Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([O:35][CH2:36][C:37]4([OH:43])[CH2:42][CH2:41][S:40][CH2:39][CH2:38]4)=[CH:30][C:29]=3[CH3:44])[CH:25]=[CH:26][CH:27]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].ClC1C=CC=C(C(OO)=[O:60])C=1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([O:35][CH2:36][C:37]4([OH:43])[CH2:42][CH2:41][S:40](=[O:60])[CH2:39][CH2:38]4)=[CH:30][C:29]=3[CH3:44])[CH:25]=[CH:26][CH:27]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[CH:5]=[CH:4][C:3]=1[CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48]
Reactant: CCOC(=O)CCc1ccc(N(Cc2cccc(-c3c(C)cc(OCC4(O)CCSCC4)cc3C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(N(Cc2cccc(-c3c(C)cc(OCC4(O)CCS(=O)CC4)cc3C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 0 °C
Yield: 96.1 %

Procedure:
To a solution of ethyl 3-(2-fluoro-4-{({4′-[(4-hydroxytetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl) [(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (2.24 g, 3.04 mmol) in ethyl acetate (15 mL) was added m-chloroperbenzoic acid (70%, 0.46 g, 1.88 mmol) under stirring at 0° C., and the mixture was stirred at room temperature for 3 days. The reaction mixture was washed with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-ethyl acetate-ethyl acetate/methanol=17/3) to give ethyl 3-(2-fluoro-4-{({4′-[(4-hydroxy-1-oxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (1.36 g, yield 60%) as a colorless amorphous powder. To a solution of the obtained ethyl 3-(2-fluoro-4-{({4′-[(4-hydroxy-1-oxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (1.36 g, 1.81 mmol) and mercaptoacetic acid (0.38 mL, 5.43 mmol) in N,N-dimethylformamide (10 mL) was added lithium hydroxide monohydrate (0.46 g, 10.86 mmol) under stirring at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-ethyl acetate) to give the title compound (0.52 g, yield 50%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([N:18]=[C:19]=S)[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC1CC2C(CC=1)=CC=CC=2N=C=S)C.[N:38]([CH2:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][C:45]=1[F:54])=[O:43])=[N+]=[N-].N(CC(C1C=CC(C(F)(F)F)=CC=1)=O)=[N+]=[N-]>>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([NH:18][C:19]3[O:43][C:42]([C:44]4[CH:49]=[CH:48][C:47]([C:50]([F:51])([F:52])[F:53])=[CH:46][C:45]=4[F:54])=[CH:41][N:38]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCc2cccc(N=C=S)c2C1
Reactant: [N-]=[N+]=NCC(=O)c1ccc(C(F)(F)F)cc1F
Agent: CCOC1=CCc2cccc(N=C=S)c2C1
Agent: [N-]=[N+]=NCC(=O)c1ccc(C(F)(F)F)cc1
Product: CC(C)(C)OC(=O)NC1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4F)o3)c2C1
Yield: 16 %

