Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[CH3:35][O:36][CH:37]([O:44][CH3:45])[C@@H:38]1[O:42][CH2:41][C@@H:40](O)[CH2:39]1.CC1C=CC(S([O-])(=O)=O)=CC=1>CN(C=O)C.CO>[CH3:35][O:36][CH:37]([O:44][CH3:45])[C@@H:38]1[O:42][CH2:41][C@H:40]([N:5]2[CH:6]=[N:7][C:8]3[C:4]2=[N:3][CH:2]=[N:1][C:9]=3[NH2:10])[CH2:39]1
Reactant: COC(OC)[C@H]1C[C@H](O)CO1
Reactant: Nc1ncnc2nc[nH]c12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(OC)[C@H]1C[C@@H](n2cnc3c(N)ncnc32)CO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a flame-dried argon blanketed round bottom flask equipped with a magnetic stir bar and condenser was added adenine (2.14 g, 15.8 mmole), K2CO3 (4.37 g, 31.6 mmole), 18-crown-6 (417 mg, 1.58 mmole) and DMF (400 mL). This mixture was allowed to stir at room temperature for 30 minutes under a stream of argon. A solution of (3S-trans)-tetrahydro-5-(dimethoxymethyl)-3-furanol-4-methylbenzenesulfonate. Compound IV(e), (5.0 g, 15.8 mmole) in 100 mL DMF was then added dropwise to the stirring mixture; the resultant mixture was warmed to 80° C., and stirred at that temperature overnight. Filtration, followed by evaporation of DMF, afforded a solid residue. This material was passed through a silica gel pad using a 7% MeOH/93% CH2Cl2 solution as eluant. Fractions containing the desired product were collected and evaporated to yield 3.0 g (71%) of Compound VI as a white solid:
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].NN>C(O)C>[NH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:25][CH:24]=1
Reactant: CC(=O)c1ccc(OCCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CCO
Product: CC(=O)c1ccc(OCCCCN)cc1
Temperature: 25 °C

Procedure:
A suspension of 13.5 g of 2-[4-(4-acetyl-phenoxy)butyl]-1H-isoindole-1,3(2H)-dione in 500 ml of ethanol is treated with 1.4 ml of anhydrous hydrazine, and the mixture stirred at reflux for 9 hours. After cooling to room temperature, the precipitate is collected. Concentration of the filtrate gives the crude title compound, which is used directly for further synthesis.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2].[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[F:26])[C:20](Cl)=[O:21]>>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[CH2:10][CH2:9][N:8]([C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:25]([F:26])=[C:17]([F:16])[CH:18]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CCOC(=O)C1=CNCCc2ccsc21
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)c(F)c2)CCc2ccsc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 by using 5,6-dihydro-4H-thieno[2,3-d]azepine-8-carboxylic acid ethyl ester and 3,4-difluoro-benzoyl chloride. 1H-NMR(CDCl3): δ 8.01 (1 H, s), 7.47 (1 H, m), 7.36 (1H, m), 7.27 (2H, m), 6.85 (1H, d), 4.23 (2H, q), 4.13 (2H, m), 3.15 (2H, t), 1.23 (3H, t). MS (ES): 364 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]([NH:23][C@H:24]([C:44](O)=[O:45])[CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:22])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>O1CCCC1>[Si:27]([O:26][CH2:25][CH:24]([NH:23][C:21]([NH:20][CH:17]1[CH2:16][CH2:15][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:19][CH2:18]1)=[O:22])[CH2:44][OH:45])([C:40]([CH3:41])([CH3:42])[CH3:43])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)N[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(=O)O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)NC(CO)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Yield: 28.2 %

Procedure:
Lithium aluminum hydride (1 M, 0.703 mL, 0.703 mmol) was added to a solution of N-({[1-(tert-butoxycarbonyl)piperidin-4-yl]amino}carbonyl)-O-[tert-butyl(diphenyl)silyl]serine (373 mg, 0.639 mmol) in tetrahydrofuran (20 mL) at −78° C. The reaction was quenched with saturated ammonium chloride solution and partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (1%→8% methanol {1% ammonium hydroxide}/dichloromethane) gave the title compound (100 mg). MS 556.3 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Br:1][C:2]1[CH:23]=[C:6]([C:7]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH:5]=[N:4][CH:3]=1
Reactant: O=C(Nc1ccccc1Nc1ccccc1)c1cncc(Br)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Brc1cncc(-c2nc3ccccc3n2-c2ccccc2)c1
Temperature: 100 °C
Yield: 88.7 %

