Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]=1.CS(O[CH2:26][CH2:27][C:28]([CH3:32])=[C:29]([F:31])[F:30])(=O)=O.C(=O)([O-])O.[Na+]>O>[CH3:6][C:7]1[C:11]([C:12]([O:14][CH2:26][CH2:27][C:28]([CH3:32])=[C:29]([F:31])[F:30])=[O:13])=[CH:10][N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]=1
Reactant: Cc1nn(-c2ccccc2)cc1C(=O)O
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCOC(=O)c1cn(-c2ccccc2)nc1C)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.57 g (2.8 mmol) of 3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid, obtained in accordance with a method described in J. Chem. Soc., page 2736 (1961), and 0.58 g (2.9 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate, followed by the addition of 0.48 g (5.7 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:6) to obtain 0.66 g (yield: 76%) of 4,4-difluoro-3-methyl-3-butenyl 3-methyl-1-phenyl-1H-pyrazole-4-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1cccc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCCCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A suspension of 1.84 g (8 mmol) of 3-(3-bromophenyl)propionic acid and 0.91 g (24 mmol) of sodium borohydride in 20 ml of THF, cooled to 0° C., is admixed in small portions with 3.2 ml (25 mmol) of trifluoroborane-diethyl ether complex. Stirring is continued in the cold for 1 hour, and then at ambient temperature for 16 hours. The reaction mixture is cooled to 0° C. and neutralized to a pH of 7˜8 by adding a 1N solution of aqueous sodium hydroxide. It is concentrated under reduced pressure and then the residue is taken up in water. It is extracted with dichloromethane and dried over sodium sulphate. Following filtration, the organic phase is concentrated under reduced pressure. This gives 1.62 g (7.53 mmol) of product in the form of an oil, which is used as it is in the following step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[F:12].CCN(C(C)C)C(C)C.[CH:22]1([C:25]2[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=2)[CH2:24][CH2:23]1>C1COCC1>[CH:22]1([C:25]2[NH:29][N:28]=[C:27]([NH:30][C:5]3[CH:4]=[C:3]([F:12])[C:2]([F:1])=[CH:7][C:6]=3[N+:8]([O-:10])=[O:9])[CH:26]=2)[CH2:24][CH2:23]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c(F)cc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 17.8 %

Procedure:
To a solution of 1,2,4-trifluoro-5-nitrobenzene (3.0 g, 18 mmol) and DIEA (4.2 ml, 24 mmol) in dry THF (20 ml) was added dropwise a solution of 5-cyclopropyl-1H-pyrazol-3-amine (2.0 g, 16 mmol) in THF (5 ml) at 0° C. After addition, the reaction mixture was stirred at 25° C. for 20 hrs. It was then heated to 40° C. for 40 hrs. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane:EtOAc=5:2). Recrystallization from EtOAc (10 ml) and hexanes (˜100 ml) gave the title compound as red crystals (0.8 g, 18%). NMR (400 MHz) 12.36 (s, 1H), 9.79 (s, 1H), 8.27 (m, 2H), 5.93 (s, 1H), 1.90 (m, 1H), 0.93 (m, 2H), 0.72 (m, 2H). MS: Calcd.: 280; Found: [M+H]+ 281.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7][CH2:6]2.[CH3:14]C(C)([O-])C.[K+].CI.[Na+].[Cl-]>CN(C=O)C>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:14])[C:8](=[O:13])[CH2:7][CH2:6]2
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2c(n1)CCC(=O)N2
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)CCC(=O)N2C
Reaction time: 0.17 h
Yield: 64.4 %

Procedure:
A solution of 1.2 g (6.7 mmol) 6-methoxy-3,4-dihydro-1H-[1,5]naphthyridin-2-one in 15 ml of DMF was cooled to 5° C. and to this solution was slowly added 6.7 ml (6.7 mmol) of potassium t-butoxide (1M solution in THF). The mixture was stirred for 10 minutes followed by addition of 0.46 ml (7.4 mmol) methyl iodide. After addition was complete, the reaction mixture was stirred for 1 hour at 5° C. The reaction mixture was poured into saturated NaCl. The mixture was extracted with ethyl acetate. The ethyl acetate extracts were dried (Na2SO4) and evaporated. The residue was chromatographed on silica using 5:1 chloroform/ethyl acetate as the elutant. Appropriate fractions were combined and evaporated to yield 0.83 g of 6-methoxy-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one. TLC Rf=0.6 (1:10 ethyl acetate/chloroform). 1H NMR (CDCl3) δ 7.2 (d, 1H), 6.6 (d, 1H), 3.9 (s, 3H), 3.3 (s, 3H), 3.0 (m, 2H), 2.7 (m, 2H). Mass Spectrum: m/e 193.2 (p+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[O:11][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)=[N:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.[Cl-].[NH4+]>O.[Fe]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:12]2[O:11][C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)=[N:14][N:13]=2)=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(OCc2nnc(Nc3ccc(Cl)c(Cl)c3)o2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc(OCc2nnc(Nc3ccc(Cl)c(Cl)c3)o2)cc1
