Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([C:8]#[N:9])[N:5]=[CH:4]1.[CH3:10][Si:11]([CH2:14][CH2:15][O:16][CH2:17]Cl)([CH3:13])[CH3:12]>C1COCC1>[CH3:10][Si:11]([CH3:13])([CH3:12])[CH2:14][CH2:15][O:16][CH2:17][N:3]1[CH:7]=[C:6]([C:8]#[N:9])[N:5]=[CH:4]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: N#Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(C#N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
To a round bottom flask was added NaH (60% in mineral oil) (200 mg, 5.22 mmol) in dry THF (12 ml), followed by the addition of 1H-imidazole-4-carbonitrile (400 mg, 4.3 mmol), SEMCl (1433 mg, 8.6 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc/sat. NaHCO3. The organic phase was separated, washed with water, brine, dried over anhy. Na2SO4, filtered and concentrated. The resulting residue was purified by flash chromatography on silica gel (0-3% MeOH/CH2Cl2). The product fractions were collected and concentrated to afford 355 mg of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile, m/z 224.6 [M+1]+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.[NH:21]([C:28]1[N:29]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:30]2[C:35]([C:36](=[O:38])[CH:37]=1)=[C:34]([CH3:39])[CH:33]=[CH:32][N:31]=2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C[O:49]CC1>>[NH:21]([C:28]1[N:29]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:30]2[C:35]([C:36](=[O:38])[CH:37]=1)=[C:34]([CH2:39][OH:49])[CH:33]=[CH:32][N:31]=2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1ccnc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nccc(CO)c12
Temperature: -78 °C
Yield: 53 %

Procedure:
A solution of LDA (38.2 mmol, freshly prepared from n-BuLi and diisopropylamine) in THF (53 mL) was added to a cooled (−78° C.) and stirred suspension of 2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (2.50 g, 7.64 mmol) in THF (100 mL). The resulting mixture was stirred for 1 h, and then oxygen gas was bubbled, through a flitted glass tube, into the bottom of the reaction vessel. The mixture was stirred overnight, with continued bubbling of oxygen with slow warming to room temperature. The reaction was quenched with water and 1M HCl (5 mL), and then extracted with CH2Cl2. The organic phase was dried over Na2SO4 and concentrated in vacuo to afford an orange solid which was recrystalized from EtOAc to obtain 2-anilino-5-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (1.38 g, 53%): LCMS RT: 2.01 min, MH+: 344.3, Rf=0.22 (95:5 CH2Cl2:MeOH).
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[Cl:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[CH:19]=[C:18]([C:25]([O:27]CC)=O)[C:17](/[N:30]=[CH:31]/N(C)C)=[CH:16]2.ClCCOC1C=C2C(C=C(/N=C/N(C)C)C(C(OCC)=O)=C2)=CC=1OC>O1CCCC1>[Cl:9][CH2:10][CH2:11][O:12][C:13]1[C:22]([O:23][CH3:24])=[CH:21][C:20]2[CH:19]=[C:18]3[C:17](=[CH:16][C:15]=2[CH:14]=1)[NH:30][CH:31]=[C:7]([C:6]#[N:8])[C:25]3=[O:27]
Reactant: CCOC(=O)c1cc2cc(OC)c(OCCCl)cc2cc1/N=C/N(C)C
Reactant: CC#N
Agent: CCOC(=O)c1cc2cc(OCCCl)c(OC)cc2cc1/N=C/N(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1OCCCl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To 2.5 mL of dry tetrahydrofuran at −78° C. is added 1.8 mL of 2.5 M n-butyllithium (4.4 mmol). Then 0.24 mL of dry acetonitrile in 4.5 mL of dry tetrahydrofuran is added dropwise over 10 minutes. This is stirred and additional 15 minutes at −78° C., then the ethyl 6-(2-chloroethoxy)-3-{[(E)-(dimethylamino)methylidene]-amino}-7-methoxy-2-naphthoate and ethyl 7-(2-chloroethoxy)-3-{[(E)-(dimethylamino)methylidene]amino}-6-methoxy-2-naphthoate (1:1 mixture) is dissolved in 3 mL of tetrahydrofuran and added dropwise over 15 minutes. The reaction mixture is stirred for 30 minutes at −78° C., then quenched with 0.57 mL of glacial acetic acid, and warmed to room temperature. To the yellow mixture is added 10 mL of water. The solids are filtered, washed with water and dried to give 0.502 g of 8-(2-chloroethoxy)-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile and 7-(2-chloroethoxy)-8-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile (1:1 mixture) as a yellow green solid (76%), m.p. 260-73° C. dec.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[Br:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][CH2:15][CH2:14][Br:13])=[CH:7][CH:6]=1
