Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[C:30]4[CH:29]=[C:28]([C:31]5[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=5)[N:27]=[CH:26][C:25]=4[CH:24]=[N:23]3)[N:17]=2)[CH2:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.Cl>CO>[CH3:36][N:34]1[CH:35]=[C:31]([C:28]2[N:27]=[CH:26][C:25]3[CH:24]=[N:23][N:22]([C:18]4[N:17]=[C:16]([C:2]5([OH:1])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]5)[CH:21]=[CH:20][CH:19]=4)[C:30]=3[CH:29]=2)[CH:32]=[N:33]1
Reactant: Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(C3(O)CCCN(C(=O)OC(C)(C)C)CC3)n2)cn1
Agent: Cl
Solvent: CO
Product: Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(C3(O)CCCNCC3)n2)cn1
Yield: 18.8 %

Procedure:
A solution of tert-butyl 4-hydroxy-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azepane-1-carboxylate (200 mg, 0.41 mmol) in a solution of HCl in MeOH (2.0 M, 10 mL) was stirred at room temperature for 1 hour, which was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude was purified by reverse phase preparative HPLC to afford 230 as a light yellow solid (30 mg, 31%). 1H NMR (500 MHz, CDCl3) δ (ppm) 9.06 (s, 1H), 8.85 (s, 1H), 8.26 (s, 1H), 8.06 (s, 1H), 8.03 (s, 1H), 7.88-7.89 (d, J=4.5 Hz, 2H), 7.56-7.58 (t, J=9 Hz, 1H), 4.00 (s, 3H), 3.31-3.38 (m, 2H), 3.10-3.13 (t, J=13 Hz, 1H), 2.81-2.83 (t, J=12 Hz, 1H), 2.37-2.46 (m, 3H), 2.10-2.17 (m, 4H), 1.82-1.85 (t, J=14.5 Hz, 1H); MS (ESI) m/z: 390 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:20])[C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[C:12]([CH3:18])[CH:11]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[NH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:20])=[O:19])=[CH:11][C:12]=1[CH3:18]
Reactant: Cc1cc(C(=O)N(C)c2ccc(Cl)cc2)ccc1C#N
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)N(C)c2ccc(Cl)cc2)ccc1CN
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
A solution of N-(4-chloro-phenyl)-4-cyano-3,N-dimethyl-benzamide from Example E115.1 (5.1 g, 17.9 mmol) in methanol (250 ml) was treated with cobalt(II) chloride hexahydrate (8.4 g, 35.8 mmol). The mixture was stirred for 15 min at room temperature then cooled down to 0° C. and sodium borohydride (6.7 g, 179 mmol) was added portionwise. The mixture was stirred for 1 h at room temperature, filtered through Celite® filter agent, washed with methanol and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:10% methanol:89% dichloromethane) to yield the title compound (3.6 g, 70%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[Si:14]([O:21][CH2:22][C@H:23]1[CH2:34][CH2:33][C:32]2[S:31][C:30]3[N:29]=[CH:28][N:27]=[C:26](Cl)[C:25]=3[C:24]1=2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1COCC1>[Si:14]([O:21][CH2:22][C@H:23]1[CH2:34][CH2:33][C:32]2[S:31][C:30]3[N:29]=[CH:28][N:27]=[C:26]([O:11][CH:8]4[CH2:9][CH2:10][C:5]5([O:4][CH2:3][CH2:2][O:1]5)[CH2:6][CH2:7]4)[C:25]=3[C:24]1=2)([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15]
Reactant: OC1CCC2(CC1)OCCO2
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCc2sc3ncnc(Cl)c3c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCc2sc3ncnc(OC4CCC5(CC4)OCCO5)c3c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-ol (379 mg, 2.40 mmol, 1.20 equiv) in freshly distilled THF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 320 mg, 8.00 mmol, 4.00 equiv) in ice/water bath and stirred for 30 min under nitrogen. A solution of (3S)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (710 mg, 2.00 mmol, 1.00 equiv) in 10 mL of anhydrous THF was added dropwise and the resulting solution was stirred for 3 h at 60° C. After cooling, the mixture was then quenched with water, extracted with EtOAc (100 mL), dried over anhydrous sodium sulfate. The solvents were evaporated under reduced pressure to obtain (3S)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-12-[1,4-dioxaspiro[4.5]decan-8-yloxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (840 mg, 88%) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-])=O.[CH3:9][CH2:10][O:11][C:12]([CH:14]1[C:18](=O)[CH2:17][CH2:16][CH2:15]1)=[O:13]>>[NH:6]1[CH:5]=[C:4]([NH:1][C:15]2[CH2:16][CH2:17][CH2:18][C:14]=2[C:12]([O:11][CH2:10][CH3:9])=[O:13])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CCOC(=O)C1CCCC1=O
Product: CCOC(=O)C1=C(Nc2cn[nH]c2)CCC1

