Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:22][NH:23][CH2:24][CH:25]([CH3:27])[CH3:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH2:24]([N:23]([CH3:22])[C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:20])[CH:25]([CH3:27])[CH3:26]
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Reactant: CNCC(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)CN(C)C(=O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added N-methylisobutylamine (0.15 ml, 1.29 mmol) and T3P (50 wt % solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (108 mg, 44% yield). Rf=0.80 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C21H31ClN2O2, 378.9, found, 379.1 (M+1) APCI; 400 MHz 1H NMR (CDCl3) 1:1 mixture of rotomers, δ 7.47-7.45 (m, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.36-7.30 (m, 1H), 3.71 (s, 2H), 3.20-3.02 (m, 3H), 2.92 & 2.90 (2 s, 3H total), 2.80-2.70 (m, 2H), 2.60-2.50 (m, 6H), 1.95-1.80 (m, 1H), 1.78-1.70 (m, 4H), 0.76-0.58 (m, 6H); 100 MHz 13C NMR (CDCl3) 1:1 mixture of rotomers, line list δ 176.6, 175.8, 146.4, 135.2, 135.1, 134.0, 130.9, 130.8, 126.4, 123.7, 123.6, 73.5, 73.3, 57.9, 56.7, 55.6, 54.3, 41.4, 41.0, 36.1, 35.0, 29.0, 28.2, 27.9, 26.9, 23.7, 20.2, 20.1.
Reaction SMILES: N.Cl.[NH2:3][NH:4][C:5]([NH2:7])=[O:6].[C:8]1(C)[C:9]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1>CO>[S:14]([C:9]1[CH:8]=[CH:13][C:12]([CH3:5])=[CH:11][CH:10]=1)([OH:17])(=[O:15])=[O:16].[NH2:3][NH:4][C:5]([NH2:7])=[O:6]
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: Cl
Agent: N
Agent: NNC(N)=O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)O)cc1
Reaction time: 1 h

Procedure:
At room temperature, NH3 (20 mL, 135 mmol, 7N in methanol) was added subsurface via syringe to a stirred slurry of semicarbazide hydrochloride (10.0 g, 90 mmol) in methanol (75 mL). After one hour, the solution was filtered to remove ammonium chloride. The filtrate was diluted with ethyl acetate (150 mL) and the resulting solution was concentrated to ˜300 mL by a reduced pressure distillation. The solution was filtered and treated with toluene sulfonic acid (17.1 g, 90 mmol). Upon acid addition, a white precipitate formed which was collected by filtration. The solid was rinsed with ethyl acetate (50 mL) and dried under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].[Br:20]Br>C(O)(=O)C.ClCCl>[NH2:1][C:2]1[C:7]([Br:20])=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][N:3]=1
Reactant: Nc1ccc(-c2ccc(F)cc2)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1ncc(-c2ccc(F)cc2)cc1Br
Yield: 105.7 %

Procedure:
To a solution of 2-amino-5-(4-fluorophenyl)pyridine (0.80 g, 4.25 mmol) in 20 ml glacial acetic acid was added sodium acetate (1.39 g, 17.0 mmol). Subsequently, a solution of bromine (0.44 mL, 8.50 mmol) in 2 ml glacial acetic acid was added dropwise to the reaction by addition funnel. After the addition, the reaction was heated to reflux for 1 hour then cooled and diluted with dichloromethane. The solution was washed with 25 ml saturated aqueous sodium hydrogen sulfate and then 25 ml water then dried over magnesium sulfate and concentrated to a brown oil. Automated purification on a silica gel ISCO column (120 g column, 2.5% MeOH—CH2Cl2) gave 1.20 g (60%) of 2-amino-3-bromo-5-(4-fluorophenyl)pyridine as an off-white/pink solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[N:30]=[C:29](S(C)(=O)=O)[N:28]=1.O>CN(C)C=O.C(O)(=O)C>[CH2:1]([O:8][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH:10]([O:15][C:29]1[N:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:27]([O:26][CH3:25])[N:28]=1)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)C(C)(OCc1ccccc1)c1ccccc1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(OCc1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
3 g (10 mmol) of methyl 3-benzyloxy-3-phenyl-2-hydroxybutyrate (compound 1.1) are dissolved in 40 ml of dimethylformamide, and 0.3 g (12 mmol) of sodium hydride are added. Stirring is carried out for 1 hour, after which 2.2 g (10 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine are added. After stirring has been carried out for 24 hours at room temperature, hydrolysis is effected carefully with 10 ml of water, the pH is brought to 5 with acetic acid and the solvent is distilled off under greatly reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed with water and dried over sodium sulfate and the solvent is distilled off. 10 ml of methyl tert-butyl ether are added to the residue and the precipitate formed is filtered off with suction. After drying, 2.4 g of a white powder remain.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:16]1(O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 63 h

