Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:37]=[CH:36][C:18]([CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:33][CH2:34][CH3:35])=[C:25]([CH:32]=2)[O:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:37]=[CH:36][C:18]([CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:33][CH2:34][CH3:35])=[C:25]([CH:32]=2)[O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:17][CH:16]=1
Reactant: CCCc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1OCC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a mixture of methyl 2-[5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-propylphenoxy]acetate (1.16 g), tetrahydrofuran (4 mL) and methanol (4 mL) was added 1N aqueous sodium hydroxide solution (4.5 mL) and the mixture was stirred at room temperature for 2 hrs. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (1.01 g, 90%) of 2-[5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-propylphenoxy]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 162-163° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[N:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Clc1ccc2ccccc2n1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reaction time: 20 h

Procedure:
10.0 g (61.1 mmol) of 2-chloroquinoline is dissolved in 34 ml of concentrated sulfuric acid. At 0° C., 8.4 g (76.4 mmol) of potassium nitrate is added in portions. After 20 hours at room temperature, the reaction mixture is poured onto ice water, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium bicarbonate solution and dried on sodium sulfate. After the solvent is removed in a vacuum and after chromatography on silica gel with hexane-ethyl acetate (10-100%), 5.06 g (40% of theory) of the product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[NH2:8].N([O-])=O.[Na+].[N-:24]=[N+:25]=[N-].[Na+].C([O-])(=O)C.[Na+]>Cl.O>[N:8]([C:7]1[CH:6]=[CH:5][C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])=[CH:3][C:2]=1[F:1])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N)c(F)c2)C(=O)O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(N=[N+]=[N-])c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
A solution of 4.0 g (14.96 mmol) of (S)-N-[3-[3-Fluoro-4-aminophenyl]-2-oxo-5-oxazolidinyl]methylacetamide from Example 9 in 40 mL of 6N HCl solution at 0° C. was treated portionwise with 4.12 g (59.84 mmol) of sodium nitrite, followed by stirring at 0° C. for 2 h. The mixture was then treated in several portions with a solution of 1.94 g (29.92 mmol) of sodium azide and 24.52 g (0.30 mol) of sodium acetate in in 50 mL of water. After addition was complete, solution was extracted with ethyl acetate, and the organic layer was dried (Na2SO4) and concentrated in vacuo to afford 4.1 g (93%) of the title compound as a light yellow solid, sufficiently pure for further use. 1H NMR (CDCl3) δ 8.22, 7.59, 7.33, 4.72, 4.10, 3.72, 3.40, 1.90.
Reaction SMILES: [CH2:1]([C:6]1[O:10][N:9]=[C:8]([CH2:11][N:12]2[C:21]3[C:20](=[O:22])[N:18]([CH3:19])[C:17](=[O:23])[N:16]([CH3:24])[C:15]=3[N:14]=[CH:13]2)[N:7]=1)[CH2:2][C:3](=O)[CH3:4].[CH:25]([NH2:28])([CH3:27])[CH3:26]>C1C=CC=CC=1>[CH:25]([NH:28][CH:3]([CH3:4])[CH2:2][CH2:1][C:6]1[O:10][N:9]=[C:8]([CH2:11][N:12]2[C:21]3[C:20](=[O:22])[N:18]([CH3:19])[C:17](=[O:23])[N:16]([CH3:24])[C:15]=3[N:14]=[CH:13]2)[N:7]=1)([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: CC(=O)CCc1nc(Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Solvent: c1ccccc1
Product: CC(C)NC(C)CCc1nc(Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Yield: 53 %

Procedure:
3.32 g. of 7-[{5-(butan-3-on-1-yl)-1,2,4-oxadiazol-3-yl}-methyl]-theophylline prepared according to the previous Example are heated in 80 cm3 benzene with 6 cm3 isopropylamine under pressure at 80° C. for 4 hours. The mixture is evaporated and the residue is dissolved in 80 cm3 methanol and reduced with 0.8 g. of sodium tetrahydroborate. 2.0 g. (53% yield) of 7-[{5-(3-isopropylamino-butan-1-yl)-1,2,4-oxadiazol-3-yl}-methyl]-theophylline are obtained. M.p.: 55°-61° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[NH:36][C:37]1[C:42]([Cl:43])=[CH:41][N:40]=[C:39](Cl)[N:38]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[NH:36][C:37]1[C:42]([Cl:43])=[CH:41][N:40]=[C:39]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)[N:38]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: Fc1cccc(OCCCOCc2ccccc2)c1Nc1nc(Cl)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4OCCCOCc4ccccc4)n3)cc2CC1

