Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:14]3([CH2:20][NH2:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1.[F:22][C:23]([F:39])([F:38])[C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[N:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:14]3([CH2:20][NH:21][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([C:26]5[N:25]=[C:24]([C:23]([F:39])([F:38])[F:22])[O:28][N:27]=5)[CH:30]=4)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: COc1ccc(-c2csc(C3(CN)CCOCC3)n2)cc1
Product: COc1ccc(-c2csc(C3(CNC(=O)c4cccc(-c5noc(C(F)(F)F)n5)c4)CCOCC3)n2)cc1
Yield: 38 %

Procedure:
This compound was synthesized from (4-(4-(4-methoxyphenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (80 mg, yield 38%). 1H NMR (400 MHz, DMSO-d6) δ 8.78 (t, J=6.3 Hz, 1H), 8.43 (s, 1H), 8.20 (d, J=7.9 Hz, 1H), 8.07 (d, J=7.9 Hz, 1H), 7.91 (s, 1H), 7.86 (d, J=8.9 Hz, 2H), 7.71 (t, J=7.8 Hz, 1H), 6.95 (d, J=8.5 Hz, 2H), 3.86 (m, 2H), 3.77 (s, 3H), 3.58 (d, J=6.4 Hz, 2H), 3.43 (t, J=10.5 Hz, 2H), 3.33 (s, 2H), 2.25 (d, J=14 Hz, 2H), 2.02 (m, 2H). MS (ESI) m/z: Calculated for C26H23F3N4O4S: 544.14. found: 545.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH2:20][O:21][C:22]3[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[CH:25]=[CH:24][C:23]=3[CH3:31])=[C:18]([CH3:32])[N:17]=[C:16]([Cl:33])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>C(Cl)Cl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[Cl:33][C:16]1[N:17]=[C:18]([CH3:32])[C:19]([CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH:28]([CH3:29])[CH3:30])[CH:25]=[CH:24][C:23]=2[CH3:31])=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[N:15]=1
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1N1CCNCC1
Reaction time: 0.33 h

Procedure:
To a solution of 4-[2-chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.05 mmol) in DCM (5 mL) is added trifluoroacetic acid (1 mL) with magnetic stirring. Gas evolution is observed and continues for ˜20 min. The light yellow colored solution is evaporated at reduced pressure, diluted with DCM (20 mL) and evaporated again. Placed under high vacuum (˜0.2 Torr) for 20 min to obtain the title compound as a colorless oil. LC/MS (Method 2), M+H=432.1, Rt=1.46 min.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[O:4].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:8]([C:7]1[O:12][CH2:2][C:3](=[O:4])[NH:5][N:6]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)C(=O)NNC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C1=NNC(=O)CO1
Temperature: 100 °C

