Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:18]1[CH2:22][CH2:21][C:20](=[O:23])[O:19]1)[CH2:10][C@H:11]([CH3:17])[CH2:12][CH2:13]C(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.O>C1C=CC=CC=1.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH:18]1[CH2:22][CH2:21][C:20](=[O:23])[O:19]1)[CH2:10][CH:11]([CH3:17])[CH:12]=[CH2:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](CCC(=O)O)CC(NC(=O)OC(C)(C)C)C1CCC(=O)O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: C=CC(C)C[C@H](NC(=O)OC(C)(C)C)C1CCC(=O)O1
Temperature: 25 °C

Procedure:
A mixture of 2.19 g (6.67 mmol) (R)-6-tert-butoxycarbonylamino-4-methyl-6-(5-oxo-tetra-hydro-furan-2-yl)-hexanoic acid, 0.293 g (1.46 mmol) copper(II)acetate monohydrate, 0.2 ml pyridine and 5.4 g (12.0 mmol) Pb(OAc)4 in 45 ml benzene is refluxed under nitrogen for 18 h. The mixture is cooled to rt, water is added and the organic phase is washed with water and 5% aqueous NaHCO3. The organic phase is dried with Na2SO4, filtered and evaporated. The residue is purified by chromatography on silica gel (EtOAc/hexane 1:6 and 1:4) to yield the title compound.
Reaction SMILES: C1(S(O)(=O)=[O:8])C=CC=CC=1.[C:11]([NH:14][NH2:15])(=O)[CH3:12].[F:16][C:17]([F:45])([F:44])[C:18]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23](=[C:28]1[C:41]3[CH:40]=[CH:39][C:38]([C:42]#[N:43])=[CH:37][C:36]=3[O:35][C:34]3[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:24]2)=[O:19].[OH-].[Na+]>CO>[CH3:12][C:11]1[NH:43][C:42]([C:38]2[CH:39]=[CH:40][C:41]3[C:28](=[C:23]4[CH2:22][CH:21]5[NH:20][CH:25]([CH2:26][CH2:27]5)[CH2:24]4)[C:29]4[C:34]([O:35][C:36]=3[CH:37]=2)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:15][N:14]=1.[C:18]([OH:8])([C:17]([F:45])([F:44])[F:16])=[O:19]
Reactant: N#Cc1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Reactant: O=S(=O)(O)c1ccccc1
Reactant: CC(=O)NN
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nnc(-c2ccc3c(c2)Oc2ccccc2C3=C2CC3CCC(C2)N3)[nH]1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of compounds 11a (0.029 g, 0.125 mmol) and 5e (0.051g, 0.124 mmol) was exposed to microwave irradition (300 W) at 200° C. for 10 min. After cooling, MeOH (1 mL) and 1N NaOH (1 mL) were added to the reaction mixture and the mixture was stirred at rt for 30 min. The crude product was purified by reverse phase HPLC to yield compound 35 as a TFA salt. MS m/z (MH+) 371.0; 1H NMR (CH3OH-d4) δ 1.40 (d, 2H), 1.85 (m, 2H), 1.41 (s, 3H), 3.02 (m, 4H), 3.91 (m, 2H), 7.19 (m, 4H), 7.33 (d, 2H), 7.84 (d, 1H), 7.85 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]3[CH:19]=[N:20][C:21]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[CH:22][CH:23]=3)[CH:12]=2)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.I[CH2:50][C:51]([NH2:53])=[O:52]>O>[NH2:53][C:51](=[O:52])[CH2:50][N:20]1[C:21](=[N:24][S:25]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][C:18]([O:17][C:13]2[CH:12]=[C:11]([NH:10][C:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[O:9])[CH:16]=[CH:15][CH:14]=2)=[CH:19]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4ncccc4C)c3)cn2)cc1
Reactant: NC(=O)CI
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc(NC(=O)c4ncccc4C)c3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A mixture of 3-methyl-N-{3-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}pyridine-2-carboxamide (12.4 g, 26.2 mmol), N,N-diisopropylethylamine (6.00 mL, 34.4 mmol) and N,N-dimethylformamide (100 mL) was stirred at room temperature for 1 hr. Iodoacetamide (6.29 g, 34.0 mmol) was added, and the mixture was stirred at room temperature for 71 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (9.72 g, 70%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)[CH3:3].[H-].[Na+].Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][C:12]2[C:13]3=[N:18][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][N:14]3[CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)c1ccc(C#Cc2cccnc2N)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1ccc(C#CC2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
