Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH:16]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[N:7]([CH3:29])[C:6]2=[O:30].[CH:31](=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH:15]1[CH2:20][CH2:19][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:17][CH:16]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[N:7]([CH3:29])[C:6]2=[O:30]
Reactant: COc1cc2nc(C3CCNCC3CCc3ccccc3)n(C)c(=O)c2cc1OC
Reactant: O=Cc1ccccc1
Product: COc1cc2nc(C3CCN(Cc4ccccc4)CC3CCc3ccccc3)n(C)c(=O)c2cc1OC

Procedure:
Formula I where U—V is —CReRf—CRgRh—N(R6)—; R1, R4, Rb and Rc to Rh are H; R2 and R3 are methoxy; R5 is methyl; and Ra is phenethyl; and R6 is benzyl: By following the procedure described in Example 3, substituting 3-benzyl-7-chloro-1-(pyrrolidine-2-carbonyl)-2,3-dihydro-1H-quinazoline-4-one with 6,7-dimethoxy-2-[3-phenethyl-piperidin-4-yl]-3-methyl-3H-quinazolin-4-one, and substituting p-tolualdehyde with benzaldehyde, there is obtained 6,7-dimethoxy-2-[1-benzyl-3-phenethyl-piperidin4-yl]-3-methyl-3H-quinazolin-4-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([F:14])=[CH:4][C:3]=1[N:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24](N(OC)C)=[O:25])=[N:16]1.[CH3:30][Mg+].[Br-]>C1COCC1>[C:24]([C:17]1[C:18](=[O:23])[C:19]([O:21][CH3:22])=[CH:20][N:15]([C:3]2[CH:4]=[C:5]([F:14])[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:7][C:2]=2[F:1])[N:16]=1)(=[O:25])[CH3:30]
Reactant: COc1cn(-c2cc(F)c(N3CCOCC3)cc2F)nc(C(=O)N(C)OC)c1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cc(F)c(N3CCOCC3)cc2F)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
A solution of 1-(2,5-difluoro-4-morpholin-4-ylphenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (0.51 g, 1.2 mmol) in THF (40 mL) was added dropwise to MeMgBr (1.0 M in THF, 5.0 mL, 5.0 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 2 h. The reaction was quenched with 1 M HCl aqueous solution (5.0 mL) at −78° C. The mixture warmed up to room temperature, diluted with AcOEt, and washed with brine. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt/MeOH (10/0 to 10/1) to give the title compound (340 mg, 75% yield) as a pale yellow solid: NMR (300 MHz, DMSO-d6): δ ppm 2.49 (3H, s), 2.91-3.21 (4H, m), 3.54-3.89 (7H, m), 7.19 (1H, dd, J=12.7, 7.7 Hz), 7.74 (1H, dd, J=12.8, 7.2 Hz), 8.46 (1H, d, J=1.5 Hz). LC-MS (ESI) m/z 366 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/[CH3:18])[CH3:13])[CH3:8])[CH3:3].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1>C(Cl)Cl>[C:29]([O:21][CH2:20]/[CH:19]=[C:17](/[CH2:16][CH2:15][CH2:14][C@@H:12]([CH2:11][CH2:10][CH2:9][C@@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:8])[CH3:13])\[CH3:18])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: O=C(Cl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/C(=C\COC(=O)c1cccnc1)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a mixture consisting of 10 0 g of phytol, 9.0 g of triethylamine and 50 ml of methylene chloride was added 7.2 g of nicotinic chloride at 30°-40° C. The resulting mixture was stirred for 2 hours at the same temperature. After the completion of the reaction, the reaction mixture was washed with dilute hydrochloric acid, 3% aqueous sodium hydrogencarbonate solution and water in this order and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant; n-hexane:ethyl acetate=9:1) to obtain 12.1 g (yield: 90%) of oily phytyl nicotinate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7]C)=[O:6].[CH:12]([C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)([CH3:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.[Cu]I>[CH:12]([C:15]1[N:16]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([OH:7])=[O:6])[CH:17]=[CH:18][N:19]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1ncc[nH]1
Reactant: COC(=O)c1ccnc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)c1nccn1-c1cc(C(=O)O)ccn1
Temperature: 120 °C
Yield: 54.9 %

