Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:8]([O:28][CH3:29])=[C:9]([NH:11][C:12](=[O:27])[NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24](O)=[O:25])=[CH:16][CH:15]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH3:64][O:65][C:66](=[O:74])[CH2:67][CH:68]1[O:73][CH2:72][CH2:71][NH:70][CH2:69]1>CN(C=O)C>[CH3:64][O:65][C:66](=[O:74])[CH2:67][CH:68]1[O:73][CH2:72][CH2:71][N:70]([C:24]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([NH:13][C:12]([NH:11][C:9]3[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=[C:7]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:8]=3[O:28][CH3:29])=[O:27])=[CH:15][CH:16]=2)=[O:25])[CH2:69]1
Reactant: COC(=O)CC1CNCCO1
Reactant: COc1c(NC(=O)Nc2ccc(C(=O)O)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC1CN(C(=O)c2ccc(NC(=O)Nc3cc(C(C)(C)C)cc(NS(C)(=O)=O)c3OC)c3ccccc23)CCO1
Reaction time: 0.08 h
Yield: 61.8 %

Procedure:
95 mg (0.24 mmol) of 4-[3-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-ureido]-naphthalene-1-carboxylic acid (Example 17) was dissolved in 1 mL of DMF. To this clear solution was added sequentially, 139 mg (0.44 mmol) of TBTU, and 102 microL (0.73 mmol) of triethylamine. The clear yellow solution was stirred for 5 min, then 50 mg (0.31 mmol) of morpholin-2-yl-acetic acid methyl ester (Loftus, F. Syn. Commun. 1980, 10, 59) was added. The reaction was stirred overnight, then concentrated in vacuo. The resulting amber oil was extracted with EtOAc and water, brine, and then dried over magnesium sulfate. Concentration in vacuo provide an amber oil which was purified on silica gel, eluting with 5% MeOH-methylene chloride to provide 93 mg (72%) of the title compound as a viscous oil.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.CO.[NH4+:14]>>[NH2:14][CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1cncc(OCC2CO2)c1
Reactant: [NH4+]
Solvent: CO
Product: NC[C@H](O)COc1cccnc1
Yield: 99.5 %

Procedure:
A solution of 3-(2-oxiranylmethoxy)pyridine (which was obtained in Example 123) (1.41 g) in 120 mL of saturated ammonium methanol was stirred at 0° C. for two days. The reaction mixture was concentrated to give a yellow semi-solid (1.56 g, 99.5% yield); 1H NMR (400 MHz, DMSO-d6) δ 1.60 (brs, 2 H), 2.55–2.59 (m, 1 H), 2.61–2.68 (m, 1 H), 3.67–3.72 (m, 1 H), 3.89–3.93 (m, 1 H), 4.00–4.04 (m, 1 H), 4.90 (brs, 1 H), 7.29–7.32 (m, 1 H), 7.36–7.38 (m, 1H), 8.13–8.14 (d, 1 H), 8.27 (s, 1 H); MS (ES) m/z: 138(M+); Anal. Calcd. for C7H10N2O: C, 57.13; H, 7.19; N, 16.66. Found: C, 57.83; H, 7.17; N, 18.98.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])=[CH:6][C:5]([CH3:18])=[CH:4][N:3]=1.Cl[CH:20]([C:26]([CH3:28])=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[C:21]([C:20]1[N:3]2[CH:4]=[C:5]([CH3:18])[CH:6]=[C:7]([O:8][CH2:9][C:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=3[CH3:17])[C:2]2=[N:1][C:26]=1[CH3:28])([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Cc1cnc(N)c(OCc2c(C)cccc2C)c1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3c(C)cccc3C)cc(C)cn12
Yield: 46.7 %

Procedure:
A mixture of 2-amino-3-(2,6-dimethylbenzyloxy)-5-methylpyridine (1.0 g, 4.13 mmol) and ethyl 2-chloroacetoacetate (0.79 g, 4.55 mmol) in 20 ml abs. ethanol was refluxed for 19 h. More ethyl 2-chloroacetoacetate (0.25 g) was added. The reaction mixture was refluxed for additional 23 h. The solvent was evaporated in vacuo and the residue was dissolved in methylene chloride and washed with aqueous NaHCO3. The organic layer was dried and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using methylene chloride:ethyl acetate (100:10) as eluent to give 0.68 g (47%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].[Li]CCCC.[CH3:16][CH:17]([O:20][CH2:21][C:22](N(OC)C)=[O:23])[CH:18]=[CH2:19]>CCOCC>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([F:10])=[C:2]([C:22](=[O:23])[CH2:21][O:20][CH:17]([CH:18]=[CH2:19])[CH3:16])[CH:7]=1
Reactant: Fc1cc(F)c(Br)cc1Br
Reactant: C=CC(C)OCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: CCOCC
Product: C=CC(C)OCC(=O)c1cc(Br)c(F)cc1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 230 %