Procedure:
The title compound was prepared using the procedure as described in Example 1H, substituting the product of Example 20F (415 mg, 1.36 mmol) for the product of Example 1F and the product of Example 22A (404 mg, 1.63 mmol) for the product of Example 1G. The crude product was purified by flash chromatography eluting with 20% to 60% EtOAc/hexanes which gave 107 mg (16%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][OH:5].[F:6][C:7]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:8]=1[NH:9][C:10]1[C:11]([C:18](O)=[O:19])=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.C1COCC1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CO>[F:6][C:7]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:8]=1[NH:9][C:10]1[C:11]([C:18]([NH:1][O:2][CH2:3][CH2:4][OH:5])=[O:19])=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1
Reactant: NOCCO
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(F)cc2F)cc1=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(C(=O)NOCCO)c(Nc2ccc(F)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
2-(Aminooxy)ethanol (0.05 g, 0.6 mmol) in MeOH (1 ml) was added to 4-(2,4-difluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (0.15 g, 0.5 mmol) in MeOH (20 ml). THF was added dropwise until the reagents dissolved. The solution was stirred at RT for 30 min, after which DMT-MM (0.18 g, 0.6 mmol) was added. After stirring at RT for 60 h, the reaction had not gone to completion. Further 2-(aminooxy)ethanol (0.05 g, 0.6 mmol) and DMT-MM (0.18 g, 0.6 mmol) were added and the reaction mixture stirred for a further 2 h at RT. The solvent was then removed under reduced pressure and the residue dissolved in EtOAc. After washing with water ×2, sat. NaHCO3 and brine, the organic layer was dried (Na2SO4), concentrated and further purified by flash chromatography on silica gel (EtOAc followed by 10% MeOH/CH2Cl2) to give 4-(2,4-difluoroanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (0.07 g, 39%) as a white solid; m.p. (EtOAc/Hexane) 232-238° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.62 (br s, 1H), 9.21 (br s, 1H), 8.11 (s, 1H), 7.51-7.38 (m, 2H), 7.17-7.11 (m, 1H), 5.30 (s, 1H), 4.76 (br s, 1H), 3.92 (t, J=4.8 Hz, 2H), 3.62 (t, J=4.8 Hz, 2H), 3.34 (s, 3H). LCMS (ACPI+) 340 (100%). Anal. Calcd for C15H15F2N3O4.0.25 H2O: C, 52.4; H, 4.5; N, 12.2. Found C, 52.6; H, 4.5; N, 12.1
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][CH:12]3[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]3)[N:7]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[N:20]=3)[C:6]=2[CH:26]=1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([C:33]([OH:37])([C:35]#[CH:36])[CH3:34])[CH:29]=1.C(N(CC)CC)C>CS(C)=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>[NH2:25][C:21]1[N:20]=[C:19]([N:7]2[C:6]3[CH:26]=[C:2]([C:36]#[C:35][C:33]([C:30]4[CH:29]=[C:28]([CH3:27])[O:32][N:31]=4)([OH:37])[CH3:34])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH2:11][CH:12]2[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]2)[CH:24]=[CH:23][N:22]=1
Reactant: CC1(C)OCC(COc2nc3ccc(Br)cc3n2-c2ccnc(N)n2)O1
Reactant: C#CC(C)(O)c1cc(C)on1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(OCC4COC(C)(C)O4)n(-c4ccnc(N)n4)c3c2)no1
Temperature: 70 °C
Reaction time: 1 h
Yield: 17.2 %

Procedure:
A mixture of 4-[6-bromo-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (150 mg, 0.32 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (300 mg, 1.98 mmol), bis(triphenylphosphine)palladium(II) dichloride (300 mg, 0.43 mmol) and triethylamine (2 mL) in dimethylsulfoxide (3 mL) was stirred for 1 h at 70° C. under a nitrogen atmosphere. The reaction mixture was cooled to room temperature then filtered through a frit filter to remove the catalyst. The filtrate was purified on a C18 column (acetonitrile/water, 5:95-80:20) to yield 27 mg (17%) of 4-[1-(2-aminopyrimidin-4-yl)-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol as a white solid: 1H NMR (400 MHz, DMSO) delta 8.38 (d, J=5.2 Hz, 1H), 8.18 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.09 (s, 2H), 7.02 (d, J=5.2 Hz, 1H), 6.44 (s, 1H), 6.38 (s, 1H), 4.69-4.54 (m, 3H), 4.11 (t, J=7.4 Hz, 1H), 3.89 (t, J=7.2 Hz, 1H), 2.41 (s, 3H), 1.81 (s, 3H), 1.32 (d, J=16 Hz, 6H); LC-MS: m/z=+491 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH:3]([CH2:20][CH3:21])[CH:4]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]=[C:15]([NH2:17])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[C:23](N1C=CN=C1)([N:25]1C=CN=C1)=[O:24].N>C(Cl)Cl.O>[CH3:1][N:2]([CH3:22])[CH:3]([CH2:20][CH3:21])[CH:4]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]=[C:15]([NH:17][C:23]([NH2:25])=[O:24])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(C(c1ccc2nc(N)sc2c1)n1ccnc1)N(C)C
Agent: N
Solvent: ClCCl
Solvent: O
Product: CCC(C(c1ccc2nc(NC(N)=O)sc2c1)n1ccnc1)N(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine (50 mg, 0.151 mmol) and carbonyldiimidazole (50 mg, 30 mmol) in DCM was stirred at RT for 5 h. Aqueous ammonia was added and the reaction was stirred over night. The reaction was diluted with water and extracted with DCM. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative TLC to afford 1-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)urea. MS ESL m/z 359.27 [M+1+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([S:20]([N:23]1[CH2:28][C@H:27]([CH3:29])[NH:26][C@H:25]([CH3:30])[CH2:24]1)(=[O:22])=[O:21])=[CH:5]2.C(N(C(C)C)CC)(C)C.[Br:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:40][C:41]1[CH:49]=[CH:48][C:44]([C:45]([N:26]2[CH:27]([CH3:29])[CH2:28][N:23]([S:20]([C:6]3[N:7]([S:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)(=[O:13])=[O:12])[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=4)(=[O:21])=[O:22])[CH2:24][CH:25]2[CH3:30])=[O:46])=[CH:43][CH:42]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: C[C@@H]1CN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)C[C@H](C)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)CC(C)N1C(=O)c1ccc(Br)cc1
Reaction time: 3 h

