Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:42](=[O:52])[N:43]([CH2:48][CH2:49][CH2:50][CH3:51])[CH2:44][CH2:45][CH2:46][CH3:47])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:41])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[C:25]([O:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)[CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10](O)=[O:11])[C:6]=1[CH3:7].[CH2:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH2:56][C@@H:55]([CH2:63][N:64]2[CH2:69][CH2:68][O:67][CH2:66][CH2:65]2)[NH:54]1>>[CH2:48]([N:43]([CH2:44][CH2:45][CH2:46][CH3:47])[C:42]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:41])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[C:25]([O:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)[CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10]([N:54]2[C@H:55]([CH2:63][N:64]3[CH2:69][CH2:68][O:67][CH2:66][CH2:65]3)[CH2:56][C:57]3[C:62](=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH2:53]2)=[O:11])[N:4]=1)=[O:52])[CH2:49][CH2:50][CH3:51]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)O)c(C)c1Cl
Reactant: c1ccc2c(c1)CN[C@H](CN1CCOCC1)C2
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN2CCOCC2)c(C)c1Cl
Yield: 72.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 91, 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(8-(2-morpholinoethoxy) naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 183B, 15 mg, 0.020 mmol) and (S)-4-((1,2,3,4-tetrahydroisoquinolin-3-yl)methyl)morpholine (Intermediate 109, 18 mg, 0.080 mmol) were converted to the title compound (14 mg, 62%). 1H NMR (CD3OD, mixture of amide rotamers) δ 9.19-9.04 (m, 1H), 8.26-7.93 (m, 4H), 7.79-7.53 (m, 3H), 7.36-7.09 (m, 4H), 6.99 (d, J=7.7 Hz, 1H), 5.37-5.16 (m, 1H), 4.75-4.41 (m, 3.5H), 4.22-2.52 (m, 27.5H), 2.37-2.16 (m, 3H), 1.75-0.48 (m, 14H); MS(ESI+) m/z 968.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:41])[C:5](F)=[C:6]([C:8](=O)[CH:9]([CH:17]([C:21]2[CH:38]=[CH:37][C:24]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])=[O:26])=[CH:23][CH:22]=2)[CH2:18][CH2:19][CH3:20])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:7]=1.O.[NH2:43][NH2:44]>CS(C)=O>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH:9]([C:8]2[C:6]3[C:5](=[C:4]([F:41])[CH:3]=[C:2]([C:3]4[CH:2]=[CH:7][C:6]([CH3:8])=[CH:5][CH:4]=4)[CH:7]=3)[NH:44][N:43]=2)[CH:17]([C:21]2[CH:38]=[CH:37][C:24]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:22]=2)[CH2:18][CH2:19][CH3:20])=[CH:15][CH:14]=1
Reactant: NN
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(C(=O)c1cc(Br)cc(F)c1F)c1ccc(Cl)cc1
Solvent: O
Solvent: CS(C)=O
Product: CCCC(c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1n[nH]c2c(F)cc(-c3ccc(C)cc3)cc12

Procedure:
To a solution of the product of Step F (600 mg, 0.925 mmol) in DMSO (10 mL) was added hydrazine hydrate (60 wt %, 2.0 mL, 24 mmol). The mixture was stirred at room temperature until all starting ketone had been consumed by LC-MS analysis. The mixture was diluted with ethyl acetate then washed with saturated NaCl (aq). The organic layer was dried over sodium sulfate, filtered, then concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-50% EtOAc/hexanes to afford the title compound as a solid. LC2 1.40 min. (M+H)+644.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][C:7]=1[CH:15]=[O:16].Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:8][C:7]=1[CH:15]=[O:16]
Reactant: Brc1cccnc1
Reactant: CN(C)CCOc1ccc(B(O)O)cc1C=O
Product: CN(C)CCOc1ccc(-c2cccnc2)cc1C=O
Yield: 13 %

