Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CC[CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:35]=[CH:34][C:15]4[N:16]([C:19]5[CH:20]=[C:21]([NH:25][C:26]([NH:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[O:27])[CH:22]=[CH:23][CH:24]=5)[CH:17]=[N:18][C:14]=4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3]C1.[CH2:36]([O:38]C(N1C=C(B2OC(C)(C)C(C)(C)O2)C=N1)C)[CH3:37]>>[CH2:36]([O:38][CH:4]([N:7]1[CH:11]=[C:10]([C:12]2[CH:35]=[CH:34][C:15]3[N:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26]([NH:28][CH2:29][C:30]([F:32])([F:31])[F:33])=[O:27])[CH:22]=[CH:23][CH:24]=4)[CH:17]=[N:18][C:14]=3[CH:13]=2)[CH:9]=[N:8]1)[CH3:3])[CH3:37]
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCNCC5)c4)ccc32)c1
Product: CCOC(C)n1cc(-c2ccc3c(c2)ncn3-c2cccc(NC(=O)NCC(F)(F)F)c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 21 (step 3) starting from N-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea (prepared from the procedure for Example 21, step 4) and 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Adesis, Cat. No. 9-243), LCMS (M+H)+: m/z=473.1.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1.[Br-].[CH2:25]([Zn+])[CH:26]([CH3:28])[CH3:27].C1COCC1>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.C1(C)C=CC=CC=1>[CH2:25]([C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)n3cnnc23)CC1
Reactant: CC(C)C[Zn+]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c2nncn12
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A 50 mL round bottom flask was charged with tert-butyl 4-(5-bromo-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)piperazine-1-carboxylate (0.5 g, 1.3 mmol), Pd(PPh3)2Cl2 (140.3 mg, 0.20 mmol) and toluene (8 mL) under N2. To the above was injected a 2 M solution of isobutylzinc(II) bromide in THF (10.4 mL, 5.2 mmol). The resulting mixture was stirred under N2 at 20° C. for 0.5 h then 100° C. overnight. Work-up: the reaction mixture was filtered. The filter cake was washed with EtOAc (10 mL) and the filtrate was extracted with more EtOAc (10 mL×3). The combined organic solutions were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 2% methanol in dichloromethane, to afford 0.30 g (64%) of tert-butyl 4-(5-isobutyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)piperazine-1-carboxylate as a yellow solid. MS m/z: 361 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:61])[CH2:7][N:8]([CH2:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:9](=[O:52])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:16][N:17]([CH2:26][C:27]1[N:28]([CH2:32][C:33](=[O:51])[N:34]([CH2:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:29]=[CH:30][N:31]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].[NH:62]1CCCCC1>CN(C=O)C>[NH2:62][C@@H:22]([CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:26][C:27]1[N:28]([CH2:32][C:33]([N:34]([CH2:43][C:44]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:50])[CH2:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:51])[CH:29]=[CH:30][N:31]=1)[CH2:16][C:12]1[N:11]([CH2:10][C:9](=[O:52])[N:8]([CH2:7][C:6](=[O:61])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[CH:15]=[CH:14][N:13]=1)[C:23]([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCCCCC(=O)O)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Yield: 79 %

