Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]>>[O:28]=[C:19]1[C:20]2[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:23])[N:18]1[CH2:17][CH2:16][N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([CH3:1])[CH:9]=2)=[N:11]1
Reactant: Cc1cc(-c2cc[nH]n2)ccc1C#N
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Product: Cc1cc(-c2ccn(CCN3C(=O)c4ccccc4C3=O)n2)ccc1C#N
Yield: 31.8 %

Procedure:
2-Methyl-4-(1H-pyrazol-3-yl)benzonitrile (0.949 g, 5.2 mmol) was reacted with N-(2-bromoethyl)phthalimide (1.58 g, 6.2 mmol) using the method of Example 27(a). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-100% EtOAc/heptane) to yield 0.590 g (32%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.36 (s, 3H), 3.99 (t, 2H), 4.44 (t, 2H), 6.76 (d, 1H), 7.44 (s, 1H), 7.46 (m, 1H), 7.62 (d, 1H), 7.83 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:26]=[CH:25][C:21]4[CH:22]=[N:23][O:24][C:20]=4[CH:19]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:34]([C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[O:24]1[C:20]2[CH:19]=[C:18]([NH:17][C:10]3[C:11]4[N:12]([CH:14]=[CH:15][N:16]=4)[CH:13]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:42](=[O:43])[C:41]5[CH:45]=[CH:46][C:38]([C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:39][CH:40]=5)[CH:7]=[CH:6][CH:5]=4)[N:9]=3)[CH:26]=[CH:25][C:21]=2[CH:22]=[N:23]1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(-c2cn3ccnc3c(Nc3ccc4cnoc4c3)n2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccc5cnoc5c4)n3)c2)cc1
Temperature: 0 °C

Procedure:
After dissolving 0.34 g (1 mmole) [6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-benzo[d]isoxazol-6-yl-amine in 20 mL anhydrous THF, 3 equivalents of triethylamine are added and the reaction solution is cooled to 0° C. A solution of 0.2 g of 4-tert-butyl-benzoyl chloride (1 mmole) in 5 mL THF is added dropwise to the 0° C. reaction solution under N2. The ice bath is removed and the reaction is allowed to warm slowly to rt for 1 hr. Diethyl ether is then added slowly to the reaction solution and the resulting solid filtered and washed with diethyl ether to provide pure N-{3-[8-(benzo[d]isoxazol-6-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}4-tert-butyl-benzamide.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]([F:25])([C:17]1[CH:24]=[CH:23][C:20]([C:21]#N)=[CH:19][CH:18]=1)[C:13]([F:16])([F:15])[F:14].S(=O)(=O)(O)[OH:27].O>C(Cl)Cl>[F:11][C:12]([F:25])([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:27])=[CH:19][CH:18]=1)[C:13]([F:16])([F:15])[F:14]
Reactant: N#Cc1ccc(C(F)(F)C(F)(F)F)cc1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Diisobutylaluminum hydride solution (1 M in hexane, 5.0 mL, 5.0 mmol) was added at 0° C. to a solution of 4-pentafluoroethyl-benzonitrile (1.00 g, 4.52 mmol) in DCM (5 mL), then after 2 h another portion of diisobutylaluminum hydride solution (5 mL) was added and the reaction stirred at RT for 16 h, then carefully poured onto 50% aq. sulfuric acid solution (4 mL). Water (45 mL) was added, and the mixture is extracted three times with DCM. The organic layer was subsequently washed with brine and 1 M potassium sodium tartrate solution, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded crude 4-pentafluoroethyl-benzaldehyde (390 mg) as a yellow liquid, which was added at RT to a solution of 2-(4-chlorophenyl)ethylamine (269 mg, 1.73 mmol) in methanol (2 mL), then after 18 h sodium borohydride (65 mg, 1.73 mmol) was added at 0° C. After 1 h the reaction mixture was partitioned between ether and water, the organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (431 mg, 26%). Light yellow oil, MS (ISP) 364.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[S:11])[CH:6]=[CH:7][CH:8]=1.Br[CH:21](Br)[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:16]([O:15][C:13]([N:12]=[C:10]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:18])([F:1])[F:19])[CH:4]=2)[CH2:22][CH2:21][S:11]1)=[O:14])[CH3:17]
Reactant: CC(Br)Br
Reactant: CCOC(=O)NC(=S)Nc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)N=C1SCCN1c1cccc(C(F)(F)F)c1
Yield: 83.1 %

