Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.[CH:20](B(O)O)=[CH2:21]>>[C:14]1([C@@H:12]([N:8]2[C:6]3=[N:7][C:2]([CH:20]=[CH2:21])=[CH:3][N:4]=[C:5]3[N:10]=[C:9]2[OH:11])[CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H](c1ccccc1)n1c(O)nc2ncc(Br)nc21
Reactant: C=CB(O)O
Product: C=Cc1cnc2nc(O)n([C@@H](C)c3ccccc3)c2n1
Temperature: 90 °C
Yield: 54 %

Procedure:
A scintillation vial equipped with a stirbar was charged with (S)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv), vinyl boronic acid (2.2 equiv), and (DPPF)PdCl2 (0.10 equiv). The vial was fitted with a septum-lined cap and purged with nitrogen for 5-10 min. To this mixture was added dioxane (16.6 volume equivalents) and degassed 2 N K2CO3 (4.2 volume equivalents) by syringe. The resulting mixture was heated to 90° C. overnight. The mixture was cooled to room temperature, diluted with 12 volume equivalents EtOAc, washed with twice with saturated aq. NaHCO3, and once with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Biotage MPLC 5%-40% EtOAc/Hexanes) provided the title compound as an off-white solid (54%). LCMS m/z (APCI)=267.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[O:10])=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[O-:25][Cr](Cl)(=O)=O.N1C=CC=CC=1>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: O=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
2-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)ethanone (2.7 g, 9.01 mmol) was dissolved in 1,2-dichloroethane (25 ml) and freshly made PCC (3.89 g, 18.02 mmol), pyridine (1.43 g, 18.02 mmol) and molecular sieves were added. The reaction mixture was refluxed under inert atmosphere overnight. The solution was cooled to 25° C., filtered through Silica and then solvent was evaporated under reduced pressure. The crude product (1.9 g, 66%) was used directly in the next step. 1H NMR (500 MHz) δ 7.97 (d, 2H), 7.84 (d, 1H), 7.52 (d, 2H), 7.46 (s, 1H), 7.44 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16]3)(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:23]([C:25]1[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=1[CH3:34])=O.N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:25]2[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=2[CH3:34])(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3cc(Cl)cc(Cl)c3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-(3,5-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (356 mg, 1 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (167 mg) and piperidine (cat. amount) in ethanol was stirred at rt for 2 days. The reaction was concentrated and triturated with HCl (2M solution) to give the titled compound.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[N:9]=1)(=O)C.N.CO>>[NH2:4][C:5]1[S:6][C:7]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])[N:9]=1
Reactant: CCOC(=O)c1sc(NC(C)=O)nc1OCc1ccccc1C(F)(F)F
Agent: N
Solvent: CO
Product: CCOC(=O)c1sc(N)nc1OCc1ccccc1C(F)(F)F
Temperature: 80 °C
Yield: 86.6 %

Procedure:
Ethyl 2-(acetylamino)-4-({[2-(trifluoromethyl)-phenyl]methyl}oxy)-1,3-thiazole-5-carboxylate (6.23 g, 16.0 mmol) was placed in a pressure vessel with a stir bar. 2N Ammonia in methanol (120 mL, 240 mmol) was added via syringe and the vessel was sealed. The solution was heated to 80° C. using an oil bath for 16 hours. The reaction was cooled and concentrated. The residue was dissolved in ethyl acetate and washed with half-saturated NaHCO3 and brine. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The solid was dissolved in approximately 50 mL of dichloromethane, and 150 mL of hexanes was added. Air was blown over the solution and hexanes added periodically to precipitate the product. The solid was filtered, washed with hexanes, and air-dried to afford 4.80 g (87%) of ethyl 2-amino-4-({[2-(trifluoromethyl)-phenyl]methyl}oxy)-1,3-thiazole-5-carboxylate as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 2H), 7.90 (d, J=7.7 Hz, 1H), 7.81-7.72 (m, 2H), 7.57 (m, 1H), 5.52 (s, 2H), 4.11 (q, J=7.1 Hz, 2H), 1.21 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>C1COCC1>[CH2:19]([CH:16]1[CH2:17][CH2:18][CH:13]([CH:10]2[CH2:11][CH2:12][CH:7]([CH2:6][CH2:5][CH2:4][OH:3])[CH2:8][CH2:9]2)[CH2:14][CH2:15]1)[CH2:20][CH3:21]
