Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)([CH3:9])[CH2:3][C:4](OCC)=[O:5].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.C(Cl)Cl>[CH3:9][C:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)([CH3:1])[CH2:3][CH2:4][OH:5]
Reactant: CCOC(=O)CC(C)(C)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(CCO)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: -10 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of ethyl 3-methyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]butanoate (15.4 g, 0.0347 mol) in THF (151 mL) at −78° C. was added 1.00 M diisobutylaluminum hydride in DCM (84.5 mL) dropwise. The reaction was stirred for 2 hours with slow warming to −10° C. The mixture was quenched with water, then was treated with potassium sodium tartrate tetrahydrate and water. The mixture was stirred for 1 hour, then was extracted with ethyl acetate. The extracts were washed with water and brine, then dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (13.8 g, 99%).
Reaction SMILES: [Na].C(O)C.[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8][CH2:9][CH3:10])=O.C([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])C.Cl>C1(C)C=CC=CC=1>[CH2:9]([O:8][CH:6]([C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:17])[C:5]([O:12][CH2:13][CH3:14])=[O:11])[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOCC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(=O)C(OCC)C(=O)OCC
Temperature: 45 °C
Yield: 87 %

Procedure:
A stirred mixture of molten sodium metal (24.15 g, 1.05 mol) in toluene is treated with ethanol (55.2 g, 1.2 mol) over a 1 hr period at 100° C.-110° C., heated at reflux temperatures for 0.5 hr, cooled to 45° C., treated with a mixture of diethyl oxalate (160.6 g, 1.1 mol) and ethyl ethoxyacetate (132 g, 98%, 0.98 mol) over a 1 hr period at 45° C.-50° C., heated at 55° C.-60° C. for 1.5 hr and poured into 328 g of 14% HCl with cooling. The resultant mixture is separated. The title product is obtained as a 32% solution in the organic phase, identified by HRGC analysis, total yield is 198.2 g (87% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[NH:9][N:8]=1.[H-].[Na+].[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>O1CCCC1>[CH3:20][N:21]([CH3:25])[C:22]([N:8]1[C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[N:11][C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[N:9]1)=[O:23]
Reactant: CN(C)C(=O)Cl
Reactant: c1cnc(-c2n[nH]c(-c3cnccn3)n2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)n1nc(-c2cnccn2)nc1-c1cnccn1

Procedure:
To 2.25 g. (0.01 mole) of 3,5-dipyrazinyl-1,2,4-triazole in 200 ml. of tetrahydrofuran is added 57% sodium hydride (.42 g., 0.01 mole). The reaction mixture is heated at reflux for one hour, cooled, and a solution of dimethylcarbamoyl chloride (1 gram, 0.01 mole) in 10 ml. of tetrahydrofuran is added dropwise. The reaction mixture is then refluxed four hours, cooled, filtered and concentrated to a solid. After recrystallization from benzene 1-dimethylcarbamoyl-3,5-dipyrazinyl-1,2,4-triazole is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][C:26]([O:28]C(C)(C)C)=[O:27]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:25][C:26]([OH:28])=[O:27])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: CC(C)(C)OC(=O)CBr
Product: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
prepared by reaction of 4-tert-butyl-N-(3-dimethylamino-phenyl)-benzene-sulfonamide with tert-butyl bromoacetate
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([CH3:15])[N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1.O.[OH-].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([CH3:15])[N+:9]=1[O-:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N)c(C(=O)OC(C)(C)C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N)c(C(=O)OC(C)(C)C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
