Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[CH:37]=[C:36]([O:38][CH3:39])[C:19]2[N:20]([CH2:32][CH2:33][O:34][CH3:35])[C:21]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=3)=[N:22][C:18]=2[CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[CH2:9]([C:16]1[CH:37]=[C:36]([O:38][CH3:39])[C:19]2[N:20]([CH2:32][CH2:33][O:34][CH3:35])[C:21]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=3)=[N:22][C:18]=2[C:17]=1[I:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Cc3ccccc3)cc(OC)c21
Solvent: CC#N
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(I)c(Cc3ccccc3)cc(OC)c21
Yield: 66.5 %

Procedure:
417 mg (1.78 mmol) N-iodo-succinimide are added to a solution of 670 mg (1.62 mmol) 5-benzyl-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole in 25 ml acetonitrile. The reaction mixture is stirred at reflux temperature for 3 h. The reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=4:1) to afford 582 mg of the title compound as a white crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][N:17]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)[N:16]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:30][CH:31]=2)[N:16]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1nn(Cc2ccc(Oc3ccccc3)cc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
After a mixture of ethyl 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (1600 mg), 1N sodium hydroxide solution (5 ml), tetrahydrofuran (10 ml), and ethanol (10 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (5 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylic acid (1470 mg, yield: 97%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 222–223° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[H-].[Na+].S(OCC)(O[CH2:21][CH3:22])(=O)=O>CN(C)C=O>[CH2:21]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:22]
Reactant: c1ccc(CNc2ccccn2)nc1
Reactant: CCOS(=O)(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(Cc1ccccn1)c1ccccn1

