Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:9][O:10][CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH3:8])=[O:6].Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]2[N:21]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=3)[N:22]=[CH:23][C:16]=12.Cl>C1COCC1>[CH:11]([O:10][CH2:9][C@H:4]([O:3][C:15]1[N:20]=[CH:19][N:18]=[C:17]2[N:21]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=3)[N:22]=[CH:23][C:16]=12)[C:5]([O:7][CH3:8])=[O:6])([CH3:13])[CH3:12]
Reactant: Cc1cccnc1-n1ncc2c(Cl)ncnc21
Reactant: COC(=O)[C@@H](O)COC(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](COC(C)C)Oc1ncnc2c1cnn2-c1ncccc1C
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 79.2 %

Procedure:
60% Sodium hydride (0.720 g, 18.00 mmol) was added to a solution of (S)-methyl 2-hydroxy-3-isopropoxypropanoate (2.353 g, 12.00 mmol) in anhydrous THF (100 mL) at 5° C., under nitrogen. The resulting suspension was stirred at 5° C. for 10 minutes and then a solution of 4-chloro-1-(3-methylpyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate J4) (2.95 g, 12 mmol) in dry THF (50 mL) was added dropwise maintaining a temperature below 5° C. The reaction mixture was stirred at 5° C. for 10 mins and then allowed to warm to room temperature. The reaction was stirred at room temperature for 1 hour. The reaction mixture was neutralised with HCl (1M, aq). The majority of the THF was evaporated in vacuo and then EtOAc (75 mL) and water (50 mL) were added. The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography (120 g), elution gradient 30 to 80% EtOAc in isohexane to afford (2S)-methyl 3-isopropoxy-2-(1-(3-methylpyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (3.53 g, 79%). 1H NMR (400 MHz, DMSO-d6) δ 1.11-1.14 (6H, m), 2.11 (3H, s), 3.68-3.74 (4H, m), 3.95-4.03 (2H, m), 5.79-5.81 (1H, m), 7.56-7.59 (1H, dd), 7.98-8.00 (1H, d), 8.49 (1H, m), 8.57 (2H, d). m/z (ESI+) (M+H)+=372; HPLC tR=1.99 min.
Reaction SMILES: [CH3:1][N:2]1[C:14]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[C:6]2=[CH:7][CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[N:5]2[CH2:4][CH2:3]1.O1CCOCC1.CO.[ClH:35]>>[ClH:35].[ClH:35].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]2[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:7]=[C:6]2[C:14]21[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2
Reactant: CN1CCn2c(C(F)(F)F)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCn2c(C(F)(F)F)ccc2C12CCNCC2

Procedure:
tert-Butyl 2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (7.8 g, 20.89 mmol) was stirred in 4M HCl in dioxane (26.10 mL of 4 M, 104.4 mmol) and methanol (22 mL) at room temperature for 1 h. The reaction mixture was evaporated to dryness and the residue was co-evaporated with 100 mL of MTBE to afford 2′-methyl-6′-(trifluoromethyl)-3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]dihydrochloride as a yellow foam/solid (7.23 g, quantitative). ESI-MS m/z calc. 273.2, found 274.5 (M+1)+; Retention time: 0.44 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:7][CH2:6]1)[C:3]#N.[C:22]1([Mg]Br)[CH:27]=[CH:26]C=[CH:24][CH:23]=1>>[CH3:1][C:2]([N:5]1[CH2:6][CH2:7][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:9][CH2:10]1)([C:3]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1)[CH3:21]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C#N)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Product: CC(C)(c1ccccc1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Yield: 59 %

