Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:16]2[C:15](=[O:17])[C:14]([C:18]([OH:20])=[O:19])=[CH:13][N:7]3[C@@H:8]([CH2:11][F:12])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:22].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][CH2:30][CH2:31][NH2:32].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:16]2[C:15](=[O:17])[C:14]([C:18]([OH:20])=[O:19])=[CH:13][N:7]3[C@@H:8]([CH2:11][F:12])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:32][CH2:31][CH2:30][NH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)[C:3]=1[F:22]
Reactant: NCCNc1ccccn1
Reactant: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3[C@@H](CF)CO2
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1c(F)c(NCCNc2ccccn2)c2c3c1c(=O)c(C(=O)O)cn3[C@@H](CF)CO2
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 67.1 %

Procedure:
A mixture of (3R)-8-amino-9,10-difluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (200 mg, 0.636 mmol), 2-(2-pyridylamino)ethylamine (131 mg, 0.955 mmol), and triethylamine (0.13 mL, 0.933 mmol) in DMSO (2.0 mL) was stirred at 120° C. for 2.5 h. After dilution of the reaction mixture with 10% MeOH in CHCl3, the whole mixture washed with water and the washing was extracted with 10% MeOH in CHCl3 three times. The combined the organic layer and the extracts washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography of the residue (10% MeOH in CHCl3) gave (3R)-8-amino-9-fluoro-3-fluoromethyl-2,3-dihydro-7-oxo-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (184 mg, 67%) as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][CH2:21][O:22][CH2:23]/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6](OC3C=CC=CC=3)[C:5]=2[N:19]=1.C([O-])(=O)C.[NH4+:36].[OH-].[K+]>>[CH3:1][C:2]1[N:3]([CH2:20][CH2:21][O:22][CH2:23]/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6]([NH2:36])[C:5]=2[N:19]=1
Reactant: [NH4+]
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOC/C=C/c3ccccc3)c2c1C
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: Cc1nc(N)c2nc(C)n(CCOC/C=C/c3ccccc3)c2c1C
Temperature: 150 °C
Yield: 31.7 %

Procedure:
1-[2,6,7-Trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]eth-2-yl [(2E)-3-phenylprop-2-enyl]ether (2.9 g, 7.013 mmol) from Part A and ammonium acetate (54 g) were combined in a glass pressure vessel. The vessel was sealed with a teflon screw cap, and the reaction mixture was heated to 150° C. for 45 hours. The reaction was complete, and the resulting reaction solution was cooled with an ice bath, basified to a pH of about 13 with 1N potassium hydroxide, and washed with dichloromethane (4×500 mL). The combined organic portions were washed with water (3×) and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a white solid. The resulting white solid was slowly passed through a column containing 200 g silica that had been heated with 1% diethyl ether in dichloromethane using 98/2 dichloromethane/methanol. Two crops of product were isolated from the eluted solution, and both were recrystallized from isopropyl alcohol. The resulting white powder was dried under vacuum for 18 hours to provide 0.7479 g of 2,6,7-trimethyl-1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 143.7-144.8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:18][CH3:19])[C:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:6](=[O:17])[CH:5]=[CH:4]1.[OH:20]O.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1([O:18][CH3:19])[C:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:6](=[O:17])[CH:5]2[CH:4]1[O:20]2
Reactant: COC1(OC)C=CC(=O)C=C1NC(=O)OC(C)(C)C
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC1(OC)C(NC(=O)OC(C)(C)C)=CC(=O)C2OC21
