Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[N+:23]([O-])=O.[H][H]>C(N(CC)CC)C.CN(C)C=O.[OH-].[Pd+2].[OH-]>[NH2:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[O:15][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: COc1cc2nccc(Oc3ccc(C)cc3[N+](=O)[O-])c2cc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(C)cc3N)c2cc1OC
Yield: 54.8 %

Procedure:
6,7-Dimethoxy-4-(4-methyl-2-nitrophenoxy)quinoline (480 mg) was dissolved in triethylamine/N,N-dimethylformamide (2 ml/10 ml), and palladium hydroxide (1.2 g) was added to the solution. The mixture was stirred at room temperature in a hydrogen gas atmosphere overnight. The reaction solution was filtered through Celite, and the solvent was removed therefrom by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 4-(2-amino-4-methylphenoxy)-6,7-dimethoxyquinoline (240 mg, yield 55%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].CC(C)([O-])C.[K+].O>C1(C)C=CC=CC=1>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:13]2[C:14]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:20][C:24](=[O:26])[CH:25]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Nc1ccccc1C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2[nH]1
Temperature: 25 °C
Yield: 32 %

Procedure:
Further, in a nitrogen atmosphere, 3′,5′-bis(trifluoromethyl)-2-aminobenzophenone (1.1 g, 3.3 mmol) was dissolved in toluene (13 mL), and acetic anhydride (0.62 mL, 6.5 mL) was added to the solution at room temperature, followed by stirring while heating and refluxing. The mixture was cooled to room temperature and then concentrated using a rotary evaporator. The residue was dissolved in ethylene glycol dimethyl ether (13 mL), and potassium tert-butoxide (1.5 mL, 13 mmol) was added to the solution at room temperature, followed by stirring for 2 hours. Water was added to the reaction solution, followed by extraction with methylene chloride. The organic layer was dried and then concentrated using a rotary evaporator. The residue was purified by silica gel column chromatography (hexane/ethyl acetate). Thus, 4-{3,5-bis(trifluoromethyl)phenyl}-2-quinolinone (372 mg, 1.04 mmol) was obtained in a yield of 32%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>N1C=CC=CC=1>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:36]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:37])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NCCCCn1c(CCCOc2ccccc2)nc2c(N)nc3ccccc3c21
Solvent: c1ccncc1
Product: Nc1nc2ccccc2c2c1nc(CCCOc1ccccc1)n2CCCCNC(=O)N1CCOCC1
Yield: 31.1 %

Procedure:
Using the general method of Example 143 except that pyridine was used in place of chloroform, 1-(4-aminobutyl)-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.25 g, 3.2 mmol) was reacted with 4-morpholinecarbonyl chloride (0.41 mL, 3.5 mmol) to provide 0.50 g of N-{4-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4, 5-c]quinolin-1-yl]butyl}morpholine-4-carboxamide as a light brown solid, m.p. 71.5-72.1° C. Analysis: Calculated for C28H34N6O3.0.5H2O: %C, 65.73; %H, 6.90; %N, 16.43; Found: %C, 65.43; %H, 6.90; %N, 16.29.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[I-].[Na+].[CH3:19][N:20]([CH3:23])[CH:21]=O.C(=O)([O-])O.[Na+]>CC(C)=O>[C:6]1([CH3:7])[CH:15]=[CH:14][C:19]([N:20]2[CH2:23][CH2:13][N:12]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3[CH:7]=[C:8]4[C:13](=[CH:14][CH:15]=3)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]4)[CH2:11][CH2:21]2)=[CH:4][CH:5]=1
Reactant: CN(C)C=O
Reactant: O=C1CCc2cc(CCCCCl)ccc2N1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ccc(N2CCN(CCCCc3ccc4c(c3)CCC(=O)N4)CC2)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