Procedure:
The title compound was prepared from 4-nitropyrazole (5.2 g, 0.046 mole) as in description 7, using ethyl 2-cyclopentanonecarboxylate instead of ethyl 2-cyclohexanonecarboxylate. The product was obtained as a white solid (9.6 g, 94%) m.p. 121°-123° C.
Reaction SMILES: BrCC(=O)CC.FC1C=C[C:11]([C:14]2[N:15]3[N:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[C:19]([C:29]4[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=4)=[C:16]3[O:17][CH:18]=2)=[CH:10]C=1.N>>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]2[C:19]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)=[C:16]3[O:17][CH:18]=[C:14]([CH2:11][CH3:10])[N:15]3[N:21]=2)=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3c(-c4ccc(F)cc4)coc23)cc1
Agent: CCC(=O)CBr
Agent: N
Product: CCc1coc2c(-c3ccc(S(C)(=O)=O)cc3)c(-c3ccc(F)cc3)nn12

Procedure:
The desired product was prepared according to the method of Example 73D-73E substituting 1-bromo-2-butanone in place of 4′-fluoro-2-bromoacetophenone. The resulting thio-ether product was then oxidized as described in Example 73F (yield: 68 mg, 10%). MP 205-208° C.; MS (DCI-NH3) m/z 357(M+H)+, m/z 374 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ1.35 (t, J=7 Hz, 3H), 2.85 (q, J=7 Hz, 2H), 3.25 (s, 3H) 7.3 (m, 2H), 7.5 (m, 4H), 7.8 (d, J=9 Hz, 2H), 8.04 (s, 1H); Anal. calc. for C20H17FN2O3S: C, 62.49; H, 4.46; N, 7.29. Found C, 62.28; H, 4.36; N, 6.95.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].Br[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])[O:29]1>CC(N(C)C)=O>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:30](=[O:31])[O:29]3)=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: O=C1OC(Br)c2ccccc21
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OC3OC(=O)c4ccccc43)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Yield: 59.2 %

Procedure:
The title compound (122 mg) was prepared from 162 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 128 mg of 3-bromophthalide in the same manner as in Example 81, except that only DMA was used as the solvent and the reaction was carried out at room temperature.
Reaction SMILES: [C:1]([O:5][C:6]([N-:8][S:9]([N:12]1[CH:17]=C[C:15](=[N+](C)C)[CH:14]=[CH:13]1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].C[NH2+]C1CC[O:26][CH2:25]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:17][N:12]([CH:13]1[CH2:14][CH2:15][O:26][CH2:25]1)[S:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])(=[O:10])=[O:11]
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Reactant: C[NH2+]C1CCOC1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C1CCOC1)S(=O)(=O)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A flask was charged with N-tert-butoxycarbonyl-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (2.19 g, 7.27 mmol), N-methyltetrahydrofuran-3-aminium chloride (1.00 g, 7.27 mmol) and triethyl amine (1.01 mL, 7.27 mmol) in 10 mL of CH2Cl2. After 2 h, the solution was concentrated in vacuo and purified by flash column chromatography (10-100% EtOAc/hexanes) to afford tert-butyl {[methyl(tetrahydrofuran-3-yl)amino]sulfonyl}carbamate. tert-butyl {[methyl(tetrahydrofuran-3-yl)amino]sulfonyl}carbamate (1.47 g, 5.23 mmol) was dissolved in 70 mL of CH2Cl2 and 45 mL of trifluoroacetic acid. After 1 h the solution was concentrated in vacuo, diluted in CH2Cl2, washed with saturated aqueous NaHCO3 and brine, then dried over Na2SO4. The solution was concentrated in vacuo to afford the title compound. 1H NMR (600 MHz, DMSO-d6) δ 4.25-4.31 (m, 1H); 3.79-3.84 (m, 1H); 3.58-3.66 (m, 2H); 3.47-3.52 (m, 1H); 2.56 (s, 3H), 2.04-2.10 (m, 1H); 1.81-1.88 (m, 1H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)O1.[NH2:22][C:23]1[C:32](Br)=[N:31][C:30]([Br:34])=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26].C([O-])([O-])=O.[K+].[K+]>>[NH2:22][C:23]1[C:32]([C:9]2[CH:14]=[N:13][C:12]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:10]=2)=[N:31][C:30]([Br:34])=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc(Br)nc(-c2ccc(N3CCOCC3)nc2)c1N
Temperature: 100 °C
Yield: 42.8 %

