Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:31])=[C:7]([C:22]([N:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27])=[O:23])[C:8]([I:21])=[C:9]([C:19]=1[I:20])[C:10]([N:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15])=[O:11])(=[O:3])[CH3:2].[OH-:32].[K+].B(O)(O)O.[O:38]1[CH2:40][CH:39]1[CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH:47]1[CH2:49][O:48]1>CO.O>[OH:38][CH:39]([CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH:47]([OH:48])[CH2:49][N:4]([C:5]1[C:19]([I:20])=[C:9]([C:10]([N:12]([CH2:13][CH2:14][OH:15])[CH2:16][CH2:17][OH:18])=[O:11])[C:8]([I:21])=[C:7]([C:6]=1[I:31])[C:22]([N:24]([CH2:25][CH2:26][OH:27])[CH2:28][CH2:29][OH:30])=[O:23])[C:1](=[O:32])[CH3:2])[CH2:40][N:4]([C:5]1[C:19]([I:20])=[C:9]([C:10]([N:12]([CH2:13][CH2:14][OH:15])[CH2:16][CH2:17][OH:18])=[O:11])[C:8]([I:21])=[C:7]([C:6]=1[I:31])[C:22]([N:24]([CH2:25][CH2:26][OH:27])[CH2:28][CH2:29][OH:30])=[O:23])[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(I)c(C(=O)N(CCO)CCO)c(I)c(C(=O)N(CCO)CCO)c1I
Reactant: [OH-]
Reactant: C(COCC1CO1)OCC1CO1
Agent: OB(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)N(CC(O)COCCOCC(O)CN(C(C)=O)c1c(I)c(C(=O)N(CCO)CCO)c(I)c(C(=O)N(CCO)CCO)c1I)c1c(I)c(C(=O)N(CCO)CCO)c(I)c(C(=O)N(CCO)CCO)c1I
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5-Acetylamino-N,N,N′,N′-tetrakis-(2-hydroxy-ethyl)-2,4,6-triiodo-isophthalamide (5 g, 6.45 mmol) was added to a stirring solution of potassium hydroxide (0.54 g, 6.5 mmol) in a mixture of methanol (3.5 ml) and water (3.5 ml). To the clear and slightly yellow solution which was obtained was added boric acid (0.35 g, 5.6 mmol). The pH was continuously maintained at pH 12.6 by addition of potassium hydroxide (10 M) and then 2-{[2-(oxiran-2-ylmethoxy)ethoxy]methyl}oxirane (0.39 g, 2.24 mmol) was added. The pH of the solution was continuously maintained within the interval 12 and 13 by addition of solid boric acid for 5 hours. And the mixture stirred at ambient temperature overnight (20 hours). LC-MS investigation showed formation of the expected product. Using 18.5 M HCl ({umlaut over ( )}50%), the mixture was made acidic, pH 3.5-4.5 and stirred overnight again. Precipitation of unreacted monomer had occurred and removed by filtration of the mixture (funnel sinter 3) and the filter cake washed with water (2×5 ml). The filtrate was then treated with ion exchangers (AMB200C, 9 ml) and (IRA-67, 10 ml). The resins were removed by filtration and rinsed with water and the combined aqueous volume was reduced in vacuo. The crude product was purified by preparative HPLC (column Phenomenex Luna C18 (2) 10 μm 250×50.0 mm, solvents: A=water and B=acetonitrile; gradient 0-10% B over 60 min; flow 50.0 ml/min, UV detection at 214 nm and 254 nm). After freeze-drying, 377 mg of the title product (21%) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].[CH:6]([N:9]1[CH2:14][CH2:13][CH:12]([NH:15][S:16]([CH2:19][CH2:20][NH:21][C:22]([C:24]2[S:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[O:23])(=[O:18])=[O:17])[CH2:11][CH2:10]1)([CH3:8])[CH3:7]>>[C:3]([CH2:2][N:15]([CH:12]1[CH2:13][CH2:14][N:9]([CH:6]([CH3:8])[CH3:7])[CH2:10][CH2:11]1)[S:16]([CH2:19][CH2:20][NH:21][C:22]([C:24]1[S:25][C:26]([Cl:29])=[CH:27][CH:28]=1)=[O:23])(=[O:17])=[O:18])(=[O:4])[NH2:5]
Reactant: NC(=O)CCl
Reactant: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Product: CC(C)N1CCC(N(CC(N)=O)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid {2-[carbamoylmethyl-(1-isopropyl-piperidin-4-yl)-sulfamoyl]-ethyl}-amide was prepared by an analogous procedure as described in example 15 starting from 48 mg (2 equiv.) 2-chloro-acetamide and 100 mg (0.25 mmol) 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid {2-[carbamoylmethyl-(1-isopropyl-piperidin-4-yl)-sulfamoyl]-ethyl}-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:20])[CH2:13][C:14]([CH2:16][O:17][CH2:18][CH3:19])=O)[CH3:10].[CH2:21]([O:23][C:24](=[O:29])/[CH:25]=[C:26](\[NH2:28])/[CH3:27])[CH3:22]>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:25]([C:24]([O:23][CH2:21][CH3:22])=[O:29])=[C:26]([CH3:27])[NH:28][C:14]=1[CH2:16][O:17][CH2:18][CH3:19])=[O:20])[CH3:10]
Reactant: O=Cc1ccccc1
Reactant: CCOCC(=O)CC(=O)OCC
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CCO
Product: CCOCC1=C(C(=O)OCC)C(c2ccccc2)C(C(=O)OCC)=C(C)N1
Yield: 65 %

