Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([NH:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([N:24]4[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26][CH2:25]4)=[O:23])=[CH:14][N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.F[P-](F)(F)(F)(F)F.[N:40]1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.N>O.C(O)C.CN(C)C=O>[C:1]12([NH:11][C:12]3[N:17]=[C:16]([C:18]([F:19])([F:21])[F:20])[C:15]([C:22]([N:24]4[CH2:25][CH2:26][CH:27]([C:30]([NH2:40])=[O:31])[CH2:28][CH2:29]4)=[O:23])=[CH:14][N:13]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C(O)C1CCN(C(=O)c2cnc(NC34CC5CC(CC(C5)C3)C4)nc2C(F)(F)F)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NC(=O)C1CCN(C(=O)c2cnc(NC34CC5CC(CC(C5)C3)C4)nc2C(F)(F)F)CC1
Reaction time: 1.5 h
Yield: 68.1 %

Procedure:
To a mixture of 1-{[2-(adamantan-1-ylamino)-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}piperidine-4-carboxylic acid (100 mg) and N,N-dimethyl formamide (2 mL) were added 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (84 mg) and N,N-diisopropyl ethylamine (77 μL) at room temperature, followed by stirring at the same temperature for 1.5 hours. To the reaction mixture was added 28% aqueous ammonia (2 mL) at room temperature, followed by stirring at the same temperature for 3 hours. To the reaction mixture was added water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol), and the obtained crude product was solidified from a mixed solvent of ethanol and water to obtain 1-{[2-(adamantan-1-ylamino)-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}piperidine-4-carboxamide (68 mg) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])\[CH3:22].O>CC(C)=O>[CH3:22][C:21]([CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])=[CH:20][CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CC(C)=CCC/C(C)=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)Cc1ccc(OCC=C(C)CCC=C(C)C)cc1
Yield: 92.2 %

Procedure:
Methyl 4-hydroxyphenylacetate (6.00 g, 36.11 mmol) was dissolved in acetone (90 ml), and then potassium carbonate (9.98 g, 72.22 mmol) and geranyl bromide(14.34 ml, 72.22 mmol) were added thereto. After being refluxed for 4 hours, the mixture, with water added thereto, was extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride water and saturated brine successively, and dried over MgSO4. The solvent was evaporated out and the obtained residue was purified by silica gel column chromatography (5% ethyl acetate/hexane), to give methyl 2-{4-[(3,7-dimethyl-2,6-octadienyl)oxy]phenyl}acetate (10.07 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: Cn1ncc2cc(C(O)c3cnc4ccc(Cl)nn34)ccc21
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CC(C)=O
Product: Cn1ncc2cc(C(=O)c3cnc4ccc(Cl)nn34)ccc21
Reaction time: 3 h
Yield: 82.2 %

Procedure:
A suspension of (6-chloroimidazo[1,2-b]pyridazin-3-yl)(1-methyl-1H-indazol-5-yl)methanol (500.0 mg, 1.60 mmol) and 2-Iodoxybenzoic acid (45% pure, 1488.0 mg, 2.39 mmol) in 10 mL acetone was heated at refluxe and stirred for 3 hours. Solvent was removed under reduced pressure. The residue was diluted with water, and the pH value of the solution adjusted to around 10 with 10% aqueous NaOH. The precipitates were collected by filtration and washed with water three times. The solid was dissolved in DCM, dried over Na2SO4, filtered and concentrated to give the title compound as a white solid (410.0 mg, 78%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.46 (s, 1H), 8.42 (m, 1H), 8.32 (m, 1H), 8.27 (d, 1H), 7.95 (dd, 1H), 7.815 (d, 1H), 7.66 (d, 1H), 4.12 (s, 2H). LCMS (method A): [MH]+=312, tR=4.64 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[C:16](=[S:17])[NH:15][N:14]=[CH:13]2)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:22]O>>[CH3:22][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([N:12]2[C:16](=[S:17])[NH:15][N:14]=[CH:13]2)[CH:10]=[CH:11][C:3]=1[O:2][CH3:1]
Reactant: CO
Reactant: COc1ccc(-n2cn[nH]c2=S)cc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(-n2cn[nH]c2=S)ccc1OC
Reaction time: 72 h

