Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:9]#[N:10])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:2].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([CH3:23])=[N:20][C:19]=2[C:24](O)=[O:25])=[CH:14][CH:13]=1>>[NH2:10][CH2:9][C@H:4]1[C@@H:3]([CH2:1][CH3:2])[CH2:8][CH2:7][CH2:6][N:5]1[C:24]([C:19]1[N:20]=[C:21]([CH3:23])[S:22][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)=[O:25]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: CCc1cccnc1C#N
Product: CC[C@H]1CCCN(C(=O)c2nc(C)sc2-c2ccc(F)cc2)[C@H]1CN

Procedure:
The title compound was synthesized following the same general protocol as described in Example 11 using 3-ethylpicolinonitrile and 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid. MS (ESI) 361.1 (M+H)
Reaction SMILES: Cl[C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.N1C2C(=CC=CC=2)C(=O)C1=O.[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=O)C2=O>>[F:25][C:26]1[CH:34]=[C:33]2[C:32](=[CH:28][CH:27]=1)[N:31]=[C:30]1[C:7](=[O:9])[C:6]3[C:5]([N:11]1[C:10]2=[O:12])=[CH:4][CH:3]=[CH:2][CH:13]=3
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: O=C1Nc2ccccc2C1=O
Product: O=C1c2ccccc2-n2c1nc1ccc(F)cc1c2=O
Yield: 57 %

Procedure:
Using the procedure in Example 12, and substituting 5-fluoroisatoic anhydride for 5-chloroisatoic anhydride and isatin for 5-fluoroisatin gave 650 mg (57%) of the title compound: mp 295° C. (dec); 1H NMR (DMSO-d6) δ 7.48-7.54 (m, 1H), 7.82-7.94 (m, 3H), 8.02-8.08 (m, 2H), 8.46-8.51 (m, 1H); MS (M+H)+ 267.1.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:9][OH:10])([CH2:7][OH:8])[C:4]([OH:6])=[O:5].[N+](=[CH2:13])=[N-].C(OCC)C>CO>[OH:1][CH2:2][C:3]([CH2:9][OH:10])([CH2:7][OH:8])[C:4]([O:6][CH3:13])=[O:5]
Reactant: O=C(O)C(CO)(CO)CO
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(CO)(CO)CO
Temperature: 25 °C

Procedure:
To a stirred solution of 3-hydroxy-2,2-bis(hydroxymethyl)propanoic acid, prepared according to EP 751223 A2, in MeOH at rt is added dropwise 2 M trimethylsilyl)diazomethane/diethyl ether (1-5 equivalents) and the mixture is stirred at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is concentrated under reduced pressure and the residue is partitioned between saturated aq sodium bicarbonate solution and dichloromethane. The organic layer is separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford methyl 3-hydroxy-2,2-bis(hydroxymethyl)propanoate.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[O:10][C:11]([C:14]2[N:19]=[C:18](S(C)=O)[C:17]([Cl:23])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1([C:27]2[NH:31][N:30]=[C:29]([NH2:32])[CH:28]=2)[CH2:26][CH2:25]1>C(O)CCC>[C:1]([NH:5][S:6]([C:9]1[O:10][C:11]([C:14]2[N:19]=[C:18]([NH:32][C:29]3[CH:28]=[C:27]([CH:24]4[CH2:26][CH2:25]4)[NH:31][N:30]=3)[C:17]([Cl:23])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: CS(=O)c1nc(-c2ccc(S(=O)(=O)NC(C)(C)C)o2)ncc1Cl
Solvent: CCCCO
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)o1
Temperature: 90 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
The mixture of the crude N-tert-butyl-5-(5-chloro-4-(methylsulfinyl)pyrimidin-2-yl)furan-2-sulfonamide and 5-cyclopropyl-1H-pyrazol-3-amine (255 mg, 2.08 mmol, 5.0 equiv.) in n-butanol (6 mL) was stirred at 90° C. for 2 h, then, partitioned between brine and ethylacetate. The organic layer was washed over brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to afford N-tert-butyl-5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)furan-2-sulfonamide (45 mg, 28% over 2 steps). LC-MS (m/z)=437.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.O[CH:17]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2>C(O)C.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]([CH:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[O:24][C:25]3[C:30]2=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Br)cc1
Reactant: OC1c2ccccc2Oc2ccccc21
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C(=O)c1ccc(Br)cc1)C1c2ccccc2Oc2ccccc21
Reaction time: 72 h

