Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=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>C(OCC)(=O)C>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(NC(=O)c3ccccc3)sc2Cc2ccccc2)cc1
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a 100 ml three-necked flask were added 0.50 g (1.69 mmol) 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1, 1.42 g (10.12 mmol) triethylamine and 40 ml ethyl acetate, and then added dropwise 0.48 g (3.38 mmol) benzoyl chloride dissolved in 10 ml ethyl acetate. The resulting mixture was magnetically stirred overnight at room temperature, filtrated, washed with ethyl acetate, the filtrate was washed with 1N aqueous sodium hydroxide solution, then washed with water until neutrality, dried over anhydrous sodium sulfate, filtered and concentrated under a reduced pressure to give a crude product, which was subjected to a silica gel column chromatography eluted with petroleum ether/ethyl acetate (5:1) to obtain a 0.39 g product as a white solid in a yield of 57.4%, mp: 146-147 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.88 (3H, s, OCH3), 4.20 (2H, s, CH2), 7.01 (2H, d, J=8.72 Hz, ArH), 7.31 (2H, d, J=8.72 Hz, ArH), 7.42˜7.65 (7H, m, 6ArH+CONH), 8.09 (2H, d, J=7.28 Hz, ArH), 8.17 (2H, d, J=7.28 Hz, ArH); EI-MS m/e (%): 400.0 (M+, 94), 104.9 (100); HREI-MS Calcd. for C24H20N2O2S: 400.1245. found: 400.1235.
Reaction SMILES: [OH:1][C:2]([CH3:29])([CH3:28])[C:3]#[C:4][C:5]1[CH:27]=[N:26][C:8]2[N:9](COCC[Si](C)(C)C)[C:10]3[CH:15]=[N:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=3[C:7]=2[CH:6]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:1][C:2]([CH3:29])([CH3:28])[C:3]#[C:4][C:5]1[CH:27]=[N:26][C:8]2[NH:9][C:10]3[CH:15]=[N:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=3[C:7]=2[CH:6]=1
Reactant: CC(C)(O)C#Cc1cnc2c(c1)c1cc(C#N)ncc1n2COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)C#Cc1cnc2[nH]c3cnc(C#N)cc3c2c1
Temperature: 60 °C
Yield: 12.2 %

Procedure:
A solution of 3-(3-hydroxy-3-methylbut-1-ynyl)-9-(2-trimethylsilanyl-ethoxymethyl)dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (254 mg, 0.624 mmol) in THF (12 mL) was treated with TBAF (3.7 mL, 12.5 mmol) and heated to 60° C. for 24 h. The reaction mixture was allowed to cool to ambient temperature and the solvent removed in vacuo. The resultant residue was dissolved in DCM, absorbed onto silica gel, and purified by flash chromatography (Biotage, 25 g, 1-100% EtOAc in hepatne). The light orange solid was further purified by preparative HPLC (5-85% MeCN in water (0.1% NH4OH) over 30 min, 35 mL/min) to afford the title compound as an off-white solid (21 mg, 12%). 1H NMR (DMSO-D6, 400 MHz): 12.99 (s, 1H), 9.04 (s, 1H), 8.93 (s, 1H), 8.86 (d, J=2.0 Hz, 1H), 8.69 (d, J=2.0 Hz, 1H), 5.53 (s, 1H), 1.55 (s, 6H). LCMS (Method D): RT=9.66 min, M+H+=277.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][CH:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[CH2:6][CH2:5]2)[O:3]C1.Cl>C1COCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:7]2[CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]2)[CH:11]=1
Reactant: c1cncc(C2CCC3(CC2)OCCO3)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(c2cccnc2)CC1