20.37 g (92.2 mmol) of 2-t-butoxycarbonyl amino-6-methylpyridine was dissolved in 100 mL of chloroform, and the resulting solution was cooled with ice water. 25 g (101.4 mmol) of a 70% by weight product of meta-chloroperbenzoic acid was added thereto. After confirming that there is no large heat generation, the temperature was raised to room temperature. After 2 hours had elapsed, 20 mL of water was added thereto. Then, the pH was adjusted to 14 by adding an aqueous solution of caustic soda having a concentration of 28%. Following liquid separation, the resulting aqueous layer was extracted with chloroform. The chloroform layer was washed with a 28% aqueous solution of caustic soda and then with water, and then dried with magnesium sulfate. Chloroform was removed by distillation under reduced pressure to obtain 21.30 g of 2-t-butoxycarbonyl amino-6-methylpyridine-N-oxide (yield: 99.6%) in a light orange oily form.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:35]C(=O)OC(C)(C)C)([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[N:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH3:31])=[C:24]([N+:32]([O-:34])=[O:33])[CH:23]=5)[O:19][N:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:4][O:3]1.ClC1C=C(C2ON=C(C3C=CC4OC(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)=CC=4C=3)N=2)C=CC=1OCCC>>[NH2:35][C:5]([C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH3:31])=[C:24]([N+:32]([O-:34])=[O:33])[CH:23]=4)[O:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)([CH2:4][OH:3])[CH2:6][OH:7]
Reactant: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1[N+](=O)[O-]
Agent: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Product: CCCOc1ccc(-c2nc(-c3ccc4oc(C(N)(CO)CO)cc4c3)no2)cc1[N+](=O)[O-]
Yield: 49 %

Procedure:
When the product of Step D was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxy phenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 49% yield, as creamy solid. 1H NMR (DMSO-d6) 8.6 (s, 1H); 8.37 (d, 1H, J=8.37 Hz); 8.31 (s, 1H); 7.94 (d, 1H, J=8.52 Hz); 7.68 (d, 1H, J=8.52 Hz); 7.59 (d, 1H, J=8.82 Hz); 6.91 (s, 1H); 4.87 (b, 2H); 4.23 (t, 2H, J=5.82 Hz); 3.67 (d, 2H, J=10.05 Hz); 3.58 (d, 2H, J=9.96 Hz); 1.78-1.71 (m, 2H); 0.97 (t, 3H, J=7.26 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(O[CH:18](OCC1C=CC=CC=1)[N:19]([CH3:21])[CH3:20])C1C=CC=CC=1>C1C=CC=CC=1>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CN(C)C(OCc1ccccc1)OCc1ccccc1
Reactant: CC(=O)c1ccncc1
Solvent: c1ccccc1
Product: CN(C)C=CC(=O)c1ccncc1

Procedure:
A mixture of 0.10 mole of 4-acetylpyridine and 0.12 mole of N,N-dimethylformamide dibenzylacetal in benzene was refluxed for 8 hours, giving 3-dimethylamino-1-(4-pyridinyl)-2-propen-1-one.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]([C:19](=[O:25])[CH2:20]S(C)(=O)=O)=[C:12]([O:26][CH2:27][CH3:28])[CH:11]=2)=[CH:4][N:3]=1.[Al].Cl>O1CCCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:26][CH2:27][CH3:28])[C:13]([C:19](=[O:25])[CH3:20])=[C:14]([O:16][CH2:17][CH3:18])[CH:15]=2)=[CH:4][N:3]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1C(=O)CS(C)(=O)=O
Agent: Cl
Agent: [Al]
Solvent: C1CCOC1
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1C(C)=O

Procedure:
A suspension of 5.8 g. of 4'-[(2,4-diamino-5-pyrimidinyl)-methyl] -2',6'-diethoxy-2-(methylsulfonyl)acetophenone in 50 ml. of 20% aqueous tetrahydrofuran is reduced with 1 g. of amalgamated aluminum at 65° over a period of 4 hours. (The aluminum chips are immersed in a 2% hydrochloric acid solution for 2 minutes, rinsed with methanol, and thereafter used in the reduction.) The reaction mixture is filtered warm, the filtrate is concentrated and adjusted to a pH of 9 with 5% sodium hydroxide. The resulting solution is then shaken with five 50 ml. portions of ethyl acetate. The resulting crude product after column chromatography (200 g. of silica gel, elution solvent comprising chloroform/N-propanol/concentrated ammonium hydroxide, 80:20:1) yields 4'-[(2,4-diamino-5-pyrimidinyl)-methyl]-2',6'-diethoxy-acetophenone, having a m.p. of 229°-231° recrystallized from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].O.CCOC(C)=O.Cl.