Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[CH:4][N:3]=1.[F:11][C:12]([F:25])([F:24])[C:13]1[NH:23][C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[CH:20]=[C:15]2[CH:14]=1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[CH:8]1([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:22][CH2:21][C:19]3[CH:20]=[C:15]4[CH:14]=[C:13]([C:12]([F:25])([F:24])[F:11])[NH:23][C:16]4=[N:17][CH:18]=3)[CH:7]=2)[CH2:10][CH2:9]1
Reactant: Clc1cc(C2CC2)ncn1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cc2cc(CNc3cc(C4CC4)ncn3)cnc2[nH]1
Temperature: 120 °C
Yield: 24.7 %

Procedure:
To a stirred solution of 4-chloro-6-cyclopropylpyrimidine (Intermediate 30, 75 mg, 0.485 mmol) in NMP (2 mL) in a 2 mL microwave vial was added and 1-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 104 mg, 0.485 mmol), DIPEA (0.169 mL, 0.970 mmol), vial de-gassed with argon and heated in a microwave at 120° C. for 2 hrs. The reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (2×20 mL). The organic layers were combined, dried (MgSO4) and evaporated to dryness in vacuo to afford the crude residues. Resulting residues were then purified via MDAP. The appropriate fractions were collected, residue washed with methanol and evaporated to dryness in vacuo to give the title compound as a brown solid (40 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([C:5](=[O:8])[CH2:6][Cl:7])[CH:3]=[O:4].[CH2:10](O)[CH2:11][OH:12].O>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:7][CH2:6][C:5](=[O:8])[C:2]([CH:3]1[O:12][CH2:11][CH2:10][O:4]1)([CH3:9])[CH3:1]
Reactant: OCCO
Reactant: CC(C)(C=O)C(=O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C(=O)CCl)C1OCCO1
Yield: 79.4 %

Procedure:
204 g (1.38 mol) of 2,2-dimethyl-4-chloro-3-keto-butanal are heated with 93 g (1.5 mols) of ethylene glycol and 0.7 g of p-toluenesulphonic acid in 400 ml of methylene chloride for 3 hours in a water separator. The organic phase is extracted with 150 ml of 5% strength sodium hydroxide solution, and thereafter with 400 ml of water. The solvent is distilled off and the residue is distilled under the vacuum from a water jet. 211 g (79.8% of theory) of 1-chloro-3-(dioxolan-2-yl)-3-methylbutan-2-one of boiling point 127°-28° C./14 mbar are obtained. ##STR24##
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:16][N:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[CH2:19][CH2:20][CH2:21][CH3:22])=[C:10]([C:34]([N:36]2[CH2:45][CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[O:35])[CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:19]([C:18]1[N:17]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:16]=[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[CH:9][C:10]=1[C:34]([N:36]1[CH2:45][CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1)=[O:35])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1c(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-(4-(tert-butoxycarbonyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5-butyl-1-phenyl-1H-pyrazole-3-carboxylate (33 mg, 0.054 mmol) in DCM (2.0 mL) was added TFA (1.0 mL). After stirring at room temperature for 1 h, the reaction mixture was concentrated in vacuo. The residue was used directly in the next step without further purification. MS(ESI+) m/z 552.3 (M+H)+.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4]1.[CH:15]([N:18](C(C)C)CC)(C)C.CS(Cl)(=O)=O.CN>ClCCl.CS(C)=O.C(Cl)(Cl)Cl>[CH3:15][NH:18][CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4]1
Reactant: CCN(C(C)C)C(C)C
Reactant: OCC1CCOC(c2ccccc2)O1
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CNCC1CCOC(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a solution of 4-hydroxymethyl-2-phenyl-1,3-dioxane (0.80 g, 4.12 mmol) in dichloromethane (20 mL) was added diisopropylethylamine (1.702 ml, 10.30 mmol) and the solution was cooled in an ice bath. Methanesulfonyl chloride (0.414 ml, 5.35 mmol) was added and the solution was allowed to warm to RT. After 1 h, it was washed with 2M aq HCl, saturated aq NaHCO3, dried and concentrated to a syrup (1.15 g). A solution of (0.9 g, 3.30 mmol) of this material in DMSO (8 mL) containing 40% aq methylamine (2.85 ml, 33.0 mmol) was stoppered and heated at ˜75-80° C. for 24 h. The solution was cooled, chloroform was added and washed twice with water, dried and concentrated. Chromatography afforded title compound (0.465 g, 2.24 mmol, 68%) as a syrup. 1H NMR (CDCl3) δ 7.50-7.47 (2H, m), 7.39-7.30 (3H, m), 5.52 (1H, s), 4.31-4.25 (1H, m), 4.09-3.93 (2H, m), 2.80 (1H, dd, J=12.3, 8.0 Hz), 2.67 (1H, dd, J=12.3, 3.4 Hz), 2.45 (3H, s), 1.96-1.83 (2H, m), 1.49 (1H, dd, J=13.2, 1.2 Hz); 13C NMR δ 139.0, 129.2, 128.6, 126.5, 101.6, 76.8, 67.2, 57.0, 36.8, 29.5.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1.O=S(Cl)[Cl:12].O.CC(C)=O>C(=O)=O>[ClH:12].[ClH:12].[Cl:12][CH2:2][CH2:3][CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1
Reactant: OCCC1CNCCN1
Reactant: O=S(Cl)Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: O
Product: Cl
Product: ClCCC1CNCCN1
Reaction time: 2 h
Yield: 96 %

