Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[S:3]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])=[O:4].[CH3:12][C:13]1([CH3:21])[O:17]C(CCO)[CH2:15][O:14]1.FC(F)(F)S([O-])(=O)=O>C(Cl)(Cl)(Cl)Cl>[F:11][C:2]([F:10])([F:1])[S:3]([O:6][CH2:7][CH2:8][CH:9]1[CH2:15][O:14][C:13]([CH3:21])([CH3:12])[O:17]1)(=[O:4])=[O:5]
Reactant: C=CCOS(=O)(=O)C(F)(F)F
Reactant: CC1(C)OCC(CCO)O1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OCC(CCOS(=O)(=O)C(F)(F)F)O1

Procedure:
2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl trifluoromethane sulfonate was prepared in carbon tetrachloride solution and used as a dried solution in this example in the same way as 2-propen-1-yl trifluoromethanesulfonate was prepared and used in Examples 41 through 44, starting with 2,2-di-methyl-4-(2-hydroxyethyl)1,3-dioxolane and trifluoromethanesulfonate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[CH2:11]1[CH2:20][O:19][C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[O:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][N:16]1[CH2:17][CH2:18][C:13]2([O:19][CH2:20][CH2:11][O:12]2)[CH2:14][CH2:15]1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: C1CC2(CCN1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Fc1ccc(CN2CCC3(CC2)OCCO3)cc1F
Yield: 94.9 %

Procedure:
A solution of 3,4-difluorobenzaldehyde (4.40 g, 30.9 mmol), 4,4-ethylenedioxy-piperidine (4.40 g, 30.9 mmol), sodium triacetoxyborohydride (6.40 g, 30.2 mmol) and acetic acid (1.8 g, 30.0 mmol) in dichloroethane (200 ml) was stirred at room temperature for 18 h. After this period, the reaction mixture was washed with 1N sodium hydroxide. The organic layer separated, dried (MgSO4) and the solvents evaporated in vacuo to give D3 (7.9 g, 98%). C14H17F2NO2 requires 269; Found 270 (MH+)
Reaction SMILES: [CH2:1]1[C:5]2([CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH:2]1[CH2:12][OH:13].C(O)C.[H][H]>O1CCCC1.[C].[Pd]>[CH2:1]1[C:5]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH:2]1[CH2:12][OH:13]
Reactant: [H][H]
Reactant: OCC1CCC2(CCC=CCC2)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: OCC1CCC2(CCCCCC2)C1
Yield: 96.6 %

Procedure:
A suspension of spiro[4.6]undec-8-ene-2-methanol (44 mg) obtained in Step 6 and 5% palladium carbon (4 mg) in tetrahydrofuran (1 mL)-ethanol (1 mL) was stirred in an atmosphere of hydrogen for 3 hours. Then, the reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by column chromatography on silica gel to give spiro[4.6]undecane-2-methanol (43 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13]Br.[NH:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(=O)CC.[Cl-].[Na+].O.[I-].[Li+].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25]
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 93.7 %

Procedure:
A stirred mixture of 2-bromomethyl-6-nitro-benzoic acid methyl ester (36.6 g, 134 mmol), di-tert-butyl iminodicarboxylate (29.1 g, 134 mmol), cesium carbonate (89.3 g, 274 mmol), and lithium iodide (0.89 g, 6.7 mmol) in 2-butanone (400 mL) was heated to reflux in a 100° C. oil bath for 12 hours while stirred with a mechanical stirrer. The mixture was allowed to cool to room temperature. To the mixture, was add brine (300 mL), water (300 mL), ethyl acetate (750 mL) and stirred for 10 minutes, then the suspension was filtered through a pad of Celite. The two layers were separated, and the organic layer was evaporated to a less volume and the aqueous layer was extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with brine (500 mL), dried over magnesium sulfate while de-colored at the same time with charcoal at room temp for 30 minutes. The black mixture was filtered through a pad of Celite. The filtrate was evaporated to give 2-(di-tert-butoxycarbonylamino-methyl)-6-nitro-benzoic acid methyl ester as a brown oil (51.53 g, 94% yield). The product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[N:11]([C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=2)[C@H:10]([CH2:29][CH3:30])[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Cl)(Cl)Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[N:11]([C:19](=[O:28])[C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)[C@H:10]([CH2:29][CH3:30])[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H]1C(=O)N(Cc2ccccc2)c2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(Cc2ccccc2)c2cc(F)ccc2N1C(=O)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 156.8 %

