Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:17]([F:18])=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:19])[CH:3]=1.C(N(C(C)C)CC)(C)C.COC1C=CC(CNC2N=CN=C(OC3C=CC(N[C:51]([NH:53][C:54](=[O:63])[CH2:55][C:56]4[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=4)=[O:52])=CC=3F)C=2)=CC=1.FC1C=CC(CC(N=C=O)=O)=CC=1>C1COCC1>[C:13]([C:9]1[CH:8]=[C:7]([O:6][C:5]2[C:4]([F:19])=[CH:3][C:2]([NH:1][C:51]([NH:53][C:54](=[O:63])[CH2:55][C:56]3[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=3)=[O:52])=[C:17]([F:18])[CH:16]=2)[CH:12]=[CH:11][N:10]=1)(=[O:14])[NH2:15]
Reactant: NC(=O)c1cc(Oc2cc(F)c(N)cc2F)ccn1
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Agent: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(Oc2cc(F)c(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Reaction time: 3.5 h
Yield: 90.8 %

Procedure:
To a homogeneous mixture of 4-(4-amino-2,5-difluorophenoxy)picolinamide (0.15 g, 0.57 mmol) in THF (5 mL) was added diisopropylethylamine (0.10 mL, 0.57 mmol). The mixture was stirred for two minutes at ambient temperature before 2-(4-fluorophenyl)acetyl isocyanate (Compound D of Example 11, 0.36 M in toluene, 2.0 mL, 0.72 mmol) was added. After 3.5 hours, 2-(4-fluorophenyl)acetyl isocyanate (0.36 M in toluene, 2.0 mL, 0.72 mmol) was added to the reaction mixture. After an additional two hours, 2-(4-fluorophenyl)acetyl isocyanate (0.36 M in toluene, 2.0 mL, 0.72 mmol) was added to the reaction mixture. The mixture was then stirred for 16 hours before being concentrated in vacuo. The residue was treated with Et2O and sonication and the resultant white solid was removed by filtration. The solid was treated with Et2O and sonication two more times before vacuum filtration afforded a white solid (0.23 g, 91%). 1H NMR (DMSO-d6) δ 11.29 (s, 1H), 10.92 (s, 1H), 8.56 (d, 1H, J=5.6 Hz), 8.21-8.26 (m, 1H), 8.16 (br s, 1H), 7.76 (br s, 1H), 7.66-7.71 (m, 1H), 7.12-7.44 (m, 6H), 3.77 (s, 2H); MS (ESI+) m/z 445 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19](OC)=[O:20])[C:11](=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:24]1([CH2:30][CH2:31][NH2:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>COCCO>[C:24]1([CH2:30][CH2:31][N:32]2[C:19](=[O:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]3[C:11](=[O:23])[C:10]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]=[C:3]3[CH2:2]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)c1ccccc1-n1c(CCl)nc2ccccc2c1=O
Solvent: COCCO
Product: O=C1c2ccccc2-n2c(nc3ccccc3c2=O)CN1CCc1ccccc1
Yield: 30.4 %

Procedure:
16.4 g (0.05 mol) of 2-chloromethyl-3-(2-methoxycarbonyl-phenyl)-4H-quinazolin-4-one and 12.1 g (0.1 mol) of 2-phenylethylamine in 100 ml of ethylene glycol monomethyl ether are heated to 100° C. for 5 hours. The solvent is evaporated off on a Rotavapor and 100 ml of water are added to the semi-solid residue. The colourless crystals are filtered off and washed with hot methanol. 5.8 g (30.5% of theory) of 6-(2-phenylethyl)-6,7-dihydro-5H,13H-quinazolino[3,2-a][1,4]benzodiazepine-5,13-dione are obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:20])=[O:19])[C:6]=1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32].[H-].[Na+].Cl[C:36]1[N:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][N:37]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:43][O:42][C:39]1[CH:38]=[N:37][C:36]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[C:9]([C:11]3[N:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:20])=[O:19])[C:6]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])=[N:41][CH:40]=1
Reactant: COc1cnc(Cl)nc1
Reactant: CCCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCO)c1Oc1ccccc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCOc2ncc(OC)cn2)c1Oc1ccccc1OC
Temperature: 75 °C
Yield: 53.7 %

