Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=S)[CH:5]=[CH:6][CH:7]=1.C1([N:39]=[C:40]=[N:41]C2CCCCC2)CCCCC1.C(N(C(C)C)CC)(C)C.N#CN>C(Cl)Cl.C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[N:41][C:40]#[N:39])[CH:5]=[CH:6][CH:7]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)Nc4cccc(C)c4)cc3)c2cc1OC
Agent: N#CN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=NC#N)Nc4cccc(C)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
N-(3-Methylphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}thiourea (18 mg) obtained in Example 171, dicyclohexylcarbodiimide (35 mg) and a catalytic amount of diisopropylethyl amine were dissolved in methylene chloride (6 ml), to which a solution of cyanamide (23 mg) in THF (1 ml) was added, and the admixture was stirred at room temperature overnight. After removing the solvent by distillation, the resulting residue was purified by column chromatography on silica gel eluting with chloroform/methanol (100/1) to obtain 19 mg of the title compound (yield: 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=1[CH:18]=[O:19].[CH2:25]([Mg]Br)[CH3:26].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=1[CH:18]([OH:19])[CH2:25][CH3:26]
Reactant: COc1cc2nccc(Oc3ccc(C)cc3C=O)c2cc1OC
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)c1cc(C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
Under an argon atmosphere, 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylbenzaldehyde (intermediate 1) (81.6 mg) was dissolved in tetrahydrofuran (3 ml), and the solution was then cooled to −78° C. A 0.96 M tetrahydrofuran solution (0.4 ml) of ethylmagnesium bromide was added dropwise thereto, and the mixture was stirred at −78° C. for 30 min. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-hexane to give the title compound (41 mg, yield 46%).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:21])=[O:4].[Se](O)(O)=[O:23]>O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH:21]=[O:23])=[O:4]
Reactant: O=[Se](O)O
Reactant: CCOC(=O)Cc1c(Cl)ccc2c1cc(C)n2C(=O)OC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c(Cl)ccc2c1cc(C=O)n2C(=O)OC
Temperature: 100 °C

Procedure:
5-Chloro-4-ethoxycarbonylmethyl-2-methyl-indole-1-carboxylic acid methyl ester (398 mg, 1.28 mmol) is dissolved under an atmosphere of argon in dioxane (18 ml). Selenious acid (331 mg, 2.56 mmol) is added, and the reaction mixture is heated to 100° C. for 18 hours. TLC analysis indicates complete conversion of the starting material. The reaction mixture is diluted with EtOAc and poured on water. The organic layer is washed with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated. The solid residue is purified by FCC (hexane/EtOAc 2:1) to afford the title compound. 1H NMR (DMSO, 400 MHz) δ 1.20 (t, J=6.6 Hz, 3H), 4.09 (s, 3H), 4.12 (q, J=6.6 Hz, 2H), 4.19 (s, 2H), 7.64 (d, J=10.8, 1H), 8.09 (d, J=10.8, 1H), 10.32 (s, 1H); ES-MS: 346.1.1 [M+Na]+.
Reaction SMILES: [CH:1]([O:4][CH:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]([CH2:22]SC(C)C)[CH2:6]1)([CH3:3])[CH3:2].O[O:28][S:29]([O-:31])=O.[K+].[CH3:33][CH:34](O)[CH3:35]>O>[CH:1]([O:4][CH:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]([CH2:22][S:29]([CH:34]([CH3:35])[CH3:33])(=[O:31])=[O:28])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CC(C)OC1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CSC(C)C)C1
Reactant: CC(C)O
Agent: [K+]
Solvent: O
Product: CC(C)OC1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CS(=O)(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A sample of benzyl (1S,2R)-4-isopropoxy-2-(isopropylthiomethyl)cyclohexylcarbamate (27.59 mMol) was dissolved in iPrOH (200 mL) prior to the addition of OXONE™ (33.92 g, 55.18 mMol) as a solution in 300 mL of water. The reaction was stirred at rt overnight. Partitioned between EtOAc and water. Aqueous layer was re-extracted with EtOAc and combined organic layer was washed with brine and dried (MgSO4). Filtered, concentrated and flash chromatographed to yield benzyl (1S,2R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexylcarbamate as a clear oil (7.73 g, 68% over Steps 5 and 6). MS found: (M+H)+=412.35.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](OB(O)O)=[C:4]([O:13][CH3:14])[CH:3]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].Br[C:27]1[N:32]2[N:33]=[C:34]([CH2:39][CH3:40])[C:35]([N+:36]([O-:38])=[O:37])=[C:31]2[C:30]([O:41][CH3:42])=[CH:29][CH:28]=1>C(OCCOCC)C.O>[CH2:39]([C:34]1[C:35]([N+:36]([O-:38])=[O:37])=[C:31]2[C:30]([O:41][CH3:42])=[CH:29][CH:28]=[C:27]([C:5]3[C:6]([CH3:8])=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=3[O:13][CH3:14])[N:32]2[N:33]=1)[CH3:40]
Reactant: COc1cc(C)cc(C)c1OB(O)O
Reactant: CCc1nn2c(Br)ccc(OC)c2c1[N+](=O)[O-]
Agent: CCOCCOCC
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: CCc1nn2c(-c3c(C)cc(C)cc3OC)ccc(OC)c2c1[N+](=O)[O-]
Temperature: 80 °C
Yield: 98.3 %

