Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=[CH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[CH:6]=1.I([O-])(=O)(=O)=[O:14].[Na+]>CO>[CH3:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][N:8]=1)[CH:4]=[O:14]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1cc(C=CN(C)C)ccn1
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C=O)ccn1
Reaction time: 1 h
Yield: 78.3 %

Procedure:
A solution of N,N-dimethyl-2-(2-methyl-4-pyridyl)ethenamine (6.4 g, 39 mmol) in methanol (25 ml) was added dropwise to a mixture of sodium periodate (25.2 g, 117 mmol) and methanol (25 ml) at room temperature. The mixture was stirred at the same temperature for 1 hr. The precipitates were filtered off, and the filtrate was concentrated. The residue was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated to give the titled compound (3.7 g, 78%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=1.[Cl:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:25]=1C(OC)=O>C1COCC1>[Cl:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:25]=1[C:20](=[O:22])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(F)cc1Cl
Reactant: COc1ccc(CC(=O)O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)c2ccc(F)cc2Cl)cc1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
230 ml of a 2M solution of NaHMDS in THF are introduced into 250 ml of THF under nitrogen. The solution is cooled to −60° C. and then 30.5 g of (4-methoxyphenyl)acetic acid in 120 ml of THF are added at this temperature. After 1 h 30 min at −60° C., 33 g of methyl 2-chloro-4-fluorobenzoate are added and the mixture is stirred at −60° C. for 45 min and then allowed to return to 0° C. The reaction medium is poured onto 500 ml of ice-cold 2N HCl and extracted with ether and the extract is washed with water and then with a saturated aqueous sodium chloride solution. After drying, concentrating to dryness and then crystallizing from pentane, 27.4 g of the expected compound are obtained.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].I[CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:1][C:2]([F:18])([C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])[CH2:3][C:4]([CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: FC(F)(F)CCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCCC(F)(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 17.9 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.2 g of 1-iodo-4,4,4-trifluorobutane were dissolved in 5 ml of dimethyl sulfoxide, 0.83 g of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.35 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(4,4,4-trifluorobutyl)malononitrile (hereinafter, referred to as the present compound (66)).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:12][C:9]2=[CH:10][N:11]=1.[H-].[Na+].C1(C)C=CC(S(O[CH2:32][CH2:33][O:34][C@@H:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([O:41][CH2:42][C:43]3[N:44]=[C:45]([C:49]4[CH:50]=[C:51]([CH3:55])[CH:52]=[CH:53][CH:54]=4)[O:46][C:47]=3[CH3:48])[CH2:36]2)(=O)=O)=CC=1>CN(C=O)C.[Na+].[Cl-].C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]([CH2:32][CH2:33][O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH:37]([O:41][CH2:42][C:43]4[N:44]=[C:45]([C:49]5[CH:50]=[C:51]([CH3:55])[CH:52]=[CH:53][CH:54]=5)[O:46][C:47]=4[CH3:48])[CH2:36]3)[C:9]2=[CH:10][N:11]=1
Reactant: CCOC(=O)c1cc2cc(OCCOC)ncc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@@H]2CCC[C@H](OCc3nc(-c4cccc(C)c4)oc3C)C2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCCOC)ncc2n1CCOC1CCCC(OCc2nc(-c3cccc(C)c3)oc2C)C1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
66 mg of ethyl 5-(2-methoxyethoxy)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate are dissolved in 2 ml of dry DMF, and 12 mg of 60 percent strength sodium hydride suspension are added. After 30 min at room temperature, 100 mg of ((1R,3S)-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl toluene-4-sulfonate ((1R,3S)-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl toluene-4-sulfonate in 2 ml of DMF are added. The mixture is stirred at 40° C. until the reaction has gone to completion (monitored by LC-MS). After cooling, the mixture is diluted with sat. NaCl solution and ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by flash chromatography on silica gel (n-heptane/ethyl acetate=1:2). This gives ethyl 5-(2-methoxyethoxy)-1-{2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxylate as a yellowish solid. C33H41N3O7 (591.71), MS (ESI): 592 (M+H+).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([CH2:17][O:18][CH2:19][CH2:20][OH:21])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:6][NH:7][C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:17][O:18][CH2:19][CH2:20][OH:21]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](COCCO)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](COCCO)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
N-((1R)-1-(2-Hydroxyethoxymethyl)-2-phenylethyl)-N-methylcarbamic acid tert-butylester (0.29 g, 0.90 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added. The solution was stirred at 0° C. for 15 min. The solvents were removed in vacuo. The residue was dissolved in dichloromethane (10 mL) and extracted with 1N sodium hydroxide (10 mL). The organic phase was dried over magnesium sulfate. The solvent was removed in vacuo to give 0.11 g of crude 2-((2R)-2-methylamino-3-phenylpropoxy)ethanol, which was used for further syntheses.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1.O1CCOCC1>[C:10]([N:4]1[C:3](=[O:9])[C:2]([F:1])=[CH:7][NH:6][C:5]1=[O:8])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)n1c(=O)[nH]cc(F)c1=O
Temperature: 0 °C
Yield: 32 %

