Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([N:26]2[CH:30]=[N:29][N:28]=[CH:27]2)[C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(O)C.C(OCC)(=O)C>C1COCC1.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([N:26]2[CH:27]=[N:28][N:29]=[CH:30]2)[C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(N(CCc2ccc(OCc3ccccc3)cc2)n2cnnc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(CCc2ccc(O)cc2)n2cnnc2)cc1
Reaction time: 72 h

Procedure:
To a stirred solution of 4-{[2-(4-benzyloxyphenyl)ethyl]-[1,2,4]triazol-4-yl-amino}benzonitrile (536 mg, 1.355 mmol) in distilled THF (15 mL) was added in succession absolute ethanol (30 mL) and Pd/C (10%, 54 mg). The black suspension was then stirred under an atmosphere of hydrogen (balloon) for 3 days. Upon removal by filtration and washings of the supported catalyst exhaustively with distilled THF, the filtrate was evaporated to give a pale yellow syrup which solidified upon standing at room temperature to a light yellow wax (192 mg). This crude was fractionated by flash chromatography (ethyl acetate) and the second fraction that separated gave 4-{[2-(4-hydroxyphenyl)ethyl]-[1,2,4]triazol-4-yl-amino}benzonitrile as a pale yellow waxy residue (115 mg, 376.6 μmol, 28%); Rf 0.46 (neat ethyl acetate), c.f. 0.59 (S.M.); δH (400 MHz, DMSO-d6) 2.70 (2H, t, J 7.4 Hz, CH2CH2N); 4.01 (2H, t, J˜7.6 Hz, CH2N), 6.59 (2H, AA′BB′), 6.69 (2H, AA′BB′), 7.06 (2H, AA′BB′), 7.71 (2H, AA′BB′), 8.78 (2H, s, C3′-H and C5′-H) and 9.29 (1H, s, exchanged with D2O, OH); LRMS (FAB+): 611.2[12, (2M+H)+], 459.1[8, (M+H+NBA)+], 306.0[100, (M+H)+]; (FAB−): 763.5[18, (2M+NBA)−], 609.4[45, (2M−H)−], 184.0[100, (HOPhCH2CH2)−]; HRMS (FAB+) 306.13477 C17H16N5O requires 306.13549.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][C:7]1=O.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.CO.C#N.[Na]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH:7]1[N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNC1
Reactant: COc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(=O)CC2
Agent: C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N1CCCC1)CC2
Yield: 25 %

Procedure:
1-(3,4-Dichlorobenzyl)-7-methoxy-3,4-dihydronaphthalen-2(1H)-one (5.5 g, 16.4 mmol, example 1), pyrrolidine (1.40 g, 19.7 mmol), and p-toluenesulfonic acid monohydrate (31.0 mg, 0.164 mmol) were dissolved in toluene (100 ml) and refluxed for 2 h using a DeanStark condenser. The solvent was removed and after addition of MeOH (50 ml) and sodium cyanohydride (1.57 g, 24.6 mmol) the mixture was stirred for 4d at room temperature under nitrogen. Water was added, the organic phase separated and the aqueous phase extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl solution, dried over MgSO4, and concentrated to afford a residue that was purified by flash chromatography (silica gel, MeOH/CH2Cl23:97→5:95). The beige solid product (1.6 g, 25%) was obtained from precipitation in ethyl acetate/diisopropylether (1:1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[OH:34])[N:17]=2)[CH2:12]1.Cl[C:36]([O:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:37].ClC([O-])=O>C1COCC1>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:34])[C:27]=1[C:18]1[N:17]=[C:16]([N:13]2[CH2:14][CH2:15][C@@H:11]([NH:10][C:36](=[O:37])[O:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:12]2)[C:25]2[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=2)[N:19]=1
Reactant: CC(C)(C)COC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3c(O)cccc3F)nc2c1
Agent: O=C([O-])Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OCC(C)(C)C)C3)nc(-c3c(O)cccc3F)nc2c1
Temperature: -60 °C
Yield: 95.1 %

