Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:21]=[C:22]([CH:25]=[N:26][C:27]([O:29][Si](C)(C)C)=[CH2:28])[CH2:23][CH3:24].CO>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]2[NH:8][C:7](=[O:11])[C:6]3([CH:12]([C:13]4[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=4)[CH2:28][C:27](=[O:29])[NH:26][CH:25]3[C:22](=[CH2:21])[CH2:23][CH3:24])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(C=NC(=C)O[Si](C)(C)C)CC
Reactant: N#Cc1cccc(/C=C2\C(=O)Nc3cc(Cl)ccc32)c1
Solvent: Cc1ccccc1
Solvent: CO
Product: C=C(CC)C1NC(=O)CC(c2cccc(C#N)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Yield: 35 %

Procedure:
E/Z-3-(6-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-benzonitrile (280 mg, 1 mmol) prepared in example 134a was heated with 1-(1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene freshly prepared in example 80a (2.06 g, 10.5 mmol) in toluene (20 mL) in a sealed tube at 135° C. for 1 h, then cooled to room temperature. Methanol (80 mL) was added, and the mixture was filtered through a short pad of celite. The filtrate was concentrated, the residue was purified by chromatography (EtOAc) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-cyano-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a solid (180 mg, 35%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Ni].O1CCCC1>[C:1]([O:5][C:6](=[O:37])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:19])=[O:18])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1OCc1ccccc1
Yield: 100 %

Procedure:
A mixture of 11.7 g (21.72 mmol) of (S)-3-(2-benzyloxy-4-nitro-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester, 2 g Raney Ni, and 200 mL tetrahydrofuran was shaken under a 50 psi hydrogen atomosphere for 16 h at room temperature. TLC analysis indicated complete reaction. The catalyst was filtered and the resulting solution was concentrated to give 11.2 g (21.72 mmol, 100%) of (S)-3-(4-amino-2-benzyloxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester as a brown oil. MS (APCI) m/z 507 (M−1).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:6]2[CH3:19].[NH3:27]>C(COC)OC.C(OCC)(=O)C>[NH2:27][C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:6]2[CH3:19]
Reactant: Cn1c(-c2cccc(F)c2)nc2c(Cl)nc(C#CC3(O)CCCC3)nc21
Reactant: N
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC3(O)CCCC3)nc21
Temperature: 70 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
1-{2-[6-Chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl)-1-ethynyl}-1-cyclopentanol (732 g) was dissolved in 16 liters of dimethoxyethane, 8 liters of a concentrated aqueous ammonia were added and the mixture was stirred at 70° C. for 5 hours using a sealed tube reactor. After the reaction solution was cooled in room temperature, it was diluted with 20 liters of ethyl acetate and washed with water twice (8 liters and 4 liters). The organic layer was concentrated to about 15 liters and the resulting residue was diluted with 15 liters of hexane, filtered and washed with hexane twice. Then it was dried at 50° C. for 2.5 hours to give 620 g of the product. The yield was 89%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](Cl)[CH:6]=[C:5]([O:10][CH3:11])[N:4]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[C:5]([O:10][CH3:11])[N:4]=1
Reactant: C1CNCCN1
Reactant: COc1cc(Cl)cc(OC)n1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(N2CCNCC2)cc(OC)n1

Procedure:
2.5 g (13 mmol) 2,6-dimethoxy-4-chloro-pyridine and 6.21 g (65 mmol) piperazine were heated at reflux in 22 ml anhydrous pyridine for 20 hours. After cooling (precipitation was detected) 50 ml of toluene was added and the suspension was filtered. The filtrate was concentrated under reduced pressure, piperazine and pyridine were azeotropically removed by repeated evaporation with toluene (five times). The residue was triturated with diethylether/petrolether (1:1) and dried in vacuo. The product was obtained as yellow solid and used directly in the next step.
Reaction SMILES: [CH3:1]N(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]2)=[CH:9][CH:8]=1.[H-].[Na+].CI>C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:17][CH2:16][CH:15]([N:18]([CH3:1])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH2:14]2)=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(F)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc(F)cc2)C1
Yield: 88 %