A mixture of 3-{[4-(1-methylethyl)phenyl]ethynyl}pyridin-2-amine (150 mg) in dehydrated THF (5 mL) was added to a mixture of sodium hydride (60%, 127 mg) and 2-chloroethanesulfonyl chloride (310 mg) in dehydrated THF (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr, and saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added. The resulting precipitate was collected by filtration, and washed with water and ethyl acetate to give the title compound (110 mg) as a white solid. The obtained solid was crystallized from acetonitrile and diisopropyl ether to give a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:29])[CH2:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([N:19]3[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][OH:28])[CH2:21][CH2:20]3)=[O:18])[CH2:13][CH2:12]2)=[N:6][CH:7]=1.[CH3:30][CH2:31][CH2:32][CH2:33][N:34]=[C:35]=[O:36]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:29])[CH2:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([N:19]3[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][O:28][C:35](=[O:36])[NH:34][CH2:33][CH2:32][CH2:31][CH3:30])[CH2:21][CH2:20]3)=[O:18])[CH2:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: CN(CC[C@H]1CC[C@H](C(=O)N2CCCN(CCO)CC2)CC1)c1ncc(Br)cn1
Reactant: CCCCN=C=O
Solvent: ClCCl
Product: CCCCNC(=O)OCCN1CCCN(C(=O)[C@H]2CC[C@H](CCN(C)c3ncc(Br)cn3)CC2)CC1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of 0.10 g (0.21 mmol) of trans-(4-{2-[(5-bromo-pyrimidin-2-yl)-methyl-amino]-ethyl}-cyclohexyl)-[4-(2-hydroxy-ethyl)-[1,4]diazepan-1-yl]-methanone in 2 mL of CH2Cl2 was cooled (0° C.) and treated with 0.048 mL (0.43 mmol, 2 eq) of N-butyl isocyanate. After 20 h and 48 h the reaction was again cooled (0° C.) and treated with 0.048 mL (0.43 mmol, 2.0 eq) and 0.024 mL (0.21 mmol, 2.0 eq) of N-butyl isocyanate, respectively. The reaction was evaporated and dissolved in 5 mL of CH2Cl2/0.5 mL of MeOH and stirred for 1.5 h. After evaporation, the reaction was purified by flash-chromatography on 5 g silica gel (CH2Cl2:MeOH 99:1 to 4:1) to give 0.081 g (68%) of pure trans-butyl-carbamic acid 2-[4-(4-{2-[(5-bromo-pyrimidin-2-yl)-methyl-amino]-ethyl}-cyclohexanecarbonyl)-[1,4]diazepan-1-yl]-ethyl ester, MS: 567 (MH+, 1Br).
Reaction SMILES: Cl.Cl.[CH3:3][CH:4]1[O:8][C:7]2[CH:9]=[C:10]([NH2:14])[C:11]([NH2:13])=[CH:12][C:6]=2[O:5]1.[OH-].[K+].C(O[C:20]([S-])=[S:21])C.[K+].C(O)(=O)C>C(O)(C)C.O>[CH3:3][CH:4]1[O:5][C:6]2=[CH:12][C:11]3[NH:13][C:20]([SH:21])=[N:14][C:10]=3[CH:9]=[C:7]2[O:8]1
Reactant: CC1Oc2cc(N)c(N)cc2O1
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1Oc2cc3nc(S)[nH]c3cc2O1
Yield: 87 %

Procedure:
9.9 g of 2-methyl-1,3-benzodioxole-5,6-diamine dihydrochloride were suspended in 125 ml of isopropanol. While stirring there was added dropwise thereto a solution of 4.75 g of potassium hydroxide in 40 ml of water and the mixture was stirred at room temperature for an additional 30 minutes. After adding 7.5 g of purified potassium ethylxanthate, the solution was boiled at reflux overnight, then diluted with 125 ml of water and made neutral with a small amount of glacial acetic acid. The cooled suspension was filtered under suction and the crystals were washed well with water. There were obtained 7.5 g (87.4% of theory) of 2-methyl-5H-1,3-dioxolo(4,5-f)benzimidazole-6-thiol with a melting point above 300° C.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.CN(C=O)C.[C:24]([O:28][C:29](=[O:44])[NH:30][C@H:31]([C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[C:37]([F:43])[CH:36]=1)[C@H:32]([OH:34])[CH3:33])([CH3:27])([CH3:26])[CH3:25].N1C=CN=C1>O.C(OCC)(=O)C>[C:24]([O:28][C:29](=[O:44])[NH:30][C@H:31]([C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[C:37]([F:43])[CH:36]=1)[C@H:32]([O:34][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([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)[CH3:33])([CH3:25])([CH3:26])[CH3:27]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In nitrogen atmosphere, tert-butyldiphenylsilyl chloride (2.0 mL) was added dividedly four times to a DMF solution (3 mL) of [(1R,2R)-2-hydroxy-1-(3,4,5-trifluorophenyl)propyl]-carbamic acid tert-butyl ester (610 mg) and imidazole (817 mg). This reaction solution was stirred at room temperature for 3 hr. To the reaction solution, ethyl acetate and water were added. The organic layer was separated, washed with 1 N hydrochloric acid, water, a saturated sodium hydrogencarbonate aqueous solution, and saturated saline in this order. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: hexane:diethylether=49:1 to 19:1) to give 684 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(NC2CCCC2)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (0.3 g, 1.33 mmol) and cyclopentanone (0.50 g, 6.6 mmol) in methanol (3 mL), acetic acid (0.159 g, 2.6 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.208 g, 3.3 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure to give the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.Cl.Cl.[NH2:19][C:20]1[CH:25]=[C:24]([CH2:26][NH2:27])[CH:23]=[C:22]([OH:28])[C:21]=1[OH:29].CCN(CC)CC.O>CN(C)C=O>[NH2:19][C:20]1[CH:25]=[C:24]([CH:23]=[C:22]([OH:28])[C:21]=1[OH:29])[CH2:26][NH:27]/[CH:14]=[C:5]1\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]2[C:4]\1=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2
Reactant: NCc1cc(N)c(O)c(O)c1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc(O)c1O
Yield: 28.7 %

Procedure:
6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (124 mg, 0.44 mmol), 3-amino-5-aminomethyl-benzene-1,2-diol dihydrochloride salt (100 mg, 0.44 mmol) and Et3N (0.15 mL, 1.1 mmol) in N,N-dimethylformamide (DMF) (5 mL) is stirred at 25° C. for 24 hours. Water (10 mL) is added to the reaction mixture. The resulting solid is filtered and washed with water. The crude solid is purified by HPLC, eluting with 20% CH3CN/H2O to 100% CH3CN over 30 minutes to give 51 mg (22%) of the title compound as a brown solid. HRMS (ESI) m/z calcd for C17H14BrN3O4 (M+H)+ 404.02405. found: 404.02336.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[CH2:15][C@@H:14]([O:16]C(=O)C)[C@H:13]([N:20]2[C:24]3[N:25]=[C:26]([NH2:30])[NH:27][C:28](=[O:29])[C:23]=3[S:22][C:21]2=[O:31])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:30][C:26]1[NH:27][C:28](=[O:29])[C:23]2[S:22][C:21](=[O:31])[N:20]([C@H:13]3[C@H:14]([OH:16])[CH2:15][C@@H:11]([CH2:10][OH:9])[O:12]3)[C:24]=2[N:25]=1.[C:1]([O:9][CH2:10][C@@H:11]1[CH2:15][C@@H:14]([OH:16])[C@H:13]([N:20]2[C:24]3[N:25]=[C:26]([NH2:30])[NH:27][C:28](=[O:29])[C:23]=3[S:22][C:21]2=[O:31])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@H]1C[C@@H](COC(=O)c2ccccc2)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](CO)C[C@H]2O)c(=O)[nH]1
Product: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](COC(=O)c3ccccc3)C[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of [(2S,4R,5R)-4-acetoxy-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl]methyl benzoate (compound 38a, 4.72 g, 10.6 mmol) and potassium carbonate (1.46 g, 10.6 mmol) in methanol (106 mL) was stirred at room temperature for 3.5 hours. The reaction was quenched by addition of acetic acid (1.5 mL). The resulting mixture was concentrated in vacuo to remove the solvent and the residue was purified by column chromatography on silica gel (eluting with 0-5% methanol in DCM) to afford 1.0 g of 5-amino-3-[(2R,3R,5S)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (compound 38b) and 2.8 g of [(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]methyl benzoate (compound 38c) as a pale solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:31]=[CH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:17][CH:16]=1.C(O)C>[Pt]=O.O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:38][CH:39]=1
Reactant: CCOC(=O)C=Cc1c(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)ccc2ccccc12
Agent: O=[Pt]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
