Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([CH2:21][OH:22])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])(C)(C)C.N1C=CC=CC=1.C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>ClCCCl.C(Cl)Cl>[O:7]=[C:6]1[NH:8][C@@H:9]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:21][O:22]1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C(C[C@H]1COC(=O)N1)OCc1ccccc1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a solution of (S)-benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate (16.3 g, 52.7 mmol) and pyridine (10.65 ml, 132 mmol) in DCE (157 mL) at 0° C. was added p-toluenesulfonic anhydride (17.10 g, 52.4 mmol) in two portions over 5 min. The mixture was stirred for a few minutes, then allowed to warm to room temperature and stirred for 1 hr. The mixture was heated for 6 hr at 92° C. and then allowed to cool to room temperature. The mixture was diluted with DCM (80 mL), washed with 1N aqueous HCl solution (2×200 mL), brine (200 mL), and saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 220 g, EtOAc/heptane=5/95 to 75/25] to provide (S)-benzyl 2-(2-oxooxazolidin-4-yl)acetate (10.0 g) as a white solid. MS m/z 236.2 (M+H)+; Rt-0.59 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])=[CH:4][CH:3]=1.CO[CH:16](OC)[CH2:17][NH:18][C:19](=[O:21])[CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]2[CH2:12][O:13][CH:16]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: OCC(CO)Cc1ccc(Cl)cc1
Reactant: COC(CNC(C)=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOCC
Product: CC(=O)NCC1OCC(Cc2ccc(Cl)cc2)CO1
Temperature: 75 °C
Yield: 30 %

Procedure:
4 g (20 mmol) of 2-[(4-chlorophenyl)methyl]propane-1,3-diol, 2.94 g (20 mmol) of N-(2,2-dimethoxyethyl)acetamide, 0.3 g of paratoluenesulphonic acid and 4 ml of diethyl ether saturated with hydrogen chloride are added to 150 ml of diethyl ether. The mixture is evaporated in vacuo, then 150 ml of benzene are added twice to the residue, it is heated to 70-80° C. under a slight vacuum and the solvent is evaporated. The residue is cooled, 150 ml of dichloromethane are added, and the solution is washed with a saturated solution of sodium hydrogen carbonate then with water and dried over magnesium sulphate. The residue is purified twice by chromatography on a silica gel column eluted with chloroform, and it is finally recrystallised in a 70:4 mixture of cyclohexane/ethyl acetate. 1.7 g (6 mmol) of product are obtained.
Reaction SMILES: [CH2:1]([C@H:8]([NH:37][C:38](=[O:48])[O:39][C@@H:40]1[C@H:47]2[C@H:43]([O:44][CH2:45][CH2:46]2)[O:42][CH2:41]1)[C@H:9]([OH:36])[CH2:10][N:11]([O:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[S:12]([C:15]1[CH:20]=[CH:19][C:18](OCCN2CCOCC2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49]([O:52][CH2:53][CH3:54])(=O)[CH3:50]>>[CH2:1]([C@H:8]([NH:37][C:38](=[O:48])[O:39][C@@H:40]1[C@H:47]2[C@H:43]([O:44][CH2:45][CH2:46]2)[O:42][CH2:41]1)[C@H:9]([OH:36])[CH2:10][N:11]([O:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35]1)[S:12]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([O:36][CH2:9][CH2:8][N:37]2[CH2:54][CH2:53][O:52][CH2:49][CH2:50]2)[CH:20]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCC1)S(=O)(=O)c1ccc(OCCN2CCOCC2)cc1)O[C@H]1CO[C@H]2OCC[C@H]21
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCC1)S(=O)(=O)c1cccc(OCCN2CCOCC2)c1)O[C@H]1CO[C@H]2OCC[C@H]21