Procedure:
A mixture of 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (400 mg, 1.379 mmol), methyl 3-amino-2,6-dibromoisonicotinate (427 mg, 1.379 mmol), tetra(triphenylphospine)palladium(0) (159 mg, 0.138 mmol), K2CO3 (762 mg, 5.51 mmol) in a microwave vial was flushed with nitrogen and DMF (4.0 mL) was added. The vial was sealed heated at 100° C. overnight. The reaction was diluted with EtOAc and water to give a precipitate. This was collected by filtration, washed with water and EtOAc to leave methyl 3-amino-6-bromo-6′-morpholino-2,3′-bipyridine-4-carboxylate (232 mg, 0.590 mmol, 42.8% yield) as a light green solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.49 (1H, d, J=1.76 Hz), 7.70-7.82 (2H, m), 6.71 (1H, d, J=8.81 Hz), 5.93 (2H, br. s.), 3.91 (3H, s), 3.76-3.86 (4H, m), 3.46-3.63 (4H, m).
Reaction SMILES: [CH3:1][C:2]1([N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C@H:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C@@H:16]4[NH:15][C:14]3=[O:22])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:30]([O:32][CH2:33][CH2:34][F:35])=[O:31]>O>[O:22]=[C:14]1[N:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:2]3([CH3:1])[CH2:6][CH2:5][N:4]([C:30]([O:32][CH2:33][CH2:34][F:35])=[O:31])[CH2:3]3)[CH2:8][CH2:9]2)[C@H:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C@@H:16]2[NH:15]1
Reactant: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCNC1
Reactant: O=C(Cl)OCCF
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCN(C(=O)OCCF)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (3aS,7aS)-1-[1-(3-methylpyrrolidin-3-yl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (1 mmol) in water (10 mL) was added with potassium carbonate (4.0 equiv.) followed by 2-fluoroethyl chloroformate (1.2 equiv.) at room temperature and stirred at rt for 30 minutes. Extracted in ethyl acetate (2×10 mL), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography by eluting with methanol in ethyl acetate (0 to 5%) to afford the title compound (93 mg). 1H NMR (CD3OD, 400 MHz): δ 4.65 (t, 2H), 4.53 (t, 1H), 4.34 (m, 1H), 4.27 (m, 1H), 3.62 (m, 3H), 3.48-3.37 (m, 2H), 3.25 (t, 1H), 3.03-2.90 (m, 3H), 2.77 (br t, 1H), 2.47 (m, 3H), 1.98-1.60 (br m, 9H), 1.43 (m, 3H), 1.11 (s, 3H); MS (M+1): 397.30.
Reaction SMILES: [Cl:1][C:2]1(NCC)[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:3]1.[Cl:16][C:17]1[C:21]([NH:22][C:23](=[O:25])[CH3:24])=[CH:20][N:19]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[N:18]=1.C(Br)C.[H-].[Na+].CC(C)([O-])C.[Na+].CC(C)([O-])C.[K+].C(OC(CC)(C)C)(CC)(C)C.[K]>O1CCCC1>[Cl:1][C:2]1[C:6]([N:22]([CH2:21][CH3:20])[C:23](=[O:25])[CH3:24])=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1.[Cl:16][C:17]1[C:21]([NH:22][C:23](=[O:25])[CH3:24])=[CH:20][N:19]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[N:18]=1
Reactant: CCNC1(Cl)C=CN(c2cccnc2)N1
Agent: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Agent: CC(C)(C)[O-]
Agent: CCC(C)(C)OC(C)(C)CC
Solvent: CCBr
Solvent: C1CCOC1
Product: CCN(C(C)=O)c1cn(-c2cccnc2)nc1Cl

