Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C(C(O)=O)C(=O)CO1)(C)(C)C.[O:14]=[C:15]1[CH2:19][O:18][CH2:17][CH:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[BH4-].[Na+].CCOCC>C(O)(C)C>[OH:14][CH:15]1[CH2:19][O:18][CH2:17][CH:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)C1COCC1=O
Agent: CC(C)(C)C1OCC(=O)C1C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)C1COCC1O
Reaction time: 2 h
Yield: 86.5 %

Procedure:
The product of Step A, tert-butyl 4-oxotetrahydrofuran-3-carboxylate (0.95 g, 5.10 mmol) was placed in isopropylalcohol (14 mL) at 0-5° C., NaBH4 (77 mg, 2.04 mmol) was added, and stirred for 2 h. NaBH (77 mg, 2.04 mmol) was added again, and stirred at rt for 1 h, NaBH4 (39 mg, 1.02 mmol) was added, and stirred for 30 min. The reaction mixture was treated with Et2O to dilute, washed with brine, and extracted with Et2O twice. The organic layer was collected, extracted with a NaHCO3 aqueous solution, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent, EtOAc/Hex=1/3) to give the title compound (0.83 g, 86.56%).
Reaction SMILES: O1CCCC1.[C:6]([C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[CH:12][CH:13]=1)#[CH:7].[F:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[O:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[N:29][OH:30])=[CH:23][CH:22]=1.C(N(CC)CC)C>O>[F:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[O:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][C:28]2[CH:7]=[C:6]([C:8]3[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[CH:12][CH:13]=3)[O:30][N:29]=2)=[CH:23][CH:22]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(Oc2cccc(F)c2)nc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4cccc(F)c4)nc3)no2)c(N)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a tetrahydrofuran (2 mL) solution of 3-ethynyl-pyridin-2,6-diamine (10 mg, 75 μLμmol) described in Manufacturing Example 13-1-3 and (6-(3-fluoro-phenoxy)-pyridin-3-yl)-acetohydroximoyl chloride (42 mg, 0.15 mmol) described in Manufacturing Example 71-1-4 was added triethylamine (21 μL, 0.15 mmol), which was stirred for 1 hour at 50° C. under nitrogen atmosphere. Water was added at room temperature to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: methanol=20:1) to obtain the title compound (27 mg, 95%).
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[S:46]([N:50]=[C:51](OC1C=CC=CC=1)OC1C=CC=CC=1)(=[O:49])(=[O:48])[NH2:47].O>ClCCl>[CH3:40][O:39][C:8]1[CH:9]=[C:10]([CH:37]=[CH:38][C:7]=1[NH:6][C:4]([C:3]1[C:2]2[N:1]=[C:51]([NH:50][S:46](=[O:49])(=[O:48])[NH2:47])[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)=[O:5])[C:11]([N:13]([CH3:36])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:28])=[O:12]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Reactant: NS(=O)(=O)N=C(Oc1ccccc1)Oc1ccccc1
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(NS(N)(=O)=O)nc12
Yield: 21.7 %

Procedure:
A mixture of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (150 mg) and diphenyl N-sulfamoylcarbonimidate (85 mg) in dichloromethane (8 ml) was refluxed for 24 hours under nitrogen. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with water, driver over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1/chloroform:methanol=6:1) to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-(2-sulfamoylamino-1H-benzimidazol-4-yl)carbonylaminobenzamide (38 mg).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)=[CH:13][CH:12]=1.[OH-].[Na+]>CCO.C1COCC1>[Cl:27][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:28])=[O:2])=[CH:12][CH:13]=2)[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: COC(=O)c1ccccc1Nc1ccc(CCCc2ccc(Cl)c(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccccc1Nc1ccc(CCCc2ccc(Cl)c(Cl)c2)cc1
Yield: 80.8 %

