Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[ClH:19].Cl.[NH2:21][CH2:22][CH2:23][O:24][NH2:25].N1C=CC=CC=1>C(O)C>[ClH:1].[ClH:19].[NH2:21][CH2:22][CH2:23][O:24][N:25]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH2:11][CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: NCCON
Reactant: O=C(CCCn1ccnc1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: NCCON=C(CCCn1ccnc1)c1ccc(Cl)c(Cl)c1
Reaction time: 3 h
Yield: 65.7 %

Procedure:
A mixture of 1-(3,4-dichlorophenyl)-4-(1-(1H)-imidazolyl)-1-butanone (2.29 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (1.45 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for three hrs. The reaction mixture was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and evaporated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized twice from absolute ethanol/ether to give 1.1 g (33%) of product, mp 205°-208° C. (dec).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][O:10][CH2:11][CH2:12][N:13]2[C:21]3[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=[C:17](OC4C=CC=CC=4)[C:16]=3[N:15]=[C:14]2[CH3:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+:36].Cl>>[CH3:31][C:14]1[N:13]([CH2:12][CH2:11][O:10][CH2:9][C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:21]2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=[C:17]([NH2:36])[C:16]=2[N:15]=1
Reactant: [NH4+]
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOCC#Cc3ccccc3)c2c1C
Agent: CC(=O)[O-]
Agent: Cl
Product: Cc1nc(N)c2nc(C)n(CCOCC#Cc3ccccc3)c2c1C
Temperature: 150 °C
Yield: 41.2 %

Procedure:
1-[2,6,7-Trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]eth-2-yl (3-phenylprop-2-ynyl) ether (5.4 g, 13.122 mmol) from Part H and ammonium acetate (54 g) were combined in a glass pressure vessel. The vessel was sealed with a teflon screw cap, and the reaction mixture was heated to 150° C. for 45 hours. The reaction was essentially complete, and the resulting reaction solution was cooled with an ice bath, acidified to a pH of 1 with 10% hydrochloric acid, and washed with dichloromethane (3×500 mL). The combined organic portions were washed with 10% hydrochloric acid (4×). The acidic aqueous portions were combined, basified with potassium hydroxide pellets to a pH of 14. The resulting brown solids were filtered off and recrystallized from methanol. A first crop of 0.6 g was collected for use in Example 5, and a second crop was collected and found to contain about 2% of the 4-hydroxy compound by NMR analysis. The second crop was returned to the mother liquor, and dichloromethane was added until all solids were dissolved. 1M Hydrochloric acid in diethyl ether (20 mL) was added to the resulting solution, and the solids that formed were filtered off, and dissolved in water, which was basified to a pH of 14 with potassium hydroxide pellets. The resulting solution was washed with dichloromethane (3×). The organic portions were combined, washed with water (2×) and brine (2×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting white solid (1.8 g) was dissolved in dichloromethane (150 mL), and 1M hydrochloric acid in diethyl ether (5.3 mL) was added to the resulting solution. The acidified solution was concentrated under reduced pressure. The resulting solids were dissolved in water, and this aqueous solution was filtered to remove an oily sludge. The filtrate was basified with a few drops of 20% potassium hydroxide and then 1N potassium hydroxide to a pH of 13. The fine white precipitate that formed was filtered off, rinsed with diethyl ether, and dried under vacuum for 18 hours to provide 1.8064 g of 2,6,7-trimethyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 186.8-187.5° C.
Reaction SMILES: [SH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].C=O.O.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=C(C)C=C(C)C=1>[S:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:8])[NH:9][CH2:13]1
Reactant: NC(=O)c1sccc1S
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: Cc1cc(C)cc(C)c1
Solvent: O
Product: O=C1NCSc2ccsc21

