Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][C:4]=1[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=1.Cl.[Cl:24]CCl>O1CCOCC1>[C:19]([C:16]1[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[C:4]([CH:15]=1)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Cl:24])=[CH:9][CH:8]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(C(C)(C)C)cc1C=Cc1ccc(CO)cc1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C(C)(C)C)cc1C=Cc1ccc(CCl)cc1
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of 2'-methoxy-5'-tert-butylstilbene-4-methanol (5.83 g, 19.7 mmol) in 1,4-dioxane (25 ml) was poured into concd. hydrochloric acid (120 ml). A colourless precipitate appeared immediately. The mixture was stirred for 1 h. Then dichloromethane (250 ml) was added. The organic layer was washed with water (500 ml), brine (250 ml), dried over anhydrous magnesium sulfate, filtered and concentrated vacuo. The residue was purified by column chromatography over silica (dichloromethane) and by recrystallisation from hot hexane to yield (19) (4.26 g, 69%) in form of colourless crystals, m.p. 103°-104° C.; (Found: C, 76.42; H, 7.42. C20H24ClO requires C, 76.30; H, 7.36%); δH (CDCl3) 1.40 (9 H, s, tert-butyl), 3.90 (3 H, s, OCH3), 4.62 (2 H, s, CH2Cl), 6.88 (1 H, d, J=8.7 Hz, Phil), 7.17 (1 H, d, J=16.5 Hz, vinylic H), 7.32 (1 H, dd, J=8.6, 2.5 Hz, PhH), 7.40 and 7.57 (4 H, AA'BB', PhH), 7.54 (1 H, d, J=16.0 Hz, vinylic H), 7.65 (1 H, d, J=2.4 Hz, PhH); m/z 316, 314 (35, M+), 301, 299 (29, 91%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Br-].[CH:12]1([Zn+])[CH2:14][CH2:13]1.O1CCOCC1>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.CO>[CH:12]1([C:2]2[CH:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH2:14][CH2:13]1
Reactant: [Zn+]C1CC1
Reactant: Ic1cnc2[nH]ccc2c1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1COCCO1
Solvent: CO
Product: c1cc2cc(C3CC3)cnc2[nH]1
Temperature: 100 °C

Procedure:
5-Iodo-1H-pyrrolo[2,3-b]pyridine (21, 0.343 g, 1.40 mmol), cyclopropylzinc bromide (22, 12.6 mL, 0.500 M in tetrahydrofuran, 6.32 mmol) and [1,3-bis(diphenylphosphino)propane]-nickel(II) chloride (76.2 mg, 0.14 mmol) and 5.37 mL of 1,4-dioxane were combined in a reaction vessel. The reaction was heated at 100° C. overnight, then methanol was added and the reaction was concentrated under vacuum. Ethyl acetate and water were added to the residue, then filtered through a bed of celite and the celite bed washed with ethyl acetate. The filtrate was separated and the aqueous layer extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fraction were combined and concentrated under vacuum to provide the desired compound. MS (ESI) [M+H+]+=159.0.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:6][CH3:7].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+]>>[CH2:5]([C:4]([CH2:8][CH2:9][CH3:10])=[CH:3][CH2:2][S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18])[CH2:6][CH3:7]
Reactant: O=S([O-])c1ccccc1
Reactant: CCCC(=CCBr)CCC
Agent: [Na+]
Product: CCCC(=CCS(=O)(=O)c1ccccc1)CCC

