Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([S:8][CH2:9][CH:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:21])=[C:17]([OH:20])[CH:18]=3)[CH2:13][CH2:12][NH:11]2)=[N:6][N:5]=[N:4]1.C(=O)(O)[O-].[Na+].O1CCCC1.Cl[C:33]([O:35][CH2:36][C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34]>O>[CH3:2][N:3]1[C:7]([S:8][CH2:9][CH:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:21])=[C:17]([OH:20])[CH:18]=3)[CH2:13][CH2:12][N:11]2[C:33]([O:35][CH2:36][C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34])=[N:6][N:5]=[N:4]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cn1nnnc1SCC1NCCc2cc(O)c(O)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnnc1SCC1c2cc(O)c(O)cc2CCN1C(=O)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
A suspension of 1-(1-methyl-1H-tetrazol-5-yl)thiomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (50 g) in water (300 ml) was dissolved at 61° to 65° C. To the solution was added sodium bicarbonate (13.3 g) over 15 minutes at the same temperature. Tetrahydrofuran (250 ml) was added to the suspension at 50° C. The suspension was cooled and weakly alkalified by adding sodium bicarbonate (30 g) at 0° to 3° C. To the mixture was added 2,2,2-trichloroethyl chloroformate (40.2 g) over 30 minutes below 3° C. The resulting mixture was stirred for 30 minutes at 0° C. Water (300 ml) was added to the reaction mixture and the mixture was twice extracted with ethyl acetate (900 ml and 600 ml). The extract was washed with a sodium chloride aqueous solution (300 ml) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized with ether to give 1-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-(2,2,2-trichloroethoxycarbonyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (40.4 g), mp 201° to 207° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5](=[O:33])[C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21](=[O:30])[CH2:22][S:23](=[O:29])(=[O:28])[NH:24][CH:25]([CH3:27])[CH3:26])=[C:9]([CH3:31])[NH:8][C:7]=1[CH3:32].[C:34]([O-:37])(=[O:36])[CH3:35].[Na+]>CN(C)C=O>[C:34]([O:37][CH2:2][CH2:3][O:4][C:5](=[O:33])[C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21](=[O:30])[CH2:22][S:23](=[O:29])(=[O:28])[NH:24][CH:25]([CH3:27])[CH3:26])=[C:9]([CH3:31])[NH:8][C:7]=1[CH3:32])(=[O:36])[CH3:35]
Reactant: CC(=O)[O-]
Reactant: CC1=C(C(=O)CS(=O)(=O)NC(C)C)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCCCl)=C(C)N1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOC(=O)C1=C(C)NC(C)=C(C(=O)CS(=O)(=O)NC(C)C)C1c1cccc([N+](=O)[O-])c1
Yield: 58.9 %

Procedure:
A solution of 3.0 g of 1,4-dihydro-5-[(isopropylsulfamoyl)acetyl]-2,6-dimethyl-4-(3-nitrophenyl)-nicotinic acid 2-chloroethyl ester in 18 ml of dimethylformamide were treated under argon with 0.75 g of dry sodium acetate and the mixture was thereupon heated to reflux for 1 hour. The mixture was then concentrated to dryness under reduced pressure and the residue was partitioned between water and methylene chloride. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The residual oil was chromatographed on 300 g of silica gel with methylene chloride/ethyl acetate (4:1) as the elution agent. The uniform fractions were combined and evaporated. After triturating the residue with ether there were obtained 1.85 g of 1,4-dihydro-5-[(isopropylsulfamoyl)acetyl]-2,6-dimethyl-4-(3-nitrophenyl)nicotinic acid 2-acetoxyethyl ester in the form of pale yellow crystals, m.p. 133°-136°. Recrystallization from isopropanol yielded a product of melting point 134°-137°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[N+:11]([C:14]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([O:24][CH3:25])[CH:18]=[CH:17][C:15]=1[NH2:16])([O-:13])=[O:12]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([O:24][CH3:25])=[C:20]([N+:21]([O-:23])=[O:22])[C:14]=2[N+:11]([O-:13])=[O:12])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1[N+](=O)[O-]
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c1[N+](=O)[O-]

