Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][CH2:9][C:10]([C@H:12]2[C@H:19]3[C@H:15]([O:16][C:17]([CH3:21])([CH3:20])[O:18]3)[CH2:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.N1C=CC=CC=1.C(O)(C(F)(F)F)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([C@H:12]3[C@H:19]4[C@H:15]([O:16][C:17]([CH3:21])([CH3:20])[O:18]4)[CH2:14][CH2:13]3)=[CH:9][N:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC1(C)O[C@@H]2[C@@H](CC[C@H]2C(=O)CNc2nccnc2Cl)O1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)O[C@@H]2[C@@H](CC[C@H]2c2cnc3c(Cl)nccn23)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(3-chloropyrazin-2-ylamino)-1-((3aS,4R,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanone (2-8) (1.2 g, 3.85 mmol, 1 equiv) was dissolved in toluene (28 mL) and the mixture was cooled to 0° C. Pyridine (3.74 mL, 46.2 mmol, 12 equiv) was added followed by TFA (2.08 mL, 26.9 mmol, 7 equiv). After 30 minutes, TFAA (3.81 mL, 26.9 mmol, 7 equiv) was added. The resulting mixture was stirred for 1 h, then was concentrated and the yellow residue was purified via flash chromatography on a silica gel column (ethyl acetate/hexanes) to yield desired 8-chloro-3-((3aS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)imidazo[1,2-a]pyrazine (2-9) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.19 (d, J=4.6 Hz, 1H); 7.84 (d, J=4.6 Hz, 1H); 7.67 (s, 1H); 4.81 (d, J=5.2 Hz, 1H); 4.57 (dd, J=6.0, 2.6 Hz, 1H); 3.47 (s, 1H); 2.52-2.41 (m, 1H); 2.09-2.05 (m, 3H); 1.58 (s, 3H); 1.34 (s, 3H). LRMS m/z (M+H) 293.9 found, 294.1 required.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([C@@:26]1([CH3:53])[CH2:31][C@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)[C@@H:29]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)[N:28]([C@@H:46]([CH:49]([CH3:51])[CH3:50])[CH2:47][OH:48])[C:27]1=[O:52])[CH:24]=[CH2:25].O>ClCCl>[CH2:23]([C@@:26]1([CH3:53])[CH2:31][C@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)[C@@H:29]([C:39]2[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=2)[N:28]([C@@H:46]([CH:49]([CH3:50])[CH3:51])[CH:47]=[O:48])[C:27]1=[O:52])[CH:24]=[CH2:25]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C(C)C)C1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)C(C)C)C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dess-Martin periodinane (938 mg, 2.212 mmol) was added as a solid to a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-3-methylbutan-2-yl)-3-methylpiperidin-2-one (Example 261, Step H, 365.4 mg, 0.794 mmol) in dichloromethane (8 mL) and water (0.04 mL, 2.220 mmol). The resulting suspension was vigorously stirred at ambient temperature for 1.5 h. The reaction was quenched with sodium thiosulfate solution (1M aq, 6 mL). Additional sodium thiosulfate solution (1M aq, 6 mL) was added and stirred until the chalky suspension became a slightly cloudy biphasic mixture. The aqueous phase was separated and back extracted with dichloromethane. The organic layer was washed with sodium thiosulfate solution, saturated aqueous sodium bicarbonate and sat. aq. NaCl solution. After drying over sodium sulfate and concentration, the residue was purified on silica gel, eluting with a gradient of 0 to 30% ethyl acetate in hexanes. Fractions containing the desired product were pooled to give the title compound as a white foam. MS (ESI) m/z=458 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([NH2:13])[CH2:12][CH2:11]1.[NH:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:16](O)=[O:17]>ClCCl>[C:22]([O:21][C:19](=[O:20])[NH:14][CH2:15][C:16](=[O:17])[NH:13][CH:10]1[CH2:12][CH2:11]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)NC1CC1
Reaction time: 17 h
Yield: 26.4 %