Procedure:
At RT, diisopropyl ethylamine (273 μL, 1.57 mmol) was added to a solution of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (266 mg, 0.79 mmol) in THF (15 mL), and the reaction was cooled to −60° C. Neopentyl chloroformate (116 μL in 2.0 μL THF, 0.79 mmol) was added dropwise over a period of 10 minutes. After addition of the chloroformate was complete, the reaction mixture was warmed to RT, quenched with H2O, and extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified via silica gel chromatography using 0-10% EtOAc in a 1:1 mixture of hexanes and CH2Cl2 to give (R)-neopentyl 1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 11) (340 mg, 94%). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.64-7.58 (m, 3H), 7.47 (q, J=7.8 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 6.87 (t, J=9.2 Hz, 1H), 4.28-3.99 (m, 5H), 3.71-3.64 (m, 2H), 2.56 (s, 3H), 2.23-2.14 (m, 1H), 2.07-1.92 (m, 1H), 0.89 (s, 9H) ppm. LC/MS: m/z 453.5 (M+H)+ at 2.66 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8].[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[NH:13][C:12]2=[O:18])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)c(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.2 %

Procedure:
To a solution of 4-(3-chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (65.4 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (89 mg, 72%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=O)[C:5]1=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](OC)[C:16]=1[N+:23]([O-])=O)(=[O:3])[CH3:2].[CH3:26][OH:27]>[Pd]>[CH3:26][O:27][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6]1[N:23]=[C:16]3[C:15](=[CH:14][C:5]=1[N:4]2[C:1](=[O:3])[CH3:2])[CH:20]=[CH:19][CH:18]=[CH:17]3
Reactant: CO
Reactant: COc1cccc(C=C2C(=O)c3ccccc3N2C(C)=O)c1[N+](=O)[O-]
Agent: [Pd]
Product: COc1cccc2c1c1nc3ccccc3cc1n2C(C)=O
Reaction time: 3 h
Yield: 53 %

Procedure:
A suspension of 1-acetyl-2-(3-methoxy-2-nitrophenylmethylene)-3-oxo-2,3-dihydroindole from Example 35 (460 mg, 1.36 mmol), 10% Pd/C (70 mg) and MeOH (17 mL) was stirred under H2 at atmospheric pressure (balloon) for 3 hours. Additional Pd/C (70 mg) was added, a fresh balloon of H2 was attached and the mixture was stirred at room temperature overnight. The Pd/C catalyst was filtered over celite and the filtrate was evaporated. The resulting crude yellow product (209 mg, >100%) was purified by LPLC, eluting with CH2Cl2, then CH2Cl2 /EtOAc (3:97), to obtain 208 mg (53%) of the title compound as a colorless solid, Rf 0.47 (hexane-EtOAc 1:1), mp 125.1-125.8° C.; 1H NMR (CDCl3) δ 9.02 (s, 1H), 8.62 (dd, J=7.6; J=0.8 1H), 8.13 (d, J=8.4, 1H), 7.65 (dt, J=8.0; J=0.8, 1H), 7.59 (d, J=8.4, 1H), 7.53 (m, 2H), 7.11 (d, J=7.6, 1H), 4.18 (s, 3H), 2.97 (s, 3H); 13C NMR (CDCl3) δ 169.8, 155.2, 146.5, 141.4, 138.1, 131.9, 130.5, 128.6, 126.3, 124.3, 124.2, 122.7, 121.6, 120.5, 115.6, 106.7, 56.2, 27.7; MS (EI, m/z) 290 (M+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14](=[O:16])(=[O:15])[N:13](C(C)(C)C)[C:12](=[O:21])[CH:11]=2)=[CH:6][CH:5]=1.C([SiH](C(C)C)C(C)C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14](=[O:16])(=[O:15])[NH:13][C:12](=[O:21])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)N1C(=O)C=C(c2ccc(CCN)cc2)S1(=O)=O
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(C2=CC(=O)NS2(=O)=O)cc1
Temperature: 25 °C
Yield: 60 %

