Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:13])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([O:37][CH3:38])[CH:31]=2)[CH2:26][CH2:25]1)=[O:23].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:13][C:3]1[C:2]([Br:1])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]([CH2:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([O:37][CH3:38])[CH:31]=3)[CH2:28][CH2:29]2)=[O:23])[N:4]=1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: Nc1n[nH]c(-c2ccccc2)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(N2CCN(C(=O)Cn3nc(N)c(Br)c3-c3ccccc3)CC2)ccc1Cl

Procedure:
Protocol T was followed using 4-Bromo-5-phenyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 7.78-7.84 (d, 2H), 7.32-7.42 (m, 3H), 7.18-7.22 (d, 1H), 6.44-6.48 (d, 1H), 6.36-6.42 (dd, 1H), 4.94 (s, 2H), 4.28 (s, 2H), 3.88 (s, 3H), 3.76-3.86 (m, 4H), 3.12-3.18 (m, 4H). 13C NMR (400 MHz, CDCl3): 164.6, 154.8, 150.2, 144.6, 130, 128.2, 128, 126.4, 109.2, 102, 56, 51, 50, 49.6, 45.6, 42.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].[NH2:29][CH2:30][CH2:31][OH:32]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([NH:29][CH2:30][CH2:31][OH:32])=[O:21]
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: NCCO
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)NCCO)c(=O)n(C)c1=O

Procedure:
The title compound was synthesized following a similar procedure described in the synthesis of Example 5 by reaction of compound 2A and 2-aminoethanol. 1H NMR (400 MHz, CDCl3) δ ppm 3.10 (s, 3 H) 3.39 (s, 3 H) 3.53-3.57 (m, 2 H) 3.78-3.81 (m, 2 H) 6.81 (t, J=8.0 Hz, 1 H) 7.47-7.52 (m, 2 H) [M+H] calc'd for C15H16FIN4O4, 463; found, 463.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:20][C:19]3[C:18]([O:21][CH2:22][CH3:23])=[C:17]4[CH:24]=[CH:25][CH:26]=[CH:27][C:16]4=[C:15]([O:28][CH2:29][CH3:30])[C:14]=3[CH2:13]2)=[CH:8][CH:7]=1)C.[OH-].[Li+]>O1CCCC1.O>[CH2:22]([O:21][C:18]1[C:19]2[CH2:20][N:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:31])=[O:3])=[CH:11][CH:10]=3)[CH2:13][C:14]=2[C:15]([O:28][CH2:29][CH3:30])=[C:16]2[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=12)[CH3:23]
Reactant: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OCC)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1c2c(c(OCC)c3ccccc13)CN(c1ccc(CC(=O)O)cc1)C2
Yield: 42.6 %

