Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[C:8](=[O:15])[C:7]([C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])=[C:6]2[OH:27])#[N:2].C(O)(C(F)(F)F)=O>O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[C:8](=[O:15])[C:7]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:6]2[OH:27])#[N:2]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(C#N)ccc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cc(C#N)ccc21
Yield: 38.9 %

Procedure:
1,1-Dimethylethyl N-((6-cyano-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-yl)carbonyl)glycinate (124 mg, 335 μmol) was stirred in TFA (1 mL, 13462 μmol) at room temperature for 15 minutes. Water was added. The resulting precipitate was filtered. The green solid was dissolved in saturated NaHCO3 and washed with DCM. The aqueous layer was separated and acidified with 10% HCl. The resulting precipitate was filtered and washed with water to give the desired product as a white solid (41 mg). MS (m/e)=315.1 (M+H)+. Calculated for C16H14N2O5 314.09.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH2:14]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH3:15]>CCOC(C)=O>[CH2:14]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:17](=[O:16])[C@H:18]([CH3:20])[NH:19][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:15]
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and L-alanine ethyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp=197-199° C.). The reaction was monitored by tlc (Rf=0.6 in EtOAc) and the product was purified from bi-products by silica gel chromatography using EtOAc as the eluent, followed by recrystallization from EtOAc.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1.C([O-])([O-])=O.[K+].[K+]>ClCCl>[Si:20]([O:1][CH2:2][C@H:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO[Si](C)(C)C(C)(C)C
Yield: 60.3 %

Procedure:
(R)-t-Butyl 2-(hydroxymethyl)piperazine-1-carboxylate (1.15 g, 5.32 mmol), t-butylchlorodimethylsilane (0.882 g, 5.85 mmol), and imidazole (0.796 g, 11.7 mmol) were stirred in dichloromethane (3 mL) for three days. The solution was added to aqueous K2CO3 (30 mL) and extracted with dichloromethane (3×30 mL). The combined organics were dried (MgSO4) and evaporated to give a yellow oil. Silica gel chromatography (gradient elution hexanes/0-50% ethyl acetate) afforded compound 308 as a colorless oil (1.06 g, 60%).
Reaction SMILES: [Cl-].[NH4+:2].[CH3:3][S:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Zn]>[CH3:3][S:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:2])=[CH:10][CH:9]=1
Reactant: [NH4+]
Reactant: CSCCNc1ccccc1
Agent: [Cl-]
Agent: [Zn]
Product: CSCCNc1ccc(N)cc1

Procedure:
0.8 g of ammonium chloride and 20 g of powdered zinc are added to 44 ml of aqueous-alcoholic solution (10% of water, 90% of alcohol). This mixture is brought to reflux with stirring, and 0.04 mole (8.5 g) of 4-nitro-N-[[β-(methylthio)ethyl]aniline is added, the addition being regulated so as to maintain the reflux without heating. The decolorized reaction medium is filtered while boiling into a flask containing 8.5 ml of strength hydrochloric acid. The expected product precipitates in the form of a dihydrochloride. It is dried under vacuum at 55° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:32]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=Cc1ccccc1
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C[C@H](Nc1cc(-c2cc3nccn3c(N3C[C@@H]4C[C@H]3CN4Cc3ccccc3)n2)ccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 100 mg (0.24 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 2.5 mL chloroform was treated with 0.25 mL (2.4 mmol) benzaldehyde and 160 mg (0.73 mmol) NaBH3(CN), followed by the addition of 2.5 mL methanol. The mixture was stirred at ambient temperature for 5 min when MS showed that all starting materials had converted to product. The reaction mixture was diluted with 50 mL DCM, washed with 50 mL satd. NaHCO3, and dried over anhydrous Na2SO4. After purification by HPLC, the title compound was obtained. MS (ES+): 502 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.CC(C)[O-].[CH3:21][C:22]1[S:23][C:24]([C:28]2[C:29](=[O:39])[NH:30][C:31](=[O:38])[N:32]([CH2:34][CH2:35][CH:36]=O)[CH:33]=2)=[C:25]([CH3:27])[N:26]=1>C(#N)C>[CH3:21][C:22]1[S:23][C:24]([C:28]2[C:29](=[O:39])[NH:30][C:31](=[O:38])[N:32]([CH2:34][CH2:35][CH2:36][N:11]3[CH2:12][C@H:13]4[C@:9]([C:6]5[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=5)([CH2:14]4)[CH2:10]3)[CH:33]=2)=[C:25]([CH3:27])[N:26]=1
Reactant: Cc1nc(C)c(-c2cn(CCC=O)c(=O)[nH]c2=O)s1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Agent: CC(C)[O-]
Solvent: CC#N
Product: Cc1nc(C)c(-c2cn(CCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41.3 %

