Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26]([O:28][CH3:29])=[O:27])[CH2:3]1.C(N(CC)CC)C.C(Cl)Cl.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>>[CH3:40][S:41]([O:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26]([O:28][CH3:29])=[O:27])[CH2:3]1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H]1C[C@@H](O)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@@H](OS(C)(=O)=O)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of dimethyl(2S,3S,5R)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (1.00 g, 0.00247 mol) and triethylamine (0.412 mL, 0.00296 mol) in methylene chloride (20.00 mL, 0.3120 mol) was added methanesulfonyl chloride (0.210 mL, 0.00271 mol). The mixture was stirred at rt overnight. After quenched with MeOH, the mixture was evaporated to dry in vacuo and diluted with ethyl acetate. The organic layers were washed with water, brine and dried, concentrated to dry. The residue was purified on silica gel, eluting with 0 to 80% EtOAc in hexane, to generate the mesylate compound (0.98 g, 82%). MS (ESI): (M+H)+=484.1.
Reaction SMILES: CO.C([O:10][CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[N:30]=[CH:29][N:28]=[C:27]([O:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:26]=1)[CH2:20][CH2:19]2)(=[O:15])=[O:14])C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[OH:10][CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[N:30]=[CH:29][N:28]=[C:27]([O:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:26]=1)[CH2:20][CH2:19]2)(=[O:14])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(=O)(=O)CCOCc5ccccc5)ccc43)ncn2)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(=O)(=O)CCO)ccc43)ncn2)CC1
Yield: 80 %

Procedure:
Palladium hydroxide (100 mg) was added to a methanol (10 mL)/ethyl acetate (10 mL) mixed solution of the tert-butyl 4-{[6-(5-{[2-(benzyloxy)ethyl]sulfonyl}indolin-1-yl)pyrimidin-4-yl]oxy}piperidine-1-carboxylate (486 mg, 0.817 mmol) produced in Reference Example 44, and the mixture was stirred for 19.5 hours in a hydrogen atmosphere. The reaction solution was filtered through Celite (trade name), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2-4:1, V/V) to obtain the title compound as white foam (330 mg, yield: 80%).
Reaction SMILES: O.NN.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[C:17]([CH2:20][O:21][N:22]4C(=O)C5=CC=CC=C5C4=O)=[N:18][N:19]=[C:15]3[CH2:14][N:13]=[C:12]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])[C:11]=2[CH:40]=1)([O-:6])=[O:5]>C(O)C>[NH2:22][O:21][CH2:20][C:17]1[N:16]2[C:10]3[CH:9]=[CH:8][C:7]([N+:4]([O-:6])=[O:5])=[CH:40][C:11]=3[C:12]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])=[N:13][CH2:14][C:15]2=[N:19][N:18]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2
Agent: NN
Solvent: O
Solvent: CCO
Product: NOCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 2, a solution of hydrazine hydrate in ethanol is reacted at 65° C. with 8-nitro-1-[(phthalimidooxy)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-[(aminooxy)methyl]-8-nitro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]=[O:25])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])(O)(O)=[O:27].[Na+].Cl([O-])=O.[Na+]>O.CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:27])=[O:25])=[CH:19][CH:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)Cc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Yield: 95.5 %

Procedure:
To a solution of 0.7 g of 4-[1-(benzyloxycarbonyl)-piperidin-4-yl]phenylacetaldehyde and 0.5 g of sodium dihydrogenphosphate in 5 ml of water and 30 ml of dimethyl sulfoxide was added a solution of 0.35 g of sodium chlorite in water (5 ml) and the resulting mixture was reacted at room temperature for 20 minutes. After adding water, the reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 0.7 g of the title compound was obtained as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([OH:13])[CH:5]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[C:6]([O:13][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: COC(=O)c1cc(O)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc([N+](=O)[O-])c1
Yield: 92.3 %

