Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:28](O)=[O:29])[CH:25]=4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.B.CO>O1CCCC1.Cl.O1CCOCC1>[CH:1]1([CH2:6][CH2:7][NH:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([N:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH2:28][OH:29])[CH:25]=4)[CH2:20]3)=[O:18])=[CH:14][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CC1CCCC1)Nc1ccc(NC(=O)N2Cc3ccc(C(=O)O)cc3C2)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1ccc(NCCC2CCCC2)cc1)N1Cc2ccc(CO)cc2C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a stirring suspension of 2-(4-(2-cyclopentylacetamido)phenylcarbamoyl)isoindoline-5-carboxylic acid (18 mg, 0.044 mmol) in tetrahydrofuran was added 1M borane in tetrahydrofuran (0.18 mL, 0.18 mml) dropwise. The mixture was heated at 60° C. for 1 hour. The reaction was cooled to room temperature and treated with several drops of 4M HCl-dioxane and methanol and then the clear solution was stirred at room temperature for 2 hours. The reaction was concentrated and purified by reverse-phase HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.92 (s, 1H), 7.27-7.31 (m, 2H), 7.24 (d, J=8.1 Hz, 1H), 7.15-7.20 (m, 2H), 6.45-6.51 (m, 2H), 5.17-5.21 (m, 2H), 4.68-4.69 (bs, 4H), 4.51 (d, J=5.4 Hz, 2H), 2.97 (q, J=6.7 Hz, 2H), 1.70-1.95 (m, 3H), 1.42-1.66 (m, 6H), 1.04-1.20 (m, 2H); MS (ESI(+)) m/e 380 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=3)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[O:35])=[CH:30][CH:29]=1.C(N(CC)CC)C>C(Cl)Cl>[F:27][C:28]1[CH:29]=[CH:30][C:31]([S:34]([CH:36]2[CH2:41][CH2:40][N:39]([C:19](=[O:20])[C:18]3[CH:22]=[CH:23][C:15]([NH:14][C:8]4[C:7]5[C:12](=[CH:13][C:4]([C:3]([F:25])([F:24])[F:2])=[CH:5][CH:6]=5)[N:11]=[CH:10][CH:9]=4)=[CH:16][CH:17]=3)[CH2:38][CH2:37]2)=[O:35])=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Reactant: O=S(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCC(S(=O)c2ccc(F)cc2)CC1
Yield: 66.2 %

Procedure:
4-[[7-(Trifluoromethyl)-4-quinolyl]amino]benzoyl chloride hydrochloride (14.7 g) was added slowly to a stirred mixture of 4-[(4-fluorophenyl)sulfinyl]piperidine hydrochloride (10.0 g) and triethylamine (26.4 ml) in dry methylene chloride (440 ml) at room temperature. The resultant mixture was stirred at the same temperature for 3 hours, and concentrated to dryness in vacuo. Water was added to the residue and the precipitated powder was collected by filtration, washed with water, and dried to give a powder. The powder was washed with methylene chloride to give 4-[(4-fluorophenyl)sulfinyl]-1-[4-[[7-(trifluoromethyl)-4-quinolyl]amino]benzoyl]piperidine (13.60 g) as colourless powder.
Reaction SMILES: [C:1]([NH:20][CH2:21][C:22](O)=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([NH:36][C:37]([C@@H:39]3[CH2:43][CH2:42][CH2:41][NH:40]3)=[O:38])[CH:34]=2)[N:29]=[CH:28][N:27]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C)C=O>[NH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([NH:36][C:37]([C@@H:39]3[CH2:43][CH2:42][CH2:41][N:40]3[C:22](=[O:23])[CH2:21][NH:20][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:38])[CH:34]=2)[N:29]=[CH:28][N:27]=1
Reactant: O=C(O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1ncnc2ccc(NC(=O)[C@@H]3CCCN3)cc12
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Nc1ncnc2ccc(NC(=O)[C@@H]3CCCN3C(=O)CNC(c3ccccc3)(c3ccccc3)c3ccccc3)cc12
Temperature: 0 °C
Reaction time: 12 h

Procedure:
N-Tritylglycine (1.58 g, 5.0 mmol) and (2S)-N-(4-amino-6-quinazolinyl)-2-pyrrolidinecarboxamide (1.15 g, 4.5 mmol) were dissolved in 11 mL N,N-dimethylformamide and cooled to 0° C. HOBt (0.770 g, 5.0 mmol) was added and pH was set to 8 with N-methylmorpholine. After 10 minutes EDC (0.978 g, 5.0 mmol) was added and the mixture was stirred for 12 hours. The solvent was evaporated and the crude product was purified with column chromatography using chloroform/methanol (9/1) as eluant.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH3:13][O:14][CH:15]([O:19][CH3:20])N(C)C>CO>[CH3:13][O:14][CH:15]([O:19][CH3:20])[N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH2:8][CH2:9]1
Reactant: c1c[nH]c(CC2CCNCC2)n1
Reactant: COC(OC)N(C)C
Solvent: CO
Product: COC(OC)N1CCC(Cc2ncc[nH]2)CC1

Procedure:
