Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.Cl.[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[O:27][CH2:26][CH2:25][NH:24][CH2:23][C:22]=2[CH:28]=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[N:24]1[CH2:23][C:22]2[CH:28]=[C:18]([Br:17])[CH:19]=[CH:20][C:21]=2[O:27][CH2:26][CH2:25]1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Brc1ccc2c(c1)CNCCO2
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(N3CCOc4ccc(Br)cc4C3)c2cc1OC
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A mixture of commercially available 4-chloro-6,7-dimethoxyquinoline (120 mg, 0.53 mmol), 7-bromo-2,3-dihydro-1,4-benzoxazepine hydrochloride (example 2, step 1) (200 mg, 0.53 mmol), diisopropylethylamine (0.14 g, 1.1 mmol), in NMP (2 mL) was stirred in a microwave reactor at 120° C. for 45 min. After cooling to room temperature, the reaction mixture was purified directly by silica gel flash chromatography (0-10% methanol-dichloromethane gradient) to give 4-[6,7-bis(methyloxy)quinolin-4-yl]-7-bromo-2,3,4,5-tetrahydro-1,4-benzoxazepine (155 mg, 70% yield), MS (EI) for C20H19N2O3: 415 (MH+).
Reaction SMILES: [CH2:1]=[C:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].C1C=C(Cl)C=C(C(OO)=[O:17])C=1.S(C1C=C(C)C(O)=C(C(C)(C)C)C=1)C1C=C(C)C(O)=C(C(C)(C)C)C=1>ClCCCl>[CH2:7]([C:2]1([C:3]([O:5][CH3:6])=[O:4])[CH2:1][O:17]1)[CH3:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CC)C(=O)OC
Agent: Cc1cc(Sc2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Solvent: ClCCCl
Product: CCC1(C(=O)OC)CO1
Temperature: 80 °C

Procedure:
A mixture of methyl 2-methylenebutanoate (140 mmol), mCPBA (77%, 67 g, 300 mmol) and 4,4′-thiobis(2-tert-butyl-6-methylphenol) (250 mg, 0.7 mmol) in 100 ml of dry 1,2-dichloroethane was refluxed at 80° C. for 2 d. It was then cooled down, solid filtered. Filtrate washed by Na2SO3, NaHCO3, brine and water until clear. It was then concentrated to a light yellow liquid (7.5 g, 41%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02 (td, J=7.4, 1.3 Hz, 3H) 1.78 (dq, J=14.6, 7.3 Hz, 1H) 2.10 (dq, J=15.4, 7.6 Hz, 1H) 2.80 (dd, J=5.8, 1.0 Hz, 1H) 3.05 (dd, J=5.8, 1.0 Hz, 1H) 3.77 (d, J=1.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.FC1C=C2C(=CC=1)NC(=O)C=N2.[H-].[Na+].CS(O[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36][CH2:35]1)(=O)=O>CN(C=O)C.O.C(OCC)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:12])[N:9]2[CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([NH:40][C:41](=[O:42])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:36][CH2:35]2)=[CH:4][CH:3]=1
Reactant: O=c1cnc2ccc(F)cc2[nH]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: O=c1cnc2cc(F)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of a 1:1 mixture of 7-fluoroquinoxalin-2(1H)-one (Intermediate 143) and 6-fluoroquinoxalin-2(1H)-one (Intermediate 144) (1.5 g total, 9.1 mmol) was treated with sodium hydride (60% in oil, 0.44 g, 11.0 mmol) at 0° C. The reaction was allowed to stir at room temperature for 2 hours. The reaction mixture was cooled to 0° C. and 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6, 1.33 mmol/mL, 11.0 mmol), dissolved in dry DMF (5 mL) was added and it was stirred at room temperature overnight. The reaction mixture was diluted with water and with diethyl ether (5×50 mL). The combined organic phases were dried over sodium sulfate and concentrated to dryness under reduced pressure. Chromatography with hexanes/acetone (5:1 to 3:1). The higher Rf material was isolated as a mixture of Intermediate 141 with an O-alkylated isomer, which was rechromatographed on silica gel with hexanes/ethyl acetate (1:3) to give pure Intermediate 141 as a colorless solid, 0.24 g, 14%. Isolation of the lower Rf material from the first column gave 0.38 g (21%) of pure Intermediate 142 as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:22]=[C:23]([NH2:34])[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([N+:31]([O-:33])=[O:32])[CH:25]=1>CN1CCCC1=O.C(OCC)(=O)C.O>[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]2[N:22]=[C:6]([CH:4]3[CH2:3][C:2](=[O:1])[CH2:5]3)[O:8][N:34]=2)=[CH:25][C:26]=1[N+:31]([O-:33])=[O:32]
Reactant: O=C1CC(C(=O)O)C1
Reactant: Cc1ccc(C(N)=NO)cc1[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2noc(C3CC(=O)C3)n2)cc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 3-oxocyclobutanecarboxylic acid (595 mg, 5.12 mmol) in 1-methyl-2-pyrrolidinone (6 mL) was added 1,1′-carbonyldiimidazole (831 mg, 5.12 mmol). The reaction was stirred for 5 minutes. Then, N′-hydroxy-4-methyl-3-nitrobenzimidamide (27) (500 mg, 2.56 mmol) was added and the reaction was stirred for 15 minutes. Next, the reaction was heated in the microwave at 130° C. for 10 minutes. The crude product was taken in ethyl acetate and water. The organic was washed with 2× water/brine mixture and dried over anhydrous sodium sulfate. The solvent was concentrated and the crude product was purified by silica chromatography to afford 3-(3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazol-5-yl)cyclobutanone (122). MS m/z 274.07 (M+1)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[N:20]=[CH:19][CH:18]=[N:17]1.[Br:22][C:23]1[CH:24]=[CH:25][C:26](Cl)=[N:27][CH:28]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([NH:2][C@H:3]2[CH2:7][CH2:6][CH2:5][C@@H:4]2[NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[N:17]=[CH:18][CH:19]=[N:20]2)=[N:27][CH:28]=1
Reactant: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1
Reactant: Clc1ccc(Br)cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(Br)cn1)c1ccccc1-n1nccn1
Temperature: 85 °C