Procedure:
To a solution of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (269 mg, 1.186 mmol) in acetonitrile (4 mL), Titanuim (IV) isopropoxide (0.434 mL, 1.482 mmol) and a solution of 3-[5-(2,4-dimethyl-1,3-thiazol-5-yl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]propanal (Prep36, 276 mg, 0.988 mmol) in acetonitrile (6 mL) were added and the mixture was stirred at rt for 20 minutes. Afterwards, it was cooled to 0° C. and Sodiumtriacetoxyboronhydride (314 mg, 1.482 mmol) was added. The mixture was stirred at rt for 1.5 h, then quenched with water. Acetonitrile was eliminated under reduced pressure and the aqueous residue was extracted with DCM. Organic phase was washed with NaHCO3 saturated solution, dried and concentrated under vacuum. Crude product was purified by flash chromatography (eluent: DCM/MeOH/NH3 97:3:0.1) affording the title compound (E37, 200 mg, 0.408 mmol) as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[NH:13][CH:12]=[N:11][CH:10]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:27])=CC=1>C1COCC1.O>[C:1]1([CH:7]([C:9]2[NH:13][C:12](=[S:27])[NH:11][CH:10]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: CC(c1ccccc1)c1cnc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccccc1)c1c[nH]c(=S)[nH]1
Reaction time: 3 h

Procedure:
A solution of 5-(1-phenyl-ethyl)-1H-imidazole (Intermediate C2) (0.20 g, 1.16 mmol) in THF (6 mL) and water (6 mL) was treated with NaHCO3 (0.98 g) at rt for 10 sm. Phenyl chlorothionoformate (0.40 mL, ˜3.0 mmol) was added and stirring was continued for 3 h. The mixture was diluted with water (10 mL) and extracted with ether (3×15 mL). The organic portions were combined, dried over MgSO4, filtered and freed of solvent. The residue was dissolved in MeOH (8 mL) and treated with NEt3 (1 mL) for 16 h. The solvent was removed under vacuum and the product was washed on a glass frit with 50% CH2Cl2:hexanes to give 4-(1-phenyl-ethyl)-1,3-dihydro-imidazole-2-thione (Compound 4)
Reaction SMILES: [Na+:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[K+].Br[CH:16]([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(O)C>[OH:22][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=[O:10])=[O:11])=[CH:5][CH:4]=1.[Na+:1]
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Reactant: CCCCCC(O)Br
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=S(=O)([O-])c1ccc(OCCCCCCO)cc1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
Into a three-necked round-bottom flask equipped with a magnetic stirring bar and a reflux condenser were added 4-hydroxybenzenesulfonicacid sodium salt (30.0 grams (g), 0.13 mol), potassium hydroxide (9.0 g, 0.16 mol) and distilled water (60 milliliter (ml)). 1-Bromohexanol (23.16 g, 0.13 mol) dissolved in ethanol (50 ml) was added drop wise into the reaction mixture at room temperature. The reaction mixture was refluxed for 24 hours and then cooled to room temperature. The precipitated product was filtered and washed with chloroform to remove excess of 1-bromohexanol. The product was dried under vacuum at 70° C. for 12 hours to provide 38.06 g of sodium 4-(6-hydroxyhexyl)oxybenzenesulfonate (92% yield).
Reaction SMILES: ClCCO.[Cl:5][C:6](Cl)(Cl)[C:7](=N)[O:8][CH:9]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]1[F:28].FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(Cl)Cl>[C:13]([O:12][C@H:11]1[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][CH:9]([O:8][CH2:7][CH2:6][Cl:5])[C@@H:10]1[F:28])(=[O:15])[CH3:14]
Reactant: CC(=O)OC[C@H]1OC(OC(=N)C(Cl)(Cl)Cl)[C@H](F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: OCCCl
Solvent: ClCCl
Product: CC(=O)OC[C@H]1OC(OCCCl)[C@H](F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-chloroethanol (1.0 mL, 14.92 mmol), 3,4,6-tri-O-acetyl-2-deoxy-2-fluoro-D-glucopyranosyl trichloroacetimidate (1.4 g, 3.09 mmol, Angew. Chem. Int. Ed. 2010, 49, 8724) and 4 Å molecular sieves in CH2Cl2 (50 mL) at −30° C. was added trimethylsilyl trifluoromethanesulfonate (0.25 mL, 1.384 mmol) dropwise. The mixture was allowed to gradually warm up to rt. After stirring for 2 hr, the reaction was quenched with TEA (0.13 mL, 0.933 mmol). The resulting mixture was filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (80 g), eluting with 0-60% EtOAc in hexanes to give the title compound. This anomeric mixture was used directly in the next step without further purification. TLC: silica gel, hexane/EtOAc: 3/1, Rf=0.35.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([C:32]([O:34][CH3:35])=O)[N:25]=[C:24]2[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].IC.C(OCC)(=O)C>CN(C)C(=O)C.O>[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([CH2:32][O:34][CH3:35])[N:25]=[C:24]2[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(COC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
0.057 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was added to a solution of 0.478 g of methyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxylate (prepared as described in Example 1) in 5 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, 0.125 ml of iodomethane were added, and the reaction mixture was stirred at 50° C. for 3 hours. The reaction mixture was then mixed with ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate; the solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and methylene chloride as the eluent, to give 0.30 g of the title compound as a gum.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11]C>CN(C=O)C.CCOC(C)=O.Cl>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(O)c(Br)c1
Temperature: 115 °C
Yield: 52.3 %

