Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=[N:11][OH:12].[CH2:13]([C:15](=[CH2:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].Cl[O-].[Na+].O>C1COCC1.C(N(CC)CC)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH2:21][C:15]([CH2:13][CH3:14])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:12][N:11]=1
Reactant: ON=Cc1cc2ccccc2s1
Reactant: C=C(CC)C(=O)OCC
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(CC)CC(c2cc3ccccc3s2)=NO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.6 %

Procedure:
Benzothiophen-2-aldehyde oxime derivative (400 mg, 2.26 mmol) prepared according to the same procedure as Preparation 1 was dissolved in THF (25 ml), and the mixture was kept at 0□. Ethyl 2-ethylacrylate (434 mg, 1.5 Eq) and triethylamine (7 drops) were dissolved in THF (5 ml), thus obtained solution was slowly added to the above, and sodium hypochlorite solution (6.0 ml) was further added. The reaction solution was warmed to room temperature and stirred for 4 hours. Water (20 ml) was added, and the mixture was extracted with ethyl acetate (40 ml×2), washed with aqueous sodium chloride solution (20 ml), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (20% ethyl acetate-hexane) to give the title compound (121 mg, Yield 18%).
Reaction SMILES: Cl.[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22](O)=[O:23])=[CH:19][C:18]=2[CH:25]=1.N>>[ClH:13].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:20]3[O:21][C:17]4[CH:16]=[CH:15][C:14]([Cl:13])=[CH:25][C:18]=4[CH:19]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2o1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc2cc(Cl)ccc2o1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 5-chlorobenzofuran-2-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 6.43-6.48 (m, 1H), 6.52 (s, 1H), 6.57-6.62 (m, 1H), 6.76 (d, J=2.0 Hz, 1H). MS (DCI/NH3) m/z 331.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[H-].[Na+].[CH3:14]N(C=O)C>>[CH3:14][NH:7][C:6]1[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CN(C)C=O
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: CNc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-2-nitroaniline (1.73 g, 10.0 mmol) in DMF (40 mL) was added NaH (60% oily, 880 mg, 22.0 mmol) at 0° C. followed by excess amount of Mel (3.0 mL). The mixture was stirred at 0° C. for 1 hr then at room temperature overnight. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (1.86 g, quant): 1H NMR (DMSO-d6) δ 2.95 (d, 3H), 6.69 (dd, 1H), 7.03 (d, 1H), 8.08 (d, 1H), 8.28 (br, 1H).
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Br[CH2:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1/[CH:31]=[CH:32]/[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].O>C1COCC1>[CH2:1]([N:8]([C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C@@H:31]1[C:25]2[C:24](=[CH:29][C:28]([CH3:30])=[CH:27][CH:26]=2)[CH2:23][C@H:32]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(/C=C/C(=O)OC(C)(C)C)c(CBr)c1
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)C[C@@H](C(=O)OC(C)(C)C)[C@@H]2N(Cc1ccccc1)[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.5 ml of (1R)—N-benzyl-1-phenylethanamine in 40 ml of THF was added 4.35 ml of n-butyllithium (1.62 M hexane solution) at −78° C., followed by stirring for 30 minutes. At the same temperature, a solution of 1.00 g of tert-butyl (2E)-3-[2-(bromomethyl)-4-methylphenyl]acrylate in 5 ml of THF was added thereto, followed by stirring for 1.5 hours. To the reaction mixture was added water, followed by warming to room temperature. The solvent was evaporated under reduced pressure and ethyl acetate was then added thereto to carry out a layer separation operation. The organic layer was washed with a 1 M aqueous citric acid solution, water, and saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.17 g of tert-butyl (1S,2R)-1-{benzyl[(1R)-1-phenylethyl]amino}-5-methylindane-2-carboxylate. Further, the present Preparation Example is in accordance with the method described in a reference (Synlett, 1999, No. 12, 1919-1920 by D. A. Price).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[CH:5]1([CH:11]2[CH2:16][CH2:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH2:12]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>CCCCCCC>[CH:5]1([CH:11]2[CH2:16][CH2:15][C:14]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:13]([C:3](=[S:4])[NH:2][CH3:1])[CH2:12]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: C1=C(N2CCOCC2)CCC(C2CCCCC2)C1
