Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22]([OH:24])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.[N+:33](=[CH2:35])=[N-:34]>>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:22](=[O:24])[CH:35]=[N+:33]=[N-:34])=[CH:19][CH:18]=1
Reactant: C=[N+]=[N-]
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Product: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)C=[N+]=[N-])cc1

Procedure:
In a manner analogous to that described in Example 19(i), 3.10 g of N-(benzyloxycarbonyl)-3-(4-methoxyphenyl)-L-alanine were treated with isobutyl chloroformate followed by diazomethane to give 2.83 g of benzyl [2-(4-methoxyphenyl)-l(S)-(2-diazoacetyl)ethyl]carbamate as a pale yellow solid of melting point 88°-90° C.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.P(Cl)(Cl)(Cl)=O.C[O:12][CH:13](OC)[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[OH-].[Na+].CNC>O.C(Cl)(Cl)Cl>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:14](=[CH:3][N:2]([CH3:5])[CH3:1])[CH:13]=[O:12])=[CH:17][CH:18]=1
Reactant: COC(COc1ccc(Cl)cc1)OC
Reactant: CN(C)C=O
Agent: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)C=C(C=O)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Dimethylformamide (109.5 g., 1.5 moles) was cooled in an ice-water bath. Phosphorus oxychloride (229.5 g., 1.5 moles) was added dropwise over 1.5 hours and the reaction mixture then allowed to stir for 45 minutes at room temperature. Chloroform (300 ml.) was added and then 4-chlorophenoxyacetaldehyde dimethylacetal (122 g., 0.5 moles) and the mixture refluxed for approximately 16 hours. The reaction was cooled to room temperature and added slowly to approximately 300 ml. of chloroform mixed with ice and water while maintaining the pH approximately 10 with sodium hydroxide. Aqueous 40% dimethylamine (400 ml.) was added, the organic layer separated and the aqueous extracted with additional chloroform. The chloroform extracts were combined, dried over anhydrous sodium sulfate, concentrated to a semisolid, and crystalline product recovered by trituration with isopropyl ether (95 g., Rf 0.25 on thin layer chromatography on silica gel with ethyl acetate as eluant).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[OH:14])([CH3:6])([CH3:5])[CH3:4].[CH2:15](Cl)[O:16][CH3:17].[Cl-].[NH4+]>CCCCCC.C1COCC1.C(OCC)(=O)C>[C:3]([C:7]1[C:8]([O:14][CH2:15][O:16][CH3:17])=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cccc(C(C)(C)C)c1O
Reactant: COCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1c(C)cccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.4 %

Procedure:
NaH (60% in mineral oil, 4.5 g, 0.12 mol) is washed twice with hexane (50 ml) and added with THF (75 ml), and the mixture was cooled to below 10° C. A solution of 2-tert-butyl-6-methylphenol 42 (16.4 g, 0.1 mol) in THF (60 ml) was then dropwise and slowly added, and the mixture was stirred for 10 minutes under the same conditions. The mixture was then dropwise added with MOMCl (9.1 ml, 0.12 mol), warmed to room temperature, and the reaction mixture was added with saturated aqueous ammonium chloride (200 ml) and ethyl acetate (200 ml). The organic layer was separated, washed sequentially with water (200 ml), 1.5N NaOH (200 ml), water (100 ml), and saturated brine (200 ml), and dried. The solvent was removed in vacuo to give 20.5 g (98.6%) of 43 as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33].O>ClCCl>[C:32]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)(=[O:34])[CH3:33]
Reactant: Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(6-aminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine, 2a (6.5 g) and triethylamine (3 ml) in dichloromethane (150 ml) cooled to 0° C. was added dropwise a solution of acetylchloride (1.7 g) in dichloromethane (50 ml). The mixture was stirred for one hour at room temperature. Water (500 ml) was added, the organic phase separated, washed with brine (2×50 ml) and finally worked-up as above. The thus isolated crude title product was purified by column chromatography on silica gel (eluted with a mixture of ethyl acetate/heptane/ triethylamine 75:25:4). Recrystallization from diethyl ether yielded 7.7 g of pure title compound 4a. Mp: 159-162° C. 1H NMR (CDCl3): δ 1.70-1.90 (m, 5 H); 2.00-2.15 (m, 1 H); 2.15 (s, 3 H); 2.20-2.30 (m, 1 H); 2.35-2.50 (m, 2 H); 2.60 (dd, 1 H); 2.70-2.90 (m, 2 H); 2.95-3.15 (m, 2 H); 3.45 (qui, 1 H); 6.95 (t, 2 H); 7.05-7.25 (m,5 H); 7.55 (s, 1 H)
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:20]=1[F:35]>C1COCC1>[F:35][C:20]1[C:21]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[CH:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1Oc1ccccc1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(Oc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.5 %

