Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]1[NH:18][C:19]([C:22]2[CH:27]=[C:26]3[CH2:28][O:29][C:30]4[CH:54]=[C:53]5[C:33]([CH:34]=[CH:35][C:36]6[N:40]=[C:39]([CH:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](OC(C)(C)C)=[O:47])[NH:38][C:37]=65)=[CH:32][C:31]=4[C:25]3=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].Cl.[CH3:56][O:57][C:58]([NH:60][C@H:61]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)C(O)=O)=[O:59].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C.C(O)C>[CH3:56][O:57][C:58]([NH:60][CH:61]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:46]([N:42]1[CH2:43][CH2:44][CH2:45][CH:41]1[C:39]1[NH:38][C:37]2[C:53]3[C:33]([CH:34]=[CH:35][C:36]=2[N:40]=1)=[CH:32][C:31]1[C:25]2[C:26]([CH2:28][O:29][C:30]=1[CH:54]=3)=[CH:27][C:22]([C:19]1[NH:18][C:17]([CH:13]3[CH2:14][CH2:15][CH2:16][N:12]3[C:10](=[O:11])[CH:6]([NH:5][C:3](=[O:4])[OH:2])[CH:7]([CH3:8])[CH3:9])=[N:21][CH:20]=1)=[CH:23][CH:24]=2)=[O:47])=[O:59]
Reactant: COC(=O)N[C@H](C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc(C6CCCN6C(=O)OC(C)(C)C)[nH]c54)cc2-3)[nH]1)C(C)C
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)NC(C(=O)N1CCCC1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc(C3CCCN3C(=O)C(NC(=O)O)C(C)C)[nH]2)ccc1-4)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.2 %

Procedure:
A solution of tert-butyl 2-[9-(2-{1-[N-(methoxycarbonyl)valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate (462 mg, 0.63 mmol), ethanol (6 mL) and concentrated HCl (2 mL) was heated to 60° C. for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (6 mL). This solution was concentrated and to this material was added a solution of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (172 mg, 0.82 mmol) and COMU (311 mg, 073 mmol) in DMF (6 mL). To the resulting solution was added diisopropylethylamine (330 μL, 1.89 mmol). After stirring for 18 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 45% ACN/H2O+0.1% TFA). The product fractions were lyophilized to give [1-(2-{5-[2-(1-{[(methoxycarbonyl)amino](phenyl)acetyl}pyrrolidin-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl]-1H-imidazol-2-yl}pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl]carbamic acid (231 mg, 45%). LCMS-ESI+: calculated for C46H48N8O78: 824.92; observed [M+1]+: 826.00.
Reaction SMILES: [NH2:1][C:2](=[N:29][N+:30]([O-:32])=[O:31])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=1)=[O:17])[NH:8]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl.O>[NH2:1][C:2](=[N:29][N+:30]([O-:32])=[O:31])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:16]([NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](=[O:28])[CH3:27])=[CH:24][CH:25]=1)=[O:17])[NH2:8]
Reactant: CC(=O)c1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccc(CNC(=O)[C@H](N)CCCNC(N)=N[N+](=O)[O-])cc1

Procedure:
Prepared analogously to Example 5e) from (R)-N5 -[amino(nitroimino)methyl]-N2 -(tert.-butoxycarbonyl)-N-[[4-(1-oxoethyl)-phenyl]methyl]-ornithinamide by treating with trifluoroacetic acid in dichloromethane. The salt thus obtained was dissolved in water, this solution was made ammoniacal and the desired base was finally precipitated from the aqueous solution by saturating with common salt. The product obtained was dried in vacuo in diphosphorus pentoxide and used in the following stage without any further purification.
