Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)/[C:9]1=[O:26])=O)(C)(C)C.[C:27]([CH:30]=[N:31][C:32]([O:34][Si](C)(C)C)=[CH2:33])([CH3:29])=[CH2:28].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[Br:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:26])[C:10]3([CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[CH2:33][C:32](=[O:34])[NH:31][CH:30]3[C:27]([CH3:29])=[CH2:28])[C:11]2=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Br)cc21
Reactant: C=C(C)C=NC(=C)O[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Yield: 40 %

Procedure:
In a manner similar to the method described in example 41b, E/Z-6-bromo-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (5 g, 12.8 mmol) prepared in example 172a was reacted with 1-isopropenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 87b in toluene, then treated with trifluoroacetic acid to give racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 2.2 g, 40%).
Reaction SMILES: O1CCCC1.[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=O)[CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=[CH:11][CH:12]=1>CO>[Br:6][C:7]1[CH:8]=[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(CCN1CCCC1)Nc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CO
Product: Brc1cccc(NCCCN2CCCC2)c1
Reaction time: 8 h

Procedure:
A 1M solution of BH3 in tetrahydrofuran (10 ml, 10 mmol) was added dropwise to N-(3-bromo-phenyl)-3-pyrrolidin-1-yl-propionamide (0.3 g, immol) and the solution was stirred overnight at reflux then subsequently hydrolysed by slow addition of excess of methanol and refluxing for a further 2 hours. The solvent was removed under reduced pressure and aqueous ammonium chloride was added. The aqueous phase was extracted twice with ethyl acetate and the organics were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was dissolved in methanol and loaded onto an SCX cartridge, which was washed with methanol and the product subsequently eluted with 2M ammonia in methanol. Removal of all solvents under rotary evaporation gave the desired product. Yield 0.23 g, 82%. LCMS method: 2, RT: 2.71 min; MI: 283-285 [M+1].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].C[CH2:15][N:16](C(C)C)[CH:17](C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CNC>CN(C=O)C.O>[CH3:15][N:16]([CH3:17])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)N(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.1 %

Procedure:
To a solution of 3-methyl-4-nitrobenzoic acid (0.5 g, 2.76 mmol) in DMF (5 mL) was added DIPEA (1.06 g, 8.28 mmol), followed by HATU (1.57 g, 4.14 mmol) and dimethylamine (0.24 g, 5.52 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with brine, then concentrated to provide crude material which was further purified by column chromatography (silica:100-200 mesh, MeOH:DCM 8-10%), to afford the title compound (0.42 g, 73.17%). LCMS (ES+) 209 (M+H)+, RT 1.92 minutes (method 3).
Reaction SMILES: FC(F)(F)C([O-])=O.[Br:8][C:9]1[C:21]2[C:20]3[CH2:19][CH2:18][NH2+:17][CH2:16][C:15]=3[CH:14]=[N:13][C:12]=2[NH:11][N:10]=1.[N:22]([C:25]1[CH:26]=[C:27]([C:31]2[N:32]=[C:33]([CH3:36])[S:34][CH:35]=2)[CH:28]=[CH:29][CH:30]=1)=[C:23]=[O:24]>>[Br:8][C:9]1[C:21]2[C:20]3[CH2:19][CH2:18][N:17]([C:23]([NH:22][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]5[N:32]=[C:33]([CH3:36])[S:34][CH:35]=5)[CH:26]=4)=[O:24])[CH2:16][C:15]=3[CH:14]=[N:13][C:12]=2[NH:11][N:10]=1
Reactant: Brc1n[nH]c2ncc3c(c12)CC[NH2+]C3
Reactant: Cc1nc(-c2cccc(N=C=O)c2)cs1
Agent: O=C([O-])C(F)(F)F
Product: Cc1nc(-c2cccc(NC(=O)N3CCc4c(cnc5[nH]nc(Br)c45)C3)c2)cs1

