Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:16])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[CH:18]1([CH2:24]O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.COC(C)(C)C>[CH2:14]([O:13][C:11]([C:10]1[C:9]([CH3:16])=[N:8][N:7]2[C:2]([O:1][CH2:24][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:3][C:4]([CH3:17])=[CH:5][C:6]=12)=[O:12])[CH3:15]
Reactant: OCC1CCCCC1
Reactant: CCOC(=O)c1c(C)nn2c(O)cc(C)cc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nn2c(OCC3CCCCC3)cc(C)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 180 mg (0.768 mmol) of 7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester from Example 8A in 7 ml of dry tetrahydrofuran was admixed with 0.189 ml (537 mmol) of cyclohexylmethanol, 423.2 mg (1.614 mmol) of triphenylphosphine and 0.32 ml (1.614 mmol) of diethyl azodicarboxylate. The resulting mixture was stirred at room temperature for 1 h. Some of the solvent was drawn off under reduced pressure and the residue was admixed with 5 ml of tert-butyl methyl ether. The resulting precipitate was filtered off and the mother liquor was partitioned between dichloromethane (15 ml) and water (10 ml). The organic phase was removed and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane-ethyl acetate 10:1 to 1:1), which gave 220 mg (60% of theory, 71% pure) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1.CS(C)=O>CC(=O)CC>[NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([CH:7]=1)[O:8][C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CS(C)=O
Product: Nc1cc(Oc2ncccn2)c(Cl)cc1F
Yield: 75.5 %

Procedure:
A mixture of 5-amino-2-chloro-4-fluorophenol (3.57 g), potassium carbonate (3.04 g), and 2-chloropyrimidine (3.20 g) suspended in butan-2-one (100 ml) and dimethylsulfoxide (10 ml) was heated at reflux overnight. The solution was processed and chromatographed on silica gel eluting with ethyl acetate:hexane, 1:2, to yield yellow crystals (4.0 g). 1H NMR (acetone-d6, TMS): 4.75(2H, br s), 6.78(1H, d, J=8.4 Hz), 7.09(1H, d, J=10.6 Hz), 7.15(1H, t, J=4.8 Hz), 8.56(2H, d, J=4.8 Hz).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C@H:14]([C:19]([OH:21])=O)[CH2:15][C:16](=[O:18])[NH2:17])=[O:12].[NH2:22][C@@H:23]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@H:24]([OH:43])[CH2:25][N:26]1[C@H:35]([C:36]([NH:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][C@H:33]2[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:27]1.ON1C(=O)C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[C:39]([NH:38][C:36]([C@@H:35]1[CH2:34][C@H:33]2[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:27][N:26]1[CH2:25][C@@H:24]([OH:43])[C@@H:23]([NH:22][C:19](=[O:21])[C@H:14]([CH2:15][C:16](=[O:18])[NH2:17])[NH:13][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12])[CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=c1c2ccccc2nnn1O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Temperature: 20 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
A solution of 287 mg of N-(2-quinolylcarbonyl)-L-asparagine and 401 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS, 8aS)- isoquinoline-3(S)-carboxamide in 3 ml of tetrahydrofuran was cooled to -10° C. and 163 mg of 3-hydroxy-1,2,3-benzotriazin-4(3H)-one and 220 mg of dicyclohexylcarbodiimide were added. The mixture was stirred at -10° C. for 2 hours and at 20° C. for 16 hours, then diluted with ethyl acetate and filtered. The liltrate was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and then evaporated. The residue was chromatographed on silica gel using 4% (by volume) methanol in dichloromethane for the elution to give 537 mg of N-tert.butyl-decahydro -2- [2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl) -L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid; MS: m/e 671 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3]S(C)=O.[O:7]=[CH:8][C@@H:9]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C1COCC1.[Cl-].[Na+].O>[O:7]1[CH2:3][CH:8]1[C@@H:9]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:10][CH:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CC1CCOCC1