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 2,3-dinitro-4-methoxyaniline as a white solid as described in Example 1. 1H NMR (CDCl3): 9.99 (s, 1H), 8.96 (d, J=2.4, 1H), 8.77 (d, J=9.3, 1H), 8.18-8.14 (m, 1H), 7.53 (d, J=9.0, 1H), 7.45 (d, J=9.3, 1H), 4.02 (s, 3H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]([F:26])([F:25])[CH:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](OCC)=[O:15].CO.[OH-].[K+]>CCCCCC.O1CCCC1>[C:19]1([CH:13]([C:12]([F:11])([F:25])[F:26])[CH2:14][OH:15])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(c1ccccc1)C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCCC
Product: OCC(c1ccccc1)C(F)(F)F
Reaction time: 1.5 h
Yield: 87.1 %

Procedure:
A 20% solution of diisobutylaluminium hydride in n-hexane (53.4 ml) was added, dropwise, to ethyl α-trifluoromethylphenylacetate (2.9 g; 12.5 mmol) (T. S. Everett, S. T. Purrington, C. L. Baumgardner, J. Org. Chem. 49, 3702 (1984)) in absolute tetrahydrofuran (50 ml) at about 60° C. The mixture was then allowed to rise to room temperature and stirred for an hour at this temperature. Then at a temperature of 5°-10° C., methanol (10.5 ml) followed by 10% aqueous potassium hydroxide (5.3 ml) was added, dropwise. After 1.5 hours, the mixture was filtered and the filtrate dried over sodium sulphate which was washed with ethyl acetate and the organic phase concentrated. There was obtained 2-phenyl-2-trifluoromethylethanol (2.07 g=87.1 of theory).
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31](I)[CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:17]([O:27][CH3:28])=[CH:16][N:15]=2)=[N:6]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:53]([Si:55]([CH3:58])([CH3:57])[CH3:56])#[CH:54]>C(N(CC)CC)C.C1(/C=C/C(=O)/C=C/C2C=CC=CC=2)C=CC=CC=1.[Pd].[Cu]I>[F:1][C:2]1[CH:32]=[C:31]([C:54]#[C:53][Si:55]([CH3:58])([CH3:57])[CH3:56])[CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:17]([O:27][CH3:28])=[CH:16][N:15]=2)=[N:6]1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cnc(-c2nn(Cc3ccc(I)cc3F)c3ccccc23)nc1Nc1ccncc1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cnc(-c2nn(Cc3ccc(C#C[Si](C)(C)C)cc3F)c3ccccc23)nc1Nc1ccncc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
144.7 mg of 2-[1-(2-fluoro-4-iodobenzyl)-1H-indazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine (2-201, 0.262 mmol, 1 eq.), 6.02 mg of (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium (2:1) (0.01 mmol, 0.04 eq.), 2.0 mg of copper (I) iodide (0.01 mmol, 0.04 eq.), and 13.7 mg of triphenylphosphane (0.052 mmol, 0.2 mmol) were suspended in 2.6 ml of dry N,N-diethylethanamine and purged with nitrogen. Then 3.86 ml of ethynyl(trimethyl)silane (1.57 mmol, 6 eq.) were added and the reaction mixture was stirred at 60° C. for 18 hours. The mixture was concentrated under vacuo. The crude product was used without further purification in step 2.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:12]2[C:13]([C:28](O)=[O:29])=[N:14][N:15]([C:18]3[C:19]([O:26][CH3:27])=[N:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=3)[C:16]=2[CH3:17])[CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:11]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[C:12]3[C:13](=[N:14][N:15]([C:18]4[C:19]([O:26][CH3:27])=[N:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=4)[C:16]=3[CH3:17])[C:28]2=[O:29])[CH:3]=1
Reactant: COc1ncc(-n2nc(C(=O)O)c(C(Nc3cc(Cl)c(=O)n(C)c3)c3ccc(Cl)cc3)c2C)c(OC)n1
Solvent: ClCCl
Solvent: CO
Product: COc1ncc(-n2nc3c(c2C)C(c2ccc(Cl)cc2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-(((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)(4-chlorophenyl)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-methyl-1H-pyrazole-3-carboxylic acid (Step 55.5). tR: 4.30 min (HPLC 1); tR: 0.98 min (LC-MS 2); ESI-MS: 527/529 [M+H]+ (LC-MS 2); Rf=0.37 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 (s, 3H) 3.44 (s, 3H) 3.92 (s, 3H) 3.96 (s, 3H) 6.24 (s, 1H) 7.29-7.42 (m, 4H) 7.93 (d, J=2.7 Hz, 1H) 7.97 (d, J=2.4 Hz, 1H) 8.53 (s, 1H).
