Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[I-].[Na+].[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[CH2:11]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[CH:26][C:27]([N:28]3[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]3)=[CH:29][CH:30]=2)[CH2:22][CH2:23]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClCCNCCCl
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(CN2CCN(c3ccc(N4CCNCC4)cc3)CC2)cc1
Reaction time: 13 h
Yield: 76.8 %

Procedure:
Bis(2-chloroethyl)amine hydrochloride (534 mg; 3.0 mmol) and sodium iodide (3.0 g; 20 mmol) were added to a solution in methanol (20 ml) of 4-(4-benzyl-1-piperazinyl)-aniline (1.1 g; 4.1 mmol) synthesized by the above process, and the mixture was stirred for 13 hours in a bath controlled at 70° C. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous solution of sodium hydrogencarbonate was added to the resultant concentrated residue to conduct extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 775 mg of impurity-containing 4-(4-benzyl-1-piperazinyl)-1-(1piperazinyl)benzene as an oil. Trimethylamine (0.3 ml; 2.2 mmol) and di-tert-butyl dicarbonate (450 mg; 2.1 mmol) were added to a solution of this oil (775 mg) in methylene chloride (5 ml) under ice cooling, and the mixture was stirred for 30 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture to conduct extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining crude crystals (738 mg; yield: 42%) of 4-(4-benzyl-1-piperazinyl)-1-(4-tert-butoxycarbonyl-1-piperazinyl)-benzene. The crude crystals were recrystallized from chloroform-diethyl ether-n-hexane to obtain colorless flakes (melting point: 132-133° C.).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH3:22])([CH2:15][CH2:16][CH2:17][CH:18]([CH3:21])[CH:19]=[CH2:20])[CH3:14])(=[O:11])[CH3:10].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](Cl)=[O:34]>C1COCC1>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](=[O:34])[CH2:10][C:9]([O:12][C:13]([CH3:22])([CH2:15][CH2:16][CH2:17][CH:18]([CH3:21])[CH:19]=[CH2:20])[CH3:14])=[O:11]
Reactant: C=CC(C)CCCC(C)(C)OC(C)=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)CCCC(C)(C)OC(=O)CC(=O)c1ccc2ccccc2c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide in the amount of (100.0 mL of a 2.0 M solution, 0.201 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is cooled to -78° C. 2,6-Dimethyl-7-octen-2-yl acetate in the amount of(18.75 g, 0.095 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min before being treated with a solution of 2-naphthoyl chloride in the amount of (17.00 g, 0.089 mol) dissolved in THF (25 mL) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (55 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 2% ethyl acetate dissolved in petroleum ether) to give an oil. Purity of the product is determined by thin layer chromatography and the structure confirmed by 1H and 13C NMR.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[C:20]([CH3:23])[N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[C:20]([CH3:23])[N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cccc(F)c3)c(=O)n12
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1csc2nc(C(C)N)c(-c3cccc(F)c3)c(=O)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a stirred solution of 7-(1-azidoethyl)-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.14 g, 0.42 mmol) (1st peak from chiral separation) in tetrahydrofuran (3 mL) and water (0.5 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.52 mL, 0.52 mmol), and the mixture was stirred at room temperature for 1 hour. To the mixtures were added ethyl acetate and the mixtures were extracted with aqueous 1 N HCl solution (three times). The combined extracts were neutralized with solid NaHCO3, and extracted with dichloromethane (three times). The combined organic layers were washed with brine, dried over MgSO4, and concentrated to give the crude product (0.125 g) used directly in next step. LCMS calculated for C15H15FN3OS (M+H)+: m/z=304.1. Found: 304.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:20]([CH2:21][C:22]3[O:23][C:24]([CH2:27][O:28][Si](C(C)(C)C)(C)C)=[CH:25][CH:26]=3)[C:19]3[CH:36]=[CH:37][CH:38]=[CH:39][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[F-].[NH4+].O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([C:16]2[N:20]([CH2:21][C:22]3[O:23][C:24]([CH2:27][OH:28])=[CH:25][CH:26]=3)[C:19]3[CH:36]=[CH:37][CH:38]=[CH:39][C:18]=3[N:17]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2Cc2ccc(CO[Si](C)(C)C(C)(C)C)o2)CC1