Procedure:
In dichloromethane (40 ml), cis-1-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3,5-dimethylpiperazine (1.30 g) was dissolved. To the resulting suspension, diisopropylethylamine (645 μl) was added under ice cooling, followed by the dropwise addition of a solution of 4-bromobenzoyl chloride (0.74 g) in dichloromethane (5 ml). Stirring was then effected at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture. The organic layer thus separated was washed with 0.5N hydrochloric acid and saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=2:1 to 1:1), whereby the title compound (1.8 g, 97%) was obtained as a pale yellow amorphous.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([N:30]5[CH:34]=[N:33][CH:32]=[N:31]5)=[CH:28][CH:29]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: BrCc1ccc(-n2cncn2)cc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Product: Cc1nc(-c2ccn(Cc3ccc(-n4cncn4)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-(4-bromomethyl-phenyl)-1H-[1,2,4]-triazole as described in Example 49 and isolated as a white solid (76 mg, 51% yield). 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.53-8.57 (m, 1H), 8.54 (s, 1H), 8.10 (s, 1H), 7.66-7.71 (m, 3H), 7.45 (bs, 1H), 7.39 (d, J=8 Hz, 1H), 7.37-7.41 (m, 1H), 6.88 (s, 1H), 6.05-6.12 (m, 1H), 5.41 (s, 2H), 4.63 (d, J=4 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=457.2; Rt=1.08 min; HRMS (M+H)+=457.16.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C:15]3([C:18]([F:21])([F:20])[F:19])[CH2:17][CH2:16]3)=[O:13])[CH:9]=[CH:8][C:7]=2[N:22]2[CH2:25][C:24]([F:27])([F:26])[CH2:23]2)[CH2:3][CH2:2]1.[CH3:28][C:29]([O-])(CC)C.[Na+].ICC>CN(C=O)C>[CH2:28]([N:14]([C:15]1([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:17]1)[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:22]2[CH2:25][C:24]([F:27])([F:26])[CH2:23]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:11]=1)=[O:13])[CH3:29]
Reactant: O=C(NC1(C(F)(F)F)CC1)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CCC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CCN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C1(C(F)(F)F)CC1
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(1-(trifluoromethyl)cyclopropyl)picolinamide (Example 16 a), 15 mg, 38 μmol) and sodium 2-methylbutan-2-olate (5 mg, 46 μmol) in DMF (150 μL) was stirred for 15 minutes at ambient temperature. Iodoethane (9 mg, 7 μL, 58 μmol) was added and stirring was continued for 1 h. The reaction mixture was poured onto ice/sat. aqueous NaHCO3 solution (15 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed with ice/brine (2×20 mL), dried over Na2SO4 and brought to dryness. The crude product was purified by preparative TLC (silica gel, 1 mm, heptan/EtOAc 2:1, elution with EtOAc) to give the title compound (12 mg, 75%) as colorless oil; MS (EI): m/e=420.2 [MH]+.
Reaction SMILES: O.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][C:6](=[O:8])[NH2:7].[OH-].[Na+].[Cl:14][CH2:15][C:16](Cl)=[O:17]>C1(C)C=CC=CC=1>[Cl:14][CH2:15][C:16]([NH:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][C:6](=[O:8])[NH2:7])=[O:17]
Reactant: O=C(Cl)CCl
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)CC[C@H](NC(=O)CCl)C(=O)O
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a mixed solvent of 1750 ml of water and 497 ml of toluene was added 733.7 g (5 mol) of L-glutamine at room temperature. The solution was cooled to 0° to 5° C. and adjusted to pH 11 with 5N sodium hydroxide. To the solution was added dropwise a solution of 565.3 g (5 mol) of chloro-acetyl chloride in 497 ml of toluene while maintaining the pH of the reaction mixture at 11 with 5N sodium hydroxide. After stirring at 0° to 5° C. for 1 hour, toluene was removed from the reaction mixture by liquid-liquid separation. The aqueous layer separated was adjusted to pH 2 by addition of 410 ml of concentrated hydrochloric acid. After seeding, the reaction mixture was subjected to crystallization at room temperature for 1 hour and then at 0° to 5° C. for 3 hours. The resulting crystals were collected by filtration and dried under reduced pressure to give 992.6 g (89.2 mole percent (mol %) yield) of crude N-chloroacetyl-L-glutamine (sodium chloride content: 13.6 weight percent (wt %)). The crystals were analyzed by high performance liquid chromatography (HPLC) (column: Shim-pack CLC-ODS, 6 ×150 mm (manufactured by Shimadzu Corporation); eluent: 0.01M sodium 1-octanesulfonate/0.01M KH2PO4 buffer (pH 2.5)/1% methanol; detection: UV 210 nm). The purity of the crystals was found to be 99.0% as calculated from the HPLC relative area ratio.
Reaction SMILES: [NH2:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[Cl:21].ClC(OCC)=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:10])=[CH:18][C:19]=1[Cl:20]
Reactant: Nc1c(Cl)cc(C(=CC(=O)O)c2ccc(F)cc2)cc1Cl
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cc(C(=CC(=O)N2CCOCC2)c2ccc(F)cc2)cc1Cl

