Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH2:5]1COC[CH2:6]1.C([Mg]Cl)C.[F:14][C:15]1[CH:29]=[CH:28][C:18]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1>C(O)(=O)C>[F:14][C:15]1[CH:29]=[CH:28][C:18]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([OH:20])[CH2:5][CH3:6])=[CH:17][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C1CCOC1
Agent: CC[Mg]Cl
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCC(O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78 %

Procedure:
Into a reactor were introduced 10.0 g (40.6 mmol) of cerium chloride and 80 mL of THF under a nitrogen atmosphere. This mixture was stirred at room temperature for 20 hours and then cooled to 0° C. Thereto was added dropwise 25.1 mL (24.3 mmol; 0.97 M THF solution) of ethylmagnesium chloride over 30 minutes. Subsequently, a solution prepared by mixing 3.54 g (16.2 mmol) of 4,4′-difluorobenzophenone with 20 mL of THF was added dropwise thereto over 40 minutes, and this mixture was stirred for 1 hour. To the resultant reaction mixture was added 10% aqueous acetic acid solution. Thereafter, the mixture was extracted with ethyl acetate, and the resultant organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, subsequently dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain 3.12 g (78%) of the target compound as a light-yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13](=O)[NH:14]2)=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:30])=O.CN(C=O)C>C(Cl)(Cl)Cl>[Cl:30][C:13]1[C:12]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][C:10]2[C:15](=[CH:16][C:7]([O:6][CH2:5][C:4]3[CH:24]=[CH:25][CH:26]=[C:2]([Cl:1])[CH:3]=3)=[CH:8][CH:9]=2)[N:14]=1
Reactant: CCOC(=O)Cc1cc2ccc(OCc3cccc(Cl)c3)cc2[nH]c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1cc2ccc(OCc3cccc(Cl)c3)cc2nc1Cl
Yield: 89 %

Procedure:
To a slurry of ethyl 2-(7-((3-chlorobenzyl)oxy)-2-oxo-1,2-dihydroquinolin-3-yl)acetate (31.4 g, 0.08 mol) in chloroform (314 mL) at ambient temperature was added oxalyl dichloride (21.7 mL, 0.25 mol) and DMF (0.66 mL, 0.01 mol). The resulting slurry was heated to reflux for 1 h. The reaction was quenched with sat. aqueous NaHCO3 (400 mL). The aqueous layer was extracted with DCM (2×200 mL) and the combined organic layers were washed with brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure to furnish a black solid that was triturated in 1:1 EtOAc:hexanes (400 mL) and filtered. The solid was recrystallized from MeOH to furnish (17.0 g, 52%). Two additional crops of product were acquired from the mother liquor to furnish a total of 27.8 g (84.3%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.59 (s, 1H), 7.51-7.37 (m, 5H), 5.31 (s, 2H), 4.13 (q, J=7.1 Hz, 2H), 3.94 (s, 2H), 1.19 (t, J=7.1 Hz, 3H). [M+H]=390.2
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[CH2:6]([O:8][C:9]([C:11]1[C:12]2[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][C:13]=2[N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:15]=1)=[O:10])[CH3:7].[Na+].[I-]>CC#N>[CH2:6]([O:8][C:9]([C:11]1[C:12]2[C:27]([O:28][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:26][CH2:25][CH2:24][CH2:23][C:13]=2[N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH:15]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)CCCC2
Reactant: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(O[Si](C)(C)C)=CCCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
TMSCl (4.03 ml, 31.74 mmol) is added slowly to a solution of 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (6.0 g, 18.67 mmol), NaI (4.76g, 31.74 mmol) and TEA (7.8 ml, 56 mmol ) in CH3CN (100 ml) at room temperature. The reaction mixture is stirred at room temperature for 18 h. It is then quenched with saturated NaHCO3 (aq., 70 ml). The layers are separated and the aqueous phase extracted with 1:1 EtOAC/hexanes. The organic layers are combined, dried (Na2SO4), and evaporated to afford the title compound as a brown oil . The title compound is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:11]3[C:12](=[O:15])[O:13][CH2:14][C:10]=3[C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23](C)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.C(OC)(=O)CS.C1CCN2C(=[N:37]CCC2)CC1>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:11]3[C:12](=[O:15])[O:13][CH2:14][C:10]=3[C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:37])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)sc3c2COC3=O)cc1
Reactant: C1CCC2=NCCCN2CC1
Agent: COC(=O)CS
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)sc3c2COC3=O)cc1
Reaction time: 5 h

