Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]2[CH:19]=[CH:20][C:21]([NH:23][C:24](=[O:26])[CH3:25])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:5])[CH3:4].I[CH3:28]>C1COCC1>[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]2[CH:19]=[CH:20][C:21]([N:23]([CH3:28])[C:24](=[O:26])[CH3:25])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C)c1ccc2c(c1)nc(C(C)(C)C)n2CC1CCCCC1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Sodium hydride (201.5 mg, 5.04 mmol) was added to a solution of N-[2-tert-butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]acetamide (549.8 mg, 1.68 mmol) (for preparation see in Example 9) in THF (50 mL) at 0° C. Stirring for 30 min., iodomethane was added. The resulting mixture was stirred overnight at room temperature and quenched with saturated NaHCO3 aqueous solution (5 mL) and water (10 mL). Two phases were separated. The aqueous was extracted with EtOAc (3×20 mL). The combined organic phases were washed with saturated NaHCO3 aqueous solution (20 mL), saturated NaCl aqueous solution (20 mL) and dried over Na2SO4. After evaporation of the solvent, the residue was purified by MPLC (EtOAc as eluent on silica gel) to give the desired title compound as a white solid (580.5 mg, 100%). 1H NMR (400 MHz, CD3OD): δ 1.26 (m, 5H), 1.67 (m, 2H), 1.69 (s, 9H), 1.71 (m, 1H), 1.78 (m, 2H), 1.87 (s, 3H), 2.14 (m, 1H), 3.30 (s, 3H), 4.49 (d, J=7.62 Hz, 2H), 7.55 (d, J=8.40 Hz, 1H), 7.71 (s, 1H), 8.00 (d, J=8.40 Hz, 1H). MS (ESI) (M+H)+: 342.3. Anal. Calcd for C21H31N3O+1.30 TFA+0.80H2O (504.14): C, 56.23; H, 6.78; N, 8.33. Found: C, 56.21; H, 6.77; N, 8.17.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19]O)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CS([Cl:34])(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][Cl:34])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(CO)cs2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2nc(CCl)cs2)CC1
Reaction time: 8 h

Procedure:
To a solution of 4-(4-hydroxymethyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (848 mg, 2.83 mmol) and DIPEA (550 mg, 1.5 eq.) in CH2Cl2 (10 mL) was added MsCl (285 □L, 1.3 eq.) dropwise. The resulting mixture was stirred overnight. The reaction solution was then concentrated in vacuo. The crude product was purified on silica gel (EtOAc:hexanes=1:4) to afford the desired product as an oil.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>C(Cl)Cl>[C:3]1([CH:2]2[CH2:1][CH:11]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClCCl
Product: CCOC(=O)C1CC1c1ccccc1
Reaction time: 24 h

Procedure:
In Example 4, a flask was charged with 1.0 g of the catalyst described in Example 1, CH2Cl2 (2.5 mL), and styrene (2.5 mL). A solution of ethyl diazoacetate (0.23 g), CH2Cl2 (12.5 mL), and styrene (12.5 mL) was added slowly dropwise and the resulting mixture was stirred for 24 hours. The reaction product was analyzed by gas chromatography and the catalyst recovered by filtration. This process was repeated for a total of ten cycles during which yields of ethyl 2-phenylcyclopropane-carboxylate remained essentially constant at about 91%. The recovered catalyst was dried in vacuo. Duplicate elemental analyses gave copper contents of the recovered catalyst of 1.83 and 1.88%.
Reaction SMILES: B(O)(O)[C@H]1N(C([C@@H](N)C(C)C)=O)CCC1.CS(O)(=O)=O.[NH:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([NH2:25])=O.C(N(CC)CC)C.[Cl:36][CH2:37][C:38](Cl)=[O:39]>C(Cl)Cl>[Cl:36][CH2:37][C:38]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]#[N:25])=[O:39]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: O=C(Cl)CCl
Agent: CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#C[C@@H]1CCCN1C(=O)CCl
Temperature: 45 °C
Yield: 75.1 %

