Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:15][C@H:16]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:18]([C:28]([OH:30])=[O:29])[CH2:17]2)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[CH3:33][Si](C=[N+]=[N-])(C)C.C(OCC)C>ClCCl>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:15][C@H:16]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[C@H:18]([C:28]([O:30][CH3:33])=[O:29])[CH2:17]2)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2cccc(OCc3ccccc3)n2)C[C@H]1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](Oc2cccc(OCc3ccccc3)n2)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A 500 mL round bottom flask under nitrogen was charged with the product of Step 2 (7.17 g, 17.30 mmol), methanol (50 ml), and dichloromethane (50 ml). Attached an addition funnel containing trimethylsilyldiazomethane in diethyl ether (2.0M) (25.9 ml, 51.9 mmol). Cooled reaction flask in an ice bath. Added contents of addition funnel dropwise. Bubbles. HPLC/MS looks good after 0.5 hours. Quenched by dropwise addition of 2.5% potassium bisulfate. Evaporated to remove methanol. Added water. Extracted three times with ethyl acetate, dried with anhydrous magnesium sulfate, filtered and rotary evaporated filtrate. Subjected to flash column chromatography eluting with 80 hexane/20 ethyl acetate. Evaporation of fractions containing product gave the title compound as a colorless oil. (6.50 g, 15.17 mmol, 88% yield). LCMS (ES+) m/z 429.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=2)[C:5]#[N:6])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: C1CNCCN1
Reactant: N#Cc1ccnc(Cl)c1
Product: N#Cc1ccnc(N2CCNCC2)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
2-Chloro-isonicotinonitrile (80 g, 0.58 mol) and piperazine (199 g, 2.32 mol, 5 equiv) were combined and heated at 70° C. for 2.5 hours. The resulting suspension was cooled to room temperature and partitioned between a solution of 50% ethyl acetate/dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were concentrated in vacuo to about half the initial volume and ether was added. The suspension was stirred overnight, then filtered. The solid was dried under vacuum to give the desired product (31 g). The mother liquors were concentrated in vacuo and the residue was triturated with ether and filtered. The solid collected in this second batch was dried under vacuum and combined with the first batch to give the total amount of desired product (46 g, 42%). MS m/z 189 (M++1).
Reaction SMILES: C(OC([N:11]1[C@@H:15]([C:16]([OH:18])=[O:17])[CH2:14][NH:13][C:12]1=[O:19])=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[Pd]>[O:19]=[C:12]1[NH:11][C@@H:15]([C:16]([OH:18])=[O:17])[CH2:14][NH:13]1
Reactant: O=C(O)[C@H]1CNC(=O)N1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1NC[C@H](C(=O)O)N1
Yield: 71.3 %

Procedure:
Under nitrogen atmosphere, to a solution of (R)-2-oxoimidazolidine-1,5-dicarboxylic acid 1-benzyl ester (1.61 g) in methanol/tetrahydrofuran (4/1, 20 ml) was added 10 wt % palladium on carbon (161 mg) at room temperature, and the mixture was stirred for 24 hours under one atmosphere of hydrogen. Under nitrogen atmosphere, palladium on carbon in this reaction solution was filtered off through Celite, and the filtrate was concentrated under reduced pressure. To the resulting residue were added diisopropyl ether and n-hexane, and the mixture was stirred. A solid was collected from this suspension by filtration, and dried under reduced pressure to give the titled compound (565 mg).
Reaction SMILES: O[CH:2](O)[C:3]([C:5]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1)=O.[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=1[NH2:27].C([O-])(O)=O.[Na+]>CCO>[Cl:19][C:20]1[C:21]2[C:22](=[N:26][C:3]([C:5]3[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=3)=[CH:2][N:27]=2)[N:23]=[CH:24][CH:25]=1
Reactant: NC(=O)c1cnc(C(=O)C(O)O)c(C(F)(F)F)c1
Reactant: Nc1nccc(Cl)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cnc(-c2cnc3c(Cl)ccnc3n2)c(C(F)(F)F)c1