Procedure:
To a solution of cis,trans-4-chloro-4-(4-fluorophenyl)-3-(4-(methylthio)phenyl)-3-buten-2-one (13.8 g) (Example 6, Step 3) and methyl thioglycolate (5.8 mL) in 350 mL of CH3CN was added 8 mL of DBU. After stirring for 5 h, the reaction was quenched with 250 mL of sat. NH4Cl and 50 mL of 1N HCl. The mixture was then extracted with 800 ml of 2:1 EtOAc/hexane. The extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography eluted with 10:1 hexane/EtOAc to provide 8.58 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[N+:16]([O-])=O)(=[O:5])=[O:4].[H][H]>[Pd].C(OCC)(=O)C>[NH2:16][C:7]1[CH:8]=[C:9]([C:12]([F:14])([F:13])[F:15])[CH:10]=[CH:11][C:6]=1[S:3]([N:2]([CH3:19])[CH3:1])(=[O:4])=[O:5]
Reactant: [H][H]
Reactant: CN(C)S(=O)(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1ccc(C(F)(F)F)cc1N
Yield: 97.1 %

Procedure:
In a pressure vessel, 109 g of N,N-dimethyl-2-nitro-4-(trifluoromethyl)benzenesulfonamide, 250 ml of ethyl acetate and 5 g of 10% palladium-on-carbon were shaken at 130° under 500 psi hydrogen pressure until no more hydrogen was absorbed, as determined by no additional pressure drop. The reaction mixture was cooled and the catalyst filtered off. The solution was stripped in vacuo to give 95.2 g of 2-amino-N,N-dimethyl-4-(trifluoromethyl)benzenesulfonamide as a slowly crystalizing oil, m.p. 65°-70° C.
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].[CH3:7][CH:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]1=O>>[C:1]([NH:5][N:6]=[C:9]1[CH2:10][C:11]([CH3:14])([CH3:13])[CH2:12][CH:8]1[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CC(C)(C)CC1=O
Reactant: CC(C)(C)NN
Product: CC1CC(C)(C)CC1=NNC(C)(C)C

Procedure:
2,4,4-Trimethylcyclopentanone t-butylhydrazone was prepared by refluxing an aqueous solution of t-butylhydrazine with an equimolar amount of 2,4,4-trimethylcyclopentanone.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5](=[O:8])[NH:6][N:7]=1)[CH3:2].Cl[CH:19]([OH:22])[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[OH:22][CH2:19][CH2:20][CH2:21][N:6]1[C:5](=[O:8])[N:4]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]([CH2:1][CH3:2])=[N:7]1
Reactant: CCC(O)Cl
Reactant: CCc1n[nH]c(=O)n1CCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCc1nn(CCCO)c(=O)n1CCOc1ccccc1

Procedure:
The product of Example 5 "5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one" (5.0 g., 23.5 mmol), chloropropanol (2.44 g., 25.8 mmol) and potassium carbonate (9.72 g., 70.4 mmol) in 50 ml. of acetonitrile is heated to reflux for a period of 48 hr. with stirring. Water (50 ml.) is added and the mixture extracted with methylene chloride which is dried over magnesium sulfate and concentrated under reduced pressure to afford 2-(3-hydroxypropyl)-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one (XIV, Y=H, X1 =0, n=2, R2 =C2H5). Purification is carried out by flash chromatography with ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].N([O-])=O.[Na+].[N-:14]=[N+:15]=[N-].[Na+]>C(O)(C(F)(F)F)=O.O>[N:4]([C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1])=[N+:14]=[N-:15]
Reactant: Nc1ccc(I)cc1F
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=Nc1ccc(I)cc1F
Yield: 99 %

