Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:44]1([CH:54]([NH2:56])[CH3:55])[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46][CH:45]=1.CN1CCOCC1>CC(N(C)C)=O>[C:44]1([CH:54]([NH:56][C:17]([C:12]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:19])[CH3:55])[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46][CH:45]=1
Reactant: O=C(O)c1cccc2c1cnn2-c1ccc(F)cc1
Reactant: CC(N)c1cccc2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: CC(NC(=O)c1cccc2c1cnn2-c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid (40.0 mg, 0.156 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (89 mg, 0.23 mmol) were combined in a 20 mL vial and dimethylacetamide (DMA) (1 mL) was added. The yellow solution was stirred at room temperature for 10 minutes and then a solution of 1-(1-napthyl)ethylamine (40.1 mg, 0.234 mmol) and N-methylmorpholine (NMM) (0.086 mL, 0.78 mmol) in DMA (0.20 mL) was added. The mixture was shaken at room temperature for 16 hours then the solution was evaporated in vacuo. The crude product was purified by preparative reversed-phase HPLC to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([N:20]=[N+]=[N-])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:42](Cl)(=[O:44])[CH3:43]>C1COCC1.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([NH:20][C:42](=[O:44])[CH3:43])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: COC(=O)c1nc2c(s1)C(N=[N+]=[N-])COc1ccc(Br)cc1-2
Reactant: CC(=O)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1nc2c(s1)C(NC(C)=O)COc1ccc(Br)cc1-2
Temperature: 65 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a solution of 4-Azido-9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (280 mg, 0.735 mmol) in THF/water (15 mL/3 mL) was added PPh3 (192.5 mg, 0.735 mmol). The reaction mixture was heated to 65° C. overnight. The mixture was cooled to −5° C., and TEA (222 mg, 2.200 mmol) was added followed by acetyl chloride (86.5 mg, 1.101 mmol). Then the mixture was stirred at room temperature for 1 h. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford crude product which was triturated with EtOAc and hexane (1:1) and then filtered to afford 4-Acetylamino-9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (160 mg, 51%). 1H NMR (400 MHz, DMSO-d6): δ 8.80 (d, J=2.5 Hz, 1H), 8.48 (s, 1H), 7.53 (dd, J1=8.7 Hz, J2=2.6 MHz, 1H), 7.13 (d, J=8.6 Hz, 2H), 5.51 (m, 1H), 4.41 (m, 1H), 4.23 (m, 1H), 3.96 (s, 3H), 1.90 (s, 3H); LC-MS (ESI & APCI): 399.1 (M+2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].C(=O)(O)[O-].[K+].[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>CN(C=O)C>[OH:21][CH2:20][CH:19]1[O:11][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=2[O:8][CH2:17]1
Reactant: BrCC1CO1
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)OC(CO)CO2
Temperature: 90 °C
Reaction time: 17 h
Yield: 3.5 %

Procedure:
17.6 g 4-nitrocatechol and 11.0 g potassium bicarbonate were stirred in 200 ml DMF at 10° C. 13.99 g epibromohydrin in 10 ml DMF were added dropwise and stirring was continued at 60° C. for another 17 hrs. DMF was evaporated and the residue diluted with 50 ml water and extracted with ethyl acetate. The combined organic phases were washed with caustic soda and water, dried and evaporated. The crude oily product was heated to 90° C. with 200 ml toluene and the supernatant decanted from insoluble parts. After cooling to RT the solution is again decanted from insoluble oils and left at RT for 3 d. A first crop of 0.75 g crystalline title product was obtained. The mother liquor was evaporated and the residue dissolved in 20 dichloromethane at RT. Seeding and chilling to 0° C. yielded another 2.78 g crystalline title product.
