Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][C:22]1[S:26][C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][N:34]=2)[CH:30]=O)=[N:24][CH:23]=1>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][N:34]=[C:27]([C:25]3[S:26][C:22]([CH3:21])=[CH:23][N:24]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: Cc1cnc(-c2cc(C=O)ccn2)s1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccnc(-c2ncc(C)s2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with 2-(5-methylthiazol-2-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.86 min.; [M+H]+: 425.99 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[N:30][C:5]2[N:6]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:7]3[C:12]([C:4]=2[CH:3]=1)=[CH:11][C:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1)=[CH:9][CH:8]=3.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[N:30][C:5]2[N:6]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:7]3[C:12]([C:4]=2[CH:3]=1)=[CH:11][C:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[CH:9][CH:8]=3
Reactant: COc1ccc(-c2ccc3c(c2)c2cc(Cl)cnc2n3S(=O)(=O)c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1c2ccc(-c3ccc(O)cc3)cc2c2cc(Cl)cnc21
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of 3-chloro-6-(4-methoxyphenyl)-9-(benzenesulfonyl)-9H-pyrido[2,3-b]indole (222 mg, 1.11 mmol, 1eq.) in CH2Cl2 at 0° C., BBr3 (4.46 ml, 1M in CH2Cl2 4.46 mmol) was added dropwise. After 3 h at room temperature, the reaction mixture is hydrolysed with H2O and extracted with AcOEt (3×50 ml), dried with MgSO4, then filtered. The solvents were removed under reduced pressure and the crude material was purified by flash chromatography (CH2Cl2 then AcOEt) to afford 4-(3-chloro-9-(benzenesulfonyl)-9H-pyrido[2,3-b]indol-6-yl)phenol (409 mg, 0.94 mmol, 85% yield. 1H NMR 1H ((CD3)2CO, 300 MHz), δ 8.67 (d, 1H, J=2.3 Hz), 8.45-8.51 (m, 4H), 8.16-8.20 (m, 2H), 7.93 (dd, 1H, J=2.1 Hz, 8.9 Hz), 7.54-7.68 (m, 5H), 6.98 (d, 2H, J=8.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1.[CH2:31](N(CC)CC)[CH3:32].C(OC(=O)C)(=O)C.[Cl-].[Na+]>CN(C)C=O.O>[CH2:23]([NH:22][C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:5]2[C:4]3[CH:3]=[C:2]4[N:1]=[C:13]([CH3:14])[N:12]([CH2:31][CH3:32])[C:11]4=[CH:10][C:9]=3[N:8]=[CH:7][N:6]=2)[CH2:16][CH2:17]1)=[S:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1N
Reactant: CCN(CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)nc2cc3c(N4CCN(C(=S)NCc5ccccc5)CC4)ncnc3cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
To a solution of 528 mg (1.25 mmol) of 4-(6-amino-7-ethylamino-4-quinazolinyl)-N-benzyl-1-piperazinethiocarboxamide obtained in Example 461 in 15 ml of dimethylformamide were added 0.57 ml (4.09 mmol) of triethylamine and 0.31 ml (3.29 mmol) of acetic anhydride, followed by overnight stirring at room temperature in an atmosphere of argon. The reaction mixture was poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=3)=[CH:9][S:8][C:7]=2[CH:24]=1.I[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]([CH3:34])[CH3:33].CC(C)(C)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:9]1[S:8][C:7]2[CH:24]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)([CH3:34])[CH3:33]
Reactant: COC(=O)/C=C/c1ccc(Oc2csc3cc(OC)ccc23)cc1
Reactant: CC(C)c1ccccc1I
Agent: CC(C)(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3C(C)C)sc3cc(OC)ccc23)cc1
Temperature: 150 °C
Yield: 63 %

Procedure:
To a flask containing (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (800 mg, 2.35 mmol) in anhydrous DMA (3.0 mL) was added 1-iodo-2-isopropylbenzene (0.751 mL, 4.70 mmol) followed by chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos palladacycle 1st generation, 188 mg, 0.24 mmol), trimethylacetic acid (0.818 mL, 7.05 mmol) and potassium carbonate (974 mg, 7.05 mmol). The flask was sealed, purged and back-filled with nitrogen and the resulting mixture was heated to 150° C. for 2 h after which time the reaction was diluted with EtOAc, and washed with water and brine. The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a red brown residue which was purified by column chromatography (SiO2, 0-30% EtOAc/heptane) to afford (E)-methyl 3-(4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (675 mg, 1.48 mmol, 63% yield).). 1H NMR (400 MHz, CDCl3) δ ppm=7.61 (d, J=15.9 Hz, 1H), 7.42-7.29 (m, 7H), 7.15 (ddd, J=8.1, 5.7, 2.8 Hz, 1H), 6.97 (dd, J=8.8, 2.3 Hz, 1H), 6.91-6.85 (m, 2H), 6.29 (d, J=16.0 Hz, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 3.26 (p, J=6.8 Hz, 1H), 1.19 (d, J=6.9 Hz, 6H). LC/MS (m/z, MH+): 459.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([CH3:11])[CH:3]=1.[N+:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[CH:15]([N+:12]([O-:14])=[O:13])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([CH3:11])[CH:3]=1
