Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].ClCCl.CO>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:17]([CH2:20][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: c1c[nH]nn1
Reactant: COC(=O)c1cc(CCl)ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(Cn2ccnn2)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine triazole (0.72 g, 10.4 mmol) and dimethylformamide (6 mL). Cool in an ice bath and add sodium hydride (0.42 g, 60% i oil, 10.4 mmol). After 30 minutes, warm to ambient temperature. Add a solution of methyl 2-methoxy-5-chloromethylbenzoate (1.85 g, 6.74 mmol) in dimethylformamide (6 mL). Heat to 75° C. After 3 hours, partition the reaction mixture between water and ethyl acetate. Extract the organic layer with water, dry over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 95/5 dichloromethane/methanol containing 0.5% concentrated aqueous ammonia to give methyl 2-methoxy-5-(1H-triazol-1-ylmethyl)benzoate: Rf=0.1 (silica gel, 1/1 hexane/ethyl acetate).
Reaction SMILES: [NH2:1][OH:2].Cl.[CH:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]3[C:20]([C:21]#[N:22])=[C:19]([CH3:23])[NH:18][C:17]([CH3:24])=[C:16]3[C:25]#[N:26])[CH:13]=2)[NH:8][N:7]=1)=O>N1C=CC=CC=1>[OH:2]/[N:1]=[CH:4]/[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]3[C:20]([C:21]#[N:22])=[C:19]([CH3:23])[NH:18][C:17]([CH3:24])=[C:16]3[C:25]#[N:26])[CH:13]=2)[NH:8][N:7]=1
Reactant: CC1=C(C#N)C(c2ccc3[nH]nc(C=O)c3c2)C(C#N)=C(C)N1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)C(c2ccc3[nH]nc(/C=N/O)c3c2)C(C#N)=C(C)N1
Yield: 68.1 %

Procedure:
A mixture of NH2OH.HCl (229 mg, 3.3 mmol) and 4-(3-formyl-1H-indazol-5-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile (200 mg, 0.66 mmol), from Synthetic Example 10B, in pyridine (5 mL) was stirred at rt overnight. After removal of pyridine under vacuum, the residue was treated with a saturated solution of NaHCO3 and extracted with CH2Cl2. The organic phases were combined, washed with brine, and concentrated. The residue was purified by column to give 1,4-dihydro-4-[3-[(E)-(hydroxyimino)methyl]-1H-indazol-5-yl]-2,6-dimethyl-3,5-pyridinedicarbonitrile (143 mg, 68%) as a powder (Cpd. No. 149, Table 2). 1H-NMR (400 MHz, DMSO-D6): δ=11.42 (s, 1H), 9.55 (s, 1H), 8.36 (s, 1H), 7.85 (s, 1H), 7.60 (d, 1H), 7.38 (d, 1H), 4.58 (s, 1H), 2.03 (s, 6H) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C@@H:23]3[CH2:25][C@H:24]3[CH2:26]O)[CH2:18][CH2:17]2)[CH2:3]1.C(N(S(F)(F)[F:35])CC)C.C(=O)([O-])O.[Na+].C(OCC)(=O)C>ClCCl.O>[F:35][CH2:26][C@@H:24]1[CH2:25][C@H:23]1[CH2:22][N:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:4]2[CH2:3][C:2]([CH3:28])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[CH2:21][CH2:20]1
Reactant: CC1(C)CC(c2ccccc2N2CCN(C[C@@H]3C[C@H]3CO)CC2)CC(C)(C)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(c2ccccc2N2CCN(C[C@@H]3C[C@H]3CF)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.2 %

Procedure:
To a solution of trans-(2-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)methanol (60 mg, 0.156 mmol) produced in Example (92a) in dichloromethane (5 mL) was added diethylaminosulfur trifluoride (DAST) (0.052 mL, 0.394 mmol), followed by stirring for 2 hours at room temperature under a nitrogen atmosphere. The reaction mixture was cooled at an external temperature of 0° C., saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was stirred. Then, ethyl acetate and water were added thereto and extraction was performed with ethyl acetate. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 17 mg of trans-1-(2-fluoromethylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH:7](C)[CH:8]=[CH:9][CH3:10])=[CH:3][CH2:4][OH:5].[CH2:12](N(CC)CC)C.[C:19]([O:22][C:23]1[C:24](=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:25](Cl)=[O:26])(=[O:21])[CH3:20].O>O1CCCC1>[CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:10])[CH3:12])=[CH:3][CH2:4][O:5][C:25](=[O:26])[C:24]1[C:23](=[CH:31][CH:30]=[CH:29][CH:28]=1)[O:22][C:19](=[O:21])[CH3:20]
