Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]1.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1>[CH2:18]([O:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](COCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74.8 %

Procedure:
To a solution of 1.4 g (6.7 mmol) of tert-butyl [(1R,3S)-3-(hydroxymethyl)cyclopentyl]carbamate in 20 mL of anhydrous THF are added portionwise under argon, at room temperature, 0.27 g (6.7 mmol) of sodium hydride at 60% in oil. After stirring for 45 minutes, the medium is cooled to 0° C. and 0.8 mL (6.7 mmol) of benzyl bromide is added. After stirring for 1 hour at room temperature, the medium is hydrolysed with 30 mL of water and extracted with 2×100 mL of EtOAc, dried over Na2SO4, concentrated under reduced pressure and then purified by chromatography on a column of silica gel, eluting with a 99/1 DCM/MeOH mixture. 1.53 g of tert-butyl {(1R,3S)-3-[(benzyloxy)methyl]cyclopentyl}carbamate are obtained in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([O-])=[C:5]([CH3:10])[C:4]=1[CH3:11].[C:12]([O:15]C(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:15][CH2:10][C:5]1[C:4]([CH3:11])=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc[n+]([O-])c(C)c1C
Product: COc1ccnc(COC(C)=O)c1C
Yield: 33.3 %

Procedure:
To 37.2 g of 4-methoxy-2,3-dimethylpyridine-1-oxide, 55.0 g (5.0 eq.) of acetic anhydride was added, and the mixture was allowed to react for 3 hours at 90 to 100° C. Acetic anhydride was distilled off, and then the resulting concentrated residue was purified on a silica gel column, to obtain 15.8 g of 2-acetoxymethyl-3-methyl-4-methoxy-pyridine as an oily matter.
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]2)=[C:9]([C:24]#[N:25])[CH:8]=1)([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][CH2:15][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:18]2)=[C:9]([C:24]#[N:25])[CH:8]=1
Reactant: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2C#N)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1CCN(c2ccc(N)cc2C#N)CC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
Ammonium chloride (2.1 g) and iron powder (11.1 g) were added to a mixed solvent of water (110 ml) and ethanol (30 ml), and the mixture was heated to 65° C. Then, ethyl 1-(4-nitro-2-cyanophenyl)piperidin-4-ylcarboxylate (17.1 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution, and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (12 g), melting point: 98° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14](=[CH:20][N:21](C)[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[C:7]([F:24])[CH:8]=2)[N:3]=1.[CH:26]1(N)C[CH2:27]1>ClC(Cl)Cl>[Cl:25][C:6]1[C:7]([F:24])=[CH:8][C:9]2[C:4]([CH:5]=1)=[N:3][C:2]1[N:21]([CH:22]3[CH2:27][CH2:26]3)[CH:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12](=[O:13])[C:11]=1[CH:10]=2
Reactant: NC1CC1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C2CC2)c2nc3cc(Cl)c(F)cc3cc2c1=O
Temperature: 78 °C
Yield: 70.8 %

Procedure:
A solution of ethyl 2-(2,7-dichloro-6-fluoro-3-quinolinecarbonyl)-3-(dimethylamino)acrylate (20.6 g) and cyclopropylamine (6 g) in trichloromethane (100 cc) is stirred at a temperature in the region of 20° C. for 24 hours. The reaction mixture is concentrated under reduced pressure (2.7 kPa) at 50° C. The residue is taken up with ethanol (180 Zcc) and DBU (10 g) and the solution obtained heated to a temperature in the region of 78° C. for 4 hours. After cooling to a temperature in the region of 20° C., the precipitate obtained is drained and washed with ethanol (2×60 cc). 8-Chloro-1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-di hydrobenzo[b][1,8]naphthyridine (13.65 g) is obtained in the form of a pale yellow solid, m.p. 256° C., which is used without further purification for the subsequent steps.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:9]([CH2:17][CH2:18][CH:19]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:21]1([N:27]2[CH2:32][CH2:31][N:30]([CH2:19][CH2:18][CH2:17][C:9]3[CH:10]=[C:11]([C:12]4[S:13][CH:14]=[CH:15][CH:16]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=CCCc1cc(-c2cccs2)n(-c2ccccc2)n1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(N2CCN(CCCc3cc(-c4cccs4)n(-c4ccccc4)n3)CC2)cc1