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[C:3]#[CH:4].C(N(CC)CC)C.[CH3:13][C:14]1([CH3:33])[O:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:23](OS(C(F)(F)F)(=O)=O)[C:17]=2[C:16](=[O:32])[O:15]1.P(=O)(O)(O)O>CN(C)C=O.O>[CH3:13][C:14]1([CH3:33])[O:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:23]([C:4]#[C:3][C:2]([CH3:5])=[CH2:1])[C:17]=2[C:16](=[O:32])[O:15]1
Reactant: C#CC(=C)C
Reactant: CC1(C)OC(=O)c2c(cccc2OS(=O)(=O)C(F)(F)F)O1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(C)C#Cc1cccc2c1C(=O)OC(C)(C)O2
Temperature: 115 °C
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
0.64 g (0.92 mmol) of bistriphenylphosphinepalladium dichloride, 4.4 ml (46 mmol) of 3-methyl-3-buten-1-yne and 24 ml of triethylamine are added under nitrogen to a solution of 15.0 g (46 mmol) of 2,2-dimethyl-5-trifluoromethylsulfonyloxy-4H-(1,3)benzodioxin-4-one in 150 ml of dimethylformamide. The mixture is heated at 115° C. for 0.5 h, a further 6.6 ml of 3-methyl-3-buten-1-yne are then added at this temperature in the course of 1 h and the reaction solution is subsequently stirred for 15 min. After cooling, it is poured into 500 ml of water containing phosphoric acid (pH 3) at 0° C. and extracted with methyl tert-butyl ether, and the combined organic phases are carefully washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated. 14 g of a dark oil remain, which is chromatographed on silica gel using n-hexane/ethyl acetate. 7.0 g of colorless crystals are obtained, m.p. 60 ° C. (cf. Table 1, No. 1.009).
Reaction SMILES: C([N:5]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])(C)(C)C.[C:15]([C:23]([OH:25])=O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:8]([N:6]([C:23]([C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:25])[NH:5][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:13])([CH3:9])[CH3:7]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
N'-t-butyl-N'-benzoylhydrazine (1 g), benzoyl formic acid (0.7 g) and methanesulfonyl chloride (0.7 g) were stirred in toluene (30 ml) and saturated sodium bicarbonate (10 ml) at approximately 5° C. Triethylamine was added slowly, dropwise to the reaction mixture and stirred 1 hour at room temperature. After stirring for 1 hour, the reaction mixture was diluted with toluene (25 ml) and washed with water several times. The organic layers were dried over magnesium sulfate, filtered and the toluene rotavapped off to afford a white solid. After column chromatography, the product was obtained as a white solid in approximately 70% yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.N([O-])=O.[Na+].[CH3:21][CH:22](C(C)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24].CC([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>O.Cl.CCO>[CH2:26]([O:25][C:23]([C:22]1[NH:16][C:13]2[C:12]([CH:21]=1)=[CH:11][C:10]([O:9][CH2:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[CH:15][CH:14]=2)=[O:24])[CH3:27]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: CN1CCC(COc2ccc(N)cc2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc2cc(OCC3CCN(C)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 71.7 %

Procedure:
To a stirred solution of 4-((1-methylpiperidin-4-yl)methoxy)phenylamine (25) (2.00 g, 9.08 mmol) in water (19 mL) and concentrated HCl (6 mL) was added dropwise a solution of NaNO2 (689 mg, 9.99 mmol) in water (2 mL) at 0° C., and stirring was continued for 50 min at 0° C. (solution A). Ethyl 2-methylacetoacetate (1.39 mL, 9.53 mmol) was added dropwise to a stirred suspension of NaOAc (7.8 g) in EtOH (15 mL) at 0° C. and stirring was continued for 30 min at this temperature; then ice (9 g) was added (solution B). Solution A was added to solution B by a transfer cannula at 0° C. and the mixture was allowed to warm to room temperature. After 2.5 h the reaction mixture was basified by slow addition of a saturated aqueous solution of Na2CO3 at 0° C. and extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with water (200 mL), dried (MgSO4), and the solvent was removed in vacuo. The residue was then dissolved in absolute EtOH (10 mL), treated with a freshly prepared saturated solution of HCl in absolute EtOH (10 mL) and heated at reflux for 50 min. After cooling to room temperature the solvent was removed under reduced pressure and the residue was partitioned between water (50 mL) and CH2Cl2 (100 mL). The aqueous layer was basified using a saturated aqueous solution of Na2CO3 and extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with brine (200 mL), dried (MgSO4), and concentrated in vacuo. Purification by crystallization from iPr2O and column chromatography (CH2Cl2/MeOH, 30:1, 2% NEt3) of the residue obtained after evaporation of the mother liquor provided 26 (2.06 g, 72% overall yield) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ=1.36-1.54 (m, 5 H, OCH2CH3, 3′-Hax, 5′-Hax), 1.73-2.06 (m, 5 H, 2-Hax, 3′-Heq, 4′-H, 5′-Heq, 6′-Hax), 2.30 (s, 3 H, NMe), 2.87-2.97 (m, 2 H, 2′-Heq, 6′-Heq), 3.83 (d, J=6.2 Hz, 2 H, ArOCH2), 4.40 (q, J=7.2 Hz, 2H, OCH2CH3), 6.98 (dd, J=8.9, 2.4 Hz, 1 H, 6-H), 7.05 (d, J=2.0 Hz, 1 H, 3-H), 7.12 (mc, 1 H, 4-H), 7.30 (d, J=8.9 Hz, 1 H, 7-H), 9.11 (sbr, 1 H, NH) ppm. —13C NMR (50.3 MHz, CDCl3): δ=14.4 (OCH2CH3), 29.2 (C-3′, C-5), 35.3 (C-4′), 46.4 (NMe), 55.5 (C-2′, C-6′), 60.9 (OCH2CH3), 73.2 (ArOCH2), 103.4 (C-4), 108.1 (C-3), 112.7 (C-7), 117.2 (C-6), 127.8 (C-2, C-3a), 132.2 (C-7a), 154.1 (C-5), 162.0 (C═O) ppm. −MS (70 eV, EI): m/z (%)=316 (6) [M]+, 112 (100) [C7H14N]+. —C18H24N2O3 (316.39): calcd. C, 68.33; H, 7.65; found C, 68.03; H, 7.84.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[C:7]([C:8]([Cl:16])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1nc(Cl)c(C(=O)O)c(Cl)n1
Product: CSc1nc(Cl)c(C(=O)Cl)c(Cl)n1
Reaction time: 18 h
Yield: 100 %

Procedure:
10 g of 4,6-dichloro-2-methylsulfanylpyrimidine-5-carboxylic acid (41.83 mmol) are placed in 61 ml of thionyl chloride (836.54 mmol) with stirring. After 18 hours at 80° C., the thionyl chloride is evaporated off and the residue is taken up twice with 15 ml of toluene and concentrated to give 10.77 g of 4,6-dichloro-2-methylsulfanylpyrimidine-5-carbonyl chloride.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=3[N+:27]([O-])=O)[CH:13]=[CH:14][CH:15]=2)=[N:5][CH:4]=[N:3]1.[H][H]>C(O)C.O=[Pt]=O>[CH3:1][N:2]1[C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17]3[C:18]([NH2:27])=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=3)[CH:13]=[CH:14][CH:15]=2)=[N:5][CH:4]=[N:3]1
Reactant: Cn1ncnc1COCc1cccc(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: Cn1ncnc1COCc1cccc(Nc2ccc(C(F)(F)F)cc2N)c1

Procedure:
To a solution of 19a (0.6 g, 1.5 mmol) in ethanol (20 ml) was added platinium oxide (0.15 g) and the resultant mixture was hydrogenated at ambient pressure until the hydrogen uptake had ceased. Filtration through celite and concentration of the filtrate in vacuo left 20a, which was taken directly into the next step. The following compounds were prepared in analogy herewith: N1-[3-(2-Ethyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-4-trifluoromethyl-benzene-1,2-diamine (20b) from 19b 4-Methyl-N1-[3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-benzene-1,2-diamine (20c) from 19c 1-{3-Amino-4-[3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenylamino]-phenyl}-ethanone (20d) from 19d
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Br:25][C:26]1[CH:32]=[C:31]([O:33][C:34]([F:37])([F:36])[F:35])[CH:30]=[CH:29][C:27]=1[NH2:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Br:25][C:26]1[CH:32]=[C:31]([O:33][C:34]([F:36])([F:37])[F:35])[CH:30]=[CH:29][C:27]=1[NH:28][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)CCCn1c(Nc2ccc(OC(F)(F)F)cc2Br)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 130 °C
Reaction time: 12 h
