Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[N+](=[CH2:13])=[N-]>CO>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:13])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ncccc1N
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
3-Aminopicolinic acid (115) (0.585 g, 4.24 mmol) was dissolved in MeOH (absolute, 45 mL). The solution was stirred while an ethereal solution of diazomethane was added until a yellow color persisted (~30 mL). The solution was stirred an additional 30 min, and the solvent rota-evaporated. The resulting residue was dried under reduced pressure at room temperature to yield 0.635 g (98.5%) of crude 116 as a yellow residue. The crude residue was chromatographed on a column of silica (12 g, Mallinckrodt, grade 62, mesh 60-200, used as received) using CHCl3 -MeOH [19:1, (180 mL), 7:3 (100 mL), 1:1 (100 mL), 100% MeOH (150 mL)]. After collecting appropriate fractions, rota-evaporating off the solvent and drying under reduced pressure at 25° C., 0.333 g (51.7%) of 116 was obtained as a yellow solid; mp 139°-146° C.; Rf =0.54 [CHCl3 -MeOH (9:1)]. IR (KBr) 3455, 3295, 3160, 1689, 1617, 1408, 1335, 1244, 1115. 1H NMR (CDCl3) δ3.98 (t, J=7.2, 3, CH3O--), 5.73 (d, J=1.8, 2, NH2), 7.05 (dd, J1 =1.2, J2 =8.4, 1, H-4), 7.22 (dd, J1 =4.2, J2 =8.4, 1, H-5), 8.07 (dd, J1 =1.2, J2 =4.2, 1, H-6).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH2:8][C:9]#[N:10].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH:8]([C:20](=[O:21])[NH:19][C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[C:9]#[N:10]
Reactant: Cn1cccc1C(=O)CC#N
Reactant: O=C=Nc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1ccc(F)cc1
Reaction time: 8 h

Procedure:
To the suspension of 4.0 g of 1-methyl-β-oxo-2-pyrrolpropionitrile in 70 ml of toluene and 3.2 g of triethylamine, 3.7 g of p-fluorophenylisocyanate are added while stirring. The mixture is warmed on the steam cone until dissolution and the red-brown solution is allowed to stand overnight at room temperature. It is evaporated on the steam cone, the residue taken up in methanol and the solution poured into the mixture of 8 ml of 5 N hydrochloric acid and 300 ml of water. The precipitated crystals are collected, washed with water, dried, triturated with methanol and recrystalllized from ethyl acetate, to yield the 1-methyl-β-oxo-α-(p-fluorophenylcarbamoyl)-2-pyrrolpropionitrile melting at 198°-199°.
Reaction SMILES: C(NNC(C1C=CN=C(NC(=O)C2C=CC=CC=2)C=1)=O)(=O)C1C=CC=CC=1.[C:28]1([CH2:34][C:35]([NH:37][NH:38][C:39]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([NH:47][C:48](=[O:55])[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:42]=2)=[O:40])=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>>[CH2:34]([C:35]1[O:40][C:39]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([NH:47][C:48](=[O:55])[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:42]=2)=[N:38][N:37]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cc1ccccc1)NNC(=O)c1ccnc(NC(=O)c2ccccc2)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: O=C(NNC(=O)c1ccnc(NC(=O)c2ccccc2)c1)c1ccccc1
Agent: [OH-]
Product: O=C(Nc1cc(-c2nnc(Cc3ccccc3)o2)ccn1)c1ccccc1
Yield: 17 %