Procedure:
63 mg (96%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-(thiophene2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142 mmol), 1-phenylpiperazine (0.021 mL, 0.142 mmol), DIPEA (0.040 mL, 0.213 mmol) and NaBH(OAc)3 (90 mg, 0.426 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[C:19](OC(=O)C)(=O)C>CN(CN(C)C)C>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([C:10](=[O:18])[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH2:19])[C:5]=1[OH:9]
Reactant: Cc1cc(C)c(O)c(C(=O)Cc2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)CN(C)C
Product: C=C(C(=O)c1cc(C)cc(C)c1O)c1ccccc1
Temperature: 0 °C

Procedure:
212.6 Grams of 4,6-dimethyl-2-(2-phenylacetyl)phenol was dissolved in 350 ml of N,N,N',N'-tetramethyldiaminomethane, then under ice-cooled condition with stirring, 350 ml of acetic anhydride was added dropwise thereto. The reaction mixture was further stirred at room temperature for 2 hours, then was poured in 1 kg of ice and stirred vigorously. The crystals separated in the mixture were collected by filtration, washes with water, then dried. Recrystallized from ethanol to obtain 186 g of 2,4-dimethyl-6-(2-phenylacryloyl)phenol. Colorless needle-like crystals. Melting point: 83°-84° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[Se](=O)=[O:14]>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:14])[C:7]2=[O:12]
Reactant: O=[Se]=O
Reactant: O=C1CCCc2c(Cl)cccc21
Product: O=C1C=Cc2c(Cl)cccc2C1=O

Procedure:
Treatment of 5-chloro-tetralone with selenium dioxide as described in Reference Example 1A yielded 5-chloro-[1,2]naphthoquinone which was coupled with 2,3-diamino-benzoic acid, diacetate salt, as described in Reference Example 1A to yield the title compound.
Reaction SMILES: [CH2:1](O)C.[Cl:4][C:5]1[CH:18]=[CH:17][C:16]2[CH:15]3[CH2:19][C:8]([C:21]([O:23][CH3:24])=[O:22])([C:9]4[C:14]3=[CH:13][CH:12]=[C:11]([OH:20])[CH:10]=4)[C:7]=2[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CI>C(OCC)C>[Cl:4][C:5]1[CH:18]=[CH:17][C:16]2[CH:15]3[CH2:19][C:8]([C:21]([O:23][CH3:24])=[O:22])([C:9]4[C:14]3=[CH:13][CH:12]=[C:11]([O:20][CH3:1])[CH:10]=4)[C:7]=2[CH:6]=1
Reactant: CCO
Reactant: COC(=O)C12CC(c3ccc(O)cc31)c1ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CI
Product: COC(=O)C12CC(c3ccc(Cl)cc31)c1ccc(OC)cc12
Yield: 90 %

Procedure:
To an ethanol solution of methyl 2-chloro-7-hydroxy-9,10-dihydro-9,10-methano-9-anthracenecarboxylate (described in example 90a) was added potassium carbonate and methyl iodide. The suspension was heated to reflux, cooled and diluted with diethyl ether, filtered to remove salts, and concentrated to a solid. The title compound was formed in 90% yield. TLC analysis (Rf 0.40, 20% ethyl acetate in hexane). MS (CI, CH4) m/z 315 (M+1,100), 343 (M+29,13), 301 (38), 287 (9), 279 (14), 265 (6), 255 (42).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6](C(OC)=O)=[CH:5][N:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:22][CH2:21]C1>C1COCC1>[OH:22][CH2:21][C:11]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(OC)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cc(CO)ccn1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a 0° C. THF (70 mL) solution of methyl 6-methoxynicotinate (6.0 g, 36 mmol) was added 36 mL of 1M LAH/THF. The reaction, after stirring at 20° C. for two hours, was quenched with aq. NH4Cl, diluted with aq. HCl until all salts dissolved, and extracted with EtOAc (3×) after adjusting the pH to 5. The crude 4-hydroxymethyl-2-methoxypyridine (1.75 g), obtained after drying and concentration of the EtOAc layers, was converted to 4-methoxy-3-pyridinylcarboxaldehyde following the procedure described in step A of Example 123. The title compound was prepared from 4-methoxy-3-pyridinylcarboxaldehyde following the procedure described in step A of Example 119.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)=[O:6].[CH3:19]O>Cl>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([O:16][CH3:19])=[O:15])=[CH:9][CH:8]=1)=[O:6]
Reactant: CO
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1
Agent: Cl
Product: COC(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Yield: 95.1 %