Procedure:
Compound 1E (20.0 g, 54.3 mmol) was dissolved in 1,4-dioxane (anhydrous, 150 mL). Phosphorous oxychloride (36 g, 235 mmol) was then added dropwise. The resulting solution was heated at about 100° C. overnight; solids formed. After cooling to RT, the mixture was poured into hexanes (250 mL) to form additional precipitate. Solids were filtered then redissolved in DCM (200 mL) and washed with potassium carbonate (200 mL, saturated solution). The organic phase was collected, dried over sodium sulfate, and loaded onto silica gel. Short silica plug (20% ethyl acetate in hexanes and precipitation from hexanes gave 16.86 g of Compound 1F; 89% yield, pure by HNMR.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH2:17][CH2:16][C@H:15]([NH:18][S:19]([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=5)[CH:23]=4)(=[O:21])=[O:20])[C:14]3=[O:34])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:35](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH2:17][CH2:16][C@H:15]([N:18]([CH3:35])[S:19]([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=5)[CH:23]=4)(=[O:20])=[O:21])[C:14]3=[O:34])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc5ccnc(Cl)c5c4)C3=O)cc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: ClCCl
Product: COc1ccc2ccc(S(=O)(=O)N(C)[C@H]3CCN(Cc4ccc5ccnc(Cl)c5c4)C3=O)cc2c1
Temperature: 25 °C
Yield: 59.2 %

Procedure:
To a solution of 7-methoxynaphthalene-2-sulfonic acid [1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide (0.151 g, 0.304 mmol) in acetone (20 mL) is added potassium carbonate (0.084 g, 0.608 mmol) followed by methyl iodide (0.12 mL, 1.93 mmol). The resulting mixture is heated to reflux overnight, then cooled to room temperature and diluted with methylene chloride. The solution is washed with saturated NaHCO3 solution, water and brine. The organic layer is dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the product (0.093 mg, 0.18 mmol) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([NH:9][NH:10][C:11]([NH:13][CH3:14])=[S:12])=O)=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].Cl>>[CH3:14][N:13]1[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:9][NH:10][C:11]1=[S:12]
Reactant: CNC(=S)NNC(=O)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1c(-c2ccncc2)n[nH]c1=S

Procedure:
1-(4-Pyridoyl)-4-methylthiosemicarbazide (10.4 g, 4.97×10-2 mole) and 1 molar aqueous NaHCO3 (480 ml, 4.80×10-1 mole) were stirred and heated to reflux. After refluxing overnight, the reaction was cooled in an ice bath before being acidified by the dropwise addition of concentrated hydrochloric acid (40 ml, 4.8×10-1 mole). The product was collected by filtration and dried by suction.
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.[O:17]=[C:18]1[O:22][C@H:21]2[CH2:23][C@@H:24]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:25]([CH:26]=O)[C@H:20]2[CH2:19]1>CC(OC)(C)C.O.ClCCl.[Zn](O)O>[F:15][C:9]([F:14])([CH2:10][CH2:11][CH2:12][CH3:13])[C:8](=[O:16])/[CH:7]=[CH:26]/[C@@H:25]1[C@@H:20]2[C@@H:21]([O:22][C:18](=[O:17])[CH2:19]2)[CH2:23][C@H:24]1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OCc1ccccc1
Agent: O[Zn]O
Solvent: O
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 76 %

