Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)(=[O:12])=[O:11])[C:8](=[O:21])[N:7]([CH:22]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:23]([NH:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)=[O:24])[C:6]=2[CH:47]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)(=[O:11])=[O:12])[C:8](=[O:21])[N:7]([CH:22]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:23]([NH:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]3)=[O:24])[C:6]=2[CH:47]=1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)NCCN3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)NCCN3CCNCC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Temperature: 25 °C

Procedure:
520 (0.76 mmol) of tert-butyl 4-(2-{2-[6-chloro-3-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydrobenzimidazol-1-yl]-2-phenyl-acetylamino}-ethyl)piperazine-1-carboxylate (Example 130) were dissolved in dichlormethane (6 ml) and, while stirring at room temperature, trifluoroacetic acid (4 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up once again in toluene, concentrated in vacuo and then dried in vacuo. The residue was dissolved in 6 ml of dichloromethane, mixed with 3 eq. of MP carbonate (Argonaut, 1.69 mmol/g) and stirred at room temperature for 2 h. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated under reduced pressure and dried in vacuo. Yield: 430 mg (97%) of colorless oil.
Reaction SMILES: [F:1][CH2:2][C@:3]1([C:18]([O:20]C(C)(C)C)=[O:19])[CH:7]([CH3:8])[C:6](=[O:9])[N:5]([C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:4]1>ClCCl.FC(F)(F)C(O)=O>[F:1][CH2:2][C@:3]1([C:18]([OH:20])=[O:19])[CH:7]([CH3:8])[C:6](=[O:9])[N:5]([C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:4]1
Reactant: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CF)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CF)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3R)-3-fluoromethyl-4-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (910 mg, 2.71 mmol) in dichloromethane (9 mL), trifluoroacetic acid (9 mL) was added dropwise in an ice bath, and the mixture was stirred at room temperature for 3 hours. After concentrating the reaction mixture under reduced pressure, saturated aqueous solution of sodium hydrogencarbonate (20 mL) was added to the concentrate in an ice bath, and the aqueous solution was washed with diethylether (50 mL). To the aqueous layer was added 1 mol/l hydrochloric acid to pH 2 to 3 in an ice bath, and the solution was extracted with chloroform (100 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The concentrate was azeotropically distilled by adding toluene (20 mL), and dried under reduced pressure to obtain 910 mg (quantitative) of the title compound as a white solid.
Reaction SMILES: CCOCC.[Mg+2].[Br-:7].[Br-].S(O[CH2:14][CH2:15][CH:16]([CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH2:24][CH2:25][CH:26]([CH2:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH3:27])[CH3:22])[CH3:17])(=O)(=O)C>C(OCC)C>[CH2:14]([Br:7])[CH2:15][CH:16]([CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH2:24][CH2:25][CH:26]([CH2:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH3:27])[CH3:22])[CH3:17]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOS(C)(=O)=O
Reactant: [Br-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCBr
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.8 %

Procedure:
To a suspension of magnesium bromide diethyl etherate (25.9 g, 100.3 mmol) in anhydrous diethyl ether (250 mL) under nitrogen at room temperature was added a solution of phytanyl mesylate (18.9 g, 50.2 mmol) in anhydrous diethyl ether (200 mL) dropwise over 15 minutes. The resulting slurry was stirred for 72 hours at room temperature. Upon completion, the reaction mixture was cooled to 0° C. and ice cold water was added dropwise until all solid dissolved and bubbling stopped. Diethyl ether (300 mL) was added, and the organic and aqueous layers separated. The aqueous layer was back-extracted with diethyl ether (200 mL). The combined diethyl ether extracts were dried on MgSO4, filtered, and concentrated. The resulting oil was purified by column chromatography (column 10″L×2″W; eluted with 100% hexanes) to afford the product as a pale yellow oil (16.3 g, 90%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:21][N:20]=[CH:19][N:18]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH2:32][CH2:33][C:34](O)=[O:35])[CH:27]=[CH:26]2.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CC#N.CN(C=O)C>[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH2:32][CH2:33][C:34]([N:4]1[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]4[S:21][N:20]=[CH:19][N:18]=4)(=[O:15])=[O:14])=[CH:11][CH:12]=3)[CH2:2][CH2:3]1)=[O:35])[CH:27]=[CH:26]2
Reactant: O=S(=O)(Nc1ncns1)c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CCn1ccc2cc(Cl)ccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: O=C(CCn1ccc2cc(Cl)ccc21)N1CCN(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CC1
Yield: 53 %

