Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[C:9]([O:33][CH3:34])=[N:10][CH:11]=[CH:12][C:13]=1[C:14]([OH:32])([CH2:30][CH3:31])[CH2:15][C:16](N1[C@H](C2C=CC=CC=2)COC1=O)=[O:17])(C)(C)C.[Li+].[OH-:38].OO.[OH-].[Na+]>C1COCC1>[OH:32][C@:14]([C:13]1[CH:12]=[CH:11][N:10]=[C:9]([O:33][CH3:34])[C:8]=1[CH2:7][OH:6])([CH2:30][CH3:31])[CH2:15][C:16]([OH:17])=[O:38]
Reactant: CCC(O)(CC(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccnc(OC)c1C(C)(C)O[SiH2]C(C)(C)C
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@](O)(CC(=O)O)c1ccnc(OC)c1CO
Reaction time: 0.5 h

Procedure:
To a solution of 3.11 g (R)-3-{3-[3-(tert-butyl-dimethyl-silanyloxymethyl)-2-methoxy-pyridin-4-yl]-3-hydroxy-pentanoyl}-4-phenyl-oxazolidin-2-one (6.04 mmol), as obtainable from example 18, in 35 mL THF were added at 0° C. 37.8 mL aqueous LiOH solution (0.8 M, 30.2 mmol, 5.0 eq) and 3.02 mL aqueous H2O2 solution (10.0 M, 30.2 mmol, 5.0 eq). After 30 min, 220 mL aqueous NaOH solution (2 M) were added and the ice bath was removed. The reaction was monitored by HPLC. After 2 h (<0.2% area (R)-3-{3-[3-(tert-butyl-dimethyl-silanyloxymethyl)-2-methoxy-pyridin-4-yl]-3-hydroxy-pentanoyl}-4-phenyl-oxazolidin-2-one), the resulting emulsion was extracted 7 times with 100 mL, in total 700 mL TBME. The aqueous phase was acidified with aqueous HCl in order to adjust pH 3.0 and extracted nine times with 100 mL, in total 900 mL dichloromethane/ethanol (4:1). After evaporation in a rotary evaporator (40° C., 5 mbar), the title product was obtained as a colorless semisolid (700 mg, 2.74 mmol, yield of 45% w/w, or 85% when calculated over the two steps) and in a purity of 89.2% as determined by HPLC (er=80.47:19.53, see Chiral HPLC method below).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([N:14]3[C:19](=[O:20])[C:18]([CH3:21])=[CH:17][C:16]([CH3:22])=[N:15]3)[C:11](O)=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:35]([C:38]1[CH:43]=[CH:42][C:41]([S:44]([NH2:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1)([CH3:37])[CH3:36].N12CCCN=C1CCCCC2>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([N:14]3[C:19](=[O:20])[C:18]([CH3:21])=[CH:17][C:16]([CH3:22])=[N:15]3)[C:11]([NH:47][S:44]([C:41]3[CH:42]=[CH:43][C:38]([CH:35]([CH3:37])[CH3:36])=[CH:39][CH:40]=3)(=[O:45])=[O:46])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1cc(C)c(=O)n(C(C(=O)O)c2ccc3c(c2)OCO3)n1
Reactant: CC(C)c1ccc(S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1cc(C)c(=O)n(C(C(=O)NS(=O)(=O)c2ccc(C(C)C)cc2)c2ccc3c(c2)OCO3)n1
Reaction time: 1 h

Procedure:
A solution of 0.8 g of 2-(1,3-benzodioxol-5-yl)-2-(4, 6-dimethyl-2,3-dihydropyridazin-3-on-2-yl)acetic acid and 0.64 g of carbonyldiimidazole in 50 ml of THF is heated at 60° for 2 hours. 0.79 g of 4-isopropylbenzenesulfonamide and 0.59 g of 1, 8-diazabicyclo[5.4.0]undec-7-ene are then added and the mixture is stirred at this temperature for a further 1 hour. After customary working up, 2-(1,3-benzodioxol-5-yl)-2-(4,6-dimethyl-2,3-dihydropyridazin-3-on-2-yl) N-(4-isopropylphenylsulfonyl)acetamide is obtained, m.p. 105°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].Cl[C:8]1[S:9][C:10]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.C(N(C(C)C)CC)(C)C.N.CO>O.C(Cl)Cl.CN(C=O)C>[N+:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])[S:9][C:10]=2[CH:16]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Reactant: NCCCCO
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc2nc(NCCCCO)sc2c1
Temperature: 100 °C
Yield: 18 %

