Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:14][CH:15]=1)[C:3](=O)OC(C)(C)C.[H-].[Na+].[Cl:24][CH2:25][S:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1>CN(C)C=O.O>[ClH:24].[ClH:24].[CH3:3][NH:2][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:14]([CH2:25][S:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH:15]=1
Reactant: CN(Cc1c[nH]c(-c2ccccc2)n1)C(=O)OC(C)(C)C
Reactant: Cc1ccc(SCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNCc1cn(CSc2ccc(C)cc2)c(-c2ccccc2)n1
Product: Cl
Reaction time: 1 h
Yield: 8.5 %

Procedure:
To a solution of tert-butyl methyl[(2-phenyl-1H-imidazol-4-yl)methyl]carbamate (350 mg) in dimethylformamide (5 mL) was added sodium hydride (60% in oil, 421 mg) and the mixture was stirred for 1 hr. 1-[(Chloromethyl)thio]-4-methylbenzene (316 mg) was added dropwise, and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with water, 3% aqueous potassium hydrogensulfate solution, saturated sodium hydrogen carbonate solution and saturated brine in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→1:4) and dissolved in methanol (10 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added and the mixture was stirred at 75° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 31 mg, yield 6.4%).
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C(N(CC)CC)C.[N+:29]([C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1)([O-:31])=[O:30]>O1CCCC1>[ClH:21].[ClH:1].[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][NH:4][C:39]([NH:38][C:35]3[CH:34]=[CH:33][C:32]([N+:29]([O-:31])=[O:30])=[CH:37][CH:36]=3)=[O:40])[CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)Nc1ccc([N+](=O)[O-])cc1
Yield: 110.5 %

Procedure:
The procedure described in Example 3 was followed, using 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), tetrahydrofuran (50 ml), triethylamine (4.2 ml; 30 mmole) and 4-nitrophenyl isocyanate (1.64 g; 10 mmole). Recrystallization from methanol/water provided the title compound (2.79 g; 55% yield) as yellow-white crystals, m.p. 230°-231° C. (dec.).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]=O.Cl.[C:16]([O:20][C:21](=[O:28])[C@H:22]([C@H:24]([CH2:26][CH3:27])[CH3:25])[NH2:23])([CH3:19])([CH3:18])[CH3:17].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][NH:23][C@@H:22]([C@@H:24]([CH3:25])[CH2:26][CH3:27])[C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:28]
Reactant: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@H](C)[C@H](NCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
To a solution of Example 32A (12.1 g) in methanol (20 mL) was added L-isoleucine tert-butyl ester hydrochloride (13.0 g, 58 mmol), sodium cyanoborohydride (7.3 g, 116 mmol), and acetic acid (2 mL). The resulting solution was stirred for 3 hrs at 25° C. and the methanol removed under vacuum, dichloromethane (500 mL) added, and the solution extracted with aq. NaHCO3 (2×300 mL). Evaporation and purification of the organic layer gave 12.9 g of the title compound.
Reaction SMILES: CS(O[CH:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH3:7])(=O)=O.[C:21]([O-:24])(=[S:23])[CH3:22].[K+].CS(C)=O>CCOCC>[C:21]([S:23][CH:6]([CH:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]1)[CH3:7])(=[O:24])[CH3:22]
Reactant: CC(OS(C)(=O)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(=O)SC(C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 84.4 %

Procedure:
To a 500 ml round bottom flask was added tert-butyl 4-{1-[(methylsulfonyl)oxy]ethyl}piperidine-1-carboxylate (19 g, 61.8 mmol), potassium thioacetate (8.47 g, 74.2 mmol) and 90 ml dimethyl sulfoxide. The resulting reaction mixture was heated at 60° C. under nitrogen for 2 hours then at 45° C. for 18 hours. After cooling to room temperature, the reaction mixture was diluted with 300 ml ether, washed with 400 ml water and then 150 ml brine. The organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column eluted with 1:20 to 1:10 ethyl acetate/hexane to give 15 g tert-butyl 4-[1-(acetylthio)ethyl]piperidine-1-carboxylate as dark yellow sticky material. This material was dissolved in 100 ml MeOH. A solution of KOH (17.3 g, 309 mmol) in 150 ml water was added. The reaction mixture was flushed with nitrogen and stirred at 50° C. for 2 hours. After cooling to room temperature, the volume of reaction was reduced to 150 ml. Hexane (300 ml) was added. The layers were separated, and the aqueous portion was poured into an Erlenmyer flask with 250 ml saturated NH4Cl, and pH of the mixture was adjusted to 7 by addition of 3N HCl. This solution was extracted with 250 ml ether. The extracts were washed with 100 ml brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column eluted with 1:20 to 1:9 ethyl acetate/hexane to give 8.3 g desire product as light yellow sticky material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C([Br:15])C=C.CCOC(C)=O>CC#N.[Cl-].[Na+].O>[Br:15][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: OCCCc1cccc(Cl)c1
