Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-:15].[Na+]>[C].[Pd].[Pd].CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:15])=[CH:3][CH:4]=4)=[CH:9][CH:10]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: [OH-]
Agent: [Pd]
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(-c2ccc(-c3ccc(-c4ccc(O)cc4)cc3)cc2)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Into an 1-liter stainless steel autoclave were added 60.0 g of 4-hydroxy-4'-bromobiphenyl, 100 g of methanol, 300 g of a 10% (by weight) aqueous solution of sodium hydroxide, and 13 g of a palladiumcarbon containing 5% by weight of palladium and a reaction was carried out at 120° C. for 4 hours under 5 atmospheric pressures. The precipitated disodium salt of 4,4"'-dihydroxy-p-quaterphenyl was filtered and dissolved into N,N-dimethyl-formamide. The catalyst was removed by filtration with heating at 60° C. An addition of dilute sulfuric acid to the filtrate gave white crystalline powder of 4,4"'-dihydroxy-p-quaterphenyl (DHQ), which was purified by washing with methanol. The liquid-crystal transition temperature of the DHQ was 336° C. and the melting point of the DHQ was 420° C. ##STR4##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].I[CH2:17][CH2:18][CH2:19][CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCI
Reactant: CCOC(=O)CCc1ccc(O)c(Br)c1
Product: CCCCOc1ccc(CCC(=O)OCC)cc1Br

Procedure:
According to the procedure described in the synthesis method of the compound 036 in Example 36 (Preparation Method 5, Step e-1), ethyl 3-(3-bromo-4-hydroxyphenyl)propionate and 1-iodobutane were reacted and treated to obtain ethyl 3-(3-bromo-4-butyloxyphenyl)propionate (400 mg). According to the procedure described in the synthesis method of Compound of Example 001 (Preparation Method 4, Step d-1) with the modifications that the reaction was carried out for 16 hours, and the purification was performed by flash column chromatography (hexane:ethyl acetate=8:1), the above product was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (360 mg), 2 M aqueous sodium carbonate (0.9 ml) and (Ph3P)4Pd (110 mg) and treated to obtain the title compound (Intermediate 66, 270 mg).
Reaction SMILES: C=O.[Cl:3][C:4]1[C:5]([F:33])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:31][CH3:32])=[C:18]([O:21][C@H:22]4[CH2:27][CH2:26][NH:25][C@H:24]([C:28]([NH2:30])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O.C(Cl)Cl>[Cl:3][C:4]1[C:5]([F:33])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:31][CH3:32])=[C:18]([O:21][C@H:22]4[CH2:27][CH2:26][N:25]([CH3:34])[C@H:24]([C:28]([NH2:30])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN[C@H](C(N)=O)C1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C)[C@H](C(N)=O)C1
Yield: 56.2 %

Procedure:
Molecular sieves (5 g) followed by aqueous formaldehyde (10 ml) were added to a stirred solution of (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxamide (5) (3.1 g, 6.97 mmol) in DCM-AcOH (100:10 ml) at room temperature. The reaction mixture was stirred for 1-2 minutes before solid sodium triacetoxyborohydride (2.93 g, 13.9 mmol) was added portionwise over 5 minutes. The reaction was essentially complete after all the sodium triacetoxyborohydride reducing agent had been added. DCM was added (100 ml) and the reaction was carefully neutralised with saturated aqueous NaHCO3(aq). The organic extract was washed with brine, dried (MgSO4) and concentrated to a yellow foam. The residue was purified by flash chromatography (silica gel, DCM-NH3/MeOH 2%) to give the title product as a white solid (1.8 g, 56%): 1H NMR Spectrum: (DMSO d6) 1.86-1.91 (m, 3H), 2.07-2.09 (m, 1H), 2.20 (s, 3H), 2.47-2.49 (m, 1H), 2.71-2.81 (m, 2H), 3.96 (s, 3H), 4.82 (m, 1H), 7.02 (s, 1H), 7.23 (s, 1H), 7.26-7.29 (m, 2H), 7.47-7.53 (m, 2H), 7.82 (s, 1H), 8.37 (s, 1H), 9.60 (s, 1H); Mass Spectrum: (M+H)+ 460.1.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][N:18]=1)[C:14]#[N:15]>>[OH:9][CH2:8][C:4]1[CH:3]=[C:2]([S:1][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][N:18]=2)[C:14]#[N:15])[CH:7]=[CH:6][CH:5]=1
Reactant: OCc1cccc(S)c1
Reactant: N#Cc1ccnc(Cl)c1
Product: N#Cc1ccnc(Sc2cccc(CO)c2)c1
Yield: 62.9 %

