Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([O:13][CH3:14])(=[O:12])[C:8]([O:10]C)=O.[C:15]([C:18]1[C:19](=[O:41])[N:20]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[F:40])[CH:21]=[C:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH:23]=1)(=[O:17])[CH3:16].Cl>C1COCC1>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[CH2:24][C:22]1[CH:23]=[C:18]([C:15](=[O:17])[CH:16]=[C:8]([OH:10])[C:7]([O:13][CH3:14])=[O:12])[C:19](=[O:41])[N:20]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[F:40])[CH:21]=1
Reactant: CC(=O)c1cc(Cc2ccc(F)cc2F)cn(Cc2ccccc2F)c1=O
Reactant: COC(=O)C(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(O)=CC(=O)c1cc(Cc2ccc(F)cc2F)cn(Cc2ccccc2F)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of sodium t-butoxide (4.49 g, 45.3 mmol) in anhydrous THF (230 ml) was added dimethyl oxalate (5.41 g, 45.3 mmol) in anhydrous THF (60 ml) under argon condition. The mixture was stirred at room temperature for 30 min and a solution of 3-acetyl-5-(2,4-difluorobenzyl)-1-(2-fluorobenzyl)pyridin-2(1H)-one 6 (4.21 g, 11.3 mmol) in THF (60 ml) was added. The reaction mixture was stirred at room temperature for 3 h and then cooled in ice bath, and then 1N HCl (230 ml) was added in one portion. The crude product was extracted with ethyl acetate (2×230 ml). The combined organic layers were washed with saturated brine (2×230 ml) and ethyl acetate was distilled off to give a brown residue, which was triturated with methanol. The product was obtained by vacuum filtration. Yield 2.59 g (50%). 1H NMR (CDCl3, 500 MHz): δ 8.18 (d, 1H, J=3.1 Hz), 7.89 (s, 1H), 7.53 (s, 1H), 7.49-7.46 (s, 1H), 7.35-7.31 (s, 1H), 7.16-7.07 (m, 3H), 6.87-6.80 (m, 2H), 5.20 (s, 2H), 3.90 (s, 3H), 3.75 (s, 2H). 13C NMR (CDCl3, 125 MHz): δ 185.0, 171.9, 162.8, 162.6, 162.2, 160.6, 160.2, 159.6, 144.8, 142.0, 131.7, 131.2, 130.6, 124.8, 123.6, 122.4, 121.9, 117.7, 115.7, 111.7, 104.3, 101.8, 53.2, 47.6, 30.6.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[OH-:9].[Na+].[CH3:11][C:12]([CH3:16])(O)[C:13]#N>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:11][C:12]1([CH3:16])[NH:8][C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:7][C:13]1=[O:9]
Reactant: [OH-]
Reactant: Nc1ccccc1N
Reactant: CC(C)(O)C#N
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1(C)Nc2ccccc2NC1=O
Temperature: 25 °C

Procedure:
5.4 parts of o-phenylenediamine and 40 parts chloroform are placed in a 250 ml flask, 20 parts 50% by weight NaOH solution is added followed by 0.5 part benzyl triethyl ammonium chloride (BTAC). The flask is cooled in an ice-bath and 5.5 parts acetone cyanohydrin in 10 parts chloroform are added dropwise over 30 minutes. The flask is cooled in the ice-bath for an additional two hours, then warmed and maintained at room temperature for another two hours. Conversion in excess of 90% is obtained. The reaction product is worked up, filtered and washed with CHCl3 several times, and dried to yield 3,3-dimethyl-1,2,3,4-tetrahydroquinoxalin-2-one, which is dissolved in ethanol and conventionally hydrogenated.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[O:10].[Cl:11][C:12]1[C:13]([O:22][C:23]2[CH:27]=[C:26]([CH2:28][CH3:29])[NH:25][N:24]=2)=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.Cl>C(OCC)(=O)C>[CH3:7][NH:8][C:9]([N:25]1[C:26]([CH2:28][CH3:29])=[CH:27][C:23]([O:22][C:13]2[C:12]([Cl:11])=[CH:17][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:15][N:14]=2)=[N:24]1)=[O:10]
Reactant: CCc1cc(Oc2ncc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: CN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCc1cc(Oc2ncc(C(F)(F)F)cc2Cl)nn1C(=O)NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
Potassium carbonate (1.16 g, 8.4 mmol) and methyl isocyanate (0.40 g, 7.0 mmol) were added to a solution of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-ethylpyrazole (2.45 g, 8.4 mmol) in ethyl acetate (30 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with diethyl ether (30 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a white solid of N-methyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-ethylpyrazole-1-carboxamide (1.97 g, yield: 80.7%). mp: 85-87° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.31 (t, J=7.5 Hz, 3H), 2.95 (d, J=5.0 Hz, 3H), 3.13 (dq, J=6.0 and 7.5 Hz, 2H), 6.08 (s, 1H), 6.85-7.15 (m, 1H), 8.02 (d, J=2.1 Hz, 1H), 8.36 (m, 1H).
