Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=1.CO.C1COCC1.O[Li].O>O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a solution of ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (25 g, 0.07 mol) in 1:1 (MeOH:THF) (400 mL) were added LiOH.H2O (6.3 g, 0.38 mol) and water (50 mL). The mixture was then stirred at RT for 1 h. The reaction mixture was then concentrated in vacuo. The residue was then acidified with aqueous HCl (1N) and extracted with EtOAc (2×300 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (9.0 g, 40%) as a solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:24]4=[N:25][C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:27][C:28](=[O:29])[N:23]4[CH2:22][CH2:21][CH2:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:6]=[CH:7][CH:8]=1.N12CCCN=C1CCCCC2.C1(P([N:61]=[N+:62]=[N-:63])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:61]([CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:24]4=[N:25][C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:27][C:28](=[O:29])[N:23]4[CH2:22][CH2:21][CH2:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:6]=[CH:7][CH:8]=1)=[N+:62]=[N-:63]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(Cc1cccc(CO)c1)Nc1nccc(N2CCCn3c2nc(-c2ccccc2)cc3=O)n1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(Cc1cccc(CN=[N+]=[N-])c1)Nc1nccc(N2CCCn3c2nc(-c2ccccc2)cc3=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring mixture of 9-{2-[2-(3-hydroxymethyl-phenyl) -1-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro -pyrimido[1,2-a]pyrimidin-4-one (230 mg, 0.49 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL, 0.88 mmol), and tetrahydrofuran (12 mL) at 0° C. under an atmosphere of nitrogen was added diphenylphosphoryl azide (0.19 mL, 0.88 mmol). Mixture stirred overnight warming to room temperature. Solvent removed under vacuum and product isolated as a white solid after purification on silica. M+1=494.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([S:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8].FC(F)(F)S(O[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)(=O)=O>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([S:10][C:5]2[CH:4]=[CH:3][C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:9][C:6]=2[CH:7]=[O:8])=[CH:12][CH:13]=1
Reactant: Cc1ccc(Sc2ccc(Br)cc2C=O)cc1
Reactant: O=S(=O)(Oc1ccccn1)C(F)(F)F
Product: Cc1ccc(Sc2ccc(-c3ccccn3)cc2C=O)cc1
Yield: 39.3 %

