Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)/[CH:3]=[CH:4]/[C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10](=[O:13])[CH2:11]2)[CH2:7][C@H:6]1[O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[F:29][C:2]([F:1])([CH2:21][O:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)/[CH:3]=[CH:4]/[C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][CH:10]([OH:13])[CH2:11]2)[CH2:7][C@H:6]1[O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/C(F)(F)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OC1C[C@@H]2[C@@H](/C=C/C(F)(F)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2O1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 106.3 %

Procedure:
(3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-phenoxybut-1-enyl)-hexahydro-5-(tetrahydro-2H-pyran-2-yloxy)cyclopenta[b]furan-2-one (47.0 g, 0.11 mol) was dissolved in toluene (500 mL), followed by cooling to −70° C., and DIBAL (1.0M in Hexane, 172 mL, 0.16 mol) was added dropwisely. Then the reaction was quenched by adding saturated aqueous solution of ammonium chloride (25 mL) at −70° C. The resulting mixture was poured into a 2M sodium bisulfate aqueous solution (500 mL) at room temperature and stirring was continued for 30 minutes. After separation of the organic layers, 500 mL of toluene was added to the aqueous layer. The combined organic layers were concentrated under reduced pressure to give 48 g of crude title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH3:20])[C:13](=[O:21])[N:12]([CH2:22][CH2:23][C:24]([O:26]C)=[O:25])[C:11]=2[N:10]=[C:9]1[C:28]([CH3:31])([CH3:30])[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[Li+].[OH-].Cl>O>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH3:20])[C:13](=[O:21])[N:12]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:11]=2[N:10]=[C:9]1[C:28]([CH3:29])([CH3:31])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCn1c(=O)c2c(nc(C(C)(C)C)n2Cc2ccccc2)n(CCC(=O)OC)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCn1c(=O)c2c(nc(C(C)(C)C)n2Cc2ccccc2)n(CCC(=O)O)c1=O
Temperature: 5 °C

Procedure:
4.6 g (10.8 mmol) of 7-benzyl-8-(tert.-butyl)-3-(2-methoxycarbonylethyl)-1-n-propyl-xanthine are dissolved 50 ml of tetrahydrofuran and 120 ml of water and 3.24 g of LiOH×H2O are added successively with stirring. After about 16 hours' stirring at ambient temperature, the mixture is cooled to about 5° C. and adjusted to pH 5 with 2N HCl (aq.). The organic solvent is largely distilled off in vacuo and the aqueous phase remaining is extracted twice with 150 ml of dichloromethane. The organic phase is dried over MgSO4 and the solvent is distilled off in vacuo. The crude product remaining is purified by chromatography on silica gel (dichloromethane:methanol 90:10). Yield: 3.1 g (88%), amorphous solid.
Reaction SMILES: [CH:1]([Si:4]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[C:5]1[O:6][CH:7]=[CH:8][N:9]=1)([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.C(O[B:31]([O:36][CH:37]([CH3:39])[CH3:38])[O:32][CH:33]([CH3:35])[CH3:34])(C)C.CC(O)(C(C)(O)C)C>C1COCC1.C(O)(=O)C>[CH3:39][C:37]1([CH3:38])[C:33]([CH3:34])([CH3:35])[O:32][B:31]([C:7]2[O:6][C:5]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:10]([CH3:12])[CH3:11])[CH:13]([CH3:15])[CH3:14])=[N:9][CH:8]=2)[O:36]1
Reactant: CC(C)[Si](c1ncco1)(C(C)C)C(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(triisopropylsilyl)oxazole (6.7 g) in THF (200 mL) was added dropwise n-butyllithium hexane solution (1.6M, 22.3 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 hr under nitrogen atmosphere, triisopropylborate (8.2 mL) was added thereto, and mixture was stirred at −78° C. for 2 hr. The mixture was allowed to be warmed to room temperature, and stirred overnight. To the reaction mixture was added a solution of 2,3-dimethylbutane-2,3-diol (3.51 g) in THF (20 mL) and acetic acid (2.3 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and 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) to give the title compound (8.8 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:19](=[O:20])[CH2:18][O:17][CH3:16])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: COCC(=O)Cl
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: COCC(=O)Nc1nc2cccc(-c3ccoc3)n2n1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 660 mg; 0.30 mmol; 1.0 eq.) and methoxyacetyl chloride (65 mg, 0.60 mmol; 2.0 eq.) as a white powder (59 mg, 72%). HPLC, Rt: 2.21 min. (purity 98.2%). LC/MS, M+(ESI): 273.4, M−(ESI): 271.4.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[C:8]1([CH3:17])[C:9]([N:14]=[C:15]=[S:16])=[CH:10][CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH3:17])[C:15]1=[S:16])[CH3:2]
Reactant: CCNCC(=O)O
Reactant: Cc1ccccc1N=C=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2ccccc2C)C1=S
Yield: 31 %

