Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][P:28](=[O:35])([O:32]CC)[O:29]CC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[Si](C)(C)C.O>ClCCl.CO>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][P:28](=[O:29])([OH:32])[OH:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(CCCCCCCCCCOCCCCCCCCOCc1ccccc1)OCC
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=P(O)(O)CCCCCCCCCCOCCCCCCCCOCc1ccccc1
Reaction time: 8 h
Yield: 97.2 %

Procedure:
Diethyl 10-(8-(benzyloxy)octyloxy)decylphosphonate (680 mg, 1.33 mmol) was dissolved in dry dichloromethane (15 mL). Bromotrimethylsilane (0.53 mL, 4.05 mmol) was added via syringe. The reaction was capped with a greased glass stopper and stirred overnight. The volatiles were removed under reduced pressure to yield a yellow oil. This was dissolved in 5:1 methanol:water (10 mL) and stirred 4 hours more. After concentration of the organic, the viscous yellow oil was recrystallized in acetonitrile to yield a white crystalline solid (590 mg, 98% yield). 1H NMR (400.14 MHz, DMSO) δ 7.40-7.19 (m, 5H), 4.42 (2H), 3.39 (t, J=6.48 Hz, 2H), 3.29 (t, J=6.46 Hz, 4H), 1.58-1.34 (m, 10H), 1.34-1.10 (m, 20H). 13C{1H} NMR (100.62 MHz, DMSO) δ 138.7, 128.2 (2C), 127.3 (2C), 127.3, 71.79, 69.91 (2C), 69.59, 30.11 (d, J=16.0 Hz), 29.25, 29.21, 29.20, 29.05, 28.89 (2C), 28.84 (2C), 28.73, 27.55 (d, J=136.5 Hz), 25.76, 25.69, 25.67, 22.74 (d, J=4.5 Hz). 31P{1H} NMR (161.97 MHz, DMSO): δ 27.74. Analysis calculated (found) %: C 65.76 (65.79), H 9.93 (10.00). MS (ESI, m/z): 455 (M−, 100%). Exact mass calculated (found) for [M−H]−, m/z): 455.2932 (455.2932).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[S:9][CH2:10][C:11](=[O:13])[N:12]=1.[CH2:14]([O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH:27]=O)[CH:25]=2)[N:20]=[C:19]([NH:29][CH3:30])[N:18]=1)[CH3:15].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:14]([O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH:27]=[C:10]3[S:9][C:8]([NH:7][CH2:6][C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[N:12][C:11]3=[O:13])[CH:25]=2)[N:20]=[C:19]([NH:29][CH3:30])[N:18]=1)[CH3:15]
Reactant: O=C1CSC(NCc2cccs2)=N1
Reactant: CCOc1nc(NC)nc2ccc(C=O)cc12
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOc1nc(NC)nc2ccc(C=C3SC(NCc4cccs4)=NC3=O)cc12
Temperature: 150 °C