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: Cc1cc(Br)ccc1N=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)C(C(=O)Nc1ccc(Br)cc1C)[N+](=O)[O-]
Yield: 25 %

Procedure:
A mixture of 9.22 grams (0.04 mole) of 4-bromo-2-methylphenyl isocyanate, 5.78 grams (0.04 mole) of ethyl nitroacetate, 6.01 grams (0.04 mole) of anhydrous potassium carbonate and 90 milliliters of benzene was stirred and heated under reflux for 3 hours then cooled and stirred at room temperature for a period of about 16 hours. The precipitated material was filtered off and thoroughly triturated with 200 milliliters of ice water, filtering to remove a precipitate which was discarded. Chilling and acidification of the filtrate with concentrated HCl caused precipitation of a yellow-white solid which was collected, water-washed and air-dried. Recrystallization from benzene-cyclohexane (3:1) gave 3.38 grams (0.01 mole) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-2-nitro-3-oxopropanoate as white crystals having a melting point of 126° C.-129° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][CH:3]=1.NC1C=CC([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[C:28](=[O:35])[CH2:27][CH2:26][CH2:25]2)=[O:23])=CC=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]([C:22]([N:24]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[C:28](=[O:35])[CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:14]=[CH:13][C:9]=2[C:10]([NH:24][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:29]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1
Product: Cc1ccc(-c2cc(C(=O)N3CCCC(=O)c4ccccc43)ccc2C(=O)Nc2ccccc2)cc1

Procedure:
Using o-(4-methylphenyl)benzoic acid and 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one as starting materials, the procedure of Reference Example 3 was repeated to obtain 2-(4-methylphenyl)-4-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]benzanilide.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].O.Cl.[NH2:14]O>C(O)C>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[O:6][N:14]=1
Reactant: NO
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(N)no1
Reaction time: 1 h
Yield: 60.7 %

Procedure:
In a 100 ml. round bottom 3-neck flask was placed 2 g. of pivalyl acetonitrile, 0.64 g. of sodium hydroxide, 35 ml. of water and 12.5 ml. of ethanol. This mixture was heated to reflux and an aqueous solution of 1.1 g. of hydroxylamine hydrochloride was added. The pH at the end of the addition was about 6.0. After 1 hour the pH was determined to be about 6.3. After 2 hours the pH was determined to be about 6.7. After 3 hours the pH was determined to be about 6.5. The following morning after the reaction mixture had refluxed overnight the pH was about 7.2. The ethanol was removed in vacuo using the rotovapor. The solid which separated was filtered off and dried. It had a melting point of 105°-106° C., and weighed 1.1 g. It was determined by vpc that the product contained 92.49% of 3-amino-5-(t-butyl)isoxazole and 4.67% of 5-amino- 3-(t-butyl)isoxazole. Yield: 60.7% of desired isomer.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:5]=1[C:6](OC)=[O:7])(=O)[CH3:2].O.[NH2:17][NH2:18]>CO.O>[CH3:15][O:14][C:11]1[CH:10]=[C:5]2[C:4]([C:1]([CH3:2])=[N:17][NH:18][C:6]2=[O:7])=[CH:13][CH:12]=1
Reactant: NN
Reactant: COC(=O)c1cc(OC)ccc1C(C)=O
Solvent: CO
Solvent: O
Product: COc1ccc2c(C)n[nH]c(=O)c2c1
Temperature: 95 °C
Reaction time: 5 h
Yield: 95.2 %

Procedure:
To a solution of methyl 2-acetyl-5-methoxybenzoate (2) (2.21 g, 10.60 mmol) in methanol (13 mL) is added hydrazine monohydrate (1.59 g, 31.80 mmol). The mixture is stirred at 95° C. under argon for 5 h, then cooled to room temperature, diluted with H2O (50 mL), and extracted with ethyl acetate (2×100 mL, 2×50 mL, and 2×30 mL). The extract is washed (brine), dried, and concentrated at reduced pressure. The residue is suspended in ethyl acetate (20 mL), heated, then cooled, and filtered to give 1.92 g (95%) of 3 as a white solid, mp 203-205° C. IR 3314, 2918, 1652, 1241 cm−1; 1H NMR (CDCl3) δ 2.60 (s, 3H, CH3), 4.01 (s, 3H, CH3O), 7.42 (dd, J=9.0, 2.7 Hz, 1H, 6-PhthH), 7.75 (d, J=9.0 Hz, 1H, 5-PhthH), 7.88 (d, J=2.7 Hz, 1H, 8-PhthH), 10.75 ppm (s, 1H, NH).