Procedure:
Following the procedure as described in Example 11, making variations as required to replace N-(4-(2-benzoylhydrazinecarbonyl)pyridin-2-yl)benzamide with N-(4-(2-(2-phenylacetyl)hydrazinecarbonyl)pyridin-2-yl)benzamide to react with (methoxycarbonylsulfamoyl)triethylammonium hydroxide, N-[4-(5-benzyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-yl]benzamide was obtained as a colorless solid in 17% yield: mp 187-189° C.; 1H NMR (300 MHz, CDCl3) δ 9.14 (br s, 1H), 8.94 (br s, 1H), 8.36 (br s, 1H), 7.94 (d, J=7.9 Hz, 2H), 7.73 (br s, 1H), 7.55-7.51 (m, 3H), 7.39-7.20 (m, 5H), 4.29 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 166.6, 166.0, 163.5, 152.4, 148.4, 133.6, 133.4, 132.7, 129.1, 128.9, 128.8, 127.7, 127.4, 116.9, 111.3, 31.9; MS (ES+) m/z 357.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH:21]1[CH2:24][CH2:23][CH2:22]1.[OH-].[Na+].Cl>CC(=O)CC>[CH:21]1([CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: BrCC1CCC1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(O)c1ccc(OCC2CCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a stirred solution of ethyl 4-hydroxybenzoate (2.493 g, 15.0 mmol) and potassium carbonate (4.15 g, 30 mmol) in 60 mL of 2-butanone at ambient temperature was added in one portion of (bromomethyl)cyclobutane (97% pure) (2.53 g, 16.5 mmol). The stirred reaction mixture was heated at reflux for 16 hr. HPLC revealed the disappearance of the starting material of ethyl 4-hydroxybenzoate. The mixture was allowed to cool to ambient temperature. The solid was filtered off. The filter cake was washed with acetone. The combined filtrate was concentrated in vacuo to nearly dryness. Methanol was added (10 mL) was added to the residue, followed by the addition of a 2-N aqueous solution of NaOH (30 mL, 60 mmol). The reaction was stirred overnight at about 40° C. HPLC indicated that the saponification was completed, and revealed one single peak signal of the expected carboxylic acid. The reaction mixture was subjected to roto-vaporation to remove methanol. Ice was added to the basic aqueous solution. The acidification with a 35 mL of HCl aqueous 2N solution (70 mmol) led to the immediate precipitation of a white solid. Stirring was continued for an additional 30 min and then the precipitation was filtered off with suction through a sintered glass funnel. The collected solid was successively washed with three 50-mL portions of water, and two 25-mL portions of hexane. The collected solid was dried in vacuo for two days at ambient temperature to afford 2.63 g (85%) of 4-(cyclobutylmethoxy)benzoic acid as a white solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.[CH2:8]([CH:12]([CH2:15][OH:16])[CH2:13][OH:14])[CH2:9][CH2:10][CH3:11]>>[CH2:8]([CH:12]1[CH2:15][O:16][CH:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[O:14][CH2:13]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCOC(=O)C=O
Reactant: CCCCC(CO)CO
Product: CCCCC1COC(C(=O)OCC)OC1

Procedure:
2-(3,5-Difluoro-4-cyanophenyl)-5-butyl-1,3-dioxane is obtained analogously to Example 1 using 5-butyl-1,3-dioxane-2-carboxylic acid chloride (obtainable by reacting ethyl glyoxylate with 2-butylpropane-1,3-diol to give ethyl 5-butyl-1,3-dioxane-2-carboxylate, saponifying the latter and reacting the resulting free acid with SOCl2).
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C.O>[C:12]([CH:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:13]
Reactant: CCOC(=O)CCCCBr
Reactant: N#CCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCC(C#N)c1cccc2ccccc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
In 125 ml of DMF was dissolved 12.54 g (75 mmol) of 1-naphthaleneacetonitrile. Then, 3.30 g (82.5 mmol) of 60% sodium hydride was added at room temperature and the mixture was heated to 60° C. and stirred for 30 minutes. After cooling to room temperature, 13.17 ml (82.5 mmol) of ethyl 5-bromovalerate was added. The reaction was further conducted at 60° C. for 30 minutes, after which the reaction mixture was cooled to <10° C. and diluted with 500 ml of pure water. The diluted mixture was extracted with 200 ml of ethyl acetate twice and the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography (hexane-CH2Cl2 -ethyl acetate=4:2:1) to provide 17.16 g (yield 77.5%) of the title compound as light-yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: BrCc1ccccc1
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCc2ccccc2)ccc(C(=O)OC)c1O

Procedure:
A solution of methyl 2,4-dihydroxy-3-propylbenzoate (3.00 grams) in 2-butanone (30 mL) was treated with benzyl bromide (1.70 mL) and potassium carbonate (1.972 grams). The mixture was refluxed for 4 hours. The reaction mixture was partitioned between isopropyl acetate and pH 4 buffer. The organic was washed once with water, then dried over magnesium sulfate. The organic was filtered and evaporated to an oil which was chromatographed over silica gel to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])[CH3:29].C(COC)OC.C(=O)(O)[O-].[Na+]>O.[Pd].C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:16])([CH3:17])[CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([C:28](=[O:30])[CH3:29])[CH:36]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1OCc1ccccc1
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(=O)c1cccc(-c2cccc(C(C)(C)C)c2OCc2ccccc2)c1
Reaction time: 3 h
Yield: 87 %