Reactant: CS(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCOCC1)C1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
A 100 mL flask was charged with NaH (116 mg, 2.9 mmol) and Me3S+OI− (639 mg, 2.9 mmol) under N2. Dry DMSO (6 mL) was added. The mixture was stirred at rt for 1 h. A second 100 mL flask was charged with (S)-tert-butyl 1-oxo-3-(tetrahydro-2H-pyran-4-yl)propan-2-ylcarbamate (500 mg, 1.9 mmol) dissolved in THF (5 mL) under N2. The solution of NaH and Me3S+OI− was added through a syringe. The resulting mixture was stirred for 1 h. at rt. Brine was added and the mixture was extracted with EtOAc (3×10 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography to give tert-butyl (1S)-1-(oxiran-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethylcarbamate (150 mg, 29%). 1H NMR (CD3OD) δ 1.45 (s, 9H), 2.60 (b, 1 h), 2.75 (m, 1H), 3.0 (b, 1H), 3.35 (m, 2H), 4.0 (m, 3H), 4.30 (b, 1H), 5.30 (s, 2H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O=[C:7]1[NH:12][N:11]=[C:10]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[CH:9]=[CH:8]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[Cl:3][C:7]1[N:12]=[N:11][C:10]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCOC(=O)c1ccc(=O)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCOC(=O)c1ccc(Cl)nn1
Temperature: 0 °C
Yield: 80 %

Procedure:
To a mixture of phosphorus oxychloride (20 ml) and acetonitrile (40 ml) heated at reflux was added a solution of n-butyl 6-oxo-1,6-dihydropyridazine-3-carboxylate (20 g) in acetonitrile (80 ml). The reaction was heated at reflux for 30 minutes, cooled and added to an ice cooled solution of K2CO3 (87.8 g) in water (600 ml) with vigorous stirring. The product was filtered off, washed with water and dried at 60° C. to give n-butyl 6-chloropyridazine-3-carboxylate (17.5 g, 80% yield), mpt 110°-111° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=1.[NH:11]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][CH2:13][CH2:12]1>O1CCOCC1>[O:18]=[C:15]1[CH2:16][CH2:17][N:11]([C:2]2[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=2)[CH2:12][CH2:13][NH:14]1
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: O=C1CCNCCN1
Solvent: C1COCCO1
Product: O=C1CCN(c2ncc(B(O)O)cn2)CCN1
Temperature: 100 °C
Yield: 48.8 %

Procedure:
(2-Chloropyrimidin-5-yl)boronic acid (200 mg, 1.26 mmol) and 1,4-diazepan-5-one (288.34 mg, 2.53 mmol) were suspended in 1,4-dioxane (3 mL) and the mixture was heated at 100° C. under microwave irradiation for 45 minutes. The resulting slurry was concentrated under vacuum and triturated with MeOH to afford the title compound (145 mg, 30%) as a cream precipitate, which was used without further purification. Method C HPLC-MS: MH+ m/z 237, RT 0.40 minutes.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]#[N:9])=[CH:5][N:6]=1.N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)Cl>[C:16]([NH:1][C:2]1[S:3][C:4]([S:7][C:8]#[N:9])=[CH:5][N:6]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: N#CSc1cnc(N)s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ncc(SC#N)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.3 %

Procedure:
To a mixture of 2-amino-5-thiocyanatothiazole (15.7 g, 0.1 mol) and pyridine (12 g, 0.15 mol) in methylene chloride (100 mL) was added acetic anhydride (1.2 g, 0.12 mol) at rt. The mixture was stirred at rt for 6 h. The mixture was concentrated to dryness and to the residue MeOH (50 mL) was added. The precipitates were collected and washed with water. The solid was dried and recrystallized from MeOH to afford 2-acetylamino-5-thiocyanatothiazole (15.2 g, 76%) as a solid, mp 212° C. 1H NMR (CD3OD) δ7.79 (s, 1 H), 2.23 (s, 3 H).