Procedure:
A 1000 mL double jacketed glass reactor equipped with a mechanical stirrer, a Pt-100 thermometer, a reflux condenser, a dropping funnel and a nitrogen inlet was charged with 50.0 g (483 mmol) of L-Prolinamide and 230 mL of methylenechloride. The suspension was stirred and treated with 51.2 g (504 mmol) of triethylamine and cooled to −40° C. to −50° C. and a solution of 58.0 g (508 mmol) of chloroacetylchloride in 50 mL of methylenechloride was added within 60 to 90 min. The dropping funnel was rinsed with 5 mL of methylenechloride. The suspension was warmed up to −5° C. to 0° C. within 1 h. The resulting (S)-1-(2-Chloro-acetyl)-pyrrolidine-2-carboxylic acid amide was dehydrated while adding the solution of the Vilsmeier-Reagent from the first reaction within 1 to 15 min at −5° C. to 5° C. The dropping funnel was rinsed with 5 mL of methylenechloride and the resulting mixture was stirred for about 1 h at −5° C. to 5° C. The reaction mixture was then poured onto 175 mL of water within 10 to 30 min and at a temperature of 5° C. to 20° C. The reactor was rinsed with 5 mL of methylenechloride. The mixture was stirred at RT for at least 30 min. The phases were separated and the aqueous phase was twice extracted with a total of 170 mL of methylenechloride. The organic phases were unified and washed with 88 mL of water. The resulting organic phase was concentrated under vacuum (500 mbar to 50 mbar) at 20° C. to 50° C. The resulting oil was treated within 10 to 30 min with 325 mL of isopropanol and heated to 45° C. Subsequently, the solution was again cooled to 25° C. to 30° C. within 20 min and inoculated where after the product started to precipitate. The suspension was stirred for 1 h at this temperature and then cooled down to −15° C. to −20° C. within 4 h. The crystallization was completed by the addition of 85 ml of n-heptane and the mixture was kept stirring for another 2 h. The precipitate was filtered with suction, the filter cake was washed with cold (−10° C. to 20° C.) n-heptane (140 mL) and dried to constant weight (50° C., 50 mbar, 3 h) to afford 62.6 g of (S)-1-(2-chloroacetyl)-pyrrolidine-2-carbonitrile. (Yield: 83%, assay: 100% (m/m) based on HPLC). The HPLC analysis was performed with an external standard of pure (S)-1-(2-chloroacetyl)-pyrrolidine-2-carbonitrile. Conditions for HPLC: Column Atlantis™ dC18 Waters, 3.9×150 mm, 3 μm, UV detection 205 nm, solutions for gradient: water (A), acetonitrile (B), pH 4.9 buffer KH2PO4 (C); flow 1.2 mL/min, 40° C.
Reaction SMILES: Cl[CH2:2][CH:3]([CH3:13])[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[K].[CH2:15]([O:17][C:18]([O:20][NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25])=[O:19])[CH3:16].CN(C)C=O>C(OCC)(=O)C.O>[CH2:24]([O:23][C:22]([N:21]([CH2:2][CH:3]([CH3:13])[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])[O:20][C:18]([O:17][CH2:15][CH3:16])=[O:19])=[O:26])[CH3:25]
Reactant: CCOC(=O)NOC(=O)OCC
Reactant: CCOP(=O)(CC(C)CCl)OCC
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)ON(CC(C)CP(=O)(OCC)OCC)C(=O)OCC
Reaction time: 3 h
Yield: 82 %

Procedure:
A mixture of diethyl 3-chloro-2-methylpropylphosphonate (22.8 g.), potassium salt of ethyl N-ethoxycarbonyloxycarbamate (21.5 g.) and dry N,N-dimethylformamide (114 ml.) was stirred at 80°-85° C. for 3 hours and then concentrated under reduced pressure to give an oily residue, to which was added a mixture of water (100 ml.) and ethyl acetate (100 ml.) The ethyl acetate layer was separated and the resultant aqueous layer was saturated with sodium chloride and extracted again with ethyl acetate (50 ml.). The combined ethyl acetate layer was washed with aqueous solution saturated with sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to give oily diethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-2-methylpropylphosphonate (30.2 g.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=1>C1COCC1>[Cl:17][C:16]1[C:11]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: Clc1cccnc1Cl
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cccnc1OC1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tetrahydro-2H-pyran-4-ol (1.03 g, 10.1 mmol) was added slowly over 1 min to a suspension of NaH (60% in mineral oil) (0.41 g, 10.16 mmol) in anhydrous THF (20 mL) at 5° C. (ice bath). The suspension was then warmed to room temperature. After 30 mins, 2,3-dichloropyridine (1.00 g, 6.76 mmol) was added, and the reaction heated at 70° C. for 18 hours. The reaction was cooled to room temperature and quenched with water (50 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organics were then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound as a yellow oil, which was taken onto the next step without further purification (1.40 g, 98%):
Reaction SMILES: [Cl-:1].[CH3:2][N:3]1[CH:7]=[CH:6][NH+:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:12]=2)=[O:10])[CH2:4]1>O.[Pd]>[Cl-:1].[OH:10][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:15][CH:16]=1)[CH2:8][NH+:5]1[CH:6]=[CH:7][N:3]([CH3:2])[CH2:4]1
Reactant: CN1C=C[NH+](CC(=O)c2ccc(NS(C)(=O)=O)cc2)C1
Agent: [Pd]
Agent: [Cl-]
Solvent: O
Product: CN1C=C[NH+](CC(O)c2ccc(NS(C)(=O)=O)cc2)C1

