Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.N[C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.C([BH3-])#[N:18].[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[OH:16][C:12]1[CH:11]=[C:10]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][C:3]=2[CH2:7][NH2:18])[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc(O)c1
Reactant: O=Cc1cccnc1
Reactant: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CO
Product: NCc1cnccc1-c1cccc(O)c1
Reaction time: 2.5 h

Procedure:
3-Pyridinecarboxaldehyde (0.550 g, 5 mmol) and 3-aminophenol (0.540 g, 5 mmol) were dissolved into methanol (15 ml). To the solution was added a mixture of sodium cyanoborohydride (0.378 g, 6 mmol) and zinc chloride (0.408 g, 3.0 mmol) in methanol at room temperature. The reaction mixture was stirred for 2.5 h. Most of the methanol was evaporated under reduced pressure. Ice water was added to the residue. It was filtered and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound. 1H NMR: 8.53 (s,1H), 8.45 (d,1H,J=3.9 Hz), 7.72 (d,1H,J=7.8 Hz), 7.24-7.30 (m,2H), 6.95-7.01 (m1H), 4.27 (s,2H). MS calcd. 200.1; MS (M+1) 201.1.
Reaction SMILES: [Si]([O:18][C@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:22]([N:29]2[C:37]([CH3:38])=[N:36][C:35]3[C:30]2=[N:31][C:32]([N:39]2[C:43]4[CH:44]=[C:45]([C:48]#[N:49])[CH:46]=[CH:47][C:42]=4[N:41]=[CH:40]2)=[N:33][CH:34]=3)[CH2:21][CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].[Cs+]>CN(C=O)C>[OH:18][C@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:22]([N:29]2[C:37]([CH3:38])=[N:36][C:35]3[C:30]2=[N:31][C:32]([N:39]2[C:43]4[CH:44]=[C:45]([C:48]#[N:49])[CH:46]=[CH:47][C:42]=4[N:41]=[CH:40]2)=[N:33][CH:34]=3)[CH2:21][CH2:20]1
Reactant: Cc1nc2cnc(-n3cnc4ccc(C#N)cc43)nc2n1[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2ccccc21
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: Cc1nc2cnc(-n3cnc4ccc(C#N)cc43)nc2n1[C@@H]1CC[C@@H](O)c2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A 50 ml round bottom flask was charged with 0.06 g (0.091 mmol) of 3-(9-((1R,4R)-4-(tert-butyldiphenylsilyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-8-methyl-9H-purin-2-yl)-3H-benzo[d]imidazole-5-carbonitrile. 20 ml of DMF was then added, followed by 0.07 g (0.45 mmol) of Cesium Fluoride, and the resulting mixture was stirred at 50° C. overnight (drying tube was attached to flask). The mixture was cooled to room temp, diluted with 100 ml EtOAc and washed with approx 10 ml water. The organic layer was dried over MgSO4 and concentrated in vacuo, and purified by column chromatography (eluting with 1% MeOH in DCM), to give 0.023 g (60%) of the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][C:12]3[C:17]([N+:18]([O-])=O)=[CH:16][CH:15]=[CH:14][N:13]=3)[C:4]=2[O:3]1>CO.C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1([CH3:21])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][C:12]3[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(Oc3ncccc3[N+](=O)[O-])c2O1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)Cc2cccc(Oc3ncccc3N)c2O1
Reaction time: 1 h
Yield: 97 %