Procedure:
Dissolve 6-(2,2-dihydroxyacetyl)-5-(trifluoromethyl)nicotinamide (8.0 g) in 100.0 mL of EtOH and then add 4-chloro-2,3-diaminopyridine (800 mg) followed by addition of NaHCO3 (3.6 g). Stir the reaction at room temperature for 18 hours under N2 atmosphere. Concentrate the reaction mixture under vacuum, and purify by column chromatography to afford the title product as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>>[Br:1][C:2]1[CH:10]=[C:9]([NH:11][S:13]([CH3:12])(=[O:15])=[O:14])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Nc1cc(Br)c2cc[nH]c2c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1cc(Br)c2cc[nH]c2c1

Procedure:
4-Bromo-1H-indol-6-amine (200 mg, 0.81 mmol) was treated with methanesulfonyl chloride (66 μl, 0.85 mmol) according to the method described in Preparation 15b.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:31])(=O)=O)=CC=1>O1CCCC1>[F:31][C:9]1[C:5]([O:4][CH2:3][O:2][CH3:1])=[N:6][O:7][C:8]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COCOc1cc(-c2ccccc2)on1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1noc(-c2ccccc2)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
3-Methoxymethoxy-5-phenylisoxazole (2.05 g) was dissolved in anhydrous tetrahydrofuran (30 ml), and the solution was cooled to -78° C. Butyllithium (1.68M hexane solution, 7.1 ml) was added dropwise thereto, and the resulting mixture was stirred at the same temperature for 15 minutes. Then, N-fluorobenzenesulfonimide (3.15 g) was added to the reaction mixture, followed by stirring of the resulting mixture at the same temperature for 15 minutes. The cooling bath was removed and the temperature of the resulting mixture was raised to room temperature. The reaction mixture was poured into ice-cold water (200 ml) and extracted with ether (200 ml×2). The organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to obtain the title compound (1.78 g, 80%) as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([N:19]2[C:23]3[CH:24]=[C:25]([Cl:29])[C:26]([Cl:28])=[CH:27][C:22]=3[N:21]=[CH:20]2)[N:11]=1>>[ClH:9].[Cl:28][C:26]1[C:25]([Cl:29])=[CH:24][C:23]2[N:19]([C:12]3[N:11]=[C:10]([NH:1][C@H:2]4[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]4)[N:18]=[C:17]4[C:13]=3[N:14]=[CH:15][NH:16]4)[CH:20]=[N:21][C:22]=2[CH:27]=1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Clc1nc(-n2cnc3cc(Cl)c(Cl)cc32)c2nc[nH]c2n1
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(-n3cnc4cc(Cl)c(Cl)cc43)c3nc[nH]c3n2)CC1
Temperature: 110 °C

Procedure:
570 mg of trans-1,4-diaminocyclohexane are brought to its melting temperature (70° C.), 170 mg of product obtained in stage 1 above are added in a single step, and the mixture is then heated at 110° C. for approximately 24 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with an MeOH—NH4OH: 98-2 mixture for eluent. The purified product is dissolved in ethanol and HCl-AcOEt (hydrochloric acid-ethyl acetate) is then added. Partial drying and drying under vacuum at 50° C. are carried out. 34 mg of expected product are obtained in the form of brown-colored crystals.
Reaction SMILES: Cl[Si](C)(C)[CH3:3].[NH2:6][C@H:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[C:14]([OH:16])=[O:15]>CO>[CH3:3][O:15][C:14]([C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:7]1[NH2:6])=[O:16]
Reactant: C[Si](C)(C)Cl
Reactant: N[C@H]1CCCCC[C@H]1C(=O)O
Solvent: CO
Product: COC(=O)[C@@H]1CCCCC[C@@H]1N
Reaction time: 2 h
Yield: 61.8 %

