Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH:13]1[C:18]2[CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH2:23][C:17]=2[CH:16]=[CH:15][CH:14]=1.[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36](CBr)=[CH:35][C:34]=1[N+:41]([O-:43])=[O:42])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH2:25]([O:32][C:33]1[CH:38]=[C:37]([CH:36]=[CH:35][C:34]=1[N+:41]([O-:43])=[O:42])[CH2:1][CH:23]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:18]=2[CH2:19][CH2:20][CH2:21][C:22]1=[O:24])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C1CCCc2ccccc2C1
Reactant: CC(C)NC(C)C
Reactant: O=[N+]([O-])c1cc(CBr)ccc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1CCCc2ccccc2C1Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of diisopropylamine (0.31 mL, 2.19 mmol) in THF (5 mL) at 0° C. is added n-butyllithium (1.6 M in hexane, 1.37 mL, 2.19 mmol) dropwise and the solution is stirred at 0° C. for 20 min then is cooled to −78° C. To this is added a solution of 5,7,8,9-tetrahydrobenzocyclohepten-6-one (J. Med. Chem. 40, 3516 (1997)) (350 mg, 2.19 mmol) in 2 THF is added dropwise. After one hour, a solution of 1-benzyloxy-4-bromomethyl-2-nitrobenzene (705 mg, 2.19 mmol) in THF (2 mL) is added dropwise and the mixture is allowed to warm to RT overnight. The mixture is quenched with saturated NaHCO3 and the solution is extracted with EtOAc. The organic layer is washed with water, brined and dried over MgSO4. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of 25-75% hexane/CH2Cl2 to give the title compound as a yellow liquid. 1H NMR (CDCl3): 7.72-7.70 (d, J=8.08 Hz, 1H), 7.42-7.11 (m, 8H), 6.92-6.90 (dd, J=1.27 Hz, 8.08 Hz, 1 H), 6.73-6.72 (m, 2H), 5.05-5.04 (d, J=2.78 Hz, 2H), 4.0-3.96 (t, J=7.08 Hz, 1H), 3.57-3.51 (q, J=7.58 Hz, 1H), 3.05-3.01 (q, J=6.06 Hz, 1H), 2.87-2.81 (m, 1H), 2.65-2.58 (m, 1H), 2.55-2.47 (m, 1H), 2.42-2.37 (m, 1H), 2.05-1.95 (m, 1H), 1.92-1.83 (m, 1H). (M−1)−=400.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][C:12]1[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][C:13]=1[NH2:20].[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>O1CCCC1.O>[CH3:11][C:12]1[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][C:13]=1[NH:20][C:28](=[O:29])[CH2:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1sc(C(=O)O)cc1N
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1sc(C(=O)O)cc1NC(=O)Cc1ccccc1
Reaction time: 24 h
Yield: 77.8 %

Procedure:
Diisopropylethylamine (3.33 g, 25.8 mmol) was added to a stirred suspension of 5-methyl-4-amino-thiophene-2-carboxylic acid hydrochloride (1.4 g, 7.0 mmol) in tetrahydrofuran (25 mL) under an inert atmosphere at room temperature. After 1½ hours, phenylacetyl chloride (1.1 g, 7.2 mmol) was added. After 24 hours, the mixture was diluted with water (200 mL) and acidified with dilute aqueous hydrochloric acid. After 12 hours the precipitate was filtered off, rinsed with water, and dried to afford 1.5 g of 5-methyl-4-phenylacetylamino-thiophene-2-carboxylic acid. Recrystallization of a sample from acetonitrile gave product with a mp 249-250° C.
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[C:11]([O-:14])(=[O:13])[CH3:12].[K+].CS(C)=O>O>[C:11]([O:14][CH:3]([CH:1]=[CH2:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)[O-]
Reactant: C=CC(Cl)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=CC(OC(C)=O)c1ccccc1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
In a one liter 3-neck round bottom flask equipped with a condenser, mechanical stirrer and thermometer, 108 grams (0.708 mol) of vinylbenzyl chloride (60/40 m-/p-) and 808 grams (0.815 mol) of potassium acetate were added, followed by 250 mLs of DMSO. The mixture was stirred at 40° C. for 48 hours. After allowing to cool to room temperature, the mixture was diluted with water and poured into a separatory funnel. The organic layer was separated, followed by an extraction of the aqueous layer with chloroform. The combined organic layer was then washed with water, dried over magnesium sulfate and placed on the rotary evaporator to remove the chloroform. 120 grams of the vinylbenzyl acetate product was recovered, to which 10 mg of MEHQ was added as an inhibitor.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][CH2:13][Cl:14])[CH2:9][N:8]([CH3:15])[C:7](=O)[C:6]=2[CH:17]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].[S-2].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][CH2:13][Cl:14])[CH2:9][N:8]([CH3:15])[C:7](=[S:19])[C:6]=2[CH:17]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1CC(CCCl)Oc2ccc(Cl)cc2C1=O
Agent: [K+]
Agent: [S-2]
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ccc(Cl)cc2C1=S
Yield: 86.1 %