Procedure:
A solution of 2-4(9H-fluoren-9-yl)methoxy)carbonylamino)-6-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (190 mg, 0.173 mmol) and piperidine (0.50 mL) in DMF (0.50 mL) was stirred at room temperature for 1 hrs. The solvent was evaporated under reduced pressure to give a crude product. The crude product was purified by Biotage SP4 with a gradient method of 5-50% methanol in DCM to give (S)-2-amino-6-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (0.120 g, 79%). 1H NMR (400 MHz, DMSO-d6). 6.92 (s, 2H), 6.76 (s, 2H), 5.01 (s, 4H), 4.32 (s, 2H), 4.31 (s, 2H), 3.92 (s, 4H), 3.44 (s, 4H), 3.01-2.99 (m, 1H), 2.30 (t, J=7.2 Hz, 2H), 1.60-1.57 (m, 2H), 1.43 (s, 18H), 1.35 (m, 18H). 1.30-1.12 (m, 4H); MS (ESI), 439.4 (M/2+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[OH:8].[C:13]1(C)[CH:18]=CC(S(O)(=O)=O)=C[CH:14]=1.CC(C)=O>C1C=CC=CC=1>[CH3:14][C:13]1([CH3:18])[O:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:9][CH2:10][OH:12])=[CH:3][C:2]=2[O:1]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1ccc(O)c(O)c1
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CC1(C)Oc2ccc(CCO)cc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.7 g of 3,4-dihydroxyphenylacetic acid, a catalytic amount of p-toluenesulfonic acid, 10 ml of acetone and 10 ml of benzene were heated under reflux for 18 h. The reflux solution was dehydrated with Molecular Sieve 4A. The reaction mixture was concentrated and the obtained dark brown oil was dissolved in 20 ml of tetrahydrofuran. The solution was added to a suspension of 0.8 g of lithium aluminum hydride in 30 ml of tetrahydrofuran under cooling with ice. The mixture was stirred at room temperature for 1 h and then cooled with ice/water. 0.8 ml of water, then 0.8 ml of a 15% aqueous sodium hydroxide solution and finally 2.4 ml of water were added thereto and an insoluble substance was filtered off. The filtrate was concentrated and treated according to silica gel column chromatography (ethyl acetate/n-hexane=1:1) to obtain 1.1 g of the intended compound in the form of a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7].C(=O)([O-])[O-:19].[Ca+2].O>O1CCOCC1>[OH:19][CH2:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7]
Reactant: CON(C)C(=O)c1cccc(CBr)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: CON(C)C(=O)c1cccc(CO)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of Intermediate 37B (3.7 g, 4.88 mmol) and calcium carbonate (2.93 g, 29.3 mmol) in dioxane (25 mL)/water (25 mL) was stirred at reflux for 5 h. The mixture was then cooled to room temperature, the solid was removed by filtration and the filtrate was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to dryness. The crude residue was purified by flash chromatography (SiO2, 80 g column, EtOAc/hexane=20-100%) to afford Intermediate 37C (1.079 g, 78%). HPLC: RT=0.75 min (CHROMOLITH® SpeedROD column 4 6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm), MS(ES): m/z=241.0 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[C:16]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[CH:17][CH:18]=[CH:19][C:12]=3[N:11]=2)=[C:6]([OH:8])[CH:7]=1.C(=O)(O)[O-].[Cs+].Br[CH2:33][C:34]#[N:35].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[C:16]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[CH:17][CH:18]=[CH:19][C:12]=3[N:11]=2)=[C:6]([CH:7]=1)[O:8][CH2:33][C:34]#[N:35]
Reactant: CCCN(CCC)c1cccc2nc(Nc3ccc(Cl)cc3O)n(C)c12
Reactant: N#CCBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCCN(CCC)c1cccc2nc(Nc3ccc(Cl)cc3OCC#N)n(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
To a solution of 48 mg (0.40 mmol) of 5-chloro-2-(7-dipropylamino-1-methyl-1H-benzimidazol-2-ylamino)phenol in 5 mL of tetrahydrofuran was added 114 mg (0.59 mmol) of cesium bicarbonate and 50 mg (0.41 mmol) of bromoacetonitrile and the reaction was stirred overnight at room temperature. Bromoacetonitrile, 200 mg (1.64 mmol), was added to the reaction and the mixture was stirred several hours at room temperature. Then 50 mg (0.36 mmol) of potassium carbonate was added to the reaction and it was stirred at room temperature overnight. The reaction was concentrated in vacuo to a residue that was dissolved in dichloromethane, washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with a solution of 20% ethyl acetate/hexanes to give 64 mg (58%) of the title compound.
Reaction SMILES: N1C=CC(C2C=[N:10][NH:9][C:8]=2C2C=CC(CCC3C=CC4C(=CC=CC=4)N=3)=CC=2)=CC=1.[Cl:30][C:31]1[CH:36]=[C:35]([CH2:37][C:38]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]3[CH:57]=[CH:56][C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[N:49]=3)=[CH:42][CH:41]=2)=O)[CH:34]=[CH:33][N:32]=1>>[Cl:30][C:31]1[CH:36]=[C:35]([C:37]2[C:38]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]4[CH:57]=[CH:56][C:55]5[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=5)[N:49]=4)=[CH:42][CH:41]=3)=[N:10][NH:9][CH:8]=2)[CH:34]=[CH:33][N:32]=1
Reactant: O=C(Cc1ccnc(Cl)c1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: c1ccc2nc(CCc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Product: Clc1cc(-c2c[nH]nc2-c2ccc(OCc3ccc4ccccc4n3)cc2)ccn1