Procedure:
tert-Butyl(cis-4-hydroxycyclohexyl)carbamate (2.00 g), phenol (1.14 g), and triphenylphosphine (3.17 g) were dissolved in tetrahydrofuran (40.0 mL). Then, to the solution, diisopropyl azodicarboxylate (6.49 mL) was added dropwise at room temperature, and the mixture was stirred at room temperature for 63 hours. The reaction solution was concentrated and then purified by silica gel column chromatography (eluting solvent: hexane-hexane/ethyl acetate-90/10) to obtain the title compound (1.80 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].[NH4+].[Cl-]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(NS(C)(=O)=O)cc1
Reaction time: 8 h
Yield: 25 %

Procedure:
Combine 3-(4-Aminophenyl)-4-cyano-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester (0.1 g, 1.0 eq) in CH2Cl2 (5 mL) and stir. Add triethylamine (1.5 eq) and methanesulfonyl chloride (1.0 eq) at room temperature. Stir the mixture overnight. Add a saturated solution of NH4Cl and extract with CH2Cl2 (2×50 mL). Dry over NaSO4, filter and evaporate to dryness. Purification by chromatography (hexane:ethyl acetate 4:1) provides the title compound (0.028 g, Yield 25%). MS (ES+, m/e): 397 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[NH:10][C:9]([C:11]([OH:13])=O)=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:7]=2)=[CH:2]1.Cl.[NH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[NH:10][C:9]([C:11]([NH:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=3)=[O:13])=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:7]=2)=[CH:2]1
Reactant: O=C(O)c1[nH]c(-c2ccoc2)cc1-c1ccc(O)cc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNC(=O)c2[nH]c(-c3ccoc3)cc2-c2ccc(O)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
A solution of 5-(3-furyl)-3-(4-hydroxyphenyl)-1H-pyrrole-2-carboxylic acid (1.45 g, 5.5 mmol) and methyl 4-(aminomethyl)benzoate hydrochloride (1.10 g, 5.5 mmol) in DMF (27.5 ml) was cooled to 0° C. Triethylamine (4.22 ml, 30.25 mol), 1-hydroxybenzotriazole (0.81 g, 6.0 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.17 g, 6.0 mmol) and N-methylmorpholine (0.61 ml, 5.5 mmol) were added subsequently, and the mixture was stirred for 2 h at 0° C., and for an additional 96 h at room temperature. Ethyl acetate (400 ml) was added, and the obtained solution was washed with water (75 ml), Na2S2O3 1N (75 ml, aqueous solution), water (75 ml), NaHCO3 (75 ml, saturated aqueous solution), and NaCl (75 ml, saturated aqueous solution), dried over Na2SO4 and evaporated under reduced pressure, to obtain 1.43 g (3.47 mmol) of methyl 4-[({[5-(3-furyl)-3-(4-hydroxyphenyl)-1H-pyrrol-2-yl]carbonyl}amino)methyl]benzoate: Yield 63%; m.p. 223-224° C.; IR 3390, 3321, 1700, 1616, 1532, 1272 cm−1; 1H-NMR (500 MHz, δ ppm, DMSO-d6) 11.51 (s, 1H), 9.35 (s, 1H), 8.13 (s, 1H), 7.91 (d, J=8.2 Hz, 2H), 7.67 (tb, 1H), 7.37 (d, J=8.3 Hz, 3H), 7.26 (d, J=8.5 Hz, 2H), 6.93 (d, J=0.9 Hz, 1H), 6.73 (d, J=8.5 Hz, 2H), 6.38 (d, J=2.6 Hz, 1H), 4.45 (d, J=5.8 Hz, 2H), 3.85 (s, 3H); 13C-NMR (126 MHz, δ ppm, DMSO-d6) 166.0, 161.2, 156.3, 145.0, 143.6, 138.5, 129.9, 129.1, 128.1, 127.5, 127.4, 126.0, 125.9, 121.3, 118.2, 115.1, 108.7, 108.3, 51.9, 42.1.
Reaction SMILES: N[C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH3:9])=[O:5].C(N=C=S)(=O)C1C=CC=CC=1>O1CCCC1.CCOCC>[CH2:7]([NH:6][C:4](=[O:5])[C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:2]=1)[CH2:8][CH3:9]
Reactant: CCCNC(=O)c1ccccc1N
Agent: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCNC(=O)c1ccccc1

