Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[CH3:31][O:32][C:33]1[CH:38]=[C:37]([O:39][C:40]([F:43])([F:42])[F:41])[CH:36]=[CH:35][C:34]=1[S:44](Cl)(=[O:46])=[O:45]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:44]([C:34]1[CH:35]=[CH:36][C:37]([O:39][C:40]([F:41])([F:42])[F:43])=[CH:38][C:33]=1[O:32][CH3:31])(=[O:45])=[O:46])[C:6](=[O:11])[C:5]2([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26]([N:28]([CH3:29])[CH3:30])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1cc(OC(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: COc1ccccc1C1(N2CCCC[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccccc1C1(N2CCCC[C@H]2C(=O)N(C)C)C(=O)N(S(=O)(=O)c2ccc(OC(F)(F)F)cc2OC)c2ccc(Cl)cc21
Yield: 44.7 %

Procedure:
With 303 mg of (2S)-1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide, which is the compound described in Preparation 3.49 (Isomer B) of the brochure Publication No. WO01/98295 and 245 mg of 2-methoxy-4-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 216 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:6]([OH:7])[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[CH3:19][C:2]1([CH3:1])[CH:6]([O:7][C:20](=[O:22])[CH3:21])[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1
Reactant: CCC1(COCc2ccccc2)CC(O)C(C)(C)O1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC1(COCc2ccccc2)CC(OC(C)=O)C(C)(C)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The alcohol of Example 3 (800 mg) was added to pyridine (20 ml) and acetic anhydride (5 ml) and the mixture was stirred at room temperature over two days. The mixture was then evaporated down under vacuum and the residue was dissolved in diethyl ether. The solution was decolourised over charcoal, and the ether was removed to give 860 mg of the desired product. NMR showed that the product was a mixture of geometric isomers.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9](OC)(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)O>>[OH:2][C:1]1[CH:8]=[CH:7][C:6]2[C:9](=[O:17])[C:10]3[C:11]([O:5][C:4]=2[CH:3]=1)=[CH:13][CH:14]=[CH:15][CH:16]=3
Reactant: Oc1cccc(O)c1
Reactant: COC(=O)c1ccccc1O
Product: O=c1c2ccccc2oc2cc(O)ccc12
Yield: 12.3 %

Procedure:
Resorcinol (5.5 g, 50 mmol) and methyl salicylate (11.0 g, 72 mmol) were refluxed for 5 h using a Dean-Stark trap to remove H2O and MeOH. The resulting black oil was chromatographed over silica with 20% ethyl acetate-hexane as eluent. A yellow solid was isolated which was subsequently recrystallized from ethyl acetate to give 1.3 g (12.3%) of 3-hydroxy-9H-xanthen-9-one (lit. mp 242° C.). Literature references to the synthesis of this compound: R. J. Patolia and K. N. Trivedi, Indian J. Chem., 22B, 444 (1983); J. S. H. Davies, F. Scheinmann, and H. Suschitzky, J. Org. Chem., 23, 307 (1958). ##STR33##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl[CH:11]([F:13])[F:12]>CC(O)C.[OH-].[K+]>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:11]([F:13])[F:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Oc1cc(F)cc(Br)c1
Reactant: FC(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: Fc1cc(Br)cc(OC(F)F)c1
Temperature: 25 °C
Yield: 79 %