Procedure:
(E. F. Rogers and H. J. Becker, U.S. Pat. No. 3,281,423 (1966).) To 25.0 g (0.192 mol) of 2-(2-hydroxyethyl)piperazine, chilled in dry ice, 125 ml SOCl2 was cautiously added dropwise. After addition was complete, the mixture was cautiously heated on a steam bath with stirring for 2 hr. The reaction was cooled and treated cautiously with H2O until a solution resulted. The reaction was evaporated to dryness, and the dark residue was redissolved in H2O and filtered. The dark filtrate was heated on the steam bath with decolorizing carbon for 30 min and filtered to yield a pale yellow solution. Acetone was added to precipitate the product in two crops: 29.3 g white solid, mp 336°-339° dec., and 11.6 g (total 96% yield) pale-yellow solid, mp 330°-350° dec. (E. F. Rogers and H. J. Becker, U.S. Pat. No. 3,281,423 (1966) mp 348°-350° dec.)
Reaction SMILES: [CH3:1][CH:2]([CH:6]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]([OH:10])[CH3:9])[C:3](O)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH3:9][CH:8]1[CH:7]([C:11]([O:13][CH3:14])=[O:12])[CH:6]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]([CH3:1])[C:3](=[O:4])[O:10]1
Reactant: COC(=O)C(C(C)O)C(NCc1ccccc1)C(C)C(=O)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C1C(C)OC(=O)C(C)C1NCc1ccccc1
Reaction time: 1 h
Yield: 17.2 %

Procedure:
(2RS,3RS,4SR,5SR)-2-Methyl-3-benzylamino-4-methoxycarbonyl-5-hydroxyhexanoic acid (340 mg; 1.1 mmole) and triphenylphosphine (393 mg; 1.5 mmole) were dissolved in dry toluene (6 ml). After addition of triethylamine (151.5 mg; 1.5 mmole), the resultant mixture was cooled to -15° C. Diethyl azodicarboxylate (261 mg; 1.5 mmole) was added thereto, and the mixture was stirred at -10° to -5° C. for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl (2RS,3SR,4RS,5RS)-tetrahydro-2,5-dimethyl6-oxo-4-benzylamino-2H-pyrane-3-c (190 mg) and methyl (2SR,3SR,4RS,5RS)-tetrahydro-2,5-dimethyl-6-oxo-4-benzylamino-2H-pyrane-3-carboxylate (55 mg). (2RS,3SR,4RS,5RS) isomer:
Reaction SMILES: C1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH2:19][CH3:20])[C:10](=[O:21])[CH:9]([NH:22][C:23]([O:25]C3C=CC([N+]([O-])=O)=CC=3)=O)[N:8]=2)CCCCC1.C(N([CH2:40][CH3:41])CC)C.CN(C)C=O.[CH3:47][S:48]([NH:51][C:52]([C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([NH2:60])[CH:55]=1)=[O:53])(=[O:50])=[O:49]>CO>[CH2:41]1[CH2:40][CH:7]([C:9]2([NH:22][C:23]([NH:60][C:56]3[CH:57]=[CH:58][CH:59]=[C:54]([C:52]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:53])[CH:55]=3)=[O:25])[N:8]=[CH:7][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH2:19][CH3:20])[C:10]2=[O:21])[CH2:13][CH2:12][CH2:17]1
Reactant: CS(=O)(=O)NC(=O)c1cccc(N)c1
Reactant: CCN(CC)CC
Reactant: CCCN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCC2)c2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: CCCN1C(=O)C(NC(=O)Nc2cccc(C(=O)NS(C)(=O)=O)c2)(C2CCCCC2)N=Cc2ccccc21

