Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[OH-].[K+].[I-].[CH3:8][S+](C)(C)=O.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[O:20][C:19]([CH3:25])([CH3:24])[C:18](=[CH2:26])[C:17]2=[O:27]>O>[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[O:20][C:19]([CH3:24])([CH3:25])[C:18]1([CH2:8][CH2:26]1)[C:17]2=[O:27]
Reactant: C=C1C(=O)c2cc(Br)ccc2OC1(C)C
Reactant: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(Br)cc2C(=O)C12CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
A 3-necked-flask was charged with dimethylsulfoxide (17 ml) and potassium hydroxide (0.84 g, 15 mmol). Then trimethylsulfoxonium iodide (3.3 g, 15 mmol) was added and the mixture was stirred at room temperature for 30 minutes. To this mixture, 6-bromo-2,2-dimethyl-3-methylene-2,3-dihydro-4H-chromen-4-one (2.0 g, 7.5 mmol) and dimethylsulfoxide (3 ml) were added. The mixture was stirred at room temperature for 15 hours and then water (30 ml) was added. The mixture was extracted with a mixture of hexane (70 ml) and ethyl acetate (70 ml). The organic layer was washed with water (50 ml) twice and then with brine (30 ml), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH-silica gel, hexane/ethyl acetate=100:1-20:1) to afford 6-bromo-2,2-dimethyl-4H-spiro[chromene-3,1′-cyclopropan]-4-one (1.2 g).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:12][CH:13]([O:20]CC)[CH2:14][C:15](OCC)=O)[CH3:11].Cl>C(Cl)Cl>[CH2:10]([O:12][C:13](=[O:20])[CH2:14][CH:15]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][O:9]1)[CH3:11]
Reactant: CCOC(=O)CC(OCC)OCC
Reactant: OCCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CC1OCCc2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of phenethyl alcohol (1.21 mL, 10 mmol, 1.0 eq.) and ethyl 3,3-diethoxy-propionate (2.59 mL, 12 mmol, 1.2 eq) in DCM (5 mL), 1N titantetrachloride solution in DCM (22 mL, 22 mmol, 2.2 eq) was added dropwise. The mixture was stirred at 0° C. for 1 hour and further at r.t. for 3 hours. The mixture was poured onto ice and 2N aq. HCl soln. (30 mL). The layers were separated. The aq. phase was extracted with DCM (2×50 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 40 fractions of 45 mL, Heptane to Heptane/AcOEt 85:15) to yield (±)-isochroman-1-yl-acetic acid ethyl ester as a colorless oil.
Reaction SMILES: [C-]#N.[Na+].Br[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1.[CH3:15][NH:16]CCNC.[OH-].[NH4+]>[Cu]I.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:12][C:11]([F:14])([F:13])[C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:15]#[N:16]
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: CNCCNC
Agent: [Cu]I
Agent: [C-]#N
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cccc(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
An oven dried screw cap test tube was charged with NaCN (125 mg, 2.551 mmol), dried KI (60 mg, 0.361 mmol, 17 mol %) and CuI (40 mg, 0.210 mmol, 10 mol %), evacuated and backfilled with argon three times. 1-Bromo-3-trifluoromethylbenzene (295 μL, 2.115 mmol), N,N′-dimethylethylenediamine (225 μL, 2.110 mmol) and anhydrous toluene (1.4 mL) were added under argon. The tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 24 h. The resulting yellow suspension was cooled to room temperature, 2 mL of ethyl acetate, 1 mL of ammonium hydroxide (30%) and 1 mL of water were added. The mixture was stirred at 25° C. for 10 min, then the organic layer was washed with 1 mL of water and dried over MgSO4. The GC analysis showed essentially complete consumption of the starting material, and formation of the title compound (as confirmed by GC-MS).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:13])([CH3:12])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:21][NH2:22]>C(O)C.N1C=CC=CC=1>[CH3:12][C:11]1([CH3:13])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[NH:22][CH3:21]
