Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH2:3][C:4]1[CH:41]=[CH:40][CH:39]=[CH:38][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[O:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]3)=[CH:21][CH:20]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:27]1[CH2:28][CH2:29][O:30][CH:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:38]=[CH:39][CH:40]=[CH:41][C:4]=4[CH2:3][C:2]([NH2:1])=[O:42])[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][N:11]=3)=[CH:20][CH:21]=2)[CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CNCCO3)cc2)ncc1C(F)(F)F
Yield: 89.8 %

Procedure:
tert-Butyl 2-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholine-4-carboxylate (I91) (23 mg, 0.039 mmol) was stirred with DCM (3 mL) and TFA (0.3 mL). After 18 hours the mixture was concentrated and the residue suspended in 10% aqueous NaOH (1 mL) and brine (1 mL). The mixture was extracted with ethyl acetate (5×3 mL), and the combined ethyl acetate phases washed with brine (20 mL), dried over sodium sulfate and evaporated to give the title compound (22) (17 mg, 89%) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.19 (s, 1H), 8.67 (s, 1H), 7.74-7.67 (m, 2H), 7.42 (s, 1H), 7.27 (d, J=8.6 Hz, 2H), 7.25-7.21 (m, 1H), 7.19-7.14 (m, 3H), 6.91 (s, 1H), 4.32 (dd, J=10.1, 2.1 Hz, 1H), 3.86 (d, J=10.9 Hz, 1H), 3.58 (dt, J=11.2, 7.2 Hz, 1H), 3.50 (s, 2H), 3.15-2.98 (m, 4H), 2.89 (dd, J=12.3, 2.2 Hz, 1H), 2.72 (d, J=5.2 Hz, 2H). LCMS Method C: rt 4.75 min; m/z 486.1 [M+H]+, 508.0 [M+Na]+; m/z 484.1 [M−H]−.
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=[O:5])[CH3:4].[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:11]>C1COCC1.C(O)C.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH2:9][C:3](=[O:5])[CH3:4])=[CH:13][CH:14]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(C(C)=O)cc1
Agent: [H-]
Agent: [Na+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a 0° C. suspension of sodium hydride (853 mg, 21.8 mmol, 60% oil dispersion) in THF (13 mL) is added ethyl acetate (2.03 mL, 20.8 mmol). The reaction is stirred at room temperature for 1 h. A solution of 4-methoxyacetophenone (1.56 g, 10.4 mmol), dibenzo-18-crown-6 (62 mg, 0.016 mmol) and ethanol (2 drops) in THF (13 mL) is added dropwise and the reaction mixture is heated to reflux. After 3 h, the reaction is cooled to room temperature, quenched with saturated aqueous NH4Cl, and concentrated under reduced pressure. The residue is partitioned between EtOAc (200 mL) and water (50 mL). The aqueous layer is extracted with EtOAc (200 mL) and the combined organic layers are washed with brine, dried (MgSO4), filtered, and concentrated. The residue is purified via chromatography (0 to 20% EtOAc/Hexanes) to yield the title compound (1.62 g, 81%). GC-ES/MS m/e 192
Reaction SMILES: [I-].[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:14]([N:16]1[CH:21]=[CH:20]C(=[N+](C)C)[CH:18]=[CH:17]1)=[O:15])[CH2:3][CH2:4][CH3:5].N1CC[O:28]CC1>O1CCOCC1>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:14]([N:16]1[CH2:21][CH2:20][O:28][CH2:18][CH2:17]1)=[O:15])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN1C(C)=C(C)S/C1=C\C(=O)n1ccc(=[N+](C)C)cc1
Reactant: C1COCCN1
Agent: [I-]
Solvent: C1COCCO1
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)N1CCOCC1
Temperature: 80 °C

