Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14](B(O)O)=[CH:15][CH:16]=2)[C:11]([CH3:21])=[CH:10][C:9]1([CH3:23])[CH3:22])=O)(C)(C)C.Br[C:25]1[C:26]([CH3:33])=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29]>>[C:28]([C:27]1[C:26]([CH3:33])=[C:25]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[NH:8][C:9]([CH3:22])([CH3:23])[CH:10]=[C:11]3[CH3:21])[CH:32]=[CH:31][CH:30]=1)#[N:29]
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(B(O)O)cc21
Reactant: Cc1c(Br)cccc1C#N
Product: CC1=CC(C)(C)Nc2ccc(-c3cccc(C#N)c3C)cc21
Yield: 20.2 %

Procedure:
This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (56.5 mg, 0.18 mmol) and 3-bromo-2-methylbenzonitrile (34.8 mg, 0.18 mmol). The crude material was purified by flash column chromatography (50 ml silica, hexane to 20% acetone/hexane) followed by a second flash column chromatography (75 mL silica, hexane to 20% acetone/hexane to afford 10.5 mg (20%) of Compound 278. Data for Compound 278: 1H NMR (400 MHz, acetone-d6) 7.59 (dd, J=7.7, 0.9, 1 H), 7.48 (dd, J=7.8, 0.8, 1 H), 7.36 (t, J=15.3, 7.7, 1 H), 6.99 (d, J=1.8, 1 H), 6.91 (dd, J=8.1, 1.9, 1 H), 6.58 (d, J=8.1, 1 H), 5.37 (s, 1 H), 5.30 (s, 1 H), 2.48 (s, 3 H), 1.97 (s, 3 H), 1.30 (s, 6 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]2[C:21]([CH:22]=[O:23])=[C:20]([OH:24])[CH:19]=[CH:18][C:10]=2[S:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].S(C1C=CC(C)=CC=1)(O[CH2:29][C@@H:30]1[O:32][CH2:31]1)(=O)=O.O>CN(C)C=O>[Cl:7][C:8]1[C:9]2[C:21]([CH:22]=[O:23])=[C:20]([O:24][CH2:29][C@@H:30]3[O:32][CH2:31]3)[CH:19]=[CH:18][C:10]=2[S:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1sc2ccc(O)c(C=O)c2c1Cl
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2ccc(OC[C@H]3CO3)c(C=O)c2c1Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
Potassium carbonate (2.62 g) was added to a stirred solution of ethyl 3-chloro-4-formyl-5-hydroxybenzo[b]thiophene-2-carboxylate (4.90 g, prepared as described above) in dry dimethylformamide (50 ml) and then a solution of (R)-glycidyl tosylate (4.12 g) in dry dimethyl formamide (50 ml) was added slowly. The mixture was then stirred at 60° C. for 3 hours, cooled and poured into water (1200 ml). The resulting pale-green solid was collected by filtration, washed with water (200 ml) and dried to give ethyl (R)-3-chloro-5-(2,3-epoxypropoxy)-4-formylbenzo[b]thiophene-2-carboxylate (5.15 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Br:20][C:21]1[CH:22]=[C:23]([C:27]2([NH2:30])[CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Br:20][C:21]1[CH:22]=[C:23]([C:27]2([NH:30][C:17]([C:16]3[C:11]4[CH:10]=[N:9][N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[C:12]=4[CH:13]=[N:14][CH:15]=3)=[O:19])[CH2:28][CH2:29]2)[CH:24]=[CH:25][CH:26]=1
Reactant: NC1(c2cccc(Br)c2)CC1
Reactant: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1(c2cccc(Br)c2)CC1)c1cncc2c1cnn2-c1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a solution of 1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (0.500 g, 1.94 mmol), 1-(3-bromophenyl)cyclopropanamine (453 mg, 2.14 mmol) and N,N-diisopropylethylamine (1.73 mL, 9.72 mmol) in DMF (18 mL) is added TBTU (0.780 g, 2.43 mmol). After 2 hours, the mixture is concentrated in vacuo, dissolved in ethyl acetate (200 mL), and washed with 2N sodium hydroxide (3×100 mL), saturated aqueous ammonium chloride (2×100 mL), saturated aqueous sodium bicarbonate (100 mL), brine (100 mL). The organic layer is dried over MgSO4, filtered through a pad of silica gel eluting with ethyl acetate (3×100 mL), and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with a gradient of 50-70% ethyl acetate in heptane to give a solid that is triturated with methylene chloride to afford the title compound as a solid.