Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].CN(C=O)C.[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[O:3]=[C:2]([CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:1]=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=CC(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
Phenylpyruvic acid (25.0 g, 152.0 mmol) was coevaporated twice with dry pyridine and then redissolved in dry pyridine (250 mL). To this solution was added acetic anhydride (170 mL, 1.8 moles) and the solution was stirred at ambient temperature for 15 h. The reaction progress was monitored by TLC. When the reaction was complete, the solution was evaporated to a viscous syrup. The syrup was dissolved in dichloromethane (700 mL) and then washed three times with 0.1 M aqueous HCl solution (3×200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to an amber-colored syrup. This product was purified by flash chromatography on silica gel (250 g) using dichloromethane as mobile phase. Appropriate fractions were pooled and evaporated to afford 24 g of a dry solid. This material was dissolved in THF (150 mL) and the solution was cooled in an ice-water bath. To the solution was added dropwise oxalyl chloride (51 mL, 580 mmol). After 10 min DMF (7.5 mL) was added to the reaction mixture and the reaction was stirred for 4 h at 0° C. Toluene (100 mL) was added and the reaction mixture was evaporated to give a thick oil. This material was coevaporated twice with toluene and the crude product was dried under vacuum for 5 h. The dried product was dissolved in a 1:1 mixture of THF-dichloromethane (200 mL) and the solution was cooled to −78° C. (dry ice-isopropanol bath) under argon. Then, lithium tri-tert-butoxyaluminohydride (152 mL of a 1.0 M solution in THF, 152 mmol) was added at a rate such that the internal temperature of the reaction was below 60° C. After addition was complete, the reaction was stirred below −60° C. for 10 h. The reaction was quenched by the slow addition of 2 M aqueous HCl solution (100 mL) and the mixture was allowed to warm to ambient temperature. The reaction mixture was diluted with dichloromethane (500 mL) and then washed twice with 0.1 M aqueous HCl solution (2×100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to give an amber-colored syrup. This material was purified by flash chromatography on silica gel (250 g) starting with 95:5 heptane-ethyl acetate, then with 9:1 heptane-ethyl acetate as mobile phase. Appropriate fractions were pooled and evaporated to afford 13.5 g (80%) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:11](=[N:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(C#N)ccc1N
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)ccc1N=C(c1ccccc1)c1ccccc1
Reaction time: 24 h
Yield: 90.3 %

Procedure:
To a solution of 4-amino-3-methyl benzonitrile (1.20 g, 9.08 mmol) in 75 mL of toluene is added benzophenone (1.74 g, 9.53 mmol) and p-toluenesulfonic acid (0.43 g, 2.1 mmol). The reaction vessel is fitted with a Dean-Stark trap and the solution is heated at reflux. After 24 h, the solution is cooled to ambient temperatures. The solution is concentrated. The crude material is purified by column chromatography eluting with a gradient of 3% EtOAc/hexanes to 10% EtOAc/hexanes. The title compound (2.43 g, 8.2 mmol) is obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:6]([C:18]2[CH:19]=[C:14]([Cl:13])[N:15]=[CH:16][N:17]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(-n2c(Cl)nc3ccccc32)ncn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To the solution of 2-Chloro-1H-benzoimidazole (3.0 g, 19.67 mmol) in 10 mL DMF at 0° C. under argon atmosphere is added with sodium hydride (60% dispersion in mineral oil, 1.18 g, 29.5 mmol) portion wise. After 20 minutes, 4,6-dichloro-pyrimidine (3.3 g, 22.1 mmol) is added. The resulting reaction mixture is allowed to warm to room temperature and stirred overnight. The reaction mixture is treated with 120 mL water and extracted three times with 100 mL dichloromethane. The organic extracts are washed with brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (0% EtOAc/hexanes to 20% EtOAc/hexanes gradient), affords the title compound as a white powder: Rf=0.35 (20% EtOAc/hexanes); 1H NMR 400 MHz (DMSO-d6) δ 9.26 (s, 1H), 8.25 (s, 1H), 7.80-7.72 (m, 2H), 7.43-7.37 (m, 2H); MS m/z 265.1 (M+1).
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[C:4]([C:12]([OH:14])=[O:13])=[CH:5][N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8].[F:16][CH:17]([F:27])[C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CO>[F:16][CH:17]([F:27])[C:18]1[CH:23]=[C:22]([C:2]2[C:3](=[O:15])[C:4]([C:12]([OH:14])=[O:13])=[CH:5][N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=2[CH3:8])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)C
Reactant: OB(O)c1cccc(C(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: Cc1c(-c2cccc(C(F)F)c2)c(=O)c(C(=O)O)cn1C(C)C
Temperature: 75 °C