Procedure:
A mixture of crude 35 (3.88 g, 10 mmol), 3-acetylphenyl boronic acid (1.8 g, 11 mmol, 1.1 equiv.), bis(triphenylphosphine)palladium(II) dichloride (20 mg), glyme (5.5 mL) and sodium bicarbonate (2.7 g) in water (55 mL) was kept at reflux under nitrogen for 2 hr. Additional palladium catalyst (20 mg) was added and reflux continued for 3 hr. After cooling the reaction mixture was diluted with ethyl acetate (150 mL) and washed with saturated sodium bicarbonate (100 mL) and water (2×100 mL). The organic extract was dried over sodium sulfate and filtered. The solvent was removed in a rotary evaporator and the crude product was purified by chromatography on silica (80 g) with 2% ethyl acetate in heptane (4 L) to afford 36 (3.12 g, 87%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:53][OH:54])=[C:19]([C:23]3[CH:24]=[C:25]([NH:31][C:32]4[N:37]=[CH:36][C:35]([N:38]5[CH:43]6[CH2:44][CH2:45][CH:39]5[CH2:40][N:41](C(OC(C)(C)C)=O)[CH2:42]6)=[CH:34][CH:33]=4)[C:26](=[O:30])[N:27]([CH3:29])[N:28]=3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]>ClCCl>[CH:39]12[N:38]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:25]4[C:26](=[O:30])[N:27]([CH3:29])[N:28]=[C:23]([C:19]5[C:18]([CH2:53][OH:54])=[C:17]([N:10]6[N:9]=[CH:8][C:7]7[C:12](=[C:13]([F:15])[CH:14]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=7)[C:11]6=[O:16])[CH:22]=[CH:21][CH:20]=5)[CH:24]=4)=[N:37][CH:36]=3)[CH:43]([CH2:44][CH2:45]1)[CH2:42][NH:41][CH2:40]2
Reactant: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(N3C4CCC3CN(C(=O)OC(C)(C)C)C4)cn2)c1=O
Solvent: ClCCl
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(N3C4CCC3CNC4)cn2)c1=O

