Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:39]([C:40]34[CH2:45][CH:44]3[CH2:43][NH:42][CH2:41]4)=[CH:38][C:15]3[N:16]([CH3:37])[C:17]([NH:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH2:27][NH:28]C(OC(C)(C)C)=O)[C:21]=4[Cl:36])=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:5][CH2:4]1.Cl>O1CCOCC1.CC(O)C>[F:47][C:2]([F:1])([F:46])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([C:12]2[C:39]([C:40]34[CH2:45][CH:44]3[CH2:43][NH:42][CH2:41]4)=[CH:38][C:15]3[N:16]([CH3:37])[C:17]([NH:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH2:27][NH2:28])[C:21]=4[Cl:36])=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)OC(C)(C)C)c2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(C34CNCC3C4)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cn1c(Nc2c(Cl)ccc(CN)c2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(C34CNCC3C4)cc21
Reaction time: 8 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-{2,6-dichloro-3-[(tert.-butoxycarbonylamino)-methyl]-phenylamino}-6-[3-aza-bicyclo[3.1.0]hex-1-yl]-1-methyl-1H-benzimidazole-5-carboxylic acid amide (compound 185, 3.3 g, 4.7 mmol), 6 mL 4M HCl in dioxane, 10 mL dioxane and 5 mL 2-propanol is stirred overnight. The resulting precipitate is collected by filtration, diluted with EtOAc and washed with 1N aq NaOH. The organic phase is dried with Na2SO4, filtered and concentrated.
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[NH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)=[O:9].[CH3:21]O>>[ClH:3].[NH2:6][CH2:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]([O:18][CH3:21])=[O:17])=[CH:19][CH:20]=1)=[O:9]
Reactant: CO
Reactant: NCC(=O)c1ccc(OCC(=O)O)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: COC(=O)COc1ccc(C(=O)CN)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
Methanol (250ml.) was stirred at -20° C. as thionyl chloride (6ml.) was added. 4-(Aminoacetyl)phenoxyacetic acid hydrochloride (5.0g) was added, and the mixture was stirred and allowed to warm to room temperature during 18 hours. The resulting solution was evaporated under reduced pressure and the residue was recrystallised from a mixture of methanol and diethyl ether to give methyl 4-(aminoacetyl)-phenoxyacetate hydrochloride, m.p. 202°-204° C. (Example 12) in 62% yield.
Reaction SMILES: [NH2:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[K+].CN(C)C(=O)C.Cl[C:22]1[N:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[OH-].[Na+]>ClC1C=CC=CC=1.O>[NH2:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:22]2[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=[CH:31][N:32]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: CC(C)(N)Cc1ccc(O)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cccnc1Oc1ccc(CC(C)(C)N)cc1
Temperature: 50 °C
Yield: 89 %

