Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[N:12]([CH3:32])[CH:13]=[C:14]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]([F:44])([F:43])C1C=CC=CC=1CN>>[CH3:32][N:12]1[CH:13]=[C:14]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)[CH:15]=[C:11]1[C:9]([NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:34]([F:44])([F:43])[F:33])=[O:10]
Reactant: NCc1ccccc1C(F)(F)F
Reactant: Cn1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1C(=O)NCc1ccccc1
Product: Cn1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1C(=O)NCc1ccccc1C(F)(F)F

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 300 using the carboxylic acid intermediate from example 310 and 2-trifluoromethyl-benzylamine to provide 311. LC-MS (M+H=492, obsd.=492).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.[CH3:39][S:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:45][C:44]1[CH:46]=[CH:47][C:41]([S:40][CH3:39])=[CH:42][CH:43]=1)=[N:6]2
Reactant: CSc1ccc(N)cc1
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Solvent: CCO
Product: CSc1ccc(Nc2ncc3c(C)nc(-c4ccccc4)n3n2)cc1
Yield: 50.8 %

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol), 4-(methylthio)aniline (0.022 mL, 0.17 mmol) and ethanol (2.5 mL) to afford 5-methyl-N-[4-(methylthio)phenyl]-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine (30 mg) as a yellow solid. MS m/z 348 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]2[N:27]([CH3:28])[N:26]=[C:25]([O:29][CH2:30][CH2:31][OH:32])[C:24]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:32][CH2:31][CH2:30][O:29][C:25]2[C:24]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[C:23]([NH:22][S:19]([C:16]3[CH:17]=[CH:18][C:13]([C:9]([CH3:11])([CH3:10])[CH3:12])=[CH:14][CH:15]=3)(=[O:20])=[O:21])[N:27]([CH3:28])[N:26]=2)=[N:6][CH:7]=1
Reactant: Cn1nc(OCCO)c(-c2ccccc2)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: Clc1ncc(Br)cn1
Product: Cn1nc(OCCOc2ncc(Br)cn2)c(-c2ccccc2)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was made according to the procedure used for Example 13 except that (63 mg) of 5-bromo-2-chloropyrimidine was used and that 4-(tert-butyl)-N-{3-(2-hydroxyethoxy)-1-methyl-4-phenyl-1H-pyrazol-5-yl}benzenesulfonamide (Example 15) (80 mg) was used in place of 4-(tert-butyl)-N-{3-(2-hydroxyethoxy)-1-methyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}benzenesulfonamide (Example 12). The crude material was purified by HPLC on a 5μ ODS Phenomenex Magellen™ column with a gradient elution of acetonitrile (5% to 95%) and 0.1M NH4OAc (95% to 5%) to yield the desired product as an off white solid (52 mg).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@@H:10]1[O:40][CH2:41][CH:42]([CH2:44][OH:45])[OH:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:66](Cl)(=[O:73])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>N1C=CC=CC=1.ClCCl>[C:66]([O:43][CH:42]([CH2:41][O:40][C@H:10]1[O:11][C@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:9]1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:44][OH:45])(=[O:73])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCC(O)CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OC(CO)CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
Glycerol 8 (900 mg, 1.47 mmol) and trityl chloride (490 mg, 1.76 mmol) were dissolved in dry pyridine (60 mL) and heated at 100° C. The disappearance of 8 was monitored by TLC and after 90 min the reaction was cooled to 0° C. and a solution of benzoyl chloride (1.0 g, 7.0 mmol) in dry dichloromethane (10 mL) was added. The reaction was warmed to room temperature and stirring was continued for 2 h. The solvent was removed and the residue was dissolved in chloroform (50 mL), washed with 2M HCl (2×20 mL), saturated sodium bicarbonate solution (2×20 mL), water (25 mL) and dried over magnesium sulfate. The solvent was removed, the residue was dissolved in mixture of dichloromethane and methanol (7:3, 50 mL) and p-TSA (75 mg) was added. The reaction was stirred at room temperature overnight and solvent was removed. The residue was purified over silica [hexane/ether, 8:2 to 7:3 as eluent] to afford the title compound 9 (816 mg, 77%) as a pale syrup; Rf 0.4 (ether/hexane, 2:1); 1H NMR (500 MHz, CDCl3) δ 8.05 br (d, 3H, J 7.5 Hz), 7.51 (t, 2H, J.5 Hz), 7.41-7.12 and 7.18-7.10 (m, 20 Hs, Ar—H), 5.30-5.20 (m, 1H, H-2′), 4.94 and 4.89 (2×d, each 1H, J 2 Hz, H-1), 4.85 and 4.83 (2×d, each 1H, J 10.5 Hz, PhCH2), 4.77-4.46 (m, 7H), 4.05-3.62 (m, 10H); 13C NMR (125 MHz, CDCl3) δ 166.1, 166.0 (CO), 138.3, 138.2, 138.1, 138.05 (ipso-C), 133.0, 132.96, 129.8, 129.7, 129.6, 129.5, 128.3, 128.2, 128.2, 128.13, 128.10, 128.07, 127.83, 127.80, 127.74, 127.65, 127.62, 127.59, 127.56, 127.41, 127.38, 127.36, 127.32 (CH—Ar), 98.0 and 97.5 (C-1), 79.7, 79.6, 74.8, 74.7, 74.6, 73.8, 73.4, 73.2, 73.1, 72.4, 72.0, 71.9, 69.0, 68.9, 65.6, 65.3, 65.25, 61.2, 57.9; νmax/cm−1 (CHCl3) 1716; LRMS-ESI (+ve) m/z 742 [MNa]+ (100); HRMS-ESI (+ve) (Found: m/z 719.3220 (MH+). C44H47O9 requires m/z 719.3220).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:28])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=O)[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:29])[C:5]([C:30]([OH:32])=[O:31])=[CH:4]1)[CH3:2].Cl.[NH2:34][OH:35].C(=O)(O)[O-].[Na+].C(Cl)Cl>CO.O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:28])=[C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][C:20](=[N:34][OH:35])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:18]3)[CH:11]=2)[C:6](=[O:29])[C:5]([C:30]([OH:32])=[O:31])=[CH:4]1)[CH3:2]
Reactant: NO
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccccc4)CC3)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=NO)c4ccccc4)CC3)cc21
Temperature: 25 °C
Yield: 68.5 %

