Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH2:20]([O:22][CH:23]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH2:27]([O:26][C:24](=[O:25])[C:23]([O:22][CH2:20][CH3:21])=[CH:13][C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([O:17][CH3:18])[CH:11]=1)[CH3:28]
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)O
Product: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)c(OC)c1)OCC
Temperature: -10 °C
Yield: 50.7 %

Procedure:
4-Benzyloxy-3-methoxybenzaldehyde (7 g; 28.8 mmole) and (1,2-diethoxy-2-oxoethyl) (triphenyl)phosphonium chloride (13.6 g; 31 mmole) was dissolved in isopropanol and the reaction mixture was cooled to −10° C. Potassium carbonate (6 g; 43 mmole) was added. The resulting mixture was stirred over night and the temperature was allowed to reach room temperature. The reaction mixture was filtered and the filtrate was evaporated. Diethyl ether was added to the residue and the resulting mixture was stirred for a while and then insoluble material was filtered off. The filtrate was washed with potassium hydrogensulfate solution and water, dried with magnesium sulfate and evaporated. Isopropylether was added to the residue. Triphenylphosphine oxide precipitated and was filtered off and the filtrate was evaporated. Chromatography of the residue on silica gel using toluene with ethyl acetate (0, 1%, 3%) as eluant gave 5.2 g of 3-(4-benzyloxy-3-methoxyphenyl)-2-ethoxyacrylic acid ethyl ester. Since the product was not pure enough it was stirred with petroleum ether, insoluble material was filtered off and the filtrate was evaporated to give 4 g (38% yield) of pure 3-(4-benzyloxy-3-methoxyphenyl)-2-ethoxyacrylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:24])[C:6]=1[C:7]1[C:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][C:16]=2[F:23])=[N:9][N:10]([CH3:14])[C:11]=1[C:12]#[N:13].S(C)C>C(Cl)Cl.B(F)(F)F>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:24])[C:6]=1[C:7]1[C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[F:23])=[N:9][N:10]([CH3:14])[C:11]=1[C:12]#[N:13]
Reactant: COc1ccc(-c2nn(C)c(C#N)c2-c2c(C)csc2C)c(F)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: Cc1csc(C)c1-c1c(-c2ccc(O)cc2F)nn(C)c1C#N
Temperature: 25 °C
Yield: 42.8 %