Procedure:
8.34 g (43.29 mmol) of N′-(chloroacetyl)-2,2-dimethylpropanehydrazide were dissolved in 800 ml of dry DMF, and 4.24 g (50.52 mmol) of sodium bicarbonate were added. The reaction mixture was heated at 100° C. overnight. After cooling, the solvent was removed on a rotary evaporator, water was added to the residue and the mixture was acidified with 1 N hydrochloric acid. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with water, dried over sodium sulfate and concentrated on a rotary evaporator. This gave 5.05 g of the target compound. The crude product was reacted further without further purification.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][NH:4][S:5]([NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11](Cl)[C:10]=1[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)(=[O:7])=[O:6].CC([O-])(C)C.[K+].C([O:33][CH2:34][CH2:35][OH:36])(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>Cl[Ti](Cl)(Cl)Cl.O.C1(C)C=CC=CC=1>[CH3:1][CH2:2][CH2:3][NH:4][S:5]([NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([O:33][CH2:34][CH2:35][OH:36])[C:10]=1[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)(=[O:7])=[O:6]
Reactant: CC(C)(C)OCCO
Reactant: CCCNS(=O)(=O)Nc1ncnc(Cl)c1-c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCNS(=O)(=O)Nc1ncnc(OCCO)c1-c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
N-(5-(4-bromophenyl)-6-chloropyrimidin-4-yl)propane-1-sulfamide (100 g; 0.246 mol; see Preparation A) and KOtBu (110 g; 0.99 mol; 4.0 eq.) were charged into a 2 L reactor. Toluene (1 L) was added. The resulting suspension was stirred at 20° C. for 5 min. 2-(tert-butoxy)ethanol (97 mL; 0.74 mol; 3.0 eq.) was added dropwise. After completion of the addition, the reaction mixture was heated to 85° C. for 2 h. After completion of the reaction, the mixture was cooled down to 20° C. Water (0.5 L) was added, followed by the addition of 10% aq. citric acid (0.5 L). The layers were separated. The org. phase was washed with brine 3 times (0.5 L each) and azeotropically dried with toluene (1 L) to a volume of approx. 1 L. The reaction mixture was heated to 50° C. A 1M solution of TiCl4 in toluene (420 mL, 0.42 mol; 1.7 eq.) was added dropwise with vigorous stirring. After completion of the addition, it was stirred at 35° C. for 20 h. Water (0.75 L) was added and the resulting beige suspension was stirred for 15 h. It was filtered off, rinsed with toluene (300 mL) and dried to afford the title compound as a white solid (91 g; 86% yield; purity (LC-MS): 100% a/a).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH2:4][N:3]1[CH2:6][C:7]([O:9]CC)=O.O.[NH3:13].C(Cl)(Cl)Cl.CCOCC>CO>[O:1]=[C:2]1[CH2:5][CH2:4][N:3]1[CH2:6][C:7]([NH2:13])=[O:9]
Reactant: CCOC(=O)CN1CCC1=O
Reactant: N
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NC(=O)CN1CCC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In 0.8 ml of methanol was dissolved 843 mg of compound (19) and 0.4 ml of conc. ammonia water was added to the solution under ice cooling followed by stirring at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (30 g of silica gel, chloroform-methanol=10:1) to obtain 550 mg of a roughly purified product. The product was treated with a solvent mixture of 3 ml of chloroform and 3 ml of ether to crystallize. Thus 360 mg of α-(2-oxo-1-azetidinyl)acetamide (22) was obtained as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH2:14][CH2:15]O)[C:12]3[C:17]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:19]=[C:20]([Cl:21])[C:11]=3[N:10]=2)=[C:4]([Cl:27])[CH:3]=1.CS(Cl)(=O)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3=[N:10][C:11]4[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:12]=4[N:13]3[CH2:14][CH2:15]2)=[C:4]([Cl:27])[CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(Br)cc3Cl)n(CCO)c12
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of 2-[2-[(4-bromo-2-chlorophenyl)amino]-4-chloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]ethanol (Reference Example 23; 1.19 g, 2.53 mmol) in pyridine (6.0 mL) was added methanesulfonyl chloride (979 μL, 12.65 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1.5 hr. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate at 0° C. and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give a solid. The resulting solid was recrystallized from n-hexane to give the title compound as a colorless powder (975.2 mg, 2.15 mmol, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.[H-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25]>>[CH2:25]([N:12]1[C:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])=[C:19]2[C:14]([C:15]([F:20])=[CH:16][CH:17]=[CH:18]2)=[N:13]1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)c(OC)c1
Agent: [H-]
Agent: [Na+]
Product: C=CCn1nc2c(F)cccc2c1-c1ccc(OC)cc1OC
Yield: 19.5 %