2.5 Grams of 6-(4-chlorobutyl)-3,4-dihydrocarbostyril and 1.8 g of sodium iodide were mixed in 80 ml of acetone and stirred at 50° C. for 2 hours. Then to the rection mixture was added 80 ml of dimethylformamide and the acetone was removed by distillation, and 2.0 g of 4-(4-tolyl)piperazine and 2.0 g of triethylamine were added to the reaction mixture, and stirred at 70°-80° C. for 5 hours. The reaction mixture was concentrated under a reduced pressure to obtain a residue. To the residue was added 50 ml of 5%-sodium hydrogencarbonate aqueous solution and stirred. The precipitates thus formed were collected by filtration, washed with water and dried. Recrystallization from isopropanol-diisopropyl ether, there were obtained 3.1 g of 6-{4-[4-(4-tolyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril in colorless prism-like crystals, having the melting point of 160°-161° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.CC(=CC)C.Cl([O-])=[O:18].[Na+].Cl>CC(O)(C)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:18])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a stirred solution of benzo[d][1,3]dioxole-5-carbaldehyde (254a, 2 g, 13.3 mmol), Na2H2PO4 (6.38 g, 53.2 mmol), and 2-methyl-2-butene (9.85 mL, 93.1 mmol) in t-BuOH (41 mL) and water (17 mL) was added sodium chlorite (7.19 g, 79.9 mmol). The resulting reaction mixture was stirred for 2 hours at room temperature. Water (100 mL) and 1M HCl (25 mL) were added and the mixture was extracted with EtOAc (2×50 mL). The organic phase was separated, dried with sodium sulfate and evaporated under reduced pressure. The resulting solid was triturated with EtOAc (20 mL) to yield the title compound 255a as a white solid (1.9 g, 86% yield). 1H NMR: (DMSO) δ 12.72 (br s, 1H), 7.53-7.50 (m, 1H), 7.34-7.32 (m, 1H), 6.99-6.95 (m, 1H), 6.10 (s, 2H).
Reaction SMILES: C(O[C:4](=O)[C:5]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[N:16]([CH3:17])[C:12]=2[C:11]=1[C:29]#[N:30])(C)[C:6](=O)[CH3:7])C.O.S(=O)(=O)(O)[OH:34].[OH-].[NH4+]>C(O)(=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:15]2[N:16]([CH3:17])[C:12]3[C:11]4[C:29](=[O:34])[NH:30][C:6]([CH3:7])=[C:5]([CH3:4])[C:10]=4[CH:28]=[CH:27][C:13]=3[N:14]=2)=[C:20]([CH3:26])[CH:21]=1
Reactant: CCOC(=O)C(C)(C(C)=O)c1ccc2nc(Nc3ccc(F)cc3C)n(C)c2c1C#N
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C)[nH]c(=O)c3c2n1C
Temperature: 100 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
To a 500 mL round-bottom flask equipped with a magnetic stir-bar was added 2-[4-cyano-2-(4-fluoro-2-methyl-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyric acid ethyl ester (8.25 g, 1.95 mmole), followed by a freshly prepared mixture of water (25 mL), acetic acid (25 mL), and concentrated sulfuric acid (25 mL) at 60° C. The flask was fitted with a reflux condenser and heated to a bath temperature of 100° C. under a nitrogen atmosphere. After 5 hours, the reaction was allowed to cool to room temperature, and stirred for an additional 14 hours. The mixture was then poured onto ice and brought to a slightly basic pH by careful addition of concentrated ammonium hydroxide, while maintaining a temperature of less than 15° C. The resulting precipitate was isolated by filtration, and washed with several volumes of water. The solid was then slurried in methanol for 1 hour, and filtered. The isolated solid was washed with cold methanol until the filtrate was colorless, to provide 2-(4-fluoro-2-methyl-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (6.11 g, 89%) as a light gray solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ 11.43 (br s, 1H), 10.49 (br s, 1H), 7.70-7.65 (m, 2H), 7.57 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.37 (dd, 1H, J1=3.1 Hz, J2=9.8 Hz), 7.27 (td, 1H, J1=3.1 Hz, J2=11.7 Hz), 4.23 (s, 3H), 2.32 (app s, 6H), 2.23 (s, 3H); ESMS (m/z): 351 (M+1)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH:6]([CH3:8])[NH2:7])[CH3:3].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:10]([NH:7][CH:6]([CH3:8])[C:5]([O:4][CH2:2][CH3:3])=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)C(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)C(C)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a mixture of DL-alanine ethyl ester hydrochloride (913 mg, 5.9 mmol) in DCE (15 mL) was added TEA (1.2 mL, 8.8 mmol) followed by benzaldehyde (0.538 mL), 5.3 mmol) and Na(OAc)3BH (2.0 g, 9.4 mmol). The mixture was stirred at room temperature overnight and then quenched with saturated aqueous NaHCO3 solution. The layers were separated and the aqueous layer extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography on SiO2 eluting EtOAc/Hex afforded the desired compound as a colorless liquid (798 mg, 73%). MS (ESI) mass calcd. C12H17NO2, 207.1. m/z found 208.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.39-7.23 (m, 5H), 4.23-4.16 (m, 2H), 3.83-3.65 (m, 2H), 3.37 (q, J=7.0 Hz, 1H), 1.34-1.27 (m, 6H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(=O)=[O:12].[C:14]([O:18][C:19](=[O:33])[N:20]([CH2:22][CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][C:31]#N)[CH2:26][CH2:25]1)[CH3:21])([CH3:17])([CH3:16])[CH3:15].Cl>C(Cl)Cl>[C:14]([O:18][C:19](=[O:33])[N:20]([CH3:21])[CH2:22][CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=[O:12])[CH2:26][CH2:25]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CN(CC[C@H]1CC[C@H](CC#N)CC1)C(=O)OC(C)(C)C
