Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][C:5]([C:6]([NH:8][C:9]2[N:13]([C@H:14]3[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]3)[C:12]3[CH:26]=[C:27]([O:30]CC4C=CC(OC)=CC=4)[CH:28]=[CH:29][C:11]=3[N:10]=2)=[O:7])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[N:13]([C@H:14]3[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]3)[C:12]3[CH:26]=[C:27]([OH:30])[CH:28]=[CH:29][C:11]=3[N:10]=2)=[O:7])=[CH:40][CH:41]=1
Reactant: COc1ccc(COc2ccc3nc(NC(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)NC(C)C)CC4)c3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2c(NC(=O)c3ccc(F)cc3)nc3ccc(O)cc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
To a solution of 4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(4-methoxybenzyloxy)-1H-benzo[d]imidazol-2-yl)benzamide (232 mg, 0.415 mmol) in DCM was added TFA (0.96 mL, 1.246 mmol), and the mixture was stirred at RT for 90 minutes. Additional TFA (0.96 mL, 1.246 mmol) was added, and the mixture was stirred at RT for 1 hour longer. The mixture was diluted with DCM, washed with 1 N aqueous NaOH, and the water layer back-extracted with DCM. The aqueous layer was adjusted to pH 8, and the pale green solid was collected and rinsed with 2 mL water. The solid was dissolved in ether and washed with brine, dried over Na2SO4, filtered, and evaporated. The title compound was obtained as a white sold (153 mg, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (d, J=8 Hz, 6H) 1.59 (m, 2H) 1.65-1.82 (m, 2H) 2.02-2.19 (m, 2H) 2.46-2.58 (m, 1H) 2.62-2.79 (m, 2H) 3.93-4.07 (m, 1H) 4.70-4.85 (m, 1H) 6.67 (dd, J=8.61, 2.15 Hz, 1H) 7.03 (d, J=2.05 Hz, 1H) 7.14-7.28 (m, 2H) 7.33 (d, J=8.51 Hz, 1H) 7.64 (d, J=7.82 Hz, 1H) 8.16-8.38 (m, 2H) 9.40 (s, 1H) 12.58 (s, 1H). M/Z calc'd for C24H27FN4O3: 438.50. found 439 [M+H].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][O:14][CH3:15].CN(C=O)C.Cl[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=1>O>[CH3:7][O:8][CH2:9][CH2:10][N:11]([CH2:12][CH2:13][O:14][CH3:15])[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=1
Reactant: COCCNCCOC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCN(CCOC)c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.7 %

