Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[C:27]1([CH:33]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]([C:43]3[CH:48]=[CH:47][C:46]([O:49][C:50]([F:53])([F:52])[F:51])=[CH:45][C:44]=3[OH:54])[C:35]2=[O:55])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([CH:33]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]([CH2:5][OH:16])([C:43]3[CH:48]=[CH:47][C:46]([O:49][C:50]([F:52])([F:53])[F:51])=[CH:45][C:44]=3[OH:54])[C:35]2=[O:55])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: O=C1C(c2ccc(OC(F)(F)F)cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(CO)c1ccc(OC(F)(F)F)cc1O

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 1-(diphenylmethyl)-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-1,3-dihydro-2H-indol-2-one, the title compound was obtained: MS (ES+) m/z 488 (M−17), 528 (M+23).
Reaction SMILES: N([O-])=O.[Na+].C(O)(=O)C.[F:9][C:10]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:11]=1N.[BrH:18]>S(=O)(=O)(O)O.[Cu](Br)Br.O>[Br:18][C:11]1[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:10]=1[F:9]
Reactant: Nc1ccc(I)cc1F
Reactant: Br
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Fc1cc(I)ccc1Br
Reaction time: 2 h

Procedure:
Sodium nitrite (51.2 g) was dissolved in sulfuric acid (390 ml), and then acetic acid (454 ml) was added thereto at 10° C. or lower. The mixed solution was kept at 20° to 25° C., and 2-fluoro-4-iodoaniline (124 g) was added for 1 hour, followed by stirring for 2 hours. The reaction solution was added dropwise to a mixed solution of copper bromide (130 g) with 48% hydrobromic acid (390 ml), and stirred overnight. Then, water (1000 ml) was added to the solution, and the resulting solution was extracted with chloroform, followed by washing with water 3 times. After distilling off chloroform, the resultant was distilled under reduced pressure (b.p. 120° to 125° C./13 mmHg), and then recrystallized from methanol to give 1-bromo-2-fluoro-4-iodobenzene (114 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]=[CH:5]2.[O:13]1[C@@H:15]([CH2:16][CH3:17])[CH2:14]1.[F-].[Cs+].CN(C=O)C>O>[OH:13][C@@H:15]([CH2:16][CH3:17])[CH2:14][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]=[CH:5]2
Reactant: O=c1occc2cc(O)ccc12
Reactant: CC[C@H]1CO1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](O)COc1ccc2c(=O)occc2c1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
A mixture of 6-Hydroxy-isochromen-1-one (405 mg), (S)-(−)-1,2-epoxybutane (361 mg), cesium fluoride (1.1 g) and DMF (5 mL) was stirred for 4 h at 130° C. After adding water it was extracted with dichloromethane, dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. In this way the product was obtained with molecular weight 234.25 (C13H1404); MS (ESI): 235 (M+H+).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:3][CH:2]=1.C1C(=O)N([Br:28])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:20][C:1]1[CH:2]=[CH:3][C:4]([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc2nc(-c3ccc(C)cc3)oc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc2nc(-c3ccc(CBr)cc3)oc12
Yield: 77.2 %

Procedure:
To a mixture of methyl 2-p-tolylbenzo[d]oxazole-7-carboxylate (1 g, 3.74 mmol) in CCl4 (7 mL) was added NBS (665 mg, 3.74 mmol) and BPO (52 mg, 0.37 mmol), heated to reflux for 24 hr, then the solvent was evaporated, and purified by silica gel chromatography (petroleum ether:ethyl acetate=100:1-50:1) to obtain methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate as a white solid (1.0 g, yield 77%). LC-MS (ESI) m/z 346 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[CH:9]=[C:10]([C:12](O)=[O:13])[O:11][C:7]=2[CH:6]=1)=[O:4].C[N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>CN(C=O)C.[Na+].[Cl-]>[NH2:18][C:12]([C:10]1[O:11][C:7]2[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:16]=[CH:15][C:8]=2[CH:9]=1)=[O:13]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1ccc2cc(C(=O)O)oc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2cc(C(N)=O)oc2c1
Reaction time: 3 h
Yield: 80.8 %

