Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([C:11]([C:13]([O:15][C:16](=[O:30])[C:17](=[O:29])[C:18]2[C:19](=[CH:21][CH:22]=[C:23]([CH2:25][CH2:26][CH2:27][CH3:28])[CH:24]=2)[NH2:20])=[O:14])=[O:12])[C:8]([NH2:31])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:34](I)[CH3:35].Cl.[CH3:38][CH2:39]CCCC>CN(C)P(=O)(N(C)C)N(C)C>[CH2:38]([NH:31][C:8]1[C:9]([C:11]([C:13]([O:15][C:16](=[O:30])[C:17](=[O:29])[C:18]2[C:19](=[CH:21][CH:22]=[C:23]([CH2:25][CH2:26][CH2:27][CH3:28])[CH:24]=2)[NH:20][CH2:34][CH3:35])=[O:14])=[O:12])=[CH:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=1)[CH3:39]
Reactant: CCCCc1ccc(N)c(C(=O)C(=O)OC(=O)C(=O)c2cc(CCCC)ccc2N)c1
Reactant: CCI
Reactant: CCCCCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCc1ccc(NCC)c(C(=O)C(=O)OC(=O)C(=O)c2cc(CCCC)ccc2NCC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.00 g of the anhydride are dissolved in 35 ml of hexamethylphosphoric acid triamide, the solution is cooled to 5° and sodium hydride (0.864 g of a 50% strength suspension in mineral oil, de-oiled with hexane) is added under nitrogen. The mixture is allowed to warm to room temperature, 2.8 g of ethyl iodide are added and stirring is then carried out for 1 hour first at room temperature, then at 40°, and the reaction mixture is poured into a mixture of 300 ml of ice-water and 20 ml of 2N hydrochloric acid, filtered with suction, washed with water and allowed to dry in the atmosphere. N-Ethyl-5-butylisatic acid anhydride having a melting point of 130°-132° is obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[CH:13]3)=[O:9])[CH2:3][CH2:2]1.[CH:19](=O)[CH2:20][CH3:21].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:19]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[CH:13]3)=[O:9])[CH2:3][CH2:2]1)[CH2:20][CH3:21]
Reactant: O=C(NC1CCNCC1)c1ccc2[nH]ncc2c1
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN1CCC(NC(=O)c2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
Acetic acid (0.048 ml) was added to a solution of the N-(4-piperidinyl)-1H-indazole-5-carboxamide (40.0 mg, 0.164 mmol) obtained in Example 58 in methanol (1.2 ml), and the resulting solution was maintained at room temperature for 30 minutes. Propionaldehyde (48.0 mg, 0.826 mmol) was added to the solution and the resulting mixture was maintained at room temperature for another 2 hours. Then, a solution of sodium cyanoborohydride (51.5 mg, 0.820 mmol) in methanol (3.0 ml) was added dropwise thereto, and the resulting mixture was stirred for 18 hours while being maintained at room temperature. A 1N-aqueous sodium hydroxide solution (0.8 ml) was added to the reaction solution, and the resulting mixture was stirred while being maintained at room temperature, and then was concentrated to dryness. The resulting crude product residue was purified by a silica gel column chromatography (eluent: chloroform/methanol/aqueous ammonia=20/1/0.1) to obtain N-(1-propylpiperidin-4-yl)-1H-indazole-5-carboxamide (31 mg, 46%).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH2:6][C:7](=[O:25])[C@@H:8]([NH:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.[Li+].[OH-].C(O)(=O)C>C1COCC1.CO>[C:17]([NH:16][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7](=[O:25])[CH2:6][CH2:5][C:4]([OH:26])=[O:3])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a stirred solution of ethyl-(5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoate (0.300 g, 0.8489 mmol, 1.0 eq) in THF-MeOH (8:2 ratio)(10 mL) was added 0.5N LiOH (10 mL) and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was then neutralized with glacial acetic acid and then extracted with EtOAc (3×25 mL). The organic extract was dried over anhydrous MgSO4 and evaporation of the solvent afforded a crude yellow residue. Column chromatography on silica gel elution with 100% EtOAc afforded (5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoic acid 4 as a white solid (0.232 g, 82%): mp 143-146° C. (lit.12 mp 142-143° C.); Rf 0.25 (EtOAc); IR (KBr) ν 1685 (CO), 1760 (CO), 3150 (COOH) cm−1; 1H NMR (400 MHz, CDCl3) δH 2.48 (2H, t, J=6.8 Hz, —CH2CO), 2.72 (2H, t, J=7.0 Hz, —CH2CO), 2.97 (1H, dd, J=6.4 and 14.4 Hz, —CHαPh), 3.18 (1H, dd, J=6.4 and 14.4 Hz, —CHβPh), 3.81 (2H, br s, —NH and —COOH), 4.87 (1H, t, J=6.8 Hz, —CH—) and 7.05-7.65 (10H, m, Ar—H); 13C NMR (100 MHz, CDCl3) δC 27.5, 34.9, 36.4, 59.5, 126.8, 126.9, 127.9, 128.4 (2C), 128.5 (2C), 129.1 (2C), 131.7, 133.5, 136.3, 167.9, 174.6 and 207.5; HRMS m/z calcd for C19H19NO4 (M+) 325.12854, found 353.13141.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH:11]=[CH:12][C:13](=O)[CH3:14].[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:17].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[C:18]([C:16]#[N:17])=[C:13]([CH3:14])[CH:12]=[CH:11][C:3]1[CH:4]=[CH:5][C:6]([CH:8]([CH3:10])[CH3:9])=[CH:7][C:2]=1[Cl:1])[CH3:23]
