Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](N(OC)C)=[O:11])=[C:7]([CH3:16])[C:6]=2[CH:17]=1.[C:18]1(C)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl.O1CCCC1.C1([Mg]Br)CCCCC1.[Cl-].[NH4+]>O1CCCC1>[CH:18]1([CH:10]([C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][C:6]=3[C:7]=2[CH3:16])[OH:11])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CON(C)C(=O)c1oc2ccc(F)cc2c1C
Reactant: Cc1ccccc1
Agent: Br[Mg]C1CCCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(C(O)C2CCCCC2)oc2ccc(F)cc12
Reaction time: 1 h
Yield: 27 %

Procedure:
To a solution (80 mL) of 5-fluoro-N-methoxy-N,3-dimethyl-1-benzofuran-2-carboxamide (4.37 g) synthesized above in tetrahydrofuran was added dropwise 1.5M diisobutylaluminum hydride toluene solution (24.5 mL) at 0° C., and the mixture was stirred for 1 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9, volume ratio) to give a pale-brown solid. To a solution (50 mL) of the obtained solid in tetrahydrofuran was added dropwise 1.0M cyclohexylmagnesium bromide tetrahydrofuran solution (21.8 mL) at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:17, volume ratio) to give the title object compound (1.32 g, 27%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:9])[CH2:8][CH:4]2[CH2:3][NH:2]1.[N:10]([CH:13]([CH3:15])[CH3:14])=[C:11]=[O:12].C(N(CC)CC)C.O>ClCCl>[CH:13]([NH:10][C:11]([N:2]1[CH2:3][CH:4]2[CH2:8][C:7](=[O:9])[CH2:6][CH:5]2[CH2:1]1)=[O:12])([CH3:15])[CH3:14]
Reactant: O=C1CC2CNCC2C1
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)NC(=O)N1CC2CC(=O)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (717 mg, 3 mmol) was dissolved in 20 mL of dichloromethane, and 2-isocyanatopropane (9 mL, 9 mmol) and triethylamine(1.7 mL, 12 mmol) were then added to the solution in an ice-water bath. Upon completion of the addition, the reaction mixture was stirred overnight at room temperature, water (50 mL) was then added to the mixture. The mixture was extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with 10% citric acid solution (50 mL) and 50 mL of saturated brine successively, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid isopropylamide 6a (0.3 g, yield 47.6%) as a colorless oil.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[C:19](=[O:25])[CH2:18]3)=[C:13]([F:26])[CH:12]=2)[CH2:6]1)=[N+]=[N-].[C:27](OCC)(=[O:29])[CH3:28]>CN(C=O)C>[F:26][C:13]1[CH:12]=[C:11]([N:7]2[CH2:6][C@H:5]([CH2:4][NH:1][C:27](=[O:29])[CH3:28])[O:9][C:8]2=[O:10])[CH:16]=[CH:15][C:14]=1[N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[C:19](=[O:25])[CH2:18]1
Reactant: CCOC(C)=O
Reactant: CCN1CCN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1=O
Solvent: CN(C)C=O
Product: CCN1CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(5R)-5-Azidomethyl-3-(3-fluoro-4-{4-ethyl-3-oxopiperazin-1-yl-}phenyl)oxazolidin-2-one (750 mg) was dissolved in a mixture of DMF (5 ml) and ethyl acetate (10 ml), and the solution purged with argon. Palladium (10% on carbon, 150 mg) was added, followed by acetic anhydride (0.4 ml) and the mixture stirred at ambient temperature under hydrogen confined in a balloon for 2 hours. The mixture was filtered through celite, evaporated to dryness, and chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated, and the residue purified by crystallisation from acetonitrile to give N-(5S)-[3-(3-fluoro-4-{4-ethyl-3-oxopiperazin-1-yl}phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (145 mg).