Procedure:
To a solution of the 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-phenacyl-1-piperazinyl)-quinoline-3-carboxylic acid (0.44 g, 1 mmole) [H. Kondo et. al., J. Med. Chem., 29, 2020 (1986)] in absolute methanol (20 ml) was added a solution of hydroxylamine hydrochloride (0.14 g, 2 mmol) and sodium bicarbonate (0.17 g, 2 mmol) in water (2 ml). The mixture was heated at reflux for 36 hr and allowed to cool to room temperature. CH2Cl2 (50 ml) was added, and the layers were separated. The organic phase was washed successively with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give a solid which was purified by flash column chromatography (silica gel, with CH2Cl2/methanol (10:1) as the eluant) and crystillization from CH2Cl2/methanol (5:1) to give 1-ethyl-6-fluoro-4-oxo-7-[4-(2-hydroxyimino-2-phenylethyl)-1-piperazinyl]-1,4-dihydroquinoline-3-carboxylic acid as an off-white amorphous solid (0.31 g, 68%). Mp: 203° C. (dec). 1H NMR (DMSO-d6) δ 1.38 (t, 3H, J=7.2), 2.64 and 3.25 (two m, 8H), 3.43 and 3.73 (two s, 2 H), 4.56 (q, 2H, J=7.2), 7.15 (d, 1H, J=7.2), 7.36-7.79 (m, 5H), 7.88 (d, 1H, J=13.2), 8.92 (s, 1H), 10.99 and 11.48 (two s, 1H), 15.07 (br s, 1H). Anal. Calcd. for C24H25FN4O4•1.5 H2O: C, 60.10; H, 5.89; N, 11.68. Found: C, 60.19; H, 5.81; N, 11.64.
Reaction SMILES: [CH:1]1([C:6]2[C:10]3[N:11]=[C:12]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[NH:13][C:14](=[O:15])[C:9]=3[O:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:25]S(O)(=O)=O>>[Cl-:25].[CH:1]1([C:6]2[C:10]3[N:11]=[C:12]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[NH:13][C:14](=[O:15])[C:9]=3[O:8][N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(O)Cl
Agent: COc1ccc(Cc2nc3c(C4CCCC4)noc3c(=O)[nH]2)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.23 g (3.78 mmol) of 3-cyclopentyl-5-(4-methoxybenzyl)-isoxazolo[4,5-d]-pyrimidin-7(6H)-one (example XI) are introduced in portions into 2.51 ml of chlorosulfonic acid at 0° C. The reaction mixture is stirred at room temperature for 16 hours. It is poured onto ice water and the precipitate is filtered off with suction and dried in vacuo.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:10][CH2:11][CH3:12])[NH:6][C:7]=1[CH:8]=[O:9])[CH3:2].[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[C:30](=[O:38])[C:31](=[O:37])[C:32]=2[O:33][CH:34]([CH3:36])[CH3:35])=[CH:19][CH:18]=1.CC(O)C>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:10][CH2:11][CH3:12])[N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[C:30](=[O:38])[C:31](=[O:37])[C:32]=3[O:33][CH:34]([CH3:36])[CH3:35])=[CH:21][CH:22]=2)[C:7]=1[CH:8]=[O:9])[CH3:2]
Reactant: CC(C)Oc1c(-c2ccccc2-c2ccc(CBr)cc2)c(=O)c1=O
Reactant: CCCc1nc(CC)c(C=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CCCc1nc(CC)c(C=O)n1Cc1ccc(-c2ccccc2-c2c(OC(C)C)c(=O)c2=O)cc1
Reaction time: 0.75 h

