Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)([O-])=O.[CH3:14]OS(OC)(=O)=O.[C:21](OC(=O)C)(=[O:23])[CH3:22]>CN(C)C=O>[CH3:14][N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[NH:1][C:21](=[O:23])[CH3:22])[CH2:9]1
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1cccc2cnccc12
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc2c1CCN(C)C2
Temperature: 90 °C
Reaction time: 15.5 h
Yield: 26 %

Procedure:
A solution of 5-nitroisoquinoline (200 g, 1.15 mol) in 1000 mL of dimethylformamide was treated with dimethylsulfate (160 g, 1.27 mol), and the resulting solution was heated to 90° C. until no starting material remained. The reaction mixture was cooled and concentrated. The residue was dissolved in 1500 mL of methanol and hydrogenated over PtO2 (1.0 g) at 52 psi for 15.5 hours. The reaction mixture was then concentrated and the residue dissolved in CHCl3 (1000 mL) and washed with aqueous 1N NaOH solution (500 mL). The aqueous phase was extracted with an additional 3000 mL of chloroform, and the combined organic extracts were dried (Na2SO4) and concentrated to give an oil. The oil was treated with acetic anhydride (700 mL) and the resulting solution stirred at room temperature overnight. The reaction mixture was concentrated and the residue was dissolved in chloroform and washed with aqueous 1N NaOH solution. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by chromatography (10:2 EtOAc:EtOH). The purified residue was recrystallized from EtOAc to give the product (60.6 g, 26%) as a white solid, mp=138-139° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:18](=[O:19])[C:17]2[C:16]([OH:20])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[N:14]3)=[C:9]([OH:21])[C:8]=2[C:7]1=[O:22].[OH-].[Na+].[CH2:31]([O:33][C:34](Cl)=[O:35])[CH3:32].[C:37]1([CH:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[N+]#N)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCOCC1.ClCCl.O>[CH2:31]([O:33][C:34](=[O:35])[O:21][C:9]1[C:8]2[C:7](=[O:22])[N:6]([CH2:5][C:4]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:3]=3[O:2][CH3:1])[C:18](=[O:19])[C:17]=2[C:16]([O:20][CH:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[CH3:32]
Reactant: COc1ccc(CN2C(=O)c3c(c(O)c4ncccc4c3O)C2=O)c(OC)c1
Reactant: CCOC(=O)Cl
Reactant: N#[N+]C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)Oc1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(OC)cc1OC)C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
7-(2,4-Dimethoxy-benzyl)-5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione 300 (1.1 g, 2.9 mmol) was dissolved in dioxane (14.5 ml) and H2O (9.7 ml) and cooled to 0° C. To this reaction mixture was added 1.0 M NaOH (5.8 ml, 5.8 mmol), followed by ethylchloroformate (347.3 mg, 3.2 mmol). After stirring at 0° C. for 30 minutes, dioxane (10 ml) and ethylchloroformate (51 mg, 0.5 mmol) were added and the reaction stirred for another 30 minutes at 0° C. The reaction mixture was quenched with the addition of acetic acid (0.6 ml) and concentrated in vacuo. The crude mixture was diluted with ethyl acetate and washed once with 5% citric Acid (aqueous), twice with water, once with brine, and dried over magnesium sulfate. The resulting residue was dissolved in 1,2-dichloroethane (30 ml) and diphenyl-methanediazonium 38 (diphenyldiazomethane, 1.1 g, 5.6 mmol) was added. The reaction mixture was then stirred overnight at room temperature. Following dilution with dichloromethane, the reaction mixture was washed with once with water, once with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (1/1-Hexanes/Ethyl Acetate) to afford carbonic acid 9-benzhydryloxy-7-(2,4-dimethoxy-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo [3,4-g]quinolin-5-yl ester ethyl ester 301 (1.2 g, 1.9 mmol, 66%). 1H NMR (CDCl3) δ 9.10 (dd, 1H), 8.40 (dd, 1H), 7.95 (s, 1H), 7.68 (m, 1H), 7.60 (d, 4H), 7.15 (m, 6H), 7.0 (d, 1H), 6.40 (d, 1H), 6.36 (d, 1H), 4.80 (s, 2H), 4.35 (q, 2H), 3.75 (s, 3H), 3.73 (s, 3H), 1.31 (t, 3H). MS: 641.2 (M+23).
Reaction SMILES: C(OC(=O)[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:27]2[C:35]3[C:34]([CH:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[N:33][CH:32]=[N:31][C:30]=3[N:29]([S:41]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH:28]=2)O)=[CH:21][N:20]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(#N)C>O>[C:44]1([S:41]([N:29]2[C:30]3[N:31]=[CH:32][N:33]=[C:34]([CH:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[C:35]=3[C:27]([CH2:25][C:22]3[CH:23]=[CH:24][C:19]([NH:7][CH2:8][C:9]4[CH:10]=[N:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=4)=[N:20][CH:21]=3)=[CH:28]2)(=[O:42])=[O:43])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1ccc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncnc(C4CCCC4)c23)cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=S(=O)(c1ccccc1)n1cc(Cc2ccc(NCc3ccc(C(F)(F)F)nc3)nc2)c2c(C3CCCC3)ncnc21