Reactant: CC1(C)C(Cl)=Nc2ccccc2C1(O)c1ccccc1
Reactant: CN
Solvent: CCO
Solvent: c1ccncc1
Product: CNC1=Nc2ccccc2C(O)(c2ccccc2)C1(C)C
Reaction time: 4 h

Procedure:
2-Chloro-3,4-dihydro-3,3-dimethyl-4-phenylquinolin-4-ol (1.43g., 0.005 mole) was dissolved in a mixture of a 33% w/v solution of methylamine in ethanol (40 ml.) and pyridine (0.79g.). The solution was stirred for four hours, after which the methylamine and ethanol were evaporated off to leave a residue, which was recrystallised twice from isopropyl alcohol to give the title compound (0.96g., m.p. 192° - 194° C).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH:5]([CH3:9])[C:6](O)=[O:7].CN(C=O)C.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH:5]([CH3:9])[C:6]([Cl:19])=[O:7]
Reactant: COC(=O)CC(C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CC(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 4-methoxy-2-methyl-4-oxobutanoic acid (1.2 g, 8.2 mmol) in oxalyl dichloride (15 mL) and DCM (15 mL) was added DMF (20 mg). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness to give the product as a yellow solid (1.3 g, 96% yield). 1H NMR (400 MHz, CDCl3): δ 3.71 (s, 3H), 3.35-3.30 (m, 1H), 2.87 (d, J=8.0 Hz, 0.5H), 2.82 (d, J=8.0 Hz, 0.5H), 2.56 (d, J=5.6 Hz, 0.5H), 2.52 (d, J=5.6 Hz, 0.5H), 1.37 (d, J=7.2 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][C@H:13]1[NH:18][CH2:17][C@H:16]([CH2:19][N:20]([CH3:22])[CH3:21])[O:15][CH2:14]1.C(N(CC)CC)C.CN1C(=O)CCC1>C(Cl)Cl>[NH2:7][C:6]1[CH:8]=[C:2]([N:18]2[C@H:13]([CH3:12])[CH2:14][O:15][C@H:16]([CH2:19][N:20]([CH3:21])[CH3:22])[CH2:17]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: C[C@@H]1CO[C@@H](CN(C)C)CN1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CO[C@H](CN(C)C)CN1c1ccc([N+](=O)[O-])c(N)c1
Temperature: 140 °C

Procedure:
A mixture of 5-fluoro-2-nitroaniline (1.1 equivalents), [((2R,5R)-5-methylmorpholin-2-yl)methyl]dimethylamine (1 equivalent), triethylamine (3 equivalents), and NMP was heated at 140° C. for 48 hours in a sealed high pressure vessel. The reaction mixture was cooled to 25° C. and dissolved in CH2Cl2. The solution was washed with water (2×) and dried (Na2SO4). Purification via chromatography on silicagel (10% MeOH in dichloromethane), afforded the desired product as a dark yellow foam. LC/MS m/z 295.1 (MH+) Rt 1.85 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[C:16]([F:21])([F:20])C([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[F:20][CH:16]([F:21])[O:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1OC(F)F
Temperature: 100 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
A mixture of methyl 2-hydroxy-4-nitrobenzoate (1.1 g, 5.6 mmol), sodium 2-chloro-2,2-difluoroacetate (1.0 g, 6.6 mmol) and Na2CO3 (710 mg, 6.7 mmol) in DMF (10 mL) was stirred at 100° C. overnight. After cooling to rt, the mixture was partitioned between water and EtOAc. The organic layer was separated and washed with twice with water, then brine, dried over Na2SO4 and concentrated, and purified by a standard method to give the title product (330 mg). 1H NMR (CHLOROFORM-d) δ: 8.15-8.19 (m, 1H), 8.13 (s, 1H), 8.06 (d, J=8.6 Hz, 1H), 6.68 (s, 1H), 3.98 (t, J=72.8 Hz, 1H).
