Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:19]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18]3)[C:12]=2[C:27]([O:29]C)=[O:28])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+]>CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:19]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18]3)[C:12]=2[C:27]([OH:29])=[O:28])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COC(=O)c1c2cccccc-2c(-c2ccccc2)c1-c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2c(C(=O)O)c3cccccc-3c2-c2ccccc2)cc1
Yield: 79.6 %

Procedure:
To a solution of methyl 2 -(4-methylsulfonylphenyl)-3-phenylazulene-1-carboxylate (0.26 g) in MeOH (10.0 ml) was added 10% aqueous NaOH (2.0 ml), and the reaction mixture was heated under reflux for 6 hr. After removal of solvent, the aqueous layer was washed with Et2O. The solution was adjusted to pH 2.0 with 10% aqueous HCl, and extracted with EtOAc. The combined EtOAc extracts were washed with water and brine, dried over Na2SO4, and concentrated. The crude product was purified by SiO2 column chromatography (EtOAc/MeOH, 30: 1) to give the title compound (0.20 g) as violet crystals; mp 168°-169° C.
Reaction SMILES: [C:1]([C:4]1[C:24]([CH3:25])=[CH:23][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C([O-])(O)=[O:27].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.O>[C:1]([C:4]1[C:24]([CH3:25])=[CH:23][C:7]2[NH:8][C:9]([S:11]([CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[O:27])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: COc1ccnc(CSc2nc3cc(C(C)=O)c(C)cc3[nH]2)c1OC
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3cc(C(C)=O)c(C)cc3[nH]2)c1OC
Reaction time: 0.17 h

Procedure:
5-Acetyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole (3.75 g, 10 mmol) was dissolved in CH2Cl2 (70 ml). NaHCO3 (1.76 g, 21 mmol) in H2O (25 ml) was added and the mixture was cooled to ≈+3° C. m-Chloroperbenzoic acid 69.5% (2.43 g, 9.8 mmol) dissolved in CH2Cl2 (20 ml) was added dropwise under stirring. Stirring was continued for 10 min. The phases were separated and the organic phase was dried over Na2SO4 and evaporated under reduced pressure. The residue was crystallized from CH3CN giving the title compound (2.25 g, 60%).
Reaction SMILES: CI.[C:3](=O)([O-])O.[K+].[O:8]=[C:9]1[C:18]2[CH:19]=[C:20]([S:23][CH2:24][C:25]([OH:27])=[O:26])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][C:14]2[CH:13]=[CH:12][S:11][C:10]1=2>CN(C=O)C>[O:8]=[C:9]1[C:18]2[CH:19]=[C:20]([S:23][CH2:24][C:25]([O:27][CH3:3])=[O:26])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][C:14]2[CH:13]=[CH:12][S:11][C:10]1=2
Reactant: O=C([O-])O
Reactant: O=C(O)CSc1ccc2c(c1)C(=O)c1sccc1CO2
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CSc1ccc2c(c1)C(=O)c1sccc1CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
Methyl iodide (6.5 mL, 104 mmol) and potassium hydrogencarbonate (17.0 g, 170 mmol) were added to a DMF (200 mL) solution of the compound obtained in Example 21 (26.1 g, 85 mmol), and the mixture was stirred at room temperature overnight. The solvents were distilled off under a reduced pressure, water was added to the residue, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvents were distilled off under a reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), to give 24.0 g (88%) of the captioned compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:47][NH:48][C@H:49]([CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:50]([NH:52][CH2:53][C:54]([F:57])([F:56])[F:55])=[O:51].C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:9])[C@@H:10]([C:11](=[O:13])[N:48]([CH3:47])[C@@H:49]([C:50](=[O:51])[NH:52][CH2:53][C:54]([F:55])([F:56])[F:57])[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN[C@H](Cc1ccccc1)C(=O)NCC(F)(F)F
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48.6 %

