Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:31]=[CH:30][C:25]([C:26](NC)=O)=[CH:24][CH:23]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:53][C:54]([CH3:58])([CH3:57])[CH2:55][OH:56]>C(Cl)Cl.O>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([C:22]2[CH:23]=[CH:24][C:25]([C:26]3[O:56][CH2:55][C:54]([CH3:58])([CH3:57])[N:53]=3)=[CH:30][CH:31]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(N)CO
Reactant: CNC(=O)c1ccc(C2(c3cccc(OC)c3)CCN(Cc3ccccc3)CC2)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COc1cccc(C2(c3ccc(C4=NC(C)(C)CO4)cc3)CCN(Cc3ccccc3)CC2)c1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a solution of 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-N-methyl-benzamide (1.01 g, 2.44 mmol), in CH2Cl2 (24 mL) was added pyridine (0.30 mL, 3.71 mmol). The reaction was cooled to −50° C. and triflic anhydride (0.45, 2.67 mmo) was added dropwise over 1 minutes. The reaction was stirred at −50° C. for 1.5 hours and at room temperature for 0.5 hours. The mixture was cooled to −50° C. and 2-amino-2-methyl propanol (0.36 mL, 3.77 mmol) was added. The reaction was allowed to warm to room temperature and stirred at room temperature for 16 hours. To the mixture was added water (5 mL) and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined extracts were dried (MgSO4) and concentrated. Purification by flash chromatography with hexanes/EtOAc (1:1) afforded 0.75 g (68% yield) of 1-Benzyl-4-[4-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-phenyl]-4-(3-methoxy-phenyl)-piperidine. 1HNMR (400 MHz, CDCl3) δ; 7.83 (d, 2H), 7.38-7.21 (comp, 7H), 7.18 (t, 1H), 6.81-6.75 (comp, 2H), 6.63 (d, 1H), 4.08 (s, 2H), 3.78 (s, 3H), 3.41 (s, 2H), 2.79-2.40 (comp, 8H), 1.38 (s, 3H); MS (M+1) 454.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:23]([C:25]3[S:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:24])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.C(N(CC)CC)C.[N:40]1[CH:45]=[CH:44][CH:43]=[C:42]([N:46]=[C:47]=[O:48])[CH:41]=1>C(Cl)Cl>[CH3:32][O:31][C:4]1[CH:3]=[C:2]([O:1][C:47]([NH:46][C:42]2[CH:41]=[N:40][CH:45]=[CH:44][CH:43]=2)=[O:48])[CH:7]=[CH:6][C:5]=1[C:8]1[C:9]([CH2:21][O:22][C:23]([C:25]2[S:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[O:24])=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])([CH3:19])[CH:12]=[C:11]2[CH3:20]
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Reactant: O=C=Nc1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC(=O)Nc2cccnc2)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.5 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(5-methylthiophen-2-ylcarbonyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-2, 31.0 mg, 0.0690 mmol) was dissolved in anhydrous methylene dichloride (1 mL), triethylamine (27 μL, 0.19 mmol) and 3-pyridyl isocyanate (17.0 mg, 0.142 mmol) were added thereto, and then the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (21.8 mg) as a pale yellow amorphous product. (Yield 57%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:19]1([C:22]2[C:27]([CH2:28][C:29](O)=[O:30])=[CH:26][N:25]=[C:24]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)[N:23]=2)[CH2:21][CH2:20]1.ClCC1C(C2CC2)=NC(C2C=CC(C(F)(F)F)=CC=2)=NC=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][NH:17][C:29](=[O:30])[CH2:28][C:27]2[C:22]([CH:19]3[CH2:20][CH2:21]3)=[N:23][C:24]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:37]=3)=[N:25][CH:26]=2)[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: O=C(O)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CCN)c1
Agent: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Product: CCOC(=O)C(C)(C)Oc1cccc(CCNC(=O)Cc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester (example 55C]) was reacted with [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid (prepared from 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) in analogy to the sequences described in examples 26D] and 26E]) to give 2-[3-(2-{2-[4-cyclopropyl-2(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetylamino}-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:17])[CH2:13][CH:12](Br)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:15]#[N:16])[CH:10]=2)[O:5]1.[N:18]1[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([OH:25])[N:19]=1>CS(C)=O>[CH3:3][C:4]1([CH3:17])[CH2:13][CH:12]([O:24][C:23]2[N:18]=[N:19][C:20]([OH:25])=[CH:21][CH:22]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:15]#[N:16])[CH:10]=2)[O:5]1
