Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH3:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:10]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:1]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]#[N:7])[CH3:11]
Reactant: CCc1cc(C#N)ccc1N
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCc1cc(C#N)ccc1N1CCCCC1
Temperature: 160 °C
Yield: 18.8 %

Procedure:
4-Amino-3-ethylbenzonitrile (3.0 g, 20.5 mmol), 1,5-dibromopentane (11.1 mL, 82.1 mmol), potassium carbonate (5.67 g, 41.0 mmol) and water (39.6 mL) were all split equally between ten microwave vials and each heated at 160° C. for 1 h. All reaction mixtures were combined and extracted twice with ethyl acetate (40 mL) and the combined organic fractions dried (phase separator) and concentrated in vacuo. Dichloromethane was added and then the mixture filtered before the filtrate was purified by silica chromatography, eluting 2-5% ethyl acetate in hexane to give the title compound as a colourless oil (823 mg, 3.85 mmol). Analysis indicated that the compound contained a small dibromopentane impurity. δH (methanol-d4, 400 MHz) 7.52 (1H, dd), 7.47 (1H, dd), 7.13 (1H, d), 2.89 (4H, dd), 2.71 (2H, q), 1.76-1.71 (4H, m), 1.64-1.56 (2H, m), 1.25 (3H, t). MS (ES): C14H18N2 requires 214; found 215 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]([NH:12][NH2:13])=O)([CH3:4])([CH3:3])[CH3:2].CO[C:27]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH2:31][CH2:30][CH2:29][N:28]=1>COCCO>[N:13]1[N:12]=[C:10]([CH2:9][C@H:8]([NH:7][C:6](=[O:24])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=2[F:23])[N:28]2[CH2:29][CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:27]=12
Reactant: COC1=NCCCc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)c(F)cc1F
Solvent: COCCO
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2n1CCCc1ccccc1-2

Procedure:
A mixture of 90 mg (0.26 mmol) of tert-butyl [(1R)-3-hydrazino-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (Intermediate 4), 45.5 mg (0.26 mmol) of 1-methoxy-4,5-dihydro-3H-2-benzazepine (Intermediate 10), and 3.5 mL of 2-methoxyethanol was stirred at reflux for 43 h. The cooled solution was concentrated, and the residue was purified by preparative HPLC (C18 reverse phase column, 20-90% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the title compound as a colorless oil. LC-MS 473 (M+1).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>CS(C)=O.CCOC(C)=O>[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:2]2[C:7]([C:8]3[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH:9]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:26][CH:25]=1
Reactant: CC(=O)N1CC=C(c2cccnc2F)CC1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)N1CC=C(c2cccnc2Oc2ccc(N)cc2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution of 1-(4-(2-fluoropyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (1.68 g, 7.63 mmol) in dimethylsulfoxide (25 mL) under argon was added cesium carbonate (2.73 g, 8.39 mmol), followed by 4-aminophenol (0.874 g, 8.01 mmol). The reaction was stirred at 80° C. for 18 h. The cooled reaction mixture was diluted with EtOAc and washed with water; the aqueous layer was back-extracted with EtOAc (1×). The organic layers were combined, dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% to 50% EtOAc/Hexanes) afforded 1-(4-(2-(4-aminophenoxy)-pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone as a tan solid. MS (ESI, pos. ion) m/z: 310.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][NH:5][CH:6]=1.[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][N:5]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=1
Reactant: Brc1c[nH]nc1-c1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccccc1
Temperature: 90 °C
Reaction time: 60 h
Yield: 62.5 %