The free base of 4-(1H-imidazol-2-yl-methyl)piperidine (1.0 g, 0.006M) and dimethylformamide dimethylacetal (15 ml) in methanol (20 ml) were heated at 90° C. for 8 hrs. The excess of dimethylformamide dimethylacetal was removed at the reduced pressure to give 4-(1H-imidazol-2-yl-methyl)piperidine carboxaldehyde dimethylacetal. To the mixture of 6-aminopenicillanic acid (1.16 g, 0.0054M) and diisopropyl ethylamine (0.96 ml) in dry chloroform (20 ml) was added the solution (10 ml CHCl3 and 2 ml MeOH) of the above piperidine carboxaldehyde dimethylacetal at 0° C. The reaction was stirred at 0° C. for 1 hr. and then at room temperature for 3 hrs. After this period, the solvent was removed in vacuo and the residue dissolved in water (20 ml). The aqueous solution, washed with ethylacetate was acidified to pH 3 with dilute aqueous HCl and purified on Sephadex LH 20 columns to give [2 S-(2alpha,5alpha,6beta)]-3,3-dimethyl-6-[[[4-(1H-imidazol-2-yl-methyl)-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride (0.84 g, 33%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)O1.Br[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([C:24]2[S:28][C:27]([N:29]([CH3:40])[CH:30]3[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]3)=[N:26][N:25]=2)=[C:18]([F:41])[CH:17]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:41][C:18]1[CH:17]=[C:16]([C:9]2[CH:13]=[N:12][NH:11][CH:10]=2)[CH:21]=[C:20]([O:22][CH3:23])[C:19]=1[C:24]1[S:28][C:27]([N:29]([CH3:40])[CH:30]2[CH2:35][C:34]([CH3:36])([CH3:37])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)=[N:26][N:25]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COc1cc(Br)cc(F)c1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2cn[nH]c2)cc(F)c1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Temperature: 120 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
Pd(Ph3P)4 (11 mg, 0.009 mmol) was added to a stirred suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (55 mg, 0.282 mmol) and 5-(4-bromo-2-fluoro-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (86 mg, 0.188 mmol) in dioxane (1.5 mL), followed by a solution of NaHCO3 (60 mg, 0.564 mmol) in water (0.375 mL). The reaction mixture was purged with nitrogen, sealed, and heated at 120° C. under microwave irradiation for 1 hour. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO3(aq) (10 mL). The organic phase was separated and SiliaMetS-DMT (0.61 mmol/g, 145 mg, 0.09 mmol) was added. The resulting suspension was stirred at room temperature for ˜2 hours then filtered. The filtrate was concentrated in vacuo to afford the crude product as a light brown oil. The crude material was purified by UV directed preparative HPLC under basic conditions (NH4OH modified), collecting at 328 nm to afford the title compound as a white solid (26 mg, 32% yield). LC-MS: Rt 0.76 min; MS m/z 445.5 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.09 (br. s., 1H), 8.26 (br. s., 2H), 7.23-7.31 (m, 2H), 4.27-4.37 (m, 1H), 3.93 (s, 3H), 2.98 (s, 3H), 1.62 (dd, J=11.87, 3.28 Hz, 2H), 1.42 (t, J=12.13 Hz, 2H), 1.20 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[NH:8][C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].[N+:24]([O-])([OH:26])=[O:25].O>C(OC(=O)C)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[NH:8][C:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:10]([N+:24]([O-:26])=[O:25])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c(=O)c1C(=O)OCC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC(=O)c1c([N+](=O)[O-])c(-c2ccccc2)[nH]c(=O)c1C(=O)OCC
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
In 13 ml of acetic anhydride was suspended 5.0 g of 3,4-diethoxycarbonyl-6-phenyl-2-pyridone; and the suspension was cooled to -10° C. Fuming nitric acid (1.32 ml; 2.0 eq.) was added dropwise over 1 hour, and the mixture was stirred for 45 minutes as it is. After 40 ml of water was added, the mixture was stirred at room temperature and left standing overnight. The resulting crystals were collected by filtration and dried. Yield: 4.61 g (80.7%). The crystals were recrystallized from ethanol, to give pale yellow needles.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[S:24][N:23]=[C:22]([CH3:25])[CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:32]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[S:24][N:23]=[C:22]([CH3:25])[CH:21]=2)[C:14]([C:17]([NH2:18])=[O:32])=[N:15][CH:16]=1
Reactant: Cc1cc(Nc2nc(N[C@@H]3CCCC(F)(F)[C@@H]3N)cnc2C#N)sn1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2nc(N[C@@H]3CCCC(F)(F)[C@@H]3N)cnc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (74 mg, 0.257 mmol), 3-methylisothiazol-5-amine hydrochloride (50 mg, 0.332 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 5 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(3-methylisothiazol-5-ylamino)pyrazine-2-carbonitrile (80 mg). The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(3-methylisothiazol-5-ylamino)pyrazine-2-carbonitrile (80 mg, 0.219 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (44 mg). MS 384.2 (M+H); UV 209.0, 270.7, 321.3 nm; t 0.362 min.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:49])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([OH:48])([CH3:47])[CH3:46])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:49])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([OH:48])([CH3:47])[CH3:46])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(-c2cccc(C(C)(C)O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2cccc(C(C)(C)O)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
