Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:26](O)[CH2:27][CH2:28][CH:29]=[CH2:30]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:10])[C:11]([O:13][CH2:30][CH2:29][CH2:28][CH:27]=[CH2:26])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCCCO
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C=CCCCOC(=O)C(C)NC(=O)OC(C)(C)C

Procedure:
N-(t-Butoxycarbonyl)alanine (3.1 g, 1 eq) and DCM (50 mL) were added to a vessel with stirring followed by the addition of CDI (3.1 g, 1.15 eq). The mixture was stirred at ambient temperature for 18 h after which time 4-penten-1-ol (1.8 g, 1.25 eq) was added. The mixture was stirred a further 18 h at ambient temperature at which point the reaction was quenched with 1N HCl. A biphasic mixture was formed and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3 solution and then concentrated to give pent-4-en-1-yl 2-((tert-butoxycarbonyl)amino)propanoate as an oil. The oil was dissolved in DCM (50 mL) and methanesulfonic acid (2.2 g, 1.4 eq) was added. The mixture was stirred at ambient temperature for ˜22 h then cooled in an ice/water bath. Ethyl 2-chloro-2-oxoacetate (3.4 g, 1.5 eq) was added followed by drop-wise addition of triethylamine (5.0 g, 3 eq). The mixture was stirred for 7 h after which time the reaction was quenched by 1N HCl to form a biphasic mixture. The layers were separated and the organic layer was washed with a saturated aqueous NaHCO3 solution. The organic layer was then concentrated under reduced pressure to provide pent-4-en-1-yl 2-(2-ethoxy-2-oxoacetamido)propanoate as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.64 (d, J=6.94 Hz, 1H), 5.66-5.83 (m, 1H), 4.90-5.05 (m, 2H), 4.49-4.62 (m, 1H), 4.31 (qd, J=7.17, 2.26 Hz, 2H), 4.13 (td, J=6.59, 2.13 Hz, 2H), 2.02-2.14 (m, 2H), 1.67-1.78 (m, 2H), 1.44 (d, J=7.19 Hz, 3H), 1.34 (t, J=7.15 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ ppm 171.64, 159.94, 155.83, 136.94, 115.40, 64.98, 63.10, 48.40, 29.71, 27.44, 17.88, 13.80; HRMS (M+Na) m/z, calcd for C12H19NO5Na, 280.1161; found, 280.1166.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH3:20])=[O:18].Cl>O.O1CCOCC1>[CH3:20][O:19][C:17]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:18]
Reactant: COC(=O)Cl
Reactant: CNCCCCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)N(C)CCCCC(=O)O
Temperature: 25 °C
Yield: 88.4 %

Procedure:
1-methyl-2-piperidone (5 ml, 44.1 mmol) was combined with barium hydroxide (3.8 g, 26.95 mmol) and water (55 ml). The suspension was warmed to 110° C. for 6 hours then cooled over an ice bath. Gaseous carbon dioxide was bubbled through the solution for 20 minutes. The suspension was filtered through a celite pad and the filtrate was concentrated to dryness. The residue was triturated with acetonitrile, collected, rinsed with ether and dried in vacuo to yield 5-(methylamino)pentanoic acid as a white solid (2.95 g). 5-(Methylamino)pentanoic acid (2 g, 15.3 mmol), and potassium carbonate (13 g, 94 mmol) were suspended in water (30 ml) and dioxane (10 ml) then cooled to 0° C. Methyl chloroformate (5 ml, 65 mmol) was added over 30 seconds, then the mixture was stirred and allowed to warm slowly to room temperature for 16 hours. Conc. HCl (20 ml) was added then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated and dried in vacuo to give 5-[(methoxycarbonyl)(methyl)amino]pentanoic acid as a thick clear oil (2.56 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6](F)[C:5]([Br:13])=[CH:4][CH:3]=1.FC1C2C(=O)[O:22][C:21](=O)NC=2C=CC=1.COC1C2C(=O)OC(=O)NC=2C=CC=1>>[NH2:1][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6]([O:22][CH3:21])[C:5]([Br:13])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(N)ccc(Br)c1F
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Agent: COc1cccc2[nH]c(=O)oc(=O)c12
Product: CNC(=O)c1c(N)ccc(Br)c1OC