Procedure:
Following the procedure for the preparation of 2-{2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline but substituting 2-(2-Chloro-pyridin-4-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.23 (m, 2H), 8.08 (d, J=8.7 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.80 (s, 1H), 7.75 (t, J=7.1 Hz, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.57 (t, J=7.1 Hz, 1H), 7.33 (d, J=9.1 Hz, 2H), 7.05 (m, 4H), 5.40 (s, 2H); MS: (M−H m/z=413.1).
Reaction SMILES: [Mg].[CH2:2]([O:4][CH:5]([O:13][CH2:14][CH3:15])[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)[CH3:3].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:34])[CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH3:27])=[CH:20][CH:19]=1.[NH4+].[Cl-]>C1COCC1.O>[CH2:2]([O:4][CH:5]([O:13][CH2:14][CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([C:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)([OH:34])[CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH3:27])=[CH:8][CH:7]=1)[CH3:3]
Reactant: CCOC(OCC)c1ccc(Br)cc1
Reactant: CCC(C(=O)c1ccc(OC)cc1)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccc(C(O)(c2ccc(OC)cc2)C(CC)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
Magnesium turnings (9.64 g, 397 mmol) were heated to 160° C. under vacuum for 2 hours, then were cooled to RT under nitrogen. THF (400 mL) was added followed by portionwise addition of 4-bromobenzaldehyde diethyl acetal (80.0 mL, 393 mmol). The mixture was heated with a heat gun to initiate the reaction, then allowed to stir at RT (while gently refluxing) for 90 min. The resulting dark red solution was cooled to 0° C. and a solution of 2 (77.27 g, 304 mmol) in THF (50 mL) was added. The mixture was stirred at RT for 3 hours. Saturated aqueous NH4Cl (150 mL) and H2O (150 mL) were added and the two layers were separated. The aqueous layer was extracted with Et2O (3×100 mL), and the combined organics were dried (MgSO4) and concentrated to provide 3 as a light yellow oil that was carried on without further purification. 1H NMR (400 MHz, CDCl3): δ 0.72 (t, J=7.3 Hz, 3H), 1.25 (t, J=7.0 Hz, 6H), 1.77 (q, J=7.3 Hz, 2H), 2.35 (s, 1H), 3.69 (s, 3H), 3.52-3.65 (m, 5H), 5.50 (s, 1H), 6.62 (d, J=8.8 Hz, 2H), 7.08 (m, 1H), 7.12 (m, 6H), 7.44 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.2 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19](F)=[C:18](Cl)[CH:17]=3)[N:12]=[CH:11][N:10]=2)C=1.[NH2:26]C1C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:26][C:2]1[N:1]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.3 %