Reactant: O=C=O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: CN(CC[C@H]1CC[C@H](CC=O)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
90.4 ml (108.5 mmol) of diisobutylaluminium hydride (1.2M in toluene) were dropped under stirring and dry-ice-cooling at −70° C. to −78° C., within 20 minutes, to a solution of 10.14 g (36.17 mmol) of crude trans-[2-(4-cyanomethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester in 90 ml of methylenechloride. The reaction mixture was stirred for 4 hours at −70° C. to −78° C. To this reaction mixture was then carefully added 40 ml of 4N HCl (in water), within 10 minutes at −78° C. The temperature was slowly raised to room temperature. After stirring for 10 minutes at room temperature, the reaction mixture was partitioned between ether, 1N HCl and water. The ether-phase was dried over sodium sulfate and concentrated under reduced pressure giving 10.14 g of crude trans-methyl-{2-[4-(2-oxo-ethyl)-cyclohexyl]-ethyl}-carbamic acid tert-butyl ester as colorless oil, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[OH:19].[C:21](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[O:19][CH3:21]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(=O)Nc2ccc(F)cc2F)c(O)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C(=O)Nc2ccc(F)cc2F)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of compound 4a (0.56 g, 2 mmole) in anhydrous acetone (10 mL) were added potassium carbonate (0.69 g, 5 mmole) and iodomethane (0.28 mL, 4.4 mmole) and refluxed 8 hr. After cooled to room temperature, the reaction mixture was filtered through Celite and concentrated. The residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, then concentrated and recrystallized with hot methanol.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:24])[C:11](=[O:23])[N:12]([CH3:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]([CH3:24])[C:11](=[O:23])[N:12]([CH3:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(-c3ccc(OC)cc3)n(C)c(=O)n2C)cc1
Agent: BrB(Br)Br
Product: COc1ccc(-c2c(-c3ccc(O)cc3)n(C)c(=O)n2C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 0.1 %

Procedure:
To a stirred −40° C. solution of 4,5-bis(4-methoxyphenyl)-1,3-dimethyl-1H-imidazol-2(3H)-one (0.6 g, 1.84 mmol) DCM (10 mL), BBr3 (0.7 mL, 7.38 mmol) was added dropwise and the reaction mixture was then stirred for 48 h at RT, quenched with 6 N HCl and washed with water. The combined organic layers were then dried over Na2SO4, filtered and then concentrated in vacuo to afford 4-(4-hydroxyphenyl)-5-(4-methoxyphenyl)-1,3-dimethyl-1H-imidazol-2(3H)-one (0.38 mg, 66%) as a solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH2:24][CH2:25][C:26](=[O:28])[CH3:27])C1C=CC=CC=1.C(=O)(O)[O-].[Na+].[H][H]>[Pd].C(O)C>[CH3:23][C:15]([C:13]1[CH:12]=[CH:11][C:10]([CH2:24][CH2:25][C:26](=[O:28])[CH3:27])=[C:9]([OH:8])[CH:14]=1)([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: [H][H]
Reactant: CCCCCCC(C)(C)c1ccc(CCC(C)=O)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc(CCC(C)=O)c(O)c1
Yield: 93 %

Procedure:
A mixture of 0.5 g. (1.31 mmols.) of 4-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-butanone, 360 mg. of solid sodium bicarbonate, 100 mg. of 10% palladium-on-carbon and 10 ml. of ethanol is stirred under one atmosphere of hydrogen pressure for one hour. The reaction mixture is filtered through diatomaceous earth with ethyl acetate and the filtrate evaporated to an oil. The oil is purified via column chromatography on 100 g. of silica gel eluted with 50% ether-cyclohexane to yield 247 mg. (93%) of the title compound as an oil.
