Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C@@H:9]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:7])=[CH:4][N:3]=1.C(NCC)C.C1COCC1.[CH3:42][N:43]([CH:45]=O)[CH3:44]>>[CH3:44][N:43]([CH3:42])[C:45]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C@@H:9]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=2)[C:10]2[C:15]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:7])=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F)c1ccc(Cl)nc1
Solvent: C1CCOC1
Solvent: CCNCC
Product: CN(C)c1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2C(F)(F)F)cn1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A glass microwave reaction vessel was charged with (S)-6-chloro-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (50 mg, 0.109 mmol, example 135), DMF (1 mL), and 2 M diethylamine in THF (0.054 mL, 0.109 mmol). The reaction mixture was stirred and heated in a Biotage Initiator at 100° C. for 30 minutes. This was repeated at 150° C. for 30 minutes at a time until LC-MS indicated complete consumption of starting material. The reaction product was purified by reverse-phase preparative HPLC (Shimadzu) on a Phenomenex Gemini column (5 micron, C18, 110 Å, Axia, 100×30 mm) eluting at 45 mL/min with a linear gradient of 20% to 70% MeCN (0.1% TFA) in water (0.1% TFA) over 20 minutes. The desired fractions were poured into 10% Na2CO3 and extracted with DCM (3×5 mL). The combined DCM layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound as a white solid. 1H NMR (CDCl3, 300 MHz) δ ppm 8.86 (d, J=3.8 Hz, 1H), 8.66 (d, J=2.2 Hz, 1H), 8.02 (d, J=7.9 Hz, 2H), 7.92 (dd, J=9.1, 2.5 Hz, 1H), 7.54 (s, 4H), 7.45 (dd, J=7.7, 4.4 Hz, 1H), 6.87 (d, J=7.9 Hz, 1H), 6.49 (d, J=9.2 Hz, 1H), 3.14 (s, 6H) MS (ESI pos. ion) m/z: 469.0 (M+H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][C:19]([NH2:21])=O)[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([C:3]1([CH2:18][CH:19]=[NH:21])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(N)=O)OCC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC=N)OCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.2 %

Procedure:
A solution of compound 6 (119 mg, 0.42 mmol) in dry THF (3 mL) was added dropwise to 1M LiAlH4 in THF (624 μL, 0.62 mmol, 1.5 eq) and stirred for two hours at room temperature under argon. Another equivalent of 1M LiAlH4 in THF (420 μL, 0.42 mmol, 1.0 eq) was then added and the reaction was stirred overnight. The resulting mixture was then slowly quenched with EtOAc and poured over water to form an emulsion. The emulsion was filtered, and the aqueous layer was separated and extracted twice with EtOAc. The three organic phases were then combined, dried with Na2SO4, concentrated, and purified by column chromatography using 50:50:EtOAc:Hexane to give a yellow-brown solid (40 mg, 36%): mp 101–103° C. 1HNMR (CDCl3, δ TMS): 0.94 (t, 3H), 1.38 (t, 3H), 1.96 (m, 2H), 2.73 (qd, 2H), 2.87 (q, 2H), 2.99 (t, 2H), 3.32 (m, 1H, CH═N), 3.87 (t, 2H), 7.04–7.43 (m, 3H, Ar—H), 7.89 (br, 1H, NH). MS+: m/z 293 (MNa+), 271 (MH+). MS−: m/z 269 ([M−H]−). Anal. (C17H22N2O.0.5H2O): C, H, N.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[N:15]=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].CCN(C(C)C)C(C)C.Cl[CH2:30][O:31][CH3:32]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:30][O:31][CH3:32])[C:14]2[N:15]=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:11])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(S(=O)(=O)Nc2cccnn2)ccc1F
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCN(c1cccnn1)S(=O)(=O)c1ccc(F)c(C#N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-cyano-4-fluoro-N-(pyridazin-3-yl)benzenesulfonamide (Preparation 6, 6.70 g, 24.1 mmol) in DCM (150 mL) at 0° C. was added DIPEA (6.48 mL, 35.18 mmol) followed by chloromethoxymethane (1.46 mL, 25.54 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by the addition of 1N NaOH (aq) solution, the organic layer was collected, washed with water, brine, and dried over Na2SO4 before concentrating in vacuo. The residue was purified using silica gel column chromatography eluting with EtOAc:Heptane 1:1 to afford the title compound as a mixture of isomers (3.85 g, 49%) that was used without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28](C)([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.C(N(C(C)C)CC)(C)C.ClC(OC(C)C)=O>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cnc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Agent: CC(C)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)N1CCC(COc2cnc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Yield: 92.3 %

