Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]([Br:8])=[CH:6][N:7]=1.[C:9]12([C:19](Cl)=[O:20])[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1.C(OCC)(=O)C>[Br:8][C:5]1[S:4][C:3]([NH:2][C:19]([C:9]23[CH2:18][CH:13]4[CH2:12][CH:11]([CH2:17][CH:15]([CH2:14]4)[CH2:16]2)[CH2:10]3)=[O:20])=[N:7][CH:6]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1ncc(Br)s1
Agent: Br
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1ncc(Br)s1)C12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
A mixture of 2-amino-5-bromothiazole monohydrobromide (3.00 g, 11.5 mmol), 1-adamantanecarbonyl chloride (2.74 g, 13.8 mmol), 4-dimethylaminopyridine (1.10 g, 0.90 mmol) and triethylamine (3.20 mL, 23.0 mmol) in 100 mL of THF was stirred at 80° C. for 48 hours. The mixture was cooled to ambient temperature, diluted with 100 mL of ethyl acetate and washed with brine. The layers were separated and the aqueous phase was extracted twice with 50 mL of ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, 20% ethyl acetate:80% hexane) afforded 2.55 g of the title compound: 1H NMR (400 MHz, DMSO-d6) δ 1.67-1.72 (m, 6 H) 1.92 (d, J=2.8 Hz, 6 H) 1.97-2.04 (m, 3 H) 7.55 (s, 1 H) 11.50 (br m, 1 H); MS (DCI/NH3) m/z 341 (M)+, 343 (M+2)+.
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14]CN(C(C)C)C(C)C.C(Cl)(Cl)=S.[Cl:27][C:28]1[C:33]([Cl:34])=[CH:32][C:31]([NH2:35])=[C:30]([NH2:36])[CH:29]=1.CI>C(Cl)Cl.CCO>[Cl:27][C:28]1[C:33]([Cl:34])=[CH:32][C:31]2[NH:35][C:14]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:13][CH:12]=3)=[N:36][C:30]=2[CH:29]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: Nc1ccc(C2CCCCC2)cc1
Agent: S=C(Cl)Cl
Solvent: ClCCl
Solvent: CCO
Solvent: CI
Product: Clc1cc2nc(Nc3ccc(C4CCCCC4)cc3)[nH]c2cc1Cl
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 4-cyclohexylaniline (10 mmol, 1.75 g) and DIEA (21 mmol, 3.65 mL) in CH2Cl2 (10 mL) at 0° C. was added thiophosgene (10 mmol, 700 μL) dropwise. The solution was allowed to reach ambient temperature for 1 h, and 4,5-dichloro-1,2-phenylenediamine (10.5 mmol, 1.86 g) was added. The reaction mixture was heated to reflux for 2 h, then concentrated in vacuo. The residue was taken up in a solution of EtOH (5 mL) and MeI (20 mmol, 1.25 muL), heated at 40° C. for 16 h, and concentrated in vacuo. Flash chromatography on silica eluting with 18-25% EtOAc in hexanes afforded the product as a red solid. LC-MS (ESI, Method C): 3.47 min, m/z 360.2 (M+1).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1.[H-].[Na+].[F:16][C:17](I)([F:22])[C:18]([F:21])([F:20])[F:19].Cl>CN(C)C=O>[CH3:12][C:9]1([CH3:11])[CH:8]=[CH:7][C:6]2[CH:13]=[C:2]([S:1][C:17]([F:22])([F:16])[C:18]([F:21])([F:20])[F:19])[CH:3]=[CH:4][C:5]=2[O:10]1
Reactant: FC(F)(F)C(F)(F)I
Reactant: CC1(C)C=Cc2cc(S)ccc2O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C=Cc2cc(SC(F)(F)C(F)(F)F)ccc2O1
Reaction time: 0.25 h
Yield: 82 %

Procedure:
