Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(OB=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10](=[O:13])([O-])[O-:11].[Na+].[Na+].Br[C:17]1[C:28]([O:29][CH3:30])=[CH:27][C:20]2C(=O)[O:22][C:23]([CH3:25])=[N:24][C:19]=2[CH:18]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O.COCCOC>[C:23]([NH:24][C:19]1[CH:18]=[C:17]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:28]([O:29][CH3:30])=[CH:27][C:20]=1[C:10]([OH:11])=[O:13])(=[O:22])[CH3:25]
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(=O)oc(C)nc2cc1Br
Reactant: O=BOc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)O)c(NC(C)=O)cc1-c1ccccc1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
Water (1.2 mL), phenylboranic acid (0.22 g), sodium carbonate (0.38 g), and bis(triphenylphosphine)palladium(II) dichloride (21 mg) were added to an ethylene glycol dimethyl ether (4 mL) suspension of the obtained 7-bromo-6-methoxy-2-methyl-4H-3,1-benzoxazin-4-one (0.40 g), followed by heating to reflux under a nitrogen atmosphere for 4 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The aqueous layer was separated, and the organic layer was extracted with a 2 mol/L aqueous solution of sodium hydroxide. The aqueous layer and the extract were combined. The resulting mixture was adjusted to a pH of 1 with 6 mol/L hydrochloric acid, and ethyl acetate was added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.27 g of 2-(acetamido)-5-methoxy-4-phenylbenzoic acid as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH4+:13].[OH-]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([NH2:13])(=[O:10])=[O:9])[CH:7]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc(F)cc1S(N)(=O)=O
Yield: 98 %

Procedure:
To a solution of 5-fluoro-2-methyl-benzenesulfonyl chloride (4.18 g, 20 mmol) in acetone (20 mL) was added, dropwise, concentrated NH4OH (3 mL) and the resulting mixture stirred for 5 min. Acetone was removed in vacuo and the precipitates were filtered, washed thoroughly with water and dried in vacuo to provide 3.7 g (Yield 98%) of the title compound as a white solid; 1H NMR (500 MHz, DMSO-D6) δ ppm: 2.55 (3 H, s) 7.33-7.40 (1 H, m) 7.40-7.46 (1 H, m) 7.54 (2 H, s) 7.59 (1 H, dd, J=9.2, 2.7 Hz); LC/MS m/z 190 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH:21]=[CH2:22]>C(#N)C>[CH2:22]([O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1])[CH2:21][CH:20]=[CH2:19]
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCCOc1ccc([N+](=O)[O-])cc1F

Procedure:
To an acetonitrile (40 mL) solution of 2-fluoro-4-nitrophenol (2.36 g; 15.1 mmol) and potassium carbonate (2.77 g; 20.1 mmol), 4-bromo-1-butene (2.81 g; 20.4 mmol) was added, and the mixture was refluxed and then reacted for 16 hours. After completion of the reaction, the solution was filtrated by Celite, and then the filtrate was concentrated under a reduced pressure. The residue was purified by flash column chromatography using methylene chloride, and then the effluent was concentrated to obtain 4-(3-butenyloxy)-3-fluoronitrobenzene (1d) (2.57 g, 81% of yield, a light yellow oil) represented by the following formula.
Reaction SMILES: [CH:1](OCC)=[O:2].C[O-].[Na+].[CH2:9]([C:16]1([C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][C:19](=[O:22])[CH:18]=[CH:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1.C(Cl)Cl.C(OCC)C>[CH2:9]([C:16]1([C:23]#[C:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[CH2:21][C:20](=[CH:1][OH:2])[C:19](=[O:22])[CH:18]=[CH:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)C#CC1(Cc2ccccc2)C=CC(=O)CC1
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: CCOCC
Product: C[Si](C)(C)C#CC1(Cc2ccccc2)C=CC(=O)C(=CO)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
Under an argon atmosphere, ethyl formate (110.6 μL, 1.33 mmol, 5 eq) then sodium methoxide (71.7 mg, 1.33 mmol, 3 eq) were successively added to a solution of 31 (75 mg, 0.265 mmol) in dry benzene (3.07 mL). This mixture was stirred at room temperature for 1 hour, during which time a color change from orange to red-brown occurred. The mixture was then diluted with a mixture of methylene chloride/ethyl ether (1:2, 20 mL) and washed with saturated aqueous ammonium chloride solution (2×8 mL). The aqueous washings were combined and extracted with methylene chloride/ethyl ether (1:2, 3×10 mL). The organic layers were then combined and washed with brine (1×10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 4-benzyl-6-hydroxymethylene-4-((trimethyl-silyl)ethynyl)cyclohex-2-enone (83 mg, 100%) as a yellow-brown oil. The product was used in the next reaction without further purification: 1H NMR (CDCl3) δ 13.67 (1H, bs), 7.45 (1H, bs), 7.23-7.16 (5H, m), 6.51 (1H, dd, J=1, 10.5 Hz), 5.98 (1H, d, J=10 Hz), 2.84 (1H, d, J=13 Hz), 2.68 (1H, d, J=13 Hz), 2.57 (1H, dd, J=1, 14.5 Hz), 2.40 (1H, d, J=15 Hz); 13C NMR (CDCl3) δ 187.5, 168.7, 151.4, 136.0, 130.8, 128.5, 128.1, 127.2, 127.1, 109.9, 108.0, 44.4, 38.9, 34.6, 0.10.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[Cl:25][C:26]1[C:31]([OH:32])=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:25][C:26]1[C:31]([O:32][C:2]2[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:13]([O:23][CH3:24])[CH:12]=3)[N:3]=2)=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: Oc1cccnc1Cl
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(Oc2cccnc2Cl)n1