Procedure:
A mixture of methyl 2-bromoisonicotinate (2.00 g, 9.26 mmol), 2-isopropyl-1H-imidazole (1.12 g, 10.2 mmol), cesium carbonate (6.03 g, 18.5 mmol) and copper (1) Iodide (176 mg, 926 umol) in DMSO was heated to 120° C. for eighteen hours, under nitrogen. The crude material was filtered, purified by preparative HPLC (10-90% CH3CN in water). The pure fractions were collected and concentrated to give 2-(2-isopropyl-1H-imidazol-1-yl)isonicotinic acid as a white sticky solid (1.176 g, 55% yield). MS 232 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:13](=[O:23])[NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[OH:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][NH:14][C:13]([C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([CH:10]([CH3:12])[CH3:11])[CH:8]=1)=[O:23]
Reactant: COC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)O
Reaction time: 15 h

Procedure:
A mixture of 5-(3-Hydroxy-benzylcarbamoyl)-3-isopropyl-thiophene-2-carboxylic acid methyl ester (70 mg, 0.21 mmol), lithium hydroxide monohydrate (89 mg, 2.10 mmol), THF (5 mL) and water (5 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 71.8 mg (100%). MS m/e 319.9 (M+H+).
Reaction SMILES: [OH-].[NH4+:2].[C:3]1([C:9](=[O:14])[CH2:10][C:11](=O)[CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[CH3:12][C:11]([NH2:2])=[CH:10][C:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:14]
Reactant: [NH4+]
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: [OH-]
Solvent: CO
Product: CC(N)=CC(=O)c1ccccc1

