Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@H:24]([OH:39])[CH2:25][O:26][C:27]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]2[C:28]=1[CH2:29][CH2:30][C:31](=[O:38])[NH:32]2>>[OH:39][C@H:24]([CH2:25][O:26][C:27]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]2[C:28]=1[CH2:29][CH2:30][C:31](=[O:38])[NH:32]2)[CH2:23][NH:22][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)c4c3CCC(=O)N4)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 228) and 5-(3-amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one (which was obtained in Example 12) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.82 (t, J=7.3 Hz, 3 H), 1.20–1.40 (m, 4 H), 1.50–1.70 (m, 2 H), 1.80–1.95 (m, 2 H), 2.39 (t, J=7.3 Hz, 2 H), 2.50–2.80 (m, 5 H), 2.85 (t, J=7.3 Hz, 2 H), 2.85–3.00 (m, 2 H), 3.45–3.60 (m, 2 H), 3.75–3.85 (m, 3 H), 6.44 (d, J=8.7 Hz, 1 H), 6.60 (d, J=8.7 Hz, 1 H), 6.89 (d, J=9.0 Hz, 2 H), 7.04 (d, J=9.0 Hz, 2 H), 8.74 (s, 1 H); MS (ES) m/z: 546.9 (MH+); HRMS Calcd. for C27H39N4O6S (MH+): 547.2590. Found: 547.2583.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=2)=[O:25])=[CH:19][CH:18]=1)=[O:6])[CH:2]=C.I([O-])(=O)(=O)=[O:39].[Na+].[BH4-].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:24](=[O:25])[NH:23][C:20]2[CH:21]=[CH:22][C:17]([N:12]3[CH:11]=[N:10][C:9]4[C:13]3=[N:14][CH:15]=[N:16][C:8]=4[NH:7][C:5]([NH:4][CH2:1][CH2:2][OH:39])=[O:6])=[CH:18][CH:19]=2)=[CH:28][C:29]=1[C:34]([F:37])([F:36])[F:35]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCNC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(-n2cnc3c(NC(=O)NCCO)ncnc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.4 %

Procedure:
In a mixed solution of 3 mL of tetrahydrofuran and 1 mL of water, 50 mg (0.09 mmol) of 1-allyl-3-(9-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl}-9H-purin-6-yl)urea was dissolved, and 19 μL of a 0.1 M osmium tetraoxide aqueous solution and 81 mg (0.19 mmol) of sodium periodate were added thereto and the mixture solution was stirred at room temperature for three hours. The reaction solution was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The residue was dissolved in 2 mL of ethanol, and 5 mg (0.13 mmol) of sodium borohydride was added thereto and the mixture solution was stirred at room temperature for one hour. The reaction solution was concentrated, and purified by a silica gel column (dichloromethane:methanol=9:1) to obtain 5 mg (13%) of a target product as a white solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:20])[CH2:6][NH:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([Cl:19])=[CH:14][CH:13]=2)=[O:9].Cl>C1COCC1>[Cl:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:8]([NH:7][CH2:6][C:5]([OH:20])=[O:4])=[O:9])=[CH:18]2
Reactant: COC(=O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1N NaOH (35 ml) was added to a suspension of [(5-chloro-1H-indole-2-carbonyl)-amino]-acetic acid methyl ester (8.0 g, 30 mmol) in THF (100 ml) and the resulting mixture stirred for 18 hours at 25° C. The solution was acidified with 6N HCl (7 mL), the mixture concentrated, the solids suspended in water, filtered, and washed with water (7.42 g, 98%): HPLC (60/40) 2.89 minutes (100 %;)
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[F:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:18])[C:12]([I:19])=[CH:11][CH:10]=1.[CH3:20]O>C1C=CC=CC=1>[F:8][C:9]1[C:14]([C:15]([O:17][CH3:20])=[O:16])=[C:13]([CH3:18])[C:12]([I:19])=[CH:11][CH:10]=1
Reactant: CO
Reactant: Cc1c(I)ccc(F)c1C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Product: COC(=O)c1c(F)ccc(I)c1C

Procedure:
Trimethylsilyldiazomethane solution (2 M in Hexane) (18 mL, 35 mmol) was added dropwise to a stirred solution of the product of Step A (7.3 g, 33.2 mmol) in benzene containing 20% of methanol (total: 100 mL) at room temperature until solution retained a yellow color. The mixture was concentrated to remove the organic solvent. The remaining oil was poured over a silica gel plug in a 60-mL filter frit funnel and eluting with 200 mL of hexane containing 10% ethyl acetate. The filtrate was then concentrated to dryness to give the title compound as a bright yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.C1(C)C=CC(S(O[CH2:37][CH2:38][Cl:39])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:37][CH2:38][Cl:39])[N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1n[nH]cc1NC(=O)c1cnn2cccnc12