Reactant: CC(=O)C=Cc1ccc(C(C)C)cc1Cl
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=C(C)C=Cc1ccc(C(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 4-(2-chloro-4-isopropylphenyl)but-3-en-2-one (50 mmol), ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether.
Reaction SMILES: F.[Si](O[C:10]1[C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][Si](C(C)(C)C)(C)C)=[C:21]([F:33])[CH:20]=3)[O:18][C:14]=2[C:13]([CH:34]=[CH2:35])=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.C1C[O:39]CC1.C(#N)C>O>[F:33][C:21]1[CH:20]=[C:19]([C:17]2[O:18][C:14]3[C:13]([CH:34]=[CH2:35])=[CH:12][C:11]([OH:39])=[CH:10][C:15]=3[N:16]=2)[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: C=Cc1ccc(O[Si](C)(C)C(C)(C)C)c2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)c(F)c3)oc12
Reactant: C1CCOC1
Agent: F
Solvent: CC#N
Solvent: O
Product: C=Cc1cc(O)cc2nc(-c3ccc(O)c(F)c3)oc12
Temperature: 65 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Hydrofluoric acid (48 wt. % in water, 1 mL) was added into a solution of 5-{([tert-butyl(dimethyl)silyl]oxy}-2-(4-{[tert-butyl(dimethyl)sily]oxy}-3-fluorophenyl)-7-vinyl-1,3-benzoxazole (1.5 g, 3.0 mmol), THF (6 mL) and acetonitrile (3 mL). The reaction mixture was stirred at 65° C. for 8 h, and then poured into water. The precipitated solid was filtered off and dried. Crystallization of the product from acetone/ethyl ether gave a white solid (0.72 g, 81% yield, m.p. 249–251° C.); MS m/e 272 (M+H)+.
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>O>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)([NH:27][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:3](=[O:12])[NH:4]2)=[CH:9][CH:8]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: NC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.27 mmol) (from example 1c supra), cyclohexylamine (40 mg, 0.41 mmol) and DIPEA (104.5 mg, 0.81 mmol) in dimethyl formide (2 mL) was stirred at room temperature for 2 h. Then water (10 mL) was added and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layer was concentrated and the residue was purified by preparative HPLC to give 51 mg of rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexylamino-1,3-dihydro-indol-2-one as a white solid. MS: 389 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:17]Br.S(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1
Reactant: N#Cc1ccc(Oc2cccnc2N)cc1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#Cc1ccc(Oc2cc(Br)cnc2N)cc1
Temperature: 0 °C
Yield: 66.3 %

Procedure:
Placed 4-(2-aminopyridin-3-yloxy)benzonitrile (13.95 g, 66.05 mmol) in acetic acid (50 mL) and cooled to 0° C. Slowly added bromine (4.229 mL, 82.56 mmol) and stirred for an hour. The reaction mixture was poured onto saturated sodium bisulfite and ice. Extracted with dichloromethane three times, washed with 2N NaOH, water, brine, dried, and concentrated. Purified by MPLC eluting with 3:2 hexane:ethyl acetate to afford the title compound (12.7 g, 66.28% yield) as a light yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13]([CH:20]=[O:21])=[CH:14][NH:15]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:22][N:23]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24](=[O:27])[CH2:25]Br.C(OCC)(=O)C>O1CCCC1.[Cl-].[Na+].O>[CH3:22][N:23]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24](=[O:27])[CH2:25][N:15]1[C:16]2[C:12](=[C:11]([O:10][CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=[CH:18][CH:17]=2)[C:13]([CH:20]=[O:21])=[CH:14]1
Reactant: O=Cc1c[nH]c2cccc(OCc3ccccc3)c12
Reactant: CN(CCc1ccccc1)C(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(CCc1ccccc1)C(=O)Cn1cc(C=O)c2c(OCc3ccccc3)cccc21