Reaction SMILES: [O:1]1CCC(=O)CC1.C(N1CCNCC1)(OC(C)(C)C)=O.[C-]#N.[K+].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2([C:43]#[N:44])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].[OH-].[Na+].OO>CO.O>[C:24]([O:28][C:29]([N:31]1[CH2:32][CH2:33][N:34]([C:37]2([C:43](=[O:1])[NH2:44])[CH2:38][CH2:39][O:40][CH2:41][CH2:42]2)[CH2:35][CH2:36]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCN(C2(C#N)CCOCC2)CC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: OO
Agent: [C-]#N
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C2(C(N)=O)CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of tetrahydro-4H-pyran-4-one (500 mg, 5.00 mmol) and 1-Boc-piperazine (930 mg, 5.00 mmol) in methanol (10 mL) at 0° C. was added dropwise a solution of potassium cyanide (325 mg, 5.00 mmol) in water (1 mL). The mixture was warmed to room temperature and stirred overnight. The mixture was partitioned between ethyl acetate and water. The combined organic layers were washed with brine, separated and dried (MgSO4) to yield a 1:1 mixture of 4-(4-cyano-tetrahydro-pyran-4-yl)-piperazine-1-carboxylic acid tert-butyl ester and unreacted starting material (1.15 g). The crude mixture was dissolved in methanol (10 mL) and 1M sodium hydroxide solution (5 mL, 5.00 mmol) was added followed by the dropwise addition of hydrogen peroxide, (30 wt % solution in water; 2.5 mL) The mixture was stirred at room temperature overnight. The mixture was evaporated in vacuo and the crude product was purified by column chromatography to yield 4-(4-carbamoyl-tetrahydro-pyran-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (307 mg). Removal of the Boc-protecting group using 2.0 M HCl in diethyl ether in dichloromethane gave the di-hydrochloride salt of the title compound as a pale solid (260 mg).
Reaction SMILES: O1C=CC(NC[C@@H]2OC(=O)N(C3C=CC(N4CC[C@H](NC(=O)C)C4)=C(F)C=3)C2)=N1.Cl.[NH2:31][C@H:32]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:47][C@H:46]([CH2:48][N:49]([C:58]4[CH:62]=[CH:61][O:60][N:59]=4)C(OCC(Cl)(Cl)Cl)=O)[O:45][C:44]3=[O:63])=[CH:39][C:38]=2[F:64])[CH2:33]1.Cl[C:66]([O:68][CH2:69][CH2:70][O:71][CH3:72])=[O:67]>>[CH3:72][O:71][CH2:70][CH2:69][O:68][C:66]([NH:31][C@H:32]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:47][C@H:46]([CH2:48][NH:49][C:58]4[CH:62]=[CH:61][O:60][N:59]=4)[O:45][C:44]3=[O:63])=[CH:39][C:38]=2[F:64])[CH2:33]1)=[O:67]
Reactant: N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Reactant: COCCOC(=O)Cl
Agent: CC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1
Agent: Cl
Product: COCCOC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1
Yield: 130.5 %

Procedure:
Using essentially the method for the intermediate of Example 12, starting from 3-(4-(3(S)-aminopyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-(2,2,2-trichloroethyloxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride salt (419 mg, 0.73 mM) and 2-methoxyethyl chloroformate (450 mg, 3.27 mM) gave the title compound (442 mg ). NMR (DMSO-d6) δ: 1.82 (hextet, 1H); 2.09 (hextet, 1H); 3.13 (m, 1H); 3.23 (s, 3H); 3.27 (m, 1H); 3.39 (m, 1H); 3.46 (t overlapping m, 3H); 3.81 (dd overlapping m, 2H); 4.05 (m, 2H); 4.13 (m, 2H); 4.32 (m, 1H); 4.97 (d, 1H); 5.02 (m, 1H); 5.08 (d, 1H); 6.71 (t, 1H); 6.88 (d, 1H); 7.08 (dd, 1H); 7.34.(dd, 1H); 7.52 (d, 1H); 8.89 (d, 1H). MS (ESP): 638 (MH+) for C24H27FN5O8Cl3
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])[CH3:3].[H-].[Na+].Br[CH2:19][C:20]1[CH:21]=[C:22]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C=O)C>[C:2]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:21]=[C:22]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])c(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
Di-tert-butyliminodicarboxylate (4.35 g, 20.0 mmol) was added to a suspension of sodium hydride (0.48 g, 20.0 mmol) in anhydrous DMF (30 mL) at RT. After 30 minutes, a solution of t-butyl 3-bromomethyl-4-nitrobenzoate (6.3 g, 20 mmol) in DMF (15 mL) was added rapidly dropwise. After 16 h, the solvent was evaporated and the residue partitioned between EtOAc (200 mL) and water (40 mL). The organic layer was extracted with water (3×50 mL) and brine (40 mL) and dried finally over Na2SO4. Removal of solvent gave the crude product which was purified on flash chromatography (15:85; EtOAc:Hexane) to give the title compound (81.5%): MS (ES) m/e 453 (M+H)+ ; 1H NMR (400 MHz, CDCl3) δ 7.97-8.10 (m, 3H), 5.16 (s, 2H), 1.62 (s, 9H), 1.49 (s, 18H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.C(N(CC)CC)C.[C:15](=[S:17])=[S:16]>>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([NH:1][C:15](=[S:16])[SH:17])=[N:3]1
Reactant: Cn1ccc(N)n1
Reactant: S=C=S
Solvent: CCN(CC)CC