Procedure:
After adding 4,6-dimethyl-2-methoxyphenylboric acid (191 mg), barium hydroxide octahydrate (334 mg) and tetrakis(triphenylphosphine)palladium(0) complex (123 mg) to a solution of 7-bromo-2-ethyl-4-methoxy-3-nitropyrazolo[1,5-a]pyridine (159 mg) in a mixture of ethyleneglycol diethyl ether (15 mL) and water (7.5 mL), the mixture was heated at 80° C. for 30 minutes. Water was added, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (20 g), and the title compound (185 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as yellow crystals.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=O)[CH3:2].C(N1CCC(C([Cl:28])=O)CC1)(=[O:21])C.[Cl-].[Cl-].[Cl-].[Al+3].[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[ClH:28].[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH:7]2[CH2:8][CH2:9][N:4]([CH2:1][CH2:2][O:21][C:39]3[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=3)[CH2:5][CH2:6]2)=[CH:12][CH:13]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cl
Product: Fc1ccc(CC2CCN(CCOc3ccc(F)cc3)CC2)cc1
Yield: 50 %

Procedure:
1-Acetyl-4-(4-fluorobenzoyl)piperidine. N-acetylisonipecotoyl chloride (2.00 g, 10.5 mmol) was slowly added to a stirred mixture of aluminum trichloride (2.80 g, 21.1 mmol) in fluorobenzene (10 mL). After addition was complete, the mixture was refluxed for 1 h. The mixture was poured into ice and the resulting layers were separated. The aqueous layer was extracted with CH2Cl2 (2×30 mL), the combined organic phase was dried and was concentrated under reduced pressure to afford the title compound as a pale yellow oil (1.30 g, 50%): 1H NMR (CDCl3) 1.50-1.70 (m, 1H), 1.70-2.00 (m, 3H), 2.10 (s, 3H), 2.81 (t, J=12.0 Hz, 1H), 3.15-3.30 (m, 1H), 3.40-3.55 (m, 1H), 3.90 (d, J=13.2 Hz, 1H), 4.57 (d, J=13.2 Hz, 1H), 7.14 (t, J=8.4 Hz, 2H), 7.97 (dd, J=5.7 and 8.4 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[N+]([O-])([O-])=[O:11].[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>CO>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[O:11])=[CH:3][CH:4]=1
Reactant: COc1ccc(C)cc1
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
p-Methyl anisole (1.22 g) and 23.0 g of ammonium cerium(IV) nitrate are placed into a reactor, and 100 ml of methanol is further placed thereinto. The mixture is stirred at room temperature for 30 minutes and thereafter distilled to remove the methanol. The residue is dissolved in benzene, and solids are separated from the solution. The solution is distilled to remove the benzene, and the residue is distilled in a vacuum, affording 1.31 g of anisaldehyde. Yield 96.3%. The separated solids are dissolved in the recovered methanol, and the solution is placed into an anode chamber. A methanol solution of 6 g of ammonium nitrate is placed into a cathode partitioned from the anode chamber by a diaphragm. The cerium salt is electrolyzed with a constant current of 60 mA, using platinum electrodes, to pass electricity across the electrodes in a quantity of 1.2 F/mole.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[Cl:19][C:20]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:21]=1[NH2:22]>>[Cl:19][C:20]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:21]=1[NH:22][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Nc1cc(F)ccc1Cl
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1cc(F)ccc1Cl

