Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.C(OC([NH:12][C@@H:13]([CH2:33][C:34](=[O:53])[NH:35]C(C1C=CC(OC)=CC=1)C1C=CC(OC)=CC=1)[C:14]([NH:16][C@@H:17]([CH2:21][NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][C:25]1[N:26]=[CH:27][NH:28][CH:29]=1)[C:18]([OH:20])=[O:19])=[O:15])=O)C1C=CC=CC=1.C(OCC)(=O)C>C(O)(=O)C>[NH2:12][C@@H:13]([CH2:33][C:34](=[O:53])[NH2:35])[C:14]([NH:16][C@@H:17]([CH2:21][NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][C:25]1[N:26]=[CH:27][NH:28][CH:29]=1)[C:18]([OH:20])=[O:19])=[O:15]
Reactant: COc1ccc(C(NC(=O)C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](CN[C@@H](Cc2c[nH]cn2)C(=O)O)C(=O)O)c2ccc(OC)cc2)cc1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NC(=O)C[C@H](N)C(=O)N[C@@H](CN[C@@H](Cc1c[nH]cn1)C(=O)O)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
A solution of 30% hydrogen bromide in acetic acid (4.0 ml) was added to (2S)-2-[[(2S)-2-benzyloxycarbonylamino-3-[N-[bis(4-methoxyphenyl)methyl]carbamoyl]propionyl]amino]-3-[[(1S)-1-carboxy-2-(4-imidazolyl)ethyl]amino]propionic acid (772 mg) in an ice-water bath. The mixture was stirred for 15 minutes and then additional portion (4.0 ml) of a solution of hydrogen bromide in acetic acid was added thereto at ambient temperature. The mixture was stirred for 2.5 hours, and poured into a mixture of ice-water (25 ml) and ethyl acetate (25 ml). The aqueous layer was separated and then the remaining organic layer was extracted with water (30 ml). The aqueous layer were combined and subjected to a column of Dowex 50W x 8 (H30 , 20 ml) and the elution was carried out with water (200 ml) and 1.4% aqueous ammonia (250 ml). The fractions containing the object compound were combined and evaporated in vacuo. The residue was dissolved in water (30 ml) and filtered. The filtrate was lyophilized to give a white powder (315 mg) of (2S)-2-[[(2S)-2-amino-3-carbamoylpropionyl]amino]-3-[[(1S)-1-carboxy-2-(4-imidazolyl)ethyl]amino]propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:21])=[C:11]([C:13]3[C:14](=[O:20])[CH2:15][CH2:16][C:17]=3[O:18][CH3:19])[N:12]=2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[F:30][C:31]1[CH:32]=[CH:33][C:34]([CH:37]=[O:38])=[N:35][CH:36]=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:21])=[C:11]([C:13]3[C:14](=[O:20])[CH:15]([CH:37]([C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:36][N:35]=4)[OH:38])[CH2:16][C:17]=3[O:18][CH3:19])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC1=C(c2nc(-c3ccc(Cl)cc3)sc2C)C(=O)CC1
Reactant: O=Cc1ccc(F)cn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1=C(c2nc(-c3ccc(Cl)cc3)sc2C)C(=O)C(C(O)c2ccc(F)cn2)C1
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a solution of 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-3-methoxy-cyclopent-2-enone (400 mg, 1.25 mmol) in anhydrous tetrahydrofuran (10 ml) at −78° C. under an atmosphere of nitrogen was added lithium diisopropylamide (1.8M in THF/heptanes/ethylbenzene; 0.76 m, 1.37 mmol) dropwise over a period of 5 minutes, and the reaction allowed to stir at 78° C. for 30 minutes. A solution of 5-fluoro-pyridine-2-carbaldehyde (171 mg, 1.37 mmol) in anhydrous tetrahydrofuran (1 ml) was then added dropwise over a period of 5 minutes before the reaction was allowed to warm to room temperature and stirred for a further 30 minutes. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (50 ml) and extracted with ethyl acetate (50 ml) and the organic later separated, dry loaded onto silica and purified by flash chromatography to give 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-5-[(5-fluoro-pyridin-2-yl)-hydroxy-methyl]-3-methoxy-cyclopent-2-enone (400 mg).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10](N)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:23]1C(Cl)=NC(Cl)=N[C:24]=1Cl.O.C(OCC)(=O)C>CN(C=O)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([C:24]#[N:23])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 139.7 %