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[CH3:16][O:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[N+:29]([O-:30])=[N:28][C:27]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])=[N:26][C:25]=2[CH:37]=1.FC(F)(F)C(O)=O>C(Cl)Cl.N>[CH3:16][O:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[N+:29]([O-:30])=[N:28][C:27]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])=[N+:26]([O-:6])[C:25]=2[CH:37]=1
Reactant: COCCOc1ccc2c(c1)nc(NCCN(C)C)n[n+]2[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOc1ccc2c(c1)[n+]([O-])c(NCCN(C)C)n[n+]2[O-]
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 48.1 %

Procedure:
Hydrogen peroxide (70%, 0.44 mL, ca. 8.7 mmol) was added dropwise to a stirred solution of trifluoroacetic anhydride (1.23 mL, 8.7 mmol) in DCM (20 mL) at 5° C. The mixture was stirred at 5° C. for 5 min, warmed to 20° C., stirred for 10 min, and cooled to 5° C. The mixture was added to a stirred solution of 1-oxide 13 (268 mg, 0.9 mmol) and trifluoroacetic acid (0.34 mL, 4.4 mmol) in DCM (20 mL) at 5° C. and the mixture stirred at 20° C. for 6 h. The solution was carefully diluted with dil. aq. NH3 solution (2.0 mL) and the mixture extracted with CHCl3 (5×50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 14 (140 mg, 50%) as a red solid, mp (MeOH/DCM) 146-149° C.; 1H NMR δ 8.21 (d, J=9.6 Hz, 1 H, H-8), 7.52 (d, J=2.6 Hz, 1 H, H-5), 7.48 (br s, 1 H, NH), 7.10 (dd, J=9.6, 2.6 Hz, 1 H, H-7), 4.31-4.36 (m, 2 H, CH2O), 3.81-3.84 (m, 2 H, CH2O), 3.61-3.65 (m, 2 H, CH2N), 3.47 (s, 3 H, OCH3), 2.62 (br t, J=6.0 Hz, 2 H, CH2N), 2.31 [s, 6 H, (CH3)2]; 13C NMR δ 165.2, 150.2, 140.2, 125.7, 123.5, 120.5, 95.6, 70.3, 68.8, 59.2, 57.5, 45.0 (2), 38.9. Anal. Calcd for C14H21N5O4¼CH2Cl2: C, 50.1; H, 6.2; N, 20.2. Found: C, 50.1; H, 6.1; N, 20.6%.