Procedure:
After heating a solution of 10.6 g of benzaldehyde, 17.4 g of γ-ethoxyacetoacetic acid ethyl ester and 13 g of β-aminocrotonic acid ethyl ester in 80 ml of ethanol for several hours, 2-ethoxymethyl-6-methyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained, in a yield of 65% of theory, in the form of yellow crystals of melting point 112°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:26])[N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=4[OH:25])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C@H:12]([CH3:26])[N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=4[OH:25])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CC1c2ccccc2-c2ccc(F)cc2N1C(=O)c1ccc(O)cc1O
Solvent: ClC(Cl)Cl
Product: C[C@H]1c2ccccc2-c2ccc(F)cc2N1C(=O)c1ccc(O)cc1O

Procedure:
The enantiomers of 4-[(3-fluoro-6-methylphenanthridin-5(6H)-yl)carbonyl]benzene-1,3-diol (800 mg, 2.29 mmol) were separated by automated, preparative, normal phase, chiral chromatography on a Chiralpak AS (20 mm×250 mm) column eluting with 15% isopropyl alcohol in hexane at a flow rate of 20 mL/min with. The fractions containing the second peak were combined and concentrated in vacuo, to provide one peak (99.3%) with a retention time of 9.345 minutes was isolated as a white solid (220 mg, 55% based upon a 1:1 ratio of enantiomers with a theoretical maximum amount of 400 mg). mp 182-184° C.; [α]D25=+618° (c=0.0101 g/mL, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (d, J=6.73 Hz, 3 H) 5.65 (d, J=6.73 Hz, 1 H) 6.16 (d, J=1.81 Hz, 1 H) 6.22 (dd, J=8.41, 2.20 Hz, 1 H) 6.75 (d, J=10.35 Hz, 1 H) 6.98 (d, J=8.28 Hz, 1 H) 7.04 (td, J=8.60, 2.72 Hz, 1 H) 7.33 (m, 2 H) 7.39 (ddd, J=7.70, 6.79, 2.07 Hz, 1 H) 7.90 (d, J=7.50 Hz, 1 H) 7.94 (dd, J=8.79, 6.47 Hz, 1 H) 9.62 (s, 1 H) 9.70 (s, 1 H) MS (ESI) m/z 350 ([M+H]+); MS (ESI) m/z 348 ([M−H]−); HRMS: calcd for C21H16FNO3, 349.1114 (M), 350.1187 ([M+H]+); found (ESI+), 350.11817.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>COCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([NH:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cc(N)nc1-c1ccco1
Reactant: NCc1ccccc1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccc2)cc(N)nc1-c1ccco1
Temperature: 80 °C
Yield: 36.3 %

