Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[N:14]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])[C:15](=[O:24])[C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:23])[N:9]=[C:10](I)[C:3]=12.[CH3:32][C@@H:33]([OH:36])[C:34]#[CH:35].N(C(C)C)C(C)C>C1COCC1.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[N:14]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])[C:15](=[O:24])[C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:23])[N:9]=[C:10]([C:35]#[C:34][C@H:33]([OH:36])[CH3:32])[C:3]=12
Reactant: C#C[C@@H](C)O
Reactant: Cc1ccccc1-n1c(Cn2nc(I)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1-n1c(Cn2nc(C#C[C@@H](C)O)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Temperature: 25 °C
Yield: 69.7 %

Procedure:
3-((4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1611)(522 mg, 1 mmol) and (R)-but-3-yn-2-ol (84 mg, 1.2 mmol) were dissolved in anhydrous THF (40 mL). The mixture was degassed and back-filled with nitrogen three times. Pd(PPh3)2Cl2 (12 mg, 0.1 mmol), CuI (47 mg 0.25 mmol) and (i-Pr)2NH (505 mg, 5 mmol) were added sequentially. The resulting mixture was degassed and back-filled with argon three times and then stirred at reflux for 4 h. The mixture was allowed to cool to RT, filtered through silica gel (10 g) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2-20% MeOH/DCM) to afford the product, 3 (R)-3-((4-amino-3-(3-hydroxybut-1-ynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1802) (324 mg, 70% yield) as a slightly yellow solid.
Reaction SMILES: [F:1][C:2]1[C:34]([F:35])=[CH:33][C:5]2[NH:6][C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[C:22]([C:23]5[CH:28]=[CH:27][N:26]=[C:25](S(C)(=O)=O)[N:24]=5)=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)[CH2:39][CH2:38]1.C(O)(C(F)(F)F)=O>CC(O)C>[F:1][C:2]1[C:34]([F:35])=[CH:33][C:5]2[NH:6][C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[C:22]([C:23]5[CH:28]=[CH:27][N:26]=[C:25]([NH:49][C:46]6[CH:45]=[CH:44][C:43]([N:40]7[CH2:39][CH2:38][N:37]([CH3:36])[CH2:42][CH2:41]7)=[CH:48][CH:47]=6)[N:24]=5)=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)(=O)c1nccc(-c2cccnc2Oc2ccc(Nc3nc4cc(F)c(F)cc4[nH]3)cc2)n1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(Nc3nccc(-c4cccnc4Oc4ccc(Nc5nc6cc(F)c(F)cc6[nH]5)cc4)n3)cc2)CC1
Temperature: 90 °C
Reaction time: 96 h

Procedure:
A resealable pressure bottle, under nitrogen, was charged with 5,6-difluoro-N-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine (0.13 g, 0.26 mmol), 4-(4-methylpiperazin-1-yl)benzenamine (0.25 g, 1.31 mmol), TFA (0.12 ml, 1.58 mmol), and 2-propanol (10.00 ml, 0.03 M). The reaction vessel was sealed and the mixture stirred at 90° C. for 4 days. The reaction mixture was cooled to RT and concentrated to brown residue. The residue was purified by Biotage silica gel chromatography (2%-8% MeOH/Dichloromethane) followed by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA). The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, and concentrated to afford 5,6-difluoro-N-(4-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine as a yellow solid. MS m/z=606.1 [M+H]+. Calc'd for C33H29F2N9O: 605.64.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[C:8]([NH2:12])([CH3:11])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[OH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[NH:12][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: C1CCC2OC2C1
Reactant: CC(C)(C)N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CC(C)(C)NC1CCCCC1O
Temperature: 120 °C
Yield: 92.4 %

