Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH3:11])[C:4](=[O:9])[CH2:5][CH:6]=[CH:7][CH3:8])[CH3:2].C(O)C.C(O)(=O)CCCCC(O)=O>N1C=CC=CC=1>[CH2:10]([N:3]([CH2:1][CH3:2])[C:4](=[O:9])[CH:5]=[CH:6][CH2:7][CH3:8])[CH3:11].[CH2:10]([N:3]([CH2:1][CH3:2])[C:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8])[CH3:11]
Reactant: CC=CCC(=O)N(CC)CC
Agent: O=C(O)CCCCC(=O)O
Solvent: CCO
Solvent: c1ccncc1
Product: CCC=CC(=O)N(CC)CC
Product: CCCCC(=O)N(CC)CC
Reaction time: 1 h

Procedure:
77.6 g of pent-3-enoic acid diethylamide, 32.2 g of ethanol, 1.58 g of pyridine and 3.42 g of Co2 (CO)8 were reacted, as described in Example 1, for 1 hour at 170° C. under a carbon monoxide pressure of 150 bar (+approx. 2% by volume of H2). After cooling, analysis indicated a conversion of pent-3-enoic acid diethylamide of 47.3 mol %. Relative to this, 61.5 mol % of C6 -dicarboxylic acid ethylester-diethylamides had been formed and these had the following composition: 64.6% (=I1) of 2-ethylsuccinic acid 1-ethylester-4-diethylamide, 29.2% of 2-methylglutaric acid 1-ethylester-5-diethylamide and 6.2% of adipic acid ethylesterdiethylamide. Furthermore, as well as isomers of pentenoic acid diethylamide, n-pentanoic acid diethylamide and C6 -dicarboxylic acid bisdiethylamides (3 isomers) were formed at selectivities of conversion of 1.7 mol % and 1.1 mol %, respectively.
Reaction SMILES: [F:1][CH:2]([F:28])[CH2:3][N:4]1[CH2:21][CH:20]([C:22](=[O:27])N(OC)C)[O:19][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5]1.[CH2:29]([Mg]Br)[CH3:30]>C1COCC1>[F:28][CH:2]([F:1])[CH2:3][N:4]1[CH2:21][CH:20]([C:22](=[O:27])[CH2:29][CH3:30])[O:19][C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[CH2:5]1
Reactant: CON(C)C(=O)C1CN(CC(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)C1CN(CC(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To tert-butyl 8-(2,2-difluoroethyl)-10-[methoxy(methyl)carbamoyl]-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (295 mg, 0.72 mmol) in THF (3 mL) at −78° C. under an atmosphere of nitrogen, was added ethylmagnesium bromide (1.7 mL of 1 M in THF, 1.7 mmol) dropwise. The reaction mixture was stirred at the same temperature for 0.5 hours, then at 0° C. for 1 hour. The reaction mixture was quenched with ethyl acetate (20 mL) and sat. aq. NaHCO3 (10 mL). The aqueous layer was further extracted with EtOAc (2×20 mL), and the combined organics were dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography (0-100% ethyl acetate/hexane) to give tert-butyl 8-(2,2-difluoroethyl)-10-propanoyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (227 mg, 83%) as a colorless oil. ESI-MS m/z calc. 376.2. found 377.3 (M+1)+; Retention time: 1.76 minutes. 1H NMR (400 MHz, CDCl3) δ 6.01-5.70 (m, 1H), 4.21-4.15 (m, 1H), 3.91-3.75 (m, 2H), 3.33-3.22 (m, 1H), 3.15-2.98 (m, 2H), 2.79-2.57 (m, 5H), 2.43-2.35 (m, 1H), 2.19-2.06 (m, 2H), 1.61-1.39 (m, 12H), 1.06 (t, J=7.3 Hz, 3H).
Reaction SMILES: C#C[CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7]C.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S(O)(=O)=[O:23])=CC=1>>[O:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:23][C:6]2[CH2:7][O:9][CH:3]=[CH:4][CH:5]=2)[CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1=COCCC1
Reactant: C#CC(O)CCCCC
Product: C1=COCC(OC2=CC=COC2)=C1

