Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].C(Cl)(C([Cl:18])=O)=O>C(Cl)Cl>[C:1]([Cl:18])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCCCCCCCCC(=O)O
Solvent: ClCCl
Product: C=CCCCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of 10-undecenoic acid (5.055 mL, 25 mmol) in CH2Cl2 (50 mL) was slowly added (COCl)2 (4.364 mL, 50 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure to give 10-undecenoyl chloride (25 mmol). The product was used for the next reaction without further purification. 1H NMR (500 MHz, CDCl3) δ 1.29-1.48 (m, 10H), 1.71 (m, 2H), 2.05 (m, 2H), 2.88 (t, J=7 Hz, 2H), 4.98 (m, 2H), 5.80 (m, 1H).
Reaction SMILES: [Li+].[OH-].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[N:30]=[C:29]([C:31]([O:33]C)=[O:32])[C:28]([O:35][CH2:36][CH2:37][CH2:38][O:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:27][CH:26]=3)[CH:23]=2)[N:18]([CH3:46])[CH2:17][CH2:16]1)=[O:14].Cl>CO.O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[N:30]=[C:29]([C:31]([OH:33])=[O:32])[C:28]([O:35][CH2:36][CH2:37][CH2:38][O:39][C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)=[CH:27][CH:26]=3)[CH:23]=2)[N:18]([CH3:46])[CH2:17][CH2:16]1)=[O:14]
Reactant: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCN3C)ccc1OCCCOc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCN(C(=O)Nc2nc3ccccc3s2)c2cc(-c3ccc(OCCCOc4ccccc4)c(C(=O)O)n3)ccc21
Temperature: 55 °C
Yield: 61.4 %

Procedure:
The title compound 6-(4-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-3-(3-phenoxypropoxy)picolinic acid (26) was prepared by the following procedure: LiOH (12 mg, 10 eq) was added to a mixture of Methyl 6-(4-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-3-(3-phenoxypropoxy)picolinate (26E) (25 mg, 0.041 mmol) in MeOH (0.5 mL) and water (0.25 mL) at rt. The mixture was heated to 55° C. for 14 hours, cooled to 0° C. and acidified with 1N HCl to pH˜4. The resulting precipitate was filtered, washed with water and dried in vacuo to provide 15 mg (61%) of the desired product 6-(4-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-3-(3-phenoxypropoxy)picolinic acid (26): 1H NMR (300 MHz, DMSO-d6) δ 8.13 (1H, bs), 7.83 (1H, d), 7.80 (1H, d), 7.65 (2H, m), 7.37 (1H, t), 7.32-7.18 (4H, m), 6.94 (3H, m), 6.79 (1H, d), 4.26 (2H, t), 4.15 (2H, t), 4.02 (2H, t), 3.41 (2H, t), 2.97 (3H, s), 2.17 (2H, t). MS (ESI(+)): m/z 596.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:16](=[O:19])[CH2:17][CH3:18])[CH:7]=[C:8]([S:10]([F:15])([F:14])([F:13])([F:12])[F:11])[CH:9]=1)[CH3:2].[Br-:20].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O.C(=O)([O-])O.[Na+]>C1COCC1.CC(=O)OCC>[Br:20][CH:17]([CH3:18])[C:16]([C:6]1[CH:7]=[C:8]([S:10]([F:11])([F:12])([F:13])([F:15])[F:14])[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:19]
Reactant: CCOc1cc(C(=O)CC)cc(S(F)(F)(F)(F)F)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)C(C)Br)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Yield: 109.8 %