Procedure:
Prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and [2-(3-Benzyloxy-propoxy)-6-fluoro-phenyl]-(2,5-dichloro-pyrimidin-4-yl)-amine in an analogous manner to Example 1221d. Title compound was isolated as a white solid, HPLC purity 99%, LCMS 516.27 (M-benzyl), 1H-NMR (DMSO-d6, 400 MHz) δ 9.63 (s, 1H), 9.32 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.38-7.35 (m, 1H), 7.28-7.25 (m, 4H), 7.18-7.15 (m, 3H), 7.14-7.12 (d, 1H), 7.01-6.99 (m, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.24 (s, 2H), 4.08-4.05 (m, 2H), 3.80-3.72 (m, 2H), 3.58-3.50 (m, 2H), 3.35-3.31 (m, 7H), 3.20-2.90 (m, 6H), 1.85-1.81 (m, 2H).
Reaction SMILES: [CH2:1]([C@@H:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C@@H:4]([CH3:8])[C:5](O)=[O:6])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[CH3:24][NH:25][CH3:26].C(N(CC)CC)C.Cl>ClCCl>[CH2:1]([C@@H:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C@@H:4]([CH3:8])[C:5]([N:25]([CH3:26])[CH3:24])=[O:6])[CH3:2]
Reactant: CC[C@@H](c1cccc(OC)c1)[C@@H](C)C(=O)O
Reactant: CNC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](c1cccc(OC)c1)[C@@H](C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
The product of Example 14 (2.2 g, 10 mmol) was dissolved in dichloromethane (10 ml), oxalyl chloride (2.6 ml, 30 mmol) was added dropwise, and the reaction was carried out at room temperature for 1 hr, then the reaction solution was concentrated to give a pale yellow oil which was thereafter dissolved in dichloromethane, and then the resulted solution was added dropwise to an ice bath cooled solution of dimethylamine hydrochloride (1.6 g, 20 mmol) and triethylamine (4.3 ml, 30 mmol) in dichloromethane. Then it was slowly warmed to room temperature to make the reaction carry out for 1 hour. The pH was adjusted to about 7 with 1N hydrochloric acid, then the reaction solution was extracted with dichloromethane, and the organic phases were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate concentrated, and recrystallized with petroleum ether and ethyl acetate to give a white solid 2.3 g, yield: 92%. 1HNMR (300 MHz, CDCl3): δ 7.2 (1H, t, J=7.9, 15.6), 6.6-6.8 (3H, m), 3.7 (3H, s), 2.8-2.9 (1H, m), 2.7-2.8 (1H, m), 2.6 (3H, s), 2.5 (3H, s), 1.7-1.8 (1H, m), 1.4-1.6 (1H, m), 1.1 (3H, d, J=6.2), 0.8 (3H, t, J=6.8, 14.3). ESI-MS: 250.4 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([OH:22])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:23]>CO>[NH2:23][C:2]1[C:11]2[N:12]=[C:13]([OH:22])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Oc1nc2c(Cl)nc3ccccc3c2n1CC1CCOCC1
Reactant: N
Solvent: CO
Product: Nc1nc2ccccc2c2c1nc(O)n2CC1CCOCC1
Temperature: 150 °C

Procedure:
4-Chloro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-ol (3.9 g, 12 mmol) and ammonia (70 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 150° C. overnight. The volatiles were removed under reduced pressure. The crude product was purified by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.4:7.6:92). The chromatographed product was triturated twice with hot acetonitrile, collected by filtration, and dried in a vacuum oven to provide 800 mg of 4-amino-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-ol as a white solid, mp greater than 250° C.
Reaction SMILES: Cl.[C:2]1([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[O:27]([CH2:34][CH2:35][CH2:36]Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)CCC>[O:27]([CH2:34][CH2:35][CH2:36][N:18]1[CH2:17][CH2:16][CH:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:20][CH2:19]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(Cc2ccccc2C2CCNCC2)cc1
Reactant: BrCCCOc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: c1ccc(Cc2ccccc2C2CCN(CCCOc3ccccc3)CC2)cc1