Procedure:
{5-[(7-Benzenesulfonyl-4-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-pyridin-2-yl}-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (52, 0.014 g, 0.020 mmol), trifluoroacetic acid (0.028 mL, 0.37 mmol), triethylsilane (0.071 mL, 0.45 mmol), and 0.21 mL of acetonitrile were combined in a round bottom flask. The reaction mixture was heated at reflux for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 25% methanol in dichloromethane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6](O)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:46])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38]S(C)(=O)=O)[C:24]=1[CH2:43][CH2:44][CH3:45])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:46])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:24]=1[CH2:43][CH2:44][CH3:45])[CH3:16]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCOCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 17.7 %

Procedure:
A mixture of 1 g (0.0052 mol) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.45 g (0.0052 mol) of 4-[4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]-ethoxy]-2-propylphenoxy]butanoic acid ethyl ester and 2.6 g (0.019 mol) of anhydrous potassium carbonate in 100 ml of anhydrous acetone and 50 ml of anhydrous dimethylformamide was stirred at reflux for 19 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was treated with ethyl acetate and sodium chloride solution. The organic phase was washed with 1N sodium hydroxide solution and sodium chloride solution. The yellow oil obtained on concentration of the ethyl acetate was purified by column chromatography, eluting with 5% ethyl acetate-toluene to yield 0.526 g (18% yield) of 4-[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester as a pale yellow oil.
Reaction SMILES: [Cl-].[NH4+].O.C(O)C.[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([N+:28]([O-])=O)=[C:19]([CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OCC)C.[Fe]>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:28])=[C:19]([CH2:21][C:22]([O:24][CH:25]([CH3:26])[CH3:27])=[O:23])[CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)OC(=O)Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CC(C)OC(=O)Cc1cc(OCc2ccccc2)ccc1N
Reaction time: 3 h

Procedure:
A mixture of ammonium chloride (5.63 g), a water/ethanol mixed solvent (1:1 v/v, 240 ml ) and powdery iron (29.3 g) was heated under reflux for one hour and a Soxhlet extractor containing isopropyl 5-benzyloxy-2-nitrophenylacetate was set and refluxing was continued for a further 3 hours and then allowed to stand at room temperature overnight. Insolubles were filtered off with Celite and the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in ethyl ether, and the solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The oily substance thus obtained (18.9 g) was purified by a silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (10.8 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:28]4[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(C(F)(F)F)cc4)c3)cnc2c1F
Yield: 7 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 4-trifluoromethylbenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[8-fluoro-3-(2-fluoro-4′-trifluoromethylbiphenyl-5-yl)imidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (10 mg, 7%): m/z (ES+) 433 [MH+].
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1.S([Cl:21])(C)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Cl:21][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH3:8])=[N:14][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(CO)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 10 h
Yield: 37.5 %