Procedure:
A mixture of 3-bromo-5-fluorophenol. (6.1 g, 31.0 mmol; see step (ii) above) and chlorodifluoromethane (13.0 g, 150.0 mmol) in i-PrOH (100 mL) and 30% KOH (80 mL) was heated in a sealed flask for 18 h at 80–85° C. The reaction mixture was cooled to room temperature and the layers were separated. The organic layer was concentrated in vacuo to afford a colourless oil. The aqueous layer was extracted with Et2O (3×30 mL). The crude oil and the combined organic extracts were washed with 2N NaOH (3×30 mL) and H2O (3×30 mL). The organics were then dried (Na2SO4), filtered through a small silica gel plug, and concentrated in vacuo to afford the sub-title compound (6.1 g, 79%) as a colourless oil that was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[B:12](OCC)([O:16]CC)[O:13]CC.[Li]CCCC.Cl>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:2]([B:12]([OH:16])[OH:13])[CH:3]=[N:4][CH:5]=1
Reactant: CCOB(OCC)OCC
Reactant: FC(F)(F)c1cncc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cncc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A cooled (−78° C.) solution of 3-bromo-5-(trifluoromethyl)pyridine (5 g, 22.1 mmol) in dry THF (50 ml), under an inert atmosphere of argon, is treated with triethyl borate (3.39 g, 23.21 mmol) followed by drop wise addition of 1.46M n-BuLi in hexanes (15.2 ml, 24.34 mmol). The reaction mixture is allowed to warm to room temperature overnight and treated with 5M HCl (100 ml). After stirring for 30 minutes, the THF is removed in vacuo and the aqueous layer is extracted with EtOAc (4×100 ml). The aqueous portion is concentrated in vacuo and dried under vacuum overnight to afford the title compound as the hydrochloride salt. [M+H]+ 168.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:21])([CH3:20])[O:6][C@@H:7]([C@@H:16]([CH3:19])[CH:17]=[O:18])[C@@H:8]([CH3:15])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])[CH3:3].[CH3:22][Mg]Br>CCOCC>[CH3:1][C:2]([Si:5]([CH3:20])([CH3:21])[O:6][C@@H:7]([C@@H:16]([CH3:19])[CH:17]([OH:18])[CH3:22])[C@@H:8]([CH3:15])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C=O
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CON(C)C(=O)[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(C)O
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of 6.9 g (21.8 mmol) of (2R,3S,4R)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-N-methoxy-N,2,4-trimethyl-5-oxo-pentanamide in 50 mL of ether is added 10.2 mL (30.5 mmol) of a 3M solution of methylmagnesium bromide in ether, dropwise, at −40° C., after which the mixture is stirred at −20° C. for 1 hour. The reaction mixture is then dilluted with 200 mL of ether and the reaction is quenched by adding the reaction mixture to 20 g of crushed ice at 0° C. The mixture is then washed with 100 mL of 1 M sodium hydrogen sulfate solution and partitioned with two 150 mL portions of ether. The organic layers are then combined and dried over sodium sulfate. The crude product mixture is then chromatographed employing an eluent mixture of 20% ethyl acetate in hexane initially and then an eluent mixture of 40% ethyl acetate in hexane to yield two diastereomers as light yellow oils which are used in the next step without further purification.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16][C:17](Cl)=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C1C=CC=CC=1.[CH:37]([OH:40])([CH3:39])[CH3:38]>CCOCC>[CH:37]([O:40][C:17](=[O:18])[CH2:16][CH:15]([C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1)[C:20]#[C:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([CH3:39])[CH3:38]
Reactant: CC(C)O
Reactant: COc1ccc(C(C#Cc2ccccc2)CC(=O)Cl)cc1OC1CCCC1
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Product: COc1ccc(C(C#Cc2ccccc2)CC(=O)OC(C)C)cc1OC1CCCC1
Reaction time: 18 h