A mixture of hydroxylammonium chloride (0.6 g), sodium hydrogen carbonate (0.92 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-1-[3-(1-hydroxy-1-methylethyl)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.54 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.19 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.33 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH2:6])=[O:5].C([Li])CCC.Cl[C:18](OC1C=CC([N+]([O-])=O)=CC=1)=[O:19].[NH2:30][C:31]1[CH:36]=[N:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=2)=[C:33]([CH3:44])[N:32]=1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:6][C:18]([NH:30][C:31]1[CH:36]=[N:35][C:34]([C:37]2[CH:38]=[CH:39][C:40]([Br:43])=[CH:41][CH:42]=2)=[C:33]([CH3:44])[N:32]=1)=[O:19])=[O:5]
Reactant: Cc1nc(N)cnc1-c1ccc(Br)cc1
Reactant: NC(=O)c1c(Cl)cccc1Cl
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)NC(=O)c2c(Cl)cccc2Cl)cnc1-c1ccc(Br)cc1
Temperature: -72 °C
Reaction time: 3 h

Procedure:
A solution of 304 mg. of 2,6-dichlorobenzamide and 25 ml. of dry tetrahydrofuran was placed in a 3-necked, 50 ml. round bottomed flask. With mechanical stirring and under nitrogen the solution was cooled to about -72° C. in a dry ice/acetone bath. To this solution was added 0.6 ml. of n-butyllithium reagent over a period of 5 minutes. After the addition was complete, the mixture was stirred for 30 minutes at about -72° C. A solution of 268 ml. of 4-nitrophenyl chloroformate in 8 ml. of dry tetrahydrofuran was added dropwise over a period of 15 to 20 minutes. A pale yellow solution formed. After the addition was complete, the mixture was stirred for 30 minutes at about -72° C. giving a colorless solution. The cooling bath was adjusted so that the temperature was raised to between -40° C. and -30° C. and stirring was continued for 3 hours. The mixture was recooled to approximately -72° C. and a solution of 351 mg. of 2-amino-5-(4-bromophenyl)-6-methylpyrazine in 6 ml. of dry tetrahydrofuran was added dropwise over a period of 10 minutes. The cooling bath was removed allowing the mixture to warm to room temperature. The mixture was then heated at 50° C. for 16 hours to complete the reaction. The solvent was removed in vacuo and the residue was taken up in ethyl acetate. The ethyl acetate solution was washed 5 times with aqueous sodium carbonate solution and twice with salt water. The solvent was again evaporated and the residue dissolved in 2 ml. of tetrahydrofuran and chromatographed over silica gel using 4:1 benzene/tetrahydrofuran. The product from chromatography was dissolved in tetrahydrofuran and the solution concentrated in vacuo to an oil. Ether was added and the solution was cooled to precipitate in 2 crops 240 mg. of product. Recrystallization from tetrahydrofuran/ether yielded 132 mg. of product, m.p. 225°-227° C. An additional 69 mg. of product was obtained from the filtrate by preparative thin-layer chromatography.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:7])([CH2:5][OH:6])[CH3:4].[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1Cl)([O-:10])=[O:9].[OH-:18].[Na+]>CS(C)=O>[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:1][CH2:2][C:3]([CH3:7])([CH3:4])[CH2:5][O:6][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N+:8]([O-:9])=[O:18])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: CC(C)(CO)CO
Reactant: [OH-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(COc1ccccc1[N+](=O)[O-])COc1ccccc1[N+](=O)[O-]

Procedure:
104 g (1 mol) neopentyl glycol, 346.5 g (2.2 mols) 2-nitrochlorobenzene and 140 g powdered sodium hydroxide were reacted following the procedure described in Example 1 in 600 ml DMSO.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][CH:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[NH2:23][C:24]1[C:29]2[N:30]=[CH:31][N:32]([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[C:28]=2[C:27]([CH3:38])=[C:26]([CH3:39])[N:25]=1.C(N(CC)CC)C.O>CN(C)C=O.CN(C)C1C=CN=CC=1>[NH2:23][C:24]1[C:29]2[N:30]=[CH:31][N:32]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:11](=[O:12])[C:10]3[CH:14]=[CH:15][C:7]([CH:6]([O:5][CH2:4][CH2:3][N:2]([CH3:22])[CH3:1])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:8][CH:9]=3)[C:28]=2[C:27]([CH3:38])=[C:26]([CH3:39])[N:25]=1