Procedure:
General procedure G using 4-(2-dimethylamino-ethoxy)-3-formyl-benzeneboronic acid and 3-bromo-pyridine gave the title product as yellow oil in 13% yield. 1H-NMR (CDCl3) δ 10.46 (s, 1H), 8.76 (d, 1H), 8.52 (dd, 1H), 8.00 (d, 1H), 7.80 (dt, 1H), 7.72 (dd, 1H), 7.30 (ddd, 1H), 7.07 (d, 1H), 4.28 (t, 2H), 2.90 (t, 2H), 2.42 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([CH3:19])[C:11]=12.Cl[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:24]=[C:23]([NH2:31])[N:22]=1.Cl.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[N:24]=[C:23]([NH2:31])[N:22]=2)[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([CH3:19])[C:11]=12
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Reactant: Cc1c[nH]c2nccc(Nc3ccc(N)cc3F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c[nH]c2nccc(Nc3ccc(Nc4cc(C(F)(F)F)nc(N)n4)cc3F)c12
Temperature: 100 °C

Procedure:
123 mg (480 mmol) of 2-fluoro-N1-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene-1,4-diamine and 123 mg (620 μmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 3.5 ml of water. 620 μl of 1 M hydrochloric acid are added, and the mixture is heated at 100° C. overnight. Using 1N aqueous sodium hydroxide solution, the suspension is then adjusted to pH 10, resulting in the precipitation of crystals. The solid is filtered off and washed with water. The crude product is purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol (7 M ammonia) 100:1 to 10:1).
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1)=[CH2:2].[CH3:20][CH:21]1[CH2:25][CH2:24][CH2:23][NH:22]1>C(O)C>[CH3:20][CH:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH2:2][CH2:1][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: C=Cc1nc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: CC1CCCN1
Solvent: CCO
Product: CC1CCCN1CCc1nc2cc(-c3ccc(C#N)cc3)ccc2o1
Yield: 99.6 %

Procedure:
A solution of 24.6 mg (0.1 mmol) of 4-(2-vinyl-benzooxazol-5-yl)-benzonitrile and 24 mg of racemic 2-methyl-pyrrolidine (Aldrich, CAS #765-38-8) in 0.25 mL of ethanol was stirred at room temperature for 1 hour, then concentrated in vacuo to a glass to give pure product racemic 4-{2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-benzooxazol-5-yl}-benzonitrile 33 mg (100%): 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=1.8 Hz, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 7.58 (d, J=7.5 Hz, 1H), 7.50 (dd, J=7.5, 1.8 Hz), 3.2-3.32 (m, 4H), 1.44-2.65 (m, 7H), 1.15 (m, 3H); Mass spectrum: [M+H]+ 332.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:8][CH2:7]2)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:8][CH2:7]2
Reactant: O=C(CN1CCc2cc([N+](=O)[O-])ccc21)OCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)CCN2CC(=O)OCc1ccccc1
Yield: 98.9 %

Procedure:
To a suspension of benzyl 2-(5-nitroindolin-1-yl)acetate (0.700 g, 2.241 mmol) in a mixture of ethanol (20 ml) and water (10 ml), iron powder (0.751 g, 13.45 mmol) and ammonium chloride (0.084 g, 1.569 mmol) were added, and the resulting mixture was heated to reflux for 1 hour and 15 minutes. The insoluble was filtered off, and the filtrate was concentrated under vacuum. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and evaporated to dryness to give benzyl 2-(5-aminoindolin-1-yl)acetate (0.626 g, 2.217 mmol, 99% yield). MS/ESI+ 283.0 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C([Li])CCC.[I:25]I.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[CH3:7][C:4]1[N:3]([C:8]2[CH:12]=[C:11]([I:25])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C)n1-c1ccn(-c2ccccc2F)n1
Reactant: II
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(I)n(-c2ccccc2F)n1
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
Under nitrogen atmosphere, a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-(2-fluorophenyl)-1H-pyrazole (1.19 g) in tetrahydrofuran (10 ml) was cooled to −78° C., n-butyllithium (3.5 ml, 1.6M solution in n-hexane) was added dropwise thereto, and the mixture was stirred for 30 minutes. To this reaction solution was added dropwise a solution of iodine (1.42 g) in tetrahydrofuran (5 ml), and the mixture was stirred for 30 minutes. To this reaction mixture was added a saturated aqueous solution of sodium sulfite and a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. To the resulting residue was added a mixed solvent of n-hexane/ethyl acetate (=6/1), the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (1.23 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N[C@@H](Cc2ccccc2)C(=O)O)cc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (5.0 g) in dimethyl sulfoxide (100 mL) were added phenylalanine (6.37 g) and cesium carbonate (13.6 g), and the mixture was stirred at 90° C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted 3 times with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 9.67 g, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][CH:16]=[C:4]2[CH2:3]1.[I:17]I.O>CN(C)C=O>[I:17][C:16]1[N:15]=[CH:14][N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12
Reactant: CN1Cc2cncn2-c2ccccc2C1=O
Reactant: II
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(I)ncn2-c2ccccc2C1=O