Procedure:
The title compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 2-chloro-3-hydroxypyridine in analogy to example 3. It was purified by column chromatography on Si—NH2 gel (Isolute) using ethyl acetate as eluent to give the title compound as a yellowish solid in 76% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:9](=[CH:15]\[CH3:16])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)C.[CH3:20][NH:21][CH3:22]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:15]([N:21]([CH3:22])[CH3:20])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C/C=C(/C(=O)OCC)c1ccc(Cl)c(Cl)c1
Reactant: CNC
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(c1ccc(Cl)c(Cl)c1)C(C)N(C)C
Temperature: 50 °C
Reaction time: 10 h

Procedure:
In a Parr bomb containing 45 g. of ethyl 2-(3,4-dichlorophenyl)crotonate in 250 ml. of ethanol add 100 ml. of aqueous 33 percent (w/v) dimethylamine and 0.8 ml. of acetic acid. The mixture is maintained with stirring at 50° C for 10 hours, then the solvent is evaporated in vacuo and the residue, after suspension in water, is extracted several times with ether. After evaporation of the dried organic layer, 60 g. of the title compound is obtained which boils at 124° C/0.2 mm Hg. The product is an approximately 50:50 mixture of the two stereoisomers
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[S:12][C:13]([CH2:15]O)=[CH:14][C:10]=2[CH:9]=1)([O-:7])=[O:6]>N1C=CC=CC=1.ClCCl>[Cl:3][CH2:15][C:13]1[S:12][C:11]2[CH:17]=[CH:18][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][C:10]=2[CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc2sc(CO)cc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2sc(CCl)cc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Thionyl chloride (1.0.ml) was added dropwise to a stirred mixture of 5-nitrobenzo[b]thiophene-2-methanol (1.0 g) and pyridine (2 drops) in dichloromethane (10 ml). The solution was stirred at room temperature for 4 hours and then washed with water followed by aqueous sodium bicarbonate solution, and then dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane gave a solid which was crystallised from ethyl acetate to give the title compound (0.73 g), m.p. 110°-112°, used directly in the next stage.
Reaction SMILES: CS.OC[CH2:5][S:6]([CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH:14]([O:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])[CH3:15])(=O)=O>C(#N)C.O.C(Cl)Cl>[CH3:5][S:6][CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH:14]([O:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1)=[O:18])[CH3:15]
Reactant: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)C1C(=O)NC1S(=O)(=O)CCO
Agent: CS
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CSC1NC(=O)C1C(C)OC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
1.17 g (16.7 mmol) of the Na salt of methyl mercaptan are added to a solution of 4.48 g (11.1 mmol) of 4-(2-hydroxyethylsulphonyl)-3-[1-(p-nitrobenzyloxycarbonyloxy)-ethyl]-azetidin-2-one in 11 ml of acetonitrile and 11 ml of H2O at 0° C., and the mixture is stirred at 0° C. for 20 minutes. The reaction mixture is diluted with 100 ml of methylene chloride and 25 ml of H2O, and, after separating off the organic phase, the aqueous phase is extracted three times with 25 ml of methylene chloride in each case. The combined organic phases are dried over MgSO4, filtered and the solvent is removed in vacuo, to give 3.80 g of the title compound as a slightly yellowish non-crystalline compound. NMR spectrum in CDCl3 : δ=1.45 (d, J=7 Hz, 3 H), 2.12 (s, 3 H), 3.3 (dd, J=7 Hz, J=2 Hz), 4.70 (d, J=2 Hz, 1 H), 5.12 (m, 1 H), 5.20 (s, 2 H), 6.45 (broad s, 1 H), 7.50 (d, J=8.5 Hz, 2 H), 8.20 (d, J=8.5 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]([OH:20])=O)[CH:12]=2.[N:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[S:23][C:22]=1[NH2:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[N:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[S:23][C:22]=1[NH:30][C:18]([C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[NH:10]2)=[CH:15][CH:14]=1)=[O:20]
Reactant: O=C(O)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: Nc1nc2cccnc2s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(Nc1nc2cccnc2s1)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 150 °C

