Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1.[NH4+:32].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCCl>[NH2:32][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: COCCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy)ethylcarbamate (10.6 g, 24.6 mmol) in 100 mL of 1,2-dichloroethane was heated to 60° C. and treated with 10 mL of concentrated NH4OH solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (7.05 g, 37.0 mmol) over a 10 min period. The reaction mixture was treated with an additional 1 mL concentrated NH4OH solution and then sealed in a pressure vessel and heating was continued for 2 h. The reaction mixture was then cooled and treated with 100 mL of CHCl13. The reaction mixture was then washed with H2O, 1% Na2CO3 solution (2×) and brine. The organic portion was dried over Na2SO4 and concentrated to give 10.6 g of tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a brown foam.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]2[CH2:31][O:30]2)=[CH:25][N:24]=1>C(O)C>[Cl:22][C:23]1[N:24]=[CH:25][C:26]([C@@H:29]([OH:30])[CH2:31][NH:1][CH2:2][CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=3)=[CH:7][CH:6]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(CCCN)cc2)cc1
Reactant: Clc1ccc([C@@H]2CO2)cn1
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(CCCNC[C@H](O)c3ccc(Cl)nc3)cc2)cc1
Yield: 47.6 %

Procedure:
A solution of ethyl 4′-(3-aminopropyl)-1,1′-biphenyl-4-carboxylate (200 mg), and 2-chloro-5-[(2R)-2-oxiranyl]-pyridine (71.5 mg) in ethanol (10 ml) was refluxed for 18 hours. The mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=100:1) to give ethyl 4′-[3-[[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]-1,1′-biphenyl-4-caroxylate (96 mg) as a colorless foam.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:10][CH2:11][F:12].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH2:10][CH2:11][F:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FCCOc1cccnc1Br
Yield: 68 %

Procedure:
A mixture of 2-bromopyridin-3-ol 27 (0.1 mmol), 1-bromo-2-fluoroethane (0.2 mmol) and K2CO3 (0.4 mmol) in acetonitrile were stirred at refluxing for one day until TLC indicated that the reaction was complete, and then filter, dried and concentrated under reduce pressure. The crude product was purified with column chromatography to afforded 28 (yield, 68%). 1H NMR (CDCl3): δ 4.25-4.34 (m, 2H), 4.73-4.89 (m, 2H), 7.20-7.22 (m, 2H), 8.01 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH3:10].C1COCC1.C([Li])CCC.C(O[B:25]1[O:33][C:30]([CH3:32])([CH3:31])[C:27]([CH3:29])([CH3:28])[O:26]1)(C)C>O>[CH2:9]([S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:25]1[O:33][C:30]([CH3:32])([CH3:31])[C:27]([CH3:29])([CH3:28])[O:26]1)[CH3:10]
Reactant: CCSc1ccccc1Br
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCSc1ccccc1B1OC(C)(C)C(C)(C)O1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A mixture of 14.1 g of l-bromo-2-ethylsulfanylbenzene and 65 mL of THF was cooled to −70° C., and 44.7 ml of n-butyl lithium (1.63M hexane solvent) was added at a rate such that the internal temperature of the mixture was kept at −60° C. or less, and the mixture was stirred at −50° C. for 30 minutes. A mixture of 14 g of isopropoxyboronic acid pinacol ester and 5 mL of THF was added at a rate such that the internal temperature of the mixture was kept at −60° C. or less, and the mixture was heated to the room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 7.9 g of 2-ethylsulfanylphenylboronic acid pinacol ester.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]45[CH2:21][CH:16]6[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]6)[CH2:13]4)[CH2:19]5)([CH2:5]3)[CH2:3]1)[CH2:9]2.[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1.[C:30]1([CH3:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]12([C:6]34[CH2:7][CH:8]5[CH2:9][CH:2]([CH2:3][C:4]([C:26]6[CH:27]=[C:28]([C:2]78[CH2:11][CH:6]9[CH2:7][CH:8]([CH2:10][C:4]([C:12]%10%11[CH2:21][CH:16]%12[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]%12)[CH2:13]%10)[CH2:19]%11)([CH2:5]9)[CH2:3]7)[CH2:9]8)[C:23]([OH:22])=[CH:24][C:25]=6[OH:29])([CH2:10]5)[CH2:5]3)[CH2:11]4)[CH2:36][CH:12]3[CH2:13][CH:34]([CH2:33][CH:32]([CH2:19]3)[CH2:31]1)[CH2:35]2
Reactant: Oc1cccc(O)c1
Reactant: BrC12CC3CC(C1)CC(C14CC5CC(CC(C5)C1)C4)(C3)C2
Reactant: Cc1ccccc1
Product: Oc1cc(O)c(C23CC4CC(C2)CC(C25CC6CC(CC(C6)C2)C5)(C4)C3)cc1C12CC3CC(C1)CC(C14CC5CC(CC(C5)C1)C4)(C3)C2
Temperature: 130 °C
Reaction time: 24 h
Yield: 66.4 %

