Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:5]([C:7]([NH:9][C:10]2[N:15]=[C:14]([CH2:16][O:17]C(=O)C)[CH:13]=[CH:12][CH:11]=2)=[O:8])[N:6]=1.[OH-].[Na+].O.Cl>CO>[OH:17][CH2:16][C:14]1[N:15]=[C:10]([NH:9][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:8])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)OCc1cccc(NC(=O)c2nc(C)sc2Nc2cccnc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(C(=O)Nc2cccc(CO)n2)c(Nc2cccnc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
A solution of acetic acid 6-{[2-methyl-5-(pyridin-3-ylamino)-thiazole-4-carbonyl]-amino}-pyridin-2-ylmethyl ester (0.046 g, 0.12 mmol) in methanol (20.00 ml) was treated with a 2N solution of NaOH in water (1.00 ml, 2.00 mmol). After 15 min stirring at room temperature, the mixture was acidified with HCl 2N, and the solvents removed. The residue was purified by flash chromatography (dichloromethane/methanol) to yield the title compound (0.035 g, 85%) as a light yellow solid, MS (ISP): m/e=342.1 (M+H+).
Reaction SMILES: [C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Br)=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:21][CH:22]([CH3:26])[CH2:23][C:24]#[CH:25].ClC(OC)=O>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C.CN(C=O)C>[C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([C:25]#[C:24][CH2:23][CH:22]([CH3:26])[CH3:21])=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C#CCC(C)C
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Oc1cc([N+](=O)[O-])c(C#CCC(C)C)cc1C1CCCC1
Reaction time: 0.33 h
Yield: 74.9 %

Procedure:
To 4-bromo-2-cyclopentyl-5-nitrophenyl methyl carbonate (100 mg, 0.29 mmol), Pd(PPh3)2Cl2 (4 mg, 0.006 mmol), and CuI (1 mg, 0.006 mmol) was added DMF (600 μL), triethylamine (750 μL), and 4-methylpent-1-yne (72 mg, 103 μL, 0.87 mmol). The reaction mixture was stirred under N2 atmosphere for 20 min, resulting in product formation with partial loss of the carbonate group. The reaction was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The solution was dried over Na2SO4 and filtered through a plug of silica. The filtrate was treated with triethylamine (29 mg, 40 μL, 0.29 mmol) and then dropwise with methyl chloroformate (14 mg, 11 μL, 0.14 mmol). The reaction mixture was stirred for 10 min, and was then dried down, diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, 0.5 M HCl, and brine. The solution was dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-cyclopentyl-4-(4-methylpent-1-ynyl)-5-nitrophenyl methyl carbonate as an orange oil (75 mg, 75% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.77 (s, 1H), 4.00 (s, 3H), 3.25-3.18 (m, 1H), 2.46 (d, J=6.3 Hz, 2H), 2.00-1.88 (m, 3H), 1.79-1.75 (m, 2H), 1.73-1.55 (m, 4H), 1.06 (d, J=6.6 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.Br[CH:13]([CH2:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH:13]([CH2:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: CCC(Br)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(Oc1ccc2ncccc2c1)C(=O)OC
Reaction time: 18 h
Yield: 92 %