Product: Cn1ccc(NC(=S)S)n1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 29.1 g of 3-amino-1-methylpyrazole and 45 ml of triethylamine was added dropwise 18 ml of carbon disulfide and the resulting mixture was stirred at 40° C. for 30 minutes to precipitate solids. To the reaction mixture was added ether, followed by pulverization of solids. After filtration, the thus pulverized solids were washed with ether to give 67 g of triethylamine salt of 1-methyl-3-pyrazolyldithiocarbamic acid (melting point: 79° to 82° C.) 31.8 g of the thus obtained triethylamine salt of dithiocarbamic acid and 11.7 g of triethylamine were dissolved in 150 ml of methylene chloride. To the resulting solution was added at one time 34.5 g of ferric chloride 6 hydrate dissolved in 100 ml of water, followed by vigorous stirring for 10 minutes. The reaction mixture was filtered to remove insoluble solids. The organic layer was separated and then the aqueous layer was extracted with methylene chloride. After the organic layers were combined, washed with water and dried, the solvent was distilled off under reduced pressure. To the thus obtained residue was added ether to filter the insoluble solids off and the filtrate was concentrated under reduced pressure to give 9.0 g of oil. The thus obtained oil was evaporated under reduced pressure to give 6.5 g of the desired compound. b.p.: 135° to 138° C./23 mmHg.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.C([Li])CCC.[CH3:17][S:18]SC.[Cl-].[NH4+]>C1COCC1>[Cl:11][C:9]1[C:10]2[C:2]([S:18][CH3:17])=[CH:3][NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Reactant: CSSC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (Example 35) (2.53 g, 10 mmol) in anhydrous THF (30 mL) was cooled to -78° C. under argon and a solution of n-butyl lithium (12 mL of 2.3M solution, 25 mmol) was added at such a rate that the reaction temperature remained below -72° C. After the addition, the reaction mixture was stirred at -78° C. for 45 min, a solution of methyl disulfide (0.95 ml, 10 mmol) in tetrahydrofuran (10 mL) was added over a period of 30 minutes maintaining the temperature below -72° C. The reaction mixture was stirred at -78° C. for 2.5 hours then allowed to warm to room temperature. A saturated solution of ammonium chloride (40 mL) was added to the reaction with stirring. The organic layer was separated, the aqueous layer extracted with ethyl acetate (2×40 mL) and the combined organic extracts were dried (MgSO4), filtered and evaporated to obtain a pale yellow solid which was crystallized from EtOH: yield 1.65 g; (70%) m.p. 166°-167° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C@@H:12]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)(C(C)(C)C)(C)C>CC#N.Cl>[Cl:32][C:28]1[CH:27]=[C:26]([C@@H:12]([C@@H:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[O:11][CH2:10][CH2:9][OH:8])[CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCO[Si](C)(C)C(C)(C)C)c2cccc(Cl)c2)C1
Agent: Cl
Solvent: CC#N
Product: OCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1

Procedure:
A solution of crude (R)-tert-butyl 3-((R)-(2-(tert-butyldimethylsilyloxy)ethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate in CH3CN (100 mL) and 2 N aq HCl (100 mL) was vigorously stirred at rt for 2 d. The solvents were removed in vacuo to give the HCl salt of 2-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)ethanol, which was used in the next step without further purification. LC-MS (3 min) tR=1.05 min m/z 272, 270 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:13][C@@H:14]2[C:19]3[CH:20]=[C:21]([P:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])[O:25]C)[CH:22]=[CH:23][C:18]=3[O:17][C:16]([CH3:35])([CH3:34])[C@H:15]2[OH:36])=[N:10][C:11]#[N:12])=[CH:4][CH:3]=1.[Li+].[OH-]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:10][C:11]#[N:12])=[N:13][C@@H:14]2[C:19]3[CH:20]=[C:21]([P:24]([OH:27])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH:22]=[CH:23][C:18]=3[O:17][C:16]([CH3:35])([CH3:34])[C@H:15]2[OH:36])=[CH:6][CH:7]=1
Reactant: COP(=O)(c1ccccc1)c1ccc2c(c1)[C@@H](NC(=NC#N)Nc1ccc(Cl)cc1)[C@H](O)C(C)(C)O2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Oc2ccc(P(=O)(O)c3ccccc3)cc2[C@@H](N=C(NC#N)Nc2ccc(Cl)cc2)[C@@H]1O
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of the title compound of Example 1 (152 mg, 0.29 mmol) in 1.5 mL of methanol was added 1.5 mL of 1M aq LiOH solution at room temperature. The reaction mixture was stirred for 18 hours (~1/2 complete by TLC) then an additional 1.5 mL of 1M aq LiOH solution was added. After 18 hours (complete by TLC) the reaction mixture was chromatographed (HP-20, 15×1.5 cm) eluting successively with 100 mL portions of water, 20% aq acetone and 40% aq acetone. The product containing fractions were combined, concentrated in vacuo then lyophilized to afford the title compound as a white solid (165 mg, 0.29 mmol, 100%). [α]D =+25° (c=0.17 in MeOH).