Procedure:
To a stirred solution of 250 mg (0.75 mmol) trifluoromethanesulfonic acid 6-amino-3-cyano-2-furan-2-yl-pyridin-4-yl ester in 10 ml DME was added 0.82 ml (7.56 mmol) benzylamine and the mixture heated at 80° C. for 72 hours. The reaction mixture was then cooled to room temperature and partitioned between dichloromethane and water. The phases were separated and the organic phase dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ether/hexane to afford 79 mg (38%) 6-amino-4-benzylamino-2-furan-2-yl-nicotinonitrile as a white crystalline solid. ES-MS m/e (%): 291 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Cl)[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[SH:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1.COC1C=C(C=CC=1OC)C(Cl)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][S:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)c1cccc(CCl)c1
Reactant: Sc1ccncc1
Agent: COc1ccc(C(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Br)ccc1NC(=O)c1cccc(CSc2ccncc2)c1
Reaction time: 12 h
Yield: 67 %

Procedure:
Subsequently, methyl 5-bromo-2-[3-(chloromethyl)benzoyl]aminobenzoate (1.5 g) was dissolved in anhydrous methylene chloride. Triethylamine (2.0 ml) and 4-mercaptopyridine (compound B′) (880 mg) were added to the solution at room temperature, and the mixture was stirred at that temperature for 12 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, was dried over sodium sulfate, and was then concentrated. Diethyl ether was added to the residue for crystallization. The crystals were filtered through Kiriyama Rohto (21 mmφ) and were washed with diethyl ether to give methyl 5-bromo-2-(3-[(4-pyridylsulfanyl)methyl]benzoylamino)benzoate (1.20 g, yield 67%) as a useful intermediate.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:6]=1.[CH:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33].C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:5]2[CH:6]=[C:2]([C:37]3[CH:38]=[CH:39][C:34]([CH:32]=[O:33])=[CH:35][CH:36]=3)[CH:3]=[N:4]2)=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: COc1ccc(C(c2ccc(OC)cc2)(c2ccc(OC)cc2)n2cc(Br)cn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C(c2ccc(OC)cc2)(c2ccc(OC)cc2)n2cc(-c3ccc(C=O)cc3)cn2)cc1
Temperature: 80 °C
Yield: 83.7 %

Procedure:
A mixture of 4-bromo-1-(tris(4-methoxyphenyl)methyl)-1H-pyrazole (1.47 g, 3.1 mmol), (4-formylphenyl)boronic acid (0.94 g, 6.3 mmol), and K2CO3 (0.65 g, 4.7 mmol) in DME-H2O (25 mL, 4:1) was degassed by alternately putting under house vacuum and argon three times for several minutes each. Tetrakis(triphenylphosphine)palladium (0.35 g, 0.3 mmol) was added then the mixture was degassed again. After heating for 16.5 hrs at 80° C. and cooling to room temperature, H2O was added. The mixture was extracted with EtOAc and the combined organics were washed with H2O, saturated aqueous NaHCO3 and brine then dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (20-30% EtOAc-hexanes; EtOAc containing 1% Et3N) gave 4-(1-(tris(4-methoxyphenyl)methyl)-1H-pyrazol-4-yl)benzaldehyde (1.31 g combined from two reactions, 33%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][CH:6]([N+:13]([O-])=O)[CH2:7][CH2:8][C:9](OC)=[O:10]>CO.[Ni]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][CH:6]1[CH2:7][CH2:8][C:9](=[O:10])[NH:13]1
Reactant: COC(=O)CCC(CCC(=O)OC)[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: COC(=O)CCC1CCC(=O)N1

Procedure:
A solution of 136 g of gamma-nitropimelic acid dimethyl ester in 500 ml of methanol is hydrogenated at approximately 3780 psi using 15 g of Raney Nickel as catalyst. The resulting slurry is filtered to remove the catalyst and the filtrate is concentrated at reduced pressure to yield crude 5-oxo-2-pyrrolidinepropanoic acid methyl ester. The 5-oxo-2-pyrrolidinepropanoic acid methyl ester is dissolved in 100 ml of methanol and 100 ml of water and is treated with 94 g of 50% sodium hydroxide solution. The reaction mixture is stirred and is heated to 98° C. with distillation of methanol. The solution is cooled, neutralized with 151 ml of concentrated hydrochloric acid and concentrated at reduced pressure. The residue containing 5-oxo-2-pyrrolidinepropanoic acid is heated at 98°-100° C. for 24 hours with 200 ml of acetic anhydride. The sodium chloride is removed by filtration after the acetic anhydride reaction. The filtrate is then concentrated at reduced pressure and 200 ml of toluene is added and concentration is repeated. The dihydro-1H-pyrrolizine-3,5-(2H,6H)-dione crystallizes and is isolated by filtration. The product is best purified by sublimation at 100° C. and 0.1 mm Hg or by recrystallization from ethanol to give melting point of 179°-182° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>CN(C)C=O.C(OCC)(=O)C>[CH2:40]([O:39][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[N:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: O=C(CCCCCBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(CCCCCC(=O)OCc1ccccc1)CN2c1ccccc1
Temperature: 55 °C
Reaction time: 18 h
Yield: 12.4 %