Procedure:
4-(2-Amino-2-methylpropyl)phenol (55.18 grams, 244.9 mmol) was added to 5.05 N KOH (97.2 mmol, 2.0 equiv). The mixture was warmed to 50° C. to give a homogeneous yellow solution. Chlorobenzene (1104 mL) and N,N-dimethylacetamide (10.7 grams, 122 mmol) were added and the mixture was heated to reflux (ca. 100° C.). The water was removed azeotropically via a Dean-Stark trap. At ca. 125° C. a solid began to form. When the pot temperature reached132° C. the water had been removed and the reaction mixture was a thick but stirrable slurry (mechanical stirring required). The Dean-Stark trap was removed and an additional 100 mL of chlorobenzene was removed and discarded. Dry chlorobenzene (50 mL) was added to the slurry, followed by ethyl 2-chloronicotinate (50.0 grams, 269 mmol) in chlorobenzene (50 mL). The slurry was heated at reflux until the reaction was complete (ca. 24, hours). As the reaction progressed the slurry thinned and became beige in color. After cooling to room temperature, water (385 mL) and 1 N NaOH (25 mL, 0.1 equiv) were added to the mixture and the phases were separated. The organic phase was washed with water (285 mL) and the solution was concentrated to a net weight of 700 grams (9.83% potency by HPLC, 89% yield) for use in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([N:14]=[CH:15][C:16]=3[C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)[N:13]=2)=[CH:4][CH:3]=1.OOS([O-])=O.[K+].CC(O)C.[CH3:35][O:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([N:14]=[CH:15][C:16]=3[C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:41][C:40]4[CH:42]=[CH:43][C:37]([O:36][CH3:35])=[CH:38][CH:39]=4)[N:18]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(N)cc1
Reactant: CSc1nccc(-c2cnn3nc(-c4ccc(F)cc4)ccc23)n1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CC(C)O
Product: COc1ccc(Nc2nccc(-c3cnn4nc(-c5ccc(F)cc5)ccc34)n2)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
To a solution of 6-(4-fluorophenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1,5-b]pyridazine (42 mg, 0.124 mmol) in MeOH (2 mL) was added Oxone (77 mg, 0.124 mmol) in water (1 mL). The reaction mixture was stirred for about 2 hours then water (10 mL) was added. The aqueous layer was washed with EtOAc (3×40 mL) and aqueous NaHCO3 (1×20 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give a brown solid. This solid was-added to iPrOH (1.0 mL) and 4-methoxyaniline (20 mg, 0.162 mmol) in a sealed tube. The reaction mixture was heated at an oil bath temperature of 130° C. for about 16 hours. The mixture was cooled to RT and the solid collected by filtration to give the title compound as a brown solid (17 mg, 339% b). 1H-NMR (300 MHz, d6-DMSO) δ 9.41 (s, 1H), 9.14 (d, 1H, J=9.1 Hz), 8.88 (s, 1H), 8.41 (d, 1H, J=5.1 Hz), 8.22 (dd, 2H, J=8.5, 5.6 Hz), 8.02 (d, 1H, J=9.3 Hz), 7.62 (d, 2H, J=8.8 Hz), 7.42 (t, 2H, J=8.8 Hz), 7.30 (d, 1H, J=5.2 Hz), 6.94 (d, 2H, J=8.8 Hz), 3.75 (s, 3H); MS (ESI) (M+H)+ 413.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH3:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:19]1[CH2:20][CH2:21][CH:16]([CH3:15])[CH2:17][CH2:18]1)=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CC1CCNCC1
Product: CC1CCN(C(=O)c2ccc3cc(O)ccc3c2)CC1

Procedure:
The title compound was synthesised from 6-hydroxy-2-naphtoic acid (commercially available) and 4-methyl-piperidine (commercially available) according to the procedure described for Example A. MS (m/e): 268.5 (MH−, 100%)
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=O)=[O:4].[OH2:14].[OH-].[K+]>CO>[OH:4][C:3]1[C:2]([OH:14])=[CH:12][C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=1
Reactant: O
Reactant: O=Cc1ccccc1NC(=O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1cc2ccccc2nc1O
Temperature: 25 °C
Yield: 26 %

Procedure:
2-Chloro-N-(2-formyl-phenyl)-acetamide (960 mg) was dissolved in a mixed solvent composed of water (60 ml) and methanol (24 ml) at 100° C. A 10% aqueous potassium hydroxide solution (12 ml) was added dropwise to the solution and was then heated under reflux for one hr. The reaction solution was cooled to room temperature, methanol was then removed under the reduced pressure, and the residue was neutralized with a 1 N aqueous hydrochloric acid solution. The precipitate was collected by filtration, was washed with ethyl acetate, and was dried under the reduced pressure to give 2,3-dihydroxyquinoline (450 mg, yield 26%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[CH2:16]Cl)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl.[CH3:29][O:30][C:31](=[O:34])[CH2:32][NH2:33].O>CN(C=O)C>[CH3:29][O:30][C:31](=[O:34])[CH2:32][NH:33][CH2:16][C:9]1[CH:10]=[C:11]([F:15])[C:12]([F:14])=[CH:13][C:8]=1[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18]
Reactant: COC(=O)CN
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1CCl
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CNCc1cc(F)c(F)cc1NC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
To a solution of (2-chloromethyl-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester) (5.65 g, 20.3 mmol) in DMF (50 mL) was added DIPEA (10.6 mL, 60.9 mmol). The resulting solution was stirred for 5 min, followed by dropwise addition of solution of glycine methyl ester hydrochloride in DMF at 0° C. The reaction mixture was stirred overnight at 50° C. After completion of the reaction as confirmed by TLC, water (60 mL) was added to the reaction mixture and crude compound was extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4. The solvents were removed in vacuo to afford the crude compound which was purified by column chromatography (silica gel: 1.5:8.5 EtOAc:Pet. ether) to obtain pure (2-tert-butoxycarbonylamino-4,5 difluoro-benzylamino)-acetic acid methyl ester (5.37 g, 80%) as thick gel.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:12].[NH3:13]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([S:8](=[O:10])(=[O:9])[NH2:13])[CH:5]=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: N
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(N)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8 g of 2-chloro-toluene-4-sulfonic acid chloride is dissolved in 25 ml of CHCl3 and slowly stirred into 100 ml of concentrated NH3 solution. After 10 minutes of stirring at room temperature, the solution is concentrated by evaporation to one-half of its original volume. The substance is suctioned off, washed with water and dried. 2-Chloro-4-sulfamoyltoluene is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:16]=[C:15]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:14]=2)=[CH:11][CH:12]=1)=O.CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:34][O:33][CH2:32][C@H:31]([CH3:35])[O:30][C:15]1[CH:14]=[C:13]([C:10]2[NH:9][C:8]([C:6]3[O:1][CH2:2][CH2:3][CH2:4][N:5]=3)=[CH:12][CH:11]=2)[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH:16]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCCCO)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCCCO3)[nH]2)c1
Temperature: 80 °C
Reaction time: 17 h
Yield: 72 %

