Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:5][CH2:6][C:7](=[O:23])[CH:8](S(C2C=CC=CC=2)=O)[CH2:9][CH2:10][C:11](=[CH2:14])[CH:12]=[CH:13]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Ca+2]>C1(C)C=CC=CC=1>[CH:1]([C@@H:4]1[CH2:5][CH2:6][C:7](=[O:23])[CH:8]=[CH:9][CH2:10][C:11](=[CH2:14])[CH:12]=[CH:13]1)([CH3:3])[CH3:2]
Reactant: C=C1C=C[C@H](C(C)C)CCC(=O)C(S(=O)c2ccccc2)CC1
Agent: C=C1/C=C/[C@H](C(C)C)CCC(=O)/C=C\C1
Agent: C=C1/C=C/[C@H](C(C)C)CCC(=O)C(S(=O)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: C=C1C=C[C@H](C(C)C)CCC(=O)C=CC1

Procedure:
After dissolving 2.6 g of the product of step 2 in 200 ml of toluene, 2.5 g of calcium carbonate were added to the solution and the mixture was refluxed under nitrogen gas stream for 5 hours. The reaction mixture was filtered to remove calcium carbonate, and the filtrate was concentrated under reduced pressure to 5 ml. Then, 10 ml of hexane were added to the concentrate. Using n-hexane-ethyl acetate as an eluent, the mixture was subjected to column chromatography using 100 g of alumina (activity: II). The fraction which eluted with n-hexane-ethyl acetate (95:5) was recovered and was evaporated to dryness to provide 760 mg of purified (8S,2Z,6E)-8-isopropyl-5-methylene-2,6-cyclodecadiene-1-one. The yield was 47%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][S:12][C:11](=[O:14])[N:10]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=3)[N:9]=2)=[CH:4][CH:3]=1.[H][H]>C1COCC1.[Ni]>[NH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][N:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:13][S:12][C:11]1=[O:14]
Reactant: [H][H]
Reactant: O=C1SCC(c2ccc(Cl)cc2)=NN1Cc1cccc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cccc(CN2N=C(c3ccc(Cl)cc3)CSC2=O)c1
Yield: 91.7 %

Procedure:
5.47 g of 5-(4-chlorophenyl)-3-(3-nitrobenzyl)-3,6-dihydro-1,3,4-thiadiazin-2-one is dissolved in 100 ml of THF, and 1.3 g of Raney nickel is subsequently added. Hydrogen is subsequently passed in until starting material is no longer detectable. For work-up, the catalyst is filtered off, washed with THF, and the filtrate is evaporated to dryness and recrystallised from dichloromethane/diethyl ether, giving 4.6 g (94%) of 3-(3-aminobenzyl)-5-(4-chlorophenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].FC1C(F)=C(OCCCCCCCC)C=CC=1C1N=CC(Br)=CN=1>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.COCCOC>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1cnc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Fc1ccc(-c2ncc(Br)cn2)cc1
Yield: 93.1 %

Procedure:
--Quantities: 5-bromo-2-iodopyrimidine 2 (4.00 g, 14.0 mmol), 4-fluorophenylboronic acid 19 (2.44 g, 17.4 mmol), tetrakis(triphenylphosphine)palladium (324 mg, 0.28 mmol), DME (50 ml), aqueous 2M sodium carbonate (50 ml). The experimental procedure was as described for compound 4. The crude product was purified by flash chromatography (5% ethyl acetate-light petroleum) to give the fluorophenylpyrimidine 20 (3.3 g, 94%) (from MeOH), m.p. 155.5° C.; νmax /cm-1 (KBr) 1595,1525, 1505, 1400s, 1220, 1150 and 785; δ7.15 (2H, dd, J 9, 3'- and 5'-H), 8.41 (2H, dd, J 9 and 4, 2'- and 6'-H) and 8.80 (2H, s, 4- and 6-H); m/z 254 (M+), 252 (M+), 227 (M+ -HCN), 225 (M+ -HCN), 146 and 121.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[NH:4][N:5]=[C:6]([Cl:9])[C:7]=1Cl.[CH2:11]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:18][NH2:19])[CH2:12][CH3:13]>C(O)C>[Cl:1][C:2]1[C:3](=[O:10])[NH:4][N:5]=[C:6]([Cl:9])[C:7]=1[NH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:15]([O:14][CH2:11][CH2:12][CH3:13])[CH:16]=1
Reactant: O=c1[nH]nc(Cl)c(Cl)c1Cl
Reactant: CCCOc1cc(CN)ccc1OC
Solvent: CCO
Product: CCCOc1cc(CNc2c(Cl)n[nH]c(=O)c2Cl)ccc1OC
Reaction time: 2 h