Procedure:
To a solution of tert-butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.4 g, 1.2 mmol) and potassium carbonate (0.25 g, 1.8 mmol) in N,N-dimethylformamide (5 mL), was added benzyl 6-bromohexanoate (0.34 g, 1.2 mmol). After stirring at 55° C. for 18 hours, the reaction mixture was diluted with ethyl acetate (25 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to obtain the title compound (0.08 g, 12%); MS for C31H41N3O5 m/z 536.16 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1COCC1.O>CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]1(=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]3[O:23][CH:27]=[CH:26][CH:25]=3)=[CH:3][CH:4]=2)[C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCCC2)c2ccc(-c3ccco3)cc2)cc1
Temperature: 25 °C
Yield: 44 %

Procedure:
The round-bottom flask was charged with 4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (9) (0.100 g, 0.28 mmol), PdCl2(PPh3)2, (0.020 g, 0.028 mmol), 2-furanylboronic acid (0.063 g, 0.56 mmol), aqueous 2 M Na2CO3, (0.06 g, 0.56 mmol), and THF/H2O mixture (4:1, 5 mL) under a nitrogen atmosphere. The reaction mixture was refluxed for 10 h. Reaction mixture was cooled to room temperature, diluted with Et2O (10 mL) and filtered. The filtrate was diluted with EtOAc (30 mL), washed with brine, dried (Na2SO4), and concentrated under reduced pressure to afford the crude product. The product was purified by silica gel chromatography using hexanes:EtOAc (19:1 to 4:1) as an eluent to give 0.0.42 g (44%) of compound 202 as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.28 (s, 1H), 7.70 (br s, 1H), 7.59 (d, J=6.0 Hz, 2H), 7.12 (d, J=6.0 Hz, 2H), 6.91 (d, J=6.3 Hz, 2H), 6.86 (d, J=2.4 Hz, 1H), 6.66 (d, J=6.3 Hz, 1H), 6.55 (br s, 1H), 2.37 (br s, 4H), 1.62 (br s, 8H). LCMS (ESI): m/z 343 (M−H)−.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[N:18]=[C:19]([CH2:27][CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[N:20]5[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=45)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Cl:43][CH2:44][C:45](Cl)=[O:46]>C(Cl)Cl>[NH2:26][C:22]1[C:21]2[N:20]([C:19]([CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([C:45](=[O:46])[CH2:44][Cl:43])[CH2:30][CH2:29]3)=[N:18][C:17]=2[C:11]2[CH:10]=[C:9]3[C:14]([CH:15]=[CH:16][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8]3)=[CH:13][CH:12]=2)[CH:25]=[CH:24][N:23]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccn2c(CC3CCN(C(=O)CCl)CC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reaction time: 0.17 h