Procedure:
The ester was prepared according to Procedure A using diethyl 2-methylmalonate (7.09 mL, 41.2 mmol), pyridine (4.45 mL, 55.0 mmol) and 2-chloro-5-fluoroaniline (4.0 g, 27.5 mmol) over 6 days. The residue was purified by column chromatography on silica gel (0-30% EtOAc/hexanes) to give ethyl 3-(2-chloro-5-fluorophenylamino)-2-methyl-3-oxopropanoate as a red oil. Mass Spectrum (ESI) m/e=274.0 (M+1).
Reaction SMILES: [NH2:1][C:2](=[O:100])[CH2:3][NH:4][C:5](=[O:99])[C@@H:6]([NH:13][C:14](=[O:98])[C@@H:15]([N:17]([CH3:97])[C:18]([C@H:20]([CH2:86][C:87]([O:89]CC1C=CC=CC=1)=[O:88])[NH:21][C:22](=[O:85])[C@H:23]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[NH:24][C:25](=[O:77])[C@H:26]([CH:74]([CH3:76])[CH3:75])[NH:27][C:28](=[O:73])[C@H:29]([CH3:72])[NH:30][C:31](=[O:71])[C@H:32]([CH2:67][CH:68]([CH3:70])[CH3:69])[NH:33][C:34](=[O:66])[CH2:35][NH:36][C:37](=[O:65])[C@H:38]([CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[N:39]([CH3:57])[C:40](=[O:56])[C@H:41]([CH3:55])[NH:42][C:43](=[O:54])[C@H:44]([CH3:53])[NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:19])[CH3:16])[CH2:7][O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(OCC)(=O)C.[H][H]>CO.O[Pd].[C]>[NH2:1][C:2](=[O:100])[CH2:3][NH:4][C:5](=[O:99])[C@@H:6]([NH:13][C:14](=[O:98])[C@@H:15]([N:17]([CH3:97])[C:18]([C@H:20]([CH2:86][C:87]([OH:89])=[O:88])[NH:21][C:22](=[O:85])[C@H:23]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[NH:24][C:25](=[O:77])[C@H:26]([CH:74]([CH3:76])[CH3:75])[NH:27][C:28](=[O:73])[C@H:29]([CH3:72])[NH:30][C:31](=[O:71])[C@H:32]([CH2:67][CH:68]([CH3:69])[CH3:70])[NH:33][C:34](=[O:66])[CH2:35][NH:36][C:37](=[O:65])[C@H:38]([CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[N:39]([CH3:57])[C:40](=[O:56])[C@H:41]([CH3:55])[NH:42][C:43](=[O:54])[C@H:44]([CH3:53])[NH:45][C:46](=[O:52])[O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:19])[CH3:16])[CH2:7][O:8][C:9]([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](COC(C)(C)C)C(=O)NCC(N)=O)C(C)C
Reactant: [H][H]
Agent: O[Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(=O)O)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](COC(C)(C)C)C(=O)NCC(N)=O)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 88 %