Procedure:
A mixture comprising 997 mg of 4,5,6-trichloro-3(2H)pyridazinone, 3.20 g of 3-n-propoxy-4-methoxybenzylamine and 30 ml of ethanol, was refluxed under stirring for 2 hours. Ethanol was distilled off under reduced pressure, and dilute hydrochloric acid was poured into the residue thereby obtained. The mixture was extracted with ethyl acetate. The extract was washed with water and dried over sodium sulfate. Then, the solvent was distilled off to obtain a light brown viscous oily substance. The residue was subjected to silica gel column chromatography, and the second fraction obtained by eluting with a solvent mixture of benzene-ethyl acetate (2.5:1 v/v) was separated to obtain a colorless solid substance. The product was crystallized from a solvent solution of methanol-diethyl ether, to obtain 513 mg of the above identified compound having a melting point of from 181° to 183° C. as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([C:10]([OH:12])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:13]([NH:20][CH2:21][C:22]([CH3:24])=[CH2:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.[O-]P1(OP([O-])(=O)OP([O-])(=O)OP([O-])(=O)O1)=O.[Na+].[Na+].[Na+].[Na+]>C(Cl)Cl>[CH2:13]([N:20]([CH2:21][C:22]([CH3:24])=[CH2:23])[C:10]([CH:9]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=2[CH2:8]1)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C1Cc2c(Cl)cccc21
Reactant: C=C(C)CNCc1ccccc1
Agent: O=P1([O-])OP(=O)([O-])OP(=O)([O-])OP(=O)([O-])O1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)CN(Cc1ccccc1)C(=O)C1Cc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 3-chloro-1,2-dihydrocyclobutabenzene-1-carboxylic acid (7.67 mmol, 1.4 g) in DCM (20 ml) was added N-benzyl-2-methylprop-2-en-1-amine (11.50 mmol, 1.854 g), triethylamine (15.33 mmol, 2.131 ml, 1.552 g) and cyclophos (50 wgt % solution in EtOAc) (9.20 mmol, 2.74 ml, 2.93 g). The mixture was stirred at ambient temperature overnight then cyclophos (50 wgt % solution in EtOAc) (0.5 ml) added and the mixture stirred for a further 1 hr. The mixture was diluted with DCM (10 ml), washed with 2 N HCl (20 ml) then 2 N NaOH (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to afford N-benzyl-3-chloro-N-(2-methylallyl)-1,2-dihydrocyclobutabenzene-1-carboxamide as a brown oil (1.8 g).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:37]=[CH:36][C:21]([CH:22]=[CH:23][C:24]([N:26]2[CH:30]([C:31]([O:33]CC)=[O:32])[CH2:29][S:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].S1CC(C(O)=O)NC1>C(=O)(O)[O-].[Na+].CC(C)=O>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH:22]=[CH:23][C:24]([N:26]2[CH:30]([C:31]([OH:33])=[O:32])[CH2:29][S:28][CH2:27]2)=[O:25])=[CH:36][CH:37]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C=CC(=O)N2CSCC2C(=O)OCC)cc1
Agent: O=C(O)C1CSCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCNc1ccc(C=CC(=O)N2CSCC2C(=O)O)cc1

Procedure:
By means of the alkaline hydrolysis method of Example 54, the ethyl ester of Example 51 is converted to the subject carboxylic acid. This acid is also prepared using the procedure of Example 51 except that the acylation of the thiazolidine-4-carboxylic acid is carried out in aqueous acetone sodium bicarbonate solution.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:23]2=[O:38])[O:11][CH:10]1[C@@H:39]([OH:70])[C@@H:40]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:62])[C@H:47]([C@@H:59]([OH:61])[CH3:60])[NH:48]C(=O)OCC1C=CC=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:48][C@@H:47]([C@@H:59]([OH:61])[CH3:60])[C:46]([NH:45][CH2:44][CH2:43][CH2:42][NH:41][C@@H:40]([C@@H:39]([CH:10]1[C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[C@@H:13]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:23]2=[O:38])[O:11]1)[OH:70])[C:63]([O:65][C:66]([CH3:68])([CH3:69])[CH3:67])=[O:64])=[O:62]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@H](C)O)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@@H](O)[C@H](NCCCNC(=O)[C@@H](N)[C@H](C)O)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 29.9 %

