Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[N+:16]([O-])([O-:18])=[O:17].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:3]([F:15])=[C:4]2[C:9]([NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2)=[C:10]([N+:16]([O-:18])=[O:17])[C:11]=1[F:12]
Reactant: O=c1[nH]c2cc(F)c(Cl)c(F)c2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2c(F)c(Cl)c(F)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 57.4 %

Procedure:
To a solution of 120 mg (5.16 mmol) of 6-chloro-5,7-difluoro-1,4-dihydroquinoxaline-2,3-dione in 1 mL of H2SO4 (97%) kept in ice bath was added portionwise 60 mg (0.59 mmol) of KNO3. The solution was stirred at room temperature for 14 h and 60 mg of KNO3 was added and it was stirred at room temperature for 24 h. It was diluted by ice-water (4 mL) and the mixture was filtered and washed by water, and dried to leave a yellow solid (94 mg, 65%). The solid was purified by NaOH/HCl precipitate to leave 63 mg of yellow solid, mp>250° C. 1H NMR (DMSO-d6), 12.11 (mb, 1), 12.503 (s, 1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18](OC)=[O:19].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH2:18][OH:19]
Reactant: COCCOCOc1c(C(=O)OC)ccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COCCOCOc1c(CO)ccc2ccccc12

Procedure:
In an analogous manner to that described in Example 5(b)-(c), from methyl 1-(2-methoxy-ethoxymethoxy)-naphthalene-2-carboxylate by reduction by means of lithium aluminium hydride there was obtained [1-(2-methoxy-ethoxymethoxy)-naphthalen-2-yl]-methanol, which was then converted into 2-chloromethyl-1-(2-methoxy-ethoxymethoxy)-naphthalene; MS: 280 (M)+.
Reaction SMILES: [Mg].[CH2:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[F:9][C:10]([F:15])([F:14])[C:11](O)=[O:12].Cl>CCOCC>[F:9][C:10]([F:15])([F:14])[C:11](=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCBr
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCCC(=O)C(F)(F)F
Reaction time: 1.5 h
Yield: 54 %

Procedure:
In a nitrogen atmosphere, 9.12 g (380 mM) of magnesium into 120 ml of ether, and 59.4 g (360 mM) of hexyl bromide dissolved in 30 ml of ether was added thereto, followed by 1.5 hours of heat refluxing. After cooling by standing and with ice, 13.68 g (120 mM) of trifluoroacetic acid dissolved in 30 ml of ether was added. After being stirred for 7 hours under cooling with ice, the system was subjected to hydrolysis with addition of hydrochloric acid, followed by extraction with ether and drying of the resultant ether layer with anhydrous sodium sulfate. The dried product was distilled under normal pressure to obtain 11.8 g of 1,1,1-trifluoro-2-octanone. Yield: 46%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:22][OH:23])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:28]=[C:29]=[O:30])(=O)=O.O>C(Cl)Cl>[C:29]([O:23][CH2:22][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)(=[O:30])[NH2:28]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CO)COc1noc2ccc(Cl)cc12
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(COC(N)=O)COc1noc2ccc(Cl)cc12
Yield: 85.5 %

Procedure:
To a suspension of 3.43 g of 3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-5-chloro-1,2-benzoisoxazole in 34 ml of methylene chloride is added 1.70 g of chlorosulfonyl isocyanate at -45° to -40° C., and the temperature thereof is elevated to 0° C., after which they are subjected to reaction at the same temperature for one hour. To the reaction mixture is added 10 ml of water and they are subjected to reaction at 20°-25° C. for one hour, after which methylene chloride is removed by distillation under reduced pressure. The crystals obtained are collected by filtration, to obtain 3.30 g of 3-(3-carbamoyloxy-2-tert-butoxycarbonylaminopropoxy)-5-chloro-1,2-benzoisoxazole.
Reaction SMILES: [CH3:1][C:2]1([CH2:12][OH:13])[O:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][O:3]1.[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][N+:20]([O-:23])=[C:19]([CH3:24])[C:18]=1[CH3:25]>CS(C)=O>[CH3:24][C:19]1[C:18]([CH3:25])=[C:17]([O:13][CH2:12][C:2]2([CH3:1])[O:3][CH2:4][C:5]3([O:6][CH2:7][CH2:8][O:9]3)[CH2:10][O:11]2)[CH:22]=[CH:21][N+:20]=1[O-:23]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: CC1(CO)OCC2(CO1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(OCC2(C)OCC3(CO2)OCCO3)cc[n+]([O-])c1C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
To a dimethylsulfoxide (15 ml) solution of the (8-methyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)methanol (1.11 g, 5.82 mmol) obtained in the step (5c), sodium hydride, in oil (326 mg, 8.15 mmol as the content was regarded as 60%) was added at room temperature in a nitrogen atmosphere. The mixture was stirred for 30 minutes in the same conditions. To the reaction mixture, 4-chloro-2,3-dimethylpyridine 1-oxide (917 mg, 5.82 mmol) was added at room temperature and the reaction mixture was stirred at 70° C. for 4.5 hours. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol=1/0-5/2 gradient) and desired fractions were concentrated to obtain the title compound (1.20 g, 66.1% yield) as a brown oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].[I-:14].[K+].[N:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[CH3:23]>CC(=O)CC>[I-:14].[CH2:2]([N+:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[CH3:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC#CCCCCCCCl
Reactant: Cc1ccnc(C)c1
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCC#CCCCCCC[n+]1ccc(C)cc1C
Temperature: 25 °C
Yield: 84 %

