Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:11](N(OC)C)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:25][CH2:26][Mg+].[Br-]>C1COCC1>[Si:1]([O:8][CH2:9][CH:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[C:11](=[O:12])[CH2:25][CH3:26])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(=O)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
tert-butyl 3-(tert-butyldimethylsilyloxy)-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (22a) (1.5 g, 4.0 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by THF (33 mL). The mixture was cooled to 0° C. via an ice bath and a 1.0 M solution of EtMgBr in THF (12.0 mL, 12.0 mmol, 3.0 equiv.) was added over 10 min. The reaction stirred for 30 min at 0° C. and the ice bath was removed. The reaction stirred for an additional 1.0 h at rt. and was again cooled to 0° C. via an ice bath. Next, the reaction was quenched by addition of 1.0 M HCl (33 mL). The solution was transferred to a separatory funnel with additional 1.0 M HCl (20 mL) and extracted with EtOAc (3×40 mL). The organic layers were washed with sat. NaCl (2×30 mL) and dried over Na2SO4. The solution was then concentrated on a rotary evaporator and dried under vacuum to give 1.4 g of crude material. The residue was purified by flash column chromatography (10% EtOAc/hexanes) to give 1.1 g (86%) of 26 as a clear oil. Rf=0.25 (10% EtOAc/hexanes); IR (film) 3431, 3371, 2975, 2953, 2930, 2883, 2856, 1711, 1492, 1172, 838 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.45 (d, J=7.0 Hz, 1H, carbamate-NH), 4.22 (m, 1H, Boc-NH—CH), 4.00 (dd, J=10.0, 3.5 Hz, 1H, CH—CH2), 3.76 (dd, J=10.0, 4.0 Hz, 1H, CH—CH2), 2.56 (m, 1H, O═C—CH2), 2.44 (m, 1H, O═C—CH2), 1.39 (s, 9H, Boc-tbutyl-CH3), 1.08 (t, J=7.0 Hz, 3H, O═C—CH2CH3), 0.79 (s, 9H, Si-t-butyl-CH3), −0.03 (s, 6H, Si—CH3); 13C NMR (125 MHz, CDCl3) δ 208.5, 155.5, 79.7, 63.6, 61.2, 33.5, 28.4, 25.8, 18.2, 7.5, −5.5, −5.5; LRMS (ESI-MS m/z): Mass calcd for C16H33NO4Si [M]+, 331.52. Found 332.
Reaction SMILES: Cl.[OH-:2].[Na+].[CH3:4][C:5]1[O:9][C:8]([CH:10]=[CH:11][CH2:12][CH2:13]O)=[CH:7][CH:6]=1.[Cl-].[Na+]>[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC.C(OCC)(=O)C.CCCCCC.O>[CH2:11]([CH:10]1[C:5]([OH:9])([CH3:4])[CH:6]=[CH:7][C:8]1=[O:2])[CH:12]=[CH2:13]
Reactant: Cc1ccc(C=CCCO)o1
Reactant: [OH-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: Cl
Agent: [Cl-]
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCC1C(=O)C=CC1(C)O
Temperature: 40 °C

Procedure:
In a reaction vessel, water (150 ml) and tri-n-octylmethylammonium chloride (450 mg) were charged, and the pH value was adjusted to 5.5 with an aqueous 1/3 N HCl solution and an aqueous 1/3 N NaOH solution. Then, 5-methyl-2-furylallylcarbinol (11.0 g) was added thereto, and the temperature was elevated up to 100° C. to reflux. The mixture was stirred under reflux for 7 hours while maintaining a pH value of 5 to 5.5 by the addition of an aqueous 1/3 N NaOH solution and an aqueous 1/3 N HCl solution. After cooling to 40° C., sodium chloride (30 g) was added, and the mixture was extracted with toluene (70 ml) five times. From the extract, toluene was removed by distillation at 60° C. under reduced pressure to give an oily substance (10.1 g), which was subjected to chromatography on silica gel (100 g) with a mixture of ethyl acetate-n-hexane (1:2 by volume) as the developing solvent to obtain 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (7.1 g). Yield, 64.5%.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21](Br)[CH3:22])=[C:17]([CH2:24]Br)[CH:16]=1>CN(C=O)C>[Br:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:19][CH:20]=1)[CH:21]([CH3:22])[N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=1)(=[O:12])=[O:11])[CH2:24]2
Reactant: CC(Br)c1ccc(Br)cc1CBr
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2Cc3cc(Br)ccc3C2C)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
