Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:2].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[F:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36]>CN(C)C=O>[F:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:2])=[O:36]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: OCCCCCCCCOCc1ccc(F)c(F)c1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCOCc1ccc(F)c(F)c1
Reaction time: 16 h
Yield: 60.8 %

Procedure:
Pyridinium dichromate (1.23 g, 3.27 mmol) was added at 0° C. to a solution of 8-(3,4-difluoro-benzyloxy)-octan-1-ol (254 mg, 0.93 mmol) in N,N-dimethylform-amide (2 mL). The reaction mixture was allowed to reach room temperature over 16 h, then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2, heptane-[ethyl acetate/formic acid 100:1] gradient) afforded 8-(3,4-difluoro-benzyloxy)-octanoic acid (162 mg, 61%). Colorless oil, m/e=285.1 ([M−H]−).
Reaction SMILES: O1C2C=CC=CC=2C=C1C1CCCOC1[N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[NH:29][N:28]=[C:27]([CH2:30][N:31]([CH3:33])[CH3:32])[N:26]=3)=[CH:22][CH:23]=2)[CH:18]=[N:17]1.O1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>Cl.C(OCC)(=O)C>[O:37]1[C:38]2[CH:39]=[CH:18][CH:19]=[CH:20][C:21]=2[CH:35]=[C:36]1[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[C:21]([C:25]3[NH:29][N:28]=[C:27]([CH2:30][N:31]([CH3:32])[CH3:33])[N:26]=3)[CH:20]=2)[NH:16][N:17]=1
Reactant: CN(C)Cc1n[nH]c(-c2ccc3c(cnn3C3OCCCC3c3cc4ccccc4o3)c2)n1
Reactant: C1COCCO1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)Cc1n[nH]c(-c2ccc3[nH]nc(-c4cc5ccccc5o4)c3c2)n1

Procedure:
([5-(3-Benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl(1H-indazol-5-yl))(1H-1,2,4-triazol-3-yl)]methyl)dimethylamine (15 mg, 0.034 mmol) in anhydrous HCl (5.0 mL of a 4 N solution in 1,4-dioxane) was vigorously stirred at ambient temperature for 18 h. The reaction mixture was neutralized with the slow addition of satd. NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give a solid which was redissolved in a minimum amount of ethyl acetate and precipitated with hexanes to give the desired product as an off-white powder. The product was further purified by preparatory HPLC using a 30–80% acetonitrile/water gradient with 0.1% CF3CO2H. Fractions containing the desired product were pooled and evaporated to give a pale yellow solid which was partitioned between ethyl acetate and satd. NaHCO3. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo to give a solid which was dissolved in a minimum amount of methanol/ethyl acetate and precipitated with hexanes. The solid was collected, washed with ethyl ether/hexanes and dried under vacuum to afford the desired product as a pale solid (5.0 mg, 41% yield) 1H NMR (DMSO-d6) δ 8.9 (s, 1H), 8.14 (dd, 1H), 7.8–7.6 (m, 3H), 7.46 (s, 1H), 7.4–7.26 (m, 2H), 4.65 (s, 2H), 1.85 (s, 6H); ES-MS (m/z) 359 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:16][N:15](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:14][CH2:13][N:12](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:11][CH2:10][N:9](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:8][CH2:7][N:6](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][CH2:4][N:3]1S(C1C=CC(C)=CC=1)(=O)=O.OS(O)(=O)=O.C(O)C>C(OCC)C>[CH3:1][C@H:2]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][NH:3]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)C[C@H](C)N(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCO
Product: C[C@H]1CNCCNCCNCCNCCN1
Temperature: 100 °C
Reaction time: 71 h
Yield: 12 %

Procedure:
A mixture of (S)-2-methyl-1,4,7,10,13-penta(p-toluenesulfonyl)-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 3C (22.9 g, 0.0229-mole) and concentrated H2SO4 (85 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 71 h. To the resulting brown solution, ethanol (100 ml) was added dropwise with stirring at 0° C. followed by ethyl ether 1l). The dark brown solid was filtered and washed thoroughly with ethyl ether. The solid was then dissolved in H2O (100 ml) and the resulting solution washed with ethyl ether. The pH of the solution was adjusted to 11 with 10 N NaOH and the solvent was removed in vacuo. Ethanol (2×500 ml) was then added and removed in vacuo. The resulting brown oily solid was extracted with hot THF (2×500 ml) and filtered. The filtrates were combined and the solvent was removed in vacuo. The residue was dissolved in hot THF (500 ml) and was filtered. The solvent was removed in vacuo and the residue was dissolved in CHCl3. After filtering to remove cloudiness, the solvent was removed in vacuo and the crude product was purified by fractional distillation in vacuo to give a pale yellow oil which crystallized on standing. The material was further purified by recrystallization from cold (-20° C.) CH3CN to give 641 mg (12% yield) of the product as a white crystalline solid: mp 87°-9° C.; [α]d20 =+37.2° (C=0.01,C6H6); 1H NMR (CDCl3) δ1.02 (d, J=6.3 Hz, 3 H), 1.81 (br s, 5 H), 2.37 (m, 1 H), 2.75 (m, 18 H); Exact mass (M+Li)+ : calcd., 236.2426; found, 236.2425 (C11H27N5Li).
Reaction SMILES: [CH3:1][SH:2].[CH3:3][O-:4].[Na+].[Na].Br[CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](OC)=O)[C:9]([O:11][CH3:12])=[O:10]>CO>[CH3:19][CH:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:1]([O:4][CH3:3])=[S:2]
Reactant: COC(=O)CCCCCCC(Br)C(=O)OC
Reactant: CS
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)CCCCCCC(C)C(=S)OC
Yield: 58 %

Procedure:
Methyl mercaptan (excess) is passed into a rapidly stirred solution of sodium methoxide (13.5 g., 0.25 mole) in dry methanol (200 ml.) at 0° C. to generate sodium methylmercaptide. The resulting solution is treated with dimethyl 2-bromoazelate (55.0 g., 0.186 mole), then stirred and heated at reflux under nitrogen for 5 hours. The reaction solution is concentrated in vacuo, diluted with ether and filtered. The filtrate is washed with water (until the washings are neutral), dried over sodium sulfate and distilled providing the title compound as a colorless liquid (28.4 g., 58%), bp 0.2 mm 128°-138° C.; pmr (CDCl3) δ 2.10 (s, 3H), 2.31 (t,2H), 3.20 (t,H), 3.63 (s,3H) and 3.71 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH:5]=1.[OH-].[Na+]>CO.C1COCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:18])=[O:2])=[N:12][CH:13]=1
Reactant: COC(=O)c1cccc(Nc2ccc(Cl)cn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
A mixture of 3-(5-chloro-pyridin-2-ylamino)-benzoic acid methyl ester (315 mg, 1.2 mmol) and NaOH (200 mg, 5.0 mmol) in methanol:THF:water (1:1:1, 3 mL) was stirred at room temperature for 8 h. Solvents were evaporated. Crude mass was taken in water (40 mL), acidified to pH 4.0 and extracted with ethyl acetate to obtain 3-(5-chloro-pyridin-2-ylamino)-benzoic acid (238 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:22]=[C:21]([C:23](O)=[O:24])[S:20][C:11]=2[N:12]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[N:13]=1.Cl.C[N:28](C)CCCN=C=NCC.[OH:38][N:39]1[C:43]2[N:44]=[CH:45][CH:46]=[CH:47][C:42]=2N=N1.CN1CCOCC1>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:22]=[C:21]([C:23]([NH:28][C@@H:46]([C:45]3[O:38][N:39]=[C:43]([CH3:42])[N:44]=3)[CH3:47])=[O:24])[S:20][C:11]=2[N:12]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[N:13]=1
Reactant: On1nnc2cccnc21
