Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:8]1(=[O:24])=[O:23].[CH3:25][NH:26][CH3:27]>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][N:26]([CH3:27])[CH3:25])[S:8]1(=[O:24])=[O:23]
Reactant: CNC
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1ccccc1F
Product: CN(C)CCOCCN1c2ccccc2N(c2ccccc2F)S1(=O)=O
Yield: 95 %

Procedure:
In an analogous manner as described in general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.07 g, 0.16 mmol) was treated with dimethylamine (10 mL) to provide 0.05 g (95%) of 2-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}-N,N-dimethylethanamine. MS (ES) m/z 380.0; HRMS: calculated for C18H22FN3O3S+H+, 380.14387; found (ESI, [M+H]+), 380.1443; HPLC purity 98.1% at 210-370 nm, 9.1 minutes; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5195 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10 minutes hold 4 minutes.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:29](=[O:33])[C:30]([NH2:32])=[O:31])=[C:9]([CH3:28])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na]>[OH-].[Na+].CO>[NH2:32][C:30](=[O:31])[C:29]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:34])=[O:2])[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:9]=1[CH3:28])=[O:33]
Reactant: COC(=O)COc1cccc2c1c(C(=O)C(N)=O)c(C)n2Cc1ccccc1-c1ccccc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
A mixture of 648 mg (1.4 mmol) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-2-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester in 10 mL of 1N NaOH and 20 mL of MeOH was heated to maintain reflux for 1 hour, cooled to room temperature and stirred 0.5 hour. The mixture was concentrated, the residue stirred with a mixture of EtOAc/water and the solid material that did not dissolve was filtered and dried to give 227 mg (35% yield) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-2-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]acetic acid, sodium salt, mp, >265° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=1.BrCC1C=C([F:28])C=C(Cl)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([F:28])[CH:19]=1)[CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=1
Reactant: COc1cc(SCc2cccc(Cl)c2)cnc1OC
Reactant: Fc1cc(Cl)cc(CBr)c1
Product: COc1cc(SCc2cc(F)cc(Cl)c2)cnc1OC

Procedure:
Prepared as described for 5-(3-chlorobenzylthio)-2,3-dimethoxypyridine (Intermediate 8) but using 1-(bromomethyl)-3-chloro-5-fluorobenzene instead of 1-(bromomethyl)-3-chlorobenzene.
Reaction SMILES: CI.[Mg].Br[CH2:5][C@@H:6]([CH3:16])[CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1.[CH3:17][CH:18]([CH3:22])[CH2:19][CH2:20]O.C1(C)C=CC(S([O-])(=O)=O)=CC=1>O1CCCC1>[CH3:16][C@H:6]([CH2:5][CH2:20][CH2:19][CH:18]([CH3:22])[CH3:17])[CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1
Reactant: CC(C)CCO
Reactant: C[C@H](CBr)CCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)CCOC1CCCCO1
Reaction time: 0.08 h