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Compound 3 (3.4 g, 12.7 mol) in tetrahydrofuran (93 mL) was cooled in an ice bath. To the stirring solution, in drop-wise fashion, was added hydrogen peroxide (30% aq., 22 mL) and aqueous sodium hydroxide (1M, 61 mL) in tandem using 2 separate addition funnels and utilizing a Claisen adapter. The reaction mixture was stirred for 30 minutes in the ice bath and then for 5 hours at room temperature. The flask was cooled in an ice bath and the peroxide was carefully quenched with manganese dioxide. After filtration of the mixture over a small bed of silica gel followed by rinsing of the silica gel with ethyl acetate, the mixture was washed with brine. The organics were then dried over anhydrous magnesium sulfate, filtered, and evaporated. The resulting oil was treated with pentane to precipitate an off white solid after solvent evaporation yielding 2 g (56%) of compound (4). 1H NMR indicated 20% starting material in the mixture, which was easily removed in the next step (treatment with TFA). The 1H NMR of the product was consistent with that reported in the literature (Synthesis 1998, 775).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([OH:28])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[N:11]2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[F:27])=[CH:6][C:5]=1[N+:29]([O-])=O)=[N+]=[N-].O1CCCC1.O.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Fe]>[Cl:26][C:22]1[C:21]([F:27])=[C:20]([N:11]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([NH2:29])[CH:6]=3)([OH:28])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:19])[CH:25]=[CH:24][CH:23]=1
Reactant: [N-]=[N+]=Nc1ccc(C2(O)c3ccccc3C(=O)N2c2cccc(Cl)c2F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(C2(O)c3ccccc3C(=O)N2c2cccc(Cl)c2F)cc1N
Temperature: 25 °C
Reaction time: 5.33 h
Yield: 55.7 %

Procedure:
To a solution of 3-(4-azido-3-nitrophenyl)-2-(3-chloro-2-fluorophenyl)-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (7.0 g, 16.00 mmol) in a mixture tetrahydrofurane-water (1:1, 15.0 ml) ammonium formate (5.0 g, 79.30 mmol), was added followed by the addition of iron (4.0 g, 71.60 mmol). The reaction mixture was heated to reflux and stirred for 320 minutes. It was cooled to room temperature and diluted with ethyl acetate (70 mL). The resulting slurry was filtered through a pad of Celite and washed with ethyl acetate (3×30 mL). It was partitioned with water and the organic layer was washed with water (30 mL), brine (30 mL) and dried over anhydrous sodium sulfate. Filtration and concentration resulted in a yellow oily product. It was crystallized from diethyl ether by the addition of hexane. The product was collected by filtration, dried in vacuo, to provide 2-(3-chloro-2-fluorophenyl)-3-(3,4-diaminophenyl)-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (3.42 g, 56% yield). 1H NMR (400 MHz, CD3OD): 7.85 (d, J=7.6 Hz, 1H), 7.65-7.58 (m, 2H), 7.41-7.34 (m, 2H), 7.17 (t, J=6.4 Hz. 1H), 7.05 (t, J=8 Hz, 1H), 6.69 (s, 1H), 6.57 (s, 2H); MS (EI) for C20H15ClFN3O2: 382 (M−).
Reaction SMILES: O.[ClH:2].Cl.C([N:11](CC1C=CC=CC=1)[CH2:12][CH2:13][CH:14]1[CH2:18][N:17]([CH2:19][CH3:20])[C:16](=[NH:21])[N:15]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[ClH:2].[ClH:2].[NH2:11][CH2:12][CH2:13][CH:14]1[CH2:18][N:17]([CH2:19][CH3:20])[C:16](=[NH:21])[N:15]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCN1CC(CCN(Cc2ccccc2)Cc2ccccc2)N(c2ccccc2)C1=N
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCN1CC(CCN)N(c2ccccc2)C1=N
Yield: 70 %

Procedure:
A solution of 10.0 g (0.023 mole) of 4-(2-dibenzylaminoethyl)-1-ethyl-2-imino-3-phenylimidazolidine dihydrochloride hydrate in 175 ml of ethanol was shaken for 7 hours in a Parr apparatus at 70° C. with palladium catalyst at 45 p.s.i. hydrogen. After filtering and concentrating the filtrate in vacuo, the solid residue was recrystallized from a 80/20% mixture of isopropanol-ethanol. The salt weighed 4.55 g (70% yield); m.p. 223°-224° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17](=[NH:20])[NH:18]O)=[N:9]1)([CH3:4])([CH3:3])[CH3:2].CC(OC(C)=O)=O>[Pd].CC(O)=O>[C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17](=[NH:18])[NH2:20])=[N:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1nc(C(=N)NO)c2cccnc21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)Cn1nc(C(=N)N)c2cccnc21

