Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][CH2:2]CCC.[C:6]([O:10][C@@H:11]([C:17]1[C:26]([CH:27]=O)=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:9])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCOC(C)=O>[C:6]([O:10][C@@H:11]([C:17]1[C:26]([CH:27]=[CH2:2])=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:7])([CH3:8])[CH3:9]
Reactant: [Li]CCCC
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C=O)cc2ccccc2c1-c1ccc(Cl)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (60 mg, 0.168 mmol) in THF (1 mL) at −78° C. was added dropwise n-BuLi (1.6 M in hexanes, 90 μL), followed after 30 min by a solution of (S)-ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-3-formylnaphthalen-2-yl)acetate (12 mg, 0.028 mmol) in THF (1 mL). The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. This mixture was added to another mixture, which was made by adding n-BuLi (1.6 M in hexanes, 300 μL) to a suspension of methyltriphenylphosphonium bromide (200 mg, 0.56 mmol) in THF (2 mL) and stirred at −78° C. for 15 min. Then the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc, washed with sat. NH4Cl, and extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, concentrated in vacuo and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to provide 7.4 mg of the desired product. 1H-MNR 400 MHz (CDCl3) δ: 7.95 (s, 1H), 7.78 (d, J=4.2 Hz, 1H), 7.57-7.50 (m, 1H), 7.43-7.17 (m, 6H), 5.62 (dd, J=8.1, 2 Hz, 1H), 5.25 (dd, J=5.3, 1.8 Hz, 1H), 5.07 (s, 1H), 4.06-4.02 (m, 2H), 1.10 (t, J=7 Hz, 3H), 0.93 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[O:7][C:8]1[N:23]=[CH:22][CH:21]=[CH:20][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[O:11])(=[O:3])[CH3:2].C[Li].[CH2:29]1COCC1.C1(C(C)C)C=CC=CC=1>O1CCCC1>[OH:3][C:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[O:7][C:8]1[N:23]=[CH:22][CH:21]=[CH:20][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[O:11])([CH3:29])[CH3:2]
Reactant: CC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccncc2)c1
Reactant: C1CCOC1
Agent: [Li]C
Solvent: CC(C)c1ccccc1
Product: CC(C)(O)c1cccc(Oc2ncccc2C(=O)NCc2ccncc2)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3-Acetyl-phenoxy)-N-pyridin-4-ylmethyl-nicotinamide (0.180 grams, 0.51 mmole) in tetrahydrofuran (20 ml) at −78° C. 1.0 M methyl lithium in THF/cumene (1.14 ml, 1.14 mmole) was added and stirred at −78° C. for 1 hour. The reaction was quenched with water and diluted with ethyl acetate. The organics were washed with water and brine, dried over MgSO4, filtered and concentrated to give a product which was purified by chromatography on silica eluting with ethyl acetate to give a white foam. MS (m/e) 364 (M++1); 1H NMR (CDCl3) d 1.58 (6H, s), 4.70 (2H, d, J=5.81 Hz), 7.0-8.7 (12H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.Br[C:29]1[CH:30]=[C:31](C(OC)=O)[C:32]2[C:33](C=O)=[N:34]NC=2C=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:50][N:51](C=O)[CH3:52]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:50][N:51]([CH3:52])[C:33]1[N:34]=[CH:29][C:30]([C:2]2[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[O:16])[C:5]3[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=3[CH:10]=2)=[CH:31][CH:32]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reactant: COC(=O)c1cc(Br)cc2[nH]nc(C=O)c12
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N(C)C)nc3)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 6-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indazole-4-carboxamide (300 mg, 0.696 mmol) in DMF (30 mL) was added 6-(dimethylamino)pyridin-3-yl-3-boronic acid, 1 (127 mg, 0.765 mmol) followed by sodium carbonate (184.4 mg, 1.74 mmol) dissolved in water (3 mL) and degassed with argon for 1 h. Then PdCl2(PPh3)2 (48.8 mg, 0.069 mmol) was added and again degassed with argon for 15 min and stirred at 110° C. for 4 h. The reaction mixture was filtered through Celite pad and washed with ethyl acetate (50 mL). The filtrate was diluted with water and extracted with ethyl acetate (4×90 mL). The combined organic layers were separated and washed with cold water (2×50 mL), brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude product (450 mg). The crude compound was purified by silica gel chromatography (eluent: 5% MeOH: DCM) to afford 100 mg of desired product which was triturated with hexane and the solid was filtered and dried to afford the title compound as an off white solid (100 mg, 30%). 1H NMR (DMSO-d6, 400 MHz): δ 1.559 (d, J=6.8 Hz, 6H), 2.102 (s, 3H), 2.403 (s, 3H), 2.539 (s, 3H), 3.125 (s, 6H), 4.616 (s, 2H), 4.754-4.820 (m, 1H), 5.893 (s, 1H), 6.557 (d, J=8.8 Hz, 1H), 7.313 (s, 1H), 7.401 (d, J=5.2 Hz, 1H), 7.448 (s, 1H), 7.707 (d, J=8.8 Hz, 1H), 8.438 (s, 1H), 11.502 (brs, 1H). 1H NMR (D2O Ex in DMSO, 400 MHz): δ 1.559 (d, J=6.8 Hz, 6H), 2.115 (s, 3H), 2.408 (s, 3H), 2.538 (s, 3H), 3.124 (s, 6H), 4.616 (s, 2H), 4.754-4.820 (m, 1H), 5.899 (s, 1H), 6.557 (d, J=8.8 Hz, 1H), 7.318 (s, 1H), 7.450 (s, 1H), 7.718 (d, J=8.8 Hz, 1H), 8.438 (s, 1H). LCMS (ES+): 473.19.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[N:3]=1.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C>CN(C)C=O>[ClH:1].[ClH:1].[Cl:19][C:14]1[CH:13]=[C:12]([C:4]2[N:3]=[C:2]([NH:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: Clc1ccc(-c2nc(Cl)c3ccccc3n2)cc1Cl
Reactant: NCCCN1CCCC1
Solvent: CN(C)C=O
Product: Cl
Product: Clc1ccc(-c2nc(NCCCN3CCCC3)c3ccccc3n2)cc1Cl