Procedure:
2-Fluoro-4-iodoaniline (1.1, 6.50 g, 27.4 mmol) was dissolved in 25 mL TFA and stirred in ice bath. Solid NaNO2 (2.07 g, 30.1 mmol) was added in small portions. The resulting mixture was stirred for 30 min in ice bath. Sodium azide (1.87 g, 28.8 mmol) was dissolved in 10 mL water and chilled in ice bath. This cold solution was then added to the TFA solution in three portions. The mixture was stirred in ice bath for 1 hr and concentrated in vacuo to remove TFA. The residue was taken into 600 mL DCM and washed with water three times. The organic phase was dried using MgSO4 and concentrated in vacuo to afford 1-azido-2-fluoro-4-iodobenzene 1.2 as a brownish waxy solid in >99% yield. In the mean time, 5-chlorothiophene-2-carboxylic acid (1.3, 9.13 g, 56 mmol) was dissolved in 200 mL dry DCM along with 0.5 mL dry DMF. To the vigorously stirred solution was carefully added oxalyl chlororide (14.7 mL, 169 mmol) dropwise. The resulting solution was stirred for 3 hrs at RT and concentrated in vacuo. The residue was pumped to dryness and then dissolved in 300 mL dry DCM. To this solution was added propargylamine (5.8 mL, 84 mmol) dropwise. The mixture was stirred at RT overnight during which time solid precipitated out. 600 mL hexane was added and the mixture was vigorously stirred for a few hours. The solid was collected by filtration and washed with hexane to give 5-chloro-N-(prop-2-ynyl)thiophene-2-carboxamide 1.4 (9.47 g, 85%) which was used directly without further purification. MS found for C8H6ClNOS as (M+H)+ 200.0, 202.0 (chlorine pattern).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:3]1.[Br:19]N1C(=O)CCC1=O>C(#N)C>[Br:19][C:7]1[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][CH:2]([CH3:1])[CH2:11][CH2:10]2
Reactant: CC1CCc2c(cccc2Oc2ccccc2)N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC1CCc2c(ccc(Br)c2Oc2ccccc2)N1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
A 50-mL round bottomed flask equipped with a magnetic stir bar and thermocouple was charged with rac-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline (0.574 g, 2.399 mmol) and acetonitrile (11.5 mL). The solution was cooled to 0° C., and N-bromosuccinimide (0.427 g, 2.399 mmol) was added in one portion. The solution turned yellow, and the internal temperature rose to 5° C. before falling back to 0° C. After 10 min, additional N-bromosuccinimide (0.021 g, 0.120 mmol) was added. After an additional 10 min, the reaction mixture was removed from the ice bath and concentrated under reduced pressure. The residue was then partitioned between ethyl acetate and 10% aqueous sodium carbonate solution. The layers were separated, and the ethyl acetate layer was washed with 5% aqueous sodium chloride solution (10 mL) and concentrated to a yellow oil (0.81 g). The crude product was purified by column chromatography on silica gel (eluting with 12:1 hexanes-ethyl acetate followed by 10:1 hexanes-ethyl acetate) to afford rac-6-bromo-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline (0.60, 79%) as a colorless syrup. MS (ESI, pos. ion) m/z 318, 320 [M+1].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH2:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=2)[CH:28]=[CH:27]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH:25][C:35]([C:32]2[CH:33]=[C:34]3[C:29]([CH:28]=[CH:27][NH:26]3)=[CH:30][CH:31]=2)=[O:36])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(N)c2ccccc2Cl)CC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Product: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2ccc3cc[nH]c3c2)c2ccccc2Cl)CC1

Procedure:
Using coupling method A, 4-[2-amino-2-(2-chlorophenyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.4 mmol) and indole-6-carboxylic acid (219 mg, 1.4 mmol) afforded, after purification (SiO2: 33% to 50% EtOAc in hexane), 579 mg (83%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][Cl:27].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[ClH:27].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 90.8 %