Procedure:
n-Propanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (92 mg) was dissolved in THF (6 ml). Sodium hydride (40 mg) and 2-chloro-5-methoxy-pyrimidine (92 mg) were added and the mixture was heated to 75° C. for 6 h, then poured onto water, acidified with solid citric acid and the precipitate was filtered off. The crude material was purified by crystallization from methanol to give n-propanesulfonic acid [6-[2-(5-methoxy-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (61 mg) as a white powder. LC-MS: tR: 4.10, [M+H]+: 570.22.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH3:11][CH:10]([CH3:12])[C:9](=[O:13])[CH:3]([NH:2][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([CH3:14])=[CH:16][CH:17]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(N)C(=O)C(C)C
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)c1ccc(C)cc1)C(=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 g of ethyl 2-amino-4-methyl-3-oxopentanoate hydrochloride and 7.4 g of 4-methylbenzoyl chloride are dissolved in 250 ml of dichloromethane, and 13.3 ml of triethylamine are slowly added dropwise at 0° C. The mixture is stirred at room temperature for one hour and then washed with water, the organic phase is separated off and dried over MgSO4, and the solvent is then removed under reduced pressure. This gives 13 g of ethyl 4-methyl-2-(4-methylbenzoylamino)-3-oxopentanoate as an oil.
Reaction SMILES: O[CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]Br>CN(C)C=O>[Br:32][CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: BrBr
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: BrCC12CC3CC(CC(C3)C1)C2
Reaction time: 8 h

Procedure:
To 1-Hydroxymethyladamantane (366 gm.) and triphenylphosphine (598 gm.) in 1600 ml. dimethylformamide was added a solution of 366 gm. bromine in 800 ml. dimethylformamide over a 5 hour period. The mixture was left overnight at room temperature and then distilled (under aspirator) to remove solvent and product. The distillate was poured into 8 liters of water and filtered. The solid was dissolved in petroleum ether (30°-60°), washed with K2CO3 solution, then with water, dried, and concentrated to dryness. The residue recrystallized from 2.5 liters methanol gave 426.6 gm., m.p. 43°-4°. (1st crop plus additional crops obtained on concentration of the mother liquors.)
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:8]([O:15][CH2:16][CH2:17][O:18][CH:19]2[CH:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[O:43][CH3:44])=[CH:27][CH:26]=3)[CH2:23][CH2:22][N:21]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:20]2)=[N:9][C:10]([CH3:14])=[N:11][C:12]=1Cl)(=[O:3])[CH3:2].C(N(CC)CC)C>C(O)C.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:8]([O:15][CH2:16][CH2:17][O:18][CH:19]2[CH:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[O:43][CH3:44])=[CH:27][CH:26]=3)[CH2:23][CH2:22][N:21]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:20]2)=[N:9][C:10]([CH3:14])=[N:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2nc(C)nc(Cl)c2CCNC(C)=O)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2nc(C)ncc2CCNC(C)=O)cc1

Procedure:
A solution of 0.191 g of tert-butyl 3-{2-[5-(2-acetylaminoethyl)-6-chloro-2-methylpyrimidin-4-yloxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.055 ml of triethylamine in 6 ml of ethanol is hydrogenated in the presence of 0.060 g of 10% Pd/C (added 4 times) at room temperature over 60 hours. The reaction mixture is clarified by filtration and the filtrate is concentrated by evaporation. The residue is taken up in ethyl acetate, washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.22 (95:5 dichloromethane-methanol); Rt=4.54.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[C:15](OCC)=[O:16])[CH:11]=[CH:10][CH:9]=[CH:8]1.O.O1CCCC1.O>C(OCC)C>[N:7]1([C:12]2[CH:13]=[C:14]([CH2:15][OH:16])[CH:20]=[CH:21][CH:22]=2)[CH:11]=[CH:10][CH:9]=[CH:8]1
Reactant: CCOC(=O)c1cccc(-n2cccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1cccc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 111.7 %

Procedure:
To a stirred mixture of 4.8 grams of lithium aluminum hydride in 150 ml of dry diethyl ether was added dropwise 23.2 grams (0.108 mole) of ethyl 3-(pyrrol-1-yl)benzoate in 160 ml of dry diethyl ether. The complete addition required 45 minutes. After this time the reaction mixture was heated under reflux for 45 minutes then allowed to cool to ambient temperature where it stood for 16 hours. The excess lithium aluminum hydride was decomposed by the careful addition of 20 ml of 50% (v/v) water-tetrahydrofuran. The addition required 20 minutes as the reaction mixture temperature was kept below 25° C. The reaction mixture was poured into 300 ml of water and the diethyl ether layer separated. The aqueous layer was extracted with three portions of 200 ml each of diethyl ether. The combined ether layers were washed with water and dried with magnesium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to give 20.9 grams of 3-(pyrrol- 1-yl)phenylmethanol; mp 64°-67° C. The ir spectrum was consistent with the proposed structure.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[C:11]([O:14][CH3:15])=[CH:10][N:9]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][C:17]=2[F:27])[N:8]=1)=O.Cl.[F:30][C:31]([F:42])([F:41])[O:32][C:33]1[CH:34]=[C:35]([NH:39][NH2:40])[CH:36]=[CH:37][CH:38]=1.C(O)(C(F)(F)F)=O>C(O)C>[F:27][C:17]1[CH:18]=[C:19]([N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)[CH:20]=[CH:21][C:16]=1[N:9]1[CH:10]=[C:11]([O:14][CH3:15])[C:12](=[O:13])[C:7]([C:5]2[N:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([O:32][C:31]([F:41])([F:42])[F:30])[CH:34]=3)[N:40]=[CH:3][CH:4]=2)=[N:8]1
Reactant: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(=O)C=CN(C)C)c1=O
Reactant: NNc1cccc(OC(F)(F)F)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(-c2ccnn2-c2cccc(OC(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.9 %