Procedure:
To 32.6 g of isatoic anhydride in 150 ml of isopropyl alcohol was added 25 ml of n-propylamine portionwise as the reaction was exothermic. Evaporation of the solution gave 30 g of 2-amino-N-propylbenzamide as colorless crystals, mp 100°-102° C. To a stirred solution of 25.0 g of 2-amino-N-propylbenzamide in 300 ml of tetrahydrofuran was added 22.9 g of benzoylisothiocyanate over 10 minutes. After 2 hours the mixture was diluted with 100 ml of ether and was filtered to give 30.7 g of 2-[[benzoylamino)thioxomethyl]amino]-N-propylbenzamide, mp 172°-174° C. Then, to a solution of 10.2 g of 2-[[benzoylamino)thioxomethyl]amino]-N-propylbenzamide in 100 ml of dichloromethane was added 30 ml of 1N sodium hydroxide to form a two-phase mixture, and to this was added 20 ml of iodomethane and then 4 drops of benzyltrimethylammonium hydroxide solution. After stirring for 3 hours, the organic phase was separated and dried over anhydrous sodium sulfate. Filtration and evaporation of the filtrate gave 9.4 g of N-benzoyl-N'-(2-propylaminocarbonylphenyl)carbamimidothioic acid, methyl ester, mp 86°-89° C. To a solution of 7.10 g of this compound in 300 ml of anhydrous dioxane was added 1.45 g of 60% sodium hydride in mineral oil suspension and the mixture was refluxed for 5 hours. The reaction mixture was then poured into 1.5 liter of water and made acidic with hydrochloric acid. The crystals that formed were collected and recrystallized from ethyl acetate-hexane to give N-(3,4-dihydro-3-propyl-4oxo-2-quinazolinyl)benzamide as colorless crystals, mp 133°-135° C.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:10]1(=[O:16])[O:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[C:11]1[CH2:12][CH2:13][CH2:14][O:15][C:10]1=[O:16]
Reactant: O=Cc1ccccc1O
Reactant: O=C1CCCCO1
Solvent: Cc1ccccc1
Product: O=C1OCCCC1=Cc1ccccc1O
Yield: 27.5 %

Procedure:
Salicylaldehyde (15.2 g) and δ-valerolactone (25 g) were dissolved in toluene (150 ml). By the reaction in the same manner as in Example 307, oily α-(2′-hydroxybenzylidene)-δ-valerolactone (7.0 g) was obtained. Dimethylformamide (70 ml) and potassium carbonate (9.5 g) were added hereto and (S) -glycidyl nosylate (8.9 g) was added. The mixture was stirred at 40° C. for 2 hr. The reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the oily title compound (7.8 g). The reaction in the same manner as in Example 307 using this product (1.0 g) and 4-(naphthalen-2-yl)piperidine (1.0 g) in methanol (50 ml) was performed and the obtained oil was recrystallized from ethyl acetate to give the title compound (0.38 g), melting point 142-144° C.
Reaction SMILES: COC1C=C2C(=CC=1)CC(C1C(C)=CC=CC=1N)CC2.Cl.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:26](Cl)=O.FC1C=[C:44](C=CC=1OCCN1CCCCC1)[CH2:45][NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[C:48]=1[CH:54]1[CH2:63][CH2:62][C:61]2[C:56](=[CH:57][CH:58]=[C:59]([O:64][CH3:65])[CH:60]=2)[CH2:55]1>>[CH2:45]([N:46]([CH2:26][C:25]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:23]([F:22])[CH:24]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[C:48]=1[CH:54]1[CH2:63][CH2:62][C:61]2[C:56](=[CH:57][CH:58]=[C:59]([O:64][CH3:65])[CH:60]=2)[CH2:55]1)[CH3:44]
Reactant: COc1ccc2c(c1)CCC(c1c(C)cccc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)c(F)c1
Agent: COc1ccc2c(c1)CCC(c1c(C)cccc1N)C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cccc(C)c1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-3-methylphenylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride according to an analogous synthetic method to Example 152, [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-3-methylphenyl]amine (578 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-3-methylphenyl]amine (449 mg). This compound (447 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (317 mg).
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:27]C)[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:9]([NH2:29])[N:8]=1)[CH2:3][CH2:4][CH3:5].Cl.O1CCOCC1>CO>[NH2:29][C:9]1[N:8]=[C:7]([O:6][C@@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:27])[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCNC3CCOCC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCC[C@H](C)Oc1nc(N)c2[nH]c(=O)n(CCCCNC3CCOCC3)c2n1
Yield: 96.3 %