Procedure:
The title compound was prepared from 2-{4-[3-(3,4-dichlorophenyl)-propyl]phenylamino}benzoic acid methyl ester (0.41 g, 0.99 mmol), 1N NaOH (4.0 mL) in EtOH (4 mL) and THF (4 mL) using the procedure described in Example 2. This procedure yielded a yellow solid, 0.32 g (0.80 mmol, 81%) of the desired product mp 120-126° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)(=[O:8])=[O:7].[CH3:17][O:18][C:19](=[O:32])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH3:31]>>[CH3:17][O:18][C:19](=[O:32])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[C:23]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])=[C:22]1[CH3:31]
Reactant: O=Cc1ccccc1S(=O)(=O)c1cccs1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2cccs2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 2-(thiophene-2-sulfonyl)benzaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][S:12][CH2:11][CH2:10]2)[C:6]([N+:15]([O-:17])=[O:16])=[C:5]([O:18][CH2:19][C:20](C)(C)C)[N:4]=1.ClC1C([N+]([O-])=[O:32])=C(OCC(C)(C)C)N=C(SC)N=1.N1CCSCC1>C(O)C>[CH2:19]([O:18][C:5]1[N:4]=[C:3]([S:2][CH3:1])[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][S:12](=[O:32])[CH2:11][CH2:10]2)[C:6]=1[N+:15]([O-:17])=[O:16])[CH3:20]
Reactant: CSc1nc(OCC(C)(C)C)c([N+](=O)[O-])c(N2CCSCC2)n1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(OCC(C)(C)C)n1
Agent: C1CSCCN1
Solvent: CCO
Product: CCOc1nc(SC)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]

Procedure:
2-Methylthio-6-neopentoxy-5-nitro-4-thiomorpholinopyrimidine from 4-chloro-2-methylthio-6-neopentoxy-5-nitro-pyrimidine and thiomorpholine. M.p. 102°-104°C (ethanol).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:12][CH2:11][CH:10]2[CH:6]1[CH2:7][CH2:8][CH:9]2[C:13](O)=[O:14])(=[O:3])[CH3:2].B#B.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:4][CH:5]1[CH2:12][CH2:11][CH:10]2[CH:6]1[CH2:7][CH2:8][CH:9]2[CH2:13][OH:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCC2C(C(=O)O)CCC12
Agent: B#B
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)OC1CCC2C(CO)CCC12
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A solution of 6-acetoxy-2-carboxybicyclo[3,3,0]octane (3.2 g; prepared as described in Reference Example 5 and predominantly in the 2β-configuration) in tetrahydrofuran (30 ml) at -40° C. was treated with a solution of diborane in tetrahydrofuran (15 ml; 1M) under an argon atmosphere. The solution was stirred for 1 hour at -40° C. and then it was allowed to warm to 0° C. during 1 hour and was maintained at 0° C. for a further period of 150 minutes. The solution was then allowed to warm to 20° C. during 17 hours. The solution was then treated with aqueous ammonium chloride solution (10% w/v) and the mixture was concentrated in vacuo. The resulting residue was treated with ethyl acetate (100 ml) and washed with water (50 ml) and then with saturated aqueous sodium bicarbonate solution, and then was dried over anhydrous sodium sulphate. The solution was concentrated in vacuo to give an oil, which was subjected to medium pressure, short column chromatography on silica gel, eluting with a mixture of ethyl acetate and toluene (1:1 v/v), to give 6-acetoxy-2-hydroxymethylbicyclo[3,3,0]octane (2.8 g), predominantly in the 2β-configuration.
Reaction SMILES: [OH:1][C:2]1([CH2:36][CH:37]=C)[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1.I([O-])(=O)(=O)=[O:40].[Na+].CC(C)=O.C(#N)C>C(OCC)(=O)C.O.[Os]=O>[OH:1][C:2]1([CH2:36][CH2:37][OH:40])[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:20][CH:21]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1
Reactant: C=CCC1(O)CCC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)CC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O)(CCO)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.5 %

