Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10](=[NH:14])OCC)[CH2:9][CH2:8]2)[CH:6]=1.[S].C(O)(=O)C.C(N(CC)CC)C.N[C:28]1[C:33]([NH2:34])=[CH:32][N:31]=[C:30]([N:35]2[CH2:40][CH2:39][O:38][C@@H:37]([C:41]([N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)=[O:42])[CH2:36]2)[N:29]=1>>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]3[NH:14][C:32]4[C:33]([N:34]=3)=[CH:28][N:29]=[C:30]([N:35]3[CH2:40][CH2:39][O:38][C@@H:37]([C:41]([N:43]5[CH2:47][CH2:46][CH2:45][CH2:44]5)=[O:42])[CH2:36]3)[N:31]=4)[CH2:8][CH2:9]2)[CH:6]=1
Reactant: CCOC(=N)C1(n2cc(Cl)cn2)CC1
Reactant: Nc1cnc(N2CCO[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: [S]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: O=C([C@H]1CN(c2ncc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)CCO1)N1CCCC1
Temperature: 100 °C

Procedure:
Ethyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbimidate (0.13 g, 0.46 mmol), sulfur (15 mg), acetic acid (0.53 mL, 9.3 mmol) and triethylamine (0.39 mL, 2.79 mmol) were added to the filtrate containing (R)-(4-(4,5-diaminopyrimidin-2-yl)morpholin-2-yl)(pyrrolidin-1-yl)methanone, prepared in the previous step, at room temperature. The reaction mixture was heated to 100° C. for 24 h. The solvent was removed under reduced pressure and the resulting crude material was purified via preparative TLC to afford the title compound (13 mg). MS (ES+APCI) (M+H) 443.0; LCMS retention time 4.485 min (Method T1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[C:12](=[O:19])[C:13]1[S:17][CH:16]=[C:15]([Cl:18])[CH:14]=1.[C:20](=[O:26])=[N:21]S(Cl)(=O)=O.C(#N)C.ClS(NC=O)(=O)=O>CS(C)=O.O>[Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:20]([NH2:21])=[O:26])[C:6](=[O:11])[CH:5]2[C:12](=[O:19])[C:13]1[S:17][CH:16]=[C:15]([Cl:18])[CH:14]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C1Nc2ccc(Cl)nc2C1C(=O)c1cc(Cl)cs1
Agent: O=CNS(=O)(=O)Cl
Solvent: O
Solvent: CC#N
Solvent: CS(C)=O
Product: NC(=O)N1C(=O)C(C(=O)c2cc(Cl)cs2)c2nc(Cl)ccc21

Procedure:
The title compound was prepared from 5-chloro-3-(4-chloro-2-thenoyl)-4-azaoxindole (Example 27) according to the procedure of Example 2C, using 5-chloro-3-(4-chloro-2-thenoyl)-4-azaoxindole (0.75 g, 2.39 mmol), N-chlorosulfonyl isocyanate (0.31 mL, 3.56 mmol), and acetonitrile (12 mL). Hydrolysis of the N-chlorosulfonyl carboxamide was achieved by stirring in DMSO (8 mL) for 4 hours at room temperature in a flask open to the air. The product was obtained by dilution of the mixture with water followed by filtration and recrystallized from acetic acid. Yield: 352 mg (41%).
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[N:9]12[CH2:14][CH2:13][CH:12]([CH2:11][CH2:10]1)[C@@H:7]([O:6][C:5]1[CH:15]=[CH:16][C:2]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:17])[CH:23]=3)=[CH:3][CH:4]=1)[CH2:8]2
Reactant: Nc1cccc(B(O)O)c1
Reactant: Ic1ccc(OC2CN3CCC2CC3)cc1
Product: Nc1cccc(-c2ccc(O[C@H]3CN4CCC3CC4)cc2)c1