Procedure:
Prepared analogously to Compound 27D replacing 5-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (Compound 27E) with 5-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (Compound 30E). 1H NMR (CDCl3, 500 MHz) δ 2.98 (d, J=4.5 Hz, 3H), 3.77 (s, 3H), 5.82 (br.s, 2H), 6.74 (d, J=9.0 Hz, 1H), 7.27 (d, J=9.0 Hz, 1H), 7.58 (br.s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][C:17](=O)[CH2:16]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.C(O)(=O)C>ClC(Cl)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:16]1
Reactant: COCOc1ccc(C2CCCC(=O)C2)c(OCOC)c1
Reactant: C1CNCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COCOc1ccc(C2CCCC(N3CCNCC3)C2)c(OCOC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexanone (80 mg) and piperazine (24 mg) were dissolved in dichloroethane (5 ml) and stirred at ambient temperature for 1 hr under argon. Tetramethylammonium triacetoxyborohydride (79 mg) was added and stirring continued under argon. After 16 hr, additional portions of piperazine (24 mg) and tetramethylammonium triacetoxyborohydride (79 mg) were added and stirring continued. After a further 6 hr, glacial acetic acid was added dropwise until a solution was obtained, and stirring continued at ambient temperature. After a further 16 hr, the reaction mixture was partitioned between sodium hydrogen carbonate (20 ml of a saturated solution) and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×20 ml), and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The crude residue was purified by flash column chromatography chromatography (SiO2, dichloromethane/methanol, 9:1 v/v) to furnish the title compound as an off white solid (52 mg, 53%) and mixture of diastereoisomers; m/z (ES+) 365 (M+H)+.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:29]5[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=5)=[C:18]4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(OC)(O[CH3:43])(=O)=O>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:29]5[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=5)=[C:18]4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH3:43])=[CH:13][CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COC(=O)c1ccc(-c2ccc3ccc(C45CC6CC(CC(C6)C4)C5)cc3c2OCCCCCCO)cc1
Reactant: COS(=O)(=O)OC
Product: COCCCCCCOc1c(-c2ccc(C(=O)O)cc2)ccc2ccc(C34CC5CC(CC(C5)C3)C4)cc12
Yield: 11.5 %

Procedure:
Following the procedure of Example 12(a), but reacting 870 mg (1.7 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxyhexyloxy-2-naphthyl]benzoate with 160 μl (1.7 mmol) of dimethyl sulphate, 100 mg (14%) of the expected compound were obtained, which compound had a melting point of 141°-3° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][NH2:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([NH:16][CH2:15][CH2:14][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: NCCC1(c2ccc(F)cc2)CCOCC1
Solvent: ClCCl
Product: Fc1ccc(C2(CCNCc3ccccc3)CCOCC2)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-[4-(4-fluorophenyl)oxan-4-yl]ethan-1-amine (250 mg, 1.12 mmol) in anhydrous CH2Cl2 (5 ml) and NA2SO4 (159 mg, 1.12 mmol) at rt was added benzaldehyde (0.17 ml, 1.68 mmol). The reaction was stirred overnight. The reaction mixture was filtered and concentrated. The residue was dissolved in 5 ml MeOH at 0° C. and NaBH4 added in one portion (51 mg, 1.34 mmol). The reaction was stirred at 0° C. for 1 h. The solution was then quenched with H2O (10 ml), extracted with CH2Cl2 (3×20 ml), washed with brine (10 ml) and dried over NA2SO4. Purified by normal phase SiO2 chromatography (0 to 10% MeOH/CH2Cl2) to give benzyl({2-[4-(4-fluorophenyl) oxan-4-yl]ethyl})amine as a colorless oil (200 mg, 60%, m/z: 314.2 [M+H]+ observed).