Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[O:5]1[C:7]([CH3:24])([CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:6]1>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][CH2:24][C:7]([CH3:6])([OH:5])[CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: NCCO
Reactant: CCCCCCCCCCCCCCOCC1(C)CO1
Solvent: CCO
Product: CCCCCCCCCCCCCCOCC(C)(O)CNCCO
Temperature: 80 °C
Yield: 67.9 %

Procedure:
A 100-ml flask equipped with a stirrer and dropping funnel was then charged with 16.8 g (280 mmol) of ethanolamine and 15 g of ethanol. While stirring the mixture at 80° C., an ethanol solution of 5.00 g (17.6 mmol) of 1,2-epoxy-2-methyl-3-tetradecyloxypropane was added dropwise over 3 hours. The contents were stirred further for 2 hours. The resultant reaction mixture was concentrated under reduced pressure, and the resultant residue was purified by column chromatography on silica gel, thereby obtaining 4.13 g (yield: 68%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]([CH3:8])[O:6][C:5](=[O:9])[C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16](Cl)(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C1COCC1>[C:16]([O:1][CH2:2][C:3]1[CH:7]([CH3:8])[O:6][C:5](=[O:9])[C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC1OC(=O)C(c2ccccc2)=C1CO
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)OCC1=C(c2ccccc2)C(=O)OC1C

Procedure:
4-Hydroxymethyl-5-methyl-3-phenyl-2(5H)-furanone (Compound 7), (73 mg, 0.36 mmol), lauroyl chloride (117 mg, 0.54 mmol), triethylamine (47 mg, 0.47 mmol) and dimethylaminopyridine (1 mg, 0.01 mmol) were stirred in anhydrous THF (2 mL) at ambient temperature under argon for 2 hours. The crude reaction mixture was concentrated, the organics were extracted into diethyl ether and solids were filtered off. The ether was removed by rotary evaporator and the resulting oil was purified by flash chromatography on silica to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[NH:22][C:21]3=[O:29])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-].[Na+]>Cl>[N:11]1([C@H:14]2[CH2:19][CH2:18][C@H:17]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[NH:22][C:21]3=[O:29])[CH2:16][CH2:15]2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN([C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2ccccc2n1[C@H]1CC[C@H](N2CCNCC2)CC1

Procedure:
A stirred solution of 0.52 g of trans-1,3-dihydro-1-{4-[4-(tert-butyloxycarbonyl)piperazin-1-yl]-1-cyclohexyl}-2H-benzimidazol-2-one in 15 mL of 1N HCl was heated to reflux for 1 h, cooled, basified to pH 10 with 6N NaOH and extracted 2×50 mL of CHCl3. The combined extracts were dried over MgSO4 and concentrated under reduced pressure. After drying overnight under vacuum, there was obtained 0.28 g of trans-1,3-dihydro-1-{4-(1-piperazinyl)-1-cyclohexyl}-2H-benzimidazol-2-one as a white solid: 1H NMR (400 MHz, CDCl3) 7.14 (m, 1H), 7.11 (m, 1H), 7.07 (m, 2H), 4.28 (m, 1H), 2.61 (s, 4H), 2.45 (t, 1H), 2.26 (q, 2H), 2.10 (d, J=12.2, 2H), 2.0 (d, J=10.8, 2H), 1.53 (q, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:14](=[O:39])[NH:15][C@H:16]([C:22](=[O:38])[NH:23][C@@H:24]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25]([C@@:27]1([CH3:30])[CH2:29][O:28]1)=[O:26])[CH2:17][O:18][CH:19]([F:21])[F:20])[CH2:9][O:10][CH:11]([F:13])[F:12])(C)(C)C.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>ClCCl>[OH:47][C:41]([C:43]([F:46])([F:45])[F:44])=[O:42].[NH2:7][C@@H:8]([CH2:9][O:10][CH:11]([F:13])[F:12])[C:14]([NH:15][C@H:16]([C:22](=[O:38])[NH:23][C@@H:24]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:25]([C@@:27]1([CH3:30])[CH2:29][O:28]1)=[O:26])[CH2:17][O:18][CH:19]([F:20])[F:21])=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)N[C@@H](COC(F)F)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@]1(C(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](COC(F)F)NC(=O)[C@@H](N)COC(F)F)CO1
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of the compound of Formula XIV(a), ((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyl-oxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxy-ethylcarbamoyl}-2-difluoromethoxy-ethyl)-carbamic acid tert-butyl ester (2.68 g, 4.62 mmol) in dichloromethane (10 mL) at 0° C. was added TFA (10 mL), and the resulting mixture was stirred for 1 hr. Excess TFA was evaporated to dryness, and the residue obtained was triturated with ether in hexanes (2×20 mL) to provide the compound of Formula XV(a), (S)-2-amino-N—{(S)-1-[(S)-1-benzyl-2-((R)-2-methyl-oxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxy-ethyl}-3-difluoromethoxy-propionamide TFA salt (2.34 g, 85%), as a pale-yellow solid. 1H NMR (300 MHz, d6-DMSO): δ (ppm) 7.42-7.32 (m, 3H), 7.23 (dd, 2H), 6.85 (wd, 1H), 6.71 (br s, 1H), 6.68 (wd, 1H), 6.10 (w t, 1H), 5.98 (wt, 1H), 5.12 (br s, 1H), 4.78 (td, 1H), 4.51 (td, 1H), 4.29 (m, 1H), 4.30-3.99 (m, 2H), 3.97 (dd, 1H), 3.85 (dd, 1H), 3.21 (d, 1H), 3.10 (dd, 1H), 2.86 (d, 1H), 2.81 (dd, 1H), 1.45 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([CH3:14])[C:11]([CH:15]=[O:16])=[N:10]2)=[CH:5][CH:4]=1.[CH:17]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1>[CH:17]1([CH:15]([C:11]2[C:12]([CH3:14])=[CH:13][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:10]=2)[OH:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1ccc(-n2cc(C)c(C=O)n2)cc1
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(-n2cc(C)c(C(O)C3CCCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution (10 mL) of 1-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carbaldehyde (0.96 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (6.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.70 g, 53%) as a pale-yellow oil.
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].O>CS(C)=O>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3]
Reactant: OCCCCCCBr
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1cnc2c1c(=O)n(CCCCCCO)c(=O)n2C
Reaction time: 0.83 h
Yield: 90.9 %

