Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1>N1C=CC=CC=1.O>[C:26]([N:8]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])[C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:20]([OH:21])=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=1)(=[O:28])[CH3:27]
Reactant: CC(C)(C)c1cc(Nc2cccc(C(=O)O)c2)cc(C(C)(C)C)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N(c1cccc(C(=O)O)c1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5.6 g of 3-(3,5-di-t-butyl-4-hydroxyanilino)benzoic acid (from Example 13) and 15 ml of acetic anhydride was heated under a nitrogen atmosphere at 70°-120° C. for about 90 minutes. The mixture was cooled to 80° C., 5 drops of pyridine were added and the reaction was reheated to 120° C. for 10 minutes. An additional 0.25 ml of pyridine was added at about 80° C., followed by the gradual addition of 10 ml of water to hydrolyze the excess acetic anhydride and the mixed anhydride of the product. Heating was continued until a precipitate formed. The reaction mixture was allowed to cool to room temperature, and the precipitate was then collected, rinsed with a cold mixture of methanol and water, and dried to give 4.3 g of off-white solid m.p. 204°-205.5° C. This material was recrystallized first from a mixture of 30 ml of ethanol and 5 ml of water, and then from a mixture of 30 ml of isopropanol and 5 ml of hexane to give 3.3 g of white solid N-acetyl-3-(3,5-di-t-butyl-4-hydroxyanilino)benzoic acid m.p. 214.5°-215.5° C. Analysis: Calculated for: C23H29NO4 ·1/2(CH3)2CHOH: % C, 71.2; % H, 8.0; % N 3.4. Found: % C, 71.4; % H, 8.1; % N, 3.2.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([F:23])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:35]([C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25]([F:24])=[CH:26][CH:27]=2)=[O:36])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[C:15]([F:23])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)c(F)c1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)c(F)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-fluoro-4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.21 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (230 mg, 1.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (347 mg, 1.81 mmol) and 1-hydroxy-1H-benzotriazole (185 mg, 1.21 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (525 mg, 86%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>CN(C=O)C>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([O:4][CH2:3][CH2:2][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])=[CH:6][CH:7]=1)#[N:10]
Reactant: N#Cc1ccc(OCCBr)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 95 °C

Procedure:
4-(2-Bromoethoxy)benzonitrile (7.3 g) was reacted with potassium phthalimide (5.98 g) in DMF (35 ml) by heating at 95° C. for 3 hours. The N-[2-(4-cyanophenoxy)ethyl]phthalimide obtained after extractive workup (7.30 g) was suspended in IMS (350 ml) and treated with hydrazine hydrate (6.25 g). The mixture was stirred for 22 hours and filtered. The solid obtained was washed with IMS and the combined filtrate and washings were evaporated to dryness. Water was added to this residue and the mixture basified with 10M sodium hydroxide solution. The mixture was extracted with dichloromethane to give 4-(2-aminoethoxy)benzonitrile as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][C:25](=[O:31])[NH:26]2>>[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[C:24](=[CH:19][C:3]1[NH:4][C:5]3[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]4[CH2:14][CH2:15][CH2:16][CH2:17]4)[C:7](=[O:18])[C:6]=3[C:2]=1[CH3:1])[C:25](=[O:31])[NH:26]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Reactant: O=C1Cc2c(Br)cccc2N1
Product: Cc1c(C=C2C(=O)Nc3cccc(Br)c32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 74.4 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-bromo-1,3-dihydro-indol-2-one (prepared according to US20030225127) as starting materials to give 2-(4-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (44 mg, 74.4%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=1)[NH:6][C:7]2=[O:12].C(N(CC)CC)C.[CH2:32]([OH:36])[CH2:33][C:34]#[CH:35]>CN(C=O)C.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.[Cu]I>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[NH:6][C:7](=[O:12])[C:8]3[C:3]([CH:4]=2)=[C:2]([C:35]#[C:34][CH2:33][CH2:32][OH:36])[CH:11]=[CH:10][CH:9]=3)=[CH:14][CH:15]=1
Reactant: C#CCCO
Reactant: CN(C)CCOc1ccc(-c2cc3c(Br)cccc3c(=O)[nH]2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(-c2cc3c(C#CCCO)cccc3c(=O)[nH]2)cc1
Yield: 38.8 %

