Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:34]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH2:35][CH2:36][CH3:37]>>[CH2:34]([N:38]1[CH2:43][CH2:42][N:41]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][NH:22][C:23]4[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:40][CH2:39]1)[CH2:35][CH2:36][CH3:37]
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NNc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: CCCCN1CCNCC1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NNc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 10 %

Procedure:
The title compound was prepared from 4-(2-(4-(3-(3-cyanophenyl)ureido)phenylsulfonyl) hydrazinyl)benzenesulfonamide following procedure C and using 2 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:9][OH:10]>F[B-](F)(F)F.C[N+](C)(C)C>[C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[O:10][CH3:9])(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)N1CCCC1
Agent: C[N+](C)(C)C
Agent: F[B-](F)(F)F
Product: COC1CCCN1C(C)=O

Procedure:
In the same manner as indicated in Example 6 there are electrolyzed 19.6 g of N-acetylpyrrolidine and 55.6 of methanol in the presence of 0.28 g of tetramethylammonium tetrafluoroborate as conducting salt. After throughput of 2.0 Faraday per mol of N-acetylpyrrolidine the current is switched off. The calculated mean cell voltage is 32.7 volts. Work-up of the electrolysis solution gives 19.9 g of 1-acetyl-2-methoxypyrrolidine (boiling point 53° C./0.1 mbar; nD25 = 1.4674), which corresponds to a product yield of 80.0% and a current efficiency of 80.0%.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:18][C:17](=[O:19])[CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:15]([O:24]CC2C=CC=CC=2)[C:14]1=[O:32])=[O:12].[H][H]>O1CCOCC1.[C].[Pd]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:18][C:17](=[O:19])[CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:15]([OH:24])[C:14]1=[O:32])=[O:12]
Reactant: [H][H]
Reactant: CC(C)CC1C(=O)NC(Cc2ccccc2)(C(=O)Nc2nc3ccccc3s2)C(=O)N1OCc1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(C)CC1C(=O)NC(Cc2ccccc2)(C(=O)Nc2nc3ccccc3s2)C(=O)N1O
Yield: 43 %

