Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][CH:20]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1
Reactant: C1CCNCC1
Reactant: Cn1c(-c2cccc(N3CCC(=O)CC3)c2)nc2ccccc21
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cn1c(-c2cccc(N3CCC(N4CCCCC4)CC3)c2)nc2ccccc21

Procedure:
1-[3-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl]piperidin-4-one (0.06 g, 0.2 mmol) and piperidine (0.034 g, 0.4 mmol) with triethylamine (27 μL, 0.2 mmol) and molecular sieves (0.5 g) were heated to 40° C. in methanol (5 ml) for 16 hours. Sodiumcyanoborohydride (0.025 g, 0.4 mmol) and zinc chloride (0.027 g, 0.2 mmol) were added and the reaction heated for a further 16 hours, the reaction mixture was evaporated and the residue partitioned between 1N sodium hydroxide (2 ml) and dichloromethane (4 ml). The organic layer was separated, evaporated and purified by preparative HPLC.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C(N)C2CCCCC2)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC([B-](C2C=CC(C)=CC=2)(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCCC1>[C:8]([C:5]1[CH:6]=[CH:7][C:2](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: C=Cc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: Cc1ccc([B-](c2ccc(C)cc2)(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(/C=C/c2ccccc2)cc1
Yield: 75.7 %

Procedure:
A 30-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 0.773 g (5 mmol) of 4′-chloroacetophenone, 1.042 g (10 mmol) of styrene, 0.034 g (0.038 mmol) of tris(dibenzylideneacetone)dipalladium (0), 1.074 g (5.5 mmol) of dicyclohexylmethylamine and 5 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.087 g (0.15 mmol) of tri-tert-butylphosphonium tetra-para-tolylborate obtained in Example B-3 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 30° C. for 37 hours. After the completion of the reaction, 5 ml of toluene and 10 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.841 g of (trans)-4-acetylstilbene (yield: 75 mol % based on 4′-chloroacetophenone). The identification of the product was made by mass spectroscopy, 1H-NMR and 13C-NMR.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)S([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)(=O)=O>O>[N:1]1([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(S(=O)(=O)C(F)(F)F)cc1
Solvent: O
Product: N#Cc1ccc(N2CCOCC2)cc1
Temperature: 120 °C
Yield: 52 %

Procedure:
A mixture of morpholine (3 g, 34 mmol) and the freshly prepared 4-[(trifluoromethyl)sulfonyl] benzonitrile (1.2 g, 5.1 mmol, Ref.: A. M. Echavarren and J. K. Stille, J. Am. Chem. Soc. 1987, 109, 5478-5486.), is heated at 120° C. The conversion of the 4-[(trifluoromethyl)sulfonyl]benzonitrile is complete after 20 hours. Water (10 ml) is than added into the reaction mixture. The precipitate is filtered off, washed with water and dried under vacuum (30° C.). Recrystallisation (50% aqueous ethanol) of the dried crude product gives 0.5 g of the title-compound. Yield: 52%, m.p. 82-83° C.; MS 188 (100, M+); H1 NMR (CDCl3): δ 7.46 (dd, 2H), 6.81 (dd, 2H), 3.79 (t, 4H), 3.22 (t, 4H); C13 NMR (CDCl3): δ 153.69, 133.71, 120.07, 114.26, 101.16, 66.65, 47.49.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)=[O:5])C.[Mg]>CO.ClCCl>[CH3:1][O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH3:16])[CH:12]=2)[NH:7]1)=[O:5]
Reactant: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Agent: [Mg]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1Cc2cc(OC)ccc2N1
Temperature: 7.5 °C
Reaction time: 3 h