Procedure:
4.7 g (0.202 mol) of magnesium shavings in a 3-necked flask under an argon atmosphere and provided with a calcium chloride tube are activated by addition of 2.0 ml of methyl iodide. After 5 minutes, the methyl iodide is removed and the magnesium washed several times with absolute tetrahydrofuran. To the activated magnesium is added dropwise a solution of 44 g (0.175 mol) of 2-[(S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran in 50 ml of absolute tetrahydrofuran at such a rate that the solvent just boils. Where the Grignard reaction does not start itself, it is warmed to 85° with the oil bath. After completed addition of 2-[(S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran, the mixture is stirred at 85° for so long (0-15 min.) until only traces of 2-[(S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran are still present in accordance with gas-chromatographical analysis. The solution obtained is cooled to -78° and treated dropwise with 21.2 g (0.0875 mol) of 3-methyl-1-butanol-p-toluenesulphonate followed by 3.6 ml of a 0.1 molar solution of Li2CuCl4 in absolute tetrahydrofuran. This reaction mixture is stirred at -78° during 10 min. then at 0° for 2 hours and subsequently at room temperature for a further 14 hours. For the working up of the 2-[(R)-3,7-dimethyloctanoxy]-tetrahydro-2H-pyran obtained the mixture is poured on to ice and brought to pH 5-6 with 2-N sulphuric acid. By three-fold extraction with ether and removal of the solvent on the rotary evaporator there is obtained a mixture of (R)-3,7-dimethyl-1-octanol and 2-[(R)-3,7-dimethyloctanoxy]-tetrahydro-2H-pyran. This mixture is treated portionwise in 100 ml of methanol at 0° with a total of 100 ml of 7-N aqueous hydrochloric acid. After 2-hours stirring at room temperature, the mixture is neutralised with dilute aqueous caustic soda and extracted with ether. After chromatography on silicagel, deactivated with 0.5% ammonia, with pentane/ether (4:1), there are obtained 10.6 g (76% based on 3-methyl-1-butanol-p-toluenesulphonate employed) of pure (R)-3,7-dimethyl-1-octanol. B.p. 58°-59°/0.05 Torr; [α]D20 = +4.0 (c = 1.03, CHCl3).
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+:6].[Na+].[Cr:8]([O-:12])([O-:11])(=[O:10])=[O:9].[Na+].[Na+].S(=O)(=O)(O)O.S(=O)(=O)(O)[O-].[Na+]>>[O-:9][Cr:8]([O:12][Cr:8]([O-:11])(=[O:10])=[O:9])(=[O:11])=[O:10].[Na+:6].[Na+:6]
Reactant: O=[Cr](=O)([O-])[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Product: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]

Procedure:
A process according to claim 7 wherein said aqueous solution of sodium sulfate is produced by treating an aqueous solution of sodium chromate with sulfuric acid, sodium bisulfate, or a mixture thereof to produce sodium bichromate, evaporating water to precipitate sodium sulfate cake, and separating said precipitated sodium sulfate from said aqueous solution of sodium sulfate.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:11]=[O:12])[CH:8]=2)[NH:3]1.S([CH2:23][N+:24]#[C-:25])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[O:12]1[C:11]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH2:10]3)=[CH:25][N:24]=[CH:23]1
Reactant: O=Cc1ccc2c(c1)CC(=O)N2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1Cc2cc(-c3cnco3)ccc2N1
Yield: 52.6 %

Procedure:
A mixture of 2-oxoindoline-5-carbaldehyde (60 mg, 0.38 mmol), tosylmethyl isocyanide (145 mg, 0.75 mmol) and potassium carbonate (103 mg, 0.75 mmol) in methanol (20 mL) was heated at reflux for 2 h. The mixture was concentrated in vacuo and diluted with an aqueous saturated solution of sodium hydrogencarbonate and extracted with methylene chloride. The combined organic layers were dried (Na2SO4) and evaporated in vacuo. The crude product was purified on a silica gel column using heptane/ethyl acetate, (1:4), as the eluent to give 40 mg (53% yield) of the title compound: 1H NMR (DMSO-d6, 300 M ) δ 10.54 (br s, 1 H), 8.36 (br s, 1 H), 7.64-7.44 (m, 3 H), 6.89 (d, J=8 Hz, 1 H), 3.54 (br s, 2 H).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([CH2:35]Br)=[CH2:34])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38]C(=O)C)(=O)C.[CH3:42][O-:43].[Na+]>CO>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:37][OH:38])[O:7]2)=[CH:20][C:21]=1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH2:35][O:43][CH3:42])=[CH2:34])=[CH:29][CH:28]=1
Reactant: C=C(CBr)c1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=C(COC)c1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1