Procedure:
By using an analogous procedure to that described in Example 2, tert-butyl (5S,12S)-12-[(S)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (77 mg, 0.076 mmol, obtained from Example 8) was hydrogenated in methanol (2 ml) using 10% palladium on carbon (15 mg). The product was purified by chromatography (flash column, silica gel, 10 methanol in methylene chloride) to provide tert-butyl (2S,3S)-2-[(3-{[(2S,3S)-2-amino-3-hydroxybutanoyl]amino}propyl)amino]-3-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-3-hydroxypropanoate (20 mg, 30%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=O.Cl.[CH3:13][O:14][C:15](=[O:21])[C@H:16]([C@@H:18]([CH3:20])[OH:19])[NH2:17].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:13][O:14][C:15](=[O:21])[C@H:16]([C@@H:18]([CH3:20])[OH:19])[NH:17][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(C)cc(C(=O)O)c1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)c1cc(C)cc(C)c1)[C@@H](C)O
Reaction time: 0.17 h

Procedure:
1.00 g (6.66 mmol/1 eq) of 3,5-dimethylbenzoic acid and 1.13 g (6.66 mmol/1 eq) of L-threonine methyl ester hydrochloride are suspended in 50 ml dichloromethane. At 0° C., 2.04 ml (14.7 mmol/2.2 eq) of triethylamine are added dropwise. After 10 minutes' stirring, 2.55 g (13.3 mmol/2 eq) of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC) are added, and after a further 15 min 1-hydroxybenzotriazole (HOBt) is added. Stirring is carried out for twelve hours, the solution assuming room temperature. The organic phase is washed with 10 ml each of H2O, hydrochloric acid (2N), and NaHCO3 solution. After drying over magnesium sulfate, the solvent is removed in vacuo. 1.70 g (6.41 mmol/96%) of a white solid are obtained, which may, if desired, be recrystallised from absolute diethyl ether.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:9][CH:8]=[C:7]([Br:20])[CH:6]=2.[C:21](Cl)(=O)[CH2:22][CH2:23][CH2:24][CH3:25]>N1C=CC=CC=1>[Br:20][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH2:14][NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:21]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: CS(=O)(=O)NCCNc1c(N)cnc2cc(Br)ccc12
Reactant: CCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCc1nc2cnc3cc(Br)ccc3c2n1CCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-[2-(3-amino-7-bromoquinolin-4-ylamino)ethyl]methanesulfonamide (46.4 g, 0.129 mol) in 1000 mL pyridine was slowly added valeryl chloride (1.1 equivalents). After 1.5 hours the mixture was yellow and turbid. The reaction mixture was then heated at reflux for 12 hours, allowed to cool to ambient temperature and concentrated under reduced pressure. The residue was mostly dissolved in 10% HCl to adjust to pH 1. The resulting suspension was adjusted to pH 12 with the addtion of 50% aqueous sodium hydroxide and stirred overnight. A precipitate formed and was isolated by filtration and air-dried to provide 45 g of N-[2-(7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide as a pale gray/green solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1COCC1.[C-:20]#[N:21].[K+].OS([O-])=O.[Na+]>C(Cl)Cl.O>[C:20]([C:10]1([OH:14])[CH2:11][CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)#[N:21]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(O)(C#N)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a solution of N-Boc-3-piperidone (5.00 g, 25.1 mmol) and THF (15 mL) was added KCN (2.34 g, 37.6 mmol) and H2O (15 mL) and the resulting solution was cooled to 0° C. To the resulting homogeneous orange solution was added a solution of NaHSO3 (1.25 g, 37.6 mmol) and H2O (15 mL). The resulting solution was stirred at 0° C. for 1 hour. The solution was twice extracted DCM and the combined extracts were dried by Na2SO4, filtered and evaporated to afford title compound 5.7 g as white solid. MS (m/z): 127 (M+H-Boc)+
Reaction SMILES: [Si](OCC1N=CN(CCF)C=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[Si:28]([O:45][CH2:46][C:47]1[N:51]([CH2:52][CH2:53]F)[CH:50]=[N:49][CH:48]=1)([C:41]([CH3:44])([CH3:43])[CH3:42])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([Li])CCC.[Cl-].[NH4+]>C1COCC1>[Si:28]([O:45][CH2:46][C:47]1[N:51]([CH:52]=[CH2:53])[CH:50]=[N:49][CH:48]=1)([C:41]([CH3:44])([CH3:42])[CH3:43])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)[Si](OCc1cncn1CCF)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[Si](OCc1cn(CCF)cn1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=Cn1cncc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -78 °C

