Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11]C(=O)OCC2C=CC=CC=2)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[H][H]>[Pd].C(O)C>[NH2:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][N:9]=1
Reactant: CCCCc1ccc(NC(=O)OCc2ccccc2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCc1ccc(N)nc1
Yield: 99.6 %

Procedure:
A mixture of benzyl (5-n-butyl-2-pyridyl)carbamate (6.5 g. 22.86 mmoles) and 10% palladium on carbon (2.7 g.) in ethanol (400 ml.) was shaken at room temperature for 2 hours in an atmosphere of hydrogen at an initial pressure of 3.52 kg./cm.2The mixture was filtered and the filtrate reduced to dryness to leave 2-amino-5-n-butylpyridine (3.42 g., 99.7%), m.p. 30°-33° (lit. m.p. 35°-36° in Helv. Chim. Acta, 39, 505 (1956).
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17](N)=[O:18])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl.C(O)(=[O:23])C>>[N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:18])=[O:23])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(=O)O
Reactant: NC(=O)Cc1ccc(-c2cn3ccccc3n2)cc1
Agent: Cl
Product: O=C(O)Cc1ccc(-c2cn3ccccc3n2)cc1

Procedure:
A mixture of 1 g of 4-(imidazo[1,2-a]pyridin-2-yl)phenylacetamide, 5 ml of glacial acetic acid and 5 ml of concentrated hydrochloric acid is heated under reflux for 1 hour. The solvent is distilled off under reduced pressure, and water is added to the residue. The mixture is alkalified with 10% sodium hydroxide, and then filtered. The filtrate is adjusted to pH 6 by addition of 10% hydrochloric acid. The crystalline precipitate is filtered off and washed with water to give 0.8 g of 4-(imidazo[1,2-a]pyridin-2-yl)phenylacetic acid as colorless crystals melting at 220°-222°C with decomposition.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][CH2:11][C@H:12]2[CH2:16][C@H:15]([O:17]S(C)(=O)=O)[CH2:14][O:13]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:24][C:25]1[CH:34]=[C:33](O)[C:32]([Cl:36])=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][C:30]2=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:24][C:25]1[CH:34]=[C:33]([O:17][C@H:15]2[CH2:14][O:13][C@@H:12]([CH2:11][O:10][C:8](=[O:9])[C:7]3[CH:22]=[CH:23][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:16]2)[C:32]([Cl:36])=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][C:30]2=[O:37]
Reactant: CS(=O)(=O)O[C@@H]1CO[C@@H](COC(=O)c2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C1NCCc2c(Cl)cc(O)c(Cl)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OC[C@H]1C[C@@H](Oc2cc(Cl)c3c(c2Cl)C(=O)NCC3)CO1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
A solution of ((2R,4S)-4-((methylsulfonyl)oxy)tetrahydrofuran-2-yl)methyl 4-nitrobenzoate (296m, 300 mg, 0.869 mmol), 5,8-dichloro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (296 g, 222 mg, 0.956 mmol), and cesium carbonate (566 mg, 1.74 mmol) in N,N-dimethylformamide (8 mL) was heated to 100° C. for three hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water (2×50 mL) and brine (50 mL), dried over sodium sulfate, concentrated to dryness, and purified by silica gel chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane) to give 2,5-anhydro-3-deoxy-4-O-(5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-O-(4-nitrobenzoyl)-L-threo-pentitol (296n, 128 mg, 31% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.18-8.33 (m, 4H), 7.03 (s, 1H), 6.09 (br. s., 1H), 4.99 (td, J=4.28, 1.96 Hz, 1H), 4.56-4.62 (m, 2H), 4.42-4.52 (m, 1H), 4.27 (d, J=10.64 Hz, 1H), 4.02 (dd, J=10.58, 4.34 Hz, 1H), 3.48 (td, J=6.36, 3.91 Hz, 2H), 2.99-3.09 (m, 2H), 2.56 (ddd, J=14.24, 8.19, 6.42 Hz, 1H), 2.18 (dd, J=14.12, 5.07 Hz, 1H). MS: 481 [M+1]