Procedure:
A mixture containing 200 ml of methanol, 50 ml of concentrated aqueous ammonium hydroxide and 50 g of 1-phenyl-1,3-butanedione (same as benzoylacetone) was stirred at ambient temperature for 22 hours after which time a tlc analysis (ether/silica gel) indicated very little remaining starting material. Some white solid 1-methyl-3-phenyl-3-oxo-1-propenamine had crystallized from the pale yellow solution. The mixture was concentrated on a rotary evaporator to dryness to yield 1-methyl-3-phenyl-3-oxo-1-propenamine as a yellow solid. To the yellow solid was added 75 ml of dimethylformamide and 25 g of methyl propiolate (same as methyl 2-propynoate) and the resulting mixture was refluxed for 10 hours, and concentrated on a rotary evaporator. The remaining solid was recrystallized from isopropyl alcohol and dried at 90°-95° C. to yield 29.6 g of 5-benzoyl-6-methyl-2(1H)-pyridinone, m.p. 185°-187° C. The mother liquor from the above recrystallization was concentrated on a rotary evaporator to yield another 6 g of the product.
Reaction SMILES: [OH:1][CH:2]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[C:7]1[S:11][C:10]([C:12](=[O:20])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:9][CH:8]=1.[BH4-].[Na+]>CO>[OH:20][CH:12]([C:10]1[S:11][C:7](/[CH:6]=[CH:5]/[CH:4]=[CH:3]/[CH:2]([OH:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:8][CH:9]=1)[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: CCCCCCCCC(O)/C=C/C=C/c1ccc(C(=O)CCCC(=O)OC)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/C=C/c1ccc(C(O)CCCC(=O)OC)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
Into 3ml of methanol was dissolved 50mg of the titled product of Example 28. The methanol solution was cooled to 0°C. (ice bath) and 5mg of NaBH4 was added. The reaction mixture was stirred for 1 hour at 0°C. and then quenched with acetone. The solvent was removed from the quenced reaction mixture under reduced pressure. Water was added to the residue and it was extracted 3x with ethyl acetate. The combined extracts were dried MgSO4, filtered, and the solvent removed under reduced pressure. The oily residue was chromatographed on a silica gel column. Elution with 3:7 ethyl acetate:hexane produced 35mg of the titled product as a light yellow oil.
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[N:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1>CCCCCC.C1COCC1>[OH:7][CH:8]=[CH:9][CH2:35][C:32]1[CH:31]=[CH:30][N:29]=[CH:34][CH:33]=1
Reactant: OCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccncc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC=CCc1ccncc1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
The starting material was prepared as follows n-Butyllithium (25 ml of a 1.6M solution in hexane, 40 mmol) was added dropwise to a stirred suspension of 2-hydroxyethyltriphenylphosphonium bromide (7.74 g, 20 mmol) in THF (50 ml) at -70° C. and the mixture allowed to warm to -30° C. and stirred for 2 hours. 4-Pyridinecarboxaldehyde (2.16 g, 20 mmol) was added to the resulting red solution and the mixture stirred for 1 hour at -30° C. and then cooled to -70° C. n-Butyllithium (12.5 ml of a 1.6M solution in hexane, 20 mmol) was added and the reaction mixture stirred at -70° C. for 1 hour. The mixture was quenched with isopropanol and allowed to warm to ambient temperature. Saturated aqueous ammonium chloride solution was added, the organic layer separated and the aqueous layer extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine and dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate to give 4-(3-hydroxyprop-2-en-1-yl)pyridine MS-ESI: 136 [MH]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[CH2:15]([Li])[CH2:16][CH2:17][CH3:18].[O:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:13][C:11]1([CH3:14])[CH2:10][O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:21]([OH:20])[CH2:22][CH2:23][CH2:24][CH2:18][CH2:17][CH2:16][CH2:15][CH2:15][CH2:16][CH2:17][CH2:18][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:3][CH:4]=2)=[N:12]1
Reactant: [Li]CCCC
Reactant: C1CCOC1
Reactant: CC1(C)COC(c2ccc(Br)cc2)=N1
Product: CCCCCCCCCCCCCCCCCC(O)c1ccc(C2=NC(C)(C)CO2)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
While under an argon atmosphere, a solution of the product of Example 3 (4 mmole) in tetrahydrofuran (100 ml) was cooled with stirring to ca. -75° C. n-Butyllithium (2 ml; 2.04M in hexane) was added dropwise using a syringe over 15 min. After stirring for 2 hours a second solution of octadecyl aldehyde (4 mmole) in tetrahydrofuran (100 ml) precooled to -5° C. was canulated to the above solution over 25 min., maintaining the temperature below -60° C. The reaction was allowed to warm to room temperature over the next 2.5 hours, then was quenched with water (10 ml) and stirred for 60 hours. Most of the tetrahydrafuran was evaporated under a stream of nitrogen. More water (100 ml) was added and the mixture was extracted into ethyl acetate. The combined extracts were dried over sodium sulfate and filtered, then the solvent was removed by a nitrogen stream to give an oil. The product was purified by chromatography on silica gel to give 0.80 g of the title compound, m.p. ca. 72°-75° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:18]=[CH:17][C:16]2[NH:15][C:14]3[CH:13]=[CH:12][C:11]4[C:19](=[O:22])[CH2:20][CH2:21][C:10]=4[C:9]=3[C:8]=2[CH:7]=1)(=[O:5])[CH3:4].[H][H].[Br:25][CH2:26][CH2:27]Br>CN(C=O)C>[C:3]([C:6]1[CH:18]=[CH:17][C:16]2[N:15]([CH2:27][CH2:26][Br:25])[C:14]3[CH:13]=[CH:12][C:11]4[C:19](=[O:22])[CH2:20][CH2:21][C:10]=4[C:9]=3[C:8]=2[CH:7]=1)(=[O:5])[CH3:4]
Reactant: BrCCBr
Reactant: CC(=O)c1ccc2[nH]c3ccc4c(c3c2c1)CCC4=O
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)c1c3c(ccc1n2CCBr)C(=O)CC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
NaH (2 g of 60%, 50 mmol) was added to a suspension of compound 91 (4 g, 15.2 mmol) in dry DMF (100 mL), and the mixture was stirred at room temperature about 1 h until the evolution of hydrogen ceased. 1,2-dibromethane (20 g, 106 mmol) was added in dropwise under nitrogen. The reaction mixture was stirred for 30 min at room temperature, then at 60° C. for 24 h, and poured into ice water (300 mL). The precipitated grey solid was filtered off and the crude product purified by column chromatography (CHCl3) to give 2 g of starting material and about 1 g (2.7 mmol, 35.5% from converted material) of the alkylated carbazole 92 as a cream solid.
Reaction SMILES: Cl.[CH3:2][C@@H:3]([NH2:11])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C1C=CC=CN=1)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:11][C@H:3]([CH3:2])[CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: C[C@@H](N)CN1CCOCC1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](CN1CCOCC1)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93 %

