Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:7]=[C:8]([C:12](=O)[CH:13]=O)[CH:9]=[CH:10][CH:11]=1)([F:4])[F:3].I.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]([NH:27][NH2:28])=[NH:26]>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]1[N:27]=[N:28][CH:13]=[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:5][C:2]([F:4])([F:3])[F:1])[CH:7]=2)[N:26]=1
Reactant: O=CC(=O)c1cccc(SC(F)(F)F)c1
Reactant: N=C(NN)c1ccc(F)cc1F
Agent: I
Product: Fc1ccc(-c2nncc(-c3cccc(SC(F)(F)F)c3)n2)c(F)c1

Procedure:
(3-Trifluoromethylsulfanylphenyl)oxoacetaldehyde was reacted with 2,4-difluorobenzenecarboximidic hydrazide hydriodide salt (1.13 g, 3.78 mmol) using the method described in Example 1 to give 3-(2,4-difluorophenyl)-5-(3-trifluoromethylsulfanylphenyl)-[1,2,4]triazine as a yellow solid (1.0 g): δH (400 MHz, CDCl3) 7.01-7.13 (2H, m), 7.68 (1H, t, J 7.8 Hz), 7.92 (1H, d, J 7.4 Hz), 8.32-8.39 (2H, m), 8.55 (1H, s), 9.67 (1H, s); m/z (ES+) 370.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=1[Cl:73])[N:37]1[CH:42]2[CH2:43][CH2:44][CH:38]1[CH2:39][C:40]([C:46]1[N:51]=[C:50]([CH2:52][NH:53]C(NCCNC(=O)OC(C)(C)C)=O)[CH:49]=[CH:48][CH:47]=1)([OH:45])[CH2:41]2>>[N:53]([CH2:52][C:50]1[N:51]=[C:46]([C:40]2([OH:45])[CH2:39][CH:38]3[N:37]([CH:36]([C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=4[Cl:73])[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Cl:29])[CH:42]([CH2:43][CH2:44]3)[CH2:41]2)[CH:47]=[CH:48][CH:49]=1)=[N+:15]=[N-:16]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)NCc1cccc(C2(O)CC3CCC(C2)N3C(c2ccccc2Cl)c2ccccc2Cl)n1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1cccc(C2(O)CC3CCC(C2)N3C(c2ccccc2Cl)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Add diphenylphosphoryl azide (272 mg, 0.99 mmol) and 1,8-diazabicyclo-[5,4,0]undec-7-ene (150 mg, 0.99 mmol) to the product from Step 4 (404 mg, 0.86 mmol) at 0° C., stir for 20 min., warm to RT then stir at 50° C. for 1 h. Cool to RT and stir overnight. Quench the reaction with H2O and saturated aqueous NH4Cl , extract with CH2Cl2, dry and concentrate. Purify the residue by column chromatography to give the desired compound.
Reaction SMILES: [OH:1][C:2]1[C:11](C(O)=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17](C(O)=O)[C:16]=1O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:3]1([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2
Reactant: O=C(O)c1cc2ccccc2c(-c2c(O)c(C(=O)O)cc3ccccc23)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc2ccccc2c1-c1cccc2ccccc12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 50 g (60 mmol) of Merrifield resin (polCH2Cl where pol=1-2% crosslinked polystyrene, 200-400 mesh beads), 2,2′-dihydroxy-1,1′-binaphthalene-3,3′-dicarboxylic acid (33.7 g), potassium carbonate (12.4 g) and DMF (dimethlyformamide) (350 ml) was heated at 90° C. with stirring for 8 hrs. The color of the resin changed from white to green-yellow. The mixture was diluted with water, filtered, washed with H2O, DMF, and acetone, and then thoroughly dried in the air to give the desired product. IR (KBr, cm−1): 1712 (vs), 1676 (vs).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[S:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=2)[CH:3]=1.[CH3:16][NH:17][C:18]([N:20]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:21]1)=[O:19].CCN(C(C)C)C(C)C>C(O)CCC>[C:14]([C:11]1[S:10][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([N:28]3[CH2:29][CH2:30][N:25]([CH:22]4[CH2:23][CH2:24][N:20]([C:18]([NH:17][CH3:16])=[O:19])[CH2:21]4)[CH2:26][CH2:27]3)[CH:3]=2)=[N:13][CH:12]=1)#[N:15]
Reactant: CNC(=O)N1CCC(N2CCNCC2)C1
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CNC(=O)N1CCC(N2CCN(c3cc(Nc4ncc(C#N)s4)ncn3)CC2)C1

