Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[C:11]([O:15][C:16]([O:18][C:19]1[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:23]([CH3:55])[C:22]([OH:56])=[C:21]([O:57][CH3:58])[C:20]=1[O:59][CH3:60])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([O:18][C:19]1[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[C:23]([CH3:55])[C:22]([O:56][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)=[C:21]([O:57][CH3:58])[C:20]=1[O:59][CH3:60])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1c(O)c(C)c(CCCCCCCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(OC(=O)OC(C)(C)C)c1OC
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(OC(=O)c2cccnc2)c(C)c(CCCCCCCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(OC(=O)OC(C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
Nicotinoyl chloride hydrochloride (2 g) was added under ice-cooling to a mixture of 1-tert-butoxycarbonyloxy-2,3-dimethoxy-4-hydroxy-6-(10-trityloxydecyl)-5-methylbenzene (10 g), triethylamine (2 g) and dichloromethane (30 ml), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water followed by an aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with ethyl acetate/hexane (1:1) to obtain 1-tert-butoxycarbonyloxy-2,3-dimethoxy-6-(10-trityloxydecyl)-5-methyl-4-nicotinoyloxybenzene (5.1 g). This compound was dissolved in methanol (35 ml). Concentrated hydrochloric acid (2 ml) was added, and the mixture was heated under reflux for 30 minutes. The mixture was concentrated under reduced pressure. Ether was added to the residue which was then separated by filtration to obtain the desired compound (2.9 g).
Reaction SMILES: Cl.[S:2]1[C:6]([C@H:7]2[NH:12][CH2:11][C@H:10]([N:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14](Cl)=[O:15])[CH2:9][CH2:8]2)=[N:5][CH:4]=[N:3]1>C(Cl)Cl>[CH2:18]([O:17][N:13]1[C:14](=[O:15])[N:12]2[CH2:11][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C:6]1[S:2][N:3]=[CH:4][N:5]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)N(OCc1ccccc1)[C@@H]1CC[C@@H](c2ncns2)NC1
Agent: Cl
Solvent: ClCCl
Product: O=C1N2C[C@@H](CC[C@H]2c2ncns2)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a mixture of ((3R,6S)-6-(1,2,4-thiadiazol-5-yl)piperidin-3-yl)(benzyloxy)carbamic chloride HCl salt in dry DCM (15 mL) at 0° C. was added TEA (606 mg, 6.0 mmol). The mixture was stirred at rt for 2 hrs and then concentrated. The residue was purified by silica gel column chromatography (3:1 petroleum ether/EtOAc) to give (2S,5R)-6-(benzyloxy)-2-(1,2,4-thiadiazol-5-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (190 mg, 51%) as a yellow solid. ESI-MS (EI+, m/z): 317 [M+H]+. 1HNMR (500 M, CDCl3): δ 8.62 (s, 1H), 7.46-7.37 (m, 5H), 5.09 (d, J=11.2 Hz, 1H), 4.92 (d, J=11.2 Hz, 1H), 4.90 (br d, J=5.5 Hz, 1H), 3.35 (m, 1H), 2.88 (br d, J=6.0 Hz, 1H), 2.79 (d, J=12.0 Hz, 1H), 2.31-2.28 (m, 2H), 2.21-2.11 (m, 1H), 1.98-1.90 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C([O-])=[O:12].[Na+]>>[OH:12][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C[O-]
Agent: [Na+]
Product: O=C(CO)c1ccccc1

Procedure:
85% Ethanolic solution (1200 mL) of 2-bromo-1-phenylethanone (99.52 g, 500 mmol) and sodium formate (215.0 g, 3160 mol) was heated to reflux for 5 hours. After the solvent was evaporated in vacuo, water (1000 mL) was added to the residue and extraction with ethyl acetate was conducted. The organic layers were combined and dried over anhydrous sodium sulfate and the solvent was evaporated therefrom in vacuo. Petroleum ether was added to the residual oily product to crystallize whereupon 2-hydroxy-1-phenylethanone (59.67 g, 88%) was produced. Mp. 86-89° C. 1H-NMR (DMSO-d6) δ: 4.81 (d, J=5.8 Hz, 2H), 5.07 (t, J=5.8 Hz, 1H), 7.50-7.55 (m, 2H), 7.63-7.67 (m, 1H), 7.92-7.95 (m, 2H)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:28][C:29]1[S:33][N:32]=[C:31]([CH2:34]Cl)[N:30]=1>CC(C)=O.CC(=O)CC>[Cl:28][C:29]1[S:33][N:32]=[C:31]([CH2:34][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])[N:30]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: ClCc1nsc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: CC(C)=O
