Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][SH:10])=[CH:7][CH:6]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23](OS(C)(=O)=O)[CH2:22][C@H:21]1[C:30](=[O:32])[NH2:31])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+]>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23]([S:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH2:22][C@H:21]1[C:30](=[O:32])[NH2:31])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1ccc(CS)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(N)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CS[C@@H]2C[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
330 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling, to a solution of 1.18 g of p-methoxybenzyl mercaptan in 25 ml of dry dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. At the end of this time, 2.14 g of (2S, 4R)-1-(t-butoxycarbonyl)-2-carbamoyl-4-methanesulfonyloxypyrrolidine [prepared as described in step (3) above] were added to the mixture, which was then stirred at room temperature for 3 hours. The reaction mixture was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography through silica gel (eluted with a 2:3 by volume mixture of cyclohexane and ethyl acetate) to afford 1.94 g of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]\[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1>CO.N1CCCCC1>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]\[CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: COc1ccc2c(c1/C=C\CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1/C=C\CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
A solution of tert-butyl (Z)-4-(3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)allyl)piperidine-1-carboxylate (0.0802 g, 0.207 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0302 g, 0.207 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-((Z)-3-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}allyl)piperidine-1-carboxylate (0.0724 g, 68%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:18]=[CH:17][C:7]2[NH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[O:11][CH2:12][C:6]=2[CH:5]=1.[CH3:19][N:20]([CH3:39])[C:21]1[CH:38]=[CH:37][C:24]([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][C@H:29](OS(C)(=O)=O)[CH2:28]2)=[CH:23][CH:22]=1>CCCCCC.CS(C)=O>[F:3][C:4]1[CH:18]=[CH:17][C:7]2[N:8]([C@@H:30]3[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][C:24]4[CH:23]=[CH:22][C:21]([N:20]([CH3:19])[CH3:39])=[CH:38][CH:37]=4)[CH2:31]3)[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[O:11][CH2:12][C:6]=2[CH:5]=1
Reactant: CN(C)c1ccc(CCN2CC[C@H](OS(C)(=O)=O)C2)cc1
Reactant: Fc1ccc2c(c1)COc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CN(C)c1ccc(CCN2CC[C@@H](N3c4ccc(F)cc4COc4ccccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% sodium hydride (100 mg, 2.5 mmol) was washed with hexane in argon stream and then suspended in dimethyl sulfoxide (8 ml), and the obtained suspension was stirred at room temperature for 30 minutes. 2-Fluoro-5,11-dihydrodibenzo[b,e][1,4]oxazepine (538 mg, 2.5 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes and then at 50° C. for additional 40 minutes. A solution of (S)-1-(4-dimethylaminophenethyl)-3-methanesulfonyloxypyrrolidine (312 mg, 1.0 mmol, prepared by a method disclosed in International Patent No. 0040570A1) in dimethyl sulfoxide (3 ml) was added dropwise to the obtained solution, and they were stirred at 50° C. for 13 hours. The reaction mixture was poured into ice/water and then subjected to the extraction with ethyl acetate. The organic layer was dried and then the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (3:1) and then with hexane and ethyl acetate (1:1) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-2-fluoro-5,11-dihydro-5-[1-(4-dimethylaminophenethyl)pyrrolidin-3-yl]dibenzo-[b,e][1,4]oxazepine in the form of a light yellow oily substance (140 mg, 32%).
