Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([CH2:23]O)[CH:20]=[C:19]([CH2:25][CH2:26][CH3:27])[C:3]=1[O:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>ClCCl>[Br:48][CH2:23][C:21]1[CH:20]=[C:19]([CH2:25][CH2:26][CH3:27])[C:3]([O:4][CH:5]([C:10]2[CH:15]=[CH:14][C:13]3[O:16][CH2:17][O:18][C:12]=3[CH:11]=2)[C:6]([O:8][CH3:9])=[O:7])=[C:2]([Cl:1])[CH:22]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCCc1cc(CO)cc(Cl)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCc1cc(CBr)cc(Cl)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0°-5° C.), magnetically stirred solution of 0.445 g (1.13 mmol) of the product of step D and 0.446 g (1.70 mmol) of triphenylphosphine dissolved in 5 mL of dichloromethane was added 0.564 g (1.70 mmol) of carbon tetrabromide in several portions. After the addition was complete, the reaction was allowed to warm to room temperature and was stirred an additional 30 minutes. The methylene chloride was then removed in vacuo, and the residue was applied to a silica gel flash chromatography column and eluted with 10% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound which was used directly in the next step without further characterization.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13]C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1>[CH2:1]([O:8][CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)COCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(COCc1ccccc1)C(=O)O
Temperature: 65 °C

Procedure:
To a stirred solution of methyl 3-(benzyloxy)-2,2-dimethylpropanoate prepared according to Step A (952 mg, 4.28 mmol), in THF (11 mL) was added aqueous 1M NaOH (5.14 mL, 5.14 mmol). Little to no progress was seen at ambient temperature. Additional NaOH (˜7 mL, ˜7 mmol) was then added and the temperature was raised to 65° C., for 20 hours. After cooling to ambient temperature, the bulk of the THF was removed in vacuo. Aqueous 3M HCl (˜5 mL, ˜15 mmol) was then slowly added, resulting in the formation of a precipitate. This mixture was filtered through filter paper, and washed with a minimal amount of water. After placing under a strong vacuum for a few hours, the title compound was obtained. MS: m/z=231 (M+23 (Na+)).
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:33]C(=O)OC(C)(C)C)([CH2:8][N:9]2[C:18]3[C:13](=[C:14]([C:19]4[N:23]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH3:32])=[CH:26][CH:25]=5)[O:21][N:20]=4)[CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH2:4][O:3]1.CC1(C)OCC(NC(=O)OC(C)(C)C)(CN2C3C(=C(C4N=C(C5C=NC(CCC)=CC=5)ON=4)C=CC=3)CC2)CO1>>[NH2:33][C:5]([CH2:8][N:9]1[C:18]2[C:13](=[C:14]([C:19]3[N:23]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][CH3:32])=[CH:28][CH:29]=4)[O:21][N:20]=3)[CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: CCCc1ccc(-c2nc(-c3cccc4c3CCCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1
Agent: CCCc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cn1
Product: CCCc1ccc(-c2nc(-c3cccc4c3CCCN4CC(N)(CO)CO)no2)cc1
Yield: 45 %

Procedure:
When the product of Step E was substituted for tert-butyl 2,2-dimethyl-5-((4-(5-(6-propylpyridin-3-yl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-1,3-dioxan-5-ylcarbamate in Example 66 Step F, the identical process afforded the title compound in 45% yield, as colourless solid. 1H-NMR (CDCl3+CD3OD) 0.89 (tr, 3H, J=7.4 Hz); 1.55-1.68 (m, 2H); 1.88 (m, 2H); 2.61 (tr, 2H, J=7.4 Hz); 2.95-3.1 (m, 8H+H2O); 3.31 (m, 4H); 3.35-3.79 (m, 4H); 7.06-7.16 (m, 3H); 7.23-7.29 (m, 2H+CDCl3); 8.02 (d, 2H, J=8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:24](O)=[O:25])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:24](=[O:25])[NH:34][CH2:33][C:32]2[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[CH:12][N:11]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccc(CN)cc1
Reactant: COc1cc2c(C(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Product: COc1ccc(CNC(=O)c2cnc(CNC(=O)OC(C)(C)C)c3cc(OC)c(OC)cc23)cc1
Yield: 79 %

Procedure:
