Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]([O-:22])=O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:57]([C:60]1[CH:65]=[CH:64][C:63]([NH:66][CH:67]2[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]2)=[CH:62][C:61]=1[C:73]([F:76])([F:75])[F:74])([O-:59])=[O:58]>CN(C)C=O.ClCCl.O1CCCC1>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]([N:70]3[CH2:71][CH2:72][CH:67]([NH:66][C:63]4[CH:64]=[CH:65][C:60]([N+:57]([O-:59])=[O:58])=[C:61]([C:73]([F:74])([F:75])[F:76])[CH:62]=4)[CH2:68][CH2:69]3)=[O:22])[CH2:14][CH2:13]2)=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:5]
Reactant: CC(C)(C)c1ccc(N2CCN(CCC(=O)[O-])CC2)cc1
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(N2CCN(CCC(=O)N3CCC(Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)CC3)CC2)cc1
Reaction time: 0.08 h

Procedure:
3-[4-(4-tert-Butyl-phenyl)-piperazin-1-yl]-propionic acid lithium salt (114 mg; 0.39 mmol, prepared in accordance with Example 34), diisopropylethyl amine (174 μL; 1.0 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (133 mg; 0.35 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (114 mg; 0.35 mmol, prepared in accordance with Example 8) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 2 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (2×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (18 mg; 0.05 mmol). The structure was confirmed using Protocol II-F. Calculated mass=562; observed mass=563; HPLC retention time=12.14 min.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:4][C:3]=1[CH3:28].[CH2:29]([Sn](CCCC)(CCCC)C=C)[CH2:30]CC.[Cl-].[Li+]>CN(C)C=O.C(OCC)(=O)C.[F-].[K+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:24]([C:5]1[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]([CH:29]=[CH2:30])=[C:3]([CH3:28])[N:4]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1c(C)nc(CCCC)n(Cc2ccc(-c3ccccc3C#N)cc2)c1=O
Temperature: 90 °C
Reaction time: 12 h
Yield: 65.9 %

Procedure:
To a solution of 4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1.9 g), tributyl(vinyl)tin (2.1 g) and lithium chloride (0.55 g) in N,N-dimethylformamide (30 mL) was added dichlorobis(triphenylphosphine)palladium (0.15 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, 15% aqueous potassium fluoride solution was added, and the mixture was stirred for 2 hr. The insoluble material was filtered off through celite, and the organic layer of the filtrate was separated, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.1 g, 63%).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.O.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([OH:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>FC(F)(F)C(O)=O>[C:20]1([CH3:30])[CH:21]=[CH:22][C:23]([S:26]([OH:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1.[S:14]1[CH:15]=[C:11]([CH2:10][C@@H:9]([C:16]([OH:18])=[O:17])[NH2:8])[N:12]=[CH:13]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N[C@@H](Cc1cscn1)C(=O)O
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (80 ml) was added to N-(tert-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine (42, 21.79 g, 80 mmol) which was synthesized in accordance with the method described in the literature (Synth. Commun., 20, 3507 (1990)) and the resulting mixture was stirred for 2 h under ice-cooling, Subsequently, to the mixture was added p-toluenesulfonic acid hydrate (15.22 g, 80 mmol) and the resulting mixture was stirred for 30 min. at room temperature. The reaction mixture was concentrated in vacuo. To the residue was added water and methanol, and excess trifluoroacetic acid was removed by concentrating in vacuo. To the residue was added diethyl ether and the precipitation which appeared was filtered off to give 29.8 g (quantitative) of the compound (43).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH:15]([CH3:14])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1Cc2ccccc2CN1
Product: CC1Cc2ccccc2CN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[Br-].[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][Zn+])=[CH:20][CH:19]=1)#[N:17]>O1CCCC1.ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][C:2]2[O:6][C:5]([C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=3)=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: N#Cc1ccc(-c2ccc(Br)o2)nc1
Reactant: N#Cc1ccc(C[Zn+])cc1
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1ccc(Cc2ccc(-c3ccc(C#N)cn3)o2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
Continuing with Scheme 7, a solution of 2 (996 mg, 4 mmol) in tetrahydrofuran (25 mL) was added palladium tetrakis(triphenyl-phosphine) (228 mg) and p-cyanobenzyl zinc bromide (12 mL, 0.5 M in THF, 6 mmol). The reaction mixture was stirred 24 h at room temperature. The mixture was diluted with dichloromethane, washed with saturated NH4Cl and the organic layer was dried over anhydrous Na2SO4. After filtration and on concentration the residue was purified by chromatography (SiO2), hexanes (100–40%)/EtOAc (0–60%), to afford 35 in 48% yield, mp 204–206° C. 1H nmr (DMSO-d6); δ 4.23 (s, 2H), 6.46 (d, J=3.3 Hz, 1H), 7.27 (d, J=3.3 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.1 Hz, 2H), 7.79 (d, J=8.4 Hz, 1H), 8.25 (dd, J=8.4 Hz, 1.8 Hz, 1H), 8.92 (d, J=1.8 Hz, 1H). 13C nmr; δ 156.3, 152.6, 150.9, 150.6, 143.2, 140.5, 132.4, 129.6, 118.6, 117.5, 117.1, 113.5, 110.3, 109.5, 106.0, 33.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]3[C:13]=2[CH2:14][CH2:15][CH2:16]3)=[CH:7][C:4]=1[CH:5]=O.[Br-].[F:26][C:27]1[CH:28]=[C:29]([CH:50]=[CH:51][C:52]=1[O:53][CH3:54])[CH2:30][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[F:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:5][C:4]2[CH:7]=[C:8]([CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[O:11][C:12]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]3[C:13]=2[CH2:14][CH2:15][CH2:16]3)[CH:50]=[CH:51][C:52]=1[O:53][CH3:54]
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1C=O
Agent: [Br-]
Product: COc1ccc(C=Cc2cc(Oc3c(C)cc([N+](=O)[O-])c4c3CCC4)ccc2OC)cc1F