3.97 g of about 60% sodium hydride was suspended in 70 ml of DMF, and 50 ml of DMF solution of 8.49 g of p-toluene sulfonamide in was added thereto, and the resulting mixture was stirred at 60° C. for 1 hour, and 50 ml of DMF solution of 17.70 g of 1-bromo-4-(1-bromoethyl)-3-bromomethylbenzene (3-7) was dropped thereto, which was stirred at the same temperature for 2 hours. The reaction solution was poured into ice water and extracted with chloroform and the resulting organic layer was dried over anhydrous magnesium sulfate, and thereafter, the solvent was distilled off under reduced pressure and the resulting residue was purified by chromatopraphy (eluent; hexane:chloroform=1:1) to obtain 14.13 g of 5-bromo-1-methyl-2-(p-toluene sulfonyl)isoindoline (3-8).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:23])[N:16]([CH2:18][CH2:19][O:20][CH2:21][CH3:22])[CH:17]=2)=O)=[C:4]([CH3:34])[CH:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:23])[N:16]([CH2:18][CH2:19][O:20][CH2:21][CH3:22])[CH:17]=2)=[N:36]\[OH:37])=[C:4]([CH3:34])[CH:3]=1
Reactant: NO
Reactant: CCOCCn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc2C)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOCCn1cc(/C(CC(c2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc2C)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)-1-(2-ethoxyethyl)pyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless foam, MS (ESI+): m/z=517.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH:12]1[N:16]=[C:15]([NH2:17])[S:14][CH:13]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([C:9]([NH:17][C:15]2[S:14][CH:13]=[CH:12][N:16]=2)=[O:11])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Nc1nccs1
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(Nc1nccs1)c1nc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
To a solution (400 ml) of 14.1 g (73.0 mmol) of 3,6-dichloro-2-pyridinecarboxylic acid in chloroform were successively added 9.00 g (89.9 mmol) of aminothiazole, 12.1 g (89.7 mmol) of N-hydroxybenzotriazole hydrate and 19.0 g (99.2 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride followed by stirring at room temperature for 24 hours. After the reaction solution was concentrated, ethyl acetate was added to the residue followed by washing with 0.2N aqueous solution of hydrochloric acid, water and saturated aqueous solution of sodium hydrogen carbonate. After drying and concentrating, the resulting residue was crystallized from a mixed solvent of hexane and ethyl acetate (5:1) to give 12.8 g (yield: 64%) of 3,6-dichloro-N-(thiazole-2-yl)-2-pyridine carboxamide as a white solid.
Reaction SMILES: Cl.[SH:2][C:3]1[C:4]([CH2:9][OH:10])=[N:5][CH:6]=[CH:7][CH:8]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[C:22]1([C:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.C(OCC)(=O)C>[C:22]1([C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[S:2][C:3]2[C:4]([CH2:9][OH:10])=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1ncccc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCc1ncccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
Into a 3 L round bottom flask equipped with mechanical stirrer and nitrogen purge was charged 3-mercapto-2-hydroxymethylpyridine hydrochloride (25.0 g, 0.141 mol, 1 eq.) followed by DMF (1.2 L) and to the cloudy suspension was charged finely powdered potassium carbonate (58.5 g, 0.423 mol, 3.0 eq.). To the resulting solution was charged triphenylmethylchloride (38.1 g, 0.137 mol, 0.97 eq) and the reactions mixture was allowed to stir at room temperature for three hours until TLC analysis showed reaction completion (ethyl acetate-hexanes). The DMF solution was poured into 3 L of 4:1 water/ethyl acetate. The aqueous layer was separated and extracted an additional time with ethyl acetate (200 mL). The organics were combined and hexane (150 mL) was added. The organic layer was washed with water (2×200 mL) then brine (2×200 mL). The organic layer was dried with sodium sulfate, filtered and evaporated in vacuo to give 48.63 g of the title compound as a brown oil which was taken directly on to the next reaction. 1H NMR (CDCl3) δ 5.05 (s, 2H); 7.1-7.4 (m, 16H); 8.20 (d, 1H); 8.58 (d, 1H).