Procedure:
6-Hydroxyquinoline (25.1 g), methyl 2-bromobutyrate (32.3 g) and anhydrous potassium carbonate (23.0 g) in dry N,N-dimethylformamide (100 ml) were stirred at 100° C. for 3 hours then stored at ambient temperature for 18 hours. The mixture was added to water, extracted with ethyl acetate (three times) and the extracts combined, washed with water (four times) then dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give the required product (39.0 g) as a red oil.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[C:19]([Br:26])[C:18]=2OC)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[Sn](Cl)Cl.[C:32](OCC)(=[O:34])C>>[Br:26][C:19]1[C:20]([O:34][CH3:32])=[C:21]([NH2:23])[CH:22]=[C:17]([C:9]2[C:10]3[C:14]([CH3:15])=[C:13]([CH3:16])[S:12][C:11]=3[C:2]([Br:1])=[C:3]3[C:8]=2[CH:7]=[CH:6][CH:5]=[CH:4]3)[CH:18]=1
Reactant: CCOC(C)=O
Reactant: COc1c(Br)cc([N+](=O)[O-])cc1-c1c2ccccc2c(Br)c2sc(C)c(C)c12
Agent: Cl[Sn]Cl
Product: COc1c(N)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1Br
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A stirred suspension of 9-bromo-4-(3-bromo-methoxy-5-nitro-phenyl)-2,3-dimethyl-naphtho[2,3-b]thiophene (0.372, 0.714 mmol), tin (II) dichloride (805 mg, 3.57 mmol) and ethyl acetate (4 mL)was heated to 70° C. where disolution occurred. After 30 min, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and silica gel was added. The ethyl acetate was removed and the adsorbate was flash chromatographed (4:1 pet. ether: ethyl acetate) to provide the title compound as a white solid (0.324 g, 92%): mp 198-200° C.: NMR (DMSO-d6); 8.18 (d, J=8 Hz, 1H), 7.64 (ddd, J=8, 6, 1 Hz, 1H), 7.58 (d, J=8 Hz, 1H), 7.50 (ddd, J=8, 6, 1 Hz, 1H), 6.70 (d, J=2 Hz, 1H), 6.64 (d, J=2 Hz, 1H), 5.46 (s, 1H), 3.80 (s, 3H), 2.44 (d,J=1 Hz, 3H), 1.73 (d, J=1 Hz, 3H); MS (EI): 2 bromine isotope pattern 489 (50%, M+), 491 (100%, M+), 493 (60%, M+); Anal. Calc. for C21H17Br2NOS: C, 51.34; H, 3.49; N, 2.85. Found: C, 51.00; H, 3.43; N, 2.71.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:31][O:32][CH2:33][CH2:34][OH:35]>>[CH3:31][O:32][CH2:33][CH2:34][O:35][CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COCCO
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Agent: [H-]
Agent: [Na+]
Product: COCCOCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
4-Chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (200 mg, 0.48 mmol) and sodium hydride (42 mg 55% dispersion in mineral oil, 0.96 mmol) were dissolved in 2-methoxy-ethanol (3.8 ml, 48 mmol) and stirred at ambient temperature for 18 h. Workup and, purification as described in the general procedure C afforded the title compound as white solid (70%), MS: m/e=458 (M+H+).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH2:14][CH2:15][CH3:16])=[N:8][C:7]2=[O:17])([O-])=O.[I:18]C1C=C(C(O)=O)C(N)=CC=1>>[I:18][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14][CH2:15][CH3:16])[NH:8][C:7]2=[O:17]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: CCCc1nc(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Product: CCCc1nc2ccc(I)cc2c(=O)[nH]1

Procedure:
Following the procedure described as in the preparation of 6-nitro-2-propylquinazolin-4(1H)-one above. 25 g of 5-iodoanthranilic acid was converted into the title compound. 1H-NMR (CDCl3, 200 MHz): δ1.02 (t, 3H, J=7.4 Hz), 1.81 (m, 2H), 2.63 (t, 2H, J=7.4 Hz), 7.40 (d, 1H, J=8.6 Hz), 8.07 (dd, 1H, J=2, 8.7 Hz).1H, J=8.6 Hz), 8.07 (dd, 1H, J=2, 8.7 Hz).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[C:8](=[O:13])([O:11]C)[O:9]C>CO>[C:8](=[O:9])([O-:13])[O-:11].[CH3:8][N+:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2].[CH3:8][N+:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: CCN(CC)CC
Reactant: COC(=O)OC
Solvent: CO
Product: CC[N+](C)(CC)CC
Product: O=C([O-])[O-]