Procedure:
A mixture of 4′-{[4-(4-hydroxy-4-prop-2-en-1-ylcyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.26 g), osmium oxide (7% immobilized catalyst, 0.19 g), sodium periodate (0.55 g), acetone (5 mL), acetonitrile (5 mL) and water (5 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate and water, and the insoluble material was filtered off through celite. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in methanol (10 mL), sodium borohydride (0.039 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.093 g, 36%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@:10]1([N:35]2[CH:43]=[C:41]([CH3:42])[C:39](=[O:40])[NH:38][C:36]2=[O:37])[O:34][C@H:14]([CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:12]([OH:13])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:45]>ClCl.CCN(CC)CC>[CH2:1]([O:8][CH2:9][C@@:10]1([N:35]2[CH:43]=[C:41]([CH3:42])[C:39](=[O:40])[NH:38][C:36]2=[O:37])[O:34][C@H:14]([CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:12]([O:13][C:44](=[O:45])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Agent: ClCl
Solvent: CCN(CC)CC
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](OC(=O)c3ccccc3)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Yield: 86.9 %

Procedure:
A stirred solution of 3 (128.0 g, 213.3 mmol) in a 4:1 mixture of CH2 Cl2 /Et3N (500 mL) was treated with (48.4 g, 40 mL, 344.6 mmol) of BzCl at 23° C. for 8 h. The resultant precipitate was removed by filtration. The filtrate was concentrated under reduced pressure to leave the crude product as a brownish syrup. Purification of the syrup by silica gel column chromatography (hexanes/AcOEt 10:1 then 1:1) gave 130.7 g (87%) of 4 as a white solid. Rf (Hexanes/AcOEt 1:1) 0.82 1H-NMR (CDCl3): 1.40 (s, 9H, C-Me3), 1.60 (s, 3H, 5-Me), 2.37 (ddd, 1H, J=13.8, 9.3, 7.2 Hz, 2'-Hβ), 2.62 (dd, 1H, J=13.8, 4.3 Hz, 2'-Hβ), 4.09 (m, 2H, 5'-H), 4.26 (m, 1H, 4'-H), 4.74 (s, 2H, O--CH2 -Ph), 5.54 (s, 2H, N--CH2 --O), 5.71 (d, 1H, J=7.2 Hz, 3'-H), 6.57 (dd, 1H, J=9.3, 4.3 Hz, 1'-H), 7.24-7.74 (m, 13H, aromatic-H), 8.05-8.15 (m, 3H, 6-H and aromatic-H). 13C-NMR(CDCl3): 12.82 (-, 5-Me), 19.54 (+, C-Me3), 27.16 (C-Me3), 38.28 (+, 2'-C), 64.41 (+, 5'-C), 70.80 (+, O--C-Ph), 72.29 (+, N--C--O), 75.60 (-, 4'-C), 85.28 (-, 1'-C and 3'-C), 110.95 (+, 5-C), 127.72, 128.23, 128.37, 128.50, 128.63 (-, aromatic-C), 129.43 (+, aromatic-C), 129.84, 130.22 (-, aromatic-C), 132.14, 133.07 (+, aromatic-C), 133.60 (-, 6-C), 133.94, 135.32, 135.65 (-, aromatic-C), 138.15 (+, aromatic-C), 151.19 (+, 2-C), 163.50 (+, 4-C), 166.11 (+, benzoyl C=O).
Reaction SMILES: [CH3:1][C:2]1([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[Li+].C[CH:17]([N-:19]C(C)C)C.C1(C)C=CC(S(C#N)(=O)=O)=CC=1.N.Cl>C1COCC1>[CH3:1][C:2]1([C:9]#[C:10][Si:11]([CH3:12])([CH3:14])[CH3:13])[CH2:7][CH:6]([C:17]#[N:19])[C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: CC(C)[N-]C(C)C
Reactant: CC1(C#C[Si](C)(C)C)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: CC1(C#C[Si](C)(C)C)CCC(=O)C(C#N)C1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 148.3 %