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:16][CH2:15][C:14]([C:17]2[C:25]3[C:20](=[CH:21][C:22]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[NH:28])=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[CH:13][CH2:12]1)C(=O)OC(C)(C)C)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([NH:3][CH:11]1[CH2:16][CH2:15][C:14]([C:17]2[C:25]3[C:20](=[CH:21][C:22]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[NH:28])=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[CH:13][CH2:12]1)[CH3:2]
Reactant: CCN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3cc(NC(=N)c4cccs4)ccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC1CC=C(c2c[nH]c3cc(NC(=N)c4cccs4)ccc23)CC1
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A solution of compound 131 (0.08 g, 0.172 mmol) was treated with 20% TFA in CH2Cl2 (10 mL) at 0° C. and stirring was continued for 2 h at same temperature. Solvent was evaporated and crude was diluted with 10% aq. NH4OH (25 mL) and product was extracted into CH2Cl2 (2 20 mL). The combined CH2Cl2 layer washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M NH3 in MeOH: CH2Cl2, 1:9) to obtain compound 132 (0.055 g, 89%) as a solid. Compound was repurified using reverse phase column chromatography (CH3CN: pH 10.6 buffer, 20:80 to 55:45) on biotage to obtain pure product. mp 95-97° C.; 1H NMR (DMSO-d6) δ 1.04 (t, 3H, J=7.2 Hz), 1.38-1.49 (m, 1H), 1.91-1.99 (m, 2H), 2.40-2.48 (m, 2H), 2.56-2.80 (m, 4H), 6.07 (s, 1H), 6.30 (s, 2H), 6.59 (d, 1H, J=8.4 Hz), 6.81 (s, 1H), 7.09 (t, 1H, J=4.5 Hz), 7.20 (d, 1H, J=2.1 Hz), 7.59 (d, 1H, J=5.1 Hz), 7.68-7.72 (m, 2H), 10.80 (s, 1H); ESI-MS (m/z, %) 365 (MH+, 7), 160 (50), 119 (100); ESI-HRMS calculated for C21H25N4S (MH+), calculated: 365.1794; observed: 365.1801.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH:13]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:14]([F:17])([F:16])[F:15])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CS(C)=O.[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([NH2:39])(=[O:38])=[O:37])#[N:29].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([NH:39][C:2]1[C:11]([O:12][CH:13]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:14]([F:17])([F:16])[F:15])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)(=[O:38])=[O:37])#[N:29]
Reactant: N#Cc1ccccc1S(N)(=O)=O
Reactant: FC(F)(F)C(Oc1nc2ccccc2nc1Cl)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: N#Cc1ccccc1S(=O)(=O)Nc1nc2ccccc2nc1OC(c1cccnc1)C(F)(F)F
Temperature: 25 °C
Yield: 68.7 %

Procedure:
According to Example 132, by use of 2-chloro-3-[2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy]-quinoxaline (Compound BJ) (70 mg, 0.21 mmol), dimethyl sulfoxide (2 mL), 2-cyanobenzenesulfonamide (38 mg, 0.21 mmol) and potassium carbonate (28 mg, 0.21 mmol), the mixture was stirred and reacted at 150° C. for 1.5 hours. The reaction mixture was allowed to cool down to room temperature, a 1% aqueous acetic acid solution was added thereto, and extraction with ethyl acetate was performed. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was evaporated off under reduced pressure. The residue was subjected to slurry purification using methanol, to give 2-cyano-N-{3-[2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy]-quinoxalin-2-yl}benzenesulfonamide (Compound 145) (70 mg, 70%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([OH:14])=O)[CH2:9][NH:8][C:7]=2[CH:15]=1.[CH2:18]([NH2:21])[CH:19]=[CH2:20]>C(O)C>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([NH:21][CH2:18][CH:19]=[CH2:20])=[O:14])[CH2:9][NH:8][C:7]=2[CH:15]=1
Reactant: C=CCN
Reactant: O=C(O)C1CNc2cc(C(F)(F)F)ccc2O1
Solvent: CCO
Product: C=CCNC(=O)C1CNc2cc(C(F)(F)F)ccc2O1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of 20.6 g of 6C, 25.7 g of 2-propenamine and 34 ml of ethanol was stirred at room temperature for 36 hours. The excess amine and solvent were evaporated under reduced pressure. The solid residue was mixed with 150 ml of ether and the remaining solid material was filtered. The filtrate was added to petroleum ether and cooled; the resulting viscous material was filtered. The filtrate was stripped and the residue was triturated with petroleum ether to give an off-white powder which was purified by dry-column chromatography (silica gel), using ether as eluent. The higher Rf band was collected and extracted with ether, the solvent was stripped and the solid residue was recrystallized from ether/hexane (4/5 v/v). Thin-layer chromatography indicated that two components were present. The