Procedure:
This compound was prepared from 4-amino-3,5-dichloro-β-(4'-fluorophenyl)-cinnamic acid (isomer ratio A:B=3:1), ethyl chloroformate, triethylamine and morpholine analogous to Example 1(c).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](#[N:18])[CH:16]=[CH2:17].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO.O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:17][CH2:16][C:15]#[N:18])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC#N
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#CCCOc1ccc(Oc2ccccc2)cc1
Yield: 34.6 %

Procedure:
3-(p-Phenoxyphenoxy)propionitrile was prepared by heating under reflux for 18 hours a mixture of 25 g of p-phenoxyphenol, 28.4 g of acrylonitrile and 5 ml of a 40% solution of benzyltrimethylammonium hydroxide in methanol. It was worked up by cooling, diluting with 400 ml water, extracting using ethyl acetate; washing the organic layer with 5% aqueous sodium hydroxide, drying, evaporating the solvent, and recrystallizing from hexane to yield 11.1 g of 3-(p-phenoxyphenoxy)propionitrile m.p. 81-3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[C:4]([F:12])[CH:3]=1.[Cl:13][C:14]1[C:15]([F:22])=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[C:15]=3[F:22])/[C:7](=[O:11])[NH:8]2)=[C:4]([F:12])[CH:3]=1
Reactant: O=C1Cc2c(F)cc(Cl)cc2N1
Reactant: O=Cc1cccc(Cl)c1F
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)cc(F)c2/C1=C/c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 74.8 %

Procedure:
To the mixture of 6-chloro-4-fluoroindolin-2-one (Natrochem, 85% purity) (1.1 g, 5.0 mmol) and 3-chloro-2-fluorobenzaldehyde (2.4 g, 15 mmol) (Oakwood) in methanol (50 mL) was added piperidine (1.7 g, 20 mmol) (Aldrich) dropwise. The mixture was then heated at 50° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, washed with cold methanol, dried to give the first batch of desired product (1.22 g). The filtrate was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (20-35% EtOAc in hexanes) to give the second batch of desired product (0.32 g). The two batches were combined to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-4-fluoro-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.54 g, 94%).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N)CCCC>ClCCl>[CH2:18]([NH:17][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: c1ccncc1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: CCCCCN
Solvent: ClCCl
Product: CCCCCNC(=O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled (0° C.) solution diphenylacetyl chloride (1.73 mmol) and pyridine (0.28 ml, 3.46 mmol) in dichloromethane (12 ml) was added pentylamine (0.39 ml, 2.60 mmol) and the reaction mixture was stirred at RT for 16 h. Aqueous work up and crystallization from ethyl acetate/hexane yielded the product as a light yellow solid, m.p. 101° C. and MS: m/e=281 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.[CH:10]1[C:18]2[C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][C:14]=2[C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].C(COC)OC>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.O>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:22]2[C:16]3[O:15][C:14]4[CH:13]=[CH:12][CH:11]=[CH:10][C:18]=4[C:17]=3[CH:19]=[CH:20][CH:21]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: Cc1cc(Br)ncc1Br
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2cccc3c2oc2ccccc23)ncc1Br
Temperature: 25 °C
Yield: 72.2 %

