Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[O:18])[CH2:8]1.N1C=CC=CC=1.S(Cl)([Cl:28])(=O)=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Cl:28][C:5]1[S:4][C:3]([CH:7]2[CH2:16][C:15]3[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=3[C:9](=[O:18])[CH2:8]2)=[C:2]([CH3:1])[CH:6]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccsc1C1CC(=O)c2c(C)ccnc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)sc1C1CC(=O)c2c(C)ccnc2C1
Reaction time: 4 h
Yield: 74.3 %

Procedure:
To a solution of 7-(3-methyl-2-thienyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.38 g) in ethyl acetate (10 ml) were added pyridine (0.023 g) and sulfuryl chloride (0.3 g) at room temperature, and the mixture was stirred at the same temperature for 4 hours. To the reaction solution was added sodium hydrogen carbonate solution, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane) to give 7-(5-chloro-3-methyl-2-thienyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.32 g), which was dissolved in ethanol (20 ml). To the solution were added aminoguanidine hydrochloride (0.15 g), concentrated hydrochloric acid (0.27 ml) and water (0.27 ml), and the mixture was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 7-(5-chloro-3-methyl-2-thienyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 122) (0.32 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26](O)=[O:27])=[C:13]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[N:14]=1)=[O:8].[CH2:31]([NH2:33])[CH3:32]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26]([NH:33][CH2:31][CH3:32])=[O:27])=[C:13]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[N:14]=1)=[O:8]
Reactant: O=C(Nc1nc(-c2c(F)c(F)c(F)c(F)c2F)c(C(=O)O)s1)c1cc(Br)ccc1O
Reactant: CCN
Product: CCNC(=O)c1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1c(F)c(F)c(F)c(F)c1F
Yield: 62.5 %

Procedure:
Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)thiazole-5-carboxylic acid and 70% aqueous ethylamine solution as the raw materials, the same operation as the example 212(2) gave the title compound.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10][CH2:9]2.[BrH:17]>O>[Br:17][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10][CH2:9]2
Reactant: Br
Reactant: Nc1ccc2c(c1)CCCC2=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of NaNO2 (2.35 g, 34 mmol) in water (10 mL) was added dropwise to the solution of 6-amino-1,2,3,4-tetrahydronaphthalen-1-one (5.0 g, 31 mmol) in 25% HBr (16 mL) at 0° C. The suspension was then transferred to a stirred mixture of CuBr (8.9 g, 62 mmol) in 48% HBr (30 mL) at 0° C. The resulting mixture was allowed to warm to rt and stirred for 1 h. The mixture was extracted with EtOAc, dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (0%-60% EtOAc/Hex) to give 5.6 g (80%) of the title compound as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 2.10-2.16 (2H, m), 2.64 (2H, t, J=6.4 Hz), 2.94 (2H, t, J=6.0 Hz), 7.42 (1H, s), 7.44 (1H, s), 7.87 (1H, d, J=8.9 Hz). [M+H] calc'd for C10H9BrO, 225, 227. found 225, 227.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[N:18]3[CH:19]=C(CO)[N:21]=[C:17]3[CH2:16][N:15]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:13]=2[CH:31]=1>N1C=CC=CC=1>[C:5]([O:4][CH2:1][C:2]1[N:21]=[C:17]2[CH2:16][N:15]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:13]3[CH:31]=[C:9]([Cl:8])[CH:10]=[CH:11][C:12]=3[N:18]2[CH:19]=1)(=[O:7])[CH3:6]
Reactant: OCc1cn2c(n1)CN=C(c1ccccc1F)c1cc(Cl)ccc1-2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1cn2c(n1)CN=C(c1ccccc1F)c1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 70 h

Procedure:
0.96 ml of acetic anhydride was added dropwise to a solution of 1.36 g of 8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol in 30 ml of pyridine. The reaction mixture was stirred at room temperature for 70 h. and then evaporated in a vacuum. The residue was treated with saturated aqueous sodium hydrogen carbonate solution and this was extracted twice with dichloromethane. The dichloromethane extracts were dried over sodium sulphate and the solution was chromatographed over 50 g of silica gel. 1.4 g of an oil were eluted with dichloromethane/ethanol 197:3 and this was crystallized from diethyl ether/diisopropyl ether. There were obtained 2.1 g of 2-acetoxymethyl-8-chloro-6-(2-fluorophenyl)-4H-imidazo [1,2-a][1,4]benzodiazepine of m.p. 134-136° C. which was converted into the hydrochloride.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:11].O>C1COCC1>[CH2:1]([NH:8][C:9]([NH2:11])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=NCc1ccccc1
Reactant: N
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)NCc1ccccc1
Yield: 108.1 %