Procedure:
The tide compound was prepared by the procedure described in Example 7 using 9.2 g of N-ethyl glycine, 7.4 g of 2-tolyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved through crystallization from ethanol. Title compound (3.6 g) was obtained as a creamy solid, m.p. 105°-108° C. Anal. Calcd. for. C12H14N2O S: C, 61.51; H, 6.02; N, 11.93. Found: C, 61.22; H, 5.96; N, 11.89. Mass spectrum (EI, M.+) m/z 234.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:28]=1[CH:29]=[O:30]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:29]([C:28]3[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:27]=3[CH3:26])[OH:30])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1C=O
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cccc(C)c1C(O)c1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 65.5 %

Procedure:
To a solution of 4-benzyl-2-(4-bromo-phenyl)-morpholine (2.1 g, 6.3 mmol) in THF (30 mL), at −78° C., was added dropwise t-butyl lithium (7.9 mL; 1.6 mol/l in heptanes; 12.6 mmol). The mixture was stirred for 20 min. at −78° C., and subsequently 2,6-dimethylbenzaldehyde (1 g, 7.6 mmol) was added. The mixture was allowed to warm to RT and stirred overnight. The resulting mixture was partitioned between water and EtOAc. The layers were separated. The organic layer was washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (EtOAc:heptanes 1:1) to afford [4-(4-benzyl-morpholin-2-yl)-phenyl]-(2,6-dimethyl-phenyl)-methanol (1.6 g), which was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.O.O.O.O.O.O.C1(=O)OOOOC(=[O:42])C2=CC=CC=C12.[Mg]>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:31])=[O:42])=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: O=c1ooooc(=O)c2ccccc12
Reactant: CSc1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Agent: [Mg]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CS(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Reaction time: 3 h

Procedure:
To a solution of 5-(4-chloro-phenyl)-6-(4-methylsulfanyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (2.10 g, 4.72 mmol) in dry dichloromethane (36 mL) and methanol (12 mL), magnesium monoperoxy phthalate hexahydrate (1.16 g, 2.36 mmol) is added at 0° C. and the resulting mixture is stirred for 3 h at that temperature. The reaction mixture is quenched with the addition of 10% sodium bicarbonate solution and extracted with dichloromethane (3×). The organic part separated is dried (Na2SO4) and concentrated. The crude product is purified by column chromatography (silica gel, 60-120 mesh) to afford 5-(4-chloro-phenyl)-6-(4-methanesulfinyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:65][N:56]4[CH2:57][CH2:58][C:59]5[C:64]([C@@H:55]4[CH2:54]3)=[CH:63][CH:62]=[CH:61][CH:60]=5)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]>CO.O1CCCC1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:30]=[N:31][N:32]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:65][N:56]4[CH2:57][CH2:58][C:59]5[C:64]([C@@H:55]4[CH2:54]3)=[CH:63][CH:62]=[CH:61][CH:60]=5)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc([C@@H]3C[C@H]4c5ccccc5CCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nc2ccc([C@@H]3C[C@H]4c5ccccc5CCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 85.5 %

Procedure:
A solution of 0.134 g of Cis-2-butyl-6-(1,5,6,10b-tetrahydro-2H-isoxazolo[3,2-a]isoquinolin-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in 2.5 ml of methanol and 0.5 ml of tetrahydrofuran is heated at reflux for 18 hours. The volatiles are evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 99:1 chloroform-methanol to give 0.082 g of the desired product as a solid. FAB MASS SPEC 610 (M+H).
Reaction SMILES: C(O[CH2:9][NH:10][C@@H:11]([CH3:24])[C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([OH:15])=[O:14])C1C=CC=CC=1>CO.[Pd]>[CH3:9][NH:10][C@@H:11]([CH3:24])[C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([OH:15])=[O:14]
Reactant: C[C@H](NCOCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CN[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 18 h
Yield: 45.1 %