Procedure:
2-{[(1S)-1-Methylbutyl]oxy}-8-(methyloxy)-9-[4-(tetrahydro-2H-pyran-4-ylamino)butyl]-9H-purin-6-amine (30.35 mg, 0.075 mmol) was dissolved in methanol (2.0 ml) and treated with 4M HCl in 1,4 dioxane (0.467 ml, 1.866 mmol) and stirred in a capped vial over the weekend. The solvent was evaporated under nitrogen and the residue was dissolved in methanol and passed down an aminopropyl SPE cartridge (2 g, pre-conditioned with 2 column volumes of methanol) and washed through with 1 column volume of methanol. The eluant was evaporated under nitrogen in a blowdown unit to give the title compound as an off-white solid (28.34 mg).
Reaction SMILES: C(O[CH:5]([O:9][C:10](=[O:12])[CH3:11])[C:6]([CH3:8])=[CH2:7])(=O)C.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[CH:17][CH:16]=1>C(OCC)(=O)C>[C:10]([O:9][CH:5]=[C:6]([CH3:7])[CH2:8][C:21]1[CH:22]=[C:15]([O:14][CH3:13])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])(=[O:12])[CH3:11]
Reactant: C=C(C)C(OC(C)=O)OC(C)=O
Reactant: COc1ccc(OC)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(OC)c(CC(C)=COC(C)=O)c1
Temperature: 53.5 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
In an argon gas atmosphere, a three necked flask having a capacity of 25 ml was charged with 1.92 g (10 m moles) of 3,3-diacetoxy-2-methylpropene having a purity degree of 89.6% by mass and 13.82 g (100 m moles) of hydroquinone dimethylether. Then, the resultant mixture was mixed with 0.14 g (1 m mole) of boron trifluoride-diethyl ether complex at an internal temperature of 54° C. over a time of one minute. The mixture was stirred at an internal temperature of 53 to 54° C. for one hour to cause the mixed compounds to react with each other. After the reaction was completed, the resultant reaction liquid was mixed with 150 ml of ethyl acetate and washed two times with 20 ml of saturated aqueous sodium chloride solution. The resultant reaction liquid was subjected to a layer separation treatment, the resultant organic layer was distilled under reduced pressure (20 mmHg, 55 to 57° C.), the resultant residue was refined by a chromatography on silica gel using an eluting solvent:hexane/ethyl acetate mixture in a mixing ratio by volume of 10/1. As a colorless liquid fraction, the target 1-acetoxy-2-methyl-3-(2,5-dimethoxyphenyl)propene was obtained in a yield of 77.4% in an amount of 1.94 g in the form of a colorless solid.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH2:21][CH3:22])[CH:15]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(Cl)(Cl)Cl>[Br:1][C:17]1[C:18]([CH3:20])=[CH:19][C:14]([O:13][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][C:16]=1[CH2:21][CH3:22]
Reactant: BrBr
Reactant: CCCCCCCCCCOc1cc(C)cc(CC)c1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCOc1cc(C)c(Br)c(CC)c1