Procedure:
Typically, 1-octyn-3-ol is allowed to react with dihydropyran in the presence of a catalytic amount of p-toluenesulfonic acid to form the 3-pyranyl ether. 3-(tetrahydropyran-2-yl)oxy-1-octyne. That material is treated with diisobutyl aluminum hydride, then with iodine, to yield the corresponding iodo-octene, 3-(tetrahydropyran- 2-yl)oxy-1-iodo-1-octene. Magnesium metal, activated with mercuric chloride, is added to the iodo-octene and that addition is followed by the addition of cuprous iodide to yield 3-(tetrahydropyran-2-yl)oxy-trans-1-octenyl copper.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH2:20])[N:14]=2)[C:9](F)=[N:10][CH:11]=1)=[CH2:5])C.[C:21]1([S:27]([C:30]2[CH:31]=[C:32]([NH2:36])[CH:33]=[N:34][CH:35]=2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.CCOC(C)=O>[NH2:20][C:15]1[N:16]=[C:17]([CH3:19])[N:18]=[C:13]([C:8]2[CH:7]=[C:6]([C:4](=[O:3])[CH3:5])[CH:11]=[N:10][C:9]=2[NH:36][C:32]2[CH:33]=[N:34][CH:35]=[C:30]([S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[CH:31]=2)[N:14]=1
Reactant: Nc1cncc(S(=O)(=O)c2ccccc2)c1
Reactant: C=C(OCC)c1cnc(F)c(-c2nc(C)nc(N)n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1cnc(Nc2cncc(S(=O)(=O)c3ccccc3)c2)c(-c2nc(C)nc(N)n2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
4-(5-(1-Ethoxyvinyl)-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (255 mg, 0.925 mmol) and 5-(phenylsulfonyl)pyridin-3-amine (260 mg, 1.110 mmol) were dissolved in THF (9.2 mL) and the resulting mixture was cooled to 0° C. and NaHMDS in THF (1.0 M, Aldrich; 2775 μL, 2.77 mmol) was added. The reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was then diluted with 100 mL of EtOAc, added to a separatory funnel, and partitioned with ammonium chloride (saturated, aqueous). The organic layer was separated, washed 2 times with 50 mL of ammonium chloride (saturated, aqueous), dried over sodium sulfate, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 3% (2 M ammonia in MeOH)/DCM) gave the title compound (44% yield) as a yellow amorphous solid. m/z (ESI, +ve ion) 462.2 (M+H)+.
Reaction SMILES: [NH2:1][C@H](C(O)=O)CCCC.C(N(CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.Cl.[CH2:35]([NH:39][C:40](=[O:53])[CH:41]([CH2:51][CH3:52])[CH2:42][C@H:43]([OH:50])[C@@H:44](N)[CH2:45][CH:46]([CH3:48])[CH3:47])[CH:36]([CH3:38])[CH3:37]>CN(C=O)C.C(OCC)(=O)C>[CH2:35]([NH:39][C:40](=[O:53])[C:41]([NH2:1])([CH2:51][CH3:52])[CH2:42][CH:43]([OH:50])[CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])[CH:36]([CH3:38])[CH3:37]
Reactant: CCC(C[C@H](O)[C@@H](N)CC(C)C)C(=O)NCC(C)C
Reactant: CCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(N)(CC(O)CCC(C)C)C(=O)NCC(C)C
Temperature: -15 °C

