Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([OH:14])=O)=[CH:9][CH:8]=[CH:7][CH:6]=2.ON1C2C=CC=CC=2N=N1.[CH2:31]([C@H:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:32].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1.CC#N.C(Cl)Cl>[CH2:31]([C@H:33]([NH:40][C:12]([C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2]=1[NH2:1])=[O:14])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:32]
Reactant: CC[C@H](N)c1ccccc1
Reactant: Nc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CC#N
Solvent: ClCCl
Product: CC[C@H](NC(=O)c1c(N)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
1.5 g (5.7 mmol) of 3-amino-2-phenylquinoline-4-carboxylic acid (CAS [36735-26-9]) were dissolved in 140 ml of a 7/3 mixture of THF/CH3CN; 1.5 g (11.1 mmol) of 1-hydroxybenzotriazole (HOBT) were added and 1.15 g (8.5 mmol) of (S)-α-ethyl benzylamine dissolved in 10 ml of CH2Cl2 were added dropwise. After cooling of the reaction mixture to 0° C., 1.4 g (6.7 mmol) of dicyclohexylcarbodiimmide (DCC) dissolved in 10 ml of CH2Cl2 were added dropwise. The solution was kept at 0° C. for 30 minutes and then at room temperature overnight. The reaction mixture was evaporated in-vacuo, the residue was dissolved in CH2Cl2 and the solution filtered off, washed with H2O, 20% citric acid, sat. sol. NaHCO3 and sat. sol. NaCl. The organic layer was separated, drive over Na2SO4 and evaporated in-vacuo to dryness to obtain 2.4 g of the crude product. This was triturated with i-Pr2O, then recrystallized with a 10:1 mixture of iPr2O/i-PrOH to yield 1.7 g of the title compound.
Reaction SMILES: B.[Na].[Br-].[Li+].B(OC)(OC)OC.C[O:13][C:14]([CH2:16][C:17]1[S:18][CH:19]=[CH:20][C:21]=1[C:22](OC)=[O:23])=O>O1CCCC1.O.C(OCC)C.CO>[OH:23][CH2:22][C:21]1[CH:20]=[CH:19][S:18][C:17]=1[CH2:16][CH2:14][OH:13]
Reactant: COC(=O)Cc1sccc1C(=O)OC
Agent: B
Agent: COB(OC)OC
Agent: [Br-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCc1sccc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
To 800 mL of anhydrous tetrahydrofuran, 31.0 g of sodium boron hydride and 71.3 g of lithium bromide were added, and then 10.6 mL of trimethyl borate was added thereto dropwise at 0° C. The resulting mixture was stirred at room temperature for 30 minutes, and then a solution obtained by dissolving 70.4 g of the compound obtained in Example 1 in 200 mL of tetrahydrofuran was slowly added over 2 hours while allowing the resulting mixture to reflux. The reaction solution was further refluxed for 2 hours then cooled to room temperature. 100 mL of anhydrous methanol was added slowly to the solution, and then 700 mL of ethyl ether and 700 mL of water were added. The organic phase was collected, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 47.1 g (yield of 90%) of the title compound as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1.O>C1COCC1>[CH:23]1([C:26]([NH:1][CH2:2][CH2:3][CH:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=3)[CH2:7][CH2:6][CH2:5]2)=[O:27])[CH2:25][CH2:24]1
Reactant: COc1ccc2c(c1)C(CCN)CCC2
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(CCNC(=O)C1CC1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of (1,2,3,4-tetrahydro-7-methoxy-1-naphthylidene)acetonitrile (1.0 g, 5.02 mmol) in ethanol (10 ml) were added a saturated ammonia/ethanol solution (5 ml) and Raney nickel (W-2, 1 g). The mixture was stirred for 4 hours at 50° C. under hydrogen atmosphere (3-4 kgf/cm2). The Raney nickel was filtered off and, then, the solvent was distilled off under reduced pressure to give 1-(2-aminoethyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene. To a solution of this 1-(2-aminoethyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene and triethylamine (0.76 g, 7.53 mmol) in THF (20 ml) was gradually added dropwise, under ice-cooling, cyclopropanecarbonyl chloride (0.63 g, 6.02 mmol). The mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into water. The organic layer was subjected to extraction with chloroform. The extract solution was washed with brine and water, which was then dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of a silica gel column chromatography (ethyl acetate:hexane=2:8) to give the above-titled compound (1.04 g, yield 76%, oil).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]#[C:26][Si](C)(C)C)[CH:22]=[N:21][CH:20]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])([CH3:9])[CH3:8]>CO.CCOC(C)=O.O>[C:25]([C:23]1[CH:22]=[N:21][CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([S:10]([CH:7]([CH3:9])[CH3:8])(=[O:12])=[O:11])=[CH:14][CH:15]=2)[N:24]=1)#[CH:26]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cncc(C#C[Si](C)(C)C)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cncc(-c2ccc(S(=O)(=O)C(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97.7 %

