Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23]C)[C:10]([C:25]#[C:26][Si](C)(C)C)=[CH:9][C:8]=1[O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41]C)(C)C.[OH-].[Na+].O>C1COCC1.CO>[C:25]([C:10]1[CH:9]=[C:8]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41])[C:7]([C:6]#[CH:5])=[CH:12][C:11]=1[O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])#[CH:26]
Reactant: CCOCCOCCOCCOc1cc(C#C[Si](C)(C)C)c(OCCOCCOCCOCC)cc1C#C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1cc(OCCOCCOCCOC)c(C#C)cc1OCCOCCOCCOC

Procedure:
1,4-bis[(trimethylsilyl)ethynyl]-2,5-bis[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]benzene (0.595 g, 1 mmol) was dissolved in 20 mL of THF and 10 mL of methanol. To the solution, 8 mL of 1M NaOH(aq) was added and refluxed for 2 hours. Water was added to the mixture and extracted with ether. The organic layer was washed with water several times, and then dried with Na2SO4. Solvent was removed by rotary evaporation to give 1,4-diethynyl-2,5-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]benzene (3), shown in FIG. 2, as a reddish solid. 1H NMR (300 MHz, CDCl3): d 3.32 (s, 2H), 3.36 (s, 6H), 3.53 (m, 4H), 3.65 (m, 8H), 3.75 (m, 4H), 3.85 (m, 4H), 4.13 (m, 4H), 6.98 (s, 2H). 13C NMR (75 MHz, CDCl3): d 59.46, 69.96, 70.03, 71.00, 71.15, 71.50, 72.39, 80.00, 83.22, 114.02, 118.75, 154.49.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].Cl.[C:21]1([C:27]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:27]([CH:29]1[CH2:34][CH2:33][N:32]([S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:31][CH2:30]1)(=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: O=C(c1ccccc1)C1CCNCC1
Agent: Cl
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCC(C(=O)c4ccccc4)CC3)s2)c(C)[nH]c1=O
Yield: 85 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with phenyl-piperidin-4-yl-methanone hydrochloride as described in Step 5, Example 24 to give the title compound as a yellow solid (85% yield). LC/MS: RT 3.27 min, m/e 471 (M+H); 1H NMR (CDCl3, δ, ppm): 11.95 (1H, s), 7.89 (2H, dd), 7.55-7.60 (1H, m), 7.44-7.52 (3H, m), 7.33 (1H, s), 7.01 (1H, d), 3.79-3.84 (2H, m), 3.27-3.36 (1H, m), 2.73-2.82 (2H, m), 2.60 (2H, q), 2.48 (3H, s), 1.89-2.05 (4H, m), 1.24 (3H, t).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]([C:12]1([O:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]2[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]2)[CH2:13]1)#[CH:11].O>CN(C)C=O.C(N(CC)CC)C.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.[Cu]I>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:11]#[C:10][C:12]1([O:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[CH:17]2[CH2:16][CH2:15][N:14]([CH2:19][CH2:18]2)[CH2:13]1)=[O:5]
Reactant: C#CC1(O[Si](C)(C)C)CN2CCC1CC2
Reactant: O=Cc1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)OC1(C#Cc2ccccc2C=O)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 21 h
Yield: 64.2 %

Procedure:
Bis(triphenylphosphine)-palladium(II) chloride (175 mg) and copper(I) iodide (85 mg) were added to a solution of 2-bromobenzaldehyde (2.03 g) and 3-ethynyl-3-trimethylsilyloxyquinuclidine (2.23 g) in dimethyl formamide (25 ml) and triethylamine (5 ml) at ambient temperature under an atmosphere of argon. The reaction mixture was stirred at ambient temperature for 21 hours. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate (2×100 ml). The ethyl acetate extracts were combined, filtered, washed with water (2×100 ml), brine (100 ml), dried (MgSO4) and evaporated. The residue was purified by column chromatography on alumina (Alumina N 32-63) using a 40:60 (v/v) mixture of ethyl acetate and isohexane as eluent to give 3-[2-{2-formylphenyl}ethynyl]-3-trimethylsilyloxyquinuclidine as an oil (2.1 g), NMR: 0.00 (9H, s), 1.1-1.3 (1H, m), 1.35-1.54 (1H, m), 1.82-1.90 (1H, m), 2.5 (4H, t), 2.73 (1H, d), 3.07 (1H,d), 7.38-7.48 (2H, m), 7.5-7.6 (1H, m), 7.68-7.75 (1H, m), 10.2 (1H, s), m/z 328 (M+H).
Reaction SMILES: CO[CH:3](OC)[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[CH3:12]>ClC1C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[C:7]3[CH:3]=[CH:4][O:5][C:6]=3[C:11]([CH3:12])=[CH:10][CH:9]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2ccc(C)c(OCC(OC)OC)c2)cc1
Solvent: Clc1ccccc1
Product: COc1ccc(-c2ccc(C)c3occc23)cc1

