Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][N:3]=1.[CH2:14]([Mg]Cl)[CH3:15].CCOCC.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6](=[O:7])[CH2:14][CH3:15])=[CH:12][CH:13]=1
Reactant: CC[Mg]Cl
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60 %

Procedure:
To a solution of 6-chloro-N-methoxy-N-methyl nicotinamide (6.0 g, 30 mmol) (produced as disclosed in Perner, R. J. J. Med. Chem. 2003, 46, 5249) in THF (100 mL) was added a 3M solution of ethyl magnesium chloride in ether (15 mL, 45 mmol). The reaction mixture was heated under reflux for 4 hours and then stirred at approximately 25° C. for 14 hours. The reaction mixture was treated with a saturated aqueous solution of ammonium chloride (100 mL) and then extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography over silica gel, eluting with 10 percent ethyl acetate in hexane to give product as a white solid. (2.8 g, 60 percent yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Fc1cnc(Cl)nc1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ncc(F)cn1

Procedure:
The title compound, MS: m/e=313.1 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-chloro-5-fluoro-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH:9]([C:15]([OH:17])=[O:16])[CH2:8][C:7]2=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C.O>[CH2:24]([O:16][C:15]([CH:9]1[CH2:8][C:7]2[C:6]3[C:14](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[NH:13][C:12]=2[CH2:11][CH2:10]1)=[O:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)C1CCc2[nH]c3c(Cl)cccc3c2C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Product: O=C(OCc1ccccc1)C1CCc2[nH]c3c(Cl)cccc3c2C1
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
A stirred mixture of crude 8-chloro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (4.45 g, 17.8 mmol) and cesium carbonate (2.90 g, 8.92 mmol) in ethanol (150 ml) and water (25 ml) is refluxed until a clear solution is obtained (15 min). Then the solvents are evaporated and the dried residue is dissolved in dry DMF. This solution is treated with benzylbromide (2.27 ml, 18.7 mmol) and stirred at 45° C. for 15 min. The resulting precipitate is filtered off and the filtrate is concentrated. The residue is purified by flash chromatography on silica gel (heptane/EtOAc 3:1) to deliver pure title compound as a yellowish solid (4.2 g) in 69% yield. tR (LC-5) 1.09 min; ESI-MS (positive ion): m/z 340.19 [M+H]+ (calcd 339.82 for C20H18NO2Cl). 1H-NMR (DMSO-d6): 1.90 (m, 1H); 2.19 (m, 1H); 2.86 (m, 5H); 5.13 (s, 2H); 6.91 (t, J=7.6 Hz, 1H); 7.04 (d, J=7.6 Hz, 1H); 7.32 (m, 6H); 11.0 (br s, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]2[CH:8]([CH:10]([CH3:12])[CH3:11])[CH2:9][CH:4]([CH:5]([C:13]([O:15]CC)=[O:14])[CH2:6]2)[N:3]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)C.[OH-].[Na+].C(O)(=O)C>O>[CH3:1][CH:2]1[CH:7]2[CH:8]([CH:10]([CH3:11])[CH3:12])[CH2:9][CH:4]([CH:5]([C:13]([OH:15])=[O:14])[CH2:6]2)[N:3]1[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1CC2C(C(C)C)CC1N(Cc1ccccc1)C2C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)C1CC2C(C(=O)O)CC1C(C)N2Cc1ccccc1
Yield: 100.5 %