Procedure:
3-Chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (1d) may be prepared through the reaction pathway sequence disclosed in Scheme 4. In step d1, N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (1c) may be alkylated with ethyl bromide (EtBr) in the presence of a base, such as sodium hydride (NaH), sodium tert-butoxide (NaOt-Bu), potassium tert-butoxide (KOt-Bu), or potassium tert-amyloxide, in a polar aprotic solvent, such as tetrahydrofuran (THF), at temperatures from about 20° C. to about 40° C., over a period of time of about 60 hours to about 168 hours, to yield N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (1c′). It has been discovered that use of an additive, such as potassium iodide (KI) or tetrabutylammonium iodide (TBAI) decreases the time necessary for the reaction to complete to about 24 hours. It was also discovered that heating the reaction at about 50° C. to about 70° C. in a sealed reactor (to prevent loss of ethyl bromide) decreases the reaction time to about 24 hours. In step d2, N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (1c′) may be treated with hydrochloric acid in water at temperatures from about 70° C. to about 90° C., to yield 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (1d). The reaction pathway sequence disclosed in Scheme 4 may also be performed without the isolation of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (1c′).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:20]([N+:21]([O-])=O)=[CH:19][N:18]([CH:24]5[CH2:29][CH2:28][CH2:27][CH2:26][O:25]5)[N:17]=4)[NH:13][C:12]=3[CH:30]=2)[CH2:4][CH2:3]1.[H][H]>CO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:20]([NH2:21])=[CH:19][N:18]([CH:24]5[CH2:29][CH2:28][CH2:27][CH2:26][O:25]5)[N:17]=4)[NH:13][C:12]=3[CH:30]=2)[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CN1CCN(c2ccc3nc(-c4nn(C5CCCCO5)cc4[N+](=O)[O-])[nH]c3c2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2ccc3nc(-c4nn(C5CCCCO5)cc4N)[nH]c3c2)CC1
Yield: 104.9 %

Procedure:
A suspension of 370 mg of 6-(4-methylpiperazin-1-yl)-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-1H-benzimidazole in 10 mL of methanol and 37 mg of palladium-on-charcoal is hydrogenated under 1 bar of hydrogen pressure at ambient temperature for 18 hours. The reaction medium is filtered through celite and the filtrate is concentrated under reduced pressure in a rotary evaporator. 360 mg of 3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine are obtained in the form of a black oil. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.50 to 2.21 (m, 6H); 2.23 (s, 3H); 2.50 (m masked, 4H); 3.08 (m, 4H); 3.61 (m, 1H); 3.94 (m, 1H); from 4.89 to 4.98 (m, 2H); 5.30 (broad d, J=10.0 Hz, 1H); from 6.85 to 7.12 (m, 2H); from 7.25 to 7.46 (m, 2H); from 12.2 to 12.35 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13]Cl)[CH:3]=1.[I-:21].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13][I:21])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1O[C@H](CCCl)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Cl)cc1O[C@H](CCI)c1ccccc1
Yield: 84 %

Procedure:
4-Chloro-2-{[(1R)-3-chloro-1-phenylpropyl]oxy}benzonitrile (220mg, 0.718 mmol) was dissolved in acetone (20 ml) which had previously been saturated with sodium iodide and the solution was heated under reflux for 18 h. The reaction mixture was cooled, filtered, evaporated and the residue partitioned between water and ethyl acetate. The organic layer was separated, washed twice with water and dried (magnesium sulphate). The solvent was evaporated to leave 0.24 g (84%) of the product as a yellow oil. This was used without purification for the next step.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=O.[CH2:18]([C:25]1([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[CH2:18]([C:25]1([OH:31])[CH2:30][CH2:29][N:28]([C:8]([C:7]2[CH:11]=[C:3]([CH3:2])[CH:4]=[CH:5][C:6]=2[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[O:10])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: Cc1ccc(-c2ccncc2)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccncc2)c(C(=O)N2CCC(O)(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
A suspension of 5-methyl-2-(pyridin-4-yl)benzoic acid hydrochloride (0.33 g), 4-benzyl-4-hydroxypiperidine (0.38 g), HATU (0.75 g) and triethylamine (0.92 mL) in DMF (5.0 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and then purified by preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)), the obtained fraction was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (0.33 g).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:40]=[CH:39][C:21]([CH2:22][CH2:23][C:24]([O:26][CH:27]2[CH2:32][O:31]C(C3C=CC=CC=3)[O:29][CH2:28]2)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H][H]>[Pd].C(O)(=O)C>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH2:23][C:24]([O:26][CH:27]([CH2:28][OH:29])[CH2:32][OH:31])=[O:25])=[CH:39][CH:40]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OC2COC(c3ccccc3)OC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OC(CO)CO)cc1

