Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)C.[Br:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:15]([OH:17])=[O:16])=[CH:11][NH:12]2)=[CH:8][CH:7]=1>CO>[CH3:1][O:16][C:15]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([Br:5])=[CH:7][CH:8]=2)[NH:12][CH:11]=1)=[O:17]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1c[nH]c2cc(Br)ccc12
Solvent: CO
Product: COC(=O)c1c[nH]c2cc(Br)ccc12
Temperature: 65 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
Acetyl chloride (29.43 g, 374 mmol) is added slowly at room temperature to a solution of 6-bromo-indole-3-carboxylic acid (45 g, 187.46 mmol) in 500 mL of methanol and the resulting solution is stirred at 65° C. overnight. The reaction is cooled to room temperature. A white precipitates appears when cooling. After stirring 2 h at room temperature, the solid is filtered off and dried under vacuum. 34.4 g (72%) of the title compound is obtained as a light brown solid. MS (m/e): 254 (M+1)
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].I[C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1.[OH-].[Na+].[NH4+].[Cl-]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC=CC=1>[OH:4][CH2:1][C:2]#[C:3][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1
Reactant: Ic1ccc(-c2cccs2)s1
Reactant: C#CCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: c1ccccc1
Product: OCC#Cc1ccc(-c2cccs2)s1
Reaction time: 2 h
Yield: 74 %

Procedure:
To the mixture of 48 mg (0.86 mmole) of propargyl alcohol, 1 ml of benzene, 0.1 g of 5-iodo-2,2'-bithiophene (0.34 mmole) was added 0.25 g of CuI, 0.05 g of benzyltriethylammonium chloride and 0.1 g of Pd(PPh3)4. To the solution, 3 ml of NaOH solution (2.5 N) was added at room temperature and stirred for 2 hours. 4 ml of NH4Cl solution was then added. The reaction solution was extracted with 50 ml of ethyl acetate. The extract was washed with 10 ml of HCl (10%) for 3 times, 50 ml of water twice and dried over anhydrous magnesium sulfate. The residual solid was purified by silica gel column chromatography. From the eluate of ethyl acetate/n-hexane (3/1) 56 mg of product (74%) was obtained.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4([C:25]#[N:26])[CH2:24][CH2:23]4)=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][C:29]1[CH:30]=[N:31][C:32]2[N:33]([N:35]=[C:36]([CH:38]=O)[N:37]=2)[CH:34]=1>CO>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4([C:25]#[N:26])[CH2:23][CH2:24]4)=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH:9]([CH2:38][C:36]3[N:37]=[C:32]4[N:31]=[CH:30][C:29]([CH3:28])=[CH:34][N:33]4[N:35]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CC1
Reactant: Cc1cnc2nc(C=O)nn2c1
Solvent: CO
Product: Cc1cnc2nc(CC3C(=O)CC(CCc4ccc(C5(C#N)CC5)c(F)c4)(C4CCCC4)OC3=O)nn2c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 1-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile (568 mg, 1.54 mmol) in anhydrous MeOH (6.0 mL) was treated with 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (324 mg, 2.0 mmol), followed by borane-dimethylamine complex (118 mg, 2.0 mmol) at room temperature. The reaction was stirred for 1 hour before it was cooled to −10° C. for 2 hours. The precipitate was removed by filtration, and the filtrate was concentrated to an oil. The oil was purified by flash chromatography (50 g SiO2, 1:3->1:0 (93.5% ethyl acetate, 6% methanol, 0.5% acetic acid):(81.5% hexanes, 12% ethyl acetate, 6% methanol, 0.5% acetic acid)) to give the desired product as an oil. It was further purified by crystallization from ethyl acetate/hexanes to give a white powder (146 mg, 18%). 1H NMR (400 MHz, CDCl3) δ: 1.41-1.64 (m, 8H), 1.84-1.88 (m, 2H), 2.22-2.28 (m, 2H), 2.42 (s, 3H), 2.49-2.59 (m, 4H), 2.65-2.74 (m, 3H), 3.97-4.05 (m, 2H), 6.72-6.82 (m, 2H), 7.05-7.10 (m, 1H), 8.55 (s, 1H), 8.67 (s, 1H).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[CH3:5][N:6]([CH3:19])[C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[CH:10]=O.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:5][N:6]([CH3:19])[C:7]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[C:9]([CH:10]=[CH:4][N+:1]([O-:3])=[O:2])[CH:8]=1
Reactant: CN(C)c1cc(C=O)cc(C(F)(F)F)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CN(C)c1cc(C=C[N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 110 °C
Yield: 36.8 %