Procedure:
The product of Example 1A (165 mg, 0.5 mmol) was treated with 3-amino-phenylboronic acid (Lancaster, 137 mg, 1 mmol) according to the procedure of Example 1B. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.25) as an oil (38 mg, yield, 26%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40-1.53 (m, 1H), 1.62-1.85 (m, 2H), 1.96-2.20 (m, 2H), 2.80-2.94 (m, 5H), 3.28-3.40 (m, 1H), 4.52-4.60 (m, 1H), 6.66 (ddd, J=7.8, 2.3, 1.0 Hz, 1H), 6.89 (ddd, J=7.3, 1.6, 1.0 Hz, 1H), 6.92-6.96 (m, 3H), 7.13 (t, J=7.8, Hz, 1H), 7.48 (dt, J=8.8, 2.1 Hz, 2H) ppm. MS (DCl/NH3) m/z 295 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[Cl:18][C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:9][CH2:10][N:11]([C:19]([Cl:18])=[O:21])[CH2:12][CH2:13]2)=[CH:5][CH:4]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: FC(F)(F)c1ccc(OC2CCNCC2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Cl)N1CCC(Oc2ccc(C(F)(F)F)cc2)CC1
Yield: 272.1 %

Procedure:
A mixture of 4-(4-trifluoromethylphenoxy) piperidine (0.6 g, 2.45 mmol), triphosgene (0.25 g, 0.86 mmol), and pyridine (0.4 ml, 4.90 mmol) in toluene (6 ml) was heated under reflux for 2.5 hours. To which ethyl acetate was added, and the mixture was washed with 10% hydrochloric acid, dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 4-(4-trifluoromethylphenoxy)piperidine-1-carbonylchloride (0.72 g, yield 96%) as a pale yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Reactant: C1CCNCC1
Solvent: CC#N
Product: O=C(CN1CCCCC1)Nc1n[nH]c2cc(Cl)ccc12

Procedure:
The process is performed as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm3 of acetonitrile and 0.61 cm3 of piperidine. The reaction medium is refluxed for 2 hours, the precipitate formed is then filtered off on a sinter funnel and the crystals, after taking up in methanol, are purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a methylene chloride/methanol mixture (93/7 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 5 cm3 of diethyl ether, filtered off and dried (90 Pa; 45° C.) to give 447 mg of N-(6-chloro-1H-indazol-3-yl)-1-piperidineacetamide in the form of a white powder melting at 153° C.
Reaction SMILES: [C:1](=[O:5])([O-:4])OC.[Mg+2].COC(=O)[O-].[CH3:12][C:13]([C:15]1[S:16][C:17]([O: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][CH2:33][CH3:34])=[CH:18][CH:19]=1)=[O:14]>CN(C)C=O>[CH2:21]([O:20][C:17]1[S:16][C:15]([C:13]([CH2:12][C:1]([OH:4])=[O:5])=[O:14])=[CH:19][CH:18]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: COC(=O)[O-]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(C)=O)s1
Agent: [Mg+2]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)CC(=O)O)s1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of magnesium methyl carbonate and dimethylformamide (300 g of a 2.0mM/g solution) is heated in a 120° C. oil bath with stirring under carbon dioxide flushing for 1/2 hour. To this mixture is added 33.8 g (0.100 mole) of 5-(tetradecyloxy)-2-thienyl methyl ketone, and the oil bath temperature is raised to 130° C. to 150° C. Dry nitrogen is flushed through the mixture for 5 hours. The mixture is allowed to cool at room temperature under carbon dioxide flushing after which it is poured slowly into 3 liters of concentrated HCl-ice (1:1) with vigorous stirring. When the evolution of gas is complete, the precipitate is collected and washed with cold water, then dried to give 5-tetradecyloxythen-2-oylacetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]1[CH2:26]Cl>CN(C)C=O>[CH3:17][N:18]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]1[CH2:26][O:10][C:4]1[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cn1c([N+](=O)[O-])cnc1CCl
Reactant: CSc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccc(OCc2ncc([N+](=O)[O-])n2C)cc1C
Temperature: 25 °C