Procedure:
The title compound (80 mg, 92%) was prepared as a white solid from 1,1-dimethylethyl 4-[({2-[4-(methylsulfonyl)phenyl]-5-pyrimidinyl}oxy)methyl]-1-piperidinecarboxylate (Example 128, 90 mg, 0.20 mmol) and TFA (1.0 mL) in CH2Cl2 (6 mL) then diisopropylethylamine (1.0 ml) and isopropyl chloroformate (1.0M in toluene, 0.22 mL, 0.22 mmol) in a manner similar to Example 74. 1H NMR (400 MHz, CDCl3): δ 8.56 (d, 2H, J=8.5 Hz), 8.48 (s, 2H), 8.02 (d, 2H, J=8.6 Hz), 4.92 (septet, 1H, J=6.2 Hz), 4.24 (bs, 2H), 3.97 (d, 2H, J=6.3 Hz), 3.08 (s, 3H), 2.85-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.40-1.20 (m, 8H); LRMS (APCI), m/z 434 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[C:23]([F:24])=[CH:22][C:21]([NH2:25])=[C:20]([Cl:26])[CH:19]=4)=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[NH2:30][CH:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:19]=[C:20]([Cl:26])[C:21]([NH2:25])=[CH:22][C:23]=4[F:24])=[C:11]3[C:10]([NH:30][CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[N:9]2)=[CH:5][CH:4]=1
Reactant: CN1CCC(N)CC1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4cc(Cl)c(N)cc4F)ccnc32)cc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4cc(Cl)c(N)cc4F)ccnc32)cc1
Temperature: 100 °C
Yield: 66.9 %

Procedure:
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2-chloro-5-fluorobenzenamine (200 mg, 0.38 mmol) was added into a suspension of 4-amino-1-methylpiperidine (131 mg, 1.14 mmol), Cu(I)I (14.5 mg, 0.0762 mmol), K2CO3 (263 mg, 1.91 mmol) and L-proline (17.6 mg, 0.152 mmol) in DMSO (6 mL) and the reaction mixture was heated at 100° C. for 12 hours. The reaction with diluted with CH2Cl2 and water (10 mL) was added. The organic layer was then washed with water (10 mL), brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (5% MeOH in CH2Cl2) to afford the product (130 mg, 66.7% yield) as a brown oil. LRMS (APCI pos) m/e 511.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([O:17][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)=[O:21])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)OCC(=O)c1cccc(Cl)c1
Yield: 81.4 %

Procedure:
The title compound (2.65 g) was prepared from (RS)-2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) and 2-bromo-3′-chloroacetophenone (1.92 g) according to the method of description 36.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[C:37]1(=O)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>O1CCCC1.C(OCC)C>[CH:37]1([NH:1][CH2:2][C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[C@H:12]3[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]3)=[C:5]([NH:22][CH2:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:4]=2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C1CCCCC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC4CCCCC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.5 %

Procedure:
(2R,3R,4S,5R)-2-{2-(Aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (110 mg, 0.22 mmol) was dissolved (using gentle heating) in dry tetrahydrofuran (20 ml) and the stirred solution treated with a solution of cyclohexanone (22 mg, 0.22 mmol) in dry tetrahydrofuran (2 ml) followed by addition of sodium triacetoxyborohydride (70 mg, 0.33 mmol) and a solution of acetic acid (0.14 ml, 0.25 mmol) in dry tetrahydrofuran (2 ml). The mixture was then stirred at room temperature for 24 hr. The reaction mixture was diluted with diethyl ether, washed with saturated aqueous sodium hydrogen carbonate, brine, dried with anhydrous magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:ammonia (95:5:0.5) changing to dichloromethane:methanol:ammonia (90:10:1) to afford the title compound as a solid (80 mg). MS: 573 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([C@H:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=1>O.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C@H:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=2)[CH:7]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: COc1ccc(F)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: O
Product: COc1ccc(F)cc1-c1ccc([C@@H](C)N)cc1
Temperature: 200 °C
Yield: 94.8 %

