Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([F:11])[C:5]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH3:26]>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]([NH2:26])=[O:9])=[C:6]([F:11])[C:5]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(N)=O)c1F

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-26 by using 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (0.400 g, 1.39 mmol), THF (25 mL), oxalyl chloride (0.14 mL, 1.67 mmol) and ammonia gas to afford 0.220 g of the product. 1H NMR (300 MHz, DMSO d6): δ 1.12 (s, 9H), 4.25 (d, J=5.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.82 (s, 1H), 8.12 (br s, 2H); MS (m/z): 287.01 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[OH:10][CH2:9][CH2:8][C:7]1[CH:11]=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CCO)cc1
Yield: 87.7 %

Procedure:
A slurry of 5 g of 4-nitrophenethyl alcohol, 0.58 g of 10% Pd on carbon in 50 mL of absolute ethanol was shaken overnight under 50 psi of H2. The mixture was filtered and concentrated to yield 3.6 g of 4-(2-hydroxyethyl) aniline, mp 101°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CCCl)CC)C.[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37]Cl)[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:37][CH2:36][N:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)[CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc(CN2CCNCC2c2ccccc2)cc1Cl
Reactant: ClCCN1CCOCC1
Agent: CCN(CC)CCCl
Product: Clc1ccc(CN2CCN(CCN3CCOCC3)CC2c2ccccc2)cc1Cl

Procedure:
1-(3',4'-Dichloro benzyl)-2-phenyl piperazine prepared according to Example 3b, is alkylated by following the procedure described in Example 3c whereby, in place of diethylamino ethylchloride, the equimolecular amount of morpholino ethylchloride is used. The resulting reaction product is obtained in the form of a light yellow oil boiling at 230° C./0.04 mm. Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH3:14]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8]([NH2:14])(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: N
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1S(N)(=O)=O
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-2-methoxybenzene sulfonyl chloride (1.0 g, 4.15 mmol) in tetrahydrofuran (10 mL) was bubbled ammonia gas until saturated. The reaction was stirred overnight. The white solid that precipitated out of solution was collected by filtration and washed with dichloromethane to give the title compound (0.52 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+].Cl>CCO>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C(=O)O)C(C)(C)C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
The commercially available 2-tert-butyl-malonic acid diethyl ester (1 g, 4.6 mmol) is dissolved in EtOH (7 mL). A 1N NaOH solution (5.06 mL, 5.06 mmol) is added and the resulting mixture is stirred at 40° C. overnight. Next, the mixture is acidified to pH=1 with HCl. Extraction with EtOAc gives an organic phase that is dried over MgSO4, filtered and evaporated to give the desired product.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][C:6]([C:8]([O:10][C:11](C)(C)C)=[O:9])=[CH:5][CH2:4][N:3]1[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16].Cl.CO.C[Si](C=[N+]=[N-])(C)C.CCCCCC.Cl.[Cl-].[Na+]>CO.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:1][C@@H:2]1[CH2:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH2:4][N:3]1[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16]
Reactant: C=CCOC(=O)N1CC=C(C(=O)OC(C)(C)C)C[C@H]1C
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CC=C(C(=O)OC)C[C@H]1C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a solution of 1-allyl 4-tert-butyl (2R)-2-methyl-3,6-dihydro-1,4(2 H)-pyridinedicarboxylate (0.64 g, 2.3 mmol) in methanol (10 ml) was added hydrochloric acid/methanol (10 ml) and the mixture was stirred overnight. Toluene was added thereto and the solvent was removed in vacuo. To the residue were added methanol and toluene, and the solvent was again removed in vacuo. The residue was dissolved in THF (10 ml) and to the solution was added at 0–5° C. a solution of trimethylsilyldiazomethane in hexane (2M, 1.15 ml, 2.3 mmol). Fifteen minutes later 1N hydrochloric acid was added thereto. Ethyl acetate and a saturated aqueous sodium chloride solution were added thereto. The mixture was separated with a separating funnel. The aqueous layer was extracted twice with ethyl acetate. The organic layer was washed twice with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel (20 g) chromatography (hexane/ethyl acetate: 1/6→1/4) to give 1-allyl 4-methyl (2R)-2-methyl-3,6-dihydro-1,4(2 H)-pyridinedicarboxylate (0.31 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][C:10](=[O:13])[CH:9]([C:14]([O:16][CH3:17])=[O:15])[S:8][C:7]=2[CH:18]=1.[C:19]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33]Cl)[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][C:10](=[O:13])[C:9]([CH2:33][CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)([C:14]([O:16][CH3:17])=[O:15])[S:8][C:7]=2[CH:18]=1
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Reactant: COC(=O)C1Sc2cc(OC)ccc2OCC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C1(CCCN2CCN(c3ccccc3)CC2)Sc2cc(OC)ccc2OCC1=O

