Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=2)[N:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[N:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)nn1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)nn1-c1ccc(O)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a solution of 2-(4-methoxyphenyl)-5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (200 mg, 0.768 mmol, Example 10, Step 1) in methylene chloride (10 mL) at −40° C. was added boron tribromide (2.3 mL). The reaction was allowed to stir for 1 hour at −40° C. and for an additional hour while warming to room temperature. The reaction was quenched with ethanol diluted with water and methylene chloride. The organic layer was dried (MgSO4) and concentrated to give 128 mg of the desired product. LC-MS (C13H14N2O3 calculated 246) m/z 247 (M+H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)[N:28]=[N:27]C=2C=1.O.NN>ClCCl>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:27][NH2:28])=[O:8]
Reactant: O=C(O)[C@H]1CCCO1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: ClCCl
Solvent: O
Product: NNC(=O)[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a round-bottom flask was added a solution of (R)-tetrahydrofuran-2-carboxylic acid (3.00 g, 25.8 mmol, 1.00 equiv) in dichloromethane (60 mL). EDC.HCl (7.37 g, 38.5 mmol, 1.50 equiv), HOBt (5.24 g, 38.8 mmol, 1.50 equiv), and hydrazine hydrate (2.60 g, 51.9 mmol, 2.00 equiv) were added to the reaction. The resulting solution was stirred overnight at 25° C. The solids were removed with filtration. The filtrate was concentrated in vacuo to yield 2.00 g (59%) of (R)-tetrahydrofuran-2-carbohydrazide as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][CH2:8][CH:9]2[C:13](=[O:14])[N:12]([CH:15]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:18])=O)[C:11](=[O:22])[NH:10]2)=[CH:4][CH:3]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:53]([O:60][NH2:61])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.Cl>CN(C=O)C>[CH2:53]([O:60][NH:61][C:16](=[O:18])[CH:15]([N:12]1[C:13](=[O:14])[CH:9]([CH2:8][O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:24][CH:23]=2)[NH:10][C:11]1=[O:22])[CH:19]([CH3:21])[CH3:20])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CC(C)C(C(=O)O)N1C(=O)NC(COCc2ccc(Br)cc2)C1=O
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)NOCc1ccccc1)N1C(=O)NC(COCc2ccc(Br)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a mixture of the compound obtained in step f above (409 mg, 1.020 mmol), NMM (0.4 mL, 3.58 mmol) and HOBt (234 mg, 1.734 mmol) in DMF (10 mL) at −15° C. was added EDCI (214 mg, 1.123 mmol). After the reaction was stirred for 30 minutes, it was allowed to warm to room temperature, BnONH2HCl (179 mg, 1.123 mmol) was then added and the reaction was stirred overnight. The solvent was removed under vacuum; the residue was diluted with EtOAc and washed with brine. The combined organic layers were dried and concentrated; the crude product was purified by silica gel column chromatography which gave the title compound as an oil (426 mg, 83% yield).
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[O:9])[CH3:7])=[O:4].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl.[NH2:45][C@@H:46]([C:48]([NH:50][CH2:51][C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:53])=[O:49])[CH3:47].Cl>CN(C=O)C>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][CH2:11][C:12]([NH:45][C@@H:46]([C:48]([NH:50][CH2:51][C:52]([O:54][CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:53])=[O:49])[CH3:47])=[O:14])=[O:9])[CH3:7])=[O:4]
Reactant: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: C[C@@H](N)C(=O)NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@H](C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