Procedure:
1.06 g (5 mmol) of 4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one are stirred at 90° for 40 hours together with 1.26 g of iodine in 20 ml of dimethylformamide. The mixture is poured into water and extracted three times with chloroform. The chloroform extracts are washed five times with water, dried over magnesium sulphate and evaporated. By chromatography of the residue on a silica gel column there is obtained 4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 174°-176°.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH2:35][OH:36]>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][CH2:32][C@H:31]4[CH2:35][OH:36])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: OC[C@@H]1CCCN1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCC[C@H]5CO)c34)cc2C)cn1
Yield: 7 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and (S)-2-pyrrolidinemethanol to give the title compound in 7% yield; NMR Spectrum: 1.50-1.54 (m, 1H), 1.61-1.67 (m, 2H), 1.77-1.82 (m, 1H), 2.19 (s, 3H), 2.32-2.36 (m, 1H), 2.43 (s, 3H), 2.55-2.60 (m, 1H), 2.77-2.80 (m, 1H), 3.15 (br t, 1H), 3.25-3.29 (m, 2H), 3.37-3.42 (m, 1H), 4.40 (t, 2H), 6.95 (d, 1H), 7.18-7.24 (m, 2H), 7.63-7.66 (m, 2H), 8.16 (s, 1H), 8.28 (s, 1H), 8.31 (s, 1H); Mass Spectrum: 476 (MH+).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]([NH2:17])([CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Br:18][CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](Cl)=[O:21]>C(N(CC)CC)C>[CH3:16][C:8]([NH:17][C:20](=[O:21])[CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[Br:18])([CH3:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15]
Reactant: CC(C)(C)C(Br)C(=O)Cl
Reactant: Cc1ccccc1C(C)(C)N
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1ccccc1C(C)(C)NC(=O)C(Br)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
Into a 200 ml four-necked flask, there were charged benzene (150 ml), α,α,2-trimethylbenzylamine (7.5 g) and triethylamine (6 g), and α-bromo-tert-butylacetyl chloride (10.2 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, the reaction mixture was washed with water to remove triethylamine hydrochloride. The benzene layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 13.8 g of N-(α,α,2-trimethylbenzyl)-α-bromo-tert-butylacetamide. M.P., 166.5°-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[C:18]([CH3:24])[CH:17]=2)=[C:12]([CH:25]([CH3:27])[CH3:26])[CH:11]=[N:10]1.[CH3:28][O:29][C:30](=[O:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:28][O:29][C:30](=[O:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]3[N:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:10]=[CH:11][C:12]=3[CH:25]([CH3:27])[CH3:26])=[CH:17][C:18]=2[CH3:24])[CH3:23])=[CH:34][CH:33]=1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: CNc1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)Cc1ccc(CN(C)c2ccc(OCc3c(C(C)C)cnn3-c3c(Cl)cccc3Cl)cc2C)cc1
Temperature: 80 °C
Yield: 67.5 %