Reactant: Cc1nc(N)c2ncn(CCCCN)c2c1C
Reactant: CN(C)CCOC(c1ccccc1)c1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)c2ncn(CCCCNC(=O)c3ccc(C(OCCN(C)C)c4ccccc4)cc3)c2c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[[2-(Dimethylamino)ethoxy](phenyl)methyl]benzoyl chloride (1 equivalent) was added dropwise to a suspension of 4-(4-amino-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butan-1-amine (0.22 g) in N,N-dimethylformamide (7 ml). At 1 hour, triethylamine (2 equivalents) was added followed by the addition at 2 hours of a small amount (approx. 10 mole %) of 4-dimethyaminopyridine. The reaction was maintained at room temperature overnight. The resulting mixture was poured into water and the pH was adjusted to 13. The aqueous fraction was extracted with chloroform (3×). The combined organic fractions were sequentially washed with water and brine; dried (magnesium sulfate); filtered; and concentrated to yield a yellow oil. The crude product was submitted to flash column chromatography [30 g silica gel, gradient elution:dichloromethane:methanol triethylamine (100:0:0 to 97:2:1 to 92:7: 1). A final HPLC purification using the method described above provided 83 mg of N-[4-(4-amino-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzamide as a trifluoroacetate salt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:16][C:17](=[O:35])[C@@H:18]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])(=[O:25])=[O:24])[CH2:19][CH:20]=[CH2:21])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.Br[CH2:38][CH2:39]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:36])[C@@H:4]([N:16]1[CH2:39][CH2:38][N:22]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])(=[O:25])=[O:24])[C@@H:18]([CH2:19][CH:20]=[CH2:21])[C:17]1=[O:35])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: BrCCBr
Reactant: C=CC[C@H](NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC[C@H]1C(=O)N([C@@H](Cc2ccc3ccccc3c2)C(=O)OC)CCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
To a solution of (S,S)-3-naphthalen-2-yl-2-[2-(2-nitro-benzenesulfonylamino)-pent-4-enoylamino]-propionic acid methyl ester, 3, (3.6 g, 7.0 mmol) and 1,2-dibromoethane (13.2 g, 70.0 mmol) in DMF (40 mL) is added potassium carbonate (9.6 g, 70.0 mmol). The reaction suspension was stirred at 65° C. for 12 h, quenched with 10% aqueous HCl and extracted with EtOAc. The extract is dried over Na2SO4, concentrated and the residue purified over silica gel (hexanes/EtOAc,1:2) to afford 3.7 g (97% yield) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[N:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[Br:15]N1C(=O)CCC1=O>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]([Br:15])=[N:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: COC(=O)C=NNc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COC(=O)C(Br)=NNc1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
A solution of [(4-chlorophenyl)hydrazono]acetic acid methyl ester (30, 13.0 g, 61.2 mmol) in anhydrous THF (100 mL) was treated with N-bromosuccinimide (NBS, 11.97 g, 67.3 mmol, 1.1 equiv) at 0–5° C. under N2, and the resulting reaction mixture was stirred at 0–5° C. for an additional 30 min. When HPLC and TLC showed the reaction was deemed complete, the solvent removed in vacuo. The residue was directly purified by column chromatography (SiO2, 0–15% EtOAc/hexane gradient elution) to afford the desired bromo[(4-chlorophenyl)hydrazono]acetic acid methyl ester (31, 15.0 g, 17.84 g theoretical, 84%) as pale-yellow solids, which was found to be essentially pure to do the following cycloaddition reaction without further purification. For 31, CIMS m/z 290/292 (M+−H, C9H8BrClN2O2).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[CH2:60]([O:67][C:68]([NH:70][CH2:71][CH2:72][CH2:73][CH2:74][C@H:75]([NH:82][C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[C:76](OCC#N)=[O:77])=[O:69])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>O.O1CCCC1>[CH2:60]([O:67][C:68]([NH:70][CH2:71][CH2:72][CH2:73][CH2:74][C@@H:75]([NH:82][C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[C:76]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:77])=[O:69])[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 18.1 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (65.6 mg, 0.103 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 6-(((benzyloxy) carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk45) (173 mg, 0.412 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (18 mL), and the mixture was stirred at room temperature for 0.75 hour. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk46) (18.6 mg, 18%).