Procedure:
A mixture of N-[(1S,2S)-2-aminocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 300 mg, 0.98 mmol), 5-bromo-2-chloropyridine (CAS number 53939-30-3; 225 mg, 1.17 mmol), sodium tert-butoxide (150 mg, 1.56 mmol), BINAP (24 mg, 0.039 mmol) and tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.019 mmol) in toluene (4 ml) was heated at 85° C. overnight. The mixture was partitioned between ethyl acetate (10 ml) and water (10 ml). The aqueous layer was further extracted ici with ethyl acetate (3×20 ml). The combined organics were washed with water (2×20 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:11])[C@H:6]([CH:8]([CH3:10])[CH3:9])[NH2:7])[CH3:3].S=C1N([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29](=[O:31])[CH3:30])=[C:24]([O:32][CH3:33])[CH:23]=2)=[O:19])CCS1.C1COCC1.C(N(C(C)C)CC)(C)C>CO.C(Cl)Cl>[C:29]([O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]([NH:7][CH:6]([CH:8]([CH3:10])[CH3:9])[C:5]([O:4][CH2:2][CH3:3])=[O:11])=[O:19])=[CH:23][C:24]=1[O:32][CH3:33])(=[O:31])[CH3:30]
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Reactant: CCOC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)OCc1ccc(OC(C)=O)c(OC)c1)C(C)C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
L-Valine ethyl ester hydrochloride (122.5 mg, 1.05×0.642 mmol) and thiazolide VII (219.2 mg, 0.642 mmol) were covered with THF (3.2 mL). To the stirred suspension was added diisopropylethylamine (166 mg, 224 μL, 2×0.642 mmol). The reaction mixture was stirred overnight. A second portion of diisopropylethylamine and four drops of anhydrous methanol were added, and the mixture was stirred for four days. A second portion of portion of valine ethyl ester hydrochloride was added, and the reaction mixture was stirred for two more days, after which time the solution was clear and colorless. The reaction solution was diluted with CH2Cl2 and extracted with 1N HCl and saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered, concentrated, and dried well under vacuum. The crude material was covered with four mL of hexanes/ethyl acetate (7:3, v/v) causing the released MTA to separate. The supernatant was drawn of, the crystals rinsed twice with fresh 7:3 hexanes/ethyl acetate, the rinsings were combined with the original supernatant, and the resulting volume concentrated. The product was purified by column chromatography on silica gel using hexanes/ethyl acetate (7:3, v/v) as eluant to give 165.8 mg (71%) of a colorless oil: Rf=0.36 (hexanes/ethyl acetate, 7:3, v/v); 1HNMR (CDCl3) δ 6.99 (d, 3J=8 Hz, 1H), 6.96 (s, 1H), 6.92 (bd, 3J=8 Hz, 1H), 5.26 (d, 8.15 Hz, 1H), 5.06 (s, 2H), 4.28-4.24 (m, 1H), 4.23-4.15 (m, 2H), 3.82 (s, 3H), 2.29 (s, 3H), 2.18-2.11 (m, 1H), 1.26 (t, 3J=7 Hz, 3H), 0.95 (d, 3J=6.8 Hz, 3H) and 0.88 (d, 6.8 Hz, 3H). Exact mass (ESI) calculated for C18H25NO7Na [M+Na]=390.1523. found 390.1515.
Reaction SMILES: ClCCl.[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O>[CH3:23][S:24]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCCCCCCCO
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCCOS(C)(=O)=O
Temperature: 0 °C
Yield: 68 %

