Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)OC(=O)[CH:5]([CH:9]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])=[CH:15][CH:14]=2)[C:10]#[C:11][CH3:12])[C:4](=[O:28])[O:3]1.N1C=CC=CC=1.Cl>O>[CH3:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][S:19][C:16]1[CH:17]=[CH:18][C:13]([CH:9]([C:10]#[C:11][CH3:12])[CH2:5][C:4]([OH:28])=[O:3])=[CH:14][CH:15]=1
Reactant: CC#CC(c1ccc(SCc2ccccc2C)cc1)C1C(=O)OC(C)(C)OC1=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC#CC(CC(=O)O)c1ccc(SCc2ccccc2C)cc1
Yield: 111 %

Procedure:
A solution of 28.3 (20 mg, 0.05 mmol) in 5:1 pyridine:water (6 mL) was heated to 80° C. for 72 hours. The reaction was poured into 500 mL of water and the solution was acidified with 1N HCl(aq) (65 mL). The aqueous solution was extracted with ethyl acetate and the combined organic layers were washed with water, followed by brine. The combined organic layers were then dried (Na2SO4) and concentrated in vacuo. The resultant residue was then purified via radial chromatography (30% ethyl acetate in hexanes) to yield 18 mg (quantitative) 3-[4-(2-Methyl-benzylsulfanyl)-phenyl]-hex-4-ynoic acid (28). LC/MSD m/e: 323.1 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[OH:18])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:20][CH2:21][C@@H:22]1[CH2:26][C@@H:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:24][N:23]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].CC(C)([O-])C.[K+]>CN(C)C(=O)C>[C:38]([O:37][C:35]([N:23]1[CH2:24][C@H:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:26][C@H:22]1[CH2:21][CH2:20][O:18][C:12]1[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=1[CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: Oc1ccc(F)cc1CCc1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCOc1ccc(F)cc1CCc1ccc(F)c(F)c1
Yield: 63.1 %

Procedure:
400 mg of 2-[2-(3,4-difluorophenyl)ethyl]-4-fluorophenol (prepared as described in Preparation 7), 690 mg of (2S,4R)-2-(2-bromoethyl)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxypyrrolidine and 208 mg of potassium t-butoxide were allowed to react together in 5 ml of N,N-dimethylacetamide and extracted in the same manner as described in step (a) of Example 2. The resulting oily substance was purified by silica gel column chromatography, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 580 mg (yield 63%) of the title compound as a colorless oily substance.
Reaction SMILES: [CH:1]([C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH:6]=[N:5][CH:4]=1)=O.[CH3:16][NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:7]2[C:3]([CH2:1][N:17]([CH3:16])[CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:4][N:5]=[CH:6]2)=[CH:9][CH:10]=1)#[N:13]
Reactant: CNCCNC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(-n2cncc2C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(CCNC(=O)OC(C)(C)C)Cc1cncn1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a solution of 4-(5-formyl-1H-imidazol-1-yl)benzonitrile (55 mg, 0.28 mmol, 1.00 equiv) and tert-butyl N-[2-(methylamino)ethyl]carbamate (58 mg, 0.33 mmol, 1.19 equiv) in 1,2-dichloroethane (20 mL) was added NaBH(OAc)3 (178 mg, 0.82 mmol, 2.95 equiv). The reaction was stirred at room temperature for 2 h and then concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-5.4% of methanol in dichloromethane to give 90 mg (91%) of tert-butyl 2-(((1-(4-cyanophenyl)-1H-imidazol-5-yl)methyl)(methyl)amino)ethylcarbamate as a colorless oil. LCMS (method D, ESI): RT=0.98 min, m/z=356.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2I)[C:12](=[O:21])[C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=1.[Br-].[CH3:31][CH:32]([CH3:36])[CH2:33][CH2:34][Zn+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)/[C:13](=[C:14](/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)\[CH2:34][CH2:33][CH:32]([CH3:36])[CH3:31])/[C:12]2=[O:21])[CH:5]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2I)c1
Reactant: CC(C)CC[Zn+]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/CCC(C)C)c3ccccc3)c3ccccc32)c1
Temperature: 40 °C
Reaction time: 6 h
Yield: 27.3 %

