Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:25])([CH3:24])[CH:9]=[CH:10][Sn](CCCC)(CCCC)CCCC)=[CH:4][CH:3]=1.[NH2:26][C:27]1[N:32]=[C:31]([NH2:33])[C:30](I)=[C:29]([CH3:35])[N:28]=1.[Cl-].[Li+].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>CN(C)C=O.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.O>[NH2:26][C:27]1[N:32]=[C:31]([NH2:33])[C:30]([CH:10]=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)([CH3:24])[CH3:25])=[C:29]([CH3:35])[N:28]=1
Reactant: CCCC[Sn](C=CC(C)(C)c1ccc(F)cc1)(CCCC)CCCC
Reactant: Cc1nc(N)nc(N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(N)c1C=CC(C)(C)c1ccc(F)cc1
Yield: 23.3 %

Procedure:
Under a nitrogen atmosphere, a stirring solution of 4.2 grams (0.009 mole) of 3-(4-fluorophenyl)-3-methyl-1-tributylstannyl-1-butene, 1.9 grams (0.077 mole) of 2,4-diamino-5-iodo-6-methylpyrimidine (prepared in Step B of Example 3), 2.0 grams (0.046 mole) of lithium chloride, 0.4 gram (catalyst) of bis(triphenyl phosphine)palladium(II) chloride, and about 0.05 gram (catalyst) of 2,6-di-tert-butyl-4-methylphenol in 80 mL of N,N-dimethylformamide is heated at 65° C. for about 2.5 days. After this time the reaction mixture is cooled and poured into 500 mL of water. The mixture then is extracted with three 100 mL portions of ethyl acetate. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on basic alumina (containing 6% water), using 10% methanol in methylene chloride as the eluant. The product-containing fractions are combined and concentrated under reduced pressure to a residue. NMR analysis of the residue indicates an impure product. The residue is subjected to column chromatography on silica gel, using 10% methanol in methylene chloride as the eluant. The product-containing fractions are combined and concentrated under reduced pressure, yielding about 0.6 gram of 2,4-diamino-6-methyl-5-[3-(4-fluorophenyl)-3-methyl-1-butenyl]pyrimidine, mp 164°-168° C. (Compound 66). The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][CH2:14][CH2:15][C:16]#[N:17]>C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:13][CH2:14][CH2:15][C:16]#[N:17]
Reactant: COCCN
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COCCNCCCC#N

Procedure:
To a stirred mixture of 2-methoxyethylamine (20.3 g, 270 mmol) and potassium carbonate (11.2 g, 81.1 mmol) was added 4-bromobutyronitrile (10.0 g, 67.6 mmol) over 20 minutes. This mixture was heated at reflux temperature for 1 h, mixed with ethyl acetate (100 mL) and filtered. The filtrate was concentrated and distilled at 109°-115° C. (0.1 mmHg) to give a clear liquid (9.78 g, quantitative).
Reaction SMILES: C([O:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:34]=[CH:33][C:15]([CH2:16][NH:17][C:18](=[O:32])[C:19]3[C:24]([Cl:25])=[CH:23][C:22]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:21][C:20]=3[Cl:31])=[CH:14][CH:13]=2)[CH:9]=[CH:8][N:7]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:31][C:20]1[CH:21]=[C:22]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:23]=[C:24]([Cl:25])[C:19]=1[C:18]([NH:17][CH2:16][C:15]1[CH:33]=[CH:34][C:12]([C:10]2[CH:9]=[CH:8][NH:7][C:6](=[O:5])[CH:11]=2)=[CH:13][CH:14]=1)=[O:32]
Reactant: COCCOc1cc(Cl)c(C(=O)NCc2ccc(-c3ccnc(OC(C)(C)C)c3)cc2)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOc1cc(Cl)c(C(=O)NCc2ccc(-c3cc[nH]c(=O)c3)cc2)c(Cl)c1

