Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[F:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[F:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[N:31]1[CH2:32][CH2:33][N:34]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:35][CH2:36]1)[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23]
Reactant: CC(C)NC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(F)c1
Temperature: 105 °C
Yield: 33.6 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-fluoro-N-isopropyl-4-(piperazin-1-yl)benzamide hydrochloride (138 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 45-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6 mL) and dried in vacuum to afford (S)-3-fluoro-N-isopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (71.4 mg, 0.153 mmol, 33.6% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6.57 Hz, 6H) 1.82-2.01 (m, 3H) 2.12-2.24 (m, 1H) 2.46-2.50 (m, 4H) 2.98-3.15 (m, 4H) 3.35-3.44 (m, 3H) 3.54-3.64 (m, 1H) 3.92-4.14 (m, 2H) 6.98 (d, J=1.77 Hz, 1H) 7.03 (t, J=8.84 Hz, 1H) 7.56-7.66 (m, 3H) 8.09 (d, J=7.83 Hz, 1H) 10.45 (s, 1H). [M+H] calc'd for C25H31FN6O2, 467. found, 467.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=[O:15].[OH-].[K+:20]>CO>[O:15]=[C:14]([CH:16]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:13]([O-:18])=[O:17].[K+:20]
Reactant: O=CC=CC=Cc1ccccc1
Reactant: CC(=O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C(=O)C=CC=CC=Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 5-phenyl-2,4-pentadienal (6.70 g) and pyruvic acid (3.0 mL) in 5 mL of methanol was stirred and chilled to 0–5° C. in an ice bath. To the chilled solution was added a solution of 35 mL of potassium hydroxide (3.5 g) in 10 mL of methanol dropwise over a period of 30 minutes. The remaining methanolic potassium hydroxide was added rapidly and the ice bath was removed. The reaction was allowed to warm to room temperature and stirred for another hour. The flask was then refrigerated overnight. The solid was collected by filtration, washed with 15 mL of methanol three times, 15 mL of ether and then air dried to afford 6.69 g of potassium 2-oxo-8-phenyl-3,5,7-octatrienoate as a yellow solid. 1H NMR (DMSO-d6, 300 MHz), δ(ppm) 7.52 (d, 2H), 7.32 (m, 3H), 7.10 (m, 2H), 6.83 (dd, 2H), 6.57 (dd, 1H), 6.13 (d, 1H).
Reaction SMILES: C([O:9][CH2:10][CH:11]([NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=2)=[CH:17][C:16]=1[Cl:36])(=O)C1C=CC=CC=1.[OH-].[Na+].O>C(O)C>[CH2:29]([O:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][CH2:12][CH:11]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:10][OH:9])=[C:16]([Cl:36])[CH:17]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(OCC(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)Nc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCC(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
The compound of Example 128-2 (560 mg) was dissolved in ethanol (10 mL). To this solution, a 1 mol/L aqueous solution of sodium hydroxide (5 mL) was added and the mixture was stirred at room temperature for 1 hour. Following addition of water, the mixture was extracted with ethyl acetate and the extract was washed with a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous sodium sulfate. The solvent was concentrated and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product as a colorless oil (290 mg).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8]3[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:9]=3[O:10][C:11]=2[CH3:12])=[C:4]([Cl:23])[CH:3]=1.[C:24]1(OB(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(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.C1(C)C=CC=CC=1>[Cl:23][C:4]1[CH:3]=[C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][C:5]=1[CH2:6][C:7]1[C:8]2[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:9]=2[O:10][C:11]=1[CH3:12]
Reactant: OB(O)Oc1ccccc1
Reactant: COC(=O)c1ccc2oc(C)c(Cc3ccc(Br)cc3Cl)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc2oc(C)c(Cc3ccc(-c4ccccc4)cc3Cl)c2c1
Yield: 92.2 %