Procedure:
N-(3-Hydroxypropyl)-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxamide (216 mg, 0.430 mmol) synthesized in Example (37a) was dissolved in tetrahydrofuran (10 mL), and anhydrous methanesulfonic acid (115 mg, 0.660 mmol) and triethylamine (0.18 mL, 1.29 mmol) were added, followed by stirring at room temperature for 4 days, further at 80° C. for 17 hours, under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (10 mL) was added, and the solution was separated with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-90%) to afford the desired product (150 mg, yield 72%) as a pale brownish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:53]=[C:54]([CH:58]=[CH:59][CH:60]=1)[CH:55]([OH:57])[CH3:56]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:57][CH:55]([C:54]2[CH:58]=[CH:59][CH:60]=[C:52]([F:51])[CH:53]=2)[CH3:56])=[C:18]([CH3:24])[CH:17]=1
Reactant: CC(O)c1cccc(F)c1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OC(C)c4cccc(F)c4)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 73.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (97 mg) was added to toluene/triethylamine=10/1 (10 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (150 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-fluoro-α-methylbenzyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (108 mg, yield 68%).
Reaction SMILES: [CH2:1]([O:4][CH:5]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[CH3:32])[N:19]=1)[CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10]CC)=O)[CH2:2][CH3:3]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[C:29]1([CH3:30])[CH:28]=[C:27]([CH3:31])[CH:26]=[C:25]([CH3:32])[C:24]=1[C:20]1[N:19]2[C:18]([CH:23]=[CH:22][CH:21]=1)=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]2=[O:10]
Reactant: CCCOC(C=C(C(=O)OCC)C(=O)OCC)c1cccc(-c2c(C)cc(C)cc2C)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCCOc1cc(C(=O)OCC)c(=O)n2c(-c3c(C)cc(C)cc3C)cccc12
Reaction time: 0.25 h
Yield: 7.1 %

Procedure:
Diethyl 2[2-propoxy-2-(6-mesitylpyridin-2-yl)-ethylidene]-malonate (0.189 g, 0.43 mmol) was dissolved in 4 mL of Dowtherm A (phenyl ether: biphenyl 2:1 ratio). The solution was placed in a pre-heated oil bath set at 220° C. The reaction stirred at this temperature for 15 minutes. The solution was cooled and flash chromatographed (20-50% ethyl acetate/hexanes) to give 0.012 g (7% yield) of the title compound.
Reaction SMILES: O.[C:2]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=[O:5])[CH:3]=[O:4].O.[O:18]=[C:19]1[CH:26]2[CH:21]([CH2:22][CH:23]=[CH:24][CH2:25]2)[NH:20]1>C1C=CC=CC=1>[OH:4][CH:3]([N:20]1[C:19](=[O:18])[CH:26]2[CH:21]1[CH2:22][CH:23]=[CH:24][CH2:25]2)[C:2]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5]
Reactant: O=C1NC2CC=CCC12
Reactant: O=CC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C(O)N1C(=O)C2CC=CCC21
Reaction time: 3.5 h