Procedure:
Prepared according to Method D step B from 3-(2,4-dimethoxyphenyl)-7-fluoro-1H-indazole (0.300 g, 1.10 mmol), sodium hydride (60% in oil, 0.058 g, 1.50 mmol) and allyl bromide (0.173 mL, 2.00 mmol) to give the title compound (0.067 g) as a white solid.
Reaction SMILES: [Na+].[Br:2][C:3]1[CH:17]=[CH:16][C:6]([CH:7]=[N:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([O-:12])=[O:11])=[CH:5][CH:4]=1.[C:18](Cl)(=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22].C(OCC)(=O)C>ClCCl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]2[N:8]([C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:9]([CH:13]([CH3:15])[CH3:14])[C:10](=[O:12])[O:11]2)=[CH:16][CH:17]=1
Reactant: CCCCC(=O)Cl
Reactant: CC(C)C(N=Cc1ccc(Br)cc1)C(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCC(=O)N1C(c2ccc(Br)cc2)OC(=O)C1C(C)C
Temperature: 40 °C
Yield: 34 %

Procedure:
12.6 g of 2-[(4-bromobenzylidene)amino]-3-methylbutyric acid sodium salt (41.1 mmoles) are suspended in 80 ml of dry dichloromethane. The mixture is refluxed (40° C.), under slight nitrogen stream. 7.9 g of valeryl chloride (65.5 mmoles) are added. After 2 hours under reflux, the mixture is cooled to 25° C. The organic phase is washed three times with 50 ml of water and concentrated under reduced pressure, at 25-30° C., to obtain an oily residue. 50 ml of ethyl acetate are added and the organic phase is washed with a weakly basic NaOH solution and/or with water to neutrality. The organic phase is washed with a sodium bisulfite solution. The organic phase is washed with water and dried over sodium sulfate, filtered and evaporated under reduced pressure. The oily residue is taken up with ethanol from which the product crystallizes as a white solid. 2-(4-Bromophenyl)-4-isopropyl-3-pentanoyl-oxazolidin-5-one is obtained (5.2 g; 14.1 mmoles; molar yield: 34%).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:18][CH3:19])[C:7]([N:9]1[CH2:16][C:15](=[O:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.N>>[SH:4][CH2:5][CH:6]([CH2:18][CH3:19])[C:7]([N:9]1[CH2:16][C:15](=[O:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CCC(CSC(C)=O)C(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: N
Product: CCC(CS)C(=O)N1CC(=O)C[C@H]1C(=O)O

Procedure:
The product from part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 2 to yield (S)-1-(3-mercapto-2-ethyl-1-oxopropyl)-4-oxo-L-proline.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[C:35]1([CH2:41][CH2:42][C:43](Cl)=[O:44])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([C:43](=[O:44])[CH2:42][CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)sc2n1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nc(N2CCN(C(=O)CCc3ccccc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (80 mg, 0.22 mmol) in dichloromethane (4 ml) was added diisopropylethylamine (0.49 mmol, 81 μL) and 3-phenylpropionyl chloride (0.25 mmol). The reaction was stirred at room temperature for 16 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (43 mg) which was characterized by its mass spectrum: MS m/z (%): 491 ([M+H]+, 100).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[F:16][C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:19][CH:18]=1>>[F:16][C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]4([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]4)=[CH:5][CH:4]=3)[CH2:25][CH2:24]2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)NC1(c2ccc(CCl)cc2)CC1
Reactant: Fc1cccc(N2CCNCC2)n1
Product: CC(=O)NC1(c2ccc(CN3CCN(c4cccc(F)n4)CC3)cc2)CC1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)cyclopropyl)acetamide obtained in Example 71(1) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2) instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=135-136° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]23[CH2:22][CH2:21][CH2:20][N:19]2[CH2:18][CH2:17][CH2:16]3)[CH:14]=1)C1C=CC=CC=1>CO.[Pt]>[OH:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]23[CH2:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][CH2:22]3)[CH:14]=1
Reactant: c1ccc(COc2cncc(C34CCCN3CCC4)c2)cc1
Agent: [Pt]
Solvent: CO
Product: Oc1cncc(C23CCCN2CCC3)c1
Reaction time: 16 h
Yield: 63.4 %