Procedure:
Nitromethane (0.473 g) is added to a solution of 3-dimethylamino-5-trifluoromethyl-benzaldehyde (0.885 g) and ammonium acetate (0.339 g) in acetic acid (3.4 mL) and the solution is heated at 110° C. for 6 hours. The reaction mixture is cooled to 0° C. and a solid forms which is filtered and washed with 1:1 water-acetic acid. This solid is recrystallized from ethanol to provide the desired product as a red solid (0.39 g).
Reaction SMILES: C([O:5][C:6](=[O:43])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29]([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[N:37]=[CH:36][CH:35]=[CH:34]3)=[O:30])[B:15]2[O:23]C3C(C)(C4CC(C3)C4(C)C)[O:16]2)[C:8]=1OC)(C)(C)C.B(Cl)(Cl)Cl>>[OH:16][B:15]1[CH:14]([NH:28][C:29]([C:31]2[CH:40]=[C:39]3[C:38](=[CH:33][CH:32]=2)[N:37]=[CH:36][CH:35]=[CH:34]3)=[O:30])[CH2:13][C:9]2[C:8](=[C:7]([C:6]([OH:5])=[O:43])[CH:12]=[CH:11][CH:10]=2)[O:23]1
Reactant: COc1c(CC(NC(=O)c2ccc3ncccc3c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: O=C(NC1Cc2cccc(C(=O)O)c2OB1O)c1ccc2ncccc2c1

Procedure:
Prepared from 2-Methoxy-3-[2-[(quinoline-6-carbonyl)-amino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic acid tert-butyl ester and BCl3 following the procedure described in Step 2 of Example 3. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 363.0 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1C[C@@H](OC)[C@H](F)[C@H]1C(O)=O)=O)(C)(C)C.ClC(N(C)C)=C(C)C.[F:45][C:46]1[C:52]([O:53][C:54]([F:57])([F:56])[F:55])=[CH:51][CH:50]=[CH:49][C:47]=1[NH2:48].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16](=[O:18])[NH:48][C:47]1[CH:49]=[CH:50][CH:51]=[C:52]([O:53][C:54]([F:55])([F:56])[F:57])[C:46]=1[F:45])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CO[C@H]1[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C[C@@H]1F
Reactant: Nc1cccc(OC(F)(F)F)c1F
Agent: CC(C)=C(Cl)N(C)C
Agent: CO[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)[C@H]1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CO[C@H]1[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2F)N(C(=O)OC(C)(C)C)C[C@@H]1F
Reaction time: 1 h

Procedure:
To a solution of (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (prepared as described in Scheme B25, 1.00 g, 3.80 mmol) in CH2Cl2 (10 mL) at 0° C. under nitrogen atmosphere was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (609 mg, 4.56 mmol) and the mixture was stirred at this temperature for 1 h. 2-Fluoro-3-(trifluoromethoxy)aniline (0.815 mg, 4.18 mmol) was then added, followed by DIPEA (1.327 mL, 7.60 mmol) and the mixture was stirred at RT for 1 h. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:0 to 1:1) to give (2S,3S,4S)-4-fluoro-2-(2-fluoro-3-trifluoromethoxy-phenylcarbamoyl)-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-d6) 2:1 mixture of rotamers δ (ppm): 10.15 (m, 1H), 7.87 (m, 1/3H), 7.77 (m, 2/3H), 7.31 (m, 2H), 5.29-5.11 (m, 1H), 4.76 (d, 1/3H), 4.70 (d, 2/3H), 4.29 (m, 1H), 3.80-3.53 (m, 2H), 3.39 (m, 3H), 1.39 (s, 3H), 1.31 (s, 6H). MS (UPLC-MS): 441 [M+H]+; tR (HPLC conditions f): 2.14 min.
Reaction SMILES: [CH:1]1(C(O)=O)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]([C:14]([OH:16])=[O:15])[CH2:3][NH:2]1.[ClH:20]>O>[ClH:20].[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]([C:14]([OH:16])=[O:15])[CH2:3][NH:2]1
Reactant: O=C(O)C1CNC(C(=O)O)c2[nH]c3ccccc3c21
Agent: Cl
Solvent: O
Product: O=C(O)C1CNCc2[nH]c3ccccc3c21
Temperature: 80 °C