Procedure:
5-Methoxyindole-2-carboxylic acid ethyl ester (2 g, 9.13 mmol) and magnesium turnings (0.432 g, 18 mmol) were suspended in dried methanol (30 ml). This mixture was stirred at 5 to 10° C. under nitrogen for 3 hours, then poured into dichloromethane (200 ml), and washed with saturated ammonium chloride solution. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (3×100 ml). The combined organic layers were dried over sodium sulphate and evaporated. A brown solid was obtained. After column chromatography on silica gel using dichloromethane as eluent, a brown solid was obtained.
Reaction SMILES: C(N(CC)CC)C.C(O[C:12](=[O:14])[CH3:13])(=O)C.[CH2:15]([NH:22][C:23](=[O:54])[NH:24][C:25]1[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][C:26]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][N:33]([CH:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:32][CH2:31]1)=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>ClCCl>[CH2:15]([NH:22][C:23](=[O:54])[NH:24][C:25]1[CH:52]=[CH:51][C:50]([NH:53][C:12](=[O:14])[CH3:13])=[CH:49][C:26]=1[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([CH:36]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:34][CH2:35]1)=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCNC(=O)Nc1ccc(N)cc1C(=O)NC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCNC(=O)Nc1ccc(NC(C)=O)cc1C(=O)NC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 24 h
Yield: 807.6 %

Procedure:
Triethylamine (0.098 ml, 0.65 mmol) and acetic anhydride (0.067 ml, 0.07 mmol) were added to a solution of the 2-(N'-n-heptylureido)-5-amino-N-(1-diphenylmethylpiperidin-4-yl)-benzamide (0.32 g, 0.59 mmol) in dichloromethane (3 ml) at room temperature. The mixture was stirred for 24 hours and then concentrated. The residue was purified by column chromatography on silica gel (50% ethyl acetate in cyclohexane) to give 2-(N'-n-heptylureido)-5acetylamino-N-(1-diphenylmethylpiperidin-4-yl)benzamide (0.33 g, 96.0%): mp 113°-115° C., 1H NMR (CDCl3)ppm: 0.86 (3H, t), 1.27 (8H, m), 1.49-1.69 (4H, m), 1.92-2.08 (4H, m), 2.17 (3H, s), 2.85 (2H, m), 3.22 (2H, q), 3.90 (1H, m), 4.28 (1H, s), 4.57 (1H, t), 6.40 (1H, d), 7.03 (1H, dd), 7.15-7.40 (11H, m), 8.06 (1H, d), 8.30 (1H, d), 10.10 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([NH:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[OH:23])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]2[O:23][C:13]([CH2:12][CH2:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:15][C:16]=2[CH:21]=1
Reactant: COc1ccc(CCC(=O)Nc2cc(Cl)ccc2O)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CCc2nc3cc(Cl)ccc3o2)cc1OC
Yield: 64.9 %

Procedure:
N-[3-(3,4-dimethoxyphenyl)propanoyl-2-hydroxy-5-chloro-aniline (2.3 g, 6.3 mmol) in toluene (30 ml) and p-toluenesulfonic acid monohydrate (0.3 g, 1.5 mmol) was heated under reflux for 3 hours. The cooled reaction mixture was decanted from some tar and the toluene was evaporated. The residue was crystallized from t-butyl methyl ether with charcoal to give 1.3 g of the title compound which was recrystallized from t-butyl methyl ether to give pure title compound (1.08 g) mp 102-105° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1Br.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].CC([O-])(C)C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.O>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][N:26]([C:4]2[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=2[C:2]([F:15])([F:14])[F:1])[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: FC(F)(F)c1ccc(Br)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 5 mmol 2,4-bis(trifluoromethyl)bromobenzene, 6 mmol N-BOC-piperazine, 8 mmol NaOtBu, 0.5 mmol rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 1 mmol tris-(dibenzylideneacetone)dipalladium chloroform complex in 20 ml toluene was stirred at 80° C. for 3 hours. The mixture was then diluted with water, extracted with ethyl acetate, dried and purified by column chromatography (SiO2; cyclohexane/ethyl acetate 9:1) to yield the title compound as a yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[H-].[Na+].[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22]Cl.[Cl-]>CN(C)C=O>[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: CN(C)CCCl
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCNc1c2c(nc3ccccc13)CCCC2=O
Temperature: 60 °C