Procedure:
A suspension of 4-bromo-3-phenyl-1H-pyrazole (6.13 g, 27.5 mmol), trityl chloride (15.3 g, 55.0 mmol), and K2CO3 (11.4 g, 82.5 mmol) in DMF (100 mL) was stirred for 60 h at 90° C. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, concentrated under reduced pressure. The residue was recrystallized from hexane/THF to give the title compound (8.00 g, 63% yield) as a white solid: mp 181-183° C.; 1H NMR (300 MHz, CDCl3): δ ppm 7.16-7.22 (6H, m), 7.28-7.41 (13H, m), 7.87-7.91 (2H, m). Anal. Calcd for C28H21BrN2: C, 72.26; H, 4.55; N, 6.02. Found: C, 72.43; H, 4.66; N, 5.91.
Reaction SMILES: [CH3:1][C@H:2]([CH2:5][CH2:6][OH:7])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].Cl>ClCCl>[CH3:15][S:16]([O:4][CH2:3][C@H:2]([CH3:1])[CH2:5][CH2:6][O:7][S:16]([CH3:15])(=[O:18])=[O:17])(=[O:18])=[O:17]
Reactant: C[C@@H](CO)CCO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](CCOS(C)(=O)=O)COS(C)(=O)=O
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-2-methylbutane-1,4-diol (30 g, 0.29 mol) in dichloromethane (600 mL) was added triethylamine (100 mL, 0.72 mol). The solution was cooled to −20° C., and methanesulfonyl chloride (49 mL, 0.63 mol) was added dropwise over 30 min with vigorous stirring. The resulting mixture was stirred for additional 1 h while the temperature was maintained between −20 and −15° C. The mixture was allowed to warm to 0° C. and then poured into cold 1N HCl solution (100 mL). The organic layer was separated, and aqueous phase was extracted with dichloromethane (100 mL). The combined organic extracts were washed with sat'd NaHCO3 solution, brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting product (75.9 g, quant) was used directly for the next step. 1H NMR (400 MHz, CDCl3): δ 4.41-4.24 (m, 2H), 4.12 (dq, 2H), 3.02 (d, 6H), 2.13 (td, 1H), 1.95 (td, 1H), 1.80-1.65 (m, 1H), 1.07 (d, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]=[C:17]=[S:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][NH:20][NH2:21].[N-]=C=S>C(OCC)C>[C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]([N:20]([CH3:19])[NH2:21])=[S:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNN
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1N=C=S
Agent: [N-]=C=S
Solvent: CCOCC
Product: CN(N)C(=S)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 91 %

Procedure:
A solution of 5.48 grams (0.02 mole) of 2-benzoyl-4-chlorophenylisothiocyanate in about 50 ml of ethyl ether was added dropwise to a solution containing 1.5 ml (0.028 mole) of methyl hydrazine (98%) in about 50 ml of ethyl ether cooled in an ice bath. Additional ethyl ether was added to facilitate stirring. Following addition of the isothiocyanate, the reaction mixture was stirred at room temperature for about 30 minutes. The solid was collected and washed with additional ethyl ether to yield 5.82 grams (91% yield) of N-(2-benzoyl-4-chlorophenyl)-methyl-hydrazinecarbothioamide as a white solid. The melting point was found to be 168.5°-170° C.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])O)O)O.C(OS(C1C=CC=CC=1)(=O)=O)CCCCCCCCCCC.[Na].C1(C)C=CC=CC=1.[ClH:43]>O>[Cl:43][CH2:11][C:9]1[O:10][C:3]([CH:2]=[O:1])=[CH:5][CH:7]=1
Reactant: Cl
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(CCl)o1
Reaction time: 7 h