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6](=[O:27])[N:7]([C@@H:9]2[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@@H:10]2[O:11][C:12](=[O:14])[CH3:13])[CH:8]=1)#[CH:2].[NH:29]1[CH:33]=[N:32][CH:31]=[N:30]1>N1C=CC=CC=1>[C:1]([C:3]1[C:4]([N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)=[N:5][C:6](=[O:27])[N:7]([C@@H:9]2[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@@H:10]2[O:11][C:12](=[O:14])[CH3:13])[CH:8]=1)#[CH:2]
Reactant: C#Cc1cn([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)c(=O)[nH]c1=O
Reactant: c1nc[nH]n1
Solvent: c1ccncc1
Product: C#Cc1cn([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)c(=O)nc1-n1cncn1
Yield: 65.9 %

Procedure:
5Ethynyl-1-(2',3',5'-tri-O-acetyl-β-D-arabinofuranosyl)uracil from Example 5 (0.6 g, 1.5 mmol), 1,2,4-triazole (0.33 g, 4.8 mmol) and p-chlorophenylphosphodichloridate (0.8 ml, 4.8 ml) were stirred together in dry pyridine (20 ml) for 72 hr. The resulting dark solution was evaporated to dryness and the residue purified by column chromatography on silica eluting with ethylacetate/hexane (9:1) to give an apparently unsatable product (0.44 g) which was used in its crude from in the next stage of the synthesis.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]#[CH:9].[OH:11][C:12]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]2[C:13]=1[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([CH3:23])[O:17]2>CC(CC)=O.[I-].[K+]>[OH:11][C:12]1[CH:21]=[C:20]([O:22][CH2:9][C:8]#[CH:7])[CH:19]=[C:18]2[C:13]=1[C:14](=[O:25])[CH2:15][C:16]([CH3:23])([CH3:24])[O:17]2
Reactant: CC1(C)CC(=O)c2c(O)cc(O)cc2O1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CCOc1cc(O)c2c(c1)OC(C)(C)CC2=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
In 60 ml of methyl-ethyl-ketone 4.2 g of 5,7-dihydroxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 3.0 g (22 millimoles) of potassium carbonate, 0.2 g of potassium iodide, and 3.0 g (2.3 ml, 25 millimoles) of propargyl bromide are added and the reaction mixture is reflexed for 4 hours. The inorganic salt is filtered off, the residue is taken up in 100 ml of carbon tetrachloride and extracted twice with 25 ml of a 5% sodium hydroxide solution each. The aqueous-alkaline layer is cooled to 0° C. The aqueous-alkaline layer is cooled to 0° C. The precipitated sodium phenolate salt is filtered off, washed twice with 20 ml of acetone each, and suspended in 25% hydrochloric acid (50 ml). The mixture is stirred at 5° C. for an hour. The precipitated white product is filtered off, washed twice with 20 ml of water each and dried to constant weight. The crude product thus obtained can be directly subjected to further reactions. Thus 3.7 g of the desired compound are obtained, yield 75% Mp.: 122°-124° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=1>C(O)CCC>[Cl:9][C:10]1[N:11]=[CH:12][N:13]=[C:14]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=2)[CH:15]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1cccc(N)n1
Solvent: CCCCO
Product: Nc1cccc(Nc2cc(Cl)ncn2)n1
Temperature: 100 °C
Yield: 32.7 %

Procedure:
A mixture of 2,6-diaminopyridine (1.530 g, 14.020 mmol) and 4,6-dichloropyrimidine (2.610 g, 17.519 mmol) in 15 mL of n-butanol in a sealed vial was heated at 100° C. for 72 h. The dark brown sample was cooled and was concentrated at reduced pressure to remove most of the n-butanol. The residue was then partitioned between EtOAc and saturated. NaHCO3 solution. An emulsion formed, the sample was filtered through a pad of Celite and the layers were separated. The organic extract was washed with sat. KH2PO4 and brine solutions, dried (MgSO4), filtered and concentrated to brown oily-solid. The sample was suspended into ˜50 mL of CH2Cl2, cooled and filtered to give 1.017 g (36%) of N-(6-chloro-pyrimidin-4-yl)-pyridine-2,6-diamine