Procedure:
A mixture of product from Example 4 (46 mg, 0.1 mmol) and morpholine (175 mg, 2 mmol) in dioxane (10 mL) was heated to 80° C. for 2 hours then concentrated in vacuo. Column chromatography over silica gel (CH2Cl2-MeOH 4:1) provided the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (t, J=7 Hz, 3H), 1.32 (sextet, J=7 Hz, 2H), 1.53 (quintet, J=7 Hz, 2H), 2.00 (s, 3H), 2.05 (s, 3H), 3.29 (t, J=6 Hz, 4H), 3.55 9t, J=6 Hz, 4H), 3.72 (t, J=7 Hz, 2H), 5.30 (s, 1H); MS (ESI) m/z 297 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:29][S:30][CH3:31])[CH:24]=[C:25]([F:28])[CH:26]=3)[NH:21][CH:20]=2)[CH:9]2C(=O)O[C:12](C)([CH3:16])[O:11][C:10]2=[O:18])=[C:4]([CH3:32])[CH:3]=1>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:29][S:30][CH3:31])[CH:24]=[C:25]([F:28])[CH:26]=3)[NH:21][CH:20]=2)[CH2:9][C:10]([O:11][CH2:12][CH3:16])=[O:18])=[C:4]([CH3:32])[CH:3]=1
Reactant: CSCc1cc(F)cc2c(C(c3ccc(Cl)cc3C)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(Cl)cc1C)c1c[nH]c2c(CSC)cc(F)cc12
Yield: 31.5 %

Procedure:
2.1 mg (34 μmol) of copper powder were added to a solution of 2.48 g of the compound from Example 92A in 28 ml of pyridine and 8 ml of ethanol. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the crude product was purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient) to result in 0.69 g of the title compound.
Reaction SMILES: C(C[C@@H]1N(C2C=CC(O[CH:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[CH:24][C:23]=4[F:31])[CH2:18][CH2:17]3)=CC=2)N=C(C2C=CC(C#N)=CC=2)[C@H]1C)#N.C([CH2:43][C@@H:44]1[N:48]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)[N:47]=[C:46]([C:56]2[CH:63]=[CH:62][C:59]([C:60]#[N:61])=[CH:58][CH:57]=2)[C@H:45]1[CH3:64])#N.C(OC1C=CC(F)=C(N2CCC(O)CC2)C=1)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC([O:105][C:106](/N=N/C(OC(C)(C)C)=O)=[O:107])(C)C>C1COCC1.CCOC(C)=O>[C:60]([C:59]1[CH:62]=[CH:63][C:56]([C:46]2[C@@H:45]([CH3:64])[C@H:44]([CH2:43][C:106]([OH:107])=[O:105])[N:48]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH:16]4[CH2:17][CH2:18][N:19]([C:22]5[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[CH:24][C:23]=5[F:31])[CH2:20][CH2:21]4)=[CH:51][CH:50]=3)[N:47]=2)=[CH:57][CH:58]=1)#[N:61]
Reactant: CCOc1ccc(F)c(N2CCC(Oc3ccc(N4N=C(c5ccc(C#N)cc5)[C@@H](C)[C@@H]4CC#N)cc3)CC2)c1
Reactant: C[C@@H]1C(c2ccc(C#N)cc2)=NN(c2ccc(O)cc2)[C@H]1CC#N
Reactant: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: CCOc1ccc(F)c(N2CCC(O)CC2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccc(F)c(N2CCC(Oc3ccc(N4N=C(c5ccc(C#N)cc5)[C@@H](C)[C@@H]4CC(=O)O)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 74 %