Procedure:
To an N,N-dimethylformamide solution (3.9 mL) of tert-butyl [1-(4-fluorophenyl)pyrrolidin-3-yl]carbamate (195 mg, 0.70 mmol) synthesized in Reference Synthesis Example 79, sodium hydride (28 mg, 0.70 mmol, purity 60%) and methyl iodide (44 μL, 0.70 mmol) were added at 0° C. and the resultant solution was stirred at room temperature for 1 day. To the reaction solution, the same amounts of sodium hydride and methyl iodide were further added and the resultant mixture was stirred for 1 day. After completion of the reaction, ethyl acetate was added to the reaction solution and the resultant mixture was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel (amino-based) column chromatography (hexane/ethyl acetate=9/1) to obtain the title compound (181 mg, yield 88%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][C:10]([F:24])([F:23])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])C1C=CC=CC=1.C(O)(C(F)(F)F)=O>CCO.[OH-].[OH-].[Pd+2]>[NH2:8][CH2:9][C:10]([F:23])([F:24])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17]
Reactant: CC(C)(C)OC(=O)CCCOCC(F)(F)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)CCCOCC(F)(F)CN
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.1 %

Procedure:
To a solution of tert-butyl 4-(3-(dibenzylamino)-2,2-difluoropropoxy)butanoate (120 mg, 0.29 mmol) in EtOH (1 mL) was added 50 mg Pd(OH)2 (10 mg, 20% on C) followed by the addition of TFA (25 μL). The reaction mixture was stirred at room temperature under H2 for 18 h. The solid was removed by filtration and the filtrate was concentrated under reduced pressure to yield tert-butyl 4-(3-amino-2,2-difluoropropoxy)butanoate (50 mg, 72% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)(=[O:3])[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH:23]=O.N1CCCCC1>C(O)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[CH:23][C:15]1[NH:14][C:22]2[C:17]([CH:16]=1)=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:3])[CH3:2]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(=O)c1ccc2c(c1)C(=Cc1cc3ccccc3[nH]1)C(=O)N2
Temperature: 90 °C
Yield: 87.6 %

Procedure:
A mixture of 5-acetyl-2-oxindole (88 mg) (prepared as described in Compound IN-06), indole-2-carbaldehyde (87 mg) and piperidine (4 mg) in ethanol (2 mL) was heated in a sealed tube at 90° C. for 3 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in oven for overnight to give 133 mg (88% yield) of 5-acetyl-3-(1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one as an orange solid.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:22])[C:4]1[CH:21]=[CH:20][C:7]2[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])[C:27](O)=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CCOC(C)=O.O>[Cl:23][C:24]1[CH:25]=[C:26]([C:27]2[O:1][N:2]=[C:3]([C:4]3[CH:21]=[CH:20][C:7]4[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:10][CH2:11][O:12][C:6]=4[CH:5]=3)[N:22]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(C(=N)NO)ccc2C1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)OCCN(C(=O)OC(C)(C)C)C4)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.8 %

Procedure:
A mixture of 1,1-dimethylethyl 8-[(hydroxyamino)(imino)methyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 33) (0.195 g, 0.634 mmol), 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (Preparation 6) (0.136 g, 0.634 mmol), EDC (0.146 g, 0.761 mmol) and HOBT (0.107 g, 0.698 mmol) DMF (4 ml) was stirred at room temperature for 20 minutes then heated at 100° C. for 17 hours. The cooled reaction mixture was diluted with EtOAc/water (40 ml of each) and the organics collected, dried (magnesium sulphate), evaporated and purified by biotage chromatography in 1:4 EtOAc/iso-hexane to give the title compound (172 mgs) as a white solid. MS (ES) C25H2835ClN3O5 requires 485; found 486 [M+H]+; C25H2837ClN3O5 requires 487; found 488 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:41][C:42]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:43])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3cccc(F)c3)n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3cccc(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3.000 g 4-((S)-4-tert-Butoxycarbonyl-2-{[1-(3-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 20 ml DMF were added 0.908 ml benzyl bromoacetate and 3.571 g cesium carbonate. After stirring at RT for 12 h the solution was reduced to a volume of 50 ml, diluted with 200 ml ethyl acetate and extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent reaction.
Reaction SMILES: [N:1]1([C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH2:11][OH:12])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1>>[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([O:12][CH2:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[N:1]2[CH:2]=[CH:3][CH:4]=[CH:5]2)[N:15]=1
Reactant: OCc1sccc1-n1cccc1
Reactant: Clc1cncc(Cl)n1
Product: Clc1cncc(OCc2sccc2-n2cccc2)n1