[CH3:32][N:33]1CCCC1=O>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:32]#[N:33])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CN1CCCC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a mixture of 1-bromo-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (2.0 g, 5.34 mmol) in 16.2 mL of N-methylpyrrolidone was heated in a 130° C. oil bath for 2 h. After cooled, the reaction mixture was poured into a mixture of 100 mL of water (containing 5% conc. NH4OH) and EtOAc (100 mL). It was vigorously stirred at room temperature for 30 min, then was acidified by conc. HCl solution until two phases became clear. Organic layer was washed with water, brine and dried over MgSO4. It was filtered and concentrated. Crude product was triturated with MeOH and white solid was collected to provide the title compound 1.20 g (3.75 mmol) in 70% yield. LC-MS ESI+: 321.31 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:30][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1.[NH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[C:35]([NH:34][CH2:33][CH2:32][NH:31][C:27]([C:24]1[CH:25]=[CH:26][C:18]2[C:17]3[S:30][C:14]([C:9]4[N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[C:12](=[O:13])[NH:11][N:10]=4)=[CH:15][C:16]=3[CH2:22][CH2:21][O:20][C:19]=2[CH:23]=1)=[O:28])(=[O:37])[CH3:36]
Reactant: O=C(O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Reactant: CC(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)NCCNC(=O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2

Procedure:
Following the procedures in Examples 47 and 235, 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with N-(2-aminoethyl)acetamide, HATU and DIPEA in THF to give 331 as a colorless solid after reverse phase HPLC. MS: (ESI+) 524.0
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@H:4]([OH:22])[C@H:5]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.[Cl:24][CH2:25][C:26](O)=[O:27].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1C=CC=CC=1.CCCCCCC>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([O:22][C:26](=[O:27])[CH2:25][Cl:24])[C@H:5]([NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1
Reactant: COC(=O)[C@H](O)[C@@H](Cc1cccc(F)c1)NC(=O)OC(C)(C)C
Reactant: O=C(O)CCl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCCCCCC
Product: COC(=O)[C@@H](OC(=O)CCl)[C@@H](Cc1cccc(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A solution of of the (2R,3R)-3-tert-butoxycarbonylamino-4-(3-fluoro-phenyl)-2-hydroxy-butyric acid methyl ester (8 g, 24.5 mmol, 1 eq), chloroacetic acid (5.79 g, 61.3 mmol, 2.5 eq), and PPh3 (16 g, 61.3 mmol, 2.5 eq) in benzene (340 mL) was cooled to 0 C followed by the addition of diethylazodicarboxylate (9.7 mL, 61.3 mmol, 2.5 eq) over a 20 min period. After the addition, the reaction mixture was stirred at ambient temperature for 2 h after which the reaction mixture was concentrated and the residue purified by column chromatography with 30% EtOAc/hexanes as eluant. Appropriate fractions were combined and concentrated to give a yellow solid which was shaken with heptane and filtered to remove the yellow DEAD residues. The product was thus obtained as a white solid (4.25 g, 43%) 1H NMR (CDCl3) 7.32 (m, 1H), 7.03–6.96 (m, 3H), 5.34 (d, J=3.5, 1H), 4.26 (s, 2H), 4.75–4.5 (series of m, 2H), 3.77 (s, 3H), 2.92 (bd, J=7, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.ClC1[C:36]2[C:31](=[CH:32][C:33]([CH3:37])=[CH:34][CH:35]=2)[N:30]=[C:29]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[OH:44])[N:28]=1.C(N(CC)CC)C>O1CCOCC1.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:24])[NH:10][CH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[C:36]3[C:31](=[CH:32][C:33]([CH3:37])=[CH:34][CH:35]=3)[N:30]=[C:29]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[OH:44])[N:28]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)OCc2ccccc2)C1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc2c(N3CC[C@H](CNC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