Reactant: C=CCBr
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Clc1cccc(CCCBr)c1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 3-(3-chloro-phenyl)-propan-1-ol (12.54 g, 73.6 mmol) and N,N′-carbonyl diimidazole (13.12 g, 81 mmol) in CH3CN was stirred at room temperature for 1 h. Allyl bromide (53.43 g, 442 mmol) was added and the reaction was heated at reflux for 24 h. The reaction was cooled to room temperature and brine and EtOAc were added. The aqueous solution was extracted with EtOAc and the organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography provided the title compound in about 85% yield. 1H NMR (400 MHz, CDCl3) δ 7.30–7.09 (m, 4H), 3.38 (t, 2H), 2.76 (t, 2H), 2.15 (t, 2H).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[CH:17]=[C:16]([OH:31])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:32]([O:34]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:37]>C1COCC1>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[CH:17]=[C:16]([OH:31])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:32](=[O:34])[NH2:37])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cc(-c3ccc(C(F)(F)F)cc3)cc1n2Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cc(-c3ccc(C(F)(F)F)cc3)cc1n2Cc1ccccc1
Yield: 19 %

Procedure:
A solution of the 9-[(phenyl)methyl]-2-(4-trifluoromethylphenyl)-4-hydroxy-5-carbomethoxy carbazole (1.10 g, 2.31 mM) in 35 ml THF and 140 mL concentrated aqueous ammonium hydroxide was sonicated for 6 hours at 30-40° C. The precipitated solid was filtered and washed with water. Trituration with Et2O, then with 2:1 Et2O/CH2Cl2 afforded 0.20 g (19%) of the 9-[(phenyl)methyl]-2-(4-trifluoromethylphenyl)-4-hydroxy-5-carbamoyl carbazole. 1H NMR (DMSO-d6) δ10.8 (s, 1H), 8.9 (bs, 1H), 8.45 (bs, 1H), 8.0 (d, J=8 Hz, 2H), 7.8 (d, J=8 Hz, 2H), 7.6 (s, 1H), 7.5 (m, 2H), 7.3-7.1 (m, 6H), 7.0 (s, 1H), 5.8 (s, 2H). MS (ES) m/e 444, 461.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N+:16]([O-:18])=O)=[CH:10][CH:9]=2)=[CH:5][CH:6]=1.CO.C[O-].[Li+].C(Cl)[Cl:25]>[Ti](Cl)(Cl)(Cl)Cl.O.O1CCCC1>[CH3:1][C:2]1[O:3][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([Cl:25])=[N:16][OH:18])=[CH:10][CH:9]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(Cc2ccc(CC[N+](=O)[O-])cc2)o1
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(Cc2ccc(CC(Cl)=NO)cc2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a mixture of 2-methyl-5-(4-(2-nitro-ethyl)-benzyl)-furan (87 mg, 0.36 mmol) described in Manufacturing Example 46-1-5 and methanol (2 mL) was added lithium methoxide (27 mg, 0.71 mmol) at room temperature, which was stirred for 15 minutes at room temperature. The solvent was evaporated from the reaction mixture under a reduced pressure. Titanium (IV) chloride (86 μL, 0.78 mmol) was added at −78° C. to a mixture of the resulting residue, methylene chloride (2 mL) and tetrahydrofuran (1 mL), which was stirred for 1 hour at 0° C. The reaction mixture was cooled to −78° C., water (5 mL) was added, and the temperature was gradually raised to room temperature. The reaction mixture was extracted by addition of ethyl acetate and water. The organic layer was washed with water until the pH became about 5. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Thereafter, the organic layer was filtered and the filtrate was concentrated under a reduced pressure to obtain the title compound (79 mg, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]1[NH:21][C:20](=[O:22])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:23])[CH:18]=2)[N:13]=1.[H-].[Na+].[CH3:26][N:27]([CH2:29][CH2:30]Cl)[CH3:28].O>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]1[N:21]([CH2:30][CH2:29][N:27]([CH3:28])[CH3:26])[C:20](=[O:22])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:23])[CH:18]=2)[N:13]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc(OC)c(Cc2nc3ccc(C)cc3c(=O)[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(OC)c(Cc2nc3ccc(C)cc3c(=O)n2CCN(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.1 %

