Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([Cl:18])[C:12]([CH3:17])([N+:14]([O-])=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([O-])(=O)C.[Na+].C(O)(=O)C.C>[H][H].[Pt](=O)=O.COCCOC>[ClH:18].[CH3:17][C:12]([NH2:14])([CH3:13])[CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc(C(Cl)C(C)(C)[N+](=O)[O-])cc1OC
Agent: O=[Pt]=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Product: COc1ccc(CC(C)(C)N)cc1OC
Product: Cl
Yield: 65 %

Procedure:
A mixture of 3.6 g of 1-(3,4-dimethoxyphenyl)-1-chloro-2-methyl-2-nitropropane, 910 mg of sodium acetate, 6.7 ml of acetic acid, 200 mg of platinum dioxide, 280 mg of activated charcoal and 35 ml of 1,2-dimethoxyethane is shaken at 60°-85° C. for 5.5 hours in hydrogen gas atmosphere under 55 atmospheric pressures. After cooling, insoluble materials are removed by filtration, and the filtrate is evaporated under reduced pressure to remove solvent. The residue (pale yellow oil) is dissolved in water, and then washed with ether. The aqueous layer is neutralized with 20% sodium hydroxide under cooling, and then extracted with ether. The extract is washed with water, dried and then evaporated to remove solvent. The residue (colorless oil) is converted into its hydrochloride with hydrogen chlorideether, and said hydrochloride is recrystallized from isopropylalcohol. 2.1 g of α,α-dimethyl-3,4-dimethoxyphenethylamine hydrochloride are thereby obtained as colorless plates.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[O:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.CCO[CH2:14][CH3:15]>C(COC)OC>[CH3:4][C@:3]12[CH2:15][CH2:14][C@H:4]3[C@@H:3]([CH2:4][CH2:7][C:8]4[CH:9]=[C:10]([OH:6])[CH:1]=[CH:2][C:3]=43)[C@@H:2]1[CH2:1][CH:1]=[CH:2]2
Reactant: [Li]CCCC
Reactant: C1CCOC1
Reactant: CCOCC
Solvent: COCCOC
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCc3cc(O)ccc3[C@H]1CC2

Procedure:
Estra-1,3,5(10),16-tetraen-3-ol, for example, may be prepared from estrone (estra-1,3,5(10)-trien-3-ol-17-one) by reacting estrone with an appropriate amount of p-toluenesulfonylhydrazide in a polar solvent such as dry methanol or ethanol under reflux to form the corresponding estrone p-toluenesulfonylhydrazone. The estrone p-toluenesulfonylhydrazone is then reacted with n-butyl lithium in an inert aprotic solvent such as dry tetrahydrofuran, ether, dimethoxyethane or the like to give estra-1,3,5(10),16-tetraen-3-ol.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][O:18][CH3:19])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:22]1OCC[O:23]1.Cl>C1COCC1>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][O:18][CH3:19])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:22]=[O:23]
Reactant: COCCNc1ccc(C#N)c(Oc2ccc(Br)c(C3OCCO3)c2)n1
Agent: Cl
Solvent: C1CCOC1
Product: COCCNc1ccc(C#N)c(Oc2ccc(Br)c(C=O)c2)n1
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a solution of 2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-(2-methoxy-ethylamino)-nicotinonitrile (8) (1.0 g, 2.38 mmol) in THF (50 mL) was added HCl solution (1M/H2O, 20 mL). After overnight, the THF was evaporated under vacuum. The aqueous solution was extracted with EtOAc (2×50 mL). The organic layer was washed with water (3×50 mL), dried over MgSO4, filtered and evaporated in vacuo. Purification was accomplished by silica gel chromatography, eluting with 25%-100% EtOAc/hexanes gradient, to afford the desired product 780 mg (87% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 10.34 (s, 1 H), 7.80 (d, J=2.7 Hz, 1 H), 7.67 (d, J=8.6 Hz, 1 H), 7.60 (d, J=8.2 Hz, 1 H), 7.30 (dd, J=8.8, 2.9 Hz, 1 H), 6.13 (d, J=8.2 Hz, 1 H), 5.24 (br. s., 1 H), 3.42 (t, J=4.9 Hz, 2 H), 3.35-3.27 (m, 5 H).
Reaction SMILES: C[SiH](C)C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].[C:12]([O-])([O-])=O.[K+].[K+].[CH3:18][C:19]([CH3:21])=O>>[CH2:18]([N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=[O:11])[CH2:19][C:21]#[CH:12]
Reactant: CC(C)=O
Reactant: Oc1ccccn1
Reactant: O=C([O-])[O-]
Agent: C[SiH](C)C
Agent: [K+]
Product: C#CCCn1ccccc1=O
Temperature: 150 °C
Yield: 5 %