Procedure:
To a suspension of 3-[3-(dimethylamino)prop-2-enoyl]-5-methoxy-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]pyridazin-4(1H)-one (200 mg) in ethanol (2.0 mL) was added dropwise a solution of [3-(trifluoromethoxy)phenyl]hydrazine hydrochloride (139 mg) and TFA (0.2 mL) in ethanol (2.0 mL), and the mixture was so stirred at room temperature for 24 hr. To the reaction mixture was added an ethanol solution (0.3 ml) of [3-(trifluoromethoxy)phenyl]hydrazine hydrochloride (16.7 mg), and the mixture was stirred at room temperature for 24 hr. The precipitated solid was collected by filtration. The mother liquor was concentrated, and the precipitated solid was collected by filtration. The solid was combined with the previously obtained solid, and recrystallized from acetone/water to give the title compound (96.1 mg).
Reaction SMILES: [CH3:1][C:2]([N:13]=C=O)([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:12])=[CH2:11])[CH:5]=1)[CH3:3].[OH-].[K+]>C(O)(C)C>[CH3:3][C:2]([NH2:13])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:12])=[CH2:11])[CH:5]=1)[CH3:1]
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: C=C(C)c1cccc(C(C)(C)N)c1
Reaction time: 3 h
Yield: 88.7 %

Procedure:
13.6 g of 1-methyl-1-[3-(1-methylethenyl)phenyl]ethyl isocyanate were dissolved in 30 ml of isopropyl alcohol, and 19.0 g of potassium hydroxide were then added to the solution, followed by stirring for 3 hours under heating and reflux. Afterward, the solution was concentrated under reduced pressure, and then poured into ice water. After extraction with dichloromethane, the resultant extract was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure again to obtain 10.5 g of 1-methyl-1-[3-(1-methylethenyl)phenyl]ethylamine.
Reaction SMILES: [CH3:1][S:2]([N:5](S(C)(=O)=O)[C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[N:8](C(OCC)=O)[C:7]=1[C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)(=[O:4])=[O:3].[OH-].[K+]>C(O)C.O>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[C:7]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[NH:8]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(N(S(C)(=O)=O)S(C)(=O)=O)c2ccc(Cl)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
To a solution of the ethyl 3-[bis(methylsulfonyl)amino]-6-chloro-2-(3-chlorobenzoyl)-1H-indole-1-carboxylate (step 1, 532 mg, 0.998 mmol) in ethanol (15 ml) was added a solution of potassium hydroxide (395 mg, 5.99 mmol) in water (8 ml) at room temperature. After stirring for 1 h at ambient temperature, the mixture was concentrated to ca. 10 ml, and partioned between with ethyl acetate (150 ml) and water (100 ml). The organic layer was separated and washed with water (100 ml), and dried (Na2SO4). Removal of the solvent by evaporation gave an crystalline residue, which was crystallized from ethanol/hexane to afford 182 mg (48%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][Si](OCC)(OCC)OCC)[CH3:2].C[Si](OCC)(OCC)OCC.C1([Si](OC)(OC)OC)C=CC=CC=1.C(O[Si](OCC)(OCC)CCCN1CCN=C1)C.Cl.[CH2:57]([O:59][CH2:60][CH:61]([OH:63])[CH3:62])C>O.CO.C(O)C.CC(C)=O>[C:1]([O:63][CH:61]([CH3:62])[CH2:60][O:59][CH3:57])(=[O:3])[CH3:2]
Reactant: CCOCC(C)O
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: CCO[Si](C)(OCC)OCC
Agent: CCO[Si](CCCN1C=NCC1)(OCC)OCC
Agent: CO[Si](OC)(OC)c1ccccc1
Solvent: CO
Solvent: O
Solvent: CC(C)=O
Product: COCC(C)OC(C)=O
Reaction time: 4 h

