Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][N:6]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[CH2:18]([N:6]1[CH2:7][CH:8]([NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C1CC(NC(=O)OC(C)(C)C)CN1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CC(C(=O)O)N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-Benzyl-4-tert-butoxycarbonylamino-pyrrolidine-2-carboxylic methyl ester and LiOH are dissolved in THF/H2O, and the resulting mixture is stirred for about 5 hours at room temperature. After removal of the solvent, the PH is adjusted to 6-7. The solid is collected and dried to afford 1-benzyl-4-tert-butoxycarbonylamino-pyrrolidine-2-carboxylic acid (40).
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][N:8]1[CH:12]=[CH:11][N+:10]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])=[C:9]1[NH2:22])=[O:6])[CH3:3].[C:23]([O-])(=O)[CH3:24].[Na+].C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>>[CH2:2]([O:4][C:5]([C:7]1[N:8]2[CH2:12][CH2:11][N:10]([C:13]3[C:14]([CH3:21])=[CH:15][C:16]([CH3:20])=[CH:17][C:18]=3[CH3:19])[C:9]2=[N:22][C:23]=1[CH3:24])=[O:6])[CH3:3]
Reactant: CCOC(=O)Cn1cc[n+](-c2c(C)cc(C)cc2C)c1N
Reactant: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1c(C)nc2n1CCN2c1c(C)cc(C)cc1C
Temperature: 160 °C
Yield: 41 %

Procedure:
A mixture of 3-ethoxycarbonylmethyl-1-(2,4,6-trimethyl-phenyl)-2-aminoimidazolium bromide (1.0 g, 2.7 mmol), sodium acetate (0.55 g, 6.75 mmol) and acetic anhydride (5.0 mL) was heated at 160° C. for 12 hr. Upon cooling, the mixture was poured into a flask containing ice. While stirring, excess sodium bicarbonate was added to the above mixture in small portions, and the resulting mixture was stirred at room temperature for 6 hr. Then, the mixture was extracted with dichloromethane (2×40 mL). The organic extracts were washed with water and dried over anhydrous sodium sulfate. Solvents were removed in vacuo and the residue was subjected to chromatography using ethyl acetate/hexanes (1:4) as eluent to afford the title compound as a light yellow oil which solidified upon cooling (0.344 g, 41% yield). 1H NMR (CDCl3, 300 MHz) δ 6.89 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 4.36–4.26 (m, 2H), 4.15–4.08 (m, 2H), 2.39 (s, 3H), 2.26 (s, 3H), 2.20 (s, 6H), 1.35 (t, J=7.1 Hz, 3H). Mass spec.: 314.15 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[O:8][C@@H:7]1[C:9]([OH:11])=O)=[O:5])[CH3:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:35][CH:36]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(OCC)(=O)C.CCCCCC>[C:37]1([CH:36]([NH:35][C:9]([C@H:7]2[O:8][C@@H:6]2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)NC(c1ccccc1)c1ccccc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,3S)-3-ethoxycarbonyloxirane-2-carboxylic acid (8.01 g, 50.0 mmol.) in ethyl acetate (120 mL) was added N-hydroxysuccinimide (5.76 g, 50.0 mmol.) and then added N,N'-dicyclohexylcarbodiimide (5.75 g, 50.0 mmol) under chilling with ice. The resulting mixture was stirred at 5° C. for one hour, and to the mixture was a solution of aminodiphenylmethane (9.17 g, 50.0 mmol.) in ethyl acetate (30 mL). The mixture was stirred at 5° C. for one hour and then at room temperature for one hour. The resulting N,N'-dicyclohexylurea (DC-Urea) was removed by filtration, and the filtrate was washed successively with 1N hydrochloric acid, an aqueous sodium hydrogen carbonate saturated solution, and an aqueous sodium chloride saturated solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystalized from ethyl acetate--n-hexane, to give the desired compound as a white crystalline product (1.25 g, yield: 77%).
