Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1([C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N+]=[N-])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)(=O)C>CO.O1CCOCC1>[C:23]1([CH:29]([O:19][C:18]([C:14]2[N:13]3[C:21](=[O:22])[C@@H:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C@H:12]3[S:17][CH2:16][CH:15]=2)=[O:20])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=CCS[C@H]12
Solvent: CO
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12

Procedure:
A solution of 1.275 g of 7β-phenylacetylamino-ceph-3-em-4-carboxylic acid in 5 ml of methanol and 20 ml of dioxane is treated with an excess of diphenyldiazomethane and allowed to stand at room temperature. The red-coloured reaction mixture is treated with a small amount of acetic acid and then evaporated to dryness under reduced pressure. The oily yellowish residue is taken up in a small amount of methylene chloride, the solution is treated with diethyl ether at an elevated temperature. The colourless precipitate (felt-like needles) is filtered off, washed with diethyl ether, then with pentane and dried to yield the 7β-phenylacetylamino-ceph-3-em-4-carboxylic acid diphenylmethylester of the formula ##STR28## m.p. 163.5°-164.5°; [α]D20 =+30°±1° (c=0.968 in dioxane); thin-layer chromatogram (silica gel): Rf=0.55 (system: toluene/acetone 4:1), Rf=0.35 (system: toluene/acetone 9:1) and Rf=0.40 (system: toluene/ethyl acetate 4:1); ultraviolet absorption spectrum: λmax =258 mμ (ε=6100) and λmin =240 mμ (ε=5250) (in methylene chloride) and λmax =259 mμ (ε=6050) and λmin =239 mμ (ε=4950); (95% ethanol) infrared absorption spectrum: characteristic bands at 2.90μ, 5.57μ, 5.76μ, 5.91μ, 6.09μ, 6.66μ, 7.13μ, 8.12μ, 8.63μ, 9.07μ, 10.43μ and 12.22μ (in methylene chloride) and at 3.01μ, 5.60μ, 5.82μ, 6.04μ, 6.08μ (shoulder), 6.51μ and 7.13μ (in mineral oil).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[C:7]=1[OH:8].CN(C)C=O.Cl[C:16]([F:21])([F:20])C(O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH:16]([F:21])[F:20]
Reactant: Oc1c(Br)cncc1Br
Reactant: O=C(O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1ccncc1Br
Temperature: 120 °C

Procedure:
To a stirred solution of 3-bromopyridin-4-ol (L); 0.5 g, 0.00287 mol) in mixture of N,N-dimethylformamide (10.0 mL), water (1 mL), was added 2-chloro-2,2-difluoroacetic acid (0.74 g, 0.00574 mol) and potassium carbonate (0.47 g, 0.00344 mol). The resulting mixture was heated under microwave irradiation at 120° C. for 45 min. The reaction mixture was cooled to room temperature and poured into water (10.0 mL) and extracted with ethyl acetate (2×50.0 mL). Combined organic phase was washed with saturated sodium bicarbonate solution, water, saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under vacuum to afford crude product. The crude was purified by silica gel (60-120) column chromatography using 0-8% methanol in dichloromethane to afford the title compound (IN-13). 1H NMR (400 MHz, DMSO-d6) δ: 8.606-8.60 (d, J=2.4 Hz, 1H), 8.08-8.05 (dd, J=5.2 Hz, 1H), 7.67-7.37 (t, J=58.8 Hz, 1H), 6.38-6.36 (dd, J=7.2 Hz, 1H). MS (M+1): 223.8.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:7]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH:13]1([S:12][C:8]2[C:6]3[N:7]=[C:2]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5]=3[N:11]=[CH:10][N:9]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(SC3CCCCC3)c2n1
Reactant: C1CNCCN1
Product: c1nc(SC2CCCCC2)c2nc(N3CCNCC3)nc(N3CCOCC3)c2n1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-cyclohexylthio-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 179°-181° C.) and piperazine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3]1.[CH3:19]O.[S:21](=[O:25])(=[O:24])([OH:23])[OH:22]>ClCCCl>[CH3:19][O:24][S:21]([O-:23])(=[O:22])=[O:25].[CH3:1][N+:2]1[N:3]([CH3:19])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: CO
Reactant: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Solvent: ClCCCl
Product: COS(=O)(=O)[O-]
Product: Cn1c(-c2ccccc2)cc(-c2ccccc2)[n+]1C
Temperature: 70 °C
Yield: 91.7 %