Reactant: CN=C=S
Solvent: CCCCCCC
Product: CNC(=S)C1=C(N2CCOCC2)CCC(C2CCCCC2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a three-neck flask there are introduced successively 2.04 g of methyl isothiocyanate, 20 ml heptane and, over the course of 5 minutes, a solution of 7.1 g 4-cyclohexyl-1-morpholyl-cyclohex-1-ene in 80 ml heptane and the reaction mixture is kept under vigourous stirring for 18 hours at room temperature.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[C:24]([O:28][C:29](=[O:35])[NH:30][CH2:31][CH2:32][CH2:33][NH2:34])([CH3:27])([CH3:26])[CH3:25]>CCO.CCOC(C)=O>[C:24]([O:28][C:29](=[O:35])[NH:30][CH2:31][CH2:32][CH2:33][NH:34][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 55.2 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (100 mg, 0.32 mmol) and (3-amino-propyl)-carbamic acid tert-butyl ester (67 mg, 0.39 mmol) in EtOH (8 mL) was refluxed for 16 h. After cooling to r.t., mixture was diluted with EtOAc and washed with a pH 3 aqueous solution until the washes became acidic. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 80 mg of the title compound as a pale yellow solid. MS: (−) m/z 451.37 (M−1).
Reaction SMILES: [C:1]([N:3]=[C:4]([N:12]1[CH2:17][CH2:16][C:15]([CH2:24][CH2:25][N:26]2[CH:31]3[CH2:32][CH2:33][CH:27]2[CH2:28][CH:29]([N:34]2[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=[C:35]2[CH3:43])[CH2:30]3)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)OC1C=CC=CC=1)#[N:2].[NH2:44][NH2:45]>C(O)(C)C>[CH3:43][C:35]1[N:34]([CH:29]2[CH2:30][CH:31]3[N:26]([CH2:25][CH2:24][C:15]4([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH2:16][CH2:17][N:12]([C:4]5[NH:45][N:44]=[C:1]([NH2:2])[N:3]=5)[CH2:13][CH2:14]4)[CH:27]([CH2:33][CH2:32]3)[CH2:28]2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=NC#N)Oc2ccccc2)CC1
Reactant: NN
Solvent: CC(C)O
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(c2nc(N)n[nH]2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
To a stirred solution of phenyl N-cyano-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboximidoate (18 mg, 0.031 mmol) in isopropyl alcohol (1 mL) was added hydrazine (3.6 μL, 0.11 mmol). The resulting mixture was then stirred at 80° C. for 4 hours. After evaporation of the solvents, the residue was purified by flash chromatography to afford 5-(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)-1H-1,2,4-triazol-3-amine as white solid (12.5 mg, 79%). 1H NMR (300 MHz, CDCl3) δ 7.67-7.64 (m, 2H), 7.39-7.29 (m, 5H), 7.25-7.13 (m, 3H), 4.66-4.55 (m, 2H), 4.28 (br, 2H), 3.56-3.49 (m, 3H), 3.27-3.21 (m, 4H), 2.57 (s, 3H), 2.42-2.22 (m, 4H), 1.96-1.82 (m, 9H), 1.64-1.62 (m, 2H). HRMS m/z (M+H)+ calcd: 511.3298, obsd: 511.3289.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[C:3](=[O:36])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](Br)([OH:32])[CH2:12][CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([CH:34]=[CH2:35])[CH:6]=1.[CH2:38]([NH2:41])[CH:39]=[CH2:40]>C(#N)C>[CH3:1][N:2]([CH3:37])[C:3](=[O:36])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:41][CH2:38][CH:39]=[CH2:40])([OH:32])[CH2:12][CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([CH:34]=[CH2:35])[CH:6]=1
Reactant: C=CCN
Reactant: C=Cc1cc(OC(=O)N(C)C)ccc1C(O)(Br)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: CC#N
