Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=O)[CH3:13]>>[CH3:12][C:13]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([Br:11])[C:2]=2[N:1]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(Br)cccc1C(=O)O
Product: Cc1nc2c(Br)cccc2c(=O)o1
Temperature: 110 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
Part A: A mixture of 19.2 g (89 mmol) of 2-amino-3-bromo benzoic acid (Beistein vol 14,369,vol IV,pg 1080) and 75 ml (0.79 mol) of acetic acid anhydride was heated to 110° C. under nitrogen with stirring for 3 hours. After cooling the mixture was concentrated in vacuo and co-evaporated twice with toluene. The product was purified over silicagel using CH2Cl2 as the eluent. A total of 17.0 g of 2-methyl-8-bromo-3,1-benzoxazin-4-one was obtained (80% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:26]([F:29])([F:28])[F:27])/[CH:10]=[CH:11]/[C:12]2[CH:24]=[CH:23][C:15]([C:16]([NH:18][CH:19]3[CH2:22]S[CH2:20]3)=[O:17])=[C:14]([F:25])[CH:13]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O[O:31][S:32]([O-:34])=O.[K+]>CC(C)=O.O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:26]([F:29])([F:28])[F:27])/[CH:10]=[CH:11]/[C:12]2[CH:24]=[CH:23][C:15]([C:16]([NH:18][CH:19]3[CH2:22][S:32](=[O:34])(=[O:31])[CH2:20]3)=[O:17])=[C:14]([F:25])[CH:13]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(NC1CSC1)c1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1F
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC1CS(=O)(=O)C1)c1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (E)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluoro-N-(thietan-3-yl)benzamide (100 mg, 0.2159 mmol) in acetone/water (1:1, 5.0 mL) was added oxone (266 mg, 0.4319 mmol) and the resultant reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% ethyl acetate/pet ether) afforded the title compound as an off white solid (70.0 mg, 66%): 1H NMR (400 MHz, CDCl3) δ 8.07 (t, J=8.4 Hz, 1H), 7.39 (t, J=1.6 Hz, 1H), 7.31 (d, J=1.2 Hz, 1H), 7.26 (m, 2H), 7.23 (m, 2H), 7.19 (d, J=1.6 Hz, 1H), 6.60 (d, J=16.8 Hz, 1H), 6.49 (dd, J=16.8, 7.6 Hz, 1H), 4.90 (m, 1H), 4.64 (m, 2H), 4.14 (m, 2H); ESIMS m/z 493.83 ([M−H]−); IR (thin film) 1527, 1113, 801, 1167, 1321 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C[Al](C)C.[CH2:13]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22](OCC)=[O:23])=[N:20][CH:21]=1)[CH3:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:13][CH3:14])=[CH:21][N:20]=1)=[O:23]
Reactant: Nc1ccccc1Cl
Reactant: CCOC(=O)c1ccc(OCC)cn1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCOc1ccc(C(=O)Nc2ccccc2Cl)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of o-chloroaniline (0.68 g, 5.3 mmol) in 20 mL of PhMe was added 3 mL of AlMe3. The mixture was stirred at ambient temperature for 0.5 h and added into a solution of ethyl 5-ethoxypyridine-2-carboxylate 3 (0.26 g, 1.33 mmol) in 10 mL of PhMe. The mixture was stirred at ambient temperature for 15 h and quenched with 20 mL of 1N HCl. The mixture was extracted with ethyl acetate. The organic layer was separated and concentrated. The residue was purified by column (2:1 of hexane/ethyl acetate) to give N-(2-chlorophenyl)-5-ethoxypyridine-2-carboxamide 4 as a solid. Yield: 310 mg, 96%.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12](C2C=CC=CC=2C(OCC)=O)[C:11](=[O:24])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:25])[CH:9]=2)[N:4]=1.[NH3:26]>C(OCCO)C>[Cl:25][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[C:3]3[CH2:2][NH:26][C:11](=[O:24])[C:10]4[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=4[N:12]3[C:11](=[O:24])[C:10]=2[CH:9]=1
Reactant: CCOC(=O)c1ccccc1-n1c(CCl)nc2ccc(Cl)cc2c1=O
Reactant: N
Solvent: CCOCCO
Product: O=C1NCc2nc3ccc(Cl)cc3c(=O)n2-c2ccccc21
Yield: 83 %

