride. The reaction mixture is stirred at ambient temperature under a nitrogen atmosphere for three days, with the addition two times of 0.50 mL of boron trifluoride etherate. The solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate and with brine, and dried over magnesium sulfate. The crude product is dissolved in 40 mL of absolute ethanol. Oxalic acid (0.30 g, 3.3 mmol) is added, and the solution is heated to 65° C. for 19 hours. The solvent is removed under reduced pressure. The oily residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate and with brine, and dried over magnesium sulfate. Chromatography on silica gel, eluting with 1:1 ethyl acetate:hexanes affords the title compound as a white solid. 1H NMR (CDCl3) δ 7.82-7.71, 7.55-7.41, 7.02-6.99, 6.57, 4.29-4.17, 3.88, 3.85-3.72, 3.60-3.56, 1.32-1.28; MS (ES+) 422.1 (M+H), (ES−) 420.1 (M−H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.B1(C=C)O[C:16](C)(C)[C:15](C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[F:12][C:4]1[CH:3]=[C:2]([CH:15]=[CH2:16])[CH:11]=[CH:10][C:5]=1[C:6]([NH:8][CH3:9])=[O:7]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CNC(=O)c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C=Cc1ccc(C(=O)NC)c(F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 119.8 %

Procedure:
A mixture of 4-bromo-2-fluoro-N-methylbenzamide (0.80 g), vinylboronic acid pinacol cyclic ester (0.80 g) and 2M aqueous sodium carbonate solution (3.45 mL) in DME (17.3 mL) was argon-purged. Bis(triphenylphosphine)palladium(II) dichloride (0.12 g) was added thereto, and the mixture was stirred overnight at 80° C. The reaction solution was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to short silica gel column chromatography, and the solvent was evaporated under reduced pressure to give the title compound (0.74 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[N:9]=[C:8]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:7]3=[C:6]([CH3:18])[C:5]=2[CH:4]=1.[Cl:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[ClH:19].[CH2:23]([O:22][C:20]([N:15]1[CH2:16][CH2:17][C:7]2[C:8](=[N:9][C:10]3[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:6]=2[CH3:18])[CH2:13][CH2:14]1)=[O:21])[CH3:24]
Reactant: COc1ccc2nc3c(c(C)c2c1)CCNCC3
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCc2nc3ccc(OC)cc3c(C)c2CC1
Product: Cl
Yield: 66 %

Procedure:
1,2,4,5-Tetrahydro-9-methoxy-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 1,2,4,5-tetrahydro-9-methoxy-11-methyl-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 63.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[F:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25](F)=[CH:24][C:23]=1[NH:32][C:33](=[O:35])[CH3:34]>O>[F:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:24][C:23]=1[NH:32][C:33](=[O:35])[CH3:34]
Reactant: COc1ccccc1O
Reactant: CC(=O)Nc1cc(F)c([N+](=O)[O-])cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
2.73 g of 2-methoxyphenol and 5.5 g of potassium carbonate were added to 20 ml of N,N-dimethylformamide, and the mixture was heated to 60° C. Into this mixture was added dropwise a solution comprising 4.3 g of N-(2,5-difluoro-4-nitrophenyl)acetamide and 30 ml of N,N-dimethylformamide at temperature from 60 to 65° C. The temperature of the mixture was kept for 1 hour while stirring, then, the mixture was cooled to room temperature, poured into water, extracted with ethyl acetate, and the organic layer was washed with dilute hydrochloric acid, washed with water, dried over magnesium sulfate, and concentrated to obtain 5.52 g of N-[2-fluoro-5-(2-methoxyphenoxy)-4-nitrophenyl]acetamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:16][C:9]2[N:10]=[C:11]([NH2:15])[N:12]=[C:13](Cl)[C:8]=2[CH:7]=1)=[O:5])[CH3:2].[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][C:27]#[N:28])=[CH:25][C:20]=2[O:19][CH2:18]1.[H-].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[S:16][C:9]2[N:10]=[C:11]([NH2:15])[N:12]=[C:13]([CH:26]([C:24]3[CH:23]=[CH:22][C:21]4[O:17][CH2:18][O:19][C:20]=4[CH:25]=3)[C:27]#[N:28])[C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(Cl)nc(N)nc2s1
Reactant: N#CCc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C(C#N)c3ccc4c(c3)OCO4)nc(N)nc2s1
Reaction time: 8 h