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11]C)=[O:9])=[C:6]([C:13]([O:15][CH2:16]C)=[O:14])[C:5]([N+:18]([O-:20])=[O:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1.C[O-].[Na+].[C:30](O)(=[O:32])C>CO>[CH3:11][O:10][C:8]([C:7]1[C:2]([O:32][CH3:30])=[N:3][C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:5]([N+:18]([O-:20])=[O:19])[C:6]=1[C:13]([O:15][CH3:16])=[O:14])=[O:9]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(OC)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 25 ml of methanol was dissolved 1.2 g of 2-chloro-3,4-diethoxycarbonyl-5-nitro-6-phenylpyridine as obtained in Reference Example 18. To the solution was added 6.34 ml (2.0 eq.) of a solution of 1N sodium methoxide in methanol, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with 0.2 ml (1.1 eq.) of acetic acid, and the solvent was distilled off. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (eluent:ethyl acetate). The resulting crystals were collected by filtration with hexane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:16]=[C:17]([O:22][CH3:23])[CH:18]=[CH:19][C:20]=1Br)[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([O:28][CH3:29])(=[O:27])[CH:25]=[CH2:26].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:16]=[C:17]([O:22][CH3:23])[CH:18]=[CH:19][C:20]=1[CH:26]=[CH:25][C:24]([O:28][CH3:29])=[O:27])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OC
Reactant: COc1ccc(Br)c(CN(CC(F)(F)F)C(=O)OC(C)(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C=Cc1ccc(OC)cc1CN(CC(F)(F)F)C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
A solution of 3-[N-(tert-butoxycarbonyl)-N-(2,2,2-trifluoroethyl)aminomethyl]-4-bromoanisole (48.19 g, 121 mmol), methyl acrylate (55 mL, 605 mmol), palladium acetate (1.36 g, 6.1 mmol), tri-o-tolylphosphine (3.69 g, 12 mol), and diisopropylethylamine (49 mL, 278 mmol) in acetonitrile (200 mL) was deoxygenated (3×evacuation/argon purge cycles), then was heated to reflux under argon in oil bath set at 80° C. After 6 hr additional palladium acetate (1.36 g, 6.1 mmol) and tri-o-tolylphosphine (3.69 g, 12 mmol) were added and the reaction was stirred under reflux for an additional 18 h. The reaction was concentrated to dryness, and the residue was taken up in 1:1 Et2O/petroleum ether (300 mL) and allowed to stand for 4 h. A gray-colored precipitate was filtered off and washed with a small volume of 1:1 Et2O/petroleum ether(˜100 mL). The orangish-red filtrate was concentrated and purified by flash chromatography on silica gel (15% ethyl acetate/hexanes). The resulting residue was taken up in hexane, and the mixture was allowed to stand for 2 hr, then was filtered to remove a yellow precipitate. Concentration of the filtrate left the title compound (45.85 g, 94%) as a yellow oil: TLC (20% EtOAc/hexane) Rf 0.50; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J=16 Hz, 1H), 7.57 (d, J=9 Hz, 1H), 6.86 (dd, 1H), 6.74 and 6.72 (2s, 1H), 6.26 (d, J=16 Hz, 1H), 4.74 and 4.70 (2s, 2H), 3.83 (s, 3H), 3.79 (s, 3H), 3.80 and 3.66 (2m, 2H), 1.51 and 1.45 (2s, 9H).
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:19]3[C:14]([C:15](=[O:28])[NH:16][C:17]([C:20]4[CH:21]=C([CH:25]=[CH:26][CH:27]=4)C#N)=[N:18]3)=[C:13]([CH2:29][CH3:30])[N:12]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C([O:35][C:36](=[O:38])[CH3:37])C>Cl>[C:1]([C@@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[N:19]3[C:14]([C:15](=[O:28])[NH:16][C:17]([C:20]4[CH:21]=[C:37]([CH:25]=[CH:26][CH:27]=4)[C:36]([OH:35])=[O:38])=[N:18]3)=[C:13]([CH2:29][CH3:30])[N:12]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc([C@H]2CC[C@@H](C(C)(C)C)CC2)n2nc(-c3cccc(C#N)c3)[nH]c(=O)c12
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1nc([C@H]2CC[C@@H](C(C)(C)C)CC2)n2nc(-c3cccc(C(=O)O)c3)[nH]c(=O)c12
Temperature: 95 °C
Reaction time: 3 h

