Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[S:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][NH:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])(C)(C)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:35]([O:34][C:32]([NH:31][CH2:30][C:10]1[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[S:21][C:22]=2[CH3:23])[CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][C:6]([OH:38])=[O:5])=[O:33])([CH3:37])[CH3:36]
Reactant: Cc1sc(N2CCOCC2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1sc(N2CCOCC2)nc1CCOc1ccc(CCC(=O)O)c(CNC(=O)OC(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of 3-{2-(isopropoxycarbonylamino-methyl)-4-[2-(5-methyl-2-morpholin-4-yl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid tert-butyl ester (387 mg, 0.706 mmol) in CH2Cl2 (10 mL) was treated with anisole (1 mL) then TFA (3 mL). The solution was stirred at room temperature for 2 h and concentrated. The residue was co-evaporated with CCl4 twice, dried under vacuum, triturated with ether, and filtered to obtain the title compound as a white solid (236 mg, 60%), isolated as the trifluoracetic acid salt: 1H NMR (400 MHz, CDCl3) δ 1.12 (d, 6H, J=6.4 Hz), 2.16 (s, 3H), 2.47 (t, 2H, J=7.6 Hz), 2.79 (t, 2H, J=7.6 Hz), 2.87 (t, 2H, J=6.4 Hz), 3.35 (t, 4H, J=4.9 Hz), 3.70 (t, 4H, J=4.9 Hz), 4.07 (t, 2H, J=6.6 Hz), 4.23 (d, 2H, J=5.4 Hz), 4.82 (heptet, 1H, J=6.1 Hz), 5.07 (bs, 1H), 6.63 (dd, 1H, J=2.7, 8.6 Hz), 6.69 (d, 1H, J=2.9 Hz), 6.98 (d, 1H, J=8.3 Hz). MS (ES) m/e 492.1 [M+1].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:25]([SH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([S:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1SCc1ccccc1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
A slurry of the product of Example 304A (15 g, 0.061 mol) in ethanol (100 mL), was treated with sodium carbonate (6.41 g, 0.061 mol) and benzyl mercaptan (7.5 mL, 0.058 mol) in water (50 mL). The reaction mixture was refluxed for 5 hours, cooled to 25° C. and poured into of distilled water (800 mL). The resulting slurry was stirred forl hour at 25° C. and filtered. The resulting yellow solid was washed with water and dried in a vacuum oven at 50° C. to give the title compound (20.53 g). 1H NMR (300 MHz, DMSO-d6) δ ppm 4.35 (s, 2 H) 5.27 (s, 2 H) 7.02 (dd, J=9.19, 2.57 Hz, 1 H) 7.16 (d, J=2.57 Hz, 1 H) 7.40 (m, 10 H) 8.24 (d, J=9.19 Hz, 1 H). ESI m/z (M+H)+: 352
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:21]([O-])([N+]([O-])=O)=[O:22]>>[Cl:1][CH2:2][CH2:3][N:4]([N:21]=[O:22])[C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N(CC1CC1)C1OC[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: O=NN(CCCl)C(=O)N(CC1CC1)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 70.8 %