Procedure:
This was prepared according to the procedure described in Example 1 using 2,2-dimethyl-2-[4-(2-keto-1-benzimidazolinyl)piperidinyl]acetonitrile and phenylmagnesium bromide. Yield was 59%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[C:21]3[C:20](=[O:31])[N:19]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:18](=[O:38])[N:17]([CH3:39])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH2:36]([O:35][C:33](=[O:34])[CH2:32][N:19]1[C:20](=[O:31])[C:21]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][C:16]=2[N:17]([CH3:39])[C:18]1=[O:38])[CH3:37]
Reactant: CCOC(=O)Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2OC)n(C)c1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cn1c(=O)c2c(nc(N3CCNCC3)n2-c2ccccc2OC)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[7-(2-Methoxyphenyl)-1-(ethoxycarbonylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (10 mg) was dissolved in trifluoroacetic acid (0.5 ml), and the reaction mixture was stirred at room temperature for 30 minutes. After the solvent was removed, the residue was purified by reversed phase high performance liquid chromatography to give 4.92 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1.II.[I:16]([O-])(=O)(=O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[NH2:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][C:7]=1[I:16]
Reactant: CCOC(=O)c1cc(C)c(N)cn1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)c(N)c(I)n1
Temperature: 60 °C
Reaction time: 144 h
Yield: 132.3 %

Procedure:
A mixture of ethyl 5-amino-4-methylpyridine-2-carboxylate (2.58 g), iodine (2.91 g) and sodium periodate (1.22 g) in N,N-dimethylformamide (20 mL) was stirred at 60° C. for 6 days. The reaction mixture was cooled to room temperature. To the reaction mixture was added 1 mol/L aqueous sodium thiosulfate solution, and the resulting mixture was extracted with ethyl acetate twice. The extracts were washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1−1/1) to give ethyl 5-amino-6-iodo-4-methylpyridine-2-carboxylate (2.31 g). To sodium hexamethyldisilazide (1.03 mol/L tetrahydrofuran solution, 10.5 mL) was added a solution of ethyl 5-amino-6-iodo-4-methylpyridine-2-carboxylate (1.51 g) in tetrahydrofuran (9 mL) in a dropwise manner at −10° C., and the mixture was stirred at the same temperature for 10 minutes. To the mixture was added a solution of di(tert-butyl)dicarbonate (1.18 g) in tetrahydrofuran (4 mL) in a dropwise manner, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1−2/1) to give the title compound (1.11 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][C:16](O)=[O:17])[CH:11]=[CH:12][C:13]=1[Cl:14].C(N(CC)CC)C.[OH-].[Na+]>O1CCCC1.O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH2:15][CH2:16][OH:17]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCCc1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
Lithium aluminum hydride (LAH) (0.57 g, 0.015 mol) were dissolved in tetrahydrofuran (30 ml) at room temperature, followed by stirring for 30 min. To the resulting solution there was slowly added dropwise a solution having 3,4-dichlorophenylacetic acid (3 g, 0.015 mol) and triethylamine (2.1 ml, 0.015 mol) dissolved in tetrahydrofuran (20 ml) and after stirring at the reflux temperature for 3 h, the mixture was cooled and water was poured into. The mixture was neutralized with an aqueous solution of sodium hydroxide and subjected to extraction with ethyl acetate to yield the end compound 3,4-dichlorophenethyl alcohol (2.53 g).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12](=O)[CH:13]([CH3:18])[CH2:14][C:15](O)=[O:16])=[CH:11][C:5]=2[O:4][CH2:3]1.[CH3:20][NH:21][NH2:22]>C(O)C>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]3[CH:13]([CH3:18])[CH2:14][C:15](=[O:16])[N:21]([CH3:20])[N:22]=3)=[CH:11][C:5]=2[O:4][CH2:3]1
Reactant: CC(CC(=O)O)C(=O)c1ccc2c(c1)OCC(=O)N2
Reactant: CNN
Solvent: CCO
Product: CC1CC(=O)N(C)N=C1c1ccc2c(c1)OCC(=O)N2