Procedure:
54.56 g (70 mol %) of tetraethoxysilane, 9.81 g (14.7 mol %) of methyltriethoxysilane, 7.74 g (5 mol %) of 3-(triethoxysilylpropyl)diallylisocyanurate, 7.42 g (10 mol %) of phenyltrimethoxysilane, 0.31 g (0.3 mol %) of N-(3-triethoxysilylpropyl)-4,5-dihydroimidazole, and 105.03 g of acetone were charged into a 300-mL flask and while stirring the mixture solution with a magnetic stirrer, 24.95 g of a 0.10-mol/L hydrochloric acid was dropped into the mixture solution. After the dropping, the flask was placed into an oil bath controlled to 85° C. and under warming-reflux, the reaction was effected for 240 minutes. Then, the reaction solution was cooled down to room temperature and to the reaction solution, 142 g of propylene glycol monoethyl ether was added. From the resultant reaction mixture, ethanol and methanol, which were reaction by-products, water, and hydrochloric acid were distilled off under reduced pressure and the resultant reaction mixture was concentrated to obtain a hydrolysis-condensation product (polymer) propylene glycol monomethyl ether acetate solution. To the obtained solution, propylene glycol monoethyl ether and propylene glycol monomethyl ether acetate were added to adjust the resultant solution to have a solid residue concentration at 140° C. of 15% by weight while a solvent ratio of propylene glycol monomethyl ether acetate/propylene glycol monoethyl ether became 20/80. The weight average molecular weight of the obtained polymer of Formula (3-7) measured by GPC was Mw 1,500 in terms of polystyrene.
Reaction SMILES: Cl.[NH2:2][OH:3].CCN(CC)CC.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>CCO>[OH:3][N:2]=[C:23]([C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)=[CH:26][CH:25]=1)[NH2:24]
Reactant: NO
Reactant: N#Cc1ccc(COC2CCCCO2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NO)c1ccc(COC2CCCCO2)cc1
Reaction time: 0.67 h
Yield: 142.7 %

Procedure:
To a suspension of hydroxylamine hydrochloride (365 mg, 5.25 mmol) in EtOH (3 mL) was added Et3N (0.78 mL, 5.6 mmol) at room temperature under argon. A white precipitate formed. It was stirred at that temperature for 40 minutes. Then 4-[(tetrahydro-2H-pyran-2-yloxy)methyl]benzonitrile (Intermediate 26; 0.76 g, 3.5 mmol) in EtOH (2 mL) was added dropwise; the reaction mixture became clear. It was stirred at RT overnight. The crude obtained was purified by column chromatography with CH2Cl2 (A) and CH2Cl2/MeOH (95:5) (B) as eluents (0% to 80% B). The appropriate fractions were collected and the solvent removed to afford 1.25 g of sticky oil with some solids. It was dissolved in EtOAc/H2O (1:1, 150 mL). The organic layer was washed again with H2O (50 mL) and brine. It was dried over sodium sulphate, filtered and evaporated to afford the title compound (840 mg, 95%) as sticky oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([F:24])[CH:20]=4)[N:15]=3)[N:7]=[CH:6][C:5]=2[S:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH2:13][CH2:12][N:8]1[C:9](=[O:11])[C:10]3[C:2]([C:28]4[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=4)=[CH:3][S:4][C:5]=3[CH:6]=[N:7]1)[CH:23]=[CH:22]2
Reactant: OB(O)c1ccncc1
Reactant: O=c1c2c(Br)csc2cnn1CCc1ccc2cc(F)ccc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=c1c2c(-c3ccncc3)csc2cnn1CCc1ccc2cc(F)ccc2n1
Temperature: 110 °C
Yield: 68.6 %

Procedure:
3-Bromo-5-(2-(6-fluoroquinolin-2-yl)ethyl)thieno[2,3-d]pyridazin-4(5H)-one (66 mg, 0.163 mmol) was dissolved in dioxane (2.1 mL) and H2O (0.7 mL), pyridin-4-yl boronic acid (20.07 mg, 0.163 mmol), K2CO3 (45.1 mg, 0.327 mmol) and Pd(dppf)Cl2 (7.23 mg, 9.80 μmol) were each added sequentially to the suspension. The suspension was heated in a microwave tube at about 110° C. for 1 h. The crude product was purified by TLC (EA) to give the title compound (45 mg, yield: 68.5%).
Reaction SMILES: CC[O-].[Na+].Cl.[CH3:6][O:7][CH2:8][C:9]([NH2:11])=[NH:10].[C:12]([CH:15]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:16](OCC)=[O:17])(=O)[CH3:13]>CCO>[CH3:13][C:12]1[N:11]=[C:9]([CH2:8][O:7][CH3:6])[NH:10][C:16](=[O:17])[C:15]=1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: COCC(=N)N
Reactant: CCOC(=O)CCC(C(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCc1c(C)nc(COC)[nH]c1=O
Yield: 41.1 %