Procedure:
4.40 g of 4-(α-phenyl-2-tolyl)piperidine hydrochloride of Example 35 and 14 g K2CO3 in 50 ml of n-butanol are heated to reflux with stirring. To this is added 5.66 g 3-phenoxypropylbromide in 10 ml of n-butanol dropwise. The mixture is then refluxed for 24 hours. After cooling the suspension is suction filtered, washing the flask and filter cake with n-butanol. The combined filtrates are evaporated to an oil which is dissolved in 20 ml of isopropanol and made acid with HCl/ether. The hydrochloride is collected by suction filtration and washed with ether. The resultant product is recrystallized from isopropanol/ether to yield 1-(3-phenoxypropyl)-4-(α-phenyl-2-tolyl)piperidine, mp 139°-140° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:6]([C:7]([NH2:9])=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.CC(C)=[O:15]>>[OH:15][N:3]1[C:4]([CH3:11])([CH3:10])[CH2:5][CH:6]([C:7]([NH2:9])=[O:8])[C:2]1([CH3:12])[CH3:1]
Reactant: CC1(C)CC(C(N)=O)C(C)(C)N1
Reactant: CC(C)=O
Product: CC1(C)CC(C(N)=O)C(C)(C)N1O
Reaction time: 2 h

Procedure:
A solution of 0.066 M DMD in acetone (9 ml, 0.59 mmol) was added to a cold stirred solution of 2,2,5,5-tetramethyl-pyrroline-3-carboxamide (Frinton, Vineland NJ, 100 mg, 0.59 mmol) in acetone (5 ml). The mixture was stirred for two hours. Evaporation of the solvent on a rotary evaporator gave a colorless crystalline solid which was dried in vacuo for 6 hours. Sublimation of the solid at 10-3 torr gave a white solid, mp 65-171.
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].ClC(OCC)=O.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:37][O:38][C:39](=[O:51])[C@H:40]([CH2:49][OH:50])[NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>C(OCC)C.C1COCC1.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].CCOC(C)=O>[CH3:37][O:38][C:39](=[O:51])[C@@H:40]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])[CH2:49][O:50][CH2:3][CH:2]=[CH2:1]
Reactant: C=CCO
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 0.33 h

Procedure:
Allyl alcohol (1.97 mL, 29.0 mmol) was dissolved in diethyl ether (20 mL). This was cooled in ice before ethyl chloroformate (0.304 mL, 31.9 mmol) and triethylamine (0.445 mL, 31.9 mmol) were added. After stirring in ice for 20 mins the resultant white precipitate was removed by suction filtration. The filtrate was concentrated in vacuo and the residue dissolved in THF (4 mL). To the resultant solution a solution of allyl palladium chloride dimer (0.0849 g, 0.232 mmol) and triphenylphosphine (0.266 g, 1.02 mmol) in THF (3 mL) was added. The mixture was stirred at rt for twenty min and to this was added a solution of N-Boc-serine methyl ester (obtained from GL Biochem (Shanghai) Ltd., Shanghai, China) (5.00 g, 2.32 mmol) in THF (20 mL). The reaction mixture was stirred at rt for a further 18 h before being concentrated in vacuo. The crude material was purified by flash chromatography on silica using a gradient of EtOAc and (50/70) petroleum ether to yield a yellow oil, 1.25 g, 21%. Rf=0.27 (1/6 EtOAc/(50/70) petroleum ether).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[CH2:11]([O:13][C:14](=[O:22])[CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:11]([O:13][C:14](=[O:22])[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:18][CH2:17]1)[CH3:12]
Reactant: CCOC(=O)CC1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a solution of 1.00 g (7.09 mmol) of 2-nitrofluorobenzene in N,N-dimethylformamide (50 mL) is added 1.3 g (7.6 mmol) of 2-(piperdin-4-yl)-acetic acid ethyl ester followed by 1.0 g (7.2 mmol) of potassium carbonate. The mixture is stirred at room temperature for 2 hours. The mixture is diluted with water and washed with ethyl acetate. The combined organic phase is washed with water followed by brine then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 1.85 g (89%) of [1-(2-nitro-phenyl)-piperidin-4-yl]-acetic acid ethyl ester as an orange oil.
Reaction SMILES: [CH3:1][C@@:2]([S:22]([CH3:25])(=[O:24])=[O:23])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH3:21])=[N:11]1)[C:3]([O:5]CC)=[O:4].[OH-].[K+]>C1COCC1.CO.O>[CH3:1][C@@:2]([S:22]([CH3:25])(=[O:23])=[O:24])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH3:21])=[N:11]1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)[C@@](C)(CCn1cc(-c2ccccc2)c(C)n1)S(C)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(CC[C@](C)(C(=O)O)S(C)(=O)=O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of the ethyl (2R)-2-methyl-4-(3-methyl-4-phenyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)butanoate (178 mg, 0.488 mmol, 1 eq) in THF: Methanol:water (2:2:1, 5 mL) was added potassium hydroxide (170 mg, 3.03 mmol) and reaction was stirred at RT overnight. The reaction was concentrated, and the residue was dissolved in aqueous 1N sodium hydroxide (20 mL) and washed with ethyl acetate (3×20 mL). The aqueous layer was acidified using concentrated HCl, and extracted with ethyl acetate (3×50 mL). The combined organics extracts were dried (MgSO4), filtered, and concentrated to afford (2R)-2-methyl-4-(3-methyl-4-phenyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)butanoic acid (129 mg, 78.6%). LC-MS M+H+382.1.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35]>>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[CH2:31][CH2:30][N:29]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CN(C)C(=O)CCl
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Product: CN(C)C(=O)CN1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Yield: 46.4 %