A solution of 1.463 g of 6-mercapto-2,2-dimethyl-2H-1-benzopyran (prepared as described in Preparation 6) in 15 ml of dimethylformamide was added dropwise, whilst ice-cooling, to a suspension of 0.366 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 15 ml of dimethylformamide under an atmosphere of nitrogen. After the reaction mixture had been stirred for 15 minutes, 5.53 g of perfluoroethyl iodide were added to it. The reaction mixture was then stirred whilst ice-cooling for 1 hour and then at room temperature for 2 hours. At the end of this time, the reaction mixture was poured into 150 ml of dilute aqueous hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of cyclohexane and ethyl acetate as the eluent, to afford 1.935 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:14][C:13](=[O:15])[CH2:12][C@@H:11]3[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[N:16]=1.[C:17](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:14]([CH3:17])[C:13](=[O:15])[CH2:12][C@@H:11]3[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[N:16]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1C[C@H]2CCCN2c2nc(Cl)ncc2N1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C[C@H]2CCCN2c2nc(Cl)ncc21
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a solution of 0.4 g (0.0017 mole) of (R)-9-chloro-2,3,3a,4-tetrahydro-1H,6H-6,8,10,10b-tetraaza-benzo[e]azulen-5-one (VI-102) in 10 mL of dimethylformamide was added 1.1 g (0.0034 mole) of cesium carbonate, followed by 0.32 mL (0.0051 mole) of iodomethane. After stirring overnight, the mixture was filtered and the filtrate concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with hexanes-ethyl acetate (40:60-0:100) gave 0.35 g of (R)-9-chloro-6-methyl-2,3,3a,4-tetrahydro-1H,6H-6,8,10,10b-tetraaza-benzo[e]azulen-5-one (VII-102) as a light yellow solid.
Reaction SMILES: [N:1]1([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:2]1[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[N:1]1([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:2]1[C:3]([N:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:4]
Reactant: CCOC(=O)CBr
Reactant: O=C(Nc1ccccc1)[C@H]1CCCCN1C(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN(C(=O)[C@H]1CCCCN1C(=O)OCc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
To a solution of Cbz-D-hPro-NHC6H5 (7.7 g, 22.8 mmol) in tetrahydrofuran (300 mL) was added ethyl bromoacetate (12.6 mL, 113.8 mmol). The solution was cooled to 0° C. and NaH 60% suspension (2 g, 50 mmol) was added in small portions over 20 minutes, with gas evolution. After gas evolution had ceased, the cold bath was left unattended and the mixture was allowed to warm slowly to room temperature. After 18 hours, 1N citric acid (50 mL) was added slowly with cooling. The mixture was partitioned between ethyl acetate (300 mL) and 1N citric acid (300 mL). The organic layer was washed twice with 1N citric acid (200 mL), twice with saturated aqueous NaHCO3, and twice with saturated aqueous sodium chloride solution. The ethyl acetate layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed over silica gel, eluting with a step gradient of hexanes through 50% ethyl acetate/hexanes. Fractions containing product (as judged by TLC) were combined and concentrated in vacuo to give a yellow oil (9.2 g, 96%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][N:6]1[C:15](=[O:16])[CH2:14][C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][C:7]1=[O:17].[ClH:18].[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>CCN(CC)CC>[OH2:5].[ClH:19].[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][O:5][N:6]3[C:15](=[O:16])[CH2:14][C:9]4([CH2:13][CH2:12][CH2:11][CH2:10]4)[CH2:8][C:7]3=[O:17])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][O:5][N:6]3[C:15](=[O:16])[CH2:14][C:9]4([CH2:13][CH2:12][CH2:11][CH2:10]4)[CH2:8][C:7]3=[O:17])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.[ClH:18]