Procedure:
To a suspension of 2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one (34.0 mg, 0.16 mmole), and 4-ethoxy-2-methylamino-quinazoline-6-carbaldehyde (example 12f, 45.5 mg, 0.20 mmole) in 2 mL of toluene in a microwave tube were added benzoic acid (2.0 mg, 0.016 mmole) and piperidine (1.5 mg, 0.02 mmole). The reaction mixture was heated to 150° C. with microwave for 30 min. The reaction mixture was then cooled to r.t. and the solid was filtered off, washed with toluene, MeOH and ether to give 5-(4-ethoxy-2-methylamino-quinazolin-6-ylmethylene)-2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one as a brown solid: 48.6 mg (69.1%), MS: m/e 426 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([F:26])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N([CH2:32][CH3:33])CC)C.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36]>O1CCCC1>[CH2:18]([O:17][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:1]([C:16]([O:25][C:33]3[CH:32]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:17])[C:35](=[O:36])[O:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:7]=2)=[CH:10][C:11]=1[F:26])=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCN(CC)CC
Reactant: Nc1cc(Oc2ccc(NC(=O)OCc3ccccc3)c(F)c2)ccn1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)cc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl [4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]carbamate (1.25 g) in tetrahydrofuran (100 ml) were added triethylamine (1.48 ml) and phenyl chloroformate (1.11 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled away to give a crude product of phenyl N-[4-(4-benzyloxycarbonylamino-3-fluorophenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate as a brown oil (ESI-MS (m/z): 616 [M+Na]+). This was dissolved in tetrahydrofuran (200 ml), 20% palladium hydroxide (497 mg) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The catalyst was removed by filtration. It was subsequently washed with tetrahydrofuran. The filtrate was concentrated to 20 ml to give a solution of phenyl N-[4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (ESI-MS (m/z): 482 [M+Na]+, 941 [2M+Na]+) in tetrahydrofuran. This was dissolved in N,N-dimethylformamide (50 ml). After then adding 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (1.58 g), benzotriazol -1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (3.13 g) and triethylamine (0.987 ml), the mixture was stirred at room temperature for 13.5 hours. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and brine in that order and dried over anhydrous sodium sulfate. It was then concentrated and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=3:2, 1:1 and 1:2) to give the title compound as a colorless foam (940 mg, 40.0%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6](O)=[CH:7][CH:8]=2)[CH:3]=1.[NH3:13].O.S([O-])([O-])=O.[NH4+].[NH4+].Cl>C(OCC)(=O)C>[NH2:13][C:6]1[CH:7]=[CH:8][C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=1
Reactant: N
Reactant: Oc1ccc2ccc(Br)cc2c1
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc2ccc(Br)cc2c1
Temperature: 150 °C
Reaction time: 27 h

Procedure:
According to the procedure described in the aforementioned reference [L. C. Anderson et al., Journal of the American Chemical Society (J. Am. Chem. Soc.), vol. 65, p.241, 1943], 2-bromo-7-hydroxynaphthalene (2.23 g, MAYB) was added with 30% aqueous ammonia (30 ml) and ammonium sulfite monohydrate (2.69 g, WAKO) and stirred in a shield tube at 150° C. for 27 hours. The reaction mixture was added with ethyl acetate (90 ml) for extraction and then added with 1 N aqueous hydrochloric acid (1.5 l). The aqueous layer was separated, washed with ethyl acetate, then neutralized by adding 5 N aqueous sodium hydroxide (300 ml) under ice cooling and extracted with ethyl acetate again. The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure to obtain the title compound (Intermediate 26, 1.00 g).
Reaction SMILES: Br[O-].[Na+].BrBr.[C:6]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:15]=2)[CH:10]=1)(=[O:8])C.S(S([O-])=O)([O-])(=O)=[O:25].[Na+].[Na+]>O.O1CCOCC1>[CH2:22]([S:19]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:6]([OH:8])=[O:25])[CH:18]=[CH:17]2)(=[O:21])=[O:20])[CH3:23]
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: CCS(=O)(=O)c1ccc2cc(C(C)=O)ccc2c1
Agent: BrBr
Agent: [Na+]
Agent: [O-]Br
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc2cc(C(=O)O)ccc2c1
Temperature: 5 °C
Yield: 94.3 %