Procedure:
A solution of 4-(3-pyridyl)cyclohexanone ethylene ketal prepared above (27 g, 120.0 mmol) in THF (200 mL) and 2 N HCl (100 mL) was stirred at 23° C. for 23 h. The reaction was quenched by adding saturated aqueous NaHCO3 and diluted with EtOAc (200 mL). The aqueous layer was extracted with CH2Cl2 (100 mL×4) and the combined organic layers were washed with brine (200 mL), dried with MgSO4 and concentrated in vacuo. The crude product was filtered through a plug of silica gel, washing with 5% MeOH in CH2Cl2, which afforded 4-(3-pyridyl)cyclohexanone.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:12]([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:24][C:25](=[O:27])[CH3:26])[CH:23]=1)[CH:19]=[CH2:20])(=[O:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>>[C:12]([O:15][C:16]1[CH:17]=[C:18](/[CH:19]=[CH:20]/[C:8]2[CH:9]=[CH:10][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[CH:21]=[C:22]([O:24][C:25](=[O:27])[CH3:26])[CH:23]=1)(=[O:14])[CH3:13]
Reactant: C=Cc1cc(OC(C)=O)cc(OC(C)=O)c1
Reactant: CC(=O)Oc1ccc(Cl)cc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(=O)Oc1ccc(/C=C/c2cc(OC(C)=O)cc(OC(C)=O)c2)cc1
Temperature: 120 °C
Reaction time: 19 h

Procedure:
A 10 ml Schlenk tube equipped with magnetic stirrer was charged with 59 mg (0.7 mmol) of 4-acetoxychlorobenzene, 100 mg (0.84 mmol, 1.2 eq) of 3,5-diacetoxystyrene, 125 mg of cesium carbonate (0.38 mmol, 1.1 eq), 5 μl of P(t-Bu)3 (0.02 mmol, 6 mol %) and 5.57 mg (0.01 mmol, 1.5 mol %) of tris(dibenzylideneacetone)-dipalladium chloroform complex. The tube was evacuated and flushed with argon three times and 1 ml de-aerated dioxane was added under inert conditions. The reaction was carried out under stirring for 19 hours at 120° C. Work-up was conducted following the procedure of Example 5 and gave (E)-3,4′,5-triacetoxystilbene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])/[C:9](=[N:15]/[NH:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)/[CH2:8][CH2:7][CH2:6]2.[CH3:26]N(C=O)C>>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[C:9]3[C:8](=[CH:26][N:16]([C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=4)[N:15]=3)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1cc2c(cc1OC)/C(=N/Nc1ccc([N+](=O)[O-])cc1)CCC2
Product: COc1cc2c(cc1OC)-c1nn(-c3ccc([N+](=O)[O-])cc3)cc1CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
Phosphorous oxytrichloride (0.2 mL) was added, over a period of 0.5 h, to a magnetically solution of (E)-1-[6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-ylidene]-2-(4-nitro-phenyl)hydrazine (56 mg, 0.16 mmol) in DMF (5 mL) maintained at 0° C. under a nitrogen atmosphere. The ensuing mixture was allowed to warm to 18° C. and left stirring at this temperature for 1 h then heated to 65° C. and stirred at this temperature for a further 16 h. The hot reaction mixture was poured onto crushed ice and the crystals so-formed were collected by filtration. Recrystallisation (ethyl acetate/hexane) of this material then afforded the title compound (31 mg, 54%) as orange crystals, m.p. 150° C. (with decomposition).
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-:12].[Na+].[Na+].O>CC(C)=O>[CH3:8][C:7]([CH3:10])([CH3:9])[C:6]#[C:5][CH:4]=[CH:3][CH2:2][OH:12]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)C#CC=CCBr
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)C#CC=CCO

Procedure:
To 5.24 g (26.0 mmol) of an approximately 3:1 mixture of the E and Z isomers of 1-bromo-6,6-dimethyl-2-hepten-4-yne was added sodium carbonate (5.52 g, 52.0 mmol) 80 ml of acetone and 170 ml of water. This mixture was heated to reflux for 3 hours. After cooling, most of the acetone was removed in vacuo and the mixture was extracted with ethyl ether three times. The combined ether layer was dried with sodium sulfate and concentrated to afford 3.97 of 6,6-dimethyl-2-hepten-4-yn-1-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22].[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:34])[NH:29]2>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28](=[O:34])[NH:29]3)=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22]
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(C)c1OC
Reactant: Nc1cccc2[nH]c(=O)ccc12
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1cccc2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(C)c1OC