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[CH:7][C:6](=[O:23])[N:5]([C:24]2[CH:25]=[N:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=2)[N:4]=1)#[N:2].[ClH:32].O1CCOCC1.CCOCC>C(Cl)Cl>[ClH:32].[C:30]([C:27]1[N:26]=[CH:25][C:24]([N:5]2[C:6](=[O:23])[CH:7]=[C:8]([O:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:3]([C:1]#[N:2])=[N:4]2)=[CH:29][CH:28]=1)#[N:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)nc3)nc2C#N)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: N#Cc1ccc(-n2nc(C#N)c(OC3CCNCC3)cc2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirring solution of tert-butyl 4-(3-cyano-1-(6-cyanopyridin-3-yl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (22 mg, 0.050 mmol) in DCM (3 mL) at room temperature under argon was added 4 M HCl in dioxane (0.375 mL, 1.5 mmol). The reaction mixture was stirred at room temperature overnight. Et2O (10 mL) was added to the reaction mixture. The solid product was collected by filtration and further washed with ether (2 mL×2). After drying under vacuum for 2 hours, 17.3 mg (100%) of 1-(6-cyanopyridin-3-yl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl salt was obtained as an off-white solid. MS (ESI) 323 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12]C)[CH:11]=1)[C:8](=[O:14])[CH2:7][CH2:6][C:5]2([CH3:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:12])[CH:11]=1)[C:8](=[O:14])[CH2:7][CH2:6][C:5]2([CH3:16])[CH3:15]
Reactant: COc1cc(Br)cc2c1C(=O)CCC2(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(=O)c2c(O)cc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
A stirred, cooled (ice bath) solution of 6-bromo-8-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 64, 0.24 g, 0.83 mmol) in anhydrous dichloromethane (4 mL) was treated with aluminum chloride (0.4 g, 3 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. It was poured into water and extracted with dichloromethane and ethyl acetate. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a brown oil that was subjected to flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title product as a pale yellow solid (0.13 g, 56%).
Reaction SMILES: [C:1]([OH:8])(=O)/[CH:2]=[CH:3]\[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:24][CH:25]1[C:38](=[O:39])[N:27]2[CH:28]([C:33]3[NH:37][N:36]=[N:35][N:34]=3)[C:29]([CH3:32])([CH3:31])[S:30][C@H:26]12>CN1CCOCC1.O1CCCC1.O>[C:4]([CH:3]=[CH:2][C:1]([NH:24][CH:25]1[C:38](=[O:39])[N:27]2[CH:28]([C:33]3[NH:34][N:35]=[N:36][N:37]=3)[C:29]([CH3:31])([CH3:32])[S:30][C@H:26]12)=[O:8])(=[O:5])[NH2:6]
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reactant: NC(=O)/C=C\C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)S[C@@H]2C(NC(=O)C=CC(N)=O)C(=O)N2C1c1nnn[nH]1
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a stirred mixture of 1.15 g. (10 m mole) of maleamic acid and 1.40 ml. of triethylamine in 40 ml. of dry tetrahydrofuran, at 0° C., is added 1.57 ml. (12 m mole) of isobutyl chloroformate followed by three drops of N-methylmorpholine. Stirring is continued for a further 30 minutes at 0° C. To this mixed anhydride is then added a solution prepared by adding 2.40 g. (10 m mole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam to a mixture of 15 ml. of water and 15 ml. of tetrahydrofuran and adjusting the pH to 7.5. The resulting mixture is then stirred for a further 1 hour at 0° C. At this point, the tetrahydrofuran is removed by evaporation in vacuo, and the residue is diluted with more water. The pH is adjusted to 8.0 with 6 N sodium hydroxide, and then the mixture is extracted with ethyl acetate. The extracts are discarded. The pH of the residual aqueous phase is adjusted to 2.0 with 4 N hydrochloric acid and then the product is extracted into ethyl acetate. The organic layer is dried and concentrated in vacuo to give 6-(3-[carbamoyl]-acrylamido)-2,2-dimethyl-3-(5-tetrazolyl)penam (1.03 g., 33% yield). The infrared spectrum (KBr disc) of the product shows absorption bands at 1818 cm-1 (β-lactam) and 1692 cm-1. The NMR spectrum (DMSO-d6) shows bands at 7.00 and 6.25 (quartet, 2H, J = 12 Hz, olefinic hydrogens), 5.80-5.48 ppm (multiplet, 2H, C-5 and C-6 hydrogens), 5.26 ppm (singlet, 1H, C-3 hydrogen), 1.65 ppm (singlet, 3H, C-2 methyl hydrogens) and 1.06 ppm (singlet, 3H, C-2 methyl hydrogens).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]3[CH:25]4[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:27][CH:19]3[CH2:20]5)[CH2:24]4)=[O:16])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:29]C(O)=O.C1(P([N:47]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[OH-].[Na+]>C1COCC1>[NH2:47][CH2:29][CH:7]1[C:6]2[C:28](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=2)[C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]3[CH:25]4[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:27][CH:19]3[CH2:20]5)[CH2:24]4)=[O:16])[CH2:11][CH2:10]2)[CH2:8]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CC1CC2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCC1CC2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 3.5 %