Procedure:
Sodium carbonate (3 mL of 2 M, 6.000 mmol) was added to a stirred suspension of 2-[6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]ethynyl-trimethyl-silane (191 mg, 0.5327 mmol) in methanol (6 mL) and the reaction was stirred at ambient temperature for 45 minutes. The reaction mixture was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give the sub-title compound as a beige solid (149 mg, 98% Yield). 1H NMR (400.0 MHz, DMSO) d H NMR (400.0 MHz, DMSO) d 9.38 (s, 1H); 8.86 (s, 1H), 8.40 (d, 2H), 8.01 (d, 2H), 4.78 (s, 1H), 3.50 (sept, 1H) and 1.18 (d, 6H) ppm; MS (ES+) 297.1
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][S:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1>[Ni]>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([S:16][CH2:15][CH2:14][N:2]([CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=2)[CH3:1])=[CH:22][CH:21]=1
Reactant: CN(CCSc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Product: CN(CCSc1ccc(N)cc1)CCc1ccc(N)cc1

Procedure:
The title compound was prepared by the hydrogenation of 2-[N-methyl-N-(4-nitrophenethyl)amino]-1-(4-nitrophenylthio)ethane over Raney nickel according to the procedure of Example 7(B).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[C@@H:11]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[F:34][C:32]1[CH:31]=[CH:30][C:29]([O:35][CH3:36])=[C:28]([C@H:11]2[CH2:10][CH:9]([OH:8])[CH2:13][N:12]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[CH:33]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CC(O[Si](C)(C)C(C)(C)C)C[C@@H]3c3cc(F)ccc3OC)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn2ccc(N3CC(O)C[C@@H]3c3cc(F)ccc3OC)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
To a solution of (R)-ethyl 5-(4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (as a mixture of the cis and trans isomers) (0.0487 g, 0.0946 mmol) in THF (1 mL) at 0° C. was added 1 M TBAF in THF (0.104 mL, 0.104 mmol). The reaction mixture was warmed to ambient temperature and stirred for 2.5 hours. The reaction mixture was diluted with EtOAc (10 mL), washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford the crude (R)-ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (as a mixture of cis and trans isomers; 37.9 mg, 100% yield). LC/MS (ES+APCI) m/z=401.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[CH:27]=[N:28][CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:23][C:24]2[CH:25]=[C:26]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH:27]=[N:28][CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cncc(CN(c3ccc(F)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-fluorophenyl)amino]piperidine (589 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:20]=[C:19]([NH2:21])[N:18]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][N:23]=2)[N:17]=1.ClCCl>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:21][C:19]2[N:18]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[CH:24][N:23]=3)[N:17]=[C:16]([CH3:15])[CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(N)n(-c2ncnc3ccccc23)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n(-c2ncnc3ccccc23)n1
Temperature: 80 °C
Yield: 23.7 %

