Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][C@H:12]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>C1COCC1.O>[OH:14][CH2:13][C@@H:12]([N:16]1[C:17](=[O:26])[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]1=[O:25])[CH2:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(C[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(C[C@@H](CO)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 92.2 %

Procedure:
To a stirred solution of (S)-3-((benzyloxy)carbonyl)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (compound 7-2, 6.07 mmol) in 30 mL of dry THF at −15° C. were successively added N-methylmorpholine (6.07 mmol), iso-butylchloroformate (6.07 mmol). After stirring for 5 min at −15° C., a solution of NaBH4 (689 mg, 18.21 mmol) in 2.73 mL of water were added at once. The reaction was stirred at −15° C. for 2 min, then hydrolyzed with water (30 mL). Extracted with EtOAc (×3), washed with water (×3), brine (×1), dried over sodium sulfate, filtered, concentrated. Purification by chromatography on silica gel column (hexane/EtOAc) to give 1.9 g of colorless oil, compound 7-3.
Reaction SMILES: N#N.Cl[C:4]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=[O:19])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[CH:9]2.[C:20]([Cu])#[N:21].Cl>C1(C)C=CC=CC=1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.CN(C=O)C.CN1CCCC1=O>[CH:18]([C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4]([C:20]#[N:21])=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2)=[O:19]
Reactant: N#C[Cu]
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Agent: Cl[Pd]Cl
Agent: Cl
Agent: N#N
Solvent: O
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: N#Cc1c2ccccc2c(C=O)c2ccccc12
Reaction time: 1.5 h
Yield: 68 %

Procedure:
A 25 mL 2-neck RB flask fitted with thermometer, condenser, N2 inlet, bubbler and stirring bar was charged with 10-chloro-9-anthraldehyde (Aldrich, 5 g, 21 mmol, CuCN (Fisher, 2.14 g, 24 mmol), N-methylpyrrolidinone (Aldrich, 100 mL), dry DMF (Aldrich, 15 mL), and bis(triphenylphosphine) palladium dichloride (Fluka Chemical Corp., 255 Hauser Ave., Hauppauge, NY, 11787, 0.08 g, 0.1 mmol). The mixture was warmed to 170° and stirred 15 h under N2. After 1.5 h, the mixture became homogeneous. The reaction was cooled to 70° and poured into a solution composed of 16 g of FeCl3.6H2O, (Mallinckrodt), 70 mL of 1.0M HCl and 400 mL H2O. The resulting mixture was stirred at 60°-70° for 1 h, filtered and a crude orange solid isolated. This material was dissolved in hot PhCH3 (1 L) and passed through a small plug (100 g) of SiO2. The filtrate was then concentrated to 75 mL and diluted with hexane (200 mL). The orange solid which formed was collected by filtration and dried at 50° to give 3.17 g (68%) of 10-formyl-9-anthracenecarbonitrile mp 270°-275°, (C, H, N).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(O)C>CS(C)=O>[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[CH:25]1[CH2:30][CH2:29][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:27][CH2:26]1
Reactant: Cc1cccc2c(C3CCNCC3)c[nH]c12
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cccc2c(C3CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c12