Procedure:
A solution of ethyl[4-(4,9-diethoxy-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate (10 mg, 0.024 mmol) in tetrahydrofuran (4 ml) and a solution of lithium hydroxide (6 mg, 0.24 mmol) in water (1 ml) were stirred vigorously for 14 h. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (2×5 ml) and the organic extracts discarded. The aqueous phase was acidified with 2N hydrochloric acid to pH=5 and extracted with ethyl acetate (3×5 ml). The combined organic extracts were dried over magnesium sulphate and the solvent removed in vacuo to give the product as a red solid (4 mg, 43%).
Reaction SMILES: [H-].[Na+].O=[C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]1.[H][H].[CH3:16][N:17]1C(=O)O[C:20](=[O:21])[C:19]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:18]12.Cl>CN(C)C=O>[CH3:16][N:17]1[C:18]2[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=2[C:20](=[O:21])[N:8]2[N:7]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[C:4]12
Reactant: CCOC(=O)C1=NNC(=O)C1
Reactant: [H][H]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2n(C)c3ccccc3c(=O)n2n1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A stirred suspension of 5.3 g of a 50% mineral oil dispersion of sodium hydride in 30 ml of dimethylformamide is treated dropwise at -10° C., under a nitrogen atmosphere, with a solution of 15.6 g of 5-oxo-2-pyrazoline-3-carboxylic acid, ethyl ester, in 65 ml of dimethylformamide. After the evolution of hydrogen ceases, the mixture is stirred for 2 hours while allowing the temperature to rise to +10° C. The mixture is recooled to -10° C. and treated dropwise, with stirring, with a solution of 21.6 g of 90% N-methylisatoic anhydride in 150 ml of dimethylformamide, then stirred for 18 hours while allowing the temperature to rise to 20°-25° C. The mixture is heated at 90° C. for 1 hour, cooled and poured into 3 liters of ice water containing 10 ml of concentrated hydrochloric acid (final pH about 5). The resulting precipitate is collected by filtration and the filtrate is extracted several times with 600 ml portions of dichloromethane. The precipitate is dissolved in 1 liter of dichloromethane and the solution is combined with the above dichloromethane extracts. The combined dichloromethane solution is washed with water, dried and evaporated. The residual oil is triturated with methanol and the resulting solid is collected, dissolved in tetrahydrofuran and the solution is decolorized by passage through an activated magnesium silicate column (Florisil R). The filtrate is concentrated to a small volume, diluted with ethanol and chilled. The resulting crystalline precipitate of 4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid, ethyl ester is collected by filtration; mp 239°-241° C., after recrystallization from dichloromethane/ethanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7]CC=C.[Mn]([O-])(=O)(=O)=O.[K+].OS(O)(=O)=O.[OH2:22].[CH3:23][C:24]([CH3:26])=[O:25]>O>[OH:25][CH:24]([CH2:26][OH:22])[CH2:23][CH2:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1
Reactant: CC(C)=O
Reactant: O
Reactant: C=CCCc1cnccn1
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: OCC(O)CCc1cnccn1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
4.15 g of 4-(2-pyrazinyl)-1-butene (1300) was dissolved in 100 ml of 1:1 water/acetone and cooled to 5° C. To this was slowly added a solution of 3.60 g of potassium permanganate in 300 ml of water. This was kept at 5° C. for 18 hours and then allowed to stir for 4 hours at R.T. It was adjusted to pH 7 with 5% H2SO4, filtered through celite and concentrated. Continuous extraction with chloroform for 2 days followed by evaporation of the solvent left 4.27 g of product (1400) which was distilled under vacuum, b.p. 174°-5° (0.2 mm). UV H2O max: 268 (3.76), 272 (3.76).
Reaction SMILES: C(N)CC.[N+:5]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[CH:17](C(=O)C)[C:18]([O:20][CH2:21][CH3:22])=[O:19])([O-:7])=[O:6]>C(Cl)(Cl)Cl>[N+:5]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([O-:7])=[O:6]
Reactant: CCOC(=O)C(C(C)=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCCN
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99 %

Procedure:
Propan-1-amine (136 mmol) was added to a solution of ethyl 2-(2,4-dinitrophenyl)-3-oxobutanoate (135 mmol) in chloroform (500 mL). The reaction mixture was maintained for 12 h at rt and was concentrated. The residue was purified by chromatography 20/1 hexane/ethyl acetate to provide ethyl 2-(2,4-dinitrophenyl)acetate in 99% yield as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].[Br:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16]>>[BrH:9].[CH3:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][N:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5][C:4]1=[NH:8]
Reactant: COCCOCCBr
Reactant: Cc1nc(N)sc1C
Product: Br
Product: COCCOCCn1c(C)c(C)sc1=N
Temperature: 80 °C

