Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[C:5]([CH3:7])=O.[CH3:19][N:20]1[C:24]([NH2:25])=[CH:23][C:22]([CH3:26])=[N:21]1>C(O)C>[CH3:1][O:2][C:3]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[C:23]2[C:22]([CH3:26])=[N:21][N:20]([CH3:19])[C:24]=2[NH:25][C:5]=1[CH3:7])=[O:18]
Reactant: Cc1cc(N)n(C)n1
Reactant: COC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(C)=O
Solvent: CCO
Product: COC(=O)C1=C(C)Nc2c(c(C)nn2C)C1c1ccccc1[N+](=O)[O-]

Procedure:
Methyl-2-(2-nitrobenzyliden)acetoacetate (10 g; 0.040 mol) is added to 1,3-dimethyl-5-pyrazolamine (4.89 g; 0.044 mol) in ethanol (40 ml) The mixture is refluxed for about 5 hours, then the solvent is evaporated under reduced pressure and the residue is taken up in ethyl ether and recovered by filtration. M.p. 216°-220° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:10][CH:9]=[N:8][CH:7]=1)CCC.[F:19][C:20]1[CH:27]=[CH:26][C:25](I)=[CH:24][C:21]=1[C:22]#[N:23].N#N>C1COCC1>[F:19][C:20]1[CH:27]=[CH:26][C:25]([C:6]2[S:10][CH:9]=[N:8][CH:7]=2)=[CH:24][C:21]=1[C:22]#[N:23]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: N#Cc1cc(I)ccc1F
Agent: N#N
Solvent: C1CCOC1
Product: N#Cc1cc(-c2cncs2)ccc1F
Temperature: 85 °C
Yield: 81.6 %

Procedure:
To 5-(tributylstannyl)thiazole (1.00 g, 2.7 mmol) in THF (10 mL) was added 2-fluoro-5-iodobenzonitrile (0.791 g, 3.2 mmol). The solution was degassed with N2 and bis(triphenylphosphine)palladium(II) chloride Pd(Ph)2Cl2 (0.187 g, 0.27 mmol) was added. The solution was further degassed for five minutes before heating to 85° C. for 2 h. Upon cooling, the reaction mixture was diluted with saturated NaHCO3 and washed with EA (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography (10% EA/Hexanes) to afford 0.450 g (82%) of 2-fluoro-5-(thiazol-5-yl)benzonitrile THZ INT-3 as a tan solid. LCMS-ESI (m/z) calculated for C10H5FN2S: 204.2; found 205.0 [M+H]+, tR=3.00 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1.CO.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[O-].[Na+]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]#[N:12])=[CH:2]1
Reactant: O=Cc1ccccc1
Reactant: N#CCc1c[nH]c2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N#CC(=Cc1ccccc1)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.4 %