Procedure:
The solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-(3-bromoprop-1-en-2-yl)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (intermediate BA) (110 mg, 0.169 mmol and 4 mL 0.3M NaOMe in MeOH (freshly-distilled) was stirred at 70° C. for 2.5 h. Then the reaction was quenched with H2O. After removing the volatiles, the aqueous layer was extracted 3× with AcOEt. The organic portion was washed 1× with a saturated solution of NH4Cl and 1× with brine prior to drying over Na2SO4. Concentration and purification of the crude product by preparative TLC gave intermediate BA (48 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([CH2:38][CH2:39][CH2:40][CH3:41])=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:27][CH:26]=3)[CH:24]=2)=[O:18])([F:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:42]>C(Cl)Cl.O1CCOCC1>[ClH:42].[ClH:42].[F:14][C:11]1([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([CH2:38][CH2:39][CH2:40][CH3:41])=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:27][CH:26]=3)[CH:24]=2)=[O:18])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CCCCc1nnc(C(=O)NCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCc1nnc(C(=O)NCC2(F)CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-({[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-methyl)-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester (70 mg) in DCM (2 mL) was added 4 N HCl in dioxane (1.0 mL), and the reaction was stirred for 1 h. The volatiles were removed under reduced pressure, and the residue was triturated with anhydrous ethyl ether and dried under high vacuum to provide 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid (4-fluoro-piperidin-4-ylmethyl)-amide dihydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[O:27]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[CH:26]=[O:27])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: O=Cc1cccc(CBr)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(C=O)c3)C2=O)cn1
Yield: 35 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 3-(bromomethyl)benzaldehyde. Yield: 35%. 1H NMR (DMSO, 400 MHz): δ2.123 (s, 3H), 2.388 (s, 3H), 4.035 (s, 2H), 4.631 (s, 2H), 5.186 (s, 2H), 7.581 (m, 1H), 7.643 (m, 1H), 7.787 (m, 3H), 8.178 (s, H), 9.997 (s, H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.2 uM.
Reaction SMILES: [Li+].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([O-:23])=O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:58]([C:61]1[CH:66]=[CH:65][C:64]([NH:67][CH:68]2[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]2)=[CH:63][C:62]=1[C:74]([F:77])([F:76])[F:75])([O-:60])=[O:59]>CN(C)C=O.ClCCl.O1CCCC1>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([N:71]3[CH2:72][CH2:73][CH:68]([NH:67][C:64]4[CH:65]=[CH:66][C:61]([N+:58]([O-:60])=[O:59])=[C:62]([C:74]([F:75])([F:76])[F:77])[CH:63]=4)[CH2:69][CH2:70]3)=[O:23])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Reactant: CC(C)(C)c1ccc(N2CCN(CCCC(=O)[O-])CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(N2CCN(CCCC(=O)N3CCC(Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)CC3)CC2)cc1
Reaction time: 0.08 h

