Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:26]([OH:28])=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:29]([C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])[C@H:30]([C:32]([NH:34][C@H:35]([C:37](ON1C(=O)CCC1=O)=[O:38])[CH3:36])=[O:33])[CH3:31]>CN(C=O)C.C(OCC)(=O)C>[NH:29]([C:47]([O:49][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:48])[C@H:30]([C:32]([NH:34][C@H:35]([C:37]([NH:1][C@H:2]([C:26]([OH:28])=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:38])[CH3:36])=[O:33])[CH3:31]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The tripeptide Z-Ala-Ala-Asn(Trt)-OH (2) was prepared according to the following procedure: To a stirred solution of H-Asn(Trt)-OH (4.97 g, 13.28 mmol, obtained from Bachem) in dry DMF (25 ml) a solution of Z-Ala-Ala-OSu (5.2 g, 13.28 mmol) in dry DMF (20 ml) was added and stirred for 14 h at room temperature. The solvent was evaporated in vacuo by using an oil pump. The obtained crude compound was dissolved in ethyl acetate (100 ml), washed with 1 N HCl (2×30 ml) and water (30 ml). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the tripeptide as a white solid (7.95 g, 92%) of m.p. 196° C. The peptide was used without further purification.—1H NMR (500 MHz, DMSO-d6): δ=1.18 (d, 3 H, J=7.1 Hz, CH3), 1.22 (d, 3 H, J=7.0 Hz, CH3), 2.62-2.88 (m, 2 H, CHCH2), 4.06-4.12 (m, 1 H, CH), 4.31-4.37 (m, 1 H, CH), 4.46-4.50 (m, 1 H, CH), 4.98-5.04 (m, 2 H, CH2O), 7.15-7.35 (m, 20 H, aryl-H). —MS(EI) m/z (%): 651 [M+H+], 673 [M+Na+], 689 [M+K+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([CH:20]=[CH:21][N:22]=3)[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:23]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([I:23])=[CH:21][N:22]=3)[N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3nccn3n2)CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3ncc(I)n3n2)CC1

Procedure:
A solution of 4-imidazo[1,2-b]pyridazin-6-yl-piperazine-1-carboxylic acid tert-butyl ester (3.6 g, 11.8 mmol) and N-iodosuccinimide [516-12-1] (3.1 g, 13.1 mmol) in DMF (120 mL) was stirred under N2 blanket at ambient temperature for 2 h then partitioned between 5% (w/v) aqueous sodium metabisulfite and ethyl acetate. The organic phase was washed with brine, dried (CaSO4), evaporated, and crystallized from ethyl acetate/heptane to provide a white crystalline powder, mp. 203-204° C. (dec.). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 9H) 3.45-3.51 (m, 4H) 3.51-3.58 (m, 4H) 7.19 (d, J=9.92 Hz, 1H) 7.61 (s, 1H) 7.85 (d, J=9.92 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 27.89, 45.06, 70.52, 78.95, 110.55, 125.66, 137.28, 137.71, 153.73, 154.88. LRMS (ESI) m/z 430.0 (M+H)]+, calc'd for C15H20IN5O2: 429.26.
Reaction SMILES: C(O)(=O)CCCCCCCCCCCCCCCCC.[C:21]1(C(O)=O)[C:38]2=[C:39]3[C:28]([C:29]4[C:40]5[C:33](=[CH:34][CH:35]=[CH:36][C:37]2=5)[CH:32]=[CH:31][CH:30]=4)=[CH:27][CH:26]=[C:25](C(O)=O)[C:24]3=[C:23](C(O)=O)[C:22]=1C(O)=O.C(O)(=O)CCCCCCCCCCCCCCCCC.C(N)CCCCCCCCCCCCCCCCC.Cl>[K].C1(C(O)=O)C2=C3C(C4C5C(=CC=CC2=5)C=CC=4)=CC=C(C(O)=O)C3=C(C(O)=O)C=1C(O)=O.[OH-].[K+].C(O)(C)C>[CH:36]1[C:37]2=[C:40]3[C:29]([C:28]4[C:39]5[C:24](=[CH:23][CH:22]=[CH:21][C:38]2=5)[CH:25]=[CH:26][CH:27]=4)=[CH:30][CH:31]=[CH:32][C:33]3=[CH:34][CH:35]=1
Reactant: O=C(O)c1c(C(=O)O)c2c(C(=O)O)ccc3c4cccc5cccc(c(c1C(=O)O)c23)c54
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCCN
Agent: Cl
Solvent: CC(C)O
Product: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54