Product: O=C1N(Cc2nsc(Cl)n2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To a stirred solution of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.33 g, 4.73 mmol) in acetone (50 mL) and 2-butanone (10 mL) were added cesium carbonate (3.10 g, 9.46 mmol) and 5-chloro-3-(chloromethyl)-1,2,4-thiadiazole (1.00 g, 5.92 mmol). The reaction was stirred at ambient temperature for 16 h, then filtered and concentrated in vacuo to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes (15% to 50% gradient) to afford 1′-[(5-chloro-1,2,4-thiadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.43 g, 22%) as a colorless solid: mp 114-116° C.; 1H NMR (300 MHz, DMSO-d6) δ7.29 (dd, J=7.7, 7.7 Hz, 1H), 7.21 (d, J=7.0 Hz, 1H), 7.08-7.03 (m, 2H), 6.71 (s, 1H), 6.32 (s, 1H), 5.93 (d, J=3.0 Hz, 2H), 5.24 (ABq, 2H), 4.78 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.2, 174.2, 170.6, 155.7, 148.8, 142.4, 142.2, 132.2, 129.3, 124.1, 123.7, 120.4, 109.8, 103.5, 101.9, 93.8, 79.9, 57.9, 41.6; MS (ES+) m/z 414.1 (M+1), 416.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH2:12]([NH:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[C:26]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:27]3[CH2:33][CH2:32][NH:31][CH2:30][C:28]=3[N:29]=2)=[CH:20][CH:19]=1)=[O:16])[CH3:13]>>[CH2:12]([NH:14][C:15]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:25]=[C:26]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[C:27]3[CH2:33][CH2:32][N:31]([C:4](=[O:6])[C:3]4[CH:7]=[CH:8][CH:9]=[N:10][C:2]=4[CH3:1])[CH2:30][C:28]=3[N:29]=2)=[CH:22][CH:23]=1)=[O:16])[CH3:13]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: Cc1ncccc1C(=O)O
Agent: Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)c2cccnc2C)C3)cc1
Yield: 58 %

Procedure:
The compound oy was obtained following the general procedure in Example 213, substituting 3-methyloxetane-3-carboxylic acid for 2-methylnicotinic acid and substituting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride salt (jk) for 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride salt (bf). The desired product oy (74 mg, 58% yield) was obtained as white solid: 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.20 (m, 2H), 7.42 (m, 2H), 6.15 (m, 1H), 4.61 (m, 2H), 3.82 (m, 1H), 3.73 (m, 4H), 3.49 (m, 5H), 3.20-3.04 (m, 2H), 2.76 (m, 2H), 2.53 (s, 3H, overlapping with DMSO peak), 1.06 (t, J=7.1 Hz, 3H); LC-MS m/z=502 (M+H).
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][C:5]([F:18])([C:14]([F:17])([F:16])[F:15])[C:6](=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].S(=O)(=O)(O)O>O.CCO>[C:1]([C:6]([OH:13])([C:5]([F:18])([F:4])[C:14]([F:15])([F:16])[F:17])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2]
Reactant: [C-]#N
Reactant: CCOC(=O)CC(=O)C(F)(F)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(O)(C#N)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of KCN (1.4 eq.) in water (0.5 M) was added with stirring to an ice-cooled solution of ethyl 4,4,5,5,5-pentafluoro-3-oxopentanoate (1 eq.) in EtOH and water (40:60 vol). The mixture was stirred for 6 h at 0° C. and then acidified with 6N sulphuric acid and extracted with Et2O. The organic phase was dried (Na2SO4), and the solvents were removed under reduced pressure. The residue was vacuum distilled. The product fraction was collected at 74-76° C./0.5 mbar. (400 MHz, CDCl3) δ: 5.88 (1H, s), 4.40-4.23 (2H, m), 3.04 (1H, s), 1.33 (3H, t, J=7.1 Hz).