Procedure:
A solution of 152.3 g (0.463 mole) of 3-methyl-1[2-[4-((methylsulfonyl)amino)phenyl]-2-oxoethyl]-1H-imidazolium chloride in 1 L of distilled water and 7.62 g 10% Pd/C catalyst are placed in a 2 L Parr bottle and hydrogenated at 50 psi pressure for ca. 5 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:13]#[N:14])=[CH:10][NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:15]N1C(=O)CCC1=O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Cl:15][C:12]1[NH:11][CH:10]=[C:9]([C:13]#[N:14])[C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: N#Cc1c[nH]cc1-c1cccc(F)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c[nH]c(Cl)c1-c1cccc(F)c1
Reaction time: 24 h
Yield: 93.7 %

Procedure:
To a solution of 41.0 g (220 mmol) of 4-(3-fluorophenyl)-1H-pyrrole-3-carbonitrile in 400 ml of tetrahydrofuran are added portionwise 33.0 g (242 mmol) of N-chlorosuccinimide (CAS 128-09-6) and the mixture is then stirred for 24 hours at reflux. After cooling, 200 ml of water containing 5 g of sodium thiosulfate are added and, after stirring for 5 minutes, the reaction product is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 45.5 g of 5-chloro-4-(3-fluorophenyl)-1H-pyrrole-3-carbonitrile in the form of a whitish powder after triturating in 200 ml of dichloromethane, filtering off and drying.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][NH:8][NH2:9])=[CH:5][CH:4]=1.[CH2:12]([CH2:14][CH2:15][CH2:16][C:17](CC([O-])=O)=[O:18])[CH3:13]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][N:8]2[C:17](=[O:18])[CH2:16][C:15]([CH2:14][CH2:12][CH3:13])=[N:9]2)=[CH:5][CH:4]=1
Reactant: CCCCCC(=O)CC(=O)[O-]
Reactant: COc1ccc(CNN)cc1
Product: CCCC1=NN(Cc2ccc(OC)cc2)C(=O)C1

Procedure:
From the reaction of 4-methoxybenzylhydrazine and ethylbutyrylacetate, 2,4-dihydro-2-(4-methoxybenzyl)-5-propyl-3H-pyrazol-3-one is obtained. Subsequent reaction with 2-ethylaniline yields 4-(2-ethylanilinomethylene)-2,4-dihydro-2-(4-methoxybenzyl)-5-propyl-3H-pyrazol-3-one, oil
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]2[CH:22]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30](O)=[O:31])[CH:24]=1.C(N(CC)C(C)C)(C)C.[Cl-].[Na+].O.O>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH:21][C:30](=[O:31])[CH2:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)[CH:18]=[CH:17][N:16]2[CH:22]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(N)cc2n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(NC(=O)Cc3cccnc3)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.6 %