Procedure:
Hydroxypalladium/carbon (250 mg, 50% wet w/w) was added to a solution of benzyl (6S,9S,12S,18S,21S,24S,27S,30S)-30-(((S)-1-(((S)-1-((2-amino-2-oxoethyl)amino)-3-(tert-butoxy)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamoyl)-12,27-dibenzyl-18-isobutyl-24-isopropyl-2,2,6,9,11,21-hexamethyl-4,7,10,13,16,19,22,25,28-nonaoxo-3-oxa-5,8,11,14,17,20,23,26,29-nonaazadotriacontan-32-oate synthesized according to a conventional method (Compound SP-502, Boc-Ala-Ala-MePhe-Gly-Leu-Ala-Val-Phe-Asp(OBn)-MeAla-Ser(tBu)-Gly-NH2) (749 mg, 0.536 mmol) in methanol (5 ml)-ethyl acetate (5 ml) under a nitrogen atmosphere, the atmosphere was replaced with hydrogen, and the mixture was then stirred at room temperature for 3.5 hours. The reaction solution was then filtered through celite, and the filtrate was concentrated under reduced pressure to afford the title compound (SP-501) (620 mg, 88%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[O:10][CH:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:2]1.[CH3:20][C:21]([NH:25][CH3:26])([CH3:24])[CH2:22]O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:21]([N:25]([CH3:26])[C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH:11]([CH3:16])[C:12]([F:13])([F:14])[F:15])[N:8]=1)=[O:19])([CH3:24])([CH3:22])[CH3:20]
Reactant: CC(Oc1nc(C(=O)O)ccc1C1CC1)C(F)(F)F
Reactant: CNC(C)(C)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(Oc1nc(C(=O)N(C)C(C)(C)C)ccc1C1CC1)C(F)(F)F

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid was reacted with 2-methyl-2-(methylamino)propan-1-ol (CAN 27646-80-6) in the presence of TBTU and DIEA to obtain the title compound as white solid; MS (EI): m/e=345.4 [MH+].
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.CN1CCCC1=O.[NH2:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22]>C(N(CC)CC)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([NH:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22])=[CH:7][C:6]=1[CH3:8])([O-:11])=[O:10]
Reactant: NC(CO)CO
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1cc(NC(CO)CO)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 49.7 %

Procedure:
2 g of 5-fluoro-2-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.4 g of 2-amino-1,3-propanediol, and 1.57 g of triethylamine. The reaction medium was heated at 60° C. for 10 hours and, after cooling to room temperature, was poured into a water/ice mixture. The resulting medium was extracted with ethyl acetate and the organic phase was then concentrated under vacuum. 1.45 g of 2-(4-nitro-3-methylphenylamino)propane-1,3-diol (11) were obtained.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[ClH:15].[ClH:15].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([O:12][CH2:11][C:10]([NH:9][CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)([CH3:14])[CH3:13])=[O:21])=[CH:18][CH:17]=1
Reactant: CC(C)(CO)NCCCn1ccnc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CC(C)(COC(=O)c1ccc(Cl)cc1)NCCCn1ccnc1
Product: Cl

Procedure:
In a similar manner to Example 78, 2-[3-(imidazol-1-yl)propylamino]-2-methyl-1-propanol (1.0 g) was reacted with 4-chlorobenzoyl chloride (0.89 g) to give 2-[3-(imidazol-1-yl)propylamino]-2,2-dimethylethyl 4-chlorobenzoate dihydrochloride, m.p. 207-209° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH:8][CH:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=O.O.[NH2:27][NH2:28]>CO>[OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH:8][CH:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:27][NH2:28])=[O:24]
Reactant: NN
Reactant: CCCCCC(O)C=CC1CCC(O)C1CCCCCCC(=O)OC
Solvent: O
Solvent: CO
Product: CCCCCC(O)C=CC1CCC(O)C1CCCCCCC(=O)NN
Yield: 62.5 %