Reactant: O=C1CC2(CCCC2)CC(=O)N1OCCCBr
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: O
Product: O=C1CC2(CCCC2)CC(=O)N1OCCCN1CCN(c2cccc(Cl)c2)CC1
Reaction time: 1 h

Procedure:
A solution of 8-(3-bromopropyloxy)-8-azaspiro[4.5]decan-7,9-dione (4.0 g) and 1-(3-chlorophenyl)piperazine hydrochloride (3.06 g) in 50 ml of Et3N was heated to reflux with stirring under N2. After 1 hour TLC (thin layer chromatography) showed the absence of starting material. The excess Et3N was removed in vacuo and the residue chromatographed on silica using ethyl acetate as the eluent. Fractions containing the desired product were combined and concentrated in vacuo.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].CN1CCN(C)CC1.[O:17]=[P:18](Cl)(Cl)Cl.[NH2:22][CH2:23][CH2:24][CH2:25][OH:26]>>[CH2:24]1[CH2:25][O:26][P:18]([N:5]([CH2:6][CH2:7][Cl:8])[CH2:4][CH2:3][Cl:2])(=[O:17])[NH:22][CH2:23]1
Reactant: NCCCO
Reactant: O=P(Cl)(Cl)Cl
Reactant: ClCCNCCCl
Agent: CN1CCN(C)CC1
Agent: Cl
Product: O=P1(N(CCCl)CCCl)NCCCO1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Bis(2-chloroethyl)amine hydrochloride (5 g, 0.028 mol) is put into a 100 mL two-necked flask, and N,N′-Dimethylpiperazine (7.1 eq) is added into the flask. After cooling the flask and the reactants therein to about 4° C., POCl3 (4.49 g, 1.04 eq) is slowly dropped into the flask, and the mixture in the flask is stirred at room temperature for 5 hours. After that, the mixture in the flask is cooled to about 4° C., and 3-aminopropanol (2.1 g, 1.0 eq) is slowly dropped into the flask for 3 hours. After adding 3-aminopropanol into the flask, the mixture in the flask is stirred at room temperature for 15 hours. (The conversion yield determined with HPLC is about 11.84%.)
Reaction SMILES: C1O[C:4]2([CH:8](OS(C)(=O)=O)[CH2:7][C:6]3([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)[N:5]2[CH3:20])[O:3]C1.[I-].[Na+].CC(C)=O.Cl>C(O)(=O)C.O>[CH3:20][N:5]1[C:6]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[CH2:7][CH2:8][C:4]1=[O:3]
Reactant: CN1C2(CCC(=O)CC2)CC(OS(C)(=O)=O)C12OCCO2
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CN1C(=O)CCC12CCC(=O)CC2
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-Mesyloxy-1-methyl-1-azaspiro[4.5]decane-2,8-dione ethylene ketal (1.28 g), sodium iodide (1.8 g) and acetone (20 mL) was refluxed with stirring for 90 min. The solvent was removed in vacuo and the residue was dissolved in methylene chloride and washed with water. After drying over magnesium sulfate the solvent was removed in vacuo. The residue was dissolved in toluene (20 mL) and treated with tri-n-butyltin hydride (1.75 g) and AIBN (20 mg) and the resulting mixture was heated at 110° C. for 1 h. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate as the eluent. The resulting produce was stirred with a mixture of water (5 mL), 3N HCl (1.5 mL) and acetic acid (2 mL) for 16 h. The resulting product was extracted 3 times with methylene chloride, washed with sodium bicarbonate solution, dried over magnesium sulfate and the solvent was removed in vacuo to afford 1 -Methyl-1-azaspiro[4.5]decane-2,8-dione as an oil.
