Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C:16]([N:17](C(=O)C2C=CC=CC=2)[C:18](=[O:26])[CH2:19][CH2:20]1)=[CH:15][CH2:14]3)[CH3:2].O.NN>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C:16]([NH:17][C:18](=[O:26])[CH2:19][CH2:20]1)=[CH:15][CH2:14]3)[CH3:2]
Reactant: CCOC(=O)CO[C@H]1CC[C@H]2[C@@H]3CC=C4N(C(=O)c5ccccc5)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: NN
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CO[C@H]1CC[C@H]2[C@@H]3CC=C4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To the product of Step C, above, (90 mg) in CH2Cl2 (2.0 ml) was added hydrazine hydrate (0.2 ml). The mixture was shaken for a few minutes and purified via preparative TLC using two silica gel plates (1500μ) developed with EtOAc to give the title product (Rf=0.54).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19]CO)=[CH:15][C:14]=2[CH3:22])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8].[H-].[Na+].[CH2:25]([O:27][CH2:28][CH2:29]Br)[CH3:26].C([OH:33])C>O1CCCC1.O>[Cl:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:33][CH2:29][CH2:28][O:27][CH2:25][CH3:26])=[CH:15][C:14]=2[CH3:22])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(CCO)ccc1OCCNc1ncnc(C)c1Cl
Reactant: CCOCCBr
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCCOCc1ccc(OCCNc2ncnc(C)c2Cl)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.1 g of 5-chloro-4-{2-[4-(2-hydroxyethyl)-2-methylphenoxy]ethylamino}-6-methylpyrimidine were dissolved in 50 ml of anhydrous tetrahydrofuran and 0.3 g of sodium hydride (which had been freed from mineral oil by washing with hexane) were added to the solution. The mixture was stirred at room temperature for 30 minutes. 1.7 g of 2-bromoethyl ethyl ether was added to the mixture and it was then stirred, whilst heating, for 3 hours. At the end of this time, any excess of sodium hydride was decomposed by adding ethanol. Water was added to the mixture, and the oily substance which separated was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was removed by distillation under reduced pressure to give an oily substance which was subjected to column chromatography (Wakogel C-200, eluted with a 2:1 by volume mixture of toluene and ethyl acetate) to afford 2.0 g of the title compound as a pale yellow oily liquid, n16.4 = 1.5591.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[N:4][N:5]([C:7]2[N:12]=[CH:11][C:10]([NH:13][CH:14]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[CH:6]=1.[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:31])=[N:4][N:5]([C:7]2[N:12]=[CH:11][C:10]([NH:13][CH:14]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[C:15]3[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[CH:6]=1
Reactant: CCOC(=O)c1ccc(C(Nc2ccc(-n3cc(Cl)c(C)n3)nc2)C2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn(-c2ccc(NC(c3ccc(C(=O)O)cc3)C3CCCC3)cn2)cc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of (+/−)-ethyl 4-((6-(4-chloro-3-methyl-1H-pyrazol-1-yl)pyridin-3-ylamino)(cyclopentyl)methyl)benzoate (78.6 mg, 0.179 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL) was added 1 N aqueous sodium hydroxide (0.36 mL, 0.36 mmol). The reaction was heated to 50° C. for 10 minutes. The heat was removed and the reaction was allowed to stir at room temperature for 1 hour. The reaction was concentrated. The residue was taken up in water and acidified to pH=4 with 1 N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (68.3 mg, 93%) as a white solid. 1H NMR (400 MHz, CD3OD, δ): 8.19 (s, 1H), 7.92-7.96 (m, 2H), 7.66-7.69 (m, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.42-7.45 (m, 1H), 7.03 (dd, J=8.9, 2.8 Hz, 1H), 4.18 (d, J=9.2 Hz, 1H), 2.22 (s, 3H), 1.98-2.07 (m, 1H), 1.43-1.74 (m, 6H), 1.23-1.38 (m, 2H). MS (M+1) 411.3.
Reaction SMILES: [OH:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([O:25][C:26]([CH3:35])([CH3:34])[C:27]([O:29]C(C)(C)C)=[O:28])[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([O:25][C:26]([CH3:35])([CH3:34])[C:27]([OH:29])=[O:28])[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cc(Nc2nccc(OC(C)(C)C(=O)OC(C)(C)C)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(OC(C)(C)C(=O)O)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To tert-butyl 2-{[2-({3-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]-5-methylphenyl}amino)-pyrimidin-4-yl]oxy}-2-methylpropanoate (Example 94A-25, 140 mg, 0.28 mmol) in DCM (1 mL) was added of trifluoroacetic acid (220 μL, 2.8 mmol). The mixture was aged for 2 hours and additional trifluoroacetic acid (500 μL, 6.4 mmol) was added. The reaction was stirred overnight. The reaction was concentrated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried, filtered and solvent removed under reduced pressure to afford 2-{[2-({3-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]-5-methylphenyl}amino)pyrimidin-4-yl]oxy}-2-methylpropanoic acid (110 mg, 0.25 mmol, 88%) as pale yellow oil. MS ESI: [M+H]+ m/z 441.2. 1H NMR (600 MHz. DMSO-d6): δ 9.50 (s, 1H); 8.18 (d, J=6 Hz, 1H); 7.96 (s, 1H); 7.66 (s, 1H); 7.44 (s, 1H); 7.05 (s, 1H); 6.27 (d, J=6 Hz, 1H); 2.52-2.27 (m, 4H); 2.46 (s, 3H); 1.86 (s, 2H); 1.66 (s, 6H). rhSYK activity=++
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[C:10]2[O:13][C@H:14]2[CH2:18][N:17](C(OC(C)(C)C)=O)[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]2)=[CH:5][CH:4]=1)=[CH2:2].[ClH:30]>O1CCOCC1>[Cl-:30].[CH3:29][O:28][C:26]([C@@H:16]1[CH2:15][C@@H:14]([O:13][C:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([CH:1]=[CH2:2])[CH:12]=3)[CH:7]=[CH:8][N:9]=2)[CH2:18][NH2+:17]1)=[O:27]
Reactant: C=Cc1ccc2ccnc(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)c2c1
Reactant: Cl
Solvent: C1COCCO1
Product: C=Cc1ccc2ccnc(O[C@H]3C[NH2+][C@H](C(=O)OC)C3)c2c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Carbamate from Step 2 was dissolved in a 4.0 M HCl solution in dioxane. The resulting mixture was stirred at RT for 0.5 h, during which time the product precipitated. The title compound was filtered off and washed with hexane/EtOAc 1/1 v/v. MS (ES+) C17H18N2O3 requires 298. Found: 299 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[CH3:9][CH:10]1[NH:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1>CS(C)=O>[Br:1][C:2]1[N:3]=[C:4]([N:15]2[CH:10]([CH3:9])[CH2:11][CH2:12][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1CCC(NC(=O)OC(C)(C)C)CN1
Reactant: Fc1cccc(Br)n1
Solvent: CS(C)=O
Product: CC1CCC(NC(=O)OC(C)(C)C)CN1c1cccc(Br)n1
Temperature: 95 °C
Yield: 39 %