Reaction SMILES: C(C(O)=O)C=C(CCC=C(CCC=C(C)C)C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:38][C:39]1[CH2:44][CH2:43][C@H:42]([C@@:45]([OH:53])([CH2:47][CH2:48][CH:49]=[C:50]([CH3:52])[CH3:51])[CH3:46])[CH2:41][CH:40]=1.C(Cl)(Cl)(Cl)[Cl:55]>O.N.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:38][C:39]1[CH2:44][CH2:43][C@H:42]([C@@:45]([OH:53])([CH2:47][CH2:48][CH:49]=[C:50]([CH3:52])[CH3:51])[CH3:46])[CH2:41][CH:40]=1.[Cl-:55]
Reactant: ClC(Cl)(Cl)Cl
Agent: [Ag+]
Agent: CC(C)=CCCC(C)=CCCC(C)=CCC(=O)O
Agent: CC(C)=CCC[C@](C)(O)[C@@H]1CC=C(C)CC1
Solvent: O
Product: [Cl-]

Procedure:
To the solution containing 1.25 g. of farnesyl carboxylic acid dissolved in 0.5 N ammonia water, 0.845 g. of silver nitrate in 3 ml. water was added. The resulting precipitate was collected by filtration and dried. The silver salt was powdered and suspended in 120 ml. of benzene, and distilled to about 60 ml. of benzene solution to remove the remaining water azeotropically. Separately, α-bisabolol chloride was prepared by adding triphenyl phosphine in an amount of 1.3 times the stoichiometric quantity, to α-bisabolol in a solution of carbon tetrachloride (1:8) and following 1 hour of reflux in water bath, the product was purified by vacuum distillation. The purified α-bisabolol chloride in an amount of 1.39 g. was dissolved in 3 ml. of benzene and added to the above solution of silver salt suspension which had been prepared previously. After 9 hours of reflux, the reaction mixture was washed with water and dried (sodium sulfate). The desired fraction was obtained by vacuum distillation (155°-156° C./0.1 mmHg) under N2 gas stream.
