Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:25][C:26]([C:28]4[C:29](=[O:43])[N:30]([CH2:34][C:35]5[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=5)[CH:31]=[CH:32][CH:33]=4)=[O:27])[CH:19]=3)=[CH:16][N:15]([S:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)(=[O:46])=[O:45])[C:12]2=[N:13][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:17]([C:18]3[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=3)[CH2:24][NH:25][C:26]([C:28]3[C:29](=[O:43])[N:30]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=4)[CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:16][N:15]([S:44]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)(=[O:45])=[O:46])[C:12]2=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1cnc2c(c1)c(-c1cccc(CNC(=O)c3cccn(Cc4ccc(F)c(F)c4)c3=O)c1)cn2S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cnc2c(c1)c(-c1cccc(CNC(=O)c3cccn(Cc4ccc(F)c(F)c4)c3=O)c1)cn2S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
Into a vial was dissolved (1-benzenesulfonyl-3-[3-({[1-(3,4-difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl}-carbamic acid tert-butyl ester (0.259 mmol) in methylene chloride (2.00 mL, Acros) and trifluoroacetic acid (2.00 mL, 0.0260 mol; Acros). The reaction was stirred for 30 min, then the reaction was evaporated to dryness to give the crude amine.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH2:11])=[S:10].Br[CH:13]([CH:19]([CH3:21])[CH3:20])[C:14](OCC)=[O:15]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][CH:13]([CH:19]([CH3:21])[CH3:20])[C:14](=[O:15])[N:11]=1
Reactant: NC(=S)NC1CC2CCC1C2
Reactant: CCOC(=O)C(Br)C(C)C
Product: CC(C)C1SC(NC2CC3CCC2C3)=NC1=O

Procedure:
Synthesis was performed from N-bicyclo[2.2.1]hept-2-ylthiourea and ethyl 2-bromoisovalerate according to Method C.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].FC(F)(F)S(O[C@H:13]([CH3:18])[C:14](OC)=[O:15])(=O)=O>>[CH3:18][C@H:13]1[C:14](=[O:15])[O:4][CH2:3][C:2]([CH3:6])([CH3:5])[NH:1]1
Reactant: COC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(N)CO
Product: C[C@@H]1NC(C)(C)COC1=O