Procedure:
46.8 g (0.2 mol) of 1-methyl-3,5-diphenylpyrazole together with 40 g (1.25 mol) of methanol are introduced into the reaction vessel. After 19.4 g (0.19 mol) of 96% strength sulfuric acid have been added, the reaction solution is brought to 160° C. by distilling off methanol. 608 g (19 mol) of methanol are metered in below the surface of the reaction mixture in the course of 7.5 hours. After the mixture has been cooled to 70° C., 25 g of 1,2-dichloroethane are added, and the mixture is cooled to room temperature with stirring. The reaction mixture is filtered and washed with 12.5 g of 1,2-dichloroethane. 67.7 g of 1,2-dimethyl-3,5-diphenylpyrazolium methylsulfate with a content of 97.5% (HPLC) of m.p. 157°-159° C. are obtained, which corresponds to a yield of 91.7% of theory.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].FC(F)(F)S([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])(=O)=O.[C:20]1([CH:27]=[CH:26][C:24](O)=[CH:23][CH:22]=1)O>CC(C)=O>[F:17][C:14]([F:15])([F:16])[CH2:13][O:12][C:20]1[CH:27]=[CH:26][C:24]([O:4][CH2:1][C:14]([F:17])([F:16])[F:15])=[CH:23][CH:22]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1
Reaction time: 2 h
Yield: 88 %

Procedure:
To a mixture of 2.42 moles (334.4 g.) of potassium carbonate, 2.2 moles (510.6 g.) of 2,2,2-trifluoroethyl trifluoromethanesulfonate in 1.02 liters of acetone is added a solution of 1.0 mole (110 g.) of hydroquinone in 1.1 liters of acetone, slowly over a 2 hour period. The reaction is then heated at reflux for 24 hours, the reaction mixture is evaporated, and 2 liters of chloroform and 2 liters of water are added to the residue. The chloroform layer is separated, the aqueous layer is washed twice with 1 liter of chloroform, and the combined chloroform solution is washed with 1 liter of water. The chloroform solution is dried over magnesium sulfate, then concentrated under vacuum. Hexane is added to the residue and the solid product is collected by filtration and washed with hexane. Additional material is collected from the concentrated residues. A yield of 88 percent, 241 g. of 1,4-bis(2,2,2-trifluoroethoxy)benzene, m.p. 75°-77° C. is obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CCOC(=O)CCc1ncc[nH]1
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: CCOC(=O)CCc1nccn1-c1ccc(C(C)=O)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 69 %

Procedure:
A mixture of 4′-fluoro-3′-nitroacetophenone 2.04 g, ethyl 3-(1H-imidazol-2-yl)propanoate 1.87 g, potassium carbonate 3.07 g and N,N-dimethylacetamide 28 mL was heated at 100° C. for 16.5 hours. The reaction liquid was allowed to cool off and to which 60 mL of diethyl ether was added, followed by filtration. Adding 100 mL of water to the filtrate, the organic layer was separated. The aqueous layer was extracted with 100 mL of diethyl ether. The extract was combined with the organic layer, washed twice with 20 mL of water and once with 10 mL of saturated brine by the order stated, and dried over magnesium sulfate. Distilling the solvent off under reduced pressure, 2.54 g of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[C:12]2=[N:20][N:21]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:22]([NH:23][CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[C:11]2[N:10]=1.CO.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.C1COCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[C:12]2=[N:20][N:21]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:22]([NH:23][CH:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)=[C:11]2[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c3nc(-c4c(F)cccc4F)c4cc(F)ccc4c3nn2COCC[Si](C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(F)ccc32)c1NC1CCNCC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
340 mg of 2-methylpropan-2-yl 4-{[5-(2,6-difluorophenyl)-7-fluoro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinolin-3-yl]amino}piperidine-1-carboxylate are introduced into 16 ml of methanol and 1.5 ml of THF. After cooling to 0° C. using an ice bath, 2.7 ml of a 4N solution of hydrochloric acid in dioxane are added and the mixture is stirred at RT for 5 h. It is poured into 200 ml of saturated sodium bicarbonate solution and then extracted with ethyl acetate, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a DCM/methanol/aqueous ammonia mixture (90/10/1 by vol.), to give 180 mg of 5-(2,6-difluorophenyl)-7-fluoro-N-(piperidin-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinolin-3-amine (yellow solid), LC-MS-DAD-ELSD: 528=(M+H).
Reaction SMILES: [OH-:1].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][C:19]#N)=[CH:7][CH:6]=1.Cl.[OH2:22]>C(O)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][C:19]([OH:22])=[O:1])=[CH:7][CH:6]=1
Reactant: [OH-]
Reactant: O
Reactant: COc1ccc(Sc2ccccc2CC#N)cc1
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: COc1ccc(Sc2ccccc2CC(=O)O)cc1
Yield: 84.3 %

