Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([S:10][CH3:11])[N:3]=1.C(N(CC)CC)C.O.[NH2:20][NH2:21]>CS(C)=O.O>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH:20][NH2:21])[N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: CSc1nc(Cl)c(F)c(Cl)n1
Reactant: NN
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CSc1nc(Cl)c(F)c(NN)n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
4,6-Dichloro-5-fluoro-2-(methylthio)pyrimidine (16.8 g, 78.85 mmol) and triethylamine (16.49 mL, 118.3 mmol) were dissolved in DMSO (200 mL) and stirred. The mixture was cooled to ˜5° C. with an ice water bath. To this solution was slowly added hydrazine monohydrate (4.59 mL, 94.62 mmol). After the addition was complete, the reaction mixture was warmed up to RT and stirring was continued for 1 h. The reaction mixture was diluted with water (500 mL), and the aqueous solution was extracted with CH2Cl2 (3×300 mL). The combined organic solution was washed with water (3×250 mL) and brine (250 mL), then dried (Na2SO4) and concentrated in vacuo to afford 4-chloro-5-fluoro-6-hydrazino-2-(methylthio)pyrimidine as a red foamy solid (9.70 g, 59%). LCMS: (M+H)+: 208.9.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[CH:7][NH:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].C1C(=O)N([Br:18])C(=O)C1.S([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([Br:18])[NH:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1c(C)c[nH]c1C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1c(C)[nH]c(Br)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 3-acetyl-2,4-dimethyl-1H-pyrrole (2.89 g, 21.1 mmol) in THF (80 mL) was added NBS (3.75 g, 21.1 mmol) at −78° C. under nitrogen. After stirring for 30 minutes at same temperature, the mixture was allowed to warm to room temperature and stirred for 1 hour. Sodium sulfite (4.3 g) was added to the mixture and volatiles were removed by evaporation. Water (100 mL) was added to the mixture, and the precipitates were collected by filtration to give 5.33 g (quant. including water) of the subtitle product.
Reaction SMILES: [C:1]1([C@H:7]([NH2:10])[CH2:8]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].ClC[C@@H]([NH3+])C1C=CC=CC=1.[CH3:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[N:32]=[C:33]=[S:34].[Cl-].ClC[C@@H]([NH3+])CC1C=CC=CC=1>>[CH3:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[N:32]=[C:33]1[NH:10][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][S:34]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: N[C@H](CO)c1ccccc1
Agent: [Cl-]
Agent: [NH3+][C@H](CCl)Cc1ccccc1
Agent: [NH3+][C@H](CCl)c1ccccc1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](c2ccccc2)CS1

Procedure:
(1S)-1-Phenyl-2-hydroxyethylamine was converted to (1S)-2-chloro-1-phenylethylammonium chloride according to Method B7b. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-2-chloro-1-benzylethylammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-phenyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-phenyl-3-isobutyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[Cl-].[Na+].[OH-].[Na+].[O:11]1[CH:20]2[CH:12]1[CH2:13][C:14]1[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOCC>[N:1]1([C@@H:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:20][C@H:12]2[OH:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CC1OC21
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O[C@@H]1Cc2ccccc2[C@H]1N1CCCC1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
A solution of 10.8 ml of pyrrolidine in 6.75 g of 2,3-epoxy-indane [described by Mousseron et al., Bull. de Soc. Chim. de France, 1946, p. 629-630] was slowly added to 10.8 ml of demineralized water and after increasing the temperature to 65° C., the mixture was stirred for 90 minutes at 65° C. 20 ml of demineralized water were then added and excess pyrrolidine was distilled off at reduced pressure to obtain an oil phase and an aqueous phase. The aqueouse phase was saturated with sodium chloride and 1 ml of 32% sodium hydroxide was added thereto. The mixture was extacted with ether and the ether phase was dried and evaporated to dryness under reduced pressure. The oil residue was chromatographed over silica and eluted with ethyl acetate containing 5% of triethylamine to obtain 8.81 g of trans (±) 2,3-dihydro-1-(pyrrolidin-1-yl)-1H-inden-2-ol.
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.[CH:9]1[CH2:13][CH:12]=[CH:11][CH:10]=1>>[CH3:11][CH2:10][CH2:9][CH2:13][CH:12]=[CH:1][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][CH3:2]
Reactant: C1=CCCC=CCC1
Reactant: C1=CCC=C1
Product: CC=CCCCCC=CCCCC