Procedure:
Sodium hydride (60% oil dispersion) (3.75 g, 94 mmol) was added in portions to a solution of di-t-butyl malonate (10.49 ml, 46.9 mmol) in THF (200 mL). After gas evolution subsided, a solution of 1,2-difluoro-4-nitro-3-(phenyloxy)benzene (10.70 g, 42.6 mmol) in THF (100 mL) was added. The mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated. Chromatography of the residue (ethyl acetate:hexanes) gave the desires product (2.38 g, 12.5%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.81 (dd, 1H), 7.53 (dd, 1H), 7.27-7.35 (m, 2H), 7.09 (t, 1H), 6.93 (d, 2H), 4.80 (s, 1H), 1.48 (s, 18H). ES MS: m/z 470 (M+23).
Reaction SMILES: C([O:8][CH2:9][C:10]([NH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][C:20]=2[N:22]2[CH2:27][CH2:26][N:25](CC3C=CC=CC=3)[CH2:24][CH2:23]2)[NH:15][CH:14]=1)=[O:11])C1C=CC=CC=1.CCN(C(C)C)C(C)C>CO.Cl.[Pd]>[OH:8][CH2:9][C:10]([NH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][C:20]=2[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[NH:15][CH:14]=1)=[O:11]
Reactant: O=C(COCc1ccccc1)Nc1c[nH]c2nccc(N3CCN(Cc4ccccc4)CC3)c12
Agent: [Pd]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(CO)Nc1c[nH]c2nccc(N3CCNCC3)c12
Yield: 99.5 %

Procedure:
2-(Benzyloxy)-N-(4-(4-benzylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (0.100 g, 0.219 mmol) was placed in MeOH (2 mL). Pd/C (0.0467 g, 0.0220 mmol) was then added, followed by the addition of 3 drops of concentrated HCl. The reaction was next placed under an H2 filled balloon for 3 hours. Additional Pd/C (0.0467 g, 0.0219 mmol) was then added, and the reaction was placed under an H2 filled balloon for an additional 3 hours to drive the reaction to completion. DIEA was added to achieve solubility. The reaction was then filtered, washed with MeOH, and concentrated to give the crude product 2-hydroxy-N-(4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (0.060 g, 99.2% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11].C1C(=O)N([Br:27])C(=O)C1>CC#N.C(Cl)Cl>[Br:27][C:17]1[CH:18]=[C:13]([O:12][CH:10]([C:3]2[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH3:11])[C:14]([NH2:19])=[N:15][CH:16]=1
Reactant: CC(Oc1cccnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC#N
Product: CC(Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
To a solution of 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine-2-amine (7.49 g, 24.87 mmol) in CH3CN/DCM (100/30 mL) was added NBS (4.43 g, 24.87 mmol) in portions at 0° C. The reaction solution was stirred at 0° C. for 10 min. The precipitate was removed by filtration. The black filtrate was concentrated to give a black residue which was purified by CombiFlash (80 g silica gel column, EtOAc/Hexane) to afford 5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (7.8 g, 82%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN.C[CH2:21][N:22](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[CH3:14][C:13]([CH3:16])([CH3:15])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]([NH:22][CH3:21])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CC#N
Product: CNC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)C
Reaction time: 0.33 h
Yield: 77.7 %

Procedure:
To a cold solution of (R)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid (0.50 g, 2.16 mmol) in acetonitrile (8 mL) was added methylamine hydrochloride (0.48 g, 7.13 mmol), followed by DIEA (1.67 g, 12.9 mmol). The resulting mixture was stirred for 20 min and TBTU (0.76 g, 2.37 mmol) was added and the stiffing continued overnight. The mixture was concentrated, diluted with EtOAc (30 mL) and washed successively with aqueous 5% KHSO4, saturated NaHCO3 solution and brine, dried over anhydrous Na2SO4, filtered and concentrated to provide Intermediate 30A (0.41 g, 77%).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])=[C:11]([F:26])[CH:10]=[C:9]([Cl:27])[C:7]=2[CH:8]=1)([OH:3])=[O:2].[C:28](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:27][C:9]1[C:7]2[CH:8]=[C:4]([C:1]([O:3][CH3:28])=[O:2])[O:5][C:6]=2[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[N:15]([CH3:24])[C:14]2=[O:25])=[C:11]([F:26])[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(C(=O)O)oc23)c1=O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
0.21 g (0.5 mmol) of 3-(2-carboxy-4-chloro-6-fluorobenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil and 0.16 g (1.1 mmol) of potassium carbonate were suspended in 10 ml of N,N-dimethylformamide, and 0.15 g (1.1 mmol) of methyl iodide was added thereto at room temperature, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.21 g (yield: 96.8%) of the desired product as yellowish brown crystals. Melting point: 194-196° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]#[C:14][CH3:15])=[CH:7][N:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1)[C:13]#[C:14][CH3:15]
Reactant: CC#CCOc1ccc(C(=O)OC)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC#CCOc1ccc(C(=O)O)nc1
Temperature: 22 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a solution of 5-but-2-ynyloxy-pyridine-2-carboxylic acid methyl ester (234 mg) in THF (20 ml) and water (15 ml) was added aqueous LiOH (1M, 2.3 ml) and the mixture was stirred at 22° C. for 1 h. The mixture was treated with aqueous HCl (1M, 2.3 ml), evaporated slowly, the suspension obtained was filtered, the residue washed with water and dried to give the title product (165 mg) as a white solid. MS: m/z=192.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][C:16]=2[N+:30]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1.O.[Fe]>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:17][C:16]=2[NH2:30])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(NC(=O)c3ccccc3)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(NC(=O)c3ccccc3)cc2N)cc1
Yield: 95.4 %

