Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:13][S:14]([O:17][CH:18]([CH:20]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:21][CH2:22][O:23][Si](C(C)C)(C(C)C)C(C)C)[CH3:19])(=[O:16])=[O:15].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CO>[CH3:13][S:14]([O:17][CH:18]([CH:20]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:21][CH2:22][OH:23])[CH3:19])(=[O:16])=[O:15]
Reactant: CC(OS(C)(=O)=O)C(CCO[Si](C(C)C)(C(C)C)C(C)C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(OS(C)(=O)=O)C(CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
0.24 g of p-toluenesulfonic acid monohydrate was added to a solution of 1.05 g of 3-phenyl-5-((tris(propan-2-yl)silyl)oxy)pentan-2-yl methanesulfonate in 15 mL of methanol, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was fractionated, and it was successively washed with water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=1/4 to 1/1), so as to obtain 0.56 g of 5-hydroxy-3-phenylpentan-2-yl methanesulfonate in the form of a colorless oily product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].I[CH2:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[CH3:21][C:20]([CH3:23])([CH3:22])[CH2:19][CH2:18][O:10][C:7]1[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: CC(C)(C)CCI
Reactant: O=Cc1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)CCOc1ccc(O)c(C=O)c1
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a solution of the 2,5-dihydroxybenzaldehyde in DMF was added K2CO3 at room temperature and the mixture was stirred for 10 min. To this solution 1-iodo-3,3-dimethylbutane was added. After stirring at 70° C. for 4 h, the solvent was removed under reduced pressure and reaction mixture was diluted with ethyl acetate. After washing with water, the organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography to give desired product in 65% yield. 1H NMR: 0.97 (s, 9H), 1.73 (t, 2H, J=7.2 Hz), 4.05 (t, 2H, J=7.2 Hz), 6.88 (d, 1H, J=9.2 Hz), 7.09 (dd, 1H, J=9.2, 3.2 Hz), 7.35 (d, 1H, J=3.2 Hz), 10.39 (s, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH2:15]C(O)=O)(=[O:14])=[O:13])=[C:7]([Cl:19])[CH:6]=1)[CH3:2].C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:6]=[C:7]([Cl:19])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:9]([Cl:11])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)c(S(=O)(=O)CC(=O)O)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Cl)c(S(C)(=O)=O)c(Cl)c1

Procedure:
3,5-Dichloro-4-[(carboxymethyl)sulfonyl]benzoic acid ethyl ester (3.1 g) was mixed with toluene (100 mL) and pyridine (1.0 mL) and the mixture was refluxed for 30 min and then evaporated to dryness (yield 2.6 g). 1H-NMR (400 MHz, DMSO-d6) d=1.34 (t, J=7.0 Hz, 3H), 3.51 (s, 3H), 4.37 (q, J=7.0 Hz, 2H), 8.05 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[O:13][CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].N(C(C1C=CC=CC=1)C1C=C(C=CC=1)OCC1C=CC(C(O)=O)=CC=1)=[N+]=[N-].Br[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH:60]1[O:64][CH2:63][CH2:62][O:61]1.ClCCCC1OCCO1>>[C:1]([O:5][C:6]([NH:8][CH:9]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[O:13][CH2:14][C:15]([O:17][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH:60]1[O:64][CH2:63][CH2:62][O:61]1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCCCC1OCCO1
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCC(=O)O)c1
Agent: ClCCCC1OCCO1
Agent: [N-]=[N+]=NC(c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1
Product: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCC(=O)OCCCCCC2OCCO2)c1

Procedure:
The title compound was prepared as described in Example 54 Step 1 with -(3-(((tert-Butoxycarbonyl)amino)(phenyl)methyl)phenoxy)acetic acid and 2-(5-bromopentyl)-1,3-dioxolane 4-((3-(azido(phenyl)methyl)phenoxy)methyl)benzoic acid and 2-(3-chloropropyl)-1,3-dioxolane respectively.
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:8][CH:9]=[O:10])C=CC=CC=1.ClC1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:34]([CH:40]=O)[NH:33][C:32]([CH3:42])=[C:31]1[C:43]([OH:45])=[O:44].[CH2:46]([Cl:48])Cl>>[Cl:48][C:46]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:34]([CH:40]=[CH:8][CH:9]=[O:10])[NH:33][C:32]([CH3:42])=[C:31]1[C:43]([OH:45])=[O:44]
Reactant: COC(=O)C1=C(C=O)NC(C)=C(C(=O)O)C1c1ccccc1Cl
Reactant: ClCCl
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)C1=C(C=CC=O)NC(C)=C(C(=O)O)C1c1ccccc1Cl
Reaction time: 0.83 h