Procedure:
Potassium carbonate (262 mg) and bis(2-methoxyethyl)amine (840 mg) were added to a DMF (2 ml) solution containing 2-chloro-5-nitropyridine (100 mg), followed by stirring at room temperature for 5 hours. Water (15 ml) was added to the reaction solution, followed by stirring at room temperature for 1 hour. Insoluble matter was collected by filtration, and a white solid of N,N-bis(2-methoxyethyl)-5-nitropyridin-2-amine (117 mg) was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12](Cl)[C:11]=2[N+:18]([O-:20])=[O:19])=[N:6][CH:7]=1.[CH3:22][NH:23][CH3:24].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([N:23]([CH3:24])[CH3:22])[C:11]=2[N+:18]([O-:20])=[O:19])=[N:6][CH:7]=1
Reactant: CNC
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)c1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
Into a solution of N-(5-chloropyridin-2-yl)-2-nitro-3,5-dichlorobenzamide (4.0 g, 12 mmol) in dimethyl sulfoxide (60 mL) was bubbled an excess of dimethyl amine gas. The mixture was sealed in a pressure tube and heated at 50° C. After 3 hours, the mixture was cooled to ambient temperature, then poured into water, and extracted with methylene chloride. The combined organic extracts were dried over MgSO4, and concentrated in vacuo to afford 3.8 g (93% yield) of N-(5-chloropyridin-2-yl)-2-nitro-3-dimethylamino-5-chlorobenzamide; NMR (CDCl3) 9.6 (s, 1), 8.2 (d, 1), 7.8 (d, 1), 7.7 (dd, 1), 7.1 (d, 1), 6.9 (d, 1), 2.8 (s, 6) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][O:8][CH2:9][CH2:10][C:11]12[CH2:18][CH2:17][C:14]([C:19]3[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=3)([CH2:15][CH2:16]1)[O:13][CH2:12]2)([CH3:4])([CH3:3])[CH3:2].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[CH2:29]([C:21]1[CH:20]=[C:19]([C:14]23[CH2:17][CH2:18][C:11]([CH2:10][CH2:9][O:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])([CH2:16][CH2:15]2)[CH2:12][O:13]3)[CH:24]=[CH:23][CH:22]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(B(O)O)c3)(CC1)OC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(Cc4ccccc4)c3)(CC1)OC2
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of (3-(4-(2-(2-(tert-butoxy)-2-oxoethoxy)ethyl)-2-oxabicyclo[2.2.2]octan-1-yl)phenyl)boronic acid (49A; 20 mg, 0.051 mmol), benzyl bromide (0.012 mL, 0.102 mmol), and Na2CO3 (16 mg, 0.15 mmol) in 1,4-dioxane (1 mL)/water (0.2 mL) was degassed under Ar for 3 min using an ultrasonicator and then (Ph3P)4Pd (59 mg, 0.051 mmol) was added. The reaction was stirred at 100° C. under Ar for 18 h, then was cooled to rt and partitioned between EtOAc (5 mL) and water, dried (MgSO4), and concentrated in vacuo to give the crude product as a yellow oil, which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH:11]1[C:16](=[CH:17][O:18]C)[CH2:15][CH2:14][O:13][CH2:12]1)=[O:4]>CO.FC(F)(F)C(O)=O>[CH:17]([CH:16]1[CH2:15][CH2:14][O:13][CH2:12][CH:11]1[CH2:10]/[CH:9]=[CH:8]\[CH2:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[O:18]
Reactant: COC=C1CCOCC1C/C=C\CCCC(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COC(=O)CCC/C=C\CC1COCCC1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-[(Z)-6-methoxycarbonyl-2-hexenyl]-4-methoxymethylenetetrahydropyran in a mixture of methanol (10 ml) and 50% aqueous trifluoroacetic acid (10 ml) was stirred at room temperature for 1 hour and the solvent was evaporated in vacuo to give 4-formyl-3-[(Z)-6-methoxycarbonyl-2-hexenyl]tetrahydropyran as a residue. The residue was dissolved in methanol (10 ml). To the solution were added 4-phenylsemicarbazide (200 mg) and sodium cyanoborohydride (100 ml) and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with chloroform (50 ml) and the solution was washed successively with saturated aqueous sodium hydrogen carbonate and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was chromatographed on a silica gel column (10 g) with a mixture of n-hexane and ethyl acetate (3:1) as an eluent to give 3-[(Z)-6-methoxycarbonyl-2-hexenyl]-4-(4-phenylsemicarbazidomethyl)tetrahydropyran (266 mg) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[Cl:27]Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[CH:10][C:9]=2[Cl:27])=[CH:6][CH:7]=1
Reactant: ClCl
Reactant: NS(=O)(=O)c1ccc(-n2nccc2-c2ccc(Cl)cc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: NS(=O)(=O)c1ccc(-n2ncc(Cl)c2-c2ccc(Cl)cc2)cc1
Yield: 75 %

Procedure:
A 100 mL three-necked round-bottomed flask equipped with reflux condenser, gas dispersion tube and provisions for magnetic stirring was charged with 4-[5-(4-chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide (500 mg, 1.2 mmol) and 50 mL of glacial acetic acid. The solution was stirred at room temperature and treated with a stream of chlorine gas for a period of 15 minutes. The solution was then stirred at room temperature for 1.25 hours and then diluted with 100 mL of water. The solution was then extracted three times with ether and the combined ethereal phase washed with brine, dried over anhyd. MgSO4, filtered, and concentrated in vacuo to give a white solid that was recrystallized from ether/petroleum ether to provide 400 mg, 75% of 4-[5-(4-chlorophenyl)-4-chloro-1H-pyrazol-1-yl]benzenesulfonamide, 1H nmr CDCl3 /300 MHz) 8.06 (s, 1H), 7.81 (d, J=8.4 Hz, 2H) 7.53 (d, J=8.4 Hz 2H), 7.43 (brs, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15].O.[BH4-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:15][CH2:14][CH:13]([O:16][CH3:17])[O:12][CH3:11]
Reactant: COC(CN)OC
Reactant: O=Cc1ccc(F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(CNCc1ccc(F)cc1Cl)OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of 2-chloro-4-fluorobenzaldehyde (3.17 g, 20 mmol, 1.0 eq.) and aminoacetaldehyde dimethyl acetal (2.18 mL, 20 mmol, 1.0 eq.) in toluene (50 mL) was stirred at 130° C. with concomitant removal of H2O (Dean-Stark) for 2.5 hours. The mixture was concentrated in vacuo and dried under h.v. The residue was dissolved in EtOH (100 mL). The solution was cooled to 0° C. and NaBH4 (1.14 g, 30 mmol, 1.5 eq.) was added portionwise. The cooling bath was removed and the solution was stirred at r.t. for 18 hours. The resulting reaction mixture was quenched with sat. aq. NaHCO3 soln. (150 mL). The mixture was extracted with DCM (3×50 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×50 mL), dried over MgSO4, and concentrated in vacuo to give (2-chloro-4-fluoro-benzyl)-(2,2-dimethoxy-ethyl)-amine as a yellow oil. The product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](=[N:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)SC)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1>C1COCC1>[CH2:19]([O:18][C:17]([N:16]=[C:13]([NH:12][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:11])[NH:27][CH:28]1[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]1)=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)c1nc(Cl)c(N)nc1N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=NC(=O)OCc2ccccc2)NC(=O)c2nc(Cl)c(N)nc2N)CC1

