Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[N:5]([CH3:14])[C:4](=[O:15])[C:3]=1[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24].C(N(CC)CC)C.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>O1CCCC1.C(OCC)(=O)C.O>[CH3:13][O:12][N:9]1[CH2:10][CH2:11][C:6]2([N:5]([CH3:14])[C:4](=[O:15])[C:3]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])=[C:2]2[O:1][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:7][CH2:8]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CON1CCC2(CC1)C(O)=C(c1c(C)cc(C)cc1C)C(=O)N2C
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CON1CCC2(CC1)C(OC(=O)C(C)(C)C)=C(c1c(C)cc(C)cc1C)C(=O)N2C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P2.2) (350 mg, 1.06 mmol) and triethylamine (0.221 ml, 160.7 mg, 1.59 mmol) in tetrahydrofuran (10 ml) at 0° C. was added pivaloyl chloride (0.143 ml, 140.1 mg, 1.16 mmol) dropwise. The suspension was stirred at 0° C. for two hours. The reaction mixture was diluted with ethyl acetate and water, the layers separated, the aqueous phase extracted with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate). Yield: 344 mg of 2,2-dimethyl-propionic acid 8-methoxy-1-methyl-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (compound P1.31) as a colorless gum.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2>C(O)C.O1CCCC1.[Pt](=O)=O>[F:1][C:2]1[CH:17]=[C:16]([CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2)[NH2:18]
Reactant: O=[N+]([O-])c1ccc(Oc2cccc3[nH]ncc23)c(F)c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(Oc2cccc3[nH]ncc23)c(F)c1
Reaction time: 2 h

Procedure:
Under argon, 60 mg (0.22 mmol) of 4-(2-fluoro-4-nitrophenoxy)-1H-indazole (from example XXV) are initially charged in 5 ml of ethanol/tetrahydrofuran (1:1), 9.97 mg (0.04 mmol) of platinum(IV) oxide are added and the mixture is hydrogenated under atmospheric pressure for 2 hours. The suspension is filtered off through CELITE (diatomaceous earth), the filtercake is washed with ethanol and the filtrate is concentrated under reduced pressure.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4].S(Cl)([Cl:18])=O>>[CH3:1][N:2]([CH3:15])[S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:18])=[O:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CN(C)S(=O)(=O)c1ccc(C(=O)O)cc1
Product: CN(C)S(=O)(=O)c1ccc(C(=O)Cl)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 4-dimethylsulfamoylbenzoic acid (688 mg) and thionyl chloride (5 mL) was stirred at 90° C. overnight. The reaction mixture was concentrated to give 4-dimethylsulfamoylbenzoyl chloride (495 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[CH:19][C:18]4=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[N:26][NH:27][CH:28]=5)[N:17]4[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>>[CH3:43][S:44]([N:26]1[CH:25]=[C:24]([C:23]2[N:17]3[C:18]([CH:19]=[N:20][C:15]([NH:14][C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)[CH:9]=4)=[N:16]3)=[CH:21][CH:22]=2)[CH:28]=[N:27]1)(=[O:46])=[O:45]
Reactant: CN1CCN(c2cccc(Nc3ncc4ccc(-c5cn[nH]c5)n4n3)c2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc(Nc3ncc4ccc(-c5cnn(S(C)(=O)=O)c5)n4n3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a solution of [3-(4-Methyl-piperazin-1-yl)-phenyl]-[7-(1H-pyrazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine (1.00E2 mg, 0.267 mmol) and N,N-Diisopropylethylamine (48.8 uL, 0.280 mmol) in N,N-Dimethylformamide (12.1 mL, 156 mmol) was added Methanesulfonyl chloride (21.7 uL, 0.280 mmol). The reaction was stirred at rt overnight. LCMS 453.0 (M+H), HPLC rt=2.180 min, 97% purity. The reaction mixture was concentrated to remove DMF, diluted with CH2Cl2, and washed with sat'd aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated. Product was isolated as a yellow solid (29 mg, 24%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.30 (s, 1H), 9.03 (s, 1H0, 8.97 (s, 1H), 8.71 (s, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.29 (d, J=4.6 Hz, 1H0, 7.22 (dd, J=8.3 Hz, 8.3 Hz, 1H), 7.05 (bm, 1H), 6.95 (d, J=4.6 Hz, 1H), 6.63 (dd, J=8.4 Hz, 1.4 Hz, 1H0, 3.62 (s, 3H), 3.12-3.10 (m, 4H), 2.45-2.43 (m, 4H), 2.21 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:11]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:14]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][C:29](O)=O)[N:27]=2)[CH:13]=[N:12]1)([CH3:10])([CH3:9])[CH3:8].[CH2:32]1[CH2:36]OCC1>[OH-].[Na+]>[C:7]([N:11]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:14]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][CH2:29][N:27]3[CH2:32][CH2:36][S:24][CH2:25][CH2:26]3)[N:27]=2)[CH:13]=[N:12]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: C1CCOC1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)n1ncc(-c2nc(CCN3CCSCC3)cs2)c1-c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 12.15 %