Procedure:
Five grams of a commercially available D-glucose and 97.6 mg of sodium laurylbenzenesulfonate were added to the same three-necked flask. Then, 5 ml of water and 30 ml of toluene were added thereto and the mixture was stirred. Thereafter, a molar excess of hydrogen chloride was passed through the mixture at room temperature for about 25 minutes. Stirring was continued at 50° C. for a further 7 hours. The reaction solution was diluted with a little water and filtered through Celite while being washed with toluene. The upper toluene layer was neutralized, dried and concentrated to obtain about 1.4 g of 5-chloromethylfurfural.
Reaction SMILES: C[Si]([CH2:5][C:6]([O-:8])=[O:7])(C)C.Cl[Si:10]1(Cl)[CH2:13][CH2:12][CH2:11]1>>[C:6]([O:8][Si:10]1([O:8][C:6](=[O:7])[CH3:5])[CH2:13][CH2:12][CH2:11]1)(=[O:7])[CH3:5]
Reactant: Cl[Si]1(Cl)CCC1
Reactant: C[Si](C)(C)CC(=O)[O-]
Product: CC(=O)O[Si]1(OC(C)=O)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 30.0 g trimethylsilylacetate was added 16.0 g 1,1-dichlorosilacyclobutane. The reactants were stirred for one hour at 25 ° C. and fractional distillation performed on the reaction mixture. The title compound was isolated as a clear, colorless fluid. The yield was 14.6 g (81.4%). The structure of the product was confirmed by mass spectroscopy and nuclear magnetic resonance spectroscopy (NMR).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(Oc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, phenol and DBU in DME. EI-MS m/e (%): 288 (M+, 100), 287 ([M—H]+, 60).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:15]2[N:19]([CH3:20])[N:18]=[C:17]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])[N:16]=2)[CH:10]=[CH:11][C:12]=1[CH2:13]Cl.C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=1[OH:46]>O>[Cl:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:21]=1[C:17]1[N:16]=[C:15]([C:9]2[CH:10]=[CH:11][C:12]([CH2:13][O:46][C:37]3[CH:38]=[CH:39][C:40]([C:42]([F:43])([F:44])[F:45])=[CH:41][C:36]=3[F:35])=[C:7]([Cl:6])[CH:8]=2)[N:19]([CH3:20])[N:18]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CCl)c(Cl)c1
Reactant: Oc1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ccc(C(F)(F)F)cc2F)c(Cl)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
To 100 ml of N,N-dimethylformamide are added 5-(3-chloro-4-chloromethylphenyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (1.60 g) and potassium carbonate (0.60 g) and 2-fluoro-4-trifluoromethyl phenol (0.80 g) is added thereto at room temperature with stirring, which is stirred at 70° C. for 3 hours. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 1.62 g of desired compound (refractive index: 1.6010).
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[I:23]N1C(=O)CCC1=O.O>CN(C=O)C>[OH:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[C:10]([I:23])[C:3]=12
Reactant: Oc1nc[nH]c2nccc1-2
Reactant: O=C1CCC(=O)N1I
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Oc1nc[nH]c2ncc(I)c1-2
Temperature: 40 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of 1.0 g of 4-hydroxypyrrolo [2,3-d]pyrimidine in 20 ml of DMF, 3.3 g (2.2 eq) of bis(trimethylsilyl)acetamide was added, and the resulting solution was stirred at 40° C. in an oil bath for about 2 h. Completeness of silylation was indicated by NMR analysis of an aliquot showing disappearance of the N-3 proton signal. The reaction was cooled to ambient temperature and 1.6 g (1.2 eq) of N-iodosuccinimide (NIS), was added in one portion. The reaction mixture was protected from light and stirred at ambient temperature until completion was indicated by NMR analysis (disappearance of pyrrole C-H doublets and emergence of a single, finely split doublet at δ7.17, about 2 h). The mixture was poured into 50 mL of water with stirring. After 1-2 hours, the product was collected by filtration, washed with water, dried, and reslurried in 10 volumes of 10% methanol in chloroform. Filtration and drying gave 1.7 g of 4-hydroxy- 5-iodopyrrolo[2,3-d]pyrimidine (88% yield), mp 248°-253° C. (dec). 1H NMR (300 MHz, DMSO-d6) δ7.17 (d, J=2.4 Hz, 1 H), 7.80 (d, J=2.3 Hz, 1 H), 11.82 (s, 1 H), 12.14 (s, 1 H). 13C NMR (75.5 MHz, DMSO-d6) δ53.8, 107.3, 125.5, 143.6, 147.9, 157.8. Anal. Calcd for C6H4IN3O: C, 27.61; H, 1.54; N, 16.10. Found: C, 27.71; H, 1.48; N, 15.85.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:20]=[CH:19][C:12]([CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>C(COC)OC>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:20]=[CH:19][C:12]([CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: CS(=O)(=O)NCc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: COc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1-c1cc(Nc2ccc(CNS(C)(=O)=O)cc2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
219 mg N-[4-(6-Chloro-pyrimidin-4-ylamino)-benzyl]-methanesulfonamide (prepared in Example 33) (0.70 mmol) was suspended in 30 cm3 dimethoxyethane and the flask was filled with argon properly. 58 mg Tetrakis(thriphenylphosphine) palladium[0] (0.05 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then 152 mg 2-methoxyphenyl-boronic acid (1 mmol), 318 mg anhydrous Na2CO3 (3 mmol) and 6 ml water was added. The mixture was ferluxed overnight while slow argon flow was being applied. The reaction mixture was poured to 80 cm3 1M NaH2PO4 solution and it was extracted three times with 50-50 cm3 of ethyl-acetate. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated to dryness. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product (173 mg, 45% yield). For analitical results and compound identification see Table 1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:7](=[CH2:26])[C:6]2([CH3:28])[CH3:27].[CH:29](OC)=[O:30]>>[CH:29]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:7](=[CH2:26])[C:6]2([CH3:27])[CH3:28])=[O:30]
Reactant: COC=O
Reactant: C=C1N(CCCCCCCCCCCCCC)c2ccc(CN)cc2C1(C)C
Product: C=C1N(CCCCCCCCCCCCCC)c2ccc(CNC=O)cc2C1(C)C
Temperature: 55 °C
Yield: 68 %