Procedure:
A mixture of 10 g of methyl 7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate, 9.8 g of 3-(4-phenylpiperazin-1-yl)propyl chloride, 6.2 g of anhydrous potassium carbonate, 3.0 g of potassium iodide and 150 ml of methyl ethyl ketone is stirred with heating under reflux for 25 hours. After the mixture is cooled, the inorganic substance is filtered off, and the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in ethyl acetate, and the solution is washed with water and dried. The solvent is evaporated off under reduced pressure, and the resulting residue is purified by column chromatography on silica gel (eluent: hexane:ethyl acetate =3:1) to give methyl 7-methoxy-3-oxo-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate. Recrystallization from methanol gives white crystals. m.p. of 110°-112° C. Yield of 2.1 g.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].[OH-].[CH2:11]([N+:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>O.CC(O)C>[CH2:2]([C:3]([CH2:8][OH:9])([CH3:7])[C:4]([O-:6])=[O:5])[OH:1].[CH2:24]([N+:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: CC(CO)(CO)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(CO)(CO)C(=O)[O-]

Procedure:
To a flask were added 3.0 g 2,2-bis(hydroxymethyl)propionic acid, 9.5 g of a 55-60% solution of tetrabutylammonium hydroxide in water and 40 ml 2-propanol. After heating to 50 C under nitrogen for 1 hour, the solvent was removed and another 40 ml of 2-propanol were added and removed by distillation under reduced pressure. After drying, a pale yellow oil was obtained.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:12][CH3:13])=[O:2].[CH:14]1([N:20]=[C:21]=[S:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([NH:20][C:21](=[S:22])[NH:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][NH:3][CH:1]=[O:2])=[C:6]([O:12][CH3:13])[CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cc(N)ccc1NNC=O
Reactant: S=C=NC1CCCCC1
Product: COc1cc(NC(=S)NC2CCCCC2)ccc1NNC=O

Procedure:
Procedure (11.) was employed with 1-formyl-2-(4-amino-2-methoxyphenyl)hydrazine (1.2 g, 0.0066 mole) and cyclohexyl isothiocyanate (0.93 g, 0.0066 mole). Yield 0.50 g (24%), m.p. 131°-133° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[NH2:12].[C:13](O)(=[O:17])[C:14](O)=[O:15]>>[CH3:11][O:10][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[O:8][CH3:9])[NH:1][C:14](=[O:15])[C:13](=[O:17])[NH:12]2
Reactant: O=C(O)C(=O)O
Reactant: COc1cc(N)c(N)cc1OC
Product: COc1cc2[nH]c(=O)c(=O)[nH]c2cc1OC