Procedure:
A 100-mL of flask was charged with (±)-2-(7-bromo-1′-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (30 mg, 0.06 mmol) dissolved in THF (3 mL) and treated with TEA (2 mL). Then diphenylphosphoryl azide (18 mg, 0.066 mmol) was added dropwise slowly. The mixture was stirred for 3 h at rt. 1 N aq NaOH solution (3 mL) was added and the reaction mixture was reflux overnight. The solvent was removed in vacuo and the aqueous residue was extracted with CH2Cl2 (3×5 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give (±)-2-adamantyl 3-(aminomethyl)-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (1 mg, 4%). LC-MS Method 5 tR=1.175 min, m/z=475; 1H NMR (400 MHz, MeOD): δ=0.71-0.83 (m, 3H), 1.46-1.57 (m. 2H), 1.61-1.81 (m, 6H), 1.81-2.06 (m, 11H), 2.39-2.51 (m, 1H), 2.83-3.00 (m, 2H), 3.41-3.57 (m, 2H), 4.07-4.14 (m, 1H), 4.79 (m, 1H), 6.99-7.10 (m, 2H), 7.37 (m, 1H), 7.95-8.30 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]=2[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[O:19])[CH:5]=[CH:4][N:3]=1.[CH2:30]([NH:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:30]([N:34]([CH2:35][CH2:36][CH2:37][CH3:38])[C:2]1[N:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[O:19])[CH:5]=[CH:4][N:3]=1)[CH2:31][CH2:32][CH3:33]
Reactant: COC(=O)c1ccc(-c2ccnc(Cl)n2)c(C(=O)N2CCc3ccccc3C2)c1
Reactant: CCCCNCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1nccc(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)n1
Temperature: 80 °C
Yield: 70.9 %

Procedure:
To a solution of methyl 4-(2-chloropyrimidin-4-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (82 mg, 0.20 mmol) in DMF (1.0 mL) were added dibutylamine (Aldrich, 52 mg, 0.40 mmol) and potassium carbonate (83 mg, 0.60 mmol). The reaction mixture was heated at 60° C. for 5 h and 80° C. for 3 h. After cooling to room temperature, the reaction mixture was quenched with cold water. The mixture was extracted with EtOAc (3×). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give the title compound (69 mg, 95%). MS (ESI+) m/z 501.2 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH:10]([OH:35])/[CH:11]=[CH:12]/[C:13]1[C:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17][N:16]2[C:25]=1[CH:26]([CH3:28])[CH3:27])[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+:37]>O.CO>[OH:1][CH:2]([CH2:9][CH:10]([OH:35])/[CH:11]=[CH:12]/[C:13]1[C:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17][N:16]2[C:25]=1[CH:26]([CH3:28])[CH3:27])[CH2:3][C:4]([O-:6])=[O:5].[Na+:37]
Reactant: CCOC(=O)CC(O)CC(O)/C=C/c1c(-c2ccccc2)c2c3ccccc3cnn2c1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccccc2)c2c3ccccc3cnn12
Yield: 81.8 %

Procedure:
A solution of a 3:2 mixture of the erythro- and threo-isomers of ethyl (E)-3,5-dihydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazin-2-yl)-hept -6-enoate (0.26 g; prepared as described in Example 1) and sodium hydroxide (22 mg) in water (1.0 ml) and methanol (10 ml) was stirred at the ambient temperature under an atmosphere of argon for 3 hours. The solution was then evaporated in vacuo and the residue was dried by treatment twice with methanol (2×10 ml) and once with diethyl ether (10 ml) followed each time by evaporation in vacuo, finally drying under high vacuum, to give sodium (E)-3,5-dihydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazin-2-yl)-hept-6-enoate (0.21 g) in the form of a yellow solid, m.p. 209°-215° C. [Elemental analysis: C, 65.8; H, 6.1; N, 5.4; H2O, 4.9%; calculated for C27H27N2O4Na:1.5H2O: C, 65.7; H, 6.13; N, 5.7; H2O, 5.5%; NMR (in a mixture of DMSO-d6 and D2O): 1.10-1.32 (2 H, m), 1.5 (6 H, d, J=7 Hz), 1.7-2.1 (2 H, m), 3.50-3.86 (2 H, m), 4.02-4.16 (1 H, m), 5.28 and 5.36 (1 H, two dd, J=16 Hz, 6 Hz), 6.46 (1 H, dd, J=16 Hz, 1 Hz), 7.16-7.60 (8 H, m), 7.78-7.88 (1 H, m), 8.57 (1 H, s)].
