Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[OH:15]O>C(O)(=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N+:6]=1[O-:15]
Reactant: Clc1ccccc1Cc1ccccn1
Reactant: OO
Solvent: CC(=O)O
Product: [O-][n+]1ccccc1Cc1ccccc1Cl
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A solution of 2-(o-chlorobenzyl)pyridine (32 g, 0.16 moles) and hydrogen peroxide (30% w/v, 10.7 g, 36.0 ml, 0.31 moles) in glacial acetic acid (100 ml) was heated at 75° C. for 17 hours. The reaction mixture was cooled to room temperature, the acetic acid evaporated under reduced pressure and the residue dissolved in chloroform. After neutralisation with potassium carbonate (30 g) the chloroform was removed to give 2-(o-chlorobenzyl)pyridine-N-oxide (34.4 g, 100%) as a viscous oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:15][C:16](=[O:18])[NH2:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl.[CH3:21][N:22]([CH2:24][CH:25]([OH:35])[CH2:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH3:23].N>CN1C(=O)CCC1>[CH3:23][N:22]([CH2:24][CH:25]([OH:35])[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:2]2[N:7]=[C:6]([N:8]([CH2:15][C:16](=[O:18])[NH2:17])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:33][CH:34]=1)[CH3:21]
Reactant: NC(=O)CN(c1ccccc1)c1ccnc(Cl)n1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Agent: Cl
Agent: N
Solvent: CN1CCCC1=O
Product: CN(C)CC(O)COc1ccc(Nc2nccc(N(CC(N)=O)c3ccccc3)n2)cc1
Temperature: 120 °C

Procedure:
2-Chloro-4-(N-(carbamoylmethyl)anilino)pyrimidine (prepared by analogy to Method A and the corresponding Reference Examples A-1–A-10) (390 mg, 1.49 mmol) was dissolved in NMP (3 ml) and 4-[3-(N,N-dimethyl)amino-2-hydroxypropoxy]aniline dihydrochloride (Reference Example D-1; 378 mg, 1.34 mmol) was added. The resulting suspension was heated at 120° C. which caused the solid to dissolve. The reaction mixture was heated at 120° C. for 12 hours and allowed to cool to ambient temperature. The reaction mixture was then basified to pH 9–10 using methanolic ammonia and then evaporated onto silica (5 ml). The residue was purified by column chromatography eluting with methanol (15%):DCM:aqueous ammonia (1%). The resulting gum was re-evaporated from EtOAc three times to give the title product as a foam (184 mg). NMR: (300 MHz) 2.31 (s, 6H), 2.49 (m, 2H), 3.8 (m, 1H), 3.92 (m, 2H), 4.42 (s, 2H), 5.68 (d, 1H), 6.79 (d, 2H), 7.4) (m, 5H), 7.58 (d, 2H), 7.82 (d, 1H), 8.93 (s, 1H); m/z: (ES+) 437.5 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[C:3]([C:9]([OH:11])=[O:10])=[CH:2]1.Cl[Si](C)(C)C.[CH3:17][CH:18]([CH3:21])[CH2:19]O>>[S:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:17][CH:18]([CH3:21])[CH3:19])=[O:7])[C:3]([C:9]([O:11][CH2:2][CH:3]([CH3:9])[CH3:4])=[O:10])=[CH:2]1
Reactant: CC(C)CO
Reactant: O=C(O)c1cscc1C(=O)O
Agent: C[Si](C)(C)Cl
Product: CC(C)COC(=O)c1cscc1C(=O)OCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A mechanically stirred slurry of 5.00 g of thiophene-3,4-dicarboxylic acid (purchased from Aldrich) in 58.2 mL of 2-methyl-1-propanol was treated with 11.0 mL of chlorotrimethylsilane at room temperature. After completion of the addition, the reaction mixture was stirred at room temperature for 1 h, then at 65° C. for one day, quenched with water at 0° C. and extracted with ether. The combined organic phases were washed with saturated water solution of sodium carbonate, brine, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator, and distilled in vacuum to give 7.86 g (95%) of the title compound of 99.6% GC-purity (bp 113° C./1 mm Hg; colorless oil).