Procedure:
A mixture of 30.1 g of cis-(+)-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one, 17.2 g of 2-(dimethylamino)ethyl chloride hydrochloride, 31.8 g of potassium carbonate and 240 ml of acetone is refluxed for 30 minutes after stirring. Then, 10 ml of water are added to the mixture, and the aqueous mixture is further refluxed for 3 hours under stirring. After the reaction is completed, the mixture is evaporated under reduced pressure to remove acetone. The residue is dissolved in toluene, and the solution is washed twice with water. The toluene layer is collected and then evaporated under reduced pressure to remove toluene. The residue is dissolved in ethanol. After cooling the solution, said solution is acidified with 10% HCl/ethanol and then stirred at a temperature below 5° C. for 5 hours. The crystalline precipitates are collected by filtration, washed with ethanol and then dried. 37.1 g of cis-(+)-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride are thereby obtained. Yield: 90.7%
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30](O)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.P(Cl)(Cl)(OCC)=O.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>O1CCCC1>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: C1COCCN1
Agent: CCOP(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a stirred solution of p-nitrobenzyl α-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-α-(1-hydroxyethylidene)acetate (4.69 g.) in tetrahydrofuran (60 ml.) under a nitrogen atmosphere at 0°-5° C. was added triethylamine (1.6 ml.) followed by dropwise addition of ethyl dichlorophosphate (1.36 ml.) over 5 minutes. After stirring for 3 hours at 20° C., the reaction mixture was cooled to 0° C. and morpholine (4.0 ml.) was added dropwise over 10 minutes with the reaction temperature maintained at 0°-5° C. After stirring for 3 hours at this temperature, the tetrahydrofuran was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with water and then with saturated sodium chloride solution, dried with magnesium sulphate and evaporated to give the title compound as a pale yellow foam in essentially quantitative yield. The product obtained was a mixture of geometric isomers (ca. 1:1.4) about the enamine double bond and was identical to that produced in example 8.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:24]=[C:23]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:23]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[CH:24][C:16]=1[F:15]
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1F
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cccc(F)c2)cc1F
Yield: 72.5 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-2-fluoro-4-(3-fluorobenzyl)benzamide was prepared according to Method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.075 g; 0.318 mmol), 2-fluoro-4-(3-fluorobenzyl)benzoic acid (0.087 g; 349 mmol), HATU (0.121 g: 0.318 mmol) and N,N-diisopropylethylamine (0.139 mL; 0.795 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 0 to 10% of ethyl acetate in dichloromethane) followed by recrystallization from a mixture of dichloromethane/heptane, furnished 0.098 g (73%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][C:23]1([CH2:28][NH2:29])[CH2:27][CH2:26][NH:25][CH2:24]1.C(N(CC)CC)C>C(#N)C>[NH2:29][CH2:28][C:23]1([CH3:22])[CH2:27][CH2:26][N:25]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([CH3:17])[C:10]=2[F:16])[CH2:24]1
Reactant: CC1(CN)CCNC1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(F)c(N2CCC(C)(CN)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A mixture of 0.60 g (2.02 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.28 g (2.45 mmol) of 3-methyl-3-pyrrolidinemethanamine, 0.61 g (6.06 mmol) of triethylamine, and 20 ml of acetonitrile was refluxed for four hours, then stirred at room temperature overnight. The precipitate was filtered, washed with ether, and dried to give 0.61 g of the title compound, mp 182°-184° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:4][CH:3]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].[N:25]1[N:26]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](O)=[O:33])[N:27]=[CH:28][CH:29]=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>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:7][CH:5]2[CH2:4][CH:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH:2]([NH:1][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[N:26]3[N:27]=[CH:28][CH:29]=[N:25]3)[CH2:6]2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: COc1ccc(COC2CC(N)C(NC(=O)OC(C)(C)C)C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(COC2CC(NC(=O)OC(C)(C)C)C(NC(=O)c3ccccc3-n3nccn3)C2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of tert-butyl N-{2-amino-4-[(4-methoxyphenyl)methoxy]cyclopentyl}-carbamate (1.71 g, 5.08 mmol) in dry DMF (17 ml) was added 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 1.06 g, 5.59 mmol), HATU (2.90 g, 7.62 mmol) and triethylamine (2.13 ml, 15.25 mmol). The reaction was stirred at room temperature for 72 hours then partitioned between ethyl acetate and water. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OCC[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.N1C=CC=CC=1>O>[C:5]([O:4][CH2:1][CH2:2][N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: OCCn1cccc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCn1cccc1
Temperature: 25 °C
Yield: 55 %

Procedure:
The resulting product is reacted with acetic anhydride in accordance with the method of F. F. Blicke and E. S. Blake, J. Am. Chem. Soc., 53, 1015(1931). A mixture of 1-(2-hydroxyethyl)pyrrole (147 g, 1.32 mole), pyridine (415 ml) and acetic anhydride (139 ml) is heated on a steam bath for 0.5 hours. The reaction mixture is cooled to room temperature, poured into water (one l) and the product is extracted into ethyl acetate (3×1 l ). The extract is washed successively with dilute hydrochloric acid, saturated sodium chloride solution, dilute sodium bicarbonate solution, and again with saturated sodium chloride solution. The extract is dried over sodium sulfate, evaporated in vacuo and the residue (150 g) is subjected to column chromatography on Florisil® activated magnesium silicate. The desired product is eluted with hexane-dichloromethane (1:1) to give 128 g (55%) 1-(2-acetoxyethyl)pyrrole, an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].CCN(CC)CC.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C1COCC1>[CH3:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:33]([NH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([F:24])([F:35])[F:36])=[O:34]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1ccccc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.9 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methylphenylacetate (927 mg, 4.19 mmol) and Et3N (645 μl, 4.63 mmol) in THF (10 ml) was added 2-trifluoromethylphenyl isocyanate (633 μl, 4.19 mmol) and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated to a small volume and diluted with n-hexane. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give tert-butyl 3-methyl-4-[N′-(2-trifluoromethylphenyl)ureido]phenylacetate (1.06 g, 62%) as a white crystalline powder. mp 178-180° C.; 1H-NMR (CDCl3) δ1.44 (s, 9 H), 2.25 (s, 3 H), 3.51 (s, 2 H), 6.38 (br s, 1 H), 7.12-7.18 (m, 3 H), 7.36-7.37 (m, 1 H), 7.49-7.53 (m, 2 H), 8.13-8.16 (m, 1 H).