Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([CH3:14])[N:5]=[C:4]([NH2:15])[CH:3]=1.[Cl:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:18]=1[C:19]([N:21]=[C:22]=[O:23])=[O:20]>C(OCC)(=O)C>[Cl:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:18]=1[C:19]([NH:21][C:22]([NH:15][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([CH3:14])[N:5]=1)=[O:23])=[O:20]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Cc1cc(N)nc(C)c1-c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)NC(=O)c2c(Cl)cccc2Cl)nc(C)c1-c1ccccc1

Procedure:
4,6-Dimethyl-5-phenyl-2-pyridylamine (500 mg) and 2,6-dichlorobenzoyl isocyanate (650 mg) were reacted in 25 ml ethyl acetate. A precipitate formed which was filtered, dried, and identified by NMR analysis as the desired product, m.p. 230°-235° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[Cl:31])[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[Cl:31])=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCC(=O)C(Cc1ccc(F)cc1Cl)C(=O)OC
Solvent: C1COCCO1
Solvent: O
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(F)cc1Cl
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (1.1 g), 2-(2-chloro-4-fluorobenzyl)-3-oxopentanoic acid methyl ester (2.4 g), polyphosphoric acid (5 g) and dioxane (10 mL) was heated at 130° C. for 17 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the solid washed with diethyl ether and dried to afford title compound, 1.5 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:24]1[N:25]([CH2:32][C@:33]2([CH3:36])[CH2:35][O:34]2)[CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[N:28]=1>CN(C=O)C>[CH3:35][C@@:33]1([CH2:36][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]3)=[CH:4][CH:3]=2)[O:34][C:24]2=[N:28][C:27]([N+:29]([O-:31])=[O:30])=[CH:26][N:25]2[CH2:32]1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 48.4 %

Procedure:
Tert-butyl 4-(4-hydroxyphenyl)piperidine-1-carboxylate (1.07 g, 3.86 mmol) was dissolved in DMF (10 ml). To the solution, sodium hydride (185 mg, 4.63 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 80° C. To the solution, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (923 mg, 4.24 mmol) was added with cooling on ice-bath, and the solution was stirred for further 20 minutes at 80° C. To the reaction mixture, ice-water was added, and the solution was stirred vigorously. The precipitates were filtered off, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and then crystallized from ethyl acetate-diisopropyl ether to afford tert-butyl (R)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]piperidine-1-carboxylate (857 mg, yield 48%) as a white powder.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:21][C:22](=[O:35])[C:23]2[CH:34]=[CH:33][CH:32]=[C:25]([C:26](N(OC)C)=[O:27])[CH:24]=2)[CH2:9][N:10]([CH3:20])[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][Mg]Cl>C1COCC1>[CH:1]1([CH2:7][C@H:8]([NH:21][C:22](=[O:35])[C:23]2[CH:34]=[CH:33][CH:32]=[C:25]([C:26](=[O:27])[CH2:41][CH2:40][CH2:39][CH2:38][O:37][CH3:36])[CH:24]=2)[CH2:9][N:10]([CH3:20])[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:17])[CH3:18])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CON(C)C(=O)c1cccc(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)c1
Reactant: COCCCC[Mg]Cl
Solvent: C1CCOC1
Product: COCCCCC(=O)c1cccc(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)c1
Reaction time: 2 h

Procedure:
To a solution of (S)—N1-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)-N3-methoxy-N3-methylisophthalamide (0.7361 g, 1.46 mmol, 1.0 equiv) in THF (15 mL) was added 1.45 M 4-methoxybutylmagnesium chloride in THF (4 mL, 5.8 mmol, 4.0 equiv) at 0° C. under N2. After 2 h, the reaction mixture was quenched with 1 N aq HCl (15 mL) and extracted EtOAc (3×). The combined EtOAc extracts were dried over Na2SO4 and concentrated to afford crude (S)—N-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)-ethoxycarbonyl)amino)propan-2-yl)-3-(5-methoxypentanoyl)benzamide (0.758 g), which was used in the next step without further purification. LC-MS (3 min) tR=2.34 min, m/z 555 (M+Na+), 534, 505.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](F)=[C:5]([CH:19]=[C:20]([F:23])[C:21]=1[F:22])[C:6]([C:8](=[CH:14][NH:15][CH:16]1[CH2:18][CH2:17]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7].[H-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[C:5]2[C:4]=1[N:15]([CH:16]1[CH2:18][CH2:17]1)[CH:14]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]2=[O:7]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(OC)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2CC2)c2c(OC)c(F)c(F)cc2c1=O
Temperature: 50 °C
Reaction time: 12 h
Yield: 74.8 %