Procedure:
To unpurified 3-(4-bromo-2-chlorobenzyl)-5-(methoxycarbonyl)-2-methylbenzo[b]furan (4.00 g) were added a solution of phenylboric acid (1.34 g) in ethanol (3 ml), tetrakis(triphenylphosphine)palladium (0.40 g), sodium carbonate (1.59 g), water (7.50 g) and toluene (30 ml) and the mixture was heated under reflux for 80 min. After cooling, the insoluble matter was removed by filtration through Celite and the filtrate was washed with ethyl acetate and water. Saturated brine was added to the filtrate. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated to give an oil (3.50 g) containing the object compound as main component. The oil was used in the next step without purification.
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:9]([O:11][CH2:12][Cl:13])[CH3:10]>CC(=O)CC>[Cl-:13].[CH2:9]([O:11][CH2:12][N+:4]1([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:10]
Reactant: CC(C)N1CCCC1
Reactant: CCOCCl
Solvent: CCC(C)=O
Product: CCOC[N+]1(C(C)C)CCCC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A 40.09 g quantity of N-isopropylpyrrolidine was dissolved in 361 g of dehydrated 2-butanone (reagent, product of Wako Pure Chemical Ind. Ltd.), followed by replacement with nitrogen. To the solution was added dropwise 33.54 g of chloromethyl ethyl ether (reagent, product of Tokyo Kasei Co., Ltd. as purified by distillation) at 5° C. over a period of 0.5 hour. The mixture was thereafter heated to a gradually elevated temperature and stirred at room temperature for 10 hours, whereby the reaction was terminated. The reaction mixture was cooled to 5° C., and the resulting solids were filtered off in nitrogen. The filter cake was washed with 200 ml of 2-butanone, further washed with 200 ml of acetone and dried in a vacuum, giving 55.72 g of the desired product.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[N:4][S:3]1.[F:8][S:9]([O:12][CH3:13])(=[O:11])=[O:10]>C(Cl)Cl>[F:8][S:9]([O-:12])(=[O:11])=[O:10].[CH3:1][N+:2]1[S:3][N:4]=[CH:5][C:6]=1[O:7][CH3:13]
Reactant: COS(=O)(=O)F
Reactant: Cn1sncc1=O
Solvent: ClCCl
Product: COc1cns[n+]1C
Product: O=S(=O)([O-])F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Methyl-1,2,5-thiadiazole-3-one (11.6 g., 0.1 mole) was dissolved in dry methylene chloride (100 ml.) and under a nitrogen atmosphere was added methyl fluorosulfonate (8.2 ml., 0.1 mole) and the reaction mixture was stirred at room temperature for 1 hour. Further, methyl fluorosulfonate (0.1 ml.) was added and the reaction continued at reflux for one further hour. The reaction was cooled, the precipitate separated by filtration and washed with several portions of cold methylene chloride. Yield 13 g. The compound was stored in a dry atmosphere, m.p., 138°-139° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7](C3C=CC=C4C=3C=CN4)[NH:8]2)=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][C@H:21]2C)[N:3]=1.[O:27]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[CH3:34]CN(C(C)C)C(C)C.O>C(O)CCC>[CH3:34][C@@H:28]1[O:27][C@H:33]([CH3:32])[CH2:31][N:30]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][NH:8]3)=[C:4]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:3]=2)[CH2:29]1
Reactant: CCN(C(C)C)C(C)C
Reactant: C1CNCCOC1
Reactant: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]c(-c3cccc4[nH]ccc34)nc12
Solvent: CCCCO
Solvent: O
Product: C[C@@H]1CN(c2nc(N3CCOCC3)c3nc[nH]c3n2)C[C@H](C)O1
Temperature: 120 °C
Reaction time: 24 h
Yield: 78.5 %

Procedure:
To the solution of 2-chloro-8-(1H-indol-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (50 mg, 0.14 mmol) in 1-butanol (300 μL) was added 1,4-oxazepane (20.6 mg, 0.20 mmol), followed by DIPEA (47.4 μL, 0.27 mmol). The mixture was stirred at 120° C. for 24 hours. Upon completion of the reaction, the solution was poured into water. The aqueous layer was extracted with CH2Cl2 three times. The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure and the crude was purified by flash column chromatography (30-100% EtOAc/cyclohexane gradient) to provide 2-((2S,6R)-2,6-dimethyl-morpholin-4-yl)-6-morpholin-4-yl-9H-purine (35 mg, 59%) as a beige solid. LC-MS at 254 nm; [M+H] 432.3; Rt 1.00 min; (LCMS method 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]([Cl:29])=[CH2:28])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([O:19]CCCC)=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].C1COCC1.[OH-].[Na+].CCOCC>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]([Cl:29])=[CH2:28])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: C=C(Cl)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)OCCCC)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: C=C(Cl)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)O)nn1
Yield: 75 %