Reactant: CC=CC(C)CC(C)=CCO
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Oc1ccccc1C(=O)OCC=C(C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7 g of 3,5-dimethyl-2,6-octadienol (geraniol) and 6.8 g of triethylamine were dissolved in 50 ml of tetrahydrofuran. 13.4 g of acetylsalicylic acid chloride was added dropwise to the solution under cooling. After stirring at room temperature for 30 minutes, water was added to the reaction mixture and the product was extracted with n-hexane.
Reaction SMILES: N[C@H:2]([CH:7]=[O:8])CCSC.[C:9]([O:13]CCO)(=[O:12])[CH:10]=[CH2:11].[O:17]=[C:18]=[N:19]C1CC(C)(C)CC(C)(CN=C=O)C1>[Zn]>[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11].[NH2:19][C:18]([O:8][CH2:7][CH3:2])=[O:17]
Reactant: CSCC[C@H](N)C=O
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: C=CC(=O)OCCO
Agent: [Zn]
Product: C=CC(=O)O
Product: CCOC(N)=O
Reaction time: 4 h

Procedure:
Metal-containing polyol from Example 6 was used to prepare a zinc salt urethane diacrylate oligomer based on isophorone diisocyanate and hydroxyethyl acrylate. Isophorone diisocyanate (IPDI, 135.41 g) was added to the polyol which was diluted with 25% ethoxylated trimethyolpropane triacrylate (polyol, 2000.0 g; SR454, 100.0 g) over 2 hours at 60° C., followed by addition of hydroxyethyl acrylate (70.8 g). The reaction mixture was kept at 90° C. for 4 hour. A viscous liquid resin was obtained. The final product is light yellow and hazy liquid. The viscosity @ 60° C. is only 920 cps.
Reaction SMILES: ClC1C=CC(C[CH:9]([C:17]([CH:19]([CH2:27][C:28]2[CH:33]=[CH:32][C:31](Cl)=[CH:30]C=2)[S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=O)SC2C=CC=CC=2)=CC=1.[Cl:35]C1C=CC=CC=1>>[Cl:35][C:24]1[CH:23]=[CH:22][C:21]2[S:20][C:19]([C:27]3[CH:28]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:17]([CH3:9])[C:26]=2[CH:25]=1
Reactant: Clc1ccccc1
Reactant: O=C(C(Cc1ccc(Cl)cc1)Sc1ccccc1)C(Cc1ccc(Cl)cc1)Sc1ccccc1
Product: Cc1c(-c2ccccc2)sc2ccc(Cl)cc12
Temperature: 180 °C
Reaction time: 3.5 h

Procedure:
55.7 parts by weight of p-chlorophenylthiophenylmethylmethyl ketone and 500 parts by weight polyphosphoric acid are combined in a stoppered flask and heated with stirring for 3.5 hours at 180° C. 350 Parts by volume of chlorobenzene is added to the reaction mixture and the resulting solution is heated at reflux temperature for an additional hour. After cooling the organic phase of this reaction solution is decanted off; the inorganic phase is dissolved in ice water and extracted once each with benzene and ethyl ether. The combined organic phases are then washed once with a saturated solution of sodium bicarbonate, washed once with brine, and dried over magnesium sulfate. Concentration of this solution in vacuo affords a dark solid. Crystallization of this solid (2xs) from heptane affords a brown solid. Sublimation at 135° C/0.1mm of this brown solid affords 5-chloro-3-methyl-2-phenylbenzo[b]thiophene, melting at 108.5°-110° C. This compound is represented by the following structural formula. ##STR10##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])(OCC)=O>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCCN1C(=O)c2ccccc2C1=O
Temperature: 52.5 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