Reaction SMILES: [C:1]1([NH:7][C:8](=[NH:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:17][C:18](=O)[CH2:19][C:20]([OH:22])=[O:21].C[Si](C)(C)N[Si](C)(C)C.[CH2:33](N(CC)CC)[CH3:34]>C(OCC)(=O)C>[C:1]1([N:7]2[CH:17]=[C:18]([CH2:19][C:20]([O:22][CH2:33][CH3:34])=[O:21])[N:15]=[C:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CC(=O)CCl
Reactant: N=C(Nc1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cn(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
A mixture of 9.8 g of N-phenylbenzamidine [prepared according to Org. Synth. Coll. IV: 769 (1963)], 8.25 g of the ethyl ester of 4-chloroacetoacetic acid, 100 ml of hexamethyldisilazane, and 7 ml of triethylamine was heated overnight under reflux. The mixture was then diluted with 400 ml of ethyl acetate and washed five times with saturated sodium bicarbonate solution as well as water. After extraction of the aqueous phases with methylene chloride, the combined organic phases were dried and concentrated under vacuum. The residue was purified by column chromatography on silica gel with methylene chloride/0.2-1% isopropanol as well as toluene/40% ethyl acetate as the eluent. Yield: 9.1 g (59%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12](O)[CH2:13][CH2:14][OH:15].C(OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>>[CH2:1]([O:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCOCc1ccccc1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: CCN(CC)CC
Solvent: O
Product: c1ccc(COCC2OCCCO2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 58 %

Procedure:
A mixture of benzyloxyacetaldehyde (3.6 g, 24 mmol), 1,3-propanediol (5.2 ml, 72 mmol), triethyl orthoformate (4 ml, 24 mmol), and p-toluenesulfonic acid monohydrate (414 mg, 2.45 mmol) was stirred at room temperature for 17 hours. To the reaction mixture, triethylamine (669 μl, 4.8 mmol) was added, which was concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to obtain the title compound (2.9 g, yield: 58%) as a light yellow oil.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[CH3:25][C:26]1[CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][N:33]([CH2:36][C:37](=[O:44])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]2=[O:45])[S:28][C:27]=1[C:46]([OH:48])=O.[NH2:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1>>[CH3:25][C:26]1[CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][N:33]([CH2:36][C:37](=[O:44])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]2=[O:45])[S:28][C:27]=1[C:46]([NH:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)=[O:48]
Reactant: Cc1cc(N2CCN(CC(=O)c3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(CC(=O)c3ccccc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 61 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 3-methyl-5-(2-oxo-3-(2-oxo-2-phenylethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a cream solid in 61% yield: mp 174-176° C.; 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.48 (d, J=4.4 Hz, 1H), 7.97-7.92 (m, 2H), 7.67 (d, J=7.8 Hz, 1H), 7.64-7.57 (m, 1H), 7.51-7.44 (m, 2H), 7.23 (dd, J=7.8, 4.4 Hz, 1H), 6.24 (t, J=5.7 Hz, 1H), 6.11 (s, 1H), 4.72 (s, 2H), 4.56 (d, J=5.7 Hz, 2H), 3.93-3.85 (m, 2H), 3.75-3.67 (m, 2H), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 193.8, 163.5, 156.2, 149.2, 148.7, 142.4, 141.6, 135.5, 134.6, 134.2, 134.0, 128.9, 127.9, 123.5, 112.6, 50.0, 43.0, 42.7, 41.1, 16.1; MS (ES+) m/z 435.4 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2([CH2:15]O)[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:23])CC)C.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]2([CH2:15][F:23])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1COCC(CO)(c2cccc(Br)n2)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COCC(CF)(c2cccc(Br)n2)N1
Reaction time: 4 h

Procedure:
To a solution of 5-(6-bromo-pyridin-2-yl)-5-hydroxymethyl-morpholin-3-one (2.8 g, 9.756 mmol) in dry THF (30 ml), diethylamino sulfur trifluoride (4.72 g, 29.268 mmol) was added at rt and stirring continued for 4 h. Na2CO3 was then added to the resultant reaction mixture and stirred for further 30 min. The reaction mixture was concentrated under reduced pressure and the product was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhy. Na2SO4 and concentrated under reduced pressure to obtain crude compound as gummy residue. Purification of the crude product with 45% ethyl acetate in hexane solvent system furnished the title compound as off-white solid. Yield=1.15 g (40%). TLC (70% ethyl acetate in hexane) Rf=0.49; LCMS: RtH7=0.383, [M+1]+=289 and 289; HPLC RtH9=3.27 min (84%); 1H NMR (400 MHz, CDCl3): δ 7.62 (t, 1H), 7.49 (dd, 1H), 7.32 (d, 1H), 7.09 (br. s, 1H), 4.92 (dd, 1H), 4.52 (dd, 1H), 4.32-4.17 (m, 3H), 3.98-3.93 (dd, 1H); 19F NMR (376.2 MHz): δ−255.65 (t, 1F).