Agent: [F-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2Cc2ccc(CO)o2)CC1
Reaction time: 20 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(5-(t-butyldimethylsilyloxy)methylfur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine (7 mmol) and methanol (40 mL). Add ammonium fluoride (42 mmol). Heat to reflux. After 20 hours, concentrate in vacuo to give a residue. Combine the residue with water and dichloromethane. Separate the layers and extract the aqueous layer twice with dichloromethane. Combine the organic layers and dry over Na2SO4, filter, and concentrate in vacuo to give 1-(t-butoxycarbonyl)-4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]1[N:11]=[CH:10][N:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[C:19](=[CH:24]\[O:25][CH3:26])/[C:20]([O:22][CH3:23])=[O:21])[CH:7]=1.O>CN(C=O)C>[N:1]([C:6]1[N:11]=[CH:10][N:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[C:19](=[CH:24]\[O:25][CH3:26])/[C:20]([O:22][CH3:23])=[O:21])[CH:7]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(N=[N+]=[N-])ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Sodium azide (0.25 g) was added to a solution of (E)-methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (1.0 g) in DMF (30 ml). The reaction mixture was stirred for 2 hours at room temperature, then for 6 hours at 50° C. After cooling, the reaction mixture was poured into water and extracted with ether (3×100 ml). The combined extracts were washed with brine, dried and concentrated to give (E)-methyl 2-[2-(6-azidopyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (1.02 g, 99%) as an oil; 1H NHR: δ 3.51 (3H, s), 3.65 (3H, s), 6.12 (1H, s), 7.0-7.35 (4H, m), 7.37 (1H, s), mass 8.47 (1H, s) ppm; IR maxima (film): 2135, 1711, 1635 cm−1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[C:9]([CH3:17])=[CH:10][CH:11]=[CH:12][C:13]=1[CH:14](O)[CH3:15])=[O:7].S(Cl)([Cl:20])=O>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[C:9]([CH3:17])=[CH:10][CH:11]=[CH:12][C:13]=1[CH:14]([Cl:20])[CH3:15])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(C(C)O)c1C(=O)c1cccs1
Solvent: c1ccccc1
Product: Cc1cccc(C(C)Cl)c1C(=O)c1cccs1

Procedure:
A mixture of 14.7 parts of 3-(1-hydroxyethyl)-o-tolyl 2-thienyl ketone and 126 parts of benzene is stirred while cooling on an ice-bath. Then 9.5 parts of thionyl chloride are added and the whole is stirred further over week-end at room temperature. The reaction mixture is evaporated in vacuo, yielding 3-(1-chloroethyl)-o-tolyl 2-thienyl ketone as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:24][CH2:25][O:26][CH3:27])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[CH2:28][CH2:29][CH3:30])=[CH:4][C:3]=1[CH2:31]O.[CH3:33][C:34]1([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH:48]([CH3:50])[CH3:49])=[CH:43][CH:42]=2)[NH:38][C:37](=[O:39])[NH:36][C:35]1=[O:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O1CCCC1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:24][CH2:25][O:26][CH3:27])([C:16]([F:17])([F:18])[F:19])[C:20]([F:23])([F:22])[F:21])=[CH:11][C:10]=2[CH2:28][CH2:29][CH3:30])=[CH:4][C:3]=1[CH2:31][N:36]1[C:35](=[O:40])[C:34]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH:48]([CH3:50])[CH3:49])=[CH:43][CH:42]=2)([CH3:33])[NH:38][C:37]1=[O:39]
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(Cl)c(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(Cl)c(CN2C(=O)NC(C)(c3ccc(OC(C)C)cc3)C2=O)c1
Yield: 50 %

Procedure:
(2-Chloro-5-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy) phenyl)methanol (10 mg, 0.0212 mmol), 5-methyl-5-(4-(1-methylethoxy)phenyl)imidazolidine-2,4-dione (16 mg, 0.0635 mmol) and triphenylphosphine (16 mg, 0.0635 mmol) were added and dried in vacuo. N, N-dimethylformamide (300 μL) was added, and under ice-cold conditions, a solution of diethyl azodicarboxylate in tetrahydrofuran (29 μL, 0.0635 mmol) was added. The resultant mixture was stirred at room temperature for 4 hours. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using preparative thin-layer chromatography (hexane/ethyl acetate). 3-(2-Chloro-5-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy) benzyl)-5-(4-(1-methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione (7.6 mg, yield >100%) was obtained as a yellow oil.
