Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11](Cl)[CH:10]=1.[Cl:19]N1N=C(OC)C=C(OC)N1>C(OCC)(=O)C>[NH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[Cl:19]
Reactant: COC1=CC(OC)=NN(Cl)N1
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)O)cc1Cl

Procedure:
Separately, 23.5 g of N-Methylmorpholine is added to a mixture of 33.1 g of 4-Amino-chloro-benzoic acid 34.4 g of 2-Chloro-4,6-dimethoxytriazine (DMT-Cl) in 300 ml of ethyl acetate over 20-30 minutes at ambient temperature for 2-3 hours at 23-27° C. to obtain the DMT active ester of 4-Amino-3-chlorobenzoic acid. The mixture is cooled to 0° to +5° C. and 300 ml of purified water are added to the solution keeping temperature in the same range. The solution of the deprotected t-leucine product as the citrate salt is added at 0° C. to +5° C. over 30-60 minutes, the reaction mixture is then brought to pH 6.5-7.5 by adding 30% sodium hydroxide (approx. amount: 71 ml), and stirred 6-7 hrs at 20° to 25° C. After completion of the reaction, the phases are separated and the organic layer added to sodium bisulfate solution (15 g of sodium bisulfate in 235 ml of water) and stirred for 3 hrs at 20° C. to 25° C. The phases are separated and the organic layer is washed four times with water (150 ml each), twice with sodium bicarbonate solution (total: 20 g of sodium bicarbonate in 400 ml of water), and once with 150 ml of water. To the solution is added 10 g of activated charcoal and 10 g of Dicalite and filtered and the solids washed with 100 ml of ethyl acetate. The filtrate was distilled under vacuum to a volume of 200 ml at <40° C. when the resultant mixture crystallizes. Ethyl acetate (150 ml) was added to a total volume of 350 ml. N-heptane (300 ml) was added over 2 hrs and after stirring the slurry for 3 hrs at 20° to 25°, the solid was filtered, washed with ethyl acetate/N-Heptane (100 ml, 1:1) and dried at 60° C. under vacuum.
Reaction SMILES: C[C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH2:11]Br)[C:5]([CH2:9]Br)=[C:6]([Br:8])[CH:7]=1.BrC1C=CC(OC)=C(C)C=1C.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC#N>[CH2:26]([N:33]1[CH2:9][C:5]2[C:4](=[C:3]([O:13][CH3:14])[CH:2]=[CH:7][C:6]=2[Br:8])[CH2:11]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1c(C)cc(Br)c(CBr)c1CBr
Reactant: NCc1ccccc1
Agent: COc1ccc(Br)c(C)c1C
Solvent: CC#N
Product: COc1ccc(Br)c2c1CN(Cc1ccccc1)C2
Temperature: 60 °C
Yield: 55 %

Procedure:
To a solution of methyl 1-bromo-2,3-bis(bromomethyl)-4-methoxybenzene (prepared as described in J. Org. Chem. 1992, 57, 6374, from commercially available 1-bromo-4-methoxy-2,3-dimethylbenzene) in CH3CN (0.1 M) were added 2.5 eq of KHCO3 and the mixture heated at 60° C. Then 1 eq. of benzylamine in CH3CN (0.9 M) was added within 15 minutes and the mixture was heated to reflux for 2 h. The reaction mixture was allowed to cool, filtered over celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (5% EtOAc in petroleum ether, then 10%) to afford the title compound (55%). 1H NMR (300 MHz, CDCl3, ppm) δ 3.77 (s, 3H), 3.92 (s, 2H), 3.98 (s, 2H), 4.01 (s, 2H), 6.60 (d, J 8.6, 1H), and 7.22-7.46 (m, 6H). MS (ES+) m/z 318, 320 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]([F:22])([F:21])[C:15]1([C:18](O)=[O:19])[CH2:17][CH2:16]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18]([C:15]3([C:14]([F:22])([F:21])[F:13])[CH2:17][CH2:16]3)=[O:19])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H) in CH2Cl2 (10 mL) was treated with 1-(trifluoromethyl)cyclopropanecarboxylic acid (161 mg, 1.04 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (332 mg, 1.30 mmol) and triethylamine (440 mg, 4.35 mmol). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo. The residue was stirred in anhydrous THF (10 mL), treated with 2M LiOH solution (3 mL) and stirred at room temperature for 1 hour. The organic solvent was removed in vacuo, and then water (10 mL) was added. The reaction was stirred for 1 hour. The solid, which separated, was filtered and washed with water and CH2Cl2 (10 mL). The filtered cake was dried to yield N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(trifluoromethyl)cyclopropanecarboxamide (229.5 mg, 72% yield). 1H NMR (400 MHz, (CD3)2SO) δ 12.15 (br s, 1H), 9.38 (s, 1H), 8.36 (d, 1H), 7.51 (s, 1H), 1.49-1.43 (m, 2H), 1.38-1.33 (m, 2H); LCMS (APCI+) m/z 366, 368 (M+H)+, Retention time=3.32 minutes (Method 3).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([O:17][CH:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29](C)([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH3:19])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.C(N(C(C)C)CC)(C)C.ClC(OC(C)C)=O>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([O:17][CH:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH3:19])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(Oc1cnc(-c2ccc(S(C)(=O)=O)cc2)cn1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)OC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(C(C)Oc2cnc(-c3ccc(S(C)(=O)=O)cc3)cn2)CC1

