Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13].Cl.Cl.[NH2:20][C:21]1[CH:53]=[CH:52][C:24]([O:25][C:26]2[CH:27]=[CH:28][C:29]3[N:33]=[C:32]([CH2:34][O:35][C:36]4[CH:49]=[CH:48][C:39]([CH2:40][CH:41]5[S:45][C:44](=[O:46])[NH:43][C:42]5=[O:47])=[CH:38][CH:37]=4)[N:31]([CH3:50])[C:30]=3[CH:51]=2)=[CH:23][CH:22]=1>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([O:25][C:26]2[CH:27]=[CH:28][C:29]3[N:33]=[C:32]([CH2:34][O:35][C:36]4[CH:37]=[CH:38][C:39]([CH2:40][CH:41]5[S:45][C:44](=[O:46])[NH:43][C:42]5=[O:47])=[CH:48][CH:49]=4)[N:31]([CH3:50])[C:30]=3[CH:51]=2)=[CH:52][CH:53]=1)=[O:13]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)c4cccc(Cl)c4)cc3)cc21

Procedure:
A reaction was conducted by a similar procedure to that described in Example 52 using triethylamine (0.32 ml), 3-chlorobenzoyl chloride (0.09 ml), 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg) and anhydrous N,N-dimethylformamide (8 ml). The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3:2→5:2 as the eluant to afford the title compound (232 mg, white powder, mp 238-239° C.).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5](O)=[CH:4][CH:3]=1)O.[C:9]([OH:14])(=[O:13])[C:10]([CH3:12])=[CH2:11].O1CCCC1.P(Cl)(Cl)(Cl)=O>CO.C(N(CC)CC)C.C1(C)C=CC=CC=1>[C:9]([OH:14])(=[O:13])[C:10]([CH3:12])=[CH2:11].[C:9]([OH:14])(=[O:13])[C:10]([CH3:12])=[CH2:11].[CH:1]1[CH:8]=[CH:7][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Agent: C=C(C)C(=O)O
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: c1ccccc1

Procedure:
Into a one liter three neck flask which was equipped with a stirrer, water condenser, thermometer and addition funnel was added 55g hydroquinone (1,4-benzenediol), 94.5g methacrylic acid (MAA), 100 ml tetrahydrofuran and 350ml toluene. Then 244 g of triethylamine was added with cooling. Then 121 g phosphorus oxychloride (POCl3) was added over a 20 minute period between 22° and 55° C. The flask contents were further reacted at 72° C. for two hours and then filtered. The filtrate was distilled to remove the volatiles, thus leaving 75 g of an amber crystalline semi solid. It was dissolved in 250 ml of methanol and crystallized in dry ice to give a white powder with a melting point of 87° to 89° C. Gel Permeation Chromatography (GPC) and NMR confirmed that the product was the 1,4-benzene dimethacrylate.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:19]([Cl:20])=[CH:18][C:16]([NH2:17])=[C:15]([N+:21]([O-])=O)[CH:14]=1.Cl>C(O)C.[Zn]>[F:24][C:2]([F:1])([F:25])[C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[C:15]([NH2:21])[C:16]([NH2:17])=[CH:18][C:19]=1[Cl:20]
Reactant: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: CCO
Product: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2C(F)(F)F)cc1N
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-4-iodo-2-nitroaniline (6 g, 20.1 mmol) in dioxane (100 ml) and water (10 ml) which was purged and maintained with an inert atmosphere of nitrogen was added[2,4-bis(trifluoromethyl)phenyl]boronic acid (10.3 g, 40.01 mmol), K3PO4 (8.6 g, 40.70 mmol) and Pd(pph3)4 (2.3 g, 2.04 mmol) at room temperature. The resulting solution was stirred overnight at 95° C. in an oil bath. The resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column, eluting with 2% to 3% ethyl acetate in petroleum ether to produce 4-[2,4-bis(trifluoromethyl)phenyl]-5-chloro-2-nitroaniline as a crude light yellow solid (2.2 g, crude). Next, to a solution of 4-[2,4-bis(trifluoro-methyl)phenyl]-5-chloro-2-nitroaniline (2.2 g, crude) in ethanol (50 ml) was added hydrogen chloride (conc, 1.5 ml) and Zn powder (2.2 g, 33.85 mmol). The resulting solution was stirred for 2 h at 90° C. in an oil bath. The reaction was then quenched by the addition of water (300 ml), adjusted pH to 8 with aqueous sodium carbonate and then extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (200 ml), dried and concentrated under vacuum to produce 4-[2,4-bis(trifluoromethyl) phenyl]-5-chlorobenzene-1,2-diamine as a crude brown solid (1.75 g, crude). Finally, a Solution of 4-[2,4-bis(trifluoromethyl)phenyl]-5-chlorobenzene-1,2-diamine (300 mg, crude) in trifluoroacetic acid (10 ml) and hydrogen chloride (conc, 2 ml) was stirred overnight at 80° C. in an oil bath. The solution was evaporated and dissolved in water (30 ml), adjusted to pH 8 with aqueous sodium carbonate and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 6-[2,4-bis(trifluoromethyl)phenyl]-5-chloro-2-(trifluoromethyl)-1H-1,3-benzodiazole as a off-white solid (132.4 mg).
