Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH3:14])[S:6]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)(=[O:8])=[O:7])[CH2:3][CH2:2]1.[O:15](C)[S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17]>>[F:20][C:19]([F:22])([F:21])[S:16]([O-:18])(=[O:17])=[O:15].[CH:1]1([CH2:4][N:5]([CH3:14])[S:6]([N:9]2[CH:13]=[CH:12][N+:11]([CH3:19])=[CH:10]2)(=[O:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CN(CC1CC1)S(=O)(=O)n1ccnc1
Reactant: COS(=O)(=O)C(F)(F)F
Product: CN(CC1CC1)S(=O)(=O)n1cc[n+](C)c1
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
3-(Cyclopropylmethyl-methyl-sulfamoyl)-1-methyl-3-H-imidazol-1-ium trifluoromethanesulfonate was prepared in accordance with step B of the general method described in example 76 from imidazole-1-sulfonic acid cyclopropylmethyl-methyl-amide and methyl triflate; MS: m/e=230.4 (M−).
Reaction SMILES: [BrH:1].[S:2]1[C:6]([CH2:7]O)=[CH:5][C:4]2[CH:9]=[CH:10][CH:11]=[CH:12][C:3]1=2.C(Cl)(Cl)Cl>C(O)(=O)C.ClCCl>[Br:1][CH2:7][C:6]1[S:2][C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[CH:5]=1
Reactant: Br
Reactant: OCc1cc2ccccc2s1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: BrCc1cc2ccccc2s1
Reaction time: 3 h

Procedure:
HBr in acetic acid (6 mL) was added to a suspension of benzo[b]thiophen-2-ylmethanol (1 g, 6.1 mmol) in dichloromethane (6 mL) at room temperature. The reaction mixture was stirred for 3 hours then diluted by addition of chloroform (20 mL). The organic phase was washed with a saturated solution of hydrogenocarbonate (20 mL), dried over sodium sulfate and concentrated to dryness. The title product was obtained as a yellow oil (1.3 g, quantitative).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[CH2:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].S(=O)(=O)(O)[OH:23]>>[C:4]([N:6]1[CH2:7][CH2:8][C:9]2([O:21][C:14](=[O:23])[CH2:13][CH:12]2[C:20]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:11]1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)N1CCC(=C2CC(=O)c3ccccc32)CC1
Product: CCOC(=O)N1CCC2(CC1)OC(=O)CC2c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-Carboxy-β-phenyl-4-piperidinehydracrylic acid diethyl ester (60 g, 0.17 mol; mp 73°-75° C.), prepared by the general procedures described in Example 1, is added portionwise to a stirred mixture of 600 ml of concentrated sulfuric acid, and stirring at room temperature is continued for 4 hours. The solution is poured onto ice, and the mixture is extracted with a copious volume of diethyl ether. The ether extract is washed with water, dried and evaporated; the residue is collected as a solid (34 g) with the aid of a small volume of ether. This product mixture is purified by partition chromatography on a Celite® diatomaceous earth column developed with a hexane-methanol solvent system. The two main fractions separated on the partition column are each, in methylene chloride solution, passed through a short column of alumina (Woelm, Activity II) and the columns are eluted with methylene chloride and then with ethylacetate. Evaporation of the eluates gives the two products described above. The more polar product is the saturated spirolactone product of the example (17 g); mp. 112° -114° C. Recrystallization from acetone-hexane gives analytically pure material, mp. 121°-122° C. The second product, present in lesser amount, is the less polar 4-(3-oxo-1-indanylidene)-1-piperidinecarboxylic acid ethyl ester described above, mp. 118°-122°; recrystallization from aqueous methanol gives the analytical sample, mp. 114°-116° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>CN(C)C=O>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]([C:13]2[CH:18]=[N:17][CH:16]=[N:15][CH:14]=2)[CH2:25][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=2)=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(Nc2cncnc2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N(Cc2ccc(C(F)(F)F)cc2)c2cncnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