Procedure:
12-Chloro-dodec-5-yne (1 mmol) was mixed with potassium iodide (3 mmol) and 2,4-lutidine (3 mmol) in butanone. The mixture was refluxed for 3 days and cooled to room temperature, filtrated. The butanone was removed in a vacuum, and the resulting residue was partitioned between water and ethyl ether. The aqueous layer was washed extensively with ether until no 2,4-lutidine was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (84%). 1HNMR (300 MHz, CDCl3, ppm), 9.40 (d, 1H), 7.75 (d, 1H), 7.66 (s, 1H), 4.78 (t, 3H), 2.88 (s, 3H), 2.60 (s, 3H), 2.05-2.15 (br, 4H), 1.80-2.00 (br, 2H), 1.30-1.50 (br, 10H), 0.86 (t, 3H); 13CNMR, 156.73, 153.05, 145.84, 136.61, 127.27, 80.86, 79.85, 58.12, 31.54, 30.94, 39.09, 26.17, 22.39, 22.30, 21.03, 18.96, 18.79, 14.02.
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:12][C:11](=[O:13])[N:10]2[CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][CH2:16][CH:9]2[CH2:8]1)=[O:6])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[C:38](OCC)(=[O:44])[C:39](OCC)=[O:40]>CN(C=O)C>[OH:44][C:38]1[C:39](=[O:40])[N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:6])[N:7]2[CH2:8][C@@H:9]3[CH2:16][CH2:15][C@H:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:10]3[C:11](=[O:13])[C:12]=12
Reactant: CC(C)NC(=O)N1CC(=O)N2C(CCC2c2ccccc2)C1
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)n1c(=O)c(O)c2n(c1=O)C[C@@H]1CC[C@H](c3ccccc3)N1C2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of racemic (6R,8aS)-N-isopropyl-4-oxo-6-phenylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide (0.187 g, 0.620 mmol) in DMF (3 mL) at 0° C. was added a 1M solution of lithium bis(trimethylsilyl)amide in THF (1.49 mL, 1.49 mmol), followed by diethyl oxalate (0.101 mL, 0.745 mmol). The mixture was stirred for 18 h, allowing the cooling bath to warm to ambient temperature. The resultant mixture was then treated with additional lithium bis(trimethylsilyl)amide in THF (1.49 mL, 1.49 mmol) and stirred at room temperature for 6 h. The product mixture was concentrated under vacuum and the residue was partitioned between aqueous HCl and ethyl acetate. The organic extract was concentrated under vacuum. The residue was subjected to HPLC purification on C18 stationary phase eluted with water/acetonitrile/TFA mobile phase to give the title compound as a solid. HPLC RT=3.19 min, 95% at 215 nm (Method A); ES MS (M+H)=356.2; 1H NMR (400 MHz, DMSO-d6) δ 7.32-7.24 (m, 2H) 7.22-7.16 (m, 3H) 5.12-5.02 (m, 2H) 4.80-4.74 (d, 1H) 3.84-3.74 (m, 1H) 2.38-2.28 (m, 1H) 2.06-1.98 (m, 1H) 1.74-1.66 (m, 1H) 1.42-1.34 (dd, 6H) 1.34-1.26 (m, 1H).
Reaction SMILES: FC(F)(F)S([C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1B(O)O>C(COC)OC.O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: O=S(=O)(C1=CCCCC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(F)c(C2=CCCCC2)c1
Temperature: 80 °C