Procedure:
To a stirred solution of (3R)-1-benzyl-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (0.17 g, 0.41 mmol) and tetrabutylammonium iodide (0.28 g, 0.76 mmol) in methylene chloride (4 mL) at −78° C. was added a 1 M solution of boron trichloride in methylene chloride (2.8 mL, 2.8 mmol). Stirring was continued at −78° C. for 5 minutes, and the reaction was warmed to 0° C., where it was stirred for 10 h. Ice water was then added and stirred thoroughly. The layers were separated. The organic layer was washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave an oil (0.26 g). The product was purified via Biotage Horizon® (SiO2, gradient from 5% EtOAc/hexane to 35% EtOAc/hexane) to quantitatively yield (3R)-1-benzyl-3-ethyl-7-fluoro-4-(4-hydroxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one as a colorless oil. [α]D25=250° (c=0.0097 G/ML, CHCl3); MS (ESI) m/z 405 ([M+H]+); MS (ESI) m/z 403 ([M−H]−); HRMS: calcd for C24H21FN2O3 0.67H2O, 416.2207; found (ESI+), 405.16006.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[NH2:39])[CH2:23][CH2:22]1.Cl.O1CCOCC1>CO>[N:24]1([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[NH:39][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:3]=2[CH3:20])[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1
Reactant: Cc1c(-c2ccccc2F)nc2cccc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2F)nc2cccc(F)c2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4-chloro-5-fluoro-2-(2-fluorophenyl)-3-methylquinoline (137 mg, 473 μmol), 2,5-dimorpholinobenzeneamine (125 mg, 473 μmol) and 4N hydrochloric acid solution in dioxane (0.12 mL, 473 μmol) in MeOH (3.00 mL) to afford product as a colorless solid after purification by chromatography on silica gel, eluting with MeOH gradient in DCM. 1H NMR (400 MHz, chloroform-d) δ ppm 8.23-8.51 (1H, m), 7.96 (1H, d, J=8.2 Hz), 7.53-7.69 (2H, m), 7.42-7.53 (1H, m, J=7.8, 7.8, 5.5, 2.0 Hz), 7.31-7.40 (1H, m), 7.13-7.26 (2H, m), 7.10 (1H, d, J=8.6 Hz), 6.47 (1H, dd, J=8.4, 2.9 Hz), 6.12-6.27 (1H, m), 3.92 (4H, t, J=4.7 Hz), 3.75-3.87 (4H, m), 3.12-3.21 (2H, m), 3.00-3.12 (4H, m), 2.69-2.98 (2H, m), 2.11 (3H, d, J=2.3 Hz). Mass Spectrum (ESI) m/e=517.3 (M+1).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[Cl:61][CH2:62][C:63]([C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([Cl:71])[CH:66]=1)=[O:64].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:61][CH2:62][C@@H:63]([C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([Cl:71])[CH:66]=1)[OH:64]
Reactant: O=C(CCl)c1cccc(Cl)c1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O[C@@H](CCl)c1cccc(Cl)c1
Temperature: 30 °C
Reaction time: 24 h
Yield: 90.5 %

Procedure:
To 50 ml of a culture solution of E. coli HB101 (pNTCMG1) prepared in the same manner as in Example 6, 5 g of glucose, 6 mg of NADP, 4 g of 2-chloro-1-(3′-chlorophenyl)ethanone and 4 g of toluene were added. The mixture was stirred at 30° C. for 24 hours while adjusting the pH of the mixture to 6.5 by adding 5 M sodium hydroxide dropwise. After completion of the reaction, the reaction solution was extracted with toluene. The solvent was removed and then an extracted material was analyzed. As a result, (R)-2-chloro-1-(3′-chlorophenyl)ethanol having an optical purity of 82.0% e.e. was obtained in a yield of 90.5%.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[NH:9][C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:65][CH:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[NH:9][C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH:65][CH:66]5[CH2:71][CH2:70][O:69][CH2:68][CH2:67]5)=[O:26])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2
Reactant: NC1CCOCC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
To a mixture of 0.06 g (0.13 mmole) of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-151), 0.08 g (0.21 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.07 mL (0.41 mmole) diisopropylethylamine. After stirring at room temperature for 30 minutes, 0.042 g (0.41 mmole) of 4-amino-tetrahydropyran was then added. The mixture was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water, then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with hot methanol to give 0.014 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-155).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>CCN(CC)CC>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([OH:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)CNC(=O)OCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H](O)CNC(=O)OCc1ccccc1
Reaction time: 17 h
Yield: 106.4 %