Procedure:
4-{3-[2-(3-Fluoro-4-methoxyphenyl)vinyl]-4-methoxyphenoxy}-5-methyl-7-nitroindane was prepared in a similar manner to those described in Reference Example 15 using 2-methoxy-5-(5-methyl-7-nitroindan-4-yloxy) benzaldehyde instead of 2-benzyloxy-5-(5-methyl-7-nitroindan-4-yloxy) benzaldehyde and using (3-fluoro-4-methoxybenzyl)triphenylphosphonium bromide instead of furfuryltriphenylphosphonium bromide.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[N:8]1)([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[CH:1]([O:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1)([CH3:3])[CH3:2]
Reactant: CC(C)OCCn1ccc([N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)OCCn1ccc(N)n1
Yield: 99.4 %

Procedure:
In a Parr shaker bottle was placed 1-(2-isopropoxy-ethyl)-3-nitro-1H-pyrazole (428 mg, 2.14 mmol), 10% palladium on activated carbon (50 mg) and ethanol (20 mL). The bottle was then placed on the Parr shaker at 50 psi of hydrogen pressure for 2 h. The reaction was then filtered through a pad of celite and washed with ethanol, concentration in vacuo afforded 1-(2-isopropoxy-ethyl)-1H-pyrazol-3-ylamine (360 mg, 99%) as a clear light yellow oil: ES-HRMS m/e calcd for C8H15N3 (M+H)+ 170.1288, observed 170.1287; 1H NMR (300 MHz, CDCl3) δ 1.10 (d, J=6.0 Hz, 6H, 2×CH3), 3.43 (br, 2 H, NH2), 3.49 (m, 1H, OCH), 3.70 (t, J=5.6 Hz, 2H, OCH2), 4.05 (t, J=5.6 Hz, 2H, NCH2), 5.57 (d, J=2.3 Hz, 1H, Ar), 7.22 (d, J=2.3 Hz, 1H, Ar).
Reaction SMILES: [ClH:1].O1CCOCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:36]3[C:37]4[CH:44]([CH3:45])[CH2:43][CH2:42][C:38]=4[N:39]=[CH:40][N:41]=3)[CH2:32][CH2:31]2)=[O:29])[CH2:16][C:17]([NH:20]C(=O)OC(C)(C)C)([CH3:19])[CH3:18])=[CH:11][CH:10]=1>O1CCOCC1>[ClH:8].[ClH:1].[NH2:20][C:17]([CH3:18])([CH3:19])[CH2:16][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=1)[C:28]([N:30]1[CH2:31][CH2:32][N:33]([C:36]2[C:37]3[CH:44]([CH3:45])[CH2:43][CH2:42][C:38]=3[N:39]=[CH:40][N:41]=2)[CH2:34][CH2:35]1)=[O:29]
Reactant: CC1CCc2ncnc(N3CCN(C(=O)[C@H](CC(C)(C)NC(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Product: CC1CCc2ncnc(N3CCN(C(=O)[C@H](CC(C)(C)N)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 167.4 %

