Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]([CH3:30])[CH3:29])[C:6]2[O:10][C:9]([C:11]3[CH:26]=[CH:25][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:27]=1)#[N:2].[CH:31]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(C(C)C)CC)(C)C>ClCCl.C(OCC)(=O)C.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]([CH3:30])[CH3:29])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:39](=[O:40])[CH2:38][CH2:37][CH:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)[CH2:21][CH2:20]4)=[O:16])=[CH:25][CH:26]=3)=[N:8][C:7]=2[CH:27]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCNCC4)cc3)oc12
Reactant: O=C(Cl)CCC1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(C(=O)CCC5CCCCC5)CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-(piperidin-4-ylmethyl)benzamide (20 mg, INTERMEDIATE 15) in 5 ml of dichloromethane was added 3-cyclohexylpropanoyl chloride (13 mg), and then diisopropylethylamine (450 μl). The reaction was stirred for 2 h at room temperature. The mixture was then diluted with 10 ml of ethyl acetate and 10 ml of water. The phases were separated and the aqueous phase was extracted with 10 ml of ethyl acetate. The combined organic phases were washed with 10 ml of brine, dried over Na2SO4, and concentrated. The residue was purified by reverse-phase HPLC on a Biotage Parallex Flex, Kromasil C18 21×100 mm column, eluting at 15 ml/min with 90% water (0.1% TFA) to 95% acetonitrile (0.1% TFA) over 10 min, hold for 2 min, then back to 90% water over 0.5 min, hold for 0.5 min, to provide the title compound (12 mg, 36%). Mass spectrum (ESI) 541.3 (M+1). 1H NMR signals are doubled and broadened because of restricted rotation about the amide C—N bond. 1H NMR (500 MHz, CDCl3): δ 8.32 (d, J=8 Hz, 2H), 8.19 (s, 1H), 7.95 (d, J=8 Hz, 2H), 7.92 (d, J=1 Hz, 1H), 7.51 (s, 1H), 6.68-6.70 (m, 1H), 6.65 (m, 1H), 3.89-3.98 (m, 1H), 3.44-3.50 (m, 2H), 3.35 (m, 1H), 3.084 (m, 1H), 2.72 (s, 1H), 2.62 (m, 1H), 2.37-2.40 (m, 3H), 1.98 (m, 1H), 1.87 (m, 2H), 1.62-1.70 (m, 7H), 1.48 (m, 3H), 1.45 (d, J=7 Hz, 6H), 1.336 (d, H=7 Hz, 2H), 1.09-1.24 (m, 10H), 0.86-0.93 (m, 3H).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:16][CH:17]([CH3:19])[CH3:18])(=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13].[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH:22]=[CH:21]1.Cl.N1C=CC=C[CH:29]=1>O1C=CCCC1>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:16][CH:17]([CH3:19])[CH3:18])(=[O:15])/[CH:10]=[CH:11]\[C:12]([O:14][CH:23]1[CH2:22][CH2:21][CH2:29][CH2:20][O:25]1)=[O:13].[C:23]1(=[O:24])[O:25][C:20](=[O:26])[CH:21]=[CH:22]1
Reactant: c1ccncc1
Reactant: CC(C)OC(=O)/C=C\C(=O)O
Agent: C1=COCCC1
Agent: Cl
Agent: O=C1C=CC(=O)O1
Solvent: C=Cc1ccccc1
Product: CC(C)OC(=O)/C=C\C(=O)OC1CCCCO1
Temperature: 25 °C