Procedure:
1-[3-Ethoxy-5-(pentafluorosulfanyl)phenyl]propan-1-one (O2.064; 150 mg) was dissolved in THF (15 ml), and phenyltrimethylammonium tribromide (185 mg) was added while stirring at RT. After stirring at RT for 5 h, the mixture was admixed with water and saturated sodium hydrogencarbonate solution, and EA was added. The EA phase was removed and the alkaline water phase was extracted three times with EA. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by means of preparative HPLC (met. A). The product fractions, each of them clean, were combined, freed of the acetonitrile under reduced pressure, alkalized with saturated sodium hydrogencarbonate solution and extracted five times with EA. The combined organic phases were dried over magnesium sulfate and, after filtering off the desiccant, dried under reduced pressure. 120 mg of the title compound were isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]1([CH3:20])[O:19][C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1.N1CCCC1C(O)=O.[CH3:29][S:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:40]=1[NH:39][CH:38]=[CH:37]2>C(#N)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]([C:37]1[C:36]2[C:40](=[C:32]([CH2:31][S:30][CH3:29])[CH:33]=[CH:34][CH:35]=2)[NH:39][CH:38]=1)[CH:16]1[C:17](=[O:18])[O:19][C:12]([CH3:20])([CH3:11])[O:13][C:14]1=[O:15]
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3Cl)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.63 g (9.31 mmol) of 2,4-dichlorobenzaldehyde, 1.34 g (9.31 mmol) of Meldrum's acid and 48.7 mg (0.42 mmol) of D,L-proline were added to a solution of 1.50 g (8.46 mmol) of the compound from Example 8A in 70 ml of acetonitrile. The reaction mixture was stirred at RT overnight. It was concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 3.99 g (98% of theory) of the title compound were obtained and were reacted without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]2[NH:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]2=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.Br[CH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:32][CH2:31]1>C1COCC1.O>[CH3:1][S:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:29][C@H:30]3[CH2:31][CH2:32][C@H:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:34][CH2:35]3)[N:10]=[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]2=[CH:5][N:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CBr)CC1
Reactant: CSc1ncc2c(-c3ccccc3)n[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CSc1ncc2c(-c3ccccc3)nn(C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
A microwave tube was charged with 6-(methylthio)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (0.073 g, 0.30 mmol), potassium carbonate (0.14 g, 0.90 mmol), and DMSO (1 mL). The resulting mixture was stirred for 20 min, then was added a solution of tert-butyl trans-4-(bromomethyl)cyclohexylcarbamate (0.10 g, 0.36 mmol) in THF (2 mL). The resulting mixture was heated at 150° C. for 10 min in microwave. The reaction mixture was poured into water and extracted with Et2O (3×). The combined ether layer was dried (Na2SO4) and concentrated. The crude mixture was purified by Isco to provide tert-butyl trans-4-((6-(methylthio)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.12 g, 88%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.90 (d, J=7.2 Hz, 2H), 7.55-7.44 (t, J=6.8 Hz, 2H), 7.41 (t, J=7.3 Hz, 1H), 4.37 (bs, 1H), 4.27 (d, J=7.1 Hz, 2H), 3.37 (bs, 1H), 2.61 (s, 3H), 2.09-1.89 (m, 3H), 1.67 (d, J=12.1 Hz, 2H), 1.39 (s, 9H), 1.19 (dd, J=24.4, 10.8 Hz, 2H), 1.04 (ddd, J=25.4, 12.7, 2.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 170.1, 155.3, 154.8, 152.3, 144.3, 132.2, 129.2, 127.1, 109.3, 79.3, 52.5, 49.7, 37.7, 32.9, 29.6, 28.5, 12.5; MS m/z 454.2 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([N:13]2[C:21]3[CH2:20][CH2:19][CH2:18][CH:17]([CH2:22][CH2:23]O)[C:16]=3[CH:15]=[N:14]2)[CH:9]=[CH:10][C:11]=1[Cl:12]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:3][CH2:23][CH2:22][CH:17]1[CH2:18][CH2:19][CH2:20][C:21]2[N:13]([C:8]3[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([Cl:5])[CH:7]=3)[N:14]=[CH:15][C:16]1=2
Reactant: O=S(Cl)Cl
Reactant: OCCC1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: ClCCC1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Yield: 85 %