Procedure:
To a solution of 2-triphenylphosphoranylideneacetaldehyde (1.9 g) in methylene chloride (15 ml) was added dropwise little by little a solution of isopropyl ester of 4-(2-chlorophenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid (2.14 g) in methylene chloride (25 ml) with stirring over a period of 50 minutes, and the stirring was continued at ambient temperature for an hour. After removal of the methylene chloride from the reaction mixture, the residue was dissolved in benzene (10 ml) and subjected to column chromatography over silica gel (120 g). Elution was carried out with a mixture of benzene and ethyl acetate (10:1 by volume), and fractions containing a desired compound were collected and evaporated to dryness under reduced pressure to give orange needles of isopropyl ester of 4-(2-chlorophenyl)-6-(2-formylvinyl)-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid (1.0 g), mp 179°-180.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].ClC([O:14][C:15](Cl)(Cl)Cl)=O.[CH2:19]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[CH2:19]([C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:15]([NH:4][C:3]2[C:2]([Cl:1])=[CH:8][C:7]([Cl:9])=[CH:6][C:5]=2[Cl:10])=[O:14])=[CH:32][CH:33]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Reactant: CCCCCCCCc1ccc(N)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCc1ccc(NC(=O)Nc2c(Cl)cc(Cl)cc2Cl)cc1
Reaction time: 2 h
Yield: 44.7 %

Procedure:
A 10 ml methylene chloride solution of 1.0 g (5.09 mmol) of 2,4,6-trichloroaniline was added dropwise over 2 minutes to a 10 ml methylene chloride solution of 0.6 ml (4.97 mmol) of trichloromethyl chloroformate cooled to 5°-6° C. After stirring at 5°-6° C. for 2 hours, the mixture was added with 1.04 g (5.06 mmol) of 4-octylaniline and then stirred at room temperature for 16 hours. The reaction mixture was extracted with chloroform, and washed with an aqueous saturated solution of sodium hydrogen carbonate and an aqueous saturated solution of sodium chloride, successively. The organic layer was dried over anhydrous magnesium sulfate. After the removal of the solvent under reduced pressure, the residue was recrystallized from a mixed solvent of n-heptane and chloroform to give 0.95 g (43% yield) of 1-(4-octylphenyl)-3-(2,4,6-trichlorophenyl)urea, the physical properties of which being shown in the following Table 3. The compounds No. 4 and No. 11 listed in Table 3 were similarly prepared as above.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Br:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:8][CH2:7][C:6]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:26].N1C=CC=CC=1>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Br:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:8][CH2:7][C:6]1=[S:26]
Reactant: COC(=O)CN1C(=O)CN=C(c2ccccn2)c2cc(Br)ccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CN1C(=S)CN=C(c2ccccn2)c2cc(Br)ccc21

Procedure:
A mixture of 0.01 mole of 7-bromo-2,3-dihydro-5-(2-pyridyl)-2-oxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester, 0.0105 mole of phosphorus pentasulfide and 100 ml. of pyridine is heated under reflux for about 24 hours. The mixture is evaporated and the residue thus obtained is dissolved in methylene chloride-water. The organic layer is separated, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The residue thus obtained is chromatographed on silica gel and eluted to give 7-bromo-2,3-dihydro-5-(2-pyridyl)-2-thioxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester.
Reaction SMILES: Cl.[O:2]=[S:3]1(=[O:9])[CH2:7][CH2:6][C@@H:5]([NH2:8])[CH2:4]1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][C:28]([Cl:34])=[CH:27][C:26]=1[F:35])(=O)=O>C1COCC1.O>[Cl:34][C:28]1[CH:29]=[C:30]([N+:31]([O-:33])=[O:32])[C:25]([NH:8][C@@H:5]2[CH2:6][CH2:7][S:3](=[O:9])(=[O:2])[CH2:4]2)=[C:26]([F:35])[CH:27]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc(F)c1OS(=O)(=O)C(F)(F)F
Reactant: N[C@@H]1CCS(=O)(=O)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(Cl)cc(F)c1N[C@@H]1CCS(=O)(=O)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 5.6 %