Procedure:
Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid (6.2 g, 23.1 mmol) in hot methanolic solution of anhydrous hydrogen chloride (42 mL of a methanol containing 3.2 g of anhydrous hydrogen chloride). Reflux for 42 minutes, evaporate the solvent in vacuo, dissolve the residue in methylene chloride and wash with water. Dry (MgSO4), filter through silica gel, washing the gel with methylene chloride. Combine the organic washings and evaporate the solvent in vacuo to give the title compound as a clear oil (6.21 g, 94%).
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[CH2:5]=[C:6]([CH2:9]O)[CH2:7][OH:8].O>CCCCCC>[CH2:2]([CH:1]1[O:8][CH2:7][C:6](=[CH2:5])[CH2:9][O:4]1)[CH3:3]
Reactant: CCC=O
Reactant: C=C(CO)CO
Solvent: O
Solvent: CCCCCC
Product: C=C1COC(CC)OC1
Yield: 73.2 %

Procedure:
A mixture of 16.3 g of propionaldehyde and 20.2 g of 2-methylene-1,3-propanediol in 1200 ml of hexane containing 0.1 g p-toluenesulfonic acid was stirred thoroughly and the mixture was heated under reflux for two hours while 5.3 g of by-product water was collected in a Dean-Stark trap. The mixture was cooled, concentrated by evaporation under reduced pressure to 50 ml and then treated with 200 ml of ether. The ethereal solution was washed with 75 ml of ten percent sodium carbonate and two 75-ml portions of water, after which it was dried over MgSO4 and concentrated to an oil. Distillation of the oil gave 21.5 g of 2-ethyl-5-methylene-1,3-dioxane, b.p. 68° C/41 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([N:19]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:27](=[O:29])[CH3:28])[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(-c2n[nH]cc2-c2ccnc(NCc3ccccc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N(Cc1ccccc1)c1nccc(-c2c[nH]nc2-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-(phenylmethyl)-2-pyrimidinamine prepared in accordance with Example A-303 (0.15 g, 0.00043 mol), DMAP (0.027 g, 0.00022 mol) and acetic anhydride (0.066 g, 0.00066 mol) in 10 mL of THF was added triethylamine (0.053 g, 0.00052 mol). The solution was stirred at room temperature overnight. After the removal of solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3, washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was triturated with ether to give 0.1 g of product, N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]-N-(phenylmethyl)acetamide, as a white solid (60% yield), mp: 176-178° C.; Anal. Calc'd for C22H18FN5: C, 68.21; H, 4.68; N, 18.08. Found: C, 67.67; H, 4.85; N, 17.79.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14]C(=O)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([SH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(S)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
2.15 g 4-Acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (272) were dissolved in 84 ml MeOH and treated with 2.1 g (55.5 mmol) sodium borohydride at 0° C. after stirring for 2 h at RT all volatiles were removed in vacuo and to the residue was added slowly water and 2.3 g (11 mmol) citric acid monohydrate. Extraction with dichloromethane, drying with Sodium sulfate and evaporation gave 1.78 g of crude 4-Mercapto-piperidine-1-carboxylic acid tert-butyl ester
Reaction SMILES: FC(F)(F)OC1C=CC(N2C(=O)C=CS2)=CC=1.[F:18][C:19]([F:35])([F:34])[O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:31](=[O:32])[CH:30]=[C:29]([Cl:33])[S:28]2)=[CH:23][CH:22]=1.S(Cl)([Cl:39])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:35][C:19]([F:18])([F:34])[O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:31](=[O:32])[C:30]([Cl:39])=[C:29]([Cl:33])[S:28]2)=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=c1cc(Cl)sn1-c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: O=c1ccsn1-c1ccc(OC(F)(F)F)cc1
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c(Cl)c(Cl)sn1-c1ccc(OC(F)(F)F)cc1
Yield: 70.2 %