Reaction SMILES: C(N(CC)CC)C.CN(C)S([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)(=O)=O.Cl[C:21]1[N:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1>C1COCC1>[N+:27]([C:24]1[CH:23]=[N:22][C:21]([CH:15]2[CH2:14][NH:13][CH2:18][CH2:17][NH:16]2)=[N:26][CH:25]=1)([O-:29])=[O:28]
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc(C2CNCCN2)nc1

Procedure:
Triethylamine (7.2 mL, 51.8 mmol) was added to a solution of piperazine-1-sulfonic acid dimethyl amide (10 g, 51.8 mmol) dissolved in 400 mL of THF. 2-chloro-5-nitropyrimidine (7.7 g, 48.3 mmol) dissolved in 20 mL of THF was added to the stirred mixture. After 24 hours stirring at room temperature (RT), THF was removed under vacuum and 600 mL of CHCl3 was added to the residue. The CHCl3 layer was washed with 0.5 N HCl and brine, dried over Na2SO4, and filtered. Solvent evaporation gave 14.1 g (92%) of straw yellow solid 1-N,N′-dimethylsulfamoyl-4-(2-(5-nitropyrimidyl)piperazine. The structure was confirmed by 1H-NMR. 1H NMR (CDCl3) δ9.08 (s, 2H), 4.09 (appt, J=5.13 Hz, 4H), 3.35 (appt, J=5.13 Hz, 4H), 2.87 (s, 6H). Step 2: NH4Cl (1.43 g, 26.76 mmol) was added to a suspension of 1-N,N′-dimethylsulfamoyl-4-(2-(5-nitropyrimidyl)piperazine (14.1 g, 44.6 mmol) in a mixture of EtOH (175 mL) and H2O (48 mL), followed by iron powder (7.5 g, 133.9 mmol). After refluxing 1 hour, the reaction mixture was filtered and concentrated to give a brown solid which was dissolved in 800 mL of CHCl3, washed with NaHCO3 and brine, dried over Na2SO4, and filtered. Solvent evaporation gave a yellow solid which after CC with 100:1 CHCl3:MeOH gave 11.5 g (90%) of solid yellow 1-N,N′-dimethylsulfamoyl-4-(2-(5-nitro-pyrimidyl)-piperazine. The structure was confirmed by 1H-NMR and EI-MS. 1H NMR (CDCl3) δ7.98 (s, 2H), 3.76 (t, J=4.88 Hz, 4H), 3.30 (t, J=4.88 Hz, 4H), 2.86 (s, 6H); EI-MS (m/z) 286 (M+). Step 3: A suspension of 1-N,N′-dimethylsulfamoyl-4-(2-(5-nitro-pyrimidyl)-piperazine (5.76 g, 20.2 mmol) in 100 mL of 2 M H2SO4 was refluxed for 1.5 hours until the suspension became clear. After cooling to RT, the solution pH was adjusted to 6-7 with 10 N NaOH, and the cloudy mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. Solvent evaporation gave a yellow solid, which was purified by CC using 1:1 EtOAc:hexane to yield 3.23 g (56%) of white solid JHX-2, mp 134-135° C. The structure was confirmed by 1H-NMR, 13C-NMR, ESI-MS and elemental analysis. 1H NMR (CDCl3) δ8.08 (s, 2H), 3.78 (appt, J=5.13 Hz, 4H), 3.29 (appt, J=5.13 Hz, 4H), 2.86 (s, 6H); 13C NMR (CDCl3) 156.9, 145.8, 143.5, 46.0, 44.3, 38.1; EI-MS (m/z) 287 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[F:11][C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[N:19]=[C:20]=S.O[Li].O.OO>O1CCCC1>[Br:18][C:16]1[CH:15]=[CH:14][C:13]([NH:19][C:20]2[O:10][C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[N:1]=2)=[C:12]([F:11])[CH:17]=1
Reactant: Fc1cc(Br)ccc1N=C=S
Reactant: Cc1cc(C)c(O)c(N)c1
Agent: OO