Procedure:
4-((4S,5S)-5-(Cyanomethyl)-1-(4-((1-(5-ethoxy-2-fluorophenyl)piperidin-4-yl)oxy)phenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile: To a stirred solution of 4-((4S,5S)-5-(cyanomethyl)-1-(4-hydroxyphenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile (310 mg, 0.970 mmol), 1-(5-ethoxy-2-fluorophenyl)piperidin-4-ol (368 mg, 1.492 mmol) and triphenylphosphine (420 mg, 1.585 mmol) in THF (5.8 mL) at rt was added di-tert-butylazodicarboxylate (375 mg, 1.596 mmol). The resulting solution was stirred at rt for 25 h and then evaporated. The residue was purified by two consecutive chromatographies (SiO2, first 95/5 CHCl3/Ether and then 4/1 to 3/2 Hex/EtOAc) to give the desired product (390 mg, 74.0% yield) as a yellow oil: LC-MS [M+H] 538.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN([CH2:18][CH3:19])CC.F[C:21]([C:24](Br)([C:31]([F:34])([F:33])[F:32])[C:25]1[CH:30]=[CH:29]C=CC=1)(F)F>ClCl>[F:32][C:31]([F:34])([F:33])[C:30]1[CH:29]=[C:18]([CH2:19][N:11]2[CH2:10][CH2:9][NH:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12]2)[CH:21]=[C:24]([C:31]([F:32])([F:33])[F:34])[CH:25]=1
Reactant: FC(F)(F)C(Br)(c1ccccc1)C(F)(F)F
Reactant: CCN(CC)CC
Reactant: c1ccc(C2CNCCN2)cc1
Agent: ClCl
Product: FC(F)(F)c1cc(CN2CCNC(c3ccccc3)C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 145.4 %

Procedure:
To a solution of 2-phenylpiperazine (4.0 gram, 24.65 mmol) in dry CH2 Cl2 (200 ml) at -78° C. under nitrogen was added Et3N (5.15 ml, 36.97 mmol) followed by the dropwise addition of a CH2 Cl2 solution(46.60 ml) of bis(trifluoromethyl)benzyl bromide (4.66 ml, 24.65 mmol). The flask was kept at -78° C. then it was gradually warmed to room temperature overnight. After TLC showed that the reaction was complete, the material was washed with brine (150 ml, 2×), dried over MgSO4, filtered, and evaporated under vacuum to yield a tan solid. The crude product was purified by flash silica gel chromatography (150 g), eluting with 2.5% MeOH/CH2Cl2 to give (±) 1-[[3,5-bis(trifluoromethyl)phenyl]methyl]-3-phenyl-piperazine (6.96 gram, 17.92 mmol, 72.7%) as an oil. A portion of this oil (0.5 gram, 1.287 mmol)) was converted to its hydrochloride salt by dissolving the oil in CH2Cl2 (20 ml) and treating with 2.3M HCl-EtOH (1.3 ml, 2.99 mmol). After stirring at room temperature for 10 minutes, all solvents were removed under high vacuum and the residue was dried overnight, m.p. 229°-233° C.; FAB mass [M+1]+ 389;
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][O:9][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[N:7]=1
Reactant: OCc1cccc(Br)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10 g of (6-bromo-pyridin-2-yl)methanol in 50 ml of N,N-dimethylformamide were successively added 4 g of imidazole and 8.4 g of tert-butyldimethylsilyl chloride at room temperature, followed by stirring the reaction mixture at room temperature for 2 hours. After adding water to the reaction mixture, the mixture was extracted with n-hexane. The resulting hexane solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as colorless oil.
Reaction SMILES: [CH2:1]=[N:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[C:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)#[N:12]>C1(C)C=CC=CC=1>[C:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17]2[O:18][CH:1]=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:15][CH:14]=1)#[N:12]
Reactant: C=NCC(=O)OCC
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncoc1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
A solution of ethyl 2-(methylideneamino)acetate (1.7 g, 14.77 mmol, 1.00 equiv) was added dropwise to a stirred mixture of sodium hydride (60%, 722 mg, 18.05 mmol, 1.22 equiv) in toluene (30 mL) at 5° C. The mixture was stirred at room temperature for 30 min. 4-cyanobenzoyl chloride (3 g, 18.12 mmol, 1.22 equiv) was then added dropwise at 5° C. The reaction was stirred at room temperature for 12 h then quenched with 30 mL of ice-water mixture. The resulting mixture was extracted with 2×15 mL of ethyl acetate. The combined organic layers was washed with 1×30 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-30% of ethyl acetate in petroleum ether to give 1.3 g (36%) of ethyl 5-(4-cyanophenyl)oxazole-4-carboxylate as a red solid. 1H-NMR (300 MHz, CDCl3): δ 8.29-8.26 (m, 2H), 8.00 (s, 1H), 7.91-7.77 (m, 2H), 4.48-4.41 (m, 2H), 1.46-1.41 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].CCN(CC)CC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:8][CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: OCC1CCCCO1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(OCC1CCCCO1)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A CH2Cl2 solution of (tetrahydro-2H-pyran-2-yl)methanol (7.91 g, 68.1 mmol), Et3N (14 mL, 102 mmol), and catalytic DMAP was treated with 4-bromobenzenesulfonyl chloride (14.3 g, 74.9 mmol). After 2 h, the reaction was quenched with water. The organic layer was washed with 1M HCl and brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by chromatography on silica gel (EtOAc/Hex) to afford ((tetrahydro-2H-pyran-2-yl)methyl 4-bromobenzenesulfonate as an oil (16 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][CH2:28]/C=C/C)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:36]CC1.[CH3:40][C:41]([CH3:43])=[O:42]>C(O)(C)(C)C.O.[Os](=O)(=O)(=O)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][CH2:28][CH:40]([OH:36])[CH:41]([OH:42])[CH3:43])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C/C=C/COc1nc(N2CCN(C(=O)OCc3ccccc3)CC2)nc2ccccc12
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC(C)(C)O
Product: CC(O)C(O)COc1nc(N2CCN(C(=O)OCc3ccccc3)CC2)nc2ccccc12