Procedure:
A mixture of ethyl 3-methyl-8-isopropyl-2-(phenylmethyl)-2-azabicyclo[2.2.2]octane-6-carboxylate (32.9 g, 100 mmol), ethanol (150 mL), water (150 mL) and NaOH (4.8 g, 120 mmol) were refluxed for 18 hours. The solvent was removed in vacuo and the residue was diluted with water and washed with ether (1×50 mL). The aqueous layer was acidified with acetic acid (6.9 mL, 120 mmol) and extracted with CH2Cl2 (3×50 mL). The organic layers were combined, washed with brine, dried over MgSO4 and concentrated in vacuo to afford 30.3 g (100%) of 3-methyl-8-isopropyl-2-(phenylmethyl)-2-azabicyclo[2.2.2]octane-6-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][N:7]=[C:8]=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[N:18]=[N:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[O:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:12][C:13]2[N:18]=[N:17][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:25](=[O:26])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:36])([F:35])[F:34])[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: O=C=NCc1ccc(F)cc1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: O=C(NCc1ccc(F)cc1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 5, making variations only as required to use 4-fluorobezylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white solid (56% yield). 1H NMR (500 MHz, CDCl3) δ 8.13, 7.78, 7.66, 7.60, 7.33, 7.21, 7.09, 6.83, 4.50, 3.91-4.00, 3.73-3.80, 3.34-3.48, 3.05-3.22. MS (ES+) m/z 503 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1N)C(=O)O
Reaction time: 4 h
Yield: 99.9 %

Procedure:
At mixture of (2S)-2-tert-Butoxycarbonylamino-3-(2-nitrophenylamino)propionic acid (12.65 g, 40.5 mmol) and 0.5 g of 10% Pd/C in 100 ml of MeOH under hydrogen at 1 atmosphere was stirred for 4 h. The solution was filtered through Celite 545 and the filtrate evaporated in vacuo to afford the 11.95 g of the title compound in quantitative yield as a dark brown solid that was used without purification: 1H NMR (CD3OD) δ6.75-6.70 (3H,m), 6.65-6.58 (1H, m), 4.35-4.3 1H, m), 3.6-3.38 (2H, m), 1.45 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:3]=1[C:22]#[N:23].[CH:24](O)=O.[OH2:27]>>[CH2:7]([N:6]1[C:2]2=[N:1][CH:24]=[N:23][C:22]([OH:27])=[C:3]2[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[N:5]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1cccc(-c2nn(Cc3ccccc3)c(N)c2C#N)c1
Reactant: O=CO
Reactant: O
Product: COc1cccc(-c2nn(Cc3ccccc3)c3ncnc(O)c23)c1
Temperature: 25 °C

Procedure:
A mixture of 2.55 g (8.38 mmol) of 5-amino-1-benzyl-4-cyano-3-(3-methoxy-phenyl)-pyrazole and 20 ml of 85% aqueous formic acid is heated under reflux for 21 hours and then cooled to room temperature and, with stirring, a small amount of water is added thereto. Filtering and washing the filter residue with water yield the title compound; m.p. 183-185° C.; FAB-MS: (M+H)+ =333.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:21][C@@H:22]([C:25]1[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1)[CH2:23][OH:24].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:21][C@@H:22]([C:25]4[CH:26]=[N:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=4)[CH2:23][OH:24])[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N[C@H](CO)c1ccc(C(F)(F)F)nc1
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Cl)c2C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)ccc1N1CCc2ncnc(N[C@H](CO)c3ccc(C(F)(F)F)nc3)c2C1
Yield: 18.9 %

Procedure:
A reaction mixture of 5-chloro-2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (150 mg, 0.49 mmol) and (S)-2-amino-2-(6-(trifluoromethyl)pyridin-3-yl)ethanol (150 mg, 0.74 mmol) (prepared similarly according to the method for Intermediate 10) in acetonitrile (3 mL) and N,N-diisopropylethylamine (170 μL, 0.98 mmol) was subjected to microwave irradiation at 180° C. for 4 h. The reaction mixture was concentrated and the residue was purified by silica gel column (100% EtOAc and then 0-20% MeOH/CH2Cl2) followed by semi-preparative HPLC (100×20.2 mm, C18 column; 30-70% acetonitrile-water [10 mM Et2NH]) to yield a light yellow foam (44 mg).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[C:4]([CH3:13])[CH:3]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:26](OCCC(C)C)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[N:9]([C:10](=[O:12])[CH3:11])[N:26]=[CH:13]2
Reactant: CC(=O)Nc1cc(F)c(Br)cc1C
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)n1ncc2cc(Br)c(F)cc21
Reaction time: 3 h

