Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([CH2:12][C:13]([OH:15])=[O:14])[CH2:11][CH2:10]1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[F:25])[CH:20]=[O:21].O>C1COCC1>[CH:9]1([CH:12]([CH:20]([C:19]2[CH:22]=[CH:23][C:24]([F:25])=[C:17]([F:16])[CH:18]=2)[OH:21])[C:13]([OH:15])=[O:14])[CH2:11][CH2:10]1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: O=C(O)CC1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(C1CC1)C(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of lithium diisopropylamide (2.0M in hexanes, 46.4 mL, 92.8 mmol) in 20 mL of THF at −40° C. under a nitrogen atmosphere was added cyclopropylacetic acid (4.65g in 20 mL of THF, 46.4 mmol), dropwise. The mixture was stirred in the cold for 15 minutes and warmed to ambient temperature. After 1 hour, the reaction slurry was cooled in an ice bath and 3,4-difluorobenzaldehyde (5.2 mL, 47.1 mmol) in 10 mL of THF was added dropwise. The mixture was warmed to ambient temperature and allowed to stir for 2 hours. The mixture was poured into 200 mL of cold water and the layers separated. The organic layer was washed with water (3X), and the combined aqueous layers were washed with ethyl ether (2X), and then acidified with 3N hydrochloric acid. The water layer was extracted with ethyl ether (3X) and the combined ether layers were dried over sodium sulfate, filtered, and evaporated to dryness to yield the title compound as an oil.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][OH:31]>CN(C=O)C.CS(C)=O.CO>[OH:31][CH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:25]1[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1
Reactant: OC[C@@H]1CCCN1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCC[C@H]3CO)n2n1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol) and (S)-pyrrolidin-2-ylmethanol (78 mg, 0.75 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (25-25% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (82.8 mg, 81%). Melting point (167.0-197.7° C.). 1H NMR (DMSO-d6) δ: 11.06 (s, 1H), 7.99 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.6 Hz, 2H), 6.80 (s, 1H), 6.21 (s, 1H), 5.01 (br. s., 1H), 3.99 (t, J=8.2 Hz, 1H), 3.77-3.92 (m, 1H), 3.55-3.62 (m, 1H), 3.49 (dd, J=10.9, 6.6 Hz, 1H), 2.36 (s, 3H), 2.02-2.18 (m, 3H), 1.88-2.00 (m, 1H), 1.46 (s, 6H); ESI-MS: m/z 410.3 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[N:17]=[N:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(N1C=CN=C1)([N:24]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[N:17]=[N:16][C:15]([C:18]([NH2:24])=[O:19])=[CH:14][CH:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)O)nn1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCc1noc(C)c1COc1ccc(C(N)=O)nn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a solution of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (100 mg, 0.31 mmol) in DMF (5 mL) was added 1,1′-carbonyldiimidazole (60 mg, 0.37 mmol). The resulting reaction mixture was stirred for 1 h at 60° C. and then treated with an ammonium hydroxide solution (476 μL, 3.1 mmol). After 2 h the reaction mixture was evaporated and purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (49 mg, 55%) as an off white solid. MS: m/e=313.2 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].Cl[C@H:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20]>[Cl-].C([N+](CCCCCC)(CCCCCC)CCCCCC)CCCCC>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH:4][C@@H:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@@H](C)Cl
Reactant: Nc1ccc(F)c(F)c1F
Agent: CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Product: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F