Procedure:
A solution containing 2-bromo-6-fluoropyridine (0.95 mL, 6.65 mmol and tert-butyl 6-methylpiperidin-3-ylcarbamate (750 mg, 3.32 mmol) in methyl sulfoxide 5.0 ml was heated 95° C. 18 h. The reaction was quenched with water then extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by flash chromatography (EtOAc/Heptane eluted at 30% EtOAc) to give tert-butyl N-[1-(6-bromo-2-pyridyl)-6-methyl-3-piperidyl]carbamate (480 mg) in 39% yield. MS (ESI) m/z: 371.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].Cl.[C:13]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[CH2:21][C:22](=[O:29])[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>ClCCl>[C:13]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:30])[CH2:21][C:22]([N:23]2[CH2:24][CH2:25][N:26]([S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:10])=[O:9])[CH2:27][CH2:28]2)=[O:29])=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC(=O)N1CCN(S(=O)(=O)c2ccccc2Cl)CC1)Nc1ccc(-c2ccccc2)cc1
Reaction time: 2 h
Yield: 35.4 %

Procedure:
2-Chlorobenzenesulfonyl chloride (35.4 mg, 0.17 mmol) was added at 0° C. to a stirred solution of N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride (60 mg, 0.17 mmol) and DIEA (24.6 mg, 0.19 mmol) in dichloromethane (2 mL). the resulting mixture was stirred for 2 hrs then the product was extracted with dichloromethane. The organics was separated and washed with saturated sodium bicarbonate solution, followed by brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography using silica gel 60-120 mesh with 60% ethyl acetate in hexane as eluant to afford 30 mg (36%) of N-Biphenyl-4-yl-3-[4-(2-chloro-benzenesulfonyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 498.12 (M+1)+ 96.7%. 1H NMR: (CDCl3): δ 9.6 (s, 1H), 8.06 (d, 1H), 7.56 (m, 8H), 7.42 (t, 3H), 7.34 (t, 1H), 3.78 (t, 2H), 3.7 (t, 2H), 3.48 (s, 2H), 3.38 (m, 4H).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([CH3:40])[C:35](=[O:41])[CH2:34]2.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[N:36]([CH3:40])[C:35](=[O:41])[CH2:34]4)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: CN1C(=O)Cc2cc(N)ccc21
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4c(c3)CC(=O)N4C)nn12