Procedure:
35-1 (0.106 g, 0.45 mmol), 45-5 (0.095 g, 0.45 mmol) and DIEA (0.18 g, 1.79 mmol) were heated at 150° C. for 3 hours in n-butanol. Upon cooling the precipitate was filtered off, washed with n-butanol and ethyl ether and then dried to afford 45-6. Hi-Res MS: calc: 414.1819 found: 414.1827. 1H-NMR (DMSO-d6): 12.08(s, 1H); 8.42(s, 1H); 8.26(s, 1H); 6.22(s, 1H); 6.02(d, 1H); 3.55(m, 4H); 3.38 (m, 1H); 3.13(m, 1H); 2.97(m, 1H); 2.78(m, 1H); 2.50(complex, 6H); 2.45(m, 2H); 2.06(m, 1H); 1.69(m, 1H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[CH2:25][O:24][C:23]3[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:22]=3[C:21](=[O:32])[C:20]=2[CH:33]=1>CC(N(C)C)=O>[CH3:31][O:30][C:28]1[CH:27]=[CH:26][C:23]2[O:24][CH2:25][C:19]3[CH:18]=[CH:17][C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:33][C:20]=3[C:21](=[O:32])[C:22]=2[CH:29]=1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: COc1ccc2c(c1)C(=O)c1cc(N)ccc1CO2
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(c1)C(=O)c1cc(NC(=O)C(C)(O)C(F)(F)F)ccc1CO2
Temperature: -10 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
In dimethylacetamide (8 ml) was dissolved 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.73 g, 4.63 mmol), and thionyl chloride (0.36 ml, 4.63 mmol) was added thereto at −15° C., followed by stirring at −15 to −5° C. for one hour. To the reaction mixture was added 9-amino-2-methoxy-6,11-dihydrodibenz[b,e]oxepin-11-one obtained in Reference Example 11 (0.59 g, 2.32 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained oily residue was dissolved in ethyl acetate (25 ml). The organic layer was washed successively with a 5% aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (hexane/ethyl acetate=3/1), followed by trituration with isopropyl ether to give Compound 1-48 (yield: 87%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:30])=[C:13]([C:15]3[S:19][C:18]([S:20][CH3:21])=[C:17]([C:22]#[N:23])[C:16]=3[C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:32][CH2:33][CH2:34][OH:35].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:35][CH2:34][CH2:33][CH2:32][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:30])=[C:13]([C:15]3[S:19][C:18]([S:20][CH3:21])=[C:17]([C:22]#[N:23])[C:16]=3[C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1sc(-c2cc(Nc3cccc(O)c3)ccc2C)c(-c2cccnc2)c1C#N
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1sc(-c2cc(Nc3cccc(OCCCO)c3)ccc2C)c(-c2cccnc2)c1C#N
Temperature: 25 °C
Yield: 98.5 %

