Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:23][O:24][C:25]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:26]=1[CH:27]=O.CCOC(C)=O>ClCCCl>[CH3:23][O:24][C:25]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:26]=1[CH2:27][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Nc1cccc(O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cccc(O)c2)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of 3-hydroxyaniline (1 equiv) in 1,2-dichloroethane is added 4Å powdered molecular sieves, followed by sodium triacetoxyborohydride (1.5 equiv). 2,4-dimethoxybenzaldehyde (1.1 equiv) is added, and the reaction is stirred at room temperature. After completion, the reaction is poured into EtOAc, washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([OH:17])=O)[O:11][CH:12]=2)=[CH:4][CH:3]=1.[CH2:18]([N:20](CC)CC)C.C(Cl)(=O)OCC.CN>C1COCC1.O>[CH3:18][NH:20][C:15](=[O:17])[CH2:14][CH2:13][C:10]1[O:11][CH:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)CCc1nc(-c2ccc(Cl)cc2)co1
Agent: CCOC(=O)Cl
Agent: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)CCc1nc(-c2ccc(Cl)cc2)co1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of 4-(4-chlorophenyl)-2-oxazolepropionic acid (0.4 g) in THF (20 ml) were added triethylamine (0.33 ml) and ethyl chlorocarbonate (0.23 ml) at -30° C., followed by stirring for 30 minutes at the same temperature. The mixture was poured into 30% methylamine aqueous solution (10 ml), and the resultant was stirred for 15 minutes at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over MgSO4. The solvent was distilled off to give crystals of N-methyl-4-(4-chlorophenyl)-2-oxazolepropion-amide (0.375 g, 89%). Recrystallization from dichloromethane-ethanol gave colorless prism crystals of mp 169°-170° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]3[CH:31]=[C:30]([C:32](=[O:44])[NH:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH3:43])[CH:29]=[C:28]([C:45]#[CH:46])[CH:27]=3)[N:20]=2)=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]3[CH:31]=[C:30]([CH:29]=[C:28]([C:45]#[CH:46])[CH:27]=3)[C:32]([NH:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH3:43])=[O:44])[N:20]=2)=[CH:10][CH:9]=1
Reactant: C#Cc1cc(Nc2nccc(Oc3ccc(NC(=O)OC(C)(C)C)c4ccccc34)n2)cc(C(=O)NCCOCCOCCOC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#Cc1cc(Nc2nccc(Oc3ccc(N)c4ccccc34)n2)cc(C(=O)NCCOCCOCCOC)c1
Reaction time: 1 h

Procedure:
To a stirred solution of the product from step (v) above (540 mg, 0.825 mmol) in DCM (8 mL) was added TFA (3.2 mL, 41.5 mmol). The reaction was stirred at it for 1 h. The solution was concentrated in vacuo and the resulting oil dissolved in the minimum of MeOH and loaded onto SCX. The column was eluted with MeOH (3 column volumes), then 1% NH3 in MeOH (3 column volumes). The product-containing portion was concentrated in vacuo to afford the sub-title compound (405 mg) as a light, brown foam.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCc1ccccc1
Solvent: CO
Product: N#CNC(=NCc1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and benzylamine (0.31 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from methanoldiethyl ether to give the title compound (0.44 g, 1.8 mmol, yield: 72%) as colorless needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[CH2:12](Br)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCBr
Reactant: COc1ccc2[nH]ccc2c1
Product: CCCCn1ccc2cc(OC)ccc21