Procedure:
A mixture of 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylic acid (362 mg, 1.18 mmol), thiazolo[5,4-b]pyridin-2-ylamine (179 mg, 1.18 mmol), EDCI (340 mg, 1.77 mmol) and HOBT (176 mg, 1.30 mmol) in THF (10 mL) was heated in a microwave apparatus at 150° C. for 3 h. The insolubles were filtered off and the filtrate was concentrated under reduced pressure. The residue was chromatographed using a 30-70% gradient of heptane/ethyl acetate to afford the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 12.95 (s, broad, 1H), 12.00 (s, broad, 1H), 8.51 (dd, J=4.7, 1.4 Hz, 1H), 8.34 (s, 1H), 8.16 (d, J=7.7 Hz, 1H), 7.88 (dd, J=8.5, 1.4 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.68 (d, J=8.3 Hz, 2H), 7.54 (m, 2H), 6.66 (m, 1H). MS (m/z) 439.0 (M+1), Retention time=1.41 min (Method 10). Anal. Calcd.: C, 57.41; H, 2.75; N, 12.75. Found: C, 57.29; H, 2.73; N, 12.54.
Reaction SMILES: O[C:2]1([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.S(=O)(=O)(O)O.C(=O)([O-])[OH:26].[Na+].[C:30](#[N:32])[CH3:31]>>[C:30]([NH:32][C:2]1([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1)(=[O:26])[CH3:31]
Reactant: O=C([O-])O
Reactant: CC#N
Reactant: OC1(CCc2ccccc2)CCC2(CC1)OCCO2
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)NC1(CCc2ccccc2)CCC2(CC1)OCCO2
Reaction time: 48 h

Procedure:
To a solution of 8-hydroxy-8-(2-phenylethyl)-1,4-dioxaspiro[4.5]decane (12.8 g) in acetonitrile (200 ml), a concentrated sulfuric acid (5.7 ml) was dropwise added under ice-cooling over 3 minutes. The reaction mixture was left standing at room temperature for 2 days, poured into a saturated aqueous sodium hydrogencarbonate solution under ice-cooling and extracted with ethyl acetate. The ethyl acetate layer was washed with water and a saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure to give 8-acetamido-8-(2-phenylethyl)-1,4-dioxaspiro[4.5]decane as a crude product. The crude product was dissolved in tetrahydrofuran (140 ml) without purifying and thereto was added a 0.1N aqueous hydrochloric acid solution (30 ml) at room temperature and the mixture was allowed to stand overnight. The mixture was carefully poured into a ice-cooled saturated aqueous sodium hydrogen-carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water and a saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled away to give crude crystals. The crystals were recrystallized from a mixed solvent (1:1) of 1,2-dimethoxyethane-diisopropyl ether to give 1/5 hydrate of the subject compound (5.1 g) as white crystals, melting at 140-143° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.O>C(#N)C>[OH:35][CH:36]1[CH2:41][CH2:40][N:39]([CH2:2][C:3]([NH:5][C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[O:19][CH:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:16]4)=[CH:10][CH:11]=2)=[O:4])[CH2:38][CH2:37]1
Reactant: O=C(CCl)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(CN1CCC(O)CC1)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 25 °C