Procedure:
A solution of (+/-)-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylethynylpropionic acid chloride (150 mg, 0.42 mmol) and dimethylaniline (100 mg, 0.83 mmol) in Et2O (5 ml) was treated with i-propanol (1 ml) and stirred at 23° for 18 hr. The solvents were evaporated, and the residue taken up in Et2O, washed with 3N HCl, H2O, dried, and the solvent evaporated. The residue was purified by flash chromatography (silica gel, 20% EtOAc/hexane), and gave the titled compound, 82 mg (54%). MP . 1H NMR (400 MHz, CDCl3) δ 7.38 (m, 2 H), 7.30 (m, 3 H), 6.94 (m, 2 H), 6.78 (d, 1 H), 5.02 (m, 1 H), 4.78 (m, 1 H), 4.30 (t, 1 H), 3.80 (s, 3 H), 2.82 (d of d, 1 H), 2.72 (d of d, 1 H), 1.78-1.96 (m, 6 H), 1.60 (m, 2 H), 1.22 (d, 3 H), 1.16 (d, 3 H).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[O:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[C:17]([O:21]C(N(C)C)N(C)C)(C)(C)C>CN(C=O)C.Cl>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([CH2:1][CH:17]=[O:21])=[CH:3][C:4]=2[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7]1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1ccc2c(=O)oc3ccccc3c2c1
Agent: Cl
Solvent: CN(C)C=O
Product: O=CCc1ccc2c(=O)oc3ccccc3c2c1
Reaction time: 0.33 h

Procedure:
A solution of 9-methyl-6H-benzo[c]chromen-6-one (100 mg, 0.476 mmol) in dry DMF (2378 μl) Was treated with TERT-BUTOXY BIS(DIMETHYLAMINO)METHANE (99 mg, 0.571 mmol) at 80° C. in a sealed tube for one hour. The solution turned a deep red color and was cooled, diluted with 2M HCl and stirred for 20 minutes. The solution was then extracted with DCM, the combind orgainc layers were dried, filtered and concentrated with out heat. Crude (6-oxo-6H-benzo[c]chromen-9-yl)acetaldehyde was used without further purification. LC-MS (IE, m/z): 239 [M+1]+.
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.[F:12][C:13]1[CH:23]=[CH:22][C:16]2S[CH2:18][CH2:19][CH2:20][O:21][C:15]=2[CH:14]=1.[S:24]([O-:28])([O-])(=O)=[O:25].[Mg+2].O>C(Cl)Cl>[F:12][C:13]1[CH:23]=[CH:22][C:16]2[S:24](=[O:28])(=[O:25])[CH2:18][CH2:19][CH2:20][O:21][C:15]=2[CH:14]=1
Reactant: Fc1ccc2c(c1)OCCCS2
Reactant: O=S(=O)([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Mg+2]
Solvent: ClCCl
Solvent: O
Product: O=S1(=O)CCCOc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
meta-Chloroperbenzoic acid (50-55%) (514 mg, 1.49 mmol) was added to a mixture of 8-fluoro-3,4-dihydro-2H-1,5-benzoxathiepine (110 mg, 0.6 mmol) and magnesium sulphate (1 spatula) in DCM (10 mL) and stirred at RT for 24 hours. Water was added and the mixture extracted into ethyl acetate. The combined organics were washed with a saturated solution of sodium bicarbonate (50 mL), brine (40 mL), dried (MgSO4), filtered and reduced in vacuo to give a white solid which was chromatographed on silica, eluting with 0-10% ethyl acetate in isohexane to give a colourless oil. The oil was redissolved in organics, washed with 2M sodium hydroxide solution (40 mL), and concentrated in vacuo to give the desired compound as a white solid (100 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:19](O)[CH2:20][OH:21].O.CC1C=CC(S(O)(=O)=O)=CC=1>CC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[O:21][CH2:20][CH2:19][O:9]2)=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1
Yield: 97.8 %

Procedure:
A mixture of (4-chlorophenyl)(4-nitrophenyl)methanone (0.0382 mol), 1,2-ethanediol (0.0764 mol) and 4-methylbenzenesulfonic acid monohydrate 96% (0.19 mol) in methylbenzene (150 ml) was stirred and refluxed in a Dean Stark apparatus for 24 hours. The mixture was washed with K2CO3 (10%) and then with water. The organic layer was dried, filtered off and evaporated. The product was used without further purification, yielding 11.42 g (98%) of 2-(4-chlorophenyl)-2-(4nitro-phenyl)-1,3-dioxolane (interm. 1).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH3:13][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=O.Cl>C(O)C>[CH3:13][C:14]12[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]1=[N:11][C:8]1[CH:7]=[CH:6][C:5]([CH:2]([CH3:4])[CH3:3])=[CH:10][C:9]=12
Reactant: CC1Cc2ccccc2C1=O
Reactant: CC(C)c1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: CC(C)c1ccc2c(c1)C1(C)Cc3ccccc3C1=N2