Procedure:
By treating in analogous manner 5-methoxy-indole with n-butyl bromide, 1-n-butyl-5-methoxy-indole is obtained (b.p.:103° -104° C., nD20 :1.5674).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][OH:6].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[Cl-].[Na+]>O1CCCC1.CCOCC>[Si:8]([O:6][CH2:5][CH2:4][CH2:3][OH:7])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: OCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
To a suspension of sodium hydride (6.29 g, 262 mmol) in dry tetrahydrofuran (400 ml) was added 1,3-propanediol (20.0 g, 262 mmol) over 5 min and the mixture was stirred at room temperature under dry nitrogen for 1.5 hr. t-Butyldimethylsilyl chloride (39.5 g, 262 mmol) was added portionwise and the mixture was stirred at room temperature for 1.5 hr. Saturated sodium chloride solution (300 ml) then ether (500 ml) were added. The organic portion was dried (magnesium sulphate), filtered and the solvent removed. The residue was purified by column chromatography on silica gel eluting with ether-hexane (1:2, 3:2) to afford 3-(t-butyldimethylsilyloxy)propan-1-ol as a colourless liquid (41.2 g, 83%); δH (CDCl3) 0.10 (6H, s, CH3), 0.93 (9H, s, C(CH3)3), 1.80 (2H, qu, J 6 Hz, CH2), 2.37 (1H, br.s, OH), 3.87 ( 4H, m, CH2O ).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16]([OH:19])(=[O:18])=[O:17])[CH:10]=[CH:9]2.[ClH:20]>O>[Cl:20][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16]([OH:19])(=[O:18])=[O:17])[CH:10]=[CH:9]2
Reactant: Cl
Reactant: Nc1ccc2cc(S(=O)(=O)O)ccc2c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)c1ccc2cc(Cl)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (2.7 g) in water (5 ml) was added during 2 hours to a stirred mixture of 6-amino-2-naphthalenesulphonic acid (8.8 g), dilute aqueous hydrochloric acid (2.8% weight/volume, 20 ml) and water (15 ml) which had been cooled to 0° C. The mixture was stirred at 0° C. for 30 minutes and then poured onto a stirred suspension of cuprous chloride (3.96 g) in dilute aqueous hydrochloric acid (2.8%, 20 ml). The mixture was stored at ambient temperature for 18 hours. The mixture was evaporated to give 6-chloro-2-naphthalenesulphonic acid which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[F:12][C:13](I)([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](=[O:8])[C:13]([F:12])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:5][CH:4]=1
Reactant: FC(F)(F)C(F)(I)C(F)(F)F
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)C(F)(C(F)(F)F)C(F)(F)F)cc1
Temperature: -10 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
Under protective gas, 27.3 g (0.16 mol) of p-methoxybenzoyl chloride and 53.3 g (0.18 mol) of perfluoroisopropyl iodide in 150 ml of CH2Cl2 are initially introduced into a round-bottomed flask. 45 g (0.18 mol) of phosphorous acid trisdiethylamide are metered in at about -20° C. during the course of 3 hours. The mixture is subsequently stirred at about -10° C. for 5 hours and, after warming, worked up analogously to Example 1. 37 g (76%) of 1-(4-methoxyphenyl)-2,3,3,3-tetrafluoro-2-trifluoromethylpropan-1-one of b.p. 97°-99° C./10 mbar are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:10]1.C1C(=O)N([Br:35])C(=O)C1>>[Br:35][CH2:20][C:13]1[NH:12][C:11]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2ncccc2F)=NC1c1ccc(Cl)cc1Cl
Product: CCOC(=O)C1=C(CBr)NC(c2ncccc2F)=NC1c1ccc(Cl)cc1Cl
Yield: 65 %

Procedure:
Ethyl 4-(2,4-dichlorophenyl)-2-(3-fluoropyridin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (3.14 g, 7.7 mmol) was reacted with NBS (1.51 g, 8.47 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (2.44 g, 65%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:22].[K+].[K+].O.[OH-].[Na+]>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)c2cccc(OCc3ccccc3)c2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(O)c2cccc(OCc3ccccc3)c2n1
Temperature: 140 °C
Yield: 80.9 %

