Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2].Br[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Reactant: Brc1ccccn1
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: [K+]
Solvent: COCCOC
Product: CCOC(=O)Cc1cccc(Oc2ccc(-c3ccccn3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Temperature: 90 °C

Procedure:
{3-[2-((4S,5R)-4-Methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-phenyl}-acetic acid ethyl ester (0.1 g, 0.18 mmol), 2-bromopyridine (0.042 g, 0.26 mmol), potassium carbonate (0.061 g, 0.44 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.02 mmol) were combined in 2:1 DME:H2O (4 mL) and degassed with N2 for 10 minutes. The reaction was then heated to 90° C. for 3.5 hours. The mixture was neutralized to pH 6 with 10% aqueous HCl and extracted with EtOAc. The crude material was purified by silica gel chromatography to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[N:6][N:5]=[C:4]2[NH:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:3]=12.O[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[N:6][N:5]=[C:4]2[N:15]([CH2:25][C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[N:16]=[C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:3]=12
Reactant: O=C(CO)N1CCCC1
Reactant: Fc1cccc(-c2nnc3[nH]nc(-c4ccccc4)c3c2Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3cccc(F)c3)nnc21)N1CCCC1

Procedure:
A mixture of 4-chloro-5-(3-fluorophenyl)-3-phenyl-1H-pyrazolo[3,4-c]pyridazine (0.33 mmol), 2-hydroxy-1-(pyrrolidin-1-yl)ethanone (0.65 mmol), diethyl azodicarboxylate (114 mg, 0.65 mmol) and triphenyl phosphine (171 mg, 0.65 mmol) in 1,4-dioxane (2 mL) was heated using microwave irradiation to a temperature between 85 and 120° C. for a 30 to 90 min period. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to provide Compound 11.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:3]=1[CH3:18].[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:26]=2[NH2:27])[CH2:21][CH2:20]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[N:22]1([C:25]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:28][C:26]=2[NH:27][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:3]=2[CH3:18])[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2ncccc2c1Cl
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2ncccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-chloro-3-methyl-2-(pyridin-2-yl)-1,8-naphthyridine (48.6 mg, 0.19 mmol), 2,5-dimorpholinoaniline (50 mg, 0.19 mmol) and XPhos precatalyst (14 mg, 0.019 mmol) in toluene (4 mL) was added sodium tert-butoxide (36 mg, 0.38 mmol) and the reaction was heated at reflux for 2 h. After this time the reaction was allowed to cool to rt and partitioned between EtOAc (60 mL) and water (20 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Purification by reverse phase HPLC gave N-(2,5-di-4-morpholinylphenyl)-3-methyl-2-(2-pyridinyl)-1,8-naphthyridin-4-amine. H NMR (500 MHz, CDCl3) δ ppm 9.08 (1H, dd, J=3.9, 1.7 Hz), 8.71 (1H, br. s.), 8.26 (1H, dd, J=8.3, 1.7 Hz), 8.16 (1H, d, J=7.8 Hz), 7.88-7.96 (1H, m), 7.39 (2H, dd, J=8.3, 4.2 Hz), 7.11 (1H, d, J=8.8 Hz), 6.45 (1H, dd, J=8.7, 2.6 Hz), 5.99 (1H, d, J=2.7 Hz), 3.90 (4H, t, J=4.4 Hz), 3.66-3.77 (4H, m), 3.05 (4H, br. s.), 2.82-2.93 (4H, m), 2.51 (3H, s). Mass Spectrum (ESI) m/e=483.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:17](OC(OCC)OCC)C>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][CH:17]=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Br)cc1
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)(O)O
Product: Brc1ccc(-c2nnco2)cc1
Temperature: 2.5 °C
Yield: 89.9 %