Reaction SMILES: [F:1][C:2]1([F:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:5]=2[O:4][C:3]1([F:14])[F:13].[CH2:16](Br)[C:17]#[CH:18].C1(C)C=CC=CC=1>FC1C=CC=CC=1>[CH2:18]([NH:12][C:10]1[CH:9]=[CH:8][C:6]2[O:7][C:2]([F:1])([F:15])[C:3]([F:13])([F:14])[O:4][C:5]=2[CH:11]=1)[C:17]#[CH:16]
Reactant: C#CCBr
Reactant: Nc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Solvent: Cc1ccccc1
Solvent: Fc1ccccc1
Product: C#CCNc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Temperature: 50 °C

Procedure:
2,2,3,3-Tetrafluoro-6-aminobenzodioxane (6.694 g, 30.0 mmol) and Aldrich basic alumina (activated, Brockmann 1, 150 mesh, CAS#1344-28-1) (51 g) were mixed in fluorobenzene (100 mL) and then treated with 80% propargyl bromide in toluene (2.56 mL, 23.0 mmol). The resulting mixture was thoroughly stirred and heated at 50° C. for 17 hours. The mixture was cooled to ambient temperature and filtered. The alumina was rinsed thoroughly with dichloromethane (150 mL), the filtrate was reduced in volume under reduced pressure, washed with concentrated aqueous NH4OH (5 mL), dried (Na2SO4), concentrated and chromatographed on silica eluting with 0-10% EtOAc/hexanes to provide the titled compound. 1H NMR (CDCl3) δ ppm 2.24 (t, 1H), 3.92 (m, 2H), 3.96 (m, 1H), 6.43 (d, 1H), 6.45 (dd, 1H), 6.96 (d, 1H); MS (DCI) 262 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[CH3:15][O-:16].[Na+]>CO>[CH3:14][O:13][C:12]1[C:3]([CH2:2][O:16][CH3:15])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[O-]
Reactant: COC(=O)c1cccc(OC)c1CBr
Agent: [Na+]
Solvent: CO
Product: COCc1c(OC)cccc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a 100 mL flask containing 10.1 g (0.039 mol) of methyl 2-bromomethyl-3-methoxybenzoate in 50 mL of CH3OH, were added 19 g of a 25% wt. solution of NaOMe (4.74 g, 0.087 mol). The reaction was stirred at room temperature for 2 hours and then evaporated on a rotary evaporator to remove the CH3OH. About 200 mL of water were added to the residue and the resulting solution was extracted with CDCl3. The CDCl3extract was dried and evaporated to yield 6.27 g of crude-methyl 3-methoxy-2-methoxymethylbenzoate (77% yield). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7-7.4 (multiple, 3H), 4.783 (s, 2H), 3.897 (s, 3H), 3.864 (s, 3H), 3.37 (s, 3H). 6.27 g of methyl 3-methoxy-2-methoxymethylbenzoate was stirred with a 20% aqueous KOH solution (6.7 g, 0.12 mol in 34 g of solution) at 50° C. in an oil bath for 4-5 hours, and then at room temperature for 16 hours. The reaction mixture was acidified with 3N HCl to pH 2 and extracted with CH2Cl2. The CH2Cl2 extract was dried and evaporated to yield 5.35 g of 3-methoxy-2-methoxymethylbenzoic acid (92% yield). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.65 (1H, d), 7.40 (t, 1H), 7.10 (d, 1H), 4.83 (s, 2H), 3.88 (s, 3H), 3.46 (s, 3H).
Reaction SMILES: FC1C(F)=C(C(F)(F)F)C(F)=C(F)C=1[O:4][C:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:6]=1.C(O)C.Cl.[OH-].[Na+]>C1COCC1.O>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C:14]2[C@:15]3([CH2:17][CH2:18][C@H:19]4[C@@H:10]([CH2:9][CH2:8][C:7]5[C@:20]4([CH3:23])[CH2:21][CH2:22][C:5](=[O:4])[CH:6]=5)[C@@H:11]3[CH2:12][CH:13]=2)[CH3:16])[CH:25]=1
Reactant: C[C@]12CCC(Oc3c(F)c(F)c(C(F)(F)F)c(F)c3F)=CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Yield: 71 %

Procedure:
To solution of 3-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy]-17-(3-pyridyl)androsta-3,5,16-triene (0.423 g, 0.75 mmol) in THF (5 ml) was added ethanol (5 ml) followed by aqueous hydrochloric acid (1M, 5 ml) and the mixture heated, with stirring, by an oil bath at 65° C. for 48h and allowed to cool. The mixture was poured into water (20 ml), neutralised with aqueous sodium hydroxide (1M), and extracted with diethyl ether (3×30 ml). The ether extracts were combined, dried (Na2CO3), and concentrated. Chromatography, on elution with diethyl ether, afforded the title compound (185 mg, 71%) which crystallised from diethyl ether, m.p. 148°-150° C. IR νmax 1674 cm- ; 1H-NMR(CDCl3) inter alia δ1.07(3H,s,18-CH3), 1.24(3H,s,19-CH3), 5.76(1H,s,4-H), 5.99(1H,m,16-H), 7.23(1H,m,Py 5-H), 7.64(1H,m,Py 4-H), 8.47(1H,m,Py 6-H), 8.62(1H,m,Py 2-H); MS m/z 347 (M+).