Product: C=CCNC(O)(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(OC(=O)N(C)C)cc1C=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 4-[1-bromo-3-(t-butyl-diphenyl-silanyloxy)-1-hydroxy-propyl]-3-vinyl-phenyl dimethylcarbamate (2.62 g, 4.62 mmol) synthesized in step (g) of Example 192 in acetonitrile (20 ml) was added allylamine (1.87 ml, 25.0 mmol) at room temperature, and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. After stirring, the reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1-0:1) as the eluent to afford the title compound (1.82 g, yield: 72%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[C:6]=1[C:7]#[N:8].[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][C:18]([CH3:20])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:8][C:7]1[C:17]([C:16]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH3:20])[N:1]=[C:2]2[S:3][CH:4]=[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[C:6]=12
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1cccc(-c2csc(N)c2C#N)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2scc(-c3cccc(C)c3)c2c1N
Temperature: 25 °C
Yield: 19.4 %

Procedure:
To a stirred solution of 2-amino-4-(3-methylphenyl)-3-thiophenecarbonitrile (Description 56) (2.98 g, 13.91 mmol) in toluene (75 mL) at RT was added ethyl acetoacetate (1.76 mL, 13.91 mmol) and SnCl4 (3.26 mL, 27.8 mmol). The reaction mixture was refluxed under a nitrogen atmosphere for ca. 4 h and was then cooled to RT and concentrated in vacuo. The residue was re-partitioned between ethyl acetate and water (ca. 80 mL each) and the aqueous layer separated and re-extracted with ethyl acetate (ca. 50 mL×2). The combined organic layer was then passed though a phase separator and the solvent removed in vacuo. The residue was purified by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in cyclohexane, to give the title compound (880 mg). LCMS (A) m/z: 327 [M+1]+, Rt 1.23 min (acidic).
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C([Li])CCC.CON(C)[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.O>O1CCCC1>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([C:13]2[CH:12]=[N:11][CH:10]=[CH:9][C:8]=2[NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:30])=[CH:24][CH:25]=1
Reactant: CC(C)(C)C(=O)Nc1ccncc1
Reactant: CON(C)C(=O)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccncc1C(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 85.4 %

Procedure:
To a solution of 4-pivaloylaminopyridine (7.0 g, 39 mmol) in tetrahydrofuran (100 ml) was added n-butyllithium (39.3 ml, 98 mmol, 2.5 M solution in tetrahydrofuran) at −78° C. under a N2 atmosphere. The reaction mixture was stirred at 0° C. for 5 h, re-cooled to −78° C. and quenched with a solution of N-methoxy-N-methyl-4-fluorobenzamide (7.9 g, 43 mmol) in 100 ml tetrahydrofuran. The reaction mixture was warmed to room temperature and poured into water. The product was extracted into ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography (10% ethyl acetate/hexanes gradient) to afford N-[3-(4-fluorobenzoyl)pyridin-4-yl]-2,2-dimethylpropanamide (10 g).
Reaction SMILES: N#N.[OH:3][CH:4]([C:6]1[O:7][C:8]([CH2:11][N:12]2[N:16]=[C:15]([NH:17][C:18]([C:20]3[N:21]=[C:22]([CH3:32])[O:23][C:24]=3[C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)=[O:19])[CH:14]=[N:13]2)=[CH:9][N:10]=1)[CH3:5]>C(C#N)(C)=O.O=[Mn]=O>[C:4]([C:6]1[O:7][C:8]([CH2:11][N:12]2[N:16]=[C:15]([NH:17][C:18]([C:20]3[N:21]=[C:22]([CH3:32])[O:23][C:24]=3[C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)=[O:19])[CH:14]=[N:13]2)=[CH:9][N:10]=1)(=[O:3])[CH3:5]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3cnc(C(C)O)o3)n2)c1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: CC(=O)c1ncc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid {2-[2-(1-hydroxy-ethyl)-oxazol-5-ylmethyl]-2H-[1,2,3]triazol-4-yl}-amide (60 mg, 0.15 mmol) in AcCN (2.0 mL) was treated at rt with MnO2 (107 mg, 1.11 mmol) and the reaction mixture was stirred at rt overnight before being filtered through Celite. The solvent was removed under reduced pressure and the residue was dissolved in EA (10 mL), washed with water (10 mL), and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow solid. LC-MS-conditions 02: tR=1.04 min; [M+H]+=407.07.
