Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:17][C:15]=1[NH2:16].[H-].[Na+].Cl>CN1CCCC1=O>[Cl:13][C:14]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]2)(=[O:22])=[O:23])=[CH:17][C:15]=1[NH:16][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cncnc1Cl
Reactant: Nc1cc(S(=O)(=O)N2CCCc3ccccc32)ccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cncnc1Nc1cc(S(=O)(=O)N2CCCc3ccccc32)ccc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
A mixture of ethyl 4-chloropyrimidine-5-carboxylate (0.4 g), 2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)aniline (0.69 g) and sodium hydride (55%, 98 mg) in 1-methyl-2-pyrrolidone (8 mL) was stirred at 100° C. for 2 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1−2/1) to give ethyl 4-[2-chloro-5-(3,4-dihydroquinolin-1(2H)-yl sulfonyl)phenylamino]pyrimidine-5-carboxylate (0.42 g). To this material were added ethanol (8 mL), tetrahydrofuran (2 mL) and 5 mol/L aqueous sodium hydroxide solution (1.77 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was acidified by adding 1 mol/L hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were washed with water, and dried under reduced pressure to give 4-[2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenylamino]pyrimidine-5-carboxylic acid (0.37 g). The obtained 4-[2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenylamino]pyrimidine-5-carboxylic acid (0.1 g) was dissolved in 1,4-dioxane (2 mL). To the solution were added triethylamine (0.094 mL) and diphenylphosphoryl azide (0.058 mL), and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2−ethyl acetate) to give the title compound (80 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(COC1C=CC=CC=1O)(O)=O.[O-]CCCC.[K+]>CC(N(C)C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CCCC[O-]
Agent: O=C(O)COc1ccccc1O
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccccc1

Procedure:
4-nitro-fluorobenzene and 2-(carboxymethoxy)phenol were reacted together in DMA in the presence of potassium butoxide for 2 hours at 150° C. to yield 4-(2-carboxymethoxy)-phenoxy)nitrobenzene.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[CH3:9][S:10][S:11](C)(=O)=O>O.C(O)C>[CH3:9][S:10][S:11][N:2]([CH3:1])[C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5]
Reactant: CN[C@@H](CS)C(=O)O
Reactant: CSS(C)(=O)=O
Solvent: CCO
Solvent: O
Product: CSSN(C)[C@@H](CS)C(=O)O
Reaction time: 2 h
Yield: 60 %

Procedure:
A solution of N-methylcysteine (7a) (Undhein, K., & Eidem, A., 23 Acta Chem. Scandinavica 3129-3133 (1970)) (1.5 g, 11.1 mmol) in H2O (20 mL) was stirred at room temperature, under an atmosphere of argon, and treated with a solution of methyl methanethiol sulfonate (3.0 mL, 29.2 mmol) in ethanol (10 mL). The reaction mixture was stirred at this temperature for two hours and then diluted with H2O (100 mL) and washed with ether (4×40 mL). The aqueous layer was acidified to pH 2 and passed through an Amberlite IRA 93 (—OH form) column. The column was washed with water and the effluent was collected and evaporated to dryness under reduced pressure to give a white solid (1.2 g, 60%), mp 194-195° C. 1H NMR (D2O, TMS ext. standard): δ2.2(3H,s), 2.5(3H,s), 3.2(2H,d), 3.7(1H,q).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH:12]=[CH2:13])=[N:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH2:12][CH2:13][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:9][C:8]=2[CH:14]=1)([O-:3])=[O:2]
Reactant: C=Cc1nc2cc([N+](=O)[O-])ccc2o1
Reactant: C1CCNC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc2oc(CCN3CCCC3)nc2c1

