Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:12]Br)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=O.Cl.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]2[C:3]=1[CH2:12][N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:5]2=[O:7]
Reactant: COC(=O)c1cccc(Br)c1CBr
Reactant: COC(=O)CCCCCN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCN1Cc2c(Br)cccc2C1=O
Reaction time: 20 h
Yield: 99 %

Procedure:
The procedure of the step 2 in Example 1 was repeated except that methyl 3-bromo-2-(bromomethyl)benzoate instead of methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate, methyl 6-aminohexanoate hydrochloride instead of methyl 4-(aminomethyl)benzoate hydrochloride, triethylamine (2.4 equiv.), and THF as a solvent were used and the reaction was conducted for 20 hrs, to obtain the title compound (99%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:38][C:39]1([F:45])[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:41]3[CH2:42][CH2:43][CH2:44][C:39]([F:45])([F:38])[CH2:40]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:8]=1
Reactant: FC1(F)CCCNC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CCCC(F)(F)C1
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 15.5 %

Procedure:
A cold (0° C.) solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (4) (1.0 g, 1.0 eq.) in CH2Cl2 (20 mL) was treated sequentially with EDC HCl (0.656 g, 1.2 eq.), 3,3-difluoropiperidine hydrochloride (0.540 g, 1.2), DIPEA (435 mg, 1.2 eq) and HOBT (25.92 g, 1.2 eq.). The clear reaction mixture was stirred at 0° C. for 1.5-2 h then quenched with 50 mL ice-water slurry and extracted with CH2Cl2 (2×25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 0.70 g of crude compound. No trans compound was formed as confirmed by LCMS and 1H NMR. Purification by column chromatography afforded 0.20 g of material that was further recrystallized/triturated using ether: petroleum ether to remove aliphatic impurity affording 0.180 g (14.1% yield) of desired pure compound.
Reaction SMILES: ClC1C=C2C(=CC=1)N([N+:11]([O-:13])=[O:12])C(C(OCC)=O)=C2.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[C:27](Cl)[CH:28]=1)[NH:25][C:24]([C:30]([OH:32])=[O:31])=[CH:23]2>>[N+:11]([C:21]1[C:20]([Cl:19])=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[C:24]([C:30]([OH:32])=[O:31])[NH:25]2)([O-:13])=[O:12]
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2[nH]1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1[N+](=O)[O-]
Product: O=C(O)c1cc2c([N+](=O)[O-])c(Cl)ccc2[nH]1

Procedure:
The title compound was prepared by hydrolysis of ethyl 5-chloro-nitro-1H-indole-2-carboxylate as described for the preparation of 5,7-dichloro-1H-indole-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:26][C@@H:27]([OH:31])[C:28]([OH:30])=[O:29])[NH:16][C:17]([C:19]3[O:23][N:22]=[C:21]([O:24][CH3:25])[CH:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.C(Cl)CCl.C1C=C2N=NN(O)C2=CC=1.O.C(Cl)Cl.[N:51]1([CH2:57][CH2:58]O)[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>>[N:51]1([CH2:57][CH2:58][O:29][C:28](=[O:30])[C@H:27]([OH:31])[CH2:26][N:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[F:32])=[CH:13][CH:12]=2)[NH:16][C:17]([C:19]2[O:23][N:22]=[C:21]([O:24][CH3:25])[CH:20]=2)=[O:18])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1
Reactant: OCCN1CCOCC1
Reactant: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)on1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)OCCN2CCOCC2)on1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7.1 %

Procedure:
A mixture of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (20.0 mg, 43 mmol), EDC (45.8 μL, 259 μmol) and HOBt hydrate (39.6 mg, 259 μmol) in DCM (0.5 mL, 8 mmol) was stirred at room temperature for 10 minutes. 4-Morpholineethanol (41.8 μL, 345 μmol) was added, and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was dissolved in AcOH (1.5 mL), filtered, and purified by reverse phase preparative HPLC to yield the title compound (14.1 mg) as a TFA salt. MS m/z [M+H]+ calc'd for C22H39ClFN4O2, 577.18. found 577.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[NH2:8][C:9]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].N1C=CC=CC=1.O>ClCCl>[Br:19][C:16]1[CH:17]=[CH:18][C:9]([NH:8][C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: CC(C)OC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(Br)ccc1NC(=O)OC(C)C
Reaction time: 1.5 h
Yield: 85.9 %

