Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][CH3:27])=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccc(C(=O)Nc2ccc3nc(N(C)CCN(C)C)sc3c2)cc1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-4-iodo-benzamide (0.15 g, 0.31 mmol) and 2-methoxyphenyl boronic acid (0.060 g, 0.38 mmol) to afford 0.050 g (35%). LC/MS, Retention time=4.49 min; (m/z): calcd for C26H28N4O2S (M+H)+: 461.6; found: 461.0.
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[C:20]3[N:19]4[CH:21]=[CH:22][CH:23]=[C:18]4[C:17](=[N:24][OH:25])[C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[CH2:26]([OH:28])[CH3:27].O>C(O)(=O)C.[Zn]>[C:26]([OH:25])(=[O:28])[CH3:27].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[C:20]3[N:19]4[CH:21]=[CH:22][CH:23]=[C:18]4[CH:17]([NH2:24])[C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: ON=C1c2cccc(-c3cnc4ccccc4c3)c2-n2cccc21
Reactant: CCO
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: NC1c2cccc(-c3cnc4ccccc4c3)c2-n2cccc21
Reaction time: 1.5 h

Procedure:
In a 100 ml round-bottomed flask, a mixture of 277 mg of 5-quinolin-3-ylpyrrolo[1,2-a]indol-9-one oxime hydrochloride obtained according to the preceding stage, in 5 ml of acetic acid, 5 ml of ethanol and 5 ml of water, is stirred at ambient temperature. 58 mg of powdered zinc are added and the resulting mixture is left to stir for 1.5 hours. A further 58 mg of powdered zinc is added and the resulting mixture is left to stir for 3.5 hours. The reaction medium is filtered through clarcel, washing being carried out with 100 ml of methanol. The filtrate is evaporated to dryness under vacuum and chromatographed on silica gel (15-40 μm), elution being carried out with a gradient of methanol (2% to 7% v/v) in dichloromethane. 116 mg of 5-quinolin-3-yl-9H-pyrrolo[1,2-a]indol-9-ylamine acetate are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([C:9]([CH2:12]Br)=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:16]12[CH:22]([SH:23])[CH:19]([CH2:20][CH2:21]1)[CH2:18][CH2:17]2.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH:19]12[CH:22]([S:23][CH2:12][C:9]3[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([O:14][CH3:15])[C:2]([Br:1])=[CH:11][CH:10]=3)[CH:16]([CH2:21][CH2:20]1)[CH2:17][CH2:18]2
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Reactant: SC1C2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1c(CSC2C3CCC2CC3)ccc(Br)c1OC
Temperature: 60 °C
Yield: 63.3 %

Procedure:
A mixture of methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89, 0.338 g), bicyclo[2.2.1]heptane-7-thiol (Intermediate 183, 0.148 g) and potassium carbonate (0.345 g) in THF (5 ml) was stirred and heated at 60° C. for 3 days. After cooling, the mixture was partitioned between ethyl acetate and water and the organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-10% to give methyl 6-(bicyclo[2.2.1]hept-7-ylthiomethyl)-3-bromo-2-methoxybenzoate (0.244 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].CN1CCOCC1.Cl[C:22]([S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[S:23]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:13])[C:11]=1[O:12][C:22]([S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[S:23])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)c(O)c(Br)c1
Reactant: S=C(Cl)Sc1ccccc1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(OC(=S)Sc2ccccc2)c(Br)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Methyl 3,5-dibromo-4-hydroxybenzoate (1000 mg, 3.23 mmol) was dissolved in THF (16 mL) and N-methylmorpholine (0.709 mL, 6.45 mmol) was added. The mixture was cooled to 0° C. and phenyl chlorodithioformate (0.549 mL, 3.87 mmol) was added. The mixture was warmed to room temperature and stirred overnight. The mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-15% EtOAc/hexanes) to yield the title compound as a clear oil (1491 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[C:3]=1[CH:12]=[O:13].[C:14]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:14][O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[C:3]=1[CH:12]=[O:13]
Reactant: O=C([O-])[O-]
Reactant: Cc1noc2c(C=O)c(O)ccc12
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc2c(C)noc2c1C=O
Temperature: 60 °C

