Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][O:26][CH3:27].[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][O:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:35]([NH:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:36])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNC(=O)Nc1ccccc1
Temperature: 0 °C

Procedure:
Under a nitrogen atmosphere a mixture of 1-(8-aminooctyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 4.06 mmol) and dichloromethane (50 mL) was cooled to 0° C. Phenyl isocyanate was added dropwise. The reaction mixture was allowed to slowly warm to ambient temperature overnight. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (110 g silica gel eluting with 9:1 dichloromethane:methanol). The resulting orange solid was triturated with hexanes, isolated by filtration and then dried. This material was recrystallized from propyl acetate with a small amount of methanol, isolated by filtration, washed with hexanes, and then dried in a vacuum oven at 60° C. for 2 days to provide 0.6 g of N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}-N′-phenylurea as an off white powder, m.p. 136–142° C. Analysis: Calculated for C28H36N6O2: % C, 68.83; % H, 7.43; % N, 17.20; Found: % C, 68.27; % H, 7.44; % N, 16.85. 1H NMR (300 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.61 (dd, J=8.3. 1.0 Hz, 1H), 7.44–7.35 (m, 3H), 7.29–7.17 (m, 3H), 6.87 (t, J=7.3 Hz, 1H), 6.52 (s, 2H), 6.08 (m, 1H), 4.51 (t, J=7.8 Hz, 2H), 3.82 (m, 2H), 3.29 (s, 3H), 3.18 (t, J=6.8 Hz, 2H), 3.05 (m, 2H), 1.81 (m, 2H), 1.42–1.29 (m, 10H);
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:14])[F:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1([CH3:27])[CH2:26][O:25][CH2:24]1>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH2:22][C:23]2([CH3:27])[CH2:26][O:25][CH2:24]2)=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:13])[F:14])=[CH:4][CH:3]=1
Reactant: CC1(CBr)COC1
Reactant: COc1c(OC(F)F)ccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(Br)c1OCC1(C)COC1
Temperature: 80 °C
Yield: 76.2 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (200 mg, 0.743 mmol) in acetonitrile (10 mL) was added potassium carbonate (307 mg, 2.229 mmol) and followed by 3-(bromomethyl)-3-methyloxetane (244 mg, 1.48 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 200 mg 3-((6-Bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)-3-methyloxetane (Int14-F6) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13](Cl)=[O:14].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[C:23]1([NH:22][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:10]([S:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH:11]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A solution of 3-(2,4-difluorophenylthio)-4-nitrobenzoyl chloride (1 g) in tetrahydrofuran (3 ml) was added to a stirred mixture of aniline (0.306 g) and sodium bicarbonate (0.51 g) in tetrahydrofuran (2 ml) and water (5 ml) at 5° C. The mixture was stirred at 5° C. for 1 hour and at room temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with water, dried and evaporated. The residue was washed with ethanol to give yellow crystals of N-phenyl3-(2,4-difluorophenylthio)-4-nitrobenzamide (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:12]1[O:29][C@H:28]([CH2:30][O:31]C(=O)C)[C@@H:23]([O:24]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@H:13]1[O:14]C(=O)C.[O:35]1[CH:39]=[CH:38][C:37]2[CH:40]=[C:41]([C:44](Cl)=O)[CH:42]=[CH:43][C:36]1=2>>[O:35]1[CH:39]=[CH:38][C:37]2[CH:40]=[C:41]([CH2:44][C:4]3[C:8]4[C:7](=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=4[Cl:11])[N:6]([C@@H:12]4[O:29][C@H:28]([CH2:30][OH:31])[C@@H:23]([OH:24])[C@H:18]([OH:19])[C@H:13]4[OH:14])[CH:5]=3)[CH:42]=[CH:43][C:36]1=2
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cc(Cl)cc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc2occc2c1
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc4occc4c3)c3c(Cl)cc(Cl)cc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
