Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][C:3]=1[O:14][CH3:15].Cl.[CH3:17][NH:18][O:19][CH3:20].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([N:18]([O:19][CH3:20])[CH3:17])=[O:11])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: COc1cc(C(C)(C)C(=O)O)ccc1Cl
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C(C)(C)C(=O)N(C)OC)ccc1Cl
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a solution of 2-(4-chloro-3-methoxyphenyl)-2-methylpropanoic acid (15) (268 g, 1.17 mol) in CH2Cl2 (1.7 L) was added N,O-dimethylhydroxylamine hydrochloride (137 g, 1.4 mol), EDCl (270 g, 1.4 mol), and DMAP (172 g, 1.4 mol ). The resulting mixture was stirred for 3 h and washed with 10% citric acid solution (1.5 L), satd NaHCO3 (1.5 L), and brine(1.5 L) successfully. The organic phase was dried over MgSO4, filtered, and concentrated at reduced pressure to afford 2-(4-chloro-3-methoxyphenyl)-N-methoxy-N,2-dimethylpropanamide (16) as a brown solid (276 g, 96%). 1H NMR (400 MHz, CDCl3): δ 7.30-7.32 (d, 1H), 6.81-6.84 (m, 3H), 3.89 (s, 3H), 3.12 (s, 3H), 2.78 (s, 3H), 1.53 (s, 6H).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[OH-].[K+]>C(O)C.O>[CH:14]1([O:13][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=2)[C:3]([OH:19])=[O:2])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
A solution of rac-cyclopentyloxy-(3,4-dichloro-phenyl)-acetic acid methyl ester (266 mg, 0.877 mmol) in ethanol (10 mL) was treated with a solution of potassium hydroxide (123 mg, 2.19 mmol) in water (1 mL) and the mixture was stirred at 25° C. After 3 h, the reaction was diluted with water (5 mL) and the ethanol was removed in vacuo. The aqueous layer was then acidified to pH 2 with 1 N hydrochloric acid and extracted with dichloromethane (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 chloroform/methanol plus 1% acetic acid) to afford rac-cyclopentyloxy-(3,4-dichloro-phenyl)-acetic acid (223 mg, 88% yield) as a white solid, mp 87.5-89.9° C.; EI-HRMS m/e calcd for C13H14Cl2O3 (M+) 288.0320, found 288.0332.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:15][CH2:14]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc(C3CCNCC3)co2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(c2coc(-c3ccc(F)cc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.3 %

Procedure:
To a solution of 4-[2-(4-fluorophenyl)-1,3-oxazol-4-yl]piperidine (220 mg, 0.90 mmol) in DCM (20 mL) was treated with DIEA (0.31 mL, 1.8 mmol) and allowed to stir at rt for 15 min. Methanesulfonyl chloride (0.2 mL, 2.7 mmol) was slowly added to the solution and the resulting mixture was stirred at rt for 2 hr. Upon completion of the reaction, DCM (20 mL) and water (40 mL) was added to the mixture and the two layers were partitioned. The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC to afford the title compound (100 mg). LC/MS: m/e 325.2 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])(C)(C)C>C(O)=O>[CH2:20]([O:19][C:17]([C:9]1[N:8]([CH2:7][C:6]([OH:22])=[O:5])[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:18])[CH3:21]
Reactant: CCOC(=O)c1cc2ccccc2n1CC(=O)OC(C)(C)C
Solvent: O=CO
Product: CCOC(=O)c1cc2ccccc2n1CC(=O)O
Temperature: 100 °C
Yield: 100 %

Procedure:
A solution of ethyl 1-(2-tert-butoxy-2-oxoethyl)-1H-indole-2-carboxylate (4.64 g) is 25 mL of formic acid (88%) was heated at 100° C. for 1 hr. TLC showed that the reaction was complete. The solvent was removed by evaporation and the residue was triturated with water and filtered to collect the solid. The beige solid was air dried overnight to afford 3.78 g of the desired product.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][CH2:5][OH:6].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:6][CH2:5][CH2:4][CH:3]([C:2]([F:13])([F:14])[F:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCC(CCO)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reaction time: 2 h
Yield: 6488.1 %