Procedure:
aad) 11.1 g of 3mercapto-thiophene-2-carboxamide, 2.2 g of 95 percent paraformaldehyde and 13.3 g of p-toluene-sulfonic acid monohydrate were heated together under reflux with 300 ml of mesitylene. After the reaction finished, the mixture was left to cool and the solvent was removed in vacuo. After chromatography of the residue on silica gel and recrystallization from ethyl acetate, there was obtained 2,3-dihydro-4H-thieno[2,3-e][1,3]thiazin-4-one as yellowish crystals of m.p. 153°-155°.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][C@@H:52]([CH2:66][C:67]1[CH:72]=[C:71]([F:73])[CH:70]=[C:69]([F:74])[CH:68]=1)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=1>C(Cl)Cl>[F:73][C:71]1[CH:72]=[C:67]([CH:68]=[C:69]([F:74])[CH:70]=1)[CH2:66][C@H:52]([NH:51][C:15]([C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][N:6]=[C:5]2[NH:4][CH2:1][CH2:2][CH3:3])=[CH:10][CH:11]=1)=[O:17])[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCNc1nccc2ccc(C(=O)O)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCNc1nccc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Reaction time: 18 h
Yield: 34 %

Procedure:
To a stirred solution of 1-(propylamino)isoquinoline-7-carboxylic acid (81 mg, 0.396 mmol) and N,N-diisopropyl ethylamine (3.75 μL, 2.16 mmol) in methylene chloride (5.0 mL) was added HBTU (152 mg, 0.396 mmol) and the reaction stirred for 0.5 h. (2R,3S)-3-Amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (150 mg, 0.36 mmol) was added in one portion and the reaction mixture was stirred under nitrogen for 18 h. The reaction mixture was then diluted with additional methylene chloride and washed with saturated sodium bicarbonate, saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 0–5% methanol/methylene chloride) gave N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-1-(propylamino)isoquinoline-7-carboxamide (67 mg) which was characterized as its bis-HCl salt: mp 262° C. dec; ESI MS m/z 547 [M+H]+
Reaction SMILES: [Br:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].C(N(CC)CC)C.[O:15]1CC[CH2:17][CH2:16]1.C(Cl)(=O)C>O>[Br:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][O:5][C:16](=[O:15])[CH3:17]
Reactant: CC(C)(CO)CBr
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)Cl
Product: CC(=O)OCC(C)(C)CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-bromo-2,2-dimethyl-1-propanol (5 mL) and triethylamine (15 mL) was added tetrahydrofuran (50 mL), acetyl chloride (3.8 mL) was added dropwise under ice-cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give acetic acid (3-bromo-2,2-dimethyl-1-propyl)ester (8.37 g). The obtained acetic acid (3-bromo-2,2-dimethyl-1-propyl)ester (8.37 g) were added sodium sulfite (5.05 g) and water (20 mL), and the mixture was stirred with heating under reflux for 20 hr. To the reaction mixture was added concentrated hydrochloric acid (5.81 mL), and the mixture was stirred with heating under reflux for 1 hr. The reaction mixture was cooled, neutralized with 4N aqueous sodium hydroxide solution (20.5 mL), and the mixture was concentrated to about 10 mL. The precipitated precipitate was collected by filtration, and the filtrate was concentrated. To the obtained residue was added phosphorus pentachloride (18.35 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Into the reaction mixture was poured ice water, and the mixture was extracted with dichloromethane. The solvent was evaporated from the organic layer to give crude 3-chloro-2,2-dimethylpropane-1-sulfonyl chloride (3.99 g). Using the obtained crude 3-chloro-2,2-dimethylpropane-1-sulfonyl chloride (3.99 g) and ethyl 4-aminobenzoate (3.21 g) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (127 mg) was obtained.
Reaction SMILES: B(O)O.O1[CH:8]=[CH:7][CH:6]=[C:5]1B(O)O.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([NH:32][S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:29]=[N:30][CH:31]=2)O1.O1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>>[O:46]1[CH:47]=[CH:48][CH:44]=[C:45]1[C:29]1[CH:28]=[N:32][C:5]2[C:31]([N:30]=1)=[CH:26][C:8]([C:26]1[CH:27]=[C:28]([NH:32][S:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)(=[O:34])=[O:35])[CH:29]=[N:30][CH:31]=1)=[CH:7][CH:6]=2
Reactant: OB(O)c1ccco1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [K+]
Product: O=S(=O)(Nc1cncc(-c2ccc3ncc(-c4ccco4)nc3c2)c1)c1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 14 %