Procedure:
Palladium acetate (56 mg, 0.25 mmol) was added to a mixture of 5-fluoro-2-methoxyphenylboronic acid (850 mg, 5.0 mmol) and (R)-1-(4-bromophenyl)ethylamine (500 mg, 2.5 mmol) in water (20 ml). This mixture was heated for 5 min at 200° C. in a Smithcreator microwave oven and then diluted with methanol (200 ml). The mixture was purified on a SCX column (20 g) using 2M ammonia in methanol to elute the intermediate amine. Evaporation of solvents under reduced pressure gave (R)-1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine as a gum (580 mg, 2.37 mmol, 96.6%). Triethylamine (41.1 μl, 0.295 mmol) and 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride (20.5 mg, 0.0984 mmol) were added to a solution of (R)-1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (20 mg, 0.082 mmol) in dichloromethane (1 ml) and the resulting solution shaken at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate solution (500 μl), the dichloromethane layer separated, dried over magnesium sulfate and the solvent evaporated. Purification by preparatory LCMS and removal of solvent under reduced pressure gave the title compound (13.8 mg, 0.033 mmol, 40%): 1H NMR (400 MHz, CDCl3): δ7.37, 7.14 (a/b, 4H), 7.02-6.87 (m, 3H), 4.68 (m, 1H), 4.48 (t, 1H), 3.78 (s, 3H), 3.55 (s, 3H), 2.35 (s, 3H), 2.22 (s, 3H), 1.50 (d, 3H) ppm; MS (ESI) m/z: 417 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][CH2:8][CH:7](O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>C(O)(=O)C.[Pd]>[CH3:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1OCC2O
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Under a nitrogen atmosphere 0.610 g (4.06 mmol) 7-methyl-2,3-dihydro-benzofuran-3-ol in 5 mL acetic acid were refluxed with 770 μL. (8.16 mmol) acetic anhydride for 2 h. After cooling to RT, 60 mg palladium on charcoal (Pd/C 10%) were added and the mixture was hydrogenated for 3.5 h under a hydrogen atmosphere (3 bar). The catalyst was filtered off and the solvent was evaporated down.
Reaction SMILES: [N:1]1C2C(=CC=CC=2)C=CC=1COC1C=CC(C(C2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)(C)CCO)=CC=1.[N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][C:43]=1[CH2:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]([C:66]2[CH:71]=[CH:70][C:69]([O:72][CH2:73][C:74]3[CH:83]=[CH:82][C:81]4[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=4)[N:75]=3)=[CH:68][CH:67]=2)(C)[CH2:61][CH2:62][CH2:63][OH:64])=[CH:56][CH:55]=1>>[N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][C:43]=1[CH2:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([CH:60]([C:66]2[CH:71]=[CH:70][C:69]([O:72][CH2:73][C:74]3[CH:83]=[CH:82][C:81]4[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=4)[N:75]=3)=[CH:68][CH:67]=2)[CH2:61][CH2:62][CH2:63][O:64][NH2:1])=[CH:56][CH:55]=1
Reactant: CC(CCO)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CC(CCCO)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: NOCCCC(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
The desired compound was prepared according to the method of Example 5, steps 1 and 2, except substituting 3,3-bis(4-(2-quinolylmethoxy)phenyl)butan-1-ol, prepared as in step 1, for 4,4-bis(4-(2-quinolylmethoxy)phenyl)pentan-1-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][C:3]=1[CH2:4][N:5](CC1C=CC=CC=1)[CH2:6][CH3:7].[H][H].C.[ClH:27]>CO>[ClH:27].[NH2:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(N)c(CN(CC)Cc2ccccc2)c1
Agent: Cl
Solvent: CO
Product: CCNCc1cc(C(=O)OCC)ccc1N

Procedure:
3.8 gm of 2-amino-N-benzyl-5-carbethoxy-N-ethyl-benzylamine were hydrogenated in a mixture of 50 ml of methanol and 1 ml of concentrated hydrochloric acid at room temperature and at a hydrogen pressure of 5 atmospheres in the presence of palladized charcoal. Then, the catalyst was filtered off, and the filtrate was evaporated to dryness in vacuo. The residue was recrystallized from ethanol by addition of ether, yielding 2-amino-5-carbethoxy-N-ethyl-benzylamine hydrochloride, m.p. 173°-176°C (decomp.).
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:27]Cl.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CN(C)C=O>[C:16]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:27][C:26]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:14][CH2:15]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(C(CCN2CCNCC2)c2ccccc2)cc1
Reactant: COc1ccc(CCl)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCN(CCC(c3ccccc3)c3ccccc3)CC2)cc1OC
Yield: 83.6 %