Procedure:
This example is a method of synthesis for inventive compound no. 3506 (see above for chemical name and structure). A mixture of theobromine (1.0 g, 5.5 mmol, available from Sigma) and 50% sodium hydride in oil (264 mg, 5.5 mmol) in dimethylsulfoxide (20 ml) was stirred for 50 minutes and then 6-bromo-1-hexanol (1.0 g, 5.5 mmol, available from Aldrich) was added. After stirring for 18 hours, the solution was treated with water (50 ml) and then extracted with two 25 ml aliquots of hexanes. The aqueous phase was extracted with three 35 ml aliquots of 25% ethanol-dichloromethane. The combined ethanol-dichloromethane extracts were dried over magnesium sulfate. The solvents were then evaporated under vacuum and remaining dimethylsulfoxide was removed by distillation under full pump vacuum, leaving 1.4 g of a white powder, 1-(6-hydroxyhexyl)-3,7-dimethylxanthine (5.0 mmol, 91% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:12][CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:14][CH2:15][CH3:16].[Na+].O>C(O)C>[CH2:15]([O:14][C:2]1[CH:3]=[C:4]([CH2:12][CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:16]
Reactant: CC[O-]
Reactant: CCc1cc(Cl)nn2c(N)nnc12
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1cc(CC)c2nnc(N)n2n1
Temperature: 45 °C
Yield: 91.3 %

Procedure:
6-Chloro-8-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.003; 700 mg) was dissolved in ethanol (100 ml) while stirring. Thereafter, the reaction mixture was admixed with sodium ethoxide (724 mg) and stirred at RT for 2 h. Subsequently, the mixture was heated to 45° C. for 3 h. After the solvent had been drawn off, the residue was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 670 mg of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:4]([CH3:26])[CH:3]=1.C(N(CC)CC)C.[Cl:34][C:35]([Cl:40])([Cl:39])[C:36](Cl)=[O:37]>ClCCl>[Cl:34][C:35]([Cl:40])([Cl:39])[C:36]([C:21]1[N:13]2[C:12]([CH2:11][N:10]([C:8](=[O:9])[CH2:7][O:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:26])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14]2)=[CH:23][CH:22]=1)=[O:37]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1cc(Cl)ccc1OCC(=O)N1Cc2cccn2Cc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1OCC(=O)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Temperature: 25 °C