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (1.31 g, 80% suspension in mineral oil, 43.8 mM) in 65 ml of tetrahydrofuran (THF), cooled in an ice bath, is added dropwise a solution of 4-benzyloxyindole-3-carboxaldehyde (10.2 g, 39.8 mM) in 55 ml of THF. The mixture is stirred in the cooling bath for an additional 30 minutes; N-methyl-N-phenethyl-2-bromoacetamide (15.3 g, 59.7 mM) is then added. The resulting mixture is stirred at room temperature for 18 hours. Ethyl acetate and 50% brine is added and the layers are separated. The organic layer is washed with brine, dried over magnesium sulfate and concentrated in vacuo to give crude product as a beige oil. Purification on preparative HPLC (silica gel column, 20% ethyl acetate in methylene chloride) gives N-methyl-N-phenethyl-2-(4-benzyloxy-3-formylindol-1-yl)acetamide. (m.p. 120°-122° C.)
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[CH:17][C:16](F)=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)=[NH:10])=[O:7])=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28].[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:31]1([C:16]2[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9](=[NH:10])[NH:8][C:6](=[O:7])[C:5]3[CH:25]=[CH:26][C:2]([N:31]4[CH:35]=[CH:34][N:33]=[CH:32]4)=[C:3]([C:27]([F:30])([F:28])[F:29])[CH:4]=3)=[O:24])=[CH:14][C:15]=2[C:20]([F:23])([F:21])[F:22])[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: c1c[nH]cn1
Reactant: N=C(NC(=O)c1ccc(F)c(C(F)(F)F)c1)NC(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N=C(NC(=O)c1ccc(-n2ccnc2)c(C(F)(F)F)c1)NC(=O)c1ccc(-n2ccnc2)c(C(F)(F)F)c1
Yield: 39.4 %

Procedure:
0.25 g of bis(4-fluoro-3-trifluoromethylbenzoyl)guanidine, 0.16 g of imidazole and 0.16 g of potassium carbonate are heated for 16 h in 5 ml of DMF, and after that the solvent is evaporated. Separation of the crude product by column chromatography yielded 0.12 g of bis[4-(1-imidazolyl)-3-trifluoromethylbenzoyl]guanidine as a colorless solid, mp 130° C. decomp., Rf (CH2Cl2/MeOH 9:1)=0.4 MS (ES):536 (M+1) and 0.07 g of N-[4-(1-imidazolyl)-3-trifluoromethylbenzoyl]-N′-(4-fluoro-3-trifluoromethylbenzoyl)guanidine as an oil. Treatment with HClg/ether yielded 0.06 g of N-[4-(1-imidazolyl)-3-trifluoromethylbenzoyl]-N′-(4-fluoro-3-trifluoromethylbenzoyl)guanidine hydrochloride as a colorless solid, mp 217-218, decomp., Rf (CH2Cl2/MeOH 9:1)=0.53; MS (ES):488 (M+1)
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:7][CH2:6][CH:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.[Li+].[CH3:17]C([N-]C(C)C)C.CI>C1COCC1>[F:1][C:2]1([F:15])[CH2:3][CH2:4][CH:5]([C:8]([CH3:17])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:7]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C(C)C1CCC(F)(F)CC1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of Intermediate 232A (0.27 g, 1.226 mmol) in THF (5 mL) was added LDA (1.226 mL, 2.452 mmol, 2M in THF) dropwise at −78° C. and the resulting solution was stirred at the same temperature for 45 min. MeI (0.307 mL, 4.90 mmol) was then added at −78° C. and the reaction mixture was allowed to warmed to RT and stir for 12 h. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (2×25 mL). The combined organic layer was dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 2% EtOAc in hexane.) Fractions containing the product were combined and evaporated to afford Intermediate 232B as a pale yellow liquid. (0.15 g, 55%). 1H NMR (300 MHz, DMSO-d6) δ ppm 4.07 (q, J=7.2 Hz, 2H), 2.01 (d, J=12.1 Hz, 2H), 1.92-1.74 (m, 2H), 1.73-1.53 (m, 4H), 1.31-1.20 (m, 2H), 1.11 (br. s., 4H), 1.03 (d, J=2.6 Hz, 6H).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=2)[NH:19][CH:18]=1)[C:9]([O:11]C)=[O:10].Cl>O.CO>[N+:26]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:16][C:15]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:5][CH3:4])([O-:28])=[O:27]
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of lithium hydroxide monohydrate (1.2 g.) in water (20 ml.) was added to a suspension of nitro ester (C) (2.0 g.) in methanol (30 ml.). The mixture was stirred at ambient temperature for 18 hours and then acidified with hydrochloric acid (1N, 50 ml.). The yellow precipitate was isolated by filtration, washed with water, and dried to give 4-(5-nitroindol-3-ylmethyl)-3-methoxybenzoic acid; partial NMR (250 MHz, DMSO-d6): 3.92 (s,3 H, OMe); 4.12 (s,2 H, ArCH2): 11.64 (br s,1 H, NH).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].Cl.[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[O:25][C:24]([CH2:26][CH2:27][NH2:28])=[CH:23][CH:22]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:28][CH2:27][CH2:26][C:24]2[O:25][C:21]([C:16]3[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=3)=[CH:22][CH:23]=2)=[O:11])[NH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: Cl