Procedure:
A solution of 1 g (5.25 mmol) of 5-nitro-2-vinylbenzoxazole and 0.66 mL (8 mmol) of pyrrolidine in 8 mL of ethanol is stirred for 2 hours at ambient temperature. Then the reaction solution is evaporated down. The purification is carried out by column chromatography on silica gel (eluant: dichloromethane/ethanol/ammonia (20:1:0.1)). Yield: 0.74 g (53.9% of theory); C13H15N3O3 (M=261.28); calc.: molecular ion peak (M+H)+: 262; found: molecular ion peak (M+H)+: 262; Rf value: 0.2 (silica gel, dichloromethane/ethanol/ammonia (20:1:0.1)).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:17][C:16](=[O:32])[CH2:15]2)[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:40][O:41][CH3:42].O>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:14]2[C:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:18]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:17][C:16](=[O:32])[CH2:15]2)[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[O:10][CH2:40][O:41][CH3:42])[CH3:2]
Reactant: CCOc1cc(C2CC(=O)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1cc(C2CC(=O)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1OCOC
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a mixture of 4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyridin-2(1H)-one (Compound 1, see Example 1) (200 mg, 0.47 mmol) and potassium carbonate (130 mg, 0.93 mmol) in DMF (5 mL) was added chloro(methoxy)methane (75 mg, 0.93 mmol) at 25° C. and then the mixture was stirred at the same temperature for 2 hours. The mixture was poured into water and a standard aqueous/EtOAc workup was followed to give product (200 mg, 98%).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[CH3:12][O:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[C:29]4[CH2:30][CH2:31][CH2:32][CH2:33][C:28]=4[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:35])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]4[O:11][CH2:1][O:2][C:3]=4[CH:4]=3)[C:24]3[C:29]4[CH2:30][CH2:31][CH2:32][CH2:33][C:28]=4[S:27][C:25]=3[N:26]=2)=[CH:19][CH:20]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c4c(sc3n2)CCCC4)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc4c(c3)OCO4)c3c4c(sc3n2)CCCC4)cc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxy-benzylamine is reacted with 4-(4-chloro-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxybenzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester, m.p. 198° C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:24])[C@@H:10]([CH3:23])[O:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14](Cl)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH:41]2[CH2:43][CH2:42]2)(=[N:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[O:33])=[CH:28][CH:27]=1.Cl>C(#N)C.O1CCOCC1>[CH2:1]([O:8][C@H:9]([CH3:24])[C@H:10]([O:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([S:32]([CH:41]3[CH2:43][CH2:42]3)(=[N:34][C:35](=[O:40])[C:36]([F:39])([F:37])[F:38])=[O:33])=[CH:30][CH:31]=2)[N:13]=1)[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Cl)ncc1C(F)(F)F
Reactant: Nc1ccc(S(=O)(=NC(=O)C(F)(F)F)C2CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Nc2ccc(S(=O)(=NC(=O)C(F)(F)F)C3CC3)cc2)ncc1C(F)(F)F
Temperature: 80 °C
Reaction time: 5 h
Yield: 56 %

Procedure:
4-((1R,2R)-2-benzyloxy-1-methylpropoxy)-2-chloro-5-trifluoromethylpyrimidine and (RS)—S-(4-aminophenyl)-S-cyclopropyl-N-(trifluoroacetyl)sulphoximide in acetonitrile were admixed with a 4N solution of hydrogen chloride in dioxane and stirred for 5 hours at 80° C. After cooling, the mixture was diluted with acetic ester and washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated by evaporation. The resulting residue was purified by means of chromatography (hexane/acetic ester 4:1) (yield: 56%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32]([CH3:43])([CH3:42])[CH2:33][O:34][Si](C(C)(C)C)(C)C)=[C:27]([C:44]([F:47])([F:46])[F:45])[CH:26]=3)=[O:23])=[CH:17][C:16]=2[F:48])=[C:11]([O:49][CH2:50][CH3:51])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32]([CH3:43])([CH3:42])[CH2:33][OH:34])=[C:27]([C:44]([F:45])([F:47])[F:46])[CH:26]=3)=[O:23])=[CH:17][C:16]=2[F:48])=[C:11]([O:49][CH2:50][CH3:51])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(OCc2ccccc2)ncc1-c1ccc(CC(=O)Nc2ccc(CC(C)(C)CO[Si](C)(C)C(C)(C)C)c(C(F)(F)F)c2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(OCc2ccccc2)ncc1-c1ccc(CC(=O)Nc2ccc(CC(C)(C)CO)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a mixture of 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (4.5 g, 4.83 mmol) in DCM (30 mL) was added TFA (4.46 mL, 57.9 mmol). The mixture was stirred at 25° C. for 2 h. Then the reaction residue was concentrated, added to MeCN (50 mL), made basic with NH4OH and concentrated. The crude material was purified by silica column chromatography (PE/EA=1:1). All fractions found to contain product by TLC (PE/EA=1:1, Rf=0.6) were combined and concentrated to yield a light yellow solid of 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (4.2 g, 4.19 mmol, 87% yield): 1H NMR (400 MHz, CD3OD) δ 7.97 (s, 1H), 7.88 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.51-7.43 (m, 3H), 7.38 (t, J=7.2 Hz, 2H), 7.35-7.29 (m, 2H), 7.26-7.16 (m, 2H), 6.50 (s, 1H), 5.38 (s, 2H), 4.14-4.11 (m, 2H), 3.77 (s, 2H), 2.80 (s, 2H), 2.03 (s, 2H), 1.32 (t, J=6.8 Hz, 3H), 0.86 (s, 6H); ES-LCMS m/z 611.2 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[N:7][C:2]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cnc(Br)c(Cl)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1cnc(-c2ccccc2)c(Cl)c1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 67.9 %

