Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[CH:18][S:19][C:13]3=[N:12][C:11]=2[CH3:20])=[CH:6][CH:5]=1)[CH3:2].[CH:21]1(CBr)C[CH2:22]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH:2]1([CH2:1][O:3][C:4]2[CH:5]=[CH:6][C:7]([C:10]3[C:15](=[O:16])[N:14]4[CH:17]=[CH:18][S:19][C:13]4=[N:12][C:11]=3[CH3:20])=[CH:8][CH:9]=2)[CH2:22][CH2:21]1
Reactant: BrCC1CC1
Reactant: CCOc1ccc(-c2c(C)nc3sccn3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc2sccn2c(=O)c1-c1ccc(OCC2CC2)cc1
Temperature: 80 °C

Procedure:
To a solution of Step 1 intermediate from Intermediate 10 (500 mg, 1.932 mmol) in DMF (5 ml) was added cyclopropylmethyl bromide (0.313 g, 2.321 mmol) at room temperature followed by Cs2CO3 (1.88 g, 5.770 mmol) and the reaction temperature was heated to 80° C. for 15.0 h overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine and purified by column chromatography using 1% methanol in chloroform to afford the desired compound; 1H NMR (300 MHz, CDCl3) δ 0.35-0.37 (m, 2H), 0.59-0.61 (m, 2H), 1.01-1.03 (m, 1H), 2.19 (s, 3H), 3.80-3.85 (m, 2H), 7.09-7.11 (m, 2H), 7.26-7.29 (m, 2H), 7.52 (d, J=4.8 Hz, 1H), 7.97 (d, J=4.5 Hz, 1H); MS (m/z) 313.25 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]2=[N:7][N:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](=[O:11])[CH:10]=[C:5]2[NH:4][N:3]=1.Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1>CN1CCCC1=O.CO>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9](=[O:11])[CH:10]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][C:21]4[N:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:6]3=[N:7]2)=[CH:13][CH:14]=1
Reactant: Clc1ncccn1
Reactant: COc1ccc(-n2nc3c(N)n[nH]c3cc2=O)cc1
Solvent: CO
Solvent: CN1CCCC1=O
Product: COc1ccc(-n2nc3c(Nc4ncccn4)n[nH]c3cc2=O)cc1
Temperature: 130 °C
Reaction time: 5 h
Yield: 56.6 %

