Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].[OH2:14].[Cl-].[Na+]>C(O)(=O)C.C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([NH:4][CH:5]1[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[C:8](=[O:14])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: O
Reactant: CC(=O)NC1CCCc2sccc21
Agent: [Cr+6]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NC1CCC(=O)c2sccc21
Reaction time: 8 h

Procedure:
A solution of 2.15 g of N-acetyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine in 12 ml of acetic acid is stirred and 3.04 g of chromium trioxide in 13.6 ml of acetic anhydride is added in 15 minutes at 10° C. to 15° C. After an hour at 20° C., 20 ml of water is added and the mixture is allowed to stand overnight. Additional water (50 ml) is added, the mixture is saturated with sodium chloride and extracted with trichloromethane (100, 150 and 50 ml volumes). The combined extract is washed with brine and then with water. The water wash is extracted with trichloromethane and the extract is combined with the main trichloromethane extract. Evaporation of the extract affords a yellow-green residue, which after trituration with ether gives 1.32 g of the title compound, m.p. 160° C. to 164° C.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:19][NH:20][C:21]([C:23]1[S:24][CH:25]=[CH:26][C:27]=1[NH:28][C:29]1[C:34]([Cl:35])=[CH:33][N:32]=[C:31](Cl)[N:30]=1)=[O:22]>>[CH:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([NH:18][C:31]3[N:30]=[C:29]([NH:28][C:27]4[CH:26]=[CH:25][S:24][C:23]=4[C:21](=[O:22])[NH:20][CH3:19])[C:34]([Cl:35])=[CH:33][N:32]=3)=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(C)OC(=O)N1CCCOc2cc(N)ccc21
Product: CNC(=O)c1sccc1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OC(C)C)ncc1Cl

Procedure:
The title compound was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid isopropyl ester and 3-(2,5-dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide in an analogous manner to Example 1410. Product isolated as an orange foam (152 mg, 87%). LCMS (m/e) 517 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 11.65 (s, 1H), 9.57 (s, 1H), 8.56-8.44 (m, 1H), 8.27 (s, 1H), 8.25 (d, 1H, J=4.3 Hz), 7.76 (d, 1H, J=5.4 Hz), 7.52 (s, 1H), 7.33-7.20 (m, 1H), 7.20-7.07 (m, 1H), 4.91-4.74 (m, 1H), 4.13-3.96 (m, 2H), 3.73-3.50 (m, 2H), 2.78 (d, 3H, J=4.3 Hz), 2.00-1.85 (m, 2H), 1.35-1.00 (m, 6H).
Reaction SMILES: Br[C:2]1[C:3]([S:13][CH3:14])=[N:4][C:5]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][CH:7]=1.[CH3:15][N:16](C=O)C>C(OCC)(=O)C.O.[Zn].[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:9]([NH:8][C:5]1[N:4]=[C:3]([S:13][CH3:14])[C:2]([C:15]#[N:16])=[CH:7][N:6]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CN(C)C=O
Reactant: CSc1nc(NC(C)(C)C)ncc1Br
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1nc(NC(C)(C)C)ncc1C#N
Temperature: 90 °C
Yield: 83 %

Procedure:
5-Bromo-N-tert-butyl-4-(methylthio)pyrimidin-2-amine (3400 mg, 12.31 mmol), zinc dust (201 mg, 3.08 mmol), zinc cyanide (940 mg, 8.00 mmol), 1,1′-bis-(diphenylphosphino)-ferrocene (552 mg, 0.985 mmol), tris(dibenzylideneacetone)dipalladium(0) (564 mg, 0.616 mmol), and DMF (20.5 mL) were combined and heated at 90° C. overnight under nitrogen. The reaction mixture was diluted with 125 mL ethyl acetate and 50 mL of water and then filtered through a pad of Celite. The layers of filtrate were separated and the aqueous layer was extracted with 75 mL ethyl acetate. The combined ethyl acetate layers were washed with 2×50 mL brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil under reduced pressure. The crude oil was purified by silica gel chromatography (0-30% ethyl acetate/hexane) to afford 2-(tert-butylamino)-4-(methylthio)pyrimidine-5-carbonitrile (2.26 g, 10.17 mmol, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.37-8.51 (m, 1H), 7.85-8.10 (m, 1H), 2.53-2.62 (m, 3H), 1.41 (s, 9H). MS (ESI) m/z 223.1 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:14]=2[F:22])([CH3:12])[N:3]=1>C(O)C.C(N(CC)CC)C.[Pd]>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:22])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C1N
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reaction time: 3 h
Yield: 98.7 %