Procedure:
A solution of N-(3-trifluoromethylphenyl)-N'-ethoxycarbonylthiourea (1.8 g), dibromoethane (1.29 g) and anhydrous potassium carbonate (2.6 g) in acetone (20 ml) was refluxed for 5 hours. The solvent was removed by distillation, and the residue was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from a mixture of hexane and ethanol to give 1.63 g of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)thiazolidine. m.p., 75.8° C.
Reaction SMILES: CO.[CH2:3]([Cl:5])Cl.C(OC(=O)[C@@H](NC(OC(C)(C)C)=O)CC1C=CC(N[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[N:26]C=3)[CH:22]=[CH:21][N:20]=2)=CC=1)C>C(OC(O)C)C>[Cl:5][C:3]1[C:22]2[C:23](=[CH:28][CH:19]=[N:20][CH:21]=2)[CH:24]=[CH:25][N:26]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(Nc2nccc3ccncc23)cc1)NC(=O)OC(C)(C)C
Reactant: ClCCl
Agent: CCOC(C)O
Solvent: CO
Product: Clc1nccc2ccncc12

Procedure:
A solution of ethyl-(S)-3-[4-aminophenyl]-2-[t-butoxycarbonylamino] propanoate (638 mg, 2.07 mmol) and Intermediate 12 (310 mg, 1.88 mmol) in ethoxyethanol (2 ml) was stirred at 120° for 15 min and at 100° for 1 h under nitrogen. The volatiles were removed in vacuo and the dark residue partitioned between EtOAc (70 ml) and saturated aqueous NaHCO3 (10 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2×30 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford a dark foam. Chromatography (SiO2; 5 to 10% MeOH/DCM) afforded a mixture of ethyl-(S)-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]-2-[(t-butoxycarbonyl) amino]propanoate and some of the title compound (730 mg). This mixture was treated with a solution of trifluoroacetic acid (5 ml) and DCM (5 ml) at room temperature for 1 h. The volatiles were removed in vacuo and the residue partitioned between EtOAc (75 ml) and saturated aqueous NaHCO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3×30 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford an orange solid. Chromatography (silica; 10% MeOH/DCM) afforded the title compound as a straw-coloured solid (420 mg, 60% over two steps). δH (CDCl3) 10.70 (1H, s), 10.31 (1H, s), 9.44 (1H, d, J 5.6 Hz), 8.94 (1H, d, J 5.6 Hz), 8.55 (1H, d, J 7.3 Hz), 8.54 (2H, d, J 8.5 Hz), 8.46 (1H, d, J 5.6 Hz), 7.94 (2H, d, J 8.5 Hz), 4.84 (2H, q, J 7.1 Hz), 4.35 (1H, t, J 6.6 Hz), 4.10 (2H, br s), 3.64 (1H, dd, J 13.5, 6.4 Hz), 3.56 (1H, dd, J 13.5, 7.0 Hz) and 1.95 (3H, t, J 7.1 Hz); m/z (ES+, 70V) 337 (MH+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1([CH2:23][CH2:24][O:25][C:26]2[CH:45]=[CH:44][C:29]([O:30][C:31]3[C:40]4[C:35](=[CH:36][C:37]([O:41][CH3:42])=[CH:38][CH:39]=4)[CH:34]=[CH:33][C:32]=3O)=[CH:28][CH:27]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C.C(Cl)Cl>[Cl-].[Na+].O>[N:16]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([O:30][C:31]3[C:40]4[C:35](=[CH:36][C:37]([O:41][CH3:42])=[CH:38][CH:39]=4)[CH:34]=[CH:33][C:32]=3[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:44][CH:45]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(O)ccc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
Add trifluoromethanesulfonic anhydride (7 mL, 42 mmol) into a solution of 1-[4-(2-azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-naphthalen-2-ol (15 g, 37 mmol), triethylamine (20 mL) and methylene chloride (500 mL) at −50° C. Warm the reaction mixture to room temperature and stir for 1 hour at that temperature. Cool the reaction mixture to −78° C. and add brine (20 mL). Warm the reaction to room temperature. Separate layer and wash the organic layer with saturated sodium bicarbonate solution (100 mL) and brine. Dry the organic layer with magnesium sulfate, filter and evaporate solvent under reduced pressure. Chromatograph the residue on a silica gel column eluting the material with a step gradient of methanol/dichloromethane (0 to 10%) to get 20 g (99%) of trifluoro-methanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-naphthalen-2-yl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:36])([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]2([C:27]#[N:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]=1)[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:37][C:38]1[CH:43]=[CH:42][C:41]([C@H:44]([NH2:46])[CH3:45])=[CH:40][CH:39]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:36])([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]2([C:27]#[N:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]=1)[C:16]([NH:46][CH:44]([C:41]1[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=1)[CH3:45])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: CC(COCc1cc(C(=O)O)cc(C2(C#N)CCCC2)c1)(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C2(C#N)CCCC2)c1)c1ccc(F)cc1