Procedure:
134a (3.27 g, 11.4 mmol) was dissolved in a 1:1 mixture of methanol and ethyl acetate (80 mL). Palladium on charcoal (10%, 1.2 g, 1.1 mmol) was added, and the mixture was stirred 1 h under hydrogen atmosphere (40 psi). The reaction mixture was filtered over Celite® and concentrated to afford 2.78 g (97% yield, 100% pure) of 134b as an off-white solid. [M+H]+=257.17; in NMR (500 MHz, deuterochloroform) δ ppm 7.53 (d, 1H, J=5.0 Hz), 6.97 (d, 2H, J=10.0 Hz), 6.95 (d, 1H, J=5.0 Hz), 6.80 (m, 2H), 3.97 (br, 2H), 3.05 (s, 2H), 1.44 (s, 6H); 13C (125 MHz, deuterochloroform) δ (ppm), 151.60, 150.18, 137.70, 135.60, 131.52, 129.47, 121.77, 121.30, 120.96, 120.27, 119.02, 87.80, 43.19, 28.08.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:11][C@H:12]([CH2:14][CH:15]=[CH2:16])[CH3:13])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([O:11][C@H:12]([CH2:14][CH:15]=[CH2:16])[CH3:13])[CH:3]=1
Reactant: C=CC[C@H](C)Oc1cc(F)c(F)cc1C=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1cc(F)c(F)cc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a solution of (S)-4,5-difluoro-2-(pent-4-en-2-yloxy)benzaldehyde (0.1295 g, 0.572 mmol) in THF (2 ml) at 0° C. was added dropwise lithium aluminum hydride (0.343 ml, 0.687 mmol) over 30 min. The mixture was stirred at rt for 2 h then cooled to 0° C. and quenched by the dropwise addition of brine. The mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated to give (S)-(4,5-difluoro-2-(pent-4-en-2-yloxy)phenyl)methanol (0.1088 g, 0.477 mmol, 83% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.15 (dd, J=10.4, 9.2 Hz, 1H), 6.72 (dd, J=12.0, 6.6 Hz, 1H), 5.99-5.70 (m, 1H), 5.24-5.07 (m, 2H), 4.75-4.49 (m, 2H), 4.41 (sxt, J=6.0 Hz, 1H), 2.60-2.35 (m, 2H), 2.26 (t, J=6.5 Hz, 1H), 1.36 (d, J=6.1 Hz, 3H).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].C(N(CC)CC)C.[C:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)(=[O:18])[CH3:17]>O1CCOCC1>[Cl:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][Cl:8])[S:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:16](=[O:18])[CH3:17])=[CH:25][CH:24]=1)(=[O:28])=[O:27]
Reactant: ClCCNCCCl
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Temperature: 80 °C
Yield: 40.44 %

Procedure:
Bis(2-chloroethyl)amine hydrochloride (0.0114 mol) and triethylamine (0.0114 mol) are added to a solution of 4-acetamidophenylsulfonyl chloride (1.34 g, 0.0057 mol) in dioxane (5 mL). The mixture is heated for 1 hour at 80° C., then part of the solvent is removed by evaporation at reduced pressure, and water is added until precipitation of the resulting sulfonamide. The product is collected by filtration as a pink solid in 40.44% yield and used without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])/[CH:3]=[CH:4]/[C:5]([O:7]CC)=[O:6].[OH-].[Na+].Cl>C1COCC1>[F:1][C:2]([F:11])([F:10])/[CH:3]=[CH:4]/[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)/C=C/C(F)(F)F

Procedure:
A solution of ethyl 4,4,4-trifluorocrotonate (9.85g, 65.9 mmole) and 1N NaOH (92.3 mL, 92.3 mmole) in THF (24 mL) was stirred at room temperature for 3 hours. The pH was brought to 1 with conc. HCl and the mixture extracted with Et2O (3×). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford the title compound as an oil. NMR (CDCl3): δ 6.55 (d, 1H); 6.89 (dq, 1H).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][C:6]([OH:8])=[O:7].C(=O)(O)[O-].[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O>[CH2:21]([O:20][C:18]([N:2]([CH3:1])[C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN[C@@H](CCC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN(C(=O)OCc1ccccc1)[C@@H](CCC(=O)O)C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-Methyl-L-glutamic acid (3.2 g) was added to water (50 ml) and the pH of the solution adjusted to 9 with solid sodium bicarbonate. The solution was cooled to 0° C. and stirred vigorously, while benzyl chloroformate (9 ml) was added dropwise over 20 min. The mixture was stirred for a further 2 h at 0° C. and an additional 2 h at room temperature, then extracted with diethyl ether (2×100 ml). The aqueous solution was then acidified to pH 3 with 5N HCl and the product isolated by extraction with ethyl acetate (2×100 ml). The pooled organic extracts were dried over anhydrous sodium sulphate and the solvent concentrated in vacuo to give a yellow oil, which crystallised on standing. Recrystallisation from water afforded N-(benzyloxycarbonyl)-N-methyl-L-glutamic acid (2.26 g), m.p. 97°-98° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](=[O:16])[CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Fc1cccc(CBr)c1
Product: O=C(Cc1cccc(F)c1)c1ccc(Br)cc1

