Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C(O[CH:14](OCC)[CH2:15][CH3:16])C.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:20]1([CH:14]([NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:15][CH3:16])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CCOC(CC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC(NC(=O)c1ccc(Cl)cc1)n1nnc2ccccc21
Temperature: 25 °C
Yield: 28.5 %

Procedure:
A suspension of 4-chlorobenzamide (1.50 g, 9.6 mmol), propionaldehyde diethyl acetal (1.53 g, 11.6 mmol), and benzotriazole (1.15 g, 9.6 mmol) in toluene (35 mL) was treated with p-toluenesulfonic acid (100 mg, 0.53 mmol). The mixture was heated at reflux under Dean-Stark conditions for 16 hours, cooled to ambient temperature, and concentrated to dryness. The crude material was purified by flash chromatography (elution with 40% ethyl acetate/hexanes) to provide 0.860 g of the desired product as a white solid.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C@H:5]([CH3:29])[N:6]2C(=O)[C@@H]1CCCN1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[OH-:30].[K+].O>CO>[C:24]1([CH3:27])[CH:23]=[CH:22][C:21]([S:18]([OH:19])(=[O:20])=[O:30])=[CH:26][CH:25]=1.[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C@H:5]([CH3:29])[NH:6]2
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N2c3ccc(F)c(F)c3C[C@@H]2C)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@H]1Cc2c(ccc(F)c2F)N1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(-)-4,5-difluoro-2-(S)-methyl-1-[(S)-N-p-toluenesulfonylprolyl]-2,3-dihydroindole, the compound (a) obtained in Example 1, 51.7 g, was added to the solution comprising 69 g of potassium hydroxide, 50 ml of water and 200 ml of methanol, and the mixture was refluxed by heating for 3.5 hours. After the reaction the mixture was allowed to cool to the room temperature, concentrated under reduced pressure to the 1/4 volume, to which was added 800 ml of water, and extracted twice with 400 ml of ether. The ether layer was washed with 300 ml of water and a saturated aqueous solution of sodium chloride, and the organic layer was dried over magnesium sulfate and filtered. To the filtrate was added 24 g of p-toluenesulfonic acid monohydrate, and stirred for 30 minutes. The precipitate was collected by filtration, and recrystallized from ethyl acetate-edthanol, to give 25.8 g of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:23]3[O:22][CH:21]=[CH:20][C:19]=3[CH:18]=[C:17]([NH2:24])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[S:30]([Cl:33])(=[O:32])=[O:31]>>[ClH:33].[ClH:33].[N:11]1([CH2:14][C:15]2[C:23]3[O:22][CH:21]=[CH:20][C:19]=3[CH:18]=[C:17]([NH:24][S:30]([C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)(=[O:32])=[O:31])[CH:16]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(N)cc3ccoc23)CC1
Product: Cl
Product: O=S(=O)(Nc1cc(CN2CCNCC2)c2occc2c1)c1cccs1
Reaction time: 1 h
Yield: 7.4 %

Procedure:
The title compound was prepared according to the procedure of Example 106, Step 3, starting from 4-(5-amino-benzofuran-7-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (40 mg, 0.12 mmol; obtained in Example 106, Step 2) and 2-thiophenesulfonyl chloride (33 mg, 0.18 mmol). Additional 2-thiophenesulfonyl chloride (10 mg, 0.05 mmol) was added with continued stirring for 1 h. The crude product was purified with preparative HPLC (System B; 10-40% MeCN). The title compound (3 mg, 6%) was obtained as a colorless solid. HPLC 95%, RT=1.25 min (System A; 10-97% MeCN over 3 min), 95%, RT=1.11 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, methanol-d4) δ ppm 3.43-3.49 (m, 4H) 3.50-3.57 (m, 4H) 4.59 (s, 2H) 6.90 (d, J=2.26 Hz, 1H) 7.05 (dd, J=5.02, 3.76 Hz, 1H) 7.35 (d, J=2.26 Hz, 1H) 7.45-7.50 (m, 2H) 7.70 (dd, J=5.02, 1.51 Hz, 1H) 7.88 (d, J=2.26 Hz, 1H). MS (ESI+) for C17H19N3O3S2 m/z 378 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1.[CH2:24](B(O)O)[CH2:25][CH:26]([CH3:28])[CH3:27].C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:24]([C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1)[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)n3cnnc23)CC1
Reactant: CC(C)CCB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)CCc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c2nncn12
Temperature: 100 °C
Yield: 44 %