Procedure:
Synthesized according to general procedure 5, method A. The reaction was set up with 0.11 mmol 4-(piperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide, 0.11 mmol 3-(5-chloro-1H-indol-1-yl)propanoic acid, 0.11 mmol BOP reagent, 0.11 mmol triethylamine and 250 μL DMF. Yield 53%. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.61-7.46 (m, 5H), 7.12 (dd, J=8.7, 2.1 Hz, 1H), 6.97 (d, J=9.1 Hz, 2H), 6.40 (d, J=2.5 Hz, 1H), 4.43 (t, J=6.8 Hz, 2H), 3.55 (t, J=5.2 Hz, 2H), 3.44 (t, J=4.9 Hz, 2H), 3.22 (t, J=5.1 Hz, 2H), 3.17 (t, J=5.0 Hz, 2H), 2.83-2.79 (m, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=531.1; tR=3.15 min.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[Cl-:7].[K+].[Pt+2:9].[Cl-:10].[Cl-]>O>[Pt+2:9].[Cl:7][C@@H:3]1[C@H:2]([NH2:1])[CH2:6][CH2:5][N:4]1[Cl:10]
Reactant: N[C@@H]1CCNC1
Reactant: [Cl-]
Agent: [Pt+2]
Agent: [K+]
Solvent: O
Product: N[C@@H]1CCN(Cl)[C@@H]1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.7 %

Procedure:
(3R)-3-Aminopyrrolidine (400 mg) prepared in Reference Example 1-(3) is dissolved in water (200 ml) and thereto is added platinum (II) potassium chloride (2.0 g), and the mixture is stirred at room temperature for 20 hours. The precipitated solid is removed by filtration, and the filtrate is concentrated under reduced pressure. To the residue is added water (3 ml), and the resulting crystals are separated by filtration and washed with water and acetone to give cis-dichloro-(3R)-3-aminopyrrolidine platinum (II) (1.28 g) as pale yellow crystal. The physical properties of the cis-dichloro-(3R)-3-aminopyrrolidine platinum (II) thus obtained are identical with those of the cis-dichloro-(3R)-3-aminopyrrolidine platinum (II) as obtained in the above (1-A).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1N.N([O-])=O.[Na+].[I-:17].[K+].Cl>C(#N)C>[Cl:1][C:2]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1[I:17]
Reactant: [I-]
Reactant: CS(=O)(=O)c1ccc(N)c(Cl)c1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(I)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.9 %

Procedure:
A solution of 2-chloro-4-(methanesulfonyl)aniline (25 g, 122 mmol) in acetonitrile (500 mL) was cooled to 0° C., then sodium nitrite (20.97 g, 303.9 mmol) and potassium iodide (50.45 g, 303.9 mmol) were added. After the reaction mixture was stirred for 30 minutes at 0° C., concentrated hydrochloric acid (50 mL) was added drop-wise via an addition funnel. The reaction was stirred at 0° C. for an additional 45 minutes. The reaction mixture was warmed to room temperature, then stirred for 2.5 hours. The reaction mixture was poured into ice water (800 mL), and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. Flash chromatography (RediSep® Flash column, 230-400 mesh, 10%-35% ethyl acetate in hexane) gave 2-chloro-1-iodo-4-methanesulfonyl-benzene (13.88 g, 36%). 1H NMR (300 MHz, CDCl3) δ ppm 8.11 (d, J=8.4 Hz, 1 H), 8.00 (d, J=1.9 Hz, 1 H), 7.51 (dd, J=8.4, 1.9 Hz, 1 H), 3.07 (s, 3 H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:17]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18].C(OCC)(=O)C>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[N+:17]([C:20]1[CH:25]=[C:24]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(-c2ccc3cc[nH]c3c2)c1