Procedure:
6,7-Dimethoxy-1,4-dihydroquinoxaline-2,3-dione was prepared from 1,2-dimethoxybenzene. Nitration of 1,2-dimethoxybenzene gave 1,2-dimethoxy-4,5-dinitrobenzene, which was reduced to 1,2-diamino-4,5-dimethoxybenzene. Condensation of the diamine with oxalic acid gave 6,7-dimethoxy-1,4-dihydroquinoxaline-2,3-dione. ##STR31##
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[CH2:3][CH:4]1[C:7]2([CH2:10][CH2:9][CH2:8]2)[CH2:6][C:5]1=[O:11].ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)Cl>[Cl:12][C:2]([Cl:1])([Cl:13])[CH2:3][CH:4]1[O:22][C:5](=[O:11])[CH2:6][C:7]21[CH2:8][CH2:9][CH2:10]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1CC2(CCC2)C1CC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C1CC2(CCC2)C(CC(Cl)(Cl)Cl)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.42 g (0.01 mol) of the 1-(2',2',2'-trichloroethyl)spiro(3.3)heptan-2-one produced according to Example 10 is placed into 30 ml of methylene chloride, and 2 g (0.012 mol) of m-chloroperbenzoic acid is added. The reaction mixture is subsequently stirred for 48 hours at room temperature (21°-26° C.), filtered, and then washed with methylene chloride. The filtrate is washed with cold (0°-5° C.) sodium carbonate solution and cold (0°-5° C.) water, dried over sodium sulphate and concentrated by evaporation. The residue is recrystallised from diethyl ether/n-hexane to yield 5-(2',2',2'-trichloroethyl)-6-oxaspiro(3.4)octan-7-one of the formula ##STR14## as white crystals, m.p. 86.5°-87.5° C.
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:20]=[C:19]([F:21])[C:18]([N+:22]([O-])=O)=[CH:17][C:5]=1[C:6]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7]>C(O)C.[Fe]>[NH2:22][C:18]1[C:19]([F:21])=[CH:20][C:4]([Cl:3])=[C:5]([CH:17]=1)[C:6]([O:8][C:9]([CH3:15])([CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7]
Reactant: CCOC(=O)C(C)(C)OC(=O)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)(C)OC(=O)c1cc(N)c(F)cc1Cl

Procedure:
A mixture of 10 g of finely powdered iron. 50 ml of ethanol, 11 ml of water and 1 ml of concentrated hydrochloric acid is heated to 65° C. while stirring. To this mixture is added dropwise during 2 hours a solution of 15 g of ethyl 2-(2-chloro-4-fluoro-5-nitro-benzoyloxy)-2-methyl-propionate in 15 ml of ethanol in such a manner that the temperature does not rise above 80° C. After completion of the addition the reaction mixture is stirred at 70° C. for a further 16 hours. After cooling the reaction mixture is suction filtered over Celite®. The Celite® is rinsed well with water and with ethyl acetate. The filtrate is adjusted to pH 8 with 2N potassium bicarbonate solution. It is once more filtered over Celite® and again rinsed with water and ethyl acetate. The filtrate is now extracted three times with 400 ml of ethyl acetate each time. The organic phases are back-washed twice with 300 ml of saturated sodium chloride solution each time, dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The residue is fractionated in a high vacuum and distilled. In this manner there is obtained ethyl 2-(5-amino-2-chloro-4-fluoro-benzoyloxy)-2-methylpropionate, b.p. 146°-151° C./0.07 torr.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:38]=[CH:37][C:16]([CH2:17][N:18]([CH2:24][C:25]3[CH:36]=[CH:35][C:28]([O:29][CH2:30][C:31]([O:33]C)=[O:32])=[CH:27][CH:26]=3)[S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CCO>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:38]=[CH:37][C:16]([CH2:17][N:18]([CH2:24][C:25]3[CH:36]=[CH:35][C:28]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)[S:19]([CH2:22][CH3:23])(=[O:20])=[O:21])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)S(=O)(=O)CC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)O)cc3)S(=O)(=O)CC)cc2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a solution of methyl (4-{[{4-[(4-butylphenyl)ethynyl]benzyl}(ethylsulfonyl)amino]-methyl}phenoxy)acetate (7 mg, 0.013 mmol) in EtOH (1 mL) was added an aqueous solution of NaOH (20 μL, 5N). The reaction mixture was stirred at 70° C. for 2 hrs. Then an aqueous solution of HCl (1N) was added and extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4 and the solvents were removed under reduced pressure to give 6 mg (90%) of the title compound as a pale yellow oil. HPLC, Rt: 5.0 min (purity: 75.0%). LC/MS, M+(ESI): 520.5, M−(ESI): 518.3.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:34])[C:12]1[CH:17]=[C:16]([O:18]CC2C=CC=CC=2)[CH:15]=[C:14]([O:26]CC2C=CC=CC=2)[CH:13]=1.[H][H]>C(O)(C)C.O.[C].[Pd]>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:34])[C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([OH:26])[CH:13]=1
Reactant: COc1ccc(CCNCC(O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(CCNCC(O)c2cc(O)cc(O)c2)cc1OC
Yield: 63.7 %