Procedure:
To a solution of 20 g (0.07 mole) of 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one in 200 ml of toluene was added a mixture of 9.55 g (0.05 mole) of phosphorus pentasulfide and 9.5 g of potassium sulfide which had been ground together. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give a yellow solid. Recrystallization from absolute ethanol gave 12.5 g (68%) of the product, m.p. 102°-104° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21]OS(C)(=O)=O)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)CO.O1CCCC1.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH:20]=[CH2:21])[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=Cn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
4-(1-Vinyl-1H-benzoimidazol-2-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester is the major product obtained from an alternative synthesis of 1-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)-[1,4]diazepane (Preparation 44.2). Treat a stirred solution of 1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-yl)-[1,4]diazepane (1.21 g, 2.77 mmol, Preparation 9), 2,2,2-trifluoroethanol (2.75 g, 27.4 numol, Aldrich Chemical Company), anhydrous tetrahydrofuran (20 mL) and dimethylformamide (2 mL) at 0-5° C. with sodium hydride (0.44 g, 11 mmol, 60% oil dispersion) under an argon atmosphere. Stir overnight at room temperature, heat at 50° C. for four hours, and stir at room temperature for two hours. Cool to 0° C., quench by addition of saturated ammonium chloride solution (5 mL) and concentrate in vacuo. Dissolve the residue in ethyl acetate (100 mL), wash with water (2×20 mL) and brine (20 mL), dry (Na2SO4) the organic phase, filter and concentrate to afford an oil. Purify the oil by flash chromatography (silica gel, 7×15 cm, ethyl acetate) to afford 0.97 g of 4-(1-vinyl-1H-benzoimidazol-2-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester as an oil, Rf=0.52 (silica gel, ethyl acetate).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8]CC)=[O:7])C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH2:23][CH2:22][CH2:21]2.[OH-].[Na+].C>O>[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:25]3[N:24]([CH:4]=[C:5]([C:6]([OH:8])=[O:7])[C:11]2=[O:13])[CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=1
Reactant: COc1ccc2c(c1)CCCN2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c3c(c1)c(=O)c(C(=O)O)cn3CCC2
Temperature: 220 °C

Procedure:
Diethyl ethoxymethylenemalonate (43.2 g., 0.20 mole) and 6-methoxytetrahydroquinoline (32.6 g., 0.20 mole) are mixed and heated at 125°-130° C. for 3 hours. Polyphosphoric acid (200 g.) is added, and the mixture is heated gradually to 220° C. then maintained at 220° C. for 1 hour. The mixture containing the product ester of Formula III is poured into about 600 ml. of water, then made basic with 40 percent sodium hydroxide solution and heated on a steam bath for 2 hours. The solution is treated with decolorizing charcoal, filtered and acidified. The solid product is isolated by filtration, washed with water and ethanol, then recrystallized from N,N-dimethylformamide to give 6,7-dihydro-9-methoxy-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 253°-257° C.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[N:35]=[C:34]([NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([CH:43]=O)=[CH:32][CH:31]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[N:35]=[C:34]([NH:36][C:37](=[O:42])[C:38]([CH3:39])([CH3:40])[CH3:41])[C:33]([CH:43]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:32][CH:31]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)C(=O)Nc1nc(OCCCCOCc2ccccc2)ccc1C=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccc(OCCCCOCc2ccccc2)nc1NC(=O)C(C)(C)C
Temperature: 25 °C
Yield: 51.6 %

