Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([O:24][N:25]1[C:31](=[O:32])[N:30]2[CH2:33][C@H:26]1[CH2:27][CH2:28][C@H:29]2[C:34]([NH:36][NH2:37])=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:17]([O:24][N:25]1[C:31](=[O:32])[N:30]2[CH2:33][C@H:26]1[CH2:27][CH2:28][C@H:29]2[C:34]([NH:36][NH:37][C:14]([C@H:11]1[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)=[O:16])=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)O)C1
Reactant: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
To a 0° C. solution of (1S,3R)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (3.8 g, 16.6 mmol) and (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbohydrazide (5.3 g, 18.26 mmol) in DMF (30 mL) were added HATU (7.6 g, 19.92 mmol) and DIPEA (11.6 ml, 66.4 mmol). The reaction mixture was stirred at 0° C. for 1.5 hrs. The reaction mixture was diluted with water and extracted with EtOAc (2×). The combined organic layer was washed with saturated sodium chloride (4×) and citric acid (5% aq.), dried over Na2SO4, and concentrated. The residue was purified by silica gel column (gradient elution 50˜80% EtOAc/petroleum ether) to afford tert-butyl (1R,3S)-3-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl) hydrazinecarbonyl)cyclopentylcarbamate (4.5 g, 55%) as a white solid. ESI-MS (EI+, m/z): 502.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([F:12])[CH3:11])=[CH:6][C:5]=1[N+:13]([O-])=O>CO.CCO.[Ni]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([F:12])[CH3:11])=[CH:6][C:5]=1[NH2:13]
Reactant: COC(=O)c1ccc(C(C)F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: CCO
Product: COC(=O)c1ccc(C(C)F)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
A solution of 4-(1-fluoro-ethyl)-2-nitro-benzoic acid methyl ester (0.6 g, 2.64 mmol) in MeOH (15 mL) was treated with Nickel-raney in EtOH (254 mL) and the mixture was stirred at r.t. for 3 h under H2 (0.1 bar). The mixture was then filtered and concentrated in vacuo to give 2-amino-4-(1-fluoro-ethyl)-benzoic acid methyl ester (334 g, 1.69 mmol, 93%) as a yellow oil. ESI-MS: m/z 198 [M+H]+, rt 4.86 min.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:24]=[CH:25][CH:26]=1)=[CH2:20])C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:19]([C:21]2[CH:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[CH:24]=[CH:25][CH:26]=2)[CH3:20])[C:9]=1[OH:8])([CH3:16])([CH3:17])[CH3:18]
Reactant: C=C(c1cccc(-c2ccccc2OC)c1)c1cccc(C(C)(C)C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccccc1-c1cccc(C(C)c2cccc(C(C)(C)C)c2O)c1
Reaction time: 3 h
Yield: 59.3 %

Procedure:
A solution of 28 (1.3 g, 2.9 mmol) in methanol (20 mL) and ethyl acetate (30 mL) was treated with 20% palladium on activated carbon (50% wet, 0.10 g) and was hydrogenated at 40 psi in a Parr shaker for 3 hr. The catalyst was filtered out and washed with ethyl acetate. The filtrate was stripped and the crude product was purified by chromatography on silica (60 g) with 2% ethyl acetate in hexane (3 L) to afford pure D3 (0.62 g, 59%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15]Br)=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].[CH3:25][NH2:26]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][NH:26][CH3:25])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CBr
Reactant: CN
Solvent: CO
Product: CNCC1=C(n2ccccc2=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Yield: 71.5 %

Procedure:
A solution of 6-nitro-2,2-dimethyl-3-bromomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.5 g, 1.27 mmol) and methylamine (40% in water, 1.1 ml, 1.397 mmol) in methanol (12 ml) was stirred at room temperature during four hours. The solvents were evaporated under reduced pressure, and water and ethyl acetate added to the residue. After stirring, the organic phase was separated and evaporated under reduced pressure. The residue was dissolved in diethyl ether and precipitated with pentane, to give 0.31 g of 6-nitro-2,2-dimethyl-3-(methylamino)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 128° C.
Reaction SMILES: [OH:1][C@@H:2]([CH2:28][C@@H:29]([NH:37][C:38](=[O:49])[C@@H:39]([NH:44][C:45]([O:47][CH3:48])=[O:46])[C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:3]([NH:17]C(=O)OCC1C=CC=CC=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.Cl>CO.[OH-].[OH-].[Pd+2]>[NH2:17][C@@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)[C@@H:2]([OH:1])[CH2:28][C@@H:29]([NH:37][C:38]([C@@H:39]([NH:44][C:45](=[O:46])[O:47][CH3:48])[C:40]([CH3:42])([CH3:43])[CH3:41])=[O:49])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccncc2)cc1)NC(=O)OCc1ccccc1)C(C)(C)C
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccc(-c2ccncc2)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution containing the product from Example 104A (0.045 mmol) in methanol (0.5 mL) was treated with Pd(OH)2 on carbon (0.010 g, 20% Pd by wt.) and HCl solution (0.035 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) for 4 hours at 25° C., filtered through a bed of celite®, rinsed with methanol, and concentrated to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([F:22])([F:21])[C:6]([F:20])([F:19])[C:7]([F:18])([F:17])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH3:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:27](O)=[O:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:27]([O:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:7]([F:17])([F:18])[C:6]([F:19])([F:20])[C:5]([F:21])([F:22])[CH2:4][O:3][CH2:1][CH3:2])=[CH:11][CH:12]=1)=[O:28]
Reactant: CCOCC(F)(F)C(F)(F)C(F)(F)COc1ccc(O)cc1
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1Cl
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(OCC(F)(F)C(F)(F)C(F)(F)COCC)cc2)cc1Cl

