Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]5[NH:28][CH:29]=[CH:30][C:23]=45)=[CH:20][N:19]([CH2:31][C:32]([OH:34])=O)[N:18]=3)=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:47]([CH2:49][NH2:50])[OH:48]>CN(C)C=O>[OH:48][CH2:47][CH2:49][NH:50][C:32](=[O:34])[CH2:31][N:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)[C:17]([C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])=[CH:12][CH:13]=2)=[N:18]1
Reactant: O=C(O)Cn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Reactant: NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(Cn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1)NCCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [3-(4-{[(phenylamino)carbonyl]amino}phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]acetic acid (0.13 mmol) in anhydrous N,N-dimethylformamide (4 mL) was added 1,1′-carbonyldiimidazole (0.156 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then ethanolamine (0.195 mmol) was added. The reaction mixture was stirred for another 3 h and concentrated in vacuo. Purification of the residue by Gilson reverse phase HPLC afforded recovered starting material and the title compound as a white solid (9%). ESMS [M+H]+: 496.4
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[C:5]([NH2:8])[CH:4]=1)C.Br[C:10]1[C:11](=[O:18])[N:12]([CH3:17])[N:13]=[C:14]([Cl:16])[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:16][C:14]1[CH:15]=[C:10]([NH:8][C:5]2[CH:4]=[C:3]([CH3:1])[NH:7][N:6]=2)[C:11](=[O:18])[N:12]([CH3:17])[N:13]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: CCc1cc(N)n[nH]1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Cl)nn(C)c2=O)n[nH]1
Yield: 75.1 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (20 mL), 5-ethyl-1H-pyrazol-3-amine (971 mg, 10.0 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (2.46 g, 11.0 mmol), and cesium carbonate (6.52 g, 20.0 mmol). After bubbling nitrogen through the suspension for 10 minutes, xantphos (1.74 g, 3.0 mmol) and tris(dibenzylideneacetone)dipalladium(0) (1.37 g, 1.5 mmol) were added. The system was subjected to three cycles of vacuum/argon flush and heated at reflux for 2 h. It was then filtered immediately when the reaction mixture was still hot. The solid was washed with dioxane (3×30 mL) and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica-gel chromatography eluting with 6:1 petroleum ether/ethyl acetate to afford 127a (1.8 g, 75%) as a yellow solid. MS-ESI: [M+H]+ 239.9
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH3:28])[N:24]=[CH:25][C:26]=4[Cl:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:29](OCC)=[O:30].[O-]CC.[Na+].Cl>C(O)C>[OH:30][CH:29]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH3:28])[N:24]=[CH:25][C:26]=4[Cl:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cn1ncc(Cl)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cn1ncc(Cl)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 70 %

Procedure:
4-Chloro-2-methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.250 g, 0.633 mmol) and ethyl formate (0.148 mL, 1.90 mmol) were dissolved in anhydrous ethanol (1.3 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (2.48 mL, 3.17 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 4-Chloro-2-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.187 g, 0.443 mmol, 70%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:15]=[CH:14][C:13]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][C:10]=3[C:9]=2[CH:8]=1>ClCCl>[OH:6][C:7]1[CH:15]=[CH:14][C:13]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][C:10]=3[C:9]=2[CH:8]=1
Reactant: COc1ccc2c(c1)c1c(n2-c2ccccc2)CCN(C)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1CCc2c(n(-c3ccccc3)c3ccc(O)cc23)CC1
Reaction time: 1 h