Procedure:
5-Bromo-3-[4-(2-dimethylaminoethoxy)phenyl]-2H-isoquinolin-1-one (50.0 mg, 0.130 mmol), triethylamine (1.1 mL, 8.36 mmol), dichlorobis(triphenylphosphine)palladium(II) (5.0 mg, 0.0065 mmol), copper (I) iodide (3.0 mg, 0.009 mmol), 3-butyn-1-ol (20 μL, 0.260 mmol) in DMF (1.1 mL) were added to a microwave vial and the reaction mixture purged with N2 for 5 min. The reaction mixture was irradiated using a microwave reactor (300 W, 100° C., 90 min). The reaction mixture was filtered through Celite® 545, diluted with DMSO and was purified by reverse phase preparative HPLC-MS to obtain 3-[4-(2-dimethylaminoethoxy)phenyl]-5-(4-hydroxybut-1-ynyl)-2H-isoquinolin-1-one as a brown solid (19.0 mg, 39%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[NH:6].Cl.[CH3:13][S:14][C:15]1[N:16]=[N:17][C:18]([C:22](OCC)=[O:23])=[C:19](Cl)[N:20]=1.C(N(CC)CC)C>C(#N)C>[CH3:13][S:14][C:15]1[N:16]=[N:17][C:18]2[C:22](=[O:23])[NH:7][C:5]([C:4]3[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=3[O:2][CH3:1])=[N:6][C:19]=2[N:20]=1
Reactant: COc1ccccc1C(=N)N
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1nc2nc(SC)nnc2c(=O)[nH]1
Temperature: 0 °C

Procedure:
A cooled (0° C.) solution of 2-methoxybenzamidine (from 1.97 g of the hydrochloride) in acetonitrile (17 ml) was added to a cooled solution of 3-methylthio-5-chloro-6-carboethoxy-1,2,4-triazine (prepared from 3-methylthio-5-oxo-6-carboethoxy-4,5-dihydro-1,2,4-triazine, 1.08 g, and thionyl chloride, 20 ml) in acetonitrile (17 ml). Triethylamine (0.51 g) was added and the reaction mixture was stirred with cooling (0° C.) for one hour and then at ambient temperature for 17 hours to afford a yellow solid which was washed with acetonitrile and ether to afford the crude title compound (1.39 g). A sample (0.35 g) of this was washed twice with boiling methanol to afford the title compound, 0.25 g, m.p. 267.5°-268.5° C. The remaining material (1.04 g) was similarly treated with boiling methanol to afford the title compound, 0.91 g, m.p. 266°-268° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:15])(=O)=O>ClCCl>[Cl:15][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 148.2 %

Procedure:
4-t-Butylphenol (2.76 g, 18.4 mmol) was dissolved in dichloromethane (25 ml). Sulfuryl chloride (1.6 ml, 9.9 mmol) was added dropwise to the obtained solution, and they were stirred at room temperature for 3 days and then concentrated under reduced pressure. After the purification by the silica gel column chromatography, 2-chloro-4-t-butylphenol (yield: 2.71 g, 80%) was obtained.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][CH:10]([CH3:18])[N:9]2[CH:19]=1)([O:3][CH2:4][CH3:5])=[O:2].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22].[OH-].[Na+]>CC(C)=O.O>[C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]([CH3:18])[N:9]2[CH:19]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1cc2n(c1)C(C)Nc1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1cc2n(c1)C(C)N(C(=O)OCC)c1ccccc1-2

Procedure:
A solution of the product of Example XXXVIII (3.0 g, 0.0117 m) and ethyl chloroformate (12.6 g, 0.117 m) in acetone (50 ml) and H2O (50 ml) was treated with NaOH (0.21 ml aq. 30%) and the mixture refluxed for 1 hr. The acetone was removed in vacuo and the aqueous residue cooled in ice-bath. A solid formed and this was filtered, washed with water, and dried in vacuo. The crude product (3.4 g) was crystallized from methanol (25 ml) to afford the desired product; m.p. 125°-127°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:26][NH2:27]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1OC

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (160 mg, 0.43 mmol) and 3,4-dimethoxy benzylamine (87 mg, 0.52 mmol). The title compound was obtained as a yellow solid (110 mg, 51% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.30 (1H, m), 8.98 (2H, m), 8.47 (1H, s), 6.87 (3H, m), 4.32 (2H, m), 3.71 (6H, m). MS m/z: 498.26, 500.25 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=O)[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:29][O:30][CH2:31][C:32]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH2:34][CH2:33]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:12]([C@@H:10]1[CH2:11][C@:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:14](=[O:16])[NH:38][S:35]([C:32]1([CH2:31][O:30][CH3:29])[CH2:34][CH2:33]1)(=[O:37])=[O:36])=[CH2:13]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COCC1(S(N)(=O)=O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1(COC)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.2 %