Procedure:
1-Trifluoromethylsulphonylcyclohex-1-ene (3 g, 13 mmol), cesium carbonate (8.4 g, 26 mmol) and 2,5-difluorophenyl boronic acid (2.88 g, 18 mmol) were dissolved in dimethoxyethane/water [9:1] (200 ml). The flask was degassed and then tetrakistriphenylphosphine palladium (125 mg) was added, the mixture warmed to 80° C. over 4 hr and then cooled to r.t. The solution was filtered through Celite™, diluted with water (20 ml) and the solution washed with ethyl acetate (2×100 ml). The organic phase washed with brine (100 ml), dried (MgSO4) and evaporated. The clear oil obtained was purified by column chromatography on silica gel eluting with hexanes, to give 1-(2,5-difluorophenyl)cyclohex-1-ene. 1H NMR (CDCl3) 6.97-6.73 (3H, m), 5.97-5.96 (1H, m), 2.35-2.31 (2H, m), 2.23-2.14 (2H, m) and 1.79-1.68 (1H, m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:38]=[CH:37][C:24]([CH2:25][N:26]4[CH2:29][CH:28]([C:30]([O:32]C(C)(C)C)=[O:31])[CH2:27]4)=[CH:23][CH:22]=3)[N:17]=2)[O:9][N:8]=1.FC(F)(F)C(O)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[CH:23][C:24]([CH2:25][N:26]4[CH2:27][CH:28]([C:30]([OH:32])=[O:31])[CH2:29]4)=[CH:37][CH:38]=3)[N:17]=2)[O:9][N:8]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A mixture of tert-butyl 1-(4-(5-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (0.450 g, 0.853 mmol) and trifluoroacetic acid (10.19 mL, 132 mmol) was stirred at room temperature for 60 min. The trifluoroacetic acid was removed under reduced pressure, and the residue was suspended in water (15 mL). The pH was adjusted to approximately 4.5 with a 1N aqueous solution of sodium hydroxide, and the resulting suspension was stirred for 2 h, filtered under reduced pressure, washed with water, and dried well overnight under reduced pressure to give 1-(4-(5-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid (0.306 g, 0.641 mmol, 75% yield) as a white solid. The product had an HPLC retention time=2.27 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. LC/MS M+1=472.4. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.21-3.27 (m, 3H), 3.40-3.46 (m, 2H), 3.66 (s, 2H) 7.53 (d, J=8.25 Hz, 2H), 7.66-7.70 (m, 1H), 7.98 (d, J=7.70 Hz, 1H), 8.04-8.12 (m, 3H), and 8.83 (d, 1H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][N:12]=[C:11]([C:23]([O:25]CC3C=CC=CC=3)=[O:24])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>O1CCCC1.O>[C:1]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][N:12]=[C:11]([C:23]([OH:25])=[O:24])[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a solution of 4,5-bis(phenylmethoxy)-2-pyridinecarboxylic acid, phenylmethyl ester (1.60 g, 3.76 mmole) in 15 ml of tetrahydrofuran and 2.2 ml of water was added 4 ml of 1N aqueous potassium hydroxide. The mixture was stirred at room temperature overnight. Water (15 ml) was added and 1N hydrochloric acid was added slowly with stirring while monitoring the pH. The pH of the mixture fell steadily to ca. 6.2 whereupon a large amount of solid began to separate and no further decrease in the pH was noted. Continued addition of hydrochloric acid eventually effected a sudden drop in pH to 3.2 and the addition was stopped. The solid was filtered and washed well with water, then ether, and dried in vacuo to afford 1.197 g of the title compound as a white waxy solid.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[NH:8]2.C(N(CC)CC)C.CS([Cl:39])(=O)=O>ClCCl>[Cl:39][CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[NH:8]2
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1ccc(-c2ccc3c(c2CO)NC(=O)C(C)(C)N3)c(OC)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1ccc(-c2ccc3c(c2CCl)NC(=O)C(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
8-Hydroxymethyl-7-(2-methoxy-4-methoxymethoxyphenyl)-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 9, 495 mg, 1.33 mmol) was dissolved in anhydrous dichloromethane (10 mL), and triethylamine (250 μL, 1.80 mmol) and methanesulfonyl chloride (113 μL, 1.46 mmol) were added thereto successively. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (239 mg) as a yellow amorphous product. (Yield 46%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:3]=1[C:14](=[O:16])[CH3:15].[O:17]=[C:18]1[NH:27][C:26]2[N:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:23]=[CH:22][C:21]=2[CH2:20][CH2:19]1>>[C:14]([C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:24]2[N:25]=[C:26]3[C:21]([CH2:20][CH2:19][C:18](=[O:17])[NH:27]3)=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1c(Cl)cccc1N1CCNCC1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Product: CC(=O)c1c(Cl)cccc1N1CCN(CCCCOc2ccc3c(n2)NC(=O)CC3)CC1