Procedure:
A suspension of 0.62 g (2 mmol) of 2-(2,5-dimethoxyphenylmethyl)-6-methyl-4(3H)-quinazolinone and 0.19 g (2 mmol) of 50% sodium hydride in dioxane (10 ml) were stirred at room temperature for 1 hour. Then, to the resulting reaction mixture was added 0.22 g (2 mmol) of dimethylaminoethyl chloride dissolved in dioxane (10 ml), followed by heating at 60° C. for 5 hours. After cooling, to the mixture obtained were added 30 ml of water. The resulting mixture was extracted with dichloromethane and the dichloromethane layer was concentrated under reduced pressure. The thus obtained residue was purified by silica gel column chromatography (eluent; dichloromethane: ethanol=97:3) to obtain 0.10 g (yield 13 %) of 2-(2,5-dimethoxyphenylmethyl)-3-(2-dimethylaminoethyl)-6-methyl-4(3H)-quinazolinone as an oily substance. The thus obtained quinazolinone was dissolved in ether and to the resulting solution was added a 5% hydrogen chloride-ethanol solution and the precipitated crystals were collected by filtration to obtain 2-(2,5-dimethoxyphenylmethyl)-3-(2-dimethylaminoethyl)-6-methyl-4(3H)-quinazolinone hydrochloride. The melting point and infrared absorption spectrum of this hydrochloride were identical with those of Compound 24 obtained in Example 24, respectively.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]1([CH3:12])[CH:11]=[CH:10]C=C[CH:7]=1.C1CC=CC=1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>O.C(OCC)(=O)C>[C:18]([NH:22][C:1]([CH:2]1[CH2:12][CH:6]2[CH2:7][CH:3]1[CH:10]=[CH:11]2)=[O:4])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)N
Reactant: Cc1ccccc1
Reactant: C=CC(=O)Cl
Agent: C1=CCC=C1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)NC(=O)C1CC2C=CC1C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.8 %

Procedure:
A 2 L three-necked flask fitted with a thermometer, a stirrer, a nitrogen inlet tube and a dropping funnel was charged with 217.2 g (2.400 mol) of acryloyl chloride and 520 g of toluene, and the internal temperature was cooled to 0° C. 190.4 g (2.880 mol) of cyclopentadiene was then added dropwise from the dropping funnel over a period of 1 hour. Following completion of the dropwise addition, the resulting mixture was stirred for 1 hour at 0° C., thereby preparing a reaction intermediate solution. A 2 L three-necked flask fitted with a thermometer, a stirrer, a nitrogen inlet tube and a dropping funnel was charged with 201.1 g (2.750 mol) of tert-butylamine and 513 g of toluene, and the internal temperature was cooled to 0° C. The reaction intermediate solution prepared previously was added dropwise thereto from the dropping funnel over a period of 1.5 hours, and the internal temperature was then raised to 25° C. To the reaction mixture were added 1.800 ml of ethyl acetate and 300 ml of water, and following 30 minutes of stirring, the resulting mixture was allowed to stand to obtain an organic layer. The resulting organic layer was concentrated under reduced pressure. To the obtained concentrate were added 750 ml of ethyl acetate and 250 ml of hexane, and the resulting mixture was heated to 40° C. Following cooling of the resultant to 2° C. with stirring, the precipitated crystals were collected by filtration. The obtained crystals were dried under reduced pressure, thereby obtaining 124.3 g (0.643 mol; yield: 26.8%) of N-tert-butylbicyclo[2.2.1]hept-5-ene-2-carboxamide having the following physical properties.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]=[C:8]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH:7]=[C:6]([CH2:19][CH2:20][CH3:21])[N:5]=1)[CH3:2].[OH:22]OS([O-])=O.[K+].[OH2:28]>CO>[CH2:1]([S:3]([C:4]1[N:9]=[C:8]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH:7]=[C:6]([CH2:19][CH2:20][CH3:21])[N:5]=1)(=[O:22])=[O:28])[CH3:2]
Reactant: O
Reactant: O=S([O-])OO
Reactant: CCCc1cc(-n2cnc3ccccc32)nc(SCC)n1
Agent: [K+]
Solvent: CO
