Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([O:30][CH3:31])[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:32].C(N(CCOC1C=CC(CCC(O)=O)=CC=1)C)CCCCCCCCCCC>>[ClH:32].[CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([O:30][CH3:31])[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)OC)c(OC)c1
Agent: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)O)cc1
Agent: Cl
Product: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)O)c(OC)c1
Yield: 62 %

Procedure:
3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-methoxyphenyl]propanoic acid, methyl ester (468 mg, 1.07 mmol) was saponified as described in the preparation of 3-[4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl]propanoic acid, hydrochloride and afforded the title compound (280 mg, 62%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C1(C)C=CC=CC=1>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:1]([C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)([CH3:3])[CH3:2])=[CH:14][CH:13]=1
Reactant: C=C(C)c1ccc(O)cc1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 134.0 grams (1.0 mole) of p-isopropenylphenol and 186.0 grams (2.0 moles) of aniline was stirred and heated to 150° C. To the mixture was added 5.0 grams of a solution obtained by adding 1.28 grams of 10% hydrochloric acid to 93 grams of aniline and stirring the mixture well. The reaction was carried out for 3.0 hours (10,800 s) at the 150° C. reaction temperature. The reaction product was cooled to 120° C. then 350 milliliters of toluene was added. The product was then cooled to 25° C. and the solid precipitated product was recovered by filtration. The crude product was slurried into 350 milliliters of methanol and heated to a reflux then maintained for 15 minutes (900 s). After cooling, the product was recovered by filtration and dried under vacuum to yield 4-(1-(4-aminophenyl)-1-methylethyl)phenol as a white powder. B. Synthesis of a Phenolic Functional Maleimide
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:23])=[CH:17][CH2:18][CH2:19][C:20](=O)[CH3:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:20]([CH3:21])[CH2:19][CH2:18][CH:17]=[C:16]([CH3:23])[CH3:15])=[CH:6][CH:7]=1
Reactant: CC(=O)CCC=C(C)C
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: CC(C)=CCCC(C)Nc1c(C)noc1-c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 6-methyl-hept-5-en-2-one.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[C:21]([CH2:22][OH:23])=[CH:20][C:11]3[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][O:14][C:10]=3[C:9]=2[F:24])[CH2:5][C@H:4]([CH3:25])[O:3]1>ClCCl.[O-2].[O-2].[Mn+4].O=[Mn]=O>[CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[C:21]([CH:22]=[O:23])=[CH:20][C:11]3[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][O:14][C:10]=3[C:9]=2[F:24])[CH2:5][C@H:4]([CH3:25])[O:3]1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO)cc12
Agent: O=[Mn]=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)cc12
Reaction time: 8 h
Yield: 81.9 %

Procedure:
Ethyl 6-((2R,6S)-2,6-dimethylmorpholino)-7-fluoro-5-(hydroxymethyl)benzo[d]isoxazole-3-carboxylate (Intermediate 262, 430 mg, 1.22 mmol) was dissolved in dichloromethane (100 ml). Manganese dioxide (2122 mg, 24.41 mmol) was added and the reaction was stirred vigorously overnight. The reaction was incomplete so an additional 2 g of MnO2 was added and the reaction was stirred for 4 hours. The reaction was still incomplete so an additional 2 g of MnO2 was added and the reaction was stirred overnight. The reaction was filtered through celite and washed through with DCM and ethyl acetate. The filtrate was concentrated to give the title compound (350 mg, 0.999 mmol, 82%)
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH3:16])[C:13](=O)[NH:14][C:10]=2[C:9]([O:17][CH3:18])=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:13]1[N:12]([CH3:16])[C:11]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=[C:9]([O:17][CH3:18])[C:10]=2[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(CC)c1ccc(OC)c2[nH]c(=O)n(C)c12
Product: CCC(CC)c1ccc(OC)c2nc(Cl)n(C)c12
Temperature: 110 °C
Reaction time: 6 h
Yield: 60 %

Procedure:
A mixture of 7-(1-ethylpropyl)-4-methoxy-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (190 mg, 0.765 mmol) in phosphorous oxychloride (2.14 mL) was stirred at 110° C. for 6 h. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate 10:1-1:1) and crystallized from ethyl acetate/n-hexane to afford the title compound as colorless crystals (123 mg, 60%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH2:12][NH:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH2:12][N:13]2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: c1ccc(CN2CC3CCNC3C2)cc1
Product: CCOC(=O)N1CCC2CN(Cc3ccccc3)CC21