Procedure:
4-(5-Ethoxy-2,2,3,3,4,4-hexafluoropentoxy)phenyl 3-chloro-4-octyloxybenzoate (Compound 5, Table 1) was prepared by esterification of 4-(5-ethoxy-2,2,3,3,4,4-hexafluoropentoxy)phenol (prepared essentially as in Example 4) with 3-chloro-4-octyloxybenzoic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[C:5]([Cl:12])=[CH:4][N:3]=1.[Cl-].[Ca+2].[Cl-]>C(O)C.[Zn]>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:11])[C:5]([Cl:12])=[CH:4][N:3]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Product: Nc1ncc(Cl)c(Cl)c1N
Yield: 67.4 %

Procedure:
2-Amino-4,5-dichloro-3-nitropyridine (Example 206b) (1.04 g, 5.0 mmol), zinc powder (2.4 g, 37 mmol) and anhydrous calcium chloride (3 g, 27 mmol) were mixed in 95% ethanol (30 ml) and heated to reflux for 1 h. When cool, the reaction mixture was filtered through celite and evaporated in vacuo. The residue was dissolved in methanol/dichloromethane 1:1 and chromatographed through a short column of silica (10 g) eluting with methanol/dichloromethane 3:7. The fraction containing the product was concentrated in vacuo and the residue dissolved in methanol/acetonitrile 1:9 and again concentrated in vacuo together with silica. The product thus adsorbed on silica gel was again subjected to chromatography on silica gel (EtOAc) to afford the pure product as a off-white powder (0.60 g, 67%).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:49]1[N:50]=[CH:51][S:52][CH:53]=1)[C:19]([NH:21][CH:22]1[C:47](=[O:48])[N:24]2[C:25]([C:31]([O:33]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:32])=[C:26]([CH:29]=[CH2:30])[CH2:27][S:28][C@H:23]12)=[O:20])=[O:14])(C)(C)C.C(OC(C)C)(C)C.CCCCCC>C(Cl)Cl.C1(OC)C=CC=CC=1>[C:13]([CH2:15][O:16][N:17]=[C:18]([C:49]1[N:50]=[CH:51][S:52][CH:53]=1)[C:19]([NH:21][CH:22]1[C:47](=[O:48])[N:24]2[C:25]([C:31]([OH:33])=[O:32])=[C:26]([CH:29]=[CH2:30])[CH2:27][S:28][C@H:23]12)=[O:20])([OH:14])=[O:12]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cscn3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3cscn3)[C@H]2SC1
Reaction time: 1.5 h
Yield: 65.7 %

Procedure:
Trifluoroacetic acid (11.2 ml) was added to a stirred suspension of benzhydryl 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.8 g) in methylene chloride (5.6 ml) and anisole (2.8 ml) at ambient temperature and the mixture was stirred for 1.5 hours at the same temperature. To the resultant solution was added diisopropyl ether (40 ml) and n-hexane (30 ml) and the mixture was stirred. The precipitates were collected by filtration, washed with a solution of diisopropyl ether and n-hexane (1:1). The precipitates were added to a mixture of ethyl acetate and water and the mixture was adjusted to pH 7.0 with a saturated aqueous solution of potassium carbonate. The separated aqueous layer was adjusted to pH 4.0 with 10% hydrochloric acid and the solution was washed with ethyl acetate. The aqueous layer was adjusted to pH 1.8 with 10% hydrochloric acid and saturated with sodium chloride. The acidic solution was extracted with ethyl acetate and tetrahydrofuran (1:1). The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to give 7-[2-carboxymethoxyimino-2-(4-thiazolyl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.22 g).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18][C:19](=[O:21])[CH3:20])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8](O)=[O:9])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:25])=O.CN(C)C=O>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18][C:19](=[O:21])[CH3:20])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8]([Cl:25])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C(=O)O)cc(OC(C)=O)c1OC(C)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc(C(=O)Cl)cc(OC(C)=O)c1OC(C)=O
Reaction time: 2 h