Procedure:
This compound was prepared from Example 44 under the same conditions used for the preparation of Example 98 (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-1-benzyl-3-((cyclopentyloxy)[4-(2-morpholinoethoxy)phenyl]sulfonylamino)-2-hydroxypropyl]carbamate. Rf=0.15 (ethyl acetate); H1-NMR (CDCl3): δ 7.44-7.14 (10H,m), 5.62 (1H,s), 5.00 (1H,m), 4.79 (2H,m), 4.16 (2H,m), 3.98-3.60 (10H,m), 3.12 (1H,bs), 3.02-2.71 (8H,m), 2.58 (4H,m), 1.90-1.72 (4H,m), 1.72-1.42 (4H, m); MS (ESI): M+H=690.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].ClCCl.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32](Cl)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(N(CC)CC)C>[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32]([N:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(OCc1ccccc1)[C@@H]1CC2=C(CCCC2)N1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C2=C(CCCC2)C[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Introduce 200 g of benzyl (2S)-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate and 1.5 liters of dichloromethane into a reactor, then bring the temperature of the reaction mixture to 0° C. and add 107 ml of triethylamine and then 162 g of (2S)-2-[(tert-butoxycarbonyl)amino]propionyl chloride. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water and then with a dilute acetic acid solution. The benzyl (2S)-1-{(2S)-2-[(tert-butoxycarbonyl)amino]propionyl}-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate solution so obtained is used as it is in the following Step.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[O-]CC.[Na+].Cl>C(O)C>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]([C:4]([OH:3])=[O:5])=[C:10](/[CH:11]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:9][N:8]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)noc1C
Reactant: O=Cc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1c(-c2ccc(Cl)cc2)noc1/C=C/c1ccccc1
Yield: 52.8 %

Procedure:
To a stirred solution of 3-(4-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (9.6 g, 36.1 mmol) and benzaldehyde (3.69 mL, 36.1 mmol) in ethanol (54 mL) was added sodium ethoxide (2.71 M, 14.6 mL, 39.7 mmol) and the reaction was heated under reflux for 10 min. Hydrochloric acid (1 N, 43.4 mL) was added and the resulting mixture was then triturated with dichloromethane and filtered to afford the title compound (6.21 g, 53%) as a light yellow solid. MS: m/e=324.1 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][N:11]([CH3:13])[CH3:12].CC(C)=O.[C:18](=[S:20])=[S:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[S:19])[S-:20])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][NH+:11]([CH3:13])[CH3:12]
Reactant: Cc1cc(Cl)ccc1N
Reactant: S=C=S
Reactant: CN(C)C
Solvent: CC(C)=O
Product: C[NH+](C)C
Product: Cc1cc(Cl)ccc1NC(=S)[S-]
Yield: 95.9 %

