Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]([CH3:30])([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)[CH2:16][O:17][CH2:18][CH2:19][CH3:20]>>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([O:21][C:15]([CH3:14])([CH3:30])[CH2:16][O:17][CH2:18][CH2:19][CH3:20])=[CH:29][CH:28]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCOCC(C)(C)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Product: CCCOCC(C)(C)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Yield: 50.3 %

Procedure:
By using 2.0 g of 2-t-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 3.0 g of 4-(1,1-dimethyl-2-propoxyethoxy)benzyl bromide and similarly to the procedures in Preparation Example 13, 2.1 g of the aimed product was obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[C:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])=[CH:12][CH:11]=1.[BH4-].[Na+]>CO.O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[OH:26])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(C=C2Cc3ccccc3C2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccccc1NC(=O)c1ccc(CC2Cc3ccccc3C2O)cc1
Temperature: 50 °C
Yield: 73.5 %

Procedure:
To a suspension of 274 (300 mg, 0.85 mmol) in MeOH (8 ml) and water (1 ml) was added NaBH4 (75 mg, 1.95 mmol). The reaction mixture was stirred at 50° C. 16 h and cooled down. Water was added to the solution and the precipitated was filtered and rinsed with cold water to afford the title compound 275 (224 mg, 74%) as a white solid. 1H NMR: (acetone) δ (ppm): 9.05 (bs, 1H), 8.00 (dd, J=8.2, 2.7 Hz, 2H), 7.47 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.38-7.30 (m, 2H), 7.22-7.12 (m, 3H), 7.01 (ddd, J=7.6, 7.6, 1.5 Hz, 1H), 6.87 (dd, J=8.0, 1.1 Hz, 1H), 6.68 (dd, J=7.6, 7.6 Hz, 1H), 4.98 (t, J=5.8 Hz, 0.4H), 4.89 (t, J=6.7 Hz, 0.6H), 4.63 (bs, 2H), 4.45 (d, J=6.9 Hz, 0.6H), 4.06 (d, J=6.0 Hz, 0.4H), 3.30-3.19 (m, 1H), 2.88-2.48 (m, 3H, CH2). LRMS: 358.2 (calc.); 359.1 (found).
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][C@@H:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[CH3:24]>>[N:9]12[CH2:14][CH2:13][CH:12]([CH2:11][CH2:10]1)[C@@H:7]([O:6][C:5]1[CH:15]=[CH:16][C:2]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[C:18]([NH2:17])[CH:19]=3)=[CH:3][CH:4]=1)[CH2:8]2
Reactant: Ic1ccc(O[C@H]2CN3CCC2CC3)cc1
Reactant: Cc1ccc(B(O)O)cc1N
Product: Cc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)cc2)cc1N

Procedure:
The product of Example 2A (165 mg, 0.5 mmol), was treated with 3-amino-4-methyl-phenylboronic acid (151 mg, 1 mmol) according to the procedure of Example 2B. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.25) as a solid (104 mg, yield, 68%). 1H NMR (MeOH-d4, 300 MHz) δ 1.45-1.58 (m, 1H), 1.64-1.89 (m, 2H), 2.00-2.13 (m, 1H), 2.15-2.23 (m, 4H), 2.76-3.02 (m, 5H), 3.30-3.40 (m, 1H), 4.51-4.59 (m, 1H), 6.6.84 (dd, J=7.8, 2.0 Hz, 1H), 6.90-6.97 (m, 3H), 7.02 (d, J=7.8 Hz, 1H), 7.47 (dt, J=8.8, 2.0 Hz, 2H) ppm. MS (DCl/NH3) m/z 309 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:14])[C:4](=[O:13])[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:6]=2[N:7]=1.[OH-].[Na+].CN(C=O)C.[Cl:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1>CO.O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33][S:1][C:2]3[N:3]([CH3:14])[C:4](=[O:13])[C:5]4[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:6]=4[N:7]=3)=[CH:31][CH:30]=2)=[O:28])=[CH:37][CH:38]=1
Reactant: Cc1sc2nc(S)n(C)c(=O)c2c1C
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: Cc1sc2nc(SCc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c(=O)c2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of 2-mercapto-3,5,6-trimethylthieno-[2,3-d]pyrimidin-4(3H)-one (1.13 g) and sodium hydroxide (205 mg) in 50% methanol (16 ml)-DMF (4 ml) was added 4-(4-chlorobenzoyl)benzyl bromide (1.69 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water, and recrystallized from ethyl acetate to provide the title compound as colorless solid (1.425 g).