Procedure:
A solution of 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)benzoic acid (10.25 mg, 0.021 mmol), (R)-1-(4-fluorophenyl)ethanamine (0.0085 mL, 0.063 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (12 mg, 0.025 mmol) and diisopropylethylamine (0.012 mL, 0.07 mmol) in 0.2 mL DMF was stirred at rt overnight. Purification by reverse phase preparative HPLC (5-95% MeCN/H2O containing 0.1% TFA, C18 PRO YMC 20×150 mm) gave 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)-N-(1-(4-fluorophenyl)ethyl)benzamide which was subsequently dissolved in 0.2 mL CH2Cl2 and 0.5 mL TFA. The reaction mixture was stirred for 1 h and concentrated. Lyophilization gave 3-((2-amino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)-N-(1-(4-fluorophenyl)ethyl)benzamide as the TFA salt. 1H NMR (400 MHz, CD3OD) δ 8.93 (d, J=8.0 Hz, 1H), 7.92 (app d, J=1.6 Hz, 1H), 7.85 (s, 1H), 7.74 (s, 1H), 7.42 (m, 2H), 7.28 (m, 3H), 7.18 (m, 2H), 7.05 (m, 2H), 5.25 (m, 1H), 4.70 (m, 2H), 3.44 (A of AB, d, J=10.1 Hz, 1H), 3.38 (B of AB, d, J=10.1 Hz, 1H), 3.09 (d, J=13.4 Hz, 1H), 2.86 (d, J=13.4 Hz, 1H), 2.50 (m, 2H), 2.18 (m, 2H), 2.03 (m, 4H), 1.58 (d, J=7.0 Hz, 3H), 1.25 (s, 3H).
Reaction SMILES: [Si]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([CH3:18])[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][C:9]1[C:14]2[CH:15]=[C:16]([CH3:18])[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cc2c(O[Si](C)(C)C(C)(C)C)cccc2o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc2c(O)cccc2o1
Temperature: 0 °C
Yield: 95.8 %

Procedure:
A solution of the crude 4-t-butyldimethylsilyloxy-2-methylbenzofuran (1.822 g, 6.99 mmol) in THF (28 mL) and cooled to 0° C. (ice water bath) was treated with TBAF (14 mL, 13.00 mmol, 1.0 M in THF). After 30 min. the solution was concentrated under reduced pressure and diluted with 150 mL of Et2O and 300 mL of H2O in a separatory funnel. The mixture was shaken and separated in a separatory funnel. The aqueous layer was extracted with Et2O (2×125 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was passed through a column of silica gel [5 to 20% EtOAc/hexanes] and concentrated under reduced pressure to give the product as a white solid (0.9923 g. 96%). A portion (0.052 g) of the material was purified by silica gel chromatography [5 to 20% EtOAc/hexanes] to give the product as a white solid (0.0382 g, 73% recovery). C9H8O2.0.3H2O
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:26])=[C:6]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[NH:7][C:8]([C:10]1[N:14](CC2C=CC=CC=2)[N:13]=[N:12][N:11]=1)=[O:9])(=[O:3])[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([C:4]1[C:5]([OH:26])=[C:6]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[NH:7][C:8]([C:10]1[NH:14][N:13]=[N:12][N:11]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)c1cc(C)cc(NC(=O)c2nnnn2Cc2ccccc2)c1O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)c1cc(C)cc(NC(=O)c2nnn[nH]2)c1O
Yield: 59.2 %