Procedure:
4-(3,4-Dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl)-4-oxo-3-methylbutyric acid (1.56 g, 6.0 mmoles) was dissolved in ethanol (300 ml) and methylhydrazine (0.33 ml, 6.0 mmoles) was added. The mixture was heated at reflux for 2 hours, and then cooled to yield to yield the titled compound. The crystals were collected by filtration, recrystallized from ethanol, and recollected by filtration. The solid was dried under vacuum to yield 1.0 g of the titled compound, mp 204°-206° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][N:9]3[C:12]([C:15]4[CH:16]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)[CH:3]=[N:2]1.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH:35]=[CH:36][C:37]#[N:38]>>[C:37]([CH2:36][CH:35]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][N:9]3[C:12]([C:15]4[CH:16]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]([F:28])([F:27])[F:29])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)[CH:3]=[N:2]1)[C:31]1[O:30][CH:34]=[CH:33][CH:32]=1)#[N:38]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cn[nH]c4)cnn23)c1
Reactant: N#CC=Cc1ccco1
Product: N#CCC(c1ccco1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 89, Step 2 starting from N-{3-[7-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and 3-(2-furyl)acrylonitrile. LCMS (M+H)+: m/z=521.0.
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.O.[CH3:25][C:26]1([CH3:38])[O:31][C:30](=[O:32])[C:29]([CH2:33][CH2:34][C:35](=[O:37])[CH3:36])=[CH:28][O:27]1>C(OCC)(=O)C>[CH3:38][C:26]1([CH3:25])[O:31][C:30](=[O:32])[C:29]([CH2:33][CH2:34][CH:35]([OH:37])[CH3:36])=[CH:28][O:27]1
Reactant: CC(=O)CCC1=COC(C)(C)OC1=O
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(O)CCC1=COC(C)(C)OC1=O
Temperature: 32 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
30 g of baker's yeast (made by Oriental Yeast Co., Ltd.) and 15 g of saccharose were added in 30 ml of tap water, and the solution was then stirred at 32° C. for 30 minutes. Afterward, 350 mg of 2,2-dimethyl-5-(3-oxobutyl)-1,3-dioxin-4-one were added thereto, and the solution was then stirred overnight at the same temperature. 7.5 g of saccharose were further added thereto, followed by stirring overnight. Water of the reaction solution was then distilled off under reduced pressure, and the resultant residue was extracted with dichloromethane and then dried over anhydrous sodium sulfate. Afterward, the solvent was distilled off, and the residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate=4:1), thereby obtaining 161 mg (yield 55%) of (-)-2,2-dimethyl-5-(3-hydroxybutyl)-1,3-dioxin-4-one [a compound having the formula (1) in which n is 2, X is a hydrogen atom, Y is a hydrogen atom, and the substituent is present at the 5-position].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[C:4]([CH3:21])[N:3]=1.[NH3:22]>C(O)C>[NH2:22][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[C:4]([CH3:21])[N:3]=1
Reactant: N
Reactant: Cc1nc(C)c(C#Cc2ccc(C(F)(F)F)cc2)c(Cl)n1
Solvent: CCO
Product: Cc1nc(C)c(C#Cc2ccc(C(F)(F)F)cc2)c(N)n1

Procedure:
A mixture of 4-chloro-2,6-dimethyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine and ethanol was saturated with ammonia gas and reacted under heating in a shield tube to obtain a target substance. The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:41]>CC(O)C>[ClH:41].[F:1][C:2]1[C:3]([CH2:25][NH:26][CH3:27])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccc(OC)n2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (136 mg) in 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 62 mg, 51%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:11][C:12](=O)[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]1[N:24]2[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]2=[N:22][N:21]=1)(C)(C)C>C1COCC1>[F:29][C:26]1[CH:27]=[CH:28][C:23]2[N:24]([C:20]([C@@H:16]3[CH2:17][CH2:18][CH2:19][N:15]3[CH2:14][CH2:13][CH2:12][OH:11])=[N:21][N:22]=2)[CH:25]=1
Reactant: CC(C)(C)OC(=O)CCN1CCC[C@H]1c1nnc2ccc(F)cn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCN1CCC[C@H]1c1nnc2ccc(F)cn12
Reaction time: 1 h
Yield: 33.5 %

Procedure:
Lithium aluminium hydride solution (2M in THF, 1.64 mL, 3.28 mmol) was added to a solution of Intermediate 84d (550 mg, 1.64 mmol) in THF (15.0 mL) at −10° C. The reaction was stirred for 1 h then quenched by dropwise addition of water (125 μL), sodium hydroxide (3M aqueous, 125μL) and water (375 μL). The reaction was stirred for 10 min then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 2-10% (2M NH3 in MeOH) in DCM, to give the title compound (145 mg, 33%). LCMS (Method 4): Rt 0.32 mins, m/z 265.2 [MH+].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:11])=[CH:2]1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:13]([O:12][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[CH:2]=1)=[O:11])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCOC(=O)c1c[nH]c2ccccc12
Reactant: O=C(CCCBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCOC(=O)c1cn(CCCC(=O)OCc2ccccc2)c2ccccc12
Yield: 92.4 %