Procedure:
To a solution of 4-isopropylphenylhydrazine hydrochloride, (6.50 g, 0.035 mmol) in absolute ethanol (140 cm3) was added dropwise 2-methyl-1-indanone, (4.6 g, 0.032 mmol) followed by conc. hydrochloric acid (2.5 cm3). The mixture was refluxed for 2 hours and the ethanol evaporated. The residue was portioned between diethyl ether (100 cm3) and water (100 cm3) and the layers separated. The aqueous phase was extracted with diethyl ether (2×30 cm3) and the organic extracts were washed sequentially with saturated sodium bicarbonate solution and brine, and then dried (Na2SO4). Removal of the solvent gave the title compound which was purified by flash chromatography on silica gel eluting with 10% ethyl acetate/60°-80° petrol, to yield a yellow gum; (1.62 g, 25%); 1H NMR (CDCl3) δ: 7.88 (1H, m), 7.55 (1H, d, J=8.1 Hz) 7.41 (3H, m) 7.30 (1H, d, J=1.8 Hz) 7.23 (1H, dd, J=1.8 Hz and 7.1 Hz) 3.10 (1H, d, J=14.7 Hz) 2.98 (1H, septet, J=7.0 Hz) 2.85 (1H, d, J=14.7 Hz) 1.39 (3H, s) 1.30 (6H, d, J=7.0 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([OH:23])[C:21]=1[OH:22])[C:5]1[O:6][C:7]2[C:12]([C:13](=[O:18])[C:14]=1[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=2.C(O[C:28](=[O:30])[CH3:29])(=O)C.Cl>N1C=CC=CC=1.ClCCl>[C:2]([O:23][C:20]1[CH:19]=[C:4]([CH:3]=[C:2]([O:1][C:28](=[O:30])[CH3:29])[C:21]=1[O:22][C:5](=[O:6])[CH3:4])[C:5]1[O:6][C:7]2[C:12]([C:13](=[O:18])[C:14]=1[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:1])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1c(-c2cc(O)c(O)c(O)c2)oc2ccccc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cc(-c2oc3ccccc3c(=O)c2C(=O)O)cc(OC(C)=O)c1OC(C)=O
Reaction time: 2 h

Procedure:
3',4',5'-Trihydroxyflavone-3-carboxylic acid was dissolved in 4 ml absolute pyridine, and the solution was reacted with 0.57 ml acetic anhydride and stirred for two hours. Then it was worked up by diluting with 20 ml dichloromethane, pouring onto a mixture of dilute hydrochloric acid/ice water and shaking with dichloromethane. Here care must be taken that the aqueous phase remains acid (if necessary some dilute hydrochloric acid must be added). The dichloromethane phase was separated, washed with water, dried over sodium sulfate and evaporated. 0.8 g crude 3',4',5'-triacetoxyflavone-3-carboxylic acid were obtained which was immediately processed further without additional purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]2[N:29]=[CH:28][C:27]([CH:30]([NH2:32])[CH3:31])=[CH:26][C:25]=2[CH3:33])=[CH:19][CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:32]([CH:30]([C:27]3[CH:28]=[N:29][C:24]([S:23][C:20]4[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=4)=[C:25]([CH3:33])[CH:26]=3)[CH3:31])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)cnc1Sc1ccc(F)cc1
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1Sc1ccc(F)cc1
Yield: 48 %