Procedure:
A solution of ethyl 4-bromobenzoylacetate (14.8 g, 0.05 mol) and 9-hydroxyxanthene (10.9 g, 0.06 mol) in ethanol-acetic acid (1:1, 150 ml) was stirred as described in Example 3 (ii) and a white solid collected. The filtrate was stirred a further 3 days and a second crop collected to give ethyl 2-(4-bromobenzoyl)-2-(9H-xanthen-9-yl)acetate.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:18][C:19]([N:21]([N:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1)[CH3:22])=[O:20])[C:7]1[C:15]([CH3:16])=[CH:14][C:13]2[C:9](=[CH:10][N:11]([CH3:17])[N:12]=2)[CH:8]=1)C.[OH-:33].[Na+].Cl>CO.O1CCCC1>[CH2:31]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][N:23]1[N:21]([CH3:22])[C:19](=[O:20])[CH2:18][N:6]([C:7]1[CH:8]=[C:9]2[C:10](=[CH:14][C:15]=1[CH3:16])[N:11]([CH3:17])[N:12]=[CH:13]2)[CH2:5][C:4]([OH:3])=[O:33]
Reactant: [OH-]
Reactant: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2cn(C)nc2cc1C
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(cnn2C)cc1N(CC(=O)O)CC(=O)N(C)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 88 %

Procedure:
The compound (631 mg, 1.45 mmol) of step C was dissolved in a methanol (5 ml)-tetrahydrofuran (2 ml) mixed solvent, 1N sodium hydroxide (5 ml) was added at room temperature, and the mixture was stirred at room temperature for 70 min. To the reaction mixture was added 1N hydrochloric acid (5 ml), and the solution was concentrated under reduced pressure. The precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound (517 mg, yield 88%) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[NH:8][C:9]([CH3:13])=[CH:10][C:11](=O)[C:6]=2[C:5](=[O:14])[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([N:21]([CH3:23])[CH3:22])[CH3:20])[C:3]1=[O:24].[N:25]1[CH:30]=CC=C[CH:26]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[CH3:1][N:2]1[C:7]2[N:8]=[C:9]([CH3:13])[CH:10]=[C:11]([N:25]([CH3:30])[CH3:26])[C:6]=2[C:5](=[O:14])[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([N:21]([CH3:23])[CH3:22])[CH3:20])[C:3]1=[O:24]
Reactant: Cc1cc(=O)c2c(=O)n(CCCC[C@@H](C)N(C)C)c(=O)n(C)c2[nH]1
Reactant: c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N(C)C)c2c(=O)n(CCCC[C@@H](C)N(C)C)c(=O)n(C)c2n1
Temperature: 55 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a mixture of (R)-1,7-dimethyl-3-(5-(N,N-dimethylamino)hexyl)pyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (315 mg, 0.947 mmol), pyridine (1 ml, 12.4 mmol) and dichloromethane (20 ml), cooled in an ice bath, was added trifluoromethanesulfonic anhydride (0.315 ml, 1.87 mmol) dropwise. After stirring for 2 hours, the cooling bath was removed. A 30% (v:v) solution of dimethylamine in tetrahydrofuran (7 ml) was added and the solution was transferred to a pressure tube (1″×8″). The tube was sealed and heated to 55° C. for 2 hours. After cooling to room temperature the solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution filtered through a pad of celite. The filtrate was rinsed with saturated sodium bicarbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate-methanol-triethylamine (85:10:5) to afford (R)-1,7-Dimethyl-5-(N,N-dimethylamino)-3-(5-(N,N-dimethylamino)hexyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)dione (300 mg, 88% yield for 2 steps) as an oil. 1H NMR (300 MHz, CDCl3) δ 0.99 (d, 3H), 1.20-1.50 (m, 3H), 1.52-1.74 (m, 3H), 2.28 (s, 6H), 2.42 (s, 3H), 2.99 (s, 6H), 3.64 (s, 3H), 4.03 (t, 2H), 6.39 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]([NH2:42])=[C:37]([NH2:43])[CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:44]=[CH:45][CH:46]=[CH:47][C:4]=2[NH:3]1.[CH3:48][C:49](O)=O>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]4[NH:42][C:48]([CH3:49])=[N:43][C:37]=4[CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:44]=[CH:45][CH:46]=[CH:47][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc(N)c1N
Reactant: CC(=O)O
Product: Cc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)N3CCC(N4CCN(C)CC4)CC3)cc(C)c2[nH]1

