Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]([F:33])([F:32])[C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1>CO.O>[F:33][C:5]([F:4])([F:32])[C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH2:19][CH2:20]3)[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
Lithium hydroxide monohydrate (0.373 g, 8.90 mmol) was added to ethyl 4-[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]benzoate (3.40 g, 8.09 mmol) in a mixture of MeOH (60 mL) and water (30 mL). The resulting suspension was stirred at 50° C. for 16 hours. Further lithium hydroxide monohydrate (0.373 g, 8.90 mmol) was added, the temperature was increased to 65° C. and the suspension was stirred for a further 6 hours. The reaction mixture was cooled to room temperature and the MeOH evaporated. The residues were dissolved in water (200 mL) and filtered. The filtrate was acidified with 1M citric acid until precipitation ceased, and the precipitate was collected by filtration, washed with water and dried under vacuum to afford 4-[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]benzoic acid (3.17 g, 100%) as a solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[NH:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:29]=1.CO.[C:32]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:32][N:25]1[N:24]=[C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:29]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:18]=2)[O:27][C:26]1=[O:28]
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3n[nH]c(=O)o3)c1)C2=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(C)c(=O)o3)c1)C2=O
Temperature: 55 °C
Reaction time: 5 h

Procedure:
(S)-5-[3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3,4-oxadiazol-2(3H)-one (280 mg, 0.68 mmol) obtained in Step 1 was suspended in THF (5.0 mL), and the mixture was stirred at 55° C. for 5 hours after adding methanol (0.082 mL, 2.04 mmol), triphenylphosphine-supported resin (Triphenylphosphine, polymer-supported; 3.08 mmol P/G, 1.02 g, 3.06 mmol), and diethyl azodicarboxylate (40% toluene solution, 0.92 mL, 2.04 mmol). The resin was separated by filtration, and the filtrate was collected, and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)-3-methyl-5-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3,4-oxadiazol-2(3H)-one (305 mg, quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:14](Cl)(=[O:18])[CH:15]([CH3:17])[CH3:16].[OH-].[Na+]>C1C=CC=CC=1.O>[C:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)(=[O:18])[CH:15]([CH3:17])[CH3:16]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CC(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)Cc1ccc(NC(=O)C(C)C)cc1
Reaction time: 3 h
Yield: 88.4 %

Procedure:
10 g of ethyl 4-aminophenylacetate was dissolved in 100 ml of benzene and to this was added 25 ml of water. To the solution were added dropwise a solution of 6 g of isobutyryl chloride in 20 ml of benzene and a solution of 2.4 g of 93% NaOH in 25 ml of water simultaneously under stirring over 15 minutes. After completion of the dropwise addition, the reaction mixture was stirred for 3 hours and allowed to stand at room temperature overnight. After separating the benzene layer, washing it with 1N-HCl solution and further washing with a saturated solution of sodium chloride, the benzene layer was dried over anhydrous sodium sulfate. After separating sodium sulfate by filteration, the solvent was distilled off under reduced pressure and the residue was dissolved in 30 ml of benzene and crystallized from 90 ml of n-hexane. The formed crystals were separated by filteration and were dried at a temperature below 60° C. under reduced pressure to give 12.3 g of ethyl 4-(isobutyrylamino)phenylacetate (Yield: 88.3%). M.P. 92.5°-93.5° C.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C@H:7]([C:14]([OH:16])=[O:15])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][CH2:3][CH2:2]1.[C:17]([C@:25]([C:40]([OH:42])=[O:41])([OH:39])[C@:26]([C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([OH:30])[C:27]([OH:29])=[O:28])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO.O>[CH2:1]1[CH2:6][C@H:5]([C@H:7]([C:14]([OH:16])=[O:15])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:4][CH2:3][CH2:2]1.[C:31]([C:26]([C:27]([OH:29])=[O:28])([OH:30])[C:25]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([OH:39])[C:40]([OH:42])=[O:41])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Agent: O=C(O)[C@H](c1ccccc1)[C@H]1CCCCN1
Solvent: CO
Solvent: O
Product: O=C(O)C(O)(C(=O)c1ccccc1)C(O)(C(=O)O)C(=O)c1ccccc1