Procedure:
[3-(N-Hydroxycarbamimidoyl)-pyrazolo[3,4-b]pyridin-1-yl]-acetic acid tert-butyl ester (6.17 g) in a 100 mL vial was charged with AcOH (45 mL) and Ac2O (4.3 mL). The resultant mixture was stirred at room temperature for 1 h at this time the initial suspension became a clear solution. To this solution was added Pd/C (10%, 900 Mg) and stirred under 1 atm H2 balloon, and resultant mixture was stirred over night at room temperature. Filtration from celite washed with DCM/MeOH and evaporation gave (3-amidino-pyrazolo[3,4-b]pyridin-1-yl)-acetic acid tert-butyl ester which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]([CH:8]([O:21][CH3:22])[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[O:10])[CH:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:11][C:9](=[O:10])[CH:8]([C:6]2[CH:7]=[C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:3]=[CH:4][C:5]=2[F:23])[O:21][CH3:22])=[CH:14][CH:15]=1)#[N:20]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1cc(Br)ccc1F
Reactant: OB(O)c1ccccc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1cc(-c2ccccc2)ccc1F

Procedure:
In analogy to example 57.1, (RS)-2-(5-bromo-2-fluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide (example 75.2) was reacted with phenylboronic acid to give (RS)-N-(4-cyano-benzyl)-2-(4-fluoro-biphenyl-3-yl)-2-methoxy-acetamide. Off-white solid. MS 374.1 (M).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC>CN(C=O)C.[Cu]I>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])=[N:3][N:4]=[CH:5]2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ccc2c(Cl)nncc2c1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: C=C(OCC)c1nncc2cc(Cl)ccc12
Temperature: 100 °C

Procedure:
In a glass tube, a mixture of 1,6-dichlorophthalazine (1.18 g, 5.93 mmol) in 7.0 mL of DMF was treated with copper(I) iodide (113 mg, 0.59 mmol), tetrakistriphenylphosphine palladium (343 mg, 0.29 mmol) followed by tributyl(1-ethoxyvinyl)stannane (2.10 mL, 6.23 mmol). The glass tube was sealed and heated at 100° C. for 25 min in a microwave. The mixture was loaded on a silica gel column, eluting with 50-100% EtOAc in Hexanes, to provide 6-chloro-1-(1-ethoxyvinyl) phthalazine as a brown oil. MS (ESI, pos. ion) m/z: 235.1 (M+1).
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[C:4]2[CH:3]=[CH:2]1>CCO.[Pd]>[O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[C:4]2[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2occc12
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1cccc2c1CCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzofuran-4-carboxylic acid (30.8 mmol, M. A. Eissenstat et al. J. Med. Chem. 1995, 38, 3094-3105) is added to a suspension of Pd/C (10%, 2.00 g) in EtOH (25 mL). Additional EtOH (75 mL) is added and the mixture is stirred at RT under a hydrogen atmosphere (4 bar) for 16 h. After filtration through celite and removal of the solvents the desired product is obtained which is used without further purification. 1H-NMR (DMSO-d6): δ=3.45 (t, J=8.79 Hz, 2H); 4.55 (t, J=8.79 Hz, 2H); 6.99 (d, J=7.78 Hz, 1H); 7.21 (t, J=7.91 Hz, 1H); 7.39 (d, J=7.78 Hz, 1H); 12.9 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH3:13].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:4]1[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc2c(c1C)OCC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(c1CBr)OCC2=O
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A solution of 6-methoxy-7-methylbenzofuran-3(2H)-one (0.670 g, 3.76 mmol) in carbon tetrachloride (38 mL) was added with N-bromosuccinimide (0.737 g, 4.14 mmol) and benzoyl peroxide (0.0456 g, 0.188 mmol), and the mixture was refluxed for 4 hours by heating. The reaction mixture was cooled to room temperature, and then filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 7-(bromomethyl)-6-methoxybenzofuran-3(2H)-one (0.411 g, 42%).