Procedure:
A solution of bromine (5.44 g, 0.034 mol) in chloroform (50 ml) was added dropwise to a stirred, refluxing solution of 1-decyloxy-3-ethyl-5-methylbenzene (9.4 g, 0.034 mol) in chloroform (200 ml). The reaction mixture was then allowed to cool, washed with water and dried (MgSO4). The solvent was removed and the residue purified by gravity column chromatography (silica gel/dichloromethane) to yield a pale orange oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:23]1CCOCC1.C(OC(Cl)=O)C(C)C.N>C1COCC1>[C:18]([O:17][C:15](=[O:16])[NH:14][C@H:10]([C:11](=[O:12])[NH2:23])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(N)=O
Temperature: -15 °C
Reaction time: 0.03 h

Procedure:
To a solution of (S)-3-benzyloxy-2-(tert butoxycarbonylamino)propionic acid (0.98 g, 3.3 mmol) in anhydrous THF (13 mL) at −15° C. was added N-methylmorpholine (0.4 mL, 3.3 mmol) and isobutylchloroformate (0.4 mL, 3.3 mmol) under a nitrogen atmosphere. After 2 minutes, 33% aqueous ammonia (0.3 mL, 5 mmol) was added and the resulting mixture stirred at −15° C. for 2 h. The reaction mixture was allowed to warm to RT and was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The combined organic fractions were washed with aqueous 5% NaHCO3, water, dried (MgSO4) and concentrated in vacuo. The resulting white solid was used without further purification (quant. yield). 1H NMR (CDCl3, 300 MHz): δ 7.41-7.25 (5H, m), 6.42 (1H, br s), 5.48 (2H, br s), 4.55 (2H, dd, J=22., 12 Hz), 4.30 (1H, br s), 3.95-3.85 (1H, dd, J=9.5, 3.9 Hz), 3.55 (1H, dd, J=9.5, 6.7 Hz), 1.42 (9H, s).
Reaction SMILES: [H-].[Na+].[C@@H:3]1([OH:9])[CH2:7][CH2:6][CH2:5][C@H:4]1[OH:8].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Br)[N:12]=1>CN(C=O)C.CCOCC>[Br:10][C:11]1[N:12]=[C:13]([CH2:17][O:8][C@@H:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[OH:9])[CH:14]=[CH:15][CH:16]=1
Reactant: O[C@@H]1CCC[C@H]1O
Reactant: BrCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O[C@@H]1CCC[C@H]1OCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.48 mg, 11.96 mmol) was suspended in DMF (12.0 mL) and cooled to 0° C. (1R,2R)-Cyclopentane-1,2-diol (1.22 g, 11.96 mmol) was added and the reaction was stirred for 30 minutes. 2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (0.30 g, 1.20 mmol) was added and the reaction mixture was allowed to warm to room temperature overnight. The reaction was then diluted with ether and quenched with water. After layer separation, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purification of the crude residue by silica gel chromatography afforded the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:13][CH:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].I[CH3:23]>>[CH3:23][N:14]([CH:12]1[CH2:13][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1)[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1CN(c2ccc([N+](=O)[O-])cc2)C1
Product: CN(C(=O)OC(C)(C)C)C1CN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
tert-Butyl [1-(4-nitrophenyl)azetidin-3-yl]carbamate was alkylated with iodomethane by method F. This resulted in the product with the molecular weight of 307.35 (C15H21N3O4); MS (ESI): 308 (M+H+).
Reaction SMILES: [CH:1]([P:3](=[O:17])([CH:15]=[CH2:16])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=1)=[CH2:2].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:18]([N:25]1[CH2:16][CH2:15][P:3](=[O:17])([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=2)[CH2:1][CH2:2]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=CP(=O)(C=C)c1ccc([N+](=O)[O-])c(OC)c1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(P2(=O)CCN(Cc3ccccc3)CC2)ccc1[N+](=O)[O-]
Temperature: 105 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.480 g, 1.90 mmol) and benzylamine (0.23 mL, 2.08 mmol) were dissolved in 50% aqueous THF (6 mL) and heated to 105° C. under nitrogen. After one hour, another portion of benzylamine was added to the reaction mixture. The reaction mixture was refluxed for an additional 2 h, and then cooled to rt. The reaction mixture was partitioned between saturated aqueous NaHCO3 and CH2Cl2. The aqueous phase was washed once with CH2Cl2 and the organic layers were combined. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-5% 7N ammonia in methanol:dichloromethane) to afford the desired product (0.449 g, 66% yield).