Procedure:
Compound N-(4-(2-tert-butoxypyridin-4-yl)benzyl)-2,6-dichloro-4-(2-methoxy ethoxy)benzamide was re-dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL) and stirred at room temperature for 1 h. after the reaction was done it was concentrated in vacuum and then purified by reverse phase chromatography to afford 2,6-dichloro-4-(2-methoxyethoxy)-N-(4-(2-oxo-1,2-dihydropyridin-4-yl)benzyl)benzamide.
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:32]3[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=3)[CH:25]=[C:26]([CH2:28][O:29][CH2:30][CH3:31])[CH:27]=2)[C:10]=1[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])C.[OH-].[Na+]>>[C:44]([CH2:43][CH2:42][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:32]3[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:39])=[O:40])=[CH:34][CH:33]=3)[CH:25]=[C:26]([CH2:28][O:29][CH2:30][CH3:31])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:49])=[O:3])([OH:46])=[O:45]
Reactant: CCOCc1cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)cc(-c2ccc(S(C)(=O)=O)cc2)c1
Agent: [Na+]
Agent: [OH-]
Product: CCOCc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(S(C)(=O)=O)cc2)c1
Yield: 96.9 %

Procedure:
A similar procedure as described in Example 24, step 2 was used, starting from 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-ethoxymethyl-4′-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (101 mg, 0.145 mmol) and 1.0 N aqueous sodium hydroxide (1.5 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(5-ethoxymethyl-4′-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (90 mg, 97%) as a white solid: ES(+)-HRMS m/e calcd for C35H44O9S (M+Na)+ 663.2598. found 663.2594.
Reaction SMILES: [OH:1][C:2]1([CH2:7][CH2:8][C@H:9]2[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[CH3:25]I>>[CH3:25][O:1][C:2]1([CH2:7][CH2:8][C@H:9]2[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCC2(O)CCCC2)COC1(C)C
Agent: [H-]
Agent: [Na+]
Product: COC1(CC[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)CCCC1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
The (S)-tert-butyl 4-(2-(1-hydroxycyclopentyl)ethyl)-2,2-dimethyloxazolidine-3-carboxylate was added to a suspension of NaH (568 mg, 14.2 mmol, 4.0 equiv) and the mixture stirred for 0.5 h. Methyl iodide (2.106 g, 14.2 mmol, 4.0 equiv) was added and the mixture stirred for 48 h at ambient temperature. The excess NaH was quenched by careful addition of water. The mixture was evaporated, and then taken up in EtOAc. The solution was washed with water, then brine and evaporated. The ether was purified by flash chromatography on silica, eluting with 0-41% EtOAc in hexanes. This afforded 1170 mg (3.4 mmol, 95% yield for two steps) of the desired (S)-tert-butyl 4-(2-(1-methoxycyclopentyl)ethyl)-2,2-dimethyloxazolidine-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH:13][CH2:14][CH:15]=[CH2:16])=[C:6]([F:17])[C:5]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=1[F:26].[Cl-].[NH4+].CO.C(=O)(O)[O-].[Na+]>[Fe].CCCCCC.CCOC(C)=O.O1CCOCC1>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH:13][CH2:14][CH:15]=[CH2:16])=[C:6]([F:17])[C:5]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=1[F:26]
Reactant: C=CCNc1c([N+](=O)[O-])cc(C(=O)OC)c(Nc2ccc(I)cc2F)c1F
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: C=CCNc1c(N)cc(C(=O)OC)c(Nc2ccc(I)cc2F)c1F
Temperature: 0 °C

Procedure:
A stirred suspension of 4-allylamino-3-fluoro-2-(2-fluoro-4-iodo-phenylamino)-5-nitro-benzoic acid methyl ester (125.0 g, 0.25 mol), ammonium chloride (300.0 g, 8.58 mol) in 1:1 v/v mixture of methanol (4.0 lit) and dioxane (4.0 lit) was heated until it became a clear solution and was added iron powder (150.0 g, 2.68 mol) under a positive stream of nitrogen gas. The reaction mixture was refluxed for 16 h (completion of reaction is confirmed by TLC-EtOAc:Hexane/3:5) and poured onto a mixture of 10 kg of crushed ice and 6.5 L of saturated sodium bicarbonate. To the mixture was added 1 kg of Celite®, stirred and the thick suspension was filtered through a Celitetbed. The Celite® bed was rinsed with water, then with ethyl acetate and ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (3 L) and the combined organic extracts are washed with water (3 L), brine (2 L), dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give the title compound as oil (light brown color), which was used in the next step without further purification. Yield: 110 (93.55%)
Reaction SMILES: [CH3:1][N:2]([C:7](=[O:31])[C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][C:16]2[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[C:19]([O:25][CH3:26])=[C:18]([N+:27]([O-])=O)[CH:17]=2)=[C:10]([Cl:30])[CH:9]=1)[CH2:3][C:4]([OH:6])=[O:5]>C(OCC)(=O)C.O=[Pt]=O>[CH3:1][N:2]([C:7](=[O:31])[C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][C:16]2[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[C:19]([O:25][CH3:26])=[C:18]([NH2:27])[CH:17]=2)=[C:10]([Cl:30])[CH:9]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COc1c(C(C)C)cc(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COc1c(N)cc(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc1C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.5 %

