Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17]OCC.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:16][CH3:17])[CH:3]=1
Reactant: CCOCCBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cccc(Br)c1

Procedure:
In DMF (96 ml) was dissolved 3-bromophenol (12 g). To the mixture was added potassium carbonate (12.5 g) and then 2-bromoethylethylether (6.7 ml), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=12/1) to give 1-bromo-3-ethoxybenzene (11.6 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C:7]([S:10][C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH:16]([NH2:21])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[C:7]([S:10][C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH:16]([NH:21][C:32](=[O:34])[CH3:33])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1ccc2c(c1)CCC(N)C2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC1CCc2cc(SC(C)(C)C(=O)OC(C)(C)C)ccc2C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
To 2-(6-amino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester (4.7 g; 14.6 mmol), dissolved in CH2Cl2 (25 mL), is added DIEA (3.3 mL; 18.9 mmol) and the reaction mixture is cooled to 0° C. Acetyl chloride (1.25 mL; 17.5 mmol) is added dropwise at a rate to maintain the temperature between 0-5° C. The reaction was allowed to warm to RT and stirred for 16 h. The reaction was diluted with CH2Cl2, washed with H2O, dried over Na2SO4 and evaporated under reduced pressure. The crude oil was purified by flash chromatography (SiO2) eluting with a hexanes-EtOAc gradient to afford 1.7 g (32%) of 2-(6-acetylamino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.[CH:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][C:32]([CH3:38])=[C:33]([CH2:35][CH2:36]O)[N:34]=2)=[CH:26][CH:25]=1)([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([O:15][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH:20]([CH3:21])[CH3:22])=[CH:25][CH:26]=3)[O:31][C:32]=2[CH3:38])=[CH:8][CH:7]=1
Reactant: CCOC(Cc1ccc(O)c2ccsc12)C(=O)OC
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccc(OC(C)C)cc3)oc2C)c2ccsc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-benzo[b]thiophen-7-yl)-propionic acid methyl ester was reacted with 2-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-yl]-ethanol [PCT Int. Appl. (2000), WO0008002A1] in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-isopropoxy-phenyl-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-propionic acid as light yellow amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([O:13]C)=[O:12])[CH2:7][CH2:6]1)=[O:4].[OH-].[K+].O>CO>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)OC)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
trans-Cyclohexane-1,4-dicarboxylic acid dimethyl ester (34.2 g, 0.171 mol) was dissolved in 400 mL of anhydrous methanol and the solution brought to reflux. Slowly (dropwise), a solution of KOH (11.2 g, 0.171 mol, 85% purity) in dry methanol was added to the refluxing solution. The solution continued to reflux for 5 hours, and was then cooled and concentrated under reduced pressure to give a white solid. Water was added to dissolve most of the solid, and the aqueous mixture was washed with ether (3×) in a separatory funnel. The aqueous layer was brought to pH ˜6, the resulting white precipitate was collected via filtration and washed (1×) with a small amount of water. Air drying afforded trans-cyclohexane-1,4-dicarboxylic acid monomethyl ester as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:18][CH:19]1[CH2:22][CH2:21][CH2:20]1)[CH:13]([OH:17])[C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:24]1[C:29](=O)[CH2:28][CH2:27]C1=O.C(Cl)CCl.C1(N)CC1>C(Cl)Cl>[CH:19]1([CH2:18][CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:13]([OH:17])[C:14]([NH:24][CH:29]2[CH2:27][CH2:28]2)=[O:16])[CH2:22][CH2:21][CH2:20]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(NC(CC1CCC1)C(O)C(=O)O)OCc1ccccc1
Agent: NC1CC1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NC(CC1CCC1)C(O)C(=O)NC1CC1)OCc1ccccc1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To a solution of 3-(benzyloxycarbonylamino)-4-cyclobutyl-2-hydroxybutanoic acid (600 mg, 1.95 mmol) in DCM (20 mL) was added HOSu (337 mg, 2.93 mmol), EDC (562 mg, 2.93 mmol). After stiffing for 1 hour, cyclopropylamine (223 mg, 3.9 mmol) was added to the above mixture. The product was extracted with EtOAc. The combined organic layer was then washed with HCl (1N), water, NaHCO3, and brine and then concentrated in vacuo to afford benzyl 1-cyclobutyl-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-ylcarbamate (530 mg). (M+1) 347.
Reaction SMILES: COC(=O)[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)[C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[Cl-].[Na+]>CS(C)=O.O>[CH:7]1([C:5](=[O:6])[CH2:4][C:13]2[CH:14]=[CH:15][C:16]([I:19])=[CH:17][CH:18]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)C(C(=O)C1CCCCC1)c1ccc(I)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(Cc1ccc(I)cc1)C1CCCCC1
Temperature: 150 °C
Yield: 96.1 %

