Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9]([OH:10])=[CH:8][C:7]([C:11]([F:14])([F:13])[F:12])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH:22]([F:24])[F:23].O>CN(C)C=O>[C:1]([N:5]1[C:9]([O:10][CH:22]([F:24])[F:23])=[CH:8][C:7]([C:11]([F:13])([F:14])[F:12])=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(C(F)(F)F)cc1O
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)n1nc(C(F)(F)F)cc1OC(F)F
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of 10.4 g (50.0 mmol) of 1-tert-butyl-5-hydroxy-3-trifluoromethyl-1H-pyrazole in 50 ml of N,N-dimethylformamide was added 7.6 g (55.0 mmol) of anhydrous potassium carbonate at room temperature. While the reaction solution was stirred, an excess amount of chlorodifluoromethane was introduced into the reaction solution at 80° C. After the confirmation of disappearance of the starting material, the introduction of chlorodifluoromethane was stopped and the reaction solution was cooled to room temperature. Thereafter, the reaction solution was poured into water and extracted with diisopropyl ether. The resulting organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was distilled under reduced pressure to obtain 10.8 g (yield: 83.7%) of 1-tert-butyl-5-difluoromethoxy-3-trifluoromethyl-1H-pyrazole as a yellow liquid.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][CH2:21][C@@H:11]1[CH2:10][C@@H:9]([OH:8])[CH2:13][N:12]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:27]
Reactant: CCOC(=O)CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
To a stirred solution of tert-butyl (2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-ethoxy-3-oxopropyl)pyrrolidine-1-carboxylate (500 mg, 1.2 mmol, step 1 of Example 8) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 1.36 mL, 1.4 mmol) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 6 h. The mixture was diluted with ethyl acetate (100 mL), washed with water (20 mL), brine (20 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (2:1) to give 338 mg (95%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]=[O:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:30]1[CH:31]=[N:32][CH:33]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)[CH:35]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:28])[C:30]4[CH:31]=[N:32][CH:33]=[C:34]([C:36]5[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:44])([F:45])[F:43])[CH:37]=5)[CH:35]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: FC(F)(F)c1cccc(-c2cncc(Br)c2)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=O)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cncc(-c5cccc(C(F)(F)F)c5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 30, Step 1, using 1-[4′-(4-formyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(3-trifluoromethyl-phenyl)-pyridine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(Cc3ccccc3)c2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
To a solution of methyl indole-6-carboxylate (1.0 g) in N,N-dimethylformamide (10 mL), potassium carbonate (1.2 g) and benzyl chloride (1.4 g) were added at room temperature, and then the reaction mixture was stirred at 60° C. for 3 hours. After cooling to room temperature, the reaction mixture was quenched with water, and the mixture was extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (681 mg) as a colorless oil.
Reaction SMILES: [N:1]1([C:7](=[O:18])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[NH2:15][C:11]1[CH:10]=[C:9]([CH2:8][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:18])[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cc1cccc([N+](=O)[O-])c1)N1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CC(=O)N2CCOCC2)c1
Reaction time: 3 h
Yield: 96.6 %

Procedure:
To a stirred suspension of (3-nitro-phenyl)-acetic acid (2 g) in CH2Cl2 (40 ml, with a catalytic amount of DMF) at 0° C. under N2 was added oxalyl chloride (1.1 ml) drop wise. The reaction mixture was stirred for 40 min morpholine (2.5 g) was added. After stirring for 20 min, the reaction mixture was filtered. The filtrate was concentrated in vacuo to yield 1-morpholin-4-yl-2-(3-nitro-pheny)-ethanone as a solid (2 g). A mixture of 1-morpholin-4-yl-2-(3-nitro-pheny)-ethanone (2 g) and 10% Pd on activated carbon (0.2 g) in ethanol (30 ml) was hydrogenated at 30 psi for 3 h and filtered over Celite. Removal of the volatiles in vacuo provided 2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g). A solution of 2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g, 7.7 mmol) was dissolved in 6 N HCl (15 ml), cooled to 0° C., and vigorously stirred. Sodium nitrite (0.54 g) in water (8 ml) was added. After 30 min, tin (II) chloride dihydrate (10 g) in 6 N HCl (30 ml) was added. The reaction mixture was stirred at 0° C. for 3 h. The pH was adjusted to pH 14 with solid potassium hydroxide and extracted with EtOAc. The combined organic extracts were concentrated in vacuo provided 2-(3-hydrazin-phenyl)-1-morpholin-4-yl-ethanone (1.5 g). 2-(3-Hydrazinophenyl)-1-morpholin-4-yl-ethanone (3 g) and 4,4-dimethyl-3-oxopentanenitrile (1.9 g, 15 mmol) in ethanol (60 ml) and 6 N HCl (1 ml) were refluxed for 1 h and cooled to RT. The reaction mixture was neutralized by adding solid sodium hydrogen carbonate. The slurry was filtered and removal of the volatiles in vacuo provided a residue that was extracted with ethyl acetate. The volatiles were removed in vacuo to provide 2-[3-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)phenyl]-1-morpholinoethanone (4 g), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)[CH:9]=2)=[CH:6][C:5]([NH:31][C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:23][CH2:22][CH2:21][N:10]1[C:11](=[O:20])[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:13][C:8]([C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[C:5]([NH:31][C:32](=[O:43])[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[CH:6]=2)=[CH:9]1
Reactant: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)c(=O)n(CCNC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)c(=O)n(CCN)c1