Yield: 86.7 %

Procedure:
To a stirred solution of N-(3,4-dichlorophenyl)-5-((4-nitrophenoxy)methyl)-1,3,4-oxadiazol-2-amine (150 mg, 0.394 mmol) in water (20 mL)/methanol (20 mL), ammonium chloride (211 mg, 3.94 mmol) and iron powder (176 mg, 3.15 mmol) were added and heated to reflux for 4 hours. The reaction mixture was passed though Celite. Solvent was removed under vacuum to obtain 5-((4-aminophenoxy)methyl)-N-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-amine (0.12 g, 87%). 1H NMR: 400 MHZ, DMSO-d6: δ 5.16 (s, 2H), 5.60 (bs, 2H), 6.62 (d, J=8.40 Hz, 2H), 6.82 (dd, J=2.00, 6.80 Hz, 2H), 7.48 (dd, J=2.40, 8.80 Hz, 1H), 7.61 (d, J=8.80 Hz, 1H), 7.89 (d, J=2.80 Hz, 1H), 11.00 (s, 1H). LCMS: RT 1.66 min. LCMS (ES-API), m/z 351.0 (M+H).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C:7]([O:9][C@@H:10]4[O:16]3)=[O:8])[CH2:4][CH2:3]1.O=[CH:22][C@@H:23]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[BH4-].[Na+].Cl[Si](C)(C)C>C(O)C>[CH3:22][CH2:23][O:8][C@H:7]1[O:9][C@@H:10]2[O:16][C:15]3([CH3:19])[O:17][O:18][C@@:11]42[C@@H:5]([CH2:4][CH2:3][C@@H:2]([CH3:1])[C@@H:12]4[CH2:13][CH2:14]3)[C@H:6]1[CH3:20]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCO[C@H]1O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]([C@H]1C)[C@@]24OO3
Temperature: 21.5 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
Artemisinin (1 g.) and polyhydroxy catalyst, dextrose (4 g.) were stirred in ethanol (15 ml). Sodium borohydride (500 mg.) was added slowly for 10 minutes and the reaction mixture was stirred for 30 minutes at room temperature (20-23° C.). After completion of the reduction step, chlorotrimethysilane (3.5 ml) was added and the reaction mixture was further stirred for 1.5 hours at room temperature. After usual work up and purification through column chromatography (1:5 ratio) a mixture of alpha and beta arteether (0.805 g., 80.5% w/w) were obtained.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]1[CH3:13])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[N+:19]([O-])([O-:21])=[O:20].[K+]>>[C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:8]([CH3:13])=[CH:9][C:10]([N+:19]([O-:21])=[O:20])=[C:11]1[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCn1c(C)ccc1C
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)NCCn1c(C)cc([N+](=O)[O-])c1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
18.0 g (0.1 mol) of 1-(2-acetylaminoethyl)-2,5-dimethylpyrrole are introduced into 54 ml of concentrated sulphuric acid at -10° C., during which the temperature rises to 9° C. After the mixture has been subsequently stirred for 5 minutes, 10.9 g (0.11 mol) of potassium nitrate are introduced at about 5° C. After further stirring for 30 minutes, the mixture is poured onto 300 g of ice and extracted with methylene chloride, the extract is concentrated and the residue is chromatographed over a short silica gel column.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)O)=[CH:7][C:6]=2[CH:19]=1.S(Cl)([Cl:22])=O>C(Cl)Cl.C1CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([Cl:22])[C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[CH:7][C:6]=2[CH:19]=1
Reactant: OC(c1ccc(Cl)cc1)c1cc2cc(Br)ccc2o1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: C1CCCCC1
Product: Clc1ccc(C(Cl)c2cc3cc(Br)ccc3o2)cc1
Reaction time: 4 h

Procedure:
To 36.2 g of (5-bromobenzofuran-2-yl)(p-chlorophenyl)methanol dissolved in 50 ml of methylenchloride, 8.5 ml of thionylchloride in 25 ml of cyclohexane are added drop by drop, under agitation. After a 4 hour rest at 10° C., the solution is brought to dryness under vacuum condition. The residue is crystallized from petroleum ether: m.p. 83°-85° C.