Procedure:
A solution of potassium hydroxide (25.9 g, 0.463 mol) in water (60 ml) was added to a stirred solution of 2-(4-methoxyphenylsulfanyl)phenylacetonitrile (31.2 g, 0.119 mol) in ethanol (185 g) and the mixture was refluxed for 7 h. Then the mixture was evaporated to dryness, the residue was dissolved in water (100 ml), the solution was filtered with charcoal to give a clear solution which was acidified to pH 1 with hydrochloric acid under cooling. The separated oil slowly provided a crystalline material which was filtered off and washed with water to neutral reaction of the washings. This procedure yielded 27.3 g (84.3%) of the required acid, m.p. 102-105° C.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[NH:9][C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1>[Br:7][C:8]1[N:9]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(Br)c(Br)c(C#N)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
Potassium t-butoxide (0.75 g, 6.7 mmol) is added in portions at room temperature to a solution of 2,4,5-tribromopyrrole-3-carbonitrile (2.0 g, 6.1 mmol) in anhydrous tetrahydrofuran (20 mL). After 30 minutes, ethyl bromoacetate (1.12 g, 6.7 mmol) is added dropwise and the mixture stirred for 4-5 hours at room temperature. Work-up as described in Example 15 gives the product as white solid (0.42 g); mp 140°-143° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][C:8]1=O.C(=O)([O-])[O-].[Na+].[Na+].O>C(Cl)Cl>[C:1]([N:10]1[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: CN1CCNCC1=O
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acryloyl chloride (90.5 g) in methylene chloride (100 ml) was added into a methylene chloride (500 ml) solution of N-methyl piperazone (100 g) over a period of one hour. The reaction temperature was kept below 25° C. with cooling. After the addition was completed, the reaction mixture was stirred at ambient temperature for two hours. Then, sodium carbonate (53 g) in 250 ml. of water was added into the reaction mixture with stirring. A crude product (76 g) of 1-acryloyl-4-methyl piperazine was recovered from the methylene chloride solution. The product was distilled and the fraction collected at 65°-69° C./1.5 mm Hg was characterized by I.R. and C13 NMR and was found to be 97% pure by G. C.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][C:2]1=S.[CH:13]([NH:15][NH2:16])=O>C(O)CCC>[CH:13]1[N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[NH:5][CH2:4][CH2:3][C:2]2=[N:16][N:15]=1
Reactant: NNC=O
Reactant: S=C1CCNc2ccccc2N1
Solvent: CCCCO
Product: c1ccc2c(c1)NCCc1nncn1-2
Yield: 37.3 %

Procedure:
A mixture of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-thione (0.8 g) and 0.80 g of N-formylhydrazine in 8 ml of n-butanol is stirred and refluxed for 18 hours and the solvent removed under vacuum. Ice water is added to the residual solid and the mixture filtered to give 0.312 g of a gray solid, m.p. 162-165° C.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH:6]1[CH:10]2[O:11][C:12](=[O:19])[CH:13]3[CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH:7]1[CH2:8][CH:9]23)=[O:4].CN(C)C=O.[C:25]([O-:30])(=[O:29])[C:26]([CH3:28])=[CH2:27].[Na+].[I-].[Na+]>O>[C:25]([O:30][CH2:2][C:3]([O:5][CH:6]1[CH:10]2[O:11][C:12](=[O:19])[CH:13]3[CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH:7]1[CH2:8][CH:9]23)=[O:4])(=[O:29])[C:26]([CH3:28])=[CH2:27]
Reactant: COC(=O)C1C2CC3C(OC(=O)C31)C2OC(=O)CCl
Reactant: C=C(C)C(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCC(=O)OC1C2CC3C1OC(=O)C3C2C(=O)OC
Reaction time: 8 h
Yield: 85.9 %