Procedure:
A slurry of 7-bromo-2-chloroquioxaline (0.82 mmol), a boronic acid such as 2-furan boronic acid (0.82 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.06 mmol), in 1,4-dioxane (4 ml) and 2M solution potassium carbonate (2 ml) was stirred at 100° C. for 3 hour. Then N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.90 mmol) was added and the reaction mixture stirred at 100° C. for 18 hours. The reaction was cooled to ambient temperature, the organic layer separated and purified directly on silica by column chromatography (50% ethyl acetate/hexanes). The desired fractions were combined and concentrated to give the title compound (50 mg, 14%) as a tan solid. MS(ES)+ m/e 429.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:11][CH:10]1[C:12](N(OC)C)=[O:13].[OH-:18].[K+].Cl>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:11][CH:10]1[C:12]([OH:13])=[O:18]
Reactant: CON(C)C(=O)C1CC1c1cc(F)ccc1Br
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)C1CC1c1cc(F)ccc1Br
Temperature: 25 °C

Procedure:
A solution of 2-(2-bromo-5-fluorophenyl)-N-methoxy-N-methylcyclopropane-carboxamide (304 mg, 1.0 mmol), 10 M potassium hydroxide (3.5 mL, 35 mmol), and dioxane (2.5 mL) was heated at 130° C. in a sealed tube for 19 h. Upon cooling to room temperature, the reaction mixture was acidified with 3 M HCl (20 mL), and the product was extracted with 5% methanol/dichloromethane (3×30 mL). The organic fractions were combined, dried over sodium sulfate, and concentrated to afford the title compound as a white solid. MS m/z: 259 & 261 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:34]([OH:36])=[O:35])CC1C(I)=CC(OC(OC(C)(C)C)=O)=C(OC(OC(C)(C)C)=O)C=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C=O.C1C=CC=CC=1>C(OCC)(=O)C>[O:36]1[CH2:34][CH2:9][NH:8][C:6]1=[O:7].[C:1]([O:5][C:6]([N:8]1[CH2:9][C:34](=[O:35])[O:36][CH2:37]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)cc1I)C(=O)O
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: C=O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1COC(=O)C1
Product: O=C1NCCO1

Procedure:
A mixture of the iodo amino acid 23 (0.86 mmol), camphorsulfonic acid (0.17 mmol), paraformaldehyde (1.29 mmol) and benzene (10 mL) was refluxed for 2 h. The mixture was diluted with ethyl acetate and was washed with 5% aqueous sodium bicarbonate solution. The organic phase was dried with anhydrous sodium sulfate, filtered and purified by silica gel column chromatography using 40% EtOAc/Hexane mixture as eluent to obtain pure oxazolidinone product 24 (N-(tert-butoxycarbonyl)-1,3-oxazolidin-5-one derivative) as an oil in 35% yield.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([CH2:10][C@@:11]([OH:21])([C:18]([OH:20])=[O:19])C[C@H](N)C(O)=O)=[CH:8][NH:9][C:4]2=[CH:3][CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1C(O)=C(C=O)C(COP(O)(O)=O)=CN=1>>[NH:9]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]([CH2:10][C:11](=[O:21])[C:18]([O-:20])=[O:19])=[CH:8]1.[C:18]([O-:20])(=[O:19])[C:11]([CH3:10])=[O:21]
Reactant: N[C@@H](C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(=O)C(=O)[O-]
Product: O=C([O-])C(=O)Cc1c[nH]c2ccccc12