Procedure:
A solution of 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-7-ylamine (92 mg, 0.32 mmol) in DMF (0.2 mL) was added to a solution containing 3-pyridylacetic acid (39.5 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uranium tetrafluoroborate (101.7 mg, 0.32 mmol), N,N-diisopropyl ethyl amine (247 μL, 1.44 mmol) in DMF (0.3 mL) and the resulting mixture stirred at room temperature overnight and then heated at 110° C. for 6 h. The resulting mixture was then poured into a mixture of brine: water (1:1) and extracted with ethyl acetate. The combined organic layers were then washed with brine, dried over sodium sulphate and evaporated to leave a brown solid. Purification by chromatography (SiO2, dichloromethane:methanol=90:10) afforded the title compound (4.3 mg, 4%) which was obtained as a yellow oil. MS: m/e=410.1 [M+H]+.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.I[C:48]1[C:49]2[C:50](=[CH:54][N:55]([CH2:57][C:58]3[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=3)[N:56]=2)[N:51]=[CH:52][CH:53]=1.[CH3:66][C:67]1[C:68]([NH2:80])=[CH:69][C:70]([C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([CH3:79])[N:74]=2)=[N:71][CH:72]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C(O[Pd]OC(=O)C)(=O)C>[CH3:66][C:67]1[C:68]([NH:80][C:48]2[CH:53]=[CH:52][N:51]=[C:50]3[CH:49]=[N:56][N:55]([CH2:57][C:58]4[CH:59]=[CH:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=4)[C:54]=23)=[CH:69][C:70]([C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([CH3:79])[N:74]=2)=[N:71][CH:72]=1
Reactant: COc1ccc(Cn2cc3nccc(I)c3n2)cc1
Reactant: Cc1cccc(-c2cc(N)c(C)cn2)n1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2ncc3nccc(Nc4cc(-c5cccc(C)n5)ncc4C)c32)cc1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
(R)-BINAP (0.478 g, 0.767 mmol) and diacetoxypalladium (0.040 g, 0.178 mmol) were combined in toluene (8 mL) and stirred at 40° C. for 10 minutes. 7-Iodo-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridine (0.65 g, 1.780 mmol) suspended in toluene (5 mL), 5,6′-dimethyl-2,2′-bipyridin-4-amine (0.355 g, 1.780 mmol) and sodium 2-methylpropan-2-olate (0.257 g, 2.67 mmol) were added. Nitrogen was sparged into the solution for about 2 minutes, and the reaction was heated at 100° C. overnight. The reaction was then cooled to give a solution of N-(5,6′-dimethyl-2,2′-bipyridin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-7-amine which was used as is in the next step.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:29])[C:21]([O:26][CH2:27][CH3:28])([CH2:24][CH3:25])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:47])[C@@H:15]2[CH2:30][CH2:31][C@H:32]2[O:37][C:36](=[O:38])[CH2:35][C@H:34]([O:39][Si](C(C)(C)C)(C)C)[CH2:33]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:29])[C:21]([O:26][CH2:27][CH3:28])([CH2:22][CH3:23])[CH2:24][CH3:25])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:47])[C@@H:15]2[CH2:30][CH2:31][C@H:32]2[O:37][C:36](=[O:38])[CH2:35][C@H:34]([OH:39])[CH2:33]2)=[CH:10]1
Reactant: CCOC(CC)(CC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(CC)(CC)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 84.5 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 263 mg of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-(2-ethoxy-2-ethylbutyryloxy)-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 157, above] and 5.3 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 149 mg of the title compound as a colorless foam.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:16](I)=[C:17]([CH3:19])[N:18]=2)[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH2:21]([CH:23]([C:26]1[C:27]2[N:28]([CH:33]=[C:34]([CH3:36])[N:35]=2)[N:29]=[C:30]([CH3:32])[CH:31]=1)[CH2:24][CH3:25])[CH3:22]>>[CH2:21]([CH:23]([C:26]1[C:27]2[N:28]([C:33]([C:16]3[N:8]4[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]4=[N:18][C:17]=3[CH3:19])=[C:34]([CH3:36])[N:35]=2)[N:29]=[C:30]([CH3:32])[CH:31]=1)[CH2:24][CH3:25])[CH3:22]
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Reactant: CCC(CC)c1cc(C(F)(F)F)nn2c(I)c(C)nc12
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C(CC)CC)cc(C(F)(F)F)nn34)c(C)nc12
Yield: 51.4 %

Procedure:
Using a procedure analogous to Example 16B, 8-(1-ethyl-propyl)-3-iodo-2-methyl-6-trifluoromethyl-imidazo[1,2-b]pyridazine (0.15 g, 0.37 mmol) and 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.082 g, 0.37 mmol) give the title compound (0.096 g, 0.19 mmol, 53%). 1H NMR (CDCl3): δ 0.89-0.97 (m, 12H), 1.80-1.97 (m, 8H), 2.47 (bs, 6H), 2.54 (s, 3H), 3.35-3.45 (m, 1H), 3.47-3.55 (m, 1H), 6.73 (s, 1H), 7.10 (s, 1H). ES-MS (m/z): calcd for C26H33F3N6 (M+H)+: 487.6. found: 487.3.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH3:14])=[O:5].[F:22][CH2:23][C:24](Cl)=[O:25]>N1C=CC=CC=1>[F:22][CH2:23][C:24]([NH:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH3:14])=[O:5])=[O:25]
Reactant: Cc1ccc(F)cc1NC(=O)c1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)CF
Solvent: c1ccncc1
Product: Cc1ccc(F)cc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Yield: 95.7 %

