Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:20]([CH2:26][O:27][CH2:28][CH3:29])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CC2C3N(CC(C)C)C(CCC)=NC=3C=[N:45]C=2C=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:20]([CH2:26][O:27][CH2:28][CH3:29])=[N:19][C:14]=3[C:15]([NH2:45])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Reactant: CCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)C

Procedure:
The general methods described in Parts H and I of Example 1 were followed using 7-benzyloxy-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (29.2 g, 78.2 mmol) in lieu of 7-benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinoline. The crude product was triturated with acetonitrile, isolated by filtration, and dried for 18 hours in a vacuum oven at 68° C. to provide 16.3 g of 7-benzyloxy-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 201.0-203.0° C.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].C(N(CC)CC)C.[N+:14](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-:15]>FC(F)(F)S([O-])(=O)=O.[Zn+2].FC(F)(F)S([O-])(=O)=O.O>[OH:6][C:2]([C:4]1[NH:15][N:14]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=1)([CH3:3])[CH3:1]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C#CC(C)(C)O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C(C)(C)O)[nH]n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
Zinc trifluoromethanesulfonate (2.378 mmol, 0.864 g), 2-methyl-3-butyn-2-ol (11.89 mmol, 1 g) and triethylamine (17.83 mmol, 1.804 g) were added into a flask under nitrogen atmosphere. Ethyl diazoacetate (14.27 mmol, 1.628 g) was added slowly and the temperature was carefully raised to 100° C. and stirred for 8 h. Water was added and the mixture was extracted twice with DCM. The combined DCM phases were dried, filtered and evaporated. The crude product was purified by flash chromatography. 0.658 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.28 (t, 3H), 1.45 (s, 6H), 4.24 (q, 2H), 5.34 (s, 1H), 6.52 (s, 1H), 13.22 (bs, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][NH2:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].CS([C:17]1[O:18][C:19]2[CH:25]=[C:24]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH:35][CH3:36])=[O:34])[CH:28]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1)=O>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][NH:13][C:17]2[O:18][C:19]3[CH:25]=[C:24]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33](=[O:34])[NH:35][CH3:36])[CH:28]=4)[CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)oc3c2)ccn1
Reactant: CCOC(=O)C1(CN)CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)C1(CNc2nc3ccc(Oc4ccnc(C(=O)NC)c4)cc3o2)CCCCC1
Reaction time: 2 h

Procedure:
To a solution of 1-aminomethyl-cyclohexanecarboxylic acid ethyl ester in THF was added 4-(2-methanesulfinyl-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide from Step 3 of Example 2. After reacting at room temperature for 2 hours the solvent was removed and the crude product was diluted with ethyl acetate and some dichloromethane, then washed three times with brine, dried with anhydrous sodium sulfate, filtered and concentrated. The final product was purified by reverse phase preparatory HPLC. MH+=453.1.
Reaction SMILES: [C:1]([N:5]1[C:23](=[O:24])[N:8]2[CH:9]=[C:10]([C:17](C)([CH3:21])[C:18](O)=O)[N:11]=[C:12]([NH:13][CH:14]([CH3:16])[CH3:15])[C:7]2=[N:6]1)([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([N:5]1[C:23](=[O:24])[N:8]2[CH:9]=[C:10]([CH:17]([CH3:21])[CH3:18])[N:11]=[C:12]([NH:13][CH:14]([CH3:15])[CH3:16])[C:7]2=[N:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)Nc1nc(C(C)(C)C(=O)O)cn2c(=O)n(C(C)(C)C)nc12
Solvent: CC(=O)O
Product: CC(C)Nc1nc(C(C)C)cn2c(=O)n(C(C)(C)C)nc12

Procedure:
A solution of 300 mg of the product of Step A in AcOH (5.0 mL) was heated at reflux for two h. The solvent was removed to afford 2-tert-butyl-6-isopropyl-8-isopropylamino-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one as a light green solid. A suspension of 240 mg of this product and 329 mg of aluminum trichloride in dichloroethane (10.0 mL) was heated at reflux for two h. The reaction was poured into water and the resulting solution was extracted with EtOAc. The organic extract was dried over magnesium sulfate, filtered, and concentrated and the residue was purified by silica gel chromatography to afford the title compound as an off-white solid. MS (M+H+)=234.1.
Reaction SMILES: [CH3:1][N:2](CC1C=CC=CC=1)[C@@H:3]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C@H:4]1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>CO.[Pd]>[CH3:1][NH:2][C@@H:3]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C@H:4]1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CN(Cc1ccccc1)[C@@H]1CCCc2ccccc2[C@H]1N1CCCC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN[C@@H]1CCCc2ccccc2[C@H]1N1CCCC1
Yield: 99.2 %