Procedure:
6-Bromo-1H-indole (1.00 g, 5.10 mmol) and potassium carbonate (1.41 g, 10.2 mmol) were dissolved in a DMF/water (4:1, 10 mL) mixture solution, and then the gas included in the mixture solution was removed using ultrasonic wave and nitrogen gas. After sequentially adding 3-nitrophenylboronic acid (853 mg, 5.61 mmol) and Pd(dppf)Cl2 (416 mg, 0.51 mmol), the mixture was stirred at room temperature in a sealed reactor. 2 hours later, after adding ethyl acetate and water, the reaction solution was filtered through a diatomite pad. The organic layer was separated from the filtrate and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried with anhydrous magnesium sulfate and then concentrated. Purification of the residue by chromatography (silica gel, EA:Hx=1:4) yielded the target compound as white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.[C:15]([CH2:20][CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:17][CH2:18][CH3:19])=[O:16]>C1C=CC=CC=1>[CH3:1][N:2]([CH3:14])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:20]([CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C)c1ccc(C=O)c([N+](=O)[O-])c1
Solvent: c1ccccc1
Product: CCOC(=O)C(C)=Cc1ccc(N(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 74.7 %

Procedure:
Into 250 ml of benzene, 20.0 g (0.10 mol) of 4-dimethylamino-2-nitrobenzaldehyde and 36.2 g (0.10 mol) of carbethoxyethylidene triphenylphosphorane (manufactured by Aldrich Chemical Co., Inc.) were dissolved, and the mixture was stirred at room temperature for one night. The solvent was evaporated under a reduced pressure, whereby 58 g of a crude product were obtained. This product was refined by a column chromatography (aminopropylated silica gel: Fuji Silysia Chem. Co., NH-DM1020), whereby 20.8 g of the aimed compound were obtained as a crystal (yield: 74.7%).
Reaction SMILES: [C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([CH:10]=[C:11]([C:16]4[CH:17]=[C:18]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)[N:19]5[C:24]=4[C:23]([NH2:25])=[N:22][CH:21]=[N:20]5)[CH:12]=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][N:33]([CH3:38])[CH2:34][C:35](O)=[O:36].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:32][N:33]([CH2:34][C:35]([N:29]1[CH2:30][CH2:31][CH:26]([C:18]2[N:19]3[C:24]([C:23]([NH2:25])=[N:22][CH:21]=[N:20]3)=[C:16]([C:11]3[CH:12]=[CH:13][C:14]4[C:9]([CH:10]=3)=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:15]=4)[CH:17]=2)[CH2:27][CH2:28]1)=[O:36])[CH3:38]
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(-c5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCC(c2cc(-c3ccc4cn(-c5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 22.2 %

Procedure:
A mixture 5-(2-phenyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0.20 mmol), N,N-dimethylglycine (22 mg, 0.22 mmol), EDCl (41 mg, 022 mmol), HOBt (29 mg, 0.22 mmol), and N,N-diisopropylethylamine (102 μL, 0.59 mmol) in DMF (1 mL) was stirred at rt for 17 h. The residue was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 22 mg (23%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1 H), 8.11 (d, 2 H), 7.93 (s, 1 H), 7.85 (d, 1 H), 7.69 (s, 1 H), 7.56-7.62 (m, 2 H), 7.45 (t, 1 H), 7.23 (dd, 1 H), 6.66 (s, 1 H), 4.31 (dd, 1 H), 3.36-3.51 (m, 1 H), 3.08-3.24 (m, 2 H), 3.01-3.06 (m, 1 H), 2.63-2.80 (m, 1 H), 2.18 (s, 6 H), 1.99-2.12 (s, 2 H), 1.44-1.77 (m, 1 H); ES-MS m/z 495.18 [M+H]+, HPLC RT (min) 2.13.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1I)=[O:5])[CH3:2].[Br:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1[C:21]1[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CCOC(=O)c1c(I)c(C#N)c(CC)n1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)c1c(-c2ccc(Br)cc2)c(C#N)c(CC)n1C
Temperature: 80 °C
Yield: 78.9 %

