Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=O)[C:7]2=[O:15].Cl.[C:17]1([NH:23][C:24](=[S:27])[NH:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=[N:26][NH:25][C:24]([NH:23][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[S:27])[C:7]2=[O:15]
Reactant: NNC(=S)Nc1ccccc1
Reactant: COc1ccc2c(=O)c(=O)c(=O)c2c1
Agent: Cl
Solvent: O
Product: COc1ccc2c(=O)c(=NNC(=S)Nc3ccccc3)c(=O)c2c1

Procedure:
5-methoxyindan-1,2,3-trione, monohydrate, 4-phenyl thiosemicarbazide hydrochloride
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:13][CH:12]([C:14]([N:16]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]([CH3:26])=O>CCO.[Pd]>[CH3:23][CH:24]([N:19]1[CH2:20][CH2:21][CH2:22][N:16]([C:14]([CH:12]2[CH2:13][N:10]([C:8]([C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[O:9])[CH2:11]2)=[O:15])[CH2:17][CH2:18]1)[CH3:26]
Reactant: CC(C)=O
Reactant: Cc1ccc(C(=O)N2CC(C(=O)N3CCCNCC3)C2)cn1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(=O)N2CC(C(=O)N3CCCN(C(C)C)CC3)C2)cn1
Yield: 27.5 %

Procedure:
To a stirred solution of 1-({1-[(6-methylpyridin-3-yl)carbonyl]azetidin-3-yl}carbonyl)-1,4-diazepane (60 mg, 0.194 mmol) in EtOH (3 mL) was added Pd/C (10% wt/wt, 6 mg) and acetone (143 μL, 1.95 mmol). The flask was purged with N2 (N2/vacuum cycle×3) and then H2 (H2/vacuum cycle×3). After 24 hours the reaction was filtered through Celite® and concentrated at reduced pressure. Purification by silica FCC (90:9:1 Et2O/MeOH/NH3) and capture and release (SCX-2, flush with MeOH, then release with 7M NH3 in MeOH) gave the title compound (18.4 mg, 27%).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([Br:29])[C:26]([OH:30])=[C:25]([Br:31])[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:33][C:34](=[O:44])[C@H:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)O>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[C:27]([Br:29])[C:26]([O:30][C@H:35]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:34]([OH:44])=[O:33])=[C:25]([Br:31])[CH:24]=2)=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Product: O=C(O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzo[b]thiophen-3-yl)-3,5-dibromo-biphenyl-4-ol, and (S)-(−)-3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp 87-89° C.; MS m/e 696 (M+);
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:30][O:31]C1C=CC=CC=1N1CCNCC1>>[CH3:30][O:31][C:6]1[CH:7]=[CH:8][CH:3]=[CH:4][C:5]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18]2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=c1c2ccccc2ncn1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Product: COc1ccccc1N1CCN(CCn2cnc3ccccc3c2=O)CC1

Procedure:
This compound was prepared in compliance with the procedure described in 1c, using 1-(2-methoxyphenyl)piperazine instead of 1-(3-(trifluoromethyl)phenyl)piperazine.
Reaction SMILES: [NH2:1][C@@H:2]([C:10](=[O:25])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C:19]2=[O:24])=[CH:14][CH:13]=1)[CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>ClCCl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:35])[NH:1][C@H:2]([CH2:3][P:4]([O:5][CH3:6])([O:7][CH3:8])=[O:9])[C:10]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C:19]3=[O:24])=[CH:16][CH:17]=2)=[O:25])=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COP(=O)(C[C@@H](N)C(=O)Nc1ccc(N2CCOCC2=O)cc1)OC
Solvent: ClCCl
Product: COP(=O)(C[C@@H](NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(N2CCOCC2=O)cc1)OC
Yield: 98.8 %