Procedure:
To a solution of 2-amino-4-chloro-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (1 equiv.) and benzo[1,3]dioxol-5-yl-acetonitrile (1 mole eq.) in DMF at room temperature, sodium hydride (1.1 mole eq., 60% in mineral oil) was added. The mixture was stirred at this temperature overnight under argon. After that, it was diluted with brine and extracted with ethyl acetate. The combined organic portions were washed with brine and water and dried with sodium sulphate. After filtration and evaporation of the solvent, brown solids were obtained which were purified either by preparative TLC or preparative HPLC.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>>[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH:20][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([NH:27][CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[O:23][C:22]([F:21])([F:32])[F:33])[CH:8]=3)[N:3]=2)=[CH:16][CH:15]=1
Reactant: NCc1ccccc1OC(F)(F)F
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3cc(NCc4ccccc4OC(F)(F)F)ccc3n2)o1

Procedure:
The title compound, MS: m/e=428.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and 2-(trifluoromethoxy)benzylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[O-2].[Mg+2].O.Cl[C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14]>C(OCC)(=O)C>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:13](=[O:14])[O:15][CH:16]([CH3:18])[CH3:17])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1cccc(O)c1
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)OC(=O)Nc1cccc(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
A mixture of 3-aminophenol (109 g), magnesium oxide (25 g), water (350 ml) and ethyl acetate (100 ml) was stirred vigorously at room temperature while isopropyl chloroformate (123 g) was added slowly. An ice bath was employed to ensure that the temperature did not exceed 30° C. After stirring for one hour at room temperature, the mixture was filtered to remove insoluble particles. These were washed thoroughly with ether, then the filtrates were combined, then separated, and the organic layers were dried over magnesium sulphate. Evaporation under reduced pressure gave a viscous, pale yellow oil which was crystallised from toluene to give 162.7 g of desired product, mp 75°-77° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:32]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][C@@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)[C:6]#[N:7]
Reactant: COc1cc(C#N)ccc1O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1O[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
4-Hydroxy-3-methoxybenzonitrile (12 g, 80.2 mmol) and triphenylphosphine (21 g, 80.2 mmol) were added portionwise to an ice-cold solution of tert-butyl(3S)-3-hydroxypyrrolidine-1-carboxylate (15 g, 80.2 mmol) in tetrahydrofuran (225 mL). A solution of diisopropyl azodicarboxylate (16.2 g, 80.2 mmol) in tetrahydrofuran (100 mL) was then added dropwise and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was treated with hydrochloric acid (4M in dioxane, 250 mL). The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated and washed with water (100 mL), and the combined aqueous solution was washed with ethyl acetate (2×150 mL), basified to pH10 with solid potassium carbonate and extracted with ethyl acetate (2×250 mL). The combined organic solution was washed with brine (100 mL), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a cream solid in 67% yield, 11.8 g. LRMS ESI m/z 219 [M+H]+
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Si:8]([O:15][C@H:16]([C:30]1[NH:34][N:33]=[N:32][N:31]=1)[C@@H:17]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:18])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>C(Cl)Cl.CO>[Si:8]([O:15][C@H:16]([C:30]1[N:34]([CH3:1])[N:33]=[N:32][N:31]=1)[C@@H:17]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:18])([C:11]([CH3:13])([CH3:14])[CH3:12])([CH3:9])[CH3:10].[Si:8]([O:15][C@H:16]([C:30]1[N:31]=[N:32][N:33]([CH3:1])[N:34]=1)[C@@H:17]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:18])([C:11]([CH3:13])([CH3:14])[CH3:12])([CH3:9])[CH3:10]
Reactant: C[C@H](NC(=O)OCc1ccccc1)[C@H](O[Si](C)(C)C(C)(C)C)c1nnn[nH]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: C[C@H](NC(=O)OCc1ccccc1)[C@H](O[Si](C)(C)C(C)(C)C)c1nn[nH]n1
Solvent: CO
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)[C@H](O[Si](C)(C)C(C)(C)C)c1nnn(C)n1
Product: C[C@H](NC(=O)OCc1ccccc1)[C@H](O[Si](C)(C)C(C)(C)C)c1nnnn1C
Reaction time: 0.25 h