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:15]=[C:11]([C:12]([OH:14])=[O:13])[C:10]([OH:16])=[CH:9][CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].CC1C=C(C(C)(C)C)[C:21]([OH:28])=[C:20](C(C)(C)C)C=1.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.Cl>C(O)(=O)C>[C:21]([C:10]1([OH:16])[CH:9]=[CH:8][C:7]([NH:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:15][CH:11]1[C:12]([OH:14])=[O:13])(=[O:28])[CH3:20]
Reactant: C=C(C)C(=O)Nc1ccc(O)c(C(=O)O)c1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C=C(C)C(=O)NC1=CC(C(=O)O)C(O)(C(C)=O)C=C1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
5-methacrylamidosalicylic acid (30 millimole, 6.7 g) was mixed with butylhydroxytoluene (20 mg), acetic anhydride (10.0 g), and acetic acid (15.0 g). After sealing the solution, its temperatures was raised to 60° C., and the solution was kept at 60° C. for 30 min while stirring. Then, a mixture (1.0 g) of concentrated sulfuric acid (1 part) with hydrochloric acid (10 parts) was added to the solution, followed by raising its temperature to 90° C., and kept at 90° C. for one hour to proceed the reaction. After the reaction was over, the solution was stood to cool to room temperature to give brown crystal. The crystal was filtrated, and recrystallized by a solution of 0.5% hydroquinone in methanol. Dried under a reduced pressure, 2-acetyl-5-methacrylamidosalicylic acid was obtained as pale reddish brown crystal having a needle shape: mp. 192.4° C., yield 2.54 g, 64.1%.
Reaction SMILES: [CH3:1][O:2][P:3](=[S:7])([O:5][CH3:6])[SH:4].[C:8]([O:17][CH2:18][CH3:19])(=[O:16])/[CH:9]=[CH:10]\[C:11]([O:13][CH2:14][CH3:15])=[O:12].C1(C=CC(O)=CC=1)O>>[CH3:19][CH2:18][O:17][C:8]([CH2:9][CH:10]([S:7][P:3]([O:5][CH3:6])([O:2][CH3:1])=[S:4])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16]
Reactant: COP(=S)(S)OC
Reactant: CCOC(=O)/C=C\C(=O)OCC
Agent: Oc1ccc(O)cc1
Product: CCOC(=O)CC(SP(=S)(OC)OC)C(=O)OCC
Temperature: 25 °C

Procedure:
The solution of dimethyl dithiophosphoric acid was added to diethyl maleate (the ratio of dimethyl dithiophosphoric acid to diethyl maleate was approximately 1-1.25 kg: 1.2 kg). Hydroquinone (approximately 3 grams) was added to the mixture. The reaction mixture which contains two separate solutions, an organic solution of diethyl maleate and an aqueous solution of dimethyl dithiophosphoric acid, was mixed for about 8 hours at 53° C. under a nitrogen atmosphere. After mixing, the reaction was cooled to ambient temperature and the organic and aqueous solutions were separated. The organic or diethyl maleate solutions which contained malathion was washed two (2) times with water (approximately 1 liter each time). The organic and aqueous solutions were separated and the malathion in the solution of diethyl maleate retained. This reaction yielded approximately 1.5-1.9 kg of malathion.
