Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]12[N:8]([C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3[O:21][N:20]=[C:19]([CH3:22])[N:18]=3)=[O:10])[CH2:7][C@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.Cl[C:24]1[N:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[N:25]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:31][C:26]1[CH:27]=[C:28]([CH3:30])[N:29]=[C:24]([N:3]2[CH2:4][CH2:5][C@H:6]3[C@H:1]([N:8]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[O:21][N:20]=[C:19]([CH3:22])[N:18]=4)=[O:10])[CH2:7]3)[CH2:2]2)[N:25]=1
Reactant: Cc1noc(-c2ccccc2C(=O)N2C[C@H]3CCNC[C@H]32)n1
Reactant: Cc1cc(C)nc(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)nc(N2CC[C@@H]3CN(C(=O)c4ccccc4-c4nc(C)no4)[C@@H]3C2)n1
Temperature: 200 °C
Yield: 59.6 %

Procedure:
A mixture of Intermediate 12 (50 mg, 0.17 mmol), 2-chloro-4,6-dimethylpyrimidine (24 mg, 0.17 mmol) and DIPEA (0.87 mL, 0.5 mmol) in ACN (1 mL) was heated in the microwave at 200° C. for 90 min. The mixture was concentrated in vacuo and was purified on a Prep Agilent system with a XBridge C18 OBD 50×100 mm column eluting with 5 to 99% 0.05% NH4OH in H2O/ACN over 17 min to afford the desired product as a colorless foam (41 mg, 60%). MS (ESI) mass calculated for C22H24N6O2, 404.20; m/z found, 405.2. 1H NMR (500 MHz, CDCl3): 8.12-8.03 (m, 1H), 7.59-7.49 (m, 2H), 7.41-7.36 (m, 1H), 6.31-6.26 (m, 1H), 4.41-4.23 (m, 3H), 4.11-4.05 (m, 1H), 4.05-3.78 (m, 2H), 3.68-3.64 (m, 0H), 3.05-2.83 (m, 2H), 2.46-2.40 (m, 3H), 2.34-2.24 (m, 6H), 2.15-2.04 (m, 1H), 2.00-1.86 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:26]1C=C(C)C=CC=1[N+]([O-])=O>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([O:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[CH3:26])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc([N+](=O)[O-])c(OC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Product: Cc1ccc([N+](=O)[O-])c(O[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 53.6 %

Procedure:
In a similar manner to that described for the preparation of (S)-2-(tert-butoxycarbonylamino)-3-(5-methyl-2-nitrophenoxy)propanoic acid except the reaction mixture was stirred at 0° C. for 4 h, (2S,3S)-2-(tert-butoxycarbonylamino)-3-hydroxybutanoic acid DCHA (2.0 g, 5.00 mmol) and 2-fluoro-4-methyl-1-nitrobenzene (1.55 g, 9.99 mmol) were converted to (2S,3S)-2-tert-butoxycarbonylamino-3-(5-methyl-2-nitro-phenoxy)-butyric acid (0.95 g, 53.6% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([C:12]2([CH3:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:21]1([OH:27])C=CC=CC=1.C(Cl)(Cl)Cl.Cl>C(O)C.O>[C:1]([C:5]1[CH:10]=[C:9]([CH:21]=[O:27])[C:8]([OH:11])=[C:7]([C:12]2([CH3:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)c1ccc(O)c(C2(C)CCCCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(C=O)c(O)c(C2(C)CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
4-t-butyl-2-(1-methylcyclohexyl)phenol (7.0 g, 0.028 mole) was dissolved in 10 ml of absolute ethanol in a 100 ml round bottom flask equipped with a water-cooled condenser. Sodium hydroxide (11.4 g, 0.28 mole) was dissolved in 10 ml water and added while still hot to the solution of phenol. Chloroform (6.8 g, 0.057 mole) was added in 2 to 3 ml portions over a 10-minute period. The resulting brown mixture was stirred for 1 hour while it cooled to ambient temperature. The mixture was added to 25 ml of 5M hydrochloric acid. The organic layer was isolated in a separatory funnel and dried over anhydrous magnesium sulfate. The mixture was filtered and rotoevaporated to a thick syrup to an assumed yield of 30% of the crude product with an IR spectrum having the characteristic aldehyde carbonyl stretching frequency. The product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:12][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:10][C:5]2=[N:6][C:7]=1[CH2:8][OH:9].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])[N:10]([CH2:18][C:19](=[O:20])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:5]2=[N:6][C:7]=1[CH2:8][OH:9]
Reactant: CCCCc1nc2nc(CO)c(Br)cc2[nH]1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc2cc(Br)c(CO)nc2n1CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.2 %