Procedure:
A mixture of cyclohexene oxide (19.6 g), t-butyl amine (37.1 g), zinc chloride (2.5 g), and 50 ml of toluene were sealed under an inert atmosphere in a Diels-Alder flask. The contents were stirred and heated in a sand bath at 120° C. for 23 hours. After cooling the slurry was diluted with 100 ml of toluene, washed with dilute ammonium hydroxide solution (3×250 ml) and water (300 ml), dried (Na2SO4), filtered, and the solvents were removed under reduced pressure to give 31.6 g of N-2-hydroxycyclohexyl-N-t-butylamine as an off-white, waxy solid, m.p. 42°-44° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1.[NH:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:25][CH2:24][CH2:23][NH:22][C:21]2=[O:26])[CH2:16][CH2:15]1>C(O)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:25][CH2:24][CH2:23][NH:22][C:21]2=[O:26])[CH2:16][CH2:15]1
Reactant: COc1ccccc1OCC1CO1
Reactant: O=C1NCCCN1C1CCNCC1
Solvent: CCO
Product: COc1ccccc1OCC(O)CN1CCC(N2CCCNC2=O)CC1

Procedure:
A solution of 9 g of 1-(o-methoxy-phenoxy)-2,3-epoxypropane and 9.15 g of 1(4-piperidyl)-2-oxo-hexahydro-pyrimidine in 7 ml of abs. ethanol is heated for 5 hours to 95° C and then evaporated in vacuo. The residue is recrystallised from ethyl acetate/petroleum ether to yield the 1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine, which melts at 130°-133° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:16])[NH:11][C:12](=[S:15])[NH:13][CH:14]=2)=[CH:4][N:3]=1.[CH3:17]C[O-].[Na+].CI>C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][C:9]2[C:10](=[O:16])[N:11]=[C:12]([S:15][CH3:17])[NH:13][CH:14]=2)=[CH:6][N:7]=1
Reactant: Cc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CSc1nc(=O)c(Cc2cnc(C)nc2)c[nH]1
Yield: 38 %

Procedure:
5-(2-Methyl-pyrimidin-5-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (210 mg, 234.28 gmol−1, 0.90 mmol, 1 eq) and NaOEt (2 eq, 128 mg) were stirred in 5 ml of absolute ethanol at room temperature for 30 minutes. In the suspension was then added methyl iodide (2.5 eq, 140 μl) and the mixture was stirred for 35 hours. Solvent was then evaporated. In the mixture was added 3 ml of water and pH was adjusted to 5-6 range using 3N HCl water solution. The resulting precipitate was collected and dried to afford 5-(2-methyl-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (85 mg, yield=36.6%, purity=96%) in form of white powder. MS: [M+H]+=249.22 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.45 (s, 3H), 2.54 (s, 3H), 3.57 (s, 2H), 7.87 (br.s., 1H), 8.56 (s, 2H), 12.79 (br.s., 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=[O:16])[N:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Nc2nc(CO)cs2)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2nc(C=O)cs2)cc1

Procedure:
The reaction described in Preparation 44 was repeated, but using 3 g of 2-p-anisidinothiazol-4-yl-methanol, 6.1 g of pyridine sulfur trioxide complex, 5.3 ml of triethylamine and 90 ml of dimethyl sulfoxide, giving the title compound as pale brown crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[CH:13][C:14]([F:27])=[C:15]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=4)=[O:19])[CH:16]=3)=[CH:6][N:5]2[CH:28]=1.[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>O1CCCC1.O>[CH2:29]([NH:31][C:32]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[CH:13][C:14]([F:27])=[C:15]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=4)=[O:19])[CH:16]=3)=[CH:6][N:5]2[CH:28]=1)=[O:33])[CH3:30]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4c3)ccc2F)n(C)n1
Reactant: CCN=C=O
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cn2cc(Oc3ccc(F)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.3 %