Procedure:
Thionyl cloride (4 mL) is slowly added at room temperature over a solution of 2-(1-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl)ethanol (512 mg, 1.65 mmol) in 20 mL of toluene. The reaction mixture is heated at 90° C. during 2 hours. The solvent is eliminated at reduced pressure. The crude is diluted in ethyl acetate and washed twice with a NaHCO3 solution. The solvent is next evaporated at reduced pressure to obtain 4-(2-chloroethyl)-4,5,6,7-tetrahydro-1-(3,4-dichlorophenyl)-1H-indazole (462 mg, 1.40 mmol, 85%, oil).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1S.[CH2:17]([O:29]S([O-])(=O)=O)CCCCCCCCCCC.[Na+].C(OC=O)=O>O>[O:29]1[C:3]2[CH:4]=[CH:5][C:6]3[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[CH:13]=[CH:14][C:15]=3[C:2]=2[N:1]=[CH:17]1
Reactant: Nc1c(S)ccc2c1ccc1ccccc12
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: O=COC=O
Agent: [Na+]
Solvent: O
Product: c1ccc2c(c1)ccc1c2ccc2ocnc21
Yield: 71 %

Procedure:
5 mmol of 1-amino phenanthren-2-thiol was added to 20 mL of water, and 20 mg of sodium dodecylsulfate was added while agitating to obtain a uniform mixture. 7.5 mmol of formic anhydride was added for 5 minutes. A precipitation product was obtained in 5-10 minutes. The precipitation product was filtrated and rinsed with 1 ml of water twice followed by drying under vacuum. A non-precipitated reaction mixture was extracted with 25 ml of ethyl acetate twice. The separated organic layer was dried with anhydrous sodium sulfate, and a solvent was removed using a rotatary evaporator under a reduced pressure to obtain phenanthro oxazole at a yield of 71%.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].C(N(CC)C(C)C)(C)C.Cl[CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1.[C:41]([N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CC(N(C)C)=O.C(OCC)(=O)C>[C:18]([C:3]1[N:4]=[C:5]([NH:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[S:6][C:2]=1[NH:1][C:36]([C:35]1[CH:39]=[CH:40][C:32]([CH2:31][N:51]2[CH2:50][CH2:49][N:48]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:53][CH2:52]2)=[CH:33][CH:34]=1)=[O:37])(=[O:19])[NH2:20]
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)Nc3sc(Nc4ccc5ccccc5c4)nc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 1.8 %

Procedure:
To a mixture of 5-amino-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (0.5 g, 1.76 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.94 mmol) in DMA (30 mL) was added 4-chloromethylbenzoyl chloride (0.37g, 1.94 mmol) at 0° C. The mixture was stirred for 3 hrs at rt. Then 1-Boc-piperazine (0.18 g, 0.95 mmol) was added to the mixture (0.083 g in 5 mL DMA), and the mixture was stirred for 16 hrs at rt. The reaction mixture was diluted with ethyl acetate (150 mL), washed with water, and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the crude residue was purified by silica gel column chromatography eluted with 5% MeOH in DCM to give 0.010 g (11% yield) of the titled compound.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:5]=2[CH:4]=1)#[CH:2].[CH2:16]([O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)[CH3:17].C(NC(C)C)(C)C.O=[Si]=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCOC(C)=O.C1COCC1>[CH2:16]([O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([C:2]#[C:1][C:3]2[CH:15]=[CH:14][C:6]3[O:7][CH2:8][C:9]([CH3:12])([CH3:13])[CH2:10][O:11][C:5]=3[CH:4]=2)=[CH:22][CH:21]=1)[CH3:17]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: C#Cc1ccc2c(c1)OCC(C)(C)CO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=[Si]=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)cc1
Temperature: 57 °C
Yield: 43.7 %

