Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[N:5][CH:4]=1)#[N:2].[NH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][OH:24]>>[C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([NH:21][C@@H:22]([CH2:25][CH3:26])[CH2:23][OH:24])=[O:18])=[CH:13][CH:14]=2)[CH:6]=[N:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)n2)cc1
Reactant: CCC(N)CO
Product: CC[C@@H](CO)NC(=O)C(C)(C)c1ccc(-c2cncc(C#N)n2)cc1
Yield: 37 %

Procedure:
Prepared in a similar manner to Example 20 from 2-(4-(6-Cyanopyrazin-2-yl)phenyl)-2-methylpropanoic acid (example 20a) and 2-aminobutan-1-ol. Yield 37%.
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+].[I-].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([O:8][C:7]1[C:9]([O:10][CH3:11])=[CH:12][C:2]([CH:1]=[O:13])=[CH:3][C:4]=1[O:5][CH3:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C=O)cc(OC)c1OCc1ccccc1
Temperature: 25 °C
Yield: 79 %

Procedure:
A mixture of syringaldehyde (3.64 g, 20 mmol), benzyl chloride (2.52 g 20 mmol), NaI (2 g) and potassium carbonate (2.76 g, 20 mmol) in anhydrous acetone (60 mL) were refluxed for 5 h and cooled to room temperature. The solid materials were removed by filtration, the filtrate was concentrated and the residue was purified by chromatography on silica gel (230-400 mesh, 50 g) using 5% EtOAc in hexane as the eluent to obtain 13j (4.3 g, 79%); mp 62°-63° C.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:27])[CH2:15][C:16]3[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](O)=[O:23])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3].ON1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.[CH2:52]([NH2:55])[CH2:53][NH2:54]>CN(C)C=O.CO.C(Cl)(Cl)Cl>[NH2:54][CH2:53][CH2:52][NH:55][C:22](=[O:23])[CH2:21][O:20][C:19]1[CH:25]=[CH:26][C:16]([CH2:15][CH:14]([C:9]2[NH:8][C:7]3[N:6]([CH2:28][CH2:29][CH3:30])[C:5](=[O:31])[N:4]([CH2:1][CH2:2][CH3:3])[C:12](=[O:13])[C:11]=3[N:10]=2)[CH3:27])=[CH:17][CH:18]=1
Reactant: NCCN
Reactant: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)NCCN)cc3)[nH]c2n(CCC)c1=O
Reaction time: 1 h

Procedure:
Dissolve (+)-2-[4-[2-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenoxy]acetic acid (0.28 g, 0.65 mmol) in dimethylformamide (10 mL) and treat with N-hydroxysuccinimide (0.074 g, 0.65 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.262 g, 1.37 mmol). Stir for 1 hour and add a solution of ethylenediamine (10 mL of a 10% solution in methanol) and stir for 1 hour. Dilute with chloroform (500 mL), wash with 5% sodium carbonate (200 mL) and dry (MgSO4). Evaporate the solvent in vacuo and purify by radial chromatography (10→20% methanol/chloroform with 1% ammonium hydroxide). Dissolve the purified material in 5% methanol/ethyl ether and treat with ethereal hydrochloric acid. Evaporate the solvent in vacuo and triturate the residue with ethyl ether. Filter the resulting solid and dry to give the title compound (88 mg); [α]d 20 =+75.7° (C=0.96, H2O).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14](O)[CH2:15][OH:16].C(OCC)(OCC)OCC>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1([CH3:12])[O:16][CH2:15][CH2:14][O:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: CC(=O)CCOCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(OCC)OCC
Product: CC1(CCOCc2ccccc2)OCCO1
Temperature: 25 °C
Reaction time: 13.5 h
Yield: 80.8 %

