Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:40]1[CH2:44][CH2:43][O:42][C:41]1=[O:45]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:40]3[CH2:44][CH2:43][O:42][C:41]3=[O:45])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OCCC1Br
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC3CCOC3=O)cc2n1Cc1ccccc1
Yield: 14 %

Procedure:
Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1 H-indole-3-carboxamide (Compound 8, 19mg, 0.044 mol) in DMF (1.0 ml) was reacted with K2CO3 (30 g, 0.22 mmol), 3-bromodihydrofuran-2(3H)-one (20 mg, 0.22 mmol) to yield the title compound (16mg, 71%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:44][C@@H:43]([CH3:45])[CH2:42][C@H:18]4[S:19](=[O:41])(=[O:40])[C:20]([CH3:39])([CH3:38])[C:21]([N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:22][C@:17]4([CH3:46])[C:15]=3[CH:16]=2)=[O:9])=[N:6][CH:7]=1.[O:47]1[CH:51]=[CH:50][N:49]=[C:48]1[CH2:52]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:38][C:20]1([CH3:39])[S:19](=[O:41])(=[O:40])[C@@H:18]2[CH2:42][C@H:43]([CH3:45])[O:44][C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:5]4[CH:4]=[CH:3][C:2]([O:1][CH2:52][C:48]5[O:47][CH:51]=[CH:50][N:49]=5)=[CH:7][N:6]=4)=[O:9])=[CH:16][C:15]=3[C@@:17]2([CH3:46])[N:22]=[C:21]1[N:23]([C:24]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:30])[C:31](=[O:32])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37]
Reactant: C[C@H]1C[C@@H]2[C@](C)(N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S2(=O)=O)c2cc(NC(=O)c3ccc(O)cn3)ccc2O1
Reactant: OCc1ncco1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H]1C[C@@H]2[C@](C)(N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S2(=O)=O)c2cc(NC(=O)c3ccc(OCc4ncco4)cn3)ccc2O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.5 %

Procedure:
To a 0° C. solution of tert-butyl N-[(4aR,6S,11bR)-10-[(5-hydroxypyridine-2-carbonyl)amino]-3,3,6,11b-tetramethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (80 mg, 0.121 mmol), 2-oxazolemethanol (0.096 mL, 1.214 mmol) and triphenylphosphine (96 mg, 0.364 mmol) in THF (3 mL) was added diisopropyl azodicarboxylate (0.072 mL, 0.364 mmol) dropwise. The reaction was stirred at ambient temperature for 16 h. The reaction mixture was partitioned between water and ethyl acetate and the organic layer was concentrated. The crude product was purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in heptane, to provide tert-butyl N-[(4aR,6S,11bR)-3,3,6,11b-tetramethyl-10-[[5-(oxazol-2-ylmethoxy)pyridine-2-carbonyl]amino]-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (19 mg, 0.026 mmol, 21.15% yield) as a colorless oil. MS m/z=762.0 (M+Na).
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[S:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].ClC1C=C(C=CC=1)C(OO)=[O:19]>C(Cl)Cl>[Cl:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[S:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:19]
Reactant: COC(=O)CSC1CCCCC1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)CS(=O)C1CCCCC1Cl
Temperature: 5 °C
Reaction time: 20 h