Procedure:
Triethylamine (96 ml, 0.69 mol) was added to a solution of (6-methyl-3-pyridyl)methanol (28.4 g, 0.23 mol) in methylene chloride (230 ml) while cooling on ice. Mesyl chloride (26.8 ml, 0.35 mol) was then slowly added dropwise over a period of 20 minutes at the same temperature and the mixture was stirred for 10 hours while gradually raising the temperature to room temperature. After confirming completion of the reaction by thin layer chromatography, the mixture was diluted with ethyl acetate and poured into saturated aqueous NaHCO3. After separating the aqueous layer, extraction was performed with ethyl acetate, and the collected organic layer was washed with saturated aqueous NaCl and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to yield the title compound (12.2 g). This was used without further purification for the following reaction.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[CH3:7][S:8]([O:11][CH2:12][CH2:13][CH3:14])(=[O:10])=[O:9]>C1(C)C=CC=CC=1>[CH3:7][S:8]([O-:11])(=[O:10])=[O:9].[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([CH2:12][CH2:13][CH3:14])[CH:3]=1
Reactant: CCCOS(C)(=O)=O
Reactant: Cn1ccnc1
Solvent: Cc1ccccc1
Product: CCCn1cc[n+](C)c1
Product: CS(=O)(=O)[O-]
Temperature: 80 °C
Reaction time: 40 h
Yield: 90 %

Procedure:
To a 50 ml four necked flask equipped with a stirrer, a dropping funnel, a cooling tube and a thermometer, 41.05 g (0.5 mol) of 1-methyl imidazole and 50 ml of toluene were charged and, after heating at 80° C., 76.00 g (0.55 mol) of propyl methane sulfonate was dropped slowly taking one hour or more. They were stirred at a refluxing temperature for 40 hours. After cooling, solvent cleaning was conducted with toluene to obtain 99.13 g of 1-methyl-3-propyl-imidazolium methane sulfonate salt by drying under a reduced pressure. Then, 99.13 g of the obtained 1-ethyl-3-propyl imidazolium.methane sulfonate salt was dissolved in 80 ml of water, and a solution in which 139.24 g of lithium bis(trifluoromethane sulfonyl) imide was dissolved in 80 ml of water was added thereto at a room temperature and stirred. From separated two layers, the lower layer was fractionated and by-products were removed by adding 40 wt % of purified water and by water washing five times, and vacuum drying was applied to obtain 178.75 g of 1-methyl-3-propyl imidazolium bis(trifluoromethane sulfonyl) imide. As a result of ICP analysis, the total alkali metal was 2.1 ppm or less, the chloride ion was 0.6 ppm and each of iodide and bromide ions was 0.1 ppm or less (less than ICP detection limit).
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH3:5].OC([N:15]1[CH2:19][CH2:18][N:17]=[CH:16]1)C.[CH2:20]([CH:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][C:24]([O-:26])=[O:25])[CH3:21].[Bi+3:31].C(C(CCCC)CC([O-])=O)C.C(C(CCCC)CC([O-])=O)C.[C:54](=[S:56])=[S:55]>>[CH2:7]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:54](=[S:55])[S-:56])[CH2:8][CH2:9][CH2:10][CH3:11].[Bi+3:31].[CH2:7]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:54](=[S:55])[S-:56])[CH2:8][CH2:9][CH2:10][CH3:11].[CH2:7]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:54](=[S:55])[S-:56])[CH2:8][CH2:9][CH2:10][CH3:11].[NH:17]1[CH2:18][CH2:19][N:15]=[CH:16]1.[CH2:20]([CH:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][C:24]([O-:26])=[O:25])[CH3:21]
Reactant: CC(O)N1C=NCC1
Reactant: S=C=S
Reactant: CCCCCNCCCCC
Agent: CCCCC(CC)CC(=O)[O-]
Agent: [Bi+3]
Product: C1=NCCN1
Product: CCCCCN(CCCCC)C(=S)[S-]
Temperature: 80 °C