Reaction SMILES: [N:1]1([C@@H:10]2[O:14][C@H:13]([CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[C@@H:12]([OH:27])[CH2:11]2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:28]([O:27][C@H:12]1[CH2:11][C@H:10]([N:1]2[C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[CH:3]=[CH:2]2)[O:14][C@@H:13]1[CH2:15][O:16][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:24]([CH3:26])[CH3:25])[CH:18]([CH3:20])[CH3:19])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)[Si](OC[C@H]1O[C@@H](n2ccc3cnccc32)C[C@@H]1O)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C[C@H](n2ccc3cnccc32)O[C@@H]1CO[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of (2R,3S,5R)-5-(1H-pyrrolo[3,2-c]pyridin-1-yl)-2-{[(triisopropylsilyl)oxy]methyl}tetrahydrofuran-3-ol (0.487 g, 1.25 mmol) and a catalytic amount of DMAP in pyridine (1.6 mL) at 0° C. was added acetic anhydride (0.130 mL, 1.38 mmol) dropwise. The reaction was stirred overnight, concentrated, dissolved in EtOAc, washed with 1 M aq HCl (1×), water (1×) and brine (1×). The combined organics were washed with water (2×), dried (Na2SO4), filtered, and concentrated to give the title compound (0.464 g, 95%) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:13])=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.C(OC([N:21]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39]C(=O)OC(C)(C)C)=[CH:35][CH:34]=1)[C:22]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][C:23]=1[O:30][CH3:31])=O)(C)(C)C.N1CCCCC1>CCO>[NH2:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][NH:21][C:22]2[CH:27]=[CH:26][C:25](/[CH:28]=[CH:13]/[C:4]3[O:3][C:2]([CH3:1])=[CH:7][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:5]=3)=[CH:24][C:23]=2[O:30][CH3:31])=[CH:34][CH:35]=1
Reactant: COc1cc(C=O)ccc1N(Cc1ccc(NC(=O)OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Reactant: CC1=CC(=C(C#N)C#N)C=C(C)O1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(/C=C/C2=CC(=C(C#N)C#N)C=C(C)O2)ccc1NCc1ccc(N)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 2-(2,6-dimethyl-4H-pyran-4-ylidene) malononitrile (1, 16.5 mg, 96 μmol) and aldehyde 2d (34.9 mg, 76.5 μmol) were dissolved in anhydrous EtOH (0.5 ml) at 65 C. Piperidine (1 μl) was added and the mixture was stirred at 80° C. for 6 hrs. The solvent was removed with a stream of N2 and the crude mixture was purified by reverse phase HPLC using water/acetonitrile 40-100% gradient. Yield: 8.1 mg (17.4%). LCMS: m/z 611 (M+H+), 623 (M+Na+). H-NMR (400 MHz, CD2Cl2): 7.45 (1H, d, J=16 Hz) 7.29 (2H, d, J=12 Hz) 7.17 (2H, d, J=8 Hz) 7.03-7.12 (2H, m) 6.69-6.79 (2H, m) 6.52-6.61 (2H, m) 4.76 (2H, brs) 3.89 (3H, s) 2.43 (3H, s) 1.52, (9H, s) 1.41 (9H, brs). C-NMR (400 MHz, CD2Cl2): 162.54, 159.01, 156.35, 152.56, 137.61, 137.21, 134.39, 133.06, 132.89, 128.82, 120.38, 118.39, 117.99, 115.03, 114.99, 107.37, 106.31, 80.21, 58.97, 55.49, 29.68, 28.00, 27.93, 19.75. The purified product (8.1 mg) was treated with a 4N HCl solution in dioxane (4 N, 0.65 ml) for 3 hrs. The mixture was diluted with hexanes, the precipitate centrifuged, re-suspended and washed with hexanes, then dried under vacuum. LCMS ESI+ m/z: 411 (M+H+). H-NMR (400 MHz, DMSO-D6) 7.22-7.28 (5H, m) 6.83-6.89 (2H, m) 6.65 (1H, d, J=16 Hz) 6.54 (1H, d, J=16 Hz) 5.54 91H, s) 5.32 (1H, s) 4.22-4.38 (2H, brs) 3.92 (3H, s) 2.39 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[N+:16]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(NC(=O)OC(C)(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
10% Palladium on carbon (120 mg) was added to a solution of 4-methoxy-2-nitrophenylcarbamic acid t-butyl ester (Reference Compound No. 11-1, 1.3 g, 4.8 mmol) in methanol (20 mL), and then the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 9 hours. The insoluble was filtered off, and then the solvent was evaporated under reduced pressure. The resulting solid was collected by filtration with hexane to give 1.1 g of the title reference compound as a pale brown solid quantitatively.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]#[N:14])=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16].C(=O)(O)[O-].