Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: O=C1NCC(c2ccc(Cl)cc2)=NN1
Agent: Cl
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: O=c1ncc(-c2ccc(Cl)cc2)n[nH]1
Yield: 83 %

Procedure:
A mixture of 3.64 g (17.4 mmol) of 6-(4-chlorophenyl)-4,5-dihydro-1,2,4-triazin-3-one, 4.0 g of sodium m-nitrobenzene sulfonate (17.8 mmol), 6.0 g of 50% sodium hydroxide (75.2 mmol) and 160 mL of water were refluxed overnight. The reaction mixture was cooled, then 1N aqueous HCl was added until the pH was slightly acidic to paper. The product was filtered, washed with water and dried to give 3.0 g of 6-(4-chlorophenyl)-1,2,4-triazin-3-one, which was used without further purification.
Reaction SMILES: [K+].Br[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O-:7])=[O:6].[I:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>COCCOCCOC.O>[I:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])=[CH:15][CH:14]=1
Reactant: O=C([O-])c1ccccc1Br
Reactant: Nc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOCCOC
Product: O=C(O)c1ccccc1Nc1ccc(I)cc1

Procedure:
A mixture of o-bromobenzoic acid potassium salt (47.8 g, 0.2 mol), 4-iodoaniline (43.8 g, 0.2 mol), K2CO3 (13.8 g, 0.1 mol), and cupric acetate (2.87 g, 6%) in diglyme (100 mL) was heated to reflux for 30 minutes. The reaction mixture was diluted with H2O (1.0 L) and filtered. The filtrate was acidified with diluted AcOH. The resulting precipitate was collected by filtration, washed with H2O and dried in a vacuum at 50° C. for 16 hours. Recrystallization from EtOAc gave the desired product, a solid (29.7 g, 0.087 mol, 44%). mp 205-206° C.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[N+:13]([O-:15])=O.Cl[O-].[Na+].N1[O:20]N=C2C=C(C(O)=O)C=CC=12.Cl.[Na+].[Cl-]>C(O)C.O.C(O)(=O)C.C(Cl)(Cl)Cl>[N+:3]1([O-:20])[O:15][N:13]=[C:5]2[CH:6]=[C:7]([C:8]([OH:10])=[O:9])[CH:11]=[CH:12][C:4]=12
Reactant: O=C(O)c1ccc2nonc2c1
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)no[n+]2[O-]
Temperature: 67.5 °C
Reaction time: 0.75 h
Yield: 88.8 %

Procedure:
In a 3 L reactor fitted with mechanical stirring, reflux condenser, thermometer and nitrogen inlet, KOH (72.46 g) was dissolved in ethanol (250 ml) and water (250 ml). 4-Amino-3-nitrobenzoic acid (100 g) was added and the orange suspension was heated to 65-70° C. within 30 minutes. The resulting suspension was stirred at the same temperature for 45 minutes and cooled to 0° C.±5° C. within 30 minutes. A commercially available (13% w/w) solution of sodium hypochlorite (448.93 g) was added drop wise within 1.5 hours at 0° C.±5° C. The reaction mixture was stirred at the same temperature for 2 hours and controlled by TLC (CHCl3 100/acetone 2/acetic acid 1). Water (350 ml) was added within 15 minutes at 0° C.±5° C. to give a fine yellow suspension. The reaction mixture was then acidified with a 6N HCl solution (239 ml) until 0.5<pH<1 was reached. NaCl (58.44 g) was added and the resulting suspension was stirred at 0° C.±5° C. for 1.5 hours under nitrogen. The solid was collected by filtration, washed with 3×400 ml water and dried (40° C., 30 mbars, 12 hours) to yield 83.6 g (88.8% yield) of 2,1,3-benzoxadiazole-5-carboxylic acid N-oxide.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:32]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14]([N:16]([CH2:24][CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>>[NH2:32][C@@H:13]([CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:11][CH:10]=1)[C:14]([N:16]([CH2:24][CH:25]([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:15]
Reactant: CCOC(CN(Cc1ccccn1)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Solvent: C1CCNCC1
Product: CCOC(CN(Cc1ccccn1)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Yield: 96.5 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (S)-(9H-fluoren-9-yl)methyl 3-(4-tert-butoxyphenyl)-1-((2,2-diethoxyethyl)(pyridin-2-ylmethyl)amino)-1-oxopropan-2-ylcarbamate (Compound III-16) (3.12 g, 4.6 mmol) was treated with piperidine and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound (1.97 g, 97%).
Reaction SMILES: Br[C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]2[C:3]=1[CH2:4][C:5](=[O:23])[NH:6][CH:7]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22].C([O-])(=O)C.[Na+].[H][H]>C(O)(=O)C.[Pd]>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:7]1[C:8]2[C:3](=[CH:2][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:9]=2)[CH2:4][C:5](=[O:23])[NH:6]1
Reactant: [H][H]
Reactant: O=C1Cc2c(cc3ccccc3c2Br)C(c2ccccc2Cl)N1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1Cc2cc3ccccc3cc2C(c2ccccc2Cl)N1
Yield: 76.9 %