Procedure:
The preparation of N4-(5-amino-2-methoxyphenyl)-N6-(3-chloro-4-fluorophenyl)pyrimidine-4,6-diamine (1) is described in Example 7 (Int-G). To a stirred solution of 1 (150 mg, 0.41 mmol) in DMF (8 mL) was added 2 (137 mg, 0.83 mmol), HATU (317 mg, 0.83 mmol) and DIPEA (215 mg, 1.67 mmol) at 0° C. The reaction mixture was stirred for 18 h at RT. After the completion of reaction (monitored by TLC), the crude mixture was diluted with water and extracted with EtOAc (4×100 mL). The organic layers were dried over anhydrous Na2SO4 and concentrated under vacuo to afford 3 (100 mg, 47.3%) as off-white solid, which was used in the next step without further purification. 1H NMR (CDCl3, 500 MHz): δ 8.35 (s, 1H), 8.12 (s, 1H), 7.48-7.43 (m, 1H), 7.24 (s, 1H), 7.16-7.10 (m, 2H), 7.03 (s, 1H), 6.84 (t, J=9.0 Hz, 2H), 6.49 (s, 1H), 6.15 (s, 1H), 5.29 (s, 1H), 3.85 (s, 3H), 3.33 (d, J=5.0 Hz, 2H), 2.80 (s, 3H). Mass: m/z 506 (M++1).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21](COCC[Si](C)(C)C)[C:22](=[O:23])[C:17]=4[C:16]=3[CH:33]3[CH2:35][CH2:34]3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3NC4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3C)C=CC=2OC(F)F)CC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH:33]3[CH2:34][CH2:35]3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(C3CC3)c2c1=O
Agent: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(C3CC3)c12
Yield: 90.8 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 4-(c) except for using 1.80 g (3.57 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-cyclopropyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 14-(b) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one, whereby 1.21 g of the title compound was obtained as a white solid. (Yield: 91%)
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[NH:14][CH:15]=[C:16]([C:18]4[O:19][C:20]([CH3:23])=[CH:21][CH:22]=4)[N:17]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[NH:14][CH:15]=[C:16]([C:18]4[O:19][C:20]([CH3:23])=[CH:21][CH:22]=4)[N:17]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccc(-c2c[nH]c(/C=C/c3nc4cccc(C)n4n3)n2)o1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(-c2c[nH]c(CCc3nc4cccc(C)n4n3)n2)o1
Yield: 27.9 %

Procedure:
To a solution of 5-Methyl-2-{(E)-2-[4-(5-methyl-furan-2-yl)-1H-imidazol-2-yl]-vinyl}-[1,2,4]triazolo[1,5-a]pyridine (20 mg, 0.07 mmol) in methanol (20 mL) was added 10% palladium on carbon (20 mg). The reaction was shaken under 3 bar atmosphere of hydrogen overnight. Filtration and evaporation of the volatiles afforded the title compound (6 mg, 30%). LC-MS: m/z=308.3 (MH+), tR=0.41 minutes, method A.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([NH:12][NH2:13])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:16]S(O)(=O)=O.C(OCC)(OCC)OCC.O1CCCC1>O>[N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]2[O:11][CH:16]=[N:13][N:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NNC(=O)COc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCOC(OCC)OCC
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2nnco2)cc1
Yield: 343.3 %

Procedure:
A mixture of 2-(4-nitrophenoxy)acetohydrazide (1.10 g), methanesulfonic acid (0.10 g), triethyl orthoformate (2.31 g) and tetrahydrofuran (50 mL) was heated under reflux for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-[(4-nitrophenoxy)methyl]-1,3,4-oxadiazole as colorless crystals (0.79 g, yield 69%) from a fraction eluted with hexane-ethyl acetate (1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 125-126° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][N:39]=[CH:38]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.CS(C)=O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][N:39]=[CH:38]3)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4[nH]ncc4c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Yield: 48.1 %