Reactant: BrCCCBr
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)Cc1ccc(OCCCBr)cc1
Yield: 82.1 %

Procedure:
This compound was produced using similar methods as those used Step 3, example 6, starting with (4-hydroxy-phenyl)-acetic acid methyl ester (5.00 g, 30.1 mmol), 1,3-dibromopropane (24.3 g, 120 mmol) and cesium carbonate (40.3 g, 120 mmol). The crude oil was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 20/80) to give [4-(3-Bromo-propoxy)-phenyl]-acetic acid methyl ester (7.10 g, 82%) as a faint-yellow oil. 1H NMR (400 MHz, DMSO-d6); δ 7.15 (d, 2H), 6.87 (d, 2H), 4.03 (t, 2H), 3.63 (t, 2H), 3.58 (s, 3H), 3.57 (s, 2H), 2.21 (m, 2H).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C@@H:8]2[CH2:12][N:11]([C:13]([NH:15][CH2:16][C:17]3[N:18]=[C:19]4[CH:25]=[CH:24][N:23]([S:26]([C:29]5[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=5)(=[O:28])=[O:27])[C:20]4=[N:21][CH:22]=3)=O)[C@H:10]([CH3:36])[CH2:9]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl.[OH-].[Na+]>>[CH3:36][C@H:10]1[N:11]([C:13]2[N:18]3[C:19]4[CH:25]=[CH:24][N:23]([S:26]([C:29]5[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=5)(=[O:28])=[O:27])[C:20]=4[N:21]=[CH:22][C:17]3=[CH:16][N:15]=2)[CH2:12][C@@H:8]([NH:7][S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:6])=[O:5])[CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)N4C[C@@H](NS(=O)(=O)C5CC5)C[C@H]4C)cnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(N4C[C@@H](NS(=O)(=O)C5CC5)C[C@H]4C)n23)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A flask was charged with (2R,4S)-4-(cyclopropanesulfonamido)-2-methyl-N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)pyrrolidine-1-carboxamide (0.11 g, 0.207 mmol, prepared using E from Preparation #14 and J from Example #5 Step C and CDI) and POCl3 (1.9 mL, 21 mmol). The reaction mixture was heated to about 60° C. resulting in a homogeneous mixture. After about 2 h, the reaction mixture was cooled to ambient temperature and crushed ice was added. After the ice had melted, 2 N aqueous NaOH was added until a pH of about 7 was obtained. The resulting precipitate was collected by filtration and dried in vacuo to provide N-((3S,5R)-5-methyl-1-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cyclopropane-sulfonamide (0.10 g, 94%) as a tan solid: LC/MS (Table 1, Method a) Rt=2.14 min; MS m/z: 515 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[B:18]([OH:20])[OH:19])=O)(C)(C)C>C(O)(C(F)(F)F)=O>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([B:18]([OH:20])[OH:19])[NH:8]2
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2c(F)cccc21
Solvent: O=C(O)C(F)(F)F
Product: OB(O)c1cc2c(F)cccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
TFA (60 mL) was added 1-(tert-butoxycarbonyl)-4-fluoro-1H-indol-2-ylboronic acid (10 g, 35.83 mmol) in portions at 0° C. and then the mixture was stirred at room temperature for 3 hours. The mixture was poured into ice water, stirred for 10 minutes and filtered through a pad to give the crude 4-fluoro-1H-indol-2-ylboronic acid (6.0 g, yield: 94%) without further purification. 1H-NMR (DMSO-d6, 400 MHz) δ 11.09 (s, 1H), 8.35 (br s, 2H), 7.22 (d, J=8.00 Hz, 1H), 7.02˜7.07 (m, 2H), 6.68˜6.72 (m, 1H). MS (M+H)+: 180.