Procedure:
A 50 mL round bottom flask was charged with tert-butyl 4-(5-bromo-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)piperazine-1-carboxylate (1.0 g, 2.61 mmol), isopentylboronic acid (484 mg, 4.18 mmol), Pd(PPh3)4 (300 mg, 0.261 mmol), 2 M aqueous K2CO3 (2.6 mL, 5.2 mmol) and toluene (15 mL) under N2. The resulting mixture was heated under N2 at 100° C. overnight. Work-up: the reaction mixture was filtered. The filter cake was washed with EtOAc (10 mL) and the filtrate was extracted with more EtOAc (10 mL×3). The combined organic solutions were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 2% methanol in dichloromethane, to afford 0.43 g (44%) of tert-butyl 4-(5-isopentyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)piperazine-1-carboxylate as a yellow solid. MS m/z: 375 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]=1[C:8]#[N:9].[NH2:16][NH2:17]>C(O)C>[C:10]1([C:6]2[CH:5]=[N:17][N:16]=[C:2]3[NH:3][N:4]=[C:8]([NH2:9])[C:7]=23)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NN
Reactant: N#Cc1c(-c2ccccc2)cnnc1Cl
Solvent: CCO
Product: Nc1n[nH]c2nncc(-c3ccccc3)c12

Procedure:
3-Chloro-5-phenyl-pyridazine-4-carbonitrile obtained from Step B was suspended in 1 mL ethanol with 23 μL hydrazine and the mixture was refluxed for several hours. The solvent was then evaporated and the title product was purified by silica gel chromatography (1:9 methanol/dichloromethane): MS (ES+) 212 (M+H); HPLC 1.121 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN1CCOCC1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.C(O)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:25]=1)=[O:6]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
3.2 g 2-Chloro-4,6-dimethoxy-1,3,5-traizine (CDMT) was charged to a mixture of 2.8 g 2-chloro-4-(methylsulfonyl)benzoic acid (Formula F) in 80 mL methylene dichloride (MDC) under nitrogen atmosphere at 25-30° C. and stirred for about 20 mins 4.9 g N-methyl morpholine (NMM) was added to the reaction mixture over period of about 15 mins maintaining temperature of 20-30° C. Reaction mixture was maintained under stirring at this temperature for about 3 hrs. 2 g 4-chloro-3-(pyridin-2-yl)benzenamine (Formula E) was then added to the reaction mixture and stirring was done for additional 3 hrs at same temperature. Then the temperature of reaction mixture was raised to 35-40° C. and stirring was done, intermittently checking reaction progress by TLC. On completion of the reaction, reaction mixture was cooled to 20-30° C. and quenched with 40 mL water. Organic layer was separated and the aqueous layer was washed with 20 mL MDC. MDC organic layer was collected and washed twice with 40 mL saturated sodium bicarbonate solution followed by a water washing (40 mL). Organic layer was dried over sodium sulphate and solvent was distilled off under vacuum at 35-45° C. to obtain a residue. To this residue, 30 mL Iso-propyl alcohol (IPA) was added and reaction temperature was raised to 60-70° C., wherein stirring was performed for about 30 mins followed by slow cooling to 20-30° C. Reaction was maintained for about 1 hr at same temperature under stirring. The precipitated product was filtered on Buchner funnel, washed with 10 mL IPA and dried at 40-45° C. under vacuum to get 2.5 g 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide (I) having HPLC area purity of 99.3%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[CH3:2].C(Cl)(Cl)[Cl:15]>>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:11][C:10]=1[Cl:15]
Reactant: ClC(Cl)Cl
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl-4-aminophenylacetate (20 g, 112 mmol) was dissolved in chloroform (300 ml) and treated with N-chlorosuccinimde (14.92 g, 112 mmol) and stirred for 15 minutes at room temperature under argon. Reaction mixture was washed with water, brine and dried over magnesium sulphate. Evaporated to a brown oil which was purified by chromatography on silica gel eluting with ethyl acetate (0-45%) in hexane to give the title compound as a orange oil (10.12 g, 47.4 mmol). LC/MS: Rt=2.59, [MH]+ 214.
Reaction SMILES: [C:1]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:16][CH2:17][CH2:18][CH2:19][C:20]1[C:24]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=2[O:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[ClH:16].[C:1]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:6][N:7]([CH2:17][CH2:18][CH2:19][C:20]2[C:24]3[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=3[O:22][N:21]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(CCCCl)noc2c1