Procedure:
Under N2, an ice-cooled flask containing THF (100 mL) was charged with sodium hydride (5.7 g, 142.5 mmol) to which ethyl 2-(diethoxyphosphoryl)acetate (32 g, 142 mmol) was added. The ice bath was removed and a solution of intermediate 7 (21.8 g, 56.7 mmol) in THF (120 mL) was slowly added to the preformed anion. The reaction was heated to reflux overnight. The reaction mixture was cooled to rt and partitioned between EtOAc and water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give ethyl 3-(6-(4-(benzyloxy)butoxy)-2-pivalamidopyridin-3-yl)acrylate (intermediate 8) (13.3 g, 52%) as a white solid. mp: 75-76° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([N:11]=[C:12]=[O:13])[CH3:10].O>CN1CCCC1=O>[CH2:9]([NH:11][C:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)=[O:13])[CH3:10]
Reactant: Nc1ccc(O)cc1
Reactant: CCN=C=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CCNC(=O)Nc1ccc(O)cc1
Reaction time: 2 h
Yield: 55 %

Procedure:
10 g of 4-aminophenol (Mw=109.13; 0.0916 mol) are suspended in 100 cm3 of anhydrous N-methylpyrrolidone, under an inert atmosphere. 6.5 g of ethyl isocyanate (Mw=71.08; 0.0914 mol) are then added dropwise. The reaction mixture is brought to a temperature of 60° C. with stirring for two hours. The mixture is poured into one litre of water and the precipitate is then filtered off and dried. After recrystallization from ethanol, 9 g of a white powder are obtained, which corresponds to a yield of 55%. The melting point of the product obtained is 173.4° C. The 200 MHz 1H NMR spectrum and the elemental analysis are in accordance with the expected product.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][NH:14][C:13](=S)[C@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1.[NH2:25][CH2:26][C:27](=O)[C:28]([CH3:31])([CH3:30])[CH3:29].C(N(CC)CC)C>C(O)C.[Hg](Cl)Cl>[C:28]([C:27]1[N:14]2[CH2:15][C@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH2:10][CH2:11][C@@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]2=[N:25][CH:26]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Reactant: CC(C)(C)C(=O)CN
Agent: Cl[Hg]Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(C)(C)C)cnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 119.2 %

Procedure:
Mercury(II) chloride (10 mg, 0.036 mmol) was added to a solution of tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-2-thioxoazepan-3-yl]carbamate (10 mg, 0.028 mmol), hydrobromide salt of 1-amino-3,3-dimethylbutan-2-one (11 mg, 0.056 mmol), and triethylamine (10 μL, 0.07 mmol) in ethanol (1 mL) at 70° C. After 18 h, the reaction was allowed to cool to ambient temperature. The mixture was filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound (14 mg). MS 420.2 (M+1).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2([C:20]([OH:22])=O)[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1>C1COCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2([C:20]([Cl:4])=[O:22])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: O=C(Cl)C1(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (291 mL) was added slowly to a cooled (approximately 5° C.) solution of 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid in THF at a rate such that the batch temperature did not exceed 10° C. When the addition was complete, the batch was allowed to warm to ambient temperature and held with stirring for approximately 2 hours, at which time in process HPLC analysis indicated the reaction was complete. The solution was used in the next step without further processing.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[C:4]([OH:6])=O.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[C:17]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[CH:20][CH:19]=1)#[N:16]
Reactant: COC(C(=O)O)c1cccc([N+](=O)[O-])c1
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1cccc([N+](=O)[O-])c1

Procedure:
(RS)-Methoxy-(3-nitro-phenyl)-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-(3-nitro-phenyl)-acetamide. Light yellow gum.
Reaction SMILES: C(ON=O)(C)(C)C.[I:8]I.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[CH:19][C:20](N)=[N:21][CH:22]=2)=[CH:13][CH:12]=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[N:21][C:20]([I:8])=[CH:19][N:18]=2)=[CH:13][CH:12]=1
Reactant: Nc1cnc(-c2ccc(Cl)cc2)cn1
Reactant: II
Agent: CC(C)(C)ON=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(-c2cnc(I)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With the exclusion of light, 4.9 mL (40.0 mmol) tert-butylnitrite and 7.6 g (30 mmol) iodine are added to a solution of 4.8 g (23.3 mmol) 5-(4-chloro-phenyl)-pyrazin-2-ylamine in 100 mL CCl4 and 50 mL DCM and the reaction mixture is stirred overnight at RT. It is combined with 100 mL water and 50 mL 10% Na2S2O3 solution, the organic phase is separated off, washed again with 50 mL 10% Na2S2O3 solution and twice with 50 mL water and dried over MgSO4. It is filtered through activated charcoal, evaporated down i.vac. and the residue is purified by chromatography (silica gel, gradient: PE to PE/EtOAc 8:2).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=O)=[CH:6][C:5]=1[O:14][CH2:15][CH2:16][CH2:17][O:18]C1CCCCO1)[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=S)[CH:29]=[CH:30][CH:31]=1.C[Si](C)(C)[Si](C)(C)C.[Li].[NH2:44][NH2:45].C(O)(=O)C>C(OCC)(=O)C.C1COCC1>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C:9]3[C:10]2=[N:44][NH:45][C:33]=3[NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=2)=[CH:6][C:5]=1[O:14][CH2:15][CH2:16][CH2:17][OH:18])[CH3:2]
Reactant: NN
Reactant: CCOc1cc2c(cc1OCCCOC1CCCCO1)CCC2=O
Reactant: Fc1cccc(N=C=S)c1
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOc1cc2c(cc1OCCCO)Cc1c-2n[nH]c1Nc1cccc(F)c1