Procedure:
The reaction was performed in accordance with a document (Tetrahedron Lett. Vol. 36, No. 50, pp. 9085-9088, 1995) and the product was treated by using 5-bromo-2-[(4-methyphenyl)thio]-benzaldehyde (0.06 g, 0.2 mmol) and 2-pyridyl trifluoromethanesulfonate (0.03 g, 0.2 mmol). The residue was purified by thin-layer chromatography (hexane: ethyl acetate=8:1)) to obtain 2-[(4-methylphenyl)thio]-5-(2-pyridyl)benzaldehyde (0.024 g, 38.5%).
Reaction SMILES: [F:1][CH:2]([F:19])[C@:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[NH:8][C:7](=[O:9])[CH2:6][CH2:5][C:4]1([F:11])[F:10].OS(O)(=O)=O.[N+:25]([O-])([OH:27])=[O:26].[OH-].[Na+]>FC(F)(F)C(O)=O>[F:19][CH:2]([F:1])[C@:3]1([C:12]2[CH:17]=[C:16]([N+:25]([O-:27])=[O:26])[CH:15]=[CH:14][C:13]=2[F:18])[NH:8][C:7](=[O:9])[CH2:6][CH2:5][C:4]1([F:11])[F:10]
Reactant: O=C1CCC(F)(F)[C@](c2ccccc2F)(C(F)F)N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(F)(F)[C@](c2cc([N+](=O)[O-])ccc2F)(C(F)F)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
(S)-6-(difluoromethyl)-5,5-difluoro-6-(2-fluorophenyl)piperidin-2-one (880 mg, 3.15 mmol) was suspended in trifluoroacetic acid (2.55 mL). The mixture was cooled to 0° C. and concentrated H2SO4 (2.46 g, 24.3 mmol) was added. Then, HNO3 (661.61 mg, 6.30 mmol) was added dropwise. After 2 hours of stirring at 25° C., the reaction mixture was poured onto 100 g ice and basified to pH>11 using 5 M NaOH (aq). The suspension was extracted with ethyl acetate (150 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×70 mL). The combined organic phases were washed with a solution of saturated aqueous NH4Cl (30 mL) and water (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford (S)-6-(difluoromethyl)-5,5-difluoro-6-(2-fluoro-5-nitrophenyl)piperidin-2-one (1.00 g, crude).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:25]([OH:27])=O)[C:11]3[C:16]([CH:17]=[CH2:18])=[N:15][N:14]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[C:28]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.CN(C)C(=O)C>[C:31]([O:30][C:28]([N:35]1[CH2:40][CH2:39][N:38]([C:25]([C:10]2[C:11]3[C:16]([CH:17]=[CH2:18])=[N:15][N:14]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[C:12]=3[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[CH:9]=2)=[O:27])[CH2:37][CH2:36]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: C=Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)O)c12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: C=Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of 6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3.12 g, 6.62 mmol) in tetrahydrofuran (44 mL) were added 1-boc-piperazine (1.35 g, 7.28 mmol), 1-hydroxybenzotriazole (0.09 g, 0.66 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.27 g, 6.62 mmol). After 2 hours, N,N-dimethylacetamide (3 ml), 1-boc-piperazine (0.24 g, 1.32 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.25 g, 1.32 mmol) were added to the reaction mixture. After 1 hour, tetrahydrofuran was evaporated under reduced pressure, water and dichloromethane were then added. The organic layer was washed with an aqueous 1M HCl solution, water, brine, dried (Na2SO4), filtered, concentrated under vacuum. The crude residue was purified on a silica gel column chromatography using a gradient of methanol (0-5%) in dichloromethane to yield the title compound as a yellow foam (3.17 g, 90%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[NH2:10])([O-:3])=[O:2].[CH2:18]([O:20][C:21](Cl)=[O:22])[CH3:19].[OH2:24]>C(O)C>[C:21]([NH:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]2[CH:17]=[CH:16][C:14]([NH:15][C:21]([O:20][CH2:18][CH3:19])=[O:24])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])([O:20][CH2:18][CH3:19])=[O:22]
Reactant: CCOC(=O)Cl
Reactant: O
Reactant: Nc1ccc(-c2ccc(N)c([N+](=O)[O-])c2)cc1
Solvent: CCO
Product: CCOC(=O)Nc1ccc(-c2ccc(NC(=O)OCC)c([N+](=O)[O-])c2)cc1
Yield: 95 %

Procedure:
Twenty nine grams 3-nitrobenzidine were dissolved in 330 ml ethanol containing 39 ml (36 grams) dimethyaniline. Thirty one grams ethylchloroformate were added to the ethanol solution in portions. The solution was then refluxed for 10 minutes after which water was added to precipitate the diurethane derivative. Forty one grams were obtained corresponding to a yield of 95%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)=[O:4].[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15]Cl.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:18])([CH3:17])[CH3:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COCC[Si](C)(C)C)cn1
Temperature: 80 °C
Reaction time: 10 h
Yield: 59.9 %

Procedure:
A flask charged with 1H-imidazole-4-carboxylic acid methyl ester (0.54 g, 4.3 mmol), 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) (1.0 mL, 5.6 mmol), K2CO3 (1.4 g, 10.4 mmol), and DMF (7 mL) was stirred for 10 h at 80° C. The mixture was diluted with EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL) and the organic layer dried over MgSO4 and concentrated. The title compound was eluted from a 20-g SPE cartridge (silica) with 50% EtOAc/hexane to give 0.66 g (60%) of a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C11H20N2O3Si, 257.1 (M+H), found 257.0.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][CH2:12][CH2:13][NH2:14].[C:15]([NH:17][C:18](=[N:21][CH3:22])SC)#[N:16]>>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][CH2:12][CH2:13][NH:14][C:18]([NH:17][C:15]#[N:16])=[N:21][CH3:22]
Reactant: CN=C(NC#N)SC
Reactant: NCCNCc1nc2ccccc2[nH]1
Product: CN=C(NC#N)NCCNCc1nc2ccccc2[nH]1

