Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]([C:11]#[N:12])[C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19]>CN(C)C=O>[CH2:1]([C:8]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])([C:9]#[N:10])[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC(C#N)Cc1ccccc1
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccccc1
Yield: 17.3 %

Procedure:
Using 0.50 g of benzylmalononitrile, 10 ml of N,N-dimethylformamide, 0.14 g of sodium hydride (60% in oil), and 0.63 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.14 g of 2-benzyl-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (12)).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C1=COCCC1
Reactant: CCOC(=O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)COC1CCCCO1
Yield: 85 %

Procedure:
To a stirred solution of 15.5 g. (0.15 mol.) of ethyl glycolate in 60 ml. of methylene chloride, cooled to 5° C., was added 12.6 g. (0.15 mol.) of dihydropyran, followed by 50 mg. of 4-toluenesulfonic acid monohydrate. After the immediate exothermic reaction which ensued had subsided, the methylene chloride solution was washed successively with water, 5% sodium bicarbonate and water. The dried solution was then evaporated to give 23.8 g. (85% yield) of ethyl 2-(2-tetrahydropyranyloxy)acetate as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21](Br)=[CH:22][CH:23]=3)[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]=2[O:32][C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[CH3:40])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:41][N:42](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([C:41]#[N:42])=[CH:22][CH:23]=3)[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]=2[O:32][C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[CH3:40])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Br)cc2n1-c1ccccc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(C#N)cc2n1-c1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of the compound of step 2 (350 mg, 0.58 mmol), zinc cyanide (135 mg, 1.15 mmol) and tetrakis(triphenylphosphin)palladium(0) (133 mg, 0.12 mmol) in DMF (8 ml) was heated to 80° C. for 1 h. After cooling to room temperature, the mixture was partitioned between water and EA and the aqueous phase extracted with EA. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC and lyophilized overnight. 151 mg of the title compound were obtained.
Reaction SMILES: C(O[C:9]([N:11]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=1)C)=O)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[CH2:23]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([CH2:13][NH:11][CH3:9])=[CH:15]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN(Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNCc1cn(Cc2ccccc2)c2ccccc12
Reaction time: 5 h
Yield: 86.8 %

Procedure:
3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl]-1-benzyl-1H-indole (0.9 g, 2.3 mmole) was added to a suspension of Pearlman's catalyst (about 0.30 g) in MeOH at RT in a Parr flask. The reaction was placed under 50 p.s.i. of H2 and shaken for 5 hr. The mixture was filtered through Celite® and the filter pad was washed with MeOH. The filtrate was concentrated to afford the title compound (0.5 g, 86%) as a light yellow solid: MS (ES) m/e 251 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[OH-].[Na+].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>O1CCOCC1.O>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:12](=[O:13])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Reaction time: 64 h

Procedure:
Trans-4-hydroxycyclohexylamine (23 g) was dissolved in 1,4-dioxane (360 ml) and water (360 ml), and cooled at 0° C. Aqueous 5 N sodium hydroxide solution (160 ml) and benzyl chloroformate (72 ml) were added to the reaction liquid successively, then restored to room temperature and stirred for 64 hours. The white solid formed in the reaction system was collected by filtration, then successively washed with water and ethyl acetate, and dried at 50° C. under reduced pressure to obtain the entitled compound (32.3 g) as a white solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C@@H:7]([CH2:23][O:24][S:25]([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:8][C@H:9]1[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[N:10]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])C.[CH3:36][CH2:37][Mg+].[Br-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.CCOC(C)=O>[OH:3][C:4]1([CH2:5][CH2:6][C@@H:7]([CH2:23][O:24][S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:26])=[O:27])[CH2:8][C@H:9]2[CH2:13][O:12][C:11]([CH3:14])([CH3:15])[N:10]2[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:37][CH2:36]1
Reactant: CC[Mg+]
Reactant: CCOC(=O)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@H](CCC2(O)CC2)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
(S)-tert-Butyl 4-((R)-5-ethoxy-5-oxo-2-(tosyloxymethyl)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (1.82 g, 3.55 mmol) and Ti(Oi-Pr)4 were dissolved in THF (30 mL) and allowed to stir at ambient temperature. A solution of EtMgBr (3.0 M, 5.91 mL, 17.8 mmol, 5.0 equiv) was added over a 6 hr period via syringe pump and the resulting mixture stirred overnight. The mixture was treated with a 50% solution of Rochelle's salt and diluted with EtOAc. The layers were separated and the aqueous layer extracted with additional EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The resulting crude (S)-tert-butyl 4-((R)-4-(1-hydroxycyclopropyl)-2-(tosyloxymethyl)butyl)-2,2-dimethyloxazolidine-3-carboxylate was used in the next step with no further purification.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:11][N:12]1C(=O)O[C:15](=[O:16])[C:14]2=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=[C:13]12>>[CH3:11][NH:12][C:13]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:14]=1[C:15]([NH:10][O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:16]
Reactant: NOCc1ccccc1
Reactant: Cn1c(=O)oc(=O)c2cc(Cl)ccc21
Agent: Cl
Product: CNc1ccc(Cl)cc1C(=O)NOCc1ccccc1
Yield: 50.6 %