Procedure:
To a solution of lithium aluminum hydride (4.93 mg, 0.13 mmol) in THF (3 mL) was added 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid (68 mg, 0.15 mmol) at room temperature, and the mixture was stirred at 80° C. for 2 hr. To the reaction mixture was added 1N aqueous sodium hydroxide solution (2 drops), and the mixture was stirred at room temperature for 1 hr. After extraction with ethyl acetate, washing with saturated brine and drying, the solvent was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give the title compound (8 mg, 0.019 mmol, 12.15%) as a pale-yellow oil.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].ClCCl.[CH:28]([C:31]1[C:39]2[C:38]3[CH:40]=[CH:41][CH:42]=[CH:43][C:37]=3[O:36][C:35]=2[C:34]([N:44]2[CH2:48][CH2:47][N:46]=[C:45]2[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[C:33]([CH:55]([CH3:57])[CH3:56])[CH:32]=1)([CH3:30])[CH3:29]>C(#N)C>[CH:28]([C:31]1[C:39]2[C:38]3[CH:40]=[CH:41][CH:42]=[CH:43][C:37]=3[O:36][C:35]=2[C:34]([N:44]2[CH:48]=[CH:47][N:46]=[C:45]2[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[C:33]([CH:55]([CH3:57])[CH3:56])[CH:32]=1)([CH3:30])[CH3:29]
Reactant: CC(C)c1cc(C(C)C)c2c(oc3ccccc32)c1N1CCN=C1c1ccccc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=[Si]=O
Agent: [Al+3]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CC(C)c1cc(C(C)C)c2c(oc3ccccc32)c1-n1ccnc1-c1ccccc1
Yield: 37.3 %

Procedure:
The potassium permanganate (5.58 g, 35.3 mmol) and Montmorillonite K-10 clay (10 g) were mixed and finely grounded. The mixture was slowly (about 15 minutes) added into the mixed solution of dichloromethane (50 mL), acetonitrile (150 mL) and 1-(1,3-diisopropyldibenzo[b,d]furan-4-yl)-2-phenyl-4,5-dihydro-1H-imidazole (7 g, 17.6 mmol), which was cooled by ice bath. Then the reaction was stirred for another hour and quenched by adding 20 mL of ethanol. Filtered through a Celite plug. The crude product was purified by silica gel column (up to 30% EtOAc in hexanes) and recrystallization from hexane. 1-(1,3-diisopropyldibenzo[b,d]furan-4-yl)-2-phenyl-1H-imidazole (2.6 g, 6.57 mmol, 37.2% yield) was obtained as white solid (99.8% HPLC).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:12][Si](C)(C)C)[C:10]#[N:11])=[CH:5][CH:4]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O.O>[CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:12])[C:10]#[N:11])=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(C(C#N)O[Si](C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(C(O)C#N)cc1
Reaction time: 1 h
Yield: 102.1 %

Procedure:
To a solution of 2-(4-(dimethylamino)phenyl)-2-(trimethylsilyloxy)acetonitrile (7.19 g, 28.9 mmol) in THF (35 mL) was added 1 M aqueous HCl (1 mL) and the mixture was stirred for 1 hour. Additional 1 M HCl (1 mL) was then added and the reaction mixture was stirred for an additional 50 minutes. The mixture was made basic with solid NaHCO3 then diluted with EtOAc and water. The layers were separated and the organics were washed with saturated aqueous NaHCO3, water and brine. The solution was dried over Na2SO4 and concentrated in vacuo to give 2-(4-(dimethylamino)phenyl)-2-hydroxyacetonitrile as an off-white solid (5.2 g, quantitative yield). The product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33].CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])=[O:33])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: COc1ccccc1N=C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 45 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml), and 2-methoxyphenyl isocyanate (27 μl) was then added to the solution. The mixture was heated under reflux overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 34 mg (yield 45%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[CH3:13].[Na+].[I-:15].CNCCNC.N>O1CCOCC1.[Cu]I.O>[I:15][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[CH3:13]
Reactant: Cc1cc(=O)[nH]c2ccc(Br)cc12
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: N
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(=O)[nH]c2ccc(I)cc12
Temperature: 110 °C