Product: CCCc1cc(-n2cnc3ccccc32)nc(S(=O)(=O)CC)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2-ethylthio-4-[benzimidazol-1-yl]-6-propylpyrimidine in MeOH (4 mL) was added a suspension of Oxone® (1.73 g) in water (4 mL). The resulting slurry was stirred at room temperature for 3.5 h. The reaction was diluted with water (10 mL) and extracted with methylene chloride (3×30 mL). The combined organic layer was washed with water, brine and dried (anhydrous Na2SO4). Removal of solvent gave 295 mg of the title compound which was used directly in the next step. 1H NMR (500 MHz, CDCl3): δ 8.76 (s, 1H); 8.37 (d, J=8.0 Hz, 1H); 7.89 (d, J=8.1 Hz, 1H); 7.57 (s, 1H); 7.51 (dd, J=7.3, 8.3 Hz, 1H); 7.46 (dd, J=7.3, 7.6 Hz, 1H); 7.28 (s, 1H); 3.64 (q, J=7.4 Hz, 2H); 2.99 (t, J=7.5 Hz, 2H); 1.92 (m, J=7.5 Hz, 2H); 1.52 (t, J=7.5 Hz, 3H); 1.08 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[C:14]([CH:16]=O)[N:13]=[C:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl-].[CH3:25][NH3+:26].[BH4-].[Na+].[C:29](=O)([O-])O.[Na+]>C(O)C>[CH3:25][N:26]([CH3:29])[CH2:16][C:14]1[N:13]=[C:12]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)nc2-c2ccccc2)cc1
Reactant: O=C([O-])O
Reactant: C[NH3+]
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(CN(C)C)nc2-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
A mixture of 1-[(4-methylphenyl)sulfonyl]-2-phenyl-1H-imidazole-4-carbaldehyde (300 mg), methylammonium chloride (225 mg), molecular sieves 3A (2.0 g) and ethanol (10 mL) was stirred at 60° C. for 1 hr. The reaction mixture was cooled, sodium borohydride (105 mg) was added at 5-10° C., and the mixture was stirred for 30 min. Saturated aqueous sodium hydrogen carbonate was added at the same temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=2:3→0:1), and crystallized by adding a solution (10 mL) of anhydrous oxalic acid in ethyl acetate to give the title compound as colorless crystals (yield 106 mg, 29%).
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1([CH3:27])[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[C:12]([CH3:20])[CH:11]=2)[C@H:5]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O.Cl>C1COCC1.CO>[CH3:3][C:4]1([CH3:27])[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:20])[CH:11]=2)[C@H:5]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(N2C(=O)OC(C)(C)[C@@H]2c2ccccc2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(N2C(=O)OC(C)(C)[C@@H]2c2ccccc2)ccc1C(=O)O
Temperature: 50 °C
Yield: 91.9 %

Procedure:
Lithium hydroxide (0.053 g, 2.210 mmol) was added to a solution of (S)-methyl 4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-2-methylbenzoate (0.150 g, 0.442 mmol) in THF (2.5 mL), MeOH (2.50 mL), and water (2.50 mL). The mixture was heated at 50° C. for 16 hours. The reaction mixture was then cooled in an ice bath and adjusted to pH˜2 by the addition of 1 N aqueous HCl solution. Water was added, leading to the formation of a white precipitate. The precipitated material was filtered away and dried to afford (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-2-methylbenzoic acid (0.132 g, 0.406 mmol, 92% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (s, 3H), 1.63 (s, 3H), 2.44 (s, 3H), 5.51 (s, 1H), 7.18-7.44 (m, 6H), 7.48 (d, J=2.15 Hz, 1H), 7.75 (d, J=8.70 Hz, 1H), 12.57 (br. s., 1H). m/z (ESI) 326 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([F:28])([F:27])([F:26])([F:25])[F:24])[CH:18]=2)=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[H-].[Na+].CI.[C:33]([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][S:2]([C:5]1[C:6]([N:16]([CH3:33])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([F:27])([F:26])([F:28])([F:24])[F:25])[CH:18]=2)=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3]
Reactant: O=C([O-])O
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Nc2cccc(S(F)(F)(F)(F)F)c2)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(N(C)c2cccc(S(F)(F)(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
150 mg of methyl 5-methanesulfonyl-2-methyl-4-(3-pentafluorosulfanyl-phenylamino)benzoate (example 5 c) were dissolved in 2 ml of DMF (anhydrous), 13.5 mg of NaH were added, and the mixture was stirred at RT for 15 minutes. Then 15 μl of CH3I were injected and the mixture was left to stand at RT for 18 h. The reaction mixture was then poured into 10 ml of a saturated aqueous NaHCO3 solution and extracted with 40 ml of EA. The organic phase was subsequently washed with 10 ml of water. Drying over MgSO4 and removal of the solvent in vacuo resulted in 120 mg of a pale yellow foam.