Reaction SMILES: Cl.[CH:2]1([C:5]2[C:13]3[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=3)[NH:7][N:6]=2)[CH2:4][CH2:3]1.N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:23])[CH3:22].O>CN(C=O)C>[Si:24]([O:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([CH:2]3[CH2:4][CH2:3]3)=[N:6][NH:7]2)=[CH:12][CH:11]=1)([C:21]([CH3:23])([CH3:22])[CH3:20])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Oc1ccc2c(C3CC3)n[nH]c2c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](Oc1ccc2c(C3CC3)n[nH]c2c1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
3-Cyclopropylindazol-6-ol hydrochloride (5.18 g) which can be prepared according to the method described in Reference example 4, etc. and imidazole (4.21 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) were dissolved in dehydrated DMF (122 mL; manufactured by Kanto Chemical Co., Inc.). Then, TBDPSCl (15.67 mL; manufactured by Tokyo Chemical Industry, Co., Ltd.) was added and the mixture was stirred overnight at 20° C. To the reaction solution, imidazole (1.8 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) and TBDPSCl (6.27 mL; manufactured by Tokyo Chemical Industry, Co., Ltd.) were added and the mixture was stirred for 2 hours at 20° C. To the reaction solution, water was added and extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=95:5→74:26) to obtain the title compound (4.71 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:29]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4([NH:40]C(=O)OC(C)(C)C)[CH2:39][CH2:38][CH2:37]4)=[CH:32][CH:31]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23](=[O:28])[C:24]([OH:27])([CH3:26])[CH3:25])[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[Cl:55]CCl>>[ClH:55].[NH2:40][C:36]1([C:33]2[CH:34]=[CH:35][C:30]([N:29]3[C:11]4=[N:12][C:13]([C:16]5[CH:17]=[C:18]([NH:22][C:23](=[O:28])[C:24]([OH:27])([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:31][CH:32]=2)[CH2:37][CH2:38][CH2:39]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(NC(=O)C(C)(C)O)c5)nc43)cc2)CCC1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)C(=O)Nc1cccc(-c2ccc3nc(-c4cccnc4N)n(-c4ccc(C5(N)CCC5)cc4)c3n2)c1
Product: Cl
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-{3-[(2-hydroxy-2-methylpropanoyl)amino]phenyl}-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (20 mg) in dichloromethane (3 mL) was added trifluoroacetic acid (0.6 mL) dropwise at room temperature. After being stirred at the same temperature for 1 h, the reaction mixture was concentrated under reduced pressure. Dichloromethane (5 mL) and MP-carbonate (Argonaout technologies 2.91 mmol/g, 200 mg) were added. The mixture was stayed for 30 min. with occasional shaking then filtered. The filtrate was concentrated under reduced pressure. To a solution of the residue in dichloromethane (5 mL) and methanol (0.5 mL) was added hydrogen chloride in ethyl acetate (4 M, 0.04 mL) at room temperature. After being stirred for 10 min., the mixture was concentrated under reduced pressure. The resulting solid was suspended with ethyl acetate and filtered to give the product (15 mg).