Procedure:
US 2011/0130569 discloses a process for the preparation of the d-threo-ritalinic acid. dl-threo-ritalinic acid treated with (+)-dibenzoyl-D-tartaric acid as resolving agent in large volume of solvents mixture of methanol/water to get d-threo-ritalinic acid-dibenzoyl tartaric acid salt. Thus obtained salt treated with 35% hydrochloric acid in mixture of toluene and water, concentrated under vacuum and isolated by treating with acetone. The volume of resolution solvent used herein is quite higher.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:24][C@H:25]([CH3:29])[C@H](O)C)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:23])(=[N:17]C(OCC)=O)=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:30]C[O-].[Na+].[Na+].[Cl-]>C(O)C>[Br:1][C:2]1[C:3]([O:24][CH2:25][CH3:29])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:23][CH3:30])(=[NH:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CC[O-]
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(Br)c(O[C@H](C)[C@@H](C)O)n2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(Nc2ccc(S(=N)(=O)CC)cc2)ncc1Br

Procedure:
28 mg (0.056 mmol) of (RS)—S-[4-({5-bromo-4-[(1R,2R)-2-hydroxy-1-methylpropoxy]pyrimidin-2-yl}amino)phenyl]-N-(ethoxycarbonyl)-S-methyl sulfoximide in 0.11 ml of ethanol is mixed with 0.32 ml (0.113 mmol) of a 0.35 molar solution of NaOEt in ethanol and stirred under reflux for 6 hours. The batch is stirred overnight at room temperature, and then added to a saturated NaCl solution. It is extracted with ethyl acetate, and the combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (DCM/EtOH 85:15). 9 mg (0.023 mmol, corresponding to 42% of theory) of the product is obtained.
Reaction SMILES: OO.[NH2:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)=[O:12]>C(O)(=O)C>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:12][N:3]=[C:4]3[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=23)=[CH:14][CH:15]=1
Reactant: Cc1cccc(C(=O)c2ccc(Br)cc2)c1N
Agent: OO
Solvent: CC(=O)O
Product: Cc1cccc2c(-c3ccc(Br)cc3)onc12
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A solution of 130 ml of 30% hydrogen peroxide in 350 ml of glacial acetic acid was heated on a steam bath for 1 hr. To the cooled solution was added a solution of 31.0 g (0.11 mole) of (2-amino-3-methylphenyl)(4-bromophenyl)methanone in 400 ml of glacial acetic acid. The reaction mixture was heated to 95° C. to dissolve all solids, then heated at 65°-70° C. for 4 hr and let stand at ambient temperature overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[S:5][C:6]=1[Cl:7].O.NN>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[S:5][C:6]=1[Cl:7]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)c(Cl)s1
Agent: NN
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: NCc1cc(Cl)c(Cl)s1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To a stirred suspension of 2-(4,5-Dichloro-thiophen-2-ylmethyl)-isoindole-1,3-dione (0.770 grams, 2.47 mmole) in methanol (30 ml) and tetrahydrofuran (10 ml) at room temperature was added hydrazine hydrate (0.395 grams, 12.3 mmole) and stirred at room temperature over night. A precipitate formed, and the mixture was concentrated to about 15 ml and filtered. The filtrate was poured into 100 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 5% methanol/methylene chloride as eluent to give an oil (0.341 g). MW 182.08; MS (m/e) 183 (M++1).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH:8]1([CH2:21][NH2:22])[C:13]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:12]=2[CH2:11][CH2:10][O:9]1>C(O)=O>[CH:1]([NH:22][CH2:21][CH:8]1[C:13]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:12]=2[CH2:11][CH2:10][O:9]1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: NCC1OCCc2c1sc1ccccc21
Solvent: O=CO