Procedure:
7-Benzyl-2,7-diazabicyclo[3.3.0]octane (Example Jc) is reacted with ethyl chloroformate analogously to Example Oa) to give ethyl 7-benzyl-2,7-diazabicyclo[3.3.0]octane-2-carboxylate, and this is then debenzylated hydrogenolytically analogously to Example Jd). A colorless oil of boiling point 90° C./0.1 mbar is obtained.
Reaction SMILES: C(S[C:5]1[C:10]([F:11])=[CH:9][N:8]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[C:7](=[O:17])[N:6]=1)C=C.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH2:26]>CO>[F:11][C:10]1[C:5]([NH:26][CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[F:18])=[N:6][C:7](=[O:17])[N:8]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:9]=1
Reactant: NCc1ccccc1F
Reactant: C=CCSc1nc(=O)n(-c2ccsc2)cc1F
Solvent: CO
Product: O=c1nc(NCc2ccccc2F)c(F)cn1-c1ccsc1
Temperature: 100 °C
Yield: 69 %

Procedure:
To a solution of 4-(allylthio)-5-fluoro-1-(thiophen-3-yl)pyrimidin-2(1H)-one (140 mg, 0.66 mmol) in MeOH (1 mL) was added (2-fluorophenyl)methanamine (50 mg, 0.186 mmol). The reaction mixture was heated at 100° C. for 30 min in a microwave. After cooling, the mixture was purified by preparative thin layer chromatography to give 5-fluoro-4-(2-fluorobenzylamino)-1-(thiophen-3-yl)pyrimidin-2(1H)-one (41 mg, 20%) as a white solid: mp 75-78° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.16 (d, J=7.0 Hz, 1H), 7.66 (dd, J=3.2, 1.4 Hz, 1H), 7.57 (dd, J=5.2, 3.2 Hz, 1H), 7.43-7.13 (m, 5H), 4.63 (d, J=5.5 Hz, 2H); ESIMS m/z 320 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[F:11].S(Cl)(Cl)=O.[Cl-].[NH4+].C([NH:21]C(C)C)(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:21])=[O:7])=[CH:4][C:3]=1[F:11]
Reactant: CC(C)NC(C)C
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc(Br)c(F)c1
Temperature: 70 °C
Reaction time: 75 h
Yield: 62.8 %

Procedure:
To a suspension of 4-bromo-3-fluorobenzoic acid (1.50 g, 6.85 mmol) in toluene (10 mL) at ambient temperature was added thionyl chloride (1.0 mL, 14 mmol). The reaction mixture was heated at 70° C. for 17 hours, at reflux for 1.5 hours, stirred at ambient temperature for 75 hours, heated at reflux for 18.5 hours, and stirred at ambient temperature for 1 hour. Thionyl chloride (0.25 mL, 3.4 mmol) was added and the reaction mixture was heated at reflux for 3 hours. The reaction was cooled and condensed to an oily solid mixture. Toluene (10 mL), ammonium chloride (0.73 g, 14 mmol) and diisopropylamine (3.6 mL, 21 mmol) were added, and the mixture was stirred at ambient temperature for 17 hours, heated at 50° C. for 5 hours, then cooled to ambient temperature. The reaction mixture was partitioned between EtOAc (10 mL) and H2O (10 mL), separated, and the aqueous layer further extracted with EtOAc (15 mL). The combined organic extracts were washed with 1N HCl (20 mL), 1N NaOH (20 mL), brine (20 mL), dried (MgSO4), filtered, and concentrated to afford 4-bromo-3-fluorobenzamide (0.938 g, 63%) as a light-yellow solid which was carried on without further purification.
Reaction SMILES: Br[C:2]1[C:3]([Cl:32])=[CH:4][C:5]([O:30][CH3:31])=[C:6]([NH:8][C@@H:9]([CH3:29])[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]3)[CH2:14][CH2:13]2)=[O:11])[CH:7]=1.[CH:33]1(B(O)O)[CH2:35][CH2:34]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:32][C:3]1[C:2]([CH:33]2[CH2:35][CH2:34]2)=[CH:7][C:6]([NH:8][C@@H:9]([CH3:29])[C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]3)[CH2:16][CH2:17]2)=[O:11])=[C:5]([O:30][CH3:31])[CH:4]=1
Reactant: COc1cc(Cl)c(Br)cc1N[C@@H](C)C(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(C2CC2)cc1N[C@@H](C)C(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 61.5 %