Procedure:
The title compound was prepared from 5-cyclohexyl-1,3-dihydro-1-propyl-3(R,S)-[(4-nitrophenyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (0.3 g, 0.65 mmol), triethylamine (90 μl, 0.65 mmol), dimethylformamide (6 ml) and 1-(methylsulphonylaminocarbonyl)-3-aminobenzene ( 0.15 g, 7.1 mmol) [Example 16, Step 2] using the procedure described in Example 11, Step 4. The product (0.16 g, 46%) was afforded as a cream solid after trituration with hot methanol. mp 205° C. (dec.). 1H NMR (360 MHz, D6 -DMSO) δ 0.73 (3H, t, J=7.3 Hz), 0.86-1.00 (1H, m), 1.08-1.42 (5H, m), 1.43-1.54 (2H, m), 1.57-1.67 (2H, m), 1.74-1.83 (1H, m), 1.87-1.96 (1H, m), 2.91-3.01 (1H, m), 3.33 (3H, s), 3.62-3.72 (1H, m), 4.16-4.26 (1H, m), 5.04 (1H, d, J=7.8 Hz), 7.34-7.43 (3H, m), 7.47 (1H, d, 7.8 Hz), 7.56-7.68 (3H, m), 7.77 (1H, d, J=7.7 Hz), 7.91 (1H, dd, J=1.9 and 1.9 Hz), 9.20 (1H, s), 12.04 (1H, brs).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].ClCCl.[Si:9]([O:26][CH2:27][CH:28]1[CH2:33][CH2:32][C@@H:31]([OH:34])[C@@H:30]([OH:35])[CH2:29]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>O>[Si:9]([O:26][CH2:27][CH:28]1[CH2:33][CH2:32][C@@H:31]([O:34][S:2]([CH3:1])(=[O:4])=[O:3])[C@@H:30]([O:35][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:29]1)([C:22]([CH3:25])([CH3:23])[CH3:24])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](OCC1CC[C@@H](O)[C@@H](O)C1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCC1CC[C@@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)C1)(c1ccccc1)c1ccccc1
Reaction time: 1.5 h

Procedure:
Methanesulfonyl chloride (2.5 ml) was added dropwise to a dichloromethane solution (300 ml) of (1R*,2S*)-4-(tert-butyldiphenylsilyloxymethyl)-1,2-cyclohexanediol (4.2 g) and triethylamine (9.1 ml) at 0° C., and the mixture was stirred for 1.5 hours. Water was added to conduct extraction with dichloromethane, and the resultant organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel (hexane:ethyl acetate=3:2) to obtain the title compound (4.9 g) as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]=[O:9].[N+:10]([C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=1[CH2:24]Br)([O-:12])=[O:11]>O1CCCC1>[N+:10]([C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=1[CH2:24][N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]=[O:9])([O-:12])=[O:11]
Reactant: O=Cc1ccc[nH]1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(Cn2cccc2C=O)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a stirred slurry of 2.2 g of sodium hydride (60% in oil, washed with hexane) in tetrahydrofuran is added at 0° C. a solution of 4.5 g of pyrrole-2-carboxaldehyde in 25 ml of tetrahydrofuran. After the addition is complete, a solution of 15 g of ethyl 4-nitro-3-bromomethylbenzoate in 30 ml of dry tetrahydrofuran is slowly added under nitrogen. The reaction mixture is stirred at 20° C. for 8 hours and carefully quenched with water. The reaction mixture is extracted with chloroform which is washed with water, dried with Na2SO4 and concentrated in vacuo to give 12 g of the desired product as a solid; mass spectrum (M+ H)349.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:5].[O:18]=[C:19]1[O:23][CH:22]([C:24](Cl)=[O:25])[CH2:21][CH2:20]1>>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[NH:1][C:24]([CH:22]2[CH2:21][CH2:20][C:19](=[O:18])[O:23]2)=[O:25])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)c2ccccc2N)cc1
Reactant: O=C1CCC(C(=O)Cl)O1
Product: COc1ccc(C(=O)c2ccccc2NC(=O)C2CCC(=O)O2)cc1

