Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=[O:33])C=1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[N+:4]([O-:33])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:11]=2[N:12]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(-c2nc3cc(C(F)(F)F)ccc3o2)c(F)c1
Temperature: 50 °C
Yield: 64 %

Procedure:
To a mixture of 0.34 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 6 ml of chloroform, 0.48 g of 65% m-chloroperbenzoic acid was added at room temperature. The solution was stirred while heating at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate, and then washed with a saturated aqueous solution of sodium hydrogencarbonate twice and a saturated sodium chloride solution once, sequentially. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.23 g of 3-fluoro-4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide (hereinafter, referred to as “active compound 26”).
Reaction SMILES: C(Cl)Cl.[F:4][C:5]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:6]=1[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH2:17][OH:18])[C:11]=2[N:10]=[C:9]1[C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[F:26]>N1C=CC=CC=1.N1C=CC=CC=1.C(Cl)Cl>[F:4][C:5]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:6]=1[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH:17]=[O:18])[C:11]=2[N:10]=[C:9]1[C:19]1[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=1[F:25]
Reactant: OCc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Reaction time: 6 h
Yield: 78 %

Procedure:
To CrO3 (1.26 g) dissolved in pyridine (1.0 mL) and CH2Cl2 (9.0 mL) was added 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-hydroxylmethylbenzimidazole (Example 112) (0.49 g, 1.27 mmol) dissolved in pyridine:CH2Cl2 (1:1) (2 mL). After stirring for 6 h, the reaction was filtered. The filtrate was diluted with CH2Cl2, and washed with NaHCO3 (sat. soln) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash chromatography eluting with 1% methanol/CH2Cl2. Recrystallization from diethylether:hexane (3:1) yielded white crystals of 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-benzimidazole-4-carbaldehyde (0.38 g, 0.99 mmol, 78% yield). M.p. 151-153° C. 1H-NMR (300 MHz, CD2Cl2): δ10.82 (d, J=0.6 Hz, 1H, CHO), 7.83 (dd, J=7.5, 1.1 Hz, 1H, H7), 7.78 (dd, J=8.1, 1.1 Hz, H5), 7.58 (m, 1H, H4′), 7.44 (ddd, J=8.1, 7.5, 0.6 Hz, 1H, H6), 7.27 (m, 1H, H4″), 7.11 (m, 2H, H3′,5′), 6.84 (m, 2H, H3″,5″), 5.42 (s, 2H, CH2PhF2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.C([OH:31])(C)(C)C>[Zn]>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:31])[CH2:9]2
Reactant: COC(=O)[C@@H](Cc1ccc2[nH]ccc2c1)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)O
Agent: [Zn]
Product: COC(=O)[C@@H](Cc1ccc2c(c1)CC(=O)N2)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 41 %

Procedure:
PyHBr3 (1.28 g, 4.02 mmol) was added in small portions over 30 min to a solution of (R)-2-benzyloxycarbonylamino-3-(1H-indol-5-yl)-propionic acid methyl ester (0.47 g, 1.34 mmol) in t-butanol (10 mL) while the reaction temperature was maintained between 25–30° C. The resulting mixture was stirred at room temperature for 3.5 h. The solvent was removed in vacuo, and the residue was extracted with ethyl acetate (2×). The combined organic phases were washed with brine and dried over sodium sulfate. After filtration, solvents were removed and the residue was azeotropically dried with anhydrous ethanol. The residue was dissolved in glacial acetic acid (10 mL) and zinc powder (0.88 g, 13.4 mmol) was added. The mixture was stirred at room temperature overnight. After the acetic acid was removed in vacuo, the residue was purified by flash chromatography on silica gel using ethyl acetate/hexanes [(1:3) first and then (3:2)] as eluent to afford the title compound as a white solid (41% for 2 steps). 1H-NMR (CDCl3, 500 MHz) δ 8.03 (s, 1H), 7.36–7.31 (m, 5H), 6.94 (s, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.73 (d, J=7.5 Hz, 1H), 5.26 (d, J=8.0 Hz, 1H), 5.11 (d, J=12.0 Hz, 1H), 5.05 (d, j=12.5 Hz, 1H), 4.61 (dd, J=13.5, 6.0 hz, 1H), 3.72 (s, 3H), 3.45 (s, 2H), 3.10 (dd, J=14.0, 5.5 Hz, 1H), 3.00 (dd, J=14.0, 6.0 Hz, 1H). 13CNMR (CDCl3, 125 MHz) δ 177.7, 172.2, 155.7, 141.7, 136.3, 129.8, 128.9, 128.6, 128.3, 128.2, 125.8, 125.6, 109.8, 67.1, 55.1, 52.5, 38.0, 36. Mass spec. 369.20 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[CH3:12].[NH2:13][C:14]1[N:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:26]([N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:12])[CH:4]=3)=[N:19][CH:18]=2)[CH2:25][CH2:24]1)(=[O:28])[CH3:27]
Reactant: Cc1cc(CC(=O)O)ccc1Br
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(Br)c(C)c3)nc2)CC1
Temperature: 25 °C