Procedure:
In the same manner as Example 35(a), O-benzylhydroxylamine hydrochloride (1.92 g, 12 mmol) reacted with N-methyl-5-chloro-isatoic anhydride (2.13 g, 10 mmol) to give 2-methylamino-5 chloro-N-benzyloxylbenzamide as a white solid (1.47 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(=O)(=O)(O)O>C1COCC1.ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CCl)cc1
Agent: [Mn+4]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
Under an argon atmosphere, 4-chloromethylbenzoic acid (15.08 g, 88.40 mmol) was dissolved in THF (150 ml), and 1M borane-THF complex (135 ml, 135.00 mmol) was slowly added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours, 1N sulfuric acid (160 ml) was added, and the mixture was stirred for 1 hour and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was dissolved in dichloromethane (300 ml). Manganese dioxide (76.94 g, 885.0 mmol) was added, and the mixture was stirred overnight at room temperature. After filtration through celite, the filtrate was concentrated under reduced pressure to give the title compound (11.93 g, 87%).
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.Br[CH2:32][CH:33]1[O:37][CH2:36][CH2:35][O:34]1>CN(C=O)C>[O:34]1[CH2:35][CH2:36][O:37][CH:33]1[CH2:32][N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][O:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5]([OH:30])=[O:4])[CH2:16][CH2:17]2)=[CH:22]1
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: BrCC1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CC3OCCO3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
0.02 g (0.42 mmol) of a dispersion of 60% NaH in mineral oil were added to a solution of 0.06 g (0.16 mmol) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester prepared in step D in 1 mL of anhydrous DMF under an inert atmosphere. After stirring 30 minutes at room temperature, 0.04 mg (0.24 mmol) of 2-bromomethyl-[1,3]dioxolane were added and the mixture was stirred for 18 hours. The solvent was removed under reduced pressure and the crude mixture was dissolved in 1 mL of ethanol. 0.1 mL of 2N NaOH were added and the mixture was stirred at 60° C. for 3 hours. 0.1 mL of 2N HCl were added and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the crude mixture was purified using a 500 mg Varian C18 chromatography column, affording 0.040 g (56% yield) of 2-{2-[4-(1-[1,3]dioxolan-2-ylmethyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:22]=[CH:21][C:20]([O:23]C)=[N:19][C:10]=3[C:11]3[C:17]([CH3:18])=[N:16][O:15][C:12]=3[CH2:13][N:14]=2)=[CH:4][CH:3]=1>CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:10]=3[C:11]3[C:17]([CH3:18])=[N:16][O:15][C:12]=3[CH2:13][N:14]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(n1)-c1c(C)noc1CN=C2c1ccc(Cl)cc1
Solvent: CC(=O)O
Product: Cc1noc2c1-c1[nH]c(=O)ccc1C(c1ccc(Cl)cc1)=NC2
Temperature: 100 °C
Yield: 39.7 %