Procedure:
A mixture of 5-bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 3c, 3.00 g, 8.32 mmol, based on 76% purity), 3-(difluoromethyl)-phenylboronic acid (2.30 g, 13 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (690 mg, 0.94 mmol) and 2 M aqueous K2CO3 solution (10 mL, 20 mmol) in acetonitrile (20 mL) is heated for 2 h at 75° C. The reaction mixture is diluted with methanol and purified by preparative reversed phase HPLC (XBridge, gradient of acetonitrile in water, 0.3% NH4OH, 30° C.). Yield: 1.46 g (55% of theory); ESI mass spectrum: [M+H]+=322; Retention time HPLC: 0.92 min (Z018_S04).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.COC1C=CC(C[N:16]([C:35]2[CH:36]=[N:37][C:38]3[C:43]([CH:44]=2)=[CH:42][CH:41]=[C:40]([O:45]CC2C=CC=CC=2)[CH:39]=3)[C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)[CH:19]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:45][C:40]1[CH:39]=[C:38]2[C:43]([CH:44]=[C:35]([NH:16][C:17](=[O:34])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)[CH:19]=3)[CH:36]=[N:37]2)=[CH:42][CH:41]=1
Reactant: COc1ccc(CN(C(=O)c2ccc(OC)c(-c3cccc(OC)c3)c2)c2cnc3cc(OCc4ccccc4)ccc3c2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2cc(C(=O)Nc3cnc4cc(O)ccc4c3)ccc2OC)c1
Yield: 42.5 %

Procedure:
Trifluoromethanesulfonic acid (120 μl, 204 mg, 1.36 mmol) was added to 32 (184 mg, 0.30 mmol) in 1:1 CH2Cl2:TFA (1.36 mL) and the solution was stirred at room temperature for two hours. The resulting solution was diluted with CH2Cl2 (100 mL), washed with saturated aqueous NaHCO3 (3×50 mL), saturated aqueous NaCl solution (2×50 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 100:1 EtOAc:MeOH to 4:1 EtOAc:MeOH) to give 34 as a yellow oil (51 mg, 43%): 1H NMR (CD3OD, 500 MHz) δ 9.01 (bs, 1H), 8.61 (bs, 1H), 8.02 (dd, J=8.5, 1.7 Hz, 1H), 7.97 (d, J=1.9 Hz, 1H), 7.74 (d, J=8.9 Hz, 1H), 7.30 (t, J=8.2 Hz, 1H), 7.27 (d, J=1.9 Hz, 1H), 7.19 (dd, J=8.9, 2.1 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.11-7.08 (m, 2H), 6.89 (m, 1H), 3.88 (s, 3H), 3.81 (s, 3H); 3C NMR (CD3OD, 125 MHz) δ 168.7, 161.2, 160.9, 160.2, 147.1, 146.2, 140.5, 132.0, 132.0, 131.5, 130.4, 130.2, 130.1, 128.5, 127.6, 124.2, 123.2, 121.5, 116.5, 113.8, 112.4, 109.7, 56.5, 55.9; IR (film) νmax 3281, 3203, 2930, 2835, 1605, 1545, 1499, 1371, 1252, 1036, 764, 735 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C24H20N2O4, 401.1501; found, 401.1481.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]=[C:5]=[O:6].[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]([N:11]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH:12]=[CH:13][CH:14]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C=NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1NCCN1c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Chloro-2-isocyanatoethane (1.18 mL, 13.8 mmol) was added dropwise to a solution of 3-bromoaniline (1.5 mL, 13.8 mmol) in DMF (30 mL) at 0° C. then stirred at room temperature for 16 hr, then 70° C. for 2 hr. The solution was cooled to room temperature and 1-chloro-2-isocyanatoethane (0.40 mL, 4.69 mmol) was added. After stirring at room temperature for 2 hr, the solution was diluted with DMF (120 mL), cooled to 0° C. and NaH (660 mg, 60% dispersion in mineral oil, 16.5 mmol) added in portions. The mixture was stirred at room temperature for 64 hr, then diluted with EtOAc. After washing with H2O three times then brine the solution was dried over Na2SO4, concentrated in vacuo and the residue purified by silica gel chromatography (EtOAc/hexanes) to give 1-(3-bromophenyl)-2-imidazolidinone as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.56-3.62 (m, 2H), 3.88-3.92 (m, 2H), 5.20 (br s, 1H), 7.15-7.20 (m, 2H), 7.49-7.51 (m, 1H), 7.71 (s, 1H).
Reaction SMILES: [CH:1]1([NH:4][CH:5]=[C:6]([C:12]([C:14]2[C:15](Cl)=[N:16][C:17]([Cl:21])=[C:18]([F:20])[CH:19]=2)=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[H-].[Na+].O>O1CCCC1>[Cl:21][C:17]1[N:16]=[C:15]2[C:14]([C:12](=[O:13])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[CH:19][C:18]=1[F:20]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.2 %