Procedure:
10 g(0.0352 mole) of the compound obtained in step 6, 7.59 g(0.0387 mole) of 2-bromoacetophenone and 9.8 g(0.0704 mole) of K2CO3 were dissolved in 50 ml of dimethyl formamide. The reaction solution was stirred for 3 hours at room temperature, diluted with 200 ml of ethyl acetate and washed with water(100 ml×3). The organic layer was dried over Na2SO4 and purified with column chromatography(silica gel, methylene chloride:ethyl acetate =1:1) to obtain 6.96 g of the title compound(yield 64%).
Reaction SMILES: C([O:4][C:5]1[C:6]([O:33]C(C)C)=[CH:7][C:8]2[C:21]3[C:12](=[C:13]4[C:18](=[CH:19][N:20]=3)[C:17]([O:22]CC3C=CC=CC=3)=[C:16]([O:30][CH3:31])[CH:15]=[CH:14]4)[CH:11]=[CH:10][C:9]=2[CH:32]=1)(C)C.[C:37]1([CH3:48])[CH:42]=[CH:41][C:40]([S:43]([O:46]C)(=[O:45])=[O:44])=[CH:39][CH:38]=1.[C:49]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[S:43]([C:40]1[CH:41]=[CH:42][C:37]([CH3:48])=[CH:38][CH:39]=1)([O-:46])(=[O:45])=[O:44].[OH:4][C:5]1[C:6]([OH:33])=[CH:7][C:8]2[C:21]3[C:12](=[C:13]4[C:18](=[CH:19][N+:20]=3[CH3:49])[C:17]([OH:22])=[C:16]([O:30][CH3:31])[CH:15]=[CH:14]4)[CH:11]=[CH:10][C:9]=2[CH:32]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc2c(cnc3c4cc(OC(C)C)c(OC(C)C)cc4ccc23)c1OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COc1ccc2c(c[n+](C)c3c4cc(O)c(O)cc4ccc23)c1O
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
2,3-diisopropoxy-7-benzyloxy-8-methoxybenzo[c]phenanthridine (compound D-6) and methyl p-toluenesulfonate were subjected to a reaction operation in a manner similar to Example 16 to produce compound E-6, which was further treated with p-toluenesulfonic acid in the presence of methanol, so that compound A-6, wherein X- =OTs-, was obtained.
Reaction SMILES: CC1C(C([NH:10][NH2:11])=O)=NC=CC=1.[CH3:12][C:13]1[C:18]([C:19]([O:21]CC)=O)=[CH:17][CH:16]=[CH:15][N:14]=1.CC1N=C(C(OCC)=O)C=CC=1>>[CH3:12][C:13]1[C:18]([C:19]([NH:10][NH2:11])=[O:21])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)c1cccnc1C
Reactant: Cc1cccnc1C(=O)NN
Agent: CCOC(=O)c1cccc(C)n1
Product: Cc1ncccc1C(=O)NN

Procedure:
2-Methyl-3-pyridinecarbohydrazide was prepared in a manner analogous to that described above for 3-methyl-2-pyridinecarbohydrazide (I22) but using ethyl 2-methyl-3-pyridinecarboxylate (CAS [1721-26-2], commercially available e.g. from Sigma-Aldirch or Alfa Aesar) in the place of ethyl 6-methyl-2-pyridylcarboxylate.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[NH:8][CH:9]=[CH:10][C:11]=1[NH2:12])=[O:6])C.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH:23]=O.[BH3-]C#N.[Na+].CCN(CC)CC.C([N:44]=[C:45]=[S:46])(=O)C1C=CC=CC=1>CO>[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:23][N:12]1[C:11]2[CH:10]=[CH:9][NH:8][C:7]=2[C:5](=[O:6])[NH:44][C:45]1=[S:46]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Reactant: CCOC(=O)c1[nH]ccc1N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=c1[nH]c(=S)n(Cc2c[nH]c3ccc(F)cc23)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
3-Amino-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride (0.10 g, 0.52 mmol) was dissolved in methanol (4 mL) and 5-fluoro-1H-indole-3-carboxaldehyde (0.10 g, 0.63 mmol), NaCNBH3 (0.033 g, 0.52 mmol) and Et3N (0.073 g, 0.52 mmol) were added. The resulting mixture was stirred at r.t. overnight. Additional NaCNBH3 (0.01 g) was added and the mixture was heated at 50° C. for 5 h. The reaction mixture was cooled to r.t. and concentrated in vacuo. The crude intermediate was dissolved in CH2Cl2 (3 mL) and methanol (1 mL). Benzoyl isothiocyanate (0.078 mL, 0.58 mmol) was added and after stirring at r.t. for 1 h the mixture was concentrated in vacuo. The residue was dissolved in ammonia (7N in methanol, 3 mL) and heated at 80° C. for 2 h. The solvent was removed in vacuo and after purification by preparative, HPLC, the title compound (0.035 g, 21%) was obtained as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].S(=O)(=O)(O)O.[C:17]([O-])(O)=O.[Na+]>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: O=C([O-])O
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Br)c(C)c1