Procedure:
To a solution of 2-Chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg) and 4-hydroxypiperidine (62 mg). The mixture was stirred at room temperature. Water was added to the reaction mixture. Solution was extracted with ethyl acetate. Organic extract was dried and evaporated. Product was purified by column chromatography using 10% methanol in methylene chloride as eluant. 2-(4-Hydroxypiperidin-1-yl)-N-[6-(2-phenyl-chroman-6-yloxy)-pyridin-3-yl]-acetamide was isolated as its hydrochloride salt. 1H-NMR (400 MHz; d4-MeOH) δ: 8.41 (s, 1H), 8.06 (dd, 1H, J 2.7, 9.0 Hz), 7.45-7.28 (m, 5H), 6.95-6.85 (m, 4H), 5.10 (dd, 1H, J 2.1, 10.0 Hz), 4.13 (s, 2H), 3.72-3.68 (m, 1H), 3.48-3.43 (m, 3H), 3.25-3.10 (m, 1H), 3.02-2.97 (m, 1H), 2.81-2.75 (m, 1H), 2.26-1.76 (m, 6H). (M)+=459 (5.8%), 360 (7.4%), 114 (100%).
Reaction SMILES: [CH:1]1([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]3[C:13]4[N:14]([CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:16][C:17]=3[C:18]([OH:20])=O)=[C:7]([F:24])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:55]([O:57][CH2:58][CH2:59][O:60][NH2:61])=[CH2:56]>C1COCC1>[CH:55]([O:57][CH2:58][CH2:59][O:60][NH:61][C:18]([C:17]1[CH:16]=[CH:15][N:14]2[CH:21]=[N:22][CH:23]=[C:13]2[C:12]=1[NH:11][C:8]1[CH:9]=[CH:10][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:6][C:7]=1[F:24])=[O:20])=[CH2:56]
Reactant: O=C(O)c1ccn2cncc2c1Nc1ccc(C2CCC2)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1ccn2cncc2c1Nc1ccc(C2CCC2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.9 %

Procedure:
A suspension of 8-(4-cyclobutyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (154 mg, 0.46 mmol), EDCI (105 mg, 0.55 mmol), HOBt (74 mg, 0.55 mmol), DIPEA (0.19 mL, 1.14 mmol) and O-(2-vinyloxy-ethyl)-hydroxylamine (52 mg, 0.50 mmol) in THF (2.5 mL) was stirred at room temperature for 18 hours. The reaction mixture was partitioned between DCM (20 mL) and saturated aqueous NaHCO3. The organic layer was isolated then washed with water (20 mL), followed by brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The resultant gum was subjected to flash chromatography (Si-PPC, gradient 0% to 100%, ethyl actetate in cyclohexane) to afford the title compound as a brown gum (149 mg, 80%). LCMS (method B): RT=3.49 min, [M+H]+=411.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:18]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24])([O-:20])=[O:19]>C1COCC1>[CH:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH:7][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[N+:18]([O-:20])=[O:19])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1cccc(NC(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
One gram of 3-isopropylaniline and 0.8 gram of triethylamine were dissolved in 50 ml of THF, cooled to 0° C. and agitated. A solution prepared by dissolving 1.37 grams of 2-nitrobenzoyl chloride in 20 ml of THF was dropwisely added. After agitating for 30 minutes, the reaction mixture was filtered and THF in the filtrate was distilled off under reduced pressure. The residue was extracted with benzene, and rinsed with 3N-HCl, a saturated sodium bicarbonate solution and water successively in this order. The benzene layer was dried by adding anhydrous magnesium sulfate and then benzene was distilled off under reduced pressure to obtain the desired product. The yield was 1.79 grams (85%), and the product had a melting point of 65.5° to 68.5° C. and an IR absorption peak at 1660 cm-1 (c=0).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([Si:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[Br:32]N1C(=O)CCC1=O.CN(C)C=O.CCOC(C)=O>O>[Br:32][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Si:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2ccccc2cc1[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c([Si](c2ccccc2)(c2ccccc2)c2ccccc2)cc2ccccc2c1Br
Yield: 94.9 %