Procedure:
6-(Methoxycarbonyl)-1-benzofuran-2-carboxylic acid (220 mg, 1.0 mmol) is combined with HATU (570 mg, 1.5 mmol) in DMF (4 mL). The mixture is treated portionwise with DIEA (350 μL, 2.0 mmol) and NH4Cl (183 mg, 3.4 mmol) and stirred for 3 h. The mixture is diluted with saturated NaCl (50 mL) and extracted with EtOAc (3×20 mL). The combined organics are washed with 2N HCl (2×10 mL), followed by water (2×10 mL), saturated NaHCO3 (2×10 mL) and additional H2O (2×10 mL) then dried (Na2SO4) and concentrated to afford 177 mg (81%) of methyl 2-(aminocarbonyl)-1-benzofuran-6-carboxylate as an orange-brown solid. HRMS (FAB) calcd for C11H9NO4+H: 220.0610, found 220.0603 M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:4](=[O:25])[N:3]=1.[CH2:26]([NH2:28])[CH3:27]>C(O)C>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]3[C:9]=2[CH2:8][N:5]2[CH:6]=[CH:7][C:2]([NH:28][CH2:26][CH3:27])=[N:3][C:4]2=[O:25])=[CH:23][CH:22]=1
Reactant: O=c1nc(Cl)ccn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: CCN
Solvent: CCO
Product: CCNc1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)n1
Temperature: 70 °C

Procedure:
A mixture of 4-chloro-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-one (50 mg, 0.13 mmol) and ethylamine (30 μl) in ethanol (2 ml) in a sealed tube was heated at 70° C. for 4 hours. Excess reagent was evaporated under reduced pressure. Crude product was dissolved in CH2Cl2 (10 mL) was washed with water, sat. NaHCO3 and brine, dried and evaporated. The crude product was purified by silica gel chromatography. M/e+ 380 for C20H19ClN5O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.42 (d, J=6.6 Hz, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.64 (d, J=9.1 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.29 (d, J=7.7 Hz, 1H), 6.87 (t, J=6.9 Hz, 1H), 6.65 (d, J=7.3 Hz, 1H), 5.37 (d, J=7.3 Hz, 2H), 4.97 (s, 1H), 3.51 (m, 2H), 3.18 (s, 1H), 1.18 (t, J=7.3 Hz, 3H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[C:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>C(O)(=O)C.[Pd]>[OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(O)cc2)S1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
To a suspension of 51 (6.00 g, 27 mmol) in glacial acetic acid (100 mL) was added ammonium formate (6.27 g, 100 mmol) and 10% Pd on carbon (5.80 g) and the mixture was heated to vigorous reflux for 16 h. The mixture was cooled to room temperature then filtered through Celite. Most of the acetic acid was removed in vacuo then the crude product was dissolved in ethyl acetate (250 mL), washed with water (2×250 mL) then brine (250 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to yield a beige solid (5.35 g, 85%). 1H NMR: (400 MHz, DMSO-d6): δ 11.98 (bs, 1H), 9.32 (s, 1H), 7.02 (d, J=8.4 Hz, 2H), 6.68 (d, J=8.4 Hz, 2H), 4.82 (dd, J=8.4 and 4.0 Hz, 1H), 3.25 (dd, J=14.4 and 4.4 Hz, 1H), 2.99 (dd, J=14.0 and 9.2 Hz, 1H).
Reaction SMILES: C([O:4][C@H:5]([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[C:16]([Br:22])=[N:15][C:14]=2[N:13]([CH3:23])[C:11]1=[O:12])(=O)C.Cl>CO.CCOCC>[Br:22][C:16]1[N:17]([CH3:21])[C:18]2[C:19](=[O:20])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:24])[C:11](=[O:12])[N:13]([CH3:23])[C:14]=2[N:15]=1
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(Br)n2C)n(C)c1=O
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: C[C@@H](O)CCCCn1c(=O)c2c(nc(Br)n2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.9 %