Procedure:
1,5-Dibromo-2,4-difluorobenzene (1.16 g, 4.28 mmol) was dissolved in Et2O (2 mL) and the solution was cooled to −78° C. nBuLi (1.26 mL 2.5M solution in hexanes) was added dropwise, maintaining the internal temperature below −70° C. Immediately after addition of nBuLi is complete, a solution of (±)-2-(but-3-en-2-yloxy)-N-methoxy-N-methylacetamide (0.5 g, 2.85 mmol) in Et2O (2 mL) was added dropwise, keeping the internal temperature below −70° C. The reaction was stirred at −78° C. for 15 minutes before quenching with saturated NH4Cl. The mixture was extracted with DCM (×3), dried (MgSO4) and concentrated in vacuo. The reaction was repeated a further 5 times on the same scale. The residues from all six reactions were combined and purified by column chromatography (Biotage SNAP 25 g 0-10% EtOAc in hexane) to leave the desired compound as a yellow oil (2 g). 1H NMR (400 MHz, CDCl3) δ ppm: 8.20 (t, J=7.46 Hz, 1H), 6.98 (dd, J=7.95, 10.15 Hz, 1H), 5.76 (ddd, J=7.70, 10.09, 17.42 Hz, 1H), 5.16-5.26 (m, 2H), 4.51-4.69 (m, 2H), 3.93-4.04 (m, 1H), 1.34-1.40 (m, 3H)
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:19]([O:21]C)=[O:20].[OH-].[Li+].Cl>CO.O>[CH3:1][C:2]1[N:10]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)c1c(C)n(C(C)c2ccccc2)c2cccnc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)c2ncccc2n1C(C)c1ccccc1
Yield: 26.4 %

Procedure:
To a solution of methyl 2-methyl-1-(1-phenylethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (80 mg, 0.27 mmol) in methanol (3 mL) and water (1 mL) was added lithium hydroxide (57 mg, 1.36 mmol). The reaction mixture was stirred with refluxing for 15 hours. The mixture was adjusted pH 3 with 1N aqueous hydrochloric acid. The aqueous phase was extracted with dichloromethane (50 mL×3). The organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue, which was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 2-methyl-1-(1-phenylethyl)-1H-pyrrolo-[3,2-b]pyridine-3-carboxylic acid (20 mg, 26%). LRMS (M−H+) m/z: calcd 279.12. found 279.
Reaction SMILES: [CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[N:6]1.S(=O)(=O)(O)[OH:15].O>O1CCOCC1.O>[CH3:1][C:2]([OH:15])([CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[N:6]1)[CH3:13]
Reactant: O=S(=O)(O)O
Reactant: CC(C)=CCn1ccc([N+](=O)[O-])n1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(O)CCn1ccc([N+](=O)[O-])n1
Temperature: 85 °C
Yield: 43 %