Procedure:
18.9 g (0.05 mol) of 2-chloromethyl-3-(2-ethoxycarbonylphenyl)-6-chloro-4H-quinazolin-4-one and 50 ml of liquid ammonia in 150 ml of ethylene glycol monoethyl ether are heated to 60° C. for 3 hours in an autoclave. After cooling the mixture, the colourless crystals are filtered off and washed several times with methanol. 13 g (83% of theory) of 11-chloro-6,7-dihydro-5H,13H-quinazolino[3,2-a][1,4]benzodiazepine-5,13-dione are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[I-:11]>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][CH2:7]2)=[CH:3][C:2]=1[NH2:1]
Reactant: Nc1ccc2c(c1)CCC2
Reactant: [I-]
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: Nc1cc2c(cc1I)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
A mixture of 5-aminoindan (423 mg, 3.17 mmol), silver sulfate (990 mg, 3.17 mmol) and iodide (805 mg, 3.17 mmol) in methanol (20 mL) was stirred at room temperature overnight. The mixture was filtered and the solid was washed with a small amount of methanol. The filtrate was quenched with saturated Na2S2O3 and then diluted with water. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried (Na2SO4) and concentrated in vacuo. Flash chromatography (Si, hexanes/EtOAc) of the residue yielded 6-iodoindan-5-amine (354 mg, 43%). LCMS calc.=258.99; found=260.0 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.51 (s, 1H), 6.69 (s, 1H), 3.97 (br, s, 2H), 3.02-2.90 (m, 1H), 2.81 (d, J=7.1 Hz, 3H), 2.12-2.02 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([CH:10]=[CH:11][Si](C)(C)C)[CH:7]=[C:6]([N+:16]([O-:18])=[O:17])[CH:5]=1.Cl>C(#N)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([CH:10]=[CH2:11])[CH:7]=[C:6]([N+:16]([O-:18])=[O:17])[CH:5]=1
Reactant: COC(=O)c1cc(C=C[Si](C)(C)C)cc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC#N
Product: C=Cc1cc(C(=O)OC)cc([N+](=O)[O-])c1

Procedure:
3-Nitro-5-(2-trimethylsilylvinyl)benzoic acid methyl ester (2.44 g, 8.71 mmol) was dissolved in acetonitrile (150 ml), the solution was heated to reflux temperature and HCl gas was bubbled through the solution until the starting material had disappeared according to HPLC analysis. The solution was allowed to cool and the solvent was removed by evaporation. The residue was >95% pure according to HPLC and was used without further purification. Yield: 2.02 g (89%).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([N:2]1[CH2:3][CH:4]2[CH2:8][N:7]([C:23]3[O:24][C:25]4[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=4[N:27]=3)[CH2:6][CH:5]2[CH2:1]1)=[O:10]
Reactant: Clc1nc2ccccc2o1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Product: O=C(c1ccccc1-c1cccs1)N1CC2CN(c3nc4ccccc4o3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-benzooxazole. MS (ESI): mass calculated for C24H21N3O2S, 415.52; m/z found 416.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.83-6.68 (m, 11H), 4.20-2.47 (m, 10H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][CH2:4][C:5]([NH:7][CH:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][CH2:9]1)=[O:6].O.Cl>CO>[Cl:3][CH2:4][C:5]([NH:7][C@H:8]1[C@H:17]([OH:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][CH2:9]1)=[O:6]
Reactant: O=C(CCl)NC1COc2ccccc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(CCl)N[C@@H]1COc2ccccc2[C@H]1O
Yield: 99.3 %

Procedure:
Sodium borohydride (0.9 g, 23.8 mol) was added to a solution of 2-chloro-N-(4-oxo-chroman-3-yl)-acetamide (3.5 g, 14.6 mmol) in methanol (30 ml). When the reaction was complete (checked by thin layer chromatography), excess reagent was decomposed by the addition of water and pH was adjusted to 5-6 with 3N aqueous hydrochloric acid. The solution was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 2-chloro-N-((3RS,4RS)-trans-4-hydroxychroman-3-yl)-acetamide (3.5 g, 14.5 mmol, 99%) as white crystals.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+].[O:14]1C=CC=[CH:16][CH:15]1OCCBr.Cl>CO.CC(N(C)C)=O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][CH2:15][OH:14])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: BrCCOC1C=CC=CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CS(=O)(=O)c1ccc(OCCO)cc1
Yield: 37.9 %