Procedure:
4-bromobut-1-ynyl)trimethylsilane (700 mg, 3 mmol), pyridin-2-ol (300 mg, 3 mmol) and K2CO3 (900 mg, 6 mmol) were poured into acetone (4.2 ml) and the resulting mixture was heated in the microwave at 150° C. for 7 min The solvent was evaporated and the crude product was dissolved DCM and the organic layer was washed with water. The crude residue was purified over silicagel chromatography (prepacked 5 g silicagel column, DCM/MeOH: 99/1 as eluent) to afford 33 mg of 1-(but-3-ynyl)pyridin-2(1H)-one as a brown oil (Yield: 5%).
Reaction SMILES: [NH2:1][C:2](=[N:15][OH:16])[C:3]1[CH:12]=[CH:11][C:6](C(OC)=O)=[CH:5][C:4]=1OC.C(C1C=C(C=CC=1)[CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])#N>>[NH2:1][C:2](=[N:15][OH:16])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:11][CH:12]=1)[CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: COCCN(Cc1cccc(C#N)c1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(C(N)=NO)c(OC)c1
Product: COCCN(Cc1cccc(C(N)=NO)c1)C(=O)OC(C)(C)C

Procedure:
Title compound was prepared following procedure and work up described for Intermediate 47 step 2 but starting from tert-Butyl 3-cyanobenzyl(2-methoxyethyl)carbamate obtained in step 2 (7.4 g, 0.0254 mol) (RT for 12 h). Title compound was obtained as a pale yellow gummy liquid (7.1 g, 86%). 1H NMR (DMSO-d6, 400 MHz) δ 9.59 (s, 1H), 7.52-7.54 (m, 2H), 7.30-7.34 (m, 1H), 7.19-7.21 (m, 1H), 5.75 (s, 2H), 4.40 (s, 2H), 3.37-3.40 (m, 2H), 3.21-3.30 (m, 5H), 1.32-1.41 (m, 9H). LC/MS (Method A): 324.0 (M+H)+. HPLC (Method B) Rt 5.23 min (Purity: 96.2%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]4[C:13](=[C:15]([C:19]([OH:21])=O)[CH:16]=[CH:17][CH:18]=4)[N:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.Cl.[NH2:24][C@H:25]1[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[N:27]12[CH2:32][CH2:31][CH:30]([CH2:29][CH2:28]1)[C@H:25]([NH:24][C:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:12]3[O:11][C:10]([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)=[N:14][C:13]=13)=[O:21])[CH2:26]2
Reactant: O=C(O)c1cccc2oc(-c3ccc4c(c3)OCO4)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(-c3ccc4c(c3)OCO4)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.4 %