Procedure:
A mixture of 5-bromo-1-(2'-chlorophenyl)-1,4-dihydrobenz[g]isoquinol-3-one (Description 7) (7.6 g), sodium acetate (3.0 g) and 10% palladium-charcoal (2.0 g) in acetic acid (750 ml) was hydrogenated at atmospheric temperature and pressure until the initial rapid uptake of hydrogen had ceased (2.5 hours). The mixture was filtered (celite) and the filtrate evaporated to dryness in vacuo and recrystallised from ethylacetate to afford the title compound (4.65 g) m.p. 234°-237° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH3:21][N:22]1[C:26]([CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:25]([C:33](O)=[O:34])[C:24](=[O:36])[N:23]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:33]([C:25]4[C:24](=[O:36])[N:23]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:22]([CH3:21])[C:26]=4[CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[O:34])=[N:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: Cn1c(CN2CCCC2)c(C(=O)O)c(=O)n1-c1ccccc1
Reactant: COc1ccc2c(Oc3ccc(N)nc3)ccnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(CN5CCCC5)n(C)n(-c5ccccc5)c4=O)nc3)ccnc2c1
Temperature: 25 °C
Yield: 8 %

Procedure:
5-(7-methoxy-quinolin-4-yloxy)pyridin-2-amine (549 mg, 2.05 mmol) and 1-methyl-3-oxo-2-phenyl-5-(pyrrolidin-1-ylmethyl)-2,3-dihydro-1H-pyrazole-4-carboxylic acid (696 mg, 2.31 mmol) were suspended in dichlormethane (10 ml) and N-ethyl-N-isopropylpropan-2-amine (0.70 ml, 4.0 mmol), DMF (0.5 ml) and more dichlormethane (5 ml) were added. Finally, HATU (1.004 g, 2.641 mmol) was added, and the reaction was stirred under nitrogen at room temperature. After stirring for 2.5 weeks, the reaction was filtered and the solid was washed with DCM and MeOH. The filtrate was concentrated and purified on silica gel (˜3 inches, dichlormethane, MeOH, 2 N ammonia in MeOH) to give the desired N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-1-methyl-3-oxo-2-phenyl-5-(pyrrolidin-1-ylmethyl)-2,3-dihydro-1H-pyrazole-4-carboxamide (90.6 mg, 0.165 mmol, 8%). MS (ESI pos. ion) m/z: 551 (MH+). Calc'd exact mass for C31H30N6O4: 550. 1H NMR (400 MHz, CDCl3): 11.44 (s, 1H), 8.61 (d, J=6.0 Hz, 1H), 8.38 (d, J=9.2 Hz, 1H), 8.30-8.21 (m, 2H), 7.62-7.37 (m, 7H), 7.24 (d, J=8.0 Hz, 1H), 6.43 (d, J=6.4 Hz, 1H), 4.35 (s, 2H), 3.98 (s, 3H), 3.57 (s, 3H), 2.73 (s, 4H), 1.84 (s, 4H).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:22])[C:4]([CH:6]1[CH2:11][CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[CH2:8][CH2:7]1)=[O:5]>CCO.[Pd].[C]>[CH3:1][O:2][N:3]([CH3:22])[C:4]([CH:6]1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)=[O:5]
Reactant: CON(C)C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CON(C)C(=O)C1CCNCC1
Reaction time: 60 h
Yield: 92.5 %