Procedure:
To a solution of (S)-2-amino-6-(2-fluoro-5-nitro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (0.55 g) in ethanol (25 ml) and triethylamine (0.25 ml) was added Pd/C (10%, 80 mg) and the mixture was hydrogenated at atmospheric pressure for 3 h. The mixture was filtered, the filtrate evaporated and the residue purified by chromatography on silica using ethyl acetate/MeOH (1:1) to give (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (0.49 g) as a pale yellow amorphous solid. MS (ESI): m/z=297.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[N:9]=[CH:8][N:7]=[C:6]2[O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[CH:27]2>C(#N)C=C.C(Cl)Cl.CO>[C:6]([CH2:5][CH2:4][N:20]1[CH2:21][CH2:22][CH:17]([O:16][CH2:15][CH2:14][O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([O:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][C:28]([CH3:33])=[CH:27]5)=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2][CH3:1])[CH2:18][CH2:19]1)#[N:7]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCOC1CCNCC1
Solvent: ClCCl
Solvent: CO
Solvent: C=CC#N
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCOC1CCN(CCC#N)CC1
Yield: 171.2 %

Procedure:
A solution of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(piperidin-4-yloxy)ethoxy)quinazoline (76 mg, 0.17 mmol), (prepared as described in Example 77), in acrylonitrile (0.5 ml), methylene chloride (1 ml) and methanol (1 ml) was stirred overnight at ambient temperature. After removal of the volatiles under vacuum the residue was purified by column chromatography eluting with methylene chloride/methanol (98/2 followed by 95/5 and 90/10). The residue was triturated with ethyl acetate and ether. The resulting solid was filtered and dried under vacuum to give 7-(2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (73 mg, 86%).
Reaction SMILES: Cl.C[O:3][C:4]1([O:20]C)[CH2:7][C:6](C(OC(C)C)=O)([C:8]([O:10]C(C)C)=[O:9])[CH2:5]1>>[OH:3][C:4]1([OH:20])[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5]1
Reactant: COC1(OC)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C1
Agent: Cl
Product: O=C(O)C1CC(O)(O)C1
Temperature: 100 °C
Yield: 46.1 %

Procedure:
To a stirred solution of 20% HCl (7 ml) was added bis(1-methylethyl) 3,3-dimethoxycyclobutane-1,1-dicarboxylate (2.5 g, 8.7 mmol) at RT. The resulting mixture was heated at 100° C. overnight and then cooled to RT and extracted with diethyl ether (3×20 ml). The organic phases were combined, dried (Na2SO4), filtered and concentrated at reduced pressure. The resulting light brown oil was slurried in DCM (2 ml) and the resulting solid collected by filtration, washed with pentane and dried at reduced pressure to yield a pale brown solid (530 mg, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.[CH2:13](O)[CH2:14][OH:15]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:10]([C:9]1([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:15][CH2:14][CH2:13][O:12]1)[CH3:11]
Reactant: CCC(=O)c1ccc(OC)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(c2ccc(OC)cc2)OCCO1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
To a solution of 4′-methoxypropiophenone (250.0 mg, 1.52 mmol) in toluene (20.0 mL) was added ethylene glycol (255.0 μL, 4.57 mmol) and p-toluenesulfonic acid monohydrate (13.0 mg, 0.04 mmol) and the reaction mixture refluxed overnight using a Dean-Stark apparatus. The reaction mixture was cooled to room temperature, then washed with saturated aqueous sodium bicarbonate solution followed by water. The toluene solution was then dried (MgSO4) and evaporated under reduced pressure to afford 2-ethyl-2-(4-methoxyphenyl)-1,3-dioxolane (16) as a yellow oil (184 mg, 58%). 1H nmr (CDCl3, 300 MHz) 0.76, t (6.6 Hz), CH3; 1.78, q (6.9 Hz), CH2; 3.65, m, CH2O, 3.73, s, 4′-OMe; 3.95, m, CH2O; 6.88, d (7.2 Hz), H3′,5′; 7.02, d, (7.5 Hz), H2′,6′. ESI (+ve) MS m/z 209 (M+H, 100%).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.O.[OH-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([SH:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=1>ClCCl>[F:31][C:32]1[CH:37]=[CH:36][C:35]([S:38][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:34]([C:39]([F:42])([F:40])[F:41])[CH:33]=1
Reactant: Fc1ccc(S)c(C(F)(F)F)c1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79 %

