Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].O.[OH-].[Na+:34]>C1COCC1>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:34]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Reaction time: 1.5 h
Yield: 82 %

Procedure:
A 100 ml round bottom flask was loaded with fluvastatin methyl ester (5 g, 11.7 mmole), water (45 ml), THF (12.5 ml) and NaOH (0.48 g). The solution was stirred for 1.5 h then extracted with ethyl acetate (20 ml) and filtered. The aqueous phase was distilled and acetonitrile (100 ml) was added and the mixture was stirred at room temperature over night. The product was isolated by filtration under nitrogen flow, washed with acetonitrile (15 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 4.16 g (82%) of fluvastatin sodium crystal Form LXXIII.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]([F:23])[CH2:21]O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:24]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:14]([Si:1]([O:18][CH2:19][CH:20]([F:23])[CH2:21][I:24])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:16])([CH3:17])[CH3:15]
Reactant: II
Reactant: CC(C)(C)[Si](OCC(F)CO)(c1ccccc1)c1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC(F)CI)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 58.4 %

Procedure:
3-{[Tert-Butyl(diphenyl)silyl]oxy}-2-fluoropropan-1-ol(2.03 g, 6.12 mmol) was dissolved in dichloromethane (20 ml). Iodine (4.66 g, 18.36 mmol), triphenyl phosphine (4.82 g, 18.36 mmol) and imidazole (1.25 g, 18.36 mmol) were added to the solution under cooling on ice and the mixture was stirred at room temperature for 23 hours. A saturated sodium thiosulfate aqueous solution was added to the reaction solution under cooling on ice and stirred for a while, the solution was extracted with dichloromethane and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 1.58 g (58%) of the title compound in the form of a yellowish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)(Cl)Cl.ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: COc1ccc(/C(=C\C=C\C(=O)O)c2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.2 %

Procedure:
As in Example 115, (2E,4Z)-5-(4-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid (0.85 g) and 4-nitrophenol (0.5 g) in 5 mL of carbon tetrachloride and 5 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (0.62 g). The mixture was stirred at room temperature for 18 hours and the usual work up furnished 1.0 g of (2E,4Z)-5-(4-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid 4-nitrophenyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=2[O:15][CH2:16][CH:17]2[CH2:19][O:18]2)[CH:6]=[CH:7][CH:8]=1.[CH3:24][NH:25][CH3:26]>O1CCCC1>[CH3:24][N:25]([CH3:26])[CH2:19][CH:17]([OH:18])[CH2:16][O:15][C:14]1[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(CCCCc2ccccc2OCC2CO2)c1
Reactant: CNC
Solvent: C1CCOC1
Product: COc1cccc(CCCCc2ccccc2OCC(O)CN(C)C)c1
Yield: 97 %

Procedure:
Following a procedure similar to that described in Example 1(b), a solution of 300 mg of 2-{2-[4-(3-methoxyphenyl) butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] in tetrahydrofuran was reacted with 50% by volume aqueous dimethylamine. After purification as described in Example 1(b), 335 mg (yield 97%) of the title compound were obtained as a colorless oil.
Reaction SMILES: [CH2:1]([S:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[C:30]([CH3:31])=[CH:29][S:28][C:16]=3[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26]C)[N:19]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([S:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[C:30]([CH3:31])=[CH:29][S:28][C:16]=3[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])[N:19]=2)[CH2:10][CH2:9]1)(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)N1CCN(c2nc(-c3ccccc3OC)nc3scc(C)c23)CC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCS(=O)(=O)N1CCN(c2nc(-c3ccccc3O)nc3scc(C)c23)CC1
Temperature: 25 °C