Reactant: CCCC1CCC(C2CCC(CCC(=O)OCC)CC2)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(CCCO)CC2)CC1

Procedure:
A solution of 3-(4′-Propyl-bicyclohexyl-4-yl)-propionic acid ethyl ester (22.0 g, 70 mmol) in THF (150 ml) is added dropwise to a suspension of lithium-aluminiumhydride (3.25 g, 86 mmol) in THF (250 ml) at reflux temperature. The reaction is heated under reflux for 1 h, cooled and poured onto sat. ammonium chloride solution. The mixture is acidified, extracted with ether and the combined organic layers are washed with brine and dried over sodium sulfate. The solvent is evaporated and the crude product is crystallised from isopropanol to give 3-(4′-propyl-bicyclohexyl-4-yl)-propan-1-ol as colourless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Li]CCCC.[Cl:15][C:16]1[CH:27]=[CH:26][C:19]([C:20](N(OC)C)=[O:21])=[CH:18][N:17]=1>C1COCC1>[Cl:15][C:16]1[N:17]=[CH:18][C:19]([C:20]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])=[O:21])=[CH:26][CH:27]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Reactant: COc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a solution of 1-bromo-2-methoxy-benzene (49.2 g, 0.263 mol) in dry THF (500 mL) was added dropwise n-BuLi (2.5 M in hexane, 105 mL, 0.263 mol) at −78° C. under N2 atmosphere. The mixture was stirred at this temperature for 1 hr and then a solution of 6-chloro-N-methoxy-N-methyl-nicotinamide (50 g, 0.25 mol) in THF (100 mL) was added dropwise. The reaction mixture was warmed to room temperature, stirred overnight and then was quenched with a saturated solution of NH4Cl (300 mL). The separated aqueous layer was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine, dried over Na2SO4, evaporated in vacuo to give the crude product that was purified by column chromatography to yield (6-chloropyridin-3-yl)-(2-methoxyphenyl)-methanone as a white solid (31 g, 47.6%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH2:20][N:21]3[CH:25]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:23]=[N:22]3)[S:18][CH:19]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7].I[CH3:32].O>CN(C)C=O.O1CCCC1>[CH3:3][O:4][CH2:5][C:6]([N:8]([CH3:32])[C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH2:20][N:21]3[CH:25]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:23]=[N:22]3)[S:18][CH:19]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7]
Reactant: CI
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(NC(=O)COC)c3)cs2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(N(C)C(=O)COC)c3)cs2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (2 mL) of sodium hydride (60% in mineral oil, 93 mg, 2.3 mmol) in N,N-dimethylformamide was added dropwise a solution (2 mL) of the compound (720 mg, 1.8 mmol) obtained in Example 26b in tetrahydrofuran, and the mixture was stirred at room temperature for 30 min. Then, iodomethane (0.22 mL, 3.6 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-ethyl acetate) to give the title compound (500 mg, 67%) as a colorless oil.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[OH:13][C:14]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)(=[O:26])=[O:25])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:53]1([CH2:59]O)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C1(C)C=CC=CC=1.CCOCC>[CH3:33][N:30]1[CH2:29][CH2:28][N:27]([S:24]([C:21]2[CH:22]=[CH:23][C:14]([O:13][CH2:59][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[C:15]([CH:20]=2)[C:16]([O:18][CH3:19])=[O:17])(=[O:26])=[O:25])[CH2:32][CH2:31]1
Reactant: COC(=O)c1cc(S(=O)(=O)N2CCN(C)CC2)ccc1O
Reactant: OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)c1cc(S(=O)(=O)N2CCN(C)CC2)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