Procedure:
108 mg (0.27 mmol) cis-3-[7-(4-tert-butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl]benzonitrile (Example 40A) are dissolved in concentrated hydrochloric acid, and the reaction mixture is stirred at 95° C. for three hours. Sodium hydroxide (10% aqueous solution) (until a pH of 6–7 is achieved) and ethylacetate are added. The organic phase is dried over sodium sulfate and evaporated to dryness in vacuo. The product is purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[NH:7][CH:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N(CC)CC)C.C(Cl)(Cl)Cl.Cl[C:35]([O:37][CH3:38])=[O:36]>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]([C:35]([O:37][CH3:38])=[O:36])[CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C1=C(Cl)NC(C)N=C1c1cccc([N+](=O)[O-])c1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(Cl)N=C(C)N(C(=O)OC)C1c1cccc([N+](=O)[O-])c1

Procedure:
To a solution of 6-chloro-5-ethoxycarbonyl-2-methyl-4-(3'-nitrophenyl)-dihydropyrimidine (0.5 g, 1.54 millimole) and triethylamine (1.6 g, 16 millimole) in 20 ml of chloroform 1.46 g (15.4 millimole) of methyl chloroformate was added dropwise with stirring in ice and the mixture was stirred at room temperature for 3 hours. The reaction solution was washed with 2% aqueous NaOH solution and then water, dried and evaporated to obtain 0.5 g of the title product as oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6]2.CC1(C)COB([C:30]2[CH:31]=[C:32]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=2)[C:33]([O:35][CH3:36])=[O:34])OC1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>C1COCC1>[CH2:15]([O:14][C:13]([NH:12][C@@H:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][C:30]3[CH:31]=[C:32]([CH:37]=[C:38]([C:40]([F:41])([F:43])[F:42])[CH:39]=3)[C:33]([O:35][CH3:36])=[O:34])[CH:4]=2)[CH2:8]1)=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(N[C@H]1Cc2ccc(CCl)cc2C1)OCc1ccccc1
Reactant: COC(=O)c1cc(B2OCC(C)(C)CO2)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1cc(Cc2ccc3c(c2)C[C@@H](NC(=O)OCc2ccccc2)C3)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 75.8 %

Procedure:
To (S)-benzyl 5-(chloromethyl)-2,3-dihydro-1H-inden-2-ylcarbamate (7.09 mmol, 2.24 g) in THF (44.9 mL) was added methyl 3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-(trifluoromethyl)benzoate (7.09 mmol, 2.242 g), Bromo(N-succinimidyl)bis-(triphenylphosphine)palladium(II) (0.355 mmol, 0.287 g) and sodium carbonate (45.0 mmol, 22.5 mL). The reaction was heated to 80° C. for 4 hrs. DCM was added before washing with water (×1) followed by brine (×1). The organics were dried over MgSO4 before removing the solvent in vacuo. The crude material was purified by silica chromatography (5:1>2:1, hep EtOAc). The solvent was removed to give the title compound as a white solid (2.6 g, 76%). MS (ESI): m/z [M+H]+ 484.2
Reaction SMILES: [N:1]1([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41][CH2:40][CH2:39][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([O:30]C(C1C=CC=CC=1)=O)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]>[Pd].C(O)C.CO>[N:1]1([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41][CH2:40][CH2:39][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(=O)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 95 %

Procedure:
A mixture of palladium on carbon (10%, 4.0 g.) in ethanol (20 ml.) was added to a solution of BocPro-DTrp-PheOBz (70.44 mmole.) in methanol (100 ml.). The mixture was diluted to 200 ml. with methanol, hydrogenated under pressure for three hours and filtered. The filtrate was stripped of volatiles. After unsuccessful attempts to crystallize the residue from ether-hexane and methanol-water it was twice dissolved in, and stripped of, chloroform and dried under high vacuum, affording BocPro-DTrp-PheOH in 95% yield as a foam (36.6 g.).
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH3:4].C([O-])(O)=O.[Na+].Cl.[NH2:12][NH:13][C:14]([NH2:16])=[O:15]>O.C1COCC1>[N:12](=[C:3]([CH3:4])[CH2:2][Cl:1])[NH:13][C:14]([NH2:16])=[O:15]
Reactant: NNC(N)=O
Reactant: CC(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(CCl)=NNC(N)=O