Procedure:
To a solution of N-{5-[(2-aminoimidazo[1,2-a]pyridin-6-yl) oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (70.0 mg, 0.184 mmol) in tetrahydrofuran (3 mL) was added ethyl isocyanate (17.5 μL, 0.221 mmol), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate-ethanol to give the title compound (21.0 mg, 25%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][CH2:20][O:21][CH3:22].C(OCC)(=O)C>CN(C=O)C>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH2:19][CH2:20][O:21][CH3:22]
Reactant: COCCCl
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1cc(C=O)ccc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of 3-hydroxy-4-methoxybenzaldehyde (8.0 g) in DMF (60 mL) was added K2CO3 (8.0 g) and 1-chloro-2-methoxyethane (5.1 g). The resulting mixture was stirred at 80° C. overnight. After reaction finished, ethyl acetate (200 ml) was added, and washed with 2 N aqueous HCl solution, brine, dried over Na2SO4, filtered, concentrated. The residue was washed with petrol ether to give 4-methoxy-3-(2-methoxyethoxy)benzaldehyde (11 g) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ: 9.84 (s, 1H); 7.49-7.43 (m, 2H); 6.98 (d, J=8.0, 1 H); 4.25-4.22 (m, 2H); 3.95 (s, 3H); 3.83-3.81 (m, 2H); 3.46 (s, 3H).
Reaction SMILES: C([Li])CCC.[O:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[CH3:11][C:12]1[CH:32]=[CH:31][CH:30]=[CH:29][C:13]=1[O:14][CH2:15][C:16]1[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=1[C:18](N1CCCC1)=[O:19]>C(OCC)C>[CH3:11][C:12]1[CH:32]=[CH:31][CH:30]=[CH:29][C:13]=1[O:14][CH2:15][C:16]1[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=1[C:18]([C:7]1[O:6][CH:10]=[CH:9][CH:8]=1)=[O:19]
Reactant: c1ccoc1
Reactant: Cc1ccccc1OCc1ccccc1C(=O)N1CCCC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ccccc1OCc1ccccc1C(=O)c1ccco1
Temperature: -20 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
27.8 g (0.1 mol) of 23% pure n-butyllithium are added dropwise within 15 minutes to a solution of 6.8 g (0.1 mol) of furan in 100 ml of diethyl ether which had been cooled to −20° C. The mixture was stirred at 20° C. for 2 hours, cooled once more to −20° C., and 14.8 g (0.05 mol) of N-[2-(2-methylphenoxymethyl)-benzoy]-pyrrolidine dissolved in 100 ml of diethyl ether are added dropwise within 15 minutes. After complete conversion (DC control), the mixture is poured into 300 ml of ice-cold ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and concentrated under reduced pressure. 13.1 g (89.7% of theory) of 2-[2-(2-methylphenoxymethyl)-benzoyl]-furan are obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[C:25]([F:29])=[C:24]([Cl:30])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)=[C:8]2[CH2:12][CH2:11][CH2:10][C:9]=12)=[O:4].O[Li].O>O.C1COCC1>[Cl:30][C:24]1[CH:23]=[C:22]([C:16]2([C:18]([F:20])([F:21])[F:19])[O:15][N:14]=[C:13]([C:7]3[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]4[CH2:10][CH2:11][CH2:12][C:8]=34)[CH2:17]2)[CH:27]=[C:26]([Cl:28])[C:25]=1[F:29]
Reactant: COC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2

Procedure:
Stir a mixture of 3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid methyl ester (26 g, 54.1 mmol) and LiOH—H2O (4.54 g, 0.108 mmol) in water (200 mL) and THF (400 mL) at 50° C. for 0.5 hour. After removal of organic solvent under vacuum, dilute the residue with ice water (100 mL). Acidify the aqueous mixture with conc. HCl to pH=1, and extract the resultant mixture with EtOAc (200 mL×3). Purify the residue by silica gel chromatograph (EtOAc:MeOH 6:1) to afford 3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid as a white solid (23 g, 91.7% for 2 steps). MS (m/z): 468 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:11]([O:13][CH:14]([Cl:16])[CH3:15])=[O:12]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:3]([N:2]([CH3:1])[C:11](=[O:12])[O:13][CH:14]([Cl:16])[CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CNCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(Cl)OC(=O)N(C)Cc1ccccc1
Yield: 54.9 %