To a solution of Boc-Gly-Ala-Gly prepared as in Example 34B (11.0 g, 36.5 mmol) in anhydrous DMF (270 ml), was added HOBT.H2O (5.46 g, 40.4 mmol), EDC.HCl (7.74 g, 40.4 mmol), and DAla-Gly-OBzl .HCl prepared as in Example 34A (9.95 g, 36.5 mmol). The pH of the resulting solution was adjusted to ~8 (measured by spotting the reaction mixture on moistened Hydrion paper) and the reaction mixture was allowed to stir at room temperature for 12 h thereafter. The solution was concentrated in vacuo and the residue was dissolved in water (50 ml). This solution was extracted with ethyl acetate (3×100 ml). The combined ethyl acetate layers were washed with 1N sodium bisulfate (50 ml), saturated sodium bicarbonate (50 ml) and brine (50 ml). The ethyl acetate solution was dried (magnesium sulfate), filtered and allowed to sit for 12 h undisturbed. Collection of the crystals by filtration and drying at high vacuum afforded 13.4 g (70% yield) of pure product: 1H NMR (DMSO-d6) δ 1.22 (d, J=7.2 Hz, 3 H), 1.23 (d, J=7.2 Hz, 3 H), 1.38 (s, 9 H), 3.58 (d, J=6.0 Hz, 2 H), 3.73 (d, J=4.8 Hz, 2 H), 3.91 (dd, J=6.0, 3.0 Hz, 2 H), 4.32 (m, 2 H), 5.14 (s, 2 H), 6.91 (t, J=4.8 Hz, 1 H), 7.38 (s, 5 H), 7.97 (d, J=8.1 Hz, 1 H), 8.02 (d, J=6.9 Hz, 1 H), 8.19 (t, J=5.4 Hz, 1 H), 8.33 (t, J=5.4 Hz, 1 H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Cl:10])=[CH:5][CH:4]=1.[OH:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].C(N(CC)CC)C>C(#N)C>[Cl:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:11][N:12]2[C:13](=[O:22])[C:14]3=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]3[C:16]2=[O:17])=[CH:4][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1ccc(CCl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1OCc1ccc(CCl)cc1
Temperature: 0 °C
Yield: 59.2 %

Procedure:
A mixture of 1,4-bis(chloromethyl)benzene (25 g.), N-hydroxyphthalimide (23.4 g.) and triethylamine (14.5 g.) in acetonitrile (200 ml.) was heated under reflux for 1.5 hours. The reaction mixture was poured into ice-water (1 l.) and the precipitates were collected by filtration. The precipitates were washed with ethanol and dried to give N-(4-chloromethylbenzyloxy)phthalimide (25.5 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[C:12]([OH:14])=O.[CH3:15][N:16]([CH3:34])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:34])[C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:27][CH:26]=2)[C:12]([CH:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)=[O:14])=[CH:21][CH:22]=1
Reactant: COc1cccc2c1CCC2C(=O)O
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: COc1cccc2c1CCC2C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1
Yield: 53.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 4-methoxyindan-1-carboxylic acid (0.20 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.27 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-4-methoxyindan-1-carboxamide (0.24 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[N:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([O:27]C(=O)CC(=O)C(NC(OC(C)(C)C)=O)C1CCOC1)C>>[CH2:18]([O:17][C:15](=[O:16])[C:14]1[CH:20]=[C:21]([Cl:24])[CH:22]=[N:23][C:13]=1[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:10]1[CH2:11][CH2:25][O:27][CH2:12]1)[CH3:19]
Reactant: CCOC(=O)c1cc(Cl)cnc1[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reactant: CCOC(=O)CC(=O)C(NC(=O)OC(C)(C)C)C1CCOC1
Product: CCOC(=O)c1cc(Cl)cnc1C(NC(=O)OC(C)(C)C)C1CCOC1

Procedure:
Procedure same as that for ethyl(S)-2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloronicotinate, using ethyl4-((tert-butoxycarbonyl)amino)-3-oxo-4-(tetrahydrofuran-3-yl)butanoate as a starting material. 1H NMR (CD3OD, 400 MHz): δ 8.73 (s, 1H), 8.24 (s, 1H), 5.66 (d, J=8.0 Hz, 1H), 4.61 (s, 1H), 4.45 (q, J=6.8 Hz, 2H), 3.92-3.86 (m, 1H), 3.82-3.56 (m, 3H), 2.82-2.86 (m, 1H), 1.95 (q, J=7.2 Hz, 1H), 1.74 (q, J=6.8 Hz, 1H), 1.44 (t, J=7.2 Hz, 3H), 1.40 (d, J=6.8 Hz, 9H).
Reaction SMILES: [CH3:1][N:2]([C@H:21]([CH3:26])[C:22]([O:24]C)=[O:23])[C:3](=[O:20])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH3:5].[Li+].[OH-].Cl.CCOC(C)=O>C1COCC1>[CH3:1][N:2]([C@H:21]([CH3:26])[C:22]([OH:24])=[O:23])[C:3](=[O:20])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH3:5]
Reactant: COC(=O)[C@@H](C)N(C)C(=O)C(C)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C(=O)N(C)[C@H](C)C(=O)O)c1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a solution of methyl 2-[N-methyl-N-((R/S)-α-methyl-4-benzyloxyphenylacetyl)amino]-(R)-propionate 45c (380 mg, 1.1 mmol) in THF (10 mL) was added 1 N LiOH (2 mL). The solution was stirred for 1 h and acidified with 1 N HCl to pH 3. EtOAc was added and the organic layer was separated, washed with brine, dried (MgSO4) and concentrated to afford the carboxylic acid (360 mg, 98%) as a solid. MS (CI—NH3): (M+H)+=342.