Reaction SMILES: [C:1]([P:5](=[O:17])([CH2:13][CH:14]([CH3:16])[CH3:15])C(OCC)OCC)([CH3:4])([CH3:3])[CH3:2]>Cl>[C:1]([PH:5](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(OCC)P(=O)(CC(C)C)C(C)(C)C
Agent: Cl
Product: CC(C)C[PH](=O)C(C)(C)C
Temperature: 25 °C

Procedure:
A solution of 1.2 g (0.005 mol) of tertiary-butyl(iso-butyl)(diethoxymethyl) phosphine oxide in 10 ml of 5% hydrochloric acid is heated at 80° C. for 9 hours. After this the mixture is allowed to cool to room temperature, evaporated under reduced pressure and the crude product is extracted into chloroform and washed with water. The organic extract is dried and evaporated to give tertiary-butyl(iso-butyl) phosphine oxide as a pale yellow oil.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:12](OC)(=O)CC(C)=O>>[CH3:12][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: COC(=O)CC(C)=O
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C)C(=O)OCC
Yield: 90 %

Procedure:
The procedure followed is as in Example 2, but 230.4 g (1.44 mol) of diethyl malonate are pumped in instead of the methyl acetoacetate. After analogous working up, 230.0 g of 90% pure diethyl methylmalonate are obtained on distillation. This corresponds to a yield of 82.6% of the theoretical yield, based on the diethyl malonate employed. The distillate also contains 9.3% of diethyl methoxymethylmalonate as a by-product. A residue of 3.1 g remains in the distillation flask.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:26][C@H:25]3[O:27][CH2:28][O:29][C@H:24]3[CH2:23]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)C=O>O>[CH2:9]([C:16]1[C:21]([I:1])=[CH:20][CH:19]=[C:18]([N:22]2[CH2:23][C@H:24]3[O:29][CH2:28][O:27][C@H:25]3[CH2:26]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc(Cc2cccc(N3C[C@@H]4OCO[C@@H]4C3)n2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Ic1ccc(N2C[C@@H]3OCO[C@@H]3C2)nc1Cc1ccccc1
Reaction time: 8 h
Yield: 53.5 %

Procedure:
143 mg of N-iodosuccinic acid imide was added little by little to a mixture of 150 mg of 2-benzyl-6-(cis-3,4-methylenedioxypyrrolidine-1-yl)pyridine and 5.0 ml of N,N-dimethylformamide under ice-cooling, followed by stirring overnight as it was. The reaction solution was poured into water, and then extracted with ethyl acetate. The organic phase was washed with sodium thiosulfate, water and brine, and the solvent was removed. The residue was subjected to silica gel column chromatography and eluted with hexane and then with hexane/ethyl acetate (4:1), to give 116 mg of the target compound.
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([Cl:38])=[C:7]([C:9](=[N:33][O:34][CH2:35][CH:36]=[CH2:37])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O1CCCC1.C(=O)(O)[O-].[Na+]>CO.O>[NH2:3][C:4]1[S:5][C:6]([Cl:38])=[C:7]([C:9](=[N:33][O:34][CH2:35][CH:36]=[CH2:37])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1nc(NC=O)sc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1nc(N)sc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
A mixture of 7-[2-(2-formamido-5-chlorothiazol-4-yl)-2-allyloxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.5 g) in methanol (15 ml), and conc. hydrochloric acid (0.52 g) and tetrahydrofuran (3.0 ml) was stirred for 3.0 hours at ambient temperature. The reaction mixture was added to water and ethyl acetata, and adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated and adjusted to pH 3.0 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and evaporated under reduced pressure to give 7-[2-(2-amino-5-chlorothiazol-4-yl)-2-allyloxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.02 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])=[CH:19][CH:18]=1
Reactant: COc1cccc2cc(C(=O)O)oc12
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)c2cc3cccc(OC)c3o2)cc1

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and p-anisidine to give N-(4-methoxyphenyl)-7-methoxybenzofuran-2-carboxamide (Compound 399a). Successively, it was formylated to give N-(4-methoxyphenyl)-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 399b), then compound 399b was reacted with cyclobutylamine to give compound 399 as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.CCN(CC)CC.Cl[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17]>C(Cl)Cl>[OH:7][CH:4]1[CH2:5][CH2:6][N:1]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:2][CH2:3]1
Reactant: OC1CCNCC1
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a stirring solution of piperidin-4-ol (5.22 g, 51.6 mmol, Aldrich), Et3N (13.2 mL, 95 mmol, Aldrich) in CH2Cl2 (50 mL) at 0° C. was added a solution of Isopropyl chloroformate (1 Molar in Toluene, 43.0 mL, 43.0 mmol, Aldrich) dropwise. The reaction mixture was stirred at room temperature for 1 h and washed with 1N HCl in H2O. The H2O layer was extracted with DCM (2×). The organic layers were combined and concentrated in vacuo to yield 5.71 g of the desired product as a light brown oil. MS (ESI) 188 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[CH:12][C:11]([CH3:27])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:12][C:11]([CH3:27])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)n(-c2ccc(F)c(Cl)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C2CCNCC2)n(-c2ccc(F)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The crude product from step A (801 mg, 2.033 mmol) was dissolved in anhydrous dichloromethane (4 mL). Trifluoroacetic acid (2 mL, 26 mmol) was added dropwise. Then the solution was stirred at room temperature for 3 hours. The solution was concentrated and volatiles were removed by azeotroping with toluene. The resulting crude product was purified by RP-HPLC(C18; 5% to 50% acetonitrile/water+0.05% TFA) to afford the title compound. HPLC/MS: 294.1/296.1 (M+1); 2.08 min (LC4).