Procedure:
A solution of (2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionic acid (1.35 g, 4.1 mmol) and 1-hydroxy-7-azabenzotriazole (0.56 g, 4.1 mmol) in N,N-dimethylformamide (5 ml) and dichloromethane (5 ml) was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.79 g, 4.1 mmol) was added. The reaction mixture was stirred for 15 min at 0° C. A solution of (2R)-2-methylamino-3-phenyl-N-(2,2,2-trifluoroethyl)propionamide (1.07 g, 4.1 mmol) in dichloromethane (5 ml) was added. Ethyldiisopropylamine (0.71 ml) was added. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (100 ml) and washed with 10% aqueous sodium hydrogen sulfate solution (100 ml). The aqueous phase was extracted with with ethyl acetate (2×50 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (170 g), using ethyl acetate/heptane 1:2 (300 ml), and then ethyl acetate/heptane/dichloromethane 1:1:1 as eluent to give 1.14 g of N-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester.
Reaction SMILES: C[O:2][C:3]1[CH:24]=[CH:23][C:6]2[N:7]=[C:8]([C:10]#[C:11][C:12]3[CH:19]=[CH:18][C:15]([NH:16][CH3:17])=[C:14]([N+:20]([O-:22])=[O:21])[CH:13]=3)[S:9][C:5]=2[CH:4]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:17][NH:16][C:15]1[CH:18]=[CH:19][C:12]([C:11]#[C:10][C:8]2[S:9][C:5]3[CH:4]=[C:3]([OH:2])[CH:24]=[CH:23][C:6]=3[N:7]=2)=[CH:13][C:14]=1[N+:20]([O-:22])=[O:21]
Reactant: CNc1ccc(C#Cc2nc3ccc(OC)cc3s2)cc1[N+](=O)[O-]
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNc1ccc(C#Cc2nc3ccc(O)cc3s2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a round bottomed flask equipped with a magnetic stir bar containing DCM (5 vol) is placed 4-((6-methoxybenzo[d]thiazol-2-yl)ethynyl)-N-methyl-2-nitroaniline (1 equiv). The reaction mixture is cooled to 0° C., BBr3 (5 equiv of 1M in DCM) is added dropwise and the reaction is stirred at RT for 8 hours. The reaction is neutralized with sat. NaHCO3, extracted into DCM (2×5 vol). The combined organic extracts are washed with water (5 vol), brine (5 vol), dried over MgSO4 and concentrated in vacuo. The residue is purified over silica gel using EtOAc:Hexanes (1:3) as an eluent to afford the desired product.
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([O:13][CH3:14])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[CH3:17])[C:6]2=[O:15].C([SnH](CCCC)CCCC)CCC.[F-].[K+]>C1C=CC=CC=1>[CH3:12][O:11][C:10]1[CH:2]=[C:3]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=1)[C:6](=[O:15])[N:5]([CH:16]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[CH3:17])[CH2:4]2
Reactant: COc1cc(OC)c2c(c1Br)CN(C(C)c1ccc(Cl)cc1)C2=O
Agent: CCCC[SnH](CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: c1ccccc1
Product: COc1cc2c(c(OC)c1)C(=O)N(C(C)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Yield: 62.5 %

Procedure:
To a solution of 4-bromo-5,7-Dimethoxy-2-[1-(4-chloro-phenyl)-ethyl]-2,3-dihydro-isoindol-1one (0.112 g, 0.27 mmol) in benzene under N2 atmosphere was added 2,2′-azobis(2-methyl proponitrile) AIBN (5.0 mg), followed by tributyl tin hydride (0.145 mL, 0.55 mmol). The resulting mixture was refluxed in an oil bath for 2 h. The reaction was monitored by GC-MS for the disappearance of starting material. The reaction mixture was cooled to room temperature and stirred with potassium fluoride (200 mg) for 45 min. The solids were filtered and the filtrate was concentrated. The resulting material was purified using column chromatography (typically 40% ethyl acetate in hexanes) to give 5,7-Dimethoxy-2-[1-(4-chloro-phenyl)-ethyl]-2,3-dihydro-isoindol-1one (0.056 g, 63%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.43 (d, 3H), 3.63 (s, 3H), 3.68 (d, 1H), 3.74 (s, 3H), 3.99 (d, 1H), 5.53 (q, 1H), 6.23 (dd, 2H), 7.15 (m, 4H). GC-MS: m/z 331 (M)+, 316 (M-15)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:11]([F:22])[CH:10]=2)[CH2:4]1.C(N(CC)CC)C.[C:30](SCC)(=[S:32])[CH3:31]>CN(C=O)C.C(OCC)(=O)C>[C:30]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])=[C:11]([F:22])[CH:10]=2)[CH2:4]1)(=[S:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Reactant: CCSC(C)=S
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=S)NC[C@H]1CN(c2ccc(C(=O)OC(C)(C)C)c(F)c2)C(=O)O1
Yield: 84.3 %