Procedure:
Treat a solution of 2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzoic acid (6.66 g, 26.5 mmol) and methanol (80 mL) under argon via syringe dropwise with thionyl chloride (2.9 mL, 40 mmol). Stir for three days and remove the methanol in vacuo. Purify the residue by flash chromatography (silica gel, 9.5×12.7 cm) eluting with 40% ethyl acetate in dichloromethane and then with ethyl acetate. Concentrate the desired fractions in vacuo to afford 4.55 g of 2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzoic acid methyl ester.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccc3ncccc3c2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ccc3ncccc3c2)c2ccccc12
Reaction time: 31.5 h
Yield: 106.4 %

Procedure:
0.283 g (6.75 mmol) of lithium hydroxide monohydrate and 30 cm3 of water are added at 22° C. to 0.68 g (2.25 mmol) of 3-methoxycarbonyl-1-(quinol-6-yl)-1H-indole dissolved in 30 cm3 of tetrahydrofuran. After stirring at the reflux point of the solvent for 31.5 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 15 cm3 of water and then triturated with 6 cm3 of N hydrochloric acid. After filtering off and drying the solid residue under reduced pressure (2.7 kPa) at 40° C., 0.69 g of 3-carboxy-1-(quinol-6-yl)-1H-indole is obtained in the form of a beige-coloured solid. Mass spectrum (DCI): m/e 289 (M+H)+, m/e 245.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][N:7]([C:15]1[S:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[N:19]=1)[CH2:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)C.[Li+].[OH-].[ClH:32]>[Cl-].[Na+].O>[ClH:32].[CH:26]([C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:15]([N:7]([CH2:8][CH2:9][C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)[CH2:6][CH2:5][C:4]([OH:29])=[O:3])[S:16][CH:17]=2)=[CH:25][CH:24]=1)([CH3:28])[CH3:27]
Reactant: CCOC(=O)CCN(CCc1cccs1)c1nc(-c2ccc(C(C)C)cc2)cs1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Product: CC(C)c1ccc(-c2csc(N(CCC(=O)O)CCc3cccs3)n2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the 3-[[4-(4-isopropyl-phenyl)-thiazol-2-yl]-(2-thiophen-2-yl-ethyl)-amino]-propionic acid ethyl ester (95 mg, 0.22 mmol) was added LiOH (3 mL; 2N LiOH-MeOH-THF=1:1:4) and the reaction was stirred at room temperature for 4 h before acidifying with 1 N HCl. Brine was added, and the mixture was extracted with DCM (3×10 ml). The combined extracts were dried over Na2SO4, concentrated and purified on silica gel column to provide 3-[[4-(4-isopropyl-phenyl)-thiazol-2-yl]-(2-thiophen-2-yl-ethyl)-amino]-propionic acid hydrochloride salt (58 mg). LCMS m/z: 402 (M+1)+.
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][N:8]1[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])(O)=[O:2].C(N(CC)CC)C.ClC(OCC(C)C)=O>O1CCCC1>[OH:2][CH2:1][CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][N:8]1[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]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCCO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of (2S,4R)-2-(carboxymethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.4 g) in tetrahydrofuran (50 ml) was added triethyamine (1.6 -ml). Isobutyl chloroformate (1.1 ml) was dropwise added to the mixture at -5° to -10° C. under nitrogen, followed by stirring for 30 minutes at the same temperature The insoluble material was filtered off and the filtrate was added to a solution of sodium borohydride (0.70 g) in water (20 ml) at 0° C. After stirring for 2 hours at the same temperature, acetic acid (3 ml) was added thereto The reaction mixture was evaporated, diluted with ethyl acetate and washed successively with water, saturated sodium bicarbonate and brine The dried organic layer was concentrated under reduced pressure, and the obtained syrup was subjected to a column chromatography on silica gel and eluted with a mixture of dichloromethane and acetone (4:1 v/v) to give (2S,4R)-2-(2-hydroxyethyloxymethyl)-4-methane- sulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.1 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[CH3:11][O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([I:22])[CH:16]=1.C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C(#N)C.C1(C)C=CC=CC=1.CC(C)=O.O>[CH3:11][O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:2][C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[CH:5]=[O:6])=[C:17]([I:22])[CH:16]=1
Reactant: O=Cc1ccccc1CBr
Reactant: COC(=O)Cc1ccc(O)c(I)c1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(OCc2ccccc2C=O)c(I)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
2-Bromomethyl-benzaldehyde (11 g, 55.26 mmol) in acetonitrile (132 ml) was added to a solution of (4-Hydroxy-3-iodo-phenyl)-acetic acid methyl ester (16.06 g, 55 mmol), K2CO3 (8.36 g, 60.50 mmol) and Nal (2.07 g, 13.80 mmol) in acetonitrile (88 ml). The mixture was heated to reflux temperature and was stirred at this temperature for 3 hours. Once the mixture cooled down to room temperature, it was filtered and was then concentrated to dryness to obtain a residue that was diluted in toluene (212 ml) and then it was washed with NaOH 0.05N. Once the layers had separated, the aqueous layer was washed with toluene (100 ml) again and the organic layers were washed with water (2×100 ml, 1×50 ml), were concentrated to dryness to obtain a residue, which was then diluted with a mixture of acetone-water at 30° C. Then the mixture was cooled until 20-22° C. The solid formed was filtered to obtain 18 g (80%) of [4-(2-Formyl-benzyloxy)-3-iodo-phenyl]-acetic acid methyl ester (98%HPLC).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].O[C:11]1[CH:12]=[C:13]([CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:14]=[CH:15][C:16]=1[NH2:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[O:5][C:11]2[CH:12]=[C:13]([CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:14]=[CH:15][C:16]=2[N:17]=1
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)C(C)c1ccc(N)c(O)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)c1ccc2nc(-c3ccccc3Cl)oc2c1