Procedure:
Add 1.0 gm chloroacetone and a solution of 0.84 gm NaHCO3 in 10 ml water to a solution of 1.1 gm semicarbazide hydrochloride in 25 ml THF and stir overnight. Two layers form. Separate the top layer and concentrate to obtain an off-white solid, 2-semicarbazono-1-chloropropane.
Reaction SMILES: CC(O)=O.[NH2:5][C@H:6]([CH3:9])[CH2:7][OH:8].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH3-]C#N.[Na+]>CO>[CH2:10]([NH:5][C@H:6]([CH3:9])[CH2:7][OH:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@@H](N)CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H](CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.1 %

Procedure:
Glacial HOAc (1.5 mL) was added dropwise at room temperature to a well stirred solution of (R)-(+)-2-amino-1-propanol (10.0 g, 133 mmol) and benzaldehyde (13.5 mL, 133 mmol) in CH3OH (260 mL). The reaction mixture was stirred at room temperature for 1.5 h followed by addition of NaCNBH3 (12.6 g, 200 mmol) and the reaction stirred at room temperature overnight. The reaction was concentrated under reduced pressure and the recovered solids dissolved in EtOAc (500 mL) and then washed with saturated bicarbonate (2×250 mL), H2O (250 mL) and saturated brine (250 mL). The organic phase was then dried over Na2SO4, filtered and concentrated to yield (R)-2-(benzylamino)propan-1-ol (19.8 g, 94%) as a colorless oil: MS consistent.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[C:4]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1.P(Cl)(Cl)([Cl:22])=O.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:22][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][C:4]=2[O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(F)cc(OC3CCOCC3)c12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Temperature: 80 °C

Procedure:
A first portion (0.25 g) of 7-fluoro-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one was added to a stirred mixture of phosphoryl chloride (1.76 ml), diisopropylethylamine (3.95 ml) and acetonitrile (10 ml) that had been heated to 80° C. The resultant mixture was heated to 80° C. for 3 hours. A second portion (0.25 g) of 7-fluoro-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one was added and the mixture was heated to reflux for a further 90 minutes. There was thus obtained a solution of 4-chloro-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline which was used without being isolated. A solution of 6-chloro-2,3-methylenedioxyaniline (0.32 g) in acetonitrile (3 ml) was added and the reaction mixture was heated to 80° C. for 2.5 hours. As the required conversion was incomplete, the reaction mixture was evaporated and toluene (15 ml) was added as reaction solvent. A second portion of 6-chloro-2,3-methylenedioxyaniline (0.32 g) was added and the reaction mixture was heated to reflux for 3 hours. The reaction mixture was cooled to ambient temperature and partitioned between methylene chloride and an aqueous sodium chloride solution. The organic phase was washed with water, dried over magnesium sulphate and evaporated. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline as a foam (0.73 g); NMR Spectrum: (DMSOd6) 1.9-2.05 (m, 2H), 2.1-2.2 (m, 2H), 3.5-3.6 (m, 2H), 3.8-3.95 (m, 2H), 5.1 (m, 1H), 6.1 (s, 2H), 7.0 (d, 1H), 7.1 (d, 1H), 7.3 (d, 1H), 7.4 (m, 1H), 8.6 (s, 1H), 9.3 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH:24]=[CH:25][CH2:26][O:27][CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:28][O:27][CH2:26][CH:25]=[CH:24][C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:29]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=CCOC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCC=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
The product (220) and KOH (1.0 g, 18 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 3 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. After the filtration, the obtained brown solid is purified by HPLC to give pure product (221) as white solid (200 mg, 62%).
Reaction SMILES: C(O)(=O)C.[CH:5](N)=[NH:6].[NH2:8][N:9]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:23])[CH:17]=2)[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:10]1>C(O)CCC>[NH2:15][C:14]1[C:13]2=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:23])[CH:17]=3)[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:10][N:9]2[N:8]=[CH:5][N:6]=1
Reactant: N=CN
Reactant: CCOC(=O)c1cn(N)c(C#N)c1-c1ccc(N)c(F)c1
Solvent: CC(=O)O
Solvent: CCCCO
Product: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(N)c(F)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
Formamidine acetate (22.4 g, 215 mmol) was added to a suspension of ethyl 1-amino-4-(4-amino-3-fluorophenyl)-5-cyano-1H-pyrrole-3-carboxylate (6.2 g, 21.5 mmol) in n-butanol (100 mL). The reaction was heated (100° C.) for 16 h and then cooled to rt. The solvent was removed under reduced pressure and then ethanol (50 mL) and water (200 mL) were added. The mixture was stirred for 30 min and the resulting precipitate was collected by filtration. The solid was washed with water (2×50 mL) and dried to afford desired product (5.80 g, 85%); 1H NMR (300 MHz, DMSO-d6) δ 8.08 (s, 1H), 8.00-8.10 (br s, 1H), 7.90 (s, 1H), 7.03 (dd, J=12.3, 1.9 Hz, 1H), 6.77-6.88 (m, 2H), 5.36 (s, 2H), 5.21-5.31 (br s, 1H), 4.06 (q, J=7.1 Hz, 2H), 1.11 (t, J=7.1 Hz, 3H); ES-MS m/z 316.4 (MH)+; HPLC RT (Method B) 2.39 min.
Reaction SMILES: [OH:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:14]C.Cl>B(Br)(Br)Br.ClCCl>[OH:14][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:10]([F:11])([F:12])[F:13])[C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: COc1cc(C=O)cc(C(F)(F)F)c1O
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution containing 2.2 g of 4-hydroxy-3-methoxy-5-trifluoromethylbenzaldehyde in 65 ml of 1 molar BBr3 in dichloromethane was stirred for 2 h at room temperature. Hydrochloric acid was added and the organic phase was separated. The solvent was evaporated in vacuo. Yield 1.4 g (68%), m.p. 188°-192° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]([CH3:10])[CH:8]=[N:9][C:5]=2[CH:4]=1.C([Li])(C)(C)C.C1C(=O)N([I:25])C(=O)C1>C1COCC1>[I:25][C:8]1[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc2c(c1)ncn2C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)nc(I)n2C
Temperature: -78 °C
Reaction time: 1 h
Yield: 24.8 %