Procedure:
1-(2-phenylquinolin-7-yl)-3-(piperidin-4-ylmethyl)-imidazo-[1,5-a]-pyrazin-8-amine (110.00 mg, 0.25 mmol) in a dried 15 mL round bottom flask was dissolved in 2.00 mL of methylene chloride and was charged with PS-DIEA (150 mg, 0.46 mmol). Chloroacetyl chloride (10 μL, 0.42 equiv) was added in one portion. After 10 min., another 5 μL of chloroacetyl chloride (0.21 equiv) was added. After another 10 min., another 2.5 μL of methoxylacetyl (0.11 equiv) was added. The reaction was filtered through a fritted funnel, and the resins were rinsed multiple times with methylene chloride. The crude product was purified by a 5 g Jones silica gel (dry loaded with silica, wetted with 100% ethyl acetate and eluted with 5% NH3 in MeOH/Ethyl Acetate) and afforded the desired product; 1H NMR (400 MHz, CHLOROFORM-d) S 8.74 (1H, s), 8.30 (1H, d, J=8.68), 8.21 (2H, d, J=7.01), 7.98 (2H, m), 7.86 (1H, dd, J=1.70, J=1.70), 7.53 (3H, m), 7.24 (1H, d, J=5.34), 7.08 (1H, d, J=5.31), 4.63 (1H, d, J=13.24), 3.90 (1H, d, J=13.2), 3.15 (1H, t), 2.97 (2H, d, J=5.64), 2.70 (1H, t), 2.34 (1H, m), 2.05 (2H, s), 1.92 (2H, t), 1.42 (2H, m); MS (ES+): m/z 511.06/513.02 (50/25) [MH+]; HPLC: tR=2.20 min (OpenLynx, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2.[CH3:22][O:23][NH2:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:22][O:23][NH:24][C:19]([C:18]1[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)=[O:21]
Reactant: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CONC(=O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid (70 mg, 0.176 mmol) and O-methyl-hydroxylamine (19 mg, 0.21 mmol) in DMF (2 mL) was added EDCI (40 mg, 0.21 mmol), HOBt (28 mg, 0.21 mmol) and DIPEA (70 μL, 0.42 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate then water, dried (Na2SO4), filtered and concentrated in vacuo. The resultant solid was triturated with a solution of hot methanol/water/NaHCO3, the solid filtered off, washed with water to give the title compound as a pale pink solid (33 mg, 44%). LCMS (Method A): RT=9.09 min, [M+H]+=427. 1H NMR (DMSO-d6, 400 MHz) 13.20 (1 H, s), 11.62 (1 H, s), 9.99 (1 H, s), 7.66 (1 H, dd, J=10.33, 1.94 Hz), 7.46-7.40 (2 H, m), 7.23 (1 H, s), 7.01 (1 H, d, J=8.78 Hz), 6.92 (1 H, t, J=8.66 Hz), 3.64 (3 H, s).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([NH:23][C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:20]=[CH:19][CH:18]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCCCC(=O)Cl
Reactant: Cc1ncoc1C(=NOCc1cccc(N)n1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCC(=O)Nc1cccc(CON=C(c2ccccc2)c2ocnc2C)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 6-[({[(4-methyl-1,3-oxazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (90 mg, 0.29 mmol) in dichloromethane (2 mL) were added pyridine (35 mg, 0.44 mmol) and after 15 min stirring n-hexanoyl chloride (43 mg, 0.32 mmol). After stirring at room temperature for 4 h the mixture was passed through a cartridge filled with basic alumina and 1 g silica. After rinsing with dichloromethane the final compound was eluted with heptane/ethylacetate (1/1) to afford after evaporation N-{6-[({[(4-methyl-1,3-oxazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}hexanamide (95 mg, 72%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[CH2:10][OH:11]>ClCCl.[O-2].[Mn+2]>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: Nc1c(Cl)cc(Br)cc1CO
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: Nc1c(Cl)cc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
A mixture of (2-amino-5-bromo-3-chlorophenyl)methanol (10.0 g, 42.5 mmol) and manganese oxide (21.9 g, 255 mmol) in dichloromethane (400 mL) was stirred at room temperature overnight. The solid was filtered off, and the filtrate was concentrated to give the title compound as a light yellow solid (9.0 g, 91%), which was directly used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]3)[C:9](=O)[NH:8][C:5]2=[CH:6][CH:7]=1.COCCO[Al]OCCOC.[Na]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)Nc1ccc(F)cc12
Agent: COCCO[Al]OCCOC
Agent: [Na]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC2(CNc3ccc(F)cc32)C1
Temperature: 75 °C
Reaction time: 3 h
Yield: 23.5 %

Procedure:
To a stirred solution of tert-butyl 5-fluoro-2-oxospiro[indoline-3,3′-piperidine]-1′-carboxylate (0.80 g, 2.5 mmol) in toluene (20 mL) was added dropwise a solution of sodium bis(2-methoxyethoxy)aluminium hybrid (Red-Al) in toluene (65% w/w, 1.1 mL, 3.5 mmol) at about 70° C. under N2. The reaction mixture was stirred at about 75° C. for 3 h. After cooling, the reaction mixture was quenched with EtOAc and concentrated in vacuo. The residue was diluted with EtOAc, washed with water and brine, dried and concentrated. The residue was purified by column chromatography (hexane:EtOAc, 3:1) to give tert-butyl 5-fluorospiro[indoline-3,3′-piperidine]-1′-carboxylate (0.18 g, 24%) as an oil. LCMS (APCI+) m/z 307 [M+H]+; Rt=3.66 min.