Procedure:
In accordance with the process of Example 2, a condensation reaction was performed by using 2,3,4-trifluoroaniline (100 mg), potassium carbonate (188 mg), methyl (2R)-chloropropionate (92 mg) and tetrahexylammonium chloride (40 mg). As the result of the analysis by reversed phase HPLC with the use of the compound of Example 1 as a specimen, the product corresponded to 56 mg (36%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:17]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19]C1>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:22]([CH:17]3[CH2:19][CH2:20][CH2:21]3)=[O:23])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Product: CCC(NC(=O)C1CCC1)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 200 mg (0.90 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 120 mg (0.90 mmol) cyclopentanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)[CH:6]=[CH:7][CH:8]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(CN)c3)cc2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(CNS(C)(=O)=O)c3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A solution of N-{5-[3-(aminomethyl)phenyl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfonamide (69 mg, 0.2 mmol) in dichloromethane (5 ml) was treated with triethylamine (40 mg, 0.4 mmol), followed by methanesulfonyl chloride (25 mg, 0.22 mmol) and the wole mix stirred at room temperature under argon for 1 h. The reaction mix was washed with 0.5M hydrochloric acid, and the organic layer was evaporated under reduced pressure to give a brown oil which was purified by column chromatography on a 1 g SCX column eluting from 0-50% ethyl acetate in 40-60° C. petroleum ether to give the title compound as a yellow oil (46 mg, 55%).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][C@H:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1.[CH3:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1.[I-].ClC1C=CC=C[N+]=1C>O.C(#N)C>[CH2:22]([C:23]1[CH:24]=[CH:25][C:26]([C:29]([NH:10][C@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:30])=[N:27][CH:28]=1)[CH2:21][CH2:20][CH3:19]
Reactant: CCCCc1ccc(C(=O)O)nc1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCc1ccc(C(=O)N[C@@H]2CN3CCC2CC3)nc1
Reaction time: 8 h
Yield: 95 %

Procedure:
1.5 ml of Acetonitrile and Triethylamine (700 uL, 5.0 mmol) was added to a flask charged with (S)-(−)-3-Aminoquinuclidine dihydrochloride (199 mg, 1.0 mmol) and Fusaric acid (197 mg, 1.1 mmol), followed by addition of 2-Chloro-1-methylpyridinium iodide (383 mg, 1.5 mmol) at room temperature. After stirring overnight, about 2 ml of water was added to reaction mixture to resolve a clear solution that was subsequently injected into a Preparative HPLC instrument for purification. Desired fractions were combined and concentrated under vacuum. (S)-5-butyl-N-(quinuclidin-3-yl)pyridine-2-carboxamide (273 mg, 95% yield) was isolated as clear brown colored oil. 1H NMR (400 MHz, Methanol-D4) δ (ppm): 8.52 (d, J=1.8 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.84 (dd, J=8.0 Hz, 1H), 4.50 (m, 1H), 3.82 (ddd, J=10.0, 3.0, 2.6 Hz, 1H), 3.49 (m, 1H), 3.37 (m, 3H), 2.76 (t, J=7.8 Hz, 2H), 2.38 (m, J=3.1 Hz, 1H), 2.26 (m, 1H), 2.12 (td, J=8.0, 3.1 Hz 2H), 1.96 (m, 1H), 1.68 (m, J=7.7 Hz, 2H), 1.40 (m, J=4.5 Hz, 2H), 0.97 (t, J=7.4 Hz, 3H). LCMS (ESI): m/z 288.1 (M+H [C17H25N3O]=288.20).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([C:17]1[CH:30]=[CH:29][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[CH:19][CH:18]=1)[NH:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2C.Br[C:33]1C=NC2C(C=1)=CC(C)=CC=2>>[CH3:31][CH:2]([CH3:1])[CH2:3][CH:4]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[CH:29][CH:30]=1)[NH:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([CH3:33])=[CH:11][CH:10]=2
Reactant: Cc1ccc2ncc(Br)cc2c1
Reactant: Cc1cccc2cc(NC(CC(C)C)c3ccc(C(=O)NCCC(=O)O)cc3)cnc12
Product: Cc1ccc2ncc(NC(CC(C)C)c3ccc(C(=O)NCCC(=O)O)cc3)cc2c1