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])[C:6]([C:17](F)(F)F)=[CH:5]1)(=O)C.[NH3:21]>O1CCOCC1>[Cl:16][C:10]1[C:11]([Cl:15])=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]([C:17]#[N:21])=[CH:5][NH:4][CH:8]=1
Reactant: N
Reactant: CC(=O)n1cc(-c2cccc(Cl)c2Cl)c(C(F)(F)F)c1
Solvent: C1COCCO1
Product: N#Cc1c[nH]cc1-c1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
6.4 g of N-acetyl-4-(2,3-dichlorophenyl)-3-trifluoromethylpyrrole, 15 ml of 25% aqueous ammonia solution and 60 ml of dioxane are stirred for 18 hours at 160° C. in an autoclave. The reaction mixture is cooled to room temperature and filtered, and the clear filtrate is concentrated by evaporation. The viscous residue is dissolved in ethyl acetate; the solutiion is washed firstly with water and then with a diluted sodium chloride solution; it is subsequently dried over sodium sulfate, filtered, and concentrated by evaporation. To the residue is added n-hexane, and the crystals which precipitate are filtered off and dried. The yield is 5.3 g of 4-(2,3-dichlorophenyl)-3-cyanopyrrole, m.p. 149°-150° C.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[S:2].[Na+:6].[Na+].[I-].[Na+].Cl[CH2:11][CH2:12][N:13]1[C:18]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH:14]1[CH3:24].O>C(O)C>[S:1]([O-:5])([S:2][CH2:11][CH2:12][N:13]1[C:18]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH:14]1[CH3:24])(=[O:4])=[O:3].[Na+:6]
Reactant: O=S([O-])([O-])=S
Reactant: Cc1ccc2c(c1)N(CCCl)C(C)CO2
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)N(CCSS(=O)(=O)[O-])C(C)CO2

Procedure:
Sodium thiosulfate (0.2 m), sodium iodide (1 g), N-(2-chloroethyl)-3,6-dimethyl-2H-1,4-benzoxazine, water (150 ml), and ethanol (75 ml) were mixed and heated at reflux for 3 hrs. The alcohol was distilled off and the reaction mixture was cooled. The product, a white solid, was collected by filtration and dried in air. The yield was essentially quantitative. Preparation of the Dyes
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].C(OCC)(=O)C>C(#N)C>[Si:20]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1

Procedure:
3-Hydroxybenzaldehyde (5.0 g, 40.9 mmol) was dissolved in acetonitrile (10.0 mL). Subsequently, potassium carbonate (11.3 g, 81.9 mmol), and then tert-butyldimethylchlorosilane (7.4 g, 49.1 mmol) were added thereto, and the resultant mixture was stirred at room temperature. After completion of reaction, ethyl acetate was added thereto, followed by washing sequentially with water and brine, and drying over anhydrous sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=20/1), whereby the target compound was obtained (9.1 g, 94%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C[Al](C)C.[CH2:10]([O:12][C:13]1[C:14]([C:25]([O:27]CC)=O)=[N:15][N:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:17]=1)[CH3:11]>>[CH2:10]([O:12][C:13]1[C:14]([C:25]([N:3]([O:4][CH3:5])[CH3:2])=[O:27])=[N:15][N:16]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[N:17]=1)[CH3:11]
Reactant: CNOC
Reactant: CCOC(=O)c1nn(-c2ccc(F)cc2)nc1OCC
Agent: C[Al](C)C
Agent: Cl
Product: CCOc1nn(-c2ccc(F)cc2)nc1C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an oven-dried flask under a nitrogen atmosphere was added N,O-dimethylhydroxylamine hydrochloride (2.8 g, 28.6 mmol) to which a solution of trimethylaluminum (2.0 M in toluene, 14.3 mL, 28.6 mmol) was added at 0° C. and stirred for 30 min. Ethyl 5-ethoxy-2-(4-fluorophenyl)-2H-1,2,3-triazole-4-carboxylate (i.e. the product of Step A, 4.0 g, 14.3 mmol) was added and the resulting solution was stirred at 23° C. for 4 h. The reaction mixture was cooled to 0° C. and carefully quenched by the dropwise addition of water (2 mL). Dichloromethane, (50 mL), sodium sulfate and water (3 mL) were added sequentially to the mixture which was then stirred for 20 min. at 23° C. The mixture was dried (Na2SO4 and MgSO4) and concentrated under reduced pressure to obtain the title compound (3.7 g) as an orange solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=O)([O-:3])=[O:2].S(Cl)(Cl)=O.[F:20][C:21]([F:29])([F:28])[C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([NH:27][C:24]1[S:25][CH:26]=[C:22]([C:21]([F:29])([F:28])[F:20])[N:23]=1)=[O:9])([O-:3])=[O:2]