Procedure:
In a manner similar to that of other examples, above, 1-(2-chloro-6-piperazin-1-yl-phenyl)-ethanone was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound, mp 115° C. MS: APCI: M+1: 457.2 (Exact Mass: 456.19).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[O:3]1.O[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2[CH:28]=[C:29]([O:32][CH2:33][CH3:34])[CH:30]=[CH:31][C:24]=2[S:23]1(=[O:36])=[O:35]>O>[O:35]=[S:23]1(=[O:36])[C:24]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][C:25]=2[C:26](=[O:27])[N:22]1[CH2:21][CH2:20][CH2:19][CH2:18][N:10]1[CH2:9][CH2:8][CH:7]([N:6]2[C:5]3[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=3[O:3][C:2]2=[O:1])[CH2:12][CH2:11]1
Reactant: O=c1oc2ccccc2n1C1CCNCC1
Reactant: CCOc1ccc2c(c1)C(=O)N(CCCCO)S2(=O)=O
Solvent: O
Product: CCOc1ccc2c(c1)C(=O)N(CCCCN1CCC(n3c(=O)oc4ccccc43)CC1)S2(=O)=O

Procedure:
From 4-(2-oxo-3-benzoxazolinyl)-piperidine and 2-(4-hydroxybutyl)-1,1-dioxido-5-ethoxy-1,2-benzothiazol-3(2H)-one using the procedure described for Example 66, Steps 4-6 there was obtained a white solid: 1H NMR (400 MHz, CDCl3) 7.79 (d, J=8.57 Hz, 1H), 7.44 (s, 1H), 7.29-7.26 (m, 2H), 7.21 (d, J=6.89 Hz, 1H), 7.16-7.06 (m, 2H), 4.24-4.11 (m, 1H), 3.81 (t, J=7.3 Hz, 2H), 3.06 (br d, J=11.76 Hz, 2H), 2.45 (t, J=7.39 Hz, 2H), 2.36 (m, 2H), 2.11 (bt, J=11.08 Hz, 2H), 1.93-1.80 (br m, 6H), 1.65 (br m, 2H), 1.48 (t, J=6.97, 3H) Analysis calculated for C25H30N3O6S·HCl·1.2 H2O C: 53.75, H: 6.03, N: 7.52 found C: 53.72, H: 5.65 N: 7.52.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH2:14][N:15]2[CH2:22][CH:21]3[O:23][CH:17]([CH2:18][NH:19][CH2:20]3)[CH2:16]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Br[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH:38]([F:40])[F:39])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:39][CH:38]([F:40])[O:37][C:29]1[CH:28]=[C:27]([CH2:26][CH2:25][N:19]2[CH2:20][CH:21]3[O:23][CH:17]([CH2:16][N:15]([CH2:14][CH2:13][NH:12][S:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)(=[O:11])=[O:10])[CH2:22]3)[CH2:18]2)[CH:32]=[CH:31][C:30]=1[O:33][CH:34]([F:36])[F:35]
Reactant: FC(F)Oc1ccc(CCBr)cc1OC(F)F
Reactant: N#Cc1ccc(S(=O)(=O)NCCN2CC3CNCC(C2)O3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1ccc(S(=O)(=O)NCCN2CC3CN(CCc4ccc(OC(F)F)c(OC(F)F)c4)CC(C2)O3)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-cyano-N-[2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]-benzenesulfonamide (0.3 g, 7.5 mmol; see Preparation E above), 4-(2-bromo-ethyl)-1,2-bis(difluoromethoxy)benzene (0.26 g, 9 mmol; see Preparation G above) and potassium carbonate (0.41 g, 30 mmol) was stirred at 60° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered and solvent was evaporated under reduced pressure. The residue was purified by column chromatography, using methanol in chloroform as eluent, to yield the title compound as a white solid. Yield: 0.23 g.
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][CH:5]=1.CCN(C(C)C)C(C)C.[CH3:21][C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>O1CCOCC1.[Cu](I)I>[CH3:21][C:22]([CH3:26])([CH3:25])[C:23]#[C:24][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:11])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: C#CC(C)(C)C
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)C#Cc1ccc(C(=O)O)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
6-Chloronicotinic acid methyl ester (500 mg; 2.93 mmol) was suspended in 1,4-dioxane (3 ml) in a 5 ml reaction vial. To the vessel was added dichlorobis(triphenylphosphine) palladium(ii) (70 mg; 3 mol %), copper iodide (12 mg), n,n-diisopropylethylamine (0.63 ml; 3.5 mmol) and 3,3-dimethylbut-1-yne (0.44 ml; 3.5 mmol). The vessel was sealed and the mixture was heated at 80° C. for 24 hrs. The solvents were evaporated to dryness and 20 ml of tetrahydrofuran and 20 ml of 10N NaOH was added. The mixture was stirred at room temperature for 30 minutes and the solvent was evaporated. The basic layer was acidified with concentrated HCl and extracted three times with EtOAc. The organic layers were washed with brine and dried over Na2SO4, filtered and evaporated to give the desired product as a brown powder (590 mg; 99%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:15][O:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>CC(C)=O>[CH3:15][O:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCc1ccc(OCc2ccccc2)cc1