Procedure:
Using the method of Preparation 155 using (3-mercaptophenyl)methanol (6.00 g, 42.8 mmol) and 2-chloroisonicotinonitrile (5.65 g, 40.8 mmol) affords the title compound (6.22 g, 63%): 243 (M+H, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9](=[C:12](OC)[CH3:13])[C:10]#[N:11])[S:8][C:4]=2[CH:3]=1.O.[NH2:19][NH2:20]>CO>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[C:12]([CH3:13])=[N:20][NH:19][C:10]=3[NH2:11])[S:8][C:4]=2[CH:3]=1
Reactant: NN
Reactant: COC(C)=C(C#N)c1nc2ccc(Br)cc2s1
Solvent: O
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(Br)cc2s1
Temperature: 25 °C
Yield: 5 %

Procedure:
A solution of 2-(6-bromobenzothiazol-2-yl)-3-methoxybut-2-enenitrile (0.96 g, 3.1 mmol) and hydrazine hydrate (0.3 mL, 5.4 mmol) in methanol (30 mL) was heated to reflux overnight. The reaction was then cooled to room temperature. The resulting solid was isolated by filtration and was purified by flash chromatography to yield the title product. MS (m/z, ES+): 308.9 (Br79M+1, 100%), 310.9 (Br81M+1, 100%). Yield=5%.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=2)[C:5]([S:15][CH:16]([CH3:18])[CH3:17])=[N:4][C:3]=1[C:19](=[O:23])[C:20]([CH3:22])=[CH2:21].I([O-])(=O)(=O)=[O:25].[Na+].O>CO>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH3:14])=[CH:11][CH:12]=2)[C:5]([S:15]([CH:16]([CH3:17])[CH3:18])=[O:25])=[N:4][C:3]=1[C:19](=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: C=C(C)C(=O)c1nc(SC(C)C)n(-c2ccc(CC)cc2)c1Cl
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=C(C)C(=O)c1nc(S(=O)C(C)C)n(-c2ccc(CC)cc2)c1Cl
Yield: 41.4 %

Procedure:
A mixture of 3.0 g (8.6 mmol) of [5-chloro-1-(4-ethylphenyl)-2-(prop-2-ylthio)-imidazol-4-yl]-2-methyl-2-propen-1-one and 2.3 g (11 mmol) of sodium metaperiodate was heated at 50° C. for 3 hours in 30 ml of 90% aqueous methanol. The mixture was cooled and poured into water. Extraction with dichloromethane yielded an oil which was purified by flash chromatography on silica (20% ethyl acetate in petroleum ether) to obtain 1.3 g (41%) of [5-chloro-1-(4-ethylphenyl)-2-(prop-2-ylsulfinyl)-imidazol-4-yl]-2-methyl-2-propen-1-one as cream-colored crystals melting at 83°-4° C.
Reaction SMILES: S(=O)(=O)(O)O.O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15](O)[CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:13]=[C:12]2[C:11]([CH2:14][CH2:15][C:16]2([CH3:18])[CH3:17])=[CH:10][CH:9]=1
Reactant: CC(C)C(O)Cc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(C)CCc2ccc(Cl)cc21
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a solution of concentrated sulfuric acid (3.00 mL, 0.056 mol) in water (0.28 mL, 0.0156 mol) was added 1-(4-chlorophenyl)-3-methylbutan-2-ol (1.00 g, 0.00503 mol) over 30 minutes. Additional sulfuric acid was added to dissolve the solid. The mixture was stirred for 2 hours. The mixture was poured onto ice then extracted with ether. The organic phase was washed (water), dried (MgSO4), filtered, and concentrated. The residue was filtered through a plug of silica with CH2Cl2 to afford the title compound (0.568 g, 63%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][CH2:16][S:17][CH3:18])[CH:10]([OH:14])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][CH2:16][S:17][CH3:18])[CH:10]([O:14][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][O:19]1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(OC1CCCCO1)C(=O)O
Yield: 28.9 %