Procedure:
The title compound is prepared in 48% yield (290 mg, off white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (400 mg, 1.4 mmol, Step-1 of Intermediate-1) and 1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethanamine hydrochloride (410 mg, 1.6 mmol, Amine-42, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]([CH2:15][C:16]3[N:24]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:19]4=[N:20][CH:21]=[CH:22][CH:23]=[C:18]4[N:17]=3)[C:9](=[O:14])[N:10]([CH:11]([CH3:13])[CH3:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:30]([Zn]C#N)#[N:31]>CN(C=O)C>[CH2:25]([N:24]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[N:17]=[C:16]1[CH2:15][N:8]1[C:7]2[C:2]([C:30]#[N:31])=[N:3][CH:4]=[CH:5][C:6]=2[N:10]([CH:11]([CH3:13])[CH3:12])[C:9]1=[O:14])[CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: N#C[Zn]C#N
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccnc(Cl)c32)nc2cccnc21
Solvent: CN(C)C=O
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccnc(C#N)c32)nc2cccnc21
Temperature: 25 °C

Procedure:
The mixture of compound 25 (0.075 g, 0.182 mmol), tetrakis(triphenyl-phosphine)palladium (41 mg, 0.036 mmol) and dicyanozinc (0.042 g, 0.363 mmol) in DMF (3 mL) under nitrogen atmosphere was irradiated for 30 minutes in a microwave reactor at 170° C. The resulting mixture was allowed to cool down to room temperature then filtered through an acrodisk filter and evaporated to dryness. The residue was purified by column chromatography using EtOAc. The title compound 29 was isolated as a white solid (60 mg, 81%).
Reaction SMILES: [Br-:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C@H:15]([CH3:56])[C@:16]([C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=3[F:55])([OH:47])[CH2:17][N:18]3[CH:22]=[N+:21]([CH2:23][C:24]4[CH:29]=[C:28]([CH3:30])[C:27]([O:31][C:32]([C@@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5C(OC(C)(C)C)=O)=[O:33])=[C:26]([CH3:46])[CH:25]=4)[CH:20]=[N:19]3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)#[N:3].[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58].ClCCl>>[F:60][C:59]([F:62])([F:61])[C:57]([OH:63])=[O:58].[Br-:1].[C:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([C@H:15]([CH3:56])[C@:16]([C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=3[F:55])([OH:47])[CH2:17][N:18]3[CH:22]=[N+:21]([CH2:23][C:24]4[CH:25]=[C:26]([CH3:46])[C:27]([O:31][C:32]([C@@H:34]5[CH2:38][CH2:37][CH2:36][NH:35]5)=[O:33])=[C:28]([CH3:30])[CH:29]=4)[CH:20]=[N:19]3)[S:13][CH:14]=2)=[CH:8][CH:9]=1)#[N:3]
Reactant: Cc1cc(C[n+]2cnn(C[C@](O)(c3ccc(F)cc3F)[C@@H](C)c3nc(-c4ccc(C#N)cc4)cs3)c2)cc(C)c1OC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Br-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C[n+]2cnn(C[C@](O)(c3ccc(F)cc3F)[C@@H](C)c3nc(-c4ccc(C#N)cc4)cs3)c2)cc(C)c1OC(=O)[C@@H]1CCCN1