Procedure:
A suspension of benzyl (3,5-diamino-6-chloropyrazine-2-carboxamido)(methylthio)methylenecarbamate (Intermediate B) (6.7 g, 17 mmol) and 4-amino-1-Boc-piperidine (4.1 g, 20.4 mmol) in dry THF (150 mL) is heated at reflux overnight. The solvent is removed in vacuo and a solid forms on concentration. The solid is separated and retained and the remaining mother liquor is concentrated to form a solid. The solid is partitioned between EtOAc and water and the organic portion is dried (MgSO4) and part concentrated in vacuo and then left to crystallise. The crystals are filtered and combined with the retained solid to afford the title product. [M+H]+ 547
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1C(=C)C(=O)NC2C=CC(OC)=CC=2C1=O.[F:20][C:21]1[CH:33]=[CH:32][C:24]2[NH:25][C:26](=[O:31])[CH2:27][CH2:28][C:29](=[O:30])[C:23]=2[CH:22]=1>>[CH3:1][N:2]([CH:19]=[C:28]1[CH2:27][C:26](=[O:31])[NH:25][C:24]2[CH:32]=[CH:33][C:21]([F:20])=[CH:22][C:23]=2[C:29]1=[O:30])[CH3:3]
Reactant: O=C1CCC(=O)c2cc(F)ccc2N1
Reactant: C=C1C(=O)Nc2ccc(OC)cc2C(=O)C1N(C)C
Product: CN(C)C=C1CC(=O)Nc2ccc(F)cc2C1=O

Procedure:
In a manner similar to that described above for 4-dimethylamino-methylene-7-methoxy-3,4-dihydro-1H-benzo[b]azepine-2,5-dione, 7-fluoro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-f) was converted to v-f (85%): MS m/z═249 (M+H).
Reaction SMILES: [CH2:1]([N:8]([C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:53])[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:25]([N:27]([CH:41]([CH3:43])[CH3:42])[C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]3)=[O:26])[C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[O:14][C:13]([CH3:50])([CH2:44][O:45]S(C)(=O)=O)[C:12]1=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:62]1(O)[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([N:8]([C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:53])[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:25]([N:27]([CH:41]([CH3:43])[CH3:42])[C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]3)=[O:26])[C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[O:14][C:13]([CH3:50])([CH2:44][O:45][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:12]1=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(COS(C)(=O)=O)C(=O)N2CCN(Cc1ccccc1)C(=O)OCc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(COc1ccccc1)C(=O)N2CCN(Cc1ccccc1)C(=O)OCc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 29.3 %

Procedure:
A solution of tert-butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-2-{[(methylsulfonyl)oxy]methyl}-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-carbonyl}(isopropyl)amino]piperidine-1-carboxylate (170 mg), phenol (18 mg) and cesium carbonate (186 mg) in N,N-dimethylformamide (2 ml) was stirred at 80° C. for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (49 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]O)=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:35])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][Cl:35])=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(-c2c(CO)n(CC(C)C)c(=O)c3ccc(OCc4ccccc4)cc23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2c(CCl)n(CC(C)C)c(=O)c3ccc(OCc4ccccc4)cc23)cc1
Yield: 95.5 %

Procedure:
To a suspension of 6-benzyloxy-3-hydroxymethyl-2-isobutyl-4-(4-methylphenyl)-1(2H)-isoquinolinone (4.28 g, 10 mmol) in toluene (50 ml) was added thionyl chloride (1.5 ml, 20 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-benzyloxy-3-chloromethyl-2-isobutyl-4-(4-methylphenyl)-1(2H)-isoquinolinone (4.26 g, 95.5%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][O:10][C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27].CN(C=O)C>O>[CH2:27]([O:18][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][O:10][C:6]=2[CH:5]=1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: Oc1cc(Cl)c2c(-c3ccccc3F)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(Cl)c2c(-c3ccccc3F)noc2c1
Reaction time: 3 h
Yield: 99.2 %

