Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[O:7]2.CC(O)C.[C:20]([CH:22]=[C:23]([O-])[CH3:24])#[N:21].[Na+].[NH2:27][C:28]([CH3:38])=[CH:29][C:30](=[O:37])[CH2:31][CH2:32][CH:33]1[CH2:36][CH2:35][CH2:34]1.C(O)(=O)C>>[CH:33]1([CH2:32][CH2:31][C:30]([C:29]2[CH:12]([C:9]3[CH:10]=[CH:11][C:2]([F:1])=[C:3]4[C:8]=3[O:7][C:6]([CH3:14])=[CH:5][C:4]4=[O:15])[C:22]([C:20]#[N:21])=[C:23]([CH3:24])[NH:27][C:28]=2[CH3:38])=[O:37])[CH2:34][CH2:35][CH2:36]1
Reactant: CC(N)=CC(=O)CCC1CCC1
Reactant: CC([O-])=CC#N
Reactant: Cc1cc(=O)c2c(F)ccc(C=O)c2o1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2ccc(F)c3c(=O)cc(C)oc23)C(C(=O)CCC2CCC2)=C(C)N1

Procedure:
A solution of 100 mg (0.49 mmol) of 5-fluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde in ml of 2-propanol is mixed with 50.96 mg (0.49 mmol) of sodium 1-cyanoprop-1-en-2-olate, 81.12 mg (0.49 mmol) of 5-amino-1-cyclobutylhex-4-en-3-one and 0.04 ml (0.73 mmol) of acetic acid and stirred under reflux for 3 h. After cooling, the mixture is concentrated. The residue is taken up in dichloromethane and washed with water. The organic phase is dried over sodium sulfate and concentrated. The resulting residue is crystallized from diethyl ether. The yellow crystals are filtered off with suction and purified further on an Analogix cartridge (F12M) (mobile phase: cyclohexane/ethyl acetate 2:1). 60.2 mg (29.5% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][CH2:34][CH2:35][NH:36][CH3:37])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:1][CH2:2][CH2:3][NH:4][C:5](=[O:6])[N:36]([CH2:35][CH2:34][O:33][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:32]=1[C:23]([NH:22][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[C:8]([Cl:7])[CH:9]=1)=[N:24][CH:25]=[N:26]2)[CH3:37]
Reactant: O=C=NCCCl
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)NCCCl
Yield: 80 %

Procedure:
The procedure described in Example 120 was repeated using 2-chloroethyl isocyanate and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give the title compound as a solid in 80% yield; NMR spectrum (DMSO-d6 @ 373K) 2.90 (s, 3H), 3.15-3.25 (q, 2H), 3.43-3.50 (t, 2H), 3.75-3.85 (t, 2H), 4.35-4,45 (t, 2H), 5.25, 6.35 (bs, 1H), 7.08-7.13 (d, 1H), 7.13-7.30 (m, 1H), 7.35-7.40 (m, 2H), 7.50-7.65 (m, 2H), 7.65-7.80 (m, 1H), 7.80-7.90 (t, 1H), 7.95 (d, 1H), 8.50 (s, 1H), 8.55-8.60 (d, 1H), 9.80 (s, 1H); Mass spectrum MH+ 541.3.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CCN(CC)CC>CS(C)=O.O>[N:19]1([C:2]2[C:3]([CH:8]3[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Reactant: C1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(c2nccnc2N2CCCCC2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75.99 %

Procedure:
To a solution of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (7) (200 mg, 0.74 mmol, see Preparation 2) and piperidine (69.2 mg, 0.84 mmol) in DMSO (5 mL) was added Et3N (149.5 mg, 1.48 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give tert-butyl 3-(3-(piperidin-1-yl)pyrazin-2-yl)azetidine-1-carboxylate (74). (194 mg, 0.56 mmol, yield 75.99%).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.[O:6]=[C:7]1[C:15](=[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]([CH2:25][CH2:26]OS(C)(=O)=O)[O:17]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8]1.O1CCOCC1.C(N(CC)CC)C>C1COCC1>[N:2]1([CH2:26][CH2:25][CH:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16](=[C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:6])[O:17]2)[CH2:5][CH2:4][CH2:3]1
Reactant: CS(=O)(=O)OCCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Reactant: C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=C1OC(CCN2CCC2)c2ccccc21
Temperature: 60 °C
Reaction time: 0.05 h

