Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][C:7]([C:10]2[N:15]=[C:14]([C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=4)=[N:18][N:17]=3)[C:13]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[N:12][CH:11]=2)=[CH:6][CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH:4]1[CH2:9][CH2:8][C:7]([C:10]2[N:15]=[C:14]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][C:24]([CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[CH:25][CH:26]=4)=[N:18][N:17]=3)[C:13]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[N:12][CH:11]=2)=[CH:6][CH2:5]1
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(C4=CCC(N=[N+]=[N-])CC4)cnc3NC(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1ccc(-c2nnc(-c3nc(C4=CCC(N)CC4)cnc3NC(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
To a solution of tert-butyl N-[[4-[5-[6-(4-azidocyclohexen-1-yl)-3-(tert-butoxycarbonylamino)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (103 mg, 0.17 mmol) in anhydrous THF (1.5 mL) was added triphenylphosphine (67 mg, 0.26 mmol) and the reaction mixture was stirred at room temperature for 1 h. Water (61 μL, 3.41 mmol) was added after 1 h, and the reaction mixture was heated at 65° C. for 3 h. The reaction mixture was allowed to cool to room temperature and was partitioned between EtOAc/aqueous brine. The layers were separated and the aqueous layer was extracted once more with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel column chromatography using 20% MeOH in EtOAc to yield tert-butyl N-[[4-[5-[6-(4-aminocyclohexen-1-yl)-3-(tert-butoxycarbonylamino)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (21 mg, 21%). LC/MS m/z 578.3 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1O)=[CH:10][C:9]([NH:14][C:15](=[O:17])[CH3:16])=[C:8]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:7]=2)#[N:2].P(Cl)(Cl)([Cl:25])=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:25][C:12]1[C:11]2[C:6](=[CH:7][C:8]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: COCCOc1cc2ncc(C#N)c(O)c2cc1NC(C)=O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCCOc1cc2ncc(C#N)c(Cl)c2cc1NC(C)=O
Temperature: 82.5 °C
Yield: 70.1 %

Procedure:
A stirred mixture of N-(3-cyano-4-hydroxy-7-(2-methoxyethoxy)quinolin-6-yl)acetamide (8.8 g, 0.029 mol, 1.00 equiv) in phosphorus oxychloride (70 mL, 0.765 mol, 26.4 equiv) was heated to 80-85° C. for 4 hours. The reaction mixture was cooled and filtrated. The filtrates were added to a cooled (0-10° C.) solution of potassium carbonate (270 g, 1.95 mol) in 470 ml water. The resulting yellow mixture was stirred for at least 12 hours. The mixture was filtered and washed with hot water. The collected solids were dried to give product 6.5 g. MS (ESI) m/z: 319 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:37](O)[CH3:38]>O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:37][CH3:38])=[C:12]([C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCO
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Solvent: O
Product: CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting ethanol in place of 2-ethyl-1-hexanol (yield: 25 mg, 12%). mp 121-123° C. 1H NMR (300 MHz, DMSO-d6) δ 1.23 (t, J=7 Hz, 3H), 3.30 (s, 3H), 4.51 (q, J=7 Hz, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 407 (M+H)+; (APCI−) m/z 441 (M+Cl)−. Anal. calc. for C19H16F2N2O4S.0.25 H2O: C, 55.53; H, 4.04; N, 6.81. Found: C, 55.58; H, 4.21; N, 6.61.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[C:31]1([CH2:37][CH2:38][NH2:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[C:8]([O:12][C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([NH:39][CH2:38][CH2:37][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: NCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCCc1ccccc1
Temperature: 0 °C

Procedure:
Triethylamine (2.8 ml.) was added with stirring to a solution of N-(tert-butyloxycarbonyl)-L-proline (4.3 g.) in tetrahydrofuran (50 ml.) maintained at 0° C. The temperature was lowered to -20° C., isobutyl chloroformate (2.7 ml.) was added, and stirring was continued for15 minutes. 2-Phenylethylamine (2.5 ml.) was then added with continued stirring, and the mixture was allowed to warm to room temperature and filtered. Concentration of the filtrate afforded a solid. Crystallization of the solid from ethyl acetate gave the product in two parts by filtration and in a third part from the filtrate, which was washed with water, aqueous citric acid (5%), saturated aqueous sodium chloride and saturated aqueous sodium bicarbonate, then dried and concentrated. High pressure liquid chromatography of the three parts on silica gel (350 g.) using hexane-ethyl acetate (7:3) as the eluant (200 ml./min.) afforded in fractions 7-8 1-(tert-butyloxycarbonyl)-N-(2-phenylethyl)-L-prolinamide (3.2 g., m.r. 153°-154° C.)
