Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:5][CH:6]=[N:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[Mg+2].[Br-].[Br-].C[Si](C)(C)[O:20][C:21]([O:29][CH2:30][CH3:31])=[C:22]([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25].C1CCCCC1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:8]([NH:7][CH:6]([CH2:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)[C:22]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[C:21]([O:29][CH2:30][CH3:31])=[O:20])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C(CC1CCC1)=NCc1ccccc1
Reactant: CCOC(OCC)=C(OCC)O[Si](C)(C)C
Agent: [Br-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(OCC)(OCC)C(CC1CCC1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.1 %

Procedure:
N-(2-cyclobutylethylidene)-1-phenylmethanamine (1.00 g, 5.3 mmol) was dissolved in 23 mL toluene, MgBr2.0Et2 (2.07 g, 8.0 mmol) was added and the mixture was stirred at room temperature for 15 minutes. Trimethyl(1,2,2-triethoxyvinyloxy)silane (1.83 g, 7.4 mmol) was added, and the mixture was stirred at room temperature. After 3 hours, the reaction was quenched with water (30 mL) and acidified to pH=2 with hydrochloric acid. The organic phase was washed with sat. NaHCO3, dried over Na2SO4 and the solvent was removed under vacuum to yield the crude product. Column chromatography (silica, cyclohexane:ethyl acetate 10:1) yielded 1.1 g ethyl 3-(benzylamino)-4-cyclobutyl-2,2-diethoxybutanoate.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]([N:24]=[C:25]=[O:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1>>[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]([NH:2][NH:1][C:3]2[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[O:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CC(C)c1cc(NN)nc2ncccc12
Product: CC(C)c1cc(NNC(=O)Nc2cc(Cl)cc(Cl)c2)nc2ncccc12

Procedure:
A 100 mg (0.5 mmol) sample of 2-hydrazinyl-4-isopropyl-1,8-naphthyridine and 94 mg (1.0 eq) of 3,5-dichlorophenyl isocyanate were reacted as outlined in Scheme 1 above to give the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.23 (d, J=6.74 Hz, 6 H) 3.56 (d, J=6.74 Hz, 1 H) 6.82 (s, 1 H) 7.04 (t, J=1.76 Hz, 1 H) 7.23 (dd, J=8.20, 4.40 Hz, 1 H) 7.59 (br. s., 2 H) 8.31 (d, J=1.47 Hz, 1 H) 8.54 (br. s., 1 H) 8.66 (d, J=1.17 Hz, 1 H) 8.99 (br. s., 1 H) 9.25 (br. s., 1 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[OH-].[Na+]>O1CCOCC1.O>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:3]=[C:2]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: CN1CCNCC1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(N3CCN(C)CC3)n2)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of 133 (0.5 g, 1.31 mmol) in 1,4-dioxane (5 mL) was added slowly a solution of 1-methylpiperizine (0.13 g, 1.31 mmol) in 1,4-dioxane (5 mL) followed by 2.5 N sodium hydroxide solution (0.5 mL, 1.31 mmol) and water (1.2 mL). The mixture was heated to reflux for 2.5-3 hours with stirring under nitrogen atmosphere and then cooled to 25° C. and diluted with water (10 mL). The mixture was then stirred for 10-15 min., the precipitated solid was filtered off and dried under vacuum to afford the title compound E18 as an off-white solid (0.5 g, 86%). mp 120-122° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns 65:35 [0.01 M KH2PO4 (0.1% TFA): CH3CN], 223 nm, Rt 10.23 min, 98.50% purity); MS (CI): m/z 446 (M+H, 100), 375 (25).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:33]1[C:37]2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.[CH:66]([N:69]([CH:72]([CH3:74])C)[CH2:70][CH3:71])([CH3:68])C.NC1CCN(C)CC1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:33][CH:37]5[CH2:71][CH2:70][N:69]([CH2:66][CH3:68])[CH2:72][CH2:74]5)=[O:27])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: On1nnc2ccccc21
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: CN1CCC(N)CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(C)c2)CC1
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
To a mixture of 0.050 g (0.116 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-184) and 8 mL of dimethylformamide was added 0.0235 g (0.174 mmole) of 1-hydroxybenzotriazole, 0.0659 g (0.174 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.060 g (0.463 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0227 g (0.177 mmole) of 4-amino-1-methylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0547 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethyl-piperidin-4-yl)-3-methyl-benzamide (I-186) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]2[CH:8]3[CH2:14][CH2:13][C:12](=[CH:15][O:16]C)[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:20])[CH3:2].C(O)=O.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]2[CH:8]3[CH2:14][CH2:13][CH:12]([CH:15]=[O:16])[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:20])[CH3:2]
Reactant: CCOc1ccc2c(c1F)OC1CC(=COC)CCC21
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1ccc2c(c1F)OC1CC(C=O)CCC21