Procedure:
TTD is prepared by reacting 1,5-cyclooctadiene with cyclopentadiene according to reaction II as follows: ##STR12##
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:17][C:16](=[C:26]([C:31]([F:34])([F:33])[F:32])[C:27]([F:30])([F:29])[F:28])[CH:15]=2)=[CH:10][CH:9]=1.O.Cl>CCOCC>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[NH:17][C:16]([CH:26]([C:27]([F:29])([F:30])[F:28])[C:31]([F:32])([F:33])[F:34])=[CH:15][C:14]=2[C:11]2[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=2)=[CH:24][CH:23]=1
Reactant: Fc1ccc(C2=CC(=C(C(F)(F)F)C(F)(F)F)N=C2c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: Fc1ccc(-c2cc(C(C(F)(F)F)C(F)(F)F)[nH]c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 0.57 g (0.015 mole) of lithium aluminum hydride in 200 ml ether under nitrogen was added dropwise a solution of 4.03 g (0.01 mole) of 4,5-bis(4-fluorophenyl)-2-[2,2,2-trifluoro-1-(trifluoromethyl)ethylidene]-2H-pyrrole in 50 ml ether. The mixture was stirred at room temperature for 2 hours, then water was added cautiously dropwise. Finally approximately 50 ml of 1 N HCl was added and the ether layer was separated. The aqueous layer was further extracted with ether. The combined ether layers were dried and concentrated under vacuum. The residue was purified by column chromatography on 450 g slica gel, eluting with 75/25 hexane/toluene to give, after recrystallization from hexane, 1.6 g (40%) of product, m.p. 123°-124°, identical by ir and tlc to product obtained by Method A.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.OC(COCC=C)CNC(C)(C)CC1C=CC(OC)=CC=1.[ClH:48].OC(COC1C=CC=CC=1C)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:26].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[C:24]([Cl:1])[CH:23]=[CH:22][C:21]=1[Cl:48])[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Agent: C=CCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cc(Cl)ccc2Cl)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 382 (M−15,0.1), 280 (11), 279 (9), 278 (64), 276 (100), 163 (9), 161 (5), 121 (29), 113 (8).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C>C(N(CC)CC)C>[C:9]([C:5]1[NH:1][N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1nc[nH]n1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: NC(=O)c1n[nH]c(C(=O)c2ccccc2)n1

Procedure:
To a cooled, stirred mixture of 3 g. of 1,2,4-triazole-3-carboxamide and 4 g. of benzoyl chloride in 125 ml. of anhydrous diethyl ether is added rapidly 2.75 g. of triethylamine. The cooling bath is removed and the mixture is stirred at room temperature for 18 hours. The heterogeneous mixture is filtered and washed successively with diethyl ether, cold water and then diethyl ether and dried in vacuo for 4 hours yielding 4 g. of colorless solid. This solid is extracted with hot, dry acetonitrile and cooled yielding a solid product which is collected, washed with acetonitrile and dried in vacuo, yielding 1 g. of product, m.p. 174°-178° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].O.[OH-].[Na+]>C(O)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:9](=[O:11])[CH3:10])=[N:3][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(Br)cn1
Reaction time: 1 h
Yield: 85.6 %

Procedure:
A solution of 2-amino-5-bromopyridine (25.0 g, 144 mmol) in acetic acid (50 ml) and acetic anhydride (25.0 g) was heated at reflux for two hours. The reaction mixture was then cooled and poured into water (750 ml) with stirring. After one hour, the solution was adjusted to pH 10 with 50% sodium hydroxide and the precipitate was filtered, washed with water and dried to give 26.5 g (85%) of the title product as a white flaky solid. mp 175-176° C. 1H NMR (CDCl3): δ=8.29 (d, 1H); 8.12 (d, 1H); 7.96 (br, 1H); 7.78 (d of d, 1H); 2.19 (s, 3H). MS (EI): m/z=214, 216 (M+, Br isotopes).
Reaction SMILES: C(Cl)(Cl)Cl.[SH:5][C:6]1[C:7]([NH:16][C:17]([C:19]2([CH2:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>N1C=CC=CC=1>[CH2:27]([CH:26]([CH2:29][CH3:30])[CH2:25][C:19]1([C:17]([NH:16][C:7]2[C:6]([S:5][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])=[CH:15][C:14]3[C:9]([CH:8]=2)=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)[CH3:28]
Reactant: CCC(CC)CC1(C(=O)Nc2cc3ccccc3cc2S)CCCCC1
Reactant: CC(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCC(CC)CC1(C(=O)Nc2cc3ccccc3cc2SC(=O)C(C)C)CCCCC1
Reaction time: 1 h

Procedure:
To a chloroform solution of the product obtained in step B) are added 1.05 mol equivalents of isobutyryl chloride and 2.5 mol equivalents of pyridine at room temperature. The mixture is stirred for 1 hour, concentrated and then n-hexane is added. The solids are filtered off and the filtrate is concentrated. The remaining residue is purified by silica gel column chromatography to obtain the desired title compound.
Reaction SMILES: Br[CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C([O-])([O-])=O.[K+].[K+].[I-].[K+]>CC(N(C)C)=O>[CH3:6][C:3]([CH3:7])([CH2:2][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:4][OH:5]
Reactant: CC(C)(CO)CBr
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(CO)CN1CCCCC1
Yield: 18.5 %

