Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][C:9]1[N:13]([CH2:14][CH:15]([OH:17])[CH3:16])[N:12]=[C:11]([Br:18])[C:10]=1[N+:19]([O-])=O)C1C=CC=CC=1.[OH-].[Na+].Br>CCO.[Pd]>[BrH:18].[NH2:19][C:10]1[CH:11]=[N:12][N:13]([CH2:14][CH:15]([OH:17])[CH3:16])[C:9]=1[NH2:8]
Reactant: CC(O)Cn1nc(Br)c([N+](=O)[O-])c1NCc1ccccc1
Agent: [Pd]
Agent: Br
Agent: [Na+]
Solvent: CCO
Product: CC(O)Cn1ncc(N)c1N
Reaction time: 2 h
Yield: 69.3 %

Procedure:
A mixture of 1-(5-benzylamino-3-bromo-4-nitropyrazol-1-yl)propan-2-ol (4-3) (5.0 g; 14.0 mmol) in EtOH (140 ml) containing 10% Pd/C as catalyst (Engelhard, 50% wet, 0.5 g dry weight) and NaOH (solid, 560 mg, 14 mmol) was hydrogenated in an autoclave (1 l) at 11 bar for 2 hours. The reaction mixture was filtered to remove the catalyst, under an inert atmosphere in an ethanolic solution containing HBr (47%, 9.7 ml, 78 mmol). The solvent was evaporated off under reduced pressure to give a solid. After washing with cold EtOH, the 1-(4,5-diaminopyrazol-1-yl)propan-2-ol was obtained in the form of the hydrobromide (3.47 eq HBr) as a white solid (2.3 g, 42%).
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)=[N:3]1.O.[NH2:25]N.O.C([O-])(O)=O.[Na+]>Cl.C(O)(=O)C>[CH3:14][O:13][C:10]1[CH:9]=[C:8]2[C:7](=[CH:12][CH:11]=1)[C:4](=[O:5])[NH:3][N:25]=[C:15]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(C(=O)c2ccccc2)c1
Reactant: NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(=O)[nH]nc(-c3ccccc3)c2c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 21.6 %

Procedure:
A suspension of [2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-methoxy-phenyl]-phenyl-methanone (3.4 g, 11 mmoles), prepared as described in example 12, in 3N HCl (45 ml) was refluxed under stirring for 2 days, then added with 36% HCl (10 ml). After 20 hours the mixture was cooled and extracted more times with CHCl3. The organic phases were anhydrified and brought to dryness. The residue was dissolved in acetic acid and treated with hydrazine monohydrate (0.96 g, 19.24 mmoles) in acetic acid (7 ml). The mixture was heated to 80° C. under dry N2 and stirring for 20 hours, then brought to small volume, poured into water, neutralised with NaHCO3 in excess and extracted with CHCl3. The organic phases anhydrified and brought to dryness yielded 0.6 g of the title compound (yield: 37%). m.p.: 230-235° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:9]1([S:15]([O:8][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[O:1])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [O-][n+]1ccccc1O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=c1ccccn1OS(=O)(=O)c1ccccc1
Yield: 77 %