Procedure:
5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.244 mmol) was reacted with 2-chloro-N,N-dimethylacetamide (33 mg, 0.269 mmol) following the procedure of Example 136. The product was then chromatographed using 0-6% (2N NH3 in methanol)/dichloromethane to yield 56 mg (46%) of product. 1H NMR (300 MHz, dichloromethane-d2) δ 8.04 (s, 1 H), 7.89 (s, 1 H), 7.80 (d 1 H), 7.77-7.73 (m, 2 H), 7.36 (m, 5 H), 7.23 (d, 1 H), 6.66 (s, 1 H), 5.62 (s, 2 H), 5.43 (bs, 2 H), 4.00 (m, 1 H), 3.45 (m, 1 H), 3.35 (t, 1H), 3.18 (s, 2 H) 2.75-26.60 (m, 8 H), 2.45 (m, 1 H), 2.00 (m, 1 H); ES-MS m/z 495.2 [M+H]+, HPLC RT (min) 2.13.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-])=[O:21])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].CN1C(=O)CCC1.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[Cl:43][C:44]1[C:52]2[N:51]([CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([CH3:60])[N:55]=3)[N:50]=[CH:49][C:48]=2[C:47]([NH2:61])=[CH:46][CH:45]=1>CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:43][C:44]1[CH:45]=[CH:46][C:47]([NH:61][C:20]([C:17]2[N:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:12][C:13]3=[N:19][CH:18]=2)=[O:21])=[C:48]2[C:52]=1[N:51]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH3:60])[N:55]=1)[N:50]=[CH:49]2
Reactant: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Reactant: Cc1cccc(Cn2ncc3c(N)ccc(Cl)c32)n1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cccc(Cn2ncc3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)ccc(Cl)c32)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A vial containing lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (0.171 g, 0.550 mmol) and NMP (3.0 mL) was warmed to provide a homogeneous solution and then cooled to ambient temperature. 2,4,6-Trichlorobenzoyl chloride (0.0803 mL, 0.513 mmol) was added and the dark solution was stirred at ambient temperature for 0.5 hours. 7-Chloro-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (0.100 g, 0.367 mmol) was added as a NMP (3.0 mL) solution and the mixture was heated to 80° C. with stirring overnight. The reaction was equilibrated to ambient temperature and the mixture was diluted with EtOAc (30 mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (15% IPA/CHCl3 adding 1% 7N NH3/MeOH) to provide N-(7-chloro-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide. This product was dissolved in MeOH (4.0 mL) and CH2Cl2 (1.0 mL), and HCl (3.67 mL, 7.33 mmol, 2.0M Et2O) was added. The mixture was stirred for 2 hours and then concentrated. The resulting solid was then washed with Et2O and finally with hexanes and dried under vacuum overnight to provide 0.140 g (50%) of the title compound. MS (ES+APCI) m/z=559 (M+H-3HCl).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[NH:11]1[CH2:15][CH2:14][CH:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH2:12]1.CN1CCOCC1.[CH3:32][N:33]([CH3:50])[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:39][CH2:38][C:37](=[CH:40][C:41](O)=[O:42])[CH2:36][CH2:35]1.C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O.[OH-].[Na+]>CN(C)C=O.O>[CH3:50][N:33]([CH3:32])[C:34]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:39][CH2:38][C:37](=[CH:40][C:41]([N:11]2[CH2:15][CH2:14][CH:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH2:12]2)=[O:42])[CH2:36][CH2:35]1
Reactant: c1ccc2c(C3CCNC3)c[nH]c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(=CC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)C1(c2ccccc2)CCC(=CC(=O)N2CCC(c3c[nH]c4ccccc34)C2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 46 %