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:43]=[CH:42][C:41](Br)=[CH:40][C:29]=1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(OCC)(=O)C.O>[CH2:20]([O:27][C:28]1[CH:43]=[CH:42][C:41]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:40][C:29]=1[C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(OCc1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Reactant: C1CCNCC1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OCc1ccccc1)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Piperidine (1.1 mL), cesium carbonate (4.9 g), tris(dibenzylideneacetone)dipalladium(0) (0.069 g), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.18 g), and palladium(II) acetate (0.034 g) were added to a toluene (30 mL) solution of benzyl 2-(benzyloxy)-5-bromobenzoate (3.0 g), followed by heating to reflux under a nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature, and then piperidine (0.37 mL), cesium carbonate (1.2 g), tris(dibenzylideneacetone)dipalladium(0) (0.069 g), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.18 g), and palladium(II) acetate (0.034 g) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 5 hours and 30 minutes. After cooling the reaction mixture to room temperature, water and ethyl acetate were added thereto, and the insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-80% hexane/ethyl acetate] to obtain 2.4 g of benzyl 2-(benzyloxy)-5-(piperidin-1-yl)benzoate as a light yellow solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:21]([NH:23][C@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:22])[CH2:10][S:11]CC1C=CC(OC)=CC=1)=O)(C)(C)C.C(OC(=O)[C@@H]1CCCN1C(=O)[C@@H](CSCC1C=CC(OC)=CC=1)NC(OC(C)(C)C)=O)(C)(C)C>>[NH2:8][C@@H:9]([C:21]([NH:23][C@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:22])[CH2:10][SH:11]
Reactant: COc1ccc(CSC[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)cc1
Agent: COc1ccc(CSC[C@@H](NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)cc1
Product: N[C@H](CS)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
By substituting N-tert-butyloxycarbonyl-S-p-methoxybenzyl-D-cysteinyl-L-tryptophane for the N-tert-butyloxycarbonyl-S-p-methoxybenzyl-D-cysteinyl-L-proline tert-butyl ester in the procedure of Example 2, D-cysteinyl-L-tryptophane is obtained.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17](I)=[N:18][C:19]=3[NH:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[O:7][C@@H:6]1[CH2:30][O:31][C:32](=[O:34])[CH3:33])(=[O:3])[CH3:2].C([Sn]([C:48]#[N:49])(CCCC)CCCC)CCC>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:48]#[N:49])=[N:18][C:19]=3[NH:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[O:7][C@@H:6]1[CH2:30][O:31][C:32](=[O:34])[CH3:33])(=[O:3])[CH3:2]
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of (2R,3R,4R,5R)-4-acetyloxy-2-(acetyloxymethyl)-5-[6-(cyclopentylamino)-2-iodopurin-9-yl]oxolan-3-yl acetate (0.9 g, 1.53 mmol) in N,N-dimethylformamide (40 ml) was added tributyltin cyanide (0.58 g, 1.84 mmol) and tetrakis(triphenylphosphine)palladium (0.27 g, 0.23 mmol), and the mixture was stirred at 120° C. f overnight. Solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate and filtered through celite. The solvent was removed under reduced pressure, and the residue was chromatographed on silica gel, eluting with a mixture of ethanol/hexane 1:1, to provide (2R,3R,4R,5R)-4-acetyloxy-2-(acetyloxy-methyl)-5-[2-cyano-6-(cyclopentylamino)purin-9-yl]oxolan-3-yl acetate (0.65 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[NH:10][CH:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[N+:27]([O-])=O)=[CH:15][CH:14]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl>>[CH2:1]([O:8][C:9](=[O:30])[NH:10][CH:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[NH2:27])=[CH:15][CH:14]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(NC(=O)OCc1ccccc1)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Product: CC(NC(=O)OCc1ccccc1)c1ccc(Oc2ccc(Cl)cc2N)cc1