Procedure:
A mixture of methyl-N-[3,5-dichloro-4-(5-isopropyl-4-methoxy-3-nitro-phenoxy)benzoyl]glycine (380 mg, 0.81 mmol) and PtO2 (40 mg) in ethyl acetate (10 mL) was stirred at room temperature under hydrogen (atmospheric pressure) for 24 h. Pt catalyst was removed by filtration through celite and the filtrate was concentrated, which was purified on column (silica gel, n-heptane/ethyl acetate, gradient elution from 98:2 to 60:40) to give 320 mg (89%) of methyl-N-[3,5-dichloro-4-(3-amino-5-isopropyl-4-methoxyphenoxy)benzoyl]glycine.
Reaction SMILES: C(C1C=[N:6][N:7]2[C:12](C3C=CC(Cl)=CC=3)=[C:11]([C:20]3C=CC=C[C:21]=3Cl)C=NC=12)(O)=[O:2].[OH2:27].C([N:30]([CH2:33][CH3:34])CC)C>C(Cl)(Cl)Cl>[OH2:2].[OH:27][N:30]1[C:33]2[CH:34]=[CH:21][CH:20]=[CH:11][C:12]=2[N:7]=[N:6]1
Reactant: O=C(O)c1cnn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc12
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: On1nnc2ccccc21

Procedure:
To a solution of 3-carboxy-6-(2-chlorophenyl)-7-(4-chlorophenyl)-pyrazolo[1,5-a]pyrimidine (compound obtained in Reference Example 1(4), 165 mg) in chloroform (1.0 mL containing amylene) was added the compound obtained in Reference Example 13(2), water-soluble carbodiimide HCl (123 mg), 1-hydroxybenzotriazole monohydrate (97 mg), and triethylamine (178 μL) and the mixture was stirred at room temperature overnight. To the reaction mixture was added an aqueous saturated sodium hydrogencarbonate solution (2 mL) and the mixture was stirred and extracted with chloroform. The extract was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=90/10 to 70/30) to give 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(4-tetrahydrothiopyranyl)carbamoyl]pyrazolo[1,5-a]pyrimidine (50 mg; yield: 24%) as a pale yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[CH2:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCCCCCCCCCOc1ccc(-c2ccc(C#N)cc2)cc1
Yield: 97 %

Procedure:
To 30 ml of methyl isobutyl ketone were added 3 g of 4-hydroxy-4'-cyanobiphenyl, 21.4 g of 1-bromodecane and 2.5 g of potassium carbonate, and the mixture was reacted under reflux for 30 hours. The reaction mixture was cooled and insoluble substances were removed by filtration. The filtrate was concentrated under a reduced pressure, ethanol was added to the residue and recrystallization was carried out to obtain 5 g of 4-decyloxy-4'-cyanobiphenyl. Thus, 4.1 g of this 4-decyloxy-4'-cyanobiphenyl was dissolved in 25 ml of ethylene glycol, 2.5 ml of 2N sodium hydroxide was added to the solution, and a reaction was carried out under reflux for 4 hours. The reaction liquid was put into dilute hydrochloric acid cooled by ice, and the precipitate was recovered by filtration, washed with water and ethanol, and dried. The dried product was recrystallized from chloroform to obtain 3.0 g of 4'-decyloxybiphenyl-4-carboxylic acid. Then, 20 g of thionyl chloride was dropped into this carboxylic acid and the mixture was reacted under reflux for 2 hours. Unreacted thionyl chloride was removed by distillation under a reduced pressure and 4'-decyloxybiphenyl-4-carboxylic acid chloride was quantitatively recovered.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[C:18]1([CH2:24][CH2:25][NH2:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[N+:15]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[NH:26][CH2:25][CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([OH:8])=[O:7])([O-:17])=[O:16]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: NCCc1ccccc1
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1NCCc1ccccc1