Procedure:
A 0.1 M solution of tert-butyl (2-(2′-methyl-5-morpholino-6-oxo-5′-(3-(trifluoromethyl)benzamido)-[3,3′-bipyridin]-1(6H)-yl)ethyl)carbamate (1.00 equiv.) in 1:1 DCM:TFA was stirred for 15 min at ambient temperature. The reaction mixture was concentrated. The residue was basified with aqueous sodium carbonate and extracted with DCM. The combined extracts were dried over sodium sulfate, filtered, and concentrated to give crude N-(1′-(2-aminoethyl)-2-methyl-5′-morpholino-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide which was used without further purification. LCMS (m/z) (M+H)=502.2, Rt=0.58 min.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[CH:10]=[C:9]([CH:11]=C)[CH:8]=[CH:7][C:6]=1[NH:13][C:14]([C:16]1[C:17]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:15])=[O:4].O.I([O-])(=O)(=O)=[O:35].[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[CH3:32][N:2]([CH3:1])[C:3]([C:5]1[CH:10]=[C:9]([CH:11]=[O:35])[CH:8]=[CH:7][C:6]=1[NH:13][C:14]([C:16]1[C:17]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=2)=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:15])=[O:4]
Reactant: C=Cc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(=O)N(C)C)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C(=O)c1cc(C=O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
To a mixed solution of 4′-trifluoromethylbiphenyl-2-carboxylic acid (2-dimethylcarbamoyl-4-vinylphenyl)amide (774 mg) in acetone (10 mL)-water (10 mL) were added osmium tetroxide (10% (w/w) microcapsule; 449 mg) and sodium metaperiodate (944 mg). The mixture was stirred at room temperature for 4 hours and filtered through a Celite pad. The filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:2, v/v) to give the title compound (570 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([N:14]2[CH:23]([C:24]([O:26]C)=[O:25])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Li+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([N:14]2[CH:23]([C:24]([OH:26])=[O:25])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)(=[O:12])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C1Cc2ccccc2CN1S(=O)(=O)c1ccc(OC)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2Cc3ccccc3CC2C(=O)O)cc1OC
Reaction time: 8 h

Procedure:
A solution of N-(3,4-dimethoxybenzenesulphonyl)-3-methoxycarbonyl-1,2,3,4-tetrahydro-isoquinoline(0.5 g) in THF (30 ml) was treated with a saturated aqueous solution of lithium hydroxide (3 ml) at room temperature. After stirring overnight, the solvent was removed in vacuo. The residue was diluted with water (10 ml), washed with ethyl acetate (10 ml) and acidified with 2M hydrochloric acid. The aqueous phase was extracted with ethyl acetate (2×30 ml); these extracts were combined and dried (magnesium sulphate). Evaporation of the solvent in vacuo and recrystallization of the residue from ethyl acetate/hexane afforded the title compound as a whim solid (0.44 g).
Reaction SMILES: F[B-](F)(F)F.[N:6]1(OC(N(C)C)=[N+](C)C)[C:10]2C=CC=C[C:9]=2N=N1.[OH:23][C:24]([CH3:57])([CH3:56])[CH2:25][C@@:26]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:31][C:30](=[O:32])[N:29]([C@H:33]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:42]=[CH:43][C:44]([C:47]([OH:49])=O)=[N:45][CH:46]=3)=[CH:37][CH:36]=2)[CH3:34])[CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.C(N)C>CN(C)C=O>[CH2:10]([NH:6][C:47]([C:44]1[CH:43]=[CH:42][C:41]([C:38]2[CH:37]=[CH:36][C:35]([C@@H:33]([N:29]3[CH2:28][CH2:27][C@:26]([CH2:25][C:24]([OH:23])([CH3:56])[CH3:57])([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[O:31][C:30]3=[O:32])[CH3:34])=[CH:40][CH:39]=2)=[CH:46][N:45]=1)=[O:49])[CH3:9]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C[C@@H](c1ccc(-c2ccc(C(=O)O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: CCN
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (75 mg) was added to a solution of 5-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]ethyl}-phenyl)-pyridine-2-carboxylic acid (0.10 g) and diisopropylethylamine (50 μL) in dimethylformamide (1 mL) at room temperature. The resulting solution was stirred for 25 min, before ethylamine (70% in water, 50 μL) was added. The solution was stirred at room temperature overnight and then concentrated under reduced pressure. The crude product was purified by HPLC on reversed phase (MeCN/H2O) to afford the title compound as a foam-like solid. Yield: 25 mg (24% of theory). Mass spectrum (ESI+): m/z=502 [M+H]+
Reaction SMILES: [CH3:1][CH:2]1[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[C:6](=[O:12])[CH2:5][CH2:4][CH2:3]1.[CH3:13][Mg]I>>[CH3:13][C:6]1([OH:12])[CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[C:7]21[CH2:11][CH2:10][CH2:9][CH2:8]2
Reactant: C[Mg]I
Reactant: CC1CCCC(=O)C12CCCC2
Product: CC1CCCC(C)(O)C12CCCC2
Yield: 82 %

