Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:19]2[O:20][CH:21]=[N:22][N:23]=2)[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])[C:7]=1C(O)=O.O>C(O)COCCO>[CH3:24][C:4]1[NH:3][C:2]([CH3:1])=[CH:7][CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])[C:5]=1[C:19]1[O:20][CH:21]=[N:22][N:23]=1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2Cl)C(c2nnco2)=C(C)N1
Solvent: OCCOCCO
Solvent: O
Product: CC1=CC(c2cccc(Cl)c2Cl)C(c2nnco2)=C(C)N1
Temperature: 25 °C

Procedure:
20 g of 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-5-(1,3,4-oxadiazol-2-yl)-pyridine-3-carboxylic acid in 100 ml of diethylene glycol are heated at 180° C. for 10 minutes. The mixture is then cooled to room temperature, 500 ml of water are added and the mixture is extracted by shaking with four times 200 ml of ethyl acetate. The organic phase is dried over sodium sulphate and concentrated and the residue is recrystallised from ethyl acetate with the addition of active charcoal. This gives 12.2 g (corresponding to 61% of theory) of 1,4-dihydro-2,6-dimethyl-3-(1,3,4-oxadiazol-2-yl)-4-(2,3-dichlorophenyl)-pyridine, melting point 235° C. with decomposition.
Reaction SMILES: Br[CH:2]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:20][C:21]([NH2:23])=[S:22].C([O-])(=O)C.[Na+]>>[CH:14]1([CH2:13][C:2]2[S:22][C:21]([NH2:23])=[N:20][C:3]=2[C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC(N)=S
Reactant: COc1ccc(C(=O)C(Br)CC2CCCCC2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(-c2nc(N)sc2CC2CCCCC2)cc1
Yield: 79.8 %

Procedure:
A procedure similar to step 5 of Example 6 was used. 2-bromo-3-cyclohexyl-1-(4-methoxy-phenyl)-propan-1-one prepared in the step 3, thiourea and anhydrous sodium acetate were used as starting materials, refluxed for 3 hours, followed by post-treatment to give a crude product, which was purified under a reduced pressure by silica gel column chromatography eluted with petroleum ether and ethyl acetate at a ratio of 3:1 (V:V) to obtain a product as a white solid in a yield of 79.8%, mp: 118-119 └. 1H-NMR (CDCl3, 400 MHz) δ: 0.80˜0.92 (2H, m), 1.05˜1.25 (3H, m), 1.40˜1.50 (1H, m, CH), 1.60˜1.80 (5H, m), 2.59 (2H, d, J=7.04 Hz, CHCH2Ar), 3.83 (3H, s, OCH3), 5.55 (2H, br, NH2), 6.93 (2H, d, J=6.72 Hz, ArH), 7.44 (2H, d, J=6.72 Hz, ArH); EI-MS m/e (%): 302.2 (M+, 59), 219.1 (100), 177.1 (44); HREI-MS Calcd. for C17H22N2OS: 302.1453. found: 302.1450. Anal. Calcd. for C17H22N2OS: C, 67.51; H, 7.33; N, 9.26. found: C, 67.41; H, 7.47; N, 9.24.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[N:20][OH:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:22](OC(=O)C)(=O)[CH3:23]>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=3)=[C:22]([CH3:23])[O:21][N:20]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(Cc2ccc(SC)cc2)=NO)cc1F
Product: COc1ccc(-c2noc(C)c2-c2ccc(SC)cc2)cc1F
Yield: 30 %

Procedure:
3-(3-Fluoro-4-methoxyphenyl)-5-methyl-4-[4-(methylthio)phenyl]isoxazole was prepared in 30% yield from 1-(3-fluoro-4-methoxypheny]-2-[4-(methylthio)phenyl]-ethan-1-one oxime from Step 2 and acetic anhydride by the procedure described in Example 4, Step 1 and used directly in the next step.