Procedure:
A solution of 5-(S)-aminomethyl-3-[4′-(tert-butoxy)carbonyl-3′-fluorophenyl]-oxazolidine-2-one (3.00 g, 9.66 mmol), triethylamine (1.35 ml, 19.3 mmol), and ethyl dithioacetate (1.22 ml, 10.6 mmol) in DMF (8 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (50 ml), washed with 3% aqueous citric acid (3×30 mL), saturated aqueous sodium bicarbonate (30 mL), brine, and dried (MgSO4). Evaporation afforded the product as a white solid (3.00 g, 84%). MS (m/z): [M+H]+=369.
Reaction SMILES: [CH:1]([Si@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10]Br)[CH2:6][CH2:5]1)=[CH:2][CH3:3].[Mg].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=2)=[CH:17][CH:16]=1>C1COCC1>[CH:1]([Si@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=3)=[CH:19][CH:20]=2)[CH2:6][CH2:5]1)=[CH:2][CH3:3]
Reactant: Fc1ccc(-c2ccc(CBr)cc2)cc1F
Reactant: CC=C[Si@H]1CC[C@H](CBr)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC=C[Si@H]1CC[C@H](CCc2ccc(-c3ccc(F)c(F)c3)cc2)CC1

Procedure:
4.7 g (20 mmol) of trans-1-(1-propenyl)-4-bromomethyl-1-silacyclohexane was dripped into a mixture of 0.5 g (21 mmol) of magnesium and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 5.7 g (20 mmol) of 4'-bromomethyl-3,4-difluorobiphenyl and a catalytic amount of cuprous chloride to obtain 4-[2-(trans-4-(1-propenyl)-4-silacyclohexyl) ethyl]-3',4'-difluorobiphenyl. The silacyclohexane rings of this product were a mixture of trans isomers and cis isomers. After a conventional after treatment, they were separated by means of chromatography to obtain 6.1 g of the trans isomers (yield 86%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:21]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:21][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)=[N:7][C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N

Procedure:
To a solution of (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (0.500 g, 1.56 mmol) in ethanol (25 mL) was added palladium on carbon 10% (500 mg) suspended in ethanol. The reaction mixture was hydrogenated using a balloon filled with hydrogen gas for 3 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[C:6]([F:8])[CH:7]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#CCc1cc(F)cc(F)c1
Solvent: C1CCOC1
Product: NCCc1cc(F)cc(F)c1

Procedure:
3,5 difluorophenylacetonitrile (5 g) was dissolved in TI-IF (100 mL) and a solution of BH3 in THF (200 mL of 1 M) was added dropwise. The mixture was refluxed overnight, cooled in an ice bath, and the reaction quenched with methanol (20 mL). The solvent was removed by rotary evaporation and the residue partitioned between ethyl acetate and water. The organic layer was washed with sat NaCl and the solvent again removed to give product, which was used in the next step without purification.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Br[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.O>C1COCC1>[C:1]([N:8]1[CH2:15][C@H:14]([O:16][CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: BrCc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2cccc3ccccc23)C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
Commercially available Boc-4(R)-hydroxyproline (5.00 g, 21.6 mmol) was dissolved in THF (100 mL) and cooled to 0° C. Sodium hydride (60% dispersion in oil, 1.85 g, 45.4 mmol) was added portionwise over 10 minutes and the suspension was stirred at RT for 1 h. Then, 1-(bromomethyl)naphthalene (8.00 g, 36.2 mmol) (prepared as described in E. A. Dixon et al. Can. J. Chem., (1981), 59, 2629-2641) was added and the mixture was heated at reflux for 18 h. The mixture was poured into water (300 mL) and washed with hexane. The aqueous layer was acidified with 10% aqueous HCl and extracted twice with ethyl acetate. The organic layers were combined and washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (49:49:2 hexane: ethyl acetate: acetic acid) to give the title compound as a colorless oil (4.51 g, 56% yield). 1H NMR (DMSO-d6) indicated the presence of two rotamers: δ 8.05 (m, 1H), 7.94 (m, 1H), 7.29 (d, J=14 Hz, 1H), 7.55-7.45 (m, 4H), 4.96 (m, 2H), 4.26 (br. s, 1H), 4.12 (dd, J=J=8 Hz, 1H), 3.54-3.42 (m, 2H), 2.45-2.34 (m, 1H), 2.07-1.98 (m, 1H:) 1.36 (S, (3/9) 9H), 1.34 (s, (6/9) 9H).
Reaction SMILES: [CH2:1]([CH2:7][CH:8]([NH2:12])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:13](Cl)(Cl)=[O:14]>C1(C)C=CC=CC=1>[O:14]=[C:13]1[NH:12][CH:8]([CH2:7][CH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[C:9](=[O:11])[O:10]1
Reactant: NC(CCCCC(=O)O)C(=O)O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(O)CCCCC1NC(=O)OC1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A suspension of 1.752 g of DL-2-aminopimelic acid, 55 ml of tetrahydrofuranand 16 ml of 1.93M phosgene in toluene is heated, in an oil bath, at 50° C. for 1 hour. Argon is bubbled through the reaction to remove the excess phosgene and the solvents are removed under house vacuum. The resulting oil is dissolved in 14 ml of ethyl alcohol, diluted with 14 ml of petroleum ether and the solution stored overnight at room temperature. The formed crystals are collected and dried to give 1.6 g of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([NH:10][CH3:11])=[CH:8][CH:9]=1)([O-])=O.[H][H]>[Pt]=O.C(O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]([NH:10][CH3:11])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CNc1ccc([N+](=O)[O-])cn1
Agent: O=[Pt]
Solvent: CCO
Product: CNc1ccc(N)cn1