Procedure:
A mixture of 4-benzyloxy-2-butanone (10 g, 56.1 mmol), ethylene glycol (40 ml, 718 mmol), triethyl orthoformate (9.3 ml, 55.9 mmol) and p-toluenesulfonic acid monohydrate (290 mg, 1.52 mmol) was stirred at room temperature for 13.5 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution (40 ml) was added and the mixture was extracted three times with chloroform (50 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (NH silica gel, elution solvent: heptane/ethyl acetate=1/0 to 4/1 gradient). Desired fractions were concentrated to obtain the title compound (10.08 g, 80.8% yield) as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH:16]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)=[CH:11][C:10]=1[O:28][CH3:29])C1C=CC=CC=1>CO.ClC1C=CC=CC=1Cl.[Pd]>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][CH:16]1[C:17]2[C:12](=[CH:11][C:10]([O:28][CH3:29])=[C:9]([OH:8])[CH:18]=2)[CH2:13][CH2:14][NH:15]1
Reactant: COc1cc2c(cc1OCc1ccccc1)C(Cc1ccc(Cl)c(Cl)c1)NCC2
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: COc1cc2c(cc1O)C(Cc1ccc(Cl)c(Cl)c1)NCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-benzyloxy-1-(3,4-dichloro-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline (14.1 g, 30 mmol) in MeOH (150 mL) and 1,2-dichlorobenzene (30 mL) is added 50% Pd on charcoal (500 mg). The reaction vessel is flushed with nitrogen and then with hydrogen at atmospheric pressure. After stirring at rt for 16 h, the reaction mixture is filtered through Hyflo, and evaporated to yield to the title compound as a beige solid which is used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]([O:23]CC)=[O:22])=[CH:13][N:12]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].Cl>O1CCCC1.CO.O.[OH-].[Na+]>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]([OH:23])=[O:22])=[CH:13][N:12]=2)=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)O
Temperature: 60 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
To a solution of ethyl 2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxylate (C1, 8.0 g) in tetrahydrofuran (240 mL) and methanol (240 mL), water (40 mL) and 5.0 mol/L aqueous sodium hydroxide (48 mL) were added at room temperature, and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled on ice, then 12 mol/L aqueous hydrochloric acid was added to the mixture until pH of the mixture became 2, and the reaction mixture was poured into ice water (2000 mL). The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain 2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxylic acid (C2, 4.0 g) as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9](=O)[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl.[C:15](O)(=O)C>C(O)C.O>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:15])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2c(Cl)cccc2o1
Reactant: CC(=O)O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc2c(Cl)cccc2o1

Procedure:
To a solution of the 4-chloro-2-benzooxazolinone (0.10 mol) in 200 mL ethanol is added LiOH (0.20 mol) in 100 mL of water. The solution is refluxed for 8 hr and cooled. The solution is neutralized with 1N HCl and extracted with ethyl acetate followed by drying over MgSO4. The solution is concentrated and taken up in 200 mL of toluene and 0.10 mol of acetic acid. The solution is refluxed in a Dean Stark trap for 12 hours, concentrated and purified by flash chromatography.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:23](O)=O)[CH:22]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)=[O:9])([CH3:3])[CH3:2].[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30].C([BH3-])#N.[Na+]>CO>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([CH2:23][NH:30][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[F:26])[CH:22]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1cc(C(=O)O)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Reactant: NCc1ccccc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)Oc1cc(CNCc2ccccc2F)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Yield: 76 %