Procedure:
A mixture of 4,5-Dimethylthiazol-2-ylamine (20 mg, 0.16 mmol) and 1-bromo-2-(2-methoxyethoxy)ethane (0.20 mmol) was heated at 80° C. overnight to afford 3-[2-(2-methoxyethoxy)-ethyl]-4,5-dimethyl-1,3-thiazol-2(3H)-ylideneamine hydrobromide, which was used without purification. The alkylated thiazolylidine hydrobromide (1.25 equiv), 1-adamantane carboxylic acid (1.0 equiv), polymer-bound dicyclohexylcarbodiimide (PS-DCC, 3 equiv), 1-hydroxybenzotriazole hydrate (HOBT, 1 equiv), N,N-diisopropylethylamine (3 equiv), were combined in dimethylacetamide (DMA, 2.8 mL) and heated in a microwave to 100° C. for 420 seconds. The mixture was filtered through Si-Carbonate (6 mL-1 g cartridge from Silicycle Chemical Division, MeOH wash) and then concentrated to dryness. Purification by reverse phase HPLC afforded the title compound. 1H NMR (DMSO-d6, 500 MHz) δ ppm 11.68 (q, J=12.27 Hz, 6 H) 1.84 (d, J=2.50 Hz, 6 H) 1.94-2.02 (m, 3 H) 2.16 (s, 3 H) 2.22 (s, 3 H) 3.19 (s, 3 H) 3.39 (dd, J=5.62, 3.74 Hz, 2 H) 3.51 (dd, J=5.62, 3.74 Hz, 2 H) 3.73-3.77 (m, 2 H) 4.25 (t, J=5.46 Hz, 2 H); MS (ESI) m/z 393 (M=H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH2:8][CH:7]1[N:15]1[CH:23]=[N:22][C:21]2[C:16]1=[N:17][C:18]([NH2:25])=[N:19][C:20]=2Cl)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[H][H]>[Pd].CO>[C:1]([O:4][CH2:5][CH:6]1[CH:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH2:8][CH:7]1[N:15]1[CH:23]=[N:22][C:21]2[C:16]1=[N:17][C:18]([NH2:25])=[N:19][CH:20]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CC(n2cnc3c(Cl)nc(N)nc32)C1COC(C)=O
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)OCC1CC(n2cnc3cnc(N)nc32)C1COC(C)=O
Reaction time: 12 h
Yield: 67.1 %

Procedure:
A mixture of 2.63 g (7.15 mmol) of the product from Example 22, 1.18 g (14.3 mmol) of anhydrous sodium acetate, 1.0 g of 10% Pd on carbon and 100 mL of methanol was stirred under 1 atmosphere of hydrogen. After 12 hours, the reaction mixture was filtered and concentrated to a residue under reduced pressure. To the residue was added water and ethyl acetate, and the phases were separated. The aqueous phase was extracted with several portions of ethyl acetate and the combined organic extracts were concentrated under reduced pressure. Chromatography of the residue on silica gel with a 100:0 to 90:10/ethyl acetate:methanol gradient afforded 1.60 g (67%) of the title compound as an oil. DCI-NH3MS, m/z 334 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15]C(=O)C)[S:14][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.[CH:21]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[CH2:24][NH:23][CH2:22]2>>[CH:21]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[CH2:24][N:23]([C:2]1[N:7]=[C:6]([C:8]3[CH:20]=[CH:19][C:11]4[N:12]=[C:13]([NH2:15])[S:14][C:10]=4[CH:9]=3)[CH:5]=[N:4][CH:3]=1)[CH2:22]2
Reactant: CC(=O)Nc1nc2ccc(-c3cncc(Cl)n3)cc2s1
Reactant: C1CC2CCC1CNC2
Product: Nc1nc2ccc(-c3cncc(N4CC5CCC(CC5)C4)n3)cc2s1
Temperature: 140 °C
Reaction time: 3 h
Yield: 24.6 %