Procedure:
To an ambient temperature solution of {4-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amine (82 mg, 0.204 mmol) in acetonitrile (3 mL) are added (4-bromomethyl-phenyl)-acetic acid methyl ester (52 mg, 0.214 mmol) and cesium carbonate (133 mg, 0.408 mmol). The reaction mixture is heated to 80° C. overnight. The reaction mixture is concentrated under reduced pressure. The residue is chromatographed (SiO2 40 g, 0% to 20% EtOAc/Hex). Reversed phase HPLC (C18 OBD 19×100 mm, 30 to 70% ACN/water (0.1% TFA) at 20 mL/min) is employed to remove approximately 10% starting amine present to yield the title compound (78 mg, 68%). LC-ES/MS m/e 566.3 (M+1), 95%
Reaction SMILES: [Cl-].[NH4+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:14])[CH2:11][CH2:12][OH:13])=[C:6]([N+:15]([O-])=O)[CH:5]=1>O.CCOC(C)=O.[Fe]>[NH2:15][C:6]1[CH:5]=[C:4]([Br:3])[CH:9]=[CH:8][C:7]=1[N:10]([CH3:14])[CH2:11][CH2:12][OH:13]
Reactant: CN(CCO)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN(CCO)c1ccc(Br)cc1N
Temperature: 25 °C
Yield: 76.3 %

Procedure:
Iron (1.5 g, 26.2 mmol) and ammonium chloride (0.39 g, 1.0 eq) in water (8 mL) was heated to reflux for 0.5 hours. 2-((4-bromo-2-nitrophenyl)(methyl)amino)ethanol (25B) (2.0 g, 7.27 mmol) was slowly added. The reaction mixture was heated to reflux for 14 hours, cooled to rt, diluted with water and EtOAc and filtered through Celite. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of PE:EtOAc 60:40-40:60, to provide 1.36 g (76%) of the desired product 2-((2-amino-4-bromophenyl)(methyl)amino)ethanol (25C): 1H NMR (300 MHz, CDCl3) δ 6.92-6.82 (3H, m), 3.68 (2H, t), 3.04 (2H, t), 2.70 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:27]=1[NH2:28])=O)C.CCOC(C)=O>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)=[N:28][C:27]3[N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:25]=[CH:24][C:23]=3[C:21]=2[OH:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1N
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: Oc1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)nc2c1cnn2-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1,2-bis-(4-chloro-phenyl)-ethanone (100 mg, 0.38 mmol) in dichloroethane (1 mL) is stirred at room temperature while TiCL4 (143 mg, 0.75 mmol) is added in dropwise. After the addition, the mixture is stirred at room temperature for 5 min and a solution of 5-amino-1-phenyl-1H-pyrazole-4-carboxilic acid ethyl ester (97 mg, 0.42 mmol) in dichloroethane (1 mL) is added dropwise. After the addition, the mixture is heated to 125° C. for 5 h. After cooling down the mixture, it is poured into a mixture of ice cold saturated aqueous NaHCO3 solution (15 mL) and EtOAc (15 mL). The resulted mixture is filtered through celite to remove the precipitate and washed with EtOAc (2×5 mL). The filtrate is extracted by EtOAc (3×5 mL). The organic layers are combined and washed with brine and dried (MgSO4). After filtering off the drying agent, the filtrate is concentrated and purified by preparative LC/MS to provide the titled compound 5,6-bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ol as light yellow solid. (55 mg, 31%). 1H NMR (MeOD) δ(ppm) 8.37 (s, 1H), 8.23 (d, 2H), 7.53 (t, 2H), 7.34 (t, 1H), 7.31 (d, 2H), 7.29 (d, 2H), 7.23 (d, 2H), 7.15 (d, 2H); HPLC-MS calculated for C24H15C12N3O (M+1+): 432.1. Found: 432.2.
Reaction SMILES: CI.[C:3]1([S:9][C:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[NH:12][C:11]=2[C:19]([NH2:21])=[O:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22]([O-])([O-])=O.[Cs+].[Cs+]>N1C=CC=CC=1>[CH3:22][N:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[C:10]([S:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[C:11]1[C:19]([NH2:21])=[O:20]
Reactant: O=C([O-])[O-]
Reactant: NC(=O)c1[nH]c2cccnc2c1Sc1ccccc1
Agent: [Cs+]
Solvent: c1ccncc1
Solvent: CI
Product: Cn1c(C(N)=O)c(Sc2ccccc2)c2ncccc21
Yield: 38.8 %