Procedure:
1-(3-Methyl-but-2-enyl)-3-nitro-1H-pyrazole (1.29 g, 7.13 mmol) was dissolved in dioxane (30 mL). While stirring, a solution containing 50% concentrated sulfuric acid/water (3 mL) was added dropwise. The reaction was heated to 85° C. while stirring for 12 h. The reaction was diluted with water (50 mL) and the product extracted into ethyl acetate (3×60 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to an oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 15% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 2-methyl-4-(3-nitro-pyrazol-1-yl)-butan-2-ol (608 mg, 43%) as a thick golden oil: H1-NMR (400 MHz, CDCl3) δ 1.30 (6H, s), 1.54 (1H, bs), 2.11-2.15 (2H, m), 4.36-4.39 (2H, m), 6.87 (1H, d, J=2.8 Hz), 7.48 (1H, d, J=2.8 Hz).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25]>CN(C)C=O>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:25]
Reactant: O=C=Nc1ccccc1Cl
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=C(NCC(c1ccccc1)c1ccccc1)Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,2-diphenylethylamine (2.0 g, 10.1 mmol) in 15 ml of N,N-dimethylformamide (DMF) was cooled to 0° C. and treated with 2-chlorophenyl isocyanate (1.46 g, 12.2 mmol) under nitrogen (N2). The reaction solution was stirred at room temperature for 15 minutes and partitioned between ethyl acetate (EtOAc) and water (H2O). The organic layer was washed with sodium bicarbonate (NaHCO3) and brine, dried over sodium sulfate (Na2SO4), filtered and concentrated in vacuo to provide a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[F:21][C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]([CH2:31][CH2:32]Cl)[CH2:28][CH2:29]Cl)=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:29][CH2:28][N:27]([CH2:26][C:25]2[CH:34]=[CH:35][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:31][CH2:32]1)=[O:20])[CH3:2]
Reactant: Fc1ccc(CN(CCCl)CCCl)cc1
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(F)cc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-fluoro-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 6). Starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (5 g, 16.9 mmol) and (4-fluoro-benzyl)-bis-(2-chloro-ethyl)-amine (5.8 g, 20.1 mmol) 5.3 g of the product was isolated. Yield 5.3 g (67%); Brown oil; MS: 474 (M+H)+
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([OH:12])=[CH:7][C:6]=1[Cl:13])(=[O:3])[CH3:2].[OH-].[K+].[F:16][C:17]([F:24])([F:23])[C:18]([F:22])=[C:19]([F:21])[F:20]>CN(C)C=O>[C:1]([NH:4][C:5]1[C:6]([Cl:13])=[CH:7][C:8]([O:12][C:19]([F:21])([F:20])[CH:18]([F:22])[C:17]([F:24])([F:23])[F:16])=[CH:9][C:10]=1[Cl:11])(=[O:3])[CH3:2]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: CC(=O)Nc1c(Cl)cc(O)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(Cl)cc(OC(F)(F)C(F)C(F)(F)F)cc1Cl
Temperature: 70 °C
Reaction time: 20 h

Procedure:
47 g of 4-acetylamino-3,5-dichlorophenol together with 154 g of 90% potassium hydroxide solution and 130 ml of dimethylformamide are stirred in an autoclave. 75.8 g of hexafluoropropylene are then pressed into the closed autoclave. The mixture is stirred for 20 hours at 70° C. under the pressure developing in the autoclave. After cooling, the mixture is concentrated by rotary evaporation and the residue is dissolved in methylene chloride. The resultant solution is washed with water, dried over Na2SO4 and concentrated. The crude product obtained as residue is chromatographed through a column of silica gel (length: 1 m; diameter: 10 cm) eluted with an 11:1 mixture of toluene and acetone, affording 4-acetylamino-3,5-dichloro-1-(1,1,2,3,3,3-hexafluoropropyloxy)benzene in the form of pale yellow crystals (m.p.: 113°-115° C.), 26 g of which are kept for 10 hours under reflux with 110 ml of ethanol and 35.6 ml of 37% hydrochloric acid. The reaction mixture is then concentrated, diluted with ice/water and made weakly alkaline. The product is extracted from the mixture with methylene chloride. The organic extract phase is washed with water, dried over Na2SO4 and concentrated. The residue is purified by distillation, thus affording the title compound of the formula ##STR12## as a colourless liquid with a boiling point of 91°-96° C./0.001 torr.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[I:11].CCO.[NH4+].[Cl-]>C1COCC1.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[I:11]
Reactant: O=[N+]([O-])c1ccc(Cl)c(I)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(Cl)c(I)c1
Temperature: 22 °C
Reaction time: 3 h

Procedure:
1-Chloro-2-iodo-4-nitro-benzene (2.00 g, 7.09 mmol) was dissolved in THF (30 mL) at 60° C. and EtOH (35 mL) was added followed by NH4Cl (0.569 g, 10.6 mmol in 30 mL of water) and iron powder (1.58 g, 28.4 mmol). This mixture was stirred vigorously for 3 h and then cooled in 22° C. and filtered though celite rinsing with EtOAc. The solution was then concentrated to ˜30 mL in vacuo and then poured into a 1:1 solution of 1N NaOH/brine (100 mL). This mixture was then extracted with EtOAc (3×50 mL) and the organics were dried over anhydrous MgSO4. Filtration and concentration gave compound 801B as a yellow solid. No purification was necessary. HPLC: 100% at 2.310 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10–90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm), MS (ES): m/z 517.6 [M+Na]+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3]1.FC(F)(F)S(O[C:25]1[CH:26](C)[O:27][C:28](=[O:31])[C:29]=1[F:30])(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:30][C:29]1[C:28](=[O:31])[O:27][CH2:26][C:25]=1[N:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:2]1=[O:1]
Reactant: CC1OC(=O)C(F)=C1OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2=O)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(F)C(=O)OC1)C2=O