Product: CC(=O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Yield: 49.7 %

Procedure:
The title compound was prepared using the method of Example 20 but starting from 3-acetyl-1H-pyrazole-5-carboxylic acid (215 mg; 1.37 mmol) and 2-(5-(3,4-dichlorophenyl)furan-2-yl)ethanamine hydrochloride (400 mg; 1.37 mmol). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-100% EtOAc/heptane) to obtain 267 mg (50%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.50 (s, 3H—overlapping with DMSO), 2.93 (t, 2H), 3.54-3.60 (m, 2H), 6.33 (d, 1H), 7.02 (d, 1H), 7.30 (s, 1H), 7.58-7.64 (m, 2H), 7.82 (d, 1H), 8.65 (broad s, 1H), 14.21 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([F:20])=[CH:15][N:14]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:12][C:13]1[N:18]=[C:17]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:3]=2[O:2][CH3:1])[C:16]([F:20])=[CH:15][N:14]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COc1ccc(N)c(OC)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2nc(Cl)ncc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2,4-dimethoxyaniline (4.1 g, 24.6 mmol) was added to a solution of 2,4-dichloro-5-fluoropyrimidine (4.1 g, 24.6 mmol) in isopropanol (16 mL). N,N-Diisopropyl-ethylamine (6.30 g, 8.50 mL, 48.8 mmol) was added and the mixture was allowed to stir at room temperature for 24 h. The solution was partitioned between ethyl acetate and water. The organic phase was separated and washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford an oil. This oil was purified via column chromatography on silica gel (gradient elution with 0-10% methanol-methylenechloride) to afford (2-chloro-5-fluoro-pyrimidin-4-yl)-(2,4-dimethoxy-phenyl) amine. MS (MH+) 284; Calculated 283.69 for C12H11ClFN3O2.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:7][C:6]([Cl:18])=[N:5][C:4]=2[CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:18][C:6]1[N:7]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[N:10]=[CH:11][C:2]([C:24]3[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=3)[NH2:19])=[CH:3][C:4]=2[N:5]=1
Reactant: Clc1nc(N2CCOCC2)c2ncc(Br)cc2n1
Reactant: Nc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a 100 mL round bottom flask, 4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (1.5 g, 0.0046 mol—Preparation 2), 3-aminophenylboronic acid (0.67 g, 0.0051 mol), sodium carbonate (0.98 g, 0.0092 mol) toluene (30 mL), ethanol (10 mL) and water (5 mL) were added. The reaction mixture was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)2Cl2 (0.14 g, 0.0002 mol) was added and again degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 90° C. for 2 hours. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude product. The crude product was purified by column chromatography (60-120 silica gel, 60% ethyl acetate in hexane) to provide the title compound (1.1 g, 70%). 1H NMR (300 MHz, DMSO-d6): δ 9.02 (d, J=2.1 Hz, 1H), 8.12 (d, J=2.1 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.01-6.99 (m, 2H), 6.68-6.17 (m, 1H), 5.33 (br s, 2H), 4.52 (br s, 4H), 3.79 (t, J=4.8 Hz, 4H). LC-MS (ESI): Calculated mass: 341.1; Observed mass [M+H]+: 342.1. (RT=0.73 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18](=O)[CH3:19])[CH2:13][C:12]=3[C:21](=[O:23])[O:22][C:5]=2[CH:4]=1.[CH3:24][NH2:25]>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH:18]([NH:25][CH3:24])[CH3:19])[CH2:13][C:12]=3[C:21](=[O:23])[O:22][C:5]=2[CH:4]=1
Reactant: CN
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CC(C)=O)C3
Product: CNC(C)CN1CCc2c(c(=O)oc3cc(OC)c(OC)cc23)C1
Yield: 291.4 %

Procedure:
Prepared by the method described for Example 51 from 1,2,3,4-tetrahydro-8,9-dimethoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (25.0 g, 0.08 moles) and methylamine (5 g, 0.016 moles). Recrystallization from acetonitrile gave the product (15.5 g), mp 137°-139° C.