Reaction SMILES: [Li].C1C2C(=CC=CC=2)C=CC=1.Cl[P:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:26][C:27]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[C:28]=1[C:29](Cl)=[O:30].[OH:38]O>C1COCC1>[CH3:26][C:27]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[C:28]=1[C:29]([P:13](=[O:38])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:30]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: OO
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]
Solvent: C1CCOC1
Solvent: c1ccc2ccccc2c1
Product: Cc1cc(C)c(C(=O)P(=O)(c2ccccc2)c2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under argon and with exclusion of moisture, 2.76 g of lithium (0.40 mol) are suspended at room temperature in 100 ml of THF and this suspension is charged with 0.10 g (0.00078 mol) of naphthalene. This mixture is then stirred for 10 minutes at room temperature. With occasional cooling and vigorous stirring, 45.2 g (0.0 mol) of P-chlorodiphenyl phosphine are added dropwise to the dark brown suspension at 10–25° C. After stirring for 4 hours, the red solution is filtered via a glass frit (G2 porosity) into a sulfonation flask with exclusion of moisture and using argon as protective gas. 38.0 g (0.2 mol) of 2,4,6-trimethylbenzoyl chloride are added dropwise, with stirring and cooling, at 10–20° C. over 1 hour and the mixture is then stirred for another 30 minutes. The organic phase is concentrated by evaporation in a Rotavap and the residue is taken up in 100 ml of toluene and charged, with vigorous stirring at a temperature from 50–60° C., with 23.0 g (0.20 mol) of hydrogen peroxide (30%). The reaction is complete after stirring for 30 minutes. The reaction emulsion is poured on water and washed with an aqueous saturated sodium hydrogencarbonate solution and then dried over magnesium sulfate and filtered. The filtrate is concentrated by evaporation in a Rotavap. The residue is crystallised from petroleum ether/ethyl acetate and dried in a vacuum drying oven at 40° C., yielding 55.0 g (79% of theory) of the title compound in the form of a yellow powder having a melting point of 89–90° C.
Reaction SMILES: [F:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.B(F)(F)F.[N+](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N-].O=C1CCCCN1>O.CCOCC.C(Cl)Cl>[F:1][CH:2]1[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:7]1=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: FB(F)F
Agent: O=C1CCCCN1
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC(F)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (20.0 g, 92.1 mmol) in 1:1 (CH2Cl2:Et2O, 250 mL) was cooled to −60° C. using an IPA/dry ice bath. In a separate flask was added BF3-Etherate (12.8 mL, 101 mmol) and Et2O (40 mL) which was cooled to 0° C., then ethyl 2-diazoacetate (12.6 mL, 120 mmol) was added. This mixture was added to the oxopiperidine solution and the reaction mixture was slowly warmed to ambient temperature over 2 hours. Water was added (100 mL) and the mixture was stirred at ambient temperature for 30 minutes. The phases were separated and the aqueous phase was extracted with EtOAc (100 mL) and the combined organic phases were washed with 1N KHSO4, followed by brine and then dried over Na2SO4, filtered and concentrated. This provided the product as a thick, yellow oil (26 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH3:2].[C:24](O)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1>C1COCC1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=1)[C:24](=[O:31])[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH3:2]
Reactant: CCOC(=O)CN(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Reactant: O=C(O)c1cccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)c1cccnc1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Temperature: -30 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To solution of 12.7 ml (1 M in THF, 13 mmol) of lithium hexamethyldisilylazide cooled to −78° C. under Ar was added, drop wise, a solution of 3.8 g (12 mmol) of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester (intermediate 7B) in 20 ml of THF. The mixture was brought to −30° C. and stirred for 1 h. Separately, 0.6 g (5 mmol) of nicotinic acid was added to 0.8 g (5 mmol) of 1,1-carbonyl diimidazole in 10 ml of CH2Cl2 and the mixture stirred for 1 h after which time it was concentrated to dryness. The crude residue was re-dissolved in 10 ml of THF under Ar and cooled to −30° C. The enolate solution of intermediate 7B (described above) was then added by cannula to the crude imidazolide solution and the mixture was allowed to reach room temperature. After 2 h the reaction was diluted with EtOAc, washed with saturated ammonium chloride solution, the organic phase dried with sodium sulfate and concentrated. Purification by flash column chromatography [n-heptane/EtOAc 1:1] afforded 1.2 g (58%) of the title compound as an orange oil. MS: 437.2 (MH+).