Procedure:
A mixture of 4-methanesulfonylphenol (1.72 g, 10 mmol), DMA (25 ml) and 4 N sodium hydroxide (7 ml) was stirred under an atmosphere of nitrogen. 2-(2-Pyranyloxy)ethylbromide (2.8 g, 14 mmol) was added dropwise and then the mixture was stirred overnight at ambient temperature. The solvent was evaporated in vacuo and the residue was taken up in water (100 ml). The aqueous mixture was extracted with ethyl acetate (2×100 ml) and the combined organic extracts were washed with a 0.5 N sodium hydroxide solution and brine. The organic phase was concentrated to give an oily residue that was dissolved in methanol (50 ml). A solution of 5 N HCl (20 ml) was added and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated and a small portion of ice was added followed by 4 N sodium hydroxide until approximately pH 10. The alkaline mixture was extracted with ethyl acetate (3×75 ml) and the combined organic extracts were washed with water and dried (MgSO4). The solvent was evaporated to give 0.82 g (38%) of 2-(4-methanesulfonylphenoxy)ethanol. M.p. 89–90° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]([OH:12])=O)=[CH:6][N:5]2[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10](=[O:12])[N:22]([CH3:21])[O:23][CH3:24])=[CH:6][N:5]2[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNOC
Reactant: Nc1nc2ccc(C(=O)O)cn2c1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc2nc(N)c(-c3ccccc3)n2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
The 2-amino-3-phenyl-6-(carboxy)imidazo-[1,2-a]-pyridine (80.4 g, 0.317 mol) and N,O-dimethylhydroxylamine hydrochloride (92.8 g, 0.951 mol) were dissolved in 500 ml DMF under N2. The diisopropylethylamine (123 g, 0.951 mol) was added and the mixture stirred for 30 minutes at RT. The 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (122 g, 0.634 mol) was added and allowed to stir for 19 hours at RT. The DMF was removed in vacuo and the residue was poured onto 4 L of H2O. The aqueous layer was extracted with CH2Cl2 (3×500 ml) and the organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was taken up in 400 ml of EtOAc and stirred for 1 hour at RT to form the precipitate. The precipitate was filtered and washed with cold EtOAc. The filter cake was dried in vacuo at 40° C. to yield 55.5 g of product. (59.2%). MS(FD), NMR.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH3:15])(=[O:5])=[O:4].[BH4-].[Na+]>C1COCC1>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][C:7]=1[O:14][CH3:15])(=[O:4])=[O:5]
Reactant: COc1cc(C=O)ccc1S(=O)(=O)N(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.4 %

Procedure:
To a solution of OBS02011 (5.5 g, 21.21 mmol) in anhydrous THF (50 mL) was added sodium borohydride (0.88 g, 23.33 mmol). The mixture was stirred at room temperature for 4 h, quenched with water (CARE!!) and filtered through a Celite pad. The filtrate was concentrated in vacuo and re-dissolved in DCM (200 mL). The organic layer was washed with brine (2×200 mL), dried (Na2SO4) and filtered. Concentration in vacuo of the combined filtrates gave OBS02014 as a pale yellow oil (5.12 g, 92%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.18; 1H-NMR (270 MHz, CDCl3)=2.44 (1H, bs, OH), 2.92 (6H, s), 3.84 (3H, s), 4.60 (2H, s), 6.85 (1H, dd, J=2.2, 8.4), 6.97 (1H, d, J=1.8), 7.25 (1H, d, J=8.1). 4-(N,N-Dimethylsulfamoyl)-3-methoxybenzyl chloride (OBS02016)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH:26]1([NH2:33])[CH2:31][CH2:30][CH2:29][CH:28]([NH2:32])[CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:32][CH:28]3[CH2:29][CH2:30][CH2:31][CH:26]([NH2:33])[CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NC1CCCC(N)C1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3CCCC(N)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and cyclohexane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (d, J=7.8 Hz, 1 H), 7.57 (d, J=7.3 Hz, 1 H), 7.53-7.47 (m, 2 H), 7.37 (t, J=7.7 Hz, 1 H), 7.32-7.26 (m, 2 H), 5.86 (s, 1 H), 5.16-5.00 (m, 2 H), 3.65-3.50 (brs, 4 H), 3.16 (brs, 1 H), 2.42 (s, 3 H), 2.45-2.38 (m, 1 H), 2.29 (d, J=11.1 Hz, 1 H), 2.03-1.85 (m, 3 H), 1.54-1.42 (m, 1 H), 1.40-1.24 (m, 3 H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]C(C)(C)C.[CH:15]1[C:20]([CH:21]=[O:22])=[CH:19][C:18]2[O:23][CH2:24][O:25][C:17]=2[CH:16]=1>C1COCC1>[S:1]1[C:5]([CH:21]([OH:22])[C:20]2[CH:15]=[CH:16][C:17]3[O:25][CH2:24][O:23][C:18]=3[CH:19]=2)=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: c1ccc2sccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: OC(c1ccc2c(c1)OCO2)c1cc2ccccc2s1