Procedure:
The solution of 3.0 g of ethyl 3-cyclopropylamino-2-(2,6-dichloro-5-fluoropyridine-3-carbonyl)acrylate in 36.4 ml of anhydrous tetrahydrofuran was cooled to 10° C. 0.36 g (1.05 eq.) of 60% sodium hydride was added to the reaction mixture, which was then stirred for 18 hours at room temperature. The reaction mixture was cooled to 5˜10° C. 36.4 ml of water was added to the reaction mixture, which was then stirred for 30 minutes. The organic layer was filtered under a reduced pressure and washed with water. The resulting wet cake was dried under a reduced pressure at 50° C. for 5 hours to give 2.34 g of ethyl 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (Yield: 87.3%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N:18]1[C:26](=[O:27])[C:25]2[C@@H:24]3[C:28]([CH3:30])([CH3:29])[C@@:21]([CH3:31])([CH2:22][CH2:23]3)[C:20]=2[NH:19]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N:18]1[C:26](=[O:27])[C:25]2[C@@H:24]3[C:28]([CH3:30])([CH3:29])[C@@:21]([CH3:31])([CH2:22][CH2:23]3)[C:20]=2[N:19]1[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCc1ccccc1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1CCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
A mixture of (2-bromoethyl)benzene (200 μL, 1.46 mmol), (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 100 mg, 0.33 mmol) and tetra-n-butylammonium iodide (94 mg, 0.25 mmol) in N,N-dimethylformamide (1 mL) was heated in a pressure tube in an oil-bath at 100° C. for 18 h. Additional portions of (2-bromoethyl)benzene (200 μL, 2.2 mmol) and tetra-n-butylammonium iodide (100 mg, 0.27 mmol) were added and the reaction mixture was heated at 100° C. for 3 days, and then allowed to stand overnight at room temperature. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (5×25 mL) and sodium thiosulfate solution (25 mL), dried (magnesium sulfate), filtered, and evaporated and the residue was purified on an Isco 40 g column, eluting with 40-100% ethyl acetate/hexanes to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-phenethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (37 mg, 28%) as a pale yellow oil that solidified on standing. ES(+)-MS (M+H) 409.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(CC)=O>[CH2:3]([N:15]([C:7]1[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=1[Br:5])[S:16]([CH3:19])(=[O:17])=[O:18])[CH:2]=[CH2:1]
Reactant: C=CCBr
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: C=CCN(c1cc([N+](=O)[O-])ccc1Br)S(C)(=O)=O
Yield: 99.8 %

