Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])=[N:5][CH3:6])C.[C:14]([NH:22][NH2:23])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)CCC>[CH3:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[N:5]([CH3:6])[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:22][N:23]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CCSC(=NC)c1ccccc1C
Solvent: CCCCO
Product: Cc1ccccc1-c1nnc(-c2ccccc2)n1C
Temperature: 120 °C
Reaction time: 15 h
Yield: 58 %

Procedure:
Into a 100-mL three-neck flask were put the total amount of N-[(ethylsulfanyl)(2-methylphenyl)methylidene]methylamine obtained in Step 3, 7.0 g (51.4 mmol) of benzoylhydrazine, and 30 mL of 1-butanol (1-BuOH), and the mixture was heated and stirred at 120° C. for 15 hours. After reaction for the predetermined time, the solvent was distilled off to give a yellow liquid. This liquid was purified by silica gel chromatography. Ethyl acetate was used as a developing solvent. The obtained fraction was concentrated to give a white solid. This solid was recrystallized with ethyl acetate, so that 7.0 g of a white solid of Hmpptz-Me (abbreviation), an objective 4H-triazole derivative, was obtained in a yield of 58%. A synthesis scheme of Step 4 is shown in (f-4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([O:23]CC)=O)[C:9]=2[S:26][CH3:27])=[CH:4][CH:3]=1.O.[NH2:29][NH2:30]>CCO.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:29][NH2:30])=[O:23])[C:9]=2[S:26][CH3:27])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1SC
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSc1c(C(=O)NN)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 90 °C
Yield: 70 %

Procedure:
To a solution of ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-(methylthio)-1H-pyrazole-3-carboxylate (6) (300 mg, 0.68 mmol) in EtOH (5 mL) was added hydrazine monohydrate (1 mL). The reaction mixture was refluxed for 2 h at 90° C. Reaction mixture was diluted with EtOAc and washed with saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to obtain 200 mg (70%) of the title compound as a white solid. The obtained compound was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][CH2:15][N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]([C:23]4[CH:24]=[C:25]([CH2:29][NH:30]C(=O)OC(C)(C)C)[CH:26]=[CH:27][CH:28]=4)=[CH:17]3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1>Cl.CCOC(C)=O>[NH2:30][CH2:29][C:25]1[CH:24]=[C:23]([C:18]2[CH:19]=[CH:20][C:21](=[O:22])[N:16]([CH2:15][CH2:14][O:13][C:7]3[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)[CH:17]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc2c(OCCn3cc(-c4cccc(CNC(=O)OC(C)(C)C)c4)ccc3=O)ccnc2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc2c(OCCn3cc(-c4cccc(CN)c4)ccc3=O)ccnc2c1
Yield: 83 %

Procedure:
This compound was prepared according to the procedure described in Example 16. A solution of tert-butyl (3-(1-(2-(7-methoxyquinolin-4-yloxy)ethyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)methylcarbamate (0.3 g, 0.6 mmol) in 10 mL of saturated HCl in EtOAc was stirred at rt for 2 hours. The mixture was then concentrated in vacuo. The residue was washed with 50% Hex/EtOAc to give the desired product (0.2 g, 83% yield) as light yellow solid. MS (ESI pos. ion) m/z (MH+): 402.1. Calc'd Exact Mass for C24H23N3O3: 401.17.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[C:22]2[N:23]([CH3:28])[N:24]=[CH:25][C:26]=2[Br:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([F:29])=[CH:31][CH:32]=3)=[CH:17][C:16]=2[C:22]2[N:23]([CH3:28])[N:24]=[CH:25][C:26]=2[Br:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OC1CCCN(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2ccc(F)cc2)ccc1OC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Yield: 31.4 %