Procedure:
A solution of 3.58 g of boron tribromide in 10 ml dichloromethane is added dropwise at -60° to a solution of 2 g 1,2,3,4,5,6-hexahydro-9-methoxy-3-methyl-6-phenyl-azepino[4,5-b]indole in 20 ml dichloromethane. The mixture is stirred at -60° for 1 hour and a dark oil separates out. The mixture is concentrated under reduced pressure and the residual oil is treated with 30 ml ethanol. The mixture is brought to reflux over 30 minutes and the hydrobromide of the title compound crystallizes out. The salt is then filtered off, washed with a little alcohol and partitioned between dichloromethane and aqueous ammonia to form the free base. The organic phase is separated off, washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure. The oily residue is dissolved in alcohol, treated with hydrochloric acid in ethanol to form the title compound in hydrochloride form, m.p. 290°-292° (decomp.).
Reaction SMILES: Br[C:2]1[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]#[N:40])[CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(#N)C.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[NH2:21][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:12]([CH:10]([C:4]3[C:3]([O:23][CH3:24])=[C:2]([C:33]4[CH:38]=[CH:37][N:36]=[C:35]([C:39]#[N:40])[CH:34]=4)[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=3)[CH3:11])[N:13]=[C:14]([CH3:22])[C:15]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Reactant: CC1(C)OB(c2ccnc(C#N)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A mixture of 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (peak 1 from Example 167, step 4, 322 mg, 0.76 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (210 mg, 0.91 mmol, from Combi-Blocks Catalog, item # PN-0143), sodium carbonate (130 mg, 1.2 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (1:1) (99 mg, 0.12 mmol) in acetonitrile (5 mL)/water (2 mL) was degassed with N2 and the reaction was stirred at 95° C. for 2 h. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The product (0.28 g, 85%) was purified by chromatography eluting with CH2Cl2/MeOH (max. MeOH 6%). LCMS calculated for C22H21ClN7O (M+H)+: m/z=434.1; Found: 434.1
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[O:12]1[CH2:17][CH2:16][CH:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]1.CN(C)C(=O)C>O>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:18]([CH:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)=[O:19])[N:10]=2)[N:7]=1
Reactant: Nc1cn2nc(I)ccc2n1
Reactant: O=C(Cl)C1CCOCC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cn2nc(I)ccc2n1)C1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-iodoimidazo[1,2-b]pyridazin-2-amine (550 mg, 2.11 mmol), tetrahydro-2H-pyran-4-carbonyl chloride (320 mg, 2.15 mmol) and N,N-dimethylacetamide (5.0 mL) was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and the precipitated solid was collected by filtration, washed with water, and air-dried to give N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)tetrahydro-2H-pyran-4-carboxamide as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1)=[O:22]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: CN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4Cl)cc23)CC1
Yield: 19.8 %

Procedure:
Beginning with 2.0 gm (8.8 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 1.9 gm (9.7 mMol) 2-chloro-4-fluorobenzoyl chloride, 0.67 gm (19.8%) of the title compound were recovered as a light: yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[C:10]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:11]=1.C(O)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:10]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])[CH3:11]
Reactant: CCc1ccccc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1ccccc1CC
Reaction time: 18 h
Yield: 84.8 %

Procedure:
To a solution of 2-ethylphenol (6.9 g, 56.5 mmol), triphenylphosphine (15.7 g, 60 mmol) and ethanol (6 mL, excess) in tetrahydrofuran (100 mL) was added dropwise DIAD (12.1 g, 60 mmol). After stirring for 18 hours, mixture was evaporated and the residue was chromatographed on silica gel (heptane/ethyl acetate 9/1) to give 1-ethoxy-2-ethyl benzene (7.2 g) as a clear liquid. GC-MS shows one peak, RT=5.6 minutes. MS 150 (M+).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[N:4]=1.[OH-].[K+].O>C(O)C>[F:17][C:2]([F:1])([F:18])[C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=[C:5]([C:13]([F:16])([F:14])[F:15])[N:4]=1
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)nc1C(F)(F)F
Yield: 90.1 %

Procedure:
7 g (0.026 mole) of the product of Example 7, 5 g of potassium hydroxide, 10 ml of H2O and 35 ml ethanol were stirred overnight at reflux. The solvent was then removed under vacuum. H2O was added to the residue. This aqueous layer was extracted 2X with ether (ether layer discarded). The aqueous layer was then acidified with conc. HCl. The product was extracted with ether. The ether layer was washed 2X with H2O and dried over MgSO4. The ether was then removed under vacuum and the resulting solid was dried to yield 6.07 g (91%) of a white solid. M.P. 102°-104° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH3:8].Cl.[NH2:20][C:21]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22]1.C(N(CC)CC)C.Cl>ClCCl.CN(C)C=O>[CH2:7]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:20][C:21]2([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22]2)=[O:16])=[CH:17][CH:18]=1)[CH3:8]
Reactant: CCOC(=O)C1(N)CC1
Reactant: CCOc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2ccc(OCC)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
Add oxalyl chloride (189 mL, 2.17 mol) to 4-ethoxybenzoic acid (334.5 g, 1.99 mol) and N,N-dimethylformamide (1 mL) in dichloromethane (3 L). After 1 hr at 25-26° C., concentrate the mixture under reduced pressure until a constant weight is achieved. Stir ethyl 1-aminocyclopropanecarboxylate hydrochloride (300 g, 1.81 mol) and dichloromethane (2.5 L) in an ice water bath. Add triethylamine (631 mL, 4.53 mol) and then add a solution of the acid chloride (ca 380 g) in dichloromethane (500 mL). Stir the reaction mixture for approximately 16 hours at ambient temperature. Dilute the reaction with aqueous 1N hydrochloric acid (1 L). Extract the aqueous layer with dichloromethane (1 L). Wash the organic layer with water (2 L) and brine (2 L). Dry the solution over sodium sulfate, filter, and concentrate under reduced pressure. Slurry the residue in hexanes and filter to give the title compound (478 g, 95%) as an ivory powder: MS (mass spectrometry) (m/z): 278 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7](=[O:21])[C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7](=[O:21])[C:8]2[CH:9]=[CH:10][C:11]([N:14]([CH3:24])[S:15]([N:18]([CH3:20])[CH3:19])(=[O:16])=[O:17])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)S(=O)(=O)Nc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CN(C)S(=O)(=O)N(C)c1ccc(C(=O)Nc2ccc(Cl)cc2)cc1
Yield: 96.2 %

