Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([Cl:41])[C:7]([NH:28][C@@H:29]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:26][CH2:25][C:20]3(OCC[O:21]3)[CH2:19][CH2:18]2)=[C:13]([CH3:27])[CH:12]=1)(=[O:3])[NH2:2].Cl.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[K+].[K+]>>[Cl:41][C:6]1[N:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:26][CH2:25][C:20](=[O:21])[CH2:19][CH2:18]3)=[C:13]([CH3:27])[CH:12]=2)=[N:8][C:7]=1[NH:28][C@@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1
Reactant: Cc1cc(Nc2nc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)c(Cl)nc2C(N)=O)ccc1N1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Product: Cc1cc(Nc2nc(N[C@@H]3CCNC3)c(Cl)nc2C(N)=O)ccc1N1CCC(=O)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
A mixture of tert-butyl (3R)-3-[(5-carbamoyl-3-chloro-6-{[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-methylphenyl]amino}pyrazin-2-yl)amino]pyrrolidine-1-carboxylate (850 mg) and 3 M hydrochloric acid (9.6 mL) was stirred at 80° C. for 3 hours. The reactant was left to be cooled, and then a saturated aqueous sodium hydrogen carbonate solution and a 10% aqueous potassium carbonate solution were added thereto, followed by stirring at room temperature for 30 minutes. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure to obtain 6-chloro-3-{[3-methyl-4-(4-oxopiperidin-1-yl)phenyl]amino}-5-[(3R)-pyrrolidin-3-ylamino]pyrazine-2-carboxamide (495 mg) as a pale yellow solid.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([CH3:9])([CH3:8])O)([CH3:3])[CH3:2].O=S(Cl)Cl.[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[S:26]>>[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]1[N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][C:6]([CH3:9])([CH3:8])[S:26]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC(C)NCC(C)(C)O
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC(C)(C)CN1C(C)C

Procedure:
Isopropylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-isopropyl-N-(2,2-dimethyl-2-hydroxyethyl)amine. N-Isopropyl-N-(2,2-dimethyl-2-hydroxyethyl)amine was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2f to afford 2-(2-methyl-4-nitrophenylimino)-3-isopropyl-5,5-dimethyl-1,3-thiazolidine.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[Cl:25][CH2:26][CH2:27][NH2:28].[C:29]1([C:35]2([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH2:43][C:42]3[N:41]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[N:40]=[C:39]([C:52](O)=[O:53])[C:38]=3[CH:37]=[CH:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl.C(N(CC)CC)C>[Cl:25][CH2:26][CH2:27][NH:28][C:52]([C:39]1[C:38]2[CH:37]=[CH:36][C:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH2:43][C:42]=2[N:41]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[N:40]=1)=[O:53]
Reactant: NCCCl
Reactant: C[Si](C)(C)CCOCn1nc(C(=O)O)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1nc(C(=O)NCCCl)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Temperature: 20 °C
Reaction time: 4 h
Yield: 58.6 %

Procedure:
0.677 g of 1-hydroxybenzotriazole hydrate, 0.958 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.16 g of 2-chloroethylamine hydrochloride and 1.4 cm3 of triethylamine are successively added to a solution of 1.8 g of 6,6-diphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazole-3-carboxylic acid in 300 cm3 of dichloromethane. After stirring the reaction mixture for about 4 hours at a temperature in the region of 20° C., it is washed with three times 60 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). After flash chromatography on a column of silica [eluent: cyclohexane/ethyl acetate (85/15 by volume)], 1.2 g of 6,6-diphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazole-3-carboxylic acid (2-chloroethyl)amide are thus obtained in the form of a resin, the characteristics of which are as follows:
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:22])[C:5](=O)[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2.[C-:23]#[N:24].[K+]>C(O)(C)C.O>[C:23]([CH2:2][C:3]1[N:4]([CH3:22])[CH2:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2)#[N:24]
Reactant: [C-]#N
Reactant: COc1ccc2c(=O)n(C)c(CBr)c(-c3ccccc3)c2c1
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc2c(c1)C(c1ccccc1)=C(CC#N)N(C)C2
