Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([C:6]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([OH:15])[C:8]=2[CH:7]=1)(=[O:5])=[O:4])[CH3:2].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:20][C@H:21]1[O:23][CH2:22]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([S:3]([C:6]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH2:20][C@H:21]3[O:23][CH2:22]3)[C:8]=2[CH:7]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: CCS(=O)(=O)c1cc2c(O)cccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)c1cc2c(OC[C@@H]3CO3)cccc2o1
Yield: 105.5 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 2-(ethylsulfonyl)-4-hydroxybenzo(b)furan (2.75 g), (S)-glycidyl nosylate (3.48 g) and potassium carbonate (5.05 g), a crude product of the title compound (3.62 g) was obtained as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:22][CH3:23])=[C:7]([O:20][CH3:21])[CH:8]=2)[N:3]=1.[CH3:24][NH2:25]>CO>[CH3:21][O:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:22][CH3:23])[N:3]=[C:2]([NH:25][CH3:24])[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=1
Reactant: CN
Reactant: COc1cc2nc(Cl)nc(-c3cccc(C=O)c3)c2cc1OC
Solvent: CO
Product: CNc1nc(-c2cccc(C=O)c2)c2cc(OC)c(OC)cc2n1

Procedure:
Starting from 1.50 g of 2-chloro-6,7-dimethoxy-4-(3-formylphenyl)quinazoline and 15 ml of 40% methylamine in methanol, 1.00 g of the title compound was obtained as yellow crystals in the same manner as in Production Example 8.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]2[O:9][CH2:10][O:11][C:5]=2[CH:4]=1.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)=O>O1CCCC1.BrBr>[Br:21][C:17]1[CH:16]=[C:15]([C:13]([C:3]2[CH:8]=[CH:7][C:6]3[O:9][CH2:10][O:11][C:5]=3[CH:4]=2)=[CH2:12])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: Brc1ccc2c(c1)OCO2
Agent: BrBr
Agent: [Mg]
Solvent: C1CCOC1
Product: C=C(c1cccc(Br)c1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of magnesium turnings (440 mg, 0.01 mol, 1.2 eq) in dry tetrahydrofuran (5 mL), was added 4-bromo-1,2(methylendioxy)benzene (3.1 g, 0.01 mol, 1.1 eq) in dry tetrahydrofuran (10 mL) and bromine (0.5 mL). The resulting solution was refluxed for 2 hours. Then the mixture was cooled at room temperature and a solution of 3-bromoacetophenone (3.0 g, 0.01 mol, 1 eq) in dry tetrahydrofuran (10 mL) was added dropwise and refluxed. After 3 hours the reaction mixture was examined by LC-MS which showed complete conversion to the desired product. The mixture was quenched with 1 M HCl solution (20 mL). The aqueous phase was extracted with ethyl acetate. (3×20 mL), dried (sodium sulfate) and the solvent removed in vacuo. The crude was dissolved in toluene (30 mL) and a catalytic amount of p-toluenesulfonic acid was added. The mixture was heated to reflux for 3 h (using a Dean-Stark water trap). The solvent was removed and the residue was purified by column chromatography (cyclohexane) to afford the title compound as a colorless oil (3.7 g, 80%);
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[C:38]1[CH:39]=[N:40][N:41]([CH2:43][CH2:44][N:45]([CH3:53])[CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:42]=1>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:3][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:38]3[CH:39]=[N:40][N:41]([CH2:43][CH2:44][N:45]([CH3:53])[CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH:42]=3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:1]
Reactant: CN(CCn1cc(Br)cn1)Cc1ccccc1
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3cnn(CCN(C)Cc4ccccc4)c3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C

Procedure:
1-Methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (300 mg, 0.721 mmol, for a preparation see Intermediate 52), potassium carbonate (149 mg, 1.081 mmol) and 2-(4-bromo-1H-pyrazol-1-yl)-N-methyl-N-(phenylmethyl)ethanamine (317 mg, 1.078 mmol, for a preparation see Intermediate 53) were stirred in ethanol (3 mL) and toluene (3.00 mL). The mixture was degassed, tetrakis(triphenylphosphine)palladium(0) (41.6 mg, 0.036 mmol) added, the mixture degassed again and heated to reflux (90° C.) under nitrogen for 4.5 hours. The mixture was cooled to room temperature, loaded on to a 5 g SCX cartridge, eluted with MeOH (50 ml), 2M methanolic ammonia (25 ml) and the basic fractions evaporated to dryness. The residue was loaded on to a 12+M Biotage silica column and eluted with a gradient of 0 to 5% 2M methanolic ammonia in DCM. The product containing fractions were evaporated to a colourless gum (223 mg).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][N:13]3[C:17]([CH2:18][OH:19])=[CH:16][N:15]=[C:14]3[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[C:1]12([CH2:11][CH2:12][N:13]3[C:17]([CH:18]=[O:19])=[CH:16][N:15]=[C:14]3[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CCCCc1ncc(CO)n1CCC12CC3CC(CC(C3)C1)C2
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCCCc1ncc(C=O)n1CCC12CC3CC(CC(C3)C1)C2