Procedure:
To a solution of ethyl 2-(3-methoxy-2,4,5-trifluorobenzoyl)-3-cyclopropylaminoacrylate (440 mg, 1.29 mmol) in anhydrous tetrahydrofuran (15 mL) at 0° C. was added sodium hydride (62 mg, 1.5 mmol, 1.1 equiv, 60% in mineral oil). The reaction mixture was allowed to stir at 50° C. for 12 hours. The mixture was cooled to room temperature and filtered. The mother liquor was concentrated and a white precipitate formed. The material was collected by suction filtration and air-dried to give 312 mg, 75% yield of a pure white solid, m.p. 178°-181° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-])=O>[Pd].C(OCC)(=O)C>[NH2:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1cc(O)ccc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(O)ccc1F
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A mixture of 4-fluoro-3-nitrophenol (2.70 g, 17.2 mmol) and palladium on charcoal (10%, 0.31 g) in 60 mL ethyl acetate is hydrogenated under 50 psi of H2 using a Parr hydrogenation reactor. After shaking for 1 hour, the reaction mixture is filtered using a diatomaceous earth pad to remove catalyst. The filtrate is concentrated in vacuo, and the residue is sublimed to yield 2.18 g (100%) of Compound 24 as a white solid. MP: 142-144° C. 1H-NMR (d6-DMSO) 8.82 (s, 1H); 6.70 (dd, 1H); 6.17 (dd, 1H); 5.85 (m, 1H); 4.92 (s, 2H). 19F-NMR (d6-DMSO) 142.78 (t, J=13.0 Hz). Anal. calc. for C6H6FNO: C, 56.69; H, 4.76; N, 11.02. Found: C, 57.28; H, 4.86; N, 10.65.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][CH:9]=1)=[O:3].[BH4-].[Na+]>CO>[CH3:1][CH:2]([C:4]1[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][CH:9]=1)[OH:3]
Reactant: CC(=O)c1cnc(-c2ccccc2)nc1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cnc(-c2ccccc2)nc1-c1ccccc1

Procedure:
To a mixture of 41.1 g (0.15 mole) of 2,4 -diphenyl-5-pyrimidyl metyl ketone in 500 ml methanol stirred at 5°-10° was added over 20 minutes 11.4 g (0.30 mole) sodium borohydride. The resulting solution was stirred at 5°-10° for 30 minutes and then stirred at ambient temperatures for 2 hours. The solvents were removed in vacuo and the residue was partitioned between 500 ml CHCl3 and 500 ml water. The aqueous layer was extracted with two 500 ml portions of CHCl3. The combined CHCl3 extracts were washed with 250 ml water, dried (MgSO4), and concentrated to dryness in vacuo.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[N:16][CH:15]=[CH:14]3)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:22]C1C=CC=C(C(OO)=O)C=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[Cl:22][C:17]1[C:18]2[C:13](=[CH:12][C:11]([NH:10][S:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:21])=[CH:6][CH:5]=3)(=[O:8])=[O:9])=[CH:20][CH:19]=2)[CH:14]=[CH:15][N:16]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc3cnccc3c2)cc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Nc2ccc3c(Cl)nccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
In chloroform (100 ml) was dissolved 3.0 g of 6-(4-toluenesulfonylamino)isoquinoline (Preparation Example 21), and m-chloroperbenzoic acid (2.57 g) was added thereto under ice-cooling, followed by stirring at room temperature overnight. The solvent was evaporated, and the resulting crystals were washed with diethyl ether, collected by filtration and dried, to give pale yellow crystals. The obtained crystals were suspended in chloroform (83 ml), and phosphorus oxychloride (19 ml) was added thereto, followed by heating under reflux for 5 hours. After cooling, the solvent was evaporated, and the residue was basified with an aquesou sodium bicarbonate in an ice-bath, followed by extracting with ethyl acetate, The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by silica gel column, to give crude crystals of the title compound (1.630 g, 49.40%). The crude crysatals were recrystallized from ethanol, to give the title compound as colorless crystals.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[CH2:5]([C:8]1[N:9]([CH2:21][CH2:22][CH2:23][CH:24]=O)[C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:20]=1)[CH2:6][CH3:7].[OH-].[Na+]>C(O)C.O>[CH3:3][O:2][N:4]=[CH:24][CH2:23][CH2:22][CH2:21][N:9]1[C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:20]=[C:8]1[CH2:5][CH2:6][CH3:7]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC=O
Reactant: CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1nc2cnc3ccccc3c2n1CCCC=NOC
Temperature: 0 °C
Reaction time: 72 h
Yield: 105.3 %