Procedure:
n-Butyl 6-[N-(5-bromo-2-(2-chloroprop-2-en-1-yloxy)benzyl)-N-ethylamino]pyridazine-3-carboxylate (0.24 g, 0.5 mmol) was dissolved in methanol (2 ml), THF (2 ml) and treated with aqueous 1N sodium hydroxide solution (2 ml). The resultant solution was left at ambient temperature for 1.5 hours, evaporated to low bulk and the resultant precipitate dissolved in water and acidified with acetic acid to give a gummy precipitate. It was extracted with methylene chloride and the organic extracts dried and evaporated to give a gum. Trituration with ether yielded a solid which was filtered and sucked dry to give the title compound as a white solid (0.16 g, 75%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:6]>>[CH2:5]([OH:1])[CH2:4][CH2:3][CH2:2][OH:6].[C:5]1(=[O:6])[O:1][CH2:2][CH2:3][CH2:4]1
Reactant: C1CCOC1
Reactant: O
Product: O=C1CCCO1
Product: OCCCCO

Procedure:
The crude product stream 21 comprising 1,4-butanediol, tetrahydrofuran, γ-butyrolactone, alkanol and water which is produced in the hydrogenation stage is fed to a first distillation stage 23. In the first distillation stage 23, the crude product stream 21, the stream comprising tetrahydrofuran and alkanol and also high boilers, is separated into a bottom stream 25 comprising high boilers and an overhead stream 27 comprising tetrahydrofuran and alkanol as azeotrope. The high boiler-comprising bottom stream 25, which comprises 1,4-butanediol, γ-butyrolactone, alkanol and water, is fed to a high boiler work-up 29 in which this stream is separated into γ-butyrolactone 31, 1,4-butanediol 33 and alkanol and water 35.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:11]#N)[CH2:10][CH2:9][CH2:8]1.[OH2:13].CC(O)=[O:16].S(=O)(=O)(O)O>CCOCC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:11]([OH:16])=[O:13])[CH2:10][CH2:9][CH2:8]1
Reactant: CC(=O)O
Reactant: N#CC1(c2ccccn2)CCC1
Reactant: O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: O=C(O)C1(c2ccccn2)CCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59 %

Procedure:
1-Pyridin-2-yl-cyclobutanecarbonitrile (4.92 g, 31.1 mmol) was combined with water (5 mL), AcOH (5 mL) and sulfuric acid (5 mL). The homogeneous solution was heated to reflux. After 2.5 h, the solution was cooled to room temperature and poured into water (20 mL) and Et2O. The layers were separated and the Et2O layer was discarded. The aqueous layer was basified to pH 4.5-5 with 10% NaOH and extracted with DCM (2×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to yield 3.28 g (59%) of 1-pyridin-2-yl-cyclobutanecarboxylic acid as pale yellow solid, m/z=178.5 [M+1]+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.[C:11]1([CH3:23])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[S:19](Cl)(=[O:21])=[O:20]>C1(C)C=CC=CC=1>[C:11]1([CH3:23])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[S:19]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:20])=[O:21]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)Oc2ccccc2)c(C)c1
Reaction time: 1 h