Procedure:
A solution of methyl 7-[2-hydroxy-5-(3-hydroxy-1-octenyl)cyclopentyl]heptanoate (0.4 g.), [prepared as described in Example 5], 100% hydrazine hydrate (0.8 ml.) and methanol (10 ml.) was refluxed for 24 hours. After 12 hours reflux a further amount of hydrazine hydrate (0.8 ml.) was added. The methanol was removed in vacuo and the residue diluted with water. The resulting solution was extracted twice with diethyl ether. The combined ether extracts were dried over magnesium sulphate to give 7-[2-hydroxy-5-(3-hydroxy-1-octenyl)-cyclopentyl]heptanohydrazide (0.25 g., 62.5%). (Found: C, 67.4; H, 10.6; N, 7.9. C20H38N2O3 requires C, 67.8; H,10.72; N, 7.9%) νmax 3300 cm-1, 1650 cm-1 (shoulder 1630 cm-1), 980 cm-1 (liquid film).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Br:10])[C:7]([OH:11])=[C:6]([Br:12])[CH:5]=1)(=[NH:3])[NH2:2].[CH2:13](Cl)[C:14]1[CH:22]=[CH:21][C:20]2[O:19][CH2:18][O:17][C:16]=2[CH:15]=1.C([O:26]CC)C>N1C=CC=CC=1>[CH2:18]1[O:19][C:20]2[CH:21]=[CH:22][C:14]([C:13]([O:11][C:7]3[C:6]([Br:12])=[CH:5][C:4]([C:1](=[NH:2])[NH2:3])=[CH:9][C:8]=3[Br:10])=[O:26])=[CH:15][C:16]=2[O:17]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: CCOCC
Reactant: N=C(N)c1cc(Br)c(O)c(Br)c1
Solvent: c1ccncc1
Product: N=C(N)c1cc(Br)c(OC(=O)c2ccc3c(c2)OCO3)c(Br)c1
Reaction time: 3 h

Procedure:
To a solution of 5 g of 4-amidino-2,6-dibromophenol in 100 ml of pyridine, while being cooled in ice and stirred, was added 2.4 g of piperonyl chloride. The mixture was stirred for 30 minutes while being cooled in ice, then for 3 hours at room temperature, and mixed with about 300 cc of ethyl ether. The precipitate which was formed was collected by filtration and recrystallized from ethanol to obtain 4.8 g of colorless crystals of 4-amidino-2,6-dibromophenyl 3,4-methylenedioxybenzoate methanesulfonate.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[N:23][C:22]([Cl:31])=[N:21][C:20]=4[N:32]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.N1CCC(N2C[CH2:43][O:42][CH2:41][CH2:40]2)CC1>>[Cl:31][C:22]1[N:23]=[C:24]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[C:19]2[S:18][C:17]([CH2:16][N:12]3[CH2:13][CH2:14][CH:9]([N:8]4[CH2:40][CH2:41][O:42][CH2:43][CH2:15]4)[CH2:10][CH2:11]3)=[N:32][C:20]=2[N:21]=1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCOCC4)CC3)nc2n1

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 4-piperidin-4-ylmorpholine in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a yellow solid (220 mg, 39%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[S:6][C:7]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[C:11]([O:18][CH3:19])=[CH:10][C:8]=2[N:9]=1.[NH:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:11]1[C:12]([O:16][CH3:17])=[C:13]([O:14][CH3:15])[C:7]2[S:6][C:5]([CH2:4][CH2:3][CH2:2][N:20]3[CH2:26][CH2:25][CH2:24][N:23]([CH2:2][CH2:3][CH2:4][C:5]4[S:6][C:7]5[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[C:11]([O:18][CH3:19])=[CH:10][C:8]=5[N:9]=4)[CH2:22][CH2:21]3)=[N:9][C:8]=2[CH:10]=1
Reactant: COc1cc2nc(CCCBr)sc2c(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc2nc(CCCN3CCCN(CCCc4nc5cc(OC)c(OC)c(OC)c5s4)CC3)sc2c(OC)c1OC