Procedure:
Into an autoclave equipped with a stirrer, triethylamine (1 mol), dimethyl carbonate (1.5 mol) and methanol (2 mol) as a solvent, were charged and reacted at a reaction temperature of 110° C. for 12 hours to obtain a methanol solution of methyltriethylammonium carbonate. Acetic acid (1 mol) was charged thereto, and as a solvent, ethylene glycol was added to a predetermined concentration. Then, by means of an evaporator, carbon dioxide formed as a byproduct and methanol were removed to obtain a solution comprising 50% methyltriethylammonium acetate and 50% of ethylene glycol.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1.Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)CCc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CC(=O)OC(C)(C)C)Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
BuLi (5.2 mL, 1.6M in hexanes) was added to a 0° C. solution of diisopropylamine (0.91 g, 9.0 mmol) in THF (40 mL). The reaction mixture was then stirred at 0° C. for 30 minutes, and then cooled to −78° C. A solution of methyl 3-(4-chlorophenyl)propanoate (1.5 g, 7.5 mmol) in THF (8 mL) was added slowly, and the reaction mixture was stirred at −78° C. for 40 minutes. A solution tert-butyl 2-bromoacetate (4.4 g, 22.7 mmol) in THF (5 mL) was then added. The reaction was then stirred for 30 minutes at −78° C. and then warmed to room temperature and stirred overnight. The reaction was then quenched with saturated NH4Cl and concentrated to remove THF. The reaction was then extracted with EtOAc, and the combined extracts were dried (Na2SO4), filtered, concentrated, and dried in vacuo to give 4-tert-butyl 1-methyl 2-(4-chlorobenzyl)succinate (1.91 g, 81%) as an oil.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH:23]=[O:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].Br[C:26]([F:33])([F:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1.[Zn]>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH:23]([OH:24])[C:26]([F:33])([F:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CCOC(=O)C(F)(F)C(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
A suspension of 4.38 g (67.0 mmol) of Zn powder in 40 mL of THF was treated with 0.58 mL (6.7 mmol) of 1,2-dibromoethane. The resulting mixture was heated at reflux for 2 min, then cooled to rt. Trimethylsilyl chloride (0.43 mL 3.4 mmol) was then added, the resulting mixture was stirred at ambient temperature for 20 min, the cooled to −5° C. A solution of 2.88 g (13.4 mmol) of 1-(t-butoxycarbonyl)-4-formyl piperidine and 9.52 g (46.9 mmol) of ethyl bromodifluoroacetate in 10 mL of THF was gradually added to the activated Zn. After the resulting exotherm subsided, the cooling bath was removed and the resulting mixture was stirred at rt for 20 h. The reaction was quenched with 50 mL of sat'd NH4Cl and the resulting mixture was partitioned between 300 mL of ether and 100 mL of H2O. The organic layer was separated, washed with 50 mL of sat'd NaHCO3, 50 mL of sat'd NaCl, dried and concentrated. Flash chromatography on 200 g of silica gel using 4:1 v/v, then 2:1 v/v hexanes/EtOAc as the eluants afforded 2.25 g (52%) of the title compound as an oil: 1H NMR (500 MHz, CDCl3) δ 1.31-1.34 (m, 1H), 1.37 (t, J=7.0, 3H), 1.45 (s, 9H), 1.69-1.72 (m, 2H), 1.86-1.92 (m, 2H), 2.40 (d, J=7.0, 1H), 2.68-2.72 (m, 2H), 3.83-3.90 (m, 1H), 4.104.20 (m, 2H), 4.36 (q, J=7.0, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[C:4]([F:20])[CH:3]=1.[H-].[Na+].FC(F)(F)S(O[CH2:29][C:30]([F:33])([F:32])[F:31])(=O)=O.O>CN(C)C(=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:29][C:30]([F:33])([F:32])[F:31])[S:10]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:11])=[C:4]([F:20])[CH:3]=1
Reactant: O=S(=O)(Cc1ccccc1)NCc1ccc(Br)cc1F
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=S(=O)(Cc1ccccc1)N(Cc1ccc(Br)cc1F)CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a solution of N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-methanesulfonamide (4.21 g, 11.8 mmol) in N,N-dimethylacetamide (40 mL) was added sodium hydride (60% in mineral oil) (611 mg, 15.3 mmol) and the reaction was stirred at ambient temperature for 30 minutes. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (2.0 mL, 14.1 mmol) was then slowly added (exothermic) and the reaction was stirred at ambient temperature for 2.5 hours. Water was added and the reaction was diluted with EtOAc, washed with water (×2), brine, dried with MgSO4, concentrated and purified by silica gel column chromatography (0-100% EtOAc in heptane) to give N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)methanesulfonamide (4.62 g, 89% yield). LCMS (m/z) ES+ 457 [M+18]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[OH:27][CH2:28][CH2:29][CH2:30][NH2:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:31][CH2:30][CH2:29][CH2:28][OH:27])=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: NCCCO
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(NCCCO)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3-hydroxypropylamine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(3-hydroxypropyl)terephthalamide. MS (Q1) 445 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([NH2:42])[CH2:41][CH2:40][CH2:39]1>>[CH:38]1([NH:42][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: NC1CCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NC3CCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and cyclobutylamine according to conditions described in general procedure C. Mp: 110-112° C.; 1H NMR (400 MHz, CDCl3) δ 1.63 (s, 2 H), 1.73-1.80 (m, 2 H), 2.42 (s, 2 H), 3.19-3.29 (m, 4 H), 3.79-3.92 (m, 4 H), 4.30 (s, 1 H), 5.27 (s, 1 H), 6.08 (s, 1 H), 6.75-6.78 (m, 1 H), 7.05 (d, J=7.6 Hz, 1 H), 7.24-7.26 m, 1 H), 7.32 (s, 1 H), 7.47-7.57 (m, 2 H), 7.88-8.02 (m, 3 H), 8.16 (m, 1 H), 8.25 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1C(OC)=O)[CH3:2].C(COC1C=CC=CC=1C(O)=O)(O)=[O:19].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>>[C:1]([O:3][C:4]1[C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[O:6][CH:5]=1)(=[O:19])[CH3:2]
Reactant: CCOC(=O)COc1ccccc1C(=O)OC
Reactant: O=C(O)COc1ccccc1C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1coc2ccccc12