DEAD (0.24 ml, 1.51 mmol) was slowly added to a mixture of methyl 2-hydroxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoate (may be prepared as described in Description 70; 430 mg, 1.37 mmol), Ph3P (395 mg, 1.51 mmol) and phenylmethanol (163 mg, 1.505 mmol) in toluene (15 ml) cooled in an ice bath at 0° C. The mixture was stirred for 2 h at room temperature. Ether was added to the mixture and the mixture was filtered. The filtrate was evaporated to yield the title compound. 260 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:15]([CH2:16]I)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]1=[O:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:15]([CH2:16][N:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]3=[O:31])[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1cccc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CI)[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](Cn2ccccc2=O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 80 °C
Yield: 12.8 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(3,4-dichlorophenyl)-7-(iodomethyl)-1,4-oxazepane-4-carboxylate (370 mg) in DMF (8.0 mL) were added 2(1H)-pyridinone (87 mg) and potassium carbonate (158 mg), and the mixture was heated at 80° C. for 4 hr. The reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.1 N hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (44 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].[CH2:29]([O:36][C:37]([NH:39][CH2:40][C:41]([NH:43][C@H:44]([C:54](O)=[O:55])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)=[O:42])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:54](=[O:55])[C@H:44]([CH2:45][C:46]2[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=2)[NH:43][C:41](=[O:42])[CH2:40][NH:39][C:37]([O:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Reactant: COc1ccc(C[C@H](NC(=O)CNC(=O)OCc2ccccc2)C(=O)O)cc1
Product: COc1ccc(C[C@H](NC(=O)CNC(=O)OCc2ccccc2)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O[C@@H]2C(=O)O)cc1
Yield: 93.6 %

Procedure:
1-(6-Benzoylamino-9H-purin-9-yl)-3-[N-(N-benzyloxycarbonylglycyl)-O-methyl-L-tyrosylamino]-1,3-dideoxy-β-D-ribofuranuronic acid (550 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (300 mg) prepared in Example 1 with N-hydroxysuccinimide ester of N-(N-benzyloxycarbonylglycyl)-O-methyl-L-tyrosine (415 mg) according to a similar manner to that of Example 5, mp. 78°-84° C.
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3]O.N1C=CC=CC=1.P(Br)(Br)[Br:28].O>CCOCC>[Br:28][CH2:3][C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH2:1]
Reactant: C=C(CO)CCCCCCCCCCCCCCCC
Reactant: BrP(Br)Br
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=C(CBr)CCCCCCCCCCCCCCCC
Temperature: -15 °C

Procedure:
A mixture of 20 g of 2-methylene-1-octadecanol, 150 ml of ether and 12.6 ml of pyridine is cooled to -15° C. in an ice-methanol bath. A solution of 7.3 ml of phosphorous tribromide in 50 ml of ether is added slowly over 1 hour, and the mixture is allowed to warm to room temperature overnight. The mixture is recooled to 0° C., 1.9 ml of water added and then allowed to warm to room temperature over 6 hours. The mixture is washed, filtered and evaporated, to give 19.2 g of the desired compound as a clear oil.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Al+3].[Cl-].[Cl-].[Cl-].[Br:20]Br>C(Cl)Cl>[Br:20][CH:2]([CH2:3][CH3:4])[C:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)=[O:5]
Reactant: BrBr
Reactant: CCCC(=O)c1ccc(NC(C)=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(Br)C(=O)c1ccc(NC(C)=O)cc1
Reaction time: 0.17 h

Procedure:
A solution of N-(4-butyryl-phenyl)acetamide (3.47 g, 16.9 mmol) in 100 mL of anhydrous DCM was cooled to 0° C. under N2 and treated with AlCl3 (180 mg, 1.35 mmol). Approximately 10 mL of Br2 was added and the mixture was stirred for 10 min. The reactor was removed from the cooling bath and the remaining Br2 was added dropwise via syringe over 5 min. After 3 hr, the dark orange color of Br2 had faded and by 3¼ hr a precipitate had formed. The reaction was quenched with saturated NaHCO3. The phases were separated and the aqueous phase extracted three times with DCM. The combined extracts were dried over Na2SO4, filtered through a Celite® pad and concentrated in vacuo to give N-(4-(2-bromobutanoyl)phenyl)acetamide which was used without purification. MS ESI: m/z 284.10 [M+].
