Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[F:17])[CH2:2][CH2:3][CH3:4].[CH2:18]([O:20][C@H:21]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29](O)=[O:30])=[CH:25][CH:24]=1)[CH3:19].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([N:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][C:8]=1[F:17])[C:29](=[O:30])[CH2:28][O:27][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@H:21]([O:20][CH2:18][CH3:19])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:33][CH:32]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCCCNCc1ccc(C(F)(F)F)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(C(F)(F)F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of N-butyl-N-[2-fluoro-4-(trifluoromethyl)benzyl]amine (0.598 g, 2.40 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.593 g, 2.00 mmol) in methylene chloride (20 mL) were added N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.674 g, 2.10 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (100 mL) and the organic phase was washed with 2 M HCl (3×75 mL), saturated aqueous NaHCO3 (2×75 mL), and brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 20 g/70 mL) with methanol (0-2% gradient) in methylene chloride as the eluent yielded 0.785 g (74%) of a pale yellowish-white oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[C:18]1([NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:25][C:18]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:24]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccccc1
Solvent: CCO
Product: Brc1ccc(-c2nc3ccccc3nc2-c2ccccc2)cc1
Yield: 69.7 %

Procedure:
8.2 g (29 mmol) of 1-(4-bromophenyl)-2-phenylethanedione, 3.1 g (31 mmol) of o-phenylenediamine, and 100 mL of ethanol were placed into a 300-mL flask, and the mixture was refluxed for 2 hours. After the reaction, the precipitated solid was collected by suction filtration. The collected solid was washed with ethanol and dried. 7.3 g of a light-yellow solid was obtained as the target substrate in 69% yield.
Reaction SMILES: Br[CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.[NH2:26][C:27]([CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1)=[S:28].CN(C=O)C>C([O-])([O-])=O.[Na+].[Na+]>[C:22]([C:19]1[N:17]2[N:18]=[C:13]([C:2]3[S:28][C:27]([CH:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)=[N:26][C:3]=3[C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=3[F:12])[CH:14]=[CH:15][C:16]2=[N:21][N:20]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)cc3F)c(-c3ccc4nnc(C(C)(C)C)n4n3)s2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.3 %

Procedure:
A mixture of 2-bromo-2-(3-tert-butyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1-(2,4-difluorophenyl)ethanone (3.78 g, 9.24 mmol; prepared using General Procedure A.2 from Preparation #K.1.1), tert-butyl 4-(aminocarbothioyl)tetrahydropyridine-1-(2H)-carboxylate (3.08 g, 12.6 mmol, Maybridge) and DMF (60 mL) was stirred at ambient temperature for about 2 d. The reaction was diluted with saturated aqueous Na2CO3 and extracted with Et2O (2×200 mL). The organic layers were combined, dried over Na2SO4 and concentrated. The crude material was loaded onto a silica gel column and eluted with a gradient of 30-100% EtOAc in heptane to give the title compound (3.5 g, 68%): LC/MS (Table 1, Method a) Rt=2.64 min; MS m/z: 555.4 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:12])=[C:8]([CH:11]=1)[C:9]#[N:10])(=[O:3])[CH3:2].[Br:13]Br>C(Cl)Cl>[Br:13][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:12])=[C:8]([CH:11]=1)[C:9]#[N:10])=[O:3]
Reactant: CC(=O)c1ccc(F)c(C#N)c1
Reactant: BrBr
Solvent: ClCCl
Product: N#Cc1cc(C(=O)CBr)ccc1F
Reaction time: 8 h