Procedure:
To a solution of 6-bromo-5-chloropyridin-3-ol (Preparation 239, 100 mg, 0.48 mmol), and phenylboronic acid (117 mg, 0.96 mmol) in 1,4-dioxane (5 mL) under nitrogen was added 2M aqueous Na2CO3 solution (1 mL) and palladium tetrakistriphenylphosphine (28 mg, 0.024 mmol). The mixture was stirred at 80° C. for 3.5 hours. The reaction mixture was allowed to cool to room temperature and partitioned between water and EtOAc. The desired product was in the aqueous phase (pH ˜11). The organic phase was washed with 10 wt % aqueous NaOH solution (2×15 mL). The combined aqueous phases were neutralised with 1N aqueous citric acid solution and extracted with EtOAc (4×30 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product. The crude product was purified by silica gel chromatography eluting with 0-30% EtOAc in heptane to give the title compound (67 mg, 68%) as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[N:17]=[C:16]([CH:18]([OH:20])[CH3:19])[CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]1[N:17]=[C:16]([C:18](=[O:20])[CH3:19])[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(C(C)O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cccc(C)n1
Temperature: -75 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To a −75° C. solution of oxalyl chloride (20 mL, 225 mmol, 1.1 equiv) in methylene chloride (300 mL) was slowly added a solution of dimethylsulfoxide (32 mL, 2.2 equiv) in methylene chloride (400 mL) over 1 hour. The resulting solution was stirred at −75° C. for 10 min, and then slowly treated with a solution of 1-(6-methyl-pyridin-2-yl)-ethanol of Step A (28 g, 204 mmol, 1 equiv) in methylene chloride (600 mL). The reaction mixture was stirred for 10 min at the same temperature, and then slowly treated with triethylamine (140 mL, 1.02 mol, 5 equiv). The resulting mixture was warmed to 20° over 2 hours, and then quenched with water (500 mL). The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo to yield the crude material. Silica gel chromatography (3:1 hexanes/ethyl acetate) yielded the title compound (25.36 g, 92%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:1]([OH:2])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(O)c2cnccc2-c2cccc(C#N)c2)cc1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (30 mg, 0.15 mmol) in THF (1.5 mL) at −78° C. was added 2.0 M 4-tert-butylphenylmagnesium bromide in THF (0.15 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[(4-tert-butyl-phenyl)-hydroxy-methyl]-pyridin-4-yl}-benzonitrile as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][C:12]([NH2:14])=[O:13])[N:3]=1.[NH3:15]>O>[NH2:15][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][C:12]([NH2:14])=[O:13])[N:3]=1
Reactant: N
Reactant: NC(=O)CCCSc1cccc(Br)n1
Solvent: O
Product: NC(=O)CCCSc1cccc(N)n1

Procedure:
A mixture of 4-(2-bromopyrid-6-ylthio)butyramide (5 g.) and concentrated aqueous ammonia (25 ml.) was heated in a sealed tube at 180° for 24 hours. The mixture was cooled and diluted with water, and then extracted twice with EtOAc. The combined extracts were extracted twice with N aqueous HCl and the aqueous acid extracts were combined, basified with 10N aqueous NaOH, and extracted with EtOAc. The EtOAc extract was dried and evaporated to dryness to give 4-(2-aminopyrid-6-ylthio)butyramide.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[C:33](B(O)O)=[C:32]([O:37][CH3:38])[CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[C:23]([C:33]3[C:32]([O:37][CH3:38])=[CH:31][CH:30]=[CH:29][C:28]=3[F:27])[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(Cl)ncn1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COc1cccc(F)c1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cccc(F)c1-c1cc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)ncn1
Temperature: 110 °C
Yield: 5.4 %