Procedure:
121.9 g of 3-bromo-1,1′-biadamantane (349 mmol), 9.58 g of 1,3-dihydroxybenzene (87.0 mmol), 25 mL of toluene and a stirrer were charged in a 300 mL recovery flask. The mixture was heated and agitated at 130° C. for 24 hours under nitrogen flow. A solid was obtained by removing a solvent under reduced pressure. The obtained solid was purified by column chromatography, thus obtaining 37.4 g of 4,6-di[3-(1-adamantyl)-(1-adamantyl)]-1,3-dihydroxybenzene (57.8 mmol; the yield was 66.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:19][C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23].[C:29](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH3:29])[CH:5]=[CH:4][C:3]=1[NH:19][C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:23])[F:24]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1
Reaction time: 64 h
Yield: 56.3 %

Procedure:
A mixture of (R)-N-[2-chloro-4-(4-methylphenylsulphonamido)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 356) (0.137 g), anhydrous potassium carbonate (0.043 g) and iodomethane (0.038 ml) in acetone (8 ml) was stirred for 64 hours. Volatile material was removed by evaporation and the residue was dissolved in ethyl acetate, washed with water and brine then dried. Volatile material was removed by evaporation and the residue was purified by elution through a Varian Isolute silica 10 g column with 30% ethyl acetate/hexane as eluent to give the title compound (0.079 g). NMR: 1.60 (s, 3H), 2.38 (s, 3H), 3.11 (s, 3H), 7.11 (d, 3H), 7.32 (s 1H), 7.43 (m, 4H), 7.94 (d, 1H), 9.67 (brs, 1H); MS (ESP−): 449.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:10])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 12.25 h

Procedure:
To a solution of 0.8 g (4.4 mmol) of 4-bromo-3-methylphenol in 20 mL of acetone was added 1.5 g (10.9 mmol) of potassium carbonate. A yellow slurry was obtained to which was added 0.55 mL (1.25 g, 8.8 mmol) of methyl iodide. The resultant reaction mixture was stirred at ambient temperature for 12.25 hours, filtered and extracted between ethyl ether and water. The layers were separated and the organic phase was washed with sat. Na2SO3 (aq.) solution, dried over MgSO4, filtered and then concentrated in vacuo to a yellow oil. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as a yellow oil.
Reaction SMILES: [C:1]([N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH2:11]([Li])[CH2:12][CH2:13]C.C(Br)C#C>C1COCC1>[C:1]([N:5]1[CH2:9][CH2:8][N:7]([CH2:13][C:12]#[CH:11])[C:6]1=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: CC(C)(C)N1CCNC1=O
Agent: C#CCBr
Solvent: C1CCOC1
Product: C#CCN1CCN(C(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dissolve 1-tert-butyl-imidazolidin-2-one (2 g, 14 mmol) in anhydrous THF (60 mL) and cool at −78° C. Slowly add n-butyllithium (6.8 mL, 17 mmol, 2.5 M solution in hexanes). Stir the solution for 30 min. Rapidly add propargyl bromide (3.2 mL, 28.2 mmol, 80% solution in toluene). Warm the solution to room temperature while stirring overnight Concentrate the reaction mixture in vacuo and filter the residue on a short pad of silica gel eluting with dichloromethane/diethyl ether (1:1) to give the title compound as a yellow oil that solidifies on standing (1.77 g, 70%). GC-MS m/z (%) 180 (M+, 7), 165 (100), 123 (12), 84 (17).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:39]1([NH2:42])[CH2:41][CH2:40]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](=[O:23])[NH:42][CH:39]3[CH2:41][CH2:40]3)=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)NC3CC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 47.1 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.2 g, 0.36 mmol), cyclopropylamine (0.05 g, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.18 g, 0.72 mmol) were dissolved in 20 mL of dichloromethane under stirring, and triethylamine (0.36 g, 3.6 mmol) was added to the solution at room temperature. The reaction mixture was reacted at room temperature for 2 hours, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-cyclopropylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 15a (0.1 g, yield 45%) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][N:10](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:9]#[N:10])[N:7]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1ccnc(C#N)n1
Temperature: 110 °C
Yield: 56 %

