Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:19]3[CH:23]=[CH:22][N:21]=[C:20]3[S:24]([CH3:27])(=[O:26])=[O:25])[O:11][C:12]=2[CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:19]3[CH:23]=[CH:22][N:21]=[C:20]3[S:24]([CH3:27])(=[O:26])=[O:25])[O:11][C:12]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1oc(-n2ccnc2S(C)(=O)=O)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a solution of methyl 3-{4-(4-chlorophenyl)-2-[2-(methylsulfonyl)-1H-imidazol-1-yl]-5-oxazolyl}propionate (1.4 g) in 1,4-dioxane (7 mL) was added 2N aqueous sodium hydroxide solution (3.5 mL) and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water, and acidified with 2N aqueous hydrochloric acid solution. The precipitated crystals were collected by filtration and recrystallized from methanol to give 3-{4-(4-chlorophenyl)-2-[2-(methylsulfonyl)-1H-imidazol-1-yl]-5-oxazolyl}propionic acid (1.22 g, yield 90%) as colorless prism crystals. melting point: 166–167° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1>CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reaction time: 8 h
Yield: 66.5 %

Procedure:
3-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-nitro-1H-indole (2.7 g, Step A) was dissolved in 50 mL MeOH, the mixture was bubbled with H2 for 10 min. 10% Pd/C (150 mg) was added and the mixture was stirred under H2 overnight. The mixture was then filtered through Celite® and concentrated in vacuo to afford a yellow oil (1.6 g). MS: 230 (M+1). Calc'd. for C14H19N3-229.3.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.Cl.[CH:16]1([C:19]2[C:20]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=2)[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]2[CH2:30][CH2:31][N:26]([C:20]3[C:19]([CH:16]4[CH2:18][CH2:17]4)=[CH:24][C:23]([CH3:25])=[CH:22][N:21]=3)[CH2:27][CH2:28]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C2CC2)c1
Yield: 94.1 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 27 and using 4-bromo-2-methanesulfonylbenzoic acid (558 mg) and 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine hydrochloride (508 mg) described in Preparation Example 48, the title compound (0.9 g) was obtained.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[CH2:6][N:7]1[C:11]([CH3:13])([CH3:12])[C:10](=[O:14])[N:9]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:19]=2)[C:8]1=[O:28].B(Br)(Br)Br>ClCCl>[CH3:27][C:22]1[C:21]([CH2:20][N:18]2[CH:19]=[C:15]([N:9]3[C:10](=[O:14])[C:11]([CH3:13])([CH3:12])[N:7]([CH2:6][C:5]4[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:3]([OH:2])[CH:4]=4)[C:8]3=[O:28])[CH:16]=[N:17]2)=[C:25]([CH3:26])[O:24][N:23]=1
Reactant: COc1cc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cc(O)cc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
1-(3,5-dimethoxybenzyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-18) (114 mg, 0.252 mmol) was dissolved in dichloromethane (1 mL). The mixture was cooled down to −78° C. and boron tribromide (1.0 M solution in dichloromethane, 1.25 mL) was added dropwise. After complete addition, the mixture was allowed to warm to room temperature and stirring continued for 3 hours. The mixture was quenched with water and the organic phase was separated, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The residue was suspended in methanol (1 mL) and purified by reverse phase HPLC (25 minute gradient: acetonitrile/water). Yield 47% (45 mg), white solid. NMR (DMSO-d6, 400 MHz): □s, 6H), 2.16 (s, 3H), 2.42 (s, 3H), 3.67 (s, 3H), 4.43 (s, 2H), 5.20 (s, 2H), 6.22 (t, J=2.4 Hz, 1H), 6.39 (m, 2H), 7.83 (d, J=0.4 Hz, 1H), 8.21 (s, 1H), 9.40 (br s, 1H). Mp. 72-74° C. MS 440 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.02 μM.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]1)(=[O:39])=[O:38]>FC(F)(F)CO>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:46][CH:43]3[CH2:44][CH2:45][N:40]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:41][CH2:42]3)[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: OCC(F)(F)F
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(NC3CCN(S(C)(=O)=O)CC3)n2)s1
Yield: 20 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.10 g, 0.19 mmol) and 1-(methylsulfonyl)-4-piperidinamine (0.30 g, 1.7 mmol) in 2,2,2-trifluoroethanol (2 mL) the title compound was obtained (0.026 g, 0.038 mmol, 20% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.84 (s, 1H), 8.03 (br. s., 1H), 7.72-7.54 (m, 1H), 7.47-7.06 (m, 7H), 3.53-3.38 (m, 2H), 2.83 (s, 3H), 2.83-2.72 (m, 3H), 1.91-1.73 (m, 2H), 1.58-1.32 (m, 2H), 1.36 (s, 9H). MS (ESI): 681 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][OH:3].Cl.[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[Cl-].[Na+]>C(N(CC)CC)C.O1CCCC1>[CH3:1][N:2]([S:11]([C:8]1[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=1)(=[O:13])=[O:12])[OH:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNO
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N(C)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.02 Grams of N-methylhydroxylamine.HCl was suspended with 70 ml of tetrahydrofuran and 6.70 g of triethylamine was added to the solution. After stirring at room temperature for 0.5 hour, 5.73 g of p-toluenesulfonyl chloride was added to the reaction solution and stirred at room temperature over night. The saturated sodium chloride solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and N-methyl-N-(p-toluenesulfonyl)hydroxylamine was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:30]1[CH:31]=[CH:32][N:33]=[CH:34][C:29]=1[C:25]1[CH:24]=[C:23]([C:22]2[CH2:21][C:20](=[O:36])[NH:19][C:9]3[CH:10]=[C:11]([N:14]4[CH:18]=[CH:17][CH:16]=[CH:15]4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1NC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cnccn3)c2)=Nc2ccc(-n3cccc3)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-4-pyrrol-1-yl-phenyl}-carbamic acid tert-butyl ester (Example M100) (0.37 g, 0.74 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (170 mg, 60%).
Reaction SMILES: N1C=CN=C1.[CH2:6]([Si:8](Cl)([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7].[N:14]([CH2:17][C@@H:18]([C:20]1[CH:21]=[CH:22][C:23]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=1)[OH:19])=[N+:15]=[N-:16].O>CN(C)C=O>[N:14]([CH2:17][C@@H:18]([C:20]1[CH:21]=[CH:22][C:23]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=1)[O:19][Si:8]([CH2:11][CH3:12])([CH2:9][CH3:10])[CH2:6][CH3:7])=[N+:15]=[N-:16]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN=[N+]=[N-])ccc1OCc1ccccc1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.3 %