Procedure:
The compound 1-bromo-N-(3-(2-methylthiazol-4-yl)phenyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxamide was prepared using 1-bromo-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7-ium 2,2,2-trifluoroacetate and 4-(3-isocyanatophenyl)-2-methylthiazole as described in general procedure M and was obtained as a pale yellow solid (0.025 g, 15%). M.p.=258-261° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.96 (s, 1H), 8.87 (s, 1H), 8.42 (s, 1H), 8.05 (m, 1H), 7.82 (m, 1H), 7.56-7.48 (m, 2H), 7.32-7.26 (m, 1H), 4.79 (s, 2H), 3.85 (t, J=6 Hz, 2H), 3.39 (t, J=6 Hz, 2H), 2.71 (s, 3H); LCMS [M+H]: 468.
Reaction SMILES: [Br:1][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:25].[Br:26]Br.O>CO>[Br:1][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH2:14][Br:26])[CH2:4][C@@H:3]1[OH:25]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Br)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: BrBr
Solvent: CO
Solvent: O
Product: C[C@]12C[C@H](Br)[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A stirred solution of 2β-bromo-3α-hydroxy-5α-pregnane-11,20-dione (5.0 g.) in methanol (100 ml.) was treated at 0° with a solution of bromine (1 ml.) in methaol (30 ml.) at such a rate that the yellow colour disappeared before further addition of the bromine solution. The mixture was then poured into water and the precipitated solid was collected by filtration, washed with water and dried over P2O5 in vacuo. The resulting solid (5.0 g.) was purified by column chromatography (silica, EtOAc/ C6H6 1:2.5) to give crude 2β,21-dibromo-3α-hydroxy-5α-pregnane-11,20-dione (3,4 g.).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]([F:38])([F:37])[O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1.O>CN(C=O)C>[CH2:17]([NH:16][C:11]1=[N:12][C:13](=[O:15])[S:14]/[C:10]/1=[CH:9]\[CH:6]1[CH2:7][CH2:8][N:3]([CH2:33][C:32]2[CH:35]=[CH:36][C:29]([O:28][C:27]([F:26])([F:37])[F:38])=[CH:30][CH:31]=2)[CH2:4][CH2:5]1)[C:18]#[CH:19]
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) was added a solution of potassium carbonate (345 mg) and 4-(trifluoromethoxy)benzyl bromide (0.113 mL) in DMF (2 mL). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (48.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][C:13]([O:15]C)=[O:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].Cl.O>CO>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)Cc1coc2c(OC)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc2c(CC(=O)O)coc12
Temperature: 25 °C
Reaction time: 13.5 h
Yield: 90.6 %

Procedure:
Methyl (7-methoxy-benzofuran-3-yl)acetate (1.12 g) was dissolved in methanol (20 ml). To this solution, 2N aqueous sodium hydroxide solution (5 ml) was added and the resulting solution was stirred at room temperature for 13.5 hours. To this solution, 1N hydrochloric acid (12 ml) was added and the reaction solution was poured into water layer (200 ml), followed by extraction twice with ethyl acetate (50 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. Sodium sulfate was removed by filtration and the solvent was removed under reduced pressure. The residue was recrystallized from hexane/chloroform to obtain the desired compound (0.95 g, yield: 91%).
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]#[CH:11])=[CH:4][N+:5]([O-:7])=[O:6].[CH3:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[CH2:18][S:19][CH2:20][CH2:21][NH2:22]>>[N+:5]([CH:4]=[C:3]([NH:8][C:9]#[C:10][CH3:11])[NH:22][CH2:21][CH2:20][S:19][CH2:18][C:17]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:12])([O-:7])=[O:6]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: C#CCNC(=C[N+](=O)[O-])SC
Product: CC#CNC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C

Procedure:
A solution of the product of Step A is treated with about an equimolar amount of 2-[(4-methyl-1H-imidazol-5-yl)-methylthio]ethylamine [prepared by the procedure described in U.S. Pat. No. 3,950,353] to produce, after workup and chromatography, the title product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]3[N:17]([CH:18]([CH3:20])[CH3:19])[N:16]=[CH:15][N:14]=3)[N:12]=2)=[C:4](F)[CH:3]=1.C1(=O)O[CH2:25][CH2:24][O:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[N:9]([CH:10]=[C:11]([C:13]4[N:17]([CH:18]([CH3:20])[CH3:19])[N:16]=[CH:15][N:14]=4)[N:12]=3)[CH2:25][CH2:24][O:23][C:4]=2[CH:3]=1
Reactant: CC(C)n1ncnc1-c1c[nH]c(-c2ccc(Br)cc2F)n1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 100 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
A solution of 5-[2-(4-bromo-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-1H-[1,2,4]triazole (10.0 g, 28.6 mmol) in DMF (100 mL) was treated with ethylene carbonate (5.3 g, 60.1 mmol) and cesium carbonate (13.9 g, 42.5 mmol) and then heated at 100° C. for 72 h. Further cesium carbonate (9.0 g, 27.5 mmol) and water (0.5 mL) were added and heating continued for 24 h before concentrating the reaction mixture in vacuo. The resultant residue was partitioned between DCM and water, the organic layer was isolated, washed with water then brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, 1% MeOH in DCM) to give 194 as an off-white solid (5.78 g, 58%). 1H NMR δ (ppm) (CDCl3): 8.04 (1H, s), 7.83 (1H, s), 7.50-7.38 (3H, m), 5.93-5.84 (1H, m), 4.07-4.02 (2H, m), 3.93-3.88 (2H, m), 1.53-1.46 (6H, m)
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13]/[C:14](=[N:17]/[H])/[NH:15][OH:16].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Cl:40][C:41]1[N:45]([CH3:46])[N:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[C:42]=1[C:51](O)=O.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13][C:14]1[N:17]=[C:51]([C:42]2[C:43]([C:47]([F:50])([F:48])[F:49])=[N:44][N:45]([CH3:46])[C:41]=2[Cl:40])[O:16][N:15]=1
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(Cl)c(C#N)ccc21)NO
Reactant: Cn1nc(C(F)(F)F)c(C(=O)O)c1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2c(C(F)(F)F)nn(C)c2Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized as described in Example 32A and Example 33 using (1Z)-2-(4-chloro-5-cyano-2-propyl-1H-indol-1-yl)-N-hydroxyethanimidamide (0.030 g, 0.1 mmol) in anhydrous THF (5 mL) with propanephosphonic acid cyclic anhydride (T3P) (0.034 g, 0.12 mmol), 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.023 g, 0.1 mmol) and DIEA (0.016 g, 0.12 mmol) and stirred at rt for 1 h and then heated at 120° C. for 2 h in the microwave: 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=8.6 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.31 (s, 1H), 4.99 (s, 2H), 3.95 (s, 3H), 2.87 (t, 2H), 1.80-1.58 (m, 2H), 1.01 (t, 3H); MS (ES) m/z 484 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccncc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 126.6 %