Procedure:
7a-(3-Benzyloxy-5-pyridinyl)-hexahydro-1H-pyrrolizine (260 mg, 0.88 mmol, from step 16b) was dissolved in methanol (9 mL), 10% Pt/C (35 mg) was added, and the mixture stirred under 1 arm of H2 for 16 hours. The catalyst was removed, the filtrate was concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH/0.5 % NH4OH, 90:10:0 to 90:10:0.5) to afford the title compound as a white solid (114 mg, 63%). 1H NMR D2O, 300 MHz) δ2.07-2.40 (m, 6H), 2.49-2.58 (m, 2H), 3.26-3.34 (m, 2H), 3.71-3.80 (m, 2H), 7.00 (dd, J=2.4, 2.0 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H): MS (CI/NH3) m/z: 205 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CO[C:12]1[C:13](=[O:19])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1>CO>[O:19]=[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=[C:12]1[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1
Reactant: COc1cccccc1=O
Reactant: OCCN1CCNCC1
Solvent: CO
Product: O=c1cccccc1N1CCN(CCO)CC1
Yield: 51.1 %

Procedure:
A mixture of 1-(2-hydroxyethyl)piperazine (10.0 g) and 2-methoxy-2,4,6-cycloheptatrien-1-one (10.9 g) in methanol (50 ml) was refluxed for 24 hr and evaporated. The residue was chromatographed on silica gel (100 g) using methanol-ethyl acetate (1:4). The eluates were evaporated and crystallized from ethyl acetate-hexane to give the title compound (9.2 g): mp 85°-86° C.; ir (CHCl3) 3440, 1616 and 1555 cm1 ; nmr(CDCl3) δ2.55 (t, 2H), 2.63 (m, 4H), 3.30 (m, 4H), 3.60 (t, 2H) and 6.40-7.65 (m, 5H); and Anal. Calcd for C13H18N2O2 : C, 66.64% H, 7.74% N, 11.96% and Found: C, 66.12% H, 7.83% N, 11.99%.
Reaction SMILES: C[Si](C)(C)[O-].[Na+].[NH2:7]/[C:8](/[C:15]([F:18])([F:17])[F:16])=[CH:9]\[C:10]([O:12]CC)=O.[NH2:19][C:20]1[C:21]([O:34][CH3:35])=[C:22]([NH:28][C:29](=O)[O:30]CC)[C:23]([F:27])=[CH:24][C:25]=1[Cl:26].C1CCN2C(=NCCC2)CC1.[H-].[Na+]>CN(C=O)C>[NH2:19][C:20]1[C:21]([O:34][CH3:35])=[C:22]([N:28]2[C:10](=[O:12])[CH:9]=[C:8]([C:15]([F:16])([F:17])[F:18])[NH:7][C:29]2=[O:30])[C:23]([F:27])=[CH:24][C:25]=1[Cl:26]
Reactant: CCOC(=O)Nc1c(F)cc(Cl)c(N)c1OC
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: C[Si](C)(C)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1c(N)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)[nH]c1=O