Procedure:
A mixture of polyphosphoric acid (approx. 0.5 g) and chlorobenzene was brought to reflux and 3-(2,2-dimethoxy-ethoxy)-4′-methoxy-4-methyl-biphenyl (1.61 g, 5.33 mmol) in chlorobenzene (12 ml) was added dropwise. After 4 h the reaction was cooled, passed through a silica plug (the plug was washed with ether), and concentrated to 1.26 g (100%) of product as a light tan solid: mp 40–41° C.; 1H NMR (300 MHz, DMSO-d6): δ 2.50 (3H, s), 3.82 (3H, s), 7.03 (1H, d, J=2.2 Hz), 7.07 (2H, d, J=9.5 Hz), 7.19 (1H, d, J=8.1 Hz), 7.23 (1H, d, J=8.1 Hz), 7.56 (2H, d, J=9.5 Hz), 8.06 (1H, d, J=2.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27]C)=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:15]=[C:16]([CH2:17][OH:18])[C:9]=23)[CH:7]=1.C([S-])C.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN1CCCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:27])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:15]=[C:16]([CH2:17][OH:18])[C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2c1c(CO)cn2COCC[Si](C)(C)C
Agent: CC[S-]
Agent: CN1CCCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(CO)c2c(-c3cc(F)ccc3O)ccnc21

Procedure:
A mixture of Example 14E (920.0 mg, 2.286 mmol) and sodium ethanethiolate (641 mg, 6.86 mmol) in N-methylpyrrolidine (40 mL) was stirred at 120° C. for 3 hours. The mixture was treated with brine, acidified to pH 4-5 with 5% citric acid, and extracted with ethyl acetate (twice). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, concentrated, and purified on silica using the ISCO Companion flash system eluting with heptanes/ethyl acetate (5:5 to 4:6) to provide the title compound. MS (ESI+) m/z 389.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:27])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]3[N:14]=2)[CH:7]=1.Br[CH2:29][CH2:30][CH2:31][N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:42].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:42]=[C:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40](=[O:41])[N:32]1[CH2:31][CH2:30][CH2:29][O:27][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]1[CH:18]=[CH:17][N:16]2[N:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]2[N:14]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3O)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OCCCN3C(=O)c4ccccc4C3=O)nc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 47.9 %