Procedure:
23-E (262 mg, 0.850 mmol) was dissolved in trifluoroacetic acid (10 mL) and triisopropylsilane (1 mL) was added. The reaction was heated to reflux under an atmosphere of nitrogen overnight. The reaction was cooled to room temperature then concentrated via rotovap. The reaction material was chromatographed on a 50 mm Luna C18 column using a 0–30% acetonitrile in water gradient with 0.05% trifluoroacetic acid at 30 mL per minute over a 20 minute period. The major fraction was lyophilized to give a white powder (0.128 g, 60%). 1H NMR (500 MHz, CD3OD): δ 7.89 (d, J=9.0 Hz, 2H), 7.51 (d, J=9.0 Hz, 2H), 7.06 (s, 1H), 3.25 (t, J=7.2 Hz, 2H), 3.06 (t, J=7.2 Hz, 2H); LCMS found for C11H13N2O3S (M+H)+: m/z=253.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21].[NH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[C:28]([NH:30][CH2:31][CH2:32][O:33][CH3:34])=O.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:22][CH2:23][CH2:24][C:25]2[CH:37]=[CH:36][CH:35]=[C:27]([CH2:28][NH:30][CH2:31][CH2:32][O:33][CH3:34])[CH:26]=2)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21]
Reactant: COCCNC(=O)c1cccc(CCN)c1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCCNCc1cccc(CCNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)c1
Temperature: 25 °C
Reaction time: 56 h

Procedure:
Benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (400 mg, 1.22 mmol) [see preparation 17] was added to a solution of 3-(2-aminoethyl)N-(2-methoxyethyl)benzamide (260 mg, 1.25 mmol) (see preparation 41] and triethylamine (0.34 ml, 2.4 mmol) in ethyl acetate (5 ml). The reaction mixture was heated to reflux for 4 hrs, after which time the mixture was cooled to room temperature and stirred for a further 56 hrs, the mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was washed with water (2×20 ml), brine (20 ml) and dried over MgSO4 the solvent was evaporated under reduced pressure. The crude product was purified by trituration with diethyl ether to afford the title compound, 365 mg, (60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[O:5][CH2:6][CH2:7][NH2:8]
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cc(Cl)cc(Cl)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cl
Product: NCCOc1cc(Cl)cc(Cl)c1
Yield: 43.2 %

Procedure:
A mixture of 105.5 g (0.31 mole) of 2-[2-(3,5-dichlorophenoxy)ethyl]-1H-isoindole-1,3-(2H)-dione and 24.5 g (0.41 mole) 85% hydrazine hydrate in 1 liter of 95% ethanol was heated at reflux for 4 hr. A white solid was filtered off and discarded. The filtrate was stripped to dryness and the residue partitioned between water and chloroform. The chloroform layer was washed with aqueous 10% sodium hydroxide solution and then extracted with 1N sulfuric acid. The aqueous acidic layer was made alkaline and extracted with chloroform. The chloroform layer was dried over magnesium sulfate and evaporated to obtain an oil, the free base of the title compound. A portion of the oil was reacted with ethereal hydrogen chloride to give white crystalline product in 43.2% yield, m.p. 229°-231° C.
Reaction SMILES: [CH2:1]([C:3]1([CH3:13])[CH:8]([CH3:9])[CH2:7][CH2:6][C:5]([CH2:11][CH3:12])([CH3:10])[NH:4]1)[CH3:2].[C:14](Cl)(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:14]([N:4]1[C:5]([CH2:11][CH3:12])([CH3:10])[CH2:6][CH2:7][CH:8]([CH3:9])[C:3]1([CH2:1][CH3:2])[CH3:13])(=[O:17])[CH:15]=[CH2:16]
Reactant: C=CC(=O)Cl
Reactant: CCC1(C)CCC(C)C(C)(CC)N1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)N1C(C)(CC)CCC(C)C1(C)CC
Reaction time: 18 h

Procedure:
36.7 g of 2,6-diethyl-2,3,6-trimethylpiperidine (Compound No. 1) are dissolved in 200 ml toluene. A solution of 19 g acrylic chloride in 50 ml toluene is added slowly within an hour and the mixture is stirred at 70°-75° C. for 18 hours. After addition of 21.2 g of triethylamine the stirring is continued for another 24 hours. After cooling the reaction mixture is washed twice with 100 ml water each. The toluene solution is dried over sodium sulfate and evaporated. The residue is distilled in vacuo and there is obtained the 1-acryloyl-2,6-diethyl-2,3,6-trimethylpiperidine (Compound No. 12) as distillate at 133°-135° C./0.6 mm Hg.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[C:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])[CH3:26]>C(O)CCC>[C:25]([N:28]1[CH2:33][CH2:32][N:31]([C:2]2[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH:10]=3)=[O:7])=[C:4]([CH3:24])[N:3]=2)[CH2:30][CH2:29]1)(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(C)n2)CC1