Procedure:
A mixture of 5.0 g (21.0 mmol) of 6-bromo-4-methyl-1H-quinolin-2-one and 400 mg (2.1 mmol) of CuI in 21 mL 1,4-dioxane is evacuated and gassed with argon. Then 6.3 g (42.0 mmol) of NaI and 0.45 mL (4.2 mmol) of N,N′-dimethylethylenediamine are added, the mixture is evacuated again and gassed with argon before being heated overnight to 110° C. HPLC analysis of the mixture shows approximately 20% reaction. Therefore another 400 mg (2.1 mmol) of CuI, 6.3 g (42.0 mmol) of NaI, 0.45 mL (4.2 mmol) of N,N′-dimethylethylenediamine, and 21 mL of 1,4-dioxane are added and this mixture is heated overnight again to 110° C. To complete the reaction, the above procedure is repeated another three times. After cooling, the suspension is combined with 10% NH3 solution and water and the precipitated product is filtered off. This is then washed with 10% NH3 solution, water, isopropanol, DIPE, EtOAc, and DCM and dried overnight in the air. The product, which still contains approximately 20% educt, is further reacted without purification. Yield: 3.0 g (40% of theoretical); C10H8INO (M=285.081); calc.: molpeak (M+H)+: 286; found: molpeak (M+H)+: 286; HPLC-MS: 5.0 min (method B).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].[Na+].Cl>O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:16]/[N+:13]([O-:15])=[O:14])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C=O)cc(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(/C=C/[N+](=O)[O-])cc(OC)c1
Temperature: 0 °C

Procedure:
A solution of 3,5-dimethoxybenzaldehyde (34.5 g., 0.208 mole) and nitromethane (12.69 g., 0.208 mole) in 40 ml. of MeOH was cooled to 0° under N2. A solution was prepared by dissolving NaOH (8.43 g., 0.211 mole) in 10 ml. of H2O then diluting to 20 ml. with ice-water. This solution was then added dropwise to the methanol mixture. After 15 minutes the reaction was diluted with ice-H2O and added slowly to a solution of 40 ml. concentrated HCl in 60 ml. H2O. The resulting precipitate (44 g.) was filtered and recrystallized from methanol to give 28.6 g. of product, m.p. 132°; reported, J. Org. Chem. 27, p. 376 (1962), m.p. 133.5-134.5.
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10](C(=O)C(F)(F)F)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[K+]>CO>[C:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(C1NCC(c2ccccc2)c2ccccc21)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: c1ccc(C2CNCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 113.8 %

Procedure:
To a solution of 55 (0.9 g, 2.94 mmol) in MeOH (10 mL) were added water (2 mL), KOH (0.33 g, 5.89 mmol), and the reaction was stirred at room temperature for 12 hours. The mixture was washed with a saturated sodium chloride solution and extracted with 7:3 CH2Cl2/MeOH (3×10 mL). The combined organic layers were dried (K2CO3) and concentrated under reduced pressure to give 56 (0.70 g.˜100%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([N:18]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]2)[N:7]=1
Reactant: OC1CCNC1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N2CCC(O)C2)c2nc(-c3ccccc3)cc-2[nH]1
Yield: 36.2 %