Procedure:
A mixture of 6-hydroxy-3-methylbenzo[d]isoxazole-7-carbaldehyde (437 mg; 2.46 mmol) and K2CO3 (409 mg; 2.96 mmol) in anh. acetone (21 ml) was treated with dimethyl sulfate (373 mg; 2.96 mmol), and the resulting mixture was heated to 60° C., under nitrogen, for 1.5 h. After cooling to rt, the resulting reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. DCM was added, and the mixture was washed successively with 1 M aq. NH4OH, water, and brine. The organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give 6-methoxy-3-methylbenzo[d]isoxazole-7-carbaldehyde as an orange solid. LC-MS (conditions A): tR=0.53 min.; [M+H]+: 192.12 g/mol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:29]=[CH:28][C:15]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)=[O:17])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Ni].CC(N(C)C)=O>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:28]=[CH:29][C:12]([C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)=[O:30])=[CH:13][CH:14]=2)=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])cc2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(NC(=O)c2ccc(C(=O)Nc3ccc(N)cc3)cc2)cc1
Temperature: 100 °C

Procedure:
Into a 300 ml. pressure-vessel of stainless steel equipped with a magnetic stirrer, a thermometer, and a hydrogen inlet tube, were placed 145 ml. of dimethylacetamide, 18 grs. of N,N'-bis(4-nitrophenyl)terephthalamide prepared in Procedure (b-ii) above, and 2 grs. of Raney nickel. While stirring the contents of the vessel, the temperature was slowly raised to 100° C. Hydrogen gas of about 600 psi was introduced to the bottom of the vessel via the hydrogen inlet tube. The above hydrogen pressure and reaction temperature were maintained for about 5 to 6 hours, so that the hydrogenation reaction could be completed. The reaction product was filtered at 100° C. to separate the Raney nickel catalyst therefrom, and cooled down to 5° C. The resulting yellowish precipitate was collected by filtration and recrystallized from the dimethylacetamide solvent to afford the titled compound in the form of beautiful needle-shaped pale yellow crystals. Yield: 15.32 grs. (97.7% of theoretical value); m.p.: 300° C. (dec.). The IR spectrum showed carbonyl absorption at 1,660 cm-1, and an amide stretch at 3,300 cm-1 (asym); 3,325 cm-1 (sym). For the NMR analysis of the compound, deuterated dimethylsulfoxide solvent was used. The chemical shift of each portion in the NMR spectra was found to be as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:23][OH:24])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:9]2=[O:22])=[C:4](O)[CH:3]=1.ClC1C=CC(Cl)=C2C=1C(C1C(O)=CC3OCOC=3C=1)(CO)C(=O)N2CCCCC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:23][O:24][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:9]3=[O:22]
Reactant: COC(=O)CN1C(=O)C(CO)(c2ccc(Cl)cc2O)c2ccccc21
Agent: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2c(Cl)ccc(Cl)c21
Product: COC(=O)CN1C(=O)C2(COc3cc(Cl)ccc32)c2ccccc21
Yield: 74 %

Procedure:
Following the procedure as described in EXAMPLE 1.22, and making non-critical variations using methyl [3-(4-chloro-2-hydroxyphenyl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate to replace 4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 74% yield as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.29 (dt, 1H), 7.14 (dd, 1H), 7.06 (t, 1H), 6.95 (d, 1H), 6.81-6.74 (m, 3H), 5.03 (d, 1H), 4.74 (d, 1H), 4.65 (d, 1H), 4.44 (d, 1H), 3.75 (s, 3H); MS (ES+) m/z 344.5 (M+1), 346.5 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@H:28]([CH:30]4[CH2:32][CH2:31]4)[OH:29])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH:35]([Si:38]([CH:53]([CH3:55])[CH3:54])([CH:50]([CH3:52])[CH3:51])[O:39][CH:40]1[CH2:44][CH2:43][C:42]([CH:48]=[CH2:49])([C:45]([OH:47])=[O:46])[CH2:41]1)([CH3:37])[CH3:36].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:30]1([C@H:28]([OH:29])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]2[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2](/[CH:49]=[CH:48]/[C:42]5([C:45]([OH:47])=[O:46])[CH2:43][CH2:44][CH:40]([O:39][Si:38]([CH:50]([CH3:52])[CH3:51])([CH:53]([CH3:55])[CH3:54])[CH:35]([CH3:36])[CH3:37])[CH2:41]5)=[CH:3][CH:4]=4)[N:9]=3)[CH3:13])=[O:16])[NH:18]2)=[O:34])=[O:33])[CH2:32][CH2:31]1
Reactant: C=CC1(C(=O)O)CCC(O[Si](C(C)C)(C(C)C)C(C)C)C1
Reactant: C[C@H](NC(=O)[C@@H](O)C1CC1)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)[Si](OC1CCC(/C=C/c2ccc3ccc([C@@H](C)NC(=O)[C@@H]4CCCN(C(=O)[C@H](C)NC(=O)[C@@H](O)C5CC5)N4)nc3c2)(C(=O)O)C1)(C(C)C)C(C)C
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 100 %