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[CH:5]1([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:24]=4)[N:19]=[CH:18]3)[CH:11]=2)[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH:5]1([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([N:28]5[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH3:4])[CH2:32][CH2:33]5)[CH:24]=4)[N:19]=[CH:18]3)[CH:11]=2)[CH2:7][CH2:6]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCNCC3)cc2c1=O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCN1CCN(c2ccc3ncn(-c4cc(C(=O)NC5CC5)ccc4C)c(=O)c3c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Iodopropane (0.039 ml) was added to a stirred mixture of N-cyclopropyl-4-methyl-3-(4-oxo-6-piperazin-1-ylquinazolin-3(4H)-yl)benzamide (0.145 g) and potassium carbonate (0.199 g) in DMA (0.50 ml). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (20 ml), the resulting solid was filtered and dried (magnesium sulphate) under vacuum at 40° C. There was thus obtained the title compound (0.109 g); NMR Spectrum: (DMSOd6) 0.54 (m, 2H), 0.68 (m, 2H), 0.87 (t, 3H), 1.48 (m, 2H), 2.12 (s, 3H), 2.28 (t, 2H), 2.50 (m, 4H), 2.84 (m, 1H), 3.27 (m, 4H), 7.45 (s, 1M), 7.50 (d, 1H), 7.62 (s, 2H), 7.80 (s, 1H), 7.87 (d, 1H), 8.06 (s, 1H), 8.41 (d, 1H); Mass Spectrum: M+H+ 446.
Reaction SMILES: [CH2:1]([C@H:4]1[C:21]2[C@:16]([CH3:23])([CH2:17][CH2:18][C:19](=[O:22])[CH:20]=2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.ClCCl>O1CCOCC1>[CH2:1]([C@H:4]1[C:21]2[C@:16]([CH3:23])([CH:17]=[CH:18][C:19](=[O:22])[CH:20]=2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3]
Reactant: C#CC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C=C12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: C#CC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C=C12
Reaction time: 6 h
Yield: 58.9 %

Procedure:
To a solution of 6β-propargyl-4-androstene-3,17-dione (1) (160 mg, 0.5 mmol) in dry dioxane (30 mL) was added dichlorodicyanobenzoquinone (DDQ, 150 mg, 0.6 mmol), and the reaction mixture was refluxed with stirring for 6 hours. Dilution with 30 mL dichloromethane followed by washing (1% NaOH, water), drying and evaporation in vacuo, gave 125 mg of crude product. The residue was purified by chromatography over silica gel and the product was recrystallized from acetone/hexane to give 95 mg (60% yield) of the title compound (12).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>[O-]CC.[Na+]>[C:9]([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]
Reactant: Cc1ccc(CC#N)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C(C#N)c1ccc(C)cc1

Procedure:
Following the procedures outlined in Examples 1 and 3, p-methylphenylacetonitrile and diethyl oxalate are reacted in alcoholic sodium ethoxide to obtain ethyl 3-cyano-3-(p-methylphenyl)-pyruvate, m.p. 86°-88° C. The latter is reacted with p-methylphenylacetonitrile to give 2,5-di-(p-methylphenyl)-3,4-dioxoadiponitrile, m.p. 270°-272° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[O:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][OH:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(N(C)C)=O>[I:8][C:5]1[CH:6]=[CH:7][C:2]([O:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3][CH:4]=1
Reactant: Clc1ccc(I)cn1
Reactant: OCc1ccccc1Oc1ccccc1
Solvent: CC(=O)N(C)C