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[CH2:3][Mg]Cl.O1CCCC1.[F:12][C:13]1[CH:14]=[C:15]([NH:25][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:27])[CH:16]=[CH:17][C:18]=1[C:19](N(OC)C)=[O:20].N1C=CC=CC=1C(O)=O>O>[F:12][C:13]1[CH:14]=[C:15]([NH:25][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:27])[CH:16]=[CH:17][C:18]=1[C:19](=[O:20])[CH2:3][C:2]([CH3:6])=[CH2:1]
Reactant: C=C(C)C[Mg]Cl
Reactant: CON(C)C(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Agent: O=C(O)c1ccccn1
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)CC(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Reaction time: 3 h

Procedure:
9.89 ml of (2-methyl-2-propen-1-yl)magnesium chloride (0.50 M tetrahydrofuran solution) was added to a tetrahydrofuran (10 ml) solution of 500 mg of N-(3-fluoro-4-((methoxy(methyl)amino)carbonyl)phenyl)pyridine-2-carboxamide obtained in the same method as in Example 145 (step 3) or in accordance with the method or by combining it with an ordinary method but using pyridine-2-carboxylic acid, with cooling with ice. The reaction liquid was stirred for 3 hours with cooling with ice, and then water was poured into the reaction solution, extracted with ethyl acetate and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to obtain the entitled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]([N:35]1[CH2:40][CH2:39][CH2:38][CH:37]([CH2:41]O)[CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:41][CH:37]2[CH2:38][CH2:39][CH2:40][N:35]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:36]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(COc2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
4-Fluorophenol (520 mg, 4.64 mmol) and triphenylphosphine (1.22 g, 4.64 mmol) were added to a solution of N-boc-piperidine-3-methanol (500 mg, 2.32 mmol) in anhydrous THF (12 mL) under nitrogen. The reaction mixture was cooled to 0° C. and DEAD (673 μL, 3.71 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure then diluted with dichloromethane and filtered. The filtrate was washed three times with NaOH 0.2N, dried over Na2SO4 and concentrated. The residue was purified on column chromatography (eluent: pentane/EtOAc 95/5) to give the title compound (300 mg, 42%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[N:3]=1.[NH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[N:26](C(OC(C)(C)C)=O)[N:25]=1.CC(O)=O>CC(N(C)C)=O>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[N:3]=[C:2]2[NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3cccc(Cl)c3n2)nc1
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(Cl)cccc23)n[nH]1
Temperature: 100 °C
Yield: 16.4 %

Procedure:
To 4,8-dichloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline (263 mg, 0.77 mmol) in DMA (2.0 mL) were added tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (300 mg, 1.53 mmol) and HOAc (0.102 mL), and the mixture was heated at 100° C. for 5 h. The mixture was allowed to cool to rt and was purified by preparative reverse-phase HPLC (diphenyl column eluting over 40 mins with a gradient of 25 to 80% acetonitrile (containing 0.05% HOAc) and water (containing 0.05% HOAc) to afford 8-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine as a colorless solid (51 mg, 16%). 1H NMR (300 MHz, DMSO-d6) δ 12.23 (br s, 1H), 10.87 (br s, 1H), 8.65-8.67 (m, 2H), 8.01-8.08 (m, 3H), 7.61 (dd, J=9, 6 Hz, 1H), 5.94 (s, 1H), 2.17 (s, 3H). LCMS (ESI) m/z 405 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][C:5]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:4][N:3]=1.CCN(CC)CC.