Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26]N)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>C(O)C.O>[CH2:12]([O:19][C:20]1[CH:25]=[C:24]2[C:23](=[CH:22][CH:21]=1)[NH:26][C:6]1[CH2:7][CH2:8][CH:3]([N:2]([CH3:10])[CH3:1])[CH2:4][C:5]2=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: CN(C)C1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: CN(C)C1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Reaction time: 18 h
Yield: 24.9 %

Procedure:
To a solution of 3.78 gm (26.8 mMol) 4-dimethylamino-1-cyclohexanone and 6.69 gm (26.8 mMol) 4-benzyloxyphenylhydrazine hydrochloride in 50 mL ethanol were added 2.17 mL (26.8 mMol) pyridine. To this solution were added 5×10 mL portions of water and the reaction mixture then stored at 0° C. for 18 hours. The reaction mixture was then diluted with an additional 50 mL of water and the mixture extracted well with dichloromethane. The combined organic extracts were dried over sodium sulfate and the volatiles removed under reduced pressure. The residual oil was subjected to flash silica gel chromatography, eluting with 9:1 chloroform:methanol. Fractions shown to contain the desired product were combined and concentrated under reduced pressure to give 2.14 gm (24.9%) of the title compound.
Reaction SMILES: Cl.[CH3:2][N:3](C)[CH2:4]CCN=C=NCC.[C:13]([NH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=1)(=[O:15])[CH3:14].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.CN[C:45]1[CH:46]=[C:47]([C:51]2[CH:56]=[CH:55][C:54]([CH:57](C)[CH:58]3[S:62][C:61](=[O:63])[NH:60][C:59]3=[O:64])=[CH:53][CH:52]=2)[CH:48]=[CH:49][CH:50]=1>ClCCl>[C:13]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([N:3]([CH2:4][C:45]2[CH:46]=[C:47]([C:51]3[CH:52]=[CH:53][C:54]([CH2:57][CH:58]4[S:62][C:61](=[O:63])[NH:60][C:59]4=[O:64])=[CH:55][CH:56]=3)[CH:48]=[CH:49][CH:50]=2)[CH3:2])=[O:23])=[CH:24][CH:25]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Reactant: CCN=C=NCCCN(C)C
Reactant: CNc1cccc(-c2ccc(C(C)C3SC(=O)NC3=O)cc2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(=O)N(C)Cc2cccc(-c3ccc(CC4SC(=O)NC4=O)cc3)c2)cc1
Reaction time: 18 h

Procedure:
320 mg (1.7 mmol) of 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride are added portionwise, at 0° C., to a solution of 270 mg (1.5 mmol) of 4-acetamidobenzoic acid, 230 μl (1.6 mmol) of triethylamine, 230 mg (1.7 mmol) of 1-hydroxybenzo-triazole and 500 mg (1.5 mmol) of 5-(3′-methylamino-methylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione in 5 ml of dichloromethane. The reaction medium is stirred at from 0° C. to room temperature for 18 hours, washed with saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 99/1 dichloromethane/methanol mixture. After evaporation of the solvents, 600 mg (80%) of 4-acetylamino-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbenzamide are obtained in the form of a white solid with a melting point of 207° C.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[O:19]=[C:20]1[CH2:25][CH:24]([CH2:26][C:27](O)=[O:28])[CH2:23][C:22](=[O:30])[NH:21]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:27](=[O:28])[CH2:26][CH:24]2[CH2:23][C:22](=[O:30])[NH:21][C:20](=[O:19])[CH2:25]2)[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(O)CC1CC(=O)NC(=O)C1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CC2CC(=O)NC(=O)C2)CC1
Temperature: 25 °C
Yield: 13 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (500 mg), (2,6-dioxopiperidin-4-yl)acetic acid (311 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (403 mg), 1-hydroxy-1H-benzotriazole monohydrate (322 mg), triethylamine (0.627 mL), and N,N-dimethylformamide (5 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to purification by high performance liquid chromatography [Column: Gilson, Ltd. High throughput purification system, YMC Combiprep ODS-A, S-5 μm, 50 mm×20 mm; Gradient cycle: H2O (contains 0.1% CF3COOH)-acetonitrile (contains 0.1% CF3COOH), 90:10 (0 min)-90:10 (1 min)-10:90 (4.2 min)-10:90 (5.4 min)-90:10 (5.5 min)-90:10 (5.6 min); Flow rate: 25 mL/min; detection wavelength: UV 220 nm] to give the title compound (47 mg, 13%) as a white solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([CH3:51])[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N:24]3[C:29](=[O:30])[C:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=5)=[CH:34][C:33]=4[F:46])=[C:27]([CH2:47][CH2:48][CH3:49])[N:26]=[C:25]3[CH3:50])[CH:20]=2)[O:15]1>C(OCC)(=O)C>[CH3:13][C:14]1([CH3:51])[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N:24]3[C:29](=[O:30])[C:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=5[C:44]5[NH:3][C:4](=[O:7])[O:5][N:45]=5)=[CH:34][C:33]=4[F:46])=[C:27]([CH2:47][CH2:48][CH3:49])[N:26]=[C:25]3[CH3:50])[CH:20]=2)[O:15]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)CCC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(-c2ccc3c(c2)CCC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
