Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH2:23])=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH:8]3[CH2:12][C:13]4([CH2:18][CH2:19][C:7]3([CH2:20][CH3:21])[C:6]=2[CH:22]=1)[O:17][CH2:16][CH2:15][O:14]4.[C:24](=O)([O-])[O-].[Cs+].[Cs+].CB1OB(C)OB(C)O1>COCCOC.O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:20]([C:7]12[CH2:19][CH2:18][C:13]3([O:14][CH2:15][CH2:16][O:17]3)[CH2:12][CH:8]1[CH2:9][CH2:10][CH2:11][C:5]1[CH:4]=[C:3]([NH2:23])[C:2]([CH3:24])=[CH:22][C:6]=12)[CH3:21]
Reactant: CCC12CCC3(CC1CCCc1cc(N)c(Br)cc12)OCCO3
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CB1OB(C)OB(C)O1
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCC12CCC3(CC1CCCc1cc(N)c(C)cc12)OCCO3
Temperature: 90 °C
Yield: 53 %

Procedure:
A mixture of rac-(4aR,11bS)-10-bromo-11b-ethyl-1,2,4,4a,5,6,7,11b-octahydrospiro[dibenzo[a,c][7]annulene-3,2′-[1,3]dioxolan]-9-amine (23, R2=Ethyl) (0.255 g, 0.670 mmol) in DME (6 mL) and water (2 mL) was degassed by bubbling nitrogen through the mixture for about 15 min. Cesium carbonate (0.655 g, 2.011 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.168 g, 1.341 mmol) and PdCl2(PPh3)2 (0.024 g, 0.034 mmol) were added and the mixture was heated to about 90° C. for about 22 h. The mixture was cooled to rt, diluted with EtOAc (25 mL) and washed with sat. aq. NaHCO3 (10 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (4 g) using a gradient of 0-15% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-(4aR,11bS)-11b-ethyl-10-methyl-1,2,4,4a,5,6,7,11b-octahydrospiro[dibenzo[a,c][7]annulene-3,2′-[1,3]dioxolan]-9-amine (24, R2=Ethyl) (0.112 g, 53%); LC/MS, method 3, Rt=2.53 min, MS m/z 316 (M+H)+. 1H NMR (400 MHz, DMSO) δ 6.72 (s, 1H), 6.35 (s, 1H), 4.61 (s, 2H), 3.88-3.70 (m, 4H), 2.79-2.72 (m, 1H), 2.54-2.47 (m, 1H), 2.33-2.27 (m, 1H), 2.13-2.04 (m, 1H), 2.00 (s, 3H), 1.97-1.88 (m, 2H), 1.72-1.57 (m, 3H), 1.53-1.46 (m, 1H), 1.41-1.14 (m, 5H), 0.59 (t, J=7.4 Hz, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.C([Li])CCC.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:25]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[C:5]1[S:1][C:2]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1)[CH2:26][CH2:27][CH3:28]
Reactant: c1csc(-c2cccs2)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 124.5 %

Procedure:
The synthesis described herein is depicted schematically in FIG. 4. 1.0 g (6 mmol) of bithiophene in 30 ml THF was treated dropwise with 3.54 ml (6 mmol) of 1.70 M n-butyllithium and stiffed for 0.5 h at −78° C. under N2 atmosphere. 1.96 ml of tributylstannyl chloride (7.2 mmol) was then added to the solution. After stirring at room temperature for 6 h, the solvent was evaporated and the residue was dissolved in 20 ml of hexane and filtered. The filtrate was evaporated to produce 3.4 g of crude 5-(tributylstannyl)-2,2-bithiophene as a light yellow liquid for the next step reaction. 1H NMR: (250 MHZ, CDCl3): d (ppm) 7.27 (d, 1H), 7.15 (2d, 2H), 7.03 (d, 1H), 6.98 (t, 1H), 1.54 (m, 6H), 1.31 (m, 6H), 1.10 (t, 6H), 0.89 (m, 9H). 13C NMR (125 MHZ, CDCl3): d (ppm) 136.28, 127.98, 127.94, 125.19, 124.56, 124.17, 123.97, 123.66, 29.10, 27.50, 13.91, 11.11. MS (FAB): (M+) found: 456, calcd for C20H32S2Sn: 455.28.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[C:12]([C:13](=[O:26])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([CH3:22])=[CH:16][C:15]=3[N+:23]([O-])=O)=[C:11]([C:27]([OH:29])=[O:28])[N:10]=[N:9]2)=[CH:5][CH:4]=1.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:23][C:15]1[CH:16]=[C:17]([CH3:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:13]([C:12]1[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=2)[N:9]=[N:10][C:11]=1[C:27]([OH:29])=[O:28])=[O:26]
Reactant: COc1ccc(Cn2nnc(C(=O)O)c2C(=O)c2cc(OC)c(C)cc2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nnc(C(=O)O)c2C(=O)c2cc(OC)c(C)cc2N)cc1
Yield: 92 %

