Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=3)[C:20]([O:22]C(C)(C)C)=[O:21])[CH2:13][C@H:12]2[O:30][CH2:31][CH3:32])=[O:9])=[N:5][C:4]=1[C:33]([F:36])([F:35])[F:34])[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([C:3]1[NH:7][C:6]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=3)[C:20]([OH:22])=[O:21])[CH2:13][C@H:12]2[O:30][CH2:31][CH3:32])=[O:9])=[N:5][C:4]=1[C:33]([F:35])([F:36])[F:34])[CH3:2]
Reactant: CCO[C@@H]1CN(c2cccc(C(=O)OC(C)(C)C)c2)CC[C@@H]1NC(=O)c1nc(C(F)(F)F)c(CC)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H]1CN(c2cccc(C(=O)O)c2)CC[C@@H]1NC(=O)c1nc(C(F)(F)F)c(CC)[nH]1
Yield: 84 %

Procedure:
The same operation as in Example (42f) was performed using tert-butyl cis(±)-3-(4-{[(5-ethyl-4-trifluoromethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)benzoate obtained in Example (48f) (80 mg, 0.16 mmol) and trifluoroacetic acid (1 ml), to obtain 61.1 mg of the title compound (86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[N:20]=2)=[CH:4][CH:3]=1.Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([C:34]([C:37]([F:40])([F:39])[F:38])=[N:35][N:36]=2)[N:33]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH:13]3[CH2:18][CH2:17][N:16]([C:28]4[CH:29]=[CH:30][C:31]5[N:32]([C:34]([C:37]([F:38])([F:40])[F:39])=[N:35][N:36]=5)[N:33]=4)[CH2:15][CH2:14]3)[C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[N:20]=2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: COc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCNCC2)n1
Product: COc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)n1

Procedure:
A mixture of 4-[5-(4-fluorophenyl)-3-piperidin-4-ylimidazol-4-yl]-2-methoxypyrimidine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[4-(4-fluorophenyl)-5-(2-methoxypyrimidin-4-yl)imidazol-1-yl]piperidin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:10]=[C:11]1[CH2:16][C:15](=[O:17])[CH2:14][CH:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12]1>ClCCl.C(N(CC)CC)C>[C:1]([O:17][C:15]1[CH2:14][CH:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][C:11](=[O:10])[CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1CC(=O)CC(=O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC(=O)C=C(OC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.75 g (55.1 mmol) Benzoyl chloride was added dropwise to 10.00 g (54.3 mmol) ethyl 3,5-dioxocyclohexanecarboxylate, dissolved in 100 ml dichloromethane and 15 ml triethylamine, at 10° C. The mixture was stirred for 3 hours at room temperature, poured into ice, separated, the organic phase shaken with 1N hydrochloric acid, saturated sodium bicarbonate and water, dried (magnesium sulphate) and concentrated. The ethyl 3-benzoyloxy-5-oxo-3-cyclohexenecarboxylate, so obtained, was dissolved in 75 ml acetonitrile and after addition of 15 ml triethylamine and 1.5 ml 2-hydroxyisobutyronitrile, was stirred at 24 hours at room temperature. The mixture was taken up in 100 ml diethyl ether and extracted with 100 ml 2N hydrochloric acid and then twice with, each time, 50 ml 5% potassium carbonate solution. After covering the aqueous phase with a layer of 100 ml diethyl ether, it was acidified with 4N hydrochloric acid until it was pH 3, separated, washed with water, dried (magnesium sulphate) and evaporated on a rotary evaporator. It was purified by recrystallising from hexane.
Reaction SMILES: C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:16][C@@H:17]([C@H:19]1[C:40](=[O:41])[N:21]2[CH:22]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)=[O:28])[C:23](=O)[C@H:24]([CH3:25])[C@H:20]12)[CH3:18].FC(F)(F)S(O)(=O)=O.[SH:50][C@@H:51]1[CH2:55][N:54]([CH3:56])[C@H:53]([C:57]([N:59]2[CH2:65][CH2:64][CH2:63][N:62]([C:66]([O:68][CH2:69][C:70]3[CH:75]=[CH:74][C:73]([N+:76]([O-:78])=[O:77])=[CH:72][CH:71]=3)=[O:67])[CH2:61][CH2:60]2)=[O:58])[CH2:52]1>C(#N)C.C(N(C(C)C)CC)(C)C>[N+:76]([C:73]1[CH:74]=[CH:75][C:70]([CH2:69][O:68][C:66]([N:62]2[CH2:63][CH2:64][CH2:65][N:59]([C:57]([C@@H:53]3[CH2:52][C@H:51]([S:50][C:23]4[C@H:24]([CH3:25])[C@@H:20]5[C@@H:19]([C@H:17]([OH:16])[CH3:18])[C:40](=[O:41])[N:21]5[C:22]=4[C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=4)=[O:28])[CH2:55][N:54]3[CH3:56])=[O:58])[CH2:60][CH2:61]2)=[O:67])=[CH:71][CH:72]=1)([O-:78])=[O:77]
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CCCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C)C3)[C@H](C)[C@H]12
Reaction time: 0.67 h
Yield: 57.4 %

