Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C(O)C.[CH2:32]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[CH3:33]>>[CH2:32]([NH+:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[CH3:33].[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([O-:13])=[O:12])=[CH:5][CH:6]=1
Reactant: CCN(CC)CC
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCO
Product: CC[NH+](CC)CC
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1=Boc, R2=H, R3=CO2H) is added to ethanol (10 ml). Triethylamine (0.264 ml) is then added and the mixture is stirred at room temperature for 30 minutes. The mixture is then concentrated in vacuo to afford (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid triethylammonium salt (1-a, R1=Boc, R2=H, R3=CO2+[NHEt3]+). 1H NMR (DMSO-d6): 0.95 (9 H), 1.04 (3H), 1.32 (9H), 1.36 (1H), 1.74 (1H), 2.38-2.50 (7 H), 2.67 (2H), 3.65 (1H), 6.29 and 6.70 (1H), 7.23-7.25 (2H), 7.33-7.37 (1H), 7.43-7.48 (2H), 7.55-7.57 (2H), 7.62-7.64 (2H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]2[CH:5]3[CH:6]2[CH2:8][CH:3]1[CH:4]3[C:9]1[NH:17][C:16]2[C:15](=[O:18])[N:14]([CH2:19][CH2:20][CH3:21])[C:13](=[O:22])[N:12]([CH2:23][CH2:24][CH3:25])[C:11]=2[N:10]=1.[NH2:26]OS(O)(=O)=O.C([O-])(O)=O.[Na+]>CC(O)=O>[O:1]=[C:2]1[NH:26][CH:3]2[CH2:8][CH:6]3[CH:5]([CH:4]2[C:9]2[NH:17][C:16]4[C:15](=[O:18])[N:14]([CH2:19][CH2:20][CH3:21])[C:13](=[O:22])[N:12]([CH2:23][CH2:24][CH3:25])[C:11]=4[N:10]=2)[CH:7]13
Reactant: CCCn1c(=O)c2[nH]c(C3C4CC5C(C4=O)C53)nc2n(CCC)c1=O
Reactant: NOS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCn1c(=O)c2[nH]c(C3C4CC5C(C(=O)N4)C53)nc2n(CCC)c1=O
Temperature: 25 °C

Procedure:
8-(5-Oxo-tricyclo[2.2.1.02,6]hept-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (150 mg) was taken in HOAc (5 ml) and H2NOSO3H (100 mg) was added and refluxed for 5 hrs. Cooled to room temperature, treated with ice, sat NaHCO3, extracted with ethyl acetate, washed with brine, and dried over MgSO4. After concentration, the crude product was crystallized from acetone/water. Yield (135 mg). Mass (ES+358).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>CO>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccncc2NC(=O)c2c(N)nn3cc(F)cnc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1cnccc1C1CCNCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of tert-butyl 4-[3-[(2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]-4-pyridyl]piperidine-1-carboxylate (555 mg, 1.218 mmol) (prepared using a procedure similar to example 2) in MeOH (2.135 mL) and DCM (2.135 mL) was added TFA (6.2 g, 4.2 mL, 54 mmol) and the resulting solution stirred at rt for 96 h. The reaction mixture was concentrated in vacuo and taken up in methanol and DCM and passed through an 25 g SCX cartridge flushing with methanol (3 column volumes) followed by 2M ammonia in methanol (3 column volumes) to elute the product. The filtrate was concentrated in vacuo to leave 2-amino-6-fluoro-N-(4-(piperidin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid that was used directly in the next step without further purification. MS (ES+) 356.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:18])[S:17][C:13]=2[C:12]([C@@H:19]([OH:22])[CH2:20][Br:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:40]1[CH:45]=[CH:44][CH2:43][CH2:42][CH2:41]1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:18])[S:17][C:13]=2[C:12]([C@@H:19]([O:22][CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45][O:40]2)[CH2:20][Br:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2c(OCc3ccccc3)ccc([C@@H](O)CBr)c2s1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=c1[nH]c2c(OCc3ccccc3)ccc([C@H](CBr)OC3CCCCO3)c2s1