Reaction SMILES: I[N:2]1[C:7]([OH:8])=[C:6]2[CH:9]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[N:11]=[C:5]2[N:4]=[CH:3]1.[C:19]([C:21]1[CH:40]=[CH:39][C:24]([C:25]([NH:27][C@H:28]([C:35]([O:37][CH3:38])=[O:36])[CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:26])=[CH:23][CH:22]=1)#[CH:20].C(N(CC)CC)C.O>CN(C)C=O.[Cu]I>[OH:8][C:7]1[N:2]([C:20]#[C:19][C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH:27][C@H:28]([C:35]([O:37][CH3:38])=[O:36])[CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:26])=[CH:39][CH:40]=2)[CH:3]=[N:4][C:5]2=[N:11][C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][C:6]=12
Reactant: C#Cc1ccc(C(=O)N[C@@H](CCC(=O)OC)C(=O)OC)cc1
Reactant: CC(C)(C)C(=O)Nc1cc2c(O)n(I)cnc-2n1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC[C@H](NC(=O)c1ccc(C#Cn2cnc3nc(NC(=O)C(C)(C)C)cc-3c2O)cc1)C(=O)OC
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a mixture of 3.6 g (10 mmol) of well-dried 3-iodo-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine in 40 mL of dimethylformamide are added 4.0 g (13.19 mmol) of dimethyl N-(4-ethynylbenzoyl)-L-glutamate, 0.38 g of copper (I) iodide, 3 mL of triethylamine, and 1.0 g of tetrakis-(triphenylphosphine)palladium. This mixture is stirred at ambient temperatures for two hours and then poured into 500 mL of water. The solid is collected by filtration, air dried, and then refluxed in 200 mL of methanol. The mixture is cooled and the solid collected by filtration, dissolved in two liters of 10% methanol in methylene chloride, and chromatographed over silica. Initial black bands are rechromatographed and the combined colorless bands from the first and second runs are evaporated to give 3.5 g of dimethyl N-[4-(4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidin-3-ylethynyl)benzoyl]-L-glutamate which can be purified further by recrystallization from 50% methanol in methylene chloride.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[C:13]1([NH:19][CH2:20]C(O)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:13]1([N:19]2[CH2:20][CH2:3][CH:2]3[CH:11]2[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=CCN(CC=O)C(=O)OCC
Reactant: O=C(O)CNc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CCN(c3ccccc3)C2C1

Procedure:
8.6 g (50 mmol) of ethyl N-allyl-N-(2-oxoethyl)-carbamate and 7.6 (50 mmol) of phenylglycine are heated under reflux overnight in 200 ml of toluene. The mixture is decanted from resinous material and concentrated, and the residue is distilled.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:27][N:28]([CH3:37])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][CH3:36])=[CH:31][CH:30]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:35]([C:32]3[CH:33]=[CH:34][C:29]([N:28]([CH3:27])[CH3:37])=[CH:30][CH:31]=3)[CH3:36])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CNc1ccc(N(C)C)cc1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(N(C)C(=O)Cn2c(-c3ccc(Cl)cc3)nc3cccnc32)cc1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) in dry dimethylformamide (75 ml) was cooled in an ice bath and oxalyl chloride (2.2 g, 0.0172 mole) was added dropwise, with stirring, under nitrogen. The reaction mixture was stirred at room temperature for 3.5 hours and then N,N,N'-trimethyl-1,4-benzenediamine (2.9 g, 0.0193 mole) was added dropwise. The reaction mixture was stirred at room temperature under nitrogen overnight, poured into 400 ml of ice water and made basic with triethylamine (6 ml). The resulting white solid was collected by filtration, dissolved in hot isopropyl alcohol, treated with charcoal, and filtered while hot. Water was added to the cloud point and upon cooling, a solid precipitated. The gray solid was collected by filtration and rinsed with water to yield 6.6 g (92%) of product. A 1.0-g sample was dried under high vacuum to give 0.6 g of title compound, mp 152°-155° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9](/[CH:10]=[CH:22]/[CH:23]=[O:24])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2cccs2)cc1
Product: O=C/C=C/c1ccc(-c2cccs2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(2-thienyl)benzaldehyde (prepared as described in J. Med. Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 215 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27].[NH:38]([C:42]1[S:43][CH:44]=[C:45]([CH2:47][S:48][CH2:49][CH2:50][NH2:51])[N:46]=1)[C:39]([NH2:41])=[NH:40]>>[NH:38]([C:42]1[S:43][CH:44]=[C:45]([CH2:47][S:48][CH2:49][CH2:50][NH:51][C:26]([NH:22][CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:8]([CH2:7][C:6]2[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH3:23])=[O:27])[N:46]=1)[C:39]([NH2:41])=[NH:40]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CN(CCN(C)CCCCN)c2ccccn2)cc1