Procedure:
Reflux a mixture of (R)-1-methyl-2-morpholin-4-yl-ethylaminehydrochloride (0.04 mol, 8.7 g), 5-bromo-2-fluoronitrobenzene (0.048 mol, 10.5 g), triethylamine (0.20 mol, 20.2 g) and dimethylaminopyridine (0.0004 mol, 0.048 g) in ethyl acetate (220 mL) for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate. Purify on a silica gel column using 10% ethyl acetate in hexanes as eluent to obtain the title compound (12.8 g, 95%) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 1.29 (d, 3H), 2.47-2.51 (m, 5H), 2.53-2.58 (m, 1H), 3.64-3.69 (m, 4H), 3.72-3.78 (m, 1H), 6.78 (d, 1H), 7.46 (dd, 1H), 8.30 (d, 1H), 8.33 (d, 1H).
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6](F)[CH:5]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([NH:2][CH3:1])[CH:5]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methylamine (2 M in tetrahydrofuran, 11.4 mL) was added to a mixture of 4-bromo-2-fluoro-1-nitro-benzene (2.50 g) and K2CO3 (1.90 g) in dimethylformamide (40 mL). The resulting mixture was stirred at ambient temperature overnight. Then, the mixture was concentrated under reduced pressure and dichloromethane was added. The resulting mixture was washed with 0.5 M aqueous HCl solution and brine and dried (MgSO4). The solvent was removed to give the product as a solid.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][C:11]([CH3:17])=[C:12]([O:15][CH3:16])[CH:13]=3)[CH2:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1>[Pd].C(O)C.O.[Pt]=O>[NH:1]1[C:5]([CH:6]2[C:14]3[C:9](=[CH:10][C:11]([CH3:17])=[C:12]([O:15][CH3:16])[CH:13]=3)[CH2:8][CH2:7]2)=[CH:4][N:3]=[CH:2]1
Reactant: COc1cc2c(cc1C)CC=C2c1cnc[nH]1
Agent: O=[Pt]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1C)CCC2c1cnc[nH]1

Procedure:
This compound was prepared in a manner analogous to that of Step E of Example 1, by the hydrogenation of 0.5 gram (0.0022 mole) of 3-(imidazol-5-yl)-5-methoxy-6-methylindene (viii) in the presence of 0.1 gram (catalyst) of 10% palladium on carbon and 0.1 gram (catalyst) of platinum oxide hydrate in 40 mL of ethanol. The yield of subject compound was 0.42 gram, mp 68-70° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].Cl.Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccn2)c1
Yield: 50.5 %

Procedure:
5-Nitroindazole (10.0 g, 61.3 mmol) was dissolved in THF (100 mL), and 2-(chloromethyl)pyridine hydrochloride (8.60 g, 52.4 mmol) and potassium carbonate (24.4 g, 184 mmol) were added. The mixture was heated for 4 h to 75° C. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (eluent: gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate) to yield 6.73 g (43%) of the title compound.
Reaction SMILES: C[C:2]1[C:3](Br)=[C:4]([C:9]([O-:11])=[O:10])[C:5](C)=[CH:6][CH:7]=1.[CH2:13]1N2CN3CN(C2)CN1C3.[C:23](O)(=[O:25])C.Cl>O>[C:9]([C:4]1[CH:3]=[CH:2][C:7]([CH:23]=[O:25])=[CH:6][CH:5]=1)([O:11][CH3:13])=[O:10]
Reactant: CC(=O)O
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: Cc1ccc(C)c(C(=O)[O-])c1Br
Agent: Cl
Solvent: O
Product: COC(=O)c1ccc(C=O)cc1
Reaction time: 2 h
Yield: 71 %

Procedure:
A mixture of 68.7 g (0.3 mole) of methyl- -bromotoluate, 84 g (0.6 mole) of hexamethylenetetramine, 150 ml of acetic acid and 150 ml of water were refluxed with stirring for two hours. Ninety ml of concentrated hydrochloric acid was then added and kept at room temperature for 15 minutes. The cooled solution was extracted with ether, washed with water, 10% NaHCO3 solution, water and dried. Evaporation of the solvent and recrystallization of the residue from petroleum ether gave 35 g of p-carbomethoxybenzaldehyde, yield 71% m.p. 61°-63° C. (lit. m.p. 61°-63° C.). The infrared spectrum showed absorption at 1720 cm-1 ##STR9## 1690 cm-1 (--CHO). NMR (CDCI3) δ3.8 (s, --COOCH3, 3), 7.8-8.2 (m, aromatic, 4), and 10.2 (s, --CHO, 1).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:34])=[C:19]([NH:21][C:22]3[N:27]=[C:26]([S:28][C:29]#[N:30])[C:25]([N+:31]([O-])=O)=[CH:24][N:23]=3)[CH:20]=2)=[O:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4])#[N:2].C(O)C.C(O)(=O)C>CN1CCCC1=O.[C].[Pd]>[NH2:30][C:29]1[S:28][C:26]2[N:27]=[C:22]([NH:21][C:19]3[CH:20]=[C:15]([NH:14][C:12](=[O:13])[C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=4)[CH:16]=[CH:17][C:18]=3[CH3:34])[N:23]=[CH:24][C:25]=2[N:31]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Agent: [Pd]
Solvent: CCO
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(N)sc2n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 58.1 %