Procedure:
4-Bromo-3-methylbenzoic acid (10 g) was suspended in methanol (50 ml) containing conc. sulphuric acid (2 ml). The mixture was heated to reflux for 18 h, On addition of 8% NaHCO3 (100 ml) to the cooled reaction, a flocculent solid was filtered off and dried in vacuo at 40°-45° to give the title compound as a liquid which recrystallised on cooling (10.25 g) m.p. 39.5°-40.5°
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][O:18][CH3:19]>N1C=CC=CC=1>[CH3:19][O:18][N:17]=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: O=C(Cc1ccncc1)c1cccc(F)c1
Reactant: CON
Solvent: c1ccncc1
Product: CON=C(Cc1ccncc1)c1cccc(F)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A solution of 1-(3-fluorophenyl)-2-(pyridin-4-yl)ethanone, (18) (3.6 g, 16.17 mmol) in pyridine (20 mL) was added NH2OMe (2.8 g, 33.4 mmol), at room temperature. The mixture was stirred at 80° C. for 3 h. The reaction was cooled to room temperature and quenched with water (20 mL). The aqueous layer was extracted with dichloromethane (3×, 100 ml). The pooled organic layer was dried over magnesium sulfate. The mixture was filtered. The solvents were removed under vacuum. Purification by MPLC (0 to 10% methanol in dichloromethane) gave 1-(3-fluorophenyl)-2-(pyridin-4-yl)ethanone O-methyl oxime, (19): as a oil (3.15 mg, 77% yield).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH3:4].Cl[C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN(C)C=O>[O:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=1
Reactant: Clc1nc2ccccc2o1
Reactant: CCCCNCCc1ccc(C#N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCN(CCc1ccc(C#N)cc1)c1nc2ccccc2o1
Yield: 24.5 %

Procedure:
A solution of 750 mg 4-(2-Butylamino-ethyl)-benzonitrile, 854 mg 2-chlorobenzooxazole and 0.95 ml N,N-diisopropylethylamine in 10 ml dimethylformamide were stirred under microwave irradiation at 200° C. for thirty minutes. The cooled reaction mixture was diluted by the addition of 60 ml ethyl acetate, then washed three times with 40 ml brine. The organic layer was dried over MgSO4, then the solvent was removed in vacuo. The residue was purified by RP-HPLC to obtain 290 mg 4-[2-(Benzooxazol-2-yl-butyl-amino)-ethyl]-benzonitrile as pale yellow amorphous solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:11][C@H:10]2[C@H:6]([N:7]=[C:8]([NH:12][CH3:13])[S:9]2)[C@@H:5]([OH:14])[C@@H:4]1[OH:15].C([O-])(O)=O.[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C1COCC1.O>[OH:15][C@@H:4]1[C@@H:3]([CH2:2][OH:1])[O:11][C@H:10]2[C@H:6]([N:7]=[C:8]([N:12]([CH3:13])[C:22](=[O:23])[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[S:9]2)[C@H:5]1[OH:14]
Reactant: CNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 96 h
Yield: 72.9 %

Procedure:
To a suspension of -(3aR,5R,6S,7R,7aR)-5-(hydroxymethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (1.50 g, 6.40 mmol) and NaHCO3 (1.01 g, 12.0 mmol) in THF/water (40 mL, 1:3) was added benzyl chloroformate (1.70 g, 10.0 mmol). The mixture was stirred at room temperature for 4 days. The organic solvent was removed under reduced pressure to result in a precipitate. The precipitated solid was collected by filtration, washed with Et2O and dried under vacuum, affording benzyl (-(3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white solid (1.72 g, 73%). 1H NMR (400 MHz, CD3OD) δ 7.44-7.32 (m, 5H), 6.13 (d, J=6.9 Hz, 1H), 5.27-5.20 (m, 2H), 4.14 (t, J=6.1 Hz, 1H), 4.02 (t, J=4.9 Hz, 1H), 3.74 (dd, J=2.4, 12.0 Hz, 1H), 3.63 (dd, J=6.1, 12.0 Hz, 1H), 3.53 (dd, J=4.5, 9.2 Hz, 1H), 3.47-3.43 (m, 1H), 3.39 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=O)[CH2:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]([O:16][CH3:17])[N:8]=1)[CH3:2].[Cl-].[NH4+]>C1COCC1.C(O)C.[Fe]>[CH2:1]([O:3][C:4]([C:5]1[NH:13][C:12]2[C:7](=[N:8][C:9]([O:16][CH3:17])=[CH:10][CH:11]=2)[CH:6]=1)=[O:19])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1nc(OC)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2nc(OC)ccc2[nH]1