Procedure:
Four (4) g; 0.16 mole of 1,2,3,4-tetrahydro-β-carboline-1,4-dicarboxylic acid (TR-8021) prepared in Example 1 was mixed with 40 ml concentrated HCl and 120 ml of water. The mixture was refluxed at 80° C. (oil-bath) for 2 hours. A white precipitate was collected by filtration, and washed with small amount of cooled water. The crude material was boiled in water, filtered through celite and cooled. The precipitate was collected and dried in the oven at 60° C. Yield: 3 g; (74%). MP 280°-281° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17](=[O:20])[CH2:16]2)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:21](=O)([O:25]CC)[O:22][CH2:23][CH3:24]>CN(C)C=O>[C:3]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17](=[O:20])[CH:16]2[C:21]([O:22][CH2:23][CH3:24])=[O:25])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)OCC
Reactant: O=C1Cc2cccc(C(=O)c3ccccc3)c2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(=O)Nc2c(C(=O)c3ccccc3)cccc21
Reaction time: 0.17 h

Procedure:
To a slurry of 365 mg. of sodium hydride in 8 ml. of dimethylformamide at 0° C. was gradually added 1.0 g. (4.22 mmoles) of 7-benzoyloxindole, and the mixture allowed to stir for 10 minutes in an ice bath. Diethyl carbonate (1.53 g., 12.7 mmoles) was added and the reaction mixture allowed to stir at ice bath temperatures for 3 hours. The mixture was then poured into 200 ml. of ice and water and the resulting precipitate filtered, washed with water and vacuum dried, 940 mg. The crude product was slurried in diethyl ether, filtered and the filtrate extracted with 0.1N aqueous sodium hydroxide solution. The base layer was separated and acidified with hydrochloric acid. The resulting precipitate was filtered and dried, 109 mg., m.p. 134° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[CH:30][CH:29]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)c1nn(Cc2ccccc2Br)c(=O)c(C(=O)NCC(=O)O)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nn(Cc2ccccc2-c2ccc(F)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 53.7 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(2-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 78(b), 75 mg, 0.177 mmol), 4-fluorobenzeneboronic acid (24.74 mg, 0.177 mmol), potassium carbonate (73.3 mg, 0.530 mmol), and tetrakis(triphenylphosphine)palladium (0) (6.13 mg, 5.30 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA)) to afford the title compound N-{[2-[(4′-fluoro-2-biphenylyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (42 mg, 0.095 mmol, 53.5% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 15.83 (s, 1H), 12.95 (s, 1H), 10.08 (t, J=5.68 Hz, 1 H), 7.44 (ddd, J=11.94, 5.37, 2.91 Hz, 2H), 7.31-7.38 (m, 2H), 7.22-7.30 (m, 3H), 7.11-7.19 (m, 1H), 5.24 (s, 2H), 4.07 (d, J=5.81 Hz, 2H), 3.13 (sept, J=6.82 Hz, 1H), 1.12 (d, J=6.82 Hz, 6H). MS (ES+) m/e 440 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>N1C=CC=CC=1>[F:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1cccc(F)c1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(Oc2cccc(F)c2)nc1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
A solution of 2-chloro-5-nitropyridine (LXV) (1.98 g, 12.5 mmol) and 3-fluorophenol (LXVI) (1.4 g, 12.5 mmol) in pyridine (20 mL) was heated at 120° C. overnight under argon. The solution was cooled to room temperature and concentrated under vacuum. The residue was dissolved in EtOAc, washed with water, brine, dried over MgSO4 and evaporated. The residue was purified by silica gel column chromatography (100% hexane→2:98 EtOAc:hexane) to give 2-(3-fluorophenoxy)-5-nitropyridine (LXVII) as a yellow viscous oil (2.27 g, 9.7 mmol, 77% yield). 1H NMR (DMSO-d6) δ ppm 7.11 (dd, J=8 Hz, J=2 Hz, 1H), 7.17 (dt, J=8 Hz, J=6 Hz, 1H), 7.23 (td, J=10 Hz, J=2 Hz, 1H), 7.31 (d, J=9 Hz, 1H), 7.52 (q, J=9 Hz, 1H), 8.64 (dd, J=9 Hz, J=3 Hz, 1H), 9.05 (d, J=3 Hz, 1H); ESIMS found for C11H7FN2O3 m/z 234.9 (M+H).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=O)([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:24])[N:3]1[CH2:25][CH2:26][CH3:27].Cl.[NH2:29][OH:30].CC([O-])=O.[Na+]>CO.O>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:15][CH2:16][C:17]([CH:22]=[N:29][OH:30])([CH2:18][CH2:19]3)[CH2:20][CH2:21]4)[NH:6][C:5]=2[C:4](=[O:24])[N:3]1[CH2:25][CH2:26][CH3:27]
Reactant: NO
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C=O)(CC3)CC4)nc2n(CCC)c1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCn1c(=O)c2[nH]c(C34CCC(C=NO)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a stirred solution of 4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde (1.6 g, 4.3 mmol) in MeOH (30 ml) was added hydroxylamine hydrochloride (1.2 eq, 5.16 mmol, 356 mg) and a solution of NaOAc (trihydrate, 1.5 eq, 6.45 mmol, 890 mg) in water (10 ml). The resulting mixture was stirred at rt overnight might. The mixture was concentrated in vacuo and the solid residue was suspended in water (15 ml), collected, washed with water and dried to afford a white powder (1.4 g, 84%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C:13]([C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])=[O:14].C([O-])(=O)C.C([O-])(=O)C.C1([I+2])C=CC=CC=1.FC(S(O)(=O)=O)(F)F>>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[C:13]1[O:14][C:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=2)=[N:9][CH:12]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)c1c(Cl)cccc1Cl
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [I+2]c1ccccc1
Product: O=[N+]([O-])c1ccc(-c2ncc(-c3c(Cl)cccc3Cl)o2)cc1