Procedure:
To 40 ml of an ethanol solution of the methylamino compound (4 g) obtained in (a) described above was added, 400 mg of platinum oxide, followed by reaction in an atmosphere of hydrogen at room temperature for 15 hours. The solvent was thereafter removed by distallation, and the residue was purified by silica gel column chromatography (eluent: chloroform, and subsequently chloroform: methanol=20:1 (v/v)) to obtain 320 mg of the intended product as brown crystals.
Reaction SMILES: [H-].[Na+].[C:3](=[N:10][OH:11])([NH2:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:12]1([C:18]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:19]2[CH2:24][CH:23]([C:25](OC)=O)[CH2:22][N:21]=[CH:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[C:35]1([C:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:19]2[CH2:24][CH:23]([C:25]3[O:11][N:10]=[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:9]=3)[CH2:22][N:21]=[CH:20]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCCCC(N)=NO
Reactant: COC(=O)C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCc1noc(C2CN=CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Prepared by a procedure similar to Example 9, where sodium hydride (95% 40 mg, 1.7 mmol) and n-hexanamidoxime (217 mg, 1.7 mmol) were suspended in dry THF in an oven dried round bottom flask with stirring under nitrogen at 0° C. After 15 minutes stirring the ice bath was removed and the grey suspension refluxed 45 minutes to give a white suspension. 1-Triphenylmethyl-1,4,5,6-tetrahydro-5-methoxycarbonylpyrimidine (640 mg, 1.7 mmol) was added, dissolved in dry THF and reflux continued 18 hours. The solvents were evaporated in vacuo and the residue was chromatographed (silica, chloroform/methanol, 9:1) to yield 1-triphenylmethyl-1,4,5,6-tetrahydro-5-(3-n-pentyl-1,2,4-oxadiazol-5-yl)pyrimidine. This product was dissolved in triflouroacetic acid (2 mL), with stirring at room temperature for 24 hours. The yellow solution was then evaporated in vacuo, and the residue recrystallized from methanol/ether to yield 110 mg (19%) white crystals, mp 97°-99° C. identified by 300 MHz nmr.
Reaction SMILES: FC1C=CC=C(F)C=1O.CCN(S(F)(F)F)CC.[F:19][C:20]1[CH:21]=[C:22]([OH:31])[CH:23]=[C:24]([F:30])[C:25]=1[O:26][CH:27]([F:29])[F:28].Br[C:33]1[CH:38]=[C:37]([F:39])[C:36]([O:40][CH:41]([F:43])[F:42])=[C:35]([F:44])[CH:34]=1.C(OO)(C)(C)C.OO>>[F:19][C:20]1[CH:21]=[C:22]([OH:31])[CH:23]=[C:24]([F:30])[C:25]=1[O:26][CH:27]([F:29])[F:28].[F:39][C:37]1[CH:38]=[CH:33][CH:34]=[C:35]([F:44])[C:36]=1[O:40][CH:41]([F:42])[F:43]
Reactant: Fc1cc(Br)cc(F)c1OC(F)F
Agent: CC(C)(C)OO
Agent: CCN(CC)S(F)(F)F
Agent: OO
Product: Fc1cccc(F)c1OC(F)F