As described in example 1E, 80 mgs of 1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid was coupled with 4-methoxybenzylamine to give 84 mgs (79%) of [6,7-Dimethoxy-4-(4-methoxy-benzylcarbamoyl)-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester: 1H NMR (CDCl3) δ 1.50 (s, 9H), 2.78 (s, 2H), 3.18 (s, 1H), 3.77 (s, 2H), 4.02 (d, 4H, J=7.17 Hz), 4.15-4.33 (m, 1H), 4.42 (s, 1H), 4.87-4.90 (m, 1H), 6.10-6.22 (m, 1H), 6.93 (s, 0.6H), 7.06-7.12 (m, 1H), 7.16 (s, 0.4H), 7.27-7.42 (m, 4H), 7.50 (d, 1H, J=7.60 Hz), 8.32 (d, 1H, J=7.19 Hz); MS: APCI (M+H) calc'd for C26H31N3O6 482.2; found 482.0.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.C([Li])CCC.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1)[C:23](Cl)=[O:24]>C1COCC1>[CH3:30][O:29][C:27]1[CH:26]=[C:22]([C:23]([C:2]2[CH:12]=[CH:11][C:5]3[N:6]([CH3:10])[CH2:7][CH2:8][O:9][C:4]=3[CH:3]=2)=[O:24])[CH:21]=[C:20]([O:19][CH3:18])[CH:28]=1
Reactant: CN1CCOc2cc(Br)ccc21
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=O)c2ccc3c(c2)OCCN3C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.9 %

Procedure:
To a solution of 7-bromo-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine (0.9 g, 3.9 mmol) in THF (10 mL) was added n-butyllithium (1.3 mL, 2.5 N, 3.3 mmol) at −78° C. After 10 min, the solution was added to a solution of 3,5-dimethoxy-benzoyl chloride (650 mg, 3.2 mmol) in THF (10 mL) at −78° C. After 1 h, the cold bath was removed and the mixture was allowed to warm to room temperature. To the mixture was added iso-propanol (2 mL), water (30 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers was washed with sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and chromatography (Silica Gel) gave (3,5-dimethoxy-phenyl)-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-methanone as a yellow solid (320 mg, 30% yield): 1H NMR (CDCl3) δ 2.86 (s, 3H, CH3), 3.42 (t, J=5 Hz, 2H, CH2), 3.82 (s, 6H, 2CH3), 4.27 (t, J=4 Hz, 2H, CH2), 6.60-6.64 (m, 2H, Ar), 6.85 (d, J=2 Hz, 2H, Ar), 7.36 (d, J=8 Hz, 1H, Ar), 7.43 (dd, J=2, 9 Hz, 1H, Ar).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:3])=[O:2].S(Cl)([Cl:21])(=O)=O.O.CCOC(C)=O>C(OCC)C>[Cl:21][CH:11]([C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(Cl)C(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
To a solution of ethyl 3-(2-nitrophenyl)-3-oxopropanoate (2.0 g, 8.4 mmol) in diethyl ether (50 mL), was added sulfuryl chloride (1.37 g, 10 mmol) at 0° C., and the mixture was stirred for 3 h at rt. To the reaction mixture were added water (200 mL) and EtOAc (100 mL), and the mixture was stirred for 30 min. The organic layer was washed with brine (10 mL) and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (1.7 g, 75%) as colorless oil.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:9]=[CH:8][C:7]2[O:10][CH2:11][CH2:12][O:13][C:6]=2[CH:5]=1.C(=O)([O-])O.[Na+].[Cl-].[Na+].[N-:21]=[N+:22]=[N-:23].[Na+]>C(OCC)(=O)C.O.CN(C)C=O.ClCCl>[N:21]([CH2:3][C:4]1[N:9]=[CH:8][C:7]2[O:10][CH2:11][CH2:12][O:13][C:6]=2[CH:5]=1)=[N+:22]=[N-:23]
Reactant: ClCc1cc2c(cn1)OCCO2
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1cc2c(cn1)OCCO2
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 30 mL of a tetrahydrofuran solution containing 0.60 g of 2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethanol, 0.40 mL of thionyl chloride was added under cooling with ice, the mixture was stirred at the same temperature for 20 minutes, and the solvent was removed under reduced pressure. The residue thus obtained was added with tetrahydrofuran, and a solid substance was collected by filtration to obtain 0.75 g of a white solid, 7-(chloromethyl)-2,3-dihydro(1,4)dioxino(2,3-c)pyridine hydrochloride. (2) A solution of 5 mL of water containing 0.75 g of 7-(chloromethyl)-2,3-dihydro(1,4)dioxino(2,3-c)pyridine hydrochloride was adjusted to pH 7.8 with an aqueous saturated sodium hydrogen carbonate solution, thereto were added dichloromethane and sodium chloride, the organic layer was separated, and the solvent was removed under reduced pressure. The residue thus obtained was