Procedure:
To a flask were added 2.5 g N-(pyridin-2-ylmethyl)pyridin-2-amine and 40 ml N,N-dimethylformamide, and the mixture was cooled to 5 C. To this mixture was added 0.65 g of 60% sodium hydride in mineral oil in small portions, and after stirring at 5-10 C for ten minutes, 2.2 g of diethyl sulfate were added. The reaction mixture was heated to 45 C for 16 hours, then cooled to 22 C and quenched with 40 ml water. The product was extracted twice with 40 ml hexane and following removal of the solvent, the product was purified by silica gel chromatography using a gradient from 50% ethyl acetate, 49% hexane and 1% methanol to 60% ethyl acetate, 39% hexane, and 1% methanol resulting in 1.4 g of a yellow oil.
Reaction SMILES: [CH:1]([N:5]1[CH:10]=[C:9]([C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)[C:8](OC)=[C:7]([C:19]#[N:20])[C:6]1=[O:21])([CH2:3][CH3:4])[CH3:2].O.[NH2:23][NH2:24]>C(O)C>[NH2:20][C:19]1[C:7]2[C:6](=[O:21])[N:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH:10]=[C:9]([C:11]3[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=3)[C:8]=2[NH:24][N:23]=1
Reactant: CCC(C)n1cc(-c2ccn(C)n2)c(OC)c(C#N)c1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCC(C)n1cc(-c2ccn(C)n2)c2[nH]nc(N)c2c1=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a mixture of 1-(sec-butyl)-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step C (140 mg) and ethanol (5 mL) was added hydrazine monohydrate (122 mg), and the mixture was stirred at 90° C. for 1 hr, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane), and recrystallized from ethyl acetate/diisopropyl ether to give the title compound (82 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:38])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([O:27]CC4C=CC(OC)=CC=4)=[CH:22][C:23]=3[O:24][CH2:25][CH3:26])=[CH:14][C:13]=2[F:37])=[CH:5][C:4]=1[C:39]([F:42])([F:41])[F:40])#[N:2].C(O)(C(F)(F)F)=O.[NH4+].[OH-]>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:38])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([O:24][CH2:25][CH3:26])=[CH:22][C:21](=[O:27])[NH:20][CH:19]=3)=[CH:14][C:13]=2[F:37])=[CH:5][C:4]=1[C:39]([F:41])([F:42])[F:40])#[N:2]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)c(F)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridine-3-yl)-2-fluorophenyl)acetamide (870 mg, 1.501 mmol) in DCM (10 mL) was added TFA (1.157 mL, 15.01 mmol) at 0° C. The mixture was stirred at rt for 1 h. The mixture was basified with NH4OH (5 mL, 20%) to pH=8, filtered to give a solid, which was washed with H2O (5 mL) and dried to afford the product N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide (462.91 mg, 0.973 mmol, 64.8% yield): 1H NMR (400 MHz, CD3OD): δ 8.24 (s, 1H), 7.96-8.05 (m, 1H), 7.90-7.96 (m, 1H), 7.36-7.40 (m, 2H), 7.20-7.28 (m, 2H), 6.00 (s, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.85 (s, 2H), 1.38 (t, J=7.2 Hz, 3H): LCMS (m/z): 459.9 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:26][NH:27][O:28][CH3:29].C(N(CC)CC)C>C(Cl)Cl>[CH3:29][O:28][N:27]([CH3:26])[C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: CNOC
Reactant: O=C(O)CCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)CCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
A suspension of 10.00 g (59.46 mmol) of 3-(4-fluorophenyl)propionic acid, 12.54 g (65.41 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 6.381 g (65.41 mmol) of N,O-dimethylhydroxylamine hydrochloride in 300 mL of CH2Cl2 was cooled to 0° C. and treated with 18.23 mL (13.23 grams, 130.8 mmol) of triethylamine. The mixture was stirred for 16 h with slow warming to rt. The mixture was concentrated, and the residue was partitioned between 300 mL of EtOAc and 200 mL of aqueous 1 N hydrochloric acid solution. The separated organic layer was washed with aqueous 1 N hydrochloric acid solution (1×100 mL), saturated aqueous sodium hydrogencarbonate solution (2×200 mL), brine (1×100 mL), dried (Na2SO4), and evaporated to give 9.56 g (76% yield) of the title compound as an oil. 1H NMR (CDCl3) d 2.70(2H, t, J=8 Hz), 2.91 (2H, t, J=8 Hz), 3.15 (3H, s), 3.59 (3H, s), 6.92-6.97 (2H, m), 7.15-7.19 (2H, m). APCI MS (m/e) 212 (M++1).
Reaction SMILES: [CH:1]1[N:9]=[C:8](Br)[C:7]2[C:3](=[N:4][S:5][N:6]=2)[C:2]=1[Br:11].[CH2:12]([C:24]1([CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[C:47]2[CH:46]=[C:45]([Sn](CCCC)(CCCC)CCCC)[S:44][C:43]=2[C:26]2[S:27][C:28]([Sn:30]([CH2:39][CH2:40][CH2:41][CH3:42])([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:29][C:25]1=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:11][C:2]1[C:3]2[C:7](=[N:6][S:5][N:4]=2)[C:8]([C:45]2[S:44][C:43]3[C:26]4[S:27][C:28]([Sn:30]([CH2:39][CH2:40][CH2:41][CH3:42])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:29][C:25]=4[C:24]([CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:47]=3[CH:46]=2)=[N:9][CH:1]=1
Reactant: CCCCCCCCCCCCC1(CCCCCCCCCCCC)c2cc([Sn](CCCC)(CCCC)CCCC)sc2-c2sc([Sn](CCCC)(CCCC)CCCC)cc21
Reactant: Brc1cnc(Br)c2nsnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCC1(CCCCCCCCCCCC)c2cc(-c3ncc(Br)c4nsnc34)sc2-c2sc([Sn](CCCC)(CCCC)CCCC)cc21
Temperature: 75 °C
Reaction time: 10 h
Yield: 32.1 %

Procedure:
To a solution of 4,7-dibromo-pyridal[2,1,3]thiadiazole (0.28 g, 0.95 mmol) and 1a (1.04 g, 0.95 mmol) in freshly distilled toluene (10 ml) was added Pd(PPh3)4 (109.8 mg, 0.095 mmol) under nitrogen, and then capped with a rubber septum. The reaction mixture was stirred at 75° C. for 10 hours. The solvent was removed and purified by column chromatography (silica was pretreated by 10 v/v % triethylamine/hexane solution) with hexane as eluent. The column separation was repeated for 3 times to give 0.31 g of viscous purple oil, yield 30%. 1H NMR (500 MHz, CD2Cl2) δ (ppm): 8.55 (s, 1H), 8.53 (s, 1H), 7.01 (s, 1H), 1.95-1.91 (m, 4H), 1.63-1.56 (m, 6H), 1.37-1.31 (m, 6H), 1.26-1.12 (m, 42H), 1.08-0.97 (m, 4H), 0.91-0.82 (m, 15H); 13C NMR (CDCl3, 125 MHz) δ (ppm): 163.11, 160.01, 156.33, 148.10, 147.92, 145.92, 143.99, 142.26, 141.81, 140.27, 129.80, 127.62, 106.17, 37.85, 31.88, 29.96, 29.61, 29.52, 29.34, 29.31, 28.98, 27.21, 24.57, 22.66, 13.85, 13.44, 10.95.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([F:15])[CH:4]=1)#[N:2].C(O[CH:19](OCC)[N:20]([CH3:22])[CH3:21])C>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:19][N:20]([CH3:22])[CH3:21])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([F:15])[CH:4]=1)#[N:2]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cc1ccc(C#N)cc1F
Product: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1F