Procedure:
To a suspension of 4-bromobenzoic hydrazide (200 g) in industrial methylated spirit (700 ml) was added triethylorthoformate (309 ml), industrial methylated spirit (100 ml) and sulphuric acid (0.8 ml). The reaction mixture was heated to reflux for 1 hour. The reaction mixture was cooled to 0-5° C. and product crystallised. Product was isolated, washed and dried to yield 2-(4-bromophenyl)-1,3,4-oxadiazole (186.1 g, 89.9%). 400 MHz NMR Spectrum: (DMSOd6) 9.35 (s, 1H), 7.98 (d, 1H), 7.95 (d, 1H), 7.84 (d, 1H), 7.81 (d, 1H); Mass Spectrum MH+ 224.9663 (calc. using 79-Br) Found 224.9701.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]1([CH2:28][CH2:29][C:30](O)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CO.CN(C)C=O>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C(O)CCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCc1ccccc1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 33.4 %

Procedure:
Preparation of example 38 from the title compound of Example 7 (0.030 g, 0.11 mmol), 3-Phenyl-propionic acid (0.025 g, 0.16 mmol), triethylamine (0.077 mL, 0.44 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (63 mg, 0.16 mmol) and N,N-dimethylformamide (0.05 M, 2.0 mL) was carried out analogously to Example 11. Silica gel chromatography (95:5 CH2Cl2/methanol) afforded the title compound (15 mg) as a yellow powder in 34% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[C:14]([F:13])([F:23])[F:24])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(F)ccc1O
Reactant: FC(F)(F)c1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(F)ccc1OCc1ccccc1C(F)(F)F
Yield: 56 %

Procedure:
A solution of 7.50 g (44.08 mmol) of methyl 5-fluoro-2-hydroxybenzoate in 40 ml of dry acetonitrile is mixed with 9.44 g (48.49 mmol) of 2-trifluoromethylbenzyl chloride and 18.28 g (132.25 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then cooled, filtered, washed with dichloromethane and concentrated, and the residue is purified by chromatography (silica gel; mobile phase: cyclohexane/ethyl acetate 5:1). 9.18 g (28 mmol, 89% purity, 56% yield) of the title compound are obtained.
Reaction SMILES: I[CH2:2][CH3:3].[OH:4][CH2:5][C@H:6]1[C@H:10]([CH3:11])[O:9][C:8]([CH3:13])([CH3:12])[N:7]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[H-].[Na+]>CN(C=O)C>[CH2:2]([O:4][CH2:5][C@H:6]1[C@H:10]([CH3:11])[O:9][C:8]([CH3:12])([CH3:13])[N:7]1[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH3:3]
Reactant: CCI
Reactant: C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC[C@H]1[C@H](C)OC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Iodoethane (0.80 mL) was added to a solution of (4S,5S)-tert-butyl 4-(hydroxymethyl)-2,2,5-trimethyloxazolidine-3-carboxylate (1.23 g), which can be synthesized by a method described in Bioorganic Chemistry 36 (2008) 4-15, in DMF (10 mL). Sodium hydride (60% in oil, 300 mg) was added under ice-cooling. Thereafter, the ice bath was removed, and the reaction solution was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution. After separation, the organic layer was washed with water twice. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain (4S,5S)-tert-butyl 4-(ethoxymethyl)-2,2,5-trimethyloxazolidine-3-carboxylate as light yellow amorphous.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][CH:10]([CH3:13])[CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:9]([O:8][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1)[CH:10]([CH3:13])[CH3:11]
Reactant: CC(C)CO
Reactant: Nc1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)COc1cccc(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.4 %