Procedure:
A solution of 2 g of the product of Step B in 40 ml of methanol and 2.6 ml of 22 Be° hydrochloric acid was hydrogenated with 1.25 g of palladium under 1800 mmbars for 45 minutes. The mixture was filtered, rinsed with methanol and concentrated under reduced pressure at 50° C. The residue was dissolved in 10 ml of water which was alkalized with 2.6 ml of sodium hydroxide solution, and extracted with methylene chloride. The extracts were washed with water, dried, filtered and concentrated under reduced pressure to obtain 1.45 g of yellow oil which was dissolved in isopropyl ether. The insoluble substance was filtered and the residue was treated with active charcoal, filtered and concentrated to dryness under reduced pressure at 50° C. to obtain 1.24 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@H:12]([CH2:17][NH2:18])[CH2:11]2)=[CH:4][CH:3]=1.C1([O:25][C:26](=O)[NH:27][C:28]2[CH:33]=[C:32]([C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)[CH:31]=[C:30]([CH2:40][CH3:41])[CH:29]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH2:40]([C:30]1[CH:29]=[C:28]([NH:27][C:26]([NH:18][CH2:17][C@H:12]2[C@H:13]([CH3:16])[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:11]2)=[O:25])[CH:33]=[C:32]([C:34]2[N:38]([CH3:39])[N:37]=[N:36][N:35]=2)[CH:31]=1)[CH3:41]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Reactant: C[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(NC(=O)NC[C@@H]2CN(CCc3ccc(F)cc3)CC[C@H]2C)cc(-c2nnnn2C)c1
Reaction time: 23 h
Yield: 86.1 %

Procedure:
A solution of trans-1-[2-(4-fluorophenyl)ethyl]-4-methyl-piperidin-3-ylmethylamine (12 mg, 46 μmol) and [3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-carbamic acid phenyl ester (15 mg, 46 μmol) in N,N-dimethylformamide (0.5 mL) was treated with triethylamine (13 μL, 93 μmol). After 23 hours, the mixture was concentrated under vacuum. The residue was purified by flash chromatography, eluting with 3% methanol in dichloromethane containing 0.3% aqueous ammonium hydroxide, provided an amorphous solid (19 mg, 86%). 1H NMR (300 MHz, CDCl3) δ7.71 (s, 1H), 7.64 (s, 1H), 7.11 (m, 3H), 6.91 (t, J=9 Hz, 2H), 4.17 (s, 3H), 3.6-3.3 (m, 3H), 3.2-2.9 (m, 6H), 2.66 (q, J=7 Hz, 2H), 2.50 (m, 1H), 1.9-1.7 (m, 3H), 1.42 (m, 1H), 1.24 (t, J=7 Hz, 3H), 1.01 (d, J=7 Hz, 3H). Mass spec (ES+) m/z 480.4 (M+H+, 100%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([OH:16])[C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)=[CH:5][C:4]=1[CH:24]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)[S:25][CH2:26][C:27](O)=[O:28].[O-]S([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[Cl:36][C:32]1[CH:31]=[C:30]([CH:24]2[C:4]3[CH:5]=[C:6]([C:9]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=4)([OH:16])[C:10]4[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=4)[CH:7]=[CH:8][C:3]=3[NH:2][C:27](=[O:28])[CH2:26][S:25]2)[CH:35]=[CH:34][CH:33]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc(N)c(C(SCC(=O)O)c2cccc(Cl)c2)c1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(=O)N2
Yield: 30.4 %