Product: Ic1ccc(OCc2ccccc2Oc2ccccc2)nc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a solution of 2-chloro-5-iodopyridine in dimethylacetamide (2 ml), 300 mg of potassium tert-butoxy and 535 mg of (2-phenoxyphenyl)methanol were added, and the reaction solution was stirred at 110° C. for 4 hours. The reaction solution was cooled, then diluted with a saturated saline solution, extracted with diethyl ether, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-10:90)) to afford the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH2:14][C:15](=[O:21])[N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[OH-].[Na+]>CO>[CH2:19]([N:16]([CH2:17][CH3:18])[C:15]([CH2:14][N:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]=2[CH:7]=[CH:8]1)=[O:21])[CH3:20]
Reactant: CCN(CC)C(=O)Cn1ccc2c(C(=O)OC)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)C(=O)Cn1ccc2c(C(=O)O)cccc21
Temperature: 50 °C

Procedure:
To a solution of Diethylcarbamoylmethyl-1H-indole-4-carboxylic acid methyl ester (480 mg, 1.665 mmol) in MeOH (5 ml) is added 2 M NaOH (5 ml). The reaction is heated at 50° C. for 20 hours and then allowed to cool to room temperature. The solvent is removed in vacuo and the residue dissolved in water (10 ml). The pH of the solution is adjusted to 5 using 1 M HCl and the resulting solid is collected by filtration to give the title compound 1-Diethylcarbamoylmethyl-1H-indole-4-carboxylic acid; [M+H]+ 275
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.S(OC)(O[CH3:16])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH:2](=[O:1])[C:3]1[CH:11]=[CH:10][C:8]([O:9][CH3:16])=[C:5]([O:6][CH3:7])[CH:4]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C=O)cc1OC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
100 g of vanillin (0.658 mol), 128 g of dimethyl sulfate (1.00 mol), and 96.0 g of sodium carbonate (0.91 mol) were heated with stirring to 80° C over b 0.5 hr. Stirring was continued at this temperature for 1.0 hr. over which time 60 ml of water were added in 5 ml portions. Work-up as in Example 1 gave a quantitative yield of veratraldehyde which contained not more than 0.1% vanillin, as determined by g.l.c. analysis.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].[C:18]([O:22][C:23](=[O:29])[N:24]([CH3:28])[CH2:25][CH:26]=O)([CH3:21])([CH3:20])[CH3:19].N1CCCC1>C1(C)C=CC=CC=1>[C:18]([O:22][C:23](=[O:29])[N:24]([CH3:28])[CH2:25][CH:26]1[CH2:16][C:15](=[O:17])[C:3]2[C:2](=[CH:7][C:6]([S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:5][CH:4]=2)[O:1]1)([CH3:20])([CH3:21])[CH3:19]
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: CC(=O)c1ccc(Sc2ccccc2)cc1O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CN(CC1CC(=O)c2ccc(Sc3ccccc3)cc2O1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 60 h
Yield: 33.5 %

Procedure:
To a solution of 1-(2-hydroxy-4-phenylsulfanyl-phenyl)-ethanone (244 mg, 1 mmol) and methyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester (259 mg, 1.5 mmol) (Tetrahedron 58, 2002, 1719-37) in toluene (25 mL) was added pyrrolidine (71 mg, 1 mmol). The reaction was stirred at room temperature for 60 hours. The mixture was concentrated in vacuo and the residue was purified via flash chromatography (hexane/Et2O, 3/1) to give methyl-(4-oxo-7-phenylsulfanyl-chroman-2-ylmethyl)-carbamic acid tert-butyl ester (134 mg, 34% yield) as clear oil.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[CH3:17])=[C:6]([NH:18][C:19](=O)[CH2:20][C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=1.Cl.O>O1CCOCC1>[CH3:17][C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[N:10]1[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:27])=[CH:5][C:6]=2[N:18]=[C:19]1[CH2:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(NC2CCCCC2C)c(NC(=O)Cc2cccs2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CCCC[C@H]1n1c(Cc2cccs2)nc2cc(C(=O)O)ccc21