Procedure:
There is prepared in a first stage a solution of sodium hypobromite by adding, at 0° C., 3 cm3 of bromine to a stirred solution containing 7.5 g of soda in 35 cm3 of water. Then, there is slowly introduced a suspension of 1 g of 2-acetyl-6-ethylsulfonyl naphthalene dispersed in 20 cm3 of dioxan in a fashion to maintain the temperature of the reaction mixture lower than 5° C. At the end of the addition, this temperature is again maintained for 1 hour and then there are slowly added at ambient temperature 15 g of sodium metabisulfite dissolved in 150 cm3 of water. On acidifying the mixture with HCl, the anticipated acid precipitates. It is filtered, washed thoroughly with water and dried. 0.95 g of 6-ethylsulfonyl-2-naphthalene carboxylic acid in the form of a white powder whose melting point is 241° C. is obtained.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.[Al+3].[Cl-].[Cl-].[Cl-].[C:26](Cl)(=[O:28])[CH3:27]>C(OCC)(=O)C>[C:26]([C:4]1[CH:5]=[CH:6][C:1]([C@H:7]2[CH2:8][CH2:9][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:12]2)=[CH:2][CH:3]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(C)=O)cc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A 500 mL round bottom flask with a stir bar was charged with the product of Example 1B (3 g, 12.2 mmol) and 60 mL of dichloromethane. The reaction solution was cooled to 0° C. and AlCl3 (4.86 g, 36.5 mmol) was added in portions. The mixture was allowed to stir for 20 min, and then acetyl chloride (954 μL, 13.4 mmol) was added dropwise. After stirring for 15 minutes, the reaction mixture was slowly pored into a beaker with ice water and diluted with 120 mL of ethyl acetate. The layers were separated and the organic layer washed with 1 N NaHCO3 (×2) brine (×2), dried over Na2SO4, and filtered. Evaporation of the solvents afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04-1.17 (m, 2 H), 1.18 (t, 3 H), 1.39-1.62 (m, 3 H), 1.68-1.88 (m, 5 H), 2.17-2.26 (m, 2 H), 2.52-2.57 (s, 3 H), 4.07 (q, J=7.12 Hz, 2 H), 7.25-7.46 (m, 2 H), 7.77-7.94 (m, 2 H) MS (ESI) m/z 247 [M+H]+.
Reaction SMILES: [C:1]1(=[O:23])[N:5]([O:6][CH2:7][C:8]2([CH:17]=[CH:16][CH:15]=[CH:14][CH2:13]2)C(OC)=O)C(=O)C2=CC=CC=C12.O.NN>CO>[CH2:7]1[C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[C:1](=[O:23])[NH:5][O:6]1
Reactant: COC(=O)C1(CON2C(=O)c3ccccc3C2=O)C=CC=CC1
Agent: NN
Solvent: O
Solvent: CO
Product: O=C1NOCc2ccccc21
Yield: 21.4 %

Procedure:
This reaction was run in the same manner as Example 6, Part B, using 52.5 grams (0.169 mole) of methyl 1-(phthalimidooxymethyl)benzoate and 17.0 grams (0.34 mole) of hydrazine hydrate in 800 ml of methanol to give 5.4 grams of 1H-2,3-benzoxazin-4(3H)-one; m.p. 123°-125° C.
Reaction SMILES: [CH3:1][Mg]I.[N:4]1[C:5]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#N)=[CH:15][CH:14]=2)=[CH:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12.S(=O)(=O)(O)O.[OH-:26].[Na+]>CCOCC.O.O1CCCC1>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([C:5]2[N:4]=[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][N:7]3[CH:6]=2)=[CH:14][CH:15]=1)(=[O:26])[CH3:1]
Reactant: [OH-]
Reactant: C[Mg]I
Reactant: N#Cc1ccc(-c2cn3ccccc3n2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1ccc(-c2cn3ccccc3n2)cc1

Procedure:
A solution of methylmagnesium iodide (prepared from 3.6 g of magnesium and 22 g of methyl iodide) in 40 ml of ether is added dropwise to a mixture of 6.5 g of 4-(imidazo[1,2-a]pyridin-2-yl)benzonitrile and 50 ml of tetrahydrofuran with stirring on an ice bath. The mixture is heated under reflux for 3 hours, and the reaction mixture is cooled with salt and ice. 100 ml of 50% sulfuric acid is added dropwise to the reaction mixture, water is added, and the whole mixture is adjusted to pH 8 by addition of 20% sodium hydroxide. The crystalline precipitate is filtered off, washed with water and recrystallized from dimethylformamide to give 4.2 g of 2-(4-acetylphenyl)-imidazo[1,2-a]pyridine as colorless crystals melting at 209°-210°C. 2.2 g of the thus-obtained 2-(4-acetylphenyl)-imidazo[1,2-a]pyridine is heated with 0.45 g of sulfur and 10 ml of morpholine under reflux for 6 hours. The reaction mixture is cooled, and ethanol is added. The crystalline precipitate is filtered off and washed with ethanol to give 1.4 g of 4-(imidazo[1,2-a]pyridin-2-yl)phenylacetothiomorpholide as yellowish brown crystals melting at 204°-206°C.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:14]1[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=1.[H-].[Na+]>CN(C)C=O>[N+:29]([C:17]1[CH:16]=[CH:15][C:14]([O:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:19][C:18]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])([O-:31])=[O:30]
Reactant: Oc1ccccc1N1CCCC1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCCC2)ccc1[N+](=O)[O-]