Procedure:
Cbz-Phe-NH2 (4.86 g, 16.29 mmoles) was dissolved in DMF under nitrogen and cooled on ice bath. Cyanuric chloride (1.95 g, 10.59 mmoles) was added with stirring, and the mixture was allowed to warm to rt overnight. Water (100 ml) and ethyl acetate (250 ml) were added to the mixture. The organic phase was separated and washed three times with water (100 ml) and then dried over magnesium sulfate. The material was filtered and concentrated in vacuo to afford Cbz-Phe-CN as a white solid (4.56 g, 99%) HPLC analysis: >99% purity; Retention time 10.1 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].Cl[CH2:12][CH2:13][CH2:14][O:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: COCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCCOc1ccccc1[N+](=O)[O-]

Procedure:
A suspension of 2.00 g of 2-nitrophenol, 1.72 g of 1-chloro-3-methoxypropane and 3.04 g potassium carbonate in 20 ml of N,N-dimethylformamide is stirred at reflux over 23 hours. The reaction mixture is concentrated by evaporation. The residue is partitioned between ethyl acetate and a 9:1 water/brine mixture. The water phase is extracted using ethyl acetate (2×). The organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.33 (1:2 EtOAc-heptane); Rt=4.08.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH3:24])=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:25]#[N:26])[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[NH4+].CO>[Fe].O>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:23][CH3:24])[N:13]=[CH:12][C:11]([C:25]#[N:26])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Yield: 8428.4 %

Procedure:
An amount of 4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-6-nitro-quinoline-3-carbonitrile (9.9 g, 0.27 mmol) was combined with ammonium chloride (11.4 g, 0.21 mol), iron powder (8.9 g, 0.16 mol), methanol (200 mL), and water (50 mL), and heated at reflux for 2 hours. An additional amount of iron (1.0 g, 0.018 mol) and ammonium chloride (1.0 g, 0.019 mol) were added and the mixture was refluxed for an additional 3.5 hours. The reaction mixture was filtered hot and the residue was washed with boiling methanol to extract the product. The filtrate was evaporated to a slurry and stirred with saturated sodium bicarbonate solution and ethyl acetate. The layers were separated, and the organic layer was dried over magnesium sulfate and evaporated to dryness to give a green powder (7.8 g, 85%), which was used without further purification.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[CH3:23].[NH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:24][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:16][C:15]=1[CH3:23]
Reactant: NCCN1CCCC1
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NCCN2CCCC2)ccc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.68 g) was added to a solution of 4-bromo-3-methyl benzoic acid (3.0 g), 1-(2-aminoethyl)pyrrolidine (1.78 ml) and 1-hydroxybenzotriazole hydrate (1.89 g) in dry N,N-dimethylformamide (30 ml). The reaction was stirred at room temperature for 24 hours. The solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluting with dichloromethane:methanol (9:1) to give the sub-title compound as an oil. (3.55 g).
Reaction SMILES: [ClH:1].[C:2]([C@@:4]1([CH:28]2[CH2:30][CH2:29]2)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[N:18][N:19]([C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=O)[CH:20]=3)[N:10]=2)[C:5]1=[O:27])#[N:3].C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:62]1[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1>CN(C)C=O>[ClH:1].[CH:28]1([C@:4]2([C:2]#[N:3])[CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]4[CH:17]=[N:18][N:19]([C:21]([CH3:25])([CH3:26])[C:22]([N:62]5[CH2:67][CH2:66][O:65][CH2:64][CH2:63]5)=[O:24])[CH:20]=4)[N:10]=3)[C:5]2=[O:27])[CH2:30][CH2:29]1
Reactant: C1COCCN1
Reactant: CC(C)(C(=O)O)n1cc(Nc2nccc(N3CC[C@@](C#N)(C4CC4)C3=O)n2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C(=O)N1CCOCC1)n1cc(Nc2nccc(N3CC[C@@](C#N)(C4CC4)C3=O)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
To a solution of 2-(4-((4-((3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-methylpropanoic acid hydrochloride (80 mg) obtained in Example 108 in N,N-dimethylformamide (2.0 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (58 mg), 1-hydroxybenzotriazole monohydrate (57 mg), N,N-diisopropylethylamine (97 μL) and morpholine (19 mg), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate). To a solution of the residue (87 mg) in ethanol (3.0 mL) was added dropwise 1 M hydrochloric acid (0.19 mL), the mixture was stirred for 5 min, and the solvent was evaporated under reduced pressure. The residue was recrystallized (ethanol/diisopropyl ether) to give the title compound (35 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH:14]([CH3:19])[CH2:13]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]3[CH:14]([CH3:19])[CH2:13][N:12]([CH3:11])[CH2:17][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1CN(C)CCC1=O
Reactant: Clc1ccc2cc[nH]c2c1
Product: CC1CN(C)CC=C1c1c[nH]c2cc(Cl)ccc12
Yield: 62.9 %