Procedure:
Dichloromethane (20 mL) was added with methyl 9-hydroxynonanoate (2.1 g) and pyridine (1.8 g), stirred at 0° C., added with methanesulfonyl chloride (1.3 mL), gradually warmed to room temperature and stirred for one day. The reaction solution was added with water and then extracted twice with dichloromethane. The resulting organic layer was washed with 1 N hydrochloric acid and saturated sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed. The resulting residue was purified by silica gel column chromatography to obtain methyl 9-(methanesulfonyloxy)nonanoate (2.1 g, yield: 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Li+].[CH3:13]C([N-]C(C)C)C.CCCCCCC.C(C1C=CC=CC=1)C.CI.Cl>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:13])[C:9]([OH:11])=[O:10]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(O)Cc1ccccc1Cl
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCCC
Product: CC(C(=O)O)c1ccccc1Cl
Temperature: 25 °C
Yield: 86 %

Procedure:
To 1 g of 2-chlorophenylacetic acid, 8.8 mL of 2M LDA heptane, THF, ethylbenzene solution was dropped under cooling with ice, and further 1.58 g of HMPA and 5 mL of THF were added followed by an hour's stirring at room temperature. Then 1.25 g of methyl iodide was added under cooling with ice and stirred at room temperature for 30 minutes. The reaction solution was poured into ice water, rendered acidic with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous magnesium sulfate and thereafter removed of the solvent by distillation under reduced pressure. The residue was purified on 30 g silica gel column chromatography (eluent, chloroform:methanol=20:1) to provide 0.928 g (yield: 86%) of the title compound as a pale yellow, oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.C[Si](C)(C)[O-].[K+].CCN(C(C)C)C(C)C.[NH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])=[C:6]([CH:11]=1)[C:7]([NH:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)=[O:9]
Reactant: Nc1cccnc1
Reactant: COC(=O)c1cc(Br)ccc1O[C@@H](C)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[Si](C)(C)[O-]
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ccc(Br)cc1C(=O)Nc1cccnc1)c1ccccc1
Reaction time: 0.75 h

Procedure:
To a solution of methyl 5-bromo-2-{[(1S)-1-phenylethyl]oxy}benzoate (may be prepared as described in Description 99; 100 mg, 0.30 mmol) in THF (2 ml) was added potassium trimethylsilanolate (115 mg, 0.90 mmol). The mixture was stirred for 45 minutes. The solvent was removed and the residue redissolved in DMF (2 ml). To the solution was added DIPEA (0.13 ml, 0.75 mmol), 3-aminopyridine (56 mg, 0.60 mmol) and HATU (170 mg, 0.45 mmol). The solution was stirred for 18 hours. The solvent was removed in vacuo and purified by MDAP to give the titled example as a colourless gum. 73 mg.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:46])=[C:9]([CH2:11][O:12][C:13]2[CH:43]=[CH:42][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]4[S:27][CH:28]=[C:29]([C:31]([O:33]CC)=[O:32])[N:30]=4)=[CH:22][N:21]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:20]=3)=[CH:15][C:14]=2[O:44][CH3:45])[N:10]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:46])=[C:9]([CH2:11][O:12][C:13]2[CH:43]=[CH:42][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]4[S:27][CH:28]=[C:29]([C:31]([OH:33])=[O:32])[N:30]=4)=[CH:22][N:21]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:20]=3)=[CH:15][C:14]=2[O:44][CH3:45])[N:10]=1
Reactant: CCOC(=O)c1csc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2nc(C(=O)O)cs2)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 64.4 %