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.280 g, 1.48 mmol) and 7-methyl-3-(piperidin-4-yl)-1H-indole (0.290 g, 1.39 mmol) using ethanol as reaction solvent. Yield 0.320 g (57%) as a tan foam. FDMS m/e=404 (M+ of free base). α[D]589 =11.6 (c=0.98, dimethylsulfoxide).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1C(=O)N([I:26])C(=O)C1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([I:26])[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(-c2nn3ccnc3s2)cc1OC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nn3c(I)cnc3s2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
2-(3,4-Dimethoxy-phenyl)-imidazo[2,1-b][1,3,4]thiadiazole (from the previous step, 0.65 g, 2.50 mmol, 1 eq) was dissolved in DMF (9 mL), and NIS (0.41 g, 1.75 mmol, 0.7 eq) was added. The mixture was stirred at RT in an argon atmosphere. After 2 hours HPLC-MS analysis indicated incomplete conversion; 0.1 g of NIS was added, and the reaction mixture was stirred at RT overnight. Another 0.08 g of NIS was added, and after another 2 h of stirring at RT the reaction mixture was poured into 20 mL of aq. sodium thiosulfate (10%) and extracted with EtOAc. The combined organic layers were washed with water, dried (Na2SO4) and concentrated, and the residue (0.888 g) was purified by column chromatography (SiO2, cyclohexane/20-100% EtOAc) to afford the desired product (white solid, 0.336 g, 36% yield, 2 steps). HPLC-MS: (10-95% B in 4 min, 0.5 mL/min+2 min 100% B, 0.7 mL/min): tR=4.42 min, [M+H]+ m/z 387.9; 1H NMR (300 MHz, DMSO) δ/ppm 7.50 (dd, J=2.2, 8.4, 1H), 7.42 (d, J=2.1, 1H), 7.37 (s, 1H), 7.16 (d, J=8.5, 1H), 3.89 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:26]([O:28][CH2:29][C:30](Cl)=O)[CH3:27]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:26]([O:28][CH2:29][C:30]1[N:12]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCOCCNc1c(N)cnc2ccccc12
Reactant: CCOCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOCc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
A solution of tert-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (18.04 g, 52.1 mmol) in 180 mL of pyridine was treated with 50 mg of 4-dimethylaminopyridine and chilled in an ice water bath. 2-ethoxyacetyl chloride (6.44 g, 52.6 mmol) was added dropwise to the solution. The reaction was stirred at room temperature for 3 h. The reaction was then heated to reflux with stirring. After 18 h the reaction was cooled and then concentrated. The residue was partitioned between CHCl3 (150 mL) and water (150 mL) and the layers were separated. The aqueous portion was extracted with CHCl3 (3×50 mL). The combined organic portions were washed with brine, dried over Na2SO4, filtered and concentrated to yield 15.47 g of tert-butyl 2-{2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a sticky yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:20]([CH3:22])[CH3:21])[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[O:11])[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][CH:3]=1.ClS([N:33]=[C:34]=[O:35])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[O:8]=[C:7]1[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:20]([CH3:22])[CH3:21])[C:14](=[O:19])[C:15]([F:16])([F:18])[F:17])=[O:11])[C:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:4][CH:3]=[C:2]1[NH:1][C:34]([NH2:33])=[O:35]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(=O)C(F)(F)F
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(N)=O)c1=O)C(=O)C(F)(F)F
Reaction time: 0.75 h
Yield: 13.8 %

Procedure:
To a solution of the compound from Example 6 (0.40 g) in tetrahydrofuran (10 mL) cooled to 0° C. was added dropwise chlorosulfonyl isocyanate (0.16 g) and the mixture was stirred for 45 min. The reaction mixture was neutralized with saturated aqueous sodium carbonate solution (3 mL), diluted with ethyl acetate (10 mL), and the separated organic phase was washed (water, brine). TLC examination revealed that the major reaction product was present in the aqueous phase. Following saturation of the aqueous phase with sodium chloride, repeated ethyl acetate extractions (4×25 mL) were performed. The combined organic layers were dried (magnesium sulfate) and evaporated. Chromatography with dichloromethane:tetrahydrofuran (10:1) as the eluent, followed by overnight drying (50° C., 27 Pa) gave the title compound (0.061 g) as an off-white solid; TLC: Rf =0.36, dichloromethane:methanol (10:1); NMR: 8.85 (d,1), 8.69 (s,1), 8.35 (s,1), 7.48 (m,5), 6.47 (broad s, 2), 4.70 (dd,1), 4.55 (dd,2), 2.2 (m,1), 0.89 (dd,6); MS: m/z=440(M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]2[C:29](=[O:33])[N:30]([CH3:32])[CH2:31][C:26]2=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:28]=[C:27]3[C:29](=[O:33])[N:30]([CH3:32])[CH2:31][C:26]3=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CN1Cc2ccc(Cl)nc2C1=O
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CN1Cc2ccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)nc2C1=O