Procedure:
To a solution of (R)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-ylamine hydrochloride (9.0 g, 52.43 mmol) in 400 mL of THF was added DIPEA (27.0 g, 210 mmol), followed by addition of a solution of 4-chloro-2-fluoro-6-nitrophenyl trifluoromethanesulfonate (20.36 g, 62.92 mmol). After being stirred at RT for 48 hours, the resulting mixture was diluted with water, and then extracted with EtOAc. The organic layer was washed by brine, and then dried over anhydrous Na2SO4, then filtered and concentrated. The residue was purified by flash chromatography to give 0.9 g of (4-chloro-2-fluoro-6-nitrophenyl)-((R)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-amine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:14]([N:21]1[CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:17]([O:16][C:14]([N:21]1[CH2:26][CH2:25][CH:24]([O:1][C:2]2[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:23][CH2:22]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)c1ccc(SC)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(SC)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
The methyl 2-hydroxy-4-(methylthio)benzoate (4.00 g, 20.2 mmol) was dissolved in THF (300 mL). The solution was cooled to 0° C. and the N-Boc-4-hydroxypiperidine (4.07 g, 20.2 mmol) and triphenylphosphine (6.35 g, 24.2 mmol) were added, followed by diethyl azodicarboxylate (4.0 mL, 25.4 mmol). After 5 minutes, the reaction was allowed to warm to room temperature and left overnight. The reaction was concentrated in vacuo and the crude material was purified by flash column chromatography (about 500 g silica, 15% EtOAc/hexanes tthrough 20% EtOAc/hexanes) to give the desired product (7.185 g, 18.83 mmol, 93%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[NH:19][N:18]=[C:17]([CH3:20])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.Cl.[CH3:35][O:36][C:37]1[CH:45]=[N:44][C:43]([N:46]2[CH:50]=[C:49]([CH3:51])[N:48]=[N:47]2)=[C:42]2[C:38]=1[C:39]([C:52](=[O:56])C(O)=O)=[CH:40][NH:41]2.C(N(CC)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[C:21]1([C:14](=[C:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:52]([C:39]3[C:38]4[C:42](=[C:43]([N:46]5[CH:50]=[C:49]([CH3:51])[N:48]=[N:47]5)[N:44]=[CH:45][C:37]=4[O:36][CH3:35])[NH:41][CH:40]=3)=[O:56])[CH2:9][CH2:10]2)[C:15]2[NH:19][N:18]=[C:17]([CH3:20])[CH:16]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cnc(-n2cc(C)nn2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: Cc1cc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2)[nH]n1
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc(-n2cc(C)nn2)c2[nH]cc(C(=O)C(=O)N3CCC(=C(c4ccccc4)c4cc(C)n[nH]4)CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
To a solution of 4-[1-phenyl-1-(3-methylpyrazol-5-yl)methylene]piperidine-1-carboxylic acid tert-butyl ester(0.0190 g, 0.0538 mmol) in CH2Cl2 (1 mL) was added TFA (0.4 mL) and the mixture was stirred at rt for 30 min. The solvent was then removed in vacuo and the material was dissolved in CHCl3 (2 mL). To this solution was added 4-methoxy-7-(4-methyl-1,2,3-triazol-1-yl)-6-azaindol-3-yl-oxoacetic acid hydrochloride salt (0.0187 g, 0.0621 mmol) and iPrNEt2 (0.050 mL, 0.287 mmol), followed by BOP—Cl (0.0221 g, 0.868 mmol). The mixture was allowed to stir at rt for 2 h and then the solvent was removed in vacuo. The resulting residue was diluted with H2O and extracted with EtOAc (×3). The combined organic layers were washed (H2O , brine), dried (Na2SO4) and concentrated, and the residue was purified by preparative HPLC (NH4OAc) to give the title compound (0.0128 g, 44%) as a colorless solid:
Reaction SMILES: O[C:2]1[C:11]2[C:6](=CC(S(O)(=O)=O)=CC=2O)[CH:5]=[C:4](S(O)(=O)=O)[CH:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[C:30]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:29][CH:28]=[CH:27]2>>[NH:21]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[C:30]([S:32]([OH:35])(=[O:33])=[O:34])=[CH:29][CH:28]=[CH:27]2)[C:2]1[CH:11]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)c1cc(O)c2c(O)cc(S(=O)(=O)O)cc2c1
Reactant: Nc1cccc2cccc(S(=O)(=O)O)c12
Product: O=S(=O)(O)c1cccc2cccc(Nc3ccccc3)c12

Procedure:
4,5-dihydroxynaphthalene-2,7-disulfonic acid; 8-amino-1-naphthol-3,6-disulfonic acid; and 8-amino-1-naphthalene sulfonic acid.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8](CC#N)[CH:9]=2)[CH2:4]1)[CH3:2].[OH-:15].[K+].[CH2:17]([OH:19])[CH3:18]>O>[CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:17]([OH:15])=[O:19])[CH:9]=2)[CH2:4]1)[CH3:2]
Reactant: [OH-]
Reactant: CCO
Reactant: CCC1Cc2ccc(CC#N)cc2C1
Agent: [K+]
Solvent: O
Product: CCC1Cc2ccc(CC(=O)O)cc2C1

