Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](=[O:31])[CH3:30])=[CH:24][C:23]=1[O:32][CH3:33]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][C:29](=[O:31])[CH3:30])=[CH:24][C:23]=4[O:32][CH3:33])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(CC(C)=O)ccc1OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC#N
Product: COc1cc(CC(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 31.8 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.8 g, 15.2 mmol), K2CO2 (3 g), 1-[4-(3-bromopropoxy)-3-methoxyphenyl]propanone (4.6 g, 18.2 mmol) in acetonitrile (100 ml) was heated at reflux for 2 hours. At the end of the reaction, the mixture was filtered and the solvent was concentrated and the residue was extracted into dichloromethane (300 ml). The dichloromethane was filtered and concentrated again. The crude material (6.4 g) was purified by flash chromatography over a silica gel column (SiO2, 50 g; eluted with dichloromethane, 700 ml; 1% methanol in dichloromethane, 1.4 l). The material thus purified (weight: 2.87 g, 51%) was recrystallized from ethanol (25 ml) to give 2.13 g of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]propanone as beige colored crystals, m.p.=118°-119° C.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].[CH3:25][NH:26][NH2:27]>C(O)(=O)C>[O:22]=[C:13]1[C:14]2[C:15](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:17])[N:12]1[CH2:11][CH2:10][C:9]1[N:26]([CH3:25])[N:27]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=1
Reactant: CCOC(=O)C(=O)CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: CNN
Agent: [Na]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CCN2C(=O)c3ccccc3C2=O)n(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A modification of the method described in Part A of Example 11 was followed. A mixture of ethyl 2,4-dioxo-6-phthalimidohexanoate, sodium salt (prepared as described in Part A of Example 23, 100 g, 295 mmol) in glacial acetic acid (0.3 L) was cooled to 9° C. before the addition of methylhydrazine (16.0 mL, 300 mmol). During the addition, the reaction temperature did not exceed 16° C. Solids were rinsed from the inside of the flask walls into the mixture with acetic acid (50 mL) and the mixture was allowed to warm to ambient temperature and stir overnight. Water was added to the mixture and additional solid precipitated. The solid was isolated by filtration, dried, and recrystallized from ethanol. The solid was isolated and dried to yield 75.2 g of ethyl 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carboxylate.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:17]=[CH:16][C:10]([O:11][CH2:12][C:13](O)=[O:14])=[CH:9][CH:8]=2)[CH2:3]1.CCN=C=NCCCN(C)C.Cl.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:30][S:31]([NH:34][C:13](=[O:14])[CH2:12][O:11][C:10]1[CH:16]=[CH:17][C:7]([C@@H:4]2[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]2)=[CH:8][CH:9]=1)(=[O:33])=[O:32]
Reactant: O=C(O)COc1ccc([C@@H]2CCC(=O)C2)cc1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)COc1ccc([C@@H]2CCC(=O)C2)cc1
Temperature: 0 °C
Yield: 95.7 %

Procedure:
(R)-[4-(3-Oxo-cyclopentyl)-phenoxy]-acetic acid (preparation 31) (2.5 mmol, 585 mg) was dissolved in DCM (30 mL) and cooled to 0° C. on an icebath. EDCI.HCl (3.75 mmol, 720 mg), methanesulfonamide (2.75 mmol, 261 mg) and DMAP (3.75 mmol, 458 mg) was added and the reaction mixture left an additional 15 min on the ice bath. The ice bath was then removed and the reaction was allowed to warm to r.t. over night. Quenched with citric acid (10% aq.) and extracted with DCM, then dried over Na2SO4 and concentrated in vacuo to yield the title compound (745 mg, 95%). 1H NMR (300 MHz, CDCl3) δ 8.84 (bs, 1H), 7.25-7.19 (m, 2H), 6.95-6.85 (m, 3H), 4.58 (s, 2H), 3.58-3.08 (m, 5H), 2.78-2.58 (m, 1H), 2.58-2.15 (m, 5H), 2.15-1.78 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[N:17]([CH2:18][O:19][CH3:20])[CH:16]=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[C:22]1([CH2:28][C:29]([N:31]=[C:32]=[S:33])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:32]([NH:31][C:29](=[O:30])[CH2:28][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[S:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[N:17]([CH2:18][O:19][CH3:20])[CH:16]=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COCn1ccc2ncnc(Oc3ccc(N)cc3F)c21
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: COCn1ccc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c21
Reaction time: 3 h
Yield: 31.9 %