Procedure:
2.6 g (0.02 mole) of 5-fluorouracil was suspended in 10 ml of absolute pyridine and 10 ml of absolute dioxane, and the suspension was warmed to 80° C and stirred. 5.6 g (0.04 mole) of benzoyl chloride was then added dropwise thereto followed by stirring at 80° C for 1.5 hours to allow the mixture to react. After completion of the reaction, the reaction mixture was poured into ice-water followed by stirring, and the thus precipitated solid was filtered, washed with water and then dissolved in benzene while hot (80° C). Any insoluble matter was removed by filtration, and the filtrate allowed to cool to precipitate crystals, which were recovered by filtration to obtain 1.5 g of 3-N-benzoyl-5-fluorouracil in a yield of 32% (the filtrate was set aside). Melting Point: 170° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[N:8]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)[CH:9]=[C:10]2[C:15]=1[C:14](=O)[N:13]([CH3:17])[C:12](=O)[N:11]2[CH2:19][CH:20]([CH3:22])[CH3:21].[H][H]>C(O)C.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)[CH:9]=[C:10]2[C:15]=1[CH2:14][N:13]([CH3:17])[CH2:12][N:11]2[CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C#CCCCO)n(Cc3cccc4ccccc34)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)CN1CN(C)Cc2c1cn(Cc1cccc3ccccc13)c2CCCCCO

Procedure:
The compound of Example 13, 5-(5-hydroxypent-1-ynyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1 H-pyrrolo[3,4-d]pyrimidine-2,4(3 H,6 H)-dione (75 mg) was suspended in ethanol (50 ml). A suspension of 10% palladium on carbon (7 mg) in ethanol (3 ml) was added and the mixture was hydrogenated. When hydrogen uptake ceased, the reaction mixture was filtered and the solvent was removed by rotary evaporation. The crude product was purified by chromatography on silica eluting with ethyl acetate:isohexane(3:1) to give the title compound (29 mg) as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:16][CH:15]([OH:17])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:18][NH:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([OH:31])=[CH:28][CH:29]=2)[N:24]([CH3:32])[C:23]=1[CH3:33])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:18][NH:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([O:31][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:16][CH:15]([OH:17])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:28][CH:29]=2)[N:24]([CH3:32])[C:23]=1[CH3:33])=[O:21]
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC(O)C1
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N5CC(O)C5)sc34)ccc12