Procedure:
tert-butyl 8-(6-(6-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (90 mg, 122 umol) was de-BOC with 50% trifluoro acid in dichloromethane (10 mL) for 2 hr. The reaction mixture was concentrated to dryness, then partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[NH:31][C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.Br[CH2:37][CH2:38][F:39].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[N:31]([CH2:37][CH2:38][F:39])[C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: FCCBr
Reactant: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1CCF
Temperature: 120 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
A mixture of 2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (150 mg, 0.3 mmol), 1-Bromo-2-fluoro-ethane (65 mg, 0.45 mmol) and Cesium carbonate (200 mg, 0.6 mmol) in N,N-Dimethyl-formamide (2 mL) was stirred at 120° C. for 1 h under the irradiation of microwave. The reaction mixture was filtered over celite and purified by pre-TLC (Hexanes/EtOAc=1:1) to afford 45 mg of 315 (yield: 28%). 1H NMR (CDCl3, 400 MHz): δ8.23 (s, 1H), 7.51-7.46 (m, 1H), 7.10-6.93 (m, 4H), 6.46 (d, J=8.8 Hz, 1H), 4.52 (t, J=5.6 Hz, 2H), 4.40 (t, J=5.6 Hz, 2H), 4.18 (t, J=4.8 Hz, 2H), 3.85-3.82 (m, 2H), 3.07-2.94 (m, 4H), 2.70 (d, J=6.0 Hz, 2H), 2.55-2.49 (m, 2H), 1.22-1.34 (d, J=6.0 Hz, 6H). LC-MS (ESI): m/z=541 [M+H]+
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=3)=[CH:11][C:10]([Br:23])=[CH:9][N:8]=1)(=O)=O.[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC.[Li+].[Cl-].CC(=O)OCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:23][C:10]1[CH:11]=[C:12]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=3)[C:7]([CH:26]=[CH2:27])=[N:8][CH:9]=1
Reactant: O=S(=O)(Oc1ncc(Br)cc1-c1cc2c(F)cccc2[nH]1)C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1ncc(Br)cc1-c1cc2c(F)cccc2[nH]1
Temperature: 60 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
A mixture of 5-bromo-3-(4-fluoro-1H-indol-2-yl)pyridin-2-yl trifluoromethanesulfonate (700 mg, 1.59 mmol), tributyl(vinyl)stannane (556 mg, 1.75 mmol), LiCl (202 mg, 4.78 mmol) and Pd(PPh3)2Cl2 (100 mg) in DMF (20 mL) was stirred at 60° C. for 3 hours under nitrogen atmosphere. The mixture was filtered through celite and concentrated in vacuo to remove DMF, and then the residue was suspended in water/EA. After extracted with EA, the combined organic phase was washed with brine, dried over sodium sulfate and concentrated to afford 2-(5-bromo-2-vinylpyridin-3-yl)-4-fluoro-1H-indole (400 mg, yield: 79%) through the column chromatography (PE:EA=20:1). 1H-NMR (CDCl3, 400 MHz) δ 8.64 (s, 1H), 8.46 (s, 1H), 7.93 (s, 1H), 7.14˜7.22 (m, 2H), 7.00˜7.07 (m, 1H), 6.82˜6.86 (m, 1H), 6.76 (s, 1H), 6.43˜6.47 (m, 1H), 5.54˜5.58 (m, 1H). MS (M+H)+: 317/319.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[C@H:12]([C:13]([CH2:15]Br)=[CH2:14])[CH2:11][N:10]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCCN(C)C1=O.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C@@:8]12[CH2:14][C:13](=[CH2:15])[C@@H:12]1[CH2:11][N:10]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(CBr)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C1C[C@@]2(C(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@@H]12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.2 %

Procedure:
(3S,4R)-1-Benzyloxycarbonyl-4-[1-(bromomethyl)vinyl]pyrrolidine-3-carboxylic acid tert-butyl ester (22.8 g, 53.7 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (19.5 mL, 161 mmol) were dissolved in a mixed solution of tetrahydrofuran (220 mL) and toluene (220 mL). Lithium hexamethyldisilazide (1.0 M solution in tetrahydrofuran) (80.6 mL, 80.6 mmol) was added dropwise at −78° C., and then the mixture was stirred at room temperature for five minutes. The reaction solution was extracted with a saturated ammonium chloride solution and ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=24:1→2:1) to give 8.34 g of the title compound as a colorless syrup.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+].[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[O:29]([C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Oc1ccccc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)c1cnc(Oc2ccccc2)c(Cl)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 60.4 %

