Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:11]=[C:10]([O:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[C:9]=1[C:31]1[O:35][N:34]=[C:33]([C:36]([O-])=[O:37])[CH:32]=1.[K+].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:62][CH:63]1[CH2:68][CH2:67][N:66]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:65][CH2:64]1>CN(C=O)C.C(OCC)(=O)C>[C:72]([O:71][C:69]([N:66]1[CH2:67][CH2:68][CH:63]([NH:62][C:36]([C:33]2[CH:32]=[C:31]([C:9]3[C:10]([O:21][C:22]4[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=4)=[CH:11][C:12]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:13][C:8]=3[O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[O:35][N:34]=2)=[O:37])[CH2:64][CH2:65]1)=[O:70])([CH3:75])([CH3:73])[CH3:74]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COCCOCOc1cc(OCOCCOC)c(-c2cc(C(=O)[O-])no2)c(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOCOc1cc(OCOCCOC)c(-c2cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)no2)c(Oc2ccc([N+](=O)[O-])cc2)c1
Reaction time: 0.33 h
Yield: 54.1 %

Procedure:
To a stirred solution of potassium 5-{2,4-bis[(2-methoxyethoxy)methoxy]-6-(4-nitrophenoxy)phenyl}isoxazole-3-carboxylate (3.8 g, 6.6 mol) in DMF (50 mL) was added portion wise TBTU (2.34 g, 7.3 mmol, 1.1 eq.) at 0° C. After stirring for 20 minutes, a solution of tert-butyl 4-aminopiperidine-1-carboxylate (1.6 g, 8 mmol, 1.2 eq.) in DMF (25 mL) was added and the reaction was set-aside at room temperature overnight. The reaction mixture was taken up in ethyl acetate and thoroughly washed with water then with brine. After drying over Na2SO4, the solvent was removed and the residue was carefully chromatographed over silica gel eluting with a mixture of ethyl acetate/hexane 4/7 to provide the title compound (3.1 g, 65% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC1C=CC2C3C(=CC=CC=3)C=2C=1>>[CH:5]1[C:4]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:3]=2[CH:2]=[CH:7][CH:6]=1
Reactant: Clc1ccc(Cl)c(-c2ccccc2)c1
Agent: Clc1ccc2c(c1)-c1ccccc1-2
Product: c1ccc2c(c1)-c1ccccc1-2

