Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[OH:8][C@@:9]1([CH3:31])[C@@:26]2([CH3:27])[C@@H:13]([CH2:14][CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[C@@H](O)C[C:20]2=[O:28])[CH2:12][C:11](=[O:30])[CH2:10]1>N1C=CC=CC=1.C(OCC)(=O)C>[C:5]([O:4][C@@H:1]1[C@H:17]2[C@H:16]3[C@H:25]([CH2:24][CH2:23][C@:21]2([CH3:22])[C:20](=[O:28])[CH2:2]1)[C@:26]1([CH3:27])[C@H:13]([CH2:12][C:11](=[O:30])[CH2:10][C@:9]1([OH:8])[CH3:31])[CH2:14][CH2:15]3)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12[C@@H](CC[C@H]3[C@@H]4[C@@H](O)CC(=O)[C@@]4(C)CC[C@@H]31)CC(=O)C[C@@]2(C)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1CC(=O)[C@@]2(C)CC[C@H]3[C@@H](CC[C@H]4CC(=O)C[C@@](C)(O)[C@@]43C)[C@H]12
Temperature: 0 °C

Procedure:
20 ml of acetic anhydride is instilled at room temperature in 10.0 g of 1β,15α-dihydroxy-1α-methyl-5α-androstane-3,17-dione in 40 ml of pyridine. The reaction mixture is stirred into ice/water after 2.5 hours. The precipitated product is suctioned off, dissolved in ethyl acetate and washed neutral with water. The crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient. 8.6 g of 15α-acetoxy-1β-hydroxy-1α-methyl-5α-androstane-3,17-dione is obtained. Melting point 170.0° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:14]3=[N:16][N:17]([CH2:19][CH2:20]OS(C)(=O)=O)[CH:18]=[C:13]3[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:14]3=[N:16][N:17]([CH2:19][CH2:20][N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])[CH:18]=[C:13]3[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c1-c1nn(CCOS(C)(=O)=O)cc1CCC2
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1c[nH]c2c1-c1nn(CCN(CC)CC)cc1CCC2
Temperature: 83 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 2-(2-methanesulfonyloxy-ethyl)-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylic acid ethyl ester (158 mg, 0.43 mmol) in CH3CN is added excess diethylamine (>3 eq) and excess K2CO3. The reaction mixture is stirred overnight at 83° C. in a sealed tube. The reaction mixture is then extracted with CH2Cl2 and washed with water. The aqueous wash is then extracted twice more with CH2Cl2. The combined extracts are dried over K2CO3 and concentrated. The crude material is purified by flash chromatography on silica gel, affording 107 mg (72%) of 2-(2-diethylamino-ethyl)-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta [e]azulene-9-carboxylic acid ethyl ester. Electrospray mass spectrum: m/z 343 [M−1]; 1H NMR (CDCl3, 300 MHz) δ8.78 (br, 1H), 7.17 (d, J=2.7 Hz, 1H), 7.15 (s, 1H), 4.27 (q, J=7.2 Hz, 2H), 4.12 (t, J=7.2 Hz, 2H), 2.91 (m, 2H), 2.81 (m, 2H), 2.65 (m, 2H), 2.59 (q, J=7.2 Hz, 4H), 1.94 (m, 2H), 1.31 (t, J=7.2 Hz, 3H), 1.02 (t, J=7.2 Hz, 6H)
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].Cl.[NH2:17][C@H:18]([C:20]([O:22][CH3:23])=[O:21])[CH3:19].C(N(CC)CC)C.C(OC(Cl)=O)C>C1COCC1>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:17][C@H:18]([C:20]([O:22][CH3:23])=[O:21])[CH3:19])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: -15 °C
Reaction time: 16 h

Procedure:
The condensation of BOC-Val-OH with HCl. Ala-OMe was carried out by a mixed anhydride method. 12 g (0.055 mol) of BOC-Val-OH was dissolved in 40 ml of dry THF and 5.6 g (0.055 mol) of triethylamine and 6.6 g (0.06 mol) of chloroformic acid ethyl ester was added to the solution after cooling to -15° C. After 10 minutes at low temperature 7.7 g (0.055 mol) of HCl.Ala-OMe and 5.6 g (0.055 mol) of triethylamine were slowly added to the mixture at -15° C. The reaction mixture was stirred for a further 16 hours at room temperature. The THF was evaporated and the product extracted with ethyl acetate. Recrystalization from ether gave 8.1 g of analytically pure BOC-Val-Ala-OMe, m.p. 138°-148° C.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[C:10]1([CH:16]2[CH2:21][CH2:20][CH:19]([C:22]3[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[C:10]1([CH:16]2[CH2:17][CH2:18][CH:19]([C:22]3[C:23]4=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]4[CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1C1CCC(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(C3CCC(c4ccccc4)CC3)C2=N1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 29.2 mg) in THF (dry) (2 mL) was added 2-chloroethanesulfonyl chloride (0.046 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-phenylcyclohexyl)pyridin-2-amine (36.8 mg) in THF (dry) (2 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. carefully and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) and crystallized from EtOAc-hexane to give the title compound (15.7 mg) as an off-white crystals.