Reaction SMILES: FC1C=CC=C(F)C=1C(Cl)=O.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1.C1(C)C=CC=CC=1>C(O)C>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[CH:41][CH:42]=1)=[S:24])=[O:21]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1c(F)cccc1F
Agent: O=C(N=C=S)c1c(F)cccc1F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4c(F)cccc4F)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
2,6-Difluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,6-difluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,6-Difluoro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (62 mg, yield 74%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:27]2[CH2:28][CH2:29][CH2:30][C@@H:26]2[CH3:25])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CCCN1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C[C@H]1CCCN1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 39.7 %

Procedure:
A solution of 4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid tert-butyl ester (8.1 g, 22.8 mmol), (S)-(+)-2-methylpyrrolidine (2.33 g, 27.36 mmol), K2CO3 (6.93 g, 50.16 mmol) in acetonitrile (76 mL) was heated to 80° C. for 20 h and then added additional (S)-(+)-2-methylpyrrolidine (834 mg, 9.79 mmol), and the temperature of the reaction mixture was maintained at 80° C. for 20 h. The heating was removed and the solution was concentrated to provide a residue which was taken up with H2O (100 mL) and extracted with CH2Cl2 (2×100 mL). The organic layers were dried over K2CO3, filtered and concentrated to provide a crude oil which was purified by flash column chromatography (0 to 5% MeOH/CH2Cl2) to provide 2.43 g (40% yield) of the title compound as a solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][NH2:11]>O>[CH3:10][NH:11][CH2:8][C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1
Reactant: CN
Reactant: ClCc1ccncc1
Agent: Cl
Solvent: O
Product: CNCc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
To 4-picolyl chloride, hydrochloride (10 g, 0.06 mol) was added methylamine (50 mL of 40% aqueous solution, 0.58 mol), and the resulting purple solution was stirred at rt for 30 min, then poured into H2O. The mixture was extracted with CH2Cl2 (6×), and the combined organic extracts were evaporated. The residue was filtered under reduced pressure through a silica gel column, eluting with a solvent gradient of 0-10% MeOH/CHCl3 to provide the title compound as a light yellow oil (4.8 g, 66%): 1H NMR (CDCl3): d 8.50 (dd, 2H); 7.20 (dd, 2H); 3.70 (s, 2H); 2.40 (s, 3H); 1.70 (br, 1H).
Reaction SMILES: C([O:8][C:9](=[O:42])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:41])[NH:29][C:30]4[CH:38]=[C:37]5[C:33]([CH:34]=[CH:35][N:36]5[CH2:39][CH3:40])=[CH:32][CH:31]=4)=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.CCO.[H][H]>[Pd].CCOC(C)=O>[CH2:39]([N:36]1[C:37]2[C:33](=[CH:32][CH:31]=[C:30]([NH:29][C:28]([C:25]3[CH:26]=[CH:27][C:22]([N:19]4[CH2:18][CH2:17][N:16]([C:13]5[CH:12]=[CH:11][C:10]([C:9]([OH:42])=[O:8])=[CH:15][CH:14]=5)[CH2:21][CH2:20]4)=[N:23][CH:24]=3)=[O:41])[CH:38]=2)[CH:34]=[CH:35]1)[CH3:40]
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(N4CCN(c5ccc(C(=O)OCc6ccccc6)cc5)CC4)nc3)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCN(c5ccc(C(=O)O)cc5)CC4)nc3)cc21
Yield: 96 %

Procedure:
A mixture of 4-{4-[5-(1-ethyl-1H-indol-6-ylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid benzyl ester (100 mg, 0.18 mmol), 10% Pd/C (50 mg) in a 1:1 mixture of EtOH and EtOAc (50 mL) was hydrogenated under 1 atm of hydrogen for 2 h. The mixture was then filtered. The solids were washed with a 1:1 mixture of THF and DMF and the combined organic layer was concentrated. The residue was passed through a silica gel plug with DMF to afford the product (85 mg; Yield: 96%). HRMS m/z calcd for C27H27N5O3I [M+H]+: 470.2187. Found: 470.2184.