Procedure:
To a suspension of 3-(6-methoxy-3-nitropyridin-2-yl)-2-oxopropionic acid ethyl ester (Preparation 34, 276 mg, 1.03 mmol) in THF (12 mL) and ethanol (5 mL) was added saturated aqueous ammonium chloride solution (5 mL) and iron powder (346 mg, 6.18 mmol) in one portion. The reaction mixture was heated under reflux for 1 h then filtered whilst still hot through a celite plug, washing with hot ethyl acetate. The filtrate was cooled and washed with brine (20 mL), dried (MgSO4), filtered and adsorbed onto silica gel in vacuo. Purification via flash column chromatography (SiO2, ethyl acetate/hexanes, 1:9) gave the title compound as a beige solid. δH (CDCl3): 1.40 (3H, t), 3.99 (3H, s), 4.41 (2H, q), 6.74 (1H, d), 7.20 (1H, m), 7.62 (1H, d), 9.27 (1H, s).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=Cc1ccc(F)cc1
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(N2CCC(CO)CC2)cc1
Temperature: 100 °C

Procedure:
A suspension of 4-fluorobenzaldehyde (4.3 mL), 4-hydroxymethylpiperidine (4.8 g), and cesium carbonate (26 g) in DMF (80 mL) was heated to 100° C. for 24 h and cooled to room temperature. Water (400 mL) was added, and the resulting precipitate was collected by filtration to give the title compound as a tan amorphous powder (4.1 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][C:11]([OH:13])=[O:12])[CH:5]=O.[CH2:14]([NH2:17])[CH2:15][CH3:16].ClC1[N:24](C)[C:23]2[CH:26]=[CH:27][CH:28]=[CH:29]C=2S(=O)(=O)N=1>>[C:11]([CH2:10][C:9]1[CH:8]=[CH:7][C:4]([CH2:5][N:24]2[CH2:23][CH2:26][CH2:27][CH2:28][CH2:29]2)=[CH:3][C:2]=1[O:1][CH2:16][CH2:15][CH2:14][NH2:17])([OH:13])=[O:12]
Reactant: CN1C(Cl)=NS(=O)(=O)c2ccccc21
Reactant: O=Cc1ccc(CC(=O)O)c(O)c1
Reactant: CCCN
Product: NCCCOc1cc(CN2CCCCC2)ccc1CC(=O)O
Yield: 24 %