Reaction SMILES: O(C=C)S(C(F)(F)F)(=O)=O.C(B(CC)[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)C.FC(F)(F)S(O[C:28]1[C@:29]2([CH2:46][CH2:45][C@H:44]3[C@@H:34]([CH2:35][CH:36]=[C:37]4[C@:42]3([CH3:43])[CH2:41][CH2:40][C@H:39]([O:47][C:48](=[O:50])[CH3:49])[CH2:38]4)[C@@H:31]2[CH2:32][CH:33]=1)[CH3:30])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C.O1CCCC1>[CH3:49][C:48]([O:47][C@@H:39]1[CH2:38][C:37]2[C@@:42]([CH3:43])([C@@H:44]3[C@@H:34]([CH2:35][CH:36]=2)[C@@H:31]2[CH2:32][CH:33]=[C:28]([C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)[C@@:29]2([CH3:30])[CH2:46][CH2:45]3)[CH2:41][CH2:40]1)=[O:50]
Reactant: CCB(CC)c1cccnc1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(OS(=O)(=O)C(F)(F)F)=CC[C@@H]32)C1
Agent: C=COS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1
Temperature: 25 °C

Procedure:
Trifluoromethanesulphonic anhydride (235 g) is dropped into a solution of prasterone acetate (250 g) in methylene chloride (5 L), maintaining the temperature between −5° C. and 0° C., and anhydrous sodium carbonate (80 g) is added in portions. The mixture is stirred for 4 h at 0-5° C. Cold water (2.5 L) is added and the organic phase is separated and washed with a 10% sodium chloride aqueous solution. The mixture is treated with decolourising carbon (120 g), and then concentrated under vacuum to obtain an oily residue (about 355 g). The vinyl triflate thus obtained is taken up with tetrahydrofuran (3.0 L), and diethyl(3-pyridyl)borane (100 g), bis(triphenylphosphine)palladium II chloride (3.3 g) and a 2M sodium carbonate aqueous solution (900 mL) are loaded in succession in an inert gas environment. The resulting mixture is refluxed for about 1 h, then cooled to room temperature, and ethyl acetate (2.5 L) and water (2.5 L) are added. The aqueous phase is back-extracted with ethyl acetate (1.4 L), and the combined organic phases are treated with decolourising carbon (about 100 g), and then concentrated under vacuum to obtain crude abiraterone acetate as an oil (304 g; purity about 92%; assay 52%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2.C1N=CN([C:18]([N:20]2[CH:24]=N[CH:22]=[CH:21]2)=[O:19])C=1.CCN(C(C)C)C(C)C.N1CC[C:37]2([C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]([CH2:48][C:49]([OH:51])=[O:50])[CH2:40]2)[CH2:36]C1>C(Cl)Cl>[CH:10]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]([CH2:5]3)[CH:3]1[NH:2][C:18]([N:20]1[CH2:21][CH2:22][C:37]3([C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:41]([CH2:48][C:49]([OH:51])=[O:50])[CH2:40]3)[CH2:36][CH2:24]1)=[O:19])[CH2:9]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC1CC2(CCNCC2)c2ccccc21
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-aminoadamantane hydrochloride (120 mg, 0.64 mmol) and CDI (141 mg, 0.87 mmol) in anhydrous CH2Cl2 (4 mL) at 0° C. was added DIEA (374 mg, 2.90 mmol). The mixture was stirred at 0° C. for 1 h. A solution of compound 2-(2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (142 mg, 0.58 mmol) was added dropwise slowly. The mixture was stirred at rt overnight and concentrated to give the crude product. A portion of the crude product was purified by preparative HPLC to give 2-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (60 mg, 36%). 1H NMR: (400 MHz, CDCl3): δ=1.56-1.73 (m, 6H), 1.74-1.90 (m, 10H), 1.95 (m, 2H), 2.10 (m, 1H), 2.45 (m, 1H), 2.60 (m, 1H), 3.01 (m, 3H), 3.65 (m, 1H), 3.87-3.99 (m, 3H), 7.15-7.26 (m, 4H); LC-MS (4 min) tR=2.70 min, m/z=423 (M++1).