added with 30 mL of N,N-dimethylformamide, and then added with 0.26 g of sodium azide at room temperature, and the mixture was stirred at 40° C. for 2 hours. The reaction mixture was cooled to room temperature, and then water and ethyl acetate was added thereto, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, and the resultant solution was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.53 g of a yellow oily substance, 7-(azidomethyl)-2,3-dihydro-(1,4)dioxino(2,3-c)pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)O)[CH2:15][CH2:14]3)[S:10][N:9]=2)=[CH:4][CH:3]=1.CCN(S(F)(F)[F:36])CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]([F:36])[C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:15][CH2:14]3)[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(O)CN2CCN(c3nc(-c4ccc(Cl)cc4)ns3)CC2)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(F)CN2CCN(c3nc(-c4ccc(Cl)cc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-(3-(4-chlorophenyl)-1,2,4-thiadiazol-5-yl)piperazin-1-yl)-1-(4-methoxyphenyl)ethanol (30 mg, 69.6 μmol) and DAST (22.4 mg, 18.4 μl, 139 μmol) in 2 mL DCM at 0-5° C. was warmed to RT and stirred for 2 h. 10% aq. Na2CO3-solution was added and stirred for 10 min. The organic layer was separated and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with a gradient formed from heptane and EtOAc to yield, after evaporation of the product containing fraction, 24 mg (80%) of the title compound as light yellow solid. MS (m/e): 433.3 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]([CH2:8][OH:9])[CH2:4][C@H:3]1[CH2:10][O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[H-].[Na+].[CH3:20]I>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:20][O:9][CH2:8][CH:5]1[C:6](=[O:7])[N:2]([CH3:1])[C@H:3]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:4]1
Reactant: CN1C(=O)C(CO)C[C@H]1COc1cccnc1
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: COCC1C[C@@H](COc2cccnc2)N(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 327 mg (139 mmol) sample of 3-(1-methyl-4-hydroxymethyl-5-oxo-2(S)-pyrrolidinylmethoxy)pyridine, prepared as in Example 48a above, was dissolved in 13 mL of anhydrous THF, 111 mg (2.77 mmol) of NaH was added, and the mixture was stirred for 30 minutes at room temperature. To this solution was added 258 mL (4.17 mmol) of methyl iodide and 256 mg of tetrabutylammonium iodide, and the reaction was stirred at room temperature for 2 hours. The reaction was quenched by the addition of water, and the mixture was extracted with chloroform. The extract was dried over MgSO4, filtered and concentrated. The solvent was removed, and the residue was purified by column chromatography on silica gel, eluting with 10:1 chloroform:methanol to give 314 mg of the title compound. MS (DCI/NH3) m/e: 251 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.37-8.25 (m, 2H), 7.35-7.25 (m, 2H), 4.18-4.0 (m, 2H), 3.99-3.84 (m, 1H), 3.73-3.58 (m, 2H), 3.37 (s, 2H), 3.36 (s, 1H), 3.05 (s, 1H), 2.95 (s, 1H), 2.94 (s, 1H), 2.90-2.63 (m, 1H), 2.49-2.24 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH2:17])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH3:24][N:25]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:17][CH2:16][C:6]1[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:8][C:9]2[C:4]([C:5]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:3][C:2]([C:24]#[N:25])=[CH:11][CH:10]=2
Reactant: CC(C)Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1CN
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)Cc1nc2ccc(C#N)cc2c(-c2ccccc2)c1CN
Temperature: 80 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