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (22.4 g), β-phenylethylamine (29 g), and water (200 ml) was refluxed for 2.5 hours. After cooling, the reaction mixture was adjusted to a pH of 9.5 and extracted with diethyl ether. The aqueous layer was then acidified by addition of 4N hydrochloric acid, and the precipitated 3-nitro-4-(β-phenylethylamino)-5-sulphamyl-benzoic acid was collected by suction. After recrystallization from aqueous ethanol, the melting point was 208°-208.5°C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:7]=1[N+:8]([O-:22])=[C:9]1[C:14](=[N+:15]2[O-:20])[C:13]([OH:21])=[CH:12][CH:11]=[CH:10]1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[N:23]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:7]=2[N+:8]([O-:22])=[C:9]2[C:14](=[N+:15]3[O-:20])[C:13]([OH:21])=[CH:12][CH:11]=[CH:10]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNCC1
Reactant: [O-][n+]1c2cccc(OCCCCl)c2[n+]([O-])c2cccc(O)c21
Solvent: ClC(Cl)Cl
Product: [O-][n+]1c2cccc(OCCCN3CCCCC3)c2[n+]([O-])c2cccc(O)c21
Reaction time: 21 h

Procedure:
6 grams of 6-(3-chloropropoxy)-1-phenazinol 5,10-dioxide and 40ml piperidine were placed in a flask and stirred at room remperature for 21 hours. The reaction mixture was diluted with 500ml of chloroform. The mixture was then washed with water until the aqueous washes were neutral, extracted with 3 × 250ml of 10 percent HCl. Combined acid extracts were neutralized with sodium carbonate and extracted with 4 × 500ml of chloroform. The chloroform extracts were washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was recrystallized from acetone and dried for 16 hours at 50°C to yield 6-(3-piperidinopropoxy)-1-phenazinol 5,10-dioxide, m.p. 92°-97°C (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:9]=1[CH3:10])=[O:4].C1C(=O)N([Br:35])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O.CCCCCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:15][CH:16]=2)[C:9]=1[CH2:10][Br:35])=[O:4]
Reactant: COC(=O)c1sc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)c1CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
A solution of 404 mg of the product of Step 5, 200 mg of NBS, and 5 mg of benzoylperoxide in 10 mL of CCl4 was heated in a 80° C. oil bath under light from a W-lamp. After 30 min, the reaction mixture was cooled to room temperature, diluted with 10 mL of 3:1 EtOAc/hexane, and filtered through a pad of silica gel. The filtrate was concentrated in vacuo to give 400 mg of the crude title compound which was used for the next step without further purification.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH2:13]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17])[CH3:14].[I:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](O)=[O:35].ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[I:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([NH:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:13][CH3:14])=[O:17])[CH2:19][CH2:20]2)=[CH:29][CH:28]=1)=[O:35]
Reactant: O=C(O)c1ccccc1I
Reactant: CCOC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCN(c2ccc(NC(=O)c3ccccc3I)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (0.096 mol) was added at room temperature to a mixture of 4-(4-aminophenyl)-1-piperazinecarboxylic acid ethyl ester (0.08 mol), 2-iodo benzoic acid (0.096 mol) and 1-hydroxybenzotriazole (HOBT) (0.096 mol) in DCM (500 ml). The mixture was stirred at room temperature overnight. Water was added. The mixture was extracted with DCM. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was taken up in DIPE. The precipitate was filtered off and dried, yielding 39 g of 4-[4-[(2-iodobenzoyl)-amino]phenyl]-1-piperazinecarboxylic acid, ethyl ester (intermediate 27).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH2:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[C:29](=[O:45])[N:30]([CH:37]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[C:31]2=[O:36].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:25][CH2:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[C:29](=[O:45])[N:30]([CH:37]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[C:31]2=[O:36])=[O:7]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc(Cl)c(Cl)c4)c3C2=O)C(=O)N1
Temperature: 40 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
3,4-Dichlorobenzoic acid (0.30 g, 1.6 mmol) was dissolved in 10 mL DMF and CDI (0.30 g, 1.9 mmol) was added. The mixture was stirred at 40° C. for 1 hour, and then 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.50 g, 1.6 mmol) and triethylamine (0.31 g, 3.1 mmol) were added. After an additional 90 minutes stirring at 40° C., the mixture was cooled. The solvent was evaporated, and the residue was dissolved in 60 mL CH2Cl2, and this solution was washed with water (2×60 mL), dried (MgSO4), and evaporated. The residue was chromatographed using a methylene chloride-methanol gradient, eluting 0.49 g of the product with 98:2 methylene chloride-methanol, in 70% yield: mp 161-163° C.; 1H NMR (DMSO-d6) δ 2.06-2.09 (m, 1H), 2.51-2.58 (m, 2H), 2.84-2.91 (m, 1H), 4.94 (d, J=5.7 Hz, 2H), 5.17 (dd, J=12.6 Hz, d=5.3 Hz, 1H), 7.74-7.95 (m, 5H), 8.17 (d, J=1.9 Hz, 1H), 9.33 (t, J=5.7 Hz, 1H), 11.10 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.5, 48.9, 122.0, 127.2, 127.7, 129.3, 130.8, 131.3, 131.6, 133.3, 134.3, 134.9, 138.8, 164.4, 167.0, 167.5, 169.8, 172.8; Anal. calcd for C21H15Cl2N3O5: C, 54.80; H, 3.28; N, 9.13. Found: C, 54.85; H, 3.36; N, 8.95.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH:18]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH2:18][N:30]2[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[CH2:32][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccccc3F)CC2)cc1-c1ccccc1