Reaction SMILES: N1CCC[C@H]1C(O)=O.[Li]CCCC.[CH3:14][C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.O>CCOCC>[CH:16]1([CH:15]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17]1
Reactant: CC(=C1C=CC=C1)c1ccccc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(c1ccccc1)C1C=CC=C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of 1.4 g. of l-proline (12 mmol) in 40 mL of ether was added 15 mL of n-BuLi (1.6M solution in hexanes, 24 mmol) at 0° C. This solution was stirred overnight at room temperature and then cooled to -78° C. 6-Methyl-6-phenylfulvene, 2.0 g, (12 mmol) in 5 mL of ether was added dropwise at -78° C. The resulting solution was stirred 6 h at -78° C. Water, 20 mL, was added dropwise at -78° C. and the solution warmed to room temperature. The organic layer was separated and washed with aqueous NaHCO3, H2O and then dried over MgSO4. Removal of the solvent gave 2.0 g (99% yield) of 1-cyclopentadienyl-1-phenylethane as a light yellow oil. D =3.0° (CHCl3), 8.7% ee.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C[N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][N:11]([CH:17]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)[C:18]1[CH:28]=[CH:27][C:21]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:20][CH:19]=1)[CH2:12][CH2:13]2>C1(C)C=CC=CC=1.C(O)(=O)C.[Zn]>[CH:9]12[NH:8][CH:14]([CH2:15][CH2:16]1)[CH2:13][CH2:12][N:11]([CH:17]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)[C:18]1[CH:28]=[CH:27][C:21]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:20][CH:19]=1)[CH2:10]2
Reactant: COc1cccc(C(c2ccc(C(=O)N(C)C)cc2)N2CCC3CCC(C2)N3C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1cccc(C(c2ccc(C(=O)N(C)C)cc2)N2CCC3CCC(C2)N3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
0.4 ml of 2,2,2-trichloroethylchloro formate and 0.52 g of K2CO3 were added to a solution of the compound obtained in Example 4.10 (1.02 g) in toluene (25 ml), kept under argon inert atmosphere. The mixture was heated at reflux for 16 hours and at the end cooled at room temperature. The mixture is washed in sequence with water, with an aqueous solution of 15% citric acid and then with brine. At the end of the washings the organic phase was recovered and dehydrated on sodium sulphate. After solvent evaporation 1.21 g of a light yellow oil (carbamate) were obtained. The oil was dissolved in 25 ml of glacial acetic acid. To the solution 0.82 g of zinc in powder were added. The mixture was kept under stirring at room temperature for 16 hours and at the end diluted with about 25 ml of toluene. The solvent was evaporated under vacuum. The residue was dissolved in the minimum volume of dichloromethane. The solution was extracted three times with an aqueous solution of 15% w citric acid. The aqueous phases were shaken with dichloromethane, then brought to an alkaline pH with conc. NH4OH and extracted again with dichloromethane. The pooled organic phases were dehydrated with sodium sulphate and the solvent evaporated. 0.52 g of the compound 4-[(3,9-diazabicyclo[4.2.1]non-3-yyl)-(3-methoxy-phenyl)methyl]-N,N-dimethylbenzamide were obtained. Yield: 62%; IR (nujol) (λ=cm−1) 1646 (C═O), 3120 (NH); 1H-NMR (CDCl3): δ 1.39-1.65 (m, 3H), 1.74-1.97 (m, 1H), 2.11-2.30 (m, 2H), 2.66 (bs, 1H), 2.75 (dd, 1H, J=2.2 and 11.0 Hz), 2.81-3.04 (m, 3H), 3.05 (s, 6H), 3.11-3.32 (m, 2H), 3.81 (s, 3H), 4.27 (s, 1H), 6.63-6.79 (m, 1H), 7.00-7.20 (m, 5H), 7.55 (d, 2H, J=8.1 Hz). Anal. calc. for C24H31N3O2: C, 73.25; H, 7.94; N, 10.68. Found: C, 73.11; H, 7.92; N, 10.65.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:17]([NH:27][CH2:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([O-:34])=[O:33])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].[Cs+]>>[C:17]([NH:27][CH2:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([O:34][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:33])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: O=C(CCCCCBr)OCc1ccccc1
Reactant: O=C([O-])CCC(=O)CNC(=O)OCc1ccccc1
Agent: [Cs+]
Product: O=C(CCC(=O)OCCCCCC(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Reaction time: 48 h

Procedure:
This compound was prepared from the product of 9a (0.77 g; 2.7 mmol) and 8b (1.0 g; 2.5 mmol) according to Procedure C. The reaction time was 2 days. The crude product was purified on a 75×45 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (1000 mL) collecting 14×50 mL fractions. Fractions containing the product (5-7) were collected, and after evaporation 0.52 g (44%) product was obtained (amber oil that solidified to a waxy solid on standing in the freezer).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[CH2:12](I)[CH3:13]>CC(C)=O>[CH2:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1)[CH3:13]