Procedure:
Next, 1-(4-methoxybenzyl)-5-(5-methoxy-4-methyl-2-nitrobenzoyl )-1,2,3-triazole-4-carboxylic acid (c-2': MP) (252 mg, 0.591 mmole) was dissolved in a mixed solvent of ethanol (10 ml) and ethyl acetate (10 ml), and reduced in the presence of 10% palladium on carbon (31 mg) under the hydrogen atmosphere at room temperature overnight to give 5-(2-amino-5-methoxy-4-methylbenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylic acid (c-2: MP) (216 mg, 92%).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:8]([F:16])=[C:9]([C:12]([F:15])=[CH:13][CH:14]=1)[CH:10]=[O:11])(C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>CN(C)C=O>[F:16][C:8]1[C:7]([OH:6])=[CH:14][CH:13]=[C:12]([F:15])[C:9]=1[CH:10]=[O:11]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(C=O)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c(F)ccc(O)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-(tert-butyl-dimethyl-silanyloxy)-2,6-difluoro-benzaldehyde (37, 3.50 g, 12.9 mmol) in N,N-dimethylformamide (50 mL) was added tetrabutylammonium fluoride trihydrate (4.40 g, 14.0 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give crude compound 38 that was used in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:40])[C:19]([C:35]([O:37]CC)=[O:36])=[CH:20][N:21]3[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][CH3:34])=[CH:16][C:15]=2[F:41])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:40])[C:19]([C:35]([OH:37])=[O:36])=[CH:20][N:21]3[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][CH3:34])=[CH:16][C:15]=2[F:41])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CC[C@H](NC(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3cc(F)c(N4CC[C@H](NC(=O)OC(C)(C)C)C4)nc32)c(OC)c1

Procedure:
A solution of Example 75A (678 mg) and 1M LiOH (4.75 mL) in THF (20 mL) was stirred for 18 hours, diluted with 10% citric acid, and extracted with dichloromethane. The extract was dried (Na2SO4), filtered, and concentrated.
Reaction SMILES: [CH:1]1([C:4]2[NH:9][C:8](=[O:10])[C:7]([CH:11]([NH:14][C:15]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=O)[CH2:12][CH3:13])=[N:6][N:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[CH:17]1([C:15]2[N:6]3[C:7]([C:8](=[O:10])[NH:9][C:4]([CH:1]4[CH2:3][CH2:2]4)=[N:5]3)=[C:11]([CH2:12][CH3:13])[N:14]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCC(NC(=O)C1CCCC1)c1nnc(C2CC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2CCCC2)n2nc(C3CC3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 370 mg (1.28 mmol) crude N-[1-(3-cyclopropyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]cyclopentanecarboxamide, 200 mg (1.28 mmol) phosphoric trichloride are stirred at reflux for 3 hours, proportionate amounts of the solvents are used.
Reaction SMILES: Cl.[CH2:2]([NH:9][C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH:16]([NH2:21])[CH2:15]2)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:30]1[C:31]2[C:38]([CH3:39])=[CH:37][S:36][C:32]=2[N:33]=[CH:34][N:35]=1>C(O)C>[CH2:2]([NH:9][C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH:16]([NH:21][C:30]1[C:31]3[C:38]([CH3:39])=[CH:37][S:36][C:32]=3[N:33]=[CH:34][N:35]=1)[CH2:15]2)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NC1Cc2ccc(C(=O)NCc3ccccc3)cc2C1
Reactant: Cc1csc2ncnc(Cl)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1csc2ncnc(NC3Cc4ccc(C(=O)NCc5ccccc5)cc4C3)c12
Yield: 63.6 %