Reactant: O=C(O)c1cc2c(-c3ccc(F)cc3F)nn(-c3cnccn3)c2s1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1noc([C@@H](C)NC(=O)c2cc3c(-c4ccc(F)cc4F)nn(-c4cnccn4)c3s2)n1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 121.1 %

Procedure:
3-(2,4-Difluorophenyl)-1-(pyrazin-2-yl)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (43.6 mg, 0.069 mmol, with 4 equivalents of sodium chloride), L-(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine bis-hydrochloride (17.2 mg, 0.086 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28.5 mg, 0.149 mmol), 1-hydroxy-7-azabenzotriazole (5.2 mg, 0.038 mmol), and N-methylmorpholine (31 μl, 0.282 mmol) were dissolved in N,N-dimethylformamide (700 μl) at 25° C. The reaction mixture was heated to 50° C. and allowed to stir for 10 min. The reaction was stopped, quenched by addition of water (ca 0.2 mL) and trifluoroacetic acid (ca 0.2 mL). The reaction mixture was purified directly by preparative HPLC (Reverse phase (C-18)), eluting with acetonitrile/water 0.05% ammonium hydroxide, to give the title compound (21.5 mg, 0.046 mmol, 66.3% yield) as a white solid. HRMS [M+1] found=468.1063. 1H. NMR (500 MHz, CDCl3): δ 9.45 (s, 1H); 8.54-8.46 (m, 2H); 8.20-8.13 (m, 1H); 7.74 (d, J=3.9 Hz, 1H); 7.10-7.04 (m, 1H); 7.03-6.97 (m, 1H); 6.89 (d, J=7.8 Hz, 1H); 5.63 (t, J=7.3 Hz, 1H); 2.44 (s, 3H); 1.74 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8](I)[N:7]=1.[CH2:15]([OH:20])[CH2:16][CH2:17][C:18]#[CH:19]>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([C:19]#[C:18][CH2:17][CH2:16][CH2:15][OH:20])[N:7]=1
Reactant: C#CCCCO
Reactant: COC(=O)CCc1nc(I)ccc1O
Product: COC(=O)CCc1nc(C#CCCCO)ccc1O
Yield: 28 %

Procedure:
Under the conditions of example 5 A, 5 g of 3-(3-hydroxy-6-iodo-2-pyridyl)-propionic acid methyl ester is reacted with 1.37 g of 4-pentyn-1-ol, worked up, and the crude product is chromatographed on silica gel with hexane/0-4% methanol. 1.2 g of 3-[3-hydroxy-6-(5-hydroxy-1-pentynyl)-2-pyridyl]-propionic acid methyl ester is obtained as colorless oil.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].O.Br[C:9]1[C:10]([NH2:17])=[N:11][C:12]([CH3:16])=[C:13]([Br:15])[N:14]=1.C(N(CC)CC)C>O1CCCC1.[Cu]I>[Br:15][C:13]1[N:14]=[C:9]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[C:10]([NH2:17])=[N:11][C:12]=1[CH3:16]
Reactant: Cc1nc(N)c(Br)nc1Br
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(N)c(C#C[Si](C)(C)C)nc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
A solution of trimethylsilylacetylene (1.03 g, 29.4 mmol) in tetrahydrofuran (2 mL) was added dropwise to a cooled (water bath at ca. 15° C.) mixture of 3,5-dibromo-6-methyl-pyrazin-2-ylamine (7.48 g, 28 mmol), copper (I) iodide (1.07 g, 5.6 mmol), bis-triphenylphosphine palladium dichloride (1.97 g, 2.3 mmol), triethylamine (3.542 g, 35 mmol) and tetrahydrofuran (75 mL). The mixture was stirred under an atmosphere of argon, for 16 hours, during which time the reaction was allowed to warm to ambient temperature. The reaction mixture was poured onto water and extracted with hexanes-ethyl acetate (2:1). The organic layer was washed successively with saturated ammonium chloride solution, water, and then again with saturated ammonium chloride solution, water, then dried over anhydrous magnesium sulfate, treated with activated charcoal, filtered through celite and concentrated under reduced pressure. Purification by chromatography (silica, 20% ethyl acetate in hexanes) gave (6.19 g, 77%) of 5-bromo-6-methyl-3-trimethylsilanylethynyl-pyrazin-2-ylamine as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.26 (s, 9H), 2.39 (s, 3H), 6.71 (br s, 2H, —NH2).