Procedure:
(Trimethylsilyl)diazomethane (2M in hexanes, 459 μL, 0.918 mmol) was added dropwise to a solution of the crude benzyl [(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(1H-tetrazol-5-yl)ethyl]carbamate and benzyl [(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(2H-tetrazol-5-yl)ethyl]carbamate in CH2Cl2/MeOH (3:2, 5 mL) at room temperature under N2. After 15 min and gas evolution had ceased, the reaction mixture was concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-70% EtOAc in hexanes gradient) to afford benzyl [(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(1-methyl-1H-tetrazol-5-yl)ethyl]carbamate and benzyl [(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(2-methyl-2H-tetrazol-5-yl)ethyl]carbamate, as a 2:1 mixture of regioisomers. LCMS calc.=406.2; found=406.2 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1)=[O:13]>C(#N)C>[OH:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:12]([NH:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:13]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: O=C1OCc2ccccc21
Solvent: CC#N
Product: O=C(NNc1ccc([N+](=O)[O-])cc1)c1ccccc1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.4 %

Procedure:
41.3 g of 4-nitrophenylhydrazine and 33 g of phthalide were dissolved in 330 ml of acetonitrile. The solution was heated under reflux with stirring over 4 hours. The reaction solution was allowed to stand for cooling to room temperature. The resulting solid was then filtered off, and recrystallized from acetonitrile to obtain 15.1 g of 1-(2'-hydroxymethylbenzoyl)-2-(4-nitrophenyl) hydrazine (yield of 21.0%).
Reaction SMILES: C(O)(=O)C(O)=O.C1(C(C2C=CC=CC=2)[N:14]2[CH2:17][CH:16]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH2:15]2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.[C:45]([Cl:48])(Cl)=[O:46]>O.C(Cl)Cl>[Cl:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH:16]1[CH2:17][N:14]([C:45]([Cl:48])=[O:46])[CH2:15]1
Reactant: Clc1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Reactant: O=C(Cl)Cl
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Cl)N1CC(Oc2cccc(Cl)c2)C1
Temperature: 0 °C
Yield: 146.7 %

Procedure:
A slurry of 15.9 g (0.036 mole) of 1-(diphenylmethyl)-3-(3-chlorophenoxy)azetidine ethanedioate in 200 ml of water was treated with 10 g of potassium carbonate and 500 ml of toluene. This mixture was heated while stirring until the emulsion which had formed cleared and formed two clear phases. The toluene phase was separated, washed with hot water and concentrated in vacuo. The residue was dissolved in 50 ml of methlene chloride and added dropwise to a stirred mixture of 4 g (0.04 mole) of phosgene and 5.5 g (0.04 mole) of potassium carbonate in 50 ml of methylene chloride under nitrogen. After 2 hr the reaction mixture was treated with ice water to destroy the excess phosgene and dissolve the inorganic salts. The methylene chloride solution was separated, dried over magnesium sulfate and concentrated in vacuo to yield 13 g of residue. A sample was crystallized by cooling to -78° C. and was used to seed the residue which formed a semi-solid paste. Trituration of the paste with petroleum ether yielded 3.5 g (66.5%) of white powder upon filtration. Recrystallization from petroleum ether yielded 0.6 g of white crystalline product, mp 64°-65° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][CH:15]([CH3:42])[C:16]([C:18]1[N:19]=[CH:20][N:21]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=1)=[O:17].[B:43](OC)([O:46]C)[O:44]C.[Cl-].[NH4+]>C1COCC1.CCCCCC>[OH:17][C:16]([C:2]1[CH:7]=[CH:6][C:5]([B:43]([OH:46])[OH:44])=[CH:4][CH:3]=1)([C:18]1[N:19]=[CH:20][N:21]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=1)[CH:15]([CH3:42])[CH3:14]
Reactant: COB(OC)OC
Reactant: Brc1ccc(Br)cc1
Reactant: CC(C)C(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.25 h