Procedure:
To a solution of 2-{[5-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)-2-methylphenyl]amino}-5-nitropyrimidin-4-yl thiocyanate (1.09 mmol, 515 mg) in 1-methylpyrrolidin-2-one (9 mL)/ethanol (6 mL) were added 10% palladium-carbon (120 mg) and acetic acid (0.5 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere (3.0 atm) for 19 hr. The insoluble material was filtered off, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL, 20 ml). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=40/60→10/90), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (281 mg, 58%) as purple crystals.
Reaction SMILES: O[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=1.S(Cl)([Cl:29])=O>C1(C)C=CC=CC=1>[Cl:29][CH2:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=1
Reactant: COc1cc(CO)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(CCl)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Yield: 97.8 %

Procedure:
To a mixture of 3-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile (10.0 g) and toluene (200 mL) was added thionyl chloride (3.74 g), and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated and ethyl acetate was added to the residue. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile (10.3 g, yield 98%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 150-151° C.
Reaction SMILES: C([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24]C3CCCCO3)[C:18]2=[O:31])[CH2:13][CH2:12]1)(OCC1C=CC=CC=1)=O.Cl.[H][H]>CO.[Pd]>[OH:24][CH2:23][CH2:22][N:19]1[CH2:20][CH2:21][N:17]([CH:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)[C:18]1=[O:31]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCN(CCOC3CCCCO3)C2=O)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C1N(CCO)CCN1C1CCNCC1

Procedure:
A solution of 59.7 g of 1-(1-carbobenzoxy-4-piperidyl)-3-[2(2-tetrahydropyranyloxy)-ethyl]-imidazolidin-2-one in 1,200 ml of absolute methanol is hydrogenated at room temperature and normal pressure with the addition of 1 mol equivalent of hydrochloric acid and 6 g of palladium-on-charcoal catalyst until 2 mol equivalents of hydrogen have been taken up. The catalyst is then filtered off and the filtrate is evaporated under reduced pressure. The residue is freed from moisture which is still adhering, by treatment with toluene. The reaction product is chromatographed on 2 kg of basic aluminium oxide using a mixture of chloroform/methanol (85:15) as the eluant mixture. In this way, 3-(2-hydroxyethyl)-1-(4-piperidyl)-imidazolidin-2-one is obtained in the form of a viscous oil, which is further used without additional purification.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].F[C:15](F)(F)[C:16](O)=O.F[C:22](F)(F)C(OC(=O)C(F)(F)F)=O>CC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:13][C:15]([CH3:16])([CH3:22])[O:10][C:9](=[O:11])[C:8]=2[CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Solvent: CC(C)=O
Product: CC1(C)OC(=O)c2cc([N+](=O)[O-])ccc2O1
Temperature: 25 °C
Yield: 91 %

Procedure:
5-Nitrosalicylic acid (25 g, 136.6 mmol) was taken up in acetone (20 ml) and trifluoroacetic acid (150 ml) and trifluoroacetic anhydride (50 ml) were added. The mixture was heated at reflux. After 1 hr more acetone (30 ml) was added, and the reaction was heated at reflux for 48 hrs. The reaction was cooled to RT and the volatiles were removed in vacuo. The resulting brown oil was dissolved in CH2Cl2 (400 ml) and washed with 1:1H2O/saturated NaHCO3 (400 ml). The aqueous phase was extracted with CH2Cl2 (2×200 ml), and the combined organic layers were dried (MgSO4) and evaporated in vacuo. The solid residue was triturated with pentane (150 ml), collected by filtration, washed thoroughly with pentane and dried in vacuo to give 6-nitro-2,2-dimethyl-4H-benzo[1,3]dioxin-4-one (27.84 g, 91%) as a dark yellow solid.