product was purified by wet-column chromatography (silica gel) using petroleum ether/ethyl ether (1:4 v/v) as eluent. The solvent was stripped and the residue was recrystallized from ether/hexane (75:100 v/v) to give 6, as a solid, mp: 95°-97° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:18])[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CCC(O)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a solution of 8-(4-fluorophenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (38 g, 0.15 mol) in dioxane (900 ml), cooled to 0° C. was added hydrogen chloride (1M in water, 1.5 L, 1.5 mol). The reaction mixture was stirred for 2 hour at RT and extracted twice with ethyl acetate. The ethyl acetate layer was washed with saturated sodium bicarbonate solution, water and brine. Drying and solvent evaporation gave 4-(4-fluorophenyl)-4-hydroxy-cyclohexanone (24.8 g, 79%); 1H NMR (CDCl3)δ 7.55-7.45 (m, 2H) 7.16-7.0 (m, 2H), 3.0-2.85 (m, 2H), 2.18-2.38 (m, 6H), 1.85 (s, 1H)
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17]#[N:18])[CH:11]=[CH:10]2)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:27][O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:27][O:28][C:29]1[CH:34]=[C:33]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12]([C:17]#[N:18])[CH:11]=[CH:10]3)[CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: COc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cccc(-c2ccc3cc(C#N)ccc3c2)c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 54 %

Procedure:
A solution of Example 28B (300 mg, 1 mmol), palladium (II) acetate (22 mg, 0.1 mmol) and 1-1′-bis(diphenyphosphino)ferrocene (111 mg, 0.2 mmol) was stirred in DMF (3 mL) for 15 min, treated with Cs2CO3 (813 mg, 2.5 mmol) and 3-methoxyphenylboronic acid (228 mg, 1.5 mmol), stirred for 20 min at 80° C., cooled, treated with pH 7 buffer (10 mL) and extracted with diethyl ether. The ether extracts were dried (MgSO4), concentrated and purified on silica gel with 10% ethyl acetate/hexane to provide 140 mg of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C1COCC1>[NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][CH:7]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: Nc1ccc2c(c1)S(=O)(=O)NC(C1CCCCC1)=N2
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)S(=O)(=O)NC(C1CCCCC1)N2
Temperature: -70 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
To a stirred solution of 7-amino-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (0.5 g; 2 mmol) in dry THF (10 ml) at −70° C. was added a solution of 1.5 M DIBALH in toluene (2.7 ml; 4 mmol) under N2. The reaction mixture was stirred for 2 h at −70° C.; 2 h at −40° C. and then warmed to 0° C. The reaction was quenched with H2O and stirred for 30 min. at 0° C. and left over night without stirring at +5° C. The mixture was evaporated to dryness, resuspended in MeOH and filtered. The isolated solid was washed thoroughly with MeOH and filtered. The combined filtrates was adsorped onto silica gel. Column chromatography (EtOAc) gave 200 mg of product.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([O-:27])=[O:26].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([N:17]([S:34]([C:31]3[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:33][CH:32]=3)(=[O:35])=[O:36])[S:34]([C:31]3[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=3)(=[O:36])=[O:35])=[N:15][CH:16]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2cnc(N(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)S(=O)(=O)c3ccc([N+](=O)[O-])cc3)c(Cc3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
Under an argon atmosphere, 5-(4-acetoxyphenyl)-2-amino-3-benzylpyrazine (c-19) (140 mg, 438 μmol) was dissolved in pyridine (2 mL) and to this was added 4-(dimethylamino)pyridine (6.0 mg, 49 μmol). To this was added p-nitrobenzenesulfonyl chloride (293 mg, 1.32 mmol) while stirring at room temperature and stirred for 1.5 h at the same temperature. To this was further added p-nitrobenzenesulfonyl chloride (195 mg, 880 μmol) and stirred for 17 h. To this was added saturated aqueous solution of sodium bicarbonate to stop the reaction and the product was extracted twice with dichloromethane. The organic layer was washed once with water and once with saturated aqueous solution of sodium sulfate and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (24 g, n-hexane/ethyl acetate=4/1→3/1→7/3→ethyl acetate alone) to give 5-(4-acetoxyphenyl)-3-benzyl-2-bis(4-nitrophenylsulfonyl)aminopyrazine (c-40) as a dark brown solid (157 mg, 52.1%). Rf=0.62 (n-hexane/ethyl acetate=3/2). Mp. 227-229.5° C. (dec.). UV (MeOH, 0.3% DMSO) λmax (log ε) 309 (3.99), 258 (4.21). 