Procedure:
Using the procedure of Example I, 1-bromo-3-propyl-2-hexene was reacted with sodium phenyl sulfinate to form (3-propyl-2-hexenyl)-phenyl sulfone which was then reacted with ethyl β,β-dimethyl-acrylate to form ethyl dl-trans 3,3-dimethyl-2-(2'-propyl-1'-pentenyl)-cyclopropanecarboxylate having a boiling point of 80° C at 0.06 mm Hg and a refractive index nD22 = 1.464. The said ethyl ester was hydrolyzed under alkaline conditions to form dl-trans 3,3-dimethyl-2-(2'-propyl-1'-pentenyl)-cyclopropane carboxylic acid having a boiling point of 116° C at 0.05 mm Hg and a refractive index nD22 = 1.4755 which was then reacted with thionyl chloride to obtain dl-trans 3,3-dimethyl-2-(2'-propyl-1'-pentenyl)-cyclopropanecarboxylic acid chloride having a boiling point of 75° C at 0.04 mm Hg and a refractive index nD24 = 1.4795.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]2.S(=O)(=O)(O)O>COCCOCCOC>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[C:14](=[CH:2][C:1]([OH:5])=[O:4])[CH2:13][CH2:12]2
Reactant: O=CC(=O)O
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: COCCOCCOC
Product: COc1ccc2c(c1)CCC(=CC(=O)O)C2=O
Temperature: 110 °C
Yield: 88.5 %

Procedure:
Glyoxalic acid (190 mL, 1702 mmol) and water (180 mL) were added to a stirred solution of 6-methoxy tetralone (300 g, 1702 mmol) in diglyme (600 mL) followed by sulfuric acid (80 mL, 1500 mmol). The reaction mixture was heated to 110° C. overnight. The reaction mixture was cooled to 0° C., and resulting solids were filtered off and washed with water (3×200 mL), dried under reduced pressure to afford the title compound (350 g, 88%) as a solid. 1H NMR (300 MHz, DMSO-d6): δ 12.9 (bs, 1H), 7.9 (d, J=8.4 Hz, 1H), 7.0 (m, 2H), 6.6 (s, 1H), 3.8 (s, 3H), 3.3 (m, 2H), 3.0 (m, 2H). ESI-MS m/z: 233 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].[CH2:28](I)[CH3:29]>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:28][CH3:29]
Reactant: CCI
Reactant: Cc1cccnc1C(=O)CCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Product: CCOc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 356 and ethyl iodide, white powdery 3-[2-(3-difluoromethoxy-4-ethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14].C(N(CC)CC)C>CN(C)C=O>[C:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:16]([NH:15][CH2:13][CH3:14])=[O:17])[S:3][C:4]=2[CH:10]=1)#[N:12]
Reactant: N#Cc1ccc2nc(N)sc2c1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(C#N)cc2s1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
2-Amino-1,3-benzothiazole-6-carbonitrile (0.2 g) was dissolved in about 5 mL dimethylformamide. About 0.2 mL of ethylisocyanate was added, followed by about 0.3 mL triethylamine and the solution was heated to about 80° C. under good agitation. The solution was allowed to stir for about 4 hours then cooled to room temperature. The solvent was removed in vacuo and the solids were washed well with ether. The product was further purified by column chromatography and after drying in vacuo, about 0.14 grams was isolated. 1H NMR 1.1 (t, 3H, J=7.2 Hz), 3.2 (m, 2H), 6.8 (s, 1H), 7.7 (m, 2H), 8.4 (s, 1H), 11.0 (s, 1H), LC/MS 2.54 min, 247 (MH+), 245 (M−H−), lab RP-HPLC RT 7.8 minutes.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[N:19](S(C(F)(F)F)(=O)=O)[N:18]=3)[N:8]=[C:9]2[O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[NH:38]1[CH2:42][CH2:41][CH2:40][C:39]1=[O:43].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.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:8]=[C:9]2[O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:38]1[CH2:42][CH2:41][CH2:40][C:39]1=[O:43]
Reactant: Cc1cc(Nc2cc3cc(OS(=O)(=O)C(F)(F)F)c(F)cc3c(OC(C)C)n2)nn1S(=O)(=O)C(F)(F)F
Reactant: O=C1CCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc3cc(N4CCCC4=O)c(F)cc3c(OC(C)C)n2)n[nH]1
Temperature: 100 °C