Reaction SMILES: [C:1]([C:4]1[C:14]2[O:13][CH2:12][CH2:11][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(O)=[O:2].O.O[N:22]1C2C=CC=CC=2N=N1.N>O1CCCC1>[C:1]([C:4]1[C:14]2[O:13][CH2:12][CH2:11][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:2])[NH2:22]
Reactant: CCOC(=O)C1=Cc2cccc(C(=O)O)c2OCC1
Reactant: On1nnc2ccccc21
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2cccc(C(N)=O)c2OCC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 31.9 %

Procedure:
A solution of ethyl 9-carboxy-2,3-dihydro-1-benzoxepin-4-carboxylate (1.0 g) in tetrahydrofuran (10 ml) was cooled in an ice bath. To this solution was added 1-hydroxybenzotriazole hydrate (0.57 g) and 1-(3-dimethylaminopropyl)-3-ethylcarboxiimide hydrochloride (0.80 g). Thereto aqueous ammonia (0.28 ml) was added dropwise at 5° C. The reaction mixture was stirred for 7 hours at ambient temperature and partitioned between ethyl acetate and 1N hydrochloric acid. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of chloroform and methanol (9:1) to give ethyl 2,3-dihydro-9-carbamoyl-1-benzoxepin-4-carboxylate (0.31 g).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.[O:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:45][CH:42]1[CH2:43][CH2:44][O:39][CH2:40][CH2:41]1)=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NC1CCOCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NC1CCOCC1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 40 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.07 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (38.2 μL, 0.348 mmol), tetrahydro-2H-pyran-4-amine (12.66 mg, 0.125 mmol), and BOP (55.4 mg, 0.125 mmol). The reaction mixture was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide (14.3 mg, 0.028 mmol, 40%): LCMS=515.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.06-8.25 (2 H, m), 7.49-7.78 (7 H, m), 5.04-5.18 (1 H, m), 3.81-4.01 (2 H, m), 3.38-3.58 (2 H, m), 1.73-1.93 (2 H, m), 1.48-1.73 (2 H, m); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 90:10 acetonitrile:water with 10 mM ammonium acetate; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.6 min.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.CCCCCC.C([Li])CCC.[F:18][C:19]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=1[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[F:18][C:19]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=1[CH:21]([OH:22])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: Brc1nccs1
Reactant: O=Cc1cc(F)ccc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1nccs1)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
To a tetrahydrofuran (10 ml) solution of 2-bromothiazole (180 μg, 2 mmol) was added dropwise a hexane solution (1.57M, 1.40 ml, 2.2 mmol) of n-butyl lithium at −78° C., followed by stirring for 10 minutes. Then, 2,5-difluorobenzaldehyde (238 μl, 2.2 mmol) was added and the temperature of the resulting mixture was raised gradually to 0° C. under stirring. An aqueous solution of ammonium chloride was added to terminate the reaction and ether was added to the reaction mixture. The ether layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. After filtration, the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (358 mg, 79%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:14])[CH2:11][C:10](=O)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.P(Br)(Br)([Br:24])=O.C(=O)([O-])O.[Na+]>C(#N)C>[Br:24][C:10]1[CH2:11][CH:12]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1
Reactant: CCCCCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Reaction time: 0.08 h
Yield: 137.5 %

Procedure:
A mixed solution comprising 1.2 g of pentyl 2-(3-chloropyridin-2-yl)-5-oxopyrazolidine-3-carboxylate, 0.59 g of phosphorus oxybromide and 18 ml of acetonitrile was gradually heated, and 25 minutes later, the mixed solution was refluxed with heating for one hour. After the reaction liquid was stood to cool, it was slowly added to a saturated sodium hydrogen carbonate aqueous solution, followed by stirring for 5 minutes. The mixed liquid was subjected to extraction with ethyl acetate, and the organic layer was washed with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 to 8/2) to obtain 1.06 g of the desired product (melting point: 39 to 42° C.) in the form of pale yellow crystals.