A solution of (6-bromo-2-isobutyl-4-phenylquinolin-3-yl)methylamine (0.20 g, 0.54 mmol) in N-methylpyrrolidone (8 ml) was stirred under a nitrogen atmosphere at 80° C. for 15 min. To the reaction mixture were added zinc cyanide (0.038 g, 0.32 mmol) and tetrakis(triphenylphosphine)palladium (0.032 g, 0.027 mmol), and the mixture was further stirred under a nitrogen atmosphere at 80° C. for 1 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and 28% aqueous ammonia (6 ml)-saturated aqueous ammonium chloride solution (22 ml)-water (22 ml). The organic layer was washed twice with 28% aqueous ammonia (6 ml)-saturated aqueous ammonium chloride solution (22 ml)-water (22 ml) and then with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by preparative HPLC and the objective fractions were combined and concentrated under reduced pressure. The residue was alkalified with saturated aqueous sodium hydrogen carbonate (50 ml) and extracted twice with ethyl acetate (50 ml). The organic layers were combined, washed with saturated brine (20 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was crystallized from n-hexane-ethyl acetate to give the title compound (0.032 g, yield 19%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]([C:18](=O)[CH3:19])[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1.N.C([BH3-])#[N:25].[Na+]>CO.C(O)(=O)C>[NH2:25][CH:18]([CH3:19])[CH:7]([CH2:6][C:5]1[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)C(=O)OCc1ccccc1
Reactant: [BH3-]C#N
Agent: N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(N)C(Cc1ccc(Cl)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Benzyl 2-(4-chlorobenzyl)-3-ketobutyrate (317 mg, 1 mmole, obtained from Step A) was added to a cooled mixture of 7M ammonia in MeOH (2.42 mL) and glacial acetic acid (1.6 mL). To this solution, at ˜10° C., was added sodium cyanoborohydride (101 mg, 1.75 mmol) in small portions. This mixture was stirred at room temperature for 40 h. The excess sodium cyanoborohydride was destroyed by the addition of 6M HCl (to pH 1). The residue obtained after removal of volatiles was taken up in a minimal amount of water and extracted with ether. The aqueous layer was basified to pH 10 using solid KOH. This layer was then saturated with sodium chloride and then extracted with EtOAc. Further analyses of the ether and the EtOAc layers suggest that the desired product resides the EtOAc layer. This material was used in the ensuing coupling reactions without further purification. Proton NMR spectrum show that the two pairs of diastereomers are obtained in ˜1:1 ratio, homogeneous by TLC, Rf=0.4 in 95:5 CH2Cl2:MeOH. LC/MS m/e=318 (M+1). 400 MHz 1H NMR (CDCl3) δ 1.27, 1.29 (2 d, J=7 Hz, 3H), 2.85 (m, 1H), 3.03 (m, 1H), 3.15 (m, 1H), 3.55 (m, 1H), 4.85 (br, 2H), 5.00-5.18 (m, 2H), 7.0-7.2 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][N:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1.N1C=CC=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:9][C:10]3[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)=[CH:14][CH:13]=[CH:12][N:11]=3)[CH:4]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: Cc1ccc(N)cc1Nc1ncccc1-c1ccncn1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cc1Nc1ncccc1-c1ccncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methyl-N3-(3-pyrimidin-4-yl-pyridin-2-yl)-benzene-1,3-diamine (40 mg, 0.14 mmol) in CH2Cl2 (2.5 mL) was added pyridine (0.012 mL, 0.14 mmol) and 4-chlorobenzenesulfonyl chloride (30 mg, 0.14 mmol). The mixture was stirred overnight at RT, concentrated and purified by flash chromatography (0→50% EtOAc/n-Hexanes) to yield 4-chloro-N-(4-methyl-3-((3-(4-pyrimidinyl)-2-pyridinyl)amino)phenyl)benzenesulfonamide. MS m/z=452 [M+1]+. Calc'd for C22H18ClN5O2S: 451.94.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:29])[C:12]3[CH:26]=[C:25]([CH2:27]Cl)[S:24][C:13]=3[N:14]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.Cl.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]1[C@H:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[OH:40]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:29])[C:12]3[CH:26]=[C:25]([CH2:27][N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[C@@H:39]([OH:40])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[S:24][C:13]=3[N:14]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:15]=2)=[O:9])=[CH:30][CH:31]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn(CCN2CCOCC2)c2sc(CCl)cc2c1=O