Procedure:
Beginning with 0.97 gm (6.4 mMol) 6-chloro-1H-indole and 1.6 gm (13.0 mMol) 1,3-dimethyl-4-piperidone, 1.05 gm (63%) of the title compound were recovered as a crystalline solid.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]1[O:23][CH2:22]1.O>CO>[OH:23][CH2:22][CH2:21][N:12]1[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:11]1
Reactant: C1CO1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Solvent: CO
Solvent: O
Product: OCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reaction time: 3 h

Procedure:
The starting material is obtained as follows. The solution of 13.35 g of 4-diphenylmethoxypiperidine in 40 ml of methanol, containing 3.52 g of ethylene oxide and 0.9 ml of water, is stirred and heated in an oil bath at 42°-44° for 4 hours. The bath temperature is raised to 50° and heating and stirring are continued for an additional 3 hours. The solution is then evaporated and the residue taken up in 1 N hydrochloric acid and washed with diethyl ether. The aqueous solution is made basic with 50% aqueous sodium hydroxide and repeatedly extracted with diethyl ether. The extract is washed with brine, dried and evaporated to give the 1-(2-hydroxyethyl)-4-diphenylmethoxypiperidine, melting at 83°-85° after recrystallization from cyclohexane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C(#N)C.[Cl:11][CH2:12][C:13](Cl)=[O:14]>ClCCCl>[Cl:11][CH2:12][C:13]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)=[O:14]
Reactant: O=C(Cl)CCl
Reactant: Nc1cncnc1
Solvent: ClCCCl
Solvent: CC#N
Product: O=C(CCl)Nc1cncnc1
Temperature: 80 °C

Procedure:
5-Aminopyrimidine (450 mg) was suspended in DCE (2 mL) and acetonitrile (2 mL) in a microwave vial. Chloroacetyl chloride (0.377 mL) was added with stirring. The vial was sealed and the reaction mixture was heated in the microwave at 80° C. for 5 minutes. The solid was filtered off, washed with acetonitrile (2×5 mL), DCE (2×5 mL) and pentane (2 ×30 mL) and then partioned between saturated sodium bicarbonate and DCE (50 mL/50 mL) ensuring the aqueous layer was still basic. The organic layer was separated and the aqueous layer was extracted with DCE (2×75 mL). The combined organic layer was dried over magnesium sulfate and evaporated to give the sub-titled compound (200 mg) as a yellow solid.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:6]([O:8]N1C(=O)CCC1=O)=O)[CH:3]([CH3:5])[CH3:4].[NH2:23][C@H:24]([C:28]([OH:30])=[O:29])[CH:25]([CH3:27])[CH3:26].CCN(CC)CC>CN(C=O)C>[NH:1]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:2]([C:6]([NH:23][C@H:24]([C:28]([OH:30])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)[C@H](N)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)O

