Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([OH:10])=[C:5]([Cl:11])[CH:4]=1.[OH-].[K+].[Cl:14][C:15]([F:19])=[C:16]([F:18])[F:17].O>CN(C)C=O>[Cl:14][CH:15]([F:19])[C:16]([F:18])([F:17])[O:10][C:6]1[C:5]([Cl:11])=[CH:4][C:3]([NH2:2])=[C:8]([Cl:9])[CH:7]=1
Reactant: Nc1cc(Cl)c(O)cc1Cl
Reactant: FC(F)=C(F)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Cl)c(OC(F)(F)C(F)Cl)cc1Cl
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
A solution of 25 g (0.12 mole) of 4-amino-2,5-dichlorophenol hydrochloride in 200 ml dimethylformamide was placed in a 500 ml 3-necked round bottom flask, fitted with a mechanical stirrer, thermometer, reflux condenser and sparger, and 13.4 g (0.24 mole) of potassium hydroxide pellets ground to powder were added. The mixture was heated to 90° C. with stirring under a nitrogen blanket. Then 21 g (0.18 mole) chlorotrifluoroethylene was bubbled in, while stirring and heating at 90° to 100° C., in about 1/2 hour. Stirring was continued for 5 minutes, the mixture cooled in an ice water bath, 500 ml of water were added and the resulting mixture extracted with 250 ml methylene dichloride and then 100 ml methylene dichloride. The extracts were combined, washed with 250 ml water and the methylene dichloride removed in a rotary evaporator. The residue was distilled through a 1"×10" Vigreaux. The cut from 110° to 120° C. at 2 mm pressure was a light tan liquid. Weight 21 grams. Yield was 59 percent. NMR analysis verified structure.
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.[Br:49][C:50]1[CH:51]=[N:52][C:53](Cl)=[N:54][CH:55]=1.C(N(C(C)C)CC)(C)C.Cl>O1CCOCC1>[Br:49][C:50]1[CH:51]=[N:52][C:53]([N:33]2[CH2:34][CH2:35][CH:30]([C:10]3[C:9]([CH:36]([F:47])[C:37]4[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=4)=[C:8]([CH:5]4[CH2:6][CH2:7][C:2]([F:1])([F:48])[CH2:3][CH2:4]4)[C:17]4[CH:16]([O:18][CH2:19][C:20]5[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=5)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=4[N:11]=3)[CH2:31][CH2:32]2)=[N:54][CH:55]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(Br)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
To a solution of 4.80 g (7.11 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, in 16 ml of 1,4-dioxane, 1.40 g (7.24 mmol) of 5-bromo-2-chloropyrimidine and 1.6 ml (9.4 mmol) of diisopropylethylamine were added, and the reaction solution was stirred at 80° C. for 3 hours. After completion of the reaction, the reaction solution was poured into 40 ml of 0.5 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. n-Heptane was added to the obtained residue and the precipitate was obtained by filtration to provide 5.09 g of the title compound as a white solid (yield: 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[S:25]([N:24]([CH3:29])[CH3:23])(=[O:27])=[O:26])=[CH:4][CH:3]=1
Reactant: CC(Nc1ccc(Cl)cc1)c1cccnc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(c1cccnc1)N(c1ccc(Cl)cc1)S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 3.5 g. portion of 3-[1-(4-chlorophenylamino)ethyl]pyridine was dissolved in dichloromethane and 2.7 g. of potassium carbonate and 2.9 g. of dimethylsulfamoyl chloride were added. The mixture was stirred at ambient temperature for 3 days, and was then diluted with 25 ml. of additional dichloromethane and was extracted with water. The organic layer was dried over magnesium sulfate and evaporated to an oil, which was taken up in dichloromethane and chromatographed over silica gel, eluting with chloroform. The product-containing fractions were combined and evaporated to obtain about 0.3 g. of the desired product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1.O>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a solution of 4-methanesulfonylbenzoic acid (100 mg, 0.50 mmol) and 2-amino-5-bromopyridine (104 mg, 0.60 mmol) in dry dichloromethane (10 mL) was added 4-(dimethylamino)pyridine (67 mg, 0.55 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (105 mg, 0.55 mmol). The mixture was stirred at room temperature overnight under N2, diluted with water (10 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate=3/1) to give the title compound as a white crystal (56 mg, yield 32%).