Procedure:
Chlorotrimethylsilane (3.96 mL, 31.2 mmol) was added dropwise to cis-2-aminocycloheptanecarboxylic acid (2.45 g, 15.6 mmol) in methanol (25 mL) at room temperature under nitrogen. After stirring for 2 h, the solvent was evaporated in vacuo and the residue was triturated with ether. The white solid was filtered and then dried under vacuum overnight to provide (1.65 g) cis-2-aminocycloheptanecarboxylic acid methyl ester: 1H NMR (CDCl3) δ 8.44 (s br, 2 H), 3.77 (s, 3 H), 3.62 (s br, 1 H), 3.27 (s br, 1 H), 2.20 (m, 2 H), 1.71 (m, 2 H), 1.66–1.47 (m, 6 H); MS m/e 172.26 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:15][CH2:14][CH2:13][CH2:12]1.[C:16]([O:20][C:21]([N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:11]=[C:6]1[C:5]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:24]3[N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH:27]=[CH:26][CH:25]=3)[CH:3]=2)[NH:7]1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: O=C1Nc2ccc(Br)cc2C12CCCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C1(CCCC1)C(=O)N2
Temperature: 80 °C
Yield: 83.2 %

Procedure:
A solution of 5′-bromospiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one (2.0 g, 7.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (430 mg, 0.3 mmol) in ethylene glycol dimethyl ether (50 mL) was stirred under a flow of nitrogen for 15 min. To the solution was added sequentially 1-t-butoxycarbonylpyrrole-2-boronic acid (2.1 g, 9.7 mmol) and potassium carbonate (2.4 g, 17 mmol) in water (10 mL). The mixture was heated to 80° C. for 3 h and allowed to cool. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine (30 mL) and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo. Crystallization from 20% ethyl acetate/hexane gave 2-(1′,2′-dihydro-2′-oxospiro[cyclopentane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (2.2 g, 83%) as a white powder, mp 179–180.5° C. 1H NMR (DMSO-d6, 400 MHz) δ 1.30 (s, 9H), 1.75–1.98 (m, 8H), 6.16 (dd, 1H, J=1.8, 3.3 Hz), 6.22 (‘t’, 1H, J=3.3, 3.3 Hz), 6.79 (d, 1H, J=7.9 Hz), 7.08 (dd, 1H, J=1.8, 7.9 Hz), 7.14 (‘d’, 1H, J=1.5 Hz), 7.28 (dd, J=1.9, 3.3 Hz), 10.30 (s, 1H). MS (EI) m/z 352 [M+]. Anal. Calcd for C21H24N2O3: C, 71.57; H, 6.86; N, 7.95. Found: C, 71.08; H, 6.83; N, 7.74.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:18]([O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:30])=[CH:27][CH:26]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCOc1ccc(C(=O)O)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CCCCCCOc1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc1
Yield: 88.1 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 30.0 mg (0.131 mMol) 4-hexyloxybenzoic acid, 16.8 mg (89%) of the title compound were recovered.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)C(C)C)(C)C.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24](Cl)=[O:25].OS([O-])(=O)=O.[K+]>CN(C)C=O.C(OCC)(=O)C>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:25]
Reactant: COC(=O)CCN