Procedure:
The above-mentioned mixture (58.87 g) of 4-(tert-butyldiphenylsilyloxymethyl)-1-(2-fluoroethyl)-1H-imidazole and 5-(tert-butyldiphenylsilyloxymethyl)-1-(2-fluoroethyl)-1H-imidazole was dissolved in THF (1000 mL), and cooled to −78° C. while stirring under nitrogen stream. To the present solution was added dropwise n-butyl lithium (2.76 M hexane solution, 167 mL), followed by stirring at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=10%→65%) using silica gel column (product name: KiloPack 40E, manufactured by Yamazen Corporation) to afford the title compound (18.8 g) and 5-(tert-butyldiphenylsilyloxymethyl)-1-vinyl-1H-imidazole (5.73 g).
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=O)[C:21]1C=CC=[CH:23][CH:22]=1>>[C:2]1([C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:8])[C:7]2[C:6](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CCCCCCC(=O)c1ccccc1
Product: CCOC(=O)CCCCCCC(=O)c1cccc2ccccc12
Yield: 58 %

Procedure:
Following a procedure analogous to that described above for 49a, but substituting 1-naphthoyl chloride for benzoyl chloride, the title compound was obtained as a white solid in 58% yield: 1H NMR (300 MHz, CDCl3) δ 8.56 (d, J=8.7 Hz, 1H), 7.42-7.92 (m, 6H), 4.10 (q, J=6.9 Hz, 2H), 2.98 (m, 2H), 2.26(t, J=7.5 Hz, 2H), 1.75 (m, 2H), 1.62 (m, 2H), 1.36 (m, 4H), 1.22 (t, J=6.9 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 14.02, 24.23, 24.55, 28.70(2), 33.98, 41.79, 59.89, 124.12, 125.51, 126.12, 126.99, 127.51, 128.14, 129.87, 132.06, 133.69, 136.00, 173.39, 204.44.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl-].[C:15]([CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH3+:18])#[N:16].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>O.C(Cl)Cl>[C:15]([CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:18][C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=1)#[N:16]
Reactant: N#CC([NH3+])c1ccccc1
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)c1ccc(CC(=O)NC(C#N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
To a 100 ml round bottom flask equipped with a magnetic stir bar were added 4-isopropylphenylacetic acid (1.786 g, 10.02 mmol), cyano(phenyl)-methanaminium chloride (1.690 g, 10.02 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.921 g, 10.02 mmol), 1-hydroxy-7-azabenzotriazole (1.364 g, 10.02 mmol) and triethylamine (3.042 ml, 30.06 mmol) into 30.0 ml of CH2Cl2. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and the two layers were separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum. Purification by preparative HPLC (20-90% CH3CN/H2O over 30 min, 0.05% added TFA, C18 column) to afford 1.6 g (54%) of the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.382 (m, 5H), 7.206 (m, 4H), 6.156 (d, J=8.6 Hz, 1H), 5.997 (br d, J=8.2 Hz, 1H), 3.632 (s, 2H), 2.895 (sept, J=7.0 Hz, 1H), 1.238 (d, J=7.0 Hz, 6H). ES-MS [M+1]+: 293.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][N:7]1[C:13](=[O:14])[C@@H:12]2[C@H:8]1[C@@H:9](OC(N1C=CN=C1)=S)[CH2:10][N:11]2[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][N:7]1[C:13](=[O:14])[C@@H:12]2[C@H:8]1[CH2:9][CH2:10][N:11]2[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16]
Reactant: COc1ccc(CN2C(=O)[C@@H]3[C@H]2[C@@H](OC(=S)n2ccnc2)CN3C(=O)OCc2ccccc2)cc1OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(CN2C(=O)[C@@H]3[C@H]2CCN3C(=O)OCc2ccccc2)cc1OC