Reaction SMILES: CN(C)[CH:3]=[C:4]([N:9]=[CH:10]N(C)C)[C:5]([O:7][CH3:8])=[O:6].[CH3:15][N:16]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17]1>C(O)(=O)C.C(O)(C(F)(F)F)=O>[CH3:15][N:16]1[C:20]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[N:9]=[CH:10][C:19]=2[C:18]([CH3:21])=[CH:17]1
Reactant: Cc1ccn(C)c1
Reactant: COC(=O)C(=CN(C)C)N=CN(C)C
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2c(cn1)c(C)cn2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
In a 500 ml round bottom flask, methyl 3-(dimethylamino)-2-((dimethylamino)methyleneamino)acrylate (1A, 12 g, 61 mmol) was dissolved in acetic acid (45 ml) and TFA (15 ml). 1,3-Dimethyl-1H-pyrrole (5.8 g, 61 mmol) was added and the mixture was stirred at room temperature for an hour and then at 110° C. for 4 hours. Volatiles were then evaporated from the reaction mixture, the residue was cooled in an ice bath and ice cold saturated K2CO3 solution (˜200 ml) was slowly added to it. The mixture was extracted with EtOAc (3×250 ml). Combined organic layers were then washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified on a silica column using hexane-EtOAc (0-100%). Desired product methyl 1,3-dimethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (1J, 6.8 g, 55%) was obtained.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.C(O[C:26]1([CH:38]=[CH:37][CH:36]=[C:35]([Br:39])[CH2:34]1)[CH:27]=[N:28][C:29](=O)[CH2:30][CH2:31][CH3:32])C>O>[Br:39][C:35]1[CH:34]=[C:26]([C:27]2[N:28]=[C:29]([CH2:30][CH2:31][CH3:32])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:10])[N:9]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: Cc1ccccc1NN
Reactant: CCCC(=O)N=CC1(OCC)C=CC=C(Br)C1
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCc1nc(-c2cccc(Br)c2)nn1-c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Next, 6.5 g of o-tolyl hydrazine hydrochloride and 100 mL of carbon tetrachloride were put into a 200-mL three-neck flask, 4.1 g of triethylamine (Et3N) was added dropwise to this mixture little by little, and the mixture was stirred at room temperature for 1 hour. After a predetermined time elapsed, 12 g of N-(1-ethoxy-3-bromobenzylidene)butyramide obtained in Step 1 above was added to the mixture, and the mixture was stirred at room temperature for 48 hours. After the reaction, water was added to the reaction mixture and the aqueous layer was subjected to extraction with chloroform. The organic layer and the obtained solution of the extract were combined and washed with water and saturated saline. Anhydrous magnesium sulfate was added to the organic layer for drying and the obtained mixture was concentrated to give an oily substance. The obtained oily substance was purified by flash column chromatography. As the developing solvent, a mixed solvent of hexane and ethyl acetate in a ratio of 5:1 (v/v) was used. The obtained fraction was concentrated to give 3-(3-bromophenyl)-1-(2-methylphenyl)-5-propyl-1H-1,2,4-triazole (a red oily substance, 80% yield). The synthesis scheme of Step 2 is shown in (G-2) below.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][CH:5]([OH:8])[CH2:6][CH3:7].Br[C:10]1[N:11]=[C:12]([O:31][CH3:32])[C:13]([C:18]2[CH:28]=[CH:27][C:21]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:20][C:19]=2[O:29][CH3:30])=[N:14][C:15]=1[CH2:16][CH3:17]>C1COCC1>[CH2:16]([C:15]1[N:14]=[C:13]([C:18]2[CH:28]=[CH:27][C:21]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:20][C:19]=2[O:29][CH3:30])[C:12]([O:31][CH3:32])=[N:11][C:10]=1[O:8][CH:5]([CH2:6][CH3:7])[CH2:4][CH3:3])[CH3:17]
Reactant: CCC(O)CC