Procedure:
8.0 g (28.7 mmol) of (±)-(4aR*, 9bS*)-7-ethoxy-6-fluoro-3-[1-methoxy-methylidene]-1,2,3,4,4a,9b-hexahydrodibenzofuran are dissolved in 200 ml of toluene and stirred vigorously at room temperature for 18 h together with 30 ml (0.80 mol) of formic acid and 0.5 ml (27.8 mmol) of water. The organic phase is separated off and washed successively with water, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. Purification by column chromatography (SiO2, toluene:ethyl acetate=99:1) gives a mixture (64:36) of (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-carbaldehyde and (±)-(3S*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-carbaldehyde.
Reaction SMILES: [CH:1]#[C:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.S(=O)(=O)(O)O>C(COC)OC>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]1[C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1.[OH:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(O)cc1
Reactant: C1=COCCC1
Agent: O=S(=O)(O)O
Solvent: COCCOC
Product: C=Cc1ccc(C2CCCCO2)cc1
Product: C=Cc1ccc(O)cc1
Yield: 93.6 %

Procedure:
To a solution of poly(p-hydroxystyrene) (9.0 g) [MARUKA LYNCUR-M, manufactured by Maruzen Petrochemical Co., Ltd., Mw 10000 and Mn 5000] in dimethoxyethane (100 ml), 3,4-dihydro-2H-pyran (12.6 g) and conc. sulfuric acid (0.5 ml) were added, followed by reaction at 30°-40° C. for 15 hours with stirring. After reaction, the mixture was evaporated in vacuo, the residue was neutralized by addition of sodium carbonate and poured into H2O (1 liter). The precipitate was filtered by suction, washed with H2O and dried under reduced pressure to give 11.0 g of the title compound as a white powder having Mw 10000 (GPC with polystyrene calibration). The composition of the polymer was found to be p-tetrahydro-pyranyloxystyrene unit and p-hydroxystyrene unit in a molar ratio of ca. 3:7 based on 1HNMR.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].C[Si]([C:31]#[N:32])(C)C.N>C(O)(=O)C>[CH3:1][C:2]1([CH3:18])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([F:19])[CH:21]=2)([C:31]#[N:32])[CH2:13][CH2:12]1
Reactant: C[Si](C)(C)C#N
Reactant: CC1(C)C2CCC(CCN3CCC(=O)CC3)C1C2
Reactant: Nc1cccc(F)c1
Agent: N
Solvent: CC(=O)O
Product: CC1(C)C2CCC(CCN3CCC(C#N)(Nc4cccc(F)c4)CC3)C1C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
A solution of 20.0 g (80.2 mmol) of (26) and 8.4 ml (87 mmol) of 3-fluoroaniline (27a) in 65 ml of acetic acid was cooled with a cold water bath. 10.7 ml (80.2 mmol) of trimethylsilylcyanide were added dropwise over a period of 10 min. maintaining the temperature below 40° C. The mixture was stirred for 2 h at room temperature and poured into a mixture of aqueous ammonia (80 ml) and ice (80 g). The pH was adjusted to 10 with concentrated NH3. The mixture was extracted with chloroform (3×200 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 40.0 g of crude product, which was purified by column chromatography (SiO2, heptane:EtOAc, 1:1) to give 28.7 g (77.7 mmol, 97%) of (28a). It is also possible to use crude product in the next step without purification.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([S:40]([NH2:43])(=[O:41])=[O:42])=[CH:38][CH:39]=3)[N:24]=2)[CH:20]=[CH:21][CH:22]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(S(N)(=O)=O)cc3)n2)c1