5.41 g (28.74 mmol) of N-(tert-butoxycarbonyl)-1,4-diaminobutane was dissolved in 100 ml of 1,4-dioxane and 4.86 g (28.74 mmol) of N-carboethoxyphthalimide was added thereto. The mixture was heated at 45 to 60° C. and stirred for 4 hours. After the reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added thereto and the resulting solution was extracted with ethyl acetate. The extract was washed with brine and dried (Na2SO4). The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform:methanol=200:1 (v/v)) to obtain 5.40 g (16.96 mmol) of N-[4-(tert-butoxycarbonylamino)butyl]phthalimide as a white solid. Its spectroscopic data are as follows:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1.[OH-].[Na+].C(N(CC)CC)C.[C:25](OC([O-])=O)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:1]2[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3][CH2:2]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: Cc1ccc(CCl)cc1
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 60.3 %

Procedure:
Piperazine (170 g, 2.0 mol) was suspended in toluene (800 mL) and warmed to 85° C. The mixture was dissolved while stirring for 10 minutes. To the solution was added 4-methylbenzyl chloride (53 mL, 0.4 mol), and the mixture was stirred at 85° C. for 2 hours and then left to stand for cooling to 50° C. A 1 N aqueous sodium hydroxide solution (440 mL) and ethyl acetate (100 mL) were added thereto, and the process of phase separation was performed. The resulting organic layer was washed with a 1 N aqueous sodium hydroxide solution (400 mL) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in tetrahydrofuran (420 mL). Triethylamine (84 mL, 0.6 mol) was added thereto, and the resulting mixture was ice cooled. t-Butyl dicabonate (97 mL, 0.42 mol) was added thereto, and the mixture was stirred overnight while elevating the temperature to room temperature. The solvent was distilled off under reduced pressure. A 4 N aqueous sodium hydroxide solution (200 mL) and ethyl acetate (300 mL) were added thereto, and the process of phase separation was performed. The resulting organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution (400 mL) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. To the residue was added a small amount of hexane, and the mixture was ice cooled. The obtained crystals were collected by filtration and washed with ice-cooled hexane to obtain the title compound (70 g, yield 60%). The mother liquor was concentrated under reduced pressure, and then the residue was purified with silica gel column chromatography (hexane to hexane:ethyl acetate=3:1). The resulting oily matter was left to stand at room temperature. The obtained crystals were collected by filtration and washed with ice-cooled hexane to obtain the title compound (22 g, yield 19%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([OH:31])=[C:21]([CH:30]=1)[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].[OH-].[Na+]>C(Cl)(Cl)Cl>[ClH:1].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:30]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(Cl)cc3C(=O)c3ccccc3)c2cc1OC
Product: Cl
Temperature: 25 °C
Yield: 11 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (1.00 g) and 5-chloro-2-hydroxybenzophenone (1.46 g) were stirred at 170° C. for one hr, and the reaction solution was cooled to room temperature. Chloroform was then added to the reaction solution, and separation was carried out with a 10% aqueous sodium hydroxide solution. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel using hexane-acetone. Thereafter, 10% hydrochloric acid-methanol (10 ml) was added to the product, followed by concentration. The concentrate was suspended in ether, and the suspension was filtered to give the title compound (225 mg, yield 11%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[N:25]1([S:31]([C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37](O)=[O:38])(=[O:33])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([NH:8][C:37](=[O:38])[C:36]1[CH:40]=[CH:41][CH:42]=[C:34]([S:31]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:33])=[O:32])[CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: NCc1ccccc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1cccc(S(=O)(=O)N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