Procedure:
Procedure F was performed using 55 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 99 mg of 1-acetylpiperazine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield 6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide. MS (Q1) 450.4 (M)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([NH2:9])[CH:3]=1.[CH3:10][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]([CH2:14][CH:15]=[CH2:16])[CH3:13].C(N(CC)CC)C.C(#N)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:10][N:11]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:12]([CH2:14]/[CH:15]=[CH:16]/[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([NH2:9])[CH:3]=1)[CH3:13]
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Reactant: Cc1ccc(Br)cc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(/C=C/CC(C)N(C)C(=O)OC(C)(C)C)cc1N
Temperature: 25 °C
Yield: 71.9 %

Procedure:
A mixture of 4-bromo-2-aminotoluene (1.55 g, 7.17 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.71 g, 8.60 mmol ), prepared as previously described, palladium(II) acetate (16 mg, 0.07 mmol), tri-o-tolylphosphine (87 mg, 0.28 mmol), triethylamine (4.5 mL, 32.28 mmol), and acetonitrile (10 mL) was heated in a sealed glass tube at 140° C. for 14 h. The reaction mixture was cooled to ambient temperature, diluted with water (40 mL) and extracted with chloroform (4×75 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The crude product was purified by column chromatography on neutral alumina eluting with ethyl acetate-hexane (2:3 to 4:1) to yield 1.57 g (72.3%) of a brown liquid.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]([C:8](=O)[CH2:9][CH3:10])[C:6]#[N:7])C.Cl.C(N)=[NH:14].C(N(CC)CC)C>C(O)C>[CH2:9]([C:8]1[C:5]([C:6]#[N:7])=[CH:4][N:2]=[CH:1][N:14]=1)[CH3:10]
Reactant: CCC(=O)C(C#N)=CN(C)C
Reactant: N=CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1ncncc1C#N
Yield: 35 %

Procedure:
A mixture of crude 2-((dimethylamino)methylene)-3-oxopentanenitrile (0.98 equiv.), formamidine hydrochloride (2.0 equiv.) and triethyl amine (2.0 equiv.) in ethanol (1.0 M) was refluxed for 36 h. The solvent was removed and the residue was purified by silica column chromatography (20% ethyl acetate in petroleum ether) to afford the title product (35% yield). 1H-NMR (400 MHz, CDCl3) δ (ppm) 9.20 (s, 1H), 8.83 (s 1H), 2.98 (d, J=7.6 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H); MS (ESI) m/z 134.1 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.[CH2:16]([O:19][N:20]=[C:21]([C:45]1[N:46]=[C:47]([NH:50]C(OC(CC)(C)C)=O)[S:48][CH:49]=1)[C:22]([NH:24][CH:25]1[C:43](=[O:44])[N:27]2[C:28]([C:40]([OH:42])=[O:41])=[C:29]([CH2:32][S:33][C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)[CH2:30][S:31][C@H:26]12)=[O:23])[CH:17]=[CH2:18]>>[CH2:16]([O:19][N:20]=[C:21]([C:45]1[N:46]=[C:47]([NH2:50])[S:48][CH:49]=1)[C:22]([NH:24][CH:25]1[C:43](=[O:44])[N:27]2[C:28]([C:40]([OH:42])=[O:41])=[C:29]([CH2:32][S:33][C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)[CH2:30][S:31][C@H:26]12)=[O:23])[CH:17]=[CH2:18]
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(NC(=O)OC(C)(C)CC)n1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 57.2 %

Procedure:
Trifluoroacetic acid (4 ml.) and anisole (2 ml.) were added under ice-cooling to 7-[2-allyloxyimino-2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.9 g.) and the mixture was stirred for 40 minutes at ambient temperature. The reaction mixture was not post-treated according to a similar manner to that of Example 17 to give 7-[2-allyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.425 g.).
Reaction SMILES: C(O[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(C)(C)C.CCCCCC.[NH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=1>C(OCC)(=O)C>[CH3:26][C:25]1[C:20]([NH:19][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Cc1cccnc1N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cccnc1NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 64.3 %

