Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:15])[CH:3]=1.[B-](F)(F)(F)[F:17].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C>[Cl:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:15])[C:3]=1[F:17]
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1c(Cl)cc(=O)n2c1CCC2
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)c(F)c(=O)n2c1CCC2
Reaction time: 1 h
Yield: 31 %

Procedure:
Compound 1b (1.36 g, 5.98 mmol) was stirred in DMF (10 mL) at 88° C. Selectfluor® (2.54 g, 7.17 mmol) in DMF (8 ml) was added dropwise, and the reaction stirred for 1 h. Additional Selectfluor® (1.2 g, 3.39 mmol) in DMF (5 mL) was added, and the reaction stirred 1 h longer. The solution was concentrated in vacuo and purified by silica gel chromatography (75% EtOAc/CH2Cl2) to give 460 mg (31%) of compound 1c as a white solid. 1H NMR (400 MHz, CDCl3): δ 4.18 (t, 2H, J=7.6 Hz), 3.86 (s, 3H), 3.37 (t, 2H, J=7.6 Hz), 2.20-2.28 (m, 2H). MS (ES) [m+H] calc'd for C10H9ClFNO3, 246, 248. found 246, 248.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]=[CH:17][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:19]=3)=[CH:10][C:9]2=[O:39])[CH:5]=[CH:6][CH:7]=1.O[CH2:41][C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[C:44]([O:50][CH3:51])[CH:43]=1.C(N(CC)C(C)C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([CH2:41][C:42]4[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[C:44]([O:50][CH3:51])[CH:43]=4)[CH:17]=[N:18][CH:19]=3)=[CH:10][C:9]2=[O:39])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)ccn1-c1cccc(Cl)c1
Reactant: COc1cc(CO)ccc1C#N
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Cn2cncc2Cc2ccn(-c3cccc(Cl)c3)c(=O)c2)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3-Chloro-phenyl)-4-(1-trityl-1H-imidazol-4-ylmethyl)-1H-pyridin-2-one (272 mg, 0.527 mmol) from step 6 and 4-hydroxymethyl-2-methoxy-benzonitrile (90.3 mg, 0.55 mmol) in CH2Cl2 cooled to -78° C. over dry ice/acetone bath was added N,N-diisopropylethylamine (192 μl, 1.1 mmol) and trifluoromethane-sulfonic anhydride(93 μl, 0.55 mmol). The reaction was allowed to slowly warm to room temperature and stirred overnight. The reaction was diluted with methanol (10 mL), heated to reflux for 2 h, cooled and the solvent evaporated in vacuo. The residue was partitioned between sat. Na2CO3 (20 ml) and CH2Cl2 (2×50 ml). The organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was chromatographed (silica gel, MeOH: CH2Cl2 3:97 to 4:96 to 10:90 gradient elution) to afford the free base which was converted to the hydrochloride salt to afford the title compound as an off white solid.
Reaction SMILES: [CH:1]1([C:7]([NH:9][CH2:10][CH2:11][C:12]2[C:16]3[CH:17]=[C:18](C(Cl)=O)[CH:19]=[CH:20][C:15]=3[S:14][CH:13]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:24]=[N+]=[N-].[Na+].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[NH2:24][C:18]1[CH:19]=[CH:20][C:15]2[S:14][CH:13]=[C:12]([CH2:11][CH2:10][NH:9][C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])[C:16]=2[CH:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Cl)c1ccc2scc(CCNC(=O)C3CCCCC3)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2scc(CCNC(=O)C3CCCCC3)c2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of the product obtained in Step G (20 mmol) in dichloromethane (30 ml) containing tetrabutylammonium bromide (20 mg) is cooled in an ice-bath. After the addition of sodium azide (25 mmol) dissolved in 5 ml of water, the solution is stirred vigorously at 0° C. for 2 hours. The organic phase is separated off, washed with water (2×5 ml) and dried over magnesium sulphate. After filtration, trifluoroacetic acid (30 mmol) is added and the solution is stirred under reflux for 60 hours. After cooling, the organic phase is washed with a saturated sodium hydrogen carbonate solution (2×5 ml) and concentrated under reduced pressure. The residue is then taken up in methanol (20 ml), and water (80 ml) and then potassium carbonate (30 mmol) are added. After stirring at room temperature for 20 hours, the reaction mixture is concentrated under reduced pressure to a volume of about 60 ml, and is then extracted 3 times with ether (3×50 ml). After drying over sodium sulphate, the organic phase is filtered and then evaporated under reduced pressure. The residue is chromatographed over silica gel to yield the title product.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23]C3CCCCO3)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=2[N:3]=1.[F:32][C:33]([F:45])([F:44])[O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl.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>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:30])[N:5]([CH3:31])[C:4]=3[N:3]=[C:2]2[C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([O:34][C:33]([F:32])([F:44])[F:45])[CH:36]=2)=[CH:17][CH:16]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1c(=O)n(CCCO)c(=O)c2c1nc(-c1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 49.4 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.195 mmol, intermediate 14) in toluene and ethanol (6 mL/2 mL) was added 3-(trifluoromethoxy)phenylboronic acid (60.2 mg, 0.293 mmol) followed by 1 mM aqueous sodium carbonate (1 mL). The mixture was degassed and refilled with a nitrogen atmosphere 3 times. Tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol) was added and the reaction was stirred at 100° C. for 16 h. The reaction was cooled and partitioned between ethyl acetate and brine The organic phase was dried and concentrated to give a crude product (110 mg). This crude product was dissolved in 1 mM ethanolic HCl (2 mL) and the mixture was stirred at room temperature for 30 min. The mixture was concentrated and purified by preparative HPLC to give 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenyl)-1H-purine-2,6(3H,7H)-dione (49 mg, 49.4% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=O)[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH:38]1([N:37]([CH3:36])[C:33]([CH:30]2[CH2:29][CH2:28][N:27]([C:24]3[N:23]=[CH:22][C:21]([C:17]4[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=4)[CH2:14][N:12]([CH3:13])[C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:26][N:25]=3)[CH2:32][CH2:31]2)=[O:35])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CN(Cc1cccc(-c2cnc(N3CCC(C(=O)O)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: CNC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(Cc1cccc(-c2cnc(N3CCC(C(=O)N(C)C4CCCCC4)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
1-{5-[3-({[N-(tert-Butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperidine-4-carboxylic acid (200 mg) and N-methylcyclohexanamine (94 mg) were suspended in methylene chloride (4 ml), and WSC hydrochloride (159 mg) and HOBt (112 mg) were added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was subjected to liquid separation with CHCl3 and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, and then the aqueous layer was extracted with CHCl3 again. These organic layers were combined and dried over Na2SO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 5% MeOH/CHCl3) to obtain tert-butyl (2-{[3-(2-{4-[cyclohexyl(methyl)carbamoyl]piperidin-1-yl}pyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (169 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]2[C:23](=[O:24])[C:22]([CH3:25])=[CH:21][NH:20][C:19]2=[O:26])[CH2:11][CH2:10]1.S(OC)(O[CH3:31])(=O)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][N:18]2[C:23](=[O:24])[C:22]([CH3:25])=[CH:21][N:20]([CH3:31])[C:19]2=[O:26])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCCn2c(=O)[nH]cc(C)c2=O)CC1
Reactant: COS(=O)(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1ccccc1N1CCN(CCCn2c(=O)c(C)cn(C)c2=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-5-methyl-2,4(1H,3H)-pyrimidinedione (550 mg, 1.53 mmol), prepared as in Example 32, dimethyl sulfate (193 mg, 1.53 mmol) and 0.1N tetrabutylammonium fluoride (100 mL, 10 mmol in THF) was stirred 4 hours at 25° C. The reaction mixture then was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with ethyl acetate to give 3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-1,5-dimethyl-2,4(1H,3H)-pyrimidinedione, as an oil. The free base was recrystallized from a solution of hydrochloric acid in alcohol to give 3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-1,5-dimethyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 256°-258° C. Anal.: Calcd. for C20H28N4O3.(HCl)2 : C, 53.93; H, 6.79; N, 12.58%; Found: C, 54.05; H, 6.87; N, 12.58%.
Reaction SMILES: [OH-].[NH4+:2].[CH2:3]([N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[CH:4]1[O:6][CH2:5]1>>[NH2:2][CH2:5][CH:4]([OH:6])[CH2:3][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9]
Reactant: CCN(CC)CC1CO1
Reactant: [NH4+]
Agent: [OH-]
Product: CCN(CC)CC(O)CN
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To the ice-cold solution of ammonium hydroxide (25 mL, 159 mmole) of 25% (w/w) was added glycidyldiethylamine dropwise (3.2 g, 24.8 mmol) over 10 minutes. The reaction mixture was stirred at 0-5° C. for 1 hour and then room temperature for 14 hours. The resulting reaction mixture was evaporated and distilled (84-90° C. at 500-600 mT) to yield 1-amino-3-diethylamino-propan-2-ol (3.3 g, 92%). MS m/z 147 ([M+1]+.).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].[Na].[CH2:18]=[C:19]1[C:24](=[O:25])[CH:23]2[CH2:26][CH2:27][N:20]1[CH2:21][CH2:22]2>C(O)C.C(O)(=O)C>[O:25]=[C:24]1[CH:23]2[CH2:26][CH2:27][N:20]([CH2:21][CH2:22]2)[CH:19]1[CH2:18][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C=C1C(=O)C2CCN1CC2
Reactant: CCOC(=O)Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(CC1C(=O)C2CCN1CC2)c1ccccc1
Reaction time: 16 h