Procedure:
In some embodiments, various compounds of the present invention may be prepared by a novel convergent synthetic approach for the preparation of 2-substituted morpholinols as outlined in Scheme 3. This approach utilizes a nucleophilic addition of Grignard reagents to (35)-3,5,5-trimethylmorpholin-2-one (15). Treatment of methyl (R)-(+)-lactate (13) with trifluoromethanesulfonic anhydride and 2,6-lutidine at 0° C., gives methyl (2R)-2-{[(trifluoromethyl)sulfonyl]oxy}propionate (14) in 77% yield. The alkylation of 2-amino-2-methyl-1-propanol with triflate 14 at −40° C. for 2 h and overnight at room temperature, and subsequent cyclization affords 15. The addition of the appropriate arylmagnesium bromide to 15 provides the desired compounds. The C-3 stereocenter of these compounds is derived from the lactate, rather than created by a synthetic transformation such as the Sharpless hydroxylation used in Scheme 1. In some embodiments, this center was then leveraged to create the second C-2 stereocenter. The resulting stereochemistry at C-2 was a result of either facial selectivity during the Grignard addition anti to the C-3 methyl group and/or a thermodynamic equilibrium of the final product to the S,S-configuration since the resulting product can ring open and close. The ring opened form loses its C-2 stereochemistry, forming a ketone. This route is more convergent than the Sharpless hydroxylation route, and in some embodiments, may be more reliable, requiring far less analytical work.
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[C:4]([CH:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:15][C:14]=2[F:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[OH-].[Na+]>CC(O)=O.O.[Pd]>[CH2:34]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:15][C:14]=2[F:27])[CH2:9][CH2:8]1)=[O:5])[CH3:35]
Reactant: CCC(CC)C(=O)Nc1ccc(C2=CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(F)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCC(CC)C(=O)Nc1ccc(C2CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
To a solution of N-{4-[1-(diethylcarbamoyl-phenyl-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-fluoro-phenyl}-2-ethyl-butyramide (10 mg, 0.021 mmol) in HOAc (1 mL), H2O (0.1 mL) and 10% Pd/C (2 mg) were added. The mixture was stirred under H2 (1 atm) at 25° C. for 16 h. The mixture was neutralized to pH ˜7 with 1 M NaOH. The mixture was extracted with DCM (2×5 mL), and the organic layer was concentrated and purified by PTLC to provide the title compound (7 mg, 70%). MS: 482.4. 1H NMR (CDCl3): 7.53-7.28 (m, 6H), 7.19-7.03 (m, 3H), 4.26 (s, 1H), 3.50-3.05 (m, 5H), 2.98-2.92 (m, 1H), 2.83-2.75 (m, 1H), 2.44-2.36 (m, 1H), 2.30-1.95 (m, 2H), 1.90-1.47 (m, 8H), 1.08 (t, J=7.0, 3H), 1.04 (t, J=7.1, 3H), 0.91 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12]O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:12])=[O:8]
Reactant: CO
Reactant: Cc1ccc(O)cc1C(=O)O
Product: COC(=O)c1cc(O)ccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 107 g 5-hydroxy-2-methylbenzoic acid (compound described in example F1 step 2) in 1000 ml methanol 251.1 g thionylchloride is added dropwise. The mixture is heated to reflux and stirred two hours at RT. After the solvent has been largely evaporated from the mixture under reduced pressure, 100 ml water are added and the reaction mixture is adjusted to pH 7 with saturated aqueous sodium hydrogen carbonate solution. The aqueous phase is extracted with 200 ml EA three times, the combined organics are dried over MgSO4, and the solvent is removed under reduced pressure yielding methyl 5-hydroxy-2-methylbenzoate, which is used for the next step without further purification.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]O>>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][Cl:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: OCCCCCCCl
Product: ClCCCCCCOC(c1ccccc1)c1ccccc1
Yield: 88 %

Procedure:
Using benzhydrol and 6-chloro-1-hexanol, the procedure of Reference Example 15 was otherwise repeated to provided the title compound. Yield 88%. Oil.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([NH2:16])[C:14]#[CH:15].C(N(CC)CC)C>C(O)C>[Cl:12][C:11]1[C:2]([NH:16][CH2:13][C:14]#[CH:15])=[N:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=1
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: C#CCN
Solvent: CCO
Solvent: CCN(CC)CC
Product: C#CCNc1nc2ccccc2nc1Cl

Procedure:
A mixture of 10 g of 2,3-dichloroquinoxaline, 4.5 ml of propargylamine, 10.5 ml of triethylamine in 50 ml of ethanol is refluxed for 4 h. After evaporating under vacuum the resulting mixture, the residue is chromatographed on SiO2 (eluent: CH2Cl2) thereby obtaining 7.0 g of 2-chloro-3-(propargylamino)quinoxaline (IR (KBr): 3441, 3282, 1518 cm-1). This product is then added with 10 ml of concentrated sulphuric acid and the resulting mixture is stirred at 90° C. for 1 h. After cooling down and cautiously neutralizing with aqueous NaOH, the resulting precipitate is filtered under vacuum, washed, dried, decolorized and recrystallized from dimethylformamide, thereby obtaining 2.4 g of 1-methylimidazo[1,2-a]quinoxaline-4(5H)-one (m.p. >300° C.).
Reaction SMILES: [CH3:1][C:2](C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[Br:14][C:15]1[C:16](CC)=[CH:17][CH:18]=[C:19]([CH:21]2[C:25](=[O:26])[CH:24]=[CH:23][CH:22]2[OH:27])[CH:20]=1>CC(C)=O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:1][CH3:2])=[C:19]([CH:21]2[C:22](=[O:27])[CH:23]=[CH:24][C:25]2=[O:26])[CH:20]=1
Reactant: CC(C)=O
Reactant: CCc1ccc(C2C(=O)C=CC2O)cc1Br
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCc1ccc(Br)cc1C1C(=O)C=CC1=O
Reaction time: 0.33 h