Procedure:
The title compound (0.21 g, 98%) was prepared as a white foam from (±)-1,1-dimethylethyl 4-[1-({5-[4-(methylsulfonyl)phenyl]-2-pyrazinyl}oxy)ethyl]-1-piperidinecarboxylate (Example 160, 0.22 g, 0.48 mmol) and TFA (0.37 mL) in CH2Cl2 (16 mL) then diisopropylethylamine (1.25 mL) and isopropyl chloroformate (1.0M in toluene, 0.57 mL, 0.57 mmol) in a manner similar to Example 74. The crude material was purified by chromatography on a silica gel column eluted with 50% EtOAc/hexanes to afford (±)-1-methylethyl 4-[1-({5-[4-(methylsulfonyl)phenyl]-2-pyrazinyl}oxy)ethyl]-1-piperidinecarboxylate as a white foam. 1H NMR (400 MHz, CDCl3): δ 8.53 (d, 1H, J=1.0 Hz), 8.24 (d, 1H, J=1.2 Hz), 8.10 (d, 2H, J=8.5 Hz), 8.02 (d, 2H, J=8.6 Hz), 5.15-5.05 (m, 1H), 4.89 (septet, 1H, J=6.3 Hz), 4.30-4.15 (m, 2H), 3.07 (s, 3H), 2.75-2.65 (m, 2H), 1.85-1.65 (m, 3H), 1.40-1.25 (m, 5H), 1.22 (d, 6H, J=6.3 Hz); LRMS (ESI), m/z 448 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][O:39][CH3:40]>CC(N(C)C)=O>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:37][CH2:38][O:39][CH3:40])[CH2:20][CH2:19]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OCC1CCNCC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COCCN1CCC(COc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)methoxy]quinazoline (Example 3, 104 mg, 0.25 mmol) was dissolved in DMA (5 ml). Potassium carbonate (138 mg, 1.00 mmol) and 1-bromo-2-methoxyethane (24 μl, 0.25 mmol) were added. The mixture was stirred at 60° C. for 4 hours. Further potassium carbonate (138 mg, 1.00 mmol) and 1-bromo-2-methoxyethane (24 μl, 0.25 mmol) were added; heating was continued at 60° C. for a further 4 hours. The solvent was evaporated and the residue was partitioned between DCM (20 ml) and water (20 ml). The aqueous layer was extracted with DCM (2×10 ml) and the extractions combined with the DCM layer. The combined DCM fractions were filtered through a silicone-treated filter paper and evaporated. The residue was purified by chromatography, eluting with 0 to 2.5% (7:1 MeOH/concentrated aqueous NH4OH) in DCM. The appropriate fractions were combined and evaporated, and the crude product (40 mg) re-dissolved in 1:1 methanol/DCM (5 ml). Ethereal HCl (1M, 0.5 ml) was added, and the mixture evaporated. Crystallisation from iso-propanol/diethyl ether gave the title product as a hydrochloride salt, a yellow solid (28 mg, 20%); 1H NMR (hydrochloride salt): 1.60-1.75 (m, 2H), 2.00-2.05 (m, 2H), 2.16 (m, 1H), 2.95-3.10 (m, 2H), 3.22 (t, 2H), 3.29 (s, 3H), 3.50-3.57 (m, 2H), 3.70 (t, 2H), 3.99 (s, 3H), 4.12 (d, 2H), 7.34 (dd, 1H), 7.39 (s, 1H), 7.51 (dd, 1H), 7.61 (dd, 1H), 8.46 (s, 1H), 8.78 (s, 1H), 10.08 (br. s, 1H); Mass Spectrum: 475.5, 477
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[OH:16].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](OS(C)(=O)=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:16][C:7]2[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[O:17])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: COC(=O)C=Cc1ccc(C(C)(C)C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(C(C)(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 104 %

