Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C.[CH2:37]([N:41]1[C:42](=[O:80])[N:43]([CH2:76][CH2:77][CH2:78][CH3:79])[C:44](=[O:75])/[C:45]/1=[CH:46]/[C:47]1[N:51]=[C:50]([CH2:52][CH2:53][CH2:54][CH3:55])[N:49](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:48]=1)[CH2:38][CH2:39][CH3:40].C(Cl)[Cl:82]>O.C(O)(=O)C>[ClH:82].[CH2:52]([C:50]1[N:51]([CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)[C:47](/[CH:46]=[C:45]2\[N:41]([CH2:37][CH2:38][CH2:39][CH3:40])[C:42](=[O:80])[N:43]([CH2:76][CH2:77][CH2:78][CH3:79])[C:44]\2=[O:75])=[CH:48][N:49]=1)[CH2:53][CH2:54][CH3:55]
Reactant: CCCCc1nc(/C=C2/C(=O)N(CCCC)C(=O)N2CCCC)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCCl
Reactant: COC(=O)c1ccc(CO)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(=O)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2CCCC)n1Cc1ccc(C(=O)OC)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of trifluoromethanesulfonic anhydride (0.094 mL, 0.56 mmol) in methylene chloride (10 mL) at -78° C. was added a solution of methyl 4-(hydroxymethyl)benzoate (0.093 g, 0.56 mmol) and N,N-diisopropylethylamine (0.098 mL, 0.56 mmol) in methylene chloride (10 mL) dropwise over 5 minutes. This solution was stirred for 15 minutes and then a solution of Z-1,3-dibutyl-5-[[2-butyl-3-(triphenylmethyl)-3H-imidazol-5-yl]methylene]-2,4-imidazolidinedione (0.330 g, 0.56 mmol) in methylene chloride (5 mL) was added dropwise. The mixture was allowed to slowly warm to room temperature within the cooling bath overnight. Glacial acetic acid (10 mL) and water (2 mL) were added and the mixture boiled for 1 hour on a steam bath. After evaporation in vacuo the residue was dissolved in ethyl acetate, washed with saturated NaHCO3 and brine, and then dried over MgSO4. Chromatography eluting with CHCl3 afforded the required product with spectral characteristics identical with the produce formed in Example 33.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](=[O:17])[NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:5][CH2:4]1.[C:18]([O:21]C(=O)C)(=[O:20])C.[C:25](=[O:28])([O-:27])[O-:26].[K+].[K+].[OH-].[Na+]>C(Cl)(Cl)Cl.O.C(O)=O>[C:18]([OH:21])(=[O:20])[C:25]([OH:27])=[O:28].[CH:25]([NH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](=[O:17])[NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)=[O:26]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@H]1CC[C@H](C(=O)Nc2ccncc2)CC1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Solvent: ClC(Cl)Cl
Product: O=C(O)C(=O)O
Product: O=CNC[C@H]1CC[C@H](C(=O)Nc2ccncc2)CC1
Temperature: 0 °C

Procedure:
A mixture of 2.33 g of trans-4-aminomethyl-1-(4-pyridylcarbamoyl)cyclohexane, 15 ml of 99% formic acid and 18 ml of acetic anhydride was stirred and then an exothermic reaction occurred by 36° C. After refluxing for 10.5 hours, the resultant mixture was poured into ice-water and alkalized with potassium carbonate and an aqueous solution of concentrated sodium hydroxide. To the precipitated water substance was added chloroform. The obtained crystals were collected by filtration, washed with water and dried. The crystals were dissolved in ethanol and a solution of oxalic acid in ethanol added thereto. The precipitated crystals were collected by filtration and dried to give trans-4-formamidomethyl-1-(4-pyridylcarbamoyl)cyclohexane oxalate 1/2 hydrate, melting at 204°-207° C. with decomposition.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[C:17]([CH3:19])[C:16]3[N:15]([CH3:20])[C:14]4[CH2:21][CH:22]5[NH:26][CH:25]([C:13]=4[C:12]=3[C:11]=2C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:34]>C(Cl)(Cl)Cl.C(OCC)C>[ClH:34].[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([CH3:19])[CH:18]=2)[N:15]([CH3:20])[C:14]2[CH2:21][CH:22]4[NH:26][CH:25]([C:13]3=2)[CH2:24][CH2:23]4)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(S(=O)(=O)c2ccccc2)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cc1cc(S(=O)(=O)c2ccccc2)cc2c3c(n(C)c12)CC1CCC3N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the product of step D (104 mg, 0.22 mmol) in chloroform (1 mL) was added 2 M HCl in diethyl ether solution (5 mL). The reaction was stirred at 0° C. for 1 h then allowed to warm to ambient temperature overnight. The mixture was concentrated in vacuo, made basic with sat. sodium bicarbonate solution