Procedure:
To a solution of N-methyl-4-nitroaniline (5 g, 32.9 mmol) in DMF (75 ml) was slowly added NaH (60% in mineral oil, 4.21 g, 105 mmol) at RT (Warning: important gaz evolution occurred!). The suspension was vigorously stirred at RT for 15 min then cooled to 0° C. (ice bath). 4-(Chloromethyl)pyridine hydrochloride (8.09 g, 49.3 mmol) was added carefully then the slurry was allowed to warm to RT and further stirred for 45 min. The reaction mixture was poured into water and extracted with Et2O (3×). The combined organic phases were dried over Na2SO4, filtered and evaporated to dryness to yield the crude title compound (10.13 g) as an orange solid, which was used in the next step without further purification. HPLC: AtRet=1.01 min; LC-MS: m/z 244.5 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 3.23 (s, 3H), 4.82 (s, 2H), 6.77-6.83 (m, 2H), 7.17-7.22 (m, 2H), 8.02-8.08 (m, 2H), 8.49-8.54 (m, 2H).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:23](=[O:38])[N:24]([CH3:37])[C@@H:25]([C:33](=[O:36])[NH:34][CH3:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH:12][C:11]([CH2:10][C@@H:9]([NH:7][CH3:6])[C:23]([N:24]([CH3:37])[C@@H:25]([C:33](=[O:36])[NH:34][CH3:35])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:38])=[CH:16][CH:15]=1
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc(-c2ccccc2)cc1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc(-c2ccccc2)cc1)NC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
((1R)-2-(1,1'-Biphenyl-4-yl)-1-(methyl-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)methyl-carbamic acid tert-butylester (1.0 g; 1.8 mmol) was dissolved in methylene chloride (4 mL). Trifluoroacetic acid (4 mL) was added and the reaction mixture was stirred for 15 min at room temperature. Methylene chloride (40 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 40 mL) and sodium hydrogen carbonate (solid) were added to the reaction mixture until pH 9. The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo to afford 0.76 g of (2R)-3-(1,1'-biphenyl-4-yl)-N-methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)propionamide.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl>O.O1CCOCC1>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][O:12][C@@H:11]1[C@@H:13]([CH2:14][OH:15])[O:16][C@@H:9]([N:8]2[CH:17]=[C:4]([F:3])[C:5](=[O:19])[NH:6][C:7]2=[O:18])[CH2:10]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reactant: ClCc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3Cl)[C@@H](CO)O2)cc1F
Temperature: 30 °C
Reaction time: 72 h
Yield: 23 %

Procedure:
A 3.75 g quantity of potassium hydroxide was dissolved in a mixture of 150 ml of water and 40 ml of dioxane. To the solution were added 1.00 g of 2'-deoxy-5-fluorouridine and 10 ml of 2-chlorobenzyl chloride, and the resulting mixture was stirred at 30° C. for 3 days. After the reaction, the same subsequent procedure as in Reference Examples 4 and 5 was carried out, and the residue was placed on a silica gel column and eluted with 2% methanol-chloroform, thereby producing 0.34 g of the title compound in a yield of 23%.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:8]([CH2:11][C:12]([CH3:17])([N+:14]([O-:16])=[O:15])[CH3:13])=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:13][C:12]([N+:14]([O-:16])=[O:15])([CH3:17])[CH2:11][C:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=3)[C:3]2=[N:10][CH:9]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(Cc1cnc2c(Br)cccn12)[N+](=O)[O-]
Product: CC(C)(Cc1cnc2c(-c3ccc(C(F)(F)F)cc3)cccn12)[N+](=O)[O-]
Yield: 101.1 %