Procedure:
22.9 mg of L-N-[(2R or S)-5-ethylsulfonyl-2-(1-naphthylmethyl)pentanoyl]norleucine was dissolved in 0.2 ml of dry DMF, and 6.23 mg of triethylamine and 16.9 mg of DPPA were added under stirring at -15° C. Then, 26.8 mg of (2RS,4S,5S)-5-amino-2-ethyl-4-hydroxy-7-methyloctanoic acid isobutylamide monohydrochloride was dissolved in 0.1 ml of dry DMF and neutralized with 8.79 mg of triethylamine. This dry DMF solution was added to the previous reaction solution, and the mixture was stirred at -10° C. for one hour and at 5° C. overnight. The reaction solution was diluted with 20 ml of ethyl acetate, and the ethyl acetate layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue thereby obtained was purified by silica gel column chromatography (chloroform/methanol=75/1) to obtain 18.2 mg of (2RS,4 S,5S)-5-{L-N-[(2R or S)-5-ethylsulfonyl-2-(1-naphthylmethyl)pentanoyl]norleucyl}-amino-2-ethyl-4-hydroxy-7-methyloctanoic acid isobutylamide as colorless solid.
Reaction SMILES: [N:1]([CH:4]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[C:8]2[CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][C:7]1=2)=[N+]=[N-].[Cl-].[NH4+]>CCO.O.[Zn]>[CH3:20][N:17]1[CH2:18][CH2:19][C:7]2[N:6]([CH2:5][CH:4]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[NH2:1])[C:14]3[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=3[C:8]=2[CH2:16]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccncc2)CCN(C)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CC(N)c2ccncc2)CCN(C)C1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 54 %

Procedure:
To a solution of 5-(2-azido-2-(pyridin-4-yl)ethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (2.4 g, 6.93 mmol) in EtOH-water (25-2.5 mL) were added zinc dust (1.8 g, 27.7 mmol) and ammonium chloride (1.5 g, 27.74 mmol) and the reaction mixture stirred at 80° C. for 45 min. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was basified with aq. ammonia and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and evaporated to yield 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanamine (1.2 g). 1H NMR (CDCl3, freebase) δ (ppm): 8.56 (d, 2H), 7.28 (d, 2H), 7.21 (m, 2H), 7.00 (d, 1H), 4.48 (t, 1H), 4.08 (m, 2H), 3.65 (q, 2H), 2.83 (m, 2H), 2.72 (m, 1H), 2.56 (m, 1H), 2.53 (s, 3H), 2.44 (s, 3H). Separation by chiral HPLC provided enantiomers 27a and 27b.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].Br[CH2:11][CH2:12][OH:13].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:11][CH2:12][OH:13])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(C)cc(NCCO)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 34.8 %

Procedure:
A mixture of 3,5-dimethyl-aniline (0.04 mol), 2-bromo-ethanol (0.033 mol) and K2CO3 (0.033 mol) in CH3CN (50 ml) was stirred at 80° C. for 12 hours. The reaction was cooled down to room temperature and the solvent was evaporated. The residue was taken up in CH2Cl2/CH3OH (95/5) and washed with a saturated solution of K2CO3 in water. The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 98/2/0.1; 20-45 μm). The pure fractions were collected and the solvent was evaporated, yielding 1.9 g of 2-(3,5-dimethyl-phenylamino)-ethanol (29%).
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Br:11])[CH:5]=[C:4]([CH3:12])[N:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CO.O1CCCC1.O>[NH2:8][C:7]1[C:2]([Br:1])=[N:3][C:4]([CH3:12])=[CH:5][C:6]=1[Br:11]
Reactant: Cc1cc(Br)c([N+](=O)[O-])c(Br)n1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Br)c(N)c(Br)n1
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
2,4-Dibromo-6-methyl-3-nitropyridine (1.0 g, 3.38 mmol) was dissolved in a mixture of methanol (4 mL) and tetrahydrofuran (6 mL), and a solution of sodium hydrosulfite (3.0 g, 17.23 mmol) in water (7 mL) was added thereto over 5 minutes with stirring at 65° C. Subsequently, the mixture was stirred for 30 minutes at 65° C. To the mixture, a solution of sodium hydrosulfite (3.0 g, 17.23 mmol) in water (7 mL) was further added over 5 minutes, and the mixture was stirred for 30 minutes at 65° C. The resultant mixture was allowed to cool, diluted with water, and then the mixture was extracted with chloroform. The organic layer was washed with saturated brine, followed by drying over sodium sulfate anhydrate and concentrating under reduced pressure, to thereby yield 0.89 g of 3-amino-2,4-dibromo-6-methylpyridine as a colorless solid (yield 99%). The product was crystallized from hexane, to thereby obtain colorless crystals.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>C(#N)C>[CH3:36][O:35][C:33](=[O:34])[CH2:32][N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([N:16]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: COC(=O)CBr
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)OC
Yield: 85.6 %