Procedure:
To 3-amino-5-(4-methoxy-phenyl)-1,5-dihydro-pyrazolo[4,3-c]pyridazin-6-one (purchased from Bionet, 67.6 mg, 0.2628 mmoles) in N-methylpyrrolidinone (263 uL) was added 2-chloro-pyrimidine (15.1 mg, 0.5 eq). The reaction was stirred for 5 hours at 130° C. to give crude desired product as evidenced by mass spectrometry. The reaction was diluted with methanol (2 ml) and purified by reverse phase chromatography to give 25 mg (28%) of pure 5-(4-methoxy-phenyl)-3-(pyrimidin-2-ylamino)-1,5-dihydro-pyrazolo[4,3-c]pyridazin-6-one (I-17) as a solid. LC/MS: tret=2.13 min, M+H+=336.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1.[OH-].[Na+]>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1
Reactant: CCOC(=O)CCCCCn1c(CCOC)nc2cnc3ccccc3c21
Agent: [Na+]
Agent: [OH-]
Product: COCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Ethyl 6-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]hexanoate (12.05 g, 32.61 mmol) was treated with sodium hydroxide (1.70 g, 42.4 mmol) according to a modification of the method described in Part A of Example 11. The reaction was stirred overnight at ambient temperature to provide 8.35 g of 6-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]hexanoic acid after the aqueous work-up procedure.
Reaction SMILES: [CH2:1]([C@:8]1([C:23]([NH:25][CH2:26][CH:27]([OH:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:24])[O:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([C@:8]1([C:23]([NH:25][CH2:26][C:27](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:24])[O:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](c1ccccc1)N1C(=O)O[C@](Cc2ccccc2)(C(=O)NCC(O)c2ccccc2)C1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1C(=O)O[C@](Cc2ccccc2)(C(=O)NCC(=O)c2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
To the product from Step A (100 mg, 0.218 mmol) in dichloromethane (3 mL) was added Dess-Martin periodinane (143 mg, 0.327 mmol) and the mixture was stirred for 30 min. A 1:1 mixture of saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate (10 mL) was added and the mixture was stirred rapidly for 15 min. The layers were separated and the aqueous phase extracted with dichloromethane (3×10 mL). The combined organic phases were washed with saturated aqueous brine (1×15 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo, to afford the crude colorless title compound as an amorphous solid. LC/MS 457.1 (M+1).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][C:15]([NH:17][C@@H:18]([CH:39]([CH3:41])[CH3:40])[C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]([NH:28][CH:29]([CH:33]([OH:38])[C:34]([F:37])([F:36])[F:35])[CH:30]([CH3:32])[CH3:31])=[O:27])=[O:20])=[O:16].ClC(Cl)C(O)=O.C(OCC)(=O)C>CS(C)=O.C1(C)C=CC=CC=1>[CH3:13][O:14][C:15]([NH:17][C@@H:18]([CH:39]([CH3:41])[CH3:40])[C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]([NH:28][CH:29]([C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])[CH:30]([CH3:32])[CH3:31])=[O:27])=[O:20])=[O:16]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)NC(C(C)C)C(O)C(F)(F)F)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)NC(C(=O)C(F)(F)F)C(C)C)C(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.84 g) was added to a solution of (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N-[2-methyl-1-(2,2,2-trifluoro-1-hydroxyethyl)propyl]pyrrolidine-2-carboxamide (0.41 g) dissolved in dimethylsulphoxide (DMSO; 5 ml) and toluene (5 ml), followed by dropwise addition of dichloroacetic acid (0.32 ml). The resulting solution was allowed to stir at 20° C. for 2 hours. The solution was then poured into ethyl acetate (200 ml) and washed successively with 1M hydrochloric acid, water and brine. The organic solution was dried (MgSO4) and concentrated under vacuum. The residue was purified by flash chromatography (gradient elution; methanol:methylene chloride, 3:97 to 5:95) to give (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N-[2-methyl-1-(2,2,2-trifluoroacetyl)propyl]pyrrolidine-2-carboxamide (0.27 g) as a white foam (as a mixture of ketone and hydrated forms); TLC, Rf =0.4 (methanol:dichloromethane, 2.5:97.5); 1H NMR (DMSO/D2O): 4.44 (m, 1H), 4.00 (m, 2H), 3.72 (m, 1H), 3.51 (m, 4H), 202-1.75 (m, 6H), 0.95-0.78 (m, 12H); Analysis for C18H28F3N3O5.0.3H2O: Calculated: C, 50.42; H, 6.72; N, 9.80; Found: C, 50.31; H, 6.28; N, 9.56.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][C:31]=1[CH3:32])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21]CC3C=CC=CC=3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1)(=[O:3])[CH3:2]>[Pd].CO.CN(C=O)C.ClC(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][C:31]=1[CH3:32])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.6 %

Procedure:
A mixture of 4-(3-acetoxy-4-methylanilino)-7-benzyloxy-6-methoxyquinazoline (2.68 g, 5.75 mmol) and 10% palladium-on-charcoal catalyst (0.27 g) in methanol (50 ml), DMF (12 ml) and trichloromethane (50 ml) was stirred at ambient temperature under hydrogen at 1.5 atmospheres pressure for 30 minutes. The catalyst was removed by filtration through diatomaceous earth and the solvent removed from filtrate by evaporation. The residue was triturated with ether, collected by filtration and dried under vacuum at 50° C. to give 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline (2.1 g, 100%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].C(N(CC)CC)C.[C:19](ON1C(=O)CCC1=O)(=[O:43])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].O.CC(C)=O.C(N(CC)CC)C>O.CC(C)=O>[C:19]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2])(=[O:43])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)NCCCC[C@H](N)C(=O)O