Product: O=CNCC1OCCc2c1sc1ccccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of formic acid (4.7 ml) and acetic anhydride (11.3 ml) is heated at 60° C. for 2 hr. 3,4-Dihydro-1H-[1]benzothieno[2,3-c]pyran-1-methylamine (1.0 g), described in Example 34, is added at room temperature and the mixture is allowed to stand overnight. The mixture is poured on ice and extracted with chloroform. The extract is washed (brine), dried (MgSO4) and evaporated to give 3,4-dihydro-N-formyl-1H-[1]benzothieno[2,3-c]pyran-1-methylamine, nmr (CDCl3) δ 3.16 and 4.95.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(Cl)(Cl)=O.Cl[CH:19](Cl)C>>[Cl:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:19])=[O:10])=[CH:12][CH:13]=1)(=[O:4])=[O:3]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
4-Chlorosulfonyl benzoic acid (5 g, 23 mmol) and thionyl chloride (20 mL) in dichloroethane (10 mL) was heated to 80° C. for 2 hr. The reaction mixture was concentrated via rotary evaporation to give a brownish solid. The solid was chilled on ice for 5 minutes and ice-cold methanol (40 mL) was added with stirring at 0° C. for 5 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred an additional 10 min. The addition of ice-cold water (40 mL), produced a white solid that was collected by filtration and dried under vacuum to afford pure methyl 4-(chlorosulfonyl)benzoate (4.5 g, 84%). 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.84 (s, 3H), 7.70 (d, 2H, J=8.4 Hz), 7.93 (d, 2H, J=8.4 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[S:4][C@H:5]2[O:11][C@H:10]([CH2:12][OH:13])[C@@H:9]([OH:14])[C@H:8]([OH:15])[C@H:6]2[N:7]=1.C(Cl)Cl.C([O-])(O)=O.[Na+].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>[Cl-].[Cl-].[Zn+2]>[CH3:1][N:2]([CH3:16])[C:3]1[S:4][C@H:5]2[O:11][C@@H:10]3[CH2:12][O:13][CH:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:14][C@H:9]3[C@H:8]([OH:15])[C@H:6]2[N:7]=1
Reactant: O=Cc1ccccc1
Reactant: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@@H]3OC(c4ccccc4)OC[C@H]3O[C@@H]2S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A suspension of -(3aR,5R,6S,7R,7aR)-2-(dimethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (0.800 g, 3.23 mmol) and anhydrous ZnCl2 (1.00 g, 7.35 mmol) in benzaldehyde (5 mL) was stirred at room temperature overnight. DCM (50 mL) and satd. aqueous NaHCO3 (50 mL) was added, and mixture was stirred for 20 min. The solid was filtered off, and the organic layer was collected from the filtrate. The aqueous layer was extracted with DCM (2×50 mL), and the combined extract was dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH/DCM, 3:100), affording -(3aR,4aR,8aS,9R,9aR)-2-(dimethylamino)-7-phenyl-3a,4a,5,8a,9,9a-hexahydro-[1,3]dioxino[4′,5′:5,6]pyrano[3,2-d]thiazol-9-ol as a pale yellow solid (0.76 g, 70%). 1H NMR (400 MHz, CDCl3) δ 7.51-7.48 (m, 2H), 7.40-7.34 (m, 3H), 6.39 (d, J=6.6 Hz, 1H), 5.58 (s, 1H), 4.31 (dd, J=5.1, 10.4 Hz, 1H), 4.10-4.03 (m, 2H), 3.86 (dd, J=8.2, 9.5 Hz, 1H), 3.76 (t, J=10.4 Hz, 1H), 3.59 (t, J=9.5 Hz, 1H), 3.00 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[NH:16][N:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:10][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[C:7]=1[CH:8]=[N:11][C:12]1[N:16]2[N:15]=[CH:14][CH:13]=1
Reactant: Nc1ccn[nH]1
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnc2c1cnc1ccnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
The product from Example 1a (1.24 g, 7.01 mmol) in 30 mL of THF was reacted with 5-aminopyrazole (0.58 g, 7.01 mmol) in 10 mL of THF under an argon atmosphere by dropwise addition. The mixture was stirred at room temperature for 1 hour and then added diisopropylethylamine (1.22 mL, 7.01 mmol) dropwise with stirring. The mixture was heated overnight at 60° C., and quenched with water and extracted with EtOAc, washed with brine, and dried over Na2SO4. The product was filtered and the solvent was removed under vacuum. The product was purified by silica gel chromatography eluting with EtOAc/hexane to give the title compound as a pale yellow solid (405 mg, 29%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:17][C:18]1[CH:19]=[N:20][NH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:20]2[CH:19]=[C:18]([I:17])[CH:22]=[N:21]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: Ic1cn[nH]c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(n2cc(I)cn2)C1
Temperature: 85 °C