Temperature: 80 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of 3-(bromomethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (6.82 g, 19.0 mmol) in 100 mL of isopropanol was added a solution of potassium cyanide (2.48 g, 38.1 mmol) in 10 mL of water. The mixture was heated at 80° C. After one hour, another portion of potassium cyanide solution (300 mg in 5 mL of water) was added, and the reaction stirred for an additional hour. The solution was cooled to room temperature, and partitioned between EtOAc and saturated NaHCO3 solution. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude solid material was triturated with EtOAc/ether to provide the titled product (5.01 g, 86% yield). HRMS (ES) exact mass calculated for C19H16N2O2 (M+H+): 305.1285. Found 305.1269.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:14][C:15]([OH:17])=[O:16])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:23]O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:14][C:15]([O:17][CH3:23])=[O:16])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])([O-:3])=[O:2]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1

Procedure:
3,5-Dinitro-4-hydroxyphenylacetic acid is refluxed in methanol in the presence of sulfuric acid, to give methyl 2-(3,5-dinitro-4-hydroxyphenyl)acetate.
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:23].[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][C:28]=1[S:41]([NH2:44])(=[O:43])=[O:42]>C1(C)C=CC=CC=1>[CH2:34]([O:33][C:30]1[CH:31]=[CH:32][C:27]2[NH:26][C:3]([C:4]3[C:13](=[O:14])[C:12]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[C:11]4[C:6]([C:5]=3[OH:23])=[CH:7][CH:8]=[CH:9][CH:10]=4)=[N:44][S:41](=[O:42])(=[O:43])[C:28]=2[CH:29]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCCC1(CCCC)C(=O)C(=C(SC)SC)C(=O)c2ccccc21
Reactant: Nc1ccc(OCc2ccccc2)cc1S(N)(=O)=O
Solvent: Cc1ccccc1
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A solution of the product of Example 5C (52 mg, 0.14 mmol) and the product of Example 2D (38 mg, 0.14 mmol) in toluene (12 mL) was stirred at reflux for 6 hours, cooled to 25° C. and concentrated in vacuo. The residue was triturated with ether-hexane and collected by filtration to give the title compound (65 mg, 84%). 1H NMR (300 MHz, CDCl3): δ 16.66 (m, 1 H), 14.33 (s, 1 H), 8.27 (d, J=8.09 Hz, 1 H), 7.66 (m, 1 H), 7.38 (m, 10 H), 5.14 (s, 2 H), 2.35 (m, 2 H), 1.96 (m, 2 H), 1.12 (m, 4 H), 0.89 (m, 2 H), 0.70 (m, 6 H), 0.55 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([N:22]4[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]4[CH3:28])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:32]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([N:22]4[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]4[CH3:28])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[CH2:9][O:10][CH3:32])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCC(CO)(c1ccc(Cl)cc1)n1ccc2c(-n3c(C)ccc3C)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(COC)(c1ccc(Cl)cc1)n1ccc2c(-n3c(C)ccc3C)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(4-chlorophenyl)-2-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-indol-1-yl)butan-1-ol (89 mg) in dry DMF (3 mL) was treated by NaH (60% in oil, 18 mg) at 0° C. for 30 min, then was added iodomethane (97 mg). The mixture was stirred at room temperature for 2 h. The solution was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (25 mL). The organic layers was washed with brine, dried over sodium sulfate, and evaporated to afford the title compound as a white solid. LC/MS m/z=407.1 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[C:14]([CH3:26])=[N:13]1.[F-].[Cs+]>COCCOC.CO.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>[CH3:11][N:12]1[CH:16]=[C:15]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=2)[C:14]([CH3:26])=[N:13]1
Reactant: Cc1nn(C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1nc(Br)ccc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: COc1nc(-c2cn(C)nc2C)ccc1N
Temperature: 150 °C
Yield: 74.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.085 g, 0.074 mmol) was added to a solution of 6-bromo-2-methoxypyridin-3-amine (0.15 g, 0.739 mmol), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.180 g, 0.813 mmol) and cesium fluoride (0.337 g, 2.216 mmol) in DME/MeOH 2/1 (4.6 mL). The reaction mixture was heated under microwave irradiation at 150° C. for 10 minutes. The reaction was concentrated in vacuo. The residue was purified via Biotage silica gel column chromatography eluting with DCM/EtOH (99/1 to 90/10, 12 g column) and then eluted through an SCX-2 column to afford the title product as a yellow solid (120 mg, 74%).