Procedure:
Under Ar, trifluoro-methanesulfonic acid 7-fluoro-1-isopropoxy-3-(5-methyl-1-trifluoromethanesulfonyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl ester (60 mg), pyrrolidin-2-one, Pd2 (dba)3 (4.8 mg), Xantphos (12 mg) and K3PO4 (61.8 mg) were added to dioxane (5 ml), the mixture was heated at 100° C. for 20 hrs. The mixture was filtrated, and the filtrate was concentrated to give crude product. It was purified by preparative LC-MS to give 1-[7-Fluoro-1-isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl]-pyrrolidin-2-one (20 mg). LC-MS: m/e 384 (MH+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[CH3:12][N:13](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:12]#[N:13]
Reactant: CN(C)C=O
Reactant: Cc1cc([N+](=O)[O-])ccc1I
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1C#N
Temperature: 120 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
To a stirred solution of 1-iodo-2-methyl-4-nitrobenzene (812 mg, 3.087 mmol) in dimethylformamide were added zinc cyanide (544 mg, 4.63 mmol) and tetrakis(triphenylphosphine) palladium (713 mg, 0.6174 mmol). The reaction mixture was stirred for 24 h at 120° C., then cooled to room temperature and diluted with ethyl acetate. The mixture was filtered using celite pad. The filtrate dissolved in ethyl acetate and extracted with NaHCO3. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography to give 2-methyl-4-nitrobenzonitrile (407 mg, 81%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:23][CH2:24][O:25]C2CCCCO2)[C:19](=[O:22])[O:20][CH3:21])=[C:14]([CH3:32])[CH:13]=1.S1C2C=CC=CC=2N=C1COC1C=CC(NC(=O)OC)=C(C)C=1.O1CCCCC1OCCBr.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:23][CH2:24][OH:25])[C:19](=[O:22])[O:20][CH3:21])=[C:14]([CH3:32])[CH:13]=1
Reactant: COC(=O)N(CCOC1CCCCO1)c1ccc(OCc2nc3ccccc3s2)cc1C
Agent: BrCCOC1CCCCO1
Agent: COC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)N(CCO)c1ccc(OCc2nc3ccccc3s2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
Methyl N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N-[2-(2-tetrahydropyranyloxy)ethyl]carbamate (Compound No. D1.119) was first prepared from methyl N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]carbamate (Compound No. C1.5, prepared as described in Example 21 below) and 2-(2-tetrahydropyranyloxy)ethyl bromide according to the general procedure of Example 13 above. A catalytic amount (approximately 10 mg) of p-toluenesulfonic acid monohydrate was added to a solution of 658.1 mg of the thus prepared methyl N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N-[2-(2-tetrahydropyranyloxy)ethyl]carbamate in 6.6 ml of methanol at room temperature. The resulting mixture was stirred for 2 hours at room temperature, and water was then added to the reaction mixture. The resulting mixture was extracted with ethyl acetate and the organic layer was washed consecutively with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a residue which was purified by column chromatography through silica gel using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 702.5 mg (yield 94.1%) of the title compound as a solid having a melting point of 109°-110° C.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])(=[O:6])=[O:5])[CH3:2].[Br:16][CH2:17][CH2:18][CH2:19]Br.[H-].[Na+].C(Cl)Cl>CN(C=O)C>[Br:16][CH2:17][CH2:18][CH2:19][N:3]([CH2:1][CH3:2])[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])(=[O:5])=[O:6]
Reactant: CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CCCBr)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 81.5 %

Procedure:
Compound 63 (7.8 g, 33.9 mmol) was dissolved in DMF (100 mL). 1,3-Dibromopropane (35 mL, 343.0 mmol) and then in portions NaH (2.7 g, 67.5 mmol) were added, whereupon the temperature rose to 50-60° C. The reaction mixture was stirred at this temperature for 1 h (TLC monitoring, CH2Cl2), carefully poured into ice/water mixture, and extracted with ethyl acetate. The extract was evaporated. The residue washed with hexane to remove the 1,3-dibromopropane. Compound 64 (9.7 g, 82%) was obtained as a viscous yellow oil.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17].Cl>CO.CC(O)=O>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:11]1[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][C:16]2=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C1CCCCC1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Temperature: 60 °C
Reaction time: 12 h
Yield: 23.3 %