Reaction SMILES: C([O:3][C:4](=[O:17])/[CH:5]=[CH:6]/[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[NH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.CO.O>[CH3:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2/[CH:6]=[CH:5]/[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)/C=C/c1c[nH]c2ccc(C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc2[nH]cc(/C=C/C(=O)O)c2c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
(E)-ethyl-3-(5-methyl-1H-indol-3-yl)acrylate (1222.4 g, 5.33 mmol) prepared at Step 1 was dissolved in 32 ml of mixture solution (THF/methanol/H2O=2:1:1), after which NaOH acqueous solution (639.8 mg, 16.0 mmol) was added. After raising temperature to 50° C., stirring for 12 hr, neutralization with 10% hydrochoric acid to pH 4, and dilution with EtOAc, washing with water and brine, drying with anhydrous MgSO4, and concentration under reduced pressure followed. The concentrated residue was refined with silica gel chromatography (n-hexane:EtOAc=2:1) and dried to give target compound. (1070.5 mg, 99.8%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][C:12](=O)[NH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2CC(=O)NC3C=CC=CC=3S2)C=CC=CC=1.[ClH:37].[CH3:38][N:39]([CH3:63])[CH2:40][CH2:41][N:42]([CH3:62])[C:43](N1C2C=CC=CC=2SC(C2C=CC=CC=2)CC1)=[O:44]>>[ClH:37].[CH3:38][N:39]([CH3:63])[CH2:40][CH2:41][N:42]([CH3:62])[C:43]([N:11]1[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13][CH2:12]1)=[O:44]
Reactant: O=C1CC(c2ccccc2)Oc2ccccc2N1
Reactant: CN(C)CCN(C)C(=O)N1CCC(c2ccccc2)Sc2ccccc21
Agent: Cl
Agent: O=C1CC(c2ccccc2)Sc2ccccc2N1
Product: CN(C)CCN(C)C(=O)N1CCC(c2ccccc2)Oc2ccccc21

Procedure:
By substituting an equivalent amount of 2,3-dihydro-2-phenyl-1,5-benzoxazepin-4-(5H)-one, m.p. 123°-125°, (prepared as described in Example 1 of U.S. patent application, Ser. No. 328,048, filed Dec. 4, 1963 now U.S. Pat. No. 3,309,361), for the 2,3-dihydro-2-phenyl-1,5-benzothiazepin-4-one in part (A) of Example 1, and carrying out the procedure of the Example, there is obtained N-(2-dimethylaminoethyl)-2,3,4,5-tetrahydro-N-methyl-2-phenyl-1,5-benzoxazepine-5-carboxamide hydrochloride
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][CH2:15][CH2:16][N:17]1C(=O)C3C(=CC=CC=3)C1=O)[C:7]([CH3:28])=[C:6]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.NN.[ClH:37]>CO.[Cl-].[Na+].O>[Cl-:37].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][CH2:15][CH2:16][NH3+:17])[C:7]([CH3:28])=[C:6]2[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cl
Reactant: COc1ccc2c(=O)n(CCCN3C(=O)c4ccccc4C3=O)c(C)c(-c3ccccc3)c2c1
Agent: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(=O)n(CCC[NH3+])c(C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[3-(6-methoxy-3-methyl-1-oxo-4-phenylisoquinolin-2(1H)-yl)propyl]-1H-isoindole-1,3(2H)-dione (0.46 g) was dissolved in 20 mL methanol, and hydrazine (0.100 mL) was added. The reaction was stirred overnight at room temp, then diluted with brine and extracted with EtOAc (3×). The combined organic solutions were dried (Na2SO4) and concentrated. Flash chromatography (5% MeOH in CH2Cl2) gave a solid, which was treated with excess HCl and recrystallized from isopropanol/diethyl ether to give the titled compound.