Procedure:
To a solution of 4-chloro-2-(3,4-dichlorophenyl)quinazoline (37.0 g., 0.12 mole) in dimethylformamide (400.0 ml) was added N-(3-aminopropyl) pyrrolidine (31.0 g., 0.24 mole). After stirring and heating the mixture for 4.0 hrs., the mixture was treated with charcoal and filtered. The solution was treated with H2O and then refrigerated. The cream colored powder removed by filtration was suspended in ethereal hydrochloric acid and treated with ethanol. After cooling, the off-white powder was removed by filtration and weighed 57.0 g., (100%). Two recrystallizations from ethanol + HCl/CH3OH + HCl/Charcoal (precipitated with ether) provided an analytical sample melting at 261°-263°. Anal. Calcd. for C21H22Cl2N4.2HCl: C, 53.18; H, 5.10; N, 11.81. Found: C, 52.96; H, 5.19; N, 11.67.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[O:16][N:15]=[CH:14][CH:13]=1.[ClH:17].[S:18](=[O:20])=[O:19]>O.C(O)(=O)C>[O:16]1[C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:18]([Cl:17])(=[O:20])=[O:19])=[CH:13][CH:14]=[N:15]1
Reactant: Nc1ccccc1-c1ccno1
Reactant: O=S=O
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(Cl)c1ccccc1-c1ccno1
Temperature: 10 °C
Reaction time: 0.4 h

