Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:16]([Li])CCC.[C:21]([Si:25]([CH3:55])([CH3:54])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[C:31]3[C:44](=[O:45])[O:43][C:42]4[CH:41]=[C:40]([O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[CH:39]=[CH:38][C:37]=4[C:32]=3[CH2:33][O:34][C:35]=2[CH:36]=1)([CH3:24])([CH3:23])[CH3:22].C[Mg]Br>C1COCC1>[C:50]([Si:47]([CH3:49])([CH3:48])[O:46][C:40]1[CH:39]=[CH:38][C:37]([C:32]2[CH2:33][O:34][C:35]3[C:30]([C:31]=2[C:44]([OH:45])([C:2]2[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)=[CH:4][CH:3]=2)[CH3:16])=[CH:29][CH:28]=[C:27]([O:26][Si:25]([C:21]([CH3:23])([CH3:24])[CH3:22])([CH3:55])[CH3:54])[CH:36]=3)=[C:42]([OH:43])[CH:41]=1)([CH3:51])([CH3:52])[CH3:53]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCc1c-2c(=O)oc2cc(O[Si](C)(C)C(C)(C)C)ccc12
Reactant: [Li]CCCC
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(C1=C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2O)COc2cc(O[Si](C)(C)C(C)(C)C)ccc21)c1ccc(OCCN2CCCC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[2-(4-bromophenoxy)-ethyl]-pyrrolidine (331 mg, 1.22 mmol) in THF (7.5 mL) at −78° C., was added n-butyl lithium (2.5 M in hexane, 478 μL, 1.19 mmol). The mixture was stirred at −78° C. for 0.5 hours. To this mixture was then added 2,8-bis-(tert-butyl-dimethyl-silyloxy)-11H-chromeno[4,3-c]chromen-5-one (153 mg, 0.30 mmol) in THF (3 mL), prepared as in Example 22. The reaction mixture was then stirred at −78° C. for 1.5 hours. To this mixture was added methyl magnesium bromide (3 M in diethyl ether, 1 mL, 2.99 mmol) at −78° C. and the reaction mixture stirred at room temperature overnight. The reaction was quenched with aqueous NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated to yield the crude product as a yellow oil. The crude product was carried to the next step without further purification.
Reaction SMILES: [S@@:1]1(=[O:10])[N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]2[CH2:3][O:2]1.[O-:11]I(=O)(=O)=O.[Na+].O>C(#N)C.C([O-])(O)=O.[Na+].CCOC(C)=O.O.[Ru](Cl)(Cl)Cl>[S:1]1(=[O:11])(=[O:10])[N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]2[CH2:3][O:2]1
Reactant: O=[S@@]1OCC2CCCCN21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: O=S1(=O)OC[C@@H]2CCCCN21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-Hexahydro-[1,2,3]oxathiazolo[3,4-a]pyridine 1-oxide (1.31 g, 8.125 mmol) in anhydrous acetonitrile (10 mL) was added sodium (meta)periodate (1.91 g, 8.9375 mmol), followed by ruthenium(III) chloride hydrate (17 mg, 0.08125 mmol), and then H2O (10 mL). The mixture was stirred at 0° C. for 10 min and at rt for 20 min, then diluted with saturated NaHCO3 (30 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (80 mL) and DCM (80 mL). The combined organic layer was dried over Na2SO4, concentrated in vacuo, and purified by flash column chromatography (silica gel, 2% EtOAc in DCM) to afforded the title product as a clear, colorless oil (1.1 g, 76%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]2[N:5]([CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[SH:12][C:13]1[NH:14][C:15]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:16]=2[N:17]=1>>[OH2:1].[N:11]1[CH:10]=[CH:9][N:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][S:12][C:13]3[NH:17][C:16]4[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:15]=4[N:14]=3)[C:4]=12.[N:11]1[CH:10]=[CH:9][N:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][S:12][C:13]3[NH:17][C:16]4[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:15]=4[N:14]=3)[C:4]=12
Reactant: Cc1ccc2nc(S)[nH]c2c1
Reactant: OCc1cccn2ccnc12
Product: Cc1ccc2[nH]c(SCc3cccn4ccnc34)nc2c1
Product: O

Procedure:
A mixture of 12.2 g (0.1 mole) of 3,4-diaminotoluene, 35 ml of carbon disulfide, and 4.0 g (0.1 mole) of sodium hydroxide was heated at reflux in 350 ml of ethanol. After 2.5 hours the mixture was concentrated in vacuo. The residue was suspended in 200 ml of 4% aqueous hydrochloric acid, collected by filtration, washed sequentially with water and diethyl ether, and air dried to yield 12.2 g of 2-mercapto-5-methylbenzimidazole, as confirmed by the nmr and infrared spectra. The title compound (796 mg) was prepared by the method of Example 6 using 8-hydroxymethylimidazo[1,2-a]pyridine as the hydrochloride salt and using 569 mg (3.5 mmole) of 2-mercapto-5-methylbenzimidazole instead of 2-mercapto-5-methoxybenzimidazole. Structure assignment was supported by elemental analysis.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[NH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:3]([CH:2]=[O:1])[C:4]=2[CH:5]=[CH:6]1