Procedure:
In the same way as in Example 130, 300 mg (0.93 mmol) of (2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 149 mg (0.93 mmol) of 5-aminoquinolin-2(1H)-one and 0.27 ml of titanium tert-butoxide are reacted to give 5-{[(2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}quinolin-2(1H)-one. 210 mg of chromatographically purified imine (silica gel, hexane/ethyl acetate 0-80%) are cyclized in the same way as in Example 130 at −30° C. with 3.6 ml (3.6 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-100%) yields 203 mg of desired product.
Reaction SMILES: C([O:3][C:4](=[O:33])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[OH:32])=[CH:20][CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])C.[Li+].[OH-]>>[Cl:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:15])[C:8]=1[C:7]([NH:6][C@H:5]([C:4]([OH:33])=[O:3])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[OH:32])=[CH:20][CH:19]=1)=[O:16]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2c(O)cccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Li+]
Agent: [OH-]
Product: COc1cccc(O)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(6-methoxy-2-hydroxyphenyl)-L-phenylalanine ethyl ester was hydrolyzed with LiOH in a similar method as described in Example 1-5) to give the title compound. mp. 224.4° C., ESMS: m/z 460 (MH+), 458 (M−H)−.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[Na+].Cl[C:20]([F:25])([F:24])C([O-])=O>CN(C=O)C.O.CCOC(C)=O>[F:24][CH:20]([F:25])[O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[I:1]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=[N+]([O-])c1ccc(I)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(I)c(OC(F)F)c1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A mixture of 2-iodo-5-nitrophenol (8.98 g), K2CO3 (18.7 g) and 2-chloro-2,2-difluoro-acetic acid sodium salt (5.17 g) in DMF-H2O (60-6 mL) was stirred at 110° C. for 3.5 h and at room temperature for 12 h. The mixture was diluted with EtOAc and washed with 1H HCl, saturated NaHCO3 aq., water and brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (Hexane/EtOAc=9/1) to obtain compound aa4-1 (9.17 g) as a brown amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2].[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C:30]#[CH:31].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:31]#[C:30][CH2:29][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:17]=[C:18]([O:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:19]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2]
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OC3CCCC3)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OC3CCCC3)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (250 mg; 0.54 mmol) and 4-prop-2-ynyl-morpholine (134.48 mg; 1.07 mmol) applying the procedure described for {4-[3-[2-(4-Chlorophenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 210 mg (95%). HPLC-MS: m/z: 510.2 (M+H)+; Rt: 2.03 min
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[C:14]([O-])(=[O:16])[CH3:15].[Tl+].C(OC=C)CCC.Cl>CN(C=O)C.C1COCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CC(=O)[O-]
Reactant: CS(=O)(=O)Nc1ccc(I)cc1F
Agent: [Pd+2]
Agent: C=COCCCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 95 °C

Procedure:
A mixture of N-(2-Fluoro-4-iodophenyl)methanesulfonamide (13-3, 5 mmol) and palladium(II)acetate (0.15 nM, 0.034 g), 1,3-bisdiphenyl phosphinoprophan (0.3 mM, 0.124 g), thallium(I)acetate (5.5 mM, 1.450 g) and butylvinyl ether (10 mM, 1.3 mL) in DMF (10 mL) was heated at 95° C. for 19 h. The reaction mixture was cooled to room temperature, diluted with THF, treated with 10% HCl (10 mL) and stirred at room temperature. A mixture was diluted with EtOAc, washed with ammonium chloride solution three times and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes as eluant to 3′-Fluoro-4′-(methylsulfonylamino)acetophenone (13-6, LJO-363).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:24][C:25]([OH:27])=[O:26])[C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH3:22])=[N:12][N:13]2C2CCCCO2)=[CH:9][C:8]=1[CH3:23])[CH3:2].S(=O)(=O)(O)O>C(O)C>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:24][C:25]([OH:27])=[O:26])[C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH3:22])=[N:12][NH:13]2)=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)O)c1cc2c(cc1C)c(C)nn2C1CCCCO1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)CN(CC(=O)O)c1cc2[nH]nc(C)c2cc1C
Yield: 93 %