4,6-Dichloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 28-(3) and benzo[b]furan-5-carbonyl chloride were treated in a manner similar to Example 3 to give the titled compound as a colorless powder. APCI-Mass m/Z 478/480 (M+H). 1H-NMR (DMSO-d6) δ 3.20-3.50 (m, 4H), 3.59 (m, 1H), 3.67 (m, 1H), 4.34 (s, 2H), 4.55 (t, J=5.7 Hz, 1H), 5.11 (d, J=5.1 Hz, 1H), 5.16 (d, J=5.1 Hz, 1H), 5.24 (d, J=5.8 Hz, 1H), 5.46 (d, J=9.0 Hz, 1H), 6.87 (d, J=1.4 Hz, 1H), 7.11 (d, J=1.6 Hz, 1H), 7.19 (dd, J=8.5, 1.4 Hz, 1H), 7.33 (s, 1H), 7.42 (s, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.93 (d, J=2.1H, z, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1.[O:16]=[S:17]1(=[O:40])[CH2:22][CH2:21][CH:20]([O:23][C:24]2[CH:29]=[C:28]([CH3:30])[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37]O)[CH:32]=3)=[C:26]([CH3:39])[CH:25]=2)[CH2:19][CH2:18]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:37][C:33]3[CH:32]=[C:31]([C:27]4[C:26]([CH3:39])=[CH:25][C:24]([O:23][CH:20]5[CH2:19][CH2:18][S:17](=[O:40])(=[O:16])[CH2:22][CH2:21]5)=[CH:29][C:28]=4[CH3:30])[CH:36]=[CH:35][CH:34]=3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: Cc1cc(OC2CCS(=O)(=O)CC2)cc(C)c1-c1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCS(=O)(=O)CC5)cc4C)c3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
A solution of methyl[(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.208 g, 1.00 mmol), {4′-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-2′,6′-dimethylbiphenyl-3-yl}methanol (0.360 g, 1.00 mmol) and tributylphosphine (0.324 g, 1.60 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.404 g, 1.60 mmol) was added, and the mixture was stirred at room temperature for 3 hr under nitrogen atmosphere. Hexane (8 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (0.432 g, yield 79%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[S:4][C:5]([N:8]=[C:9]=[O:10])=[N:6][N:7]=1.[CH3:13][NH:14][CH2:15][CH2:16][OH:17]>C1C=CC=CC=1>[OH:17][CH2:16][CH2:15][N:14]([CH3:13])[C:9]([NH:8][C:5]1[S:4][C:3]([C:2]([F:11])([F:1])[F:12])=[N:7][N:6]=1)=[O:10]
Reactant: O=C=Nc1nnc(C(F)(F)F)s1
Reactant: CNCCO
Solvent: c1ccccc1
Product: CN(CCO)C(=O)Nc1nnc(C(F)(F)F)s1
Reaction time: 0.17 h

Procedure:
2-Trifluoromethyl-1,3,4-thiadiazol-5-yl isocyanate dimer (8 grams), N-methyl-N-β-hydroxyethylamine (3.1 grams) and benzene (40 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, reflux condenser and thermometer. The reaction mixture was heated at reflux, with stirring for a period of about 10 minutes. After this time the reaction mixture was stripped of solvent under reduced pressure to yield the desired product N-(β-hydroxyethyl)-N-methyl-N'-(2-trifluoromethyl-1,3,4-thiadiazol-5-yl)urea as an oily residue.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][CH2:15][C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:41][N:42]([C@@H:59]([C:67](=[O:70])[NH:68][CH3:69])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:43](=[O:58])[C@H:44]([NH:56][CH3:57])[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][CH2:15][C:16](=[O:18])[N:56]([CH3:57])[C@@H:44]([C:43](=[O:58])[N:42]([CH3:41])[C@@H:59]([C:67](=[O:70])[NH:68][CH3:69])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)COC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
To a solution of (2S)-2-(((carboxy)methoxy)methyl)-pyrrolidin-1-carboxylic acid tert-butylester (1.2 g, 4.5 mmol) in dichloromethane (20 ml) were added 1-hydroxy-7-azabenzotriazole (612 mg, 4.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (950 mg, 4.95 mmol) and the mixture was stirred for 30 min. (2R)-N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (605 mg, 1.5 mmol) in dichloromethane (10 mL) was added followed by diisopropylethylamine (0.33 ml, 2.0 mmol) and the mixture was stirred for 2 hours at room temperature. The mixture was washed with water (10 ml), aqueous sodium bicarbonate (10 ml), water (2×10 ml), brine (10 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (40 g) with ethyl acetate/heptane 4:1 to give 760 mg of (2S)-2-([N-methyl-N-{(1R)-1-(N-methyl-N-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl}carbamoyl]methoxymethyl)pyrrolidine-1-carboxylic acid tert-butylester. The obtained product was taken up in 50% trifluoroacetic acid in methylene chloride (5 ml) and stirred for 10 min. Then saturated sodium bicarbonate was added until pH 8 and the phases were separated. The aqueous phase was extracted with dichloromethane (2×10 ml) and the combined organic phases were washed with brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The product was redissolved in water (30 ml) and acetic acid (2 ml) was added and the mixture was liophilized to give 720 mg of the acetate salt of the title compound as an amorphous powder.