Reaction SMILES: O[Li].O.Cl.Cl.[NH2:6][CH:7]([C:48]([O:50]C)=[O:49])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:29]2[C:30]3=[C:31]4[C:26](=[CH:27][CH:28]=2)[C:25]([OH:32])=[CH:24][C:23]([OH:33])=[C:22]4[CH:21]=[CH:20][C:19]3=[C:18]([S:34](=[O:47])(=[O:46])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]([C:42]([O:44]C)=[O:43])[NH2:41])[CH:17]=1)(=[O:15])=[O:14]>O.CO>[NH2:41][CH:40]([C:42]([OH:44])=[O:43])[CH2:39][CH2:38][CH2:37][CH2:36][NH:35][S:34]([C:18]1[C:19]2[C:30]3=[C:31]4[C:22](=[CH:21][CH:20]=2)[C:23]([OH:33])=[CH:24][C:25]([OH:32])=[C:26]4[CH:27]=[CH:28][C:29]3=[C:16]([S:13](=[O:15])(=[O:14])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([C:48]([OH:50])=[O:49])[NH2:6])[CH:17]=1)(=[O:46])=[O:47]
Reactant: COC(=O)C(N)CCCCNS(=O)(=O)c1cc(S(=O)(=O)NCCCCC(N)C(=O)OC)c2ccc3c(O)cc(O)c4ccc1c2c43
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: NC(CCCCNS(=O)(=O)c1cc(S(=O)(=O)NCCCCC(N)C(=O)O)c2ccc3c(O)cc(O)c4ccc1c2c43)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
A solution of LiOH.H2O (1.319 g, 31.43 mmol) in water (20 mL) was added to a solution of the dihydrochloride 6 (2.443 g, 3.250 mmol) in methanol (80 mL). The mixture was stirred vigorously at room temperature for 3 h and then concentrated by evaporation. The residue was taken up in 80 ml of water and 4 ml of conc. hydrochloric acid were added. The reaction mixture was concentrated by evaporation once again and then taken up in 100 ml of water, added to a 4 cm×40 cm column packed with acidic Dowex 50WX2-200, washed with 1.5 L of water and then eluted with 1.5 L of 1N ammonia solution. The emerald green solution of 7, which was evaporated under reduced pressure at 50° C., was dried over phosphorus pentoxide overnight to give the dark brown powder 7 (2.0350 g, 96%). The powder was stirred in 20 ml of water at 70° C. for 20 min, cooled and centrifuged. The sediment was stirred in ice-cold water, centrifuged off and dried overnight over phosphorus pentoxide (1.1907 g). Melting point: 210-212° C. (decomposition). 1H NMR (300 MHz, [D6]-DMSO): δ=8.84 (s, 1H), 8.53 (d, J=9.0 Hz, 2H), 8.46 (d, J=9.0 Hz, 2H), 8.15 (br. s, 2H, 2 NH), 7.27 (s, 1H), 3.12 (m, 2H, 2 CHN; overlapping with HOD and NH2), 2.65 (t, J=7.5 Hz, 4H, 2 CH2N), 1.57-1.35 (m, 4H, 2 CH2), 1.30-1.00 (m, 8H, 4 CH2). HRMS (ESI): m/z [M+Na]+ calculated for C28H34N4NaO10S2 673.1614; found 673.1609; m/z [M−H]+ calculated for C28H33N4O10S2 649.1638; found 649.1644.