Procedure:
A solution of o-chlorobenzaldehyde (4.3 g.) and ethyl 2-(3-hydroxy-4-aminophenyl)propionate (6 g.) in toluene (100 ml.) was heated, using a Dean and Stark apparatus to collect the water formed. After 30 minutes the solution was evaporated to dryness. The residue was dissolved in acetic acid (100 ml.), lead tetracetate (15 g.) was added and the solution was heated on a steam bath for 1 hour. The solution was poured into ice/water and extracted with ether to give the oil, ethyl 2-(2-o-chlorophenyl-6-benzoxazolyl)propionate, a sample of which gave a satisfactory micro-analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[S:8][CH2:7][C:6]2=1.[CH2:20](I)[CH3:21]>>[CH2:20]([N:12]1[C:11]2[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[S:8][CH2:7][C:6]=2[C:5]2[C:13]1=[CH:14][CH:15]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:21]
Reactant: CCI
Reactant: COc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Product: CCn1c2c(c3cc(OC)ccc31)CSc1ccccc1-2

Procedure:
Following the procedure as in Example 33, using 8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (1.00 g, 3.75 mmol) and EtI (878 mg, 5.63 mmoL) as the starting material, the title compound was prepared as a white solid.
Reaction SMILES: [Si]([O:8][CH:9]1[CH:14]([NH:15][C:16]([C:18]2[NH:19][C:20]([CH3:25])=[C:21]([Cl:24])[C:22]=2[Cl:23])=[O:17])[CH2:13][CH2:12][N:11](C(OCC)=O)[CH2:10]1)(C(C)(C)C)(C)C.[OH-].[Na+].Cl>CO.O1CCOCC1>[Cl:23][C:22]1[C:21]([Cl:24])=[C:20]([CH3:25])[NH:19][C:18]=1[C:16]([NH:15][CH:14]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[OH:8])=[O:17]
Reactant: CCOC(=O)N1CCC(NC(=O)c2[nH]c(C)c(Cl)c2Cl)C(O[Si](C)(C)C(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1[nH]c(C(=O)NC2CCNCC2O)c(Cl)c1Cl
Temperature: 0 °C

