Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:44])[C@@H:13]([NH:26]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1CCOCC1>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:44])[C@@H:13]([NH2:26])[CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCCCOCc2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCCCOCc2ccccc2)CC1
Reaction time: 2 h

Procedure:
To a solution of 663 mg (S)-4-[6-Benzyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoyl]-piperazine-1-carboxylic acid ethyl ester in 4.9 ml DMF were added at room temperature 0.97 ml morpholine. After stirring for 2 h the reaction mixture was evaporated and the crude product thus obtained used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:15])[CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[OH-].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>CN(C)C=O>[F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:15])[CH:10]=3)[N:5]([CH2:18][CH:20]3[CH2:21][O:22]3)[C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(c1)[nH]c1ccc(F)cc12
Reactant: BrCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)c1ccc(F)cc1n2CC1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a stirred solution of 2,6-difluoro-9H-carbazole (0.460 g, 2.3 mmol) in N,N-dimethylformamide (5 mL) at 0° C. was added 85% potassium hydroxide (0.179 g, 2.7 mmol) and the mixture was stirred for 1 hr. Epibromohydrin (0.375 mL, 4.5 mmol) was added and the mixture was slowly warmed to room temperature and stirred for 16 hrs. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10-50% methylene chloride/hexanes) to afford the desired product as a white solid (0.55 g, 94%). 1H NMR (300 MHz, CDCl3) δ 7.95 (dd, 1H, J=8.7, 5.7 Hz), 7.68 (dd, 1H, J=8.7, 2.7 Hz), 7.38 (dd, 1H, J=8.7, 4.2 Hz), 7.20 (td, 1H, J=9.0, 2.7 Hz), 7.13 (dd, 1H, J=9.9, 2.1 Hz), 6.98 (ddd, 1H, J=9.6, 9.0, 2.4 Hz), 4.64 (dd, 1H, J=15.9, 2.7 Hz), 4.29 (dd, 1H, J=15.9, 5.1 Hz), 3.35 (m, 1H), 2.85 (t, 1H, J=4.5 Hz), 2.56 (dd, 1H, J=4.8, 2.4 Hz).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:19][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([CH3:18])[CH:15]=1)[O:11][CH2:10][CH2:9][O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: Cc1cc(C)cc(OCCO[Si](C)(C)C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(CBr)cc(OCCO[Si](C)(C)C(C)(C)C)c1

Procedure:
To a solution of tert-butyl-[2-(3,5-dimethyl-phenoxy)-ethoxy]-dimethylsilane (2.22 g, 7.91 mmol) in carbon tetrachloride (50 mL) under nitrogen was added N-bromosuccinimide (1.57 g, 8.70 mmol) and benzoyl peroxide (0.38 g, 1.58 mmol). The resulting mixture was heated at reflux for 3 hours with simultaneous illumination by a sun lamp. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The crude material (3.99 g) was purified by column chromatography (silica gel 230-400 mesh; 1/0 to 4/1 hexanes/EtOAc as eluent) to give [2-(3-bromomethyl-5-methyl-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane as a light yellow oil. Yield: 2.17 g (75%).
Reaction SMILES: C1COCC1.C([Si](C)(C)[O:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([CH2:34][C:35]5[CH:36]=[C:37]6[C:42](=[CH:43][C:44]=5[F:45])[N:41]=[CH:40][CH:39]=[CH:38]6)=[CH:32][N:33]=4)[N:30]=3)[CH:22]=[N:21]2)[CH2:16][CH2:15]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOC(C)=O>[F:45][C:44]1[CH:43]=[C:42]2[C:37]([CH:38]=[CH:39][CH:40]=[N:41]2)=[CH:36][C:35]=1[CH2:34][C:31]1[N:29]2[N:30]=[C:25]([C:23]3[CH:22]=[N:21][N:20]([CH:17]4[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][OH:11])[CH2:15][CH2:16]4)[CH:24]=3)[CH:26]=[CH:27][C:28]2=[N:33][CH:32]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCN1CCC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A flask was charged with THF (5 mL), 6-[6-(1-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-piperidin-4-yl}-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-7-fluoro-quinoline (Stage 147.1, 96 mg, 0.164 mmol) and tetrabutylammonium fluoride (819 μL of a 1 M solution, 0.819 mmol). The mixture was stirred at rt for 2 h. The RM was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by MPLC, then taken up in NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated to afford the title compound (tR 2.99 min (conditions 3), MH+=472.1, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.50 (s, 1H); 8.34 (m, 1H); 8.08 (m, 2H); 8.06 (m, 1H); 7.76 (d, 1H); 7.60 (s, 1H); 7.53 (d, 1H); 7.47 (m, 1H); 4.55 (s, 2H); 4.41 (t, 1H); 3.50 (m, 2H); 2.97 (m, 2H); 2.42 (t, 2H); 2.13 (m, 2H); 1.97 (m, 4H)).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]([C:17]#[N:18])([CH3:16])[CH2:12][CH:13]1[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[NH2:28][OH:29]>C(O)C>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]([C:17](=[NH:18])[NH:28][OH:29])([CH3:16])[CH2:12][CH:13]1[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(C#N)(CC1CC1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(CC1CC1)(NC(=O)OCc1ccccc1)C(=N)NO
Temperature: 60 °C
Reaction time: 18 h
Yield: 71.3 %