Yield: 29 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 3.00 g, 8.08 mmol), 2-bromo-4-(trifluoromethoxy)aniline (2.44 mL, 16.16 mmol), p-toluenesulfonic acid monohydrate (1.64 g, 8.65 mmol) and xylene (7.0 mL) was stirred at 130° C. for 12 hr. After cooling, the reaction mixture was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give the title compound as a pale red oil (1.38 g, 2.34 mmol, 29%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][N:11]([C:23]2[C:32]([N:33]3[CH2:38][C@@H:37]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C@@H:35]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:34]3)=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH2:55])[CH:29]=3)[N:24]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:56]([C:59]1[CH:67]=[CH:66][C:62]([C:63](Cl)=[O:64])=[CH:61][CH:60]=1)([O-:58])=[O:57].C(N(C(C)C)C(C)C)C.CCCCCC.CCOC(C)=O>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][N:11]([C:23]2[C:32]([N:33]3[CH2:34][C@@H:35]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:36][C@@H:37]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38]3)=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH:55][C:63](=[O:64])[C:62]4[CH:61]=[CH:60][C:59]([N+:56]([O-:58])=[O:57])=[CH:67][CH:66]=4)[CH:29]=3)[N:24]=2)[CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc3ccc(N)cc3nc2N2C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C2)C1
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc3ccc(NC(=O)c4ccc([N+](=O)[O-])cc4)cc3nc2N2C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
2,3-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-quinoxalin-6-ylamine (246) (0.067 g, 0.087 mmol) and p-nitro-benzoylchloride (0.0167 g, 0.09 mmol) were combined and dissolved in DMF (0.45 mL). iPr2EtN (0.016 mL, 0.09 mmol) was added and the mixture was shaken at room temperature for 16 h. TLC (Rf: 0.8 compared to Rf: 0.05 for compound 246 in 1:1 hexane/EtOAc) and LC-MS indicated complete coupling at this point. The mixture was diluted with EtOAc (30 mL), washed with saturated aqueous NaHCO3 (2×10 mL) and brine (2×10 mL) via extraction, dried over MgSO4 and concentrated to give the desired product (251) as an orange solid (0.063 g, 0.068 mmol, 78.6% yield). LC-MS (ESI): (exact mass: 920.48) m/e=921.8 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[NH:7][CH:6]2[S:10][CH:11]=[C:12]([C:13]3[CH:25]=[CH:24][C:16]([CH:17]=[N:18][O:19][CH2:20][C:21]([OH:23])=O)=[CH:15][CH:14]=3)[CH:5]2[C:4]=1[OH:26])#[N:2].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH2:34].C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.C(O)C(N)(CO)CO>ClCCl.CN(C)C(=O)C>[C:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]2[S:10][CH:11]=[C:12]([C:13]3[CH:14]=[CH:15][C:16](/[CH:17]=[N:18]/[O:19][CH2:20][C:21]([NH:34][CH2:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=4)=[O:23])=[CH:24][CH:25]=3)[C:5]=2[C:4]=1[OH:26])#[N:2]
Reactant: NCc1ccccn1
Reactant: N#CC1=C(O)C2C(c3ccc(C=NOCC(=O)O)cc3)=CSC2NC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: N#Cc1c(O)c2c(-c3ccc(/C=N/OCC(=O)NCc4ccccn4)cc3)csc2[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[4-(5-Cyano-4-hydroxy-6-oxo-3a,6,7,7a-tetrahydro-thieno[2,3-b]pyridin-3-yl)-benzylideneaminooxy]-acetic acid (0.035 g, 0.1 mmol) and C-pyridin-2-yl-methylamine (0.013 g, 0.12 mmol) were added to a suspension of resin bound 1,3-dicyclohexyl carbodiimide (0.166 g, 1.2 mmol/g, 0.2 mmol) and 1-hydroxybenzotriazole hydrate (0.013 g, 0.1 mmol) in 1:1 dichloromethane/N,N-dimethylacetamide (4 mL) at room temperature. After complete reaction, resin bound trisamine (4.7 mmol/g, 0.053 g, 0.25 mmol) was added to the reaction mixture, shaken at room temperature for 1 hour, filtered, concentrated and purified by RP-HPLC to afford the title compound. MS (ESI) m/e 457.8 (M−H)+; 1H NMR (500 MHz, DMSO-d6): δ ppm 12.15 (br s, 1H), 8.52–8.56 (m, 2H), 8.42 (s, 1H), 7.88 (dt, J=10.5, 1H), 7.61 (d, J=10, 2H), 7.51 (d, J=10, 2H), 7.38–7.43 (m 2H), 7.01 (s, 1H), 4.65 (s, 2H), 4.50 (d, J=5, 1H).
Reaction SMILES: CC1(C)CC(=O)CC(=O)C1.O1CCOCC1.P(OCC)(OCC)OCC.C([O:30][C:31]([C:33]1[N:37]2[C:38](=[O:50])[C@H:39]([C@H:40]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH3:41])[C@H:36]2[C@@H:35]([CH3:51])[C:34]=1[S:52][C@H:53]1[CH2:57][NH:56][C:55](=[S:58])[CH2:54]1)=[O:32])C=C.C(=O)([O-])O.[Na+:63]>O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C(OCC)C>[Na+:63].[NH:56]1[CH2:57][C@H:53]([S:52][C:34]2[C@H:35]([CH3:51])[C@@H:36]3[C@@H:39]([C@H:40]([O:42][Si:43]([C:46]([CH3:48])([CH3:47])[CH3:49])([CH3:44])[CH3:45])[CH3:41])[C:38](=[O:50])[N:37]3[C:33]=2[C:31]([O-:32])=[O:30])[CH2:54][C:55]1=[S:58]
Reactant: C=CCOC(=O)C1=C(S[C@H]2CNC(=S)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)CC(=O)CC(=O)C1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@H]3CNC(=S)C3)[C@H](C)[C@H]12
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
Dimedone (169 mg) is dissolved in a solution of sodium hydrogen carbonate (169 mg) in water (2 ml) by ultrasonic treatment, and thereto are added dioxane (16 ml), palladium diacetate (23 mg) and triethyl phosphite (0.12 ml) under nitrogen atmosphere, and further added thereto (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid allyl ester (1.03 g). The mixture is stirred at 30° C. for 30 minutes, and thereto is added diethyl ether (32 ml), and the mixture is stirred at 25° C. for 15 minutes, and further stirred at 5° C. for 30 minutes. The precipitated crystals are collected by filtration, washed with diethyl ether, and dried under reduced pressure at 25° C. for 17 hours to give (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid sodium salt (885 mg).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[NH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>>[OH:30][C:6]1[C:5]([C:3]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:10](=[O:23])[N:11]2[C@@H:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16]
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2[C@H](C)c2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: C[C@H](c1ccccc1)n1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCC(=O)O)ncc21
Temperature: 25 °C
Yield: 64.1 %

Procedure:
A mixture of (R)-5-hydroxy-2-oxo-3-phenyl-1-(1-phenyl-ethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.075 mmol), β-alanine (535 mg, 6.0 mmol) and NaOMe solution (9 mL, 4.5 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 22 mg of the title compound. MS: (+) m/z 458.36 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[C:7]([N+:25]([O-:27])=[O:26])[CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:28])[C:3]([OH:29])=[O:2])=[CH:6][C:7]=1[N+:25]([O-:27])=[O:26]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)c([N+](=O)[O-])c1
Yield: 79.2 %

Procedure:
A solution of 4-[2-(2-naphthalenyloxy)ethoxy]-3-nitro-alpha-oxobenzeneacetic acid methyl ester (0.55 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 5 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from acetone-hexane provided 0.42 g of purified 4-[2-(2-naphthalenyloxy)ethoxy]-3-nitro-alpha-oxobenzeneacetic acid as a yellow solid, mp 164° C. with decomposition.