Procedure:
Benzyl bromide (12.9 mL, 108 mmol), K2CO3 (15.0 g, 109 mmol) and the 3-(4-hydroxyphenyl)propionic acid methyl ester from Step 1 above were combined in acetone (300 mL) and refluxed 40 h. The crude reaction mixture was filtered and the cake washed with acetone (2×100 mL). The filtrate was evaporated and the residue was triturated with MeOH (50 mL, 6 mL, 4 mL) to provide the product as a solid which was used without further purification.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1.[C:16]([Si:18]([CH3:21])([CH3:20])[CH3:19])#[CH:17]>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>[CH3:19][Si:18]([C:16]#[C:17][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1)([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1cn2cc(I)ccc2n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)c1cn2cc(C#C[Si](C)(C)C)ccc2n1
Temperature: 50 °C
Reaction time: 50 h

Procedure:
A mixture of 4 g of ethyl 6-iodoimidazo[1,2-a]pyridine-2-carboxylate, 2.63 mL of ethynyltrimethylsilane and 888 mg of dichlorobis(triphenylphosphine)palladium is degassed under vacuum. 240 mg of degassed N,N-dimethylformamide and 3.52 mL of triethylamine are added. The reaction mixture is degassed under argon, stirred at 50° C. for 50 hours and then cooled and diluted with 20 mL of water. The precipitate is filtered off by suction and washed with 5 mL of water and then chromatographed on silica, eluting with mixtures of ethyl acetate and hexane (from 50/50 to 90/10). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 3.6 g of ethyl 6-[(trimethylsilyl)ethynyl]imidazo[1,2-a]pyridine-2-carboxylate in the form of an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[S:9]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[C:13]=2[OH:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)Cl.[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.[BH4-].[Na+]>C(O)(C)C>[Cl:19][C:14]1[C:13]([OH:20])=[C:12]([S:9]([N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([F:34])=[CH:36][CH:37]=3)=[CH:30][CH:29]=2)(=[O:11])=[O:10])[CH:17]=[C:16]([Cl:18])[CH:15]=1
Reactant: NCc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1ccc(CNCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To a solution of N-(4-(aminomethyl)benzyl)-3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxybenzenesulfonamide (235 mg, 0.50 mmol) in a mixed solvent (10 mL of CH2Cl2 and 2 mL of i-propanol) at rt was added 4-fluorobenzaldehyde (62 mg, 0.50 mmol). The reaction mixture was stirred at rt overnight. The next morning, sodium borohydride (37 mg, 1.00 mmol) was added, and the mixture was stirred at rt for 2 h. The reaction mixture was quenched by adding 3 mL of MeOH and 3 ml of saturated aq NaHCO3. The reaction mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were dried, concentrated and purified by prep HPLC to give the title compound (164 mg, 57%) as a white solid. MS (ESI): 577.0 (M+H)+.