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]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[CH:23]([OH:26])[CH2:24][CH3:25].C1CCN2C(=NCCC2)CC1.[Cl-].O>C(Cl)Cl>[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]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[C:23](=[O:26])[CH2:24][CH3:25]
Reactant: CCC(O)c1cc(C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCC(=O)c1cc(C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 84.2 %

Procedure:
Under an argon atmosphere, 1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-1-propanol (compound 9) (31.3 mg) was dissolved in methylene chloride (2 ml), and 1,8-diazabicyclo[5.4.0]-7-undecene (30.7 mg) was then added to the solution, followed by cooling to −78° C. N-Tert-butylbenzenesulfineimidoyl chloride (30.4 mg) was dissolved in methylene chloride to prepare a solution, the solution was added thereto, and the mixture was stirred at −78° C. for 50 min. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (26.2 mg, yield 84%).
Reaction SMILES: [CH:1]1[C:10]2[C@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][C@H:12]3[N:8]4[C:9]5[C:4](=[CH:3][CH:2]=[CH:1][C:10]=5[C@H:11]3[CH2:16]2)[CH2:5][CH2:6][CH2:7]4)=[CH:23][CH:24]=1
Reactant: Fc1ccc(OCCCCl)cc1
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(OCCCN2CC[C@@H]3[C@H](C2)c2cccc4c2N3CCC4)cc1
Yield: 31.8 %

Procedure:
The title compound (0.14 g, 32%) was prepared by the general method of Example 402 from (±)-cis-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.25 g, 1.2 mmol), 1-(3-chloropropoxy)-4-fluorobezene (0.37 g, 2.0 mmol), KI (catalytic) and K2CO3 (0.28 g, 2.0 mmol) after chromatographic purification as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ1.78-2.08 (m, 7H), 2.10-2.30 (m, 1H), 2.32-2.50 (m, 3H), 2.51-2.72 (m, 3H), 2.75-2.82 (m, 1H), 3.00-3.12 (m, 1H), 3.12-3.25 (m, 2H), 3.89 (t, J=6.3 Hz, 2H), 6.55 (t, J=7.5 Hz, 1H), 6.70-6.92 (m, 6H) ppm.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[C:7](=O)[CH:8]([CH:10]([CH3:12])[CH3:11])[CH2:9][C:4]=2[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH:10]([C:8]1[CH2:7][C:5]2[S:6][C:2]([CH3:1])=[C:3]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:4]=2[CH:9]=1)([CH3:12])[CH3:11]
Reactant: Cc1sc2c(c1-c1ccccc1)CC(C(C)C)C2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1sc2c(c1-c1ccccc1)C=C(C(C)C)C2
Temperature: 80 °C
Reaction time: 12 h
Yield: 104.6 %

Procedure:
A solution of 2-methyl-5-(isopropyl)-3-phenyl-4,5-dihydrocyclopenta[2,1-b]thiophen-6-one (18.5 g, 0.068 mol) in 80 mL of ether was treated with 40 mL of an ether solution of LiAlH4 (1 M, 0.04 mol). After sting for 12 h, water (˜20 mL) was added cautiously and the mixture was filtered through celite. The filter pad was washed with dichloromethane (3×100 mL) and the combined organic fractions were dried (MgSO4). Solvents were evaporated and the residue was dissolved in 150 mL of toluene. p-TSA (1.0 g) was added and the mixture was stirred at 80° C. for 2 h. After cooling, the mixture was washed with a saturated aqueous solution of NaHCO3, brine solution, and dried (MgSO4). Evaporation of solvent gave 18.1 g of product (93% purity by GC/MS). 1H-NMR δ (CD2Cl2): (major isomer) 7.3–7.5 (m, 5H), 6.48 (s, 1H), 3.2 (s, 2H), 2.8 (m, 1H), 2.5 (s, 3H), 1.22 (d, 6H). EIMS: m/z (%) 254 (M+, 55), 239 (100), 224 (25), 211 (5), 191 (5), 178 (9), 165 (7).
Reaction SMILES: [CH2:1]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH:30]O>C(O)CC>[CH2:16]([N:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[OH:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: OO
Reactant: CCCCCCCCCCCCCCNCCCCCCCCCCCCCC
Solvent: CCCO
Product: CCCCCCCCCCCCCCN(O)CCCCCCCCCCCCCC