Procedure:
A mixture of 1.7 g (8.6 mmol) of 3-hydroxy-5-nitrobenzoic acid methyl ester [prepared as described by D. J. Abraham, D. M. Gazze, P. E. Kennedy and M. Mokotoff, J. Med. Chem. 27, 1549 (1984)], 3.2 g (9.5 mmol) of 1-bromooctadecane and 1.8 g (12.9 mmol) of potassium carbonate in 35 ml of anhydrous DMF was stirred and heated at 75° for 25 hours. After cooling, 150 ml of methylene chloride was added and the insoluble salts were removed by filtration. The filtrate was concentrated at reduced pressure to a solid which was purified by HPLC using 30% methylene chloridehexane to give 3.57 g (92% yield, mp 64°-66°) of 3-nitro-5-(octadecyloxy)benzoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])[C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]cc(I)c2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
5-Chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (150, 31.2 g, 0.112 mol) was dissolved in N-methylpyrrolidinone (800 mL) and NaH (60% dispersion, 4.93 g, 0.123 mol) was added at room temperature. The resulting mixture was stirred for 30 minutes. To this mixture was then added triisopropylsilylchloride (24.0 mL, 0.112 mol) and the resulting mixture was stirred for 2 hours. The reaction was quenched with water and extracted with ethyl acetate three times, washed by brine, dried, filtered, and concentrated in vacuo. The residue was subjected to silica gel flash chromatography (eluted by heptane to 5% ethyl acetate/heptane) to afford the desired compound (43 g 88%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:18]1[CH:30]=[CH:29][C:21]([C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1.[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br.[I-].[Na+].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+].O>>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[F:31])[C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])=[O:23])=[CH:29][CH:30]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1
Reactant: Fc1ccccc1CBr
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(OC)c2)N2C[C@@H](C)NC[C@@H]2C)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(OC)c2)N2C[C@@H](C)N(Cc3ccccc3F)C[C@@H]2C)cc1
Yield: 96.2 %

Procedure:
By a procedure essentially identical to that of Example 3, the title compound was prepared from 1.23 g (3.00 mmol) of 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide, 2-fluorobenzyl bromide (724 μL, 6.0 mmol), sodium iodide (45 mg, 0.30 mmol), and triethylamine (1.51 mL, 10.8 mmol). The crude product was slurried with 1:1 saturated sodium carbonate/water for several hours with manual crushing of suspended solids. Crystalline product was collected by filtration, washed with water and dried to give 1.494 g of 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide as a white solid. Calc. for C32H40FN3O2 0.1 H2O: C, 73.99; H, 7.80; N, 8.09; F, 3.66. Found C, 73.98; H, 7.86; N, 8.00; F, 3.77. 1H NMR (CDCl3, 300 MHz); δ 1.09 (d, J˜7 Hz, 3H); 1.11 (d, J˜7 Hz, 3H); 1.945 (apparent t, J˜9 Hz, 1H); 2.07 (apparent t, J˜9 Hz, 1H); 2.59 (m, 2H); 2.63 (d, J˜11 Hz, 1H); 2.73 (d, J˜11 Hz, 1H); 3.28 (brd m, 2H); 3.33 (half of ABq, J˜14 Hz, 1H); 3.54 (brd m, 2H); 3.78 (s, 3H); 3.88 (half of ABq, J˜14 Hz, 1H); 5.14 (s, 1H); 6.74 (s, 1H); 6.80 (m, 2H); 7.00 (t, J˜8 Hz, 1H); 7.07 (t, J˜7 Hz, 1H); 7.22 (m, 2H); 7.29 (half of ABq, J˜8 Hz, 2H); 7.37 (t, J˜7 Hz, 1H); 7.47 (half of ABq, J˜8 Hz, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[C:11]([CH3:17])[CH:12]=2)[N:7]=1)(=[O:3])[CH3:2].[H-].[Na+].I[CH3:22]>CN(C=O)C.ClCCl>[C:1]([O:4][CH2:5][C:6]1[N:15]([CH3:22])[C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[C:11]([CH3:17])[CH:12]=2)[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1nc2cc(Cl)c(C)cc2c(=O)[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)OCc1nc2cc(Cl)c(C)cc2c(=O)n1C
Reaction time: 0.02 h
Yield: 66.8 %

