Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:37]=[N:36][C:5]2[NH:6][C:7]3[CH:35]=[CH:34][CH:33]=[CH:32][C:8]=3[C:9]3[N:10]([C:11]([C:14]4[CH:19]=[CH:18][C:17]([C:20]5([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:22][CH2:21]5)=[CH:16][CH:15]=4)=[N:12][N:13]=3)[C:4]=2[CH:3]=1.[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:38]1([C:2]2[CH:37]=[N:36][C:5]3[NH:6][C:7]4[CH:35]=[CH:34][CH:33]=[CH:32][C:8]=4[C:9]4[N:10]([C:11]([C:14]5[CH:19]=[CH:18][C:17]([C:20]6([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:23][CH2:22][CH2:21]6)=[CH:16][CH:15]=5)=[N:12][N:13]=4)[C:4]=3[CH:3]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nnc4n3-c3cc(Br)cnc3Nc3ccccc3-4)cc2)CCC1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nnc4n3-c3cc(-c5ccccc5)cnc3Nc3ccccc3-4)cc2)CCC1

Procedure:
A solution of tert-butyl (1-(4-(6-bromo-9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (100 mg, 0.18 mmol), phenyl boronic acid (44 mg, 0.36 mmol) and tetrakis(triphenylphosphine) palladium (0) (21 mg, 0.018 mmol) in toluene (2 mL), ethanol (2 mL and saturated aqueous sodium bicarbonate (0.2 mL) was stirred at 100° C. for 6 hours. The mixture was partitioned between ethyl acetate (80 mL) and water (30 mL). The phases were separated and the organic phase was washed with brine (30 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 25% ethyl acetate in dichloromethane). The tert-butyl (1-(4-(6-phenyl-9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo [4,3-d][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate was obtained as a white solid (60 mg). M.p.=140-142° C.; 400 M Hz 1H NMR (DMSO-d6) δ: 8.94 (br.s, 1H), 8.44 (br.s, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.75 (br.s, 1H), 7.65-7.40 (m, 6H), 7.38-7.24 (m, 4H), 7.15 (t, J=7.4 Hz, 1H), 7.04-6.96 (m, 2H), 2.48-2.30 (m, 4H), 2.10-1.90 (m, 1H), 1.85-1.75 (m, 1H), 1.33 (s, 9H); LCMS[M+H]: 557.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.Cl.[NH2:17][OH:18].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[OH:18][N:17]=[CH:1][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C=NO)CC1
Temperature: 14 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A solution of tert-butyl 4-formylpiperidine-1-carboxylate (50.0 g, 234 mmol) in MeOH (200 mL) and water (200 mL) was cooled in an ice-bath and then hydroxylamine hydrochloride (19.5 g, 272 mmol) and sodium carbonate (12.4 g, 117 mmol) were added. The resulting mixture was stirred at 13-15° C. overnight. The solution was concentrated in vacuo to an aqueous suspension, which was extracted with EtOAc. The organic extract was washed with 100 mL brine, dried (MgSO4), filtered, concentrated to provide tert-butyl 4-((hydroxyimino)methyl)piperidine-1-carboxylate (53.1 g, 99.2% yield) as a white crystalline solid.
Reaction SMILES: C[O-].[Na+].[C:4]([NH:7][NH2:8])([NH2:6])=[NH:5].Cl.[Si]([O:17][CH2:18][C@@H:19]([N:28]1[CH:32]=[C:31]([C:33](OC)=O)[N:30]=[CH:29]1)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(C(C)(C)C)(C)C>CO>[NH2:5][C:4]1[NH:7][N:8]=[C:33]([C:31]2[N:30]=[CH:29][N:28]([C@@H:19]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][OH:17])[CH:32]=2)[N:6]=1
Reactant: N=C(N)NN
Reactant: COC(=O)c1cn([C@@H](CCc2ccccc2)CO[Si](C)(C)C(C)(C)C)cn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Nc1nc(-c2cn([C@H](CO)CCc3ccccc3)cn2)n[nH]1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 35.8 %