Procedure:
To a mixture under Ar of 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (1.0 g), ethyl-4-bromobenzoate (1.13 g), [PdCl2(PPh3)2] (174 mg) and copper(I) iodide (94 mg) is added a degassed solution of diisopropylamine (20 ml) and THF (20 ml). The reaction mixture is stirred over night at 57° C. After addition of AcOEt (100 ml) and filtration over dicalite, the solution is washed with 1 N aq. HCl sol. (3×50 ml) and H2O (3×50 ml). The organic layer is dried over MgSO4 and the solvent is evaporated. The crude product is purified by flash chromatography (silica gel, heptane/AcOEt 9:1) followed by preparative HPLC. 756 mg of 4-(3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylethynyl)-benzoic acid ethyl ester are obtained as a white solid, MS (ESI) 350.2 (M•)+.
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].C(N(CC)CC)C.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>C(Cl)Cl>[S:29]([O:21][CH2:1][CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4])(=[O:31])(=[O:30])[CH3:32]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOS(C)(=O)=O
Temperature: -15 °C
Reaction time: 1.5 h

Procedure:
Phytanol (20.0 g, 66.7 mmol), triethylamine (18.6 mL, 133 mmol), and a stir bar were added to a 1000 mL round bottom flask. The flask was sealed and flushed with nitrogen. Anhydrous DCM (250 mL) was added, and the mixture cooled to −15° C. (ice and NaCl). Mesyl Chloride (10.4 mL, 133 mmol) was added slowly via syringe over a 30 minute period, and the reaction stirred at −15° C. for a further 1.5 hours. At this point TLC showed that the starting material had been used up. The solution was diluted with DCM (250 mL) and washed with saturated NaHCO3 (2×200 mL). The organic phase was then dried (MgSO4), filtered, and concentrated (rotovap). The crude product was purified by column chromatography. Yield: 21.5 g, 85.7%.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([O:13][CH:10]2[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)=[CH:17][CH:16]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(F)cc2)C1
Yield: 95.2 %

Procedure:
The title compound (D36) (1.43 g) was prepared according to the experimental procedure described in Description 34 starting from 1-Boc-3-pyrrolidinol (1 g, 5.34 mmol) and 4-Fluorophenol (598 mg, 5.34 mmol).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:3]1.Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(Br)C1C=CC=CC=1>>[CH2:31]([O:15][C:10]1[CH:9]=[CH:8][C:7]2[C:2](=[O:1])[CH2:3][C:4]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[O:5][C:6]=2[C:11]=1[CH2:12][CH2:13][CH3:14])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCBr
Reactant: CCCc1c(O)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Agent: BrCc1ccccc1
Product: CCCCCCOc1ccc2c(c1CCC)OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O

Procedure:
The title compound (388 mg) was prepared by the method of Example 18 substituting the title product of Example 1 (406 mg; 1.00 mmol) for the title product of Example 2, and further substituting 1-bromohexane (198 mg, 1.20 mmol for benzyl bromide.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[S:10][C:11]([F:20])=[C:12](/[C:14](=[N:18]/[OH:19])/[C:15]([OH:17])=[O:16])[N:13]=1.[CH:21]([O:24]C(C)C)(C)C>C(O)=O>[F:20][C:11]1[S:10][C:9]([NH:8][CH:1]=[O:3])=[N:13][C:12]=1/[C:14](=[N:18]/[O:19][CH:21]=[O:24])/[C:15]([OH:17])=[O:16]
Reactant: CC(C)OC(C)C
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(/C(=N/O)C(=O)O)c(F)s1
Solvent: O=CO
Product: O=CNc1nc(/C(=N/OC=O)C(=O)O)c(F)s1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
A mixture of acetic anhydride (2.7 ml) and formic acid (2.2 ml) was stirring for 30 minutes at 30° C. 2-(2-Amino-5-fluorothiazol-4-yl)-2-(Z)-(hydroxyimino)acetic acid (1.2 g) was added thereto with stirring under ice cooling, and the mixture was stirred for 3 hours at 25 to 35° C. The reaction mixture was poured into an isopropyl ether (50 ml). The resulting precipitate was collected by filtration, dried under reduced pressure to give 2-(5-fluoro-2-formylaminothiazol-4-yl) -2-(Z)-(formyloxyimino) acetic acid (0.65 g).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([NH:8]C(OC(C)(C)C)=O)[CH2:6][CH2:5][C:4](=[O:16])[NH:3]1.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[C:17]([OH:23])=[O:18].[NH2:8][CH:7]1[CH2:6][CH2:5][C:4](=[O:16])[NH:3][C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)NC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
2,6-Dioxo-3-aminopiperidine trifluoroacetate (4) was prepared and isolated as follows. Compound 3 (59 mg) was suspended in CH2Cl2 (5 mL). CF3COOH (0.5 mL) was added. The reaction solution was stirred at room temperature for 4 h. The solvent was removed to give 4 (62 mg, 99%): 1H NMR (DMSO-d6) δ 11.42 (s, 1H), 8.70 (br, 2H), 4.31 (dd, J=5.4 Hz, J=13 Hz), 2.88-2.72 (m, 2H), 2.25-2.09 (m, 2H).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH3:14][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([O:22][C:19]3[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1cc(-c2cccnc2F)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(-c2cccnc2Oc2ccc(N)cc2)ccn1