Procedure:
A solution of 4-(4-(butylsulfonyl)piperazin-1-yl)-2-(2-methoxyphenyl)-5-methylthieno[2,3-d]pyrimidine (0.12 g, 0.26 mmol) in CH2Cl2 (2 mL) was cooled to −50° C., and a solution of BBr3 in CH2Cl2 (1 M, 1.5 mL, 1.5 mmol) was slowly added. The reaction was allowed to gradually warm to room temperature over 2.5 h, and saturated aqueous NaHCO3 was slowly added. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 2-(4-(4-(butylsulfonyl)piperazin-1-yl)-5-methylthieno[2,3-d]pyrimidin-2-yl)phenol. LC/MS: m/z 447.2 (M+H)+ at 4.11 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[C:6]([OH:19])=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:11]=[CH:10][CH:9]=3.[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>CN(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.O>[CH2:15]([O:14][C:12]1[N:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[C:4]1[CH:3]=[C:2]([C:26]3[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=3)[CH:21]=[CH:20][C:5]=1[C:6]([OH:19])=[N:7]2)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOc1nccc2nc(O)c3ccc(Br)cc3c12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1nccc2nc(O)c3ccc(-c4cnn(C)c4)cc3c12
Temperature: 135 °C
Reaction time: 2 h

Procedure:
To a mixture of 9-bromo-1-butoxybenzo[c]-1,6-naphthyridin-6-ol (251 mg, 0.723 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (256 mg, 1.229 mmol), lithium chloride (184 mg, 4.34 mmol), and tetrakis(triphenylphosphine)palladium (251 mg, 0.217 mmol) in DMF (7229 μl) in a sealed tube, sodium carbonate (3615 μl, 7.23 mmol, 2 M) was added, and the reaction mixture was heated to 135° C. After 2 h, the reaction mixture was allowed to cool to room temperature and poured into water. This mixture was then filtered through a frit. The filter cake was washed with dichloromethane. The filter cake was then collected and dried under high vacuum to afford 1-butoxy-9-(1-methyl-1H-pyrazol-4-yl)benzo[c]-1,6-naphthyridin-6-ol as a white solid. LRMS (APCI) calc'd for (C20H21N4O2) [M+H]+, 349.2; found 349.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]=O)[CH:8]=2)[O:3]1.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>>[CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]=[C:19]3[C:18]4[C:22](=[CH:23][CH:24]=[C:16]([F:15])[CH:17]=4)[NH:21][C:20]3=[O:25])[CH:8]=2)[O:3]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CC1(C)CCc2cc(C=O)ccc2O1
Product: CC1(C)CCc2cc(C=C3C(=O)Nc4ccc(F)cc43)ccc2O1

Procedure:
2,2-Dimethyl-6-formylchromane (commercially available) was condensed with 5-fluoro-2-oxindole to give 0.3 g of 3-(2,2-Dimethylchroman-6-ylmethylene)-5-fluoro-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[NH:11][C:12]([Br:16])=[C:13]([Br:15])[CH:14]=1)=[O:9])C.[OH-].[K+]>O1CCOCC1.O>[Br:15][C:13]1[CH:14]=[C:10]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:17])=[O:3])=[O:9])[NH:11][C:12]=1[Br:16]
Reactant: CCOC(=O)CCNC(=O)c1cc(Br)c(Br)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCNC(=O)c1cc(Br)c(Br)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[(4,5-dibromo-1H-pyrrole-2-carbonyl)-amino]-propionic acid ethyl ester (7.80 g, 21.1 mmol) in 160 mL of 1:1 mixture of dioxane-H2O is added KOH (4.72 g, 84.2 mmol). The mixture is stirred at room temperature overnight. The solution is extracted with Et2O (100 mL) and the aqueous layer is then acidified with HCl to a pH of less than 2 followed by extraction with EtOAc (80 mL×3). The EtOAc layers are combined, washed with brine, and dried with Na2SO4. After removal of solvent, 3-[(4,5-dibromo-1H-pyrrole-2-carbonyl)-amino]-propionic acid is obtained. It was used without further purification; 1H NMR (DMSO-d6) δ 2.47 (t, 2H, J=7.2 Hz), 3.39 (q, 2H, J=6.0 Hz), 6.90 (s, 1H), 8.17 (t, 1H, J=4.8 Hz); m/z [M++1] 340.9.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([C:23]([O:25]CC2C=CC=CC=2)=[O:24])[CH:17]=3)=[C:9]([CH3:33])[CH:8]=1)=[O:4]>[Pd].C(OCC)(=O)C.C(O)C>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH3:33])[C:10]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([C:23]([OH:25])=[O:24])[CH:17]=3)=[C:11]([CH3:13])[CH:12]=1)=[O:4]
Reactant: COC(=O)/C=C/c1cc(C)c(-c2cc3ccc(C(=O)OCc4ccccc4)cc3[nH]2)c(C)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cc(C)c(-c2cc3ccc(C(=O)O)cc3[nH]2)c(C)c1
Reaction time: 18 h