Procedure:
In a similar manner to that described in Reference Example 27, a reaction was carried out using 2-pyrrolidinophenol (1.88 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (3.34 g), sodium hydride (55 wt. %, 0.52 g) and anhydrous N,N-dimethylformamide (22 ml) and the reaction mixture was purified to afford t-butyl N-[2-nitro-5-(2-pyrrolidinophenoxy)phenyl]-N-methylcarbamate, of which Rf value was 0.25 in thin layer chromatography on a silica gel plate using c-hexane/ethyl acetate=10/1. In a similar manner to that described in Reference Example 27, a reaction was carried out using this product, palladium on carbon (10%, 0.45 g) and toluene/methanol=7/3 (50 ml) and the reaction mixture was purified to give the title compound (3.0 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17](OCC)=[O:18])[CH:13]=[N:14]2)=[N:9][CH:8]=1.OC1C=C2C(C=C(C(OCC)=O)C=N2)=[N:28]C=1.C([O-])([O-])=O.[Cs+].[Cs+].FC1C=C(C=CC=1)CCl>CN(C=O)C.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][O:6][C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:17]([NH2:28])=[O:18])[CH:13]=[N:14]3)=[N:9][CH:8]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1cnc2cc(O)cnc2c1
Reactant: CCOC(=O)c1cnc2cc(OCc3cccc(F)c3)cnc2c1
Agent: Fc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)c1cnc2cc(OCc3cccc(F)c3)cnc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
Ethyl 7-((3-fluorobenzyl)oxy)-1,5-naphthyridine-3-carboxylate. To a solution of ethyl 7-hydroxy-1,5-naphthyridine-3-carboxylate (Intermediate 4, 1.0 g, 4.59 mmol) in DMF (20 mL) was added Cs2CO3 (2.2 g, 6.75 mmol), followed by 3-fluorobenzyl chloride (0.6 mL, 5.02 mmol). The reaction was stirred at ambient temperature for 72 h. The crude reaction mixture was poured into EtOAc and water. The aqueous later was extracted with EtOAc and the combined organic fractions were washed with brine and concentrated under reduced pressure onto silica. Purification (FCC, SiO2, 0-60%, EtOAc/hexanes) afforded the title compound as a white solid (1.0 g, 69%). 1H NMR (400 MHz, CDCl3) δ 9.44 (t, J=2.0 Hz, 1H), 9.00-8.94 (m, 1H), 8.88 (t, J=2.3 Hz, 1H), 7.74-7.65 (m, 1H), 7.47-7.33 (m, 1H), 7.28-7.26 (m, 1H), 7.21 (d, J=9.4 Hz, 1H), 7.07 (t, J=8.6 Hz, 1H), 5.25 (s, 2H), 4.59-4.38 (m, 2H), 1.52-1.41 (m, 3H). [M+H]=327.2.
Reaction SMILES: O[CH2:2][C:3]1[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[C:6]([O:14][CH3:15])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[Cl-].[SH:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>C(Cl)Cl.O>[CH3:15][O:14][C:6]1[C:7]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]=2[C:3]([CH2:2][S:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:4][CH:5]=1
Reactant: COc1ccc(CO)c2c1OC(C)(C)C2
Reactant: Sc1ccncc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(CSc2ccncc2)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
Compound 48a (2.0 g) obtained in Step A was dissolved in methylene chloride (100 ml), and then diisopropylethylamine (5.0 ml) and methanesulfonyl.chloride (0.8 ml) were added thereto, followed by stirring at room temperature for one hour. At the same temperature, 4-mercaptopyridine (1.4 g) was added to the reaction solution, and the mixture was stirred for 30 minutes. Water was added to the reaction solution and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) to give Compound 48 (1.4 g, 48.3%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:10]=1[CH2:11][NH:12]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[C:23](#[N:25])[CH3:24].ClCCl>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:10]=1[CH2:11][NH:12][C:23](=[NH:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: ClNCc1cc(Br)ccc1OCc1ccccc1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=N)NCc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-benzyloxy-5-bromobenzylamino hydrochloride (10 g) in toluene (75 ml) at 4° C. was added a solution of trimethylaluminium in toluene (2M, 15.2 ml). The mixture was stirred at ambient temperature for 2 hours, acetonitrile (6.5 ml) added and the mixture heated at 80° C. for 18 hours. The mixture was cooled and poured onto a slurry of silica gel (300 g), and dichloromethane. The solvent was filtered off and the product eluted from the silica gel with methanol to give N1 -[2-benzyloxy-5-bromobenzyl]acetamidine (5.51 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:28])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:24])=[CH:26][CH:27]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(C(=O)O)cc2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(C(=O)Nc3ccccc3)cc2)cs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.5 %