Procedure:
In substantially the same manner as in Example 8 (1), 8 g of 2-amino-4'-methoxybenzophenone was allowed to react with 5-oxotetrahydrofuran-2-carbonyl chloride to give 12 g of 4'-methoxy-2-(5-oxotetrahydrofuran-2-carbonyl)aminobenzophenone as an oily product.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28][C:29](Cl)=O.C(N(CC)CC)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])[C:29]([CH2:28][CH2:27][O:26][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: COCCC(=O)Cl
Reactant: O=C1CCCN1CCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Solvent: CCN(CC)CC
Product: COCCc1nc2cnc3cc(Br)ccc3c2n1CCCN1CCCC1=O

Procedure:
1-[3-(7-Bromo3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one was treated according to the methods described in Parts B, C, and D of Examples 152–156. 3-Methoxypropionyl chloride was used in Part C, and triethylamine (1.3 equivalents) was added to the reaction mixture. The crude product obtained in Part D was purified by flash chromatography on silica gel (eluting sequentially with 100:0 and 92.5:7.5 chloroform:methanol) followed by recrystallization from acetonitrile. The crystals were washed with acetonitrile and diethyl ether and dried in a vacuum oven at 60° C. to provide 1-{3-[7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a light grey solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21]([C:23]3([C:26]([OH:28])=O)[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C[N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[Br:62][C:63]1[CH:64]=[C:65]([CH2:70]N)[CH:66]=[CH:67][C:68]=1[Cl:69]>C(Cl)Cl>[Br:62][C:63]1[CH:64]=[C:65]([CH2:70][N:20]([CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:29][CH3:30])[C:21]([C:23]2([C:26]([NH2:32])=[O:28])[CH2:24][CH2:25]2)=[O:22])[CH:66]=[CH:67][C:68]=1[Cl:69]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)O)CC1
Reactant: NCc1ccc(Cl)c(Br)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(Cl)c(Br)c1)C(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.2 %

Procedure:
A mixture of 1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropanecarboxylic acid (600 mg, 1.444 mmol), HBTU (657 mg, 1.733 mmol), Et3N (1006 μL, 7.22 mmol) and 1-(3-bromo-4-chlorophenyl)methanamine (350 mg, 1.589 mmol) in DCM was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give the crude residue. It was then purified with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined and washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-[(3-bromo-4-chlorophenyl)methyl]-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide (20 mg, 2.24%). LC-MS m/z 617 M+, 0.92 min (ret time).
Reaction SMILES: Cl.Cl.[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1NC.[CH2:10]([N:12](CC)CC)C.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[N:25]1[C:30]2[N:31]=[C:32](S(C)(=O)=O)[N:33]=[C:34]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[CH3:42])[C:29]=2[CH:28]=[CH:27][C:26]1=[O:47]>CN1C(=O)CCC1>[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[N:25]1[C:30]2[N:31]=[C:32]([NH:12][CH2:10][C:4]3[NH:3][CH:7]=[CH:6][N:5]=3)[N:33]=[C:34]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[CH3:42])[C:29]=2[CH:28]=[CH:27][C:26]1=[O:47]
Reactant: CCN(CC)CC
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CNc1ncc[nH]1
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1cc(F)ccc1-c1nc(NCc2ncc[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
(1H-Imidazol-2-yl)-methylamine dihydrochloride (184 mg, 1.1 mmol), NMP (1 mL), and triethylamine (0.31 mL, 2.2 mmol) were stirred at 23° 10 min. The product of Example 48 (100 mg, 0.22 mmol) was added and the mixture was reacted at 1000 for 16 h to give the crude material. Preparative hplc afforded the title compound, 36 mg (29%). LC-MS: 463.2 (MH+, m/z), 1.42 (Rt, min).
Reaction SMILES: [CH3:1][C:2]([O-])(C)[CH3:3].[K+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[C:15](\[CH3:18])/[CH2:16][OH:17])=[CH:10][CH:9]=1.C(Br)C=C>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:3]([O:17][CH2:16]/[C:15](/[CH3:18])=[CH:14]/[C:11]1[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=1)[CH:2]=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: C/C(=C\c1ccc(C)cc1)CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCOC/C(C)=C/c1ccc(C)cc1
Temperature: 5 °C
Yield: 95 %