Procedure:
This compound was prepared using 4.0 grams (0.036 mole) of sodium trimethylsilanolate, 6.6 grams (0.036 mole) of ethyl 3-amino4,4,4-trifluorocrotonate, 8.5 grams (0.032 mole) of ethyl N-(3-amino4-chloro-6-fluoro-2-methoxyphenyl)carbamate, and 2.2 grams (0.014 mole) of DBU in 75 mL of DMF. This preparation differs from well-known literature preparations for pyrimidinedione rings in that sodium trimethylsilanolate and DBU were used rather than sodium hydride. The yield of title compound was 1.7 grams. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][CH:5]=1.O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Li+]>C1COCC1>[NH2:10][C:7]1[N:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(N)nc1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) mixture of 6-Aminonicotinic acid methyl ester (0.511 g, 3.36 mmol) and Cerium(III) chloride heptahydrate (1.25 g, 3.36) in dry THF was slowly added lithium borohydride (8.4 mL, 1 M in THF) over a 30 minute period. The mixture was allowed to warm to room temperature overnight then slowly quenched by the addition of ice water (20 mL). After stirring for 1 hr the mixture was filtered through Celite diluted with EtOAc (30 mL) and layers were separated. The aqueous layer was further extracted with EtOAc (1×). The combined EtOAc extracts were washed with brine, dried over MgSO4, evaporated in vacuo and provide a crude semi-solid. The white solid product was triturated with diethyl ether, filtered and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][NH2:30].[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:30][CH2:29][C:25]2[S:24][CH:28]=[CH:27][CH:26]=2)[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: NCc1cccs1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CNCc2cccs2)c1
Yield: 73.7 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-((thiophen-2-ylmethylamino)methyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol), thiophen-2-ylmethanamine (0.051 mL; 0.5 mmol), and sodium iodide (0.015 g; 0.1 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 10 minutes. Flash chromatography on silica gel (eluent 0 to 10% methanol in dichloromethane) furnished 0.045 g (73%) of the title compound as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:17]([NH2:26])=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19]3)[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([N:15]2[C:16]3[CH:25]=[CH:24][C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:17]=3[NH:26][C:2](=[O:3])[C:1]2=[O:5])[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc(Nc2ccc3ccccc3c2N)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(-n2c(=O)c(=O)[nH]c3c4ccccc4ccc32)c1
Temperature: 25 °C

Procedure:
To an anhydrous tetrahydrofuran (10 mL) solution of oxalyl chloride (162 μL, 1.89 mmol) was dropwise added an anhydrous tetrahydrofuran (10 mL) solution of N2-(3-methoxyphenyl)naphthalene-1,2-diamine (500 mg, 1.89 mmol) under cooling in an ice-bath. The mixture was stirred under cooling in an ice-bath for 30 minutes and at room temperature for one hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and purified by silica gel chromatography (chloroform/methanol=97/3) after removing the solvent by evaporation under reduced pressure. The obtained solid was washed with ethyl acetate/methanol (=1/1) to obtain the titled compound as a slightly beige crystal (572 mg, yield 95%).
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH:3]([NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH:12]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].C1COCC1.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:12]=[C:11]([C:9]([NH:8][CH:3]([CH:2]([CH3:25])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])=[O:10])[O:15][N:14]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)no1)C(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(N)cc2)no1)C(C)C
Temperature: 80 °C
Yield: 65.7 %

Procedure:
Methyl 3-methyl-2-(3-(4-nitrophenyl)isoxazole-5-carboxamido)butanoate (2 g) was dissolved in EtOH (20 ml), THF (8 ml), and water (8 ml). Then ammonium chloride (925 mg) and Iron (756 mg) was added and refluxed at 80° C. for 3 h. The reaction mixture was cooled, filtered through celite and solvent removed under reduced pressure to get dark brown residue. Residue was taken in water and extracted with ethyl acetate, organic layer separated, dried over Na2SO4 and concentrated to get dark brown residue which was purified by silica gel column chromatography in 1:1 EtOAc:Pet ether to get yellow solid which was crystallized from methylene chloride/Pet ether to yield 1.2 g (65%) pale yellow solid. MS (ES+): m/z 318 (M+1); 1HNMR (DMSO-d6, 300 MHz): δ 9.1 (d, 1H), 7.55 (d, 2H), 7.51 (s, 1H), 6.63 (d, 2H), 5.63 (bs, 1H), 4.27 (m, 1H), 3.65 (s, 3H), 2.19 (m, 1H), 0.94 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].Cl.[NH2:28][C@H:29]([C:35]([OH:37])=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34]>O>[NH2:28][C@H:29]([C:35]([OH:37])=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Agent: Cl
Agent: NCCCC[C@H](N)C(=O)O
Agent: [Na+]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 139.8 %

Procedure:
Sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 1.21 g.) was added to a solution of lysine hydrochloride (0.55 g.) in water (12 ml.). The solution was lyophilized to give a lysine salt of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.6 g.).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)(=[O:8])=[O:9])[CH:11]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: COc1ccccc1N
Product: COc1ccccc1NC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 2-methoxyaniline as the starting materials.