Procedure:
2-(3-isopropyloxy-5-carboxy-benzoyl) amino-5-pyridine carboxylic acid (0.10 g, 0.30 mM), 4A molecular sieves (0.3 g) and 2-fluorobenzylamine were stirred in MeOH at ambient temperature for 2 hrs then sodium cyanoborohydride (0.023 g, 0.36 mM) added. After a further 2 hrs the reaction mixture was filtered, residue washed with MeOH and the filtrate concentrated in vacuo. Water was added, then acidified with 2M HCl to precipitate a colourless solid which was filtered, washed with water and dried under high-vacuum to give the title compound as a light brown solid (00.10 g, 76%); 1H NMR δ (d6-DMSO): 1H NMR δ (d6-DMSO): 1.29 (d, 6H), 4.13 (d, 2H), 4.74 (m, 1H), 7.20–7.30 (m, 3H), 7.43 (m, 1H), 7.58 (m, 2H), 7.68 (s, 1H), 8.28 (s, 2H), 8.87 (s, 1H), 11.10 (bs, 1H).
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:20][C@H:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27].Cl.Cl.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([NH:20][C@H:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:27])[NH2:28])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@@H](N)CCCNC(=N)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Z-Leu-OH 172.5 g and H-Arg-OEt.2HCl 178.9 g were added to 800 mL of a DMF/THF(1/1) mixed solution. The solution was neutralized by adding 143 mL of N-methylmorpholine at 0° C. Next 147.5 mL of DCC was added to the solution and then it was stirred at 0° C. for 5 minutes and at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure then 1000 mL of water was added to the residue obtained. After the product was washed twice with 500 mL of ethyl acetate, the aqueous layer was extracted three times with 1000 mL of n-butanol. The obtained n-butanol layer was concentrated under reduced pressure to obtain Z-Leu-Arg-OEt.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[O:11][C:10]2=[O:24])=[CH:5][CH:4]=1)#N.C[O:26]C1C=CC(N2[C@@H](C)[C@@H](COC3C=CC(C#N)=CC=3)OC2=O)=CC=1>>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[O:11][C:10]2=[O:24])=[CH:5][CH:4]=1)=[O:26]
Reactant: COc1ccc(N2C(=O)O[C@H](COc3ccc(C#N)cc3)[C@@H]2C)cc1
Reactant: N#Cc1ccc(N2CC(COc3ccc(C=O)cc3)OC2=O)cc1
Product: O=Cc1ccc(OCC2CN(c3ccc(C=O)cc3)C(=O)O2)cc1
Yield: 89 %

Procedure:
The same procedure of Example 16 was repeated except that 4-[3-(4-cyanophenyl)-2-oxooxazolidin-5-yl]methoxybenzaldehyde (compound 34) obtained in Example 2 was used in lieu of 4-[(4S, 5S)-(-)-3-(4-methoxyphenyl)-4-methyl-2-oxooxazolidin-5-yl]methoxybenzonitrile to give the title compound (compound 173) in a yield of 89%.
Reaction SMILES: ClC(OCC)=O.[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[CH2:23][C@H:22]2[C:24]([OH:26])=O)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[N-:34]=[N+:35]=[N-:36].[Na+]>CC(C)=O.O>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[CH2:23][C@H:22]2[C:24]([N:34]=[N+:35]=[N-:36])=[O:26])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
Ethyl chloroformate (143 mL, 1.48 mol) was added to a solution of (trans)-2-(4-(benzyloxy) phenyl)cyclopropanecarboxylic acid (Intermediate S, 190 g, 0.70 mol), Triethyl amine (229 mL, 1.63 mol) in acetone (2.8 L) at −20° C. and stirred for 1 h, then a solution of NaN3 (138 g, 2.1 mol) in water (200 mL) was added and stirred at RT for 30 mins. After completion, the solvent was evaporated, residue was dissolved in EtOAc (2 L), washed with water (2 L), brine (1 L), dried over anhydrous Na2SO4, filtered and evaporated to afford (trans)-2-(4-(benzyloxy)phenyl)cyclopropanecarbonyl azide (178 g, 85.9%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:9](=[O:20])[N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)[C:7]2=[O:32])(=[O:3])[CH3:2].[I-].[K+].[Cl-].[Li+].[Ga].[CH3:38][Si:39]([CH:42](Br)[C:43]#[CH:44])([CH3:41])[CH3:40]>C1COCC1>[CH3:31][O:30][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[O:28][CH3:29])[CH2:21][N:8]1[C:7](=[O:32])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([C:1]([OH:3])([CH3:2])[CH2:44][C:43]#[C:42][Si:39]([CH3:41])([CH3:40])[CH3:38])[CH:5]=2)[N:10]([CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:9]1=[O:20]
Reactant: COc1ccc(Cn2c(=O)c3cc(C(C)=O)ccc3n(C3CCOCC3)c2=O)cc1OC
Reactant: C#CC(Br)[Si](C)(C)C
Agent: [Cl-]
Agent: [Ga]
Agent: [I-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c3cc(C(C)(O)CC#C[Si](C)(C)C)ccc3n(C3CCOCC3)c2=O)cc1OC
Reaction time: 48 h
Yield: 89.2 %