Procedure:
A mixture of 3-[4-amino-2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (90 mg, 0.2 mmol), 4-fluorobenzoic acid (34 mg, 0.24 mmol), HATU (99 mg, 0.26 mmol) and triethylamine (0.3 mL) in DMF (2 mL) was heated in microwave at 100° C. for 15 min. The crude was purified by HPLC to give 3-[2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-benzoylamino)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (36 mg, 32%) as a white solid. MS found, 573.5 and 575.5.
Reaction SMILES: [CH:1]1[C:6]([C:7](O)=[O:8])=[C:5]([C:10]([OH:12])=O)[CH:4]=[N:3][CH:2]=1.C(OC(=O)C)(=O)C.C([NH2:23])(=O)C>>[C:7]1(=[O:8])[C:6]2[CH:1]=[CH:2][N:3]=[CH:4][C:5]=2[C:10](=[O:12])[NH:23]1
Reactant: O=C(O)c1ccncc1C(=O)O
Reactant: CC(N)=O
Solvent: CC(=O)OC(C)=O
Product: O=C1NC(=O)c2cnccc21
Temperature: 145 °C
Yield: 95.1 %

Procedure:
A suspension of cinchomeronic acid (30)(50 g, 300 mmol) in acetic anhydride (123.5 g, 1200 mmol) was heated to reflux (140-150° C.) until all solid material dissolved and the mixture was homogeneous. The mixture was then cooled and concentrated in vacuo. Acetamide (50 g, 846 mmol) was then added and the mixture heated to 140° C. for 3 hours whereupon it was then cooled to room temperature. The solid residue that formed upon cooling was pulverized and triturated with water (100 ml), filtered and washed with more water and dried in a desiccator to give the title compound (42.26 g, 95.1%) in suitably pure form to be used without any further purification. m/z (LC-MS, ESP): 149 [M+H]+, R/T=0.44 mins.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22](=[O:25])[CH2:23]Br)[CH3:20].[OH-].[K+].S(=O)(=O)(O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:19]([O:21][C:22](=[O:25])[CH2:23][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]1=[O:12])[CH3:20]
Reactant: O=c1[nH]c2cc(Cl)ccc2cc1-c1ccccc1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(=O)c(-c2ccccc2)cc2ccc(Cl)cc21
Temperature: 0 °C

Procedure:
18 g of 7-chloro-1,2-dihydro-2-oxo-3-phenylquinoline, 11.7 g of bromoacetic acid ethyl ester, 2.3 g of tetrabutylammonium bromide and 5.6 g of powdered potassium hydroxide are stirred in 250 ml of tetrahydrofuran at room temperature for 16 hours. The mixture is poured into 1 l of ice-water, acidified to pH 3 to 4 with dilute sulphuric acid and extracted with methylene chloride (2×200 ml) and the organic phase is dried over sodium sulphate and concentrated. The solid brown residue is stirred with 100 ml of cyclohexane, filtered off and recrystallised from ethanol. 10.0 g of the title compound of m. 142°-143° C. are obtained.
Reaction SMILES: [CH2:1]([C:3]1([CH2:21][CH3:22])[CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:5]=[CH:4]1)[CH3:2].Cl.Cl.[NH2:25][OH:26]>O>[CH2:1]([C:3]([CH2:21][CH3:22])([CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:5])[CH:4]=[N:25][OH:26])[CH3:2]
Reactant: CCC1(CC)C=NC(c2ccccc2)CC=CCCC=CC1
Reactant: NO
Agent: Cl
Solvent: O
Product: CCC(C=NO)(CC)CC=CCCC=CCC(N)c1ccccc1
Yield: 97.5 %