Procedure:
A solution of 3.00 g (17.96 mmol) of 3-bromo-2,2-dimethyl-propan-1-ol, 17.78 ml (179.59 mmol) of piperidine, 2.48 g (17.96 mmol) of K2CO3 and 2.69 g (17.96 mmol) of potassium iodide in 20 ml of DMA were stirred at 70° C. for 20 h. After filtration and evaporation of the solvents, the crude product was dissolved in diluted aqueous HCl solution and washed with EtOAc (3×). The aqueous phase was basified with KHCO3 and some drops of 1N NaOH and extracted with EtOAc (3×). The organic phase was dried (Na2SO4) and evaporated to give 0.57 g (18%) of the title compound as yellow liquid. MS: 172.0 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[N:3]=1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][N:4]1[CH:5]=[CH:6][C:2]([NH:1][C:21]([NH:20][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[S:22])=[N:3]1
Reactant: Nc1ccn(CCCCO)n1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1ccn(CCCCO)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
A mixture of 3-amino-1-(4-hydroxybutyl)pyrazole (0.966 g.) and benzoylisothiocyanate (1.0 g.) in acetone (30 ml.) was stirred at room temperature for 18 hours. The solvent was evaporated and the residue purified by column chromatography on silica gel using EtOAc as eluant to give 1-(4-hydroxybutyl)-3-(3-benzoylthioureido)pyrazole (30% yield).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[CH:3]=1.[CH2:13](Br)[CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[Cl:1][C:2]1[N:7]([CH2:13][CH2:14][CH2:15][CH3:16])[C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[CH:3]=1
Reactant: CCCCBr
Reactant: CCCn1c(=O)cc(Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(Cl)cc(=O)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of 7 g of 6-chloro-3-propyluracil, 10.28 g of butyl bromide, 10.28 g of potassium carbonate, 6 g of potassium iodide and 80 ml of dimethylformamide was stirred at room temperature for 23 hours. After the reaction solution was concentrated to dryness under reduced pressure, 300 ml each of chloroform and water were added to the residue, and the mixture was shaken. The chloroform layer was washed with water and then concentrated to dryness under reduced pressure to give 6-chloro-1-butyl-3-propyluracil as a brown oily substance. This product, without being purified, was dissolved in 20 ml of ethanol, and 20 ml of 100% hydrazine hydrate was added to the solution, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure and the residue was washed with water and recrystallized from a mixture of ethanol, ethyl acetate and isopropyl ether to give 7 g of yellow prisms of 6-hydrazino-1-butyl-3-propyluracil melting at 146°-147° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N+:29]([CH3:32])([O-:31])=[O:30]>O1CCCC1.C(OCC)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH2:32][N+:29]([O-:31])=[O:30])=[O:4]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C1=CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C1CCCCC1C[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of cyclohex-1-enecarboxylic acid methyl ester 1 (5.15 g; 36.7 mmol), tetrabutyl ammonium fluoride (55.10 mL; 1 M in THF; 55.1 mmol) and nitromethane (3.97 mL; 73.5 mmol) in tetrahydrofuran (60 mL) was heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was diluted with diethyl ether (500 mL), washed with 2N HCl (2×100 mL) and then with brine (2×100 mL). The phases were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. The crude mixture was purified over silica gel chromatography (EtOAc/heptane 1:4) to give 2 (5.46 g; cis and trans isomers; 73%) as a pale yellow liquid.
Reaction SMILES: [CH2:1]([O:4][C:5]([CH2:7][N:8]1[C@H:11]([C@@H:12]([CH3:31])[C:13](N2C3(CCCCC3)OC3C=CC=CC=3C2=O)=[O:14])[C@@H:10]([C@H:32]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH3:33])[C:9]1=[O:42])=[O:6])[CH:2]=[CH2:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C[Si](Cl)(C)C.[C:58]1([P:64](Cl)([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[O:65])[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.P([O-])([O-])([O-])=O>O1CCCC1>[CH2:1]([O:4][C:5]([C:7]1[N:8]2[C:9](=[O:42])[C@H:10]([C@H:32]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH3:33])[C@H:11]2[C@@H:12]([CH3:31])[C:13]=1[O:14][P:64]([C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:65])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)CN1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=O)N1C(=O)c2ccccc2OC12CCCCC2
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(OP(=O)(c2ccccc2)c2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Temperature: -50 °C
Reaction time: 0.03 h
Yield: 89.2 %