Procedure:
To a mixture of dimethyl(3,3-difluoro-2-oxoheptyl)phosphonate (210 mg, 0.81 mmoL) in MTBE/H2O (3/0.1 mL) was added Zn(OH)2 (100 mg, 0.81 mmoL) and the mixture was stirred under nitrogen for 1 h. A solution of (3aR,4R,5R,6aS)-hexahydro-2-oxo-5-(phenylmethoxy)-2H-cyclopenta[b]furan-4-carboxaldehyde (200 mg, 0.77 mmoL) in dichloromethane (3 mL) was added and the mixture was stirred for 24 h. After completion of the reaction, the reaction was then quenched with cold 1N HCl (12 mL). The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated to dryness under vacuum. The crude material was further purified by column chromatography [25% ethyl acetate in heptanes] to yield (3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-oxo-1-octenyl)-2-oxo-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan (7, R1 is phenyl, and R2 and R3 are H) in 76% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][C:3]=1[C:13]#[N:14].[CH:15]([Sn](CCCC)(CCCC)CCCC)=[CH2:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F-].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][N:8]1[C:6]2=[N:7][C:2]([CH:15]=[CH2:16])=[C:3]([C:13]#[N:14])[CH:4]=[C:5]2[C:10]([CH3:11])=[N:9]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nn(C)c2nc(Cl)c(C#N)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=Cc1nc2c(cc1C#N)c(C)nn2C
Temperature: 25 °C
Yield: 96.3 %

Procedure:
6-Chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (2.71 g, 13.1 mmol) was dissolved in toluene (45 mL). Vinyl tributyltin (5 g, 15.8 mmol) and triphenylphosphine (103 mg, 3.93 mmol) were added, followed by Pd(PPh3)4 (151 mg, 0.13 mmol). The reaction mixture was heated at reflux for 2 hours, allowed to cool to room temperature, and then treated with saturated aqueous KF solution for 30 minutes. The precipitated solid (tributyltin fluoride) was removed by filtration. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was washed with hexane to give 1,3-dimethyl-6-vinyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (2.50 g, 96%) as a pale yellow powder.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12]O>>[CH2:5]=[CH:4][CH2:3][CH2:2][CH2:1][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:5][CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: C=CCCC[Mg]Br
Reactant: OCCCCCO
Product: C=CCCCCCCCCCCCC=C
Yield: 81 %

Procedure:
The copper catalyzed coupling reaction of a Grignard reagent with an organic halide, which is commonly referred to as a halide displacement reaction, was first reported in 1971 by Kochi and Tamura (J. Am. Chem. Soc. 1971, 93, 1487, Synthesis 1971, 303, J. Organomet. Chem. 1972, 42, 205). In the Synthesis paper the authors reported the coupling reaction of n-butylmagnesium bromide with n-hexyl bromide in the presence of dilithiumtetrachlorocuprate (Li2CuCl4). Since that report the use of Li2CuCl4 in coupling reactions has been quite extensive and is prominent in the synthesis of pheromones as well as in the synthesis of α,ω-olefins. One of the more interesting uses of this copper catalyzed coupling reaction may be found in U.S. Pat. No. 4,912,253 where sorbyl acetate was coupled with the Grignard prepared from the magnesium salt of chlorohexanol to form the codling moth (Laspeyresia pomonella) sex pheromone 8,10-dodecadien-1-ol on a metric ton scale. α,ω-olefins have been formed by coupling 4-pentenylmagnesium bromide with the bis-tosylate of 1,5-pentanediol to form 1,14-pentadecadiene in 81% yield (Tetrahedron 1991, 47, 6287-6292). 1,9-Decadiene has been prepared by the Li2CuCl4 catalyzed coupling reaction of 1,4-dibromobutane with allylmagnesium bromide at 25° C. in 38% yield (Synthetic Communications 1994, 24, 459-463).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11]2[C:12]([NH2:18])=[N:13][C:14]([NH2:17])=[N:15][CH:16]=2)[CH:7]=[C:6]([O:19][CH2:20][CH3:21])[C:5]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([N+:29]([O-])=O)[CH:23]=1)[CH3:2].O.C(O)C>C(O)(=O)C.[Pd]>[NH2:29][C:24]1[CH:23]=[C:22]([C:5]2[C:4]([O:3][CH2:1][CH3:2])=[CH:9][C:8]([CH2:10][C:11]3[C:12]([NH2:18])=[N:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:7][C:6]=2[O:19][CH2:20][CH3:21])[CH:27]=[CH:26][C:25]=1[CH3:28]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccc(C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccc(C)c(N)c1
Reaction time: 0.5 h