Procedure:
4-(2,4-dimethylthiophen-3-yl)-3-(2-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carbonitrile (17 mg, 0.05 mmol) was dissolved in dry DCM (2 mL) and BF3.Me2S (1 M solution in DCM, 0.3 mL, 0.3 mmol) was added and the mixture was stirred at room temperature over night. The mixture was concentrated and MeOH was added to quench the reaction The crude product was purified on silica gel to give -(2,4-dimethylthiophen-3-yl)-3-(2-fluoro-4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbonitrile (7.0 mg, 43%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[F:11])[CH3:2].C([Li])(CC)C.[O:17]1[C:21]2([CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)[O:20][CH2:19][CH2:18]1.[Cl-].[NH4+]>C1COCC1>[F:10][C:6]1[C:5]([F:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][C:7]=1[CH:24]1[CH2:25][CH2:26][C:21]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:22][CH2:23]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCOc1cccc(F)c1F
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1ccc(C2CCC3(CC2)OCCO3)c(F)c1F
Temperature: 30 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
1-Ethoxy-2,3-difluorobenzene (s6) (102.8 g) and THF (1,000 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00M; in n-hexane-cyclohexane; 780 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Then, 1,4-dioxaspiro[4.5]decan-8-one (s7) (101.5 g) in THF (500 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. The reaction mixture was treated with an aqueous solution of ammonium chloride, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was mixed with p-toluenesulfonic acid (3.0 g) and toluene (500 ml). The mixture was heated to reflux for 2 hours while distilled water was removed. After the reaction mixture had been cooled to 30° C., it was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. The purified product was dissolved in a mixed solvent of toluene (250 ml) and Solmix A-11 (250 ml), to which Pd/C (5.0 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and then by recrystallization from heptane to give 8-(2,3-difluoro-4-ethoxyphenyl)-1,4-dioxaspiro[4.5]decane (s8) (136.1 g). The yield based on the compound (s6) was 70.2%.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CC(C)([O-])C.[K+].[CH3:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](=[S:23])[CH2:21]Br)=[CH:18][CH:17]=1>CC(O)(C)C.C1C=CC=CC=1>[CH3:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](=[S:23])[CH2:21][CH:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH3:8])=[O:6])=[CH:18][CH:17]=1
Reactant: COC(=O)CC(C)=O
Reactant: Cc1ccc(C(=S)CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: c1ccccc1
Product: COC(=O)C(CC(=S)c1ccc(C)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
2.28 g (19.7 mmol) of methyl acetoacetate were dissolved in 40 ml of 2-methyl-2-propanol, and 2.21 g (19.7 mmol) of potassium t-butoxide were added to the resulting solution under a nitrogen atmosphere. The mixture was then stirred at room temperature for 1 hour, after which a solution of 4.82 g (19.7 mmol) of 4-methylthiophenacyl bromide in 30 ml of benzene was added dropwise to the resulting mixture. The mixture was then stirred at 60° C. for 3 hours, after which it was cooled. It was then poured into ice-water and extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The resulting residue was applied to a silica gel chromatography column and eluted with a 1:4 by volume mixture of ethyl acetate and hexane, to give 4.42 g (yield 80%) of the title compound as a slightly yellow powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4](=[O:17])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:28]([F:31])([F:30])[F:29])=[C:23](B(O)O)[CH:24]=1>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>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:28]([F:29])([F:30])[F:31])=[C:23]([C:2]2[CH:7]=[CH:6][N:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4](=[O:17])[CH:3]=2)[CH:24]=1
Reactant: OB(O)c1cc(Cl)ccc1C(F)(F)F
Reactant: CC(C(=O)OC(C)(C)C)n1ccc(Br)cc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C(=O)OC(C)(C)C)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
2.0 g (6.4 mmol) of tert-butyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)propanoate (racemate) and 1.7 g (7.7 mmol) of 5-chloro-2-(trifluoromethyl)phenylboronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) were reacted according to General Method 2A. Yield: 2.3 g (purity 91%, 82% of theory)
Reaction SMILES: [CH:1]1[C:10]2[C:9]3[CH2:11][CH2:12][CH:13]=[CH:14][C:8]=3[N:7]=[CH:6][CH2:5][C:4]=2[S:3][CH:2]=1.[CH3:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH:1]1[C:10]2[C:9]3[CH2:11][CH:12]([C:25]([C:24]4[CH:23]=[CH:22][C:21]([NH:20][C:18](=[O:19])[C:17]5[CH:30]=[CH:31][CH:32]=[CH:33][C:16]=5[CH3:15])=[CH:29][CH:28]=4)=[O:26])[CH:13]=[CH:14][C:8]=3[N:7]=[CH:6][CH2:5][C:4]=2[S:3][CH:2]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: C1=CC2=C(CC1)c1ccsc1CC=N2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)C2C=CC3=C(C2)c2ccsc2CC=N3)cc1
Yield: 59.4 %

Procedure:
A mixture of 400 mg of 9,10-dihydro-4H-thieno[2,3-d][1]benzazepine and 600 mg of 4-[(2-methylbenzoyl)amino]benzoyl chloride is stirred in 30 ml of methylene chloride in the presence of 3 ml of triethylamine for 8 hours. The volatiles are removed in vacuo to give a residue which is partitioned between water and chloroform. The organic layer is dried (Na2 SO4) and the filtrate evaporated in vacuo to give a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 518 mg of the desired product. M+1=439.
Reaction SMILES: [OH:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[C:5]([CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]([CH2:31][CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)[C:18](=[O:30])[CH2:19][CH2:20][O:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[OH:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[C:5]([CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]([CH2:31][CH:32]2[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]2)[C:18](=[O:30])[CH2:19][CH2:20][O:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN(CCNCCc2ccc(O)c3[nH]c(=O)sc23)C(=O)CCOCCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCOCCc1ccccc1)N(CCNCCc1ccc(O)c2[nH]c(=O)sc12)CC1CCNCC1
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
To a solution of 4-{[{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-(3-phenethyloxy-propionyl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (Example 1, 0.2 g) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL) and the reaction mixture was stirred for 30 minutes and then concentrated. The residue was dissolved in methanol (5 mL) and purified by reverse phase HPLC eluting with 5% to 95% acetonitrile in 0.2% trifluoroacetic acid. The fractions containing the product were concentrated and dissolved in methanol where 4N hydrogen chloride in 1,4-dioxane was added. The mixture was concentrated and the residue was triturated with ether, the ether was decanted and further concentration afforded the titled compound (0.13 g) as a hygroscopic solid.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.Cl.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][NH:28][CH2:29]4)=[CH:24][CH:23]=3)[N:19]=[C:18]([NH2:32])[N:17]=2)[CH2:12][CH2:11]1>>[CH:1]1([CH2:4][C:5]([N:28]2[CH2:27][CH2:26][C:25]3[C:30](=[CH:31][C:22]([C:20]4[CH:21]=[C:16]([N:13]5[CH2:12][CH2:11][N:10]([CH3:9])[CH2:15][CH2:14]5)[N:17]=[C:18]([NH2:32])[N:19]=4)=[CH:23][CH:24]=3)[CH2:29]2)=[O:7])[CH2:2][CH2:3]1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(O)CC1CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from cyclopropylacetic acid (Oakwood, Cat. #003710) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=407.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([F:41])=[C:16]([NH:18][C:19]([C:21]2[N:25]3[CH:26]=[CH:27][C:28]([C:30]4[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[C:32]([F:40])[CH:31]=4)=[CH:29][C:24]3=[N:23][CH:22]=2)=[O:20])[CH:17]=1)=[O:11].[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:42])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([F:41])=[C:16]([NH:18][C:19]([C:21]2[N:25]3[CH:26]=[CH:27][C:28]([C:30]4[CH:39]=[CH:38][C:33]([C:34]([OH:36])=[O:35])=[C:32]([F:40])[CH:31]=4)=[CH:29][C:24]3=[N:23][CH:22]=2)=[O:20])[CH:17]=1)=[O:11]
Reactant: COC(=O)c1ccc(-c2ccn3c(C(=O)Nc4cc(C(=O)NCCN5CCCC5(C)C)ccc4F)cnc3c2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCCN1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(C(=O)O)c(F)c4)ccn23)c1