Procedure:
A solution of 5-acetyl-2-fluorobenzonitrile (20.0 g, 0.123 mol) in 500 mL of DCM was heated to reflux for 2 h, and then a solution of bromine in 300 mL DCM was added dropwise into the boiling mixture. The reaction mixture was heated to reflux and stirred under N2 protection overnight. The reaction mixture was washed with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified via silica gel column chromatography to give 5-(bromoacetyl)-2-fluorobenzonitrile.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:32]I.O>CN(C=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([N:21]([CH3:32])[C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: CI
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C)c(N(C)C(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
To a solution of N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (200 mg, 0.51 mmol) synthesized in Example 1 in DMF (3 mL) was added sodium hydride (a 60% dispersion in liquid paraffin, 24 mg, 0.6 mmol) at 0° C. and the resulting mixture was stirred at room temperature for 30 minutes. To the reaction solution was added methyl iodide (78 mg, 0.55 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution and the product was extracted with diisopropyl ether. The extracts were washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 25 mg (yield: 12%) of the desired product having low polarity, of two rotational isomers of the title compound. Melting point: 122-123° C. (petroleum ether).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH:10](O)[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2C=CC=C3C=2CCC3O)C=CC=CC=1>>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH:10]=[CH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1Cc2cccc(-c3ccccc3)c2C1
Agent: OC1CCc2c(-c3ccccc3)cccc21
Product: C1=Cc2cccc(-c3ccccc3)c2C1

Procedure:
Under a dry nitrogen atmosphere, a solution of 5.45 g (0.04 mole) of (+)-α-pinene in 15 ml of tetrahydrofuran was stirred and cooled to 0° C. Twenty ml of a 1 M solution of borane-tetrahydrofuran complex (0.02 mole) was added slowly, and the reaction mixture was stirred at 0° C. for 1 hour. To this was added dropwise a solution of 3.28 g (0.017 mole) of 7-phenyl-1H-indene in 15 ml of tetrahydrofuran. The reaction mixture was stirred at 0° C. for 2.5 hours, then at room temperature for 2 hours. The mixture was cooled to 0° C., and 6.9 ml of water, 10.3 ml of a 3 N sodium hydroxide solution, and finally 10.3 ml of 30% hydrogen peroxide were added in sequence slowly. The mixture was stirred at room temperature for two days, then poured into water, and extracted with two 100 ml portions of diethyl ether. The ether extracts were washed with 100 ml of water, dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated to give an oil. The oil was distilled using a Kugelrohr distillation apparatus (95° C./2.5 mm) to leave 2.62 g of an oily pot residue. The nmr spectrum of the oily residue indicated a 3:1 ratio of 4-phenyl-2-indanol to 4-phenyl-1-indanol (99% purity by gas chromatography).
Reaction SMILES: C(O[C:4]([C:6]1[S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[N:14]=1)=[O:5])C.[CH:15]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22])([CH3:17])[CH3:16].C[Al](C)C.CCCCCC>ClCCl>[CH:15]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH:22][C:4]([C:6]1[S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[N:14]=1)=[O:5])([CH3:17])[CH3:16]
Reactant: CC(C)Oc1ccccc1CN
Reactant: CCOC(=O)c1nc2ccncc2s1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)Oc1ccccc1CNC(=O)c1nc2ccncc2s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of thiazolo [5,4-c]pyridine-2-carboxylic acid ethyl ester (34 mg, 0.16 mmol) and 2-isopropoxy benzyl amine (67 mg, 0.41 mmol)in dichloromethane(1.7 mL) was added a solution of trimethylaluminum in hexane(0.203 mL, 2.0 M., 0.41 mmol). The solution was then stirred for 5 hours at room temperature. After usual work-up, the product was purified by flash chromatography (CH2Cl2/EtOAc 2:1) to give 30 mg of the thiazolo derivative.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH:7]([N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:19]([F:22])([F:21])[F:20])[CH:10]1[C:23]#[N:24])[CH3:8])(C)(C)C.[H][H].[ClH:28]>[Pd].CO>[ClH:28].[NH2:24][CH2:23][CH:10]1[C:11]2[C:16](=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:14]=[CH:13][CH:12]=2)[C:17](=[O:18])[N:9]1[CH:7]([CH3:8])[C:6]([OH:25])=[O:5]
Reactant: CC(C(=O)OC(C)(C)C)N1C(=O)c2c(cccc2C(F)(F)F)C1C#N
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C(=O)O)N1C(=O)c2c(cccc2C(F)(F)F)C1CN
Reaction time: 4 h