Procedure:
Using N-benzyl-2-amino-5-indan carboxamide hydrochloride (660 mg, 2.2 mmol), ethanol (19 ml), triethylamine (0.94 ml, 6.7 mmol), and 4-chloro-5-methylthieno[2,3-d]pyrimidine (410 mg, 2.2 mmol), a similar procedure to b) in Production Example 208 was carried out. A solid obtained by purifying the product by silica gel chromatography (methylene chloride:ethanol=95:5) was washed with ether to obtain the title compound (580 mg, 1.4 mmol) having the following physical properties:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:32]C(=O)OC(C)(C)C)[C:9](=[O:31])[NH:10][C:11]2[CH:12]=[C:13]3[C:29](=[O:30])[NH:28][N:27]=[CH:26][C:15]4=[C:16]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[NH:17][C:18]([CH:19]=2)=[C:14]34)=[CH:4][CH:3]=1.[ClH:40].C(N(CC)CC)C>O1CCOCC1>[ClH:40].[NH2:32][C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:9]([NH:10][C:11]1[CH:12]=[C:13]2[C:29](=[O:30])[NH:28][N:27]=[CH:26][C:15]3=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:17][C:18]([CH:19]=1)=[C:14]23)=[O:31]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1ccc(O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N[C@@H](C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1ccc(O)cc1
Yield: 60 %

Procedure:
Preparation of example 175 from the title compound of Example 153 (38 mg, 0.072 mmol) and 4M HCl in dioxane (10 mL) was carried out analogously to Example 91. Isolation, also in an analogous manner, included freebasing with triethylamine and subsequent silica gel chromatography eluting with 3:1:1 hexane:ethyl acetate:ethanol. With ice bath cooling, the purified freebase in CH2Cl2 (10 mL) was treated with 4M HCl in dioxane (0.1 mL). After removal of the volatile components, the title compound (20 mg, 0.043 mmol) was obtained as an orange/yellow powder in 60% yield.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[CH:12][C:11]([C:14](OCC)=[O:15])=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[OH:15][CH2:14][C:11]1[CH:10]=[N:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:13][CH:12]=1
Reactant: CCOC(=O)c1cnc(Nc2ccccc2)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: OCc1cnc(Nc2ccccc2)nc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
Ethyl 2-(phenylamino)pyrimidine-5-carboxylate (0.590 g, 2.42 mmol) obtained in Step 2 was dissolved in toluene (25 mL). After cooling to −78° C., a 1 mol/L diisobutyl aluminum hydride-toluene solution (7.30 mL, 7.30 mmol) was added to the solution, followed by stirring at −78° C. for 3 hours. The reaction mixture was added with ethyl acetate followed by stirring vigorously at room temperature. The mixture was sequentially washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to obtain 5-hydroxymethyl-2-(phenylamino)pyrimidine (386 mg, 79%).
Reaction SMILES: [CH2:1]([N:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C@H:7]([NH:15]C(OC(C)(C)C)=O)[C:5]1=[O:6])[CH:2]=[CH2:3].[ClH:23]>O1CCOCC1>[ClH:23].[CH2:1]([N:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C@H:7]([NH2:15])[C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)Cc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: C=CCN1C(=O)[C@@H](N)Cc2ccccc21

Procedure:
(S)-1-allyl-3-t-butyloxycarbonylamino-3,4-dihydrocarbostyril (9.7 mg) was dissolved in 4 M hydrogen chloride in 1,4-dioxane solution (2 mL) at room temperature, and a white precipitate soon formed. After 30 min the solvent was evaporated under vacuum, and the residue was twice taken up in toluene (5 mL) and evaporated to provide (S)-1-allyl-3-amino-3,4-dihydrocarbostyril hydrochloride (7.6 mg).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[N:18]=[C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]4[CH:26]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([NH:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[N:18]=[C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]4[CH:26]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccn2cc(CCc3ccc4nc(N)oc4c3)nc2c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(CCc3cn4ccc(C)cc4n3)cc2o1
Temperature: 0 °C
Yield: 58.3 %