To a suspension of 40 mg of sodium hydride in 2 ml of N,N-dimethylformamide was added 0.22 g of 5-[(4-nitrophenyl)amino]pyrimidine in small portions. After stirring at room temperature for 30 minutes, 0.24 g of 4-trifluoromethylbenzyl bromide was added thereto, followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to recover crude crystals from the chloroform eluate. Recrystallization of the crude crystals from a mixed solvent of ethyl acetate and ethyl ether yielded 0.19 g of 5-[N-(4-nitrophenyl)-N-(4trifluoromethylbenzyl)amino]pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1.[CH2:12]([CH:14]([CH2:18][CH2:19][CH2:20][CH3:21])[C:15](Cl)=[O:16])[CH3:13]>>[CH2:12]([CH:14]([CH2:18][CH2:19][CH2:20][CH3:21])[C:15]([NH:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1)=[O:16])[CH3:13]
Reactant: CCCCC(CC)C(=O)Cl
Reactant: NC1=NC(=O)C2=CC=NC2=N1
Product: CCCCC(CC)C(=O)NC1=NC(=O)C2=CC=NC2=N1

Procedure:
Using 2-aminopyrrolo(2,3-d)pyrimidin-4-one and 2-ethylhexanoyl chloride, the above-identified compound is produced by the same procedure as Reference Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:5][CH:4]=1.[NH3:21]>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[CH:10]=[C:11]([S:15]([NH2:21])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2cccc(S(=O)(=O)Cl)c2)cc1
Reactant: N
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C(=O)c2cccc(S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
3-(4-Methoxy-benzoyl)-benzenesulfonyl chloride is dissolved in dichloromethane (10 ml) and treated with 1.7 mL of a 2 M solution of ammonia in methanol. The reaction is stirred at ambient temperature for 2 hours and quenched with 1N HCl. The organic phase is separated and evaporated under reduced pressure to give the crude sulfonamide. Purification by silica gel chromatography (gradient of ethyl acetate in hexanes 5-25%) yielded 100 mg (50% yield) of the title compound. 1H NMR (CDCl3, 300 MHz): δ 8.3 (t, 1H, J=1.6 Hz), 8.1 (m, 1H), 7.95 (m, 1H), 7.8 (d, 2H, J=6.98 Hz), 7.65 (t, 1H, J=7.8 Hz), 7.0 (d, 2H, J=6.98 Hz), 4.95 (s, 2H), 3.9 (s, 3H). MP: 119-122° C. LCMS Elution time 0.81 MS (m/z): 291 (M+1). CHN Calc C, 57.72; H, 4.50; N, 4.81. Found C, 57.65; H, 4.33; N, 4.69
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[C:6]1[CH:10]=[CH:9][S:8][CH:7]=1.[C:21]([CH2:23][NH:24][C:25](=[O:32])[C@@H:26]([OH:31])[CH2:27][CH:28]([CH3:30])[CH3:29])#[N:22].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.O>ClCCl>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([CH:5]([C:6]2[CH:10]=[CH:9][S:8][CH:7]=2)[O:31][C@@H:26]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:25]([NH:24][CH2:23][C:21]#[N:22])=[O:32])=[CH:16][CH:15]=1
Reactant: N=C(OC(c1ccc(Br)cc1)c1ccsc1)C(Cl)(Cl)Cl
Reactant: CC(C)C[C@H](O)C(=O)NCC#N
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: ClCCl