Reactant: c1cnc2[nH]ccc2c1
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCn1ccc2cccnc21
Temperature: 25 °C
Reaction time: 0.04 h
Yield: 90.2 %

Procedure:
10 grams (0.0846 moles) of 7-azaindole (Aldrich (trademark)) were dissolved in 200 mL of reagent grade acetone at room temperature and treated with 10 grams (0.178 moles) of powdered KOH. After~2-3 minutes, 67 mL (0.846 moles) of ethyl iodide was added over a period of 5-10 minutes and the reaction mixture was stirred at room temperature for 30-40 minutes. Thin layer chromatography (TLC) using 95% methylene chloride/5% ethyl acetate showed complete consumption of the starting material and formation of a single less polar product. The reaction mixture was concentrated in vacuo and the residue was partitioned between water and methylene chloride (350 mL). The organic layer was separated and washed with water and brine and dried (sodium sulfate). Concentration of the organic extract in vacuo gave a yellow-brown oil which was purified on a silica gel column eluting with methylene chloride/ethyl acetate (95%/5%). A total of 11.15 grams (90%) of pure final product (light yellow oil) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22].C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH:20][C:24]([NH:23][CH2:21][CH3:22])=[O:25])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Reactant: CCN=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCNC(=O)Nc1nc(-c2cc(C)cc(C)c2)c(-c2ccncc2)s1
Temperature: 80 °C
Reaction time: 14 h
Yield: 42.6 %

Procedure:
To a solution of [4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.51 g, 1.8 mmol) in N,N-dimethylacetamide (10 mL) was added ethyl isocyanate (0.20 g, 2.8 mmol) and the mixture was stirred at 80° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.27 g, yield 42%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[C@@H:10]([C@H:31]([CH3:33])O)[NH:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)(=O)=O.C(OC(=O)C)C>C1(C)C=CC=CC=1>[C:12]([N:11]1[C@@H:31]([CH3:33])[C@@H:10]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:34])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[C@H](O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O=S(=O)(Cl)Cl
Product: C[C@H]1[C@H](C(=O)OCc2ccccc2)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
N-Trityl-D-threonine benzyl ester (2.5 g, 5.5 mmol), TEA (2.8 ml, 20 mmol) were dissolved in 100 ml of dry toluene at −50° C. A solution of sulfuryl chloride (800 ul, 8 mmol) in toluene (20 ml) was added in 15 min. The reaction was allowed to warm up to r.t. Ethylacetate (100 ml) was added and this was washed with sat. NaCl, dried over Na2SO4. The product was crystallized in MeOH (10 ml) to give benzyl N-trityl-3(S)-methylaziridine-2(R)-carboylate. NMR (500 MHz, CDCl3) δ: 1.37 (d, 3H), 1.64 (m, 1H), 1.95 (d, 1H), 5.15(d, J=12 Hz, 1H), 5.28(d, J=12 Hz, 1H), 7.19˜7.28 (m, 12H), 7.33˜7.36 (m, 1H), 7.36˜7.39 (m, 3H), 7.51˜7.54 (m, 4H).
Reaction SMILES: C1(O[C:8](=[O:19])[NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[CH3:18])C=CC=CC=1.[CH3:20][C:21]([CH3:37])([CH3:36])[CH2:22][CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH3:35])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH2:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:24]([CH2:23][CH2:22][C:21]([CH3:20])([CH3:37])[CH3:36])[C:8]([NH:9][C:10]2[C:11]([CH3:18])=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=2[CH3:16])=[O:19])=[CH:31][CH:30]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCc1ccc(CNCCC(C)(C)C)cc1
Reactant: Cc1cc(Cl)cc(C)c1NC(=O)Oc1ccccc1
Solvent: Cc1ccccc1
Product: CCCCc1ccc(CN(CCC(C)(C)C)C(=O)Nc2c(C)cc(Cl)cc2C)cc1

Procedure:
A solution of 825 mg of phenyl-N-(4-chloro-2,6-dimethylphenyl]carbamate and 740 mg of N-[3,3-dimethylbutyl]-4-n-butylbenzenemethanamine in 40 ml of toluene was refluxed for 1 hour, cooled, and the solution was washed with 1N sodium hydroxide, brine, dried, and evaporated to dryness to yield a solid. The solid was recrystallized from hexane to yield 1-[(4-butylphenyl)methyl]-1-[3,3-dimethylbutyl]-3-[4-chloro-2,6-dimethylphenyl]urea as a white solid, mp 138°-139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([C:10]#[C:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:8][N:9]=1)[CH:5]=[O:6].[CH3:20][Mg]Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH3:20])[C:7]([C:10]#[C:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:8][N:9]=1