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-cyclopropyl-2-hydroxy-acetylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (795.0 mg, 1.493 mmol), 3-triisopropylsilanyloxy-1-vinyl-cyclopentanecarboxylic acid (466.6 mg, 1.493 mmol), tri(o-tolyl)phosphine (91.0 mg, 0.299 mmol) and triethylamine (0.63 mL, 4.479 mmol) in 1,4-dioxane (20 mL) was deoxygenated by bubbling through nitrogen for 5 min. The reaction mixture was then treated with tris(dibenzylideneacetone)dipalladium(0) (136.7 mg, 0.149 mmol). After stirring at 100° C. for 40 min, the reaction was cooled to room temperature and filtered through Celite. The solid was rinsed with ethyl acetate and the volatiles were removed in vacuo to provide the crude title compound (1.493 mmol) as an orange foam. LCMS (m/z) 764.4 [M−H], Tr=3.53 min.
Reaction SMILES: NC1C=C2[C:9](=CC=1)[N:8]=[CH:7]C(C(NCC1C=CC(Cl)=CC=1)=O)=C2O.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33]([C:35]2[CH:36]=[N:37][C:38]3[C:43]([C:44]=2[OH:45])=[CH:42][CH:41]=[C:40](N(C)C)[CH:39]=3)=[O:34])=[CH:27][CH:26]=1.NC1C=C2C(C(O)=C(C(NCC3C=CC(Cl)=CC=3)=O)C=N2)=CC=1>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][NH:32][C:33]([C:35]2[CH:36]=[N:37][C:38]3[C:43]([C:44]=2[OH:45])=[CH:42][C:41]([N:8]([CH3:9])[CH3:7])=[CH:40][CH:39]=3)=[O:34])=[CH:29][CH:30]=1
Reactant: Nc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reactant: CN(C)c1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Agent: Nc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Product: CN(C)c1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1

Procedure:
This compound is prepared from 6-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide using a procedure similar to that used to prepare N-[(4-chlorophenyl)methyl]-7-(dimethylamino)-4-hydroxy-3-quinolinecarboxamide from 7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide (29805JT118). The product is obtained as a tan powder.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[Na].[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22]#[N:23])=[CH:16][CH:15]=1.C(OCC)(=O)C>C(O)C.O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:20]([C:17]3[CH:18]=[CH:19][C:14]([S:13][CH3:12])=[CH:15][CH:16]=3)[CH2:21][C:22]([NH2:23])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(C=CC#N)cc1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1ccc(C2CC(N)=NN2c2ccc(F)cc2)cc1
Yield: 67.6 %

Procedure:
4-Fluorophenylhydrazine hydrochloride 4 g) was added to a solution of sodium (1.13 g) in ethanol (50 ml), and the mixture was refluxed for 1 hour. To the cooled mixture was added 3-[4-(methylthio)phenyl]acrylonitrile (4.3 g), and the resulting mixture was refluxed overnight. Ethyl acetate and water were added, and the organic layer was separated, dried and concentrated. The oily residue (7.6 g) was purified by column chromatography on silica gel (76 g) eluting with a mixture of toluene and ethyl acetate (2:1) to give brown crystals of 4,5-dihydro-1-(4-fluorophenyl)-5-[4-(methylthio)phenyl]pyrazol-3-amine (5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH2:12]([O:14][C:15](=[O:23])[N:16]([CH2:20][CH2:21]Br)[CH2:17][CH2:18]Br)[CH3:13].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]1([CH2:21][CH2:20][N:16]([C:15]([O:14][CH2:12][CH3:13])=[O:23])[CH2:17][CH2:18]1)[CH2:5]2
Reactant: O=C1CCc2cc(F)ccc21
Reactant: CCOC(=O)N(CCBr)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC2(CC1)Cc1cc(F)ccc1C2=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 32.1 %