Procedure:
To a degassed refluxing solution of 3-{[(2-iodo-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester (100 mg, 0.2 mmol) and Ni(PPh3)2I2 (16 mg, 0.02 mmol) in CH2Cl2 (8 ml) was added 3-methylbutylzinc bromide (151 mg, 0.7 mmol) in CH2Cl2 (1 ml). The reaction was stirred at 40° C. for 6 h and then the solution was cooled to room temperature. The resultant solution was diluted with ethyl acetate (50 ml). The organic layer was washed with aqueous HCl solution (4%, 10 ml), brine (3×10 ml). The aqueous layer was back-extracted with ethyl acetate (3×10 ml). The combined organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with petrol ether-ethyl acetate, to give 3-{3-[4-methyl-1-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester (24 mg, 28%) as light yellow solid. 1H NMR (300 Hz, CDCl3): δppm 0.88 (d, 6H), 1.43-1.55 (m, 2H), 1.68-1.72 (m, 1H), 2.93-2.99 (m, 2H), 3.91 (s, 3H), 4.89 (s, 2H), 6.64 (d, 1H), 7.05 (t, 1H), 7.15 (t, 1H), 7.28-7.38 (m, 4H), 7.40-7.47 (m, 3H), 7.62 (d, 1H), 7.91 (d, 1H), 7.95 (s, 1H); and 3-{3-[4-methyl-1-phenyl-pent-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester (29 mg, 33%) as light yellow solid. 1H NMR (300 Hz, CDCl3): δ ppm 0.88 (d, 6H), 1.36-1.44 (m, 2H), 1.64-1.68 (m, 1H), 3.33-3.38 (m, 2H), 3.91 (s, 3H), 5.04 (s, 2H), 6.01 (d, 1H), 6.58-6.61 (m, 2H), 6.96-7.02 (t, 1H), 7.26-7.29 (m, 2H), 7.37 (t, 2H), 7.43-7.52 (m, 3H), 7.93 (d, 1H), 8.03 (s, 1H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:9]=2)[N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:3]=1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(N(CC)CC)C>C1COCC1.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]I>[CH3:16][N:14]1[CH:15]=[C:11]([C:8]2[N:9]=[C:10]3[C:2]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[CH:3][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:5]3=[N:6][CH:7]=2)[CH:12]=[N:13]1
Reactant: C#C[Si](C)(C)C
Reactant: Cn1cc(-c2cnc3c(n2)c(I)cn3C(=O)OC(C)(C)C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cnc3c(n2)c(C#C[Si](C)(C)C)cn3C(=O)OC(C)(C)C)cn1

Procedure:
2.4 Reaction of tert-butyl 7-iodo-2-(1-methyl-1H-pyrazol-4-yl)pyrrolo-[2,3-b]pyrazine-5-carboxylate with bis(triphenylphosphine)palladium dichloride, copper(I) iodide, trimethylsilylacetylene and triethylamine in THF analogously to Example 1.3 gives tert-butyl 2(1-methylpyrazol-4-yl)-7-(2-trimethylsilylethynyl)pyrrolo[2,3-b]pyrazine-5-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[O-:14][CH2:15][CH3:16].[Na+]>C(O)C>[CH2:15]([O:14][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[CH3:16]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
To an equimolar amount of chloro-2,4-dinitrobenzene acid is added sodium ethoxide in ethanol to yield 2,4-dinitrophenyl ethyl ether. Next, to a weighed aliquot of poly (glycidol) containing 0.2 mole polymer in 300 ml of ethanol is added 0.2 mole 2,4-dinitrophenyl ethyl ether, and the reactants heated to reflux and maintained at reflux reaction conditions for 1 to 2 hours. Then dry benzene is added and distillation initiated and continued until nearly all ethanol and water are azeotropically removed, to form the product identified as (I) where n is greater than 10. ##STR34##
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:13][C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=1[CH2:29][CH2:30][CH3:31].N1C=CC=CC=1>ClCCl>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:16]2[CH:15]=[C:14]([NH:13][S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)(=[O:11])=[O:10])[CH:34]=[CH:33][CH:32]=2)=[C:20]([CH2:29][CH2:30][CH3:31])[C:21]=1[OH:28])(=[O:27])[CH3:26]
Reactant: CCCc1c(OCc2cccc(N)c2)ccc(C(C)=O)c1O
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1c(OCc2cccc(NS(=O)(=O)c3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Temperature: 25 °C
Yield: 106.3 %