Procedure:
A solution of acetyl chloride (1.94 g) in dichloromethane (6 ml) was added dropwise to a solution of 2-amino-6-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (6.00 g) and pyridine (4.92 ml) in dichloromethane (60 ml) with stirring at 0° C. The mixture was stirred for two hours at the same temperature and further 22 hours at ambient temperature. Saturated aqueous sodium hydrogen carbonate solution (100 ml) was added thereto and that was stirred for 2.5 hours at 0° C. The resulting precipitate was collected by filtration and washed with water. Recrystallization from a mixture of ethanol and diethyl ether gave 2-acetylamino-6-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (4.00 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:24]1[C:25](=[O:39])[N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:27]=[C:28]([NH2:30])[CH:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:40][C:41]1[CH:55]=[CH:54][C:44]([CH2:45][N:46]2[CH:50]=[C:49]([C:51](Cl)=[O:52])[CH:48]=[N:47]2)=[CH:43][CH:42]=1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:24]1[C:25](=[O:39])[N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[CH:27]=[C:28]([NH:30][C:51]([C:49]2[CH:48]=[N:47][N:46]([CH2:45][C:44]3[CH:54]=[CH:55][C:41]([CH3:40])=[CH:42][CH:43]=3)[CH:50]=2)=[O:52])[CH:29]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(Cn2cc(C(=O)Cl)cn2)cc1
Reactant: CN1CCN(c2ccc3c(c2)cc(-c2cc(N)cn(COCC[Si](C)(C)C)c2=O)n3C(=O)OC(C)(C)C)CC1
Product: Cc1ccc(Cn2cc(C(=O)Nc3cc(-c4cc5cc(N6CCN(C)CC6)ccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1

Procedure:
The title compound was prepared by the route outlined in Scheme 10 and using the experimental from Example 115, Step 4, with intermediate (10e), 2-[5-amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(4-methyl-piperazin-1-yl)-indole-1-carboxylic acid tert-butyl ester (0.1 g, 0.18 mmol) and 1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl chloride (0.047 g, 0.2 mmol). The resultant crude product was purified by flash chromatography on SiO2 eluting with dichloromethane—8% methanol/dichloromethane (gradient) to afford the desired title compound as a pale brown solid, 0.107 g, 79%.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([OH:28])=[O:27]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:33]5[CH:32]=[CH:31][CH:30]=[C:29]([C:26]([OH:28])=[O:27])[CH:34]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4cccc(C(=O)O)c4)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 397, starting from 2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine and 3-carboxyphenyl boronic acid. Mass spectrum (ESI) 436.1 (M+1).
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.FC(F)(F)CO.[C:46]([OH:53])(=[O:52])/[CH:47]=[CH:48]/[C:49]([OH:51])=[O:50]>>[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:46]([O-:53])(=[O:52])/[CH:47]=[CH:48]/[C:49]([O-:51])=[O:50]
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: OCC(F)(F)F
Product: O=C([O-])/C=C/C(=O)[O-]
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a 50 ml flask was added Nilotinib base (0.5 g, 0.94 mmol) and 2,2,2-trifluoroethanol (TFE) (5 ml). A clear solution was obtained. Fumaric acid (0.11 g, 1.03 mmol) was added, and the reaction was stirred at 40° C. for 1 hour. Then it was cooled to room temperature (20-30° C.) and stirred for 2 days. The solvent was then evaporated. A thick yellow paste was obtained, which was dried in a vacuum oven at 60° C. for 2 days to give Nilotinib fumarate form I.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.C(N1CCCC(NC2C=C(N(CC3C=CC(OC)=CC=3)C3C=CC=CC=3)C3N(C(C#N)=CN=3)N=2)C1)C1C=CC=CC=1.[C@H:66]1([NH2:73])[CH2:71][CH2:70][C@H:69]([NH2:72])[CH2:68][CH2:67]1>C(Cl)Cl>[NH2:72][C@H:69]1[CH2:70][CH2:71][C@H:66]([NH:73][C:2]2[CH:3]=[C:4]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[C:5]3[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:67][CH2:68]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CNS(=O)(=O)c1ccc(Nc2cc(Cl)nn3c(C#N)cnc23)cc1
Agent: COc1ccc(CN(c2ccccc2)c2cc(NC3CCCN(Cc4ccccc4)C3)nn3c(C#N)cnc23)cc1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(Nc2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C#N)cnc23)cc1
Temperature: 165 °C