Procedure:
The title compound was prepared according to the procedure of step 1 in the Example 169 using 3-fluorobenzyl bromide and 4-bromobenzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[C:11]([CH2:12][O:13][C:14]3[C:19]([F:20])=[CH:18][C:17]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][C:15]=3[F:28])=[C:10]([C:29]([F:32])([F:31])[F:30])[S:9][N:8]=2)=[N:4][CH:3]=1.[CH3:33][OH:34]>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[C:11]([CH2:12][O:13][C:14]3[C:15]([F:28])=[CH:16][C:17]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:19]=3[F:20])=[C:10]([C:29]([F:32])([F:31])[F:30])[S:9][N:8]=2)=[N:4][CH:3]=1.[F:28][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:18]=[C:19]([F:20])[C:14]=1[O:13][CH2:12][C:11]1[C:7]([C:5]2[S:6][C:2]([O:34][CH3:33])=[CH:3][N:4]=2)=[N:8][S:9][C:10]=1[C:29]([F:32])([F:31])[F:30]
Reactant: CO
Agent: CCOC(=O)CCc1cc(F)c(OCc2c(-c3ncc(Cl)s3)nsc2C(F)(F)F)c(F)c1
Product: COc1cnc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)s1

Procedure:
The title compound was prepared according to the procedure described in Example 1 Step 6 by hydrolysis of ethyl 3-(4-((3-(5-chlorothiazol-2-yl)-5-(trifluoromethyl)isothiazol-4-yl)methoxy)-3,5-difluorophenyl)propanoate in MeOH instead of THF to afford compound 267 as an off-white solid. 1H NMR (400 MHz, CDCl3) δ: 7.91 (s, 1H), 6.75 (d, J=8.0 Hz, 2H), 5.26 (s, 2H), 4.12 (s, 3H), 2.88 (t, J=6.8 Hz, 2H), 2.62 (t, J=6.0 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C18H13F5N2O4S2, 481.0 (M+H). found 481.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16](Cl)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[NH:19]1[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([N:19]3[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1cc(-c2ccc(Br)cc2)nc2ccccc12
Reactant: NC(=O)C1CCNCC1
Solvent: CCO
Product: NC(=O)C1CCN(c2cc(-c3ccc(Br)cc3)nc3ccccc23)CC1