Procedure:
—TBTU (5.1 g, 16.5 mmol), DIPEA (2.9 ml, 16.5 mmol) and cyclopropylamine (2.2 ml, 33 mmol) were added to a solution of BOC-Gly-OH (2.63 g, 15 mmol) in dry dichloromethane (10 ml). After 17 h stirring, the reaction mixture was concentrated under reduced pressure and water was added to the residue. The product was extracted into ethyl acetate. The combined organic phases were washed with an aqueous solution of 2M hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, brine, dried over sodium sulfate and concentrated under reduced pressure to give 2-cyclopropylcarbamoylmethyl-carbamic acid tert-butyl ester (847 mg). The product was used in the following step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]2[N:11]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([O:21]C)=[C:16]([CH3:23])[CH:15]=3)[O:13][C:7]=2[CH:6]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]2[N:11]=[C:12]([C:14]3[CH:15]=[C:16]([CH3:23])[C:17]([OH:21])=[C:18]([CH3:20])[CH:19]=3)[O:13][C:7]=2[CH:6]=1
Reactant: COc1c(C)cc(-c2nc3cnc(Oc4ccccc4F)cc3o2)cc1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4F)cc3o2)cc(C)c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 60 mg of 6-(2-fluorophenoxy)-2-(4-methoxy-3,5-dimethylphenyl)oxazolo[4,5-c]pyridine in 2 ml of dichloromethane was cooled to 0° C., and 0.4 ml of a 1 M solution of boron tribromide in dichloromethane were added over a period of 10 min. The mixture was stirred at 0° C. for 1 h and a further 0.2 ml of a 1 M solution of boron tribromide in dichloromethane was then added. The reaction was then stirred at room temperature for 16 h. For work-up, saturated aqueous sodium bicarbonate solution was added slowly to the reaction mixture. The precipitate was filtered off, washed with water and dried under reduced pressure. This gave 41 mg (71%) of the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH3:12].[CH:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)=[O:14]>C(=O)([O-])[O-].[Na+].[Na+].C(O)C.C1(C)C=CC=CC=1.O.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>[CH3:12][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[C:19]1[CH:20]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH:13]=[O:14]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Cc1ccc2ccccc2c1Br
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: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc2ccccc2c1-c1cccc(C=O)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 64.7 %

Procedure:
1-Bromo-2-methylnaphthalene (3.32 g, 15.0 mmol) and (3-formylphenyl)boronic acid (2.13 g, 15.0 mmol) was dissolved in a mixture of 1 M sodium carbonate aqueous solution (30 mL), ethanol (15 mL) and toluene (30 mL) and, after argon substitution, tetrakis(triphenylphosphine)palladium (0) (0.867 g, 0.750 mmol) was added. The reaction mixture was stirred under an argon atmosphere at 80° C. for 24 hrs. The reaction mixture was cooled, diluted with water and ethyl acetate, and the insoluble material was filtered through celite. The organic layer of the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-20% ethyl acetate/hexane) to give the title compound (2.39 g, yield 65%) as a pale-yellow oil.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])C1C=CC=CC=1>CO.[Pd]>[CH3:24][C:23]([CH3:26])([CH3:25])[C:22]([NH:21][NH:20][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[OH:8])=[O:19])=[O:27]
Reactant: CC(C)(C)C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 8 h
Yield: 102.2 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-N′-(2,2-dimethylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 254 (0.32 g, 0.86 mmol) and Pd/C (0.15 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature overnight. The mixture was filtered through Celite pad and concentrated to provide 255 (0.25 g, quant. yield) as a white foam.
Reaction SMILES: [CH3:1][C@H:2]([NH:20]C(=O)OC(C)(C)C)[C:3](=[O:19])[NH:4][C:5]1[CH:18]=[CH:17][C:8]2[O:9][C:10]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:7]=2[CH:6]=1.ClCCl.O1CCO[CH2:33][CH2:32]1>Cl>[CH:6]1[C:7]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:10]=3[O:9][C:8]=2[CH:17]=[CH:18][C:5]=1[NH:4][C:3](=[O:19])[C@@H:2]1[CH2:1][CH2:33][CH2:32][NH:20]1
Reactant: C1COCCO1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc2oc3c(c2c1)CCCCC3)[C@@H]1CCCN1