Procedure:
To a solution of (R)-1-(5-acetoxyhexyl)-8-bromo-3,7-dimethylxanthine (5.88 g, 14.7 mmol) in methanol (200 ml) was added a solution of hydrogen chloride in ether (1.0 M, 20 ml). The reaction mixture was stirred at room temperature for 24 hours. Evaporation of the solvent under reduced pressure provided (R)-8-bromo-3,7-dimethyl-1-(5-hydroxyhexyl)xanthine (4.8 g, 91% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:12].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[F:11][C:9]1[CH:8]=[C:7]2[C:3]([CH2:4][O:5][C:6]2=[O:12])=[C:2](/[N:1]=[CH:18]/[C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)[CH:10]=1
Reactant: Nc1cc(F)cc2c1COC2=O
Reactant: O=Cc1ccc(F)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: O=C1OCc2c(/N=C/c3ccc(F)cc3)cc(F)cc21
Yield: 34.6 %

Procedure:
4-amino-6-fluoroisobenzofuran-1(3H)-one (1.5 g, 8.98 mmol), 4-fluorobenzaldehyde (1.67 g, 13.47 mmol) and 12.75 g of MgSO4 were added into 40 ml of DCM and stirred under reflux overnight, then the mixture was evaporated under reduced pressure and the residues was dried in vacuum. 850 mg of (E)-6-fluoro-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one was obtained. 1H-NMR (400 MHz, CDCl3) δ (ppm): 5.37 (s, 2); 7.09-7.12 (dd, 1H), 7.19-7.23 (t, 2H), 7.43-7.45 (dd, 1H), 7.92-7.95 (m, 2H), 8.49 (s, 1H); LC-MS (ESI) m/z: 274 (M+1)+.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25](C)([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:10][N:9]=2)=[CH:6][CH:5]=[C:4]([CH3:29])[N:3]=1.C(O)(C(F)(F)F)=O.C(N(C(C)C)CC)(C)C.ClC(OC(C)C)=O>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][CH:25]([CH3:26])[CH3:27])=[O:23])[CH2:20][CH2:21]3)=[CH:10][N:9]=2)=[CH:6][CH:5]=[C:4]([CH3:29])[N:3]=1
Reactant: Cc1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c(F)n1
Agent: CC(C)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cn2)c(F)n1

Procedure:
The title compound (0.166 g, 96%) was prepared as a white solid from 1,1-dimethylethyl 4-{[(2′-fluoro-6′-methyl-2,3′-bipyridin-5-yl)oxy]methyl}-1-piperidinecarboxylate (0.18 g, 0.45 mmol) and TFA (0.35 mL) in CH2Cl2 (10 mL) then diisopropylethylamine (2.0 mL) and isopropyl chloroformate (1.0M in toluene, 0.54 mL, 0.54 mmol) in a manner similar to Example 74. The crude material was purified by chromatography on a silica gel column eluted with 1:10 acetone/CH2Cl2 to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.45-8.35 (m, 2H), 7.82 (d, 1H, J=8.6 Hz), 7.30-7.25 (m, 1H), 7.20-7.10 (m, 1H), 4.91 (septet, 1H, J=6.3 Hz), 4.22 (bs, 2H), 3.89 (d, 2H, J=6.4 Hz), 2.85-2.70 (m, 2H), 2.53 (s, 3H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.40-1.20 (m, 8H); LRMS (ESI), m/z 388 (M+H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.Cl.[NH2:15][C:16]([CH3:25])([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].O>ClCCl>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:15][C:16]([CH3:25])([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc(Br)s1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)C(C)(C)NC(=O)c1ccc(Br)s1

Procedure:
2.63 g (12.3 mmol) 5-bromo-thiophene-2-carboxylic acid are refluxed in 15 ml dichloromethane together with 7.0 ml of thionyl chloride for 2 h with stirring. The mixture is then evaporated down i. vac. and the residue is twice taken up in toluene and evaporated down completely i. vac. The residue is added dropwise to 10 ml dichloromethane with stirring at ambient temperature in a mixture of 2.41 g (12.3 mmol) tert.-butyl 2-amino-isobutyrate hydrochloride in 20 ml dichloromethane with 5.14 ml (36.9 mmol) TEA and stirred for 16 h. The mixture is poured into water and extracted with dichloromethane, the combined organic phases are dried over magnesium sulphate and evaporated down i. vac.
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[I-].[K+].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CNCCN1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Yield: 11.1 %