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[C:12]([O:22][C:23](=[O:27])[CH2:24][CH2:25][CH3:26])[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3]>[Pd].C(O)C>[C:23]([O:22][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH:8]([OH:9])[CH2:7][NH:6][C:2]([CH3:3])([CH3:5])[CH3:4])(=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1OC(=O)CCC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCC(=O)Oc1ccc(C(O)CNC(C)(C)C)cc1OC(=O)CCC
Reaction time: 8 h

Procedure:
A mixture of 30 g. of 3,4-bis(butyryloxy)phenyl N-tert-butylaminomethyl ketone hydrochloride, 200 ml. of 90 percent ethyl alcohol, and 2 g. of 10 percent palladium-on-charcoal hydrogenation catalyst was hydrogenated for 2 hours at 50° C. under an initial hydrogen pressure of 50 pounds per square inch. The hydrogenation mixture was filtered to remove the catalyst. The solvent was evaporated from the filtrate under reduced pressure and the resulting residue was taken up in 50 ml. of isopropyl alcohol, allowed to stand overnight at 5° C., and filtered to remove 3 g. of solid. The filtrate was evaporated under reduced pressure, the residue thus obtained was dissolved in 50 ml. of isopropyl acetate, and this solution was filtered to remove a small amount of insoluble solid. When the filtrate was diluted with anhydrous diethyl ether, a solid separated from solution. This solid was collected on a filter. There was thus obtained 20 g. of crude 3,4-bis(butyryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride. This salt was dissolved in water and then ammonium hydroxide was added, resulting in precipitation of the free base, 3,4-bis(butyryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol. This precipitate was collected on a filter and washed well first with water and then with n-hexane. This base, which melted at 97°-99° C. (uncorr.), was dissolved in isopropyl alcohol and this solution was concentrated under reduced pressure. The resulting residue was dissolved in 30 ml. of isopropyl acetate and there was added ethereal hydrogen chloride solution in an amount affording a slight excess of the required amount of hydrogen chloride for conversion of the base to the hydrochloride. The mixture was cooled and the inside of the container was scratched to induce crystallization. The mixture was diluted with 100 ml. of diethyl ether and the solid precipitate was collected on a filter and washed with anhydrous diethyl ether and dried at 70° C. There was thus obtained 11 g. of 3,4-bis(butyryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a white crystalline solid which melted at 136°-138° C. (uncorr.). This salt was soluble in water to the extent of at least 20 percent. The pH of a 1 percent aqueous solution of this salt was 6.0; and a precipitate formed when the pH of this solution was raised to 7.0 by addition of N/10 sodium hydroxide solution.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)[C:13]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:12]=2[N:11]=1)[CH3:9])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:22][C:17]1[CH:16]=[C:15]([N:14]2[C:13]3[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:12]=3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH:20]=[C:19]([F:21])[CH:18]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1cc(F)cc(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1cc(F)cc(F)c1
Yield: 100.4 %

Procedure:
A solution of {(S)-1-[1-(3,5-difluorophenyl)-6-fluoro-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (668 mg, 1.7 mmol) in TFA (4 mL) and DCM (12 mL) was stirred for 1 h at RT. The reaction solution was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford the title compound as a pale yellow oil (497 mg, 99%). Marfey's test: 97% de. LCMS (Method C): RT 1.96 min [M+H]+ 292. 1H NMR (CDCl3, 400 MHz): δ 7.70 (1H, dd, J=9.0, 5.0 Hz), 7.08-7.00 (2H, m), 6.97-6.93 (2H, m), 6.80 (1H, dd, J=8.0, 2.5 Hz), 6.19 (2H, bs), 4.51 (1H, q, 7.0 Hz), 1.55 (3H, d, J=7.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]12(O)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.S(=O)(=O)(O)O>ClCCl>[C:9]12([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[OH:8])[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2