Procedure:
N-3,3-Diphenylpropylpiperazine in the amount of 2.8 g (0.01 mole), 1.87 g (0.01 mole) 9f 3,4-dimethoxybenzyl chloride, 0.5 g (0.005 mole) of triethylamine, 1.4 g (0.01 mole) of potassium carbonate, and 2 ml of dimethylformamide were mixed with 20 ml of toluene, and the resulting mixture was heated at the refluxing temperature for 2 hours. The reaction liquid was left to cool, washed by shaking with water, and the organic solvent layer was concentrated under reduced pressure to obtain 3.6 g (83.6% yield) of oily 1-(3,3-diphenylpropyl)-4-(3,4-dimethoxybenzyl)piperazine.
Reaction SMILES: N1C=C2C(N=CN2)=NC=1.[O:10]([CH3:20])[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13].O=C[C@@H]([C@@H]([C@@H](CO)O)O)O.CC1C(=O)NC(=O)N([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C=1.[Si:49](Cl)([C:62]([CH3:65])([CH3:64])[CH3:63])([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[Si:49]([CH:18]([OH:19])[C@H:16]1[O:17][C@@H:11]([O:10][CH3:20])[C@H:12]([OH:13])[C@@H:14]1[OH:15])([C:62]([CH3:65])([CH3:64])[CH3:63])([C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Agent: O=C[C@H](O)[C@H](O)[C@H](O)CO
Agent: c1ncc2[nH]cnc2n1
Product: CO[C@@H]1O[C@H](C(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H]1O

Procedure:
The triple substitution of adenosine, i.e., at 5'-, 2-, and N6 -positions, can be carried out by a synthetic strategy in which a 5'-uronamide sugar moiety is condensed with a purine moiety, such as a substituted adenosine derivative. The key sugar intermediate, N-methyl 1-O-acetyl-2,3-dibenzoyl-β-D-ribofuronamide, was synthesized starting from methyl β-D-ribofuranoside, which is commercially available or can be synthesized from D-ribose (Baker et al., J. Org. Chem., 26, 4605-4609 (1961)), in 8 steps. The primary alcohol of β-D-ribofuranoside can be selectively protected with tert-butyldiphenylsilyl chloride (Chaudhary et al., Tet. Lett., 20(2), 99-102 (1979)) to provide 1-O-methyl 5-(t-butyldiphenylsilyl)-β-D-ribofuranoside, and other alcohols can be followed with benzoyl protection to provide 1-O-methyl 5-(t-butyldiphenylsilyl)-2,3-dibenzoyl-β-D-ribofuranoside, the desilylation of which with TBAF/THF will give 1-O-methyl 2,3-dibenzoyl-β-D-ribofuranoside. The 5'-position of 1-O-methyl 2,3-dibenzoyl-β-D-ribofuranoside can be oxidized using ruthenium tetroxide (Singh et al., Tet. Lett., 33(17), 2307-2310 (1992)) to yield 1-O-methyl-2,3-dibenzoyl-β-D-ribofuronic acid which can be purified after methylation on a silica gel column chromatography. Methylamide at 5-position can be introduced by nucleophilic displacement of methyl 1-O-methyl-2,3-dibenzoyl-β-D-ribofuronate with methylamine in THF and benzoyl reprotection of resulting 2,3-diol to yield the sugar intermediate N-methyl 1-O-acetyl-2,3-dibenzoyl-β-D-ribofuronamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[NH:9][N:10]=[C:11]([C:16](=[O:20])[CH2:17][O:18][CH3:19])[C:12]([O:14][CH3:15])=[O:13].[CH3:21]OC(OC)N(C)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N:9]1[CH:21]=[C:17]([O:18][CH3:19])[C:16](=[O:20])[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10]1
Reactant: COC(OC)N(C)C
Reactant: COCC(=O)C(=NNc1cc(I)ccc1F)C(=O)OC
Product: COC(=O)c1nn(-c2cc(I)ccc2F)cc(OC)c1=O
Temperature: 0 °C
Yield: 78 %