Procedure:
A solution of Example 11A (1.62 g, 5.8 mmol), 3,4-dihydro-2H-pyran (0.64 mL, 70 mmol), and pyridinium p-toluenesulfonate (0.15 mL, 0.60 mmol) in dichloromethane (30 mL) was heated to 35° C. for 16 hours and concentrated. The concentrate was diluted with aqueous sodium hydroxide (0.25M, 15 mL) and extracted twice with ethyl acetate. The aqueous layer was adjusted to pH 3 with aqueous H3PO4 (1.0M) and extracted three times with ethyl acetate. These three extracts were combined, washed sequentially with water (20 mL) and brine (20 mL), dried (MgSO4), filtered, and concentrated to provide the desired product (0.61 g). MS (APCI(+)) m/e 364 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=[S:8].C(O[CH:14]1[NH:17][C:16](=[O:18])[CH2:15]1)(=O)C.N#N>[OH-].[K+].O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([O:9][CH:14]1[NH:17][C:16](=[O:18])[CH2:15]1)=[S:8]
Reactant: COCCOCC(O)=S
Reactant: CC(=O)OC1CC(=O)N1
Agent: N#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COCCOCC(=S)OC1CC(=O)N1
Yield: 96 %

Procedure:
To a solution of 2-methoxyethoxythioacetic acid (990 mg.; 6.60 mmoles) in 1N KOH (6.0 ml.) and water (30 ml.) was added in an ice-bath under nitrogen atmosphere 4-acetoxy-2-azetidinone (777 mg.; 6.00 mmoles). The reaction mixture was stirred at room temperature (N2) for 1 hr. and then extracted with methylene chloride (30 ml.×3). The extracts were washed with brine, dried (Na2SO4) and evaporated yielding 4-(2-methoxyethoxythioacetoxy)-2-azetidinone (1.26 g.; 5.76 mmoles; 96% yield) as a yellow oil. nmr (CDCl3): δppm 2.8-3.8 (2H, m, H-3), 3.40 (3H, s, -OCH3), 3.4-3.9 (4H, m, -CH2CH2 -O), 4.25 (2H, s, O=CCH2O-), 5.25 (1H, dd, J3-4 cis =5 Hz, J3-4 trans =3 Hz, H-4), 7.3 (1H, br.s, -NH); ir (neat): 3280 cm-1 (νN-H), 1770 (νc=o, β-lactam), 1690 (νc=o, thioester).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:13]=[C:7]2[CH:6]=1)=[O:4].[OH-].[Na+]>CO.O>[C:28]([O:27][C:25]([NH:24][C:20]1([C:17]2[CH:16]=[CH:15][C:14]([C:12]3[N:13]=[C:7]4[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][N:8]4[C:11]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:19][CH:18]=2)[CH2:21][CH2:22][CH2:23]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)c1ccn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(C(=O)O)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 107.9 %

Procedure:
A solution of 2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (2.30 g, 4.60 mmol) in MeOH (77 mL) was added a solution of NaOH (3.7 g, 9.24 mmol, 2.0 equiv) in water (15 mL). The resulting mixture was stirred at room temperature for 12 h. The resulting clear solution was concentrated under pressure. The remaining material was treated with water (50 mL), made acidic with an aqueous 2N HCl solution, and extracted with a 4:1 CH2Cl2/isopropanol solution (4×25 mL). The combined organic phases were dried (Na2SO4 anh) and concentrated under reduced pressure to give 2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-7-carboxylic acid (2.4 g, 107%):
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([CH2:12][C:13]#[CH:14])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:26]#[C:27][C:28](O)=[O:29])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].C(Cl)CCl.Cl.CN(C)CCCN=C=NCC>CO>[NH2:8][C:7]1[N:6]([CH2:9][CH3:10])[C:5](=[O:11])[N:4]([CH2:12][C:13]#[CH:14])[C:3](=[O:15])[C:2]=1[NH:1][C:28](=[O:29])[C:27]#[C:26][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=1
Reactant: C#CCn1c(=O)c(N)c(N)n(CC)c1=O
Reactant: COc1ccc(C#CC(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCCl
Solvent: CO
Product: C#CCn1c(=O)c(NC(=O)C#Cc2ccc(OC)c(OC)c2)c(N)n(CC)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the 5,6-diamino-1-ethyl-3-propargyluracil (4.2 g, 20 mmol), 3,4-dimethoxyphenylacetylencarboxylic acid (4.2 g, 20 mmol) and EDC ((1-(3-dimethylaminopropyl)-3-ethyl-carbodiimid hydrochloride; 4.2 g, 22 mmol) in methanol (100 ml) was stirred at room temperature for 2 h. The colorless product was precipitated by adding water (ca. 150 ml), filtered under reduced pressure, washed thoroughly with ether (TLC-control indicated the purity of the product; eluent: dichloromethane/methanol 9:1) and dried at 60° C. Yield: 6 g (76%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([OH:31])=[C:25]([CH:30]=1)[C:26]([O:28][CH3:29])=[O:27].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([OH:31])=[C:25]([CH:30]=1)[C:26]([O:28][CH3:29])=[O:27])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(N)ccc1O
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(=O)C(CC(C)C)NC(=O)OCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.4 %