Reaction SMILES: [CH3:1][N:2]([C:14]([O:16][C@@H:17]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:18]([N:20]([CH3:46])[C@H:21]([C:28]([NH:30][C@H:31]([C@@H:39]([OH:45])[CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:29])[CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1)=[O:19])=[O:15])[CH2:3][CH2:4][N:5](C(OC(C)(C)C)=O)[CH3:6]>FC(F)(F)C(O)=O>[CH3:1][N:2]([C:14]([O:16][C@@H:17]([CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:18]([N:20]([CH3:46])[C@H:21]([C:28]([NH:30][C@H:31]([C@@H:39]([OH:45])[CH2:40][CH2:41][CH:42]([CH3:43])[CH3:44])[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:29])[CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1)=[O:19])=[O:15])[CH2:3][CH2:4][NH:5][CH3:6]
Reactant: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)N(C)C(=O)[C@H](Cc1ccccc1)OC(=O)N(C)CCN(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNCCN(C)C(=O)O[C@@H](Cc1ccccc1)C(=O)N(C)[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CCC(C)C
Yield: 89.3 %

Procedure:
A solution of 2(S)-[Nα -[2(S)-[N-methyl-N-{2-(N-t-butoxycarbonyl-N-methylamino)ethyl}aminocarbonyloxy]-3-phenylpropionyl]-Nα -methyl-L-histidyl]amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (114 mg) in trifluoroacetic acid (10 ml) was stirred at 0° C. for 1 hour. After evaporation of the solvent, the residue was dissolved in ethyl acetate (20 ml) and the solution was washed with 1M sodium bicarbonate solution and water successively, and dried over magnesium sulfate. Evaporation of the solvent gave 2(S)-[Nα -[2(S)-{N-methyl-N-(2-methylaminoethyl)aminocarbonyloxy}-3-phenylpropionyl]-Nα -methyl-L-histidyl]amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (88 mg) as an amorphous powder.
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][CH2:7][CH2:8][OH:9])([CH3:5])[CH3:4].[CH3:10][C:11]1[CH:16]=[C:15]([C:17]2[NH:26][C:25](=[O:27])[C:24]3[C:19](=[CH:20][C:21](F)=[CH:22][C:23]=3[O:28][CH3:29])[N:18]=2)[CH:14]=[C:13]([CH3:31])[N:12]=1.O>CS(C)=O>[CH3:10][C:11]1[CH:16]=[C:15]([C:17]2[NH:26][C:25](=[O:27])[C:24]3[C:19](=[CH:20][C:21]([O:9][CH2:8][CH2:7][O:6][CH:3]([CH3:5])[CH3:4])=[CH:22][C:23]=3[O:28][CH3:29])[N:18]=2)[CH:14]=[C:13]([CH3:31])[N:12]=1
Reactant: COc1cc(F)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Reactant: CC(C)OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(OCCOC(C)C)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of sodium hydride (60% suspension in mineral oil, 0.24 g, 6.00 mmol) in anhydrous DMSO (10 mL) was added 2-isopropoxy-ethanol at room temperature under nitrogen. The mixture was stirred for 20 minutes at room temperature, then 2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one (0.30 g, 1.00 mmol) was added and the reaction mixture was stirred at 80° C. for 16 hours, then cooled to room temperature. Water (50 mL) was added, and the mixture was extracted with a mixture of ethyl acetate and THF (4:1, 200 mL). The organic phase was washed with brine and dried over anhydrous sodium sulfate. Solvent was evaporated, and the crude compound was purified by the Simpliflash system (3:15:82 methanol, ethyl acetate and dichloromethane as eluent) to give the title compound as a white solid. Yield: 127 mg (33%). MP 188-189° C. 1H NMR (400 MHz, CDCl3): δ 11.14 (br s, 1H), 7.72 (s, 2H), 6.86 (d, J=2.34 Hz, 1H), 6.59 (d, J=2.34 Hz, 1H), 4.35-4.15 (m, 2H), 3.97 (s, 3H), 3.89-3.79 (m, 2H), 3.78-3.64 (m, 1H), 2.66 (s, 6H), 1.23 (d, J=5.85 Hz, 6H). MS (ES+) m/z: 384.20 (100%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[NH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][OH:44])=[CH:39][CH:38]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:12][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([CH2:43][OH:44])=[CH:39][CH:38]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: NCc1ccc(CO)cc1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(C(=O)NCc2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