Procedure:
The product from Example 252a (1.50 g, 3.3 mmol), Fe powder (0.78 g, 13.4 mmol) and NH4Cl (0.71 g, 13.4 mmol) in a mixture of THF (7.5 mL) and H2O (3 mL) was gradually heated to reflux and refluxed for 19 hours. The reaction mixture was portioned between EtOAc and 10% NaHCO3 and then filtered (through celite). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under vacuum giving the crude title compound which was purified by column chromatography on silica gel eluting with 1:1 n-hexane/EtOAc to give the title compound as a yellow foam (1.32 g, 94%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([O:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[Cl:63])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[Cl:63][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=1[O:56][CH:53]1[CH2:52][CH2:51][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:21]([C:19]2[CH:18]=[N:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:23])[CH2:55][CH2:54]1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Reactant: O=C(O)c1cnn(-c2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cnn(-c2ccccc2)c1
Reaction time: 0.03 h
Yield: 46.9 %

Procedure:
DIPEA (223 mg, 0.3 mL, 1.72 mmol) was added to a stirred solution of 1-phenyl-1H-pyrazole-4-carboxylic acid (65 mg, 0.34 mmol) in DMF (5 mL) followed by HOBt (51 mg, 0.38 mmol) and EDCI (165 mg, 0.86 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride salt (116 mg, 0.38 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (using 60-120 silica gel and 70% EtOAc in hexane as eluent) to afford 70 mg (46.35% yield) of 1-phenyl-1H-pyrazole-4-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 439.15, 95.23%. 1H NMR (300 MHz, CDCl3): δ 8.4 (s, 1H), 8.06 (s, 1H), 7.76 (d, 2H), 7.54 (t, 2H), 7.42 (m, 2H), 7.2 (d, 1H), 7.1 (t, 1H), 7.0 (t, 2H), 4.7 (t, 1H), 4.4-4.2 (m, 2H), 4.1 (m, 1H), 3.8-3.5 (m, 2H), δ 3.5 (m, 1H), 2.1-1.8 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([CH:7](C(OC)=O)[C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.C(O)(=O)CCCCCCCCCCC(O)=O>>[O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:3]1
Reactant: COC(=O)C(C(=O)OC)C1CCC(=O)C1
Agent: O=C(O)CCCCCCCCCCC(=O)O
Product: COC(=O)CC1CCC(=O)C1
Temperature: 210 °C
Yield: 71 %