Reaction SMILES: [CH2:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]1=[O:11])[CH2:2][CH3:3].N1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH:23]=[CH:24][CH:25]=1>C1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][C:29](=[O:32])[CH2:30][CH2:31][C:4]2([CH2:1][CH2:2][CH3:3])[C:5](=[O:11])[CH2:6][CH2:7][CH2:8][C:9]2=[O:10])[CH:23]=[CH:24][CH:25]=1
Reactant: CCCC1C(=O)CCCC1=O
Reactant: C=CC(=O)CCCc1cccc(OC)c1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCC1(CCC(=O)CCCc2cccc(OC)c2)C(=O)CCCC1=O

Procedure:
Dissolve 2-propylcyclohexane-1,3-dione (36.3 g) in benzene (400 cc) containing pyridine (21.2 cc). Add 6-m-methoxyphenylhex-1-en-3-one (43.2 g) and reflux the solution over night. Cool the reaction mixture, wash with water, aqueous sodium carbonate, and 10% aqueous sulfuric acid, dry and remove the solvents under reduced pressure to obtain 2-(6-m-methoxyphenyl-3-oxohexyl)-2-propylcyclohexane-1,3-dione.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2CC#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([OH:22])(=[O:21])[CH3:20].S(=O)(=O)(O)O>O>[C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2[CH2:20][C:19]([OH:22])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: N#CCc1oc2cccc-2cc1-c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1oc2cccc-2cc1-c1ccccc1

Procedure:
As an illustration of an acid hydrolysis of nitrile intermediates a mixture of 5 g. of 3-phenyl-7-benzofuranacetonitrile in 30 ml. of acetic acid, 20 ml. of water and 20 ml. of sulfuric acid is stirred and heated at reflux overnight. On cooling and diluting with water one obtains 3-phenyl-7-benzofuranacetic acid, purified by crystallization from benzenehexane.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1)C.[H-].[Na+].Br[CH2:36][CH2:37][O:38][CH2:39][CH3:40]>>[CH2:37]([O:38][CH2:39][CH2:40][N:23]1[C:24]2[C:29](=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][O:12][C:6]3[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=3[C:4]([OH:3])=[O:32])[CH2:16][CH2:17]2)=[CH:22]1)[CH3:36]
Reactant: CCOC(=O)c1cc(C)ccc1OCCN1CCC(c2c[nH]c3ccc(OC)cc23)CC1
Reactant: CCOCCBr
Agent: [H-]
Agent: [Na+]
Product: CCOCCn1cc(C2CCN(CCOc3ccc(C)cc3C(=O)O)CC2)c2cc(OC)ccc21

Procedure:
This compound was prepared following the procedure described in Example 138 (part B) starting with 1.4 g (3.2 mmol) of 2-{2-[4-(5-methoxy-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-5-methyl-benzoic acid ethyl ester (prepared as in Example 138, part A), 0.17 g (4.2 mmol) of NaH in 60% of mineral oil and 0.43 mL (3.8 mmol) of bromoethylethyl ether. The crude mixture was hydrolised following the procedure described in Example 138 (part C) and purified by chromatography over silica gel affording 0.470 g (35% of yield) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=2)=[CH:6][N:5]=[C:4]([NH2:16])[N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)Cl.O>[CH3:15][S:14]([C:10]1[N:9]=[C:8]([C:7]2[C:2]([CH3:1])=[N:3][C:4]([NH2:16])=[N:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1)=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-c2cnc(N)nc2C)n1
Solvent: ClCCl
Solvent: O
Product: Cc1nc(N)ncc1-c1ccnc(S(C)=O)n1
Yield: 17.2 %

Procedure:
To a suspension of 4′-Methyl-2-methylsulfanyl-[4,5]bipyrimidinyl-2′-ylamine (19) (380 mg, 1.629 mmol) in DCM (3.258 mL) was added mCPBA (402 mg, 1.629 mmol). The reaction turned to a brown solution, and immediately the reaction was complete. The reaction mixture was diluted with DCM and water. The organic layer was washed with saturated sodium bicarbonate and brine, dried with sodium sulfate, and concentrated. The crude residue was purified by flash chromatography with a gradient of 2-10% MeOH in DCM to give the desired product (70 mg, 17%). MS (ES+): m/z=250.1 (100) [MH+]. HPLC: tR=0.64 minute over 3 minutes.