Procedure:
To a solution of 77.0 g of N-(4-bromo-5-fluoro-2-methylphenyl)acetamide in 930 mL of toluene were added 93.0 mL of acetic anhydride and 37.0 g of potassium acetate at room temperature, and the resultant solution was heated at 90° C., slowly added dropwise with 67.0 mL of isoamyl nitrite, and stirred at this temperature for 3 hours. After diluting with ethyl acetate, washing successively with water and saturated brine, and drying over anhydrous magnesium sulfate, the solvent was evaporated. The precipitated crystals were washed with diethyl ether:n-hexane=1:10, the filtrate concentrated and purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=0:100-1:5) and finally combined with the previous crystals, to afford 22.5 g of the title compound as pale brown crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[C:14](=[O:15])[N:13]([CH2:16][C:17]3[CH:22]=[CH:21]C(C(F)(F)F)=CC=3)[N:12]=[CH:11]2)[S:5][C:6]=1[C:7]([OH:9])=O.C1(CN2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)CC1.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][NH2:53])[CH:47]=1>>[CH:17]1([CH2:16][N:13]2[C:14](=[O:15])[N:10]([C:4]3[S:5][C:6]([C:7]([NH:53][CH2:52][C:48]4[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=4)=[O:9])=[C:2]([CH3:1])[N:3]=3)[CH:11]=[N:12]2)[CH2:22][CH2:21]1
Reactant: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(-n2cnn(CC3CC3)c2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(CC3CC3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 49 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(cyclopropylmethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 49% yield: mp 116-117° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.57 (br s, 1H), 8.47 (br s, 1H), 8.24 (s, 1H), 7.79-7.71 (m, 1H), 7.44-7.27 (m, 1H), 6.38 (t, J=5.8 Hz, 1H), 4.62 (d, J=5.8 Hz, 2H), 3.70 (d, J=7.2 Hz, 2H), 2.65 (s, 3H), 1.34-1.14 (m, 1H), 0.63-0.52 (m, 2H), 0.46-0.31 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 161.8, 153.4, 151.2, 149.9, 149.2, 148.9, 135.8, 130.5, 123.8, 121.4, 117.9, 50.6, 41.6, 17.2, 10.2, 3.7; MS (ES+) m/z 371.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[C@@H:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][NH:23][C@@H:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: COc1cc(CN[C@H]2CCCc3ccccc32)cc(OC)c1

Procedure:
3,5-Dimethoxybenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH2:12][C:13]([NH2:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCOC(C)=O>CN1CCCC1=O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:11]=[C:10]([CH2:12][C:13]([NH2:15])=[O:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:19][CH2:18]1
Reactant: NC(=O)Cc1cc(Cl)nc2ccccc12
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CN1CCN(c2cc(CC(N)=O)c3ccccc3n2)CC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
2-(2-chloro-quinolin-4-yl)-acetamide (500 mg, 2.27 mmol) is dissolved in 1-methyl-2-pyrrolidinone (3.0 mL). N-methylpiperazin (1.3 mL, 5 eq.) is added and the reaction is stirred at 80° C. for 48 h. AcOEt (20 mL) is added and the precipitate is purified by FCC (AcOEtVEtOH/28% NH40H 80:18:1) to afford 2-[2-(4-methyl-piperazin-1-yl)-quinolin4-yl]-acetamide as a solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[N-:15]=[N+]=[N-].[Na+]>CO.C(O)C>[N+:7]1([O-:9])[O:8][N:15]=[C:2]2[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:6]=12
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Br)s1
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)c1cc2c(no[n+]2[O-])s1
Temperature: 70 °C
Yield: 33.7 %