Procedure:
A stirring degassed solution of 2-(1-cyano-3-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid tert-butyl ester (390 mg, 1.1 mmol) and 10% palladium on carbon (20 mg) in methanol (10 mL) and conc. hydrocloric acid (1 mL) was added 80 psi of hydrogen. The reaction was stirred for 4 h and then filtered. The filtrated was conc. in vacuo to a white solid. The solid was dissolved in water and lypholized to give 352 mg of the desired product as a white solid. MS (ESI) 303 (M−Cl).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:28])[C:19](=[N:26][OH:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15](=[O:29])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].[C:30]1([C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N+]=[N-])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O)(=O)C>O1CCCC1>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:28])[C:19](=[N:26][OH:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15](=[O:29])[N:10]2[C:11]=1[C:12]([O:14][CH:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)ceph-3-em-4-carboxylic acid (syn-isomer)(2.0 g) in tetrahydrofuran (50 ml.) maintained at 37° was added portionwise a solution of diphenyldiazomethane in petroleum (b.p. 60°-80°) until the purple colour persisted for one hour. After addition of acetic acid to destroy excess diphenyldiazomethane, the solution was evaporated to dryness, taken up in ethyl acetate, then washed with sodium bicarbonate, and brine, dried and evaporated. The residue was triturated with petroleum spirit, and the resulting solid filtered and dried to give diphenylmethyl 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)ceph-3-em-4-carboxylate (syn-isomer) (1.93 g 69%), [α]D +24° (c 1, DMSO), λmax. (EtOH) 253 nm (ε 16,150), νmax. (CHBr3) 3610 (OH), 1796 cm.-1 (β-lactam), τ (DMSO-d6) values include 0.27 (doublet, J 9 Hz; NH), 8.03 (singlet; OCOCH 3).
Reaction SMILES: [CH3:1][C:2]([S@:5](/[N:7]=[CH:8]/[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][C@@H:14]([NH:19][C:20](=[O:34])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C@@H:29]3[CH2:33][CH2:32][CH2:31][O:30]3)=[CH:23][CH:22]=1)[CH2:13][CH2:12]2)=[O:6])([CH3:4])[CH3:3].[CH2:35](OCC)C.ClCCl.C[Mg]Br>O>[CH3:4][C:2]([S@:5]([NH:7][C@H:8]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][C@@H:14]([NH:19][C:20](=[O:34])[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][C@@H:29]3[CH2:33][CH2:32][CH2:31][O:30]3)=[CH:25][CH:26]=1)[CH2:13][CH2:12]2)[CH3:35])=[O:6])([CH3:1])[CH3:3]
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: O
Solvent: ClCCl
Product: C[C@H](N[S@](=O)C(C)(C)C)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension, cooled to −45° C., of N-((S)-6-{[(E)-(R)-2-methylpropane-2-sulfinylimino]methyl}-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (0.34 g), diethyl ether (15 ml) and dichloromethane (15 ml) was admixed with methylmagnesium bromide (1.1 ml; 1.4 M in toluene). After warming to room temperature, the mixture was stirred for another 5 hours. The reaction mixture was hydrolyzed cautiously with water and extracted with ethyl acetate. The organic phase was washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: ethyl acetate). The product was thus obtained with the molecular weight of 498.69 (C28H38N2O4S); MS (ESI): 499 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.O.[NH2:20][NH2:21].O>C(O)C>[N+:16]([C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[NH:21][N:20]=[C:4]2[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:18])=[O:17]
Reactant: NN
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1Cl
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]nc(-c3ccccc3)c2c1
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a solution of 2-chloro-5-nitrobenzophenone (15 g, 57 mmol) in ethanol (300 mL) was added hydrazine monohydrate (50 mL, 1 mol). The resultant solution was stirred overnight (16 hrs.) at ambient temperature, then poured into water (2 L) and stirred for an additional 2 hours. The precipitate that formed was collected by filtration, washed with water (2×100 mL) and air dried to give 5-Nitro-3-phenyl-1H-indazole 11a (13.1 g, 80%) as a yellow solid: 1H NMR (DMSO-d6) δ 7.48 (tt, 1H, J=1.3, 7.4 Hz), 7.58 (dd, 2H, J=7.1, 7.4 Hz), 7.78 (d, 1H, J=9.2 Hz), 8.01 (dd, 2H, J=1.3, 7.1 Hz), 8.25 (dd, 1H, J=2.1, 9.2 Hz), 8.91 (d, 1H, J=2.1 Hz), 13.88 (s, 1H). Anal. (C13H9N3O2) C, H, N.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=[O:6])[CH3:5].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]CC.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[CH3:5][C:4](=[O:6])[CH2:3][CH2:2][CH2:1][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: CC(=O)CC(C)=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCCC(C)=O
Temperature: 95 °C
Yield: 95 %