Procedure:
Prepared analogous to 3-{4-[3-Methyl-1-(8-methyl-quinolin-3-ylamino)-butyl]-benzoylamino}-propionic acid, Example 25, using 3-bromo-6-methylquinoline. m/z (M+1)=420.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:22]=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[NH:20][N:19]=3)[C:14]([N+:27]([O-])=O)=[CH:13][CH:12]=2)[CH3:9])=[N:6][CH:7]=1.[CH2:30](O)C.C(O)(=O)C.C(N)=N.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]3[N:17]([C:18]4[CH:22]=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[NH:20][N:19]=4)[CH:30]=[N:27][C:14]3=[CH:13][CH:12]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: CCO
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Agent: [Pd]
Agent: N=CN
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(-n2cnc3ccc(N[C@@H](C)c4ccc(F)cn4)nc32)n[nH]1
Temperature: 25 °C

Procedure:
N6-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-N2-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridine-2,6-diamine (Intermediate 8, 0.5 g) was dissolved into ethanol (20 mL) with Pd—C (60 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 85° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.29 g of the title compound. MS (electrospray): 382 (M+1) for C19H20FN7O. 1H NMR (300 MHz, CD3OD) δ ppm 8.45 (s, 1H) 8.35 (s, 1H) 7.75 (d, 1H) 7.50 (s, 1H) 6.70 (d, 1H) 6.00 (s, 1H) 5.10 (m, 1H) 4.50 (m, 1H) 1.55 (d, 3H) 1.35 (d, 6H).
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:29]1[N:33]=[C:32]([NH2:34])[S:31][N:30]=1)[C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:11]2[C:12]([C:24]([OH:26])=[O:25])=[C:13]([CH2:16]OC(=O)CC(C)=O)[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2].C(=O)(O)[O-].[Na+].[I-].[K+].[C:42]([C:45]1[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=1)(=[O:44])[NH2:43].Cl>O.C(OCC)(=O)C>[CH2:1]([O:3][N:4]=[C:5]([C:29]1[N:33]=[C:32]([NH2:34])[S:31][N:30]=1)[C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:11]2[C:12]([C:24]([O-:26])=[O:25])=[C:13]([CH2:16][N+:48]3[CH:49]=[CH:50][C:45]([C:42](=[O:44])[NH2:43])=[CH:46][CH:47]=3)[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2]
Reactant: NC(=O)c1ccncc1
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1nsc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(C(N)=O)cc3)CS[C@H]12)c1nsc(N)n1
Temperature: 55 °C
Reaction time: 2.75 h
Yield: 31.9 %

Procedure:
A mixture of 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer) (14.2 g), sodium bicarbonate (2.33 g), potassium iodide (140 g) and 4-carbamoyl-pyridine (5.08 g) in water (140 ml) was stirred for 2.75 hours at 55° C. After cooling, ethyl acetate (100 ml) and 6 N hydrochloric acid were added thereto under stirring to adjust the pH of the mixture to 2. The aqueous layer was separated out, washed with ethyl acetate and concentrated under reduced pressure. An insoluble substance was filtered off and the filtrate was subjected to column chromatography on a non ionic adsorption resin, Diaion HP20 (300 ml). After the column was washed with water (500 ml), the elution was carried out with 30% aqueous methanol. The eluates containing an object compound were collected, evaporated to remove methanol under reduced pressure and lyophilized to give 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido] -3-(4-carbamoyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (4.7 g), mp 160° to 165° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[C:12]([CH:13]([CH3:15])[CH3:14])=[CH:11][CH:10]=[C:9]([CH3:16])[C:3]=1[C:4](OCC)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>COCCOC.O>[CH3:1][C:2]1[C:12]([CH:13]([CH3:15])[CH3:14])=[CH:11][CH:10]=[C:9]([CH3:16])[C:3]=1[CH2:4][OH:5]
Reactant: CCOC(=O)c1c(C)ccc(C(C)C)c1C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(C(C)C)c(C)c1CO
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of ethyl 2,6-dimethyl-3-(1-methylethyl)benzoate (2.8 g) in dry 1,2-dimethoxyethane (40 ml) was added dropwise under a nitrogen atmosphere to a stirred solution of lithium aluminum hydride in dry 1,2-dimethoxyethane (80 ml) at approximately -78°. The mixture was allowed to warm to ambient temperature. The mixture was heated to reflux and maintained under reflux for one hour. After cooling to ambient temperature, a solution of 1,2-dimethoxyethane (20 ml) in water (5 ml) was added dropwise to the reaction mixture, followed by additional water (25 ml). The reaction mixture was acidified with 3 N hydrochloric acid and extracted with diethyl ether. The combined ether extracts were dried over magnesium sulfate, filtered, and the solvent evaporated to give [2,6-dimethyl-3-(1-methylethyl)phenyl]methanol (1.7 g). The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([CH3:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(OCC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(OCC(=O)OC(C)(C)C)ccc1N