Procedure:
To a vigorously stirred suspension of N-methylbenzylamine (0.260 mL, 2 mmol) in EtOAc (3 mL) and 3 mL of saturated NaHCO3 solution was added 1-chloroethyl chloroformate (0.160 mL, 2 mmol). Effervescence was observed. Once gas production had ceased, the reaction mixture was diluted with hexanes (10 mL). The aqueous phase was removed and the organic phase was washed with brine (5 mL), dried and concentrated to give the crude product as an oil (˜0.250 g). The compound was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:15]=[O:16])[CH2:5][CH3:6].[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:17])[CH:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:15]1[O:20][CH2:19][CH2:18][O:16]1)[CH2:5][CH3:6]
Reactant: CCC(Oc1ccc(Cl)cc1C=O)C(=O)OC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OC
Reaction time: 3 h
Yield: 68.2 %

Procedure:
A mixture of 2-(4-chloro-2-formyl-phenoxy)-butyric acid methyl ester (50 g, 0.195 mol), ethylene glycol (89 mL, 1.56 mol) and p-toluenesulfonic acid (2.8 g, 16.5 mmol) in toluene (400 mL) was refluxed with a Dean-Stark trap attached to remove the water. After 3 h, the reaction was cooled and washed with water, saturated NaHCO3 and water, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light yellow oil (40 g).
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](Br)#[C:19][CH2:20][CH3:21]>CN(C)C=O>[C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([O:11][C:2]#[C:1][CH2:6][CH3:5])[C:8]([O:10][C:18]#[C:19][CH2:20][CH3:21])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC#CBr
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCC#COC(=O)C(OC#CCC)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 122.1 %

Procedure:
Into a suspension of 1.5 g of 66% sodium hydride-paraffin in 20 cc of dimethylformamide was added a solution of 4.5 g of α-phenyl-α-hydroxyphenylacetic acid in 10 cc of dimethylformamide under cooling, and the mixture was stirred for 1 hour. Successively, 5.8 g of butynyl bromide was added thereto and the stirring was continued for 1 hour. The reaction mixture was poured in ice-water, and the resultant was subjected to extraction with ether. The ether extract was washed with an aqueous solution saturated with sodium chloride, and dried over sodium sulfate. Thereafter ether was distilled out and paraffin was removed to obtain 4.0 g of oily 1-butynyl α-phenyl-α-(1-butynyloxy)phenylacetate, nD25 1.5581.
Reaction SMILES: C([O:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][N:15]1[CH:23]=[N:22][C:21]2[C:20](=[O:24])[NH:19][C:18]([NH2:25])=[N:17][C:16]1=2)(=O)C1C=CC=CC=1>CN>[OH:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][N:15]1[CH:23]=[N:22][C:21]2[C:20](=[O:24])[NH:19][C:18]([NH2:25])=[N:17][C:16]1=2
Reactant: Nc1nc2c(ncn2COCCCOC(=O)c2ccccc2)c(=O)[nH]1
Agent: CN
Product: Nc1nc2c(ncn2COCCCO)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
A mixture of 9-(3-benzoyloxypropoxymethyl)guanine (0.5 g) and aqueous 45% methylamine (10 ml) was stirred overnight at room temperature. Excess methylamine and water was evaporated at <30° C. under reduced pressure and the residue recrystallized from ethanol to give 9-(3-hydroxypropoxymethyl)guanine (0.24 g), m.p. 223° C. (with resolidification), as the 1/2 hydrate.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:10][CH2:9][CH2:8][N:7]([C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[CH:18]=2)=[O:12])[CH2:6]1)=[N+]=[N-].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][CH2:4][C@@H:5]1[O:10][CH2:9][CH2:8][N:7]([C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[CH:18]=2)=[O:12])[CH2:6]1
Reactant: CCCCc1nnc(C(=O)N2CCO[C@@H](CN=[N+]=[N-])C2)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCc1nnc(C(=O)N2CCO[C@@H](CN)C2)cc1-c1ccc(OC2CCCCC2)cc1
Yield: 91.3 %