Procedure:
4M HCl/dioxane (0.609 ml, 2.43 mmol) was added to a solution of (R)-tert-butyl 4-(4-chlorophenyl)-2-methyl-5-(4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-5-oxopentan-2-ylcarbamate (0.044 g, 0.0812 mmol) in dioxane (1 mL). The reaction mixture was stirred at room temperature for 2 days, after which it was concentrated to dryness. The resulting residue dissolved in minimal MeOH, and the product was triturated by the addition of ether. The solids were isolated by filtration through quantitative membrane filter paper with nitrogen pressure, rinsed with ether, and dried in vacuo to give (R)-4-amino-2-(4-chlorophenyl)-4-methyl-1-(4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)pentan-1-one dihydrochloride (0.035 g, 83.7% yield) as a white powder. LC/MS (APCI+) m/z 442 [M+H]+. 1:1 mixture of diastereomers.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-:3])=[O:2].S(=O)(=O)(O)O>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:13]([O:15][CH2:13][CH2:6][CH2:7][CH3:8])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([O:10][CH2:5][CH2:4][CH2:12][CH3:11])=[O:9])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCCCOC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OCCCC
Temperature: 120 °C
Yield: 136.7 %

Procedure:
4-nitrophthalic acid (2.0 g, 9.5 mmol) was dissolved in 30 ml of absolute ethanol and then 0.3 ml of concentrated sulfuric acid was added. The mixture was heated at 120° C. for 24 hours, and the solvent was evaporated under reduced pressure. The oily residue was dissolved in diethyl ether and washed three times with water and once with 10% Na2CO3 solution. The ether solution was dried over anhydrous sodium sulfate. After evaporation of the solvent, a light yellow crude solid was obtained. The crude product was purified by silica gel column chromatography (n-hexane: acetic acid =10:1) to give 2.1 g (68.4%) of di-n-butyl 4-nitrophthalate (compound 403).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:20]([O:34][CH:35]4[CH2:38][CH2:37][CH2:36]4)=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29]([O:31][CH3:32])=[O:30])[C@@H:24]([CH3:33])[CH2:23][CH2:22]4)[CH:16]=[N:15]2)[CH:10]([OH:39])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:40]N(C)C=O.[H-].[Na+].CI>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:20]([O:34][CH:35]4[CH2:38][CH2:37][CH2:36]4)=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29]([O:31][CH3:32])=[O:30])[C@@H:24]([CH3:33])[CH2:23][CH2:22]4)[CH:16]=[N:15]2)[CH:10]([O:39][CH3:40])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=O
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4O)c3)c(OC3CCC3)c2CC[C@@H]1C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC(=O)N1c2ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4OC)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A 50-mL round-bottom flask was charged with methyl (2S)-6-(1-[1-[(tert-butoxy)carbonyl]-3-hydroxypiperidin-4-yl]-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (250 mg, 0.46 mmol,) and N,N-dimethylformamide (5 mL). Sodium hydride (78 mg, 3.25 mmol,) was added, and the mixture stirred at room temperature for 30 minutes. Methyl iodide (0.079 mL, 1.28 mmol) was added, and the resulting solution stirred for 4 h at room temperature. The reaction mixture was then poured into 20 mL of water and extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 1:5, ethyl acetate/petroleum ether) to afford (2S)-methyl 6-(1-(1-(tert-butoxycarbonyl)-3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (80 mg, 31%) as colorless oil. MS (ESI, pos. ion) m/z 555 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1>O1CCOCC1.ClCCl.CCOCC>[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([O:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][C:3]([N:2]([CH3:1])[CH3:12])=[CH:4][CH:5]=2)[N:15]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CN(C)c1ccc(CCO)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)c1ccc(CCOc2cncc(Cl)n2)cc1
Temperature: 0 °C
Reaction time: 0.2 h
Yield: 80 %