Procedure:
200 g (0.38 mol) of benzyl (1S,4S,5S)-6-(3,4-dimethoxy-benzyl)-7-oxo-4-[[(1-imidazolyl)thiocarbonyl]oxy]-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate were heated to 80° C. in 4.21 liters of toluene. A solution of 213 ml (0.8 mol) of tributyltin hydride and 6.9 g (0.04 mol) of AIBN in 320 ml of toluene were added dropwise thereto while stirring. After completion of the dropwise addition the mixture was stirred at this temperature for a further 45 minutes before the solvent was removed under reduced pressure. There remained behind a yellowish turbid oil which was chromatographed over 1100 g of silica gel (0.063-0.2 mm particle size with 1) ethyl acetate: hexane 1:10; 2) ethyl acetate: hexane 2:1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C@@H:12]1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[H-].[Na+].Br[CH2:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([Cl:34])=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:23][C:24]2[CH:33]=[C:32]3[C:27]([C:28]([Cl:34])=[CH:29][CH:30]=[N:31]3)=[CH:26][CH:25]=2)[C:13](=[O:17])[C@@H:12]1[CH3:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccnc2cc(CBr)ccc12
Reactant: C[C@H]1C(=O)NCCN1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1C(=O)N(Cc2ccc3c(Cl)ccnc3c2)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
4-(Benzyloxycarbonyl)-3-(S)-methylpiperazin-2-one (1.0 g, 4.0 mmol), EXAMPLE 46, is dissolved in THF (60 mL), cooled in an ice bath and treated with tretrabutylammonium iodide (0.10 g, 0.27 mmol) and 60% sodium hydride (0.18 g, 4.4 mmol). The reaction mixture is stirred at 0° C. for 30 minutes then treated dropwise with a solution of 7-bromomethyl-4-chloroquinoline (1.12 g, 4.4 mmol), EXAMPLE 14, in THF (5 mL). The resulting solution warmed to room temperature over approximately 1 h then quenched with sodium bicarbonate solution and concentrated. The residue is partitioned between ethyl acetate and water; the organic layer is dried (sodium sulfate) and concentrated. The residue is chromatographed (5% methanol/methylene chloride) to yield solid 4-(Benzyloxycarbonyl)-1-(4-chloroquinolin-7-ylmethyl)-3-(S)-methyl-piperazin-2-one (1.32 g, 3.1 mmol). A portion of this material (0.10 g, 0.23 mmol) is dissolved in acetonitrile (6 mL) and treated with iodotrimethyl-silane (0.1 mL, 0.75 mmol) at room temperature for 2 hours. The reaction is quenched with methanol and concentrated to dryness. Methanol addition and concentration is repeated six times. The final residue is taken up is 2M aqueous HCl; the solution is washed with ether and concentrated to yield the title compound. MS m/z: M+=289; 1H NMR (CD3OD, 300 MHz) δ9.2 (d, 1H), 8.6 (d, 1H), 8.2-8.3 (m, 2H), 8.0 (d, 1H), 5.1 (q, 1H), 4.3-4.4 (m, 1H), 3.8-4.0 (m, 2H), 3.6-3.8 (m, 3H), 1.75 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[OH:14].[F:15][C:16]1[CH:23]=[C:22](F)[C:21]([F:25])=[CH:20][C:17]=1[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:15][C:16]1[CH:23]=[C:22]([O:14][C:4]2[CH:5]=[CH:6][C:7]([O:9][C:10]([F:12])([F:11])[F:13])=[CH:8][C:3]=2[O:2][CH3:1])[C:21]([F:25])=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: N#Cc1cc(F)c(F)cc1F
Reactant: COc1cc(OC(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(OC(F)(F)F)ccc1Oc1cc(F)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of 2-methoxy-4-(trifluoromethoxy)phenol (Preparation 54, 331 mg, 1.59 mmol) in dimethylsulfoxide (10 mL) was added 2,4,5-trifluorobenzonitrile (250 mg, 1.59 mmol) and potassium carbonate (220 mg, 1.59 mmol) This suspension was stirred for 18 hours at room temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL), and extracted with dichloromethane (3×40 mL). The combined organic layers were dried over sodium sulphate, filtered and evaporated to afford the title compound as a clear oil (549 mg, 100%). This was used in the next reaction with no further purification.