Procedure:
5-aminomethyl-3,3-dimethyl-2-methylene-1-tetradecyl-indoline (14.88 g, 38.75 mmol) was dissolved in methyl formate (75 ml) and heated to reflux (55° C.) under argon for 24 hours. The solution was then cooled to room temperature and the methyl formate evaporated. The residue was recrystallized from hexane to yield 5-(N-formylaminomethyl)-3,3dimethyl-2-methylene-1-tetradecyl-indoline (4) (10.85 g, 68%).
Reaction SMILES: [CH3:1][O:2][P:3]([C@@H:6]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH3:7])(=O)[OH:4].C(Cl)(=O)C(C)(C)C.[OH:26][C@@H:27]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:28]([O:30][CH3:31])=[O:29].NCCCCC(O)C(O)=O>O1CCCC1.C(N(CC)CC)C>[CH2:12]([O:11][C:9]([NH:8][C@H:6]([P:3]([O:2][CH3:1])([O:26][C@@H:27]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:28]([O:30][CH3:31])=[O:29])=[O:4])[CH3:7])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COP(=O)(O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](O)CCCCNC(=O)OC(C)(C)C
Agent: CC(C)(C)C(=O)Cl
Agent: NCCCCC(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)OP(=O)(OC)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.6 %

Procedure:
(R)-1-(benzyloxycarbonylamino)ethylphophonic acid monomethyl ester (40.7 mg) described in Biochemistry, 6294(1989) was dissolved in tetrahydrofuran (1 ml), and pivaloyl chloride (71.8 mg) and triethylamine (90.4 mg) were added. The mixture was stirred at room temperature for 30 minutes, then added with a tetrahydrofuran (1 ml) solution of methyl (S)-2-hydroxy-6-(tert-butoxycarbonylamino)hexanoate (38.9 mg), which is obtainable from 6-amino-2-hydroxyhexanoic acid described in Chem. Pharm. Bull., 621(1976) by a conventional method, and stirred at room temperature overnight. The organic substances were extracted with ethyl acetate and the extract was washed with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. The residue was purified by silica gel thin-layer chromatography to obtain methyl (S)-2-(((R)-1-(benzyloxycarbonylamino)ethyl)(methoxyphosphinoyl)oxy)-6-(tert-butoxycarbonylamino)hexanoate (9.7 mg, 13%). This compound was subjected to the measurement of molecular weight and then used in the following reaction.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:13]=[C:12](O)[C:11]2[C:6](=[N:7][C:8]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][CH:10]=2)[N:5]=1.O=P(Cl)(Cl)[Cl:27].N1C(C)=CC=CC=1C>C(Cl)(Cl)Cl>[Cl:27][C:12]1[C:11]2[C:6](=[N:7][C:8]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:3][O:2][CH3:1])[CH:13]=1
Reactant: COCc1cc(O)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: COCc1cc(Cl)c2ccc(-c3ncccc3C(F)(F)F)nc2n1