Procedure:
Allyl bromide (1.36 g, 11.25 mmol) was added to a mixture of N-(2-bromo-5-nitrophenyl)methanesulfonamide (1.66 g, 5.62 mmol) and cesium carbonate (5.49 g, 16.86 mmol) in methylethylketone (20 ml). The mixture was heated to reflux for 2 hr. The mixture was cooled and poured onto water. The product was extracted into ethyl acetate (2×75 ml) and the extracts were dried (anhydrous MgSO4) and concentrated to provide 1.88 g of N-allyl-N-(2-bromo-5-nitrophenyl)methanesulfonamide which required no purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]=1[C:38](Cl)=[O:39]>>[CH3:26][C:27]1[O:31][N:30]=[C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]=1[C:38]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH:15]=2)[CH2:10][CH2:9]1)=[O:39]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCO)CC2)c1
Product: Cc1onc(-c2ccccc2)c1C(=O)OCCCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(6-hydroxyhexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride: ESMS m/e: 532.1 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:9]=[C:8]([CH2:18][CH2:19][CH3:20])[N:7]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[O:15]1[CH2:14][CH2:13][N:12]([C:10]2[N:9]=[C:8]([CH2:18][CH2:19][CH3:20])[N:7]=[C:6]([NH:5][C:1](=[O:3])[CH3:2])[N:11]=2)[CH2:17][CH2:16]1
Reactant: CC(=O)Cl
Reactant: CCCc1nc(N)nc(N2CCOCC2)n1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCc1nc(NC(C)=O)nc(N2CCOCC2)n1
Reaction time: 6 h
Yield: 43.3 %

Procedure:
4 g (0.05 mole) of acetyl chloride are added dropwise into a solution of 11.2 g (0.05 mole) of 2-amino-4-morpholino-6-propyl-1,3,5-triazine in 100 ml of anhydrous pyridine at room temperature. The mixture is stirred for 6 hours and then allowed to stand for 48 hours. The pyridine hydrochloride is filtered off and the filtrate is evaporated under reduced pressure. The residue obtained is taken up once in toluene, and the mixture is evaporated again. The residue is then taken up in dichloromethane and the solution is washed with water and dried over sodium sulfate. The residue obtained after evaporation of the solvent is purified by chromatography over silica (eluent: 90:10 v/v) dichloromethane-ethanol) and the product is finally recrystallized from ethyl acetate. 5.75 g of N-(4-morpholino-6-propyl-1,3,5-triazin-2-yl)-acetamide are obtained. Yield: 43.4%. M.P.: 141°-142° C. (Compound 21a). Hydrochloride: M.P.: 145°-146° C. (isopropyl alcohol-ether). (Compound 21b).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1C(O)=O.CS(C)=O>O>[F:12][C:8]1[CH:9]=[C:10]([F:11])[C:2]([F:1])=[CH:3][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1c(F)cc(F)c(F)c1C(=O)O
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 27.5 h

Procedure:
A 250 mL single-neck flask equipped with a condenser and a magnetic stirrer was charged with 30.00 g of 3,4,6-trifluorophthalic acid, and 200 mL of dimethyl sulfoxide. The reaction mixture was then heated with stirring for 27.5 hr. at a bath temperature of 149° C. The flask was then allowed to cool to room temperature and the contents were poured into 500 mL of water, and extracted with 4×200 mL of ethyl acetate. The combined organic extracts were washed with water (2×200 mL), dried over magnesium sulfate, filtered, and the solvent removed on a rotary evaporator followed by drying at the pump overnight. The crude product was then dissolved in 25 mL of ethyl acetate and introduced at the top of a silica column (4.5 cm ID×56 cm, flushed with hexane). The product was then eluted with 90:10 hexane:ethyl acetate under a slight nitrogen pressure, and the fractions (500 mL each) were monitored by gas chromatography. The fractions containing the product were combined, the solvent removed on a rotary evaporator, and then dried at the pump overnight to give 2,4,5-trifluorobenzoic acid as a light yellow solid. Recrystallization of the product from toluene (50 mL, ca. 60° C.) gave a white product (66.9% overall yield).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.CO[CH:11]1[CH2:15][CH2:14][CH:13](OC)O1>C(O)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH:11]=[CH:15][CH:14]=[CH:13]2)=[CH:4][CH:3]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc(F)cc1
Solvent: CC(=O)O
Product: Fc1ccc(-n2cccc2)cc1
Temperature: 0 °C
Yield: 72.4 %