Reactant: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(OC)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(OC)nc1OC(CC)CC

Procedure:
60% Sodium hydride (12 mg, 0.3 mmol) is added to a stirred solution of 3-pentanol (88 mg, 1 mmol) in THF (1 mL). After 0.5 hours [4-(5-bromo-6-ethyl-3-methoxypyrazin-2yl)-3-methoxyphenoxy]trifluoromethane (41 mg, 0.1 mmol) is added. The mixture is heated to 50 C for 12 hours, cooled and partitioned between ethyl acetate and water. The organic layer is washed with water, brine, dried (sodium sulfate), filtered and concentrated. The residue is purified by preparative TLC eluting with 50% ether in hexanes to give {4-[6-Ethyl-5-(ethylpropoxy)-3-methoxypyrazin-2-yl]-3-methoxyphenoxy}trifluoromethane, a colorless oil (19 mg). NMR (CDCL3, 400 MHz) δ 0.98 (t, 6H), 1.22 (t, 3H), 1.78 (m, 4H) 2.80 (q, 2H), 3.80 (s, 3H), 3.88 (s, 3H), 5.05 (quintet, 1H), 6.8 (s, 1H), 6.90 (d, 1H), 7.37 (d, 1H); MS 345 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([C:30]3[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=3)[CH2:28][CH2:29]2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3F)CC2)c1
Product: CC(=O)c1ccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2F)cc1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(4-hydroxyphenyl)ethanone and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 559.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[NH:12][C:13]([CH3:31])=[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[C:38]([N:16]1[CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:13]([CH3:31])[N:12]=[C:11]1[S:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCOC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)N=C(SCc2ccc(OC)cc2)N(C(=O)c2ccccc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A cold solution (5°) of 2.0 g. (0.0045 mole) of 1,4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester in 25 ml. of dichloromethane containing 0.72 g. (0.0091 mole) of pyridine is treated slowly with a solution of 0.76 g. (0.0054 mole) of benzoyl chloride in 3 ml. of dichloromethane. After stirring at room temperature for 16 hours, the solution is diluted with dichloromethane and washed with water, 1N hydrochloric acid, sodium bicarbonate and brine. The dried solution is evaporated to give 2.37 g. of a viscous oil which is not purified.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)CCC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[C:3]=3[F:17])[N:6]=2)[CH2:11][CH2:10]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)c(F)c2oc(C3CC3)nc2c1C#N
Yield: 92.6 %

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (200 mg, 0.68 mmol) was dissolved in toluene (4 ml), then 2-tributylstannylpyridine (299 mg, 0.81 mmol) and 2,6-di-tert-butylcresol (2 mg) and bis(triphenylphosphine)palladium(II) dichloride (24 mg, 0.03 mmol) were added, followed by heating under reflux for 17 hours under nitrogen atmosphere. The reaction liquid was cooled, the insoluble matter was separated by filtration through Celite, the solvent was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, followed by removing tin-derived side products with n-hexane and by elution with a mixed solvent of n-hexane/ethyl acetate (5:1-3:1, v/v) to obtain 2-cyclopropyl-7-fluoro-5-methyl-6-(2-pyridyl)-1,3-benzoxazole-4-carbonitrile (184 mg, 0.63 mmol, 92%) as a pale yellow transparent oily substance, A part of this (183 mg, 0.62 mmol) was dissolved in dimethyl sulfoxide (3.7 ml), triethylamine (219 μl, 1.56 mmol) and (3S)-3-(dimethylamino)pyrrolidine (103 μl, 0.81 mmol) were added, followed by stirring at 90° C. under nitrogen atmosphere for 15 hours. After cooling to room temperature, ethyl acetate was added, followed by fractionation with water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away, the resulting residue was recrystallized and purified with a mixed solvent of diisopropyl ether/n-hexane/ethyl acetate to obtain the entitled compound (108 mg, 45%) as a pale brown solid.