Procedure:
12.8 g of 2-ethyl-5-indan-acetonitrile are dissolved in 350 cc of ethanol, a solution of 26.7 g of potassium hydroxide in 45 cc of water is added, and the mixture is boiled at reflux for 20 hours. The solution is concentrated to 50 cc, diluted with water and extracted with ether, and the ether phase is discarded. The aqueous phase is then acidified with 2 N hydrochloric acid and extracted with ether. The crude 2-ethyl-5-indanacetic acid, obtained after concentrating the ether extract, is purified by chromatography on a 50-fold quantity of silica gel using chloroform containing 1.5% of methanol as eluant. After recrystallization from hexane the title compound has a M.P. of 44°-46°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])[C:13]=1[OH:28])([O-])=O.C1(C)C=CC=CC=1.[OH-].[Na+].[H][H]>[Ni].O.C(O)(C)C>[OH:28][C:13]1[C:14]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])=[CH:15][C:16]([C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Reactant: [H][H]
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)CC)c1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
38.39 g (0.1 mol) of 2-nitro-2'-hydroxy-3',5'-di-t-amylazobenzene, 5 g of Raney nickel, 100 ml of toluene, 100 ml of isopropyl alcohol (referred to as "IPA" hereinafter) 100 ml of water and 8 g (0.2 mol) of caustic soda were charged into a 500-ml stainless autoclave with an agitator. After the air in the flask had been replaced by hydrogen, the pressure of hydrogen was set to 10 kg/cm2. The temperature was increased at a rate of 20° to 40° C./hour and then 40° to 50° C./hour while the resultant mixture being agitated. Reaction was then effected at 50° to 90° C. for 2 hours and then 90° C. for 7 hours and was stopped when no more hydrogen was absorbed by the reaction solution. The autoclave was cooled, and the catalyst was filtered off. After the filtrate had been allowed to stand, the toluene layer was separated, and most part of the toluene was distilled off. The residual solid obtained was crystallized by IPA and the dried to obtain 28.8 g of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole (yield, 82%; melting point, 79° to 80° C.).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].[NH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([OH:38])=[O:37])[CH2:31]1.C1CCN2C(=NCCC2)CC1>CS(C)=O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([OH:38])=[O:37])[CH2:31]1
Reactant: O=C(O)C1CCCNC1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCCC(C(=O)O)C4)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C

Procedure:
To a mixture of 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) and piperidine-3-carboxylic acid (25.6 mg, 0.198 mmol) in DMSO (2 mL) was added DBU (0.030 mL, 0.198 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 18 mg 1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (2H, dd, J=8.35, 1.98 Hz), 7.83 (2H, dd, J=7.91, 1.54 Hz), 7.56-7.75 (5H, m), 5.13-5.39 (1H, m), 4.11-4.31 (2H, m), 3.21-3.41 (3H, m), 2.96-3.05 (2H, m), 2.70-2.85 (1H, m), 1.75-2.14 (4H, m), 1.62-1.77 (2H, m), 1.36-1.56 (1H, m), 0.98 (3H, t, J=7.36 Hz). MS (m+1)=503. HPLC Peak RT=3.35 minutes (Analytical Method A). Purity=90%.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[CH3:21][C:22]1[C:31]2[C:26](=[C:27]([OH:32])[CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>O1CCCC1>[CH2:21]([C:22]1[C:31]2[C:26](=[C:27]([OH:32])[CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCBr
Reactant: Cc1ccnc2c(O)cccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCCCc1ccnc2c(O)cccc12
Temperature: 0 °C
Reaction time: 5 h
Yield: 98.8 %