Procedure:
In a 200 ml autoclave were charged 40 g (0.13 mol) of ethyl 4-benzyloxycarbonylamino-3-oxobutyrate, 120 ml of ethanol, and 173 mg (0.102 mmol) of Ru2Cl4((R)-Tol-BINAP)2.NEt3, and asymmetric hydrogenation was carried out at 50° C. under a hydrogen pressure of 30 torr. for 17 hours (conversion: 98.4%; optical purity: 94%e.e.). Ethanol was evaporated under reduced pressure to furnish 38.9 g of the title compound as liquid. An aliquot of the product was purified to find that the yield was 91%.
Reaction SMILES: C(O[CH:10]=[C:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:16][CH:17]=2)[C:12]1=[O:31])(=O)C1C=CC=CC=1.C1CCCCC=1>[Pd]>[CH2:21]([C:15]1[CH:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([CH3:10])=[C:12]2[OH:31])=[CH:17][CH:16]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCc1ccc2c(c1)C(=O)C(=COC(=O)c1ccccc1)CC2
Agent: [Pd]
Solvent: C1=CCCCC1
Product: CCCCCCCCCCc1ccc2ccc(C)c(O)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a mixture of 2-benzoyloxymethylene-7-n-decyl-1-tetralone (14 g, 33.5 mmoles) and Pd/C (3.5 g) under inert atmosphere was added cyclohexene (175 mL). The mixture was heated to reflux while maintaining the inert atmosphere. The conversion of starting material to product was determined by TLC after 3 hours. After all the starting material reacted, the mixture was cooled down to RT. The catalyst was removed by filtration and washed twice with 50 mL hot toluene. The combined filtrate was evaporated to a small volume. The product was purified with a Prep-500 silica gel column (a high pressure silica gel preparative column, obtained from Waters Association, Milford, MA). Toluene was used as the mobile phase. The product fractions were pooled and evaporated to dryness under vacuum overnight. Cream white solid (9.0 g; 90% yield) was recovered. The melting point was 65°-67° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH:43]=[O:44])=[C:24]2[C:28]=1[N:27]=[C:26]1[N:29]([C:33]3[C:34]([CH3:42])=[N:35][C:36]([O:40][CH3:41])=[N:37][C:38]=3[CH3:39])[CH2:30][CH2:31][CH2:32][N:25]21.C[Si](C)(C)[C:47]([F:50])([F:49])[F:48].Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:19][C:20]1[C:28]2[N:27]=[C:26]3[N:29]([C:33]4[C:34]([CH3:42])=[N:35][C:36]([O:40][CH3:41])=[N:37][C:38]=4[CH3:39])[CH2:30][CH2:31][CH2:32][N:25]3[C:24]=2[C:23]([CH:43]([OH:44])[C:47]([F:50])([F:49])[F:48])=[CH:22][CH:21]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C(O)C(F)(F)F)c23)c(C)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80.7 %

Procedure:
Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 1.1 mL, 1.1 mmol) was added dropwise to a stirred solution of 9-chloro-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (4.12 g, 11.1 mmol) and trimethyl(trifluoromethyl)silane (3.16 g, 22.2 mmol) in tetrahydrofuran (45 mL) at 0° C., and the mixture was stirred at 0° C. for 20 min. 1N Hydrochloric acid (35 mL) was added to the mixture at 0° C., and the mixture was stirred at 0° C. for 30 min. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 75-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with ethyl acetate/diisopropyl ether to give the title compound as a colorless powder (3.96 g, 8.96 mmol, 81%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1CCCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1CCCN1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
A solution of tert-butyl (Z)-4-(3-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}propyl)piperazine-1-carboxylate (0.0393 g, 0.0758 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[3-(piperazin-1-yl)propyl]benzofuran-3(2H)-one (0.0273 g, 86%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:46]=[CH:45][C:29]([CH2:30][N:31]2[CH2:36][CH2:35][C:34]3([C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37]3)[CH2:33][CH2:32]2)=[CH:28][CH:27]=1>C(#N)C>[N:31]1([CH2:30][C:29]2[CH:45]=[CH:46][C:26]([CH2:25][O:1][C:2]3[CH:3]=[CH:4][C:5]([C@@H:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=3)=[CH:27][CH:28]=2)[CH2:36][CH2:35][C:34]2([C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[CH:37]2)[CH2:33][CH2:32]1
Reactant: BrCc1ccc(CN2CCC3(C=Cc4ccccc43)CC2)cc1
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc(CN3CCC4(C=Cc5ccccc54)CC3)cc2)cc1
Temperature: 90 °C
Yield: 38.5 %