Procedure:
A suspension of (R)-ethyl 5-(2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (280 mg, 0.756 mmol), 2-(3-bromopropyl)isoindoline-1,3-dione (263 mg, 0.983 mmol) and K2CO3 (104 mg, 0.756 mmol) in DMF (0.4 mL) was stirred at ambient temperature for 15 hours. The reaction was directly purified by reverse-phase column chromatography (5-80% acetonitrile/H2O) to afford (R)-ethyl 5-(2-(2-(3-(1,3-dioxoisoindolin-2-yl)propoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (202 mg, 48% yield) as clear oil. MS (apci) m/z=558.0 (M+H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[S:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[S:34][N:33]=[CH:32][N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ncns2)cc1F
Yield: 83.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (340 mg, 0.574 mmol) prepared in Example 8b, triethylsilane (0.4 mL), trifluoroacetic acid (4.0 mL) and dichloromethane (4.0 mL), to yield the title compound (211 mg, 83%) as a colorless solid.
Reaction SMILES: O1CCOCC1.[F:7][C:8]([F:57])([F:56])[C:9]1[CH:10]=[C:11]([CH:49]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:51]=1)[CH2:12][N:13]1[C@H:17]([CH3:18])[C@@H:16]([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[C:29]2[CH:30]=[C:31]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([O:45]C)=[O:44])=[CH:39][C:38]=3[Cl:47])[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[O:15][C:14]1=[O:48].O.[OH-].[Li+].Cl>O.ClCCl>[F:57][C:8]([F:7])([F:56])[C:9]1[CH:10]=[C:11]([CH:49]=[C:50]([C:52]([F:54])([F:55])[F:53])[CH:51]=1)[CH2:12][N:13]1[C@H:17]([CH3:18])[C@@H:16]([C:19]2[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:22]=[CH:21][C:20]=2[C:29]2[CH:30]=[C:31]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([OH:45])=[O:44])=[CH:39][C:38]=3[Cl:47])[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[O:15][C:14]1=[O:48]
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3[C@H]3OC(=O)N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C(=O)O)cc2Cl)cc1-c1ccc(C(F)(F)F)cc1[C@H]1OC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
To a 1,4-dioxane solution (2 mL) of starting methyl 2″-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-2-chloro-4′-methoxy-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (65 mg, 0.087 mmol) was added a solution of lithium hydroxide monohydrate (36.5 mg, 0.87 mmol) in water (1 mL). The resulting mixture turned to a cloudy, slightly purple mixture (from a light yellow solution). Aliquot at reaction time=22 min indicated completion of reaction. Reaction crude was acidified (1N HCl, aq.). Volatiles were removed from the crude mixture. The resulting mixture was purified by a preparative reverse phase HIPLC (Kromasil 100-5C18, 100×21.1 mm) eluting w/a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture. Related fractions were pooled & evaporated in vacuo to afford a colorless glass. The glass was dissolved in dichloromethane and washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to afford 2″-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-2-chloro-4′-methoxy-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS calc.=731.11; found=732.08 (M+1)+. 1H NMR signals are doubled because of atropoisomerism. 1H NMR (CDCl3, 500 MHz) 8.22, 8.13 (d, J=1.5 Hz, 1H), 8.05-7.99 (m, 1H), 7.79 (s, 1H), 7.74 (s, 1H), 7.70-7.64 (m, 1H), 7.60 (s, 0.6H), 7.54-7.51 (m, 1.8H), 7.50-7.44 (m, 1H), 7.42-7.30 (m, 2H), 7.13 (d, J=2.5 Hz, 0.6H), 7.10 (d, J=9.0 Hz, 0.6H), 7.17 (d, J=8.5 Hz, 0.4H), 5.22 (d, J=4.5 Hz, 1H), 4.82, 4.77 (d, J=16 Hz, 1H), 4.27, 4.22 (d, J=16 Hz, 1H), 3.87 (s, 1.8H), 3.59 (s, 1.2H), 3.49-3.43 (m, 0.4H), 3.32-3.25 (m, 0.6H), 0.86 (d, J=6.0 Hz, 1.2H), 0.73 (d, J=6.5 Hz, 1.8H).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=[C:20]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:7]=1.[OH-].[Na+]>C1COCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[C:14]3[C:13]([NH:12][C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=4)[O:5][CH2:4][C:3]([OH:36])=[O:2])=[N:18][CH:17]=[N:16][C:15]=3[O:19][C:20]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(OCC(=O)O)c4)c23)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Dissolve 1000 mg (2.08 mmol) of 3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenoxyacetic acid methyl ester in 10 ml of THF, add 4.2 ml of 1N sodium hydroxide solution at RT and stir at 50° C. for 1 h. Cool to RT and remove the THF under reduced pressure. Add water to the residue and then, with ice cooling, 1N hydrochloric acid. Filter off the precipitated solid, wash repeatedly with water and dry at 40° C. under reduced pressure. 913.7 mg (92.5% of theory) of the target compound are obtained as a white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)=[O:9])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(Sc3ccc(F)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccc(F)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is dropped to a solution of 4.07 g of 4,5-bis(4-methoxyphenyl)-2-(4-fluorophenylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus obtaining 3.86 g of 4,5-bis(4-methoxyphenyl)-2-(4-fluorophenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH:22]2[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23]2)[C:14](=[O:21])[C:15]([CH3:20])([CH3:19])[C:16](=[O:18])[CH3:17])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:30][Mg]Br.Cl>C1COCC1>[C:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH:22]2[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23]2)[C:14](=[O:21])[C:15]([CH3:19])([CH3:20])[C:16]([OH:18])([CH3:30])[CH3:17])[CH2:9]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(=O)C(C)(C)C(=O)N(C1CCC(C)(C)CC1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)CCC(N(C(=O)C(C)(C)C(C)(C)O)C2CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(2,2-dimethyl-3-oxobutanoyl)amino]pyrrolidine (100 mg, 0.25 mmol) prepared in Step A of Example C5 in THF was slowly added dropwise methylmagnesium bromide (in diethylether, 3.0M, 0.1 ml, 0.3 mmol) at 0° C., and the solution was stirred at rt for 2 h. After the reaction finished, to the solution was added 1N-HCl at 0° C., and extracted with EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/Hex=1/3) to give the title compound (97 mg, 92%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:23])[CH:19]=[C:20]([CH3:22])[CH3:21])[CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:11]1[CH:12]=[C:13]2[C:14]([C:20]([CH3:22])([CH3:21])[CH2:19][C:18](=[O:23])[NH:17]2)=[CH:15][CH:16]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2]
Reactant: CCCCCC(C(=O)OCC)c1cccc(NC(=O)C=C(C)C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCC(C(=O)OCC)c1ccc2c(c1)NC(=O)CC2(C)C
Temperature: 0 °C
Yield: 95.9 %