Procedure:
To a 2 L two-necked round bottom flask equipped with water condenser, calcium chloride guard tube and mechanical stirrer, 100 g of 2,4-pentanedione, 600 g of 1-bromooctadecane, 10 g of 18-crown-6, anhydrous potassium carbonate 125 g and 550 ml of absolute ethanol were added with stirring. The mixture was refluxed at 95° C. with continuous stirring for 24 hrs, after refluxing at the said temperature, the mixture was cooled to ambient temperature (25° C.), 550 ml of water was added to it and the 2-heneicosanone was extracted with dichloromethane from the mixture. On distillation of dichloromethane, 2-heneicosanone was obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH:16]=2)[C:13](=[O:26])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:27])[N:6]=1)[CH2:3][CH3:4].Br[C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][NH:33]2.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:37]1[C:29]([NH:1][C@H:2]([C:5]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:23])[F:24])[CH:16]=3)[C:13](=[O:26])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:27])[N:6]=2)[CH2:3][CH3:4])=[C:30]2[C:34]([NH:33][CH:32]=[N:31]2)=[N:35][CH:36]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 24 h
Yield: 38.2 %

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(3-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (38 mg, 0.10 mmol, 1.0 equiv) in t-BuOH (0.2 mL) at 23° C. was added 6-bromo-9H-purine (24 mg, 0.12 mmol, 1.2 equiv) and diisopropylethylamine (35 μL, 0.20 mmol, 2.0 equiv). After stirring for 24 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 19 mg of the title compound (38% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]([NH2:28])=[N:26][OH:27])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C[C:37](CC(O)=O)(C(O)=O)[OH:38]>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([C:25]1[NH:28][C:37](=[O:38])[O:27][N:26]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C(N)=NO)ccc2c1=O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3noc(=O)[nH]3)ccc2c1=O
Yield: 93 %