Procedure:
3-(4-tert-Butyl-2-hydroxyphenyl)acrylic acid methyl ester (24.7 mg, 0.105 mmole), 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester (58.7 mg, 0.210 mmol), potassium carbonate (43.7 mg, 0.316 mmol) was added in DMF. The reaction mixture was stirred overnight. The reaction mixture was purified according to step 1 of Example 30 to give solid (45.6 mg, 100%).
Reaction SMILES: [Cl:1][CH:2]=[C:3]([C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[O:4][Si](C(C)C)(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:1][CH2:2][C:3]([C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1)=[O:4]
Reactant: CC(C)[Si](OC(=CCl)c1ncccn1)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C(CCl)c1ncccn1
Yield: 66.7 %

Procedure:
2-{2-Chloro-1-[(triisopropylsilyl)oxy]ethenyl}pyrimidine (19.4 g, 62.2 mmol) was dissolved in acetonitrile (90 ml) and treated with 48% HF (10 ml) for 4 hr. Sat. sodium bicarbonate solution (ca. 250 ml) was then added carefully to pH7 and the mixture extracted with CH2Cl2 (3×200 ml). After drying (Na2SO4), filtration and evaporation two oils were obtained, the upper colorless oil was decanted off and discarded and the lower oil crystallized to an oily solid. Chromatography over silica gel (500 g) eluting with 2.5% MeOH—CHCl3 gave the product as a pale yellow solid (6.50 g) mp:73-80°.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].N.[OH:21]O>C(O)C>[NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:5]=[CH:4][C:3]=1[C:18]([NH2:19])=[O:21]
Reactant: OO
Reactant: CC(CCCc1ccccc1)n1ncc(C#N)c1N
Agent: N
Solvent: CCO
Product: CC(CCCc1ccccc1)n1ncc(C(N)=O)c1N

Procedure:
512 mg (2.02 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-pyrazole-4-carbonitrile are stirred for 3 hours at room temperature with 25 ml of concentrated aqueous NH3, 20 ml of ethanol and 5 ml of 30% strength H2O2. The non-aqueous solvent is removed in vacuo, and the solid which has precipitated is filtered off with suction and dried.
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3([CH2:27][OH:28])[CH2:26][CH2:25]3)[O:15][N:14]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3([CH:27]=[O:28])[CH2:26][CH2:25]3)[O:15][N:14]=2)=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2noc(C3(CO)CC3)c2-c2ccccc2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2noc(C3(C=O)CC3)c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture consisting of (1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropyl)-methanol (Example 1, Compound E, 4.0 g) in dichloromethane (60 mL) is added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (7.0 g.) The mixture is stirred overnight at room temperature. The mixture is treated with aqueous sodium thiosulfate (20 mL) and the layers are thoroughly mixed and separated. The organic layer is washed sequentially with water and brine solution and is dried over anhydrous sodium sulfate. The mixture is filtered and the filtrate is concentrated under reduced pressure to afford the solid common synthetic intermediate (4.1 g.)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:17]C=O)=[O:4].[CH:20]([O:25][CH3:26])([O:23][CH3:24])OC>CO>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:17][CH:20]([O:23][CH3:24])[O:25][CH3:26])=[O:4]
Reactant: COC(OC)OC
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)nc1CC=O
Solvent: CO
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)nc1CC(OC)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Mix 2-(4-chloro-phenyl)-4-(2-oxo-ethyl)-thiazole-5-carboxylic acid methyl ester (96.4 g, 308 mmol), Dowex™ 50×8 ion exchange resin (33.3 g), and trimethyl orthoformate (147 mL) in MeOH (670 mL). Stir the slurry overnight at room temperature. Filter through a plug of diatomaceous earth and rinse with MeOH (3×300 mL). Stir the filtrate at 0° C. for 2 h and then concentrate to a volume of approximately 250 mL. Collect the solid by filtration, rinse with cold MeOH, and dry overnight at room temperature to obtain 88.2 g (84%) of the titled compound. ES/MS m/z (35Cl) 342.0 [M+1]+.
Reaction SMILES: C(OC[O:5][C:6]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])C.CC(C)=O.Cl>O>[OH:5][C:6]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: CCOCOc1cc(C(F)(F)F)ccc1C=O
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=Cc1ccc(C(F)(F)F)cc1O
Temperature: 40 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
A mixture of 1.90 g of 2-ethoxymethoxy-4-trifluoromethylbenzaldehyde, 10 ml of acetone, and 9 ml of 6 N hydrochloric acid was stirred at room temperature for 3 hours and subsequently at 40° C. for 1 hour. The reaction mixture was cooled to room temperature, then water was added to the reaction mixture. This mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure, to obtain 1.05 g of 2-hydroxy-4-(trifluoromethyl)benzaldehyde.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[N:19]1([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH2:34])=[NH:33])=[CH:27][CH:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:34]=[C:32]([NH:31][C:28]3[CH:27]=[CH:26][C:25]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:30][CH:29]=3)[N:33]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: N=C(N)Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Solvent: O=[N+]([O-])O
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)s1