Procedure:
To a mixture of ethyl 2-((E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenyl)-1,3-thiazole-4-carboxylate (0.13 g), tetrahydrofuran (1 mL) and ethanol (1 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was heated under reflux for 1 hr. To the reaction mixture were added 1N hydrochloric acid (1 mL) and water, and the precipitated crystals were collected by filtration to give 2-((E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenyl)-1,3-thiazole-4-carboxylic acid as yellow crystals (0.08 g, yield 67%). Recrystallization from tetrahydrofuran-hexane gave yellow prism crystals. melting point: 170-172° C.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[CH3:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:19])[NH:16]2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])O.[Na+]>O.C(OCC)(=O)C.CS(C)=O>[O:4]1[CH2:5][CH2:6][O:7][CH:3]1[CH2:2][N:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([CH3:8])[CH:18]=2)[CH:13]=[CH:14][C:15]1=[O:19]
Reactant: BrCC1OCCO1
Reactant: Cc1ccc2ccc(=O)[nH]c2c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc2ccc(=O)n(CC3OCCO3)c2c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To 6.3 mL of a dimethyl sulfoxide solution containing 1.1 g of 2-bromomethyl-1,3-dioxolane, 1.0 g of 7-methylquinolin-2(1H)-one and 3.1 g of cesium carbonate were added, and the mixture was stirred at 60 to 70° C. for 1 hour. The reaction mixture was added with ethyl acetate, water and an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=2:3] to obtain 0.60 g of a brown oily substance, 1-(1,3-dioxolan-2-ylmethyl)-7-methylquinolin-2(1H)-one.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.CN(C=O)C.CCN(CC)CC.[CH2:33](Br)[CH2:34][CH2:35][CH2:36][CH3:37]>C(OCC)(=O)C>[CH2:33]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=3)[CH:6]=2)[CH2:1]1)[CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCNC3)cc1
Reactant: CCCCCBr
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCN1CCc2cc(Oc3ccc(C(N)=O)cc3)ccc2C1
Yield: 76.8 %

Procedure:
Combine 4-(1,2,3,4-tetrahydro-isoquinolin-6-yloxy)-benzamide (80.0 mg, 0.30 mmol), DMF (4 mL), Et3N (0.2 mL, 1.32 mmol), and pentylbromide (0.1 mL, 0.66 mmol) in a 7 mL vial. Place the vial on a shaker at 70° C. for 72 hours and then add ethyl acetate to the reaction vial. Wash with water and several times with 10% LiCl (aq), and dry over Na2SO4. Concentrate the organic mixture and flash chromatograph using 2% 1.0 N NH3 in MeOH, 20% THF, 78% CH2Cl2 to afford 78.0 mg (77% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 0.9-1.0 (3H, m), 1.3-1.4 (4H, m), 1.5-1.7 (2H, m), 2.4-2.6 (2H, m), 2.7-2.8 (2H, m), 2.8-3.0 (2H, m), 3.5-3.6 (2H, m), 6.8-6.8 (2H, m), 6.9-7.1 (3H, m), 7.7-7.9 (2H, m); MS m/z 339 (M+1).
Reaction SMILES: B.O1CCCC1.Cl.C([C:11]1([CH2:24][C:25]([O:27][CH2:28]C)=[O:26])[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)(O)=O.CO>O1CCCC1>[C:18]1([CH2:17][N:14]2[CH2:13][CH2:12][C:11]3([CH2:28][O:27][C:25](=[O:26])[CH2:24]3)[CH2:16][CH2:15]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CC1(C(=O)O)CCN(Cc2ccccc2)CC1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CC2(CCN(Cc3ccccc3)CC2)CO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.2 %