Procedure:
A mixture comprising methyl 4-(3-(5-(2-(2,2-dimethylpyrrolidin-1-yl)ethylcarbamoyl)-2-fluorophenylcarbamoyl)imidazo[1,2-a]pyridin-7-yl)-2-fluorobenzoate (step 2) (409 mg, 0.711 mmol) and sodium hydroxide (142 mg, 3.55 mmol) in MeOH (5 ml) was heated at 60° C. overnight. The reaction mixture was concentrated under vacuum and the resulting residue was dissolved in water and adjusted to pH 5 using 1M HCl. The solid precipitate was collected by filtration and dried at 45° C. The aqueous portion was concentrated in vacuo and the residue was sonicated in 5% MeOH in DCM. The resulting suspension was filtered and the filtrate was combined with the solid precipitate from the first filtration. The combined product were evaporated to dryness and dried at 45° C. in the vacuum oven.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:31](Cl)(=[O:33])[CH3:32]>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:31](=[O:33])[CH3:32])[CH2:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCC(C)(C)C)c1
Reactant: CC(=O)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC(C)(C)C)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: {2′-[(2,2-dimethyl-propylamino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [C:1]1([CH:7]2[S:16][CH2:15][CH2:14][C:9]3(OCC[O:10]3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.Cl>[C:1]1([CH:7]2[CH2:8][C:9](=[O:10])[CH2:14][CH2:15][S:16]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2CC3(CCS2)OCCO3)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C1CCSC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
7-Phenyl-1,4-dioxa-8-thiaspiro[4.5]decane was dissolved in acetic acid (50 mL) and 2 N aqueous hydrochloric acid (70 mL). After being stirred at room temperature for 15 h, the mixture was extracted with ether (300 mL), and the ether extract washed with water (2×50 mL), 10% aqueous sodium hydroxide (3×50 mL), and finally with water (2×50 mL). The dried (Na2SO4) solution was evaporated, and the residue was crystallized upon standing overnight in ether, giving 3.5 g (21.1% over two steps) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:5]=[CH:6][CH:7]=1.[N+:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35])([O-:27])=[O:26]>>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:4]2[CH:3]=[C:2]([NH:1][S:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N+:25]([O-:27])=[O:26])(=[O:35])=[O:36])[CH:7]=[CH:6][CH:5]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Product: O=C1CC(=O)N(c2cccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])c2)c2ccc3ccccc3c2N1

Procedure:
By using 5-(3-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 53, (1), and 2-nitrobenzenesulfonyl chloride, the title compound was obtained in the same manner as that of Example 145.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([F:31])[CH:20]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:15][CH2:16][CH2:17][C:3]3=[C:2]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([F:31])[CH:20]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: CCOC(=O)Cc1ccc(N)cc1F
Product: CCOC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1F
Yield: 67 %