Reactant: CC1(C)CC(Br)c2cc(C#N)ccc2O1
Reactant: Oc1ccc(O)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)CC(Oc2ccc(O)nn2)c2cc(C#N)ccc2O1
Reaction time: 72 h

Procedure:
1.2 g of 80% NaH are added to a solution of 2.66 g of 2,2-dimethyl-4-bromo-6-cyanochroman (m.p. 89-92°; obtainable by reduction of 2,2-dimethyl-6-cyano-4-chroma-none with NaBH4 in CH3OH to give oily 2,2-dimethyl-6-cyano-4-chromanol and reaction with PBr3 in toluene at 20°) and 2.5 g of pyridazine-3,6-diol in 70 ml of DMSO and the mixture is stirred at 20° for 3days. After customary working up, 2,2-dimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-cyanochroman, m.p. 221-224°, is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:16][C:17]([F:20])([F:19])[F:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:29]B(O)O>CN(C=O)C.O>[CH3:29][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:16][C:17]([F:20])([F:19])[F:18]
Reactant: Nc1cnc(Oc2ccc(Br)c(OC(F)(F)F)c2)nc1
Reactant: CB(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ncc(N)cn2)cc1OC(F)(F)F
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
To a solution of 2-({4-bromo-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinamine (Intermediate 162, 270 mg) in DMF (4 mL) were added K3PO4 (490 mg, 2.31 mmol), Pd(tBu3)2 (197 mg, 0.385 mmol) and methyl boronic acid (276 mg, 4.62 mmol) and the reaction mixture was stirred for 30 minutes at 110° C. under microwave irradiation. After cooling the reaction was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layer was washed with ice cold brine (2×5 mL), dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography on silica gel (SNAP 10 g) eluting from 80:20 to 50:50 cyclohexane/ethyl acetate to afford the title compound as white solid (135 mg).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][NH:6][N:7]([CH3:18])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:9].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:5][N:6]1[C:1](=[S:2])[N:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8](=[O:9])[N:7]1[CH3:18]
Reactant: CNN(C)C(=O)Nc1ccc(Cl)cc1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)n(-c2ccc(Cl)cc2)c(=S)n1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 118.5 %

Procedure:
A solution of 3.8 g (0.033 mol) thiophosgene in 10 ml chloroform was added dropwise to a stirred solution of 7 g (0.033 mol) 1,2-dimethyl-4-(4-chlorophenyl)semicarbazide and 6.67 g (0.066 mol) triethylamine in 200 ml chloroform. After completion of the addition, the reaction mixture was heated under reflux for 2 hours and stirred at about 25° C. for 3 days. The reaction mixture was then washed with water, dilute hydrochloric acid solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 10 g of a semi-solid residue. The residue was diluted with 100 ml dichloromethane and filtered. The filtate was chromatographed on 200 g of silica gel. Elution with 1% methanol in dichloromethane gave the product, 3.9 g, as light tan crystals, m.p. 143°-144° C. Infrared analysis showed strong carbonyl absorption at 5.8 micron. The product is tabulated in Table I as Compound No. 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1S(O)(=O)=O.[CH2:21]([NH2:24])[CH:22]=[CH2:23]>O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH:5][C@@H:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[NH:24][CH2:21][CH:22]=[CH2:23]
Reactant: C=CCN
Reactant: O=S(=O)(O)C1CCCCCC1Nc1ccc(Cl)c(Cl)c1
Solvent: O
Product: C=CCN[C@@H]1CCCCC[C@H]1Nc1ccc(Cl)c(Cl)c1
Product: Cl

Procedure:
A mixture of 0.20 mole of 3,4-dichloro-N-(2-sulfocycloheptyl)aniline and 250 ml. of a 50 percent allylamine in water solution is heated at 125° C. in an autoclave for forty-eight hours. The resulting reaction mixture is washed from the autoclave 1500 ml. solution of methanol. This solution is evaporated until material therefrom oils out as a separate layer. The oil is extracted with 500 ml. of methylene chloride. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an orange oil. The oil is chromatographed on 600 ml. of silica gel eluting with 2 liters of chloroform and 4 liters of ethyl acetate. The ethyl acetate fraction is separated and evaporated to an oil; the trans-3,4-dichloro-N-[2-(N-allylamino)cycloheptyl]aniline. This amine oil is converted to its hydrochloride salt with excess ether-hydrogen chloride mixture and recrystallized from a mixture of 450 ml. of methanol and about 2000 ml. of ethyl ether to obtain trans-3,4-dichloro-N-[2-(N-allylamino)cycloheptyl]aniline hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8](OC)(OC)[O:9]C>O>[CH3:8][O:9][N:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH2:3]1