Procedure:
A suspension of 25.0 g (90 mmol) of ethyl 2-bromo-3-nitro-5-thiophenecarboxylate (Tetrahedron 21 (1965) 1061) and 29.0 g (450 mmol) of sodium azide in 300 ml of methanol is stirred at room temperature for 4 hours in 300 ml of ethanol. The mixture is poured into 4 l of ice-water, the precipitate is filtered off and the residue is heated at 70° C. for 3 hours in 700 ml of toluene. Subsequent purification by flash chromatography yields 6.5 g (34%) of ethyl thieno[2,3-c][1,2,5]oxadiazole-5-carboxylate-1-oxide and -3-oxide, m.p. 72°-74° C.
Reaction SMILES: C(OC(N[C@H:9]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:26]([F:29])([F:28])[F:27])=[N:20][C:21]([C:22]([O:24]C)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=O)(C)(C)C.[OH-:40].[Na+].Cl.[CH3:43][OH:44]>>[C:31]([O:40][C:43]([C@H:9]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:26]([F:27])([F:29])[F:28])=[N:20][C:21]([C:22]([OH:24])=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:44])([CH3:36])([CH3:32])[CH3:30]
Reactant: COC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Reactant: CO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CC(C)(C)OC(=O)[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reaction time: 1 h
Yield: 100 %

Procedure:
Methyl(R)-7-[3-tert-butoxycarbonylamino 5-trifluoro-phenyl)-butyryl]-3-trifluoro methyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-formate 1p (1.8 g, 3.2 mmol) was dissolved in 50 mL of methanol, followed by addition of 10 mL of aqueous sodium hydroxide (4 M). The reaction mixture was stirred for 1 hours. The reaction mixture was adjusted to pH=3-5 with 2 M hydrochloric acid in an ice bath. The mixture was extracted with ethyl acetate (100 mL×3). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (R)-7-[3-tert-butoxycarbonyl-4-(2,4,5-trifluorophenyl)butanoyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 1q (1.76 g, yield 100%) as a light yellow solid. MS m/z (ESI): 550.9 [M+1]. 1H NMR (400 MHz, CD3OD, ppm): δ 7.29-7.23 (m, 1H), 7.121-7.08 (m, 1H), 5.15-5.03 (m, 2H), 4.41-4.06 (m, 5H), 2.98-2.77 (m, 4H), 1.42-1.26 (m, 9H).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O>C(O)C>[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=[N:30][NH:29][C:16]1[CH:15]=[C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[C:18]2[N:17]=1
Reactant: O=Cc1ccccc1Cl
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccccc1C=NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.3 mg, 0.0563 mM), then 2-chloro-benzaldehyde (6.3 μL, 0.056 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methylene chloride) to thus give the title compound (4.3 mg, yield: 18%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([S:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=3)[C@@H:12]([CH3:32])[CH2:11]2)(=[O:9])=[O:8])=[CH:5][N:6]=1.[NH4+:33].[OH-]>CCO.CCOC(C)=O>[NH2:33][C:2]1[S:3][C:4]([S:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=3)[C@@H:12]([CH3:32])[CH2:11]2)(=[O:9])=[O:8])=[CH:5][N:6]=1
Reactant: C[C@H]1CN(S(=O)(=O)c2cnc(Cl)s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@H]1CN(S(=O)(=O)c2cnc(N)s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 140 °C