A mixture of hydroxylammonium chloride (0.91 g), sodium hydrogen carbonate (1.4 g) and dimethyl sulfoxide (7 mL) was stirred at 50° C. for 30 min, 4′-{[1-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.73 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (7 mL), N,N′-carbonyldiimidazole (0.34 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.42 g, 52%) as a colorless solid.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].CCN(CC)CC.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(Cl)Cl>[CH2:1]([NH:5][S:22]([C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=1)(=[O:23])=[O:24])[CH:2]([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of isobutylamine (5 mL, 0.052 mol) in CH2Cl2 (100 mL) was added Et3N (5.07 mL) and 4-nitrobenzenesulfonyl chloride (11.7 g, 0.052 mol) and the mixture was stirred at room temperature overnight. The resulting solution was washed with H2O (3×), dried and concentrated to afford the desired product (9.41 g, 70%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([OH:3])=[O:2].[CH3:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16]=1[CH:24]=O.N1CCCCC1>C(O)C>[CH3:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16]=1[CH:24]=[C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)[NH:9][C:8]1=[O:13]
Reactant: Cc1c(C=O)[nH]c2ccccc12
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C=C2C(=O)Nc3ccc(C(=O)O)cc32)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of 5-carboxy-2-oxindole (113 mg), 3-methylindole-2-carbaldehyde (56 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (30 mg) in ethanol (1 mL) was held in a sealed tube at 90° C. overnight. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 75 mg (58% yield) of 3-(3-methyl-1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid (piperidine salt).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH2:29][O:30][CH3:31]>C(Cl)Cl.O>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:33]([NH:32][C:23]3[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[C:21]([F:20])[CH:22]=3)=[O:34])=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: COCCOc1ccc(NC(=O)Oc2ccccc2)cc1F
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COCCOc1ccc(NC(=O)NCc2cc(C(F)(F)F)nn2-c2cccc(Cl)c2)cc1F
Reaction time: 16 h
Yield: 53.4 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (102 mg, 0.327 mmol, 1.0 eq.) in DCM (5.0 mL) was added TEA (1.36 mL, 0.981 mmol, 3.0 eq) followed by phenyl 3-fluoro-4-(2-methoxyethoxy)phenylcarbamate (100 mg, 0.327 mmol, 1.0 eq.) at RT and stirred for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL) and brine (5 mL), dried over anhydrous Na2SO4, and the solvent evaporated under vacuum. The crude product obtained was purified by neutral alumina column chromatography using MeOH/CHCl3 (1:9) as eluent to yield 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(2-methoxyethoxy)-phenyl)urea (example A18) (85 mg, 53%) as a white solid (TLC system: MeOH/CHCl3 (1:9), Rf: 0.5).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[CH2:19]=O>C(O)C>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1
Reactant: C=O
Reactant: O=C1COc2cc(O)ccc21
Reactant: CN1CCNCC1
Solvent: CCO
Product: CN1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
A solution of 6-hydroxybenzofuran-3(2H)-one (2.00 g, 13.3 mmol) in ethanol (25 mL) was added with N-methylpiperazine (1.33 g, 13.3 mmol), and 37% aqueous formaldehyde (1.08 g, 13.3 mmol) at room temperature. The mixture was stirred overnight at room temperature, and then subjected to suction filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 6-hydroxy-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (1.87 g, 54%).