Procedure:
A mixture of 2-(benzyloxycarbonylamino)-4-methylpentanoic acid (1 g, 3.8 mmol), methyl 5-amino-2-hydroxybenzoate (0.66 g, 3.95 mmol) and Et3N (0.76 g, 7.6 mmol) were dissolved in CH3CN (10 mL) and HATU (1.503 g, 3.95 mmol) was added. The mixture was stirred (RT, 16 h). The solvent was removed under reduced pressure. Brine (50 mL) was added to the resulting residue, and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed successively with 2N aq. HCl (3×50 mL), brine (50 mL), 5% NaHCO3 (50 mL×3), brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica chromatography on (CH2Cl2) to give methyl 5-(2-(benzyloxycarbonylamino)-4-methylpentanamido)-2-hydroxybenzoate as a white solid (0.81 g, 51.8%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[Cl:16][C:17]1[C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[S:20][C:21]=1[CH2:22]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:22][C:21]2[S:20][C:19]3[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=3[C:17]=2[Cl:16])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: OCc1sc2ccccc2c1Cl
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCc2sc3ccccc3c2Cl)c1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.9 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.0 g, 4.8 mmol), (3-chloro-benzo[b]thiophen-2-yl)-methanol (1.9 g, 9.5 mmol), and polymer-supported triphenyl phosphine (3.0 g, 9.5 mmol) in THF (30 mL) in an ice-bath was slowly added diisopropyl azodicarboxylate (1.9 mL, 9.5 mmol) and stirred at r.t. overnight. The mixture was filtered and the solid was washed with ethyl acetate (10 mL). The filtrate was evaporated and the residue was purified by flash column chromatography (EtOAc/Hexane) to give 3-(3-chloro-benzo[b]thiophen-2-ylmethoxy)-phthalic acid dimethyl ester (2.1 g, 109% crude yield). The product was used in the next step without further purification.
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH2:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH2:11]1>>[CH:6]1[C:3]2[C@H:4]3[C@H:16]([CH2:15][C:14]4[CH:13]=[CH:12][CH:11]=[CH:10][C:19]=4[O:5]3)[CH2:17][CH2:18][C:2]=2[CH:9]=[CH:8][CH:7]=1
Reactant: C1=Cc2ccccc2CC1
Reactant: OCc1ccccc1O
Product: c1ccc2c(c1)C[C@@H]1CCc3ccccc3[C@@H]1O2
Yield: 6.9 %