Reactant: O[C@@H](c1ccccc1)[C@H]1COCCN1
Agent: Cl
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCN2CCOCC2)c2sc(CN3CCOC[C@@H]3[C@@H](O)c3ccccc3)cc2c1=O

Procedure:
Analogous to the procedures described in Example 15, N-(4-chlorobenzyl)-2-(chloromethyl)-7-(2-morpholin-4-ylethyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Preparation 23) is treated with (S)-(3R)-morpholin-3-yl(phenyl)methanol hydrochloride (Preparation 9) to afford the title compound.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16](N)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=O)CCC.N([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=O>[Cu](Cl)Cl.[Cl-].[NH4+]>[C:28]([O:27][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:18]=2)[CH2:12][CH2:13]1)=[O:5])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)ON=O
Reactant: CCCCOC(=O)N1CCC(c2cc(C(=O)OCC)c(N)s2)CC1
Agent: Cl[Cu]Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CCOC(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
4-(5-Amino-4-ethoxycarbonyl-thiophen-2-yl)-piperidine-1-carboxylic acid butyl ester (13.4 g, 38 mmol) was added to t-butyl nitrite (56.4 mmol) and copper(II)chloride (38 mmol) in IMS (500 mL). The reaction was stirred for 1 hour then saturated aqueous ammonium chloride (70 mL) was added and the resulting mixture stirred for a further 15 minutes. The solution was filtered and the filtrate was evaporated under vacuum. The residue was then partitioned between DCM and water. The organic layer was separated and dried over magnesium sulphate, filtered and the solvent evaporated. The product was purified by column chromatography on silica, eluting with 0%-40% ethyl acetate in cyclohexane to give a clear oil (11.7 g). 1H NMR (400 MHz, CHCl3-d): δ 7.9 (s, 1H), 7.2 (s, 1H), 4.3 (q, 2H), 4.2 (m, 2H), 2.9-2.7 (m, 3H), 2.0 (m, 2H), 1.7 (m, 2H), 1.5 (s, 9H), 1.4 (t, 3H).
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.[CH3:24][C:25]1[N:26]=[CH:27][N:28]([C:30]2[CH:31]=[C:32]([NH2:40])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=2)[CH:29]=1.C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C>C(OCC)(=O)C.O.CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:40][C:32]2[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=[C:30]([N:28]3[CH:27]=[N:26][C:25]([CH3:24])=[CH:29]3)[CH:31]=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: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid (55 gm), 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzenamine (45 gm), diethylcyanophosphonate (63 ml), triethylamine (78 ml) and N,N-dimethylformamide (1100 ml) were added at room temperature. The contents were heated to 60° C. and maintained for 13 hours at 60° C. The reaction mass was then cooled to room temperature and quenched with sodium bicarbonate solution (8%) and ethyl acetate. Then the layers were separated and ethyl acetate layer washed with sodium chloride solution. The separated ethyl acetate layer was then concentrated to obtain a residual solid. To the residual solid was added water (500 ml) and stirred for 30 minutes at room temperature. The separated solid was filtered and dried to obtain a solid. To the solid was added to teterahydrofuran (900 ml) and stirred for 30 minutes at 50 to 55° C. The teterahydrofuran solvent was distilled off under vacuum to obtain a residual solid. To the residual solid was added ethyl acetate (900 ml) and stirred for 1 hour at room temperature. The solid obtained was collected by filtration and dried to obtain 54 gm of nilotinib.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([OH:19])[CH:6]=1)[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29]O)[CH:25]=[CH:26][CH:27]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([O:19][CH2:29][CH2:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)c(O)c1
Reactant: OCCc1cccc(Cl)c1
Product: CCOC(=O)c1ccc(OCc2ccccc2)c(OCCc2cccc(Cl)c2)c1

Procedure:
The compound of step 3 was coupled to 2-(3-chloro-phenyl)-ethanol in analogy to step 1 of example 1 to yield the title compound.