Procedure:
To a suspension of 245 (18 mg, 0.062 mmol) in THF (1 mL) was added 2-phenylacetyl isothiocyanate (12 mg, 0.069 mmol). The reaction mixture was stirred for 3 hours, concentrated under reduced pressure and the residue was purified by flash chromatography, eluent hexane/EtOAc (3:2) followed by recrystallization (MeCN/water), and preparative HPLC (Aquasil C-18, gradient: 60% MeOH to 95% MeOH in water), to afford title compound 246 (9.2 mg, 33% yield) as a white solid. 1HNMR: (CD3OD) δ (ppm): 8.35 (s, 1H), 8.03 (d, J=12.4 Hz, 1H), 7.96(d, J=3.13 Hz, 1H), 7.44-7.26 (m, 6H), 6.69 (d, J=3.13 Hz, 1H), 5.29 (quintuplet, J=6.65 Hz, 1H), 3.75 (s, 2H), 3.60 (d, J=10.96 Hz, 3H), 1.63(d, J=6.65 Hz, 6H). MS (m/z): 464.16 (M+1).
Reaction SMILES: [F:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[C:3]1[CH3:13].P([O-])([O-])([O-])=[O:15].[K+].[K+].[K+]>C(O)C>[OH:15][C:2]1([F:1])[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[C:3]1[CH3:13]
Reactant: CCCCCC1=C(C)C(F)CC1=O
Reactant: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCC1=C(C)C(O)(F)CC1=O
Reaction time: 0.03 h

Procedure:
Experimental description: 4-fluoro-3-methyl-2-pentylcyclopent-2-enone was obtained according to the experimental described in Example 5. 180 mg 4-fluoro-3-methyl-2-pentylcyclopent-2-enone was dissolved in 900 μL ethanol and added to 120 mL potassium phosphate buffer pH 8.0. Var2 was added to the mixture at a final concentration of 2 μM. The mixture was split in 4.8 mL aliquots into 15 mL scintillation vials equipped with a stir bar. 600 μL 10 mM NADPH in KPi buffer was added to each vial and stirred for 2 minutes. 600 μL cofactor regeneration solution containing 500 mM glucose-6-phosphate and 10 units/mL glucose-6-phosphate dehydrogenase were then added to each vial. The resulting mixtures were stirred at room temperature. After 36 hours, the reaction mixtures were joined together and extracted with chloroform (3×50 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (0-30% ethyl acetate/hexane) afforded the activated product (4-hydroxy-4-fluoro-3-methyl-2-pentylcyclopent-2-enone, 135 mg). 100 mg (0.54 mmol) of activated product was dissolved in 2 mL dry dichloromethane (CH2Cl2) and a catalytic amount (4 drops) of ethanol was added to the solution. The solution was cooled to −78° C. (dry ice) and then 100 μL DAST (0.7 mmol) was added. The reaction was stirred in dry ice for 12 hours. The reaction mixture was then added with 5 mL saturated sodium bicarbonate (NaHCO3) and extracted with dichloromethane (3×15 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (0-30% ethyl acetate/hexane) afforded the fluorinated product, 4,4-difluoro-3-methyl-2-pentylcyclopent-2-enone (85 mg, 85% yield, yellow oil). MS (EI+): m/z 202. Mw for C11H16F2O: 202.24.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1
Reactant: CN1CCNCC1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCN(C)CC1

Procedure:
A mixture of 1-(2-chloroethoxy)-2-methoxy-4-nitrobenzene (Step A, 1 eq), N-methylpiperazine (3 eq) and K2CO3 (2.5 eq) in CH3CN was stirred and heated under reflux until HPLC indicated the reaction was complete. The resulting solid was filtered, rinsed well with CH2Cl2 and the filtrate and washings were combined, concentrated and purified by column chromatography giving 1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-4-methyl-piperazine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[CH:21]=[CH:22][S:23][C:8]=2[C:7]=1Cl)=[O:5])[CH3:2].N12CCN(CC1)CC2.[N:33]1([C:39]([C:41]2[S:42][CH:43]=[CH:44][CH:45]=2)=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[CH:21]=[CH:22][S:23][C:8]=2[C:7]=1[N:36]1[CH2:37][CH2:38][N:33]([C:39]([C:41]2[S:42][CH:43]=[CH:44][CH:45]=2)=[O:40])[CH2:34][CH2:35]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2sccc2n(Cc2cccc(F)c2)c1=O
Reactant: O=C(c1cccs1)N1CCNCC1
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2sccc2n(Cc2cccc(F)c2)c1=O
Yield: 90.6 %