Procedure:
To a mixture of 8-(benzyloxy)-4-chloro-2-methylquinoline (3.09 g, 10.9 mmol), potassium carbonate (3.22 g, 32.8 mmol) in DMSO (30 mL) was added water (1.00 mL) to dissolve the solid. The mixture was heated at 140° C. for 2 h and was added 2N NaOH (12 mL, 24.0 mmol) and heated at 130° C. overnight. The mixture was poured into ice/NaHCO3. Solid precipitated and was filtered, washed with water and dried to give 8-(benzyloxy)-2-methylquinolin-4-ol (2.34 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]3[N:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[C:25](O)(=[O:29])[CH2:26][CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:15]([C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])=[CH:24][CH:23]=3)[N:17]([CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:10]=2[N:11]=1)#[N:16]
Reactant: CCCC(=O)O
Reactant: CC(C)(C)Cn1c(Cc2ccc(N)cc2)cc2cnc(C#N)nc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(=O)Nc1ccc(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
To a solution of 6-(4-amino-benzyl)-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.3 mmol) in DMF (4 ml), butyric acid (0.36 mmol), water soluble carbodiimide (0.45 mmol) and 1-hydroxybenzotriazole hydrate (0.45 mmol) are added at 0° C. and then the reaction mixture is stirred at room temperature for 1 day. The reaction mixture is quenched with ammonium chloride and extracted with AcOEt. The organic layer is washed with brine, dried over sodium sulfate and evaporated in vacuo to give 129 mg of crude product. Purification of the residue by silica gel column chromatography affords the title compound in 96% yield. Rf=0.46 (n-hexane:AcOEt=1:1)
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>C1(C)C=CC=CC=1>[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([O:18][C:17](=[O:19])[CH2:16][C:13]1[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:15][CH:14]=1)=[O:23]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)OC(=O)Cc1ccc([N+](=O)[O-])cc1

Procedure:
Pyridine (14 g, 0.18 Mol) and 4-nitrophenylacetic acid (32 g, 0.18 Mol) were stirred in toluene (100 ml) whilst trimethylacetylchloride (21 g, 0.18 Mol) was added. The toluene was evaporated to yield 4-nitrophenylacetic-trimethylacetic anhydride. 3-Aminophenol (20 g, 0.18 Mol) was stirred in DMF (100 ml) and treated with the mixed anhydride and pyridine (14 g) in dimethylformamide (DMF) dropwise. The solution was diluted with water and the product isolated by filtration and dried (19 g, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:20]12([C:30](Cl)=[O:31])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>>[C:20]12([C:30]([N:10]3[CH2:11][CH:12]4[C:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)([CH2:13]4)[CH2:9]3)=[O:31])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Clc1ccc(C23CNCC2C3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(N1CC2CC2(c2ccc(Cl)cc2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
A sample of 19.35 g of 1-p-chlorophenyl-3-azabicyclo[3.1.0]hexane, 10.59 g of sodium carbonate and 19.87 g of 1-adamantanecarboxylic acid chloride are reacted in accordance with Example 36, yielding the product 3-(1-adamantylcarbonyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane as a white solid, mp 163°-165° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([I:13])[C:7]1=[O:14].C([O-])([O-])=O.[K+].[K+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=2)=[C:8]([I:13])[C:7]1=[O:14]
Reactant: Fc1ccc(CBr)cc1
Reactant: O=c1c(I)c(O)ccn1Cc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1c(I)c(OCc2ccc(F)cc2)ccn1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-(3-fluorobenzyl)-4-hydroxy-3-iodopyridin-2(1H)-one (0.5 g, 1.44 mmol) in DMF (5 mL) was added K2CO3 (0.199 g, 1.44 mmol) followed by the addition of 4-fluorobenzyl bromide (0.189 mL, 1.51 mmol). The reaction mixture stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate (50 mL) and washed with water. The organic extracts were dried over anhydrous Na2SO4 and concentrated to dryness. 1H-NMR (CD3OD, 400 MHz) δ 7.75 (d, 1H, J=7.6 Hz), 7.49 (q, 2H), 7.34 (q, 1H), 7.11 (m, 5H), 6.40 (d, 1H, J=7.6 Hz), 5.26 (s, 2H), 5.19 (s, -2H); ES-HRMS m/z 454.0098 (M+H calculated for C19H15NO2F2I requires 454.0110).
Reaction SMILES: [F:1][C:2]([F:25])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:3]1[N:7]2[N:8]=[C:9]([C:12](=O)[CH3:13])[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[NH2:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>CO>[F:1][C:2]([F:25])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:3]1[N:7]2[N:8]=[C:9](/[C:12](=[N:26]/[N:27]3[CH2:31][CH2:30][NH:29][C:28]3=[O:32])/[CH3:13])[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: NN1CCNC1=O
Reactant: CC(=O)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Solvent: CO
Product: C/C(=N\N1CCNC1=O)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Yield: 32.1 %