Reaction SMILES: [C:1]1([OH:9])[C:2]([CH3:8])=[CH:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[CH:10]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:8][C:2]1[C:1]([OH:9])=[C:6]([C:16]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:17])[CH:5]=[C:4]([CH3:7])[CH:3]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Cc1ccc(O)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C)c(O)c(C(=O)C2CCCCC2)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
A mixture of 194 g of 2,4-xylenol and 233 g of cyclohexylcarbonyl chloride was stirred at 110° C. for 1 hour and then thereto was gradually added 318 g of anhydrous aluminum chloride, followed by stirring for further 1 hour at 110° C. The reaction mixture was added to 2 liters of ice water and the organic layer was extracted with 2 liters of chloroform. The extract was washed successively with water and then with a saturated aqueous sodium chloride solution and thereafter dried with anhydrous magnesium sulfate. The chloroform was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: n-hexane) to obtain 256.2 g of cyclohexyl 3,5-dimethyl-2-hydroxyphenyl ketone. Brown oily substance.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][SH:13].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][OH:20]>CN(C)C=O>[CH2:12]([S:13][CH2:17][CH2:18][CH2:19][OH:20])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: OCCCBr
Reactant: CCCCCCCCCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCSCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
Dodecylthiol (5 g) was dissolved in 50 ml of dry N,N-dimethylformamide and 1 g of 60% sodium hydride was added thereto under ice-cooling. The mixture was stirred at room temperature for 1 hour. Further, a solution of 3.45 g of 3-bromopropanol in 10 ml of dry N,N-dimethylformamide was dropwise added thereto under ice-cooling and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice, extracted with ether and washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution. The ether layer was dehydrated and concentrated. The resultant mixture was purified by silica gel column chromatography using hexane-ethyl acetate (10:1→3:1) as an eluent to give 6.071 g of 3-dodecylthiopropanol as a colorless powder.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[N:7][C:8]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])=[CH:9][CH:10]=1)=[N+]=[N-].[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[N:26]=[C:27]=S>C1COCC1.CCOC(C)=O>[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[NH:26][C:27]1[N:6]2[N:7]=[C:8]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[F:18])[CH:9]=[CH:10][C:5]2=[CH:4][N:1]=1
Reactant: S=C=Nc1cnccc1Cl
Reactant: [N-]=[N+]=NCc1ccc(-c2c(F)cccc2F)nn1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cccc(F)c1-c1ccc2cnc(Nc3cnccc3Cl)n2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.9 %

Procedure:
N-(4-chloro-3-pyridinyl)-2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-amine PMe3 (0.62 mL of 1.0 M solution in THF, 0.62 mmol) was added dropwise to a solution of 3-(azidomethyl)-6-(2,6-difluorophenyl)pyridazine (Preparation I, 140 mg, 0.57 mmol) in THF (2.5 mL) at RT. The reaction turned purple and an evolution of gas was observed. It was stirred for 15 min at RT. A solution of 4-chloro-3-isothiocyanatopyridine (Preparation XXIV, 106 mg, 0.62 mmol) in THF (1 mL) was added. After 15 min at RT, the reaction was diluted with EtOAc (50 mL) and washed with H2O (10 mL). The aqueous phase was extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine (15 mL), dried over anh. Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-3% MeOH in CH2Cl2) to provide N-(4-chloro-3-pyridinyl)-2-(2,6-difluorophenyl)-imidazo[1,5-b]pyridazin-7-amine (110 mg, 54% yield) as an orange crystalline solid. MS (ESI, pos. ion) m/z: 350.8 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 9.90 (s, 1 H), 8.17 (d, J=5.09 Hz, 1 H), 7.79 (d, J=9.59 Hz, 1 H), 7.64 (s, 1 H), 7.40-7.51 (m, 1 H), 7.37 (s, 1 H), 7.32 (d, J=5.09 Hz, 1 H), 7.07 (m, 2 H), 6.57 (dt, J=9.44, 1.64 Hz, 1 H).