Procedure:
Imidazole (0.46 g) and triethylsilyl chloride (0.82 g) were added to a solution of N-[5-((R)-2-azido-1-hydroxyethyl)-2-benzyloxyphenyl]methanesulfonamide (1.64 g) in N,N-dimethylformamide (20 mL), and the mixture was stirred at room temperature for 12 hrs. Imidazole (0.15 g) and triethylsilyl chloride (0.21 g) were added to the reaction mixture. After being stirred for additional 3 hrs, water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to afford the title compound (1.84 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:12][CH:13]=2)=[C:4]([F:17])[CH:3]=1.C1(C)C=CC=CC=1>[Pd].CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9]2)=[C:4]([F:17])[CH:3]=1
Reactant: CCCC1CC=C(c2ccc(Br)cc2F)CC1
Agent: [Pd]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCCC1CCC(c2ccc(Br)cc2F)CC1
Yield: 78 %

Procedure:
A mixture of compound (69) (39.2 g, 131.9 mmol) and 5%-palladium on carbon (0.5% sulfur, 50% water-containing article) (1.18 g, 3 wt %) was agitated for 18 hours under a hydrogen atmosphere in a toluene (200 mL)-IPA (100 mL) solvent. The reaction mixture was filtered and a solvent in a filtrate was distilled off by an evaporator. The residue was passed through silica gel column chromatography and then a low-boiling-point material was distilled off by distillation, and thus 4-bromo-2-fluoro-1-(4-propylcyclohexyl)benzene (70) (30.8 g, yield 78.1%) was obtained.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][NH2:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O>C(O)(=O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:12](=[O:17])[CH2:13][C:14]([CH3:16])=[N:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: NNc1ccc2c(c1)CCC2
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: CC1=NN(c2ccc3c(c2)CCC3)C(=O)C1
Temperature: 100 °C
Yield: 62.2 %

