Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([CH3:34])[C:29]([O:31]CC)=[O:30])=[CH:23][CH:22]=3)[C:11]3[O:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]=3[CH:18]=2)=[CH:4][CH:3]=1.CO.[OH-].[Li+].Cl>O1CCCC1.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH:28]([CH3:34])[C:29]([OH:31])=[O:30])=[CH:25][CH:26]=3)[C:11]3[O:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]=3[CH:18]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)Cc1ccc(OCc2cc(-c3ccc(Cl)cc3)cc3c2OC(C)(C)C3)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(Cc1ccc(OCc2cc(-c3ccc(Cl)cc3)cc3c2OC(C)(C)C3)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of ethyl 3-(4-((5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-methylpropanoate (110) (80 mg, 0.179 mmol), 4-chlorophenyl boronic acid (30.8 mg, 0.197 mmol), Pd(PPh3)4 (7 mg, 00.006 mmol), saturated sodium bicarbonate (0.64 mL), methanol (1.5 mL), and toluene (0.64 mL) was heated in a microwave reactor for 40 minutes at 110° C. To the solution was added water and ethyl acetate and the two layers were separated. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (30%) to afford ethyl 3-(4-((5-(4-chlorophenyl)-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-methylpropanoate. The ester was dissolved in tetrahydrofuran (1.0 mL), methanol (1.0 mL) and water (3 mL). Lithium hydroxide was added and the reaction was stirred at room temperature for 24 hours. The mixture was acidified with 1M HCl and diluted with EtOAc (3 mL). The organic layer was washed with brine (3 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield 3-(4-((5-(4-chlorophenyl)-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-methylpropanoic acid (111). 1H NMR (400 MHz, CDCl3) δ 7.43-7.39 (m, 3H), 7.34 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.3 Hz, 1H), 7.09 (d, J=8.2 Hz, 2H), 6.94 (d, J=8.3 Hz, 2H), 5.05 (s, 2H), 3.07 (s, 2H), 3.00 (dd, J=13.4, 6.4 Hz, 1H), 2.73-2.67 (m, 1H), 2.62-2.58 (m, 1H), 1.51 (s, 6H), 1.17 (d, J=6.8 Hz, 3H). LC-MS ESI m/z: found 449.1 [M−H]−.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[N:10]([CH3:20])[CH2:11][CH2:12][NH:13]C(=O)C(F)(F)F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.O>[CH2:1]([O:8][C:9](=[O:21])[N:10]([CH2:11][CH2:12][NH2:13])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCNC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(CCN)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.7 %