Procedure:
9.4 g of phenol is added to a mixture containing 9.17 g of 48% NaOH, 50 ml of water and 50 ml of toluene. To the resulting mixture is added 22.9 g of mesitylenesulfonyl chloride, and reaction is carried out at 60° to 65° C. for 1 hour. After separating the aqueous layer, toluene is removed from the toluene layer by distillation. The resulting desired compound is purified with methanol.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][N:16]([CH2:25][CH3:26])[CH2:17][CH2:18][CH2:19]OS(C)(=O)=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31]>C(#N)C>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[CH2:15][N:16]([CH2:25][CH3:26])[CH2:17][CH2:18][CH2:19][NH:27][CH2:28][CH2:29][CH2:30][OH:31])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: NCCCO
Reactant: CCN(CCCOS(C)(=O)=O)Cc1c2ccccc2cc2ccccc12
Solvent: CC#N
Product: CCN(CCCNCCCO)Cc1c2ccccc2cc2ccccc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
The mesylate 17 (384 mg, 1.04 mmol) and 3-amino-propanol (392 mg, 5.25 mmol) were dissolved in acetonitrile (20 mL). The mixture was then stirred at 75° C. under a N2 atmosphere overnight. After the confirmation of the disappearance of the mesylate by TLC, the solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (20 mL) and washed three times with aqueous sodium carbonate. The organic layer was separated, dried with anhydrous Na2SO4, filtered and concentrated under vacuum. Flash column chromatography of the residue gave 18 as a light yellow oil. Yield 65%; Rf=0.35 (1:6:83 NH4OH:MeOH:CH2Cl2); 1H NMR (CDCl3) δ 8.32 (d, 2H), 8.23 (s, 1H), 7.83 (d, 2H), 7.37 (m, 2H), 7.30 (m, 2H), 4.28 (s, 2H), 3.48 (t, 2H), 2.56 (q, 2H), 2.30 (t, 2H), 2.12 (t, 2H), 2.06 (t, 2H), 1.36 (q, 2H), 1.21 (q, 2H), 1.09 (t, 3H); 13C NMR (CDCl3) δ 131.3, 131.2, 130.5, 129.3, 129.0, 127.3, 125.5, 125.3, 124.8, 124.8, 63.8, 50.8, 50.5, 49.5, 48.3, 47.7, 30.5, 26.6, 11.7. HRMS (FAB) m/z calcd. for C23H30N2O (M+H)+ 351.2431; found 351.2430.
Reaction SMILES: [C:1]([OH:10])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)(=O)C(Cl)=O.[CH3:17][C:18]1[CH:27]=[C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[CH3:17][C:18]1[CH:27]=[C:26]([N:28]2[CH2:33][CH2:32][N:31]([C:1](=[O:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:30][CH2:29]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: Cc1cc(N2CCNCC2)c2ccccc2n1
Reactant: CCCCC/C=C/C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC/C=C/C(=O)N1CCN(c2cc(C)nc3ccccc23)CC1
Yield: 75.6 %

Procedure:
(E)-Oct-2-enoic acid (71.1 mg, 0.5 mmol) was dissolved in dichloromethane (1 ml) and a 2M solution of oxalyl chloride in dichloromethane was added (0.3 ml, 0.6 mmol). The solution was stirred at room temperature for one hour after which a drop of DMF was added. Stirring was continued for another hour, the mixture was evaporated to dryness under reduced pressure. The residue was dissolved in dichloromethane (1 ml), the resulting solution was added to a solution of 2-methyl-4-piperazin-1-yl-quinoline (103 mg, 0.45 mmol) and triethylamine (90 μl, 0.64 mmol) in dichloromethane (1 ml). The resulting mixture was stirred at room temperature overnight, diluted with dichloromethane (1 ml), washed with water and 2M NaOH (2 ml each) and evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile) to yield 121.3 mg of a solid (0.34 mmol, 77%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH2:10][C:11]([CH3:13])=[CH2:12])[CH:4]=1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]2[O:9][C:11]([CH3:13])([CH3:12])[CH2:10][C:5]=2[CH:4]=1)[CH3:2]
Reactant: C=C(C)Cc1cc(CC)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCc1ccc2c(c1)CC(C)(C)O2

Procedure:
A solution of 4-ethyl-2-(2-methylallyl)phenol (812) (4 g, 22.7 mmol), p-toluenesulfonic acid monohydrate (400 mg, 2.10 mmol), and chloroform (120 mL) was stirred overnight at room temperature. The reaction was concentrated in vacuo, and purified by flash column chromatography on silica gel eluting with hexanes and ethyl acetate to give 5-ethyl-2,2-dimethyl-2,3-dihydrobenzofuran (813).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:42]1[CH:58]=[N:57][C:45]2[NH:46][C:47](=[O:56])[N:48]([CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:49][C:44]=2[CH:43]=1>C(#N)CC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:54]([O:53][C:51](=[O:52])[CH2:50][N:48]1[CH2:49][C:44]2[CH:43]=[C:42](/[CH:3]=[CH:2]/[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:58]=[N:57][C:45]=2[NH:46][C:47]1=[O:56])[CH3:55]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCOC(=O)CN1Cc2cc(Br)cnc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCC#N
Product: CCOC(=O)CN1Cc2cc(/C=C/C(=O)OC(C)(C)C)cnc2NC1=O
Yield: 59.8 %