Procedure:
A mixture of 2-chloro-4-methylpyrimidine (725 mg, 5.63 mmol, 1 eq), zinccyanide (396 mg, 3.38 mmol, 0.6 eq) and tetrakis(triphenylphosphine)palladium(0) (716 mg, 0.562, 0.1 eq) in DMF (10 ml) was heated at 110° C. under nitrogen for 1 hr. The mixture was cooled to r.t., diluted with EtOAc and washed twice with 2N ammonium hydroxide (50 ml). The organic layer was washed with brine (20 ml) dried over sodium sulphate and concentrated in vacuum to provide the crude mixture. The crude product was then purified by column chromatography (30% EtOAc in Hexane) to afford 4-methylpyrimidine-2-carbonitrile Yield: 380 mg (56%). 1H NMR (400 MHz, CDCl3): δ 2.61 (s, 3H), 7.36 (d, 1H, J=5.2 Hz), 8.66 (d, 1H, J=5.2 Hz),
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)([O-:11])=[O:10].O>C(Cl)Cl>[N:7]([C:1]1([O:17][CH2:16][C:15]2[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: ON=C1CCCCC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: ClCCl
Product: O=NC1(OCc2ccc([N+](=O)[O-])cc2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
A solution of cyclohexanone oxime (2.66 g, 23.51 mmol) in methylene chloride (50 mL) was added dropwise with stirring to a solution of LTA (10.42 g, 23.51 mmol) and 4-nitrobenzoic acid (39.29 g, 235.1 mmol) in methylene chloride (300 mL) at 0° C. A blue color gradually appeared with the addition of the oxime. After 1 h at 0° C., the reaction mixture was warmed to room temperature. After 3 h at room temperature, water (50 mL) was added and the organic layer was extracted with water (2×50 mL) and 3% sodium bicarbonate solution (2×50 mL). The organic layer was dried over Na2SO4, the solvent evaporated and the residue was recrystallized in diethyl ether/petroleum ether (1:1) in a −5° C. freezer to give 1-Nitroso-1-para-nitrobenzoxycyclohexane as bright blue crystals (20-25% yield): Rf 0.55 (pentane/ethyl acetate=20:1); 1H NMR (300 MHz, Benzene-d6) δ 1.17-2.04 (m, 10H), 7.38-7.98 (d, 4H); 13C NMR (300 MHz, Benzene-d6) δ 22.1 (2CH2), 25.0 (CH2), 29.7 (2CH2), 123.8 (2Ph-CH), 125.3 (O—C—N), 131.1 (2Ph-CH), 135.3 (Ph-C), 151.1 (Ph-C), 162.6 (C═O).
Reaction SMILES: Cl[C:2]1[S:12][C:5]2[CH:6]3[CH:10]([CH2:11][C:4]=2[C:3]=1[C:13]#[N:14])[CH2:9][NH:8][CH2:7]3.N([O:17][C:18]([CH3:21])(C)C)=O.C[CH2:23][OH:24]>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:18]([O:17][C:23]([N:8]1[CH2:7][CH:6]2[CH:10]([CH2:11][C:4]3[C:3]([C:13]#[N:14])=[CH:2][S:12][C:5]=32)[CH2:9]1)=[O:24])[CH3:21]
Reactant: CC(C)(C)ON=O
Reactant: N#Cc1c(Cl)sc2c1CC1CNCC21
Reactant: CCO
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: CCOC(=O)N1CC2Cc3c(C#N)csc3C2C1
Temperature: 60 °C
Yield: 27 %