Procedure:
A solution of benzyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (5.0 g, 16.32 mmol) in absolute EtOH (75 mL) was charged with 10% Pd-carbon (500 mg). The flask was evacuated and backfilled with hydrogen. The mixture was stirred for 60 h under 1 atmosphere of hydrogen (latex balloon). The catalyst was removed by filtration and the filtrate concentrated and azeotroped twice with MeOH (50 mL) to give the title compound (2.6 g, 15.10 mmol, 92% yield) as a pale yellow oil. LC-MS: (Waters Sunfire C18 4.6 mm×30 mm). 313.20, [M+H]; tR=0.12 min; 2 min gradient from 10/90/0.1 MeOH/H2O/TFA to 90/10/0.1 MeOH/H2O/TFA at 5 mL/min flow rate. 1H-NMR (400 MHz, CDCl3) δ ppm 3.65 (3H, s), 3.12 (3H, s), 3.08 (2H, dt, J=12.59, 3.27 Hz), 2.76 (1H, s), 2.61 (2H, td, J=12.21, 3.27 Hz), 1.57-1.69 (5H, m).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[CH2:8]([O:10][C:11]([C:13]1[C:14]([CH2:37][CH2:38]Br)=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)=[CH:20][C:19]([O:33][CH3:34])=[C:18]([O:35][CH3:36])[CH:17]=2)=[O:12])[CH3:9].O>CN(C)C=O>[CH2:8]([O:10][C:11]([C:13]1[C:14]([CH2:37][CH2:38][N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)=[CH:20][C:19]([O:33][CH3:34])=[C:18]([O:35][CH3:36])[CH:17]=2)=[O:12])[CH3:9]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1c(CCBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(CCn2ccnc2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
Oily sodium hydride (60%, 0.044 g) was added to a solution of imidazole (0.075 g) in N,N-dimethylformamide (5 ml), followed by stirring at room temperature for 15 minutes. Then 2-(2-bromoethyl)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylic acid ethyl ester (0.4 g) was added. After stirring at 80° C. for 1 hour, the reaction mixture was poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (10:1, v/v) to yield 2-[2-(1-imidazolyl)ethyl]-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylic acid ethyl ester (0.295 g, 66%), which was then recrystallized from ethyl acetate-hexane to yield a colorless prismatic crystal having a melting point of 173° to 174° C.
Reaction SMILES: [C:1]([NH:24][C@@H:25]([CH3:30])[C:26]([O:28]C)=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].[OH-].[Na+]>C1COCC1.O>[C:1]([NH:24][C@@H:25]([CH3:30])[C:26]([OH:28])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N[C@@H](C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-methyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propanoate (2.0 g, 4.8 mmol) was taken up in THF (8 mL) along with 5M aqueous NaOH (5 mL) and stirred vigorously at room temperature for 3 h. The reaction mixture was diluted with water and concentrated under reduced pressure. Enough 6N HCl was then added to adjust the pH to 2. The resulting mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford (S)-2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propanoic acid. This was taken up in CH3CN (15 mL) along with N-Boc-L-threonine methyl ester (1.11 g, 4.78 mmol), HATU (2.0 g, 5.3 mmol) and DIEA (1.2 mL). The resulting reaction mixture was stirred at room temperature for 6 h and diluted with EtOAc. The organic layer was washed with NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (CH2Cl2) afforded (2S,3R)-methyl 2-(tert-butoxycarbonyl)-3-((S)-2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propanoyloxy)butanoate (1.0 g).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18](O)=[O:19])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18]([NH:31][C:30]4[CH:32]=[CH:33][CH:34]=[C:28]([C:27]([F:26])([F:35])[F:36])[CH:29]=4)=[O:19])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[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: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 99.5 %

Procedure:
In the same manner as in Example 278 and using 2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoic acid (150 mg, 0.42 mmol), 3-(trifluoromethyl)aniline (191 mg, 1.2 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (230 mg, 0.6 mmol), N,N-diisopropylethylamine (160 mg, 1.3 mmol) and N,N-dimethylformamide (5 mL) as starting materials, the title compound (208 mg, 99%) was obtained as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH:24](=[C:28]1[CH2:34][CH:33]2[NH:35][CH:30]([CH2:31][CH2:32]2)[CH2:29]1)[CH2:25][CH2:26][CH3:27]>C(Cl)Cl.CO>[CH:24](=[C:28]1[CH2:29][CH:30]2[N:35]([CH2:2][CH2:3][CH2:4][N:5]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:15])[CH:33]([CH2:32][CH2:31]2)[CH2:34]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCC=C1CC2CCC(C1)N2
Reactant: O=C1COc2ccccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CCCC=C1CC2CCC(C1)N2CCCN1C(=O)COc2ccccc21
Yield: 41.2 %