Procedure:
A solution of 28% NaOMe in methanol (772 mg) was added to an ice cooled solution of aminoguanidine hydrochloride (332 mg) in methanol (5 ml). After 10 minutes, methyl (S)-1-[1-(tert-butyldimethylsilyloxy)-4-phenyl-2-butyl]-imidazole-4-carboxylate (obtained in Example 6) (389 mg) in methanol (2 ml) was added to the mixture and the resulting mixture was stirred at reflux for 22 hours. After cooling, the insoluble material was removed and then the filtrate was evaporated. The residue was diluted with water and the solution was acidified to pH 4 with 6N HClaq. The resulting mixture was washed with CHCl3. The aqueous layer was purified by HP-20 (50 cc) column chromatography eluting with water/2-propanol (9:1) and lyophilized to give (S)-2-[4-(5-amino-1,2,4-triazol-3-yl)-1-imidazolyl]-4-phenylbutan-1-ol (107 mg).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])(O)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[C:43]1([CH:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(#N)C>[C:43]1([CH:49]2[CH2:50][CH2:51][N:52]([C:1](=[O:2])[CH2:4][N:5]3[CH2:27][CH2:26][CH2:25][C@H:6]3[C:7]([N:9]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])[CH2:53][CH2:54]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)N1CCC(c2ccccc2)CC1
Yield: 59 %

Procedure:
Using the procedure described above, a solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (0.124 g, 0.33 mmol, 1.0 eq), and N-methylmorpholine (43 uL, 40 mg, 0.40 mmol, 1.20 eq), in acetonitrile (3 mL) was treated with isobutyl chloroformate (45 uL, 47 mg, 0.35 mmol, 1.05 eq) followed by 4-phenylpiperidine (69 mg, 0.43 mmol, 1.3 eq). Workup as above provided 101 mg (59%) of L-isoleucine, N-[1-(2-(4-phenylpiperidyl)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1COCC1.[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:19]([C:21]3[C:22]([O:38][CH3:39])=[C:23]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]([OH:37])=O)[CH:30]=4)[C:24]([CH3:28])=[C:25]([Cl:27])[CH:26]=3)[CH3:20])[N:17]=[CH:18][C:11]=12.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:19]([C:21]3[C:22]([O:38][CH3:39])=[C:23]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]([N:2]([CH3:3])[CH3:1])=[O:37])[CH:30]=4)[C:24]([CH3:28])=[C:25]([Cl:27])[CH:26]=3)[CH3:20])[N:17]=[CH:18][C:11]=12
Reactant: COc1c(C(C)n2ncc3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C(=O)O)c1
Reactant: CNC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1c(C(C)n2ncc3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C(=O)N(C)C)c1
Reaction time: 1 h

Procedure:
Dimethylamine (2.0 M) in THF (0.14 mL, 0.28 mmol) was added to a solution of 4-{3-[1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylic acid (18.6 mg, 0.042 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (10 mg, 0.03 mmol) in N,N-dimethylformamide (0.7 mL) at room temperature followed by the addition of triethylamine (8.8 μL, 0.064 mmol). The reaction was stirred for 1 hour, then quenched with water. The mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C23H25ClN7O2 (M+H)+: m/z=466.2; Found: 466.2.
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([NH2:22])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([NH:22][S:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:31])=[O:30])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCC1(c2c[nH]c3c(N)cccc23)CCc2cc(F)ccc21
Product: CCC1(c2c[nH]c3c(NS(=O)(=O)c4ccccc4)cccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 3-(1-ethyl-5-fluoro-indan-1-yl)-1H-indol-7-ylamine and benzenesulfonyl chloride, the title compound is prepared as in example 15. 0.21 g (33%). LC-MS m/z 295.1 (M++1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[N:11][NH2:12].[N:22]([O-])=O.[Na+].[OH-].[Na+]>Cl.O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[N:11][N:12]=[N:22]1
Reactant: NN=C(Nc1cccc(F)c1F)c1c[nH]c2ncccc12
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc(-n2nnnc2-c2c[nH]c3ncccc23)c1F
Yield: 57.1 %

Procedure:
N-(2,3-Difluoro-phenyl)-N′-amino-1H-pyrrolo[2,3-b]pyridine-3-carboxamidine (prepared by using procedures described in Method G) (20 mg, 0.07 mmol) was dissolved in 2N HCl (2 mL)). A solution of NaNO2 (6 mg) in water (1 mL) was added at 0° C. The mixture was stirred at 0° C. for 30 min and neutralized with 6N NaOH. The precipitate was collected by filtration and the crude product was purified by HPLC to afford a white solid (12 mg, 0.04 mmol).
Reaction SMILES: [OH-].[Na+].C([NH:11][C:12]([NH:14][C:15]1[CH:20]=[C:19]([I:21])[CH:18]=[C:17]([I:22])[CH:16]=1)=[S:13])(=O)C1C=CC=CC=1>O.C1COCC1>[I:21][C:19]1[CH:20]=[C:15]([NH:14][C:12]([NH2:11])=[S:13])[CH:16]=[C:17]([I:22])[CH:18]=1
Reactant: O=C(NC(=S)Nc1cc(I)cc(I)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)Nc1cc(I)cc(I)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 76.2 %