Procedure:
To a suspension of 9-amino-3,4-dihydroacridin-1-(2H)-one (10.0 g) in 100 ml of dimethylformamide was added a 50% suspension of sodium hydride in oil (2.9 g). To this was added 2-dimethylaminoethyl chloride (6.5 g). The mixture was heated to 60° C pot temperature for 2.5 hours, an additional 2.7 g of the chloride was added and this was heated for an additional 1 hour.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[Br:17][C:18]1[S:22][C:21]([C:23]2[O:24][CH:25]=[C:26]([CH2:28]Cl)[N:27]=2)=[CH:20][C:19]=1[CH3:30]>>[Br:17][C:18]1[S:22][C:21]([C:23]2[O:24][CH:25]=[C:26]([CH2:28][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[CH:13]4)=[CH:4][CH:3]=3)[N:27]=2)=[CH:20][C:19]=1[CH3:30]
Reactant: Cc1cc(-c2nc(CCl)co2)sc1Br
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Product: Cc1cc(-c2nc(COc3ccc(CCCCn4ccnc4)cc3)co2)sc1Br
Yield: 93 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with 2-(5-bromo-4-methyl-2-thienyl)-4-chloromethyloxazole to give 2-(5-bromo-4-methyl-2-thienyl)-4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]oxazole. The yield was 93%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 85-86° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[C:20]([NH2:28])(=[S:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:28]=[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[S:27][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccncc1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CC#N
Product: CSc1ccc(-c2sc(-c3ccncc3)nc2-c2ccc(F)cc2)cc1

Procedure:
A solution of the intermediate from Example 1, Step 3, 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-bromoethanone, (1.58 g, 4.66 mmol) and thioisonicotinamide (670 mg, 4.84 mmol) in 25 mL of acetonitrile was heated to reflux for 23 hours. The solution was filtered, concentrated in vacuo and the residue taken up in dichloromethane. The dichloromethane solution was washed with sat. aq. NaHCO3, and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a brown oil that was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane to provide the desired thiazole as an oil that solidified upon standing (640 mg, 36%): mp 107°-109° C. 1H NMR (CDCl3) 300 MHz 8.75 (br s, 2H), 7.85 (d, J=5.9 Hz, 2H), 7.56 (m, 2H), 7.26 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 7.01 (t, J=8.5 Hz, 2H), 2.50 (s, 3H); 19F NMR (CDCl3) -113.23 (m). High resolution mass spectrum Calc'd. for C21H15FN2S2 : 379.0661. Found: 379.0691.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:26])=[CH:4][C:5]([O:24][CH3:25])=[C:6]([CH:23]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][N:13](C(OCC)=O)[CH2:12][C@H:11]1[O:21][CH3:22])=[O:8].[OH-].[K+]>CC(O)C>[NH2:1][C:2]1[C:3]([Cl:26])=[CH:4][C:5]([O:24][CH3:25])=[C:6]([CH:23]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]1[O:21][CH3:22])=[O:8]
Reactant: CCOC(=O)N1CC[C@H](NC(=O)c2cc(N)c(Cl)cc2OC)[C@H](OC)C1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1cc(Cl)c(N)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Reaction time: 6 h
Yield: 85 %

Procedure:
A mixture of 81 parts of ethyl cis-4-[(5-amino-4-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinecarboxylate, 122 parts of potassium hydroxide and 800 parts of 2-propanol was stirred for 6 hours at reflux temperature. The whole was stirred overnight at room temperature. The reaction mixture was evaporated. The residue was taken up in water and heated for a while. The mixture was evaporated again. The residue was taken up in water and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed with water, dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 58 parts (85%) of cis-5-amino-4-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide; mp. 191.8° C. (interm. 15).
Reaction SMILES: [Li][CH2:2]CCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH:16]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[C:19](=[O:33])[C:18](=O)[CH2:17]1.[NH4+].[Cl-]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH:16]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:32])[F:31])=[CH:24][CH:23]=2)[C:19](=[O:33])[C:18](=[CH2:2])[CH2:17]1
Reactant: COc1cccc(OC)c1C1CC(=O)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C1CC(c2c(OC)cccc2OC)N(Cc2ccc(OC(F)(F)F)cc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A cooled (−78° C.) mixture of methyltriphenylphosphonium bromide (754 mg; 2.11 mmol) in anh. THF (6 ml) was treated dropwise with a solution of n-BuLi (1.6 M in hexanes; 1.32 ml; 2.11 mmol). Stirring was then continued at rt, under nitrogen, for 30 min. The resulting mixture was then cooled to 0° C., and treated with a solution of 5-(2,6-dimethoxyphenyl)-1-(4-(trifluoromethoxy)-benzyl)pyrrolidine-2,3-dione (800 mg; 1.95 mmol) in anh. THF (4 ml). Stirring was continued at 0° C. for 25 min., and at 60° C. for 1 h. After cooling to rt, aq. sat. NH4Cl (25 ml) was added, and this mixture was extracted with AcOEt (3×50 ml). The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=30/1) afforded rac-(S*)-5-(2,6-dimethoxyphenyl)-3-methylene-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one as a colorless oil. LC-MS (conditions A): tR=0.93 min.; [M+H]+: 408.29 g/mol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27]C1C=CC(COC2C=CNC(=O)C=2)=CC=1.BrCC(C1C=CC(CO)=CC=1)=O>>[F:27][C:5]1[CH:4]=[CH:3][C:2]([CH2:1][O:8][C:9]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][OH:25])=[CH:22][CH:23]=3)=[O:17])[C:11](=[O:26])[CH:10]=2)=[CH:7][CH:6]=1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Agent: O=C(CBr)c1ccc(CO)cc1
Product: O=C(Cn1ccc(OCc2ccc(F)cc2)cc1=O)c1ccc(CO)cc1