Procedure:
10-methyl-spiro[4.5]decan-6-one was alkylated by means of methyl-magnesium iodide under the reaction conditions commonly used in a Grignard reaction. 6,10-dimethyl-spiro[4.5]-decan-6-ol was thus obtained with an yield of 82 %.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH2:21][CH3:22].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH2:21][CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cc(-c2ccccc2)ccc1O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCc1cc(-c2ccccc2)ccc1OC(C)=O
Yield: 90 %

Procedure:
4.6 g (45 mmol) of acetic anhydride are added dropwise to a solution of 7.3 g (37 mmol) of 4-hydroxy-3-ethyl-biphenyl and 3.2 g (40 mmol) of pyridine in 60 ml of chloroform, and the mixture is boiled under reflux for 3 hours. The solution is allowed to cool and then washed with water and dilute hydrochloric acid and the organic phase is dried and concentrated. 8.0 g (yield: 90% of theory) of 4-acetoxy-3-ethyl-biphenyl are obtained as a very clear oil of log p=3.92 (pH=2.3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:31]1([N:41]=[C:42]=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:42]([NH:41][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)=[O:43])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Reactant: O=C=Nc1cccc2ccccc12
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)Nc4cccc5ccccc45)nc3n2)CC1
Yield: 70.5 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.378 g of 1-naphthyl isocyanate according to the general procedure of Example 37. Chromatography, eluting first with ethyl acetate:methyl alcohol:triethylamine (90:10:1) then switching to ethyl acetate:ethanol:triethylamine (9:2:1) gave 0.97 g of the title compound 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]-pyrimidin-7-yl}-3-naphthalen-1-yl-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=615 (Base), 446; mp 186.5-189° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:11][CH2:12][NH2:13].[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15]>O1CCCC1>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:3]=12
Reactant: Cc1c(CCN)[nH]c2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1c2n(c3ccccc13)C(=O)NCC2
Temperature: 100 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
To a solution of 2-(3-methylindol-2-yl)ethylamine 1.74 g) in tetrahydrofuran (200 ml) at room temperature was added 1,1'-carbonyldiimidazole (1.6 g) in small portions. After one hour of stirring, the reaction mixture was evaporated in vacuo. The residue was dissolved in toluene and the solution was evaporated in vacuo. The oil obtained was heated at 100° C. for 40 minutes and then cooled. Purification of the residue with silica gel column chromatography (chloroform) gave 3,4-dihydro-5-methylpyrimido[1,6-a]indol-1(2H)-one (0.8 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[S:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[S:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(O)=S)cc1
Solvent: c1ccccc1
Product: Cc1ccc(C(=S)Cl)cc1
Yield: 80 %