Procedure:
A mixture of 2-phenyl-1,3-dioxan-5-yl 4-(hexadecylamino)hydrocinnamate, 10% palladium-on-carbon and acetic acid is treated with hydrogen in a Parr apparatus at room temperature until hydrogen uptake ceases. The mixture is filtered and the filtrate is evaporated. Recrystallization of the residue from chloroform provides the title compound.
Reaction SMILES: [C:1]1([C:11]2[CH:23]=[C:14]3[NH:15][CH:16]=[C:17](C(O)=O)[C:18](=[O:19])[N:13]3[N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CS(C)=O.[Cl-].[Na+]>O>[C:1]1([C:11]2[CH:23]=[C:14]3[NH:15][CH:16]=[CH:17][C:18](=[O:19])[N:13]3[N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1c[nH]c2cc(-c3cccc4ccccc34)nn2c1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1cc[nH]c2cc(-c3cccc4ccccc34)nn12
Yield: 86.5 %

Procedure:
2-(1-naphthyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylic acid (2.00 g, 6.55 mmol) is stirred in dimethyl sulfoxide (5.06 mL, 71.2 mol) in a 350 mL sealed reaction vessel. Sodium chloride (0.545 g, 9.33 mol) is dissolved in water (2.26 mL) and added to the reaction mixture. The reaction is heated at 150° C. for 3 days during which time an additional 8 mL of DMSO is added along with 15 mL of additional water. The resulting precipitate is collected in a Buchner funnel to provide 2-(naphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (1.48 g, 87%). LCMS: (AA) M+1 262.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].C([N:14]1[CH2:28][CH:17]2[C:18]3[CH:19]=[C:20]([O:26][CH3:27])[CH:21]=[CH:22][C:23]=3[C:24](=O)[CH:16]2[CH2:15]1)C1C=CC=CC=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.CCOCC>[CH3:27][O:26][C:20]1[CH:21]=[CH:22][C:23]2[CH:24]([CH2:1][CH3:2])[CH:16]3[CH2:15][NH:14][CH2:28][CH:17]3[C:18]=2[CH:19]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2c(c1)C1CN(Cc3ccccc3)CC1C2=O
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: CCC1c2ccc(OC)cc2C2CNCC12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyltriphenylphosphonium bromide (0.6 g, 1.6 mmol) and potassium tert-butoxide (0.18 g, 1.6 mmol) were added to a solution of 2-benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (from Example 1, Step C) (0.32 g, 1.1 mmol) in anhydrous ether (2.2 mL). The reaction mixture was stirred for 1 hour at room temperature then filtered through celite. The celite was washed with ether (10 mL), and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% EtOAc-hexanes gradient to afford the subtitle compound in quantitative yield. MS calculated for C21H23NO+H: 306, observed: 306.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1.CO>ClCCl>[NH:12]1[C:16]2=[N+:17]([O-:9])[CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: [O-][n+]1cccc2cc[nH]c21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(Antonini, Ippolito; Claudi, Francesco; Cristalli, Gloria; Franchetti, Palmarisa; Grifantini, Mario; Martelli, Sante; J. Med. Chem. 1982, 25, 1258-1261.) 540 g (2.35 mol) of 3-chloroperbenzoic acid are dissolved in 6.11 l of dichloromethane, and the water that separates off is removed. The organic phase is dried over sodium sulfate and cooled to 0° C. A solution of 163 g (1.38 mol) of 1H-pyrrolo[2,3-b]pyridine (Hands, D.; Bishop, B.; Cameron, M.; Edwards, T. S.; Cottrell, I. F.; Wright, S. H. B.; Synthesis 1996, 877-882.) in 1.00 l of dichloromethane is then added, and the temperature is allowed to rise to room temperature. After 2 hours, methanol is added in such an amount that the precipitate formed redissolves. The mixture is filtered through silica gel (mobile phase:dichloromethane/methanol 95:5) and the product fractions are, after concentration, dried under high vacuum.