Procedure:
To a slurry of azetidine hydrochloride (126 mg, 1.35 mmol) in THF (1.0 ml) was added a scoop of Aberlite-IRA-93 ion exchange resin, which was shaken 3 minutes to give a solution, dried with anhydrous Na2SO4 and filtered to remove resin. Then methanesulfonic acid 2-[3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-ethyl ester (50.0 mg, 0.135 mmol) was added to the amine solution and heated at 60° C. for 18 hours (no reaction had occurred). After standing at room temperature for 2 days, to the mixture were added dioxane (0.3 ml), azetidine hydrochloride (63 mg, 0.675 mmol), and triethylamine (132 μl, 0.945 mmol). The resulting mixture was stirred at room temperature for 3 days, and heated at 60° C. for 24 hours. The reaction was partitioned between water and EtOAc. The EtOAc layer was extracted with 4% HCl aqueous solution, and then the aqueous layer was basified with saturated NaHCO3 aqueous solution. The basified aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and rotary evaporated to give a film. The film was chromatographed (2.5% to 5% MeOH/CHCl3 gradient) to provide 3-[3-(2-azetidin-1-yl-ethyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow film (8.7 mg, 19%).
Reaction SMILES: [O:1]=[C:2]1[NH:14][C:5]2[CH:6]=[CH:7][C:8]3[CH:9]=[CH:10][CH:11]=[N:12][C:13]=3[C:4]=2[O:3]1.S(=O)(=O)(O)O.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([N:14]1[C:5]2[CH:6]=[CH:7][C:8]3[CH:9]=[CH:10][CH:11]=[N:12][C:13]=3[C:4]=2[O:3][C:2]1=[O:1])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]c2ccc3cccnc3c2o1
Agent: O=S(=O)(O)O
Product: CC(=O)n1c(=O)oc2c3ncccc3ccc21
Yield: 80 %

Procedure:
A suspension of 2-oxo-3H-oxazolo[4,5-h]quinoline (1.86 g, 10.0 mmol), acetic anhydride (50 ml) and sulfuric acid (0.5 ml) was refluxed overnight. The reaction was filtered and the filtrate concentrated. Methylene chloride was added and the resulting solution was washed (3×) with water, brine; dried over MgSO4 and concentrated to a solid. The solid was crystallized from ethanol to give 1.82 g (80% yield) of product. M.P. 192°-193° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]([CH3:27])[CH2:15]2)[C:3]=1[CH3:28].[O:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[C:37]([NH2:41])[CH:38]=[N:39][CH:40]=2)[CH2:31][CH2:30]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:41][C:37]1[CH:38]=[N:39][CH:40]=[C:35]([N:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)[CH:36]=1)=[C:3]([CH3:28])[C:4]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[C@@H:16]([CH3:27])[CH2:15]1)=[N:5]2
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using (S)-tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-2-methylpiperazine-1-carboxylate (350 mg, 0.85 mmol) and 5-morpholinopyridin-3-amine in toluene to give (S)-tert-butyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-2-methylpiperazine-1-carboxylate. 1H NMR (CDCl3) δ ppm 7.93 (1H, d, J=2.3 Hz), 7.69 (1H, d, J=2.2 Hz), 7.29 (1H, ddd, J=10.0, 2.5, 1.4 Hz), 6.89 (1H, d, J=13.1 Hz), 6.80 (1H, ddd, J=13.9, 8.6, 2.5 Hz), 6.57 (1H, t, J=2.4 Hz), 4.38 (1H, br. s.), 3.98 (1H, d, J=13.3 Hz), 3.79-3.91 (4H, m), 3.64-3.75 (1H, m), 3.49-3.61 (1H, m), 3.32 (1H, td, J=12.7, 3.1 Hz), 3.16 (4H, dd, J=5.7, 3.9 Hz), 3.10 (1H, dd, J=12.8, 3.8 Hz), 2.92 (1H, td, J=12.5, 3.3 Hz), 2.09 (3H, s), 1.50 (9H, s), 1.29 (3H, d, J=6.7 Hz). Mass Spectrum (ESI) m/e=555.3 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[C:12]3([C:25]4[CH:24]=[C:23]([CH2:26][OH:27])[CH:22]=[CH:21][C:20]=4[C:19]4[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:28][OH:29]>C1(C)C=CC=CC=1.[O-2].[Cr+6].[O-2].[O-2]>[CH:24]1[C:25]2[C:12]3([C:13]4[CH:1]=[C:2]([CH:28]=[O:29])[CH:3]=[CH:4][C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]=2[CH:21]=[CH:22][C:23]=1[CH:26]=[O:27].[OH:29][CH2:28][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C:12]4([C:25]5[CH:24]=[C:23]([CH:26]=[O:27])[CH:22]=[CH:21][C:20]=5[C:19]5[C:14]4=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=2[CH:1]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: OCc1ccc2c(c1)C1(c3ccccc3-2)c2ccccc2-c2ccc(CO)cc21
Agent: [Cr+6]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=Cc1ccc2c(c1)C1(c3ccccc3-2)c2ccccc2-c2ccc(C=O)cc21
Product: O=Cc1ccc2c(c1)C1(c3ccccc3-2)c2ccccc2-c2ccc(CO)cc21