Procedure:
tert-Butyl acrylate (1.25 mL, 8.53 mmol), diisopropylethylamine (730 μL, 4.26 mmol) and P(o-tolyl)3 (130 mg, 0.43 mmol) were successively added to a suspension of ethyl 2-(6-bromo-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)yl)acetate (670 mg, 2.13 mmol) in propionitrile (11 mL) and dimethylformamide (2.5 mL). The resulting mixture was purged with argon prior to the addition of palladium acetate (48 mg, 0.213 mmol). The mixture was purged with argon a second time and refluxed overnight. The reaction mixture was then filtered on Celite® and washed with ethyl acetate (75 mL) and dichloromethane (75 mL). The filtrate was concentrated to dryness and the residue was partitioned between dichloromethane (50 mL) and water (50 mL). The aqueous phase was separated and extracted with dichloromethane (2×100 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was precipitated from a mixture dichloromethane/diethylether to afford the title product as a white solid (460 mg, 60%).
Reaction SMILES: [O:1]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:14]=1[O:21][CH3:22])[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[K].[C:24]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37](=[O:38])[CH2:36][S:35][C:34]2=[S:39])=[CH:29][CH:28]=1)([OH:26])=[O:25]>C(O)C.N1CCCCC1>[C:24]([C:27]1[CH:28]=[CH:29][C:30]([N:33]2[C:37](=[O:38])[C:36](=[CH:19][C:16]3[CH:17]=[CH:18][C:13]([O:1][C@@H:2]4[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]4[OH:4])=[C:14]([O:21][CH3:22])[CH:15]=3)[S:35][C:34]2=[S:39])=[CH:31][CH:32]=1)([OH:26])=[O:25]
Reactant: COc1cc(C=O)ccc1O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=C(O)c1ccc(N2C(=O)CSC2=S)cc1
Agent: [K]
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(C=C2SC(=S)N(c3ccc(C(=O)O)cc3)C2=O)ccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 24.3 %

Procedure:
To a stirred suspension of 4-formyl-2-=methoxyphenyl β-D-galactopyranoside (1c)(0.47 g, 1.5 mmol) in absolute ethanol (25 ml) containing piperidine (1 drop), was added the potassium salt of 3-(4-carboxyphenyl)-2-thioxothiazolidin-4-one (0.44 g, 1.5 mmol) and the suspension was heated under gentle reflux for 2 h. A yellow solid separated which was filtered hot and washed with small portions of boiling methanol and ethyl acetate followed by ether to give the product (0.2 g, 22%) as the potassium salt, m.p. decomp.>230° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([N:22]=C(C4C=CC=CC=4)C4C=CC=CC=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=1)[CH2:2]2.Cl>C1COCC1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[CH:12][CH:11]=1)[CH2:2]2
Reactant: c1ccc(C(=Nc2ccc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)cc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1

Procedure:
The product of Example 29E (360 mg, 0.78 mmol) was treated with HCl (aq. 10%, 5 mL) in THF (5 mL) at ambient temperature for 4 h. It was then concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.1) as solid (210 mg, yield, 90%). 1H NMR (300 MHz, CD3OD) δ 1.44-1.66 (m, 1H), 1.65-1.94 (m, 2H), 1.95-2.16 (m, 1H), 2.20-2.40 (m, 1H), 2.68-3.06 (m, 5H), 3.37-3.57 (m, 1H), 5.15-5.37 (m, 1H), 6.65-6.89 (m, 2H), 7.18 (d, J=9.5 Hz, 1H), 7.55-7.81 (m, 2H), 7.93 (d, J=9.2 Hz, 1H) ppm. MS (DCl/NH3): 297 (M+H)+.