Procedure:
To a solution of 15.4 g (0.1 mol) of 3-methyl-4-methylmercaptophenol in 30 ml of dimethylformamide, 13.8 g (0.1 mol) of potassium carbonate powder are added, and then a solution of 17.6 g (0.1 mol) of 1-methyl-2-chloromethyl-5-nitro-imidazole in 40 ml of dimethylformamide is added dropwise while stirring at 25° C. The temperature of the faintly exothermal reaction is adjusted to at most 35° C. by cooling with ice water. The mixture is then stirred for another hour at 25° C., poured onto ice/water, the precipitate is suction-filtered, washed with water and recrystallized from methanol with an addition of charcoal to yield 21.7 g (74% of the theoretical yield) of 1-methyl-2-(3-methyl-4-methylthiophenyl-oxymethyl)-5-nitro-imidazole in the form of yellow crystals, m.p. 108° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[O:11]1[C:15]2[CH:16]=[CH:17]C=CC=2N=C1>>[O:11]1[CH2:15][CH:16]1[CH2:17][O:10][C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[CH:2][S:1][C:5]=2[CH:6]=1
Reactant: c1ccc2ocnc2c1
Reactant: Oc1ccc2ncsc2c1
Product: c1nc2ccc(OCC3CO3)cc2s1

Procedure:
Compound 48 was prepared in the manner of compound 6 substituting compound 16 for compound 8 in partC-5 of Example 1.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][C:19](O)=O)=[CH:16][C:3]1=2.S(Cl)([Cl:24])=O>CN(C)C=O.C(Cl)Cl>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][Cl:24])=[CH:16][C:3]1=2
Reactant: O=C(O)CCc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1c2ccccc2COc2ccc(CCCCl)cc21
Reaction time: 8 h

Procedure:
To a flask was added a few drops of N,N-dimethylformamide and 35.25 g of 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propanoic acid in 500 ml of dry methylene chloride. The chilled stirring suspension was treated dropwise over several minutes with 11.0 ml of thionyl chloride. The suspension was warmed intermittently on a steam bath until all gas evolution ceased. The resulting solution was then allowed to reflux for 15 minutes and was allowed to stand at room temperature under nitrogen atmosphere overnight. The solution was concentrated in vacuo to an oil. The oil was dissolved in 500 ml of methylene chloride and was treated with another 11.0 ml of thionyl chloride. The solution was allowed to reflux for 3 hours and was again concentrated to an oil in vacuo. The oil still contained a significant amount of crystalline impurity, which was filtered away after triturating with a hexane/ether solution. The supernatant was concentrated to an oil in vacuo which solidified overnight in refrigeration. The purified solids were recrystallized from three portions of cyclohexane to give 25.03 g of 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propanyl chloride, m.p. 69-72° C.
Reaction SMILES: Br.[F:2][C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH2:20][C:21]3[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=3)[C:12]2=[NH:29])=[CH:5][CH:4]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:46][C:47]1[CH:59]=[CH:58][CH:57]=[CH:56][C:48]=1[CH2:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>ClCCCl>[Cl:46][C:47]1[CH:59]=[CH:58][CH:57]=[CH:56][C:48]=1[CH2:49][N:50]1[CH2:51][CH2:52][N:53]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([CH2:20][N:13]3[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:11]([CH2:10][CH2:9][CH2:8][O:7][C:6]4[CH:5]=[CH:4][C:3]([F:2])=[CH:31][CH:30]=4)[C:12]3=[NH:29])=[CH:28][CH:27]=2)[CH2:54][CH2:55]1
Reactant: Clc1ccccc1CN1CCNCC1
Reactant: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccc(C=O)cc1
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccc(CN2CCN(Cc3ccccc3Cl)CC2)cc1
Reaction time: 8 h
Yield: 18.6 %