Procedure:
To a stirred solution of ((R)-2-azidomethyl-morpholin-4-yl)-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yl]-methanone (0.799 mmol, 0.39 g) in ethyl acetate (4 mL) was added 10% palladium on carbon (0.1 g, wet), and the resulting reaction mixture was subjected to catalytic hydrogenation using a balloon full of hydrogen for 3 h. The catalyst was filtered through a pad of celite, and the celite pad was washed with methanol. The combined filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using ethyl acetate followed by 10% methanolic solution of ammonia (2 M ammonia in methanol) in ethyl acetate to provide ((S)-2-aminomethyl-morpholin-4-yl)-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yl]-methanone (0.33 g) which was converted into dihydrochloride salt using 4 N HCl in dioxane. LCMS: m/z 452.8 [M+1]. 1H NMR (400 MHz, CD3OD) δ 8.12 and 8.13 (1H, s), 7.46 (2H, dd), 7.12 (2H, d), 4.42-4.66 (2H, m), 3.42-4.16 (5H, m), 2.91-3.25 (5H, m), 1.99 (2H, m), 1.83 (2H, m), 1.3-1.69 (10H, m), 0.85 (3H, t)
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1.[C:9]1([C:15](Cl)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1.CN(C=O)C>[C:15]([N:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1c[nH]cn1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a RT solution of 1H-imidazole-4-carboxylic acid (1.12 g, 9.99 mmol) in pyridine (15 mL) and DMF (30 mL) was added triphenylmethyl chloride (3.06 g, 11.0 mmol). The reaction mixture was stirred at RT overnight, then was partitioned between EtOAc (500 mL) and H2O (50 mL). The organic phase was washed with H2O (20 mL), 10% citric acid (20 mL) and brine (5 mL), dried (MgSO4) and concentrated in vacuo. The residue was triturated with EtOAc to afford 1-trityl-1H-imidazole-4-carboxylic acid (2.78 g, 79% yield) as a white solid. LCMS Method A (ESI, positive ion spectrum): (M+H)/z=not observed, tR=3.27 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C1([O:18][C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)C=CC=CC=1.Cl>C1COCC1.O>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([CH:7]2[CH2:8][C:2]3[S:1][CH:5]=[CH:4][C:3]=3[C:6]2=[O:9])=[O:18])=[CH:21][CH:22]=1
Reactant: O=C(Oc1ccccc1)c1ccc(Br)cc1
Reactant: O=C1CCc2sccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(Br)cc1)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 69.8 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (3.34 g, 24.2 mmol) in 40 mL of THF was treated with NaH (60 percent, 1.45 g, 36.3 mmol). After the addition of 4-Bromo-benzoic acid phenyl ester (6.7 g, 24.2 mmol), the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was extracted with ethyl acetate. The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(4-Bromo-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (5.4 g, 16.9 mmol) as yellow solid in 70% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][CH2:11][CH2:12][Cl:13]
Reactant: Oc1ccccc1Cl
Reactant: ClCCCBr
Product: ClCCCOc1ccccc1Cl

Procedure:
Prepared by Procedure U and Scheme AK using 2-chlorophenol and 1-bromo-3-chloropropane.
Reaction SMILES: [C:1]1([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[CH3:19]>>[CH2:18]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[S:8]([CH3:11])(=[O:10])=[O:9])[CH3:19]
Reactant: CCBr
Reactant: CS(=O)(=O)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCN(c1ccccc1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 10 h
Yield: 89.8 %

Procedure:
16.7 g(100 mmol) of N-phenylmethanesulfonamide and 27.6 g (212 mmol) of K2CO3 were dissolved in 200 ml of dimethylform-amide(DMF) and the resulting solution was cooled to 0° C. 11.7 g(110 mmol) of ethylbromide was added dropwise thereto, which was stirred for over 10 hours at room temperature. DMF was distilled off under a reduced pressure and the residue was dissolved in dichloromethane. The resulting solution was washed with water and the organic layer was dried over anhydrous MgSO4. The organic solvent was distilled off under a reduced pressure to obtain 17.9 g of the title compound(yield 92%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[N:3]=1.[CH3:20][CH:21]([OH:23])[CH3:22]>>[CH:21]([O:23][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[N:3]=1)([CH3:22])[CH3:20]
Reactant: Cc1cc(Nc2cc3c(C)cccc3c(Cl)n2)n[nH]1
Reactant: CC(C)O
Product: Cc1cc(Nc2cc3c(C)cccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-Chloro-5-methyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2-propanol to give (1-Isopropoxy-5-methyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 297(MH+).