Procedure:
1-hydroxybenzotriazole (810 mg, 6.0 mmole), 3-pyrrolidine-3-yl-1H-indole (558 mg, 3.0 mmole) and N-methylmorpholine (0.666 ml, 6.0 ml) were added in succession to a solution of 4-dimethylamino-4-phenylcyclohexylidene-acetic acid (891 mg, 3.0 mmole) in dry dimethylformamide (15 ml) under argon. The solution was cooled in an ice bath and dicyclohexylcarbodiimide (1.2 g, 6.0 mmole) was added. The reaction mixture was stirred for 4 days at RT, the dicyclohexylurea precipitating out little by little. The reaction mixture was worked up by separating the precipitated urea and adding the filtrate to a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Further urea thereby precipitated out, which was separated. The aqueous phase was diluted with water (300 ml), 5M sodium hydroxide (7 ml, 35 mmole) was added, and the whole was kept for three days at 5° C. The crude product consisting of the amide precipitated out as a beige-coloured solid (994 mg). After chromatographic separation on silica gel (80 g) with EE/methanol (1:1), 2-(4-dimethylamino-4-phenylcyclohexylidene)-1-[3-(1H-indol-3-yl)pyrrolidine-1-yl]ethanone was isolated as a colourless solid with an m.p. of 94°-97° C. in a yield of 46% (585 mg). The compound was obtained as a diastereoisomer mixture.
Reaction SMILES: [CH:1]1[C:6]([C@@H:7]2[O:16]C3C=C(O)C=C(O)C=3C[C@@H]2O)=[CH:5][C:4]([OH:20])=[C:3]([OH:21])[CH:2]=1.[CH2:22](O)C>>[O:16]=[CH:7][C:6]1[CH:1]=[CH:2][C:3]([OH:21])=[C:4]([O:20][CH3:22])[CH:5]=1
Reactant: Oc1cc(O)c2c(c1)O[C@@H](c1ccc(O)c(O)c1)[C@@H](O)C2
Reactant: CCO
Product: COc1cc(C=O)ccc1O

Procedure:
Standard epicatechin solution: Prepare fresh epicatechin stock solution at 1.0 mg/ml in 50% ethanol.
Reaction SMILES: FC([Si:5]([CH3:8])([CH3:7])[CH3:6])(F)F.[Si:9]([O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]2[C@@:23]3([CH:49]=[CH2:50])[C@H:32]([C@@H:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41](=[O:46])[C:42]([F:45])([F:44])[F:43])[CH2:34][C@:18]12[CH3:19])[C:31]1[CH:30]=[CH:29][C:28]([O:47][CH3:48])=[CH:27][C:26]=1[CH2:25][CH2:24]3)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>>[Si:9]([O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]2[C@@:23]3([CH:49]=[CH2:50])[C@H:32]([C@@H:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([C:42]([F:45])([F:44])[F:43])([O:46][Si:5]([CH3:6])([CH3:7])[CH3:8])[C:42]([F:44])([F:43])[F:45])[CH2:34][C@:18]12[CH3:19])[C:31]1[CH:30]=[CH:29][C:28]([O:47][CH3:48])=[CH:27][C:26]=1[CH2:25][CH2:24]3)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCCCC(=O)C(F)(F)F)C[C@]1(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]12
Product: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCCCC(O[Si](C)(C)C)(C(F)(F)F)C(F)(F)F)C[C@]1(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]12

Procedure:
In the reaction with (trifluoromethyl)-trimethylsilane analogously to instructions 1.1, 135 mg of alcohol 16c yields 159 mg of trimethylsilyl ether 17c as a yellow, viscous mass (GC-MS: m/z theor.: 748, pract.: 748). The latter is, without the reaction being performed with tetrabutylammonium fluoride-trihydrate, used in the next stage.