Procedure:
2-Methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-[1,8]napthyridin-4-ol (191 mg, 0.569 mmol) is dissolved in a solution of chloroform (15 mL), POCl3 (0.212 mL, 2.28 mmol) and 2,6-lutidine (0.256 mL, 2.28 mmol). The reaction is heated at reflux overnight. The mixture is concentrated under reduced pressure. The resulting residue is dissolved in EtOAc (50 mL) and extracted with water (50 mL), saturated NaHCO3(aq) (50 mL) and brine (50 mL). The organic extract is dried over Na2SO4 and the solvent removed under reduced pressure. The crude product is purified by column chromatography on silica gel eluting with hexanes/EtOAc (1:1) to yield the title compound as a white solid.
Reaction SMILES: Cl.[C:2]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].C(N(CC)CC)C.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34])([O-:26])=[O:25]>C(Cl)Cl>[C:5]([O:4][C:2](=[O:3])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N+:24]([O-:26])=[O:25])(=[O:34])=[O:35])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.2 %

Procedure:
To a stirred solution of N-Boc 1, 6-diaminohexane hydrochloride (1.51 g, 6 mmol) and triethyl amine (1.31 g, 13 mmol) in 50 mL methylene chloride was added 2-Nitrobenzenesulfonyl chloride (1.326 g, 6 mmol). The reaction mixture was stirred for 6 h at room temperature, quenched with brine, and extracted with methylene chloride (2×50 mL). The organic layer was washed with brine (a saturated solution of sodium chloride in water, unless otherwise specified), dried over anhydrous sodium sulfate, and concentrated in vacuo to yield the titled compound as yellow oil (2.1 g, 87%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[C:5](=[O:17])[CH2:4]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C([O-])(O)=O.[Na+]>ClCCl>[CH:14]([C:11]1[CH:12]=[CH:13][C:8]([N:6]2[C:5](=[O:17])[CH2:4][CH:3]([CH2:2][O:1][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:7]2)=[CH:9][CH:10]=1)([CH3:15])[CH3:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1ccc(N2CC(CO)CC2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(N2CC(COS(C)(=O)=O)CC2=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A mixture of 4-hydroxymethyl-1-(4-isopropyl-phenyl)-pyrrolidin-2-one obtained in step 3 (0.5 g, 2.14 mmol), dichloromethane (8 ml) and triethyl amine (0.30 g, 3.0 mol) was cooled to 0° C. and stirred for 15 min at that temperature. Methane sulfonyl chloride (0.3 g, 2.56 mmol) was added to the mixture over a period of 5 min and the reaction mixture was stirred for 1.5 hrs at 10-15° C. To this reaction mixture saturated NaHCO3 solution (10 ml) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (20 ml). The combined organic layer was washed with saturated brine solution, dried over Na2SO4 and evaporated to obtain methanesulfonic acid 1-(4-isopropyl-phenyl)-5-oxo-pyrrolidin-3-ylmethyl ester as a brown oil (0.6 g, 90%).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])([O-])=O.[CH3:25]C(C)([O-])C.[K+].CI>CN(C)C=O>[NH2:1][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[N:6]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:25]
Reactant: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2ccccc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1c(N(C)c2ccccc2N)sc2ccccc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
Ethyl 2-(2-nitroanilino)benzo[b]thiophene-3-carboxylate (6.0 g) was dissolved in N,N-dimethylformamide (120 ml) and the mixture was stirred at 0° C., during which potassium tert-butoxide (3.0 g) was added portionwise. Methyl iodide (12.4 g) was added dropwise under ice-cooling and the mixture was stirred at 0° C. for 5 min and heated to room temperature. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. After natural filtration, the solvent was evaporated under reduced pressure, and the residue was separated by silica gel column chromatography (hexane:ethyl acetate=4:1) to give crude crystals (2.8 g) of ethyl 2-(N-methyl-2-nitroanilino)benzo[b]thiophene-3-carboxylate. Without purification, the crystals were treated in the same manner as in Starting Material Synthesis Example 21 using ethanol (50 ml), 18% hydrochloric acid (50 ml) and tin(II) chloride-dihydrate (12.6 g) to give ethyl 2-(2-amino-N-methylanilino)benzo[b]thiophene-3-carboxylate (3.2 g).