Procedure:
A solution of (2S,3S)-3-((benzyloxy)methylamino)-2-(tert-butoxyformamido)butyric acid 9 (2.4 g, 14.8 mmol) in 20 mL methanol was added under nitrogen to a suspension of 10% palladium on charcoal (0.6 g, 25 wt %) in 20 mL methanol in a Parr hydrogenator flask. The mixture was placed on the Parr hydrogenator and hydrogenated at 50 psi for 18 hours. The catalyst was removed by filtration and the filtrate evaporated in vacuo. The residue was then lyophilized, affording 1.55 g of (2S,3S)-3-methylamino-2-(tert-butoxyformamido)butyric acid 10 as a white solid (95% yield).
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[H-].[Na+].CS(O[CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH3:26])(=O)=O.O>CS(C)=O>[CH2:26]([N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3])[CH2:25][CH2:24][CH:23]=[CH:22][CH3:21]
Reactant: CC=CCCCOS(C)(=O)=O
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC=CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A mixture of theobromine (2.16 g, 12 mmol) and sodium hydride (288 mg, 12 mequivalents) in dimethylsufoxide (10 mL) was stirred for 30 minutes and then a solution of 1-methansulfonyloxy-4-hexene in dimethylsulfoxide (10 mL) was added. After 84 hours of stirring, water (70 mL) is added and the mixture extracted with ether (3×50 mL). The combined extracts were washed with water (50 mL) and dried over magnesium sulfate. The solvent was then evaporated under vacuum. The residue was purified by flash chromatography (22 g silica gel using an ethyl acetate eluant, 500 mL), yielding 2.1 g (67%) 1-(4-hexenyl)-3,7-dimethylxanthine. To a solution of 1-(4-hexenyl)-3,7-dimethylxanthine (270 mg, 1.03 mmol) in dichloromethane (10 mL) was added saturated aqueous sodium bicarbonate solution (10 mL), followed by a solution of 50-60% 3-chloroperoxybenzoic acid (889 mg, 2.58 mmol) in dichloromethane (5 mL) over 1 minute. After 20 hours of stirring, 20% aqueous sodium metabisulfite solution (15 mL) was added over 1 minute. The mixture was then extracted with dichloromethane (3×15 mL). The combined extracts were washed with saturated aqueous sodium bicarbonate solution (3×20 mL) and dried over magnesium sulfate. The sovent was evaporated under vacuum. The residue was purified by flash chromatography using 14 g of silica gel and eluting with ethyl acetate (100 ml) followed by 8% methanol-dichloromethane (60 mL), yielding 80 mg (28% yield) of 1-(4,5-oxohexyl)-3,7-dimethylxanthine as a white powder.
Reaction SMILES: [N@:1]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3][CH:2]1[C:4]([O:6][CH3:7])=[O:5].[C:18]1([CH:24]([OH:26])[CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.B(F)(F)F.CCOCC>ClCCl>[CH3:7][O:6][C:4](=[O:5])[CH:2]([NH:1][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])[CH2:3][O:26][CH:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:25]
Reactant: CC(O)c1ccccc1
Reactant: COC(=O)C1CN1C(=O)OCc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C(COC(C)c1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 46.9 %

Procedure:
To a stirred solution of 1-benzyl 2-methyl (S)-(−)-1,2-aziridinedicarboxylate (1.88 g) in dichloromethane (30 ml) were added at 0° C. 1-phenyl-ethanol (9.77 g) and boron trifluoride etherate (2.0 ml). After stirring the mixture for one hour the cooling bath was removed and stirring was continued overnight. Then the reaction mixture was poured onto saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and concentrated. The crude product was purified by column chromatography (SiO2; gradient: heptane/EtOAc 100:0->90:10) to give S)-2-benzyloxycarbonylamino-3-(1-phenyl-ethoxy)-propionic acid methyl ester (1.34 g, 47%) as a light yellow oil. MS (ISP): 358.2 ([M+H]+)).
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[C:29]([OH:36])[C:28]=2[CH2:37][CH2:38][CH3:39])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[C:29]([OH:36])[C:28]=2[CH2:37][CH2:38][CH3:39])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2ccc(C(C)=O)c(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1c(OCCCOc2ccc(C(C)=O)c(OCCCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 61.4 %