Procedure:
To a mixture of 2-(4-bromo-3-methylphenyl)acetic acid 24-5 (100 mg, 0.44 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (96 mg, 0.44 mmol) and HATU (200 mg, 0.53 mmol) in DMF (2 mL) was added DIEA (230 uL, 1.32 mmol) and the mixture was stirred at room temperature over night. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over Na2SO4 and the solvent was evaporated. The residue was subject to silica gel flash chromatography to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-bromo-3-methylphenyl)acetamide 159-1. MS m/z 431.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH2:15])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[C:18](=S)=[S:19]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:18]([SH:19])=[N:15][N:14]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: S=C=S
Reactant: NNc1ncc(-c2cccc(F)c2)nn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Fc1cccc(-c2cnc3nnc(S)n3n2)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a suspension of [6-(3-fluoro-phenyl)-[1,2,4]triazin-3-yl]-hydrazine (400 mg, 0.789 mmol) in ethanol (12 mL) was added 2 N aqueous potassium hydroxide (1 mL) followed by carbon disulfide (1 mL). The reaction mixture was stirred at reflux for 1 h, then cooled to room temperature and concentrated in vacuo. The residue was dissolved with 1 N aqueous potassium hydroxide, heated and sonicated then the insolubles were filtered. The filtrate was acidified to pH 2-3 with 1 N aqueous HCl. The resulting precipitate was filtered, washed with water, and dried in vacuo to return title compound as an orange solid (242 mg, 50% yield): 1H NMR (DMSO-d6): δ 7.52 (dt, 1H), 7.70 (dt, 1H), 7.97-8.04 (m, 2H), 9.36 (s, 1H), 14.05 (s, 1H); MS (m/z) 248 [M+H+]+.
Reaction SMILES: [O:1]([CH:8]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[O:1]([CH:8]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][Br:20])=[CH:15][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(Oc1ccccc1)c1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Oc1ccccc1)c1ccc(CBr)cc1
Yield: 16.3 %

Procedure:
To a CCl4 solution (1 mL) of the product of Step B (126 mg, 0.495 mmol) was added N-bromosuccinimide (44 mg, 246 mmol) and a catalytic amount of AIBN. The solution was refluxed for 30 minutes and then concentrated in vacuo. The residue was purified on a silica gel flash chromatography column (150×30 mm) eluted with 5% ethyl acetate/hexane to afford 27 mg (33%) of the title compound.
Reaction SMILES: C([O:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:20]C(=O)C)[C:10](=[O:24])[C:9]=2[CH:8]=[C:7]([C:25]([OH:27])=O)[CH:6]=1)(=O)C.Cl>C(O)CCC>[CH2:5]([O:4][C:25]([C:7]1[CH:6]=[C:5]([OH:4])[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[OH:20])[C:10](=[O:24])[C:9]=2[CH:8]=1)=[O:27])[CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)Oc1cccc2c1C(=O)c1c(OC(C)=O)cc(C(=O)O)cc1C2=O
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)c1cc(O)c2c(c1)C(=O)c1cccc(O)c1C2=O