Procedure:
2-Bromo-4-nitroanisole (20 g, 0.086 mol) was dissolved in DMF (414 mL) at rt under N2. Sodium ethylthiolate (17.4 g, 0.207 mol) was added and the reaction mixture was warmed to 115° C. for 2 h. The reaction was cooled to rt and diluted with EtOAc (200 mL) and 1 M HCl (aq., 200 mL). The phases were separated, and the desired product was extracted into 1 M NaOH (aq, 150 mL×3). The basic aqueous extracts were combined and acidified using conc. HCl. The desired product was extracted from the acidic aqueous solution using EtOAc (250 mL×2). The combined organic layers were washed with brine and dried over sodium sulfate. The volatiles were removed in vacuo to afford a light brown semi-solid (9.8 g, 52% yield). 1H NMR (DMSO-d6) δ 8.33 (m, 1H); 8.09 (m, 1H); 7.07 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[N:3]=1.[OH-].[NH4+]>O1CCCC1.[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][C:4]1[N:3]=[C:2]([Cl:1])[NH:6][N:5]=1
Reactant: O=[N+]([O-])c1ccccc1Cc1n[nH]c(Cl)n1
Agent: [Ti+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Nc1ccccc1Cc1n[nH]c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6.27 g of 5-chloro-3-(o-nitrobenzyl)-1,2,4-triazole in 146 ml of tetrahydrofuran is added to 0° with stirring 146 ml of 20% aqueous solution of titanium trichloride. The mixture is stirred at room temperature overnight basified with concentrated ammonium hydroxide and extracted 3 times with methylene chloride. The combined extracts are dried, evaporated and the residue is crystallized from ether to give 3-(o-aminobenzyl)-5-chloro-1,2,4-triazole, m.p. 162°-165°.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Cl>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:32][C:31]5[CH:34]=[CH:35][CH:36]=[C:29]([O:28][CH3:27])[CH:30]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1cccc(CCl)c1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: COc1cccc(CN2CCn3c(cc4cc(OC5CCN(C(C)C)CC5)ccc43)C2=O)c1
Yield: 74 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 3-methoxybenzyl chloride, to give the desired product as a white solid (74%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:35])[C:26]([NH:30][CH:31]4[CH2:34][CH2:33][CH2:32]4)=[N:27][C:28]([Cl:29])=[C:23]3[C@H:22]([CH2:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])(C)(C)C.Cl.O1CCOCC1>CO>[ClH:29].[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:35])[C:26]([NH:30][CH:31]4[CH2:34][CH2:33][CH2:32]4)=[N:27][C:28]([Cl:29])=[C:23]3[C@H:22]([CH2:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:21]2)=[O:19])=[CH:14][CH:15]=1)(=[NH:7])[NH2:9]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2C[C@@H](CCCc3ccccc3)c3c(Cl)nc(NC4CCC4)c(=O)n32)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N=C(N)c1ccc(CNC(=O)[C@@H]2C[C@@H](CCCc3ccccc3)c3c(Cl)nc(NC4CCC4)c(=O)n32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution the compound (54 mg, 0.085 mmol) obtained from Step G was added HCl in dioxane (4.0 M, 0.38 mL, 1.5 mmol) and 2 drops of methanol. The mixture was stirred at rt overnight. Solvent was removed to give a white solid as product in quantitative yield. 1HNMR (300 MHz, CDOD3) δ 9.35 (s, 2H), 9.07 (s, 2H), 7.80 (d, 2H, J=8.5 Hz), 7.47 (d, 2H, J=6.6 Hz), 7.30–7.16 (m, 5H), 4.96 (t, 1H, J=7.3 Hz), 4.42–4.23 (m, 3H), 3.24 (m, 1H), 2.60 (m, 2H), 2.2–1.6 (m, 12H). MS m/e 533.4 (M+H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].CN1CCCC1=O.[CH2:19]([NH:22][CH2:23][CH:24]=[CH2:25])[CH:20]=[CH2:21].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:19]([N:22]([CH2:23][CH:24]=[CH2:25])[C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:4]([NH2:5])[CH:3]=1)[CH:20]=[CH2:21]
Reactant: C=CCNCC=C
Reactant: Nc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C=CCN(CC=C)c1cc(N)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 98.6 %

