Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[CH:15][C:14](=[O:26])[C:10]([C:11]([OH:13])=[O:12])=[CH:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34]([O:40][CH2:41][CH2:42]I)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([C:17]3[CH:18]=[CH:19][C:20]([N:23]([CH3:24])[CH3:25])=[CH:21][CH:22]=3)=[CH:15][C:14](=[O:26])[C:10]([C:11]([O:13][CH:41]([O:40][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH3:42])=[O:12])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CN(C)c1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(F)cc2)cc1
Reactant: CC(C)(C)C(=O)OCCI
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(OC(=O)c1cn(-c2ccc(F)cc2)c(-c2ccc(N(C)C)cc2)cc1=O)OC(=O)C(C)(C)C
Yield: 44 %

Procedure:
In 10 ml of chloroform was dissolved 1 g of 1-(4-fluorophenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinic acid, and to the resulting solution were then added 0.32 g of triethylamine and 0.76 g of pivaloyloxyethyl iodide at room temperature, after which the resulting mixture was subjected to reaction at the same temperature for 2 hours. After completion of the reaction, the reaction mixture was washed successively with 20 ml of a 0.1N aqueous sodium hydroxide solution and 20 ml of water and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation under reduced pressure, and to the residue was added 20 ml of a diethyl ether/n-hexane (1:1 by volume) mixed solvent, after which insolubles were removed by filtration to obtain 0.6 g of 1-pivaloyloxyethyl 1-(4-fluorophenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinate having a melting point of 117°-120° C.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][C:6]1[CH:20]=[CH:19][C:9]([S:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15]O)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1>CCOCC>[CH3:5][C:6]1[CH:20]=[CH:19][C:9]([S:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][Br:2])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1
Reactant: Cc1ccc(Sc2ccc(CO)cc2)cc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: Cc1ccc(Sc2ccc(CBr)cc2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 183.9 %

Procedure:
To a stirred mixture of phosphorus tribromide (1.20 g, 4.43 mM) and dry ether (100 ml) was added a solution (20 ml) of 4-(4-methylthiophenoxy)benzyl alcohol (3.00 g, 12.1 mM) in dry ether at the room temperature, and the mixture was stirred for 12 h at the same temperature. The mixture was poured into ice water, and the mixture was extracted with ether. The extract was washed with saturated sodium hydrogen carbonate solution and brine, dried with magnesium sulfate, and concentrated in vacuo to give 4-(4-methylthiophenoxy)benzyl bromide (2.39 g, 64%) as colorless crystals, m.p.32.9° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[O:15])=[C:9]3[N:8]=[C:7]([C:16]3[CH:17]=[CH:18][C:19]([F:25])=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH:6]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[O:15])=[C:9]3[N:8]=[C:7]([C:16]3[CH:17]=[CH:18][C:19]([F:25])=[C:20]([C:21]([N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[O:22])[CH:24]=3)[CH:6]=2)[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(F)c(C(=O)O)c3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(F)c(C(=O)N4CCOCC4)c3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)-2-fluorobenzoic acid (75 mg, 0.22 mmol 0 in DMF (3 mL) was added EDCI (46 mg, 0.24 mmol), HOBt (33 mg, 0.24 mmol), and morpholine (21 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed 1× with saturated sodium bicarbonate, 2× with brine, dried over MgSO4, filtered and evaporated to dryness to provide 92 mg of 7-(cyclopropylamino)-5-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1=410)
Reaction SMILES: [O-]Cl=O.[Na+].[CH2:5]([O:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[C:16]([F:22])[CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(=O)(=O)([OH:26])N.Cl>O.CC#N>[CH2:5]([O:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:26])=[O:21])=[C:16]([F:22])[CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)cc1F
Reactant: NS(=O)(=O)O
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(C(=O)O)c(F)c1
Reaction time: 1 h