Procedure:
Methoxylamine hydrochloride (3.37 g, 40.3 mmol) was added to a stirred solution of 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde (10.0 g, 35.5 mmol) in ethanol (100 mL) cooled to 0° C., followed by addition of 50% sodium hydroxide solution (12.5 M, 3.2 mL, 40 mmol) in water (7 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 3 days. The reaction mixture was then concentrated under reduce pressure and diluted with dichloromethane (150 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (50 mL). The combined organics were dried over potassium carbonate, filtered and concentrated to afford 11.6 g of 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-butyraldehyde O-methyloxime as a reddish oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[N:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:4]2[C:5]3[C:10](=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=3)[C:2]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)=[N:3]2)=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:16]=1
Reactant: O=Cc1ccc2c(c1)c(Br)nn2Cc1ccc(Cl)cc1C(F)(F)F
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccc2c(c1)c(-c1ccc(F)cc1)nn2Cc1ccc(Cl)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 3-bromo-1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazole-5-carbaldehyde (0.311 mmol from Example 407), 4-fluorophenylboronic acid (0.498 mmol), Pd(dppf)Cl2 dichloromethane complex (0.0311 mmol) and sodium carbonate (0.933 mmol) in DME/H2O (4 mL; 4:1) under argon was stirred at 100° C. for 6 h, then concentrated. The residue was purified by chromatography (silica gel, hexanes to hexanes:EtOAc, 1:1) to afford 1-(4-chloro-2-trifluoromethylbenzyl)-3-(4-fluorophenyl)-1H-indazole-5-carbaldehyde as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28]Cl)=[O:26])=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:32].[Na+]>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][I:32])=[O:26])=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCc1ccc(C(=O)OCCl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCc1ccc(C(=O)OCI)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chloromethyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethyl)benzoate (0.5 g, 1.11 mmole). In dry acetone (10 ml) was added sodium iodide (0.75 g, 5.0 mmole) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl actate/water. The organic phase was washed with a 5% sodium thiosulfate solution, dried with sodium sulfate and evaporated under reduced pressure. Yield: 0.53 g=88%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16](Cl)[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>O1CCOCC1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([Br:22])=[CH:24][CH:25]=3)[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1
Reactant: Nc1ccc(Br)cc1
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(c2ncnc(Nc3ccc(Br)cc3)c2[N+](=O)[O-])CC1