Reactant: COC(OC)OC
Reactant: Nc1cccnc1
Solvent: O
Product: CON=C1C=CC=NC1
Yield: 90 %

Procedure:
A mixture of 3-aminopyridine (7.14 g, 0.076 mol) and trimethyl orthoformate (40 mL) was refluxed for approximately 60 hr. To the cooled reaction mixture was added water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine and dried with MgSO4. The suspension was filtered and concentrated to yield the 3-methoxyiminopyridine as a white solid (9.3 g, 90%).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:16](=[O:19])[NH:17][N:18]=2)[C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.Cl[CH2:21][C:22]1[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[C:3]2[N:4]([C:16](=[O:19])[N:17]([CH2:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=3)[N:18]=2)[C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CCl
Reactant: Cc1cc(-c2ccc(Cl)cc2)c(Br)c2n[nH]c(=O)n12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(Cl)cc3)cc(C)n2c1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 8-bromo-7-(4-chlorophenyl)-5-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (42 mg, 0.124 mmol), and 3-(chloromethyl)-2-methyl-6-(trifluoromethyl)pyridine (39 mg, 0.186 mmol) in anhydrous DMF (0.5 mL) was added anhydrous potassium carbonate (34.6 mg, 0.25 mmol). The resulting suspension was stirred under argon at 80° C. for 1 h. After cooling to room temperature, the reaction mixture was diluted with water (10 mL). The resulting precipitate was filtered, washed with water, and dried in a vacuum oven at 60° C. for 16 h to afford 56 mg (89%) of the title compound as an off-white solid. HPLC/MS: retention time=4.15 min, [M+H]+=512.2.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[N:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=4)[CH:13]=3)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C(=O)([O-])[O-].[Na+].[Na+].O>>[Br:24][C:21]1[CH:20]=[N:19][C:18]([C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[CH2:11][N:8]2[C:6]3=[N:7][C:2]([C:29]4[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=4)=[CH:3][N:4]=[C:5]3[N:10]=[N:9]2)=[N:23][CH:22]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cnc(-c2cccc(Cn3nnc4ncc(Br)nc43)c2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cn1cc(-c2cnc3nnn(Cc4cccc(-c5ncc(Br)cn5)c4)c3n2)cn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
2.00 g (3.67 mmol) of 6-bromo-1-[3-(5-bromopyrimidin-2-yl)benzyl]-1H-1,2,3-triazolo[4,5-b]pyrazine, 840 mg (4.04 mmol) of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 778 mg (7.34 mmol) of sodium carbonate are suspended in 3.7 ml (204 mmol) of water and 15 ml of N,N-dimethylformamide, degassed, evacuated and flushed with nitrogen a number of times. 257 mg (0.367 mmol) of bis(triphenylphosphine)palladium-(II) chloride are added, and the mixture is again evacuated and flushed with nitrogen. The reaction mixture is stirred at 80° C. for 24 h. The reaction mixture is filtered and washed with ethyl acetate and evaporated. The residue is stirred with isopropanol and reacted further without additional purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:20][CH:11]2[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].[OH-].[K+]>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11](=[O:20])[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc(C2OC2C(=O)c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Cc1ccc(C(=O)O)cc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a solution of 5.63 g of 3-(4-carboxyphenyl)-1-phenyl-2,3-epoxy-1-propanone in 100 ml of ethanol at 85°-90° C was added a solution of 6 g of potassium hydroxide in 100 ml of ethanol with stirring over 5 min. The reaction mixture was heated at 85°-90° C for 5 min. and then allowed to cool to room temperature. The solution was evaporated to dryness and the residue was dissolved in 300 ml of ice-water and acidified with 125 ml of hydrochloric acid. After stirring for 30 min., the precipitate was collected and washed with water. The precipitate was dissolved in 600 ml of ethyl acetate and the solution was dried and filtered. The filtrate was evaporated to give 5.63 g (100%) of 3-(4-carboxyphenyl)-1-phenyl-1,2-propanedione as a yellow solid.