Procedure:
General Procedure I is followed, where the monomer is 2,5-dichlorobiphenyl (11.5 mmol). 1.15 mmol of the endcapper 2-chlorobiphenylene is employed, yielding a biphenylene-terminated rigid-rod macromonomer.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@@H:12]([CH2:16][CH:17]=[CH2:18])[C:13]([OH:15])=O.CCN=C=NCCCN(C)C.Cl.CC1C=CN=C(N)C=1C.[C:40]1([C@@H:46]([NH:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[CH:47]=[CH2:48])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH:50]1([N:49]([C@H:46]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:47]=[CH2:48])[C:13](=[O:15])[C@H:12]([N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH2:16][CH:17]=[CH2:18])[CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: C=C[C@H](NC1CCCC1)c1ccccc1
Reactant: C=CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccnc(N)c1C
Agent: Cl
Solvent: ClCCl
Product: C=CC[C@H](C(=O)N(C1CCCC1)[C@@H](C=C)c1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pent-4-enoic acid (361 mg), EDAC.HCl (408 mg), and dimethyl aminopyridine (8 mg) in DCM (4 ml) at −20° C. under N2 was added a solution of N-[(1S)-1-phenylprop-2-en-1-yl]cyclopentanamine in DCM (3 ml). The mixture was allowed to stir at −20° C. for 1 hr then RT overnight. The next day the reaction was diluted with DCM and extracted with 0.1 N HCl. The aqueous layer was back extracted with DCM (×2). All organics were combined, dried (Na2SO4), filtered and evaporated. The resulting residue was purified by column chromatography (10% EtAOc/Hexane) to afford a mixture (85:15) (SS:RS) of the title compound and it's diasteromer (2R)-N-cyclopentyl-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-[(1S)-1-phenylprop-2-en-1-yl]pent-4-enamide (249 mg) as determined by NMR. 1H NMR (300 MHz, d6-DMSO at 110° C.) δ 1.10-2.12 (m, H9), 2.38-3.15 (m, 2H), 4.88-5.21 (m, 4H), 5.30-5.45 (m, 3H), 5.70-5.90 (m, 1H), 6.00-6.18 (m, 1H), 6.21-6.38 (m, 0.17H), 6.95-7.12 (m, 1H), 7.19-7.41 (m, 5H), 7.18-7.95 (m, 4H). MS APCI, m/z=429 (M+1), LC/MS, 3.04 min.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH:18]([CH:21]1[CH2:26][CH2:25][O:24][C:23](=[O:27])[N:22]1[C:28](=[O:39])[CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])([CH3:20])[CH3:19].C(N(C(C)C)CC)(C)C.[CH2:49]([N:55]1[C:59]([CH:60]=[O:61])=[CH:58][N:57]=[CH:56]1)[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>ClCCl>[CH2:49]([N:55]1[C:59]([C@@H:60]([OH:61])[C@@H:29]([C:28]([N:22]2[C@H:21]([CH:18]([CH3:20])[CH3:19])[CH2:26][CH2:25][O:24][C:23]2=[O:27])=[O:39])[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:58][N:57]=[CH:56]1)[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCn1cncc1C=O
Reactant: COC(=O)CC/C=C\CCC(=O)N1C(=O)OCCC1C(C)C
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCn1cncc1[C@@H](O)[C@H](C/C=C\CCC(=O)OC)C(=O)N1C(=O)OCC[C@H]1C(C)C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A 1M solution of dibutylboron triflate in dichloromethane (1.56 ml) was added to a solution of the product of step (iv) (422 mg, 1.42 mmol) in dry dichloromethane (9 ml) at 5° C. under argon, followed by diisopropylethylamine (0.295 ml, 1.7 mmol). The reaction mixture was stirred at 5° C. for 30 minutes and then cooled to -78° C. A solution of the product of step (iii) (280 mg, 1.56 mmol) in dichloromethane (2 ml) was added dropwise. The mixture was stirred at -78° C. for 30 minutes before being allowed to warm to room temperature. The reaction was quenched by the addition of pH7.2 phosphate buffer solution (1.36 ml) followed by hydrogen peroxide (0.4 ml, 30% w/v aqueous solution). The mixture was stirred for 30 minutes and then poured into water and extracted three times with dichloromethane. The combined extracts were dried (MgSO4), filtered, and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate, to give methyl (7S,4Z)-7-[(S)-(1-hexylimidazol-5-yl)hydroxymethyl]-8-[(S)-4-isopropyl-2-oxo-1,3-oxazinan-3-yl]-8-oxo-oct-4-enoate (450 mg, 66% yield) as an oil;
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1.[C:16]([O:20][C:21]([NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27](O)[CH2:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCCCCC.C(OCC)(=O)C>[C:16]([O:20][C:21]([NH:23][C@@H:24]1[CH2:29][CH2:28][C@H:27]([O:15][C:7]2[CH:6]=[C:5]([O:4][CH2:3][CH2:2][F:1])[CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])[CH2:26][CH2:25]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1ccc(OCCF)cc1O
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCF)cc1O[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using a procedure similar to that of Example 6-D, methyl 4-(2-fluoroethoxy)-2-hydroxybenzoate (5.0 g, 24.75 mmol), trans-4-tert-butoxycarbonylaminocyclohexanol (5.02 g, 24.75 mmol), and triphenylphosphine (1.2 equivalents) in THF (125 mL) is treated with diethyl azodicarboxylate (1.3 equivalents) in THF (25 mL). After having stirred overnight at room temperature, the reaction mixture was heated 8 h at 40-50° C., then stirred overnight at room temperature. The crude product was isolated by elution from silica gel with a gradient of 0 to 40% ethyl acetate in hexane to afford crude methyl 2-(cis-4-tert-butoxycarbonylaminocyclohexyloxy)-4-(2-fluoroethoxy)benzoate (7.30 g), which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH2:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[NH2:12].[CH3:13][O:14][CH2:15][C:16](Cl)=[O:17]>N1C=CC=CC=1>[CH3:13][O:14][CH2:15][C:16]([NH:12][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([NH:11][C:16](=[O:17])[CH2:15][O:14][CH3:13])[C:2]=1[Cl:1])[C:6]([NH2:8])=[O:7])=[O:17]
Reactant: NC(=O)c1cc(N)c(Cl)c(N)c1
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Product: COCC(=O)Nc1cc(C(N)=O)cc(NC(=O)COC)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-3,5-diaminobenzamide (2.8 g) in pyridine (40 ml) is added dropwise methoxyacetyl chloride (3.0 ml) at room temperature. The mixture is stirred at room temperature for 3 hours, and thereafter, pyridine is distilled off under reduced pressure. To the residue is added water, and the resulting solid substance is separated by filtration and washed with water. The resulting crude crystals are recrystallized from ethanolethyl acetate-hexane to give the title compound (4.0 g) having the following physical properties.
Reaction SMILES: [SH:1][CH2:2][C:3]([NH2:5])=[O:4].[H-].[Na+].[NH2:8][CH2:9][C:10]1[N:11]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:12](=[O:27])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16](Br)=[CH:15][CH:14]=2>CN(C)C=O>[NH2:8][CH2:9][C:10]1[N:11]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:12](=[O:27])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16]([S:1][CH2:2][C:3]([NH2:5])=[O:4])=[CH:15][CH:14]=2
Reactant: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Reactant: NC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(SCC(N)=O)ccc2c1=O
Yield: 49.8 %