Procedure:
Solid potassium tert-butylate (47 g, 0.411 mol) was added portion-wise to a solution of E-3-(4-methylphenyl)-2-methyl-2-propen-1-ol (68.05 g, 0.420 mol) in dry THF (800 ml) at room temperature under nitrogen (exothermic to 30° C.). After 1 more hour at room temperature, the reaction was cooled to 5° C. and tetra butyl ammonium iodide (7.9 g, 0.021 mol) was added followed by allyl bromide (102.65 g, 0.840 mol) drop-wise. The reaction was warmed up to room temperature overnight and poured onto water (800 ml). The reaction was extracted twice with ethyl acetate. Each organic phase was washed with water and brine. Combined extracts were dried over solid anhydrous sodium sulfate. The solid was filtered off, rinsed with diethyl ether and the solvents were removed under vacuum. The product was purified by distillation under vacuum through a 20-cm Widmer column. 79 g of the desired product were obtained (yield=93%).
Reaction SMILES: [CH:1]([C:3]1[C:4](=[O:13])[NH:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)=O.Cl.[NH2:15]O.C([O-])=O.[Na+].O>C(O)=O>[C:1]([C:3]1[C:4](=[O:13])[NH:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)#[N:15]
Reactant: O=Cc1cc(C(F)(F)F)c[nH]c1=O
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#Cc1cc(C(F)(F)F)c[nH]c1=O
Temperature: 25 °C

Procedure:
A solution of 3-formyl-5-trifluoromethyl-2-pyridone (3.5 g), hydroxylamine hydrochloride (1.42 g) and sodium formate (1.39 g) in 98% formic acid (42 ml) was heated to reflux for a period of 20hrs. After cooling to ambient temperature, the reaction mixture was poured into water, and rigorously extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution, followed by brine, and dried over anhydrous magnesum sulphate. Removal of the solvent under reduced pressure gave 3-cyano-5-trifluoromethyl-2pyridone as an off-white solid (m.p. 170-175° C.) which was used without further purification. The compound showed (DMSO) 8.54 (1H,d) 8.30 (1H,d).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br.C([Li])CCC.[O:22]1[C:26]2([CH2:31][CH2:30]C(=O)[CH2:28][CH2:27]2)[O:25][CH2:24][CH2:23]1>O1CCCC1.CCCCCC.O>[C:4]1([CH:3]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:1]3([CH2:30][CH2:31][C:26]4([O:25][CH2:24][CH2:23][O:22]4)[CH2:27][CH2:28]3)[O:2]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(c1ccccc1)c1ccccc1Br
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(C2OC3(CCC4(CC3)OCCO4)c3ccccc32)cc1
Temperature: -50 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
To a cooled (-50° C.) stirred solution of 27.7 g of 2-bromobenzhydryl methyl ether in 80 ml of dry tetrahydrofuran is added dropwise under nitrogen 60 ml of 2.4 M n-butyllithium in hexane. The mixture is stirred for 2 hours and a solution of 15.9 g of 1,4-dioxaspiro[4.5]decan-8-one in 50 ml of dry tetrahydrofuran is added dropwise, maintaining the temperature at -40° to -30° C. The mixture is stirred overnight at -70° to +10° C., diluted with 100 ml of water and extracted with 100 ml of dichloromethane. The organic phase is washed with water (2×50 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. A solution of the residue in 400 ml of ethanol is stirred with 50 ml of hydrogen bromide/ether at room temperature for 3 hours. The solvent is removed under reduced pressure and the remaining oil crystallizes from 100 ml of methanol to give 39.6% of product, mp 130°-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:16])[N:3]=1.[N:17]1([CH2:23][CH2:24][OH:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[H-].[Na+].[ClH:28].C(O)C>O1CCCC1.C(O)C>[ClH:1].[ClH:28].[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([O:25][CH2:24][CH2:23][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:3]=[C:4]([CH3:16])[N:5]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2cc(Cl)nc(C)n2)cc1
Reactant: OCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(OCCN3CCCCC3)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.17 g of 4-chloro-6-(4-methoxyphenyl)-2-methylpyrimidine and 0.65 g of 2-piperidinoethanol were dissolved in 10 ml of dried tetrahydrofuran. After the addition of 60% sodium hydride 0.2 g, the mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into ice-water, and then was extracted with ethyl acetate. The extract was washed with water and was dried with anhydrous magnesium sulfate, and then this was evaporated in vacuo. The residue was purified with column chromatography with silica gel(Wako gel c-200 150 g, elution with chloroform and then chloroform: methanol=99:1), resulting 1.3 g of oily substance. This was dissolved in 10 ml of ethanol, 3 ml of 20% ethanol hydrochloride was added and evaporated in vacuo. Ether was added to the residue to crystallize. Whereby 1.32 g of crystals were obtained. These were recrystallized with isopropanol, resulting to obtain 0.83 g of crystals. Melting point is 165° to 167° C.