Procedure:
27.4 parts of crude perylenetetracarboxylic dianhydride in the form of the potassium salt of perylenetetracarboxylic acid are dissolved in aqueous potassium hydroxide solution as described in Example 1. To this solution are added 2 parts of stearic acid, dissolved in 60 parts by volume of 1% potassium hydroxide solution. With stirring, the alkaline perylenetetracarboxylic acid/stearic acid solution is added dropwise in the course of 15 minutes at 60° C. to a suspension consisting of 1.4 parts of MgCl2.6H2O, 0.7 parts of stearylamine, 35 parts by volume of about 37% aqueous hydrochloric acid and 60 parts by volume of isopropanol. The formation of the anhydride imide is brought to completion by stirring the acid suspension for 31/2 hours at reflux temperature. The red pigment suspension is then filtered at about 70° C. The filter cake is washed neutral with cold water and dried in a vacuum cabinet at 80° C., affording 29.8 parts of a perylene pigment with properties as good as those of the pigment of Example 1.
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].C(N(CC)CC)C.[CH:30]1(C=O)[CH2:32][CH2:31]1.C(O)=O>C(#N)C>[CH2:30]1[CH:32]([CH2:1][N:2]2[C@@H:12]3[CH2:13][C:14]4[CH:19]=[CH:18][C:17]([OH:20])=[C:16]5[O:21][CH:6]6[C:7]([CH2:9][CH2:10][C@:11]3([OH:22])[C@:5]6([C:15]=45)[CH2:4][CH2:3]2)=[O:8])[CH2:31]1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Reactant: O=CC1CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=CO
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)C1O5
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.4 %

Procedure:
Into a round bottom flask was charged noroxymorphone (2.00 g, 0.007 moles), triethylamine (3.52 g, 0.035 mole, 4.85 mL), acetonitrile (15 mL), and cyclopropanecarboxaldehyde (0.98 g, 0.014 mole, 0.92 mL). The mixture was stirred for about 5 minutes at room temperature then >96% formic acid (4.0 g, 0.87 mole, 3.28 mL) was added dropwise. After stirring the mixture for 15 minutes at room temperature, dichloro(p-cymene)Ru(II) dimer (10 mg, 0.000014 moles) was added. The mixture was then stirred at room temperature for about 24 hours. HPLC indicated the reaction was complete. The reaction mixture was evaporated to a thick oil, and distilled water (5.0 mL) was added. The pH was adjusted to 9.4 using 29% NH3/H2O where a precipitate formed. The mixture was stirred overnight at room temperature. The precipitate was filtered, washed with distilled water (10 mL), and dried at 90° C. for about 24 hours. The dried precipitate yielded naltrexone base (2.28 g, 95% yield).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:11]=2[O:10][CH2:9][C:8]1=[O:24])=[N+]=[N-].[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[C:35](O)=[O:36].Cl.CN(C)CCCN=C=NCC>C(O)C.CN(C=O)C.C(OCC)(=O)C.[C].[Pd]>[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[C:35]([NH:1][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:11]=2[O:10][CH2:9][C:8]1=[O:24])=[O:36]
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: [N-]=[N+]=NCCCN1C(=O)COc2c(OC3CCCCO3)cccc21
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(NCCCN1C(=O)COc2c(OC3CCCCO3)cccc21)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 51.7 %