Reaction SMILES: C(N)C=C.[CH3:5][O:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[C:15]1[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH:20]=1.C([Li])CCC.[C:27]1(=[O:32])[O:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[CH3:5][O:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[C:15]1([C:30](=[O:31])[CH2:29][CH2:28][CH2:27][OH:32])[CH:16]=[CH:17][N:18]([CH3:21])[CH2:19][CH2:20]1
Reactant: O=C1CCCO1
Reactant: COc1cccc(C2=CCN(C)CC2)c1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C=CCN
Product: COc1cccc(C2(C(=O)CCCO)C=CN(C)CC2)c1OC
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
A solution of 9.32 g (0.04 mol) of the allylamine, Compound IV, in 75 mL of dry tetrahydrofuran was cooled to -10° and treated with 40 mL of 1.65 M solution (0.066 mol) of n-butyl lithium. The resulting red solution was stirred at -10° for 15 min and transferred under nitrogen to a solution of 18.4 g (0.21 mol) of γ-butyrolactone in 40 mL of dry tetrahydrofuran at -76° over a period of 5 min. After the addition was complete the reaction mixture was stirred at -70° for 15 min and then quenched with 100 mL of 20% sodium hydroxide solution and stirred at room temperature for 1 hour. At the end of this period the reaction mixture was diluted with 200 mL of dichloromethane and the organic layer was separated. The aqueous layer was extracted with an additional 200 mL portion of dichloromethane. The organic layers were washed with brine, dried (K2CO3) and concentrated under reduced pressure to afford 12.6 g of product (98.8% yield) which contained Compound V and was used for the next step without further purification. A sample prepared in another experiment was purified by HPLC to afford a pure sample of Compound V; NMR (90 MHz, CDCl3): 2.63 (s, 3), 3.45 (br., 3), 3.73 (s, 3), 3.88 (s, 3), 4.3 (d, j=8 Hz, 1), 6.15 (d, J=8 Hz, 1), 6.7-7.2 (br., 3); IR (film): 3440, 2940, 1700, 1630 cm-1.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3][CH2:4][NH2:5].[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1.[I-].ClC1C=CC=C[N+]=1C.CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3][CH2:4][NH:5][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCN
Reactant: O=C(O)c1cccnc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=CCCC(C)=CCCC(C)=CCNC(=O)c1cccnc1
Reaction time: 3 h
Yield: 65.2 %

Procedure:
A mixture of 2 mmol of N-(3,7,11-trimethyl-2,6,10-dodecatrienyl)amine (hereinafter abbreviated as farnesylamine), 2.2 mmol of nicotinic acid, 562 mg (2.2 mmol) of 2-chloro-1-methylpyridinium iodide, and 444 mg (4.4 mmol) of Et3N in 20 ml of CH2Cl2 is heated with stirring for 3 hours. The reaction mixture is washed twice with 20 ml of saturated aqueous NaHCO3 and twice with 20 ml of water. The mixture is dried and evaporated under reduced pressure. The residual oil is purified by silica-gel column chromatography and eluted with AcOEt to give 426 mg of the titled compound I-85.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]([NH:26][C:27](=O)[CH3:28])=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:30]([O-:32])=[O:31].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]([NH:26][C:27](=[S:42])[CH3:28])=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:30]([O-:32])=[O:31]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)Nc1cnc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl
Solvent: COCCOC
Product: CC(=S)Nc1cnc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl

Procedure:
1 mmol of N-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]acetamide and 2 mmol of Lawesson's reagent were stirred in 2 ml of DME at 80° C. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, and purified by column chromatography eluting with 5-10% methanol/methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[P:10]([Cl:14])(Cl)(Cl)=[O:11]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][P:10]([Cl:14])(=[O:11])[O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: O=P(Cl)(Oc1ccc(Cl)cc1Cl)Oc1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared by the general method of Example 1 with the following modifications. (1) The molar ratio of 2,4-dichlorophenol to phosphorus oxychloride was increased from 1.33 to 1.85 by using 189.99 g (1.165 mole) of 2,4-dichlorophenol and 96.60 g (0.63 mole) of phosphorus oxychloride. (2) The reaction time at 120° was increased to about 24 hours. (3) The product was crystallized using a larger quantity of hexane (570 ml, or 3 ml per gram of starting 2,4-dichlorophenol) at -15°. Analysis by GLPC indicated 82% purity (by weight) of bis(2,4-dichlorophenyl)phosphorochloridate, with contamination by a trace of 2,4-dichlorophenyl phosphorodichloridate and 18% (by weight) of tris(2,4-dichlorophenyl)phosphate. The yield of the bis(2,4-dichlorophenyl)phosphorochloridate when corrected for purity was 125 g (53%). Subsequent reactions were unaffected by the presence of the tris(2,4-dichlorophenyl)phosphate, as illustrated by Examples 3 and 4.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][OH:23]>ClCCl>[CH3:1][S:2]([O:23][CH2:22][CH2:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[F:13])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
Methanesulphonyl chloride (3.3 ml; 0.043 mol) and triethylamine (5.9 ml; 0.043 mol) were added to a solution of 2-(2,4-difluorophenyl)ethanol (6.4 g; 0.0426 mol) in dichloromethane (100 ml). The solution was cooled for 1 h at 0° C. and then brought to room temperature for 1 h. The reaction mixture was then treated by washing, successively, with 5N sulphuric acid (20 ml), water (50 ml), a 5% solution of NaHCO3 (50 ml) and water (50 ml). The organic phase was then dried over Na2SO4, filtered and concentrated at reduced pressure. The residue was taken up twice in CCl4, thus obtaining 6.42 g of 2-(2,4-difluorophenyl)ethyl methanesulphonate.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:11][C:12]1[N:16]([CH:17]([CH3:19])[CH3:18])[N:15]=[CH:14][CH:13]=1>CN(C=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:17]([N:16]1[C:12]([NH:11][C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:13][CH:14]=[N:15]1)([CH3:19])[CH3:18]
Reactant: CC(C)n1nccc1N
Reactant: O=C(O)c1ccccc1I
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1nccc1Nc1ccccc1C(=O)O
Yield: 97.3 %

Procedure:
To 2-iodobenzoic acid (54 g, 0.218 mol) in DMF (570 ml) was added K2 CO3 (33.4 g, 0.242 mol), then 5-amino-1-isopropylpyrazole (27.3 g, 0.218 mol) and finally copper (II) acetate monohydrate (0.9 g, 4.5 mmol). The reaction mixture was refluxed overnight and then the DMF was evaporated. The residue was poured into ice/water and then the mixture was acidified with acetic acid and concentrated HCl to a pH of about 4. A precipitate formed which was collected by filtration, washed with water and dried in a vacuum oven at 40° C. to afford 52 g (97.2%) of N-(1-isopropylpyrazol-5-yl)anthranilic acid.
Reaction SMILES: C([N:8]1[C:13](=[O:14])[N:12](CC2C=CC=CC=2)[C:11](=[O:22])[N:10]([NH:23][C:24](=[O:47])[C@@H:25]([C@@H:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:31][CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:26][CH:27]([CH3:29])[CH3:28])[C:9]1=[O:48])C1C=CC=CC=1>CO.C(O)(=O)C.[OH-].[Pd+2].[OH-]>[C:43]([O:42][C:40]([C@H:30]([C@@H:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:24]([NH:23][N:10]1[C:11](=[O:22])[NH:12][C:13](=[O:14])[NH:8][C:9]1=[O:48])=[O:47])[CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)C[C@@H](C(=O)Nn1c(=O)n(Cc2ccccc2)c(=O)n(Cc2ccccc2)c1=O)[C@H](CC=Cc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)C[C@@H](C(=O)Nn1c(=O)[nH]c(=O)[nH]c1=O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Yield: 97.5 %

Procedure:
A solution of 0.830 g of N-(3,5-dibenzyl-hexahydro-2,4,6-trioxo-1,3,5-triazin-1-yl)-2(R)-[1(S)-(tert-butyloxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleramide in 50 ml of methanol and a few drops of acetic acid was hydrogenated in the presence of 0.08 g of palladium (II) hydroxide for 8 hours. The mixture was filtered and evaporated to give 0.588 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methyl-N-(2,4,6-trioxo-1,3,5-triazin-1-yl)valeramide in the form of white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:11])[N:3]=1.[NH2:12][CH:13]1[CH:17]([OH:18])[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)CCC>[CH3:9][N:8]([CH3:10])[C:6]1[CH:5]=[C:4]([CH3:11])[N:3]=[C:2]([NH:12][CH:13]2[CH:17]([OH:18])[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)[N:7]=1