Procedure:
By condensation between 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and N-(4-morpholin-4-yl-phenyl)-guanidine nitrate. Pale solid. 1H-NMR (CDCl3) δ: 2.69 (s, 3H, CH3), 2.70 (s, 3H, CH3), 3.14 (t, 4H, J=4.8 Hz, CH2), 3.72 (t, 4H, J=4.9 Hz, CH2), 6.89 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 6.95 (d, 2H, J=8.8 Hz, Ph-H), 6.98(br. s, 1H, NH), 7.53 (d, 2H, J=9.1 Hz, Ph-H), 8.38 (d, 1H, J=5.1 Hz, pyrimidinyl-H). MS (ESI+) m/z 368 [M+H]+ (C19H21N5OS requires 367.5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=2)=[CH:12][C:11]([CH:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[O:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[N:10]1.[OH-].[Na+]>CO.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]2[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[CH:12][C:11]([CH:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[O:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[N:10]1
Reactant: CCOC(=O)c1ccc(-c2cc(C3CC(C)(C)OC(C)(C)C3)nn2-c2ccccc2OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(C(=O)O)cc1
Temperature: 50 °C
Yield: 99 %

Procedure:
To a solution of ethyl 4-[1-(2-methoxyphenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]-benzoate (Example 17) (200 mg, 0.43 mmol) in 3 mL of methanol was added 0.07 mL of 50% NaOH soln (1.30 mmol) and the mixture heated at 50° C. for 8 hrs. The mixture was diluted with 50 mL of EtOAc and washed with 50 mL of 1N HCL and 50 mL of brine. The organic layer was dried over Na2SO4 and concentrated to give 185 mg (93%) of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:5]2[N:6]=[C:7](Cl)[NH:8][C:4]=2[CH:3]=1.Cl.[Cl:17][C:18]1[C:19]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1>>[Br:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:5]2[NH:6][C:7]([N:27]3[CH2:28][CH2:29][N:24]([C:19]4[C:18]([Cl:17])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:25][CH2:26]3)=[N:8][C:4]=2[CH:3]=1
Reactant: Clc1cccnc1N1CCNCC1
Reactant: FC(F)(F)c1cc2nc(Cl)[nH]c2cc1Br
Agent: Cl
Product: FC(F)(F)c1cc2[nH]c(N3CCN(c4ncccc4Cl)CC3)nc2cc1Br