Reactant: CC(=O)C1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)C1(c2ccccc2)CCN(CCCc2noc3cc(F)ccc23)CC1
Product: Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
To 35 ml of dimethylformamide was added 4.06 g of 4-acetyl-4-phenylpiperidine, 5.0 g of 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 10 g of milled anhydrous potassium carbonate, and a few crystals of potassium iodide. After stirring at 80° C. for two hrs, the mixture was filtered. The filtrate was evaporated and the residue was stirred with 100 ml of water and then extracted into ether. The ether solution was washed with water (2×), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solution was acidified with ethereal hydrogen chloride and the resultant precipitate was collected and dried to yield 5.5 g (66%) of product, mp 170° C. (dec). Three recrystallizations from ethyl acetate:methanol (9:1) gave the analytical sample, mp 200°-203° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.S(=O)(=O)(O)[OH:19].[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]([C:8]([NH2:9])=[O:19])=[N:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ncccc1Oc1cc(Br)cnc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ncccc1Oc1cc(Br)cnc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A flask was charged with 5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (60 g, 207 mmol) and sulfuric acid (203 g, 2068 mmol). The reaction was stirred at ambient temperature overnight. Water (500 mL) was added carefully and neutralized using 50% sodium hydroxide to pH 5.0. The mixture was extracted with dichloromethane and ethyl acetate, dried and concentrated to afford 5-bromo-3-(2-methylpyridin-3-yloxy)picolinamide (63.0 g, 204 mmol, 98.9% yield) as yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=2)[NH2:35])[CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:24][C:12]1[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[C:32]([N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)[CH:33]=3)=[O:23])=[CH:19][CH:20]=2)=[CH:14][C:9]([NH:8][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:7])=[CH:10][CH:11]=1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)Nc2cccc(N3CCN(C)CC3)c2)cc1

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (50 mg, 0.156 mmol), 3-(4-methylpiperazin-1-yl)aniline (29.8 mg, 0.156 mmol), HATU (59.2 mg, 0.156 mmol), HOBT (21 mg, 0.156 mmol) and DIPEA (27 μl, 0.156 mmol) in DMF (2 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with water (2×30 ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue chromatographed on a silica flash column eluting with DCM/methanol/triethylamine (96:2:2). Concentration of the product fractions under vacuum N-(6-methyl-4′-{[3-(4-methylpiperazin-1-yl)anilino]carbonyl}-1,1′-biphenyl-3-yl)-3-furamide (59.5 mg, 77%). NMR; δH [2H6]-DMSO 10.13,(1H, s), 9.93,(1H, s), 8.36,(1H, s), 8.02,(2H, d), 7.78,(1H, t), 7.68,(1H, dd), 7.63,(1H, d), 7.51,(2H, d), 7.43,(1H, m), 7.30-7.26,(2H, m), 7.17,(1H, t), 6.99,(1H, m), 6.70,(1H, dd), 3.12,(4H, m), 2.46,(4H, m), 2.22,(6H, s). LCMS: retention time 2.43 min, MH+495.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-one (244 g, 1.56 mol, 1.0 eq.) in MeOH (5 L) was slowly added NaBH4 (59 g, 1.56 mol, 1.0 eq.) keeping the internal temperature <10° C. using an ice bath. The ice bath was removed and the mixture was stirred for 30 min at room temperature. The solvent was then removed under reduced pressure and the resulting solid was dissolved in 50% diethyl ether in EtOAc (5 L), washed with saturated aqueous NH4Cl (800 mL×3), brine (800 mL), dried over Na2SO4, filtered, and evaporated to give 215 g (87% yield) of 1,4-dioxaspiro[4.5]decan-8-ol. GC-MS: 159 (M+1).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9](=[S:11])[NH2:10])[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4]1.CO[CH:23](OC)[CH2:24]Br.[OH-].[K+].C1C=CC=CC=1>O>[F:20][CH2:19][C:3]1([CH2:2][F:1])[CH:8]=[C:7]([C:9]2[S:11][CH:23]=[CH:24][N:10]=2)[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4]1
Reactant: NC(=S)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Reactant: COC(CBr)OC
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)C(c1nccs1)=CC(CF)(CF)O2