Reaction SMILES: [NH:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)[C:4](=[O:26])[NH:3]1.[CH:27]1(N)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CC(N(C)C)=O>[CH:27]1([NH:1][C:2]2[C:6]3([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:10][CH2:11]3)[N:5]([C:19]3[CH:20]=[CH:21][C:22]([I:25])=[CH:23][CH:24]=3)[C:4](=[O:26])[N:3]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=N)NC(=O)N2c1ccc(I)cc1
Reactant: NC1CCCCC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(NC1CCCCC1)=NC(=O)N2c1ccc(I)cc1
Temperature: 25 °C

Procedure:
A solution of tert-butyl 4-imino-1-(4-iodophenyl)-2-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (10 g, 21.3 mmol) in cyclohexylamine (97 mL, 852 mmol) and DMA (100 mL) was stirred at 140° C. for 3 days, sealed, under argon. The reaction mixture was cooled to rt, poured onto ice/water (1000 mL), filtered to afford the desired product as a white solid, after washing with water and drying. LRMS (M+1)=553.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[C:3]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23].CC([O-])(C)C.[K+].[CH3:32][N:33]([CH3:36])[CH:34]=O.S(OC)(OC)(=O)=O.CCOCC>COCCOC>[CH3:1][C:2]1[C:3]([C:21](=[CH:32][N:33]([CH3:36])[CH3:34])[C:22]([O:24][CH3:25])=[O:23])=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[N:5]=[CH:6][N:7]=1
Reactant: CN(C)C=O
Reactant: COC(=O)Cc1c(C)ncnc1Oc1cccc(-c2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOC
Solvent: COS(=O)(=O)OC
Product: COC(=O)C(=CN(C)C)c1c(C)ncnc1Oc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
Methyl [6-methyl-4-(3-phenylphenoxy)-5-pyrimidinyl]-acetate (60 g, 0.18 mol) is added in one portion to a solution of t-BuOK (60 g, 0.53 mol) in 1,2-dimethoxyethane (0.51) at -40° C. After 1 hour dimethylformamide-dimethyl sulfate (1:1 adduct, 120 ml) is added at -50° C. The reaction mixture is allowed to warm to room temperature to give a yellow suspension. Addition of ether, washing repeatedly with brine and drying gives the crude methyl α-[4-methyl-6-(3-phenylphenoxy)-5-pyrimidinyl]-β-dimethylaminoacrylate (67 g, 95%) as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[C:16]2[C:15](=[O:17])[N:14]([C:18]3[CH:19]=[C:20]([C:24]4[O:28][C:27](=[O:29])[N:26]([CH3:30])[N:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:6]=[C:5](SC)[N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+].[CH2:50]([NH2:52])[CH3:51].C1COCC1>ClCCl.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:33])[C:3]1[C:16]2[C:15](=[O:17])[N:14]([C:18]3[CH:19]=[C:20]([C:24]4[O:28][C:27](=[O:29])[N:26]([CH3:30])[N:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:6]=[C:5]([NH:52][CH2:50][CH3:51])[N:4]=1
Reactant: CCN
Reactant: CSc1nc(N(C)C)c2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(C)c(=O)o3)c1)C2=O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCNc1nc(N(C)C)c2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(C)c(=O)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71 %

Procedure:
(S)-5-[3-(7-Dimethylamino-9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-methyl-1,3,4-oxadiazol-2(3H)-one (26.8 mg, 0.0573 mmol) obtained in Step 1 was dissolved in dichloromethane (5.0 mL), and the mixture was stirred at room temperature for 20 minutes after adding 3-chloroperbenzoic acid (22.8 mg, 0.0860 mmol). A saturated aqueous sodium bicarbonate solution and chloroform were added to the mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in THF (2.0 mL), and the mixture was stirred at 90° C. for 30 minutes under microwave (CEM; Discover; 250 watts) irradiation after adding a 2.0 mol/L ethylamine/THF solution (1.0 mL, 2.00 mmol). The mixture was further stirred at 90° C. for 135 minutes under microwave (CEM; Discover; 250 watts) irradiation after adding a 2.0 mol/L ethylamine/THF solution (1.0 mL, 2.00 mmol). The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (Compound 159) (18.9 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:5][CH:4]([C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[O:7])[CH2:3]1.Cl.[NH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].O.N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1>[CH3:17][C:2]1([CH3:1])[CH2:3][CH:4]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:14])=[CH:15][CH:16]=2)=[O:7])[CH2:5]1
Reactant: CC1(C)CC(C(=O)c2ccc(C(=O)O)cc2)C1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(C(=O)C2CC(C)(C)C2)cc1
Reaction time: 16 h
Yield: 63.6 %

Procedure:
Tetrahydrofuran (138 mL) was added to a vial containing 4-(3,3-dimethylcyclobutanecarbonyl)benzoic acid (3.20 g, 14.0 mmol), ethyl 3-aminopropanoate hydrochloride (3.17 g, 20.7 mmol) and 1,2,3-benzotriazol-1-ol monohydrate (2.22 g, 14.5 mmol). Triethylamine (9.11 mL, 4.75 mmol) was then added. The reaction was stirred for 16 h, and was then concentrated. Purification by column chromatography (0-35% ethyl acetate in heptane) afforded impure ethyl 3-(4-(3,3-dimethylcyclobutanecarbonyl)benzamido)propanoate (4.22 g, approximately 8.90 mmol pure) as an oil. MS (M+1) 332.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.O(S(C)(=O)=O)S(C)(=O)=O.[CH3:49][C:50]1[C:54]2[CH:55]=[C:56]([NH2:60])[CH:57]=[C:58]([CH3:59])[C:53]=2[O:52][N:51]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:60][C:56]2[CH:57]=[C:58]([CH3:59])[C:53]3[O:52][N:51]=[C:50]([CH3:49])[C:54]=3[CH:55]=2)[C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: Cc1noc2c(C)cc(N)cc12
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(Nc1cc(C)c2onc(C)c2c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a stirred solution of ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylate (Step 46.11) (500 mg, 1.085 mmol) and triethylamine (0.756 mL, 5.42 mmol) in CH2Cl2 (10 mL) cooled down to 0° C. was added Ms2O (378 mg, 2.170 mmol) and the reaction was stirred for 1 hr at this temperature. 3,7-dimethylbenzo[d]isoxazol-5-amine (Step 46.6) (194 mg, 1.193 mmol) was added and the reaction mixture was allowed to warm up to RT and stir for 1 hr. The reaction was quenched with aq. NaH2PO4 solution and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/EtOAc 10-100%) to afford the title product (460 mg, 0.684 mmol, 63% yield) as yellow amorphous solid. tR: 1.38 min (LC-MS 2); ESI-MS: 605 [M+H]+ (LC-MS 2); Rf=0.25 (hexane/EtOAc 1:1).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:37]3[CH:38]=[C:33]([CH3:32])[CH:34]=[CH:35][CH:36]=3)[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cccc(-n2c(C(=O)N3CCS(=O)(=O)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)c1