Reaction SMILES: C([N:3]1C[CH2:6][C:5](=O)[CH2:4]1)C.C(N)C.C([NH:14][CH:15]1C2C=CC(N3CCCC3)=CC=2OC2[C:16]1=[CH:17][CH:18]=CC=2)C>>[CH2:4]([NH2:3])[CH2:5][CH3:6].[CH2:15]([NH2:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCNC1c2ccccc2Oc2cc(N3CCCC3)ccc21
Reactant: CCN1CCC(=O)C1
Agent: CCN
Product: CCCCN
Product: CCCN

Procedure:
In the procedure of Example 2, using 1-ethyl-3-pyrrolidinone and ethylamine, the product obtained is N-ethyl-N-(N-ethyl-3-pyrrolidinyl-9-xanthenylamine. Using propylamine and butylamine, the products obtained are N-propyl-N-(N-ethy-3-pyrrolidinyl)-9-xanthenylamine and N-butyl-N-(N-ethyl-3-pyrrolidinyl)-9-xanthenylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N+:3]=1[O-:10].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:4][N+:3]=1[O-:10]
Reactant: C1COCCN1
Reactant: [O-][n+]1cc(CCl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: [O-][n+]1cc(CN2CCOCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.2 %

Procedure:
A mixture of 2-chloro-5-(chloromethyl)pyridine 1-oxide (1.16 g, 6.52 mmol; described in: Tilley, J. W. et al, J. Heterocyclic Chem. 1979, 16, 333), morpholine (1.14 g, 13.0 mmol), and potassium carbonate (0.90 g, 6.52 mmol) in acetonitrile (30 mL) was stirred at room temperature for 72 h. The solvent was removed in vacuo and the residue was purified on a silica gel column using chloroform/ethanol, (9:1), as the eluent affording 1.21 g (81% yield) of the title compound as a colorless solid: mp 72-74° C.; 1H NMR (CDCl3, 400 MHz) δ 8.34 (s, 1 H), 7.39 (d, J=8 Hz, 1 H), 7.16 (dd, J=8, 2 Hz, 1 H), 3.65 (t, J=5 Hz, 4 H), 3.40 (s, 2 H), 2.40 (t, J=4 Hz, 4 H); 13C NMR (CDCl3, 100 MHz) δ 140.4 (br), 135.9, 126.6, 126.6, 66.8, 59.2, 53.4; MS (ESP) m/z 229 (M++1).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.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>C(O)CCC>[C:1]1([N:7]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH:16]([NH:18][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC(N)c1nc2ccncc2n1-c1ccccc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccncc2n1-c1ccccc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 14.7 %

Procedure:
A mixture of 1-(3-phenyl-3H-imidazo[4,5-c]pyridin-2-yl)ethylamine (254 mg, 1.07 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.35 g, 1.49 mmol) and DIPEA (0.34 mL, 1.92 mmol) in 1-butanol (3 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, 1.3 mL, 5.35 mmol) and stirred for 20 minutes. The mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo. The resulting residue was purified by chromatography (SiO2, 0-15% (2M ammonia in methanol) in DCM) to give a waxy solid which was triturated with EtOAc/diethyl ether to give 237 as a brown solid (0.056 g, 15%). LCMS (method K): Rt 1.98 min, [M+H]+ 357. 1H NMR (DMSO-d6): δ 13.10-12.60 (1H, bs), 8.43 (1H, s), 8.37 (1H, d, J=5.53 Hz), 8.13 (1H, s), 8.07 (1H, s), 7.70-7.68 (3H, m), 7.61-7.50 (3H, m), 5.49 (1H, m), 1.59 (3H, d, J=6.87 Hz)