1H NMR (400 MHz, DMSO-d6) δ 2.30 (s, 3H), 4.22 (s, 2H), 7.19-7.27 (m, 1H), 7.29-7.35 (m, 6H), 8.05-8.10 (AA′BB′, 4H), 8.14-8.19 (AA′BB′, 2H), 8.39-8.44 (AA′BB′, 4H), 9.13 (s, 1H). 13C NMR. (75.5 MHz, DMSO-d6) δ 20.9, 38.0, 122.8 (2C), 124.8 (2C×2), 126.6, 128.3 (2C), 128.7 (2C), 129.6 (2C), 130.7 (2C×2), 131.9, 137.3, 139.8, 140.3, 142.1 (1C×2), 151.1 (1C×2), 151.9, 152.7, 156.2, 169.0. I,R (KBr, cm−1) 548, 598, 617, 687, 737, 775, 810, 854, 880, 897, 916, 935, 1013, 1165, 1180, 1206, 1315, 1348, 1368, 1385, 1404, 1418, 1435, 1530, 1603, 1755, 3107. HRMS (FAR) m/z 690.0975 (M+H, C31H24N5O10S2 requires 690.0965).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][N+:5]1([CH3:10])[CH2:9][CH2:8][CH2:7][CH2:6]1.[F:11][C:12]([F:18])([F:17])[S:13]([OH:16])(=[O:15])=[O:14]>C(Cl)(Cl)Cl>[F:11][C:12]([F:18])([F:17])[S:13]([O-:16])(=[O:15])=[O:14].[CH3:2][O:3][CH2:4][N+:5]1([CH3:10])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=S(=O)(O)C(F)(F)F
Agent: COC[N+]1(C)CCCC1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: O=S(=O)([O-])C(F)(F)F
Yield: 95.4 %

Procedure:
In 116 g of dehydrated chloroform (reagent, Wako Pure Chemical Ind. Ltd.) was dissolved 24.3 g of N-methoxymethyl-N-methylpyrrolidinium chloride. To the solution was added dropwise 24.3 g of trifluoromethane sulfonic acid (reagent, Aldrich Corp.) at 5° C. over a period of 1 hour. The mixture was reacted at room temperature for 2 hours with gradual increase of temperature. The reaction mixture was concentrated and dried in a vacuum. The residue was purified through alumina column (ICN Biomedicals. GmbH, ICN Alumina N, Act.1/eluent acetonitrile). The eluate was concentrated and dried in a vacuum to obtain 39.1 g of the desired product (colorless liquid).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[N:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([N:22]3[CH:30]([OH:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])=[N:19]2)=[CH:14][CH:13]=1>N1C=CC=CC=1>[Cl:11][C:12]1[N:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([N:22]3[CH:30]([O:31][C:2]([O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:3])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])=[N:19]2)=[CH:14][CH:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 20 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
Phenyl chloroformate (126 g.) is added to a suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (86.5 g.) in pyridine (980 cc.), whilst keeping the temperature at about 25° C. The reaction mixture is stirred for 3 hours at a temperature of about 20° C. and then poured into ice-water (9,000 cc.). The product which crystallises is filtered off, washed with water (6×500 cc.) and then with acetonitrile (3×200 cc.). After drying, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (96.7 g.), which melts at 235° C. with decomposition, is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.Cl.[NH2:16][OH:17]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10][CH2:9]1
Reactant: NO
Reactant: COCCCCCN1CCC(=O)CC1
Agent: Cl
Product: COCCCCCN1CCC(=NO)CC1

Procedure:
1-(5-Methoxypentyl)-4-piperidone oxime is prepared from 1-(5-methoxypentyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([NH:26][C:27](=S)[CH2:28][C:29](=O)[CH3:30])[CH2:24][C:23]([CH3:34])([CH3:33])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[NH2:35][NH2:36].CC(O)=O>CCO.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([NH:26][C:27]4[CH:28]=[C:29]([CH3:30])[NH:36][N:35]=4)[CH2:24][C:23]([CH3:34])([CH3:33])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: NN
Reactant: CC(=O)CC(=S)NC1CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CCO
Product: Cc1cc(NC2CC(C)(C)Oc3nc(-c4ccc(Cl)cc4Cl)c(-c4ccc(Cl)cc4)cc32)n[nH]1
Temperature: 25 °C

Procedure:
A mixture of the product of Step B (56 mg, 0.11 mmol), hydrazine (6.6 μL, 0.21 mmol), and AcOH (12.0 μL, 0.21 mmol) in 5.0 mL of EtOH was refluxed for 16 h. The reaction mixture was then cooled to rt, diluted with Et2O (50 mL), and washed with saturated aq NaHCO3 (2×50 mL) and brine (50 mL). After phase separation, the organic phase was dried over MgSO4 and concentrated. Chromatography on a Biotage 40+S cartridge using 2:3 v/v acetone/hexanes as the eluant afforded the title compound: 1H NMR δ 1.48 (s, 3H), 1.54 (s, 3H), 1.82 (t, J=12.4, 1H), 2.26 (s, 3H), 2.41 (dd, J=5.9, 13.3, 1H), 3.86 (br. s, 1H), 4.92 (m, 1H), 5.45 (s, 1H), 7.00 (d, J=8.4, 2H), 7.15-7.26 (m, 5H), 7.97 (s, 1H).