Procedure:
To a solution of 1.10 ml (7.88 mmol) of diisopropylamine in 20 ml of tetrahydrofuran at 0° C. under argon was added 4.1 ml (6.23 mmol) of 1.52M n-butyl lithium in hexanes dropwise. To the lithium diisopropylamide solution was added 502.0 mg (3.15 mmol) of 4-methyl-8-quinolinol (see example 1A) in 10 ml of tetrahydrofuran over 15 minutes at 0° C. The dark solution, which contained some insoluble material, was allowed to stir for five hours at 0° C., cooled to -78° C. and 0.46 ml (3.31 mmol) of 1-bromohexane was added. After 30 minutes at -78° C., the reaction was allowed to warm gradually from -30° C. to room temperature over 1.5 hours. The solution was allowed to stir for 45 minutes at room temperature, quenched with pH 6.5 phosphate buffer and extracted with ether. The ether extract was washed with water and brine, dried (magnesium sulfate) and evaporated to afford 757 mg of a yellow-brown solid. This material was dissolved in hot hexane, filtered to remove an insoluble residue and the filtrate was evaporated. Recrystallization from heptane provided 511.7 mg of the title compound as yellow plates: melting point 92°-93.5° C.
Reaction SMILES: [Na].CS([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)=O.[CH2:17](O)[CH2:18][OH:19]>COCCOC.O>[O:10]([CH2:9][CH2:8][CH2:7][O:6][CH2:17][CH2:18][OH:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OCCCOc1ccccc1
Reactant: OCCO
Agent: [Na]
Solvent: COCCOC
Solvent: O
Product: OCCOCCCOc1ccccc1
Reaction time: 2 h
Yield: 98.7 %

Procedure:
Sodium (2.80 g) was dissolved in 1,2-ethanediol (22.00 g) at ca 100° under nitrogen and 3-phenoxy-1-propanol methanesulphonate (25.5 g) in 1,2-dimethoxyethane (50 ml) was added dropwise at 100° under nitrogen. The mixture was stirred at 150° for 2 h and then carefully diluted with water (150 ml) and extracted with diethyl ether (2×150 ml). The combined organic extracts were washed with water (2×150 ml), dried and evaporated in vacuo to give the title compound (21.45 g) as an oil. T.l.c. System B (1:1) Rf 0.13.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.O=S(Cl)Cl.[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22].C(Cl)(Cl)Cl>C1C=CC=CC=1>[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:12]([C:3]1[C:2]([NH2:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=[O:14]
Reactant: Nc1cc2ccccc2cc1C(=O)O
Reactant: Nc1ccccc1Cl
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Nc1cc2ccccc2cc1C(=O)Nc1ccccc1Cl
Yield: 53.9 %

Procedure:
Prepared according to Procedure A using 3-amino-2-napthoic acid (2.0 g, 10.7 mmol) and SOCl2 (1.9 mL, 26.7 mmol) in benzene (50 mL), followed by 2-chloroaniline (2.3 mL, 21.4 mmol) and CHCl3 (50 mL). The product was recrystallized from MeOH to provide 1.71 g of a brown solid (54%). 1H NMR (CDCl3) δ: 10.88 (br s, 1H); 9.21 (s, 1H); 8.91 (s, 1H); 8.70 (dd, J=1.0, 8.3 Hz, 1H); 7.95-8.01 (m, 1H); 7.87-7.94 (m, 1H); 7.60-7.68 (m, 2H); 7.41 (dd, J=1.3, 8.0 Hz, 1H); 7.34 (dt, J=1.2, 7.8 Hz, 1H); 7.07 (dt, J=1.4, 7.7 Hz, 1H). MS (ES): m/z 297.1 (M+).
Reaction SMILES: O1CCC1.[CH:5]1([C:11]2([CH2:15][OH:16])[CH2:14][O:13][CH2:12]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.Br[CH:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)[CH2:19]Br>>[CH:5]1([C:11]23[CH2:12][O:13][C:25]([C:24]4[CH:28]=[CH:29][C:21]([C:18]#[CH:19])=[CH:22][CH:23]=4)([O:16][CH2:15]2)[O:26][CH2:14]3)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)c1ccc(C(Br)CBr)cc1
Reactant: OCC1(C2CCCCC2)COC1
Agent: C1COC1
Product: C#Cc1ccc(C23OCC(C4CCCCC4)(CO2)CO3)cc1

Procedure:
Utilizing Procedure 2, 4-cyclohexyl-1-(4-ethynylphenyl)-2,6,7-trioxabicyclo[2.2.2]octane was prepared from its respective oxetane. The 3-cyclohexyl-3-hydroxymethyloxetane was reacted with 4-(1,2-dibromoethyl)benzoyl chloride by the method of Procedure 2. The resulting product was characterized by NMR (300 MHz, CDCl3): δ 1.0-1.4 and 1.6-2.0 (11H, m, cyclohexyl CH2), 3.9-4.1 (2H, m, CH2Br), 4.4 (2H, s, CH2O), 4.55 (4H, d of d, CH2OCH2), 5.1 (1H, d of d, ArCHBr), 7.45 (2H, d, aromatic), 8.1 (2H, d, aromatic).