Procedure:
[6-chloro-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester (415 mg, 1.32 mmol) and 4-bromoaniline (309 mg, 1.80 mmol) were dissolved in anhydrous 1,4-dioxane (0.5-1 ml) and irradiated in a sealed microwave reaction tube at 250° C. for 300 seconds. The reaction mixture was passed through a silica plug [SiO2; EtOAc/hexane; 20:80]. Yield 0.070 g, 12%. Yellow solid. 1H NMR 400 MHz CDCl3 δ(ppm): 9.98 (s, 1H); 8.03 (s, 1H); 7.41 (m, 2H); 7.17 (m, 2H); 4.09 (m, 2H); 3.83 (m, 2H); 3.16 (m, 2H); 2.77 (m, 1H); 1.97 (m, 2H); 1.78 (m, 2H); 1.20 (m, 3H). LCMS (ESI) m/z 451, 452 (M+H+, 100%)
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:18]([C:22]1[NH:23][C:24]2[C:29]([C:30](=[O:32])[N:31]=1)=[CH:28][C:27]([CH:33]=[O:34])=[CH:26][CH:25]=2)[CH2:19][CH2:20][CH3:21]>O1CCCC1>[CH2:18]([C:22]1[NH:23][C:24]2[C:29]([C:30](=[O:32])[N:31]=1)=[CH:28][C:27]([CH:33]([OH:34])[CH:4]1[CH2:5][CH2:6][N:2]([CH3:1])[C:3]1=[O:7])=[CH:26][CH:25]=2)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Reactant: CN1CCCC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(C(O)C3CCN(C)C3=O)ccc2[nH]1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.834 ml of 1-methyl-2-pyrrolidinone in 10 ml of tetrahydrofuran is added dropwise with stirring 8.69 ml of lithium bis(trimethylsilyl)amide (1.0M in tetrahydrofuran) at -78° C. Following complete addition, 500 mg of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde is rapidly added and the reactants stirred at -78° C. for 4 1/2 hours. The reaction mixture is quenched with 10 ml of saturated ammonium chloride and allowed to warm to room temperature followed by evaporation of the volatiles in vacuo to a residue. The residue is diluted with 5 ml of water and extracted with ethyl acetate. The extract is washed with water, brine and dried with anhydrous Na2SO4.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C(N(C(C)C)CC)(C)C.[N+:20]([C:23]1[C:24]([C:28](Cl)=[O:29])=[N:25][NH:26][CH:27]=1)([O-:22])=[O:21]>ClCCl>[NH2:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=1[NH:10][C:28]([C:24]1[C:23]([N+:20]([O-:22])=[O:21])=[CH:27][NH:26][N:25]=1)=[O:29]
Reactant: Cc1cc(N)c(N)cc1C
Reactant: O=C(Cl)c1n[nH]cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N)c(NC(=O)c2n[nH]cc2[N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
Method A A stirred solution of 4,5-dimethylphenylenediamine (4.32 g) and diisopropylethylamine (30 ml) in dichloromethane (200 ml) was treated with 4-nitropyrazole-3-carboxylic chloride (5 g) portionwise at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 30 minutes. The solvent was removed in vacuo and the oily residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and concentrated. The residual oil was re-crystallised from ethyl acetate and methanol (10%) to give 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethylphenyl)amide (6.58 g) as an orange solid. LC-MS (METHOD B): RT=2.36 minutes, 276.09 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])O[C:9]=2[CH3:16])=[CH:4][CH:3]=1.[CH3:17][NH2:18]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[N:18]([CH3:17])[C:9]=2[CH3:16])=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1cc(=O)c(-c2ccc(Cl)cc2)c(C)o1
Solvent: CCO
Product: Cc1cc(=O)c(-c2ccc(Cl)cc2)c(C)n1C

Procedure:
3-(4-Chlorophenyl)-2,6-dimethylpyran-4-one (2.27 g) was heated at 150° with a solution of methylamine in ethanol (35 ml; 33% w/w) in an autoclave for 12 hr. The mixture was concentrated in vacuo, triturated with ether and filtered, to afford the title compound (1.2 g), m.p. 221°-222°, NMR δH (d6 -DMSO) 7.42 (2H, d, J 5 Hz), 7.1 (2H, d, J 5 Hz), 6.1 (1H, s), 3.5 (3H, s), 2.32 (3H, s), 2.15 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([CH3:13])[C:11]3[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=[C:17]([O:18][CH3:19])[C:10]=3[O:9]2)=[CH:4][C:3]=1[O:23][CH3:24].[CH2:25]([N:28]1[CH2:32][CH2:31][O:30][CH2:29]1)[CH:26]=[CH2:27]>>[CH3:19][O:18][C:17]1[C:10]2[O:9][C@@H:8]([C:5]3[CH:4]=[C:3]([O:23][CH3:24])[C:2]([OH:1])=[C:7]([CH2:29][N:28]([CH2:32][CH2:31][OH:30])[CH2:25][CH:26]=[CH2:27])[CH:6]=3)[C@H:12]([CH3:13])[C:11]=2[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=1
Reactant: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1ccc(O)c(OC)c1)O2
Reactant: C=CCN1CCOC1
Product: C=CCN(CCO)Cc1cc([C@@H]2Oc3c(OC)cc(/C=C/C)cc3[C@H]2C)cc(OC)c1O
Yield: 53.5 %