Procedure:
AT-103 transaminase was part of a transaminase library purchased from BioCatalytics (Pasadena, Calif.) and the enzyme was tested for production of monatin in coupled reactions using the ProA aldolase from C. testosteroni. The aldolase was prepared as described in WO 03/091396 A2. AT-103 is a broad specificity D-transaminase (EC 2.6.1.21) from a Bacillus species that requires a D-amino acid (such as D-glutamate, D-aspartate, or D-alanine) as the amino acid donor. Enzymes and additional components/substrates were added directly to the reaction buffer provided in the kit, which contained 100 mM potassium phosphate buffer pH 7.5, 100 mM amino donor, and 0.1 mM pyridoxal-5′-phosphate (“PLP”). To one mL of reaction buffer were added: 4 mg indole-3-pyruvate, 20 mg pyruvate, approximately 50 μg ProA provided in a cellular extract, 1 μL. 2 M MgCl2, and 2 mg of the aminotransferase enzyme (AT-103). Reactions were performed in duplicate. The reactions were incubated overnight at 30° C. with gentle shaking (100 rpm). The samples were filtered and submitted for reversed-phase LC/MS/MS analysis as described in Example 1. The results indicated that approximately 370 μg/mL monatin were produced using AT-103 enzyme. The results were further analyzed to determine ratios of S,R/R,S versus R,R/S,S monatin, on the basis of the peak areas of the two stereoisomer pools that resolve during the chromatographic separation. Of the total monatin produced by AT-103, 69% was R,R/S,S monatin in comparison to the mixed isomers. This enzyme (AT-103) is homologous to the Bacillus subtilis DAT enzyme described in WO 03/091396 A2, which is known to have a broad specificity for D-amino acids. Chiral analysis was performed using the FDAA methodology described in Example 1, which verified that the D-aminotransferase was making predominantly R,R monatin, and some S,R monatin as expected. Further transamination experiments with S,S monatin or R,R monatin and α-ketoglutarate as substrates verified that the BioCatalytics enzyme was highly selective for the D-configuration at carbon 4, as expected. In these experiments, no glutamate was detected in the reaction with S,S monatin and α-ketoglutarate as substrates.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([O:16]C)=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1.O[Li].O>C1COCC1.CO.O>[I:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1
Reactant: COC(=O)Cc1ccc(-n2cnnn2)c(I)c1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccc(-n2cnnn2)c(I)c1
Temperature: 25 °C

Procedure:
A solution of methyl [3-iodo-4-(1H-tetrazol-1-yl)phenyl]acetate (1 g, 2.9 mmol) in a co-solution 50 mL of THF/methanol/water (2:2:1) was added added LiOH.H2O (0.6 g, 14.5 mmol), and the mixture was stirred at ambient temperature over night. Concentrated and the residue was dissolved in water and then adjusted pH=3 with 2N HCl. Extracted with DCM, and orgianc layers were washed with water, brine and dried over anhydrous sodium sulfate, concentrated to get crude product [3-iodo-4-(1H-tetrazol-1-yl)phenyl]acetic acid, which was used for the next step without purification.
Reaction SMILES: [N+](=[CH2:3])=[N-].[F:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH2:15][O:16][C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:34])[CH2:25][C:26]([CH2:32][CH3:33])([CH2:30][CH3:31])[C:27]([OH:29])=[O:28])[CH:20]=[CH:21][CH:22]=3)=[N:12]2)=[CH:7][CH:6]=1>C(OCC)C.O1CCCC1>[CH3:3][O:28][C:27](=[O:29])[C:26]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:25][C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH2:15][C:11]2[CH:10]=[CH:9][C:8]3[C:13](=[CH:14][C:5]([F:4])=[CH:6][CH:7]=3)[N:12]=2)[CH:18]=1)=[O:34]
Reactant: C=[N+]=[N-]
Reactant: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1)C(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1)C(=O)OC