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c2oc(Nc3ccc(Br)cc3F)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An ambient solution of 2-amino-4,6-dimethylphenol (0.85 g, 6.2 mmol) and 2-fluoro-4-bromophenyl isothiocyanate (1.44 g, 6.20 mmol) in tetrahydrofuran (20 mL) was stirred for 16 h. The reaction was cooled (0° C.), and LiOH.H2O (0.521 g, 12.41 mmol) was added, followed by the dropwise addition of 30% H2O2 (3.41 mL, 31.0 mmol) over 15 minutes. The reaction was warmed to room temperature and stirred for 16 h. The reaction was then quenched by the addition of 20% aqueous sodium sulfite solution (50 mL) and ethyl acetate (75 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×75 mL). The combined organics were, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 25% ethyl acetate in hexane, to give the title compound. MS (ESI) m/z 335[M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].O([C:17]1[C:18]2[C:23]([N:24]=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)=[CH:22][CH:21]=[CH:20][CH:19]=2)C1C=CC=CC=1.CCOCC>C1(O)C=CC=CC=1>[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:17]1[C:18]2[C:23]([N:24]=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:9])=[O:8]
Reactant: NCCCCCC(=O)O
Reactant: c1ccc(Oc2c3ccccc3nc3ccccc23)cc1
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: O=C(O)CCCCCNc1c2ccccc2nc2ccccc12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
6-Aminohexanoic acid (1.47 g, 11.2 mmol) was added to a solution of 9-phenoxyacridine (2.7 g, 10 mmol) in phenol (15 g). The suspension was stirred at 120° C. for 2 h. The solution was cooled to room temperature and poured into ether whereby the product precipitated as a yellow-green solid. It was triturated with hot ethanol, filtered then washed with ethanol, giving crude 9-(5-carboxypentyl) aminoacridine.Yield 2.4 g (78%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)([O-:18])=[O:17]>C(Cl)Cl>[CH3:8][O:9][CH:10]1[CH2:15][CH2:14][N:13]([S:25]([C:22]2[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][C:21]=2[C:29]([F:30])([F:31])[F:32])(=[O:27])=[O:26])[CH2:12][CH2:11]1
Reactant: COC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (1.0 g) and 4-methoxypiperidine (1.15 g) were added to a solution of 4-nitro-2-trifluoromethyl-benzene sulphonyl chloride (2.89 g) in methylene chloride (40 ml). The mixture was stirred at 25°C. for 2 hours and then evaporated to dryness in vacuo. The residual oil was triturated with 1:1 aqueous isopropanol and the resulting solid was recrystallized from isopropanol to give 1-(4-methoxypiperidinosulphonyl)-4-nitro-2-trifluoromethyl-benzene, m.p. 141°-143°C.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([CH3:16])=[N:9][C:10]3[N:11]([N:12]=[C:13]([CH3:15])[CH:14]=3)[C:6]=2[N:5]=[CH:4][C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH:22]([NH2:26])([CH2:24][CH3:25])[CH3:23]>>[CH3:15][C:13]1[CH:14]=[C:10]2[N:9]=[C:8]([CH3:16])[C:7]3[C:2]([NH:26][CH:22]([CH3:23])[CH2:24][CH3:25])=[C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:4]=[N:5][C:6]=3[N:11]2[N:12]=1
Reactant: CCOC(=O)c1cnc2c(c(C)nc3cc(C)nn32)c1Cl
Reactant: CCC(C)N
Product: CCOC(=O)c1cnc2c(c(C)nc3cc(C)nn32)c1NC(C)CC
Reaction time: 1 h

Procedure:
3.0 g. of 6-chloro-2,5-dimethylpyrazolo[1,5-a]-pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester of Example 1c (0.01 mol.) are dissolved in 20 ml. of alcohol. 2.1 g. of sec. butylamine (0.03 mol.) are added and the mixture is refluxed with stirring for 1 hour. The solvent and excess amine is removed in vacuo and the crystalline residue is treated with water and filtered off to obtain 2,5-dimethyl-6-[(1-methylpropyl)amino]pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester, yield 3.1 g. (91%), m.p. 113°-115° (ethyl acetate).