Procedure:
Intermediate 4 was coupled with 4-(2-Amino-ethyl)-benzenesulfonamide following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 519. 1H NMR (Varian 300 MHz, CDCl3-CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.0 (m, 2H) 7.8 (m, 1H) 7.6 (m, 4H) 7.4 (m, 1H) 7.2 (m, 2H) 4.3 (s, 2H) 3.8 (m, 2H) 3.4 (m, 2H) 2.9 (m, 2H) 2.8 (s, 3H) 2.6 (m, 2H) 1.6 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]#[N:13])[C:5]2[C:6](I)=[N:7][NH:8][C:9]=2[CH:10]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.[CH2:20]1COCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]#[N:13])[C:5]2[C:6]([CH3:20])=[N:7][N:8]([CH:19]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:9]=2[CH:10]=1
Reactant: C1=COCCC1
Reactant: C1CCOC1
Reactant: N#Cc1cc(Cl)cc2[nH]nc(I)c12
Product: Cc1nn(C2CCCCO2)c2cc(Cl)cc(C#N)c12
Temperature: 80 °C
Yield: 78.4 %

Procedure:
A mixture of 6-chloro-3-iodo-1H-indazole-4-carbonitrile (2.0 g, 6.59 mmol), dihydropyran (1.09 g, 13.18 mmol), and TsOH monohydrate (127 mg, 0.659 mmol) in THF (40 mL) under nitrogen was heated at 80° C. overnight. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (50 mL×3). The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (5:1) to afford 6-chloro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile as white solid (2 g, 78.4%). MS (ESI): m/z=388 [M+1]+.
Reaction SMILES: [CH3:1][CH:2](C(O)=O)[CH2:3][C@@H:4](N)CC1C=CC=CC=1.CC(C)[N:18]=C=NC(C)C.CO.C([O:30][C:31](=[O:33])[CH3:32])(=O)C>Cl.O1CCOCC1>[NH2:18][C@H:32]([C:31]([OH:30])=[O:33])[C@H:2]([CH2:3][CH3:4])[CH3:1]
Reactant: CC(C[C@@H](N)Cc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC[C@H](C)[C@H](N)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The acid obtained above was coupled with the hydrochloride salt of tubuphenylalanine (Tup) methyl ester (22.5 mg, 0.09 mmol) following the DIC/PFP protocol in a similar way as described for the synthesis of compound 5 to give after reverse phase HPLC purification the peptoid 9 (8.0 mg, 9.8 μmol). HRMS calculated for C44H67N6O7S [M+H]+: 823.4795. found: 823.4789. Subsequently, the obtained oil was dissolved in a commercially available 4 N solution of HCl in dioxane (2 mL) and the mixture was stirred for 1 h. Afterward, MeOH (2 mL) was added and the stirring was continued for an additional 3 h. (The hydrolysis of the convertible Ugi-Armstrong-amides alternatively can also be performed on the stage of intermediates like 8 etc.). The solvent was removed under reduced pressure and the residue was dissolved in pyridine (4.0 mL) and the solution was cooled to 0° C. Acetic anhydride (84 μL, 0.90 mmol) was added and the reaction was stirred overnight and allowed to reach gradually rt. The solvent was removed under reduced pressure and the crude mixture submitted to reverse phase HPLC purification to render 6.3 mg of tubugi H (7.9 μmol, 4.0% yield overall). 1H-NMR (599.8 MHz, CD3OD, representative signals): δ=0.79 (d, 3H, J=6.6 Hz), 0.90 (t, 3H, J=7.4 Hz), 0.98 (d, 3H, J=7.0 Hz), 1.01 (d, 3H, J=6.6 Hz), 1.14 (d, 3H, J=7.4 Hz), 1.18-1.23 (m, 1H), 1.38 (m, 1H), 2.16 (s, 3H), 2.41 (s, 3H), 3.59 (s, 3H), 3.61 (s, 3H), 3.63 (d, 1H), 4.35 (m, 1H), 4.42 (d, 1H, J=9.9 Hz), 4.58 (br m, 1H), 4.83 (overlap signal), 6.32 (dd, 1H, J=11.6/1.9 Hz), 7.16 (m, 1H), 7.21 (m, 4H), 8.01 (s, 1H) ppm. HRMS calculated for C41H62N5O9S [M+H]+: 800.4277. found: 800.4280.