Reaction SMILES: C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[NH:16]([C:23]1[O:24][CH2:25][C:26](=O)[C:27]=1[C:28]([OH:30])=[O:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.[NH2:39][C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1.Cl>C(Cl)Cl>[C:17]1([NH:16][C:23]([C:27]2[C:28](=[O:30])[O:29][CH2:25][C:26]=2[NH:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(O)C1=C(Nc2ccccc2)OCC1=O
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC2=C(C(=O)Nc3ccccc3)C(=O)OC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, BOP-Cl (5.09 grams, 0.02 mol) was added in one portion to a well-stirred solution of 2-anilino-4-oxo-3-furoic acid (4.38 grams, 0.02 mol) and triethylamine (2.8 ml, 20 mmol) in 34 ml methylene chloride, at 0° C. The reaction mixture was stirred at 0° C. for 45 min after which time 2.35 grams (0.022 mol) of p-toluidine in 17 ml methylene chloride were added over a period of 15 min. followed by the dropwise addition of triethylamine (2.8 ml, 20 mmol). The reaction mixture was stirred at 5°-10° C. for 30 min and at room temperature for 2 hours, poured into ice-water, acidified with 2N hydrochloric acid (pH 1), and then extracted with methylene chloride. The organic extract was washed with 5% aqueous sodium bicarbonate solution, dried over sodium sulfate, and the solvent evaporated under reduced pressure leaving the crude product which was recrystallized from ethanol. Yield: 3.37 grams, mp 181°-183° C. (R=C6H4CH3 --p).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(OC)c1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(OC)c2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.20 g, 0.006 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (4.06 g, 0.031 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(3-methoxy-phenoxy)-but-2-enoic acid ethyl ester (2.00 g, 0.006 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (1.12 g, 46%) as a yellow oil.
Reaction SMILES: [CH:1]1[C:5]2=[C:6]3[C:10]([CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[C:13]([O:15][CH3:16])=[O:14])=[N:9][CH:8]=[CH:7]3.N1CCCCC1>CN(C=O)C>[CH2:7]1[C:6]2=[C:5]3[C:4](=[CH:12][CH:11]=[C:10]2[NH:9][CH2:8]1)[NH:3][C:2]([C:13]([O:15][CH3:16])=[O:14])=[CH:1]3
Reactant: COC(=O)C1=Cc2c3c(ccc2=N1)=NC=C3
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c3c(ccc2[nH]1)NCC3
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 370 %

Procedure:
A solution of 3 (15 mg, 0.014 mmol) in DMF (2 mL) was treated with 5% piperidine in DMF (2 mL). The reaction mixture was stirred for 5 min at 25° C. The final product was purified by Prep HPLC (SymmetrPrep C18, 7 μm, 19×150 mm column), eluted at 10 ml/min (0.01% TFA in water/acetonitrile) with a gradient: 10% acetonitrile in 5 min, 10% to 50% acetonitrile in 15 min, maintaining 50% acetonitrile in 5 min, 50% to 100% acetonitrile in 5 min, to obtain 4 (11.2 mg, 95%). MS: calcd for C44H48ClN7O7 (M+H) m/z 822.33 found 822.6.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](C1[N-]C=CN=1)=[O:12].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[NH:26][C:27]1[NH:28][CH2:29][CH2:30][N:31]=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([N:31]1[CH2:30][CH2:29][N:28]=[C:27]1[NH:26][C:20]1[C:21]([Cl:25])=[CH:22][CH:23]=[CH:24][C:19]=1[Cl:18])=[O:12]
Reactant: O=C(c1ccc2ccccc2n1)c1ncc[n-]1
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Product: O=C(c1ccc2ccccc2n1)N1CCN=C1Nc1c(Cl)cccc1Cl
Yield: 84.4 %

Procedure:
Using the process described in Example 57, 5.36 g (24 millimoles) of quinolin-2-oyl-imidazolide and 4.6 g (20 millimoles) of 2-(2',6'-dichlorophenylamino)-2-imidazoline give 6.5 g of pure 1-(quinolin-2-oyl)-2-(2',6'-dichlorophenylamino)-2-imidazoline of melting point 193.5°-196° C.; the material is identical with the product obtained according to Example 45.