Procedure:
To a solution of 5-(4-chlorophenyl)-2-methoxy-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine (0.050 g, 0.147 mmol) in AcOH (1 mL) was added concentrated 48% hydrobromic acid (1 mL) at room temperature. The reaction was heated to 100° C. for 2 h before it was diluted with water, and the desired product was extracted with a mixture CH2Cl2/trifluoroethanol (19:1) (repeated 4 times). The organic layers were combined, dried over Na2SO4 and concentrated to dryness. The residue was purified by flash chromatography (hexane/EtOAc 7:3 to 0:10) to give the title compound as a white solid (0.019 g). LC/MS m/z 326 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 11.79 (br. s, 1H), 7.51-7.41 (m, 4H), 7.36 (br. s, 1H), 6.41 (br. s, 1H), 4.53 (br. s, 2H), 2.55 (s, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:16]=[CH:15][C:9]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1>>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][CH2:11][C:12](=[O:14])[CH2:8][C:9]([CH3:15])([CH3:10])[C:15]=2[CH:16]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Solvent: O=S(Cl)Cl
Product: CC1(C)CC(=O)CCc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
19.0 ml of thionyl chloride are added to 30 g of p-bromohydrocinnamic acid and heated to reflux for 30 minutes. After cooling, the excess reagent is removed by evaporation (finally at 0.5 Torr) and the crude acid chloride is dissolved in 300 ml of carbon disulfide. After cooling to -10°, 3.5 ml of tin tetrachloride are added under an argon atmosphere. Thereafter, 25 ml of isobutylene are introduced and the reaction mixture is warmed slowly to room temperature. After renewed cooling to 0°, 35 g of aluminum trichloride are added. The reaction mixture is stirred overnight, poured on to ice, extracted with diethyl ether and the extract is washed with water and phosphate buffer (pH 7) and dried. After evaporation, the residue is chromatographed on silica gel with petroleum ether (low-boiling) and ethyl acetate (9:1). There is obtained 2-bromo-5,6,8,9-tetrahydro-9,9-dimethyl-7-benzocycloheptenone in the form of yellowish crystals of m.p. 67°-68° (from hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]Br)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[OH:22][C:23]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:29][C:27]3[CH:26]=[CH:25][NH:24][C:23](=[O:22])[CH:28]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: Oc1ccnc(O)c1
Reactant: FC(F)(F)c1cc(Oc2ccc(CCBr)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Temperature: 25 °C
Yield: 16.6 %

Procedure:
A solution of 4-(2-bromoethyl)phenyl 4-Chloro-3-(trifluoromethyl)phenyl ether (335 mg, 0.883 mmol), 2,4-dihydroxypyridine (200 mg, 1.800 mmol), and cesium Carbonate (600 mg, 1.842 mmol) in N,N-dimethylformamide (DMF) (10 mL) was stirred at 120° C. for 4 h, then cooled to rt, Purification via Biotage-C18 system afforded the title product (60 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10].[NH2:12][C:13]([NH2:15])=[S:14]>>[NH2:15][C:13]1[S:14][CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:12]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Product: Nc1nc(-c2ccc(Cl)cc2Cl)cs1
Yield: 97.1 %

Procedure:
Using 2′,4′-dichloroacetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Reaction SMILES: C([N:4]([C:12]1[S:13][C@H:14]2[O:20][C@H:19]([CH2:21][OH:22])[C@@H:18]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C@H:17]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[C@H:15]2[N:16]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])C=C.CCN(CC)CC.C(O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1.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.ClCCl>[OH:22][CH2:21][C@H:19]1[O:20][C@H:14]2[C@H:15]([N:16]=[C:12]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[S:13]2)[C@@H:17]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C@@H:18]1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1
Reactant: C=CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](OCc3ccc(OC)cc3)[C@@H](CO)O[C@@H]2S1
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: [Na+]
Solvent: O=CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(CO[C@@H]2[C@H]3N=C(NC(=O)OC(C)(C)C)S[C@H]3O[C@H](CO)[C@H]2OCc2ccc(OC)cc2)cc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 63.4 %

Procedure:
To a solution of 148 (10.5 g, 18 mmol) in 1,4-dioxane (100 mL) was added Pd(PPh3)4 (4.2 g, 3.6 mmol), Et3N (4.6 g, 45 mmol) and formic acid (4.9 g, 107 mmol) at room temperature under N2 atmosphere. After 20 minutes at 60° C., additional formic acid (24.5 g, 535 mmol) was added. The reaction was stirred at 60° C. for additional 3 hours. Removal of volatiles gave a residue, which was dissolved into dichloromethane (100 mL) and neutralized with saturated aqueous NaHCO3 solution (30 mL). The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography with 10%-50% ethyl acetate in petroleum ether to afford the title compound as a white syrup (6.4 g, 65%). (ES, m/z): [M+H]+ 561.0; 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 4H), 6.92-6.87 (m, 4H), 6.14 (d, J=6.9 Hz, 1H), 4.56-4.52 (m, 3H), 4.36-4.32 (m, 1H), 4.25-4.19 (m, 1H), 4.13-4.07 (m, 1H), 3.82-3.80 (m, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.76-3.51 (m, 3H), 1.54 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13](Cl)=[O:14]>>[OH:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:13](=[O:14])[C:12]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=1[F:10]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Reactant: Nc1ccc(F)cc1O
Product: O=C(Nc1ccc(F)cc1O)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by the method of Example 15a), from 2-amino-5-fluorophenol (508 mg, 4.0 mmol) and 2-fluoro-5-nitrobenzoyl chloride (814 g, 4.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.[CH2:34]([N:38]1[C:46]2[N:45]=[C:44]([Cl:47])[NH:43][C:42]=2[C:41](=[O:48])[N:40]([CH2:49][CH2:50][CH2:51]/[C:52](=[N:55]/[H])/[NH:53]O)[C:39]1=[O:57])[CH2:35][CH2:36][CH3:37]>CN1CCCC1=O>[CH2:34]([N:38]1[C:46]2[N:45]=[C:44]([Cl:47])[NH:43][C:42]=2[C:41](=[O:48])[N:40]([CH2:49][CH2:50][CH2:51][C:52]2[N:53]=[C:9]([CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[O:11][N:55]=2)[C:39]1=[O:57])[CH2:35][CH2:36][CH3:37]
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: [H]/N=C(/CCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Product: CCCCn1c(=O)n(CCCc2noc(Cc3cccc(Cl)c3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 27.2 %