Procedure:
A mixture of methyl 2-[(2-fluoro-5-iodophenyl)hydrazono]-4-methoxy-3-oxobutanoate (14.2 g, 35.9 mmol) in N,N-dimethylformamide dimethyl acetal (142 mL) was heated to reflux for 1.5 h and cooled to 0° C. The precipitates were collected by filtration, washed with hexane and dried to yield the title compound (11.3 g, 78% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.80 (3H, s), 3.82 (3H, s), 7.37 (1H, dd, J=10.6, 8.7 Hz), 7.90-8.01 (1H, m), 8.14 (1H, dd, J=7.2, 2.3 Hz), 8.55 (1H, s).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)CCC.Br[C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH2:22]>>[F:27][C:25]1[CH:26]=[CH:20][C:21]([NH2:22])=[C:23]([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)[CH:24]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Nc1ccc(F)cc1Br
Product: Nc1ccc(F)cc1-c1nccs1
Yield: 7.7 %

Procedure:
2-Tributylstannanyl-thiazole (600 mg, 1.6 mmol) was reacted with 2-bromo-4-fluoroaniline (220 mg, 1.2 mmol) according to general procedure [B] for the preparation of substituted anilines described above, which gave the title compound (18 mg, 8%). [M+1] 195.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[C-]#N.[Na+].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].C(O)(=O)C>CN(C)C=O.O>[O:8]=[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:14][CH2:13][C:12]([O:16][CH3:17])=[O:15]
Reactant: C=CC(=O)OC
Reactant: O=Cc1cccnc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)c1cccnc1
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
A solution of 3-pyridinecarboxaldehyde (10.7 g) in dimethyl formamide (DMF, 20 mL) was added over 10 min. to a stirred solution of sodium cyanide (2.45 g) in DMF (80 mL) at room temperature under dry nitrogen. The solution was stirred for 30 min. and methyl acrylate (18.6 g) in DMF (80 mL) was added dropwise over 50 min. The reaction mixture was stirred for 3 h. Acetic acid (6.6 mL) and water (30 mL) were added and stirring was continued for 5 minutes. The mixture was concentrated, dissolved in water (360 mL), and pH was adjusted to 7.5 with sodium bicarbonate. The aqueous layer was extracted with chloroform (3×300 mL). The chloroform layers were combined, washed with saturated sodium chloride solution (brine), dried (MgSO4), filtered, concentrated and purified by flash chromatography (SiO2, 30% ethyl acetate in hexanes) to yield 4.3 g (22%) of the title compound; ESMS (M+1)+194.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>CO.C(OCC)C>[Cl:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: O=C(O)c1ncc(Cl)nc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1ncc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of 3,5-dichloropyrazine-2-carboxylic acid (0.304 g, 1.58 mmol) in MeOH (5 mL) and diethyl ether (5 mL) at room temperature was added (trimethylsilyl)diazomethane (2.0 M solution in hexanes, 4.00 mL, 8.00 mmol). The reaction mixture was stirred at RT for 30 min and concentrated. Purification by flash column chromatography on silica gel (5% to 20% EtOAc in hexanes) gave methyl 3,5-dichloropyrazine-2-carboxylate (0.312 g, 1.51 mmol, 96% yield) as a white solid. LC/MS
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C(O)C.[ClH:14].C(=O)([O-])[O-].[NH4+:19].[NH4+]>O1CCOCC1>[ClH:14].[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]([NH2:19])=[NH:6]
Reactant: N#Cc1ccc(O)c(F)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: C1COCCO1
Product: N=C(N)c1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To 3-fluoro-4-hydroxybenzonitrile (7.56 g, 55.2 mmol) were added ethanol (20 mL) and 4N-Hydrogen chloride in 1,4-Dioxane (100 mL), and the mixture was stirred at room temperature. After 5 days, the mixture was concentrated and dried with a vacuum pump. Then, the mixture was dissolved in ethanol (100 mL), ammonium carbonate (11.0 g, 115 mmol) was added, and the mixture was stirred at room temperature. After 12 hours, the solvent was evaporated, and the residue was dissolved in water (100 mL). The mixture was lyophilized to give the title compound (11.2 g, quantitative).