Procedure:
A stirred mixture of diphenylmethyl bromide (40 g, 0.16 mol), piperazine (27.8 g, 0.32 mol), potassium iodide (26.8 g, 0.16 mol) and sodium carbonate (86 g, 0.81 mol) in toluene (400 ml) was heated at reflux for 3.5 hr. The reaction mixture was filtered. The filtrate was evaporated to dryness to give 40 g of crude product. The crude product was purified by chromatography using 10% methanol in chloroform as the eluant. Pooling of the appropriate fractions gave 4.5 g of the title compound, NMR (CDCl3) δ1.82 (s,1H), 2.3(t,J=5 Hz,4H), 2.85 (t,J=5 Hz, 4H), 4.2 (s,1H), 7.3 (m,10H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Product: CC1(C)CC(Nc2nccc(-c3ccc(Br)cc3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 4-bromophenylboronic acid according to Method C (Example 178).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8]Cl)[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:10][C:11]1[CH:12]=[C:13]([N:20]=[C:21]=[S:22])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]>>[CH3:10][C:11]1[CH:12]=[C:13]([N:20]=[C:21]2[S:22][CH2:8][C:3]3([CH2:7][CH2:6][CH2:5][CH2:4]3)[NH:2]2)[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: NC1(CCl)CCCC1
Reactant: Cc1cc(N=C=S)ccc1[N+](=O)[O-]
Agent: Cl
Product: Cc1cc(N=C2NC3(CCCC3)CS2)ccc1[N+](=O)[O-]

Procedure:
3-Methyl-4-nitroaniline was converted to 3-methyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 3-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(3-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(3-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[Na].[CH3:21][OH:22]>ClCCl.CO>[N+:17]([C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:2]=1[O:22][CH3:21])([O-:19])=[O:18]
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccccc1
Reactant: CO
Agent: [Na]
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2ccccc2)cc1[N+](=O)[O-]

Procedure:
Prepared according to the procedure described for Example 10, Step A from N-(4-fluoro-3-nitrophenyl)-benzamide (5.2 g, 20 mmol) and sodium (1.3 g, 57 mmol) using methanol in place of ethanol to afford the product (3.7 g) after chromatography on silica gel in dichloromethane/methanol 99:1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)N=N[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:27]1(C)C=CC(C)=C[CH:28]=1.C12CC(C=C1)C=C2.O>C(OCC)(=O)C.CCCCCC>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:27]=[CH:28][C:10]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: Brc1ccc(-c2nnc(-c3cccnc3)nc2-c2ccc(Br)cc2)cc1
Reactant: Cc1ccc(C)cc1
Agent: C1=CC2C=CC1C2
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Brc1ccc(-c2ccc(-c3cccnc3)nc2-c2ccc(Br)cc2)cc1
Temperature: 150 °C
Yield: 28 %

Procedure:
Into a 200 mL three-neck recovery flask, 2.4 g (5.0 mmol) of 5,6-bis(4-bromophenyl)-3-(3-pyridyl)-1,2,4-triazine, 60 mL of para-xylene, and 2.5 mL (23 mmol) of 2,5-Norbornadiene were put. This solution was refluxed at 150° C. for 20 hours under a nitrogen stream. After a certain time, water was added to the mixture, and an aqueous layer was extracted with toluene. The obtained extract was washed with a saturated saline together with an organic layer and the organic layer was dried over magnesium sulfate. The mixture was subjected to gravity filtration, and the obtained filtrate was concentrated to give a solid. The obtained solid was refined with silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized with chloroform/hexane, so that an objective substance, 0.68 g of yellow powder was obtained in a yield of 28%.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:15]1([C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:22][CH:23]=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[ClH:31]>O1CCCC1.C(OCC)C.C(O)C>[ClH:31].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:23]3[N:26]4[C:25]([CH:30]=[CH:29][CH:28]=[CH:27]4)=[C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:22]=3)[CH2:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: O=CC=C(c1ccccc1)c1ccccn1
Reactant: Cc1ccc(CN2CCNCC2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(CN2CCN(c3cc(-c4ccccc4)c4ccccn34)CC2)cc1
Temperature: 66 °C
Reaction time: 8 h