Procedure:
A solution (2 mL) of 2-mercaptoacetamide (0.27 g, 3.0 mmol) in N,N-dimethylformamide was ice-cooled under a nitrogen atmosphere and sodium hydride (0.12 g, 3.0 mmol) (60% in oil) was added thereto. The resulting mixture was stirred under ice-cooling for 30 min. To the obtained suspension was added 3-(aminomethyl)-6-bromo-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (1.06 g, 2.74 mmol), and the mixture was stirred at 80° C. for 24 h. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (50 mL), and the aqueous layer was extracted twice with ethyl acetate (50 mL). The extracts were combined and washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate (12 g) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0–10:1 (v/v)) and recrystallized from n-hexane-ethyl acetate (1:1) to give the title compound (0.54 g, 50%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12](O)([C:13]([O:15][CH3:16])=[O:14])[CH2:11][C:10]([CH2:18]O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O=S(Cl)[Cl:22]>CC#N>[Cl:22][CH2:18][C:10]1[CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1
Reactant: COC(=O)C1(O)CC(CO)=NN1c1ncccc1Cl
Reactant: O=S(Cl)Cl
Solvent: CC#N
Product: COC(=O)c1cc(CCl)nn1-c1ncccc1Cl
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Methyl 1-(3-chloropyridin-2-yl)-5-hydroxy-3-(hydroxymethyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (28.5 g, 0.1 mol) was dissolved in 100 ml of CH3CN and the solution was heated to 70° C. (26 g, 0.22 mol) of SOCl2 (0.12 mol) was slowly added dropwise at this temperature. The mixture was after-stirred for 1 hour at 70° C. and concentrated by evaporation in vacuo. This gave 27.6 g (92%) of the product as viscous oil with a purity of 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+:16].[Na+]>[Zn].O>[Na+:16].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Product: O=S([O-])c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 12 g zinc dust in 300 ml boiling water was added portion-wise 21.1 g p-chlorobenzene-sulphonylchloride. After stirring 1 hour at 90° C., the mixture was cooled down and excess Na2CO3 added. The water was evaporated off leaving a mixture of white powder and zinc compound. The powder was repeatedly extracted with methanol and the extract was evaporated off. Acetone was then added and the precipitate was filtered, washed with acetone and dried. Yield 18 g.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[N:10]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[N:10]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccc3ccccc3n2)c2ccc(C)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c(C(=O)O)cn2-c1ccc2ccccc2n1
Yield: 116.4 %

Procedure:
0.342 g (8.15 mmol) of lithium hydroxide monohydrate and 45 cm3 of water are added at 25° C. to 0.86 g (2.7 mmol) of 3-methoxycarbonyl-5-methyl-1-(quinol-2-yl)-1H-indole dissolved in 45 cm3 of tetrahydrofuran. After stirring at reflux for 19 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 cm3 of water and then triturated with 8.2 cm3 of N hydrochloric acid. After filtering off and drying the solid residue under reduced pressure (2.7 kPa) at 40° C., 0.95 g of 3-carboxy-5-methyl-1-(quinol-2-yl)-1H-indole is obtained in the form of a white solid. Mass spectrum (EI): m/e 302 (M+·).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]([C:18]2[C:19]3[CH:34]=[CH:33][CH:32]=[CH:31][C:20]=3[S:21][C:22]=2[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[O:17])=[CH:12][CH:11]=1>>[N:4]1([CH2:3][CH2:2][O:1][C:10]2[N:15]=[CH:14][C:13]([C:16]([C:18]3[C:19]4[CH:34]=[CH:33][CH:32]=[CH:31][C:20]=4[S:21][C:22]=3[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[O:17])=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: OCCN1CCCC1
Reactant: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(Cl)nc2)cc1
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OCCN3CCCC3)nc2)cc1
Temperature: 25 °C
Yield: 160.6 %