Procedure:
A solution of tert-butyl [(1S)-1-methyl-2-oxo-2-(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylamino)ethyl]carbamate (0.10 g) in 4 N HCl in dioxane (3 mL) and dichloromethane (3 mL) was stirred at room temperature for 30 min and then concentrated to provide N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-yl-L-prolinamide (46 mg) as its hydrochloric acid salt. MS (ESI) m/z 299 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[NH:23]1[C:27]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[CH:31]=O)=[N:26][N:25]=[N:24]1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:31][C:30]4[CH:33]=[CH:34][CH:35]=[C:28]([C:27]5[NH:23][N:24]=[N:25][N:26]=5)[CH:29]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cccc(-c2nnn[nH]2)c1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4cccc(-c5nnn[nH]5)c4)c23)c1

Procedure:
Analogously to Example 32, 260 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine and 172 μl of acetic acid are dissolved in 25 ml of methanol and reacted with 261 mg (1.5 mmol) of 3-(tetrazol-5-yl)-benzaldehyde (Step 59.1) to form 4-(3-chloro-phenylamino)-3-{[3-(tetrazol-5-yl)-phenyl)-methyleneamino}-1H-pyrazolo[3,4-d]pyrimidine. With ice-cooling, 8 ml (8 mmol) of DIBAL-H are added to the above intermediate in 15 ml of DMEU and the reaction mixture is stirred for 30 min. 15 ml of ethyl acetate are added and the mixture is stirred for 15 min, diluted with 150 ml of methanol and 1 ml of water and concentrated by evaporation in a rotary evaporator. The residue is poured into 0.5 liter of water and 0.5 liter of ethyl acetate, and acidified to pH=3 with 1 N HCl, and the aqueous phase is separated off and extracted a further 3× with ethyl acetate. The organic phases are washed several times with water and finally with brine, dried (Na2SO4) and concentrated by evaporation. Stirring in ether yields 4-(3-chloro-phenylamino)-3-[3-(tetrazol-5-yl)-benzylamino-]-1H-pyrazolo[3,4-d]pyrimidine; TLC: Rf=0.13 (CHCl3/methanol/H2O/acetic acid=85:13:1.5:0.5); HPLC: tRet(grad20-100)=7.4; FAB-MS: (M+H)+=419.
Reaction SMILES: [OH:1][CH:2]1[CH2:16][C:4]2([CH2:7][CH:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5]2)[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:1]=[C:2]1[CH2:3][C:4]2([CH2:7][CH:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:5]2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CC2(CC(O)C2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC2(CC(=O)C2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
To a solution of tert-butyl (6-hydroxyspiro[3.3]heptan-2-yl)carbamate (1.00 g, 4.40 mmol) in DCM (10 mL) was added Dess-Martin periodinane (2.80 g, 6.60 mmol) at ˜0° C. to 10° C. The resulting reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was treated with aqueous sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration under vacuum gave the crude product, which was purified by silica gel column chromatography (22% ethyl acetate in petroleum ether) to afford the title compound (800 mg, 3.55 mmol, 80% yield) as a pale yellow solid. MS (ESI) m/z 226.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH:10]([C:12]2[C:13](=[O:18])[NH:14][CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19](=O)[NH2:20])[CH:8]=2)[O:3]1.O=P(Cl)(Cl)Cl>ClCCCl>[CH3:1][C:2]1([CH3:22])[CH2:11][CH:10]([C:12]2[C:13](=[O:18])[NH:14][CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]#[N:20])[CH:8]=2)[O:3]1
Reactant: CC1(C)CC(c2ccc[nH]c2=O)c2cc(C(N)=O)ccc2O1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CC1(C)CC(c2ccc[nH]c2=O)c2cc(C#N)ccc2O1
Reaction time: 0.75 h