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:34])[CH:12]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[N:6][CH:5]=1.[OH-].[Na+]>CO.O>[CH3:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:35])=[O:2])=[CH:5][N:6]=2)=[O:34])=[CH:21][C:22]=1[C:30]([F:31])([F:33])[F:32])(=[O:28])=[O:27]
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCCO2)c2ccc(S(C)(=O)=O)c(C(F)(F)F)c2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCCO2)C(=O)Nc2ccc(C(=O)O)cn2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
A solution of 6-[2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionylamino]-nicotinic acid methyl ester (prepared as in Example 15, 21 mg, 0.04 mmol) in methanol (0.40 mL) was treated with a 1N aqueous sodium hydroxide solution (0.20 mL, 0.20 mmol). The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was then diluted with water and concentrated in vacuo to remove methanol. The resulting aqueous residue was acidified to pH=2 with a 1N aqueous hydrochloric acid solution and then extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford pure 6-[2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionylamino]-nicotinic acid (15 mg, 75%) as a colorless gum: EI-HRMS m/e calcd for C22H23F3O6S (M+H)+ 501.1302. found 501.1305.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](/[CH:21]=[C:22]2\[O:23][C:24]3[C:31]([CH2:32][N:33]4[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]4)=[C:30]([OH:46])[CH:29]=[CH:28][C:25]=3[C:26]\2=[O:27])=[CH:13]1)(=[O:11])=[O:10].FC(F)(F)C(O)=O>C(Cl)Cl>[ClH:1].[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](/[CH:21]=[C:22]2\[O:23][C:24]3[C:31]([CH2:32][N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[C:30]([OH:46])[CH:29]=[CH:28][C:25]=3[C:26]\2=[O:27])=[CH:13]1)(=[O:10])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(=O)(=O)c4cccc(Cl)c4Cl)c4ccccc24)C3=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C1/C(=C/c2cn(S(=O)(=O)c3cccc(Cl)c3Cl)c3ccccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 180.5 %

Procedure:
A solution of tert-butyl (Z)-4-[(2-{[1-(2,3-dichlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.152 g, 0.222 mmol) in methylene chloride (6 mL) was added with trifluoroacetic acid (6 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, then a solution of the resulting residue in methanol (8 mL) was added with a 5% solution of hydrogen chloride in methanol (2 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the resulting solid was suspended in acetonitrile and thereby washed to obtain (Z)-2-{[1-(2,3-dichlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.0878 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][C:5]([S:10]([NH2:13])(=[O:12])=[O:11])=[C:4]([F:14])[CH:3]=1.P(Br)(Br)[Br:16]>C(Cl)Cl>[Br:16][CH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:14])=[C:5]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:6]=1
Reactant: NS(=O)(=O)c1cc(CO)c(Cl)cc1F
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(CBr)c(Cl)cc1F
Reaction time: 24 h
Yield: 88.1 %

Procedure:
To a solution of 2-chloro-4-fluoro-5-sulfamoylbenzoic acid (3.2 g, 12.65 mmol) in THF (10 mL) was added 1M BH3.THF (38 mL, 38.0 mmol). After stirring 12 h, the reaction mixture was quenched with MeOH and concentrated in vacuo. The residue was purified by chromatography (silica, EtOAc-Hex) to afford 4-chloro-2-fluoro-5-(hydroxymethyl)benzenesulfonamide (1.9 g). To a suspension of 4-chloro-2-fluoro-5-(hydroxymethyl)benzenesulfonamide (1.78 g, 7.43 mmol) in DCM (10 mL) was added PBr3 (2.21 g, 8.17 mmol). The reaction was stirred for 24 h when it was determined to be complete by GCMS. The reaction was carefully quenched with H2O and then partitioned between THF and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford 5-(bromomethyl)-4-chloro-2-fluorobenzenesulfonamide (1.98 g) as an off-white solid. 1H-NMR (DMSO-d6, 400 MHz) δ 8.08 (d, J=7.8 Hz, 1H), 7.84 (s, 2H), 7.80 (d, J=9.9 Hz, 1H), 4.83 (s, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH:26]=O)=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:28]1([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.CO.CC(O)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH2:26][NH:36][CH2:35][CH2:34][CH2:33][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccccc1-c1ccc(C(=O)Nc2ccc3cccnc3c2)cc1