Procedure:
Add isopropyl chloroformate (36.9 mL, 36.9 mmol, 1.0 M in toluene) dropwise to a solution of methyl 2-amino-5-bromobenzoate (5.0 g, 24.6 mmol) and pyridine (80.0 mL, 36.9 mmol) in dichloromethane (80 mL) at room temperature under an atmosphere of nitrogen and stir for 1.5 h. Pour the reaction into water (100 mL) and separate the layers. Extract the aqueous layer with dichloromethane (2×40 mL) and combine the organic extracts and wash with 2 N hydrochloric acid, saturated sodium hydrogen carbonate, and brine (80 mL each). Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure to afford the title compound as a pale yellow solid (6.68 g, 86%). 1H NMR (CDCl3) δ 1.31 (d, J=6.3 Hz, 6H), 3.92 (s, 3H), 5.03 (septet, J=6.3 Hz, 1H), 7.61 (dd, J=1.9, 8.5 Hz, 1H), 8.11 (d, J=1.9 Hz, 1H), 8.40 (d, J=8.5 Hz, 1H), 10.31 (br s, 1H). ESI MS m/z 316 [C12H14BrNO4+H]+.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([OH:17])(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:11].[CH:18](O)=[O:19]>CCCCCC>[CH:18]([NH:11][C:10]1[C:9](=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([OH:17])=[O:16])=[O:19]
Reactant: O=CO
Reactant: Nc1ccccc1C(=O)O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=CNc1ccccc1C(=O)O

Procedure:
A toluene (1100 ml) solution of anthranilic acid (205.5 g) and formic acid (170 ml) was heated under reflux for 4.5 hours. After the solution was allowed to cool, hexane was added to crystals deposited. The crystals were collected by filtration and washed with hexane. The resulting crystals were dried at 110° C. under reduced pressure to obtain N-formyl-anthranilic acid (244.0 g, crude product) as white crystals.
Reaction SMILES: [CH3:1][CH:2]([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[CH:7]1)[C:3]([NH2:5])=[O:4].[ClH:15].C(O[CH:20]([CH3:22])[CH3:21])(C)C>C(O)(C)C>[OH2:4].[ClH:15].[Cl:15][C:21]1[CH:20]=[CH:22][C:14]([C:7]2[N:6]([C@@H:2]([CH3:1])[C:3]([NH:5][CH2:1][CH2:2][N:6]([CH3:10])[CH3:7])=[O:4])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:13][CH:12]=1
Reactant: CC(C)OC(C)C
Reactant: CC(C(N)=O)n1cnc2cccnc21
Agent: Cl
Solvent: CC(C)O
Product: C[C@@H](C(=O)NCCN(C)C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Product: O
Temperature: 25 °C

Procedure:
A solution of crude (S)-2-(4-chlorophenyl)-N-[2-dimethylamino) ethyl]-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide (1.49 g, 0.00335 mole) in hot isopropyl alcohol was treated with hydrogen chloride in isopropyl alcohol until the solution was acidic. Upon addition of isopropyl ether, solid precipitated. After cooling to room temperature, the solid was collected by filtration, rinsed with isopropyl ether, and dried under high vacuum to give 1.64 g of title compound, mp 252°-255° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:16](=O)([O-])[O-].[K+].[K+].Br[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>CN(C)C=O.O>[C:5]([C:4]1[CH:3]=[C:2]([CH:15]=[CH:14][CH:13]=1)[O:1][CH2:16][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2cccc(C(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.9 %