Procedure:
3.08 mg of 3-trifluoromethyl-1-nonanol was dissolved in 453 mg of pyridine, and the solution was cooled with ice, followed by addition of 276 mg of p-toluenesulfonic chloride, stirring for 2 hours under cooling with ice and stirring overnight at room temperature. After the reaction, the product was acidified with 2N-hydrochloric acid and extracted with diethyl ether. The resultant diethyl ether solution was washed with water and dried with magnesium sulfate, and the solvent was distilled off. The crude product was purified by thin layer chromatography with benzene as the developer to obtain 345 mg (yield: 65%) of 3-trifluoromethylnonyl p-toluenesulfonate, which showed: [α]D28 +1.63 (c 5.04, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([F:13])[CH:19]=2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CSc1nc(N)nc(Cl)c1C#N
Reactant: OB(O)c1cccc(F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CSc1nc(N)nc(-c2cccc(F)c2)c1C#N

Procedure:
From 2-amino-4-chloro-6-methylsulfanyl-pyrimidine-5-carbonitrile, m-fluorobenzeneboronic acid, tetrakis(triphenylphosphine)palladium(O) and potassium carbonate in toluene. EI-MS m/e (%): 260 (M+, 40), 259 ([M—H]+, 100).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([F:11])[C:3]=1[NH2:4].Br[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([F:11])[C:3]=1[NH:4][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1
Reactant: Nc1c(F)cc(F)c(F)c1F
Reactant: Cc1ccc(Br)cc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2c(F)cc(F)c(F)c2F)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
A mixture of 2,3,4,6-tetrafluoroaniline (0.72 g, 4.4 mmol), 4-bromotoluene (0.8 g, 4.7 mmol), toluene (55 ml), sodium tert-butoxide (0.8 g, 8.3 mmol), tri-tert-butylphosphine (130 mg, 0.64 mmol) and bis-dibenzylideneacetone-palladium(0) (125 mg, 0.2 mmol) is heated under nitrogen to 85° C. for 3 h. After cooling, water (50 ml), concentrated aqu. HCl (10 ml) and hyflo (1 g) is added and stirring is continued for about one hour followed by filtration. The organic phase is washed with water twice, evaporated and the residue is subjected to flash chromatography on silica (45 g) using heptane/toluene (2:1) as the eluent to afford N-(2′,3′,4′,6′-Tetrafluorophenyl)-4-methylaniline (0.92 g, 3.6 mmol) as an oil which crystallises (mp. 64-65° C.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([SH:44])=[CH:40][CH:39]=1>CN(C)C(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[S:44][C:41]1[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][CH:40]=1)#[N:2]
Reactant: COc1ccc(S)cc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Sc2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3ncns3)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
3-Cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 1, 0.100 g, 0.230 mmol) and potassium carbonate (0.0668 g, 0.483 mmol) were stirred in N,N-dimethylacetamide (3 mL). 4-Methoxythiophenol (0.0322 g, 0.230 mmol) was added to the reaction mixture and stirred under a nitrogen atmosphere at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with a 1M aqueous solution of sodium hydroxide, then brine (×3). The organic layer was dried, filtered and concentrated in vacuo to afford the title compound as a solid (0.13 g, 100%), which was used without purification.
Reaction SMILES: Cl[C:2]([O:4]CC)=[O:3].[CH3:7][CH2:8][N:9](C(C)C)C(C)C.[CH3:16][C:17]1[CH:18]=[CH:19][C:20]2[CH:21]([CH3:29])[CH:22]3[CH2:26][NH:25][CH2:24][CH:23]3[C:27]=2[CH:28]=1>C(Cl)Cl>[CH2:8]([NH:9][C:2](=[O:3])[O-:4])[CH3:7].[CH3:16][C:17]1[CH:18]=[CH:19][C:20]2[CH:21]([CH3:29])[CH:22]3[CH2:26][NH:25][CH2:24][CH:23]3[C:27]=2[CH:28]=1
Reactant: CCOC(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Agent: Cc1ccc2c(c1)C1CNCC1C2C
Solvent: ClCCl
Product: CCNC(=O)[O-]
Reaction time: 2 h