Procedure:
A mixture of nonyl indole-3-carboxylate (251 mg) obtained in Pre. Ex. 30, benzyl 4-bromobutyrate (449 mg) and potassium carbonate (362 mg) in N,N-dimethylformamide was stirred at 50° C. for 6 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated. Silica gel column chromatography of the concentrate afforded benzyl 4-(3-nonyloxycarbonyl-1-indolyl)butyrate (374 mg) as an oil.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[H-].[Na+].Br[CH2:15][CH2:16][O:17][CH3:18].Cl>CN(C=O)C.CS(C)=O>[CH3:18][O:17][CH2:16][CH2:15][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:4][C:2]1=[O:3]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: COCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COCCN1C(=O)Cc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.7 %

Procedure:
To a solution of isatin (2.94 g, 20 mmol) in DMF (40 mL) at 0° C. was added 60% NaH (1.00 g, 25 mmol) portionwise. After addition, the resulting mixture was stirred for 15 min at 0° C. and 1-bromo-2-methoxyethane (2.35 mL, 25 mmol) was added dropwise over 2 min. The resulting mixture was stirred for 10 min at 0° C., warmed to rt and stirred O/N. The reaction was then cooled to 0° C., quenched with sat. NH4Cl, ice, H2O, extracted with EtOAc (150 mL×2), dried over Na2SO4 and concentrated to give a dark orange red liquid which was redissolved in DMSO (10 mL). N2H4-xH2O (2 mL) was added dropwise over 7 min. After addition, the reaction mixture was stirred for 5 min at rt, then 2 h at 140° C. (oil temp.) before cooling to rt. Ice/H2O (20 mL) was added, followed by 6 M HCl (7 mL, 42 mmol) and the resulting mixture was stirred for 30 min at rt. Additional ice/H2O (40 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The crude product was purified by flash chromatography (gradient: EtOAc/hex 0 to 40%) to afford the title compound as an orange liquid (2.32 g, 61% over 2 steps). 1H NMR (400 MHz, DMSO-d6) δ 7.26-7.20 (m, 2H), 7.03 (d, J=8.0 Hz, 1H), 6.98 (t, J=7.4 Hz, 1H), 3.82 (t, J=5.6 Hz, 2H), 3.55 (s, 2H), 3.52 (t, J=5.8 Hz, 2H), 3.22 (s, 3H); MS ESI 191.8 [M+H]+, calcd for [C11H13NO2+H]+ 192.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11]#[N:12].C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#CCOc1ccc(F)cc1
Yield: 82.7 %

Procedure:
A mixture of 4-fluorophenol (22.4 g, 200 mmol), chloroacetonitrile (17.1 g, 220 mmol) and excess powdered potassium carbonate was refluxed for 7 h then the mixture was concentrated under reduced pressure. The residue was mixed with H2O and was extracted with Et2O. The combined organic layers were dried, filtered and concentrated under reduced pressure. The residue was Kugelrohr distilled to provide 2-(4-Fluorophenoxy)acetonitrile (25 g, 84%). The 2-(4-Fluorophenoxy)acetonitrile (25 g, 185 mmol) was reduced with alane [generated from lithium aluminum hydride (19.6 g, 516 mmol) and sulfuric acid (25.3 g, 258 mmol) according to the procedure in Example 1]. The crude product was purified by Kugelrohr distillation to provide the titled compound (12 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[C:7]([O:9]C)[CH:8]=1.C(CN)O>CCCCCC.C1COCC1>[CH:16]([C:11]1([C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]([CH:6]=2)[OH:9])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC=CC1(c2cc(OC)cc(OC)c2)CCCC1
Solvent: CCCCCC
Solvent: NCCO
Solvent: C1CCOC1
Product: CCCCC=CC1(c2cc(O)cc(O)c2)CCCC1
Temperature: 27 °C
Reaction time: 3.5 h
Yield: 82 %