Procedure:
A mixture of 2-benzo[1,3]dioxol-5-yl-benzoxazole-4-carboxylic acid (29 mg, 0.10 mmol), (S)-3-aminoquinuclidine dihydrochloride (24 mg, 0.12 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38 mg, 0.20 mmol) and 1-hydroxybenzotriazole (27 mg, 0.20 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then DIPEA (66 μL, 0.40 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-benzo[1,3]dioxol-5-yl-benzoxazole-4-carboxamide (17 mg, 42%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.54 (d, J=7.0 Hz, 1H), 8.17 (dd, J=7.5, 1.0 Hz, 1H), 7.82 (dd, J=8.0, 1.5 Hz, 1H), 7.68 (dd, J=8.0, 1.0 Hz, 1H), 7.64 (d, J=1.5 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.11 (s, 2H), 4.33-4.29 (m, 1H), 3.56-3.48 (m, 1H), 3.13-2.99 (m, 2H), 2.95-2.88 (m, 2H), 2.85-2.79 (m, 1H), 2.18-2.13 (m, 1H), 1.80-1.59 (m, 4H); MS (ESI+) m/z 392 (M+H); HPLC 97.4% (AUC), tR=12.51 min.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20]C)=[CH:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:26](=[O:28])[CH3:27])OC(=O)C)[CH3:2].[Li].N.CO>O1CCOCC1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[C:26](=[O:28])[CH3:27])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@]2(OC(C)=O)C(C)=O
Agent: N
Agent: [Li]
Solvent: C1COCCO1
Solvent: CO
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2C(C)=O
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
Add 13β-ethyl-3-methoxy-17α-acetyl-17β-acetoxy-gona-1,3,5(10)-triene (0.24 g.) in dioxan (5 cc.) to a stirred solution of lithium (0.15 g.) in liquid ammonia (100 cc.). After 30 minutes and methanol (8 cc.) followed by lithium (0.5 g.) in small pieces. Add water, extract with ether and work up to a gum (0.218 g.). Reflux this product with 4N hydrochloric acid (5 cc.) and methanol (8 cc.) for 15 minutes. Add water, extract with ether, work up and dissolve the resulting gum in acetone (30 cc.) containing anhydrous magnesium sulphate (0.5 g.) and add 8N-chromic acid dropwise with swirling until the solution assumes a permanent yellowish-orange color. Add excess isopropanol and evaporate the solution almost to dryness. Add water, extract with ether, wash, dry and evaporate the organic solution, filter the product through alumina with benzene-ether and recrystallize the product from ethyl acetate to obtain the title product (0.072 g.), m.p. 138°-142°; infrared absorption peaks at 5.9, 6 μ.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[N:4][N:3]=1.C(Cl)(Cl)Cl.CC#N.I([O-])(=O)(=O)=[O:26].[Na+]>O.O.[Ru](=O)=O>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:10](=[O:26])[C:5]2=[N:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)nnc2C1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCn2c(Br)nnc2C1=O
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a vigorously stirred solution of tert-butyl 3-bromo-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (1.0 g, 3.3 mmol) in 1:1 CHCl3:MeCN (25 mL) was added ruthenium (IV) oxide hydrate (65 mg, 0.43 mmol) and sodium metaperiodate (3.3 g, 15.5 mmol) in water (31 mL). After 1 h, additional ruthenium (IV) oxide hydrate (50 mg) was added. After another hour, a final portion of ruthenium (IV) oxide hydrate (30 mg) was added. Stirring was maintained for 30 minutes and then water was added. The entire mixture was extracted with CHCl3. The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford a green oil. Purification by chromatography (SiO2; hexanes—100% EtOAc) provided the desired product as a white solid (663 mg, 63%). MS (ESI): mass calcd. for C10H13BrN4O3, 316.0; m/z found, 317.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 4.41-4.28 (m, 2H), 4.26-4.22 (m, 2H), 1.58 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[OH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:36](=[O:37])[C:35]3[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][OH:23])=[CH:40][CH:39]=3)[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: O=C(O)c1ccc(CCCCCCCCO)cc1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCCCCCO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 154 %

Procedure:
A solution of Intermediate 7 (182 mg, 0.6 mmol), 4-(8-hydroxyoctyl)benzoic acid (100 mg, 0.4 mmol, e.g. preparable according to K. Fukai JP11174621), (1H-1,2,3-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP, 208 mg, 0.4 mmol, e.g. available from Aldrich) and N,N-diisopropylethylamine (0.276 ml, 1.6 mmol) in dry N,N-dimethylformamide (3 ml) was allowed to stir at room temperature for 4 hours. The solvent was evaporated and the residue partitioned between chloroform (10 ml) and saturated aqueous sodium bicarbonate solution (10 ml); the organic fraction was collected by passing through a hydrophobic frit and evaporated. The residue was dissolved in chloroform (20 ml), and the solution passed through a 10 g aminopropyl SPE cartridge under gravity. The cartridge was further eluted with 10% methanol in chloroform, and product containing fractions evaporated to give the title compound (330 mg). LCMS showed MH+=536; TRET=2.92 min.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[C:9]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1.[Cl:23][C:24]1[N:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>CN1C(=O)CCC1>[Cl:23][C:24]1[N:29]=[CH:28][C:27]([O:30][C:8]2[C:9]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:26][CH:25]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(=O)N1CCC(c2nccnc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(Cl)nc2)CC1
Temperature: 130 °C

Procedure:
To a mixture of cesium carbonate (0.505 g, 1.55 mmol), 1-(4-(3-chloropyrazin-2-yl)piperidin-1-yl)ethanone (0.129 g, 0.538 mmol), and 6-chloropyridin-3-ol (0.140 g, 1.08 mmol) was added NMP (2 mL). The reaction mixture was degassed and heated to 130° C. for 2 h. The reaction mixture was diluted with EtOAc. The organic phase was washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (50% to 100% EtOAc (10% MeOH) in hexanes) gave 1-(4-(3-(6-chloropyridin-3-yloxy)pyrazin-2-yl)piperidin-1-yl)ethanone as a colorless oil that was used in the next step without further purification. MS (ESI, pos. ion) m/z: 333.2 (M+1).
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:41])[NH:20][C:21](=[O:40])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:32][CH2:33][CH2:34]OS(C)(=O)=O)[CH:24]=2)=[CH:10]1>>[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:41])[NH:20][C:21](=[O:40])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:32][CH2:33][CH2:34][S:1][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH:24]=2)=[CH:10]1
Reactant: Sc1ncccn1
Reactant: Cn1cc(C2=C(c3cn(CCCOS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Product: Cn1cc(C2=C(c3cn(CCCSc4ncccn4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Yield: 43.5 %