Procedure:
3.1 g of 1-(2-chloroethyl)-3-cyclopropylmethyl-3-(L-arabinopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 23-(2). 2.4 g of 1-(2-chloroethyl)-1-nitroso3-cyclopropylmethyl-3-(L-arabinopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[N:8].[CH3:9][O-:10].[Na+]>CO>[CH3:9][O:10][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[NH:8]
Reactant: N#Cc1ccccn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Pyridine-2-carbonitrile (Sigma-Aldrich, St. Louis, USA) (1 eq, 190 mmol, 20 g) is dissolved in MeOH (150 ml), then NaOMe (5.4 M in MeOH, 1.1 eq, 209 mmol, 38.7 ml) is added. The resulting mixture is stirred for 16 h at r.t. The solvents are removed in vacuo, then water is added, and the resulting aqueous mixture is extracted with DCM. The organic layer is dried with MgSO4, filtered, and the solvent is removed in vacuo yielding the title compound; [M+H]+=138.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]([F:33])([F:32])[C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1>C1COCC1>[F:33][C:11]([F:10])([F:32])[C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:23]3=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]3[CH:25]=[CH:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4cccc(C(F)(F)F)c4)cc3)C2=N1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 210 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.331 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyridin-2-amine (347 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. carefully. Water was added to form precipitates which were washed with water and hexane, collected and dried in vacuo to give the title compound (234 mg) as a white powder. A part of this product was crystallized from MeCN-THF/IPE as colorless crystals.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[CH2:8]([O:10][C:11]([C:13]1[CH:24]=[CH:23][C:16]2[S:17][C:18]([CH2:21]Cl)=[C:19]([CH3:20])[C:15]=2[CH:14]=1)=[O:12])[CH3:9]>CN(C)C=O>[CH2:8]([O:10][C:11]([C:13]1[CH:24]=[CH:23][C:16]2[S:17][C:18]([CH2:21][C:4]3[NH:3][CH:7]=[CH:6][N:5]=3)=[C:19]([CH3:20])[C:15]=2[CH:14]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1ccc2sc(CCl)c(C)c2c1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2sc(Cc3ncc[nH]3)c(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
Sodium hydride (0.5 g of 50% dispersion in mineral oil) was added portionwise to a stirred solution of imidazole (0.68 g) in dry N,N-dimethylformamide (DMF) (30 ml) and the mixture was stirred at room temperature for 30 minutes. A solution of 2-chloromethyl-3-methylbenzo[b]thiophene-5-carboxylic acid ethyl ester (2.70 g) in dry N,N-dimethylformamide (5 ml) was added, the mixture was stirred for 2 hours and then evaporated. The residue was dissolved in ethyl acetate and the solution was washed well with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform/petrol (b.p. 40°-60° C.) (3:1) first gave some impurity followed by pure product. Evaporation of the product containing fractions gave a solid which was crystallized from ethyl acetate/petrol (b.p. 60°-80° C.) to give 2-(1-imidazolylmethyl)-3-methylbenzo[b]thiophene-5-carboxylic acid ethyl ester (1.40 g), m.p. 126°-127° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[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)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:35]>>[NH2:35][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCCO
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCCO

Procedure:
The methods described in Parts B and C of Example 1 can be used to treat 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol with mCPBA and ammonium hydroxide to provide 4-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH2:21][CH3:22])=[CH:25][CH:26]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(-c2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 191.6 %

Procedure:
Couple 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (0.726 g, 2.43 mmol) and 4-ethoxyphenylboronic acid (0.95 g, 5.991 mmol), in the presence of triphenylphosphine (0.202 g, 0.770 mmol), palladium acetate (0.056 g, 0.243 mmol), sodium carbonate (3.8 mL of a 2 N solution in water) in a mixture of acetonitrile (42 mL) and water (8 mL). Reflux for 3 hr. Purify by silica gel chromatography, eluting with 0:100 to 25:75 ethyl acetate:hexanes, to give 3′-(4-ethoxyphenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (1.79 g, 96%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[I-].[C:14]1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>C1C=CC=CC=1>[CH:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1)=[CH2:14]
Reactant: O=Cc1ccnc2ccccc12
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: C=Cc1ccnc2ccccc12
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-quinolinecarboxaldehyde (5 g; 3.18×10-2 mol) in 32 ml of benzene, containing triphenylmethylphosphonium iodide (26 g; 6.36×10-2 mol), is added under an inert atmosphere to sodium hydroxide solution (96 ml; 5N). The two-phase system is stirred at 45° C. for 30 minutes. After allowing the phases to separate by settling, the aqueous phase is extracted with ethyl acetate (3×100 ml). The organic phases are combined and washed with 1N HCl solution (2×30 ml), then the aqueous phase is neutralized with NaHCO3 and extracted with methylene chloride (3×100 ml). The organic phase is dried over MgSO4. The desired product is purified by chromatography on a MERCK F254 silica column (eluent=cyclohexane/AcOEt, 8:2). Yield=2.8 g (60%).
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.CCCCCC.[CH:19]1([C:29]([O:31][CH3:32])=[O:30])[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20]1.C(I)C=C>C1COCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:32][O:31][C:29]([C:19]1([CH2:7][CH:5]=[CH2:6])[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20]1)=[O:30]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Agent: C=CCI
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCC1(C(=O)OC)CCC(C(=O)OC)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 102.4 %