Procedure:
To a stirred solution of 56.6 g. (0.40 mole) of 4-chloro-2-methylaniline, 103.2 g. (0.48 mole) of 27.5% aqueous trimethylamine and 28 ml. of acetone at 25°C. is added dropwise 34.4 g. (0.44 mole) of carbon disulfide. The reaction mixture is stirred for 1 hour upon completion of the addition of the carbon disulfide and then filtered. The resulting solid is washed with 75 ml. of ethyl acetate and air dried to obtain 106 g. (95.9% yield) of trimethylammonium 4-chloro-2-methyphenyl dithiocarbamate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.ClC(Cl)(O[C:30](=[O:36])OC(Cl)(Cl)Cl)Cl.[CH2:38]([NH2:41])[CH2:39][CH3:40].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30]([NH:41][CH2:38][CH2:39][CH3:40])=[O:36])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCN
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (50 mg) was dissolved in chloroform (10 ml) and triethylamine (0.2 ml), and a solution of triphosgene (43 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, propylamine (18 μl) was added to the reaction solution, and the mixture was further stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 24 mg (yield 38%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:22])=[N:4][N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN(C=O)C>[Cl:22][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:21])[C:15]=1[CH2:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[N:3][N:4]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(N3CCN(C)CC3)c2c1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A solution of 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (1 g, 2.82 mmoles), prepared as described in example 45, in DMF (25 ml) was stirred under dry N2 at room temperature, and dropwise added with 1-methylpiperazine (0.848 g, 8.46 mmoles). The mixture was heated at 100° C. for 20 hours, then brought to small volume and partitioned between water and CH2Cl2. The organic phase was washed with water, anhydrified and concentrated to give a residue which was flash chromatographed (eluent: CH2Cl2/CH3OH/NH4OH 95:5:0.5). The resultant solid was crystallised from tert-butyl-methyl ether (35 ml) to give 0.4 g of the title compound (yield: 34%). m.p.: 160-162° C.
Reaction SMILES: B(F)(F)F.CCOCC.[CH:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])OCC.[CH3:20][C:21]([O:26][C:27](=[O:29])[CH3:28])([CH3:25])[C:22](=[O:24])[CH3:23].C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:18]([O:17][CH:10]([O:14][CH2:15][CH3:16])[CH2:23][C:22](=[O:24])[C:21]([O:26][C:27](=[O:29])[CH3:28])([CH3:25])[CH3:20])[CH3:19]
Reactant: CC(=O)OC(C)(C)C(C)=O
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(CC(=O)C(C)(C)OC(C)=O)OCC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Boron trifluoride etherate (17.03 g, 120.0 mmol) was added drop-wise over 15 min to a cooled (−40° C.) solution of triethyl orthoformate (14.82 g, 100.0 mmol) in dichloromethane (50 ml). Stirring was continued for 10 min then the solution was transferred to an ice-water bath and stirred at 0° C. for 20 min. The mixture was cooled to −78° C., and acetic acid 1,1-dimethyl-2-oxopropyl ester (7.21 g, 50.0 mmol) added followed by drop-wise addition of N,N-diisopropylethylamine (19.39 g, 150.0 mmol) over 15 min. Stirring was continued for 1 h then the solution was poured onto a vigorously stirred mixture of saturated sodium hydrogencarbonate solution (500 ml) and dichloromethane (200 ml). The organic phase was separated, washed with ice-cold 1N sulfuric acid solution (2×500 ml) and ice-cold water (2×500 ml), dried over anhydrous sodium sulfate solution and evaporated to give acetic acid 4,4-diethoxy-1,1-dimethyl-2-oxobutyl ester (12.32 g, 100%) as a yellow oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:12]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=[CH:9][N:8]=1.C(N(CC)CC)C.S([Cl:32])(C)(=O)=O>ClCCl.[Cl-].[Na+].O>[Cl:32][CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:12]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)Cc1cccnc1Oc1cccc(CO)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)Cc1cccnc1Oc1cccc(CCl)c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 2-(3-hydroxymethylphenoxy)-3-pyridinylacetate (0.6 g) and triethylamine (0.45 ml) in dichloromethane (2 ml) was added dropwise over 20 minutes to a stirred solution of mesyl chloride (0.26 ml) in dichloromethane (6 ml) at ca. 5° C. The mixture was stirred at 5° C. for 30 minutes, warmed to room temperature and then allowed to stand over the weekend. GC analysis of an aliquot indicated complete reaction. The reaction mixture was stirred with brine for 30 minutes and then the organic layer was dried, filtered and evaporated to give methyl 2-(3-chloromethylphenoxy)-3-pyridinylacetate as a pale yellow oil (0.55 g) which was used directly.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1.O1CCC[CH2:49]1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:13][CH2:14][C:15]([C:20]([N:43]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:49]3)=[O:21])([CH2:18][CH2:19]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: C1CCOC1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)N3CCCCC3)(CC1)CC2
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
(2S,4S)-1-[[N-Benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (20.0 mg) and pyrrolidine (4.4 μL) were dissolved in tetrahydrofuran (0.4 mL) and the mixture was stirred at room temperature for 25 minutes. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. The organic layer washed sequentially with 0.1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine. The organic layer was then dried over anhydrous sodium sulfate and was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluant:ethyl acetate:methanol=20:1) to give (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(piperidin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (16.0 mg).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([O:29][CH3:30])[CH:22]=1.[OH-].[Na+]>C(Cl)Cl.O>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([OH:20])[CH:28]=[CH:27][C:24]=1[CH2:25][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: COc1cc(O)ccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(O)ccc1CN1CCCC1