Procedure:
The title compound was prepared according to the procedure in Example 1 Step 5 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.32 mmol) and 2-chloro-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (52.6 mg, 0.29 mmol) as the starting materials.
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[C:3](=[O:9])[CH2:4][C:5](OC)=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:22]([OH:25])([CH3:24])[CH3:23]>>[CH3:1][CH:2]([CH3:10])[C:3](=[O:9])[CH2:4][C:5]([O:25][CH:22]([CH3:24])[CH3:23])=[O:6]
Reactant: COC(=O)CC(=O)C(C)C
Reactant: CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)OC(=O)CC(=O)C(C)C
Temperature: 90 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
Methyl 4-methyl-3-oxo-pentanoate (304 g), isopropyl alcohol (500 ml) and p-toluenesulfonic acid (3.8 g) were stirred together and heated to reflux at 90° C. After 3 hours, 400 ml of solvent was collected by distillation at atmospheric pressure. Fresh isopropyl alcohol was added and the mixture refluxed for a further 3 hours. The cycle of distillation, addition of fresh solvent and refluxing was continued until the conversion had reached 95%, determined by a peak area ratio of product: starting material of 95:5 measured by LC. The remaining volatile solvents were removed by distillation and the resultant liquid washed with 10% sodium carbonate solution and dried over anhydrous sodium sulfate and filtered to give isopropyl 4-methyl-3-oxo-pentanoate as a clear liquid (301 g, 83%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.[F:15][C:16]([F:25])([F:24])[CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1>C1COCC1>[CH3:14][O:13][C:10]1[N:11]=[CH:12][C:7]([C:20]2([OH:23])[CH2:19][CH2:18][CH:17]([C:16]([F:24])([F:25])[F:15])[CH2:22][CH2:21]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(Br)cn1
Reactant: O=C1CCC(C(F)(F)F)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCC(C(F)(F)F)CC2)cn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (3 mL of a 2.5 M solution in hexanes, 7.5 mmol) was added dropwise to 5-bromo-2-methoxy pyridine (6.0 mmol, 0.78 mL) in 40 mL of THF cooled in a dry ice/acetone bath. After aging for 15 min, 4-trifluoromethylcyclohexanone (6.0 mmol, 1 g) was added and the reaction mixture was allowed to slowly warm to 0° C. over 2 h. The reaction was cooled in a dry ice/acetone bath and the reaction was quenched by addition of sat. ammonium chloride (aq), then saturated sodium bicarbonate (aq). The reaction mixture was extracted with hexanes/EtOAc. The organic phase was concentrated and the resultant residue was purified by flash chromatography on silica gel using a step gradient of 4:1, 2:1 and 1:1 (v/v) EtOAc/hexanes to give the title compound as a mixture of isomers. LC-MS (ESI): m/z=276.2 [M+1]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:15][C:14](=[O:16])[CH2:13][CH:12]([OH:17])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[C:24]([O:17][CH:12]1[CH2:11][CH:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[O:15][C:14](=[O:16])[CH2:13]1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(O)CC(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC1CC(=O)OC(CO[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h

Procedure:
To 6-t-butyldimethylsilyloxymethyl-4-hydroxytetrahydropyran-2-one (0.50 parts) in dichloromethane (10 parts) at ambient temperature was added pyridine (0.20 parts) followed by a solution of acetylchloride (0.20 parts) in dichloromethane (2 parts). After 1 hour at 20°-25° C. less than 2% starting material remained by GLC analysis. The reaction mixture was then washed with water, dried over magnesium sulphate and evaporated to give 4-acetoxy-6-t-butyldimethylsilyloxymethyltetrahydro pyran-2-one (0.6 parts).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[N+:7]([O-:9])[CH:8]=1.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([CH3:10])=[N+:7]([O-:9])[CH:8]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C)[n+]([O-])c1
Solvent: CC(=O)O
Product: COc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 6 h