Procedure:
4-[4-(4-tert-Butyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (15 mg; 0.05 mmol, prepared in accordance with Example 167), diisopropylethyl amine (25 μL; 0.15 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (16 mg; 0.05 mmol, prepared in accordance with Example 8) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 2 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (3×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (16 mg; 0.03 mmol). The structure was confirmed using Protocol I-C. Calculated mass=576; observed mass=576; HPLC retention time=3.16 min.
Reaction SMILES: Br[C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[C:3]=1[CH3:11].[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[NH:6][CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[C:3]=2[CH3:11])=[C:15]([C:22]([F:23])([F:24])[F:25])[CH:14]=1
Reactant: OB(O)c1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)c1c[nH]c(Br)c1C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1c[nH]c(-c2ccc(F)cc2C(F)(F)F)c1C
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
A mixture of methyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate (0.27 g, 1.2 mmol), [4-fluoro-2-(trifluoromethyl)phenyl]boronic acid (0.61 g, 2.9 mmol), Na2CO3 (0.6 g, 5.7 mmol) and palladium tetrakis(triphenylphosphine) (96 mg, 0.083 mmol) in toluene/water (10:1, 10 ml) was stirred at 110° C. for 1.5 h under N2. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with water and brine, then dried over sodium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by silica-gel column chromatography (3:1 to 1:3 hexane:ethyl acetate) to give the title compound (0.23 mg, 62%) as a pale yellow solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[CH3:9].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[N:31]1([CH2:37][CH2:38][CH2:39][N:40]2[CH2:46][C:45]3[CH:47]=[C:48](/[CH:51]=[CH:52]/[C:53](O)=[O:54])[CH:49]=[N:50][C:44]=3[NH:43][C:42](=[O:56])[CH2:41]2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[CH3:9])[C:53](=[O:54])/[CH:52]=[CH:51]/[C:48]1[CH:49]=[N:50][C:44]2[NH:43][C:42](=[O:56])[CH2:41][N:40]([CH2:39][CH2:38][CH2:37][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[CH2:46][C:45]=2[CH:47]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCCN1CCOCC1)CC(=O)N2
Reactant: CNCc1oc2ccccc2c1C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCCN2CCOCC2)CC(=O)N3)oc2ccccc12
Yield: 78 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(3-methyl-benzofuran-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[4-(3-morpholin-4-yl-propyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.28 g, 78%) was prepared as an off-white powder: 1H NMR (300 MHz, DMSO-d6) δ 10.74-10.54 (m, 2H), 8.61 (s, 1H), 8.29 (s, 1H), 7.63-7.47 (m, 3H), 7.34-7.23 (m, 3H), 5.03-4.80 (m, 2H), 4.02 (br s, 2H), 3.87-3.79 (m, 4H), 3.65 (br s, 2H), 3.48-3.38 (br s, 4H), 3.20-2.93 (m, 5H), 2.72-2.57 (br s, 2H), 2.26 (s, 3H), 1.95 (s, 2H); MS (ESI) m/e 518 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([C:12]3[CH:13]=[N:14][NH:15][CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22]Br>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([C:12]3[CH:16]=[N:15][N:14]([CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])[CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN(C)CCBr
Reactant: Brc1ccc2ncc(-c3cn[nH]c3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(-c2cnc3ccc(Br)cc3n2)cn1
Reaction time: 0.08 h
Yield: 65.4 %

Procedure:
To a solution of 7-bromo-2-(1H-pyrazol-4-yl)quinoxaline (0.225 g, 0.808 mmol) in dry N,N-dimethylformamide (5 mL) under a nitrogen atmosphere was added 60 wt % sodium hydride (92 mg, 2.27 mmol) portionwise. After 5 minutes of stirring with purging, 2-dimethylaminoethylbromide (0.37 g, 0.908 mmol) was added and the reaction mixture stirred at rt for 30 min, concentrated in vacuo and taken into dichloromethane. The organic solution was washed with water (2×), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 0-5% methanol in ethyl acetate to furnish the title compound (0.183 g, 66% yield). ESMS m/e: 345.9; 347.8 [M]+.
Reaction SMILES: [C:1]([NH:8][CH2:9][C@H:10]([OH:17])[CH2:11][C:12](OCC)=[O:13])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[NH2:19][NH2:20]>CO>[C:1]([NH:8][CH2:9][C@H:10]([OH:17])[CH2:11][C:12]([NH:19][NH2:20])=[O:13])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)NC[C@H](O)CC(=O)OCC
Reactant: NN
Solvent: O
Solvent: CO
Product: CCCCCC(=O)NC[C@H](O)CC(=O)NN
Temperature: 65 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A 6.50 g (24.9 mmol) of ethyl (R)-4-hexanoylamino-3-hydroxybutyrate (optical purity: 95%e.e.) was dissolved in 26 ml of methanol, and 1.87 g (37.3 mmol) of hydrazine monohydrate was added thereto dropwise at room temperature. After the addition, the mixture was heated to 65° C. and then stirred for 2 hours. After the mixture was cooled to room temperature, stirring was conducted overnight to give 4.09 g (66%) of the title compound as a crystal. Melting point: 172.5° C. Optical purity: >99.9%e.e.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH3:27][C@H:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([CH3:34])[N:29]1[C:35]([O:37][CH2:38]Cl)=[O:36].C(OCC)(=O)C>CS(C)=O.[Cl-].[Na+].O>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:38][O:37][C:35]([N:29]3[C@H:30]([CH3:34])[CH2:31][CH2:32][CH2:33][C@@H:28]3[CH3:27])=[O:36])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: C[C@@H]1CCC[C@H](C)N1C(=O)OCCl
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H]1CCC[C@H](C)N1C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.7 %