Procedure:
20.0 g of trans-2,3-dihydro-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-3-methyl-5-(E)-propenylbenzofurane and 13.6 g of 3-allyl-1,3-oxazolidine are held in 240 ml of absolute alcohol for 48 hours at 70° C. and subsequently the solvent and excess 3-allyl-1,3-oxazolidine are removed in vacuum. After purification by means of a chromatographic column there is obtained 14.4 g of N-(5-(trans-2,3-dihydro-7-methoxy-3-methyl-5-(E)-propenyl-benzofuran-2-yl)-2-hydroxy-3-methoxyphenyl-methyl)-N-(2-hydroxyethyl)-N-allylamine, a colourless oil.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([CH2:11][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:14]2)[CH2:9]1)C1C=CC=CC=1>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH2:16]1[CH:15]2[CH:10]([CH2:11][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:14]2)[CH2:9][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCC2CN(Cc3ccccc3)CC2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2CNCC2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
To a solution of tert-butyl 2-benzylhexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate (1.60 g) in EtOAc was added a catalytic amount of 20% Pd(OH)2/C. The suspension was stirred for 3 h at room temperature under H2 and filtered. The filtrate was concentrated in vacuo to give the title compound as colorless oil (0.68 g, 60%). The crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 227.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>C1COCC1.C(O)C>[Cl:17][C:18]1[N:23]=[C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(=O)Nc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)Nc1ccc(Nc2ccnc(Cl)n2)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
To a stirred solution of N-(4-aminophenyl)acetamide (5 g, 0.033 mol) and NaHCO3 (5.6 g, 0.067 mol) in THF (20 mL) and ethanol (80 mL) was added 2,4-dichloropyrimidine (5.95 g, 0.04 mol) at room temperature. The reaction was gradually heated to 85° C. After the reaction was stirred for four hours at 85° C. under N2, the suspension was filtered and washed thoroughly with ethanol. The filtrate was concentrated under reduced pressure, and the resulting solid was washed with EtOAc to remove excess 2,4-dichloropyrimidine to yield 8.35 g (95.5% yield) of N-{4-[(2-chloropyrimidin-4-yl)amino]phenyl}acetamide as an off-white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]=[O:11].[CH2:12](O)[CH:13]=[CH:14][CH3:15].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>>[CH2:12]([O:11][CH2:10][C:3]1[C:4]([O:8][CH3:9])=[N:5][CH:6]=[CH:7][C:2]=1[I:1])[CH:13]=[CH:14][CH3:15]
Reactant: CC=CCO
Reactant: COc1nccc(I)c1C=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC=CCOCc1c(I)ccnc1OC
Temperature: 22 °C
Reaction time: 12 h

Procedure:
A 500 mL 3-necked round-bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the flask is charged with 4-iodo-2-methoxy-pyridine-3-carbaldehyde (75.0 g, 0.29 mol) prepared as in example 1, crotyl alcohol (75 mL, 0.88 mol), and triethylsilane (70 mL, 0.44 mol). To the stirred suspension at 0° C. is added trifluoroacetic acid (175 mL, 2.27 mol) dropwise via an addition funnel. The resulting solution is stirred at about 22° C. for approximately 12 hr. The reaction mixture is slowly poured into a rapidly stirring saturated sodium bicarbonate solution (2 L). The mixture is extracted with 3×500 mL of hexane. The combined organic layers are dried over sodium sulfate, filtered, and concentrated in vacuo to give an oil. Purification of this oil by vacuum distillation (about 0.4 mm Hg, about 120°-130° C.) yields 3-(but-2-enyloxymethyl)-4-iodo-2-methoxy-pyridine as a pale yellow oil: 1H-NMR (400 MHz, CDCl3) δ7.69 (d, J=5 Hz, 1H), 7.34 (d, J=5 Hz, 1H), 5.71 (m, 2H), 4.58 (s, 2H), 4.02 (d, J=1 Hz, 2H), 3.94 (s, 3H), 1.72 (d, J=6 Hz, 3H); IR (neat) 2948, 2859, 1561, 1459, 1381, 1361, 1301, 1233, 1169, 1094, 1052 cm-1 ; Elemental analysis: calculated for C11H14NO2I: C 41.40, H 4.42, N 4.39, I 39.76; Found: C 41.31, H 4.45, N 4.37, I39.71.