A mixture of ethyl 3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]-2-propenoate (1.51 g), platinum oxide (0.18 g), ethanol (5 mL) and tetrahydrofuran (10 mL) was stirred at room temperature overnight under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated to give crystals (1.36 g, 90%) of ethyl 3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]propionate. Recrystallization from acetone-hexane gave colorless needle crystals. melting point: 86-87° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:24]/[O:25][CH3:26])/[C:7]([NH:9][C@@H:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH2:17][OH:18])[CH2:15][S:16][C@H:11]12)=[O:8].ClP([N:31]=[C:32]=[O:33])(Cl)=O.C([O-])(O)=O.[Na+].Cl>O1CCOCC1.ClCCCl.O>[CH3:26][O:25]/[N:24]=[C:6](\[C:7]([NH:9][C@@H:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH2:17][O:18][C:32]([NH2:31])=[O:33])[CH2:15][S:16][C@H:11]12)=[O:8])/[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NP(=O)(Cl)Cl
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1COCCO1
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.25 h
Yield: 75 %

Procedure:
A solution of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (3.81 g) in dioxan (20 ml) was added over ca. 1 minute to a stirred solution of dichlorophosphinyl isocyanate (1.46 ml) in 1,2-dichloroethane (30 ml) at 19°, the temperature rising to 28°. The resulting solution was stirred for 15 minutes and then added to a solution of NaHCO3 (5.1 g) in water (70 ml). This mixture was stirred at ca. 30° for 1 hour, and then heated at 40° to 45° for a total of 4.5 hours, the pH being adjusted to 5.0 with hydrochloric acid after 3 hours. The two-phase mixture was adjusted from pH 5.8 to 7.0 with aqueous NaHCO3 solution and the aqueous phase was washed with 1,2-dichloroethane (20 ml) and ethyl acetate (50 ml), and acidified to pH 1.9 with dilute hydrochloric acid in the presence of ethyl acetate. The aqueous phase was re-extracted with ethyl acetate, and the combined ethyl acetate extract washed with 25% aqueous sodium chloride solution and evaporated. The solid residue was slurried with diethyl ether to give the title compound (3.18 g, 75.0%); purity by HPLC 91.6% and by TLC 89.5%.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([O:31]C)=[O:30])[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:33]=[CH:34][N:35]=[C:36]([F:37])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>O1CCOCC1.CO.O>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([OH:31])=[O:30])[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:33]=[CH:34][N:35]=[C:36]([F:37])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CC1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)CC1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 5.1 %

Procedure:
Compound 258 (0.100 g, 0.20 mmol) was suspended in dioxane (4.8 mL) and methanol (4.8 mL). A solution of lithium hydroxide, monohydrate (0.0092 g, 0.22 mmol) in 2.0 mL of water was added to the suspension. The reaction was warmed to 70° C. After 1 hour, solvent was removed in vacuo. The residue was dissolved in water (3 mL). Dichloromethane was added (1 mL) and the pH was brought to ca. pH 10 with dilute NaOH. The organics were removed and the aqueous was brought to ca. pH 4 with dilute HCl. The resulting precipitate was filtered. Purification by RP-HPLC on C18 column (10-90% CH3CN in water with 0.1% TFA) provided compound 259 (5 mg) as a TFA salt. 1H NMR (500 MHz, DMSO-d6) δ 1.28-1.41 (m, J=12.17, 12.01, 12.01, 3.18 Hz, 2 H) 1.68-1.94 (m, 5 H) 1.99-2.09 (m, 2 H) 2.09-2.19 (m, 2 H) 2.21-2.34 (m, 4 H) 2.81 (t, 11.49 Hz, 2 H) 3.71 (d, J=12.23 Hz, 2 H) 5.53 (quin, J=9.11 Hz, 1 H) 7.72 (d, J=9.05 Hz, 1 H) 7.98 (br. s., 1 H) 8.06 (d, J=8.56 Hz, 1 H) 8.11-8.18 (m, 1 H) 8.25 (dd, J=4.65, 2.93 Hz, 1 H) 9.51 (s, 1 H) 11.43 (br. s., 1 H) ppm. LCMS-ESI (POS), M/Z, M+1: Found 490.1, Calculated 490.2.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[CH3:15])=[CH:5][N:4]([CH3:16])[C:3]=1[C:17]#[N:18].[C:19](OC(=O)C)(=O)[CH3:20].C(O)(=[O:28])C>>[CH3:19][C:20]1[N:18]=[C:17]([OH:28])[C:3]2[N:4]([CH3:16])[CH:5]=[C:6]([C:7]3[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=3[CH3:15])[C:2]=2[N:1]=1