Reaction SMILES: CC(C)([O-])C.[K+].CS(C)=O.[CH2:11]([O:18][CH2:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[C:31]12[O:42][CH2:41][CH2:40][CH2:39][O:38]1)(=[O:27])=[O:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[CH2:44][C:45]([CH3:49])([CH3:48])[C:46]#[N:47]>O>[CH2:11]([O:18][CH2:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH2:44][C:45]([CH3:49])([CH3:48])[C:46]#[N:47])[C:32](=[O:37])[C:31]12[O:38][CH2:39][CH2:40][CH2:41][O:42]1)(=[O:26])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C#N)CCl
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COCc3ccccc3)cc2C12OCCCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C#N)CN1C(=O)C2(OCCCO2)c2cc(S(=O)(=O)N3CCC[C@H]3COCc3ccccc3)ccc21
Temperature: 132 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
To a solution of potassium t-butoxide (3.58 g, 31.9 mmol, 1.2 eq) in anhyd DMSO (72 mL) was added 5′-({(2S)-2-[(benzyloxy)methyl]pyrrolidin-1-yl}sulfonyl)spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (12.20 g, 26.6 mmol ) all at one time under a dry N2 atmosphere. After stirring 20 minutes, 3-chloro-2,2-dimethylpropionitrile (9.38 g, 79.8 mmol, 3 eq) was added drop-wise and the reaction was heated at 132° C. for 21 hr. After cooling in an ice bath, the reaction mixture was poured into H2O and extracted with Et2O. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was purified on Biotage KP silica gel using a step gradient of CH2Cl2/CH3OH/NH4OH (99.25/0.5/0.25 to 96/2/1) to give the title compound as a yellow solid (9.48 g, 66% yield). NMR (400 MHz, DMSO-d6): consistent.
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH:4]([CH3:5])[CH2:3][CH2:2]1.Cl[C:9]1[C:10](Cl)=[C:11]([CH3:16])[C:12]([CH3:15])=[CH:13][CH:14]=1.CCOCC.[ClH:23]>C1COCC1.CS(C)=O>[Cl:23][CH2:15][C:12]1[CH:13]=[CH:14][CH:9]=[CH:10][C:11]=1[CH2:16][N:6]1[CH:4]([CH3:5])[CH2:3][CH2:2][C:1]1=[O:7]
Reactant: CC1CCC(=O)N1
Reactant: Cc1ccc(Cl)c(Cl)c1C
Reactant: Cl
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1CCC(=O)N1Cc1ccccc1CCl
Temperature: 25 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
A solution of γ-valerolactam (7 g, 70.5 mmol) in THF (150 mL) and DMSO (20 mL) was treated with Nail (2.83 g of a 60% oil dispersion) at 0° C. under nitrogen atmosphere. After a total of 15 min, α,α(-dichloro-o-xylene (25 g, 140 mmol) was added and the solution was allowed to warm and stir at room temperature. After 4 h, 100 mL of ether and 100 mL of 0.2N HCl were added. The water was withdrawn, and the organic layer was washed 2× more with water, dried (MgSO4), filtered and concentrated. This material was purified on ca. 400 g of silica gel (flash chromatography; EtOAc/hexane 7:3) to yield N-[2-(chloromethyl)benzyl]-γ-valerolactam (6.6 g, 40%). 1H NMR and mass spectral analysis supported the assigned structure. A solution of this lactam (5.0 g, 21.09 mmol), 2-(isopropoxy)phenylpiperazine fumarate (6.38 g, 18.99 mmol), and triethylamine (8.82 mL, 62.37 mmol)in DMF (75 mL) was heated for 3 h at 50°-60° C. After 3 h, the solution was added to a 3:1 solution of ether/ethyl acetate (ca. 100 mL) and extracted 3× with water, dried (MgSO4), filtered and concentrated. The residual oil was purified on ca. 400 g of silica gel (flash chromatography, EtOAc/hexane, 6:4) to give 5.41 g of white semi-solid, pure by thin layer chromatography. It was then dissolved in iPrOH, filtered through a Millipore filter, treated with 2.44 mL of conc. aqueous HCl (ca. 26 mmol), and then triturated out of solution by the addition of ether. The resultant white solid was recrystallized in MeOH/ether to give 1-[[2-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-piperidin-2-one hydrochloride (3:2) as a white powder (5.50 g, 61%), m.p. 249.5°-252.5° C. 1H NMR and mass spectral analysis supported the assigned structure.
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[F:20][C:21]1[CH:26]=[C:25]([I:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29]1[CH:37]=[N:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])[C:30]=1[C:31]([NH2:33])=O>O1CCOCC1>[F:20][C:21]1[CH:26]=[C:25]([I:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29]1[CH:37]=[N:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])[C:30]=1[C:31]#[N:33]
Reactant: NC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Product: N#Cc1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
Pyridine (28 μL, 0.35 mmol) and trifluoroacetic anhydride (27 μL, 0.19 mmol) were added to a solution of 3-(2-fluoro-4-iodo-phenylamino)-5-(2-fluoro-phenyl)-isonicotinamide (78 mg, 0.17 mmol) in dioxane (2 mL) at 0° C. The resulting solution was stirred for 3 h at room temperature. The reaction was quenched with 2M NaOH and stirred for 10 minutes. The reaction solution was diluted with EtOAc and satd. NH4Cl, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated to provide a precipitate. The precipitate was washed with MeOH and dried under vacuum to afford the desired product (60 mg, 80%). LC-MS (M+H=434, obsd.=434).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:11]([CH3:10])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CNc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN(c1ccccc1)c1ccc(C#N)cc1
Reaction time: 12 h
Yield: 91.7 %

Procedure:
The above general procedure was followed using 4-chlorobenzonitrile (137 mg, 1.00 mmol) and N-methylaniline (107 mg, 1.00 mmol) with 1 mol % Pd(dba)2 and 0.8 mol % tri-t-butylphosphine in 1.0 mL of toluene. After 12 hours, the reaction mixture was adsorbed onto silica gel and chromatographed with 10% ethyl acetate/hexanes to give 191 mg (92%) of N-(4-cyanophenyl)-N-methylaniline.