Procedure:
To a stirred solution of 4-(benzyloxy)-7-[(1R)-2-bromo-1-hydroxyethyl]-1,3-benzothiazol-2(3H)-one (31 mg) in dry DCM (5 ml) under nitrogen, was added pyridinium p-toluenesulphonate (5 mg), followed by 3,4-dihydro-2H-pyran (30 μl). The mixture was evaporated in vacuo after 18 h and purified on a 2 g silica SPE cartridge, eluting with a stepped gradient 10% to 100% DCM-cyclohexane mixtures, to give the title compound (42 mg). LCMS RT=3.72 and 3.78 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([Sn](CCCC)(CCCC)CCCC)=[CH2:29].[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[CH:28]=[CH2:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)c2cccc(OCc3ccccc3)c2n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=Cc1cc(C)nc2c(OCc3ccccc3)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A mixture of 8-benzyloxy-2-methyl-4-(trifluoromethanesulfonyloxy)quinoline (300 mg), vinyltributyltin (263 mg), tetrakis(triphenylphosphine)palladium (0) (43.6 mg) and lithium chloride (96 mg) in 1,4-dioxane (6 ml) was refluxed for three hours and then left at ambient temperature overnight. The mixture was diluted with ethyl acetate and was added silica gel (70-230 mesh, 5 g) and stirred at ambient temperature for half an hour. The silica gel was removed by filtration and the filtrate was concentrated in vacuo. The residue was chromatographed on a silica gel column eluting with ethyl acetate-n-hexane (1:4, V/V) to give a solid. This solid was crystallized from diisopropyl ether to give 8-benzyloxy-2-methyl-4-vinylquinoline (110 mg) as pale yellow solid.
Reaction SMILES: [C:1]1([C:7]#C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]([CH2:12][CH2:13][CH2:14][CH2:15]CCN1C=CC=C(OCC2C=CC=CC=2)C1=O)=[N+:10]=[N-:11].[C:33]1([N:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][C:47]3N=NN[CH:51]=3)=[C:41]([O:52]C)[C:40]2=[O:54])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1([N:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][CH2:51][CH2:15][CH2:14][C:13]3[N:11]=[N:10][NH:9][CH:12]=3)=[C:41]([O:52][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:40]2=[O:54])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: [N-]=[N+]=NCCCCCCn1cccc(OCc2ccccc2)c1=O
Reactant: COc1c(CCc2c[nH]nn2)ccn(-c2ccccc2)c1=O
Reactant: C#Cc1ccccc1
Product: O=c1c(OCc2ccccc2)c(CCCCCCc2c[nH]nn2)ccn1-c1ccccc1
Yield: 56 %

Procedure:
Reaction of phenylacetylene (0.80 g, 0.78 mmol) and 157e (0.21 g, 0.65 mmol) within 4 h as described for synthesis of 158a gave compound 158e (0.16 g, 56%) as a white solid. NMR (400 MHz, CDCl3) δ 7.66 (m, 3H), 7.20 (m, 8H), 6.68 (dd, J=6.9, 1.5 Hz, 1H), 6.46 (dd, J=7.4, 1.5 Hz, 1H), 5.82 (t, J=7.1 Hz, 1H), 4.92 (s, 2H), 4.18 (t, J=6.8 Hz, 2H), 3.75 (t, J=6.8 Hz, 2H), 1.76 (m, 2H), 1.56 (m, 2H), 1.19 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 157.64, 148.46, 147.27, 135.95, 130.36, 128.57, 128.48, 128.19, 127.72, 127.60, 126.96, 125.32, 119.37, 115.02, 104.37 70.45, 50.03, 49.35, 29.90, 28.66, 25.87, 25.78. HRMS (FAB) calcd for C26H29N4O2 [M+H]+ 429.2290. found 429.2291.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[CH:12]([C:14](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:15])=[O:13].C(OCC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:14]([CH3:15])[CH:12]=[O:13])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=O)cc1
Reactant: CC(C=O)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOc1ccc(C=C(C)C=O)cc1