Procedure:
To a stirred solution of 4-ethyl-2-propyl-1H-imidazole-5-carboxaldehyde (0.15 g; preparable as described in WO92/00977; Dupont) in dry dimethylformamide (3 ml) was added sodium hydride (60% dispersion in mineral oil; 36 mg) and stirring was continued for approximately 45 minutes. The resulting solution was then added via canula to a stirred solution of 3-(4'-bromomethylbiphenyl-2-yl)-4-isopropoxycyclobut-3-ene-1,2-dione (0.35 g; preparable as in Example 1(c)) in dry dimethylformamide (3 ml). After stirring for 1 hour, 2-propanol (0.1 ml) was added. The mixture obtained was poured into ethyl acetate (20 ml) then washed with water (15 ml). The aqueous washings were extracted with ethyl acetate (10 ml) and the combined organic phases were washed with water (5×15 ml) and dried over magnesium sulphate. The solvent was removed under reduced pressure and the residue obtained was purified by flash chromatography on silica gel (eluting with ethyl acetate/petroleum ether (b.p. 60°-80° C.) (75:25)) to give 4-ethyl-1-[2'-(3,4-dioxo-2-isopropoxycyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-2-propyl-1H-imidazole-5-carboxaldehyde, an active compound of the present invention, as a foam (0.194 g).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[NH:24][C:25]1[S:26][C:27]2[CH:33]=[C:32]([NH2:34])[CH:31]=[CH:30][C:28]=2[N:29]=1>O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[NH:24][C:25]1[S:26][C:27]2[CH:33]=[C:32]([NH:34][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[CH:31]=[CH:30][C:28]=2[N:29]=1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Reactant: O=C=Nc1ccccc1
Solvent: O
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)Nc5ccccc5)cc4s3)c2cc1OC

Procedure:
1-[2-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]-3-phenylurea was prepared from phenyl isocyanate (13 μL, 0.113 mmol) and N2-(6,7-di-methoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 3. The mixture was poured into water (20 mL) and the resulting precipitate was purified by preparative HPLC to obtain a yellow solid (10 mg, 21 μmol, 19%). LC/ESI-MS: m/z=473 [M+H]+; m/z=471 [M−H]−; Rt=3.10 min.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[NH2:14][CH2:15][C:16]([OH:18])=[O:17]>>[I:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:11]2=[O:13]
Reactant: O=C(O)c1ccc(I)cc1C(=O)O
Reactant: NCC(=O)O
Product: O=C(O)CN1C(=O)c2ccc(I)cc2C1=O
Temperature: 200 °C

Procedure:
4-Iodo-phthalic acid, 10 g, was mixed intimately with 2.63 g of glycine and the mixture was heated to 200° C. for 10 min. After cooling, the solid reaction mixture was extracted with ethyl acetate to give, after concentration, 6.40 g of tan solid: MS-(−)-ion, Proton NMR (200 MHz, methanol-d-4): δ 8.26-8.18 (m, 2H), 7.68-7.61 (m, 1H), 4.39 (s, 1H).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:9]=[C:10]([CH2:15][CH2:16][OH:17])[CH:11]=[CH:12][C:13]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:9]=[C:10]([CH2:15][CH2:16][O:17][S:28]([CH3:27])(=[O:30])=[O:29])[CH:11]=[CH:12][C:13]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCO)ccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCOS(C)(=O)=O)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
To a sol. of 2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethanol (2.00 g, 6.65 mmol) in CH2Cl2 (66 mL) at 0° C. were added dropwise Et3N (1.02 mL, 7.31 mmol) and methanesulfonyl chloride (0.57 mL, 7.3 mmol). The reaction was stirred at 0° C. for 1 h, and was diluted with CH2Cl2 (40 mL). The resulting mixture was washed with aq. sat. NH4Cl (2×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to yield the crude title compound (2.55 g, quantitative yield) that was used further without purification. LC-MS: tR=1.13 min; ES+: 379.29.
Reaction SMILES: [C:1]1(=O)[C:12]2[C:4](=[CH:5][C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:3][CH2:2]1.Cl.[H][H]>[Pd].C(O)C>[CH2:3]1[C:4]2[C:12](=[CH:11][C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)[CH2:1][CH2:2]1
Reactant: [H][H]
Reactant: O=C1CCc2cc3c(cc21)CCC3
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1c2c(cc3c1CCC3)CCC2
Yield: 73.8 %