Procedure:
The title compound was prepared in a manner similar to Example Preparation 10 using ethyl 2-(4-cyano-2-fluorophenyl)acetate and 1,1-diethoxy-N,N-dimethylmethanamine to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.07 Hz, 3 H) 2.71 (br. s., 6 H) 4.00 (quin, J=6.76 Hz, 2 H) 7.37 (t, J=7.71 Hz, 1 H) 7.60 (dd, J=7.96, 1.64 Hz, 1 H) 7.64 (s, 1 H) 7.75 (dd, J=9.47, 1.64 Hz, 1 H). MS m/z [M+H]+ 236.2, 263.2.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[C:6](Cl)=[N:5][S:4][N:3]=1.[CH3:10][O-:11].[Na+]>CO>[Cl:1][C:2]1[C:7](=[O:8])[C:6]([O:11][CH3:10])=[N:5][S:4][N:3]=1
Reactant: O=c1c(Cl)nsnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nsnc(Cl)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.66 g of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one in 30 ml of methanol is kept at 0°-5° C. and stirred while a solution of 2.40 g of sodium methoxide in 30 ml of methanol is added dropwise to it. The reaction mixture is stirred at room temperature 2 hours longer, then mixed with 200 ml of ice water. The precipitate is collected, washed with water, dried, and recrystallized from hexane to yield pale yellow needles, mp 159°-161°.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:21]=[C:22]1[C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][N:23]1[CH2:39][C:40](O)=[O:41].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[OH:8][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:9]1[CH2:14][CH2:13][N:12]([C:40](=[O:41])[CH2:39][N:23]2[CH2:24][CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:22]2=[O:21])[CH2:11][CH2:10]1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(C(O)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diphenyl(piperidin-4-yl)methanol (0.27 g, 1.00 mmol) in dichloromethane (20 mL) was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) under nitrogen. To the reaction was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (6.1 mg, 0.005 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate:water (8:2). The organic layer was separated, washed with water and then brine, dried over MgSO4, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexanes (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.50-7.57 (m, 4H), 7.18-7.36 (m, 14H), 7.11-7.16 (m, 2H), 5.35 (s, 1H), 4.33-4.40 (m, 1H), 4.17 (d, J=16.6 Hz, 1H), 4.10 (d, J=15.7 Hz, 1H), 3.77-3.85 (m, 1H), 3.34 (t, J=6.7 Hz, 2H), 2.93-3.02 (m, 1H), 2.75-2.85 (m, 1H), 2.72 (t, J=6.4 Hz, 2H), 2.53-2.64 (m, 1H), 1.19-1.40 (m, 4H).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:7]=1[C:8]([OH:10])=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[NH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:7]=1[C:8]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:10]
Reactant: Nc1ccccc1
Reactant: Cc1cccc(N)c1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cccc(N)c1C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
Thionyl chloride (14.5 mL, 198 mmol) was added to a solution of 2-amino-6-methylbenzoic acid (10.0 g, 66.1 mmol) in benzene (250 mL). The resulting suspension was heated to reflux and stirred overnight. After cooling, the reaction was concentrated in vacuo, and the resulting residue was dissolved in chloroform (300 mL). Aniline (15 mL, 165 mmol) was added, and the mixture heated to reflux. After three hours, the reaction was allowed to cool and the resulting suspension was filtered. The filtrate was subjected to flash chromatography, and the crude product recrystallized from isopropanol to provide compound 15 as a yellow crystalline solid. MS (ES): m/z 227 (M+H), 134. 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.75 (d, 2H, J=7.9 Hz), 7.32 (t, 2H, J=7.8 Hz), 7.07 (t, 1H, J=7.3 Hz), 7.00 (t, 1H, J=7.8 Hz), 6.58 (d, 1H, J=8.1 Hz), 6.46 (d, 1H, J=7.4 Hz), 4.98 (br. s, 2H), 2.21 (s, 3H). The reaction described above and compound 15 are shown below.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[Cl:11])[C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[Br:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[Cl:11])[C:5]([Cl:16])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(Cl)c(Br)c1Cl
Product: O=C(Cl)c1cc(F)c(Cl)c(Br)c1Cl