Reactant: OCc1cccc2[nH]ccc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Tetrapropylammonium perruthenate (0.3 g, 0.85 mmol) was added in portions to a mixture of alcohol product from Step A (2.5 g, 17 mmol), N-methylmorpholine N-oxide (3.0 g, 25 mmol) and 4 Å molecular sieves (3.0 g) in anhydrous methylene chloride (30 mL) at room temperature. The mixture was stirred at room temperature under nitrogen for 1 h and then filtered. The filtrate was concentrated in vacuo, and the residue was purified by chromatography (SiO2, CH2Cl2) to provide indole-4-aldehyde as a white powder (2.0 g, 80%): 1H NMR (300 MHz, CDCl3) δ 10.2 (s, 1H), 8.52 (br s, 1H), 7.64-7.69 (m, 2H), 7.31-7.44 (m, 3H); CI MS m/z=146 [C9H7NO+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:11])[C:3]([NH:5][CH2:6][C:7]([F:10])([F:9])[F:8])=[O:4].[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[CH:15][N:14]=1>C(O)(C)C.C(OCC)(=O)C>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C@@H:2]([CH3:11])[C:3]([NH:5][CH2:6][C:7]([F:8])([F:9])[F:10])=[O:4])[CH:16]=[CH:15][N:14]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[C@H](N)C(=O)NCC(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: C[C@H](Nc1ccnc(Cl)n1)C(=O)NCC(F)(F)F

Procedure:
To a solution of (S)-2-amino-N-(2,2,2-trifluoroethyl)propanamide (FF) (1 g, 3.35 mol, 1 equiv.) in iso-propanol (10 mL), Huning's base (1.5 mL) was added, followed by 2,4-dichloropyrimidine (JJ). The resulting mixture was refluxed for 18 h. The reaction mixture was then diluted in ethyl acetate, washed with aqueous HCl 0.5 M and water, and dried over anhydrous Na2SO4. The crude oil was then purified by flash chromatography on silica gel, eluting with hexanes/ethyl acetate mixtures (100:0 to 0:100). The title compound HH was isolated as a white solid (600 mg, 63%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:12][C:13]1[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>ClCCl.CN(C=O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][C:15]=1[NH:20][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:11]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: Nc1ccc(Cl)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1ccc(Cl)cc1NC(=O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
Method 7—Step a A mixture of 5-Bromo-2-fluoro-benzoic acid (3.00 g, 13.70 mmol), 4-chloro-benzene-1,2-diamine (2.42 g, 16.99 mmol), HATU (5.47 g, 14.38 mmol) and TEA (1.91 mL, 13.83 mmol) in dichloromethane (70 mL) and DMF (16 mL) was stirred at room temperature overnight, then water was added (80 mL) and left standing at room temperature overnight. The organic layer was divided and solvent removed under reduced pressure and the crude oil obtained was crystallized from the mixture of solvents dichloromethane:cyclohexane/3:1 (30 mL) to afford 2.19 g of the title compound (52%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[N:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[NH:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[C:29]([NH:1][C:2]1[CH:3]=[C:4]([C:8](=[N:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[NH:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#CNC(=NCCc1ccccc1Cl)c1cncc(N)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CNC(=NCCc1ccccc1Cl)c1cncc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.3 %

Procedure:
To a solution of 5-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide (100 mg, 0.33 mmol) in DMF (3 ml) were added triethylamine (101 mg, 1 mmol) and benzoyl chloride (94 mg, 0.67 mmol), and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was neutralized by adding ice and a saturated aqueous sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (Wako Gel C-200, 30 g; eluted with chloroform:methanol=200:1) to give the title compound (38 mg, 0.09 mmol, yield 29%).