Procedure:
To a vigorously-stirred solution of L-lysine monohydrochloride (13 mmol, 2.4 g, commercially available) and triethylamine (39 mmol, 3.9 g) in 50 mL of water-acetone (1:1), was added succinimidyl nervonate (13 mmol, 6.0 g, prepared as in Example 1A) in portions during 0.5 h. During the addition, more water-acetone-triethylamine (10:10:2) was added in order to prevent the product from precipitating as a thick voluminous mass. Stirring was continued for an additional hour. The mixture was then acidified with hydrochloric acid in water (1:1, v/v) to pH 4 and chilled. The light foamy product was separated by filtration and washed with water and hot dioxane to yield the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([NH:8][C:9]2[C:17]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[N+:22]([O-])=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:22][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([S:18](=[O:21])(=[O:20])[NH2:19])[C:9]=1[NH:8][C:7]1[CH:6]=[CH:5][C:4]([C:1]([OH:3])=[O:2])=[CH:26][CH:25]=1)[C:13]([OH:15])=[O:14]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccc(C(=O)O)cc1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Nc1ccc(C(=O)O)cc1

Procedure:
By substituting 4-(p-carboxyanilino)-3-nitro-5-sulphamyl-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained with a melting point of 262° C (decomp.) after drying in vacuo at 115°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.Cl.[C:22](N)(=N)[CH3:23].CC1NC=CN=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:22]([CH3:23])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: CC(=N)N
Agent: Cc1ncc[nH]1
Agent: Cl
Solvent: O
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 160 °C

Procedure:
A mixture of 2.8 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, 2.8 parts of acetamidine hydrochloride and 2.5 parts of 2-methylimidazole is fused under heating at 160° C for 10 minutes. Water is added to the mixture, followed by extraction with methylene chloride. The methylene chloride layer is washed with water and dried over sodium sulfate. The solvent is evaporated, whereby 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine is yielded. Recrystallization from ethyl acetate yields colorless needles melting at 223° C to 225° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.[C:39]([O:43][C:44]([N:46]1[C@H:51]([CH3:52])[CH2:50][CH2:49][C@H:48]([C:53](O)=[O:54])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].C[C@H]1NC[C@@H](C(O)=O)CC1>ClCCl.O>[CH3:52][C@H:51]1[CH2:50][CH2:49][C@@H:48]([C:53]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:54])[CH2:47][N:46]1[C:44]([O:43][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:45]
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1C(=O)OC(C)(C)C
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[C@@H]1CC[C@H](C(=O)O)CN1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@H]1CC[C@@H](C(=O)N2CCCC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (7.50 g, 19.72 mmol), diisopropylethylamine (7.08 mL, 39.45 mmol) and pyrrolidine (1.40 g, 19.72 mmol) were added to a solution of cis-1-(tert-butoxycarbonyl)-6-methylpiperidine-3-carboxylic acid (synthesized by N-Boc protection of cis-6-methylpiperidine-3-carboxylic acid, analogously prepared by the method described in J. Med. Chem. 2011, 54, 1871-1895.) (4.0 g, 16.44 mmol) in anhydrous dichloromethane (40 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 h. Water was added and the mixture was extracted with dichloromethane. The organics were dried over sodium sulfate and concentrated under reduced pressure to afford cis-tert-butyl 2-methyl-5-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate (4.0 g). The material was used without further purification.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].Cl.[C:12](Cl)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1.N>>[N:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:4]=[C:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[O:1][N:2]=2)=[CH:6][N:7]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NC(=NO)c1ccnnc1
Agent: Cl
Agent: N
Product: c1cncc(-c2nc(-c3ccnnc3)no2)c1