Procedure:
Ethyl phenylacetate, 49.2 g was added to a solution of sodium ethoxide previously prepared from metallic sodium, 2.9 g and ethanol, 100 ml. The mixture was cooled to 5°, then a solution of 2-methylenequinuclidin-3-one, 39.4 g, in ethanol, 50 ml. was added dropwise and with stirring. After 16 hours at room temperature, the solution was neutralized with acetic acid then subjected to evaporation at reduced pressure. Water, 100 ml. was added to the residue and the mixture was extracted with chloroform. Evaporation of this solvent gave ethyl (3-oxoquinuclidin-2-yl)methylphenylacetate, 54 g (60%); b.p. 195°-200° at 1 mm Hg; m.p. of methiodide salt, 194.7-195.6°.
Reaction SMILES: [CH3:1][C:2]([CH:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O)([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4]>FC(F)(F)C(O)=O.[Pd].C(OCC)(=O)C>[CH3:1][C:2]([CH:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C(=O)OC)C(Cc1ccccc1[N+](=O)[O-])c1ccc(OC)cc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C(=O)OC)C(Cc1ccccc1N)c1ccc(OC)cc1
Yield: 95.8 %

Procedure:
A solution of α-methyl-[2-(2-nitrophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (2.47 g, 6.38 mmol) in 24 ml of trifluoroacetic acid was catalytically hydrogenated (42 psi, 0.25 g of 10% palladium on charcoal) for 11/2 hours. The reaction suspension was filtered through a pad of Celite and concentrated in vacuo to yield a viscous brown oil. The crude product was dissolved in ethyl acetate and washed several times with saturated aqueous potassium carbonate solution. Evaporation of the ethyl acetate layer in vacuo yielded 2.27 g of a light tan solid. Recrystallization from methanol (3 crops) yielded 1.82 g of an off-white solid, melting point 165°-167° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:26][C:27]([C@H:29]([C@@:47]([OH:59])([CH2:55][C:56]([O-:58])=[O:57])[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](=[O:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:28])[C:14]([O:16][CH2:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].Br[CH2:61][C:62]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:63].CCN(CC)CC>C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:26][C:27]([C@H:29]([C@@:47]([OH:59])([CH2:55][C:56]([O:58][CH2:61][C:62](=[O:63])[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)=[O:57])[C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](=[O:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:28])[C:14]([O:16][CH2:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CC(=O)[O-])C(=O)OC(C)(C)C)C(=O)OCC(=O)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CC(=O)OCC(=O)c2ccccc2)C(=O)OC(C)(C)C)C(=O)OCC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.9 %