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=[CH2:2].I[CH2:14]I>[Cu].[Zn].C(OCC)C>[CH:1]1([C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)[CH2:14][CH2:2]1
Reactant: ICI
Reactant: C=Cc1ccc2ccccc2c1
Agent: [Cu]
Agent: [Zn]
Solvent: CCOCC
Product: c1ccc2cc(C3CC3)ccc2c1

Procedure:
A mixture of 15.5 g. of 2-vinylnaphthalene, 23 g. of diiodomethane, 19.6 g. of zinc-copper couple (comprising 19.5 g. of zinc and 0.1 g. of copper) and 500 ml. of diethyl ether is refluxed for eight hours; the cooled mixture is then filtered, washed with dilute hydrochloric acid, washed with water to neutrality, dried and evaporated to yield 2-cyclopropylnaphthalene.
Reaction SMILES: Cl.C(CC([N:8]=[C:9]1[NH:13][C:12]([C:14](=[N:35][O:36]C(=O)C)[C:15]([NH:17][CH:18]2[C:33](=[O:34])[N:20]3[C:21]([C:30]([OH:32])=[O:31])=[C:22]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[CH2:23][S:24][C@H:19]23)=[O:16])=[CH:11][S:10]1)=S)(=N)N.C(=O)([O-])O.[Na+:44]>O>[NH:8]=[C:9]1[NH:13][C:12]([C:14](=[N:35][OH:36])[C:15]([NH:17][CH:18]2[C:33](=[O:34])[N:20]3[C:21]([C:30]([O-:32])=[O:31])=[C:22]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[CH2:23][S:24][C@H:19]23)=[O:16])=[CH:11][S:10]1.[Na+:44]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(C)=O)c3csc(=NC(=S)CC(=N)N)[nH]3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NO)c3csc(=N)[nH]3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In 20 m of water there was suspended 0.525 g of 7-[2-(2-amidinothioacetylimino-4-thiazolin-4-yl)-2-acetoxyimino-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid hydrochloride (syn-isomer), followed by the addition of 0.252 g of sodium hydrogen carbonate. The mixture was stirred at room temperature for 15 hours. The reaction mixture, as such was subjected to column chromatography on polystyrene resin (Amberlite XAD-2, Rohm and Haas Co.) and the fractions containing the desired product were pooled and lyophilized.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[Cl:11][CH2:12][CH2:13][N:14]=[C:15]=[O:16]>C(OCC)C>[Cl:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: Nc1ccc2c(c1)CCC2
Reactant: O=C=NCCCl
Solvent: CCOCC
Product: O=C(NCCCl)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
To a solution of 2 g of 5-aminoindane in 125 mL of anhydrous ethyl ether was added dropwise, 1.25 g of 2-chloroethyl isocyanate. This solution is stirred for 16 h at room temperature, cooled at -20° C., and filtered. A white solid separated and was recrystallized from ethanol (white flakes), yield 40%, mp 155°-157° C., IR (KBr pellet): 3300 (NH), 1730 (C=O, ester), and 1640 cm-1 (C=O, ureido); 1H NMR (DMSO-d6 : CDCl3): 6.96 ppm, 3.52 ppm, 3.49 ppm, 3.46 ppm, 3.43 ppm, 2.74 ppm, 2.72 ppm, 1.93 ppm. In this spectrum hydrogen present on NH groups have exchanged with the presence of DMSO-d6.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]2[N:10]=[C:11]([C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[O:21])[C:12]3[S:17][C:16]([CH:18]=[CH2:19])=[CH:15][C:13]=3[N:14]=2)[CH:2]=1.Cl>C(O)C.[Pd]>[CH2:18]([C:16]1[S:17][C:12]2[C:11]([C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[O:21])=[N:10][C:9]([NH:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:14][C:13]=2[CH:15]=1)[CH3:19]