Procedure:
A mixture of 600 mg of 2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-carbothioamide, 1.2 ml of bromo-acetoaldehyde dimethylacetal, 11 mg of potassium hydroxide and 3 ml of benzene was refluxed with heating for 1 hour. Water was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, hexane:ethyl acetate=2:1) to obtain 380 mg of 2-(2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-yl)thiazol represented by the following formula.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[NH:18][CH:17]=[CH:16][N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:44][C:45]([N:47]1[CH2:52][CH:51]([CH3:53])[CH2:50][CH:49]([CH3:54])[CH2:48]1)=[O:46]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:18]([CH2:44][C:45]([N:47]3[CH2:52][CH:51]([CH3:53])[CH2:50][CH:49]([CH3:54])[CH2:48]3)=[O:46])[CH:17]=[CH:16][N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4]
Reactant: COC(=O)c1nc2[nH]ccn2c(=O)c1OC(C)=O
Reactant: CC1CC(C)CN(C(=O)CBr)C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1nc2n(CC(=O)N3CC(C)CC(C)C3)ccn2c(=O)c1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
6-Acetoxy-5-oxo-1,5-dihydro-imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester (3 g, 11.95 mmol) was mixed with K2CO3 (3.3 g, 23.9 mmol), 18-crown-6 ether (0.3 g) and 2-Bromo-1-(3,5-dimethyl-piperidin-1-yl)-ethanone (4.2 g, 17.93 mmol) in acetonitrile (60 ml). The resulting mixture was stirred overnight at room temperature. The solvents were removed, and the residue taken up in ethylacetate; washed with water and 1N HCl. After drying over MgSO4, the organic phase was evaporated to dryness and the residue was purified on silica gel to give 6-acetoxy-1-[2-(3,5-dimethyl-piperidin-1-yl)-2-oxo-ethyl]-5-oxo-1,5-dihydro-imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester (2.92 g, 60.5% yield).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([OH:11])[CH2:9]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(C1C=C(C(C)C)C=C(C(C)C)C=1S(Cl)(=O)=O)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOCC>[CH:1]1([CH2:7][C@H:8]2[CH2:9][O:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OC[C@@H](O)CC1CCCCC1
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C1CCC(C[C@H]2CO2)CC1
Temperature: 0 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
To a solution of (S)-3-cyclohexyl-1,2-propanediol in CH2Cl2 was added triethylamine (6.6 mL), 2,4,6-triisopropylbenzenesulfonyl chloride (11.5 g), and DMAP (0.386 g). After 14 h, the reaction was diluted with ether, chilled to 0° C., filtered through celite and concentrated. The residue was dissolved in ethanol (100 mL), and 1M NaOH was added (32 mL). After 30 min, the reaction was carefully concentrated, diluted with water (100 mL) and extracted into ether (3×50 mL). The organic extracts were washed with brine (20 mL), dried (MgSO4), filtered and concentrated to give a colorless aromatic oil which was purified first by passage through a plug of silica gel eluting with 5%EtOAc/hexane, then by bulb-to-bulb distillation under reduced pressure to give a colorless aromatic oil (3.3 g, 75%). 1H NMR (300 MHz, CDCl3) δ0.90-1.09 (m, 2H), 1.10-1.85 (m, 11H), 2.43 (dd, J=5.1, 2.7 Hz, 1H), 2.75 (dd, J=5.1, 4.5 Hz, 1H), 2.94 (m, 1H).
Reaction SMILES: N[C@H:2]([C:6]([OH:8])=[O:7])[CH:3](C)C.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=O>>[O:18]=[C:16]([CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=1)[CH2:3][CH2:2][C:6]([OH:8])=[O:7]
Reactant: O=C(O)Cc1ccccn1
Reactant: CC(C)[C@H](N)C(=O)O
Product: O=C(O)CCC(=O)Cc1ccccn1