Reaction SMILES: ClC1C=CC(C2C3C=C(OC)C=CC=3N3C(C)=NN=C3[C@H](CC(O)=O)N=2)=CC=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:42]3[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:41]=3[N:40]3[C:49]([CH3:52])=[N:50][N:51]=[C:39]3[C@H:38]([CH2:53][C:54]([NH:56][CH2:57][CH3:58])=[O:55])[N:37]=2)=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.NC[CH2:94][CH2:95][CH2:96][NH:97][C:98](=[O:104])[O:99][C:100]([CH3:103])([CH3:102])[CH3:101]>>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[C:42]3[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:41]=3[N:40]3[C:49]([CH3:52])=[N:50][N:51]=[C:39]3[C@H:38]([CH2:53][C:54]([NH:56][CH2:57][CH2:58][CH2:94][CH2:95][CH2:96][NH:97][C:98](=[O:104])[O:99][C:100]([CH3:103])([CH3:102])[CH3:101])=[O:55])[N:37]=2)=[CH:34][CH:35]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2-n2c(C)nnc21
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)NCCCCCNC(=O)OC(C)(C)C)c1nnc(C)n1-2
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
A mixture of [(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetic acid (for a preparation see Reference compound H) (1.0 g, 2.5 mmol), HATU (1.9 g, 5 mmol) and DIPEA (0.88 ml, 5 mmol) was stirred for 80 minutes at room temperature, to this was added 1,1-dimethylethyl (4-aminobutyl)carbamate (1.05 ml, 5.0 mmol, available from Aldrich). The reaction mixture was stirred at room temperature for 2 h before it was concentrated. The residue was taken up in dichloromethane and washed with 1N HCl. The aqueous layer was extracted with dichloromethane twice. Organic layer was washed with 1N sodium hydroxide, followed by a saturated solution of sodium chloride, dried over sodium sulphate and concentrated. The residue was purified by flash-chromatography on silica using dichloromethane/methanol 95/5 to give the title compound as a yellow solid (1.2 g). LC/MS (Method A): rt=3.04 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:10]=1)[C:5]([OH:7])=O.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH2:41]([NH:44][CH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)[CH:42]=[CH2:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:44]([CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[CH2:41][CH:42]=[CH2:43])=[O:7])[CH:8]=[C:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(=O)O)c1
Reactant: C=CCNC1CCCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(C(=O)c1cc(Cl)cc(O[Si](C)(C)C(C)(C)C)c1)C1CCCC1
Reaction time: 0.08 h
Yield: 99.4 %

Procedure:
To a solution of 3-chloro-5-(tert-butyldimethylsilyloxy)benzoic acid (17.5 g, 60 mmol), as prepared in the preceding step, and CH2Cl2 (250 mL) were added triethylamine (33.8 mL, 0.24 mol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (17.0 g, 66 mmol). The resulting mixture was stirred for 5 min, then N-allylcyclopentylamine (9.8 mL, 66 mmol) was added. After 1 h, the solution was filtered. The filtrate was washed with 10% aqueous HCl (100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL). The organic layer was dried over anhydrous MgSO4, concentrated in vacuo, and flash chromatographed to provide the title compound as a colorless oil (23.5 g, 97%). 1H NMR (CDCl3) δ 6.95 (s, 1H), 6.84 (s, 1H), 6.71 (s, 1H), 5.93 (br s, 1H), 5.16 (d, 2H), 3.95 (br s, 3H), 1.4-1.9 (m, 8H), 0.97 (s, 9H), 0.20 (s, 6H). Mass spectrum (CI) calcd. for C21H32NO2SiCl: 394 (M+H). Found: 394.