Procedure:
8-Bromo-3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridine (1.0 g, 3.35 mmol) and 4-trifluoromethyl-benzeneboronic acid (0.96 g, 5.05 mmol) are coupled as described in Amine 14 to give 1.23 g of 3-(2-methyl-2-nitropropyl)-8-(4-trifluoromethyl-phenyl)imidazo[1,2-a]pyridine (100%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:5]=1[O:17][CH3:18].[Cl:19]OC(C)(C)C.S([O-])([O-])=O.[Na+].[Na+]>ClCCl.O>[Br:1][CH2:2][CH2:3][C:4]1[C:5]([O:17][CH3:18])=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:15]([Cl:19])[CH:16]=1
Reactant: CC(C)(C)OCl
Reactant: CCOC(=O)COc1ccc(CCBr)c(OC)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)COc1cc(OC)c(CCBr)cc1Cl
Reaction time: 0.5 h

Procedure:
To a stirred solution of ethyl 2-[4-(2-bromoethyl)-3-methoxyphenoxy]acetate (640 mg) in dichloromethane (4 ml) was added tert-butyl hypochlorite (251 μl) at room temperature, and the mixture was stirred for 30 minutes. To the reaction mixture was added a solution of sodium sulfite (504 mg) in water (2 ml) and the resulting mixture was stirred for 30 minutes at room temperature. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/ethyl acetate=7/1) gave ethyl 2-[4-(2-bromoethyl)-2-chloro-5-methoxyphenoxy]acetate (685 mg).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O-2].[Zn+2:22].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Zn+2:22].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 70 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A molten stearic acid (202 grams of Hystrene 4516) was added gradually to a stirred slurry of zinc oxide (32 grams), citric acid (0.5 gram), Methocel F50 (3 grams), and water (560 grams) at 65° C. The mixture was stirred at 65-75° C. for 1 hour to afford after filtering and drying a 100% yield of zinc stearate as indicated by its infrared spectrum. The resulting product was a white powder having free fatty acid content of 0.22% by weight.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(#N)C>[N:25]1([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([C:11]3[C:15]4[S:16][CH:17]=[CH:18][C:14]=4[O:13][N:12]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(OCCN2CCCCC2)cc(-c2noc3ccsc23)c1
Reaction time: 8 h

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, piperidine and acetonitrile essentially as described above in example 18 except that the reaction is run overnight and the compound is purified by column chromatography using a graded solvent mixture of 5% ethyl acetate in dichloromethane to 10% methanol in ethyl acetate. Purity by LC/MS (APCI)=98%, [M+H]+=329.
Reaction SMILES: [Br:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[C:6]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[O:10])=[CH:7][O:8][C:4]=2[C:3]=1[Br:21].[N+]([O-])(O)=[O:23].O>CC(O)=O>[Br:1][C:2]1[C:19](=[O:20])[C:18](=[O:23])[C:5]2[C:6]([C:9](=[O:10])[C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)=[CH:7][O:8][C:4]=2[C:3]=1[Br:21]
Reactant: O=[N+]([O-])O
Reactant: O=C(c1ccc(F)cc1)c1coc2c(Br)c(Br)c(O)cc12
Solvent: CC(=O)O
Solvent: O
Product: O=C1C(=O)c2c(C(=O)c3ccc(F)cc3)coc2C(Br)=C1Br
Temperature: 60 °C
Yield: 21.8 %

Procedure:
To a solution of (6,7-dibromo-5-hydroxybenzofuran-3-yl)(4-fluorophenyl)methanone (62 mg, 0.150 mmol) in AcOH (1 mL) was added nitric acid—69% (46.2 μl, 0.749 mmol) at room temperature. The mixture was heated to 60° C. for 3 hours, cooled to room temperature, poured onto iced water and the suspension filtered. A solid was isolated which was dried under vacuum to afford the product (14 mg, 17%).
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=O)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C:31]1=O)(OC(C)(C)C)=O>>[CH2:1]([N:3]([CH2:21][CH3:22])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:33]3[CH2:32][CH2:31][NH:30][CH2:35][CH2:34]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[C:13]([NH:3][C:4](=[O:5])[CH3:6])[CH:12]=3)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc2c(=O)c3ccccc3oc2c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccc(NC(C)=O)cc1C2=C1CCNCC1

Procedure:
Compound 10f was synthesized by an adaptation of Procedure 7, substituting compound 7f for compound 6a, and substituting N-Boc-piperidone for N-carbethoxynortropinone. MS m/z=420.3 (M+1).