Procedure:
In an oven fried vial charged with 4-amino-1-butanol (172 μl, 2 eq.), 2-chloro-6-nitro-benzothiazol (200 mg, 0.93 mmol) and diisopropyl-ethylamine (1 mL) was added DMF (5 mL). The dark brown mixture was heated at 100° C. for 2 hours. After cooling, the mixture was diluted with 20 mL of water and extracted with ethyl-acetate (50 mL). The ethyl acetate layer was washed with brine, dried over MgSO4 and then evaporated to give a dark residue. This residue was subjected to silica gel chromatography (7% 2M ammonia/methanol in CH2Cl2) to give the desired product (45 mg, 18%). 1H NMR (CD3OD) δ: 8.55 (d, 1H, J=2.3 Hz), 8.17 (dd, 1H, J=2.3, 8.9 Hz), 7.47 (d, 1H, J=8.9 Hz), 3.63 (m, 3H), 3.53 (t, 2H, J=6.8 Hz), 1.80–1.75 (m, 2H), 1.70–1.65 (m, 2H); MS (M+1, 268).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.[CH2:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH2:22][NH2:23])[CH3:16].[ClH:24]>CO>[ClH:24].[ClH:24].[CH2:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH2:22][NH:23][C:12]([C:5]1[C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]=2[C:2]([NH2:1])=[CH:3][CH:4]=1)=[O:14])[CH3:16]
Reactant: CCN1CCCC1CN
Reactant: Nc1ccc(C(=O)O)c2c1OCCO2
Agent: Cl
Solvent: CO
Product: CCN1CCCC1CNC(=O)c1ccc(N)c2c1OCCO2
Yield: 72.7 %

Procedure:
According to the method described in Example 2, 42 g of 8 -amino-1,4-benzodioxane-5-carboxylic acid were treated with methanol and the resulting compound treated with 33 g of 1-ethyl-2-aminomethylpyrrolidine and then a solution of 13 g of hydrochloric acid in absolute alcohol. 49 g of N-(1-ethyl-2-pyrrolidylmethyl)-8-amino-1,4-benzodioxane-5-carboxamide dihydrochloride were obtained (M.P.: 173° C.; yield: 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17](=[O:23])[C:18]([CH3:22])([CH3:21])[CH:19]=[CH2:20]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17](=[O:23])[C:18]([CH3:22])([CH3:21])[CH:19]=[CH2:20])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C=CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CC(C)(C)C(=O)COc1ccc(Cl)cc1
Temperature: 20 °C
Yield: 79 %

Procedure:
92.9 g (0.723 mol) of 4-chlorophenol were heated to the boil with 99.7 g (0.723 mol) of finely powdered potassium carbonate in 500 ml of acetone. 106 g (0.723 mol) of 5-chloro-3,3-dimethylpent-1-en-4-one were added dropwise to the mixture in the course of 30 minutes, while stirring vigorously. After the mixture had been heated under reflux for four hours, it was cooled to 20° C. and filtered off from the inorganic salts, and the filtrate was concentrated. After the liquid residue had been distilled, 136.3 g (79% of theory) of 5-(4-chlorophenoxy)-3,3-dimethylpent-1-en-4-one of boiling point 111° to 113° C./0.07 mm Hg were obtained. ##STR28##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:31])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28]>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:31][C:14](=[O:16])/[CH:13]=[CH:12]/[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)CCc1ccc(N)cc1Cl
Solvent: CN(C)C=O
Product: CCN(CC)CCc1ccc(NC(=O)/C=C/c2ccc(C(F)(F)F)cc2Cl)cc1Cl

Procedure:
Prepared in DMF analogously to Example 143 starting from (E)-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylic acid (Z37b) and 3-chloro-4-(2-diethylamino-ethyl)-phenylamine (Z44d). The reaction mixture was poured onto ice water, the precipitate was filtered off, washed with water and dried in a HV. The residue was triturated with ether, the precipitate was filtered off, washed with ether and dried in a HV.
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:20](Br)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[O:3]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)Cc1ccc(Oc2ccccc2)cc1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)C(CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Yield: 61 %