Procedure:
The product from Example 12, step a) (105 mg, 0.38 mmol) was dissolved in EtOH (1.9 ml) and treated with t-butyl nitrite (59 mg, 0.57 mmol) followed by Cu(OAc)2 (103 mg, 0.57 mmol). The contents were heated to 60° C. for 1 hour and then the reaction mixture was cooled and the EtOH was concentrated. The residue was partitioned between brine (5 ml) and EtOAc (10 ml). The brine layer was washed with EtOAc (4×10 ml) and the combined organic layers were dried (MgSO4), filtered and concentrated. The crude residue was passed through a plug of silica gel (7:3) hexanes:EtOAc (150 ml) providing the subtitled product as an orange oil (26.7 mg, 27%). MS calculated for C13H14N2O2S+H 263, observed 263.
Reaction SMILES: [I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH3:9].[OH-].[K+].[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O.O>C(O)C>[I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH:9]=[CH:18][C:14]1[N:13]([CH3:12])[CH:17]=[CH:16][CH:15]=1
Reactant: CC1N(C)C=C[NH+]1C
Reactant: Cn1cccc1C=O
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1C=C[NH+](C)C1C=Cc1cccn1C
Yield: 74.3 %

Procedure:
A mixture of 12.0 g of 1,2,3-trimethyl-1H-imidazolium iodide, 2g of potassium hydroxide and 12.0 g of N-methylpyrrole-2-carboxaldehyde in 60 ml of absolute ethanol is refluxed for 15 minutes during which time a precipitate is formed. The mixture is cooled and 10 ml of water is added. The solid is filtered off and crystallized from absolute ethanol to yield 12.3 g of the title compound, melting point 289°-291° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]2)[S:5][CH:6]=1.[F:18][C:19]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C(O)C>[F:18][C:19]1[C:24]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[N:3]=[C:4]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]2)[S:5][CH:6]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(Br)cs2)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3F)cs2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
Under a nitrogen atmosphere, to a mixed solution of the compound (300 mg, 0.95 mmol) obtained in Example 30c and 2-fluoro-3-(trifluoromethyl)phenylboronic acid (260 mg, 1.1 mmol) in 1,2-dimethoxyethane/ethanol (v/v=3/1, 4 mL) were added 2N aqueous sodium carbonate solution (0.57 mL, 1.1 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (78 mg, 0.095 mmol), and the mixture was stirred at 90° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=70/30) to give the title compound (320 mg, 84%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[C:13]([F:24])=[CH:12][N:11]=1>>[F:24][C:13]1[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)=[N:15][C:10]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=2)=[N:11][CH:12]=1
Reactant: Cc1ccc(Nc2nc(Cl)ncc2F)nc1
Reactant: Nc1cccc(O)c1
Product: Cc1ccc(Nc2nc(Nc3cccc(O)c3)ncc2F)nc1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 3-hydroxyaniline with 2-chloro-5-fluoro-N4-(5-methylpyridin-2-yl)-4-pyrimidineamine gave 5-fluoro-N2-(3-hydroxyphenyl)-N4-(5-methylpyridin-2-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 11.39 (bs, 1H), 10.59 (bs, 1H), 8.58 (s, 1H0, 8.41 (d, 1H, J=3 Hz), 8.12 (d, 1H, J=8.7 Hz), 7.82 (d, 1H, J=8.7 Hz), 7.29 (s, 1H), 7.16 (d, 1H, J=9 Hz), 7.05 (t, 1H, J=8.4 Hz), 6.38 (dd, 1H, 1.2 and 6.9 Hz); LCMS: purity: 99%; MS (m/e): 312 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[CH:4][N:3]=1.Cl.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:24][C:22]=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]([NH:24][CH3:22])=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: On1nnc2ccccc21
Reactant: Nc1ncncc1C(=O)O
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CNC(=O)c1cncnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To the mixture of 4-aminopyrimidine-5-carboxylic acid (0.75 g, 5.39 mmol), methylamine hydrogen chloride (0.44 g, 1.2 eq), EDC (1.67 g, 1.5 eq), HOBt (0.87 g, 1.2 eq) in DMF (20 mL) was added DIEA (3.8 mL, 4.0 eq). The mixture was stirred at room temperature overnight. The crude was concentrated and dissolved in EtOAc. It was washed with saturated NaHCO3 solution. The solvent was removed and the crude was purified by silica gel chromatography (0%˜20% MeOH/DCM) to obtain the desired product 4-amino-N-methylpyrimidine-5-carboxamide (0.701 g, isolated yield 85%).
Reaction SMILES: FC1C(N2CCNCC2)=CC2NC=C3C(=O)N(C4C=CC=CC=4)N=C3C=2C=1.F[C:29]1[C:30]([F:48])=[CH:31][C:32]2[C:33]3[C:34]([C:39](=[O:47])[N:40]([C:42]4[CH:46]=[CH:45][S:44][CH:43]=4)[N:41]=3)=[CH:35][NH:36][C:37]=2[CH:38]=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>>[F:48][C:30]1[C:29]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[CH:38][C:37]2[NH:36][CH:35]=[C:34]3[C:39](=[O:47])[N:40]([C:42]4[CH:46]=[CH:45][S:44][CH:43]=4)[N:41]=[C:33]3[C:32]=2[CH:31]=1
Reactant: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccsc1
Reactant: C1COCCN1
Agent: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1
Product: O=c1c2c[nH]c3cc(N4CCOCC4)c(F)cc3c-2nn1-c1ccsc1