Procedure:
A solution of 7-chloro-4-(3-fluoro-benzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (17) (45 g, 123 mmol), 1,4-diazabicyclo[2.2.2]octane (15.9 g, 141 mmol) and piperazin-1-yl-thiophene-2-yl-methanone (27.8 g, 141 mmol) in dry DMF was heated at 110° C. for 7 h under argon. The solution was cooled and poured into 2% ammonium chloride solution. The solids formed were filtered and washed by cold water. The solids were dissolved in dichloromethane and washed by water. The organic phase was dried over MgSO4 and concentrated under vacuum to yield 58.6 g (91%) of 4-(3-fluoro-benzyl)-5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester. 1H-NMR (DMSO-d6): δ 1.29 (t, J=7.2 Hz, 3H), 3.37 (m, 4H), 3.82 (m, 4H), 4.27 (q, J=7.2 Hz, 2H), 5.38 (s, 2H), 7.05-7.16 (m, 4H), 7.33 (d, J=5.6 Hz, 1H), 7.36 (m, 1H), 7.48 (dd, J=1.2, 3.6 Hz, 1H), 7.79 (dd, J=1.2, 5.2 Hz, 1H), 8.03 (d, J=5.6 Hz, 1H); EIMS m/z 526 (M+1). Anal. (C26H24FN3O4S2) C, H, N.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12](=[O:45])[CH:13]([N:20]3[CH2:26][CH2:25][CH2:24][C:23]4[CH:27]=[C:28]([O:32][CH3:33])[C:29]([OH:31])=[CH:30][C:22]=4[CH:21]3[CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[CH:47]([CH3:49])[CH3:48]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12](=[O:45])[CH:13]([N:20]3[CH2:26][CH2:25][CH2:24][C:23]4[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:31][CH:47]([CH3:49])[CH3:48])=[CH:30][C:22]=4[CH:21]3[CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)Br
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(C(C(=O)NCc1ccc3c(c1)OCO3)c1ccccc1)CCC2
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCCN2C(C(=O)NCc2ccc3c(c2)OCO3)c2ccccc2)cc1OC

Procedure:
prepared by reaction of N-benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide with 2-bromopropane.
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1)=[N+:2]=[N-:3].[CH3:14][Si:15]([CH3:20])([CH3:19])[C:16]#[C:17]C>>[O:11]1[C:7]2([CH2:6][CH2:5][CH:4]([N:1]3[CH:17]=[C:16]([Si:15]([CH3:20])([CH3:19])[CH3:14])[N:3]=[N:2]3)[CH2:13][CH2:12]2)[O:8][CH2:9][CH2:10]1
Reactant: [N-]=[N+]=NC1CCC2(CC1)OCCO2
Reactant: CC#C[Si](C)(C)C
Product: C[Si](C)(C)c1cn(C2CCC3(CC2)OCCO3)nn1
Reaction time: 2 h
Yield: 104.7 %

Procedure:
A mixture of 8-Azido-1,4-dioxa-spiro[4.5]decane (1.00 g, 5.43 mmol) and 1-(trimethylsilyl)propyne (3.76 mL, 27.1 mmol) was submitted to microwave at 120° C. for 2 h. The mixture was concentrated under vacuum to remove the excess of 1-(trimethylsilyl)propyne and crude 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-4-trimethylsilanyl-1H-[1,2,3]triazole (1.6 g, 105%) was obtained.
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[CH2:11][OH:12])[CH2:2][CH3:1]
Reactant: CCC(=O)c1ccccc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC(O)c1ccccc1CO

Procedure:
This compound was prepared in an analogous manner to Example XI from 10 g (56 mM) of propiophenone-2-carboxylic acid and lithium aluminium hydride to yield the title compound as an oil. 1H-nmr δ (CDCl3) 7.5-7.2 (4H, m); 4.8-4.5 (3H,m); 3.9-3.5 (2H, broad s, exchanges with D2O); 1.9-1.6 (2H, m); 0.86 (3H,t).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][C:10]2[C:24]([CH:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:32]([O:36][C:37]([NH:39][CH2:40][C:41](O)=[O:42])=[O:38])(C)(C)[CH3:33]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:24]([CH:25]3[CH2:29][CH2:28][CH2:27][N:26]3[C:41](=[O:42])[CH2:40][NH:39][C:37](=[O:38])[O:36][CH2:32][CH3:33])=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:30][CH:31]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: CCOC(=O)NCC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1