Procedure:
A mixture of NaOEt (0.088 mol) in EtOH (prepared from 2.0 g of Na and 70 mL of EtOH), methoxyacetamidine hydrochloride (5.4 g, 0.044 mol), and diethyl acetylglutarate (10.0 g, 0.044 mol) was heated under reflux for 24 h. The mixture was concentrated, taken up in water, acidified to pH 4 with conc. HCl, and extracted with CH2Cl2. The extracts were washed with brine, dried (MgSO4), and concentrated. Trituration with ether gave 4.6 g (42%) of product as an off-white solid, mp 87°-90° C.
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=1)[O:6][CH3:7])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][NH:3][C:4]1[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=1)[O:6][CH3:7]
Reactant: COc1ccccc1NC=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1ccccc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a cold solution of 9.0 g of N-formyl o-anisidine in 50 mL of THF was added 66 mL of a 1M solution of LAH in THF dropwise at 0° C. After complete addition the reaction mixture was stirred at 0° C. for one h. The reaction was then quenched with ethyl acetate, then with a saturated solution of NH4Cl. The mixture was extracted with ether, the combined extracts were dried over magnesium sulfate, and the solvent was removed to give 6.0 g of product. 1H NMR (300 MHz, CDCl3) δ 2.85 (s, 3H), 3.83 (s, 3H), 4.16 (s, 1H), 6.61 (dd, 1H), 6.69 (m, 1H), 6.75 (dd, 1H), 6.87 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1.[CH:18]12[CH2:26][CH:22]([CH2:23][CH2:24][CH2:25]1)[C:21](=[O:27])[O:20][C:19]2=O>>[N:17]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]2[C:19](=[O:20])[CH:18]3[CH2:26][CH:22]([CH2:23][CH2:24][CH2:25]3)[C:21]2=[O:27])[CH2:11][CH2:10]1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Reactant: O=C1OC(=O)C2CCCC1C2
Product: O=C1C2CCCC(C2)C(=O)N1CCCCN1CCN(c2ncccn2)CC1
Yield: 46.5 %

Procedure:
Following substantially the procedure of Example 1, 2.78 g (11.8 mmol) of 1-(4-aminobutyl)-4-(2-pyrimidinyl) piperazine was reacted with 1.88 g (12.2 mmol) of 3-oxabicyclo[3.3.1]nonan-2,4-dione. The product was chromatographed on silica gel, eluting with dichloromethane/methanol (90:10), to give 2.04 g (47% yield) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:19])[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[CH:8]3.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[N:20]([CH2:2][C:3]1([CH3:19])[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[CH:8]3)=[N+:21]=[N-:22]
Reactant: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(C)(CBr)O3
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(C)(CN=[N+]=[N-])O3
Temperature: 150 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To 2-bromomethyl-2,5,8-trimethyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (3.93 g, 12.2 mmol) and sodium azide (5.15 g, 79.3 mmol), dimethylformamide (85 ml) was added, and the mixture was stirred for 3 hours in a bath at 150° C. After cooling, post-treatment and recrystallization (chloroform-n-hexane) were performed in a manner similar to that described in Example 278 to obtain 3.28 g of the title compound as colorless crystals (94.7%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=2)[O:3]1.[Br:18]Br>CC(O)=O>[Br:18][C:5]1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=[C:9]2[C:4]=1[O:3][C:2]([CH3:17])([CH3:1])[CH2:11][C:10]2([CH3:12])[CH3:13]
Reactant: CC1(C)CC(C)(C)c2cc(C(=O)O)ccc2O1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC1(C)CC(C)(C)c2cc(C(=O)O)cc(Br)c2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,2,4,4-tetramethyl-6-chromanoic acid (200 mg, 0.85 mmol) in 0.5 ml of AcOH was added Br2 (0.07 ml, 1.28 mmol). The resulting dark-orange solution was stirred at room temperature for overnight. The excess bromine was removed under reduced pressure. Then the solution was poured into 5 ml of water and extracted with ethyl acetate (3×3 ml). The combined ethyl acetate layers were further washed with NaHCO3 (sat.), brine and dried over MgSO4. After concentration, the residue was purified by column chromatography (silica gel, ethyl acetate/hexane 1/3) to yield the desired product (170 mg, as white solids.