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and nicotinoyl chloride hydrochloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.75 (ddd, J=8.0, 4.9, 0.7 Hz, 1 H), 8.32 (dd, J=5.3, 2.2 Hz, 1 H), 8.61 (dt, J=8.2, 1.8 Hz, 1 H), 8.93 (dd, J=5.1, 1.7 Hz, 1 H), 9.39 (dd, J=2.2, 0.8 Hz, 1 H), 9.55 (dd, J=5.4, 1.4 Hz, 1 H), 9.85 (dd, J=2.2, 1.2 Hz, 1 H) ppm; MS (DCI/NH3) m/z 226 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[C:14]1([NH:24][CH2:25][CH2:26][NH2:27])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[C:14]1([NH:24][CH2:25][CH2:26][NH:27][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: NCCNc1cccc2ccccc12
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Product: O=C(NCCNc1cccc2ccccc12)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-(naphthalen-1-ylamino)ethylamine. The product was purified by mass directed purification to give the title compound as a brown solid. δH (CD3OD): 3.55 (2H, t), 3.80 (2H, t), 6.68 (1H, d), 7.04 (1H, s), 7.14 (1H, d), 7.28 (1H, t), 7.36-7.42 (2H, m), 7.65 (1H, s), 7.70-7.74 (1H, m), 7.98-8.02 (1H, m), 8.58 (1H, s); m/z (ES+)=365 [M+H]+.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([Cl:29])[CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:24]=[C:23]([Cl:22])[CH:28]=[C:27]([Cl:29])[CH:26]=3)[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Product: CCc1cc(NC(=O)N2CCN(c3cc(Cl)cc(Cl)c3)CC2)c(OC)nc1C
Yield: 69 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:28][C:29](=[O:38])[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]Cl)[CH:31]=2)=[C:6]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][N:27]=2)[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[O:12])[CH:7]=1.ClCC1C=C(C=CC=1)C(NC1C=CC(N2CCCCC2)=CC=1C1C=C(C=CN=1)C(NCC1C=CC=C(C(F)(F)F)C=1)=O)=O.[SH:82][C:83]1[CH:84]=[C:85]([CH:89]=[CH:90][CH:91]=1)[C:86]([OH:88])=[O:87].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:28][C:29]([C:30]2[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=2)[CH2:36][S:82][C:83]2[CH:84]=[C:85]([CH:89]=[CH:90][CH:91]=2)[C:86]([OH:88])=[O:87])=[O:38])=[C:6]([C:8]2[CH:9]=[C:10]([C:11](=[O:12])[NH:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=3)[CH:25]=[CH:26][N:27]=2)[CH:7]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(Cl)ccc2NC(=O)c2cccc(CCl)c2)c1
Reactant: O=C(O)c1cccc(S)c1
Agent: Cl
Agent: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CCl)c2)c1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccc(SCc2cccc(C(=O)Nc3ccc(Cl)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)c1
Reaction time: 2 h
Yield: 43.9 %

Procedure:
A mixture of 173 mg of 2-(5-chloro-2-(3-(chloromethyl)benzamido)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide, which was made from intermediate 21b in a similar manner as the synthesis of 8.1a, 52 mg of 3-mercaptobenzoic acid, and 128 mg of K2CO3 in 2 mL of DMF was stirred for 2 h and then poured into 20 mL of water. The solution was acidified with hydrochloric acid. A precipitate formed and was collected by filtration and dried. The resulting solid was dissolved in acetone and filtered. Evaporation of the solvent gave 92 mg of product. MS (ES, m/z) 676 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][CH:12]([OH:15])[C:11]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])([CH3:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>CO.[OH-].[OH-].[Pd+2]>[F:22][C:19]([F:20])([F:21])[C:18]([NH:17][C:11]1([CH3:16])[CH:12]([OH:15])[CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1)=[O:23]
Reactant: CC1(NC(=O)C(F)(F)F)CCN(Cc2ccccc2)CCC1O
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CC1(NC(=O)C(F)(F)F)CCNCCC1O
Reaction time: 72 h
Yield: 66.6 %