Procedure:
A 10 mL, CEM microwave vial was charged with N-(6-(6-chloropyrazin-2-yl)benzo[d]thiazol-2-yl)acetamide (0.0657 g, 0.22 mmol), 3-aza-bicyclo[3.2.2]nonane (0.032 g, 0.26 mmol), 1 mL dry TFE and a stirbar. The vessel was flushed with Ar, sealed and heated using a 110° C. heat block for 12 h. The reaction was cooled and 4 mL EtOH was added. The vial was sealed and the slurry was heated to 140° C. using a heat transfer block for 5 minutes and cooled. The slurry was filtered using a course glass filter fitted with a 0.22 μm teflon filter. The solid was dried at 60° C. and <1 mm Hg for 3 h and then dissolved in warm DMF. The turbid solution was filtered through a 0.22 μm teflon filter, and the solvent was removed in vacuo to afford 6-(6-(3-aza-bicyclo[3.2.2]nonan-3-yl)pyrazin-2-yl)benzo[d]thiazol-2-amine (19 mg). 1H NMR (400 MHz, Pyr) δ ppm 1.48-1.68 (m, 8H) 2.01 (s, 2H) 3.83 (d, J=4.11 Hz, 4H) 7.92 (dd, J=8.41, 0.39 Hz, 1H) 8.28 (dd, J=8.41, 1.86 Hz, 1H) 8.34 (s, 1H) 8.71 (s, 1H) 8.75 (dd, J=1.37, 0.49 Hz, 1H) 8.89 (s, 2H). 13C NMR (101 MHz, Pyr) δ ppm 25.05 (s, 4 C) 30.68 (s, 2 C) 53.39 (s, 2 C) 118.92 (s, 1 C) 119.97 (s, 1 C) 125.11 (s, 1 C) 128.54 (s, 1 C) 128.71 (s, 1 C) 131.27 (s, 1 C) 133.33 (s, 1 C) 149.01 (s, 1 C) 155.03 (s, 1 C) 155.42 (s, 1 C) 169.00 (s, 1 C).
Reaction SMILES: C([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][C:16]=32)[CH2:9]1)C1C=CC=CC=1.[ClH:20].CCOC(C)=O>CO.[OH-].[OH-].[Pd+2]>[ClH:20].[ClH:20].[CH:17]12[CH2:19][CH:10]([CH2:9][NH:8][CH2:18]1)[C:11]1[CH:12]=[CH:13][N:14]=[CH:15][C:16]2=1
Reactant: c1ccc(CN2CC3CC(C2)c2cnccc23)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: c1cc2c(cn1)C1CNCC2C1

Procedure:
10-Benzyl-4,10-diaza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene (900 mg, 3.6 mmol) and HCO2NH4 (4 g) were dissolved in methanol (35 mL) and treated with Pd(OH)2/C (10 wt %, 200 mg). The mixture was stirred and warmed to reflux for 2 h, cooled, filtered through Celite™ and rinsed with methanol. The filtrate was stripped, slurried in dichloromethane and filtered through a fritted-glass filter. The filtrate was concentrated and azeotroped from methanol (2×50 mL). A sample of this material was isolate and found to melt at 104–105° C. The material was dissolved in methanol and treated with 3N HCl/EtOAc. This was concentrated and azeotroped from methanol (2×50 mL). This residue was dissolved in a minimum of methanol then Et2O until cloudy and allowed to stir for 60 h. Product was collected by filtration (370 mg, 52%). (TLC 1% NH4OH/7% MeOH/dichloromethane Rf 0.18); 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.83 (d, J=5.9 Hz, 1H), 8.16 (d, J=5.9 Hz, 1H), 3.75 (m, 2H), 3.60 (m, 2H), 3.40 (d, J=12.4 Hz, 2H), 2.57 (m, 1H), 2.34 (d, J=12.0 Hz, 1H); 13C NMR (100 MHz, CDCl3, free base) δ 151.4, 149.5, 144.5, 137.7, 119.7, 45.8, 45.2, 41.0, 38.4, 36.4; GCMS m/z 160 (M)+; Anal. Calcd. for C10H12N22. HCl: C, 51.52; H, 6.05; N, 12.02. Found C, 51.35; H, 6.05; N, 12.05.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([I:21])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]([O:34][C:35](=[O:38])[CH2:36]Br)([CH3:33])([CH3:32])[CH3:31].O>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([I:21])[CH:17]=3)[N:12]([CH2:36][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:38])[CH:11]=2)=[O:9])=[CH:22][CH:23]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cc2c1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Reaction time: 8 h