Procedure:
A 5 g sample of poly(styrene [50 mol %], isopropyl hydrogen maleate [32 mol %], maleic anhydride [18 mol %]) was suspended in 75 mL of 3,4-dihydro-2H-pyran and treated with 0.1 g of pyridine hydrochloride. The mixture was stirred at reflux for 18 hours, during which time a homogeneous solution was formed. After cooling to room temperature, the solution was stirred for 1 hour with crosslinked poly(dimethylaminomethylstyrene) to remove the catalyst. After filtration, the product was isolated from the filtrate by precipitation in methanol and dried to give 3 g of poly(styrene, isopropyl tetrahydropyranyl maleate, maleic anhydride). Titration of the starting material with 0.1N sodium hydroxide shows 4.32 meq/g of anhydride and acid. Titration of the product shows 2.49 meq/g of anhydride. IR analysis of the product shows absorption characteristic of anhydride (1855 and 1780 cm-1), but no absorption characteristic of carboxylic acid. Differential scanning calorimetry (DSC) of the product shows a sharp decomposition endotherm peaking at 153.9° C. (104.1 J/g) which is absent from the starting material. Thermal gravimetric analysis (TGA) shows a 13.36% weight loss centered at 154.54° C. which is not seen in the TGA of the starting material. The thermal event at 154° C. is the thermal loss of dihydropyran to form polymeric carboxylic acid groups.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH:9]1[CH2:18][CH2:17][N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10]1)#[N:8].O.[OH-].[Na+]>C1COCC1>[CH2:10]1[CH:11]2[N:16]([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:17][CH2:18][CH:9]1[CH2:7][NH2:8]
Reactant: N#CC1CCN2CCCCC2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC1CCN2CCCCC2C1

Procedure:
A stirred suspension of lithium aluminium hydride (400 mg, 0.010 mole) in THF (20 ml) at room temperature under nitrogen was treated with a solution of eq-2-cyanoquinolizidine (E. Koshinaka et al, Yakugaku Zasshi 1980, 100, 88) in THF (3 ml) and the mixture then heated under reflux for 20 minutes. The mixture was allowed to cool then treated cautiously with water (0.4 ml), 10% NaOH solution (0.4 ml) and water (1.2 ml). The resulting mixture was filtered and the filtrate concentrated in vacuo. The residue was distilled in a Kugelrohr apparatus to afford the title compound (D13); as a colourless oil (700 mg, 97%).
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26](OC3C=CC([N+]([O-])=O)=CC=3)=[O:27])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH:39]1[CH2:42][CH:41]([OH:43])[CH2:40]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:43][CH:41]1[CH2:42][N:39]([C:26]([N:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])[CH2:11]2)=[O:27])[CH2:40]1
Reactant: OC1CNC1
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1)c1ccccc1

Procedure:
80 mg (0.16 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidine-1-carboxylate were initially charged in 1.7 ml of DMF, and 51 mg (0.47 mmol) of azetidin-3-ol hydrochloride and 22 mg (0.16 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 15 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CC([O-])(C)C.[K+]>[Ru].CC(O)C>[C:4]1([C@@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Agent: [Ru]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: C[C@H](O)c1ccccc1
Temperature: 30 °C
Reaction time: 0.17 h

Procedure:
Under nitrogen stream, acetophenone (20 mmol), RuCl[(S)-xylbinap][(S)-daipen] (1/100 molar fold of acetophenone) and t-BuOK (5 molar folds of the ruthenium catalyst) were added to a Schlenk tube. 2-propanol (8.3 mL per 100 mg of acetophenone) was added, then stirred for 10 minutes at 30° C. As a result of analysis of the reaction mixture by gas chromatography (Chirasil-DEX CB), it was found that the conversion rate is 94%, and the optical purity is 98.4% ee.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].C(=O)([O-])[O-].[K+].[K+].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CN(C=O)C.O>[Cl:5][CH2:4][CH2:3][CH2:2][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1-bromo-3-chloropropane (3.4 mL, 34.5 mmol) in DMF (40 mL), was added potassium carbonate (6.4 g, 69 mmol) and morpholine (2.0 mL, 23.0 mmol). The solution was stirred at RT for 15 h, then diluted with H2O (150 mL). The mixture was extracted with EtOAc (3×25 mL) and the organic extracts were washed with H2O and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give title compound as a colorless oil. MS (ESI, pos. ion) m/z: 164 (M+1). Mass Calc'd for C7H14ClNO: 163.08.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[N:15]=[C:14]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C1C(=O)N([I:38])C(=O)C1.O>CC(O)=O.C(Cl)Cl.C(Cl)Cl>[I:38][C:13]1[C:14]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[N:15][N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[C:12]=1[NH:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc(-c2cc(Nc3ccc(C)cc3C(=O)O)n(-c3ccccc3C)n2)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2nn(-c3ccccc3C)c(Nc3ccc(C)cc3C(=O)O)c2I)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.4 %