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(CCCl)cc1NC(=O)c1cnn2cccnc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
A suspension of N-(3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (1.0 g, 2.7 mmol, 1 equiv), 2-chloroethyl para-toluenesulfonate (745 μL, 4.11 mmol, 1.5 equiv), and cesium carbonate (2.16 g, 6.62 mmol, 2.4 equiv) in N,N-dimethylformamide (10 mL) was heated at 50° C. After 3 h, the reaction mixture was concentrated in vacuo, and the resulting residue was partitioned between ethyl acetate (30 mL) and half-saturated aqueous sodium chloride solution (30 mL). The aqueous was extracted with ethyl acetate (2×20 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (ethyl acetate) provided product (950 mg, 77% yield). LCMS (ESI): M+H=432.1.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[C:15]3[CH:14]=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl[C:29]([O:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:30].C(N(CC)CC)C>CN(C=O)C>[CH3:34][C:33]([CH3:36])([CH3:35])[CH2:32][O:31][C:29]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]3[N:12]([C:9]4[CH:10]=[CH:11][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=4)[N:13]=[CH:14][C:15]=23)[CH2:23][CH2:24]1)=[O:30]
Reactant: CC(C)(C)COC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)COC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (0.17 mmol, 70 mg), neopentyl chloroformate (0.25 mmol, 37 μL) and triethylamine (0.51 mmol, 72 μL) were dissolved in DMF (2 mL) and stirred for 60 minutes at room temperature. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was quenched with water. The product was extracted with ethyl acetate. Removal of organic solvents in vacuo and purification by HPLC provided Compound A124 as a white solid (28 mg, 27%). Exact mass calculated for C23H29N5O5S 487.57, found 488.20 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=2[CH2:9][CH2:8]1.[N:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[N+:19]=[N-:20]>CO>[CH3:25][O:24][C:22](=[O:23])[C:21]([N:18]=[N+:19]=[N-:20])=[CH:16][C:14]1[CH:13]=[CH:12][C:11]2[O:7][CH2:8][CH2:9][C:10]=2[CH:15]=1
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccc2c(c1)CCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C(=Cc1ccc2c(c1)CCO2)N=[N+]=[N-]
Temperature: -10 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a cold (-10° C.) stirred solution of potassium tert-butoxide (6.06 g) in dry methanol (40 ml) was added dropwise a mixture of 2,3-dihydrobenzofuran-5-carboxaldehyde (2 g) and methyl azidoacetate (6.21 g). The mixture was stirred for 1 h at -10° C. and then stored at 0° C. for 18 h. The resulting pale yellow microcrystals were collected by filtration to give the title compound (3.12 g), m.p. 77°-80° C.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[S:7][C:6]=1[C:17]([NH2:19])=[O:18])=[O:3].Cl[CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25]>>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:11]=2)[S:7][C:6]=1[C:17]([NH2:19])=[O:18])=[O:3]
Reactant: CN(C)CCCCl
Reactant: NC(=O)Nc1cc(-c2cccc(O)c2)sc1C(N)=O
Product: CN(C)CCCOc1cccc(-c2cc(NC(N)=O)c(C(N)=O)s2)c1

Procedure:
Prepared by the method of Example 9(b) using the product of Example 6 and N-(3-chloropropyl)dimethylamine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([OH:16])=O)[O:11][N:10]=2)=[C:5]([F:17])[CH:4]=1)#[N:2].[C:18]([C:22]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][CH:30]([NH:33][CH:34]3[CH2:36][CH2:35]3)[CH2:29][CH2:28]2)[O:24][N:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[N:26]=[C:25]([N:27]2[CH2:28][CH2:29][CH:30]([N:33]([CH:34]3[CH2:36][CH2:35]3)[C:14]([C:12]3[O:11][N:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[F:17])[CH:13]=3)=[O:16])[CH2:31][CH2:32]2)[O:24][N:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: N#Cc1ccc(-c2cc(C(=O)O)on2)c(F)c1
Reactant: CC(C)(C)c1noc(N2CCC(NC3CC3)CC2)n1