Procedure:
0.89 ml of diphenylphosphoryl chloride and 0.75 ml of diisopropylethylamine were simultaneously added dropwise, whilst ice-cooling, to a solution of 1.4 g of 4-nitrobenzyl (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 14 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 40 minutes. A solution of 2.68 g of (2S, 4S)-4-mercapto-1-methyl-2-[4-(4-nitrobenzyloxycarbonyl)-1-homopiperazinylcarbonyl]pyrrolidine trifluoromethanesulfonate (prepared as described in Preparation 49) in 14 ml of dry acetonitrile and 1.64 ml of diisopropylethylamine were then simultaneously added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 5 hours, after which it was allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was diluted with ethyl acetate. The dilute solution was then washed with an aqueous solution of sodium hydrogencarbonate, with a phosphate buffer solution (pH 6.86), with water and with an aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel (Merck Art No. 7734), using a gradient elution method with mixtures of ethyl acetate and methanol ranging from 85:15 to 80:20 by volume as the eluent, to give 1.7 g of the title compound, as a powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH2:6][C:7]1[N:11]=[CH:10][NH:9][CH:8]=1)[NH2:5].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH2:6][C:7]1[N:11]=[CH:10][NH:9][CH:8]=1)[N:5]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1c[nH]cn1)N=Cc1ccccc1

Procedure:
Histidine methyl ester, 185 mg (1 mmole), is treated with 1.06 g (1 mmole) of benzaldehyde in 25 ml of CHCl3 for 3 hours. MgSO4, 0.2 g, is added for the last hour. The mixture is filtered and the solvent is evaporated, to leaving compound 2·I as a residue.
Reaction SMILES: [Br:1]Br.[CH:3]1([C:6]2[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][N:12]=3)[N:10]=2)[CH2:5][CH2:4]1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:8]1[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]([CH:3]2[CH2:4][CH2:5]2)=[N:10][C:9]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccncn2)nc1C1CC1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc(-c2ccncn2)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
Bromine was added to a cooled solution of 4-(2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyrimidine (1.36 g, 4.30 mmol) in DCM at 0° C. followed by saturated aqueous Na2CO3 solution (16 mL, 4.30 mmol). The reaction mixture was stirred for 3 hours at room temperature. After the reaction was judged complete by LCMS analysis, the reaction mixture was allowed to stand and partition. The resulting layers were separated and the aqueous layer was extracted with EtOAc (2×). The combine organic layers were washed with brine, dried (Na2SO4), and concentrated. The resulting residue was by flash chromatography using an EtOAc-hexanes gradient (20-80%) to give 4-(5-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyrimidine (1.07 g, 2.71 mmol, 63%) as a yellow oil: LCMS (m/z): 395.0 (MH+), tR=1.09 minutes; 1H NMR (400 MHz, CDCl3) δ 0.00 (s, 9H) 0.80-1.50 (m, 4H) 2.06-2.25 (m, 1H) 3.49-3.65 (m, 2H) 6.05 (s, 2H) 7.95-8.07 (m, 1H) 8.82-8.94 (m, 1H) 9.27-9.34 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:23]=[N:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:26][CH:27]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:28]([C:25]1[N:24]=[CH:23][C:22]([NH:21][C:18]([C@@H:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:19])=[CH:27][CH:26]=1)[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: CCCCCc1ccc(N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCCc1ccc(NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)cn1
Reaction time: 8 h