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.250 mL, 0.00144 mol) and 5-Amino-1-methyl-1,3-dihydro-indol-2-one (0.141 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (0.500 mL, 0.00512 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 5-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-1-methyl-1,3-dihydro-indol-2-one as a lyophilized powder. (M+H)=386.1. 1H NMR (400 MHz, DMSO, d6) δ 9.33 (s, 1H), 8.93 (s, 1H), 7.78 (m, 2H), 7.50 (m, 2H), 7.24 (d, 1H, J=8.28 Hz), 7.15 (t, 1H, J=7.61 Hz), 6.91 (m, 2H), 6.82 (d, 1H, J=8.28 Hz), 3.78 (s, 3H), 3.46 (s, 2H), 3.08 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[OH-].[K+].Cl[C:12]1C=CC([N+]#[C-])=C[CH:13]=1.[OH:20][C:21]1[C:22](=[O:32])[C:23]2[C:28]([C:29](=[O:31])[CH:30]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.C=O>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:12]2[O:20][C:21]3[C:22](=[O:32])[C:23]4[C:28]([C:29](=[O:31])[C:30]=3[CH:13]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:4][CH:3]=1
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: [C-]#[N+]c1ccc(Cl)cc1
Reactant: Nc1ccc(Cl)cc1
Agent: C=O
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)c2oc(Nc3ccc(Cl)cc3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-chlorobenzenamine 12.7 g (0.1 mol), and 470 mg BnEt3NCl was suspended in the mixture of 200 ml DCM, 200 ml CH3C1 and 200 ml 50% KOH (aq.), then was stirred at room temperature for 2 h. The organic phase was separated, washed with water (500 ml), dried with Na2SO4 and concentrated to afford yellow oil, which was purified by chromatography; 1-chloro-4-isocyanobenzene 500 mg, 2-hydroxynaphthalene-1,4-dione 635 mg (1.0 eq) and Paraformaldehyde 109 mg (1.0 eq) was dissolved in 30 ml toluene, stirred and refluxed under N2 for 4 h. After removing all solvents under reduced pressure, the residue was purified by chromatography to afford 2-(4-chlorophenylamino)naphtho[2,3-b]furan-4,9-dione as black solid. 1H NMR (300 MHz, DMSO) δ6.39 (s, 1H); 7.24˜7.29 (m, 2H); 7.41˜7.43 (dd, 2H); 7.54 (br, 1H); 7.69˜7.73 (t, 1H); 7.78˜7.82 (t, 1H); 8.13˜8.17 (t, 3H) ppm. MS-ESI: cal. 323; found: 346 (M+Na).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-])=O)[CH:10]=1)[N:7]([C:14]([C:16]([O:18]CC)=O)=[O:15])[CH2:6][CH2:5]2.O.C(O)(=O)C>C1COCC1.[Cl-].[Cl-].[Cl-].[Ti+3]>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:5][CH2:6][N:7]3[C:14](=[O:15])[C:16](=[O:18])[NH:11][C:9]([CH:10]=1)=[C:8]23
Reactant: CCOC(=O)C(=O)N1CCc2cc(Br)cc([N+](=O)[O-])c21
Agent: [Ti+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2cc(Br)cc3c2n(c1=O)CC3
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.6 %