and extracted with chloroform. The organic extract was dried over anhydrous sodium sulfate, concentrated in vacuo and the resulting residue purified by flash column chromatography (SiO2, 90:9.9:0.1 dichloromethane/methanol/ammonium hydroxide). The free-base was treated directly with 1.25 M HCl in methanol (2 mL) and the resulting solution concentrated in vacuo to give 2-phenylsulfonyl-4,5-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (65 mg, 72%, AUC HPLC 98.7%) as a white solid: mp 244-248° C.; 1H NMR (CD3OD, 300 MHz): δ 8.08 (d, J=1.5 Hz, 1H), 7.90-7.98 (m, 2H), 7.49-7.63 (m, 3H), 7.38-7.43 (m, 1H), 5.26 (d, J=4.8 Hz, 1H), 4.49-4.58 (m, 1H), 3.94 (s, 3H), 3.44 (dd, J=17.1 Hz, J=4.5 Hz, 1H), 3.02 (d, J=17.4 Hz, 1H), 2.99 (s, 3H), 2.19-2.52 (m, 3H), 1.91-2.20 (m, 1H); APCI MS m/z 367 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N+:9]([O-])[C:10]3[C:15]([C:16]=2[N+:17]([O-:19])=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.N1C=CC=CC=1.C(OC(=O)C)(=[O:29])C>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8](=[O:29])[NH:9][C:10]3[C:15]([C:16]=2[N+:17]([O-:19])=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1c(N2CCOCC2)c[n+]([O-])c2ccccc12
Solvent: c1ccncc1
Product: O=c1[nH]c2ccccc2c([N+](=O)[O-])c1N1CCOCC1

Procedure:
The 3-morpholino-4-nitroquinoline-N-oxide (4 g, 0.015 mol) obtained in Example 5-(b) was dissolved in acetic anhydride (20 ml) and pyridine (20 ml) and the solution was heated on an oil bath at 80° C. for 3 hours. Excess acetic anhydride and pyridine were distilled off from the whole reaction mixture in vacuum and the residue was washed with ether to obtain 3-morpholino-4-nitro-2-quinolone in an amount of 3.5 g (yield, 88%),
Reaction SMILES: FC(F)(F)C(O)=[O:4].[C:8]1([S:14](/[CH:16]=[C:17](\[C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)/[C:18]([F:21])([F:20])[F:19])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:30]([N:37]([CH2:41][Si](C)(C)C)[CH2:38]OC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[CH2:30]([N:37]1[CH2:38][CH:16]([S:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)(=[O:4])=[O:15])[C:17]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)([C:18]([F:21])([F:19])[F:20])[CH2:41]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=S(/C=C(\c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccccc1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)C1CN(Cc2ccccc2)CC1(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Yield: 83 %

Procedure:
Trifluoroacetic acid (38 μL, 513 μmol) was added to (1E)-2-(3,5-dichlorophenyl)-3,3,3-trifluoroprop-1-en-1-yl phenyl sulfoxide (4.00 g, 98% purity, 10.3 mmol) in toluene (20 mL). N-Benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (3.65 g, 15.4 mmol) in toluene (18 mL) was added at room temperature over two hours. After two more hours additional N-Benzyl-1-methoxy-N-[(trimethylsilyl)-methyl]methanamine (0.2 eq.) was added and the reaction left stirring for another hour. The solvents of the reaction mixture were removed and the crude product was taken up in n-heptane. The formed crystals were filtered off. 1-Benzyl-3-(3,5-dichlorophenyl)-4-(phenylsulfinyl)-3-(trifluoromethyl)-pyrrolidinium chloride (4.40 g, >99% purity, 83% yield, E/Z [not assigned]=53/47) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:26])([F:25])[F:24])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18](=O)[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[F:27][C:28]([F:33])([F:32])[CH2:29][CH2:30][NH2:31].C([BH3-])#N.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:26])([F:25])[F:24])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[CH:18]([NH:31][CH2:30][CH2:29][C:28]([F:33])([F:32])[F:27])[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Reactant: NCCC(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Product: Fc1c(Cl)cc(C(/C=C/c2ccc3c(c2)CCC3NCCC(F)(F)F)C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2,3-dihydro-1H-inden-1-one (0.15 g, 0.35 mmol) in DCE (10 mL), was added trifluoropropyl amine (0.048 g, 0.42 mmol) and sodium cyanoborohydride (0.055 g, 0.875 mmol) in cooling and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with DCE, was washed with water and brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the crude compound, which was purified by flash column chromatography (SiO2, 100-200 mesh; 10-15% EtOAc in petroleum ether) to afford the title compound as a colorless gummy material (0.042 g, 24%): 1H NMR (400 MHz, CDCl3) δ 7.38-7.20 (m, 5H), 6.62 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 5.83 (br, 1H), 5.52 (m, 1H), 4.12 (m, 1H), 3.02 (m, 3H), 2.82 (m, 1H), 2.50 (m, 2H), 1.82 (m, 1H), 1.42 (m, 1H); ESIMS m/z 497.98 ([M−H]−); IR (thin film) 3027, 1654, 815 cm−1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:33])=[C:9]([CH2:11][O:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([OH:30])=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1.