Procedure:
A solution of 3'-acetyl-1-benzyl-2'-hydroxy-5'-methyl-1H-tetrazole-5-carboxanilide (5.0 g) in glacial acetic acid was hydrogenated at 4.1 kg/cm2 and 28° C., using a 5% w/w palladium on charcoal catalyst. The reaction was carefully monitored, and when the theoretical quantity of hydrogen had been used (after 9.5 hours) the catalyst was filtered off and extracted with acetic acid in a Soxhlet apparatus. The acetic acid solutions were then combined and evaporated, and the resulting residue was recrystallised from a mixture of dimethylformamide and water to give 3'-acetyl-2'-hydroxy-5'-methyltetrazole-5-carboxanilide (2.2 g), m.p. 257° C. (with decomposition).
Reaction SMILES: [C:1]([OH:7])(=O)/[C:2](=[CH:4]/[CH3:5])/[CH3:3].C(Cl)(=O)C(Cl)=O.[NH2:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][NH:20]/[CH:21]=[C:22]2\[C:23](=[O:34])[NH:24][C:25](=[O:33])[C:26]3[C:31]\2=[CH:30][C:29]([I:32])=[CH:28][CH:27]=3)=[CH:17][C:16]=1[O:37][Si](C(C)C)(C(C)C)C(C)C.C(N(C(C)C)CC)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.O1CCCC1>[OH:37][C:16]1[CH:17]=[C:18]([CH2:19][NH:20]/[CH:21]=[C:22]2\[C:23](=[O:34])[NH:24][C:25](=[O:33])[C:26]3[C:31]\2=[CH:30][C:29]([I:32])=[CH:28][CH:27]=3)[CH:35]=[CH:36][C:15]=1[NH:14][C:1](=[O:7])/[C:2](/[CH3:3])=[CH:4]/[CH3:5]
Reactant: C/C=C(\C)C(=O)O
Reactant: CC(C)[Si](Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)ccc1N)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(Cl)C(=O)Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C/C=C(\C)C(=O)Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 21.1 %

Procedure:
To a suspension or solution of carboxylic acid, in this case tiglic acid (0.11 g, 1.1 mmol) in anhydrous acetonitrile (3 mL) is added oxalyl chloride (neat, 100 μL, 1.1 mmol). The mixture is shaken at 65° C. for 30 minutes and then reduced to half volume under reduced pressure. The resulting acetonitrile solution is then added to a solution of (4Z)-4-[({4-amino-3-[(triisopropylsilyl)oxy]benzyl}amino)methylene]-6-iodoisoquinoline-1,3(2H,4H)-dione (65 mg, 0.11 mmol) and diisopropylethylamine (380 μL, 2.2 mmol) in tetrahydrofuran (3 mL) After stirring overnight at room temperature, the reaction mixture is concentrated to dryness under reduced pressure. Tetrabutylammonium fluoride solution (1.0 M, 2.0 mL, 2.0 mmol) is added and the mixture is shaken at 55° C. for 2 hours and then allowed to cool to room temperature. Following concentration, the residue is triturated with water and the resulting solid collected by filtration, washed with acetonitrile, and dried under house vacuum to give (2E)-N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]-2-methylbut-2-enamide (12 mg, 21%).
Reaction SMILES: [C:1]([OH:6])#[C:2][CH2:3][CH2:4][CH3:5].C(Cl)Cl.[C:10](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]>CN(C1C=CN=CC=1)C.CCN(CC)CC>[C:10]([O:6][CH2:1][CH2:2][CH2:3][C:4]#[CH:5])(=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC#CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCCOC(=O)c1ccccc1
Temperature: 0 °C
Yield: 89.2 %

Procedure:
To a flame-dried round-bottomed flask was added pentynol (1 equiv., 24 mmol, 2.0 g) and CH2Cl2 (80 mL). The solution was cooled to 0° C. and BzCl (1.2 equiv., 28 mmol, 3.3 mL) was added dropwise, followed by DMAP (0.1 equiv., 2.4 mmol, 300 mg), and Et3N (7 mL). The reaction was warmed to ambient temperature over 12 h, quenched with 2N HCl (10 mL), extracted with EtOAc (2×40 mL), washed with brine (40 mL) and dried over Na2SO4. The purified product was isolated by concentrating in vacuo and purifying by flash chromatography (2.5% EtOAc/Hex) to afford pent-4-yn-1-yl benzoate (4.02 g, 21.4 mmol, 89%). TLC Rf=0.57 (10% EtOAc/Hex); 1HNMR (600 MHz): δ 8.03-8.07 (2H), 7.53-7.60 (1H), 7.42-7.48 (2H), 4.44 (t, 2H, J=6.1 Hz), 2.40 (td, 2H, J=7.3, 2.7 Hz), 1.98-2.05 (overlapping signals, 3H); 13CNMR (150 MHz): δ166.5, 132.9, 130.3, 129.6, 128.3, 83.0, 69.1, 63.4, 27.7, 15.4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:20]1([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:26]([N:27]1[CH2:32][CH2:31][N:30]([CH2:18][CH2:17][CH2:16][CH2:15][CH:13]2[O:12][N:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:14]2)[CH2:29][CH2:28]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=CCCCC1CC(c2cccc([N+](=O)[O-])c2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(C2=NOC(CCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)C2)c1
Yield: 54.8 %