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:6][C:5]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:4][N:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1cc(-c2ccc3nccc(N4CCOCC4)c3c2)cnc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1cc(-c2ccc3nccc(N4CCOCC4)c3c2)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(Some starting materials may be obtained from Adesis Inc., New Castle, Del.) To a mixture of (2-chloro-5-(4-morpholinoquinolin-6-yl)pyridin-3-yl)methanamine (50 mg, 141 μmol) and Et3N (300 μl, 2152 μmol) in DCM (5 mL) was added pivaloyl chloride (100 μL, 813 μmol). The solution was stirred at rt for 1 h. The mixture was partitioned between DCM (10 mL) and aqueous NaHCO3 (20 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified on silica with 1-5% (2N NH3-MeOH) in DCM to give the product as a yellow solid after concentration (20 mg, 32%). LCMS (ESI, pos. ion): calc'd for C24H27ClN4O2:438.2; found: 439.2 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.21-1.28 (m, 12 H) 3.19-3.35 (m, 4 H) 3.95-4.08 (m, 4 H) 4.58 (d, J=6.06 Hz, 2 H) 6.37 (br. s., 1 H) 6.93 (d, J=4.89 Hz, 1 H) 7.83 (dd, J=8.90, 1.66 Hz, 1 H) 8.00 (d, J=2.15 Hz, 1 H) 8.10-8.25 (m, 5 H) 8.61 (d, J=2.15 Hz, 2 H) 8.79 (d, J=4.89 Hz, 2 H)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:15][CH2:16][OH:17])[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:20]([CH3:22])=[CH2:21]>COC(OC)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@@H:12]([CH2:15][CH2:16][OH:17])[CH2:13][O:14][C:20]1([CH3:22])[CH3:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)OC
Reactant: O=C(N[C@H](CO)CCO)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC1(C)OC[C@H](CCO)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 95.6 %

Procedure:
A solution of (S)—N-(benzyloxycarbonyl)-2-aminobutane-1,4-diol (8.00 g, 33.4 mmol) and toluene-4-sulfonic acid monohydrate (318 mg, 1.67 mmol) in 2,2-dimethoxypropane (320 mL) was stirred at room temperature, then after 2 h 2-methoxypropene (7.71 g, 107 mmol) was added, then after 72 h the reaction mixture was partitioned between EtOAc and sat. aq. sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was taken up in DCM (200 mL), then after addition of SiO2 (80 g) and water (4.8 mL) the slurry was stirred for 64 h at room temperature. After dilution with DCM and addition of anhydrous magnesium sulfate, insoluble material was removed by filtration through diatomaceous earth. The filtrate was evaporated and chromatographed (SiO2; heptane/EtOAc 1:1) to afford the title compound (8.92 g, 96%). Light yellow oil, MS (ISP)=280.1 (M+H)+.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][CH2:20][CH:21]1[CH2:24][C:23](=[O:25])[CH2:22]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:26](O)[CH2:27][OH:28].O>C1C=CC=CC=1>[CH2:12]([O:19][CH2:20][CH:21]1[CH2:24][C:23]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:22]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CC(COCc2ccccc2)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: c1ccc(COCC2CC3(C2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
p-Toluene sulphonic acid (2.0 gm) was added to a solution of 3-[(benzyloxy)methyl]cyclobutanone (25.0 gm, 131.6 mmol) (step b) and 1,2-ethanediol (8.98 gm, 144.7 mmol) in benzene and the reaction mixture was refluxed with removal of water through dean-stark apparatus. After about 6 hours, the reaction mixture was cooled to room temperature and washed with saturated sodium bicarbonate solution, followed by water and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to get a crude product, which was purified by column chromatography.