Procedure:
A mixture of (S)-tert-butyl 3-(4-(2-((5-bromo-4-chloro-2-methoxyphenyl)amino)propanoyl)piperazin-1-yl)azetidine-1-carboxylate (700 mg, 1.32 mmol), cyclopropylboronic acid (114 mg, 1.32 mmol), Pd(OAc)2 (15 mg, 0.066 mmol), tricyclohexylphosphine (37 mg, 0.132 mmol), K3PO4.3H2O (974 mg, 4.62 mmol) in DMF (10 mL) and H2O (0.5 mL) was stirred under argon at 80° C. for 16 h. The mixture was allowed to cool to RT, and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (methanol/dichloroethane=1:100) to afford the desired product (400 mg, 62%). ESI-MS m/z: 493.2[M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[OH:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[CH2:24][OH:23])=[O:6]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Reactant: OCC1CCCCN1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)N1CCCCC1CO
Yield: 93.2 %

Procedure:
The procedure of Example 1 was repeated except that 6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid and 3.5 g of 2-hydroxymethylpiperidine were used as starting materials. 7.5 g (yield 94%) of the title compound was obtained as a colorless oil.
Reaction SMILES: [F-].[K+].CN1CCCC1.[F:9][C:10]([Si](C)(C)C)([F:12])[F:11].[Br:17][C:18]1[CH:23]=[C:22](I)[C:21]([F:25])=[CH:20][N:19]=1.N>[Cu](I)I>[Br:17][C:18]1[CH:23]=[C:22]([C:10]([F:12])([F:11])[F:9])[C:21]([F:25])=[CH:20][N:19]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Fc1cnc(Br)cc1I
Agent: I[Cu]I
Agent: CN1CCCC1
Agent: N
Product: Fc1cnc(Br)cc1C(F)(F)F
Reaction time: 0.33 h
Yield: 49.5 %

Procedure:
Copper iodide (1.51 g) and potassium fluoride (0.46 g) were subjected to a reduced pressure (1 Ton) using a vacuum pump, and were heated with a heat gun for 20 minutes while stirring slowly. Under the argon atmosphere, 13 ml of N-methylpyrrolidine and 1.13 g of trifluoromethyltrimethylsilane were added at room temperature, and a temperature was elevated to 50° C. over 20 minutes. After further stirring for 1 hour, 2 g of 2-bromo-5-fluoro-4-iodopyridine was added, and the mixture was stirred for 23 hours. After allowing to cool; the reaction solution was poured into a 12% aqueous ammonia solution, and the resultant solution was extracted with diethyl ether three times, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.8 g of 2-bromo-5-fluoro-4-trifluoromethylpyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16](I)=[N:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1([S:30]([O-:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Na+]>[Cu]I.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])=[N:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]nc(I)c23)CC1
Reactant: O=S([O-])c1ccccc1
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]nc(S(=O)(=O)c4ccccc4)c23)CC1
Temperature: 125 °C
Yield: 18 %