Procedure:
First, a mixture containing 6.4 g of 2-(4-trifluoromethoxyphenyl)-4-isothiazolin-3-on and 5.1 g of 2-(4-trifluoromethoxyphenyl)-5-chloro-4-isothiazolin-3-on was suspended in 100 ml of dichloromethane, after which 19 g of sulfuryl chloride was then added dropwise to the suspension dropwise at room temperature, and the resultant mixture was stirred for 12 hours. After completion of the reaction, 200 ml of a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and the dichloromethane layer was separated. The aqueous layer was extracted with 150 ml of dichloromethane. The combined dichloromethane layer was washed with water, dried with magnesium sulfate, and concentrated. The concentrate was purified by column chromatography (hexane:ethyl acetate=6:1) to give 4 g of 2-(4-trifluoromethoxy-phenyl)-4,5-dichloro-4-isothiazolin-3on (compound (13); m.p., 129°-130° C.).
Reaction SMILES: I[C:2]1[C:3]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])=[N:4][CH:5]=[N:6][CH:7]=1.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([OH:34])[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[F:27][C:28]1[CH:29]=[C:30]([C:2]2[C:3]([NH:8][C@H:9]([C:11]3[N:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15](=[O:23])[C:14]4=[CH:24][CH:25]=[CH:26][N:13]4[N:12]=3)[CH3:10])=[N:4][CH:5]=[N:6][CH:7]=2)[CH:31]=[C:32]([OH:34])[CH:33]=1
Reactant: OB(O)c1cc(O)cc(F)c1
Reactant: C[C@H](Nc1ncncc1I)c1nn2cccc2c(=O)n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@H](Nc1ncncc1-c1cc(O)cc(F)c1)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 33.9 %

Procedure:
(S)-2-(1-((5-Iodopyrimidin-4-yl)amino)ethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (30 mg, 0.07 mol) was treated with (3-fluoro-5-hydroxyphenyl)boronic acid (15 mg, 0.10 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (87 mg, 0.1 mmol) and sodium carbonate (2M, 147 μl, 0.29 mol) according to the method described in Example 3 to give 15 mg (52% yield) of the title compound as a white solid. Purity 99%.
Reaction SMILES: [OH:1][C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].S(=O)(=O)(O)O.[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH2:18]1[CH2:23][CH2:22][C:21]2([O:8][CH:7]([C@H:9]3[O:10][C@@H:2]4[O:1][C:18]5([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)[O:4][C@@H:3]4[C@H:11]3[OH:12])[CH2:5][O:6]2)[CH2:20][CH2:19]1
Reactant: O=C1CCCCC1
Reactant: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=S(=O)(O)O
Product: O[C@@H]1[C@H]2OC3(CCCCC3)O[C@H]2O[C@@H]1C1COC2(CCCCC2)O1
Temperature: 20 °C
Reaction time: 12 h
Yield: 29 %

Procedure:
DCG was prepared according to the procedure described in J. Am. Chem. Soc., 1949, 71, 3072. A mixture of 90 g of α-D-glucose, 200 mL of cyclohexanone and 13 mL of sulfuric acid was allowed to stir at 20° C. for 12 h to afford 43.9 g (29%) of the above-titled compound, after two crystallizations: mp.=130.5-131.5° C. (lit. 131.1-132.4° C.).
Reaction SMILES: C(=O)([O-])O.[Na+:5].[CH2:6]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]([CH3:27])[C:24]([OH:26])=[O:25])=[CH:15][C:14]1=[O:28])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[CH2:6]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]([CH3:27])[C:24]([O-:26])=[O:25])=[CH:15][C:14]1=[O:28])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[Na+:5]
Reactant: CC(C(=O)O)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C(=O)[O-])c1cc(=O)n(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An aqueous solution (1.63 ml.) of 1 M-sodium hydrogen carbonate was added to a stirred suspension of powdered α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)propionic acid (0.50 g.) in distilled water (3.37 ml.), and the mixture was stirred overnight, at ambient temperature. The solid which had formed was separated and dried in vacuo over phosphorus pentoxide to give sodium α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)-propionate (0.52 g.) as its monohydrate (m.p., indefinite;
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C@H:4]1[O:6][CH2:5]1.[Cl-:15].[Li+].P([O-])([O-])([O-])=O>O1CCCC1>[Cl:15][CH2:5][C@@H:4]([C:3]1[C:2]([F:1])=[C:10]([F:11])[C:9]([F:12])=[C:8]([F:13])[C:7]=1[F:14])[OH:6]
Reactant: Fc1c(F)c(F)c([C@@H]2CO2)c(F)c1F
Reactant: [Cl-]
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O[C@@H](CCl)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.3 %