Procedure:
1-tert-Butyl (S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-(2-oxo-2-phenyl-ethoxycarbonyl)-ethylcarbamoyl]-10-oxo-heptadec-2-enyl}-2-hydroxy-succinate (88.3 mg) was dissolved in ethyl acetate (5 mL), and a commercially available reagent of 2-bromoacetophenone (32 mg) and Et3N (24 μL) were added. The mixture was stirred at room temperature for 18 hours. To the reaction solution was added ethyl acetate and the mixture was washed with water and a saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The product was purified by silica gel chromatography (Megabondelute was used, elution solvent 20%-40% ethyl acetate/n-hexane) to obtain 56.6 mg (56%) of the title compound (LCMS m/z 937 (M+1) Rt 3.80 min.).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13](=O)[CH2:14][C:15](=O)[CH3:16])[C:9]([CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:20][CH2:21][CH2:22][NH:23][NH2:24]>>[OH:20][CH2:21][CH2:22][N:23]1[C:13]([C:10]2[C:9]([CH3:19])=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[OH:12])=[CH:14][C:15]([CH3:16])=[N:24]1
Reactant: CC(=O)CC(=O)C1C(=O)N(c2ccccc2)N=C1C
Reactant: NNCCO
Product: Cc1cc(-c2c(C)nn(-c3ccccc3)c2O)n(CCO)n1

Procedure:
Prepare the title compound from 1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione and 2-hydroxy-ethyl hydrazine according to the procedure of Example 28.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C@H:11]([N:29]([C:37](=[O:39])[CH3:38])[C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[CH2:12][C@H:13]([CH3:28])[N:14]2[C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.C(COC1C=C2C(=CC=1)N(C(=O)C1C=CC(F)=CC=1)[C@@H](C)C[C@H]2N(C1C=CC(Cl)=CC=1)C(=O)CC)(=O)[NH2:42]>>[C:37]([N:29]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C@H:11]1[C:10]2[C:15](=[CH:16][C:7]([O:6][CH2:5][C:4]([NH2:42])=[O:3])=[CH:8][CH:9]=2)[N:14]([C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([N:24]([CH3:25])[CH3:26])=[CH:20][CH:19]=2)[C@@H:13]([CH3:28])[CH2:12]1)(=[O:39])[CH3:38]
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(OCC(N)=O)cc21
Reactant: CCOC(=O)COc1ccc2c(c1)N(C(=O)c1ccc(N(C)C)cc1)[C@@H](C)C[C@H]2N(C(C)=O)c1ccc(Cl)cc1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N(C)C)cc2)c2cc(OCC(N)=O)ccc21

Procedure:
(±)-Cis-2-[4-[acetyl-(4-chloro-phenyl)-amino]-1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-7-yloxy]-acetamide was prepared from (±)-cis-[4-[acetyl-(4-chloro-phenyl)-amino]-1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-7-yloxy]-acetic acid ethyl ester, via the same amidation procedure used in the synthesis of (±)-cis-N-[6-carbamoylmethoxy-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-(4-chloro-phenyl)-propionamide.
Reaction SMILES: F[C:2](S(OC)(=O)=O)(F)F.[OH:10][CH:11]([CH2:18][C:19]([O:21]CC)=O)[CH2:12][C:13](OCC)=[O:14].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.Cl>C(Cl)Cl.C1COCC1>[CH3:2][O:10][CH:11]([CH2:18][CH2:19][OH:21])[CH2:12][CH2:13][OH:14]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)CC(O)CC(=O)OCC
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(CCO)CCO
Temperature: -5 °C
Reaction time: 16 h