A solution of benzyl((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (0.20 g, 0.60 mmol) and 4 M HCl in dioxane (10 mL) was stirred for 3 h at room temperature. After evaporating the solvent under reduced pressure, the resulting solid was triturated with Et2O and dried under vacuum, then taken up in CH2Cl2 (10 mL). To this solution was added 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.16 g, 0.60 mmol) and triethylamine (0.25 mL, 1.8 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with CH2Cl2 and washed with water. The CH2Cl2 solution was dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-40% EtOAc in hexanes gave benzyl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate as a colorless oil (0.19 g, 68%). LC/MS: m/z 469.1 (M+H)+ at 2.58 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:3]=1.[CH2:19]([Sn](CCCC)(CCCC)CCCC)[CH:20]=[CH2:21].CN1C(=O)CCC1>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH2:21]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:3]=1)[CH:20]=[CH2:19]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(I)cc1-c1ccccc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: C=CCc1ccc(C(=O)OC)c(-c2ccccc2C)c1
Yield: 74 %

Procedure:
Methyl 4-iodo-2-(2-methylphenyl)benzoate (10.0 g, 28.4 mmol), allyltributyl tin (11.3 g, 34.1 mmol), and dichlorobis(triphenylphosphine)palladium (II) (1.0 g, 1.42 mmol) were combined in 50 mL toluene and 20 mL NMP and heated at 125° C. for 18 hours. The reaction was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and chromatographed (5% EtOAc in hexanes) to provide the title compound in 74 % yield. MS m/e 284 (M+NH4)+.
Reaction SMILES: O.[NH2:2][NH2:3].C(O)C.[CH3:7][C:8]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)([CH3:14])[C:9](OCC)=[O:10].C(OCC)(=O)C>O>[CH3:7][C:8]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)([CH3:14])[C:9]([NH:2][NH2:3])=[O:10]
Reactant: CCOC(=O)C(C)(C)c1cccs1
Reactant: NN
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C(=O)NN)c1cccs1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
Hydrazine monohydrate (2.6 ml) was added to an ethanol (10 ml) solution of ethyl 2-methyl-2-(2-thienyl)propanoate (530 mg), followed by stirring at 70° C. for 48 hours. After the reaction solution and ethyl acetate were added to water, the organic layer was separated. Furthermore, the organic layer washed with saturated brine and, after drying over anhydrous sodium sulfate and filtration, the solvent was removed by evaporation under reduced pressure to obtain 447 mg of 2-methyl-2-(2-thienyl)propanohydrazide (colorless oil).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1ccc(-c2nc(-c3cccnc3)no2)c(F)c1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,3,4-trifluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.37-7.48 (m, J=9.3, 9.3, 7.1, 2.4 Hz, 1H), 7.64 (ddd, J=7.9, 5.0, 1.0 Hz, 1H), 8.08-8.18 (m, 1H), 8.56 (dt, J=8.0, 1.9 Hz, 1H), 8.75 (dd, J=5.0, 1.8 Hz, 1H), 9.30 (dd, J=2.0, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 278 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(=O)C)=[CH:8][C:7]=1[C:16]1[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=1.[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[C:16]1[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=1
Reactant: CC(=O)Nc1ccc(OCCN(C)C)c(-c2ccnn2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)CCOc1ccc(N)cc1-c1ccnn1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