Procedure:
A mixture of 56 mmol (8.85 g) p-methylthiobenzoic acid, 40 ml benzene and 112 mmol (7.4 ml) thionyl chloride is boiled under reflux for 24 hours. The benzene and excess thionyl chloride are removed under vacuum to give p-methylthiobenzoyl chloride mp 48-52 in 80% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:5]2[N:6]=[C:7]([NH2:16])[CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:4]2[N:3]=1.[C:18]([C:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([CH3:22])[CH3:21])#[N:19].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[C:18]([C:20]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:16][C:7]2[CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:4]3[N:3]=[C:2]([CH3:1])[CH:17]=[C:5]3[N:6]=2)=[O:28])=[CH:30][CH:31]=1)([CH3:22])[CH3:21])#[N:19]
Reactant: Cc1cc2nc(N)cc(-c3ccccc3)n2n1
Reactant: CC(C)(C#N)c1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)C#N)cc3)cc(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
In a 50 ml pear flask was added 2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-amine (10A, 450 mg, 2.0 mmol) in pyridine (10 ml). To this mixture was added 4-(2-cyanopropan-2-yl)benzoyl chloride (550 mg, 2.6 mmol) and the mixture was stirred at room temperature for 2 h. Saturated NaHCO3 was then added and pyridine was removed in vacuo. The residue was partitioned between saturated NaHCO3 and ethyl acetate, and the aqueous layer was extracted one more time with ethyl acetate. Combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, 15-25% EtOAc/hexanes) to give the titled compound (380 mg, 48%). 1H NMR (DMSO-d6) δ: 11.35 (s, 1H), 8.10-8.16 (m, 2H), 8.04-8.09 (m, 2H), 7.96 (s, 1H), 7.67-7.73 (m, 2H), 7.60-7.66 (m, 3H), 6.41 (s, 1H), 2.41 (s, 3H), 1.74 (s, 6H); ESI-MS: m/z 396.3 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][CH3:16])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([CH3:26])[CH:20]=1>C(O)CO.O>[CH3:26][C:21]1[CH:20]=[C:19]([O:18][CH3:17])[CH:25]=[CH:24][C:22]=1[N:23]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH3:16])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: COc1cccc2c1=NC(=O)C1CCOC=21
Reactant: COc1ccc(N)c(C)c1
Solvent: O
Solvent: OCCO
Product: COc1ccc(N2CCc3c2c2cccc(OC)c2[nH]c3=O)c(C)c1
Temperature: 210 °C
Yield: 80.3 %

Procedure:
4-Oxo-6-methoxy-2,3-dihydrofuro[3,2-c]quinoline (217 mg, 1.0 mmol) was dissolved in 10 ml of ethylene glycol and 4-methoxy-2-methylaniline (322 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 210° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 270 mg of desired compound as solid in 81% of yield.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[NH4+]>N1C=CC=CC=1>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15]
Reactant: [N-]=[N+]=NCCOCCOCCOCCO
Agent: [NH4+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: NCCOCCOCCOCCO
Reaction time: 1 h

Procedure:
To a solution of Compound XXV (15.94 g; 72.7 mmole) in 100 ml of pyridine was added triphenylphosphine (29 g; 111 mmole). After stirring for one hour, at which time gas evolution had subsided, 50 ml of concentrated aqueous ammonium hydroxide was added and the mixture stirred overnight. The reaction mixture was concentrated under vacuum and the residue partitioned between 200 ml of water and 200 ml of ether (aqueous layer at pH 2). The aqueous layer was washed twice with 200 ml ether each time. The aqueous layer was adjusted to pH 11 with solid sodium hydroxide and extracted three times with 150 ml n-butanol each time. The butanol extract was dried over sodium sulfate, filtered and concentrated. The residue was taken up in tetrahydrofuran and filtered. The filtrate was evaporated to a syrup which was azeotroped with toluene.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12]2[N:15]=[CH:16][CH:17]=[N:18][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2-:19].[Na+]>CN(C)C1C=CC=CC=1>[NH2:19][C:16]1[CH:17]=[N:18][C:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][CH2:13][C:12]=2[N:15]=1
Reactant: c1ccc(CN2CCc3nccnc3CC2)cc1
Reactant: [NH2-]
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Product: Nc1cnc2c(n1)CCN(Cc1ccccc1)CC2
Temperature: 170 °C

Procedure:
2.4 gm (0.01 mol) of 7-benzyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine were dissolved in 20 ml of dimethylaniline, 3.9 gm (0.1 mol) of sodium amide were added, and the mixture was heated for four hours at 170° C. Thereafter, the dimethylaniline was distilled off in a high vacuum, the residue was taken up in 4 N sodium hydroxide, and the solution was extracted with chloroform. The chloroform extract solution was dried and column-chromatographically purified on silicagel with methanol/methylene chloride (3:1) as the mobile phase.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:7]=1[CH:8]=O.CCOCC>FC(F)(F)C(O)=O>[CH3:14][C:11]1[CH:12]=[CH:13][C:6]2[O:5][C:4]([CH:3]=[O:2])=[CH:8][C:7]=2[CH:10]=1
Reactant: COC(COc1ccc(C)cc1C=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cc1ccc2oc(C=O)cc2c1
Yield: 68.8 %

Procedure:
154 mg (0.69 mmol) of 2-(2,2-dimethoxy-ethoxy)-5-methyl-benzaldehyde were dissolved in trifluoroacetic acid and the reaction mixture was heated to reflux for 15 min. After cooling to RT ether was added and the mixture was washed with water and 10% aqueous KHCO3 solution. The organic layer was then dried (MgSO4) and concentrated and the residue was purified by column chromatography (silica gel; ethyl acetate/cyclohexane 4:1) to yield 76 mg (48%) of 5-methyl-benzofuran-2-carbaldehyde as brown oil. 1HNMR (CDCl3, 300 MHz): δ 2.47 (s, 3H), 7.34 (d, J=8.7 Hz, 1H), 7.50 (m, 3H), 9.85 (s, 1H).