Procedure:
The above prepared compound (5.4 g) was stirred at room temperature with potassium hydroxide (5.2 g) in ethanol (200 ml) for one hour. The mixture was concentrated, poured into water, stirred and filtered to give 1-[2-(1-adamantyl)ethyl]-2-n-butyl-5-hydroxymethyl-imidazole. The hydroxymethyl group was oxidized by refluxing the imidazole compound (51.1 g) with manganese dioxide (20.3 g) in toluene (200 ml) to give 1-[2-(1-adamantyl)ethyl]-2-n-butyl-imidazol-5-carboxaldehyde.
Reaction SMILES: [C:1]([O:4][C:5]1[CH2:9][N:8]([C:10]([CH3:18])([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:19])[C:6]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:3])[CH3:2]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[C:1]([O:4][CH:5]1[CH2:9][N:8]([C:10]([CH3:18])([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:19])[CH:6]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1=C(c2ccccc2)C(=O)N(C(C)(C)c2ccccc2)C1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CC(=O)OC1CN(C(C)(C)c2ccccc2)C(=O)C1c1ccccc1
Yield: 14.8 %

Procedure:
6.4 g (20 mmol) of 4-acetoxy-1-(α,α-dimethylbenzyl)-2-oxo-3-phenyl-3-pyrroline prepared by the method of reference Example 14, was dissolved in 100 ml of methanol and subjected to hydrogenation at normal temperature under atmospheric pressure by an addition of 0.4 g of Pd-BaSO4. After completion of the reaction, the catalyst was removed by filtration, and methanol was distilled off. The residue was purified by silica gel column chromatography to obtain 1.0 g (yield: 15%) of the desired compound.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([O:32][CH3:33])[CH:24]=3)[CH2:18]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(O)(=O)C.CCOC(C)=O.[BrH:44]>>[BrH:44].[CH3:33][O:32][C:25]1[CH:24]=[C:23]([N:19]2[CH2:20][CH2:21][CH2:22][CH:17]([N:14]3[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]3)[CH2:18]2)[CH:28]=[CH:27][C:26]=1[N+:29]([O-:31])=[O:30]
Reactant: COc1cc(N2CCCC(N3CCN(C(=O)OCc4ccccc4)CC3)C2)ccc1[N+](=O)[O-]
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(N2CCCC(N3CCNCC3)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-[1-(3-methoxy-4-nitro-phenyl)-piperidin-3-yl]-piperazine-1-carboxylic acid benzyl ester (300 mg, 0.66 mmol) in 4 M of hydrogen bromide in acetic acid (6 mL, 20 mmol) was heated at 40-45° C. for 45 min, then allowed to cool to room temperature while being stirred overnight. The orange homogenous solution was added dropwise to a vigorously stirred flask of EtOAc (50 mL) and the resulting precipitate was filtered, washed with EtOAc and dried in-vacuo to give 294 mg of an orange solid, used without further purification. MS=322 (M-HBr+1).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9]([C:29]([F:32])([F:31])[F:30])=[N:10][N:11]([CH2:13][C:14]([NH:16][C:17]2[S:21][C:20]3[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[C:18]=2[C:26](=[O:28])[NH2:27])=[O:15])[CH:12]=1)(=O)=O.[CH3:33][NH2:34].C(O)=O>CN(C=O)C>[CH3:33][NH:34][CH2:6][CH2:7][C:8]1[C:9]([C:29]([F:30])([F:32])[F:31])=[N:10][N:11]([CH2:13][C:14]([NH:16][C:17]2[S:21][C:20]3[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[C:18]=2[C:26]([NH2:27])=[O:28])=[O:15])[CH:12]=1
Reactant: CS(=O)(=O)OCCc1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Reactant: CN
Solvent: O=CO
Solvent: CN(C)C=O
Product: CNCCc1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: 120 °C
Yield: 13.1 %