Procedure:
7.4 g (0.02 mole) of 4,5-bis(acetoxy)-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid are dissolved in 150 ml of butanol. Gaseous HCl is bubbled through the obtained solution until saturation. The reaction mixture is left to react for half an hour at room temperature, then it is heated to 60°-70° C. for 3 hours, while continuing HCl bubbling. The desired product precipitates, which is cooled, filtered and crystallized from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)=[CH:13][C:12]([C:22]([O:24]C(C)(C)C)=[O:23])=[C:11]2[CH3:29])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]2[C:14]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)=[CH:13][C:12]([C:22]([OH:24])=[O:23])=[C:11]2[CH3:29])=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)OC(C)(C)C)cc(C2CCN(C)CC2)n1CCc1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)O)cc(C2CCN(C)CC2)n1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 230 mg portion of tert-butyl 1-[2-(4-fluorophenyl)ethyl]-2-methyl-5-(1-methylpiperidin-4-yl)-1H-pyrrole-3-carboxylate was dissolved in 2 ml of dichloromethane, and 1 ml of trifluoroacetic acid was added under ice-cooling, followed by stirring at room temperature for 1.5 hours. The reaction liquid was concentrated under a reduced pressure, and a saturated sodium bicarbonate aqueous solution was added, followed by three times extractions with chloroform. After drying the organic layer with anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (methanol:chloroform=10:90-15:85-20:80) to obtain 124 mg of 1-[2-(4-fluorophenyl)ethyl]-2-methyl-5-(1-methylpiperidin-4-yl)-1H-pyrrole-3-carboxylic acid as a colorless solid.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.CC([Mg]Cl)C.[O:15]=[C:16]1[CH2:19][O:18][CH2:17]1.[NH4+].[Cl-]>C1COCC1>[OH:15][C:16]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:19][O:18][CH2:17]1
Reactant: O=C1COC1
Reactant: N#Cc1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(O)COC2)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-iodobenzonitrile (5.0 g, 21.8 mmol) in dry THF (100 mL) was added 2-propyl magnesium chloride (2M solution in diethyl ether, 11 mL, 21.8 mmol) dropwise at −40° C. After stirring for 1.5 h at this temperature, the reaction mixture was cooled to −78° C. before it was canulated to a solution of 3-oxooxetane (80% in dichloromethane, 2.95 g, 32.7 mmol; preparation described in: G. Wuitschik et al., Angew. Chem. Int. Ed. Engl. 45 (46), 7736-7739 (2006)) in dry THF (100 mL) which was likewise cooled to −78° C. After the slow addition of the Grignard reagent was completed, the reaction mixture was stirred at −78° C. for additional 10 minutes, then at 0° C. for 2 h, and finally at rt for 30 minutes. A few mL saturated aqueous NH4Cl were added and then most of the solvent was evaporated. The residue was partitioned between water and ethyl acetate (200 mL each). After separation, the aqueous layer was extracted using ethyl acetate. The combined organic layers were successively washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the crude material was crystallized from cyclohexane/ethyl acetate 10:1. The title compound was obtained in pure form (2.42 g, 63%): 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, 2H), 7.80 (d. 2H), 6.63 (s, 1H), 4.79 (d, 2H), 4.65 (d, 2H); DCI(NH3)-MS m/z 193 (M+NH4)+; HPLC RT (Method I) 3.09 min.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:14]CCC)[C:10](=[O:18])[C:9]([C:19]([OH:21])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:24])=O>>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH3:14])[C:10](=[O:18])[C:9]([C:19]([Cl:24])=[O:21])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: CCCCn1c(=O)c(C(=O)O)nn(-c2ccccc2)c1=O
Product: Cn1c(=O)c(C(=O)Cl)nn(-c2ccccc2)c1=O
Yield: 88 %

Procedure:
Intermediate g (3.0 g, 0.01 mol) was added to thionyl chloride (10 V/W, 30 mL). The mixture was warmed up under stirring to react under reflux for 6 h. The solvent was evaporated off to produce a clear yellow crystal (3 g) in a yield of 88%,
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=S)=[CH:15][CH:14]=1.IC>CO>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[NH:11][C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=3[N:10]=2)=[CH:15][CH:14]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Solvent: CI
Solvent: CO
Product: O=[N+]([O-])c1ccc2nc(Nc3ccc(Br)cc3)[nH]c2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of the 4-nitrobenzene-1,2-diamine in methanol was treated with 4-bromo phenyl isothiocyanate (1 eq) and stirred at 60° C. for 2 hours. The reaction mixture was cooled down to room temperature and iodomethane (1 eq) was added and stirred overnight at 60° C. The reaction was concentrated and purified on silica gel to yield (4-bromophenyl)(5-nitrobenzimidazol-2-yl)amine. The product was taken in methanol and hydrogenated with catalytic amount of 10% Pd/C to give ((5-aminobenzimidazol-2-yl)(4-bromophenylamine). MS: MH+=302.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Br:12])[CH:6]=1)(=O)C>C(N(C(C)C)CC)(C)C.CO>[Br:12][C:7]1[CH:6]=[C:5]([OH:4])[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: CC(=O)Oc1ccc(F)c(Br)c1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc(F)c(Br)c1