Procedure:
A 1000 mL flask was charged with dimethyl 2-(3-oxocyclopentyl)malonate (329.1 g, 1536 mmol), and dodecanedioic acid (283 g, 1229 mmol). The mixture was heated (210° C., oil bath) under a nitrogen atmosphere for 20 hrs, then distilled (˜1 torr, 180° C. oil bath) to give the title compound (170.4 g, 1091 mmol, 71.0% yield) as a pale yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 3.68 (3 H, s), 2.55-2.66 (1 H, m), 2.40-2.51 (3 H, m), 2.27-2.35 (1 H, m), 2.13-2.26 (2 H, m), 1.87 (1 H, ddd, J=18.23, 10.30, 1.37 Hz), 1.53-1.63 (1 H, m). 13C NMR (126 MHz, CDCl3) δ ppm 218.36, 172.58, 51.78, 44.70, 39.53, 38.40, 33.52, 29.31.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10][CH:9]1[C:17]([O-:19])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C(=O)(O)[O-].[NH4+].C[N:27](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.C([O-])(O)=O.[Na+].[OH-].[Na+]>[C:17]([CH:9]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1)(=[O:19])[NH2:27]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1c2ncccc2CC1C(=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1c2ncccc2CC1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
To a suspension of lithium 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (100 mg, 370 μmol, Eq: 1.00) in DMF (5.00 mL) was added sequentially ammonium bicarbonate (90.0 mg, 1.14 mmol, Eq: 3.08), HATU (210 mg, 552 μmol, Eq: 1.49) and triethylamine (100 μL, 717 μmol, Eq: 1.94). The resulting dark yellow mixture was stirred at rt for 2 h. The reaction mixture was diluted with saturated aqueous NaHCO3 (10 mL) and 1 M aqueous NaOH (0.5 mL) and extracted with DCM. The combined organic layers were dried (Na2SO4) and concentrated in vacuo, using n-heptane to azeotrope off residual DMF. The resulting residue was purified by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM) to give tert-butyl 2-carbamoyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate as a white solid (100 mg), m/z=264 (M+H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[C:27]([CH2:30][S:31][C:32]1[N:33]=[CH:34][N:35]2[CH:39]=[C:38]([Sn](CCCC)(CCCC)CCCC)[S:37][C:36]=12)(=[O:29])[NH2:28]>>[C:27]([CH2:30][S:31][C:32]1[N:33]=[CH:34][N:35]2[CH:39]=[C:38]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[S:37][C:36]=12)(=[O:29])[NH2:28]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCC(N)=O)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCC(N)=O)c4s3)[C@H](C)[C@H]12
Yield: 59.9 %

Procedure:
The procedure of Example 1a) was repeated, except that 231 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 336 mg of 7-carbamoylmethylthio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 213 mg of 4-nitrobenzyl (1S,5R,6S)-2-(7-carbamoylmethylthioimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12]([CH:14]([O:16]C(=O)C)[CH3:15])=[O:13])[NH:7][C:6](=[O:20])[CH2:5]2.[OH-].[Na+].[CH3:23]O>O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12](=[O:13])[C:14]([OH:16])([CH3:15])[CH3:23])[NH:7][C:6](=[O:20])[CH2:5]2
Reactant: CO
Reactant: CC(=O)OC(C)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
A stirred mixture of acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-ethyl ester (720 mg, 2.45 mmol) in methanol (5 ml) and water (5 ml) was added with sodium hydroxide (200 mg, 50 mmol). The resulting mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was extracted with ethyl acetate (100×3) and water (100×3). The organic extracts were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propionamide (220 mg, 35.6%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=1[C:13]([OH:15])=O)[C:4](=[O:6])[CH3:5])[CH3:2].C[O-].[Na+]>O1CCOCC1>[CH2:1]([N:3]1[C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:13]([OH:15])=[CH:5][C:4]1=[O:6])[CH3:2]
Reactant: CCN(C(C)=O)C1=C(C(=O)O)CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1c2c(c(O)cc1=O)CCCC2

Procedure:
A solution of the ethyl and methyl esters (60:40 ratio) of 2-(N-ethyl-acetamido) cyclohex-1-ene-1-carboxylic acid (10 g; 0.043 mole) in dry dioxan (100 ml) was treated with sodium methoxide (2.54 g; 0.047 mole) and the mixture heated for 2 hrs. at 100° C. A white solid separated within a few minutes. After cooling the precipate was filtered free of dioxan, taken up in a minimum of water and brought to pH 4 with concentrated hydrochloric acid. The product separated as a white solid which after filtration was recrystallised from glacial acetic acid, m.p. 355° - 358° C (d).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)=[N:4][NH:5][C:6]=1[CH3:7].[H-].[Na+].I[CH3:17].[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[C:3]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)=[N:4][N:5]([CH3:17])[C:6]=1[CH3:7]
Reactant: CI
Reactant: Cc1[nH]nc(-c2ccc(Cl)s2)c1Br
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1c(Br)c(-c2ccc(Cl)s2)nn1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
4-Bromo-3-(5-chloro-2-thienyl)-5-methyl-1H-pyrazole (35.3 mmol) was dissolved in 30 mL dry N,N-dimethylformamide and cooled to 0° C. under nitrogen atmosphere. Sodium hydride (37.1 mmol, 60% dispersion in mineral oil) was added in portions at 0° C. After stirring for 30 min, iodomethane (42.4 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The solution was poured into saturated aqueous ammonium chloride solution and extracted with diethyl ether, dried over MgSO4, filtered and evaporated. The crude product was purified by chromatography on silica gel (100% dichloromethane) to afford 5.6 g 4-bromo-3-(5-chloro-2-thienyl)-1,5-dimethyl-1H-pyrazole (54% yield)