Reaction SMILES: [CH3:1][Si:2](Cl)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:16][Si:17]([Li])([C:24]1C=CC=CC=1)[C:18]1C=CC=CC=1.[Si](Cl)(C)(C)C>O1CCCC1>[CH3:1][Si:2]([Si:17]([CH3:24])([CH3:18])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [Li][Si](C)(c1ccccc1)c1ccccc1
Reactant: C[Si](Cl)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: C[Si](C)(C)[Si](C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
A slurry 89.3 g of Li metal cut into small pieces in 1500 ml dry tetrahydrofuran (THF) under an Ar atmosphere was treated dropwise with neat Ph2MeSiCl (1302.2g, 5.59 moles). During the addition, agitation was provided via a mechanical stirrer and an ice bath was employed as necessary to hold the reaction temperature under 40° C. The mixture was then allowed to stir overnight (16 hr.) at room temperature. The dark red solution of Ph2MeSiLi was then treated with 607.7g (5.59 moles) of Me3SiCl dissolved in 700 ml dry THF. Again an ice bath was utilized to maintain the reaction mixture temperature under 40° C. Near the end of the Me3SiCl addition, the red color of Ph2MeSiLi was completely discharged. Upon completion of the addition, the now essentially colorless mixture was filtered to remove precipitated LiCl and unreacted Li metal. Solvent was removed from the resulting clear solution at reduced pressure and the residual oil fractionally distilled at 0.3 mm Hg to afford 1074.1 g of title compound (71%), bp 108°-110° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][C:32]1([CH3:39])[C:36]([CH3:38])([CH3:37])[O:35][BH:34][O:33]1>C(#N)C>[CH3:31][C:32]1([CH3:39])[C:36]([CH3:38])([CH3:37])[O:35][B:34]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[CH:4][CH:3]=2)[O:33]1
Reactant: CC1(C)OBOC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(CCCc2ccc(Br)cc2)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of tert-butyl 4-(3-(4-bromophenyl)propyl)piperazine-1-carboxylate (2.4 g, 6.26 mmol) in acetonitrile (12 ml) was added triethylamine (2.62 ml, 18.78 mmol) and Pd-118 (0.122 g, 0.19 mmol). Reaction mixture was stirred at RT under nitrogen for 10 min. 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.363 ml, 9.39 mmol) added and reaction mixture heated to 80° C. for 1 h. The reaction mixture was evaporated to dryness and redissolved in EtOAc and washed with water and saturated brine. The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography using Isco Companion, 100 g silica column, elution gradient 40 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford sub-title compound as a brown oil. Yield: 0.9 g
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH:15]1[CH:20]2[CH:16]1[CH2:17][N:18]([C:21]1[N:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][N:22]=1)[CH2:19]2)(=[O:13])=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:52][CH2:53][N:54]1[CH:58]=[CH:57][N:56]=[C:55]1[CH3:59].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH3:59][C:55]1[N:54]([CH2:53][CH2:52][N:14]([S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:13])=[O:12])[CH:15]2[CH:16]3[CH:20]2[CH2:19][N:18]([C:21]2[N:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][N:22]=2)[CH2:17]3)[CH:58]=[CH:57][N:56]=1
Reactant: CCOC(=O)c1cnc(N2CC3C(C2)C3NS(=O)(=O)c2ccc3ccccc3c2)nc1
Reactant: Cc1nccn1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cnc(N2CC3C(C2)C3N(CCn2ccnc2C)S(=O)(=O)c2ccc3ccccc3c2)nc1