Procedure:
5-Methoxy-2-methylpyridine-1-oxide [35392-66-6] (6 g, 43.1 mmol) and nitric acid (18.4 mL, 431 mmol, 1.48 g/mL) was added to acetic acid (50 mL) and the reaction was stirred at 90° C. for 6 h. The mixture was concentrated (1/4) and neutralized at 0° C. was addition of ammonium hydroxide. The mixture was extracted with EtOAc, washed with brine and water, dried (Na2SO4), filtered and concentrated. The product crystallised during concentration. ESI-MS: tR=0.50 min, [M+H]+ 185.1 (LC-MS 1).
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O.N[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>N1C=CC=CC=1>[OH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:7][N:6]=1
Reactant: NCCCCCO
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCCCO)[nH]c2=O)cn1

Procedure:
Reaction of 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone with 5-aminopentanol in refluxing pyridine gives 2-(5-hydroxypentylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone which can be converted into 2-[5-(O-isoureido)pentylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone by the procedure of Example 5(iii).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>CN(C=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:1][C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=2)=[O:19])=[CH:13][CH:12]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Nc1cccc(C=O)c1
Solvent: CN(C)C=O
Product: O=Cc1cccc(NC(=O)Nc2ccc(Cl)cc2)c1
Temperature: 110 °C

Procedure:
a mixture of 360 mg of 3-aminobenzaldehyde (0.3 mmoles) and 460 mg of 4-chloro-phenylisocyanate (0.3 mmoles) in 3 ml of DMF is heated under microwave irradiation at 110° C. for 10 minutes. The precipitate formed is filtered giving the desired 1-(4-Chloro-phenyl)-3-(3-formyl-phenyl)-urea. Analytical LC/MS method A: ([M+H]+): 351, RT: 5.30 min (gradient 5 to 85% acetonitrile in 7 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:25]=[CH:26][C:27]([C:29]#[N:30])=[CH:28][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:25]=[CH:26][C:27]([C:29](=[N:32][OH:33])[NH2:30])=[CH:28][C:17]=3[N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCC1
Yield: 72 %

Procedure:
2-(4-Benzyloxyphenyl)-5-cyano-1-cyclopentylbenzimidazole (400 mg) obtained in Example 14 was suspended in ethyl alcohol (3 ml) and water (1.5 ml), and hydroxylamine hydrochloride (141 mg) and sodium hydrogencarbonate (170 mg) were added. The mixture was refluxed under heating overnight. The reaction mixture was allowed to cool and the precipitated crystals were collected by filtration to give the title compound (312 mg, yield 71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].CI.[C:16](=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH3:16])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [Cs+]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 5-fluoro-2-nitro-phenol (369 mg, 2.35 mmol) in 5 mL THF, sodium hydride (96 mg, 2.46 mmol) was added at room temperature, followed by methyl iodide (0.88 ml, 14 mmol). The mixture was stirred at room temperature for 10 hours, and then cesium carbonate (744 mg, 2.35 mmol) was added. The mixture was stirred at room temperature for additional 4 hours, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give a crude residue, which was purified by column chromatography (silica 5-25% EtOAc/hexane) to give pure 4-fluoro-2-methoxy-1-nitro-benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[O-:24][C:25]#[N:26].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:25]([NH2:26])=[O:24])[CH2:14][CH:13]2[CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNCC1CN1CCCC1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C(CN2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
A solution of 1-[(3,4-dichlorophenyl)acetyl]-2-(1-pyrrolidinylmethyl) piperazine (200 mg) in acetic acid (0.5 ml) and water (1 ml) was treated with a solution of sodium cyanate (73 mg) in water (0.5 ml). The resulting solution was stirred at room temperature for 2 h. The solvent was removed in vacuo, the residue was basified with aqueous 2N sodium carbonate solution and extracted with dichloromethane (2×25 ml). The combined organic extracts were dried and evaporated to give a foam (206 mg) which was purified by flash column chromatography eluting with dichloromethane:methanol:0.880 NH3 (200:8:1) to give a solid (120 mg). Crystallisation from ethyl acetate/methanol gave the title compound as a solid (58 mg) m.p. 206°-209° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:26])[NH:24][NH2:25]>>[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:26])[NH:24][N:25]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: NNC(=O)Nc1ccccc1Br
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccccc1Br