Procedure:
96.3 g (366 mmoles) of benzylisothiocyanate were dissolved in 100 ml o THF and treated with 44.2 ml (732 mmoles) of 32% ammonia solution After 0.5 hour at 40-45° C., 300 ml of water were added and the THF removed in vacuo. The gummy suspension is treated with 200 ml of ether, the crystals collected and washed with water and ether. Suspension in 30 ml of methylenechloride and collection gave 65.77 g (64.2%) of benzyl-2-thiourea with mp 144-5° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:19](=[S:21])[NH2:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(C)(C)C.Br[CH2:24][C:25](=O)[CH2:26][CH3:27].C(OCC)C>CC#N>[CH2:26]([C:25]1[N:20]=[C:19]([C@@H:8]([NH2:7])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[S:21][CH:24]=1)[CH3:27]
Reactant: CCC(=O)CBr
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(N)=S
Solvent: CCOCC
Solvent: CC#N
Product: CCc1csc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Yield: 90 %

Procedure:
A mixture of [2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]-carbamic acid tert-butyl ester, 2, (0.245 g, 0.753 mmol), 1-bromo-2-butanone (0.125 g, 0.828 mmol) in CH3CN (5 mL) is refluxed 3 hours. The reaction mixture is cooled to room temperature and diethyl ether is added to the solution and the precipitate which forms is removed by filtration. The solid is dried under vacuum to afford 0.242 g (90% yield) of the desired product. ESI+MS 278 (M+1).
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][CH2:9][C:10]#[C:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH:24]=[O:25].C[Si]([O:30][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])(C)C.C([O-])(O)=O.[Na+]>ClCCl.C(OCC)C>[F:35][C:34]([F:37])([F:36])[S:31]([O:33]/[C:11](=[C:10]1/[CH:24]([C:15]2[CH:16]=[CH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[O:25][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]/1)/[CH3:12])(=[O:32])=[O:30]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC#CCCC(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C/C(OS(=O)(=O)C(F)(F)F)=C1/CCC(c2ccccc2)OC1c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
In dichloromethane (3.0 mL) were dissolved 1-phenylhex-4-yn-1-ol (0.28 mmol) and 2-naphthalenealdehyde (0.34 mmol) and the solution was cooled to −78° C. before the addition of trimethylsilyltriflate (TMSOTf) (0.86 mmol) thereto. After being stirred for 1 hour at the same temperature, the reaction solution was slowly heated to room temperature over 3 hours. Stirring was further conducted at room temperature for an additional one to two hours in the reaction solution. After the addition of an aqueous NaHCO3 solution, the reaction solution was diluted with diethylether. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. The purification of the concentrate through column chromatography afforded the title compound (Yield 81%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:18][OH:19])=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: Cc1cnc(C)c(C(=O)c2ccccc2)n1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cnc(C)c(C(=NO)c2ccccc2)n1
Yield: 99 %

Procedure:
A solution of (3,6-dimethylpyrazin-2-yl)(phenyl)methanone (3.02 g, 14.2 mmol) and hydroxylamine hydrochloride (2.47 g, 35.5 mmol) in pyridine (50 mL) was stirred 7 h at 70° C. After removal of the solvent in vacuo, addition of water (100 mL) and extraction with ethyl acetate (2×100 mL), the combined organic layers were washed with water (100 mL), dried over MgSO4 and concentrated in vacuo to afford 1-(3,6-dimethylpyrazin-2-yl)-N-hydroxy-1-phenylmethanimine as an orange honey [3.39 g, yield 99%; HPLC/MS: m/z=228 (M+H); log P(HCOOH)=1.70].
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH2:3][C:4]([O-:6])=[O:5].[C:15]([O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[S:27])=[CH:24][CH:23]=1)(=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-:32].[Na+].[Na+]>C(O)(C)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2([OH:32])[CH:2]([CH2:3][C:4]([OH:6])=[O:5])[S:27][C:26]([C:25]3[CH:24]=[CH:23][C:22]([O:21][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:30][CH:29]=3)=[N:28]2)=[CH:9][CH:10]=1
Reactant: CCCCC(=O)Oc1ccc(C(N)=S)cc1
Reactant: O=C([O-])[O-]
Reactant: O=C([O-])CC(Br)Cc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CC(C)O
Product: CCCCC(=O)Oc1ccc(C2=NC(O)(c3ccc(Cl)cc3)C(CC(=O)O)S2)cc1