[H-].[Na+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>CN(C)C=O>[CH2:36]([O:30][C:20]1[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][N:18]([CH2:17][C:16]2[CH:31]=[CH:32][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[O:7][C:8]=3[CH3:33])=[CH:14][CH:15]=2)[N:19]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of ethyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-hydroxy-1H-pyrazol-4-yl]propionate (452 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 40.0 mg) was added at 0° C., and the solution was stirred at room temperature for 30 minutes. Benzyl bromide (0.178 ml) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-benzyloxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-1H-pyrazol-4-yl]propionate (383 mg, yield: 71%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[I:11].[NH3:12].CO.C(Cl)[Cl:16]>CO.C1COCC1>[ClH:16].[NH2:12][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[I:11]
Reactant: N
Reactant: ClCCl
Reactant: N#Cc1ccc(CBr)c(I)c1
Solvent: C1CCOC1
Solvent: CO
Product: Cl
Product: N#Cc1ccc(CN)c(I)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
12.1 g (37.6 mmol) of 4-bromomethyl-3-iodobenzonitrile in 200 ml of MeOH/THF 1:1 were slowly added dropwise to 200 ml of conc. ammonia solution/MeOH (saturated with NH3) 1:1, simultaneously passing NH3 into the reaction mixture. The temperature was maintained at 50° C. After 4 h, the solvent was stripped off, and the product was taken up in DCM, dried and precipitated with ethereal HCl. 8.6 g of 4-aminomethyl-3-iodobenzonitrile hydrochloride were obtained.
Reaction SMILES: [N:1]([C:4]1([CH3:17])[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1)=[C:2]=[S:3].[NH3:18]>>[CH3:17][C:4]1([NH:1][C:2]([NH2:18])=[S:3])[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1
Reactant: Cc1cc(N2CCC(C)(N=C=S)CC2)ncn1
Reactant: N
Product: Cc1cc(N2CCC(C)(NC(N)=S)CC2)ncn1
Temperature: 50 °C
Yield: 853.2 %

Procedure:
A solution of 4-(4-isothiocyanato-4-methylpiperidin-1-yl)-6-methylpyrimidine (1.18 g, 0.53 mmol) in ammonia (7 M in MeOH, 13.6 mL, 95.0 mmol) was stirred in a sealed tube at room temperature for 3 h and then heated at 50° C. for 18 h. After cooling to room temperature the mixture was evaporated. Purification by chromatography (silica gel, 50 g, 0 to 20% methanol in dichloromethane) afforded the title compound (1.2 g, 100%) as a white foam.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[S:17])[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].Cl.[Cl:23][CH2:24][C:25]([N:28]([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C)C=O>[ClH:23].[CH3:29][N:28]([CH3:30])[C:25]([CH3:27])([CH3:26])[CH2:24][S:17][C:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: CN(C)C(C)(C)CCl
Reactant: S=c1[nH]c2ccccc2cc1-c1ccccc1
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(C)(C)CSc1nc2ccccc2cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3-Phenylquinolin-2-thione (1.4 g.) was added to a suspension of sodium hydride (0.68 g. of a 50% w/w dispersion in mineral oil) in dimethylformamide (10 ml.) at 0°-5°. When all the hydrogen had evolved, a slurry of 1-chloro-2-dimethylamino-2-methylpropane hydrochloride (1.1 g.) in dimethylformamide (10 ml.) was added and the mixture was stirred at ambient temperature for 20 hr. The mixture was then poured into ice-water (100 ml.) and extracted with ethyl acetate (3×30 ml.). The ethyl acetate extract was washed with brine (30 ml.) and then dried (MgSO4). The solvent was evaporated and the residual oil was chromatographed on basic alumina (125 g., Brockmann Grade III), eluted with increasing concentrations of methylene dichloride in petroleum ether. The eluate obtained with 10% v/v methylene dichloride in petroleum ether was evaporated, the residual oil was dissolved in diethyl ether (20 ml.), and ethereal hydrogen chloride was added until precipitation was complete. The mixture was filtered and the solid residue was crystallised from ethyl acetate to give 2-(2-dimethylamino-2-methylpropylthio)-3-phenylquinoline hydrochloride, m.p. 199°-201°.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([O:1][CH2:2][C@H:3]2[O:8][C:7]([CH3:9])([CH3:10])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COS(=O)(=O)c2ccc(Cl)cc2)OC(C)(C)O1