Procedure:
K-t-BuO (2.27 g, 20.3 mmol) was added to a stirred solution of 4-(dimethylamino)phenethyl alcohol (3.55 g, 21.5 mmol) in dioxane (35 mL) at 0° C. (ice-bath). After being stirred for 5 min at 0° C. and 12 min at room temperature, the mixture was chilled to 0° C. (ice-bath) and 2,6-dichloropyrazine (2.62 g, 17.6 mmol) was added. The reaction mixture was stirred at 0° C. for 5 min and at room temperature for 20 min and diluted with dichloromethane/ether (1:1). Filtration through a pad of Celite, covered with K2CO3, and concentration in vacuo furnished a yellow oil. This material was purified by chromatography on silica gel (15×5 cm) using n-hexane/ethyl acetate (85:15). A second chromatograhic run on silica gel (14×5 cm) using n-hexane/ethyl acetate (88:12) furnished 3.91 g (80%) of the title compound as a colorless oil. Anal. (C14H16ClN3O) C, H, N.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([CH:18]=[O:19])=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)[CH:6]=[CH:5][N:4]=1.[C:20]1([Mg]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[OH:19])=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)[CH:6]=[CH:5][N:4]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CSc1nccc(-c2c(C=O)nn3ccccc23)n1
Solvent: C1CCOC1
Product: CSc1nccc(-c2c(C(O)c3ccccc3)nn3ccccc23)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a cold (−78° C.) solution of 3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine-2-carbaldehyde (520 mg, 1.92 mmol) in tetrahydrofuran (40 mL) was added phenylmagnesium bromide (2.88 mL 1.0 M in tetrahydrofuran, 2.88 mmol). The reaction was warmed to 0° C. and stirred for 1 hour. The reaction mixture was then recooled to −78° C. and additional phenylmagnesium bromide (2.00 mL, 1.0 M in tetrahydrofuran, 2.00 mmol) was added and stirred at room temperature for 14 hours. The reaction was quenched with water and the resulting mixture was concentrated in vacuo to remove the excess tetrahydrofuran. The resulting aqueous mixture was extracted with dichloromethane. The organic layer was washed with water and dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (49:1 dichloromethane:methanol) provided {3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-2-yl}(phenyl)methanol (550 mg, 82%) as a white solid. Rf 0.31 (49:1 dichloromethane:methanol); 1H NMR (CDCl3) δ 8.52 (d, 1H), 8.40 (d, 1H), 7.87 (d, 1H), 7.43–7.13 (m, 7H), 6.93 (t, 1H), 6.21 (s, 1H), 2.60 (s, 3H); MS m/349 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][N:19]4[C:25]([C:26]5[C:27]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)=[N:28][O:29][C:30]=5[CH3:31])=[N:24][N:23]=[C:20]43)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[CH3:31][C:30]1[O:29][N:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]=1[C:25]1[N:19]2[CH2:18][C:17]3[C:21]([C:20]2=[N:23][N:24]=1)=[CH:22][C:14]([C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1)=[CH:15][CH:16]=3
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc1-2
Solvent: O=C(O)C(F)(F)F
Product: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(C3=CCNCC3)cc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
4-[3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-α]isoindol-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (750 mg, 1.52 mmol) was dissolved in TFA (10 ml) and stirred at room temperature for 30 minutes. The reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated K2CO3 (aq). The organic layer was dried (MgSO4), filtered, concentrated in vacuo. The residue was purified by alumina chromatography, using dichloromethane→5% methanol/dichloromethane (in 1% methanol gradient) as the eluant, to yield the title compound (460 mg, 77%). 1H NMR (360 MHz, CDCl3) δ 8.02 (1H, d, J=1.04 Hz), 7.54–7.52 (2H, m), 7.47–7.38 (4H, m), 7.21 (1H, d, J=8.1 Hz), 6.23 (1H, t), 4.00 (2H, s), 3.59–3.58 (2H, m), 3.16 (2H, m), 2.71 (3H, s), 2.52–2.50 (2H, m). m/z (ES) 396 (M+H)+. d) 3-(5-Methyl-3-phenylisoxazol-4-yl)-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-[1,2,4]triazolo[3,4-α]isoindole Under nitrogen atmosphere, 3-(5-Methyl-3-phenylisoxazol-4-yl)-8-(1,2,3,6-tetrahydropyridin-4-yl)-5H-[1,2,4]triazolo[3,4-α]isoindole (50 mg, 0.13 mmol) was dissolved in methanol (2 ml) and formalin solution (65 μl, 0.8 mmol) and sodium cyanoborohydride (32 mg, 0.52 mmol) were added. The reaction was stirred at room temperature for 3 hours. The reaction was concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was washed with saturated NaCl (aq), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by alumina chromatography eluting with dichloromethane→2% methanol/dichloromethane (in 0.5% methanol gradient) to yield the title compound (21 mg, 41%). 1H NMR (400 MHz, d4 McOH) δ 8.01 (1H, d, J=1.3 Hz), 7.59 (1H, dd, J=1.6, 8.2 Hz), 7.52–7.42 (5H, m), 7.40 (1H, d, J=8.2 Hz), 6.28–6.27 (1H m), 4.31 (2H, s), 3.21–3.20 (2H, m), 2.78 (2H, m), 2.69–2.66 (2H, m), 2.64 (3H, s), 2.43 (3H, s).
Reaction SMILES: Cl.[C:2]1([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([CH:19]=[O:20])C>>[C:2]1([N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH:19]=[O:20])=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 200 %