Procedure:
Jones' reagent (75 ml of 1.67 M solution, 125 mmol) is added dropwise over 30 minutes to a cooled (ice-bath) solution of 5-(5-bromo-4-ethylphenyl)-4-hydroxycyclopent-2-enone (33 g, 117 mmol) in acetone (400 ml). The mixture is stirred for 20 minutes, then the cooling bath is removed and the mixture is stirred for 1 hour at room temperature. Isopropanol (150 ml) is added to the yellow slurry and the mixture is stirred at room temperature for 2 hours. The mixture is diluted with ethyl acetate and washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure to give 2-(5-bromo-2-ethylphenyl)cyclopent-4-ene-1,3-dione.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH2:9])[N:5]=2)[CH2:3][CH2:2]1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:23](OCC)=[O:24])[C:18](OCC)=[O:19])=[CH:13][CH:12]=1.C(N(CCCC)CCCC)CCC>[OH-].[Na+].O>[CH:1]1([C:4]2[N:5]=[C:6]3[N:9]=[C:23]([OH:24])[C:17]([C:14]4[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=4)=[C:18]([OH:19])[N:7]3[N:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1n[nH]c(C2CC2)n1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: Oc1nc2nc(C3CC3)nn2c(O)c1-c1ccc(F)cc1

Procedure:
10.2 g (81.9 mmol) 5-Cyclopropyl-1,2,4-triazole-3-ylamine, 25 g (98.3 mmol) diethyl (4-fluorophenyl)malonate and 32.2 mL (135.2 mmol) tributylamine are stirred at 180° C. for 18 hours. The solution is diluted with 120 mL 2N NaOH solution and 120 mL water and the resulting mixture is extracted three times with methyl-tert. butylether. These organic extracts are discarded. The aqueous phase is acidified to pH 1 with 2N HCl. The precipitate is collected by filtration, washed with plenty of water and dried. This material (13.5 g=57.6%) is used without further purification.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6]N=O.[CH2:9]=[C:10]=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN1CCCC1=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:10]([CH3:9])=[O:11]
Reactant: CCCCCON=O
Reactant: C=C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: CCCCCOC(C)=O
Reaction time: 6 h
Yield: 25 %