Procedure:
The general procedure of Example 5 is followed using, at 50 to 55° C., 50 grams (0.12 mol) of ditetradecylamine, 200 ml of n-propanol and 8.3 grams (0.12 mol) of 50% aqueous hydrogen peroxide solution. The above-named product is obtained in a yield of 33.4 grams (64%) as white needles melting at 97-99° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH:10]([CH2:15]Br)[C:9]=2[C:17]=1[CH3:18])(=[O:3])[CH3:2].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].O>CN(C)C=O>[C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH:10]([CH2:15][N:25]3[C:24](=[O:26])[C:23]4=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]4[C:21]3=[O:31])[C:9]=2[C:17]=1[CH3:18])(=[O:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(CBr)C(C)(C)O2
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(CN1C(=O)c3ccccc3C1=O)C(C)(C)O2
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A mixture of 4.75 g of 5-acetoxy-3-bromomethyl-2,3-dihydro-2,2,4,6,7-pentamethyl-1-benzofuran (see Example 3) and 2.58 g (1 equivalent)of potassium phthalimide in 50 ml of dry dimethylformamide is stirred at 60° C. for 48 hours. Water is added and the product is extracted twice with ethyl ether. The extract is washed with water and brine, and is dried over anhydrous sodium sulfate. After filtration, evaporation of the solvent leaves a residue that is crystallized from ethyl acetate/heptane. The first crop contains free phthalimide, but subsequent crops yield 2,3-dihydro-2,2,4,6,7-pentamethyl-3-phthalimidomethyl-1-benzofuran-5-ol acetate.
Reaction SMILES: [F:1][C:2]1([F:31])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH:25]6[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]6)[CH:24]=5)[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:4]=2[O:3]1.C(N(CC)CC)C.[CH2:39]([S:42](Cl)(=[O:44])=[O:43])[CH2:40][CH3:41]>C(Cl)Cl>[F:31][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH:25]6[CH2:26][CH2:27][N:28]([S:42]([CH2:39][CH2:40][CH3:41])(=[O:44])=[O:43])[CH2:29][CH2:30]6)[CH:24]=5)[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:4]=2[O:3]1
Reactant: FC1(F)Oc2ccc(-c3c[nH]c4ncc(-c5cnn(C6CCNCC6)c5)cc34)cc2O1
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N1CCC(n2cc(-c3cnc4[nH]cc(-c5ccc6c(c5)OC(F)(F)O6)c4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 324 (50 mg, 0.1182 mmol) in DCM was added triethylamine (17.9 mg, 0.1773 mmol) and propane sulfonyl chloride 339 (16.7 mg, 0.1182 mmol) and stirred for 2 h at rt. The RM was diluted with dichloromethane and washed with water twice. The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified by flash column using 100-200 mesh silica gel. The compound was eluted at 2% Methanol in chloroform as off white coloured solid 345. 1HNMR (400 MHz, DMSO) δ: 11.95 (s, 1H), 8.55 (d, 1H), 8.39 (m, 2H), 8.03 (s, 1H), 7.88 (d, 1H), 7.78 (d, 1H), 7.58 (m, 1H), 7.44 (d, 1H), 4.35 (m, 1H), 3.69 (m, 2H), 3.03 (m, 4H), 2.14 (m, 2H), 1.97 (m, 2H), 1.70 (m, 2H), 1.00 (m, 3H) and MS ES+530.1.
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1[NH:11][CH2:12][CH2:13][CH3:14].C([CH:18]([C:22](Cl)=[O:23])[C:19](Cl)=[O:20])C.[CH2:25]([O:27]CC)[CH3:26]>>[CH2:25]([O:27][C:22]([C:18]1[C:19](=[O:20])[N:11]([CH2:12][CH2:13][CH3:14])[C:5]2[C:4]([C:3]=1[OH:15])=[CH:9][CH:8]=[C:7]([CH3:10])[N:6]=2)=[O:23])[CH3:26]
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: CCCNc1nc(C)ccc1C(=O)OC
Reactant: CCOCC
Product: CCCn1c(=O)c(C(=O)OCC)c(O)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 30.7 g. (0.015 mole) of methyl-2-propylaminonicotinic acid methyl ester in 250 ml. of anhydrous diethyl ether was added 11.25 g. (0.0075 mole) of ethyl malonyl chloride. The mixture was stirred at room temperature for 2 hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was dissolved in 20 ml. of ethanol and this solution was added to a solution of 3.4 g. (0.015 g. atom) of sodium in 200 ml. of ethanol. After stirring at room temperature for 5 minutes, the mixture was diluted with water and was acidified with concentrated hydrochloric acid. The precipitate which formed was collected, air dried and was recrystallized from heptane to afford 3.4 g. of the title compound, m.p. 128°-30° C.
Reaction SMILES: O[CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.C(N(CC)CC)C.[Cl-].[Li+].CS([Cl:37])(=O)=O>O1CCCC1.C(OCC)(=O)C>[Cl:37][CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: NS(=O)(=O)c1ccc(-c2oc(CO)nc2-c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(-c2oc(CCl)nc2-c2ccccc2)cc1
Reaction time: 3 h