Procedure:
Add methyl iodide (20 mg, 0.14 mmol) at r.t. to a mixture of 3-phenylsulfanyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid amide (Ia-1, 27 mg, 0.1 mmol), Cs2CO3 (43 mg, 0.13 mmol) in pyridine (0.5 ml). Heat the reaction at 80° C. in a sealed vessel for 15 minutes. Cool the mixture cooled and extract into ethyl acetate from water. Separate the organic solution and evaporate. Purify the residue (33 mg) by flash chromatography (silica gel, 3 gm, elute with MeOH 0-4% in dichloromethane) to provide the title compound (11 mg) as a white solid, 1H NMR (CDCl3) and LC-MS (m/e=283) are consistent for the title compound structure.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[CH:14]=2)=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[NH:31]1[CH:35]=[C:34]([CH2:36][CH2:37][CH2:38][CH2:39][C:40](Cl)=[O:41])[N:33]=[N:32]1>C(Cl)Cl>[NH:31]1[CH:35]=[C:34]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[CH:14]=3)=[O:10])[CH2:5][CH2:4]2)=[O:41])[N:33]=[N:32]1
Reactant: O=C(Cl)CCCCc1c[nH]nn1
Reactant: N#Cc1cc(Cl)cc(COC(=O)N2CCC(N)CC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(COC(=O)N2CCC(NC(=O)CCCCc3c[nH]nn3)CC2)c1
Reaction time: 20 h

Procedure:
To a suspension of 3-chloro-5-cyanobenzyl 4-aminopiperidine-1-carboxylate hydrochloride salt (195 mg, 0.591 mmol) in DCM (5 mL) at RT under nitrogen was added Huenig's Base (0.206 mL, 1.182 mmol). 5-(1H-1,2,3-Triazol-4-yl)pentanoyl chloride (111 mg, 0.591 mmol) in DCM (2 mL) was then added and the reaction mixture stirred for 20 hours. The reaction mixture was diluted with DCM and washed with a 10% solution of citric acid, a saturated solution of brine and the organic portion was then dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-10% MeOH in DCM to afford the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.Cl.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O>[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH:8]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: Clc1ccc2ccccc2c1
Reactant: O=C(Cl)C1CCNCC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1ccc2cc(Cl)ccc2c1)C1CCNCC1
Temperature: 0 °C

Procedure:
To a stirred suspension of 3.15 g (19.4 mmoles) of 2-chloronaphthalene and 4.46 g (24.2 mmoles) of 4-piperidinecarbonyl chloride hydrochloride in 60 ml nitrobenzene is added gradually 9.7 g (73 mmoles) of aluminum chloride. The mixture is heated to 65°-70° C. for 2 hours and cooled. Ice water and concentrated HCl are added to the reaction mixture. The solid precipitate is partitioned between aqueous sodium hydroxide solution and ether and the organic phase washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue is recrystallized from cyclohexane to yield 6-chloro-2-naphthyl 4-piperidyl ketone. M.P. 98°-100°-5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][NH2:16])[CH:10]=1.[CH3:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1)=O>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][N:16]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[CH3:17])[CH:10]=1
Reactant: COc1ccccc1-c1cc(NN)ncn1
Reactant: CC(=O)c1ccc(N(C)C)cc1
Solvent: CCO
Product: COc1ccccc1-c1cc(NN=C(C)c2ccc(N(C)C)cc2)ncn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.8 %

Procedure:
[6-(2-Methoxy-phenyl)-pyrimidin-4-yl]-hydrazine (500 mg, 2.3 mmol) and 4-dimethylaminoacetophenone (380 mg, 2.3 mmol) were dissolved in 4 mL of ethanol. The resultant reaction mixture was heated in the microwave (CEM Discover, 135 C, QuickTest Method) for 3 hours. The reaction mixture was cooled to room temperature and after standing for three days yellow crystals formed. The crystalline solid was isolated by filtration and dried in vacuo to yield 580 mg (70%) of the title compound. HPLC Purity: 93%.