Procedure:
2-Hydroxypyridine-1-oxide (1.0 g, 9.1 mmol) was reacted with benzenesulfonyl chloride (1.27 mL, 10.0 mmol) in 75 mL of pyridine to afford PZBG-1a in 77% yield (1.75 g, 7.0 mmol). 1H NMR (500 MHz, CDCl3) δ=8.02 (d, J=8.0 Hz, 2H), 7.75 (t, J=8.0 Hz, 1H), 7.59 (m, 3H), 7.28 (dt, J1=6.9 Hz, J2=2.3 Hz, 1H), 6.52 (d, J=9.8 Hz, 1H), 6.15 (t, J=7.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ=157.0, 139.7, 137.1, 136.0, 133.8, 130.0, 129.5, 123.4, 105.4. ESI-MS(+): m/z 252.01 [M+H]+, 273.95 [M+Na]+. Anal. calcd for C11H9NO4S: C, 52.58; H, 3.61; N, 5.57. Found: C, 52.21; H, 3.99; N, 5.44.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1([CH3:18])[CH2:12][CH:11]([NH:13][CH2:14][CH3:15])[CH2:10][C:9]([CH3:17])([CH3:16])[NH:8]1.[OH-].[Na+]>C(Cl)Cl.O>[Cl:1][CH2:2][C:3]([N:13]([CH2:14][CH3:15])[CH:11]1[CH2:12][C:7]([CH3:6])([CH3:18])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CCNC1CC(C)(C)NC(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCN(C(=O)CCl)C1CC(C)(C)NC(C)(C)C1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of 23.16 g (0.205 mol) of chloroacetyl chloride in 30 ml of methylene chloride is slowly added to a solution of 36.85 g (0.2 mol) of N-(2,2,6,6-tetramethyl-piperidin-4-yl)-ethylamine in 160 ml of methylene chloride cooled to -20° C., taking care that the temperature does not rise above -10° C. The mixture is stirred for one hour and then left to stand, allowing the temperature to rise to 0° C.; a solution of 8.4 g (0.21 mol) of sodium hydroxide in 35 ml of water is then added in the course of 1 hour.
Reaction SMILES: CC1(C)[N:6](C([O-])=O)CCO1.[N+](C1C=C([N+]([O-])=O)C=CC=1[N:23]1[C:27]([CH2:28][C@@H:29]([C:31]([OH:33])=O)N)=[CH:26][N:25]=[CH:24]1)([O-])=O>>[NH:25]1[CH:26]=[C:27]([CH2:28][CH2:29][C:31]([NH2:6])=[O:33])[N:23]=[CH:24]1
Reactant: CC1(C)OCCN1C(=O)[O-]
Reactant: N[C@@H](Cc1cncn1-c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O
Product: NC(=O)CCc1c[nH]cn1