Procedure:
In an oven dried nitrogen purged 3 neck 50 mL round bottom flask, 0.500 g (1.75 mmol) of 5-methoxy-1-methylbenzimidazole in 10 mL of dry THF is cooled to −78° C. 2.47 mL (4.20 mmol) of 1.7 M t-butyllithium in hexanes is added and the reaction mixture is stirred at −78° C. for 1 h. 0.472 g (2.1 mmol) of NIS in 10 mL of dry tetrahydrofuran is added. Reaction is removed from bath and stirred at room temperature for 1 hour, quenched with saturated aqueous solution of ammonium chloride, and diluted with dichloromethane. The layers are separated, the aqueous is extracted 3×50 mL dichloromethane, dried (MgSO4), and concentrated. The crude mixture is purified by chromatography using hexanes:ethyl acetate as a solvent system. The product containing fractions are combined to obtain 0.125 g of the title compound, 25% yield. MS, ES+=289.0 (M+1); 1H NMR (DMSO-d6) δ 7.439-7.417 (d, 1H); 7.147-7.141 (m, 1H); 6.771-6.743 (m, 1H); 3.794 (s, 3H); 3.707 (s, 3H) ppm.
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH2:13][CH3:14])(=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19](S(C)(=O)=O)[N:18]=1.O>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]([O:12][CH2:13][CH3:14])=[O:11])[N:18]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CCOC(=O)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccccc1Oc1nc(OC)cc(OC)n1
Temperature: 100 °C
Yield: 85.6 %

Procedure:
After washing with petroleum ether, 3.9 grams (0.079 mole) of 60% sodium hydride in mineral oil was suspended in 15 mL of dimethylformamide. The suspension was cooled, and a solution of 10.8 grams (0.065 mole) of ethyl salicylate in 20 mL of dimethylformamide was added dropwise with stirring. Upon completion of addition, the reaction mixture was stirred at ambient temperature for one hour, and then 10.5 grams (0.048 mole) of 4,6-dimethoxy-2-methylsulfonylpyrimidine (prepared as in Example 1, Steps A-C) was added. Upon completion of addition, the reaction mixture was heated at 100° C. for 2.5 hours. The reaction mixture was cooled and poured into 250 mL of water. The mixture was extracted with ethyl acetate, and the extract was dried with magnesium sulfate. The mixture was filtered, and the filtrate was subjected to column chromatography on silica gel. Elution was accomplished using in succession 25% hexane in methylene chloride and 30% ethyl acetate in hexane. The appropriate fractions were combined and concentrated under reduced pressure to yield 12.5 grams of ethyl 2-(4,6-dimethoxypyrimidin-2-yloxy)benzoate. The nmr spectrum was consistent with the proposed structure.