Procedure:
A solution of 80% NaClO2 (0.19 mol) in H2O (100 mL) is added dropwise to a solution of crude 3-fluoro-4-formyl benzoic acid benzyl ester (6, 0.19 mol) and sulfamic acid (0.19 mol) in H2O (300 mL) and CH3CN (150 mL). After stirring for 1 h, the reaction mixture is poured into 1 N HCl and extracted three times with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, and evaporated in vacuo. Crystals are collected by filtration and washed with ether/hexane (1:1) to give 2-fluoroterephthalic acid 4-benzyl ester (7) as white solid.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([N:15]=[C:16]=[O:17])[CH2:12][CH2:13][CH3:14]>>[CH2:11]([NH:15][C:16]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]1=[S:1])=[O:17])[CH2:12][CH2:13][CH3:14]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCCCN=C=O
Product: CCCCNC(=O)n1c(=S)[nH]c2ccccc21
Temperature: 135 °C
Yield: 89.4 %

Procedure:
The mixture of 2-mercaptobenzimidazole (29.30 g, 0.195 mole) and butyl isocyanate (48.3 mL, 0.33 mole) in a 500 ml of round-bottom flask equipped with a condenser was heated to 130-140° C. in an oil bath for 45 min. After the reaction mixture was cooled to room temperature, the solid was filtered, washed with hexane, and dried under vacuum to give 43.48 g (89%) of 1-(butylcarbamoyl)-1,3-dihydrobenz-imidazole-2-thione as white crystals: mp 179-180° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH2:16])([C:13]([OH:15])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[CH3:17][O:14][C:13]([C:10]1([NH2:16])[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(=O)O)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1(N)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 102.6 %

Procedure:
In a round-bottomed flask 3-aminopyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (0.20 g, 0.87 mmol) was dissolved in dichloromethane (3.2 mL) and MeOH (1.6 mL). (Trimethylsilyl)diazomethane (2.0 M in hexanes, 0.75 mL, 1.5 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with a small portion of acetic acid and concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated aqueous Na2CO3. The aqueous layer was extracted with dichloromethane and the combined organics were dried over Na2SO4 and concentrated to afford 0.218 g of 3-amino-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:17]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:8]([O:10][CH3:17])=[O:9])=[N:6][CH:7]=1
Reactant: CO
Reactant: Cc1cc(O)cnc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ncc(O)cc1C
Temperature: 95 °C
Reaction time: 24 h

Procedure:
A sealable reaction vessel was charged with 5-hydroxy-3-methylpicolinic acid (0.651 g, 4.25 mmol) and MeOH (35 mL). The reaction vessel was placed in a water bath, and concentrated sulfuric acid (0.854 mL, 15.94 mmol) was added. The vessel was sealed and heated in a 95° C. oil bath. After 24 h, the reaction mixture was concentrated and the residue was taken up in 30 mL of 0.5M aqueous Na2CO3. The aqueous phase was extracted with 10% MeOH-EtOAc (100 mL). The aqueous layer was separated and saturated with NaCl. The aqueous phase was extracted with 10% MeOH-EtOAc (7×100 mL). The combined organic fractions were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography, eluting with 3% to 4% MeOH-DCM to afford the title compound (593 mg). MS m/z=168 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:22])=[C:11]([CH3:21])[C:12]2[O:17][C:16]([CH3:19])([CH3:18])[O:15][CH2:14][C:13]=2[CH:20]=1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[CH3:18][C:16]1([CH3:19])[O:15][CH2:14][C:13]2[CH:20]=[C:9]([OH:8])[C:10]([CH3:22])=[C:11]([CH3:21])[C:12]=2[O:17]1
Reactant: [H][H]
Reactant: Cc1c(OCc2ccccc2)cc2c(c1C)OC(C)(C)OC2
Agent: [Pd]
Solvent: CCO
Product: Cc1c(O)cc2c(c1C)OC(C)(C)OC2
Yield: 89.4 %

Procedure:
To a solution of 6-benzyloxy-2,2,7,8-tetramethyl-4H-benzo[1,3]dioxine (86 mg, 0.29 mmol) in 10 mL EtOH was added Pd/C (15 mg, 10%). It was stirred in a hydrogen atmosphere for 1.5 h and filtered. The solution was concentrated and the crude product was purified on silicagel column chromatography to afford 2,2,7,8-tetramethyl-4H-benzo[1,3]dioxin-6-ol as a white solid (54 mg). 1H-NMR (CDCl3, 300 MHz) δ (ppm): 6.28 (s, 1H), 4.77 (s, 1H), 4.76 (s, 2H), 2.17 (s, 3H), 2.13 (s, 1H), 1.55 (s, 3H), 1.54 (s, 3H); 13C-NMR δ (ppm): 147.1, 142.9, 126.1, 122.7, 116.6, 107.5, 99.1, 60.9, 24.8, 11.9, 11.5.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1O>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:8][C:11]2[CH:12]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:18]=[CH:19][C:10]=2[N:9]=1
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: O=C(O)c1cccs1
Product: COC(=O)c1ccc2nc(-c3cccs3)oc2c1