Procedure:
To a solution of ethyl 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]butanoate (example 1, 1.7 g) in ethanol (5 ml) was added a solution of sodium hydroxide (0.38 g) in water (5 ml). The mixture was heated on water-bath for 10 minutes, poured into ice water, made acidic with concentrated hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography, eluting with dichloromethane-methanol (10:1). Recrystallization from benzene-n-hexane afforded the title compound (0.99 g, 61.4%) as colorless crystals, mp 50°-53° C.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[N:12]([S:13](=[O:18])(=[O:17])[N:14]([CH3:16])[CH3:15])[C:11]([Si](C(C)(C)C)(C)C)=[N:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(OCC)(=O)C.CCCCCC>C1COCC1>[CH:1]1([CH2:7][C:8]2[N:12]([S:13](=[O:18])(=[O:17])[N:14]([CH3:15])[CH3:16])[CH:11]=[N:10][CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)S(=O)(=O)n1c(CC2CCCCC2)cnc1[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cncc1CC1CCCCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
2-Tert-butyldimethylsilyl-1-dimethylsulfamoyl imidazole (1) (4.1 g, 14.2 mmol) is taken up in 47 mL of anhydrous THF and cooled to −20° C. n-BuLi (8.9 mL, 14.2 mmol) is added dropwise to the solution of (1). The resultant solution is stirred at −20° C. for 45 min. Cyclohexylmethyl iodide (2) (3.14 g, 14 mmol) is then added dropwise to the reaction mixture. Then reaction is warmed to rt and stirred overnight. The next day the reaction is quenched with saturated ammonium chloride and diluted with water. The mixture is extracted with ethyl acetate (3×100 mL). The organic layers are combined and washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (4:1 ethyl acetate/hexane) affords 2.26 g (5.6 mmol) of 5-cyclohexylmethyl-2-tert-butyldimethylsilyl-1-dimethylsulfamoyl imidazole (3). (3) (2.26 g, 5.6 mmol) is taken up in 56 mL of THF and cooled to 0° C. A 1M solution of TBAF in THF (5.6 mL, 5.6 mmol) is added dropwise to the solution of (3). The reaction is warmed to rt and stirred overnight. The next day the reaction is quenched with water and then extracted with ethyl acetate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (1:1 ethyl acetate/hexane) affords 1.2 g (4.42 mmol) of 5-cyclohexylmethyl-1-dimethylsulfamoyl imidazole (4). (4) (1.2 g, 4.42 mmol) is taken up in 25 mL of a 1.5N HCl solution and heated at reflux for 2 h. The reaction is cool to rt and diluted with ethyl acetate. The mixture is brought to pH 13 with 2N NaOH and then extracted with chloroform (4×100 mL). The organic layers are combined and washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (9:1 chloroform/methanol) affords 700 mg (4.27 mmol) of 4(5)-cyclohexylmethyl-1H-imidazole (5) (J-1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:21]1[C:33]2[CH:32]([CH2:34]O)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1.C(N=C=NC(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([O:19][CH2:34][CH:32]2[C:33]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Reactant: OCC1c2ccccc2-c2ccccc21
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)OCC2c3ccccc3-c3ccccc32)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
To a solution of {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid (160 g) obtained in Example 3 in dichloromethane (500 mL) were added 9H-fluorene-9-ylmethanol (98 g) and 4-dimethylaminopyridine (3.1 g), diisopropylcarbodiimide (78 ml) was added dropwise under ice-cooling, and the mixture was stirred at 0° C. for 1 hr and further stirred at room temperature for 2 hr. The precipitate was removed from the reaction mixture by filtration, and the filtrate was concentrated under reduced pressure and purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (260 g) as a yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:19]2[CH:18]=[CH:17][C:16]([S:13]([C:6]3([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]3)(=[O:14])=[O:15])=[CH:21][CH:20]=2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCC(C(=O)O)(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC1

Procedure:
4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4-carboxylic acid was prepared starting from 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4-carboxylic acid ethyl ester (4.3 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (100 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.5 g (86 %); white solid; mp 185° C.; MS:410(M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)(O)[O-].[Na+].[CH3:22][C:23](CC(C)C)=[O:24].O.ClCC(Cl)=O>C(Cl)(Cl)Cl>[CH2:13]([N:12]1[C:3]2[C:2](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)[NH:1][CH2:22][C:23]1=[O:24])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCNc1cc(C(=O)OC)ccc1N
Reactant: CC(=O)CC(C)C
Agent: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCN1C(=O)CNc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold, stirred solution of methyl 4-amino-3-(butylamino)benzoate (950 mg) and sodium bicarbonate (862 mg) in 1:1 isobutyl methyl ketone/water (20 mL) was added chloroacetyl chloride (0.41 mL), and the mixture was stirred for 1 h. The mixture was warmed to room temperature and refluxed for 14 h. The mixture was cooled to room temperature, diluted with chloroform, and separated. The organic layer was washed with water, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:1 ethyl acetate/hexanes) afforded 850 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.89, 7.72, 6.80, 3.97, 3.88, 3.30–3.25, 1.68–1.58, 1.47–1.35, 0.94–0.88.