Procedure:
4-Bromophenyl hydrazine hydrochloride (0.3 g, 1.3 mmol) in MeOH (3 mL) was heated to 60° C. and 1,2-cyclohexanedione (0.16 g, 1.4 mmol), dissolved in AcOH (4 mL) and conc. HCl (1.5 mL) were added while maintaining the temperature at 60° C. After the addition was completed, the reaction mixture was cooled to room temperature and stirred for 12 h during time a solid precipitated out. The mixture was basified with aq NaHCO3 and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water, dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by column chromatography to give the title compound as a pale yellow solid (0.080 g, 22%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.8 (bs, 1H), 7.8 (s, 1H), 7.43 (dd, J=10.0, 2.0 Hz, 1H), 7.24 (d, J=9.5 Hz, 1H), 2.98 (t, J=8.0 Hz, 2H), 2.63 (t, 8.0 Hz, 2H), 2.24 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([O-])(C)C.[K+].[Br:7][C:8]1[S:12][CH:11]=[C:10]([C:13](=O)[CH3:14])[CH:9]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[Br:7][C:8]1[S:12][CH:11]=[C:10]([C:13]([CH3:14])=[CH:1][CH3:2])[CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)c1csc(Br)c1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC=C(C)c1csc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of ethyl-triphenyl-phosphonium bromide (27.0 mmol, 10.02 g) in anhydrous THF (90 mL) was added at 0° C. a solution of KOtBu (27.0 mmol, 27 mL, 1 M in THF). The solution was stirred for 1 h at room temperature, cooled down to −78° C. and treated with a solution of 1-(5-bromo-thiophen-3-yl)-ethanone (19.1 mmol, 3.92 g) in anhydrous THF (30 mL) at the temperature. The reaction mixture was slowly warmed to room temperature overnight with stirring. After dilution of the reaction mixture with EtOAc (200 mL), it was washed with water (70 mL×2) and brine (70 mL), dried (MgSO4) and concentrated in vacuo. Chromatography on SiO2 (Hexanes/EtOAc, 20/1) gave 4.15 g (100%) of 2-bromo-4-(1-methyl-propenyl)-thiophene as a liquid of isomeric mixture (Z/E isomer, 9/1). Z isomer; 1H NMR (400 MHz, CDCl3) δ 7.04 (d, J=1.7 Hz, 1H), 6.98 (d, J=1.7 Hz, 1H), 5.55 (m, 1H), 1.97 (quint, J=1.5 Hz, 3H), 1.72 (dq, J=7.0, 1.5 Hz, 3H). E isomer; 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J=1.7 Hz, 1H), 6.94 (d, J=1.7 Hz, 1H), 5.90 (m, 1H), 1.94 (quint, J=1.1 Hz, 3H), 1.77 (d, J=6.9, 1.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:27])=[C:11]([CH3:26])[C:12]3[O:16][C:15]([CH3:17])=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:13]=3[C:24]=2[CH3:25])=O)=[CH:4][CH:3]=1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:8][C:9]2[C:10]([CH3:27])=[C:11]([CH3:26])[C:12]3[O:16][C:15]([CH3:17])=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:13]=3[C:24]=2[CH3:25])=[CH:28][CH:29]=1
Reactant: Cc1oc2c(C)c(C)c(NC(=O)c3ccc(F)cc3)c(C)c2c1-c1ccccc1
Solvent: CO
Product: Cc1oc2c(C)c(C)c(NCc3ccc(F)cc3)c(C)c2c1-c1ccccc1
Yield: 56 %

