Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:15][CH3:16])[CH:10]([OH:14])[C:11]([OH:13])=O)=O)(C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O[NH:32][C:33](=[NH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN1CCOCC1.C1C2C(C3ON=C(N)N=3)CN(C2)C1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:15][CH3:16])[C:10]([C:11]1[O:13][N:40]=[C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:32]=1)=[O:14]
Reactant: N=C(NO)c1ccccc1
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C(=O)O
Agent: Nc1noc(C2CN3CCC2C3)n1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC[C@H](N)C(=O)c1nc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (500 mg, 2.14 mmol) was combined with EDC (600 mg, 3.14 mmol), HOBt (600 mg, 3.92 mmol), and N-hydroxy-benzamidine (292 mg, 2.14 mmol). Dichloromethyl (10 mL) was added and then 4-methylmorpholine (1 mL). The mixture was stirred at ambient temperature for 16 hours. After dilution with ethyl acetate (200 mL), the solution was washed with water (30 mL), saturated aqueous NaHCO3 solution and brine, dried with MgSO4 and evaporated under vacuum. The crude product was dissolved in pyridine (10 mL) and heated at 80° C. for 15 hours. The pyridine was evaporated under vacuum and the residue was purified by flash chromatography on silica gel (eluent: ethyl acetate) to yield 290 mg (0.83 mmol). The oxadiazole (145 mg, 0.41 mmol) was dissolved in CH2Cl2 (4 mL) and TFA (4 mL) was added. After stirring for 1 hour, the mixture was evaporated to dryness to yield (S)-2-Amino-1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14]>C1COCC1>[OH:14][CH:13]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccccn2)CC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 33.5 %

Procedure:
Placed 2-bromopyridine (0.833 g, 5.27 mmol) in THF (25 mL) and cooled to −78° C. Butyllithium (2.11 mL, 5.27 mmol) was slowly added and stirred for 5 minutes. Dissolved tert-butyl 4-formylpiperidine-1-carboxylate (0.500 g, 2.34 mmol) in THF (3 mL) and added slowly to the above solution then stirred at −78° C. for 30 minutes. Added ammonium chloride and extracted with CH2Cl2. Concentrated and purified by silica gel to give the title compound (0.229 g, 33.4% yield)
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12](Cl)[C:13]([C:16]#[N:17])=[N:14][CH:15]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:21][C:22]1[CH:23]=[CH:24][C:25](B2OC(C)(C)C(C)(C)O2)=[C:26]([NH:28]C(=O)OC(C)(C)C)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C(O)C.O>[NH2:17][C:16]1[C:13]2[N:14]=[CH:15][C:10]([CH2:9][CH2:8][C:7]3[CH:19]=[CH:20][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=3)=[CH:11][C:12]=2[C:25]2[CH:24]=[CH:23][C:22]([CH3:21])=[CH:27][C:26]=2[N:28]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Reactant: CC(=O)c1ccc(CCc2cnc(C#N)c(Cl)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Temperature: 25 °C

Procedure:
To a solution of 5-(4-acetylphenethyl)-3-chloropicolinonitrile (from the previous step) (1 eq) and tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (10 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (1:1, 0.09 M) was heated under microwave condition using a BIOTAGE INITIATOR 2.0 at 150° C. for 20 minutes. After cooling to ambient temperature, the reaction mixture was diluted with ethanol/water. The insoluble solids were filtered off, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone as a yellow solid. 1H NMR (Methanol-d4) TFA Salt: δ 8.69 (d, 2H), 8.30 (d, 1H), 7.80 (d, 2H), 7.38 (s, 1H), 7.36 (d, 1H), 7.28 (d, 2H), 3.25 (t, 2H), 3.13 (t, 2H), 2.47 (s, 3H), 2.45 (s, 3H). LRMS [M+H]=356.2
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)[C:7]([CH3:17])=[C:6]1[CH3:18].[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[C:32]([C:2]2[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=2[CH2:4][N:5]2[C:13]3[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=3)[C:7]([CH3:17])=[C:6]2[CH3:18])[CH:31]=[CH:30][CH:29]=1)=[O:27])[CH3:24]
Reactant: Cc1c(C)n(Cc2ccccc2Br)c2ccc(C(=O)O)cc12
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Product: CCOC(=O)c1cccc(-c2ccccc2Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 38, using 1-(2-bromobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the (S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide and the (3-(ethoxycarbonyl)phenyl)boronic acid instead of the phenylboronic acid. ESI-MS (m/z): 428 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][C:9]([C:15]#[N:16])=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[OH-].[K+].[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>C1COCC1.O>[O:1]=[C:2]1[C:14]2[N:13]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:12]3[C:7](=[CH:8][C:9]([C:15]#[N:16])=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CCCC3=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c3c(c4cc(C#N)ccc42)CCCC3=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.4 %