Procedure:
Boc-Val-OSu (12.6 g, 40 mmol) and H-Val-OH (4.68 g, 40 mmol) were condensed in DMF (250 ml) for 96 hours in the presence of 2 ml Et3N. More Et3N was added when needed to maintain the reaction slightly basic. The remaining insoluble material was filtered off and the filtrate evaporated to dryness (45°). The residue was partitioned between ether and dilute H2SO4 (~1%) and the organic layer washed with water (3×), dried over Na2SO4 and evaporated to a foamy glass. The product was crystallized from ether and petroleum ether: Yield, 12.2 g (96.4 %); mp 155°-158°; [α]D25 = +1.10° (c 1, DMF.
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])([CH3:20])[O:4][C:5]2[CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:6]=2[C:7]=1[OH:8].[OH-].[Na+].O>O1CCOCC1>[O:8]1[CH:7]2[CH:2]1[C:3]([CH3:21])([CH3:20])[O:4][C:5]1[CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:6]=12
Reactant: COCOc1cc2c(cc1[N+](=O)[O-])C(O)=C(Br)C(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COCOc1cc2c(cc1[N+](=O)[O-])C1OC1C(C)(C)O2
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 3-bromo-7-methoxymethoxy-2,2-dimethyl-6-nitro-1-benzopyran-4-ol (550 mg, 1.52 mmol) in dioxane (5.5 mL), 1 mol/L sodium hydroxide aqueous solution (1.82 mL, 1.82 mmol) was added at room temperature, and the resulting mixture was stirred for 2 hours. Upon the completion of the reaction, water was added thereto, the resulting solution was extracted with ethyl acetate, washed with saturated sodium thiosulfate aqueous solution and then with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=4/1) and the aimed product was obtained (yield: 78%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[CH:20]=O.N1CCCCC1>C(O)C>[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[CH:20]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1cc2ccccc2[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccccc2C1=Cc1cc2ccccc2[nH]1
Temperature: 95 °C

Procedure:
A mixture of 2-oxindole (133 mg), indole-2-carbaldehyde (174 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (10 mg) in ethanol was heated in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in vacuum oven for overnight to give 3-(1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:6][N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([CH:24]=[O:25])[CH:21]=[N:20]2)=[CH:15][CH:14]=1.C[Si](C)(C)[C:34]([F:37])([F:36])[F:35].[F-].[Cs+].Cl>ClCCl>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:6][N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([CH:24]([OH:25])[C:34]([F:37])([F:36])[F:35])[CH:21]=[N:20]2)=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)c1cn(Cc2ccc(-n3cc(C=O)cn3)cc2)c2cccc(F)c2c1=O
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Product: CCOC(=O)c1cn(Cc2ccc(-n3cc(C(O)C(F)(F)F)cn3)cc2)c2cccc(F)c2c1=O
Reaction time: 3 h

Procedure:
To a solution of ethyl 5-fluoro-1-[4-[4-formyl-1H-pyrazol-1-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.100 g, 0.238 mmol) in 2 mL of dichloromethane was added trimethyl(trifluoromethyl)silane (0.045 g, 0.25 mmol) and cesium fluoride (3.6 mg, 0.024 mmol). After 3 hours, 4 N HCl (0.36 mL, 1.4 mmol) was added. After 1 hour, the reaction mixture was diluted with an additional 20 mL dichloromethane and washed with water and brine. The organic extracts were dried, filtered and concentrated in vacuo to provide the title compound (crude) which gave a mass ion (ES+) of 489.9 for M+H+. This compound could be further hydrolyzed to the corresponding carboxylic acid, as described in Example 1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N:24]2[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=3)[CH:14]=2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:38]([F:55])([F:54])([O:43][C:44]([F:53])([F:52])[C:45]([S:48](F)(=[O:50])=[O:49])([F:47])[F:46])[C:39]([F:42])([F:41])[F:40]>CN(C)C=O>[F:47][C:45]([F:46])([S:48]([O:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:9]3[CH:8]=[C:7]([N:24]4[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]4=[O:31])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]=3[O:11][CH3:12])[CH:14]=2)[CH:19]=1)(=[O:50])=[O:49])[C:44]([F:52])([F:53])[O:43][C:38]([F:54])([F:55])[C:39]([F:42])([F:41])[F:40]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Reactant: COc1c(-c2ccc3cc(O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(-c2ccc3cc(OS(=O)(=O)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C