Procedure:
The title compound was prepared following the procedure described in the synthesis of 28a using 27d and morpholine. 1H-NMR (DMSO-d6) δ (ppm): 3.11 (4H, brm), 3.79 (4H, brm), 7.21 (1H, m), 7.58 (1H, m), 7.79 (3H, m), 8.67 (1H, m). m/z 371.2
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].[C:12](Cl)(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>N1C=CC=CC=1.ClCCl>[C:12]([NH:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7])(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC(=O)Cl
Reactant: N#Cc1ccc(N)cc1C#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ccc(C#N)c(C#N)c1
Reaction time: 2 h
Yield: 70.7 %

Procedure:
4-Aminophthalonitrile (3.60 g, 25.2 mmole) was dissolved in 8.6 mL of pyridine. Hexanoyl chloride (8.6 mL, 61.5 mmole) was added and the mixture was stirred under N2 for 2 hours. The pyridine was distilled under vacuum until a yellow-orange residue was obtained. This residue was dissolved in dichloromethane and washed with 0.1 M HCI (5×15 mL) and then neutralized with aqueous sodium bicarbonate (3×50 mL). The organic solution was separated and dried over magnesium sulfate. Purification by column chromatography (silica, dichloromethane:methanol 5%) afforded 4.3 g (71% yield) of 4-hexanamidophthalonitrile as a light yellow compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:7])=[O:6].C([Li])CCC>C1COCC1>[CH:4]1([S:5]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: CCCCOS(=O)(=O)CCCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCOS(=O)(=O)C1CC1
Temperature: 0 °C
Yield: 84.7 %

Procedure:
Solutions of 1-butyl 3-chloro-1-propanesulfonate (4.6 g, 21.39 mmol) in 25 ml THF) and of butyllithium (14.7 ml, 23.53 mmol, 1.6M, THF) were simultaneously added to THF (150 ml) at −78° C. under nitrogen atmosphere. The solution was allowed to warm to 0° C. and then quenched with water (2 ml). The volatiles evaporated under reduced pressure and the residue extracted with CH2Cl2 (150 ml). The extract was washed with water and dried (MgSO4) and evaporated to give crude desired product (3.23 g, 78.22%) in almost pure form as pale yellow oil which was used for next step without further purification. 1H NMR (300 MHz, CDCl3) δ 0.94 (t, J=7.5 Hz, 3H), 1.07 (m, 2H), 1.25 (m, 2H), 1.45 (sextet, 2H), 1.74 (quintet, 2H), 2.45 (heptet, 1H), 4.23 (t, J=6.6 Hz, 2H).