Procedure:
Add 3-cyano-benzenesulfonyl chloride (673 mg, 3.34 mmol) to a solution of 1-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (1.00 g, 3.34 mmol) and pyridine (0.98 mL) in dichloromethane (20 mL) at 0° C. Warm to room temperature. Partition the mixture between dichloromethane and 2N hydrochloric acid (60 mL). Wash the organic layer with saturated sodium bicarbonate and brine. Dry and concentrate to afford the title compound as an orange solid (1.65 g): 1H NMR (DMSO-d6) δ 0.85 (t, 3H), 1.47 (sextet, 2H), 2.55 (t, 2H), 2.57 (s, 3H), 5.19 (s, 2H), 6.62 (d, 1H), 7.05 (d, 1H), 7.14 (d, 1H), 7.23 (s, 1H), 7.29 (t, 1H), 7.73 (t, 1H), 7.77 (d, 1H), 7.98 (d, 1H), 8.07 (d, 1H) 8.12 (s, 1H), 10.55 (s, 1H), 12.86 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[C@@H:3]([CH2:8][NH:9][C:10]([O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])[C:4]([O:6]C)=[O:5].[Li+].[OH-]>C1COCC1>[CH3:1][CH:2]([CH3:19])[C@@H:3]([CH2:8][NH:9][C:10]([O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:16])[CH3:17])=[O:11])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)[C@H](CNC(=O)OCC[Si](C)(C)C)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[C@@H](CNC(=O)OCC[Si](C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (S)-methyl 3-methyl-2-(((2-(trimethylsilyl)ethoxy)carbonylamino)methyl)butanoate (459 mg, 1.586 mmol) in THF (4 mL) was added 2 M LiOH (4.0 mL, 8.00 mmol). Upon completion of addition, the mixture was stirred at rt for 20 hrs. After this time, the reaction mixture was quenched with sat'd NH4Cl (about 4 ml) and then 1 N HCl (8 ml) was added. The crude product was extracted with EtOAc and the extract was washed with brine. The combined aqueous layers were back extracted with EtOAc. The EtOAc extracts were combined, dried over Na2SO4 and evaporated to give the title compound as an oily residue, which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1.[CH:15]1(B(O)O)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+].N1C=CC=CC=1C1C=CC=CN=1>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][N:8]([CH:15]3[CH2:17][CH2:16]3)[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2[nH]ccc12
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(Br)cc2c1ccn2C1CC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 71.7 %

Procedure:
In a oven dried 100 ml RBF equipped, stir bar, septum and Nitrogen inlet was added methyl 6-bromo-1H-indole-4-carboxylate (0.508 g, 2.0 mmol) and 1,2-dichloroethane (7 mL). The solution was stirred for 15 min, then cyclopropylboronic acid (0.344 g, 4.00 mmol) and sodium carbonate (0.424 g, 4.00 mmol) were added. Diluted copper(II) acetate (0.363 g, 2.000 mmol) and 2,2′-bipyridine (0.312 g, 2.000 mmol) in 1,2-dichloroethane (12 mL), heated the mixture, and added the hot suspension to the reaction. The reaction was heated at 70° C. and monitored by LCMS. Stopped heating after 6 h and allowed to sit for 3 days at RT. Added to reaction saturated NH4C1 and water. Extracted with DCM (2×). The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography (24 g Isco silica column; gradient B: 3-25%. A:hexane. B:ethyl acetate) to give methyl 6-bromo-1-cyclopropyl-1H-indole-4-carboxylate (0.43 g, 1.433 mmol, 71.6% yield) as a yellow residue. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.01 (m, 2H) 1.06-1.12 (m, 2H) 3.52 (dt, J=7.20, 3.47 Hz, 1H) 3.90 (s, 3H) 6.85-6.91 (m, 1H) 7.57 (d, J=3.03 Hz, 1H) 7.82 (d, J=1.77 Hz, 1H) 8.04 (d, J=1.01 Hz, 1H). MS(ES) [M+H]+ 294.1.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:20])[NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[S:2]1.[OH-].[Na+]>CO>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:20])[NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[S:2]1
Reactant: COC(=O)CCCNC(=O)NCCCCC1CCSS1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCNC(=O)NCCCCC1CCSS1
Yield: 74 %