Procedure:
A solution of 2.35 g (8.8 mmol) of the title A compound, (3-methyl-4-nitrophenoxy)-acetic acid t-butyl ester in 40 mL of EtOH is hydrogenated at 45 psi for 18 h in the presence of 10% Pd/C. The catalyst is removed by filtration through Celite and the filtrate is concentrated to give (4-amino-3-methylphenoxy)-acetic acid t-butyl ester as an oil: 1H-NMR (CDCl3) δ 6.68 (br s, 1H), 6.61 (s, 2H), 4.43 (s, 2H), 2.15 (s, 3H), 1.48 (s, 9H); [M+1]+=238.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])[CH:5]=O.[NH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[SH:23]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[S:23][C:14]3[CH:15]=[CH:16][C:17]([C:19]([F:20])([F:21])[F:22])=[CH:18][C:13]=3[N:12]=2)[CH:7]=[C:8]([Br:11])[C:9]=1[OH:10]
Reactant: Nc1cc(C(F)(F)F)ccc1S
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Solvent: CN(C)C=O
Product: Oc1c(Br)cc(-c2nc3cc(C(F)(F)F)ccc3s2)cc1Br
Temperature: 100 °C

Procedure:
In a N,N-dimethylformamide (DMF) solvent, a suspension of 3,5-dibromo-4-hydroxybenzaldehyde (1.0 eq.) and 2-amino-4-(trifluoromethyl)benzenethiol (1.0 eq.) was heated at a temperature of 100° C. After cooling, DMF was removed therefrom under reduced pressure. Methylene chloride was added to the resultant solid, and the produced precipitate was filtered, and washed with methylene chloride to obtain a solid target product.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH2:10][CH2:9][C:8]1=[O:20])[CH3:2].O.NN>CO.[Ni]>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:7]([CH2:6][CH2:5][CH2:4][N:3]([CH2:21][CH3:22])[CH2:1][CH3:2])[C:8](=[O:20])[CH2:9][CH2:10]2
Reactant: CCN(CC)CCCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CCN(CC)CCCN1C(=O)CCc2cc(N)ccc21
Temperature: 25 °C

Procedure:
1-(3- (Diethylamino)propyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (93 mg, 0.305 mmol) in dry methanol (5 mL) was treated with Ra—Ni (slurry in water, ˜0.05 g) followed by hydrazine hydrate (95 uL, 3.05 mmol) at room temperature and the resulting mixture was refluxed for 30 minutes. The reaction was cooled to room temperature, filtered through a celite bed, washed with methanol (2×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 2.5:97.5). Yield: 62 mg of yellow oil (74%). 1H NMR (CDCl3) δ: 6.87 (d, J=8.4 Hz, 1H), 6.56 (dd, J=2.7, 8.4 Hz, 1H), 6.52 (d, J=2.1 Hz, 1H), 3.91 (m, 2H), 2.81-2.76 (m, 2H), 2.61-2.54 (m, 2H), 2.52-2.46 (m, 6H), 1.78-1.61 (m, 2H), 1.01 (t, J=7.2 Hz, 6H). MS (ESI): 276.2 (M+1).
Reaction SMILES: [C-]#N.[K+].C[NH:5][CH2:6][CH2:7]NC.BrC1[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=1.CCCCCCCCCCCC.N>C(OCC)(=O)C.[Cu]I.C1(C)C=CC=CC=1>[CH3:18][C:13]1[CH:12]=[C:7]([CH:16]=[C:15]([CH3:17])[CH:14]=1)[C:6]#[N:5]
Reactant: CNCCNC
Reactant: Cc1cc(C)cc(Br)c1
Agent: [Cu]I
Agent: N
Agent: [C-]#N
Solvent: Cc1ccccc1
Solvent: CCCCCCCCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(C#N)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 15 %