Procedure:
To a mixture of 6-Ethoxy-5-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-indan-1-one (Intermediate AA) (0.100 g, 0.0003 mol), 3-fluorophenyl isothiocyanate (Compound 4a) (0.043 mL, 0.00036 mol) and THF (3 mL) was added lithium hexamethyldisilane (0.360 mL, 0.00036 mol) dropwise at room temperature with stirring. The reaction mixture was stirred for 48 h. Hydrazine (0.011 mL, 0.00036 mol) and acetic acid (0.021 mL, 0.00036 mol) was added to the reaction mixture, which was then heated at reflux temperature for 12 h. The reaction solution was then diluted with ethyl acetate, washed with water and dried over MgSO4. The solvent was removed in vacuo and the crude material was purified on the reverse phase HPLC and converted to the desired product upon standing in the 0.1% TFA solution. Lyophilization yielded the title compound as a white powder. MS m/z 384.2 (M+H)+;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>O1CCOCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Yield: 58 %

Procedure:
A mixture of 5-bromo-2-chloropyrimidine (5.17 mmol) and 1,1-dimethylethyl 1-piperazinecarboxylate (11.4 mmol) in 1,4-dioxane (10 ml) was heated at reflux for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (100 ml) and ethyl acetate (100 ml). Separation of the organic layer, drying (MgSO4), filtration and concentration in vacuo provided a residue which was purified by silica gel chromatography (40 g silica gel, CHCl3/EtOAc) to give the title compound as a white solid (58%). ESMS [M+H-Boc]+: 245.0/243.0.
Reaction SMILES: [Mg:1].[CH2:2]1[O:10][C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[O:3]1.C1OC2C(=C([Br:21])C=CC=2)O1>BrBr.O1CCCC1>[CH2:2]1[O:10][C:9]2[CH:8]=[CH:7][C:6]([Mg:1][Br:21])=[CH:5][C:4]=2[O:3]1
Reactant: [Mg]
Reactant: Brc1cccc2c1OCO2
Reactant: Brc1ccc2c(c1)OCO2
Agent: BrBr
Solvent: C1CCOC1
Product: Br[Mg]c1ccc2c(c1)OCO2

Procedure:
1.35 g. magnesium chips and 20 ml. tetrahydrofuran are added in a nitrogen atmosphere to a flask provided with a stirrer, a drip funnel, a thermometer and a reflux condenser and a potassium hydroxide drying tube. The whole is then heated to 50° - 60°C and a few drops of bromine and a few drops of a solution of 11 g. 3.4-methylene dioxybromo-benzene in 50 ml. tetrahydrofuran are added. When the reaction has started, the remainder of the methylene dioxy bromo-benzene solution in tetrahydrofuran is added drop by drop for approximately 10 minutes and the resultant mixture is then left to react for 1 hour at 50° - 60°C. The Grignard solution obtained is used immediately for the reaction described below:
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH2:15][CH3:16])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].C1C(=O)N([Cl:24])C(=O)C1>CN(C=O)C>[CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH2:15][CH3:16])[C:7]=2[N:6]=[C:5]1[Cl:24])[CH:2]=[CH2:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CC
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CC
Temperature: 25 °C
Reaction time: 5 h
Yield: 145.6 %