Reaction SMILES: C(C1C=CC=CC=1N[C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=O)C.[CH3:21][C:22](C)([O-:24])[CH3:23].[K+].[NH4+:27].[Cl-]>C(O)(C)(C)C>[NH2:27][C:16]1[CH:17]=[CH:12][CH:13]=[CH:14][C:21]=1[C:22](=[O:24])[CH2:23][C:11]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)=[O:20]
Reactant: COc1ccc(C(=O)Nc2ccccc2C(C)=O)cc1
Reactant: CC(C)(C)[O-]
Reactant: [NH4+]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COc1ccc(C(=O)CC(=O)c2ccccc2N)cc1
Temperature: 70 °C
Yield: 49 %

Procedure:
To a suspension of N-(2-acetylphenyl)-4-methoxybenzamide (0.865 g, 3.2 mmol) in t-butanol (12 mL), was added potassium t-butoxide (1.57 g, 12.8 mmol). The reaction mixture was heated at 70° C. for 24 h under N2, The mixture was cooled to rt and poured into 30 mL of saturated NH4Cl. The solids were collected and purified by column chromatography using 10% MeOH in DCM to give 398 mg of 1-(2-amino-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (49%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[OH:14].[CH2:15]([C@H:20]1[CH2:25][CH2:24][C@H:23]([CH2:26]Br)[CH2:22][CH2:21]1)[CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:10]([O:9][C:6]1[CH:5]=[CH:4][C:3]([O:14][CH2:26][C@H:23]2[CH2:24][CH2:25][C@H:20]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:21][CH2:22]2)=[C:2]([F:1])[C:7]=1[F:8])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCOc1ccc(O)c(F)c1F
Reactant: CCCCC[C@H]1CC[C@H](CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC[C@H]1CC[C@H](COc2ccc(OCCCC)c(F)c2F)CC1

Procedure:
0.1 mol of 2,3-difluoro-4-butoxyphenol, 0.11 mol of trans-4-pentylcyclohexylmethyl bromide and 0.11 mol of potassium carbonate are heated at 100° in 100 ml of dimethylformamide (DMF) for 16 hours. After cooling, the inorganic salts are filtered off with suction, the filtrate is concentrated and water is added. Extraction with methylene chloride gives 1-butoxy-2,3-difluoro-4-(trans-4-pentylcyclohexylmethoxy)benzene.