Procedure:
To a solution of ethyl(3S)-3-(4-hydroxyphenyl)hex-4-ynate (0.350 g, 1.5 mmol) in acetonitrile (25 mL) is added potassium carbonate (0.621 g, 4.5 mmol) and 1′-[4-(bromomethyl)benzyl]spiro[indene-1,4′-piperidine] (0.77 g, 2.1 mmol). The reaction mixture is heated for 16 hours at 90° C. The mixture is concentrated, diluted with water, and extracted with EtOAc (2×200 mL). The combined extracts are washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered, and concentrated to dryness to give the title compound (0.3 g, 38%). ESI/MS m/z 520 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[C:13]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:18][CH:19]=1)=[N:7][N:6]=[CH:5]2
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: Clc1nncc2cc(Br)ccc12
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(Nc2nncc3cc(Br)ccc23)cc1

Procedure:
Heat a mixture of 6-bromo-1-chloro-phthalazine (500 mg, 2.05 mmol) and 4-(tert-butyl)aniline (611 mg, 4.10 mmol) in 2-propanol (10 mL) at reflux for 3 hours. Evaporate the mixture, add 1M NaOH (10 mL), extract twice with EtOAc (10 mL each), dry (Na2SO4), and evaporate to provide the crude product. Purify by silica gel chromatography, eluting with dichloromethane followed by 95% CH2Cl2-MeOH to provide (6-Bromo-phthalazin-1-yl)-(4-tert-butyl-phenyl)-amine as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][O:16]S(C)(=O)=O)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:13][N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)OCc1ccc(Oc2ccc([N+](=O)[O-])cc2)nc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(COc3ccc(C(F)(F)F)cc3)cn2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Methanesulfonic acid 6-(4-nitrophenoxy)-pyridin-3-ylmethyl ester (4.86 g, 15 mmol) was dissolved in DMF (250 mL), and to the resulting solution were added 4-hydroxybenzotrifluoride (2.92 g, 18 mmol) and potassium carbonate (3.11 g, 22.5 mmol). The resulting solution was stirred under a nitrogen atmosphere for 1 hour at 50° C. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, and washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=80:1), to thereby yield 5.8 g of the title compound.
Reaction SMILES: [CH2:1]([Mg]Br)[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][CH2:16][CH2:17][CH3:18].BrCCCCCCCCCCCCCCCCCC.[Mg].II.[CH3:43][Si:44]([CH3:53])([CH3:52])[C:45]1[O:49][CH:48]=[C:47]([CH:50]=[O:51])[CH:46]=1>C(OCC)C.O1CCCC1>[OH:51][CH:50]([C:47]1[CH:46]=[C:45]([Si:44]([CH3:53])([CH3:52])[CH3:43])[O:49][CH:48]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: CCCCCCCCCCCCCCCCCC[Mg]Br
Agent: CCCCCCCCCCCCCCCCCCBr
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of octadecylmagnesium bromide (10.2 ml of a 0.34M solution in ethyl ether, 3.46 mmol, generated from 1-bromooctadecane and magnesium using iodine as an initiator) at 0° under argon, was added dropwise 5-trimethylsilyl-3-furaldehyde (0.265 g., 1.57 mmol) in 2 ml tetrahydrofuran. This solution was allowed to warm to room temperature, stirred for 30 minutes, and quenched with a 5% ammonium chloride solution. The resulting mixture was partitioned between ethyl ether and 5% sodium bicarbonate. The organic portion was washed with 10% sodium bisulfite, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a residue. This was taken up in ethyl ether and filtered. The ether portion was concentrated to give a waxy residue which was purified by flash chromatography (silica, 10% ethyl ether/petroleum ether) to give the desired alcohol.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3]1.[Br:10][C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:14][NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[Br:10][C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:14][N:15]([CH:16]1[CH2:17][CH2:18][CH2:19]1)[C:7]([C:5]1[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=1)=[O:9]
Reactant: Fc1ccc(CNC2CCC2)cc1Br
Reactant: Cn1cnc(C(=O)O)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: Cn1cnc(C(=O)N(Cc2ccc(F)c(Br)c2)C2CCC2)c1
Yield: 13.8 %

Procedure:
A solution of methyl-1H-imidazole-4-carboxylic acid (1.17 g), N-(3-bromo-4-fluorobenzyl)cyclobutanamine (2.40 g) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (3.09 g) in methanol (25 mL) was stirred at room temperature for 4 hr. After the reaction mixture was concentrated under reduced pressure, the resulting residue was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate solution. After extraction with chloroform, the organic phase was dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was then distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, chloroform:methanol=98:2-92:8) to afford the title compound (469 mg).