Reaction SMILES: O1C2C=CC=C[C:4]=2[CH:3]=N1.[OH:10][C:11]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=2[O:13][N:12]=1.C(O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:3]([O:10][C:11]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=2[O:13][N:12]=1)[CH3:4]
Reactant: COc1ccc2c(O)noc2c1
Reactant: c1ccc2oncc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1noc2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
Benzisoxazole from part (b) (193 mg, 1.17 mmol), ethanol (75 μl, 1.29 mmol) and triphenylphosphine (460 mg, 1.75 mmol) were dissolved in anhydrous THF (4 ml) and cooled (0°). Diisopropylazodicarboxylate (345 μl, 1.75 mmol) was added slowly and after 10–15 min the reaction flask was removed from the ice bath and the reaction mixture was stirred at room temperature overnight under an argon atmosphere. The solution was evaporated to dryness and the residue pre-absorbed onto silica, and chromatographed on silica (19 g); eluent: hexane (300 ml), 10–30% ethyl acetate/hexane to give 3-ethoxy-6-methoxy-1,2-benzisoxazole (101 mg, 44%) as white crystals.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:26])[CH:4]=[CH:5][C:6](=[O:25])[CH:7]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].Cl>N1C=CC=CC=1>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C:16](=[O:19])[CH2:17][O:18][S:28]([CH3:27])(=[O:30])=[O:29])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:26])[CH:4]=[CH:5][C:6](=[O:25])[CH:7]=1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(C(=O)COS(C)(=O)=O)[C@@]3(C)C[C@H](O)[C@@]12F

Procedure:
A solution of 16 grams of 9-fluoro-11β,21-dihydroxypregna-1,4,16-triene-3,20-dione in dry pyridine (200 ml) is reacted with methanesulfonyl chloride (5.0 ml) for 2 hours at 0° C. The mixture is poured into an excess of cold 2N-hydrochloric acid. The solid that separates from the resulting solution is isolated yielding 17.5g of the title compound, which is characterized by its nmr spectrum.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)(=[O:4])=[O:3].[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[Cl:25])[CH:18]=[C:17]([C@@H:26]([NH:28]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[CH3:27])[N:16]=1.O>C1COCC1>[Cl:25][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:24]=1[C:15]([O:11][CH:8]1[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]1)=[N:16][C:17]([C@@H:26]([NH2:28])[CH3:27])=[CH:18]2
Reactant: CS(=O)(=O)N1CCC(O)CC1
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](N)c1cc2cccc(Cl)c2c(OC2CCN(S(C)(=O)=O)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 1-(methylsulfonyl)piperidin-4-ol (618 mg, 3.45 mmol, 1.6 eq) in THF (5 mL) at 0° C., NaH (60% in mineral oil, 173 mg, 4.32 mmol, 2.0 eq) was added and the resulting mixture was stirred for 10 min. To this mixture, (S)-(9H-fluoren-9-yl)methyl 1-(1,8-dichloroisoquinolin-3-yl)ethylcarbamate 69 (1.0 g, 2.16 mmol, 1.0 eq) was added and the resulting mixture was stirred at reflux for 2 h. The mixture was cooled to RT and poured into water (20 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (3% MeOH-DCM) to afford the product (S)-1-(8-chloro-1-(1-(methylsulfonyl)piperidin-4-yloxy)isoquinolin-3-yl)ethanamine (175).
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=[S:13])[NH:10][C:9](=[O:14])[C:8]=2[CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:16]([CH2:24][CH2:25][CH2:26][CH2:27]C1C=C(S([O-])(=O)=O)C=CC=1C)[Si](C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[OH:16][CH2:24][CH2:25][CH2:26][CH2:27][N:12]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([CH3:15])[C:9](=[O:14])[NH:10][C:11]1=[S:13]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1CCCCO[Si](C)(C)C(C)(C)C
Reactant: Cc1c(-c2ccccc2)[nH]c(=S)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)n(CCCCO)c(=S)[nH]c1=O
Reaction time: 1.5 h
Yield: 4.1 %

Procedure:
To 2 ml of dimethyl sulfoxide, 468 mg (2.0 mmol) of 6-phenylthiothymine, 358 mg (1.0 mmol) of 4-(t-butyldimethylsiloxy)-butyl-p-toluenesulphonate and 276 mg (2.0 mmol) of potassium carbonate were added and heated to react for 4 hours at 80° C. The reaction mixture was concentrated under reduced pressure, added with methanol and filtered. The filtrate was concentrated under reduced pressure, added with 20 ml of tetrahydrofuran and 1 ml of 1N hydrochloric acid and stirred for 90 minutes. The reaction mixture was concentrated under reduced pressure and adsorbed on a silica gel column and eluted with 2% methanol/chloroform. The eluate was concentrated and crystallized from acetone/hexane to obtain 12.0 mg of the target compound (Yield: 4%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([O:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:13]=2)=[CH:7][N:6]=1)(=[O:4])=[O:3]>C(O)C.O1CCCC1.[C].[Pd]>[CH3:1][S:2]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:13]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(OC3CCOCC3)c2)cn1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2ccc(N)c(OC3CCOCC3)c2)cn1
Temperature: 50 °C
Reaction time: 6 h
Yield: 100.7 %

Procedure:
To a solution of 2-(methylsulfonyl)-5-[4-nitro-3-(tetrahydro-2H-pyran-4-yloxy)phenoxy]pyridine (25.8 g) in ethanol (250 mL) and tetrahydrofuran (250 mL) was added 10% palladium carbon (3 g), and the mixture was stirred under hydrogen pressure of 0.5 MPa at 50° C. for 6 hr. Palladium carbon was removed, and the mixture was concentrated under reduced pressure to give the title compound (24 g, yield 100%) as a white powder.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:18]=[C:17](F)[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:4]=1[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].O>C1COCC1>[NH2:1][C:17]1[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:4]([C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])=[C:3]([F:2])[CH:18]=1
Reactant: N
Reactant: O=C(OCc1ccccc1)c1cc([N+](=O)[O-])c(F)cc1F
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(F)c(C(=O)OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2M Ammonia (25.6 mL, 51.2 mmol) was added to Benzyl 2,4-difluoro-5-nitro-benzoate in 200 mL THF at 0° C. and the mixture stirred for 16 h at ambient temperature. Then 100 mL water were added, the preticipate was filtered off, washed with water and dried at 60° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13]([F:18])([F:17])([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[C:19](=[O:21])=[O:20].Cl>CCCCCC.CCOCC>[F:14][S:13]([F:18])([F:17])([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:19]([OH:21])=[O:20])=[CH:8][CH:9]=1
Reactant: O=C=O
Reactant: FS(F)(F)(F)(F)c1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(O)c1ccc(S(F)(F)(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
A solution of n-butyllithium (9.4 ml of a 1.6 M solution in hexane) was added to a stirred solution of 4-bromophenylsulphur pentafluoride (3.87 g) in ether at -78° C. under an inert atmosphere. After maintaining at -78° C. for 1 hour, solid carbon dioxide (20 g) was added and the mixture allowed to warm to 5° C. during 1.5 hours. Hydrochloric acid (2 M) was added, the mixture stirred for 0.5 hour and the organic phase separated and itself extracted with sodium carbonate solution. The basic extract was washed (ether) and acidified (hydrochloric acid). The precipitated solid was extracted (ether), dried (magnesium sulphate) and evaporated. The residue was triturated (hexane) to give 4-pentafluorosulphanylbenzoic acid as a fawn solid (1.2 g), m.p.188-190° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH2:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.C([Li])CCC.[Cl-].[CH3:24][C:25]([NH:28][SiH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:10]([Si:29]([CH3:31])([CH3:30])[NH:28][C:25]([CH3:27])([CH3:26])[CH3:24])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:6][CH:7]=1
Reactant: C[SiH](C)NC(C)(C)C
Reactant: Fc1ccc(CC2=Cc3ccccc3C2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Product: CC(C)(C)N[Si](C)(C)C1C(Cc2ccc(F)cc2)=Cc2ccccc21
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a mixture of 2-(4-fluorophenylmethyl)indene (2.21 g, 9.9 mmol) in 45 mL of hexanes were added 6.5 mL of butyl lithium (1.6 M hexane; 10.4 mmol). The mixture was stirred overnight, the mother liquor decanted and the solid dissolved in THF. To this was added N-(1,1-dimethylethyl)dimethylsilanamine chloride (1.80 g, 10.8 mmol) and the reaction heated at reflux for three hours. The volatiles were removed in vacuo, the residue extracted with hexane, filtered and the volatiles removed in vacuo to give 3.39 g (97 percent) of a yellow oil.