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.Cl[Si:16]([CH3:19])([CH3:18])[CH3:17]>C(OCC)C>[CH3:17][Si:16]([CH3:19])([CH3:18])[N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: C[Si](C)(C)Cl
Reactant: CNCc1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN(Cc1ccccc1)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
Step 1—To a stirring solution of N-methylbenzylamine (100 ml, 93.9 g, 0.77 mol) in diethyl ether (500 ml) cooled at −78° C. was added n-butyl lithium (2.4 M in hexanes, 355 ml, 0.85 mol) keeping the temperature below −60° C. The resulting slurry was stirred for 1 hour then chlorotrimethylsilane (118 ml, 0.93 mol) was added while keeping the temperature below −70° C. The reaction was allowed to warm to room temperature overnight then filtered to remove the precipitated white solid. The filtrates were concentrated in vacuo then distilled under high-vacuum to yield the N-trimethylsilyl-N-methylbenzylamine (102 g, 94%) as a colorless liquid: b.p. 54° C./0.5 mmHg; 1H NMR (CDCl3) 0.19 (s, 9H), 2.37 (s, 3H), 3.90 (2, 2H) 7.22-7.39 (m, 5H)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14]C)=O)=[CH:6][C:5]=1[F:18])(=[O:3])[NH2:2].[F:19][C:20]([F:33])([F:32])[C:21]1[CH:28]=[C:27]([N:29]=[C:30]=[S:31])[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>CS(C)=O.O>[C:23]([C:22]1[CH:25]=[CH:26][C:27]([N:29]2[C:12](=[O:14])[C:11]([CH3:17])([CH3:16])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([F:18])[CH:6]=3)[C:30]2=[S:31])=[CH:28][C:21]=1[C:20]([F:19])([F:32])[F:33])#[N:24]
Reactant: COC(=O)C(C)(C)Nc1ccc(C(N)=O)c(F)c1
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(C(N)=O)c(F)c1
Reaction time: 0.03 h

Procedure:
A solution of methyl 2-(4-carbamoyl-3-fluorophenylamino)-2-methylpropanoate and 2-(trifluoromethyl)-4-isothiocyanatobenzonitrile (1.5 equivalents) in dry DMSO (5 mL per mmol) was heated to 80-82° C. for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 40% Acetone-Hexanes. MS (m/z): 451 (M+1). HPLC: Column, YMC ODS A, 4.6×150 mm, 5 μm, Mobile Phase A: 10 mM Ammonium acetate, Mobile Phase B: Acetonitrile, Gradient, 10% B up to 2 min, 10% to 90% B in 3 min, hold for 3 min, 90% to 10% B in 5 min, Retention time, 2.782 min, HPLC Purity, 99.4%, Flow Rate, 1 mL/min. 1H NMR (CDCl3, Freebase): δ (ppm) 8.3 (t, 1H), 8.0 (d, 1H) 7.98 (s, 1H), 7.8 (d, 1H), 7.27 (d, 1H), 7.2 (d, 1H), 6.65 (d, 1H), 6.0 (s, 1H), 1.62 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][CH2:18][NH:19][C:20]2[CH:25]=[C:24]([O:26]C)[CH:23]=[CH:22][C:21]=2[CH:28]2[CH2:37][CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:38]C)[CH:34]=3)[CH2:29]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.F[C:41]1C=C(CCNCC2C=C(OC)C=CC=2C2CCC3C(=CC=C(OC)C=3)C2)C=CC=1OCCN1CCCCC1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:17][CH2:18][N:19]([CH3:41])[C:20]2[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=2[CH:28]2[CH2:37][CH2:36][C:35]3[CH:34]=[C:33]([OH:38])[CH:32]=[CH:31][C:30]=3[CH2:29]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CNCCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Product: CN(CCc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(O)ccc1C1CCc2cc(O)ccc2C1

Procedure:
Synthesized from {2-[3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl]ethyl}[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine according to an analogous synthetic method to Preparation Example 18, {2-[3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl]ethyl}[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]methylamine (180 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (110 mg).