Procedure:
To a mixture of 4-t-butylbenzenesulfonyl chloride (0.084 g, 0.36 mmol) and 3-methyl-1-(quinazolin-4-yl)-1H-pyrazol-5-amine (0.067 g, 0.30 mmol) in pyridine (0.6 mL) was heated at 80° C. for 15 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 5-60% ethyl acetate in hexanes) to give the title compound as a white solid (0.30 g, 0.071 mmol, 24%). 1H NMR (400 MHz, CDCl3) δ 10.92 (s, 1H), 9.27 (dd, J=1.2, 8.8 Hz, 1H), 9.98 (s, 1H), 7.99 (dd, J=0.8, 8.4 Hz, 1H), 7.89 (ddd, J=1.2, 6.8, 8.4 Hz, 1H), 7.66-7.61 (m, 2H), 7.28-7.25 (m, 2H), 6.34 (s, 1H), 2.37 (s, 3H), 1.13 (s, 9H); MS: (ES) m/z calculated for C22H24F3N5O2S [M+H]+ 422.2. found 422.3.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([OH:16])[CH:14]=3)[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=2)[CH:4]=[N:3]1.Br[CH2:26][CH3:27].C([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CC(C)=O>[CH2:26]([O:16][C:13]1[CH:14]=[C:15]2[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:8][N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:10]2=[N:11][CH:12]=1)[CH3:27]
Reactant: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncc(O)cc23)cn1
Reactant: CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CCOc1cnc2c(c1)c(-c1cnn(C)c1)cn2COCC[Si](C)(C)C
Yield: 60.2 %

Procedure:
According to the general procedure using: 27 (60 mg, 0.174 mmol), bromoethane (114 mg, 1.05 mmol), K2CO3 (241 mg, 1.74 mmol) and n-Bu4NI (6.4 mg, 17 μmol) in acetone (4.0 mL) were heated at reflux for 18 h. Purification by PTLC using AcOEt:hexane=6:4 (v/v) as eluent gave 28h as a clear oil (39 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([C:23]#[N:24])[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:23]#[N:24])[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:20])([F:22])[F:21])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=C(C#N)c2ccc(OC(F)(F)F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(C#N)c2ccc(OC(F)(F)F)cc2)cc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A solution of 4-[2-cyano-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid methyl ester (9.0 g, 25.92 mmol) in THF (50 mL) was stirred and cooled to −20° C. A solution of sodium borohydride in THF (100 mL) was added during 20 minutes. The cooling bath was removed and the mixture was stirred for two hours at room temperature and then kept at 5° C. for 16 hours. Ice (100 g) was added and the mixture was neutralised (pH 4-5) with 1 M hydrochloric acid (50 mL). The resulting mixture was extracted with DCM and washed with brine. The organic phase was dried (MgSO4), purified (Norite A), filtered and evaporated. The residue was dried at 40° C. in vacuo to afford 8.8 g (97%) of 4-[2-cyano-2-(4-trifluoromethoxyphenyl)ethyl]benzoic acid methyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:12]=[CH:13][CH:14]=1.Cl.[CH3:43][N:44]([CH3:51])[CH2:45]/[CH:46]=[CH:47]/[C:48](Cl)=[O:49].CCN(C(C)C)C(C)C>C1COCC1>[CH3:43][N:44]([CH3:51])[CH2:45]/[CH:46]=[CH:47]/[C:48]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:10]=1)=[O:49]
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(N)c3)c2n1
Reactant: CN(C)C/C=C/C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(NC(=O)/C=C/CN(C)C)c3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.1 %