Procedure:
Ethyl 3-{[tert-butyl(dimethyl)silyl]oxy}-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidine-1-carboxylate (Intermediate 114, 0.805 g) was dissolved in a mixture of MeOH (10 mL) and 1,4-dioxane (15 mL), to which was added 1N NaOH (10 mL) and heated to reflux for twenty-four hours. An additional 5 mL of 1N NaOH was added, with 5 mL of 1,4-dioxane, and the reaction was heated for an additional forty-two hours, then cooled to 0° C. and acidified to ˜pH 9 with 2N HCl (6 mL). The cold mixture was filtered and washed with deionised water, yielding the title compound as a crude product. MS (ES) MH+: 292, 294 for C11H15Cl2N3O2.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH3:5].[C:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])(=[O:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.[I-].[Na+]>[CH2:2]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:6](=[O:8])[CH3:7])[C:3]#[C:4][CH3:5]
Reactant: CC(=O)Nc1ccccc1O
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC#CCOc1ccccc1NC(C)=O
Yield: 74 %

Procedure:
A mixture of 1-bromo-2-butine (1.39 g (10.4 mmol), 2-acetamidophenol (1.58 mg, 10.4 mmol), anhydrous potassium carbonate (1.44 g, 10.4 mmol) and sodium iodide (30 mg) in butanone (50 ml) was heated over night to reflux. After that the reaction mixture was filtrated, the filtrate was evaporated and the resulting residue was taken up by ethyl acetate. The obtained solution was washed with 5-proz. sodium hydroxide, brine and water, dried over sodium sulfate and evaporated. The crude was recrystallized out of heptane/MTB (1:1) yielding in 1.57 g (74%) of a light brown needles.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:42][C:39]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:41][C:36]([O:35][C:34]([F:45])([F:44])[F:33])=[CH:37][CH:38]=3)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Br)cc3)CC2)c1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(Br)cc4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-bromophenyl)-5-oxopentyl]-4-piperidinyl]phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 642 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]([CH2:7][CH2:8][OH:9])[C:4](=O)[O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][C:32]([C:35]1[CH:36]=[C:37]([S:46][C:47]([S:50][C:51]2[CH:56]=[C:55]([C:57]([CH3:60])([CH3:59])[CH3:58])[C:54]([OH:61])=[C:53]([C:62]([CH3:65])([CH3:64])[CH3:63])[CH:52]=2)([CH3:49])[CH3:48])[CH:38]=[C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:40]=1O)([CH3:34])[CH3:33].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:57]([C:55]1[CH:56]=[C:51]([S:50][C:47]([S:46][C:37]2[CH:36]=[C:35]([C:32]([CH3:34])([CH3:33])[CH3:31])[C:40]([O:9][CH2:8][CH2:7][C@H:5]3[CH2:4][O:3][C:2]([CH3:11])([CH3:1])[O:6]3)=[C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:38]=2)([CH3:49])[CH3:48])[CH:52]=[C:53]([C:62]([CH3:65])([CH3:64])[CH3:63])[C:54]=1[OH:61])([CH3:60])([CH3:59])[CH3:58]
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC1(C)OC(=O)[C@H](CCO)O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](CCOc2c(C(C)(C)C)cc(SC(C)(C)Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc2C(C)(C)C)O1
Temperature: 0 °C
Reaction time: 18 h
Yield: 28.4 %

Procedure:
A 1 L round bottom flask equipped with a nitrogen adapter, temperature probe and addition funnel was charged with 9.3 g (58 mmol, 1.3 eq) of (s)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-ethanol (Ex-10A), 500 mL of anhydrous THF, 25.6 g (98.3 mmol, 2.2 eq) of triphenylphosphine and 23.1 g (44.7 mmol, 1 eq) of probucol. The reaction mixture was cooled to 0° C. with an ice bath, 14.0 mL (89.4 mmol, 2.0 eq) of diethyl azodicarboxylate was charged to the addition funnel and then added dropwise to the reaction mixture. The dark reaction mixture was warmed to ambient temperature and stirred for 18 hours. The reaction mixture concentrated under reduced pressure and the residue was purified by silica gel chromatography (2% EtOAc/hexanes gradient to 5% EtOAc/hexanes) to yield 8.2 g of 2,6-di-tert-butyl-4-(1-{3,5-di-tert-butyl-4-[2-(2,2-dimethyl-[1,3]dioxolan-4(S)-yl)-ethoxy]-phenylsulfanyl}-1-methyl-ethylsulfanyl)-phenol as a white solid, mp 44–46° C. 1H NMR (300 MHz, CDCl3) δ: 7.56 (s, 2H), 7.47 (s, 2H), 5.38 (s, 1H), 4.61 (dd, J=9.17 and 3.75 Hz, 1H), 3.92–4.00 (m, 1H), 3.79–3.87 (m, 1H), 2.50–2.61 (m, 1H), 2.15–2.27 (m, 1H), 1.47 (s, 6H), 1.46 (s, 18H), 1.45 (s, 18H). HRMS (EI+) m/z+Na: calc. 681.3623; found 681.3619.
Reaction SMILES: [CH3:1][O:2][C:3](=[S:17])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([N+:13]([O-])=O)[C:5]=1[CH3:16]>[Fe]>[CH3:1][O:2][C:3](=[S:17])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[C:6]([NH2:13])[C:5]=1[CH3:16]
Reactant: COC(=S)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C
Agent: [Fe]
Product: COC(=S)c1cc(N)cc(N)c1C