Procedure:
11.2 g of 60% oily sodium hydride was suspended in 200 ml of dimethylformamide, and a solution of 56.0 g of 4-phenoxyphenylacetone in 100 ml of dimethylformamide, was added under cooling with ice with stirring, followed by stirring at the same temperature for 5 minutes and at room temperature for 30 minutes. Then, the reaction solution was again cooled with ice, and 52.0 g of phenethyl bromide was added. The reaction solution was gradually returned to room temperature and then stirred for 30 minutes, and water was added to the reaction solution, followed by extraction with ethyl ether. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain 50.6 g (yield: 61%) of the above identified compound as a pale yellow oily substance.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:14]=[C:13](OS(C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)(=O)=O)[C:12]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C:42]#[N:43])=[CH:37][CH:36]=2)=[C:11]([CH3:44])[N:10]=1.[CH2:45]([NH2:50])[CH2:46][CH2:47][CH2:48][CH3:49].[Li+].[OH-]>C(OCCCC)(=O)C.C1(C)C=CC=CC=1.C1COCC1>[NH2:8][C:9]1[N:10]=[C:11]([CH3:44])[C:12]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([CH2:41][C:42]#[N:43])=[CH:39][CH:40]=2)=[C:13]([NH:50][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[N:14]=1
Reactant: CCCCCN
Reactant: Cc1nc(N)nc(OS(=O)(=O)c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1Cc1ccc(CC#N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2.19 g, 19.2 mmol) was added to a suspension of the product from step (iii) (10.0 g, 19.2 mmol) and n-pentylamine (5.0 g, 57.6 mmol) in butyl acetate (65.0 g), and the mixture was heated at 120° C. for 6 hours. The mixture was cooled and concentrated under reduced pressure to give a solid. A suspension of the solid in toluene (30.0 g) was concentrated under reduced pressure again to give a solid. 5% aq. LiOH (60.0 g) was added to the solution of the solid in toluene (55.0 g) and THF (14.0 g), and the mixture was stirred at 40° C. The separated organic layer was washed with water (60.0 g) at 40° C. and concentrated under reduced pressure to afford a solid. A suspension of the obtained solid in toluene (42.0 g) was stirred at 54° C. for 1 hour and cooled to 5° C. and stirred at 5° C. for 10 hours. The resulting precipitate was collected by filtration and washed with acetonitrile (5.0 g) and water (12.0 g) respectively to give the subtitle compound as wet crystals. 5.90 g. This product was used in the next step without desiccation.
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][NH:7][CH2:8][C@@H:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:33]=1)[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])=[O:23].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[CH3:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][NH:24][C:22]([C:21]1[CH:33]=[C:17]([N:7]2[CH2:6][C@@H:5]3[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C@@H:4]3[CH2:8]2)[CH:18]=[N:19][CH:20]=1)=[O:23]
Reactant: Cc1ccccc1CNC(=O)c1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1CNC(=O)c1cncc(N2C[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C2)c1
Temperature: 95 °C
Yield: 90.4 %

Procedure:
The product from Example 1C (80 mg, 0.38 mmol), the product from Example 31A (155 mg, 0.51 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (34 mg, 0.034 mmol), tris(dibenzylideneacetone)dipalladium(0) (10.4 mg, 0.011 mmol), and sodium tert-butoxide (54.2 mg, 0.054 mmol) were combined with toluene (5 mL). The suspension was evacuated and purged with nitrogen. The mixture was heated at 95° C. under nitrogen for 4 h. The residue was partitioned between saturated sodium bicarbonate solution(aq) (100 mL) and EtOAc (2×50 mL). The combined organic extract was washed with brine (100 mL), dried (Na2SO4) and concentrated under vacuum. The residue was purified by flash chromatography (eluted with EtOAc) on silica to provide the title compound (150 mg, 91%). MS (APCI) m/z 437 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=2OS(C(F)(F)F)(=O)=O)[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](=[N:47][NH2:48])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOCC.O.Cl[Pd]Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=2[NH:48][N:47]=[C:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(-c2ccc(Cl)c(OCc3ccccc3)c2)n1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1ccc(NN=C(c2ccccc2)c2ccccc2)c(-c2ccc(Cl)c(OCc3ccccc3)c2)n1
Temperature: 90 °C
Yield: 88.5 %