To a mixture of 4-(dimethylamino)benzoic acid (915 mg, 5.54 mmol) and triethylamine (772 μL, 5.54 mmol) in CH2Cl2 (25 mL) at 0° C. was added BOP-Cl (1.50 g, 6.09 mmol), and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture was added (4-aminomethylphenyl)methanol (760 mg, 5.54 mmol) and triethylamine (1.54 mL, 11.08 mmol), and the mixture was stirred at room temperature overnight. To the reaction mixture was added a 50% aqueous NaHCO3 solution (50 mL), and the mixture was extracted with 5% MeOH in CHCl3 (100 mL×1, 40 mL×2). The organic layer was dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by MPLC on silica gel (2% MeOH in CHCl3) to afford the titled compound (1.04 g, 66%) as a white solid.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[C:12]1=[O:37])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C@H:9]([CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:30]([F:36])=[CH:31][CH:32]=[CH:33][C:34]=2[F:35])[C:12]1=[O:37]
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C3CCCCC3)c2=O)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](N)C3CCCCC3)c2=O)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To compound 4c (300 mg, 0.5 mmol) in dichloromethane (2 mL) was added TFA (2 mL) and the reaction mixture was stirred at ambient temperature for 1 hour. Volatiles were evaporated and the residue was partitioned between saturated NaHCO3/water and EtOAc. The organic layer was dried (sodium sulfate), evaporated, purified by reverse phase HPLC(C-18 column, 15-75% ACN/water) to give compound 4d . MS (CI) m/z 502.2 (MH+).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([OH:19])=O)=[N:15][CH:16]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[CH:45]1([C@H:48]([NH2:53])[C:49]([F:52])([F:51])[F:50])[CH2:47][CH2:46]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([NH:53][C@@H:48]([CH:45]2[CH2:47][CH2:46]2)[C:49]([F:52])([F:51])[F:50])=[O:19])=[N:15][CH:16]=1
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: N[C@@H](C1CC1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](C1CC1)C(F)(F)F)c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
N,N-Diisopropylethylamine (1.3 mL, 7.5 mmol) was added to a mixture of 5-chloropyrazine-2-carboxylic acid (0.40 g, 2.5 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.0 g, 2.8 mmol) and (1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride (0.44 g, 2.5 mmol) (ASIBA Pharmatech, Cat. #: 70092-HCl) in methylene chloride (10 mL). The reaction mixture was stirred at room temperature overnight. The mixture was worked up with saturated aqueous NaHCO3, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-20%) to afford the desired product (0.51 g, 72%). LCMS (M+H)+: m/z=280.0/282.0.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]([CH3:24])[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7])[CH2:2][CH3:3].[C:25]([C@:27]1([C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)[CH2:29][C@@H:28]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])#[N:26].N1C=CC=CC=1.CCOCC>ClCCl>[CH2:1]([O:4][C@@H:5]([CH3:24])[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([O:42][C:39]3[CH:38]=[CH:37][C:36]([C@@:27]4([C:25]#[N:26])[CH2:29][C@@H:28]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:41][CH:40]=3)=[O:20])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7])[CH2:2][CH3:3]