Procedure:
A solution of NaOH (1.30 g, 0.033 mol) dissolved in 35 mL of H2O was added to a solution of 1-benzoyl-3-(3,5-diiodo-phenyl)-thiourea (6.30 g, 0.013 mol) in 75 mL of THF. The resulting reaction mixture was stirred at 70° C. for 12 hours. THF was distilled off and extracted with ethyl acetate (×3). The combined organic layer was dried over Na2SO4, filtered and distilled off to get the crude residue that was washed with hexane to obtain the desired compound (4.0 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH3:9][C:10]([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][C:26]#[CH:27])=[CH:18][C:17]=1[CH3:28])([CH3:14])[C:11]([OH:13])=[O:12].C(N(CC)CC)C>C(#N)C.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([C:27]#[C:26][CH2:25][CH2:24][CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:10]([CH3:14])([CH3:9])[C:11]([OH:13])=[O:12])=[C:17]([CH3:28])[CH:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C#CCCCOc1ccc(OC(C)(C)C(=O)O)c(C)c1
Reactant: Fc1cccc(I)c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(OCCCC#Cc2cccc(F)c2)ccc1OC(C)(C)C(=O)O
Reaction time: 2.5 h
Yield: 67.5 %

Procedure:
A degassed (argon) solution of 0.098 g (0.44 mmol) 1-fluoro-3-iodobenzene in 4 ml acetonitrile was treated with 0.111 g (0.40 mmol) 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid (example 26B]), 0.014 g (0.02 mmol) PdCl2(Ph3P)2, 0.004 g (0.02 mmol) of CuI and 0.17 ml (1.20 mmol) triethylamine. The reaction was stirred for 2.5 h and then extracted with chilled aqueous 10% KHSO4/ether (three times). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Purification was done by flash-chromatography on silica gel (1. n-heptane/EtOAc 4:1 and 2. CH2Cl2/MeOH 2%-10%). The pure fractions were evaporated, dissolved in ether and washed with aqueous 10% KHSO4/ether (three times). The organic phase was dried (Na2SO4) and evaporated to yield 0.10 g of the title compound as an orange viscous oil.
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][C:16]1[CH:41]=[CH:40][C:19]([CH2:20][NH:21][C:22]2[C:32]3[CH2:31][CH2:30][N:29]([C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])[CH2:28][CH2:27][C:26]=3[CH:25]=[CH:24][C:23]=2[Cl:39])=[CH:18][CH:17]=1)=O)(C)(C)C.C(OCC)C>O1CCOCC1.C(Cl)Cl>[ClH:39].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:22]2[C:32]3[CH2:31][CH2:30][N:29]([C:33](=[O:38])[C:34]([F:37])([F:35])[F:36])[CH2:28][CH2:27][C:26]=3[CH:25]=[CH:24][C:23]=2[Cl:39])=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 229.2 %

Procedure:
Add 4M hydrogen chloride in dioxane (20 mL, 20 mmol) to a solution of 6-(4-tert-butoxycarbonylamino-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]-azepine (0.219, 0.44 mmol) in 1,4-dioxane/DCM (1:1, 40 mL). Stir overnight at room temperature, add diethyl ether and concentrate in vacuo to obtain the title compound (0.219 g, 100%) that was dried in vacuo.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1.C([O-])(=O)C.[Na+].C(O)(=O)C>CCOCC>[Br:1][C:6]1[C:7]([O:10][CH3:11])=[N:8][CH:9]=[C:4]([Br:3])[CH:5]=1
Reactant: COc1ccc(Br)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1ncc(Br)cc1Br
Temperature: 80 °C
Reaction time: 4 h
Yield: 62.2 %