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9](O)=[C:8]([Cl:14])[CH:7]=1.[O:16]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:14][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH:3]=[C:2]([Cl:15])[Cl:1])[CH:11]=[C:10]([Cl:12])[C:9]=1[CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:24]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOc1cc(Cl)c(Cc2cccc(Oc3ccccc3)c2)c(Cl)c1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a solution of 0.33 g of 4-(3,3-dichloro-2-propenyloxy)-2,6-dichlorophenol, 0.23 g of m-phenoxybenzyl alcohol and 0.34 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran was added dropwise a solution of 0.26 g of diisopropylazodicarboxylate dissolved in 5 ml of tetrahydrofuran, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was concentrated, and then mixed with 20 ml of diethyl ether. The precipitate was filtered, and the filtrate was concentrated. The residue was subjected to silica gel chromatography, which afforded 0.31 g of 3,5-dichloro-4-(3-phenoxybenzyl)-1-(3,3-dichloro-2-propenyloxy)-benzene (57% yield), nD25.5 1.6066.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:11][C@@H:10]([N:12]=[N+]=[N-])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:11][C@@H:10]([NH2:12])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N=[N+]=[N-])C1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of tert-butyl(cis-3-azidocyclobutyl)carbamate (7.0 g, 33.0 mmol) and palladium 10% on activated carbon (3.51 ml, 33.0 mmol) in a three necked 1000 mL flask was flushed with nitrogen and 2M ammonia in methanol solution (200 mL) was added. The flask was evacuated and a balloon filled with hydrogen was introduced. The mixture was stirred at room temperature for 18 h, filtered, and the filtrate was evaporated under reduced pressure to give the desired product tert-butyl(cis-3-aminocyclobutyl)carbamate (6.1 g, 99% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.64 (br. s., 1 H), 3.72 (d, J=6.85 Hz, 1 H), 3.12 (t, J=7.73 Hz, 1 H), 2.71 (d, J=7.24 Hz, 2 H), 1.51 (q, J=9.85 Hz, 2 H), 1.43 (br. s., 11 H).
Reaction SMILES: C(OC([N:8]1[CH2:32][CH2:31][C:12]2[C:13]3[C:14](O)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[C:15]([F:21])([F:20])[CH2:16][C:17]=3[CH:18]=[CH:19][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:15]1([F:20])[CH:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[C:13]2[C:12]3[CH2:31][CH2:32][NH:8][CH2:9][CH2:10][C:11]=3[CH:19]=[CH:18][C:17]=2[CH2:16]1
Reactant: COc1ccccc1C1(O)c2c(ccc3c2CCN(C(=O)OC(C)(C)C)CC3)CC1(F)F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1c2c(ccc3c2CCNCC3)CC1(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
Into a glass vial, the product from step (c) (112 mg, 0.251 mmol) dissolved in 2 ml DCM was added. To this stirred solution, triethylsilane (603 μL, 3.77 mmol) was added, followed by TFA (290 μL, 3.77 mmol). After stirring at room temperature for 16 hours, additional triethylsilane (603 μL, 3.77 mmol) and TFA (290 μL, 3.77 mmol) were added. The reaction mixture was stirred for an additional 16 hours. The volatiles were then evaporated in vacuo and the residue diluted with 2M HCl (20 ml). The aqueous mixture was washed with diethyl ether (2×), basified with 2M NaOH to pH 10, and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the title compound as a white semi-solid (52 mg). 1H NMR (300 MHz, CDCl3) δ 7.23-7.20 (m, 1H); 7.08-7.02 (m, 2H); 6.95-6.91 (m, 1H); 6.78 (t, J=7.5 Hz, 1H); 6.51 (bs, 1H); 5.15 (d, J=21.0 Hz, 1H); 3.91 (s, 3H); 3.47-3.28 (m, 2H); 2.97-2.81 (m, 4H); 2.72-2.62 (m, 2H); 2.51-2.46 (2H); 1.68 (bs, 1H); MS: ESI (positive): 330 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH:7]([N:22]([CH2:34][CH:35]=[CH2:36])[S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH:8]([CH2:19]C=C)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]>ClCCl.[Ru]>[C:1]([O:5][C:6]([CH:7]1[CH:8]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:19][CH:36]=[CH:35][CH2:34][N:22]1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:24])=[O:25])=[O:37])([CH3:3])([CH3:2])[CH3:4]