Procedure:
4-Fluoroaniline (117 g) and 2,5-dimethoxytetrahydrofuran (139 g) were added to acetic acid (120 ml), stirred at reflux temperature for an hour and then the reaction solution was poured into ice water (1 l). The precipitated solid was filtered, dissolved in methanol and water was added therein. The precipitated solid was collected again by filtration to give 1-(4-fluorophenyl)pyrrole (122.7 g).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[C:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])[CH3:26]>>[C:25]([C:28]1[CH:33]=[CH:32][C:31]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)=[CH:30][CH:29]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: CC(=O)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 29.9 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 4-acetylphenylboronic acid (available from Combi-Blocks Inc.; 66 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4′-acetyl-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (28 mg, 30%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.23 (br s, 1H), 8.48 (s, 1H), 8.40 (d, J=1.5 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.25 (dd, J=8.0, 2.0 Hz, 1H), 8.10 (dd, J=8.3, 2.0 Hz, 1H), 8.03 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.5 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.3 Hz, 2H), 2.63 (s, 3H).
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=[CH:11][C:10]=1[N:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=[CH:11][C:10]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3ccccn3)cc2Cl)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(N2CCNCC2)c(Cl)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
According to Scheme 5 Step 4: HCl 4 M in dioxane (12.3 mmol, 3.07 mL) was added to a solution of tert-butyl 4-(2-chloro-4-(picolinamido)phenyl)piperazine-1-carboxylate (2.46 mmol, 1.02 g) in DCM (10 mL). The reaction mixture was stirred at room temperature overnight. After evaporation, DCM was added and then a NaOH 1 M solution. The aqueous phase was extracted with DCM. The organic phase was washed with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (60:40) as eluent to afford N-(3-chloro-4-(piperazin-1-yl)phenyl)picolinamide (0.97 mmol, 308 mg, 40%) as an orange solid.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:18][CH2:19][N:20]([CH2:3][CH2:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][CH:6]=2)[CH2:21][CH2:22]1
Reactant: Nc1ncc(CCCl)s1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(CCN2CCN(c3ccccn3)CC2)s1
Reaction time: 18 h

Procedure:
A mixture of 5.84 g of 5-(2-chloroethyl)-2thiazolamine, monohydrochloride (Example C), and 5.27 g of 1-(2-pyridyl)piperazine in 100 ml of dimethylformamide containing 12.3 g of sodium bicarbonate is stirred at 80°-90° C. for 18 hours. The mixture is filtered and the filtrate concentrated to dryness. Chromatography (medium-pressure liquid chromatography, silica gel, 5% methanol-95% chloroform) of the resulting oil affords 5-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]-2-thiazolamine as a tan solid; mp 158°-161° C.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)\[C:11](=[NH:15])[N:12]([OH:14])[CH3:13])[N:6]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>C(#N)C>[Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)\[C:11]2[N:12]([CH3:13])[O:14][C:22](=[O:23])[N:15]=2)[N:6]=1
Reactant: CN(O)C(=N)/C(=N\OCc1csc(Br)n1)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cn1oc(=O)nc1/C(=N\OCc1csc(Br)n1)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
To a solution of (2Z)-2-{[(2-bromo-1,3-thiazol-4-yl)methoxy]imino}-N-hydroxy-N-methyl-2-phenylethanimidamide (1.8 g, 4.87 mmol, 1 eq.) in acetonitrile (120 ml), was added 1,1′-carbonyldiimidazole (1.58 g, 9.75 mmol, 2 eq.). After stirring at 80° C. for 1 hour, the reaction was quenched by addition of water (100 ml) and extracted with EtOAc (2×100 ml). The organics were combined, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give 3-[(Z)-{[(2-bromo-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-2-methyl-1,2,4-oxadiazol-5(2H)-one (2 g, 100% yield).