Procedure:
5.4 The solution of 0.2 g (0.54 mmol) of dimethyl (S)-{2-amino-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]ethyl}phosphonate and 0.092 g (0.54 mmol) of 4-chlorophenyl isocyanate in 10 ml of dichloromethane is stirred at room temperature for 12 hours. The methylene chloride solution is subsequently washed successively with 10 ml of each of 1N hydrochloric acid, saturated sodium hydrogencarbonate solution and water and dried over sodium sulfate. After the solvent has been stripped off, 10 ml of diethyl ether are added to the residue, and the white precipitate deposited is filtered off, giving 0.28 g (100%) of (S)-2-[3-(4-chlorophenyl)ureido]-N-[4-(3-oxomorpholin-4-yl)phenyl]-3-(dimethoxyphosphoryl)propionamide (“1D”), ESI 525.
Reaction SMILES: C([O:5][C:6](=[O:18])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:17])[CH:13]([CH3:16])[CH2:14][SH:15])(C)(C)C.C(OC(=O)[C@@H]1CCCN1C(=O)CCS)(C)(C)C>>[SH:15][CH2:14][CH:13]([CH3:16])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:18])=[O:5])=[O:17]
Reactant: CC(CS)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CCS
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
By substituting 1-(3-mercapto-2-methylpropanoyl)-L-proline tert. butyl ester for the 1-(3-mercaptopropanoyl-L-proline tert.butyl ester in the procedure of Example 18C, 1-(3-mercapto-2-methylpropanoyl)-L-proline is obtained. Rf 0.35 (Silica gel, Benzene/acetic acid 3:1), Rf 0.5 (Silica gel, Methyl-ethylketone/Acetic acid/Pyridine/Water 14:1:2:1), identical to the compound of Example 34.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([O:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCc1oc(Oc2ccccc2)nc1-c1ccc(Cl)cc1
Temperature: 140 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g), phenol (0.94 g), potassium carbonate (2.10 g) and N,N-dimethylformamide (10 ml) was stirred at 140° C. for 3 hours. Water was added to the reaction mixture, which was then acidified with 6 N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-phenoxy-5-oxazolepropionic acid (1.60 g, 93%). This was recrystallized from ethyl acetate to give colorless needles. mp 136-137° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[C:20]([CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[C:21]1([C:20]2[CH:28]=[C:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:6]3[N:5]=[C:4]([C:7]4[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=4)[C:3]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)=[C:2]3[N:1]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(-c2nn3c(-c4ccccc4)cc(-c4ccccc4)nc3c2-c2ccncc2)cc1
Temperature: 0 °C
Yield: 93.9 %

Procedure:
A mixture of 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (153 mg), dibenzoylmethane (162 mg) and conc. hydrochloric acid (0.1 ml) in ethanol (5 ml) was refluxed for 4 hours. The reaction mixture was cooled and poured into ice-water. The mixture was neutralized with an aqueous saturated sodium bicarbonate solution. The separated oil was extracted with dichloromethane and the extract was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from methanol to give 5,7-diphenyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine (250 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:34][OH:35])=[C:19]([N:23]3[C:27]4[N:28]=[CH:29][N:30]=[CH:31][C:26]=4[C:25]([C:32]#[N:33])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:38])C.O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:34][OH:35])=[C:19]([N:23]3[C:27]4[N:28]=[CH:29][N:30]=[CH:31][C:26]=4[C:25]([C:32]([NH2:33])=[O:38])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5cncnc54)c3CO)ncc2c1
Reactant: CCO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5cncnc54)c3CO)ncc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
In a 10 mL round-bottomed flask, 7-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (39 mg, 83.2 μmol, Eq: 1.00) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (1 mg, 2.33 μmol, Eq: 0.0280) were combined with Ethanol (2 ml) and Water (1 ml) to give a colorless solution. The reaction mixture was heated to 80° C. and stirred for 2 h. The reaction mixture was diluted with DCM. The reaction mixture was filtered through glass fiber paper. HPLC purification done to obtain 7-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid amide (33 mg, 66%, [M+H]+ 487).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]([OH:36])=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([C:34]([OH:36])=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2ccc(C(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-carboxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: CN(C)C=O.[CH:6]1[CH:11]=[C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([SH:16])[C:9]2=[CH:8][CH:7]=1.Br[C:18]1[O:22][CH:21]=[C:20]([C:23]([OH:25])=[O:24])[CH:19]=1>O>[C:15]1([S:16][C:18]2[O:22][CH:21]=[C:20]([C:23]([OH:25])=[O:24])[CH:19]=2)[C:9]2[C:10](=[CH:11][CH:6]=[CH:7][CH:8]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: Sc1cccc2ccccc12
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1coc(Sc2cccc3ccccc23)c1