Procedure:
In an analogous manner to that described in Example 59, from 25 mg of 2-mercaptopyrimidine and 100 mg of the product of Example 58, there were obtained 45 mg of 3-(1-methyl-3-indolyl)-4-[1-[3-(2-pyrimidinylthio)propyl]-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 125°-127° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[NH:23]([C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccc2ccc(Nc3ccccc3)nc2n1
Reactant: COc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)Nc2ccc3ccc(Nc4ccccc4)nc3n2)cc1
Temperature: 4 °C
Yield: 41 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 4-methoxybenzoic acid (6.1 g), N,N'-carbonyldiimidazole (6.5 g) and 2-amino-7-anilino-1,8-naphthyridine (7 g). The product obtained by precipitation in water (12 g) is dissolved in boiling ethanol (140 cc). After cooling for 1 hour at 4° C., the crystallized solid is separated by filtration, washed with ethanol (10 cc), and dried at 45° C. under reduced pressure (0.07 kPa). N-(7-Anilino-1,8-naphthyridin-2-yl)-4-methoxybenzamide (4.5 g), m.p. 245° C., is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].I[CH3:17].[H-].[Na+].[CH2:20]1COC[CH2:21]1>>[CH3:20][CH2:21][C:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)([CH3:17])[C:12]([OH:14])=[O:13]
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Reactant: C1CCOC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CCC(C)(C(=O)O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of methyl 4-tert-butylphenylacetate (30.00 g, 0.145 mol) and iodomethane (45.41 g, 0.320 mol) in 125 mL of dry THF was added to a slurry of NaH (8.72 g, 0.363 mol) in 200 mL of THF dropwise over 30 minutes. After completion of the addition, the reaction mixture was heated at reflux for 1.5 hr. The reaction was allowed to cool to room temperature, filtered through Celite and concentrated. The residue was diluted in ether, washed with H2O, and dried over MgSO4. Evaporation of the solvent afforded the desired product as an oil. A mixture of the crude methyl 4-tert-butylphenylisobutyrate and 4:1 EtOH/H2O containing KOH (10.07 g, 0.179 mol) were heated to reflux for 4 hr. The EtOH was evaporated in vacuo, the residual solution was acidified to pH 2 with 2N HCl, and the precipitated solid filtered. The white solid was the dried (60° C., 1 mm Hg, 24 hr) to give the desired product (23.45 g, 73.2% from methyl 4-tert-butylphenylacetate). 1H NMR (CDCl3) 1.34 (s, 9H), 1.62 (s, 6H), 7.37 (s, 4H), 11.4-12.4 (brs, 1H). 13C NMR (CDCl3) 26.16, 31.30, 34.35, 45.81, 125.31, 125.48, 140.64, 149.66, 183.57.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:9][CH:8]=1.CCN(CC)CC.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CC#N>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][N:15]1[CH2:16][CH2:17][O:18][CH:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]3[C:3]([Cl:2])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:23])=[CH:12][CH:11]=2)[CH2:14]1)[CH3:37]
Reactant: Clc1cccc(Cl)c1COc1ccc(C2CNCCO2)cc1
Reactant: CCOC(=O)CBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCOC(c2ccc(OCc3c(Cl)cccc3Cl)cc2)C1
Temperature: 85 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine hydrochloride (0.65 g; 1.68 mmol), Et3N (0.58 mL; 4.2 mmol), and ethyl bromoacetate (0.24 ml; 2.19 mmol) in CH3CN (65 mL) was stirred at 85° C., overnight. After cooling to RT the mixture was concentrated in vacuo and the residue partitioned between water and CH2Cl2. The layers were separated and aqueous layer was extracted once more with CH2Cl2. The combined organic layers were concentrated in vacuo and the residue was purified by column chromatography (SiO2, Et2O:hexanes 2:1) to afford {2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-acetic acid ethyl ester (0.62 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH:31]=[CH:32][N+]([O-])=O>CCO.C1(C)C=CC=CC=1>[CH2:15]([N:22]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:31]([C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[Cl:23])=[CH:32]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: Clc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)c(Cl)c1