Procedure:
A synthesis of (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13) is illustrated in Scheme 2A. According to the synthesis, methyl salicylate reacts with ethyl chloro acetate in the presence of potassium carbonate to give methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6). Hydrolysis of methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6) followed by a consecutive cyclization of 2-(carboxymethoxy)benzoic acid (7) with acetic anhydride in the presence of sodium acetate gives benzofuran-3-yl acetate (8) which is converted to benzofuran-3(2H)-one (9) by methanolysis. Treatment of benzofuran-3(2H)-one (9) with O-methylhydroxylamine and sodium acetate affords benzofuran-3(2H)-one O-methyl oxime (10) which is oxidized with tert-butyl nitrate in hydrochloric acid to yield (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A). In the presence of potassium hydroxide, (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A) opens ethylene oxide resulting (3E)-benzofuran-2,3-dione O2-(2-hydroxyethyl) O3-methyl dioxime (12A) that undergoes potassium hydroxide-catalyzed cyclization to provide (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([N:5]([CH2:12][PH:13](O)=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].P(Cl)(Cl)[Cl:19]>C1C=CC=CC=1>[Cl-:19].[Cl-:19].[F:1][C:2]([F:16])([F:17])[C:3]([N:5]([CH2:12][PH2:13])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4]
Reactant: ClP(Cl)Cl
Reactant: CCOC(=O)CN(C[PH](=O)O)C(=O)C(F)(F)F
Solvent: c1ccccc1
Product: CCOC(=O)CN(CP)C(=O)C(F)(F)F
Product: [Cl-]

Procedure:
N-trifluoroacetyl-N-(hydroxyphosphinylmethyl)-glycine, ethyl ester (2 g, 0.0072 mol), was dissolved in benzene and added to phosphorous trichloride dropwise with stirring. The liquid was filtered and the supernatant liquid evaporated under vacuum to yield N-trifluoroacetyl-N-carboethoxymethylaminomethylphosphine dichloride. The dichloride was dissolved in tetrahydrofuran and a solution of 2.91 g (0.0288 mol) of di-n-propylamine in tetrahydrofuran was added dropwise with stirring. After stirring for two hours, 134 mg (0.0072 mol) of sulfur was added and the reaction stirred overnight. The reaction was then filtered and concentrated to dryness. The residue was dissolved in methanol and centrifuged to remove the unreacted sulfur; the supernatent liquid was decanted and concentrated to dryness. The residue was dissolved in ether and washed with 5% aqueous sodium bicarbonate and hydrochloric acid, then dried over magnesium sulfate, filtered and concentrated to dryness. The residue was chromatographed on silica gel with hexane, then dichloromethane, then ether to yield N-trifluoroacetyl-N-[bis(di-n-propylamino)phosphinothioylmethyl]-glycine, ethyl ester, as a brown oil, ND25 =1.5724, having the following analysis:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][S:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([CH3:20])[N:14]=1.[NH4+].[Cl-].C(Cl)Cl>C(Cl)Cl.CCO.O.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][S:12][C:13]2[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([CH3:20])[N:14]=2)=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1cc(O)nc(SCc2ccc([N+](=O)[O-])cc2Cl)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Cc1cc(O)nc(SCc2ccc(N)cc2Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.5 %