Procedure:
Ethyl chloroformate (0.29 mL, 3.0 mmol) and DIEA (1.6 mL, 9.0 mmol) were added to a solution of 5-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 13, Step F) (0.56 g, 3.0 mmol) in CH2Cl2 (15 mL) at 0° C. The reaction was stirred for 2 hours from 0° C. to room temperature. The reaction was quenched with aqueous HCl (15 mL, 1M). The desired product was extracted with CH2Cl2 (3×15 mL). The organic extracts were washed with brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (SiO2) using a 10-60% EtOAc-hexanes gradient to afford 0.36 g (46%) of the subtitle compound. MS calculated for C16H21NO2+H: 260, observed: 260.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:12].Cl[C:14]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:17]=[C:16]([Cl:25])[CH:15]=1.Cl>CCO>[Cl:25][C:16]1[CH:15]=[C:14]([NH:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[Cl:1])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:17]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: Nc1ccc2ccccc2c1Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccc2ccccc2c1Cl
Yield: 22 %

Procedure:
1-Chloro-2-naphthalenamine and ethyl 4,6-dichloronicotinate were reacted in a mixture of EtOH and conc. HCl as described for example 33, step A. The resultant solid was isolated by filtration and washed with 10% Et2O/Hexane, giving ethyl 6-chloro-4-[(1-chloro-2-naphthyl)amino]nicotinate (22%). 1H NMR [400 MHz, (CD3)2SO] δ 10.07 (br s, 1H), 8.75 (s, 1H), 8.23 (d, J=8.7 Hz, 1H), 8.09-8.05 (m, 2H), 7.77-7.71 (m, 2H), 7.66 (ddd, J=8.0, 6.9, 1.1 Hz, 1H), 6.75 (s, 1H), 4.41 (q, J=7.1 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([NH:5][C:6]1[N:11]=[C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([F:26])=[C:19]([N+:23]([O-])=O)[C:20]=3[CH3:22])[C:15](=[O:27])[C:14]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:13]2)[C:9]([F:33])=[CH:8][C:7]=1[F:34])([CH3:4])([CH3:3])[CH3:2]>[Fe].C(O)(=O)C>[NH2:23][C:19]1[C:20]([CH3:22])=[C:21]2[C:16]([C:15](=[O:27])[C:14]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:13][N:12]2[C:10]2[C:9]([F:33])=[CH:8][C:7]([F:34])=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[N:11]=2)=[CH:17][C:18]=1[F:26]
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(C)c([N+](=O)[O-])c(F)cc2c1=O
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(C)c(N)c(F)cc2c1=O
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 101.4 %

Procedure:
Acetic acid (5 ml) and iron powder (180 mg) were added to ethyl 1-(6-tert-butylamino-3,5-difluoropyridin-2-yl)-6-fluoro-8-methyl-7-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate (200 mg), and the mixture was stirred at 80° C. for 20 minutes. After the catalyst in the reaction mixture was removed by filtration through Celite, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent; ethyl acetate:hexane=1:4) to obtain the title compound (190 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(Cc2ccccc2)c2cc([N+](=O)[O-])c(N)cc21