Procedure:
A solution of 120 mg (0.16 mmol) (R)-1-(3,4-diamino-5-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate were refluxed in 2 mL AcOH for 2 h and then evaporated down i.vac. The residue was purified by HPLC, the fractions containing the product were combined and lyophilised.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH2:16])[N:9]=[C:10]([NH:20][CH2:17][CH2:18][CH3:19])[C:11]=1[I:12]
Reactant: CCCN
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1CCOC1
Product: CCCNc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine and propylamine in THF. ES-MS m/e (%): 345 (M+H+, 100).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:27][CH2:26][C:11]2([C:15](=O)[N:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.[Cl:29][C:30]1[C:31]([C:40]([F:43])([F:42])[F:41])=[N:32][N:33]([CH2:36]C(O)=O)[C:34]=1[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCOCC1.CCOC(C)=O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:13][CH2:12][C:11]3([CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:36][N:33]4[C:34]([CH3:35])=[C:30]([Cl:29])[C:31]([C:40]([F:42])([F:43])[F:41])=[N:32]4)[CH2:27][CH2:26]3)[CH2:15]2)=[CH:18][C:19]=1[O:24][CH3:25]
Reactant: COc1cc(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)ccc1Cl
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(N2CCC3(CCN(C(=O)Cn4nc(C(F)(F)F)c(Cl)c4C)CC3)C2)ccc1Cl
Temperature: 0 °C

Procedure:
2-(4-Chloro-3-methoxy-phenyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (90 mg, 1 equiv) was treated with 4 mL of 4N HCl in dioxane at rt for 1 h. The volatile was removed and to the residue were added 3 mL of THF and 3 mL of dichloromethane. After cooling to 0° C., the solution was treated with 2 mL of 1M LiAlH4 in THF over night (allowed to warm to room temperature). 10 drops of water, 10 drops of 1N NaOH, and then 10 drops of water were added. The organic layer was collected and dried under vacuum. The residue was taken up in 1 mL of DMF, and to the solution were added (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (55 mg, 1 equiv), HATU (95 mg, 1.1 equiv), TEA (150 μL, 3 equiv). After stirring at rt over night, the mixture was taken up in EtOAc, washed with saturated sodium NaHCO3. Purification by reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) gave 1-[2-(4-Chloro-3-methoxy-phenyl)-2,8-diaza-spiro[4.5]dec-8-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone. LCMS observed for (M+H)+: 505. Retention time: 5.28 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using a 4.5 minutes gradient of 20% to 95% B with a 1.1 minutes wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/99.9% acetonitrile).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2([CH2:17][CH2:16][C:15](=[CH:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]2)[S:11][CH:10]([CH2:23][C:24]([OH:26])=[O:25])[C:9]1=[O:27])([CH3:4])([CH3:3])[CH3:2].I[CH:30]([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2([CH2:17][CH2:16][C:15](=[CH:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]2)[S:11][CH:10]([CH2:23][C:24]([O:26][CH:30]([CH3:32])[CH3:31])=[O:25])[C:9]1=[O:27])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)I
Reactant: CC(C)CC=C1CCC2(CC1)SC(CC(=O)O)C(=O)N2CC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CC=C1CCC2(CC1)SC(CC(=O)OC(C)C)C(=O)N2CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 1.0 g of 2-[4-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-acetic acid. After adding 0.42 ml of 2-iodopropane and 0.67 g of anhydrous potassium carbonate at ambient temperature, the resulting mixture was stirred at ambient temperature for 17 hours. The reaction mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=17:3] gave 1.0 g of isopropyl 2-[4-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-acetate as a light yellow oily product.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]2)=[N:6][CH:7]=1.C1C(=O)N([Br:21])C(=O)C1.O>C(#N)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)=[N:6][C:7]=1[Br:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cnc([C@@H]2CC[C@H](O)C2)cn1
Solvent: O
Solvent: CC#N
Product: Nc1ncc([C@@H]2CC[C@@H](O)C2)nc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N,N-Di-tert-butyl (5-((1R,3S)-3-hydroxycyclopentyl)pyrazin-2-yl)carbamate (35 mg, 0.092 mmol) in DCM (461 μl) was added HCl (922 μl, 3.69 mmol), the reaction mixture was stirred at room temperature overnight and concentrated to dryness yielding HCl salt. The crude product was used in next step reaction without purification. LCMS (m/z): 180.1 (MH+), 0.22 min. (+/−)-(1S,3R)-3-(5-aminopyrazin-2-yl)cyclopentanol (15 mg, 0.084 mmol) was dissolved in acetonitrile (2 mL), then NBS (16.39 mg, 0.092 mmol) was added, the reaction mixture was stirred at room temperature for 30 min, water was added, the reaction mixture was then extracted by EtOAc, the organic was dried and concentrated, the crude material was used in next step reaction. LCMS (m/z): 258.1/260.2 (MH+), 0.45 min. Following the above method, using (+/−)-N,N-Di-tert-butyl (5-((1R,3S)-3-hydroxycyclopentyl)pyrazin-2-yl)carbamate, (+/−)-(1R,3R)-3-(5-amino-6-bromopyrazin-2-yl)cyclopentanol was obtained. LCMS (m/z): 258.1/260.1 (MH+), 0.50 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:23]=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:22]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([Cl:15])[CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)c(Cl)c2)CC1
Temperature: 120 °C
Yield: 44.8 %