Procedure:
To a solution of 5-[5-(3-hydroxy-phenylamino)-2-methyl-phenyl]-2-methylsulfanyl-4-pyridin-3-yl-thiophene-3-carbonitrile (330 mg, 0.77 mmol) in DMF (anhydrous, 5 mL) was added 3-bromo-propan-1-ol (214 mL, 1.54 mmol). The reaction was stirred at 70° C. in the presence of excess K2CO3 overnight then cooled to ambient temperature and partitioned between water and DCM. The mixture was extracted with DCM (30 ml×3) and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (2% MeOH-DCM) afforded desired product (370 mg, 99%). 1H NMR (CDCl3): δ8.6(d, 1H), 8.5 (d, 1H), 8.1 (s, 1H), 7.7 (d, 1H), 7.4 (s, 1H), 7.3-7.2 (m, 3H), 7.0 (d, 1H), 6.6 (d, 1H), 4.1 (t, 2H), 3.9 (t, 2H), 2.7 (s, 3H), 2.0 (m, 2H), 1.5 (s, 3H)
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].CO.[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)[CH2:12][CH3:13]>O>[C:15]1([C:11](=[N:2][OH:3])[CH2:12][CH3:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NO
Reactant: CCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Hydroxylamine hydrochloride (17.1 g, 246 mmol) and sodium acetate (20.2 g, 246 mmol) were added to 110 mL of methanol and the resulting white slurry was stirred at room temperature for 30 min. Propiophenone (30 g, 224 mmol) was added and the mixture was stirred at room temperature for 20 hours. Water (100 mL) was added and the mixture was stirred for 10 min. The product was extracted with EtOAc and the organic layer was washed with saturated NaHCO3 solution and dried over MgSO4. The solvent was evaporated in vacuo to give 32.4 g of the title compound. 1H NMR (CDCl3, 200 MHz): δ=9.21 (s, 1H), 7.60-7.72 (m, 2H), 7.38-7.50 (m, 3H), 2.91 (q, 2H, J=7.8 Hz), 1.23 (t, 3H, J=7.4 Hz).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CON
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCCC1CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added tert-butyl 2-[(aminooxy)methyl]piperidine-1-carboxylate 105 (0.312 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 106 (0.40 g, 91%) as a white foam.
Reaction SMILES: [O:1]=[S:2]1(=[O:37])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][N:27]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH3:28])=[CH:20][CH:19]=2)[C:13]([O:15]C)=[O:14])=[N:3]1.[Li+].[OH-].Cl.O>C1COCC1.CO.O>[O:37]=[S:2]1(=[O:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][N:27]([C:29]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)=[O:30])[CH3:28])=[CH:20][CH:19]=2)[C:13]([OH:15])=[O:14])=[N:3]1
Reactant: COC(=O)[C@H](Cc1ccc(SCCN(C)C(=O)C2CCCCC2)cc1)NC1=NS(=O)(=O)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(CCSc1ccc(C[C@H](NC2=NS(=O)(=O)c3ccccc32)C(=O)O)cc1)C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
The crude product from Step A was dissolved in a THF/MeOH/H2O mixture (6:0.1:1; 2 ml). Aqueous 1M LiOH solution (1.6 ml) was added and the mixture was stirred for 3 days at room temperature. Then the reaction mixture was neutralized with 1M HCl, a small amount of water was added and the mixture extracted with ethyl acetate. The solvent was evaporated. The product was purified by chromatography (SiO2/ethyl acetate/hexane). The yield was 40%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:24]O)=[N:21][C:22]=3[CH3:23])[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:51]1[CH2:54][CH:53]([C:55]([O:57][CH3:58])=[O:56])[CH2:52]1.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:24][N:51]4[CH2:54][CH:53]([C:55]([O:57][CH3:58])=[O:56])[CH2:52]4)=[N:21][C:22]=3[CH3:23])[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: Cc1nc(CO)ccc1-c1noc(-c2ccc(CC(C)C)c(Cl)c2)n1
Reactant: COC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2ccc(-c3noc(-c4ccc(CC(C)C)c(Cl)c4)n3)c(C)n2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 23 (23g) using {5-[5-(3-chloro-4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-6-methylpyridin-2-yl}methanol (0.15 g, 0.42 mmol) that was obtained in Example 24 (24i), carbon tetrabromide (0.22 g, 0.67 mmol), triphenylphosphine (0.18 g, 0.67 mmol), methyl 3-azetidinecarboxylate hydrochloride (96 mg, 0.63 mmol), and N,N-diisopropylethylamine (0.22 ml, 1.3 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1 to 2:1 or 3:1) as the eluent to afford the title compound (0.11 g) in a yield of 58% as a pale yellowish oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][N:11]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[C:12]2[C:19]([O:21]CC)=O)=[CH:5][CH:4]=1>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]23[NH:16][CH2:14][CH2:15][N:11]2[C:19](=[O:21])[C:12]2[N:11]([CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=2)[CH2:10]3)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cn1CC(=O)c1ccc(OC)cc1
Solvent: C1COCCO1
Product: COc1ccc(C23Cn4cc([N+](=O)[O-])cc4C(=O)N2CCN3)cc1
Temperature: 105 °C
Reaction time: 24 h
Yield: 67.7 %