Reactant: Oc1ccc(Br)cc1
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 6.92 g (40.0 mmol) of 4-bromophenol and 6.08 g (40.0 mmol) of 1-adamantanol in 20 ml of dichloromethane (anhydrous) was added 2.0 ml of conc. sulfuric acid over a span of 2 minutes. The solution became orange in color and a white precipitate was formed. The solution was allowed to stir at room temperature for 8 hours, partitioned between 250 ml of water and 100 ml of ethyl ether, diluted with approximately 60 ml of sat. aqueous NaHCO3 solution and allowed to stir at room temperature. The layers were separated and the aqueous phase was washed with 3×75 ml-portions of dichloromethane. All organic phases were combined, dried over MgSO4, filtered and concentrated in vacuo to yield a yellow solid. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) yielded the title compound as a light yellow solid. PMR (CDCl3): d 1.77 (6H, s), 2.08 (9H, s), 4.76 (1H, s), 6.53 (1H, d, J=8.4 Hz), 7.14 (1H, dd, J=8.4, 2.4 Hz), 7.29 (1H, d, J=2.4 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[CH2:9]([O:11][CH2:12][CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]=[C:15]1[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]=[C:33]=[S:34])[CH2:26][CH2:25]1)[CH3:10]>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:8][C:33]([NH:32][CH2:31][CH2:30][N:27]1[CH2:28][CH2:29][N:24]([CH2:23][C:15]2[N:14]([CH2:13][CH2:12][O:11][CH2:9][CH3:10])[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH2:25][CH2:26]1)=[S:34]
Reactant: CCOCCn1c(CN2CCN(CCN=C=S)CC2)nc2cccnc21
Reactant: Nc1ccncc1N
Solvent: C1CCOC1
Product: CCOCCn1c(CN2CCN(CCNC(=S)Nc3cnccc3N)CC2)nc2cccnc21
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 3.8 parts of 3,4-pyridinediamine, 13.1 parts of 3-(2-ethoxyethyl) -2-[[4-(2-isothiocyanatoethyl)-1-piperazinyl]methyl]-3Himidazo[4,5-b]-pyridine and 135 parts of tetrahydrofuran was stirred overnight at reflux temperature. The whole was evaporated, yielding 16.9 parts (100%) of N-(4-amino-3-pyridinyl)-N'-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperazinyl]ethyl]thiourea as a residue (compound 122).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][C:25]=2[C:24]([C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)=[CH:23][CH:22]=1.[OH-].[Na+]>>[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][C:25]=2[C:24]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[CH:36][CH:35]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1ccc(-c2cccc3c2oc2ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from 0, Step A was treated with 4-Dibenzofuran-4-yl-phenol from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C31H30O6 [M+Na]+: 519.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH2:15][CH3:16].C(O)(=O)C.[O-]S([O-])(=O)=O.[Mg+2]>CO.CCOC(C)=O>[CH3:16][NH:15][C:3]([CH3:5])=[CH:2][C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: CN
Reactant: CC(=O)CC(=O)OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CNC(C)=CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of benzyl acetoacetate (57.6 g, 300 mmol) in MeOH (50 mL) in a 350 mL pressure vessel was added H2NMe (150 mL of a 2M solution in MeOH, 300 mmol) and acetic acid (2 mL). The capped vessel was placed in an oil bath at 70° C. and the reaction mixture was stirred for 16 hours. After the mixture had cooled to room temperature, the solvent was evaporated in vacuo leaving a yellow emulsion, which was dissolved in EtOAc (500 mL) and MgSO4 was added to remove water. The drying agent was filtered off, and the solvent evaporated in vacuo to give benzyl 3-(Methylamino)but-2-enoate as a viscous yellow oil in quantitative yield 60 g which was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[Si:7]([O:14][CH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].C([BH3-])#N.[Na+].O>C(O)(=O)C>[Si:7]([O:14][CH:15]1[CH2:16][CH2:17][CH:18]([NH:6][C:3]2[NH:4][CH:5]=[N:1][N:2]=2)[CH2:19][CH2:20]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: Nc1nc[nH]n1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCC(Nc2nnc[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.8 %

Procedure:
To a solution (30 mL) of 1H-1,2,4-triazol-3-amine (3 g) and 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanone (10 g) in acetic acid was added sodium cyanoborohydride (9.3 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (2.2 g, 20%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7](Cl)[C:8]3[N:9]2[CH:12]=[CH:13][N:14]=3)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].[CH2:20]([CH2:23][OH:24])[CH2:21][NH2:22]>O1CCOCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([NH:22][CH2:21][CH2:20][CH2:23][OH:24])[C:8]3[N:9]2[CH:12]=[CH:13][N:14]=3)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: NCCCO
Reactant: FC(F)(F)c1cc2nc(Cl)c3nccn3c2cc1Br
Solvent: C1COCCO1
Product: OCCCNc1nc2cc(C(F)(F)F)c(Br)cc2n2ccnc12
Temperature: 25 °C
Yield: 89.1 %

Procedure:
8-Bromo-4-chloro-7-(trifluoromethyl)imidazo[1,2-a]quinoxaline (7.8 g, 0.0222 mol) is stirred under nitrogen with 3-propanolamine (4.2 mL, 0.0540 mol) in 1,4-dioxane (156 mL) at 95° C. for 2 hours. The reaction mixture is then cooled down to room temperature and concentrated. The residue is partitioned between a saturated ammonium chloride aqueous solution (150 mL) and ethyl acetate (150 mL). The aqueous phase is extracted twice with ethyl acetate (50 mL) and the combined organic phases are dried over sodium sulfate. The organic solution is concentrated to about 100 mL and cyclohexane (300 mL) is added at room temperature. The mixture is filtered at 0-5° C. and the cake is washed three times with cyclohexane (50 mL) and dried under vacuum to afford the title compound as a yellow solid (7.7 g, 88.9%)
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[CH3:5][C:6]1[O:10][N:9]=[C:8]([C:11](=[O:13])[CH3:12])[N:7]=1>C1COCC1>[CH3:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])([C:1]#[CH:2])[CH3:12])[N:7]=1
Reactant: CC(=O)c1noc(C)n1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(C)(O)c1noc(C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
To a solution of ethynylmagnesium bromide (0.5 M in THF, 800 mL, 400 mmol) at 0° C. was added 1-(5-methyl-1,2,4-oxadiazol-3-yl)ethanone (33.5 g, 266 mmol) in THF (533 mL) slowly. The reaction was allowed to warm to room temperature and stirred for 5 hours. After being quenched with saturated NH4Cl (750 mL) at 0° C., the THF was removed in vacuo and the aqueous residue was extracted with ethyl acetate (600 mL×2). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give dark brown oil. The dark brown oil was purified by silica gel column chromatography use 10% of ethyl acetate in hexanes as eluent to give the title compound (36 g, 89%), 1H NMR (CDCl3, 400 MHz): delta 3.93 (s, 1H), 2.63 (s, 1H), 2.61 (s, 3H), 1.91 (s, 3H).
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])[CH2:41][CH2:42][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])[CH2:41][CH2:42][C:43]([O-:45])=[O:44]
Reactant: O=C(O)CCC(=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-])CCC(=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 succinic acid (0.033 g, 0.28 mmol) in TFE (1 mL) at 40° C. The resulting clear solution was stirred for about 4 h at 40° C. and the solution was 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 succinate form I.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH2:39][CH3:40])([C:24]3[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]([CH2:36][CH3:37])([OH:35])[CH2:33][CH3:34])=[C:26]([CH3:38])[CH:25]=3)[CH2:22][CH3:23])=[CH:17][CH:16]=2)[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:22]([C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:9]2[C:10]([O:13][CH3:14])=[CH:11][CH:12]=[C:7]([CH2:6][C:5]([OH:41])=[O:4])[CH:8]=2)=[CH:20][CH:19]=1)([C:24]1[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]([CH2:33][CH3:34])([OH:35])[CH2:36][CH3:37])=[C:26]([CH3:38])[CH:25]=1)[CH2:39][CH3:40])[CH3:23]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cc(CC(=O)OC)ccc3OC)cc2)cc1C)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cc(CC(=O)O)ccc3OC)cc2)cc1C)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.150 mL, 0.150 mmol) was added to a solution of (4′-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-6-methoxy-biphenyl-3-yl)-acetic acid methyl ester (Example 175-(2); 26.2 mg, 0.050 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (24.1 mg, 94%).