Benzylamine (12 mg), triethylamine (0.047 mL) and 25% dichloromethane solution of 2-chloro-1,3-dimethylimidazolinium chloride (0.11 mL) were added in that order to a chloroform (0.30 mL) solution of 3-(piperidin-1-ylsulfonyl)benzoic acid (30 mg), and stirred at room temperature for 1 hour. The reaction liquid was concentrated and purified through reversed-phase HPLC (0.1% TFA acetonitrile/H2O=from 10% to 95%, gradient) to give the entitled compound (26 mg, 65%) as a white crystal.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][CH3:35])[CH2:11][S:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].[CH3:36][N:37]1[CH:41]=[CH:40][N:39]=[CH:38]1>>[I-:1].[CH3:35][O:34][CH:10]([CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][NH+:39]1[CH2:40][CH2:41][N:37]([CH3:36])[CH2:38]1)(=[O:7])=[O:6])[CH2:11][S:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CNS(=O)(=O)CCCI)OC
Reactant: Cn1ccnc1
Product: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CNS(=O)(=O)CCC[NH+]1CCN(C)C1)OC
Product: [I-]
Yield: 91 %

Procedure:
A solution of 100 mg of 3-(3-iodopropylsulfonylamino)-2-methoxy-1-octadecylcarbamoylthiopropane IIa6 in 0.3 ml of N-methylimidazole is stirred at 25° C. overnight. After the solvent is evaporated, the residue is washed with water to give 102 mg of 2-methoxy-1-octadecylcarbamoylthio-3-(3-N-methylimidazoliniopropylsulfonylamino)propane iodide Ia24 in 91% yield.
Reaction SMILES: O.NN.[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][O:10][N:11]1C(=O)C2=CC=CC=C2C1=O.[OH-].[NH4+].C(Cl)[Cl:25]>>[ClH:25].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][O:10][NH2:11]
Reactant: ClCCl
Reactant: O=C1c2ccccc2C(=O)N1OCc1ccco1
Agent: NN
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cl
Product: NOCc1ccco1
Reaction time: 0.75 h
Yield: 50 %

Procedure:
100% Hydrazine hydrate (20 ml.) was added to a stirred solution of N-(fur-2-ylmethoxy)phthalimide (42.0 g.) in methylene chloride (600 ml.). A copious precipitate formed immediately, and the mixture was stirred for 45 min. 5N Ammonium hydroxide solution (500 ml.) was added to dissolve the precipitate, the two layers were separated, and the aqueous layer was washed twice with methylene chloride. The combined methylene chloride extracts were washed (saturated brine) and dried. Methylene chloride was evaporated off, and the residual liquid was dissolved in ether (250 ml.). Dry hydrogen chloride was passed into this solution for one hour. The precipitated solid was filtered off, washed with ether, dried, and recrystallised from isopropanol to give fur-2-ylmethoxyamine hydrochloride (12.89 g., 50%), m.p. 135°-136° (decomp) τ values (DMSO-d6) include 4.87 (CH2), 2.20,. 3.27, 3.44 (furyl protons).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=O.Cl.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][NH:29][CH2:30]4)=[CH:25][CH:24]=3)[N:20]=[C:19]([NH2:33])[N:18]=2)[CH2:13][CH2:12]1>>[CH3:1][CH:2]([CH2:7][CH3:8])[CH2:3][C:4]([N:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][C:23]([C:21]3[CH:22]=[C:17]([N:14]4[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]4)[N:18]=[C:19]([NH2:33])[N:20]=3)=[CH:24][CH:25]=2)[CH2:30]1)=[O:6]
Reactant: CCC(C)CC(=O)O
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CCC(C)CC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from 3-methylpentanoic acid (Aldrich, Cat. #223453) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=423.2.