Reaction SMILES: [CH3:1][C:2]1([CH2:14][OH:15])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]1=[O:13].[CH:16]1[CH:21]=[C:20]2[C:22]([O:24][S:25](=[O:27])(=[O:26])[C:19]2=[CH:18][CH:17]=1)=[O:23].O>C(#N)C>[S:25]([C:19]1[CH:18]=[CH:17][CH:16]=[CH:21][C:20]=1[C:22]([O:15][CH2:14][C:2]1([CH3:1])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]1=[O:13])=[O:23])([OH:27])(=[O:26])=[O:24]
Reactant: O=C1OS(=O)(=O)c2ccccc21
Reactant: CC1(CO)CN(c2ccccc2)NC1=O
Solvent: O
Solvent: CC#N
Product: CC1(COC(=O)c2ccccc2S(=O)(=O)O)CN(c2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 4-methyl-4-hydroxymethyl-1-phenyl-3-pyrazolidinone (Dimezone-S®) (10 g, 48.5 mmol) in neat acetonitrile (200 ml), there is added 2-sulfobenzoic acid cyclic anhydride (8.9 g, 48.5 mmol) all at the same time, at room temperature, while stirring. The reaction mixture is heated to reflux under nitrogen until complete dissolution is observed. The process is continued for 24 hours and the mixture is cooled in a bath of ice and water for 2 hours. A solid precipitant is obtained that is collected by filtration and washed with acetonitrile cooled by means of ice. After drying under vacuum, 17.9 g (95%) of 4-methyl-3-oxo-l-phenyl-pyrazolidin-4-yl)methyl 2-sulfobenzoate (Compound II) is isolated in the form of a whitish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 37 °C

Procedure:
To a 2-liter, 3-necked, round-bottom flask is added 680 ml of concentrated H2SO4 and 400 g of p-chlorobenzoic acid. The mixture is stirred and brought to 0° C. by means of a constant temperature bath. A solution of concentrated HNO3 (216 ml) and concentrated H2SO4 (216 ml) is added dropwise to the reaction mixture at such a rate as to maintain the temperature between 10° C. and 25° C. Upon completion of the addition, the reaction temperature is raised to 37° C. and the mixture is allowed to stir for a period of 10-14 hours. The reaction mixture is then poured over crushed ice and the product, 4-chloro-3-nitrobenzoic acid, is filtered and dried, having a yield of 525.7 g or 98.7 percent with a melting point of 178° C.-180° C. This material is used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11](C1C=C(C3C=CC(C#N)=CC=3)C=C(F)C=1)[C:10]([CH3:32])([CH3:31])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH3:31][C:10]1([CH3:32])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH2:11]1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(-c3ccc(C#N)cc3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)CNc2ccc(C(=O)O)cc2C1
Temperature: 60 °C
Reaction time: 12 h
Yield: 69.6 %

Procedure:
A mixture of 2-(4′-cyano-5-fluoro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.15 g, 0.35 mmol), lithium hydroxide hydrate (0.15 g, 3.5 mmol), water (1 mL) in methanol (3 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 244′-cyano-5-fluoro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (50 mg, 36%) as a white solid: LC/MS m/e calcd for C25H21FN2O2 (M+H)+: 401.5, observed: 401.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20]([OH:22])=O)=[O:14])[N:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]=1)=[O:5])[CH3:2].CN(C(ON1N=NC2[CH:40]=[CH:41][CH:42]=[N:43][C:38]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.NCC1CC1>CN(C=O)C.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20](=[O:22])[N:43]([CH:42]2[CH2:40][CH2:41]2)[CH3:38])=[O:14])[N:8]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)O)n(-c2ccccc2)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)N(C)C2CC2)n(-c2ccccc2)n1

Procedure:
To a solution of 1.3 g 5-[2-((S)-2-carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester in 20 ml DMF were added 1.28 g HATU and 0.56 ml DIPEA. After 10 minutes 0.29 ml aminomethylcyclopropane were added. After 12 h the reaction mixture was diluted with dichloromethane and extracted with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent reaction. Yield: 1.45 g.