Procedure:
3-Bromo-3-(4-chlorobenzyl)propionate acid and an equimolar amount of 4-valeryloxythio-benzamide are stirred in isopropyl alcohol solvent containing sodium carbonate to give 4-(4-chlorophenyl)-4-hydroxy-2-(4-valeryloxyphenyl)-2-thiazolin-5-acetic acid. This compound is dehydrated by heating to give the title compound.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:12]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:11][CH:10]2[N:18]([CH3:19])[CH:7]1[CH2:8][CH2:9]2)=O)C.C1(C)C=CC=CC=1.COCCO[AlH2-]OCCOC.[Na+].[OH-].[Na+]>O>[CH3:19][N:18]1[CH:10]2[CH2:9][CH2:8][CH:7]1[C@H:6]([CH2:4][OH:3])[C@@H:12]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:11]2
Reactant: CCOC(=O)[C@H]1C2CCC(C[C@@H]1c1cccs1)N2C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1C2CCC1[C@H](CO)[C@@H](c1cccs1)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of (2R,3S)-8-methyl-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane-2-carboxylic acid ethyl ester (3.65 g, 13.75 mmol) and toluene (75 ml), Red-Al (6 ml, 65%, 20 mmol) was added at 0° C. The mixture was stirred at 0° C. for 1 h. A solution of aqueous sodium hydroxide (20 ml, 4 M) was added dropwise followed by warm water (50° C., 150 ml). The mixture was extracted with toluene (2×100 ml). The mixture was dried (MgSO4) and evaporated. The product was isolated as crystals. Mp: 153.7-157.5° C. Yield 2.04 g (63%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)c1ccc(OCCCCl)cc1
Yield: 96.8 %