Procedure:
To a solution of 1-oxo-2,3,4,9-tetrahydro-1H-carbazole-6-carbonitrile (intermediate 2a) (0.20 g, 0.95 mmol) in THF (2.0 mL), KOH (0.27 g, 4.8 mmol) in water was added followed by TsCl (0.27 g, 1.4 mmol). The reaction mixture was stirred at room temperature for 12 h and then extracted with EtOAc (3×15 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude compound which was purified by column chromatography [EtOAc-hexane (1:4) as eluant] to obtain the title compound as an off-white solid (0.23 g, 65%). 1H NMR (200 MHz, CDCl3, δ in ppm) 8.0 (d, J=8.4 Hz, 2H), 7.82 (d, J=2.0 Hz, 1H), 7.43 (dd, J=12.0, 2.0 Hz, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.30 (d, J=12.5 Hz, 1H), 2.95 (t, J=9.0 Hz, 2H), 2.66 (t, J=9.0 Hz, 2H), 2.40 (s, 3H), 2.30 (m, 2H).
Reaction SMILES: [CH2:1]([CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)#[N:15]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[CH2:1]([CH:9]1[CH2:10][O:11][CH:20]([C:19]2[CH:22]=[CH:23][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)[O:13][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCCCCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCC1COC(c2ccc(C#N)cc2)OC1
Yield: 72.9 %

Procedure:
In a 500-ml egg-plant type flask were put 32.3 g of 2-octyl-1,3-propanediol, 22.5 g of p-cyanobenzaldehyde, 0.11 g of p-toluenesulfonic acid monohydrate and 300 ml of benzene, and the mixture was heated. The generated water was removed by azeotropy with benzene. Then, benzene was distilled away, and the residue was neutralized with aqueous saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the extract was washed with water and then dried over anhydrous sodium sulfate. Dichloromethane was distilled away to give a solid which was then recrystallized from isooctane to give 37.7 g of colorless crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=[CH:25][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.[CH3:38][NH:39][CH3:40]>>[CH3:38][N:39]([CH3:40])[C:26]([C:23]1[CH:24]=[CH:25][C:19]2[CH:18]=[C:17]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:30])[C:2]([CH3:32])([CH3:31])[CH3:1])=[C:7]([CH3:29])[CH:8]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])[S:21][C:20]=2[CH:22]=1)=[O:27]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)O)cc2s1
Reactant: CNC
Agent: Cl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)N(C)C)cc2s1
Yield: 75.4 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-6-carboxylic acid (175 mg, 0.387 mmol), DIMAP (142 mg, 1.16 mmol), EDC (111 mg, 0.580 mmol), and dimethylamine hydrochloride (47 mg, 0.580 mmol) are reacted analogous to Example 3 to afford the title compound (140 mg, 76%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22](Cl)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=1)CCC>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22]([C:32]4[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=4)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Product: Cn1cncc1-c1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1

Procedure:
Prepared according to Procedure B from 4-(4-benzyloxyanilino)-6-chloropyrido[3,4-d]pyrimidine and 5-(tri-n-butylstannyl)-N-methylimidazole (prepared according to the published method: Acta Chem. Scand., (1993), 47(1), 57); δH [2H6]-DMSO 10.00 (1H,s), 9.15 (1H,s), 8.65 (1H,s), 8.60 (1H, s), 7.80 (1H,s), 7.61(2H,d), 7.50 (1H,s), 7.25-7.49 (5H,m), 7.10 (2H,d), 5.13 (2H,s), 3.98 (3H,s); m/z (M+1)+409.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: OB(O)c1cc(F)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1ccc(F)c(-c2cc(F)ccc2F)n1
Yield: 80 %