Reaction SMILES: CCCCCC.[H-].[Na+].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[C:17]#[N:18])=[N:14][CH:15]=1.Br[CH2:28][CH2:29][CH2:30][Cl:31]>CN(C=O)C.CCOCC.O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)([CH2:28][CH2:29][CH2:30][Cl:31])[C:17]#[N:18])=[N:14][CH:15]=1
Reactant: COc1cccc(C(C#N)c2ccc(Br)cn2)c1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C(C#N)(CCCCl)c2ccc(Br)cn2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a suspension of hexane washed 60% sodium hydride (0.35 g, 8.6 mmol) in DMF (2 mL) at 0° C. was added a solution of (5-bromo-pyridin-2-yl)-(3-methoxy-phenyl)-acetonitrile (1.75 g, 5.76 mmol) in DMF (5 mL). The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 1 h. 1-bromo-3-chloropropane (0.69 mL, 6.91 mmol) was added and the mixture was stirred at room temperature for 4 h. To the reaction mixture was added H2O (5 mL) and Et2O and the organic layer was washed with brine (5×5 mL), dried over Na2SO4 and concentrated. Purification by flash chromatography with hexanes/EtOAc (10:1) yielded 1.81 g of 2-(5-bromo-pyridin-2-yl)-5-chloro-2-(3-methoxy-phenyl)-pentanenitrile. 1HNMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.76 (dd, 1H), 7.36 (d, 1h), 7.27-7.21 (m, 1H), 7.03 (d, 1H), 6.98 (s, 1H), 6.82 (dd, 1H), 4.77 (s, 3H), 3.55 (t, 2H), 2.79-2.70 (comp, 1H), 2.62-2.52 (comp, 1H), 1.89-1.79 (comp, 2H); MS (M+1) 378.8, 380.8.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.[C:21]([C:23]1[S:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[F-].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(COC)OC>[C:21]([C:23]1[S:27][C:26]([C:2]2[CH:20]=[CH:19][C:5]([O:6][C@@H:7]3[CH2:11][CH2:10][CH2:9][C@@H:8]3[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:4][CH:3]=2)=[CH:25][CH:24]=1)#[N:22]
Reactant: CC(C)S(=O)(=O)N[C@H]1CCC[C@H]1Oc1ccc(Br)cc1
Reactant: N#Cc1ccc(B(O)O)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: COCCOC
Product: CC(C)S(=O)(=O)N[C@H]1CCC[C@H]1Oc1ccc(-c2ccc(C#N)s2)cc1

Procedure:
To a microwave vial was added N-[(1S,2R)-2-(4-bromophenoxy)cyclopentyl]propane-2-sulfonamide (150.0 mg, 0.414 mmol), (5-cyano-2-thienyl)boronic acid (95.0 mg, 0.621 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (20.2 mg, 0.0410 mmol), palladium(II) acetate (7.4 mg, 0.033 mmol) and potassium fluoride (120 mg, 2.07 mmol). Dimethoxyethane (1.5 mL) was added and the reaction mixture was purged three times with nitrogen/vacuum. The reaction was subjected to microwave irradiation at 120° C. for 2 hours, then solvent was removed in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, dried over calcium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel (Eluant: 40% ethyl acetate in heptane), to afford the title compound as a yellow oil which subsequently solidified. Yield: 104 mg, 0.266 mmol, 64%. LCMS m/z 391.0 (M+1). 1H NMR (500 MHz, CDCl3) δ 1.36 (d, J=6.8 Hz, 3H), 1.39 (d, J=6.8 Hz, 3H), 1.66 (m, 1H), 1.81-1.94 (m, 3H), 1.99 (m, 1H), 2.14 (m, 1H), 3.15 (septet, J=6.8 Hz, 1H), 3.89 (m, 1H), 4.64 (d, J=9.5 Hz, 1H), 4.69 (m, 1H), 6.95 (d, J=8.7 Hz, 2H), 7.18 (d, J=4.0 Hz, 1H), 7.54 (d, J=8.7 Hz, 2H), 7.57 (d, J=3.9 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[NH:12][C:11]([C:20]([F:23])([F:22])[F:21])=[C:10]2[C:24]([O-:26])=[O:25])[CH:6]=[CH:7][CH:8]=1)#[N:2].NC(OCC)=O>>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[NH:12][C:11]([C:20]([F:22])([F:23])[F:21])=[C:10]2[C:24]([OH:26])=[O:25])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(C2C3=C(CCCC3=O)NC(C(F)(F)F)=C2C(=O)[O-])c1
Agent: CCOC(N)=O
Product: N#Cc1cccc(C2C3=C(CCCC3=O)NC(C(F)(F)F)=C2C(=O)O)c1

Procedure:
In the invented process, an ester of 4,4,4-trifluoro-3-oxobutanoate is reacted with 1,3-cyclohexanedione and 3-cyanobenzaldehyde to form an ester of 4-(3-cyanophenyl)-2-hydroxy-5-oxo-2-(trifluoromethyl)-1,2,3,4,5,6,7,8-octahydroquinoline-3-carboxylate. The 4-(3-cyanophenyl)-2-hydroxy-5-oxo-2-(trifluoromethyl)-1,2,3,4,5,6,7,8-octahydroquinoline-3-carboxylate ester is dehydrated to form a urethane, which is an ester of 4-(3-cyanophenyl)-5-oxo-2-(trifluoromethyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate. The urethane is de-esterified to form 4-(3-cyanophenyl)-5-oxo-2-(trifluoromethyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH2:15][C:16]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:23](OCC)[N:24]([CH3:26])[CH3:25])C>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[CH:23][N:24]([CH3:26])[CH3:25])[C:16]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)N(C)C
Reactant: O=C1CCCc2ccc(OCc3ccccc3)cc21
Product: CN(C)C=C1CCc2ccc(OCc3ccccc3)cc2C1=O

Procedure:
7-Benzyloxy-3,4-dihydro-2-dimethylaminomethylene-1(2H)naphthalenone was prepared from 7-benzyloxy-3,4-dihydro-1(2H)naphthalenone (6.0 g, 23.8 mmol) and N,N-dimethylformamide diethylacetal (20 ml, 119.4 mmol) to give the desired compound as a pale yellow solid (4.56 g) m.p. 85-86°. MS(ES+) 308 (MH+, 100%).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Br:7][C:8]1[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:18][CH2:17]1.N1C=CC=CC=1.Cl>C(Cl)Cl>[Br:7][C:8]1[CH:9]=[C:10]([NH:19][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:11]=[N:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:18][CH2:17]1
Reactant: Nc1cnc(OCC2CC2)c(Br)c1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cnc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
Ethylsulfonyl chloride (170 uL, 1.8 mmol) was added to a stirred solution of 5-bromo-6-(cyclopropylmethoxy)pyridin-3-amine (440 mg, 1.8 mmol) and pyridine (725 uL) in DCM (4.5 mL) at 0° C. under nitrogen. After the mixture was allowed to warm to rt and stir for 12 h, it was treated with 1N HCl (15 mL) and extracted with DCM (3×15 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (0 to 100%) in DCM to afford the title compound (181 mg, 88%) as a tan solid. LCMS (M+H)+=336.
Reaction SMILES: Cl[CH2:2][SiH:3]([CH3:5])[CH3:4].[Mg].[CH3:7][SiH:8](Cl)Cl.O>O1CCCC1>[CH3:4][SiH:3]([CH2:2][SiH:8]([CH3:7])[CH2:2][SiH:3]([CH3:5])[CH3:4])[CH3:5]
Reactant: C[SiH](C)CCl
Reactant: C[SiH](Cl)Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: C[SiH](C)C[SiH](C)C[SiH](C)C
Temperature: 25 °C
Yield: 91.4 %

Procedure:
A solution of 70 g of chloromethyldimethylsilane in 400 ml of anhydrous tetrahydrofuran (THF) was added dropwise to 20 g of magnesium powder in a flask equipped with a mechanical stirrer and a condenser. The rate of addition was regulated to maintain reflux for the Grignard solution. To this Grignard reagent solution was then added dropwise 37 g of methyldichlorosilane in 300 ml THF. The resultant mixture was stirred overnight with gentle reflux. After cooled down to room temperature, the reaction was worked up by adding water. The organic phase was separated and dried over anhydrous sodium sulfate. Solvent (THF) was removed by atmospheric pressure distillation. Vacuum distillation at 85° C./20 mm yielded 56 g of 2,4,6-trimethyl-2,4,6-trisila-heptane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][C:10]([CH3:12])=[CH2:11])[CH:3]=1.II>C(Cl)Cl.C(OC)(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:10]([CH3:12])([CH3:11])[CH2:9][C:4]=2[CH:3]=1
Reactant: C=C(C)Cc1cc(Br)ccc1O
Agent: II
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CC1(C)Cc2cc(Br)ccc2O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
To a solution of 4-bromo-2-(2-methylallyl)phenol (7) (4.5 g, 19.8 mmol) in CH2Cl2 (250 mL) was added iodine (1.3 g, 4.95 mmol) and the mixture stirred at room temperature for 48 h. The mixture was then diluted with methyl tert-butyl ether (100 mL) and washed with H2O (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, eluting with 5% ethyl acetate in hexanes) to give the title compound (8) (4.0 g, 88%) as yellow liquid. 1H NMR (CDCl3, 400 MHz) δ 7.24 (s, 1H), 7.20 (d, J=8.4 Hz, 1H), 6.61 (d, J=8.4 Hz, 1H), 3.00 (s, 2H), 1.47 (s, 6H); MS (ESI, M+H+) C10H12BrO, calcd. 227.1. found 227.0, 229.0.