Procedure:
Sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate (300 mg) was added to 5 ml of a solution of 183 mg of (cis-2,6-dimethylpiperidin-1-yl)carbonyloxymethyl chloride in DMSO, and the mixture was stirred at room temperature for 18 hr. Ethyl acetate (20 ml) and 20 ml of 20% brine were added thereto, followed by separation. The organic layer was washed twice with 20% brine, was dried over anhydrous magnesium sulfate, and was filtered, and ethyl acetate was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=15:1) to give 273 mg of the title compound.
Reaction SMILES: FC(F)(F)C([O-])=O.C([O:15][C:16]1[C:17]([C:34]([NH:36][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:35])=[N:18][N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:21](=[O:33])[C:20]=12)C1C=CC=CC=1>>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:22]2[CH2:23][CH2:24][N:19]3[N:18]=[C:17]([C:34]([NH:36][CH2:37][CH2:38][N:39]4[CH2:40][CH2:41][O:42][CH2:43][CH2:44]4)=[O:35])[C:16]([OH:15])=[C:20]3[C:21]2=[O:33])=[CH:31][CH:30]=1
Reactant: O=C(NCCN1CCOCC1)c1nn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)CC2
Agent: O=C([O-])C(F)(F)F
Product: O=C(NCCN1CCOCC1)c1nn2c(c1O)C(=O)N(Cc1ccc(F)cc1)CC2
Reaction time: 0.67 h

Procedure:
The title compound was prepared as the trifluoroacetate salt from 3-benzyloxy-5-(4-fluorobenzyl)-N-[(2-morpholin-4-yl)ethyl]-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide using a hydrogenation procedure similar to that found in Example 1, Step 5, except that the reaction time totaled 40 minutes. 1H NMR (400 MHz, CD3OD) δ 7.41-7.38 (m, 2H), 7.12-7.07 (m, 2H), 5.49 (s, 2H), 4.72 (br s, 2H), 4.28 (br s, 2H), 3.90 (br s, 6H), 3.75-3.71 (m, 6H); ES MS (M+1)=418.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][O:4][C:5]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][C:6]=1[C:7]([N:9]([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:8]>[Pt].C(O)(=O)C>[F:29][C:2]([F:1])([F:28])[CH2:3][O:4][C:5]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][C:6]=1[C:7]([N:9]([CH3:17])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]1)=[O:8]
Reactant: CN(Cc1ccccn1)C(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Agent: [Pt]
Solvent: CC(=O)O
Product: CN(CC1CCCCN1)C(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
2,5-Bis(2,2,2-trifluoroethoxy)-N-methyl-N-(2-pyridylmethyl)benzamide (0.015 mole, 6.33 g.) in 200 ml. of glacial acetic acid is mixed with 0.2 g. of platinum oxideacetic acid paste and the mixture is shaken on a Parr hydrogenation apparatus at a temperature of about 23° C. for about 3.5 hours. The resulting material is filtered and the filtrate is evaporated, toluene being added to form an azeotrope and facilitate evaporation. The residue of the evaporation is mixed with 5 percent sodium hydroxide solution and diethyl ether, and the organic layer is separated, washed with saturated sodium chloride solution, dried and evaporated to provide a white solid, 2,5-bis(2,2,2-trifluoroethoxy)-N-methyl-N-(2-piperidylmethyl)benzamide, m.p. 104°-107° C.