Procedure:
A solution of 0.80 gm (3.43 mMol) O-acetyl 3-bromo-4-fluorophenol in 10 mL 6% diisopropylethylamine in methanol was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure at 0° C. to provide the desired compound.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:41]=[CH:40][CH:39]=[CH:38][C:10]=1[O:11][C:12]1[N:17]=[CH:16][C:15]2[N:18]=[C:19]([C:21]3[CH:35]=[C:34]([CH3:36])[C:24]([O:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[C:23]([CH3:37])[CH:22]=3)[O:20][C:14]=2[CH:13]=1>ClCCl>[F:8][C:9]1[CH:41]=[CH:40][CH:39]=[CH:38][C:10]=1[O:11][C:12]1[N:17]=[CH:16][C:15]2[N:18]=[C:19]([C:21]3[CH:22]=[C:23]([CH3:37])[C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[C:34]([CH3:36])[CH:35]=3)[O:20][C:14]=2[CH:13]=1
Reactant: Cc1cc(-c2nc3cnc(Oc4ccccc4F)cc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4F)cc3o2)cc(C)c1OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.8 ml of trifluoroacetic acid was added to a solution of 90 mg of tert-butyl {4-[6-(2-fluorophenoxy)oxazolo[4,5-c]pyridin-2-yl]-2,6-dimethylphenoxy}acetate in 2 ml of dichloromethane, and the mixture was stirred at room temperature for 2 h. The reaction was then concentrated under reduced pressure and freeze-dried. This gave 101 mg (100%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([F:24])[C:21]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])=[CH:20][C:3]=1[O:4][C:5]1[N:10]=[C:9]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:8]([N+:17]([O-])=O)=[CH:7][CH:6]=1>[Pd].C(OCC)(=O)C>[NH2:17][C:8]1[C:9]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:10][C:5]([O:4][C:3]2[CH:20]=[C:21]([N:25]3[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[N:27]([CH3:36])[C:26]3=[O:37])[C:22]([F:24])=[CH:23][C:2]=2[Cl:1])=[CH:6][CH:7]=1
Reactant: COC(=O)COc1nc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)COc1nc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)ccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
A mixture of 2.25 g of 6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxy-3-nitropyridine, 0.3 g of 10% palladium/carbon and 40 ml of ethyl acetate was stirred for 3 hours at room temperature under hydrogen atmosphere. The reaction system was purged with nitrogen, then, the reaction solution was filtrated through Celite, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 1.38 g of 3-amino-6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]([CH:26]1[CH2:31][CH2:30][CH:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27]1)[C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[CH:21][C:22]([O:24]C)=[CH:23][C:16]=2[N:15]=1)[C:5]([O:7][CH3:8])=[O:6].B(Br)(Br)Br>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]([CH:26]1[CH2:27][CH2:28][CH:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:30][CH2:31]1)[C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[CH:21][C:22]([OH:24])=[CH:23][C:16]=2[N:15]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(CN(c2nc3cc(OC)ccc3n2C)C2CCC(C(C)(C)C)CC2)c(Br)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(CN(c2nc3cc(O)ccc3n2C)C2CCC(C(C)(C)C)CC2)c(Br)c1
Temperature: 25 °C