Procedure:
The compound (2.53 g, 6.06 mmol) of step D was dissolved in ethanol (75 ml), concentrated sulfuric acid (0.5 ml) was added at room temperature, and thereafter the mixture was heated under reflux for 70 min. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed with sodium bicarbonate water and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the solution was concentrated under reduced pressure, and the obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (1.72 g, yield 85%) as a yellow oil.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:32][O:33][C:34]([C:36]1[NH:37][C:38](=[O:50])[NH:39][C:40]=1[CH2:41][S:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)=[O:35].[CH3:51][C:52]1[CH:61]=[C:60]([CH2:62]O)[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[N:53]=1>C1COCC1.CN(C=O)C>[CH3:32][O:33][C:34]([C:36]1[NH:37][C:38](=[O:50])[NH:39][C:40]=1[CH2:41][S:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH2:62][C:60]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[N:53]=[C:52]([CH3:51])[CH:61]=2)=[CH:45][CH:44]=1)=[O:35]
Reactant: COC(=O)c1[nH]c(=O)[nH]c1CSc1ccc(O)cc1
Reactant: Cc1cc(CO)c2ccccc2n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c(=O)[nH]c1CSc1ccc(OCc2cc(C)nc3ccccc23)cc1
Reaction time: 2 h
Yield: 8 %

Procedure:
To a solution of DEAD (81 mg, 0.46 mmol) in 3 mL of THF at 0° C. was added PPh3 (120 mg, 0.46 mmol). After dissolution of PPh3, 4d (100 mg, 0.31 mmol) was added and the solution was stirred for 15 min. (2-methyl-4-quinolinyl)methanol was then added as a solid. After stirring for 2 h, 3 mL of DMF was added to aid dissolution. The mixture was stirred at room temperature overnight before it was quenched with water. The solution was extracted with CH2Cl2 and the organic layer was dried over MgSO4. After filtration and concentration, the residue was purified by flash column chromatography to provide 5-[4-(2-methyl-quinolin-4-ylmethoxy)-phenylsulfanylmethyl]-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid methyl ester 4e (11 mg, 8%). MS (ESI+) (M+1)=436.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.[N:56]12[CH2:63][CH2:62][CH:59]([CH2:60][CH2:61]1)[C@@H:58](O)[CH2:57]2>O1CCCC1>[N:56]12[CH2:63][CH2:62][CH:59]([CH2:60][CH2:61]1)[C@@H:58]([O:14][C:13](=[O:15])[CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=1)[CH2:57]2
Reactant: O=C(NC(C(=O)O)c1cccc(OCc2ccccc2)c1)OCc1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1cccc(OCc2ccccc2)c1)OCc1ccccc1
Reaction time: 96 h
Yield: 56.5 %

Procedure:
A solution of 2-(((benzyloxy)carbonyl)amino)-2-(3-(benzyloxy)phenyl)acetic acid (2.1 g, 5.3 mmol), N,N′-dicyclohexylcarbodiimide (1.20 g, 5.83 mmol), 1-hydroxybenzotriazole hydrate (787 mg, 5.83 mmol) and (R)-quinuclidin-3-ol (1.70 g, 13.5 mmol) in dry tetrahydrofuran (27 mL) was stirred at room temperature for 18 h. Additional (R)-quinuclidin-3-ol (1.70 g, 13.5 mmol) was then added to the mixture and stirred for 4 days. The white slurry was then filtered through a pad of Celite®, rinsed with ethyl acetate (100 mL) and the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (100 mL) and saturated sodium carbonate (50 mL). The layers were separated and the aqueous phase back-extracted with ethyl acetate (2×50 mL). The combined organic fractions were dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography, eluting with 0-40% ethyl acetate/10% methanolic ammonia solution in ethyl acetate to afford the title compound (1.5 g, 56%) as a clear thick oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=2[Cl:25])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[Cl:25][C:17]1[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=1[O:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc([N+](=O)[O-])ccc2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(Cl)c(OCC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(2-Chloro-5-nitro-phenoxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (14.58 g, 39.3 mmol) was dissolved in TFA (100 mL). After stirring for 2 h at RT, the mixture was concentrated in vacuo and taken up into EtOAc and washed with NaOH, then NaHCO3 (sat). The organic layer was dried with Na2SO4, filtered and evaporated to yield the title compound as a yellow solid. MS(MH+)=NA; Calc'd 269.07 for C12H15ClN2O3.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[CH3:24][S:25]([N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)(=[O:27])=[O:26]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:34][CH:31]2[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH2:30]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2cc(Cl)ccc2OC)c(N)n1
Product: COc1ccc(Cl)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 90 was used, starting with (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(5-chloro-2-methoxy-phenyl)-methanone, Example 110, and 1-methanesulfonyl-piperidin-4-ylamine (with trifluoro-acetic acid), Example 162, to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-chloro-2-methoxy-phenyl)-methanone. MS (M+H)+, 404.
Reaction SMILES: C1(C2C=C(N)ON=2)CC1.[CH:10]([C:13]1[CH:17]=[C:16]([NH:18][C:19](=[O:27])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:15][N:14]=1)([CH3:12])[CH3:11]>>[CH:10]1([C:13]2[CH:17]=[C:16]([NH:18][C:19](=[O:27])[O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:15][N:14]=2)[CH2:12][CH2:11]1
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Agent: Nc1cc(C2CC2)no1
Product: O=C(Nc1cc(C2CC2)no1)Oc1ccccc1
Yield: 71 %