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].[CH2:9]([N:12]([CH:19]([OH:34])[C@H:20]1[O:26][C@:24]([CH2:27][CH:28]([CH3:30])[CH3:29])([OH:25])[C@H:23]([OH:31])[C@@H:22]([OH:32])[C@@H:21]1[OH:33])[C:13](=[O:18])[NH:14][CH2:15][CH2:16][Cl:17])[CH2:10][CH3:11].O1CCOCC1.S(=O)(=O)(O)O>CO>[CH2:9]([N:12]([CH:19]([OH:34])[C@H:20]1[O:26][C@:24]([CH2:27][CH:28]([CH3:29])[CH3:30])([OH:25])[C@H:23]([OH:31])[C@@H:22]([OH:32])[C@@H:21]1[OH:33])[C:13](=[O:18])[N:14]([CH2:15][CH2:16][Cl:17])[N:1]=[O:2])[CH2:10][CH3:11]
Reactant: CC(C)CCON=O
Reactant: CCCN(C(=O)NCCCl)C(O)[C@H]1O[C@@](O)(CC(C)C)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CO
Product: CCCN(C(=O)N(CCCl)N=O)C(O)[C@H]1O[C@@](O)(CC(C)C)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 68.4 %

Procedure:
Isoamyl nitrite (4 ml) was dropped into a solution of the above synthesized 3-n-propyl-3-(isobutyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)urea (3.47 g, 9.06 mmol) in a mixture of methanol (50 ml), dioxane (150 ml), and 10% sulfuric acid (50 ml), with well stirring at 0° to 5° C. After stirring for further 3 hours to complete reaction, which was confirmed by TLC, the reaction mixture was vacuum-concentrated at 25° C. and crystallized from ethanol and water, giving 2.55 g of 3-n-propyl-3-(isobutyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)-1-nitrosourea; yield 68.4%, m.p. 58°-60° C., [α]D20 +71.7° (C 1.0, methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:40])([C:31]([F:39])([F:38])[C:32]([F:37])([F:36])[CH:33]([F:35])[F:34])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[NH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:28]1[CH:27]=[N:26][N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:40])[C:31]([F:38])([F:39])[C:32]([F:37])([F:36])[CH:33]([F:35])[F:34])=[CH:24][CH:23]=2)[C:29]1=[O:30])[CH3:13]
Reactant: O=c1[nH]cnn1-c1ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1cnn(-c2ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 61.7 %

Procedure:
In the same manner as in Reference Example 5, starting from 345 mg of (1S)-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 410 mg of 2-[4-(2,2,3,3,4,4,5,5-octafluoropentoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 371 mg of 4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-2-[4-(2,2,3,3,4,4,5,5-octafluoropentoxy)phenyl]-3(2H,4H)-1,2,4-triazolone was obtained as colorless prisms.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](O)(=O)[CH2:16][CH3:17]>P(Cl)(Cl)(Cl)=O>[CH2:16]([C:17]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]=1)[CH3:15]
Reactant: Nc1cnccc1Nc1ccccc1
Reactant: CCC(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc2cnccc2n1-c1ccccc1
Yield: 19.3 %

Procedure:
A mixture of N4-phenylpyridine-3,4-diamine (8.0 g, 37.2 mmol), propionic acid (2.7 g, 37.2 mmol) and phosphorous oxychloride (50 mL) was stirred at reflux for 10 h. The reaction was purified by silica gel chromatography using ethyl acetate to afford the product as a solid (1.6 g, 19%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([CH2:13][S:14](Cl)(=[O:16])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br.[Br:19][CH2:20][CH2:21][NH2:22].O>C(Cl)Cl>[Br:19][CH2:20][CH2:21][NH:22][S:14]([CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:16])=[O:15]
Reactant: NCCBr