Reactant: CCCCCC[C@H]1C[C@]1(C#N)c1ccc(O)cc1
Reactant: CCCO[C@@H](C)C(=O)Oc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCC[C@H]1C[C@]1(C#N)c1ccc(OC(=O)c2ccc(-c3ccc(OC(=O)[C@H](C)OCCC)cc3)cc2)cc1
Reaction time: 3 h
Yield: 46 %

Procedure:
In 10 ml of dichloromethane were dissolved 83 mg of (S)-4-[4-(2-propoxypropanoyloxy)phenyl]benzoyl chloride and 65 mg of (1R,2S)-1-cyano-2-hexyl-1-(4-hydroxyphenyl)cyclopropane. To this solution was added 0.5 ml of pyridine. The resulting mixture was stirred for 3 hours under reflux. The reaction mixture was cooled, and then ether was added thereto. The ethanol phase was separated, washed with diluted hydrochloric acid, water, and then saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate=5/1). Recrystallization from ethanol afforded, thereby obtaining 61 mg of the desired compound as colorless crystals.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][N:6]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:14])=[O:13])[CH2:5][CH:4]1[OH:21].[NH:22]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:23]([C:28](O)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:34]([O:33][C:31](=[O:32])[NH:22][C@H:23]([C:28](=[O:29])[NH:2][CH:3]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][N:6]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:14])=[O:13])[CH2:5][CH:4]1[OH:21])[CH2:24][CH:25]([CH3:26])[CH3:27])([CH3:35])([CH3:37])[CH3:36]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1(C)CC(N)C(O)CN(S(=O)(=O)c2ccccn2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CC(C)(C)CN(S(=O)(=O)c2ccccn2)CC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
4-Amino-6,6-dimethyl-1-(pyridine-2-sulfonyl)-azepan-3-ol HCl salt from Example 92g (0.22 g, 0.6 mmol) was dissolved in 5 ml DMF. To this solution, was added Boc-Leu-OH (0.22 g, 0.9 mmol) and HBTU (0.34 g, 0.9 mmol) and then NMM (0.24 g, 2.4 mmol). The mixture was stirred at r.t. overnight. DMF was removed under high vacuum. The residue was diluted with EtOAc and washed with H2O, 10% NaHCO3 and brine. Purification by column chromatography gave 0.22 g of the title compound (72% yield); MS (M+H+): 512.9; 1H-NMR (400 MHz, CDCl3): •8.68-8.67(d, 1H), 7.97-7.88(m, 2H), 7.69-7.64(m, 1H), 6.62-6.53(m, 1H), 5.06-5.00(m, 1H), 4.03-3.18(m, 7H), 1.80-1.42(m, 15H), 1.04-0.92(m, 12H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2].Cl.[NH2:15]O.[OH-].[K+]>O.CO.CCO>[NH2:15][C:11]1[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: NO
Reactant: O=[N+]([O-])c1cccc2ncccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCO
Product: Nc1ccc([N+](=O)[O-])c2cccnc12
Temperature: 55 °C

Procedure:
To a five liter round bottom flask fitted with an air stirrer, condenser, addition funnel, thermometer and hot water bath were charged 40 g. (.23 mole) 5-nitroquinoline and 100 g. (1.44 mole) hydroxylamine hydrochloride. Then 1950 ml. of 95% EtOH was added and the solids dissolved after which 200 g. KOH in 1200 ml. MeOH was added over a 50 minute period at 54°-57° C. The mixture was allowed to stir at 55° C. for an additional hour and then dumped into 10 liters of water, allowed to cool and filtered. An orange solid was crystallized out of 95% ethanol. Such product was 8-amino-5-nitroquinoline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:34]([O-])=O)[C:5]([OH:33])=[C:6]([C:8]([CH3:32])([CH3:31])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[O:23])[O:21][N:20]=[C:19]([CH3:24])[C:18]=3[CH:25]=2)=[O:12])[CH:7]=1.[CH2:37](OC(OCC)OCC)C.C(OCC)(=O)C>O1CCCC1.C(O)(=O)C.[Fe]>[F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:31])([CH3:32])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:27])[F:28])[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[O:23])[O:21][N:20]=[C:19]([CH3:24])[C:18]=3[CH:25]=2)=[O:12])[C:5]2[O:33][CH:37]=[N:34][C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cc(F)cc([N+](=O)[O-])c3O)C(F)(F)F)cc12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cc(F)cc4ncoc34)C(F)(F)F)cc12