Procedure:
Tert-butyl{6-[amino(hydroxyimino)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl}methylcarbamate (0.25 g, 0.54 mmol) was dissolved in ethyl acetate (10 ml) and N,N′-carbonyldiimidazole (0.26 g, 1.6 mmol) was added. The mixture was refluxed under heating for 3 h. To the reaction mixture were added 0.1 M aqueous citric acid solution (25 ml) and ethyl acetate (50 ml). The organic layer was washed with 0.1 M aqueous citric acid solution (25 ml), and then saturated brine (25 ml), dried over anhydrous magnesium sulfate (12 g) and concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether-ethyl acetate=2:1 (v/v) to give tert-butyl[2-isobutyl-1-oxo-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.24 g, 93%) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:21]([OH:23])=[O:22].[C:25]([O:44][CH2:45][CH2:46][CH2:47]O)(=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.ClCCl.CCCCCC>[CH3:1][C:2]1([CH3:24])[S:6][CH:5]2[N:4]([C:8](=[O:9])[CH:7]2[NH:10][C:11](=[O:12])[CH2:13][O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:3]1[C:21]([O:23][CH2:47][CH2:46][CH2:45][O:44][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:22]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCOC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)C2SC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of penicillin V (1 g, 2.9 mmol), 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (860 mg, 2.6 mmol), 1,3-dicyclohexylcarbodiimide (620 mg, 3 mmol) and 4-(N,N-dimethylamino)pyridine (catalytic amount) in dichloromethane (30 ml) was stirred overnight at room temperature. The reaction mixture was diluted with hexane (50 ml), filtered and concentrated to dryness. The residue was washed with hexane (3×50 ml) to remove unreacted 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane. The semisolid residue was disolved in diethyl ether (150 ml), washed with water (100 ml) and dried. The ether solution was diluted with hexane (125 ml) and the solution filtered through a bed of silica (4 cm×4 cm). The filtrate was concentrated, yielding 1-(3,3-dimethyl-7-oxo-6([phenoxyacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptan-2-oyloxy)-3-(z,z,z-octadeca-6,9,12-trienoyloxy)propane as a viscous colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8](C)[CH2:7][C:6]12[CH2:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16]1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][C:6]12[CH2:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16]1
Reactant: CCOC(=O)Cl
Reactant: COc1cc2c(cc1OC)C1(Cc3ccccc3O1)CN(C)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)N1Cc2cc(OC)c(OC)cc2C2(Cc3ccccc3O2)C1
Yield: 61 %

Procedure:
A mixture of 6',7'-dimethoxy-2'-methylspiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (20.6 g), ethyl chloroformate (10.9 g) and potassium carbonate (20 g) in dry benzene (400 ml) is heated under reflux overnight. The reaction mixture is cooled and stirred with water (200 ml) for 15 minutes. The organic phase is washed with water, diluted hydrochloric acid, saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solvent is removed to yield 14.9 g of product as an oil. An analytical sample is obtained by passing 2.0 g of the oil through a silical gel dry column using ethyl acetate as the eluent and chloroform as the extractor. Removal of the solvent yields 1.8 g of an oil which crystallizes in the cold over petroleum ether, yielding a solid, mp, 72°-76°. The solid is recrystallized from hexane to yield white crystals, mp 75°-76°.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][C@H:11]([CH2:13]OS(C)(=O)=O)[C@H:10]([CH2:19]OS(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-2:25].[Na+].[Na+]>CS(C)=O>[C:1]1([CH2:7][N:8]2[CH2:9][CH:10]3[CH2:19][S:25][CH2:13][CH:11]3[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [S-2]
Reactant: CS(=O)(=O)OC[C@@H]1CN(Cc2ccccc2)C[C@@H]1COS(C)(=O)=O
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(CN2CC3CSCC3C2)cc1
Temperature: 120 °C
Yield: 78.4 %

Procedure:
To a stirred solution of cis-1-(phenylmethyl)-3,4-di(methylsulfonyloxy)methylpyrrolidine (9.2 g, mmol), in dry DMSO (48 mL) was added anhydrous sodium sulfide (5.7 g, 73.3 mmol). The dark reaction mixture was heated at 120° C. for 18 h. The cooled reaction mixture was poured into ice H2O (150 mL). The resulting mixture was washed with ether (3×200 mL). The combined organics were dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash chromatography using ethyl acetate as the eluent to afford 4.2 g (19.1 mmol, 78%) of the desired product as a thick yellow oil. HRMS (EI) calcd for C13H17NS 219.1082, found 219.1080. Anal. calcd for C13H17NS: C, 71.19; H, 7.81; N, 6.39. Found: C, 70.82; H, 7.83; N, 6.35.