Procedure:
To a mixture of 3-aminophenol (500 mg, 4.60 mmol), 2-methylpropan-1-ol (1.40 g, 18.9 mmol) and triphenylphosphine (4.80 g, 16.2 mmol) in THF (10 mL) was added dropwise diethylazodicarboxylate (3.20 g, 18.3 mmol) over a 30 min period. The mixture was stirred at room temperature for 3 h. The solvent was evaporated and the residue was diluted with water, acidified with aqueous 2N HCl and extracted with ether. The aqueous phase was basified with aqueous 2N NaOH and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated. The resulting crude product was purified by silica gel column chromatograph (petroleum ether/EtOAc 15:1) to afford 3-isobutoxybenzenamine as yellow oil (330 mg, 45%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[CH3:2].CC(C)([O-])C.[K+].[F:22][C:23]([F:32])([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:25][CH2:26]I.O>C1COCC1>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:26][CH2:25][CH2:24][C:23]([F:32])([F:22])[C:28]([F:31])([F:30])[F:29])[C:6](=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[CH3:2]
Reactant: C=CCCCCCC(=O)CC(=O)OCC
Reactant: FC(F)(F)C(F)(F)CCCI
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCCCC(=O)C(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
On the other hand, to a solution of 3-oxo-dec-9-enoic acid ethyl ester (4.32 g, 20.3 mmol) in THF (15 ml) at 0° C. was added potassium tert-butoxide (2.73 g, 24.3 mmol) This resulting mixture was stirred at room temperature under nitrogen for 30 min. The mixture of 4,4,5,5,5-pentafluoro-iodopentane was added and mixture was refluxed under nitrogen for 2 days, and then poured into H2O. The mixture was extracted with hexane. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (silica gel, 60% CHCl3/hexane) to afford 3-oxo-2-(4,4,5,5,5-pentafluoropentyl)-dec-9-enoic acid ethyl ester (4.46 g, 59%).
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].CN(C)[CH:11]=[C:12]([CH:22]=O)[CH:13]([CH:19]([CH3:21])[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[NH2:7][C:6]1[N:8]=[CH:11][C:12]([CH:13]([CH:19]([CH3:20])[CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:22][N:5]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(C(C=O)=CN(C)C)C(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(c1cnc(N)nc1)C(C)C
Reaction time: 70 h

Procedure:
A solution of sodium methoxide (0.9 g) in ethanol (5 cm3) was added dropwise to a stirred suspension of guanidine hydrochloride (1.58 g) and ethyl (RS)-4-dimethylamino-3-formyl-2-(1-methylethyl)-3-butenoate in ethanol (10 cm3). The reaction mixture was heated at the reflux temperature for 2 hours, then stood at the ambient temperature for 70 hours. The solvent was evaporated under reduced pressure and water added to the residue.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[F:32][C:33]([F:42])([F:41])[C:34]1[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=1.C([O-])([O-])=O.[K+].[K+]>[I-].[Na+]>[C:23]1([C:20]2[CH:21]=[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=2)[NH:16][CH:15]=[C:14]3[CH:11]2[CH2:12][CH2:13][N:8]([S:5]([CH2:4][CH2:3][CH2:2][O:40][C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:32])([F:41])[F:42])[CH:35]=3)(=[O:7])=[O:6])[CH2:9][CH2:10]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCOc4cccc(C(F)(F)F)c4)CC3)c[nH]c12
Yield: 49.1 %

Procedure:
Following the general procedure of example 159, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (40.0 mg, 0.087 mmol), 3-trifluoromethylphenol (162 mg, 0.87 mmol), K2CO3 (35.0 mg, 0.35 mmol) and sodium iodide (0.5 mg) were reacted to give the title compound (25.0 mg, 49%).
Reaction SMILES: C(C1C=CC([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:21]=[C:20]([OH:30])[CH:19]=2)=CC=1)C(C)C.[CH:31]([C:34]1[CH:41]=[CH:40][C:37](C=O)=[CH:36][CH:35]=1)([CH3:33])[CH3:32]>>[CH:31]([C:34]1[CH:41]=[CH:40][C:37]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]2[N:23]=[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:21]=[C:20]([OH:30])[CH:19]=2)=[CH:36][CH:35]=1)([CH3:33])[CH3:32]
Reactant: CC(C)Cc1ccc(-c2ccccc2Cc2cc(O)nc(-c3ccccc3)n2)cc1
Reactant: CC(C)c1ccc(C=O)cc1
Product: CC(C)c1ccc(-c2ccccc2Cc2cc(O)nc(-c3ccccc3)n2)cc1