Procedure:
To an ice-cooled solution of 10.51 g of (R)-(+)-2,3,4,5,6-pentafluorostyrene oxide was dissolved in 100 ml of tetrahydrofuran, was added dropwise a solution of Li2CuCl4, which was prepared by adding 10.08 g of cupric chloride to a suspension of 6.36 g of lithium chloride in 150 ml of tetrahydrofuran. After completion of addition, the solution was stirred for 20 hours at room temperature. The resulted reaction mixture was poured into a 0.05 mol phosphate buffer, and was extracted with ether. The resulted extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 12.00 g of (R)-(-)-2-chloro-1-(pentafluorophenyl)ethanol containing 20% of (+)-2-chloro-2-(pentafluorophenyl)ethanol. This was subjected to isolation by silica gel column chromatography, thereby obtaining (R)-(-)-2-chloro-1-(pentafluorophenyl)-ethanol and (+)-2-chloro-2-(pentafluorophenyl)ethanol respectively possessing the aforementioned physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([S:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[CH3:25][N:26]=[C:27]=[O:28]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([S:17][C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:27]([NH:26][CH3:25])=[O:28])=[CH:22][CH:23]=2)[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(SC(CCc2ccc(Cl)cc2)Cn2ccnc2)cc1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(SC(CCc2ccc(Cl)cc2)Cn2ccnc2)cc1

Procedure:
A solution of 1-[4-(4-chlorophenyl)-2-(4-aminophenylthio)-n-butyl]imidazole (360 mg) in dry tetrahydrofuran (10 ml) was treated with 0.16 ml of methyl isocyanate. The solution was warmed at gentle reflux overnight and the solvent evaporated. The residue was chromatographed on silica gel eluting with 2.2% water in ethyl acetate to give 1-[4-(4-chlorophenyl)-2-(4-methylaminocarbonylaminophenylthio)-n-butyl]imidazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH:18]([CH2:23][CH:24]=[CH2:25])[C:19]([O:21][CH3:22])=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([NH:17][CH:18]([CH2:23][CH:24]3[O:35][CH2:25]3)[C:19]([O:21][CH3:22])=[O:20])(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(NS(=O)(=O)c1ccc(-c2ccc(Br)cc2)cc1)C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 72 h

Procedure:
To a solution of methyl 2-[(4′-bromo[1,1′-biphenyl]-4-yl)-sulfonylamino]-pent-4-eneoate 13c (10.2 g, 24.1mmol) in CH2Cl2 (150 mL), NaHCO3 (11.0 g, 50 mmol) and water (140 mL) at 0° C., is slowly added m-chloroperbenzoic acid (57-86%) (19.4 g, ˜80 mmol). The reaction is stirred for 72 hours. The mixture is diluted with aqueous NaHCO3 and this mixture is extracted with ethyl acetate (3×250 mL). The combined ethyl acetate layer is washed with brine, dried over MgSO4, filtered and concentrated to an oil. Purification of this compound is accomplished by column chromatography with 40% ethyl acetate in hexanes as the eluent to give the desired product.
Reaction SMILES: C(O[C:6]([C:8]1[CH:20]=[C:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:24]([F:32])[CH:23]=2)[C:11]2[CH2:12][C:13]([CH2:16][O:17][CH3:18])([CH3:15])[O:14][C:10]=2[CH:9]=1)=[O:7])(C)(C)C.[NH2:33][C:34]1[CH:38]=[CH:37][N:36]([CH3:39])[N:35]=1>>[CH3:39][N:36]1[CH:37]=[CH:38][C:34]([NH:33][C:6]([C:8]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[C:24]([F:32])[CH:23]=3)[C:11]3[CH2:12][C:13]([CH2:16][O:17][CH3:18])([CH3:15])[O:14][C:10]=3[CH:9]=2)=[O:7])=[N:35]1
Reactant: Cn1ccc(N)n1
Reactant: COCC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)c(F)c3)cc(C(=O)OC(C)(C)C)cc2O1
Product: COCC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)c(F)c3)cc(C(=O)Nc3ccn(C)n3)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 4-(3-fluoro-4-methanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (237a) and 3-amino-1-methyl-pyrazole. 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1 H) 7.92 (t, J=8.38 Hz, 1 H) 7.29 (d, J=2.26 Hz, 1 H) 7.12 (d, J=1.13 Hz, 1 H) 7.08 (d, J=1.13 Hz, 1 H) 6.88 (dd, J=8.76, 2.35 Hz, 1 H) 6.76-6.84 (m, 2 H) 3.81 (s, 3 H) 3.42-3.56 (m, 2 H) 3.41 (s, 3 H) 3.23 (s, 3 H) 3.15 (d, J=16.58 Hz, 1 H) 2.79 (d, J=16.58 Hz, 1 H) 1.48 (s, 3 H); LCMS for C23H24FN3O6S m/z 490.00 (M+H+).