Procedure:
To a mixture of 4-{3-[3-(4-fluoro-phenoxy)-propyl]-2-imino-2,3-dihydro-benzoimidazol-1-ylmethyl}-benzaldehyde, hydrobromide salt (0.39 g, 0.81 mmol) and sodium triacetoxyborohydride (0.322 g, 1.52 mmol) in 1,2-dichloroethane (5 ml) at rt was added 1-(2-chloro-benzyl)-piperazine (0.20 g, 0.95 mmol). The reaction was stirred for 8 h and then washed with a saturated solution of NaHCO3, H2O, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by chromatography provided 1-{4-[4-(2-chloro-benzyl)-piperazin-1-ylmethyl]-benzyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (90 mg, 19%). HPLC-MS 598 [M+1]+, 300.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][C:10]([CH3:18])([CH2:14][C:15](O)=O)[C:11]([OH:13])=[O:12].[OH-].[Na+]>Cl.O>[CH3:9][C:10]([CH3:18])([CH2:14][C:15]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1)[C:11]([OH:13])=[O:12]
Reactant: CC(C)(CC(=O)O)C(=O)O
Reactant: Nc1ccccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(Cc1nc2ccccc2[nH]1)C(=O)O
Yield: 82.5 %

Procedure:
A solution of o-phenylenediamine (5.4 g, 0.05 mole) and 2,2-dimethylsuccinic acid (7.5 g, 0.05 mole) in 50 mL of 4.8 N HCl was refluxed without condenser until the total volume was reduced to about 20 mL. Evaporation at 100° and 40 torr afforded a green paste which was taken up in 100 mL H2O and made alkaline (pH 9) with 20% NaOH. The mixture was filtered removing tarry matter and the clear yellow filtrate was concentrated, cooled and the pH adjusted to about 6 by addition of acetic acid. A light yellow solid precipitated and was isolated by filtration and dried in air to give 9 g of α,α-dimethyl-1H-2-benzimidazolepropanoic acid, m.p. 223°-226° (dec). Recrystallization from acetonitrile-methyl ethyl ketone-methanol (30-30-40) afforded 6.7 g (61%) of colorless needles, m.p. 266°-267° (dec).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]=[C:13]1[CH2:21][C:20]2[C:15](=[C:16]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[CH:18][CH:19]=2)[NH:14]1>C(Cl)(Cl)Cl>[O:12]=[C:13]1[CH2:21][C:20]2[C:15](=[C:16]([S:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:9])[CH:17]=[CH:18][CH:19]=2)[NH:14]1
Reactant: O=C1Cc2cccc(Sc3ccccc3)c2N1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C1Cc2cccc(S(=O)c3ccccc3)c2N1

Procedure:
m-Chloroperbenzoic acid (purity: 85%, 0.76 g.) was added to a solution of 2-oxo-7-phenylthioindoline (0.9 g.) in chloroform (20 ml.) with stirring under ice cooling. The mixture was stirred at the same temperature for an hour. To the reaction mixture was added chloroform (50 ml.), and the solution was washed with a saturated aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate and then evaporated. The resultant crystals (1.0 g.) were recrystallized from dioxane twice to give white prisms of the captioned compound (0.6 g.).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16]C(=O)OC(C)(C)C)=[CH:5][C:4]=1[NH:24][C:25]1[CH:34]=[CH:33][C:32]2[C:31](O)([CH3:35])[CH2:30][CH2:29][CH2:28][C:27]=2[N:26]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl.C1(C)C=CC=CC=1>[NH2:16][C@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]1[NH:9][C:6]1[CH:5]=[C:4]([NH:24][C:25]2[CH:34]=[CH:33][C:32]3[C:31]([CH3:35])=[CH:30][CH2:29][CH2:28][C:27]=3[N:26]=2)[C:3]([C:1]#[N:2])=[N:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Nc2ccc3c(n2)CCCC3(C)O)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1=CCCc2nc(Nc3cc(N[C@@H]4CCCC[C@@H]4N)cnc3C#N)ccc21
Reaction time: 0.33 h