Procedure:
Method 1 was followed using 6-bromo-5-fluoropicolinic acid (1.0 equiv.) and 2,5-difluorophenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give 6-(2,5-difluorophenyl)-5-fluoropicolinic acid in 80% yield. LC/MS=254.1 (M+H), Rt=0.74 min.
Reaction SMILES: C[Al](C)C.CCCCCC.Cl.[CH3:12][NH:13][CH3:14].[C:15]([C:17]1[C:22]2[N:23]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[O:25][C:21]=2[C:20]([CH2:29][C:30]([O:32]C)=O)=[C:19]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:18]=1[CH3:40])#[N:16].Cl>C1(C)C=CC=CC=1>[C:15]([C:17]1[C:22]2[N:23]=[C:24]([CH:26]3[CH2:27][CH2:28]3)[O:25][C:21]=2[C:20]([CH2:29][C:30]([N:13]([CH3:14])[CH3:12])=[O:32])=[C:19]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:18]=1[CH3:40])#[N:16]
Reactant: CNC
Reactant: COC(=O)Cc1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1c(-c2ccccc2)c(CC(=O)N(C)C)c2oc(C3CC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
At room temperature, trimethylaluminium/n-hexane solution (1.03 mol/l) (547 μl, 0.563 mmol) was added to a toluene (2 ml) suspension of dimethylamine hydrochloride (38.3 mg, 0.469 mmol), followed by stirring at room temperature for 30 minutes. Methyl (4-cyano-2-cyclopropyl-5-methyl-6-phenyl-1,3-benzoxazol-7-yl)acetate (I-295) (65.0 mg, 0.188 mmol) was added to the reaction liquid, followed by heating under reflux in an oil bath at 120° C. for 15 hours. With cooling with ice, 1 N hydrochloric acid was added to the reaction liquid. After extraction with ethyl acetate, the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, then the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v) to obtain the entitled compound (56.0 mg, 83%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH2:7].[C:17]([O:21][C:22]([N:24]1[CH2:30][CH2:29][CH2:28][C:27](=O)[C:26]2[CH:32]=[C:33]([C:36]([F:39])([F:38])[F:37])[CH:34]=[CH:35][C:25]1=2)=[O:23])([CH3:20])([CH3:19])[CH3:18].[BH4-].[Na+]>CO.O.C(OCC)(=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:17]([O:21][C:22]([N:24]1[CH2:30][CH2:29][CH2:28][CH:27]([NH:7][CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:15])([F:16])[F:1])[CH:10]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:8]=2)[C:26]2[CH:32]=[C:33]([C:36]([F:39])([F:37])[F:38])[CH:34]=[CH:35][C:25]1=2)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)c2cc(C(F)(F)F)ccc21
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (0.1 g, 0.4 mmol) followed by titanium isopropoxide (1.0 mL) to 5-Oxo-7-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.13 g, 0.4 mmol) and stir at room temperature overnight. Dilute the mixture with 5 mL of Methanol and add sodium borohydride (0.8 mmol). Stir the suspension at room temperature for 30 min then dilute with water (20 mL) and ethyl acetate (20 mL). Filter the resulting emulsion through celite and wash with ethyl acetate (3×20 mL). Separate the organics, dry over sodium sulfate, and filter. Remove the solvent under vacuum to afford (+/−)-t-butyl-5-(3,5-bistrifluoromethylbenzylamino)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate crude (0.2 g, MS (ES+): 557 (M+H)). Without further purification, add acetyl chloride (0.8 mmol) and pyridine (0.8 mmol) to a solution of (+/−)-t-butyl-5-(3,5-bistrifluoromethylbenzylamino)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate in dichloromethane. After stirring for 2 h remove solvent under vacuum and chromatograph over silica gel using ethyl acetate/hexane (5-40%) to elute. This affords the title compound as an oil (0.2 g, 83%) which foams under vacuum: MS (ES−): 597 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[CH:10]=[N:11][N:12]([CH:19]([CH3:21])[CH3:20])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH3:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:23][C:24]2[CH:25]=[C:26]([CH3:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=2)[C:9]2[CH:10]=[N:11][N:12]([CH:19]([CH3:21])[CH3:20])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)cnn1C(C)C
Reactant: Cc1cc(N)cn(C)c1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(Nc2cc(C)c(=O)n(C)c2)c2ccc(Cl)cc2)cnn1C(C)C

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-isopropyl-1H-pyrazole-5-carboxylate (Step 36.3) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.94 min (HPLC 1); tR: 1.14 min (LC-MS 2); ESI-MS: 443 [M+H]+ (LC-MS 2); Rf=0.23 (EtOAc).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:14][N:13]=1.S(Cl)(Cl)=O.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([NH2:42])[CH:33]=[C:34]([N:36]2[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]2)[CH:35]=1.[OH-].[Na+]>CN1CCCC1=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:42][C:32]2[CH:31]=[C:30]([C:29]([F:44])([F:43])[F:28])[CH:35]=[C:34]([N:36]3[CH:37]=[N:38][C:39]([CH3:41])=[CH:40]3)[CH:33]=2)=[O:8])=[CH:4][C:3]=1[NH:11][C:12]1[N:13]=[CH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)[N:17]=1
Reactant: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2cccnc2)n1
Reactant: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CN1CCCC1=O
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Temperature: 60 °C
Yield: 90.2 %