Procedure:
The procedure described in Example (1b) is repeated, except that 95.3 g(0.323 mol) of 3,3-diethyl-12-phenyl-1-aza-1,5,9-cyclododecatriene, 20 g of37% hydrochloric acid, 22.4 g (0.322 mol) of hydroxylamine hydrochloride and 250 ml of water are used. Working up yields 103.1 g (0.314 mol) of 2,2-diethyl-11-phenyl-11-amino-undeca-4,8-dienal oxime; yield 97.5% of theory.
Reaction SMILES: C([Li])CCC.CCCCCC.C(O)(C)(C)C.[C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:38]([CH2:39][OH:40])=[C:37]([Cl:41])[N:36]=[C:35]2[CH2:42][CH2:43][CH2:44][CH3:45])=[CH:29][CH:28]=1)([O:19][CH3:20])=[O:18].[CH3:46][O:47][CH2:48][CH2:49][O:50][CH2:51]Cl>O1CCCC1.C(OCC)C>[C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:38]([CH2:39][O:40][CH2:46][O:47][CH2:48][CH2:49][O:50][CH3:51])=[C:37]([Cl:41])[N:36]=[C:35]2[CH2:42][CH2:43][CH2:44][CH3:45])=[CH:29][CH:28]=1)([O:19][CH3:20])=[O:18]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: COCCOCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: CCCCc1nc(Cl)c(COCOCCOC)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reaction time: 16 h

Procedure:
To a solution of 7.50 mL of 1.6M n-butyllithium/hexane in 50 mL of tetrahydrofuran at 0° was added dropwise 1.50 mL of t-butanol. To this solution was added 4.52 g of 1-[(2'-carbomethoxybiphenyl-4-yl)-methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole followed by 1.50 ml of 2-methoxyethoxymethyl chloride. The resulting solution was stirred at 25° for 16 hours. The mixture was diluted with diethyl ether, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography afforded 3.50 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-(2-methoxyethoxymethoxymethyl)imidazole. NMR (200 MHz, CDCl3) δ7.83 (d, 1H); 7.52 (t, 1H); 7.40 (t, 1H), 7.28 (m, 3H); 7.00 (d, 1H); 5.19 (s, 2H); 4.68 (s, 2H); 4.48 (s, 2H); 3.67 (m, 2H); 3.64 (s, 3H); 3.54 (m, 2H); 3.37 (s, 3H); 2.58 (t, 2H); 1.67 (quint., 2H); 1.34 (sext., 2H); 0.88 (t, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][C:12]=1[O:24][CH3:25].C(OCC)(=O)C>O1CCCC1>[Cl:17][C:15]1[C:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][C:12]([O:24][CH3:25])=[C:11]([CH2:10][CH2:9][OH:8])[CH:16]=1
Reactant: COC(=O)Cc1cc(Cl)c(C2CCCCC2)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C2CCCCC2)c(Cl)cc1CCO
Reaction time: 18 h

Procedure:
7 g of LiAlH4 are added in portions at 0° under an inert gas atmosphere to 16 g of (5-chloro-4- cyclohexyl-2-methoxyphenyl)-acetic acid methyl ester in 350 ml of dry tetrahydrofuran. Stirring is then effected for 18 hours at 22° . 20 ml of ethyl acetate are carefully added in drops so as to destroy the excess LiAlH4. The mixture is then poured onto a solution of NH4Cl in ice water, acidified with 2N H2SO4 and extracted three times with acetic ester. The organic phases are washed with water, dried over Na2SO4 and concentrated. The residue is chromatographed on 250 g of silica gel. The product, which is extracted with methylene chloride, is distilled in a bulb tube. M.p. 78°-79°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.O>COCCOC>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(C2=NC2c2ccc(C(F)(F)F)cn2)c1
Solvent: COCCOC
Solvent: O
Product: Fc1cccc(-c2cc3ccc(C(F)(F)F)cn3n2)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a solution of 2-[3-(3-fluorophenyl)-2H-azirin-2-yl]-5-trifluoromethylpyridine (2.2 g, 7.85 mmol) in DME (10 ml) was added FeCl2 (10 mg, 0.079 mmol). The solution was warmed to 75° C. and stirred for 2 hours. The reaction was cooled to room temperature and added to H2O (180 ml). The resultant suspension was cooled to 0° C. and stirred for 30 min. The solid was isolated by filtration and partially dried via airflow. Recrystallization of the crude product in IPA afforded 1.34 g (60%) of the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].[Li+].CC([N-]C(C)C)C.[CH:19](N1CCCCC1)=[O:20]>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([C:5]([F:9])=[C:6]([F:8])[CH:7]=1)[CH:19]=[O:20]
Reactant: Fc1cc(F)c(Br)cc1F
Reactant: O=CN1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(F)c(F)cc(Br)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
To a solution of 1-bromo-2,4,5-trifluoro benzene (25 g, 0.12 mol) in THF (200 mL at -78° C. was added LDA (80 mL, 1.5 M) dropwise. The mixture was stirred at -78° C. for 1 hour, then N-formylpiperidine (16 g, 0.144 mol) was added in one portion and stirring continued for 2 hours. An additional 15 g of N-formylpiperidine was then added every 0.5 hour in 5 g portions. The reaction was quenched with 3N HCl (pH 3) at -78° C. The reaction was warmed to 0° C. and partitioned between H2O and ether. The ether layer was dried and concentrated and the residue was distilled to provide 13 g (45%) of the desired aldehyde; bp 63°-65° C. (0.2 mm).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2.[C-:13]#[N:14].[Na+].[Cl-].[NH4+]>CN1CCCC1=O.O>[C:13]([C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2)#[N:14]
Reactant: Oc1ccc2ncc(Br)cc2c1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cnc2ccc(O)cc2c1
Temperature: 150 °C
Reaction time: 7 h