Procedure:
3-[2-Carboxymethyl-5-(piperidinomethyl)phenoxy]propylamine was prepared by the same procedures as in Reference Example 1 and Example 1 using 3-hydroxy-4-carboxymethylbenzaldehyde in place of the 3-hydroxybenzaldehyde used in Reference Example 1. This propylamine was reacted with the 3-chloro-4-methyl-1,2,4-benzothiadiazine-1,1-dioxide obtained in Reference Example 4 in the same manner as in Example 1. The reaction mixture was purified by silica gel column chromatography using chloroform:methanol (20:1) to isolate 3-[N-[3-[2-carboxymethyl-5-(piperidinomethyl)phenoxypropyl]-N-(4-methoxybenzyl)]amino]-4-methyl-1,2,4-benzothiadiazine-1,1-dioxide in a yield of 24%. The product was dissolved in ethyl acetate, and a solution of 4N hydrochloric acid and ethyl acetate was added dropwise to the solution with ice cooling to obtain a white crystalline hydrochloride. Thus, a compound 27 listed in Table 1 was prepared in a yield of 75%. M.p.: 93°~97° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:29][C:30]2[O:34][N:33]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH:31]=2)[C:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1)[CH3:13]>ClCCl>[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:29][C:30]2[O:34][N:33]=[C:32]([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[CH:31]=2)[C:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N+:21]([O-:9])=[CH:20][C:19]=2[N:28]=1)[CH3:13]
Reactant: CCOCc1nc2cnc3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOCc1nc2c[n+]([O-])c3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
mCPBA (1.7 g of 75% pure material) was added to a solution of 2-(ethoxymethyl)-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c][1,5]naphthyridine (1.74 g, 4.31 mmol) in dichloromethane (50 mL). The reaction was stirred at room temperature for 30 minutes; an analysis by TLC then indicated the presence of starting material. Additional mCPBA (0.25 g of 75%) was added, and the reaction was stirred for another 30 minutes and found to be complete. The solvent was removed under reduced pressure, and the residue was triturated with diethyl ether and isolated by filtration to provide 1.64 g of 2-(ethoxymethyl)-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine as a pale yellow solid.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][C:12](=[O:14])[C:11]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C([N:34](CC)CC)C.[CH:39]1[C:52]2C3[C:46](=[CH:47][CH:48]=CC=3)[CH2:45][NH:44][C:43]=2C=C[CH:40]=1>ClCCl.C(OCC)(=O)C>[C:20]1([C:21]([NH2:34])=[O:23])[C:19]2[C:18]3[C:46](=[CH:47][CH:48]=[CH:16][CH:17]=3)[CH2:45][NH:44][C:43]=2[CH:52]=[CH:39][CH:40]=1.[Si:1]([O:8][CH:9]1[CH2:13][C:12](=[O:14])[C:11]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: c1ccc2c(c1)CNc1ccccc1-2
Reactant: CCN(CC)CC
Agent: CC(C)(C)[Si](C)(C)OC1C=C(SCCCCCC(=O)O)C(=O)C1
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)c1cccc2c1-c1ccccc1CN2
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
2.12 g (5.92 mmoles) of 4(RS)-t-butyldimethylsilyloxy-2-(5-carboxypentylthio)-2-cyclopentenone was dissolved in 30 ml of dichloromethane, and the solution was cooled to -40° C. To the solution were added 970 mg (920 microliters; 7.10 mmols) of isobutyl chloroformate and 896 mg (1.24 ml, 8.88 mmoles) of triethylamine were added, and the mixture was stirred at -40° C. for 30 minutes. Then, 10 ml of a dichloromethane solution of 1.29 g (7.10 mmoles) of 5,6-dihydrophenanthridine was added to the resulting mixture. The temperature was gradually raised to room temperature over 20 hours. After the reaction, ethyl acetate was added to the reaction mixture to perform extraction. The extract was washed with dilute hydrochloric acid, an aqueous solution of sodium bicarbonate and then an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The resulting crude product was chromatographed on a silica gel column using hexane/ethyl acetate (4/1) as an eluent to give 2.657 g (5.1 mmoles; yield 86%) of 4(RS)-t-butyldimethylsilyloxy-2-(5-carboxypentylthio)-2-cyclopentenone 5,6-dihydrophenanthridinamide.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[C:5]([CH3:19])[N:6]2[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CC#N>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[N:6]([CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[C:5]=2[CH3:19])=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(Oc2ccc(Cl)cc2)c2c(N)cccc2n1CC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(Oc2ccc(Cl)cc2)c2c(NS(C)(=O)=O)cccc2n1CC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of the product from step (iv) (70 mg) in MeCN (1 ml) was added triethylamine (50 ul) and methanesulfonyl chloride (24 ul) and the reaction stirred at 50° C. for 3 h. The residue was partitioned between diethylether/water, the organics were separated, washed with aq potassium hydrogensulfate solution, brine, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5-30% ethylacetate/iso-hexane.
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[CH:7]1.CN(C)[CH:17]=[O:18].Cl>CCCCCC.C(OCC)C>[S:6]1[C:7]([CH:17]=[O:18])=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: CN(C)C=O
Reactant: c1ccc2sccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1cc2ccccc2s1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a solution of 31.25 ml of a 1.6M solution of n-butyl lithium in hexane and 100 ml of dry diethyl ether at -20° C. was added a solution of 6.7 g of 1-benzothiophene in 100 ml of dry diethyl ether. The mixture was stirred at -20° C. for 2 hours. A solution of 3.8 ml of dimethylformamide and 10 ml of dry diethyl ether was added and the reaction was allowed to warm to 0° C. The reaction was stirred an additional 1 hour at 0° C., at which time 75 ml of 1N hydrochloric acid were added. After stirring for 15 minutes, the layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate and evaporated to dryness. The resulting oil was stored at about 0° C. for 3 days, at which time a solid formed. The solid weighed 8.5 g and was identified as the desired subtitled intermediate based upon the mass spectral and proton NMR data.