Procedure:
A mixture of 3-methanesulfonyloxyazetidine-1-carboxylic acid tert-butyl ester (4.00 g, 15.9 mmol), 4-iodopyrazole (3.1 g, 15.9 mmol), potassium carbonate (2.85 g, 20.6 mmol) and 18-crown-6 (400 mg) in dry DMF (15 mL) was heated at 85° C. for 24 h. The reaction mixture was cooled to RT, poured into water and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexanes/dichloromethane/ethyl acetate (8:1:1) to give the pure title compound. 1H NMR (300 MHz, CDCl3): δ=1.47 (s, 9H), 4.29 (m, 2H), 4.36 (m, 2H), 5.05 (m, 1H), 7.59 (s, 1H), 7.60 (s, 1H).
Reaction SMILES: [OH-].[Na+].C([O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C@H:16]([CH2:17][C:18]([CH3:26])=[CH:19][CH2:20]1)[CH2:15][CH2:14]3)(=O)C.O>CO>[CH3:26][C:18]1[CH2:17][C@H:16]2[C@:21]([CH3:22])([CH2:20][CH:19]=1)[C@@H:23]1[C@H:13]([C@H:10]3[C@@:8]([CH2:25][CH2:24]1)([CH3:9])[C@@H:7]([OH:6])[CH2:12][CH2:11]3)[CH2:14][CH2:15]2
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(C)=CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1=CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)C1

Procedure:
Aqueous sodium hydroxide solution (50 ml; 4N) was added to a solution of 3-methyl-5α-androst-2-en-17β-ol acetate (50 g) in methanol (400 ml) and the solution was heated under reflux for 1 h. The solution was cooled and water was added to precipitate the product (43 g). Recrystallisation of a sample from ether gave pure 3-methyl-5α-androst-2-en-17β-ol, m.p. 128°-130°; [α]D +68° (c 0.31 in EtOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:6]=[C:7](I)[C:8]=1[O:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[C:38]([Cu])#[N:39]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:6]=[C:7]([C:38]#[N:39])[C:8]=1[O:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1
Reactant: COc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(I)c1OCCSc1ccc(Cl)cc1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(C#N)c1OCCSc1ccc(Cl)cc1

Procedure:
trans-2-(3-Methoxy-4-p-chlorophenylthioethoxy-5-iodophenyl)-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (2.35 g, 3.58 mmole) and CuCN (0.358 g, 4.30 mmole) in DMF (20 mL) were heated at 140° C. for 16 hours. The reaction mixture was cooled and quenched with water and extracted with ethyl acetate. The organic layer was washed with water and saturated NaCl solution, dried over MgSO4, filtered and evaporated in vacuo to oil which was purified by column chromatography (silica, 2:1 hexane/ethyl acetate) (1.79 g, 90.0%). 1H NMR (CDCl3): 1.99 (m, 2H); 2.47 (m, 2H); 3.32 (t, 2H); 3.85 (s, 6H), 3.89 (s, 6H); 4.27 (t, 2H); 5.17 (m, 2H); 6.61 (s, 2H); 7.16 (s, 2H); 7.28 (d, 2H); 7.32 (d, 2H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:13](O)[C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Br)(Br)(Br)[Br:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:13]([Br:22])[C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl [3,5-bis(trifluoromethyl)phenyl](hydroxy)acetate (300 mg, 0.993 mmol) was dissolved in CH2Cl2 (10 mL). The solution was cooled to 0° C. and CBr4 (659 mg, 1.986 mmol) was added followed by PPh3 (521 mg, 1.986 mmol). After 1 hour, the reaction was warmed to room temperature and stirred at room temperature for 1 hour. The reaction was filtered through a short plug of silica gel with CH2Cl2. The filtrate was concentrated and the residue was purified by flash chromatography with 5% EtOAc/hexanes to afford methyl [3,5-bis(trifluoromethyl)phenyl](bromo)acetate. Rf=0.24 (5% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 8.02 (s, 2H), 7.87 (s, 1H), 5.41 (s, 1H), 3.83 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])[CH2:22][CH2:21]1>C(O)(C)C>[OH:19][CH:17]([CH2:16][O:15][C:14]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:18][N:20]1[CH2:21][CH2:22][CH:23]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])[CH2:24][CH2:25]1
Reactant: O=C1NCCN1C1CCNCC1
Reactant: c1ccc(COc2ncccc2OCC2CO2)cc1
Solvent: CC(C)O
Product: O=C1NCCN1C1CCN(CC(O)COc2cccnc2OCc2ccccc2)CC1
Reaction time: 16.5 h