Procedure:
The 2-(1-(2-(3-carbamoyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino)-2-oxoethyl)-3-(trifluoromethyl)1H-pyrazol-4-yl)ethyl methanesulfonate (30 mg, 0.061 mmol) was dissolved in DMF (1 mL) and methylamine (2 M in THF, 1 mL, 2 mmol) added. The reaction mixture was heated at 120° C. for 5 min in the microwave. The THF was removed in vacuo and the reaction mixture filtered and purified by preparative reverse phase HPLC to give the formic acid salt of the desired product (3.6 mg, 0.008 mmol, 12%).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]([Cl:18])=[C:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:8](O)=[O:9].N1C=CC=CC=1>C(OCC)C>[Cl:5][C:6]([Cl:18])=[C:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:8]([Cl:3])=[O:9]
Reactant: O=C(O)C(=C(Cl)Cl)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(Cl)C(=C(Cl)Cl)c1ccc(Cl)cc1
Temperature: 22.5 °C
Reaction time: 6 h
Yield: 78.4 %

Procedure:
35.5 g (0.298 mol) of thionyl chloride were added dropwise at 0° C. to the solution of 50 g (0.199 mol) of the acid of Example 4 in 200 ml of diethyl ether and 23.6 g (0.298 mol) of pyridine. The solution was stirred for 6 hours at 20 to 25° C. and then filtered. After the solvent had been distilled off, 42.1 g of the product were obtained, and this was reacted further without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=1
Reactant: OCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=Cc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-(5-bromo-2-chlorobenzyl)phenyl)methanol (intermediate AK) (1 g) in CH2Cl2 (10 mL), the solution of Dess-Martin periodinane (DMP) (1.22 g) in CH2Cl2 (10 mL) was added dropwise at 0° C. The mixture was warmed to room temperature, and the reaction was monitored by TLC. After 1 h, CH2Cl2 was added to dilute the solution and 1 M NaOH was added to quench the reaction. The CH2Cl2 layer was separated and washed with aqueous NaHSO3 and brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography to obtain pure intermediate AL (0.62 g).
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][C:7]([NH2:9])=[O:8])[C:3](O)=[O:4].C([N:12](CC)CC)C.ClC(OCC)=O>C(Cl)(Cl)Cl>[C:3]([NH2:12])(=[O:4])[C:2]([CH2:6][C:7]([NH2:9])=[O:8])=[CH2:1]
Reactant: CCN(CC)CC
Reactant: C=C(CC(N)=O)C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: C=C(CC(N)=O)C(N)=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
38.7 grams (0.3 mole) of 2-methylenesuccinamic acid, prepared as described in Example 1, were dissolved in 150 ml of chloroform in a 500 ml. 3-necked round bottom flask equipped with a magnetic stirrer, condenser, drying tube, thermometer, and dropping funnel. The solution was cooled to about 5° C. and a mixture of 41.7 ml. (1 equivalent) of triethylamine and 90 ml. of chloroform was added dropwise over 1/2 hour to the stirring solution. The solution was then cooled to about -45° C. by means of a dry ice-acetone bath. A mixture of 28.5 ml. (1 equivalent) of ethyl chloroformate and 70 ml. of chloroform was added to the solution over a 1/2 hour period, maintaining the solution temperature at about -45° C. The reaction mixture was allowed to stir at -45° C., ±15° C., for an additional 2 hours. The reaction mixture was then transferred to a 1-liter 3-necked round bottom flask fitted with a mechanical stirrer, gas inlet, thermometer, condenser, and drying tube. The solution was maintained at -10° C. while ammonia gas was bubbled into the reaction mixture for 1/2 hour. Additional portions of chloroform, totaling 400 ml., were then added. The reaction mixture was allowed to warm to room temperature and the precipitated product was isolated by suction filtration and air-dried overnight. Repeated recrystallizations from water, methanol/water, and water gave 16.3 gms of itaconamide, a white solid melting at 226°-229° C.
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][CH:6]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:41])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])=[O:30])=[C:24]([O:39][CH3:40])[CH:23]=2)=[CH:15][CH:14]=1)[CH2:7][C:8]([O:10]CC)=[O:9])C.[OH-].[Na+].Cl>CO>[CH3:40][O:39][C:24]1[CH:23]=[C:22]([CH2:21][C:20]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([CH:6]([CH2:5][C:4]([OH:42])=[O:3])[CH2:7][C:8]([OH:10])=[O:9])=[CH:18][CH:17]=2)=[O:41])[CH:27]=[CH:26][C:25]=1[NH:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])=[O:30]
Reactant: CCOC(=O)CC(CC(=O)OCC)c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(CC(=O)Nc2ccc(C(CC(=O)O)CC(=O)O)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 40 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A mixture of 3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-pentanedioic acid di-ethyl ester [8.40 g, Reference Example 12(x)] and methanol (400 ml) was heated to 40° C. and then treated with 10% aqueous sodium hydroxide solution (110 ml). After stirring at 40° C. for 1 hour, the reaction mixture was cooled and then acidified to pH 1.0 by addition of hydrochloric acid (1M). The resultant white solid was collected, washed with water and then dried in vacuo. Recrystallisation from ethanol gave the title compound as a white crystalline solid (4.7 g), m.p. 218-220° C. [Elemental analysis:—C, 64.5; H, 5.6; N, 7.9%. Calculated for C28H29N3O7:—C, 64.7; H, 5.6; N, 8.1%].
Reaction SMILES: C(O)C.[N+:4]([C:7]1[C:8](=[O:25])[N:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:12]=1)([O-])=O>[H][H].[C].[Pd]>[NH2:4][C:7]1[C:8](=[O:25])[N:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:12]=1
Reactant: O=c1c([N+](=O)[O-])cc(-c2ccccn2)cn1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Yield: 83.8 %