Procedure:
A mixture of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[trans-(2-buten-1-yl)oxy]quinazoline (1.30 g), a solution of osmium tetroxide in t-butanol (osmium tetroxide 106 mg/t-butanol 8.36 g) (312 mg) and 4-methylmorpholine N-oxide (382 mg) in water (2 ml)--acetone (15 ml) is stirred at room temperature for 14 hours. Acetone is distilled off from the reaction mixture under reduced pressure, and the resultant product is diluted with ethyl acetate, and the mixture is washed with 10% aqueous sodium sulfite solution and water. The ethyl acetate solution is dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography (eluent, chloroform:methanol=100:1, v/v) to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(2RS,3RS)-(2,3-dihydroxybutan-1-yl)oxy]quinazoline (1.02 g) as foam.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:41])[CH2:19][N:20]2[C:26](=[O:27])[C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[CH:23](CC(OC)=O)[C:22]3[CH:37]=[CH:38][CH:39]=[CH:40][C:21]2=3)=[CH:12][CH:11]=1.[OH-:42].[K+].[O:44]1[CH2:49][CH2:48]OCC1.O>>[C:49]([O:44][CH:23]1[C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[C:26](=[O:27])[N:20]([CH2:19][C:18]([NH:17][CH2:16][C:13]2[CH:14]=[N:15][C:10]([C:2]3[NH:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)=[CH:11][CH:12]=2)=[O:41])[C:21]2[CH:40]=[CH:39][CH:38]=[CH:37][C:22]1=2)(=[O:42])[CH3:48]
Reactant: [OH-]
Reactant: C1COCCO1
Reactant: COC(=O)CC1c2ccccc2C(=O)N(CC(=O)NCc2ccc(-c3nc4ccccc4[nH]3)nc2)c2ccccc21
Agent: [K+]
Solvent: O
Product: CC(=O)OC1c2ccccc2C(=O)N(CC(=O)NCc2ccc(-c3nc4ccccc4[nH]3)nc2)c2ccccc21

Procedure:
Methyl {5-[2-({[6-(1H-benzimidazol-2-yl)-3-pyridinyl]methyl}-amino)-2-oxoethyl]-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl}acetate (1.4 g) was dissolved in 30 ml of 5:1 dioxane/H2O and, after addition of 2.15 eq. of KOH (0.2 g), heated to reflux. After the reaction was complete (12 h), the mixture was evaporated, and the resulting crude product was purified by MPLC (silica gel: Bischoff Prontoprep 60–2540-C18E, 32 μm; eluent: CH3CN/H2O+0.1% acetic acid) and then lyophilized.
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]([CH3:28])[O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH:16]=1)[C:12]#N)([CH3:4])([CH3:3])[CH3:2].[OH2:29].[OH-:30].[Na+]>C(O)C>[C:1]([O:5][CH2:6][C@H:7]([CH3:28])[O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH:16]=1)[C:12]([OH:30])=[O:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: O
Reactant: C[C@@H](COC(C)(C)C)Oc1cc(C#N)cc(Oc2ccc(S(C)(=O)=O)cc2)c1
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](COC(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Yield: 69.9 %