Procedure:
A solution of 4-(3-azidopropyl)-3-oxo-8-(tetrahydropyran-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine (1.0 g) in ethanol (10 ml) was added to a suspension of 10% palladium carbon (containing 50% water) (100 mg) in ethanol (20 ml), and the mixture was stirred at room temperature for 22 hours under a hydrogen atmosphere. The reaction solution was filtered with Celite, and the solvent was distilled off under reduced pressure to obtain a crude amine. The thus-obtained crude amine was dissolved in DMF (10 ml), and 2-naphthalenecarboxylic acid (780 mg) and 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (865 mg) were added to the resultant solution, and the mixture was stirred at room temperature for 19 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by column chromatography (silica gel:ethyl acetate/n-hexane=3:2) to obtain the object compound (717 mg, yield 55%).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([OH:35])=[C:13]2[C:18](=[CH:19][N:20]=1)[N:17]([CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:16](=[O:28])[C:15]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:14]2)=[O:10])C.[OH-].[Na+].CO.C1COCC1>C([O-])(O)=O.[Na+]>[CH:22]1([CH2:21][N:17]2[C:18]3[C:13](=[C:12]([OH:35])[C:11]([C:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([OH:36])=[O:3])=[O:10])=[N:20][CH:19]=3)[CH:14]=[C:15]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:16]2=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCOC(=O)CCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
A mixture of 4-[(1-cyclohexylmethyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-butyric acid ethyl ester (39 mg, 0.079 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 18 mg of the title compound. MS: (+) m/z 464.41 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]([OH:22])[CH:20]=[CH2:21])[CH:5]=[C:6]([Br:18])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[Br:1][C:2]1[CH:3]=[C:4]([C:19](=[O:22])[CH:20]=[CH2:21])[CH:5]=[C:6]([Br:18])[C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1
Reactant: C=CC(O)c1cc(Br)c(OCc2ccc(OC)cc2)c(Br)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: C=CC(=O)c1cc(Br)c(OCc2ccc(OC)cc2)c(Br)c1
Reaction time: 2 h
Yield: 40.2 %

Procedure:
To a stirred solution of 1-(3,5-dibromo-4-(4-methoxybenzyloxy)phenyl)prop-2-en-1-ol (D) (2.45 g, 5.73 mmol) in chloroform (35 mL) under nitrogen was added manganese(IV) oxide (6.47 g, 74.4 mmol) and the mixture was stirred vigorously for 2 h. The mixture was filtered through glass fibre paper and the solid was washed with more chloroform (5×15 mL). The combined filtrates were evaporated and the residue was purified by flash chromatography (silica gel, 15% EtOAc/pet. ether) to afford 0.9804 g (40%) of the title compound as a white solid. 1H NMR δ (ppm) (CDCl3): 3.84 (3 H, s), 5.04 (2 H, s), 5.99 (1 H, dd, J=10.56, 1.51 Hz), 6.47 (1 H, dd, J=17.06, 1.52 Hz), 6.91-6.97 (2 H, m), 7.07 (1 H, dd, J=17.06, 10.57 Hz), 7.52 (2 H, d, J=8.41 Hz), 8.12 (2 H, s).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:18])[CH:10]=2)=[C:5](S(C)(=O)=O)[C:4]([CH3:23])=[N:3]1.CN1CCCC1=[O:30].[OH-].[Na+]>O>[OH:30][C:5]1[C:4]([CH3:23])=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:18])[CH:10]=1
Reactant: CN1CCCC1=O
Reactant: Cc1nn(C)c(=O)c(-c2cn(C)c3ccccc23)c1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nn(C)c(=O)c(-c2cn(C)c3ccccc23)c1O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a 20 ml volume two-necked flask, 2,6-dimethyl-4-(1-methyl-1H-indol-3-yl)-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-203)-(13)-28) (0.30 g), N-methyl-2-pyrrolidone (1.17 ml), and an aqueous solution of sodium hydroxide (0.14 g) in water (0.6 ml) were added under a nitrogen atmosphere, and stirred at 70° C. for 2 hours. The reaction mixture was added to iced water, and washed with ethyl acetate. The pH of the resulting aqueous layer was adjusted to 5 with cold dilute hydrochloric acid under ice-cooling. The precipitated solids were collected by filtration, washed with water, and dried to give 0.18 g of 5-hydroxy-2,6-dimethyl-4-(1-methyl-1H-indol-3-yl)-2,3-dihydro-3-pyridazinone ((1-201)-(12)-10).
Reaction SMILES: CN(C)C([S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:16])([CH3:15])[CH2:13][CH3:14])=[CH:8][CH:7]=1)=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:16][C:12]([C:9]1[CH:8]=[CH:7][C:6]([SH:5])=[CH:11][CH:10]=1)([CH3:15])[CH2:13][CH3:14]
Reactant: CCC(C)(C)c1ccc(SC(=O)N(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCC(C)(C)c1ccc(S)cc1
Temperature: 25 °C
Yield: 26.4 %