Procedure:
Methyl [(2-chlorocyclohexyl)thio]acetate (2.5 g, 0.0112 mole) was added to methylene chloride (35 ml) and the mixture was cooled to 5° C. with an ice bath. 3-Chloroperoxybenzoic acid (85%, 2.3 g, 0.0112 mole) was added, and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was cooled to 5° C. with an ice bath, and filtered. Solid sodium thiosulfate was added to the filtrate and the mixture was stirred for several minutes then filtered. The filtrate was dried over anhydrous magnesium sulfate. After filtering, the filtrate was concentrated in a rotary evaporator to give the product as a solid. The structure was supported by NMR.
Reaction SMILES: [CH2:1](/[C:3](/[C:10](=[O:12])[CH3:11])=[C:4](/[CH2:8][CH3:9])\[C:5]([NH2:7])=[O:6])[CH3:2].O.[BH4-].[Na+].Cl>CO>[CH2:1](/[C:3](/[CH:10]([OH:12])[CH3:11])=[C:4](/[CH2:8][CH3:9])\[C:5]([NH2:7])=[O:6])[CH3:2]
Reactant: CC/C(C(C)=O)=C(/CC)C(N)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC/C(C(N)=O)=C(/CC)C(C)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
26 (diethyl (2E)-4-oxopent-2-enamide) (5.92 g, 35 mmol) is dissolved in MeOH (14 ml) and H2O (56 ml) and cooled to 0° C. To the resulting solution is added NaBH4 (0.50 g, 13.1 mmol) in portions over 5 minutes. After 15 minutes of additional stirring at 0° C., the reaction mixture is acidified with 2 M HCl (30 ml) and extracted with AcOEt (1 l and 2×0.75 l). The organic phases are washed with H2O (100 ml), saturated NaHCO3 (100 ml) and brine (100 ml) successively. The combined organic phases are dried with Na2SO4 and evaporated under reduced pressure at 40° C. 27 (rac-Diethyl (2E)-4-hydroxypent-2-enamide) (5.66 g, 94%) is obtained as a pale yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=2[O:18][C@@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[O:7])[CH2:3]1.F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1>>[CH3:17][S:14]([C:12]1[CH:11]=[CH:10][C:9]([O:18][C@@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[C:8]([C:6]([N:4]2[CH2:3][CH:2]([O:1][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH2:5]2)=[O:7])[CH:13]=1)(=[O:15])=[O:16]
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CC(O)C1)C(F)(F)F
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1)C(F)(F)F
Yield: 5 %

Procedure:
Prepared in analogy to Example 21(b) from (3-hydroxy-azetidin-1-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone and 4-fluorobenzotrifluoride. The crude material was purified by flash chromatography (methanol/dichloromethane) to yield the title compound as a white crystalline solid (yield 5%). MS (m/e): 512.5 (M+H+, 100%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:15]=[C:16]([C:20]2[N:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1>C(Cl)Cl>[CH2:31]([O:30][C:28](=[O:29])/[CH:27]=[CH:26]/[C:23]1[CH:22]=[CH:21][C:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:33])([F:12])[F:34])[CH:15]=2)=[N+:25]([O-:9])[CH:24]=1)[CH3:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)/C=C/c1ccc(-c2cccc(C(F)(F)F)c2)nc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccc(-c2cccc(C(F)(F)F)c2)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.9 %

Procedure:
m-CPBA (13.9 g, 80.97 mmol) was added portion wise to a solution of trans-ethyl 3-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)acrylate (13 g, 40.47 mmol) in DCM (150 mL) at 0° C. over a period of 30 min. and stirred at RT for 16 h. After completion, the reaction mixture was poured into ice water (100 mL), extracted with DCM (2×100 mL). Combined organic extracts were treated with sodium metabisulphite, washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography (SiO2) by using MeOH:chloroform (1:99) to afford (9 g, 66%) (E)-5-(3-ethoxy-3-oxoprop-1-enyl)-2-(3-(trifluoromethyl)phenyl)pyridine 1-oxide as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:58])[C:5]([S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][C:34]=2[F:35])[C:31]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:30][CH:29]=[CH:28]3)[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:59](Cl)(Cl)=[O:60]>C(#N)C.ClCCl>[C:39]([O:38][C:37]([N:36]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[C:4]([F:58])[C:5]=4[S:52]([CH:55]4[CH2:56][CH2:57]4)(=[O:53])=[O:54])[NH:1][C:59](=[O:60])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[C:34]([F:35])[CH:33]=2)[CH:28]=[CH:29][N:30]=1)[C:44](=[O:45])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:43])([CH3:41])([CH3:40])[CH3:42]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C(Nc2cc3ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3cc2F)C(=O)N(C)Cc2cc(N)cc(F)c2S(=O)(=O)C2CC2)ccc1[C@@H](C)CO
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1cc(F)c(S(=O)(=O)C3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1cc2ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2cc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 32.3 %