Procedure:
Diisopropylamine (4.55 g, 6.36 mL, 45.0 mmol) was dissolved in THF (100 mL) and cooled to −78° C. To this solution was added 2.5 M n-butyl lithium in hexane (18 mL, 45.0 mmol). The solution was stirred for 15 min, warmed up to 0° C. and stirred for an additional 20 min, then re-cooled to −78° C. Dimethyl 1,4-cyclohexanedicarboxylate (7.5 g, 37.50 mmol) in THF (10 mL) was then added and the reaction mixture was allowed to stir at −78° C. for 1.0 h followed by the addition of a mixture of hexamethyl-phosphoramide (HMPA) (5.0 g, 4.85 mL, d=1.03) and allyl iodide (8.19 g, 4.48 mL, 48.8 mmol). This mixture was stirred at −78° C. for 20 min. Then, the dry ice bath was removed and the stirring was continued to allow the reaction mixture to warm to room temperature over 1 h. The reaction mixture was poured into ice-water (100 mL) and ether (50 mL). The two layers were separated and the aqueous layer was extracted with ether (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to afford 9.23 g (97%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].CO>C1COCC1.C(Cl)Cl>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:6][CH2:5]1
Reactant: OCCN1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCN(CCO)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 250 mL round bottomed flask was charged with N-(2-hydroxyethyl)piperazine (3.00 g, 24.4 mmol) followed by anhydrous THF (150 mL) and triethylamine (3.40 mL, 24.4 mmol). The resulting solution was cooled to 0° C. and a solution of benzyl chloroformate (3.10 mL, 21.8 mmol) in anhydrous THF (10 mL) was slowly added via syringe resulting in the formation of a cloudy white suspension. This suspension was stirred at 0° C. for 30 minutes, then allowed to warm to room temperature with stirring over 3 h. The reaction mixture was then concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with 5% MeOH in CH2Cl2, afforded 5.76 g (100%) of Preparation 2 as a colorless oil. Rf=0.60 (SiO2, 5% MeOH in CH2Cl2). 1H NMR (500 MHz, CDCl3): δ=7.34 (m, 5H), 5.13 (s, 2H), 3.62 (t, J=5.2 Hz, 2H), 3.52 (t, J=5.2 Hz, 4H), 2.64 (br s, 1H), 2.55 (t, J=5.2 Hz, 2H) and 2.47 (br s, 4H). m/z=265 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH:19]([CH3:21])[CH3:20])[CH:10]=2)[C:5]([CH3:22])=[CH:4][C:3]=1[OH:23].CN.[I:26]I>CCO.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH:19]([CH3:20])[CH3:21])[CH:10]=2)[C:5]([CH3:22])=[C:4]([I:26])[C:3]=1[OH:23]
Reactant: COCOc1ccc(Cc2cc(C)c(O)cc2C)cc1C(C)C
Reactant: II
Agent: CN
Solvent: O
Solvent: CCO
Product: COCOc1ccc(Cc2cc(C)c(O)c(I)c2C)cc1C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a stirred solution of 2,5-dimethyl-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)phenol (intermediate for the synthesis of compound 7-17; 0.35 g, 1.11 mmol) in EtOH (5.0 mL) and CH3NH2 40% in water (2.5 mL) was added iodine (0.34 g, 1.33 mmol) and KI (0.27 g 1.66 mmol) in H2O (3 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 h, quenched with brine (50 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:3) to afford 2,5-dimethyl-6-iodo-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)phenol as a colorless oil (0.32 g, 64%): 1H NMR (300 MHz, CDCl3): δ 7.02 (d, J=2.4 Hz, 1 H), 6.95 (d, J=8.7 Hz, 1 H), 6.88 (s, 1 H), 6.75 (dd, J=2.4, 8.4 Hz, 1 H), 5.20 (s, 2 H), 3.95 (s, 2 H), 3.51 (s, 3 H), 3.35-3.30 (m, 1 H), 2.39 (s, 3 H), 2.30 (s, 3 H), 1.22 (d, J=6.9 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-ethylacetate (9:1); Rf=0.6.
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:37]=[N:38][C:39]([CH2:43][CH3:44])=[CH:40][C:41]=2[CH3:42])[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:37]=[N:38][C:39]([CH2:43][CH3:44])=[CH:40][C:41]=2[CH3:42])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1cc(C)c(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCc1cc(C)c(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1