Procedure:
A reaction vessel was charged with diamylamine, 65.2 g, tall oil 1-hydroxyethyl-2-imidazoline, 145 g, and bismuth 2-ehtylhexyl-carboxylate, 103.3 g. Carbon disulfide, 45 g, was charged with cooling to control the exothermic reaction and then was maintained at 80° C. The reaction was stripped under vacuum to yield bismuth diamyldithiocarbamate and imidazoline salt of 2-ethylhexyl-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:27][NH:28][CH3:29]>C(O)C>[NH3:9].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][N:28]([CH3:29])[CH3:27])=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNC
Reactant: Fc1ccc(Nc2ncnc3[nH]c(-c4ccc(CCl)cc4)cc23)cc1Cl
Solvent: CCO
Product: CN(C)Cc1ccc(-c2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3[nH]2)cc1
Product: N
Yield: 1 %

Procedure:
A mixture of 200 mg (0.5 mmol) crude (3-chloro-4-fluoro-phenyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine in 15 ml absolute ethanol is treated with 0.8 ml (5 mmol) of a 33% solution of dimethylamine in ethanol (Fluka, Buchs, Switzerland) and then heated under reflux for 1 h. The almost clear solution is cooled and the solvent evaporated. The residue is dissolved in a mixture of dichloromethane and ethanol (95:5), washed with water, dried over sodium sulfate and the solvent evaporated. Purification of the crude material through flash chromatography using first dichloromethane/ethanol 95:5 plus 1% conc. ammonia and then dichloromethane/ethanol 9:1 plus 1% conc. ammonia gives the title compound; m.p. 274-276° C.; MS-ES+: (M+H)+=396.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:35]=[CH:36][C:37]=1[C:38](=[N:40]O)[NH2:39])[CH2:23][N:24]1[CH2:27][CH:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>CN(C)C=O.ClCCl>[Cl:19][C:20]1[CH:21]=[C:22]([CH:35]=[CH:36][C:37]=1[C:38]1[N:40]=[C:16]([C:10]2[O:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]=2[C:12]([F:13])([F:14])[F:15])[O:18][N:39]=1)[CH2:23][N:24]1[CH2:27][CH:26]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:25]1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NO)c(Cl)c2)C1
Reactant: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
A mixture of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (1-D, 0.027 g, 0.105 mmol), tert-butyl 1-(3-chloro-4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (0.036 g, 0.105 mmol), BOP-Cl (0.035 g, 0.136 mmol), and triethylamine (0.044 mL, 0.315 mmol) in N,N-dimethylformamide (1 mL) was shaken on platform shaker at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was loaded on a fitted funnel containing a pad of CELITE® topped with a pad of silica gel, eluted with a 5% mixture of ethyl acetate in hexane, eluted with dichloromethane, and then eluted with a 20% mixture of ethyl acetate in hexane to give tert-butyl 1-(3-chloro-4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (0.013 g, 0.023 mmol, 22% yield) as a white solid. The compound had an HPLC ret. time=2.13 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=561.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([O:13]COC)=[C:10]([O:17][CH3:18])[CH:9]=[CH:8]2)[CH3:2].C[C:20](C)=[O:21]>Cl>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([OH:13])=[C:10]([O:17][CH3:18])[CH:9]=[C:8]2[CH:20]=[O:21])[CH3:2]
Reactant: CC(C)=O
Reactant: CCc1cccc2ccc(OC)c(OCOC)c12
Agent: Cl
Product: CCc1cccc2c(C=O)cc(OC)c(O)c12
Reaction time: 5 h