Procedure:
A solution of 4-[2-hydroxymethyl-4-phenyloxazol-5-yl]benzenesulfonamide (Step 2) (1.0 g, 3 mmol) and triethylamine (0.61 g, 6 mmol) was stirred in tetrahydrofuran (100 mL) at 0° C. Lithium chloride (0.25 g, 6 mmol) was added, followed by the dropwise addition of methanesulfonyl chloride (0.38 g, 3.3 mmol). After stirring for 3 h from 0° C. to 25° C., ethyl acetate (100 mL) was added, and the mixture was washed with 1N hydrochloric acid, brine and water, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with a 1:1 mixture of ethyl acetate:hexanes. The appropriate fractions were concentrated to a clear oil which solidified upon standing to give 4-[2-chloromethyl-4-phenyloxazol-5-yl]benzenesulfonamide as a white solid which was used in the next step without further purification or characterization.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)[O:3]1.C(N/C(=N/C(C)C)/O[C:26]([CH3:29])([CH3:28])[CH3:27])(C)C>C1COCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:19])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:17])=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Reactant: CC(C)/N=C(/NC(C)C)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (0.250 g, 0.954 mmol) was dissolved in 10 mls of dry THF. To this solution was added (Z)-tert-butyl N,N′-diisopropylcarbamimidate (3.82 g, 19.08 mmol) and the mixture was allowed to stir at room temperature for 16 hours. The mixture was then filtered, filtrate concentrated under reduced pressure and purified by a 50 g Snap cartridge (Biotage, 10% EtOAc/Hexanes) to give 280 mgs (92%) of tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate as a thick oil.
Reaction SMILES: N1C=CN=[CH:2]1.Cl[Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9].[CH3:17][O:18][C:19]([C:21]1[C:22]([OH:36])=[C:23]2[C:28](=[C:29]([OH:35])[C:30]=1[C:31]([O:33][CH3:34])=[O:32])[N:27]=[CH:26][CH:25]=[CH:24]2)=[O:20].C([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:17][O:18][C:19]([C:21]1[C:22]([O:36][CH3:2])=[C:23]2[C:28](=[C:29]([O:35][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[C:30]=1[C:31]([O:33][CH3:34])=[O:32])[N:27]=[CH:26][CH:25]=[CH:24]2)=[O:20]
Reactant: COC(=O)c1c(C(=O)OC)c(O)c2ncccc2c1O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(=O)OC)c(O[Si](C(C)C)(C(C)C)C(C)C)c2ncccc2c1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 59 %

Procedure:
Imidazole (0.74 g, 10.8 mmol) and chlorotriisopropylsilane (TIPSCl, 1.15 g, 6.0 mmol) were added to 5,8-dihydroxy-quinoline-6,7-dicarboxylic acid dimethyl ester (prepared by the method in Oguchi, S. Bulletin of the Chemical Society of Japan 1974, 47, 1291, 1.5 g, 5.4 mmol) in 20 mL DMF. The reaction was stirred for 48 h at rt and then the reaction was partitioned between 0.5 L methyl t-butyl ether and 150 mL saturated aq. LiCl. The organic layer was dried over Na2SO4 and the solvent removed by rotary evaporation. The residue (1.4 g, 3.2 mmol) was redissolved in 25 mL DMF and treated with K2CO3 (0.66 g, 4.8 mmol) followed by methyl iodide (MeI, 0.6 g, 4.8 μL) at rt. After 2 h, the reaction mixture was concentrated and purified by introduction of the reaction mixture onto silica gel for flash chromatography (4/1 hexanes/ethyl acetate) to give 5-methoxy-8-triisopropylsilanyloxy-quinoline-6,7-dicarboxylic acid dimethyl ester (1.4 g, 59% overall yield): 1H NMR (CDCl3) δ 8.85 (d, 1H), 8.45 (d, 1H), 7.50 (dd, 1H), 4.05 (s, 3H), 3.95 (s, 3H), 3.90 (s, 3H), 1.45 (septet, 3H), 1.05 (d, 9H); MS: 448 (M+H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([C:10]#[N:11])=[N:6][CH:7]=[CH:8][CH:9]=1)#[N:2].[O-:12][CH2:13][CH3:14].[Na+]>C(O)C>[CH2:13]([O:12][C:1]1[CH:3]=[C:4]2[C:5](=[C:10]([NH2:11])[N:2]=1)[N:6]=[CH:7][CH:8]=[CH:9]2)[CH3:14]
Reactant: CC[O-]
Reactant: N#CCc1cccnc1C#N
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc2cccnc2c(N)n1
Yield: 14 %