Procedure:
Reflux a mixture of 1-dimethylcarbamoylthio-4-(1,1-dimethyl-propyl)-benzene (520 mg, 2.1 mmol) and K2CO3 (1.28 g, 9.3 mmol) in methanol (40 mL) for 6 h. Cool to room temperature and concentrate in vacuo. Suspend the residue in water and acidify to pH 1 with 1M aqueous HCl. Extract the aqueous phase with EtOAc (3×40 mL). Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 97:3) to obtain the title compound (100 mg, 26%).
Reaction SMILES: [O:1]=[C:2]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][C:5]([O:7][CH2:8]C(C)C)=[O:6].[OH-].[Na+]>CO>[O:1]=[C:2]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: CCCCCCC(=O)CCC(=O)OCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCC(=O)CCC(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the resulting isobutyl 4-oxodecanoate were added 1 L of methanol and 250 g of 25% sodium hydroxide, and the mixture was stirred at 25° C. for 1 hour, followed by distilling off methanol in vacuo. Subsequently, thereto were added 2 L of water and 1 L of toluene. The resulting mixture was stirred at room temperature for 1 hour and then allowed to stand to separate the water phase. To the water phase were added 175 g of concentrated hydrochloric acid and 1.8 L of toluene. The resulting mixture was stirred for 10 minutes and then allowed to stand to separate the organic phase. Toluene in the organic phase was distilled off in vacuo and 1 L of toluene and 47.5 mL of concentrated sulfuric acid were added. The resulting mixture was heated under reflux for 1 hour and then cooled to 25° C. Thereto was gradually added 155 g of sodium hydrogencarbonate followed by stirring for 10 minutes at 25° C. Methanol was distilled off in vacuo and then 3 L of water and 1.8 L of toluene were added. The resulting mixture was stirred for 10 minutes at room temperature and then allowed to stand to separate the organic phase. Toluene in the organic phase was distilled off, yielding methyl 4-oxodecanoate (a compound in which R17 represents an n-pentyl group, and R18 represents a methyl group in the above formula (12)). Gas chromatographic analysis showed that the yield of methyl 4-oxodecanoate relative to isobutyl 4-oxodecanoate was 95%.
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][C@@H:11]2[N:12]([CH3:22])[C:13]3[C:14]([C:20]#[N:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[Br-].[CH2:26]([Zn+])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][N:12]1[C:13]2[C:18](=[CH:17][C:16]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:15][C:14]=2[C:20]#[N:21])[C@@H:10]2[CH2:9][NH:8][CH2:24][CH2:23][C@H:11]12
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: [Zn+]CCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CN1c2c(C#N)cc(CCc3ccccc3)cc2[C@@H]2CNCC[C@@H]21

Procedure:
Following the general procedure for Examples 127–146, the title compound was prepared (8 mg, 25%) as a light yellow oil using (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 40 mg, 0.10 mmol), phenethylzinc bromide (0.5 M in THF, 2.5 mole equivalent) and Pd(PPh3)4 (0.06 mole equivalent).: MS (ESI): 318 (base, M+H).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH3:7])[CH:3]=[CH2:4].[N+:8]([O-])([OH:10])=[O:9]>>[CH3:1][C:2]([CH2:5][CH2:6][CH3:7])=[CH:3][CH2:4][N+:8]([O-:10])=[O:9]
Reactant: C=CC(C)CCC
Reactant: O=[N+]([O-])O
Product: CCCC(C)=CC[N+](=O)[O-]
Temperature: 65 °C