Procedure:
79 mg (55%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.312 mmol), 1-(2-fluorophenyl)piperazine (56 mg, 0.312 mmol), DIPEA (82 mL, 0.468 mmol) and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CO>[NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1ccnc(N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccnc(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
To a mixture of 1-(2-aminopyridin-4-yl)ethanone (36) (168 mg, 1.234 mmol) in MeOH (10 mL), under nitrogen at 0° C., was added sodium borohydride (46.7 mg, 1.234 mmol). The reaction mixture was stirred at RT for 2 hr, and the volatiles were removed under reduced pressure. The residue was taken up into EtOAc (25 mL), and extracted with saturated aq NaHCO3 solution (30 mL). The aqueous layer was back extracted with EtOAc (2×20 mL), and the combined organic extracts were washed with brine (30 mL), dried and the solvents removed in vacuo to give the title compound (37) (77 mg, 45%) as a yellow oil: m/z 139 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][CH:9]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16](=[O:24])[CH:15]=2)[C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.C([N:29](CC)CC)C.ClC(OCC(C)C)=O.N>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16](=[O:24])[CH:15]=2)[C:10]([NH2:29])=[O:12])=[O:7])=[CH:25][CH:26]=1
Reactant: CCN(CC)CC
Reactant: O=C(NC(Cc1cc(=O)[nH]c2ccccc12)C(=O)O)c1ccc(Cl)cc1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)C(Cc1cc(=O)[nH]c2ccccc12)NC(=O)c1ccc(Cl)cc1

Procedure:
1.8 Grams of 2-(4-chlorobenzoylamino)-3-(2-quinolon-4-yl)propionic acid was dissolved in 80 ml of N,N-dimethylformamide. To this solution was added 0.6 g of triethylamine. Then, under ice-cooled condition with stirring, 0.8 g of isobutyl chloroformate was added to the above-mentioned mixture. At the same temperature condition, 10 ml of N,N-dimethylformamide solution containing 0.4 g of ammonia was added dropwise to the reaction mixture, and stirred for 3 hours. After the removal of N,N-dimethylformamide by distillation, water was added to the residue and the crystals precipitated were collected by filtration, and were washed with an aqueous solution of sodium hydroxide. Recrystallized from dimethylformamide-water to obtain 0.7 g of 2-(4-chlorobenzoylamino)-3-(2-quinolon-4-yl)propionamide in the form of light yellowish powdery product.