Reaction SMILES: [CH2:1]=O.[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[NH2:10][C:11]1[C:16]2=[C:17]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][N:37]=4)=[O:34])=[CH:28][CH:27]=3)[C:18]([C:20]([N:22]([O:24][CH3:25])[CH3:23])=[O:21])=[CH:19][N:15]2[N:14]=[CH:13][N:12]=1>CC(O)=O>[NH2:10][C:11]1[C:16]2=[C:17]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][N:37]=4)=[O:34])=[CH:28][CH:27]=3)[C:18]([C:20]([N:22]([O:24][CH3:25])[CH3:23])=[O:21])=[C:19]([CH2:3][N:4]3[CH2:9][CH2:8][N:7]([CH3:1])[CH2:6][CH2:5]3)[N:15]2[N:14]=[CH:13][N:12]=1
Reactant: C=O
Reactant: CN1CCNCC1
Reactant: CON(C)C(=O)c1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccn2)cc1
Solvent: CC(=O)O
Product: CON(C)C(=O)c1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)ncnn2c1CN1CCN(C)CC1
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A solution of formaldehyde (0.22 mL, 3.0 mmol, 37% in H2O) and 1-methylpiperazine (0.33 mL, 3.0 mmol) in AcOH (0.5 mL) was added to a stirring solution of 4-amino-N-methoxy-N-methyl-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}-carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide (150 mg, 0.30 mmol) in AcOH (1.5 mL) at 80° C. The reaction was allowed to stir overnight until all starting material had been consumed as shown by HPLC (15 hrs). The reaction mixture was worked up by diluting with EtOAc and washing 1× with saturated sodium carbonate solution, 1× with saturated sodium bicarbonate solution, and 1× with brine. The organic layer was dried over Na2SO4 and concentrated to a brown powder. The crude product was purified by HPLC (10-70% ACN/H2O) to yield 100 mg (0.16 mmol, 54.5%) of the title compound. 1H-NMR (DMSO-d6). δ 10.02 (s, 1H), 9.89 (s, 1H), 8.59 (d, J=5.4 Hz, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.42-7.37 (m, 3H), 3.87 (s, 2H), 2.51-2.38 (m, 4H), 2.35-2.20 (m, 4H), 2.14 (s, 3H). MS [M+H]+=613; LCMS RT=2.37 min.
Reaction SMILES: I[C:2]1[CH:13]=[C:12]([CH3:14])[C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[C:15]([Cu])#[N:16]>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][C:12]1[C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=[C:2]([C:15]#[N:16])[CH:13]=1
Reactant: N#C[Cu]
Reactant: Cc1cc(I)cc2c(=O)oc(=O)[nH]c12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc2c(=O)oc(=O)[nH]c12
Yield: 61.2 %

Procedure:
600 mg (1.98 mmol) 6-iodo-8-methyl-1H-benzo[d][1,3]oxa zine-2,4-dione (prepared according to known procedures, see G. M. Coppola, Synthesis, 1980, 505), 212 mg (2.37 mmol) CuCN, 377 mg (1.98 mmol) Cul and 114 mg tetrakis(triphenylphosphine) palladium in 60 ml THF are heated 5 h at reflux. After cooling down, the mixture is filtered on Hyflo. The organic phase is washed with water and evaporated. The residue is crystallized from a mixture of dichloromethane, ethyl acetate and hexane to afford 245 mg 8-methyl-2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carbonitrile, which is directly used in the next step.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].CS[C:17](=[N:20][N+:21]([O-:23])=[O:22])[NH:18][CH3:19]>CO>[CH3:19][NH:18][C:17]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[S:6][CH:7]=1)=[N:20][N+:21]([O-:23])=[O:22]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: CNC(=N[N+](=O)[O-])SC
Solvent: CO
Product: CNC(=N[N+](=O)[O-])NCCSCc1csc(CN(C)C)n1

Procedure:
A reaction mixture was prepared containing 1.2 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine, 0.77 g. of S-methyl-N-methyl-N'-nitroisothiourea and 10 ml. of methanol. The reaction mixture was heated under reflux for 4.25 hours, after which time the solvent was removed by evaporation. The partially solid residue was chromatographed over silica using a gradient elution technique employing ethyl acetate containing increasing quantities of methanol as the eluant. Fractions shown by tlc to contain N-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-nitroguanidine formed in the above reaction were pooled and the solvent removed from the pooled fractions. Trituration of the resulting residue with ether yielded a crystalline solid which, upon recrystallization from a methanol-ethyl acetate solvent mixture, yielded 0.83 g. of crystals melting at about 