as yellow-orange solid. MS: m/z 222/224 (M+1, 100/63%). To a solution of N-(6-chloro-pyrimidin-4-yl)-pyridine-2,6-diamine (100 mg, 0.45 mmol) in DMF (1 mL) was added 3-methylphenol (88 mg, 0.8 mmol) and anhydrous K2CO3 (93 mg, 0.6 mmol). The reaction mixture was heated at 145° C. for 16 h. It was then cooled and DMF was removed under reduced pressure to get a yellow gummy residue. The residue was taken in EtOAc (20 mL), was washed sequentially with water (5 mL) and brine (5 mL) and was dried over Na2SO4. Filtration followed by concentration under reduced pressure afforded a yellow gum which was further purified by column chromatography (SiO2, 60-120, EtOAc/hexane, 5/5) to give 100 mg of 2-[6-(3-methylphenoxy)-pyrimidin-4-yl]amino-6-aminopyridine (IR-12) as a pale yellow solid. MS: m/z 294 (M+H)
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH:11]([O:14][CH3:15])[O:12][CH3:13])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:13][O:12][CH:11]([O:14][CH3:15])[C:6]1[C:5]([CH2:4][OH:3])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CCOC(=O)c1cccnc1C(OC)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COC(OC)c1ncccc1CO
Reaction time: 3 h
Yield: 48.6 %

Procedure:
A mixture of 11.3 g (0.05 mol) of 2-dimethoxymethyl-nicotinic acid ethyl ester dissolved in 150 mL of ether and 2.09 g (0.055 mol) of lithium aluminum hydride is stirred at room temperature for 18 hours. An additional 530 mg of lithium aluminum hydride is added and the reaction mixture stirred for another 3 hours. The reaction mixture is cooled using an ice bath and quenched with 6 mL of 1N NaOH and 8 g of sodium sulfate decahydrate. After a ½ hour the reaction mixture is filtered and the filtrate evaporated. The residue is chromatographed on 180 g of silica gel using ethyl acetate as the eluant. Appropriate fractions are combined and evaporated to yield 4.45 g of (2-dimethoxymethyl-pyridin-3-yl)methanol. 1H NMR (CDCl3) δ 8.40 (d, 1H), 7.70 (d, 1H), 7.20 (m, 1H), 5.35 (s, 1H), 4.75 (s, 2H), 3.40 (s, 3H). Step 4:
Reaction SMILES: [BH4-].[Li+].NCC[N:6]1[C:10](=[O:11])/[C:9](=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)/[S:8][C:7]1=[O:22].Cl>C1COCC1.N1C=CC=CC=1>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH:9]2[S:8][C:7](=[O:22])[NH:6][C:10]2=[O:11])=[CH:14][CH:15]=1)[CH3:21]
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a suspension of lithium borohydride (0.22 g, 10.04 mmol) in 40 mL of THF-pyridine (ratio 1:1), compound 3 (1.00 g, 4.02 mmol) was added at 0° C. The reaction mixture was stirred at 80° C. for 12 h and then cooled to 0° C. 21 mL of 4 N HCl aqueous solution was added carefully and the resulting suspension was stirred at 0° C. for 10 min, and refluxed for 1 h. After cooling down at room temperature, the solvent was removed by evaporation. The residue was dissolved in ethyl acetate and washed with water. The organic layer was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (50% ethyl acetate in hexanes) to afford compound 4 in 76.6% (0.77 g) yield as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([NH2:41])[CH2:40][CH2:39]1>>[CH:38]1([NH:41][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:40][CH2:39]1
Reactant: NC1CC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NC3CC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl) pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and cyclopropylamine according to conditions described in general procedure C. Mp: 118-120° C.; 1H NMR (400 MHz, CDCl3) δ 0.42-0.49 (m, 2 H), 0.70 (d, J=5.6 Hz, 2 H), 2.65 (s, 1 H), 3.25 (t, J=4.0 Hz, 4 H), 3.86 (t, J=4.8 Hz, 4H), 5.25 (s, 1 H), 6.15 (d, J=4.8 Hz, 1 H), 6.78 (d, J=11.6 Hz, 1 H), 7.06 (d, J=8.4 Hz, 2 H), 7.26-7.31 (m, 2 H), 7.49-7.57 (m, 2 H), 7.89 (d, J=8.0 Hz, 1 H), 7.96 (d, J=8.0 Hz, 1 H), 8.15 (s, 1 H), 8.20 (d, J=4.4 Hz, 1 H).