Reaction SMILES: C([O:5][NH:6][C:7]([C:9]1[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[F:23])=[C:13]([F:24])[C:12](=[O:25])[N:11]([CH3:26])[CH:10]=1)=[O:8])(C)(C)C.C(O)(C(F)(F)F)=O>>[OH:5][NH:6][C:7]([C:9]1[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[F:23])=[C:13]([F:24])[C:12](=[O:25])[N:11]([CH3:26])[CH:10]=1)=[O:8]
Reactant: Cn1cc(C(=O)NOC(C)(C)C)c(Nc2ccc(Br)cc2F)c(F)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(C(=O)NO)c(Nc2ccc(Br)cc2F)c(F)c1=O
Reaction time: 96 h
Yield: 33 %

Procedure:
4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid hydroxyamide was prepared from 4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid tert-butoxyamide by TFA mediated deprotection. 4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid tert-butoxyamide (35 mg, 0.081 mmol) was treated with TFA (0.63 mL). After 4 days stirring, the reaction mixture was concentrated under reduced pressure. Purification by flash column chromatography (10% MeOH in methylene chloride) followed by saturated NaHCO3 solution wash of an ethyl acetate solution of the product gave clean desired product (10 mg, 33%); MS APCI (+) m/z 356, 358 (M−OH, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 7.84 (s, 1H), 7.35 (dd, 1H), 7.28 (d, 1H), 7.01 (td, 1H), 3.57 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([F:29])[C:5]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[Cl:28])=[C:6]([CH:19]=1)[C:7]([NH:9][O:10][CH2:11][CH:12]1[CH2:16][O:15]C(C)(C)[O:13]1)=[O:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[Cl:1][C:2]1[C:3]([F:30])=[C:4]([F:29])[C:5]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[Cl:28])=[C:6]([CH:19]=1)[C:7]([NH:9][O:10][CH2:11][CH:12]([OH:13])[CH2:16][OH:15])=[O:8]
Reactant: CC1(C)OCC(CONC(=O)c2cc(Cl)c(F)c(F)c2Nc2ccc(I)cc2Cl)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: O=C(NOCC(O)CO)c1cc(Cl)c(F)c(F)c1Nc1ccc(I)cc1Cl

Procedure:
To a stirring solution of 5-chloro-2-(2-chloro-4-iodo-phenylamino)-N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-benzamide (3.7 g, 6.45 mmol) in methanol (20 mL) and water (2 mL) was added p-toluenesulfonic acid (0.12 g, 0.65 mmol). After 20 hours the reaction was concentrated in vacuo. The afforded residue was partitioned between ethyl acetate and water. The organic layer was washed twice with saturated NaHCO3 solution and twice with saturated brine solution. The organic layers were collected, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by crystallization with methanol/water and the solids were dried in a vacuum oven at 40° C. to afford 5-chloro-2-(2-chloro-4-iodo-phenylamino)-N-(2,3-dihydroxy-propoxy)-3,4-difluoro-benzamide: m.p.=152-154° C.; 1NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.83 (s, 1H), 7.76 (s, 1H), 7.66 (d, 1H, J=6.8), 7.47 (d, 1H, J=8.5), 6.68 (t, 1H, J=6.6), 4.83 (bs, 1H), 4.60 (bs, 1H), 3.89-3.92 (m, 1H), 3.68-3.76 (m, 2H), 3.30 (2H, partially hidden by HDO); MS(APCI+)=533.0/535.0; Anal.calcd/found for C16H13Cl2F2IN2O4: C, 36.05/36.23; H, 2.46/2.40; N, 5.25/5.03; F, 7.13/7.14.