Product: CC(C)(C)c1noc(N2CCC(N(C(=O)c3cc(-c4ccc(C#N)cc4F)no3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from 3-(4-cyano-2-fluoro-phenyl)-isoxazole-5-carboxylic acid and [1-(3-tert-butyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-cyclopropyl-amine following a procedure analogous to that described in Example 18. LC (method 18): tR=1.29 min; Mass spectrum (ESI+): m/z=479 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[O:8]([C:11]1[CH2:12][CH2:13][CH2:14][C:9](=[O:15])[CH:10]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: O=C1C=C(Cl)CCC1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1C=C(Oc2ccccc2)CCC1

Procedure:
To a stirred solution of 3-chloro-cyclohex-2-enone (3.00 g, 23.0 mmol) and phenol (2.16 g, 23.0 mmol) in 25 mL of acetone was added powdered, anhydrous K2CO3 (3.81 g, 27.6 mmol). After refluxing for 18 h, the mixture was cooled and filtered. The filtrate was concentrated under reduced pressure and chromatographed on silica gel eluting with hexanes/EtOAc (4:1) to give 3-phenoxy-cyclohex-2-enone as a white solid: 1H NMR (CDCl3) δ 2.10 (quint, 2H, J=6.3 Hz), 2.40 (t, 2H, J=6.2 Hz), 2.68 (t, 2H, J=6.3 Hz), 5.14 (s, 1H), 7.05 (d, 2H, J=7.5 Hz), 7.26 (t, 1H, J=7.3 Hz), 7.41 (t, 2H, J=7.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[CH3:37][C:38]([CH3:40])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][N:34]([CH:38]([CH3:40])[CH3:37])[CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: CC(C)=O
Reactant: COc1cc(-c2nn(C3CCNC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(C3CCN(C(C)C)C3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.3 %

Procedure:
A suspension of N2-[4-(4-amino-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide (0.250 g, 0.518 mmol) in dichloroethane (5 mL) was treated with acetone (1.96 g, 33.15 mmol) and sodium triacetoxy borohydride (0.220 g, 1.04 mmol). The reaction mixture was stirred at room temperature for 18 h under a nitrogen atmosphere. Sodium hydroxide (1N, 15 mL) was added to the reaction mixture and was stirred for 1 h. The organic layer was removed under reduced pressure and dichloromethane was added. The layers were partitioned and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using 10% methanol in dichloromethane (15 min), 15% methanol in dichloromethane (15 min), 20% methanol in dichloromethane (20 min) and 50% methanol in dichloromethane (5 min) as the eluent. The column afforded 0.123 g (44%) of pure N2-{4-[4-amino-1-(1-isopropyltetrahydro-1H-3-pyrrolyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.449 (s, 1H), 8.265 (s, 1H), 8.127-8.1068 (d, 1H, J=8.08 Hz), 7.7196-7.6999 (d, 1H, J=7.88 Hz), 7.6013-7.5803 (d, 1H, J=8.4 Hz), 7.351-7.299 (m, 4H), 7.173-7.135 (m, 1H), 5.394 (m, 1H), 4.042 (s, 3H), 3.961 (s, 3H), 2.793 (m, 3H), 2.337 (m, 3H), 1.068 (br.s, 6H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) R 2.38 min (100%), MH+ 525.3.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].C(N(CC)CC)C.[Br:20][CH2:21][C:22](Br)=[O:23]>C(Cl)Cl>[Br:20][CH2:21][C:22]([O:3][C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([O:11][CH3:12])=[O:10])=[O:23]
Reactant: COC(=O)[C@H](O)c1ccccc1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](OC(=O)CBr)c1ccccc1
Temperature: -78 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
To a stirred solution of DCM, (R)-methyl mandelate (1.48 g, 8.92 mmol), and triethylamine (2.02 g, 20.0 mmol), in DCM (30 ml) under a nitrogen atmosphere at −78° C. was added dropwise bromoacetyl bromide (3.03 g, 15.0 mmol). After stirring at −78° C. for 5 h, the reaction mixture was allowed warm up to −20° C. and quenched by addition of water (20 mL). The organic phase was washed with distilled water (3×20 mL), saturated ammonium chloride (3×20 mL), saturated sodium bicarbonate (3×20 mL) and brine (2×20 mL). The organic phase was then dried over magnesium sulfate, filtered and solvents removed via rotary evaporation to yield a crude product in 84% yield (2.13 g, 7.42 mmol). Column chromatography was performed on the crude product (mobile phase: DCM:Hexane, 50:50) to give a pale yellow liquid at RT in 73% yield (1.85 g, 6.45 mmol).