Procedure:
Reacting N-(2-benzimidazolylmethyl)ethylenediamine with N-cyano-N',S-dimethylisothiourea by the procedure of Example 36 gives N-[2-(2-benzimidazolylmethylamino)ethyl]-N'-cyano-N"-methylguanidine. Treating with hydrobromic acid gives the hydrobromide salt. Hydrolysis of this compound by the procedure of Example 3(e) gives N-[2-(2-benzimidazolylmethylamino)-ethyl]-N'-methylguanidine trihydrochloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([CH2:17][CH2:18]O)[N:13]=[CH:14]3)=[CH:9][CH:8]=2)[CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:38][C@@H:39]1[CH2:43][CH2:42][CH2:41][NH:40]1>C(Cl)Cl.C(#N)C>[CH3:38][C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[CH2:18][CH2:17][C:12]1[N:13]=[CH:14][C:15]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH:16]=2
Reactant: OCCc1cc2ccc(-c3cccnc3)cc2cn1
Reactant: C[C@@H]1CCCN1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CCCN1CCc1cc2ccc(-c3cccnc3)cc2cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The product from Example 63A (0.25 g, 1.0 mmol) and triethylamine (0.15 g, 1.5 mmol) in methylene chloride (10 mL) at −5° C. were treated with methanesulfonyl chloride (0.12 g, 1.2 mmol) and stirred at 0° C. for 2 hours and then stirred at room temperature for 15 hours. The mixture was concentrated under reduced pressure and the residue was treated with K2CO3 (0.21 g, 1.5 mmol) and (2R)-2-methylpyrrolidine (0.13 g, 1.5 mmol) in acetonitrile (15 mL), and then heated at 60° C. for 5 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in 30 mL methylene chloride, washed with 10 mL 15% NaCl, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10:90:1 MeOH:CHCl3:Et3N) to provide the title compound. 1H NMR (CDCl3, 400 MHz) δ 9.27 (s, 1H), 8.95 (m, 1H), 8.64 (dd, J=2, 4 Hz, 1H), 8.12 (s, 1H), 7.98 (m, 1H), 1.90-1.86 (m, 2H), 7.56 (s, 1H), 7.44-7.40 (m, 1H), 3.37-3.28 (m, 2H), 3.26-3.18(m, 2H), 2.68-2.61(m, 2H), 2.51-2.46(m, 1H), 2.38-2.31 (m, 1H), 2.00-1.93(m, 1H), 1.88-1.82(m, 1H), 1.80-1.72(m, 1H), 1.55-1.46 (m, 1H), 1.14(d, 3H); 13C NMR (CDCl3, 400 MHz) δ 9.27 153.8, 151.9, 148.4, 147.9, 135.6, 135.5, 135.4, 134.1, 129.1, 127.0, 126.9, 125.2, 123.4, 118.2, 60.4, 54.1, 54.0, 37.2, 32.8, 21.9, 19.0.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[CH:23]([C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)=O>>[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH:22][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[NH:1][CH2:23][C:25]3[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=3)[N:9]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(CN)o1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: NS(=O)(=O)c1cccc(C=O)c1
Product: Cc1ccc(CNc2ccc3c(NCc4cccc(S(N)(=O)=O)c4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=423.1 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and 3-formylbenzenesulfonamide (CAS 1778-37-6) as described in example 26.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ClC(Cl)C(O)=O>C1(C)C=CC=CC=1.CS(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:9](=[O:10])[N:11]1[CH2:14][C:13](=[O:15])[CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CC(O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CC(=O)C1
Temperature: 10 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
[(1S)-Benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (320 mg, 1 mmol) was added in one portion to a mixture of 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (DEC, 575 mg, 3 mmol) and dichloroacetic acid (192 mg, 1.5 mmol) in anhydrous toluene (2 mL) and anhydrous dimethylsulfoxide (2 mL). The mixture was stirred at 0-20° C. for 1 h, diluted with ethyl acetate, the resulting solution washed twice with 1N HCl, twice with saturated aqueous NaHCO3, dried and concentrated giving a colorless solid (304 mg, 96%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH:14]=1)[CH2:7]NC(C)(C)CO.ClN1C(=[O:29])CCC1=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH:14]=1)[CH:7]=[O:29]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(CO)NCc1cc(Br)ccc1CCc1ccccc1
Solvent: ClCCl
Product: O=Cc1cc(Br)ccc1CCc1ccccc1
Reaction time: 4 h
Yield: 48.6 %