Procedure:
A solution of 1-(4-methylbenzyl)piperazine (14 g) in tetrahydrofuran (30 cc) is added in the course of 15 minutes at a temperature in the region of 20° C. to a stirred solution of 3-phenyl-3-(2-pyridyl)propenal (5.4 g) in tetrahydrofuran (150 cc), and the mixture is left with stirring for 8 hours at a temperature in the region of 66° C. After the solution is cooled to a temperature in the region of 20° C., the reaction mixture is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in ethyl ether (50 cc) and the solution obtained poured onto silica (400 g) contained in a column 4.7 cm in diameter. Elution is performed with a mixture (300 cc) of ethyl ether and petroleum ether (40°-65° C.) (80:20 by volume) and the corresponding eluate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The oil obtained is dissolved in boiling ethyl ether (200 cc). A boiling 2.5N solution (3 cc) of hydrochloric acid in ethyl alcohol is added. After the mixture is cooled to a temperature in the region of 20° C, the precipitate formed is separated by filtration and then recrystallized in boiling ethyl alcohol (400 cc). 3-[4-(4-Methylbenzyl)-1-piperazinyl]-1-phenylindolizine hydrochloride (3.1 g), m.p. 210° C. with decomposition, is thereby obtained.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Cl:20][C:21]1[C:29]([Cl:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Cl:20][C:21]1[C:29]([Cl:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(c1cc(Cl)cc(Cl)c1Cl)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,3,5-Trichlorobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,3,5-trichlorobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([CH3:21])[CH2:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15][O:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.N1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([CH3:21])[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH2:15][O:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(CCCCOCc2ccccc2)CCCC(O)CO1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(CCCCOCc2ccccc2)CCCC(=O)CO1
Reaction time: 2 h
Yield: 101.6 %

Procedure:
Dry celite (50 g) and 2-(4'-benzyloxybutyl)-2-methyloxepane-6-ol (6.9 g, 0.02 mol) in methylene chloride are added to a pyridine-chromium trioxide solution [prepared from pyridine (22.4 g, 0.284 mol) and chouromium trioxide (14.2 g, 0.142 mol)] in dry methylene chloride (800 ml) at 10° C. in a nitrogen atmosphere. After 2 hours of stirring the mixture is filtered and the celite cake is washed with methylene chloride (10×50 ml). The solvent is removed at reduced pressure. The residue is diluted with ether (200 ml), filtered and the solvent is removed at reduced pressure. The crude product is chromatographed on SilicAR CC-7 (150 g) in hexane. Elution with 10% ethyl acetate/hexane gives 2-(4'-benzyloxybutyl)-2-methyl-oxepan-6-one (11) as a clear colorless oil (5.9 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([C:16]2[CH:20]=[CH:19][NH:18][N:17]=2)[C:12]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)=[N:11]1.O.NN>[Ni].CO>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([C:16]2[CH:20]=[CH:19][NH:18][N:17]=2)[C:12]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=2)=[N:11]1
Reactant: O=C(NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1c1cc[nH]n1)c1cccc([N+](=O)[O-])c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1cccc(C(=O)NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2c2cc[nH]n2)c1
Reaction time: 1.5 h
Yield: 68.6 %

Procedure:
Next, 197.5 g (0.4 mol) of the 1-(2,4,6-trichlorophenyl)-3-(3-nitrobenzamido)-4-pyrazolyl-5-oxo-2-pyrazoline was added to 2l of methanol, to which was added a small amount of Raney nickel. Then 120 ml of hydrazine hydrate was slowly added dropwise with heating and stirring, the mixture rcacted for about 1.5 hours, after which the insolubles were filtered out (while the mixture was hot). The filtrate was poured into water, and the deposited crystals were then filtered and washed with methanol to obtain 127.2 g (68%) of 1-(2,4,6-trichlorophenyl)-3-(3-aminobenzamido)-4-pyrazolyl-5-oxo-2-pyrazoline.