Procedure:
Following General Procedure B2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.100 g, 0.33 mmol) was reacted with ethyl 2-(4-amino-2-fluorophenyl)acetate (0.098 g, 0.50 mmol) to afford the title compound (0.094 g, 94%). MW=424.90. 1H NMR (CD3OD, 300 MHz) δ 7.79-7.75 (m, 1H), 7.66-7.60 (m, 1H), 7.45-7.36 (m, 2H), 7.30 (t, J=8.4 Hz, 1H), 7.20 (s, 1H), 7.11-7.05 (m, 1H), 7.04-6.97 (m, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.68 (s, 2H), 3.02 (t, J=7.6 Hz, 2H), 2.89 (t, J=7.6 Hz, 2H), 2.30-2.13 (m, 2H), 1.26 (t, J=7.6 Hz, 3H); APCI MS m/z 425 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>COCCOC>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: OB(O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1-c1ccccc1Cl
Yield: 91.1 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (45 mg, 0.12 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 2-chloro-phenylboronic acid (27 mg, 0.17 mmol) and Pd[PPh3]4 (13 mg, 0.012 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (46 mg, 94%). LC-MS m/e 421.27 (M+H+)
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[CH:14]=[C:13]([CH3:17])[NH:12]2)=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[CH3:18]I>CO>[S:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15](=[O:16])[CH:14]=[C:13]([CH3:17])[N:12]2[CH3:18])=[CH:9][CH:10]=1)([OH:4])(=[O:2])=[O:3]
Reactant: Cc1cc(=O)n(-c2ccc(S(=O)(=O)O)cc2)[nH]1
Reactant: CI
Solvent: CO
Product: Cc1cc(=O)n(-c2ccc(S(=O)(=O)O)cc2)n1C
Temperature: 130 °C
Reaction time: 15 h
Yield: 44.2 %

Procedure:
3.0 g of 1-(4-sulfophenyl)-3-methyl-5-pyrazolone (manufactured by ALDRICH CHEMISTRY Co., Ltd.: 134163-25G), 3.4 g of methyl iodide (manufactured by KANTO CHEMICAL Co., Inc.: 10060), 100 mL of methanol were put in a high-pressure reactor, and stirred for 15 hours at 130° C. under heating. The reaction mixture was evaporated to dryness, and then recrystallized from ethanol to yield 1.4 g of a desired product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([Cl:25])[CH:24]=2)[C:21](=[O:26])[N:20]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[CH2:19]3)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)=O>[Cl:25][C:23]1[CH:24]=[C:16]([NH:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:17]=[C:18]2[C:22]=1[C:21](=[O:26])[N:20]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:37])([F:36])[F:38])=[CH:30][CH:29]=1)[CH2:19]2
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Cl)c3c(c2)CN(Cc2ccc(OC(F)(F)F)cc2)C3=O)CC1
Solvent: O=CO
Product: O=C1c2c(Cl)cc(NCC3CCNCC3)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Yield: 75.3 %

Procedure:
4- {[7-Chloro-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindol-5-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (47 mg, 0.0848 mmol) was stirred in formic acid (4 mL) overnight at room temperature and the solvent was removed under vacuum. The resulting residue was triturated with ether to provide the title compound (29 mg, 74%) as a colorless solid. 1H NMR (300 MHz, CDCl3): δ 8.44 (s, 2H), 7.59 (s, 1H), 7.53 (s, 1H), 7.46 (d, 2H), 7.29 (d, 2H), 4.84 (s, 2H), 4.41 (s, 2H), 4.08 (s, 2H), 3.43-3.39 (m, 2H), 3.03-2.94 (m, 2H), 2.77 (d, 2H), 2.05-2.00 (m, 2H), 1.46-1.42 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](=[O:13])([O-])[O-].[Na+].[Na+]>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>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=1[C:8]1[C:10](=[O:13])[CH2:5][CH2:6][C:7]=1[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(N)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Product: CC1=C(c2cc(C)ccc2N)C(=O)CC1

Procedure:
1.607 g (8.031 mmol) of 2-bromo-4-methylaniline, 1.180 g (8.432 mmol) of 5-methyl-1-cyclopenten-2-one boronic acid compound, 0.093 g (0.080 mmol) of tetrakis(triphenylphosphine)palladium, and 1.277 g (12.047 mmol) of sodium carbonate were loaded to 250 mL schlenk flask, and then 24 mL of degassing DME and 8 mL of H2O that had been purged with N2 were added thereto using a syringe. The mixture was reacted at 90° C. for 12 hours. The work-up was the same as in Example 3 (1.66 g, 96%).