Procedure:
Following the procedure of Example 9, except that a total volume of 90 ml. of dimethylformamide was used, 1-thionaphthol (5.02 g., 31.4 mmoles) was reacted with 5-bromofuran-3-carboxylic acid. Crude product was isolated as an oil according to Example 16. The oil was solidified by trituration with water (988 mg.). Recrystallization from hexane gave purified 5-(1-naphthylthio)furan-3-carboxylic acid (250 mg., m.p. 118°-120° C., m/e 270).
Reaction SMILES: [SH2:1].C(O)C.[C:5]([CH:7]([C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)[NH:8][C:9]([C:11]1[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=1)=[O:10])#[N:6]>C(N(CC)CC)C>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[CH:7]([C:5](=[S:1])[NH2:6])[NH:8][C:9]([C:11]1[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=1)=[O:10]
Reactant: S
Reactant: Cn1cc(C(=O)NC(C#N)c2ccco2)cn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)NC(C(N)=S)c2ccco2)cn1
Reaction time: 1 h

Procedure:
Hydrogen sulfide was blown into an ethanol solution containing 1.4 g of the N-(cyano-2-furanylmethyl)-1-methyl-1H-pyrazol-4-carboxamide as obtained in the above process and 0.7 g of triethylamine, for 1 hour, and the whole was stirred for 1 hour under cooling with ice and then for a further 2 hours at room temperature. Afterwards, the crystal formed was taken out by filtration, washed with chloroform and then dried, to obtain 1.1 g of the intended N-[2-furanyl(thiocarbamoyl)-methyl]-1-methyl-1H-pyrazole-4-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19]([O:21]CCCC)=[O:20])=[CH:4][CH:3]=1.[CH:28](O)([CH3:30])[CH3:29].C1COCC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19]([O:21][CH:28]([CH3:30])[CH3:29])=[O:20])=[CH:26][CH:27]=1
Reactant: CCCCOC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1
Reactant: CC(C)O
Solvent: C1CCOC1
Product: Cc1nc2ccccc2c(NCc2ccc(Br)cc2)c1C(=O)OC(C)C