Procedure:
A suspension of 4-ethoxybenzaldehyde (20 g, 0.133 mol) and α-formylethylidenetriphenylphosphorane (46.6 g, 0.146 mol) in dried toluene (400 ml) was heated with stirring at reflux under an atmosphere of nitrogen for 40 h. The mixture was cooled, diethyl ether added and filtered through a pad of celite. The filtrate was evaporated and the residue taken up in diethyl e;her and the resulting suspension purified on flash silica eluting with hexane-diethyl ether (4:1). The resulting oil was crystallised from hexane-diethyl ether to give 3-(4-ethoxyphenyl)-2-methylpropenaldehyde as yellow crystals.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][C:11]1([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1.[CH:25]([O:28][C:29]1[CH:30]=[C:31]([CH2:35][C:36](O)=[O:37])[CH:32]=[CH:33][CH:34]=1)([CH3:27])[CH3:26].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[OH:8][CH2:9][CH2:10][C:11]1([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][N:13]([C:36](=[O:37])[CH2:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH:25]([CH3:26])[CH3:27])[CH:30]=2)[CH2:12]1
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCCNC1
Reactant: CC(C)Oc1cccc(CC(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1cccc(CC(=O)N2CCCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
22.5 ml of triethylamine and then 22 g of the 3-(2-hydroxyethyl)-3-(3,4-dichlorophenyl)piperidine (-) prepared above according to PREPARATION III (f) are added to a solution of 16 g of 3-isopropoxyphenylacetic acid in 500 ml of CH2Cl2. The mixture is cooled to 0° C., 42.6 g of BOP are then added and the reaction mixture is allowed to warm up to room temperature. After 30 minutes, the mixture is concentrated under vacuum and the residue is taken up in ether and washed successively with water, a dilute solution of NaOH, a saturated solution of NaCl, a dilute solution of HCl, a saturated solution of NaCl and a solution of NaHCO3. The ether phase is dried over MgSO4, filtered and concentrated under vacuum to give 36 g of optically pure product.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[N:13]([CH:27]=[CH:28][N:29]=3)[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[NH:21][CH2:20]4)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1.ClC1N2C=CN=C2C(NC2C=CC(N3CCN(C(C)C)CC3)=CC=2)=CC=1.O.[OH-].[Li+]>CCO.CCOC(C)=O>[O:26]=[C:22]1[C:23]2[C:19](=[CH:18][C:17]([C:14]3[N:13]4[CH:27]=[CH:28][N:29]=[C:12]4[C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[CH:5][CH:6]=4)=[CH:16][CH:15]=3)=[CH:25][CH:24]=2)[CH2:20][NH:21]1
Reactant: COC(=O)c1ccc(Nc2ccc(-c3ccc4c(c3)CNC4=O)n3ccnc23)cc1
Agent: CC(C)N1CCN(c2ccc(Nc3ccc(Cl)n4ccnc34)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Nc2ccc(-c3ccc4c(c3)CNC4=O)n3ccnc23)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Crude 4-[5-(1-oxo-2,3-dihydro-1H-isoindol-5-yl)-imidazo[1,2-a]pyridin-8-ylamino]-benzoic acid methyl ester (500 mg, 1.256 mmol), prepared using methods similar to those described for compound 12, and lithium hydroxide hydrate (263.5 mg, 6.281 mmol) in solution in THF/water (1/1: 10 mL) is stirred at room temperature for 36 hours then heated 4 hours at 60° C. The mixture is concentrated and then acidified to pH 1 with aqueous 2N HCl. The resulting precipitate is filtrated to yield the title compound, which is used as such for the next step.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N[C:17](=[O:52])[C@H:18]([CH3:51])[CH2:19][C@H:20]([OH:50])[C@@H:21]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:22][C@@H:23]([CH:39]([CH3:41])[CH3:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH:26]=1)CCC>C(Cl)(Cl)Cl>[C:46]([O:45][C:43]([NH:42][C@H:21]([CH:20]1[CH2:19][C@@H:18]([CH3:51])[C:17](=[O:52])[O:50]1)[CH2:22][C@@H:23]([CH:39]([CH3:40])[CH3:41])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH:26]=1)=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(OCCCOC)c1)C(C)C)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C2C[C@@H](C)C(=O)O2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.02 g of p-toluenesufonic acid (monohydrate) are added to 5.6 g of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid (N-butyl)-amide (Example 32) in 240 ml of chloroform at room temperature and the mixture is stirred at room temperature for a further 18 hours. The reaction mixture is concentrated by evaporation and the residue is partitioned between diethyl ether and 0.1N hydrochloric acid. The organic phases are concentrated by evaporation and the title compound is obtained from the residue after FC (160 g of silica gel, eluant: ethyl acetate/hexane 1:1): Rf (ethyl acetate/hexane=2:1)=0.47; m.p. 86°-87° C.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:31][N:32]4[CH2:37][CH2:36][O:35][CH2:34][C:33]4=[O:38])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=CC=1>OS(C(F)(F)F)(=O)=O.C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[C:18]([CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][C:33]3=[O:38])[CH:19]=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCOCC4=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(CN3CCOCC3=O)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 80 °C
Yield: 54.6 %