Procedure:
5 g of chromium(VI) oxide on graphite (Seloxcette, Alpha Inorganics) were added to a solution of 380 mg of 9,9′-spirobifluorene-2,2′-dimethanol in 15 ml of toluene, and the mixture was refluxed under nitrogen for 48 h. The mixture was then filtered with suction using a glass suction filter, and the filtrate was evaporated. Chromatography on silica gel using chloroform and crystallization from methylene chloride/ether produced 152 mg of 9,9′-spirobifluorene-2,2′-dicarbaldehyde (m.p. >300° C.) and 204 mg of 2′-hydroxymethyl-9,9′-spirobifluorene-2-carbaldehyde (m.p. 262 to 263° C.).
Reaction SMILES: Cl.[F:2][C:3]1([F:7])[CH2:6][NH:5][CH2:4]1.C(N(C(C)C)C(C)C)C.[Br:17][C:18]1[CH:19]=[C:20]([S:25](Cl)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[F:24]>ClCCl>[Br:17][C:18]1[CH:19]=[C:20]([S:25]([N:5]2[CH2:6][C:3]([F:7])([F:2])[CH2:4]2)(=[O:26])=[O:27])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Br)c1
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)c(Br)c1)N1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a suspension of 3,3-difluoroazetidine hydrochloric acid (0.947 g, 7.31 mmol) in 20 mL dichloromethane at 0° C. was added N-ethyl-N-isopropylpropan-2-amine (2.80 mL, 16.1 mmol) followed by the addition of a solution of 3-bromo-4-fluorobenzene-1-sulfonyl chloride (2.0 g, 7.3 mmol) in 4 mL dichloromethane. The mixture was stirred at room temperature overnight and then heated at 55° C. for 5 hours, diluted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 10-50% ethyl acetate/heptanes gradient) to give the title compound (1.5 g, 62.1% yield)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][C:31]([CH:36]=O)=[CH:30]3)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([C:13](=[CH:36][C:31]3[NH:32][C:33]4[C:29]([CH:30]=3)=[CH:28][C:27]([O:26][CH2:25][CH2:24][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:35][CH:34]=4)[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
6-(2-Methoxy-phenyl)-1,3-dihydro-indol-2-one was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.[I-].[K+]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)CCl
Reactant: Oc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)COc1ccc(F)cc1Br
Yield: 109.3 %

Procedure:
A mixture of 1.9 gm (10 mMol) 2-bromo-4-fluorophenol, 0.92 gm (10 mMol) chloroacetone, 0.1 gm potassium iodide, and 1.4 gm (10 mmol) potassium carbonate in 100 mL tetrahydrofuran was heated at reflux for 4 hours. The mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane and 1 N sodium hydroxide. The phases were separated and the aqueous phase extracted well with dichloromethane. The organic phases were combined, washed with 1 N sodium hydroxide, dried over sodium sulfate and concentrated under reduced pressure. The residual was subjected to silica gel chromatography, eluting with hexane containing 20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 2.7 gm (100%) of the desired compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[CH2:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([Cl:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.C([NH:30][NH:31][C:32]([NH2:34])=[O:33])C.O.[CH2:36](O)[CH3:37]>C(O)(=O)C>[CH2:36]([N:31]([C:32]([NH2:34])=[O:33])[N:30]=[CH:18][C:17]1[CH:20]=[CH:21][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:23]([F:24])([F:25])[F:26])[CH2:13][N:12]=2)=[CH:15][C:16]=1[Cl:22])[CH3:37]
Reactant: CCO
Reactant: O=Cc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Reactant: CCNNC(N)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCN(N=Cc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl)C(N)=O
Temperature: 70 °C
Yield: 93 %