Reaction SMILES: [Br:1][CH:2]([C:4]1[N:5]=[C:6]2[S:13][CH:12]=[C:11]([CH3:14])[N:7]2[C:8](=[O:10])[CH:9]=1)[CH3:3].[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:9]1[C:8](=[O:10])[N:7]2[C:11]([CH3:14])=[CH:12][S:13][C:6]2=[N:5][C:4]=1[CH:2]([Br:1])[CH3:3]
Reactant: Cc1csc2nc(C(C)Br)cc(=O)n12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1csc2nc(C(C)Br)c(Br)c(=O)n12
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
A mixture of 7-(1-bromoethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (16.2 g, 59.3 mmol) and N-bromosuccinimide (15.8 g, 89.0 mmol) in acetonitrile (500 mL) was stirred at 80° C., under nitrogen, overnight. After removal of acetonitrile in vacuum, the resulting solid was dissolved in methylene chloride, washed with water, saturated Na2S2O3, saturated sodium bicarbonate, and brine; and then the organic layers dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to provide the desired product (19.5 g, 93.4%). LCMS calculated for C9H9Br2N2OS (M+H)+: m/z=350.9. Found: 351.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[NH:22][C:23]([NH:25][C@H:26]([CH3:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=S.[NH3:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[NH:22][C:23]([NH:25][C@H:26]([CH3:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[NH:34]
Reactant: COc1cc2c(NC(=S)N[C@H](C)c3ccccc3)ncnc2cc1OCC1CCN(C)CC1
Reactant: N
Product: COc1cc2c(NC(=N)N[C@H](C)c3ccccc3)ncnc2cc1OCC1CCN(C)CC1

Procedure:
Using an analogous procedure to that described in Example 29, 1 [6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]-3-[(R)-(+)-α-methylbenzyl]thiourea was reacted with ammonia to give the title compound; NMR Spectrum: (CDCl3)1.38-1.42 (m, 2H), 1.61 (d, 3H), 1.86-2.01 (q, 5H), 2.29 (s, 3H), 2.89 (d, 2H), 3.95 (m, 3H), 4.0 (d, 2H), 4.7 (q, 1H), 6.5 (br s, 1H), 7.12 (s, 1H), 7.29-7.31 (m, 5H), 7.79 (s, 1H), 8.53 (s, 1H); Mass spectrum: M+H+ 449.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:20])[C:10]2([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21]I.[H-].[Na+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]([O:20][CH3:21])[C:10]2([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:11][CH2:12]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)C1(C(O)c2ccc(Cl)c(Br)c2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(c1ccc(Cl)c(Br)c1)C1(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
16.0 g (44.2 mmol) of (+/−)-tert-butyl 1-[(3-bromo-4-chlorophenyl)(hydroxy)methyl]cyclopropanecarboxylate were dissolved in 80 ml of DMF, and 4.1 ml (66.6 mmol) of methyl iodide were added at RT. The reaction mixture was cooled to +10° C., and 1.95 g (60% in mineral oil, 48.7 mmol) of sodium hydride were added in several portions. Ten minutes after the addition had ended, the mixture was warmed to RT and stirred at RT for a further 1.5 h. The reaction mixture was then added to water and extracted three times with ethyl acetate. The combined organic phases were concentrated under reduced pressure and the residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1). This gave 15.3 g of the target compound (92.2% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH2:10])[CH3:9].Br[C:12]1[CH:13]=[C:14]([C:18]2([CH3:31])[C:23]([CH3:25])([CH3:24])[O:22][C:21](OCC)=[N:20][S:19]2(=[O:30])=[O:29])[CH:15]=[CH:16][CH:17]=1>ClCCl.