Temperature: 135 °C
Yield: 92 %

Procedure:
0.77 g 4-(2-Methyl-cyclohexylamino)-3-(2-thiophen-2-yl-acetylamino)-benzoic acid methyl ester were reacted with 5 ml of 4M hydrochloric acid in dioxane at 100° C. in a microwave reactor for 5 min. 1 ml water was added and the mixture was heated to 135° C. for 15 min. The reaction was concentrated and the residue purified by chromatography (silica, ethyl acetate/heptane) to yield 0.65 g (91%) of 1-((1R,2R)-2-Methyl-cyclohexyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:39])[C:12]=1[CH2:13][S:14][C:15]1[N:16]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:17]([C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][CH3:31])[CH:24]=2)([CH3:22])[CH3:21])=[CH:18][N:19]=1)[O:5][CH2:6][CH2:7][CH2:8][OH:9].CCN(C(C)C)C(C)C.[CH3:49][S:50](Cl)(=[O:52])=[O:51]>C(Cl)Cl>[CH3:49][S:50]([O:9][CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:10]=[C:11]([F:39])[C:12]([CH2:13][S:14][C:15]2[N:16]([C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)[C:17]([C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][CH3:31])[CH:24]=3)([CH3:22])[CH3:21])=[CH:18][N:19]=2)=[C:2]([Cl:1])[CH:3]=1)(=[O:52])=[O:51]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCO)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCOS(C)(=O)=O)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
To a stirred solution of 3-(3-chloro-5-fluoro-4-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)phenoxy)propan-1-ol (420 mg, 0.73 mmol) and DIPEA (0.32 mL, 1.83 mmol) in DCM (10 mL) at 0° C. was added dropwise methanesulfonylchloride (113 μL, 1.45 mmol). After stirring 30 min, the reaction mixture was partitioned in DCM (20 mL) and water (20 mL). The aqueous layer was re-extracted with DCM (20 mL×2). The combined organic layers were dried over MgSO4, concentrated and purified by column chromatography (EtOAc/Hex=1:2) to give 3-(3-chloro-5-fluoro-4-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)phenoxy)propyl methanesulfonate (470 mg, 99% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J=8.65 Hz, 1H), 6.87 (dd, J=11.04, 8.48 Hz, 1H), 6.81-6.73 (m, 2H), 6.69-6.66 (m, 1H), 6.58 (dd, J=8.13, 2.23 Hz, 1H), 6.50-6.43 (m, 2H), 6.38-6.31 (m, 1H), 4.42 (t, J=6.04 Hz, 2H), 4.18 (s, 2H), 4.03 (t, J=5.88 Hz, 2H), 3.77 (d, J=5.83 Hz, 2H), 3.68 (s, 4H), 3.10-2.98 (m, 3H), 2.22 (p, J=5.94 Hz, 2H), 1.51 (t, J=4.73 Hz, 5H).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:4]([CH3:21])([CH2:5][CH2:6][CH:7](O)[CH2:8]2)[CH:3]1C.Cl.[NH2:24][OH:25]>CCO>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:4]([CH3:21])([CH2:5][CH2:6][C:7](=[N:24][OH:25])[CH2:8]2)[CH2:3]1
Reactant: NO
Reactant: COc1cccc(C23CCN(C)C(C)C2(C)CCC(O)C3)c1
Agent: Cl
Solvent: CCO
Product: COc1cccc(C23CCN(C)CC2(C)CCC(=NO)C3)c1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
N-Methyl-4aβ-(3-methoxyphenyl)octahydro-6-oxadecahydroisoquinoline 17 (1.41 g, 4.9 mmol) and hydroxylamine hydrochloride (1.70 g, 24.5 mmol) in EtOH (absolute, 100 mL) were heated to reflux for 5 h. The reaction mixture was allowed to cool to room temperature. Ethanol was removed under reduced pressure. The crude product was taken in to aqueous 2N NaOH solution (100 mL) and extracted with 3:1 CH2Cl2/THF (4×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure yielding crude product. The crude product was purified by flash chromatography (neutral alumina, Brockmann activity II-III) eluting with 9:1 ethyl acetate/hexane to afford 1.43 g (96%) of 19 as a white solid (mixture of E/Z): LCMS (ESI): m/z 303.5 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[C:7]([OH:13])[CH:6]=[CH:5]2.Br[C:15]1C=C2C(=CC=1)C=C(O)C=C2.CNC.C=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:15])=[C:7]([OH:13])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1Cl