Procedure:
2-(1H-Indol-3-yl)-3-phenylacrylonitrile was prepared by the addition of 3-indolylacetonitrile (2.02 g, 12.9 mmol), MeOH (18 mL), benzaldehyde (1.60 mL, 15.5 mmol), and a 25% wt solution of sodium methoxide in MeOH (3.2 mL, 14.2 mmol) to a 50 mL flask. The solution was allowed to stir at ambient temperature under N2 for 16 h. The reaction solution was diluted with DCM (20 mL), molecular sieves (250 mg) were added, and the solution was allowed to reflux for 1 hour. The reaction was quenched with the addition of sat. NH4Cl (20 mL). The organic phase was partitioned, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was chromatographed (SiO2, 100% hexane to 5% EtOAc) to yield 1.4 g (44% yield) of 2-1H-indol-3-yl-3-phenyl-acrylonitrile; 1H NMR (CDCl3) δ 8.42 (1H, br s), 7.97 (1H, d), 7.87 (2H, m), 7.63 (1H, s), 7.60 (1H, d), 7.37-7.48 (4H, m), 7.25-7.33 (2H, m); TLC (SiO2 plate, 5:1 hexane/EtOAc) Rf=0.35; MS (ESI): 245 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:29]2[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 81.9 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate (30 mg, 0.11 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 34 mg of the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 2.43 (s, 3H), 3.22-3.29 (m, 4H), 3.73-3.87 (m, 4H), 4.13 (s, 3H), 6.87-7.74 (m, 9H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[Li]CCCC.CCCCCC.[CH2:20]([C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][CH:31]2[CH2:33][O:32]2)=[CH:27][CH:26]=1)[CH2:21][CH2:22][CH2:23][CH3:24].Cl>CN(P(N(C)C)(N(C)C)=O)C>[OH:32][CH:31]([CH2:30][O:29][C:28]1[CH:27]=[CH:26][C:25]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:35][CH:34]=1)[CH2:33][C:6]#[C:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7]
Reactant: CCCCCc1ccc(OCC2CO2)cc1
Reactant: C#CCCCC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCc1ccc(OCC(O)CC#CCCCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a dry flask under N2 was placed 150 ml of HMPA (distilled over NaH) and 15.61 g (0.14 mole) of 5-hexynoic acid, the product of Example 1b, and the mixture cooled in an ice-water bath. A solution of 190 ml of n-BuLi in hexane (0.295 mole) was added dropwise into the flask with stirring. Stirring was continued for an additional 2 hr and 37 g of 2-(4-pentylphenoxymethyl)oxirane, the product of Example 7a, was added. After 2 days stirring, the resulting reaction mixture was poured into an ice water mixture and acidified with 3N HCl. The aqueous solution was extracted with Et2O three times. The organic layers were combined and then washed with aqueous 3N NH4OH. The NH4OH solution was acidified with 3N HCl and was extracted with Et2O. The ether solution was dried over MgSO4 and solvent removed to give an oil. The oil was purified by silical gel column chromatography (CHCl3 -MeOH) and then recrystallized in petroleum ether-EtOAc to give the title compound, mp 54°-57° C.
Reaction SMILES: [CH:1](=[N:8][C@@H:9]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:10]([O:12]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([NH2:33])(=[O:32])[CH:30]=[CH2:31].CC(C)([O-])C.[K+]>C1COCC1>[CH:1](=[N:8][C:9]1([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:20])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:31][CH2:30][C:29](=[O:32])[NH:33][C:10]1=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)N=Cc1ccccc1
Reactant: C=CC(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CCC(CCCCNC(=O)OCc2ccccc2)(N=Cc2ccccc2)C(=O)N1
Reaction time: 3.5 h
Yield: 82.1 %

Procedure:
To a solution of 2 (4 g, 10.4 mmol) and acrylamide (1.11 g, 15.7 mmol) in THF (40 mL) was added portionwise potassium tert-butoxide (1.23 g, 11.0 mmol) over a period of 15 min at 0° C. After 3.5 h, the mixture was quenched with aqueous NH4Cl and extracted into EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated to afford 3 (3.6 g, 82%) without further purification. Rf=0.33 (95:5 DCM:MeOH).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].F[B-](F)(F)F.[O:15]=[N+:16]=[O:17]>C(#N)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:16]([O-:17])=[O:15])[C:4]=1[OH:9])[CH3:2]
Reactant: CCc1ccccc1O
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CCc1cccc([N+](=O)[O-])c1O
Reaction time: 0.33 h
Yield: 59.8 %