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[C:6]=1[NH:13][C:14]([C:16]1[C:17](=[O:27])[CH:18]=[C:19]([CH3:26])[N:20]2[C:25]=1[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:15])[CH3:4].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:1][C:18]1[C:17](=[O:27])[C:16]([C:14]([NH:13][C:6]2[C:7]([CH2:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:3][CH3:4])=[O:15])=[C:25]2[N:20]([C:19]=1[CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24]2
Reactant: BrBr
Reactant: CCc1cccc(CC)c1NC(=O)c1c2n(c(C)cc1=O)CCCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCc1cccc(CC)c1NC(=O)c1c2n(c(C)c(Br)c1=O)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A mixture of 0.11 ml of bromine and 8 ml of methylene chloride was dropwise added to a mixture of 0.70 g of N-(2,6-diethylphenyl)-6,7,8,9-tetrahydro-4-methyl-2-oxo-2H-quinolizine-1-carboxamide, 1.27 g of sodium carbonate and 12 ml of methylene chloride at room temperature taking 30 minutes and further stirred for 5 hours at room temperature. After filtering the insoluble material off, the solution was concentrated and the resulting crystalline residue was recrystallized from a mixture of ethyl acetate and methanol to afford 0.64 g (Yield 75%) of the title compound.
Reaction SMILES: [N+:1]([N:4]1[C:8]2=[C:9]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:10]3[CH:11]=[CH:12][C:13]([N:48]=3)=[C:14]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:15]3[N:19]([N+:20]([O-])=O)[C:18]([C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[C:24]4[N:35]=[C:27]([C:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[C:5]1[CH:6]=[CH:7]2)[CH:26]=[CH:25]4)=[CH:17][CH:16]=3)([O-])=O>C1(C)C=CC=CC=1.[Ru]>[NH2:20][N:19]1[C:15]2=[C:14]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:13]3[CH:12]=[CH:11][C:10]([N:48]=3)=[C:9]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:8]3[N:4]([NH2:1])[C:5]([C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:27]4[N:35]=[C:24]([C:23]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)=[C:18]1[CH:17]=[CH:16]2)[CH:25]=[CH:26]4)=[CH:6][CH:7]=3
Reactant: O=[N+]([O-])n1c2ccc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc(c(-c4ccccc4)c4nc(c2-c2ccccc2)C=C4)n3[N+](=O)[O-])C=C1
Agent: [Ru]
Solvent: Cc1ccccc1
Product: Nn1c2ccc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc(c(-c4ccccc4)c4nc(c2-c2ccccc2)C=C4)n3N)C=C1
Temperature: 25 °C

Procedure:
Dinitrotetraphenylporphyrin (2.0 g 2.83 m mol) was added to a hydrogenation flask (500-ml) and dissolved in dry toluene (200-ml). To this solution was added the catalyst about 10% ruthenium on alumina pellets (4.0 g, from Engelhard Industries, Iselin, N.J.). After evacuation, and flushing with hydrogen, the reduction was performed at 70° at 60 psi for 8-hr. Next, the flask was cooled to ambient temperature, filtered in the dark to remove the catalyst. The solid catalyst was washed repeatedly with toluene to obtain the product. The organic solvent was removed under reduced pressure in the dark at 50° C. to produce the crude solid residue. This residue showed one spot above the two spots near the base line for the product. An additional brown spot very close to the starting material was also observed. The residue was 1.6 g.