Procedure:
1.4 g of α-(3,4-dimethoxyphenethylaminomethyl)-3,5-dibenzyloxybenzylalcohol hydrochloride are suspended in a mixture of 32 ml of isopropanol and 8 ml of water. 0.42 g of 10 % palladium-carbon is added to the solution. Then, the mixture is subjected to catalytic hydrogenation in a hydrogen atmosphere at room temperature for 1 hour under atmospheric pressure. After the reaction is completed, the mixture is filtered to remove the catalyst. The filtrate is concentrated under reduced pressure, and the residue thus obtained is recrystallized from a mixture of methanol and ether. 0.6 g of α-(3,4-dimethoxyphenethylaminomethyl)-3,5-dihydroxybenzylalcohol hydrochloride is obtained. Yield: 63.5 % M.p. 193° - 194°C
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:39][O:40][CH2:41][C:42](Cl)=[O:43]>C(Cl)Cl>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([CH2:30][O:31][C:42](=[O:43])[CH2:41][O:40][CH3:39])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)OCc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Reaction time: 1 h
Yield: 40.5 %

Procedure:
{6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-yl}-methanol (80 mg, 0.194 mmol), CH2Cl2 (1 mL), and triethylamine (40 μL, 2.916 mmol) are added to a flask. Add methoxyacetyl chloride (23.2 mg, 0.214 mmol) dropwise at room temperature. Stir 1 h. The crude mixture is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (38 mg, 40%).
Reaction SMILES: [C:1]([NH:18][CH2:19][CH2:20][C:21](O)=[O:22])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:57][C:58]1[C:59]([NH:76][CH:77]2[CH2:82][CH2:81][N:80]([CH2:83][CH2:84][C:85]#[N:86])[CH2:79][CH2:78]2)=[C:60]2[CH:66]=[CH:65][N:64]([S:67]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)(=[O:69])=[O:68])[C:61]2=[N:62][CH:63]=1>CN(C=O)C>[CH:7]1[C:6]2[CH:5]([CH2:4][O:3][C:1](=[O:2])[NH:18][CH2:19][CH2:20][C:21](=[O:22])[NH:57][C:58]3[C:59]([NH:76][CH:77]4[CH2:78][CH2:79][N:80]([CH2:83][CH2:84][C:85]#[N:86])[CH2:81][CH2:82]4)=[C:60]4[CH:66]=[CH:65][N:64]([S:67]([C:70]5[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=5)(=[O:69])=[O:68])[C:61]4=[N:62][CH:63]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: N#CCCN1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Reactant: O=C(O)CCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CCCN1CCC(Nc2c(NC(=O)CCNC(=O)OCC3c4ccccc4-c4ccccc43)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97 %