Procedure:
Compound 6 was prepared using synthesis described for the Compound 5 using 4-isopropylbenzaldehyde in procedure 5. Purification was accomplished using column chromatography to provide the title compound as a solid (mp 106-108° C.). 1H-NMR (CDCl3) δ 8.15 (m, 2H); 7.45 (m, 3H); 7.3-7.1 (m, 9H); 6.3 (s, 1H); 5.4 (s, 1H); 2.9 (m, 1H); 1.2 (d, 6H). 13C-NMR (CDCl3) δ 171.0; 165.9; 156.6; 147.5; 141.5; 138.2; 132.1; 132.0; 129.5; 129.3; 128.9; 128.5; 128.0; 126.8; 126.6; 112.4; 58.5, 33.6; 23.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:19]=1)=[O:5])[CH3:2].[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[C:8]2[CH:13]=[N:12][C:11]([NH:39][C:36]3[CH:35]=[CH:34][C:33]([N:30]4[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]4)=[CH:38][CH:37]=3)=[N:10][C:9]=2[N:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C2CCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CC(C)O
Product: CCOC(=O)c1cn(C2CCCC2)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Temperature: 80 °C
Reaction time: 14 h
Yield: 34.6 %

Procedure:
8-Cyclopentyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (45 mg, 0.12 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (23 mg, 0.12 mmol) were combined in i-PrOH (1 mL) and heated to 80° C. After 14 h, the solution was concentrated and purified by preparative HPLC (30 mL/min 0-100% H2O/MeCN gradient over 10 min) to provide 19.8 mg of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. The ester was dissolved in MeOH (2 mL) and cooled to −78° C. in a high pressure vessel. Ammonia was bubbled into the solution for 1 min and the vessel was sealed and allowed to warm to rt. After 14 h, the solution was cooled to −78° C., the vessel was opened and the solution was allowed to warm to rt. The solution was concentrated to provide 5.4 mg of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide. 1H-NMR (400 MHz, CDCl3:) δ ppm 9.30 (s, 1H), 8.51 (s, 1H), 8.34 (s, 1H), 7.53 (d, 2H, J=8.9 Hz), 6.94 (d, 2H, J=9.0 Hz), 5.23-5.52 (m, 4H), 4.38 (q, 2H, J=7.1 Hz), 3.34-3.36 (m, 4H), 3.00-3.01 (m, 4H), 2.60 (s, 3H), 2.21-2.28 (m, 2H), 1.80-1.93 (m, 6H), 1.40 (t, 3H, J=7.1 Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H32N6O3: 476.25, found: (M+H) 477.3.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]2[N:10]=[C:11]([NH:13][C:14]3[C:15](=[O:30])[N:16]([CH3:29])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[CH:12]=[C:6]2[CH2:5]1)(=[O:3])[CH3:2].[C:31]([O:34][CH2:35][C:36]1[C:37]([N:45]2[CH2:57][CH2:56][N:48]3[C:49]4[CH2:50][CH2:51][CH2:52][CH2:53][C:54]=4[CH:55]=[C:47]3[C:46]2=[O:58])=[N:38][CH:39]=[CH:40][C:41]=1B(O)O)(=[O:33])[CH3:32].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:31]([O:34][CH2:35][C:36]1[C:37]([N:45]2[CH2:57][CH2:56][N:48]3[C:49]4[CH2:50][CH2:51][CH2:52][CH2:53][C:54]=4[CH:55]=[C:47]3[C:46]2=[O:58])=[N:38][CH:39]=[CH:40][C:41]=1[C:18]1[CH:19]=[C:14]([NH:13][C:11]2[CH:12]=[C:6]3[CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8][N:7]3[N:10]=2)[C:15](=[O:30])[N:16]([CH3:29])[CH:17]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)N1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C(C)=O)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 100 °C
Yield: 48 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 209d (185 mg, 0.50 mmol), (4-chloro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino-[1,2-a]indol-2(1H)-yl)pyridine-3-yl)methyl acetate 113h (192 mg, 0.50 mmol), Pd(dppf)Cl2 (41 mg, 0.050 mmol), sodium acetate (82 mg, 1.0 mmol,), K3PO4 (212 mg, 1.0 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 209e (150 mg, 48%) as a yellow solid. MS-ESI: [M+H]+ 625.4
Reaction SMILES: [CH3:1][C@:2]1([C:12]([OH:14])=[O:13])[CH2:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[C:3]1([CH3:11])[CH3:10].S(Cl)(Cl)=O.O.[OH-].[Na+].[CH3:22]O>>[CH3:22][O:8][C:7]([C@@H:4]1[CH2:5][CH2:6][C@:2]([CH3:1])([C:12]([OH:14])=[O:13])[C:3]1([CH3:10])[CH3:11])=[O:9]