Procedure:
200 g of 8-ethyl-2-methoxy-1-methoxymethoxynaphthalene was dissolved in 1 liter of acetone, to which dilute hydrochloric acid (concentrated hydrochloric acid 81 ml/water 200 ml) was added under ice-cooling conditions, after which the ice bath was removed, followed by agitation at room temperature for 5 hours. The reaction solution was poured into iced water and extracted with ethyl acetate. The resultant organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate. After removal of the solvent by distillation, 178 g of the resultant oily substance was dissolved in dichloromethane, to which 178 ml of titanium tetrachloride was gently added under ice-cooling conditions. After agitation for 30 minutes, 121 ml of dichloromethyl methyl ether was gradually added and agitated for 30 minutes. Iced water was gently added to the reaction solution, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate. After removal of the solvent by distillation, the resultant residue was washed with a mixture of hexane/isopropyl ether (1:1) to obtain 110 g of the caption compound as yellowish brown crystals.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:21][N:22]1[C:26]([CH2:27][CH:28]([C:30]2[S:31][CH:32]=[CH:33][N:34]=2)O)=[CH:25][N:24]=[CH:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([O:18][CH:28]([C:30]3[S:31][CH:32]=[CH:33][N:34]=3)[CH2:27][C:26]3[N:22]([CH3:21])[CH:23]=[N:24][CH:25]=3)=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: Cn1cncc1CC(O)c1nccs1
Reactant: COC(=O)c1cc(O)ccc1CCc1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC(Cc2cncn2C)c2nccs2)ccc1CCc1ccc(F)cc1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
A mixture of methyl 2-(4-fluorophenethyl)-5-hydroxybenzoate (1.83 g, 6.7 mmol), 2-(1-methylimidazol-5-yl)-1-(thiazol-2-yl)ethanol (1.40 g, 6.68 mmol) and triphenylphosphine (2.10 g, 8.0 mmol) in tetrahydrofuran (25 ml) was stirred at ambient temperature under a nitrogen atmosphere. DEAD (1.39 g, 1.25 ml 8.0 mmol) was added dropwise to the solution. (The reaction was maintained at ambient temperature ±2° C.). The orange solution was then stirred at ambient temperature under a nitrogen atmosphere for 16 hours. The tetrahydrofiran solution was evaporated to dryness to give an oil. Purification by flash column chromatography eluting with ethyl acetate, ethyl acetate/methanol (9:1 and 4:1) gave methyl 2-(4-fluorophenethyl)-5-[2-(1-methylimidazol-5-yl)-1-(thiazol-2-yl)ethoxy]benzoate (2.07 g, 67%) as a clear oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:10])[C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[Cl:10][C:4]1[C:5]([S:8][CH3:9])=[N:6][CH:7]=[C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: CSc1ncc(Br)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CSc1ncc(C#C[Si](C)(C)C)cc1Cl
Temperature: 80 °C
Reaction time: 17 h
Yield: 70.6 %

Procedure:
A mixture of 5-bromo-3-chloro-2-methylthio-pyridine (7.5 g, 0.031 mol), trimethylsilylacetylene (5.3 g, 0.053 mol), copper (I) iodide (60 mg, 0.32 mmol), bis(triphenylphosphine) palladium (II) chloride (0.42 g, 0.6 mmol) and triethylamine (100 mL) was sealed in a 300 mL Hastelloy steel bomb and heated with stirring at 80° C. for 17 hours. The mixture was cooled, filtered, and the precipitate washed with ethyl acetate (100 mL). The combined organic solutions were evaporated to dryness under reduced pressure. The resultant dark oil was dissolved in hexane (100 mL) and washed with water and brine, and evaporated under reduced pressure. Purification of the residue by chromatography over silica (0-2% ethyl acetate:hexane) gave the desired product (5.6 g, 71%) as a yellow oil.