Procedure:
To a stirred solution of (S)—N-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (0.666 g, 2.40 mmol) and 3-amino-6-pentylpyridine (0.330 g, 2.01 mmol) in chloroform (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.460 g, 2.40 mmol) and a catalytic amount of 4-(dimethylamino)pyridine. The reaction was allowed to proceed overnight and then partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organic layer was dried (sodium sulfate) and concentrated to afford a faint green foam.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:17][C:18]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:19](O)=[O:20])=[O:16])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.C[Si](C)(C)[O:28][CH2:29][CH2:30][NH2:31]>>[CH2:24]([C:18]([NH:17][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[N:8]=1)=[O:16])([C:19](=[O:20])[NH:31][CH2:30][CH2:29][OH:28])[CH2:22][CH3:23])[CH3:25]
Reactant: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)O
Reactant: C[Si](C)(C)OCCN
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)NCCO

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoic acid (Example 274 a) and 2-(trimethylsilyloxy)ethanamine (CAN 5804-92-2)-as starting materials. MS (EI): m/e=390.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([CH:15]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=2[F:28])[C:23]#[N:24])[C:16](=[O:19])[C:17]#[CH:18])[CH:12]=[CH:11][CH:10]=1>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[C:13]([CH:12]=[CH:11][CH:10]=1)=[C:15]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[C:23]#[N:24])[C:16](=[O:19])[CH:17]=[CH:18]2
Reactant: C#CC(=O)C(c1cccc(-c2ccc(F)cc2F)n1)c1cc(C#N)ccc1F
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(F)c(-c2c(=O)ccn3c(-c4ccc(F)cc4F)cccc23)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of 3-{1-[6-(2,4-difluorophenyl)pyridin-2-yl]-2-oxobut-3-yn-1-yl}-4-fluorobenzonitrile (From Step E above, 24 g, 63.8 mmol) in NMP was heated to 90° C. for ½ hour. LCMS analysis revealed the reaction was complete and the reaction was poured into ice water (4 L). After stirring for 12 h, the solid precipitate was collected by filtration. The solid was purified via silica gel chromatography (CH2Cl2/EtOAc/MeOH). The aqueous filtrate was extracted with EtOAc. The organic layer was washed with H2O (4×), brine (2×), dried over MgSO4, and condensed in vacuo. The crude residue was purified using silica gel chromatography (CH2Cl2/EtOAc/MeOH). A combined 7.8 g of the title compound was collected.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([C:14](O)([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:9]=[CH:10][C:11]([C:14]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=1
Reactant: CCCCCCC(O)(c1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCC=C(c1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of 3-{4-[1-Hydroxy-1-(4′-trifluoromethyl-biphenyl-4-yl)-heptyl]-benzoylamino}-propionic acid methyl ester (150 mg, 0.28 mmol) in dichlormethane (10 mL) is added TFA (160 mg, 1.4 mmol) dropwise, followed by the addition of triethylsilane (161 mg, 1.4 mmol). After 2 h, the reaction is quenched by 1N HCl, extracted with ethyl acetate, dried, concentrated, and purified by column chromatography to afford the titled compound (130 mg).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C@H:3]1[CH3:17].C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:17][C@H:3]1[C:2](=[O:1])[CH2:6][CH2:5][N:4]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: C[C@H]1[C@@H](O)CCN1C(=O)OCc1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: C[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution of benzyl (2S,3S)-3-hydroxy-2-methylpyrrolidine-1-carboxylate (20.5 g) in acetonitrile (150 mL) were added powdery molecular sieves 4 A (25 g) and 4-methylmorpholine-N-oxide (20.4 g). After cooling to 0° C., tetra-n-propylammonium perruthenate (3.0 g) was added, and the mixture was stirred at 0° C. for 1 hr, and at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate. Insoluble materials were filtered through Hyflo Super-Cel. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1→2/1) to give the title compound as a colorless oil (yield: 18.0 g, 89%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[NH:12][C:13]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21](=[N:25][OH:26])[CH2:20][CH2:19]4)[N:15]=2)[CH2:7][CH2:6]1.[CH3:33]ON=C1C2C(=CC(C(=O)C(C3C=CN=CC=3)=O)=CC=2)CC1>>[CH3:33][O:26][N:25]=[C:21]1[C:22]2[C:18](=[CH:17][C:16]([C:14]3[N:15]=[C:11]([CH:8]4[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:10][CH2:9]4)[NH:12][C:13]=3[C:27]3[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=3)=[CH:24][CH:23]=2)[CH2:19][CH2:20]1
Reactant: COCCN1CCC(c2nc(-c3ccc4c(c3)CCC4=NO)c(-c3ccncc3)[nH]2)CC1
Reactant: CON=C1CCc2cc(C(=O)C(=O)c3ccncc3)ccc21
Product: COCCN1CCC(c2nc(-c3ccc4c(c3)CCC4=NOC)c(-c3ccncc3)[nH]2)CC1
Yield: 32 %