Procedure:
To the stirred mixture of 4-(6-chloro-pyrimidin-4-ylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (VIII) (0.75 g, 2 mmol) and 6-fluoro-2-methoxy-phenyl boronic acid (0.37 g, 2.2 mmol) in saturated sodium carbonate solution (4 ml) and 1,4-dioxane (4 ml) was added palladium(II) acetate (0.09 g, 0.4 mmol) followed by triphenylphosphine (0.105 g, 0.00 mmol) at room temperature under an atmosphere of nitrogen. The resulting mixture was heated to reflux at 110° C. for one hour and the reaction monitored by TLC. The reaction mixture was filtered through a celite bed and the filtrate was extracted with ethyl acetate (3×100 ml). The organic layers were separated, combined, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by preparative HPLC (C-18, AcN:H2O with 0.05% TFA) to afford 4-[6-(2-fluoro-6-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XXIII) (0.05 g, 4%).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.I[C:28]1[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[CH:41][C:29]=1[C:30]([NH:32][CH2:33]/[CH:34]=[CH:35]\[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:31]>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:46][O:45][C:43]1[CH:44]=[C:28]2[C:29](=[CH:41][C:42]=1[O:47][CH3:48])[C:30](=[O:31])[NH:32][CH2:33]/[C:34]/2=[CH:35]\[C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCOC(=O)/C=C\CNC(=O)c1cc(OC)c(OC)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)/C=C1\CNC(=O)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A stirred solution of Pd(OAc)2 (16 mg, 0.07 mmol), PPh3 (61 mg, 0.23 mmol), Et3N (0.58 mL, 4.2 mmol) and (Z)-ethyl 4-(2-iodo-4,5-dimethoxybenzamido)but-2-enoate (860 mg, 2.1 mmol) in dry CH3CN (20 mL) was heated at 70° C. overnight under an argon atmosphere. The reaction was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by flash chromatography using DCM/MeOH 100:1 (v:v) as eluent to give (Z)-ethyl 2-(6,7-dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetate (510 mg, 83%). LC-MS (ES-API); rt 7.56 min; m/z calculated for C15H17NO5 [M+H]+ 292.1, found 292.1.
Reaction SMILES: [CH2:1]([C:3]([NH2:8])([CH2:6][CH3:7])[C:4]#[CH:5])[CH3:2].[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([F:23])[C:18]=1[O:19][CH2:20][C:21]#[CH:22])[C:13](Cl)=[O:14]>>[CH2:4]([C:3]([NH:8][C:13](=[O:14])[C:12]1[CH:16]=[C:17]([F:23])[C:18]([O:19][CH2:20][C:21]#[CH:22])=[C:10]([F:9])[CH:11]=1)([CH2:6][CH3:7])[C:1]#[CH:2])[CH3:5]
Reactant: C#CC(N)(CC)CC
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1F
Product: C#CCOc1c(F)cc(C(=O)NC(C#C)(CC)CC)cc1F

Procedure:
According to the same method as that of Production Example 1, 1,1-diethyl-2-propynylamine was used in place of 2,2-dimethylpropylamine, 3,5-difluoro-4-(2-propynyloxy)benzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-(1,1-diethyl-2-propynyl)-3,5-difluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 52 of the present invention) represented by the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[C:10]([O:15][CH2:16][CH2:17][CH3:18])(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=1)[CH2:17][CH3:18]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCCOC(=O)C(C)=O
Product: CCCOC(=O)[C@H](C)Nc1cc(Cl)cc(Cl)c1

Procedure:
Following General Procedure AA above and using 3,5-dichloroaniline (Aldrich) and n-propyl pyruvate (which can be prepared by following General Procedure AO above using n-propanol in place of iso-butanol), the title compound could be prepared.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:16])([F:15])[C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1)[N:21]=[CH:20][N:19]=[C:18]2[CH:9]1[C:8]2[C:12](=[CH:13][C:5]([C:4]([F:3])([F:15])[F:16])=[CH:6][CH:7]=2)[NH:11][C:10]1=[O:14]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: O=C1Cc2ccc(C(F)(F)F)cc2N1
Agent: [H-]
Agent: [Na+]
Product: COc1cc2c(C3C(=O)Nc4cc(C(F)(F)F)ccc43)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.6 %

Procedure:
Sodium hydride (53 mg, 1.33 mmol) was added to a solution of 6-trifluoromethyloxindole (200 mg, 0.995 mmol), (prepared as described for the starting material in Example 49), in dry, degassed DMF and the suspension stirred for 15 minutes at ambient temperature. A solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (111 mg, 0.332 mmol), (prepared as described for the starting material in Example 5), in a dry, degassed mixture of DMF (5 ml) and THF (2 ml) was added dropwise and the reaction mixture was heated at 60° C. for 3 hours. The mixture was allowed to cool, the DMF was removed by evaporation, 1M hydrochloric acid was added until the aqueous phase was pH8 and ethyl acetate was added to dissolve the resulting precipitate. The organic phase was separated and the aqueous phase re-extracted with ethyl acetate (50 ml×3). The ethyl acetate fractions were combined, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash column chromatography eluting with methylene chloride/methanol (10/1). The purified product was triturated with boiling ether and collected by filtration to give 6-methoxy-7-(3-morpholinopropoxy)-4-(6-trifluoromethyloxindol-3-yl)quinazoline (51 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][CH3:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:17]1([CH2:23][CH2:24][C:25]([NH:27][CH2:28][C:29]([OH:31])=O)=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:15]([CH3:16])[C:29]([CH2:28][NH:27][C:25](=[O:26])[CH2:24][CH2:23][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:31])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CNC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)CNC(=O)CCc1ccccc1
Product: CN(C(=O)CNC(=O)CCc1ccccc1)C(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.1 from rac-[(4-chloro-phenyl)-phenyl-methyl]-methylamine (CA [118762-04-2]) and (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]).