Procedure:
Isopropyl 4-(4-bromobenzylamino)-2-methylquinoline-3-carboxylate was prepared in analogy to n-butyl 4-(4-bromobenzylamino)-2-methylquinoline-3-carboxylate (see Example 6) by transesterification of the corresponding methyl ester in an isopropanol/THF mixture, resulting in the title compound as a colorless oil. MS(ES+): 413/415.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:27])=[CH:8][N:7]=1)=[O:5].[CH3:32][S:33](Cl)(=[O:35])=[O:34].Cl.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>N1C=CC=CC=1.C1COCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:11]2[C:6]([C:4](=[O:5])[C:3]3[CH:28]=[CH:29][CH:30]=[CH:31][C:2]=3[NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[N:7][CH:8]=[C:9]([Cl:27])[CH:10]=2)(=[O:15])=[O:14])=[CH:17][C:18]=1[C:23]([F:26])([F:25])[F:24]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-[2-(2-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide (24 mg, 0.048 mmol) in anhydrous pyridine (1 mL) was added methane sulfonyl chloride (9 mg, 0.075 mmol). The resulting mixture was stirred at room temperature for 2 h was poured into 1 M HCl and extracted with EtOAc. The extracts were concentrated under reduced pressure and the residues was purified by flash column chromatography to trissulfonamide Mass spectrum m/z: 515.0 (M+H). To this trisulfonamide (14 mg, 0.021 mmol) in THF was added TBAF (1 M in THF, 40 μL, 0.04 mmol) and the resulting mixture was stirred overnight. The reaction mixture was quenched with 1 M HCl and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (combi-flash) to provide 4-Chloro-N-[5-chloro-2-(2-methanesulfonylamino-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 9.60 (br, 2 H), 8.38 (d, J=2.0 Hz, 1 H), 8.16 (d, J=2.0 Hz, 1 H), 8.04 (d, J=2.0 Hz, 1 H), 7.87 (dd, J=8.4, 2.4 Hz, 1 H), 7.72-7.70 (m, 1 H), 7.62-7.57 (m, 1 H), 7.53 (d, J=8.4 Hz, 1 H), 7.29 (dd, J=8.0, 2.4 Hz, 1 H), 7.08-7.05 (m, 1 H), 3.07 (s, 3 H); Mass spectrum m/z: 515.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])[CH:11]=[C:12](I)[C:6]=2[N:5]=1)[CH3:2].[CH3:21][N:22]1[C:26](B2OC(C)(C)C(C)(C)O2)=[C:25]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:24]=[N:23]1.COCCOC>O>[CH2:1]([O:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])[CH:11]=[C:12]([C:26]3[N:22]([CH3:21])[N:23]=[CH:24][C:25]=3[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2c(I)cc(-c3c(C)noc3C)cc2[nH]1
Reactant: Cn1ncc(-c2ccccc2)c1B1OC(C)(C)C(C)(C)O1
Solvent: COCCOC
Solvent: O
Product: CCOc1nc2c(-c3c(-c4ccccc4)cnn3C)cc(-c3c(C)noc3C)cc2[nH]1
Temperature: 130 °C
Yield: 14.9 %