Procedure:
The title compound (454.6 mg) was prepared from 0.52 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 280 μL of benzylamine, and 0.57 g of 2,4-dichloro-1-(2-nitro-vinyl)-benzene, using a 5:1 EtOH/toluene mixture as the solvent. MS (ESI): exact mass calculated for C20H18Cl2N2, 356.08; found, m/z 357.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.53 (d, J=2.2 Hz, 1H), 7.36-7.32 (m, 3H), 7.30-7.28 (m, 2H), 7.20-7.17 (m, 2H), 7.04 (s, 1H), 5.16 (s, 2H), 4.13 (s, 2H), 3.50 (t, J=6.3 Hz, 2H), 2.88 (t, J=6.3 Hz, 2H).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[Cl:6][C:7]1[CH:8]=[C:9]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]([NH:13][C:14]([NH2:16])=[S:15])=[N:11][CH:12]=1.C(N(CC)CC)C>C(O)C>[Cl:6][C:7]1[CH:8]=[C:9]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]([NH:13][C:14]2[S:15][CH:2]=[C:3]([CH3:4])[N:16]=2)=[N:11][CH:12]=1
Reactant: NC(=S)Nc1ncc(Cl)cc1Oc1ccccc1
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1csc(Nc2ncc(Cl)cc2Oc2ccccc2)n1
Yield: 88.9 %

Procedure:
A mixture of 1-chloropropan-2-one (3.827 g, 41.36 mmol), 1-(5-chloro-3-phenoxypyridin-2-yl)thiourea (8.265 g, 29.54 mmol), triethylamine (7.001 mL, 50.23 mmol), and ethanol (30 mL) was refluxed for 3 hours. The ethanol was removed to about one third original volume, and then the reaction mixture was cooled in an ice bath and filtered. The solids were washed with cold ethanol and dried to afford the title compound (8.35 g, 88.96% yield) as a light yellow powder. 1H NMR (d6-DMSO) δ 10.94 (bs, 1H), 8.15 (d, 1H), 7.43 (t, 2H), 7.32 (d, 1H), 7.20 (t, 1H), 7.19 (d, 2H), 6.60 (s, 1H), 2.23 (s, 3H); Mass spectrum (apci) m/z=318.2 (M+H).
Reaction SMILES: O[CH:2]([CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[H-].[Na+].CCCCC.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1.[O:37]1CCCC1>>[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][O:37][CH:5]2[N:4]([CH2:3][CH2:2][CH2:9][O:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:8]=[CH:7][NH:6]2)=[CH:31][CH:30]=1
Reactant: C1CCOC1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1ccc(COCC(O)Cn2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Product: COc1ccc(COCCCN2C=CNC2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-[2-hydroxy-3-[(4-metoxyphenyl)methoxy]propyl]-1H-imidazole (206 g, 0.79M) in dry tetrahydrofuran (3700 ml) was added dropwise to a stirred slurry of sodium hydride (38 g of a 60% dispersion in oil, 0.95M; prewashed with pentane) in dry tetrahydrofuran (200 ml) at below 5° C. and under a gentle stream of dry nitrogen. The resulting mixture was stirred at room temperature for 1 hour and 4-methoxybenzyl chloride (123.2 g, 0.79M) in dry tetrahydrofuran (100 ml) was added. The resulting mixture was stirred at room temperature, protected from light, for 3 days.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].CC(C)(C)C([OH:11])C.ON1[C:19](=O)[C:18]2=CC=[CH:23][CH:24]=[C:17]2C1=O.O=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(#N)C>[OH:11][CH:2]1[CH2:3][C:6]2([CH2:19][CH2:18][CH2:17][CH2:24][CH2:23]2)[O:5][C:1]1=[O:4]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C=CC(=O)OC
Reactant: CC(O)C(C)(C)C
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: CC#N
Product: O=C1OC2(CCCCC2)CC1O
Yield: 83 %

Procedure:
A mixture of 3 mmol of methyl acrylate, 15 mmol of 3,3-dimethyl-2-butanol, 0.3 mmol of N-hydroxyphthalimide, 0.003 mmol of cobalt(II) acetate, 0.03 mmol of acetylacetonatocobalt(III), and 1 ml of acetonitrile was stirred at 50° C. in an oxygen atmosphere (1 atm) for 5 hours. A reaction mixture was subjected to column chromatography on a silica gel to yield 3-hydroxy-2-oxo-1-oxaspiro[4.5]decane in a yield of 83%.