Procedure:
4-(3-Chloropropyl)-4H-benzo[1,4]oxazin-3-one (81MF08) (0.030 g, 0.13 mmol), K2CO3 (0.037 g, 0.26 mmol), NaI (0.040 g, 0.27 mmol) and 3-butylidene-8-azabicyclo[3.2.1]octane (0.029 g, 0.17 mmol) were mixed according to GP12. Prep TLC (SiO2; CH2Cl2/MeOH 10:1) gave the title compound (81MF24) (0.019 g, 41%). 1H NMR (CDCl3) δ 7.22-7.19 (m, 1H), 7.05-6.96 (m, 3H), 5.24 (t, J=7.2 Hz, 1H), 5.08 (s, 2H), 4.06 (t, J=6.4 Hz, 2H), 2.61 (t, J=6.8 Hz, 2H), 2.30 (s, 2H), 2.03-1.83 (m, 7H), 1.58-1.43 (m, 2H), 1.39-1.22 (m, 3H), 0.89 (m, 3H); 13C NMR (CDCl3) δ 164.5, 145.5, 131.4, 128.7, 127.9, 124.0, 123.0, 117.1, 115.5, 67.8, 60.4, 60.2, 48.8, 41.0, 39.6, 33.7, 29.5, 26.8, 26.4, 25.8, 23.2, 13.9.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:15]([NH:22][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.1 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (10.0 g, 50.2 mmol) and benzylamine (2.7 mL, 25.1 mmol) in MeOH (30 mL) was added HOAc (1.9 mL, 32.6 mmol), followed by NaCNBH3 (2.0 g, 32.6 mmol) and the reaction was stirred at room temperature overnight. The resulting mixture was quenched with H2O (5 mL) and concentrated in vacuo. The residue was diluted with 0.1 N HCl and washed with Et2O. The aqueous layer was then basified with 2 N NaOH and extracted with Et2O. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, to afford tert-butyl 4-(benzylamino)piperidine-1-carboxylate (8.1 g, 56%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[CH:10]=2)[N:5]=[C:4]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:3]=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]2[CH2:38][NH:37][C:36](=[O:39])[CH2:35]2)[CH:30]=[CH:31][C:32]=1[Cl:33].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]2[CH2:38][N:37]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:12]5[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=5)[CH:10]=4)[N:5]=[C:4]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[N:3]=3)[C:36](=[O:39])[CH2:35]2)[CH:30]=[CH:31][C:32]=1[Cl:33]
Reactant: COc1cccc(-c2ccc3nc(-c4cccnc4)nc(Cl)c3c2)c1
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1cccc(-c2ccc3nc(-c4cccnc4)nc(N4CC(c5ccc(Cl)c(Cl)c5)CC4=O)c3c2)c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a mixture of 4-chloro-6-(3-methoxyphenyl)-2-(pyridin-3-yl)quinazoline (40 mg, 0.12 mmol), 4-(3,4-dichlorophenyl)pyrrolidin-2-one (100 mg, 0.437 mmol) and Cs2CO3 (42 mg, 0.127 mmol) in dry toluene (6 mL) was added Pd(OAc)2 (3 mg, 0.01 mmol) and Xantphos (10 mg, 0.02 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 12 h. After cooling, the mixture was filtered through a pad of celite. The residue was purified by silica gel chromatography, eluted with petroleum ether/ethyl acetate (5:4) to give the desired product as a yellow solid. 14 mg of the desired product was obtained in a 22.5% yield, LCMS: retention time=1.802 min, [MH]+=541.0, 543.0. 1H-NMR (400 MHz, DMSO-d6): δ 9.73 (s, 1H), 9.05-9.04 (m, 1H), 8.86-8.85 (m, 1H), 8.42-8.38 (m, 2H), 8.19 (d, J=8.8 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.82-7.81 (m, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.58 (dd, J=8.0, 1.6 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.41-7.36 (m, 2H), 7.07 (dd, J=8.0, 2.0 Hz, 1H), 4.57-4.46 (m, 2H), 4.06-4.03 (m, 1H), 3.20-3.01 (m, 2H), 3.88 (s, 3H).
Reaction SMILES: C([N:8]([CH2:30][C@H:31]([OH:41])[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([CH2:39][OH:40])[CH:33]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)C1C=CC=CC=1>CO.[Pd]>[OH:41][C@H:31]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([CH2:39][OH:40])[CH:33]=1)[CH2:30][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: NS(=O)(=O)c1cccc(CCCOCCCCCCCN(Cc2ccccc2)C[C@H](O)c2ccc(O)c(CO)c2)c1
Agent: [Pd]
Solvent: CO
Product: NS(=O)(=O)c1cccc(CCCOCCCCCCCNC[C@H](O)c2ccc(O)c(CO)c2)c1
Yield: 87.3 %