Procedure:
A mixture of intermediate (3) (0.0103 mol) and MgSO4 (6.2 g) in toluene (155 ml) was stirred and refluxed for 5 hours, then filtered and washed with CH2Cl2/CH3OH 1/2. The organic layer was separated, washed with K2CO3 10%, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (3.35 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone and diethyl ether. The precipitate was filtered off and dried, yielding 1.6 g (30%) of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-4,1-benzothiazepin-2(3H)-one, mp. 210° C.
Reaction SMILES: C(O[C:4]([CH3:13])=[CH:5][C:6](=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])C.[C:14]([CH2:16][C:17]([NH2:19])=[O:18])#[N:15].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[C:14]([C:16]1[C:17](=[O:18])[NH:19][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[CH3:13])#[N:15]
Reactant: N#CCC(N)=O
Reactant: CCOC(=O)C(=O)C=C(C)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(C)c(C#N)c(=O)[nH]1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To a stirred solution of ethyl 4-ethoxy-2-oxopent-3-enoate (22.5 g, 121 mmol) and 2-cyanoacetamide (9.0 g, 107 mmol) in acetone (250 mL) was added potassium carbonate (15.8 g, 114 mmol). The reaction was refluxed (85° C. oil bath) for 10 hr (the reaction formed a thick ppt. in a deep red solution). The slurry was added to cold 1N HCl (230 mL) in ice. After stirring for 30 min. the suspension was filtered, washed with water and dried under vacuum to give the product ethyl 5-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate (14.51 g, 70.4 mmol, 65.7% yield) as a light pink solid. 1H NMR (400 MHz, DMSO-d6) δ12.60 (br. s., 1H), 7.05 (br. s., 1H), 4.34 (q, J=7.1 Hz, 2H), 2.45 (s, 3H), 1.32 (t, J=7.1 Hz, 3H). MS(ES)+ m/e 206.8 [M+H]+.
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C[C@H]2N(C[C@H]3[C@@H]4CCCCN4C[C@@H]2C3)CC1.[Li]C(CC)C.Br[C:36]1[C:37]([O:43][CH3:44])=[N:38][CH:39]=[C:40]([F:42])[CH:41]=1.[NH4+].[OH-]>CC(OC)(C)C.[Cl-].[Cl-].[Zn+2].CC([O-])=O.CC([O-])=O.[Pd+2].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[H+].[B-](F)(F)(F)F>[F:42][C:40]1[CH:41]=[C:36]([C@H:2]2[CH2:3][CH2:4][CH2:5][N:1]2[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C:37]([O:43][CH3:44])=[N:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1
Reactant: COc1ncc(F)cc1Br
Agent: [Pd+2]
Agent: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Agent: CC(=O)[O-]
Solvent: COC(C)(C)C
Product: COc1ncc(F)cc1[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
A solution of tert-butyl pyrrolidine-1-carboxylate (4.09 mL, 23.4 mmol) and (−)-sparteine (6.44 mL, 28.0 mmol) in MTBE (50 mL) was cooled to −78° C. and sec-BuLi (20 mL, 28.0 mmol, 1.4 M in cyclohexane) was introduced drop-wise by cannula, keeping the internal temperature under −78° C. The resulting solution was stirred for 3 hours at −78° C., followed by addition of a solution of ZnCl2 (21.0 mL, 21.0 mmol, 1M in Et2O) drop-wise with rapid stirring, keeping the internal temperature below −65° C. The resulting light suspension was stirred at −78° C. for 10 minutes and then warmed to ambient temperature. The resulting mixture was sequentially charged with 3-bromo-5-fluoro-2-methoxypyridine (5.05 g, 24.5 mmol), Pd(OAc)2 (0.262 g, 1.17 mmol) and t-Bu3P-HBF4 (0.407 g, 1.40 mmol) in one portion. After stirring overnight at ambient temperature, concentrated NH4OH (1 mL) was added and the reaction was stirred for 1 hour. The resulting slurry was filtered through Celite® and washed with Et2O. The organic layer was filtered and concentrated, and the crude product was purified by silica column chromatography, eluting with 5% EtOAc/hexanes to give product (R)-tert-butyl 2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidine-1-carboxylate as yellow oil (4.34 g, 63% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=1)[CH2:14][OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(OCc2ccccc2)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(OCc2ccccc2)cc1CO
Yield: 94.8 %

Procedure:
5-Benzyloxy-2-methoxybenzaldehyde (150.4 g) was suspended in methanol (600 ml) and to the gently warmed stirred mixture was added, in portions, sodium borohydride (15.0 g). The methanol was evaporated and the residue partitioned between dichloromethane and water. The organic layer was washed with water, then saturated sodium chloride, dried with anhydrous magnesium sulphate and evaporated to dryness. The residue crystallised from dichloromethane/petroleum spirit (40-60°) to give 5-benzyloxy-2-methoxybenzyl alcohol (143.8 g, 95%), m.p. 50-51°.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[C:19]=1[CH:31]([F:33])[F:32]>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[C:19]=1[CH:31]([F:32])[F:33]
Reactant: C=C(c1cc(Cl)c(C(F)F)c(Cl)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)c(C(F)F)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 28 %