Reactant: NCCCN1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2ccccc2CNCCCN2CCCC2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2′-formyl-biphenyl-4-carboxylic acid quinolin-7-ylamide, Example 28, (50 mg, 0.14 mmol), 3-pyrrolidin-1-yl-propylamine (54 mg, 0.42 mmol, Aldrich) in DMF (1 mL) and MeOH (1 mL) was added glacial AcOH (1 drop), and the mixture was stirred at 50° C. for 30 min. Sodium triacetoxyborohydride (136 mg, 0.64 mmol) was added in small portions and the reaction mixture was stirred at 50° C. for 30 min. The reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was dissolved in EtOAc (60 mL) and washed with 0.5 N NaOH (10 mL). The EtOAc layer was separated, washed with brine, dried over MgSO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (gradient, 5 to 10% (2 M NH3 in MeOH) in CH2Cl2) to provide the title compound as light-yellow oil. MS (ESI, pos. ion.) m/z: 465 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][CH:10]([C:17]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)=[O:18])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]2[O:18][C:17]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(OC)cc1)C(=O)c1ccco1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(OC)cc2)oc1-c1ccco1
Yield: 31.7 %

Procedure:
To a solution of 10 g of ethyl 3-(4-methoxybenzoylamino)-3-(2-furylcarbonyl)propionate in 60 ml of chloroform are dropwise added 15 ml of thionyl chloride at room temperature. The mixture is refluxed at 60° to 70° C. for 6 hours under stirring. After the reaction is completed, the mixture is treated in the same manner as described in Example 1. 3.0 g of ethyl 2-[2-(4-methoxyphenyl)-5-(2-furyl)-4-oxazolyl]acetate are thereby obtained. Yield: 31.6%
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]([O:13]CC)=[O:12])=[CH:7][N:6]=[CH:5]1)[CH:2]=[CH2:3].[OH-].[Na+]>CO.O>[CH2:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]([OH:13])=[O:12])=[CH:7][N:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cncc(C(=O)OCC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCn1cncc(C(=O)O)c1=O
Reaction time: 16 h

Procedure:
To the compound of Example 21 (5.00 g, 0.024 mole), suspended in methanol (25 mL) and cooled in an ice bath, 1.0N NaOH (29 mL, 0.029 mole) is added dropwise rapidly with stirring. After 16 hours, the solvent is reduced under vacuum, residue diluted with water (50 mL), and washed with ethyl acetate (2×15 mL). The aqueous layer is acidified with 2.0N HCl to pH 1, extracted with ethyl acetate (3×50 mL). The combined organic extracts are washed with water, then brine (twice). The solvent is removed in vacuo to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:50]=[CH:51][CH:52]=2)[CH2:44][O:45]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:53][NH:54][CH3:55].[CH2:56]1C[O:59]CC1>>[CH:44]([OH:45])=[O:59].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:52]=[CH:51][CH:50]=[C:43]([CH2:53][N:54]([CH3:56])[CH3:55])[CH:42]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: C1CCOC1
Reactant: CNC
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CN(C)C)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 50 °C
Reaction time: 24 h
Yield: 16 %

Procedure:
To a solution of Intermediate 167b (0.16 mmol) in THF (2.5 mL) was added dimethylamine solution (2M THF, 1.6 mL, 3.27 mmol) and the reaction stirred at 50° C. for 24 h in a sealed vessel. The crude reaction mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by FCC on silica, using a gradient of 0-10% (2M NH3 in MeOH) in DCM, followed by MDAP (Method 7) purification, to give the title compound (20 mg, 16%). LCMS (Method 5): Rt 3.58 min, m/z 676 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.86 (3H, d, J=6.2 Hz), 1.23 (9H, s), 1.42-1.50 (2H, m), 1.58-1.67 (2H, m), 1.70-1.90 (4H, m), 1.94-2.03 (1H, m), 2.04-2.12 (2H, m), 2.11 (6H, s), 2.86 (1H, ddd, J=12.7, 9.0, 3.9 Hz), 3.12 (1H, dt, J=11.9, 4.1 Hz), 3.39 (2H, s), 4.77 (1H, td, J=8.4, 5.7 Hz), 5.46 (1H, t, J=4.2 Hz), 6.27 (1H, s), 7.02 (1H, d, J=8.6 Hz), 7.15 (1H, dd, J=9.8, 2.1 Hz), 7.20-7.29 (4H, m), 7.29-7.34 (1H, m), 7.35-7.41 (3H, m), 7.59 (1H, d, J=10.0 Hz), 7.64 (1H, d, J=1.8 Hz), 8.07 (1H, s), 8.25 (0.3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=2)[OH:24])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1.ClCCl>CO.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=2)=[O:24])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3C(O)c3cccc(C)n3)c2cc1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(C)nc3C(=O)c3cccc(C)n3)c2cc1OC
Temperature: 25 °C
Reaction time: 144 h
Yield: 30.1 %

Procedure:
[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-(6-methyl-pyridin-2-yl)-methanol (20 mg) was dissolved in methanol (0.4 ml) and dichloromethane (1.2 ml) to prepare a solution. Manganese dioxide (300 mg) was added to the solution, and the mixture was stirred at room temperature for 6 days. The reaction solution was filtered through Celite and was then washed with chloroform and methanol. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (6 mg, yield 28%).