Procedure:
8-(3-Aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (1b, 255 mg, 0.56 mmol) was added in one portion as a solid to a suspension of (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride (283 mg, 1.538 mmol) in THF (10 mL) at 0° C. The resulting orange suspension was treated with DIEA (0.39 mL, 2.23 mmol) slowly and stirred for 30 min at 0° C. The reaction mixture was removed from the ice bath and stirred at RT for 30 min. The reaction mixture was treated with silica gel, concentrated on the rotovap and purified on an ISCO Combiflash RF (40 g Redisep column, using a gradient of 0-20% MeOH in DCM) affording enriched product as a yellow solid. This sample was repurified on the Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5 u, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water). The product containing fractions were concentrated in the genevac overnight and the resulting orange solid was then passed through a Silicycle SPE-R66030B-20× SiliaSep OT, 5 g/25 mL carbonate column using 10% MeOH/DCM then concentrated and dried again in the genevac for 3 h affording (E)-4-(dimethylamino)-N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)but-2-enamide (35 mg, 0.062 mmol, 11% yield) as an orange solid. m/z (ESI, +ve ion) 569.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.25 (1H, s), 8.74 (1H, s), 8.14 (1H, s), 7.90 (1H, d, J=9.4 Hz), 7.79-7.88 (1H, m), 7.59 (1H, s), 7.49 (1H, t, J=8.0 Hz), 7.27 (1H, d, J=9.0 Hz), 6.98 (1H, d, J=8.6 Hz), 6.73 (1H, dt, J=15.4, 5.8 Hz), 6.51 (1H, d, J=2.3 Hz), 6.44 (1H, Hz), 6.27 (1H, d, J=15.3 Hz), 6.02 (1H, br. s.), 3.77 (3H, s), 3.04 (6H, d, J=5.7 Hz), 2.36-2.46 (4H, m), 2.22 (3H, s), 2.16 (6H, s).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9]COC)=[CH:7][C:6]([O:13]COC)=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]=1[CH2:23][CH2:24][C:25]1[O:29][CH:28]=[N:27][C:26]=1[CH2:30][OH:31])[CH3:2].O1CCOCC1.Cl.[OH-].[Na+]>CO>[CH2:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([OH:13])=[C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:4]=1[CH2:23][CH2:24][C:25]1[O:29][CH:28]=[N:27][C:26]=1[CH2:30][OH:31])[CH3:2]
Reactant: CCc1c(OCOC)cc(OCOC)c(-c2ccccc2)c1CCc1ocnc1CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCc1c(O)cc(O)c(-c2ccccc2)c1CCc1ocnc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
(5-{2-[2-Ethyl-3,5-bis(methoxymethoxy)-6-phenylphenyl]ethyl}-1,3-oxazol-4-yl)methanol (200 mg) was dissolved in methanol (5.0 mL), and 1,4-dioxane solution (1 ml) of 4.0 mol/L hydrochloric acid was added thereto and stirred at room temperature for 3 hours. The reaction liquid was neutralized with aqueous sodium hydroxide solution (1 mol/L), and then extracted with chloroform. The organic layer was washed with aqueous saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through preparative thin-layer column chromatography (chloroform/methanol=9/1) to obtain Compound 210 (53 mg, 39%).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.CC(C)=O.[C:18]([O:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[C:34]([N+:45]([O-:47])=[O:46])[CH:33]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(OCC)(=O)C.O>[C:18]([O:22][C:23]([N:25]([CH3:1])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[C:34]([N+:45]([O-:47])=[O:46])[CH:33]=1)=[O:24])([CH3:19])([CH3:20])[CH3:21]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CN(C(=O)OC(C)(C)C)c1ccccc1-c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 21.9 %

Procedure:
Potassium carbonate (0.16 g) and dimethyl sulfate (0.094 mL) were added to an acetone (4.0 mL) solution of tert-butyl 4-(2-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate (0.27 g), followed by heating to reflux for 2 hours. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-85% hexane/ethyl acetate] and then purified by silica gel column chromatography [eluent: 91-85% hexane/ethyl acetate] to obtain 0.061 g of tert-butyl 4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)-2-nitrobenzoate as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9]2[C:10]3[C:15]([N:16]=[C:17]4[C:22]=2[C:21](=[O:23])[CH2:20][CH2:19][CH2:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[C:10]3[C:15]([N:16]=[C:17]4[C:22]=2[CH:21]([OH:23])[CH2:20][CH2:19][CH2:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:24][CH:25]=1
Reactant: COc1ccc(CNc2c3c(nc4ccccc24)CCCC3=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CNc2c3c(nc4ccccc24)CCCC3O)cc1
Temperature: 0 °C