Procedure:
To a solution of compound B (˜311 mmol) in MeOH (1.2 L) was added a solution of LiOH (14.9 g, 622 mmol) in water (120 mL). The reaction mixture was stirred at ambient temperature for 3 h. Solvents were evaporated to 75% of the initial volume followed by dilution with water (400 mL). The solution was extracted with EtOAc (2×300 mL). The organic layer was washed with brine (200 mL), dried over MgSO4 and evaporated in vacuo. The residue was dissolved in ether (300 mL) and treated with 2 N HCl/ether (200 mL). Formed precipitate was filtrated, washed with ether and dried in vacuo to provide the hydrochloric salt of compound C (67.8 g, 89%) as a white solid. LC-MS [M+H] 209.0 (C11H16N2O2+H, calc: 209.3). Compound C was used directly in the next reaction without purification as a DMF solution.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C@H:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:13]2)=O)[CH2:9][CH2:8]1.S([O-])([O-])(=O)=O.[Na+].[Na+].[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43]>O1CCCC1.CO.CC(C)=O.CCOCC.C(O)C>[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43].[CH:7]1([CH2:10][N:12]2[CH2:17][CH2:16][C@@H:15]([O:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[C@H:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:13]2)[CH2:8][CH2:9]1
Reactant: O=C(C1CC1)N1CC[C@@H](Oc2ccc(F)cc2)[C@H](c2ccccc2)C1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCO
Product: Fc1ccc(O[C@@H]2CCN(CC3CC3)C[C@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 0.79 g of lithium aluminum hydride in 60 ml of anhydrous tetrahydrofuran is added, dropwise at room temperature under nitrogen, a solution of 3.53 g of trans-1-cyclopropylcarbonyl-4-(4-fluorophenoxy)-3-phenylpiperidine in 60 ml of tetrahydrofuran. After the addition is complete the mixture is stirred at room temperature for 2 hours and cooled in ice/isopropanol to -5° C. Ether is added (60 ml), followed by cautious, dropwise addition of saturated sodium sulfate solution. The flocculent white precipitate thus obtained is filtered and washed well with ether. The filtrate is concentrated in vacuo. The residue is dissolved in ether (200 ml) and the solution is washed with saturated sodium chloride solution (100 ml), dried overnight over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a nearly colorless oil. The oil is dissolved in 25% methanol/acetone solution and passed through a small silica gel column. The resulting oil is dissolved in ether (50 ml) and treated dropwise with a solution of 0.98 g of fumaric acid in a mixture of ether (60 ml) and absolute ethanol (15 ml) and the resulting mixture is stirred at room temperature overnight. The salt is filtered, washed with ether and dried to afford product as colorless solid, mp 185.5°-187° C. dec.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[CH3:20])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:12][CH2:11][C@H:10]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[CH3:20])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:31])=[O:30]
Reactant: Cc1cc(Br)ccc1[C@@H](CO)COCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Br)ccc1[C@H](COCc1ccccc1)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To 16F (0.6 g, 1.790 mmol) in CH2Cl2 (15 mL) was added triethylamine (0.299 mL, 2.148 mmol) and MsCl (0.167 mL, 2.148 mmol). The reaction was stirred at rt for 2 h. The solvent was removed and residue was redissolved in EtOAc. The solution was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0-40% ETOAc/hexanes) to give 24A (0.74 g, 1.790 mmol, 100% yield) as an oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.28-7.40 (m, 7H) 7.13 (d, J=8.34 Hz, 1H) 4.39-4.59 (m, 4H) 3.69 (d, J=5.81 Hz, 2H) 3.52-3.62 (m, 1H) 2.85 (s, 3H) 2.33 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[O:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:10]2[C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][C:1]=3[CH2:7][CH2:8][N:9]=2)=[CH:13][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cc1ccc(Oc2ccccc2)cc1)NCCC1=CCCCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: c1ccc(Oc2ccc(CC3=NCCC4=C3CCCC4)cc2)cc1

Procedure:
A mixture of 2.5 g (0.01 mol) N-[2-(1-cyclohexen-1-yl)ethyl]-4-phenoxyphenyl acetamide, 5.0 ml of POCl3 and 20 ml of toluene was heated at reflux under nitrogen for 2 hrs. After evaporation of the solvent and excess reagent there was obtained (±)-1-(p-phenoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline as residue. The residue was triturated with pet ether (2×10 ml). The pet ether insoluble hexahydro compound was dissolved in methanol and immediately reduced by portionwise addition of 1.0 g of sodium borohydride. The reaction mixture was stirred at room temperature for 4 hrs. The methanol was distilled off and the residue was partitioned between ether (60 ml) and dilute aqueous ammonium hydroxide. The ether solution was washed with water, dried and evaporated to give 1.6 g (69%) of crude (±)-1-(p-phenoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21](OCC)=[O:22])[CH:9]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][NH2:27]>C(O)C>[C:1]([O:5][C:6]([N:8]([CH2:20][C:21]([NH:26][NH2:27])=[O:22])[CH:9]1[CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)C1CN(C(=O)OC(C)(C)C)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(N(CC(=O)NN)C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 17 h
Yield: 92.9 %

Procedure:
A mixture of tert-butyl 3-(tert-butoxycarbonyl(2-ethoxy-2-oxoethyl)amino)azetidine-1-carboxylate (7.2 g, 20 mmol), hydrazine (5.0 g, 100 mmol) and ethanol (50 mL) was stirred at 80° C. for 17 hrs. The reaction mixture was then concentrated to afford the crude tert-butyl 3-(tert-butoxycarbonyl(2-hydrazinyl-2-oxoethyl)amino)azetidine-1-carboxylate (6.4 g, 94%) as a white solid, which was used directly in the next step. ESI-MS (EI+, m/z): 345.0 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:20])[CH:13]=2)[CH:9]=[N:8][CH:7]=1.Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26]Br>C(#N)C.C(N(CC)CC)C>[F:20][C:14]1[CH:13]=[C:12]([CH2:11][N:10]2[C:6]([CH2:5][CH2:4][N:3]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:7][N:8]=[CH:9]2)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1ccc(Cn2cncc2CCN)cc1F
Reactant: BrCCOCCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2CCN2CCOCC2)cc1F