Procedure:
A mixture of 2-(2-((2S)-4-((2-chloro-1,3-thiazol-5-yl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (185 mg, 0.352 mmol) in 2 mL of EtOH and 2 mL of 30% NH4OH was heated to 140° C. for 30 min. Afterwards, the solution was diluted with EtOAc (20 mL). The solution was transferred to a reparatory funnel and washed with water (10 mL) and brine (10 mL). The combined organics were dried over MgSO4, filtered, and concentrated. The crude material was absorbed onto silica gel and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 2-(2-((2S)-4-((2-amino-1,3-thiazol-5-yl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (132 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=1[O:35][CH3:36])(=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl>O1CCCC1>[CH2:37]([N:20]1[C:21]2[C:17](=[CH:16][C:15]([NH:14][C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:23][CH:22]=2)[C:18]([CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=2[O:35][CH3:36])=[CH:19]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCCCCC(=O)Nc1ccc2[nH]cc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCC(=O)Nc1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2Cc1ccccc1
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
Potassium t-butoxide (0.04 g.) was added to a stirred solution of methyl 4-(5-hexanamidoindol-3- ylmethyl)-3-methoxybenzoate (0.15 g.) in dry tetrahydrofuran (5 ml.), under an atmosphere of nitrogen. The resulting dark-green mixture was stirred for 30 minutes. Benzyl bromide (0.062 g.) was added, causing the color to change to light brown. After 1 hour, the mixture was poured into 1M hydrochloric acid (20 ml.). This mixture was extracted with ethyl acetate (2×25 ml.). The combined extracts were dried (MgSO4) and evaporated. The brown oil obtained was purified by flash chromatography on silica gel (50 ml.), eluting with 3:7 v/v ethyl acetate:hexane, to give the title compound (0.04 g, 17%) as an oil; NMR: 0.86 (t,3H, CH2.CH3) 1.27(m,4H, CH2.CH2.CH3), 1.57(m, 2H), CH2.CH2.CON), 2.24(t,2H, CH2.CH2. CON), 3.82(s,3H, CO.OCH3), 3.91(s,3H, OCH3), 3.99(s,2H, CH2.Ar), 5.32 (s,2H, NCH2Ph), 7.21(m,1OH), 7.44(m,2H), 7.75(d, 1H), 9.64(s,1H, NH).
Reaction SMILES: [Br:1][CH:2](O)[CH3:3].[Si:5](Cl)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].C(N(CC)CC)C.[OH2:20]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][O:20][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O
Reactant: CC(O)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCBr
Temperature: 25 °C
Yield: 55 %

Procedure:
To a stirred solution of bromoethanol (9.912 g, 79.32 mmol) in dry DCM (25 ml) was added in one portion tert-butyldimethylsilyl chloride (13.212 g, 85.03 mmol) and the reaction mixture stirred at room temperature. A solution of triethylamine (8.865 g, 12.3 ml, 87.61 mmol) in dry DCM (40 ml) was then added dropwise over 1 h and 20 min. The reaction mixture was stirred at room temperature for 3 d, then water (30 ml) was added. The organic phase was separated and the aqueous phase was extracted with DCM (2×20 ml). The combined organic extracts were washed with brine (30 ml), dried (Na2SO4), and the solvent removed under reduced pressure to give a pale yellow oil. Distillation under reduced pressure gave the title compound (10.54 g, 55%) as a colourless oil.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=1[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cccc(F)c1B(O)O
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cccc(F)c1-c1nc2c(C)cccc2cc1C=O

Procedure:
Prepared according to Procedure A using 2-chloro-8-methylquinoline-3-carbaldehyde (1.07 g, 5.21 mmol), 2-fluoro-6-methoxyphenylboronic acid (0.9738 g, 5.73 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium (0.3011 g, 5% mmol), and sodium carbonate (2.76 g, 26.1 mol, 5 eq) in MeCN (37.5 mL) and water (12.5 mL). After purification, 2-(2-fluoro-6-methoxyphenyl)-8-methylquinoline-3-carbaldehyde was obtained as white solid. 1H NMR (DMSO-d6) δ ppm 9.88 (1H, s), 8.95 (1H, s), 8.10 (1H, d, J=8.1 Hz), 7.82 (1H, d, J=7.1 Hz), 7.62-7.69 (1H, m), 7.49-7.59 (1H, m), 6.96-7.10 (2H, m), 3.71 (3H, s), 2.70 (3H, s). Mass Spectrum (ESI) m/e=296.0 (M+1).