Reaction SMILES: [NH2:1][C@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25](O)=[O:26])[CH:21]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@H:2]([NH:1][C:25]([C:22]3[CH:21]=[C:20]([CH3:19])[O:24][N:23]=3)=[O:26])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cc1cc(C(=O)O)no1
Product: Cc1cc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (240 mg, 0.921 mmol) and 5-methylisoxazole-3-carboxylic acid (140 mg, 1.105 mmol). The product was purified with flash-chromatography. Yield 46 mg (13%). 1H-NMR (400 MHz; d6-DMSO): δ 1.15 (d, 3H), 4.28-4.35 (m, 2H), 4.40-4.50 (m, 1H), 6.45 (d, 1H), 6.93 (d, 1H), 7.81 (d, 1H), 7.91-7.93 (m, 1H), 7.98 (d, 1H), 8.07 (d, 1H), 8.71 (d, 1H).
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:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([OH:45])=[O:44]>CC(OC)(C)C>[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-:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([O-:45])=[O:44]
Reactant: O=C(O)/C=C\C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: COC(C)(C)C
Product: O=C([O-])/C=C\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 maleic acid (0.066 g, 0.57 mmol) in TFE (1 mL) at 40° C. The resulting clear solution was stirred for about 4 h at 40° C. and subsequently cooled to 5° C. The mixture was kept at 5° C. overnight and then MTBE (1.5 v/v) was added to the mixture at room temperature leading to precipitation. The precipitate was filtered and the filter cake was dried at 40° C. in a vacuum oven overnight to give Nilotinib maleate form III.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:39])=[C:16]([NH:18][C:19]2[N:23]([CH3:24])[C:22]3[CH:25]=[CH:26][C:27]([C:29]([NH:31][CH2:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:30])=[CH:28][C:21]=3[N:20]=2)[CH:17]=1>CC#N.C(Cl)Cl>[Cl:39][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][NH:10][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])=[CH:17][C:16]=1[NH:18][C:19]1[N:23]([CH3:24])[C:22]2[CH:25]=[CH:26][C:27]([C:29]([NH:31][CH2:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:30])=[CH:28][C:21]=2[N:20]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(C(=O)NCC3CCCCC3)ccc21
Solvent: ClCCl
Solvent: CC#N
Product: Cn1c(Nc2cc(CNS(=O)(=O)c3cccs3)ccc2Cl)nc2cc(C(=O)NCC3CCCCC3)ccc21

Procedure:
Thiophene-2-sulfonyl chloride (64 mg, 0.35 mmol) in MeCN (1 mL) was added to a mixture of 2-(5-aminomethyl-2-chlorophenylamino)-N-cyclohexylmethyl-1-methylbenzimidazole-5-carboxamide (150 mg, 0.35 mmol), TEA (150 L, 1.1 mmol) and MeCN (2 mL). After 12 h at rt the mixture was diluted with DCM and washed with NH3 (aq, sat) and brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give the title compound. Yield: 36 mg (18%). 200 MHz 1H-NMR (DMSO-d6, ppm) 8.50-8.36 (2H, m) 8.35-8.22 (1H, m) 7.94-7.82 (3H, m) 7.69-7.57 (2H, m) 7.42 (1H, d, J=8.2 Hz) 7.37 (1H, d, J=8.2 Hz) 7.18-7.11 (1H, m) 7.04-6.95 (1H, m) 4.09-3.96 (2H, m) 3.71 (3H, s) 3.14-3.00 (2H, m) 1.77-1.47 (7H, m) 1.29-1.07 (4H, m). MS m/z: 572 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[O:23])=[CH:17][CH:16]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:22](=[O:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)Nc2ccc3sc(C)nc3c2Cl)cc1
Yield: 56 %