Procedure:
100 mg of 10% palladium-carbon was added to 20 ml of an ethanol solution containing 546 mg of 3-nitro-1-phenyl-5-(pyridin-2-yl)-1,2-dihydropyridin-2-one, followed by stirring overnight in hydrogen atmosphere. The reaction mixture was filtered through silica gel and concentrated, to give 411 mg of the title compound.
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)=O.[Br:19][C:20]1[CH:25]=[CH:24][C:23](O)=[C:22]([O:27][CH3:28])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([O:5][CH2:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:22]([O:27][CH3:28])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Reactant: COc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)ccc1OC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 22 h

Procedure:
To a solution of (S)-tert-butyl 2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (279 mg, 1.00 mmol) and 4-bromo-2-methoxyphenol (325 mg, 1.57 mmol) in N,N-dimethylformamide (5.55 mL) was added cesium carbonate (651 mg, 2.00 mmol). The mixture was heated to 100° C. After 22 h, the mixture was allowed to cool to 23° C. and diluted with water (30 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organics were dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. Purification by column chromatography (silica gel, 0-50% ethyl acetate in dichloromethane) afforded the title compound as an amber oil. MS (ES+) 408.2 (M+Na)+. 1H NMR (400 MHz, CDCl3): δ 7.07-6.79 (m, 3H), 4.25-4.10 (m, 2H), 4.01-3.73 (m, 1H), 3.84 (s, 3H), 3.48-3.26 (m, 2H), 2.16-1.80 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH2:35])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH2:23]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH:35][C:18]2[C:13]3[CH:12]=[CH:11][N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[C:14]=3[N:15]=[CH:16][C:17]=2[N+:20]([O-:22])=[O:21])[CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCN(Cc2ccccc2)C1
Yield: 88 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (2 g, 5.9 mmol), (R)-1-Benzyl-pyrrolidin-3-ylamine (2.4 g, 15.3 mmol), and diisopropylethylamine (6 mL, 35.4 mmol) in propan-2-ol (50 mL) was heated to reflux for 4 hours. Volatile components were removed under vacuum and the residue was purified by column chromatography on silica gel (gradient: 0 to 5% methanol in dichloromethane), gave 2.48 g (88%) of (R)—N-(1-benzylpyrrolidin-3-yl)-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-amine. LCMS (Method J, ESI): RT=0.98 min, M+H+=478.1; 1H NMR (400 MHz, CDCl3) δ: 9.29-9.27 (s, 1H), 9.10 (s, 1H), 8.20-8.17 (m, 2H), 7.63-7.57 (m, 2H), 7.53-7.49 (m, 2H), 7.36-7.25 (m, 6H), 6.77-6.76 (d, J=4.4, 1H), 4.55-4.54 (m, 1H), 3.73-3.63 (m, 1H), 2.94-2.91 (m, 1H), 2.78-2.77 (m, 2H), 2.49-2.41 (m, 4H), 1.90-1.88 (m, 1H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:18])[C:8](=O)[CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[C:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[NH:3][N:2]=1)=[O:18])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)C1CCCCCC1=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1n[nH]c2c1CCCCC2
Yield: 72.3 %