Procedure:
4-(4-Fluoro-benzyloxy)-1-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one is prepared following preparation 15b (DMSO as solvent) from 1.10 g (5.00 mmol) 4-(4-fluoro-benzyloxy)-1H-pyridin-2-one (preparation 22.1) and 1.15 g (5.00 mmol) 2-bromo-1-(4-hydroxymethylphenyl)-ethanone (preparation 15a).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[N:38]1([CH2:43][CH2:44][NH2:45])[CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:45][CH2:44][CH2:43][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: NCCN1CCCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NCCN3CCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 2-pyrrolidin-1-yl-ethylamine according to conditions described in general procedure C. Mp: 95-97° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.59 (bs, 4 H), 2.08-2.2 (m, 2 H), 2.37-2.47 (m, 4 H), 2.92 (bs, 1 H), 3.23-3.25 (m, 5 H), 3.74 (t, J=4.4 Hz, 4 H), 6.32 (bd, 1 H), 6.59 (bs, 1 H), 7.04 (d, J=11.4 Hz, 1 H), 7.24 (d, J=8.8 Hz, 1 H), 7.38 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.53-7.58 (m, 3 H), 7.80 (d, J=6.6 Hz, 1 H), 7.98 (d, J=7.7 Hz, 1 H), 8.22 (s, 1 H), 10.43 (s, 1 H).
Reaction SMILES: BrC1C=CC(OC2C=CC(C#N)=C(Cl)N=2)=CC=1C1OCCO1.BrC1C=CC(OC2C=CC(C#N)=C(Cl)N=2)=CC=1C1OCCO1.[Br:45][C:46]1[CH:61]=[CH:60][C:49]([O:50][C:51]2[N:58]=[C:57](Cl)[CH:56]=[CH:55][C:52]=2[C:53]#[N:54])=[CH:48][C:47]=1[CH:62]1[O:66][CH2:65][CH2:64][O:63]1.[CH3:67][O:68][CH2:69][CH2:70][NH2:71]>C(#N)C>[Br:45][C:46]1[CH:61]=[CH:60][C:49]([O:50][C:51]2[N:58]=[C:57]([NH:71][CH2:70][CH2:69][O:68][CH3:67])[CH:56]=[CH:55][C:52]=2[C:53]#[N:54])=[CH:48][C:47]=1[CH:62]1[O:66][CH2:65][CH2:64][O:63]1
Reactant: N#Cc1ccc(Cl)nc1Oc1ccc(Br)c(C2OCCO2)c1
Reactant: COCCN
Agent: N#Cc1ccc(Oc2ccc(Br)c(C3OCCO3)c2)nc1Cl
Solvent: CC#N
Product: COCCNc1ccc(C#N)c(Oc2ccc(Br)c(C3OCCO3)c2)n1
Temperature: 80 °C
Yield: 36.1 %