Procedure:
Indan-5-yl-hydrazine 1h (2.05 g, 13.8 mmol) was dissolved in 50 mL of acetic acid followed by addition of ethyl acetoacetate (1.76 mL, 13.8 mmol). The reaction mixture was heated at 100° C. overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound 2-indan-5-yl-5-methyl-2,4-dihydro-pyrazol-3-one 1i (1.84 g, yield 62.3%) as a yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.[F:10][C:11]([F:23])([F:22])[C:12](=O)[CH2:13][C:14]([C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)=O>C(O)(=O)C>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)[N:9]=[C:12]([C:11]([F:10])([F:22])[F:23])[CH:13]=1
Reactant: NNc1cccc(I)c1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(-c2ccco2)n(-c2cccc(I)c2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a stirred suspension of 61 (3.63 g, 8.57 mmol) in acetic acid (34 mL) was added 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (1.3 mL, 8.57 mmol). The resulting suspension was allowed to stir at 120° C. overnight turning clear upon heating. The mixture was then evaporated to dryness. The crude product was added to a silica gel column and eluted with 5% to 10% EtOAc/hexanes. The title product 62 (3.00 g, 87% yield) was isolated as a colorless oil that solidified upon standings. LRMS (ESI): calc. 404.1; found 405.2 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].S(Cl)(Cl)=O.C(Cl)Cl.C[N:23](C=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([NH2:23])=[O:13])[S:10][C:3]=12
Reactant: CN(C)C=O
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: NC(=O)c1cc2nccc(Cl)c2s1
Yield: 100 %

Procedure:
A solution of lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate (1.0 g, 4.7 mmol), thionyl chloride (7.0 mmol, 3.5 mL), CH2Cl2 (40 mL), and DMF (0.4 mL) was heated to reflux. After 3 h the resulting yellow solution was concentrated under reduced pressure, the resulting residue was suspended in CH2Cl2 (60 mL), and NH3 gas was bubbled through the mixture for 10 min. The reaction mixture was filtered to give the title compound as a white solid (1.17 g, 100%). MS: 213.0/215.1 (MH+); HPLC Rf: 3.44 min; HPLC purity: 98%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][N:3]=1.C(Cl)(Cl)Cl.[C:27](Cl)(=[O:29])[CH3:28].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:27]([NH:1][C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[CH:4][N:3]=1)(=[O:29])[CH3:28]
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cnc(NC(C)=O)c(Cc3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 32.9 %

Procedure:
Under an argon atmosphere, 2-amino-3-benzyl-5-(4-methoxyphenyl)pyrazine (c-11) (prepared by the method described in Adamczyk, M. et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (199 mg, 681 μmol) was dissolved in anhydrous pyridine (1.4 mL) and chloroform (4 mL) and cooled to 0° C. To this was added acetyl chloride (365 μL, 5.13 mmol) and stirred for an hour after warming to room temperature. To this was added saturated aqueous solution of sodium bicarbonate to stop the reaction, and extracted 3 times with dichloromethane. The organic layer was washed with saturated aqueous solution of sodium sulfate and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was recrystallized from methanol to give 2-acetylamino-3-benzyl-5-(4-methoxyphenyl)pyrazine (c-24) as a colorless solid (74.6 mg, 32.9%). Rf=0.14 (n-hexane/ethyl acetate=3/2). UV (MeOH) λmax (log ε) 329.5 (4.18), 293 (4.18), 274 (4.16). UV (pH 7.4 PB) λmax (log ε) 328 (4.11), 289.5 (4.01), 270.5 (4.05). 1H NMR (400 MHz, DMSO-d6) δ 2.04 (s, 3H), 3.81 (s, 3H), 4.15 (s, 2H), 7.02-7.08 (AA′BB′, 2H), 7.15-7.22 (m, 3H), 7.23-7.29 (m, 2H), 8.00-8.05 (AA′BB′, 2H), 8.87 (s, 1H), 10.25 (s, 1H). IR (KBr, cm−1) 698, 744, 833, 1032, 1157, 1175, 1213, 1256, 1285, 1327, 1368, 1416, 1450, 1499, 1543, 1587, 1609, 1670, 3258. HRMS (FAB+) m/z 334.1557 (M+H, C20H20N3O2 requires 334.1556).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH3:32][CH:33]([SH:35])[CH3:34]>O>[CH:33]([S:35][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)([CH3:34])[CH3:32]
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Sc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 60 °C
Yield: 77.4 %