Procedure:
To a solution of 7 (163 mg, 0.78 mmol) in THF (8.8 mL) was added LDA (2M solution in THF/n-heptane/ethylbenzene, 1.08 mL, 2.16 mmol) at −78° C. (in an isopropanol-dry ice bath). The mixture was allowed to reach room temperature over 20 min. To the mixture was added a cloudy solution of p-toluenesulfonyl cyanide (95%, 591 mg, 3.1 mmol) in THF (6.8 mL) at −78° C. The mixture was stirred at −78° C. for 30 min. To the reaction mixture was added saturated aqueous ammonia solution (4.5 mL) at −78° C. The mixture was allowed to reach room temperature. The mixture was acidified with 10% aqueous HCl solution. The mixture was extracted with ethyl acetate (30 mL ×3). The extract was washed with saturated aqueous sodium bicarbonate solution (40 mL ×2) and brine (40 mL), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo to give 5-methyl-2-oxo-5-((trimethylsilyl)ethynyl)cyclohexanecarbonitrile (270 mg).
Reaction SMILES: [ClH:1].CCOCC.C(OC([N:14]1[CH2:17][CH2:16][C@H:15]1[CH2:18][O:19][C:20]1[CH:21]=[C:22]([C@@H:26]2[CH2:28][C@H:27]2[CH2:29][CH2:30][OH:31])[CH:23]=[N:24][CH:25]=1)=O)(C)(C)C>CO>[ClH:1].[NH:14]1[CH2:17][CH2:16][C@H:15]1[CH2:18][O:19][C:20]1[CH:21]=[C:22]([C@@H:26]2[CH2:28][C@H:27]2[CH2:29][CH2:30][OH:31])[CH:23]=[N:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@@H]2C[C@H]2CCO)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: OCC[C@@H]1C[C@H]1c1cncc(OC[C@@H]2CCN2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2M anhydrous HCl/ether (2.0 mL) was added to a stirred solution of 2-[(1S,2R)-2-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]cyclopropyl]ethanol (200 mg, 0.57 mmol) in dry MeOH (2.0 mL) at 0° C. The mixture was stirred at room temperature for 12 h and concentrated, and the residue was purified by HPLC to obtain pure 2-[(1S,2R)-2-[5-[(2(S)-azetidinyl)methoxy]-3-pyridyl]cyclopropyl]ethanol hydrochloride (115 mg). 1H NMR (CD3OD, 400 MHz) δ 8.53 (s, 1H), 8.37 (s, 1H), 7.99 (s, 1H), 5.05-4.90 (m, 1H), 4.75-4.51 (m, 2H), 4.23-4.05 (m, 2H), 3.76-3.64 (m, 2H), 2.83-2.59 (m, 2H), 2.11-1.99 (m, 1H), 1.79-1.58 (m, 2H), 1.55-1.39 (m, 1H), 1.34-1.23 (m, 1H), 1.21-1.09 (m, 1H). MS m/z (ESI) 271 (M+Na+).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[N:6][C:5]1=O)([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1C=CC=CC=1>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[N:6][C:5]1=[S:37])([CH3:3])[CH3:2]
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2C(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=S)n2C(C)C
Temperature: 70 °C

Procedure:
A suspension of 50 mg (0.139 mmol) 1-isopropyl-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-one and 56 mg (0.139 mmol) Lawesson's reagent in 2 ml benzene is heated to 70° C. overnight. The reaction mixture is extracted (water/di-chloromethane) and the organic layer is dried and evaporated.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)=[C:10]([NH:26][C:27]([NH:29][C:30]2[C:35]([CH:36]([CH3:38])[CH3:37])=[CH:34][CH:33]=[CH:32][C:31]=2[CH:39]([CH3:41])[CH3:40])=[O:28])[C:9]1=[O:42].[F-].[K+].O>CN(C=O)C>[CH2:7]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)=[C:10]([NH:26][C:27]([NH:29][C:30]2[C:31]([CH:39]([CH3:40])[CH3:41])=[CH:32][CH:33]=[CH:34][C:35]=2[CH:36]([CH3:38])[CH3:37])=[O:28])[C:9]1=[O:42])[CH2:6][CH2:5][C:4]#[CH:3]
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CCCC#C[Si](C)(C)C)c3ncccc23)c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 105.3 %