Reaction time: 4 h

Procedure:
103 mg of (−)-6-[4-(5-fluoro-2-hydroxy-3-nitrophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)valeroyl-amino]-4-methyl-2,3-benzoxazin-1-one in 5 ml of tetrahydrofuran and 1 ml of acetic acid are stirred for 2.5 hours with 300 mg of iron, mixed with 0.5 ml of orthoformic acid triethyl ester and ethyl acetate, suctioned off and concentrated by evaporation after standing for 4 hours at room temperature. The residue is dissolved in ethyl acetate and mixed with 0.05 ml of orthoformic acid. After 20 hours at room temperature, 72 mg of (+)-6-[4-(5-fluorobenzoxazol-7-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)valeroylamino]-4-methyl-2,3-benzoxazin-1-one is suctioned off. MS, flash point 276–277° C., (+)-enantiomer with [α]D+53.0° (c=0.25, THF).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:13][CH2:14][O:15][C:16](/[CH:18]=[CH:19]/[CH2:20]P(OCC)(OCC)=O)=[O:17]>>[CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:20]/[CH:19]=[CH:18]/[C:16]([O:15][CH2:14][CH3:13])=[O:17])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(C=O)cc1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Product: CCOC(=O)/C=C/C=C/c1ccc(OC(C)C)cc1
Yield: 58 %

Procedure:
According to the same manner as that described in Reference Example 1, 4-isopropoxybenzaldehyde was reacted with triethyl 4-phosphonocrotonate to give ethyl (E,E)-5-(4-isopropoxyphenyl)pentadienoate as crystals (yield: 58%). The crystals were recrystallized from ether-hexane. Colorless prisms, mp: 64-65° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:18][N:19]1[CH:24]=[CH:23][C:22]2[O:25][C:26]([CH3:28])=[CH:27][C:21]=2[C:20]1=[O:29].Cl[CH2:31][CH2:32][O:33][C:34]1[CH:51]=[CH:50][C:37]2[N:38]([CH2:48][CH3:49])[C:39](=[O:47])[C:40]([CH3:46])([CH3:45])[C:41](=[O:44])[N:42]([CH3:43])[C:36]=2[CH:35]=1>CN(C=O)C>[CH2:48]([N:38]1[C:39](=[O:47])[C:40]([CH3:46])([CH3:45])[C:41](=[O:44])[N:42]([CH3:43])[C:36]2[CH:35]=[C:34]([O:33][CH2:32][CH2:31][N:9]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[N:11]=[C:10]3[CH2:18][N:19]3[CH:24]=[CH:23][C:22]4[O:25][C:26]([CH3:28])=[CH:27][C:21]=4[C:20]3=[O:29])[CH:51]=[CH:50][C:37]1=2)[CH3:49]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCl)ccc21
Reactant: Cc1cc2c(=O)n(Cc3nc4ccccc4[nH]3)ccc2o1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCn3c(Cn4ccc5oc(C)cc5c4=O)nc4ccccc43)ccc21
Temperature: 65 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
Potassium carbonate(0.58 g), sodium iodide(0.21 g), and 5-(1H-benzimidazol-2-ylmethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one(0.39 g) were added to a DMF solution(30 ml) of 7-(2-chloroethoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.47 g). The mixture was stirred at 65° C. overnight. The mixture was further stirred at 100° C. overnight. After the reaction mixture was condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: methanol=95:5→85:15). The purified product was condensed to dryness under reduced pressure to give the title compound(0.44 g) as a white amorphous solid.