Reactant: C[Mg]Cl
Reactant: Cc1ccc(F)cc1C#Cc1cnc(Cl)cc1C=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)ncc1C#Cc1cc(F)ccc1C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a solution of 2-chloro-5-((5-fluoro-2-methylphenyl)ethynyl)isonicotinaldehyde (705 mg, 2.6 mmol) in tetrahydrofuran (11 mL) cooled at −15° C. was added a solution of 3.0M methylmagnesium chloride in tetrahydrofuran (1 mL, 3.1 mmol) dropwise over 1 minute. The reaction mixture was stirred at this temperature for 15 minutes and then quenched with a few drops of saturated aqueous ammonium chloride solution, tetrahydrofuran was evaporated in vacuo, and the resulting residue was redissolved in dichloromethane (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a colorless oil that was redissolved in dichloromethane (10 mL) and treated with Dess-Martin periodinane (1.4 g, 3.4 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then diluted with dichloromethane (100 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 40 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a pale yellow solid (700 mg, 90%), which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:8][C:7]1[C:2]([C:13]2[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cn1cc(-c2nccnc2Cl)cn1
Temperature: 90 °C
Yield: 53.3 %

Procedure:
To 2,3-dichloropyrazine (1.12 g, 7.52 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.56 g, 7.52 mmol), bis(triphenylphosphine)palladium(II) dichloride (270 mg, 0.38 mmol), and Na2CO3 (2.4 g, 22.56 mmol) in a pressure tube were added 1,2-dimethoxyethane (15 mL) and water (2 mL). The flask was evacuated and flushed with argon (3×) and then sealed and heated at 90° C. overnight. The mixture was concentrated under reduced pressure and purified by silica gel chromatography eluting with 20-100% EtOAc/hexanes to afford 2-chloro-3-(1-methyl-1H-pyrazol-4-yl)pyrazine (780 mg, 53%). LCMS (ESI) m/z 195 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1.[Cl:21][CH2:22][CH2:23][CH2:24]Br>O1CCCC1>[Cl:21][CH2:22][CH2:23][CH2:24][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][C:9]([CH3:8])=[CH:14][CH:13]=2)[CH2:16][CH2:17]1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: ClCCCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(N2CCN(CCCCl)CC2)cc1
Reaction time: 6 h

Procedure:
55.4 ml (0.4 mol) triethylamine were added to a solution of 35.2 g (0.2 mol) 1-(4-methylphenyl)-piperazine and 31.5 g (0.2 mol) 1-chloro-3-bromopropane in 41 ml anhydrous tetrahydrofuran and the reaction mixture then stirred for six hours at 60°-65°C. Thereafter, the crystals which had precipitated out were filtered off with suction and the filtrate was evaporated in a vacuum. There was obtained a quantitative yield of crude 1-(3-chloropropyl)-4-(4-methylphenyl)-piperazine which was purified by rapid distillation at an efficient oil pump vacuum. The yield was 41.23 g (80% of theory); b.p. 147°-150°C/0.05 mm HG; m.p. 34°-36°C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.C([Li])CCC.[C:24]([Si:28]([O:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([N:38]=[C:39]=[O:40])[CH2:34][CH2:33]1)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25]>O1CCCC1.C(OCC)(=O)C>[C:24]([Si:28]([CH3:30])([CH3:29])[O:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([N:38]2[C:6]3=[N:7][C:2]([Cl:1])=[N:3][CH:4]=[C:5]3[CH2:9][N:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:39]2=[O:40])[CH2:34][CH2:33]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N=C=O)CC1
Reactant: COc1ccc(NCc2cnc(Cl)nc2Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(N2Cc3cnc(Cl)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of [(2,4-dichloropyrimidin-5-yl)methyl](4-methoxy-phenyl)amine (1.0 g, 3.52 mmol) (from Example 1d supra) in tetrahydrofuran (50 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 1.7 mL, 4.22 mmol) (Aldrich). After stirring at −78° C. for 20 minutes, tert-butyl-(trans-4-isocyanato-cyclohexyloxy)-dimethyl-silane (1.1 g, 4.22 mmol) (from Example 17b supra) was added. The mixture was stirred at −70° C. for 1 hour and then at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate-hexanes (3:7 then 2:3) to give 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-7-chloro-3-(4-methoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.61 g, 34%).