Procedure:
To a stirred solution of 3-hydroxybenzophenone (1.00 g, 5.04 mmol) in dimethyl formamide (10 mL), was added potassium carbonate (1.05 g, 7.61 mmol), and the mixture was stirred for 10 minutes at room temperature. Methyl 4-bromobenzoate (1.30 g, 6.05 mmol) in dimethyl formamide (5 mL) was added, and the reaction mixture allowed to stir at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-17% ethyl acetate in iso-hexane to afford the title compound (1.64 g, 99%).
Reaction SMILES: Br[CH:2]([C:7](=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH2:18]([N:25]1[CH2:30][NH:29][C:28](=[S:31])[NH:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH2:18]([N:25]1[CH2:30][N:29]2[C:7]([OH:17])([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=3)[CH:2]([CH2:3][C:4]([OH:6])=[O:5])[S:31][C:28]2=[N:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: S=C1NCN(Cc2ccccc2)CN1
Reactant: O=C(O)CC(Br)C(=O)c1cccc([N+](=O)[O-])c1
Solvent: CO
Product: O=C(O)CC1SC2=NCN(Cc3ccccc3)CN2C1(O)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of 3-bromo-3-(m-nitrobenzoyl)propionic acid (3.78 g, 0.0125 mole) in methanol (50 ml) was mixed with a suspension of 5-benzyl-3,4,5,6-tetrahydro-s-triazin-2(1H)thione (2.6 g, 0.0125 mole) in the same solvent (150 ml). The mixture was warmed until a clear solution was obtained and allowed to stand for two hours. Evaporation of the solvent gave a yellow solid foam (5.3 g, 83%). 2.5 Grams of this material were dissolved in warm ethanol and a colourless solid gradually crystallised and was collected to give 3-benzyl-7-carboxymethyl-6-hydroxy-6-(m-nitrophenyl)-3,4,6,7-tetrahydro-2H-thiazolo[3,2-a]-s-triazine hydrobromide (1.2 g), m.p. 147°-148° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9](O)=[O:10].S(Cl)(Cl)=O.C1C=CC=CC=1.C[N:25](C)C=O>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([NH2:25])=[O:10]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cnccc1C(F)(F)F
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cnccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution comprising 3 g of 4-trifluoromethyl-3-pyridine carboxylic acid, 6.7 ml of thionyl chloride and 20 ml of benzene, was refluxed under heating for 1.5 hours in the presence of a catalytic amount of dimethylformamide. Excess thionyl chloride and benzene were distilled off. Then, the residue was dissolved in 5 ml of ethyl acetate. This solution was gradually dropwise added to 20 ml of ammonia under cooling with ice. After completion Of the dropwise addition, the mixture was stirred at room temperature for 30 minutes. Then, water and ethyl acetate were distilled off under reduced pressure. The residue was extracted with heated ethyl acetate to obtain 2.1 g of 4-trifluoromethyl-3-pyridine carboxamide (melting point: 162.7° C.) as the desired product.
Reaction SMILES: [CH2:1]([Si:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][OH:9])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl>O>[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([O:9][CH2:8][CH2:7][CH2:6][Si:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH3:10])[CH3:11])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCC[Si](C)(C)CCCO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCC[Si](C)(C)CCCOS(=O)(=O)c1ccc(C)cc1
Yield: 81.7 %

Procedure:
5.0 g (28.68 mM) of butyldimethyl-3-hydroxypropylsilane was added 50 ml of pyridine, followed by stirring. To the mixture, 5.4 g (28.32 mM) of p-toluenesulfonyl chloride was added under cooling on an ice bath, followed by stirring for 0.5 hour and further stirring for 4 hours at room temperature. After the reaction, the reaction mixture was poured into water, acidified with hydrochloric acid (pH≈2) and extracted with ethyl acetate, followed by washing with water and drying with anhydrous magnesium sulfate. The magnesium sulfate in the resultant mixture was filtered off and the filtrate was condensed into a solid to obtain 3-(butyldimethylsilyl)propyl p-toluenesulfonate (Yield: 81.7 %).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7]C(=O)OC(C)(C)C)[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][CH2:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](/[CH:31]=[CH:32]/[C:33]2[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:40])[CH2:27][CH2:26]1)=[O:24]>C(#N)C>[ClH:21].[ClH:21].[CH3:40][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]([CH3:39])[C:33]=1/[CH:32]=[CH:31]/[CH:28]1[CH2:29][CH2:30][N:25]([C:23](=[O:24])[CH2:22][N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([NH2:7])[CH2:2]2)[CH2:26][CH2:27]1
Reactant: Cc1cccc(C)c1/C=C/C1CCN(C(=O)CCl)CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(C)c1/C=C/C1CCN(C(=O)CN2CCC[C@H](N)C2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 161.1 %