Procedure:
A solution of 1.2 g of 3-{(2R)-2-[(3S,4R)-1-allyloxycarbonylmethyl-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one in 6 ml of tetrahydrofuran is added dropwise to 4.4 ml of 1M sodium bis(trimethylsilyl)amide solution (solvent:tetrahydrofuran) at a temperature from -20° C. to -30° C. during one minute. 261 mg of trimethylsilyl chloride are added thereto at -50° C. and the mixture is stirred for 2 minutes. Then, 645 mg of diphenylphosphoryl chloride are added thereto at -50° C. and the mixture is stirred for 2 hours at 0° C. The reaction mixture is poured into 50 ml of 0.2M phosphate buffer (pH 7.0) and the mixture is extracted with ethyl acetate. The extract is washed, dried and evaporated to remove the solvent. Isopropyl ether is added to the residue and the resulting precipitates of 355 mg of spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one are removed by filtration. The filtrate is condensed to obtain 1.04 g of (1R,5R,6S)-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-1-methyl-2-diphenylphosphoryloxy-carbapen-2-em-3-carboxylic acid-allyl ester as syrup.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[C:5]([C:11]([OH:13])=O)[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.Cl.[NH2:44][CH:45]1[CH:52]2[CH2:53][CH:48]3[CH2:49][CH:50]([CH2:54][CH:46]1[CH2:47]3)[CH2:51]2>ClCCl.CN(C=O)C.O>[CH:46]12[CH2:54][CH:50]3[CH2:49][CH:48]([CH2:53][CH:52]([CH2:51]3)[CH:45]1[NH:44][C:11]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([F:10])([F:9])[F:8])=[O:13])[CH2:47]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: Cn1ncc(C(=O)O)c1C(F)(F)F
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1C(F)(F)F
Reaction time: 1 h
Yield: 64.9 %

Procedure:
Methyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (77 mg, 0.4 mmol, CAS#: 119083-00-0, purchased from Bionet) was dissolved in a mixture of dry dichloromethane (3.2 mL) and dry DMF (0.8 mL). DIPEA (0.28 mL, 1.6 mmol) and TSTU (145 mg, 0.44 mmol) were added to the above mixture. After the mixture was stirred for 1 h, the appearance of active ester was detected by LC-MS. Then 2-aminoadamantane hydrochloride (75 mg, 0.4 mmol) was added. After another 2 hours water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic phases were dried under vacuum and purified by C-18 reversed phase HPLC with a gradient of 10-100% acetonitrile/water to give 1-methyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (85 mg, 65%). Mass spectrum: m/z: 328.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([N:9]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,4-difluoro-phenylamine (42, 10.0 g, 77.4 mmol) in N,N-dimethylformamide (130 mL) were added potassium carbonate (32.1 g, 0.23 mol) and benzyl bromide (21.2 mL, 0.18 mol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane. The appropriate fractions were combined and concentrated to provide the compound (52, 12.0 g, 50%). MS (ESI) [M+H+]+=310.2.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7](=[N:9][O:10][CH2:11][CH2:12][OH:13])[CH3:8])=[CH:3][CH:2]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7](=[N:9][O:10][CH2:11][CH2:12][O:13][C:21]2[CH:53]=[CH:52][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]3=[O:51])=[CH:23][CH:22]=2)[CH3:8])=[CH:3][CH:2]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1ccc(-c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccccc2)cc1
Yield: 71.5 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 170 mg of 2-[1-(4-biphenylyl)-ethylideneaminooxy]ethanol (prepared as described in Preparation 15), 238 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 175 mg of triphenylphosphine and 116 mg of diethyl azodicarboxylate, 257 mg of the title compound were obtained as a crystalline powder, melting at 145° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][NH2:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C#N)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CN)c1ccc(F)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 4-fluorophenylacetonitrile (50 g, 370 mmol, 1.0 equiv) and iodomethane (70 mL, 1.1 mol, 3 equiv) in THF (370 mL) was added potassium t-butoxide (124 g, 1.1 mol, 3 equiv) as a solid in portions such that the reaction mixture did not exceed 50° C. The reaction mixture was stirred overnight and then quenched by the addition of brine. The mixture was diluted with EtOAc and washed twice with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-(4-fluorophenyl)-2-methylpropanenitrile as a yellow oil (57 g, 94%), which was used without further purification in the next step. To a solution of the nitrile in dry THF (800 mL) was added a solution of lithium aluminum hydride (210 mL, 2 M in ether, 420 mmol, 1.2 equiv). After the mixture was heated at reflux overnight, the reaction was allowed to cool to room temperature, and a Fieser and Fieser work-up (300 uL water/mmol, 1.0 mL 3N NaOH/mmol, 300 uL water/mmol) was performed. Filtration of the resulting solids provided the title compound as an orange oil (57 g, 92%).