Procedure:
To a 1 liter reactor was fed 40 g of 4-methyl-3-(4-(pyridine-3-yl)pyrimidin-2-ylamino)benzoic acid (0.13 mol), 200 ml of N-methyl pyrrolidone (NMP) (5V) and 13 ml of thionyl chloride (0.18 mol). The reactor was heated to 60° C. and maintained at 60° C. for 1.5 hr. After 1.5 hr of heating, 31.5 g of 3-(trifluoromethyl)-5-(4-methyl-1H-imidazol-1-yl)benzenamine (0.13 mol) was fed into the reactor. The reactor was then heated to 90° C., and maintained for 30 minutes at this temperature. Then 200 ml (5V) of water was added. The resulting mixture was maintained for 2 hours at 90° C. Then, an additional 240 ml (6V) of N-methyl pyrrolidone was added, followed by 26.5 ml of sodium hydroxide (47% aqueous) to raise the pH to 6.5-7. The reactor was then cooled to 40° C. and maintained for 3 hours. The mixture was then filtered and the filter cake was washed with ethanol and water. The washed material was then dried in a vacuum tray oven overnight to provide dry Nilotinib base (62.1 g, Yield 90%)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])=[CH:28][CH:29]=4)[CH2:24][CH2:23]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)C(=O)Nc1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)C(=O)Nc1ccc2c(c1)CCN2c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cn1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate 6) and N-(indolin-5-yl)isobutyramide (intermediate 50) (0.017 g, 14%).
Reaction SMILES: [Si]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[S:18])[CH3:16])[N:13]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[C:12]1=[O:34])[CH3:10])(C(C)(C)C)(C)C.B(F)(F)F>C(Cl)Cl>[OH:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[S:18])[CH3:16])[N:13]([CH2:26][C:27]([OH:29])=[O:28])[C:12]1=[O:34])[CH3:10]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(CC(=O)OC(C)(C)C)[C@@H]1[C@@H](C)C(=S)c1ccc(Cl)cc1
Agent: FB(F)F
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N(CC(=O)O)[C@@H]1[C@@H](C)C(=S)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1-p-chlorophenylthiocarbonylethyl]-1-(t-butyloxycarbonylmethyl)azetidin-2-one (200 mg) in dry methylene chloride (1.5 ml), there was added BF3 -ET2O complex (263 mg), followed by stirring at room temperature for 1 hour. After evaporation of the solvent, the residue was dissolved in methanol (0.5 ml), diluted with brine and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated to give (3S,4S)-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-p-chlorophenylthiocarbonylethyl]-1-(carboxymethyl)azetidin-2-one as a crude product. The crude product, t-butyldimethylsilyl chloride (246 mg) and imidazole (151 mg) were dissolved in dry dimethylformamide (2.5 ml) and allowed to stand at room temperature overnight. The reaction mixture was poured into cold brine, adjusted with 1M potassium hydrogensulfate to pH 2 and extracted with diethyl ether three times. The organic layer was washed with brine two times, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography to give (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1-p-chlorophenylthiocarbonylethyl]-1-(carboxymethyl)azetidin-2-one.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C@@H:12]([C:13]#[C:14][CH3:15])[CH2:11][CH2:10][C@H:6]1[C:7]([NH2:9])=O)=[O:4].N1C=CN=C1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:5]1[C@@H:12]([C:13]#[C:14][CH3:15])[CH2:11][CH2:10][C@H:6]1[C:7]#[N:9])=[O:4]
Reactant: CC#C[C@H]1CC[C@@H](C(N)=O)N1C(=O)CCl
Agent: c1c[nH]cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reaction time: 1 h

Procedure:
To a stirred solution of (5R)-1-(chloroacetyl)-5-propynyl-L-prolinamide (0.28 g, 1.23 mmol) and imidazole (0.084 g, 1.23 mmol) in dry pyridine (6 mL) at −35° C. under nitrogen was added POCl3 (0.23 mL, 2.46 mmol) dropwise. The reaction mixture was stirred between −35° C. to −15° C. for 1 hour and evaporated. The residue was diluted with dichloromethane and washed with H2O (2×), dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash chromatography (10% ethyl acetate/hexane) provided the titled compound. MS (DCI) m/z 211 (M+H)+.