Procedure:
A mixture of 2-(N-(5-bromo-2-(phenethyl)benzyl)amino)-2-methylpropan-1-ol (9.13 g), N-chlorosuccinimide (3.38 g) and dichloromethane (50 ml) was stirred for 4 hours. Aluminia (10 g) was added and the mixture stirred for 6 days, filtered and the solvent evaporated. The residue was dissolved in dichloromethane (200 ml) and alumina (60 g) added in 6 portions over 8 hours. The mixture was filtered, the filtrate evaporated and the residue purified by MPLC eluting with dichloromethane/hexane (1:1) to give 5-bromo-2-(phenethyl)benzaldehyde (3.54 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][S:21]([C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH2:27])(=[O:23])=[O:22].FC(F)(F)C(O)=O.CC(O)C>Cl>[NH2:20][S:21]([C:24]1[CH:25]=[C:26]([NH:27][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)[CH:28]=[CH:29][C:30]=1[CH3:31])(=[O:22])=[O:23]
Reactant: C#CCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: C#CCOc1ccc(Nc2nc(Nc3ccc(C)c(S(N)(=O)=O)c3)ncc2F)cc1
Temperature: 100 °C

Procedure:
2-Chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine (0.514 g, 1.85 mmol), 3-(aminosulfonyl)-4-methylaniline (0.689 g, 3.70 mmol), and trifluoroacetic acid (0.186 mL, 2.41 mmol) were combined with iPrOH (6.0 mL) in a sealed vial and heated at 100° C. for 3 h. The reaction mixture was cooled to room temperature and diluted with 1N HCl (80 mL). N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine VI-53) was isolated as a white solid by suction filtration (0.703 g). 1H NMR (DMSO-d6): δ 10.08 (bs, 2H), 8.19 (d, J=4.5 Hz, 1H), 7.89 (s, 1H), 7.74 (dd, J=2.4 and 8.4 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.32 (bs, 2H), 7.23 (d, J=8.4 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H), 4.79 (d, J=2.1 Hz, 2H), 3.59-3.55 (m, 1H), 2.53 (s, 3H); LCMS: purity: 97%; MS (m/e): 428 (MH+).
Reaction SMILES: Br.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[C:9]([O:11]CC)=O.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].[C:25](=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH2:18]([O:17][C:15](=[O:16])[NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[C:9](=[O:11])[CH3:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: Br
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)C1CCCCC1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
To a 0° C. solution of ethyl cis-2-amino-1-cyclohexanecarboxylate HBr salt (22.34 g, 88.6 mmol) in 250 mL of methylene chloride, was added benzyl chloroformate (12.6 mL, 88.3 mmol) and 250 mL of an aqueous sodium carbonate solution. The reaction mixture was stirred for 24 h at ambient temperature. The organic layer was separated and washed with 250 mL of water, dried over sodium sulfate, filtered and concentrated to give a crude liquid. The product was purified by column chromatography (10-50:90-50 ethyl acetate/hexanes) to give 26.45 g of (2-acetyl-cyclohexyl)-carbamic acid benzyl ester as a clear liquid. Yield: 98%, MS: 306 (M+H+).
Reaction SMILES: [C:1]1([CH3:35])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:2]=1.CO.[OH-].[Na+].Cl>C1COCC1.O>[C:1]1([CH3:35])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[CH:2]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3cccc(C)c3)c(-c3ccc(C)cc3)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2nc3c(nc2-c2cccc(C)c2)CCCN3CCCCCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 7-(2-m-tolyl-3-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1)(69 mg, 0.146 mmol) in THF (1 ml) and water (0.5 ml) at RT was treated with LiOH monohydrate (18.42 mg, 0.439 mmol) and stirred at RT for 4 hours. MeOH (1 ml) and 2M NaOH (1 ml) were added and the mixture was stirred at RT overnight. The resulting mixture was added to water (20 ml) and the pH was adjusted to pH1 with 2M HCl. The aqueous portion was extracted with DCM (×3) and the organic extracts were passed through a phase separating column. The organic solvent was concentrated in vacuo. The crude product was purified by preparative LC-MS (low pH). The appropriate fraction was collected and extracted with DCM (×3), passing the organics through a phase separating column. The solvent was removed in vacuo to afford the title compound;
Reaction SMILES: [Li].[H-].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][C:14]1[CH:23]=[C:22]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16](OC)=[O:17].Cl>C(OCC)C.O1CCCC1>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][C:14]1[CH:23]=[C:22]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[CH2:16][OH:17]
Reactant: COC(=O)c1ccc(COc2ccccc2)cc1Cc1ccc2ccccc2c1
Agent: Cl
Agent: [H-]
Agent: [Li]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1ccc(COc2ccccc2)cc1Cc1ccc2ccccc2c1
Reaction time: 0.5 h