Procedure:
By using 4-fluoro-N-(2,4,6,7-tetramethyl-3-phenyl-1-benzofuran-5-yl)benzamide, the title compound was synthesized according to Example 2b. Yield: 56%. Melting point: 135-136° C. (Methanol).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C[Si](C=[N+]=[N-])(C)C.[H-].C([Al+]CC(C)C)C(C)C.N1C=CN=C1.[C:34]([Si:38]([CH3:41])([CH3:40])Cl)([CH3:37])([CH3:36])[CH3:35]>ClCCl.CCOCC.C(OCC)(=O)C.CO>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[CH2:4][O:6][Si:38]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:41])[CH3:40]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)c1cc(I)ccc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [H-]
Solvent: CCOCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(I)ccc1Br
Temperature: 25 °C
Yield: 61.9 %

Procedure:
To a solution of 2-bromo-5-iodobenzoic acid (11.4 g, 34.8 mmol) in dichloromethane (140 mL) was added methanol (17 mL) followed by trimethylsilyldiazomethane solution (2M in hexanes, 19.2 mL, 38.4 mmol). The reaction was stirred at room temperature for twelve hours, quenched by the dropwise addition of acetic acid (5 mL) and thoroughly concentrated. The resulting residue was dissolved in tetrahydrofuran. To this solution was added diisobutylaluminum hydride solution (1M in DCM, 50 mL, 50 mmol) and the reaction was stirred at room temperature. After sixteen hours, more diisobutylaluminum hydride solution (1M in DCM, 50 mL, 50 mmol) was added. After 96 more hours at room temperature the reaction was diluted with ether (100 mL) and quenched by the sequential addition of water (4 mL), 15% aqueous NaOH solution (4 mL) and water (10 mL). After thirty minutes the mixture was filtered through Celite and the filtrate was concentrated. The resulting residue was dissolved in dimethylformamide (75 mL). To this solution was added imidazole (6.1 g, 89.6 mmol) and t-butyldimethylchlorosilane (6.8 g, 45.1 mmol). The reaction was stirred at room temperature for two hours and then diluted with ethyl acetate. The organics were washed with saturated aqueous NH4Cl solution, water and brine. The organic layer was dried (MgSO4) and concentrated, and the resulting residue was purified by flash column chromatography to yield (2-bromo-5-iodobenzyloxy)-(tert-butyl)dimethylsilane (9.2 g, 62%).
Reaction SMILES: C([NH:9][C@@H:10]([CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH2:11][OH:12])(=O)C1C=CC=CC=1>Cl>[NH2:9][C@@H:10]([CH2:13][C:14]1[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=1)[CH2:11][OH:12]
Reactant: O=C(N[C@H](CO)Cc1ccncc1)c1ccccc1
Agent: Cl
Product: N[C@H](CO)Cc1ccncc1
Yield: 94.7 %

Procedure:
To Compound A2 (550 mg, 2.15 mmol) obtained in Reference Example 2 was added concentrated hydrochloric acid (10 mL), and the mixture was stirred with heating for 7 hours. After the reaction mixture was cooled and the deposited solid was removed by filtration, the filtrate was concentrated under reduced pressure. The resulting oil was dissolved in methanol (20 mL) and water (1 mL), and to the solution was added BioRad AG-X8 (hydroxide form) until the solution became alkaline. After the resin was removed by filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (310 mg, 95%).
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[C:7]([Br:14])=[N:8][CH:9]=[C:10]([S:12][CH3:13])[N:11]=1>O.C(O)(=O)C>[Br:14][C:7]1[C:6]([OH:2])=[N:11][C:10]([S:12][CH3:13])=[CH:9][N:8]=1
Reactant: CSc1cnc(Br)c(N)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSc1cnc(Br)c(O)n1
Temperature: 25 °C