Procedure:
According to the method of W. Steglich and P. Gruber (Angew. Chem., 1971, 83, 727-728), 4-oxo-5-(pyridin-2-yl)pentanoic acid is synthesized from valine and 2-(pyridin-2-yl)-acetic acid.
Reaction SMILES: C([O:5][NH:6][C:7](=[O:32])[CH2:8][N:9]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)(C)(C)C.C(O)C>C(Cl)Cl>[OH:5][NH:6][C:7](=[O:32])[CH2:8][N:9]([S:21]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)(=[O:23])=[O:22])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)NOC(C)(C)C)Cc2ccc3ccccc3n2)cc1
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(CC(=O)NO)Cc2ccc3ccccc3n2)cc1
Reaction time: 8 h

Procedure:
N-(t-Butyloxy)-2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetamide (1.15 g, 2.42 mmol) is dissolved in methylene chloride (30.0 mL) and ethanol (0.20 mL) in a glass sealed tube. Hydrochloric acid gas (from a lecture bottle) is bubbled through the solution for 20 minutes, and then the tube is sealed and stands at room temperature overnight. The next day, additional hydrochloric acid gas is bubbled through the solution for 20 minutes, more ethanol (0.20 mL) is added, and then the tube is sealed and stands at room temperature for two days. After that time, the solvent is removed. The product is purified by silca gel chromatography (5% to 15% methanol/methylene chloride with ~1% ammonium hydroxide) to give N-hydroxy-2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetamide, m.p. 177°-178° C.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:6]=[CH:7][C:8]=1[C:9]1[CH2:14][CH2:13]S[C:11](=[O:15])[CH:10]=1)C.[OH:27]C1C=C(N2C[C@H](CNC(=O)C)OC2=O)C=CC=1C1CCNC(=O)C=1>>[O:27]=[C:11]1[CH:10]=[C:9]([C:8]2[CH:3]=[CH:4][C:5]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]3=[O:26])=[CH:6][CH:7]=2)[CH2:14][CH2:13][O:15]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CC(=O)NCC3)c(O)c2)C(=O)O1
Reactant: CCc1cc(N2C[C@H](CNC(C)=O)OC2=O)ccc1C1=CC(=O)SCC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CC(=O)OCC3)cc2)C(=O)O1

Procedure:
N-((5S)-3-(3-ethyl-4-(2-oxo-5,6-dihydrothiapyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide and N-((5S)-3-(3-hydroxy-4-(2-oxo-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide are excluded.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[NH:25][C:24]2=[O:32])=[CH:19][CH:18]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CN(CCN(C)C)C>C1COCC1>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[NH:25][C:24]2=[O:32])=[CH:21][CH:22]=1
Reactant: C[Si](C)(C)CCOCn1c(Oc2ccc(-n3c(=O)[nH]c4cccnc43)cc2)nc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)CCN(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: O=c1[nH]c2cccnc2n1-c1ccc(Oc2nc3ccccc3[nH]2)cc1
Temperature: 50 °C
Yield: 34.5 %

Procedure:
A mixture of 3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg), 1 M TBAF in THF (6.3 mL), and TMEDA in THF (20 ml) was heated at 50° C. for 24 h. After cooling to rt, the mixture was partitioned between AcOEt and H2O. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2, hexane/AcOEt=1/3 then AcOEt/MeOH=95/5). The obtained product was recrystallized from MeOH-iPr2O to give 3-[4-(1H-benzimidazol-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (75 mg) as white crystals.