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1nc(C(F)(F)F)cs1)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
A mixture of 3,4-dinitrobenzoic acid (1.78 g, 8.4 mmol) and thionyl chloride was stirred for 2 h at reflux. The mixture was concentrated i.vac., toluene and 4-trifluoromethyl-thiazol-2-ylamine (1.49 g, 8.4 mmol) were added and the mixture was stirred at 120° C. for 3 days. Then the mixture was filtered and dried i.vac.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4]([NH:20][CH2:17][CH2:18][CH3:19])[N:3]=1
Reactant: CCC(CC)n1cnc2c(Cl)nc(Cl)nc21
Reactant: CCCN
Solvent: CCCCO
Product: CCCNc1nc(Cl)nc2c1ncn2C(CC)CC
Reaction time: 5 h

Procedure:
The operation is carried out as in Stage 2 of Example 3 from 200 mg of the product obtained in Stage 1 of Example 3 and 4 ml of butanol and using 0.129 ml of propylamine in place of the benzylamine. Agitation is carried out at ambient temperature then the reaction medium is taken to a temperature of 80 to 85° C. for 5 hours, left to return to ambient temperature, followed by evaporating to dryness then impasting in 5 ml of pentane at ambient temperature, separating, washing and drying at a temperature of approximately 50° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 90/10, 145 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH:11]=O)[C:6]=2[C:5]([F:13])=[C:4]([F:14])[CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:21]O.C(OC(=O)C)(=O)C>C(O)(=O)C>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([C:11]#[N:21])[C:6]=2[C:5]([F:13])=[C:4]([F:14])[CH:3]=1
Reactant: NO
Reactant: O=Cc1coc2c(Br)cc(F)c(F)c12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: N#Cc1coc2c(Br)cc(F)c(F)c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
The compound (360 mg, 1.38 mmol) obtained in Step 3 was dissolved in acetic acid (5 mL), and sodium acetate (450 mg, 5.5 mmol) and hydroxylamine hydrochloride (140 mg, 2.1 mmol) were added thereto, and stirred at 60° C. for 2 hours. After that, acetic anhydride (0.26 mL, 2.75 mmol) was added thereto, and stirred at 100° C. for 2 hours. After cooling, the solvent was distilled away, and the resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:28])[CH2:16][CH:15]([OH:17])[CH2:14][C:13]([CH3:19])([CH3:18])[N:12]1[N:20]=[N:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:18][C:13]1([CH3:19])[CH2:14][CH:15]([O:17][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][C:11]([CH3:10])([CH3:28])[N:12]1[N:20]=[N:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)CC(O)CC(C)(C)N1N=Nc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1N=Nc1ccccc1
Temperature: 23 °C
Reaction time: 4 h

Procedure:
2.15 ml Benzoylchloride are dropwise added to a solution of 4.42 g 2,2,6,6-tetramethyl-1-phenyldiazenyl-piperidin-4-ol (see example 1) and 0.1 g 4-dimethylaminopyridine in 35 ml pyridine. The resulting mixture is stirred 4 hours at 23° C., then diluted with 300 ml ice-water. The precipitate is filtered off and recrystallized twice from methanol to afford 4.43 g of benzoic acid 2,2,6,6-tetramethyl-1-phenyldiazenyl-piperidin-4-yl ester as an off-white solid, m.p. 89-91° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:12][O:13]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][N:4]1[CH:11]=[N:10][C:8]([NH2:9])=[N:7][C:5]1=[O:6].S(O[CH2:44][P:45](=[O:54])([O:50]C(C)C)[O:46]C(C)C)(C1C=CC(C)=CC=1)(=O)=O.[H-].[Na+].Br[Si](C)(C)C>CN(C=O)C.C(O)(=O)C>[OH:13][CH2:12][C@@H:2]([O:1][CH2:44][P:45]([OH:54])([OH:50])=[O:46])[CH2:3][N:4]1[CH:11]=[N:10][C:8]([NH2:9])=[N:7][C:5]1=[O:6]
Reactant: Cc1ccc(S(=O)(=O)OCP(=O)(OC(C)C)OC(C)C)cc1
Reactant: Nc1ncn(C[C@H](O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)n1