Procedure:
Preparation is carried out analogously to 4.1.a from thiophene-2-carboxylic acid and methyl 4-amino-3-hydroxybenzoate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:17][OH:18])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)=[N:4][O:5][N:6]=1.C(N(CC)C(C)C)(C)C.[CH2:28]([N:35]=[C:36]=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[NH2:1][C:2]1[C:3]([C:7](=[N:17][O:18][C:36]([NH:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:37])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)=[N:4][O:5][N:6]=1
Reactant: Nc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Reactant: O=C=NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nonc1C(=NOC(=O)NCc1ccccc1)Nc1ccc(F)c(Cl)c1
Reaction time: 3 h
Yield: 24.7 %

Procedure:
A solution of 4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (50 mg, 0.18 mmol) and N,N-diisopropylethylamine (64 μL, 0.37 mmol) in dichloromethane (2 mL) was treated with benzyl isocyanate (29 mg, 0.22 mmol) and stirred for 3 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (18 mg, 24%). LCMS for C17H15ClFN6O3 (M+H)+: m/z=405.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:14]([N:21]([S:28](Cl)(=[O:30])=[O:29])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C(Cl)Cl>[CH2:14]([N:21]([S:28]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)(=[O:29])=[O:30])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)Cl
Reactant: C1COCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)N1CCOCC1
Yield: 6 %

Procedure:
A solution of morpholine (1.05 ml, 12 mmol) and triethylamine (1.84 ml, 12 mmol) in methylene chloride (10 ml) was added to a solution of ethyl 2-[benzyl-(chlorosulfonyl)amino]acetate (2.3 g, 8.3 mmol), [prepared as described in Step 1 above], in methylene chloride (30 ml) at 0° C. The reaction mixture was slowly allowed to warm to RT and after 6 h 1M HCl was added. The product was extracted into methylene chloride, washed with brine, and dried over MgSO4. The organics were removed in vacuo and the crude product was chromatographed (PTLC, SiO2, 25% ethyl acetate/hexane) to give ethyl 2-[benzyl-(morpholine-4-sulfonyl)amino]acetate as a colorless oil (6%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:14]([O:16]C(C)(C)C)=[O:15])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:21]([CH3:23])([CH3:22])[CH3:24])[C:14]([OH:16])=[O:15])[C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product of Example 111-5 in dichloromethane (1.5 L) was added triflouroacetic acid (810 mL). The mixture was stirred at room temperature for 3 hours and concentrated. The residue was chased with heptanes (4×500 mL). The product was partitioned between dichloromethane (1.5 L) and 5% KH2PO4 (1.1 L). The organic layer was washed with 5% KH2PO4 (900 mL) and brine (900 mL), and concentrated. A solution of the residue in dichloromethane (500 mL) was dried over MgSO4, filtered and concentrated. The residue was recrystallized twice from isopropyl alcohol/water to afford the title compound. 1H NMR (DMSO-d6): δ 7.2-7.4(m, 5H), 4.28(d, 2H), 4.21(s, 1H), 3.47-3.64(m, 2H), 3.08-3.2(m, 2H), 1.0(s, 9H).
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[OH-].[Na+].[CH2:16](Br)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:16]([O:12][C:1](=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Reactant: BrCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1ccccc1
Reaction time: 1 h