Procedure:
A solution of 1-(3-(difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (20 mg, 0.059 mmol) and 1-aminoimidazolidin-2-one (12 mg, 0.12 mmol) in MeOH was stirred at room temperature for overnight. Solvent was evaporated and the crude product was purified on flash chromatography (CH2Cl2:MeOH 9:1) to give the title compound as a white solid (8 mg, 32%). 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.98 (s, 1H), 8.52 (d, 1H), 8.43 (s, 1H), 8.26 (d, 2H), 8.19 (m, 1H), 8.06 (d, 1H), 7.66 (d, 1H), 3.55 (t, 2H), 3.38 (t, 2H), 2.30 (s, 3H). LCMS (method A): [MH]+=423.0, tR=4.63 min.
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].S(O)(O)(=O)=O.Cl[C:27]1[NH:28][CH2:29][CH2:30][N:31]=1>CC(O)C>[CH:1]([NH:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:27]3[NH:31][CH2:30][CH2:29][N:28]=3)=[CH:18][CH:19]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)N1CCC(Cc2ccc(N)cc2)CC1
Reactant: ClC1=NCCN1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)NC(=O)N1CCC(Cc2ccc(NC3=NCCN3)cc2)CC1
Yield: 59.2 %

Procedure:
A mixture of 4-(1-isopropylaminocarbonylpiperidin-4-ylmethyl)-phenylamine (0.64 g, 2.31 mmol) and 2-chloro-2-imidazoline sulfate (0.70 g, 3.47 mmol) in 2-propanol (20 mL) was heated under reflux for 30 minutes. The reaction mixture was concentrated in vacua. The residue was diluted with water, basified with 10% sodium hydroxide solution and extracted into dichloromethane. The organic layer was washed with water and brine, dried (Na2SO4), and concentrated in vacua. The crude product was chromatographed on neutral aluminum oxide, eluting with 5% methanol/dichloromethane, and crystallized from ethyl acetate containing some ethanol, to give 2-[4-(1-isopropylaminocarbonylpiperidin-4-ylmethyl)-phenyl]amino-imidazoline (0.47 g, 59%) as a white solid, m.p. 191-192° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])N.[CH3:10][S:11]SC.N(OC(C)(C)C)=O.O>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([S:11][CH3:10])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CSSC
Reactant: Cc1ccc(N)cc1F
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: ClCCCl
Product: CSc1ccc(C)c(F)c1
Reaction time: 2 h
Yield: 525.5 %