Procedure:
To a cold (0° C.) solution of 10-[(4-chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of step B (2.70 mmol) and triethylamine (0.76 mL) in dichloromethane (15 mL) was added trichloroacetyl chloride (0.90 mL). This was stirred and allowed to warm to room temperature overnight. The reaction mixture was washed with water (2×), 0.1N hydrochloric acid (2×), dilute aqueous sodium bicarbonate (2×) and finally, with water (1×). The organic phase was dried over anhydrous sodium sulfate and evaporated. The product was purified by crystallization from warm ethyl acetate/hexane (3/1), m.p. 156-158° C. MS [(+)ESI, m/z]: 511 [M+H]+ Anal. Calcd for C23H18Cl4O3: C, 53.93; H, 3.54; N, 5.47. Found: C, 53.90; H, 3.45; N, 5.40.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]1([C:13]([NH:15][NH:16][C:17](=[S:20])[NH:18][CH3:19])=O)[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl>[OH-].[Na+]>[Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]1([C:13]2[N:18]([CH3:19])[C:17](=[S:20])[NH:16][N:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CNC(=S)NNC(=O)C1(c2scc(C)c2Cl)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1csc(C2(c3n[nH]c(=S)n3C)CCCC2)c1Cl
Yield: 97.5 %

Procedure:
An 1M aqueous sodium hydroxide solution (10 ml) of 2-{[1-(3-chloro-4-methyl-2-thienyl)cyclopentyl]carbonyl}-N-methylhydrazinecarbothioamide (167 mg) was refluxed for 20 hours. An 1M aqueous hydrochloric acid solution was added to the reaction solution to acidify the solution and precipitated crude crystals were collected by filtration and washed with water to obtain 154 mg of 5-[1-(3-chloro-4-methyl-2-thienyl)cyclopentyl]-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-thione (pale brown solid).
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:29])[CH:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[CH3:18])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:29])[CH:17]([O:19][C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)[CH3:18])=[O:11])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCOC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(N)cc1)C(=O)OCCOC(=O)COc1ccc(N)cc1
Yield: 53.4 %

Procedure:
2-(4-Nitrophenoxy)propionic acid 2-[2-(4-nitrophenoxy)acetoxy]-ethyl ester 38 (20 g, 50 mmol) was dissolved in dry dimethylformamide (150 ml) in a pressure vessel. Palladium on carbon (5%, 5 g) was added and the mixture stirred under an atmos-phere of hydrogen (4 kg) for 3 hrs. The catalyst was removed by filtration and ice water (1 L) added to the filtrate. Crude 39 was extracted into ethyl acetate, dried over Na2SO4, distilled and purified by column chromatography on silica gel using chloroform:ethyl acetate (8:2) to give pure 39 (10 g, 58%) as a dark brown syrup.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=2)[CH:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)[CH:7]=1.[OH-:26].[Na+]>CO.O.OO>[OH:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([NH2:25])=[O:26])=[N:22][CH:23]=2)[CH:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)[CH:7]=1
Reactant: [OH-]
Reactant: N#Cc1ccc(Nc2cc(O)cc(-c3cccc4[nH]ccc34)c2)cn1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc(Nc2cc(O)cc(-c3cccc4[nH]ccc34)c2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
To a solution of 5-[3-hydroxy-5-(1H-indol-4-yl)-phenylamino]-pyridine-2-carbonitrile (83 mg, 0.25 mmol) in MeOH (1 mL) was added 50% NaOH solution in H2O (200 μL) and 30% H2O2 (500 μL), and the mixture was stirred for 16 h at room temperature. The solution was concentrated to half the volume with a gentle stream of nitrogen, and the solution was diluted by addition of water (2 mL). The aqueous solution was extracted with ethyl acetate (2 mL, three times). The combined solution of organic layer was dried and concentrated to give 5-[3-hydroxy-5-(1H-indol-4-yl)-phenylamino]-pyridine-2-carboxylic acid amide (58 mg, 0.168 mmol, 66%) as a solid. 1H NMR (400 MHz, CD3OD) δ 8.34 (dd, J=2.4, 0.4 Hz, 1H), 7.91 (dd, J=8.8, 0.4 Hz, 1H), 7.55 (m, 1H), 7.35 (dd, J=8.0, 0.4 Hz, 1H), 7.25 (d, J=3.2 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H), 7.06 (dt, J=7.2, 0.8 Hz, 1H), 6.97 (m, 1H), 6.82 (m, 1H), 6.67 (m, 1H), 6.63 (dd, J=2.4, 0.4 Hz, 1H).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:9]2[C:10](=[O:23])[N:11]([CH3:22])[CH2:12][C:13]3[N:14]([CH:15]=[N:16][C:17]=3[C:18]#[C:19][CH2:20][OH:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1.Br[CH2:25][CH:26]1[CH2:28][CH2:27]1.O>CN(C)C=O>[Cl:3][C:4]1[C:9]2[C:10](=[O:23])[N:11]([CH3:22])[CH2:12][C:13]3[N:14]([CH:15]=[N:16][C:17]=3[C:18]#[C:19][CH2:20][O:21][CH2:25][CH:26]3[CH2:28][CH2:27]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: BrCC1CC1
Reactant: CN1Cc2c(C#CCO)ncn2-c2cccc(Cl)c2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(C#CCOCC3CC3)ncn2-c2cccc(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.2 %