Procedure:
3-Methyl-1-hexene (22.2 mL, 0.15 moles) was mixed with concentrated nitric acid (18 mL, 0.28 moles) at room temperature. With rapid stirring the solution was heated to 65° C. for 3 hours. The heat was removed and the solution stirred an additional 30 min. The organic layer was separated and washed with a saturated sodium chloride solution (3×15 mL) then dried over magnesium sulfate. Vacuum distillation (20 Torr, 28° C.) removed unreacted 3-methyl-1-hexene. A yellow oil remained. Gas chromatography and IR spectroscopy indicate both cis- and trans-3-methyl-1-nitro-2-hexene are present along with a small amount of 1-nitro-2-hexanol. These structures were confirmed by IR and GC analysis.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:40]2[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH:41]=2)O1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C([O-])(O)=O.[Na+].CC([O-])=O.CC([O-])=O.[Pd+2]>[NH:43]1[CH2:42][CH:41]=[C:40]([C:2]2[N:7]=[C:6]([O:8][C:9]3[C:14]4[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=4[CH:12]=[CH:11][CH:10]=3)[CH:5]=[C:4]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[N:3]=2)[CH2:45][CH2:44]1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(Cl)n3)cccc2s1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: COCCOC
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(C4=CCNCC4)n3)cccc2s1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A mixture of N-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide (300 mg, 0.645 mmol, Example 7(d)), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (216 mg, 0.70 mmol, Aldrich), Pd(OAc)2 (7.2 mg, 0.03 mmol, Aldrich), PPh3 (17 mg, 0.065 mmol) and 2N aqueous Na2CO3 (0.65 mL) in 1,2-dimethoxyethane (3.0 mL) was heated at 120° C. in a microwave synthesizer for 25 min. The reaction mixture was cooled to room temperature, diluted with saturated aqueous solution of NaHCO3 (10 mL) and extracted with EtOAc (2×50) mL. The combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The yellow solid residue was dissolved in DCM (4 mL) and treated with trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 1.5 h and the volatiles were evaporated in vacuo. The residue was partitioned between 1N HCl (5 mL) and Et2O (5 mL). The aqueous layer was separated, basified with 2N NaOH, and extracted with EtOAc (3×15 mL). The combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel column chromatography (gradient 1-25% (2N NH3 in MeOH)/EtOAc) afforded the title compound as an off-white solid. MS (ESI, pos. ion.) m/z: 512 (M+1).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:9])=[O:8].C(N(CC)CC)C.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([F:27])=[C:22]([CH:26]=1)[C:23](Cl)=[O:24].CO.C(Cl)(Cl)Cl>C(#N)C.C(Cl)(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([F:27])=[C:22]([CH:26]=1)[C:23]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:9])=[O:8])=[O:24]
Reactant: O=C(Cl)c1cc(Cl)ccc1F
Reactant: NC(=O)c1cccn1N
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NC(=O)c1cccn1NC(=O)c1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
1-Amino-1H-pyrrole-2-carboxylic acid amide (1.25 g, 10 mmole) was partially dissolved in 45 ml acetonitrile, triethylamine (1.39 ml, 10 mmole) was added followed by dropwise addition of 5-chloro-2-fluorobenzoyl chloride (1.93 g, 10 mmole) in 3 ml chloroform. The reaction mixture was stirred at room temperature overnight, the solvent was removed under vacuum and the residue was taken up in chloroform, washed with 10% sodium bicarbonate, water, and dried over sodium sulfate (anh.). A solid crystallized from solution upon standing. Additional product was obtained by chromatographing the filtrate on silica gel eluting with 3% methanol/chloroform. 600 mg of product was obtained (yield: 21%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[F:9])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:23][CH2:24][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=2)[CH2:26][CH2:27]1
Reactant: Oc1ccccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3F)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccccc3F)c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluorophenol and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 535.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH:13]([OH:23])[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClC(Cl)=C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([N:8]1[C:12]([C:13](=[O:23])[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(CCCc1ccccc1)c1cncn1Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)=C(Cl)Cl
Product: O=C(CCCc1ccccc1)c1cncn1Cc1ccccc1
Reaction time: 4 h

Procedure:
The mixture of 27,5 g of 1-benzyl-5-(1-hydroxy-4-phenylbutyl)-1H-imidazole and 34,4 g of manganese dioxide in 550 ml of tetrachloroethylene is refluxed stirring for four hours. The reaction mixture is filtered and the filtrate is evaporated to dryness. The product is crystallized from ethyl acetate as hydrochloride salt.