Procedure:
The named compound was made in a manner analogous to that of Example 8(d) using (2-(4-bromophenyl)-4-chloroquinoline and isonipecotamide as starting materials. It was obtained as white needles, mp 247°-249° dec on recrystallization from ethanol.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[CH2:5][CH2:6][OH:7].I[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1>O1CCCC1.[Cu]I>[F:3][C:4]([F:9])([F:8])[CH2:5][CH2:6][O:7][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1
Reactant: Ic1cccs1
Reactant: OCCC(F)(F)F
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)CCOc1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a suspension of hexanes-washed sodium hydride (918 mg, 22.95 mmol) in 10 mL anhydrous tetrahydrofuran at 0° C. was added 3,3,3-trifluoropropanol (3.5 g, 30.60 mmol) dropwise. After the addition was complete, the mixture was stirred at room temperature for 30 minutes. 2-Iodothiophene (3.21 g, 15.30 mmol) and copper(I) iodide (728 mg, 3.82 mmol) were added, the reaction vessel was flushed with argon, sealed and stirred at 100° C. for 48 h. The reaction mixture was allowed to cool to room temperature and poured into 150 mL of 5% aqueous potassium cyanide solution. Organics were extracted with 1:1 ether/hexanes (3×100 mL), dried with magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel (100% hexanes) to give 2-(3,3,3-trifluoropropoxyl)thiophene (1.70 g, 57%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[C:29](=[O:30])[C:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=5)=[CH:34][CH:33]=4)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]3[CH3:49])=[CH:20][C:19]=2[F:50])[CH2:15][CH2:14]1>O.C(OCC)(=O)C>[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[C:29](=[O:30])[C:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=5[C:44]5[NH:3][C:4](=[O:7])[O:5][N:45]=5)=[CH:34][CH:33]=4)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]3[CH3:49])=[CH:20][C:19]=2[F:50])[CH2:15][CH2:14]1
Reactant: CCCc1nc(C)n(-c2ccc(OCC3CC3)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(-c2ccc(OCC3CC3)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A mixture of hydroxylammonium chloride (1.31 g), sodium hydrogen carbonate (1.90 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(cyclopropylmethoxy)-3-fluorophenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.95 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.37 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.74 g, 70%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](C(O)=O)=[CH:2]1.[C:13](=O)([O-])[O-].[K+].[K+].[C:19](=[O:24])(OC)[O:20][CH3:21].N1C2C(=CC=CC=2)C=C1>CN(C)C=O>[CH3:21][O:20][C:19]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH3:13])[CH:2]=1)=[O:24]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: COC(=O)OC
Agent: [K+]
Agent: c1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C)c2ccccc12
Temperature: 130 °C
Reaction time: 5 h
Yield: 50 %

Procedure:
To a three-necked round bottom flask was charged 3-indolecarboxylic acid (2.5 g, 15.51 mmol), potassium carbonate (powder, 1.25 g), N,N-dimethylformamide (20 mL) and dimethyl carbonate (3.9 mL, 46.3 mmol). As the stirred mixture was heated to reflux (130° C.), the disappearance of starting indole was monitored by HPLC. After 5 h the reaction was complete, then the mixture was cooled to room temperature and was partitioned between water (50 mL) and tert-butyl methyl ether (100 mL). The separated organic layer was washed with water (2×50 mL) and the volatiles were evaporated under reduced pressure. Purification of the obtained crude by using column chromatography over silica gel furnished 1-methylindole-3-carboxylic acid methyl ester (50% yield) and the decarboxylated byproduct 1-methylindole (45% yield).
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5](=[C:8]1[C:13](=[O:14])[CH:12]=[C:11]([CH2:15][CH3:16])[O:10][C:9]1=[O:17])[CH2:6][CH3:7])[CH3:2].C(Cl)(Cl)Cl.CC(C)=[O:24]>O.[Hg]>[CH2:1]([O:3][NH:4][C:5]([CH:8]1[C:13](=[O:14])[CH:12]=[C:11]([CH2:15][CH3:16])[O:10][C:9]1=[O:17])([OH:24])[CH2:6][CH3:7])[CH3:2]
Reactant: CCONC(CC)=C1C(=O)C=C(CC)OC1=O
Reactant: CC(C)=O
Agent: [Hg]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCONC(O)(CC)C1C(=O)C=C(CC)OC1=O