Procedure:
Put 2 g (4 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate in 10 mL of anhydrous toluene in a screw-top bottle. To the solution, under argon, add successively 938 mg (4.78 mmol) of benzophenone hydrazone, 1.95 g (6 mmol) of caesium carbonate and 65 mg (0.08 mmol) of PdCl2 (dppf). Heat the reaction mixture for 3 h at 90° C. while stirring, then distribute in 100 mL of ether/water 1:1 mixture. Dry the organic phase over Na2SO4 and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a DCM/acetone gradient from 0 to 5% of acetone. After concentration under reduced pressure, we obtain 1.94 g of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-[2-(diphenylmethylidene)hydrazino]pyridine-2-carboxylate in the form of oil.
Reaction SMILES: [OH-].[NH4+:2].C(OC([NH:10][C@H:11]([C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([F:34])[CH:27]=3)=[CH:25][C:19]=2[N:18]=1)[C@@H:12]([CH3:16])[C:13](O)=[O:14])=O)(C)(C)C>C(Cl)Cl.C1CCCCC1>[NH2:10][C@H:11]([C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([F:34])[CH:27]=3)=[CH:25][C:19]=2[N:18]=1)[C@@H:12]([CH3:16])[C:13]([NH2:2])=[O:14]
Reactant: [NH4+]
Reactant: C[C@@H](C(=O)O)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(-c3ccc(C#N)c(F)c3)ccc2[nH]1
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C[C@@H](C(N)=O)[C@H](N)c1nc2cc(-c3ccc(C#N)c(F)c3)ccc2[nH]1

Procedure:
The title compound was prepared according to Preparation 28 using ammonium hydroxide and (2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-[5-(4-cyano-3-fluorophenyl)-1H-benzimidazol-2-yl]-2-methylpropanoic acid (Preparation 32). The residue was sonicated in DCM:cyclohexane 5:1 to afford the boc protected amide intermediate. The residue was dissolved in 4M HCl in dioxane and stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue dissolved in MeOH and passed through an SCX cartridge eluting first with MeOH followed by 3M NH3 in MeOH. The residue was purified using silica gel column chromatography eluting with DCM:MeOH:NH3 (90:10:0.5) to afford the title compound (55 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12]([O:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=1[F:26])(=[O:14])=[O:13])=[CH:7][CH:6]=2.OO.NC(N)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.P(Br)(Br)([Br:48])=O>O.C(Cl)Cl>[Br:48][C:4]1[C:5]2[C:10](=[CH:9][C:8]([S:12]([O:15][C:16]3[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=3[F:26])(=[O:14])=[O:13])=[CH:7][CH:6]=2)[CH:11]=[C:2]([Cl:1])[N:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2cnc(Cl)cc2c1
Agent: NC(N)=O
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Br)nc(Cl)cc2c1
Reaction time: 15 h
Yield: 33.4 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 3-chloroisoquinoline-6-sulfonate (1.21 g, 2.95 mmol) and DCM (11.81 ml) to give a clear solution. Urea compound with hydrogen peroxide (1:1) (0.556 g, 5.91 mmol) was added, resulting in a suspension. The flask was cooled in an ice-water bath for 10 min, then 2,2,2-trifluoroacetic anhydride (0.834 ml, 5.91 mmol) was added over 20 s. The cooling bath was removed, the flask was sealed, and the mixture was stirred overnight for 15 h. An additional portion of TFAA (0.3 mL) was added, and the mixture was stirred for 5 h. The mixture was carefully quenched with saturated aq. sodium bicarbonate solution (50 mL), then diluted with water and extracted with DCM (3×). The cloudy organic layer was stirred over sodium sulfate for 2 min, which resulted in the formation of an orange solution. The mixture was filtered, and the filtrate was concentrated under a vacuum. The residue was dissolved in DCM (5 mL) to give an orange solution. Phosphoryl tribromide (1.693 g, 5.91 mmol) was added in one portion, and the mixture was stirred further at room temperature. After 1 h, the mixture was poured into ice, then diluted with water and DCM. When it had achieved room temperature, the layers were separated. The aq. layer was extracted with DCM (2×), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The aq. layer was further diluted with water and extracted with DCM (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated with residue from the first organic extraction. The combined residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 25-g loading column, 0-40% EtOAc/Heptane) to give perfluorophenyl 1-bromo-3-chloroisoquinoline-6-sulfonate (0.482 g, 0.986 mmol, 33.4% yield) as a white solid: m/z (ESI) 488.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1CCCCC1.[N+:21]([CH2:24][CH3:25])([O-:23])=[O:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]=[C:24]([N+:21]([O-:23])=[O:22])[CH3:25])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)o1
Solvent: C1CCNCC1
Product: CC(=Cc1ccc(-c2ccc(Cl)cc2)o1)[N+](=O)[O-]