Procedure:
To a solution of 4-[5-(2-amino-ethyl)-imidazol-1-ylmethyl]-2-fluoro-benzonitrile dihydrochloride (0.92 g, 0.0029 mmol) in acetonitrile (150 mL) and triethylamine (3.2 mL) was added 2-bromoethyl ether (0.839 mL, 0.0067 mmol) and the mixture was refluxed for 48 hr. The solvents were removed in uacuo and the residue was dissolved in EtOAc which was washed twice with 1M HCl (100 mL). The HCl layers were combined and adjusted to pH=9 with solid Na2CO3 and extraxcted 3 times with EtOAc. The EtOAc layers were combined and dried with brine and MgSO4. Removal of the EtOAc in vacuo yielded the title compound which was used as is in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.C([N-]C(C)C)(C)C.[Li+].I[CH2:23][CH2:24][CH2:25][CH3:26]>O1CCCC1>[CH2:23]([CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCI
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC1CCc2cc(OC)ccc2C1=O
Temperature: -78 °C

Procedure:
A solution of 6-methoxy-3,4-dihydro-1(2H)-naphthalenone (5.29 g, 30 mmol) in anhydrous tetrahydrofuran (THF, 150 mL) was placed under a N2 atmosphere, cooled in an ice bath, stirred, and treated with lithium diisopropylamide (90 mL of a 0.4M solution in THF, 36 mmol) dropwise over 13 minutes. The mixture was stirred at 0-5° C. for 30 minutes, then cooled in a dry ice-acetone bath to −78° C. and treated all at once with iodobutane (17.04 mL, 150 mmol). The resulting mixture was allowed to slowly warm to room temperature and stirred at room temperature overnight. The mixture was quenched with saturated aqueous NH4Cl and concentrated under vacuum. The residue in EtOAc was washed with 5% NaHCO3 and brine, dried over MgSO4, filtered, and evaporated under vacuum. The crude product was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40M (4×15 cm) silica gel column, eluting successively with 1000 mL portions of 0.1%, 0.2%, 1%, 2%, and 5% EtOAc in hexane. The product-containing fractions were evaporated under vacuum to afford 2-butyl-6-methoxy-3,4-dihydro-1(2H)-naphthalenone as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][S:6][C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][S:6]([C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)=[O:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C)c1ccccc1CSc1cnc2ccccc2n1
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccccc1CS(=O)c1cnc2ccccc2n1
Yield: 21.3 %

Procedure:
In 50 ml of chloroform was dissolved 1.47 g of 2-(2-dimethylaminobenzylthio)quinoxaline. To the chilled solution kept at --10° C. was portionwise added 1.54 g of m-chloroperbenzoic acid (purity: 80%). To the reaction liquid were washed successively with saturated aqueous NaHCO3 solution, water and saturated aqueous sodium chloride solution, and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (hexane/acetone) to give 330 mg of 2-(2-dimethylaminobenzylsulfinyl)quinoxaline as a yellow powder, m.p. 114°-115° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(O)(C)(C)C>C(Cl)Cl>[Cl:1][CH2:2][C@@H:3]([OH:12])[CH2:4][C:5]([O:7][C:8]([CH3:10])([CH3:9])[CH3:11])=[O:6]
Reactant: CC(C)(C)OC(=O)CC(=O)CCl
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H](O)CCl
Temperature: 100 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
In a 100 ml Hastelloy-made autoclave having been purged with nitrogen were charged 58.35 g (0.3 mol) of t-butyl 4-chloroacetoacetate and 120 ml of t-butyl alcohol, and solution of 250 mg (0,00015 mol) of Ru2Cl4 [(R)-(+)-BINAP]2Et3N in 2 ml of methylene chloride was added thereto. The mixture was stirred at 100° C. under a hydrogen pressure of 10 to 15 kg/cm2 for 2 hours to conduct hydrogenation, The solvent was evaporated, and the residue was distilled under reduced pressure to give 53.0 g (percent yield: 90%) of t-butyl (S)-(-)-4-chloro-3-hydroxybutyrate as a colorless clear liquid.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH3:17])=[CH:9][CH:10]=3)[C:5]3([CH2:21][O:20][C:19]([NH2:22])=[N:18]3)[C:4]=2[CH:3]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([NH2:32])=[O:31])=[N:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC.[Cl-].[NH4+]>[Cu]I.C(Cl)Cl.O1CCOCC1>[NH2:22][C:19]1[O:20][CH2:21][C@@:5]2([N:18]=1)[C:4]1[CH:3]=[C:2]([NH:32][C:30]([C:27]3[CH:26]=[CH:25][C:24]([Cl:23])=[CH:29][N:28]=3)=[O:31])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([O:16][CH3:17])=[CH:9][CH:10]=1
Reactant: NC(=O)c1ccc(Cl)cn1
Reactant: COc1ccc2c(c1)C1(COC(N)=N1)c1cc(Br)ccc1O2
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1O2