Reaction SMILES: [C:1]1([CH:7]2[C:12]3[C:13]([C:16]([O:18]CC)=[O:17])=[N:14][O:15][C:11]=3[CH2:10][CH2:9][N:8]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[Li].O>C(O)C.O>[C:24]([O:23][C:21]([N:8]1[CH2:9][CH2:10][C:11]2[O:15][N:14]=[C:13]([C:16]([OH:18])=[O:17])[C:12]=2[CH:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)c1noc2c1C(c1ccccc1)N(C(=O)OC(C)(C)C)CC2
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2onc(C(=O)O)c2C1c1ccccc1

Procedure:
5-tert-Butyl 3-ethyl 4-phenyl-6,7-dihydroisoxazolo[4,5-c]pyridine-3,5(4H)-dicarboxylate (1.75 mmol) was hydrolyzed to corresponding acid by using LiOH.H2O (1.5 eq.) as a base in ethanol-water (10 ml, 4:1). Yield: quantitative.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.Cl.[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:27][C:26]3[CH:25]=[N:24][N:23]([CH3:28])[C:22]=3[NH:21][C:20]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:19]2=3)=[O:17])=[CH:12][C:11]=1[F:34].C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].CCN(C(C)C)C(C)C>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:19]2[N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])=[C:11]([F:34])[CH:12]=3)=[O:17])[CH2:27][C:26]3[CH:25]=[N:24][N:23]([CH3:28])[C:22]=3[NH:21][C:20]=2[CH:29]=1
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(F)c1)C2
Reactant: O=C(Cl)C1CC1
Agent: Cl
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CNC(=O)C3CC3)c(F)c1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
Cyclopropanecarbonyl chloride (0.045 ml, 0.5 mmol) was added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E102.2 (210 mg, 0.5 mmol) in dichloromethane (40 ml) and DIEA (0.30 ml, 1.7 mmol) at 0° C. The mixture was stirred for 1 h at room temperature then washed with saturated NaHCO3, brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to give a white powder identified as the title compound (134 mg, 59%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH:7]([N:10]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:11](=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Br)=[C:14]([O:20][CH3:21])[CH:13]=1)([CH3:9])[CH3:8].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1>CN(C)C=O.O>[CH:23]1([N:10]([CH:7]([CH3:9])[CH3:8])[C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][O:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=3)=[C:14]([O:20][CH3:21])[CH:13]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1cccc(O)c1
Reactant: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(OCc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2OC)c1

Procedure:
A slurry of K2CO3 (0.75 g, 5.43 mmol) in a solution of 4-bromomethyl-3-methoxybenzoic acid N-isopropyl-N-cyclohexyl amide (1.0 g, 2.7 mmol) and 3-methoxy phenol (0.35 g, 2.74 mmol) in dimethylformamide (DMF) (15 ml) was stirred overnight at room temperature. The reaction mixture was diluted with water (50 ml), extracted twice with ethyl acetate and dried (Na2SO4) The drying agent was filtered and the filtrate concentrated in vacuo to give the crude product as a dark oil. This material was purified by chromatography on silica gel using mixtures of ethyl acetate, CH2Cl2 and hexane as eluents to give the title compound as a glass.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16](=[O:32])[N:17]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:18]3=[O:23])[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16](=[O:32])[N:17]([CH2:24][C:25]([OH:27])=[O:26])[C:18]3=[O:23])[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2cccc(N(CCN3CCOCC3)S(C)(=O)=O)c2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N(CCN1CCOCC1)c1cccc2c1C(=O)N(CC(=O)O)C2=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of tert-butyl 2-(4-(N-(2-morpholinoethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (256 mg, 0.548 mmol) and TFA (844 μl, 10.95 mmol) in DCM (5 ml) was stirred at room temperature for 48 hours. The mixture was evaporated and so obtained crude of 2-(4-(N-(2-morpholinoethyl)-methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid 2,2,2-trifluoroacetic acid salt (MS/ESI+ 412 [MH]+) was used as such in the following reaction.