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:52]=[CH:51][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28](=[O:35])[N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:25][C:19]=3[N:18]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([N:45]4[CH2:49][CH:48]=[CH:47][CH2:46]4)=[O:44])=[CH:39][CH:38]=3)[C:17](=[O:50])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.C=O.[C:55](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28]([N:29]4[CH2:34][CH2:33][N:32]([CH3:55])[CH2:31][CH2:30]4)=[O:35])=[CH:25][C:19]=3[N:18]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([N:45]4[CH2:46][CH:47]=[CH:48][CH2:49]4)=[O:44])=[CH:39][CH:38]=3)[C:17](=[O:50])[CH2:16]2)=[O:14])=[CH:51][CH:52]=1
Reactant: CC(=O)O
Reactant: O=C(CCc1ccc2c(c1)N(Cc1ccc(C(=O)N3CC=CC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2)N1CCNCC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C(=O)CCc2ccc3c(c2)N(Cc2ccc(C(=O)N4CC=CC4)cc2)C(=O)CN(C(=O)c2ccc(Cl)cc2)C3)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 mg (0.014 mmol) of 4-(4-chlorobenzoyl)-1-[4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzyl]-8-[3-oxo-3-(1-piperazinyl)propyl]-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on trifluoroacetate was dissolved in 2 ml of dichloromethane. 5 mg of paraformaldehyde and 0.005 ml (0.09 mmol) of acetic acid were added to the obtained solution and they were stirred at room temperature for 30 minutes. 24 mg (0.12 mmol) of sodium triacetoxyborohydride was added to the obtained mixture and they were stirred at room temperature overnight. The solvent was evaporated and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:9]2.[Cl:26][CH:27]=[CH:28][CH2:29]Cl>CN(C=O)C>[Br:3][C:4]1[C:5]([N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:29][CH:28]=[CH:27][Cl:26])=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:9]2
Reactant: ClC=CCCl
Reactant: COC(=O)c1ccc2ccc(NC(=O)OC(C)(C)C)c(Br)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccc(N(CC=CCl)C(=O)OC(C)(C)C)c(Br)c2c1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
NaH (57 mg, 1.42 mmol, 60% in oil) was added to a solution of bromide 180 (450 mg, 1.18 mmol) in DMF (5 mL) at 0° C. 1,3-Dichloropropene (260 mg, 2.37 mmol) was added and the mixture was allowed to warm to room temperature over 1 h, then concentrated under reduced pressure CH2Cl2 and water were added and the organic phase was washed with water (×2), brine (×2), dried, and filtered through silica gel to give methyl 8-bromo-7-[(tert-butoxycarbonyl)(3-chloro-2-propen-1-yl)amino]-2-naphthoate (181) (520 mg, 97%) as a yellow oil; 1H NMR (CDCl3) (mixture of rotamers and E and Z forms) δ 9.07 (s, 10H), 8.18-8.08 (m, 1H), 7.93-7.78 (m, 2H), 7.42-7.32 (m, 1H), 6.15-5.98 (m, 2H), 4.01 (s, 3H), 4.63-4.48 (m, 2H), 1.26, 1.24 (2 s, 9H). HRMS (FAB) calcd. for C20H2179Br35ClNO4 (MH+) m/z 454.0421, found 454.0421.