Procedure:
Triphenylmethanol (39.7 g, 149.4 mmol) was dissolved in the solution of crude 4-fluoro-2-trifluoromethyl-benzenethiol in dichloromethane (ca. 260 mL) of the preceding step and a solution of trifluoroacetic acid (21.2 g, 186 mmol) in dichloromethane (20 mL) was added at room temperature. After stirring for 15 h, the mixture was basified by subsequent addition of water (20 mL), concentrated aqueous sodium hydroxide solution (32% m/m, 26.9 g, 215 mmol) and water again (240 mL). Phases were separated, the aqueous layer was extracted with dichloromethane (100 mL) and the combined organic extracts concentrated in vacuo at 50° C. to a volume of ca. 330 mL. Ethanol (400 mL) was continuously added to the distillation, while the overall volume was kept constant (solvent exchange). The solution (ca. 300 mL) was allowed to cool to room temperature, crystallization started at 42° C. The suspension was stirred for 18 h at room temperature and for 1 h at 0° C. After filtration, the precipitate was washed with cold ethanol (100 mL) and dried in vacuo at 40° C. to give rise to the title compound as a white crystalline solid (52.5 g, 79%). MS (EI): m/z=243 [CPh3]+. 1H NMR (CDCl3, 600 MHz): δ 6.73 (ddd, J=2.8 Hz, 8.3 Hz, 8.3 Hz, 1H), 7.04 (dd, J=5.4 Hz, 8.8 Hz, 1H), 7.18-7.25 (m, 10H), 7.35-7.37 (m, 6H). Anal. Calcd for C26H18F4S: C, 71.22; H, 4.14; S, 7.31; F, 17.33. Found: C, 71.16; H, 4.26; S, 7.15; F, 17.09.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[Cl:6].C(N(CC)CC)C.[CH2:22]([N:24]([CH2:28][CH3:29])[C:25](Cl)=[O:26])[CH3:23]>C1C=CC=CC=1>[Cl:6][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[C:4]([O:14][C:25](=[O:26])[N:24]([CH2:28][CH3:29])[CH2:22][CH3:23])=[N:3][O:2][CH3:1]
Reactant: CCN(CC)C(=O)Cl
Reactant: CONC(=O)C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCN(CC)C(=O)OC(=NOC)C(Cl)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
N-Methoxy-α-(4-chlorophenyl)-α-chloroacetamide (23.3 grams; 0.1 mole), benzene (100 ml), and triethylamine (12 grams; 0.12 mole) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. N,N-Diethylcarbamoyl chloride (13.5 grams; 0.1 mole) dissolved in benzene (25 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-1-(4-chlorophenyl)-2-(N,N-diethylcarbamoyloxy)-2-methoxyiminoethane.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14].C(N1C=CN=C1)([N:23]1C=CN=C1)=O.C([O-])(=O)C.[NH4+]>CN(C=O)C>[F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH2:23])=[O:14]
Reactant: O=C(O)c1cccc(-c2ccccc2OC(F)(F)F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(-c2ccccc2OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.94 g (3.36 mmol) of 3-(2-trifluoromethoxyphenyl)-benzoic acid in 17 mL of DMF was added 0.55 g (3.36 mmol) of carbonyldiimidazole (CDI) and the reaction was stirred at RT for 4 h. To the reaction mixture was added 2.6 g (33.6 mmol) of ammonium acetate and the reaction mixture was stirred over night at RT. The reaction mixture was partitioned between ethyl acetate and water and the organic fraction was washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 30%, 50% successively EtOAc: hexanes) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([Br:10])=[CH:4][C:3]=1[NH2:11].O.O.[C:14](O)(=[O:18])[C:15](O)=[O:16]>Cl.[OH-].[Na+]>[Br:10][C:5]1[CH:4]=[C:3]2[C:2]([NH:1][C:14](=[O:18])[C:15](=[O:16])[NH:11]2)=[C:7]([CH2:8][CH3:9])[CH:6]=1
Reactant: O=C(O)C(=O)O
Reactant: CCc1cc(Br)cc(N)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 62.5 °C
Yield: 31.9 %