Procedure:
In a flask, 64 g of 2,3-dichloro-5-trifluoromethyl pyridine, 250 ml of dimethyl sulfoxide, 81.8 g of anhydrous potassium carbonate and 33.4 g of phenol were charged. The flask was heated in an oil bath at 100° C. to react them with stirring for 4 hours. The reaction mixture was poured into suitable amount of water and the reaction product was extracted with methylene chloride. The extracted phase was washed with water, with 5% sodium hydroxide aqueous solution and then, with water and dried over anhydrous sodium sulfate. Methylene chloride was distilled off under a reduced pressure and the residue was distilled to obtain 49 g of 2-phenoxy-3-chloro-5-trifluoromethyl pyridine. The product was mixed with 100 ml of 98% sulfuric acid and the mixture was cooled with ice water. A mixture of 11.3 g of 60% nitric acid and 30 ml of 98% sulfuric acid was added dropwise to the sulfuric acid solution of the reaction product at a temperature of 0° to 10° C. A mild exothermic reaction was performed. After the reaction, the reaction mixture was poured into suitable amount of ice water and neutralized with 10% sodium hydroxide aqueous solution. The reaction product was extracted with methylene chloride. The extracted phase was dried over anhydrous sodium sulfate. Methylene chloride was distilled off under a reduced pressure to obtain 38.5 g of the object compound having a melting point of 90° to 91° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([NH:21][C:22](=[O:25])CC)[C@@H:18]([OH:26])[C@H:17]2[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6].COC(C1N=C2C(N=CN2[C@@H]2C[C@H](N(C([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=O)C(=O)CC)[C@@H](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1)=O>>[C:69]([O:68][C:22](=[O:25])[NH:21][C@H:19]1[CH2:20][C@@H:16]([N:13]2[CH:12]=[N:11][C:10]3[C:14]2=[N:15][C:7]([C:5](=[O:6])[NH:4][CH2:3][CH2:2][NH2:1])=[N:8][C:9]=3[NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@H:17]([OH:27])[C@@H:18]1[OH:26])([CH3:72])([CH3:71])[CH3:70]
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Reactant: CCC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to 9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-ethyl)-amide by replacing 9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester with 9-[(1R,2S,3R,4S)-4-(tert-butoxy-carbonyl-propionyl-amino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[C:11](SC)=[N:12][CH2:13][CH2:14][C:9]=3[C:8]([CH2:17][CH3:18])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([NH:27][NH2:28])(=O)[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>N1C=CC=CC=1>[CH:1]1([N:6]2[C:10]3[C:11]4[N:12]([C:19]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[N:27][N:28]=4)[CH2:13][CH2:14][C:9]=3[C:8]([CH2:17][CH3:18])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn(C2CCCC2)c2c1CCN=C2SC
Reactant: NNC(=O)c1cccnc1
Solvent: c1ccncc1
Product: CCc1nn(C2CCCC2)c2c1CCn1c(-c3cccnc3)nnc1-2
Temperature: 135 °C

Procedure:
1-Cyclopentyl-4,5-dihydro-3-ethyl-7-methylthio-1H-pyrazolo[3,4-c]pyridine (0.036 grams, 0.14 mmoles) and nicotinic acid hydrazide (0.021 grams, 0.15 mmoles) was dissolved in anhydrous pyridine (5 ml) in a flame dried flask. An oven-dried condenser was added, which was septa sealed and had an outlet to a bubbler. A long stainless steel needle was pierced through the septa and condenser center into the magnetically stirred solution. Nitrogen was bubbled through the long needle. The flask was heated to 135° C. for 4 hours. The pyridine was then removed under nitrogen purge. The resulting oil was heated to 150° C. for 4 hours. The flask was cooled to ambient temperature and contained 0.045 grams of the crude title compound as a white solid. The crude product did not contain any impurities measurable by thin layer chromatography. The product can be purified by either column chromatography on a silica gel column using a gradient mixture of ethyl acetate/hexane as eluent or by recrystallization from a mixture of ethyl acetate in hexane. Melting Point 140-5° C. (crude); 1H NMR (300 MHz, CDCl3) δ 1.24 (t, J=7.6 Hz, 3H), 1.72 (m, 2H), 1.94 (m, 2H) 2.16 (m, 4H), 2.66 (q, J=7.6 Hz, 2H), 2.98 (t, J=7.0 Hz, 2H), 4.25 (t, J=7.0 Hz, 2H), 5.60 (quintet, J=7.7 Hz, 1H), 7.48 (dd, J=4.9 and 7.8 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 8.75 (dd, J=1.4 and 4.9 Hz, 1H), 8.9 (d, J=1.7 Hz, 1H); Anal. calcd. for C19H22N6 : C, 68.23; H, 6.63; N, 25.13. Found: C, 67.39; H, 6.87; N, 24.00.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])C.C(OC(=O)C(OC1C=CC=C([N+]([O-])=O)C=1)CCCCCCCCCCCC)C.[OH-].[Na+].Cl>C(O)C>[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:4]([OH:28])=[O:3])=[CH:24][CH:23]=1)([O-:27])=[O:26]
Reactant: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Agent: CCCCCCCCCCCCC(Oc1cccc([N+](=O)[O-])c1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 980 g of 2-(p-nitrophenoxy)-myristic acid ethyl ester (synthesized analogously to the 2-(m-nitrophenoxy)-myristic acid ethyl ester of Preparation 1), 375 ml of 10N sodium hydroxide, and 1500 ml of ethanol is stirred for 1 h at room temperature and next acidified with 5000 ml of 1N hydrochloric acid. The resulting precipitate is filtered off, rinsed with water until neutral, and dried. The product (845 g) was recrystallized from n-hexane.