Procedure:
To a solution of N-(1-benzyl-5-hydroxy-4-methylazepan-4-yl)-2,2,2-trifluoroacetamide (1.7 g, 5.0 mmol) in MeOH (30 mL) was added 1M HCl (1 mL) and palladium hydroxide on carbon (0.25 g). The mixture was shaken under an atmosphere of hydrogen gas (40 psi) for 72 hr. The mixture was filtered through Celite® washing with MeOH (30 mL). The solvent was removed under reduced pressure and the residue passed through an SCX column eluting with (1-10% (7 M NH3 in MeOH)/DCM) to give 2,2,2-trifluoro-N-(5-hydroxy-4-methylazepan-4-yl)acetamide as a yellow gum (0.8 g, 66%). 1H (400 MHz, CDCl3) δ 6.90 (br s, 1H), 4.22-4.16 (m, 1H), 3.70-3.60 (m, 1H), 3.40-3.35 (m, 1H), 3.15-2.99 (m, 1H), 2.90-2.75 (m, 2H), 2.20-2.05 (m, 1H), 1.99-1.75 (m, 4H), 1.53 (s, 3H).
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([O:11][C:12]1[CH:29]=[CH:28][C:27]2[C@@H:26]3[C@H:17]([C@H:18]4[C@@:22]([CH2:24][CH2:25]3)([CH3:23])[C:21](=[O:30])[CH:20]=[CH:19]4)[C@H:16]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[CH2:15][C:14]=2[CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.[Cu]I>[CH2:4]([O:11][C:12]1[CH:29]=[CH:28][C:27]2[C@@H:26]3[C@H:17]([C@H:18]4[C@@:22]([CH2:24][CH2:25]3)([CH3:23])[C:21](=[O:30])[CH2:20][C@H:19]4[CH3:1])[C@H:16]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[CH2:15][C:14]=2[CH:13]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC2=O
Reactant: C[Mg]Br
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H]1CC(=O)[C@@]2(C)CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCO)[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5.35 g of copper(I) iodide is added to an ice-cooled solution of 11.9 ml of a 3-molar methylmagnesium bromide solution in 68 ml of tetrahydrofuran under a nitrogen stream. Then, a solution of 4.26 g of 3-benzyloxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-17-one (see Example 6b) in 50 ml of tetrahydrofuran is added in drops and stirred for 30 minutes at a bath temperature of 0° C. Then, the excess reagent is decomposed with saturated ammonium chloride solution, diluted with ethyl acetate, washed with ammonium chloride solution and water, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/acetone. 3.6 g of 3-benzyloxy-7α-(5-hydroxypentyl)-15β-methyl-estra-1,3,5(10)-trien-17-one is obtained as oil. [α]D22 =+66.4° (c=0.515% in chloroform).
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1[CH:24]=[C:23]([NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[CH:21][C:8]=1[O:9][C:10]1[CH:11]=[C:12]([CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:40])C=1>>[CH3:28][C:27]([CH3:30])([CH3:29])[C:26]([NH:25][C:23]1[CH:22]=[CH:21][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=2[OH:16])=[C:7]([CH2:6][S:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[O:40])[CH:24]=1)=[O:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1Oc1cc(CC(=O)O)ccc1O
Product: CC(C)(C)C(=O)Nc1ccc(Oc2cc(CC(=O)O)ccc2O)c(CS(=O)C(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 2 using {3-[2-tert-butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-hydroxy-phenyl}-acetic acid and 3-chloroperbenzoic acid (1 equivalent).
Reaction SMILES: [NH2:1][C@:2]12[CH2:38][CH2:37][C@@H:36]([C:39]([CH3:41])=[CH2:40])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:35])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[CH2:42](Br)[CH2:43][OH:44].[I-].[K+].P(=O)(O)(O)O.[K]>C(#N)C>[OH:44][CH2:43][CH2:42][NH:1][C@:2]12[CH2:38][CH2:37][C@@H:36]([C:39]([CH3:41])=[CH2:40])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:35])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: OCCBr
Agent: O=P(O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(NCCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C
Yield: 86 %

Procedure:
To a sealable vial was added ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.156 g, 0.278 mmol), ethylene bromohydrin (0.059 mL, 0.833 mmol), potassium iodide (0.138 g, 0.833 mmol), and phosphoric acid, potassium salt (0.295 g, 1.388 mmol). The mixture was diluted with acetonitrile (2 mL), was flushed with nitrogen, then was sealed and heated to 100° C. After 15 h of heating, the mixture was cooled to rt. LC/MS still showed starting material present, so an additional 0.059 mL of ethylene bromohydrin was added, the mixture was diluted with 1 mL of acetonitrile, and it was sealed and heated to 120° C. After heating the mixture for an additional 20 h, it was cooled to rt, and diluted with 10 mL of water. The solids that formed were collected by filtration and were washed with water to give ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-hydroxyethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.145 g, 0.239 mmol, 86% yield) as an off-white solid. LCMS: m/e 606.7 (M+H)+, 2.18 min (method 1).