Procedure:
To a solution of 5-bromo-7-nitro-N-ethoxalylindoline (2.0 g, 5.83 mmol) in a mixture of THF (50 mL), water (10 mL), and acetic acid (10 mL) was added aqueous 20% titanium trichloride (31 mL, 40.8 mmol) and the mixture was stirred for 4 h at room temperature. The precipitates formed were collected by filtration, washed with diluted aqueous hydrochloric acid and then distilled water, and dried in vacuo to give 772 mg of the title compound (50%): mp>300° C.; 1H NMR (270 MHz, DMSO-d6) δ11.91 (bs, 1H), 7.21 (d, 1H, J=1 Hz), 7.02 (d, 1H, J=1 Hz), 4.22 (t, 2H, J=7 Hz), 3.32 (t, 2H, J=7 Hz).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)=O.N1([C:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=2)CCCC1.Cl.[OH2:28]>C1C=CC=CC=1>[O:28]=[C:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: O
Reactant: CCOC(=O)C(C)c1ccc(C=O)cc1
Reactant: C1=C(N2CCCC2)CCCC1
Agent: Cl
Solvent: c1ccccc1
Product: CCOC(=O)C(C)c1ccc(C=C2CCCCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.15 g of ethyl 2-(p-formylphenyl)propionate, 4.5 g of pyrrolidinocyclohexene and 20 ml of benzene was heated under reflux for 18 hours. After cooling, the reaction mixture was admixed with a mixture of 5 ml of conc. hydrochloric acid and 5 ml of water under ice-cooling and then stirred at room temperature overnight. 100 ml of benzene were added thereto, the organic layer was separated and then washed with water. After drying over anhydrous sodium sulfate, the benzene was distilled off to leave an oily substance. The substance was distilled under reduced pressure to afford 2.3 g of the desired product as a yellow oily substance having a boiling point of 160°-170° C./0.3 mmHg (bath temp.).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:19])[O:4][N:3]=1.C(N(CC)CC)C.[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30][C:29]=1[NH2:35].O>ClCCl>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:35][C:29]3[CH:30]=[N:31][C:32]([CH3:34])=[CH:33][C:28]=3[CH3:27])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C)c(N)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)cn1
Temperature: 70 °C
Yield: 97.7 %

Procedure:
4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (247 mg, 0.819 mmol) was added to a solution of triethylamine (0.114 mL, 0.819 mmol) and 4,6-dimethyl-3-pyridinamine (100 mg, 0.819 mmol) in dichloromethane (1 mL). The mixture was heated at 70° C. for 2 hours. To the mixture was added water (5 mL) then the organic layer separated and purified by silica (Si) chromatography (100% ethyl acetate). The relevant fractions were combined and concentrated to give the title product (310 mg) as a yellow solid. LCMS (2 min, formic) Rt 0.63 mins, m/z (ES+) 388 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].[CH:15]1([NH2:18])[CH2:17]C1.FC1C=[CH:22][C:23]2[NH:28]C(=O)OC(=O)C=2C=1>>[CH:7]1([NH:6][C:4](=[O:5])[C:3]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:2]=2[NH:1][CH2:17][C:15]2[NH:18][CH2:22][CH2:23][N:28]=2)[CH2:9][CH2:8]1
Reactant: Nc1ccc(F)cc1C(=O)NC1CC1
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1cc(F)ccc1NCC1=NCCN1

Procedure:
2-Amino-N-cyclopropyl-5-fluorobenzamide (prepared from cyclopropylamine and 6-fluoro-2H-3,1-benzoxazine-2,4(1H)-dione using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give N-cyclopropyl-2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]-5-fluorobenzamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]#[CH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CON(C)[C:20]([C:22]1[N:23]([CH2:33][CH3:34])[N:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:26]=1)=[O:21]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]#[C:11][C:20]([C:22]1[N:23]([CH2:33][CH3:34])[N:24]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:26]=1)=[O:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)cc1C(=O)N(C)OC
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1nc(-c2ccccc2)cc1C(=O)C#CCNC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a −10° C. solution of N-t-butoxycarbonyl propargylamine (502 mg, 3.24 mmoles) in THF (5 mL) was added nBuLi (3.7 mL of a 1.6 M solution in hexanes, 5.94 mmoles) dropwise over 10 minutes. The resulting dianion mixture was stirred at −10° C. for 15 minutes, then treated with a THF solution (2 mL) of the above-prepared 2-ethyl-5-phenyl-2H-pyrazole-3-carboxylic acid methoxy-methyl-amide (125 mg, 482 μmoles), allowed to warm to room temperature, and stirred at room temperature for 2 hours. The resulting mixture was cooled to 0° C., quenched with 2 M NaH2PO4, diluted with ethyl acetate, and vigorously stirred for 5 minutes. The phases were separated, the organic phase dried over Na2SO4, filtered, and concentrated in vacuo. The crude title compound was used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([CH:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6]1)=[O:4].N>CCOC(C)=O.CO>[F:22][C:2]([F:1])([F:21])[C:3]([CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)=[O:4]
Reactant: O=C(OCc1ccccc1)N1CCC(C(=O)C(F)(F)F)CC1
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(C1CCNCC1)C(F)(F)F