Procedure:
To a suspension of 2-acetoxymethyl-7-chloro-6-methyl-3,4-dihydroquinazolin-4-one 0.428 g, 1.6 mmol) in anhydrous DMF (13 ml) was added sodium hydride (60% dispersion, 0.070 g, 1.76 mmol) under argon. Stirring was continued at room temperature for 1 min and then iodomethane (0.20 ml, 3.2 mmol) was added into the reaction mixture with a syringe via a septum. Stirring was continued at room temperature for 1 hour and the reaction mixture was then partitioned between ethyl acetate (130 ml) and brine (80 ml). The organic layer was washed with dilute brine (80 ml), dried (Na2SO4) and concentrated in vacuo to leave an orange residue. This orange residue was dissolved in dichloromethane and to this solution silica gel (Art 7734, 1.7 g) was added. The solvent was removed in vacuo and the orange free running powder was placed on a silica gel column made up in 5% ethyl acetate in dichloromethane. The column was eluted with 5% ethyl acetate in dichloromethane to afford a pale yellow solid (0.300 g, 67%), mp 110-112° C.; 1H-NMR (DMSO-d6) 2.17 (s, 3H, CH3CO), 2.47 (s, 3H, 6-CH3), 3.54 (s, 3H, N3—CH3), 5.23 (s, 2H, 2-CH2O), 7.71, 8.09 (2×s, 2H, 5-H, 8-H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.Cl.[CH3:13][O:14][C:15](=[O:30])[C@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N>CO.C(Cl)(Cl)Cl>[CH3:13][O:14][C:15](=[O:30])[C@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH:20][C:9](=[O:11])[CH2:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Reactant: O=C(O)Cc1cccnc1
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1cccnc1

Procedure:
Following General Procedure C and using 3-pyridylacetic acid hydrochloride (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl ester hydrochloride (prepared from N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester hydrochloride (Sigma) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=150-152° C.). The reaction was monitored by tlc (Rf=0.3 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent, followed by recrystallization from acetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:9])[CH:8]=1)[NH2:5].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][N:12]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:5][C:4]2[CH:6]=[C:7]([I:9])[CH:8]=[C:2]([F:1])[CH:3]=2)=[O:16])=[CH:13][N:12]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1cc(F)cc(I)c1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: O=C(Nc1cc(F)cc(I)c1)c1ccc(Cl)nc1

Procedure:
6-Chloro-N-(3-fluoro-5-iodo-phenyl)-nicotinamide was prepared from 3-fluoro-5-iodo aniline and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after suspension in small volume of CH2Cl2, filtration and then a wash with hexanes. HRMS m/z calcd for C12H7N2OClFI [M+H]+: 376.9349. Found: 376.9348
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[Cl:14][CH2:15][C:16](=[O:21])[C:17](Cl)=[N:18][OH:19]>C(#N)C>[Cl:14][CH2:15][C:16]([C:17]1[CH2:1][CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:19][N:18]=1)=[O:21]
Reactant: O=C(CCl)C(Cl)=NO
Reactant: C=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C(CCl)C1=NOC(c2ccccc2)C1
Reaction time: 1 h