Procedure:
4-(2-{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}ethoxy)benzoic acid (500 mg) obtained in Example 60-2 and aniline (132 mg) were dissolved in dichloromethane (6 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (339 mg) and 4-dimethylaminopyridine (DMAP) (217 mg) were successively added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (480 mg) as a white solid.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[N:23]=[N:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([C:22]2[N:23]=[N:24][N:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[N:26]=2)[OH:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1nnn(-c2ccccn2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(CCCCCCc1ccccc1)c1nnn(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
2-(5-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)-2H-tetrazol-2-yl)-pyridine (4.4 mg, 0.009 mmol) was dissolved in THF (122 μL), treated with Bu4NF (1 M in THF, 0.013 mL, 0.013 mmol) and stirred at room temperature for 2 h under Ar. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude alcohol that was purified by flash chromatography (SiO2, 0.5×4 cm, 20-50% EtOAc-hexanes) to afford 7-phenyl-1-(2-(pyridin-2-yl)-2H-tetrazol-5-yl)-heptan-1-ol (2.7 mg, 79%) as a white solid: 1H NMR (CDCl3, 600 MHz) δ 8.69 (dd, 1H, J=1.1, 4.7 Hz), 8.18 (d, 1H, J=8.1 Hz), 8.00 (m, 1H), 7.50 (ddd, 1H, J=0.7, 4.8, 7.4 Hz), 7.26 (m, 2H), 7.16 (m, 3H), 5.16 (m, 1H), 2.59 (t, 2H, J=7.7 Hz), 2.48 (d, 1H(—OH), J=6.1 Hz), 2.07 (m, 2H), 1.61 (m, 2H), 1.52 (m, 2H), 1.40 (m, 4H); 13C NMR (CDCl3, 150 MHz) δ 169.5, 149.6, 148.8, 142.9, 139.6, 128.5, 128.4, 125.7, 125.3, 115.3, 67.0, 36.7, 36.1, 31.5, 29.3 (2C), 25.2; HRMS-ESI-TOF m/z 338.1966 ([M+H]+, C19H23N5O requires 338.1975).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:13])[CH:5]=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=12.C(N(CC)CC)C.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(#N)C>[CH3:13][C:4]1[CH:5]=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]2=[C:2]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[N:3]=1
Reactant: Cc1cc2c(c(Cl)n1)C(=O)OCC2
Reactant: C1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc2c(c(N3CCCCC3)n1)C(=O)OCC2
Yield: 95 %

Procedure:
8-chloro-6-methyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on (250 mg, 1.265 mmol) was suspended in 8 mL of anhydrous acetonitrile and then dropwisely added with 1.0 mL of triethylamine and piperidine (0.19 mL, 1.898 mmol) in this order and heated to reflux for about 3 hours under the nitrogen atmosphere. The mixture was concentrated under reduced pressure, added with 10 mL of a saturated solution of ammonium chloride and 10 mL of distilled water and then extracted twice with 30 mL of methylene chloride. The resulting organic layer was dried using anhydrous sodium sulfate, filtered and concentrated. A silica gel column chromatography (10% EtOAc/MC) was performed on the resulting residue and 296 mg (95%)of 6-methyl-8-piperidine-1-yl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on was obtained in white solid.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17].O>C(O)C>[CH2:1]([NH:3][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17])[CH3:2]
Reactant: O=c1[nH]cnc2cc(Cl)c([N+](=O)[O-])cc12
Reactant: CCN
Solvent: CCO
Solvent: O
Product: CCNc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
A 70% aqueous ethylamine solution (40 ml) was added to a solution (70 ml) of 7-chloro-6-nitro-4(3H)-quinazolone (6.31 g, 28.0 mmol) in ethanol and the mixture was heated with stirring at 110° C. for 4 hours in a sealed tube. After cooling to room temperature, the reaction mixture was poured into water and the precipitated crystals were collected by filtration. The crystals were washed with ethanol and dried to give the title compound (2.6 g, 39%).