Reaction SMILES: [CH2:1]([CH:3]([C:7](Cl)=[O:8])[C:4](Cl)=[O:5])[CH3:2].[CH2:10]([NH2:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C([N:21](CC)CC)C>C(Cl)Cl>[CH2:1]([CH:3]([C:7]([NH2:21])=[O:8])[C:4]([NH:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: CCCCCCCCN
Solvent: ClCCl
Product: CCCCCCCCNC(=O)C(CC)C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a stirred, cooled (0° C.) solution of 21.5 g (0.143 mol) of ethyl malonyl chloride in 250 mL of methylene chloride under nitrogen was added dropwise a solution of 18.47 g (0.143 mol) of n-octylamine in 100 mL of methylene chloride over a half-hour period. After the addition the reaction mixture was allowed to warm to room temperature and stir for 2 h. The reaction mixture was cooled to 0° C. and a solution of 20 mL (0.143 mol) of triethylamine in 100 mL of methylene chloride was added dropwise over 2 h. Additional methylene chloride was added to keep the slurry of salts stirring efficiently. After the addition the reaction mixture was kept cold in a freezer. After 12 h the reaction was allowed to warm to room temperature and was immediately washed with water three times to remove the salts. The organic layer was dried over magnesium sulfate and filtered. Removal of solvent gave 29.5 g (84% yield) of ethyl N-n-octylmalonamide as a pale yellow solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1.BrC[CH2:18][CH:19]1[CH2:21][CH2:20]1.Cl>C1COCC1>[CH:19]1([CH2:18][C:9]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]2)[CH2:21][CH2:20]1
Reactant: O=C(O)C1CCC1
Reactant: BrCCC1CC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)C1(CC2CC2)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 124.5 %

Procedure:
To a solution of LDA (100 ml, 2.0 M THF solution) in THF (100 ml) was added dropwise over a period of 20 minutes at 0° C., a solution of cyclobutane carboxylic acid (10 g, 0.1 mol) in THF (15 ml). The resulting mixture was stirred at RT for 2 h then bromoethylcyclopropane (15 g, 0.11 mol) was added dropwise and the mixture was stirred at RT. overnight. To the reaction mixture was added 2N HCl and the mixture was extracted with EtOAc. The organic layer was washed with water and brine to afford the title compound as light yellow oil (19.2 g), which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][CH:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1)[CH3:6].O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][CH:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[CH3:6]
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(Oc1ccccc1F)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 74.4 %

Procedure:
A mixture of methyl 4-(1-(2-fluorophenoxy)ethyl)benzoate (0.45 g, 1.6 mmol), lithium hydroxide monohydrate (0.57 g, 13.6 mmol), tetrahydrofuran (15 mL), methanol (5 mL) and water (5 mL) was stirred at 20° C. for 4 hours. The mixture was turned to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give 4-(1-(2-fluorophenoxy)ethyl)benzoic acid (0.31 g, 74%).