Procedure:
Prepared from 3-cyclopropylisoxazol-5-amine (300 mg, 2.42 mmol) according to the method described for phenyl 3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to afford phenyl 3-cyclopropylisoxazol-5-ylcarbamate as a yellow oil (420 mg, 71%). 1H NMR (300 MHz, CDCl3) δ 7.99 (brs, 1H), 7.39-7.44 (m, 2H), 7.29 (m, 1H), 7.15-7.20 (m, 2H), 5.84 (s, 1H), 1.98 (m, 1H), 1.01-1.05 (m, 2H), 0.82-0.88 (m, 2H); LC-MS (ESI) m/z 245 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:19])[S:18][C:12]2=[N:11][C:10]=1[C:20]1[S:21][C:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:23][N:24]=1)C1C=CC=CC=1>C(Cl)Cl>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][C:22]2[S:21][C:20]([C:10]3[N:11]=[C:12]4[S:18][C:17]([CH3:19])=[CH:16][N:13]4[C:14](=[O:15])[C:9]=3[OH:8])=[N:24][CH:23]=2)=[CH:27][CH:28]=1
Reactant: Cc1cn2c(=O)c(OCc3ccccc3)c(-c3ncc(Cc4ccc(F)cc4)s3)nc2s1
Solvent: ClCCl
Product: Cc1cn2c(=O)c(O)c(-c3ncc(Cc4ccc(F)cc4)s3)nc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product of example 3 (0.135 mmol) in CH2Cl2 (4 ml) was added FeCl3 (66 mg, 0.402 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours, after which CH2Cl2 was evaporated under reduced pressure and ethyl acetate (30 ml) was added. Then the mixture was washed by 1N HCl (10 ml), H2O (10 ml) and brine (10 ml) successively, dried over Na2SO4 and concentrated into about 1 ml. The resulting solids were collected by filtration and washed with cold ethyl acetate (2-3 ml) to give the desired product
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@H:8]([C@@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=[O:12])C)C=O)(=[O:3])[CH3:2].O[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].B(F)(F)F.CCOCC>C(Cl)Cl>[C:25]([O:24][C@H:23]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:8]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:9][C@@H:10]1[O:12][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])(=[O:27])[CH3:26]
Reactant: CCOC(=O)CCCCCO
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C=O)OC(C)=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CCCCCO[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 56.8 %

Procedure:
To mannose pentaacetate (10.00 g, 25.64 mmol) dissolved in 60 mL of CH2Cl2, ethyl 6-hydroxyhexanoate (8.3 mL, 51.28 mmol) was added at room temperature and then BF3.Et2O at 0° C. After 4 days under stirring at room temperature, the reaction mixture was washed twice with NaHCO3 (2×20 mL) and then with brine (20 mL). The organic layer was dried (MgSO4) and concentrated under vacuum. Compound 1 (7.14 g, 57%) was obtained after column chromatography on silica gel (hexane/AcOEt; 6:4).