Procedure:
A solution of (1R,2S)-1-[(tert-butoxycarbonyl)amino]-2-ethenylcyclopropanecarboxylic acid (132 mg) in THF (3 mL) was added 1,1′-carbonyldiimidazole (283 mg). The mixture was stirred 4 hours at reflux. The mixture was cooled to room temperature and a solution of 1-(methoxymethyl)cyclopropanesulfonamide (125 mg; Li et al., 2006, Synlett 5:725) and DBU (0.438 mL) in THF (3 mL) was added via cannula. The mixture was stirred for 40 hours at room temperature. The reaction was quenched with 1N HCl and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (ISCO) to give the desired product (120 mg). 1H NMR (400 MHz, CDCl3): 5.71-5.62 (m, 1H), 5.29 (d, 1H), 5.16 (d, 1H), 3.36 (s, 2H), 2.15 (dt, 1H), 1.89 (dd, 1H), 1.75-1.68 (m, 2H), 1.49 (s, 9H), 1.34-1.30 (m, 1H), 1.08-1.03 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH3:15])[CH:7]=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2=[O:21].[F:22][B-:23]([F:26])([F:25])[F:24].[H+].[N:28](OCCC(C)C)=O>C(O)C.CCOCC>[F:22][B-:23]([F:26])([F:25])[F:24].[CH2:19]([O:18][C:16]([C:6]1[C:5](=[O:21])[C:4]2[C:9](=[N:10][C:11]([O:12][CH3:13])=[C:2]([N+:1]#[N:28])[CH:3]=2)[N:8]([CH2:14][CH3:15])[CH:7]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)c1cn(CC)c2nc(OC)c(N)cc2c1=O
Reactant: CC(C)CCON=O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cn(CC)c2nc(OC)c([N+]#N)cc2c1=O
Reaction time: 0.5 h

Procedure:
A solution of 12.0 g of ethyl 6-amino-1-ethyl-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate in 120 ml of ethanol and 60 ml of aqueous 42% tetrafluoroboric acid was cooled to 0° C. To the solution kept at 0°-3° C. was added 6.0 g of isoamyl nitrite. The mixture was stirred for 30 minutes at the same temperature, and then diluted with 600 ml of ether to give a precipitate which was collected and washed with ether to give 12.8 g of 3-ethoxycarbonyl-1-ethyl-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-6-diazonium tetrafluoroborate, decomposing at 142°-147° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([N+:14]([O-])=O)=[CH:13][C:8]=3[S:7](=O)[C:6]=2[CH:18]=1.C(O)(=O)C.O.O.Cl[Sn]Cl>Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=3[S:7][C:6]=2[CH:18]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)c1cc(Br)ccc1-2
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)sc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask equipped with a stirrer and a thermometer was charged with 26.98 g of the intermediate 3-bromo-7-nitrodibenzothiophene-5-oxide prepared in Example 1-2 and 269.8 g of glacial acetic acid in a nitrogen atmosphere. 112.7 g of SnCl2.2H2O dissolved in 158 g of concentrated hydrochloric acid was added dropwise at 14 to 18° C. over 1 hour, and stirred overnight at room temperature. The resulting reactant was filtered, washed with 1:1 glacial acetic acid/concentrated hydrochloric acid, and neutralized with 1100 g of a 7 wt % aqueous solution of sodium hydroxide. The reactant was extracted with ethyl acetate, washed with water, concentrated, and purified by silica gel chromatography using 1:1 hexane/chloroform mixed with 0.1 wt % triethylamine as an eluting solvent, to thereby obtain 17.31 g of objective 7-bromodibenzothiophene-3-yl-amine. The product was subjected to elemental analysis, the results of which are as follows:
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=2)[C:12]([CH3:20])=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C.C([Li])CCC>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([B:21]([OH:26])[OH:22])=[CH:16][CH:17]=2)[C:12]([CH3:20])=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn(COCc2ccccc2)c2ccc(Br)cc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nn(COCc2ccccc2)c2ccc(B(O)O)cc12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 72.8 %