Procedure:
Borane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 60 mL, 60 mmol) was added to a suspension of α-ethyl 4-carboxy-1-(phenylmethyl)-4-piperidineacetate hydrochloride (Helv. Chim. Acta 1972, 55, 2432–2438, 10.24 g, 30 mmol) in tetrahydrofuran (150 mL) and the mixture was stirred at room temperature for 3 days. Further borane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 60 mL, 60 mmol) was added and the mixture was stirred at room temperature for 1 day. Methanol (20 mL) was added and the solvent was evaporated under reduced pressure. Methanol (200 mL) was added and the solvent was evaporated under reduced pressure. Methanol (200 mL) was added and the solvent was evaporated under reduced pressure. Hydrochloric acid (2M, 200 mL) was added and the mixture was heated under reflux for 4 hours. The mixture was cooled. Ether (200 mL) was added and the layers were separated. The organic layer was extracted with hydrochloric acid (2M, 2×100 mL) and the combined aqueous fractions were washed with ether (2×100 mL), adjusted to pH 10 with saturated aqueous potassium carbonate and extracted with dichloromethane (3×100 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3(aq.) (96:4:0.4), to give the title compound (3.4 g, 46%). m/z (ES+) 246 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:31][N:32]1[CH2:36][CH2:35][CH2:34][C:33]1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:10]4[CH2:34][CH2:35][CH:36]([N:32]5[CH2:31][CH2:27][O:26][CH2:23][CH2:33]5)[CH2:12][CH2:11]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: CN1CCCC1=O
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCOCC2)CC1
Temperature: 105 °C

Procedure:
Following the procedure of Example 11, a mixture of 150 mg (0.33 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile and 170 mg (1.0 mmol) of 1-methyl-4-piperidin-4-ylmorpholine in 1.0 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 24 hours to yield the crude product. Purification by silica gel chromatography (gradient 97:3 methylene chloride/methanol to 9:1 methylene chloride/methanol) gave 100 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-methoxy-7-(4-morpholin-4-ylpiperidin-1-yl)quinoline-3-carbonitrile as a beige solid, mp 219-221° C.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CC(C)COc1cc(Cl)ccc1CO
Product: CC(C)COc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-2-(2-methylpropoxy)phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.00 (6H, d, J=6.8 Hz), 2.06-2.12 (1H, m), 3.77 (2H, d, J=6.0 Hz), 5.24 (2H, s), 5.77 (1H, d, J=2.0 Hz), 6.89 (1H, d, J=1.6 Hz), 6.95 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.34 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=0.8 Hz, 4.8 Hz), 7.57 (1H, d, J=2.0 Hz), 8.03 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H19ClN4O2, 383. Found, 383.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.OO.NC(N)=[O:13].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[O-]S([O-])=O.[Na+].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N+:3]=1[O-:13]
Reactant: Brc1cccc(Br)n1
Reactant: NC(N)=O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: [O-][n+]1c(Br)cccc1Br
Temperature: 5 °C
Reaction time: 20 h
Yield: 57.4 %

Procedure:
2,6-dibromo pyridine (79 g, 334 mmol) was dissolved in 800 ml of dry dichloromethane and cooled under nitrogen to 5° C. then urea hydrogen peroxide (104 g, 1.1 mol) was added in one portion. When the mixture had cooled again to 3° C., a solution of trifluoro acetic acid anhydride (140 mL, 1 mol) in 100 ml DCM was added via dropping funnel over 45 min, whilst keeping the temperature between 5-7° C. The mixture was allowed to warm to room temperature and stirred for 20 hours. The mixture was cooled in an ice bath to 10° C. and 10% aq. Na2SO3 (˜50 g/500 ml) was added dropwise over 60 minutes until test with starch iodide paper was negative. The resulting mixture was filtered to remove a quantity of fluffy solid and the layers were separated. The aqueous layer was extracted with dichloromethane (2×200 ml) and the combined extracts were dried over MgSO4 and concentrated under reduced pressure to give a light brown solid. Recrystallisation of crude product using 600ml of boiling acetone gave 48.47 g of the title compound.