Procedure:
5-(2,6-Diethoxy-4′-methyl-3′-nitro-biphenyl-4-ylmethyl)-pyrimidine-2,4-diamine (105 mg; 0.25 mmol) is dissolved in acetic acid conc. (6 ml), water (0.3 ml) and ethanol (1.5 ml) and hydrogenated over Pd/C 10% (85 mg). The catalyst is then filtered off with suction and rinsed thoroughly with ethanol and the solvent is evaporated off. The residue is taken up in water (20 ml) and the pH is adjusted to approx. 9-10 with NH4OH conc., whereupon the product precipitates out. After stirring for 30 minutes, the product which has precipitated out is filtered off with suction, washed with water and dried under a high vacuum.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:13]([NH:14][CH:15]([CH3:17])[CH3:16])=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([CH3:18])[CH:5]=1)=[O:3].[OH-].[Na+].Cl>CO>[NH2:1][C:2]([C:4]1[C:13]([NH:14][CH:15]([CH3:16])[CH3:17])=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:18])[CH:5]=1)=[O:3]
Reactant: COC(=O)c1cc(NC(C)C)c(C(N)=O)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(N)=O)c(NC(C)C)cc1C(=O)O
Temperature: 25 °C
Yield: 51.9 %

Procedure:
Methyl 4-aminocarbonyl-5-(isopropylamino)-2-methylbenzoate (202 mg, 0.81 mmol) was dissolved in methanol (3 mL) and was treated with 1M sodium hydroxide (3 mL, 3 mmol) at 45° C. for 1.5 h. The reaction mixture was cooled to ambient temperature and was concentrated to afford an aqueous residue that was acidified with 1N hydrochloric acid to pH 3. The precipitate was collected by filtration, washed with water and dried to afford 4-aminocarbonyl-5-(isopropylamino)-2-methylbenzoic acid (99.5 mg, 0.42 mmol, 52% yield). 1H NMR (400 MHz, d6-DMSO): δ 12.95 (br s, 1H), 7.90 (br s, 1H), 7.72 (d, 1H), 7.49 (s, 1H), 7.28 (br s, 1H), 7.06 (s, 1H), 3.64-3.54 (m, 1H), 2.33 (s, 3H), 1.15 (s, 3H), 1.14 (s, 3H); MS (EI) for C12H16N2O3: 237 (MH+).
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.[Si:7]([O:24][CH2:25][CH2:26][C:27]#[N:28])([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)Cl>C1C=CC=CC=1.C1(C)C=CC=CC=1>[Si:7]([O:24][CH2:25][CH2:26][C:27]([NH2:1])=[NH:28])([C:20]([CH3:22])([CH3:23])[CH3:21])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](OCCC#N)(c1ccccc1)c1ccccc1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCC(=N)N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of NH4Cl (5.35 g, 0.1 mol) in dry benzene (60 mL) at 0° C. was slowly added a solution of trimethylaluminum in toluene (50 mL of 2 M). After the addition was complete, the reaction mixture was allowed to warm up to room temperature and was stirred for 2 h until gas evolution had ceased. A solution of 3-(tert-butyldiphenylsilyloxy)propanenitrile (9.27 g, 0.03 mol) in dry benzene (20 mL) was added to the aluminum amide reagent and the resulting mixture was heated up to 80° C. for 20 h. The reaction mixture was slowly cooled to room temperature and then carefully poured into a slurry of 300 mL of DCM and 200 g of silica gel. It was then filtered and washed thoroughly with MeOH/DCM (1:2). After concentration, flash chomatography (SiO2, EtOAc to EtOAc/MeOH=100:20 to 100:30 to EtOAc/2M NH3 in MeOH=100:30) gave the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:4][CH:3]=1.C1C(=O)N([Br:33])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:33][CH2:12][C:6]1[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(Cl)ccc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(Cl)ccc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1CBr
Yield: 80.5 %