Reaction SMILES: CC(C)([O-])C.[CH:6]1([C@H:9]([OH:31])[C:10]([N:12]2[CH2:16][C:15]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])=[CH:14][C@H:13]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:11])[CH2:8][CH2:7]1.C(N(CC)CC)C.[P:39](Cl)([O:43]C)([O:41]C)=[O:40]>ClCCl>[P:39]([OH:43])([OH:41])([O:31][C@@H:9]([CH:6]1[CH2:8][CH2:7]1)[C:10]([N:12]1[CH2:16][C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:14][C@H:13]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:11])=[O:40]
Reactant: COP(=O)(Cl)OC
Reactant: O=C([C@@H](O)C1CC1)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C([C@@H](OP(=O)(O)O)C1CC1)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Reaction time: 2 h

Procedure:
Titianium(IV) tert-butoxide (0.022 mL, 0.065 mmol, 0.100 equiv) was added to a solution of (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethanol (6-2,230 mg, 0.647 mmol, 1 equiv) in dichloromethane (5 mL) at 23° C. followed by triethylamine (0.271 mL, 1.94 mmol, 3.00 equiv) and dimethyl chlorophosphate (0.140 mL, 1.29 mmol, 2.00 equiv). The resulting mixture was stirred for 2 h, then partitioned between saturated sodium bicarbonate solution (50 mL) and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and were concentrated. The residue was dissolved in dimethyl sulfide (0.5 mL) and to the resulting solution was added methanesulfonic acid (1 mL). The resulting mixture was stirred for 10 min, then diluted with acetonitrile (3 mL). Purification by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) provided (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl dihydrogen phosphate (10-1) as a white solid. 1H NMR (500 MHz, CDCl3) major rotamer: δ 7.42-7.04 (m, 8H), 6.46 (s, 1H), 5.95 (m, 1H), 5.14 (br d, 1H, J=14 Hz), 5.04 (br d, 1H, J=14 Hz), 4.46 (t, 1H, J=8.2 Hz), 1.32 (m, 1H), 0.62 (m, 4H). LRMS m/z (M+H) 436.4 found, 436.1 required.
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.[OH-].[Na+]>O1CCCC1.O>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([OH:26])(=[O:8])=[O:25])=[CH:20][CH:19]=1.[C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C(c1ccccc1)C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(O)c1ccc(Br)cc1

Procedure:
The analogous reaction of 0.1 mole of benzoin with 0.105 mole of p-bromobenzenesulfonyl chloride in 30 ml of tetrahydrofuran and 5 ml of water with the addition of 0.11 mole of 30% NaOH yields the same compound.
Reaction SMILES: [F:1][C:2]([F:22])([C:18]([F:21])([F:20])[F:19])[CH2:3][CH2:4][CH2:5]OC1C=CC=C(C)C=1S([O-])(=O)=O.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:1][C:2]([F:22])([C:18]([F:21])([F:20])[F:19])[CH2:3][CH2:4][CH2:5][NH:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: Cc1cccc(OCCCC(F)(F)C(F)(F)F)c1S(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: FC(F)(F)C(F)(F)CCCNCc1ccccc1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
4,4,5,5,5-Pentafluoropentyloxytoluenesulfonate (1 g, 3 mmol) was dissolved in acetonitrile (10 ml). Benzylamine (646 mg, 6 mmol) and potassium carbonate (829 mg, 6 mmol) were added. The mixture was refluxed for 10 h under nitrogen atmosphere. When the reaction was completed, the mixture was cooled to room temperature. Water was added to reaction solution which was then extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography (dichloromethane:ethyl acetate=19:1) to give 590 mg (yield: 74%) of the title compound as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([S:13](Cl)(=[O:15])=[O:14])[CH:8]=2)[N:3]=1.[F-:18].[K+]>C(Cl)Cl.[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([S:13]([F:18])(=[O:15])=[O:14])[CH:8]=2)[N:3]=1
Reactant: [F-]