Procedure:
To a 1 L round bottom flask was added 3-(cyanomethyl)picolinonitrile (3.56 g, 24.9 mmol), absolute ethanol (400 mL), followed by sodium ethoxide (11.1 mL, 21% solution w/v, 29.9 mmol). The mixture was stirred at reflux for 3 h. The solvent was then concentrated and the resultant residue was dissolved in ethyl acetate (200 mL), washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel to yield 6-ethoxy-1,7-naphthyridin-8-amine as a pale yellow solid (0.66 g, 3.49 mmol, 14%). 1H NMR (400 MHz, CDCl3): δ ppm 8.53 (dd, J=3.95, 1.76 Hz, 1H), 7.83 (dd, J=8.35, 1.76 Hz, 1H), 7.39 (dd, J=8.35, 4.39 Hz, 1H), 6.15 (s, 1H), 5.87 (br. s., 2H), 4.22 (q, J=7.03 Hz, 2H), 1.45 (t, J=7.03 Hz, 3H). LC/MS m/z 190 [M+H].
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[S:13][C:12]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:11][CH:10]=1.[C:23](Cl)(=[O:27])[C:24]([CH3:26])=[CH2:25]>C(Cl)Cl>[Br:8][C:9]1[S:13][C:12]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])=[CH:11][CH:10]=1
Reactant: C=C(C)C(=O)Cl
Reactant: OCCCCCCOCc1ccc(Br)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCOCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
Triethylamine (2.10 g, 20.8 mmol) is added dropwise to a solution of 6-(5-bromothiophen-2-yl)methoxyhexanol (3.10 g, 10.62 mmol) and methacryloyl chloride (1.20 g, 11.54 mmol) in DCM (30 mL) at −10° C. This mixture is allowed to warm to room temperature and stirred overnight before it is quenched by the addition water (50 mL) The organic layer is separated and the liquid phase is extracted with DCM (2×30 mL). The organic layers is combined, washed with brine (50 mL), dried (Na2SO4) and evaporated under reduced pressure. The product is purified by column chromatography on silica, eluting with petroleum ether (40-60° C.)/ethyl acetate (90:10) to afford the product as a pale yellow oil (3.27 g, 86%). NMR and MS showed the expected signals.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:18]4)=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:27]>CC(O)C>[C:21]1([C:17]2[CH:16]=[CH:15][C:14]3[C:19](=[CH:20][C:11]([C:10]4[C:3]5[C:2]([NH2:27])=[N:7][CH:6]=[N:5][C:4]=5[S:8][CH:9]=4)=[CH:12][CH:13]=3)[N:18]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: N
Reactant: Clc1ncnc2scc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Solvent: CC(C)O
Product: Nc1ncnc2scc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Temperature: -78 °C

Procedure:
From 7-(4-chlorothieno[2,3-d]pyrimidin-5-yl)-2-phenylquinoline: Gaseous NH3 was bubbled into a iPrOH (1 ml) solution of 7-(4-chlorothieno[2,3-d]pyrimidin-5-yl)-2-phenylquinoline (56 mg, max. 0.084 mmol) in a sealable tube, cooled to −78° C. in a dry ice/acetone bath, for 15 min. The sealed tube was equipped with a Teflon washer, sealed and heated at 110° C. for 8 h. After that time, the excess NH3 and the solvent were evaporated. The remaining material was purified by HPLC to give the title compound as an off-white solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:8]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([Cl:17])=[CH:9]2)[C:7]1([CH3:19])[CH3:18])=[O:5])C.[OH-].[K+]>C(O)C.O>[Cl:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2([C:7]([CH3:18])([CH3:19])[CH:6]2[C:4]([OH:5])=[O:3])[CH:9]=1
Reactant: CCOC(=O)C1C(C)(C)C12C=C(Cl)c1ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)C(C(=O)O)C12C=C(Cl)c1ccccc12
Yield: 86.2 %