Procedure:
In a 2 dram vial was added 4-(6-chloro-3-cyanoimidazo[1,2-b]pyridazin-8-ylamino)-N-methylbenzenesulfonamide (0.025 g, 0.069 mmol) from (1b) and (trans)-cyclohexane-1,4-diamine (0.700 g, 6.13 mmol). The mixture was heated to 165° C. for 1 hour. Upon cooling, The mixture was diluted with CH2Cl2, then washed with water, dried over Na2SO4, filtered, concentrated and purified by HPLC to provide the titled compound (0.008 g, 26.4% yield). 1H NMR (400 MHz, MeOD) δ ppm 7.91-7.99 (1H, s), 7.82-7.88 (2H, m), 7.48-7.55 (2H, m), 6.42-6.56 (1H, s), 3.68-3.84 (1H, m), 3.06-3.21 (1H, m), 2.49-2.59 (3H, s), 2.23-2.38 (2H, m), 2.04-2.17 (2H, m), 1.48-1.66 (2H, m), 1.28-1.45 (2H, m). LC/MS, m/z 441 (M+1). HPLC Rt, 2.30 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH3:17][S-:18].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[CH2:11][CH:12]([S:18][CH3:17])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(C(=O)C=CC(=O)O)cc1Cl
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CSC(CC(=O)c1cc(Cl)c(C)c(Cl)c1)C(=O)O
Yield: 98.7 %

Procedure:
2.59 g (0.01 mole) of 4-(3,5-dichloro-4-methylphenyl)-4-oxo-2-butenoic acid, prepared as described in step (b) above, were suspended in 10 ml of water, and then 3.5 g (0.01 mole) of a 20% w/v aqueous solution of sodium methanethiolate were poured into the suspension, whilst water-cooling and stirring. The mixture was then stirred for a further 30 minutes, after which 2 ml of concentrated hydrochloric acid were added dropwise to the mixture, whilst water-cooling, and the resulting crystals were collected by filtration, washed with water and air-dried, to give 3.03 g (yield 98.7%) of the desired 4-(3,5-dichloro-4-methylphenyl)-2-methylthio-4-oxobutyric acid, melting at 158°-160° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[OH:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[CH:42]=[C:41]([C:46]([O:48][CH3:49])=[O:47])[CH:40]=[CH:39]3)O1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:13]([O:12][C:11]([N:10]([CH2:18][C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[OH:20])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[CH:42]=[C:41]([C:46]([O:48][CH3:49])=[O:47])[CH:40]=[CH:39]3)=[CH:3][CH:4]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc2c1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](O)c1cccc(Cl)c1
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(-c3ccc(CCN(C[C@H](O)c4cccc(Cl)c4)C(=O)OC(C)(C)C)cc3)ccc2c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 74.5 %

Procedure:
To a solution of tert-butyl [2-(4-bromophenyl)ethyl]-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate (560 mg) and methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthoate (461 mg) in N,N-dimethylformamide (5.6 ml) were added [1′,1′-bis(diphenylphosphino)ferrocene]-palladium(II) dichloride dichloromethane complex (151 mg), 1,1′-bis(diphenylphosphino)ferrocene (102 mg) and 2M sodium carbonate (2.0 ml) at room temperature, and the mixture was stirred at 80° C. for 4 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water three times and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give methyl 6-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]-2-naphthoate (514 mg).
Reaction SMILES: [OH-].[Na+].O.NN.[C:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)(=O)[CH3:7]>C(O)COCCO>[Br:15][C:13]1[CH:12]=[N:11][CH:10]=[C:9]([CH2:6][CH3:7])[CH:14]=1
Reactant: CC(=O)c1cncc(Br)c1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCc1cncc(Br)c1
Temperature: 140 °C
Yield: 62.3 %

Procedure:
A mixture of NaOH (10 g, 0.25 mol), hydrazine monohydrate (10 mL) and 3-acetyl-5-bromopyridine (5 g, 25 mmol) suspended in diethylene glycol (18 mL) was heated to 140° C. for 6 hours. The mixture was cooled to room temperature and partitioned between H2O and ether. The ether extracts were dried over MgSO4 and concentrated to a clear oil. Flash column chromatography (0% to 15% EtOAc in hexanes) gave the product as a clear oil (2.9 g, 58%). 1H NMR (400 MHz, CDCl3): δ 1.26 (t, J=7.6 Hz, 3H), 2.65 (d, J=7.6 Hz, 2H), 7.67 (t, J=2.0 Hz, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.51 (d, J=2.0 Hz, 1H).