Compound N-[4-(2-dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide (0.50 g, 1.7 mmol) was dissolved in ethanol (25 mL), sodium hydroxide (1.5 g, pallets) in 8 mL of water was added and reaction mixture stirred at 80° C. overnight then concentrated. Water and brine were added then extracted with EtOAc four times. Organic layers were combined, dried over anhydrous Na2SO4 then solvent removed under reduced pressure to afford 4-(2-dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine as a light brown oil in 87.5% yield. LCMS m/z (%)=261 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 9.82 (s, 1H), 9.71 (bs, 1H), 7.48-7.45 (m, 3H), 6.93 (d, J=8.74 Hz, 1H), 6.23 (s, 1H), 3.7 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:5]=1[O:6][CH2:7][C:8](=[O:14])[C:9]([O:12][CH3:13])([CH3:11])[CH3:10].S(=O)(O)[O-].[Na+]>C(OCC)C>[Br:1][CH:7]([O:6][C:5]1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:4]=1[Cl:3])[C:8](=[O:14])[C:9]([O:12][CH3:13])([CH3:11])[CH3:10]
Reactant: BrBr
Reactant: COC(C)(C)C(=O)COc1ccc(Cl)cc1Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: COC(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
Bromine (10.73 g, 0.067 mole) was slowly added to a stirred solution of 18.6 g (0.067 mole) of 1-(2,4-dichlorophenoxy)-3-methoxy-3-methyl-2-butanone in 350 ml diethyl ether containing 0.2 g aluminum chloride at about 3° C. After the addition, the mixture was stirred an additional 30 minutes, then poured into aqueous sodium bisulfite. The organic layer was separated, extracted with sodium bicarbonate solution, dried using MgSO4, and the solvent evaporated. There was thus obtained 23.6 g (99% yield) of 1-bromo-1-(2,4-dichlorophenoxy)-3-methoxy-3-methyl-2-butanone.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][CH2:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl>C(O)C>[NH2:8][C@@H:12]([CH2:13][CH2:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)(=[O:17])=[O:16])[CH2:11][OH:10]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCS(=O)(=O)c2ccc(F)cc2)COC1(C)C
Agent: Cl
Solvent: CCO
Product: N[C@H](CO)CCS(=O)(=O)c1ccc(F)cc1
Reaction time: 4 h
Yield: 74.6 %

Procedure:
To (S)-4-[2-(4-fluoro-phenylsulfonyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.21 g) was added under an argon atmosphere 5.5 M HCl solution in ethanol (2 ml). The mixture was stirred for 4 h. The mixture was concentrated. The residue was dissolved in dichloromethane and an excess of ammonia in methanol and some silica gel was added. The solvents were evaporated and the crude product was purified by column chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: dichloromethane/methanol=90:10) to give (S)-2-amino-4-(4-fluoro-phenylsulfonyl)-butan-1-ol (0.10 g) as a colourless oil. MS (ISP): 248.1 ([M+H]+).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15]([C:18](Cl)=[O:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:39]([Li])[CH2:40][CH2:41][CH3:42].O1CCCC1.Cl>C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15]([C:18](=[O:19])[CH2:39][CH2:40][CH2:41][CH3:42])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(=O)Cl)CS[C@H]12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
The reaction of these carbanionic reagents with activated 3-carboxycephem intermediates (acid chlorides and mixed anhydrides) is carried out under the same conditions as discussed hereinabove for the process of this invention. A typical procedure is illustrated by reaction of benzhydryl 7-phenylacetamido-3-chlorocarbonyl-3-cephem-4-carboxylate with n-butyllithium. A ethereal solution of 3 equivalents of n-butyllithium is added to a solution of 1 mmole of benzhydryl 7-phenylacetamido-3-chlorocarbonyl-3-cephem-4-carboxylate in 30 ml. of tetrahydrofuran at -73° C. After approximately 5 minutes 10 ml. of 1N. hydrochloric acid is added, and the acidified mixture is then allowed to warm to about 0° C. Ethyl acetate is added, and the resulting mixture is washed with dilute hydrochloric acid and brine and dried over anhydrous sodium sulfate. Chromatographic purification provides benzhydryl 7-phenylacetamido-3-valeroyl-3-cephem-4-carboxylate.