Procedure:
A solution of 2-[3-(3-methyl-but-2-enoylamino)-phenyl]-heptanoic acid ethyl ester (3.822 g, 11.5 mmole) in 60 mL of dichloromethane was treated with 4.613 g of aluminum chloride and heated at reflux for four hours. The reaction mixture was poured onto 200 mL of ice-water and extracted with two 100 mL portions of dichloromethane. The combined organic extracts were washed with 200 mL of saturated aqueous sodium bicarbonate solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 25% ethyl acetate in hexanes) to yield 3.657 g of 2-(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-heptanoic acid ethyl ester as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]#[C:10][CH3:11])=[CH:4][CH:3]=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])/[CH:9]=[CH:10]\[CH3:11])=[CH:6][CH:7]=1
Reactant: CC#CC(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Product: C/C=C\C(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Under nitrogen, hydrogenate a mixture of 10 g (0.055 mole) of 1-(4-chlorophenyl)-2-butyn-1-ol and 0.6 g Lindlar catalyst. Following the reaction vic NMR the reaction is complete in about two days. The hydrogenation is stopped and the reaction stirred under N2 at room temperature overnight. Filter off the catalysts, wash with methylene chloride combine the filtrate and evaporate to yield the title compound.
Reaction SMILES: C(OC([N:11]([C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=1)[CH2:12][C:13]([NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[O:14])=O)C1C=CC=CC=1>CO.[Pd]>[CH3:26][C:24]1[CH:23]=[C:22]([CH3:27])[N:21]=[C:20]([NH:11][CH2:12][C:13]([NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[O:14])[CH:25]=1
Reactant: Cc1cc(C)nc(N(CC(=O)NCC(N)=O)C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)nc(NCC(=O)NCC(N)=O)c1

Procedure:
1 g (2.6 mmol) of the product of Example 24 is dissolved in 60 ml of methanol. Palladium-on-carbon is added and the whole is stirred under a hydrogen atmosphere. Filtration is then carried out, the methanol is evaporated and the title product is recovered.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1.C([Li])CCC.[CH2:13]([N:20]1[CH2:24][C@H:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:22][C@H:21]1[CH:33]=[O:34])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C.CCCCCC>[CH2:13]([N:20]1[CH2:24][C@H:23]([O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27])[CH2:22][C@H:21]1[CH:33]([C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1)[OH:34])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C=O)N(Cc2ccccc2)C1
Reactant: Cn1cc(Br)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cn1cc(C(O)[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2Cc2ccccc2)cn1
Reaction time: 0.75 h
Yield: 64.6 %