Procedure:
3-(3-{[7-(Benzyl{(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamide (87.2 g) in methanol (800 ml) was hydrogenated over 5% Pd/C catalyst (28 g, 50% wet) at atmospheric pressure and ambient temperature. The catalyst was removed by filtration through a Hyflo pad and the filtrate concentrated in vacuo to give the title compound (64.4 g)—LC RT=3.46 min.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].Cl.[NH2:13][OH:14]>C(O)C.O>[CH2:2]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[NH:1][C:2](=[O:3])[C:4]2=[N:13][OH:14])[CH2:4][CH2:6][CH2:7][CH3:8]
Reactant: NO
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCCc1cccc2c1NC(=O)C2=NO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
A suspension of the isatin described in Example 10c (5.51 g) in ethanol (Z0 ml) was warmed slightly followed by addition of hydroxylamine hydrochloride (2.47 g) dissolved in water (10 ml). The mixture was warmed to about 80° with stirring for 10 minutes, followed by cooling to ambient temperature and stirring for 30 minutes. The precipitated yellow solid was filtered off, washed with water and dried to afford the title product (4.50 g, 76%) as a fluffy yellow powder: tlc, Rf =0.16, silica gel, ethyl acetate:hexane (2:3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[CH:15][N:14](/[CH:17]=[CH:18]\[C:19]([NH:21][NH2:22])=[O:20])[N:13]=2)[CH:5]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1.[CH3:23]OC(OC)OC.CS(O)(=O)=O.CCOC(C)=O.CCCCCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[CH:15][N:14](/[CH:17]=[CH:18]\[C:19]3[O:20][CH:23]=[N:22][N:21]=3)[N:13]=2)[CH:5]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1
Reactant: CC(C)Oc1cc(Cl)cc(-c2ncn(/C=C\C(=O)NN)n2)c1
Reactant: COC(OC)OC
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)Oc1cc(Cl)cc(-c2ncn(/C=C\c3nnco3)n2)c1
Temperature: 70 °C
Yield: 1050.7 %

Procedure:
In a 25-mL, 3N round-bottomed flask equipped with nitrogen inlet, and a rubber septum, (Z)-3-(3-(3-chloro-5-isopropoxyphenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.3 g, 1.0 eq.) was dissolved in THF (7.5 mL, 25V) and trimethylorthoformate (0.109 g, 1.1 eq) and added Methanesulphonic acid (0.053 g, 0.5 eq) was added into it. The Reaction mixture was refluxed at 70° C. for 2-3 h. The progress of the reaction was followed by TLC analysis on silica gel with 50% EtOAc-hexane as mobile phase. SM Rf=0.40 and Product Rf=0.5. Reaction mixture was poured into ice water (10 mL) slurry and compound was extracted with EtOAc (3×15 mL). The combined organic layers was washed with brine solution (3×15 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation (25° C., 20 mmHg) to afford 0.28 g of Crude compound. evaporation (25° C., 20 mmHg) to afford 3.25 g of a yellow oil. The resulting crude compound was subjected to column purification. The crude reaction mixture was purified by column chromatography using silica 60/120 using ethyl acetate:hexane as mobile phase. The column (5×10 cm) was packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection (25-mL fractions) from 35% to 40% ethyl acetate in hexane. Compound started eluting with 35% ethylacetate in hexane. Fraction containing such TLC profile was collected together to obtain pure compound (50 mg), Yield (16.18%). 1H NMR (400 MHz, CDCl3) δ 10.3 (s, 1H), 8.50 (s, 1H), 8.46 (s, 1H), 7.74 (s, 1H), 7.63 (s, 1H) 7.50-7.53 (d, J=12 Hz, 1H) 7.01 (s, 1H) 6.27-6.30 (d, J=12 Hz, 1H) 4.65-4.71 (m, 1H) 1.39-1.40 (d, J=4 Hz, 6H) LCMS C11H7ClF3N3 (331.76)[M+1] found 331.85 at 3.910. (LCMS 99.67%).