Procedure:
This compound was prepared according to the method described in Example 2 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (70.0 mg, 0.29 mmol), 3-pyrrolidinol (Aldrich Chemical Company) (0.12 mL, 1.44 mmol) and K2CO3 (0.40 g, 2.87 mmol) in H2O (2 mL). The crude material was purified by flash chromatography on silica gel with 10:1 CHCl3:MeOH as eluant to give 30.9 mg (37%) of the title compound as an off-white solid. An analytical sample was obtained by recrystallization from EtOH. Mp: 234-235° C. 1H NMR (DMSO-d6; 500 MHz): δ 1.96-2.05 (m, 2), 2.39 (s, 3), 3.77-3.93 (m, 4), 4.43 (s, 1), 5.03 (s, 1), 6.71 (s, 1), 7.38-7.50 (m, 3), 7.88 (d, 2, J=7.6), 10.64 (br s, 1). MS m/z: 295 (M+1), 293 (M−1). HRMS: Calcd for M+H: 295.1923. Found: 295.1910.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:26]=1)[O:7][CH2:8][C:9]1[N:25]=[CH:24][CH:23]=[CH:22][C:10]=1/[C:11]/2=[C:12](\[C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1)/[CH2:13][CH3:14].N1C=CC=CC=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:26]=1)[O:7][CH2:8][C:9]1[N:25]=[CH:24][CH:23]=[CH:22][C:10]=1/[C:11]/2=[C:12](\[C:15]1[CH:16]=[C:17]([NH:21][S:34]([CH3:33])(=[O:36])=[O:35])[CH:18]=[CH:19][CH:20]=1)/[CH2:13][CH3:14]
Reactant: CC/C(=C1\c2ccc(Cl)cc2OCc2ncccc21)c1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC/C(=C1\c2ccc(Cl)cc2OCc2ncccc21)c1cccc(NS(C)(=O)=O)c1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
A 50 L three neck round bottom flask is equipped with a mechanical stirrer, nitrogen inlet, thermocouple and drying tube placed in a cooling tub. (E)-3-[1-(8-chloro-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-phenylamine (1800 g, 4.96 mol) (prepared essentially as described for Intermediate 10 using the Alternate Procedure) dichloromethane (18 L) and pyridine (588.5 g, 7.44 mol) are added to the flask. The reaction mixture is cooled to 0 to 5° C. and neat methanesulfonyl chloride (681.8 g, 5.952 mol) is added dropwise over about 20-30 min, maintaining the temperature ≦5° C. After the addition is complete, the reaction mixture is stirred at 0 to 5° C. for one hour. The cooling bath is removed and the reaction stirred at room temperature for a minimum of 12 h. The progress of the reaction is followed by TLC (straight EtOAc). Once the reaction is deemed complete, the reaction mixture is washed with a 10% aqueous citric acid solution (14 L) using a 40 L separatory funnel. The aqueous layer is back extracted with dichloromethane (1.5 L). The combined organic layers are washed with a 10% aqueous citric acid solution (2 L). The aqueous layer is back extracted with dichloromethane (1.5 L). The combined organic layers are washed with a 15% aqueous sodium chloride solution (5 L) and the aqueous layer back extracted with dichloromethane (1.5 L). The combined organic layers are washed with a half saturated aqueous sodium bicarbonate solution (5 L). The sodium bicarbonate wash should be performed for a minimum of 30 min. The aqueous layer is back extracted with dichloromethane (1.5 L). The combined organic layers are dried over sodium sulfate and filtered. A 50 L three neck round bottom flask is equipped with a mechanical stirrer, nitrogen inlet, thermocouple and drying tube placed in a cooling tub. The dichloromethane solution containing the product is charged to the flask, followed by trithiocyanuric acid, trisodium salt (630 g, 0.35 g/g of starting material), sodium sulfate (3.6 kg, 2 g/g of starting material) and charcoal (180 g, 0.1 g/g of starting material) to the flask. The suspension is stirred for 12 h at room temperature. The suspension is filtered and the filter cake slurried with dichloromethane (3×3 L). The filtrates are combined and concentrated to an off white solid. The product is dried in a vacuum oven at 40° C. overnight.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[C:3]=1[CH3:10].O.[CH3:12][N:13](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]#[N:13])=[C:4]([F:9])[C:3]=1[CH3:10]
Reactant: CN(C)C=O
Reactant: Cc1c(Br)ccc(I)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: Cc1c(Br)ccc(C#N)c1F
Temperature: 100 °C
Reaction time: 5.5 h
Yield: 89 %

Procedure:
To a solution of 1-bromo-3-fluoro-4-iodo-2-methylbenzene (2.00 g) in DMF (15 mL) were added zinc cyanide (336 mg) and tetrakis(triphenylphosphine)palladium(0) (367 mg), and the mixture was stirred under an argon atmosphere at 100° C. for 5.5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (yield: 1.21 g, 89%).
Reaction SMILES: Br[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]([C:4]#[N:5])[C:2]=1[C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[F:11]
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: N#Cc1cccc(F)c1Br
Product: N#Cc1cccc(F)c1-c1cc([N+](=O)[O-])ccc1F