Procedure:
To a suspension of tert-butyl (1S,2R)-2-(6-cyano-5-(5-hydroxy-5-methyl-5,6,7,8-tetrahydroquinolin-2-ylamino)pyridin-3-ylamino)cyclohexylcarbamate (25 mg, 0.051 mmol) in dichlormethane (1.5 mL) was added trifluoroacetic acid (0.5 mL). After 20 minutes, the reaction mixture was diluted with toluene (1 mL) and dichloromethane (10 mL), and then concentrated under reduced pressure. The residue was dissolved in methanol (1 mL) and toluene (1 mL) and then concentrated under reduced pressure. This entire procedure was repeated again to afford 5-((1R,2S)-2-aminocyclohexylamino)-3-(5-methyl-7,8-dihydroquinolin-2-ylamino)picolinonitrile which was used without further purification. MS ESI calc'd. for C22H27N6 [M+H]+ 375. found 375.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:46]>CN(C)C=O>[Br:46][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:25]
Reactant: COc1cccc2nc(-c3cc(C)c(OCCO)c(C)c3)[nH]c(=O)c12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cccc2nc(-c3cc(C)c(OCCBr)c(C)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy3H-quinazolin-4-one (1.10 g, 3.20 mmol) in anhydrous N,N-dimethylformamide (16 mL) were added triphenylphosphine (0.92 g, 3.50 mmol) and carbontetrabromide (1.17 g, 3.50 mmol). The reaction mixture was stirred at room temperature for 16 hours. DMF was removed under reduced pressure. The residue was purified by column chromatography (silica gel 230-400 mesh; 3% methanol in dichloromethane as eluent) to give 2-[4(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy3H-quinazolin-4-one as an off-white solid. Yield: 0.60 g (46%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])/[CH:14]=[C:15](\[C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)/[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2].[C:31]([O:35][C:36](=[O:52])[CH2:37][N:38]=[C:39]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH3:34])([CH3:33])[CH3:32].O.[OH-].[Cs+].C=CCO[C@H](C1C2C(=CC=CC=2)N=CC=1)[C@H]1[N+]2(CC3C4C(=CC=CC=4)C=C4C=3C=CC=C4)C[C@H](C=C)[C@@H](CC2)C1.[Br-]>ClCCl.O>[C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])[CH2:14][C:15]([CH:37]([N:38]=[C:39]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:52])([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:16]([F:17])([F:19])[F:18])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C=CCO[C@H](c1ccnc2ccccc12)[C@@H]1C[C@@H]2CC[N+]1(Cc1c3ccccc3cc3ccccc13)C[C@@H]2C=C
Agent: [Br-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(=O)CC(c2cc(Cl)cc(Cl)c2)(C(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
Similarly, 4-[(E)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (1 gl) and (benzhydrylidene-amino)-acetic acid tert-butyl ester (322 mg) were dissolved in dichloromethane (13 ml). Cesium hydroxide hydrate (1.82 g) and O-Allyl-N-(9-anthracenylmethyl)cinchonidinium bromide (66 mg) were added and the resulting mixture was stirred at −75 C for 18 hours. At this time water was added and the reaction mixture was extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and evaporated in vacuo to give a crude residue which was purified by flash chromatography (0% to 05% dichloromethane in heptane) to afford 4-[3-[(Benzhydrylidene-amino)-tert-butoxycarbonyl-methyl]-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-benzoic acid tert-butyl ester (426 mg) as a yellow foam and a single diastereoisomer. 19F NMR (376 MHz, CDCl3) δ −61 ppm (1 diastereoisomer).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11](I)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH2:24]([OH:28])[CH2:25][C:26]#[CH:27]>>[NH2:8][C:6]1[N:7]=[C:2]([Cl:1])[C:3]2[C:11]([C:27]#[C:26][CH2:25][CH2:24][OH:28])=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=1
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Reactant: C#CCCO
Product: COc1c(C)cnc(Cn2cc(C#CCCO)c3c(Cl)nc(N)nc32)c1C