Procedure:
A mixture of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (427 mg; 2.13 mmol), 2-chloro-4-fluoro-benzonitrile (302 mg; 1.94 mmol) and potassium carbonate (1.07 g; 7.76 mmol) is diluted in dimethylsulfoxide (5 mL) and is heated to 120° C. for 7 hours. After cooling to room temperature, the mixture is diluted with dichloromethane (50 mL) and is filtered. The filtrate is washed with 1N aq. hydrochlorid acid (2×15 mL), with water (20 mL) is then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is finally purified by column chromatography on silica gel (dichloromethane:methanol 1:0 and then 98:2) to afford the desired product (290 mg; 0.87 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=O)=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[CH3:16][C:17]([NH2:24])([C:19]1[N:23]=[CH:22][O:21][N:20]=1)[CH3:18]>>[CH3:16][C:17]([NH:24][C:13]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12]2)[N:6]=1)=[O:15])([C:19]1[N:23]=[CH:22][O:21][N:20]=1)[CH3:18]
Reactant: CC(C)(N)c1ncon1
Reactant: O=C(O)c1ccc(Cl)c(OCC2CC2)n1
Product: CC(C)(NC(=O)c1ccc(Cl)c(OCC2CC2)n1)c1ncon1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid and 1-methyl-1-[1,2,4]oxadiazol-3-yl ethylamine (CAN 1153757-41-5) as starting materials, MS (LC/MS): m/e=337.1 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([CH2:6][NH:7][C:8]([NH2:10])=[O:9])[NH:4][C:3]1=[O:11].C(=O)(O)[O-].[Na+].Cl.[Cl:18][CH2:19][C:20]([NH:22][C:23]1[S:24][CH:25]=[C:26](/[C:28](=[N:32]/[O:33][C:34]([CH3:49])([C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:37])[CH3:35])/[C:29](Cl)=[O:30])[N:27]=1)=[O:21]>O.O1CCCC1>[Cl:18][CH2:19][C:20]([NH:22][C:23]1[S:24][CH:25]=[C:26](/[C:28](=[N:32]/[O:33][C:34]([CH3:49])([C:36]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=2)=[O:37])[CH3:35])/[C:29]([NH:1][C@H:2]2[C@@H:5]([CH2:6][NH:7][C:8]([NH2:10])=[O:9])[NH:4][C:3]2=[O:11])=[O:30])[N:27]=1)=[O:21]
Reactant: CC(C)(O/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)NC[C@H]1NC(=O)[C@H]1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N[C@@H]1CNC(N)=O)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 66.4 %

Procedure:
A 350 mg portion of the thus-obtained cis-3-amino-4-ureidomethyl-2-azetidinone (433 mg) is dissolved in a mixture of 25 ml of water and 25 ml of tetrahydrofuran and, under ice-cooling and stirring, 628 mg of sodium bicarbonate is added. Then, 1.43 g of 2-(2-chloroacetamido-4-thiazolyl)-2-(Z)-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethoxyimino]acetyl chloride hydrochloride is added and the mixture is stirred at room temperature for 2 hours. The tetrahydrofuran is distilled off under reduced pressure, 50 ml of water is added to the residue, and the mixture is stirred. The crystalline precipitate is collected by filtration, washed with aqueous sodium bicarbonate, water and hexane in that order, and dried to give 1.1 g of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-(Z)-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethoxyimino]acetamido]-4-ureidomethyl-2-azetidinone as colorless crystals.
Reaction SMILES: [2H]C(S(C([2H])([2H])[2H])=O)([2H])[2H].[2H]O[2H].[Si](C)(C)(C)C.[C:19]([NH:22][C@@H:23]1[C@@H:31]([OH:32])[C@H:30]([O:33][C@@H:34]2[O:71][C@H:70]([CH2:72][O:73]C(=O)C)[C@H:45]([O:46][C@H:47]3[O:64][C@H:63]([CH2:65][O:66]C(=O)C)[C@H:58]([O:59]C(=O)C)[C@H:53]([O:54]C(=O)C)[C@H:48]3[O:49]C(=O)C)[C@H:40]([O:41]C(=O)C)[C@H:35]2[O:36]C(=O)C)[C@@H:29]([CH2:77][OH:78])[O:28][C@H:24]1[O:25][CH2:26][CH3:27])(=[O:21])[CH3:20]>>[C:19]([NH:22][C@@H:23]1[C@@H:31]([OH:32])[C@H:30]([O:33][C@@H:34]2[O:71][C@H:70]([CH2:72][OH:73])[C@H:45]([O:46][C@H:47]3[O:64][C@H:63]([CH2:65][OH:66])[C@H:58]([OH:59])[C@H:53]([OH:54])[C@H:48]3[OH:49])[C@H:40]([OH:41])[C@H:35]2[OH:36])[C@@H:29]([CH2:77][OH:78])[O:28][C@H:24]1[O:25][CH2:26][CH3:27])(=[O:21])[CH3:20]
Reactant: CCO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](COC(C)=O)[C@H](O[C@H]3O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@H](O)[C@H]1NC(C)=O
Agent: [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H]
Agent: [2H]O[2H]
Solvent: C[Si](C)(C)C
Product: CCO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1NC(C)=O
Yield: 82 %