Procedure:
A solution of 11.4 grams (0.030 mole) of methyl 6-chloro-2-methyl-3-[1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl]benzoate and 5.4 grams (0.030 mole) of NBS in the presence of 0.03 gram of benzoyl peroxide in 250 mL of carbon tetrachloride was irradiated with a sun lamp as it stirred at reflux for about 18 hours. The reaction mixture was then cooled and washed with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to NMR analysis, which indicated that the reaction was about 15% complete. The residue was recharged to the reaction vessel and treated with the same amounts of NBS, benzoyl peroxide, and carbon tetrachloride under the same conditions as described above. Upon completion of the second 18 hour reflux period, a small sample was washed with water, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to NMR analysis, which indicated that the reaction was about 70% complete. An additional 2.0 grams (0.011 mole) of NBS was added, and the solution was irradiated at reflux for an additional 18 hours. The reaction mixture was then cooled and washed with water. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, and the fractions containing product were combined and concentrated under reduced pressure, yielding 11.0 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1]CC(C1N=C(NC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)SC=1)C(O)=O.[CH:32]1([N:38]=[C:39]=[N:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>O1CCCC1>[CH:41]1([NH:40][C:39]([NH:38][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[O:1])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: O=C(O)C(CO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
In 20 ml of tetrahydrofuran were dissolved 430 mg of 3-hydroxy-2-(2-tritylaminothiazol-4-yl)propionic acid and 270 mg of 7β-aminodesacetoxycephalosporanic acid tert-butyl ester and after adding thereto 206 mg of N,N'-dicyclohexylcarbodiimide, the mixture was stirred for 2 hours at room temperature. The solvent was distilled off from the reaction mixture under reduced pressure and 60 ml of ethyl acetate was added to the residue. Insoluble N,N'-dicyclohexylurea thus formed was filtered off and the filtrate was washed with an aqueous hydrochloric acid solution, an aqueous solution of sodium hydrogencarbonate, and then water followed by drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was dissolved in 2 ml of dichloromethane. After adding 4 ml of trifluoroacetic acid and 0.5 ml of anisole to the solution followed by stirring the mixture for 10 minutes at room temperature, 0.5 ml of water was added and the mixture was stirred vigorously. The solvent was distilled off from the reaction mixture under reduced pressure and ether was added to the residue to facilitate the formation of a powder, which was recovered by filtration. The powder was dissolved in 20 ml of ethanol, the insoluble materials which had formed were filtered off, the filtrate was adjusted to pH 4 by pyridine, the solvent was distilled off under reduced pressure, and isopropyl alcohol was added to the residue to form precipitates, which were recovered by filtration. The product was purified by a column chromatography using Diaion HP 20 (trade name) to provide 7β-[2-(2-aminothiazol-4-yl)-3-hydroxypropionamido]-3-methyl-Δ3 -cephem-4-carboxylic acid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[O:2]1.[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH:1]1([Br:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[O:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2ccccc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2ccccc21
Temperature: 25 °C

Procedure:
1H-Isobenzofuran-3-one (40.2 g, 0.3 moles), N-bromosuccinimide (53.4 g., 0.03 moles) and azo-bisisobutyronitrile (1g) were combined in 500 mL of CCl4 and refluxed under nitrogen for 2 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate concentrated in vacuo to a solid residue. The latter was crystallized from cyclohexane to yield title product, 34.5 g., m.p. 78°-80° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[C:5]([C:20]([F:23])([F:22])[F:21])[CH:4]=1.[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29]([CH2:32][C:33]2[C:34](=[O:40])[NH:35][C:36](=[S:39])[NH:37][CH:38]=2)=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>ClCCCl>[CH3:24][O:25][C:26]1[N:27]=[CH:28][C:29]([CH2:32][C:33]2[C:34](=[O:40])[N:35]=[C:36]([S:39][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([O:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=4)=[C:5]([C:20]([F:23])([F:22])[F:21])[CH:4]=3)[NH:37][CH:38]=2)=[CH:30][N:31]=1
Reactant: COc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Reactant: FC(F)(F)c1cccc(Oc2ccc(CCl)cc2C(F)(F)F)c1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4cccc(C(F)(F)F)c4)c(C(F)(F)F)c3)nc2=O)cn1
Yield: 4.4 %

Procedure:
The same procedure as E63 from 4-(chloromethyl)-2-(trifluoromethyl)-1-{[3-(trifluoromethyl)phenyl]oxy}benzene (425 mg, 1.199 mmol), 5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (200 mg, 0.799 mmol) and DIPEA (0.279 mL, 1.598 mmol) in DCE (3.0 mL), except that the reaction time was prolonged to 1.5 h, to afford the title compound (20 mg, 4.40% yield). LCMS: rt=3.66 min, [M+H+]=569