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH:10][C:21]1[O:22][C:23]([CH3:25])([CH3:24])[C:18]([CH3:31])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:12][CH:13]=2)[S:19](=[O:30])(=[O:29])[N:20]=1)[CH3:9]
Reactant: C[C@H](N)c1ccccc1F
Reactant: CCOC1=NS(=O)(=O)C(C)(c2cccc(Br)c2)C(C)(C)O1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H](NC1=NS(=O)(=O)C(C)(c2ccccc2)C(C)(C)O1)c1ccccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.9 %

Procedure:
In a round-bottom flask, 92 mg of 5-(3-bromophenyl)-2-ethoxy-5,6,6-trimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide stereomer 1 were dissolved in 1.3 ml of dichloromethane and admixed with 45 mg of (S)-1-(2-fluorophenyl)ethylamine. After stirring at room temperature and under a gentle argon stream for 18 hours, the conversion was checked by LCMS. Since it was incomplete, the reaction mixture was taken up in 1.5 ml of THF and stirred at 50° C. for 5 hours. After the removal of the solvent under reduced pressure, the oily residue was stirred at 95° C. for 2 hours and then at room temperature for 48 hours. According to LCMS, the reaction remained incomplete. The residue was dissolved under inert gas in 2 ml of ethanol and, with addition of 50 mg of 10% Pd/C, stirred under a hydrogen atmosphere at room temperature for 16 hours. After the addition of a further 50 mg of 10% Pd/C, the reaction mixture was stirred under the same conditions for a further 24 hours. After filtration to remove solid constituents, the filtrate was concentrated by rotary evaporation and the residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was lyophilized. This gave the product (45.7 mg) with a molecular weight of 390.5 g/mol (C20H23FN2O3S); MS (ESI): m/e=391 (M+H+).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[C:9]([NH:12][C:13]([NH2:15])=[NH:14])(=[O:11])[CH3:10]>CC#N>[NH:14]1[C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=2[N:15]=[C:13]1[NH:12][C:9](=[O:11])[CH3:10]
Reactant: O=C1CCCCC1Cl
Reactant: CC(=O)NC(=N)N
Solvent: CC#N
Product: CC(=O)Nc1nc2c([nH]1)CCCC2
Reaction time: 0.08 h
Yield: 14.7 %

Procedure:
To a solution of 5 g (38 mmol) of 2-chloro-cyclohexanone in MeCN (150 mL) was added 7 g (69 mmol) of N-acetyl-guanidine. The mixture was refluxed for 24 h. After removal of all the solvent, the residue was stirred with sat. aq. Na2CO3 (50 mL) for 5 min, filtered, and the solid was dried to provide 1 g (14%) of N-(4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl)-acetamide. LCMS: 180 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 2.38 (m, 4H), 2.00(s, 3H), 1.65 (m, 4H) ppm.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].S(=O)(=O)(O)O.[CH3:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([OH:24])=[CH:21][C:22]=1[OH:23])=O>CO>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[NH:1][N:2]=[C:15]([C:17]1[CH:18]=[CH:19][C:20]([OH:24])=[CH:21][C:22]=1[OH:23])[CH3:14]