Procedure:
a-(2-Benzo[b]thienyl)-3,4-(methylenedioxy)benzyl alcohol was prepared by the method of Example 40A using benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 9.7 mmoles, 5.7 ml), piperonal (8.9 mmoles, 1.0 g) and THF (20 ml). Flash chromatography (20% ethyl acetate/hexanes) provided 1.6 g (74%) of a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][CH2:7]2.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl.[OH-].[Na+].O>COCCO>[O:1]=[C:2]1[C:11]2[C:10]([O:12][CH2:13][CH:15]3[O:17][CH2:16]3)=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: ClCC1CO1
Reactant: O=C1CCCc2cccc(O)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: O=C1CCCc2cccc(OCC3CO3)c21

Procedure:
To the solution heated to 80° C. of 3.2 g of 8-hydroxy 1-tetralone and 20 ml of epichlorohydrin in 20 ml of 2-methoxy ethanol is added 1.8 g of sodium hydroxide and the mixture is heated to reflux for 1 hour. Water is added and the mixture is extracted with methylene chloride. The organic phase is separated, dried and the solvent is evaporated.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([OH:15])=O)=[CH:8][CH:7]=[CH:6]2)[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][CH:30]=1)[O:20][CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23].C([O-])(=O)C>>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([NH:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][CH:30]=1)[O:20][CH2:21][C:22]([O:24][CH:25]([CH3:26])[CH3:27])=[O:23])=[O:15])=[CH:8][CH:7]=[CH:6]2)[CH3:2]
Reactant: CC(C)OC(=O)COc1cccc(N)c1
Reactant: CCc1ccc2c(C(=O)O)cccc2c1
Agent: CC(=O)[O-]
Product: CCc1ccc2c(C(=O)Nc3cccc(OCC(=O)OC(C)C)c3)cccc2c1

Procedure:
In accordance with the procedure of Example 1, step 5, 6-ethyl-1-naphthoic acid (51 mg, 0.25 mmol) and isopropyl 2-(3-aminophenoxy)acetate (64 mg, 0.31 mmol) were converted into 34 mg (34%) of isopropyl 243-(6-ethyl-1-naphthamido)phenoxy)acetate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:8]Cl)=[N:4][CH:5]=[CH:6][N:7]=1.C[Si]([C:14]#[N:15])(C)C>C(#N)C>[Cl:1][C:2]1[C:3]([S:8][C:14]#[N:15])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: ClSc1nccnc1Cl
Reactant: C[Si](C)(C)C#N
Solvent: CC#N
Product: N#CSc1nccnc1Cl
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1.81 grams (0.01 mole) of 3-chloro-2-pyrazinesulfenyl chloride was dissolved in acetonitrile with stirring under nitrogen at 0° C. To the stirred solution, 0.99 gram (0.01 mole) of trimethylsilyl cyanide was added rapidly and the stirring continued for 18 hours. At the end of this period, the acetonitrile and residual trimethylsilyl cyanide were removed by blowing a stream of nitrogen over the reaction mixture and the desired product recovered as residue. The product was crystallized from ethanol to obtain a purified product, m.p. 70°-71° C., in an amount of 0.64 gram. The product had elemental analyses as follows.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:15])[C:11]([OH:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[P:16]([O:23]CC)([O:20]CC)[O:17]CC.C[Si](Br)(C)C>ClCCl>[OH:14][C:11]([CH3:13])([CH3:12])[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][P:16](=[O:17])([OH:23])[OH:20])=[CH:5][CH:6]=1)=[O:15]
Reactant: CC(C)(O)C(=O)c1ccc(CCBr)cc1
Reactant: CCOP(OCC)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CC(C)(O)C(=O)c1ccc(CCP(=O)(O)O)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
A mixture of 10 g of 1-[4-(2-bromoethyl)phenyl]-2-hydroxy-2-methylpropan-1-one (0.037 moles) and 6.7 g (0.041 mol) of triethyl phosphite is heated externally at 140° C. for 24 hours. The reaction mixture is distilled to give 12.1 g of 2-[4-(2-hydroxy-2-methylpropionyl)phenyl]ethyl}phosphonic acid dimethyl ester. The ester is dissolved in 50 ml of dichloromethane, and a solution of 6.2 g (0.0405 mol) of trimethylsilyl bromide in 10 ml of dichloromethane is added drop wise at room temperature. The reaction mixture is stirred overnight. The reaction mixture is concentrated, and methanol (200 ml) is added. The mixture is stirred at temperature for 24 hours, and then concentrated to give 5.0 g of the title compound, a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11].O.[C-:17]#[N:18].[Na+]>CN(C=O)C>[C:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])#[N:18]
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CC#N
Yield: 84.4 %