Reaction SMILES: NC1C2N=C(COCC)N(CC(C)(O)C)C=2C2N=CC(Br)=CC=2N=1.[Br:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30]([NH:39][CH2:40][C:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:43])[CH3:42])=[C:31]([N+:36]([O-])=O)[CH:32]=[N:33]2)=[N:28][CH:27]=1>C(#N)C>[NH2:36][C:31]1[CH:32]=[N:33][C:34]2[C:29]([C:30]=1[NH:39][CH2:40][C:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:43])[CH3:42])=[N:28][CH:27]=[C:26]([Br:25])[CH:35]=2
Reactant: CC(C)(CNc1c([N+](=O)[O-])cnc2cc(Br)cnc12)NC(=O)OC(C)(C)C
Agent: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Solvent: CC#N
Product: CC(C)(CNc1c(N)cnc2cc(Br)cnc12)NC(=O)OC(C)(C)C
Yield: 99.5 %

Procedure:
A modification of the method described in Part B of the preparation of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol was used to reduce tert-butyl 2-[(7-bromo-3-nitro[1,5]naphthyridin-4-yl)amino]-1,1-dimethylethylcarbamate (138.0 g, 313.4 mmol). The reaction was placed under hydrogen pressure for 5.5 hours. The reaction yielded 128 g of tert-butyl 2-[(3-amino-7-bromo[1,5]naphthyridin-4-yl)amino]-1,1-dimethylethylcarbamate containing some acetonitrile.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4](=O)[CH2:5][O:6][CH2:7][CH2:8][C:9]1[C:17]([F:18])=[CH:16][C:12]2[S:13][CH:14]=[CH:15][C:11]=2[CH:10]=1)[CH3:2].Cl.O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:20]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]1[C:17]([F:18])=[CH:16][C:12]2[S:13][CH:14]=[CH:15][C:11]=2[CH:10]=1)[CH3:21]
Reactant: CCN(CC)C(=O)COCCc1cc2ccsc2cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(CC)CCOCCc1cc2ccsc2cc1F
Temperature: 5 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
In 20 mL of tetrahydrofuran is dissolved 1.24 g of N,N-diethyl-2-[2-(6-fluorobenzo[b]thiophen-5-yl)ethoxy]-acetamide. The solution is cooled to 5° C., and 7.86 mL of a 1 mol/L solution of borane-tetrahydrofuran complex in tetrahydrofuran is dropwise added thereto. After stirring the resulting mixture at ambient temperature for 2 hours, 4.00 mL of 2 mol/L hydrochloric acid is dropwise added, and the resulting mixture is heated under reflux for 30 minutes. After cooling, water and ethyl acetate are added to the reaction mixture, pH is adjusted to 13 with 5 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent:chloroform:methanol=30:1 to 10:1) to obtain 0.90 g of N,N-diethyl-N-{2-[2-(6-fluorobenzo[b]thiophen-5-yl)ethoxy]ethyl}-amine as an oily product.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:35])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].[C:36](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[F:1][C:2]1[C:3]([O:35][CH3:36])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(O)c(F)c3o2)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Yield: 78.2 %

Procedure:
348 mg (0.710 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl )-7-hydroxy-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 86 (3) was dissolved in 35 mL of acetone, 166 mg (1.20 mmol) of potassium carbonate and 0.45 mL (7.1 mmol) of iodomethane were added and the mixture was heated at reflux for 40 minutes. The reaction solution was filtered, the filtrate was concentrated, water was added to the residue and the mixture was extracted once with ethyl acetate. The organic layer was washed twice with a 1N aqueous solution of sodium hydroxide, once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform) to give 280 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methoxy-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 78%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3(O)[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C([O-])(O)=O.