Procedure:
A solution of 0.50 mL (4.30 mmol) of 1-(2-hydroxyethyl)pyrrolidine in 10 mL of xylenes was treated with 50 mg (2.20 mmol) of Na. The mixture was heated to 50° C. until all the Na had disappeared, cooled to room temperature, and then treated with a solution of 420 mg (1.10 mmol) of 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 6-chloropyrid-3-yl ketone (Part A) in 5 mL of xylenes. The reaction was heated to 50° C. for 2 h and was evaporated in vacuo. The residue was partitioned between H2O (50 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were dried over K2CO3 and evaporated in vacuo to give 810 mg of a yellow solid. Purification by radial chromatography (SiO2; gradient of 1-5% MeOH in CH2Cl2) gave 525 mg (1.09 mmol; 99%) of the title compound as an amber oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[C:18]1([O:24][CH2:25][CH3:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.O.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:21]2[CH:22]=[CH:23][C:18]([O:24][CH2:25][CH3:26])=[CH:19][CH:20]=2)=[O:9])[CH:10]=1
Reactant: CCOc1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 66.6 %

Procedure:
N,N-Dimethylforamide (9 mL) was added to a suspension of 5-bromo-2-chlorobenzoic acid (1500 g, 6.41 mol) and oxalyl chloride (975 g, 7.69 mol) in a 5 L 4-necked flask containing dichloromethane (2.8 L) at room temperature. Once the vigorous evolution of gas ceased, the reaction was stirred for 10 h at room temperature. The reaction mixture was concentrated under vacuum to give a yellow residue. The residue was dissolved in dichloromethane (1.2 L) in a 5 L 4-necked flask equipped with an internal thermometer and a water condenser. The stirred mixture was cooled to −3° C. and phenetole (799 g, 6.54 mol) was added. Aluminum (III) chloride (973 g, 6.54 mol) was added to the above solution via a solid addition funnel over 1 h while maintaining the internal temperature below 4° C. After the addition was complete, the reaction mixture was stirred for 2 h at 5˜10° C. The reaction was poured into ice (10 kg). The mixture was further stirred at 4° C. for 1 h, diluted with water (3 L), transferred to a 50 L extraction funnel and extracted with dichloromethane (10 L×2). The combined organic layers were washed with 1 N HCl (7.5 L×2), water (10 L), 1N sodium hydroxide (7.5 L×2), brine (10 L×2), dried over sodium sulfate (1000 g), and concentrated. The residue was recrystallized in absolute ethanol (3.5 L) to give the title compound as a white solid (1.450 kg, yield 67%, HPLC purity>99%). 1H NMR (CDCl3, 400 MHz): δ 7.77 (d, J=9 Hz, 2H), 7.49-7.53 (m, 1H), 7.47 (d, J=2.1 Hz, 1H), 7.30 (d, J=9 Hz, 1H), 6.90 (d, J=9 Hz, 2H), 4.10 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[C:13](O)(=O)[CH3:14]>>[CH3:13][C:14]1[N:4]2[C:5]3[C:10]([CH:11]=[CH:12][C:3]2=[N:1][N:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: CC(=O)O
Reactant: NNc1ccc2ccccc2n1
Product: Cc1nnc2ccc3ccccc3n12