Procedure:
A mixture of 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-chloro-benzaldehyde (121 mg, 0.29 mmol) and ethyl semicarbazide hydrochloride (60 mg 0.43 mmol) in ethanol (5 mL) and glacial acetic acid (0.1 mL) was heated at 70° C. for 4 h. Then, water was added and cooled, upon which a precipitate formed. The latter was collected by filtration and dried in vacuum to obtain the title compound (137 mg, 93%).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15](CN3CCC(F)CC3)=[CH:16][CH:17]=2)[O:12][CH2:11][CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+:31]([CH2:40][CH2:41][CH2:42][CH3:43])([CH2:36]CCC)[CH2:32]CCC.[F-:44]>C1COCC1.O>[F:44][CH:42]1[CH2:43][CH2:36][N:31]([CH2:32][CH:11]2[CH2:10][CH:9]([OH:8])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12]2)[CH2:40][CH2:41]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: [F-]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCOc2cc(CN3CCC(F)CC3)ccc21
Solvent: C1CCOC1
Solvent: O
Product: OC1CC(CN2CCC(F)CC2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (5)-1-((4-(tert-butyldimethylsilyloxy)-3,4-dihydro-2H-chromen-7-yl)methyl)-4-fluoropiperidine (4.54 g, 12.5 mmol) and TBAF (7.92 g, 37.49 mmol) in THF (50 mL) was stirred for 16 h at RT. The reaction mixture was taken up in H2O, and extracted with EtOAc (3×). The organic layers were extracted with 10% aqueous HCl. The combined aqueous extracts were neutralized with 2N NaOH, and extracted with CH2Cl2 (3×). The combined organic extracts were dried over MgSO4 and concentrated to give the title compound as a yellow oil. MS (m/z, m+1): 282.4.
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:36]=[CH:35][C:15]([C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH:19]=3)=[O:17])=[CH:14][C:13]=2[O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[O:53][CH3:54])[CH2:43][CH2:42]2)=[CH:6][CH:5]=1)[CH3:3].CO.[OH-].[K+]>O1CCCC1>[ClH:1].[CH2:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:36]=[CH:35][C:15]([C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:19]=3)=[O:17])=[CH:14][C:13]=2[O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[O:53][CH3:54])[CH2:43][CH2:42]2)=[CH:6][CH:5]=1)[CH3:3]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(NCc3ccc(CC)cc3)c(OCCCN3CCN(c4ccccc4OC)CC3)c2)c2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(CNc2ccc(C(=O)c3cn(CCCC(=O)O)c4ccccc34)cc2OCCCN2CCN(c3ccccc3OC)CC2)cc1
Yield: 86 %

Procedure:
Ethyl 4-{3-{4-(4-ethylphenyl)methylamino-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}indol-1-yl}butanoate hydrochloride (40.8 g) was dissolved in tetrahydrofuran (200 ml), and methanol (200 ml) and potassium hydroxide (11.3 g) were added to the solution. The resultant mixture was refluxed for one hour and 30 minutes. The reaction mixture was cooled and concentrated under reduced pressure. Water (1.2 l) was added to dilute the residue, and the resultant solution was poured into 1N hydrochloric acid (400 ml), to thereby precipitate crystals. The crystals were collected by filtration. The collected crystals were washed with water, dried, and recrystallized from 95% ethanol, to thereby obtain 33.8 g of 4-{3-{4-(4-ethylphenyl)methylamino-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}indol-1-yl}butanoate hydrochloride as pale yellow crystals.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3]C(C)=O.[CH:10]([SH:13])([SH:12])[CH3:11].B(F)(F)F.[CH3:18][CH2:19]OCC>CO>[CH3:11][C:10]1([CH2:3][CH2:2][C:1]([O:8][CH3:9])=[O:7])[S:13][CH2:19][CH2:18][S:12]1
Reactant: CCOCC
Reactant: COC(=O)CCC(C)=O
Reactant: CC(S)S
Agent: FB(F)F
Solvent: CO
Product: COC(=O)CCC1(C)SCCS1
Reaction time: 8 h

Procedure:
Into a mixture of about 100 g of methyl levulinate and about 100 ml of ethanedithiol was slowly poured boron trifluoride etherate until reflux began. An about 500 ml portion of methanol was added followed by sufficient boron trifluoride etherate to make a total of about 100 ml of this reagent. The mixture was stirred overnight, the solvent removed and the residue poured into saturated sodium bi-carbonate. The mixture was extracted with ether. The ether extract was dried, the solvent removed and the residue distilled at about 97°-100° C., at about 0.55 mm, giving about 147 g of the desired title compound.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][NH2:45])[CH:34]=1>O1CCCC1>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:10])[CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(OC)c2)c1
Reactant: NCCCCCCc1cccnc1
Solvent: C1CCOC1
Product: COc1cccc(C(=C/C=C/C(=O)NCCCCCCc2cccnc2)c2cccc(OC)c2)c1
Yield: 76.4 %