Procedure:
A 150 mL Schlenk flask was charged with 4.68 g of (3-methoxy-2-naphthyl)(triphenyl)silane (11.23 mmol) and 2.20 g of N-bromosuccinimide (NBS) (12.36 mmol) under argon followed by addition of 10 mL of dimethylformamide (DMF). The resultant mixture was stirred overnight at room temperature, then diluted with 500 mL of water and extracted with 3 times 50 mL of CH2Cl2. The combined organic extracts were washed with 200 mL of water, brine and dried over Na2SO4. The product was purified by passing through short column (silica) using a mixture heptane:EtOAc in a ratio of 15:1 as eluent to afford 5.28 g of product as off-white solid (10.66 mmol) with a yield of 96%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:19][CH2:20][O:21][C:22]([CH2:24][CH:25]1[C:30](=O)[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]>>[Br:16][C:13]1[CH:12]=[C:11]2[C:10](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:6]1[CH:17]=[CH:18][C:3]([Cl:2])=[CH:4][CH:5]=1)[C:26]1[CH:25]([CH2:24][C:22]([O:21][CH2:20][CH3:19])=[O:23])[CH2:30][CH2:29][CH2:28][C:27]2=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(Br)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-bromophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound is prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([C:32]#[C:33][CH2:34][N:35]([CH3:37])[CH3:36])=[CH:27][C:26]=3[F:38])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:39][CH3:40].[C:41]1([CH3:52])[CH:46]=[CH:45][C:44]([S:47]([O:50]C)(=[O:49])=[O:48])=[CH:43][CH:42]=1>CCOCC>[CH3:52][C:41]1[CH:42]=[CH:43][C:44]([S:47]([O-:50])(=[O:49])=[O:48])=[CH:45][CH:46]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:26]([F:38])=[CH:27][C:28]([C:32]#[C:33][CH2:34][N+:35]([CH3:41])([CH3:36])[CH3:37])=[CH:29][C:30]=3[F:31])=[N:13][CH:12]=2)([CH3:9])[CH3:10])=[CH:4][C:3]=1[O:39][CH3:40]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C#CCN(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCOCC
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C#CC[N+](C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 1 h

Procedure:
To a solution of 3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenyl)-N,N-dimethylprop-2-yn-1-amine (50 mg, 0.09 mmol, 1.0 eq) in Et2O (0.1 mL) was added methyl p-toluenesulfonate. After 1 h, an additional 1.0 eq methyl p-toluenesulfonate was added and the reaction mixture stirred 30 min. The mixture was filtered to provide 3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenyl)-N,N,N-trimethylprop-2-yn-1-aminium 4-methylbenzenesulfonate (20 mg) as a white crystalline solid: 1H NMR (400 MHz, DMSO) δ 7.52-7.44 (m, 2H), 7.40 (d, J=7.6 Hz, 2H), 7.26 (d, J=8.3 Hz, 1H), 7.19 (s, 1H), 7.12 (d, J=7.8 Hz, 2H), 7.03-6.92 (m, 2H), 6.55 (d, J=2.0 Hz, 1H), 6.51-6.40 (m, 3H), 4.64 (s, 2H), 3.98 (s, 2H), 3.69 (s, 3H), 3.20 (d, J=13.8 Hz, 9H), 2.29 (s, 3H), 1.46 (s, 6H); MS (EI) m/z 598.3 (M+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:12]1([C:15]2[CH:20]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[CH:20]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[N:24]2[CH2:25][CH2:26][N:27]([C:6]([C:5]3[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=3[CH3:11])=[O:8])[CH2:28][CH2:29]2)[CH2:13][CH2:14]1
Reactant: Cc1cc(F)ncc1C(=O)O
Reactant: c1cc(N2CCNCC2)c(C2CC2)cc1C1CC1
Product: Cc1cc(F)ncc1C(=O)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Yield: 103.8 %

Procedure:
Using 6-fluoro-4-methylnicotinic acid (386 mg) and 1-(2,4-dicyclopropylphenyl)piperazine (650 mg) described in Preparation Example 101 and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (980 mg) was obtained.