Procedure:
2-Hydroxybenzyl alcohol (5.0 g) and 1,2-dihydronaphthalene (5.2 g.) were heated together at 190° for 2 hr. the reaction mixture was chromatographed on neutral alumina, eluting with toluene/60°-80° petroleum ether 1:1to give a solid product which was recrystallised from ethanol to yield colourless crystals of cis-5,6,6a,12a-tetrahydro-7H-benzo(c)xanthene(0.65 g., m.pt. 71°-72°)identified and characterised by 1H- and 13C n.m.r. spectra.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=1[CH2:12]Br.[CH2:15]([NH2:24])[C:16]1[CH:23]=[CH:22][C:19]([O:20][CH3:21])=[CH:18][CH:17]=1>C1COCC1.CCOC(C)=O>[CH3:21][O:20][C:19]1[CH:22]=[CH:23][C:16]([CH2:15][N:24]2[CH2:12][C:5]3[C:4](=[CH:9][CH:8]=[C:7]([C:10]#[N:11])[CH:6]=3)[C:3]2=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(C#N)cc1CBr
Reactant: COc1ccc(CN)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3cc(C#N)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-bromomethyl-4-cyano-benzoic acid methyl ester (18.1 g, 71.24 mmol) in THF (300 mL) was added PMBNH2 (23.4 g, 178.1 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 16 hours. After vacuum filtration, the filtrate was concentrated in vacuo. The residue obtained was re-dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product which was purified by column chromatography (11.69 g, 56.0%) as a solid.
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:16]([OH:18])=O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:19][O:20][C:21](=[O:42])[C@H:22]([CH2:36][C:37]1[N:41]=[CH:40][NH:39][CH:38]=1)[NH:23][C:24](=[O:35])[C@H:25]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH:26][CH3:27]>>[CH3:19][O:20][C:21](=[O:42])[C@H:22]([CH2:36][C:37]1[N:41]=[CH:40][NH:39][CH:38]=1)[NH:23][C:24](=[O:35])[C@H:25]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:26]([C:16](=[O:18])[C@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])[CH3:27]
Reactant: CC(C)(C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CN[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)OC
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)C(C)(C)C

Procedure:
N-Pivaloyl-L-phenylalanine and N-methyl-L-phenylalanyl-L-histidine methyl ester are treated in the same manner as described in Example 1 to give N-pivaloyl-L-phenylalanyl-N-methyl-L-phenylalanyl-L-histidine methyl ester.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([O:22][CH3:23])[CH2:20][OH:21])[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][CH3:16].[Br:24][CH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].N1C=CC=CC=1>O1CCCC1>[Br:24][CH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([O:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][O:17][CH2:1][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][CH3:16])=[O:30]
Reactant: O=C(Cl)c1cccc(CBr)c1
Reactant: CCCCCCCCCCCCCCCCOCC(CO)OC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOCC(COC(=O)c1cccc(CBr)c1)OC
Reaction time: 48 h
Yield: 78.3 %

Procedure:
A mixture of 8 g of 3-(hexadecyloxy)-2-methoxypropanol, 6.22 g of m-bromomethylbenzoyl chloride, 2.11 g of pyridine and 80 ml of tetrahydrofuran was stirred for 48 hours, then filtered and evaporated. The residue was purified by chromatography and crystallized giving 10 g of 3-(bromomethyl)benzoic acid, 3-(hexadecyloxy)-2-methoxypropyl ester as white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](C#C)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:13]C1C=C(C=CC=1)C(O)=O.C[Al](C)C>CCCCCC>[C:1]([C:5]1[CH:6]=[C:7]([Br:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: C#Cc1cccc(C(C)(C)C)c1
Agent: C[Al](C)C
Solvent: CCCCCC
Product: CC(C)(C)c1cccc(Br)c1

Procedure:
Reaction Scheme 4 discloses a specific synthetic route to 3-tert-butylphenylethyne (Compound 24) starting with meta bromobenzoic acid (Compound 25), which is treated with trimethylaluminum in hexane to yield 3-tert-butyl bromobenzene (Compound 26). 3-Tert-butyl bromobenzene 26 is thereafter converted into the ethyne derivative 24 through the trimethylsilyl ethyne intermediate 27 in steps similar to the steps described in connection with Reaction Scheme 3.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6]1=[O:16].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([C:17](=[O:19])[CH3:18])[C:6]1=[O:16]
Reactant: COCCn1cc(-c2ccccc2)[nH]c1=O
Reactant: CC(=O)OC(C)=O
Product: COCCn1cc(-c2ccccc2)n(C(C)=O)c1=O

Procedure:
Approximately 21.8 g of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one and 120 ml. of acetic anhydride is refluxed together for 4 hours. The acetic anhydride is distilled out at reduced pressure. The residual semisolid is recrystallized from ether to yield the title compound as a white solid; m.p. 73°-75° C.