Procedure:
Using the method described in Example 1.30, 3,5-dinitro-2-methylthiobenzoic acid methyl ester is reduced using iron turnings to give the title compound which has a melting point of 102°-104° C.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][OH:16])[CH:8]=2)=[CH:4][C:3]=1[F:19].N1C=CN=C1.[CH3:25][C:26]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C>[NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][O:16][Si:29]([C:26]([CH3:28])([CH3:27])[CH3:25])([CH3:31])[CH3:30])[CH:8]=2)=[CH:4][C:3]=1[F:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(Oc2ccnc(NCCO)c2)cc1F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCNc1cc(Oc2ccc(N)c(F)c2)ccn1
Yield: 66.7 %

Procedure:
A mixture of Example A8 (0.263 g, 1.0 mmol), imidazole (0.0749 g, 1.1 mmol) and TBSCl (0.181 g, 1.2 mmol) in DMF (10 mL) was stirred at RT overnight. Solvent was removed under reduced pressure. The residue was quenched with H2O (10 mL) and the pH was adjusted to ˜8 by using NaHCO3. The aqueous solution was extracted with EtOAc (3×20 mL) and the combined organic layers were dried (MgSO4), concentrated in vacuo and purified by chromatography to afford 4-(4-amino-3-fluorophenoxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)pyridin-2-amine (0.252 g, 67% yield) as a light yellow oil. MS (ESI) m/z: 378.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH:48]([CH3:50])[CH3:49])=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH:48]([CH3:49])[CH3:50])=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)C)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)C)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.3 %

Procedure:
p-Methoxyaniline (0.077 g, 0.626 mmol), triethylamine (0.063 g, 0.626 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.106 g, 0.626 mmol) were added to a methylene chloride solution (10 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-isopropoxybenzoic acid (0.117 g, 0.313 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexane:ethyl acetate=1:2) to obtain the titled compound (0.095 g, 0.198 mmol, 63%).
Reaction SMILES: [N:1]1([C:18]([O:20]C(C)(C)C)=O)[CH2:17][CH2:16][CH2:15][C@H:2]1[C:3]([N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])=[O:4].[NH:25]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:26](C(O)=O)[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:43])[NH:32][S:33]([C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1)(=[O:35])=[O:34].CS(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClC1C=CC=CC=1>[NH:25]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:26]([C:18]([N:1]1[CH2:17][CH2:16][CH2:15][C@H:2]1[C:3]([N:5]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:6][CH3:7])=[O:4])=[O:20])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:43])[NH:32][S:33]([C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1)(=[O:35])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CCN(Cc1ccccc1)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CCN(Cc1ccccc1)C(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Boc-Arg(Ts)-Pro-NEtBn was prepared by a similar procedure to Example 1 from Boc-Pro-NEtBn and Boc-Arg(Ts). To the solution composed of the compound (1.00 g), chlorobenzene (5.8 ml) and DBF (1.5 ml), methanesulfonic acid (1.41 g, 9.8 equivalents) was added at room temperature, and the resulting mixture was stirred at room temperature for 24 hours, thereby the Boc group was removed (reaction conversion ratio: 100.0%). After the reaction, 10% aqueous sodium carbonate solution (12 ml) was added thereto, and the resulting mixture was stirred for 15 minutes for neutralization. Then, the aqueous layer was separated off, thereby a solution containing Arg(Ts)-Pro-NEtBn (8.58 g) was obtained.