Procedure:
A solution of 29A (133 mg, 0.161 mmol) in acetonitrile (3 mL) and dichloromethane (6 mL) was cooled to 0° C. To this solution was added phosgene (20% in toluene, 0.088 mL, 0.178 mmol). The mixture was stirred at 0° C. for 5 min, and rt for 1 h. The mixture was bubbled with Ar for 10 min to remove excess phosgene. The resulting solution was added dropwise over 3 h via a syringe pump into a solution of TEA (0.225 mL, 1.614 mmol) in CH2Cl2 (260 mL). The solution was stirred for 16 h, concentrated and purified by flash chromatography to give a mixture of diastereoisomers (96 mg, 0.113 mmol, 70.0% yield). The diastereoisomers were separated by a prep chiral HPLC equipped with a IA column to give 29B (44 mg, 0.052 mmol, 46.3% yield). MS (ESI) m/z: 850.2 [M+1]+. 1H NMR (500 MHz, methanol-d4) δ ppm 8.09 (1H, d, J=5.8 Hz), 7.77 (1H, d, J=7.7 Hz), 7.53 (1H, d, J=6.1 Hz), 7.50 (1H, d, J=8.0 Hz), 7.42 (1H, d, J=11.8 Hz), 7.00-7.09 (2H, m), 6.61 (2H, dd, J=12.1, 1.9 Hz), 6.24 (1H, s), 5.76 (1H, d, J=17.9 Hz), 5.72 (1H, t, J=2.9 Hz), 4.62 (1H, t, J=11.1 Hz), 4.21 (1H, d, J=17.9 Hz), 3.96 (1H, dd, J=10.6, 4.3 Hz), 3.47 (1H, ddd, J=11.4, 7.0, 4.4 Hz), 3.32-3.38 (3H, m), 2.97 (1H, dd, J=4.8, 3.2 Hz), 2.22-2.33 (3H, m), 1.25-1.37 (24H, m), 1.03-1.13 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:19](=O)[CH3:20])=[CH:10][C:11]([CH3:18])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH:19]([NH2:28])[CH3:20])=[CH:10][C:11]([CH3:18])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(C)c2cccnc2c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Cc1cc(C(C)N)c(-c2cccc(F)c2)c2ncccc12
Temperature: 65 °C

Procedure:
A mixture of 1-[8-(3-fluorophenyl)-5-methylquinolin-7-yl]ethanone (50 mg, 0.2 mmol) and ammonium acetate (138 mg, 1.79 mmol) in methanol (1.0 mL) and acetonitrile (1.0 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (22.5 mg, 0.358 mmol). The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step. LCMS calculated for C18H18FN2 (M+H)+: m/z=281.1; Found: 281.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:68]=[CH:67][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[C:60]([C:62]([F:65])([F:64])[F:63])[CH:59]=[CH:58][C:57]=2[F:66])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:49]=[CH:50][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[C:60]([C:62]([F:65])([F:63])[F:64])[CH:59]=[CH:58][C:57]=2[F:66])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:67][CH:68]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2cc(C(F)(F)F)ccc2F)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2cc(C(F)(F)F)ccc2F)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 118 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(2-fluoro-5-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF was added. After 3¾ h stirring at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:9) to give 120 mg light yellow viscous oil (77%). MS (EI) 496.3 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:9].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C(#N)C.O>[CH2:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[O:9])=[CH:15][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C(c1ccc(O)cc1)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(c1ccc(OCc2ccccc2)cc1)c1ccccc1F
Temperature: 70 °C
Reaction time: 15 h