Reaction time: 2.5 h
Yield: 130.1 %

Procedure:
To a stirring, 0°-5° C. solution of the (4R-cis)-1,1-dimethylethyl 6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate (European Patent Application 0319,847) (10 g, 38 mmol) in methylene chloride (250 mL) containing triethylamine (10 mL, 72 mmol) is added 4-chlorobenzenesulfonyl chloride (12.7 g, 60 mmol). Stirring is continued at 0°-5° C. for 2.5 hours and the solution slowly warmed to 20°-25° C. over a period of 2 hours. The solution is poured onto 200 mL of water and the layers separated. The upper aqueous layer is extracted with 200 mL of methylene chloride and the combined organic layers are washed with 200 mL each of saturated sodium bicarbonate solution to ensure complete removal of 4-chlorobenzenesulfonyl chloride and then saturated sodium chloride solution. Drying the solution with magnesium sulfate and concentration in vacuo gives 21.5 g of the product as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([O:32][CH3:33])=[N:14][NH:15][C:16]=3[N:17]([CH2:29][O:30][CH3:31])[S:18]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:11][C:6]=2[O:5][CH2:4]1.[C:34]([O:37][CH2:38][CH2:39]Br)(=[O:36])[CH3:35]>O1CCCC1>[C:34]([O:37][CH2:38][CH2:39][N:14]1[C:13]([O:32][CH3:33])=[C:12]([C:10]2[CH:9]=[CH:8][C:7]3[O:3][CH2:4][O:5][C:6]=3[CH:11]=2)[C:16]([N:17]([CH2:29][O:30][CH3:31])[S:18]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:20])=[O:19])=[N:15]1)(=[O:36])[CH3:35]
Reactant: COCN(c1[nH]nc(OC)c1-c1ccc2c(c1)OCO2)S(=O)(=O)CCc1ccccc1
Reactant: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCN(c1nn(CCOC(C)=O)c(OC)c1-c1ccc2c(c1)OCO2)S(=O)(=O)CCc1ccccc1
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% dispersion in oil, 162 mg) was added at room temperature under an atmosphere of nitrogen to a solution of N-[4-(1,3-benzodioxol-5-yl)-3-methoxy-1H-pyrazol-5-yl]-N-(methoxymethyl)-2-phenyl-1-ethanesulfonamide (Preparation 55) in anhydrous tetrahydrofurane. After 10 minutes, 2-bromoethyl acetate (446 μl) was added and the reaction mixture was refluxed overnight. At room temperature, some more 2-bromoethylacetate (446 μl) was added and the reaction was refluxed for 24 h. Then at room temperature, some more sodium hydride (50 mg) was added and the reaction was refluxed for 24 h. At room temperature, the reaction was quenched by the addition of an aqueous saturated solution of ammonium chloride (5 ml), water (10 ml) and the mixture was extracted with ethyl acetate (3×10 ml). The combined organic fractions were washed with brine (20 ml), dried on sodium sulfate and concentrated under reduced pressure to yield a dark oil which was purified by column chromatography (silica, 10 g), eluted with hexane:ethyl acetate (4:1) then (2:1) yielding the title compound as a colourless oil (92 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH:11][CH3:12])=[CH:6][C:5]=1[F:13].[NH2:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:19]=2[N:20]=1.[C:30](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:1][O:2][C:3]([C:4]1[C:5]([F:13])=[CH:6][C:7]2[N:11]([CH3:30])[C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([O:25][C:26]([F:29])([F:27])[F:28])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:10][C:8]=2[CH:9]=1)=[O:14]
Reactant: CNc1cc(F)c(C(=O)OC)cc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Solvent: ClCCCl
Product: COC(=O)c1cc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2cc1F
Yield: 64.7 %

Procedure:
6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (140 mg) was prepared by following General Procedure D starting from 5-amino-2-fluoro-4-methylamino-benzoic acid methyl ester (115 mg), 2-amino-6-(trifluoromethoxy)benzothiazole (115 mg), 1,1′-thiocarbonyldiimidazole (126 mg), and EDC (153 mg). LC/MS: m/z 441.8.