Procedure:
To a mixture of styrene (6.79 g, 65.3 mmol) and sodium bicarbonate (32.1 g, powder) in acetonitrile (100 mL), 3-chloro-N-hydroxy-2-oxo-propanimidoyl chloride (i.e. the product of Example 7, Step B) (10 g, 64.1 mmol) was added in 10 portions over 20 minutes. The reaction mixture was then stirred for additional 1 h and filtered. The filtered solid was rinsed with acetonitrile, and the combined filtrates were concentrated under reduced pressure to leave an oil, which was triturated first with hexanes and then with 1-chlorobutane to give 13.6 g of the title compound as a white solid.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH:13]=[CH:12][N:11]=1)=O)(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([CH2:9][NH2:8])[CH:15]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(-c2ccnc(CNC(=O)OC(C)(C)C)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccnc(CN)c2)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-[2-(tert-butoxycarbonylamino-methyl)-pyridin-4-yl]-benzoic acid methyl ester (1.96 g, 5.72 mmol, reference example 56) in CH2Cl2 (19 ml) was added TFA (6 ml). The reaction solution was stirred 3 hrs then concentrated under reduced pressure. The residue was purified by trituration with ether. The solids were collected by filtration, washed with ether and dried under vacuum to give 1.68 g of product. MS (EI) m/z 243 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])[CH:6]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:43][N:44]1[CH2:49][CH2:48][CH:47]([C:50](O)=[O:51])[CH2:46][CH2:45]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])[C:50]([CH:47]2[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]2)=[O:51])[CH:6]=1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCc3cccc(CC(=O)OC)c3)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(=O)C3CCN(C)CC3)c2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The product from step (iii) (0.1 g), diisopropyl ethylamine (0.1 ml) and 1-methylpiperidine-4-carboxylic acid hydrochloride (45 mg) were dissolved in NMP (3 ml) then HATU (130 mg) added to the mixture. The mixture was stirred at rt for 5 h then purified by SCX and RPHPLC, which afforded the title compound. Yield 70 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[CH:34]=[C:33]([C:35]([CH3:41])([CH3:40])[C:36]([F:39])([F:38])[F:37])[O:32][N:31]=3)=[O:28])=[C:22]([F:42])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10]CC1C=CC(OC)=CC=1)[CH3:2]>Cl>[CH2:1]([O:3][C:4]1[C:9](=[O:10])[NH:8][CH:7]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[CH:34]=[C:33]([C:35]([CH3:41])([CH3:40])[C:36]([F:39])([F:37])[F:38])[O:32][N:31]=3)=[O:28])=[C:22]([F:42])[CH:21]=2)[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3cc(C(C)(C)C(F)(F)F)on3)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: Cl
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(C(C)(C)C(F)(F)F)on3)c(F)c2)c[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A mixture of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (20 mg, 0.034 mmol) and HCl (4 M in dioxane, 20 mL) was stirred at 25° C. for 2 h. The mixture was concentrated and the crude material was purified by preparative HPLC (MeCN/H2O as eluants, acidic condition) to give a white solid of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (7.9 mg, 0.017 mmol, 49.7% yield): 1H NMR (400 MHz, CD3OD) δ: 7.42-7.36 (m, 1H), 7.35 (s, 2H), 7.29 (d, J=2.2 Hz, 1H), 7.22 (d, J=2.2 Hz, 1H), 6.87 (s, 1H), 4.12 (q, J=7.0 Hz, 2H), 3.81 (s, 2H), 1.56 (s, 6H), 1.46 (t, J=6.8 Hz, 3H); ES-LCMS m/z 468 (M+1).
Reaction SMILES: [CH:1]1([C:6]([OH:8])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[H-].[Na+].[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1COCC1>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([C:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:8])[C:15]([O:23][CH2:24][CH3:25])=[O:22])[CH3:21]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(O)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(=O)C1CCCC1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
Cyclopentanecarboxylic acid (10.0 g, 87.7 mmol) was heated under reflux with thionyl chloride (13 mL, 176 mmol). After 2 hrs the thionyl chloride was distilled under reduced pressure to give the crude acid chloride (9.8 g, 74.2 mmol) as a liquid. In another vessel, 50% sodium hydride (4.28 g, 89.09 mmol) was taken up in THF (100 mL) and diethyl malonate (11.88 g, 74.24 mmol) was added dropwise at 0° C. Into this mixture the previously-prepared acid chloride (9.8 g, 74.2 mmol) was added dropwise at 0° C. and the reaction mixture was stirred at r.t. for an hour. The reaction was quenched with cold water and extracted with ethyl acetate. The combined organic layer was washed with water, sodium bicarbonate solution, brine solution, dried over sodium sulfate, filtered and concentrated to afford 2-cyclopentanecarbonyl malonic acid diethyl ester (19.2 g, 85.5%) as a liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[NH:26][CH2:25][CH2:24][O:23][C:22]=4[N:27]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:20][C:21]4[N:26]([C:42](=[O:44])[CH3:43])[CH2:25][CH2:24][O:23][C:22]=4[N:27]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NCCO4)cc2)CCC1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCOc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a solution of tert-butyl(1-(4-(7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (22 mg, 0.05 mmol) in dry DCM (1 ml) was added triethyl amine (10 μl, 0.07 mmol) and acetyl chloride (5 μl, 0.07 mmol) under nitrogen. The resulting mixture was stirred for 1 h at room temperature. A saturated solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3×10 ml) using a phase separator (Isolute® SPE). The combined organic phases were concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 80% EtOAc in cyclohexane) to give the title compound (20 mg, 83%). 1H NMR (500 MHz, CDCl3): 8.50 (1H, br s), 7.25 (2H, d), 7.19-7.17 (5H, m), 7.11-7.10 (2H,m), 4.95 (1H, s), 4.43 (2H, t), 3.94 (2H, br s), 2.55-2.25 (7H, m), 2.06-1.98 (1H, m), 1.82-1.73 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:44]2[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]2)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN1CCN(CCCOc2cc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c(c2Cl)CNC3=O)CC1
Yield: 61.5 %

Procedure:
In a similar manner to Step 2 of Example 440, 4-chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (87.1 mg, 0.152 mmol) was dissolved in N,N-dimethylacetoamide (0.9 mL), and the solution was treated with N-methylpiperazine (0.138 mL, 1.58 mmol). The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-[3-(4-methylpyperazin-1-yl)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (59.5 mg, yield 68%).