Procedure:
2-Hydrazinoquinoline (5.0 grams) was placed in a 250-milliliter three-necked flask equipped with a mechanical stirrer and a reflux condenser. To this flask was added 100 milliliters of acetic acid. The reaction mixture was refluxed for twelve hours, then allowed to cool; acetic acid was removed by evaporation. The solid which remained consisted of pure 1-methyl-s-triazolo(4,3-a)quinoline. The product was recrystallized from ethanol, m.p., 166°-7°C.
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.CC(OC)(C)C.[C:46]([OH:55])(=[O:54])[C@@H:47]([C@H:49]([C:51]([OH:53])=[O:52])[OH:50])[OH:48]>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:51]([C@@H:49]([C@H:47]([C:46]([O-:55])=[O:54])[OH:48])[OH:50])([O-:53])=[O:52]
Reactant: O=C(O)[C@H](O)[C@@H](O)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
Solvent: CCO
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Nilotinib base form A (4.00 g, 7.55 mmol) was mixed with ethanol absolute (40 mL, 10V) in a 250 mL reactor equipped with a mechanical stirrer and a reflux condenser to obtain a suspension. The suspension was heated to 80° C. and stirred at the same temperature for 30 min. To the suspension was added a solution of L-tartaric acid (1.25 g, 8.31 mmol, 1.1 mol eq) in ethanol absolute (10 mL, 2.5V) in one portion. The resulting mixture was stirred at 80° C. for 1 hour. Then the heating source was removed and the mixture was allowed to cool to room temperature. The stirring was continued at ambient temperature over a period of 6 h, during which time the mixture became viscous. To the viscous mixture was added another 80 mL ethanol. The mixture was then transferred to the refrigerator and was kept at about 5° C. for 5 days (in a closed vessel) A yellow precipitate formed and was isolated by vacuum filtration to give Nilotinib L-tartrate form IV as indicated by XRD (wet sample). The obtained Nilotinib L-tartrate form IV was dried in a vacuum oven (35 mmHg) at 60° C. for 16 h. The sample was then analyzed by PXRD using a Bruker X-Ray powder diffractometer model D8 and was found to be Nilotinib L-tartrate form IV (4.7 g).
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][N:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[N:21]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]3[CH:26]=[CH:27][C:28]([C:30]4[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=4)=[CH:29][C:19]=3[N:18]=2)=[N:9][C:8]([CH3:37])=[N:7]1)C>C(#N)C>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:28]2[CH:27]=[CH:26][C:20]3[N:21]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:17]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[C:10]4[N:6]([CH2:5][C:4]([OH:38])=[O:3])[N:7]=[C:8]([CH3:37])[N:9]=4)=[N:18][C:19]=3[CH:29]=2)=[CH:31][N:32]=1
Reactant: CCOC(=O)Cn1nc(C)nc1-c1ccccc1-c1nc2cc(-c3cnc(N)nc3)ccc2n1C(C)(C)C
Solvent: CC#N
Product: Cc1nc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n(CC(=O)O)n1
Reaction time: 3 h
Yield: 98.3 %

Procedure:
(5-{2-[5-(2-Amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-phenyl}-3-methyl-1,2,4-triazol-1-yl)-acetic acid ethyl ester (40 mg, 0.078 mmol) and Amberlyst A26 (OH− form) (450 mg, 0.6 mmol) are combined in acetonitrile (5 mL) and the mixture is agitated for 3 hours, filtered, and the isolate is washed with acetonitrile (2×5 mL). The product is purified by silica gel flash column chromatography eluting with 20% formic acid in acetonitrile (1 mL). The eluent is concentrated to afford the title compound (37 mg, 38%) LCMS (ESMS): m/z 483.2 (M++1)
Reaction SMILES: [Br:1]/[CH:2]=[CH:3]/[C:4](=[O:14])[C:5]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].[BH4-].[Na+]>CO>[Br:1]/[CH:2]=[CH:3]/[CH:4]([OH:14])[C:5]([CH3:6])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:13]
Reactant: CC(C)(C(=O)/C=C/Br)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(c1ccccc1)C(O)/C=C/Br
Temperature: 0 °C

Procedure:
An ice-cold solution of 7.8 g. of 1-bromo-4-methyl-4-phenyl-trans-1-penten-3-one in 100 ml. of methanol was treated with 1.4 g. of sodium borohydride and stirred at 0° for one hour. The solvent was evaporated and the residue was dissolved in water then extracted with ether. The ether extract was dried with MgSO4 and evaporated to afford 8.0 g. of the title product as a colorless oil, λmaxfilm 2.95, 3.4, 6.12, 6.20, 6.62, 6.88, 7.18, 7.28, 7.82, 9.30, 9.68, 10.00, 10.55, 12.95, 13.45 and 14.24 μ.
Reaction SMILES: [CH2:1]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[CH2:25][CH2:26][OH:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.[OH-].[Na+]>O1CCOCC1>[CH2:1]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[CH2:25][CH2:26][O:27][S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=1)(=[O:36])=[O:35])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCN1CCCCC1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCCN1CCCCC1CCOS(=O)(=O)c1ccc(C)cc1

Procedure:
1,4-Dioxane solution of 2-(1-octadecyl-2-piperidyl)ethan-1-ol and p-toluenesulfonyl chloride is added to sodium hydroxide solution and then the mixture is reacted at room temperature to obtain 1-octadecyl-2-[2-(tosyloxy)ethyl]piperidine.