Reactant: NNc1ccccn1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(=NNc1ccccn1)c1ccc(O)cc1O
Reaction time: 8 h
Yield: 46.9 %

Procedure:
A total of 33.8 g (0.309 mol) of 2-hydrazinopyridine and 2 L of methanol were charged into a four-neck flask with a capacity of 3 L equipped with a reflux condenser, a thermometer, and a stirrer, and 1 mL of concentrated sulfuric acid was then dropwise added at room temperature under stirring. Then, 44.0 g (0.289 mol) of 2,4-dihydroxyacetophenone was charged and a reaction was conducted for 8 h at 40° C. under stirring. The precipitated crystals were taken out by filtration, washed with methanol and water and dried at 60° C. to obtain 33.0 g of 4-{1-[(2-pyridine-2-yl)hydrazono]ethyl}benzene-1,3-diol in the form of light-yellow crystals. The yield was 50%. GC/MS, 1H-NMR, and IR measurements were performed with respect to the obtained crystals. The results are shown below.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4]I.C[O-].[Na+].[F:15][C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[CH:19]=[CH:18][C:17]=1[C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>CO>[F:15][C:16]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:26][CH:27]=2)[CH:19]=[CH:18][C:17]=1[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:31][CH:30]=1
Reactant: CC(C)CCC[C@H](C)CCI
Reactant: Oc1ccc(-c2ccc(-c3ccc(O)cc3)c(F)c2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCCC(C)CCOc1ccc(-c2ccc(-c3ccc(OCCC(C)CCCC(C)C)cc3)c(F)c2)cc1
Reaction time: 5 h

Procedure:
80.5 g (0.3 mol) of (S)-3,7-dimethyl-1-iodoctane are added dropwise to a solution of 16.2 g (0.3 mol) of sodium methylate and 24.8 g (0.1 mol) of 1-fluoro-2,5-di(4-hydroxyphenyl)-benzene in 150 ml of methanol at the boiling point. After 5 hours, the mixture is worked up in the customary manner. Recrystallization gives pure 1-fluoro-2,5-di-[4-(3,7-dimethyloctyloxy)-phenyl]-benzene.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N+:11]([O-])=[CH:12]2>C(Cl)(Cl)Cl>[Cl:3][C:12]1[C:13]2[C:8](=[C:7]([Br:6])[CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccc2c(Br)cccc2c1
Solvent: ClC(Cl)Cl
Product: Clc1nccc2c(Br)cccc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Phosphorus oxychloride (5 ml) was added to a suspension of compound (1a) (7.83 g) in chloroform (120 ml), and the mixture was stirred overnight at 50° C. The solvent was distilled off under reduced pressure, and chloroform was added to the residue. The reaction solution was neutralized with an aqueous sodium hydroxide solution with cooling in an ice bath and partitioned into organic and aqueous layers. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and small amounts of chloroform and diethyl ether were added to the residue. The deposit was filtrated to obtain compound (1b) (5.83 g, 65%) as a white solid.