Procedure:
In an analogous manner to that described in Example 16, by reacting t-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(R or S)-hydroxy-[(R or S)-tetrahydro-2-furyl]-methyl]-2,2-dimethyl-3-oxazolidinecarboxylate with N-](S)-α-[(t-butylsulphonyl)methyl]hydrocinnamoyl]-3-(2,4-dinitrophenyl)-L-histidine there is obtained (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3R or S)-1-(cyclohexylmethyl)-2,3-dihydroxy-3-[(R or S)-tetrahydro-2-furyl]propyl]imidazole-4-propionamide in the form of a yellow amorphous powder, MS: 827 (M+H)+. The cleavage of the dinitropheyl group with thiolactic acid is effected in an analogous manner to Example 13 and yields (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hudrocinnamamido]-N-[(1S,2R,3R or S)-1-(cyclohexylmethyl)-2,3-dihydroxy-3-[(R or S)-tetrahydro-2-furyl]propyl]imidazole-4-propionamide as a pale yellow amorphous solid, MS: 661 (M+H)+.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:21]([N:22]2[CH2:27][CH2:26][CH:25]3[NH:28][CH2:29][CH2:30][CH:24]3[CH2:23]2)=[CH:20][C:19]([C:31]#[N:32])=[CH:18][C:17]=1[NH:33][C:34]1[N:39]=[C:38]([N:40]([CH:50]2[CH2:52][CH2:51]2)[CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:37]2=[N:53][CH:54]=[C:55]([C:56]#[N:57])[N:36]2[N:35]=1.C=O.C(O)(=O)C>ClCCl>[Cl:15][C:16]1[C:21]([N:22]2[CH2:27][CH2:26][CH:25]3[N:28]([CH3:1])[CH2:29][CH2:30][CH:24]3[CH2:23]2)=[CH:20][C:19]([C:31]#[N:32])=[CH:18][C:17]=1[NH:33][C:34]1[N:39]=[C:38]([N:40]([CH:50]2[CH2:52][CH2:51]2)[CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=2)[C:37]2=[N:53][CH:54]=[C:55]([C:56]#[N:57])[N:36]2[N:35]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC5NCCC5C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC5C(CCN5C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
Sodium triacetoxyborohydride (20.66 mg, 0.097 mmol) was added to a solution of 2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 442F, 29 mg, 0.049 mmol), paraformaldehyde (14.63 mg, 0.487 mmol) and acetic acid (5.58 μl, 0.097 mmol) in dichloromethane (2 mL) and the reaction mixture was stirred at room temperature for 5 hours. More paraformaldehyde (14.63 mg, 0.487 mmol) and sodium triacetoxyborohydride (20.66 mg, 0.097 mmol) were added and stirring continued overnight. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The aqueous layer was extracted with dichloromethane two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (80 g column, eluting with 5-30% ethyl acetate/hexanes). 2-((2-chloro-5-cyano-3-(1-methylhexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (27 mg) was obtained as a white solid.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]2)=[N:27][CH:28]=1>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:35][CH:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][N:27]=3)[CH2:30][CH2:31]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCN(c2ccc(F)cn2)CC1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(c3ccc(F)cn3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 130 °C
Yield: 57.5 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.175 g, 0.58 mmol), 1-(5-fluoropyridin-2-yl)piperidin-4-amine dihydrochloride (0.155 g, 0.58 mmol) and TEA (0.23 g, 2.31 mmol) was dissolved in dry DMF (3 ml) and heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was purified by preparative HPLC to yield the title compound (0.153 g, 58%). 1H NMR (500 MHz, CDCl3): δ 8.01-7.95 (m, 1H), 7.56-7.49 (m, 2H), 7.48-7.39 (m, 3H), 7.23-7.16 (m, 1H), 6.56-6.48 (m, 1H), 5.25-5.15 (m, 1H), 3.98-3.86 (m, 2H), 3.17-3.04 (m, 1H), 2.47-2.36 (m, 2H), 1.80-1.64 (m, 2H), 1.72 (s, 9H), 1.43-1.30 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 159.9, 156.1, 154.7, 152.7, 134.8, 134.6, 134.1, 131.9, 130.1, 128.9, 125.3, 108.3, 107.3, 61.8, 50.5, 45.0, 32.0, 27.8; Mass Spectrum: M−H+ 459.
Reaction SMILES: [C:1](OC1C2C(=CC=CC=2)N(CCC)C1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:28](=[O:39])[C:27]2=[O:40]>>[C:1]([O:40][CH:27]1[C:26]2[C:30](=[CH:31][CH:32]=[C:24]([CH3:23])[CH:25]=2)[N:29]([CH2:33][CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38])[C:28]1=[O:39])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCCC(C)C
Product: Cc1ccc2c(c1)C(OC(=O)c1ccccc1)C(=O)N2CCCC(C)C

Procedure:
Was made in a similar way to 2-oxo-1-propylindolin-3-yl benzoate starting from 5-methyl-1-(4-methylpentyl)indoline-2,3-dione. 1H-NMR δ 8.11 (d, 2H), 7.58 (dt, 1H), 7.45 (m, 2H), 7.25 (s, 1H), 7.15 (dd, 1H), 6.77 (d, 1H), 6.17 (s, 1H), 3.70 (m, 2H), 2.31 (s, 3H), 1.73 (m, 2H), 1.61 (m, 1H), 1.29 (m, 2H), 0.90 (d, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([C@H:21]1[C@@H:25]([CH2:26][OH:27])[O:24][C:23](=[O:28])[NH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>C1COCC1.CN1CCOCC1>[CH2:14]([C@H:21]1[C@@H:25]([CH2:26][O:27][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[O:24][C:23](=[O:28])[NH:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)[C@@H](CO)O1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C1N[C@@H](Cc2ccccc2)[C@@H](COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)O1
Reaction time: 4.5 h
Yield: 94.2 %