Reaction SMILES: [Br:1][CH:2]([CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)[C:3]([OH:5])=[O:4].[CH3:12]O>>[Br:1][CH:2]([CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)[C:3]([O:5][CH3:12])=[O:4]
Reactant: CO
Reactant: O=C(O)C(Br)Cc1c[nH]cn1
Product: COC(=O)C(Br)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydrogen chloride was bubbled through an ice-cooled solution of 2-bromo-3-(1H-imidazol-4-yl)propanoic acid (500 mg, 2.3 mmol) in methanol (15 ml) for 10 minutes, and the mixture was stirred at room temperature for 18 hours. The solution was evaporated under reduced pressure, the residue was suspended in ice-cooled sodium bicarbonate solution, and the suspension was extracted with dichloromethane (4×20 ml). The combined organic solutions were dried (Na2SO4) and evaporated under reduced pressure to afford the title compound as an oil, 600 mg. 1H-NMR (CDCl3, 300 MHz) δ: 3.24 (dd, 1H), 3.44 (dd, 1H), 3.78 (s, 3H), 4.58 (dd, 1H), 6.92 (s, 1H), 7.60 (s, 1H). LRMS: m/z (ES+) 233, 235 [MH+].
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH:13]3[O:15][CH:12]3[CH2:11]2)=[O:8])=[CH:4][CH:3]=1.S([O-])(O)(=O)=[O:21].[K+]>C(O)(=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH:13]([OH:21])[CH:12]([OH:15])[CH2:11]2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)([O-])O
Reactant: COC(=O)C1(NC(=O)c2ccc(Cl)s2)CC2OC2C1
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)C1(NC(=O)c2ccc(Cl)s2)CC(O)C(O)C1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A mixture of 0.76 g (1.84 mmol) methyl 1-[(5-chloro-thiophen-2-yl)-carbonylamino]-3,4-epoxy-cyclopentane-1-carboxylate, 3.0 ml acetic acid and 0.38 g potassium hydrogen sulphate are stirred for 4 h at 40° C. Then the mixture is concentrated by evaporation, dissolved in DMF, acidified with trifluoroacetic acid and purified by preparative HPLC.
Reaction SMILES: Cl.C[O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].[CH3:11][O:12][C@@H:13]1[C@@H:17]([O:18][N+:19]([O-:21])=[O:20])[CH2:16][C@H:15]([C:22](O)=[O:23])[CH2:14]1.C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:11][O:12][C@@H:13]1[C@@H:17]([O:18][N+:19]([O-:21])=[O:20])[CH2:16][C@H:15]([C:22]([NH:6][C@H:5]([C:4]([OH:3])=[O:10])[CH:7]([CH3:9])[CH3:8])=[O:23])[CH2:14]1
Reactant: CO[C@H]1C[C@@H](C(=O)O)C[C@@H]1O[N+](=O)[O-]
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@H]1C[C@@H](C(=O)N[C@H](C(=O)O)C(C)C)C[C@@H]1O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of L-valine methyl ester hydrochloride (633 mg, 3.78 mmol), (1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylic acid (755 mg, 3.78 mmol), and triethylamine (1.05 mL, 7.55 mmol) in dichloromethane (30 mL) was added PyBOP (2.95 g, 5.67 mmol). After stirring at rt overnight, the mixture was washed saturated NaHCO3 (3×50 mL) and brine (50 mL), dried over MgSO4, and concentrated. The residue was purified by flash chromatography (RediSepRf 80 g) using 0-40% EtOAc/hexane gradient, affording the title compound (1.04 g, yield 86%): 1H NMR (500 MHz, CDCl3) δ 6.50 (d, J=8.6, 1H), 5.40 (d, J=6.0, 1H), 4.55 (dd, J=4.7, 8.8, 1H), 3.92 (m, 1H), 3.77 (s, 3H), 3.47 (s, 3H), 2.96-2.91 (m, 1H), 2.52-2.46 (m, 1H), 2.38-2.32 (m, 1H), 2.24-2.17 (m, 2H), 2.07-2.01 (m, 1H), 0.97 (d, J=6.9, 3H), 0.92 (d, J=6.9, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:32])([F:31])[C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][CH2:28][CH2:29]O)=[CH:21][CH:20]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:29][CH2:28][CH2:27][C:26]#[C:25][C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:31])[F:32])=[CH:24][CH:23]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: OCCCC#Cc1ccc(C(F)(F)F)cc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCCCC#Cc3ccc(C(F)(F)F)cc3)cc21