Procedure:
The entitled compound was obtained in the same method as in Example 171 and 181 or in accordance with the method or by combining it with an ordinary method but using 5-(4-methanesulfonyl-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole obtained in Example 162 (step 7) and N-t-butoxycarbonyl-glycine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:21]3[C:20](=[O:28])[NH:19][C:18](=[O:29])[N:17]([CH3:30])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]([O:41]CC)=[O:40]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:21]3[C:20](=[O:28])[N:19]([CH2:38][C:39]([OH:41])=[O:40])[C:18](=[O:29])[N:17]([CH3:30])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CC(C)=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(CC(=O)O)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[3-Methyl-7-(3-methylbut-2-enyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (70 mg) and potassium carbonate (28 mg) were dissolved in N,N-dimethylformamide (1.5 ml), and ethyl bromoacetate (22 μl) was added thereto. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was concentrated by distillation, and ethanol (1.5 ml) and 2 N sodium hydroxide aqueous solution (0.5 ml) were added to the resulting residue. The reaction mixture was stirred at room temperature for 3 hours, diluted with water, and neutralized with 2 N hydrochloric acid. After the mixture was extracted with ethyl acetate, the organic layer was concentrated by distillation to give 75 mg of 4-[1-carboxymethyl-3-methyl-7-(3-methylbut-2-enyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester. Then, the resulting 4-[1-carboxymethyl-3-methyl-7-(3-methylbut-2-enyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (10 mg) was dissolved in trifluoroacetic acid (0.5 ml), and the reaction mixture was stirred at room temperature for 30 minutes. After the solvent was removed by distillation, a half of the residue was purified by HPLC with a reversed phase column using water-acetonitrile-trifluoroacetic acid system as eluent to give 5.9 mg of the title compound.
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[C:14]([OH:16])=O)[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].[CH2:23]([C:27]1[N:32]=[C:31]([N:33]([CH3:35])[CH3:34])[N:30]=[C:29]([NH:36][NH2:37])[N:28]=1)[CH2:24][CH:25]=[CH2:26].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:23]([C:27]1[N:32]=[C:31]([N:33]([CH3:35])[CH3:34])[N:30]=[C:29]([NH:36][NH:37][C:14]([C@H:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[CH2:12][N:3]([O:4][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:1]=[O:2])=[O:16])[N:28]=1)[CH2:24][CH:25]=[CH2:26]
Reactant: C=CCCc1nc(NN)nc(N(C)C)n1
Reactant: C=CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C=CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)NNc1nc(CCC=C)nc(N(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2R)-2-({N-formyl-N-benzoxy-amino}methyl)-7-octenoic acid (233 mg, 1.121 mmol), 4-(3-buten-1-yl)-6-(dimethylamino)-2-hydrazino-1,3,5-triazine (342 mg, 1.121 mmol), NMM (0.62 mL, 5.61 mmol) and HOAt (183 mg, 1.345 mmol) in DMF (11 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (258 mg, 1.345 mmol). After stirring at room temperature overnight, the reaction mixture was then purified by HPLC to afford the title compound as a white solid. MH+496.
Reaction SMILES: ClC[CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10]Cl.[OH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)[CH:4]=[CH2:3]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: ClCCCCOCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOCCCCOc1ccc(C(=O)O)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A solution comprising 14 g of allyl (4-chlorobutyl ether, 14 g of 4-hydroxybenzoic acid, 14 g of potassium carbonate and 50 ml of dimethylformamide was stirred at 90° C. for 3 hours. Water was added thereto, and the liquid was extracted with toluene. The toluene layer was washed well with water, and toluene was distilled off. Sodium hydroxide 20 g, water 50 ml and ethanol 200 ml were added to the resulting residue, and the solution was refluxed for 2 hours. Ethanol was distilled off, and hydrochloric acid was added to acidify the solution. It was extracted with diethyl ether and dried on anhydrous magnesium sulfate. The solvent was distilled off, and a residue thus obtained was recrystallized from a mixed solvent of ethanol and water to obtain 29 g of 4-(4-allyloxybutyloxy)benzoic acid. Phase transition temperature: C 94 N 107 I
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:17])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:26](=[O:27])[CH2:25][Cl:24])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)CCl)cc1
Yield: 99.1 %