Procedure:
329 mg of tert-butyl (3S)-piperidin-3-ylcarbamate and 189 mg of potassium carbonate were added to a solution of 400 mg of 1-(chloroacetyl)-4-[(E)-2-(2,6-dimethylphenyl)vinyl]piperidine in 10 ml of acetonitrile, followed by heating under reflux for 2 hours. After the reaction mixture was concentrated under reduced pressure, chloroform and saturated aqueous sodium hydrogencarbonate solution were added to the residue, then the organic layer was fractionated. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol-ammonia water). The obtained oil was dissolved in 10 ml of ethanol, and 10 ml of 4N hydrochloric acid-ethyl acetate was added to the solution, followed by stirring at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was crystallized from 2-propanol-diisopropyl ether. The crystals were recrystallized from water-ethanol to give 473 mg of (3S)-1-(2-{4-[(E)-2-(2,6-dimethylphenyl)vinyl]piperidin-1-yl}-2-oxoethyl)piperidine-3-amine dihydrochloride.
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[C:11]=1[C:12]([NH2:14])=[O:13])(=[O:5])[CH2:2][CH2:3][CH3:4].[H][H]>[Pd].CO>[C:1]([NH:6][C:7]1[NH:8][CH:9]=[C:10]([C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[C:11]=1[C:12]([NH2:14])=[O:13])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Nc1[nH]cc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCC(=O)Nc1[nH]cc(-c2ccc(N)cc2)c1C(N)=O
Yield: 118.5 %

Procedure:
0.195 g (0.61 mmol) of 2-butyrylamino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide is added at a temperature in the region of 25° C. to a suspension of 0.068 g (0.064 mmol) of 10% palladium on carbon in 20 cm3 of methanol. After hydrogenating for 5 hours in an autoclave under 2 bar of hydrogen, at a temperature in the region of 25° C., the reaction mixture is filtered, the catalyst is rinsed with twice 10 cm3 of methanol and then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give 0.207 g of 2-butyrylamino-4-(4-aminophenyl)-1H-pyrrole-3-carboxamide, in the form of a cream solid. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm) 0.94 (t, J=7.5 Hz, 3H); 1.63 (m, 2H); 2.37 (t, J=7.5 Hz, 2H); 5.11 (broad s, 2H); from 6.05 to 8.45 (very broad m, 2H); 6.24 (d, J=2.5 Hz, 1H); 6.60 (d, J=8.5 Hz, 2H); 6.99 (d, J=8.5 Hz, 2H); 10.8 (broad s, 1H); 11.3 (broad s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C@@H:16]([NH2:18])[CH3:17].Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][N:24]2C1CCCCO1.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CC(O)C>[N:28]1[C:20]([NH:18][C@H:16]([C:8]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH3:17])=[C:21]2[C:25]([NH:24][CH:23]=[N:22]2)=[N:26][CH:27]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2cccnc2n1-c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccnc2n1-c1ccccn1
Temperature: 90 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
A mixture of (S)-1-(3-pyridin-2-yl-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine (0.134 g, 0.56 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.186 g, 0.78 mmol) and DIPEA (0.18 mL, 1.01 mmol) in IPA (2 mL) was stirred at 90° C. in a sealed tube for 16 h. The resulting mixture was concentrated in vacuo and residue was purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM). The product was dissolved in methanol and treated with HCl/dioxane (4M, 1.0 mL, 4.00 mol) and stirred for 30 min. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo to give 293 as a white solid (0.160 g, 80%). LCMS (method K): Rt 2.28 min, [M+H]+ 358. 1H NMR (DMSO-d6): δ 13.20-12.70 (1H, bs), 8.59 (1H, s), 8.31 (1H, m), 8.13 (2H, m), 8.03 (2H, tm), 7.81-7.81 (1H, m), 7.47 (1H, s), 7.36 (1H, m), 5.99 (1H, m), 1.67 (3H, d, J=6.82 Hz)
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([NH:16][CH:17]2[CH2:22][CH2:21][CH:20]([C:23](O)=[O:24])[CH2:19][CH2:18]2)[N:4]=1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[CH2:34][NH2:35].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[CH2:34][NH:35][C:23]([C@H:20]1[CH2:21][CH2:22][C@@H:17]([NH:16][C:5]2[N:4]=[C:3]([NH:2][CH3:1])[N:8]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[N:6]=2)[CH2:18][CH2:19]1)=[O:24]
Reactant: CNc1nc(NC2CCC(C(=O)O)CC2)nc(N2CCN(C)CC2)n1
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CNc1nc(N[C@H]2CC[C@@H](C(=O)NCc3ccc(Cl)cc3Cl)CC2)nc(N2CCN(C)CC2)n1
Reaction time: 8 h
Yield: 35.7 %