Reaction SMILES: [C:1]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH3:4])=[O:2].O=[C:26]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:27][C:28]([O:30][CH3:31])=[O:29]>C1(C)C=CC=CC=1>[CH3:31][O:30][C:28](=[O:29])[CH2:27][C:26](=[CH:5][C:1]([O:3][CH3:4])=[O:2])[CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CC(=O)CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C=C(CC(=O)OC)CC(=O)OC
Temperature: 120 °C

Procedure:
Carbomethoxymethylenetriphenylphosphorane (167 g, 0.5 mol) in toluene (600 ml) was treated with dimethyl 3-oxoglutarate (87 g, 0.5 mol) and the reaction heated to 100° C. on an oil bath at 120° C. under an atmosphere of nitrogen for 36 h. The reaction was then concentrated in vacuo and the oily residue triturated with 40/60 petrol ether/diethylether 1:1, 600 ml. Triphenylphosphine oxide precipitated out and the supernatant liquid was decanted/filtered off. The residue on evaporation in vacuo was Kugelrohr distilled under high vacuum Bpt (oven temperature 180-200° C. at 0.2 torr) to give 3(methoxycarbonylmethylene)glutaric acid dimethylester in 89.08 g, 267 mM, 53%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[N:14]=[C:15]([NH:18][C:19](=[O:22])[CH2:20][Cl:21])[S:16][CH:17]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[C:29]1([CH:35]([O:42][C:43]([C:45]2[N:50]3[C:51](=[O:54])[C@@H:52]([NH2:53])[C@H:49]3[S:48][CH2:47][C:46]=2[CH:55]([S:57][C:58]2[NH:62][N:61]=[N:60][N:59]=2)[CH3:56])=[O:44])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1C=CC=CC=1>C(Cl)Cl>[C:29]1([CH:35]([O:42][C:43]([C:45]2[N:50]3[C:51](=[O:54])[C@@H:52]([NH:53][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:13]4[N:14]=[C:15]([NH:18][C:19](=[O:22])[CH2:20][Cl:21])[S:16][CH:17]=4)[C@H:49]3[S:48][CH2:47][C:46]=2[CH:55]([S:57][C:58]2[NH:62][N:61]=[N:60][N:59]=2)[CH3:56])=[O:44])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1csc(NC(=O)CCl)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(NC(=O)OC(C)(C)C)c3csc(NC(=O)CCl)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To a suspension of 349 mg of α-t-butyloxycarbonylamino-α-[2-(chloroacetamido)thiazol-4-yl]acetic acid in 5 ml of methylene chloride is added 249 mg of phosphorous pentachloride, and the mixture is stirred at room temperature. The mixture is added dropwise under stirring to the solution of 494 mg of 7β-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester dissolved in 5 ml of methylene chloride, followed by the addition of 474 mg of pyridine. After that, the stirring is continued for further 1 hour at room temperature. The reaction solution is washed with 0.5N hydrochloric acid and then with water, and dried. The oily product obtained by the distillation of the solvent is purified by a column chromatography packed with silica gel. The procedure gives 513 mg of 7β-{α-t-butyloxycarbonylamino-α-[2-(chloroacetamido)thiazol-4-yl]acetamido}-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[N:10]O)=[CH:4][CH:3]=1.C(C1N=[C:17]([C:27]2[C:28]([O:34][CH3:35])=[N:29][CH:30]=[CH:31][C:32]=2[I:33])[N:18]([OH:26])C=1C1C=CC=CC=1)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:18]([OH:26])[C:17]([C:27]3[C:28]([O:34][CH3:35])=[N:29][CH:30]=[CH:31][C:32]=3[I:33])=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(C=NO)c1ccc(Br)cc1