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of ethyl 2-[6-(naphthalene-2-sulfonylamino)-3-aza-bicyclo[3.1.0]hex-3-yl]-pyrimidine-5-carboxylate (0.182 g, 0.47 mmol) in DCM (10 ml) was added triphenylphosphine (0.26 g, 1 mmol) and 1-(2-hydroxyethyl)-2-methylimidazole (0.084 mg, 0.75 mmol). Diisopropylazodicarboxylate (0.167 ml, 0.85 mmol) was then added and the solution stirred overnight. The mixture was loaded directly onto a silica gel column and purified eluting with 2% MeOH/DCM to give the title compound (0.242 g, 90%). 1H NMR (300 MHz, CDCl3) δ: 1.36 (3H, t), 1.60-1.80 (3H, m), 2.57 (3H, s), 3.43 (2H, t), 3.48-3.62 (2H, m), 3.70 (2H, d), 4.35 (2H, t), 4.33 (2H, q), 6.90 (1H, d), 6.98 (1H, d), 7.60-7.80 (2H, m) 7.82 (1H, dd), 7.95 (1H, dd), 8.02 (2H, d), 8.43 (1H, s), 8.72 (2H, s).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Sc1ccccc1Br
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=Cc1ccc(Sc2ccccc2Br)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
4-fluorobenzaldehyde (10 mL, 93 mmol), 2-bromobenzenethiol (12 mL, 102 mmol) and potassium carbonate (15.4 g, 111 mmol) were combined in dimethylsulfoxide (50 mL) under nitrogen and heated to 120° C. After 2 hours, the temperature had reached 210° C. so the reaction was stopped. The cooled reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4 and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica, eluting with 10% ethyl acetate/isohexane, to give 4-[(2-bromophenyl)thio]benzaldehyde (23.83 g, 87%). δH (360 MHz, d6 DMSO): 9.97 (1H, s), 7.89-7.82 (3H, m), 7.55-7.33 (5H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])[CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C.CCO>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:28]([CH2:27][CH2:26][CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:29]2=[O:30])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCCCc1cccnc1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=c1c(CCCc2cccnc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(pyridin-3-yl)pentanoate (1.1 eq., prepared in Synthetic Example 9) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(pyridin-3-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 172 to 173° C./DMF-EtOH. 1H NMR(CDCl3) δ: 2.02-2.11(2H, m), 2.71-2.79 (4H, m), 7.18-7.24 (2H, m), 7.54-7.92(5H, m), 8.19-8.20 (1H, m), 8.34-8.49(4H, m).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][P:13](=[O:18])([O:16][CH3:17])[O:14][CH3:15].[CH3:19][CH:20]([CH2:26][C:27]#[C:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:21](OCC)=[O:22]>C1COCC1.O.C(O)(=O)C>[CH3:19][CH:20]([CH2:26][C:27]#[C:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:21](=[O:22])[CH2:12][P:13](=[O:18])([O:16][CH3:17])[O:14][CH3:15]
Reactant: COP(C)(=O)OC
Reactant: CCCCC#CCC(C)C(=O)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: O
Product: CCCCC#CCC(C)C(=O)CP(=O)(OC)OC
Temperature: -78 °C

Procedure:
Under argon atmosphere, a solution of n-butyllithium in hexane (1.71N, 29.8 ml, 0.051 mol) was dropwise added to a solution of dimethyl methylphosphonate (6.32 g, 0.051 mol) in anhydrous THF (120 ml) with stirring at -78° C., and the mixture was stirred for 30 minutes. At -78° C., a solution of ethyl 2-methyl-4-nonynoate (4.0 g, 0.02 mol) in anhydrous THF (10 ml) was dropwise added, and the mixture was stirred for 30 minutes. Acetic acid (3.1 ml) and water (20 ml) were then added to the reaction mixture at 0° C. After concentration, water (20 ml) was added to the residue and the resulting mixture was extracted with ethyl acetate (50 ml×2). The ethyl acetate layers were combined, washed with water (20 ml) and with brine (20 ml), and dried over anhydrous sodium sulfate to concentrate. Vacuum distillation of the residue (b.p.=128°-130° C. at 0.16 mmHg) gave dimethyl 3-methyl-2-oxo-5-decynylphosphonate as a colorless, transparent oil (4.75 g, 0.0173 mol, 85% yield). The structure of this product was confirmed by the following data.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[C:15](=[NH:28])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[C:15](=[N:28][C:2]1[CH:3]=[CH:4][C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: O=c1ccc(Br)cn1-c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=c1ccc(N=C(c2ccccc2)c2ccccc2)cn1-c1ccccc1