Product: COc1ccc(CN(CCN(C)CCCCNC(=O)NCCSCc2csc(NC(=N)N)n2)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 63, using 0.54 g (1.58 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,4-butanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=600 ([M+H]+, 1), 121 (100); IR (KBr): 1599 cm-1 (C=O). For further analysis, a portion of the compound is converted into the picric acid salt and recrystallised from ethanol; m.p.: 104°-106° C. (ethanol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH2:15][CH2:16][OH:17])([O-:3])=[O:2].[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[Si:22]([O:17][CH2:16][CH2:15][NH:14][C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of the product of Step A (2.4 g, 9.6 mmol) and TBSCl (1.73 g, 11.5 mmol) in DMF (15 mL) was added imidazole (1.3 g, 19.2 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (100 mL), and washed with brine (30 mL×3) and dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluted with PE) to obtain the title compound (3.5 g, 100%) as yellow solid. 1H NMR (600 MHz, CDCl3) δ 8.56 (s, 1H), 8.50 (d, J=1.2 Hz, 1H), 7.63 (dd, J=9.0, 2.2 Hz, 1H), 7.00 (d, J=9.0 Hz, 1H), 4.02-3.87 (m, 2H), 3.52-3.48 (m, 2H), 0.94 (s, 9H), 0.13 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][CH:4]([SH:8])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)#[N:17]>C(#N)C.O>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][CH:4]([S:8][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([C:16]#[N:17])=[CH:19][CH:20]=2)[CH2:3]1
Reactant: CC1(C)CCCC(S)C1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC1(C)CCCC(SCc2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.1 %

Procedure:
To a solution of 3,3-dimethylcyclohexanethiol (0.6 g, 4.16 mmol) in acetonitrile (50 mL) add potassium carbonate (1.72 g, 12.48 mmol) and stir at room temperature for 10 min. Add 4-cyanobenzyl bromide (816 mg, 4.16 mmol) and stir the suspension for 18 h. Dilute with water (50 mL) and extract with EtOAc (50 mL). Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1) to obtain the desired intermediate as a clear oil (0.4 g, 37%).
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)(=O)C.CCCCCC>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: Ic1ccc2oc3ccccc3c2c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1ccc(Nc2ccc3oc4ccccc4c3c2)cc1

Procedure:
The Rf values of the object of the synthesis, 2-iododibenzofuran, and aniline were respectively 0.28, 0.59, and 0.07, which were found by silica gel thin layer chromatography (TLC) (ethyl acetate:hexane (1:10) as the developing solvent).
Reaction SMILES: [H-].[Na+].[CH3:3][SH:4].Br[C:6]1[C:13]([O:14][CH2:15][CH3:16])=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:17][CH2:18][CH3:19].Cl>CN(C=O)C>[CH2:18]([O:17][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:14][CH2:15][CH3:16])[C:6]=1[S:4][CH3:3])[CH:10]=[O:11])[CH3:19]
Reactant: CCOc1cc(C=O)cc(OCC)c1Br
Reactant: CS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc(OCC)c1SC
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
To a suspension of sodium hydride (2.62 g, 60.0 mmol, 2.0 equiv; 55% free-flowing powder moistened with oil) in DMF (50 mL) under Ar was added carefully methanethiol (2.88 g, 60.0 mmol, 2.0 equiv). After 15 min, a solution of 4-bromo-3,5-diethoxy-benzaldehyde (8.2 g, 30.0 mmol, 1.0 equiv; prepared according to S. P. Dudek, H. D. Sikes, C. E. D. Chidsey J. Am Chem. Soc. 2001, 123, 8033-8038) in DMF (30 mL) was added, and the reaction mixture stirred overnight. The mixture was acidified to pH 2 by addition of a solution of 1 M HCl and extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, the solvent removed by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with heptane/ethyl acetate (1:1) providing 6.9 g (96%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.50 (t, J=7.0 Hz, 6H), 2.50 (s, 3H), 4.18 (q, J=7.0 Hz, 4H), 7.02 (s, 2H), 9.88 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.66, 17.50, 64.88, 105.71, 122.00, 135.90, 159.54, 191.31. MS (ISP): 240.9 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:21])([C:14]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])=[O:15])[CH2:6][CH2:5]2.[O:23]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:23][C:7]([CH3:21])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:22])[C:14]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCO)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCCO)=C(C)C1=O
Yield: 83.5 %

Procedure:
Oxidation as described in protocol B, using 56.7 mg (0.184 mmol) of 6-hydroxy-N-(3-hydroxypropyl)-2,5,7,8-tetramethylchroman-2-carboxamide and 222 mg CAN (0.406 mmol) yielded 49.7 mg of 2-hydroxy-N-(3-hydroxypropyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid.