Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:46]=[CH:45][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[S:39][C:38]([C:40]([O:42]CC)=[O:41])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:47][CH3:48])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:46]=[CH:45][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[S:39][C:38]([C:40]([OH:42])=[O:41])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:47][CH3:48])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(CC)n4)cc3OC)c(C)o2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccc(C(=O)O)s4)oc3C)c(OC)c2)cs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a mixture of ethyl 5-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]thiophene-2-carboxylate (0.63 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (5 mL) and water, and the precipitated crystals were collected by filtration to give 5-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]thiophene-2-carboxylic acid as colorless crystals (0.51 g, yield 85%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 150-151° C.
Reaction SMILES: [C:1]([NH:6][CH:7]([CH3:11])[C:8]([OH:10])=O)(=[O:5])[CH2:2][CH2:3][CH3:4].[O:12]1[CH2:16][CH2:15]C[CH2:13]1.N1C=CC=CC=1.C([O-])(O)=[O:24].[Na+]>CN(C1C=CN=CC=1)C.CO>[C:1]([NH:6][CH:7]([CH3:11])[C:8](=[O:10])[C:13]([O:12][CH2:16][CH3:15])=[O:24])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])O
Reactant: CCCC(=O)NC(C)C(=O)O
Reactant: C1CCOC1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CCCC(=O)NC(C)C(=O)C(=O)OCC
Temperature: 50 °C

Procedure:
The compound of formula VI (9.54 g, 0.06 mol) was dissolved into dried tetrahydrofuran (60 mL), and DMAP (0.24 g, 2.0 mmol) and pyridine (15 mL) were added therein. The mixture was heated for 30 minutes at 50° C., cooled, and slowly dropped with ethyl oxalyl monochloride (16.4 g, 0.12 mol) under an ice bath. After the dropping, the mixture was heated for 4 hours at 70° C., filtered to remove the solid, and evaporated to remove the solvent under reduced pressure. Water (100 mL) was added therein, and the product was extracted with ethyl acetate (120 mL×3). The liquid was separated, and the combined organic phase was washed by water (90 mL) and saturated saline (50 mL×2) respectively, dried over anhydrous sodium sulfate, and rotarily evaporated to remove the solvent. NaHCO3 (3.8 g, 0.045 mol) and methanol (50 mL) were added therein, and the reaction mixture was refluxed for 2 hours, filtered, and evaporated off the solvent under reduced pressure to obtain a yellow oil, i.e., ethyl 3-butyramido-2-oxo-butyrate, which was directly used in the next step without separation.
Reaction SMILES: [F-].[K+].[CH3:3][O:4][CH:5]([O:12][CH3:13])/[CH:6]=[CH:7]\[C:8]([O:10][CH3:11])=[O:9].[C:14]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=[O:17]>C(O)(C)(C)C>[C:21]([O:20][C:14]([CH:15]([C:16](=[O:17])[CH3:18])[CH:6]([CH:5]([O:12][CH3:13])[O:4][CH3:3])[CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: COC(=O)/C=C\C(OC)OC
Agent: [F-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)CC(C(OC)OC)C(C(C)=O)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 48 h

Procedure:
Into a 500-ml reactor are placed 40 g of potassium fluoride, 40 ml of dry tert-butanol, 123 g of methyl cis-4,4-dimethoxy-2-butenate and 36 g of tert-butyl acetoacetate. The mixture is heated at 100° C. with stirring on an oil bath for two days. On completion of the reaction, the tert-butanol is distilled off from the mixture. The residue is dissolved in ethyl acetate, and the solution washed with an aqueous solution of common salt and then dried. The solvent is removed from the product. The resulting residue is purified by a silica gel column and distilled at reduced pressure, giving methyl 4-tert-butoxycarbonyl-3-dimethoxymethyl-5-oxohexanoate (compound (5), R1 =t-Bu, R2 =R3 =CH3) in a yield of 95.4%, b.p. 72°-76° C./0.014 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:9]1[C:10]([CH:12]([CH3:14])[CH3:13])=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1cc(C(C)C)ccc1C(=O)O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1cc(C(C)C)c(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methoxy-4-iso-propyl benzoic acid (7.0 g. 36.0 mmol) in chloroform (100 ml) was added bromine (1.86 ml) in chloroform (20 ml) dropwise. The reaction was stirred at room temperature overnight. Evaporation in vacuo afforded an oil (9.27 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C@@H:15]([NH2:24])[C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:8]=1[F:14].[C:25]([O:29][C:30]([NH:32][C@H:33]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:39][CH:38]=1)[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[C:25]([O:29][C:30](=[O:31])[NH:32][C@H:33]([C:37]1[CH:38]=[CH:39][C:40]([O:43][CH2:44][CH2:45][O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:41][CH:42]=1)[C:34](=[O:35])[NH:24][C@H:15]([C:4]1[NH:5][C:6]([C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:8]=2[F:14])=[C:2]([Cl:1])[N:3]=1)[C@H:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:17])([CH3:27])([CH3:28])[CH3:26]
Reactant: C[C@@H](c1ccccc1)[C@H](N)c1nc(Cl)c(-c2ccc(I)cc2F)[nH]1
Reactant: CC(C)(C)OCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(OCCOC(C)(C)C)cc1)c1nc(Cl)c(-c2ccc(I)cc2F)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
To a solution of (1S,2S)-1-[4-chloro-5-(2-fluoro-4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propylamine (550 mg, 1.21 mmol) in N,N-dimethylformamide (12 mL) was added (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid (532 mg, 1.45 mmol) (prepared as described below), N,N-diisopropylethylamine (841 μL, 4.83 mmol), N-hydroxybenzotriazole (212 mg, 1.57 mmol) and O-benzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophosphate (595 mg, 1.57 mmol). The mixture was stirred under an atmosphere of nitrogen at room temperature for 3 hours. The reaction was poured into water (20 mL) and extracted with ethyl acetate (2×25 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted with 20 to 50% v/v ethyl acetate/hexanes to give ((R)-[4-(2-tert-butoxy-ethoxy)-phenyl]-{(1S,2S)-1-[4-chloro-5-(2-fluoro-4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propylcarbamoyl}-methyl)-carbamic acid tert-butyl ester (440 mg, 45%).
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[N:9]=[C:8]([C:10]([NH:13]C(=O)[O-])([CH3:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1.CO.O>C(#N)C>[F:17][CH:2]([F:1])[O:3][C:4]1[N:9]=[C:8]([C:10]([NH2:13])([CH3:11])[CH3:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(NC(=O)[O-])c1cccc(OC(F)F)n1
Solvent: CC#N
Solvent: O
Solvent: CO
Product: CC(C)(N)c1cccc(OC(F)F)n1
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of 2-(6-(difluoromethoxy)pyridin-2-yl)propan-2-ylcarbamate (12.4 g, 48 mmol) in acetonitrile (50 mL) was added TMST (10 mL). The reaction was stirred 30 min and then poured into methanol (100 mL) and water (5 mL). The mixture was concentrated, dissolved in ethyl acetate (200 mL), and then washed with 1N NaOH (2×30 mL). The organic layer was separated, dried over Na2SO4, concentrated, and chromatographed with silica gel (50% EtOAc/hex, then 5-20% MeOH/CH2Cl2) to afford 2-(6-(difluoromethoxy)pyridin-2-yl)propan-2-amine (8.8 g, 92%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH3:14])[S:11][C:10]=2[C:15](OC)=[O:16])=[CH:5][CH:4]=1)[CH3:2].CCOCC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:13]=[C:12]([CH3:14])[S:11][C:10]=2[CH2:15][OH:16])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2cc(C)sc2C(=O)OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1ccc(-c2cc(C)sc2CO)cc1
Temperature: 0 °C

Procedure:
Into a 100-mL 3-necked round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed methyl 3-(4-ethylphenyl)-5-methylthiophene-2-carboxylate (1.5 g, 5.76 mmol), anhydrous ether (50 mL). This was followed by the addition of a solution of LiAlH4 (1 M in THF, 7.9 mL, 7.86 mmol) in tetrahydrofuran dropwise with stirring at 0° C. The resulting solution was stirred for 2.0 h at 25° C. The reaction progress was monitored by LCMS/TLC (ethyl acetate/petroleum ether=1:6). The reaction was then quenched by the addition of 10 mL of water and 5 mL of 2N HCl. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 1.26 g (94%) of (3-(4-ethylphenyl)-5-methylthiophen-2-yl)methanol as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:21]([O:22][CH3:23])=[CH:20][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[CH:6]=1)[NH:14][CH:13]=[C:12]([C:17]#[N:18])[C:11]3=O.N1C2C(=CC=CC=2)C=C(C#N)C=1.P(Cl)(Cl)([Cl:38])=O>CN(C)C=O>[Cl:38][C:11]1[C:10]2[C:15](=[CH:16][C:7]3[CH:6]=[C:5]([O:4][CH2:3][CH2:2][Cl:1])[C:21]([O:22][CH3:23])=[CH:20][C:8]=3[CH:9]=2)[N:14]=[CH:13][C:12]=1[C:17]#[N:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1OCCCl
Agent: N#Cc1cnc2ccccc2c1
Solvent: CN(C)C=O
Product: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1OCCCl
Yield: 87 %

Procedure:
To a slurry of 1.11 g of 8-(2-chloroethoxy)-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile and 7-(2-chloroethoxy)-8-methoxy-4-oxo-1,4-dihydrobenzo]quinoline-3-carbonitrile (1:1 mixture) and 5 mL of phosphorus oxychloride is added 0.15 mL of anhydrous dimethylformamide. This is stirred and heated to reflux for 20 minutes using an oil bath, followed concentration in vacuo. The dark residue is quenched with 30 mL of cold water. The solid formed is collected, washed with water and dried to give 1.02 g (87%) of 4-chloro-7-methoxy-8(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile and 4-chloro-8-methoxy-7(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile (1:1 mixture) as a greenish yellow solid, m.p. 195–209° C. dec.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:30][CH2:31][C@H:32]2[CH2:36][CH2:35][CH2:34][N:33]2C(OC(C)(C)C)=O)=[CH:5][C:6]2[NH:12][C:11]3[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH3:27])[CH:18]=4)[CH:15]=[CH:16][C:10]=3[C:9](=[O:28])[NH:8][C:7]=2[CH:29]=1.Cl.O1CCOCC1>CO>[CH3:1][O:2][C:3]1[C:4]([O:30][CH2:31][C@H:32]2[CH2:36][CH2:35][CH2:34][NH:33]2)=[CH:5][C:6]2[NH:12][C:11]3[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH3:27])[CH:18]=4)[CH:15]=[CH:16][C:10]=3[C:9](=[O:28])[NH:8][C:7]=2[CH:29]=1
Reactant: COc1cc2c(cc1OC[C@H]1CCCN1C(=O)OC(C)(C)C)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc2c(cc1OC[C@H]1CCCN1)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
A mixture of Example 489B in methanol (2 mL) was treated with 4.0N HCl/dioxane (0.15 mL, 0.6 mmol), stirred overnight at room temperature, concentrated under vacuum, and purified by preparative HPLC to give 3.9 mg (9%) of the desired product as the TFA salt. MS (ESI) m/e 491 (M+H)+; 1H NMR (300 MHz, DMSO-d6) □ 9.72 (s, 1H), 8.70 (s, 1H), 8.02 (d, J=8.1 Hz, 1H), 7.77-7.80 (m, 2H), 7.53 (d, J=1.4 Hz, 1H), 7.29-7.36 (m, 3H), 6.75 (s, 1H), 6.71 (s, 1H), 4.15 (m, 1H), 4.03 (s, 3H), 3.83-3.96 (m, 1H), 3.71 (s, 3H), 3.17-3.27 (m, 3H), 2.13 (m, 1H), 1.84-2.01 (m, 2H), 1.72 