Procedure:
0.80 g of 10% palladium-carbon was added to 30 ml of a solution of 1.56 g of (3RS,6SR)-3-(benzothiazol-2-yl)carbamoyl-3-benzyl-1-benzyloxy-6-isobutylpipera- zine-2,5-dione in dioxane. The mixture was stirred at room temperature for 4 hours in a hydrogen current. The reaction mixture was filtered to remove the catalyst. The filtrate was subjected to distillation to remove the solvent. The resulting light brown oily substance was recrystallized using dichloromethane, to obtain 0.56 g of (3RS,6SR)-3-(benzothiazol-2-yl)carbamoyl-3-benzyl-1-hydroxy-6-isobutylpiperazine-2,5-dione.
Reaction SMILES: C(O)(=O)C.[O:5]1[CH2:8][C:7](=O)[CH2:6]1.C([BH3-])#N.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:23]=[C:22]([NH:24][C:25]3[N:26]=[CH:27][C:28]4[S:33][C:32]([C:34]([NH2:36])=[O:35])=[C:31]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[O:43][C:44]([F:47])([F:46])[F:45])[C:29]=4[N:30]=3)[N:21]([CH:48]([CH3:50])[CH3:49])[N:20]=2)[CH2:15][CH2:14]1>C1COCC1>[O:5]1[CH2:6][CH:7]([N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[CH:23]=[C:22]([NH:24][C:25]4[N:26]=[CH:27][C:28]5[S:33][C:32]([C:34]([NH2:36])=[O:35])=[C:31]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=6[O:43][C:44]([F:45])([F:46])[F:47])[C:29]=5[N:30]=4)[N:21]([CH:48]([CH3:50])[CH3:49])[N:20]=3)[CH2:17][CH2:18]2)[CH2:8]1
Reactant: O=C1COC1
Reactant: CC(C)n1nc(C2CCNCC2)cc1Nc1ncc2sc(C(N)=O)c(-c3ccccc3OC(F)(F)F)c2n1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)n1nc(C2CCN(C3COC3)CC2)cc1Nc1ncc2sc(C(N)=O)c(-c3ccccc3OC(F)(F)F)c2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1 ml of acetic acid, 6 microliters of 3-oxetanone and 190 mg of amberlite resin IRA400 cyanoborohydride (Aldrich, loading 2×10−3 mol/g) are added, at ambient temperature, to a solution of 50 mg of 2-{[3-(piperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamide in 3 ml of anhydrous THF, under an argon atmosphere. After stirring for 4 h at ambient temperature, 10 microliters of 3-oxetanone and 186 mg of the same amberlite resin IRA400 cyanoborohydride are added and the mixture is left to stir for a further 15 h. A further 6 microliters of 3-oxetanone and 100 mg of amberlite resin IRA400 cyanoborohydride are added and the mixture is then left to stir for 2 h. The mixture is filtered and the resin is washed with 50 ml of ethyl acetate then 20 ml of ethanol. The filtrate is concentrated under vacuum and the crude product is purified by flash chromatography on silica gel, elution being carried out with a dichloromethane/methanol/NH4OH (96/4/0.1%) mixture, so as to obtain 30 mg of 2-({3-[1-(oxetan-3-yl)piperidin-4-yl]-1-(propan-2-yl)-1H-pyrazol-5-yl}amino)-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamide in the form of a yellow solid.
Reaction SMILES: [CH2:1]([N:8]([C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C@H:9]([CH3:18])[CH2:10][C:11](OC(C)(C)C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH2:1]([N:8]([C@@H:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:20])[C@H:9]([CH3:18])[CH2:10][CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](CC(=O)OC(C)(C)C)N(Cc1ccccc1)[C@H](C)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H](CCO)N(Cc1ccccc1)[C@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
tert-Butyl(3R)-3-{benzyl[(1R)-1-phenylethyl]amino}butanoate (6.2 g, 17.6 mmol) was dissolved in THF (100 mL). The 1 L-flask was purged with N2 and cooled to 0° C. Lithium aluminum hydride (2.7 g, 69.8 mmol) was slowly added over 5 minutes. The reaction was allowed to stir at 0° C. for 1 hour, and then heated to 60° C. for 1 hour. The reaction was cooled to room temperature and diluted with Et2O (500 mL). This solution was quenched with a mixture of celite:Na2SO4 10H2O (1:1) added over 15 minutes. The solution was then filtered and the mother liquor condensed to yield 3.9 g (13.8 mmol, 78%) of the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]1COCC1.[CH2:8]([O:10][CH2:11][CH2:12][CH2:13][NH:14][CH:15]=[O:16])[CH3:9].CI>CCCCCC>[CH2:8]([O:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:3])[CH:15]=[O:16])[CH3:9]
Reactant: C1CCOC1
Reactant: CCOCCCNC=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCCCCC
Product: CCOCCCN(C)C=O
Reaction time: 0.5 h

Procedure:
NaH (washed with n-hexane in advance, 2.01 g, 76.24×1.1 mmol) was added to a dry THF (100 mL) solution of N-(3-ethoxypropyl)formamide (10.00 g, 76.24 mmol) under an argon atmosphere with ice-bath cooling, and stirred for 30 minutes. A dry THF (10 mL) solution of methyl iodide (5.7 mL, 76.24×1.2 mmol) was added dropwise to the reaction mixture under an argon atmosphere with ice-bath cooling, it was then stirred for 30 minutes, and further stirred at room temperature for 90 minutes. NaH (washed with n-hexane in advance, 0.20 g, 76.24×0.1 mmol) was again added and it was stirred at room temperature for 1 hour. After cooling with ice-bath, n-hexane (100 mL) was added to the reaction mixture and it was stirred for 1 hour, and insoluble materials were then removed by filtration with a pad of Celite. A residue obtained by concentrating the filtrate to dryness was purified by vacuum distillation (fraction at 0.6 kpa, 91° C. collected), and FEP (4.17 g, 28.68 mmol, 38%) was obtained as a pale yellow clear liquid.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:10](Cl)(=[O:13])[CH:11]=[CH2:12]>C1(C)C=CC=CC=1>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[C:10](=[O:13])[CH:11]=[CH2:12])[CH2:2][CH2:3][CH3:4]
Reactant: C=CC(=O)Cl
Reactant: CCCCNCCCC
Solvent: Cc1ccccc1
Product: C=CC(=O)N(CCCC)CCCC
Temperature: 25 °C