Procedure:
A Schlenk tube was charged with CuI (19.5 mg, 0.102 mmol, 20 mol %), KCN (78 mg, 1.20 mmol), evacuated, backfilled with Ar. N,N′-Dimethylethylenediamine (21.5 μL, 0.202 mmol, 20 mol %), 5-bromo-m-xylene (136 μL, 1.00 mmol), and toluene (1.0 mL) were added under Ar. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 24 h. Dodecane (internal GC standard, 230 μL), ethyl acetate (2 mL), and 30% aq ammonia (1 mL) were added. A 0.1 mL sample of the supernatant solution was diluted with ethyl acetate (1 mL) and analyzed by GC to provide a 15% yield of 3,5-dimethylbenzonitrile.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1([C:16]([F:19])([F:18])[F:17])[O:7][C:6]([F:11])([CH2:8][CH2:9]I)[C:5]([F:15])([CH2:12][CH2:13]I)[O:4]1.[OH-].[K+]>>[F:19][C:16]([F:17])([F:18])[C:3]1([C:2]([F:1])([F:20])[F:21])[O:4][C:5]([F:15])([CH:12]=[CH2:13])[C:6]([F:11])([CH:8]=[CH2:9])[O:7]1
Reactant: FC(F)(F)C1(C(F)(F)F)OC(F)(CCI)C(F)(CCI)O1
Agent: [K+]
Agent: [OH-]
Product: C=CC1(F)OC(C(F)(F)F)(C(F)(F)F)OC1(F)C=C
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
In a flask was charged above compound 9 (95 g, 0.17 mole), 10 M KOH (189 ml, 1.89 mole) and phase transfer catalyst (Note) (24.6 g as 60% w/w aqueous solution, 0.034 mole). The reaction mixture was vigorously stirred at ambient temperature for 4 hrs. The bottom organic layer was separated and was further purified by distillation giving 25.0 g (49.3% yield) of the desired product was obtained as a clear, colorless liquid, bp. 90° C./200 mm.
Reaction SMILES: C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][OH:49])=[CH:43][CH:42]=1.O[C:51]1[CH:64]=[CH:63][C:54]([CH2:55][CH:56]([CH2:61][CH3:62])[C:57]([O:59][CH3:60])=[O:58])=[CH:53][CH:52]=1>ClCCl.C(OCC)(=O)C>[CH3:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][O:49][C:51]2[CH:64]=[CH:63][C:54]([CH2:55][CH:56]([CH2:61][CH3:62])[C:57]([O:59][CH3:60])=[O:58])=[CH:53][CH:52]=2)=[CH:43][CH:42]=1
Reactant: COCc1ccc(CCO)cc1
Reactant: CCC(Cc1ccc(O)cc1)C(=O)OC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(Cc1ccc(OCCc2ccc(COC)cc2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 23.2 %