Procedure:
A mixture of the product of example 28 (˜90% pure, 729 mg, 2.46 mmol) in a mixture of DMF:H2O (3 mL:2 mL) and sodium cyanide (362 mg, 7.4 mmol) was stirred at room temperature overnight. The resulting mixture was quenched with saturated NaHCO3 (12 mL) and extracted with ethylacetate (3×30 mL). The extracts were combined and washed with saturated NaCl (2×30 mL) and water (2×30 mL). The organic layer was separated, dried over anhydrous MgSO4 and concentrated under reduced pressure to give the titled product as colourless oil (503 mg, 85% yield).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[CH:6][CH:5]=1)([O-])=O.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:1][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([O:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]3)=[CH:6][CH:5]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc([N+](=O)[O-])c3ccccc23)C1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(NS(=O)(=O)c3ccc(Cl)cc3)c3ccccc23)C1
Yield: 88.4 %

Procedure:
The compound was prepared from tert-butyl (3R)-3-[(4-nitro-1-naphthyl)oxy]pyrrolidine-1-carboxylate (0.3 g, 0.9 mmol) and 4-chloro-phenylsulfonylchloride (0.23 g, 1.1 mmol). Yield: 0.4 g (87%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (d, J=4.52 Hz, 9H) 2.15-2-34 (m, 2H) 3.54-3.74 (m, 4H) 5.05 (br s, 1H) 6.60-6.66 (m, 2H) 7.17-7.23 (m, 1H) 7.33 (d, J=8.53 Hz, 1H) 7.39-7.43 (m, 2H) 7.62-7.64 (m, 2H) 7.65-7.70 (m, J=6.02 Hz, 1H) 8.18 (d, J=8.53 Hz, 1H) MS (ESI+) for C25H27ClN2O5S m/z 520.2 (M+NH4)+, 447.0 (M−tBu)+. HPLC 100%, RT=2.769 min (System A1, 10-97% MeCN over 3 min).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[C:4]([NH2:21])[N:3]=1.CO.[OH-].[Na+].Cl[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1>CN(C)C=O>[CH3:27][C:28]1[N:29]=[C:30]([CH2:34][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C:10]3[CH:9]=[C:8]([C:7]4[C:2]([NH2:1])=[N:3][C:4]([NH2:21])=[CH:5][CH:6]=4)[O:12][N:11]=3)=[CH:15][CH:16]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Cc1cccc(CCl)n1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cccc(COc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)n1
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 51.6 %

Procedure:
To 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (150 mg, 0.53 mmol) described in Manufacturing Example 18-1-1 were added methanol (3 mL) and 1 N aqueous sodium hydroxide solution (0.53 mL), which was then dissolved by irradiating ultrasonic wave. This solution was concentrated under a reduced pressure. To the resulting residue was added 2-chloromethyl-6-methyl-pyridine (90.2 mg, 0.64 mol.) described in manufacturing Example 10-1-1 and N,N-dimethylformamide (2 mL), which was stirred for 2 hours and 50 minutes at 60° C. The reaction solution was partitioned into water and ethyl acetate. The organic layer was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2, then ethyl acetate) to obtain the title compound (106 mg, 51.5%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12](Cl)(=[O:14])=[O:13])=[CH:4][CH:3]=1.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(Cl)Cl>[CH:16]1([NH:22][S:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:14])=[O:13])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC2CCCCC2)c2ccccc12
Yield: 66.1 %

Procedure:
To a solution of 4-methyl-naphthalene -1-sulfonyl chloride (2.4 g, 10.0 mnmol) in CH2Cl2 (30 mL), was added cyclohexylamine (1.4 g, 11.0 mmol) and triethylamine (2.8 mL, 20.0 mmol) and the resultant solution was stirred at room temperature overnight. The solution was quenched with water and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by Flash columin chromatography (hexane/ethyl acetate, gradient elution) to give the title compound 40 (2.0 g) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.63 (d, 1H), 8.18 (d, 1H1), 8.10 (d, 1H1), 7.64 (m, 2H), 7.38 (d, 1H), 3.08 (m, 1H), 2.76 (s, 3H), 1.52 (m, 5H), 1.09 (m, 5H); LC/MS m/z 304 (M+H)+.