Procedure:
NaB(OAc)3H (8.7 g, 0.041 mol) was added in portions for 30 min to a mixture of pyrrolidine (3.4 mL, 0.0.41 mol) and 4-hydroxy-2-methoxybenzaldehyde (5 g, 0.033 mol) in CH2Cl2 (50 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 2 h and cooled. Then 10 N NaOH (4.1 mL) and water (30 mL) were added. The organic layer was separated, the aqueous one was extracted with chloroform (2×50 mL). The organic fractions were evaporated. The residue was distributed between water and CH2Cl2. Concentrated HCl (2.98 mL) was added. The organic layer was separated and discarded. The aqueous one was alkalized with 10 N NaOH to pH 6 and extracted with chloroform (2×50 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (3.37 g, 07%) as yellow crystals. 1H-NMR (400 MHz)-data (dmso-d6, j, Hz): 9.25 (s, 1H ArOH), 7.02 (d, 1H, J=8.3, Ar—H), 6.36 (d, 1H, J=2.2, Ar—H) 6.30 (dd, 1H, J1=8.3, J2=2.2, Ar—H), 3.70 (s, 3H, ArOCH3), 3.44 (s, 2H, ArCH2), 2.38-2.44 (m, 4H, pyrrolidine (CH2)2N), 1.62-1.68 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: [C:1]1([C:7]2[CH:25]=[C:24]3[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]4[S:23][CH2:22][C:16]5([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]5)[O:15][C:14]=43)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([N:19]1[CH2:20][CH2:21][C:16]2([O:15][C:14]3[C:24]4[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]=3[S:23][CH2:22]2)=[CH:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:25]=4)[CH2:17][CH2:18]1)=[O:33]
Reactant: O=C1C(=O)c2ccc(-c3ccccc3)cc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: O=C1C(=O)c2ccc(-c3ccccc3)cc2C2=C1SCC1(CCN(C(=O)c3cccc(Cl)c3)CC1)O2

Procedure:
Compound 64 was synthesized using 9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. Mp.: 240-241° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.01 (d, J=1.6 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.87 (dd, J=1.6, 7.6 Hz, 1H), 7.83-7.76 (m, 2H), 7.60-7.46 (m, 6H), 7.41 (dt, J=1.6, 7.6 Hz, 1H), 4.32 (br, 1H), 3.49 (br, 2H), 3.14 (s, 2H), 3.35-3.28 (m, 1H), 2.15 (br, 1H), 2.03 (br, 1H), 1.90 (br, 2H); LCMS: 516 [M+H].
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:22](OC=C)(=[O:24])[CH3:23]>COC(C)(C)C>[C:22]([O:14][C@@H:11]1[CH2:12][CH2:13][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10]1)(=[O:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](O)C1
Reactant: C=COC(C)=O
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CC(=O)O[C@@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)C1
Yield: 49 %

Procedure:
Combine (+/-)-cis-3-tert-butyldimethylsilyloxycyclopentanol (2.119 g, 9.8 mmol, prepared in example 29), pancreatin (6.2 g, 3 weight equivalents), triethylamine (0.9 mL, 6.5 mmol) and vinyl acetate (4.3 mL) in tert-butyl methyl ether (12 mL) and stir for 27 hours at room temperature. Then filter the reaction through diatomaceous earth and concentrate the filtrate under vacuum (room temperature/15 mmHg). Purify the residue by column chromatography [silica gel, 55 g, hexane (300 mL) followed by 5% ethyl acetate/hexane (500 mL)] to provide the (1R,3S)-(+)-3-tert-butyldimethylsilyloxycyclopentanyl acetate (1.23 g, 49% yield, 98% ee as determined from gas chromatography with a chiral column) and (1S,3R)-(-)-3-tert-butyldimethylsilyloxycyclopentanol (771 mg, 37% yield, 92% ee as determined from its acetate derivative followed by GC chiral column analysis, see example 30a).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([SH:16])[CH:13]=[CH:14][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[CH2:43][CH:44]=[O:45]>O.O1CCCC1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([S:16][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]2[CH2:43][CH:44]=[O:45])[CH:13]=[CH:14][CH:15]=1
Reactant: O=CCC1CCCCC1Br
Reactant: COc1cccc(S)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(SC2CCCCC2CC=O)c1
Reaction time: 1 h
Yield: 134.9 %