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]2[S:8][C:9]([CH3:20])=[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[C:6]=2[CH:5]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:35]([S:40]([NH2:43])(=[O:42])=[O:41])[CH2:36][CH2:37][CH2:38][CH3:39].C1CCN2C(=NCCC2)CC1>CN(C)C=O>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[CH2:11][C:10]1[C:6]2[CH:5]=[C:4]([C:1](=[O:3])[NH:43][S:40]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=[O:42])=[O:41])[CH:22]=[CH:21][C:7]=2[S:8][C:9]=1[CH3:20]
Reactant: Cc1sc2ccc(C(=O)O)cc2c1Cc1ccc(Cl)cc1Cl
Reactant: CCCCCS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2sc(C)c(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
In the same manner as in Example 1, 5-carboxy-3-(2,4-dichlorobenzyl)-2-methylbenzo[b]thiophene (440 mg, 1.25 mmol) was suspended in dimethylformamide and carbonyldiimidazole (305 mg, 1.88 mmol) was added, which was followed by stirring at room temperature for 1 hr. Then, 1-n-pentanesulfonamide (284 mg, 1.88 mmol) and DBU (286 mg, 1.88 mmol) were added and the mixture was refluxed under heating at 100° C. for 15 hr. The reaction mixture was concentrated under reduced pressure and water and 3N hydrochloric acid were added to acidify the mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residual oil was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/2) and recrystallized from 2-propanol-n-hexane to give 3-(2,4-dichlorobenzyl)-2-methyl-5-(1-n-pentanesulfonylcarbamoyl)benzo[b]thiophene (410 mg, 68%) as colorless crystals.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:6]([F:22])=[C:7]([O:14]CC2C=CC=CC=2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)(=O)[CH3:2]>C(O)C.C(O)(=O)C.[Pd]>[F:22][C:6]1[C:7]([OH:14])=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[C:1]([CH3:2])[NH:11]2
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc2c(F)c(O)ccc2[nH]1
Reaction time: 2 h

Procedure:
A solution of 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene (300 mg, 0.99 mmol) in ethanol (10 ml) and acetic acid (1 ml) containing 10% palladium on charcoal (30 mg) was hydrogenated at 2 atmospheres pressure for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in ethyl acetate and the organic layer was washed with aqueous sodium hydrogen carbonate, brine and evaporated to give 4-fluoro-5-hydroxy-2-methylindole. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (3/7) to give 4-fluoro-5-hydroxy-2-methylindole (63 mg, 30%). Analytical data as above.
Reaction SMILES: F[NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[F:15][C:16]1C=[CH:22][CH:21]=[CH:20][C:17]=1C#N.[CH3:24][N:25]([CH:27]=O)C>O>[F:15][C:16]1[CH:17]=[CH:20][CH:21]=[CH:22][C:24]=1[NH:25][C:27]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[C:3]#[N:2]
Reactant: FNc1ccccc1
Reactant: N#Cc1ccccc1F
Reactant: CN(C)C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1ccccc1Nc1ccccc1F
Temperature: 23 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
A solution of fluoroaniline (6.8 ml, 71 mmol) in DMF (100 ml) was treated with potassium tert-butoxide (12.7 g, 113 mmol) and then with 2-fluorobenzonitrile (7.5 ml, 71 mmol) that was slowly added to the stirring reaction with a syringe and stirred at 23° C. for 16 h. The reaction mixture was diluted with H2O (100 mL) and extracted with ethyl ether (3×50 mL), dried with (MgSO4), and evaporated. Flash chromatography (SiO2, 2-100% dichloromethane/heptane) provided 2-[(2-fluorophenyl)amino]benzonitrile (8.4 g 56%) as an orange solid:
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:21])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:20])=[CH:11]/[CH2:12][S:13][CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C1COCC1>[N:29]1([C:35]([NH:19][C@@H:15]([CH2:14][S:13][CH2:12]/[CH:11]=[C:10](\[CH3:20])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:21])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:22])[CH3:1])[C:16]([OH:18])=[O:17])=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: O=C(Cl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)N1CCOCC1)C(=O)O
Temperature: 25 °C
Reaction time: 47 h
Yield: 27 %

Procedure:
In 100 mL round bottom flask, S-trans, trans-farnesyl-L-cysteine (325 mg, 1.0 mmole) and potassium carbonate (1.3 g, 10 mmole) were dissolved in THF (50 mL). 4-morpholine carbonyl chloride (160 mg, 1.2 mmole) was added. The reaction mixture was stirred at room temperature for 47 hours. THF was removed by rotary evaporation. The crude material was washed with water (10 mL) and 1N HCl solution (10 mL). The remaining crude material was purified by preparative HPLC (120 mg, 27% yield) to yield Compound H: 1H-NMR (500 MHz, CDCl3) δ 1.60 (bs, 6H), 1.66 (s, 3H), 1.67 (s, 3H), 1.95-2.12 (m, 8H), 2.94-3.02 (m, 2H), 3.10-3.20 (m, 2H), 3.40-3.44 (m, 4H), 3.71 (t, J=4.8 Hz, 4H), 4.55 (dd, J=6.3, 11.6 Hz, 1H), 5.09 (t, J=6.9 Hz, 2H), 5.19 (t, J=7.6 Hz, 1H). 13C-NMR (125 MHz, CDCl3): δ 16.0, 16.2, 17.7, 25.7, 26.4, 26.7, 29.9, 33.0, 39.6, 39.7, 44.0, 53.0, 66.3, 119.4, 123.7, 124.3, 131.3, 135.4, 140.2, 157.7, 174.1; ES-MS: mass calcd for Chemical Formula: C23H38N2O4S 438.3 (M+). Found (M+Na) m/z 461.4.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH:14]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1.C(N(CC)CC)C>ClCCl>[O:11]=[CH:12][CH2:13][CH:14]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC(CCO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CC=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of oxalyl chloride (488 μl, 5.58 mmol) in 40 ml dichloromethane at −78° C. was added dimethyl sulfoxide (792 μl, 11.16 mmol) dropwise by syringe. The mixture was stirred for 15 minutes at −78° C. when a solution of tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (936 mg, 4.65 mmol) in 10 ml dichloromethane was added dropwise by syringe. After 1 hour at −78° C., triethylamine (3241 μl, 23.25 mmol) was added and the suspension was warmed to room temperature and stirred for an additional hour. The mixture was quenched with water (25 ml) and saturated aqueous potassium carbonate (10 ml), stirred vigorously and separated. The aqueous layer was extracted with dichloromethane (2×20 ml) and the combined organic layers were dried with magnesium sulfate, filtered and concentrated. The crude material was flash chromatographed to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[I:30][C:31]1[CH:32]=[C:33]([OH:42])[CH:34]=[C:35]([C:37]2[CH:41]=[CH:40][S:39][CH:38]=2)[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.CC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:42][C:33]2[CH:34]=[C:35]([C:37]3[CH:41]=[CH:40][S:39][CH:38]=3)[CH:36]=[C:31]([I:30])[CH:32]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: Oc1cc(I)cc(-c2ccsc2)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a mixture of 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.99 g, 6.35 mmol), 3-iodo-5-thiophen-3-yl-phenol (1.92 g, 6.35 mmol), and potassium carbonate (1.75 g, 12.7 mmol) were added N,N-dimethylformamide (50 mL) and acetone (100 mL) at room temperature. The resulting suspension was heated to reflux for 2 days. Then, the reaction mixture was cooled to room temperature and diluted with water (200 mL). The organic compound was extracted into ethyl acetate (3×100 mL) and the combined organic extracts were washed with water (300 mL) and brine solution (200 mL). The organic layers were dried over anhydrous magnesium sulfate and filtration of the drying agent and concentration of the solvent gave the crude product which was purified by using an ISCO 80 g column, eluting with 0-20% ethyl acetate in hexanes to afford 4-{3-[6-(3-iodo-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (4.39 g, 99%) as a colorless oil: ES(+)-HRMS m/e calculated for C33H41IO6S (M+Na)+ 715.1561, found 715.1561.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][C:15]3[NH:14][C:13](=[O:17])[CH:12]=[CH:11][C:10]=3[C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:9]1[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][C:15]2[NH:14][C:13](=[O:17])[CH:12]=[CH:11][C:10]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: O=C1CC(c2ccccc2)Cc2[nH]c(=O)ccc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: N=C(N)NN=C1CC(c2ccccc2)Cc2[nH]c(=O)ccc21
Yield: 79.7 %

Procedure:
A mixture of 7-phenyl-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.19 g), aminoguanidine hydrochloride (0.092 g), concentrated hydrochloric acid (0.04 ml), water (0.04 ml) and ethanol (20 ml) was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 5-guanidinoimino-7-phenyl-1,2,5,6,7,8-hexahydroquinolin-2-one hydrochloride (Compound 99) (0.21 g) as colorless crystals.