Reaction SMILES: [N:1]1[NH:2][C:3](NC)=[CH:4][CH:5]=1.[C:8]([N:16]=[C:17]=[S:18])(=O)C1C=CC=CC=1.[NH3:19]>CO>[NH:1]1[CH:5]=[CH:4][C:3]([CH2:8][NH:16][C:17]([NH2:19])=[S:18])=[N:2]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CNc1ccn[nH]1
Reactant: N
Solvent: CO
Product: NC(=S)NCc1cc[nH]n1
Yield: 72 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(a) by using 2H-pyrazol-3-yl-methylamine (1.20 g, 12.4 mmol), benzoyl isothiocyanate (1.8 mL, 13.6 mmol) and ammonia in methanol (7N, 60 mL) with the exception that the crude product isolated by filtration (1.39 g, 72% yield) was used in the next step without further purification. MS (ESI) m/z 157 (M+1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][N:16]=1)[CH2:9][C:10]#[CH:11]>>[C:17]1([C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:6]3[CH:5]=[CH:4][N:3]=[CH:2][CH:7]=3)=[N:16][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1.[C:17]1([C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C#CCCc1ncc(-c2ccccc2)o1
Reactant: Brc1ccccn1
Product: C(#Cc1ccccn1)CCc1ncc(-c2ccccc2)o1
Product: C(#Cc1ccncc1)CCc1ncc(-c2ccccc2)o1
Yield: 18.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (25 mg, 0.16 mmol) and 2-(but-3-ynyl)-5-phenyloxazole (31 mg, 0.16 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) and SCX column (DCM/MeOH 95:5, DCM/MeOH/NH4OH 90:5:0.1 to 90:9:1) to yield 4.0 mg (15 μmol, 9%) of 2-(4-(5-phenyloxazol-2-yl)but-1-ynyl)pyridine as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:14])[CH2:12]O)=[O:4].C(OC([N+](C(OCC)=O)=[N-])=O)C.C1(P([N:47]=[N+:48]=[N-:49])(C2C=CC=CC=2)=O)C=CC=CC=1.P>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:14])[CH2:12][N:47]=[N+:48]=[N-:49])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)CO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: P
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(C)CN=[N+]=[N-]

Procedure:
A mixture of 3-(2-Hydroxy-1-methyl-ethylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (213 mg, 0.257 mmol), diethyldiazodicarboxylate (250 μL, 1.59 mmol, 2 eq), diphenylphosphoryl azide (343 μL, 1.59 mmol, 2 eq) and trphenyl phosphine (417 mg, 1.59 mmol, 2 eq) was stirred at 21° until all starting alcohol was consumed. The reaction was evaporated to dryness and the crude residue purified on biotage with 5% EtOAc/hexane followed by 100% toluene as eluent. 3-(2-Azido-1-methyl-ethylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester was isolated as a solid (181 mg, 78%); 1H NMR (300 MHz, CDCl3) 1.33 (d, J=6.6 Hz, 3H), 3.38-3.46 (m, 2H), 3.78-3.81 (m, 1H), 6.82 (s, 1H), 7.36-7.41 (m, 3H), 7.60-7.62 (m, 2H).
Reaction SMILES: [CH:1]1([CH:6]([OH:9])[CH:7]=[CH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:10][C:11]1[CH:16]=[C:15](Br)[CH:14]=[CH:13][C:12]=1[CH:18]([F:20])[F:19].C([O-])(O)=O.[Na+].O>CN1C(=O)CCC1>[CH:1]1([C:6](=[O:9])[CH2:7][CH2:8][C:15]2[CH:14]=[CH:13][C:12]([CH:18]([F:20])[F:19])=[C:11]([F:10])[CH:16]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CC(O)C1CCCC1
Reactant: Fc1cc(Br)ccc1C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(CCc1ccc(C(F)F)c(F)c1)C1CCCC1
Temperature: 140 °C
Yield: 33.4 %

Procedure:
A mixture of 1-cyclopentyl-2-propen-1-ol (34 g, 0.266 mol), 2-fluoro-4-bromo-difluoromethyl benzene, (40 g, 0.177 mol, 1.5 equiv), and NaHCO3 (17.8 g, 0.212 mol, 1.2 equiv) in anhydrous NMP (200 mL) was heated to 140° C. for 1 h, resulting in complete conversion by TLC. The reaction mixture was poured into water and extracted with CH2Cl2. The organic layer was separated, washed with brine and dried over anhydrous Na2SO4. After the removal of the solvent, the residue was purified by column chromatography using hexanes/ethyl acetate, and the product-containing fractions combined and concentrated. The residue was fractionally distilled through a Vigreux column to give 16 g (33%) of the desired product (bp 100° C./0.2 Torr). 1H NMR (CDCl3) d 1.57 (m, 8H), 2.81 (m, 4H), 3.09 (m, 1H), 6.86 (t, 1H, J=57 Hz), 6.95 (m, 2H), 7.51 (t, 1H, J=7.5 Hz). MS (APCI) calcd for C15H17F3O, 270.29; found [M−19(−F)]: 251.02 m/z.