Procedure:
A mixture of 0.1 g of 6-acetyl-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-quinazoline-2,4(1H,3H)-dione, 0.057 g of potassium iodide, 0.01 g of lithium chloride, 0.019 g of gallium and 0.065 g of trimethylsilylpropargyl bromide in 1 ml of THF is refluxed for 2 hours and then left for 2 days at room temperature. The reaction mixture is filtered through Celite and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (70/30, v/v) to give 0.112 g of the expected product.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:22][C:23]4[NH:24][CH:25]=[CH:26][N:27]=4)=[CH:19][CH:20]=3)[C:15](=[O:28])[N:14]([CH2:29][C:30]([O:32]CC)=[O:31])[C:13]2=[O:35])[CH:7]=[CH:8][C:9]=1[Cl:10]>C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:22][C:23]4[NH:27][CH:26]=[CH:25][N:24]=4)=[CH:19][CH:20]=3)[C:15](=[O:28])[N:14]([CH2:29][C:30]([OH:32])=[O:31])[C:13]2=[O:35])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CCOC(=O)Cn1c(=O)c2cc(Cc3ncc[nH]3)ccc2n(Cc2ccc(Cl)c(Cl)c2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cn1c(=O)c2cc(Cc3ncc[nH]3)ccc2n(Cc2ccc(Cl)c(Cl)c2)c1=O
Yield: 74.7 %

Procedure:
In 1.6 ml of 1N aqueous solution of sodium hydroxide and 20 ml of ethanol were refluxed 0.71 g of ethyl 1-(3,4-dichlorophenyl)methyl-1,4-dihydro-2,4-dioxo-6-imidazolylmethyl-3(2H)-quinazolineacetate for 1 hour. Ethanol was distilled off and the reaction mixture was neutralized with 3N hydrochloric acid. The crystals deposited were collected by filtration, washed with water and dried. They were recrystallized from acetic acid to obtain 0.50 g of title compound. m.p. 243°-244° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[C:15]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[N:14]=1)=O)(C)C>C1COCC1>[CH3:24][O:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[C:13]([CH2:11][OH:10])=[N:14][C:15]([NH:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1)=[CH:16]2
Reactant: COc1ccc2c(C(=O)OC(C)C)nc(Nc3cc(C)[nH]n3)cc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(CO)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
LiAlH4 (0.67 g) was added in portions to a solution of 6-Methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-1-carboxylic acid isopropyl ester (1.5 g) in 50 mL THF at 0° C. The mixture was stirred at r.t. overnight. Ice-water was added carefully to the mixture until no gas produced. The pH of the solution was adjusted to 7˜8, and then extracted with ethyl acetate three times. The organic layer was washed with saturated NaCl(aq), dried over NaSO4, and concentrated to give the crude product for the next step reaction without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1[C:14]([Cl:15])=[N:13][C:11](Cl)=[N:10][C:8]=1[Cl:9].[F:16][C:17]([F:27])([F:26])[C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21]>C1COCC1.O>[Cl:15][C:14]1[N:7]=[C:8]([Cl:9])[N:10]=[C:11]([NH:21][C:20]2[CH:22]=[CH:23][C:24]([F:25])=[C:18]([C:17]([F:27])([F:16])[F:26])[CH:19]=2)[N:13]=1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1C(F)(F)F
Temperature: 2.5 °C
Yield: 27.5 %