Procedure:
(2-Fluorophenyl)(4-hydroxyphenyl)methanone (9.0 g, 41.6 mmol), benzyl bromide (7.1 g, 41.6 mmol), and potassium carbonate (5.8 g, 41.6 mmol) were mixed in acetonitrile (60 mL). The resulting mixture was shaken at 70° C. overnight (15 h). After cooling to ambient temperature, EtOAc (200 mL) and water (100 mL) were added. The phases were separated, and the aqueous phase was further extracted with EtOAc (200 mL). The combined organic phase was washed with Na2CO3 (3×100 mL, saturated aqueous solution) and brine (100 mL), dried over Na2SO4 and filtered. Evaporation of the solvent under reduced pressure yielded 12.1 g, 95% as a slightly yellow solid. 1H-NMR (CDCl3) δ; 7.83 (dd, 2H, J=8.8 Hz and 1.2 Hz), 7.54-7.46 (m, 2H), 7.46-7.32 (m, 5H), 7.25 (m, 1H), 7.15 (m, 1H), 7.02 (d, 2H, J=9.0 Hz), 5.14 (s, 2H); 13C-NMR (CDCl3) δ 191.9, 163.1, 159.7 (d, J=251 Hz), 136.1, 132.5 (d, J=8.1 Hz), 132.3 (d, 2C, J=0.8 Hz), 130.4 (d, J=3.1 Hz), 130.4, 128.7 (2C), 128.3 (2C), 127.5, 127.5 (d, J=16.8 Hz), 124.2 (d, J=3.8 Hz), 116.1 (d, J=21.9 Hz), 114.6 (2C), 70.2.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]([N:22]1[C:27](=[O:28])[CH:26]=[CH:25][N:24]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:23]1=[O:39])[CH3:21])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C(O)C>[OH:18][CH2:19][C@H:20]([N:22]1[C:27](=[O:28])[CH:26]=[CH:25][N:24]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=2)[C:23]1=[O:39])[CH3:21]
Reactant: C[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)n1c(=O)ccn(-c2cccc(C(F)(F)F)c2)c1=O
Agent: Cl
Solvent: CCO
Product: C[C@H](CO)n1c(=O)ccn(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
To a solution of (R)-3-[1-(tert-butyldiphenylsilyloxy)propane-2-yl]-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 101) (7.1 g) in ethanol (50.0 ml) was added 1N hydrochloric acid (64.0 ml) and the resulting mixture was stirred at 90° C. for two hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol) to afford (R)-3-(1-hydroxypropan-2-yl)-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (2.6 g).
Reaction SMILES: C(C1C=CC(CC(O)=O)=CC=1)=[O:2].C(O)C1C=CC=CC=1.[CH:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:25][CH:24]=1)=[O:22]>>[CH2:33]([O:32][C:30]([CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]([OH:2])=[O:22])=[CH:28][CH:27]=1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=Cc1ccc(CC(=O)OCc2ccccc2)cc1
Reactant: O=Cc1ccc(CC(=O)O)cc1
Solvent: OCc1ccccc1
Product: O=C(Cc1ccc(C(=O)O)cc1)OCc1ccccc1
Yield: 80.6 %

Procedure:
Synthesized from (4-formylphenyl)acetic acid (1 g) and benzyl alcohol (730 mg) according to an analogous synthetic method to Example 806, benzyl (4-formylphenyl)acetate (1.4 g) was used according to an analogous synthetic method to Preparation Example 53 to provide the title compound (1.2 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[CH2:10][N:11]1[CH:20]=[C:14]2[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][C:13]2=[N:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([O:8][C:9](=[O:21])[CH2:10][N:11]1[C:20]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][C:18]=2[CH:13]=[N:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCc2nn(CC(=O)OCc3ccccc3)cc2C1
Solvent: CO
Product: CN1CCc2c(cnn2CC(=O)OCc2ccccc2)C1

Procedure:
The final compound was prepared using a method analogous to that of Example 14 step 14.2, (5-methyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-2-yl)-acetic acid benzyl ester replacing intermediate 14.1 and using MeOH instead of MeOH/AcOH. LC-MS (B): tR=0.17 min; [M+H]+: 196.29.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](I)[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>COCCOC.C(=O)(O)[O-].[Na+]>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:28][CH:29]=2)[CH:8]=[CH:9][CH:10]=1)=[O:12])[CH3:2]
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)c1cccc(I)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1cccc(-c2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
To a solution of ethyl-3-iodobenzoate (2.5 g, 1 equiv) in ethylene glycol dimethyl ether (20 mL) are added 2 M sodium carbonate solution (40 mL), 4-benzyloxybenzene boronic acid (2.5 g, 1.2 equiv) and tetrakistriphenylphosphine palladium(0) (1.05 g, 0.1 equiv). The reaction mixture is heated to reflux for 2 h. The reaction mixture is allowed to cool to room temperature and is diluted with 300 mL 50% sodium bicarbonate solution. The product is extracted three times with methylene chloride. The combined organic layers are dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified via flash chromatography eluting with ethyl acetate/hexanes (2:98 to 8:92) to give the desired product (2.3 g, 76%) as a white solid.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([Cl:12])[C:8]([CH2:10]Cl)=[CH:9][C:3]=2[O:2]1.[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=2)[CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:12][C:7]1[C:8]([CH2:10][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=3)[CH:22]=[CH:21]2)=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1.[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=2)[CH:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClCc1cc2c(cc1Cl)OCO2
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3cc4c(cc3Cl)OCO4)c2c1