Procedure:
ADDP (1,23 g, 4,89 mmole) and triphenylphosphine (1,03 g, 3,92 mmole) were added to a solution of 2-[4-(methoxymethyl)phenyl]ethanol (0,54 g, 3,26 mmole) and methyl 2-(4-hydroxybenzyl)butanoate (0,68 g, 3,26 mmole) in dry dichloromethane (10 ml) under argon. After 5 minutes, more dichloromethane (10 ml) was added. The reaction mixture was stirred at room temperature for 5.5 hours and then filtered. Purification by chromatography on silica gel using heptan:ethyl acetate (1:1) as eluent gave a mixture of product and starting material wich was dissolved in ethyl acetate and washed 3 times with 1 N sodium hydroxide. The organic phase was washed with brine, dried (sodium sulphate), filtered and solvent was evaporated to give 0,27 g (yield 60%) of the desired product.
Reaction SMILES: N#[C-].C(N(CC)CC)C.Cl[SiH](Cl)Cl.C(Cl)Cl.[F:17][C:18]1[C:19]([Si:27]([CH3:30])([CH3:29])[CH3:28])=[C:20]([N:24]=[C:25]=O)[CH:21]=[CH:22][CH:23]=1.N>>[F:17][C:18]1[C:19]([Si:27]([CH3:30])([CH3:29])[CH3:28])=[C:20]([N+:24]#[C-:25])[CH:21]=[CH:22][CH:23]=1
Reactant: C[Si](C)(C)c1c(F)cccc1N=C=O
Agent: Cl[SiH](Cl)Cl
Agent: N
Agent: [C-]#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [C-]#[N+]c1cccc(F)c1[Si](C)(C)C
Reaction time: 0.08 h

Procedure:
A deoxygenation then afforded the expected isonitrile. See Baldwin, J. E. et al., Tetrahedron , 39, 2989 (1983). Triethylamine (4.10 mL, 29.3 mmol) was added slowly at 0° C. to a 2 N solution of trichlorosilane in CH2Cl2 (8.40 mL, 16.8 mmol) followed, 5 min latter, by the compound prepared in Example (3) (2.35 g. 11.2 mmol). After 1 h 30 at 0° C. and 30 min at room temperature, the solution was saturated with NH3, filtered over Celite, washed with 5% NaH2PO4 and dried (Na2SO4). The crude obtained after evaporation of the solvent was then subjected to flash-chromatography (hexanes/AcOEt 95:5) to afford 1.42 g (66%) of a slighly purple liquid: IR (neat, cm-1) 2114, 1598, 1440, 1254, 1237, 1110, 943, 848, 793; 1H NMR (300 MHz, CDCl3) 6 0.45 (d, J=1.8 Hz, 9H), 7.01 (br t, J=8.3 Hz, 1H), 7.17 (br d, J=7.7 Hz, 1H), 7.32 (ddd, J1 =J2 =8.0 Hz, J3 =6.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 0.1, 116.5 (d, JCF =26 Hz), 124.3, 131.6, 166.8 (d, JCF =243 Hz), 166.9; HRMS (EI) m/z calcd for C10H12FNSi (M+) 193.0723, found 193.0715; LRMS (EI) m/z 193 (M+), 178, 150, 116, 105.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17](COCC[Si](C)(C)C)[CH:18]=3)[S:13][C:6]=12.Cl>CCO>[F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[S:13][C:6]=12
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4c[nH]cn4)sc23)c(F)c1
Temperature: 85 °C
Yield: 99 %

Procedure:
To a suspension of 92 (3.3 g, 6.8 mmol) in EtOH (8 ml) was added concentrated HCl (7 ml) and distilled water (4 ml). The mixture was heated at 80-90° C. for 2.5 h, cooled to room temperature and concentrated under reduced pressure. The remaining residue was subjected to azeotropic distillation with EtOH followed by neutralization with saturated aqueous NaHCO3. The solid that precipitated was filtered and washed with water, and the filtrate was extracted with EtOAc. The solid and EtOAc extract were combined, evaporated under reduced pressure and the residue was collected and dried to afford the title compound 93 (2.4 g, 100% yield) as a yellow solid. MS (m/z) 357.0 (M+H).