Procedure:
15.4 g of p-nitrobenzenesulphonyl chloride are added in portions at 20-25° C. to a stirred suspension of 12.0 g of the alcohol from Example 8 in 35 ml of THF and 7.66 ml of N-methylmorpholine and stirred for 4.5 hours. The suspension is again treated with 0.77 ml of N-methylmorpholine and stirred at 22° C. for 4.5 hours. The mixture is treated with 70 ml of a 2% sodium bicarbonate solution, stirred for 1.5 hours, filtered, the residue is washed with water and ethanol and dried to give 21.4 g (94%) of 98.5% p-nitrobenzenesulphonic acid (4S,5S)-4-benzyl-2-oxo-oxazolidin-5-ylmethyl ester, m.p. 148-149.5° C., [α]D20 : +10.0° (1% acetone).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15](Cl)(=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25]>C1(C)C=CC=CC=1>[C:15](=[O:26])([S:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25]
Reactant: C=CCCCCCCCCC(=O)Cl
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCCCCCCCCC(=O)Sc1ccccc1

Procedure:
A 50-mL, one-necked, round-bottomed flask was charged with 10 mL toluene, triethylamine (0.70 mL, 5.0 mmol) and thiophenol (0.51 mL, 5.0 mmol). A solution of 10-undecenoyl chloride (1.10 mL, 5.1 mmol) in 15 mL toluene was added by a pressure-equalizing dropping funnel over 30 min while stirring the solution with a magnetic stirrer.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=2[C:26]([O:28][CH3:29])=[O:27])[CH:5]=[CH:4][N:3]=1.P(Br)(Br)[Br:31]>ClC(Cl)C(Cl)Cl>[Br:31][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=2[C:26]([O:28][CH3:29])=[O:27])[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(Cl)c2)c1C(=O)OC
Reactant: BrP(Br)Br
Solvent: ClC(Cl)C(Cl)Cl
Product: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(Br)c2)c1C(=O)OC
Temperature: 100 °C
Reaction time: 10 h

Procedure:
A mixture of 1-(2-chloro-4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene (22.7 g), phosphorus tribromide (52 ml) and 1,1,2,2-tetrachloroethane (100 ml) is stirred at 100° C. for 10 hours. After the reaction is complete, the mixture is concentrated under reduced pressure to remove the solvent, and thereto are added methylene chloride and an aqueous potassium carbonate solution. The methylene chloride layer is separated, and concentrated under reduced pressure to remove the solvent. The residue is crystallized from methanol to give 1-(2-bromo-4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene (17.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:34])([CH3:33])[C:13](=[O:32])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:25]=4[CH3:31])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)=O.C1COCC1.Cl[CH:44]([F:46])[F:45]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CO.O1CCOCC1.O.C(OCC)C>[F:45][CH:44]([F:46])[O:30][C:28]1[CH:27]=[CH:26][C:25]([CH3:31])=[C:24]([C:22]([N:19]2[CH2:20][CH2:21][CH:16]([N:14]3[C:13](=[O:32])[C:12]([CH3:34])([CH3:33])[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:15]3)[CH2:17][CH2:18]2)=[O:23])[CH:29]=1
Reactant: FC(F)Cl
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(O)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C=O
Agent: [I-]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OC(F)F)ccc4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
In a pressure vessel 0.47 g of 5-(3,4-dimethoxyphenyl)-2-{1-[(5-hydroxy-2-methylphenyl)carbonyl]piperidin-4-yl}-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 85) and 37 mg tetrabutylammonium iodide are solved in a mixture of 20 ml methanol and 5 ml dioxane. After the reaction mixture has been frozen to a solid block upon cooling with dry ice, a layer of 4 ml THF is placed above the frozen reaction mixture and the pressure vessel is charged with 2.8 g of chloro(difluoro)methane. The pressure vessel is heated for 90 minutes to 70° C. and after the reaction mixture has reached RT, it is portioned between diethyl ether and water. After separation of the phases, the organic phase is washed with brine, dried over MgSO4, and the solvents are removed under reduced pressure. The crude product is purified by chromatography (silica gel and DCM) to yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:12]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1>[Br:8][C:9]1[CH:10]=[C:11]([CH2:12][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc([N+](=O)[O-])c(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CN1CCN(Cc2ccc([N+](=O)[O-])c(Br)c2)CC1
Reaction time: 2 h
Yield: 87.8 %