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([S:15]([NH:18][C@H:19]([C:27](Cl)=[O:28])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:17])=[O:16])=[CH:12]2)=[CH:7][CH:6]=1.Cl.Cl.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([S:15]([NH:18][C@H:19]([C:27]([N:42]3[CH2:41][CH2:40][N:39]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[Cl:32])[CH2:44][CH2:43]3)=[O:28])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:16])=[O:17])=[CH:12]2)=[CH:7][CH:6]=1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2c1
Agent: Cl
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N3CCN(c4ccccc4Cl)CC3)cc2c1
Reaction time: 0.17 h
Yield: 26.6 %

Procedure:
The thus obtained N2 -(7-methoxy-2-naphthalene-sulfonyl)-L-arginyl chloride (2.4 g) is immediately added to a solution of 1.64 g (0.00608 mole) 1-(2-chlorophenyl)piperazine dihydrochloride and 2.56 g (0.0253 mole) triethylamine in 50 ml chloroform under ice chilling. After 10 minutes, the mixture is brought to room temperature, and allowed to stand overnight. Then the reaction mixture is washed with water and the solvent is distilled off. The residue is washed with ethyl ether and dissolved in a 30%-ethanol/50 ml water mixture, and made basic with a 2N sodium hydroxide aqueous solution to pH 10. Thus an oily substance is deposited and is crystallized on standing. The crystals are collected by filtration, dried, and recrystallized from 20 ml THF, and 0.83 g of 1-[N2 -(7-methoxy-2-naphthalenesulfonyl)-L-arginyl]-4-(2-chlorophenyl)piperazine is obtained. Yield 28%. m.p. 219°~221° C. (decomp.) IR(KBr): 3330, 1625, 1480 cm-1.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:42]([O:49][C:50]1[C:51]([CH:56]=O)=[N:52][CH:53]=[CH:54][CH:55]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C1COCC1>[CH2:42]([O:49][C:50]1[C:51]([CH:56]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:31][CH:30]=2)=[N:52][CH:53]=[CH:54][CH:55]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ncccc1OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=Cc2ncccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(4-Methoxycarbonylbenzyl)triphenylphosphonium bromide (4.42 g, 9.00 mmol) was suspended in THF (50 ml) under argon. Lithium bis-(trimethylsilyl)amide (1M in THF, 10.8 ml) was added and the deep orange reaction was stirred at ambient temperature for 1 hour. A solution of 3-benzyloxy-2-pyridinecarbaldehyde (2.0 g, 9.4 mmol) in THF (20 ml) was added and the reaction was stirred at ambient temperature for 2 hours 30 minutes. The reaction was partitioned between EtOAc/water, the aqueous phase was extracted with EtOAc, the organic layers were combined, dried (MgSO4) and evaporated. The residue was purified by chromatography (EtOAc/CH2Cl2) to give methyl 4-[2-(3-benzyloxy-2-pyridyl)ethenyl]benzoate as a yellow oil. (3.01 g) .