Procedure:
p-Nitrobenzyl glyoxylate hydrate (9.08 g) was refluxed in benzene (150 ml) with provision for the removal of water. After 1 hour 8-oxo-7-azabicyclo [4.2.0]oct-3-ene (1) (2.46 g) was added and refluxing continued for 3.5 hours. The cooled solution was washed with water (x2), then brine. After back extraction of the first aqueous extract with ethyl acetate, the organic solutions were dried over magnesium sulphate, filtered combined, and evaporated. Chromatography on silica, eluting with ethyl acetate-petroleum ether mixtures gave two separate isomers of the alcohol (54) (43%). Less polar isomer I m.p. 153°-5° (crystalline plates ex ethyl acetate/ether). νmax (CHCl3) 3400 (broad), 1760, 1745, 1520, 1350 cm-1. δppm (CDCl3) 1.90-2.83 (4H, m, 2-CH2), 3.23-3.55 (1H, m, β-lactam proton), 4.00-4.20 (1H, m, β-lactam) proton), 4.27 (1H, d, J 8 Hz, exchangeable with D2O, OH), 5.33 (2H, s, CH2Ar)obscuring 1H, CHOH; 5.67-5.88 (2H, m, CH=CH), 7.55 (2H, d, J 8.5 Hz, Ar), 8.23 (2H, d, J 8.5 Hz, Ar) (Found: C, 58.07; H, 5.15; N, 8.51%, C16H16N2O6 requires C, 57.83; H, 4.85; N, 8.43%). More polar isomer II m.p. 118°-120° (fine crystalline needles ex ethyl acetate/ether). νmax (CHCl3) 3400 (broad), 1760-1745, 1520, 1350 cm-1. δ ppm (CDCl3) 1.83-2.77 (4H, m, 2-CH2), 3.25-3.55 (1H, m, β-lactam proton), 4.02-4.37 (2H, m, β-lactam proton and CHOH, --OH exchangeable with D2O), 5.31-5.98 [5H, 5.35 (2H, s, CH2Ar), obscuring, 1H, which sharpens to s, at δ 5.40 on D2O exchange, CHOH, and 2H, m, CH=CH], 7.56 (2H, d, J 8 Hz, Ar), 8.23 (2H, d, J 8 Hz, Ar) (Found: C, 57.95; H, 4.95; N, 8.50%. C16H16N2O6 requires C, 57.83; H, 4.85; N, 8.43%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:35])[C:15]2[O:21][C:20]3[C:22]([Cl:31])=[CH:23][C:24]([NH:26][C:27](=[O:30])[CH2:28]Cl)=[CH:25][C:19]=3[CH2:18][S:17](=[O:33])(=[O:32])[C:16]=2[CH:34]=1)=[O:11]>CN(C=O)C>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:35])[C:15]2[O:21][C:20]3[C:22]([Cl:31])=[CH:23][C:24]([NH:26][C:27](=[O:30])[CH2:28][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:32])(=[O:33])[C:16]=2[CH:34]=1)=[O:11]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CN3CCN(C)CC3)cc(Cl)c1O2

Procedure:
N-Methyl piperazine (0.140 g, 0.675 mmol) was added to a solution of Example 133 (0.3 g, 1 mmol) in DMF (1 mL) and refluxed for 1.5 h. The reaction mixture was concentrated, treated with water and filtered to obtain the crude title compound, which was purified using flash chromatography (silica gel). Yield: 0.237 g, (70%); 1H NMR (DMSO-d6): δ 2.2 (s, 3H, CH3), 2.4 (s, 4H, 2CH2), 2.8 (s, 4H, 2CH2), 3.2 (s, 2H, CH2), 3.9 (s, 3H, CH3), 5.2 (s, 2H, CH2). 7.8 (s 1H Ar), 7.9 (s, 1H, Ar), 8.2 (s, 1H, Ar); MS: m/e (ES+) 508 (M+1).
Reaction SMILES: [N+](C1C=C[C:7]([O:10][P:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=O)[O:12]C2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]1[C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([OH:47])[CH:45]=2)[NH:40][N:39]=1.N12CCCN=C1CCCCC2.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>ClCCl>[CH3:7][O:10][P:11]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:12])[O:47][C:44]1[CH:45]=[C:46]2[C:41](=[CH:42][CH:43]=1)[NH:40][N:39]=[C:38]2[C:30]1[NH:29][C:37]2[C:32]([CH:31]=1)=[CH:33][CH:34]=[CH:35][CH:36]=2
Reactant: O=[N+]([O-])c1ccc(OP(=O)(Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)cc1
Reactant: Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COP(=O)(Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
Phenylphosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester methyl ester is prepared according to procedure F using 230 mg of phenyl-phosphonic acid bis-(4-nitrophenyl) ester in solution in 4 ml of dichloromethane to which is added a solution of 120 mg of 3-(1H-indol-2-yl)-1H-indazol-5-ol and 72 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene in 4 ml of dichloromethane. After stirring for 2 hours at ambient temperature, the medium is treated with 4 times 50 ml of a saturated sodium bicarbonate solution, and then with 2×50 ml of a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and then concentrated to dryness to obtain 200 mg of crude phenylphosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester methyl ester.
Reaction SMILES: CS(O[C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=[C:15]3[CH:22]=[CH:23][S:24][C:14]=23)[CH2:8][CH2:7]1)(=O)=O.[C-:25]#[N:26].[Na+]>CS(C)=O>[N+:19]([C:18]1[C:13]([NH:12][C@@H:9]2[CH2:10][CH2:11][C@H:6]([C:25]#[N:26])[CH2:7][CH2:8]2)=[C:14]2[S:24][CH:23]=[CH:22][C:15]2=[N:16][CH:17]=1)([O-:21])=[O:20]
Reactant: [C-]#N
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#C[C@H]1CC[C@@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 90 °C
Reaction time: 6 h
Yield: 33.1 %