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1 g) is alkylated using benzyl bromide (0.46 ml; 3.9 mmol) and K2CO3 (1.5 g; 10.9 mmol) at RT for 20 h. After filtration and evaporation of the solvent the crude material is de-acetylated under reflux conditions in 2-propanol (10 ml) and hydrochloric acid (6 N, 30 ml). Pure 5-amino-1-benzyl-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (1.04 g) precipitates by pouring the reaction mixture into ice-water.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[OH-].[Na+]>ClCCl>[C:1]([NH:5][C:9](=[O:10])[CH2:8][CH2:7][Cl:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of tert-butyl amine (1.0 gm, 13.6 mmol) in dichloromethane (50 ml) was added 3-chloropropionyl chloride (2.06 g, 16.3 mmol) and NaOH (650 mg, 16.25 in 2.0 ml H2O) solution simultaneously at −20 deg C. for 1 h. The reaction mixture was allowed to stir for 1 h at RT. The organic layer was washed with 5% HCl followed by 5% aqueous sodium bicarbonate. The organic layer was dried and concentrated to get 2.23 g (yield: 99%) N-tert-butyl-3-chloropropanamide as white solid. To a solution of p-Tolylhydrazine hydrochloride (500 mg, 3.16 mmol) in ethanol (15 ml) was added triethylamine (1.31 ml, 9.4 mmol) and N-tert-butyl-3-chloropropanamide (510 mg, 3.12 mmol). The resulting reaction mixture was heated at 90 deg C. for 14 hrs. The reaction mixture was concentrated to dryness and basified with aqueous saturated sodium bicarbonate, extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to obtain the crude, which was purified by silica gel chromatography (Eluent: 10% MeOH in dichloromethane) to obtain 500 mg (yield: 63.3%) of 3-(1-p-tolylhydrazinyl)-N-tert-butylpropanamide. The amide obtained (500 mg, 2.0 mmol) and N-methyl-4-piperidone hydrochloride (298 mg, 2.0 mmol) were dissolved in ethanolic HCl (20 ml) and stirred at RT for 15 minutes. The solvent was removed in vacuo. The reaction mixture obtained was dissolved in ethanol and heated at 90 deg C. for 14 h. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated to dryness and basified with aqueous saturated sodium bicarbonate, extracted with ethyl acetate, the organic layer was dried over sodium sulfate and concentrated. The crude obtained was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml) to obtain 10 mg (yield: 1.12%) of the desired product as TFA salt. 1H NMR (DMSO-D2O) TFA SALT 7.30-7.25 (d, 1H), 7.20 (s, 1H), 7.0-6.95 (d, 1H), 4.5 (m, 1H), 4.30-4.15 (m, 3H), 3.70-3.65 (m, 1H), 3.50-3.30 (m, 1H), 3.20-3.10 (m, 2H), 2.90 (s, 3H), 2.50-2.40 (d, 2H), 2.30 (s, 3H), 1.10 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH2:7][N:8]([CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=O)=[CH:36][CH:35]=1)[C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[C:27]([F:30])([F:29])[F:28])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.O[N:60]=[C:61]([C:63]1[CH:68]=[CH:67][C:66]([C:69]2[CH:74]=[CH:73][C:72]([CH3:75])=[CH:71][CH:70]=2)=[CH:65][CH:64]=1)[NH2:62].C([O-])(O)=O.[Na+]>O1CCOCC1.CN(C=O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:17]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]([N:8]([CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:43])[CH2:33][C:34]3[CH:35]=[CH:36][C:37]([C:38]4[O:40][N:62]=[C:61]([C:63]5[CH:64]=[CH:65][C:66]([C:69]6[CH:74]=[CH:73][C:72]([CH3:75])=[CH:71][CH:70]=6)=[CH:67][CH:68]=5)[N:60]=4)=[CH:41][CH:42]=3)=[O:32])=[CH:11][CH:12]=2)=[O:31])=[C:20]([C:27]([F:29])([F:30])[F:28])[CH:21]=1
Reactant: Cc1ccc(-c2ccc(C(N)=NO)cc2)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=O)O)cc3)cc2)c(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(-c4nc(-c5ccc(-c6ccc(C)cc6)cc5)no4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a stirring solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid INT-37 (150 mg, 0.25 mmol) in dioxane (4 mL) were added N-methylmorpholine (60.0 μl, 0.55 mmol) and isobutyl chloroformate (34.0 μl, 0.26 mmol). After stirring at room temperature for 1 h, the reaction mixture was added drop wise to a stirring solution of N′-hydroxy-4′-methyl-[1,1′-biphenyl]-4-carboximidamide INT-40 (62.0 mg, 0.275 mmol) in dioxane (2 mL) and DMF (2 mL). The reaction mixture was allowed to stir at room temperature for 1 h, then heated to 90° C. for 2 h, and then heated to 120° C. for 16 h. The reaction mixture was allowed to cool to room temperature then poured into NaHCO3 (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (EA/isohexanes) to yield 77 mg (35%) of tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-41. LCMS-ESI (m/z) calculated for C45H41F3N4O6: 791; no m/z observed, tR=3.26 min (Method 10). 1H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 8.35-8.04 (m, 4H), 8.04-7.80 (m, 2H), 7.80-7.28 (m, 11H), 7.28-7.08 (m, 2H), 4.80 (s, 1H), 4.70 (s, 1H), 4.00 (s, 2H), 3.92-3.79 (m, 5H), 2.40 (s, 3H), 1.47 (s, 4.5H), 1.33 (s, 4.5H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].O>CN(C=O)C>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C)Br
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)n1ncc2ccc([N+](=O)[O-])cc21