Procedure:
In a 2 liter 3-necked flask were combined 129 g (1 mol) di-(n-butyl)amine (Fisher Scientific) and 0.1 l dry toluene and cooled to 5° C. 46 g (0.5 mol) acryloyl chloride dissolved in 50 ml toluene were added slowly so the temperature remained below 10° C. After the addition the flask was warmed to 25° C. and the precipitate removed by filtration. 1 g DNPD was added, and after concentration on a rotary evaporator the product was distilled at 20 m torr and 61°-63° C. Yield 77 g (84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12](C)=[CH:11][CH:10]=1)=[O:8].Br[C:20]1C=CC(OC)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:20])[CH:14]=1)=[O:8]
Reactant: COc1ccc(Br)cc1
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(C)cc1
Product: COc1ccc(Br)cc1C(=O)c1cccc(C)c1

Procedure:
Employing the same general procedure as for the preparation 5-bromo-2-methoxy-4'-methylbenzophenone (Compound H), 1.0 mL (1.5 g, 8.0 mmol) of 4-bromoanisole was converted into the title compound using 0.5 g (4.0 mmol) of aluminum chloride, 1.3 mL (1.5 g, 9.6 mmol) of m-toluoyl chloride and 20 mL of dichloromethane. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][C@@H:12]([CH3:22])[CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:4]([C:7](OC)=[O:8])[S:5][CH:6]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Br:1][C:2]1[C:3]([O:11][C@@H:12]([CH3:22])[CH2:13][NH:14][C:15](=[O:16])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:4]([CH2:7][OH:8])[S:5][CH:6]=1
Reactant: COC(=O)c1scc(Br)c1O[C@@H](C)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](CNC(=O)OC(C)(C)C)Oc1c(Br)csc1CO
Temperature: 50 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a solution of methyl 4-bromo-3-{(1S)-2-[(tert-butoxycarbonyl)amino]-1-methylethoxy}thiophene-2-carboxylate (15.36 g) in THF-MeOH (5:1, 180 mL) was added 8 N aqueous sodium hydroxide solution (7.5 mL) at room temperature, and the mixture was stirred at 50° C. for 1 hr. The reaction solution was cooled to room temperature, neutralized with 6 N hydrochloric acid (10 mL), and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution (250 ml) of the residue in THF were added isobutyl chloroformate (5.6 mL) and triethylamine (6.5 ml), and the mixture was stirred at room temperature for 30 min. The reaction solution was filtered, a solution (10 ml) of sodium borohydride (4.42 g) in water was added to the filtrate, and the mixture was stirred at room temperature for 30 min. Saturated aqueous ammonium solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 10→25% ethyl acetate/hexane) to give the title compound (12.82 g, 90%) as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25]1([CH:31](Cl)[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:8][CH2:9][CH2:10][NH:11][CH:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCNC(c1ccccc1)c1ccccc1
Reactant: CC(Cl)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(NCCNC(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
11 g of N-diphenylmethyl-ethylenediamine, 10.1 g of triethylamine and 7.0 g of 1-phenylethyl chloride are dissolved, while stirring, in 85 ml of acetonitrile and heated under reflux for 30 hours. The solution is concentrated by evaporation under reduced pressure, 50 ml of 10% sodium hydroxide solution are added and the mixture is extracted thoroughly by shaking with diethyl ether. The ether extracts are combined, dried over sodium sulphate and concentrated by evaporation. N-diphenylmethyl-N'-(1-phenylethyl)-ethylenediamine is obtained in the form of a yellow oil which can be purified chromatographically over silica gel with methanol/ethyl acetate (1:1) as the eluant and, for characterisation, can be converted into the dihydrochloride, having a melting point of 160° C., as described in Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][F:27])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1.CCOC(C)=O>CCO.[Pt]>[Cl:1][C:2]1[C:3]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][F:27])[CH2:23][CH2:24]3)[CH2:15][CH2:14]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-{1-[2-Chloro-5-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(2-fluoroethyl)piperazine (0.370 g, 0.923 mmol) was taken up in EtOH (50 mL) and EtOAc was added to help with solubility. The catalyst, 5% sulfided platinum on carbon (150 mg) was added. The reaction was placed on a Fischer-Porter Hydrogenator under 50 psi of H2 gas and was allowed to stir at rt overnight. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the title compound of step F without further purification (0.300 g, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.62 (d, J=7.0 Hz, 2H), 4.51-4.79 (m, 3H), 4.37-4.51 (m, 1H), 3.73 (s, 3H), 2.95-3.21 (m, 2H), 2.20-2.80 (m, 13H), 1.72-1.85 (m, 2H), 1.37-1.61 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]#[N:12])=[C:6]2[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[CH2:18][CH2:19]Cl.[CH:21]([NH2:25])([CH2:23][CH3:24])[CH3:22]>>[CH:21]([N:25]1[C:2]2[N:7]3[N:8]=[CH:9][C:10]([C:11]#[N:12])=[C:6]3[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=2[CH2:18][CH2:19]1)([CH2:23][CH3:24])[CH3:22]
Reactant: CCOC(=O)c1nc2c(C#N)cnn2c(Cl)c1CCCl
Reactant: CCC(C)N
Product: CCOC(=O)c1nc2c(C#N)cnn2c2c1CCN2C(C)CC
Yield: 95.6 %