Procedure:
To a −78° C. stirred solution of the compound from step A (0.72 g, 2.18 mmol) in anhydrous toluene/THF (5 mL/3 mL) under nitrogen was added triisopropyl borate (0.53 g, 2.83 mmol) and then butyl lithium (2.5 M in hexanes, 1.22 mL, 3.05 mmol) slowly over about 10 min. After 10 min the dry ice bath was removed and stirring was continued for 20 min. The mixture was cooled at −78° C. and triisopropyl borate (0.32 g, 1.71 mmol) and butyl lithium (2.5 M in hexanes, 0.85 mL, 2.14 mmol) were added. The dry ice bath was removed and the mixture was allowed to warm to ambient temperature and was stirred for additional 20 min before quenching with a saturated solution of sodium bicarbonate (30 mL). The mixture was extracted with ethyl acetate (50 mL×2). The extracts were dried and contracted to give a solid. The solid was triturated with ethyl acetate/hexane (1:1) and dried to give the title compound (0.47 g, 81%).
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[CH2:9][C:8]1=[O:18]>CN(C)C=O>[CH3:17][O:16][C:12]1[CH:13]=[CH:14][C:15]2[N:7]3[C:8]([O:18][CH2:4][CH2:5][CH2:6]3)=[CH:9][C:10]=2[N:11]=1
Reactant: COc1ccc2c(n1)CC(=O)N2CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(cc3n2CCCO3)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under an inert atmosphere, 160 mg (4 mmol) of sodium hydride (60% in oil) are added slowly at 0° C. to a solution of 380 mg (1.34 mmol) of the compound obtained in Step E in 10 ml of N,N-dimethylformamide. The reaction mixture is stirred at 0° C. for 30 minutes before being hydrolysed with ice and then extracted with ethyl acetate. The organic phase is washed several times with water, dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant:ethyl acetate/petroleum ether, 95:5) to yield the title compound in the form of a brown solid.
Reaction SMILES: [C:1]([O-])(=[O:3])[CH3:2].[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[N:14]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](=[N+]=[N-])[C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=1)[CH3:15].C(O)C>C1C=CC=CC=1>[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[N:14]([CH2:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH:26]([O:3][CH2:1][CH3:2])[C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:24]=1)[CH3:15]
Reactant: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)=[N+]=[N-]
Reactant: CC(=O)[O-]
Solvent: CCO
Solvent: c1ccccc1
Product: CCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Rodium (II) acetate dimer (33 mg) was added to a mixture of methyl 3-[4-[2- [N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-diazopropanoate (2.80 g), ethanol (2.16 mL) and benzene (50 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 15 minutes, heated at reflux for a further 15 minutes, then cooled and evaporated in vacuo. The residue was chromotographed on silica gel using 1.5% methanol in dichloromethane as eluent to afford the title compound as a gum. 1H NMRδ(CDCl3) 1.14 (3H,t); 2.93 (2H,app d); 3.31 (1H,complex); 3.32 (3H,s); 3.57 (1H,complex); 3.69 (3H,s); 3.93 (3H,complex); 4.23 (2H,t);6.79 (2H,d); 7.00 (1H,t); 7.14 (3H,complex); 7.25 (1H,d); and 7.36 (1H,d).
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](NCC3C=CC=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:25]1([C@@H:31]([NH2:33])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:33][C@H:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:32])[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: C[C@H](N)c1ccccc1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: Cc1nc(N[C@@H](C)c2ccccc2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [(1S)-1-phenylethyl]amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03-1.87 (m, 16H), 2.13 (s, 3H), 3.80 (s, 1H), 4.95-5.02 (m, 1H), 6.73 (s, 1H), 7.14-7.41 (m, 5H), 8.38 (s, 1H); MS (ESI) m/z 325.8 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[C:8]([C:15]([O:17][CH3:18])=[O:16])=[N:7][C:6]=1[C:19]([O:21][CH3:22])=[O:20])=[O:4]>C(O)C.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH:6]([C:19]([O:21][CH3:22])=[O:20])[NH:7][CH:8]([C:15]([O:17][CH3:18])=[O:16])[CH:9]([C:11]([O:13][CH3:14])=[O:12])[NH:10]1)=[O:4]
Reactant: COC(=O)c1nc(C(=O)OC)c(C(=O)OC)nc1C(=O)OC
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1NC(C(=O)OC)C(C(=O)OC)NC1C(=O)OC

Procedure:
A solution of tetrakis-methoxycarbonylpyrazine (5.3g, 16.9 mmol) (prepared in accordance with J. Org. Chem. 37 (19) , p2963 (1972)) in 800 ml of dry ethanol, was hydrogenated at 50 bar in the presence of 10 g 5% palladium on charcoal at 80 ° C. for 16 hours. After cooling, the solution was filtered and evaporated to give slightly yellow crystals. Yield: 4.8 g (90%) , mp. 162°-163° C. (Lit. 162°-163° C.). NMR confirmed the structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([O:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[N:9]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1ccc(CCCC(=O)O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc(CCCC(=O)OCc2ccccc2)n1
Reaction time: 24 h
Yield: 68.4 %

Procedure:
To a stirred solution of 60.0 g (236 mmol) of 4-[1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl]butanoic acid from step C above in 400 mL of DMF was added 48.9 g (354 mmol) of potassium carbonate followed by dropwise addition of 40.0 mL (300 mmol) of benzyl bromide. The resulting mixture was stirred for 24 h, quenched with water, and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The crude residue was purified by silica gel chromatography eluting with 30% ethyl acetate in hexanes to afford the title compound as a yellow oil (55.6 g. 68.4%). LC-MS: m/z (ES) 345 (MH)+.