Procedure:
A solution of 4-{[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (150 mg, 0.43 mmol), [(2,4-dichlorophenyl)methyl]amine (95 mg, 0.54 mmol) and DMAP (8 mg, 0.06 mmol) in DCM was stirred at room temperature. To this was added EDCl (90.8 mg, 0.47 mmol) and the resulting mixture was allowed to stir overnight. The solution was washed with water. The organic layer was dried and purified by HPLC to afford 78 mg (36% yield) of the product as a white solid. MS (ES+): m/e 507.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](OB(O)O)=[CH:11][C:10]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[N:22]=[C:23]([N:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]2)[C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH2:37]([N:34]1[CH2:33][CH2:32][N:31]([C:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:30]=[C:21]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:10]([F:19])[CH:11]=3)[N:22]=2)[CH2:36][CH2:35]1)[CH3:38]
Reactant: OB(O)Oc1ccc(OCc2ccccc2)c(F)c1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
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: [Na+]
Solvent: Cc1ccccc1
Product: CCN1CCN(c2nc(-c3ccc(OCc4ccccc4)c(F)c3)cc3ccccc23)CC1
Yield: 96.1 %

Procedure:
4-Benzyloxy-3-fluorophenylboric acid (1.97 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (2.57 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.09 g) in toluene (250 ml) and a 10% aqueous solution of sodium carbonate (150 ml) in nitrogen atmosphere for 2 hr. 4-Benzyloxy-3-fluorophenylboric acid (0.99 g) was additionally added thereto, and the mixture was heated under reflux for 30 min. 4-Benzyloxy-3-fluorophenylboric acid (1.43 g) was again added thereto, and the mixture was heated under reflux overnight. The organic layer was separated and extracted with 2N hydrochloric acid twice, and the resulting aqueous layer was washed with ethyl acetate. Then, it was adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give obtain 1-(4-ethylpiperazin-1-yl)-3-(4-benzyloxy-3-fluorophenyl)isoquinoline (3.19 g) as a brown viscous oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:44])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH:40][CH2:41][CH2:42][OH:43])[N:34]=2)[CH:28]=1)=O)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH:40][CH2:41][CH2:42][OH:43])[N:34]=4)[CH:28]=3)[CH2:24][C:23](=[O:44])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nc(NCCO)n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)nc(NCCO)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (128 mg, 0.5 mmol) and 3-{3-[2-(2-hydroxy-ethylamino)-6-methyl-pyrimidin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K50) (251 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (136 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O>[CH2:26]([O:25][C:23]([CH2:22][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(C=Cc2cccc3cncn23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(C=Cc2cccc3cncn23)cc1

Procedure:
A solution of 5-[2-(p-hydroxyphenyl)ethen-1-yl]imidazo[1,5-a]pyridine (2.36 g) in 10 ml of dimethylformamide is added to a slurry of 0.5 g of sodium hydride in 30 ml of dry dimethylformamide at 0° under nitrogen. After warming to room temperature ethyl bromoacetate (1.67 g) is added and the reaction is heated to 60° for 5 hours. Water (200 ml) is added and the solution is extracted with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and evaporated to yield 5-[2-(p-[ethoxycarbonylmethoxy]phenyl)ethen-1-yl]imidazo[1,5-a]pyridine.