Procedure:
To a solution of crude N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (156 mg, 0.65 mmol) and 1,3-dichloro-2-(difluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (210 mg, 0.72 mmol) in DMF (8 mL) at rt was added TEA (100 μL, 0.72 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by combiflash to give the title compound 5-(5-(3,5-dichloro-4(difluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol (90 mg; yield 28% over 3 steps) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 9.268 (s, 1 H), 7.796 (s, 2H), 7.757-7.771 (m, 2 H), 7.694-7.710 (m, 1H), 7.389 (t, J=52.0 Hz, 1 H), 4.451 (d, J=18.0 Hz, 1 H), 4.344 (d, J=18.0 Hz, 1 H), 1.476 (s, 6 H); HPLC purity: 99.28% at 220 nm and 100% at 254 nm; MS: m/z=494.0 (M+1, ESI+).
Reaction SMILES: [N+]([C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1)([O-])=O.[CH3:12][C:13]1([CH2:16][NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][O:14]1.C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)C.C(Cl)Cl>[CH3:15][C:13]1([CH2:16][NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:14][C:4]2=[N:8][C:7]([N+:9]([O-:11])=[O:10])=[CH:6][N:5]2[CH2:12]1
Reactant: CC1(CNC(=O)OCc2ccccc2)CO1
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC1(CNC(=O)OCc2ccccc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 70 °C
Reaction time: 8 h
Yield: 4.7 %

Procedure:
2,4-Dinitro-1H-imidazole (3 g, 19 mmol) and benzyl (2-methyloxiran-2-ylmethyl)carbamate (4.31 g, 19 mmol) were dissolved in ethanol (20 ml). To the solution, sodium acetate (1.56 g, 19.0 mmol) was added followed by stirring at 70° C. overnight. To the reaction mixture, a saturated sodium hydrogencarbonate solution and methylene chloride were added, and the solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1, methylene chloride/methanol=50/1) and recrystallized from ethyl acetate-methylene chloride to afford benzyl (2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)carbamate (0.298 g, yield 4.7%) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:14][F:15])([CH2:12][F:13])[CH:9]=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:7]=2[CH:22]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:31])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:14][F:15])([CH2:12][F:13])[CH:9]=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N+:17]=3[O-:31])[C:7]=2[CH:22]=1)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1ccc2c(c1)C(c1ccccn1)=CC(CF)(CF)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)C(c1cccc[n+]1[O-])=CC(CF)(CF)O2
Yield: 35.6 %

Procedure:
In 3 ml of methylene chloride was dissolved 80 mg of 6-cyano-2,2-bisfluoromethyl-4-(2-pyridyl)-2H-1-benzopyran and 75.7 mg of m-chloroperbenzoic acid (70%) was added thereto with stirring under ice-cooling. The mixture was stirred at room temperature for 15 hours. After addition of 28 mg of m-chloroperbenzoic acid (70%), the mixture was further stirred for 19 hours. Sodium bicarbonate solution was added thereto and the mixture was extracted with methylene chloride. After the organic layer was washed with water and dried, the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 30 mg of 2-(6-cyano-2,2-bisfluoromethyl-2H-1-benzopyran-4-yl)pyridine N-oxide represented by the following formula having a melting point of 204°-207° C. NMR(CDCl3)δ: 4.63(4H,d), 5.89(1H,s), 6.82-7.62(6H,m), 8.13-8.47(1H,m). MS m/z: 314(M+) ##STR50##
Reaction SMILES: Cl.CN.CS([C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[CH:11]=[CH:10][N:9]=1)(=O)=O.C[CH2:31][N:32](C(C)C)C(C)C>CC(O)C>[CH3:31][NH:32][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[CH:11]=[CH:10][N:9]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=O)c1nccc(-c2ccccc2Oc2ccc([N+](=O)[O-])cc2)n1
Agent: CN
Agent: Cl
Solvent: CC(C)O
Product: CNc1nccc(-c2ccccc2Oc2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C