Procedure:
2-Bromo-3-fluorobenzonitrile (2.50 g, 12.5 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as described in Example 4 to give 6,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile as a black solid: 1H NMR (360 MHz, CDCl3) δ 7.40-7.44 (1H, m), 7.47-7.52 (1H, m), 7.59-7.67 (2H, m), 8.37-8.44 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:4](=[N:13][N:14]([CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([Cl:35])[CH:33]=4)[N:28]=[CH:27][CH:26]=3)[C:15]=2[C:16]2[N:20]([CH3:21])[CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[N:5]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[C:6](=[O:8])[N:7]=1.[CH2:36]1[CH2:46]CN2C(=NCCC2)C[CH2:37]1.ClCC(=O)C.O>CN(C=O)C.C(OCC)(=O)C>[Cl:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[C:25]2[CH2:24][N:14]1[C:15]([C:16]2[N:20]([CH3:21])[CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)=[C:3]2[C:2]3[N:7]([C:36]([CH3:46])=[CH:37][N:1]=3)[C:6](=[O:8])[N:5]([CH2:9][CH:10]3[CH2:12][CH2:11]3)[C:4]2=[N:13]1
Reactant: Cn1cc(C#N)cc1-c1c2c(N)nc(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Reactant: C1CCC2=NCCCN2CC1
Agent: CC(=O)CCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc2c3c(-c4cc(C#N)cn4C)n(Cc4ccnc5ccc(Cl)cc45)nc3n(CC3CC3)c(=O)n12
Temperature: 125 °C
Yield: 25.5 %

Procedure:
5-[4-amino-2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-6-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile (75 mg, 0.15 mmol) was dissolved in 1.5 mL anhydrous DMF with 30 mg DBU. Chloroacetone (28 mg, 0.3 mmol, 2.0 eq.) was added and the resulting solution heated in the microwave for 90 minutes at 125° C. Two addition eq. chloroacetone were added, and the reaction returned to the microwave and heated an additional 90 minutes at 125° C. The reaction mixture was diluted with 50 mL. water and 50 mL ethyl acetate. The aqueous layer was washed 3×50 mL with ethyl acetate. The combined organic fractions were washed with 50 mL brine and dried over sodium sulfate. The crude product was purified by chromatography on silica (gradient: dichloromethane to 10% methanol in dichloromethane), followed by reverse phase HPLC using 40% aqueous acetonitrile, yielding 20 mg product. 1H NMR (300 MHz, CHLOROFORM-D) d ppm 0.55 (m, 4H) 1.48 (m, 1H) 2.27 (d, J=0.94 Hz, 3H) 3.42 (s, 3 H) 4.13 (m, 2H) 5.82 (m, 2H) 6.62 (dd, J=4.52, 1.88 Hz, 1H) 6.76 (d, J=4.33 Hz, 1H) 7.36 (d, J=1.51 Hz, 1H) 7.44 (d, J=1.13 Hz, 1H) 7.70 (dd, J=9.04, 2.26 Hz, 1H) 7.90 (d, J=2.26 Hz, 1H) 8.10 (m, 1H) 8.81 (d, J=4.52 Hz, 1H); ES M+H+=524.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:30])[CH:15]([NH:17][C:18](=[O:29])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([NH2:28])=[NH:27])[OH:16].Cl.CO.Cl.Cl.Cl.N[CH2:38]CCC(N)CCCNC(=O)C(NC(=O)CCCCCCNC(N)=N)OC>CO>[NH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:30])[CH:15]([NH:17][C:18](=[O:29])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([NH2:28])=[NH:27])[O:16][CH3:38]
Reactant: N=C(N)NCCCCCCC(=O)NC(O)C(=O)NCCCCNCCCN
Reactant: COC(NC(=O)CCCCCCNC(=N)N)C(=O)NCCCC(N)CCCN
Agent: Cl
Solvent: CO
Product: COC(NC(=O)CCCCCCNC(=N)N)C(=O)NCCCCNCCCN
Temperature: 25 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
To a solution of 920 mg (1.85 mmoles) of N-[4-(3-aminopropyl)aminobutyl]-2-(7-guanidinoheptanamido)-2-hydroxyethanamide trihydrochloride in 20 ml of anhydrous methanol was added 2 ml of 2N hydrogen chloride-methanol. The mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and the resulting white powder was dissolved in 15 ml of water. The aqueous solution was adjusted to pH 6 with 1N aqueous sodium hydroxide solution, then passed through a column (25 mm inner diameter) packed with 300 ml of CM-Sephadex® C-25 (Na-type) and fractionated by the gradient elution method with each 2 liters of water and 1M aqueous sodium chloride solution (fraction size, 17 ml). The fractions No. 138 to No. 152 corresponding to the sodium chloride concentrations of 0.59-0.65M were combined, evaporated to dryness and extracted twice with 10 ml of methanol. The methanol layer was passed through a column (25 mm inner diameter) packed with 300 ml of Sephadex® LH-20 and developed with methanol (fraction size, 7 ml). Fractions No. 18 to No. 32 were combined and evaporated to dryness, yielding 607 mg (64% yield) of a white powder of N-[4-(3-aminopropyl)-aminobutyl]-2-(7-guanidinoheptanamido)-2-methoxyethanamide trihydrochloride.