Product: CC(C)C[C@H](OC(c1ccc(Br)cc1)c1ccsc1)C(=O)NCC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-bromophenyl)(thien-3-yl)methyl 2,2,2-trichloroethanimidoate from step 2 (970 mg, 2.36 mmol) in dichloromethane (12 mL) was added (2S)-N-(cyanomethyl)-2-hydroxy-4-methylpentanamide (402 mg, 2.36 mmol) and camphorsulfonic acid (137 mg, 0.59 mmol). The reaction was stirred overnight at room temperature and the resulting mixture was poured into water. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried and evaporated and the crude residue was chromatographed on silica gel using 50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=O)[CH3:5].COC(OC)[N:11]([CH3:13])C.O1CCCC1.Cl.[C:22]([NH:26]N)([CH3:25])([CH3:24])[CH3:23]>O.C(OCC)(=O)C>[C:22]([N:26]1[C:4]([CH3:5])=[C:3]([C:2](=[O:7])[CH3:1])[CH:13]=[N:11]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)NN
Reactant: CC(=O)CC(C)=O
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cnn(C(C)(C)C)c1C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of pentane-2,4-dione (5.01 g) and 1,1-dimethoxy-N,N-dimethylmethanamine (6.26 g) was stirred at 80° C. for 1 hr. Tetrahydrofuran (10 mL) was added to the reaction mixture, tert-butylhydrazine hydrochloride was added by small portions under ice-cooling, and the mixture was stirred at 60° C. for 30 min. The reaction mixture was allowed to cool to room temperature, ethyl acetate (100 mL) and water (100 mL) were added, and the separated aqueous layer was extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (7.47 g) as a colorless oil.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][NH:3][CH2:2]2.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][N:12]=1>>[Cl:10][C:11]1[N:12]=[CH:13][C:14]([N:3]2[CH2:4][CH:5]3[CH2:9][CH:1]([CH2:8][NH:7][CH2:6]3)[CH2:2]2)=[CH:15][CH:16]=1
Reactant: C1NCC2CNCC1C2
Reactant: Clc1ccc(I)cn1
Product: Clc1ccc(N2CC3CNCC(C3)C2)cn1
Yield: 10 %

Procedure:
3,7-Diazabicyclo[3.3.1]nonane, prepared as described in (Garrison, G. L. et. al., J. Org. Chem. 58, 27, (1993) 7670), and 2-chloro-5-iodopyridine were processed as described in Example 57A. The crude was purified by flash chromatography (silica gel; CHCl3:MeOH:NH4OH; 90:5:1) to provide the title compound (10% yield). MS (DCI/NH3) m/z 238 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][N:5]([CH3:9])[CH2:6][CH2:7][OH:8].[H-].[Na+].[C:13]([NH2:17])(=[O:16])[CH:14]=[CH2:15].S(=O)(=O)(O)O>>[CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][N:5]([CH3:9])[CH2:6][CH2:7][O:8][CH2:15][CH2:14][C:13]([NH2:17])=[O:16]
Reactant: CN(C)CCN(C)CCO
Reactant: C=CC(N)=O
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCN(C)CCOCCC(N)=O
Temperature: 25 °C

Procedure:
A 50 ml 3 neck round bottom flask was fitted with the following: magnetic stirrer, reflux condenser, air bubbler, and a temperature controlled oil bath. The flask was charged with 7.3 g of 2-{[2-(dimethylamino) ethyl]methylamino}ethanol. Sodium hydride, 0.014 g, was then added carefully to the of 2-{[2-(dimethylamino) ethyl]methylamino}ethanol with stirring. The mixture was stirred at a constant rate for two minutes before 3.55 g of acrylamide was added. After the addition of acrylamide, the reaction mixture was stirred at 50° C. for 6 hours. The mixture was cooled to ambient temperature. Concentrated sulfuric acid, 0.034 g, then was added to neutralize the product mixture. The resulting mixture was filtered through a Celite layer. The filtrate was collected for foam application. Quantitative 1H NMR showed that the product was 94% pure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=1
Reactant: C1=COCCC1
Reactant: CC(C)(C)c1cc(Br)ccc1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(Br)ccc1OC1CCCCO1
Temperature: 25 °C
Reaction time: 26.5 h

Procedure:
To a solution of 18.92 g (82.6 mmol) of 4-bromo-2-t-butylphenol (Compound E) in 110 ml of dichloromethane was added dropwise 10.42 g (11.3 ml, 123.9 mmol) of 3,4-dihydro-2H-pyran. To this clear, colorless solution was added 1.86 g (7.4 mmol) of pyridinium p-toluenesulfonate. The resulting mixture was stirred at room temperature under a blanket of argon for 26.5 hours, partitioned between 250 ml of water and 400 ml of hexane, and the layers were separated. The organic phase was washed with 2×250 ml-portions of water and 150 ml of brine solution, dried over MgSO4, filtered and concentrated in vacuo to a yellow oil. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) yielded the title compound as a light yellow, crystalline solid. PMR (CDCl3):d 1.39 (9H, s), 1.6-2.1 (6H, m), 3.6-3.7 (1H, m), 3.8-3.9 (1H, m), 5.43 (1H, t, J=2.7 Hz), 7.06 (1H, d, J=8.8 Hz), 7.24 (1H, dd, J=8.8, 2.7 Hz), 7.36 (1H, d, J=2.7 Hz).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:8].[C:9](#[N:12])[CH:10]=[CH2:11].N(OC(C)C)=O>C(#N)C>[Cl:8][CH:10]([CH2:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]#[N:12]
Reactant: C=CC#N
Reactant: Cl
Reactant: Nc1ccccc1
Agent: CC(C)ON=O
Solvent: CC#N
Product: N#CC(Cl)Cc1ccccc1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
A mixture of 2.28 g (25 mmols) of distilled aniline, 30 mL of acetonitrile, 2.6 mL (31 mmols) of concentrated hydrochloric acid, 30 mL (456 mmols) of distilled acrylonitrile (AN), and 0.36 g (2.5 mmols) of cuprous oxide was stirred for five minutes under nitrogen. A mixture of 2.8 g (31 mmols) of isopropyl nitrite (IPN) and 30 mL of acetonitrile was added dropwise over a period of 20 minutes. The mixture warmed to 45° C. and nitrogen gas evolved. After stirring at ambient temperature for two hours, the dark mixture was worked up to provide an 84% yield of 2-chloro-3-phenylpropionitrile (CPPN).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[C:17]1([CH2:23][CH2:24][NH:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:26][NH:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: NNCCc1ccccc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1nc(NNCCc2ccccc2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[2-phenethylhydrazino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-phenylethylhydrazine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[N:3]=1.Cl.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[CH2:19][NH:18][CH2:17][CH2:16]2.[C:25](=[O:28])([O-])[O-].[Na+].[Na+]>O1CCOCC1.[Cl-].[Na+]>[ClH:1].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[CH2:19][N:18]([C:2]1[N:7]=[C:6]([N:18]3[CH2:17][CH2:16][C:15]4[C:20](=[CH:21][C:22]([O:28][CH3:25])=[C:13]([O:12][CH3:11])[CH:14]=4)[CH2:19]3)[N:5]=[C:4]([NH2:9])[N:3]=1)[CH2:17][CH2:16]2
Reactant: Nc1nc(Cl)nc(Cl)n1
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)CN(c1nc(N)nc(N3CCc4cc(OC)c(OC)cc4C3)n1)CC2

Procedure:
2,4-Dichloro-6-amino-1,3,5-triazine (5.13 g, 31.1 mM) and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (14.72 g, 64 mM) were stirred in dioxane (40 mL) with sodium carbonate solution (2N, 65 mL) at reflux for 3 hr. The mixture was cooled and diluted with saturated sodium chloride solution (1000 mL) and extracted with methylene chloride (3×75 mL). Filtration through a cotton plug and concentration followed by evaporation from benzene (2×20 mL) provided a foam, 16.5 g. This material was combined with 7.8 g of crude product prepared analogously and recrystallized from chloroform/methanol to provide 13.85 g(61%). Recrystallization of free base (2.6 g) from hydrochloric acid/methanol (1N) provided a yellow powder, 2.17 g(78%), mp=259°-261° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([C@H]3CCCNC3)[CH3:33])[N:27]=2)=[CH:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15]C(=O)OCC3C=CC=CC=3)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.C(O[C:44](=[O:46])[CH3:45])(=O)C.