Procedure:
The title compound (0.27 g, 32%) was prepared from the product of Step 1 and the product of Example 1 Step 4 as described in Example 1 Step 5; MS(AP+) m/e 446 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9](Cl)[N:8]2[N:12]=[CH:13][CH:14]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].O.[NH2:16][NH2:17]>>[CH2:1]([C:5]1[CH:10]=[C:9]([NH:16][NH2:17])[N:8]2[N:12]=[CH:13][CH:14]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NN
Reactant: CCCCc1cc(Cl)n2nccc2n1
Solvent: O
Product: CCCCc1cc(NN)n2nccc2n1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Hydrazine monohydrate (50 ml) was slowly added dropwise to 21.0 g of 5-n-butyl-7-chloropyrazolo[1,5-a]pyrimidine prepared in step (2) of Reference Example 1 at room temperature and stirred at room temperature for 10 hours. After completion of the reaction, the crystals precipitated were collected, washed with water and recrystallized from chloroform-n-hexane to provide 12.6 g of the object compound as colorless crystals (melting point: 126°-129° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)[CH3:6])[CH3:2].Cl.O1CCOCC1>>[NH:10]1[CH2:11][CH2:12][CH:7]([CH:5]([CH3:6])[C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH2:8][CH2:9]1
Reactant: CCOC(=O)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C(C)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
A sample of tert-butyl 4-(1-ethoxy-1-oxopropan-2-yl)piperidine-1-carboxylate (1.4 g, 4.91 mmol) was dissolved in 4 M hydrogen chloride/dioxane (5 mL, 165 mmol) and stirred at RT for 2 h. At the conclusion of this period, the mixture was concentrated on a rotary evaporator and the resultant residue was treated with saturated NaHCO3 and then 1 M NaOH to bring the pH to 9. The mixture was extracted with EtOAc. The extract was washed with brine, dried (MgSO4) and concentrated to give ethyl 2-(piperidin-4-yl)propanoate (0.85 g, 93%). 1H-NMR (400 MHz, CDCl3) δ ppm 4.05-4.13 (2 H, m), 2.99-3.08 (2 H, m), 2.54 (2 H, td, J=12.09, 2.52 Hz), 2.16-2.25 (1 H, m), 1.75 (1 H, s), 1.57-1.66 (2 H, m), 1.52 (1 H, dt, J=12.90, 2.86 Hz), 1.09-1.22 (1 H, m), 1.21 (3 H, t, J=7.18 Hz), 1.07 (3 H, d, J=7.05 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:15][CH:16]1[CH2:18][O:17]1>CN(C)C=O.O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:15][CH:16]([OH:17])[CH3:18])[N:5]=1)([O-:3])=[O:2]
Reactant: CC1CO1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)Cn1ccc([N+](=O)[O-])n1
Temperature: 100 °C
Yield: 54.8 %