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[C:8]([CH3:15])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH2:16]([C:18]1[CH:33]=[C:32]([C:34](=[NH:37])[NH:35]O)[CH:31]=[C:30]([CH3:38])[C:19]=1[O:20][CH2:21][C@@H:22]([OH:29])[CH2:23][NH:24][C:25](=[O:28])[CH2:26][OH:27])[CH3:17]>>[CH2:16]([C:18]1[CH:33]=[C:32]([C:34]2[N:37]=[C:12]([C:10]3[CH:9]=[C:8]([CH3:15])[CH:7]=[C:6]([CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[N:11]=3)[O:14][N:35]=2)[CH:31]=[C:30]([CH3:38])[C:19]=1[O:20][CH2:21][C@@H:22]([OH:29])[CH2:23][NH:24][C:25](=[O:28])[CH2:26][OH:27])[CH3:17]
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reactant: CCC(CC)c1cc(C)cc(C(=O)O)n1
Product: CCc1cc(-c2noc(-c3cc(C)cc(C(CC)CC)n3)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Yield: 21.8 %

Procedure:
The title compound (35 mg) is prepared by coupling and cyclizing 6-(1-ethyl-propyl)-4-methyl-pyridine-2-carboxylic acid (67 mg, 323 μmol) and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide (137 mg, 420 μmol) as described in Example 1; LC-MS*: tR=1.01 min, [M+H]+=497.23; 1H NMR (CDCl3): δ0.85 (t, J=7.5 Hz, 6H), 1.31 (t, J=7.3 Hz, 3H), 1.79 (quint, J=7.0 Hz, 4H), 2.38 (s, 3H), 2.49 (s, 3H), 2.70-2.80 (m, 3H), 3.48-3.56 (m, 2H), 3.75-3.93 (m, 3H), 4.18-4.24 (m, 3H), 7.11 (t, J=5.5 Hz, 1H), 7.16 (s, 1H), 7.90 (s, 1H), 7.91 (s, 1H), 8.00 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:45][S:46][CH2:47][CH2:48][CH2:49][NH2:50].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:1]([C:5]1[N:10]=[C:9]([NH:50][CH2:49][CH2:48][CH2:47][S:46][CH3:45])[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:34])[CH3:35])[C@@H:15]2[CH2:20][NH:19][CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2Cl)CN(C(=O)OC(C)(C)C)C1
Reactant: CSCCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1CNC[C@@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCCCSC)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 1-tert-butyl 3-methyl (3R*,5S*)-5-{[(2-tert-butyl-4-chloropyrimidin-5-yl)carbonyl](isobutyl)amino}piperidine-1,3-dicarboxylate (51.1% mg) and diisopropylethylamine (38 mg) in DMF (0.5 ml) was added a solution of 3-methylthiopropylamine (21 mg) in DMF (0.5 ml), and the mixture was stirred at 80° C. overnight. To the reaction mixture was added 2% aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate, and the extract was concentrated by a nitrogen gas blower. The residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated by a nitrogen gas blower. The residue was dissolved in trifluoroacetic acid/acetonitrile solution (20% (V/V), 1.0 ml), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated by a nitrogen gas blower. The residue was neutralized with triethylamine (1 ml), saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was concentrated by a nitrogen gas blower. The residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated by a nitrogen gas blower to give the object compound (6.4 mg).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]([F:17])=[CH:15][C:10]3[NH:11][C:12](=[S:14])[NH:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[CH2:24]1COCC1.CI>C(N(CC)CC)C>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]([F:17])=[CH:15][C:10]3[NH:11][C:12]([S:14][CH3:24])=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: Fc1cc2[nH]c(=S)[nH]c2cc1-c1ccc(-c2ccccc2)cc1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CI
Product: CSc1nc2cc(-c3ccc(-c4ccccc4)cc3)c(F)cc2[nH]1
Temperature: 40 °C

Procedure:
To a solution of 5 (2.23 g, 6.9 mmol) in 40 ML of THF was added triethylamine (2.2 mL) followed by the dropwise addition of methyliodide (0.43 mL, 6.9 mmol). The reaction mixture was heated to 40° C. for 2 h. The solvent was then removed in vacuo and the residue was taken up in EtOAc and washed two times with 100 mL portions of saturated aqueous ammonium chloride and one 100 mL portion of brine. The combined organic layers were dried over MgSO4 filtered and concentrated to dryness in vacuo. Then 150 mL of CH2Cl2 were added and the resulting precipitate was collected by vacuum filtration to give title compound 6.