Procedure:
Using the procedure described in example 5, treatment of L-proline-L-isoleucine benzylamide (47 mg, 0.15 mmol), with sodium carbonate (31 mg, 0.29 mmol, 2.0 eq), and methyl alpha-bromoacetate (113 mg, 0.74 mmol, 5.0 eq) in acetonitrile (5 mL), provided 50 mg (87%) of L-isoleucine, N-[1-(2-methoxy-2-oxoethyl)-L-prolyl] benzylamide as a white foam.
Reaction SMILES: [NH4+:1].[Cl-:2].C[Al](C)C.[C:7]1([C:13]2([CH2:18][C:19]#[N:20])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[ClH:2].[C:7]1([C:13]2([CH2:18][C:19]([NH2:1])=[NH:20])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: N#CCC1(c2ccccc2)CCCC1
Reactant: [Cl-]
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cl
Product: N=C(N)CC1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a stirred suspension of NH4Cl (2 g, 37.29 mmol) in dry toluene (50 mL) was added tri-methyl aluminium (2M in toluene) (18.6 mL, 37.29 mmol) at 5° C. The reaction mixture was then warmed to room temperature and stirred for 2 h. A solution of (1-phenyl-cyclopentyl)-acetonitrile (280) (2.3 g, 12.4 mmol) in toluene (10 mL) was added to the reaction mixture and stirring continued at 80° C. for 14 h. After completion of the reaction, the reaction mixture was quenched with a suspension of silica gel (8 g) in chloroform (8 mL) at 0° C. The reaction mixture was further stirred for 30 min at room temperature and filtered through a short bed of celite, washed with methanol and the combined filtrates were concentrated. The residue was stirred with 10% methanol in dichloromethane (200 mL). The white solid was discarded by filtration and filtrate was concentrated to get 2-(1-phenyl-cyclopentyl)-acetamidine hydrochloride salt (281) 2.5 g, 99.4% (crude yield) as a yellow gummy oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][NH2:12].[CH:13](OCC)=[O:14]>>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][NH:12][CH:13]=[O:14]
Reactant: CCOC=O
Reactant: COc1cccc(CCN)c1C
Product: COc1cccc(CCNC=O)c1C

Procedure:
{2-[2-Methyl-3-(methyloxy)phenyl]ethyl}amine (Preparation 10; 1.75 g; 10.6 mmol) was heated under reflux with ethyl formate (97%; 15 ml) for 15 h. Removal of the solvent gave the crude product (ca. 2 g), which was purified by chromatography on silica gel, eluting with a gradient of 13-63% ethyl acetate in cyclohexane, to give the title compound (1.57 g).
Reaction SMILES: [C:1]([NH:4][N:5]1[CH:9]=[N:8][N:7]=[C:6]1[N:10]([C:21](=[O:23])[CH3:22])[N:11]=[CH:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])(=[O:3])[CH3:2].[C:24](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O>O>[CH3:24][N:4]([N:5]1[CH:9]=[N:8][N:7]=[C:6]1[N:10]([C:21](=[O:23])[CH3:22])[N:11]=[CH:12][C:13]1[C:14]([Cl:20])=[CH:15][CH:16]=[CH:17][C:18]=1[Cl:19])[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Nn1cnnc1N(N=Cc1c(Cl)cccc1Cl)C(C)=O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CC(=O)N(N=Cc1c(Cl)cccc1Cl)c1nncn1N(C)C(C)=O
Reaction time: 8 h