Procedure:
A mixture of 3-fluoro-4-nitroaniline (1.56 g, 10 mmol), 1-methylpyrolidinone (10 mL), diallylamine (1.94 g, 20 mmol) and potassium carbonate (1.38 g, 10 mmol) was heated to 115-125° C. for 9.5 h. The mixture was diluted with water, and extracted with ethyl ether. The combined extracts were washed with water, washed with saturated brine solution, and dried over magnesium sulfate. The extract was concentrated to give N,N-diallyl-6-nitro-1,3-benzenediamine as an orange oil (2.3 g).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH3:32])[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.P(Cl)(Cl)(Cl)(Cl)[Cl:41]>C(Cl)Cl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH3:32])[C:27]([Cl:41])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON=C(C(=O)Cl)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred solution of anhydrous methylene chloride (70 ml) containing 2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetic acid (syn-isomer) (4.43 g; 0.01 mole) and triethylamine (1.41 ml; 0.01 mole), was cooled to 0° C., and phosphorus pentachloride (2.08 g; 0.01 mole) was added portionwise. After 10 minutes of stirring at 0° C. and 1 hour at room temperature, the mixture was evaporated under reduced pressure, taken up in acetone/benzene, evaporated again in order to remove any traces of phosphorus oxychloride, and taken up in 50 ml of anhydrous acetone. Triethylamine hydrochloride was then removed by filtration. The acetone solution of 2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetyl chloride thus obtained was dropped into a vigorously stirred, ice-cooled solution of 7-amino-3-[(8-amino-6-tetrazolo-[1,5-b]pyridazinyl)thiomethyl]-3-cephem-4-carboxylic acid (3.8 g; 0.01 mole), NaHCO3 (0.84 g) and triethylamine (2.82 ml) in a mixture of water and acetone (75 ml:50 ml). The slurry was stirred for 1/2 hour at 0°-5° C. and then for 11/2 hours at room temperature, taken up in ethyl acetate (500 ml), washed with dilute hydrochloric acid (50 ml), then aqueous sodium chloride (100 ml), dried with sodium sulphate and evaporated to dryness. The residue was stirred in methylene chloride (5 ml); then ethyl acetate (50 ml) and diethyl ether (50 ml) were added. The precipitated produced was collected, dissolved in warm methylene chloride (30 ml), cooled and treated with stirring with diethyl ether (100 ml). After 20 minutes of stirring, the white solid was filtered, washed with ether and dried, thus giving 4.3 g of 3-[(8-amino-6-tetrazolo[1,5-b]pyridazinyl)-thiomethyl]-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer) as a white powder.
Reaction SMILES: CO[C:3](=[O:21])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1([F:12])[F:11].[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:20][C:15]1[CH:14]=[C:13]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][C:7]2([F:11])[F:12])[C:3]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: Nc1nccs1
Reactant: COC(=O)C(CC1CCCC1(F)F)c1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCCC1(F)F)c1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Yield: 11.4 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-3-(2,2-difluoro-cyclopentyl)-propionic acid methyl ester (265 mg, 0.73 mmol) and 2-aminothiazole (18 mg, 0.18 mmol) in a solution of magnesium methoxide in methanol (7.4 wt. % , 0.28 iL, 0.19 mmol) was heated to 110° C. for 18 h. At this time, the reaction mixture was cooled to 25° C. and then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(2,2-difluoro-cyclopentyl)-N-thiazol-2-yl-propionamide (8.3 mg, 23%) as a yellow oil: EI-HRMS m/e calcd for C17H16F2Cl2N2OS (M+H)+ 405.0402. found 405.0407.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([F:17])([F:16])[C:11](OCC)=[O:12].[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C(OCC)(=O)C.Cl>O>[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:11](=[O:12])[C:10]([F:16])([F:17])[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:24])[CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 24.3 %

Procedure:
A mixture of 100 mg of ethyl 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrate and 370 mg of 4-chloroaniline was subjected to reaction at 150°-160° C. for 5 hours. The reaction mixture was cooled to room temperature. Thereto were added 10 ml of ethyl acetate and 5 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: toluene/ethyl acetate=1/1) to obtain 30 mg of N-(4-chlorophenyl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]1[C:24]([F:25])=[C:23]([F:26])[CH:22]=[CH:21][C:18]=1[CH2:19]Br>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:19][C:18]2[CH:21]=[CH:22][C:23]([F:26])=[C:24]([F:25])[C:17]=2[F:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: Fc1ccc(CBr)c(F)c1F
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(Cc2ccc(F)c(F)c2F)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 2,3,4-trifluorobenzyl bromide