Procedure:
A mixture of trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl methanesulfonate (0.12 g, 0.32 mmol) and sodium cyanide (0.061 g, 1.2 mmol) in dimethyl sulfoxide (1 mL) was stirred at 90° C. for 6 h. After dilution with EtOAc, the resulting mixture was washed with sat. NaHCO3 solution, water and brine, and then concentrated. The residue was purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (32 mg). LCMS calculated for C14H15N4O2S (M+H)+: m/z=303.1. Found: 303.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.[Li]CCCC.CCCCCC.[CH3:25][O:26][CH2:27]Br>C1COCC1>[CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[C@H:7]([CH2:25][O:26][CH3:27])[N:8]=1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: COCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC[C@@H]1N=C(OC)[C@@H](C(C)C)N=C1OC
Reaction time: 8 h

Procedure:
To a solution of (R)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-pyrazine (5.53 g, 30 mmol) in anhydrous THF (80 ml) a 1.6M solution of n-BuLi in hexane (10.85 ml, 17.36 mmol) was added at -78° C. After 30 minutes a solution of bromomethyl methyl ether (4.5 g, 36 mmol) in THF (20 ml) was added dropwise. The reaction mixture was allowed to come to 20° C. overnight and was quenched by addition of 1M phosphate buffer (pH 7, 80 ml). The turbid mixture was stirred for 10 minutes, diluted with water (250 ml) and diethyl ether (180 ml). The layers were separated and the aqueous phase extracted with diethyl ether (2×150 ml). The combined organic layer was dried (Na2SO4), concentrated and purified by flash chromatography (silica gel; hexane:diethyl ether 5:1) to yield 5.61 g. To remove final impurities of the other diastereomer the material was crystallized from acetonitrile at -30° C. and the cold precipitate redissolved in CH2Cl2, dried (Na2SO4) and concentrated.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:17])=[S:16])=[CH:10][C:9]=2[O:18][CH3:19])=[C:5]([CH3:7])[N:6]=1.Br[CH:21]1[CH2:26][CH2:25][CH2:24][CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22]1=O>C(O)C>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[S:16][C:29]4[CH2:30][CH2:31][CH2:32][CH:27]([C:23]5[CH:24]=[CH:25][CH:26]=[CH:21][CH:22]=5)[C:28]=4[N:17]=3)=[CH:10][C:9]=2[O:18][CH3:19])=[C:5]([CH3:7])[N:6]=1
Reactant: COc1cc(NC(N)=S)ccc1-c1sc(C)nc1C
Reactant: O=C1C(Br)CCCC1c1ccccc1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-c1sc(C)nc1C
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A solution of [4-(2,4-dimethyl-thiazol-5-yl)-3-methoxy-phenyl]-thiourea (88 mg, 0.30 mmol) and 2-bromo-6-phenyl-cyclohexanone (80 mg, 0.32 mmol) in ethanol (3 ml) was heated to reflux over night. The precipitated solid was filtered off after cooling to room temperature and dried to yield the title compound (100 mg, 100%) as a yellow solid. MS ISP (m/e): 448.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.27 (br s, 1H, NH), 7.59 (s, 1H), 7.28 (t, 2H), 7.12-7.19 (m, 4H), 6.85 (d, 1H), 4.00 (m, 1H), 3.37 (s, 3H), 2.74 (m, 2H), 2.66 (s, 3H), 2.20 (s, 2H), 2.13 (m, 1H), 1.70-1.93 (m, 3H).