Procedure:
ninhydrin, 4-(2-bromophenyl)-semicarbazide hydrochloride
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].O>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: OB(O)c1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2ccc(F)cc2F)cc1
Yield: 95.8 %

Procedure:
The general procedure described in Example 3 was used with 4-chloro-benzenesulfonamide (192 mg, 1.00 mmol), 2,4-difluorophenylboronic acid (205 mg, 1.30 mmol), Pd(OAc)2 (2.2 mg, 0.010 mmol, 1 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (10.0 mg, 0.020 mmol, 2 mol %), K2CO3 (414 mg, 3.00 mmol), water (2.0 mL), 12 h, 80° C. The product was isolated as a white solid (258 mg, 96%). Mp=143° C. 1H NMR (400 MHz, d4-MeOH) δ: 7.98 (d, 2H, J=8.4 Hz), 7.87 (d, 1H, J=8.4 Hz), 7.63 (d, 2H, J=7.2 Hz), 7.49 (d, 2H, J=8.4 Hz), 7.05-6.99 (m, 2H). 13C NMR (125 MHz, d4-MeOH) δ: 165.5 (d), 163.0 (d), 162.3 (d), 159.8 (d), 144.0, 143.6, 140.0, 139.3, 133.1 (d), 133.0 (d), 130.5 (d), 130.2, 128.9, 127.4, 125.1 (d), 124.9 (d), 113.2 (d), 113.0 (d), 105.4 (t). IR (neat, cm−1): 3362, 3257, 1619, 1599, 1516, 1487, 1302, 1103, 965, 849, 809. Anal. Calcd for C12H9F2NO2S: C, 53.53; H, 3.37. Found: C, 53.34; H, 3.36.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[OH:16])[C:7]1=[O:17].Cl.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:16][CH2:28][CH2:27][N:26]([CH3:30])[CH3:25])[C:7]1=[O:17]
Reactant: COc1ccc(CN2C(=O)c3cccc(O)c3C2=O)c(OC)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)c3cccc(OCCN(C)C)c3C2=O)c(OC)c1
Temperature: 60 °C
Yield: 60.8 %

Procedure:
A mixture of 2-(2,4-dimethoxy-benzyl)-4-hydroxy-isoindole-1,3-dione (317 mg, 1.01 mmol), 2-dimethylaminoethyl chloride hydrochloride (160 mg, 1.11 mmol) and potassium carbonate (350 mg, 2.5 mmol) in DMF (4 mL) was heated at 60° C. for 18 hours. The mixture was concentrated in vacuo, taken up in ethyl acetate and extracted twice with 1N hydrochloric acid. The aqueous extracts were made basic with solid potassium carbonate and extracted with ethyl acetate (×2). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to give the title compound (236 mg, 61%) as an off-white solid. 1H NMR (methanol-d4) 7.73 (1H, t), 7.44-7.40 (2H, m), 7.02 (1H, d), 6.51 (1H, d), 6.42 (1H, dd), 4.72 (2H, s), 4.33 (2H, t), 3.80 (3H, s), 3.76 (3H, s), 2.87 (2H, t), 2.40 (6H, s). MS: [M+H]+ 385.