Yield: 80.8 %

Procedure:
The product from Example 182b (1.0 g, 2.34 mmol) was reacted with SnCl2 as described in Example 237E to give the title compound (0.75 g, 80%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:38])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[CH:37])[CH:31]=3)[CH2:25][CH2:24]2)[CH:18]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)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]I.CN(C)C=O>[C:12]([O:11][C:9]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:38])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[C:37][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:31]=3)[CH2:25][CH2:24]2)[CH:18]=1)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: C#Cc1cccc(C(=O)N2CCC(c3cccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3)CC2)c1
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1cccc(C2CCN(C(=O)c3cccc(C#Cc4ccccc4)c3)CC2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
A mixture of N,N-bis-(tert-butoxycarbonyl)-3-[1-(3-ethynyl-benzoyl)-piperidin-4-yl]-benzylamine (0.24 g, 0.46 mmol), iodobenzene (95 mg, 0.46 mmol), dichlorobis(triphenylphosphine)palladium (II) (35 mg, 0.05 mmol), copper (I) iodide (26 mg, 0.14 mmol), triethylamine (0.57 ml, 4.1 mmol) and anhydrous dimethylformamide (8 ml) was stirred at ambient temperature under nitrogen for 18 hours. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate (3 lots of 50 ml) and water (20 ml). The combined organic layers were washed with brine (50 ml), then dried over magnesium sulfate and then concentrated under vacuum. The residue was subjected to chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (3:2, v/v) to give N,N-bis-(tert-butoxycarbonyl)-3-[1-(3-phenylethynyl-benzoyl)-piperidin-4-yl]-benzylamine as a yellow oil (0.23 g). 1H NMR (CDCl3, 500 MHz): δ 7.58 (m, 4H), 7.40 (m, 5H), 7.25 (m, (m, 1H), 7.10 (m, 3H), 4.90 (br m, 1H), 4.79 (s, 2H), 3.80 (br m, 1H), 3.15 (br m, 1H), 2.84 (br, m, 1H), 2.78 (br m, 1H), 1.95 (m, 1H), 1.80 (m, 3H), 1.42 (s, 18H). MS(EI): 617(M++Na).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1[S:13][C:14]([CH2:32][CH3:33])=[C:15]([C:30]#[N:31])[C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])=[CH:19][CH:18]=1)=[O:11])[CH3:8].[CH2:34](I)[CH2:35][CH3:36].Cl>CN(C=O)C>[CH2:7]([O:9][C:10]([C:12]1[S:13][C:14]([CH2:32][CH3:33])=[C:15]([C:30]#[N:31])[C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:34][CH2:35][CH3:36])=[CH:21][CH:22]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1sc(CC)c(C#N)c1-c1ccc(-c2ccccc2O)cc1
Reactant: CCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccccc1-c1ccc(-c2c(C(=O)OCC)sc(CC)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add K2CO3 (220 mg, 1.6 mmol) to a solution of 4-cyano-5-ethyl-3-(2′-hydroxy-biphenyl-4-yl)-thiophene-2-carboxylic acid ethyl ester (200 mg, 0.53 mmol) in 2 mL of dry DMF at 0° C. and stir at this temperature for 1 hour. Treat with n-propyl iodide (0.2 mL, 2 mmol) and allow to warm to room temperature. After 3 hours pour into 25 mL cold 0.2N HCl. Extract with EtOAc (2×50 mL) and wash the combined EtOAc layers with water (2×20 mL) and brine (1×20 mL). Dry over Na2SO4, filter and evaporate to an oil. Chromatograph on silica gel (1/9-1/3 EtOAc/hexanes) to give the title compound as a tan solid, 158 mg (71%). HPLC=99%.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH2:34][CH2:35][Br:36])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O1CCCC1>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH2:34][CH2:35][Br:36])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCCBr)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOCCBr)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Yield: 80.2 %

Procedure:
N.M.R. δ(DMSO-d6, ppm): 3.3-3.9 (4H, m), 4.1-4.8 (4H, m), 5.23 (1H, d, J=5Hz), 5.84 (1H, dd, J=5 Hz, 9 Hz), 7.63 (1H, s), 8.72 (1H, s), 9.57 (1H, s), 9.71 (1H, d, J=9 Hz), 12.71 (1H, broad s). (2) A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-bromoethoxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.5 g.), conc. hydrochloric acid (0.99 g.), tetrahydrofuran (10 ml.) and methanol (22 ml.) was treated in similar manner to that of Example 9 (2), to give 7-[2-(2-aminothiazol-4-yl)-2-(2-bromoethoxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.15 g.).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[NH:8])[CH3:7])[CH2:2][CH2:3][CH3:4].[N+:9](=[C:11]1[N:15]=[CH:14][N:13]=[C:12]1[C:16]([NH2:18])=[O:17])=[N-:10]>C(O)C>[CH2:1]([N:5]([C:6](=[NH:8])[CH3:7])[N:10]=[N:9][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[C:16]([NH2:18])=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(C)=N
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Solvent: CCO
Product: CCCCN(N=Nc1[nH]cnc1C(N)=O)C(C)=N
Reaction time: 0.17 h

Procedure:
1.2 g. of N-butyl-acetamidine (Bp.: 76°-78° C./0.4 torr) are dissolved in 50 ml of anhydrous ethanol, whereafter 1.4 g. of 5-diazo-imidazole-4-carboxamide are added at 25° C. under stirring within 10 minutes. After 2.5 hours the orange-colored solution is clarified with activated characoal and evaporated in vacuo. 2.6 g. of a slowly crystallizing resin are obtained, which is twice crystallized from an ethanol-acetone mixture. Thus, a colorless, crystalline product, the 5-[3-n-butyl-3-(alpha-iminoethyl)-1-triazeno]-imidazole-4-carboxamide, melting at 191° C., is obtained (decomposition)
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.O[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:41])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C(NCCCO)OCc1ccccc1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccccc1C(=O)OCCCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a solution of 2-acetoxybenzoic acid (2.0 g, 11.1 mmol) and triethylamine (1.8 mL, 11.1 mmol) in CH2Cl2 (40 mL) at 0° C. was slowly added ClCO2Et (1.1 mL, 167 mmol). The reaction mixture was stirred (0° C., 2 h) and filtered. The filtrate was added to a solution of benzyl 3-hydroxypropylcarbamate (2.1 g, 10.0 mmol) and triethylamine (15 mL) in CH2Cl2 (40 mL). The reaction mixture was stirred (RT, 4 h) and quenched with H2O (50 mL). The organic layer was washed with 1 M HCl, saturated Na2CO3 (30 mL) and H2O (50 mL). The organic solution was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica chromatography, (PE-EtOAc, 5:1) to afford 3-(benzyloxycarbonylamino)propyl 2-acetoxybenzoate (2.0 g, 54%) as a colorless oil. Mass calculated for C20H21NO64=371.38. found: [M+H]+=372.3.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([OH:31])[CH:30]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:27]5[CH:28]=[C:29]([OH:31])[CH:30]=[C:25]([F:24])[CH:26]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: OB(O)c1cc(O)cc(F)c1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cc(O)cc(F)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 3-fluoro-5-hydroxyphenylboronic acid (Combi-Blocks, San Diego, USA, 21 mg, 0.132 mmol) to give the title compound as a white solid. (HPLC: tR 2.58 min (Method A); M+H=404 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 10.09 (s, 1H), 8.96 (s, 1H), 8.17 (s, 1H), 8.10-8.03 (m, 1H), 7.87-7.80 (m, 1H), 7.52-7.46 (m, 1H), 6.75-6.64 (m, 2H), 6.63-6.52 (m, 1H), 3.92 (s, 3H), 3.57 (s, 3H), 1.94 (s, 3H))
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH2:17][C:18]([OH:20])=[O:19]>>[C:18]([CH2:17][NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)([OH:20])=[O:19]
Reactant: NCC(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)CNc1nc2ccc(Cl)cc2cc1C(=O)O
Yield: 52 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with glycine to provide the title compound in 52% yield as yellow needles (recrystallization from EtOH/water).