Procedure:
The product was obtained analogously to IP 2b starting from 900 mg (2.85 mmol) of benzyl 4-(2,2,2-trifluoroacetyl)piperidine-1-carboxylate. Yield: 516 mg (quant. yield); C7H10F3NO (M=181.156); calc.: molpeak (M+H)+: 182; found: molpeak (M+H)+: 182; Rf value: 0.18 (silica gel, EtOAc/MeOH/conc. aqueous ammonia 5:5:0.5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13]C(=O)C)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.C(O)C.[ClH:20]>>[Cl-:20].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([NH3+:13])[NH:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Cl
Reactant: CC(=O)Nc1nc(-c2ccc(F)cc2)c[nH]1
Solvent: CCO
Product: [Cl-]
Product: [NH3+]c1nc(-c2ccc(F)cc2)c[nH]1

Procedure:
1.0 g (4.56 mmol) N-[4-(4-fluorphenyl)-1H-imidazole-2-yl]acetamide were suspended in 30 ml 2 N HCl and 30 ml ethanol and were stirred at 80° C. for 2 hours. After removal of the solvent under vacuum, 0.97 g 4-(4-fluorphenyl)-1H-imid azole-2-aminium chloride were obtained, which was used in the following reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=O)=[CH:4][C:3]=1[O:22][CH3:23].[C:24](OC(=O)C)(=[O:26])[CH3:25]>O>[C:24]([O:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:17][C:15](=[O:16])[C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[N:12]=2)=[CH:4][C:3]=1[O:22][CH3:23])(=[O:26])[CH3:25]
Reactant: COc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc(/C=C/c2nc3ccccc3c(=O)o2)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A solution of (E)-2-[[3-(4-hydroxy-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.5 g, 1.6 mmol) in acetic anhydride (3 mL) was heated to reflux and stirred for 3 h. The reaction was cooled to rt and the resulting suspension was diluted with water. The suspension was stirred at rt for 1 h and the precipitate was collected by filtration, providing (E)-2-(4-acetoxy-3-methoxystyryl)-4H-benzo[d][1,3]oxazin-4-one (0.52 g, 97%) as a pale brown solid; mp 185-186° C.; δH (400 MHz, DMSO-d6) 2.63 (s, 3H, COCH3), 3.85 (s, 3H, OCH3), 7.08 (d, J=16.0 Hz, 1H, CH═CHCO), 7.17 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.38 (d, J5′,6′=8.0, 1H, H6′), 7.59 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.61 (d, J3,4=8.0 Hz, 1H, H3), 7.63 (s, 1H, H2′), 7.76 (d, J=16.0 Hz, 1H, CH═CHCO), 7.92 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.11 (d, J5,6=8.0 Hz, 1H, H6); δC (100 MHz, DMSO-d6) 20.4, 56.0, 111.9, 116.9, 119.5, 121.4, 123.3, 126.6, 128.1, 128.4, 133.5, 136.8, 140.5, 140.9, 146.6, 151.2, 156.8, 168.4; HRMS (ESI) calculated for C19H5NO5 [M+H]+ 338.1023; found 338.1023; νmax 1197, 1214, 1593, 1635, 1748 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[NH:25][C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=2[N:30]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:35][C:33]2[CH:32]=[CH:31][C:29]3[N:30]=[C:26]([NH:25][C:16]4[C:15]5[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=5)[N:19]=[CH:18][N:17]=4)[S:27][C:28]=3[CH:34]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)c5ccc(Cl)cc5)cc4s3)c2cc1OC

Procedure:
4-Chloro-N-[2-(6,7-dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl ]benzamide was prepared from p-chlorobenzoyl chloride (15 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 2 (yellowish solid, 41 mg, 83 μmol, 74%). LC/ESI-MS: m/z=492 [M(35Cl)+H]+; m/z=490 [M(35Cl)−H]−; Rt=3.45 min.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][C:21]3[O:24][CH:25]=[CH:26][C:20]=3[CH2:19]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][NH:28][CH3:29].[CH2:30]=O>C(O)(=O)C>[CH3:27][N:28]([CH2:30][C:25]1[O:24][C:21]2[CH2:22][CH2:23][N:18]([S:15]([C:12]3[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:14][CH:13]=3)(=[O:17])=[O:16])[CH2:19][C:20]=2[CH:26]=1)[CH3:29]
Reactant: C=O
Reactant: CNC
Reactant: O=C(c1ccccc1)c1ccc(S(=O)(=O)N2CCc3occc3C2)cc1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(S(=O)(=O)c1ccc(C(=O)c3ccccc3)cc1)C2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.210 g (0.572 mmol) of 5-(4-benzoylphenylsulfonyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 10 ml of acetic acid, 77 mg (0.86 mmol) of 50% aqueous dimethylamine and 70 mg (0.86 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 0.5 hours. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was crystallized from diethyl ether-hexane to yield the desired product.