Procedure:
3-[(1S)-2-tert-Butoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]benzonitrile (23.7 mmol; 9.56 g) was dissolved in ethanol (95.60 ml), and transferred to a 250 ml round bottomed flask, using ethanol (5 ml) to wash the residual solid from the flask. Water (6.25 ml) and sodium hydroxide (118.5 mmol; 6.30 ml) was added and the reaction was heated to reflux for 18 hours. The ethanol was removed in vacuo. The residual yellow suspension was dissolved in MTBE (162.5 ml) and water (162.5 ml). The two layers were separated, the MTBE layer was discarded and the aqueous layer was acidified with 2M HCl (100 ml). The aqueous layer was extracted twice with MTBE (162.5 ml). The organic extracts were combined and dried with magnesium sulfate, the MTBE was removed in vacuo, to give the desired product (7.0 g, 69.9% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].Cl.[CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19]Cl)([CH3:16])[CH3:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][CH2:18][N:17]([CH:21]([CH3:23])[CH3:22])[CH:14]([CH3:16])[CH3:15])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: Cl
Product: CC(C)N(CCN1C(=O)C(=O)c2cc(Br)ccc21)C(C)C
Yield: 82.9 %

Procedure:
By using 5-bromoisatin and 2-diisopropylaminoethyl chloride hydrochloride, a method analogous to that described in Reference Example 7 was carried out to obtain 5-bromo-1-(2-diisopropylaminoethyl)isatin having a melting point of 91°-93° C. (yield: 82.9%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][C:18]([O:20][CH2:21][CH3:22])=[CH:17][C:16]3=[O:23])[C:7]=2[CH:24]=1)#[N:2].N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].O>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[C@@H:9]([O:14][C:31](=[O:33])[CH3:32])[C@H:8]([N:15]3[CH2:19][C:18]([O:20][CH2:21][CH3:22])=[CH:17][C:16]3=[O:23])[C:7]=2[CH:24]=1)#[N:2]
Reactant: CCOC1=CC(=O)N([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCOC1=CC(=O)N([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2OC(C)=O)C1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a suspension of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-3-hydroxy-4-(4-ethoxy-2-oxo-3-pyrrolin-1-yl)-2H-1-benzopyran (0.5 g) in 25 ml of methylene chloride at 0° C. was added pyridine (0.415 g) and acetic anhydride (0.56 g), and the mixture stirred at room temperature for 5 days. The reaction mixture was then stirred with a mixture of 50 ml of water and 40 ml of methylene chloride. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and solvent removed under reduced pressure. The residue was triturated with ether followed by pentane to give 6-cyano-3,4-dihydro-2,2-dimethyl-trans-3-acetyloxy-4-(4-ethoxy-2-oxo-3-pyrrolin-1-yl)-2H-1-benzopyran, m.p. 156° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].[CH3:15][O:16][CH2:17][CH2:18][NH2:19].O>C(O)CCC>[CH3:15][O:16][CH2:17][CH2:18][NH:19][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(-c2ccccc2)nnc1Cl
Reactant: COCCN
Solvent: CCCCO
Solvent: O
Product: COCCNc1nnc(-c2ccccc2)cc1C