Procedure:
A mixture of 2.98 g of 2,2-dimethyl-4-(1,2-dihydro-2-oxo-3-pyridyl)-6-carbamoylchroman,2 ml of POCl3 and 200 ml of 1,2-dichloroethane is boiled for 45 min. Cooling and customary working up gives 2,2-dimethyl-4-(1,2-dihydro-2-oxo-3-pyridyl)-6-cyanochroman, m.p. 174°-175.5°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)=[C:4]([F:15])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:24][S:25]([CH2:28][CH2:29][C:30](O)=[O:31])(=[O:27])=[O:26].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.[Cl-].[Na+].O.CCCCCCC.CCOC(C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:3]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)=[C:4]([F:15])[C:5]([N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:30](=[O:31])[CH2:29][CH2:28][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: Cc1cnc(-c2c(Cl)cnc(N3CCC(N)CC3)c2F)c(C)c1
Reactant: CS(=O)(=O)CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cnc(-c2c(Cl)cnc(N3CCC(NC(=O)CCS(C)(=O)=O)CC3)c2F)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 1-(5′-chloro-3′-fluoro-3,5-dimethyl-[2,4′-bipyridin]-2′-yl)piperidin-4-amine (81.5 mg, 0.20 mmol), 3-(methylsulfonyl)propanoic acid (45.7 mg. 0.30 mmol), and NMM (80.9 mg, 0.80 mmol) in DMF (2 mL) was treated with HATU (91.3 mg, 0.24 mmol) portionwise. The reaction solution was stirred at rt under nitrogen for 2 h. EtOAc (30 mL) and brine (10 mL) were added and layers were separated. The organic layer was washed with brine (2×), dried over sodium sulfate, and concentrated. Purification on ISCO separation system with a 4-gram column using 0-8% MeOH in EtOAc afforded a colorless gum, which was sonicated in heptane/EtOAc to furnish a solid. After solvent removal, 56 mg (60%) of waxy, white solid was obtained: LRMS (M+H)+: 469.1; 1H NMR (400 MHz, CDCl3) δ 1.52 (dd, J=12.51, 3.66 Hz, 2 H), 2.02 (d, J=12.38 Hz, 2 H), 2.15 (s, 3 H), 2.39 (s, 3 H), 2.74 (t, J=6.95 Hz, 2 H), 2.96 (s, 3 H), 2.97-3.12 (m, 2 H), 3.42 (t, J=7.07 Hz, 2 H), 3.89-4.12 (m, 3 H), 5.63 (d, J=7.33 Hz, 1H), 7.47 (d, J=0.76 Hz, 1 H), 8.10 (s, 1 H), 8.40 (d, J=1.26 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].C(N(CC)CC)C.Cl.[N:40]12[CH2:48][C:44]([CH2:49][NH:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([CH2:45][CH2:46][CH2:47]1)[CH2:43][CH2:42][CH2:41]2>C(Cl)Cl>[N:40]12[CH2:48][C:44]([CH2:49][N:50]([CH:18]=[C:17]3[C:16]4[C:15]([CH3:30])([C:14]5[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]6([CH3:31])[CH:8]([C:13]=5[C:21](=[O:22])[C:20]=4[OH:19])[CH2:9][CH2:10][CH:11]6[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]3=[O:24])[CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)([CH2:43][CH2:42][CH2:41]1)[CH2:45][CH2:46][CH2:47]2
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: c1ccc(CNCC23CCCN(CCC2)C3)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN(Cc2ccccc2)CC23CCCN(CCC2)C3)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin and triethylamine (65 μL, 0.46 mmol) in 2 mL CH2Cl2 is added (1-aza-bicyclo[3.3.1]non-5-ylmethyl)-benzyl-amine hydrochloride (114 mg). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 676 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[C:8](/[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCC/C(=C\C=C\C(=O)O)c1cccc(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.6 %

Procedure:
As in Example 115, (E,E)-5-(3-fluorophenyl)-2,4-decadienoic acid (3.55 g) and 4-nitrophenol (2.33 g) in 20 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (2.81 g) and the mixture was stirred at room temperature for 3 days. After the usual work up. crystallization of the crude ester from hexane gave 3.51 g of (E,E)-5-(3-fluorophenyl)-2,4-decadienoic acid 4-nitrophenyl ester, mp 46°-47° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH3:29])[C:7]=2[CH:30]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH3:29])[C:7]=2[CH:30]=1
Reactant: CCCCCCC(Nc1ccc(C(=O)OC)cc1)c1oc2ccc(OC)cc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCC(Nc1ccc(C(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a mixture of methyl 4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)heptyl]amino}benzoate (1.17 g) synthesized above, tetrahydrofuran (20 mL) and ethanol (20 mL) was added 1N aqueous sodium hydroxide solution (20.0 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved is in water (20 mL), and 1N hydrochloric acid (20.0 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (1.02 g, 90%) as a pale-brown solid.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH2:13](O)C1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:10]([C:6]1[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)([O:12][CH3:13])=[O:11]
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cccc2c1OCC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cccc2c1OCC2
Yield: 142.6 %