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-(6-ethyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K35) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous red substance (184 mg, 44%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9]1[N:27]=[C:12]2[C:13]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[CH:14][CH:15]=[CH:16][N:11]2[N:10]=1>>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:13]1[C:12]2[N:11]([N:10]=[C:9]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[N:27]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccccc1CNc1cccn2nc(Cl)nc12
Reactant: Nc1ccncc1
Product: COc1ccccc1CNc1cccn2nc(Nc3ccncc3)nc12

Procedure:
N(8)-(2-Methoxy-benzyl)-N(2)-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from 4-aminopyridine (36.47 mg, 0.3875 mmol) and (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methoxy-benzyl)-amine (99.9 mg, 0.346 mmol) in a manner analogous to Example 2d. Product isolated as a off-white foam (4.14 mg, 3.5%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.04 (s, 1H), 8.32 (m, 2H), 8.01 (d, J=6.7 Hz, 1H), 7.68 (m, 2H), 7.24 (m, 2H), 7.03 (d, J=8.2 Hz, 1H), 6.87 (t, J=14.9, 7.6 Hz, 1H), 6.80 (t, J=14.3, 7.6 Hz, 1H), 6.40-6.31 (m, 2H), 4.47 (d, J=5.8 Hz, 2H), 3.87 (s, 3H). MS=347 (MH)+.
Reaction SMILES: C[O:2][CH2:3][CH2:4][N:5]([CH3:53])[CH2:6][CH2:7][N:8]([CH3:52])[C:9](=[O:51])[C:10]1[CH:50]=[CH:49][CH:48]=[C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][C:17]=2[C:28]2[CH:33]=[C:32]([C:34](=[O:47])[NH:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=3)[CH:31]=[CH:30][N:29]=2)=[O:14])[CH:11]=1.CNCCO>>[OH:2][CH2:3][CH2:4][N:5]([CH3:53])[CH2:6][CH2:7][N:8]([CH3:52])[C:9](=[O:51])[C:10]1[CH:50]=[CH:49][CH:48]=[C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][C:17]=2[C:28]2[CH:33]=[C:32]([C:34](=[O:47])[NH:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:44])([F:46])[F:45])[CH:38]=3)[CH:31]=[CH:30][N:29]=2)=[O:14])[CH:11]=1
Reactant: COCCN(C)CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CNCCO
Product: CN(CCO)CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared by the procedure described for the preparation of N1-(2-((2-methoxyethyl)(methyl)amino)ethyl)-N1-methyl-N3-(4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)isophthalamide 4.20.2, using 2-(methylamino)ethanol in place of N-methyl-2-(methoxyethyl)amine. MS (ES, m/z): 717 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1.N1C=CC=CC=1.Cl[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[CH3:16][C:14]1[N:15]=[C:8]2[C:7]([NH:6][CH2:5][C:4]3[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:3]=3[CH2:2][NH:1][C:30](=[O:31])[O:32][CH3:33])=[CH:12][CH:11]=[CH:10][N:9]2[C:13]=1[CH3:17]
Reactant: COC(=O)Cl
Reactant: Cc1cccc(CN)c1CNc1cccn2c(C)c(C)nc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)NCc1cccc(C)c1CNc1cccn2c(C)c(C)nc12
Temperature: 12 °C
Reaction time: 1.5 h
Yield: 25.4 %