Procedure:
To a stirred solution of 0.53 g of 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (1.27 mmol, 1.0 equivalent) in 5 mL of N,N-dimethylformamide was added 0.35 g of 325-mesh potassium carbonate (2.6 mmol, 2.0 equivalents). Perfluoro(2-ethoxyethane)sulfonyl fluoride (0.46 g, 1.4 mmol, 1.1 equivalents) was added in one portion, and the mixture was stirred for an hour. The inorganic solids were separated by filtration, and the flask and filter cake were rinsed with 1 mL of N,N-dimethylformamide followed by 2 mL of ethyl acetate. The solution was diluted with 30 mL of ethyl acetate and the resultant solution was washed twice with 20 mL portions of 10 wt % aqueous sodium chloride, followed by 20 mL of saturated aqueous sodium chloride solution. The washing procedure was repeated once. The organic solution was dried over sodium sulfate, the drying agent was filtered off and the organic solution was concentrated in vacuo. The resultant solid was purified by chromatography over silica gel with gradient elution (30% ethyl acetate/hexanes to 60% ethyl acetate/hexanes). The title compound was isolated as a white solid (0.76 g, 84% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.54 (d, J=1.7 Hz, 1H), 8.04 (s, 1H), 7.95 (d, J=9.4 Hz, 1H), 7.92 (d, J=10.1 Hz, 1H), 7.83 (dd, J=8.5, 1.7 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.40 (dd, J=9.0, 2.5 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.27-7.23 (m, 2H), 5.81 (dd, J=7.9, 2.4 Hz, 1H), 3.29 (s, 3H), 1.46 (s, 9H). 13C NMR (101 MHz, CDCl3) δ ppm 162.6 (C), 157.5 (C), 149.8 (C), 147.1 (C), 145.0 (C), 144.5 (CH), 137.2 (C), 135.1 (C), 133.0 (C), 132.2 (C), 132.2 (C), 130.5 (CH), 128.5 (CH), 128.1 (CH), 127.4 (CH), 127.2 (CH), 124.4 (CH), 119.9 (CH), 118.9 (CH), 102.4 (CH), 60.9 (CH3), 35.8 (C), 30.8 (CH3). 19F NMR (564 MHz, CDCl3) δ ppm −81.61 (2F), −86.42 (3F), −88.11 (2F), −112.90 (2F). LC-MS m/z 715.0 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>>[C:1]1([S:7]([N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][CH:26]4[CH2:27][O:28]4)[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1c2ccccc2c2c(O)cccc21
Reactant: ClCC1CO1
Product: O=S(=O)(c1ccccc1)n1c2ccccc2c2c(OCC3CO3)cccc21

Procedure:
reaction of 9-benzenesulfonyl-9H-carbazol-4-ol with epichlorohydrin under basic conditions to give 9-benzenesulfonyl-4-oxiranylmethoxy-9H-carbazole;
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[CH:6][CH:5]=2.ClC1C(=O)C([C:36]#[N:37])=C(C#N)C(=O)C=1Cl.Cl[CH2:40]Cl>C(OCC)(=O)C>[NH:1]=[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=2)[C:9]2[C:4](=[CH:5][C:6]([N:37]([CH3:36])[CH3:40])=[CH:7][CH:8]=2)[O:3]1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: ClCCl
Reactant: COc1cc(C2C(C#N)=C(N)Oc3ccccc32)cc(Br)c1OC
Solvent: CCOC(C)=O
Product: COc1cc(-c2c(C#N)c(=N)oc3cc(N(C)C)ccc23)cc(Br)c1OC
Reaction time: 0.25 h
Yield: 79 %

Procedure:
4 Å Molecular sieves (20 mg) were added to 2-amino-3-cyano-4-(3-bromo-4,5-dimethoxyphenyl)-4H-chromene (20 mg, 0.05 mmol) in dichloromethane (1 mL). The solution was stirred for approximately 15 min. Then 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (10 mg, 0.05 mmol, 1 eq.) was added and stirred continuously at room temperature for approximately 1 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL) and brine (20 mL), and dried over sodium sulfate and concentrated to yield 17 mg (79%) of the desired compound. 1H NMR (DMSO-d6): 8.33 (s, 1H), 7.28 (d, J=1.9 Hz, 1H), 7.21 (d, J=1.9 Hz, 1H), 6.87 (d, J=9.1 Hz, 1H), 6.56 (dd, J=2.5, 9.1 Hz, 1H), 6.40 (d, J=2.5 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.03 (s, 6H).