Procedure:
A vial was charged with 2′-bromo-7′-methoxyspiro[1,3-oxazole-4,9′-xanthen]-2-amine (90.0 mg, 249 μmol), 5-chloropicolinamide (59 mg, 374 μmol), cesium carbonate (244 mg, 748 μmol), copper(I) iodide (47 mg, 249 μmol), dioxane (2 mL), and N1,N2-dimethylethane-1,2-diamine (27 μl, 249 μmol). The vial was sealed under a blanket of Ar (g) and placed in a 110° C. oil bath for 5 days. The reaction mixture was then poured into a mixture of ammonium chloride solution (10 mL) and DCM (10 mL). The layers were separated, and the aqueous layer was extracted with DCM (2×5 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was dissolved in DMSO and filtered, and the filtrate was purified by reverse-phase HPLC (10-90% CH3CN/H2O with 0.1% TFA). The fractions containing the desired product were poured into saturated sodium bicarbonate solution and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give N-((4R)-2-amino-7′-methoxyspiro[1,3-oxazole-4,9′-xanthen]-2′-yl)-5-chloro-2-pyridinecarboxamide as a white solid. MS m/z=437.2 [M+H]+. Calc'd for C22H18ClN4O4: 437.1.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]\[CH:10]=[O:11])/[CH3:8])[CH3:3].CN(C=O)C.[H-].[Na+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:8]/[C:7](/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])=[CH:9]/[CH2:10][O:11][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)=CCC/C(C)=C\C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COC/C=C(/C)CCC=C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Neral (150 g, 972 mmol) was added dropwise to a DMF (1.501) suspension of sodium hydride (60%, 38.9 g, 973 mmol) under nitrogen gas stream at room temperature. The reaction solution was stirred at room temperature for one hour and then cooled to 0° C. After tetra-n-butyl ammonium iodide (35.9 g, 97.2 mmol) was added to the reaction solution, 4-methoxybenzyl chloride (148 g, 926 mmol) was added dropwise. The reaction solution was stirred at 0° C. for one hour and then at room temperature for six hours. Water was added to the reaction solution, which was then extracted with n-heptane. After the obtained organic layer was washed with water and brine (saturated solution of sodium chloride) sequentially, it was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Kanto Chemical, commercial name Silica gel 60N, granular, neutral, 0.040 mm-0.100 mm; n-heptane:ethyl acetate=1:0→30:1→25:1) to obtain the title compound (246.7 g) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:16]=3[NH:15][C:14]2=[O:24])=[CH:3]1.C([O-])([O-])=O.[K+].[K+].CC(N(C)C)=O.[C:37]([O:44][CH2:45][CH3:46])(=[O:43])/[CH:38]=[CH:39]/[CH2:40][CH2:41][CH3:42]>C(OCC)(=O)C>[CH2:45]([O:44][C:37](=[O:43])[CH2:38][CH:39]([N:15]1[C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=2[N:13]([CH2:12][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][C:6]=3[CH3:11])[N:2]([CH3:1])[CH:3]=2)[C:14]1=[O:24])[CH2:40][CH2:41][CH3:42])[CH3:46]
Reactant: Cc1cc2[nH]c(=O)n(Cc3cn(C)c4cccc(C)c34)c2cc1C
Reactant: CCC/C=C/C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cc(C)c(C)cc21
Temperature: 130 °C