Procedure:
To di t-butylcarbonate (32.29 g, 147.95 mmol) was added hexane (35 ml) and the solution was refluxed under heating at 80° C. Under refluxing, 2-amino-3-methylpyridine (10.00 g, 92.47 mmol) in ethyl acetate (10 ml) was dropped in a period of 15 minutes. After the mixture was refluxed for 2 hours and cooled to room temperature, thereto was added hexane (20 ml). The resulting crystals were filtered and dried in vacuo to give the subject compound (12.39 g, 64%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[NH:8][C:7](=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:24])=O.C(N(CCC)CCC)CC>>[C:1]([C:5]1([Cl:24])[NH:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])=[N:8][CH:7]=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(=O)[nH]c(-c2ccccc2C(F)(F)F)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCN(CCC)CCC
Product: CC(C)(C)C1(Cl)C=CN=C(c2ccccc2C(F)(F)F)N1
Temperature: 115 °C
Yield: 65.5 %

Procedure:
A solution of 6-tert-butyl-2-(2-trifluoromethyl-phenyl)-3H-pyrimidin-4-one (0.47 g, 1.59 mmol) in phosphorous oxychloride (1.65 mL, 15.9 mmol) was treated with tri-n-propylamine (0.61 mL, 3.17 mmol) and heated at 110-120° C. for 1 hour. The solvent was removed by evaporation then azeotroped three times with toluene. The residue was taken up in ethyl acetate, washed sequentially with 1 N sodium hydroxide, water and brine, then dried over sodium sulfate and concentrated. Purification by flash chromatography [SiO2, ethyl acetate:hexanes (1:9)] provided the title compound (0.33 g, 66% yield) as a yellow oil.
Reaction SMILES: N1C=CN=C1.[OH:6][C:7]1[C:8](=[O:13])[C:9](=[O:12])[C:10]=1[CH3:11].[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].O>CN(C=O)C>[O:12]([C:9]1[C:8](=[O:13])[C:7](=[O:6])[C:10]=1[CH3:11])[Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(O)c(=O)c1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(O[Si](C)(C)C(C)(C)C)c(=O)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Imidazole (11 mmol) is added to a solution of compound 93 (5 mmol) and tert-butyldimethylchlorosilane (5.5 mmol) in 5 mL of DMF cooled by an ice bath. The mixture is allowed to warm to room temperature. After 16 hours, the mixture is poured into water (50 mL) and extracted with ether (3×50 mL), the organic phases are washed with brine (50 mL) and dried over anhydrous MgSO4, and the solvent is evaporated in vacuo. The residue is purified by flash chromatography to give the product as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:25]([N:29]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32]Cl)[CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>CCOCC.O>[CH2:34]([N:29]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:30][CH2:31][CH2:32][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:7])=[CH:23][CH:24]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCN(CCCC)CCCCl
Reactant: O=C(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CCC(C)=O
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1

Procedure:
A mixture of 2.0 g. (6.4 mmol.) of 3-(4-hydroxybenzoyl)-2-phenylbenzofuran, 1.3 g. (6.4 mmol.) of 3-di-n-butylaminopropyl chloride and 4.0 g. (0.04 mol.) of anhydrous potassium carbonate in 20 ml. of dry 2-butanone is refluxed for 18 hours. The reaction mixture is cooled, water and ether are added and the layers are separated. The organic phase is extracted with 10% aqueous sodium hydroxide and the aqueous layers are combined and extracted again with water. The combined ether extracts are concentrated under reduced pressure to give the title compound.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]1([S:13][CH:14]2[C:22]3[N:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:20]=[C:19]([CH3:29])[C:18]=3[C:17](=[O:30])[CH2:16][C:15]2([CH3:32])[CH3:31])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH2:33]>CO>[C:7]1([S:13]([CH:14]2[C:22]3[N:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:20]=[C:19]([CH3:29])[C:18]=3[C:17](=[O:30])[CH2:16][C:15]2([CH3:32])[CH3:31])(=[O:1])=[O:33])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S([O-])OO
Reactant: Cc1nn(-c2ccccn2)c2c1C(=O)CC(C)(C)C2Sc1ccccc1
Reactant: O
Agent: [K+]
Solvent: CO
Product: Cc1nn(-c2ccccn2)c2c1C(=O)CC(C)(C)C2S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
A solution of Oxone (2 g, 3.2 mmol) in 6 ml of water was added dropwise to a solution of 7-phenylthio-1-(2-pyridyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazole (0.24 g, 0.66 mmol), prepared as described in example 8, in methanol (6 ml), maintained under stirring at 0° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirring was continued for about 1.5 hours. Water was then added and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate end evaporated. The residue was chromatographed on silica gel (cyclohexane:ethyl acetate=7:3), to yield the title compound as a colourless solid (0.175 g, 61%): m.p. 165-166° C.