Procedure:
A mixture of 28.9 g of the 2-chloroacetic ester obtained in Example 1-1-1 and 40 g of dimethylformamide was added dropwise to a mixture of 12.4 g of sodium methacrylate, 3.0 g of sodium iodide and 50 g of dimethylformamide at a temperature below 30° C. The mixture was stirred at the temperature for 8 hours. 100 ml of water was added below 30° C. This was followed by ordinary post-treatment and recrystallization from toluene and n-hexane, obtaining 29.1 g of the target compound (yield 86%).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([O:12][CH3:13])[CH:3]=1.[C:14]([Cu])#[N:15].N>CN(C=O)C>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1)[C:14]#[N:15]
Reactant: N#C[Cu]
Reactant: COc1cc(I)cc(C(F)(F)F)c1
Agent: N
Solvent: CN(C)C=O
Product: COc1cc(C#N)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of 1-iodo-3-methoxy-5-(trifluoromethyl)benzene (200 mg, 0.66 mmol) in DMF (2 mL) was added CuCN (300 mg, 5.0 mmol). The reaction was stirred at 100° C. for 24 hours and then poured into aq. NH3 (40 mL). The mixture was extracted with EtOAc (70 mL) and the organic extracts were washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 5% to 80% EtOAc/hexanes afforded 3-methoxy-5-(trifluoromethyl)benzonitrile. Rf=0.64 (50% EtOAc/hexanes). 1H NMR (CDCl3, 600 MHz) δ 7.47 (s, 1H), 7.34 (s, 1H), 7.31 (s, 1H), 3.89 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]3[O:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=4)=[CH:16][C:10]=3[C:9]2=[O:24])=[CH:4][C:3]=1[CH3:25].[N:26]([O-])=O.[Na+]>CC(O)=O.O>[Cl:23][C:19]1[CH:18]=[C:17]([C:15]2[O:14][C:11]3[CH:12]=[CH:13][N:8]([C:5]4[CH:4]=[C:3]5[C:2](=[CH:7][CH:6]=4)[NH:1][N:26]=[CH:25]5)[C:9](=[O:24])[C:10]=3[CH:16]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(-n2ccc3oc(-c4cccc(Cl)c4)cc3c2=O)ccc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1c2cc(-c3cccc(Cl)c3)oc2ccn1-c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 39 %

Procedure:
A solution of 5-(4-amino-3-methylphenyl)-2-(3-chlorophenyl)furo[3,2-c]pyridine-4(5H)-one (1.02 g, 2.91 mmol) in AcOH (23 mL) was treated with a solution of NaNO2 (0.20 g, 2.9 mmol) in H2O (0.65 mL). After stirring at ambient temperature for 12 h, the reaction mixture was concentrated. The resulting solid was partitioned in CH2Cl2 and water. Any solids were removed by filtration. The filtrate was extracted with CH2Cl2 (4×30 mL). The organics were dried (Na2SO4), filtered, recombined with the removed solids and concentrated. Purification by flash chromatography (silica gel, CH2Cl2/MeOH, 100:0 to 90:10) gave the title compound (0.409 g, 40%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 13.29 (s, 1H), 8.17 (m, 1H), 7.96 (t, J=1.8 Hz, 1H), 7.87-7.83 (m, 2H), 7.73-7.71 (m, 2H), 7.65 (d, J=8.7 Hz, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.46-7.43 (m, 1H), 7.38 (dd, J=9.0, 2.1 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H).
Reaction SMILES: C([O:5]O)(C)(C)C.C(CC(C)(C)C)(C)C.[CH2:15]([OH:27])/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(Cl)Cl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:18]([C@@H:17]1[O:5][C@H:16]1[CH2:15][OH:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCC/C=C/CO
Reactant: CC(C)(C)OO
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: ClCCl
Solvent: CC(C)CC(C)(C)C
Product: CCCCCCCCC[C@@H]1O[C@H]1CO
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A suspension of 1.00 g of 4a powdered molecular sieves in 50 ml of dry CH2Cl2 was cooled to 0.° C. under argon. To the cooled suspension was added 308 mg (1.09 mmole) of Ti(OiPr)4 and 356 mg (1.52 mmole) of L(+)diisopropyl tartrate via syringe. The mixture was stirred for 15 min and cooled to -20° C. A solution of tert-butyhydroperoxide in isooctane (3.8M, 4.30 ml, 16.4 mmole) was added slowly to the mixture and the catalyst was allowed to "age" for 30 min at -20° C. A solution fo 2.00 g (10.9 mmole) of E-2-dodecen-1-ol in 10 ml of CH2Cl2 was dried over 3A molecular sieves for 15 min before being added to the mixture slowly, with stirring, at -20°. The solution was then placed in the freezer (-30° C.) and allowed to stand for 24 H. The mixture was warmed to 0° C. and poured into a solution of 1.00 g of citric acid and 3.50 g of FeSO4 in 15 ml H2O. The organic layer was separated and the aqueous layer washed twice with 20 ml of CH2Cl2. The CH2Cl2 layers were combined, dried over MgSO4, filtered and evaporated to yield a sticky white solid. Recrystallization from Et2O: petroleum ether afforded 1.98 g of white solid, mp 62°-4° C. 1H NMR δ3.92 (ddd, 1, J=2.5, 6, 12 Hz), 3.63 (ddd, 1, J=4, 7, 12 Hz), 2.95 (m, 2), 1.69 (dd, 1, J=7, 6 Hz), 1.6-1.2 (m, 16), 0.88 (t, 3, J=6 Hz). Mass Spectra: M-31(-CH2OH)(0.4)169, M(100)55.1.
Reaction SMILES: [CH:1]1([N:7]=[C:8](Cl)[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClS(O)(=O)=O.[CH3:22][N:23]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]1[CH2:29][C:30]([O:32][CH3:33])=[O:31].[Cl:34]([OH:38])(=[O:37])(=[O:36])=[O:35]>>[Cl:34]([OH:38])(=[O:37])(=[O:36])=[O:35].[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:8](=[N:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:27]2[N:23]([CH3:22])[C:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:25][C:26]=2[CH3:28])=[CH:10][CH:11]=1
Reactant: ClC(=NC1CCCCC1)c1ccc(Cl)cc1
Reactant: COC(=O)Cc1cc(C)cn1C
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)Cc1cc(C)c(C(=NC2CCCCC2)c2ccc(Cl)cc2)n1C