Procedure:
The procedures of Example 14 were followed, except that 80 ml (536.9 mmoles) of n-amyl nitrite was used and that ketene was introduced at the rate of 11.3 ml/min (0.50 mmole/min). During the reaction, however, 15 ml, of a solution of triphenylphosphine (0.092 g, 0.375 mmole) and stannous chloride (0.072 g, 0.375 mmole) in N-methylpyrrolidone was added to the reaction system in 2.5 ml portions every 1 hour, and the reaction was effected at 90° C. for 6 hours. The gas chromatographic analysis revealed that di-n-amyl malonate (136.0 mmoles, 74.8%) and n-amyl acetate (45.4 mmoles, 25.0%) were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]([C:17]([OH:19])=O)[CH2:15][CH2:14][CH2:13][CH:12]1[C:20]([OH:22])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OC(=O)C)(=O)C>O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:16]1[C:17](=[O:19])[N:33]([CH2:32][CH2:31][CH2:30][CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20]2=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCC(C(=O)O)N1C(=O)OCc1ccccc1
Reactant: NCCCCc1ccccc1
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Product: O=C1C2CCCC(C(=O)N1CCCCc1ccccc1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Anhydride 2 (0.54 g, 1.89 mmol, prepared from Compound 1) was dissolved in 1 mL of dioxane. 4-Phenylbutylamine (0.28 g, 1.89 mmol) was added from the top. The mixture was stirred at room temperature for 1 hour. After this time, acetic anhydride (0.62 mL, 3.78 mmol) was added, and the reaction was refluxed for 5 hours. The dioxane was evaporated, and flash chromatographic purification of the residue (40% EtOAc/hexanes) gave Compound 13 (0.75 g, 95% yield) as a colorless thick oil. Rf=0.66 (40% EtOAc/hexanes); IR: 2935, 2863, 1710, 1688, 1430, 1341, 1311, 1256, 1126, 1096, 1069, 749, 699 cm−1; 1H NMR: δ 1.41-2.04 (m, 8H), 2.61 (t, 2H, J=6.9), 3.79 (t, 2H, J=6.9), 4.96 (s, 2H), 5.14 (s, 2H), 7.14-7.37 (m, 10H).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]2[C:21]=1I)[CH3:12])C1C=CC=CC=1.CSC.[C:27](O)([C:29](F)(F)F)=O>>[N:10]1[CH:29]=[CH:27][CH:21]=[CH:13][C:11]=1[C:21]1[N:16]2[CH:17]=[CH:18][CH:19]=[N:20][C:15]2=[N:14][C:13]=1[CH:11]([NH2:10])[CH3:12]
Reactant: CC(NC(=O)OCc1ccccc1)c1nc2ncccn2c1I
Reactant: O=C(O)C(F)(F)F
Solvent: CSC
Product: CC(N)c1nc2ncccn2c1-c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of [1-(3-iodo-imidazo[1,2-a]pyrimidin-2-yl)-ethyl]-carbamic acid benzyl ester (900 mg, 2.4 mmol) and dimethylsulfide (0.9 mL) in TFA (4.5 mL) was stirred at rt overnight. The mixture was concentrated in vacuo, dissolved in EtOAc washed with satd. sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo to provide 1-(3-pyridin-2-yl-imidazo[1,2-a]pyrimidin-2-yl)-ethylamine: LC-MS (ESI) m/z 240.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[S:39](=[O:42])(=[O:41])[NH2:40])=[CH:29][CH:28]=2)[C:7](=[O:25])[N:8]([C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH:13]=[CH:12][C:11]=2[C:21]([F:24])([F:23])[F:22])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:43][C:44]1[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=1[C:46](O)=[O:47].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[S:39](=[O:42])(=[O:41])[NH:40][C:46](=[O:47])[C:45]3[CH:49]=[CH:50][CH:51]=[CH:52][C:44]=3[Cl:43])=[CH:31][CH:32]=2)[C:7](=[O:25])[N:8]([C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH:13]=[CH:12][C:11]=2[C:21]([F:24])([F:23])[F:22])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCc1nn(-c2cc(NC(=O)CC)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Yield: 50 %

Procedure:
Following the procedure of Example 51, 5-n-butyl-2,4-dihydro-2-[5-(propionylamino)-2-(trifluoromethyl)phenyl]-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step F) was reacted with 2-chlorobenzoic acid (3 equivalents), CDI (3 equiv), and DBU (3 equiv). Flash chromatography of the crude product on silica gel (gradient elution with 0.5-2% MeOH in CH2Cl2) afforded a 50% yield of the title compound as a solid, mp 102°-105° C.; homogeneous by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 740 (M+1)+.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]=[C:9]([CH2:13][C:14](O)=[O:15])[C:10]([OH:12])=[O:11].[OH-].[Na+]>O>[CH:1]1([N:7]2[C:14](=[O:15])[CH2:13][CH:9]([C:10]([OH:12])=[O:11])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: C=C(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CC(=O)N(C2CCCCC2)C1
Temperature: 110 °C
Yield: 58.1 %