Procedure:
The title compound was prepared by Sonogashira coupling of 4-chloro-5-iodo-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (see Example 1) with 3-butyn-1-ol according to the General Procedure A. tR: 4.54 min. 1H-NMR (DMSO-d6) δ 8.04 (s, 1H), 7.22 (s, 1H), 6.69 (br.s., 2H), 5.25 (s, 2H), 4.82 (d, 1H), 3.70 (s, 3H), 3.55 (q, 2H), 2.49 (t, 2H), 2.23 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:8]O)=[N:4][N:5]([CH3:7])[CH:6]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[Cl:12][CH2:8][C:3]1[C:2]([F:1])=[CH:6][N:5]([CH3:7])[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1cc(F)c(CO)n1
Solvent: ClCCl
Product: Cn1cc(F)c(CCl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 25 mL round-bottomed flask containing (4-fluoro-1-methyl-1H-pyrazol-3-yl)methanol (285 g, 2.2 mmol) in dry DCM (10 mL), was added thionyl chloride (0.3 mL, 4.4 mmol). The reaction mixture was stirred at RT for 2 h then concentrated to dryness to provide the title compound, which was carried forward without further purification.
Reaction SMILES: C1C2C(COC([NH:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][C:25]([C:29]([NH:31][C:32]5[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=5)[C:35]([O:37][CH3:38])=[O:36])=[O:30])=[CH:26]4)=[CH:21][CH:20]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.ClCCl.N1CCCCC1>C1COCC1>[NH2:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25]([C:29]([NH:31][C:32]3[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=3)[C:35]([O:37][CH3:38])=[O:36])=[O:30])=[CH:26]2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1cccc(NC(=O)c2ccc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3c2)c1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COC(=O)c1cccc(NC(=O)c2ccc3ccc(N)cc3c2)c1
Reaction time: 3 h

Procedure:
To 380 mg (0.70 mmol) of compound 109 was added 30 mL of dichloromethane, 3 mL of THF and 1 mL of piperidine. The resulting clear solution was allowed to stir for 3 hours. Then, the reaction was extracted with ethyl acetate and 1N HCl (aqueous). The dried organic layer (magnesium sulfate) was filtered and the volatiles removed in vacuo. The resulting residue was dissolved in dichloromethane and 3 mL of 1 N HCl in diethyl ether and 50 mL of diethyl ether were added to form a precipitate that was collected by vacuum filtration. After drying, this provided 212 mg of compound 111 as the hydrochloride salt.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][C@H:11]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[CH:13]([C:14](=O)[CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C:20]2=[O:30])[CH2:12]1)=[O:4].Cl.[NH2:35][OH:36]>>[F:32][C:2]([F:33])([F:1])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][C@H:11]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[CH:13](/[C:14](=[N:35]/[OH:36])/[CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C:20]2=[O:30])[CH2:12]1)=[O:4]
Reactant: C[C@]12CC[C@H](SCCCCNC(=O)C(F)(F)F)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: NO
Agent: Cl
Product: C[C@]12CC[C@H](SCCCCNC(=O)C(F)(F)F)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 40 %

Procedure:
Following the reaction conditions described in Example 1 and starting from 3β-(4-trifluoroacetamidobutylthio)androstane-6,17-dione and hydroxylamine hydrochloride, 3β-(4-trifluoroacetamidobutylthio)-6-(E)-hydroxyiminoandrostane-17-one (240 mg, 40%) was obtained. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.35 (1H, s), 9.40 (1H, t), 3.20 (4H, m), 2.55-0.90 (25H, m), 0.76 (3H, s), 0.67 (3H, s).