Procedure:
A mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (150 mg, 0.590 mmol), 4-fluoro-2-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (148 mg, 0.590 mmol), xantphos (34.1 mg, 0.059 mmol), water (0.032 mL, 1.77 mmol) in toluene (20 mL) was degassed by nitrogen followed by addition of palladium acetate (6.6 mg, 0.029 mmol).
Reaction SMILES: [NH2:1][C@H:2]([CH3:31])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:32][C@H:33]1[CH2:38][CH2:37][O:36][C:34]1=[O:35]>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][CH2:3][C@H:2]([NH:1][C:34](=[O:35])[C@@H:33]([OH:32])[CH2:38][CH2:37][OH:36])[CH3:31])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: C[C@@H](N)COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C1OCC[C@@H]1O
Product: C[C@H](COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)NC(=O)[C@@H](O)CCO
Yield: 79 %

Procedure:
The procedure described in Example 63 was repeated using 5-{[(2R)-2-aminopropyl]oxy}-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 2.4, preparation of starting materials) and (S)-(−)-α-hydroxy-γ-butyrolactone to give the title compound in 79% yield; NMR spectrum (DMSO-d6 400 MHz) 1.24 (d, 3H), 1.30-1.41 (m, 1H), 1.63-1.74 (m, 1H), 3.32-3.46 (m, 2H), 3.91-3.98 (m, 1H), 4.24 (dd, 1H), 4.31 (t, 1H), 4.38 (t, 1H), 4.47-4.57 (m, 1H), 5.30 (s, 2H), 5.43 (d, 1H), 7.16 (d, 1H), 7.23 (d, 1H), 7.31-7.41 (m, 2H), 7.56 (dd, 1H), 7.60 (d, 1H), 7.73 (t, 1H), 7.89 (dt, 1H), 7.95 (d, 1H), 8.06 (d, 1H), 8.48 (s, 1H), 8.61 (d, 1H) 9.79 (s, 1H); Mass spectrum MH+ 538.0.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]([C:14]1[C:19]([Br:20])=[CH:18][N:17]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.Cl.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40]Cl)[CH2:34][CH2:33]1>CS(C)=O>[NH:7]([C:14]1[C:19]([Br:20])=[CH:18][N:17]=[C:16]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:40][CH2:39][CH2:38][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[CH:26][CH:27]=2)[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN1CCN(CCCCl)CC1
Reactant: Oc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(CCCOc2ccc(Nc3ncc(Br)c(Nc4ccccc4)n3)cc2)CC1
Temperature: 100 °C
Yield: 16.8 %

Procedure:
A mixture of potassium carbonate (180 mg, 1.3 mmol), 4-anilino-5-bromo-2-(4-hydroxyanilino)pyrimidine (Method 4, 150 mg, 0.42 mmol) and 3-(4-methyl-1-piperazinyl)propyl chloride dihydrochloride (120 mg, 0.48 mmol) in DMSO (2 ml) was heated at 100° C. for 12 hours. Silica (1 g) was added and volatile material was removed by evaporation. The residue was loaded onto a Varian Mega Bond Elut column and the column was eluted with 50:50 iso-hexane: DCM (2×20 ml), DCM (2×20 ml), 2% 2M NH3/MeOH/DCM (2×20 ml), 4% 2M NH3/MeOH/DCM (2×20 ml), 6% 2M NH3/MeOH/DCM (2×20 ml) and 10% 2M NH3/MeOH/DCM (8×20 ml). Concentration of the appropriate fractions gave the product as a yellow solid (35 mg, 17%). MS (MH+): 497, 499; HPLC (RT): 2.74.
Reaction SMILES: [CH3:1][C@@H:2]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:3]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:4]([O:6]N1C(=O)CCC1=O)=O.[NH2:30][C@H:31]([C:39]([N:41]1[CH2:48][CH2:47][CH2:46][C@H:42]1[C:43]([OH:45])=[O:44])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C>CN(C)C=O>[NH:14]([C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C@H:3]([C:4]([NH:30][C@H:31]([C:39]([N:41]1[CH2:48][CH2:47][CH2:46][C@H:42]1[C:43]([OH:45])=[O:44])=[O:40])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:6])[C@@H:2]([CH3:1])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 8 h