Temperature: 80 °C

Procedure:
Into a dried flask were added 5-bromo-1-phenyl-1H-pyridin-2-one (125 mg, 0.500 mmol), benzophenone imine (100 μl, 0.600 mmol), tris(dibenzylideneacetone)-dipalladium(0) (1.14 mg, 1.25 μmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (2.33 mg, 3.75 μmol), sodium tert-butoxide (67.2 mg, 0.700 mmol), and toluene (3 ml). The above mixture was flushed with N2 for 5 min and was then heated at 80° C. under an atmosphere of nitrogen for 5 h. After that time, the heating was stopped and the reaction mixture was diluted with ethyl ether (30 ml), filtered and concentrated to obtain light-brown oil, which was then purified by chromatography on silica gel (10 g) eluting with 100 ml of 10%, 20%, 30% and 40%, and 300 ml 50% EtOAc/hexane to obtain the title compound as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ=6.45 (d, 1H, J=9.6 Hz), 6.89 (d, 1H, J=2.8 Hz), 7.00 (dd, 1H, J=2.8 & 10.4 Hz), 7.13-7.16 (m, 2H), 7.19-7.22 (m, 2H), 7.33-7.48 (m, 9H), 7.69-7.72 (m, 2H). MS(ES+): m/z 351.05 (100) [MH+]. HPLC: tR=3.46 min (ZQ2000, polar—5 min).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:5]=2[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:18][O:19][CH:20]([O:24][CH3:25])[CH2:21][NH:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:17][C:15]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:3]([CH2:2][N:22]([CH2:21][CH:20]([O:24][CH3:25])[O:19][CH3:18])[CH3:23])[C:4]=2[CH:16]=1
Reactant: CCOC(=O)c1sc2ccc(Cl)cc2c1CBr
Reactant: CNCC(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1sc2ccc(Cl)cc2c1CN(C)CC(OC)OC
Reaction time: 48 h
Yield: 96.2 %

Procedure:
A mixture of ethyl 3-bromomethyl-5-chlorobenzo[b]thiophene-2-carboxylate (11.0 g, 0.033 mol), methylaminoacetaldehyde dimethyl acetal (4.76 g, 0.04 mol) and potassium carbonate (11.4 g, 0.8 mol) in dry acetone (200 ml) was stirred for 48 hours, filtered and the filtrate concentrated to give 11.8 g (96%) of ethyl 5-chloro-3-[N-(2,2-dimethoxyethyl)-N-methyl-(aminomethyl)]benzo[b]thiophene-2-carboxylate.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:10]([O:12]C)=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].CO>C(#N)C>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](Cc1cccnc1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: O=C(N[C@@H](Cc1cccnc1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.5 g of Z-Pal-OMe (18.2 mMol) are dissolved in 100 ml of acetonitrile, mixed with 20 ml of 1N NaOH and stirred for 3 hours at ambient temperature. The mixture is neutralised by adding 20 ml of 1N NaOH, the solvent is largely removed on the rotary evaporator and the solid residue is mixed with ice cold water. After suction filtering the mixture is washed with a little water and the residue is dried in the desiccator whereby Z-Pal-OH is obtained in the form of white crystals. M.p.: 82° C.; [α]D20 (MeOH)=-9.4°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)Cl>[O:22]1[CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:13]1
Reactant: C=CCCCCOC1CCCCO1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C(CCC1CO1)COC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 11.57 g of 6-(2-tetrahydropyranyloxy)-hex-1-ene in 200 ml of methylene chloride is added 10.8 g m-chloroperbenzoic acid and the mixture is stirred at room temperature for 18 h. The reaction is quenched by the addition of saturated aqueous sodium bicarbonate solution followed by saturated sodium sulfite solution. The organic phase is dried, filtered and evaporated to give a clear oil which is purified by chromatography over silica gel using hexane/ether (4:1) as eluent to obtain 1,2-epoxy-6-(2-tetrahydropyranyloxy)-hexane; IR (CH2CH2): 1450, 1135, 1033 cm-1.