Procedure:
A mixture of 82 g (0.4 mole) of 5-(p-chlorophenyl)-2-furaldehyde in 400 ml of nitroethane together with 4 ml of piperidine was heated at reflux for 2 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=O)[NH:6][CH:5]2[OH:13].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[F:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[F:1])[C:5](=[O:13])[NH:6][CH2:7]2
Reactant: O=C1NC(O)c2cc(F)c(F)cc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
748 mg of 5,6-difluoro-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (crude product, about 4.04 mmol) were initially charged in 50 ml of dichloromethane, 3.8 ml (48.5 mmol) of trifluoroacetic acid and 1.3 ml (8.08 mmol) of triethylsilane were added and the mixture was stirred overnight at RT. The reaction mixture was then concentrated, and the residue was dissolved in dichloromethane and washed with sodium bicarbonate solution. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 1:1 to 0:1). This gave 72 mg (10.6% of theory) of the target compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH:14][CH3:15])=[O:13])[CH:3]=1.CCN(C(C)C)C(C)C.[F:28][C:29]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:30]=1[O:31][CH:32]1[CH2:35][NH:34][CH2:33]1>C(O)(C)C>[Cl:40][C:38]1[CH:37]=[CH:36][C:30]([O:31][CH:32]2[CH2:35][N:34]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=4)[C:12]([NH:14][CH3:15])=[O:13])[CH:3]=3)[CH2:33]2)=[C:29]([F:28])[CH:39]=1
Reactant: CNC(=O)c1cccc(Nc2cc(Cl)ccn2)c1
Reactant: Fc1cc(Cl)ccc1OC1CNC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc(Nc2cc(N3CC(Oc4ccc(Cl)cc4F)C3)ccn2)c1
Temperature: 80 °C
Yield: 20.5 %

Procedure:
To a solution of 3-((4-chloropyridin-2-yl)amino)-N-methylbenzamide (0.300 g, 1.14 mmol) in Isopropanol (4 mL) was added DIPEA (0.3 mL, 1.71 mmol) and 3-(2-fluoro-4-chlorophenoxy)azetidine (0.230 g, 1.14 mmol) [prepared as described in Example AAA] and the reaction mixture was heated at 80° C. for 7 h. The mixture was concentrated under reduced pressure and extracted with EtOAc (2×20 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 3-((4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)pyridin-2-yl)amino)-N-methylbenzamide (0.10 g, 3%) as a solid. Observed mass (M+1): 427.1
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.Cl.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]2[N:9]=[C:10]3[C:5]([CH:4]=[CH:3][C:2](=[O:1])[NH:11]3)=[CH:6][CH:7]=2)[CH2:29][CH2:28]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2[nH]1
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a solution of 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (crude from previous reaction) in dichloroethane (6 mL) was added 2,3-dichlorophenylpiperazine hydrochloride (321 mg, 1.20 mmol) followed by Et3N (0.34 mL, 2.40 mmol, 2 equiv). The resulting suspension was stirred for 5 min and NaBH(OAc)3 (356 mg, 1.68 mmol, 1.4 equiv) was added as a powder. The reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated NaHCO3 and H2O and the mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography (4–5% MeOH/CH2Cl2) gave the title compound as a white foam (378 mg, 0.845 mmol, 70% over 2 steps). The foam was dissolved in Et2O/CH2Cl2 and 1 N HCl in Et2O (0.82 mL) was added. The resulting white precipitate was collected by filtration, washed with Et2O and dried to give a white solid (355 mg). MS: APCI: M+1: 447.1 (Exact Mass: 446.13).