Procedure:
Hydrazine hydrate (0.142 mL, 2.94 mmol) was added to a stirring room temperature solution of 13 (0.6229 g, 2.94 mmol) in EtOH (2.9 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by TLC (4.5 h): The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 70:30:2 Hexanes:CH2Cl2:2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 0.4428 g (72.3%) of 14. 1H (CDCl3, 400 MHz): δ 8.56 (1H, broad s), 4.30 (2H, q, J=7.1 Hz), 2.92-2.86 (2H, m), 2.73-2.78 (2H, m), 1.84-1.76 (2H, m), 1.65-1.57 (4H, m), 1.30 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 162.11, 150.70, 134.97, 124.58, 60.85, 32.33, 28.63, 28.32, 27.39, 24.42, 14.47 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 14.47; CH2 carbons: 60.85, 32.33, 28.63, 28.32, 27.39, 24.42; ppm. HPLC: 9.19 min.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].[CH3:8][NH:9][CH:10]([OH:12])[CH3:11]>CC1C=CC(C)=CC=1>[CH3:8][N:9]([CH:10]([OH:12])[CH3:11])[C:3](=[O:4])[C:2]([F:7])([F:6])[F:1]
Reactant: CNC(C)O
Reactant: O=C(O)C(F)(F)F
Solvent: Cc1ccc(C)cc1
Product: CC(O)N(C)C(=O)C(F)(F)F
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (10 ml; 129 mmol) was added to a stirred solution of N-methylaminoethanol (9.72 g; 129 mmol) in p-xylene (10 ml) at 0° C. The mixture was heated under reflux for 12 hours, then allowed to cool and stand at room temperature overnight. All the volatiles were removed and the product distilled under high vacuum to afford the product as a clear liquid. Yield 9.8 g (44%); b.p. 110° C./1 mm.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[CH:15]=[C:14]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][CH2:43]Cl>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[CH:15]=[C:14]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:43][CH2:42][CH2:41][N:40]([CH3:45])[CH3:39])=[CH:29][CH:30]=3)[N:13]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)cc(-c3ccc(O)cc3)n2)cc1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)cc(-c3ccc(OCCCN(C)C)cc3)n2)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of the above-prepared [2-(4-acetamido-phenyl-sulfanyl)-6-(4-hydroxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (70 mg, 1.62.10−4 mol) in DMF (3 mL) is added potassium carbonate (134 mg, 9.71.10−4 mol). The reaction mixture is heated to 80° C. before 1-dimethylamino-3-chloropropane hydrochloride (77 mg, 4.86.10−4 mol) is added. The mixture is stirred at 80° C. for 4 hours, cooled to room temperature and the solvent is evaporated. The residue is purified by flash chromatography to afford the desired product {2-(4-acetamido-phenyl-sulfanyl)-6-[4-(3-dimethylamino-propoxy)-phenyl]-pyrimidin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [O:1]=[C:2]1[C:5](=O)[C:4]([NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[C:3]1[O:16]CC.[CH3:19][C@@H:20]([NH2:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>C(O)C>[O:1]=[C:2]1[C:3](=[O:16])[C:4]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=2)=[C:5]1[NH:25][C@H:20]([CH3:19])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: C[C@@H](N)C(C)(C)C
Reactant: CCOc1c(Nc2ccc(C#N)cc2)c(=O)c1=O
Solvent: CCO
Product: C[C@@H](Nc1c(Nc2ccc(C#N)cc2)c(=O)c1=O)C(C)(C)C
Yield: 75.5 %

Procedure:
4-(3,4-Dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile (1 g, 4.1 mmol) and a solution of (R)-1,2,2-trimethylpropylamine (8.2 mmol) in ethanol (50 mL) were stirred at room temperature for 24 hours. The resulting yellow slurry was filtered and rinsed with ethyl acetate to yield 0.92 g (75%) of (+)-(R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-benzonitrile as a yellow solid: spectral data was identical to the product of Example 1, paragraph 2, except with [α]D25 =+12° (DMSO, c 0.009).