Procedure:
The title compound was prepared according to the procedure of example 50, step 1, starting from 3-(pyrrol-1-yl)thiophene-2-methanol (2.5 g, 14 mmol), K-t-BuO (1.43 g, 12.7 mmol) and 2,6-dichloropyrazine (1.73 g, 11.6 mmol). The yield of the title compound was 3.05 g (90%) and was obtained as an oil. Anal. (C13H10ClN3OS) C, H, N.
Reaction SMILES: Cl[CH:2]([C:7](=O)[C:8]([O:12]C)(OC)[CH3:9])[C:3]([O:5][CH3:6])=[O:4].[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[C:8]([C:7]1[N:15]=[C:16]([NH2:18])[S:17][C:2]=1[C:3]([O:5][CH3:6])=[O:4])(=[O:12])[CH3:9]
Reactant: NC(N)=S
Reactant: COC(=O)C(Cl)C(=O)C(C)(OC)OC
Solvent: CCO
Product: COC(=O)c1sc(N)nc1C(C)=O

Procedure:
A solution of 4.37 g (19 mmol) methyl 2-chloro-4,4-dimethoxy-3-oxopentanoate (Intermediate 221) and 1.8 g (24 mmol) thiourea in 50 ml EtOH was heated at reflux for 3 h. Solvent was removed and the residue was dissolved in 1:1 acetone-5N HCl and the solution was heated at reflux for 4 h. Acetone was removed and the aqueous residue was neutralized with 50% NaOH and then basified with aqueous Na2CO3. Precipitated solids were filtered, washed with water and dried in vacuo. NMR (d6-DMSO): 2.4 (s, 3H), 3.7 (s, 3H), 8.0 (s, 2H).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH:6]([C:21]1[CH:22]=[N:23][C:24]([CH3:27])=[N:25][CH:26]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1)C.[OH-].[Na+].Cl>O1CCOCC1>[CH3:27][C:24]1[N:25]=[CH:26][C:21]([CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)[CH2:5][C:4]([OH:28])=[O:3])=[CH:22][N:23]=1
Reactant: CCOC(=O)CC(CCCCCCCNc1ncccn1)c1cnc(C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ncc(C(CCCCCCCNc2ncccn2)CC(=O)O)cn1
Yield: 57.1 %