Procedure:
Fmoc-beta-Alanine (3.1 g, 9.90 mmol), HATU (3.8 g, 9.90 mmol), and diisopropylethylamine (2.1 ml, 12.0 mmol) were added sequentially to a solution of 3-[4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-propionitrile (4.2 g, 9.90 mmol) in DMF (100 ml) at 25° C. The reaction mixture was stirred for 14 h at 25° C., then was concentrated under reduced pressure. The residue was partitioned between half-saturated NaHCO3 (200 ml) and EtOAc (2×200 ml). the combined organic layers were dried over Mg2SO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 7% CH3OH in CH2Cl2) afforded (2-{1-benzenesulfonyl-4-[1-(2-cyano-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamoyl}-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (6.89 g, 97%) as a white foam. LCMS (Method G, ESI): RT=0.85 min, m+H=718.5. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.14 (t, J=10.3 Hz), 7.84 (s), 7.75 (dd, J=15.2, 7.5 Hz), 7.60-7.54 (m), 7.50 (d, J=4.1 Hz), 7.44 (t, J=7.8 Hz), 7.37 (t, J=7.4 Hz), 7.28 (t, J=5.8 Hz), 6.52 (t, J=4.7 Hz), 5.50 (d, J=11.4 Hz), 4.70 (s), 4.40 (s), 4.33 (d, J=7.1 Hz), 4.19 (t, J=6.6 Hz), 3.64 (td, J=13.3, 6.7 Hz), 3.51 (d, J=21.9 Hz), 3.39 (d, J=5.4 Hz), 2.80-2.47 (m), 2.35 (s), 2.30-2.07 (m), 1.93 (d, J=12.0 Hz), 1.51 (dt, J=13.5, 6.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[F:17])(=[O:26])=[O:25])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1F
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1F

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)phenyl-methanone and 2-fluoro-benzenesulfonyl chloride. 1H NMR (CDCl3): δ (ppm): 6.88-6.93 (m, 1H), 7.16-7.20 (m, 1H), 7.38 (d, J=6.4 Hz, 1H), 7.41-7.46 (m, 4H), 7.52 (m, 2H), 7.58-7.62 (m, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.81-7.85 (m, 1H), 10.10 (s, 1H). MS: m/z 390.0 (M++1).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:22])[C:4]([CH:11]([OH:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].C([O-])(=O)C.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(OCC)C>CC(C)=O.S(=O)(=O)(O)O.O>[CH3:1][C:2]1[C:3](=[O:22])[C:4]([C:11](=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: CC(=O)OCCCCCC(O)C1=C(C)C(=O)C(C)=C(C)C1=O
Agent: O=[Cr](=O)=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: CC(=O)OCCCCCC(=O)C1=C(C)C(=O)C(C)=C(C)C1=O

Procedure:
A solution of 2,3,5-trimethyl-6-(6'-acetoxy-1'-hydroxyhexyl)-1,4-benzoquinone (formula IV-3 wherein R=H3C, n=4, in the form of acetate at --CH2OH) (0.74 part) in acetone (20 volume parts) was oxidized at 5° C. for 5 minutes with Jones reagent (0.6 volume part) prepared by dissolving chromic trioxide (26.72 parts) in concentrated sulfuric acid (23 volume parts) diluted with water to a volume of 100 volume parts. The resulting precipitate was decomposed with water, and the product was taken up with diethyl ether. The organic layer was washed with water and dried over anhydrous sodium sulfate. The residue upon removal of the solvent was subjected to column chromatography on silica gel and eluted with methylene chloride and the resulting product was crystallized from petroleum ether to give 2,3,5-trimethyl-6-(6'-acetoxy-1'-oxohexyl)-1,4-benzoquinone (formula IV-1 wherein R=H3C, n=4, in the form of acetate) (0.638 part) as yellow crystals melting at 57° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].O.[F:25][C:26]([F:31])([F:30])[C:27](O)=O>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:27]([C:26]([F:31])([F:30])[F:25])=[N:15][C:14]=2[CH:16]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Solvent: O
Product: FC(F)(F)c1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Yield: 55.5 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.20 g, 0.646 mmol) in trifluoroacetic acid (7 mL) was heated to reflux for 4.5 hours. The reaction mixture was cooled, water was added, and this was extracted with ethyl acetate. The organic layer was washed with aqueous sodium carbonate solution and water, then dried over magnesium sulfate, and concentrate. The residue was purified by silica gel column chromatography to yield the title compound (139 mg, 55.5% yield) as white crystals.