[C:47](O)([C:49](F)(F)F)=O>[Pd].C(Cl)Cl.CO>[NH2:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([NH:8][C:5]2[CH:4]=[C:3]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][CH2:33][C@H:49]4[CH2:47][CH2:4][CH2:5][N:6]([C:44](=[O:46])[CH3:45])[CH2:7]4)[N:27]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:10][CH2:11]1
Reactant: CN(c1cccc(-c2cc(N[C@H]3CC[C@H](NC(=O)OCc4ccccc4)CC3)ncc2Cl)n1)[C@H]1CCCNC1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C(F)(F)F
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCC[C@H](CNc2cccc(-c3cc(N[C@H]4CC[C@H](N)CC4)ncc3Cl)n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of benzyl trans-4-(5′-chloro-6-((S)-piperidin-3-yl-methylamino)-2,4′-bipyridin-2′-yl-amino)cyclohexylcarbamate (15 mg, 0.027 mmol), DCM (2 mL), TEA (0.011 mL, 0.082 mmol) and acetic anhydride (3.09 μL, 0.033 mmol) was stirred at ambient temperature for 2 hours and the reaction progress was followed by LCMS. The solvent was concentrated off. The reaction mixture flask was flushed with argon, 10% palladium on activated carbon (5 mg, 4.70 μmol) was added and followed by careful addition of MeOH (0.8 mL). The resulting mixture was stirred under hydrogen for 45 minutes at ambient temperature and monitored by LCMS. To the crude reaction mixture was added 2 ml of DCM, filtered and the solvent was concentrated off. The resulting residue was dissolved in 1.0 ml of DMSO, filtered and purified by prep HPLC to give two fractions corresponding to the two title compounds respectively. After lyophilization, 4.0 mg of 1-((R)-3-((2′-(trans-4-aminocyclohexylamino)-5′-chloro-2,4′-bipyridin-6-yl-amino)methyl)piperidin-1-yl)ethanone, was obtained as a TFA salt. LCMS (m/z): 457.2 (MH+), retention time=0.46 min. In addition, 1.0 mg of 1-((R)-3-((2′-(trans-4-aminocyclohexylamino)-2,4′-bipyridin-6-yl-amino)methyl)piperidin-1-yl)ethanone, as TFA salt was also obtained. LCMS (m/z): 423.2 (MH+), retention time=0.45 min. This reaction yielded two products which are separated and purified by HPLC.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([OH:16])=[C:14]([C:17](=O)[CH3:18])[C:13]([CH3:20])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]([C:25]1[S:29][C:28]([C:30]([NH:32][NH2:33])=[O:31])=[CH:27][CH:26]=1)=[O:24]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14](=[C:17]([NH:33][NH:32][C:30]([C:28]3[S:29][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:26][CH:27]=3)=[O:31])[CH3:18])[C:13]([CH3:20])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)NN)s1
Reactant: CC(=O)c1c(C)nn(-c2ccc(C(C)(C)C)cc2)c1O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(C(C)(C)C)cc3)N=C2C)s1
Temperature: 110 °C
Reaction time: 12 h
Yield: 35.2 %

Procedure:
54.5 mg (0.20 mmol) of 1-(1-(4-tert-butylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-ethanone and 40.0 mg (0.20 mmol) of 5-methoxycarbonyl-2-thiophenecarboxylic acid hydrazide were dissolved in 2.0 mL of DMF and stirred at 110° C. for 12 hours. After cooling, the solvent was removed by evaporation, and the crude product was washed with ethyl acetate and collected by filtration to obtain 32.0 mg of the desired product as a yellow solid (yield 35%).