Procedure:
3-Bromo-6-hydroxyquinoline (1.12 g) in dry N-methylpyrrolidin-2-one (10 ml) was treated with cuprous cyanide (0.55 g) and stirred at 150° C. for 7 hours under an atmosphere of nitrogen then stored at ambient temperature for 18 hours. The mixture was treated with sodium cyanide (1.5 g) in water (5 ml) and heated at 75° C. for 15 minutes. 10% Aqueous ammonium chloride solution (25 ml) was added and the mixture cooled to ambient temperature. The reaction mixture was extracted with ethyl acetate and the organic phase separated, washed with water, dried over magnesium sulphate and evaporated under reduced pressure to give a yellow brown solid. The solid was fractionated by chromatography to give the required product as a yellow solid.
Reaction SMILES: [Na].[Cl:2][C:3]1[N:4]=[N:5][C:6](Cl)=[C:7]([CH3:10])[C:8]=1[CH3:9].[CH2:12]([OH:14])[CH3:13]>>[CH2:12]([O:14][C:6]1[N:5]=[N:4][C:3]([Cl:2])=[C:8]([CH3:9])[C:7]=1[CH3:10])[CH3:13]
Reactant: CCO
Reactant: Cc1c(Cl)nnc(Cl)c1C
Agent: [Na]
Product: CCOc1nnc(Cl)c(C)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.69 g(0.03 mol) of metallic sodium was dissolved in 100 ml of absolute ethanol and then 5.31 g(0.03 mol) of 3,6-dichloro-4,5-dimethylpyridazine was added thereto and completely dissolved. The reaction solution was stirred for 4 hours at room temperature and then treated according to the same manner as Preparation 5 to obtain the title compound as a pale white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.CS(CCO)(=O)=[O:24].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:24])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: CS(=O)(=O)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(O)cc2OC1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To the mixture of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (6 g, 18.5 mmol) and 2-(methylsulfonyl)ethanol (3.45 g, 27.7 mmol) in 125 mL of anhydrous DMF at 0° C. was added sodium hydride (60%, 2.22 g, 55.5 mmol) slowly. After stirring at 0° C. for 45 min, LCMS indicated that majority of starting material was gone. The reaction was warmed to room temperature, and stirred for another 20 min. The reaction was dumped into a dilute hydrochloric acid/ice mixture with vigorously stirring. The product was then extracted with EtOAc. The resulting organic phase was washed with brine, dried over anhydrous magnesium sulfate. After removing the solvent, the residue was purified on silica gel column with 1:1 EtOAc/hexane containing 1% HOAc. The desired product was obtained as a green yellowish solid, 1.0 g (16.7%). M.P.=118.0-125.0° C. 1H NMR(CDCl3/400 MHz) 7.61(s, 1H), 7.18(s, 1H), 6.66(s, 1H), 5.65(q, 1H, J=6.8 Hz), 4.30(m, 2H), 1.33(t, 3H, J=7.2 Hz). 13C NMR(CDCl3/400 MHz) 164.1, 155.2, 153.8, 136.0, 129.3, 123.5(q, J=287.7 Hz), 115.1, 114.1, 113.6, 104.5, 71 .0(q, J=33.2 Hz), 61.7, 14.4. 19F NMR(CDCl3/400 MHz) −78.9(d, J=6.8 Hz). LC-MS (ES+) 323.7 (M+H, 80%), 295.2(M−27, 100%). HRMS (EI+) m/z calcd for (C13H10ClF3O4) 322.0220, found 322.0231.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CO[C:7]1[C:8]([N+:41]([O-:43])=[O:42])=[C:9]([C:19]2[O:20][C:21]([C:24]3[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][C:27]([N+:33]([O-:35])=[O:34])=[C:26](OC)[C:25]=3[N+:38]([O-:40])=[O:39])=[N:22][N:23]=2)[C:10]([N+:16]([O-:18])=[O:17])=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]>CO>[OH:2][CH2:1][CH2:3][NH:4][C:28]1[C:29]([N+:30]([O-:32])=[O:31])=[C:24]([C:21]2[O:20][C:19]([C:9]3[C:10]([N+:16]([O-:18])=[O:17])=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:7]([NH:4][CH2:3][CH2:1][OH:2])[C:8]=3[N+:41]([O-:43])=[O:42])=[N:23][N:22]=2)[C:25]([N+:38]([O-:40])=[O:39])=[CH:26][C:27]=1[N+:33]([O-:35])=[O:34]