Procedure:
A few drops of triflic acid were added to a solution of 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-((6-methoxy-3-pyridinyl)amino)-3-pyridinyl)methyl)-3-morpholinone (0.115 g, 0.174 mmol) in 2 mL of TFA at RT. The mixture was heated to 80° C. for 1 h. The reaction was cooled and concentrated, but not to dryness. A few ice cubes were added and saturated NaHCO3 (aq.) was added until pH=7. The yellow solid was filtered washed with water, CH2Cl2, MeOH and Et2O and collected and dried under vacuum. The aqueous layer was extracted with 3/1 CHCl3/n-BuOH (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with a gradient of 0% to 10% MeOH in CH2Cl2. This material was combined with the yellow solid collected above to provide 4-((5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-((6-methoxy-3-pyridinyl)amino)-3-pyridinyl)methyl)-3-morpholinone (0.040 g, 0.095 mmol, 54.6% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.76 (s, 1H); 8.70 (dd, J=2.15, 0.39 Hz, 1H); 8.53 (dd, J=2.54, 0.39 Hz, 1H); 8.24 (dd, J=2.05, 0.49 Hz, 1H); 8.13-8.19 (m, 1H); 7.88 (br. s., 1H); 7.72 (br. s., 1H); 6.82 (d, J=8.80 Hz, 1H); 4.52 (s, 2H); 4.10 (s, 2H); 3.84 (s, 3H); 3.79-3.83 (m, 2H); 3.27-3.32 (m, 2H); 2.43 (s, 3H). m/z (ESI, +ve ion) 423.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8](OCC)(OCC)[O:9][CH2:10][CH3:11]>Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:1]=[CH:8][O:9][CH2:10][CH3:11])[CH:3]=1
Reactant: Nc1cccnc1
Reactant: CCOC(OCC)OCC
Agent: Cl
Product: CCOC=Nc1cccnc1

Procedure:
A solution of 3-aminopyridine (20.0 g, 0.21 m) in excess triethyl orthoformate (100 ml) and ethanolic hydrogen chloride (0.3 ml) was heated under reflux for 72 hours. Ethanol and excess triethyl orthoformate were then removed by distillation over a period of 5 hours. Solid potassium carbonate (100 mg) was added to the residue, and the lasttraces of triethyl orthoformate were removed in vacuo. The residue was then distilled under reduced pressure to yield the desired imido ester, ethyl N-(3-pyridyl)-formimidate, as a colourless liquid, (b.p. 62°/0.5 mm)(24 g, 75%), n.m.r. (CDCl3): δ = 1.4 (t, --CH2CH3), 4.32 (q, --CH2CH3), 7.73 (s, --N=CH--O).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[C:7]([NH:11][C:12]([C:14]1[S:47][C:17]2[N:18]=[C:19]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29](OC4C=CC([N+]([O-])=O)=CC=4)=[O:30])[CH:23]=3)[C:16]=2[C:15]=1[NH2:48])=[O:13])([CH3:10])([CH3:9])[CH3:8]>ClCCl>[C:7]([NH:11][C:12]([C:14]1[S:47][C:17]2[N:18]=[C:19]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29]([N:1]4[CH2:6][CH2:5][S:4][CH2:3][CH2:2]4)=[O:30])[CH:23]=3)[C:16]=2[C:15]=1[NH2:48])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)NC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(NC(=O)Oc4ccc([N+](=O)[O-])cc4)c3)c2c1N
Reactant: C1CSCCN1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(NC(=O)N4CCSCC4)c3)c2c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiomorpholine (300 μl) was added to a solution of tert-butyl 5-amino-2-phenyl-4-(3-(p-nitro-phenoxycarbonylamino)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 31(h), 150 mg) in dichloromethane (5 ml) and the reaction mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was diluted with CH2Cl2 and washed with H2O. The organic layer was concentrated under reduced pressure. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: H2O/CH3CN=80/20 to 0/100 (v/v) in 45 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: [Cl:1][C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[C@H:11]([CH3:34])[C@@H:12]4[C@@H:29]([C@H:30]([OH:32])[CH3:31])[C:28](=[O:33])[N:13]4[C:14]=3[C:15]([O:17]CC3C=CC([N+]([O-])=O)=CC=3)=[O:16])=[CH:8]2)=[C:4]([C:35]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[O:36])[N:3]=1.[N+](C1C=CC(COC([NH:54][S:55]([NH:58][CH2:59][CH2:60][CH2:61]O)(=[O:57])=[O:56])=O)=CC=1)([O-])=O>>[Cl:1][C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[C@H:11]([CH3:34])[C@@H:12]4[C@@H:29]([C@H:30]([OH:32])[CH3:31])[C:28](=[O:33])[N:13]4[C:14]=3[C:15]([O-:17])=[O:16])=[CH:8]2)=[C:4]([C:35]([C:37]2[CH:38]=[N+:39]([CH2:61][CH2:60][CH2:59][NH:58][S:55](=[O:57])(=[O:56])[NH2:54])[CH:40]=[CH:41][CH:42]=2)=[O:36])[N:3]=1
Reactant: O=C(NS(=O)(=O)NCCCO)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4c(Cl)nc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4c(Cl)nc(C(=O)c5ccc[n+](CCCNS(N)(=O)=O)c5)c4s3)[C@H](C)[C@H]12
Yield: 29.3 %