Procedure:
A mixture of 3,5,6,7-tetrahydro-2H-s-indacen-1-one (90 grams), ethanol (1 L), 10% palladium on carbon (1-2 grams) and concentrated hydrochloric acid (50 mL) was hydrogenated on a Parr shaker at room temperature until hydrogen uptake ceased. The mixture was filtered through a Celite pad. The pad was washed with 1 L diethyl ether. The filtrate was diluted with water and the organic phase was separated. The aqueous phase was extracted with 1 L of ether, and the combined ether extracts were washed with water, saturated sodium bicarbonate solution and brine. The ether extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting pale yellow solid was recrystallized from methanol to afford 61 grams of the title compound as colorless crystals, m.p. 56.6-58.5° C.
Reaction SMILES: C(OC(C1C(O)(CC)CCCN1S(C1C=CC(OCC2C=CC(F)=CC=2)=CC=1)(=O)=O)=O)(C)(C)C.[OH:35][NH:36][C:37]([CH:39]1[C:44]([OH:47])([CH2:45][CH3:46])[CH2:43][CH2:42][CH2:41][N:40]1[S:48]([C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][C:62]([F:65])=[CH:61][CH:60]=2)=[CH:53][CH:52]=1)(=[O:50])=[O:49])=[O:38]>>[OH:35][NH:36][C:37]([C@H:39]1[C@@:44]([OH:47])([CH2:45][CH3:46])[CH2:43][CH2:42][CH2:41][N:40]1[S:48]([C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][C:62]([F:65])=[CH:61][CH:60]=2)=[CH:53][CH:52]=1)(=[O:50])=[O:49])=[O:38]
Reactant: CCC1(O)CCCN(S(=O)(=O)c2ccc(OCc3ccc(F)cc3)cc2)C1C(=O)NO
Agent: CCC1(O)CCCN(S(=O)(=O)c2ccc(OCc3ccc(F)cc3)cc2)C1C(=O)OC(C)(C)C
Product: CC[C@@]1(O)CCCN(S(=O)(=O)c2ccc(OCc3ccc(F)cc3)cc2)[C@H]1C(=O)NO

Procedure:
Using the methods of Example 4, 1-[4-(4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-ethyl-piperidine-2-carboxylic acid tert-butyl ester was converted to 1-[4-(4-Fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-ethyl-piperidine-2-carboxylic acid hydroxyamide.
Reaction SMILES: O[CH2:2][CH2:3][C@@H:4]([CH3:14])[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].C(P(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[CH3:14][C@@H:4]1[CH2:3][CH2:2][N:7]([C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)[C:5]1=[O:6]
Reactant: C[C@H](CCO)C(=O)Nc1ccn(C)n1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H]1CCN(c2ccn(C)n2)C1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.4 %

Procedure:
To a solution of (2R)-4-hydroxy-2-methyl-N-(1-methyl-1H-pyrazol-3-yl)butanamide (216 mg) and tri-n-butylphosphine (0.54 mL) in THF (10 mL) was added 40% diethyl azodicarboxylate toluene solution (1.0 mL). The reaction mixture was stirred at room temperature for 15 hr, and diluted with ethyl acetate. The diluted solution was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and then HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)), and to the obtained fraction was added ethyl acetate. The mixture was washed with saturated aqueous sodium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give the title compound (97 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:13].[CH3:14][C:15]1[S:19][C:18]([CH:20]=O)=[CH:17][CH:16]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)C>[CH2:11]([S:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:13][C:20]([C:18]3[S:19][C:15]([CH3:14])=[CH:16][CH:17]=3)=[N:1][C:2]=2[CH:7]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: CCS(=O)(=O)c1ccc(O)c(N)c1
Reactant: Cc1ccc(C=O)s1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CCO
Product: CCS(=O)(=O)c1ccc2oc(-c3ccc(C)s3)nc2c1
Temperature: 70 °C
Yield: 0.3 %