Procedure:
A mixture of 4-cyano-5-ethyl-3-iodo-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.0 g, 6.0 mmol, prepared in preparation 38), 4-bromophenyl boronic acid (1.32 g, 6.6 mmol), 10 mL of Na2CO3 (2M) and 20 mL of dioxane is degassed under reduced pressure (−29 inches) for 30 minutes till no bubbles. Recharge with nitrogen. Add PdCl2 (PPh)4 (0.24 mmol). Well seal the flask and heat the mixture at 80° C. overnight. After cooling, water and methylene chloride are added to the reaction mixture. It is then extracted with methylene chloride. The organic layers are combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by flash chromatography to provide the title compound (1.71 g, 78%). MS(ES, m/e) 361.1(M+1), 380.1(M+18). Rf=0.35 (50% ether in hexanes).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][C:24]([OH:26])=O)([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30].C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][C:24]([NH2:32])=[O:26])([CH2:16][CH2:15]3)[CH2:18][CH2:19]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CCC(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCC(N)=O)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a solution of 3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro 1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-propionic acid(510m, 1.22 mmol) and HATU (1.1 eq, 1.34 mmol, 511 mg) in DMF (10 ml) was added Hunig's base (1.3 eq, 1.60 mmol, 205 mg). After the resulting suspension had been stirred for 1 h, excess ammonia (0.5 M in dioxane, 4.0 ml) was added and the mixture was stirred overnight (14 h). The solvent was removed in vacuo and the resulting residue was partitioned between CH2Cl2 (10 ml) and 1 N HCl (10 ml) with the aid of 2 ml MeOH to assist in the transfer and improve solubility. The aqueous phase was extracted with CH2C2 (2×10 ml), the combined organic phases were washed with 1 N HCl (2×10 ml), dried (MgSO4), filtered and evaporated in vacuo to give an off-white solid (455 mg, 90%). MS: 416 (MH+).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:25]1[C:33]2[C:28](=[N:29][CH:30]=[N:31][C:32]=2[NH2:34])[N:27]([C@H:35]2[CH2:40][CH2:39][C@@H:38]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)[CH2:37][CH2:36]2)[N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)/C=C\C(O)=O>COCCOC.O.C(O)C>[NH2:34][C:32]1[N:31]=[CH:30][N:29]=[C:28]2[N:27]([C@H:35]3[CH2:40][CH2:39][C@@H:38]([N:41]4[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]4)[CH2:37][CH2:36]3)[N:26]=[C:25]([C:12]3[CH:11]=[CH:10][C:9]([C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[O:8])=[CH:14][CH:13]=3)[C:33]=12
Reactant: CC1(C)OB(c2ccc(C(=O)c3ccccc3)cc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(=O)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C