Procedure:
The reaction was carried out as described in Example 48, but using 0.65 g of methyl 4-{3-[4-(1,2-dithiolan-3-yl)butyl]ureido}butanoate (prepared as described in Example 75), 13 ml of methanol and 7.10 ml of a 1 N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from ethyl acetate, to obtain 0.46 g of the title compound as a pale yellow powder, melting at 94 to 99° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:27]([O:30][CH2:31][C:32]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[CH:34][C:33]=1[N:47]1[CH2:59][CH2:58][N:50]2[C:51]3[CH2:52][CH2:53][CH2:54][CH2:55][C:56]=3[CH:57]=[C:49]2[C:48]1=[O:60])(=[O:29])[CH3:28].CC(O[Na])=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:59][CH2:58][N:50]3[C:51]4[CH2:52][CH2:53][CH2:54][CH2:55][C:56]=4[CH:57]=[C:49]3[C:48]2=[O:60])=[CH:34][CH:35]=[CH:36][C:37]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][N:18]([C:19]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:25])[CH3:26])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN(CCn1ccc(Nc2cc(Br)cn(C)c2=O)n1)C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)O[Na]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccn(CCN(C)C(=O)OC(C)(C)C)n3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 61.6 %

Procedure:
A mixture of 206f (800 mg, 1.9 mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (114a) (873 mg, 1.9 mmol), CH3COONa (309 mg, 3.8 mmol), PdCl2(dppf) (153 mg, 0.19 mmol) and K3PO4 (1 g, 3.8 mmol) suspended in CH3CN (30 mL) and H2O (2 mL) was heated at 110° C. for 15 h under argon atmosphere. It was then evaporated and the residue was purified by reverse phase Combi-flash eluting with 0.3% NH4HCO3 in 1:4 water/CH3CN to give 206g as a brown solid (800 mg, 63%). MS: (M+H)+ 684
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:28]3[C:29]([C:32](O)=[O:33])=[CH:30][CH:31]=[C:27]3[C:8]3([CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[C:17]([CH3:25])[CH:16]=4)[CH2:10][CH2:9]3)[O:7][C:6]=2[CH:35]=1.Cl.CN.C[CH2:40][N:41](CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:28]3[C:29]([C:32]([NH:41][CH3:40])=[O:33])=[CH:30][CH:31]=[C:27]3[C:8]3([CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:23])[CH3:24])=[C:17]([CH3:25])[CH:16]=4)[CH2:10][CH2:9]3)[O:7][C:6]=2[CH:35]=1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2c(C(=O)O)ccc23)ccc1OC(C)C
Reactant: CCN(CC)CC
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)c1ccc2n1-c1ccc(Cl)cc1OC21CCN(C(=O)c2ccc(OC(C)C)c(C)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
7-Chloro-1′-(4-isopropoxy-3-methylbenzoyl)spiro[benzo[b]-pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carboxylic acid (17 mg, 0.034 mmol), methanamine hydrochloride (2.3 mg, 0.034 mmol), and Et3N (19 μL, 0.14 mmol) were taken up in dry dichloromethane (0.5 mL). HATU (13 mg, 0.034 mmol) was added and the mixture was allowed to stir for 15 min at room temperature. The mixture was purified by prep-HPLC to provide 7-chloro-1′-(4-isopropoxy-3-methylbenzoyl)-N-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carboxamide. ESI-MS m/z calc. 507.2. found 508.0 (M+1)+. Retention time: 1.92 minutes (3 min run).
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].[N+:27]([C:30]1[CH:68]=[CH:67][C:33]([CH2:34][O:35][C:36]([NH:38][S:39]([NH:42][CH2:43][CH2:44][S:45][C:46]2[N:47]=[CH:48][N:49]3[CH:53]=[C:52]([Sn](CCCC)(CCCC)CCCC)[S:51][C:50]=23)(=[O:41])=[O:40])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C: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]([C:52]3[S:51][C:50]4=[C:46]([S:45][CH2:44][CH2:43][NH:42][S:39]([NH:38][C:36]([O:35][CH2:34][C:33]5[CH:67]=[CH:68][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=5)=[O:37])(=[O:40])=[O:41])[N:47]=[CH:48][N:49]4[CH:53]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCNS(=O)(=O)NC(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1
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
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCNS(=O)(=O)NC(=O)OCc5ccc([N+](=O)[O-])cc5)c4s3)[C@H](C)[C@H]12
Yield: 26.6 %