Procedure:
A mixture of 50 g (0.365 mole) of 4-hydroxybenzamide, 114.8 g (0.729 mole) of 1-bromo-3-chloropropane and 151.3 g (1.1 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 20 hr. The mixture was concentrated under reduced pressure and the residue was stirred with 1.2 liter of water to remove inorganic solids. The mixture was filtered and te filter cake was washed with water and petroleum ether and dried to yield 75.5 g (97%) of white solid. The solid was recrystallized from ethylacetate, m.p. 142°-143° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([OH:17])[C:11]([OH:18])=[CH:10][C:7]=1[C:8]#[N:9])=[O:5].[C:23](Cl)(=[O:27])[O:24][CH2:25][CH3:26].CN(C)C=O.O>C(OCC)(=O)C>[CH2:25]([O:24][C:23]([O:18][C:11]1[C:12]([OH:17])=[C:13]([N+:14]([O-:16])=[O:15])[C:6]([C:4](=[O:5])[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=2[F:1])=[C:7]([CH:10]=1)[C:8]#[N:9])=[O:27])[CH3:26]
Reactant: N#Cc1cc(O)c(O)c([N+](=O)[O-])c1C(=O)c1ccccc1F
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Oc1cc(C#N)c(C(=O)c2ccccc2F)c([N+](=O)[O-])c1O
Temperature: 50 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
A mixture of 2-(2-fluorobenzoyl)-4,5-dihydroxy-3-nitrobenzonitrile (compound 1-29) (70 mg), ethyl chloro-carbonate (30 mg) and N,N-dimethylforamide (1 mL) was stirred at 50° C. for 3 hours. Water and ethyl acetate were added to the mixture. The organic layer was washed with water, and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 50-100% ethyl acetate/hexane, gradient elution) to give the title compound (60 mg). The structural formula was illustrated in table 10.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([O:32]C)=[O:31].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:29][C:30]([OH:32])=[O:31])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2ccccc2CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-2-(2-furyl)-5-methyloxazole (1.84 g), methyl 2-(2-hydroxyphenyl)acetate (1.00 g), anhydrous potassium carbonate (1.66 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature overnight. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. To a mixture of the obtained residue, tetrahydrofuran (10 mL) and methanol (10 mL) was added a 1N aqueous sodium hydroxide solution (10 mL) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to the residue. The precipitated solid was collected by filtration and dried with air to give crystals (2.08 g, 82%) of 2-[2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 167-168° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[CH3:59][O:60][C:61](=[O:85])[CH:62]=[CH:63][CH:64]([NH2:84])[CH2:65][C:66]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[N:68]([CH2:75][CH:76]=[CH:77][C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)[CH:67]=1>C1COCC1>[CH3:59][O:60][C:61](=[O:85])[CH:62]=[CH:63][C@H:64]([NH:84][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:65][C:66]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[N:68]([CH2:75][CH:76]=[CH:77][C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)[CH:67]=1
Reactant: COC(=O)C=CC(N)Cc1cn(CC=Cc2ccccc2)c2ccccc12
Reactant: O=C(O)CCCCCCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C=C[C@@H](Cc1cn(CC=Cc2ccccc2)c2ccccc12)NC(=O)CCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
A solution of 7-phenylheptanoic acid (87 mg, 0.422 mmol), BOP (205 mg, 0.464 mmol) and DIPEA (65.38 mg, 88 μL, 0.506 mmol) in THF (2.5 mL) was stirred for 10 min. To this was added a solution of the trifluoroacetic acid salt of 4-amino-5-[1-(3-phenyl-allyl)-1H-indol-3-yl]-pent-2-enoic acid methyl ester (200 mg, 0.422 mmol) and DIPEA (163 mg, 220 μL, 1.27 mmol) in THF (2.5 mL). The mixture was stirred overnight at room temperature. The solvent was removed and the crude material subject to column chromatography (50% EtOAc/petroleum ether, Rf 0.66) to afford the title compound (133 mg, 55%). 1H NMR (CDCl3) δ 7.58 (1H, d, J=8.1 Hz), 7.36-7.09 (12H, m), 7.02-6.95 (2H, m), 6.45 (1H, d, J=15.78 Hz), 6.29 (1H, dt, J=5.63, 15.78 Hz), 5.82 (1H, d, J=15.69 Hz), 5.52 (1H, d, J=8.25 Hz), 5.01-5.09 (1H, m), 4.82 (2H, d, J=5.49 Hz), 3.66 (3H, s), 3.12 (1H, dd, J=6.35, 14.69 Hz), 3.04 (1H, dd, J=6.17, 14.69 Hz), 2.55 (2H, t, J=7.69 Hz), 2.07 (2H, t, J=7.64 Hz), 1.59-1.46 (4H, m), 1.25-1.23 (4H, m). 13C NMR (CDCl3) δ 172.5, 166.6, 148.1, 142.7, 136.4, 136.1, 132.5, 128.6, 128.4, 128.2, 127.9, 126.5, 125.6, 124.6, 120.8, 122.0, 119.5, 118.8, 109.8, 109.2, 51.6, 50.2, 48.3, 36.7, 35.8, 31.2, 29.9, 29.0, 28.9, 25.4. ISMS: 549 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[C:10]2[C:11]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:12][N:13]([C:18]3[C:19]([O:27][CH3:28])=[N:20][C:21]([N:24]([CH3:26])[CH3:25])=[N:22][CH:23]=3)[C:14]=2[CH:15]([CH3:17])[CH3:16])=[CH:5][C:4]=1[F:35])#[N:2].[NH2:36][C:37]1[CH:38]=[C:39]([Cl:53])[C:40](=[O:52])[N:41]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[CH:42]=1>>[Cl:53][C:39]1[C:40](=[O:52])[N:41]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[CH:42]=[C:37]([NH:36][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:35])[CH:5]=2)[C:10]2[C:11]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:12][N:13]([C:18]3[C:19]([O:27][CH3:28])=[N:20][C:21]([N:24]([CH3:26])[CH3:25])=[N:22][CH:23]=3)[C:14]=2[CH:15]([CH3:17])[CH3:16])[CH:38]=1
Reactant: COc1ccc(Cn2cc(N)cc(Cl)c2=O)cc1
Reactant: CCOC(=O)c1nn(-c2cnc(N(C)C)nc2OC)c(C(C)C)c1C(O)c1ccc(C#N)c(F)c1
Product: CCOC(=O)c1nn(-c2cnc(N(C)C)nc2OC)c(C(C)C)c1C(Nc1cc(Cl)c(=O)n(Cc2ccc(OC)cc2)c1)c1ccc(C#N)c(F)c1