Procedure:
To a solution of 5-methyl-2-{[1-(2-methylphenyl)-3-(4-methylphenyl)-1H-pyrazol-5-yl]amino}benzoic acid (Example 65), (49.5 mg, 0.13 mmol) in AcOH/DCM (1:1, v/v) (2 mL) was added a solution of NIS (28 mg, 0.13 mmol) in DCM (1 mL). The reaction was stirred at rt for 3 h. Water (1 mL) was added to the reaction mixture. The water layer was extracted with DCM (2 mL), and the combined organic layers were washed with sodium sulfite and brine, and concentrated under reduced pressure. The crude product was subjected to HPLC purification with a gradient elution from 30% to 95% acetonitrile in water to afford 9.1 mg (14%) of the title compound. 1H NMR (300 MHz, CD2Cl2) δ 8.88 (s, 1H), 7.85 (d, 2H), 7.74 (s, 1H), 7.18-7.32 (m, 7H), 6.58 (d, 1H), 2.41 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H). ES-MS m/z 524.1 (MH+); HPLC RT (min) 4.35.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2].C1C(=O)N([Cl:24])C(=O)C1.O>CN(C=O)C>[C:1]([O:4][C:5]1[C:6]([O:15][CH3:16])=[CH:7][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[C:9]([Cl:24])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(CC(=O)O)ccc1OC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CC(=O)O)c(Cl)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of [4-(acetyloxy)-3-methoxyphenyl]acetic acid (650 mg, 2.90 mmol) in DMF (10 mL) was added a solution of NCS (428 mg, 3.192 mmol) in DMF (5 mL) dropwise at 0° C. The mixture was stirred at ambient temperature for 6 hrs, and then poured into water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were washed with 1 N HCl, brine, dried over Na2SO4 and then concentrated to obtain [4-(acetyloxy)-2-chloro-5-methoxyphenyl]acetic acid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.Br[C@@H:18]([CH3:22])[C:19]([OH:21])=[O:20]>C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C@H:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH2:13][CH2:14]2)=[N:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: C[C@H](Br)C(=O)O
Solvent: ClCCl
Product: C[C@H](C(=O)O)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
A solution of 1-(5-trifluoromethyl-pyridin-2-yl)-piperazine (2.77 g, 11.99 mmoles) in DCM (42 mL) and TEA (4.2 mL) was treated with (2S)-2-bromo-propionic acid (1.19 mL, 13.2 mmoles) and stirred overnight at 35° C. The DCM was removed under reduced pressure to provide crude title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3=[O:17])=[C:5]([CH3:18])[O:4][N:3]=1.[C:19]1([Mg]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([OH:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(=O)C(=O)N2
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(O)(c1ccccc1)C(=O)N2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
5-(3,5-Dimethylisoxazol-4-yl)indoline-2,3-dione (24.2 g, 0.1 mol) was dissolved in anhydrous THF (400 mL) and cooled to 0° C. followed by dropwise addition of a 2.0 M solution of PhMgBr in THF (110 mL, 220.0 mmol). The ice-bath was removed, and the reaction was stirred under N2 for 30 min at which point TLC analysis indicated complete consumption of the starting material. The reaction mixture was quenched with saturated aqueous NH4Cl (100 mL), and extracted with EtOAc (3×100 ml). The combined organic layers were washed with saturated aqueous NaHCO3 (100 ml), brine (100 ml), dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was evacuated under high vacuum to give the crude alcohol (30 g, 94%). 1H NMR (400 MHz, DMSO-d6): δ 10.50 (s, 1H), 7.22-7.32 (m, 6H), 7.09 (d, J=1.2 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 6.71 (brs, 1H), 2.32 (s, 3H), 2.15 (s, 3H) MS (ESI) m/e [M+1]+ 321.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:29]2([CH3:30])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:32][C:33](=[O:35])[CH3:34])[CH2:6]1)(=[O:3])[CH3:2].CCCCCC.BrN1C(C)(C)C(=O)N(Br)C1=O.CC1C=C(C)N=C(C)C=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[C:1]([O:4][C@@H:5]1[C@@:29]2([CH3:30])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[CH2:8][C@@H:7]([O:32][C:33](=[O:35])[CH3:34])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: Cc1cc(C)nc(C)c1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reaction time: 0.33 h
Yield: 93.8 %