Procedure:
To a solution of 31.5 g of 4-acetamido-3-[1-acetyl-2-(2,6-dichlorobenzylidene) hydrazino]-1,2,4-triazole and 53.0 g of sodium carbonate in 400 ml of water is added dropwise, while stirring and cooling in an ice bath, 40 ml of dimethyl sulphate (2 h). After the addition the mixture was stirred for 2.5 h while cooling in ice and left overnight at room temperature. The obtained precipitate is collected and recrystallized twice from dioxane-isopropyl ether.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH2:8])=[N:5][NH:6][CH:7]=1)[CH3:2].[Br:9][CH:10]([CH:13]=O)[CH:11]=O.C(O)(=O)C>C(O)C>[Br:9][C:10]1[CH:11]=[N:8][C:4]2[N:5]([N:6]=[CH:7][C:3]=2[CH2:1][CH3:2])[CH:13]=1
Reactant: CCc1c[nH]nc1N
Reactant: O=CC(Br)C=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1cnn2cc(Br)cnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-ethyl-1H-pyrazol-3-amine (0.50 g, 4.50 mmol) and 2-bromo-malonaldehyde (1.47 g, 9.72 mmol) in ethanol (8.0 mL) was added acetic acid (1.21 mL, 21.2 mmol). The reaction mixture was refluxed for 4 h, then stored in a freezer overnight. The mixture was warmed to rt, the resulting precipitate was removed by filtration and the filtrate concentrated. The resulting residue was portioned between ethyl acetate and 1M sodium hydroxide and the organic layer was washed with brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 50% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C8H9BrN3: 226.0 (M+H+); Found: 226.1 (M+H+).
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]I.[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>>[I-:1].[I-:1].[CH2:2]([N+:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N+:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: ICCCCCCCCCCI
Reactant: c1ccc2ncccc2c1
Product: [I-]
Product: c1ccc2c(c1)ccc[n+]2CCCCCCCCCC[n+]1cccc2ccccc21
Temperature: 65 °C
Yield: 91 %

Procedure:
1,10-Diiododecane (mmol) was added to a solution (30 mL) of dry quinoline, and the solution heated for 24 hours at 65° C. The resulting precipitate was filtered, and the product washed five times with dry diethyl ether. The resulting yellow solid was isolated in a 91% yield. 1H NMR (300 MHz, DMSO-D6) δ 9.53 (1H, d, C2-H), 9.29 (1H, d, C3-H), 8.61 (1H, d, C8-H), 8.50 (1H, d, C4-H), 8.29 (1H, t, C7-H), 8.18 (1H, t, C5-H), 8.06 (1H, d, C6-H), 5.04 (2H, t, C′1-CH2), 1.96 (2H, m, C′2-CH2), 1.32 (6H, m, C′3-5-CH2); 13C NMR (75 MHz, DMSO-D6) δ 149.5, 147.4, 137.4, 135.6, 130.7, 129.9, 129.7, 122.1, 118.9, 57.3, 29.5, 28.9, 28.5, 25.7.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@@H:11]([CH3:12])[CH:10]=[C:9]([C:13]2[N:14]=[C:15]([S:18][C:19]3[C@H:25]([CH3:26])[C@H:24]4[N:21]([C:22](=[O:34])[C@@H:23]4[C@H:27]([O:29][Si](C)(C)C)[CH3:28])[C:20]=3[C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36])[S:16][CH:17]=2)[CH2:8]1)=[O:6])[CH:2]=[CH2:3].O.Cl.C(=O)([O-])O.[Na+]>C1COCC1>[CH2:1]([O:4][C:5]([N:7]1[C@@H:11]([CH3:12])[CH:10]=[C:9]([C:13]2[N:14]=[C:15]([S:18][C:19]3[C@H:25]([CH3:26])[C@H:24]4[N:21]([C:22](=[O:34])[C@@H:23]4[C@H:27]([OH:29])[CH3:28])[C:20]=3[C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36])[S:16][CH:17]=2)[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(Sc2nc(C3=C[C@H](C)N(C(=O)OCC=C)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)C1=C(Sc2nc(C3=C[C@H](C)N(C(=O)OCC=C)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 0.17 h
Yield: 80.6 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(4-{(5S)-1-[(allyloxy)carbonyl]-5-methyl-2,5-dihydro-1H-pyrrol-3-yl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (85 mg, 0.14 mmol) in THF (6 ml) was added at 0° C. water and then the solution was adjusted to pH about 3 with 1N hydrochloric acid and stirred for 10 minutes. To the reaction solution was added an aqueous sodium hydrogen carbonate solution and the reaction mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate=1/2) to give allyl (4R,5S,6S)-3-[(4-{(5S)-1-[(allyloxy)carbonyl]-5-methyl-2,5-dihydro-1H-pyrrol-3-yl}-1,3-thiazol-2-yl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (60 mg, 80%) as a pale yellowish amorphous.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[C:9](Cl)([CH3:11])=[O:10].CCN(C(C)C)C(C)C.C(Cl)Cl>[Pd].CCO>[C:9]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([NH:2][CH3:1])[CH2:4]1)(=[O:10])[CH3:11]
Reactant: CC(=O)Cl
Reactant: CNC1CCCNC1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: ClCCl
Product: CNC1CCCN(C(C)=O)C1