Procedure:
A mixture of 7 g of 3-chloro 4-methyl 6-phenyl pyridazine and 7 g of 2-methoxy ethylamine in 50 ml of butanol is taken to reflux for 4 days. The hot solution is poured into 200 ml of water and extracted with ethyl acetate. The organic solution is dried over magnesium sulfate then evaporated to dryness.
Reaction SMILES: [N:1]([C:4]1[N:9]=[C:8]([NH:10][CH3:11])[C:7]([C:12]#N)=[CH:6][N:5]=1)=[N+]=[N-].[H][H].C(O)=[O:17]>[Ni]>[NH2:1][C:4]1[N:9]=[C:8]([NH:10][CH3:11])[C:7]([CH:12]=[O:17])=[CH:6][N:5]=1
Reactant: O=CO
Reactant: [H][H]
Reactant: CNc1nc(N=[N+]=[N-])ncc1C#N
Agent: [Ni]
Product: CNc1nc(N)ncc1C=O
Reaction time: 0.5 h

Procedure:
To a suspension of 2-azido-5-cyano-4-methylamino-pyrimidine (22.24 g) from Example 5 in 400 mL of 50% aqueous formic acid was added Raney Nickel catalyst (5 g). The reaction mixture was shaken under an atmosphere of hydrogen (40.1 psi) in a Parr hydrogenation apparatus. There was a vigorous evolution of gas as the mixture was shaken at room temperature. After 30 minutes the apparatus was vented, additional Raney Nickel (5 g) was added, the apparatus recharged with hydrogen, and the mixture shaken overnight. The catalyst was removed by filtration and the filtrate was evaporated under high vacuum. The residue was suspended in water and filtered. The insoluble material was collected and dissolved in 450 mL of boiling water. The aqueous solution was filtered and the pH of the filtrate was adjusted to 7 with 1N sodium hydroxide. The precipitated product was collected by filtration and recrystallized from ethanol to give 5.0 g of 2-amino-4-methylamino-5-pyrimidinecarboxaldehyde.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[OH:19][C:20]1[CH:21]=[C:22]([C:27]2[C:28](=[S:33])[NH:29][CH:30]=[N:31][CH:32]=2)[CH:23]=[CH:24][C:25]=1[OH:26].B(F)(F)F.CCOCC>S1(CCCC1)(=O)=O.ClCCl>[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C@@H:9]1[S:14][CH2:15][C:6]([CH2:5][S:33][C:28]1[C:27]([C:22]3[CH:23]=[CH:24][C:25]([OH:26])=[C:20]([OH:19])[CH:21]=3)=[CH:32][N:31]=[CH:30][N:29]=1)=[C:7]2[C:16]([OH:18])=[O:17]
Reactant: Oc1ccc(-c2cnc[nH]c2=S)cc1O
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: ClCCl
Solvent: O=S1(=O)CCCC1
Solvent: CCOCC
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3ncncc3-c3ccc(O)c(O)c3)CS[C@H]12
Yield: 88.8 %

Procedure:
7-Aminocephalosporanic acid (220 mg) (0.81 mmol) and 250 mg (1.04 mmol) of 5-(3,4-dihydroxyphenyl)-4(3H)-pyrimidinethione are suspended in 8 ml of sulpholane/dichloromethane (1:1 v/v) and treated with 5 ml of boron trifluoride diethyl etherate while stirring. After 18 hours the mixture is concentrated in a vacuum and the residue is washed with diethyl ether. Then, 2 ml of ethanol and 4 ml of water are added thereto and sodium hydrogen carbonate is added until pH 5 has been reached. The product is filtered off under suction, washed with water and diethyl ether and dried in a high vacuum at room temperature. There are obtained 311 mg of (6R,7R)-7-amino-3-[[[5-(3,4-dihydroxyphenyl)-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:22]([CH3:23])=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][C:16]=2[CH3:24])[C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:16]([CH3:24])=[CH:17][C:18]([CH2:19][OH:20])=[CH:21][C:22]=2[CH3:23])[C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C=O)cc2C)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(CO)cc2C)c1C
Temperature: 25 °C

Procedure:
A mixture of 4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzaldehyde and sodium borohydride in methanol was stirred at room temperature. After standard work-up procedure and purification, the title compound was obtained as a solid. 1H NMR(CDCl3) d 7.06(s,2H), 6.08(s,1H), 4.64(s,2H), 3.74(d,1H), 3.33(m,1H), 2.14(s,3H), 2.13(s,3H), 2.11 (s,6H) ppm.