Reaction SMILES: C(OCCCCCCOC1C=CC([C:19]2[C:20]([C:37]([O-:39])=[O:38])=[C:21]([NH2:36])[C:22]3[C:23](=[O:35])[C:24]4[C:29]([C:30](=[O:34])[C:31]=3[C:32]=2[NH2:33])=[CH:28][CH:27]=[CH:26][CH:25]=4)=CC=1)(=O)C=C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:23]([C:22]1[CH:21]=[CH:20][C:19]([O:39][C:37]([C:20]2[CH:19]=[C:32]([NH:33][C:40](=[O:43])[CH:41]=[CH2:42])[C:31]3[C:30](=[O:34])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23](=[O:35])[C:22]=3[C:21]=2[NH2:36])=[O:38])=[CH:32][CH:31]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: C=CC(=O)Cl
Reactant: C=CC(=O)OCCCCCCOc1ccc(-c2c(N)c3c(c(N)c2C(=O)[O-])C(=O)c2ccccc2C3=O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(C(=O)Oc2ccc(CCCCCCC)cc2)c(N)c2c1C(=O)c1ccccc1C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 199.8 %

Procedure:
To a stirred solution of 0.91 g of (4-heptylphenyl)-1,4-diaminoanthraquinone-2-carboxylate (preparation analogous to example 1) in 80 ml of methylenechloride, cooled to 0° C. was added dropwise (over a period of 30 min) a solution of 0.36 g of acryloylchloride in 20 ml of methylenechloride. After stirring for 1 h at 0° C. and 30 min at room temperature, DMAP was added and stirring was continued for further 60 min. The reaction mixture was then concentrated to half its volume and passed through a silica gel column using methylenechloride as the eluent. The afforded violet solid was further recrystallised from ethanol/methylenechloride 9/1 (v/v) to give 0.88 g (4-heptylphenyl)-4-acrylamido-1-aminoanthraquinone-2-carboxylate as violet crystals; λmax. (CB 483): 572 nm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:10]([CH3:18])([CH3:17])[CH2:11]/[CH:12]=[CH:13]/[C:14]([OH:16])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH:41][CH2:42][CH2:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:51][CH2:52][N:53]([CH3:70])[C:54](=[O:69])[C@H:55]([NH:67][CH3:68])[CH2:56][C:57]1[CH:66]=[CH:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([C:10]([CH3:18])([CH3:17])[CH2:11]/[CH:12]=[CH:13]/[C:14](=[O:16])[N:67]([C@@H:55]([C:54](=[O:69])[N:53]([CH2:52][CH2:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[O:44][CH2:43][CH2:42][OH:41])[CH3:70])[CH2:56][C:57]1[CH:66]=[CH:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=1)[CH3:68])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1OCCO
Reactant: CN(C(=O)OC(C)(C)C)C(C)(C)C/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(CCc1ccccc1OCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
(2E)-5-(N-(tert-Butoxycarbonyl)-N-methylamino)-5-methylhex-2-enoic acid (133 mg, 0.52 mmol) was dissolved in N,N-dimethylformamide (2 ml) and dichloromethane (2 ml). 1-Hydroxy-7-azabenzotriazole (71 mg, 0.52 mmol) was added. The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) was added. The solution was stirred for 10 min at 0° C. A solution of (2R)-N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide (262 mg, 0.52 mmol) in dichloromethane (2 ml) and ethyldiisopropylamine (0.09 ml, 0.52 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (30 ml) and washed with 10% sodium hydrogen sulfate solution (20 ml). The aqueous phase was extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (100 g), using ethyl acetate/heptane (2:1) as eluent, to give 261 mg of N-((3E)-4-(N-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)-N-methylcarbamic acid tert-butyl ester.