Reactant: CCc1nc(-c2c(I)ccnc2OC)n(O)c1-c1ccccc1
Product: COc1nccc(I)c1-c1ncc(-c2ccc(Br)cc2)n1O
Yield: 18 %

Procedure:
(4-Bromo-phenyl)-oxo-acetaldehyde oxime (0.242 g, 1.06 mmol) was reacted as described for the synthesis of 4-ethyl-2-(4-iodo-2-methoxy-pyridin-3-yl)-5-phenyl-imidazol-1-ol and gave the title material (0.090 g, 18%). LCMS (+ESI, M+H+) m/z 472, 474.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]2[O:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl[C:22]([O:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]>>[CH:25]1([O:24][C:22]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH2:11][C:12]3[O:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=3)=[CH:4][CH:3]=2)=[O:23])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)c1ccc(Cn2ccc3ccc(N)cc32)o1
Reactant: O=C(Cl)OC1CCCC1
Product: COC(=O)c1ccc(Cn2ccc3ccc(NC(=O)OC4CCCC4)cc32)o1
Yield: 53 %

Procedure:
Using a similar procedure to that described in Ex. 22, but starting from methyl 5-(6-aminoindol-1-ylmethyl)furan-2-carboxylate and cyclopentyl chloroformate, there was obtained methyl 5-[6-(cyclopentyloxycarbonyl)aminoindol-1-ylmethyl]furan-2-carboxylate in 53% yield, as an off-white solid; partial NMR: 1.5-2.0 [br m, 8H, (CH2)4 ], 6.2 (d, 1H, CH.CH=C), 6.6 (br.s, 1H,NH).
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N(C(C)C)C(C)C.[Si:29]([C:33]#[CH:34])([CH3:32])([CH3:31])[CH3:30]>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:5]1[C:4]([F:20])=[C:3]([F:21])[C:2]([C:34]#[C:33][Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)c1cc(C#C[Si](C)(C)C)c(F)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
To an oven dried flask charged with a solution of methyl 5-bromo-2-(2-fluorophenylamino)-3,4-difluorobenzoate (21.68 mmol, 8.1 g) in THF (116 ml), was added CuI (2.16 mmol, 0.4 g) and iPr2NH (43.36 mmol, 6.1 ml). After addition is completed, reaction was purged with Argon and Pd(PPh3)2Cl2 (3.73 mmol, 2.62 g) and TMS-acetylene (26.88 mmol, 3.7 ml) are added. The reaction mixture was stirred at room temperature for 16 h, concentrated and taken up in EtOAc. The organic fraction was washed with sat NH4Cl, brine, dried over MgSO4 and conc. The crude was purified by flash chromatography using 5% to 20% EtOAc in Hexane to afford the desired product 6.96 g (85%).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:16][C:15]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([O:24]CC[Si](C)(C)C)[N:19]=3)=[C:14]([C:31]([NH2:33])=[O:32])[CH:13]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:16][C:15]([NH:17][C:18]3[CH:23]=[CH:22][NH:21][C:20](=[O:24])[N:19]=3)=[C:14]([C:31]([NH2:33])=[O:32])[CH:13]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2]
Reactant: CC(C)(C#N)c1ccc(-c2cc(C(N)=O)c(Nc3ccnc(OCC[Si](C)(C)C)n3)s2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(-c2cc(C(N)=O)c(Nc3cc[nH]c(=O)n3)s2)cc1

Procedure:
5-[4-(1-Cyano-1-methylethyl)phenyl]-2-({2-[2-(trimethylsilyl)ethoxy]pyrimidin-4-yl}amino)thiophene-3-carboxamide (107 mg, 0.223 mmol) was stirred in a mixture of DCM (5 mL) and TFA (2 mL) at room temperature for 30 minutes. Saturated NaHCO3 was added and the resulting precipitate collected by filtration and washed with water and DCM to give the title compound as a yellow solid.