Procedure:
(3-Chlorophenyl)acetic acid (0.1 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (21 mg, 0.11 mmol) and 1H-1,2,3-benzotriazol-1-ol (15 mg, 0.11 mmol) were stirred in 1-methyl-2-pyrrolidinone (1 ml). To this was added (1Z)-4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxybutanimidamide (34 mg, 0.1 mmol) and the mixture stirred at rt for 17 h and then at 80° C. for 24 h. The reaction mixture was purified, without further modification, by preparative HPLC (auto prep) to give the title compound (13 mg, 27%).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][C:11]#[CH:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[CH3:17][N:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[OH-].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH2:10]([O:9][CH2:8][CH2:7][N:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=[C:2]1[N:21]1[CH2:22][CH2:23][CH2:24][N:18]([CH3:17])[CH2:19][CH2:20]1)[C:11]#[CH:12]
Reactant: C#CCOCCn1c(Cl)nc2ccccc21
Reactant: CN1CCCNCC1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C#CCOCCn1c(N2CCCN(C)CC2)nc2ccccc21
Temperature: 120 °C
Reaction time: 5 h
Yield: 60.8 %

Procedure:
A mixture of 2-chloro-1-[2-(propargyloxy)ethyl]-benzimidazole (3.70 g) and N-methylhomopiperazine (9.00 g) is stirred at 120° C. for 5 hours. A 5% aqueous sodium hydroxide (50 ml) is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and then concentrated. The residue is dissolved in a small amount of chloroform and subjected to column chromatography using silica gel (60 g), and then eluted with chloroform-methanol (10:1 by volume). The eluate is concentrated to give a pale yellow oily substance (1.90 g). The pale yellow oily substance is dissolved in ethanol (3 ml) and the solution is added to a solution of fumaric acid (1.50 g) in hot ethanol (18 ml). After the mixture is allowed to cool, the precipitated crystals are separated by filtration and recrystallized from ethyl acetate-ethanol to give 1-[2-(propargyloxy)ethyl]-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (2.14 g) as colorless needles, m.p. 122°-124.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH2:26]([O:28][C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[F:37])=[O:30])[CH3:27]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH2:26]([O:28][C:29](=[O:30])[C:31]1[CH:32]=[C:33]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:25])[C:10]([C:16]3[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)([OH:15])[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=2)[CH:34]=[CH:35][C:36]=1[F:37])[CH3:27]
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Reactant: CCOC(=O)c1cc(B(O)O)ccc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Oc2ccc(C(C)C(O)(c3cc(C)c(=O)n(C)c3)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
In analogy to Example 151, step 8, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with 3-ethoxycarbonyl-4-fluorophenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless solid. MS (m/e)=542.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:14].[CH3:15][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>C(Cl)Cl.CO.CCCCCC>[CH3:15][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([NH2:1])=[C:3]([CH3:14])[CH:4]=1
Reactant: Cc1cc(C(=O)O)cc([N+](=O)[O-])c1N
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COC(=O)c1cc(C)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 mg (2.50 mmol) 4-Amino-3-methyl-5-nitro-benzoic acid were dissolved in a mixture of 8 mL CH2Cl2 and 2 mL MeOH. At 0° C. 1.3 mL of a 2 M trimethylsilyldiazomethane-solution in hexane were added. After 1 h at 0° C. the reaction mixture was allowed to warm to room temperature. The next day further 1.3 mL of a 2 M trimethylsilyldiazomethane-solution in hexane were added. After stirring for 3 h at room temperature a solution of 0.22 mL acetic acid in 1.8 mL CH2Cl2 was added dropwise to destroy excess trimethylsilyldiazomethane. The reaction mixture was concentrated under reduced pressure. The residue was digerated with heptane and the crystalline material was filtered off to give pure 4-Amino-3-methyl-5-nitro-benzoic acid methyl ester. Yield: 496 mg MS (ES+): m/e=211.