Reactant: O=C(Cl)Cc1cccs1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice-bath-cooled solution of 0.45 g (3.2 mmol) of methyl β-alaninate hydrochloride and 1.14 mL of N,N-diisopropylethylamine (DlEA) in 10 mL of dimethylformamide (DMF) was added dropwise a 2 mL DMF solution of 0.51 g (3.2 mmol) of 2-thiopheneacetyl chloride. After 16 hours of stirring at room temperature, the reaction mixture was added to 50 mL of ethyl acetate (EtoAc) and 50 mL of 1M KHSO4, and the resulting layers were separated. The organic layer was washed with 2×50 mL of 1M KHSO4, 2×50 mL of a saturated KHCO3 solution, and 2×50 mL of H2O. The organic layer was then dried over Na2SO4 (anhydrous), filtered, and then concentrated under reduced pressure.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:30])[C@@H:12]([OH:29])[CH2:13][O:14][C@H:15]([CH3:28])[CH2:16][O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[N:8][CH:9]=1.[Cl:31][C:32]1[C:33]([N:40]2[C:44]3=[N:45][CH:46]=[N:47][C:48](Cl)=[C:43]3[CH:42]=[N:41]2)=[C:34]([CH:37]=[CH:38][CH:39]=1)[C:35]#[N:36].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:34]([C:35]#[N:36])[C:33]=1[N:40]1[C:44]2=[N:45][CH:46]=[N:47][C:48]([O:29][C@@H:12]([CH2:13][O:14][C@H:15]([CH3:28])[CH2:16][O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:19]([CH3:21])[CH3:20])[CH:22]([CH3:23])[CH3:24])[C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][N:8]=3)=[O:30])=[C:43]2[CH:42]=[N:41]1
Reactant: N#Cc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Reactant: CC(C)[Si](OC[C@@H](C)OC[C@H](O)C(=O)Nc1ccc(Cl)cn1)(C(C)C)C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](OC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1c(Cl)cccc1C#N)C(=O)Nc1ccc(Cl)cn1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (93 mg, 2.32 mmol) was added to (S)—N-(5-chloropyridin-2-yl)-2-hydroxy-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AY2) (500 mg, 1.16 mmol) in anhydrous THF (25 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 3-chloro-2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile (Intermediate AH6) (370 mg, 1.28 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was adjusted to pH 7 by addition of 1M citric acid and then diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane to afford the product (626 mg, 79%). 1H NMR (400 MHz, CDCl3) δ 0.98-1.09 (21H, m), 1.13-1.17 (3H, m), 3.60-3.77 (3H, m), 4.20-4.33 (2H, m), 5.99-6.03 (1H, m), 7.60-7.70 (2H, m), 7.78-7.81 (1H, m), 7.85-5 7.87 (1H, m), 8.22-8.25 (2H, m), 8.50 (1H, d), 8.60 (1H, d), 8.82 (1H, s); m/z (ES−) (M−H)−=682; HPLC tR=4.04 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][CH:33]=[C:29]4[N:28]=[C:27]([C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=4)[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[NH2:43][O:44][CH2:45][C:46]1[NH:47][CH:48]=[C:49]([OH:53])[C:50](=[O:52])[N:51]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:44][CH2:45][C:46]2[NH:47][CH:48]=[C:49]([OH:53])[C:50](=[O:52])[N:51]=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][CH:33]=[C:29]4[N:28]=[C:27]([C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=4)[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4cc(-c5ccc(O)c(O)c5)nc5ccnn45)CS[C@H]23)cs1
Reactant: NOCc1nc(=O)c(O)c[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc(/C(=N/OCc2nc(=O)c(O)c[nH]2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4cc(-c5ccc(O)c(O)c5)nc5ccnn45)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 14 h
Yield: 104.6 %