Reactant: CC1(C)[C@H](C(=O)O)CC[C@]1(C)C(=O)O
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CC[C@](C)(C(=O)O)C1(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of (1S,3R)-1,2,2-trimethylcyclopentane-1,3-dicarboxylic acid (5.1 g, 25.5 mmol) in methanol (63.7 ml) at −78° C. was added thionyl chloride (2.045 ml, 28.0 mmol). After stirring at −78° C. for 30 minutes, the reaction was allowed to warm to room temperature. Stirring was continued for 14 hrs. The reaction mixture was concentrated under reduced pressure, yielding a yellow oil. The oil was taken into water. The solution was adjusted to pH 12 with 1.0 N NaOH and was washed with ethyl acetate. The basic aqueous layer was acidified with 1.0 N HCl, and was extracted with ethyl acetate (3×, 100 ml). The ethyl acetate extracts were combined, dried with sodium sulfate, filtered, and concentrated under reduced pressure to afford (1S,3R)-3-(methoxycarbonyl)-1,2,2-trimethylcyclopentanecarboxylic acid (5.35 g, 24.97 mmol, 98% yield) as a colorless oil. ESI-MS m/z 237.1 ([M+H]+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].N1C=CC=CC=1>>[C:16]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:18])[CH3:17]
Reactant: CN(CCCCCCO)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCCCCCN(C)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 210 g (1.01 mol) of N-(6-hydroxyhexyl)-N-methylaniline (Example 1), 112 g (1.10 mol) of acetic anhydride, and 86 g (1.1 mol) of pyridine was heated at reflux with stirring for 2 hours. After cooling, the solution was poured onto 500 g of ice and extracted with ethyl acetate (4×300 mL). The combined extracts were dried (MgSO4) and the solvent was removed at reduced pressure. The residue was distilled in vacuo, collecting the fraction boiling at 130° C. (0.01 mm). Yield: 231 g (93%) of a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[O:14]1CCOC[CH2:15]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([CH2:15][OH:14])=[CH:3][CH:4]=1
Reactant: C1COCCO1
Reactant: Clc1ccc(-c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Product: OCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a mixture of 4-chlorobiphenyl (23 mg, 0.12 mmol), 1,4-dioxane (2 ml) and water (200 μl) were added potassium acetoxymethyl trifluoroborate (44 mg, 0.24 mmol), palladium (II) acetate (14 mg, 0.061 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (50 mg, 0.12 mmol), and potassium phosphate (170 mg, 0.73 mmol) at room temperature. The reaction mixture was heated to reflux overnight under the nitrogen atmosphere. After the reaction mixture was cooled at room temperature, water and ethyl acetate were added to the mixture. After the organic layer was washed with an aqueous saturated sodium chloride solution, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (18 mg, 0.098 mmol, 80%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.O=S(Cl)Cl.[NH3:16]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]([NH2:16])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: Cc1ccnc(Cl)c1C(=O)O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1ccnc(Cl)c1C(N)=O
Temperature: 25 °C
Yield: 91 %

Procedure:
To a mixture of 2-chloro-4-methyl-3-pyridinecarboxylic acid (24.7 g, 157 mmol) and 75 mL of toluene at 70° C. was added 75 mL of SOCl2 (22.6 g, 190 mmol) within a period of 1 hour. The reaction mixture was refluxed for 4 hours and the resulting solution was cooled to room temperature. Dry NH3 gas was introduced at such a rate so as to maintain the internal temperature below 30° C. After removing toluene, the solid residue was washed successively with cold water and methanol, and dried to yield 22.72 g of the title compound (91%, m.p. 168°-170° C.).