Procedure:
A mixture of 3-fluoro-4-methylaniline (25 g), dimethyl disulphide (375 g) and t-butyl nitrite (30 ml) in 1,2-dichloroethane was warmed to start the reaction. A solution of 3-fluoro-4-methylaniline (225 g) in 1,2-dichloroethane was added dropwise, simultaneously with t-butyl nitrite (241 ml) at such a rate as to maintain the temperature below 60° C. The mixture was stirred for 2 hours, then water was added. The organic layer was washed with water, hydrochloric acid, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was distilled to give 2-fluoro-4-(methylsulphenyl)toluene (164 g) as a yellow oil; NMR (acetone-d6); 2.2 (3H,d), 2.5 (3H,s), 7.05 (3H,m).
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]2[C:5]([NH:6][C:7]([CH3:17])([CH3:16])[C:8](=[O:15])[N:9]2[CH3:14])=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23](O)[CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[Br:1][C:2]1[C:11]([CH2:12][O:13][C:21]2[CH:20]=[C:19]([F:18])[CH:24]=[CH:23][C:22]=2[CH3:26])=[C:10]2[C:5]([NH:6][C:7]([CH3:17])([CH3:16])[C:8](=[O:15])[N:9]2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1O
Reactant: CN1C(=O)C(C)(C)Nc2ccc(Br)c(CO)c21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(F)cc1OCc1c(Br)ccc2c1N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
A mixture of 7-bromo-8-hydroxymethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 1, 805 mg, 2.69 mmol), 5-fluoro-2-methylphenol (382 μL, 3.50 mmol), and tri-n-butylphosphine (874 μL, 3.50 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), 1,1′-(azodicarbonyl)dipiperidine (883 mg, 3.50 mmol) was added thereto, and then the mixture was stirred at room temperature for 1 hour. 5-Fluoro-2-methylphenol (382 μL, 3.50 mmol), tri-n-butylphosphine (874 μL, 3.50 mmol), and 1,1′-(azodicarbonyl)dipiperidine (890 mg, 3.53 mmol) were added thereto and it was furthermore stirred for 20 minutes. After hexane (15 mL) was added to the reaction mixture and the precipitated solids were filtered out, the filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (900 mg) as a colorless solid. (Yield 82%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:33])[CH:10]([C:31]#[N:32])[C:11]([C:13]2[C:14]3[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:15]=3[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].N1C=CC=CC=1>CN(C)C=O>[C:34]([NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:33])[CH:10]([C:31]#[N:32])[C:11]([C:13]2[C:14]3[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:15]=3[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: N#CC(C(=O)Nc1cccc(N)c1)C(=O)c1nn(-c2ccccc2)c2c1Cc1ccccc1-2
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(NC(=O)C(C#N)C(=O)c2nn(-c3ccccc3)c3c2Cc2ccccc2-3)c1
Temperature: 0 °C

Procedure:
N-(3-Amino-phenyl)-2-cyano-3-(1,4-dihydro-1-phenyl-indeno [1,2-c]pyrazol-3-yl)-3-oxo-propanamide (1.8 g) dissolved in dimethylformamide (30 ml) is reacted with acetic anhydride (5 ml) in the presence of pyridine (5 ml) at 40° C. for 8 hours. The reaction mixture is diluted with ice water and the precipitate is filtered and washed with water crystallization from dimethylformamide gives 1.2 g of N-(3-acetylamino-phenyl) -2-cyano-3-(1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-yl)-3-oxo-propanamide.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]=[C:13]([CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH:19]=[CH2:20]>C(Cl)(Cl)Cl>[CH2:18]([O:17][CH2:16][CH2:15][CH2:14][C:13](=[O:12])[CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[CH:19]1[O:9][CH2:20]1
Reactant: C=CCOCCCC(=O)CCC(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)CCC(=O)CCCOCC1CO1
Yield: 78.8 %

Procedure:
A 1000-ml round bottom flask equipped with a magnetic stirrer and a dropping funnel was charged with 130 g (0.38 mol) of 50-% m-chloroperbenzoic acid and 450 ml of chloroform. The dropping funnel was charged with 36.10 g (0.18 mol) of allyl 4,7-dioxooctyl ether. The contents of the dropping funnel were added drop-wise to the flask within 1 hour. During the addition the contents of the flask were stirred and kept at about 0° C. by cooling with an external cooling bath. After additional stirring overnight, during which the mixture was allowed to adopt room temperature, the mixture was filtered. The filtrate was extracted with an equal volume of 10-% aqueous sodium hydroxide and with an equal volume of water, dried over magnesium sulphate and evaporated to dryness, leaving 30.4 g of 4,7-dioxooctyl glycidyl ether as a colourless oil. The structure was confirmed by 1H-NMR spectroscopy. The signals were assigned to the underlined hydrogen atoms (shifts relative to TMS, chloroform-d1 solvent): ##STR9##