Procedure:
This material was prepared by the reaction of (7-chloro-thieno [3,2-b]pyridin-2-yl)-(3-hydroxy-azetidin-1-yl)-methanone 9d with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide 16e and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ 8.41 (1H, d, J=5.5 Hz), 7.78–7.74 (2H, m), 7.29 (1H, d, J=2.1 Hz), 6.95(1H, dd, J=2.1, 8.6 Hz), 6.62 (1H, d, J=5.5 Hz), 4.76–4.73 (2H, m), 4.63 (1H, bs), 4.35–4.32 (2H, m), 3.9.7–3.94(1H, m), 3.62(3H, s), 2.89(3H, s), 2.57 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 451. found 451.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[CH:6][C:7]=1[CH:8]1[O:13][CH2:12][CH2:11][NH:10][CH2:9]1.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17]>CC#N>[C:20]([O:19][C:15](=[O:18])[CH2:16][CH2:17][N:10]1[CH2:11][CH2:12][O:13][CH:8]([C:7]2[CH:6]=[CH:5][C:4]([OH:14])=[CH:3][C:2]=2[CH3:1])[CH2:9]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Cc1cc(O)ccc1C1CNCCO1
Solvent: CC#N
Product: Cc1cc(O)ccc1C1CN(CCC(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A mixture of 3-methyl-4-morpholin-2-yl-phenol (14.26 g; 73.8 mmol) and tert-butyl acrylate (21.4 ml; 147.6 mmol) in CH3CN (250 mL) was heated under reflux overnight. After cooling to RT the mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and 5% aqueous NaHCO3 solution. The organic layer was dried (Na2SO4), filtered, concentrated in vacuo, and purified by column chromatography (SiO2, CH2Cl2>Et2O/hexanes 1:1>Ether) to afford 3-[2-(4-hydroxy-2-methyl-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (22.62 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.Cl[CH2:25][CH:26]1[O:31][CH2:30][CH2:29][N:28](CC2C=CC=CC=2)[CH2:27]1>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][CH:26]3[O:31][CH2:30][CH2:29][NH:28][CH2:27]3)=[CH:21][CH:22]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(O)cc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCC2CNCCO2)cc1

Procedure:
The title compound was prepared by alkylation of 2-(2,6-difluorophenyl)-5-(4-hydroxyphenyl)oxazole-4-carboxamide with 2-chloromethyl-4-benzylmorpholine, according to the procedure described in example S-1, step b, followed by subsequent deprotection using the H-cube hydrogenation system (full H2 mode, 10% Pd\C catalyst, 1 ml/min, 0.05M in MeOH, 70° C.). 1H NMR (DMSO) δ 2.59-2.70 (2H, m), 2.90-3.00 (2H, m), 3.41-3.51 (1H, m), 3.69-3.79 (2H, m), 4.00 (2H, d), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.21-8.30 (2H, m). LCMS (2) 2.38 min; m/z (ES+) 416.
Reaction SMILES: [C:1](O)(=O)[CH:2]([CH3:4])[CH3:3].[NH2:7][CH2:8][CH:9]([NH2:11])[CH3:10]>>[CH:2]([C:1]1[NH:7][CH2:8][C@H:9]([CH3:10])[N:11]=1)([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O
Reactant: CC(N)CN
Product: CC(C)C1=N[C@@H](C)CN1
Yield: 80 %

Procedure:
The procedure described in Example 5 is followed except that 176 parts of isobutyric acid and 162.8 parts of 1,2-diaminopropane are employed. 201 parts of 2-isopropyl-4(5)-methylimidazoline (80% of theory, based on isobutyric acid employed) of boiling point 105°-106° C./32 mbar are obtained.
Reaction SMILES: CC1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[OH-].[Na+].[CH3:17][C:18]([OH:20])=[O:19]>OS(O)(=O)=O.O>[N+:12]([C:5]1[CH:4]=[CH:3][C:17]([C:18]([OH:20])=[O:19])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)([O-:14])=[O:13]
Reactant: Cc1ccc([N+](=O)[O-])c2cccnc12
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])c2cccnc12
Temperature: 0 °C
Yield: 66 %