Procedure:
Bromine (17.8 g, 111 mmol) was added to a solution of 5-bromo-2-methoxypyridine (12.0 g, 63.8 mmol), sodium acetate (5.23 g, 63.8 mmol), and acetic acid (65 mL). The mixture was stirred at 80° C. for 4 h and then at room temperature for 12 h. The mixture was diluted with ether and washed with water, sodium bicarbonate and hypo solution. The organic layer was dried over sodium sulphate, filtered and concentrated. Purification by chromatography using 1-5% ethyl acetate in pet ether provided 10.6 g of the desired compound: 1H NMR (300 MHz, DMSO-d6) 8.20-8.40 (m, 2H), 3.92 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C@:4]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8](=[CH2:9])[C:7](=[O:10])[N:6]([C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[CH2:5]1.[I-].[CH3:27][S+](C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O.O>[CH3:3][C@:4]1([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[C:8]2([CH2:27][CH2:9]2)[C:7](=[O:10])[N:6]([C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[CH2:5]1
Reactant: C[S+](C)C
Reactant: C=C1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(C)C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](c1ccccc1)N1C[C@@](C)(C(=O)OC(C)(C)C)C2(CC2)C1=O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
Sodium hydride (60% in oil, 76.1 mg, 1.74 mmol) and a solution of tert-butyl (3S)-3-methyl-4-methylene-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (500 mg, 1.59 mmol) in dimethylsulfoxide (24 mL) were added sequentially to a solution of trimethylsulfonium iodide (401 mg, 1.82 mmol) in dimethylsulfoxide (8 mL), and the mixture was stirred at 90° C. for 30 minutes. 10% Aqueous citric acid (32 mL) and water (96 mL) were added to the reaction mixture at room temperature, followed by extraction with ethyl acetate (200 mL×2). The obtained organic layer was washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried over sodium sulfate anhydrate. After filtration, the filtrate was evaporated to dryness under reduced pressure. The residue was purified through silica gel column chromatography (eluent; hexane:ethyl acetate 3:1 to 2:1), to thereby yield the title compound as colorless crystals (315 mg, 60.3%). 1H-NMR and IR spectral data of this product were found to coincide with those obtained in Example 5.
Reaction SMILES: [C@@H:1]1([C:8]([OH:10])=[O:9])[CH2:4][CH2:3][C@@H:2]1[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH2:16](O)[CH2:17][CH2:18][CH3:19]>>[C@@H:1]1([C:8]([O:10][CH2:4][CH2:1][CH2:2][CH3:3])=[O:9])[CH2:4][CH2:3][C@@H:2]1[C:5]([O:7][CH2:16][CH2:17][CH2:18][CH3:19])=[O:6]
Reactant: CCCCO
Reactant: O=C(O)[C@H]1CC[C@H]1C(=O)O
Agent: O=S(=O)(O)O
Product: CCCCOC(=O)[C@H]1CC[C@H]1C(=O)OCCCC

Procedure:
1 g (6.94 mmol) of cis-cyclobutane-1,2-dicarboxylic acid in 50 ml of n-butanol were heated under reflux with 0.3 g of conc. H2SO4 for 90 min. The mixture was then concentrated to about 5 ml and poured into dil. NaHCO3 solution, extracted with ethyl acetate, dried over sodium sulphate and concentrated. Purification was carried out chromatographically over silica gel (mobile phase: petroleum ether:ethyl acetate 100:2>100:5).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]([F:10])([F:9])[F:8])=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:7]([F:10])([F:9])[F:8])=[N:4][N:5]([CH2:18][C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:25][CH2:26]2)=[O:20])[CH:6]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: FC(F)(F)c1n[nH]cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cn1cc(Cl)c(C(F)(F)F)n1)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 4-Chloro-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as colorless oil. 1H NMR (400 MHz, CDCl3): 7.64-7.68 (d, 1H), 6.98-7.4 (m, 2H), 6.86-6.92 (m, 2H), 6.98-7.2 (m, 1H), 5.4 (s, 2H), 3.78-3.84 (m, 2H), 3.68-3.92 (m, 2H), 3-3.1 (m, 4H). 13C NMR (400 MHz, CDCl3): 164.4, 158, 152.2, 144, 132, 118.2, 116, 54, 50.2, 50.0, 46.0, 42.2.
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[OH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[C:17]([OH:19])=[O:18]>CN1CCN(C)C1=O>[CH:1]1([O:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=2[N+:23]([O-:25])=[O:24])[C:17]([O:19][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Product: O=C(OC1CCCC1)c1ccc([N+](=O)[O-])c(OC2CCCC2)c1
Reaction time: 14 h
Yield: 63.9 %