Procedure:
To a solution of 3 g of 3,5-dimethyl-4-hydroxybenzyl bromide in CH3CN(30 mL) was added 1.2 g of (1R,2R)-4-[2-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-[1,2,4]triazol-1-yl-propyl]thiazol-4-yl]benzonitrile and stirring was continued for 2 h at room temperature. The precipitate was filtered and washed with ether to give 1.37 g(81% y.) of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-(3,5-dimethyl-4-hydroxy)benzyl-1H-[1,2,4]triazol-4-ium bromide(Ro09-3846) as a white solid. To a mixture of 30 g of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-diflouro-phenyl)-2-hydroxybutyl]-4-(3,5-dimethyl-4-hydroxybenzyl)-1H-[1,2,4]triazol-4-ium bromide, 10.9 g of Boc-(L)-proline and 2.8 g of N,N-dimethylaminopyridine in 1.2 L of dichloromethane was added 17.6 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the mixture was stirred for 1.5 h at room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (Wakogel C-200, solvent: CH2Cl2 /MeOH=14/1) to give 30.9 g(79% y.) of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(N-tert-butoxycarbonylpyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide as a white solid. 30.9 g of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(N-tert-butoxycarbonylpyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide was stirred in 600 mL of 10% TFA -dichloromethane for 5 h at room temperature and the solvent was removed in vacuo. The residue was diluted with ether and the precipitate was washed with ether to give 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5dimethyl-4-(pyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide trifluoroacetic acid salt as a white solid.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[NH:6]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])[C:7]([NH2:9])=[NH:8].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:34][S:35]([O:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[C:44]([C:49](=[NH:51])[NH2:50])[CH:45]=2)[CH:40]=1)(=[O:37])=[O:36]>N1C=CC=CC=1>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:34][S:35]([OH:38])(=[O:37])=[O:36].[NH:6]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O:15][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[C:44]([C:49](=[NH:50])[NH2:51])[CH:45]=2)[CH:40]=1)=[O:14])[C:7]([NH2:9])=[NH:8]
Reactant: N=C(N)Nc1cccc(C(=O)O)c1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Product: N=C(N)Nc1cccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)c1
Yield: 34.7 %

Procedure:
To a solution of 4.7 g of m-guanidinobenzoic acid methanesulfonate in 50 ml of anhydrous pyridine, was added 4.4 g of DCC. To the mixture, while being cooled in ice and stirred, was added 5.0 g of 6-amidino-2-naphthol methanesulfonate. After having been stirred for 24 hours, the reaction mixture was freed from the insolubles by filtration and the filtrate was mixed with ether. The oily substance which was formed was crystallized by adding ethyl acetate. Recrystallization from a mixture of methanol and ether gave 3.2 g of 6-amidino-2-naphthyl 3-guanidinobenzoate dimethanesulfonate.
Reaction SMILES: [ClH:1].Cl.[C:3]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:19]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][Cl:28])=[CH:25][CH:24]=1)[C:20]([CH3:22])=[O:21].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[ClH:28].[ClH:1].[C:20]([NH:19][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:18][CH2:17]2)=[CH:25][CH:24]=1)(=[O:21])[CH3:22]
Reactant: O=C(CCN1CCNCC1)c1ccccc1
Reactant: CC(=O)Nc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(CN2CCN(CCC(=O)c3ccccc3)CC2)cc1
Yield: 65 %

Procedure:
A mixture of N-benzoylethyl piperazine dihydrochloride (1.5 g, 5 mmol), 4-acetamino-benzylchloride (1.1 g, 6 mmol) and K2CO3 (3.2 g, 24 mmol) in 60 ml of acetone was treated according to general preparation 2 to give compound (IV-21) yield 65%, mp 238-240° C. M+ 351.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37]S(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:22])([O:14][C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)[C:4]([OH:23])=[O:3])=[CH:12][CH:11]=3)[N:34]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(C4CCCCC4)oc3C)cc2)C(=O)O)cc1

Procedure:
The representative procedure (B) was utilized to prepare the title compound from 3-(4-hydroxyphenyl)-2-methyl-2-p-tolyloxypropionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 10.90 (bs, 1H), 7.18 (d, 2H, J=8.4 Hz), 7.05 (d, 2H, J=8.4 Hz), 6.79 and 6.79 (d of Abq, 4H, J=8.0 Hz), 4.15 (t, 2H, J=6.0 Hz), 3.23 and 3.11 (d of Abq, 2H, J=13.8 Hz), 3.02-2.93 (m, 3H), 2.34 (s, 3H), 2.29 (s, 3H), 2.10-2.00 (m, 2H), 1.89-1.80 (m, 2H), 1.77-1.70 (m, 1H), 1.64-1.51 (m, 2H), 1.45-1.19 (m, 3H), 1.38 (s, 3H). IR (KBr) 3450, 1734, 1509, 1228 cm−1. HRMS (ES+) m/z exact mass calcd for C29H36NO5 478.2593, found 478.2613.