Procedure:
Compound 12A (1.0 g, 5.3 mmol) was dissolved in concentrated H2SO4 (7 mL), cooled to 0° C., and then CrO3 (2.12 g, 21.3 mmol) was added portionwise over 30 min. After the addition, the reaction mixture was warmed to rt and then heated to 80° C. for 1 h. After cooling to rt, the reaction was diluted with water, basified with 15% aqueous NaOH, then reacidified to pH=3 with AcOH, and extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield the title compound (760 mg, 66%) as a yellow solid. LC/MS m/z 219 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2.Br[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.CC(C)([O-])C.[Na+]>O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[C:9](=[O:15])[CH:8]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH2:7][CH2:6]2
Reactant: COc1cc2c(c(OC)c1)C(=O)CCC2
Reactant: COc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1CCOC1
Product: COc1ccc(C2CCc3cc(OC)cc(OC)c3C2=O)cc1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 78.8 %

Procedure:
The title compound was synthesized by referring to J. Am. Chem. Soc., 1997, 119 (45), 11108. To a solution of 6,8-dimethoxy-3,4-dihydro-2H-naphthalen-1-one (11.9 g) in tetrahydrofuran (200 ml) were sequentially added 4-bromoanisole (16.2 g), sodium tert-butoxide (11.1 g), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.3 g) and tris(dibenzylidene)acetone dipalladium(0) (792 mg), and the solution was stirred for 1.5 hours at 75° C. under a nitrogen atmosphere. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo; the resulting crude crystal was suspended in diethyl ether and then filtered. The mother liquor was concentrated in vacuo, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate system); the resulting crystal was suspended in diethyl ether, then filtered, and combined to provide the title compound (14.2 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.CO[CH:35](OC)[N:36]([CH3:38])[CH3:37]>N1C=CC=CC=1>[ClH:28].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[N:2]=[CH:35][N:36]([CH3:38])[CH3:37])=[CH:17][CH:16]=2)=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)C=Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 224.7 %

Procedure:
In 10 mL of pyridine, 463 mg (0.957 mmol) of 1-[4-(6-amino-purin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride was dissolved, and 455 mg (3.83 mmol) of dimethylformamide dimethylacetal was added thereto and the mixture solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and then the residue was triturated with ethyl acetate and collected by filtration, and vacuum dried. The white solid was dissolved in 10 mL of methanol and 4N hydrochloric acid and concentrated under reduced pressure. The residue was triturated with ethyl acetate, collected by filtration, and then vacuum dried to obtain 580 mg (quantitative) of N′-(9-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl}-9H-purin-6-yl)-N,N-dimethylformamidine hydrochloride (Table 1, Compound No. 95) as a white solid.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH2:17]([O:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N#N>ClCCl>[CH2:17]([O:24][N:25]=[CH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NOCc1ccccc1
Reactant: CCCCCCCC=O
Agent: N#N
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCC=NOCc1ccccc1
Reaction time: 8 h
Yield: 46.9 %

Procedure:
Octanal (385 mg, 469 μL, 3.0 mmol) was weighed into a 10 mL round bottom flask previously flushed with N2 and containing a stifling bar. To the flask was anhydrous Na2SO4 (4.26 g, 30 mmol), 6 mL of dry dichloromethane and finally, O-benzylhydroxylamine (369 mg, 349 μL, 3 mmol) over 2 min while maintaining positive N2 pressure. The reaction mixture was stirred overnight. The salt was filtered off and rinsed with dichloromethane. The combined filtrates and rinsings were concentrated. The crude material was purified by column chromatography on silica gel eluting with hexanes/ethyl acetate (95:5) to give 328 mg (47%) of a clear oil: Rf=0.45 and 0.51 (two isomers) (hexanes/ethyl acetate, 95:5, v/v); 1H NMR (CDCl3) δ 7.43 (t, 3J=6.3 Hz, 0.5H), 7.36-7.25 (m, 5H), 6.66 (t, 3J=5.5 Hz, 0.5H), 5.08 (s, 1H), 5.03 (s, 1H), 2.37-2.32 (m, 1H), 2.18-2.14 (m, 1H), 1.49-1.41 (m, 2H), 1.33-1.18 (m, 8H), and 0.86 (t, 3J=7 Hz, 3H). Exact mass (FAB+) calculated for C15H24NO [M+H] 234.1852. Found 234.1856.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10]O)=[N:7][CH:8]=1)#[N:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH2:10])=[N:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(CCO)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C#N)cn1
Yield: 36.3 %