Procedure:
2-(3-Bromopropyl)-5,6,7-trimethoxybenzothiazole (444 mg) and homopiperazine (64 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][CH:16]([F:18])[F:17])(=O)=O)=CC=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]2[C@H:31]([OH:32])[C@@H:30]([OH:33])[C@H:29]([OH:34])[C@@H:28]([CH2:35][OH:36])[O:27]2)=[CH:22][C:21]=1[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]2[C@H:31]([OH:32])[C@@H:30]([OH:33])[C@H:29]([OH:34])[C@@H:28]([CH2:35][OH:36])[O:27]2)=[CH:22][C:21]=1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:44][CH2:12][CH2:13][O:14][CH2:15][CH:16]([F:18])[F:17])=[CH:42][CH:43]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOCC(F)F)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 6.3 %

Procedure:
2-(2,2-difluoroethoxy)ethyl 4-methylbenzenesulfonate (53 mg, 0.19 mmol) dissolved in anhydrous DMF (3 mL) was added to a reaction flask containing (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (57 mg, 0.15 mmol) in DMF (3 mL) at room temperature. Cesium carbonate (98 mg, 0.30 mmol) was added to the flask, and the resulting mixture was stirred for 48 hr at room temperature. The reaction was diluted with diethyl ether (50 mL) and the organic layer was washed with an aqueous solution of ammonium chloride (50 mL), sodium bicarbonate (50 mL), and NaCl (50 ml), after which it was dried over sodium sulfate, filtered and concentrated en vacuo. The residue was purified by preparative TLC using 15% methanol in dichloromethane as the mobile phase to yield the title compound (4.6 mg, 5.0%). 1H NMR (CDCl3, 300 MHz); δ 7.33 (d, 1H, J=11.2 Hz), 7.15 (d, 1H, J=11.2 Hz), 7.14 (s, 1H), 7.06 (d, 2H, J=11.6 Hz), 6.79 (d, 2H, J=11.6 Hz), 5.86 (tt, 1H, J1=5.2 Hz, J2=66.4 Hz), 4.07-3.98 (m, 3H), 3.87-3.84 (m, 3 H), 3.84-3.71 (m, 2H), 3.74 (td, 2H, J1=5.6 Hz, J2=18.4 Hz), 3.66-3.54 (m, 3 H), 3.30-3.36 (m, 2H), 2.78 (br s, 1H), 2.42 (br s, 1H), 1.65 (s, 2H); LC/MS: theoretical mass=488.14; observed M+1=489.2, M+Na=511.4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH2:10].C([O:19][C@@H:20]1[C@H:24]([O:25]C(=O)C2C=CC=CC=2)[C@@H:23]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[O:22][C@H:21]1[N:44]1[CH:52]=[N:51][C:50]2[C:45]1=[N:46][C:47]([Cl:54])=[N:48][C:49]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:54][C:47]1[N:48]=[C:49]([NH:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:50]2[N:51]=[CH:52][N:44]([C:45]=2[N:46]=1)[C@@H:21]1[O:22][C@H:23]([CH2:34][OH:35])[C@@H:24]([OH:25])[C@H:20]1[OH:19]
Reactant: COc1ccccc1CN
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: N
Product: COc1ccccc1CNc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 45.9 %

Procedure:
The title compound was prepared by reacting (2-methoxyphenyl)methylamine (0.55 g, 4.0 mmol) with 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.01 g, 1.6 mmol), followed by debenzoylation of the purified product using methanolic ammonia to provide the title 2-chloro- N-[(2-methoxyphenyl)methyl]adenosine (0.31 g, 45%)(after column chromatography) as a solid, mp 116°-119° C., 1H NMR (DMSO-d6)δ 3.51-3.60 (1H, m, H-5'a), 3.61-3.70 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.13 (1H, m, H-3'), 4.52 (1H, q, H-2'), 5.06 (1H, t, 5'-0H), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.85 (1H, d, H-1'), 6.83-7.25 (4H, 2t, 2d, Ar--H), 8.43 (1H, s, H-8), 8.72 (1H, t, N--H).