Procedure:
As in Example 134. a solution of (E)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (3.0 g) and 3-pyridinehexanamine (1.25 g) in tetrahydrofuran (20 mL) was stirred for 1.5 hours at room temperature and was then worked up in the usual manner. The product was purified by HPLC (ethyl acetate) and triturated with ether to give 2.5 g of (E)-5,5-bis(3-methoxyphenyl)-N-[6-(3-pyridinyl)hexyl]-2,4-pentadienamide mp 66°-70° C. Crystallization of a portion from ethyl acetate-hexane afforded of the pure amide, mp 71°-72° C. Anal. Calculated for C30H34N2O3 : C, 76.57; H, 7.28; N, 5.98 Found: C, 76.39; H, 7.28; N, 5.90.
Reaction SMILES: [C:1]([O:18]NCC(OC1CC(=O)NC1=O)=O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:31][C@H:32]([C:39]([OH:41])=[O:40])[CH2:33][C:34]1[N:38]=[CH:37][NH:36][CH:35]=1.[CH2:42]([N:44](CC)CC)[CH3:43].[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]>CN(C=O)C.O>[NH:44]([C: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][CH2:14][CH2:15][CH3:16])=[O:18])[CH2:42][C:43]([NH:31][C@H:32]([C:39]([OH:41])=[O:40])[CH2:33][C:34]1[N:38]=[CH:37][NH:36][CH:35]=1)=[O:52].[F:49][C:50]([C:51]([OH:53])=[O:52])([F:55])[F:54]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCCCCCC(=O)ONCC(=O)OC1CC(=O)NC1=O
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)NCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Temperature: 0 °C
Yield: 54 %

Procedure:
A total amount of 198 g of N-palmitoyloxy-glycyloxysuccinimide synthesized above was suspended in DMF, and a suspension of 113 g (0.728 mol) of L-histidine and 55.6 ml (0.400 mol) of triethylamine in 350 ml of water was added with stirring while cooling with ice. Then, the whole was stirred while cooled with ice for 30 minutes, then allowed to reach room temperature, and further stirred for 17 hours. A precipitated solid was collected by filtration without treatment to give a solid. The solid was added into a solution mixed with 120 ml of trifluoroacetic acid and 1.5 L of ice water. The whole was stirred, and then an insoluble was collected by filtration. The obtained solid was charged into a jug, washed with 2 L of water three times, and then dried under reduced pressure. The obtained dried solid was dissolved in 400 ml of trifluoroacetic acid, and a small amount of insoluble was filtered off with a membrane-filter. The filtrate was concentrated under reduced pressure to about half the volume. Then, a solid was washed with diethyl ether and dried under reduced pressure. The solid was washed with water several times, and the obtained solid was dried under reduced pressure to give 112 g (54%) of a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][CH2:9][CH3:10])=[CH:5][N:6]=1.Cl[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([Cl:19])[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:19][C:14]1[N:13]=[C:12]([N:8]([CH2:7][C:4]2[S:3][C:2]([Cl:1])=[N:6][CH:5]=2)[CH2:9][CH3:10])[C:17]([Cl:18])=[CH:16][CH:15]=1
Reactant: CCNCc1cnc(Cl)s1
Reactant: Clc1ccc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(Cc1cnc(Cl)s1)c1nc(Cl)ccc1Cl
Yield: 39.5 %

Procedure:
18.0 g of 2-chloro-5-ethylaminomethylthiazole, 18.6 g of 2,3,6-trichloropyridine, 30.0 g of potassium carbonate and 200 mL of N,N-dimethylformamide (DMF) were added in a 500 mL single neck flask equipped with a magnetic stirrer. After stirred at reflux temperature for 4 to 6 hours, the reaction mixture was extracted with ethyl acetate, the organic layer was separated while the aqueous layer was extracted with ethyl acetate twice. The organic phases were combined, and dried over anhydrous sodium sulfate after washed with an iced aqueous sodium chloride solution twice, then remove the solvent under reduced pressure to obtain 25.0 g of crude product which was purified by a silica gel column chromatography using a petroleum ether/ethyl acetate (20/1) as an eluent to obtain 13.0 g of 6-chloro-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-chloropyridin-2-amine, having the content 91.0%, as a yellow viscous liquid, and rod-like crystals were generated after standing, m.p.: 95.8-96.8 □ GC-MS (M+) (EI, 70 eV, m/z) calc: 321. found: 321. 1H NMR (CDCl3/TMS, 300 MHz) δ (ppm) 1.179 (t, J=7.2 Hz, 3H, CH3), 3.413 (q, J=7.2 Hz, 2H, CH2), 4.726 (s, 2H, CH2), 6.378 (d, J=8.7 Hz, 1H, Py H), 7.447 (d, J=8.7 Hz, 1H, Py H), 7.497 (s, 1H, Thiazole-H).