Procedure:
A solution of 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine (886 mg, 3.86 mmol), pyridine (465 μL, 5.80 mmol) and chloroacetyl chloride (462 μL, 5.80 mmol) in DCM (5 mL) was stirred at RT for 2 h. The reaction mixture was diluted with aq. sat. sodium bicarbonate and DCM and the resulting aqueous layer was extracted twice with DCM. The combined organic layers were dried (MgSO4) and concentrated in vacuo to afford the title compound (1.17 g, 100%) as a yellow solid. LCMS (Method 5): Rt 4.41 min, m/z 306 [MH+].
Reaction SMILES: [CH2:1]([CH:8]1[CH2:15][NH:14][C:13](=[O:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[CH2:10][N:9]1[S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])(=[O:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34]I>CN(C=O)C>[CH2:1]([CH:8]1[CH2:15][N:14]([CH3:34])[C:13](=[O:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[CH2:10][N:9]1[S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])(=[O:23])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1S(=O)(=O)N1Cc2ccccc2C(=O)NCC1Cc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1S(=O)(=O)N1Cc2ccccc2C(=O)N(C)CC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87.2 %

Procedure:
To a solution of compound 2g (120 mg, 0.28 mmol) in DMF (15 mL) at 10° C., NaH (60% in mineral oil; 13 mg, 0.33 mmol) was added in portions. The mixture was stirred for an additional 45 min and then MeI (116 mg, 0.82 mmol) was added dropwise. The resulting mixture was stirred at 10° C. for 30 min and warmed to rt overnight. The reaction was quenched with water (30 mL) and extracted with EA (40 mL). The organic layer was washed with brine (2×20 mL) and dried over anhydrous Na2SO4. Concentration in vacuo and purification by prep-TLC (PE:EA=1:1) gave compound 2h as a white solid (110 mg, 89% yield). 1H-NMR (400 MHz, CD3OD) δ 7.82 (dd, 1H, J=8.0, 1.6 Hz), 7.51 (t, J=8.8 Hz, 1H), 7.36-7.23 (m, 4H), 7.05-6.99 (m, 5H), 6.72-6.70 (m, 2H), 5.41 (d, J=18.8 Hz, 1H), 4.55 (d, J=19.2 Hz, 1H), 4.10 (m, 1H), 3.82 (s, 3H), 3.28 (dd, J=14.4, 11.6 Hz, 1H), 2.98 (dd, J=15.2, 4.8 Hz, 1H), 2.86 (s, 3H), 2.61 (dd, J=12.8, 9.6 Hz, 1H), 2.47 (dd, J=12.8, 4.8 Hz, 1H). MS (ESI+) m/z: 451 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][N:16]=1>>[Cl:14][C:15]1[CH:20]=[C:19]([O:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:18]=[CH:17][N:16]=1
Reactant: COC(=O)c1ccccc1O
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccccc1Oc1ccnc(Cl)c1
Yield: 70.4 %

Procedure:
Using the method of Example 3, Step A, methyl 2-hydroxybenzoate (2.88 mg, 18.9 mmol), 60% sodium hydride in mineral oil (757 mg, 18.9 mmol), and 2-chloro-4-nitropyridine (3.00 g, 18.9 mmol) were reacted to provide methyl 2-(2-chloropyridin-4-yloxy)benzoate (3.51 g, 70% yield) as an oil. 1H NMR (CDCl3) δ 8.22 (d, 1H), 8.05 (d, 1H), 7.63 (t, 1H), 7.40 (t, 1H), 7.16 (d, 1H), 6.72-6.74 (m, 1H), 3.77 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[OH:12].[H][H]>C(OCC)(=O)C.[C].[Pd]>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([F:1])=[C:3]([OH:12])[CH:4]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(O)c(F)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(O)c(F)cc1F
Yield: 96.1 %

Procedure:
24.9 g (142 mmol) of the resulting 2,4-difluoro-5-nitrophenol was dissolved in 150 ml of ethyl acetate, 5.0 g of 10% palladium-carbon was added and the mixture was stirred at 50° to 60° C. for 27 hours under a stream of hydrogen. The reaction vessel was filled with nitrogen, the reaction solution was filtered by means of suction, the solvent was distilled off under reduced pressure, and the residue was triturated with n-hexane to give 19.8 g (96%) of 5-amino-2,4-difluorophenol.