Procedure:
1.98 g of caffeic acid was dissolved in 100 mL of dimethylformamide. 2.28 mL of 25% aqueous sodium hydroxide solution was added while stirring. Stirring continued for 1 hr. At the end of this period a solution of 5.7 mL of phenethyl bromide in 10 mL dimethylformamide was added slowly in 30 minutes. The resulting reaction mixture was stirred at room temperature for 50 hrs. Next, the reaction mixture was poured into 200 mL of water and extracted with ethyl acetate (3×100 mL). The combined organic extract was washed with 100 mL of 1N HCl and water (3×100 mL). After drying over sodium sulfate, the solvent was distilled off under vacuum. The residue was crystallized from ethyl acetate/hexane by treatment with activated carbon to obtain caffeic acid phenethyl ester. The yield was 600 mg and the purity was greater than 90%.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(Cl)Cl>[S:20]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)([O:10][CH2:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
4-Nitrophenethyl alcohol (15 g, 89.7 mmol) was dissolved in 450 mL methylene chloride. Triethylamine (37.5 mL, 269 mmol) was added over 10 min and the reaction mixture was stirred at 0° C. for 1 hour (h). Tosyl chloride (20.52 g, 110 mmol) was added slowly to the mixture at 0° C. The reaction was stirred at room temperature (rt) overnight and was concentrated. The residue was dissolved in methylene chloride and washed with water, 1 N HCl, then water. The organic layer was dried over sodium sulfate and evaporated. The residue was triturated with hexanes and 25.32 g of white solid was collected. Yield 88%; 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8 Hz, 2H), 7.63 (d, J=8 Hz, 2H), 7.24 (d, 4H), 4.26 (t, J=6 Hz, 2H), 3.04 (t, J=6 Hz, 2H), 2.41 (s, 3H).
Reaction SMILES: [NH2:1]O.[F:3][C:4]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=O.[OH-].[Na+]>CO.C(O)(C(F)(F)F)=O.[Zn]>[F:3][C:4]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[NH2:1]
Reactant: NO
Reactant: O=C(CCC(F)(F)C(F)(F)F)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NC(CCC(F)(F)C(F)(F)F)c1ccccn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Hydroxylamine (0.216 mL, 3.53 mmol) was added to a solution of 4,4,5,5,5-pentafluoro-1-(pyridin-2-yl)pentan-1-one (0.894 g, 3.53 mmol) in MeOH (10.87 mL) and the resulting solution was stirred at 25° C. for 5 h. Another 1 eq. hydroxylamine was added and the reaction was stirred overnight. Another 2 eq hydroxylamine was added and the reaction was stirred overnight. The reaction mixture was concentrated in vacuo and the resulting residue was diluted with EtOAc and the resulting organic phase was washed with water and brine, then dried (Na2SO4) and concentrated in vacuo to give the crude oxime, as a colorless solid. This was redissolved in TFA (6.52 mL) and cooled to 0° C. Zinc (1.155 g, 17.66 mmol) was added in one portion. After 3 h at 0° C. the reaction mixture was poured into a mixture of ice and 5 N aq. NaOH. The pH was adjusted to pH 10. The mixture was extracted with DCM (3×). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the desired amine product. m/z=255.1 (M+H).
Reaction SMILES: Br[C:2]1[N:3]([C:34]2[N:35]=[CH:36][N:37]=[C:38]([NH2:41])[C:39]=2[N:40]=1)[C@@H:4]1[O:33][C@H:23]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@H:5]1[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH2:42]([O:49][C:50]1[CH:51]=[C:52]([C:56]2[CH:61]=[CH:60][C:59]([CH2:62][NH2:63])=[CH:58][CH:57]=2)[CH:53]=[CH:54][CH:55]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)C(C)C)(C)C>C(O)CC>[CH2:42]([O:49][C:50]1[CH:51]=[C:52]([C:56]2[CH:57]=[CH:58][C:59]([CH2:62][NH:63][C:2]3[N:3]([C:34]4[N:35]=[CH:36][N:37]=[C:38]([NH2:41])[C:39]=4[N:40]=3)[C@@H:4]3[O:33][C@H:23]([CH2:24][O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27])[C@@H:14]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[C@H:5]3[O:6][Si:7]([C:10]([CH3:13])([CH3:11])[CH3:12])([CH3:9])[CH3:8])=[CH:60][CH:61]=2)[CH:53]=[CH:54][CH:55]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: NCc1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(Br)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(NCc3ccc(-c4cccc(OCc5ccccc5)c4)cc3)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 62 h
Yield: 83.3 %