Procedure:
A mixture of 4-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole (7.7 g), potassium carbonate (7.1 g), allyl bromide (6.0 g) and DMF (100 ml) was stirred at 50°-60° C. for 3 hours. After cooling the mixture, water was added and the mixture was extracted with ether. The ether layer was washed with water and dried, and the solvent was distilled off to obtain 8.8 g of 6-allyloxy-4-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole. This compound (8.8 g) was refluxed in 100 ml of aniline for 3.5 hours. After cooling the mixture, concentrated hydrochloric acid and then water were added and the mixture was extracted with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was purified by column chromatography using 1% methanol/methylene chloride as an eluant, and 6.3 g of 7-allyl-4-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole (m.p. 211°-212° C.) was obtained. This compound (6.4 g) was dissolved in 300 ml of methylene chloride and 10.2 g of m-chloroperbenzoic acid was slowly added to the solution while it was stirred and cooled, and the stirring was continued for 3 hours. After cooling, water and then 50 ml of a 2N sodium hydroxide aqueous solution were added to the mixture, which was extracted with methylene chloride. The mehtylene chloride layer was washed with water and dried, then the solvent was distilled off to yield 5 g of 4-chloro-7,8-dihydro-3-(2-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-methanol. m.p. 109.5°-111° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 319.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:16]/[CH2:17][O:18][C:19]2[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:21]([CH3:31])[CH:20]=2)=[CH:11][CH:10]=1.[CH2:38]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)[C:39]#[CH:40]>O1CCCC1.[Cu]I.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>[CH3:31][C:21]1[CH:20]=[C:19]([O:18][CH2:17]/[CH:16]=[C:15](/[C:12]2[CH:13]=[CH:14][C:9]([C:40]#[C:39][CH2:38][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[CH:10][CH:11]=2)\[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][C:22]=1[O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: C#CCN1CCOCC1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccccc2)c2ccc(Br)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(\c2ccccc2)c2ccc(C#CCN3CCOCC3)cc2)cc1C
Temperature: 50 °C

Procedure:
Dry triethylamine (8 mL), copper(I) iodide (29 mg, 0.152 mmol) and tetrakis(triphenylphosphine)palladium (68 mg, 0.059 mmol) were added to a degassed solution of the above ester (448 mg, 0.931 mmol) and N-propargylmorpholine (291 mg, 2.32 mmol) in dry tetrahydrofuran (18 mL). In atmosphere of argon, the resulting mixture was heated at 50° C. for 10 h, cooled down and subsequently evaporated in vacuo. The residue was dissolved in dichloromethane (20 mL); the solution was washed with water (3×10 mL), dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 4:1-1:1) yielding methyl (E)-[2-methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-phenylallyloxy]phenoxy]acetate as an oil.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.Cl.[CH3:29][O:30][C@@H:31]1[CH2:35][NH:34][CH2:33][C@H:32]1[NH2:36]>>[NH2:36][C@H:32]1[C@H:31]([O:30][CH3:29])[CH2:35][N:34]([C:2]2[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:33]1
Reactant: CO[C@@H]1CNC[C@H]1N
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Agent: Cl
Product: CO[C@@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C[C@H]1N

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 48 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1) and trans-4-methoxypyrrolidin-3-amine dihydrochloride (Stage 78.1) to afford a beige solid. HPLC (Condition 7) tR=5.797 min, UPLC-MS (Condition 3) tR=0.81 min, m/z=479.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.86-2.98 (m, 1H) 3.06-3.19 (m, 1H) 3.21 (s, 3H) 3.25-3.43 (m, 2H) 3.43-3.59 (m, 2H) 6.32-6.46 (m, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.50-7.92 (m, J=8.99 Hz, 3H) 8.03 (s, 1H) 8.62-8.86 (m, 1H) 10.18 (s, 1H) 12.72-13.25 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1>CC(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7][O:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(OCC(=O)c2ccc(Br)cc2)c1

Procedure:
11.5 g of 4-bromophenacyl bromide are dissolved in 250 ml of acetone and, after the addition of 5.75 g of potassium carbonate and 4.5 ml of 3-methoxyphenol, the reaction mixture is stirred and subsequently filtered. The filtrate is concentrated and the residue is chromatographed over silica gel with ethyl acetate/hexane (5:95 to 10:90). There are obtained 7.3 g of 1-(4-bromo-phenyl)-2-(3-methoxy-phenoxy)-ethanone, MS: m/e 320 (M+, 1 Br).
Reaction SMILES: [CH3:1][NH:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[N+:12]([O-])([OH:14])=[O:13]>>[CH3:1][NH:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CNc1nc2ccccc2o1
Reactant: O=[N+]([O-])O
Product: CNc1nc2ccc([N+](=O)[O-])cc2o1
Reaction time: 8 h

Procedure:
2-Methylaminobenzoxazole (2.0 g, Hetzheim, Annemarie; Schlaak, G.; Kerstan, Christa., Pharmazie, (1987), 42, 80) was added in portions to conc. nitric acid (15 ml) at room temperature. Stirring was continued over 8 h. The reaction mixture was poured onto crushed ice/sodium hydrogen carbonate with vigorous stirring. The precipitated title compound (1.76 g) was collected by filtration and dried in vacuo at 40° C. m/z (API+): 194 (MH+).