Reaction SMILES: [F:1][CH:2]([F:47])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([O:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:42])[C@@H:29]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:31][S:32][CH3:33])[CH2:23][CH2:22]3)[CH:9]=2)[C:6]2[CH:43]=[CH:44][CH:45]=[CH:46][C:5]=2[N:4]=1.[CH3:48][I:49]>>[I-:49].[C:37]([O:36][C:35]([NH:34][C@H:29]([C:28]([NH:27][C@H:24]1[CH2:23][CH2:22][C@H:21]([O:20][C:10]2[CH:9]=[C:8]([N:7]3[C:6]4[CH:43]=[CH:44][CH:45]=[CH:46][C:5]=4[N:4]=[C:3]3[CH:2]([F:1])[F:47])[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=2)[CH2:26][CH2:25]1)=[O:42])[CH2:30][CH2:31][S+:32]([CH3:48])[CH3:33])=[O:41])([CH3:40])([CH3:38])[CH3:39]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@H](Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Reactant: CI
Product: C[S+](C)CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@H](Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl [(2S)-1-{[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]amino}-4-(methylsulfanyl)-1-oxobutan-2-yl]carbamate (760 mg) was added methyl iodide (3.5 mL), followed by stirring at room temperature overnight. Methyl iodide was evaporated under reduced pressure to obtain a desired compound [(3S)-3-[(tert-butoxycarbonyl)amino]-4-{[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]amino}-4-oxobutyl](dimethyl)sulfonium iodide (919 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)=[N:8][CH:7]=[C:6]2[C:25]([OH:27])=O.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[OH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C(OCC)(=O)C.CN(C)C=O>[OH:43][CH:44]1[CH2:49][CH2:48][N:47]([C:25]([C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)=[O:24])=[N:8][CH:7]=2)=[O:27])[CH2:46][CH2:45]1
Reactant: COc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OC)c(OC)cc23)c1
Reactant: OC1CCNCC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)c2ncc(C(=O)N3CCC(O)CC3)c3cc(OC)c(OC)cc23)c1
Temperature: 25 °C
Yield: 3.4 %

Procedure:
A solution of 6,7-dimethoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (30.0 mg, 61.75 mmol) in dry, N,N-dimethylformamide (2 mL) was chilled in an ice bath under argon. With stirring, triethylamine (14.4 uL, 102 mmol) and isobutylchloroformate (13.4 uL, 102 mmol) were added. The solution was stirred for 30 min and then 4-hydroxypiperidine (165 mg, 1.633 mmol) was added. The solution was allowed to warm to room temperature with stirring for 1 hr. and then diluted with ethyl acetate (30 mL). The ethyl acetate solution was washed sequentially with saturated aqueous sodium bicarbonate solution (2×5 mL), water (5 mL), and saturated aqueous sodium chloride solution (5 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford 35 mg of an off white solid. This crude material was purified by flash chromatography eluting with 50% ethyl acetate in hexanes (containing 1% acetic acid) and then increasing gradually to 80% ethyl acetate in hexanes. After tlc analysis, fractions were pooled and evaporated to yield 25 mg (68%) of product as an acetic acid salt: APCI-MS m/e calcd for C25H26N2O6 (M+H) 451.5, found 451, H NMR (300 MHz) compatible.