Procedure:
A solution of diazomethane in diethyl ether is added at 0° to a solution of 1.9 g of 4-[3-(7-fluoro-2-quinolinylmethoxy)phenylamino]-2,2-diethyl-4-oxobutanoic acid (Example 3) in 150 ml of tetrahydrofuran until a yellow colour remains established. The yellow solution is immediately concentrated by evaporation to give the title compound in the form of a colourless oil which crystallises on being left to stand in a refrigerator, m.p. 92°-93°; IR (methylene chloride): 1735 cm-1 (C=O).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:25]=3)=[CH:17][N:16]=2)=[CH:11][CH:10]=1)[C:3]([O:5]C)=[O:4].[OH-].[Na+].C(O)(=O)C>O1CCCC1.CO>[CH3:1][C:2]([CH3:30])([CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][N:25]=3)=[CH:17][N:16]=2)=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc(-c3ncc(C(F)(F)F)[nH]3)cn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(COc1ccc(-c2ccc(-c3ncc(C(F)(F)F)[nH]3)cn2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
In tetrahydrofuran (0.85 mL) and methanol (0.85 mL) was dissolved methyl 2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoate (85 mg), 2N aqueous sodium hydroxide solution (1013.35 μL) was added to the solution, and the mixture was stirred at room temperature overnight. Acetic acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. To the residue were added acetic acid, water, and a phosphate buffer (pH 6.8), and after stirring the mixture, the organic layer was separated and concentrated under reduced pressure. After purification of the residue by LC-MS, it was dissolved in water and ethyl acetate, and the liquids were separated by adding 0.1 N phosphate buffer (pH 7.0). The organic layer was separated and concentrated under reduced pressure, and the obtained residue was pulverized by cooled ethyl acetate and collected by filtration to obtain 2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoic acid (29.3 mg).
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[O:23][CH3:24]>CN(C=O)C.CCOC(C)=O>[CH3:24][O:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[O:4][CH2:3][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:5])[CH3:1]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(C)(CO)N1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1OCC(C)(C)N1CCCC1
Temperature: 25 °C
Yield: 12.3 %

Procedure:
2-Methyl-2-pyrrolidin-1-ylpropan-1-ol (0.3776 g, 2.0682 mmol) was taken up in anhydrous DMF (5 mL). Sodium hydride (0.083 g of a 60% dispersion, 2.0682 mmol) was added. The reaction was stirred at RT until gas evolution was complete. 1-Chloro-2-methoxy-4-nitrobenzene (0.3578 g, 2.0682 mmol) was added. The reaction was heated to 80° C. and stirred for 72 h. Cooled to RT and diluted with EtOAc, (50 mL) and washed with water (3×50 mL). Organics were dried over MgSO4, filtered and concentrated. Crude product was purified by chromatatron (100% CH2Cl2 to 95:5 CH2Cl2:MeOH) to give 0.075 g (0.2551 mmol, 12%) of the product. 1H NMR (CDCl3) δ 7.81 (d, 1H, J=8.8 Hz), 7.73 (s, 1H), 7.15 (d, 1H, J=8.8 Hz), 3.88 (s, 3H), 2.76 (s, 2H), 2.68 (bs, 4H), 1.75 (bs, 4H), 1.38 (s, 6H).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(N(CC)CC)C>ClCCl>[C:15]([Si:18]([CH3:20])([CH3:19])[O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])([CH3:17])([CH3:16])[CH3:14]
Reactant: OCCOCCOCCOCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
Tetraethylene glycol, 4c (1.12 g, 5.77 mmol) and TBDMSCl (0.87 g, 5.77 mmol) were dissolved in dichloromethane (25 ml) followed by triethyl amine (1.46 g, 14.4 mmol). The solution was stirred at room temperature for 2 hours. After standard workup with dichloromethane, the residue was purified by silica gel column chromatography (50% ethyl acetate in hexane) to afford 5c (744 mg, 42%): 1H NMR δ 3.66 (m, 16H), 2.51 (t, 1H, J=5.86 Hz), 0.89 (s, 9H), 0.07 (s, 6H).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][C:20]1[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]1([N:7]([CH2:19][C:20]2[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=2)[C:8](=[O:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(CBr)cc(OC)c1OC
Reactant: O=C(C#Cc1ccccc1)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
3-Phenyl-propynoic acid phenylamide (951.4 mg, 4.3 mmol), 5-bromomethyl-1,2,3-trimethoxy-benzene (1.35 g, 5.16 mmol), and Cs2CO3 (2.1 g, 6.45 mmol) were dissolved in DMF (20 ml). The mixture was stirred at room temperature for 16 h. The mixture was poured into water and extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification was by flash column chromatography on silica gel, eluting with hexanes-EtOAc (6:1 and then 4:1) afforded 3-phenyl-propynoic acid phenyl-(3,4,5-trimethoxy-benzyl)-amide 1.03 g (65%).