Procedure:
To a solution of 4-bromo-1-methylpyrazole (170.7 g) in diethyl ether (2 l) was added dropwise n-butyllithium (1.6N) in hexane (713 ml) keeping the temperature below -60° C. After stirring for 45 minutes, a solution of (2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy)-2-formylpyrrolidine (260 g) in diethyl ether (200 ml) was added dropwise. After stirring for 30 minutes, the mixture was warmed to 0°~5° C. over 2.5 hours and stirred for 45 minutes. The reaction mixture was quenched with ice water (1 l) and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (×2), and the combined organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel (3.5 kg, eluting with n-hexane:AcOEt=3:2 to 1:1 to 0:1) to give (2S,4R)-1-{1-benzyl-4-(t-butyldimethyl-silyloxy) pyrrolidin-2-yl}-1-(1-methyl-4-pyrazolyl)methanol (211.2 g) as a 1:1 mixture of diastereomers.
Reaction SMILES: CO[C:3]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:9]([F:18])=[CH:8][C:4]=1[C:5]([O-:7])=[O:6].[OH-].[Na+].Cl>C1COCC1.O>[F:17][C:14]([F:15])([F:16])[CH2:13][O:12][C:10]1[C:9]([F:18])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][CH:11]=1
Reactant: COc1cc(OCC(F)(F)F)c(F)cc1C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OCC(F)(F)F)c(F)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
The above methoxy-4-trifluoroethoxy-5-fluorobenzoate (420 mg, 1.7 mmol) was dissolved in freshly distilled THF (50 mL) and water was added (20 mL) and 2N NaOH (2 mL) was dropped into the rapidly stirring solution at room temperature. The solution was warmed to 50° C. and stirred rapidly for 18 hours. The biphasic result was reduced to a smaller volume under reduced pressure and water was added to the aqueous residue to a volume of 50 mL and was then acidified with 4 N HCl to a pH of 1-2. The product was extracted with methylene chloride (3×50 mL). The combined organics were extracted with brine (50 mL) and the organic solvent was dried over MgSO4 and filtered and the solvent was removed under reduced pressure to give the desired 4-trifluoroethoxy-5-fluorobenzoic acid.
Reaction SMILES: O.O.[Na+:3].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([O-:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>[OH-].[Na+].C(O)C>[Na+:3].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:4][C:5]2[CH:10]=[CH:9][C:8]([S:11]([O-:14])(=[O:12])=[O:13])=[CH:7][CH:6]=2)=[CH:18][CH:17]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])c1ccc(OCc2ccc(F)cc2)cc1
Temperature: 22 °C
Yield: 73.6 %

Procedure:
To a stirred solution of 4-hydroxybenzenesulfonic acid sodium salt dihydrate (5.13 g, 22.1 mmol) in 23 mL of 1 N sodium hydroxide was added a solution of 4-fluorobenzyl bromide (3.3 mL, 26.5 mmol) in 20 mL of ethanol. The mixture was heated at reflux for two days, then cooled to ambient temperature (22° C.), whereupon a white precipitate formed. The flaky white solids were collected by filtration, rinsed with ethyl acetate and diethyl ether, and dried to give 4.95 g of 4-(4-fluoro-benzyloxy)-benzenesulfonic acid sodium salt. A stirred solution of 4-(4-fluoro-benzyloxy)-benzenesulfonic acid sodium salt (13.0 g, 42.7 mmol) in 50 mL of thionyl chloride and two drops of dimethylformamide was heated at a gentle reflux for 8 hours. The mixture was concentrated to a yellow solid which was suspended in ethyl acetate and filtered. The filtrate was concentrated to 11.2 g of 4-(4-fluorobenzyloxy)benzenesulfonyl chloride as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.95-7.98 (m, 2 H), 7.38-7.41 (m, 2 H), 7.06-7.12 (m, 4 H), 5.12 (s, 2 H).