Procedure:
In analogy to the procedure described for example 1 d], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 1 c]) was reacted with 5-(4-trifluoromethyl-phenyl)-pent-4-yn-1-ol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give the title compound as yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[I:13][C:14]1[C:15]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[I:13][C:14]1[C:15]([C:19]([F:25])([F:24])[C:20]([F:21])([F:22])[F:23])=[N:16][N:17]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:3]=2)[CH:18]=1
Reactant: FC(F)(F)C(F)(F)c1n[nH]cc1I
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Cn2cc(I)c(C(F)(F)C(F)(F)F)n2)ccc1[N+](=O)[O-]
Yield: 21.6 %

Procedure:
3-Methyl-4-nitrobenzyl chloride (8.57 g), 4-iodo-3-pentafluoroethyl-1H-pyrazole (16.00 g) and potassium carbonate (7.66 g) were stirred in DMF (70 ml) at 70° C. for 1 hour. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with sodium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 4-iodo-1-(3-methyl-4-nitrobenzyl)-3-pentafluoroethyl-1H-pyrazole (4.60 g).
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:18]([O:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(-c2ccccc2)nc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A mixture of ethyl 3-hydroxy-1-phenyl-1H-pyrazole-4-carboxylate (7.76 g), benzyl bromide (3.97 ml), potassium carbonate (6.91 g) and N,N-dimethylformamide (75 ml) was stirred overnight at 50° C. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dilute hydrochloric acid, and then washed successively with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-benzyloxy-1-phenyl-1H-pyrazole-4-carboxylate (8.29 g, yield 77%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 113–114° C.
Reaction SMILES: [C:1]1(/[C:7](=[N:41]/[O:42][CH3:43])/[C:8]([NH:10][CH:11]2[C:39](=[O:40])[N:13]3[C:14]([C:23]([O:25]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:24])=[C:15]([CH:19]=[N:20][O:21][CH3:22])[C@@H:16]([CH3:18])[S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>[C:1]1(/[C:7](=[N:41]/[O:42][CH3:43])/[C:8]([NH:10][CH:11]2[C:39](=[O:40])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH:19]=[N:20][O:21][CH3:22])[C@@H:16]([CH3:18])[S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC)c3ccccc3)[C@H]2S[C@@H]1C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CON=CC1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3ccccc3)[C@H]2S[C@@H]1C
Yield: 53.7 %

Procedure:
A solution of 294 mg of diphenylmethyl 7-[2-phenyl-(Z)-2-methoxyiminoacetamido]-2α-methyl-3-methoxyiminomethylceph-3-em-4-carboxylate in 0.3 ml of anisole and 10 ml of CF3COOH was stirred at room temperature for 20 minutes. After distilling off the CF3COOH under reduced pressure, the residue was dissolved in AcOEt and then transferred into 5% aqueous NaHCO3. The water layer was adjusted to pH 2.0 with 5% H3PO4 added, and extracted again with AcOEt. The AcOEt layer was washed with H2O and saturated aqueous NaCl solution, successively, and dried over Na2SO4, followed by distilling off the AcOEt under reduced pressure. The residue was treated with Et2O, thus yielding 114 mg (54%) of 7-[2-phenyl-(Z)-2-methoxyiminoacetamido]-2α-methyl-3-methoxyiminomethylceph-3-em-4-carboxylic acid as crystals.