Procedure:
N-methyl piperazine (0.95 mL, 8.56 mmol) was added dropwise to a suspension of 3-bromo-4-nitrobenzaldehyde (0.985 g, 4.28 mmol) and acetic acid (0.29 mL, 5.14 mmol) in toluene (5.5 mL) at room temperature. The reaction mixture was stirred for 1 h at room temperature before the addition of sodium triacetoxyborohydride (1.36 g, 6.42 mmol). The reaction mixture was stirred for 2 h. Further toluene (2.1 mL) and sodium triacetoxyborohydride (0.18 g, 0.86 mmol) was added and the reaction mixture was stirred for 2 hours and then quenched by the addition of MeOH (0.99 mL). The reaction mixture was stirred for 30 min, saturated aqueous NaHCO3 (6.01 mL) was then added and the reaction mixture was stirred overnight. The phases were separated and the aqueous layer was extracted with toluene (4.0 mL). The combined organic extracts were concentrated under reduced pressure and purified by flash column chromatography (EtOAc:MeOH:NEt3 9:1:0.1) to give the title compound (1.18 g, 88%) as a low melting point waxy brown solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]#[N:13])=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([NH:25][NH2:26])=O)[CH:19]=[CH:20][CH:21]=1>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][C:23]1[NH:13][C:12]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][N:4]=2)=[N:26][N:25]=1
Reactant: COc1cccc(CC(=O)NN)c1
Reactant: N#Cc1ncc2cccnc2c1O
Product: COc1cccc(Cc2nnc(-c3ncc4cccnc4c3O)[nH]2)c1

Procedure:
The title compound was prepared in a similar manner to that described in example 1 from of 8-hydroxy-1,6-naphthyridine-7-carbonitrile (50 mg, 0.29 mmol) and 2-(3-methoxyphenyl)acetic hydrazide (270 mg, 1.5 mmol) as a yellow solid (20 mg, 21%). 1H NMR (CDCl3): δ 9.19 (m, 1 H), 8.91 (s, 1 H), 8.31 (d, J=7.6 Hz, 1 H), 7.63 (m, 1 H), 7.22 (m, 1 H), 7.01-6.97 (m, 2 H), 6.83-6.79 (m, 2 H), 4.23 (s, 2 H), 3.79 (s, 3 H); MS m/z 334 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:3]=1[O:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.C=O.[BH3-][C:21]#N.[Na+].CC(O)=O>CC#N>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:3]=1[O:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH3:21]
Reactant: O=[N+]([O-])c1ccc(Cl)c(OC[C@@H]2CCCN2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCC[C@H]1COc1cc([N+](=O)[O-])ccc1Cl
Reaction time: 1 h

Procedure:
To (S)-2-(2-chloro-5-nitro-phenoxymethyl)-pyrrolidine (4.82 g, 18.77 mmol) in 167 mL CH3CN at RT was added 37% aqueous formaldehyde (7.58 mL) then NaCNBH3 (1.887 g, 30.03 mmol). The reaction was stirred for 1 h, as the reaction pH was adjusted every 10 min to about 7 by adding small amounts of HOAc. The reaction was concentrated to small aqueous volume and dissolved in 2 N NaOH (aq) and Et2O. The layers were separated, and the organic layer was washed twice with 2 N NaOH then extracted twice with 1 N HCl (aq). The combined acidic aqueous layers were basified to pH>12 with solid NaOH and extracted 3 times with EtOAc. The EtOAc layers were washed once with 2 N NaOH and then once with mix of brine and 2 N NaOH, combined, dried over Na2SO4, filtered, and concentrated to dryness, to yield the title compound.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:28]([C:32]1[CH:33]=[C:34]([CH:61]=[C:62]([C:64]([CH3:67])([CH3:66])[CH3:65])[CH:63]=1)[CH:35]=[CH:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([CH:45]=[CH:46][C:47]2[CH:52]=[C:51]([C:53]([CH3:56])([CH3:55])[CH3:54])[CH:50]=[C:49]([C:57]([CH3:60])([CH3:59])[CH3:58])[CH:48]=2)[CH:44]=1)[CH:40]=O)([CH3:31])([CH3:30])[CH3:29]>O1CCCC1>[C:28]([C:32]1[CH:33]=[C:34]([CH:61]=[C:62]([C:64]([CH3:67])([CH3:66])[CH3:65])[CH:63]=1)[CH:35]=[CH:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([CH:45]=[CH:46][C:47]2[CH:52]=[C:51]([C:53]([CH3:56])([CH3:55])[CH3:54])[CH:50]=[C:49]([C:57]([CH3:60])([CH3:59])[CH3:58])[CH:48]=2)[CH:44]=1)[CH:40]=[CH2:2])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1cc(C=Cc2cc(C=O)cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)c2)cc(C(C)(C)C)c1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1cc(C=Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)cc(C=Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.3 %