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[S:43]1[CH:47]=[CH:46][N:45]=[C:44]1[CH:48]([NH2:50])[CH3:49]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:50][CH:48]([C:44]2[S:43][CH:47]=[CH:46][N:45]=2)[CH3:49])=[O:41])=[C:18]([F:23])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: CC(N)c1nccs1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4nccs4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (35 mg, yield 79%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([NH:13][C:14](=[O:35])[CH:15]([CH2:19][C:20]([N:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:17][CH3:18])[CH:9]([OH:12])[CH2:10][F:11])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([NH:13][C:14](=[O:35])[CH:15]([CH2:19][C:20]([N:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:17][CH3:18])[C:9](=[O:12])[CH2:10][F:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Reaction time: 3 h

Procedure:
A stirred solution of [3S/R, 4S/R, (2R)]-3-[2-(2-carbazol-9-yl-2-oxo-ethyl)-pentanoylamino]-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester (2.51 g, 5.03 mmol) in anhydrous DCM (60 ml) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (2.35 g, 5.53 mmol) at 0° C. The resulting mixture was kept at 0° C. for 3 h, diluted with DCM, and then washed sequentially with saturated aqueous sodium thiosulphate, NaHCO3 solution and brine. The organics were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (25% ethyl acetate in 40/60 hexanes) to afford the sub-title compound as an off white solid (1.437 g, 57%): IR (solid) 1722, 1689, 1636, 1531, 1441, 1365, 1279, 1155 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.85-1.50 (3H, m), 1.35-1.54 (11H, m), 1.55-1.69 (1H, m), 1.78-1.95 (1H, m), 2.67-3.28 (4H, m), 3.60-3.79 (1H, m), 4.80-5.59 (3H, m), 6.89-7.04 (1H, m), 7.33-7.54 (4H, m), 7.98-8.04 (2H, m), 8.15-8.28 (2H, m); 13C (100 MHz, CDCl3) δ 14.12, 14.40, 14.47, 14.60, 20.78, 20.84, 21.47, 28.32, 28.42, 28.48, 29.77, 33.63, 34.58, 34.91, 40.05, 43.05, 43.26, 43.29, 52.60, 53.00, 53.64, 66.90, 66.99, 82.62, 82.69, 85.53, 116.88, 116.94, 120.28, 120.31, 124.27, 127.76, 127.86, 128.69, 128.77, 128.99, 138.80, 171.21, 171.29, 172.21, 172.25, 175.53, 176.03, 203.04, 203.20, 203.30, 203.46; 19F (376 MHz, CDCl3) δ −232.12 , −233.24.
Reaction SMILES: C[O-].[Na+].CO.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[NH:14][S:15]([C:18]1[N:29]=[C:21]2[CH:22]=[C:23](Cl)[CH:24]=[C:25]([O:26][CH3:27])[N:20]2[N:19]=1)(=[O:17])=[O:16].[C:30](O)(=[O:32])C>CS(C)=O.ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[NH:14][S:15]([C:18]1[N:29]=[C:21]2[CH:22]=[C:23]([O:32][CH3:30])[CH:24]=[C:25]([O:26][CH3:27])[N:20]2[N:19]=1)(=[O:17])=[O:16]
Reactant: CC(=O)O
Reactant: COc1cc(Cl)cc2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nn12
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2c1

Procedure:
Sodium methoxide in methanol (3.0 mL of 25 percent solution, 0.71 g, 0.013 mol) was added to a solution of N-(2,6-dichlorophenyl)-5-methoxy-7-chloro[1,2,4]triazolo[1,5-a]pyridine-2-sulfonamide (0.66 g, 0.0016 mol) in dimethyl sulfoxide (30 mL) with stirring over several hours. The mixture was allowed to react and was then acidified with acetic acid and diluted with dichloromethane. The resulting organic phase was recovered and washed with water and the volatiles were removed by evaporation under reduced pressure. The residue obtained was chromatographed on silica gel starting with 0.5 percent acetic acid in dichloromethane and gradually increasing the strength to 0.5 percent acetic acid plus 1.0 percent ethanol in dichloromethane. The product fractions were concentrated by evaporation under reduced pressure to obtain 118 mg (13 percent of theory) of the title compound as a pale yellow powder melting at 252°-253° C.(d).