Procedure:
After 1g of 3-(1-ethoxyaminopropylidene)-6-ethyl-3,4-dihydro-2H-pyrane-2,4-dione was dissolved in 50ml of acetone containing 5% of water, it was irradiated with high-pressure mercury arc for a day. Chloroform was added to the residue after the distillation of acetone and the insoluble crystal was obtained by filtration of chloroform solution containing the residue. The crude product was recrystallized from the mixture of benzene and petroleum ether, and thereby 0.6g of 3-(1-ethoxyamino-1-hydroxypropyl)-6-ethyl-3,4-dihydro-2H-pyrane-2,4-dione having a melting point of 63° to 64°C as a white plate was obtained.
Reaction SMILES: [C:1]([O:36]C(C)(C)C)(=[O:35])[C:2]([O:4][C:5]([CH3:34])([CH3:33])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[C:18]3[S:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)=[CH:23][C:17]=3[N:16]=[CH:15]2)=[CH:10][C:9]=1[O:31][CH3:32])=[O:3]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[S:21][C:18]3[C:19](=[O:20])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]([CH3:34])([O:4][C:2](=[O:3])[C:1]([OH:36])=[O:35])[CH3:33])=[C:9]([O:31][CH3:32])[CH:10]=4)[CH:15]=[N:16][C:17]=3[CH:23]=2)=[CH:25][CH:26]=1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)OC(=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)OC(=O)C(=O)O
Yield: 91 %

Procedure:
A solution of tert-butyl 1-(4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)-2-methylpropan-2-yl oxalate (124 mg; 0.212 mmol) in 0.5 mL of TFA and 1 mL of CH2Cl2 was stirred at rt for 1.5 h. The solution was concentrated under reduced pressure to afford 102 mg (91%) of the title compound as a white foam. 1H NMR (CDCl3) δ 1.70 (s, 6H), 3.86 (s, 3H), 4.30 (s, 2H), 6.91-6.94 (m, 2H), 7.09 (d, J=8.80 Hz, 1H), 7.45 (d, J=8.79 Hz, 2H), 7.66-7.69 (m, 3H), 8.74 (s, 1H); 13C NMR (CDCl3) δ 22.76, 56.26, 74.60, 85.93, 111.25, 116.62, 119.30, 122.64, 127.93, 129.47, 129.70, 130.35, 136.86, 148.88, 151.00, 151.55, 155.17, 155.98, 157.04, 158.59, 159.55, 159.95; HPLC (Method #1) 4.13 min retention time, (99%); MS (ES): m/z 529 [M+H]+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1(=[N:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>CN(C=O)C>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:15][N:14]=[C:7]2[CH2:1][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: ON=C1CCCCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(ON=C2CCCCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 43.5 %

Procedure:
The core molecule was synthesized by the following procedure. Potassium t-butoxide (5.9 g, 53 mmol) was added in portions to a cooled (5° C.) solution of cycloheptanone oxime (7.5 g, 53 mmol) in DMF (100 mL). The cooled reaction mixture was stirred for 50 minutes and then 1-chloro-4-nitrobenzene (7.9 g, 50 mmol) in DMF (25 mL) was added over 5 minutes. The reaction mixture was stirred at ˜10° C. for 30 minutes and then allowed to warm to room temperature and stirred for an additional 4 hours. The reaction mixture was concentrated under reduced pressure and the crude material was dissolved in ether and washed with water and brine. The organic phase was dried (Na2SO4) and concentrated to provide cyclooctanone O-(4-nitro-phenyl)-oxime (5.7 g). Cyclooctanone O-(4-nitro-phenyl)-oxime (5.3 g, 20 mmol) was dissolved in warm isopropanol (120 mL) and 12 N hydrochloric acid (6.8 mL) was added. The reaction mixture was heated to reflux for 5 hours and then cooled in an ice bath. The solid was collected by filtration, washed with water and cold isopropanol, and dried in an oven. The crude solid was purified by flash column chromatography (elution with 2% ethyl acetate-hexanes) to give 2-nitro-6,7,8,9,10,11-hexahydro-benzo[b]-cycloocta[d]furan (3.5 g, 14 mmol). A mixture of 2-nitro-6,7,8,9,10,11-hexahydro-benzo[b]-cycloocta[d]furan (3.4 g, 14 mmol) and Raney nickel (-4.1 g wet weight) in ethanol (170 mL) was hydrogenated at 50 PSI on a Parr shaker overnight. The mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was purified by flash column chromatography (elution with 20% ethyl acetate-hexanes) to give 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (2.3 g). Mp 97-98° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[CH3:18][O:19][C:20](=[O:30])[C:21]([OH:29])([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22](O)=[O:23].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[CH3:18][O:19][C:20](=[O:30])[C:21]([OH:29])([C:22](=[O:23])[NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: COC(=O)C(O)(CC(C)C)C(=O)O
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(O)(CC(C)C)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 76 %