Procedure:
A mixture of benzyl 2-[4-((E)-2-methoxycarbonylvinyl)-2,6-dimethylphenyl]-1H-indole-6-carboxylate (950 mg, 2.16 mmol) and 10% palladium on carbon (95 mg) in 100 mL of 1:1 ethyl acetate/ethanol was stirred under a hydrogen balloon for 18 h. The catalyst was filtered through Celite and the filtrate was removed under reduced pressure to leave the title compound. MS: m/z 352.2 (M+1); Retention time=1.35 min (Method 10).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[CH:33]1[CH:38]=[C:37]([CH2:39]Br)[C:36]([Cl:41])=[CH:35][CH:34]=1.[H-].[Na+]>C(#N)C.O>[Cl:41][C:36]1[CH:35]=[CH:34][CH:33]=[CH:38][C:37]=1[CH2:39][N:23]([C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:16])=[CH:22][CH:21]=1)[C:24](=[O:32])[CH2:25][N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: Clc1ccccc1CBr
Reactant: O=C(CN1CCOCC1)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(CN1CCOCC1)N(Cc1ccccc1Cl)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Yield: 126.9 %

Procedure:
A mixture of 0.11 g of N-[4-(5H-pyrrolo-[2,1-c][1,4]benzodiazepin10(11H)-ylcarbonyl)phenyl]4-morpholineacetamide, 56 mg of O-chlorobenzyl bromide and 0.41 g of K2 CO3 in 5 ml of acetonitrile is heated at reflux for 18 hours. An additional 30 mg of O-chlorobenzyl bromide and 0.4 mmol of sodium hydride is added followed by heating for 24 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried with Na2SO4 and evaporated to give 0.18 g of a residue which is purified by chromatography on silica gel with 1:1 ethyl acetate-methylene chloride to give 80 mg of off white solid. MS(CI): 555(M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]1[CH:29]=[CH:28][C:6]([CH:7]([C:16]2[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.O.[OH-].[Na+].OO>C(O)(C)C>[CH3:30][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]2([C:8]3[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=3)[C:16]3[C:17](=[CH:21][C:22]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:24]=3)[C:18](=[O:20])[O:19]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(C2(c3ccc(N(C)C)cc3)OC(=O)c3cc(N(C)C)ccc32)cc1
Reaction time: 8 h
Yield: 68.2 %

Procedure:
A stirred mixture of 8.1 g of 2-(4-dimethylamino-4'-methoxybenzhydryl)-5-dimethylaminobenzoic acid from part A above, 40.0 ml of water, 1.6 g of 50 percent aqueous sodium hydroxide and 2.7 ml of isopropyl alcohol was maintained at a temperature in the range of 85°-96° C. while 20.3 g of ten percent aqueous hydrogen peroxide was added over a period of approximately six hours. The reaction mixture was set aside at ambient temperature overnight. The solid was collected by filtration, washed free of alkali with water and dried in vacuo to obtain 5.5 g of 3-(4-dimethylaminophenyl)-3-(4-methoxyphenyl)-6-dimethylaminophthalide, a yellow-colored solid which melted at 156°-161° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH:18]([O:22][CH2:23]C)[O:19][CH2:20]C)[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([CH3:13])=[CH:6][C:5]=1[N+:14]([O-:16])=[O:15])[CH3:2].C(O)CO.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(OCC)(=O)C>[CH2:1]([N:3]([CH2:17][CH:18]1[O:19][CH2:20][CH2:23][O:22]1)[C:4]1[C:5]([N+:14]([O-:16])=[O:15])=[CH:6][C:7]([CH3:13])=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: CCOC(CN(CC)c1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-])OCC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: OCCO
Solvent: CCOC(C)=O
Product: CCN(CC1OCCO1)c1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
N-Ethyl-N-(2,2-diethoxyethyl)-2,6-dinitro-p-toluidine (5.2 grams; 0.0132 mole), ethylene glycol (0.82 grams; 0.0132 mole) and toluenesulfonic acid (200 mg) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture was heated at 110° C. for a period of one hour. After this time the mixture was dissolved in ethyl acetate and the resulting solution washed with aqueous base, dried and stripped of solvent to yield the desired product N-ethyl-N-1,3-dioxolan-2-ylmethyl-2,6-dinitro-p-toluidine as a brown oil.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Si:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][OH:26])=[CH:23][CH:22]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].O[N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C.CCCCCC.C1(C)C=CC=CC=1>[Si:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:26][N:30]2[C:31](=[O:40])[C:32]3=[CH:39][CH:38]=[CH:37][CH:36]=[C:33]3[C:34]2=[O:35])=[CH:23][CH:22]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CO)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Reaction time: 18 h
Yield: 44.1 %