Procedure:
The title compound (64 mg) was prepared in the same manner as in steps a) and b) of Example 4, except that 218 mg of 4-nitrobenzyl (1S,5R,6S)-2-[5-chloro-7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate and 160 mg of 3-(4-nitrobenzyloxycarbonylaminosulfonyl)aminopropanol were used as the starting compounds.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].[CH2:12]([NH:19][CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:12]([N:19]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11])[CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)c1ccc([N+](=O)[O-])cc1F
Yield: 66.7 %

Procedure:
A solution of 1,2-difluoro-4-nitro-benzene (0.96 g, 6.0 mmole) and benzyl methylamine (0.79 g, 6.6 mmole) in 4 mL of anhydrous DMF is heated with K2CO3 (0.41 g, 3.0 mmole) at 80° C. for 16 hours. After removal of the solvent, the residue is purified on flash chromatography with EtOAc/Hexanes (0-15%), yielding yellow oil 1.05 g (4.0 mmole) 67% of benzyl-(2-fluoro-4-nitro-phenyl)-methylamine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[CH:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=CC1CCCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCC1CCCN1C(=O)OC(C)(C)C

Procedure:
A solution of tert-butyl 2-(3-ethoxy-3-oxoprop-1-enyl)pyrrolidine-1-carboxylate (4 g, 14.9 mmol) and Pd/C (1 g, 10% weight) in MeOH was stirred at room temperature. Hydrogen from a balloon was ventilated to the suspension continuously and the completion of the reaction was monitored by TLC. After the suspension was filtered, the organic phases was concentrated to give the desired product, which was directly used for the next step without further purification. MS (ESI): 272 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32]Cl)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[CH2:39][OH:40]>COCCO.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:34]3[CH2:38][CH2:37][CH2:36][C@@H:35]3[CH2:39][OH:40])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: OC[C@H]1CCCN1
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Solvent: COCCO
Solvent: ClCCl
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCC[C@@H]4CO)c(OC)cc23)c2c1OCO2
Temperature: 110 °C
Yield: 182.6 %

Procedure:
N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (0.165 g) was dissolved in 2-methoxyethanol (5 ml) then (R)-(−)-2-pyrrolidinemethanol (0.516 g) was added and the mixture heated to 110° C. for 50 minutes. The reaction mixture was cooled to room temperature and diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol with methanolic ammonia as eluent. There was thus obtained the title compound (0.341 g) as a pale yellow gum; NMR Spectrum: (CDCl3) 1.761 (m, 3H), 1.88 (m, 1H), 2.12 (m, 2H), 2.30 (m, 1H), 2.48 (m, 1H), 2.63 (m, 1H), 3.04 (m, 1H), 3.21 (m, 1H), 3.39 (dd, 1H), 3.46 (s, 3H), 3.64 (dd, 1H), 3.98 (s, 3H), 4.25 (m, 2H), 4.35 (s, 2H), 6.07 (s, 2H), 7.01 (s, 1H), 7.06 (s, 1H), 7.12 (s, 1H), 7.28 (s, 1H), 8.62 (s, 1H). Mass Spectrum: M+H+ 555/557.