Reactant: COc1c([N+](=O)[O-])cc([N+](=O)[O-])c(-c2nnc(-c3c([N+](=O)[O-])cc([N+](=O)[O-])c(OC)c3[N+](=O)[O-])o2)c1[N+](=O)[O-]
Reactant: NCCO
Solvent: CO
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(-c2nnc(-c3c([N+](=O)[O-])cc([N+](=O)[O-])c(NCCO)c3[N+](=O)[O-])o2)c([N+](=O)[O-])c1NCCO
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.3 g (0.0049 mole) of ethanolamine in 20 ml of methanol was stirred in an ice bath during the addition of 1.0 g (0.0018 mole) of 2,5-bis(3-methoxy-2,4,6-trinitrophenyl)-1,3,4-oxadiazole. After 10 min. at 0° C., the mixture was stirred at room temperature for 5 hr. before the crude product [1.1 9 (94%), mp 250° dec] was removed by filtration. Digestion with boiling acetone gave the purified product, as an insoluble yellow solid, mp 264° C. dec.; 1H NMR (DMSO-d6 +D2O): 3.22 (t, 4H), 3.70 (t, 4H), 9.32 (s, 2H); IR(KBr): 3700-3200 (OH and NH), 1610, 1625 (C=N), 1545, 1340 (NO2). Anal. Calcd. for C18H14N10O15 : C, 35.42; H, 2.31; N, 22.95. Found: C, 35.62; H, 2.30; N, 22.93.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([N:22]([C:32]4[CH:36]=[CH:35][O:34][N:33]=4)[CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:37])=[C:4]([OH:38])[CH:3]=1.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[C:44]([F:46])[CH:45]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C.O>[O:34]1[CH:35]=[CH:36][C:32]([N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[S:19]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[N:9]([C:5]2[C:4]([OH:38])=[CH:3][C:2]([C:42]4[CH:41]=[C:40]([F:39])[CH:45]=[C:44]([F:46])[CH:43]=4)=[C:7]([F:8])[CH:6]=2)[C:10](=[O:37])[CH:11]=[CH:12]3)(=[O:21])=[O:20])=[N:33]1
Reactant: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(Br)cc3O)c2)cc1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(-c4cc(F)cc(F)c4)cc3O)c2)cc1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1-(4-bromo-5-fluoro-2-hydroxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.037 g, 0.062 mmol) and (3,5-difluorophenyl)boronic acid (0.015 g, 0.092 mmol) in DMF (0.246 ml) and water (0.062 ml) was added potassium carbonate (0.026 g, 0.185 mmol) followed by PdCl2dppf, DCM adduct (2.255 mg, 3.08 μmol). The resulting mixture was heated to 50° C. and stirred for 2.5 hours. The solution was then cooled to room temperature and transferred to a sep. funnel containing water. The aqueous layer was washed 2× with DCM. The aqueous layer was subsequently neutralized and washed 3× with DCM. The organic layers were combined, dried with MgSO4, filtered and concentrated to an oil. The crude product was used without further purification assuming quantitative yield. m/z (ESI) 634.2 (M+H)+.
Reaction SMILES: [ClH:1].[C:2]([O:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:31])[CH2:11][CH2:12][CH:13]([NH:20]C(OCC1C=CC=CC=1)=O)[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15])(=[O:4])[CH3:3]>CO.[C].[Pd]>[ClH:1].[C:2]([O:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:31])[CH2:11][CH2:12][CH:13]([NH2:20])[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15])(=[O:4])[CH3:3]
Reactant: CCCNC(=O)C(CCC(=O)NCCCOC(C)=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCNC(=O)C(N)CCC(=O)NCCCOC(C)=O