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][SH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=1>O1CCCC1.O>[CH2:9]([S:10][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(SCc2ccccc2)nc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (60% in oil, 440 mg) in tetrahydrofuran (40 mL) was added dropwise phenylmethanethiol (1.37 g) at room temperature, 2-bromo-5-fluoropyridine (1.76 g) was added to the reaction mixture, and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was diluted with water and concentrated under reduced pressure. The residual aqueous layer was extracted twice with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-hexane-ethyl acetate=97:3) to give the title compound as a crude brown oil (yield 244 mg).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[C@@H:10]([CH3:28])[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24](=[O:25])[C:23]2[N:22]([CH3:26])[CH:21]=[N:20][C:19]=2[N:18]([CH3:27])[C:16]1=[O:17])(=O)=O.O>CS(C)=O>[N:1]([C@H:10]([CH3:28])[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24](=[O:25])[C:23]2[N:22]([CH3:26])[CH:21]=[N:20][C:19]=2[N:18]([CH3:27])[C:16]1=[O:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](CCCCn1c(=O)c2c(ncn2C)n(C)c1=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](CCCCn1c(=O)c2c(ncn2C)n(C)c1=O)N=[N+]=[N-]
Temperature: 50 °C
Reaction time: 12 h
Yield: 78.8 %

Procedure:
Sodium azide (7.11 g, 0.1 mol) was added to a solution of (S)-1-(5-methanesulfonyloxyhexyl)-3,7-dimethylxanthine (19.6 g, 54 mmol) in dimethylsulfoxide (100 ml) and stirred at 50° C. for 12 hours. The mixture was treated with water (200 ml) and extracted with ethyl acetate (3x 100 ml). The combined extracts were washed with water (125 ml), with saturated aqueous sodium chloride solution (150 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to give (R)-1-(5-azidohexyl)-3,7-dimethylxanthine (13 g).
Reaction SMILES: CCN(CC)CC.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[C:19]([O:23][C:24]([N:26]1[CH2:29][CH2:28][C@H:27]1[CH2:30][O:31][C:32]1[CH:33]=[C:34]([C@@H:38]2[CH2:40][C@H:39]2[CH2:41][CH2:42][OH:43])[CH:35]=[N:36][CH:37]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:43][CH2:42][CH2:41][C@@H:39]2[CH2:40][C@H:38]2[C:34]2[CH:35]=[N:36][CH:37]=[C:32]([O:31][CH2:30][C@@H:27]3[CH2:28][CH2:29][N:26]3[C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH:33]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@@H]2C[C@H]2CCO)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@H]2c2cncc(OC[C@@H]3CCN3C(=O)OC(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
4-(Dimethylamino)pyridine (DMAP; 14 mg, 0.11 mmol, 0.2 equiv.), Et3N (0.24 mL, 1.7 mmol, 3.0 equiv.), and p-toluenesulfonyl chloride (164 mg, 0.86 mmol, 1.5 equiv.) were added to a stirred solution of 2-[(1S,2R)-2-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]cyclopropyl]ethanol (200 mg, 0.57 mmol) in dry CH2Cl2 (5 mL) at 0° C. The reaction mixture was stirred at room temperature overnight, then diluted with CH2Cl2 (50 mL). The organic phase was washed with aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated. The residue was purified by CC (SiO2, 60-70% EtOAc in hexane as the eluent) to give 2-[(1S,2R)-2-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]cyclopropyl]ethyl p-toluenesulfonate (175 mg, 82%), which was directly used for the next reaction.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=2)=[O:14])[O:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Product: CCOC(=O)Cc1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cc1
Yield: 86 %

Procedure:
In the same manner as that of Example 2, 4,5-diisopropylfuran-2-carboxylic acid (60 mg, 0.306 mmol) was condensed with ethyl 4-aminophenylacetate, and the resultant was purified by silica gel chromatography [hexane-ethyl acetate (4:1)] to obtain ethyl 4-[(4,5-diisopropylfuran-2-carbonyl)amino]phenylacetate (94 mg, 86%) as colorless needles.