Procedure:
3,4,5-Triacetoxybenzoic acid (296.23 g, 1 mol) was slurried in a 2 L flask in CH2Cl2 (1.0 L), and oxalyl chloride (113 mL, 1.3 mol) as added, followed by slow, dropwise addition of N,N-dimethylformamide (1.5 mL). After 2 hours at RT, gas evolution had ceased, and 3,4,5-triacetoxybenzoyl chloride was isolated by evaporation under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH:8]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[CH3:9].[CH3:22]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([CH3:22])=[CH:6][C:7]=1[CH:8]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[CH3:9]
Reactant: CC(c1cc(Cl)nnc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(C)N2C(=O)c3ccccc3C2=O)c(Cl)nn1
Temperature: 110 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
2-[1-(3,6-Dichloropyridazin-4-yl)ethyl]isoindoline-1,3-dione (161 mg, 0.5 mmol), trimethylboroxine (0.209 mL, 1.5 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane complex (35.1 mg, 0.05 mmol) and potassium carbonate (82.9 mg, 0.6 mmol) were mixed with water (0.2 mL) and 1,4-dioxane (0.9 mL) and stirred at 110° C. for 8 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and the solvent was removed by vacuum distillation. The resulting residue was mixed with 4 M hydrogen chloride/1,4-dioxane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (hexane/ethyl acetate=1/1) to give the desired product (29 mg, 19% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH:42]3[CH2:43][CH2:44][CH2:45][CH2:46]3)[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C3CCCC3)c2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C4CCCC4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(2-cyclopentyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K61) (274 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (369 mg, 86%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C@:14]3([CH2:31][CH2:30][C@H:29]4[C@@H:19]([CH2:20][CH:21]=[C:22]5[C@:27]4([CH3:28])[CH2:26][CH2:25][C@H:24]([OH:32])[CH2:23]5)[C@@H:16]3[CH2:17][CH:18]=2)[CH3:15])[N:12]=1.Br.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C@:14]3([CH2:31][CH2:30][C@H:29]4[C@@H:19]([CH2:20][CH:21]=[C:22]5[C@:27]4([CH3:28])[CH2:26][CH2:25][C:24](=[O:32])[CH2:23]5)[C@@H:16]3[CH2:17][CH:18]=2)[CH3:15])[N:12]=1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3csc(N)n3)=CC[C@@H]12
Agent: Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C[C@]12CCC(=O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3csc(N)n3)=CC[C@@H]12
Temperature: -55 °C
Reaction time: 0.5 h