Procedure:
A mixture of phenyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-methanone (Intermediate AL) (0.241 g, 0.00078 mol), cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AC) (0.30 g, 0.00068 mol), tetrakis(triphenyl-phosphine)palladium (0.047 g, 0.000041 mol) and sodium carbonate (0.18 g, 0.0017 mol) was heated in a mixture of ethylene glycol dimethyl ether (10 mL) and water (5 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate, the organic layer separated and the aqueous layer further extracted with ethyl acetate twice. The combined organic extracts were dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a tan solid which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (95:4:1) as a mobile phase to give cis-{4-[4-amino-1-(4-(4-methylpiperazino)cyclohexy)]-1H-pyrazolo[3,4-d]pyrimidin-3-yl-]-phenyl}(phenyl)methanone as a white solid (0.195 g, 0.0004 mol). It was dissolved in refluxing ethanol (17 mL) and a preheated solution of maleic acid (0.137 g, 0.0018 mol) was added. The mixture was refluxed for 10 min, cooled to ambient temperature and the precipitate collected by filtration, washed with ethyl acetate and dried to give cis-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methanone dimaletate as a white solid (0.221 g, 0.0003 mol): 1H NMR (DMSO-d6, 400 MHz) 8.28 (s, 1H), 7.90 (d, 2H), 7.83 (m, 4H), 7.73 (t, 1H), 7.61 (m, 2H), 6.15 (s, 4H), 4.88 (m, 1H), 3.1 (br, 9H), 2.71 (s, 3H), 2.28 (m, 2H), 2.07 (m, 2H), 1.74 (m, 4H); RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 12.63 min. MS: MH+ 496.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:4]([CH3:22])=[CH:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[Cl-].[Cl-].C([Al+2])C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[C:34]([C:5]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:15])=[O:16])=[C:2]([CH3:1])[N:3]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:4]=1[CH3:22])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)Cn1c(C)cc(Cc2ccccc2S(=O)(=O)N2CCCC2)c1C
Agent: CC[Al+2]
Agent: CC[Al](Cl)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C(=O)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 5.25 h
Yield: 91.5 %

Procedure:
In a small vial charged with ethyl 2-(2,5-dimethyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (143.7 mg, 0.355 mmol) in DCM (4 mL), at 0° C., was added dropwise a solution of ethylaluminum dichloride (444 μL, 0.444 mmol) in toluene. The reaction mixture turned deep rose color and benzoyl chloride (61.9 μL, 0.533 mmol) was added. The resulting mixture became orange and slowly was allowed to warm to rt. The reaction was stirred 5.25 h and then cooled once again and an additional 800 μL of EtAlCl2 and 150 μL of benzoyl chloride were added. The reaction was once again allowed to warm to room temperature slowly with stirring and stirred an additional 15.25 h at room temperature. The reaction was then quenched by the addition of water and dichloromethane and the water layer was extracted with DCM (3×). The organic layer was dried with MgSO4, and concentrated under vacuum. The crude product was added to a 40 g ISCO silica gel column and purified with a gradient of 0% to 60% EtOAc/hexanes. The product was obtained as a light orange foam (165.2 mg, 0.325 mmol, 91% yield). 1H NMR (CDCl3/400 MHz) δ (ppm) 7.92 (dd, 1H), 7.68 (dd, 2H), 7.46 (t, 1H), 7.38-7.32 (m, 3H), 7.20 (t, 1H), 7.10 (d, 1H), 4.56 (s, 2H), 4.30 (s, 2H), 4.24 (q, 2H), 3.23-3.17 (m, 4H), 2.03 (s, 3H), 1.98 (s, 3H), 1.84-1.78 (m, 4H), 1.29 (t, 3H). MS m/z: 509.40 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:25][N:26]([CH3:35])[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:31]([C:30]3[CH:33]=[CH:34][C:27]([N:26]([CH3:35])[CH3:25])=[CH:28][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.043 g, 0.11 mmol), ethanol (4 ml), and 4-dimethylaminobenzaldehyde (0.021 g, 0.14 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 3.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 90% ethyl acetate in dichloromethane and then 3% and 5% methanol in ethyl acetate. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.012 g, 22%); 1H-NMR (500 MHz, DMSO-d6) 2.61 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.61 (s, 2H, NCH2CO), 3.63 (br s, 4H, piperazine N(CH2)2), 6.81 (d, J=9.00 Hz, 2H) and 8.01 (d, J=8.80 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 7.40 (dd, J=7.06, 3.92 Hz, 1H, pyridyl 5-H), 7.78 (d, J=8.64 Hz, 1H, pyridyl 4-H), 8.15 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.50 (dd, J=4.75, 1.50 Hz, 1H, pyridyl 6-H), 8.56 (d, J=1.50 Hz, 1H, pyridyl 2-H), 13.15 (s, 1H, imidazo[4,5-b]pyridine N—H);