Procedure:
To a solution of p-dibromobenzene (66.0 g) in THF (700 ml) was added dropwise a solution (1.6 M; 180 ml) of n-butyllithium in hexane at —78° C., and the mixture was stirred at the same temperature for 15 min. A solution of 2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanone (85.0 g) in THF (250 ml) was added dropwise, and the mixture was further stirred for 15 min. To the reaction mixture was added dropwise a solution (1.6 M; 270 ml) of n-butyllithium in hexane at −78° C., and the mixture was stirred at the same temperature for 15 min, which was followed by addition of trimethyl borate (196 ml). The reaction mixture was stirred at room temperature for 2 h, and an aqueous ammonium chloride solution was added. The mixture was stirred at room temperature for 12 h, and the organic layer was separated, washed with 1N sodium hydroxide and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a crude product (126 g) of the title compound as an amorphous powder. This product was used in a reaction without purification.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[C:6]3[C:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)=[CH:9][N:8]([C:14]1[N:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[N:16]=[CH:17][N:18]=1)[N:7]=3.ClC1N(C2C=CC(F)=CC=2F)N=CN=1.[Br:43]C1C=CC2OCCC3C(=NNC=3)C=2C=1.C(OCC)(=O)C>C1CCCCC1>[Br:43][C:28]1[CH:2]=[CH:3][C:4]2[O:13][CH2:12][CH2:11][C:10]3[C:6](=[N:7][N:8]([C:14]4[N:15]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[N:16]=[CH:17][N:18]=4)[CH:9]=3)[C:5]=2[CH:27]=1
Reactant: Brc1ccc2c(c1)-c1n[nH]cc1CCO2
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(Br)cc2OCC3)c(F)c1
Agent: Fc1ccc(-n2ncnc2Cl)c(F)c1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2cc(Br)ccc2OCC3)c(F)c1
Yield: 62 %

Procedure:
9-Bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene was prepared similarly to 8-bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene from 5-chloro-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole (1.33 g, 6.16 mmol) and 9-bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (1.36 g, 5.13 mmol), the crude product was subjected to flash chromatography (SiO2, gradient 0 to 35% ethyl acetate in cyclohexane) to give 9-Bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen (1.42 g, 62%). LCMS RT=4.80 M+H+=444/446.
Reaction SMILES: Br[C:2]1[C:3]2[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.C([Li])CCC.[Cl:17][CH2:18][C:19](N(OC)C)=[O:20]>O1CCCC1.CCOCC>[Cl:17][CH2:18][C:19]([C:6]1[S:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:3]=2[CH:2]=1)=[O:20]
Reactant: Fc1cccc2scc(Br)c12
Reactant: CON(C)C(=O)CCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CCl)c1cc2c(F)cccc2s1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
A solution of 3-bromo-4-fluorobenzo[b]thiophene (0.76 g) in tetrahydrofuran (5 ml) was added dropwise under nitrogen at −60-−50° C. over 10 minutes to a stirred solution of n-butyllithium (2.5M solution in hexanes; 1.71 ml) in ether (40 ml), then the mixture was stirred at −50° C. for 30 minutes. A solution of 2-chloro-N-methoxy-N-methylacetamide (0.39 g) in tetrahydrofuran (10 ml) was added dropwise over 10 minutes, the mixture was stirred at −50° C. for 30 minutes and at 0° C. for 1 hour, then it was quenched by the addition of saturated aqueous ammonium chloride solution (30 ml). The organic layer was separated, washed with saturated aqueous sodium chloride solution (30 ml), dried (MgSO4) and the solvent was removed in vacuo. The residue was purified by flash chromatography over silica using a 10:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 2-chloro-1-(4-fluorobenzo[b]thiophen-2-yl]ethan-1-one (0.1 g) as a colourless solid which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][C:7]=2[CH:15]=1.S(Cl)([Cl:19])(=O)=O>ClCCl>[Cl:19][C:15]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1cc2cc(OC)ccc2o1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc2c(Cl)c(OC)ccc2o1
Temperature: 20 °C
Reaction time: 5 h
Yield: 95.4 %