Procedure:
A mixture of 1,2-diamino-4-bromo-6-ethylbenzene (40 mg, 0.14 mmol) and oxalic acid dihydrate (25 mg, 0.20 mmol, used as received) in 4N HCl (1.5 mL) was refluxed at 120-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the liquid layer was removed. The yellow solid was washed with cold water (2×1 mL), collected by filtration, and dried at 60° C. under reduced pressure for 2 h, affording 40 mg of crude product (80%) as a yellow powder. The crude product was dissolved in 1N NaOH (2 mL) and filtered. The filtrate was acidified to pH=5, affording 12 mg of pure title compound; mp: >350° C. (dec. from 300° C.); IR (KBr, cm-1):3410, 3164, 2919, 1740, 1705, 1600. 1H NMR (DMSO-d6): δ 1.099 (t, 3H; J=6 Hz), 2.741 (q, 2H, J=7.2 Hz), 7.117 (d, 1H, J=1.8 Hz), 7.138 (d, 1H, J=1.8 Hz); 11.343 (s, 1H); 11.958 (s, 1H). HRMS: calcd for C10H9BrN2O2 (M+) m/z: 267.9846; found 267.9853.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:21]=[O:22])[N:9]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[C:10](=[O:12])[CH:11]=1.[Br:28]NC(=O)CCC(N)=O>C(#N)C>[Br:28][C:11]1[C:10](=[O:12])[N:9]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[C:8]([CH:21]=[O:22])=[CH:7][C:6]=1[O:5][CH2:4][C:3]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:2]=1[F:1]
Reactant: O=Cc1cc(OCc2ccc(F)cc2F)cc(=O)n1-c1c(F)cccc1F
Reactant: NC(=O)CCC(=O)NBr
Solvent: CC#N
Product: O=Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 50 ml one neck round bottom flask 4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2-carbaldehyde (0.36 g, 0.95 mmol) was dissolved in acetonitrile (5 mL). The reaction mixture was cooled to 0° C. in ice bath and charged with N-bromosuccinamide (0.17 g, 0.95 mmol). The mixture was allowed to stir at 0° C. for 2 hours under nitrogen atmosphere After 2 hours, the solvent was evaporated under vacuum. 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 7.73-7.67 (m, 2H), 7.62-7.54 (m, 1H), 7.35 (dt, J=10.40, 2.56 Hz, 1H), 7.27 (t, J=8.35 Hz, 2H), 7.19 (dt, J=8.60, 2.44 Hz, 1H), 5.72 (s, 1H), 5.50 (s, 2H); ES MS m/z 455.9836 (M+H calcd for C19H11BrF4NO3, requires 455.9859).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cc(F)c(F)cc3F)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 2,4,5-trifluorobenzoyl chloride (29 μL, 0.229 mmol) and mixing for 24 h, 46.2 mg (>100%) of the title compound were recovered.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][N:9]([C:11]([C:13]3[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=3[O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:12])[CH2:10][C:5]2=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)CCC>>[F:41][C:38]1[CH:39]=[CH:40][C:35]([C:2]2[N:7]=[C:6]3[CH2:8][N:9]([C:11]([C:13]4[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=4[O:23][C@@H:24]([CH3:29])[C:25]([F:26])([F:27])[F:28])=[O:12])[CH2:10][C:5]3=[CH:4][CH:3]=2)=[CH:36][CH:37]=1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(Cl)nc2C1)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(F)cc1
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(-c3ccc(F)cc3)nc2C1)C(F)(F)F