Procedure:
To an ice cooled solution of 8-(2-aminomethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (0.17 g, 0.58 mmol), pyridine (0.046 g, 0.58 mmol) in methylene chloride (8 ml) was added methyl chloroformate (0.055 g, 0.58 mmol) and the reaction mixture was stirred for 1.5 h. and the temperature was allowed to raise to 12° C. Methylene chloride was added and the solution was washed twice with water. The organic layer was separated, washed with saturated sodium bicarbonate, dried and evaporated under reduced pressure. The residue was purified by by column chromatography on silica gel using methylene chloride:methanol (100:5) as eluent. Recrystallization from diethyl ether gave 0.052 g (25%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: CCN1CCCC(N)C1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: CCN1CCCC(NS(=O)(=O)c2ccc(Br)cc2)C1
Reaction time: 8 h
Yield: 98.4 %

Procedure:
3-Amino-1-ethylpiperidine (0.4 mL, 3.13 mmol) was added to a solution of 4-bromo-benzenesulfonyl chloride (0.4 g, 1.56 mmol) in methylene chloride (10 mL) at room temperature. The mixture was stirred overnight. The reaction solution was extracted three times with a aqueous saturated sodium hydrogen carbonate solution, dried (MgSO4) and evaporated to give 0.533 g (93% yield) of the title compound as a light brown solid: 1H NMR (CDCl3) δ 7.74 (d, J=9 Hz, 2H), 7.62 (d, J=9 Hz, 2H), 3.45 (br s, 1H), 2.46 (br s, 1H), 2.27 (m, 2H), 2.23 (m, 2H), 2.13 (m, 1H), 1.64 (m, 1H), 1.45 (m, 3H), 0.93 (t, J=7 Hz, 3H); 13C NMR (CDCl3) δ 140.7, 132.5, 128.7, 127.5, 53.2, 52.3, 49.7, 21.9, 12.1; MS (ESP) m/z 347, 349 (M++1).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]1[CH2:31][O:30][C:9]2([CH2:26][CH2:25][C@@:24]3([CH3:27])[C:11](=[CH:12][CH2:13][C@@H:14]4[C@:23]3([OH:28])[CH2:22][CH2:21][C@@:19]3([CH3:20])[C@H:15]4[CH2:16][CH2:17][C:18]3=O)[CH2:10]2)[O:8]1.[N+:32]([CH:34](P(=O)(OCC)OCC)[CH3:35])#[C-:33].[Cl-].[Na+]>O1CCCC1.O>[N+:32]([C:34](=[C:18]1[C@:19]2([CH3:20])[C@H:15]([C@H:14]3[C@:23]([OH:28])([CH2:22][CH2:21]2)[C@:24]2([CH3:27])[C:11]([CH2:10][C:9]4([O:30][CH2:31][CH2:7][O:8]4)[CH2:26][CH2:25]2)=[CH:12][CH2:13]3)[CH2:16][CH2:17]1)[CH3:35])#[C-:33]
Reactant: C[C@]12CCC3(CC1=CC[C@H]1[C@@H]4CCC(=O)[C@@]4(C)CC[C@@]12O)OCCO3
Reactant: [C-]#[N+]C(C)P(=O)(OCC)OCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: [C-]#[N+]C(C)=C1CC[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]12C)OCCO5
Temperature: 3 °C
Reaction time: 5 h
Yield: 69.8 %

Procedure:
Under a nitrogen atmosphere potassium tert. butoxide (2.80 g) was added to a stirred solution of 3,3-ethylenedioxy-9α-hydroxyandrost-5-en-17-one (3.70 g) in dry tetrahydrofuran (75 ml) at 0° C. After stirring at this temperature for 10 minutes a solution of diethyl α-isocyanoethylphosphonate (8.09 g) in dry tetrahydrofuran (20 ml) was added dropwise over 45 minutes, while keeping the temperature below 3° C. The reaction mixture was stirred at 3° C. for 5 hours. Stirring was continued at room temperature for 40 hours, then the reaction mixture was poured into a mixture of water (300 ml) and saturated sodium chloride solution (225 ml) and extracted twice with diethyl ether. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed (silica gel, toluene/acetone 5/1) to obtain the title compound (2.86 g) as a mixture of 2 diastereomers.