Procedure:
Diethyl azodicarboxylate (40% toluene solution, 54.0 g) was added dropwise to a solution of 4-(tert-butyldimethylsilyloxy)benzylalcohol (27.5 g), N-hydroxyphthalimide (16.8 g) and triphenylphosphine (31.1 g) in tetrahydrofuran (450 ml) at room temperature and stirred for 18 hours. After the reaction mixture was concentrated, diisopropyl ether (200 ml) was added and the residual crystals were removed by filtration. The filtrate was concentrated, and the residue was subjected to silica gel chromatography to obtain N-[4-(tert-butyldimethylsilyloxy)benzyloxy]phthalimide (17.4 g, yield 43%) as crystals from an ethyl acetate-hexane-toluene (1:10:10, v/v)-eluted fraction. The crystals were recrystallized from ethyl acetate-hexane to obtain colorless crystals. m.p. 76-77° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CC(C)([O-])C.[Na+]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CC(C)(C)c1ccc(N2CCOCC2)cc1
Yield: 80.1 %

Procedure:
According to the general procedure B, 4-tert-butylbromobenzene (94 mg, 0.44 mmol) reacted with morpholine (36 mg, 0.41 mmol) using 1 mol % of catalyst and sodium tert-butoxide (42 mg, 0.44 mmol) at 100° C. for 21 h to give the title compound (72 mg, 82%) as a white solid: 1H-NMR (300 MHz, CDCl3): δ 7.35 (d, 2H, J=8.7 Hz), 6.91 (d, 2H, J=8.7 Hz), 3.89 (t, 4H, J=4.5 and 4.8 Hz), 3.17 (t, 4H, J=4.5 and 4.8 Hz), 1.34 (s, 9H). 13C{1H}-NMR (100 MHz, CDCl3): δ 148.89, 142.76, 125.95, 115.38, 66.99, 49.54, 33.94, 31.42. GC/MS(EI): m/z 219 (M+), 204 (M+−CH3), 146 (M+−morpholine).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.Cl.[C:27]([C:29]1[C:30]([C:43]([F:46])([F:45])[F:44])=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH2:38][C:39](=[NH:42])[NH:40]O)[CH:33]=[CH:32]2)#[N:28]>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]1[O:6][N:42]=[C:39]([CH2:38][N:34]2[C:35]3[C:31](=[C:30]([C:43]([F:46])([F:44])[F:45])[C:29]([C:27]#[N:28])=[CH:37][CH:36]=3)[CH:32]=[CH:33]2)[N:40]=1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCCl
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(C(F)(F)F)ccc3F)n2)c1C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
2-Fluoro-5-(trifluoromethyl)benzoic acid (0.016 g, 0.075 mmol) and EDCl (0.015 g, 0.078 mmol) were stirred in DCE (2 mL) for 5 min at rt and then 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (0.020 g, 0.071 mmol) was added. After 1 h at rt, the reaction was heated to 80° C. for 15 h. Direct purification (SiO2, EtOAc/hexanes) provided the title compound (0.016 g): MS (ESI): m/z 455 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20](Cl)=[N:19][CH:18]=1)[CH3:14]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C>[CH2:13]([O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=2)=[N:19][CH:18]=1)[CH3:14]
Reactant: C#Cc1ccc(C(C)(C)C)cc1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C(C)(C)C)cc2)nc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 477.7 mg (3.02 mmol) of 4-tert-butylphenylethyne (Compound 19), 556.5 mg (3.01 mmol) of ethyl-6-chloronicotinate (Compound 54), 27.8 mg (0.15 mmol) of cuprous iodide, 58.7 mg (0.08 mmol) of bis(triphenylphosphine)palladium (II) chloride and 2 ml of triethylamine was degassed under nitrogen and then stirred under nitrogen at room temperature for 40 hours. The mixture was then heated at 65 degrees C. for 12 hours, cooled to room temperature and the excess triethylamine removed under vacuum. The residue was taken up in water and extracted with ether. The solvent was then removed in-vacuo and the residue purified by flash chromatography (silica 5% ethyl acetate in hexane) to give the title compound as a pale brown solid. PMR (CDCl3): & 1.33 (9H, s), 1.42 (3H, t, J~7.1 Hz); 4.42 (2H, q, J~7.1 Hz), 7.40 (2H, d, J~8.4 Hz), 7.53-7.61 (3H, m), 8.28 (1H, dd, J~8.1 Hz, 2.0 Hz), 9.20 (1H, d, J~2.0 Hz).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH3:17])[NH:14][C:13](=[O:15])[NH:12][C:11]3=[O:16])=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([O:31][C:32]([C:41]1[N:46]=[CH:45][C:44]([N:47]2[CH2:52][CH2:51][N:50]([C:53](=[O:56])[CH2:54]Br)[CH2:49][CH2:48]2)=[C:43]([CH2:57][CH2:58][CH3:59])[CH:42]=1)([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[CH2:24]([O:31][C:32]([C:41]1[N:46]=[CH:45][C:44]([N:47]2[CH2:52][CH2:51][N:50]([C:53](=[O:56])[CH2:54][N:12]3[C:11](=[O:16])[C:10]([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][CH2:3][C:4]=5[CH:9]=4)([CH3:17])[NH:14][C:13]3=[O:15])[CH2:49][CH2:48]2)=[C:43]([CH2:57][CH2:58][CH3:59])[CH:42]=1)([C:33]([F:34])([F:35])[F:36])[C:37]([F:38])([F:40])[F:39])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCCc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ncc1N1CCN(C(=O)CBr)CC1
Reactant: CC1(c2ccc3c(c2)CCO3)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ncc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(c3)CCO4)C2=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.3 %