Reactant: C=CCC(C(=O)OCc1ccccc1)C(C(=O)OC(C)(C)C)N(CC=C)S(=O)(=O)c1ccc(OC)cc1
Agent: [Ru]
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)OCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
2-Allyl-3-(allyl-(4-methoxy-benzenesulfonyl)-amino)-succinic acid 1-benzyl ester 4-tert-butyl ester (5.5 g, 10.4 mmol) are solved in 40 ml Dichloromethane and deoxygenated and flushed with Argon three times. The catalyst (RuCl2 (PCy3)2 =--Ph) (100 mg, 0.12 mmol) is added and the reaction is deoxygenated and flushed with Argon one more time. The reaction solution is stirred for 7 h at room temperature. Another (90 mg, 0.11 mmol) of the Ruthenium catalyst are added and the reaction is stirred over night. Evaporation of the solvent followed by flash-chromatography, Hexane/Ethylacetate (3:1) afforded the product: 1H NMR (CDCl3 400 Mhz), ppm: 7.81 (d, 2H), 7.37 (m, 5H), 6.93 (d, 2H), 5.60 (m, 2H), 5.10 (m, 3H), 4.18 (dd, 1H), 4.05 (dd, 1H), 3.88 (s, 3H), 3.20 (ddd, 1H), 2.68 (m, 2H), 1.32 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH2:17]([NH2:19])[CH3:18].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:19][CH2:17][CH3:18]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
3,5-Bis-trifluoromethylbenzaldehyde (3.00 g) is dissolved in 1,2-dichloroethane (50 ml), and thereto are added 70% aqueous ethylamine solution (0.80 ml) and acetic acid (2.1 ml), followed by an addition of triacetoxy-sodium borohydride (13.1 μg) at room temperature over 1 hour with stirring. The mixture is stirred at room temperature for additional 30 minutes, and to the reaction mixture is then added a saturated aqueous sodium bicarbonate solution, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with a saturated aqueous sodium bicarbonate solution and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane ethyl acetate=4:1) to give (3,5-bis-trifluoromethyl-benzyl)-ethyl-amine (1.52 g). MS (m/z): 272 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:6]=1)=[O:4].[H-].[Na+].[CH3:25]OS(OC)(=O)=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][N:14]([C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH3:25])[CH:6]=1)=[O:4]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(=O)n(CCN(C)C(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a round bottomed 25 ml flask fitted with a magnetic stirrer bar and nitrogen inlet was added 1,6-dihydro-l-[2-(3-pyridinylcarbonylamino)ethyl]-6-oxo-3-pyridinecarboxylic acid methyl ester (0.211 g, 0.70 mmol) and dimethylformamide (7.0 ml). At room temperature with stirring, sodium hydride (0.018 g, 0.77 mmol, 98% dry) was added. After 45 minutes, the reaction was quenched with dimethylsulfate (0.073 ml, 0.78 mmol). Stirring was continued for 3.75 hours at which time the mixture was concentrated. The crude product was purified by medium pressure liquid chromotography (silica gel, 3% methanol/dichloromethane) and triturated with ether to give the product, MP: 120°-122° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7](Cl)=[O:8].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:8]
Reactant: Cc1oncc1C(=O)Cl
Reactant: C1COCCN1
Product: Cc1oncc1C(=O)N1CCOCC1

Procedure:
of melting point 42° to 44° C., prepared from 5-methyl-4-isoxazolecarboxylic acid chloride and morpholine.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([CH3:12])=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]([NH:16][NH2:17])(=[O:15])[CH3:14]>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10](=[N:17][NH:16][C:13](=[O:15])[CH3:14])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NOC)C(C)=O
Reactant: CC(=O)NN
Solvent: CCO