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(Cc1ccccc1)NCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
K2CO3 (8.7 g, 62 mmol) was added into a mixture of phenylmethanesulfonyl chloride (6 g, 31 mmol) and 2-bromoethanamine hydrobromide (6.4 g, 31 mmol) in DCM (100 mL) at 0° C. And the resulting mixture was stirred at r.t. for 4 hours and left standing overnight. Upon the completion of reaction, water (100 mL) was added in and DCM phase was separated. The aqueous phase was extracted with DCM. The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo to provide a crude which was separated with column chromatography (silica gel with 200-300 mesh, 0 to 50% of EtOAc in petroleum ether) to provide compound N-(2-bromoethyl)(phenyl)methanesulfonamide (7.0 g, 80%) as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.40 (m, 5H), 4.58 (m, 1H), 4.29 (s, 2H), 3.34-3.29 (m, 4H). LCMS (ESI), 300, 302 [M+Na]+, Br pattern found.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][OH:16])[CH2:12][OH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CCN(CC)CC.[CH3:30][C:31](OC(C)=O)=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:31]([O:13][CH2:12]/[C:11](/[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1)=[C:14](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)\[CH2:15][OH:16])(=[O:32])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)c1ccc(C(CO)=C(CO)c2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC/C(=C(\CO)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-(4-(methylsulfonyl)phenyl)-3-phenyl-2butene-1,4-diol (149 mg) and Et3N (0.2 mL) in 20 mL of CH2Cl2 was treated with Ac2O (0.05 mL) and DMAP (5 mg). After stirring for 10 min at r.t., the mixture was concentrated, and the residue was purified by flash chromatography eluted with 3:2 EtOAc/hexane to afford 40 mg of the title compound as a white solid along with 30 mg of its regioisomer as a syrup.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.CC(C)([O-])C.[K+].F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[C:24]([F:27])([F:26])[F:25]>O1CCCC1>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([O:1][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=2[C:24]([F:25])([F:27])[F:26])[CH2:3][CH2:4]1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CN1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc(C#N)cc2C(F)(F)F)CC1
Reaction time: 0.17 h
Yield: 55.1 %

Procedure:
A mixture of 4-hydroxy-N-methylpiperidine (133 mg, 1.15 mmol) and potassium tert-butoxide (150 mg, 1.27 mmol) in tetrahydrofuran (2.5 mL) was stirred under nitrogen for 10 min. 4-Fluoro-3-(trifluoromethyl)benzonitrile (218 mg, 1.15 mmol) was added, and the reaction mixture was stirred at ambient temperature for 1 h. The solvent was removed in vacuo, and the residue was partitioned between a 1 M NaOH solution and ethyl acetate. The organic layer was dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (eluent: CHCl3/MeOH/conc. NH3, 95:5:0.5) affording 0.18 g (54% yield) of the pure product as a colourless solid. MS (APCI) m/z 285 [M+H]. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.67-1.74 (m, 2 H), 1.89-1.95 (m, 2 H), 2.16 (s, 3 H), 2.26-2.31 (m, 2 H), 2.44-2.48 (m, 2 H), 4.78-4.82 (m, 1 H), 7.51 (d, J=8.8 Hz, 1 H), 8.08 (dd, J=8.8, 2.0 Hz, 1 H), 8.14 (d, J=2.0 Hz, 1 H).