Procedure:
To a flask containing N-(4-chlorobenzyl)-6-iodo-4-hydoxy-3-quinolinecarboxamide (0.22 g) obtained as described in Preparation No. 4 in DMF (5 mL) is added potassium carbonate (0.21 g) and tert-butylbromoacetate (0.11 mL). After stirring overnight, the reaction is diluted with dichloromethane and partioned against water. The organic phase is washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and dried in vacuo to give 0.26 g of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]#[N:22].[O:23]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[N:5]=[CH:4][C:3]([C:21]#[N:22])=[C:2]2[NH:34][C:33]1[CH:32]=[CH:31][C:30]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:36][CH:35]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1N1CCN(C)CC1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnc2cc1N1CCN(C)CC1
Temperature: 115 °C
Reaction time: 0.75 h
Yield: 62.2 %

Procedure:
A reaction mixture of 0.12 g (0.38 mmol) of 4-chloro-6-methoxy-7-(4-methylpiperazin-1-yl)-quinoline-3-carbonitrile, 0.077 g (0.42 mmol) of 4-phenoxyaniline and 0.044 g (0.38 mmol) of pyridine hydrochloride in 2 ml of 2-ethoxyethanol is heated at 115° C. for 45 minutes. After cooling, the mixture is filtered, washed with cold 2-ethoxyethanol, then ethyl acetate. After drying in vacuo, the solid is suspended in a saturated solution of sodium carbonate, stirred for 45 minutes and collected by filtration. The reaction product is washed with water and dried in vacuo, to provide 0.11 g of 6-methoxy-7-(4-methylpiperazin-1-yl)-4-(4-phenoxyphenylamino)-quinoline-3-carbonitrile as a yellow solid, mp softens at 93° C.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:25]([CH3:33])([CH2:26][CH2:27][C:28]=32)[C@@H:18]([C@H:19]([CH3:24])[CH2:20]CCO)[CH2:17][CH:16]=4)[C:10]1([CH3:35])[CH3:34])(C(C)(C)C)(C)C.[C:36]([O:39][C:40](=O)[CH3:41])(=[O:38])[CH3:37]>N1C=CC=CC=1>[CH3:35][C:10]1([CH3:34])[C@@H:9]([OH:8])[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:11]1[CH2:12][CH2:13][C:14]1[C:15]3[C@:25]([CH3:33])([CH2:26][CH2:27][C:28]=12)[C@@H:18]([C@H:19]([CH3:24])[CH2:20][CH2:41][CH2:40][O:39][C:36](=[O:38])[CH3:37])[CH2:17][CH:16]=3
Reactant: C[C@H](CCCO)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-ol (150 mg) is acetylated in a mixture of 2 ml of pyridine and 1 ml of acetic anhydride. The tert-butyldimethylsilyl protecting group is split of by treatment with tetra-butylammonium fluoride hydrate according to the procedure outlined in example 2. After column chromatography and crystallisation from acetone/water, the title compound (36 mg) is obtained. 1H-NMR (CDCl3, 300 MHz): δ=5.35 (1H, s); 4.05 (2H, m); 3.23 (1H, m); 2.04 (3H, s). MS: Calculated: 428.7. Found 428.3.
Reaction SMILES: [CH:1]#[C:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.S(=O)(=O)(O)O>COCCOC>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1.[OH:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(O)cc1
Reactant: C1=COCCC1
Agent: O=S(=O)(O)O
Solvent: COCCOC
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OC2CCCCO2)cc1