Procedure:
To a solution of compound mixture, 6-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-2-chloro-nicotinonitrile and 2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-chloro-nicotinonitrile (4+5, 2.5 g, 6.6 mmol) in acetonitrile (anhydrous, 50 mL) was added 2-methoxy-ethylamine (5.7 mL, 66 mmol). The reaction was heated at 80° C. for 2 hours. After the reaction, all volatile components were evaporated under vacuum. Purification was achieved by silica gel chromatography, eluting with 10%-80% EtOAc/hexanes gradient, affording 1.0 g (36% yield) of the title compound. 1H NMR (400 MHz, chloroform-d) δ ppm 7.58-7.47 (m, 2H), 7.41 (d, J=3.1 Hz, 1H), 7.04 (dd, J=8.6, 2.7 Hz, 1H), 6.09-6.03 (m, 2H), 5.37 (t, J=5.1 Hz, 1H), 4.14-3.99 (m, 4H), 3.37 (t, J=5.1 Hz, 2H), 3.31-3.23 (m, 5H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11].O.[NH2:14][NH2:15].C(O)C>CCCCCC>[Cl:10][C:8]1[CH:9]=[C:4]([C:3]([NH:14][NH2:15])=[O:2])[C:5]([OH:11])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: NN
Solvent: O
Solvent: CCCCCC
Solvent: CCO
Product: NNC(=O)c1cc(Cl)ccc1O
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A mixture of 5-chloro-2-hydroxybenzoic acid methyl ester (0.50 g, 2.7 mmol), hydrazine monohydrate (0.3 mL, 6.2 mmol) and ethanol (5 mL) was refluxed for 6 hours. After the reaction mixture was cooled to room temperature, n-hexane was added and the separated crystal was filtered to give the title compound (395.9 mg, 79.2%) as a white crystal.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:5]2[C:16](=[O:31])[CH:17]([NH:18][C:19](=[O:30])[C:20](=[N:27][O:28][CH3:29])[C:21]3[N:22]=[C:23]([NH2:26])[S:24][CH:25]=3)[C@H:4]2[S:3]1.C(O)(=O)C>O1CCCC1.[Zn]>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:16](=[O:31])[CH:17]([NH:18][C:19](=[O:30])[C:20](=[N:27][O:28][CH3:29])[C:21]3[N:22]=[C:23]([NH2:26])[S:24][CH:25]=3)[C@H:4]2[S:3]1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12)c1csc(N)n1
Agent: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12)c1csc(=N)[nH]1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(N)n1

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as 2,2,2-trichloroethyl 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), (0.1 g.) in tetrahydrofuran (2 ml.) and glacial acetic acid (0.25 ml.) was added zinc powder (0.1 g.) all at once with stirring at keeping the temperature below 25° C. in an ice-bath and then the mixture was stirred for 1 hour at room temperature. To the reaction mixture was further added zinc powder (0.1 g.) and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was filtered, and the insoluble material was washed with a small amount of tetrahydrofuran. After the filtrate and the washing were combined together, the solvents were distilled off. To the residue were added 5% aqueous sodium bicarbonate solution and ethyl acetate so that the aqueous layer became pH 7 to 8, and the mixture was filtered, and then the aqueous layer was separated. The aqueous layer was adjusted to pH 2 to 3 with 2 N hydrochloric acid and then concentrated slightly. Thus obtained aqueous layer was subjected to column chromatography (non-ionic adsorption resin, Diaion HP 20 prepared by Mitsubishi Chemical Industries) and the column was washed with water and then eluted with 20% methanol and 40% methanol in turn. The eluates containing the object compound were collected and then lyophilized to give white powder of 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (0.015 g.), mp 230° to 235° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[CH:22]=[O:23])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH2:27]([Mg]Cl)[CH:28]=[CH2:29]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[CH:22]([OH:23])[CH2:29][CH:28]=[CH2:27])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/C=O
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Product: C=CCC(O)/C=C/n1c(C(C)C)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Reaction time: 2.5 h

Procedure:
To a solution of (E)-3-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-2-propenal (430 mg) in dry THF (7 ml) at 0° under nitrogen, allylmagnesium chloride (2M in THF, 0.86 ml) was added. The mixture was stirred for 2.5 h at 0° and then quenched with saturated aqueous ammonium chloride. Extraction with ether (4×) gave, after drying and rotary-evaporation, the crude product (466 mg). FCC eluting with 20% then 30% System A afforded the title product (331.9 mg) as a white solid. Rf 0.41 (System A 1:1); νmax (CHBr3) 3587 cm-1 (OH).