Procedure:
The procedure of Example 1a) was repeated, except that 54 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 116 mg of 7-[2-(4-nitrobenzyloxycarbonyl)aminosulfonylaminoethyl]thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 31.8 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[2-(4-nitrobenzyloxycarbonyl)aminosulfonylaminoethyl]thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Cl.Cl[CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[Na+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:4][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:2]#[CH:3]
Reactant: C#CCO
Reactant: ClCCN1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Product: C#CCOCCN1CCCC1
Temperature: 90 °C

Procedure:
Propargyl alcohol (1.40 g, 25 mmol) in toluene (30 ml) was treated with 1-(2-chloroethyl)pyrrolidine hydrochloride (8.55 g, 50 mmol), 10 N aqueous sodium hydroxide solution (30 ml) and tetrabutylammonium bromide (150 mg, 1.2 mmol) and heated at 90° C. for 18 h. The layers were separated and the organic layer was dried over sodium sulphate and concentrated under reduced pressure to give a gum. The gum was distilled on a kugelrohr at 160° C. at 22 mbar to give two fractions. Fraction 1 (4.01 g, 25 mmol), the higher boiling, was found to be a mixture of the desired compound I-(2-prop-2-ynoxyethyl)pyrrolidine with some toluene and 2-pyrrolidine-lylethanol. Fraction 2 (2.7 g) was found to be mainly the 2-pyrrolidine-lylethanol and toluene and a trace of the desired compound I-(2-prop-2-ynoxyethyl)pyrrolidine. A portion of fraction 1 (1 g) was repurified by chromatography on silica in a gradient of 2-12% methanol in dichloromethane on a 100 g silica column collecting column volumes. 1-(2-Prop-2-ynoxyethyl)pyrrolidine was isolated as a yellow oil (0.419 g).
Reaction SMILES: [Mg].[CH2:2]([CH:4]([CH2:7][CH3:8])[CH2:5]Br)[CH3:3].[C:9](=[O:11])=[O:10]>C1COCC1.C(OCC)(=O)C.C(Cl)Cl>[CH2:2]([CH:4]([CH2:7][CH3:8])[CH2:5][C:9]([OH:11])=[O:10])[CH3:3]
Reactant: O=C=O
Reactant: CCC(CC)CBr
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(CC)CC(=O)O
Reaction time: 3.5 h
Yield: 99.8 %

Procedure:
Into a 2 L 3-necked flask equipped with a condenser attached to a nitrogen inlet tube, a mechanical stirrer, and a 500 mL addition funnel, was added magnesium turnings (18.7 g, 0.769 mol), which were crushed in a mortar and pestle. The reaction was placed under argon. Enough THF was added to just cover the magnesium turnings. With the mechanical stirrer turned off, 2-ethyl-1-bromobutane (155.5 g 0.70 mol) was placed in the addition funnel and about 2-3 mL was added to the magnesium turnings. This area of the THF solution was then heated with a heat gun until vigorous boiling occurred. The remaining 2-ethyl-1-bromobutane was diluted with THF (200 mL) and added dropwise to the stirred reaction mixture at a rate that maintained a gentle reflux. The addition was completed in approximately 3-4 h. After 24 h, the gray slurry was diluted with THF (500 mL), and gently heated with a hot water bath until a homogeneous solution was formed. The warm solution was then poured into two 4 L Nalgene beakers each containing crushed solid carbon dioxide (1 L). The slush was stirred well with a Teflon rod and allowed to stand at room temperature. After 18 h, the solutions were diluted with ethyl acetate (500 mL), and washed with 2N hydrochloric acid (500 mL). The aqueous layer was saturated with sodium chloride and extracted once more with ethyl acetate (500 mL). The combined ethyl acetate layers were dried (Na2SO4). Concentration under reduced pressure gave a wet residue, which was taken up in methylene chloride (600 mL), dried (Na2SO4), and concentrated at 56° C. under reduced pressure to give the title compound as an oil (91 g, 99.8%): 1H NMR (DMSO-d6, 500 MHz): δ11.95 (broad s, 1H), 2.11 (d, J=6.9 Hz, 2H), 1.60 (septet, J=6.5 Hz, 1H), 1.28 (m, 4H), 0.81 (t, J=7.5 Hz, 6H); MS(−ESI): [M—H]−, 129 (100%); Anal. Calc. for C7H14O2: C, 64.58; H, 10.84. Found: C, 64.61; H, 11.11.