Reaction SMILES: [C:1]([CH:5]1[CH2:12][CH2:11][NH:10][C:8](=[O:9])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:13]OS(OC)(=O)=O>>[CH3:3][C:1]([CH:5]1[CH2:6][CH2:7][C:8]([O:9][CH3:13])=[N:10][CH2:11][CH2:12]1)([CH3:4])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)C1CCNC(=O)CC1
Product: COC1=NCCC(C(C)(C)C)CC1

Procedure:
A sample of 4-tertbutylcaprolactam (Bader, 2.5 g, 14.8 mmol) was reacted with dimethylsulfate (1.4 mL, 14.8 mmol) by the method of EXAMPLE 69 to yield, after chromatography, 2.7 g of the title material.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[NH:17][O:18][C:19](=[O:21])[N:20]=2)[CH:11]=1)([CH3:9])[O:4][Si](C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.[F-].Cl>O.O1CCCC1>[F:23][C:2]([F:1])([F:22])[C:3]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[NH:17][O:18][C:19](=[O:21])[N:20]=2)[CH:11]=1)([CH3:9])[OH:4]
Reactant: CC(O[Si](C)(C)C)(c1ccnc(-c2nc(=O)o[nH]2)c1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(c1ccnc(-c2nc(=O)o[nH]2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 3.1 %

Procedure:
To 3 ml of tetrahydrofuran was added 12 g of 3-{4-[2,2,2-trifluoro-1-methyl-1-(trimethylsilyloxy)ethyl]pyridin-2-yl}-1,2,4-oxadiazol-5-one, and 1.3 ml of tetrabutylammonium=fluoride (1M tetrahydrofuran solution) was added at 0° C. After stirring at room temperature for 4 hours, water and 10% HCl were added to the reaction solution, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.29 g of 3-[4-(2,2,2-trifluoro-1-methyl-1-hydroxyethyl)pyridin-2-yl]-1,2,4-oxadiazol-5-one (present compound (62)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([NH:17][NH2:18])=[O:16])=[N:8][C:7]=3[C:6]=2[CH:19]=1.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>C(OC)(OC)OC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[O:16][CH:20]=[N:18][N:17]=4)=[N:8][C:7]=3[C:6]=2[CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NNC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Solvent: CCOCC
Solvent: COC(OC)OC
Product: Brc1ccc2c(c1)-c1nc(-c3nnco3)sc1CCO2
Temperature: 100 °C

Procedure:
To a solution of 9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid hydrazide (400 mg) in trimethyl orthoformate (10 mL) was added p-toluenesulfonic acid (100 mg) and the reaction heated at 100° C. for 16 h. After cooling to room temperature, the solvent was reduced in vacuo and diethyl ether (10 mL) was added. The resulting solid was filtered and air-dried to give 9-bromo-2-[1,3,4]oxadiazol-2-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.O>COCCOC>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OS(=O)(=O)C(F)(F)F)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(-c3cccnc3)c12
Temperature: 85 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butyl ester (285 mg, 0.75 mmol) in 3 mL of 1,2-dimethoxyethane was added K2CO3 (363 mg, 3.5 eq), pyridine-3-boronic acid (138 mg, 1.13 mmol), Pd(Ph3)4 (43 mg, 0.05 eq), and 0.5 mL of water. The mixture was heated and stirred in an 85° C. oil bath for 3 h. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic extract was washed with water and dried over sodium sulfate. Removal of the solvent in vacuo gave the crude product, which was purified by column chromatography to give 202 mg of 3-methyl-4-pyridin-3-yl-benzofuran-2-carboxylic acid tert-butyl ester, obtained as white solid.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5](=[O:34])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([OH:29])=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=2)=[O:18])=[CH:8][CH:7]=1)C.[OH-].[Na+]>CO>[CH3:28][C:25]([C:23]1[CH:24]=[C:19]([C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:9]2[CH:8]=[CH:7][C:6]([C:5](=[O:34])[C:4]([OH:35])=[O:3])=[CH:11][CH:10]=2)[CH:20]=[C:21]([C:30]([CH3:31])([CH3:32])[CH3:33])[C:22]=1[OH:29])([CH3:26])[CH3:27]