Procedure:
To a 300 ml four-neck flask were added 17.0 g (77 mmol) of 1,1-diphenylhydrazine hydrochloride obtained in Comparative Example 2, 21.1 g (77 mmol) of p-diphenylaminobenzaldehyde, and 70 g of DMF, followed by stirring at 40 to 45° C. for 3 hours. The reaction was traced by thin-layer chromatography. After, the completion of the reaction, 100 g of methanol was added and precipitated crystals were filtered off to obtain 32.3 g of p-diphenylaminobenzaldehyde=diphenylhydrazone. The yield was 95.4% based on the starting 1,1-diphenylhydrazine, the over all yield from the starting diphenylamine was 77.0%, and the purity determined by high-performance liquid chromatography was 98.2%.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]#[N:15])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]#[N:15])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[N:3]=1
Reactant: [H][H]
Reactant: Cc1nc2ncccc2cc1CCC#N
Agent: [Pd]
Solvent: CCO
Product: Cc1nc2c(cc1CCC#N)CCCN2

Procedure:
A mixture of the product of STEP 1 (2 g), 10% Pd/C (250 mg) and ethanol (15 mL) was stirred under a balloon of hydrogen gas for 2 hr. Filtration and evaporation prodiuced the title product. 1H (CDCl3) δ 1.83 (2H, p); 2.24 (3H, s); 2.43 (2H, t); 2.62 (2H, t); 2.73 (2H, t); 3.31 (2H, m); 4.81 (1H, broad s); 6.88 (1H, s).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:33]4[CH:34]=[C:35]5[C:30]([CH:29]=[CH:28][CH:27]=[N:26]5)=[CH:31][CH:32]=4)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1ccc2cccnc2c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc5cccnc5c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and quinoline-7-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.