Procedure:
The reaction of 5-bromo-2-chloro-6-(trifluoromethyl)benzoimidazole (100 mg, 0.3 mmol, Example 89f) with 1-(3-chloropyridin-2-yl)piperazine hydrochloride (186 mg, 0.61 mmol, Example 3b) under the conditions of Example 3c afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 461.7, 464.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][NH2:18])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][NH:18][C:25](=[O:27])[CH3:26])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](CNC(C)=O)NC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of methyl 2(S)-benzyloxycarbonylamino-3-aminopropionate (2.5 g) in methylene chloride was added pyridine (20 mL) and acetic anhydride (5 mL). After stirring for 2 h the solution was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was extracted w/50 mL each of 2% potassium hydrogen sulfate, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo. Upon evaporation pyridine hydrochloride precipitated and was removed by filtration. The filtrate was evaporated to obtain the title compound. 1H NMR (300 MHz, CDCl3) δ 7.28 (5H, s), 6.14 (1H, s), 5.97 (1H, d), 5.10 (2H, s), 4.41 (1H, m), 3.78 (3H, s), 1.93 (3H, s).
Reaction SMILES: N1C=CC=NC=1.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[C:15]1[C:20]([C:21]2[NH:22][CH:23]=[CH:24][N:25]=2)=[CH:19][N:18]=[C:17]([CH2:26][NH:27][CH2:28][CH2:29][NH:30]C(=O)C(F)(F)F)[N:16]=1.[OH-].[K+].O>CO>[NH2:30][CH2:29][CH2:28][NH:27][CH2:26][C:17]1[N:16]=[C:15]([C:9]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=2[Cl:7])[C:20]([C:21]2[NH:25][CH:24]=[CH:23][N:22]=2)=[CH:19][N:18]=1
Reactant: O=C(NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: c1cncnc1
Solvent: O
Product: NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The aforementioned pyrimidine, N-(2-{[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]methylamino}ethyl)-2,2,2-trifluoroacetamide (114 mg, 0.25 mmol) was dissolved in 2 mL methanol and potassium hydroxide (40 mg, 1 mmol) added. This suspension was stirred at room temperature for 1 hour. Water was added, and the solution extracted with methylene chloride. The aqueous layer was thoroughly extracted with methylene chloride and the organic layers washed with brine, dried and concentrated to give the deprotected primary amine, (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]methylamine in quantitative yield.
Reaction SMILES: O.NN.C([O:7][C@H:8]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:11]([CH2:22][O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:10][C@@H:9]1[N:32]1[CH:39]=[CH:38][C:36](=[O:37])[NH:35][C:33]1=[O:34])(=O)C.CC(C)=O>N1C=CC=CC=1.C(O)(=O)C>[C:14]([O:13][C@@H:12]1[C@H:11]([CH2:22][O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:10][C@H:9]([N:32]2[CH:39]=[CH:38][C:36](=[O:37])[NH:35][C:33]2=[O:34])[C@H:8]1[OH:7])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)O[C@H]1[C@H](OC(=O)c2ccccc2)[C@H](COC(=O)c2ccccc2)O[C@@H]1n1ccc(=O)[nH]c1=O
Agent: NN
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: O
Product: O=C(OC[C@@H]1O[C@H](n2ccc(=O)[nH]c2=O)[C@@H](O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Hydrazine hydrate (1.4 mL, 28.7 mmol) was added to a solution of 1-(2-O-acetyl-3,5-di-O-benzoyl-β-L-xylofuranosyl)uracil 10 [Ref.: Gosselin, G.; Bergogne, M.-C.; Imbach, J.-L., “Synthesis and Antiviral Evaluation of β-L-Xylofuranosyl Nucleosides of the Five Naturally Occuring Nucleic Acid Bases”, Journal of Heterocyclic Chemistry, 1993, 30 (Oct.-Nov.), 1229-1233] (4.79 g, 9.68 mmol) in pyridine (60 mL) and acetic acid (15 mL). The solution was stirred overnight at room temperature. Acetone was added (35 mL) and the mixture was stirred for 30 min. The reaction mixture was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (0-4%) in dichloromethane to give 11 (3.0 g, 68%) which was crystallized from cyclohexane/dichloromethane: mp=111-114° C.; 1H-NMR (DMSO-d6): δ 11.35 (br s, 1H, NH), 7.9-7.4 (m, 1H, 2 C6H5CO, H-6), 6.38 (d, 1H, OH-2′, JOH-2′=4.2 Hz), 5.77 (d, 1H, H-1′, J1′-2′=1.9 Hz), 5.55 (d, 1H, H-5, J5-6=8 Hz), 5.54 (dd, 1H, H-3′, J3′-2′=3.9 Hz and J3′-4′=1.8 Hz), 4.8 (m, 1H, H-4′), 4.7 (m, 2H, H-5′ and H-5″), 4.3 (m, 1H, H-2′); MS: FAB>0 (matrix GT) m/z 453 (M+H)+, 105 (C6H5CO)+; FAB<0 (matrix GT) m/z 451 (M−H)−, 121 (C6H5CO2)−, 111 (B)−; Anal. Calcd for C23H20N2O8.H2O: C, 58.09; H, 4.76; N, 5.96. Found: C, 57.71; H, 4.42; N, 5.70.