Reaction SMILES: [OH:1][CH:2]([CH3:8])[CH2:3][P:4](=[O:7])([OH:6])[OH:5].[OH2:9].[NH3:10]>Cl.CO>[OH:1][CH:2]([CH2:8][NH:10][OH:9])[CH2:3][P:4](=[O:6])([OH:5])[OH:7]
Reactant: CC(O)CP(=O)(O)O
Reactant: N
Reactant: O
Agent: Cl
Solvent: CO
Product: O=P(O)(O)CC(O)CNO

Procedure:
A solution of 3-N-ethoxycarbonyl-N-hydroxyamino)-2-hydroxypropylphosphonic acid (2.4 g.) in 1 N hydrochloric acid (100 ml.) was heated to reflux for 14 hours. The reaction mixture was evaporated to dryness under reduced pressure to give a residue, to which was added water (20 ml.), washed twice with chloroform (each 10 ml. portion) and decolorized with activated charcoal (200 mg.). The activated charcoal was filtered off and the filtrate was evaporated to dryness under reduced pressure to give a dark reddish oil, to which was added water (3 ml) and adjusted to pH 4.0 with 28% aqueous ammonia. This aqueous solution was diluted with methanol and allowed to stand at ambient temperature, and then the precipitating crystals were collected by filtration to give 2 -hydroxy-3-(N-hydroxyamino)propylphosphonic acid (0.62 g.).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:20])[NH:3]1.Br[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=1>CC(N(C)C)=O.[Cu]=O>[C:15]([C:14]1[CH:13]=[C:12]([C:5]2([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:20])[N:3]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:31])([F:33])[F:32])[CH:23]=3)[C:2](=[O:1])[NH:6]2)[CH:19]=[CH:18][CH:17]=1)#[N:16]
Reactant: N#Cc1ccc(Br)cc1C(F)(F)F
Reactant: C=CCOCC1(c2cccc(C#N)c2)NC(=O)NC1=O
Agent: O=[Cu]
Solvent: CC(=O)N(C)C
Product: C=CCOCC1(c2cccc(C#N)c2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 130 °C

Procedure:
To a solution of 579 mg of 3-[2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-4-yl]benzonitrile and 534 mg of 4-bromo-2-(trifluoromethyl)benzonitrile in DMAC (2.5 mL), 183 mg of copper oxide are added. The mixture is refluxed overnight at 130° C. The mixture is concentrated, taken in DCM, washed with a solution of 10% aqueous ammonia solution and brine. The organic phase is dried over magnesium sulfate, concentrated under vacuum and purified on silica gel (ethyl acetate/cyclohexane 0/100 to 50/50) to give the desired compound.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][C:5]1=[O:11])[CH2:2][CH3:3].C([O-])(=O)C.[NH4+:16]>>[NH2:16][C:7]1[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:11])[CH:6]=1
Reactant: [NH4+]
Reactant: CCCC1CCC(=O)CC1=O
Agent: CC(=O)[O-]
Product: CCCC1CCC(N)=CC1=O

Procedure:
In close analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 4-propylcyclohexane-1,3-dione was reacted with ammonium acetate to give the title compound as a colorless solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:25])[CH:7]=[CH:8][C@@H:9]([CH3:24])[C@H:10]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[CH3:4].[CH3:26]I.OS([O-])(=O)=O.[Na+]>C1COCC1.CN(C=O)C.CCOCC>[CH2:3]([O:5][C:6](=[O:25])[CH:7]=[CH:8][C@@H:9]([CH3:24])[C@H:10]([N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:26])[C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[CH3:4]
Reactant: CI