Procedure:
16.2 Grams of poly(p-hydroxystyrene) [Mw: about 15000, Mw/Mn: 1.14 (GPC method: polystyrene as standard); Nippon Soda Co., Ltd.] was dissolved in 180 ml of 1,2-dimethoxyethane, and 4.1 g of 3,4-dihydro-2H-pyrane and 0.7 ml of sulfuric acid were added thereto, followed by conducting a reaction at 30 to 40° C. for 15 hours with stirring. After the reaction, the resultant was concentrated under reduced pressure, and the residue was neutralized in sodium carbonate and poured into 2000 ml of water to precipitate out. The precipitated polymer was filtered, washed with water and dried under reduced pressure to give 18.0 g of poly(p-tetrahydropyranyloxystyrene/p-hydroxystyrene) as white powders. A ratio of p-tetrahydropyranyloxystyrene unit and p-hydroxystyrene unit of the obtained polymer was about 30:70 by 1HNMR. Mw: about 18000, Mw/Mn:1.14 (GPC method: polystyrene as standard).
Reaction SMILES: [NH:1]([C:5]1[C:22](=[O:23])[CH:21]=[CH:20][C@@:19]2([CH3:24])[C:6]=1[CH:7]=[CH:8][C@@H:9]1[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]1[CH2:11][CH2:12][C:13]2=[O:25])[C:2]([CH3:4])=[O:3].B([O-])([O-])[O-:27].ClC1C=CC=C(C(OO)=O)C=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[NH:1]([C:5]1[C:22](=[O:23])[CH:21]=[CH:20][C@@:19]2([CH3:24])[C:6]=1[CH:7]1[O:27][CH:8]1[C@@H:9]1[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]1[CH2:11][CH2:12][C:13]2=[O:25])[C:2]([CH3:4])=[O:3]
Reactant: [O-]B([O-])[O-]
Reactant: CC(=O)NC1=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)C=CC1=O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NC1=C2C3OC3[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)C=CC1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
To a stirred solution of 4-acetamino-androsta-1,4,6-triene-3,17-dione (3.384 g, 10 mmol) in CH2Cl2 (100 ml) was added borate buffer of pH 8 (50 ml) and then gradually 50% m-chloroperbenzoic acid (6.9 g, 20 mmol) under cooling. The mixture was stirred for 6 h at room temperature until total conversion (TLC monitoring). The mixture was then stirred with 20% sodium metabisulfite solution for 1 h at room temperature. Finally the organic phase was separated, dried and evaporated under vacuum. The residue was submitted to flash chromatography on silica gel with EtOAc thus giving pure title compound in 50% yield (1.772 g).
Reaction SMILES: [NH2:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]([CH3:37])[C:8]([O:10][C@H:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH2:33][CH:34]3[CH2:36][CH2:35]3)[CH:23]=2)[CH2:12][C:13]2[C:18]([Cl:19])=[CH:17][N+:16]([O-:20])=[CH:15][C:14]=2[Cl:21])=[O:9])=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>N1C=CC=CC=1.C(Cl)Cl.[NH4+].[Cl-]>[Cl:19][C:18]1[CH:17]=[N+:16]([O-:20])[CH:15]=[C:14]([Cl:21])[C:13]=1[CH2:12][C@@H:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:30])[F:31])=[C:24]([O:32][CH2:33][CH:34]2[CH2:35][CH2:36]2)[CH:23]=1)[O:10][C:8](=[O:9])[N:7]([CH3:37])[CH2:6][C:5]1[CH:38]=[CH:39][C:2]([NH:1][S:41]([CH3:40])(=[O:43])=[O:42])=[CH:3][CH:4]=1
Reactant: CN(Cc1ccc(N)cc1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(Cc1ccc(NS(C)(=O)=O)cc1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
(S)-4-(2-((4-aminobenzyl)(methyl)carbamoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (for reference procedure see Example 3, Table 5) (73.2 mg, 0.126 mmol) was dissolved in pyridine (3 ml) and cooled at 0° C. Methanesulfonyl chloride (13.71 μl, 0.176 mmol) was added, and the reaction was stirred RT for 1 hour. The reaction was diluted with DCM and aqueous sat. NH4Cl. The aqueous phase was extracted twice with DCM, the combined organic layers were dried and evaporated. The residue was purified by flash chromatography on silica gel cartridge (DCM/AcOEt=80/20 to 50/50) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(methyl(4-(methylsulfonamido)benzyl)carbamoyloxy)ethyl)pyridine 1-oxide (69 mg, 0.104 mmol, 83% yield, MS/ESI+ 660.0 [MH]+.