Procedure:
25 ml of methyl trifluoromethylsulfonate are added to a solution of 30 g of diethyl 3-hydroxyglutarate and 33 ml of 2,6-di-tert-butylpyridine in 500 ml of DCM and the mixture is refluxed for 5 hours. After cooling, 500 ml of a 0.5N solution of HCl are added, the organic phase is decanted and dried over magnesium sulfate and the solvent is evaporated off under vacuum. The solid obtained is taken up with 200 ml of anhydrous THF, the mixture is filtered and the filtrate is then cooled to -5° C. 160 ml of a 1M solution of lithium aluminum hydride in THF are then added slowly and the mixture is stirred for 16 hours, the temperature being allowed to rise to RT. The reaction mixture is cooled to 0° C. and 5.5 ml of water, 18 ml of a 15% solution of NaOH and 5.5 ml of water are added successively. The mineral salts are filtered off and the filtrate is evaporated under vacuum to give the expected product after distillation under reduced pressure. B.p.=104° C. under 1.5 Pa.
Reaction SMILES: [OH-].[NH4+:2].Cl[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5]>>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])[NH2:2]
Reactant: [NH4+]
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)CC1
Agent: [OH-]
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(N)=O)cc2)CC1

Procedure:
Ammonium hydroxide (large excess) was added to the product from Example 1C (8.43 g, 27.3 mmol) at room temperature. White solids precipitated out and were collected by filtration and washed with water to afford the title compound (7.9 g, 100%) as a white solid which was taken on to the next step without further purification. MS (DCI) m/z 290.1 [M+H]+.
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.[H-].[Na+].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1)#[N:10]>O1CCOCC1>[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH2:18][C:1]([O:4][CH3:5])=[O:6])=[O:19])=[CH:13][CH:12]=1)#[N:10]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)CC(=O)c1ccc(C#N)cc1
Reaction time: 2 h

Procedure:
Dimethyl carbonate (126 g, 1.4 moles) was added dropwise to a slurry of NaH (50% in mineral oil, 13.44 g, 0.28 mole) slurried in 280 ml of dry dioxane. The reaction mixture was warmed to 80°-85° and p-cyanoacetophenone (40.7 g, 0.28 mole) in 140 ml dioxane added dropwise (at about 3/4 addition, mechanical loss due to foaming occurred; such losses are avoided by slower addition, e.g., over 1 hour). After addition was complete, heating at 80° was continued for 2 hours and crude product recovered by hot filtration. The cake was distributed between dilute CH3CO2H and ether. The ether layer was separated; washed in sequence with H2O, saturated NaHCO3, H2O and brine; dried; and stripped to yield title product: 39 g, (68.6%); m.p. 93°-98°; tlc (4:1 toluene:ethyl acetate) Rf 0.58. Recrystallization of 0.5 g from 2-propanol gave 0.403 g; m.p. 96°-99°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[N:21]=[N:22][C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=1>>[Cl:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[N:21]=[N:22][C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Cl
Reactant: CCc1ccc(Br)nn1
Product: CCc1ccc(-c2cc(C)c(Cl)c(C)c2)nn1

Procedure:
The title compound is prepared from 2-cloro-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 3-bromo-6-ethyl-pyridazine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 11): tR=1.00 min; Mass spectrum (ESI+): m/z=247/249 (Cl) [M+H]+.
Reaction SMILES: ClCCl.[I-].[Cl:5][C:6]1[N:7](C)[CH:8]=[N+:9]2[CH:13]=[C:12]([C:14]3[CH2:15][C@@H:16]4[C@@H:33]([C@H:34]([OH:36])[CH3:35])[C:32](=[O:37])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])[S:11][C:10]=12>CN(C=O)C>[Cl:5][C:6]1[N:7]=[CH:8][N:9]2[CH:13]=[C:12]([C:14]3[CH2:15][C@@H:16]4[C@@H:33]([C@H:34]([OH:36])[CH3:35])[C:32](=[O:37])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)=[O:20])[S:11][C:10]=12
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3c[n+]4cn(C)c(Cl)c4s3)C[C@H]12
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(Cl)c4s3)C[C@H]12

Procedure:
In the same manner as in Example 4-a) except that 98 mg of 4-nitrobenzyl (5R,6S)-2-(7-chloroimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate and a mixed solvent of dichloromethane and DMF (1:1), the crude 4-nitrobenzyl (5R,6S)-2-(7-chloro-6-methylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate iodide was obtained as a yellowish brown oil in a yield of 99 mg.