Procedure:
Cyclopentyl bromide (20g, 134 mmol) is added slowly (over 30 minutes) to a stirred suspension of potassium carbonate (27.6 g, 200 mmol) in N,N'-dimethylimidazolidinone (75 mL) containing 3-hydroxy-4-nitrobenzoic acid (9.15 g, 50 mmol) at 85° C. and then stirring is continued for 14 hours. The mixture is allowed to cool and then filtered. The filtrate is diluted with water (100 mL) then extracted with toluene (2×100 mL). The combined organic extract is dried over magnesium sulfate and then the solvent is removed under reduced pressure to give a brown mobile oil. This oil is subjected by flash chromatography on silica gel (dichloromethane as eluent) and the eluent evaporated under reduced pressure to give cyclopentyl 3-cyclopentyloxy-4-nitrobenzoate (10.2 g, 81.6%) as a yellow solid m.p. 45.5°-46.5° C. [Elemental analysis: C,63.7; H,6.66;N,4.37%; calculated: C,63.93; H,6.63;N, 4.39%].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:52])(=[O:51])[CH2:41][C:42]([CH2:47][C:48]([OH:50])=[O:49])([C:44]([OH:46])=[O:45])[OH:43]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([O-:52])(=[O:51])[CH2:41][C:42]([CH2:47][C:48]([O-:50])=[O:49])([C:44]([O-:46])=[O:45])[OH:43]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. to obtain a mixture. The mixture was stirred and added to a solution of citric acid (0.036 g, 0.19 mmol) in TFE (1 mL) at 40° C. The resulting clear solution was stirred for about 4 h and it was subsequently cooled to 5° C. The mixture was kept at 5° C. overnight while stirring and then a sample (1 ml) was taken from the mixture and evaporated to dryness under reduced pressure at 40° C. to give amorphous Nilotinib citrate.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:28])[C:14]([NH:17][C:18]([O:20]CC1C=CC=CC=1)=O)([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C(Cl)(=O)[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1>CO.C(Cl)Cl.[Pd]>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:28])[C:14]([NH:17][C:18](=[O:20])[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)([CH3:15])[CH3:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)C1CCCN1C(=O)C(C)(C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C(=O)NC(C)(C)C(=O)N2CCCC2C(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To solution of 49 (1.00 g, 2.56 mmol) in MeOH (20 ml) was added 10% Pd/C (200 mg) and the mixture was stirred under H2 for 2 hours. The mixture was filtered through a 0.45 μm PTFE filter and the solvent removed in vacuo to yield a colorless oil. This oil was dissolved in CH2Cl2 (25 mL) and DIEA (660 μl, 3.79 mmol) and p-anisoyl chloride (480 mg, 2.8 mmol) were added. The solution was stirred at room temperature under N2 for 18 hours. The solvent was removed in vacuo and the oil dissolved in EtOAc. The organic phase was washed with 0.5N NaHSO4 (2×), water, saturated NaHCO3 (2×) and brine. The organic phase was dried over Na2SO4, filtered and evaporated to give a white solid which was purified by flash column chromatography, eluting with CH2Cl2/MeOH (99/1 to 98/2%) to give the title compound as a white solid (655 mg, 65% yield). 1H-NMR (500 MHz, CDCl3) δ 1.47 (s, 9H), 1.68-2.24 (m, 5H), 1.80 (d, 6H), 3.55-3.68 (m, 1H), 3.72-3.93 (m, 1H), 3.84 (s, 3H), 4.43-4.55 (m, 1H), 6.90 (d, 2H), 7.60 (br s, 1H), 7.77 (d, 2H) Analytical HPLC (C18 column) 8.98 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:24][C:13]2=[CH:14][C:15]3[C:16](=[O:23])[N:17]([CH3:22])[C:18](=[O:21])[C:19]=3[CH:20]=[C:12]2[N:11]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:10]1[NH:11][C:12]2=[CH:20][C:19]3[C:18](=[O:21])[N:17]([CH3:22])[C:16](=[O:23])[C:15]=3[CH:14]=[C:13]2[N:24]=1
Reactant: COc1nccc(Cl)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C)C3=O
Agent: Cl
Solvent: C1COCCO1
Product: CN1C(=O)c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C1=O

Procedure:
2-(4-Chloro-2-methoxypyridin-3-yl)-6-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (2.0 g, 5.84 mmol) was suspended in 50 mL of 1,4-dioxane at rt. Concentrated HCl (10 mL) was added. The reaction mixture was stirred and heated to reflux for 6 h. Then, it was evaporated to dryness to afford a pale-yellow solid product as a HCl salt. MS: 327.9 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 8.11 (s, 2H), 8.01 (s, 1H), 7.77 (d, 1H, J=7.0 Hz), 6.63 (d, 1H, J=7.0 Hz), 3.06 (s, 3H).