Procedure:
To a stirred solution of 5-fluoro-1-indanone (302 mg, 2.013 mmol) and bis-(2-bromo-ethyl)-carbamic acid ethyl ester (610 mg, 2.01 mmol) in DMF (5 mL) at 50° C. was added NaH (121 mg, 5.03 mmol) by small portions. After being stirred at 50° C. for 16 hr, the reaction was cooled to 25° C. The reaction was diluted with 15 mL of ethyl acetate and washed twice with 10 mL of water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column (gradient of 85:15 to 60:40 heptane/ethyl acetate in 20 min to give the title compound (188 mg, 0.645 mmol, 32.1% yield). MS (ESI) [m/e, (M+H)+]=292.4. HPLC retention time=1.46 minutes (Agilent 1100 HPLC system; 3.0 cm×3.0 mm×3.0 um C8 column; flow rate of 2.0 mL/min; gradient of 5-95% acetonitrile/water with 0.1% formic acid over 2 minutes).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Br)[CH:13]=2)[N:8]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:7]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:13]=2)[N:8]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:7]=1
Reactant: COC(=O)CCc1cn(S(=O)(=O)c2ccccc2)c2ccc(Br)cc12
Reactant: OB(O)c1ccccc1
Product: COC(=O)CCc1cn(S(=O)(=O)c2ccccc2)c2ccc(-c3ccccc3)cc12

Procedure:
The ester 93 was prepared from the methyl ester 89 by following the procedure as described in example 70 by substituting 3-Thienyl boronic acid with Phenyl boronic acid, (M+1=420).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:43][N:44]([CH2:51][C@H:52]1[CH2:57][CH2:56][C@H:55]([NH2:58])[CH2:54][CH2:53]1)[CH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([NH:58][C@H:55]3[CH2:54][CH2:53][C@H:52]([CH2:51][N:44]([CH3:43])[CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[CH2:57][CH2:56]3)=[O:18])[CH:11]=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCOCC1
Reactant: Cc1ccc(-c2cncc(/C=C/C(=O)O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cncc(/C=C/C(=O)N[C@H]3CC[C@H](CN(C)C4CCOCC4)CC3)c2)cc1
Reaction time: 2 h