Procedure:
2,5-Dibromo-4-methylpyridine (30 g, 118 mmol), dibenzo[b,d]furan-4-ylboronic acid (25 g, 118 mmol), Pd(PPh3)4 (1.4 g, 1.18 mmol), and K2CO3 (49 g, 354 mmol) were added to a flask with dimethoxyethane (450 mL) and water (100 mL) and degassed with nitrogen. The reaction mixture was heated to reflux for 15 h before cooling to room temperature. EtOAc and water were added, the organic layer separated and the aqueous layer was extracted with 3×50 mL dichloromethane and dried over sodium sulfate. After removing the solvent under reduced pressure, the crude product was chromatographed on silica gel with dichloromethane and 29.7 g of crude product was obtained. The product was crystallized from hexane to give 28.8 g (72%) of pure product. The product was confirmed by NMR and HPLC (99.3% pure)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].Cl.[C:20]1(=[O:37])[N:24]([CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:23](=[O:32])[C:22]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:21]12.C(N(CC)CC)C>O1CCOCC1>[C:23]1(=[O:32])[N:24]([CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=4)=[CH:4][C:3]=3[N+:16]([O-:18])=[O:17])[CH2:30][CH2:31]2)[C:20](=[O:37])[C:21]2=[CH:36][CH:35]=[CH:34][CH:33]=[C:22]12
Reactant: O=C1c2ccccc2C(=O)N1CC1CCNCC1
Reactant: CC1CC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1CC(=O)NN=C1c1ccc(N2CCC(CN3C(=O)c4ccccc4C3=O)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
2.68 g (10 mmol) of 6-(4-chloro-3-nitro-phenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 2.81 g (10 mmol) of 4-phthalimidomethyl-piperidine hydrochloride are suspended in 30 ml of dioxane. After the addition of 2.8 ml (20 mmol) of triethylamine, the mixture is boiled under reflux for 4 hours. After it has cooled to room temperature, the solution is filtered from the residue and concentrated by evaporation under vacuum. After recrystallization of the solid residue from acetonitrile, 3.76 g (79%) of an orange yellow solid, m.p. 256°-258° C., are obtained.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[NH2:29][NH2:30].C(OCC)C>C(Cl)Cl>[NH:29]([C:26]([CH:23]1[CH2:24][CH2:25][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:21][CH2:22]1)=[O:28])[NH2:30]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NN
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reaction time: 2 h

Procedure:
Carbonyl diimidazole (3.57 g, 22 mmol) was added to a solution of 1-(tert-butoxycarbonyl)-piperidine-4-carboxylic acid (4.59 g, 20 mmol) in methylene chloride (50 mL) and stirred for two hours until gas evolution ceased. Then hydrazine (0.8 mL, ˜26 mmol) was added to the reaction and the reaction was stirred at room temperature for another two hours. The reaction was diluted with more methylene chloride and washed with sat'd aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4, filtered and the solvent evaporated to give a viscous residue. Trituration with diethyl ether afforded tert-butyl 4-(hydrazinocarbonyl)-piperidine-1-carboxylate as an off-white solid. 1H NMR (500 MHz, CDCl3): 6.77 (1H, br s), 4.15 (2H, br s), 3.90 (2H, v br s), 2.75 (2H, b s), 2.22 (1H, m), 1.78 (2H, br d, J=11.9 Hz), 1.66 (2H, br q, J=12.2 Hz, J=27.5 Hz), 1.47 (9H, s).