Procedure:
3.34 g (59 mmol) of freshly powdered potassium hydroxide were suspended in 25 ml of N,N-dimethylformamide and treated with 4.0 g (13.2 mmol) of 7-chloro-4,5-dihydro-3-(3-hydroxy-1-propynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one. After stirring at room temperature for 5 minutes the mixture was cooled to 2°, whereupon 4.95 g (31.1 mmol) of bromomethylcyclopropane were added thereto. The reaction mixture was stirred at room temperature for 1 hour and then poured into water. The mixture was extracted three times with methylene chloride, the combined organic extracts were washed with water, dried over magnesium sulfate and evaporated. By crystallization of the residue from ethyl acetate and ether there were obtained 4.0 g (84%) of 7-chloro-3-[3-(cyclopropyl-methoxy)- 1-propynyl]-4,5-dihydro-5 methyl6H-imidazo-[1,5-a][1,4]benzodiazepin-6-one of melting point 124-126°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9](SC)[NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)[CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:28].CO>>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[NH:28])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)[CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CSC(=Nc1cccc(F)c1)Nc1ccc(C(C(C)C)n2ccnc2)cc1
Solvent: CO
Product: CC(C)C(c1ccc(NC(=N)Nc2cccc(F)c2)cc1)n1ccnc1
Temperature: 40 °C
Yield: 46 %

Procedure:
A solution of methyl N′-(3-fluorophenyl)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-phenyl]carbamimidothioate (0.0094 mol) in NH3/CH3OH (60 ml) was stirred and heated in autoclave at 40° C. for 3 days. The solvent was evaporated and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 94/6/0.2 to 90.10/0.5). The pure fractions were collected and evaporated. The residue was crystallized from 2-propanone and (C2H5)2O and filtered off, yielding 0.89 g (46%) N′-(3-fluorophenyl)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]guanidine (compound 744).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[CH2:16]1[C:29]2[C:20](=[N:21][C:22]3[C:23](=O)[CH2:24][CH2:25][CH2:26][C:27]=3[CH:28]=2)[C:19](=O)[CH2:18][CH2:17]1>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([N:6]=[C:19]2[C:20]3[C:29](=[CH:28][C:27]4[CH2:26][CH2:25][CH2:24][C:23](=[N:6][C:5]5[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=5)[C:22]=4[N:21]=3)[CH2:16][CH2:17][CH2:18]2)[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCCc2cc3c(nc21)C(=O)CCC3
Product: FC(F)(F)c1cc(N=C2CCCc3cc4c(nc32)C(=Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCC4)cc(C(F)(F)F)c1

Procedure:
was synthesized by methods similar to those in Examples 3 and 4: 3,5-bis-trifluoromethylaniline was condensed with 2,3,7,8-tetrahydro-1H,6H-acridine-4,5-dione to yield 4,5-bis[3,5-bistrifluoromethylphenylimino]-1,2,3,4,5,6,7,8-octahydroacridine (5). The complexation of (5) with FeCl2.4H2O was carried out with azeotropic removal of methanol in benzene. The structure of the final complex was proved by direct probe GC. Exact mass direct probe calculated for C29H19Cl2F12FeN3: 763.01. Found: 763.01.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.I[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>>[CH2:11]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCI
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCN1CCC(C(N)=O)CC1
Yield: 102.8 %