Procedure:
Potassium carbonate (2.76 g, 20 mmol) was added to a solution of cyanuric chloride (II) (1.84 g, 10 mmol) in THF (30 mL) and the mixture cooled to 0-5° C. in an ice bath. 3-Trifluoromethyl-4-fluoroaniline (XVI) (1.79 g, 10 mmol) was added dropwise with stirring. The mixture was stirred for 16 h, diluted with water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extract was rinsed with brine (20 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography (silica gel; EtOAc/hexane (1:4)) to afford 4,6-dichloro-N-(3-trifluoromethyl-4-fluoro-phenyl)-1,3,5-triazine-2-amine (XVII) as an off-white solid (0.9 g, 19% yield): m.p. 114-117° C.; 1H NMR (CDCl3) δ 7.80 (s, 1H), 7.86 (m, 2H), 7.65 (bs, 1H), 7.27 (t, 1H); ESI/MS 326 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:28][C:29]([NH:31][C@H:32]([C:37](OC2C=CC([N+]([O-])=O)=CC=2)=[O:38])[CH2:33][C:34]([NH2:36])=[O:35])=[O:30])=[CH:23][CH:22]=1>CN(C)C=O>[NH:31]([C:29]([O:28][CH2:27][C:24]1[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=1)=[O:30])[C@H:32]([C:37]([NH:1][C@H:2]([C:10]([NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:38])[CH2:33][C:34](=[O:35])[NH2:36]
Reactant: CC(C)(C)OC(=O)NNC(=O)[C@@H](N)Cc1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
1.4 g of H-Phe-NHNH-BOC, 1.94 g of Z-Asn-ONP and 3 ml of dimethylformamide are stirred at room temperature until the mixture solidifies. After allowing to stand overnight, the material is triturated with ether, and the dipeptide derivative is filtered off and washed with ether until free of nitrophenol. The product begins to melt at 211°C with decomposition. Rf = 0.55 in chloroform-methanol (8:2) on silica gel.
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.[CH2:14]([O:16][C:17]([CH2:19][CH2:20][N:21]([S:30]([C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[CH:35][CH:34]=1)(=[O:32])=[O:31])[C:22]1([C:27]([O-:29])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:18])[CH3:15].Cl>ClCCl>[CH2:14]([O:16][C:17]([CH2:19][CH2:20][N:21]([S:30]([C:33]1[CH:34]=[CH:35][C:36]([O:39][C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:31])[C:22]1([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)CCN(C1(C(=O)[O-])CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CCN(C1(C(=O)O)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.0 g (4.5 mmol) of 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic acid, dicyclohexylaminium salt in 30 mL of dichloromethane was treated with 30 mL of 2N hydrochloric acid at ambient temperature causing immediate precipitation of solids. This mixture was stirred at ambient temperature for three hours. The solids were filtered, the aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with water, dried over sodium sulfate, and concentrated under vacuum to 2.2 g (100%) of 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic acid as a clear oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH:9]1[CH2:12][CH2:11][C:10]1=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:12][CH2:11][C:10]2=[O:13])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: O=C1CCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1CCN1c1ccc(Br)cn1
Temperature: 90 °C
Reaction time: 18 h
Yield: 62.6 %

Procedure:
A solution of 2,5-dibromopyridine (500 mg, 2.10 mmol), 2-azetidinone (140 mg, 1.97 mmol) and Cs2CO3 (1.27 g, 3.89 mmol) in toluene (15 ml) was added Pd2(dba)3 (36 mg, 0.039 mmol), Xantphos (45 mg, 0.078 mmol) and the reaction mixture was purged with nitrogen for 10 minutes, then was heated at 90° C. for 18 h in seal tube. The progress of the reaction was monitored by TLC. After 18 h of stirring, the mixture was cooled to 20-35° C., filtered on celite and concentrated. The resultant residue was diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (50 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 50% ethyl acetate/pet ether as an eluent to get the desired compound as a creamy white solid (280 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J=1.9 Hz, 1H), 7.76 (dd, J=8.8, 2.5 Hz, 1H), 7.67 (d, J=8.8 Hz, 1H), 3.78 (t, J=4.9 Hz, 2H), 3.13 (t, J=4.9 Hz, 2H); MS (ES) m/e 229.0 (M+2H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][NH2:25].[OH:26][CH2:27][CH2:28][CH:29]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][N:25]=[CH:29][CH2:28][CH2:27][OH:26]
Reactant: O=CCCO
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1
Product: CC1=C(CCON=CCCO)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylsulfinylphenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 3-hydroxypropanal by the method of Example 1.