Reactant: CCOC(=O)C=C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)c1ccco1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C=C[C@@H](C)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of NaH (0.707 g, 17.7 mmol) in THF (10.7 mL) at 0° C. was added 2.12b (1.14 g, 3.53 mmol) in DMF (1 mL), followed by MeI (1.33 mL, 21.2 mmol). After stirring at 0° C. for 1 hour, the reaction mixture was poured onto a ice cold mixture of 1.0 M aq. NaHSO4 solution and Et2O. The separated organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography (0-50% EtOAc/heptane) to give 2.12c (1.08 g, 91% yield). MS m/z (M+23) 360.1
Reaction SMILES: CC1CS[C@@H]2C(NC(=O)C(C3N=C(N[C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)SC=3)=NOC(C)(OC)C)C(=O)N2C=1C(OC(C)(C)C)=O.FC(F)(F)C(O)=[O:57]>C(O)=O>[C:34]1([C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[OH:57])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(C)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2 g of the product of Step B were added with stirring at room temperature to 20 ml of trifluoroacetic acid held under nitrogen and after stirring for 10 minutes at room temperature, the mixture was concentrated under vacuum to a volume of 8 ml. The mixture was cooled in an ice water bath and 60 ml of isopropyl ether were slowly added thereto. The mixture was stirred for 10 minutes at room temperature and was vaccum filtered and the filter was rinsed with isopropyl ether. The filtrate was evaporated to dryness under reduced pressure to obtain 1.5 g of raw product. The latter was placed under an argon atmosphere and 7.5 ml of 50% aqueous formic acid were added thereto. The mixture was stirred at 40° C. for 15 minutes and was then vacuum filtered. The recovered product was rinsed twice with 1 ml of 50% aqueous formic acid and 3 times with 1 ml of distilled water to obtain 319 mg of triphenyl carbinol. The filtrate was distilled to dryness and ethanol was added. The mixture was triturated with 15 ml of ether and was vacuum filtered. The recovered product was rinsed with ether and dried to obtain 0.973 g of the syn isomer of 3-methyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3 -eme-4-carboxylic acid with an RF=0.3 (acetone containing 10% water).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[Cl:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH:36]=1)[C:33](O)=[O:34]>>[Cl:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH:36]=1)[C:33]([NH:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2)=[O:34]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cncc(Cl)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cncc(Cl)c2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 5-chloro-nicotinic acid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH2:13](O)CCO.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:10][O:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]1[O:11][CH2:12][CH2:13][CH2:1][O:2]1
Reactant: OCCCO
Reactant: COC(=O)CCCC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)CCCC1OCCCO1
Temperature: 25 °C
Yield: 103.9 %

Procedure:
Methyl 5,5-dimethoxyvalerate (20.0 g, 0.114 mol), propane-1,3-diol (13 g, 0.17 mol) and para-toluene sulphonic acid (2.17 g, 0.0114 mol) were heated under Dean-Stark conditions in toluene (100 ml) for 4 h. The mixture was cooled to room temperature and diluted with diethyl ether (100 ml) and then neutralized with solid sodium bicarbonate. The solid was filtered and the filtrate evaporated to give a pale yellow oil (22.3 g). A 10 g portion of this was then purified by silica gel chromatography (eluent 30% EtOAc:hexane) which gave the title compound as a colourless oil (6.82 g).