Procedure:
A solution of 0.2 g (1.22 mmol) of 7-dihydrobenzofuran carboxylic acid, 0.13 g (1.22 mmol) of benzyl alcohol, 0.3 g (2.44 mmol) of DMAP and 0.46 g (2.44 mmol) of 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride in 5 mL of CH2Cl2 was stirred at rt for 12 h. The reaction mixture was partitioned between CH2Cl2 and water and the pH was adjusted to pH=1 with 1N HCl solution. The reaction mixture was extracted with CH2Cl2 and the combined organic fraction was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes: ethyl acetate, 6:1) to give 0.31 g of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:25][C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:31](I)[CH3:32]>>[CH2:31]([N:28]1[CH:27]=[C:26]([CH2:25][N:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:30]=[N:29]1)[CH3:32]
Reactant: CCI
Reactant: COc1ccc2c(c1)C(C(=O)N(Cc1cn[nH]c1)c1ccc(C(C)C)cc1)CCC2
Product: CCn1cc(CN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using N-(4-isopropylphenyl)-7-methoxy-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.44 g) and ethyl iodide (0.09 mL) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.31 g) was obtained. This was dissolved in ethyl acetate, and oxalic acid (0.07 g) was added. The precipitated solid was collected by filtration to give N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide oxalate (0.06 g).
Reaction SMILES: [O:1]=[C:2]([O:12][C:13]1[CH:14]=[C:15]([N+:31]([O-])=O)[CH:16]=[CH:17][C:18]=1[O:19][C:20](=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[H][H]>[Pd].C(OCC)(=O)C.C1COCC1>[O:1]=[C:2]([O:12][C:13]1[CH:14]=[C:15]([NH2:31])[CH:16]=[CH:17][C:18]=1[O:19][C:20](=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: [H][H]
Reactant: CCCCCCCCCC(=O)Oc1ccc([N+](=O)[O-])cc1OC(=O)CCCCCCCCC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)Oc1ccc(N)cc1OC(=O)CCCCCCCCC
Yield: 92.2 %

Procedure:
A mixture of 2.9 g of 3,4-bis[(1-oxodecyl)oxy]nitrobenzene and 0.5 g of 10% palladium on carbon in 50 ml of ethyl acetate and 10 ml of THF was stirred in a hydrogen atmosphere at room temperature for 5 hours when uptake ceased. The catalyst was removed by filtration and the filtrate was concentrated to an oil which was crystallized from ethyl acetate-hexane to give 2.5 g (92% yield, mp 44°-46°) of 3,4-bis[(1-oxodecyl)oxy]benzenamine.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:15])[CH2:10][CH2:11][CH2:12][NH:13][CH3:14].O1CCCC1.[Cl:21][C:22]1[CH:23]=[C:24]([S:29](Cl)(=[O:31])=[O:30])[CH:25]=[N:26][C:27]=1[Cl:28]>O>[Cl:21][C:22]1[CH:23]=[C:24]([S:29]([N:13]([CH2:12][CH2:11][CH2:10][N:9]([CH3:15])[CH3:8])[CH3:14])(=[O:31])=[O:30])[CH:25]=[N:26][C:27]=1[Cl:28]
Reactant: CNCCCN(C)C
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)CCCN(C)S(=O)(=O)c1cnc(Cl)c(Cl)c1
Reaction time: 0.08 h
Yield: 68.6 %

Procedure:
With cooling with ice, triethylamine (0.57 ml, 4.06 mmol) and N,N,N′-trimethylpropane-1,3-diamine (0.34 ml, 2.23 mmol) were added to a tetrahydrofuran solution (5 ml) of 5,6-dichloropyridin-3-sulfonyl chloride (500 mg, 2.03 mmol), and stirred for 5 minutes. Saturated saline water was added to the reaction solution, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate=6:1 to 4:1) to obtain 5,6-dichloro-N-[3-(dimethylamino)propyl]-N-methylpyridine-3-sulfonamide (454 mg, yield: 69%) as a red solid.