Yield: 56 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 3-methylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (56%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[Cl:20])=[C:4](C(O)=O)[NH:5][C:6]=1C(O)=O.N1C2C(=CC=CC=2)C=CC=1.Cl>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[Cl:20])=[CH:4][NH:5][CH:6]=1
Reactant: O=C(O)c1[nH]c(C(=O)O)c(-c2cccc(Cl)c2Cl)c1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: Clc1c[nH]cc1-c1cccc(Cl)c1Cl
Yield: 84.8 %

Procedure:
The mixture of 53 g of 4-chloro-3-(2,3-dichlorophenyl)pyrol-2,5-dicarboxylic acid, 2.65 g of cupric acid and 80 ml of quinoline was heated at 140°-150° C. for 30 minutes with stirring. To the resulting reaction mixture were added ethyl acetate, ice and concentrated hydrochloric acid which of molar amount was 1.1-time that of employed quinoline. The ethyl acetate layer was washed with successive, water, aqueous sodium carbonate and water. After dehydration, the ethyl acetate layer was evaporated to dryness under reduced pressure to obtain 33.1 g of brown product. The crude product was purified by silicagel chromatography and countercurrent distribution to obtain pale yellow oily substance. The oily substance was recrystallized from n-hexane to obtain 22.5 g of the desired product (colorless or pale yellow needles, m.p. 58°-59° C.).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: Ic1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 Grams of p-iodophenol, 8 ml of dihydropyrane and a catalytic amount of p-toluenesulfonic acid was dissolved in 30 ml of anhydrous diethyl ether, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water, dried then the solvent was removed by evaporation to yield 12.4 g of 4-(2-tetrahydropyranyloxy)-1-iodobenzene in the form of yellow oily substance. Boiling point: 84°-87° C. (at 25 mm Hg).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9]([OH:11])=[O:10])[S:7][CH:8]=[C:4]2[CH2:3]1.[CH2:15](I)[CH3:16].O.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C([Li])(C)(C)C>[CH2:15]([C:8]1[S:7][C:6]([C:9]([OH:11])=[O:10])=[C:5]2[CH2:12][CH2:13][C:2]([CH3:14])([CH3:1])[CH2:3][C:4]=12)[CH3:16]
Reactant: CCI
Reactant: CC1(C)CCc2c(csc2C(=O)O)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCc1sc(C(=O)O)c2c1CC(C)(C)CC2
Temperature: -78 °C
Reaction time: 3 h
Yield: 58.8 %

Procedure:
To a cooled solution (−78° C.) of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (960 mg, 4.57 mmol) in THF (19 mL), tert-butyllithium (8 mL, 1.5 M solution in pentane) is added. The mixture is stirred at −78° C. for 10 min before ethyliodide (3.80 g, 24.37 mmol) is added. The reaction mixture is stirred at −78° C. for 3 h. Water/methanol 1:1 (8 mL) followed by 10% aq. citric acid solution is added and the mixture is extracted with EA. The combined organic extracts are washed with brine, dried over Na2SO4 and evaporated. The remaining solid is suspended in acetonitrile (6 mL), heated to 60° C., cooled to rt, filtered and dried to give 3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (640 mg) as a slightly beige solid; LC-MS: tR=1.01 min, [M+1+CH3CN]=280.10.