Procedure:
The intended compound was obtained in 95.6% yield in the same manner as in Synthesis Example (5) using ethyl 7-chloro-6-(2-chloroethyl)-3-cyanopyrazolo[1,5-a]pyrimidine-5-carboxylate and sec-butylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:15]Br>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][Br:15])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(-c2ccccc2)c(F)c1
Reactant: BrBr
Product: Fc1cc(CBr)ccc1-c1ccccc1

Procedure:
In this instance the 2-fluoro-4-methylbiphenyl was heated to 140° to 170° C. with a heating mantle and under irradiation with light without a solvent while one equivalent of Br2 was added dropwise. Subsequent NMR analysis showed the starting material:monobromide:dibromide ratio to be 25:58:18.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([NH:20][C:21]#[N:22])=[N:9][C:10]2[CH:19]=[CH:18]C=[C:16]3[C:11]=2C=CC=[N:15]3)=[CH:4][CH:3]=1.[S:25](Cl)([C:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[C:33]([N:34]([CH3:36])[CH3:35])[C:32]=2[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26]>N1C=CC=CC=1.C(OCC)(=O)C>[C:21]([N:20]=[C:8]([NH:9][C:10]1[CH:11]=[CH:16][N:15]=[CH:18][CH:19]=1)[NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:25]([C:28]2[C:40]3[C:32](=[C:33]([N:34]([CH3:36])[CH3:35])[CH:37]=[CH:38][CH:39]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[CH:24][CH:23]=1)#[N:22]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: N#CNC(=Nc1cccc2ncccc12)NCc1ccc(N)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C)c1cccc2c(S(=O)(=O)Nc3ccc(CNC(=NC#N)Nc4ccncc4)cc3)cccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
N-(4-Amino-benzyl)-N′-cyano-N″-quinolin-5-yl-guanidine (400 mg, 1.50 mmol) and dansyl chloride (405 mg, 1.50 mmol) were combined in pyridine (15 mL). An exothermic reaction occurred and the suspension became homogeneous. This solution was shaken at room temperature for 12 hours. The reaction mixture was then diluted with ethyl acetate (80 mL) and washed with water (40 mL×3). The organic phase was dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give a solid product which was purified by HPLC (yield=60%). 1H NMR (DMSO-d6, ppm): 10.73 (s, 1H), 9.09 (bs, 1H), 8.57 (d, 2H), 8.44 (d, 2H), 8.36 (d, 1H), 8.21 (d, 1H), 7.61 (m, 3H), 7.50 (s, 2H), 7.27 (d, 1H), 7.17 (d, 2H), 7.03 (d, 2H), 4.38 (d, 2H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32](O)=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].CC(CC)=[O:37].C1(C)C(C)=CC=CC=1>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33]([OH:37])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(O)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CCC(C)=O
Solvent: Cc1ccccc1C
Product: CCCCc1nc2c(O)cccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
tert.butyl 4'-[(2-n-butyl-5-hydroxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.60 (Silica gel: methylethylketone/xylene=1:2)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1.O.[NH2:25][NH2:26]>C(O)C>[NH:25]([C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1)[NH2:26]
Reactant: NN
Reactant: FC(F)(F)c1nc(Cl)c(-c2ccccc2)c(-c2ccccc2)n1
Solvent: CCO
Solvent: O
Product: NNc1nc(C(F)(F)F)nc(-c2ccccc2)c1-c1ccccc1
Yield: 97.1 %