Procedure:
A solution of 2-ethylphenol (2.44 g, 20 mmol) in 80 mL of anhydrous acetonitrile was treated with nitronium tetrafluoroborate (2.93 g, 22 mmols) in portions over a period of 5 minutes at −30° C. to −40° C. After 20 minutes, the mixture was quenched with ice, treated with cold water and extracted with three 100 mL portions of dichloromethane. The combined organic layers were washed with two 30 mL portions of water, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on SiO2 (20% ethyl acetate in hexanes) gave 2.0 g of 2-ethyl-6-nitrophenol as a yellow oil (60% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[O:23]C(=O)O[C:20]2=O)=[CH:15][CH:14]=1.C[O-].[Na+].CO>C1COCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:23])[C:20]2[N:6]=[C:4]([OH:5])[C:3]3[C:2](=[CH:10][C:9]([CH3:11])=[CH:8][CH:7]=3)[N:1]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(N)=O)c(N)c1
Reactant: O=C1OC(=O)C(c2ccc(F)cc2)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c(O)nc(C(O)c3ccc(F)cc3)nc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a solution of 2-amino-4-methylbenzamide (3 g, 20.0 mmol) in THF (40 mL) was added 5-(4-fluorophenyl)-1,3-dioxolane-2,4-dione from Example 16 (4.7 g, 24 mmol) and the solution was stirred for 2 h at 50° C. Sodium methoxide in MeOH (25%, 5.2 mL, 24 mmol) was then added and the solution was stirred at 50° C. overnight. The reaction mixture solution was concentrated, 2N HCl was added and the mixture was filtered. The collected solid was dried to give 2-((4-fluorophenyl)(hydroxy)methyl)-7-methylquinazolin-4-ol (5.14 g, 91%) which was used without further purification. LC-MS (ESI) m/z 285 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH:3]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH3:13])=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[N:37]#[C:38]Br.C(=O)(O)[O-].[Na+].[Cl-].[Na+].O>O1CCOCC1.O.O.O1CCOCC1>[CH3:31][C:2]([CH3:30])([CH3:1])[CH:3]([C:20]1[CH:21]=[CH:22][C:23]([C:24]2[O:25][C:38]([NH2:37])=[N:27][N:26]=2)=[CH:28][CH:29]=1)[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH3:13])=[CH:8][CH:9]=1
Reactant: CCC(Oc1ccc(C(c2ccc(C(=O)NN)cc2)C(C)(C)C)cc1)c1ccccn1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCC(Oc1ccc(C(c2ccc(-c3nnc(N)o3)cc2)C(C)(C)C)cc1)c1ccccn1
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
Crude 3d (40.0 mg, 0.0967 mmol) was suspended in dioxane/water (1.3 mL of a 3:1 mixture) and cooled to approximately 5° C. A solution of aqueous sodium bicarbonate (22.0 mg, 0.237 mmol) in water (150 μL) was added followed by a solution of cyanogen bromide (15.0 mg, 0.142 mmol) in dioxane (100 μL). After 5 min, the reaction mixture was warmed to ambient temperature and aged for approximately 1 h. The reaction mixture was poured into saturated aqueous sodium bicarbonate/brine (1:1) and extracted twice with DCM. The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (isocratic elution; 80% EtOAc/hexanes as eluent) afforded the title compound 3e. m/z (ES) 443 (M)+. 1HNMR (500 MHz, CDCl3): δ 1H NMR (500 MHz, CDCl3) δ 8.61 (t, 1H, J==2.6 Hz), 7.79 (d, 2H, J=8.8 Hz), 7.66 (m, 1H), 7.48 (d, 2H, J=8.7 Hz), 7.40 (d, 1H, J=7.7 Hz), 7.25 (d, 2H, J=8.7 Hz), 7.20 (m, 1H), 6.81 (d, 2H, J=8.7 Hz), 5.5-5.8 (bs, 2H), 5.18 (t, 1H, J=6.9 Hz), 3.67 (s, 1H), 2.0 (m, 2H), 1.05 (t, 3H, J=7.3 Hz), 1.0 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:15][C:14]([C:16]([O:18]CC)=[O:17])=[C:13]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:12]=2[C:29]#[N:30])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:15][C:14]([C:16]([OH:18])=[O:17])=[C:13]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[C:12]=2[C:29]#[N:30])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccnc(NC(C)=O)c2)c(C#N)c1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2sc(C(=O)O)c(Cc3ccc(Cl)cc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
To a solution of ethyl 5-[2-(acetylamino)pyridin-4-yl]-3-(4-chlorobenzyl)-4-cyanothiophene-2-carboxylate (0.080 g, 0.18 mmol) in tetrahydrofuran (1.28 mL) and water (0.85 mL) was added lithium hydroxide (1.0M solution in water, 0.236 mL, 0.236 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was acidified to pH 6 using aqueous 1N HCl (0.300 mL). The mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, and then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (0.058 g, 78%). LCMS: (FA) ES+, 412. 1H NMR (400 MHz, d6-DMSO) δ: 10.72 (s, 1H), 8.46-8.41 (m, 2H), 7.42-7.39 (m, 1H), 7.36-7.32 (m, 4H) 4.53 (s, 2H), 2.11 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)C>Cl>[Cl:14][C:9]1[CH:8]=[C:7]([NH:6][CH2:5][C:4]([OH:15])=[O:3])[CH:12]=[CH:11][C:10]=1[Cl:13]
Reactant: CCOC(=O)CNc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=C(O)CNc1ccc(Cl)c(Cl)c1
Yield: 100 %

Procedure:
The suspension of (3,4-dichloro-phenylamino)-acetic acid ethyl ester (0.38 g, 1.5 mmol) in 10% HCl (7 mL) was refluxed for 4 h. Water was removed under reduced pressure and the resulting solids were collected by filtration, washed with ether, and dried in vacuo to afford 0.33 g (84%) of the title compound as its hydrochloride salt. 1H-NMR (400 MHz, DMSO-d6) δ: 7.26 (d, 1H), 6.75 (d, 1H), 6.56 (d, 1H), 5.85 (brs, 2–3H), 3.83 (s, 2H).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1)(=O)=O.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][CH2:6][C:7]2[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=2)=[CH:20][CH:19]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1cccc(COS(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cccc(CNCc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.3 %