Procedure:
20.2 g of Z-Thr(tBu)-OSU, 13.3 g of H-Phe-Pro-OH (monohydrate) and 6.54 ml of triethylamine are dissolved in 80 ml of dimethylformamide, allowed to stand overnight at about 20°C and then concentrated in a high vacuum until a sticky mass forms. The latter is dissolved in 500 ml of ethyl acetate and washed five times with 100 ml at a time of 5 % strength tartaric acid solution and subsequently with water until neutral. The organic phase is concentrated to dryness and the remaining solid foam is powdered and dried in a high vacuum at 40°C. On twice reprecipitating from ethyl acetate-peptroleum ether 13.3 g of amorphous chromatographically pure tripeptide derivative having an unsharp melting range at about 75°-85°C are obtained. In a thin layer chromatogram on silica gel RF115 = 0.68; Rf121A = 0.57.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](O)[N:5]2[N:9]=[C:10]([S:22][CH3:23])[C:11]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])=[C:4]2[N:3]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:6]1[N:5]2[N:9]=[C:10]([S:22][CH3:23])[C:11]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)(=[O:14])=[O:13])=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nn2c(O)cc(C)nc2c1S(=O)(=O)c1ccc(C)cc1
Product: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A suspension of 3.8 g (10.8 mmol) of 5-methyl-2-methylsulphanyl-3-(toluene-4-sulphonyl)-pyrazolo[1,5-a]pyrimidin-7-ol in 20 l of POCl3 was heated at reflux for 1 hr. The reaction solution was cooled to RT and evaporated. The residue was treated with 100 ml of ice-water and the pH value of the solution was adjusted to 8 with sat. NaHCO3 solution. The aqueous phase was extracted three times with CH2Cl2, and the organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/AcOEt 25:1) of the residue yielded 3.8 g (95%) of 7-chloro-5-methyl-2-methylsulphanyl-3-(toluene-4-sulphonyl)-pyrazolo[1,5-a]pyrimidine as pale yellow crystals, m.p. 197-198°.
Reaction SMILES: O[CH2:2][CH:3]1[N:9]2[C:10](=[O:13])[O:11][N:12]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:15][CH2:2][CH:3]1[N:9]2[C:10](=[O:13])[O:11][N:12]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=c1onc2n1C(CO)CCCC2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=c1onc2n1C(CBr)CCCC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of the product of Example 5 in dichloromethane was added carbon tetrabromide (460 mg, 1.3 mmol). This solution was cooled in an ice bath and stirred for minutes. Triphenylphosphine (437 mg, 1.6 mmol) was added to the solution and stirring was continued for 5 minutes at 0° C. before allowing it to warm slowly to room temperature. The solvent was removed under reduced pressure. The residue was placed on a filter and washed three times with ether. The filtrate solvent was then removed under reduced pressure to yield the title compound.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])/[C:3](/[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[CH:20][CH:19]=1)=[CH:4]\[C:5]1[NH:6][CH:7]=[C:8]([CH2:10][C:11]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12]2)[N:9]=1.[H][H]>[Pd].C(O)C>[F:30][C:2]([F:1])([F:29])[CH:3]([C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[CH:22][CH:23]=1)[CH2:4][C:5]1[NH:6][CH:7]=[C:8]([CH2:10][C:11]2([C:14]([F:15])([F:16])[F:17])[CH2:12][CH2:13]2)[N:9]=1
Reactant: FC(F)(F)/C(=C\c1nc(CC2(C(F)(F)F)CC2)c[nH]1)c1ccc(-n2cccn2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)C(Cc1nc(CC2(C(F)(F)F)CC2)c[nH]1)c1ccc(-n2cccn2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
In a 25-mL round-bottom flask, a mixture of 1-{4-[(Z)-1-(trifluoromethyl)-2-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)vinyl]phenyl}-1H-pyrazole (52.8 mg, 0.124 mmol) and palladium on carbon (11.4 mg, 0.107 mmol) was suspended in ethanol (5 mL), and a hydrogen balloon was put on top of the flask. It was cooled to −78° C., degassed and saturated with hydrogen three times. The reaction is mostly complete 2 hours after operation. The reaction mixture was filtered through syringe filter to afford the title compound. LCMS (M+H) found: 429.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13](O)[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[O:5]1[CH2:13][CH2:14][O:15][CH:4]1[C:3]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=1[OH:1]
Reactant: OCCO
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(O)c(C2OCCO2)c1

Procedure:
The solution of 25 g (149.6 mmol) of 2-hydroxy-5-nitrobenzaldehyde in 500 ml of toluene is mixed with 100 ml of ethylene glycol, 2.85 g of p-toluenesulfonic acid monohydrate, and it is refluxed in a water separator for 5 hours. After cooling, it is poured into saturated sodium bicarbonate solution, extracted several times with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution and dried on sodium sulfate. The residue that is obtained after filtration and removal of the solvent is further reacted without being purified.