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=[O:5])[CH3:4].[C:9]([C:12]1[C:13]([CH3:24])=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:15][C:16]=1[S:17][CH3:18])(=[O:11])[CH3:10].Cl>O1CCCC1.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.C(O)C>[CH3:24][C:13]1[C:12]([C:9](=[O:11])[CH2:10][C:3](=[O:5])[CH3:4])=[C:16]([S:17][CH3:18])[S:15][C:14]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1sc(SC)c(C(C)=O)c1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1sc(SC)c(C(=O)CC(C)=O)c1C
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a suspension containing 60% sodium hydride (0.64 g, 15.9 mmol) and ethyl acetate (8.16 g, 92.9 mmol) in tetrahydrofuran (5 ml) were added in turn at room temperature a solution containing ethyl 4-acetyl-3-methyl-5-(methylthio)thiophene-2-carboxylate (2.0 g, 7.7 mmol) and ethanol (0.5 ml) in tetrahydrofuran (10 ml) and a solution containing dibenzo-18-crown-6 ether (0.04 mg) in tetrahydrofuran (5 ml), and the mixture was heated under reflux for 2 hours. The reaction solution was allowed to cool down to room temperature, made acidic by addition of 3N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed (with water and saturated aqueous sodium chloride, in turn), dried (over anhydrous magnesium sulfate) and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=20:1) to afford ethyl 3-methyl-5-methylthio-4-(3-oxobutyryl)thiophene-2-carboxylate (1.91 g, 82%) as yellow -crystals.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Si:13]([N:20]1[CH:23]([S:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][C:21]1=[O:44])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[CH:45]([C:47]1[CH:48]=[N:49][N:50]([CH3:52])[CH:51]=1)=[O:46].[Cl-].[NH4+].N1CCC1=O.C(NCC)C>C1COCC1.C(Cl)(Cl)Cl>[Si:13]([N:20]1[CH:23]([S:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:22]([CH:45]([OH:46])[C:47]2[CH:48]=[N:49][N:50]([CH3:52])[CH:51]=2)[C:21]1=[O:44])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Cn1cc(C=O)cn1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C1CCN1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCNCC
Solvent: ClC(Cl)Cl
Product: Cn1cc(C(O)C2C(=O)N([Si](C)(C)C(C)(C)C)C2SC(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyl lithium (1.06M. in hexane, 1.13 ml) was added to a solution of diisopropylamine (0.17 ml) in dry THF (8 ml) at -30° C. under dry argon. After stirring at -30° C. for 10 minutes the mixture was cooled to -76° C. and treated with a solution of 1-t-butyldimethylsilyl-4-tritylthioazetidin-2-one (1) (459 mg) in dr THF (4 ml). After a further 15 minutes at -76° C. the stirred mixture was treated with a solution of 4-formyl-1-methylpyrazole (132 mg) (I. L. Finar and G. H. Lord, J. Chem. Soc. 1957, 3314) in dry THF (1 ml). After 20 minutes at -76° C. the stirred mixture was treated with saturated ammonium chloride solution (5 ml) and worked up as for Preparation 1(a) to give two fractions. The less polar fraction contained a trans-isomer (Isomer A) of the title azetidinone (12) (165 mg), an amorphous solid, νmax (CHCl3) 3600-3100, 1735 cm-1 ; δppm (CDCl3) 0.92 (9H, s), 1.1-1.8 (1H, br. signal, exch. D2O), 3.32 (1H, dd, J2 and 2 Hz), 3.50 (1H, d, J2 Hz), 3.76 (3H, s), 4.46 (1H, d, J2 Hz), 7.10-7.60 (17H, m), the Me2Si signals were obscured by the TMS signal. [Found (diethylamine chemical ionisation): MH+, 570 and M+Et2NH]+, 643]. The more polar fraction contained the other trans-isomer (Isomer B) of the title azetidinone (12) (185 mg), an amorphous solid, νmax (CHCl3) 3600-3100, 1735 cm-1 ; δppm (CDCl3) 0.80 (9H, s), 1.7-2.5 (1H, br. signal, exch. D2O), 3.59 (1H, dd, J6 and 2 Hz), 3.70 (3H, s), 3.87 (2H, 2d, J2 Hz and J6 Hz), 6.91 (1H, s), 7.10-7.50 (16H, m), the Me2Si signals were obscured by the TMS signal. [Found (diethylamine chemical ionisation): MH+, 570].
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15](OCC)=[O:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B([O-])([O-])[O-].[Li+].[Li+].[Li+].B(OC)(OC)OC.O>C1COCC1>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(C(=O)c2ccccc2)CC1
Agent: COB(OC)OC
Agent: [Li+]
Agent: [O-]B([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 88.9 %

Procedure:
10.4 g (0.04 mol) of ethyl 1-benzoyl-4-piperidine-carboxylate were dissolved in 90 ml of THF and treated with a solution of 0.871 g (0.04 mol) of lithium borate in 20 ml of THF. 0.45 ml (0.004 mol) of trimethyl borate was added and the mixture was stirred at room temperature for 60 hrs. The reaction mixture was treated with water and stirred for 1.5 hrs. The mixture was extracted with ethyl acetate and the organic phase was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue was chromatographed on silica gel with ethyl acetate/hexane (1:1). 7.8 g (90%) of 1-benzoyl-4-hydroxymethyl-piperidine were obtained as white crystals; m.p. 84°-87°.