Procedure:
A solution of 350 mg (1.56 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 327 mg (1.72 mmol) (R/S)-2-hydroxy-2-isobutyl-malonic acid monomethyl ester in 30 ml tetrahydrofuran were cooled to 0° C. and 232 mg (1.72 mmol) 1-hydroxy-benzotriazole hydrate, 584 μl (3.43 mmol) diisopropylethylamine and 329 mg (192 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight at room temperature. Extraction with water/ethylacetate and chromatography on silicagel with heptane/ethylacetate (gradient 90/10 to 50/50) yielded 470 mg (76%) (R/S)-2-hydroxy-4-methyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid methyl ester as a colorless foam, MS (m/e): 397.3 (M+H)+.
Reaction SMILES: [OH-].[Li+].C([O:6][CH2:7][C:8]([NH:10][C@H:11]1[C@@H:16]2[C@@H:14]([C@H:15]2[C:17]([O:19]CC)=[O:18])[C@:13]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:22]([O:24]CC)=[O:23])[C@@H:12]1[O:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=1)=[O:9])(=O)C.Cl>O1CCCC1>[C:31]([O:30][C:28]([NH:27][C@@:13]1([C:22]([OH:24])=[O:23])[C@H:12]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=2)[C@@H:11]([NH:10][C:8](=[O:9])[CH2:7][OH:6])[C@@H:16]2[C@H:14]1[C@H:15]2[C:17]([OH:19])=[O:18])=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOC(=O)[C@H]1[C@@H]2[C@H](NC(=O)COC(C)=O)[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@H]12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](NC(=O)CO)[C@H]1OCc1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
Add 1M aqueous lithium hydroxide (4.0 mL, 4.0 mmol) to a solution of diethyl (1S,2R,3R,4S,5R,6S)-4-[(2-acetoxyacetyl)amino]-2-(tert-butoxycarbonylamino)-3-[(3,4-dichlorophenyl)methoxy]bicyclo[3.1.0]hexane-2,6-dicarboxylate (0.42 g, 0.67 mmol) in tetrahydrofuran (7.0 mL) at room temperature and stir overnight. Acidify the reaction to approximately pH 1 with 5N aqueous HCl. Extract with ethyl acetate (3×25 mL). Dry the combined organic layers, filter, and conc. under reduced pressure. HPLC analysis of crude reaction mixture shows starting material present. Add a 1M aqueous lithium hydroxide (4.0 mL, 4.0 mmol) to a solution of the crude reaction mixture in tetrahydrofuran (7.0 mL) and heat at 50° C. After 17 hours, acidify reaction to approximately pH 1 with 5N aqueous HCl. Extract with ethyl acetate (3×25 mL). Dry the combined extracts, filter, and conc. under reduced pressure. Purify by preparative reverse-phase high performance liquid chromatography using a gradient of 95% water (with 0.03% HCl)/5% acetonitrile to 5% water (with 0.03% HCl)/95% acetonitrile over 40 min. to provide (1S,2R,3R,4S,5R,6S)-2-(tert-butoxycarbonylamino)-3-[(3,4-dichlorophenyl)methoxy]-4-[(2-hydroxyacetyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (0.181 g, 0.34 mmol, 51%) as a white solid. MS (m/z): 531 (M−H).