Procedure:
The title compound was prepared as in Example X from N-cyclohexyl 4-chlorobenzimidoyl chloride (7.4 g, 29 mmole), chlorosulfonic acid (0.34 g, 3 mmole), methyl 1,4-dimethyl-1H-pyrrole-2-acetate (4.82 g, 28.86 mmole), and 70% perchloric acid (4.6 g, 32 mmole) to yield 1.97 g (14%) of a lime green solid, m.p. 196°-202° C. (dec).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:36]2[CH2:37][CH2:38][N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][CH2:35]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccccc3)CC2)c2ccccc2-c2ccccc21
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A suspension of 0.4 g (0.93 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide, 0.153 ml (1 mmol) of 1-phenylpiperazine, 0.8 g of potassium carbonate and 1 ml water in 30 ml dimethylformamide is stirred for 10 hours at 80° C. The reaction mixture is then poured onto water, extracted with ethyl acetate and the organic phase is dried over sodium sulphate. Purification is by column chromatography on silica gel (eluant: dichloromethane/methanol=15:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([CH:16]=1)[C:7]([NH:12][CH2:13][CH2:14][CH3:15])=[N:8][CH2:9][CH2:10][CH3:11].[H][H]>C1COCC1.[Ni].CCO>[NH2:17][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][C:6]=1[C:7]([NH:12][CH2:13][CH2:14][CH3:15])=[N:8][CH2:9][CH2:10][CH3:11]
Reactant: [H][H]
Reactant: CCCN=C(NCCC)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCN=C(NCCC)c1cc(Cl)ccc1N

Procedure:
27.4 g (0.097 mol) of 5-chloro-2-nitro-N,N′-dipropylbenzamidine are dissolved in 200 ml of THF and are hydrogenated in the presence of 15 g Ra—Ni/EtOH at room temperature for 5 hours (take up of hydrogen: 94%). Then the catalyst is filtered off and the solvent removed in a water jet vacuum. The residue is purified by column chromatography on silica gel (eluant: hexane/THF 1:1, then THF). Yield: 11.9 g of 2-amino-5-chloro-N,N′-dipropylbenzamidine in the form of a brown oil (1H-NMR (CDCl3);.ppm/multiplicity/number of H's): 0.91/m/6H; 1.56/m/4H; 3.10/m (broad)/4H, 3.75/s(broad)/2H; 6.63/d/1H; 7.02/d/1H; 7.10/dd/1H.
Reaction SMILES: [CH:1](=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[C:10](=O)[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][NH2:20]>C(O)C>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[C:10](=[O:9])[NH:20][N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C1OC(=Cc2ccccc2)c2cc(Br)ccc21
Solvent: CCO
Product: O=c1[nH]nc(Cc2ccccc2)c2cc(Br)ccc12

Procedure:
To a solution of EXAMPLE 1D (778 mg, 2.58 mmol) in ethanol (10 mL) was added hydrazine (83 mg, 2.58 mmol) and the mixture was refluxed for 2 hours. After cooling, the precipitated solid was collected by filtration and dried under vacuum to yield the title compound. MS (ESI) m/z 316 (M+H)+.