Procedure:
A mixture of 1-(1,4-Dimethyl-1H-indol-3-ylmethyl)-5,6-dimethyl-1,3-dihydro-benzimidazol-2-one (0.1 g, 0.31 mmol), K2CO3 (87 mg, 0.63 mmol) and ethyl trans-2-hexenoate (0.45 g, 3.1 mmol) was heated to 130° C. for 20 min in a microwave. Since the starting material was not soluble in ethyl trans-2-hexenoate even after heating, DMA (2 mL) was added to the reaction mixture and heated again at 150° C. for 30 min. Although the un-reacted starting material was present, the reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting heterogeneous residue was purified by silica gel prep TLC using 4:1 hexanes:ethyl acetate as an eluent to afford 25 mg of the desired product as an oil. LCMS (ESMS): m/z 462.88 (M+H+).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1Cl.[NH2:12][C:13]1[CH:18]=[N:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[N:12]=[C:13]3[CH:18]=[N:17][CH:16]=[CH:15][N:14]3[C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: Nc1cnccn1
Reactant: O=[N+]([O-])c1ccc(Cl)c(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2nc3cnccn3c2c1
Yield: 51.1 %

Procedure:
A mixture of 0.6 g (2.12 mmol) of 2-iodo-4-nitrochlorobenzene (XXI) (G. A. Olah, J. Org. Chem., 1993 (58), 3194-3195), 0.2 g (2.1 mmol) of 2-aminopyrazine (XXII), 2.8 g (8.5 mmol) of cesium carbonate, 0.15 g (0.25 mmol) of Xantphos® (9,9-dimethyl-4,5-bis-(diphenylphosphino)xanthene) and 30 mg (0.13 mmol) of palladium diacetate in 20 ml of dry toluene is heated at 120° C. for 12 hours. After this period of time, the mixture is concentrated under reduced pressure and then taken up in 350 ml of dichloromethane and 200 ml of water. The organic phase is separated, washed with 100 ml of a saturated solution of sodium chloride, dried over magnesium sulphate, and then concentrated under reduced pressure. The resulting product is taken up in 10 ml of dichloromethane, and 0.23 g of the expected product is isolated in the form of a precipitate which is recovered by filtration. The filtrate is purified by silica column chromatography, elution being carried out with a mixture of ethyl acetate and heptane. A further 25 mg of product are thus isolated.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([OH:26])=[O:25])[CH:21]=2)[NH:16][CH:15]=1.[CH3:27]O>S(=O)(=O)(O)O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=2)[NH:16][CH:15]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
A solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-acetic acid (1 g) in methanol (50 ml) containing sulphuric acid (2 drops) was boiled under reflux for 1.5 h under nitrogen. Removal of the solvent gave a solid (1.2 g). Part of this material (0.5 g) was purified by column chromatography (Whatman MFC silica, 25 g). Elution with ethyl acetate-light petroleum (1:1) gave the title compound as yellow crystals (0.4 g) m.p. 121°-124°.
Reaction SMILES: [N:1]1[N:2]=[C:3]([NH2:6])[NH:4][CH:5]=1.[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[C:19]([F:21])[C:18]([CH2:22][CH:23]([C:28](=O)[CH2:29][CH2:30][CH2:31][CH3:32])[C:24](OC)=[O:25])=[C:17]([F:34])[CH:16]=1)#[N:8]>ClC1C=CC(Cl)=CC=1Cl>[CH2:29]([C:28]1[N:2]2[N:1]=[CH:5][N:4]=[C:3]2[NH:6][C:24](=[O:25])[C:23]=1[CH2:22][C:18]1[C:17]([F:34])=[CH:16][C:15]([C:10]2[C:9]([C:7]#[N:8])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:20][C:19]=1[F:21])[CH2:30][CH2:31][CH3:32]
Reactant: Nc1nnc[nH]1
Reactant: CCCCC(=O)C(Cc1c(F)cc(-c2ccccc2C#N)cc1F)C(=O)OC
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CCCCc1c(Cc2c(F)cc(-c3ccccc3C#N)cc2F)c(=O)[nH]c2ncnn12
Yield: 41.3 %

Procedure:
A solution of 4H-1,2,4-triazol-3-amine (2.4 g) and methyl 2-[(2′-cyano-3,5-difluorobiphenyl-4-yl)methyl]-3-oxoheptanoate (10 g) in 1,2,4-trichlorobenzene (50 mL) was stirred at 180° C. for 6 hr. After evaporation of the solvent under reduced pressure, ethyl acetate was added to the obtained residue. The precipitated solid was collected by filtration to give the title compound as a colorless solid (4.5 g, 57%).