Procedure:
In 200 ml of methanol was dissolved 14.6 g of the DL-N5 -(3-acetoxypropyl)-2-(benzyloxycarbonylamino)-N1 -n-propylpentane-1,5-diamide, and thereto were added 1.5 g of 5% palladium-carbon and 8 ml of conc. hydrochloric acid, after which the resulting mixture was subjected to catalytic reduction at room temperature. Subsequently, the palladium-carbon was removed by filtration and the solvent was removed by distillation under reduced pressure to obtain oily DL-N5 -(3-acetoxypropyl)-2-amino-N1 -n-propylpentane-1,5-diamide hydrochloride. This product was dissolved in 50 ml of methylene chloride, and the resulting solution was added dropwise at -20° C. to -10° C. to the mixed acid anhydride in methylene chloride separately prepared in the same manner as in Example 8-(2) from 4.3 g of β-(2-furyl)acrylic acid, 10 ml of triethylamine and 3.7 g of ethyl chlorocarbonate, after which the resulting mixture was stirred at the same temperature for 30 minutes. Subsequently, the mixture was further stirred at room temperature for 30 minutes, and washed successively with 50 ml of diluted hydrochloric acid, 50 ml of a saturated aqueous sodium hydrogencarbonate solution and 50 ml of water, and thereafter dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure to obtain 4.2 g (yield 24%) of DL-N5 -(3-acetoxypropyl)-2-[β-(2-furyl)acrylamido]-N1 -n-propylpentane-1,5-diamide having a melting point of 154°-156° C.
Reaction SMILES: FC1(F)CCN(C(C2NC3C(C=2)=CC(O[CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=CC=3)=O)CC1.[CH2:30]([O:32][C:33]([C:35]1[NH:36][C:37]2[C:42]([CH:43]=1)=[CH:41][C:40]([OH:44])=[C:39]([Cl:45])[CH:38]=2)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1[NH:36][C:37]2[C:42]([CH:43]=1)=[CH:41][C:40]([O:44][CH:20]1[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]1)=[C:39]([Cl:45])[CH:38]=2)=[O:34])[CH3:31]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: CCOC(=O)c1cc2cc(O)c(Cl)cc2[nH]1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)c(Cl)cc2[nH]1

Procedure:
In analogy to the procedure described for the synthesis of intermediate 1, step 2, the title compound was synthesized from 6-chloro-5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (example 39, step 2). The title compound was obtained in 66% yield as light yellow foam. MS (m/e): 365.0 (MH+, 100%).