Procedure:
A mixture of 300 mg of 4'-chloro-4-[(dimethylaminosulfonyl)amino]benzanilide 7, 140 mg of potassium carbonate, 130 mg of dimethyl sulfate 8, and 10 ml of dried acetone is refluxed for 30 minutes. Acetone is distilled off from the reaction mixture, the residue is basified with 10% sodium hydroxide solution and extracted with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue is crystallized from ethyl acetate-isopropyl ether to give 300 mg of 4'-chloro-4-[methyl(dimethylaminosulfonyl)amino]benzanilide 9 as crystals, m.p. 155°-156° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][N:8]([CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=1)[CH2:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[CH2:51]([N:54]([CH2:60][CH2:61][CH3:62])[CH2:55][CH2:56][CH2:57][CH2:58][NH2:59])[CH2:52][CH3:53]>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][N:8]([CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:59][CH2:58][CH2:57][CH2:56][CH2:55][N:54]([CH2:60][CH2:61][CH3:62])[CH2:51][CH2:52][CH3:53])=[O:23])=[CH:19][CH:18]=1)[CH2:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1
Reactant: CCCN(CCC)CCCCN
Reactant: Cn1ccnc1CN(Cc1ccc(C(=O)O)cc1)Cc1nccn1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCCNC(=O)c1ccc(CN(Cc2nccn2C)Cc2nccn2C)cc1
Reaction time: 6 h

Procedure:
The compound (75.0 mg) obtained in Example 40-1 was dissolved in DMF (2.0 ml) and then added with DCC (46.0 mg) and HOBt (36.0 mg), followed by stirring for 6 hours. A solution of the compound (76.0 mg) obtained in Example 1-2 in DMF was added to the reaction system and then the whole was stirred for 15 hours. After completion of the reaction, DMF was distilled off and the residue was then dissolved in chloroform, followed by extraction with 1 mol/l hydrochloric acid. The aqueous layer was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. The extract was dried with anhydrous magnesium sulfate and the solvent was then distilled off, followed by treating with hydrochloric acid. Subsequently, the treated product was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (23.9 mg) of the subject compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7]([CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:15]=1.Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:17][O:16][C:3]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)=[CH:15][C:6]2[C:7]([CH:12]([CH3:13])[CH3:14])=[CH:8][C:9](=[O:11])[O:10][C:5]=2[CH:4]=1
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Reactant: COc1cc2oc(=O)cc(C(C)C)c2cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2oc(=O)cc(C(C)C)c2cc1OCCCN1CCN(c2ccccc2)CC1
Yield: 88 %

Procedure:
4.0 g (17 mmol) 6-hydroxy-7-methoxy-4-(1-methylethyl)-2H-1-benzopyran-2-one (example 105), 4.7 g (20.5 mmol) 1-(3-chloropropyl)-4-phenylpiperazine, 4.7 g (34 mmol) potassium carbonate and 1.0 g potassium iodide are agitated in 300 ml DMF for 44 h under nitrogen at 60° C. After filtration and removal of the solvent in vacuum, the residue is taken up in chloroform and washed with dilute sodium hydroxide solution and with water, dried over sodium sulfate and then evaporated again. Yield 5.5 g (74%) of crystals with a fusion point of 94°-96° C. (from isopropanol and TBME). Fumarate: method E; yield 88%; fusion point 175°-176° C. (from isopropanol and ethanol).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8]([C:22]2[CH:23]=[N:24][C:25]([N:28]([CH3:30])[CH3:29])=[N:26][CH:27]=2)[CH:7]=1)=[O:5])C.C(OC(C1[N:41]2C=C(NC(NC(C)C)=O)N=[C:40]2[CH:39]=C(C2C=NC(N(C)C)=NC=2)C=1)=O)C.N1C=CN=C1>C(N)C.O>[CH2:40]([NH:41][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH:19]([CH3:20])[CH3:21])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8]([C:22]2[CH:23]=[N:24][C:25]([N:28]([CH3:29])[CH3:30])=[N:26][CH:27]=2)[CH:7]=1)=[O:5])[CH3:39]
Reactant: CCOC(=O)c1cc(-c2cnc(N(C)C)nc2)cc2nc(NC(=O)NC(C)C)cn12
Reactant: CCOC(=O)c1cc(-c2cnc(N(C)C)nc2)cc2nc(NC(=O)NC(C)C)nn12
Agent: CCN
Agent: c1c[nH]cn1
Solvent: O
Product: CCNC(=O)c1cc(-c2cnc(N(C)C)nc2)cc2nc(NC(=O)NC(C)C)nn12
Temperature: 100 °C