Reaction SMILES: [AlH4-].[Li+].[N+:3]([C:6]1[C:7]([NH:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([C:21](OCC)=[O:22])[CH2:17]2)=[C:8]2[S:14][CH:13]=[CH:12][C:9]2=[N:10][CH:11]=1)([O-:5])=[O:4]>O1CCCC1>[N+:3]([C:6]1[C:7]([NH:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([CH2:21][OH:22])[CH2:17]2)=[C:8]2[S:14][CH:13]=[CH:12][C:9]2=[N:10][CH:11]=1)([O-:5])=[O:4]
Reactant: CCOC(=O)[C@@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)C1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@@H](CO)C1
Temperature: 0 °C
Yield: 53 %

Procedure:
Lithium tetrahydroaluminate (20.4 mg, 0.537 mmol) was added to a solution of ethyl (1R,3S)-3-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclopentanecarboxylate (0.15 g, 0.45 mmol) in tetrahydrofuran (4.0 mL) with stirring at about 0° C. The resulting mixture was kept cold and stirred for 40 min. Fieser workup was performed followed by filtration through Celite and concentrated. The crude was purified using silica gel, eluted with 40-100% EtOAc in hexanes to give 70 mg (50%) of the desired product. LCMS calculated for C13H16N3O3S (M+H)+: m/z=294.1. Found: 294.0.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][C:7]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)=[O:8])[CH2:5][CH2:4]1.[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>C1COCC1.CN(C=O)C>[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:11]3[CH:10]=[C:9]([C:7]([NH:6][CH:3]4[CH2:4][CH2:5]4)=[O:8])[CH:13]=[N:12]3)(=[O:35])=[O:36])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(NC1CC1)c1cn[nH]c1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)NC4CC4)cn3)ccc2n1CC1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
Sodium hydride (0.98 g, 60%, 25 mmol) was added to a solution of N-cyclopropyl-1H-pyrazole-4-carboxamide (0.49 g, 3.5 mmol) (see following steps B and C for preparation) in 40 mL of THF-DMF (3:1) at 0° C. Stirring for 1 h at 0° C. and 0.5 h at room temperature, 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (1.30 g, 3.5 mmol) was added. The reaction mixture was stirred for 2 h at 0° C., quenched with NaHCO3 (10 mL) and extracted with EtOAc (3×50 mL). The combined organic phases were washed with NaCl (20 mL) and dried over Na2SO4. The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 0.54 g (33%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.52-0.59 (m, 2 H), 0.71-0.79 (m, 2 H), 1.39-1.57 (m, 4 H), 1.60 (s, 9 H), 2.22-2.37 (m, 1 H), 2.71-2.79 (m, 1 H), 3.26-3.34 (m, 2 H), 3.86-3.93 (m, 2 H), 4.43 (d, J=7.62 Hz, 2 H), 7.91-7.95 (m, 1 H), 7.97-8.01 (m, 1 H), 8.03 (d, J=0.78 Hz, 1 H), 8.34 (d, J=1.37 Hz, 1 H), 8.74 (d, J=0.59 Hz, 1 H); MS (ESI) (M+H)+=485.8.