Procedure:
58.3 g (0.2 mol) of 3-bromo-2,4-dichloro-5-fluorobenzoic acid are refluxed for 4 hours in 350 ml of thionyl chloride until the gas evolution ceases. Excess thionyl chloride is removed by distillation, and the residue is fractionated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[N+:10]([C:13]1[C:14]([CH:23]=[O:24])=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)([O-:12])=[O:11]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:23]([C:14]2[C:13]([N+:10]([O-:12])=[O:11])=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[N:21]3)=[CH:16][CH:15]=2)[OH:24])[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2cccnc2c1[N+](=O)[O-]
Reactant: Fc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(C(O)c2cccc(F)c2)ccc2cccnc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.1 %

Procedure:
3-Fluorophenyl magnesium bromide (1 M solution in THF; 0.86 ml, 4.33 mmol) was added dropwise to a solution of 8-nitroquinoline-7-carbaldehyde (Intermediate 204) (0.35 g, 1.73 mmol) in dry THF (5 ml) at −78° C. and the mixture was stirred at −78° C. for 1 h. The reaction was quenched with saturated NH4Cl solution and the aqueous phase was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM as the eluent to give the title compound (0.3 g, 58%).
Reaction SMILES: [CH3:1][NH2:2].S(O[CH2:14][CH2:15][O:16][C@H:17]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:19]([CH2:20][CH2:21][C@@H:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@:23]3([OH:41])[CH2:24][CH2:25][C@@H:26]2[C:36]2[CH:40]=[CH:39][O:38][CH:37]=2)[CH2:18]1)(C1C=CC(C)=CC=1)(=O)=O>CO>[CH3:1][NH:2][CH2:14][CH2:15][O:16][C@H:17]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:19]([CH2:20][CH2:21][C@@H:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@:23]3([OH:41])[CH2:24][CH2:25][C@@H:26]2[C:36]2[CH:40]=[CH:39][O:38][CH:37]=2)[CH2:18]1
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Reactant: CN
Solvent: CO
Product: CNCCO[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1

Procedure:
To 7 ml of a solution of methylamine 3.2 M in methanol, 0.090 g of 3β-(2-tosyloxyethoxy)-17β-(3-furyl)-5β-androstan-14β-ol, prepared as an intermediate in Ex.7, were added. The solution was kept at reflux under nitrogen for 11 hrs, then was evaporated. The resulting solid was washed with n-hexane to give 0.045 g of the title compound (I-an) as a light yellow pasty solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[S:7][C:8]([Br:12])=[CH:9][C:10]=1[CH3:11])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[Br:12][C:8]1[S:7][C:6]([CH2:5][OH:4])=[C:10]([CH3:11])[CH:9]=1
Reactant: CC(=O)OCc1sc(Br)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc(Br)sc1CO
Temperature: 25 °C
Yield: 82.3 %

Procedure:
A mixture of 62.4 (3.58 mmol) and K2CO3 (0.99 g, 7.16 mmol) in MeOH (18 mL) was stirred for 5 Hours at room temperature. The mixture was filtered (DCM) and concentrated, and the crude product was chromatographed on silica gel (0-30% EtOAc/hexane) to afford 62.5 (0.61 g, 82%) as a yellow liquid. 1H NMR (400 MHz, CDCl3) δ 6.78 (s, 1H), 4.68 (s, 2H), 2.18 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:13]([OH:14])=[CH:12]C=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1C(OC)=O)([O-:3])=[O:2].[C:19]([O:22][CH2:23]C)(=[O:21])[CH3:20].C(Cl)Cl>>[OH:14][C:13]1[CH:12]=[C:20]([C:19]([O:22][CH3:23])=[O:21])[C:6](=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1C(=O)OC
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(O)c([N+](=O)[O-])cc1C(=O)OC