Procedure:
4-(2-ethoxy-4-iodo-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole (100 mg, 0.26 mmol) and 1-methyl-4-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (37 mg, 0.13 mmol) was added to a solvent mixture of 1,2-dimethoxyethane (2 ml) and water (1 ml). To the above mixture were added PEPPSI-Ipr (18 mg, 0.026 mmol) and CsCO3 (127 mg, 0.39 mmol). The reaction mixture was heated at 130° C. in microwave reactor for 30 mins. The reaction mixture was then filtered and organic solvent was evaporated and the residue was purified with Prep HPLC (0-100% CH3CN/H2O) to afford 8 mg product 4-(2-ethoxy-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[C:25]2[C@:20]([CH3:28])([C@H:21]3[CH2:27][C@H:22]3[C:23](=[O:26])[CH:24]=2)[C@@H:19]2[C@H:8]([C@H:9]3[C@:16]([CH3:29])([CH2:17][CH2:18]2)[C@@:12]([OH:30])([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)[CH:7]=1.C(O)(=O)C.[Cl:35]C1C2[C@](C)(CCC(=O)C=2)[C@@H]2[C@H]([C@H]3[C@](C)(CC2)[C@@](O)(C(=O)C)CC3)C=1>>[Cl:35][C:24]1[C:23](=[O:26])[C@@H:22]2[CH2:27][C@@H:21]2[C@@:20]2([CH3:28])[C:25]=1[C:6]([Cl:5])=[CH:7][C@@H:8]1[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:29])[C@H:9]1[CH2:10][CH2:11][C@:12]2([OH:30])[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C
Solvent: CC(=O)O
Product: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C=C(Cl)C4=C(Cl)C(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
Preferred compounds of formula (I) are 6-chloro-17-hydroxy-1α,2α-methylene-pregna-4,6-diene-3,20-dione acetate (cyproterone acetate) and 6-chloro-17-hydroxy-pregna-4,6-diene-3,20-dione acetate (chlormadinone acetate).
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:19]3[C:11](=[N:12][NH:13][C:14]=3[N:15]=[C:16]([S:20][CH3:21])[N:17]=2)[CH:10]([C:22](O)=[O:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:25]([NH:32][C:22]([CH:10]1[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:18]2[C:19]3[C:11]1=[N:12][NH:13][C:14]=3[N:15]=[C:16]([S:20][CH3:21])[N:17]=2)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CSc1nc2c3c(n[nH]c3n1)C(C(=O)O)CN2Cc1ccccc1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1nc2c3c(n[nH]c3n1)C(C(=O)NCc1ccccc1)CN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
5-Benzyl-7-(methylthio)-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylene-3-carboxlic acid (0.71 g, 2.1 mmol) and DMF (20 ml) were placed in a round-bottomed flask. To the stirring mixture was slowly added benzylamine (0.34 mL, 3.2 mmol), HBTU (1.03 g, 3.4 mmol), diisopropylethyl amine (1.1 mL, 6.3 mmol) and the solution was allowed to stir at room temperature for 16 h. The reaction was quenched by addition of EtOAc (200 mL) and washing with water (2×500 mL). The organic layer was combined, dried over MgSO4, and concentrated under reduced pressure to yield a yellow solid (0.84 g, 2.0 mmol). 1H-NMR (DMSO-d6): 8.56 (t, J=2.0 Hz, 1H), 7.40-7.22 (m, 10H), 4.36 (dd, J=8.1 & 21.2 Hz, 3H), 4.38-4.21 (m, 3H), 4.19 (t, J=5.2 Hz, 2H), 3.86-3.76 (m, 3H), 3.17 (d, J=5.2 Hz, 1H). LC: Rt=1.42 min. MS 431.53 [M+H].
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([F:12])[F:11])=[C:4]([NH2:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B2OCCCO2)=[C:17]([F:27])[C:16]=1[O:28][CH3:29].[F-].[Cs+].O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:6]1[C:5]([O:9][CH:10]([F:12])[F:11])=[C:4]([NH2:13])[CH:3]=[C:2]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([O:28][CH3:29])[C:17]=2[F:27])[N:7]=1
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Reactant: Nc1cc(Br)nc(Cl)c1OC(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: COc1c(Cl)ccc(-c2cc(N)c(OC(F)F)c(Cl)n2)c1F
Yield: 84.2 %

Procedure:
6-Bromo-2-chloro-3-(difluoromethoxy)pyridin-4-amine (368 mg, 1.346 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (395 mg, 1.615 mmol), PdCl2(PPh3)2 (47.2 mg, 0.067 mmol), and CsF (409 mg, 2.69 mmol) were combined in DME (2 mL) and H2O (2 mL) and heated in a Biotage microwave reactor at 110° C. for 15 min. The cooled reaction mixture was partitioned between EtOAc and H2O. The organic phase was dried, concentrated onto silica gel, and purified by flash chromatography (SiO2, EtOAc/hexane gradient). This process yielded the title compound as a white solid (0.4 g, 84%): mp 152-154° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.63-7.50 (m, 1H), 7.42 (dd, J=8.7, 1.6, 1H), 7.16 (d, J=1.8, 1H), 7.02 (t, J=73.4, 1H), 6.70 (s, 2H), 3.93 (d, J=0.8, 3H); ESIMS m/z 354 ([M+H]+), 352 ([M−H]−).
Reaction SMILES: Cl.[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH2:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[CH:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH:16][C:33]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a solution of (1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) were added cyclohexanecarbonyl chloride (87.8 ml, 0.59 mmol) and saturated-aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give the title compound (141 mg, 79%).