Procedure:
Ethyl 1-[2-(4-methoxyphenyl)-2-oxoethyl]-4-nitro-1H-pyrrole-2-carboxylate (610 mg, 1.8 mmol) was mixed with 1,4-dioxane (7 mL) and ethylene-1,2-diamine (1.7 mL) and the mixture heat at 105° C. After 24 hours the reaction was complete (monitored by LCMS). The reaction was concentrated in vacuo and the resultant residue purified by flash chromatography (Biotage SP4, gradient 0-10% MeOH in EtOAc) to give 10a-(4-methoxyphenyl)-7-nitro-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (200 mg, yield 34%). ESI-MI m/z [M+H]+ 328.9.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li]CCCC.CC([O-])(C)C.[K+].[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:45][CH3:46])=[C:27]([C:29]([CH3:44])([CH3:43])[CH2:30]/[C:31](=[N:36]/S(C(C)(C)C)=O)/[C:32]([F:35])([F:34])[F:33])[CH:28]=1>C(OCC)C.C1COCC1>[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:45][CH3:46])=[C:27]([C:29]([CH3:43])([CH3:44])[CH2:30][C:31]([NH2:36])([CH2:1][C:2]2[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:32]([F:35])([F:34])[F:33])[CH:28]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: COc1ccc(F)cc1C(C)(C)C/C(=N/S(=O)C(C)(C)C)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(N)(Cc1cc2ccccc2[nH]1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 33 %

Procedure:
To a chilled (−78 C.) solution of 40 mg (0.30 mmol) of 2-methylindole in 3 mL of diethyl ether was added 0.56 mL (0.91 mmol) of a 1.6 M solution of n-BuLi in hexanes. The resulting orange solution was stirred for 5 min and treated with 0.60 mL (0.60 mmol) of a solution of 1 M solution of KOt-Bu in THF. The reaction was slowly warmed until a bright yellow precipitate formed. After 5 min, the reaction mixture was cooled to −78° C. and treated with 138 mg (0.362 mmol) of a solution of 2-methyl-propane-2-sulfinic acid [3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-trifluoromethyl-but-(Z)-ylidene]-amide in 0.5 mL of diethyl ether. Next, the mixture was warmed to room temperature, quenched with aqueous ammonium chloride and extracted with EtOAc (3×). The combined organic layers were dried over (MgSO4), filtered and concentrated. The residue was dissolved in 2 mL of methanol, 3 drops of concentrated HCl were added and the reaction warmed at 75° C. in a sealed tube. After 1 h, the reaction was cooled to room temperature, concentrated in vacuo, neutralized with aqueous sodium bicarbonate and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered and concentrated to leave an oil. The residue was purified by preparative thin layer chromatography eluting with toluene to afford an oil that had to be further purified by preparative thin layer chromatography eluting with hexanes-EtOAc (9:1) to afford 40 mg (33%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[O:11][CH2:12][C:13](=[O:20])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[F:8].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.C(O)C.[OH-].[Na+]>CC(O)C.Cl>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:12]2[O:11][C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:22]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(F)c(F)c2)OCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)O
Product: CCOC(=O)C1=C(Nc2ccc(F)c(F)c2)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 44.3 %

Procedure:
To a solution of ethyl 2-[(3,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.084 g, 0.30 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.041 g, 0.28 mmol) in 2-propanol (2.0 mL), 2M hydrochloric acid in ethanol (0.14 mL, 0.28 mmol) was added at ambient temperature. The mixture was refluxed for 18 h. Cooled with ice bath, aqueous 2M sodium hydroxide solution (0.13 mL, 0.26 mmol) was added dropwise to neutralize, ethanol (5.0 mL) was added and the mixture was refluxed for 1.5 h. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.051 g, y. 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]3[CH2:13][CH2:14][CH:15]([C:18]([O-:20])=[O:19])[CH2:16][CH2:17][CH:11]3[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:21](O)(=O)C>S(=O)(=O)(O)O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:17][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])C1CCC2ON=C(c3ccc(Cl)cc3)C2CC1
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Product: COC(=O)C1CCc2onc(-c3ccc(Cl)cc3)c2CC1
Temperature: 90 °C