Procedure:
Compound (251) can be prepared in the same manner as in Preparation Example 248, except for replacing 3-fluoro-4-difluoromethoxyphenol with 3,5-difluoro-4-difluoromethoxyphenol. The 3,5-difluoro-4-difluoromethoxyphenol can be obtained by converting 2,6-difluorophenol to a formic ester, fluorinating the ester with DAST, brominating the resulting 2,6-difluoro-1-difluoromethoxybenzene, preparing a Grignard reagent from the resulting 4-bromo-2,6-difluoro-1-difluoromethoxybenzene, and reacting the Grignard reagent with t-butyl hydroperoxide or converting the Grignard reagent to a boric ester, and oxidizing the ester with hydrogen peroxide under a basic condition. Alternatively, 3,5-difluoro-4-difluoromethoxyphenol can also be obtained by nitrating 3,5-difluoro-4-difluoromethoxybenzene, reducing the product to 3-fluoro-4-trifluoromethoxyaniline, and decomposing a diazonium salt of the 3-fluoro-4-trifluoromethoxyaniline in sulfuric acid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:19])[C:15]([O:17]C)=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:20])=[O:4].B(Br)(Br)Br>ClCCl>[F:21][C:2]([F:1])([F:22])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:19])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:20])=[O:4]
Reactant: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)C(C)C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1CN(C(=O)C(F)(F)F)C(C)Cc2cc(O)c(Br)cc21
Reaction time: 8 h
Yield: 81.7 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.383 g, 1.01 mmol) in dichloromethane (30 mL) was treated with BBr3 (2.35 mL of a 1.0M solution in CH2Cl2, 2.35 mmol) and stirred overnight while warming to 20 C. The excess BBr3 is quenched with water, and the resulting mixture was diluted with ether (100 mL), washed with saturated aqueous Na2CO3 (50 mL) and brine (50 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 0.302 g of a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.22 (m, 1H), 6.77 (m, 1H), 5.34 (s, 1H), 4.35 (m, 1H), 3.62 (m, 1H), 3.24 (m, 1H), 3.13 (m, 2H), 2.69 (m, 1H), 1.31 (m, 3H), 1.22 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:37][C:38]1([C:43]2[CH:48]=[C:47]([NH:49][CH2:50][CH2:51][NH2:52])[CH:46]=[CH:45][N:44]=2)[O:42][CH2:41][CH2:40][O:39]1>CN(C=O)C.C1COCC1.C(OCC)(=O)C>[F:12][C:2]([F:1])([C:8]([F:11])([F:10])[F:9])/[CH:3]=[CH:4]/[C:5]([NH:52][CH2:51][CH2:50][NH:49][C:47]1[CH:46]=[CH:45][N:44]=[C:43]([C:38]2([CH3:37])[O:42][CH2:41][CH2:40][O:39]2)[CH:48]=1)=[O:7]
Reactant: O=C(O)/C=C/C(F)(F)C(F)(F)F
Reactant: CC1(c2cc(NCCN)ccn2)OCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(c2cc(NCCNC(=O)/C=C/C(F)(F)C(F)(F)F)ccn2)OCCO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(E)-4,4,5,5,5-Pentafluoropent-2-enoic acid (133 mg, 0.7 mmol) and HBTU (265 mg, 0.7 mmol) were dissolved in a 2:1 mixture of anhydrous DMF and anhydrous THF (3 ml) and stirred at room temperature for 15 minutes. N-[2-(2-Methyl-1,3-dioxolan-2-yl)-4-pyridyl]ethane-1,2-diamine (100 mg, 0.45 mmol) was added and stirring was continued for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 47 mg (0.12 mmol, 26%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Yield: 98.1 %

Procedure:
(S)-4-benzyl-2-oxazolidinone (2.26 g, 15.0 mmol) and 30 ml of dehydrated tetrahydrofuran were mixed, which was cooled to −78° C. under an atmosphere of argon. Under stirring, 1.6 mol/l solution of n-butyl lithium in hexane (10.3 ml, 16.5 mmol) was added dropwise for over 10 minutes and the mixture was stirred for 30 minutes as it was. Next, butyryl chloride (1.56 ml, 15.0 mmol) dissolved into 30 ml of dehydrated tetrahydrofuran was added dropwise for over 10 minutes and the mixture was stirred for 30 minutes, followed by stirring for 3 hours at room temperature. Saturated aqueous solution of ammonium chloride was added to the reaction mixture and concentrated. Water was added to the residue, which was extracted with ethyl acetate. The extract was washed with water and with brine, then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=1:1 v/v) to obtain 3.64 g (98%) of the title compound as a colorless oil.