Procedure:
To a solution of 1-(3,5-dimethoxyphenyl)-1-(hex-1-enyl)-cyclopentane (1 equiv.) in dry hexane (0.05M) at 0° C. under an argon atmosphere was added 9-iodo-9-BBN (2.3 equiv., 1M solution in hexane). The mixture was stirred at the same temperature for 3.5 h and then the reaction temperature was raised to 27° C. Stirring was continued at that temperature until completion of the reaction. The volatiles were removed in vacuo, the residual oil was dissolved in diethyl ether, and a solution of ethanolamine (2.4 equiv.) in THF (1.4 M) was added causing spontaneous precipitation of the 9-BBN.ethanolamine adduct. The suspension was stirred for 2.5 h, the white precipitate was filtered off and the filtrate was evaporated under reduced pressure to give an oil. Purification by flash column chromatography on silica gel using 40% diethyl ether—petroleum ether as eluent afforded the title compound in 82% yield.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](Cl)(=[O:13])[C:10]([Cl:12])=[O:11]>C1C=CC=CC=1>[O:13]=[C:9]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:10]([Cl:12])=[O:11]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: c1ccccc1
Product: O=C(Cl)C(=O)Nc1ccccc1
Reaction time: 8 h
Yield: 76.6 %

Procedure:
Similar to Referential Example 1, aniline hydrochloride (3.0 g) was dissolved in benzen (10 mL), and oxalyl chloride (10 mL) was added thereto under cooling with ice. The temperature of the mixture was then returned to room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, to thereby give the title compound (3.26 g, 76.6%) as a brown oil.
Reaction SMILES: CON(C)[C:4](=[O:21])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1.[CH3:23][Li]>C1COCC1.CCOCC>[CH:16]1([O:15][C:9]2[CH:8]=[C:7](/[CH:6]=[CH:5]/[C:4](=[O:21])[CH3:23])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: [Li]C
Reactant: COc1ccc(/C=C/C(=O)N(C)OC)cc1OC1CCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(/C=C/C(C)=O)cc1OC1CCCC1
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To a solution of (E)-N-methoxy-N-methyl-3-(3-cyclopentoxy-4-methoxyphenyl)-prop-2-enamide (318 mg, 1.05 mmol) in 2.5 mL of THF cooled to 0° C. was added CH3Li (1.5 mL of 1.4M ether solution). The resulting solution was stirred for 5 min, diluted with ether and transferred to a separatory funnel. After washing with H2O, 1M H3PO4, and brine, the organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (3:1, hexanes:ethyl acetate) provided (E)-4-(3-cyclopentoxy-4-methoxyphenyl)-but-3-en-2-one as a white solid (234 mg, 90%). 1H-NMR (300 MHz): δ 2.38 (s, 3), 3.89 (s, 3), 6.59 (d, 1, J=16), 7.46 (d, 1, J=16).
Reaction SMILES: [C:1]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:8][C:7]=1[NH:17][C:18]([NH:20][CH2:21][CH2:22]Cl)=[O:19])([O:3][CH2:4][CH3:5])=[O:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(C(C)C)CC)(C)C>C(#N)C>[C:1]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:8][C:7]=1[NH:17][C:18]([NH:20][CH2:21][CH2:22][N:35]1[CH2:34][CH2:33][N:32]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])[CH2:37][CH2:36]1)=[O:19])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)c1cc(-c2ccccc2)sc1NC(=O)NCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1cc(-c2ccccc2)sc1NC(=O)NCCN1CCN(c2ccccc2OC)CC1
Yield: 40.5 %

Procedure:
A solution of Example 5A (462 mg, 1.37 mmol), 1-(2-methoxyphenyl)piperazine (1.7 mmol), diisopropylethylamine (0.29 mL) in acetonitrile (5 mL) was processed as in Example 1B. Purification of the residue on silica gel with ethyl acetate provided 282 mg (41%) of the title compound.