Procedure:
A solution of 3-nitro-1H-pyrazole (prepared in Example 3, 400 mg, 3.54 mmol) in N,N-dimethylformamide (5 mL) was treated with solid potassium carbonate (734 mg, 5.31 mmol) and 2-methyl-oxirane (500 μL, 3.54 mmol) and placed in a sealed tube and heated at 100° C. for 1 h in an oil bath. After this time the reaction was cooled to 25° C. and diluted with water (30 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were then combined and washed with saturated aqueous brine solution (2×20 mL) and then dried over sodium sulfate, filtered and concentrated in vacuo with silica gel (2 g) and purified by Biotage Flash Chromatography (40S column, Silica gel, 60% ethyl acetate/hexanes) to afford 1-(3-nitro-pyrazol-1-yl)-propan-2-ol (332 mg, 55%) as a clear colorless oil: ES-HRMS m/e calcd for C6H9N3O3 (M+H)+ 172.0717, observed 172.0716; 36730-255 1H NMR (300 MHz, CDCl3) δ ppm 1.28 (d, J=6.3 Hz, 3H, CH3), 2.15 (br. s., 1H, OH), 4.03-4.13 (m, 1H, CH of CH2), 4.23-4.38 (m, 2H, OCH and CH of CH2), 6.91 (d, J=2.4 Hz, 1H, Ar), 7.56 (d, J=2.4 Hz, 1H, Ar).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](=[NH:10])[NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C[O-].[Na+].[C:16](OCC)(=[O:23])[CH2:17][C:18](OCC)=[O:19]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[N:9]=[C:18]([OH:19])[CH:17]=[C:16]([OH:23])[N:10]=2)=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N=C(N)c1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(-c2nc(O)cc(O)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
In a 50 mL round-bottomed flask was placed 4-nitrobenzimidamide (55, 0.435 g, 2.63 mmol) in MeOH (4 mL) to give a yellow suspension. Sodium methanolate (25% by wt in MeOH) (1.867 mL, 8.17 mmol) was added. The mixture was stirred at room temperature for 30 min. Diethyl malonate (0.480 mL, 3.16 mmol) was added in drops and stirring was continued at room temperature over 6 days, resulting in an orange suspension. The mixture was concentrated, dissolved in hot water and filtered. The filtrate was made acidic with AcOH to pH3. The resulting light yellow solids were collected by filtration and dried under vacuum to give the title compound (499 mg, 81%) as a light yellow solid. HRMS: For [M+H]+ mass error=−0.0 mDa or −0.17 ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[Li+].[CH3:11][Si]([N-][Si](C)(C)C)(C)C.IC>O1CCCC1>[CH3:1][C:2]1([CH3:9])[CH2:7][CH:6]([CH3:11])[C:5](=[O:8])[CH:4]=[CH:3]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC1(C)C=CC(=O)CC1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1CC(C)(C)C=CC1=O
Temperature: 23 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A solution of 4,4-dimethyl-cyclohex-2-en-1-one (5.00 g, 40.3 mmol, 1 equiv) in tetrahydrofuran (130 mL) was added to a solution of LHMDS (1 M in tetrahydrofuran, 58.4 mL, 58.4 mmol, 1.45 equiv) in tetrahydrofuran (60 mL) at −78° C. After stirring for 1 h, iodomethane (5.02 mL, 80.6 mmol, 2.0 equiv) was added dropwise to the flask. The cooling bath was immediately removed and the reaction mixture was allowed to warm to room temperature (23° C.). After stirring 11 h, saturated aqueous ammonium chloride solution (50 mL) and distilled water (10 mL) were added to the flask. The layers were separated and the aqueous layer was extracted with three 50-mL portions of ether. The combined organic layers were washed once with brine (10 mL) and dried over sodium sulfate (15 min). Following filtration, volatiles were removed in vacuo, leaving a brown residue which was distilled at 22 torr furnishing 4,4,6-trimethyl-cyclohex-2-en-1-one (10, 3.93 g, 72%) as a clear oil, bp 82-86° C. (Torri, J.; Azzaro, M. Bull. Soc. Chem. Fr. 1978, 283; incorporated herein by reference).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][C:8]2[NH:13][N:12]=[CH:11][C:10](=O)[CH:9]=2)[CH:4]=[CH:5][N:6]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:10]1[CH:9]=[C:8]([CH2:7][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])[N:13]=[N:12][CH:11]=1
Reactant: Cc1nccn1Cc1cc(=O)cn[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nccn1Cc1cc(Cl)cnn1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 72.5 %

Procedure:
6-(2-Methyl-imidazol-1-ylmethyl)-1H-pyridazin-4-one (3.9 g, 20.5 mmol)) was treated with phosphorus oxychloride (18 ml, 205 mmol) under argon. The mixture was stirred in a 60° C. oilbath for 1.5 hours. The solvent was removed in vacuo and the residue was dissolved in water (100 ml) under icebath cooling. The brown solution was neutralized with solid NaHCO3 and the aqueous layer was extracted with MeCl2 (6×50 ml). The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo to provide 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine (3.1 g, 73%) as a brown solid, MS: m/e=209.3 (M+H+).