Procedure:
1-Acetyl-3-(methylamino)piperidine was prepared from N3—Cbz protected 3-methylamino-piperidine: i) AcCl, i-Pr2NEt, CH2Cl2; ii) H2 (1 atm), 10% Pd/C, EtOH. 1H-NMR (CD3OD): δ (ppm) 4.0 (m, 1H), 3.6 (m, 1H), 3.4-3.2 (m, 2H), 3.0 (m, 1H), 2.6 (s, 3H), 2.1 (s, 3H), 1.8-1.6 (m, 4H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([OH:19])[CH3:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:20](I)[CH2:21][CH3:22]>C(Cl)(Cl)Cl.[Ag].[Ag]=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([O:19][CH2:20][CH2:21][CH3:22])[CH3:18])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCCI
Reactant: CC(=O)c1ccc(-c2ccc(CC(C)O)cc2)cc1
Agent: O=[Ag]
Agent: [Ag]
Solvent: ClC(Cl)Cl
Product: CCCOC(C)Cc1ccc(-c2ccc(C(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 360 h
Yield: 30.4 %

Procedure:
Into a four-necked flask provided with a stirrer and a thermometer, 25.4 g of (-)-4-acetyl-4'-(2-hydroxypropyl)biphenyl (XXIII-43) [0.1 mol, [α]D20 =-11.2° (C=1, CHCl3)], 69.5 g (0.3 mol) of silver oxide and 255 g (1.5 mol) of propyl iodide were charged, and then stirred at room temperature for 15 days. Thereafter, the reaction mixture was diluted with 300 ml of chloroform, and silver salt was filtered off, and thereafter, the filtrate was concentrated under a reduced pressure. The resulting residue was subjected to a silica gel column chromatography (elution medium: toluene/ethyl acetate=10/1) to obtain 9.0 g of (-)-4-acetyl-4'-(2-propoxypropyl)biphenyl (XXII-43) [yield=30.5%, [α]D20 =-10.2° (C=1, CHCl3), m.p.=53°-55° C.] and 17.4 g of the starting material (XXIII-43) with recovery of 68.5%.
Reaction SMILES: [OH:1][C:2]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.N1C=CC=CC=1.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1CCN2C(=NCCC2)CC1.Cl>C(Cl)Cl>[CH3:16][S:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[C:2]3([CH2:6][CH2:5][CH2:4][CH2:3]3)[O:1][C:30](=[O:31])[C:29]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][CH:11]=1
Reactant: CSc1ccc(C(=O)C2(O)CCCC2)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSc1ccc(C2=C(c3ccccc3)C(=O)OC23CCCC3)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To the alcohol from Step 2 (924 mg, 3.91 mmol) in 10 mL CH2Cl2 at 0° C. was added pyridine (928 mg, 11.7 mmol) followed by phenylacetyl chloride (1.51 g, 9.77 mmol). The ice bath was removed and the mixture was stirred at room temperature for 15 h. Aq. NH4Cl (100 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in 16 mL CH2Cl2, DBU (595 mg, 3.91 mmol) was added and the brown solution was stirred at room temperature for 0.5 h. 5% aq. HCl (100 mL) was added and the mixture was extracted with EtOAc (4×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give 1.40 g (quantitative) of the title compound as a yellow solid, used directly in the next step. An analytical sample had mp. 147-148° C. after stirring with Et2O/hexane (2:1).