Procedure:
A diazonium salt was prepared by adding a solution of 14.5 g of sodium nitrite in 30 ml of water to a suspension of 32 g of 5-(2-aminophenyl)isoxazole, prepared in Example 3, and 72 ml of concentrated hydrochloric acid in 210 ml of glacial acetic acid cooled at 0° to 5° C. After stirring about 0.4 hour, the diazonium salt suspension was poured in one portion into a mixture consisting of 150 ml of acetic acid, 8.4 g of cupric chloride dihydrate and 60 ml of sulfur dioxide and cooled at 10° C. by an ice-water bath. The mixture was stirred at 10° to 15° C. for 0.2 hour then at about 20° to 30° C. for 3 hours. The suspension was poured into ice-water (about 700 ml) and stirred to form a solid. The mixture was filtered and the solid was washed 3×100 ml of water and suction dried to give 37 g of crude 2-(isoxazol-5-yl)benzenesulfonyl chloride; m.p. 63°-65° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19].[CH2:22]1C[O:25][CH2:24][CH2:23]1>C(Cl)Cl>[C:17]([O:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([O:9][C:24](=[O:25])[CH:23]=[CH2:22])[CH:4]=1)(=[O:20])[CH:18]=[CH2:19]
Reactant: C1CCOC1
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1ccc(Cl)c(OC(=O)C=C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-chlororesorcinol (86.76 g, 0.60 mol) in anhydrous THF (750 mL) in a 2-liter three neck round bottom flask equipped with dry nitrogen purge, thermo-couple, condenser, and ice-water bath, triethylamine (163.6 g, 1.62 mol) in anhydrous THF (100 mL) was added dropwise in 10 minutes. After 10 minutes, acryloyl chloride (136 g, 1.5 mol) in anhydrous THF (300 mL) was added dropwise in 30-60 minutes (maintain 0-5C of the solution). A precipitate formed immediately, and the mixture was warmed to room temperature and stirred overnight (˜15 hrs). The resulting mixture was filtered to remove the solid, and the filtrate was concentrated by rotary evaporation to give a darkly colored viscous liquid. The liquid was dissolved in methylene chloride (200 mL), cooled in an ice bath, washed with 1.0 N sodium hydroxide until pH>10, washed with 1.0 N HCl until pH<2, washed with DI water until pH>5, and dried over anhydrous sodium sulfate. The compound was purified by column chromatography and vacuum concentrated at room temperature to give a pale yellow or colorless liquid.
Reaction SMILES: [CH3:1][C:2]([CH3:7])(C)[C:3]([Cl:5])=[O:4].[CH:8](=[O:12])[CH:9]([CH3:11])[CH3:10].Cl[CH2:14]Cl>>[CH3:10][C:9]([CH3:14])([CH3:11])[C:8]([O:4][CH:3]([Cl:5])[CH:2]([CH3:7])[CH3:1])=[O:12]
Reactant: CC(C)C=O
Reactant: ClCCl
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)C(Cl)OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To freshly fused zinc chloride (70 mg) and trimethylacetylchloride (12.3 mL, 100 mmol) cooled in an ice bath in dichloromethane (25 mL) was added isobutyraldehyde (9.08 mL, 100 mmol), keeping the reaction temperature <25° C. The solution was allowed to warm to room temperature and stirred one hour, washed with a solution of sodium acetate (50 mL, 20%), dried (magnesium sulfate), and concentrated under low vacuum to remove dichloromethane (yield 16.18 g, 84 mmol, 84%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:18]([O:20][CH:21]([Cl:23])[CH3:22])=[O:19].N1C=CC=CC=1>C(Cl)Cl>[Cl:23][CH:21]([O:20][C:18](=[O:19])[O:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)[CH3:22]
Reactant: CC(Cl)OC(=O)Cl
Reactant: OCc1ccc(OCc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)OCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.07 g (5.0 mmol) 4-benzyloxybenzyl alcohol and 0.786 g (5.5 mmol) 1-chloroethyl chloroformate in 25 ml CH2Cl2 is cooled to 0° C. and 0.435 g (5.5 mmol) pyridine added. After stirring at rt for 2 h the reaction mixture is quenched with 1N HCl, the organic phase separated and washed with sat. NaHCO3 solution and brine, dried over Na2SO4 and evaporated: 1.58 g (98%) (RS)-carbonic acid 4-benzyloxy-benzyl ester 1-chloro-ethyl ester as light yellow oil. 1H-NMR (CDCl3): 1.81 d, J=6 Hz, 3H; 5.07 s, 2H; 5.14 and 5.17, AB-system J=15 Hz, 2H; 6.43 q, J=6 Hz, 1H; 6.97 d, J=8.5 Hz, 2H and 7.30–7.45 m, 7H.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[CH2:10]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17]>>[CH2:10]([N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18]
Reactant: O=C(O)c1cnccn1
Reactant: CC(C)CCCCCCNCCCCCCC(C)C
Product: CC(C)CCCCCCN(CCCCCCC(C)C)C(=O)c1cnccn1