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[O:12][C@@H:11]([N:23]2[C:52]3[N:51]=[C:45]([NH:46][C:47](=[O:50])[NH:48][CH3:49])[N:44]=[C:27]([O:28][C:29](=[O:43])[N:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)(C(C)(C)C)(C)C.C(N(CC)CC)C.C1(C)C=CC=CC=1>O1CCCC1>[C:37]1([N:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:29]([O:28][C:27]2[C:26]3[N:25]=[CH:24][N:23]([C:52]=3[N:51]=[C:45]([NH:46][C:47](=[O:50])[NH:48][CH3:49])[N:44]=2)[C@@H:11]2[O:12][C@H:13]([CH2:14][OH:15])[C@@H:9]([OH:8])[CH2:10]2)=[O:43])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CNC(=O)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O3)c2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CNC(=O)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.4 %

Procedure:
The above-obtained 3′,5′-bis-O-(tert-butyldimethylsilyl)-6-O-diphenylcarbamoyl-2-N-methylcarbamoyldeoxyguanosine (1.13 g, 52 mmol) was azeotroped with anhydrous tetrahydrofuran three times and then dissolved in anhydrous tetrahydrofuran (15 mL), and triethylamine 3 hydrogen fluoride (743 μL, 4.56 mmol) was added thereto. The mixture was stirred at room temperature overnight. Then, after addition of toluene (5 mL), the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (C200) with methanol/5% to 6% chloroform, and then ethyl acetate (5 mL) and diethyl ether (15 mL) were added thereto for precipitation. Then, the precipitate was purified by filtration to give 6-O-diphenylcarbamoyl-2-N-methylcarbamoyldeoxyguanosine (643 mg, 81%).
Reaction SMILES: Cl.[F:2][C:3]1([F:31])[CH2:5][CH:4]1[CH2:6][N:7]1[C:15]2[C:10](=[N:11][C:12]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)[N:9]([CH3:28])[S:8]1(=[O:30])=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:56]1[CH:60]=[CH:59][C:58]([C:61](O)=[O:62])=[N:57]1.CCN(C(C)C)C(C)C>CO.CN1C(=O)CCC1>[F:31][C:3]1([F:2])[CH2:5][CH:4]1[CH2:6][N:7]1[C:15]2[C:10](=[N:11][C:12]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:23][CH2:24][N:25]([C:61]([C:58]5[CH:59]=[CH:60][O:56][N:57]=5)=[O:62])[CH2:26][CH2:27]4)=[CH:20][CH:21]=3)=[CH:13][CH:14]=2)[N:9]([CH3:28])[S:8]1(=[O:29])=[O:30]
Reactant: CN1c2nc(-c3ccc(N4CCNCC4)cc3)ccc2N(CC2CC2(F)F)S1(=O)=O
Reactant: O=C(O)c1ccon1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1c2nc(-c3ccc(N4CCN(C(=O)c5ccon5)CC4)cc3)ccc2N(CC2CC2(F)F)S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a microwave vial was added 1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-(4-piperazin-1-ylphenyl)-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide hydrochloride (8-3) (0.028 g, 0.059 mmol), HATU (0.029 g, 0.077 mmol), isoxazole-3-carboxylic acid (0.0087 g, 0.077 mmol), NMP (1 mL), and finally DIPEA (0.060 mL, 0.344 mmol). The reaction mixture was then stirred at room temperature for 1 hour. The crude reaction mixture was then diluted with methanol, then filtered. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) to give 1-[(2,2-difluorocyclopropyl)methyl]-5-{4-[4-(isoxazol-3-ylcarbonyl)piperazin-1-yl]phenyl}-3-methyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (34-1) as a tan solid. HRMS (M+H)+: observed=531.1613, calculated=531.1621.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:4]([Cl:9])[CH:3]=1
Reactant: CCCCCCCCI
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 77.9 %

Procedure:
1-Bromo-3-chloro-4-hydroxybenzene (0.50 g, 2.41 mmol) was dissolved in acetonitrile (20 mL) and stirred at rt. Potassium carbonate (0.47 g, 3.37 mmol) and iodooctane (0.57 mL, 3.13 mmol) were added and the reaction was heated to 80° C. for 4 h. The reaction was diluted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. Silica gel chromatography eluting with 1% ethyl acetate/hexane yielded 0.6 g of product: ESI-MS 317.0 (M+H).