Reaction SMILES: C(OC(=O)NCCCNC(C1N(CC2C=CC=CC=2)C(=O)C2C=CC=NC=2N=1)C(C)C)(C)(C)C.CCN(C(C)C)C(C)C.C1(C)C=CC(C(Cl)=O)=CC=1.C(OC(=O)[NH:60][CH2:61][CH2:62][CH2:63][N:64]([CH:74]([C:78]1[N:79]([CH2:89][C:90]2[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=2)[C:80](=[O:88])[C:81]2[CH:87]=[CH:86][CH:85]=[N:84][C:82]=2[N:83]=1)[CH:75]([CH3:77])[CH3:76])[C:65](=[O:73])[C:66]1[CH:71]=[CH:70][C:69]([CH3:72])=[CH:68][CH:67]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:60][CH2:61][CH2:62][CH2:63][N:64]([CH:74]([C:78]1[N:79]([CH2:89][C:90]2[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=2)[C:80](=[O:88])[C:81]2[CH:87]=[CH:86][CH:85]=[N:84][C:82]=2[N:83]=1)[CH:75]([CH3:76])[CH3:77])[C:65](=[O:73])[C:66]1[CH:71]=[CH:70][C:69]([CH3:72])=[CH:68][CH:67]=1
Reactant: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nc3ncccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: CC(C)C(NCCCNC(=O)OC(C)(C)C)c1nc2ncccc2c(=O)n1Cc1ccccc1
Agent: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N(CCCN)C(c2nc3ncccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-{3-[1-(3-benzyl-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2-methyl-proplyamino]-propyl}-carbamic acid tert butyl ester (110 mg, 0.236 mmol), DIEA (82 μL, 0.473 mmol) and dichloromethane (2 mL) was added p-toluoyl chloride (47 μL, 0.354 mmol) dropwise. The reaction mixture was stirred at room temperature overnight, and then diluted with dichloromethane and washed with saturated sodium bicarbonate, water and brine. After concentration, the residue was subjected to flash silica gel chromatography using hexane-EtOAc (1:2) and EtOAc-MeOH (20:1) as eluent to give the corresponding crude acylated product, {3-[[1-(3-benzyl-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2-methyl-propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester, which was then treated with 30% TFA in dichloromethane (3 mL) for 15 minutes, diluted with dichloromethane, washed with saturated sodium bicarbonate, water, and brine, and dried (Na2SO4). Concentration of the dichloromethane solution gave the title product, N-(3-amino-propyl)-N-[1-(3-benzyl-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2-methyl-propyl]-4-methyl-benzamide, as a white solid (89 mg, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[C@H:9]1([NH2:16])[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]1>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([NH2:16])[CH2:10][CH2:11]2)[CH:3]=1
Reactant: Clc1cc(Br)ccn1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(Br)ccn2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-2-chloropyridine (1500 mg, 7.79 mmol), DMSO (15 ml), and trans-cyclohexane-1,4-diamine (4450 mg, 39.0 mmol)was stirred at 100° C. until the formation of the product, as indicated by LCMS. The reaction mixture was cooled to room temperature, filtered and purified by prep LC, and lyapholized to yield 393 mg of the title compound as a TFA salt. LCMS (m/z): 270.2/272.2 (MH+), retention time=0.31 min.