Procedure:
Triethylamine 481 ml is added to the mixture of 3-methoxythiophenol 322.5 g, triphenylphosphine 241.3 g, water 204 ml and tetrahydrofuran 2.3 liter under nitrogen atmosphere while cooling with ice under stirring, and then 2-bromocyclohexylacetaldehyde 518.9 g is dropwise added. Stirring is carried out at a room temperature for one hour, and then stirring is further continued at 60° C. for 2.5 hours. Water 200 ml is added, and the mixture is shaken. The organic layer is separated and washed twice with 10% hydrochloric acid 500 ml and twice with saturated brine 400 ml, and then it is dried on magnesium sulfate anhydrous. The solvent is distilled off under reduced pressure, and the residue is dissolved in hexane 2 liter and stirred at a room temperature for 13 hours. After cooling with ice, deposited crystals are filtered off, and the solvent is distilled off under reduced pressure, whereby yellow oily 2-(3-methoxyphenylthio)cyclohexylacetaldehyde 820.3 g is obtained.
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([O:12]C(C)=C)(=O)[CH3:10].CC(C)(O)[C:18]#[N:19]>C1(C)C=CC=CC=1>[C:9]([O:8][NH:7][C:1]1([C:18]#[N:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:12])[CH3:10]
Reactant: C=C(C)OC(C)=O
Reactant: ON=C1CCCCC1
Reactant: CC(C)(O)C#N
Solvent: Cc1ccccc1
Product: CC(=O)ONC1(C#N)CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
A mixture of 0.115 g (1 mmole) of cyclohexanone oxime, 0.1 g (1 mmole) of isopropenyl acetate, 0.085 g (1 mmole) of acetone cyanohydrin, 0.045 g (0.1 mmole) of di(η5 -pentamethylcyclopentadienyl)samarium [Cp*2Sm(THF)2 ], and 1 ml of toluene was stirred at 25° C. for 3 hours. 1-acetyloxyamino-1-cyanocyclohexane was formed in the reaction mixture in a 60% yield, and the conversion of cyclohexanone oxime was 72%.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[C:4]([N:6]1[CH:11]=[CH:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5].C(N(CC)CC)C.C(O)=O>CN(C=O)C>[Cl:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:2]2[C:3]=1[C:4](=[O:5])[N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH:7]12
Reactant: O=C1C=CN(C(=O)c2c(Cl)cccc2Br)CC1
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CN(C)C=O
Product: O=C1CCN2C(=O)c3c(Cl)cccc3C2C1
Temperature: 80 °C
Yield: 31.1 %

Procedure:
A mixture of 1-(2-bromo-6-chlorobenzoyl)-2,3-dihydro-4-pyridinone (Preparation 3) (300 mg, 0.954 mmol), triethylamine (0.39 mmol, 0.54 ml), formic acid (0.05 ml, 1.3 mmol) and di(triphenylphosphine)diacetoxypalladium (47 mg, 0.063 mmol) in DMF (3 ml) was heated to 80° C. for 2 h. The cooled solution was filtered through celite, diluted with water, extracted twice with ethyl acetate, the extracts dried over sodium sulphate and evaporated. The residue was purified by flash column chromatography on silica eluting with 50% ethyl acetate in hexane to yield the title compound as a colourless oil (70 mg). MS (+CI) m /z 235/237 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(N)CN.O>COCC(O)C>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH2:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Solvent: COCC(C)O
Solvent: NCCN
Solvent: O
Product: COC1=CC[C@H]2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 110 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Thebaine (4.0 g dry basis, 12.9 mmol) is placed in a mixture of 1-methoxy-2-propanol (13.0 g) and ethylenediamine (1.3 g, 21.6 mmol, 1.68 equiv) and is heated to 110° C. p-Toluenesulfonylhydrazide (4.8 g, 25.8 mmol, 2.0 equiv) is dissolved at room temperature in a mixture of ethylenediamine (9.6 g, 159.7 mol, 12.4 equiv) and 1-methoxy-2-propanol (0.8 g) and the solution is added in portions to the thebaine mixture over 1 hour 20 minutes at such a rate that the batch temperature is maintained at ˜110° C. The reaction mixture is held at this temperature for 1 hour then cooled to room temperature and then water (24 g) is added while maintaining the batch temperature at ≦30° C. The resulting slurry (pH 11.4) is filtered and the product is washed with water (3×8 g) and dried at 40° C. to a constant weight to give 8,14-dihydrothebaine (3.68 g, 91.3% yield; 99.1 area % purity by HPLC).