Procedure:
To a solution of N-[1-(5-trimethylsilyl-4-pentynyl)-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (81 mg, 0.133 mmol) in DMF (4 ml) was added potassium fluoride (138 mg, 2.38 mmol), and the mixture was stirred at room temperature for 7 hours. The mixture was poured into water, and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and purified by preparative thin layer chromatography to give the title compound (58 mg, 0.14 mmol).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][S-:13].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:12][S:13][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc([N+](=O)[O-])c(N)c1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
5-Chloro-2-nitroaniline (15 g, 87.2 mmol) was dissolved in 250 mL of DMF with stirring. Sodium thiomethoxide (9.8 g, 140 mmol) was added and the reaction stirred at 65° C. for 20 h. The reaction was cooled to rt and diluted with EtOAc. then washed with water (5×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 12.9 g (81%) of 5-(methylthio)-2-nitroaniline as a red-orange solid. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=8.97 Hz, 1H), 7.45 (br s, 2H), 6.78 (d, J=1.83 Hz, 1H), 6.47 (dd, J=1.83 and 9.16 Hz, 1H), 2.47 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2([C:39]([F:42])([F:41])[F:40])[O:28][N:27]=[C:26]([C:29]3[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[C:31]([CH3:38])[CH:30]=3)[CH2:25]2)[CH:20]=[C:21]([Cl:23])[CH:22]=1>ClCCl>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([C:26]3[CH2:25][C:24]([C:19]4[CH:20]=[C:21]([Cl:23])[CH:22]=[C:17]([Cl:16])[CH:18]=4)([C:39]([F:42])([F:41])[F:40])[O:28][N:27]=3)=[CH:30][C:31]=2[CH3:38])=[N:3][CH:4]=1)#[N:9]
Reactant: N#Cc1ccc(N)nc1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ccc(C#N)cn1
Reaction time: 1 h
Yield: 71.2 %

Procedure:
In a solution of 0.39 g of 2-amino-5-cyanopyridine and 0.71 g of pyridine in 20 mL of dichloromethane, a solution of 1.31 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 in 20 mL of dichloromethane was added dropwise. After the completion of the addition dropwise, it was continued to stir at the same temperature further for 1 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, precipitated insoluble material was removed through silica gel column, and the solvent was distilled off under reduced pressure. The residual solid was washed with diisopropyl ether to obtain 1.11 g of the aimed product as colorless resinous substance.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:5][S:6][CH3:7].C(N(CC)CC)C.[F:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[CH:22]=[CH:23][C:24](O)=[O:25].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[CH:22]=[CH:23][C:24]([NH:2][C@H:3]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:5][S:6][CH3:7])=[O:25]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: COC(=O)[C@@H](N)CCSC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCSC)NC(=O)C=Cc1ccccc1F
Yield: 94.9 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-methioninate hydrochloride (2.5 g), triethylamine (2.1 mL), 2-fluorocinnamic acid (2.5 g), WSC.HCl (2.9 g, 15.0 mmol), and methylene chloride (80 mL), to give the captioned compound (3.7 g, 95%) as an oily product.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1.[CH3:23][C@H:24]1[NH:29][C@@H:28]([CH3:30])[CH2:27][NH:26][CH2:25]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:25][C@H:24]([CH3:23])[NH:29][C@H:28]([CH3:30])[CH2:27]2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)c(N)c2c1=O
Product: CCOC(=O)c1cn(C2CC2)c2cc(N3C[C@@H](C)N[C@@H](C)C3)c(F)c(N)c2c1=O

Procedure:
Ethyl 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate and cis-3,5-dimethylpiperazine were reacted in the same way as in Example 4 to give ethyl 5-amino-1-cyclopropyl-6-fluoro-7-(cis-3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate. It was recrystallized from ethyl acetate. m.p. 194°-196° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:15]([O-])=O)=[CH:4][C:5]([O:12][CH2:13][CH3:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]>C(O)C.[C].[Pd]>[NH2:15][C:3]1[C:2]([NH2:1])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:12][CH2:13][CH3:14])[CH:4]=1
Reactant: CCOc1cc([N+](=O)[O-])c(N)cc1C(=O)OC
Agent: [Pd]
Solvent: CCO
Product: CCOc1cc(N)c(N)cc1C(=O)OC
Temperature: 25 °C

Procedure:
A suspension of 873 mg of methyl 5-amino-2-ethoxy-4-nitrobenzoate and 50 mg of 10 % palladium carbon in 50 ml of ethanol was stirred at room temperature under a hydrogen atmosphere. After the absorption of hydrogen was completed, the catalyst was removed by filtration, and the filtrate was evaporated to dryness under reduced pressure to give crude methyl 4,5-diamino-2-ethoxybenzoate.