Procedure:
A mixture of 4-[4-(t-butoxycarbonyl)piperazin-1-yl]-3-iodo-1H-indazole (0.110 g, 0.257 mmol), sodium benzene sulfinate (0.068 g, 0.411 mmol), copper(I) iodide (0.073 g, 0.386 mmol) and N,N-dimethylformamide is added to a screw-capped test-tube with Teflon-lined septum. The tube is evacuated and backfilled with argon. This procedure is repeated twice, then the tube is heated to 125° C. for 4 h. The reaction mixture is cooled, partitioned between ethyl acetate and water and filtered through a pad of diatomaceous earth. The filtrate is separated. The organic phase is washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting crude material is purified by column chromatography (silica gel, 40:60 ethyl acetate/hexanes) to afford the title compound as a pale yellow foam, 0.022 g (18% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH3:13])=[O:4].C(O)C.O.C(=O)=O.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([N+:21]([O-:23])=[O:22])=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH3:13])=[O:4]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(F)cccc1NC(=O)CCl
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: Cc1c(F)ccc([N+](=O)[O-])c1NC(=O)CCl
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A solution of 2-chloro-N-(3-fluoro-2-methylphenyl)acetamide (47.2 g, 234 mmol) in conc. sulphuric acid (220 ml) was treated at ca. −20° C. (ethanol/water/CO2(s) bath) with conc. nitric acid (69%, 15.25 ml, 19 g, 235 mmol) over 30 minutes, keeping internal temperature ≦9° C. The reaction was complete at the end of the addition. The mixture was added to ice with vigorous stirring then left to stand overnight. Filtration, washing of the solid with water and drying afforded the product (54.6 g, 95%) containing ˜9% impurity.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]=1[O:16]CC1C=CC=CC=1)C.[OH-].[Na+]>O1CCOCC1.[C].[Pd]>[F:11][C:9]1[CH:8]=[C:7]([C:12]([F:13])([F:14])[F:15])[C:6]([OH:16])=[C:5]([CH:10]=1)[C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)c1cc(F)cc(C(F)(F)F)c1OCc1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cc(F)cc(C(F)(F)F)c1O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
4.28 g (12.3 mmol) of 2-benzyloxy-5-fluoro-3-(trifluoromethyl)-benzoic acid ethyl ester is dissolved in 20 ml of dioxane, 7.5 ml (I5 mmol) of 2N sodium hydroxide solution is added and it is stirred for 1 hour at 50° C. The reaction solution is then mixed with 200 mg of palladium-carbon (10%) and hydrogenated for 1 hour at normal temperature. The catalyst is then filtered off, the alkaline filtrate is mixed with 30 ml of water and extracted with dichloromethane. The aqueous phase is acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is dried on magnesium sulfate, filtered and evaporated to dryness. The crystalline residue is dried in a vacuum at 50° C. for 24 hours. 2.27 g (10.15 mmol)=82.5% of the theoretical yield is obtained. Melting range 76-83° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([C@@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC#C[Si](C)(C)C)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC#C[Si](C)(C)C)[C@@H](C=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (2S,3S)-2-(tert-butyldimethylsilyloxy)-1-hydroxy-6-(trimethylsilyl)hex-5-yn-3-ylcarbamate (1.83 g, 4.4 mmol) in DCM (20 mL) were added sodium bicarbonate-(1.5 g, 18 mmol) and Dess-MartinPeriodinane (2.4 g, 5.7 mmol) and the reaction was stirred at rt for 1 h. The mixture was quenched with sat NaHCO3 followed by the addition of sodium thiosulfate (3.5 g, 22 mmol) and stirred for an additional 1 h. The reaction was extracted with DCM and the combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated to afford a light yellow oil as tert-butyl (2S,3S)-2-(tert-butyldimethylsilyloxy)-1-oxo-6-(trimethylsilyl)hex-5-yn-3-ylcarbamate. MS m/z: 316.2 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][C:21]#[N:22].Cl>C(Cl)Cl>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:19]2[NH:15][C:16]([CH2:20][C:21]#[N:22])=[CH:17][CH:18]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N#CCc1ccc[nH]1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: N#CCc1ccc(C(=O)c2ccc(Cl)cc2)[nH]1
Temperature: 0 °C

Procedure:
To a chilled suspension of 26.80 g. (0.2 mole) of aluminum chloride in 110 ml. of methylene chloride is added dropwise 35 g. (0.2 mole) of p-chlorobenzoyl chloride. The mixture is added dropwise to a solution of 21.22 g. (0.2 mole) of pyrrole-2-acetonitrile in 125 ml. methylene chloride which is cooled externally with an ammonium chloride ice bath. After addition is complete, the reaction mixture is stirred for ten minutes at 0° C. and then poured into ice acidified with dilute hydrochloric acid. A solid precipitate, 5-(p-chlorobenzoyl)-pyrrole-2-acetonitrile, which is filtered off, washed with hot methanol and dried, m.p. 203-205° C.
Reaction SMILES: C([O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=O)C>Cl.C(O)C>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CC(=O)Oc1ccc(OC(C)C(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: CC(Oc1ccc(O)cc1)C(=O)O
Yield: 93.2 %