Procedure:
A soluton of 1α,3β-diacetoxycholest-5-ene (972 mg, 2 m moles), dry hexane (15 ml) and 1,3-dibromo-5,5-dimethyl hydantoin (343 mg, 1.2 m moles) was reacted at the oil bath temperature of 95° C. under the irradiation of infrared rays for 15 minutes. The reaction mixture was cooled, and the resulting 5,5-dimethyl hydantoin and the excessive 1,3-dibromo-5,5-dimethylhydantoin were removed by filtration. The filtrate was concentrated at reduced pressure to afford a residual product. Xylene (6 ml) was added to this substance to form a solution. The resulting solution was added dropwise to a solution held at 170° C. of s-collidine (5 ml) in dry xylene (6 ml), and the reaction was carried out for additional 20 minutes. After the reaction, the hydrobromide of s-collidine was removed by filtration and filtrate was concentrated under reduced pressure to give residual product. The residue was dissolved in ethyl acetate (30 ml). The ethyl acetate solution was washed with 1 N hydrochloric acid (2×10 ml), saturated sodium bicarbonate and water, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give 908 mg of residual product.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19]1[C:22]2([CH2:25][NH:24][CH2:23]2)[CH2:21][O:20]1>CN(C)C=O.O>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:24]2[CH2:25][C:22]3([CH2:19][O:20][CH2:21]3)[CH2:23]2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: C1NCC12COC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CC2(COC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.7 %

Procedure:
2-Fluoro-5-nitrobenzonitrile (1.0 g, 6.02 mmol, purchased from Combi-Blocks AN1040) was dissolved in dimethylformamide (25 mL) under nitrogen. Potassium carbonate (3.50 g, 25.3 mmol) and 2-oxa-6-azaspiro[3.3]heptane (1.05 g, 7.22 mmol, purchased from Ryan Scientific EN300-89755) were added to the mixture. The resulting mixture was stirred at room temperature overnight. The reaction was then diluted with water (75 mL) and extracted with ethyl acetate (4×75 mL). The organic layer was washed with water (5×75 mL) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by Combiflash, eluting with hexane and ethyl acetate to provide the desired product as a bright yellow solid (350 mg, 24% yield).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:9]1([CH2:15][CH2:16][CH2:17][C:18]#[CH:19])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C.O>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]Cl>[CH:9]1([CH2:15][CH2:16][CH2:17][C:18]#[C:19][C:2]2[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=2)[NH2:5])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C#CCCCC1CCCCC1
Reactant: Nc1cccc(I)c1
Agent: Cl[Cu]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1cccc(C#CCCCC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 123.2 %