Reactant: Cc1cc(C)c(-c2cn(C)c(C#N)c2N)c(C)c1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Product: Cc1cc(C)c(-c2cn(C)c3c(O)nc(C)nc23)c(C)c1
Temperature: 130 °C

Procedure:
A mixture of 3-amino-1-methyl-4-(2,4,6-trimethylphenyl)-1H-pyrrole-2-carbonitrile (0.4 mmol) and acetic anhydride (0.043 ml) in acetic acid (0.01 ml) was heated at reflux untill all the starting material was consumed. The reaction mixture was concentrated to dryness. The residue was quenched with water and extracted with ethyl acetate. The organic extracts was washed with brine and concentrated to dryness. The residue was suspended in 0.5 ml of 85% phosphoric acid and heated at 130° C. for 1 hour. The mixture was cooled and poured into ice-water, stirred until solid formed. The solid was filtered to give 2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol. The alternative way for the work up is via extraction technique. The ice water was extracted with chloroform. The organic layer was dried and concentrated to dryness to give the desired product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2([NH2:16])[CH2:15][CH2:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].[BH-](OC(C)=O)(OC(C)=O)O[C:33](C)=O.[Na+].C=O.[OH-].[Na+]>C1COCC1.CC(O)=O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([N:16]([C:13]2([C@@H:10]3[CH2:11][CH2:12][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9]3)[CH2:14][CH2:15]2)[CH3:33])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: NC1([C@@H]2CCN(Cc3ccccc3)C2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1([C@@H]2CCN(Cc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of (R)-1-(1-benzyl-pyrrolidin-3-yl)-cyclopropylamine (18.6 g, 87 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (22.7 g, 113 mmol) in THF (500 mL) was added glacial HOAc (31 mL). The solution was stirred at room temperature for one hour and then NaBH(OAc)3 (65 g, 306 mmol) was added. The resulted suspension was stirred at room temperature overnight before 37% aqueous solution of formaldehyde (30 mL, 262 mmol) was added. The reaction mixture was allowed to stir for 3 hrs and completed, then added aqueous 20% NaOH (300 mL) at 0° C. The mixture was allowed to stir for 2 h, and layers were separated. The aqueous layer was extracted with EtOAc (3×300 mL). The combined organic phase was dried over sodium sulfate, concentrated in vacuo. The residue was purified by flash chromatography (gradient eluation, 1% to 10% methanol in dichloromethane) to give the title compound as a pale yellow oil (27 g): ESI MS m/z 414.3 (M+H+). 1H NMR (400 MHz, CDCl3) δ 7.33-7.23 (m, 5H), 4.24-4.02 (m, 2H), 3.88-3.80 (m, 1H), 3.60 (d, JAB=12.8 Hz, 1H), 3.53 (d, JAB=12.8 Hz, 1H), 2.82-2.57 (m, 5H), 2.31 (s, 3H), 2.28-2.22 (m, 1H), 1.94-1.80 (m, 4H), 1.44 (s, 9H), 1.42-1.28 (m, 3H), 0.55-0.53 (m, 4H). The chiral purity of the product was analyzed by Chiral-Cel OD column (0.46 cm×25 cm, Daicel Chemical industries, Ltd, column catalog no. OD00CE-E1031) with acetonitrile in the presence of 0.1% diethylamine as mobile phase (flow rate 1 mL/min; retention time 5.23 min desired, 5.93 isomer) to be 95% ee.
Reaction SMILES: [C:1]([CH2:3][CH:4]=[C:5]1[CH:10]([CH3:11])[CH:9]2[CH2:12][CH:6]1[CH2:7][CH2:8]2)#[N:2].[H][H]>[Pd]>[C:1]([CH2:3][CH2:4][CH:5]1[CH:10]([CH3:11])[CH:9]2[CH2:12][CH:6]1[CH2:7][CH2:8]2)#[N:2]
Reactant: [H][H]
Reactant: CC1C(=CCC#N)C2CCC1C2
Agent: [Pd]
Product: CC1C2CCC(C2)C1CCC#N
Yield: 94.8 %

Procedure:
A mixture of 10.0 g (0.062 mol) of 2-(2-cyanoethylidene)-3-methylbicyclo[2.2.1]heptane, 10 ml of 2B alcohol and 0.1 g of palladium supported on charcoal (5%) catalyst was hydrogenated under 50 psi of hydrogen until 1 equivalent of hydrogen was aborbed. The mixture was then filter, concentrated under reduced vacuum. The residual oil was distilled under vacuum to give 9.6 g (89% yield) of 2-(2-cyanoethyl)-3-methylbicyclo[2.2.1]heptane: b.p. 55°-57° C./0.5 mm; ir 2940, 2870, 2250, 1700, 1460, 1430, 1380; nmr 0.95, 1.1 (3H.5), 1.2-2.5 (14H, m); ms 163.