Procedure:
6-Nitroindazole (10 g) was dissolved in dry DMF (200cm3) and 50% sodium hydride (2.94 g) added portionwise with stirring. After 20 minutes ethyl 2-bromopropionate (8cm3) was added and the mixture stirred at room temperature for 4 hours, poured into water (1L) and extracted with ethyl acetate four times. The combined organic extracts were washed with water, dried (MgSO4), filtered and the filtrate concentrated under vacuum. The residue was purified by chromatography (SiO2 ; hexane: t-butylmethyl ether, 7:3) to give ethyl 2-(6-nitroindazol-1-yl)propionate (1.3 g) m.p. 99.7°-100.1° C.; M+ =263;
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)=O.O>CS(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[N:8]=[C:4]2[CH:3]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(-c2cn3cnc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56 %

Procedure:
6-Chloropyrimidin-4-amine (50 mg, 0.39 mmol) and 2-bromo-1-(3-nitrophenyl)ethanone (94 mg, 0.39 mmol) were dissolved in 2 mL of DMSO and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into 5 mL of water and it was then extracted with ethyl acetate. The filtrate was dried (Na2SO4) and evaporated. The compound was purified by silica gel column chromatography by using hexane/ethyl acetate (3:1) as eluent (60 mg, 56% Yield). MS m/z 275.00 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]([Mg]Br)([CH3:13])=[CH2:12].[NH4+].[Cl-]>C1COCC1>[CH3:13][C:11]1[NH:8][C:3]2[C:4]([CH:12]=1)=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1]
Reactant: C=C(C)[Mg]Br
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc2cccc(Cl)c2[nH]1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
42.1 g of 2-chloronitrobenzene are placed in 850 ml of THF under a nitrogen atmosphere. The mixture is cooled to −40° C. and then 1.61 of 0.5M isopropenylmagnesium bromide in THF are added dropwise. After stirring at −40° C. for 1 hour, the mixture is hydrolysed with 400 ml of a saturated NH4Cl solution. The aqueous phase is extracted twice with ether. The organic phase is dried and then evaporated and the residue is chromatographed on silica while eluting with toluene. 20.3 g of the expected compound are obtained.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[P:5](Cl)(=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]>C1(C)C=CC=CC=1>[CH2:7]([O:6][P:5]([N:3]=[C:2]=[S:1])([O:9][CH2:10][CH3:11])=[O:12])[CH3:8]
Reactant: N#C[S-]
Reactant: CCOP(=O)(Cl)OCC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(N=C=S)OCC
Temperature: 25 °C

Procedure:
To a mixture of 8.02 g of dry sodium thiocyanate in 100 ml of dry toluene at 0° C., under a nitrogen atmosphere is added 13.1 ml (16.6 g) of diethyl phosphorchloridate dropwise with stirring. The mixture is warmed to ambient temperature and stirred 20 hours. The mixture is filtered through a pad of Celite and the pad is washed with two 50 ml portions of toluene. The filtrate is washed with 50 ml of ice cold 10% sodium bicarbonate solution, 50 ml of ice water and dried over anhydrous magnesium sulfate. The mixture is filtered and the filtrate used without further purification in subsequent reaction.