Reactant: CCOC(=O)C(=O)c1ccc(OCCCCC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(C(=O)CCCCOc2ccc(C(=O)C(=O)O)cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 92.9 %

Procedure:
As in example 10, a solution of 4-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-5-oxopentyloxy]-alpha-oxobenzeneacetic acid ethyl ester (0.8 g) in hot methanol (80 mL) was treated with 2N sodium hydroxide (1.75 mL) was stirred at room temperature for 75 minutes. The methanol was removed in vacuo, then the mixture was acidified with 3N hydrochloric acid and extracted with dichloromethane-tetrahydrofuran (2:1). The dried (MgSO4) extracts were evaporated and the solid residue was triturated from hexane, and then crystallized from acetone-hexane to provide 0.7 g of 4-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-5-oxopentyloxy]-alpha-oxobenzeneacetic acid, mp 144°-145° C.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][C@H:12]([O:21][Si](C(C)(C)C)(C)C)[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)(=O)=O)=CC=1.[H-].[Na+].[CH:32]1([CH2:35][O:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[C:43]([F:47])=[C:42](O)[CH:41]=[CH:40]3)[CH2:34][CH2:33]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.O1CCCC1.O>[CH:32]1([CH2:35][O:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[C:43]([F:47])=[C:42]([O:10][CH2:11][C@H:12]([OH:21])[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:41]=[CH:40]3)[CH2:33][CH2:34]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](CCc2cccnc2)O[Si](C)(C)C(C)(C)C)cc1
Reactant: Oc1ccc2cc(OCC3CC3)ccc2c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O[C@H](CCc1cccnc1)COc1ccc2cc(OCC3CC3)ccc2c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
Prepared according to the method described in Example 26e) from (2R)-2-(tert-butyldimethylsilyloxy)-4-(3-pyridyl)-1-butyl para-toluenesulfonate (0.215 g), sodium hydride (60% dispersion in mineral oil, 0.02 g) and 6-cyclopropylmethoxy-1-fluoro-2-hydroxynaphthalene (0.115 g) in dimethylformamide (3 ml). The adduct was dissolved in tetrahydrofuran (5 ml) and tetrabutylammonium fluoride (0.25 g) was added. The reaction was stirred at room temperature for 2 hours and was then poured into water and extracted with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with acetone:hexane (2:3) to give the title compound as a solid (0.077 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20](Cl)(=[O:24])/[CH:21]=[CH:22]/[CH3:23]>O1CCCC1>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:1][C:20](=[O:24])[CH:21]=[CH:22][CH3:23])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C/C=C/C(=O)Cl
Reactant: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Solvent: C1CCOC1
Product: CC=CC(=O)Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 31.2 %

Procedure:
To an ice cold solution of 0.158 g of 7-amino-4(3-bromoanilino)-quinazoline (J Med Chem, 1985:3482) in 5 mL of tetrahydrofuran was added dropwise a solution of 0.105 g of crotonic acid chloride in 5 mL of tetrahydrofuran. When the addition was complete, the ice bath was removed and the reaction stirred at room temperature for 15 hours. The reaction was filtered to remove the yellow solid which was washed with tetrahydrofuran and recrystallized from 20 mL of boiling methanol to afford 0.060 g of the desired product, mp >250° C.