Procedure:
To a mixture of methylamine hydrochloride (0.863 g, 12.8 mmol), 2-(methylsulfonyl)-4-(2-(4-nitrophenoxy)phenyl)pyrimidine (0.791 g, 2.13 mmol) in iPrOH was added n,n-diisopropylethylamine (2.60 ml, 14.9 mmol). The reaction was sealed and heated to 70 deg. C. overnight. The resulting clear yellow solution was judged complete by LCMS in the morning. The reaction was cooled to ambient temperature, resulting in the formation of white crystals. Filter, rinsing with isopropanol. Concentrate filtrate, partition between EtOAc and 1N NaOH. Dry over anhyd. Na2SO4, filter, concentrate to give N-methyl-4-(2-(4-nitrophenoxy)phenyl)pyrimidin-2-amine as a light yellow solid. MS m/z=323 [M+1]+. Calc'd for C17H14N4O3: 322.32.
Reaction SMILES: BrC1C=C2C(=CC=1)N=C(C1C=CC=CC=1O)N=C2N[C@H]1CCN(C(OC(C)(C)C)=O)C1.[CH3:32][C:33]([OH:37])([CH3:36])[C:34]#[CH:35].Br[C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[N:45]=[C:44]([C:49]1[CH:54]=[C:53]([F:55])[CH:52]=[CH:51][C:50]=1[OH:56])[N:43]=[C:42]2[NH:57][C@H:58]1[CH2:62][CH2:61][N:60](C(OC(C)(C)C)=O)[CH2:59]1.OC1C=CC=CC=1C1N=C(N[C@H]2CCN(C(OC(C)(C)C)=O)C2)C2C(=CC=C(C#CCO)C=2)N=1>>[F:55][C:53]1[CH:52]=[CH:51][C:50]([OH:56])=[C:49]([C:44]2[N:43]=[C:42]([NH:57][C@H:58]3[CH2:62][CH2:61][NH:60][CH2:59]3)[C:41]3[C:46](=[CH:47][CH:48]=[C:39]([CH2:35][CH2:34][C:33]([OH:37])([CH3:36])[CH3:32])[CH:40]=3)[N:45]=2)[CH:54]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3cc(F)ccc3O)nc3ccc(Br)cc23)C1
Reactant: C#CC(C)(C)O
Agent: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(Br)cc23)C1
Agent: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(C#CCO)cc23)C1
Product: CC(C)(O)CCc1ccc2nc(-c3cc(F)ccc3O)nc(N[C@H]3CCNC3)c2c1

Procedure:
The title compound was prepared using methods analogous to those described in Synthesis 59 and 60, replacing propargyl alcohol and (S)-tert-butyl 3-(6-bromo-2-(2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate with dimethyl propargyl alcohol and (S)-tert-butyl 3-(6-bromo-2-(5-fluoro-2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate in Synthesis 59-A.
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.[CH:40]([OH:42])=[O:41]>>[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.[CH:40]([O-:42])=[O:41]
Reactant: O=CO
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Product: O=C[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 formic acid (0.0261 g, 0.57 mmol) in TFE (1 mL) at 40° C. The resulting solution was stirred for about 4 h and subsequently cooled to 5° C. The mixture was kept at 5° C. overnight and then a sample (1 mL) was taken from the mixture and evaporated to dryness under reduced pressure at 40° C. to give amorphous Nilotinib formate as characterized by the powder X-ray diffractogram depicted in FIG. 49.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([C@@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Br:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[CH2:33][O:34][CH3:35]>C1COCC1>[CH2:11]([C@@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:31])[C@H:25]([CH2:33][O:34][CH3:35])[CH2:26][CH2:27][CH2:28][CH2:29][Br:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COCCl
Reactant: O=C(CCCCCBr)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC[C@H](CCCCBr)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a round-bottom flask containing THF (80 ml) cooled to −78° C. and purged with a continuous stream of N2 gas was added KHMDS (1 M in THF, 22.6 ml, 4 eq.). In a separate flask purged with a continuous stream of N2 gas was added (R)-4-benzyl-3-(6-bromohexanoyl)oxazolidin-2-one (2.00 g, 1 eq.) dissolved in THF (10 ml) and cooled to −78° C. The solution containing (R)-4-benzyl-3-(6-bromohexanoyl)oxazolidin-2-one was transferred to the KHMDS solution, and chloro(methoxy)methane (7.2 g, 15.8 eq.) was added dropwise. The reaction mixture was allowed to stir for an additional 2 h, quenched with saturated aqueous NH4Cl and concentrated. Water was added. The mixture was extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated. Silica gel chromatography using 30-100% DCM-heptane yields the title compound.