Procedure:
Compound 87 (58 mg, 0.06 mmol) was O-deacetylated in methanolic sodium methoxide (0.036M, 5.5 ml) at room temperature for 21 h. The mixture was neutralized with Duolite C-26 (H) resin, filtered and concentrated. The residue was dissolved in water and lyophilized to give 88 (21 mg, 60%) with [α]D22 +25° (c 0.7, water). 1H-NMR [(CD3)2SO+D2O, 50°, Me4Si] δ inter alia 4.80 (d, 1H, J=3.5 Hz, H1"), 4.37 (d, 1H, J=8 Hz, H1 or H1'), 4.29 (d, 1H, J=7.5 Hz, H1 or H1'), 4.07 (bt, 1H, J~6.5 Hz), 1.81 (s, 3H, MeCON), 1.08 (t, 3H, J=7 Hz, CH3CH 2). 13C-NMR (D2O, TSP) δ 177.4, 106.1, 103.4, 103.1, 81.6, 80.1, 78.2, 77.7, 75.4, 75.0, 73.7, 73.6, 72.0, 71.7, 71.4, 69.1 (CH2), 63.3 (CH2), 63.2 (CH2), 62.9 (CH2), 58.1, 25.0, 17.1. b: Compound 86 (15 mg, 0.017 mmol) was O-deacetylated and worked-up as above to give 88 (8.0 mg, 81%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:16][C:17]1[C:20](=[O:21])[C:19](=O)[C:18]=1[NH:23][C:24]1[C:25]([OH:40])=[C:26]([CH:37]=[CH:38][CH:39]=1)[C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[C:34]([OH:36])=[O:35])=[O:28])C>CO.C(OCC)C>[OH:40][C:25]1[C:24]([NH:23][C:18]2[C:17](=[O:16])[C:20](=[O:21])[C:19]=2[NH:13][CH:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:8]2([CH3:12])[CH2:9][O:10][CH2:11]2)=[CH:39][CH:38]=[CH:37][C:26]=1[C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[C:34]([OH:36])=[O:35])=[O:28]
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Reactant: CCOc1c(Nc2cccc(C(=O)N3CCC[C@@H]3C(=O)O)c2O)c(=O)c1=O
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cccc(C(=O)N4CCC[C@@H]4C(=O)O)c3O)c(=O)c2=O)C2(C)COC2)o1
Reaction time: 72 h
Yield: 58.6 %

Procedure:
494 mg (2.73 mmol) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine in 3 ml of methanol were added to a solution of 500 mg (1.34 mmol) of (R)-1-[3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-benzoyl]pyrrolidine-2-carboxylic acid in 47 ml of methanol at 50° C. After 3 days, 248 mg (1.37 mmol) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine were added. After 4 days, the reaction medium was concentrated to dryness. The reaction medium was taken up in ethyl acetate and was washed with a saturated aqueous ammonium chloride solution and then with a 1 M aqueous solution of sodium dihydrogen phosphate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The solid obtained was taken up, with stirring, in diethyl ether and a little ethyl acetate and was filtered. 400 mg of a beige solid were obtained. This solid was chromatographed on silica gel (ethyl acetate/acetone/water: 50/50/2 then 50/50/5). 240 mg were obtained in the form of a beige solid. Yield=35%, HPLC=52.43%+45.15% (mixture of the two diastereoisomers), Mp=198-205° C.