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: C=O
Agent: CNC
Product: Cc1c(O)ccc2cc(Br)ccc12

Procedure:
Preparation of 6-bromo-1-chloro-2-naphthol 4 from the corresponding 6-bromo-2-naphthol 4a is described in the literature (Buu-Hoi, JOC 1951, 16, 185). 6-Bromo-1-methyl-2-naphthol 7 was prepared as depicted in reaction Scheme I. Reaction of 6-bromo-2-naphthol 4a with aqueous dimethyl amine and aqueous formaldehyde in alcohol afforded the Mannich product 5. Reaction of 5 with acetyl chloride in methylene chloride or chloroform afforded the acetate 6. Hydride reduction of 6 in a solvent such as ethanol followed by basic work-up yielded the desired 6-bromo-1-methyl-2-naphthol 7.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]([OH:16])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([NH2:14])=[C:9]([Cl:15])[CH:8]=1)[CH:2]=[CH2:3].[C:17](Cl)(Cl)=[O:18]>>[NH2:14][C:10]1[C:11]([Cl:13])=[CH:12][C:7]([CH:6]2[O:16][C:17](=[O:18])[N:4]([CH2:1][CH:2]=[CH2:3])[CH2:5]2)=[CH:8][C:9]=1[Cl:15]
Reactant: C=CCNCC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: O=C(Cl)Cl
Product: C=CCN1CC(c2cc(Cl)c(N)c(Cl)c2)OC1=O

Procedure:
In the same manner, α-[(allylamino)methyl]-4-amino-3,5-dichlorobenzyl alcohol is allowed to react with phosgene to afford 5-(4-amino-3,5-dichlorophenyl)-3-allyl-2-oxazolidinone.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:7]=3[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si](C)(C)C)[C:9]=2[CH:10]=1.[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][NH:41][C:40](=[O:44])[CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CS(C)=O>[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][N:41]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:7]=4[N:8]([CH2:11][O:12][CH2:13][CH3:14])[C:9]=3[CH:10]=2)[C:40](=[O:44])[CH:39]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(c3ccc(Br)cc3n2COCC[Si](C)(C)C)C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOCn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 130 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
To a solution of tert-butyl 7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.66 g, 1.9 mmol) in DMF (8 mL) was added NaH (60% weight dispersion in mineral oil, 113 mg, 2.82 mmol) followed by SEMCl (0.50 mL, 2.8 mmol). The reaction was stirred at room temperature until complete. The reaction was quenched with H2O, and the aqueous mixture was extracted with CH2Cl2. The organic phase was washed with H2O and brine and dried over Na2SO4. After filtration and concentration, the residue was dried under vacuum to give tert-butyl 7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate, which and used directly in the next step. To a mixture of tert-butyl 7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.75 g, 1.6 mmol), 4-benzyloxypyridone (0.31 g, 1.6 mmol), 8-hydroxyquilinine (34 mg, 0.23 mmol), K2CO3 (0.26 g, 1.9 mmol) and CuI (45 mg, 0.23 mmol) was added DMSO (6 mL). The reaction mixture was degassed and back-filled with N2. The reaction was stirred at 130° C. overnight. The mixture was cooled and filtered through a layer of Celite. The filtrate was diluted with CH2Cl2, washed with H2O and 5% aqueous LiCl and dried over