Procedure:
A SOLUTION OF SODIUM NITRITE (842 MG, 12.2 MMOL) IN WATER (100 ML) WAS ADDED TO A STIRRED SOLUTION OF 3-AMINO-2-BROMO-5-METHYLTHIOPYRAZINE (2.44 G, 11.1 MMOL) IN ACETIC ACID (100 ML) AT 0°C. THE REACTION WAS WARMED TO RT AND AFTER 16 H THE REACTION MIXTURE WAS PARTITIONED BETWEEN WATER AND METHYLENE CHLORIDE. THE ORGANIC LAYER WAS DRIED (NA2SO4) AND EVAPORATED IN VACUO. THE CRUDE PRODUCT WAS PURIFIED BY FLASH COLUMN CHROMATOGRAPHY ON SILICA GEL (40% ETHYL ACETATE/HEXANES) TO GIVE THE TITLE COMPOUND AS A CRYSTALLINE SOLID:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][CH2:10][C:11]([CH3:13])=[CH2:12].S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:11]([CH3:13])([CH3:12])[CH2:10][Cl:9])[CH:3]=1
Reactant: C=C(C)CCl
Reactant: Oc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(CCl)c1cc(Br)ccc1O
Reaction time: 1 h
Yield: 41.7 %

Procedure:
To a stirred, cooled (ice bath) mixture of 4-bromophenol (0.512 g, 3 mmol) and 3-chloro-2-methylpropene (0.32 mL, 3.3 mmol), concentrated sulfuric acid (0.1 mL, 1.5 mmol) was added and the dark reaction mixture was stirred for 1 h. The reaction mixture was diluted with cold water and extracted with ether. The ethereal extract was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to an oil. Flash column chromatography of the oil over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent afforded the title compound as an oil (0.33 g, 42.6%). Some dialkylated product was also formed and some starting material was recovered.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([CH3:14])=[CH:4][N:3]=1.C1(C2[N:25]([CH:26]([CH3:28])[CH3:27])[CH2:24][CH:23]([CH2:29][OH:30])[O:22]2)C=CC=CC=1.[H-].[Na+]>CN(C)P(=O)(N(C)C)N(C)C>[CH:26]([NH:25][CH2:24][CH:23]([OH:22])[CH2:29][O:30][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([CH3:14])=[CH:4][N:3]=1)([CH3:28])[CH3:27]
Reactant: CC(C)N1CC(CO)OC1c1ccccc1
Reactant: Cc1cnc(Cl)c(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1cnc(OCC(O)CNC(C)C)c(N2CCOCC2)n1
Temperature: 0 °C

Procedure:
10.7 g of 2-chloro-3-morpholinyl-5-methyl-pyrazine and 16.6 g of 2-phenyl-3-isopropyl-5-hydroxymethyloxazolidine are dissolved in 130 ml of hexamethylphosphoric acid triamide. 3.6 g of a 50% strength suspension of sodium hydride in paraffin oil are introduced into this solution over the course of 30 minutes at 0°-5° C., whilst stirring. The mixture is then stirred for 1 hour at 0°-5° C. and 24 hours at room temperature. The reaction mixture is then poured onto 500 ml of ice water and extracted by shaking with ether. The ether extracts are washed with water and evaporated in a waterpump vacuum. The residue is taken up in 200 ml of 1 N sulphuric acid and the reaction mixture is stirred for 15 hours at room temperature and then extracted by shaking with ether. The acid aqueous phase is rendered alkaline with concentrated sodium hydroxide solution and is then extracted by shaking with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in a waterpump vacuum. The residue crystallises from etherpentane. 2-(3'-Isopropylamino-2'-hydroxy-propoxy)-3-morpholinyl-5-methyl-pyrazine, melting point 77°-78° C., is thus obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:22][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[C:9]([CH3:21])[CH:8]=1)[CH3:2]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:22][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:21])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)c(C)c1)OC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(O)c(C)c1)OC
Reaction time: 2 h

Procedure:
A solution of 3-(4-Benzyloxy-3-methyl-phenyl)-2-methoxy-propionic acid ethyl ester in ethyl acetate was treated with a catalytic amount of C—Pd (0.1 eq) and then H2 was bubbled through the mixture and stirred 2 hours. The mixture reaction was filtered through a pad of celite and concentrated in vacuo to give the title compound.