Reaction SMILES: [F:1][C:2]1([F:55])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([OH:42])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[C@@H:43]([F:54])[C:44]2[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=2)[CH2:4][CH2:3]1.Cl.C(=O)([O-])O.[Na+]>O1CCOCC1>[F:55][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][C:39]([OH:42])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[C@@H:43]([F:54])[C:44]2[CH:45]=[CH:46][C:47]([C:50]([F:51])([F:53])[F:52])=[CH:48][CH:49]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(CO[C@H]2CC(C)(C)Cc3nc(C4CCN(c5ncc(O)cn5)CC4)c([C@@H](F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 94.2 %

Procedure:
To a solution of 453 mg (0.589 mmol) of 2-[4-((5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-2-yl)piperidin-1-yl]pyrimidin-5-ol, which was prepared by a method similar to that of Reference Example 14, in 5 ml of 1,4-dioxane, 1 ml of 6 N hydrochloric acid was added, and the mixture was stirred at 80° C. for 4.5 hours. After completion of the reaction, the reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=76/24-40/60 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 360 mg of the title compound as a white solid (yield: 94%).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][CH:13]=2)[N:8]=[C:7]1[CH2:19]O)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH:21]1([N:24]2[C:32]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[NH:26][C:25]2=[O:33])[CH2:23][CH2:22]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1>[CH:21]1([N:24]2[C:32]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[N:26]([CH2:19][C:7]3[N:6]([CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])[C:14]4[C:9]([N:8]=3)=[N:10][C:11]([C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=4)[C:25]2=[O:33])[CH2:23][CH2:22]1
Reactant: CC(C)CCn1c(CO)nc2nc(C(F)(F)F)ccc21
Reactant: O=c1[nH]c2cnccc2n1C1CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.2 %

Procedure:
To a suspension of (1-isopentyl-5-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol 44-3 (1.0 g, 3.5 mmol (73% purity)), 1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 10-d (731.8 mg, 4.2 mmol) and triphenylphosphine (1.1 g, 4.2 mmol) in 24 ml dry THF was added (E)-diisopropyl diazene-1,2-dicarboxylate (1.0 ml, 5.2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness and purified by preparative column chromatography to obtain 44 as a white solid (578.0 mg, 37%). m/z=445 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02 (m, J=6.50 Hz, 8H) 1.13-1.24 (m, 2 H) 1.48-1.64 (m, 2 H) 1.73 (dquin, J=13.19, 6.49, 6.49, 6.49, 6.49 Hz, 1 H) 2.92 (tt, J=6.81, 3.48 Hz, 1 H) 4.35-4.52 (m, 2 H) 5.41 (s, 2 H) 7.13 (d, J=5.27 Hz, 1 H) 7.61 (d, J=8.28 Hz, 1 H) 7.79 (d, J=8.28 Hz, 1 H) 8.34 (d, J=5.27 Hz, 1 H) 8.68 (s, 1 H).
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:7]=[CH:8][C:9]([F:18])=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:11]=1)[CH3:5])=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:18][C:9]1[CH:8]=[CH:7][C:6]([CH:4]([NH2:1])[CH3:5])=[CH:11][C:10]=1[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: CC(N=[N+]=[N-])c1ccc(F)c(N2CCOCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(N)c1ccc(F)c(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of 4-[5-(1-azido-ethyl)-2-fluoro-phenyl]-morpholine (1 g) in THF (20 mL) at 40° C. was added LiAlH4 (500 mg). The reaction mixture was warmed to room temperature and then stirred for 1 hour. The reaction was quenched with water, 10 N sodium hydroxide followed again by water. The resulting mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was extracted with CH2Cl2, and the organic layer was washed with water, dried over Na2SO4, filtered and concentrated in vacuo to give 890 mg of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](OC2C=CC=CC=2)=[N:18][C:19]#[N:20])=[CH:12][CH:11]=1>C(O)(C)C>[C:19](/[N:18]=[C:17](\[O:16][C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1)/[NH:5][C:4]1[CH:6]=[CH:7][C:8]([F:9])=[C:2]([F:1])[CH:3]=1)#[N:20]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1ccc(F)c(F)c1
Solvent: CC(C)O
Product: N#C/N=C(/Nc1ccc(F)c(F)c1)Oc1ccccc1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a solution of 3,4-difluoroaniline (646 mg, 5 mmol) in isopropanol (10 mL) was added diphenyl cyanocarbonimidate (1.19 g, 5 mmol) and the suspension was stirred at room temperature over night. The precipitate was filtered off, washed with isopropanol and dried under reduced pressure to yield the title compound as a white solid (1.18 g, 86%).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([O:14][C@@H:15]1[C@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@:20]([CH3:41])([CH2:31][O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:19][C@H:16]1OC)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:42]([OH:45])(=[O:44])[CH3:43]>C(OC(=O)C)(=O)C.C(OCC)(=O)C.[Cl-].[Na+].O>[C:42]([O:45][C@@H:16]1[O:19][C@:20]([CH3:41])([CH2:31][O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:15]1[O:14][C:6](=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)O