Procedure:
A mixture of cyclohexanamine (3.70 mL; 31.94 mmol) and 2-methylenesuccinic acid (5.04 g; 41.62 mmol) in water (10 ml) was heated in a sealed tube at 110° C. for 21 hours. After cooling to room temperature, 6N NaOH (10 mL) was added and the resulting precipitate was filtered off. The filtrate was acidified with 6N hydrochloric acid to pH 1 and the resulting precipitate was filtered, washed with water, and dried to yield 3.92 g (58%) of 1-cyclohexyl-5-oxopyrrolidine-3-carboxylic acid as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[C:39](=[O:40])[N:4]2[C:5]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:6]([C:9]3[C:12](=[O:13])[C:11](=[O:14])[C:10]=3[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7][S:8][C@H:3]12.[NH2:41][C:42]1[S:43][CH:44]=[C:45](/[C:47](=[N:57]/[O:58][CH3:59])/[C:48](N2C(=S)N(C)N=N2)=[O:49])[N:46]=1>O1CCCC1>[NH2:41][C:42]1[S:43][CH:44]=[C:45](/[C:47](=[N:57]/[O:58][CH3:59])/[C:48]([NH:1][CH:2]2[C:39](=[O:40])[N:4]3[C:5]([C:23]([O:25][CH:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:24])=[C:6]([C:9]4[C:12](=[O:13])[C:11](=[O:14])[C:10]=4[O:15][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:7][S:8][C@H:3]23)=[O:49])[N:46]=1
Reactant: CO/N=C(\C(=O)n1nnn(C)c1=S)c1csc(N)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(OCc4ccccc4)c(=O)c3=O)CS[C@H]12
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(OCc4ccccc4)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Yield: 40.1 %

Procedure:
Diphenylmethyl 7-amino-3-(2-benzyloxy-3,4-dioxo-1-cyclobutenyl)-3-cephem-4-carboxylate (544 mg, 0.984 mmol) was acylated with 1-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetyl]-4-methyltetrazole-5-thione (295 mg, 0.984 mmol) in tetrahydrofuran (3 mL), as described in Example 13, to afford the title compound (290 mg, 40% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccnc1N
Reactant: Cc1ccccc1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccccc1CNc1cccnc1N
Temperature: 25 °C
Reaction time: 96 h
Yield: 34.4 %