Procedure:
4-[3-(3-Nitrophenyl)-4,5-dihydroisoxazol-5-yl]butanal (30.0 mg, 0.114 mmol), 1-(diphenylmethyl)piperazine (26.2 mg, 0.104 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (66.1 mg, 0.312 mmol) were reacted in 3 mL of methylene chloride 3 mL for about 12 hr. With the following processes the same as in Example 1, 28.4. mg (54.8%) of the target compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)c(OC)cc2nc1OC
Reactant: Clc1cccc(N2CCNCC2)c1
Product: COc1cc2nc(NC(=O)N3CCN(c4cccc(Cl)c4)CC3)c(OC)nc2cc1OC
Yield: 74 %

Procedure:
Ethyl N-(2,6,7-trimethoxyquinoxalin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 190 to obtain the titled compound (yield, 74%) H NMR (300 MHz, CDCl3) δ 3.29-3.31 (m, 4H), 3.79 (m, 4H), 3.97 (s, 3H), 4.00 (s, 3H), 4.12 (s, 3H), 6.82 (m, 1H), 6.86-6.88 (m, 1H), 6.89-6.91 (m, 1H), 7.14 (s, 1H), 7.19-7.22 (m, 3H).
Reaction SMILES: C1(P([N:15]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[Cl:18][C:19]1[C:28](C(O)=O)=[CH:27][C:26]2[C:21](=[CH:22][C:23]([C:32]([F:35])([F:34])[F:33])=[CH:24][CH:25]=2)[N:20]=1.CCCCCC.CC(=O)OCC>C1C=CC=CC=1>[Cl:18][C:19]1[C:28]([NH2:15])=[CH:27][C:26]2[C:21](=[CH:22][C:23]([C:32]([F:35])([F:34])[F:33])=[CH:24][CH:25]=2)[N:20]=1
Reactant: O=C(O)c1cc2ccc(C(F)(F)F)cc2nc1Cl
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Nc1cc2ccc(C(F)(F)F)cc2nc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
20.6 g (75 mmol) of diphenyiphosphoryl azide were added at RT to a solution of 1.4 g (5 mmol) of 2-chloro-7-(trifluoromethyl)quinoline-3-carboxylic acid in benzene (500 ml), and the mixture was then heated for 5 h at 90° C. Concentration in vacuo was then carried out and the residue was taken up in THF (80 ml). 4N aq. LiOH soln. (30 ml) was added to this solution, and stirring was carried out for 1 h at RT. Dilution with water and extraction with EA were then carried out. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 9:1) of the residue yielded 310 mg (1.3 mmol, 26%) of 2-chloro-7-(trifluoromethyl)quinolin-3-amine.
Reaction SMILES: CCN(C(C)C)C(C)C.C(S[C:18](=[O:39])[CH2:19][C@H:20]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])C1C=CC=CC=1.Cl.[NH2:41][C@@H:42]([CH2:48][SH:49])[C:43]([O:45][CH2:46][CH3:47])=[O:44]>CN(C=O)C.O>[C:35]([O:34][C:32]([NH:31][C@@H:20]([CH2:19][C:18]([NH:41][C@@H:42]([CH2:48][SH:49])[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:39])[C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])=[O:33])([CH3:36])([CH3:37])[CH3:38]
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)SCc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)[C@H](CS)NC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
DIPEA (0.098 ml, 0.563 mmol) was added to a solution of (S)-benzyl 4-(benzylthio)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (Compound 5b-1) (201.5 mg, 0.469 mmol) and (R)-ethyl 2-amino-3-mercaptopropanoate hydrochloride (104.5 mg, 0.563 mmol) in DMF (1.2 ml) and water (0.3 ml), and the mixture was stirred at 50° C. for three hours. Water was then added to the reaction solution, and the mixture was purified by reverse phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=80/20→0/100) to afford (S)-benzyl 2-((tert-butoxycarbonyl)amino)-4-(((R)-1-ethoxy-3-mercapto-1-oxopropan-2-yl)amino)-4-oxobutanoate (Compound 5c-1) (133 mg, 67%).