Product: CCOC(=O)C(=NOC)C(C)=NNC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of ethyl 2-methoxyiminoacetoactate (a mixture of syn and anti isomer) (226.6 g.) and acetohydrazide (78.5 g.) in ethanol (500 ml.) was stirred for 1.5 hours at ambient temperature. Precipitates were collected by filtration, washed with ethanol and ether and dried to give ethyl 2-methoxyimino-3-acetylhydrazonobutyrate (a mixture of syn and anti isomers) (155.7 g.), mp 190° to 191.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[CH2:21][CH2:20]3)=[CH:15][C:16]([C:17]#[N:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C:40]([N:42]1CCN2C(C3CCN(C(OCC4C=CC=CC=4)=O)CC3)=C(C#N)C=C2C1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[CH2:23][CH2:24]3)=[C:15]([C:40]#[N:42])[C:16]([C:17]#[N:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCn2c(C3CCN(C(=O)OCc4ccccc4)CC3)cc(C#N)c2C1
Reactant: CC(C)(C)OC(=O)N1CCn2c(cc(C#N)c2C2CCN(C(=O)OCc3ccccc3)CC2)C1
Product: CC(C)(C)OC(=O)N1CCn2c(c(C#N)c(C#N)c2C2CCN(C(=O)OCc3ccccc3)CC2)C1

Procedure:
By proceeding in a similar manner to that described in Reference Example 8 but using a mixture of 6-(1-benzyloxycarbonylpiperidin-4-yl)-8-cyano-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester and 6-(1-benzyloxycarbonylpiperidin-4-yl)-7-cyano-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (5.00 g, Reference Example 15) the title compound (4.71 g) was prepared as a yellow oil, MS: 490 [MH]+. 1H NMR [(CDCl3]: δ 7.42–7.30 (m, 5H), 5.15 (s, 2H), 4.71 (s, 2H), 4.50–4.28 (bs, 2H), 3.92 (t, 2H), 3.86 (t, 2H), 2.93–2.72 (m, 3H), 2.20–1.93 (bs, 2H), 1.80 (d, 2H) and 1.51 (s, 9H).
Reaction SMILES: C(OC([NH:8][C:9](=[N:55]C(OC(C)(C)C)=O)[NH:10][C:11]1[CH:54]=[CH:53][C:14]([C:15]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[C:23]([C:28]([N:30]([CH2:39][C:40]2[CH:41]=[C:42]([CH:50]=[CH:51][CH:52]=2)[C:43]([O:45]C(C)(C)C)=[O:44])[CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])=[O:29])[CH:22]=[CH:21]3)=[O:16])=[CH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:10]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[C:23]([C:28]([N:30]([CH2:39][C:40]2[CH:41]=[C:42]([CH:50]=[CH:51][CH:52]=2)[C:43]([OH:45])=[O:44])[CH2:31][C:32]([OH:34])=[O:33])=[O:29])[CH:22]=[CH:21]3)=[O:16])=[CH:53][CH:54]=1)[C:9]([NH2:55])=[NH:8]
Reactant: CC(C)(C)OC(=O)CN(Cc1cccc(C(=O)OC(C)(C)C)c1)C(=O)c1ccc2cc(OC(=O)c3ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc3)ccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)Nc1ccc(C(=O)Oc2ccc3nc(C(=O)N(CC(=O)O)Cc4cccc(C(=O)O)c4)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a solution of tert-butyl 3-{[{[6-({4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoyl}oxy)quinolin-2-yl]carbonyl}(2-tert-butoxy-2-oxoethyl)amino]methyl}benzoate (659 mg) in dichloromethane (5.00 mL) was added trifluoroacetic acid (2.40 mL), followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, and then to the residue was added acetonitrile (20.0 mL), followed by concentrating under reduced pressure again. This operation was repeated twice, and then acetonitrile (20.0 mL) was added thereto, followed by stirring at room temperature for 1 hour, and further heating and refluxing at 100° C. for 2 hours. The reaction solution was ice-cooled, and then 1 M sodium hydroxide (1.54 mL) was added thereto. Subsequently, a saturated aqueous sodium hydrogen carbonate solution was added thereto to adjust the pH to around 5. After stirring for 1 hour under ice-cooling, the insoluble matter was collected by filtration, and the filtrate was washed with a 50% aqueous acetonitrile solution and then dried at 50° C. for under reduced pressure. The dried product (354 mg) was suspended in a 33% aqueous acetonitrile solution (9.00 mL), and then methane sulfonic acid (0.100 mL) was added thereto. After stirring at 60° C. for 30 minutes, water (6.00 mL) was added thereto, followed by stirring at room temperature overnight. The precipitated crystals were collected by filtration, washed with a 10% aqueous acetonitrile solution, and then dried under reduced pressure to obtain 3-{[({6-[(4-carbamimidamidobenzoyl)oxy]quinolin-2-yl}carbonyl)(carboxymethyl)amino]methyl}benzoic acid (236 mg).