Procedure:
Into a suspension of (E)-3-[5-(4-methylphenyl)pyridin-3-yl]acrylic acid (150 mg) and 1-hydroxybenzotriazole (134 mg) in acetonitrile (15 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.19 g), and the resulting mixture was stirred for 2 hours. Into the reaction mixture was added a solution of trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexylamine dihydrochloride (198 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (0.2 g) and triethylamine (0.18 ml) in acetonitrile (20 ml), and the resulting mixture was stirred for 64 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with chloroform. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After the resulting organic layer was concentrated under reduced pressure to remove the solvent, the precipitated crystals were purified by recrystallization (ethanol/ethyl acetate) to obtain (trans, E)-3-[5-(4-methylphenyl)pyridin-3-yl]-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexyl]acrylamide (compound 73) (226 mg) as colorless crystals.
Reaction SMILES: C(O[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([CH3:19])([C:15]([F:18])([F:17])[F:16])[O:10][CH2:9][CH2:8]2)(=O)C.C([OH:24])(CC)C.C(OC1C=C2C(=CC=1)[C@](C)(C(F)(F)F)OCC2)(=O)C>CCCCCC>[OH:24][CH:8]1[C:7]2[C:12](=[CH:13][CH:14]=[CH:5][CH:6]=2)[C@@:11]([CH3:19])([C:15]([F:18])([F:17])[F:16])[O:10][CH2:9]1
Reactant: CC(=O)Oc1ccc2c(c1)CCOC2(C)C(F)(F)F
Reactant: CCC(C)O
Agent: CC(=O)Oc1ccc2c(c1)CCO[C@@]2(C)C(F)(F)F
Solvent: CCCCCC
Product: C[C@]1(C(F)(F)F)OCC(O)c2ccccc21
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of racemic 6-acetoxy-1-methyl-1-trifluoromethylisochroman (38.4 g, 0.140 mol), 10% sec-butanol solution in hexane (1.3 L), and lipase PS (35 g) was stirred vigorously at room temperature for 23 hr. After filtration, the filtrate was concentrated under reduced pressure to give a mixture. This was purified by silica-gel column chromatography eluted with gradient of hexane and ethyl acetate (15:1,5:1,2:1) to give, first, (1R)6-acetoxy-1-methyl-1-trifluoromethyl-isochroman as a colorless oil (17.3 g, 45%, 94%ee). The 1H-NMR spectra of this compound was identical with that of racemate. The second fraction gave (1S)-4-hydroxy-1-methyl-1-trifluoromethyl-isochroman as crystals (16.9 g, 52%, 83%ee). The 1H-NMR spectra of this material was identical with that of racemate.
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.CN(C)C=O.[C:45]([OH:50])(=[O:49])[C:46]([OH:48])=[O:47]>CCO>[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:45]([O-:50])(=[O:49])[C:46]([O-:48])=[O:47]
Reactant: O=C(O)C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C([O-])C(=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Nilotinib base Form A (4.00 g, 7.55 mmol) was suspended in EtOH abs. (40 mL, 10V) at room temperature. The suspension was heated to 80° C. and stirred at that temperature for 30 min. A solution of oxalic acid (1.38 g, 15.33 mmol, 2.03 mol eq) in EtOH abs. (10 mL 2.5V) was added in one portion and a suspension was obtained. Stirring of the suspension was continued for 1 h at 80° C. The reaction vessel was then allowed to cool to ambient temperature by removal of the reaction vessel from the heating source, and the mixture was stirred at ambient temperature for 6 h. Another 20 mL EtOH abs. was added during this time to improve the stirring. A yellow precipitate formed and was isolated by vacuum filtration and dried in a vacuum oven (35 mmHg) at 70° C. for 24 h to give Nilotinib oxalate form I (5.3 g) as a yellow solid. The sample was analyzed by PXRD (Bruker X-Ray powder diffractometer model D8 advance equipped with lynxEye). Di oxalate salt was obtained according to assay determination.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([F:23])[CH:22]=1)[O:5][C:6]1[C:11]2[CH2:12][C:13]([CH3:16])([CH3:15])[O:14][C:10]=2[CH:9]=[C:8]([C:17]([OH:19])=O)[CH:7]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH3:53][N:54]1[CH:58]=[CH:57][C:56]([NH2:59])=[N:55]1>C(Cl)Cl>[CH3:53][N:54]1[CH:58]=[CH:57][C:56]([NH:59][C:17]([C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:20]=[C:21]([F:23])[CH:22]=[C:2]([F:1])[CH:3]=3)[C:11]3[CH2:12][C:13]([CH3:15])([CH3:16])[O:14][C:10]=3[CH:9]=2)=[O:19])=[N:55]1
Reactant: Cn1ccc(N)n1
Reactant: CC1(C)Cc2c(Oc3cc(F)cc(F)c3)cc(C(=O)O)cc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cn1ccc(NC(=O)c2cc(Oc3cc(F)cc(F)c3)c3c(c2)OC(C)(C)C3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a mixture of 4-(3,5-difluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (113b) (0.308 g, 0.00096 mol), EDCl (0.28 g, 0.0015 mol), HOBt (0.21 g, 0.0015 mol) and NMM (0.49 g, 0.0048 mol) in CH2Cl2 (15 mL) was added 1-methyl-1H-pyrazol-3-amine (0.11 g, 0.001 mol) in one portion. The mixture was stirred at room temperature overnight. The reaction mixture was washed with water, aq. citric acid and then sat. NaHCO3. The organic phase was dried over Na2SO4 and concentrated to give a brown oil. The crude oil was purified by prep. HPLC to give the title compound (95 mg, 51% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.82 (s, 1H), 7.20 (m, 2H), 7.03 (d, 2H), 6.73 (s, 1H), 6.42 (m, 3H), 3.72 (s, 3H), 2.84 (s, 2H), 1.42 (s, 6H);
Reaction SMILES: CON(C)[C:4](=[O:47])[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:8][N:7]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38].[CH2:49]([Mg]Br)[CH3:50]>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:10]2[C@@H:9]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:8][N:7]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@@H:6]([CH2:5][C:4](=[O:47])[CH2:49][CH3:50])[CH2:11]2)=[CH:13][CH:14]=1
Reactant: CC[Mg]Br
Reactant: COCCCN1CCOc2ccc(COC3CN(S(=O)(=O)c4ccc(C)cc4)C(CC(=O)N(C)OC)CC3c3ccc(OC)cc3)cc21
Product: CCC(=O)C[C@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1S(=O)(=O)c1ccc(C)cc1

Procedure:
Similar to example 29b by, 1.0 g of N-methoxy-2-[4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-N-methyl-acetamide (from example 29c) in the presence of ethyl magnesium bromide are used to afford the title compound after flash chromatography (SiO2 60 F) as a colourless oil. Rf=0.20 (EtOAc-heptane 1:1); Rt=5.13.