Agent: C[Si](C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Nc1ncn(C[C@@H](CO)OCP(=O)(O)O)c(=O)n1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A solution of 1-[(2S)-2-hydroxy-3-(triphenylmethoxy)propyl]-5-azacytosine (934 mg, 2.18 mmol) and diisopropyl tosyloxymethylphosphonate (1.05 g, 3 mmol) in DMF (30 ml) was cooled to −20° C. and 60% oil dispersion of NaH (240 mg, 6 mmol) was added. The mixture was stirred at −20° C. for 15 min, then the temperature was let to rise to approx. 25° C. (room temperature) and the stirring continued for additional 15 h. Acetic acid was added drop wise to pH 7, the mixture evaporated and the residue coevaporated with toluene (2×50 ml). Acetonitrile (30 ml) was added, followed by bromotrimethylsilane (2.7 ml, 20 mmol), the resulting suspension stirred in dark at room temperature for 48 h and evaporated. The residue was coevaporated with acetonitrile (3×50 ml). 90% Aqueous solution of methanol (50 ml) was added and the solution neutralized to pH 7.0 with 0.2 M triethylammonium hydrogencarbonate. The solution was concentrated to minimal volume (approx. 5 ml) and partitioned between water (100 ml) and ether (100 ml). An aqueous layer was concentrated to a volume 5 ml and applied onto a column of Dowex 1 (AcO− form, 60 ml). Elution was performed with water (300 ml), then with a linear gradient of acetic acid (0.5-1 M, 1 l) and lastly, the pure product was eluted with 1 M formic acid. UV absorbing fractions were taken down in vacuo and the residue coevaporated several times with water till a complete removal of acid. The residue was crystallized from aqueous ethanol, crystals collected by suction, washed with ethanol and ether and dried in vacuo. Yield: 200 mg (33%) of pure HPMP-5-azaC.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:4]2=[C:3]([C:10]([NH2:12])=O)[CH:2]=1.C(=O)([O-])O.[Na+].[OH-].[Na+]>P(Cl)(Cl)(Cl)=O>[N:1]1[N:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:4]2=[C:3]([C:10]#[N:12])[CH:2]=1
Reactant: NC(=O)c1cnn2ccncc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cnn2ccncc12
Yield: 52.4 %

Procedure:
A suspension of crude pyrazolo[1,5-a]pyrazine-3-carboxamide (Preparation 24a, 6.66 g) in phosphoryl trichloride (80 mL) was heated to reflux for 2.5 hours. The reaction mixture was then poured onto a saturated aqueous sodium hydrogen carbonate solution (200 mL) and then the pH was adjusted to 7-8 by addition of a 10% aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, the organic layer was dried (MgSO4) and evaporated and the resulting residue was purified by flash chromatography (1:1 hexanes/ethyl acetate) to give the title compound (3.10 g, 52%) as a yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:5][C:4]=1[CH3:21])=O.[CH3:22][C:23]1([CH2:29][OH:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:30][CH2:29][C:23]1([CH3:22])[CH2:28][CH2:27][N:26]([CH2:1][C:3]2[CH:20]=[CH:19][C:6]([O:7][CH:8]3[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]3)=[CH:5][C:4]=2[CH3:21])[CH2:25][CH2:24]1
Reactant: CC1(CO)CCNCC1
Reactant: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1CN1CCC(C)(CO)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.4 %

Procedure:
To a solution of 69A (3.00 g, 10.3 mmol) in DCM (50 mL) was added (4-methylpiperidin-4-yl)methanol (2.56 g, 15.5 mmol) followed by DIPEA (3.60 mL, 20.6 mmol). The reaction mixture was stirred at RT for 20 min and then sodium triacetoxyborohydride (6.55 g, 30.9 mmol) was added. The mixture was stirred at RT overnight and then washed with a saturated aqueous solution of Na2CO3. The aqueous layer was extracted several times with DCM. The organic layers were filtered through a phase separator and then evaporated. There was obtained 3.1 g (74%) of the product as an oil. 1H NMR (500 MHz, CDCl3): δ 0.95 (s, 3H), 1.33 (m, 2H), 1.45 (s, 9H), 1.51 (m, 2H), 2.26 (m, 2H), 2.30 (s, 3H), 2.51 (m, 2H), 3.38 (s, 2H), 3.39 (s, 2H), 3.99 (m, 2H), 4.27 (m, 2H), 4.84 (m, 1H), 6.48 (dd, 1H), 6.56 (d, 1H), 7.16 (d, 1H), MS (APCI+) m/z 405 [M+H]+.