Procedure:
Dissolve oxalyl chloride (8.86 mL of a 2.0M solution in methylene chloride, 17.73 mmol) in methylene chloride (65 mL) under an atmosphere of nitrogen and cool the solution to -55° C. Add dimethylsulfoxide (1.47 mL, 20.68 mmol) dropwise and stir for 3 minutes. Then add a solution of (3β)-17-(2-amino-4-thiazolyl)-androsta-5,16-dien-3-ol.HBr.CH3 CH2OH (2.94 g, 5.91 mmol) prepared in either example 1a or 1b, dissolved in methylene chloride (20 mL) and dimethylsulfoxide (10 mL) to the reaction slowly over 4 minutes and stir for 30 minutes. Then add triethylamine (5.77 mL, 41.36 mmol) and after 5 minutes of stirring allow the reaction to warm to room temperature. Dilute the reaction with methylene chloride (180 mL) and wash with dilute sodium bicarbonate (4×225 mL) and brine/saturated sodium bicarbonate, 3:1 (200 mL). Dry the organic phase over anhydrous magnesium sulfate, filter and concentrate under vacuum to provide a brown foam. Purify by flash chromatography (ethyl acetate/hexane, silica gel) followed crystallization from ethyl acetate/hexane to provide the title compound (135 mg) as a light orange solid after drying under high vacuum at 56° C. for 2 hours, (Rf=0.38, 50% ethyl acetate/hexane, SiO2); 1H NMR (DMSO-d6) δ6.85 (broad singlet, 2H), 6.45 (s, 1H), 6.06 (broad triplet, 1H, J=1.9, 3.0 Hz), 5.35-5.31 (m, 1H), 3.43 (dq, 1H, J=2.6, 15.9 Hz), 2.67 (dd, 1H, J=1.8, 16.0 Hz), 1.21 (s, 3H), 0.97 (s, 3H); MS (CI/CH4) m/z (rel. intensity) 369 (MH+, 100), 368 (23); HRMS C22H29N2OS (MH+) calcd 369.2001, observed 369.1989.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][NH:7][C:8](=[O:29])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[N+:26]([O-])=O)[CH:10]=1>CO.[Pd]>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][NH:7][C:8](=[O:29])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH2:26])[CH:10]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCC3)ccc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-nitro-5-(pyrrolidin-1-yl)phenyl)isonicotinamide (400 mg, 0.85 mmol, 1.00 equiv) in methanol (20 mL). The solution was treated with Pd/C (400 mg) and stirred under an atmosphere of hydrogen for 3.5 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The product was obtained as 300 mg (80%) of a yellow to green solid.
Reaction SMILES: Br[CH2:2][C:3]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH:4]([NH:12][CH:13]=[S:14])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(C)=O>[OH:19][C@:3]1([C:15]([F:18])([F:17])[F:16])[CH2:2][S:14][CH:13]=[N:12][C@@H:4]1[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)C(NC=S)C(O)(CBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H]1N=CSC[C@]1(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of 3.67 gms of (2R,3S) and 2S,3R)-t-butyl 4-bromo-3-hydroxy-2-thioformamido-3-trifluoromethylbutyrate in 65 ml acetone was added 4.15 g powdered anhydrous potassium carbonate. The reaction mixture was stirred for 30 minutes at room temperature, filtered and evaporated to dryness under reduced pressure. The crude brown oil was then purified by chromatography on silica gel using 80:20 hexane:ethyl acetate as the eluting solvent to give 0.781 gms of white solid, (4R,5S) and (4S,5R)-t-butyl 5-hydroxy-5-trifluoromethyl-4,5-dihydro-6H-1,3-thiazine-4-carboxylate (yield 27%) m.p. 126.5°-127.5° C. NMR (CDCL3): δ=1.55 (s, 9H), 2.93, 3.13 (AB-q, J=13.8 Hz, 2H), 4.13 (d, J=2.7 Hz, 1H), 5.33 (s, 1H), 8.25 (d-d, J=2.7, 1.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[O:32]1[C:36]2[C:37]([S:41](Cl)(=[O:43])=[O:42])=[CH:38][CH:39]=[CH:40][C:35]=2[CH2:34][CH2:33]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:41]([C:37]1[C:36]2[O:32][CH2:33][CH2:34][C:35]=2[CH:40]=[CH:39][CH:38]=1)(=[O:42])=[O:43]
Reactant: O=S(=O)(Cl)c1cccc2c1OCC2
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccc2c1OCC2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 2,3-dihydrobenzofuran-7-sulfonyl chloride (15 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH2:27][NH:26][CH2:25][CH2:24]4)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8].[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C.O.NN>CN(C=O)C.O>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH2:27][N:26]([S:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:39])=[O:38])[CH2:25][CH2:24]4)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1ccc2c(c1)CCNC2
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1ccc2c(c1)CCN(S(=O)(=O)c1ccccc1)C2
Yield: 64.8 %

Procedure:
25 mg (0.049 mmol) of 1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide, 0.01 mL of (0.07 mmol) benzenesulfonyl chloride, and 0.07 mL of (0.5 mmol) triethylamine in 0.5 mL DMF was stirred at room temperature for 1 h. The reaction mixture was then treated with 0.024 mL of hydrazine hydrate and diluted with water. The precipitated solid was filtered and washed with water to give 2-benzenesulfonyl-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide (17.2 mg, 65%). LCMS: 542 (M+1)+.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][CH:7]([C:9]([O:11][CH3:12])=[O:10])C)[C:3](O)=[O:4].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:1][CH:2]([CH2:6][CH2:7][C:9]([O:11][CH3:12])=[O:10])[C:3]([Cl:15])=[O:4]
Reactant: COC(=O)C(C)CC(Cl)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)CCC(Cl)C(=O)Cl
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 7.6 g of 2-chloro-4-methoxycarbonyl valeric acid, 9.2 ml of thionyl chloride and 30 ml of toluene was stirred for 30 minutes at 80° C., followed by distilling off the solvent under reduced pressure to leave 2-chloro-4-methoxycarbonyl butyryl chloride. A mixture of this compound, 5.0 g of 2-benzylaminobenzophenone, 100 ml of ethyl acetate and 100 ml of a saturated aqueous solution of sodium hydrogencarbonate was stirred for 30 minutes at room temperature. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluent, hexane:ethyl acetate=5:1) to give 1.2 g of 2-[N-benzyl-N-(2-chloro-4-methoxy carbonyl)butyryl]aminobenzophenone as an oily product.