Procedure:
2-{[(2-chloro-4-nitrophenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (282 mg, 1.0 mmol) was dissolved in DCM/EtOH/H2O (20 mL/20 mL/10 mL). Iron (550 mg, 10 mmol) and NH4Cl (540 mg, 10 mmol) were added. The mixture was stirred at room temperature for 3 hours. DCM (200 mL) was added to extract the product. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by CombiFlash (0 to 8% MeOH/DCM) to provide the title compound as a yellow solid (100 mg, 35% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.22 (s, 3H), 4.37 (s, 2H), 5.95 (br, 1H), 6.65 (d, 1H), 6.92 (s, 1H), 7.38 (d, 1H); M+ 282.
Reaction SMILES: C(C1COC(=O)N1[C:14](=[O:49])[CH:15]([C:20]1[CH:21]=[C:22]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=2)[CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[C:35]([F:38])([F:37])[F:36])[CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])C1C=CC=CC=1.O[Li].O.OO.[O-:55]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][O:26][C:24]2[CH:25]=[C:20]([C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([OH:55])=[O:49])[CH:21]=[C:22]([C:39]3[CH:40]=[CH:41][C:42]([C:45]([F:47])([F:46])[F:48])=[CH:43][CH:44]=3)[CH:23]=2)=[C:29]([C:35]([F:37])([F:38])[F:36])[CH:30]=1
Reactant: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OCc2ccc(F)cc2C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)c1cc(OCc2ccc(F)cc2C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.2 %

Procedure:
To a solution of 4-benzyl-3-{2-[5-(4-fluoro-2-trifluoromethyl-benzyloxy)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoyl}-oxazolidin-2-one (0.535 g, 0.78 mmol) in THF (9 mL) was added water (3 mL). The system was cooled to 0° C. To this cold solution was added LiOH.H2O (33 mg, 0.78 mmol) and 30% H2O2 (0.354 mL, 3.12 mmol,) and stirred at 0° C. for 20 min. The excess H2O2 was quenched by adding 1.5 M aqueous Na2SO3 solution (2.08 mL, 3.12 mmol) and stirred at room temperature for 5 min. The organic solvent was removed in vacuo. The resulting liquid was acidified to pH 2 by adding 1 N aqueous HCl solution. The aqueous layer was extracted with EtOAc (3×50 mL) and dried (MgSO4). The mixture was concentrated in vacuo to receive a crude mixture which was purified by ISCO silica gel column chromatography to yield (R)-2-[5-(4-Fluoro-2-trifluoromethyl-benzyloxy)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid (310 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12].CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:64]([CH:66]([CH2:74][CH2:75][CH2:76][CH3:77])[CH2:67][O:68][C:69](=[O:73])[CH2:70][CH2:71][SH:72])[CH3:65]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:64]([CH:66]([CH2:74][CH2:75][CH2:76][CH3:77])[CH2:67][O:68][C:69](=[O:73])[CH2:70][CH2:71][S:72][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12])[CH3:65]
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: CCCCC(CC)COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCCCC(CC)COC(=O)CCSc1ccc(C(F)(F)F)cc1F

Procedure:
A solution of 1-bromo-2-fluoro-4-trifluoromethyl-benzene (5.0 g, 20.6 mmol) and DIEA (7.2 mL, 41.1 mmol) in toluene (100 mL) is degased under N2 atmosphere. To this mixture, Pd2 dba3 (753 mg, 0.82 mmol), Xantphos (952 mg, 1.65 mmol) and 3-mercapto-propionic acid 2-ethyl-hexyl ester (5.9 mL, 25.7 mmol) are added and the reaction is heated at reflux overnight. The resulting mixture is filtered over a plug of silica (EtOAc) and the organic is concentrated in vacuo. Purification by silica chromatography (EtOAc/petroleum ether; 3:97) affords the desired product.