Procedure:
A mixture of 0.163 g (1.1 mmol) 5-cyano-2-(2-hydroxyethyl)pyridine and 0.029 g (0.15 mmol) p-toluenesulfonic acid hydrate in 10 mL toluene was heated to reflux for five hours in a flask equipped with a Dean-Stark trap. The cooled mixture was neutralized with 5 mL saturated sodium bicarbonate solution and extracted with ether (3×15 mL). The extract was washed with 3 mL brine, dried over sodium sulfate, and filtered. The filtrate was concentrated to give an oil which was purified by flash chromatography on silica gel elating with 1:3 ethyl acetate:hexane to give 0.052 g (36%) 5-cyano-2-vinylpyridine, mp 29°-30° C.
Reaction SMILES: [CH:1]([CH:3]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH:4]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=O.[C:20]([CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(P(N(C)C)(N(C)C)=O)C>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:4]1[CH:3]([CH:1]=[CH:28][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:27])[CH2:11][CH2:10][C:5]21[O:9][CH2:8][CH2:7][O:6]2
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: O=CC1CCC2(OCCO2)C1CCCCCCCO
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(C=CC1CCC2(OCCO2)C1CCCCCCCO)c1ccccc1

Procedure:
A mixture of 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane [4.0 g; prepared as hereinbefore described in Example 1(iv)] and benzoylmethylenetriphenylphosphorane (5.6 g; prepared according to the method of F. Ramirez and S. Dershowitz, J. Org. Chem. 1957, 22, 41) in hexamethylphosphotriamide (35 ml.) was heated on a steam bath under dry nitrogen for 48 hours then poured into water (200 ml.). The mixture was extracted with diethyl ether and the ethereal solution was washed with water, dried over anhydrous magnesium sulphate and evaporated. The residue was triturated with a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether, allowed to stand at 0° C, then filtered to remove triphenylphosphine oxide. The filtrate was evaporated to give 6-(7-hydroxyheptyl)-7-(3-phenyl-3-oxoprop-1-enyl)-1,4-dioxaspiro[4,4]nonane (5.5 g.) (νmax 950 cm-1, 985 cm-1, 1615 cm-1, 1660 cm-1, 3380 cm-1).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]3[N:16]([CH3:31])[C:17](=[O:30])[N:18]([C:20]4[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:21]=4[CH3:29])[CH2:19][C:13]3=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.CN(C=O)C>[Pd].CO>[NH2:26][C:24]1[CH:23]=[CH:22][C:21]([CH3:29])=[C:20]([N:18]2[CH2:19][C:13]3[C:14](=[N:15][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:1])[CH3:32])[CH:4]=4)=[N:11][CH:12]=3)[N:16]([CH3:31])[C:17]2=[O:30])[CH:25]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1Cc2cnc(Nc3cccc(N(C)C)c3)nc2N(C)C1=O
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(N)cc1N1Cc2cnc(Nc3cccc(N(C)C)c3)nc2N(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.6 %

Procedure:
To a solution of 7-(3-dimethylamino-phenylamino)-1-methyl-3-(2-methyl-5-nitro-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (80 mg, 0.18 mmol) in the mixed solvent of DMF (3 ml) and methanol (3 mL) is added 10% Pd/C, and the reaction mixture was stirred for 12 hours at room temperature under a hydrogen balloon. The reaction mixture is filtered and the filtrate is concentrated in vacuo to give 3-(5-amino-2-methyl-phenyl)-7-(3-dimethylamino-phenylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (60 mg, 81%) as a dark yellow solid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:11]=[C:12]([S:17](Cl)(=[O:19])=[O:18])[CH:13]=[CH:14][C:15]=1[Cl:16]>>[Cl:9][C:10]1[CH:11]=[C:12]([S:17]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)c1Br
Yield: 60 %

Procedure:
3,4-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 3,4-dichlorobenzenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 144-146° C., yield 60%.