Procedure:
To a 5-mL microwave vial were added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (59.4 mg, 0.243 mmol), DMSO(1.5 mL) and sodium carbonate (0.281 mL, 0.562 mmol), and the mixture was degassed with nitrogen for 10 min. Next was added bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol). The contents were sealed and irradiated (microwave) at 140° C. overnight. The mixture was filtered and the residue was washed with DMSO. The crude product in DMSO was purified using reverse-phase HPLC. The TFA salt of the product was neutralized using saturated NaHCO3, filtered, washed with water and dried under high vacuum to give 41 mg (48%) of product. LCMS E-S (M+H)=456.0 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (d, J=6.8 Hz, 6 H), 2.14 (s, 3 H), 2.23 (s, 3 H), 4.38-4.53 (m, 2 H), 5.27-5.49 (m, 1 H), 5.91 (s, 1 H), 7.59-7.75 (m, 1 H), 8.24 (s, 2 H), 8.37 (s, 2 H), 8.69 (s, 1 H), 8.95-9.09 (m, 1 H), 11.49-11.67 (m, 1 H), 13.21-13.35 (m, 1 H).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][C:18]=4[O:27][CH3:28])=[N:11][C:10]=3[N:9]([CH3:29])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][O:31]CC(O)=O>>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH2:25][O:31][CH3:30])=[CH:19][C:18]=4[O:27][CH3:28])=[N:11][C:10]=3[N:9]([CH3:29])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCC(=O)O
Reactant: COc1cc(NC(C)=O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Product: COCC(=O)Nc1ccc(-c2nc3c(c(C4CCCCC4)nn3C)c(=O)[nH]2)c(OC)c1
Yield: 96 %

Procedure:
The same reaction procedure as in Example 12 was performed, except that the compound obtained in Example 45 was used in place of the compound obtained in Example 6, and methoxyacetic acid was used in place of 4-(4-methyl-1-piperazinyl)benzoic acid. In this manner, 82 g (96%) of the captioned compound was obtained.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C:14]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:17](=[O:28])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[C:33]([O:32][C:30](=[O:31])[NH:29][C:14]1([C:17](=[O:28])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:26])[CH3:27])=[CH:21][CH:20]=2)[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)([CH3:35])([CH3:34])[CH3:36]
Reactant: CC(C)c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCNCC2)cc1
Yield: 89.4 %

Procedure:
A mixture of 2.84 g (6 mmol) 4-tert-Butoxycarbonylamino-4-(4-isopropyl-phenylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (example 82, step 1) in 80 mL methanol was hydrogenated with H2 over Pd/C (10%) for 2 h at room temperature. The mixture was filtered off and evaporated to dryness to yield 1.94 g (94%) of the title compound as off-white crystals. MS (m/e): 362.4 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=[O:9].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8][OH:9]
Reactant: O=Cc1c(Cl)cncc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
A solution of 3,5-dichloropyridine-4-carboxaldehyde (1.34 g, 7.6 mmol) in MeOH (10 ml) was treated with NaBH4 (0.29 g, 7.6 mmol) and stirred at room temperature for 2 h. The reaction was quenched with water (5 ml) and concentrated in vacuo. The residue was partitioned between EtOAc (20 ml) and 10% HCl (10 ml). The aqueous layer was extracted with EtOAc and the combined organic extracts washed with 10% NaHCO3 solution, dried (MgSO4) and concentrated in vacuo to give the title compound as a white solid (1.05 g, 78%): δH (CDCl3) 8.52 (2H, s), 4.94 (2H, br. s), 2.28 (1H, br. s).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1>[Ni]>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: c1ccc2cnccc2c1
Agent: [Ni]
Product: c1ccc2c(c1)CCNC2
Yield: 88.9 %

Procedure:
In an autoclave, 1.2 kg of the same crude isoquinoline as used in Example 2 and 180 g of the aforementioned stabilized nickel catalyst were subjected to hydrogenation at a temperature of 180° C. under a hydrogen pressure of 135 kg/cm2 ·G for 65 hours. The amount of hydrogen absorbed was 29.9 moles and the molar ratio of the hydrogen absorption (by molar ratio based on raw material) was 3.22. The resultant reaction mixture was separated by filtration and then distilled. Consequently, 1.1 kg of 1,2,3,4-tetrahydroisoquinoline (purity 94.6% and total sulfur content 0%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[Cl:17][C:18]1[CH:19]=[C:20]([S:25](Cl)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[Cl:24]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([C:20]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=1)(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 123 mg of 3,4-Dichloro-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.25 (d, 1H, J=8.8 Hz), 7.36-39 (m, 3H), 7.43-47 (m, 3H), 7.53 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.61 (m, 1H), 7.65 (m, 1H), 7.73 (d, 1H, J=8.8 Hz), 9.56 (s, 1H). MS: m/z 440.7 (M++1).