Procedure:
5-(2,3-Dihydrobenzofuran-5-yl)-5-methylimidazolidine-2,4-dione (5.6 mg, 0.0240 mmol) was dissolved in N,N-dimethylformamide (500 μL), and potassium carbonate (7.5 mg, 0.0545 mmol) was added under ice-cold conditions. The mixture was stirred at room temperature for 5 minutes. Then, under ice-cold conditions, 1-(4-{6-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-4-propylpyridin-3-yl}piperazin-1-yl)-2-bromoethanone (13 mg, 0.0218 mmol) was added and stirred at room temperature for 18 hours. Under ice-cold conditions, the reaction solution was added water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone), and the title compound (13 mg (yield 78%)) was obtained as a yellow oil.
Reaction SMILES: C[C:2]1[C:3]([OH:19])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]1[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[O:14][CH:7]21.[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24].Cl>CN(C=O)C.O>[CH:23]([O:19][C:3]1[CH:2]=[C:11]2[C:6]([CH:7]3[O:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[CH:8]3[CH2:9][O:10]2)=[CH:5][CH:4]=1)([CH3:24])[CH3:22]
Reactant: Cc1c(O)ccc2c1OCC1c3ccccc3OC21
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc2c(c1)OCC1c3ccccc3OC21
Yield: 60.4 %

Procedure:
Compound 4-methyl-6a,11a-dihydro-6H-benzo[4,5]furo[3,2-c]chromen-3-ol (100 mg, 0.34 mmol) was dissolved in DMF (5 ml) and NaH (8.1 mg, 0.34 mmol) was added to the solution at room temperature, followed by allyl bromide (0.06 ml, 0.68 mmol). The reaction mixture was stirred at room temperature to 6 hours and poured into iced water and neutralized with 10% HCl to get the white precipitate. Precipitate were washed with water and purified by silica gel column chromatography using hexane-chloroform as the eluent to give 3-isopropoxy-6a,11a-dihydro-6H-benzofuro[3,2-c]chromene (58 mg, 50%) as white solid.