Procedure:
5.3 g (0.053 mol) of chromium trioxide were added to a solution of 6.14 g (0.02 mol) of methyl 3-(4-chlorophenyl-3a,5,6,7,8,8a-hexahydro-4H-cyclohept[d]isoxazole-6-carboxylate (mixture of two diastereoisomers, prepared as described in the last paragraph of Example 1) in 110 ml of acetic acid and 0.5 ml of concentrated sulfuric acid. The mixture was heated to 90° C. for 40 minutes. Excess acetic acid was removed by evaporation, water and 2N sodium carbonate solution were added and the mixture was extracted with diethyl ether. Purification by column chromatography on silica gel using diethyl ether/hexane (1:1) for the elution gave 2.57 g or pure methyl 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]-isoxazole-6-carboxylate of melting point 70°-71° C.
Reaction SMILES: [C:1]1([NH:7][C:8]([CH2:10][C:11](=[CH2:15])[C:12](O)=[O:13])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])=O.[Na+]>CC(OC(C)=O)=O>[CH2:15]=[C:11]1[CH2:10][C:8](=[O:9])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]1=[O:13]
Reactant: C=C(CC(=O)Nc1ccccc1)C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: C=C1CC(=O)N(c2ccccc2)C1=O
Temperature: 89 °C
Reaction time: 14 h

Procedure:
A suspension of the 2-[(N-phenylcarbamoyl)methyl]prop-2-enoic acid (700 mg, 3.41 mmol) in Ac2O (15 mL) was then treated with NaOAc (327 mg, 3.98 mmol) and shaken for 14 hours at 89° C. The resulting clear solution was dried on a Savant™, dissolved in EtOAc and washed with H2O and brine. The organic layers were then dried down on Savant™ to yield 3-methylene-1-phenylazolidine-2,5-dione, a compound of formula (7′).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([O:15]C(C)(C)C)=[O:14])[N:10]([C:20](=[O:39])[C@@H:21]([NH:23][C@H:24]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:22])[C:9]1=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([OH:15])=[O:14])[N:10]([C:20](=[O:39])[C@@H:21]([NH:23][C@H:24]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:22])[C:9]1=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](N[C@@H](C)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C[C@H](N[C@@H](C)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)O)C(=O)OCc1ccccc1
Yield: 87.5 %

Procedure:
0.7 g of tert.-butyl (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-isopentyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate and 20 ml of a 13% hydrogen chloride-dioxane solution are treated in the same manner as described in Example 10-(3), whereby 0.55 g of (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-isopentyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid is obtained as colorless viscous oil. This oil (0.55 g) and 20 mg of palladium black are treated in the same manner as described in Example 10-(5), whereby 0.35 g of (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-carboxy-isopentyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid is obtained as colorless cyrstals. Yield: 68% This product begins to gradually decompose at about 141° C.
Reaction SMILES: C([O:4][CH:5]([CH:37]([O:43]C(=O)C)[CH2:38][O:39]C(=O)C)[C:6]([NH:8][C:9]1[C:10]([I:36])=[C:11]([CH2:31][O:32]C(=O)C)[C:12]([I:30])=[C:13]([C:28]=1[I:29])[C:14]([NH:16][CH2:17][CH:18]([O:24]C(=O)C)[CH2:19][O:20]C(=O)C)=[O:15])=[O:7])(=O)C.[OH-].[Na+]>>[OH:4][CH:5]([CH:37]([OH:43])[CH2:38][OH:39])[C:6]([NH:8][C:9]1[C:10]([I:36])=[C:11]([CH2:31][OH:32])[C:12]([I:30])=[C:13]([C:28]=1[I:29])[C:14]([NH:16][CH2:17][CH:18]([OH:24])[CH2:19][OH:20])=[O:15])=[O:7]
Reactant: CC(=O)OCc1c(I)c(NC(=O)C(OC(C)=O)C(COC(C)=O)OC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCC(O)CO)c1c(I)c(CO)c(I)c(NC(=O)C(O)C(O)CO)c1I

Procedure:
5-[N′-(2,3,4-Triacetoxybutanoyl)amino]-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide (13.8 g, 14.0 mmol) was hydrolysed using sodium hydroxide (4.0 g, 0.10 mol) according to the procedure given in Example 79c. The product was isolated in 68% yield after purification.