Procedure:
Prepared in analogy to Example A54(a) from (2-chloro-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone (Example C4) and tributyl(4-fluorophenyl)stannane. White solid. MS (m/e): 509.1 [M+H]+, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH2:21][CH2:22][N:23]=3)[C:8]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)=[N:9][C:10]=2[CH:11]=1.Cl[CH2:25][CH2:26][CH2:27][S:28]([N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)(=[O:30])=[O:29]>>[CH3:37][N:34]1[CH2:33][CH2:32][N:31]([S:28]([CH2:27][CH2:26][CH2:25][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:7]([CH2:21][CH2:22][N:23]=4)[C:8]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)=[N:9][C:10]=3[CH:11]=2)(=[O:30])=[O:29])[CH2:36][CH2:35]1
Reactant: O=C(NC1=Nc2cc(O)ccc2C2=NCCN12)c1cccnc1
Reactant: CN1CCN(S(=O)(=O)CCCCl)CC1
Product: CN1CCN(S(=O)(=O)CCCOc2ccc3c(c2)N=C(NC(=O)c2cccnc2)N2CCN=C32)CC1

Procedure:
The procedure used for the preparation of Example 24 was used to prepare the title compound from N-(8-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (Example 2-5 in WO2004029055) and 1-[(3-chloropropyl)sulfonyl]-4-methylpiperazine (Intermediate D) (70 mg, 16%). TLC: Rf=0.08 in 10% MeOH/CH2Cl2, HPLC MS RT=1.06 min, MH+=512.1; 1H NMR (DMSO-d6) δ: 2.12-2.37 (2H, m), 2.37 (3H, s), 3.15-3.23 (6H, m), 3.30-3.33 (4H, m), 4.00-4.20 (6H, m), 6.84 (1H, d), 7.29 (1H, s), 7.51 (1H, dd), 7.75 (1H, d), 8.41 (1H, d), 8.70 (1H, m), 9.28 (1H, s), 12.29 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][N:33]1[CH2:39][CH:38]2[NH:40][CH:35]([CH2:36][CH2:37]2)[CH2:34]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:40]5[CH:35]6[CH2:36][CH2:37][CH:38]5[CH2:39][N:33]([CH3:32])[CH2:34]6)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: CN1CC2CCC(C1)N2
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN1CC2CCC(C1)N2C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 3-methyl-3,8-diaza-bicyclo[3.2.1]octane following General Procedure C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[C:12]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13]1.O>CN(C)C(=O)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CCOC(=O)C1(Br)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)C1(n2cc([N+](=O)[O-])cn2)CCC1
Reaction time: 0.5 h
Yield: 8.1 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (8.2 g) in N,N-dimethylacetamide (70 mL) was added sodium hydride (60% in mineral oil, 3.2 g) in an ice bath, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added ethyl 1-bromocyclobutanecarboxylate (15 g) in an ice bath, and the mixture was stirred at room temperature for 10 hr. Water was poured into the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:11][CH:12]=1)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: N#CCC(=O)c1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)CC#N)cc1
Temperature: 80 °C

Procedure:
A mixture of p-aminobenzoylacetonitrile, 1-bromohexadecane, potassium carbonate and hexamethylphosphoramide is heated to 80° C. for 20 hours and worked up as in Example 1, providing 4-hexadecylaminobenzoylacetonitrile. This material is dissolved in isopropanol and treated with an excess of sodium borohydride. After stirring at room temperature for 3 hours, the solution is concentrated, diluted with water and extracted with chloroform. The chloroform extract yields the crude carbinol which is heated to reflux for 1 hour with ethanol containing an equal volume of 2 N aqueous hydrochloric acid. The solution is then cooled, diluted with water and extracted with chloroform. The organic extract is washed successively with water and aqueous sodium bicarbonate, then dried and evaporated to afford 4-(hexadecylamino)cinnamonitrile.