Procedure:
4-Nitrobenzonitrile and 2,6-dichlorophenyl methyl ketone can be reacted with phenyliodine (III) diacetate and trifluoromethylsulfonic acid by the method of R. S. Varma, et al, J. Heterocyclic Chem., 1998, 35(6), 1533-1534 to give 5-(2,6-dichlorophenyl)-2-(4-nitrophenyl)-1,3-oxazole. The nitrophenyl group can be reduced to the corresponding aniline with tin (II) dichloride or iron powder and ammonium chloride. Reaction of this aniline with 2,2-dichloroacetyl chloride and triethylamine can then give 2,2-dichloro-N-[4-[5-(2,6-dichlorophenyl)-2-(1,3-oxazolyl)]phenyl]acetamide.
Reaction SMILES: F[C:2]1[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[NH:18]1[CH2:20][CH2:19]1>O1CCOCC1>[N:18]1([C:2]2[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=2)[C:7]([NH2:9])=[O:8])[CH2:20][CH2:19]1
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])c(C(N)=O)cc1F
Reactant: C1CN1
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cc([N+](=O)[O-])c(C(N)=O)cc1N1CC1
Yield: 76.1 %

Procedure:
A stirred suspension of 5-fluoro-4-(methysulfonyl)-2-nitrobenzamide (Atwell et al., Anti-Cancer Drug Design, 1996, 11, 553-567) (262 mg, 1.00 mmol) in dry dioxane (15 mL) was treated with aziridine (207 μL, 4.00 mmol) at 35° C. for 1 h. The solvent was then removed under reduced pressure, and the residue was shaken with water and recrystallized from MeOH to give 12 (217 mg, 76%) mp 222-224° C., 1H NMR [(CD3)2SO]δ68.39 (s, 1H, H-3), 8.14 & 7 86 (2xbr s, 2H, CONH2), 7.33 (s, 1H, H-6), 3 41 (s, 3H, CH3), 2.57 (s, 4H, aziridine-H). Anal. Calcd for C10H11N3O5S: C, 42.10,H, 3.89, N, 14.73. Found. C, 45.25;H, 3.71; N, 14 98%.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:29]=[CH:30]/[C:31](O)=[O:32]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31](=[O:32])/[CH:30]=[CH:29]/[C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=3[O:20][CH3:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1cccc(/C=C/C(=O)O)c1OC
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: COc1cccc(/C=C/C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)c1OC