Procedure:
To a solution of 7-allyl-3-ethyl-1H-purine-2,6(3H,7H)-dione (7 g, 31.82 mmol) in DMF (50 mL) was added NCS (5 g, 37.45 mmol) in portions at 0° C. The resulting mixture was stirred at room temperature for 5 h under nitrogen. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give 7-allyl-8-chloro-3-ethyl-1H-purine-2,6(3H,7H)-dione (11.8 g, ˜50% pure) as light yellow oil. LCMS retention time 0.764 min; LCMS MH+ 255.
Reaction SMILES: CCC([O-])(C)C.[K+].[N:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]CC)=O)=[N:10][CH:9]=1.Cl.[C:20]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:21]>C1(C)C=CC=CC=1.O>[O:16]=[C:14]([C:11]1[CH:12]=[CH:13][N:8]=[CH:9][N:10]=1)[CH2:21][C:20]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1ccncn1
Agent: CCC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccncn1
Yield: 76 %

Procedure:
To a 25% solution (5.31 g, 10.52 mmol) of potassium tert-amylate in toluene was added dropwise a solution of ethyl pyrimidine-4-carboxylate (1.00 g, 6.57 mmol) and ethyl acetate (1.09 mL, 11.1 mmol) in toluene (2.4 ml) at room temperature. Disappearance of the ethyl ester was confirmed by HPLC analysis, water (5 mL), ethyl acetate (5 mL) and concentrated hydrochloric acid (0.45 mL) were added, and the mixture was extracted with ethyl acetate (4 mL). The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give ethyl 3-oxo-3-(pyrimidin-4-yl)propionate (0.97 g, 76%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH:3]=1.[Cl:9][SiH:10]([Cl:12])[Cl:11].N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>>[CH3:1][CH:2]1[CH2:7][CH:6]([Si:10]([Cl:12])([Cl:11])[Cl:9])[CH2:5][CH:4]([CH3:8])[CH2:3]1
Reactant: CC1=CC(C)CCC1
Reactant: Cl[SiH](Cl)Cl
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Product: CC1CC(C)CC([Si](Cl)(Cl)Cl)C1
Yield: 80 %

Procedure:
A one-liter autoclave equipped with a stirrer was charged in a nitrogen atmosphere with 39 grams (0.35 mol) of 1,3-dimethylcyclohexene, 94 grams (0.69 mol) of trichlorosilane and 18 grams (74 mmol) of 1,1'-azobis(cydohexane-1-carbonitrile) and the mixture was reacted at a temperature of 130° C. for 3 days. The resulting reaction mixture was purified by distillation thereby obtaining 69 grams (0.28 mol) of 2,6-dimethyl-4-cyciohexyltrichlorosilane, The structure of the resulting product was Identified by 1H-NMR analysis.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH2:11][CH2:12][C:13]3[C:18]([C:9]=2[N:8]([CH3:20])[C:7]=1I)=[N:17][C:16]([NH2:19])=[N:15][CH:14]=3)=[O:5])[CH3:2].C(O[Na])=O>CN(C=O)C.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH2:11][CH2:12][C:13]3[C:18]([C:9]=2[N:8]([CH3:20])[CH:7]=1)=[N:17][C:16]([NH2:19])=[N:15][CH:14]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c2c(n(C)c1I)-c1nc(N)ncc1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=CO[Na]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2c1CCc1cnc(N)nc1-2
Temperature: 100 °C
Yield: 83 %

Procedure:
To a solution of 8-amino-2-iodo-1-methyl-4,5-dihydro-1H-1,7,9-triaza-cyclopenta[a]naphthalene-3-carboxylic acid ethyl ester N1 (0.62 mmol) in DMF (5 mL) and under argon, HCOONa (1.4 mmol) and Pd(Ph3P)4 (0.04 mmol) were added and the mixture was heated at 100° C. for 4 h. The mixture was cooled to rt, diluted with dichloromethane and washed with water. The organic phase was dried (Na2SO4) and evaporated to dryness. Chromatography on silica gel (eluant: AcOEt/hexane 1:1) afforded the title compound (83% yield). ESI (+) MS: m/z 273 (MH+). 1H NMR: 1.32 (t, J=7.07, 3H), 2.70 (t, J=7.70, 2H), 2.90 (t, J=7.70, 2H), 4.18 (s, 3H), 4.25 (q, J=7.07, 2H), 6.35 (bs, 2H), 7.73 (s, 1H), 8.01 (s, 1H).