Procedure:
According to a modified literature procedure (Collins, I. et al J. Med. Chem. 2002, 45, 1887–1900) a solution of 5.06 g (13.1 mmol) of 3-cyclohexyl-2-(4-iodo-phenyl)-3-oxo-propionic acid methyl ester in 80 mL of dimethylsulfoxide (DMSO) was added a solution of 1.53 g (26.2 mmol) of sodium chloride (NaCl) in 5.8 mL of water (H2O), and the resulting mixture was heated at 150° C. for 3 h during which time a white solid formed. The reaction mixture was cooled to rt, poured into 500 mL of water, and extracted thoroughly with ethyl acetate. The combined organic extracts were washed with water (3 times), brine, dried over sodium sulfate and concentrated to give 4.13 g (96% yield) of desired 1-cyclohexyl-2-(4-iodo-phenyl)-ethanone as a yellow solid as indicated by 1H NMR (containing small traces of impurities). The product was used without any further purification in the next step.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH:6]([C:24]1[CH:25]=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:7][C:8](=[O:23])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:21][CH2:20][CH2:19][NH:18][C:17]=2[N:22]=1)C.[OH-].[Na+].Cl>CCO>[N:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[C:24]([CH:6]([NH:7][C:8](=[O:23])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][CH2:20][CH2:19][NH:18][C:17]=3[N:22]=2)[CH2:5][C:4]([OH:34])=[O:3])[CH:25]=1
Reactant: CCOC(=O)CC(NC(=O)CCCCc1ccc2c(n1)NCCN2)c1cnc2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC(NC(=O)CCCCc1ccc2c(n1)NCCN2)c1cnc2ccccc2c1

Procedure:
A solution of 5-8 (0.141 g, 0.305 mmol) and 1.0 N NaOH solution (0.367 mL, 0.367 mmol) in EtOH (1.5 mL) was stirred overnight. The reaction was neutralized by adding 1.0 N HCl solution (0.0.367 mL, 0.367 mmol) then concentrated. Preparative HPLC followed by lyophilization yielded a yellow solid.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[Si](C)(C)C.Cl[C:26]([O:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[O:34][C:35](=[O:37])[CH3:36])=[O:27]>ClCCl>[C:35]([O:34][C@@H:30]1[CH2:31][CH2:32][CH2:33][C@H:29]1[O:28][C:26]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:27])(=[O:37])[CH3:36]
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: CC(=O)O[C@@H]1CCC[C@H]1OC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1CCC[C@H]1OC(=O)NCC1(CC(=O)O)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
In a separate reaction flask, to a stirred solution of gabapentin (1.8 g, 10 mmol) and triethylamine (4.3 mL, 31 mmol) in dichloromethane (100 mL) at 0° C. under nitrogen atmosphere, was added dropwise a solution of chlorotrimethylsilane (2.6 mL, 21 mmol) in dichloromethane (10 mL). After stirring for 30 min at 0° C., 2(R)-acetoxycyclopent-1(R)-yl chloroformate was added dropwise into the reaction mixture. The resulting mixture was stirred at 0° C. for 2 h and then at room temperature for 2 h (monitored by TLC). The reaction mixture was then concentrated in vacuo and the resulting residue was poured into cold water (50 mL), acidified to about pH 5.0 using 0.1 N HCl, then extracted using ethyl acetate (2×50 mL). The combined extracts were washed with brine (40 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified using flash chromatography on silica gel using hexane/ethyl acetate (2:1) as eluant to afford 2.0 g (84%) of compound 48 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ1.31-1.78 (14H, m); 2.03-2.04 (5H, m); 2.31 (2H, s); 3.20 (2H, t, J=6.4 Hz); 5.07-4.97 (2H, m), 5.20 (1H, broad s). MS (ESI): m/z=340.25 (M−H−).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][O:19][CH2:20][CH3:21].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][O:19][CH2:20][CH3:21])=[C:4]([Cl:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOc1ccc(Br)cc1Cl
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a mixture of 4-bromo-2-chlorophenol (15.92 g) and potassium carbonate (15.9 g) in DMF (100 ml) was added at room temperature 2-bromoethylethyl ether (9.51 ml), and the mixture was stirred at 60° C. for 18 hours. To the mixture was added water, and the mixture was extracted with diethylether. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give pale yellow oil of 4-bromo-2-chloro-1-(2-ethoxyethoxy)benzene (21.76 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[N:14]([CH3:16])[C:13]3[C:12](=[O:17])[N:11]([CH3:18])[CH2:10][CH2:9][C:8]=3[C:7]=2[C:6]([C:19]([OH:21])=[O:20])=[CH:5][CH:4]=1.[CH:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24](O)[CH:23]=1.CCN=C=NCCCN(C)C.Cl.O>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:1][O:2][C:3]1[C:15]2[N:14]([CH3:16])[C:13]3[C:12](=[O:17])[N:11]([CH3:18])[CH2:10][CH2:9][C:8]=3[C:7]=2[C:6]([C:19]([O:21][C:24]2[CH:23]=[CH:22][C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=2)=[O:20])=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(C(=O)O)c2c3c(n(C)c12)C(=O)N(C)CC3
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2c3c(n(C)c12)C(=O)N(C)CC3

Procedure:
A solution of 8-methoxy-2,9-dimethyl-1-oxo-1,2,3,4-tetrahydro-β-carboline-5-carboxylic acid (from step 5) (1 mmol), p-nitrophenol (1.5 mmol), EDCl (1.5 mmol) and DMAP (0.1 mmol) in dry THF was stirred at r.t. for 18 h. Minimum water was then added and the precipitated p-nitrophenylester was filtered and washed with water and dried (50-60%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[CH3:16][NH:17][CH3:18]>C1COCC1>[CH3:16][N:17]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])[CH3:18]
Reactant: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: CNC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl 4-(bromomethyl)-3-nitrobenzoate (100 mg) in THF (5 mL) was added dimethyl amine (2 mL, 2 M in THF) and the resulting reaction mixture was stirred at room temperature overnight. The solvent was then removed to afford methyl 4-((dimethylamino)methyl)-3-nitrobenzoate which was carried on to the next step without further purification.
Reaction SMILES: [NH2-].[Na+].[CH3:3][CH:4]([CH3:8])[C:5](=[O:7])[CH3:6].[CH3:9][O:10][CH:11]([CH3:16])[C:12](OC)=[O:13].O>C(O)(=O)C>[CH3:9][O:10][CH:11]([C:12](=[O:13])[CH2:6][C:5](=[O:7])[CH:4]([CH3:8])[CH3:3])[CH3:16]
Reactant: COC(=O)C(C)OC
Reactant: CC(=O)C(C)C
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(C)C(=O)CC(=O)C(C)C
Reaction time: 0.25 h
Yield: 51.6 %

Procedure:
In a 200 mL-volume flask equipped with a stirrer, a thermometer and a dropping funnel was placed 5.15 g (132 mmol) of sodium amide, and the flask was purged with argon. Then, 80 mL of toluene was placed in the flask. Subsequently, 12.0 g (139.3-mmol) of 3-methyl-2-butanone was slowly dropped into the flask, and the resulting mixture was stirred for 15 minutes. Into the flask was further dropped 5.65 g (47.8 mmol) of methyl 2-methoxy-propionate (prepared by the method of Reference Example 1), and the mixture was stirred for 30 minutes for carrying out a reaction. After the reaction was complete, 50 mL of water was placed in the flask under cooling with ice. The aqueous portion was taken out, neutralized with acetic acid, and subjected to extraction with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and distilled under reduced pressure (41° C., 27 Pa) to give 4.25 g (yield: 52%) of 2-methoxy-6-methyl-3,5-heptanedione as colorless liquid.
Reaction SMILES: OP([O-])(O)=O.[K+].[Br:7][C:8]1[CH:9]=[N:10][S:11][C:12]=1[N:13](C(OCC(Cl)(Cl)Cl)=O)[C@H:14]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17]>C1COCC1.C(OCC)(=O)C.[Zn]>[Br:7][C:8]1[CH:9]=[N:10][S:11][C:12]=1[NH:13][C@H:14]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1sncc1Br
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)Nc1sncc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 164.6 %

Procedure:
A 1.0 M aqueous solution of KH2PO4 (1.8 mL) was added dropwise over several minutes to zinc dust (1.13 g, 17.8 mmol) and methyl N-(4-bromoisothiazol-5-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate (172 mg, 0.356 mmol) in THF (3.2 mL) with rapid stirring at rt for 30 min. The slurry was diluted with ethyl acetate and filtered (Celite), and the filtrate was washed with water, then saturated sodium chloride solution and dried (Na2SO4). Solvent removal in vacuo afforded 180 mg of methyl N-(4-bromoisothiazol-5-yl)leucinate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:22]([O:23][CH3:24])=[N:21][CH:20]=[CH:19][C:10]=3[C:11]3[C:17]([CH3:18])=[N:16][O:15][C:12]=3[CH2:13][N:14]=2)=[CH:4][CH:3]=1.[C:25]1(O)[CH:30]=[CH:29]C=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:22]([O:23][C:24]4[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=4)=[N:21][CH:20]=[CH:19][C:10]=3[C:11]3[C:17]([CH3:18])=[N:16][O:15][C:12]=3[CH2:13][N:14]=2)=[CH:4][CH:3]=1
Reactant: COc1nccc2c1C(c1ccc(Cl)cc1)=NCc1onc(C)c1-2
Reactant: Oc1ccccc1
Product: Cc1noc2c1-c1ccnc(Oc3ccccc3)c1C(c1ccc(Cl)cc1)=NC2

Procedure:
A procedure similar to 6-(4-chlorophenyl)-7-methoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepine (Compound 170) was followed, except that phenol was used instead of methanol. LC/MS m/z 402 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J=5.40 Hz, 1H), 7.56 (d, J=5.40 Hz, 1H), 7.41 (s, 4H), 7.31 (tt, J=2.20, 8.00 Hz, 2H), 7.14 (tt, J=1.40, 7.50 Hz, 1H), 6.79 (d, J=8.00 Hz, 2H), 5.31 (d, J=13.3 Hz, 1H), 4.25 (d, J=13.29 Hz, 1H), 2.58 (s, 3H).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:19])[CH3:4].Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([CH3:31])=[CH2:30])[CH:22]=1>>[ClH:1].[CH3:4][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:8][C:7]1([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([CH3:31])=[CH2:30])[CH:22]=1)[OH:19])[CH3:2]
Reactant: CN(C)CC1CC(Oc2ccccc2)CCC1=O
Reactant: C=C(C)COc1cccc(Br)c1
Agent: Cl
Product: C=C(C)COc1cccc(C2(O)CCC(Oc3ccccc3)CC2CN(C)C)c1
Yield: 51 %

Procedure:
The base of compound (27) was reacted with 1-bromo-3-(2-methyl-allyloxy)-benzene corresponding to the conditions described in Example 1. The base obtained was purified with ether via a silica gel column and was taken up in 2-butanone. After adding trimethylchlorosilane/water, compound (31) was obtained in a yield of 51% theoretical. melting point: 193° C.-195° C.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Si:13]([O:20][C@@H:21]1[CH2:26][C@H:25]2[C@H:27]3[C@H:36]([CH2:37][CH2:38][C@:23]2([CH3:24])[C@H:22]1[OH:40])[C:35]1[CH:34]=[CH:33][C:32]([OH:39])=[CH:31][C:30]=1[CH2:29][CH2:28]3)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>>[Si:13]([O:20][C@@H:21]1[CH2:26][C@H:25]2[C@H:27]3[C@H:36]([CH2:37][CH2:38][C@:23]2([CH3:24])[C@H:22]1[O:40][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:35]1[CH:34]=[CH:33][C:32]([O:39][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:31][C:30]=1[CH2:29][CH2:28]3)([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]2(C)[C@H]1O
Reactant: CCCCCCCCCC(=O)Cl
Product: CCCCCCCCCC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]2OC(=O)CCCCCCCCC

Procedure:
With decanoyl chloride, under the conditions described in Example 3(a), 750 mg of 16α-(tert-butyldimethylsilyloxy)-1,3,5(10)-estratriene-3,17β-diol yields 1.10 g of 16α-(tert-butyldimethylsilyloxy)-3,17β-didecanoyloxy-1,3,5(10)-estratriene.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=C(O)c1ccc(-c2ccc(O)c(F)c2)cc1
Reactant: CCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1F
Yield: 86.2 %

Procedure:
To 75 ml of an aqueous solution of 13% potassium hydroxide were added 120 ml of ethanol and 10 g (43.1 mmol) of the above 3'-fluoro-4'-hydroxybiphenyl-4-carboxylic acid, which were refluxed for 30 minutes and added with 25.0 g (129 mmol) of 1-bromooctane and then refluxed for 15 hours. After the air cooling, the precipitated crystal was filtered and recrystallized with acetic acid containing 5% hydrochloric acid and further with acetic acid to obtain 12.8 g (yield: 86.4%) of 3'-fluoro-4'-octyloxybiphenyl-4-carboxylic acid. This compound had the following properties:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH:15][CH:16]([CH3:19])[CH2:17][NH2:18]>>[OH:15][CH:16]([CH3:19])[CH2:17][NH:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(O)CN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Product: CC(O)CNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with 2-hydroxypropylamine to provide 4-(2-hydroxypropylamino)-3-nitroquinoline.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=2[O:8][CH2:9][CH:10]=[C:11]2[CH2:16][CH2:15][CH:14]([C:17]#[N:18])[CH2:13][CH2:12]2)[N:3]=[CH:2]1.C([O-])([O-])=[O:24].[K+].[K+].OO>CS(C)=O>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=2[O:8][CH2:9][CH:10]=[C:11]2[CH2:12][CH2:13][CH:14]([C:17]([NH2:18])=[O:24])[CH2:15][CH2:16]2)[N:3]=[CH:2]1
Reactant: O=C([O-])[O-]
Reactant: N#CC1CCC(=CCOc2ccccc2-c2c[nH]cn2)CC1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)C1CCC(=CCOc2ccccc2-c2c[nH]cn2)CC1
Reaction time: 16 h
Yield: 42 %

Procedure:
To a solution of 4-(2-(2-(1H-imidazol-4-yl)phenoxy)ethylidene)cyclohexanecarbonitrile (90 mg, 0.307 mmol) in DMSO (3 mL) at room temperature was added K2CO3 (42 mg, 0.307 mmol) followed by H2O2 (30%, 0.7 mL, 6.14 mmol). After stirring for 16 h, the reaction was concentrated and the crude product was purified by flash column chromatography (silica gel, 10% MeOH/DCM) to yield the desired amide as a white solid (40 mg, 0.129 mmol, 42%). 1H NMR (DMSO-d6): 1.41-1.51 (m, 4H), 1.71-1.82 (m, 4H), 2.17-2.20 (m, 1H), 4.05-4.11 (m, 2H), 6.66 (d, 1H, J=10.5 Hz), 6.93 (t, 1H, J=7.5 Hz), 7.02 (d, 1H, J=8.1 Hz), 7.11 (d, 1H, J=7.2 Hz), 7.15 (s, 2H), 7.51 (s, 1H), 7.68 (s, 1H), 8.08 (d, 1H, J=7.5 Hz), 12.05 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH3:14]COC=O>C(N(CC)CC)C>[Br:8][C:7]1[C:2]2[N:1]=[CH:14][NH:13][S:10](=[O:12])(=[O:11])[C:3]=2[CH:4]=[C:5]([Br:9])[CH:6]=1
Reactant: CCOC=O
Reactant: Nc1c(Br)cc(Br)cc1S(N)(=O)=O
Solvent: CCN(CC)CC
Product: O=S1(=O)NC=Nc2c(Br)cc(Br)cc21

Procedure:
2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by Method G (using ethylformiat and a catalytic amount of triethylamine). M.p. 289–292° C.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11]([Cl:13])=[N:10][CH:9]=[N:8][C:7]=2[CH:6]=[CH:5]1)[CH:2]=[CH2:3].[Br:14]N1C(=O)CCC1=O>C1COCC1>[CH2:1]([N:4]1[C:12]2[C:11]([Cl:13])=[N:10][CH:9]=[N:8][C:7]=2[C:6]([Br:14])=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1ccc2ncnc(Cl)c21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: C=CCn1cc(Br)c2ncnc(Cl)c21
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a room temperature solution of 5-allyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (960 mg, 5 mmol, 1 equiv.) in 100 mL of THF was added N-bromosuccinimide (1.1 g, 6 mmol, 1.1 equiv.). After 1 hour, the THF was concentrated and the residue diluted with water and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The solids were sonicated in water/saturated aqueous NaHCO3/MeOH and filtered to provide 1.26 g (93%) of 5-allyl-7-bromo-4-chloro-5H-pyrrolo[3,2-d]pyrimidine as an off-white solid which was used without further purification.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[N:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])[S:11][N:10]=1.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>O1CCCC1>[CH2:19]([NH:21][C:22]([N:10]1[C:9](=[O:8])[N:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])[S:11]1)=[O:23])[CH3:20]
Reactant: CCCCOc1nc(O)ns1
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCOc1nc(=O)n(C(=O)NCC)s1

Procedure:
1 ml of triethylamine was added to a solution of 17.4 g of 3-hydroxy-5-n-butoxy-1,2,4-thiadiazole in 150 ml of tetrahydrofuran and then 12 ml of ethyl isocyanate were added dropwise with stirring. The mixture was stirred for 2 hours at 20° C and was concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel and elution with a 7-3 benzene-ethyl acetate mixture yielded 18.5 g of 2-(N-ethylcarbamoyl)-5-n-butoxy-1,2,4-thiadiazole-3-one.