Reactant: Cc1cc(N(C)C)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(N(C)C)nc(NC2CN(C(=O)OC(C)(C)C)CC2O)n1
Yield: 85.7 %

Procedure:
2-Chloro-4-dimethylamino-6-methylpyrimidine (3.5 g), t-butyl (3RS,4RS)-3-amino-4-hydroxypyrrolidine-1-carboxylate (4.5 g), N,N-diisopropylethylamine (5.3 mL), and n-butanol (10 mL) were stirred at 120° C. for 8 days. To the reaction mixture were added chloroform and saturated aqueous sodium hydrogencarbonate to separate the layers. The aqueous layer was extracted with chloroform, then the organic layer was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=9:1) to obtain t-butyl (3RS,4RS)-3-(4-dimethylamino-6-methylpyrimidin-2-ylamino)-4-hydroxypyrrolidine-1-carboxylate (5.9 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][N:25]1[C:29]2[N:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[N:26]1.N1CC=C(C2NC3N=CN=C(ON4C5=NC=CC=C5N=N4)C=3C=2)CC1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.CCN(C(C)C)C(C)C>C(O)CCC.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([O:24][N:25]4[C:29]5=[N:30][CH:31]=[CH:32][CH:33]=[C:28]5[N:27]=[N:26]4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2cccnc21
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Agent: C1=C(c2cc3c(On4nnc5cccnc54)ncnc3[nH]2)CCNC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(On4nnc5cccnc54)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (11.5 mg, 0.0343 mmol, 1 eq) and 1-hydroxy-7-azabenzotriazole (HOAt) (5.6 mg, 0.041 mmol, 1.2 eq) in n-butanol (1 mL) was stirred at 80° C. for 15 h. Solid that had formed during the course of the reaction was filtered over a Hirsh funnel and washed with minimal n-butanol. The filtrate was concentrated in vacuo. To a solution of the solid (3-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-3H-[1,2,3]triazolo[4,5-b]pyridine) (6.4 mg, 0.015 mmol, 1 eq) in DMSO (1 mL), di-tert-butyldicarbonate (5.0 mg, 0.023 mmol, 1.5 eq) and DiPEA (20 μL, 0.1 mmol, 7 eq) were added and the reaction was stirred at rt for 2 h. This solution was combined with the concentrated filtrate and purified on the MDPS yielding the title compound. 1H NMR (400 MHz, MeOH-d4): δ=1.51 (s, 9H), 2.64 (s, br, 2H), 3.70 (s, br, 2H), 4.17 (s, br, 2H), 6.46 (s, br, 1H), 6.74 (s, 1H), 7.61 (dd, J=8.4, 4.4 Hz, 1H), 8.13 (s, 1H), 8.61 (d, J=8.0 Hz, 1H), 8.74 (d, J=4.4 Hz, 1H). MS (ES+): m/z 435.00 (62) [MH+]. HPLC: tR=3.36 min (ZQ2000, polar—5 min).
Reaction SMILES: [C:1]1(=[O:5])[CH2:4][CH2:3][CH2:2]1.[CH2:6]([Mg]Br)[CH:7]=[CH2:8].CCOCC.O([Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])S(C(F)(F)F)(=O)=O.C(=O)=O.Cl>CO.C1COCC1>[CH2:6]([C:1]1([O:5][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:4][CH2:3][CH2:2]1)[CH:7]=[CH2:8]
Reactant: O=C1CCC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=CC[Mg]Br
Agent: Cl
Agent: O=C=O
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: C=CCC1(O[Si](C)(C)C(C)(C)C)CCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 2 L three-necked round bottom flask was added cyclobutanone (12.47 g, 178 mmol) and THF (1200 mL). The solution was cooled to −78° C. Allylmagnesium bromide, 1 M in ether (196 ml, 196 mmol) was added via an addition funnel over 30 min. The reaction was allowed to stir for 30 min. MeOH (30 mL) was added to the reaction and the cooling bath was removed. The solution was stirred for about 10 min, then HCl (0.5 M, 500 mL) was added. The reaction was transferred to a separatory funnel and extracted with Ether (2×1 L). The organic extracts were dried over MgSO4 and concentrated in vacuo (Note: Volatile Product). The final ˜100 mL of concentrate were re-dissolved in 1 L of DCM, dried over MgSO4 and filtered. TEA (61.5 ml, 442 mmol) was added followed by tert-butyldimethylsilyl triflate (66.0 ml, 287 mmol). The reaction was cooled in the warming dry ice bath used earlier in the experiment. After 30 min, the reaction was checked by TLC and found to be complete. HCl (0.5 M, 500 mL) was added to quench the reaction. The reaction layers were separated and the aqueous layer extracted with 600 mL of ether. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The resulting oil was loaded onto a 600 mL Frit almost full of silica gel and purified, eluting with 1400 mL of hexane. The hexane filtrate was carefully concentrated in vacuo to give (1-allylcyclobutoxy)(tert-butyl)dimethylsilane, as a colorless liquid that also contained residual hexane. The crude material was carried on without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:23][C:8]([CH2:9][C:10]2[CH2:11][S:12][C@@H:13]3[CH:20](N)[C:19](=[O:22])[N:14]3[C:15]=2[C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1)=[O:4].C([N:28](CCCC)CCCC)CCC.[Cl:37][CH2:38][CH2:39][N:40]=[C:41]=[O:42]>CN(C)C=O>[Cl:37][CH2:38][CH2:39][NH:40][C:41]([C@@H:20]1[C:19](=[O:22])[N:14]2[C:15]([C:16]([OH:18])=[O:17])=[C:10]([CH2:9][C:8]3[O:23][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[CH:11]([NH2:28])[S:12][C@H:13]12)=[O:42]
Reactant: CCCCN(CCCC)CCCC
Reactant: O=C=NCCCl
Reactant: COC(=O)c1ccc(CC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)o1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CC2=C(C(=O)O)N3C(=O)[C@@H](C(=O)NCCCl)[C@H]3SC2N)o1
Reaction time: 1.5 h

Procedure:
A 10% suspension of 0.100 g of 3-(5-methoxycarbonyl-furfuryl)-7-amino-ceph-3-em-4-carboxylic acid and 0.0644 g of tri-n-butylamine in absolute dimethylformamide is treated with a 5% solution of 0.0633 g of 2-chloroethylisocyanate. The reaction mixture is vibrated in an ultrasonics bath for 90 minutes at room temperature. The yellowish brown reaction solution is evaporated to dryness under a high vacuum and the residue is partitioned several times between 25 ml of a 0.5 molar aqueous dipotassium hydrogen phosphate solution and 10 ml of ethyl acetate. The aqueous extracts are covered with fresh ethyl acetate, acidified to pH 2 by dropwise addition of 5-molar aqueous phosphoric acid and extracted with three portions of ethyl acetate. The organic extracts are washed with water, dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The residue is placed onto preparative thin-layer plates (silica gel, with fluorescence indicator). The plates are developed during approximately 5 hours in the system n-butanol/glacial acetic acid/water (44:12:44). After drying, the main band absorbing ultraviolet light (λ = 254 mμ) is scraped from the plates and extracted several times with acetone. The extracts are filtered through a filter having a diatomaceous earth preparation as filter auxiliary and evaporated to dryness. The 7β-(2-chloroethylamino-carbonyl)-amino-3-(5-methoxycarbonyl-furfuryl)-ceph-3-em-4-carboxylic acid is obtained in the form of a glassy, colourless residue; ultraviolet absorption spectrum (95% aqueous ethanol): λmax = 269 mμ (ε = 22100).
Reaction SMILES: C[C:2](P(OC)(O)=O)([C:4]([O-:6])=[O:5])[CH3:3].[H-].[Na+].[CH:14]([O:17][CH:18]1[CH2:23][CH2:22]C(=O)[CH2:20][CH2:19]1)([CH3:16])[CH3:15].[CH2:25]1COCC1>>[CH3:25][O:6][C:4](=[O:5])[CH:2]=[C:3]1[CH2:22][CH2:23][CH:18]([O:17][CH:14]([CH3:16])[CH3:15])[CH2:19][CH2:20]1
Reactant: C1CCOC1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: CC(C)OC1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C=C1CCC(OC(C)C)CC1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Trimethylphosphonoacetate (700 mg, 3.87 mmol) was solved in 10 ml of THF and added into a cold (0-5° C.) mixture of sodium hydride (169 mg, 3.87 mmol, 55%) in 10 ml THF. After 1 hour stirring at 0-5° C. 4-isopropoxy-cyclohexanone (550 mg, 3.5 mmol) in 5 ml THF was added drop wise. The reaction mixture was quenched after 1 hour at room temperature with saturated NaHCO3-solution and extracted two times with ethyl acetate. The organic extracts were washed with brine, dried with sodium sulfate, filtered and evaporated. The crude product was purified with column chromatography on silica gel using heptane:ethyl acetate 90:10->20:80. The product fractions were concentrated to give 550 mg (74% yield) of a colorless liquid. MS (m/e): 213.3 (M+H+).