Procedure:
Dry tetrahydrofuran (300 ml) was added to a mixture of methyltriphenylphosphonium iodide (17.00 g, 42.0 mmoles) and potassium t-butoxide (4.72 g, 42.0 mmoles) and stirred at room temperature for 10 minutes. 3,5-bis(3′,5′-di-t-butylstyryl)benzaldehyde (17.00 g, 42.0 mmoles) was then added and the reaction mixture was stirred at room temperature for 75 minutes. The solvent was then evaporated and the remaining sludge was triturated with dichloromethane—pet.ether (40-60) (1:9) and filtered through silica, rinsing thoroughly with the same solvent mixture. The solvent was evaporated to give 3,5-bis(3′,5′-di-t-butylstyryl)styrene (14.83 g, 99%), mp 150° C. (Found: C, 90.03; H, 9.98. C40H52 requires C, 90.16; H, 9.84%); λmax (CHCl3)/nm 318 (ε/dm3 mol-1 cm-1 68500); δH(500 MHz; CDCl3) 1.39 (36 H, s, tBu), 5.34 (1 H, d, J 11, 8-H), 5.88 (1 H, d, J 18, 8-H), 6.79 (1 H, dd, J 11 and 18, 7-H), 7.15 (2 H, d, J 16, 7′-H), 7.25 (2H, d, J 16, 8′-H), 7.38 (2 H, t, J 1.75, 1′-H), 7.42 (4 H, d, J 1.75, 3′,5′-H), 7.49 (2 H, d, J 1.3, 3,5-H), 7.63 (1H, m, 1-H).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[Br:19][C:20]1[CH:21]=[C:22]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]([NH:26][C:27]([NH2:29])=[S:28])=[N:24][CH:25]=1.C(N(CC)CC)C>C(O)C>[Br:19][C:20]1[CH:21]=[C:22]([O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:23]([NH:26][C:27]2[S:28][CH:2]=[C:3]([CH2:4][CH:5]3[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[N:29]=2)=[N:24][CH:25]=1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)CBr)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Cc2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
Heated a mixture tert-butyl 4-(3-bromo-2-oxopropyl)piperidine-1-carboxylate (1.38 g, 4.32 mmol), 1-(5-bromo-3-phenoxypyridin-2-yl)thiourea (1.0 g, 3.08 mmol), triethylamine (0.731 mL, 5.24 mmol), and ethanol (50 mL) at reflux overnight. Cooled to ambient temperature and partitioned between into water and ethyl acetate. Washed the organic layer with water, brine, dried and concentrated. Purified by MPLC (Biotage) eluting with 3:1 hexane:ethyl acetate to afford the title compound (1.54 g, 92%) as a white powder: 1H NMR (CDCl3) δ 8.66 (s, 1H), 8.13 (s, 1H), 7.43 (t, 2H), 7.25 (t, 1H), 7.12 (s, 1H), 7.06 (d, 2H), 6.45 (s, 1H), 4.08 (m, 2H), 2.67 (m, 2H), 2.56 (d, 2H), 1.85 (m, 1H), 1.66 (m, 2H), 1.44 (s, 9H), 1.15 (m, 2H).