Procedure:
A mixture of dimethyl 4-hydroxyphthalate (25.0 g, 0.119 mol) and concentrated sulfuric acid at 0°-5° C., is treated dropwise with nitric acid (90%, 6.10 mL, 0.142 mo)), stirred for 10 minutes, poured into ice water and extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and concentrated in vacuo to give the title product mixture as a viscous yellow oil, 29.7 g (98.0%), identified by NMR spectral analysis. Flash chromatography (silical gel, 2% ethyl acetate/methylene chloride) of the mixture gives dimethyl 4-hydroxy-5-nitrophthalate as a yellow solid 3.70 g, mp 82°-85° C. and dimethyl 3-nitro-4-hydroxyphthalate as a pale yellow solid, 3.80 g, mp 108°-111° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([OH:10])[CH2:3]1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:10][CH:4]2[CH2:3][C:2]([CH3:11])([CH3:1])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5]2)=[O:21])=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CC1(C)CC(O)CC(C)(C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)CC(OC(=O)Cc2ccc(O)cc2)CC(C)(C)C1
Yield: 48.2 %

Procedure:
3,3,5,5-Tetramethylcyclohexanol (7.81 g, 0.05 mol), 4-hydroxyphenylacetic acid (7.6 g, 0.05 mol), p-toluenesulfonic acid (2 g) and benzene (200 mL) were refluxed with continuous water separation for 8 hours. The reaction mixture was evaporated, the oily residue was dissolved In ethyl acetate (100 mL), washed first with aqueous 5% NaHCO3 solution (100 mL) and then twice with water (200 mL), then dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure to give 3,3,5,5-tetramethylcyclohexyl 4-hydroxyphenylacetate as a solid (7.00 g, 82.0% yield).
Reaction SMILES: Br.[Br:2][C:3]1[C:12]([OH:13])=[C:11]([CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH3:15])=[N:8]2.[O:16](S(C(F)(F)F)(=O)=O)[S:17]([C:20]([F:23])([F:22])[F:21])(=O)=[O:18]>ClCCl.N1C=CC=CC=1>[F:21][C:20]([F:23])([F:22])[S:17]([O:13][C:12]1[C:3]([Br:2])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:14])[N:8]=[C:7]([CH3:15])[CH:6]=[CH:5]2)(=[O:18])=[O:16]
Reactant: Cc1ccc2c(Br)c(O)c(C)cc2n1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc2c(Br)c(OS(=O)(=O)C(F)(F)F)c(C)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-bromo-2,7-dimethylquinolin-6-ol-HBr (1.04 g, 3.1 mmol) in dichloromethane (50 mL) and pyridine (10 mL) was added Tf2O (1.1 mL, 6.2 mmol) at 0° C. The mixture was stirred at room temperature for 2 hours, quenched with slow addition of NaHCO3 solution at 0° C. The mixture was extracted with dichloromethane. The organic layer was washed with brine and dried with Na2SO4. Concentration gave 5-bromo-2,7-dimethylquinolin-6-yl trifluoromethanesulfonate as a brown solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[N:26]=[CH:25][CH:24]=[CH:23]5)[N:17]=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH2:30][OH:31].[CH3:32]I>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[N:26]=[CH:25][CH:24]=[CH:23]5)[N:17]=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH2:30][O:31][CH3:32]
Reactant: CI
Reactant: OCc1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
Sodium hydride (0.010 g, 0.259 mmol) was added at 0° C. to a solution of example 16 (0.100 g, 0.259 mmol) in DMF (1 ml) and stirred for 30 min. Methyl iodide (0.073 g, 0.518 mmol) was added and the reaction mixture was warmed to RT. After 12 h, the reaction mixture was poured into ice-cold water and extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as an off-white solid (0.033 g, 32%). M.P.: 200-201° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.68 (d, J=8.8 Hz, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.11-8.00 (m, 4H), 7.83 (dd, J=8.7, 1.9 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.53 (dd, J=8.4, 4.2 Hz, 1H), 6.22 (s, 2H), 4.53 (s, 2H), 3.33 (s, 3H).