Procedure:
To a 25 mL round bottomed flask was added 2-fluoro-3-(2-methylpyridin-4-yl)pyridine (0.7204 g, 3.828 mmol), 4-aminophenol (0.4254 g, 3.832 mmol), and cesium carbonate (1.6144 g, 4.593 mmol) in dimethyl sulfoxide at 90° C. Upon completion, the reaction was filtered through Celite™ and the filtrate was condensed. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3×20 mL). The organic extract was washed with water (3×15 mL), brine (3×15 mL), dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (40M), eluting with a gradient of 1% to 5% methanol in DCM, to provide 4-(3-(2-methylpyridin-4-yl)pyridin-2-yloxy)benzenamine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1(OB(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: OB(O)Oc1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccccc2)nc1
Temperature: 50 °C
Yield: 88.3 %

Procedure:
2,5-dibromopyridine (7.11 g, 30 mmol), toluene (130 mL), phenylboric acid (4.57 g, 37.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.73 g, 1.5 mmol) were weighed into a reaction container, and the reactants were dissolved, while being stirred at 50° C. under a nitrogen gas flow. A 2 M aqueous sodium carbonate solution (30 mL) was added to the solution, and the mixture was stirred at 80° C. for 6 hours. The organic layer of the obtained reaction solution was recovered, and washed with an aqueous sodium carbonate solution and a saturated saline solution. The organic layer was dried with sodium sulfate, filtered, and then distilled off. The residue was purified by silica gel column chromatography (hexane/toluene), and the solvent was distilled off to obtain 5-bromo-2-phenylpyridine (6.21 g, 26.5 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH:11]([CH3:13])[CH3:12].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24].O>ClCCl>[Cl:21][CH2:22][C:23]([N:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:24]
Reactant: O=C(Cl)CCl
Reactant: CC(C)CNc1ccc(F)cc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)CN(C(=O)CCl)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
A solution of the above amine (15.0 g, 74 mmol) and triethylamine (12.0 g, 119 mmol) in dichloromethane (200 ml) was cooled to -10° C. and chloroacetyl chloride (11.3 g, 113 mmol) was carefully added while the temperature was kept below 10° C. The mixture was then stirred at ambient temperature for 1 h. The reaction mixture was poured into water (200 ml) and extracted with dichloromethane (2×100 ml). The organic phase was washed with 4N hydrochloric acid (2×50 ml), water (100 ml) and saturated aqueous sodium hydrogencarbonate (50 ml) and dried (MgSO4). The solvent was evaporated in vacuo to give 13.6 g of 2-chloro-N-(2-chloro-4-fluorophenyl)-N-(2-methyl-1-propyl)acetamide.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.O=S(Cl)[Cl:18]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([Cl:18])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Product: Cc1onc(-c2ccccc2)c1C(=O)Cl

Procedure:
5-Methyl-3-phenyl-isoxazole-4-carboxylic acid (0.54 g, 2.56 mmol) was treated with SOCl2 (2 mL) at 70° C. for 1 hr. Concentration in vacuum gave a yellow oil which was used without purification.