Reaction SMILES: Br[C:2]1[C:12]([O:13][CH2:14][CH2:15][CH3:16])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:17].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[C:12]([O:13][CH2:14][CH2:15][CH3:16])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[OH:17])=[CH:29][CH:28]=1
Reactant: CCCOc1cc(C(=O)OCC)cc(O)c1Br
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCOc1cc(C(=O)OCC)cc(O)c1-c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Palladium acetate (1.11 g) was added to a mixture of ethyl 4-bromo-3-hydroxy-5-propoxybenzoate (30.0 g), tripotassium phosphate (63.0 g), (4-fluorophenyl)boronic acid (34.6 g), and tricyclohexylphosphine (20% toluene solution, 17.6 mL) in toluene (200 mL) and water (100 mL), and the resultant mixture was heated with stirring overnight at 90° C. in an argon atmosphere. The reaction mixture was allowed to cool to room temperature, then diluted with ethyl acetate, and washed with water and saturated saline in this order. The organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (31.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([O:7][C:8]2[S:14][CH:13]3[N:10]([C:11](=[O:15])[CH2:12]3)[C:9]=2[C:16]([O:18]CC2C=CC([N+]([O-])=O)=CC=2)=[O:17])=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+:35]>O1CCOCC1.O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[S:14][CH:13]3[N:10]([C:11](=[O:15])[CH2:12]3)[C:9]=2[C:16]([O-:18])=[O:17])=[CH:29][CH:30]=1.[Na+:35]
Reactant: COc1ccc(OC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)CC3S2)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(OC2=C(C(=O)[O-])N3C(=O)CC3S2)cc1

Procedure:
A mixture of a solution of 60 mg of 4-nitrobenzyl 3-(4-methoxyphenoxy)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in dioxan and 15 mg of sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25° for 60 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C1C[O:15][CH2:14]C1.Cl.C(Cl)(Cl)=O>O>[Br:1][C:2]1[CH:10]=[C:6]2[C:7]([O:9][C:14](=[O:15])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: C1CCOC1
Agent: Cl
Agent: O=C(Cl)Cl
Solvent: O
Product: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
To a stirred solution of 5-bromo-2-amino-benzoic acid (25 g, 0.115 mmol) in a mixed solvent of THF:H2O:conc. HCl (4:2:1, 350 mL), was added a solution of phosgene (0.23 mmol, 20% in toluene) dropwise. The reaction mixture was allowed to stir at room temperature for 4 h. The resulting precipitate was filtered, washed with water and dried under reduced pressure to give the title compound (22.5 g, 78%) as a gray solid.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:7]=[C:8]1[O:12][C:10](=[O:11])[CH2:9]1>>[C:10]([NH:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])(=[O:11])[CH2:9][C:8]([CH3:7])=[O:12]
Reactant: CC(C)C(N)=O
Reactant: C=C1CC(=O)O1
Product: CC(=O)CC(=O)NC(=O)C(C)C
Yield: 38.7 %

Procedure:
A 250 ml, three-necked, round bottom flask, was equipped with a condenser, drying tube, mechanical stirrer, gas inlet tube, thermometer and heating mantle. Toluene (100 ml) was introduced and hydrogen chloride gas was bubbled through the solvent until the solution was saturated. Isobutyramide (8.70 g, 0.10 mole) was added and the mixture was heated to 92°. Diketene (8.40 g, 0.10 mole) was added over a 6 minute period and after heating for 15 minutes, a 38.7% yield of N-acetoacetylisobutyramide was obtained.