Procedure:
To a solution of methyl 6-((methylsulfonyloxy)methyl)picolinate (0.4 g, 1.63 mmol) in CH3CN (15 mL) were added 4-fluorobenzylamine (0.75 mL, 6.52 mmol) and Cs2CO3 (0.8 g, 2.45 mmol). The reaction mixture was stirred at rt for 4 h, filtered and the filtrate solution was concentrated in vacuo. The residue was purified by preparative HPLC. Fractions containing the desired product were combined and concentrated to give the desired compound (140 mg, 31%) as an oil. 1H NMR (CDCl3) δ 8.02 (d, J=8.0 Hz, 1H), 7.81 (t, J=8.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.35-7.31 (m, 2H), 7.04-6.99 (m, 2H), 4.02 (s, 2H), 3.99 (s, 3H), 3.82 (s, 2H). MS (ESI): 275.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:25]=1[NH2:26].Cl>C(O)(C)C>[F:23][C:24]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:25]=1[NH:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(N)c(F)c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(C)cc3F)ncnc2cc1OCC1CCN(C)CC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (200 mg, 0.622 mmol), (prepared as described for the starting material in Example 2c) and 2-fluoro-4-methylaniline (94 mg, 0.764 mmol) in isopropanol (5 ml) containing 6.2M hydrogen chloride in isopropanol (110 μl) was stirred at 80° C. for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with isopropanol, followed by ether and dried under vacuum. The solid was purified by column chromatography, eluting with methylene chloride/methanol (90/10) followed by 5% ammonia in methanol/methylene chloride (10/90). Evaporation of the fractions containing the expected product gave 4-(2-fluoro-4-methylanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (170 mg, 61%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:28]([O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:12][CH:11]=1)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOC(=O)C=Cc1ccc(O)cc1
Temperature: 25 °C
Yield: 21.3 %

Procedure:
4-Hydroxy cinnamic acid (10 g, 61 mmol) was combined with 1-hexadecanol (14.0 g, 58 mmol), p-toluenesulfonic acid (1.2 g, 6.3 mmol) and 100 ml toluene and heated to 140° C. for 24 h with continual removal of water using a Dean-Stark distillation apparatus. The mixture was cooled to room temperature and 50 ml ethyl acetate added. The solution was washed with water, 5% sodium hydrogen carbonate, brine and then dried over magnesium sulfate. The product was recrystallized from ethyl acetate to give 4.8 g 3-(4-hydroxy-phenyl)-acrylic acid hexadecyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][OH:19])[CH:12]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]>CC#N.O=[Mn]=O>[C:1]([O:5][C:6](=[O:20])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH:18]=[O:19])[CH:12]=1)[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(Cc1ccc(Cl)c(CO)c1)C(=O)OC(C)(C)C
Agent: O=[Mn]=O
Solvent: CC#N
Product: CCN(Cc1ccc(Cl)c(C=O)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.9 %

Procedure:
MnO2 (475 mg, 4.92 mmol) was added to a sol. of (4-chloro-3-hydroxymethyl-benzyl)-ethyl-carbamic acid tert-butyl ester (295 mg, 0.984 mmol) in CH3CN (20 mL). The mixture was stirred at rt for 5 h and MnO2 (475 mg, 0.984 mmol) was added again. The mixture was stirred for 1 h, and the mixture was filtered over Celite, and washed with CH3CN and CH2Cl2. Evaporation of the solvents under reduced pressure yielded the crude title compound (240 mg, 82%) that was used further without purification. LC-MS: tR=1.02 min.
Reaction SMILES: [CH2:1]([C:4]1[S:5][CH:6]=[C:7]([C:9](OCC)=[O:10])[N:8]=1)[CH2:2][CH3:3].[BH4-].[Na+]>C(O)C>[CH2:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][OH:10])[N:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(C(=O)OCC)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1nc(CO)cs1
Yield: 76 %