Procedure:
Reaction of 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in THF (1.5 mL) with 4-methoxyphenylacetyl chloride (46 μL, 0.30 mmol) in presence of triethylamine (42 μL, 0.30 mmol) according to method A gave N-(4-chloro-2methyl-benzothiazol-5-yl)-2-(4-methoxy-phenyl)-acetamide (50 mg, 0.14 mmol, 56% yield) as a white powder after crystallisation in hexane/DCM.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].C(O)(=O)C[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1.CC([O-])=O.[Na+]>>[C:12]([O:14][CH:17]=[CH2:18])(=[O:13])[CH2:11][CH2:10][CH2:9][CH2:2][C:1]([O:4][CH:5]=[CH2:6])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCCCC(=O)O
Reactant: C=COC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: C=COC(=O)CCCCC(=O)OC=C
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
In a 3-necked 1000 ml round bottom flask equipped with a reflux condenser, thermometer and magnetic stirrer was added vinyl acetate (320 g, 3791 mmol), adipic acid (17.5 g, 120 mmol), [pyridine]2Pd(OAc)2 (1.2 g, 3.1 mmol) and p-toluenesulfonic acid (4.4 g, 25.6 mmol). The temperature was held at 65° C. for 4 hours. After cooling to room temperature, NaOAc (3.0 g) was added to the solution. Volatiles were removed by a roto-vac. The non-volatiles were diluted with 200 ml hexane, extracted with 2×100 ml 2% NaOH, extracted with 100 ml distilled water and then dried over Na2SO4. The hexane was removed with a roto-vac. TLC showed on component. The divinyl adipate weighed 23.7 g (99.7% yield). IR(NaCl plate): 2940, 1750, 1640, 1370 cm-1.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][CH2:36][CH2:37][C@@H:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[OH:39]>>[OH:39][C@H:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:37][CH2:36][NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: NCC[C@H](O)c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCC[C@H](O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and (1S)-3-amino-1-phenyl-1-propanol, the title compound was obtained in 91% purity by HPLC. MS(ESI+): m/z=486.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]=[CH:11][CH3:12])[N:5]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:19]=2)[N:3]=1.[NH2:29][C:30]1[CH:34]=[C:33]([CH3:35])[NH:32][N:31]=1>>[CH3:35][C:33]1[NH:32][N:31]=[C:30]([NH:29][C:2]2[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]=[CH:11][CH3:12])[N:5]=[C:4]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH:19]=3)[N:3]=2)[CH:34]=1
Reactant: CC=CCCc1cc(O)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Reactant: Cc1cc(N)n[nH]1
Product: CC=CCCc1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1

Procedure:
Starting materials: 4-hydroxy-6-(pent-3-en-1-yl)-2-[2-{3-(pyrid-2-yl)isoxazol-5-yl}pyrrolidin-1-yl]pyrimidine (Method 35) and 3-amino-5-methyl-1H-pyrazole.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[NH:10][C:9](=[O:13])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]=[O:15].O>CO.C(Cl)Cl>[C:1]1([N:7]2[C:11](=[O:12])[N:10]([CH2:14][OH:15])[C:9](=[O:13])[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c(=O)n(-c2ccccc2)o1
Reactant: C=O
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=c1on(-c2ccccc2)c(=O)n1CO
Reaction time: 2 h

Procedure:
2-Phenyl-1,2,4-oxadiazolidin-3,5-dione (6.75 grams; 0.044 mole) dissolved in methanol (100 ml) and aqueous formaldehyde (5.67 ml of 37% conc.; 0.06 mole) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux, with stirring for a period of about 2 hours. After this time the reaction mixture was stripped of methanol and water to yield a solid residue. The residue was then dissolved in methylene chloride, and the resulting solution was washed with water. The washed solution was dried over anhydrous magnesium sulfate and stripped of solvent to yield the desired product 2-phenyl-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione as a solid residue.