Procedure:
2-(4-Acetoxyphenoxy)propanoic acid (1.2 g, 5.3 mmol) is hydrolyzed by refluxing ethanol (15 mL) and 2 drops of concentrated hydrochloric acid (36%) for 2 hours. Ethanol is removed under reduced pressure to give 2-(4-hydroxyphenoxy)propanoic acid (0.9 g yield 93%): m.p. 136°-137.5° C., IR (KBr) 3265 (vs), 1707 (vs); 1H NMR (acetone-d6) delta 1.52 (d, J=6.8 Hz, 3H), 4.67 (q, J=6.8 Hz, 1H), 6.75 (M, 4H).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([C:21]([NH2:23])=[O:22])[C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([O:25][CH3:26])=[CH:12][C:13]=2[OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:30][C:31]#[N:32]>CN(C=O)C.C1COCC1.CCOC(C)=O>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([C:21]([NH2:23])=[O:22])[C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([O:25][CH3:26])=[CH:12][C:13]=2[O:24][CH2:30][C:31]#[N:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(O)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c2c1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(OCC#N)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c2c1
Reaction time: 4 h
Yield: 62.2 %

Procedure:
To a stirred solution of 9-benzyl-5-hydroxy-7-methoxycarbazole-4-carboxamide (0.75 g, 2.17 mmol) in DMF (76 ml) and THF (16 ml) and added 60% NaH (0.11 g, 2.71 mmol). After 15 min bromoacetonitrile (0.20 ml, 2.93 mmol) was added and the reaction was allowed to stir for 4 h. The reaction was diluted with EtOAc, extracted with water, then brine, dried (Na2SO4), and chromatographed on silica gel using a CH2Cl2-EtOAc-methanol gradient to give the titled compound (0.52 g, 63%). MS (ES+) 386
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[C:14]([NH:19][C:20](=O)[CH2:21][CH2:22][CH3:23])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].N1C=CC=CC=1>CCCCCCC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[S:27][C:20]([CH2:21][CH2:22][CH3:23])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCC(=O)Nc1cnc2cc(OCc3ccccc3)ccc2c1O
Solvent: c1ccncc1
Solvent: CCCCCCC
Product: CCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2s1
Yield: 59 %

Procedure:
A mixture of the N-(7-benzyloxy-4-hydroxyquinolin-3-yl)butyramide prepared in Part E (2.97 g, 8.83 mmol), P2S5 (1.96 g, 4.41 mmol), and pyridine was placed under a nitrogen atmosphere and heated to reflux. The resulting solution was cooled and the excess P2S5 was quenched slowly with 10% aqueous Na2CO3 (10 mL). The reaction mixture was partitioned between water (40 mL) and CH2Cl2 (100 mL). The organic layer was washed with 0.1 M aqueous HCl (50 mL), dried over MgSO4, filtered and concentrated to yield a brownish-yellow solid. The solid was treated with boiling heptane (40 mL) and filtered. The filtrate was allowed to cool and a solid formed. The light yellow solid was isolated by filtration and washed with cold heptane to provide 7-benzyloxy-2-propylthiazolo[4,5-c]quinoline (1.74 g, 59%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=1[Br:1]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(F)ccc1Br
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)ccc1Br
Reaction time: 0.08 h

Procedure:
To a solution of 2-bromo-5-fluorobenzoic acid (7.92 g, 36.2 mmol) in N,N-dimethylformamide (75 mL) was added potassium carbonate (6.91 g, 50.0 mmol) as a solid in one portion at room temperature. The mixture was stirred for 5 minutes and iodomethane (6.39 g, 45.0 mmol) was added in one portion. The mixture was stirred at ambient temperature for 22 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted with additional ethyl acetate (3×) and the combined organic extracts were washed successively with 10% potassium carbonate solution, water and brine. The organic portion was dried (Na2SO4) and concentrated to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.87 (s, 3H) 7.41 (td, J=8.56, 3.22 Hz, 1H) 7.65 (dd, J=8.99, 3.22 Hz, 1H) 7.81 (dd, J=9.16, 5.09 Hz, 1H); MS (+DCI/NH3) m/z 250.0 [M+NH4]+.