Procedure:
Prepared from isonipecotamide (4.04 g, 31.6 mmol), 1-iodohexane (6.7 g, 31.6 mmol) and potassium carbonate (4.36 g, 31.6 mmol) according to the procedure used for Example 8 (Step A) to give 6.9 g of the title compound as a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[O:7].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH3:44])[CH:37]=[C:38]([O:42]C)[C:39]=1[O:40][CH3:41].Cl>[N+](C1C=CC=CC=1)([O-])=O.O>[OH:42][C:38]1[C:39]([O:40][CH3:41])=[C:34]([O:33][CH3:32])[CH:35]=[C:36]([CH3:44])[C:37]=1[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:7]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: COc1cc(C)cc(OC)c1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cc(C)c(C(=O)CCCCCCCCCCCCCCCCCCCCC(=O)O)c(O)c1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Aluminum chloride (2.5 g) is added portionwise in a nitrogen atmosphere to a solution of 1 g of methyl 21-chloroformylheneicosanoate and 1.7 g of 3,4,5-trimethoxytoluene in 50 ml of nitrobenzene, and the resulting mixture is stirred at room temperature for 48 hours. To the reaction mixture are added water and diluted hydrochloric acid, and the whole mixture is extracted with ether. After distilling of the solvent, the residue is dissolved in methanol, 4.6 ml of a 30% sodium hydroxide solution is added, and the mixture is stirred at 60° C. for an hour. The reaction mixture is washed with ether, then made acidic with diluted hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and dried, the solvent distilled off, and the residue chromatographed on silica gel. The crystals recovered from the chloroform-ethanol (17:1) eluate are recrystallized from ether-hexane to give colorless crystals of 21-(2-hydroxy-3,4-dimethoxy-6-methylbenzoyl)heneicosanoic acid. m.p. 103°-150° C.
Reaction SMILES: Cl[C:2]1[O:6][C:5]([C:7]2[C:12]([C:13]#[N:14])=[C:11]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:16]=3[F:23])[N:10]=[C:9]3[NH:24][N:25]=[C:26]([CH3:27])[C:8]=23)=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:27][C:26]1[C:8]2[C:9](=[N:10][C:11]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:16]=3[F:23])=[C:12]([C:13]#[N:14])[C:7]=2[C:5]2[O:6][C:2]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:3][CH:4]=2)[NH:24][N:25]=1
Reactant: C1COCCN1
Reactant: Cc1n[nH]c2nc(-c3c(F)ccc(F)c3F)c(C#N)c(-c3ccc(Cl)o3)c12
Product: Cc1n[nH]c2nc(-c3c(F)ccc(F)c3F)c(C#N)c(-c3ccc(N4CCOCC4)o3)c12
Yield: 35 %

Procedure:
A solution of 2.0 g (5.0 mmol) of 4-(5-chlorofuran-2-yl)-3-methyl-6-(2,3,6-trifluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile in 11 ml of morpholine is refluxed for 20 h. The mixture is then concentrated, dissolved in dichloromethane and washed three times with 1N hydrochloric acid solution. The organic phase is dried over magnesium sulfate, filtered, and concentrated. The residue obtained is purified by chromatography on silica (ethyl acetate gradient in dichloromethane: 10 to 20%) to give 0.76 g (35%) of 3-methyl-4-(5-morpholinofuran-2-yl)-6-(2,3,6-trifluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile in the form of yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][CH:32]=[CH:31][C:5]=1[C:6]([NH:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]([CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=[N:15][C:11]=2[CH:10]=1)=[O:7])([O-])=O.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[NH2:1][C:4]1[CH:34]=[CH:33][CH:32]=[CH:31][C:5]=1[C:6]([NH:8][C:9]1[CH:30]=[CH:29][C:12]2[N:13]([CH:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=[N:15][C:11]=2[CH:10]=1)=[O:7]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccccc3[N+](=O)[O-])ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccccc3N)ccc21
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-{5-[(2-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (30 mg, 66 μmol) in a mixture of ethanol and water (4:1, 5 mL), was added palladium on carbon (6.0 mg, 10% w/w Pd) and ammonium formate (20 mg, 317 μmol). The suspension was heated to reflux for 3 hours, then cooled to room temperature, and filtered through a pad of Celite®. The filtrate was evaporated in vacuo to afford the title compound, 1H NMR: (CD3OD), 8.48 (s, 1H), 8.06 (s, 1H), 7.64 (dd, J=7.69, 1.46, 1H), 7.50-7.35 (br, 7H), 7.28-7.24 (m, 1H), 6.82 (dd, J=8.42, 0.73 1H), 6.74-6.70 (m, 1H), 6.18 (dd, J=9.52, 5.86, 1H), 4.09 (1, J=7.32, 2H), 3.66 (dd, J=16.11, 9.52, 1H), 3.51 (dd, J=16.11, 5.86, 1H), 1.13 (t, J=7.32, 3H).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:14])/[C:10](=[CH:12]/[CH3:13])/[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:14])/[C:10](=[CH:12]/[CH3:13])/[CH3:11])=[CH:3][CH:2]=1
Reactant: C/C=C(\C)C(=O)Cl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C/C=C(\C)C(=O)c1ccc(OC)cc1
Yield: 28 %

Procedure:
Anisole (128 mg), tigloyl chloride (140 mg), and aluminium chloride (155 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (63 mg).