Procedure:
A mixture of 8-bromo-2′,3′,5′-tris-O-(tert-butyl-dimethylsilyl)adenosine (0.660 g), 3′-benzyloxybiphenyl-4-ylmethylamine (0.832 g) and N,N-diisopropylethylamine (0.667 mL) in 1-propanol (9.6 mL) was heated under reflux with stirring for 62 hours. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate (35 mL) and 10% aqueous citric acid (10 mL). The organic layer was washed successively with 10% aqueous citric acid (10 mL×2), saturated aqueous sodium hydrogen carbonate (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on aminopropylated silica gel (eluent: hexane/ethyl acetate=2/1) to give the title compound (0.716 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[C:14]([C:19]#[N:20])=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:2].[N-:21]=[N+:22]=[N-:23].[Na+].O>ClC1C=CC=CC=1>[N:20]1[NH:21][N:22]=[N:23][C:19]=1[C:14]1[C:13]([CH2:12][O:11][C:4]2[C:3]([CH:1]=[O:2])=[CH:8][C:7]([O:9][CH3:10])=[N:6][CH:5]=2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: COc1cc(C=O)c(OCc2cccnc2C#N)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: O
Product: COc1cc(C=O)c(OCc2cccnc2-c2nn[nH]n2)cn1
Temperature: 110 °C

Procedure:
To TEA hydrochloride salt (123 mg, 0.89 mmol, 4 equiv.) and 3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (70 mg, 0.26 mmol, 1 equiv.) in chlorobenzene (5.0 mL) was added NaN3 (48 mg, 0.89 mmol, 4 equiv.) at rt. The mixture was heated to 110° C. for 2 h, cooled to rt, and added water (5.0 mL). The precipitate was filtered and washed with EtOAc and water and dried under high vacuo to give 5-((2-(2H-tetrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde as a white solid. 1H NMR (400 MHz; DMSO) δ=10.23 (s, 1H), 8.61 (d, 1H), 8.16 (s, 1H), 8.10 (d, 1H), 7.38 (dd, 1H), 6.96 (s, 1H) 5.73 (s, 2H), 3.83 (s, 3H). LRMS (M+H+) m/z 313.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[O:10]=[C:11]([CH3:17])[CH2:12][CH2:13][CH2:14][C:15]#[N:16].O.Cl>C(OCC)C>[OH:10][C:11]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:17])[CH2:12][CH2:13][CH2:14][C:15]#[N:16]
Reactant: CC(=O)CCCC#N
Reactant: Clc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CC(O)(CCCC#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
One hundred mL (0.1 mole) of a 1.0 molar solution of 4-chlorophenyl-magnesium bromide in diethyl ether is stirred, and a solution of 11.4 mL (0.1 mole) of 5-oxohexanenitrile in 125 mL of diethyl ether is added dropwise. The exothermic reaction causes the reaction mixture temperature to rise to about 31° C. The reaction mixture is then cooled in an ice-bath, and the dropwise addition of the nitrile solution is continued. The complete addition requires about 30 minutes. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature where it is stirred for two hours. The reaction mixture is then poured into 500 mL of water and made acidic with aqueous 2N hydrochloric acid. The organic layer is separated, and the aqueous layer is extracted with one 250 mL portion of diethyl ether. The organic layers are combined and dried with magnesium sulfate. The mixture is filtered, and the filtrate is concentrated under reduced pressure to a residual oil. The oil is subjected to column chromatography on silica gel, using methylene chloride as the eluant. The product-containing fractions are combined and concentrated under reduced pressure, yielding 15.0 grams of 5-hydroxy-5-(4-chlorophenyl)hexanenitrile. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:31]1([NH:30][C:26]([C:22]2[CH:21]=[C:20]([N:17]3[CH2:16][CH2:15][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:19][CH2:18]3)[N:25]=[CH:24][N:23]=2)=[O:27])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)Nc4ccccc4)ncn3)CC1)C(=O)N2

Procedure:
120.0 mg (0.30 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 30 μL (0.33 mmol) aniline, 120.0 mg (0.37 mmol) TBTU and 100 μL (0.71 mmol) triethylamine in 2 mL DMF were stirred overnight at RT. The mixture was filtered through a syringe filter and purified by preparative HPLC. The product fractions were combined and lyophilised.