Procedure:
4.5 g of N-(2-amino-5-nitrobenzoyl)-2-methyl-5-fluoroaniline, 1.85 g of pyridine and 2.26 g of fluoroacetyl chloride are treated in the same manner as described in Example 1-(1), whereby 5.2 g of N-(2-fluroacetamido-5-nitrobenzoyl)-2-methyl-5-fluoroaniline are obtained as colorless needles.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH2:16])[C:14](=[O:17])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+:2]=[N-:3].C(N)=O.C1N2CCN(CC2)C1.I.N1C=CC=CC=1.[C:36]([NH:55][C:56]1[S:57][CH:58]=[C:59]([C:61](=[N:65][O:66][CH2:67][CH2:68][S:69][CH:70]=[N:71][NH2:72])[C:62](O)=[O:63])[N:60]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.CN(C)C=O>[N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:62](=[O:63])[C:61]([C:59]3[N:60]=[C:56]([NH:55][C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[S:57][CH:58]=3)=[N:65][O:66][CH2:67][CH2:68][S:69][CH:70]=[N:71][NH2:72])[C:14](=[O:17])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: NN=CSCCON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CN2CCN1CC2
Agent: I
Solvent: ClC(Cl)Cl
Solvent: NC=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCSC=NN)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 45.6 %

Procedure:
A mixture of 255 mg of 3-azidomethyl-7-amino-ceph-3-eme-4-carboxylic acid and 3 ml of anhydrous formamide was stirred for 15 minutes and then 168 mg of triethylenediamine were added in fractions. 412 mg of pyridine hydroiodide were added to the resulting solution and after cooling the mixture to 15° C., 532 mg of 2-(2-tritylamino-4-thiazolyl)-2-(2-aminoiminomethylthioethoxyimino)-acetic acid, 207 mg of pyridine hydroiodide and 3 ml of dimethylformamide were added all at once to the mixture. 412 mg of dicyclohexylcarbodiimide were added to the mixture which was stirred at 15° C. for 20 minutes, at 20° C. for 40 minutes and was then vacuum filtered. 100 ml of water were added to the filtrate and the mixture was stirred for 30 minutes, let stand for 30 minutes and was then vacuum filtered. The recovered product was washed with water and dried to obtain 437 mg of raw product which was stirred with 8.6 ml of chloroform for 30 minutes. The mixture was vacuum filtered and the filtrate was treated with activated carbon and was vacuum filtered. The filtrate was evaporated to dryness to obtain 350 mg of internal salt of syn isomer of 3-azidomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(2-aminoiminomethylthioethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.FC(F)(F)S(O)(=O)=O.[O:18]1[CH2:23][CH2:22][CH:21]([CH2:24]O)[CH2:20][CH2:19]1.C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH2:24][CH:21]2[CH2:22][CH2:23][O:18][CH2:19][CH2:20]2)[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(F)c1
Reactant: OCC1CCOCC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1cc(COCC2CCOCC2)ccn1
Reaction time: 1 h
Yield: 24.8 %

Procedure:
To a mixture of (2-fluoropyridin-4-yl)methanol (300 mg), triethylamine (239 mg), and dichloromethane (24 mL) was added anhydrous trifluoromethanesulfonic acid (666 mg) under ice-cooling, followed by stirring at the same temperature for 1 hour. (Tetrahydro-2H-pyran-4-yl)methanol (1.37 g) was added to the reaction liquid at room temperature, followed by stirring at the same temperature for 8 hours. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, followed by extraction with chloroform (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=8/1) to obtain 2-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethoxy)methyl]pyridine (132 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8](Cl)[N:7]=[CH:6][N:5]=1)([OH:3])=[O:2].[CH3:11][NH:12][CH3:13]>>[C:1]([C:4]1[CH:9]=[C:8]([N:12]([CH3:13])[CH3:11])[N:7]=[CH:6][N:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1cc(Cl)ncn1
Reactant: CNC
Product: CN(C)c1cc(C(=O)O)ncn1
Reaction time: 72 h

Procedure:
A 40% aqueous dimethylamine solution (2000 cc) is added to 4-carboxy-6-chloropyrimidine (93.6 g). The mixture is allowed to stand for 3 days and then concentrated to dryness under reduced pressure. The residue is dissolved in water (300 cc). The solution is made alkaline by the addition of sodium bicarbonate powder to a pH of 8 to 9. The solution is then extracted with diisopropyl ether (1000 cc). The aqueous phase is acidified with 12N hydrochloric acid to a pH of 2 to 3. The precipitate is filtered off, washed with ice-water (30 cc) and then with isopropanol (120 cc). 4-Carboxy-6-dimethylaminopyrimidine (73.6 g), melting at 250° C, is obtained.