Procedure:
The title compound was prepared in analogy to the procedure described in step 184.2 but using ethyl 4-((4-cyano-3-fluorophenyl)(hydroxy)methyl)-1-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylate (intermediate 191.3) and 5-amino-3-chloro-1-(4-methoxy-benzyl)-1H-pyridin-2-one (product from step 155.4). After the extraction, the crude product was purified by chromatography (Silicagel, Hexane/EtOAc 50:50 to 20:80). Pure fractions were collected and evaporated to dryness to afford a brown solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])CCC.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=1)[CH:21]=[O:22]>O.O1CCCC1.CCCCCC>[S:1]1[C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[C:5]1[CH:21]([C:20]1[CH:23]=[C:16]([Br:15])[CH:17]=[CH:18][C:19]=1[F:24])[OH:22]
Reactant: c1ccc2sccc2c1
Reactant: O=Cc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(c1cc2ccccc2s1)c1cc(Br)ccc1F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
Into a tetrahydrofuran (20 ml) solution of benzo[b]thiophene (5.0 g) was dropwise added a n-hexane solution (25 ml) of n-butyl lithium (1.58 M) at −78° C. in an argon atmosphere, followed by stirring at −78° C. for 10 minutes. Into this solution was dropwise added a tetrahydrofuran (80 ml) solution of 5-bromo-2-fluorobenzaldehyde (8.0 g), followed by stirring at −78° C. for 2.5 hours. The temperature of the reaction mixture was elevated to room temperature. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol (10.5 g, yield: 83.6%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH2:11])=[N:8][CH:9]=1)([O-:3])=[O:2].[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH:17]=O.C(O)(=O)C>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][N:11]=[CH:17][C:13]2[NH:12][CH:16]=[CH:15][N:14]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1ncc[nH]1
Reactant: NNc1ccc([N+](=O)[O-])cn1
Solvent: CCO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(NN=Cc2ncc[nH]2)nc1
Reaction time: 8 h

Procedure:
3.10 g (20.1 mmol) of 5-nitro-2-pyridylhydrazine and 2.00 g (20.8 mmol) of 2-imidazolecarbaldehyde were dissolved in 50 ml of ethanol. To this mixture, 1 ml of acetic acid was added and heated under reflux for 2 hours while being stirred. After the resultant reaction mixture was allowed to stand still overnight, coarse crystals precipitated were filtrated by the suction-filtration. The obtained coarse crystals were recrystallized from a hot ethanol solution to obtain a desired product.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.C([O:21][C:22](=O)[C:23]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Cl:36])[CH:30]=2)[C:26]([O:37][CH2:38][CH2:39][OH:40])=[C:25]([Br:41])[CH:24]=1)C>C1COCC1.O.Cl>[CH2:1]([NH:13][C:22](=[O:21])[C:23]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Cl:36])[CH:30]=2)[C:26]([O:37][CH2:38][CH2:39][OH:40])=[C:25]([Br:41])[CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)c1cc(Br)c(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Reactant: CCCCCCCCCCCCN
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
Into a flamed dried round bottom flask charged with n-dodecylamine (586 mg, 3.16 mmol) in 7 mL THF at −20° C. was added n-BuLi (1.8 mL, 3.6 mmol) as a solution in hexanes. After the addition, the reaction was warmed up to room temperature and stirred for one-half hour. Then the solution was cooled to −20° C. and was added to a solution of 3-bromo-4-(2-hydroxyethoxy)-5-(3-chloro-4-fluorophenyl)benzoic acid ethyl ester (400 mg, 0.957 mmol) in 8 mL THF that had been previously cooled to −40° C. The resulting mixture was stirred at −40° C. for 5 min after which point the reaction mixture was allowed to warm up to room temperature. The reaction was diluted with water and 2N HCl then extracted with EtOAc three times. The combined organic extracts were, washed with sat NaHCO3 then dried over Na2SO4. After filtering and removal of solvent in vacuo, there yielded a yellow oil that was subjected to column chromatography on silica gel (10% EtOAc:90% Hexanes followed by 25% EtOAc:75% Hexanes). There resulted 300 mg, 58% of the amide as a yellow oil. 1H NMR (CDCl3) 0.868 (t, J=8.13 Hz, t); 1.20-1.40 (m, 18H); 1.48-1.67 (m, 2H); 1.895-2.00 (bs, 1H); 3.427 (q, J=8.13 Hz, 2H); 3.636-7.71 (m, 4H); 6.014 (m, 1H); 7.20-7.24 (m, 1H); 7.40-7.454 (m, 1H); 7.586-7.668 (m, 2H); 7.868 (d, J=2.04 Hz, 1H).