Procedure:
A solution of 3'-chloro-3,3-dimethyl-spiro[cyclopropane-1,1'-indene]-2-carboxylic acid ethyl ester (2.0 g; 0.007 mole) in ethanol (10 ml) is added to a mixture of 50% aqueous potassium hydroxide (1.2 ml) and water (1.2 ml), and the mixture is heated at reflux for 11/2 hours, then cooled down, diluted with water and extracted with ether. The aqueous phase is then made acid with concentrated hydrochloric acid and extracted with ether. The ethereal extract is washed with water, saturated salt solution, dried over magnesium sulfate and is stripped to afford 1.5 g of title product, a read-brown semisolid.
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[N:11][C:6]2=[N:5][CH:4]=1)=O.[NH2:12]/[C:13](/[CH3:19])=[CH:14]\[C:15]([O:17][CH3:18])=[O:16].[C:20]([O:26][CH3:27])(=[O:25])[CH2:21][C:22]([CH3:24])=O>C(O)(C)C.CCOCC>[CH3:19][C:13]1[NH:12][C:22]([CH3:24])=[C:21]([C:20]([O:26][CH3:27])=[O:25])[CH:1]([C:3]2[N:7]3[CH:8]=[CH:9][CH:10]=[N:11][C:6]3=[N:5][CH:4]=2)[C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=Cc1cnc2ncccn12
Reactant: COC(=O)CC(C)=O
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Solvent: CCOCC
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cnc2ncccn12
Reaction time: 1 h

Procedure:
To 0.5 g (3.4 mmol) (2) in 10 ml isopropanol was added 0.39 g (3.4 mmol) methyl 3-aminocrotonate and 0.39 g (3.4 mmol) methyl acetoacetate and the resulting solution refluxed overnight. The cooled reaction mixture was then diluted with 15 ml ether and stirred for 1 hour. The tan solid was filtered off and recrystallized from ethyl acetate to give pure (3), m.p. 202°-205° (dec).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[CH2:17]([C:19]1[O:23][C:22]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([O:37][CH3:38])[C:31](N(OC)C)=[O:32])=[CH:26][CH:25]=2)=[N:21][N:20]=1)[CH3:18]>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:31](=[O:32])[CH:30]([C:27]3[CH:28]=[CH:29][C:24]([C:22]4[O:23][C:19]([CH2:17][CH3:18])=[N:20][N:21]=4)=[CH:25][CH:26]=3)[O:37][CH3:38])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: CCc1nnc(-c2ccc(C(OC)C(=O)N(C)OC)cc2)o1
Product: CCc1nnc(-c2ccc(C(OC)C(=O)c3ccc(-c4cc(OC)c(Br)c(OC)c4)o3)cc2)o1
Yield: 12 %

Procedure:
The method used for the final coupling step of Example 12 was followed for the reaction of 2-(4-bromo-3,5-dimethoxyphenyl)furan with 2-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide. Purification by chromatography (20-100% EtOAc-hexanes) gave 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxyethanone as a yellow foam (0.037 g, 12% yield). MS: m/z 527.1 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].C([O-])(=O)C.[NH4+]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:14][C:15]([OH:17])=[O:16])[CH:2]=1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CCc1cnc2ccccc2c1
Temperature: 25 °C
Yield: 56 %

Procedure:
A solution containing quinoline-3-carboxaldehyde 4-1 (5 g, 31.8 mmol), malonic acid (3.6 g, 35.0 mmol), and ammonium acetate (5.0 g, 63.6 mmol) in anhydrous ethanol (125 mL) was heated at reflux for 12 h. After cooling to room temperature, the resulting white solid was collected by filtration and washed with cold ethanol (150 mL) and then dried under vacuum to provide 4-2 as a white solid (3.84 g, 17.8 mmol, 56%). 1H NMR (300 MHz, D2O):δ 8.91 (d, J=2 Hz 1H), 8.21 (d, J=2 Hz, 1H), 8.12 (d, J=8 Hz, 1H), 7.84 (d, J=7 Hz, 1H), 7.72 (t, J=7 Hz, H), 7.54 (t, J=7 Hz, 1,H), 4.72 (m, 1H), 2.73 (m, 2H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.CN(C)C=O.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].O>C(Cl)(Cl)Cl>[C:25]1(=[O:35])[N:29]([CH2:2][CH2:3][CH2:4][CH:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:9]=[CH:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]2=3)[C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12
Reactant: ICCCC1c2ccccc2C=Cc2ccccc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CCCC1c2ccccc2C=Cc2ccccc21

Procedure:
5-(3-Iodopropyl)-5H-dibenzo[a,d]cycloheptene, 1.8 g. (0.005 mole), is dissolved in 10 ml. of dimethylformamide. The solution is stirred while 930 mg. (0.0051 mole) of potassium phthalimide is added. When the addition is complete, the mixture is heated to 85°-90°C. for 40 minutes, then cooled, diluted with chloroform and poured into water. The chloroform layer is separated and the aqueous layer extracted further with chloroform. Evaporation of the chloroform gives the product as an oily crystalline solid. Several recrystallizations from isopropyl alcohol gave product, m.p. 125.5°-131.5°C.