Procedure:
To the suspension of zinc (710 mg) in tetrahydrofuran (2 ml) was added dibromoethane (1 drop) under an atmosphere of argon. The mixture was heated and then added trimethylsilyl chloride (1 drop). The reaction mixture was cooled to 0° C. and added dropwise a solution of 2-bromomethylnaphthalene (1.20 g) in tetrahydrofuran (3 ml). The mixture was stirred at room temperature for 1.5 hour to give the zinc reagent. To a solution of [bis(benzylidene)acetone]palladium (156 mg) and diphenylphosphinoferrocene (151 mg) in tetrahydrofuran (2 ml) was added the compound prepared in Reference Example 17 (1.00 g) in tetrahydrofuran (3 ml) under an atmosphere of argon. To the mixture was added the above-mentioned zinc reagent. The mixture was stirred at room temperature for 30 minutes. To the mixture was added a saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride subsequently, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel to give methyl 2-(2-naphthylmethyl)-4-phenoxymethylbenzoate. To a suspension of lithium alminium hydride (206 mg) in (2 ml) was added dropwise a solution of the above-mentioned methyl 2-(2-naphthylmethyl)-4-phenoxymethylbenzoate in diethyl ether (3 ml)-tetrahydrofuran (3 ml) under an atmosphere of argon. The mixture was stirred for 30 minutes. To the mixture was added 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride subsequently, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (974 mg) having the following physical data.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[Br:8][C:9]1[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>CCOCC.O>[Br:8][C:9]1[CH:10]=[C:11]([N:15]2[C:4](=[O:5])[CH:3]=[CH:2][C:1]2=[O:7])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1cccc(Br)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: O=C1C=CC(=O)N1c1cccc(Br)c1
Temperature: 100 °C
Yield: 64.8 %

Procedure:
To a solution of maleic anhydride (1.71 g, 17.4 mmol) in dry ether (25 ml) was added a solution of 3-bromo-phenylamine (3.0 g, 17.4 mmol) in ether (5 ml), via slow drop-wise addition. The material was stirred for 1 hour at ambient Sodium acetate (721 mg, 8.8 mmol) and then acetic anhydride (6 ml, 63 mmol) were added and the mixture was heated for 2 hours (oil bath, 100° C.). The material was cooled to ambient and then in an ice bath. Water (50 ml) was added with vigorous stirring and the resultant precipitate was collected by filtration. The precipitate was washed with several volumes of water and finally with hexane (30 ml). The material was dried over night in the vacuum oven to afford 2.84 g of 1-(3-bromo-phenyl)-pyrrole-2,5-dione as a light yellow-white powder.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[N:3]=1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([C:4]2[N:3]=[C:2]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: NCc1ccncc1
Reactant: COc1ccc(-c2cc3nccn3c(Cl)n2)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1ccc(-c2cc3nccn3c(NCc3ccncc3)n2)cc1OC
Temperature: 90 °C
Reaction time: 20 h
Yield: 52.6 %

Procedure:
The mixture of 5-chloro-7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidine (57.94 mg, 0.2 mmol), 4-aminomethylpyridine (23.79 mg, 0.22 mmol), and diisopropylethylamine (38.78, 0.3 mmol) in 2-propanol was stirred at 90° C. for 20 h, and cooled to room temperature. The solvent was evaporated, and 5 ml of ice water was added. Then the resulting product was extracted with 2×10 ml of ethyl acetate. The combined extract was dried over MgSO4. Then the solvent was evaporated and 2 ml of ether was added. The produced solid was collected by filtration and dried to give pure product (38 mg, 52.6%) of [7-(3,4-dimethoxy-phenyl)-imidazo[1,2-c]pyrimidin-5-yl]pyridin-4-ylmethyl-amine.