Procedure:
To a stirring solution of the title compound of Example 224 Step D (0.1 mmol, 54 mg) in 1 mL of DCM cooled to −78° C. under N2 was added dropwise BBr3 (0.3 mmol, 0.3 mL of a 1M solution in DCM). The reaction was allowed to warm to ambient temperature. After 1 h the reaction was taken up in 10 mL of MeOH and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 50% EtOAc/hexanes, affording the product as a white solid. HPLC A: 2.54 min.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[NH2:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[CH2:44][N:43]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:42][CH2:41]2>ClCCl>[C:51]([O:50][C:48]([N:43]1[CH2:42][CH2:41][C:40]2[C:45](=[CH:46][CH:47]=[C:38]([NH:37][C:18]([C@@H:13]3[CH2:12][CH2:11][C@@H:10]4[CH2:17][N:14]3[C:15](=[O:16])[N:9]4[O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:20])[CH:39]=2)[CH2:44]1)=[O:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)[C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)ccc2C1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (53.3 mg, 0.193 mmol) in dry dichloromethane (2 mL) was added triethylamine (0.067 mL, 0.482 mmol), 2-chloro-1-methylpyridinium iodide (58.7 mg, 0.230 mmol), and 6-amino-2-N-BOC-1,2,3,4-tetrahydro-isoquinoline (54.8 mg, 0.221 mmol) sequentially at room temperature under nitrogen. The reaction mixture was then heated to 50° C. for 45 minutes then the reaction product was concentrated in vacuo. Attempts to dissolve the reaction product in eluant (2:1:1 CH3CN/DMSO/water) for HPLC were unsuccessful, so it was partitioned between aqueous layer and dichloromethane. The organic layer was collected, dried over sodium sulfate, concentrated in vacuo and set aside for separate purification. The aqueous layer was also collected and purified by HPLC (30×100 mm Waters Sunfire column; 5 micron; 35 mL/min.; 210 nM; 15% to 100% CH3CN+0.05% TFA/water+0.05% TFA over 15 minutes; the title compound eluted at 80% CH3CN+0.05% TFA/water+0.05% TFA). Fractions containing the title compound were lyophilized overnight to afford the title compound as a white sticky solid. The organic layer from partitioning the crude product was purified by preparative TLC (1000 micron silica gel plate eluted with 50% ethyl acetate/hexane) to afford the title compound. Both batches of the title compound were combined and used without further purification in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([O:17]C)=[O:16])[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2cc(C(C)(C)C)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1ccc2cc(C(=O)O)ccc2c1
Temperature: 60 °C
Yield: 77.3 %

Procedure:
A mixture of methyl 6-tert-butyl-2-naphthoate (843 mg, 3.48 mmol) and 2M sodium hydroxide solution (6.96 mmol, 3.48 mmol) in MeOH (30 ml) was heated at 60° C. for 3 hours. After cooling to ambient temperature, the solvent was evaporated in vacuo and the residue was acidified to pH 2 with 2M hydrochloric aqueous solution. The aqueous layer was extracted with EtOAc and the combined solution was washed with brine, dried over sodium sulfate and evaporated in vacuo to give the crude product which was recrystallized from EtOAc and hexane to furnish the title compound as a white solid (614 mg, 77%). 1H NMR (DMSO): δ 1.39 (9H, s), 7.70-7.76 (1H, m), 7.90-8.08 (4H, m), 8.55 (1H, br, s), 13.00 (1H, br, s).
Reaction SMILES: [BH4-].[Li+].[CH2:3]([C:5]([NH:27][C:28](OC)=[O:29])([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[C:6]([O:8]CC)=O)[CH3:4].Cl.C(OCC)(=O)C>O1CCCC1>[CH2:3]([C:5]1([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:18]=2)[CH2:6][O:8][C:28](=[O:29])[NH:27]1)[CH3:4]
Reactant: CCOC(=O)C(CC)(CCc1ccc(OCc2ccccc2)cc1)NC(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC1(CCc2ccc(OCc3ccccc3)cc2)COC(=O)N1
Reaction time: 2.5 h
Yield: 46.6 %

Procedure:
Lithium borohydride (3.2 g) was added to a solution of ethyl 2-ethyl-2-methoxycarbonylamino-4-(4-benzyloxyphenyl)butanoate (29 g) in tetrahydrofuran (370 ml) and the mixture was refluxed under heating for 5 hours. 2 M Hydrochloric acid (40 ml) was added to the reaction mixture and the mixture was stirred for 2.5 hours. Ethyl acetate was added to the reaction mixture, the mixture was washed with water and a saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. Treatment of the residue with hexane and ethyl acetate gave the subject compound (11 g). Then, the mother liquid was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:2) to give the subject compound (11 g).