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2,3-dimethoxy-phenyl)-acrylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[NH:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:54]2[CH2:55][CH2:56][CH:51]([NH:50][C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:52][CH2:53]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OS(C)(=O)=O)c1OC
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OS(C)(=O)=O)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4-dimethoxy-5-methanesulfonyloxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[O:28]1[CH2:32][CH2:31][O:30][CH:29]1[C:33]1[N:34]=[CH:35][C:36]([NH2:39])=[N:37][CH:38]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:39][C:36]2[CH:35]=[N:34][C:33]([CH:29]3[O:30][CH2:31][CH2:32][O:28]3)=[CH:38][N:37]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1cnc(C2OCCO2)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C3OCCO3)cn2)cc1Cl
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 51.1 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 200 mg, 0.604 mmol) in methylene chloride (5 mL) and N,N-dimethylformamide (2 drops) was cooled to 5° C. and then treated with oxalyl chloride (105 μL, 1.2 mmol). The solution was stirred at 5° C. for 5 min, the cooling bath was removed, and the stirring was continued for 10 min. At this time, the reaction mixture was concentrated in vacuo, the residue was dissolved in benzene (10 mL), and the solvent was concentrated in vacuo again. The resulting acid chloride was dissolved in methylene chloride (5 mL), cooled to 5° C., and then treated with a solution of 5-[1,3]dioxolan-2-yl-pyrazin-2-ylamine (105 μL, 0.628 mmol), pyridine (100 μL, 1.23 mmol) in methylene chloride (5 mL). After 5 min, the cooling bath was removed, and the stirring was continued for 18 h. The reaction mixture was then diluted with methylene chloride (50 mL), and the solution was washed with a saturated aqueous sodium bicarbonate solution (25 mL), a 0.5M aqueous hydrochloric acid solution (25 mL), and a saturated aqueous sodium chloride solution (25 mL). Each aqueous wash was extracted with a small portion of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford a yellow oil. Flash chromatography (Merck Silica gel 60, 230–400 mesh, various concentrations of ethyl acetate/hexanes) afforded the 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-[1,3]dioxolan-2-yl-pyrazin-2-yl)-propionamide (148 mg, 51%) as a colorless foam: (ES)+-HRMS m/e calcd for C22H26ClN3O5S (M+H)+ 480.1355, found 480.1357.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]([C:12]([O:14]CC)=[O:13])[CH:2]=1.O.[OH-].[Na+].Cl>O1CCOCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]([C:12]([OH:14])=[O:13])[CH:2]=1
Reactant: CCOC(=O)C1C=Nc2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1C=Nc2ccccc2C1=O
Yield: 100.2 %

Procedure:
A suspension of ethyl 4-quinolone-3-carboxylate (900 mg) (Maybridge Chemical Co. Ltd) in dioxan (6 ml)/water (6 ml) was treated with 40% NaOH solution (8 ml) and refluxed 6 hours. The solution was cooled, acidified to pH2 with conc. HCl and the solid filtered off and dried under vacuum in the presence of P2O5 to provide the title compound (785 mg). MS (−ve ion chemical ionisation) m/z 188([M−H]−, 100%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].[N:19]1([C:25]2[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([N:22]1[CH2:23][CH2:24][N:19]([C:25]2[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=2)[CH2:20][CH2:21]1)=[O:10])[CH:2]([CH3:3])[CH3:4]
Reactant: N#Cc1cnc(N2CCNCC2)s1
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C#N)s2)CC1
Yield: 61 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isobutoxy-5-methanesulfonyl-benzoic acid (Example A8) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 61%). MS (m/e): 449.4 (M+H+, 100%).