Procedure:
A solution of 24-8 (170 mg, 0.441 mmol) in 1,4-dioxane (2 mL) was treated with 1M aqueous NaOH (1.50 mL) at room temperature (90 min). The reaction was neutralized with 1M aqueous HCl (1.50 mL) and the solvents were removed in vacuo. PCTLC (SiO2, 2 mm, 10% MeOH; 25% EtOAc, 65% CHCl3) afforded 24-9 (90 mg).
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@@H:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14].[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([I:39])[CH:36]=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([I:39])[CH:36]=[CH:35][C:31]=3[C:32]([NH:15][C@@H:5]([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=3[Cl:14])[C:4]([OH:3])=[O:16])=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)cc1Cl
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(Cl)cc1Cl)C(=O)O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-(2,4-dichloro-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (S)-2-amino-3-(2,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled to 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=10.19 min. MS (ESI−): mass calcd. for C22H15Cl2IN4O5S2, 677.32; m/z found, 675/677 [M−H]−. H NMR (500 MHz, CDCl3): 11.16 (s, 1H), 8.34 (d, J=7.1, 1H), 8.21 (d, J=8.8, 1H), 8.07-8.05 (m, 1H), 7.71 (dd, J=8.8, 7.1, 1H), 7.40-7.39 (m, 1H), 7.32-7.26 (m, 1H), 7.24-7.22 (m, 2H), 6.94 (d, J=8.3, 1H), 6.53 (d, J=7.5, 1H), 5.02-4.95 (m, 1H), 3.53-3.44 (m, 1H), 3.34-3.24 (m, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[O:43]=[C:44]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)[CH2:45][NH:46][C:47](=[O:61])[C:48]1[CH:53]=[CH:52][C:51]([O:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:50][CH:49]=1>CN(C=O)C.O>[CH3:10][C:11]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=1[C:13]([N:65]1[CH2:66][CH2:67][N:62]([C:44](=[O:43])[CH2:45][NH:46][C:47](=[O:61])[C:48]2[CH:49]=[CH:50][C:51]([O:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)=[CH:52][CH:53]=2)[CH2:63][CH2:64]1)=[O:15]
Reactant: Cc1ccc(C(=O)O)c(C)c1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(C(=O)N2CCN(C(=O)CNC(=O)c3ccc(Oc4ccccc4)cc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
DIPEA (0.138 mL, 0.80 mmol) was added drop wise to 2,4-Dimethylbenzoic acid (48 mg, 0.32 mmol) in DMF (5 mL). EDCI (127 mg, 0.67 mmol) and HOBT (43 mg, 0.32 mmol) were added consecutively. After 10 mins, N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide hydrochloride (100 mg, 0.27 mmol) was added and the resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (silica gel of mesh size of 60-120 using 60:40 EtOAc:hexane as eluent) afforded N-{2-[4-(2,4-dimethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenoxy-benzamide in 56% yield. LC-MS purity: 98%, 1H NMR (DMSO-D6): δ 8.5 (t, 1H), 7.9 (d, 2H), 7.4 (t, 2H), 7.2 (t, 1H), 7.1 (m, 7H), 4.1 (d, 2H), 3.6 (m, 4H), 3.4 (m, 2H), 3.2 (m, 2H), 2.3 (s, 3H), 2.2 (s, 3H).
Reaction SMILES: [Na+].[CH2:2]([O:5][C:6]1([CH3:35])[CH2:11][CH2:10][N:9]([C:12]2[N:17]3[CH:18]=[C:19]([C:21]([O-:23])=O)[N:20]=[C:16]3[CH:15]=[C:14]([CH3:24])[C:13]=2[C@H:25]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:26]([O:28][CH3:29])=[O:27])[CH2:8][CH2:7]1)[CH:3]=[CH2:4].[CH2:36]([O:40][C:41]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:42]=1[CH2:43][NH2:44])[CH2:37][CH:38]=[CH2:39].C(OC1C=CC=CC=1CNC(C1N=C2C=C(C)C([C@H](OC(C)(C)C)C(OC)=O)=C(N3CCC(CCC=C)(C)CC3)N2C=1)=O)C=C>>[CH2:36]([O:40][C:41]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:42]=1[CH2:43][NH:44][C:21]([C:19]1[N:20]=[C:16]2[CH:15]=[C:14]([CH3:24])[C:13]([C@H:25]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[C:26]([O:28][CH3:29])=[O:27])=[C:12]([N:9]3[CH2:10][CH2:11][C:6]([CH3:35])([O:5][CH2:2][CH:3]=[CH2:4])[CH2:7][CH2:8]3)[N:17]2[CH:18]=1)=[O:23])[CH2:37][CH:38]=[CH2:39]
Reactant: C=CCCOc1ccc(F)cc1CN
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)[O-])cn23)CC1
Agent: C=CCCC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)NCc4ccccc4OCC=C)cn23)CC1
Agent: [Na+]
Product: C=CCCOc1ccc(F)cc1CNC(=O)c1cn2c(N3CCC(C)(OCC=C)CC3)c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc2n1
Yield: 61 %