Procedure:
3,4-Dihydro-9-(4-methoxybenzylamino)acridin-1(2H)-one (4.25 g) was dissolved in 75 ml of dry THF and chilled with ice-water. 1M lithium aluminum hydride in THF (7.0 ml) was then added dropwise. After 15 minutes the reaction was quenched by the sequential dropwise addition of 0.4 ml of water, 0.4 ml of 15% sodium hydride and 1.2 ml of water. The inorganic salts were filtered off, the solvents were evaporated, and the residue recrystallized from dichloromethane-ether to give 3.0 g of analytically pure product, mp 163°-165° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)[NH:10][C:9]=3[C:8](=[O:22])[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:6]2=[O:31])[CH2:3][CH2:2]1.[CH:32](=O)[CH3:33]>[Pd].O1CCCC1>[CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:16]=[CH:17][C:18]([NH:21][CH2:32][CH3:33])=[CH:19][CH:20]=4)[NH:10][C:9]=3[C:8](=[O:22])[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:6]2=[O:31])[CH2:3][CH2:2]1
Reactant: CC=O
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.6 %

Procedure:
To a suspension of 10% palladium on carbon (0.10 g) in tetrahydrofuran (50 mL) was added 3-cyclopropylmethyl-8-[4-aminobenzyl]-1-(2-fluorobenzyl)-3,7-dihydro-purine-2,6-dione (prepared as described in example 64, step 1) (0.21 g, 0.50 mmol) and acetaldehyde (72.6 μL, 1.3 mmol). The mixture was shaken under an atmosphere of hydrogen at 1 atmosphere pressure and ambient temperature for 3 days. The catalyst was removed by filtration through celite, washing the filter pad through with tetrahydrofuran and methanol. The combined filtrate was concentrated in vacuo and the residue purified by chromatography using silica eluted with 1:1 hexanes/ethyl acetate. Concentration of the appropriate fractions gave the product as a colorless solid (0.14 g, 62%). MS, m/z(M+H)=553.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(N(CC)CC)C.[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>C(C(C)=O)C(C)C>[C:20]([O:12][C:2]1([CH3:1])[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Reactant: C=C(C)C(=O)Cl
Solvent: CC(=O)CC(C)C
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1(C)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A vessel was charged with 83.1 g of 2-methyl-2-adamantanol and 101 g of triethylamine, and 200 g of methyl isobutyl ketone was added thereto to form a solution. To the solution was added dropwise 78.4 g of methacrylic acid chloride(1.5 times the molar amount of 2-methyl-2-adamantanol), followed by stirring for about 10 hours at room temperature. After filtration, the resulting organic layer was washed with an aqueous solution of 5 wt % sodium bicarbonate and then washed with water twice. The organic layer was concentrated and then distilled under reduced pressure to obtain 2-methyl-2-adamantyl methacrylate represented by the following formula.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:24]=[CH:25]/[C:26](OCC)=[O:27])=[CH:4][N:3]=1.CC(C[AlH]CC(C)C)C.CO>C1COCC1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:24]=[CH:25]/[CH2:26][OH:27])=[CH:4][N:3]=1
Reactant: CCOC(=O)/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)csc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ncc(/C=C/CO)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Yield: 4.9 %

Procedure:
A solution of Example 223 (0.45 g, 10.8 mmol) in THF at −78° C. was treated with 5.4 mL DIBAL-H solution (1.0M in toluene, 5.4 mmol) and methanol (1 mL), warmed to room temperature, and concentrated. The residue was dissolved in methanol (100 mL), treated with silica gel (5 g), and concentrated. The preabsorbed silica gel was subsequently transferred to a silica gel column and chromatographed (ethyl acetate/heptane 3:1) to provide 200 mg (49%) of the product.