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:43])[C@H:8]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:35])[NH:26][O:27]C(OCC(C)C)C)=[CH:13][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[CH:1]1([O:6][C:7](=[O:43])[C@H:8]([CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:35])[NH:26][OH:27])=[CH:13][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)COC(C)ONC(=O)CCCCCCC(=O)Nc1ccc(CN[C@H](C(=O)OC2CCCC2)C2CCCCC2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCCCCC(=O)Nc1ccc(CN[C@H](C(=O)OC2CCCC2)C2CCCCC2)cc1)NO

Procedure:
Material from step 6b (50 mg, 0.083 mmol, 1 eq) was dissolved in DCM/methanol (2 mL:2 mL) and stirred with TFA (1.0 mL) for 2 h. The resulting salt was concentrated, dissolved in methanol and purified by preparative HPLC to yield compound (86). LCMS purity 100%, m/z 502 [M++H]+, 1H NMR (300 MHz, MeOD), δ: 1.28-1.98 (26H, m, 13×CH2), 2.10-2.15 (2H, m, CH2), 2.40 (2H, t, J=7.8 Hz, CH2), 3.81 (1H, d, J=3.9 Hz, CH), 4.21 (2H, m, CH2), 5.01 (1H, s, CH), 5.23-5.25 (1H, m, CH), 7.43 (2H, d, J=8.4 Hz, Ar—H), 7.68 (2H, d, J=8.7 Hz, Ar—H)
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:23])([F:22])[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:9]>CCOC(C)=O>[F:23][C:7]([F:6])([F:22])[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: O=C(N1CCC(c2ccccc2)CC1)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: CCOC(C)=O
Product: O=C(N1CCC(c2ccc(S(=O)(=O)Cl)cc2)CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
Chlorosulfonic acid (2 mL) was added to 2,2,2-trifluoro-1-(4-phenylpiperidin-1-yl)ethanone (1.0 g, 3.9 mmol) in a single portion, and the reaction was stirred for 20 minutes until gas evolution ceased (exothermic reaction). The solution was poured into a mixture of ice water (200 mL) and EtOAc (20 mL). The organic layer was concentrated and purified via silica gel chromatography using 8/2 hexanes/EtOAc to obtain 4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzene-1-sulfonyl chloride as a clear oil (1.3 g, 94%).
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[C:3](/[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])\[CH3:9])\[CH3:4].[O:17]1C[CH2:20][CH2:19][CH2:18]1>CN(C)P(N(C)C)(N(C)C)=O.C(OCC)C>[CH3:4]/[C:3](/[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:9])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:2]\[CH2:1][CH2:20][CH2:19][CH2:18][OH:17]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCl
Reactant: C1CCOC1
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCCCO
Reaction time: 1 h

Procedure:
A solution of 37.5 mL (20.3 mmol, 5.1 eq.) of a 0.54M solution of Grignard reagent (Part B) in tetrahydrofuran and 9 mL of hexamethylphosphoramide at room temperature under argon was treated over 10 minutes with a solution of 955.5 mg (3.97 mmol) of (E,E)-farnesyl chloride (Part A) in 5 mL of tetrahydrofuran. After one hour, the reaction mixture was diluted with a mixture of 1:1 diethyl ether : hexane and quenched with 1M HCl. The organic phase was washed with three 25 mL portions of saturated NaHCO3, three 25 mL portions of H2O, and 25 mL of brine, dried over MgSO4 and evaporated to obtain 995.0 mg of crude product. Purification required two chromatographies. The first was run on 70 g of silica gel, eluting with 1:99 ethyl acetate:CH2Cl2 to provide 484.3 mg of impure material and 307.7 mg of pure title compound. The second chromatography, of the impure fractions, on 50 g of silica gel eluted with 0.75:99.25 ethyl acetate:CH2Cl2 gave 117.2 mg of slightly impure material and 302.8 mg of pure title compound. Combination of pure material from both columns gave a yield a yield of 610.5 mg (58%) of pure desired title isomer.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[O:1]=[CH:2][C@H:3]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](C=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl [(1R)-2-hydroxy-1-phenylethyl]carbamate (200 mg, 0.844 mmol) in CH2Cl2 (20 mL) at 0° C. was added Dess-Martin periodinane (447 mg, 1.05 mmol). The reaction was stirred at 0° C. for 15 minutes and then at room temperature for 30 minutes. The reaction was then diluted with EtOAc (75 mL) and washed rapidly with 10% K2CO3 (2×30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue on a short column of silica gel with 50% EtOAc/hexanes gave tert-butyl [(1R)-2-oxo-1-phenylethyl]carbamate. 1H NMR (CDCl3, 600 MHz) (a major and a minor conformer observed). Data for major conformer given) δ 9.53 (s, 1H), 7.29-7.40 (m, 5H), 5.80 (bs, 1H), 5.31 (m, 1H), 1.42 (s, 9H). This material was used immediately in the following reaction.