Reactant: O=S(=O)(Cl)c1cc2nc(Cl)c(Cl)nc2cc1Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(F)c1cc2nc(Cl)c(Cl)nc2cc1Cl
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 80.1 %

Procedure:
To a solution of 46 g of 2,3,7-trichloro-6-quinoxalinesulfonyl chloride in 200 ml of methylene chloride were added 0.42 g of benzyltriethylammonium bromide and a solution of 20.2 g of potassium fluoride in 20.9 ml of water. The resulting mixture was stirred for 17.5 hours at ambient temperature, filtered, dried over magnesium sulfate, treated with activated carbon and filtered again. Solvent was removed under vacuum, leaving a yellowish solid which was recrystallized from hexane to provide 35 g of 2,3,7-trichloro-6-quinoxalinesulfonyl fluoride as a light-yellow solid, having a melting point of 111°-113°.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:13])[CH2:11][CH3:12])=[CH:5][CH:4]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CCC(=O)Cc1ccc(SC)cc1
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCC(=O)C(=Cc1ccccc1)c1ccc(SC)cc1
Yield: 61.2 %

Procedure:
A mixture of 1-(4-methylthiophenyl)-2-butanone from Step 2 (9.74 g, 50 mmol), benzaldehyde (5.85 g, 55 mmol) and piperidine (0.5 mL) in toluene (200 mL) was heated at reflux with a Dean-Stark trap for 16 hours. The mixture was cooled and solvent was removed in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was washed successively with saturated ammonium chloride solution, water and brine, dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The crude pentenone was recrystallized from ethyl acetate and hexane to give 8.64 g of 2-(4-methylthiophenyl)-1-phenyl-1-pentene-3-one (60%) as light yellow crystals: mp 98°-99° C. Anal. Calc'd. for C18H18OS: C, 76.56; H, 6.42; N, 11.35. Found: C, 76.58; H, 6.17; N, 11.35.
Reaction SMILES: C([O:8][CH:9]1[CH2:15][CH:14]2[N:16]([CH2:17][C@H:18]3[CH2:23][N:22]([S:24]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)(=[O:26])=[O:25])[CH2:21][CH2:20][N:19]3[C:32]3[CH:37]=[CH:36][C:35]([C:38]([OH:44])([CH3:43])[C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=3)[CH:10]1[CH2:11][O:12][CH2:13]2)C1C=CC=CC=1.C(Cl)Cl.B(Cl)(Cl)Cl>CO>[S:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[S:24]([N:22]1[CH2:21][CH2:20][N:19]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([OH:44])([CH3:43])[C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=2)[C@@H:18]([CH2:17][N:16]2[CH:10]3[CH:9]([OH:8])[CH2:15][CH:14]2[CH2:13][O:12][CH2:11]3)[CH2:23]1)(=[O:25])=[O:26]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3COCC2C(OCc2ccccc2)C3)cc1)C(F)(F)F
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3COCC2C(O)C3)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
A 100 mL round-bottomed flask was charged with 2-(4-((2S)-2-((6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.350 g, 0.537 mmol) and 5 mL of CH2Cl2. After cooling to 0° C., BCl3 (1M in CH2Cl2, 2.15 mL, 2.15 mmol, Sigma-Aldrich, St. Louis, Mo.) was added drop-wise. This mixture was allowed to warm to room temperature then stirred for an additional 15 min. 10 mL of MeOH was added and the mixture was concentrated onto silica gel and purified via column chromatography (0-7% MeOH in CH2Cl2) to give 8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (endo) (0.210 g) as a mixture of four isomers. 1H NMR (400 MHz, CD3OD) δ 7.92 (d, J=4.9 Hz, 1H), 7.67 (d, J=3.5 Hz, 1H), 7.54 (t, J=7.2 Hz, 2H), 7.28 (t, J=5.3 Hz, 1H), 7.06 (t, J=9.1 Hz, 2H), 4.43-4.62 (m, 2H), 3.39-4.24 (m, 13H), 2.66-2.98 (m, 2H), 2.55 (d, J=3.91 Hz, 1H), 1.69 (br. s., 3H). m/z (ESI, +ve ion) 562.1 (M+H)+. GK-GKRP IC50 (Binding)=0.028 μM; GK-GKRP EC50 (LC MS/MS-2)=0.031 μM.