86.5°-88° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.Cl[CH2:32][C:33](=[O:40])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].Cl>O1CCCC1.C(O)(C)C>[CH2:38]([O:37][C:35]([CH2:34][C:33]([CH2:32][O:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:10][CH2:11]1)=[O:40])=[O:36])[CH3:39]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: OCCN1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOC(=O)CC(=O)COCCN1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.9 g of Sodium hydride was added to 15 ml of dry tetrahydrofuran stirring at room temperature under nitrogen. A solution of 1-(2-hydroxyethyl)-4-triphenylmethylpiperazine in 5 ml of dry tetrahydrofuran was added dropwise and then stirred a further 1 hour after the addition was complete. Finally, a solution of 1.8 g of ethyl 4-chloroacetoacetate in 5 ml of dry tetrahydrofuran was added over 1 hour and the mixture stirred at room temperature for 18 hours. 5 Drops of isopropanol were added to the mixture which was then poured onto 100 g of ice and carefully neutralised with concentrated hydrochloric acid. After extraction with ethyl acetate, the residual oil was dissolved in acetonitrile, washed three times with petroleum ether (40°-60°) and evaporated to give 2.6 g of 1-[2-(ethoxycarbonylacetylmethoxy)ethyl]-4-triphenylmethylpiperazine as an orange-red oil, used directly.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)=[N+:13]=[N-:14]>>[ClH:1].[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[CH2:15][N:12]1[CH:5]=[C:4]([CH2:3][CH2:2][C:6]2[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=2)[N:14]=[N:13]1
Reactant: [N-]=[N+]=NCc1ccco1
Reactant: C#CCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCc2cn(Cc3ccco3)nn2)c[nH]1
Yield: 72.3 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.068 g, 0.399 mmol) was reacted with 2-azidomethyl furan (0.059 g, 0.478 mmol) following the general procedure for click reactions outlined above to produce 4-[2-(1-Furan-2-ylmethyl-1H-[1,2,3]triazol-4-yl)-ethyl]-1H-imidazol-2-ylamine hydrochloride (0.085 g, 72%) of a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.06 (s, 1H), δ 7.53 (s, 1H), δ 6.59 (t, 1H), δ 6.49 (s, 1H), δ 6.44 (dd, 1H), δ 3.05 (t, 2H), δ 2.89 (t, 2H) ppm; 13C (75 MHz, CD3OD) δ 156.4, 154.9, 147.5, 144.1, 126.0, 125.1, 123.8, 110.7, 109.3, 69.8, 23.8, 17.4 ppm; HRMS (ESI) calcd for C12H14N6O (M+) 259.1301, found 259.1305.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[Cl:10][CH2:11][C:12](Cl)=[O:13]>O>[Cl:10][CH2:11][C:12]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:13]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CCl)Nc1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-aminopyridine (350 mg) and sodium hydroxide (0.6 g) were dissolved in water (8 mL) and the reaction mixture was cooled in an ice bath. Chloroacetyl chloride (1.19 mL) was added dropwise and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was extracted with dichloromethane and organic layer was concentrated and purified by column chromatography, eluting with 0-60% ethyl acetate/cyclohexane to give the title compound (0.10 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Cl:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[CH:4][CH:3]=1.[F:21][C:22]([F:27])([F:26])[S:23]([O-])=O.[Na+].S(C1C=CC(C)=CC=1)(O)(=O)=O.CNC.S(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Cl:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[CH:4][C:3]=1[S:23][C:22]([F:27])([F:26])[F:21]
Reactant: O=S([O-])C(F)(F)F
Reactant: Nc1ccnn1-c1cc2c(cc1Cl)C(F)(F)OC2(F)F
Agent: CNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1c(SC(F)(F)F)cnn1-c1cc2c(cc1Cl)C(F)(F)OC2(F)F
Temperature: 55 °C
Yield: 38.6 %

Procedure:
To a suspension wherein 5-amino-1-(6-chloro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)pyrazole (391 mg, 1.27 mmol), sodium trifluromethanesulfinate (397 mg, 2.54 mmol) and dimethylamine tosylate (690 mg, 3.17 mmol) are in toluene (4 ml), thionyl chloride (302 mg, 2.54 mmol) was added dropwise under ice cooling over a period of about 10 minutes and then stirred under heating at 50 to 60° C. for 14 hours. After allowing to cool, the reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give 200 mg of 5-amino-1-(6-chloro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)-4-trifluoromethylsulfenylpyrazole.