Procedure:
The titled compound (46 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 6-chloropiperonyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.[CH2:8]1[O:10][CH2:9]1>[Cr].CC(CC(C)C)=O>[OH:10][CH2:9][CH2:8][N:5]1[C:4](=[O:6])[CH2:3][CH2:2][C:1]1=[O:7]
Reactant: O=C1CCC(=O)N1
Reactant: C1CO1
Agent: [Cr]
Solvent: CC(=O)CC(C)C
Product: O=C1CCC(=O)N1CCO

Procedure:
N-2-Hydroxyethyl succinimide was prepared by reacting 49.5g (0.5 mole) of succinimide with 26.5g (0.60 mole) of ethylene oxide in the presence of 0.49g (1%) of active chromium III tri-2-ethylhexanoate and 400 ml of methylisobutyl ketone for 2 hours at 160° to 165°C in an autoclave. N-2-Hydroxyethyl succinimide was obtained by filtration in 87.5% yield. The reaction did not proceed in the absence of COT.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=2)[C:16]([O:18]CC)=[O:17])=[N:4][NH:3]1.Cl>[OH-].[K+]>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=2)[C:16]([OH:18])=[O:17])=[N:4][NH:3]1
Reactant: CCOC(=O)c1cccc(Oc2n[nH]c(=O)c3ccccc23)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cccc(Oc2n[nH]c(=O)c3ccccc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 3-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)benzoate (2d) (1 g, 3.2 mmol) obtained in the last step was dissolved in 1M potassium hydroxide solution, stirred for two hours at room temperature, and then concentrated hydrochloric acid was added dropwise to adjust pH=3, stirred for two hours at room temperature, filtrated to give a white solid intermediate 3-(4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (2e), 893 mg white solid (yield 99%). 1H NMR (600 MHz, DMSO-d6): δ 11.96 (s, 1H), 8.26 (d, 1H, J=7.9 Hz), 8.12 (d, 1H, J=7.9 Hz), 8.02-7.99 (m, 1H), 7.97-7.94 (m, 1H), 7.82-7.81 (m, 2H), 7.56-7.55 (m, 2H); ESI-MS m/z: calculated for 282.1. found 281.1 [M−H]+.
Reaction SMILES: [C:1]([O-:4])([O-:3])=O.[C:5]([O-:8])([O-])=[O:6].OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[F:19][S:20]([C:23](C(F)=O)([F:25])[F:24])(=[O:22])=[O:21]>C(Cl)(F)(F)C(Cl)(Cl)F>[F:25][C:23]([F:24])([S:20]([F:19])(=[O:21])=[O:22])[C:1]([O:4][O:8][C:5](=[O:6])[C:23]([F:25])([F:24])[S:20]([F:19])(=[O:22])=[O:21])=[O:3]
Reactant: O=C(F)C(F)(F)S(=O)(=O)F
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: O=C(OOC(=O)C(F)(F)S(=O)(=O)F)C(F)(F)S(=O)(=O)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
A round-bottom flask is charged with 50 ml of CFC-113 and 2.0 g of sodium percarbonate (13 mmoles or 19 mmoles of H2O2 equivalent). After chilling the contents of the flask to 0° C., 2.83 ml of FSO2CF2(C═O)F (25 mmoles) is added and the resulting slurry is stirred magnetically for 3 hours. The reaction mixture is filtered through a pad of Drierite® on glass wool, washing through with fresh CFC-113, an operation assumed to remove any unreacted percarbonate and any free H2O2. The filtrate, now measuring 52 ml in volume, is found to be 0.10 M in peroxide for a 42% yield based on starting FSO2CF2(C═O)F.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH2:18]C)=[CH:15][CH:14]=[C:13]([N+:20]([O-:22])=[O:21])[C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(OC)=CC=[C:35]([N+:41]([O-:43])=[O:42])C=1C=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([N+:20]([O-:22])=[O:21])[C:10]=1[CH:11]=[CH:35][N+:41]([O-:43])=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1OCc1ccccc1
Reactant: CCOc1ccc([N+](=O)[O-])c(C=O)c1OCc1ccccc1
Product: COc1ccc([N+](=O)[O-])c(C=C[N+](=O)[O-])c1OCc1ccccc1
Yield: 83 %

Procedure:
This compound is obtained according to the operating method described in Example 1b, in which the 2-benzyloxy-3-ethoxy-6-nitrobenzaldehyde is replaced with 2-benzyloxy-3-methoxy-6-nitrobenzaldehyde. A pale yellow powder (yield=83%, m.p.=118°-119° C.) is obtained.