Na2SO4. The organic solution was filtered and concentrated, and the residue was purified by flash column chromatography (silica gel, 5% CH3OH in CH2Cl2) to give the title compound as a yellow oil (0.12 g, 13%): 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J=8.5 Hz, 1H), 7.44-7.37 (m, 6H), 7.31 (d, J=7.5 Hz, 1H), 7.09 (m, 1H), 6.12 (s, 1H), 6.07 (d, J=6.5 Hz, 1H), 5.40 (s, 2H), 5.07 (s, 2H), 4.65 (m, 2H), 3.86 (m, 2H), 3.51 (t, J=8.0 Hz, 2H), 2.73 (m, 2H), 1.53 (s, 9H), 0.89 (t, J=8.0 Hz, 2H), −0.04 (s, 9H); ESI MS m/z 602 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6])[CH3:2].C([O-])(O)=O.[Na+].[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[NH:6][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=1[Cl:21])[CH3:2]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 2L round bottom flask was added 21 g (100 mmol) of (L)-tyrosine ethyl ester (1) (Bachem) and 500 mL of tetrahydrofuran (THF). The mixture was magnetically stirred at room temperature until dissolved, and 500 mL of aqueous NaHCO3 (0.5 M) was added. The mixture was cooled in an ice bath and 19.3 g (110 mmol) of 2-chlorobenzoyl chloride (Aldrich) was added slowly via a glass syringe. The ice bath was removed and the reaction was allowed to warm to room temperature with stirring. After 30 min., the reaction mixture was rotory evaporated under reduced pressure to remove the THF and the remaining aqueous bicarbonate solution was extracted twice with 400 mL ethyl acetate. The combined extracts were washed with 400 mL of satd. aqueous NaHCO3, 400 mL of 0.1 N HCl, 400 mL of water, and 400 mL of satd. aqueous NaCl. The remaining organic layer was dried over Na2SO4 and evaporated to dryness to afford ˜40 g of crude (2) as a pale yellow oil. The crude product (2) was recrystallized from ˜800 mL of boiling ethyl acetate/hexane (˜1:3) and cooled to 4° C. overnight. The resulting crystalline product was filtered and dried under a stream of nitrogen to afford 32 g (92% isolated yield) of purified (2). The N-(2-chlorobenzoyl)-(L)-tyrosine ethyl ester product (2) was confirmed by NMR and electrospray mass spectrometry (see attached) and judged >95% pure by HPLC and TLC (Rf=0.6, 1:1 ethyl acetate/hexane). The remaining 5% impurity (Rf=0.7) was identified as 2-chlorobenzoic acid by HPLC and TLC versus authentic material. Synthesis of Thiochloroformate Intermediate (3)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([Br:11])=[C:6]([OH:12])[CH:5]=1.Cl[CH2:15][C:16]([CH3:18])=[CH2:17]>CO>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH2:17][C:16]([CH3:18])=[CH2:15])[C:7]([Br:11])=[C:6]([OH:12])[CH:5]=1
Reactant: C=C(C)CCl
Reactant: COC(=O)c1cc(O)c(Br)c(O)c1
Solvent: CO
Product: C=C(C)COc1cc(C(=O)OC)cc(O)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
Na pieces (41.4 g, 1.82 mol) were added slowly to MeOH (3 L). The resulting mixture was stirred at room temperature for 30 min and then 4-bromo-3,5-dihydroxy-benzoic acid methyl ester (197a) (450 g, 1.82 mol) was added portion wise. The mixture was warmed to 60° C. 3-Chloro-2-methyl-propene (202.5 mL, 2 mol) was added drop wise. The mixture was refluxed for 6 h. TLC (petroleum ether/EtOAc=5/1) showed the reaction was complete. The solvent was removed and the residue was purified by column chromatography (petroleum ether/EtOAc=15/1) to give the title compound (75 g, 13.6% yield). 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1 H), 7.06 (s, 1 H), 5.72 (s, 1 H), 5.11 (s, 1 H), 4.96 (s, 1 H), 4.47 (s, 2 H), 3.84 (s, 3 H), 1.79 (s, 3 H).