Reaction SMILES: [CH2:1]([C:3]1([CH2:21][OH:22])[CH2:8][O:7][C:6]2([CH2:13][C:12]([CH2:15][CH3:16])([CH3:14])[NH:11][C:10]([CH2:18][CH3:19])([CH3:17])[CH:9]2[CH3:20])[O:5][CH2:4]1)[CH3:2].[C:23](Cl)(=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>N1C=CC=CC=1.O>[C:23]([O:22][CH2:21][C:3]1([CH2:1][CH3:2])[CH2:4][O:5][C:6]2([CH2:13][C:12]([CH2:15][CH3:16])([CH3:14])[N:11]([O:7][C:6](=[O:5])[CH3:9])[C:10]([CH2:18][CH3:19])([CH3:17])[CH:9]2[CH3:20])[O:7][CH2:8]1)(=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCC1(CO)COC2(CC(C)(CC)NC(C)(CC)C2C)OC1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC1(CC)COC2(CC(C)(CC)N(OC(C)=O)C(C)(CC)C2C)OC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
12 g (0.037 mol) of 3,8,10-triethyl-7,8,10-trimethyl-1,5-dioxa-9-azaspiro[5.5]undec-3-ylmethanol (for method of preparation, see U.S. Pat. No. 4,105,626) are dissolved in 40 ml of pyridine and admixed with 11.7 g (0.039 mol) of stearoyl chloride. After stirring for 18 hours at room temperature, the reaction mixture is diluted with 200 ml of water and extracted with 2×50 ml of methyl-t-butylether. After distilling off the solvent, the resulting stearoyl nitroxide is converted by a method analogous to Example A 30 into the compound 144 which is obtained in the form of a colourless oil.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:67][N:68]1[CH:72]=[C:71]([CH:73]=O)[CH:70]=[N:69]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:73]([C:71]3[CH:70]=[N:69][N:68]([CH3:67])[CH:72]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Cn1cc(C=O)cn1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cn1cc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cn1
Reaction time: 6 h
Yield: 26.7 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (75 mg, 0.19 mmol), DMF (0.85 mL), ethanol (0.15 mL), 1M Na2S2O4 (3 eq, 0.57 mmol, 0.57 mL) and 1-methyl-1H-pyrazole-4-carboxaldehyde (1.1 eq, 0.21 mmol, 23 mg). After 6 h, concentration in vacuo and preparation by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (23 mg, 24%) as a colourless solid; 1H-NMR (500 MHz, DMSO-d6) 2.60 (br s, 4H, piperazine N(CH2)2), 3.60 (t, J=4.5 Hz, 4H, piperazine N(CH2)2), 3.61 (s, 2H, CH2), 3.93 (s, 3H, NCH3), 7.40 (dd, J=7.6, 4.8 Hz, 1H, pyridine H-5), 7.78 (d, br, J=7.7 Hz, 1H, pyridine H-4), 8.06 (s, 1H, pyrazole H-2 or H-4), 8.19 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.35 (s, 1H, pyrazole H-2 or H-4), 8.50 (d, br, J=4.7 Hz, 1H, pyridine H-6), 8.57 (s, br, 1H, pyridine H-2), 13.21 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)[N:12]=[C:11]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:36]([F:47])[CH:35]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[F:47][C:36]1[CH:35]=[C:34]([NH:33][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([CH2:14][N:13]3[C:9]([CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:10][C:11]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=4)=[N:12]3)=[CH:16][CH:17]=2)[CH:39]=[CH:38][C:37]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]
Reactant: O=Cc1ccc(Cn2nc(-c3ccc(C(F)(F)F)cc3)cc2CCc2ccccc2)cc1
Reactant: CCOC(=O)CCc1ccc(N)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ccc(NCc2ccc(Cn3nc(-c4ccc(C(F)(F)F)cc4)cc3CCc3ccccc3)cc2)cc1F
Reaction time: 1 h

Procedure:
To a mixture of 4-({5-(2-phenylethyl)-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)benzaldehyde (868 mg, 2.0 mmol), ethyl 3-(4-amino-2-fluorophenyl)propanoate (420 mg, 2.0 mmol), acetic acid (300 mg, 5.0 mmol) and 1,2-dichloroethane (15 mL) was added sodium triacetoxyborohydride (1.20 g, 6.0 mmol) by small portions at room temperature and the mixture was stirred for 1 hr. The reaction mixture was poured into 10% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane) to give the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]([NH:30][S:31]([C:34]1[S:35][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[S:35][C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([C:22]([F:24])([F:23])[F:25])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=4[Cl:21])[N:13]=3)[CH:3]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2Cl)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4Cl)cc(C(F)(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[6-(2,4-dichloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-(2,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.106) (0.45 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.414 g, 1.2 mmol) according to the general procedure VI. Obtained as an off-white solid (0.4 g), which was subsequently deprotected.