Procedure:
A mixture of the compound from step 27c (1.2 g (6 mmol) and NaBH4 (490 mg, 13 mmol) in 15 mL of ethanol was stirred at reflux for 16 hours, then cooled and quenched with water. The mixture was extracted with ether, and the ether extract was washed with water and brine and dried over MgSO4. The solvent was removed under vacuum to give 0.72 g (76% yield) of the title compound. MS: 156(M+H)+, 173(M+NH4)30 . NMR (CDCl3) ,δ:7.04 (t, J=0.5 Hz, 1H), 4.74 (dd, J=0.5, 6 Hz, 2H), 2.96 (t, J=8 Hz, 2H), 2.70 (t, J=6 Hz, 1H), 1.82 (sx, J=8 Hz, 2H), 1.03 (t, J=8 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Fc1cccc(CBr)c1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Product: Cc1nc(-c2ccn(Cc3cccc(F)c3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-bromomethyl-3-fluoro-benzene as described in Example 49 and isolated as white solid (0.068 mg, 49% yield). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.56 (d, J=4 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 7.42 (d, J=2 Hz, 1H), 7.26-7.35 (m, 2H), 6.99-7.06 (m, 2H), 6.93 (d, J=8 Hz, 1H), 6.86 (d, J=2 Hz, 1H), 6.05-6.13 (m, 1H), 5.35 (s, 2H), 4.63 (d, J=8 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=408.2; Rt=1.25 min; HRMS (M+H)+=408.13.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: O=C(C=Cc1ccccc1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared by heating a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and benzaldehyde (64 ul, 0.633 mmol) similar to Example 1 and isolated as a yellow solid (7.2 mg, 2.8%). 1H NMR (CDCl3): 7.70 (d, J=16.2 Hz, 1H), 7.62-7.59 (m, 2H), 7.45 (d, J=15.9 Hz, 1H), 7.41 (t, J=3.2 Hz, 3H), 7.29 (d, J=3.3 Hz, 1H), 7.13 (dd, J=3.3, 9.3 Hz, 1H), 6.96 (d, J=9.0 Hz, 1H), 4.45-4.34 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:14]4([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH2:13][N:12](CC4C=CC(OC)=CC=4)[C:11](=[O:38])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:44]1[S:45][CH:46]=[CH:47][N:48]=1)CCC>>[S:45]1[CH:46]=[CH:47][N:48]=[C:44]1[C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:14]4([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:13][NH:12][C:11](=[O:38])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)c3[nH]c(-c4ccnc(Cl)n4)cc3C2=O)cc1
Product: O=C1NCC2(CCNCC2)c2[nH]c(-c3ccnc(-c4nccs4)n3)cc21

Procedure:
The title compound was prepared following the general procedure reported for Example 9—1 using A5 and 2-(tributylstannyl)thiazole, purified by semi-preparative HPLC (Method A) and was isolated as TFA-salt. 1H NMR (400 MHz, DMSO-D6, 300K): δ=1.90 (2H, d, J=14.1 Hz), 2.27 (2H, dt, J1=4.3 Hz, J2=14.4 Hz), 3.12 (2H, q, J=11.7 Hz), 3.30 (2H, s), 3.52 (2H, d, J=2.3), 7.36 (1H, d, J=1.9 Hz), 7.44 (1H, br s), 7.92 (1H, d, J=5.5 Hz), 8.01 (1H, d, J=3.1 Hz), 8.10 (1H, d, J=3.1 Hz), 8.26 (1H, br d, J=10.2 Hz), 8.78 (1H, br d, J=9.4 Hz), 8.83 (1H, d, J=5.5 Hz), 11.84 (1H, s); MS (ES) C18H18N6OS requires: 366. found: 367.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:18][C:19]1[CH:24]=[C:23]([CH:25]=[O:26])[CH:22]=[CH:21][C:20]=1B(O)O>>[CH:25]([C:23]1[CH:22]=[CH:21][C:20]([C:2]2[CH:17]=[CH:16][CH:15]=[C:4]([CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=2)=[C:19]([CH3:18])[CH:24]=1)=[O:26]
Reactant: CN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Reactant: Cc1cc(C=O)ccc1B(O)O
Product: Cc1cc(C=O)ccc1-c1cccc(CN(C)C(=O)OC(C)(C)C)c1

Procedure:
In a manner similar to that of Example 1(e), by reacting 6.1 g (20.3 mmol) of tert-butyl (3-bromo benzyl)-N-methylcarbamate with 4.3 g (26.2 mmol) of 2-methyl-4-formylbenzene boronic acid, and after purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (8/2), 4 g (58%) of the expected product are obtained in the form of an orange oil.