Procedure:
N,N-diisononylpyrazine-2-carboxamide was prepared from pyrazine-2-carboxylic acid and commercial di-isononylamine using the general method of Example 11. The product had a boiling range of 163°-165° C. at 0.15 mm of mercury pressure.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-:13].[Na+]>C1(C)C=CC(C)=CC=1>[NH2:13][C:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=[CH:10][N:9]=1.[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][N:9]=1
Reactant: c1ccc(-c2cccnc2)cc1
Reactant: [NH2-]
Agent: [Na+]
Solvent: Cc1ccc(C)cc1
Product: Nc1ccc(-c2ccccc2)cn1
Product: Nc1ncccc1-c1ccccc1
Yield: 55.8 %

Procedure:
2-amino-3-phenyl pyridine was prepared as follows: 3-phenyl pyridine (300 mg, 2 mmol) was dissolved in para-xylene (6 ml), and sodamide (84 mg, 2.1 mmol) was then added. The reaction mixture was heated to reflux temperature for 8 hours. The reaction mixture was cooled, poured onto ice/water (25 ml), and extracted with dichloromethane. The organic extracts were washed with water and brine, and dried over anhydrous sodium sulphate. The sodium sulphate was removed by filtration, and the filtrate was evaporated to dryness and recrystallized from a mixture of diethyl ether and petroleum ether to provide 2-amino-5-phenyl pyridine (95 mg). The mother liquors from the crystallization were evaporated to dryness and subjected to purification by column chromatography (silica), thereby eluting the solvent ethyl acetate:petroleum ether (30:70). The desired product, 2-amino-3-phenyl pyridine, was obtained as a fine yellow powder (15 mg).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:12][CH2:13][C:14]1[N:15]([CH2:27][C:28]2([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1)[CH3:11]>ClCCl>[CH2:10]([O:12][CH2:13][C:14]1[N:15]([CH2:27][C:28]2([OH:34])[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[CH2:30][CH2:29]2)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1)[CH3:11]
Reactant: O=C=Nc1ccccc1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCNCC1
Solvent: ClCCl
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Yield: 101.3 %

Procedure:
Under a nitrogen atmosphere phenyl isocyanate (1.00 mL, 9.25 mmol) was added dropwise to a chilled mixture of 4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidin-4-ol (3.00 g, 8.81 mmol) and dichloromethane (90 mL). The reaction mixture was allowed to warm to ambient temperature. After 2 hours the reaction mixture was concentrated under reduced pressure to provide an orange oil. This material was triturated with diethyl ether to provide 4.1 g of 4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-4-hydroxy-N-phenylpiperidine-1-carboxamide as a light orange solid.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH+:7]=1.[C:16](=[C:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=O)([CH3:18])[CH3:17]>CO>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:18][C:16]1[C:19]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[N+:7]2[CH2:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[CH:17]=1
Reactant: CC(C)=C1Cc2ccccc2C1=O
Reactant: C1=[NH+]CCc2ccccc21
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Product: Cc1cc2[n+](c3c1Cc1ccccc1-3)CCc1ccccc1-2