Procedure:
4-Chloro-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (1.8 g, 5.3 mmol) (synthesized according to the procedure described in example 1) was stirred in ethanol (10 ml) containing hydrazine hydrate (0.64 g, 12.8 mmol) for 2 hours at 35° C. The crystals thus obtained in the reaction mixture was filtered under vacuum, washed with ethanol (5 ml) and dried to yield the title compound (1.7 g, 95.7%, HPLC purity 99.2%), mp: 182-186° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH2:30]([O:32][CH:33](O)[CH3:34])[CH3:31].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7](=[O:9])[O:8][CH2:31][CH2:30][O:32][CH2:33][CH3:34])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CCOC(C)O
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOCCOC(=O)C#C[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[3-hydroxy-3-oxo-1-propynyl]-cyclopropane-carboxylate, 20 ml of methylene chloride and 0.7 ml of ethoxyethanol cooled to 0 to +5° C. was admixed with a mixture of 1.1 g of dicyclohexylcarbodiimide, 5 ml of methylene chloride and 15 mg of 4-dimethylamino-pyridine and the mixture was stirred for 1 hour at +5° C. and for 2 hours at room temperature and was filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel and eluted with a 3-1 mixture of cyclohexane-ethyl acetate to obtain 1.3 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[3-oxo-3-ethoxyethoxy-1-propynyl]-cyclopropane-carboxylate.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:37]4[CH2:38][CH2:39][C@H:35]([F:34])[CH2:36]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1
Reactant: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: F[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CC[C@H](F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-cyclohexylmethyl)-amide, DIPEA and (S)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.75 (m, 1H), 7.55 (2H), 7.05 (1H), 5.43-5.56 (1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 426 [M+H]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[CH2:12][C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[NH2:28][OH:29]>O1CCCC1>[OH:29][NH:28][C:13](=[O:14])[CH2:12][CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]
Reactant: NO
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2C(=O)c3ccccc3C2=O)cc1OC
Yield: 80.2 %

Procedure:
N-Hydroxy-3-(3,4-dimethoxyphenyl)-3-phthalimidopropionamide was prepared by the procedure of Example 1 from 3-(3,4-dimethoxyphenyl)-3-phthalimidopropanoic acid (1.82 g, 5.12 mmol), N,N′-carbonyldiimidazole (870 mg, 5.39 mmol) and hydroxylamine hydrochloride (391 mg, 5.63 mmol) in tetrahydrofuran (8 mL) to afford N-hydroxy-3-(3,4-dimethoxyphenyl)-3-phthalimidopropionamide as a white solid (1.52 g, 80% yield): mp, 186.5–188.0° C.; 1H NMR (DMSO-d6) δ 3.12 (d, J=7.8 Hz, 2H, CH2), 3.72 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 5.69 (t, J=7.8 Hz, 1H, NCH), 6.91–6.92 (m, 2H, Ar), 7.03 (br s, 1H, Ar), 7.85 (br s, 4H, Ar), 8.82 (s, 1H, OH), 10.62 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 34.33, 50.25, 55.52, 111.27, 111.67, 119.65, 123.17, 131.26, 134.63, 148.41, 148.56, 166.07, 167.69. Anal. Calcd for C19H18N2O6: C, 61.62; H, 4.90; N, 7.56. Found: C, 61.29; H, 4.72; N, 7.47.