Procedure:
4.8 g of 2-benzyloxy-3-(2,3-epoxypropoxy)-pyridine and 3.0 g of 1-(4-piperidyl)-imidazolidin-2-one are dissolved in 50 ml of isopropanol and the solution is stirred for 15-18 hours at 20-30°. The crystals which have precipitated out are filtered off with suction and washed with ether and yield 1-{1-[2-hydroxy-3-(2-benzyloxy-3-pyridyloxy)-propyl]-4-piperidyl}-imidazolidin-2-one with a melting point of 145°-147°.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)(=[O:9])=[O:8])=[O:5])[CH3:3]>[Pd].O.C(O)C>[CH3:3][C:2]([CH3:19])([C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)(=[O:9])=[O:8])=[O:5])[CH3:1]
Reactant: CC(C)(C)C(=O)NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C(=O)NS(=O)(=O)c1cccc(N)c1
Yield: 74.9 %

Procedure:
In the same way as that described in Example 11, Step 2, using 1-(1,1-dimethylethylcarbonylaminosulphonyl)-3-nitrobenzene (5 g, 17.5 mmol), 10% palladium on carbon (0.5 g, 10% (w/w)) in water (4 ml) and ethanol (100 ml), the title compound (3.36 g, 75%) was afforded as a pale yellow solid after recrystallisation from ethanol. mp 147°-150° C. 1H NMR (360 MHz, D6-DMSO) δ 1.07 (9H, s), 5.62 (2H, brs), 6.78 (1H, dd, J=8.0 and 2.0 Hz), 6.94 (1H, d, J=8.0 Hz), 7.08 (1H, t, J=2.0 Hz), 7.19 (1H, t, J=7.9 Hz), 11.47 (1H, brs).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9](=[O:25])[CH2:10][N:11]=C(C1C=CC=CC=1)C1C=CC=CC=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>O1CCCC1>[CH3:7][O:8][C:9](=[O:25])[CH:10]([NH2:11])[C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(N)C(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
Dry tetrahydrofuran (250 ml) was cooled to -78° C. Potassium tert-butoxide (6.37 g; 56.72 mmol) was dissolved in dry tetrahydrofuran (100 ml) and added. (Benzhydrylideneamino)acetic acid methyl ester (14.35 g; 56.72 mmol) was added and the reaction mixture was stirred 30 min at -78° C. Benzoyl chloride (6.59 g; 56.72 mmol) was added dropwise and the reaction mixture was stirred 30 min at -78° C. Hydrochloric acid (1.0 M; 175 ml) was added dropwise. The reaction mixture was heated to room temperature and 2/3 of the solvent was removed in vacuo. Water (700 ml) was added and the reaction mixture was washed with diethyl ether (400 ml). The aqueous phase was evaporated in vacuo and the residue was dissolved in methanol and evaporated (2×150 ml). Methanol (80 ml) was added. The mixture was filtrated and the filtrate was evaporated in vacuo. The residue was recrystallised from tetrahydrofuran/diethyl ether to afford 8.86 g of 2-amino-3-oxo-3-phenylpropionic acid methylester as a hydrochloride.