Procedure:
3,4-Dihydroisoquinolinium perchlorate (2 g) and 2-isopropylidene-indan-1-one (2 g) were heated together at 150° for 2 hours. The reaction mixture was cooled and diluted with methanol. The product was collected by filtration and recrystallized from methanol.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([Sn](CCCC)(CCCC)CCCC)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].Br[C:27]1[N:28]=[C:29]([N:37]2[CH2:42][CH2:41][N:40]([CH:43]=[O:44])[CH2:39][CH2:38]2)[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:43]([N:40]1[CH2:39][CH2:38][N:37]([C:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:36]=[C:27]([C:10]3[CH:9]=[CH:8][C:7]([S:4](=[O:5])(=[O:6])[NH:3][CH2:1][CH3:2])=[CH:12][CH:11]=3)[N:28]=2)[CH2:42][CH2:41]1)=[O:44]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(S(=O)(=O)NCC)cc1
Reactant: O=CN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCNS(=O)(=O)c1ccc(-c2cc3ccccc3c(N3CCN(C=O)CC3)n2)cc1
Yield: 41.4 %

Procedure:
N-Ethyl-4-tributylstannylbenzenesulfonamide (1.42 g) and 3-bromo-1-(4-formylpiperazin-1-yl)isoquinoline (0.82 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.12 g) in xylene in nitrogen atmosphere overnight. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 5N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate. Then, it was adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (toluene/acetone system), to give 1-(4-formylpiperazin-1-yl)-3-[4-(N-ethylsulfamoyl)phenyl]isoquinoline (0.45 g).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][C:13]3=[O:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][CH:18](O)[CH:19]=[CH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:17]([CH:12]1[CH2:11][C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[C:13]1=[O:16])[CH:18]=[CH:19][CH3:20]
Reactant: C=CC(C)O
Reactant: O=C1CCc2ccc(-c3ccccc3)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccc(-c3ccccc3)cc2C1=O
Yield: 72 %

Procedure:
A solution of 13.2 g of 6-phenyl-1-indanone, 11 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110ml of 2,2-dimethoxy-propane was boiled under reflux for 48 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 12.0 g (72%) of (RS)-2-(2-buten-1-yl)-6-phenyl-1-indanone was obtained as a light yellow solid which was used without further purification in the next reaction.
Reaction SMILES: OC(CO)CN(CC(O)CO)CCCN.OC(CO)CN(CC(O)CO)CCCN(CC(O)CO)CCCN.[CH:40]12[CH2:47][CH2:46][CH:43]([CH2:44][CH2:45]1)[CH2:42][CH:41]2[CH2:48][CH2:49][CH:50]([NH:61][CH2:62][CH2:63][CH2:64][N:65]([CH2:80][CH:81]([OH:84])[CH2:82][OH:83])[CH2:66][CH2:67][CH2:68][N:69](CC(O)CO)CC(O)CO)[CH2:51][CH2:52][CH:53]1[CH2:58][CH:57]2[CH2:59][CH2:60][CH:54]1[CH2:55][CH2:56]2>>[CH:54]12[CH2:60][CH2:59][CH:57]([CH2:56][CH2:55]1)[CH2:58][CH:53]2[CH2:52][CH2:51][CH:50]([NH:61][CH2:62][CH2:63][CH2:64][N:65]([CH2:80][CH:81]([OH:84])[CH2:82][OH:83])[CH2:66][CH2:67][CH2:68][NH2:69])[CH2:49][CH2:48][CH:41]1[CH2:42][CH:43]2[CH2:46][CH2:47][CH:40]1[CH2:45][CH2:44]2
Reactant: OCC(O)CN(CCCNC(CCC1CC2CCC1CC2)CCC1CC2CCC1CC2)CCCN(CC(O)CO)CC(O)CO
Agent: NCCCN(CC(O)CO)CC(O)CO
Agent: NCCCN(CCCN(CC(O)CO)CC(O)CO)CC(O)CO
Product: NCCCN(CCCNC(CCC1CC2CCC1CC2)CCC1CC2CCC1CC2)CC(O)CO