Procedure:
Prepared from (S)-5-(4-(allyloxy)-4-methylpiperidin-1-yl)-6-(1-(tert-butoxy)-2-methoxy-2-oxoethyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylic acid sodium salt and 2-(but-3-en-1-yloxy)-5-fluorobenzylamine in 61% yield using the same procedure as (S)-methyl 2-(2-((2-(allyloxy)benzyl)carbamoyl)-5-(4-(but-3-en-1-yl)-4-methylpiperidin-1-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. LCMS (ESI, M+1):651.35.
Reaction SMILES: [CH:1]([C@:3]1([CH3:27])[S:9][C@H:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[C@H:4]1[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=O.[CH2:28]([O:35][C:36]([CH:38]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:28]([O:35][C:36](/[CH:38]=[CH:1]/[C@:3]1([CH3:27])[S:9][C@H:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[C@H:4]1[C:11]([O:13][CH:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[C@@]1(C=O)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Solvent: C1CCOC1
Product: C[C@@]1(/C=C/C(=O)OCc2ccccc2)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
763 mg (2.0 mmol) of benzhydryl (2S,3R,5R)-3-formyl-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate were dissolved in 15 ml of THF under argon, treated with 821 mg (2.0 mmol) of benzyloxycarbonylmethylene-triphenylphosphorane and the orange solution was stirred at 50° C. for 2 hours. It was left to cool to room temperature, the solvent was removed on a rotary evaporator and the red-brown oil was chromatographed over silica gel (particle size 0.040-0.063 mm) with ethyl acetate:hexane (9:16) as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][C:14]([O:16]C)=[O:15])[CH:7]=[CH:6]2.C(=O)([O-])[O-].[Na+].[Na+].CO>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2
Reactant: COC(=O)Cc1ccc2cc(OC)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2cc(CC(=O)O)ccc2c1

Procedure:
A mixture of 25 g. of methyl 6-methoxy-2-naphthylacetate, 15 g. of sodium carbonate, 200 ml. of methanol, and 25 ml. of water are stirred for 24 hours. The reaction mixture is then acidified with 200 ml. of 2 N hydrochloric acid and extracted with methylene chloride. The extracts are combined, washed with water, dried over sodium sulfate, and evaporated to yield 6-methoxy-2-naphthylacetic acid.
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:14][N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.[OH-].[Na+].[O:19]([CH2:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:19]([CH2:26][C:27]([NH:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:11][N:12]=[N:13][N:14]=3)[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]12)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1c1nnn[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A stirred slurry of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam (480 mg.) inwater (10 ml.) is cooled to 0° C., and then the pH is adjusted to 8.0 using 1N sodium hydroxide. To this solution is then added phenoxyacetyl chloride, (0.25 ml.) in portions, with the pH of the solution being maintained between 7 and 8 during the addition, using 0.1N sodium hydroxide. The solution is stirred a further 30 minutes at 0° C. at pH 8. It is then extracted with chloroform, and the extracts are discarded. The aqueous phase is acidified to pH 2 with dilutehydrochloric acid, and then it is further extracted with chloroform. The latter extracts are dried using calcium sulfate and then evaporated in vacuo to give the crude product as a gummy solid. This is purified by dissolving it in chloroform (20 ml.), and adding the resultant solution dropwise to hexane (250 ml.). The precipitate which forms is filtered off,giving 385 mg. of 6-(2-phenoxyacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamas a white amorphous solid. The infrared spectrum (KBr disc) of the productshows absorption bands at 1785 cm-1 (β-lactam carbonyl), 1670 cm-1 (amide I band) and 1540 cm-1 (amide II band). The NMR spectrum (in DMSO-d6) shows absorption bands at 7.50- 6.70 ppm (multiplet, aromatic hydrogens), 5.70 ppm (multiplet, C-5 and C-6hydrogens), 5.35 ppm (singlet, C-3 methyl hydrogens), 4.66 ppm (s, 2, φ-OCH2) and 1.66 + 1.16 (s, 3H, each, C-2 methyls)ppm.