Procedure:
Under a nitrogen atmosphere, a mixture of 4.4 mL (0.037 mole) of 3-iodoaniline, 6.5 grams (0.043 mole) of 1-cyclohexyl-4-pentyne, 0.3 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, 0.7 gram (catalyst) of copper(I) chloride, and 20.4 mL (0.146 mole) of triethylamine in 100 mL of acetonitrile was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was poured into 200 mL of water, and this mixture then was extracted with three 100 mL portion of diethyl ether. The combined extracts were washed with three 100 mL portions of aqueous 10% citric acid solution and then with one 100 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using 10% methylene chloride in diethyl ether as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 11.0 grams of 3-(5-cyclohexylpentyn-1-yl)aniline that was about 91% pure. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:43])[CH:4]=[C:5]([C:8]([NH:10][N:11]2[CH2:15][CH2:14][N:13]([C:16]([NH:18][NH:19][S:20]([NH:23][C:24]([N:26]3[CH2:29][C@H:28]([NH:30]C(=O)OCC4C=CC=CC=4)[C:27]3=[O:41])=[O:25])(=[O:22])=[O:21])=[O:17])[C:12]2=[O:42])=[O:9])[NH:6][CH:7]=1.C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O>>[NH2:30][C@H:28]1[CH2:29][N:26]([C:24]([NH:23][S:20]([NH:19][NH:18][C:16]([N:13]2[CH2:14][CH2:15][N:11]([NH:10][C:8]([C:5]3[NH:6][CH:7]=[C:2]([OH:1])[C:3](=[O:43])[CH:4]=3)=[O:9])[C:12]2=[O:42])=[O:17])(=[O:22])=[O:21])=[O:25])[C:27]1=[O:41]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)N2CCN(NC(=O)c3cc(=O)c(O)c[nH]3)C2=O)C1=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)N2CCN(NC(=O)c3cc(=O)c(O)c[nH]3)C2=O)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.5 g of (S)-[1-[[[[2-[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1imidazolidinyl]carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester was added to a mixture of 0.5 ml of thioanisole and 2 ml of trifluoroacetic acid. The mixture was stirred overnight at room temperature and evaporated in vacuo. The residue was triturated with ethyl acetate to provide the title compound in quantitative yield.
Reaction SMILES: [CH:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C)(C)N[Si](C)(C)C.[Li].[CH2:27](Br)[CH:28]=[CH2:29].Cl>O1CCCC1.O>[CH2:29]([C:1]1([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: O=C(OCc1ccccc1)C1CCCCC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl cyclohexanecarboxylate (1.44 g) in tetrahydrofuran (40 mL) was added a 1M solution of lithium hexamethyldisilazane in tetrahydrofuran (9.9 mL) under ice cooling. The solution was stirred at room temperature for 1 hour under ice cooling, to which hexamethylphosporamide (2.3 mL) was added. The solution was then stirred for additional 10 minutes. To the solution was added allyl bromide (1.4 mL). The solution was stirred under ice cooling for 1 hour, to which allyl bromide (1.4 mL) was further added. The solution was stirred at room temperature for 18 hours. Water and 3N hydrochloric acid were added to the solution, and it was extracted with diethyl ether. The organic layer was washed in turn with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=99:1) to give the title compound (550 mg). This product was subjected to the subsequent step without further purification.
Reaction SMILES: [OH:1][CH:2]1[C@@H:6]2[CH:7]([NH:10][C:11](=[O:32])[CH:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[C:18](=[O:24])[C:17]3=[O:25])=[O:15])[C:8](=[O:9])[N:5]2[CH:4]([C:33]([O:35]CC2C=CC3C(=CC=CC=3)C=2)=[O:34])[CH:3]1[CH3:47].O1CCOCC1.C(=O)(O)[O-].[Na+:58]>[Pd].C(O)(=O)C.C(O)C.C(Cl)(Cl)Cl.O.CC(C)=O>[OH:1][CH:2]1[C@@H:6]2[CH:7]([NH:10][C:11](=[O:32])[CH:12]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[C:18](=[O:24])[C:17]3=[O:25])=[O:15])[C:8](=[O:9])[N:5]2[CH:4]([C:33]([O-:35])=[O:34])[CH:3]1[CH3:47].[Na+:58]
Reactant: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)OCc4ccc5ccccc5c4)C(C)C(O)[C@H]23)c2ccccc2)C(=O)C1=O
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)[O-])C(C)C(O)[C@H]23)c2ccccc2)C(=O)C1=O
Reaction time: 0.5 h

Procedure:
2-Naphthylmethyl 1-hydroxy-2-methyl-6-[2-phenyl-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)acetamido]carbapenam-3-carboxylate (36 mg., 0.056 mmole) was dissolved in 2 ml. of dioxane. Water (1 ml.), sodium bicarbonate (4.7 mg., 0.056 mmole) and hydrogenation catalyst (36 mg. of 10% palladium on carbon) were added and the mixture was hydrogenated at 50 psig and room temperature for 30 minutes. Monitoring by tlc (9:1 acetone:water and 90:10:2 chloroform:ethanol:acetic acid) indicated that hydrogenation was incomplete. An additional 36 mg. of 10% palladium on carbon was added and hydrogenation, under the same conditions, resumed for 30 minutes, at which time tlc monitoring indicated reaction was complete. Catalyst was recovered by filtration and the filtrate freeze dried to yield sodium 1-hydroxy-2-methyl-6-[2-phenyl-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)acetamido]carbapenam-3-carboxylate [10 mg., 34%; Rf 0.3 (9:1 acetone:water; Rf 0.3 (90:10:2 chloroform:ethanol:acetic acid); ir (nujol mull) 1770, 1750, 1710 cm-1 ].