[Na+]>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=[C:9]2[C:13]#[N:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-n2cccc2C#N)cc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(-n2cc([N+](=O)[O-])cc2C#N)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(4-methylphenyl)pyrrole-2-carbonitrile (1.0 g) in acetic anhydride (4 ml) was added nitric acid (231 μl, 94%) dropwise at 5° C. The mixture was stirred at the same temperature for 3 hours and then poured into ice water. The pH was adjusted to 5-7 by the addition of saturated aqueous sodium bicarbonate solution. The separated oil was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine, dried, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to yield 1-(4-methylphenyl)-4-nitropyrrole-2-carbonitrile (471 mg) as a solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:9][CH2:10][CH:11]=1)=[O:5])C.[OH-].[Na+].Cl.[Cl:35]CCl>C(O)C>[ClH:35].[CH:28]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:18]=2[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)C1=CCCN(CCOCCC2c3ccccc3CCc3ccccc32)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1=CCCN(CCOCCC2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above ester (1.3 g, 3.1 mmol) was dissolved in ethanol (10 ml) and a 4 N sodium hydroxide solution (2.3 ml) was added. The mixture was stirred at room temperature for 4 h. A 4 N hydrochloric acid solution was added until pH 1. Dichloromethane (400 ml) was added and the mixture was stirred vigorously for a few minutes and the phases were separated. The organic phase was dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was re-evaporated with acetone, dissolved in acetone (50 ml) and left for crystallization. This afforded 0.45 g of the title compound as a solid.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Cl:7][CH2:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](O)=[O:12]>CN(C=O)C.C(Cl)Cl>[Cl:7][CH2:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([Cl:4])=[O:12]
Reactant: O=C(O)C(CCCl)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C(CCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (1.56 mL) and DMF (1 drop) were added to a solution of 4-chloro-2-phenylbutyric acid (2.28 g) in methylene chloride (40 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure to obtain 4-chloro-2-phenylbutyric acid chloride. A solution of 4-chloro-2-phenylbutyric acid chloride in THF (10 mL) was added to a solution of tert-butyl carbazate (1.5 g) and triethylamine (7.8 mL) in THF (40 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was added to a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain tert-butyl N′-(4-chloro-2-phenylbutyryl)hydrazinecarboxylate (3.17 g). A solution of 4 N hydrogen chloride in ethyl acetate (50 mL) was added to tert-butyl N′-(4-chloro-2-phenylbutyryl)hydrazinecarboxylate (3.17 g). The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure to obtain 4-chloro-2-phenylbutyric acid hydrazide hydrochloride (2.52 g). A solution of 4-chloro-2-phenylbutyric acid hydrazide hydrochloride (2.52 g) and triethylamine (5.7 mL) in ethanol (40 mL) was added to a solution of ethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride (3.00 g) and triethylamine (6.0 mL) in ethanol (50 mL) at room temperature, and the reaction solution was stirred at 80° C. for 24 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 231 mg of the racemic title compound. The property values of the compound are as follows.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([O:19][CH3:20])=[O:18])[N:12]1[C:21](=[O:26])[CH:22]([Br:25])[CH2:23]Br)=O)C1C=CC=CC=1.Br>C(O)(=O)C>[Br:25][CH:22]1[CH2:23][N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([O:19][CH3:20])=[O:18])[N:12]2[C:21]1=[O:26]
Reactant: COC(=O)C1CCCN(C(=O)OCc2ccccc2)N1C(=O)C(Br)CBr
Agent: Br
Solvent: CC(=O)O
Product: COC(=O)C1CCCN2CC(Br)C(=O)N12
Yield: 77.8 %

Procedure:
5.8 g of methyl 1-benzyloxycarbonyl-2-(2,3-dibromopropionyl)-hexahydro-3-pyridazinecarboxylate (2 racemates) were stirred for 1 hour at room temperature with 15 ml of 45% hydrogen bromide solution in glacial acetic acid and the mixture was then evaporated. The resulting oily solid was washed with diethyl ether and then partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel. Elution with tert.butyl methyl ether gave firstly 0.4 g (12%) of methyl 2-bromo-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (racemate A) in the form of a white solid of melting point 115°-117° C. (from ethyl acetate/hexane) and secondly 2.54 g (78%) of methyl 2-bromo-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (B) in the form of a white solid of melting point 109°-112° C. (from ethyl acetate/n-hexane).