Procedure:
In a like manner and using analogous quantities, but employing N,N-di-(2,3-dihydroxypropyl)trimethylenediamine and 1,1,5-tri-(2,3-dihydroxypropyl)-1,5,9-triazanonane instead of 3,3'-(2,3-dihydroxypropylimino)bispropylamine there are prepared respectively N-[1,5-di-(bicyclo[2.2.2]oct-2-yl)-3-pentyl]-N'-di-(2,3-dihydroxypropyl)trimethylenediamine, and 1-[1,5-di-(bicyclo[2.2.2]oct-2-yl)-3-pentyl]-5-(2,3-dihydroxypropyl)-9,9-di-(2,3-dihydroxypropyl)-1,5,9-triazanonane.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])[CH2:2][CH2:3][CH3:4].[CH3:19][N:20]([CH3:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25]>C(OC(=O)C)(=O)C>[CH2:1]([O:5][C:6]1[CH:13]=[C:12]([N:14]([CH2:15][CH3:16])[CH2:17][CH3:18])[CH:11]=[CH:10][C:7]=1[CH:8]1[C:27]2[C:23](=[CH:22][C:21]([N:20]([CH3:30])[CH3:19])=[CH:29][CH:28]=2)[C:24](=[O:25])[O:9]1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: CCCCOc1cc(N(CC)CC)ccc1C=O
Solvent: CC(=O)OC(C)=O
Product: CCCCOc1cc(N(CC)CC)ccc1C1OC(=O)c2cc(N(C)C)ccc21

Procedure:
Employing a procedure similar to that described in Example 1, part A above, 13.3 g of 2-butoxy-4-diethylaminobenzaldehyde and 9.7 g of m-dimethylaminobenzoic acid were refluxed in acetic anhydride to obtain 3-(2-butoxy-4-diethylaminophenyl)-6-dimethylaminophthalide (Formula I: R=CH3 ; X=Z=H; Y=2-C4H9O-4-(C2H5)2NC6H3) as a tarry residue.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:12]=[O:13]>N1C=CC=CC=1.CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:11])([CH2:12][OH:13])[C:9]#[N:10])=[CH:6][CH:7]=1
Reactant: C=O
Reactant: CC(C#N)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: CC(C#N)(CO)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
To a stirred solution of 2-(4-bromo-phenyl)-propionitrile (27 g, 128.5 mmol) in pyridine (225 mL) was added paraformaldehyde (15.7 g, 514.3 mmol) and a 40% Triton-B solution (in methanol) (14.4 mL). Then the reaction mixture stirred at room temperature for 16 h. At this time, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with a 2N aqueous hydrochloric acid solution (2×200 mL), water (2×100 mL), sodium bicarbonate (2×50 mL), a saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. Flash chromatography afforded 2-(4-bromo-phenyl)-3-hydroxy-2-methyl-propionitrile as colorless oil (25.9 g, 84%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:21])[F:22])[CH:15]=1)[CH:6]=[O:7]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: COc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 84.4 %

Procedure:
To a solution of 4-fluoro-3-(methyloxy)benzaldehyde (1.07 g, 6.94 mmol) and 3-(trifluoromethyl)phenol (1.238 g, 7.64 mmol) in DMF (25 mL) was added K2CO3 (2.88 g, 20.83 mmol) under argon. The mixture was heated at 90° C. for 0.5 h. After removing the solvent, the residue was diluted with water, extracted with DCM. The organic phase was dried over sodium sulfate, filtered, and concentrated to afford the title compound (1.735 g, 5.86 mmol, 84% yield). LCMS: rt=3.53 min, [M+H+]=297