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[N:8][C:7](Cl)=[N:6][C:5]=2[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:14][CH2:13]2)[CH:3]=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29].C([O-])([O-])=O.[K+].[K+].[F:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>C(O)(C)C.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.O>[CH2:26]([NH:30][C:7]1[N:8]=[CH:9][C:10]2[C:2]([C:41]3[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=3)=[CH:3][N:4]([C@H:12]3[CH2:13][CH2:14][C@H:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])[CH2:16][CH2:17]3)[C:5]=2[N:6]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(Br)c3cnc(Cl)nc32)CC1
Reactant: CCCCN
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CCCCNc1ncc2c(-c3ccc(F)cc3)cn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2n1
Temperature: 150 °C

Procedure:
To a solution of 5-bromo-7-(trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.082 g, 0.18 mmol) in isopropyl alcohol (2.0 mL) was added n-butylamine (0.033 g, 0.45 mmol) in a microwave tube. The resulting mixture was heated under microwave irradiation at 150° C. for 1.5 h. After the reaction cooled to room temperature, the solvent and excess amine was evaporated under vacuum. The residue was dissolved in THF and concentrated under vacuum (3×). Then it was dissolved in THF (2.0 mL) in a microwave tube. To this solution was added K2CO3 (0.050 g, 0.36 mmol), Pd(PPh3)4 (0.021 g, 0.018 mmol), (4-fluorophenyl)boronic acid (0.038 g, 0.27 mmol), and H2O (0.5 mL). The resulting mixture was heated under microwave irradiation at 150° C. for 10 min. After cooled to room temperature, it was washed with brine and extracted with EtOAc (5×). The combined organic layer was dried (Na2SO4) and concentrated. The residue was filtered through a short column of silica gel to provide N-butyl-7-(trans-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-5-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine which was used for next step without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CCCCC(F)(F)C(O)CC[C@@H]1[C@@H:20](CCCCCCC(O)=O)[C:18](=[O:19])[CH2:17][C@H:16]1[OH:30].C1CCC(NC2CCCCC2)CC1.[NH:47]([CH2:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]>C(Cl)Cl.CN1CCOCC1>[C:60]([O:59][C:57]([CH2:56][N:47]([CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C:16](=[O:30])[C@@H:17]1[O:19][C@@H:18]1[CH3:20])=[O:58])([CH3:62])([CH3:63])[CH3:61]
Reactant: CC(C)(C)OC(=O)CNCC(=O)OC(C)(C)C
Reactant: CCCCC(F)(F)C(O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H]1O[C@H]1C(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
A solution of 11.6 g of oxalyl chloride in 25 ml of methylene chloride is added dropwise, in the course of 15 minutes, to a mixture, cooled to -25°, of 20 g of dimethylforinaniide and 115 ml of methylene chloride. The white suspension is stirred for a further 20 minutes at -25°, and a solution of 28.5 g of the dicyclohexylammonium salt of (2R,3R,)-2,3-epoxybutyric acid in 115 ml of methylene chloride is then added in the course of 10 minutes. The reaction mixture is stirred for a further 20 minutes at the same temperature, and a solution of 17.87 g of di-tert-butyl iminodiacetate in 90 ml of methylene chloride and 9.22 ml of N-methylmorpholine are then added dropwise simultaneously in the course of 15 minutes. The cooling bath is removed and the reaction mixture is stirred for 3 hours at room temperature. The white suspension is then filtered through a sintered glass suction filer, the residue is washed with methylene chloride, and the filtrate is diluted with methylene chloride and washed successively with water, 5% aqueous citric acid, saturated aqueous sodium bicarbonate solution and water. The aqueous phases are subsequently extracted twice with methylene chloride, and the combined organic phases are dried and evaporated under a water pump vacuum. The yellow-brown crude product is purified by flash chromatography over silica gel (Merck 9385) using a 9:1 mixture of methylene chloride and ethyl acetate as the mobile phase. (2R,3R)-N,N-Bis-(tert-butoxy-carbonylmethyl)-2,3-epoxybutyramide is obtained in the form of a pale yellow oil, [α]D =+52° (c=1.250% in chloroform).