Procedure:
(6R, 7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-(3,4-dihydroxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (125 mg) (0.2 mmol), 41 mg (0.26 mmol) of 2-(aminooxy)methyl-5-hydroxy-4(1H)-pyrimidinone and 50 mg (0.26 mmol) of p-toluenesulphonic acid hydrate are dissolved in 3 ml of absolute dimethylacetamide. After stirring at room temperature for 14 hours the mixture is concentrated in a high vacuum at room temperature and the residue is treated with water. The product is filtered off and washed in succession with water, ethanol and diethyl ether. There are obtained 160 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyrimidinyl)methoxy]imino]acetamido]-3-[[[5-(3,4-dihydroxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].[Cl-].C([Al+]CC)C.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[C:3]([C:11]([O:13][CH3:14])=[O:12])[CH:4]=2)[NH:8][CH:7]=1)(=[O:23])[CH3:22]
Reactant: COC(=O)c1cc2cc[nH]c2cc1Cl
Reactant: CC(=O)Cl
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1cc2c(C(C)=O)c[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
To a solution of methyl 6-chloro-1H-indole-5-carboxylate (0.5 g, 2.4 mmol) in dichloromethane at 0 C, was added drop-wise, a solution of diethyl aluminum chloride (3.6 mL, 1M) and stirred under nitrogen for 45 min. To this mixture, added a solution of acetyl chloride (0.3 g, 3.8 mmol) in dichloromethane (3 mL). The resulting mixture was stirred for 3 h and at room temperature for 30 min. The reaction was quenched by the addition of cold Tris buffer (pH 7.5, 1 mM and added dichloromethane (2×15 mL). The solid that separated was removed by filtration, washed with water and dried to give the title compound (0.44 g, 73%), m/z=252 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(Cl)cc2)n1

Procedure:
A mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, step 1) (12.1 g, 39.2 mmol), sodium bicarbonate (6.58 g, 78.3 mmol), and 90% ethyl bromopyruvate (16.9 g) in 480 ml of 2-propanol was stirred at reflux overnight. After cooling, the mixture was concentrated. The residue was partitioned between dichloromethane and water and the aqueous layer further extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. Trituration of the residue with ethyl acetate gave the title compound as a pale beige, crystalline solid (6.61 g): mp (DSC) 218° C. Anal. Calc'd. for C19H17ClN2O4S (MW 404.87): C, 56.37; H, 4.23; N, 6.92. Found: C, 56.28;.H, 4.13; N, 6.80.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[C:8]1[S:9][C:10]([CH2:24][CH2:25][C:26]([CH3:32])([CH3:31])[CH2:27][C:28]([OH:30])=O)=[C:11](CCCC2C=CC(C)=CC=2)[C:12]=1C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C(Cl)(Cl)Cl.CCOCC>[O:36]1[CH2:37][CH2:38][N:33]([C:28]([CH2:27][C:26]([CH3:31])([CH3:32])[CH2:25][CH2:24][C:10]2[S:9][CH:8]=[CH:12][CH:11]=2)=[O:30])[CH2:34][CH2:35]1
Reactant: C1COCCN1
Reactant: Cc1ccc(CCCc2c(CCC(C)(C)CC(=O)O)sc(C)c2C)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(C)(CCc1cccs1)CC(=O)N1CCOCC1
Temperature: 50 °C
Yield: 72 %

Procedure:
2 g (0.0157 mol) of oxalyl chloride dissolved in 10 ml of CHCl3 are placed in a 100 ml single-necked flask. After having brought the mixture to 0° C. with an ice bath, 3.9 g (0.0105 mol) of 2,3-dimethyl-4-(3-p-methylphenylpropyl)-5-(4-carboxy-3,3-dimethylbutyl)thiophene (see above, paragraph B of the synthesis of the starting materials) are added. The reaction mixture is then stirred at room temperature and subsequently at 50° C. until the evolution of gas has ceased. The solvent is distilled off at a temperature below 50° C. The acid chloride prepared above dissolved in 60 ml of ether, and 1.82 g (0.021 mol) of morpholine dissolved in 60 ml of ether, are simultaneously poured into a 500 ml three-necked flask while stirring. The morpholinium hydrochloride precipitates instantaneously. After one hour's stirring, the solid is removed by filtration. The filtrate is washed with water, dried over MgSO4, rendered colourless with carbon black and concentrated to dryness. The crude product obtained is purified by chromatography on silica (eluant: CH2Cl2 /CH3COOC2H5 -95/5, then CH2Cl2 /CH3OH-98/2). 3.31 g of 2,3-dimethyl-4-3-p-methylphenylpropyl)-5-(4-morpholinocarbonyl-3,3-dimethylbutyl)thiophene are obtained in the form of a colourless oil, yield: 72%.