Reactant: C=Cc1cc2nc(NCc3cccnc3)nc(C(=O)c3cccs3)c2s1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCc1cc2nc(NCc3cccnc3)nc(C(=O)c3cccs3)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A stirred solution of Example 10 (0.025 g, 0.066 mmol) in ethanol (5 ml) was treated with palladium/activated carbon (10%, 0.0025 g) and HCl (1.25M in MeOH, 0.19 mmol). The Flask was thoroughly evacuated and placed under 1 atmosphere of hydrogen gas. The mixture was stirred under hydrogen overnight at room temperature, evacuated and filtered through celite. The filtrate was reduced in vacuo to give the title compound as a yellow solid in 70% yield, >95% purity. LC-MS m/z=381.0 [M+H]+; RT=3.19; LC-MS method 1. 1H NMR: δH (400 MHz, D6-DMSO) 1.33 (3H, t, J 7.5 Hz), 2.95 (2H, q, J 7.5 Hz), 4.71 (2H, b), 7.08 (1H, s), 7.28-7.35 (2H, m), 7.78 (1H, d, J 8.0 Hz), 8.06 (1H, bt), 8.17 (1H, d, J 4.5 Hz), 8.43 (1H, d, J 4.5 Hz), 8.63 (1H, bd), 8.40-8.65 (1H, b).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C@@H:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=2)[N:12]=1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[O:23]=[C:24]1[CH2:29][CH2:28][C:27]([CH:33]=[CH2:34])([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@@H:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15](/[CH:34]=[CH:33]/[C:27]3([C:30]([OH:32])=[O:31])[CH2:28][CH2:29][C:24](=[O:23])[CH2:25][CH2:26]3)=[CH:16][CH:17]=2)[N:12]=1)[CH3:10])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC1(C(=O)O)CCC(=O)CC1
Reactant: C[C@H](c1ccc2ccc(Br)cc2n1)N(C)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@H](c1ccc2ccc(/C=C/C3(C(=O)O)CCC(=O)CC3)cc2n1)N(C)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
A solution of [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-methyl-carbamic acid tert-butyl ester (200 mg, 0.55 mmol), 4-oxo-1-vinyl-cyclohexanecarboxylic acid (138 mg, 0.82 mmol), palladium(II) acetate (25 mg, 0.11 mmol), tri-(o-tolyl)phosphine (50 mg, 0.16 mmol) in anhydrous 1,4-dioxane (2 mL) was treated with triethylamine (267 μL, 1.91 mmol). After stirring at 100° C. under microwave irradiation for 30 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The residue was partitioned between ethyl acetate and a 5% citric acid solution, the aqueous layer was extracted with ethyl acetate (2 x), the organics were combined and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 25 g Biotage cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:1 to afford the title compound (235 mg, 94%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.48 (s, 9H), 1.68 (d, J=7.1 Hz, 3H), 2.07-2.22 (m, 2H), 2.44-2.70 (m, 6H), 2.75 (br s, 3H), 5.61 (br s, 1H), 6.68 (ABq, ΔδAB=0.31, JAB=16.3 Hz, 2H), 7.36 (d, J=8.5 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 8.05-8.12 (m, 2H). LCMS (m/z) 453.1 [M+H], Tr=2.48 min.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[O:16][CH:10]([CH2:11][N:12]([CH2:17][CH2:18][N:19]([CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)[C:20]([NH2:22])=[O:21])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][N:19]([CH2:18][CH2:17][N:12]2[CH2:11][CH:10]3[O:16][CH:14]([CH2:15][NH:8][CH2:9]3)[CH2:13]2)[C:20]([NH2:22])=[O:21])=[CH:31][CH:30]=1)#[N:33]
Reactant: CC(C)(C)OC(=O)N1CC2CN(CCN(CCOc3ccc(C#N)cc3)C(N)=O)CC(C1)O2
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(OCCN(CCN2CC3CNCC(C2)O3)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-(2-{1-[2-(4-Cyanophenoxy)ethyl]ureido}ethyl)-9-oxa-3,7-diazabicyclo-[3.3.1]nonane-3-carboxylic acid tert-butyl ester (6.44 g; see step (i) above) was added to a solution of HCl-saturated, dry dioxane (300 mL) at 0° C. The reaction was then stirred at rt for 1 hr. The resulting precipitate was filtered under N2, washed with dry ether and then dried under vacuum to provide the title compound. Yield: 6 g.