Procedure:
A suspension of the product of Example 116, 7-(2-dimethylamino-pyrimidin-5-yl)-2-(3-isopropyl-ureido)-imidazo[1,2-a]pyridine-5-carboxylic acid ethyl ester (0.149 g, 0.361 mmol) in ethylamine (2 mL of a 70% aqueous solution) was treated with imidazole (2 g) and heated to 100° C. for 1 min until it became a homogeneous solution. The reaction was cooled to 23° C. and diluted with water (15 mL). The precipitated solid was collected by vacuum filtration then dried in vacuo to give 7-(2-dimethylamino-pyrimidin-5-yl)-2-(3-isopropyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethylamide. MS (APCI+)=412.2
Reaction SMILES: [CH:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([O:6][CH3:7])=[O:5])=[O:2].[C:19](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.N>CC(C)=O.O>[CH2:15]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:3](=[CH:1][O:2][CH3:19])[C:4]([O:6][CH3:7])=[O:5])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOc1ccccc1C(C=O)C(=O)OC
Reactant: O=C([O-])[O-]
Agent: N
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CCCCOc1ccccc1C(=COC)C(=O)OC
Reaction time: 2 h
Yield: 82.4 %

Procedure:
10 g of methyl α formyl-(2-butoxyphenyl)acetate are dissolved in 100 ml of acetone. 15 g of potassium carbonate are added, followed gradually with stirring by an equimolar amount of dimethyl sulfate. After 12 hours of refluxing, 50 ml of H2O are added, followed carefully by 30 ml of concentrated NH3 solution. After 2 hours of stirring, about 100 ml of solvent are drawn off, poured onto ice and extracted with dichloromethane. Drying of the organic phase leaves 8.7 g of oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:11].[Br:12]N1C(=O)CCC1=O>O1CCCC1.O>[Br:12][C:5]1[C:4]([OH:11])=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(O)c1OC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Br)c(O)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 2,3-dimethoxy-phenol (6 g, 38.70 mmol) in tetrahydrofuran (30 mL) at 25° C., was added N-bromosuccinimide (6.89 g, 38.70 mmol) and the resultant reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 6-Bromo-2,3-dimethoxyphenol as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1Cl)=[CH:10][C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=2)#[N:2].[NH2:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Br:25])[CH:24]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>COCCO>[Br:25][C:23]1[CH:24]=[C:19]([NH:18][C:12]2[C:11]3[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:1]#[N:2])[CH:20]=[N:21][CH:22]=1
Reactant: Nc1cncc(Br)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCO
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3cncc(Br)c3)c2cc1OC
Temperature: 153 °C

Procedure:
A mixture of 249 mg (1 mmole) of 3-cyano-4-chloro-6,7-dimethoxy quinoline, 346 mg (2 mmoles) of 3-amino-5-bromo pyridine and 20 mg (about 0.1 mmole) of p-toluenesulfonic acid monohydrate in 5 ml of 2-methoxy ethanol was stirred and refluxed in an oil bath at 153° C. for 7 hours. On cooling overnight to room temperature, the solid was filtered and washed with ethanol, then with ether to give 287 mg (74.5%) of N-[4-[(5-bromo-3-pyridinyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile, which melted at 272-275° C. mass spectrum (electrospray, m/e) M+H=384.9, 386.8.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14](OCC)=[O:15].C(Cl)(=O)C>>[Br:12][C:8]1[CH:7]=[C:3]2[C:4]([O:6][C:14](=[O:15])[NH:1][C:2]2=[CH:10][C:9]=1[Cl:11])=[O:5]
Reactant: CCOC(=O)Cl
Reactant: Nc1cc(Cl)c(Br)cc1C(=O)O
Solvent: CC(=O)Cl
Product: O=c1[nH]c2cc(Cl)c(Br)cc2c(=O)o1
Yield: 70 %

Procedure:
7.5 g (30 mmol) of 2-amino-5-bromo-4-chloro-benzoic acid was heated under reflux with 18 mL of ethyl chloroformate for 6 h, and was further heated under reflux for another 3 h after addition of 18 mL of acetyl chloride. The solid was collected and washed with hexanes to produce 5.8 g (70%) of 5-bromo-4-chloroisatoic anhydride. LCMS: 277 (M+1)+.