Procedure:
Molecular Sieves (16 g) was added to a solution of 2,3-diaminopyridine (8 g), 2-methylbenzaldehyde (8.81 g), and acetic acid (4.2 ml) in methanol (160 ml) and the mixture was stirred for 96 hours at room temperature. Sodium cyanoborohydride (4.61 g) was added portionwise to the mixture with stirring under ice-cooling over a period of 20 minutes. After being stirred for 3 hours, the mixture was made alkaline with aqueous sodium bicarbonate solution and filtered by suction. The filtrate was evaporated in vacuo, and to the residue was added water and then extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The crystalline residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 2-amino-3-(2-methylbenzylamino)pyridine (5.38 g).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C:17](=[O:18])[CH2:16][CH2:15][CH:14]3[C:19]([OH:21])=O)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[CH3:24].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:58][C:59]1[CH:60]=[C:61]([NH2:71])[CH:62]=[C:63]([C:65]2[N:69]([CH3:70])[N:68]=[N:67][N:66]=2)[CH:64]=1>CN(C=O)C>[Br:58][C:59]1[CH:60]=[C:61]([NH:71][C:19]([CH:14]2[CH2:15][CH2:16][C:17](=[O:18])[N:13]2[CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:22]=[CH:23][C:2]([Cl:1])=[C:3]([CH3:24])[CH:4]=3)[CH2:8][CH2:9]2)=[O:21])[CH:62]=[C:63]([C:65]2[N:69]([CH3:70])[N:68]=[N:67][N:66]=2)[CH:64]=1
Reactant: Cn1nnnc1-c1cc(N)cc(Br)c1
Reactant: Cc1cc(CN2CCC(N3C(=O)CCC3C(=O)O)CC2)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(CN2CCC(N3C(=O)CCC3C(=O)Nc3cc(Br)cc(-c4nnnn4C)c3)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carboxylic acid as DIPEA salt (2.6 g) in DMF (100 ml) was added DIPEA (2.1 g), and HATU (4 g). 3-Bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenylamine (1.4 g) was added and the reaction stirred overnight at rt. The reaction mixture was filtered and the filtrate partitioned between water and EtOAc. The organic layer was separated, dried and concentrated in vacuum and the residue purified by flash chromatography (DCM:MeOH 100:0 to 95:5 gradient) to give the title compound (400 mg). Rf=0.19 (95:5 DCM:MeOH).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([O:6][CH3:7])[C:4]=1[Cl:11].[F:12][C:13]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[Cl:11][C:4]1[C:3]([OH:2])=[C:10]([CH:9]=[CH:8][C:5]=1[O:6][CH3:7])[C:15]([C:14]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:13]=1[F:12])=[O:16]
Reactant: COc1cccc(OC)c1Cl
Reactant: O=C(Cl)c1cccc(F)c1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2cccc(F)c2F)c(O)c1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 4 g of 2-chlororesorcinol dimethyl ether and 3.7 g of 2,3-difluorobenzoyl chloride in 60 ml of 1,2-dichloroethane at 5° C., 3.06 g of AlCl3 is added in portions. The mixture is allowed to warm to room temperature and then refluxed for 30 minutes. The reaction mixture is poured into concentrated HCl-ice and is permitted to stand about 72 hours. The aqueous layer is extracted with additional organic solvent, dried over Na2SO4 and evaporated to give 3-chloro-2-hydroxy-4-methoxy-2',3'-difluorobenzophenone, mp 161°-162° C.
Reaction SMILES: C[Si](C)(C)Br.C(OC([N:11]([CH2:13][CH:14]([O:24]C1CCCCO1)[CH2:15][P:16](=[O:23])([O:20]CC)[O:17]CC)[OH:12])=O)C>C(Cl)Cl>[OH:24][CH:14]([CH2:13][NH:11][OH:12])[CH2:15][P:16](=[O:17])([OH:23])[OH:20]
Reactant: CCOC(=O)N(O)CC(CP(=O)(OCC)OCC)OC1CCCCO1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=P(O)(O)CC(O)CNO
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 29.9 %

Procedure:
Trimethylbromosilane (122 g) was added dropwise to a solution of diethyl 3-(N-ethoxycarbonyl-N-hydroxyamino)-2-(tetrahydro-2H-pyran-2-yloxy)propylphosphonate (79.4 g) in methylene chloride (160 ml) under ice-cooling with stirring over a period of 15 minutes. The mixture was further stirred for an hour at 0°-5° C. and for additional 2.5 hours at ambient temperature, and then evaporated under reduced pressure. The oily residue was dissolved in water (500 ml) stirred at ambient temperature for an hour, and then washed twice with chloroform (200 and 100 ml portions) to remove off bis(trimethylsilyl)ether. The combined chloroform washings were back extracted once with water (50 ml). The combined aqueous layers were evaporated under reduced pressure. The dark brown oily residue was dissolved in water (300 ml) washed twice with chloroform (each 150 ml portion) and ethyl acetate (100 ml) successively, treated with activated charcoal (2.5 g), and evaporated under reduced pressure. The oily residue was dissolved in 1N hydrochloric acid (750 ml) treated with activated charcoal (2.5 g) and then heated to reflux for 13.5 hours. The mixture was evaporated under reduced pressure. The oily residue was dissolved in a mixture of water (50 ml) and methanol (100 ml) adjusted to pH about 4 with propylene oxide, and diluted with ethanol (300 ml). The oily precipitates were collected by decantation and dissolved in water (60 ml). This aqueous solution was diluted with methanol (120 ml) under heating at 60° C. and then allowed to stand overnight at ambient temperature. The precipitates were collected by filtration, washed twice with 80% aqueous methanol (each 20 ml portion) and methanol (20 ml) and then dried on phosphorus pentoxide to give 2-hydroxy-3-(N-hydroxyamino)-propylphosphonic acid (10.60 g). M.P. 153°-155° C.