Procedure:
To a stirred solution of 2-amino-4-(ethylsulfonyl)phenol (452.7 mg, 2.25 mmol) in ethanol (17 mL) was added 5-methyl-2-thiophenecarboxaldehyde (242 μL, 2.25 mmol). The mixture was heated at 70° C. for 70 min. After cooling, a small amount of precipitate was formed. After filtration and evaporation of the filtrate, the resulting product was dissolved in acetonitrile (9.8 mL) and lead tetraacetate (887 mg, 2 mmol) was added. The resulting mixture was heated at 100° C. for 5 min. After cooling, the reaction mixture was filtered off, and the filtrate evaporated in vacuo. The resulting mixture was purified by column chromatography eluting with ethyl acetate/hexanes 20:80 v/v, and then purified by reverse phase HPLC to afford 2.2 mg (0.3%) of the title product (LCMS RT=6.41 min, MH+ 308.1)
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:31])[C@@H:6]([O:11][C@H:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].ClC1C=C(C=CC=1)C(OO)=[O:37]>ClCCl>[C:1]([CH2:3][NH:4][C:5](=[O:31])[C@@H:6]([O:11][C@@H:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N+:21]([O-:37])[CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2]
Reactant: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(-c2cccnc2)cc1)C(=O)NCC#N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(-c2ccc[n+]([O-])c2)cc1)C(=O)NCC#N
Reaction time: 1.5 h
Yield: 101.2 %

Procedure:
To a solution of (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4-pyridin-3-ylphenyl)methyl]oxy}pentanamide from example 38 (95 mg, 0.23 mmol) in dichloromethane (10 mL) was added 77% quality 3-chloroperoxybenzoic acid (51.5 mg, 0.23 mmol) at 5° C. The temperature was permitted to gradually rise to r.t. over 1.5 h. The mixture was concentrated and the residue partitioned between ethyl acetate and 1M Na2CO3. The ethyl acetate layer was dried (Na2SO4) and concentrated to yield 100 mg of the title compound. Purification by chromatography on silica gel using 10% methanol in dichloromethane and concentrating with diethyl ether 2 times gave a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:13][S:14](Cl)(=[O:16])=[O:15].Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH:5][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc([N+](=O)[O-])ccc1N
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc([N+](=O)[O-])ccc1NS(C)(=O)=O
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 2-methoxy-4-nitroaniline (5 g) in pyridine (25 ml) at 0° C. was added dropwise methanesulfonyl chloride (3.5 ml). The mixture was left at 0° C. for 1 hour, then brought to RT for 2 h. The mixture was poured onto ice (100 g) and dilute hydrochloric acid (3M, 100 ml), the solid formed was filtered then washed with water and dried to give 2-methoxy-4-nitro-methanesulfonylaminobenzene (7.32 g, 98%) as an off-white crystalline solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1.C(N(C(C)C)CC)(C)C.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[Br:1][C:2]1[C:3]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([NH:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1F
Reactant: Nc1cccnc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1F
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-2-{[(2,4-difluorophenyl)methyl]oxy}-4-(4-morpholinylmethyl)benzoic acid (may be prepared as described in Description 22; 150 mg, 0.34 mmol) in N,N-dimethylformamide (4 ml) was added 3-aminopyridine (38.3 mg, 0.41 mmol), diisopropylethylamine (0.12 ml, 0.68 mmol), 1-hydroxy-7-azabenzotriazole (55.4 mg, 0.41 mmol) and EDC (98 mg, 0.51 mmol). The mixture was stirred overnight and the solvent removed in vacuo to give a residue. Purification by column chromatography (SiO2; 10% 7M NH3 in methanol/dichloromethane) yielded the title compound as a solid. 162 mg.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:22][O:23][CH3:24])[CH2:20]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].ClCCCS([NH:32]CC(OC)CSCCCCCCCCCCCCCCCC)(=O)=O.C1(=O)NC(=O)C2=CC=CC=C12>>[CH2:1]([S:17][CH2:18][CH:19]([CH2:22][O:23][CH3:24])[CH2:20][NH2:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(CO)COC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Agent: O=C1NC(=O)c2ccccc21
Product: CCCCCCCCCCCCCCCCSCC(CN)COC

Procedure:
3-Hexadecylthio-2-methoxymethylpropanol IVk3 is allowed to react and worked up by the same procedure as described in (4). The phthalimide compound m.p. 45° C. The summary of the experimental condition and the physical data of the product are listed in Tables 5 and 6.