Procedure:
To a mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.50 g of potassium carbonate and 2 ml of DMF, a mixture of 0.15 g of 2-propanethiol and 0.5 ml of DMF was added. The reaction mixture was stirred while heating at 60° C. for two hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with 5% aqueous solution of potassium carbonate and a saturated sodium chloride solution, sequentially, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.26 g of 2-(3-isopropylthiopyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 43”).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]([OH:27])[C:24]([OH:26])=O)[CH:20]=[CH:21][CH:22]=1.[CH3:28][C:29]([CH3:32])([NH2:31])[CH3:30].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:28][C:29]([NH:31][C:24](=[O:26])[CH:23]([OH:27])[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=1)([CH3:32])[CH3:30]
Reactant: CC(C)(C)N
Reactant: O=C(O)C(O)c1cccc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)C(O)c1cccc(Cl)c1

Procedure:
Dicyclohexylcarbodiimide (11.0Sg) was added in portions to a cooled, stirred mixture of 3-chloro-α-hydroxybenzeneacetic acid (10g), 1,1-dimethylethanamine (3.92g, 5.63ml) and 1-hydroxybenzotriazole (7.24g) in dry dimethylformamide (100ml). The mixture was stirred at ambient temperature for 20h., filtered and the filtrate evaporated. The residual oil was taken up in ethyl acetate, filtered, and the filtrate washed sequentially with sodium carbonate solution, hydrochloric acid (2N) and water. The organic layer was dried (MgSO4), filtered, and evaporated to an oil which was chromatographed on silica. Elution with chloroform gave N-[1,1-dimethylethyl]-3-chloro-α-hydroxybenzeneacetamide, 1.71g, as an oil which crystallized on standing, m.p. 93-99° C.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:15]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH:15]([S:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: Fc1ccc(C(Cl)Cn2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
965 mg of methyl 4-mercaptobenzoate were dissolved in 6 ml of dry dimethylformamide. 250 mg of a 55% w/w suspension of sodium hydride in mineral oil were added to the resulting solution, whilst ice-cooling, and the mixture was then stirred at room temperature for 30 minutes. A solution of 1.1 g of 1-[2-chloro-2-(4-fluorophenyl)ethyl]imidazole dissolved in 16 ml of dry dimethylformamide was added to the resulting mixture. The mixture was then heated at 70° to 75° C. for 2.5 hours. At the end of this time, the resulting mixture was treated and purified similarly to the procedure described in Example 1, to give 866 mg of the title compound as a powder.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[CH2:25]([SH:27])[CH3:26].B(F)(F)F.C(=O)(O)[O-].[K+]>CCOCC>[CH2:25]([S:27][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])[CH3:26]
Reactant: CCS
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Product: CCS[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (50 mg.) in dry ether was treated with ethanethiol (0.8 mls.) and BF3 etherate (3 drops). The reaction mixture was stirred at room temperature for 20 minutes; then ether (5 mls.) and potassium bicarbonate solution (10%, 2.5 ml.) were added. The ether layer was evaporated to about 5 mls. and purified by preparative t.l.c. in ethyl acetate/petroleum ether (2:1) to give a colourless oil (200 mgs.) which was triturated with acetone and petroleum ether to give the title compound (174mg); fine white crystals; m.p. 170°-173°; [α]D + 93° (c 0.6).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([C@H:23]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:24]1)=[N+]=[N-].O>O1CCCC1>[NH2:20][C@H:23]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[C@H:25]([CH2:35][O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:24]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])C[C@H]1COCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](N)C[C@H]1COCc1ccccc1
Yield: 53.6 %

Procedure:
Triphenylphosphine (421 mg) was added to a solution of tert-butyl (2S,4R)-4-azido-2-[(benzyloxy)methyl]pyrrolidine-1-carboxylate (455 mg) [see Preparation 33] in dry tetrahydrofuran (10 ml). The reaction mixture was then stirred until the evolution of nitrogen gas had ceased, water (0.036 ml) was added, the mixture was then stirred for a further 72 hours. The solvent was then removed under reduced pressure and the residue was dissolved in diethyl ether and hexane added until the mixture became cloudy. The supernatant liquid was separated and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 90:10, by volume, dichloromethane:methanol to afford tert-butyl (2S,4R)-4-amino-2-[(benzyloxy)methyl]pyrrolidine-1-carboxylate (225 mg) as a colourless oil.