Reactant: CO[C@@H]1O[C@](C)(COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)O[C@@H]1O[C@](C)(COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
Concentrated sulfuric acid (97%, 99 mL) was added to a solution of 2,3,5-tri-O-benzoyl-1-O-methyl-4-C-methyl-β-D-ribofuranose (1.8 g, 3.6 mmoles) in a mixture of acetic acid (9.0 mL) and acetic anhydride (0.90 mL) at 0° C. The reaction mixture was stirred at 25° C. for 16 h and diluted with ethyl acetate (50 mL) and brine (10 mL). The organic extract was washed with brine (3 times), with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was dissolved with a mixture of ethyl acetate and hexanes (1:4, v/v) and the b anomer of the title compound crystallized instantaneously. The white crystals were filtered to give 1.1 g (56%) of the title compound in its pure b anomer form. The filtrate was subjected to silica gel chromatography [ethyl acetate (20%) in hexanes] to give 0.6 g (32%) of the titled compound as an oil (3:1 mixture of a/b anomers).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([Br:12])[CH:11]=1)[CH:7]=[O:8].Cl>CO>[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([Br:12])[CH:11]=1)[CH2:7][OH:8]
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(Br)cc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Sodium borohydride (0.75 g) was added portionwise to a stirred suspension of 3,5-dibromobenzaldehyde (10.46 g) in methanol (50 ml) at 0° C. The mixture was stirred at 0° C. for 30 minutes, allowed to warm to room temperature and then its pH was adjusted to 2 using concentrated hydrochloric acid. Evaporation under vacuum provided a residue which was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4), then evaporated under vacuum to furnish the title compound as a solid (10.0 g), m.p. 103°-104° C. Found: C,31.98; H,2.23. C7H6Br2O requires C,31.61; H,2.77%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](I)[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:12][CH2:13][CH3:14])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cc(F)ccc1[N+](=O)[O-]

Procedure:
5-fluoro-2-nitrophenol (300 mg), n-propyl iodide (0.50 ml) and potassium carbonate (500 mg) were dissolved in dimethylformamide (DMF, 3 mL) and reacted at 50° C. overnight. The dimethylformamide of the reaction mixture was concentrated under reduced pressure, added with water and the organic layer was extracted with ethyl acetate. The organic layer was washed with brine, and the water was removed with sodium sulfate, and the solvent was removed under reduced pressure. The thus obtained compound was used in the subsequent reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:3]=1[C:29](=[O:31])[CH3:30].[CH3:32]I>CN(C=O)C>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]([CH:23]2[CH2:24][CH2:25][N:26]([CH3:32])[CH2:27][CH2:28]2)[C:3]=1[C:29](=[O:31])[CH3:30]
Reactant: CI
Reactant: CC(=O)c1c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Solvent: CN(C)C=O
Product: CC(=O)c1c(C2CCN(C)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Reaction time: 1 h

Procedure:
To a solution of 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone (25 mg, 0.06 mmol), DEA (52 μL, 0.3 mmol) in DMF (1 mL) was added MeI (15 μL, 0.24 mmol). The reaction mixture was stirred for one hour and directly purified by HPLC to provide the title compound. LC/MS RT=2.76 min. Mass calculated for M+H 427.2, observed 427.3.
Reaction SMILES: Cl.Cl.[C:3]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:4]=1.[F:21][C:22]([F:46])([F:45])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43]Br)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:21][C:22]([F:45])([F:46])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43][N:12]2[CH2:11][CH2:10][N:9]([C:5]3[CH:4]=[C:3]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:8]=[CH:7][CH:6]=3)[CH2:14][CH2:13]2)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26]
Reactant: c1ccc(-c2cccc(N3CCNCC3)c2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cccc(-c4ccccc4)c3)CC2)c2ccccc2-c2ccccc21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A suspension of 0.2 g (0.643 mmol) of 1-biphenyl-3-yl-piperazine-dihydrochloride, 0.256 g (0.6 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide and 0.1 g potassium carbonate in 20 ml of acetonitrile and 0.1 ml of water is stirred for 24 hours at 60° C. The reaction mixture is poured onto water, extracted with ethyl acetate and dried over sodium sulphate. Purification is by column chromatography on silica gel (eluant: dichloromethane/ethanol=30:1).