[Na+]>O>[O:31]=[S:27]1(=[O:30])[CH2:26][CH:25]=[C:24]([C:22]2[S:23][C:19]([C:4]3[CH:5]=[C:6]([NH:8][C:9]4[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=4)[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:20][N:21]=2)[CH2:29][CH2:28]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCS(=O)(=O)CC3)s2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3=CCS(=O)(=O)CC3)s2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
The product from Step 1 (210 mg, 0.433 mmol) was combined with Eaton's reagent (1.00 ml, 6.30 mmol) and stirred at 100° C. for 16 hrs. The reaction was cooled to room temperature and slowly neutralized with aqueous saturated NaHCO3 (4 mL). It was then diluted with water (4 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. Upon addition of CH2Cl2, the title compound precipitated and was isolated by filtration (0.185 g, 0.397 mmol, 91% yield). MS ESI: [M+H]+ m/z 467.0. 1H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.83 (d, J=4.9, 1H), 8.12 (d, J=2.7, 1H), 8.03 (bs, 1H), 7.47 (bs, 1H), 7.29 (d, J=4.9, 1H), 7.21 (bs, 1H), 6.53 (m, 1H), 4.00 (m, 2H), 3.39 (m, 2H), 3.14 (m, 2H), 2.32 (s, 3H). rhSYK activity=+++.
Reaction SMILES: [CH2:1]([CH:11]([C:17]([O-:19])=O)[C:12]([O:14]CC)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][NH2:26]>C(O)C>[CH2:1]([CH:11]1[C:12](=[O:14])[NH:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][NH:20][C:17]1=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: NCCNCCN
Reactant: CCCCCCCCCCC(C(=O)[O-])C(=O)OCC
Solvent: CCO
Product: CCCCCCCCCCC1C(=O)NCCNCCNC1=O
Yield: 62.1 %

Procedure:
A one litter round bottomed flask was charged with 0.076 mol (22.80 g) of ethyl α-decylmalonate (from above), 0.076 mol (7.74 g) diethylene triamine and 500 ml absolute ethanol. The mixture was refluxed for 42 days. During this period two ml aliquotes of solution were removed by hyperdermic syringe on days 7,15,22, and 37 for NMR analysis to determine the completeness of the reaction. After termination of the reflux, the ethanol was removed under reduced pressure and the product recrystallized from cold acetonitrile to yield 14.71 grams of a white heavy precipitate representing approximately a 62.1% conversion and having NMR characterizations in CDCL3, with signals reported in ppm downfield relative to TMS:
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1.CCOCC>[C:4]1([C:2](=[CH2:3])[C:1]([NH:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:11])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C=C(C(=O)O)c1ccccc1
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: C=C(C(=O)NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
A stirred solution of atropic acid (10.3 g, 69.5 mmol) in dry tetrahydrofuran (100 ml) was treated under nitrogen with N-methylmorpholine (7.7 ml, 70.0 mmol), cooled to -10°, treated dropwise with iso-butylchloroformate (9 ml, 69.4 mmol), treated dropwise with benzylamine (7.6 ml, 69.6 mmol), warmed to room temperature over 1 hour, filtered and evaporated in vacuo to give a yellow oil which was dissolved in ether (100 ml). The solution was washed with 0.1N--HC1 (200 ml) , brine (100 ml) , 0.1N--NaOH (100 ml) and brine (100 ml), dried (MgSO4), and evaporated in vacuo to give a yellow liquid. Purification by chromatography (silica; di-iso-propyl ether) gave the product as white crystals (7.3g), m.p. 84-86° (from di-iso-propyl ether).