Procedure:
Methyl 5-methoxybenzofuran-2-carboxylate (5.22 g, 25.3 mmol) was dissolved in dichloromethane, and sulfuryl chloride (3.76 g, 27.9 mmol) was added at such rate to maintain a temperature of 20° C. After stirring for 5 h the solution was dripped slowly onto ice water (70 mL). The organic phase was then washed with water, aqueous saturated NaHCO3 and again with water. The layers were separated and the organic portion was passed through a phase separation cartridge and evaporated to afford a solid (5.81 g), which was taken through to the next step with no further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:12]1(S(OCCC)(=O)=O)[CH:17]=CC=C[CH:13]=1.[NH2:25]O>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:25][CH2:13][CH2:12][CH3:17])[C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCCOS(=O)(=O)c1ccccc1
Reactant: NO
Reactant: CCOC(=O)c1cnoc1C
Product: CCCNc1noc(C)c1C(=O)OCC

Procedure:
Ethyl 5-methylisoxazole-4-carboxylate is quaternized with propyl benzenesulfonate and the resulting quaternary salt is reacted with hydroxylamine to give the title compound according to the procedure of A. Alberola et al., Synthesis 203 (1988).
Reaction SMILES: [NH3:1].[NH2-].[Na+].[CH3:4][CH2:5][CH2:6][CH2:7][CH:8]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>CN(C)C1C=CC=CC=1>[CH3:12][CH2:11][CH2:10][CH2:9][CH:8]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH2:7][CH2:6][CH2:5][CH3:4].[NH2:1][C:15]1[CH:14]=[C:13]([CH:8]([CH2:7][CH2:6][CH2:5][CH3:4])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:18]=[CH:17][N:16]=1
Reactant: [H][H]
Reactant: N
Agent: CCCCC(CCCC)c1ccncc1
Agent: [NH2-]
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Product: CCCCC(CCCC)c1ccnc(N)c1
Temperature: 150 °C
Reaction time: 4.5 h

Procedure:
Liquid ammonia, containing one mole of freshly prepared sodamide, was replaced with 500 cc of N,N-dimethylaniline. The mixture was heated to 150° C. and 102.5 g (0.5 moles) of 4-(5-nonyl)pyridine was rapidly added through a dropping funnel. This mixture was heated to 175° C. at which point a fast evolution of hydrogen gas began. The reaction mixture was kept at 175°-180° C. for 4.5 hours and then allowed to cool over night with little hydrogen gas evolution during the last hour of the heating period. The cooled mixture was then hydrolyzed with 200 cc of water and the organic phase was separated and distilled to give 8.7 g of unreacted 4-(5-nonyl)pyridine and 39.2 g of 2-amino-4-(5-nonyl)pyridine, with most of the aminopyridine product boiling at 162°-164° C. and 2 mm Hg. Also obtained from such distilling was 18.6 g of 4,4'-di-(5-nonyl)-2,2'-bipyridyl, such 2,2' -bipyridyl product boiling at 237°-250° C. and 1 mm Hg. Based on the recovered 4-(5-nonyl)pyridine, yields were calculated for the amino product of 38.9% and for the 2,2'-bipyridyl product of 19.9%. Upon subsequent testing, the 2,2'-bipyridyl product performed effectively as a metal chelating agent and exhibited significant and valuable fungicidal properties.