Procedure:
To a solution of (1-Cyano-2-cyclopropyl-1-methyl-ethyl)-carbamic acid benzyl ester (Example 66b, 795 mg, 3.08 mmol) in ethanol (10 ml) were added triethylamine (343 mg, 472 μl, 3.39 mmol) and hydroxylamine hydrochloride (214 mg, 3.08 mmol). The reaction mixture was stirred at 60° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (640 mg, 71%) as a white solid. MS (ESI, m/z): 292.5 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([CH3:14])([S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([OH:29])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][N:26]([CH2:2][CH2:3][C:4]([CH3:14])([S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:25](=[O:29])[CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(C)(CCBr)S(C)(=O)=O
Reactant: Oc1cc(OCc2ccccc2)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CCn1ccc(OCc2ccccc2)cc1=O)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (345 mg, 1.20 mmol) and 4-(benzyloxy)pyridin-2-ol (201 mg, 1.00 mmol) in tetrahydrofuran (10 mL) was added cesium carbonate (652 mg, 2.00) at ambient temperature. The resulting mixture was stirred at 50° C. overnight. The mixture was allowed to cool to ambient temperature and filtered through a celite pad. The pad was washed with ethyl acetate; the filtrates were combined and concentrated to a crude residue. The material was purified via filtration through a silica gel pad and eluted with heptanes/ethyl acetate. The desired fractions were isolated and the solvent removed via rotary evaporation affording ethyl 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate as a white solid. 302.2 mg. 1H NMR (CD3OD) 7.47, (1H, d), 7.41-7.29 (5H, m), 6.15-6.13, (1H, dd), 5.96 (1H, d), 5.07 (2H, s), 4.20-4.12 (2H, m), 4.00-3.93 (1H, m), 3.47 (1H, q), 3.21 (3H, s), 2.60-2.53 (1H, m), 2.32-2.25 (1H, M), 3.20 (3H, s), 1.26 (3H, t) ppm.
Reaction SMILES: [CH2:1]([C:5]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)([C:11]([O:13]CC)=[O:12])[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[K+]>O.CO>[CH2:1]([C:5]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)([C:11]([OH:13])=[O:12])[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(CC1CCCCC1)(C(=O)OCC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCC(CC1CCCCC1)(C(=O)O)C(=O)O
Temperature: 0 °C

Procedure:
A mixture of diethyl 2-n-butyl-2-(cyclohexylmethyl)malonate (1.8 g) and potassium hydroxide (10 g) in water (10 ml) and methanol (10 ml) were heated under reflux for 4 hours. The methanol was evaporated under reduced pressure and the residue treated with water (50 ml), cooled to 0° C., and acidified with concentrated hydrochloric acid. The product was extracted with ethyl acetate and the extracts washed with brine, dried (MgSO4) and evaporated to give 2-n-butyl-2-(cyclohexylmethyl)malonic acid. Without further purification the acid was heated to about 160° until the evolution of carbon dioxide ceased, and cooled to give 2-(cyclohexylmethyl)hexanoic acid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23]>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:28]4[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH:22]([CH3:23])[CH3:21])[CH2:27]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(C)NCC1CCNC1
Solvent: CC#N
Product: CC(C)NCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 88.5 %

Procedure:
A suspension of 1.1 g (3.9 mmole) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.4 g (10 mmole) of N-(2-propyl)-3-pyrrolidinemethanamine and 50 ml of acetonitrile was refluxed for 2 hours. The precipitate was removed by filtration, washed with acetonitrile, ether, and dried in vaco to give 1.4 g of the title compound, mp 218°-221° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9](O)=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ClC(OCC(C)C)=O.C(OCC)(=O)C>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[CH2:9][OH:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(CO)c1ccc(-c2ccccc2)c(F)c1
Reaction time: 1 h
Yield: 95 %

Procedure:
To a chilled (0° C.) solution of 2-(2-fluoro-biphenyl-4-yl)propionic acid in THF was added isobutyl chloroformate followed by dropwise addition of TEA. The resulting white slurry was allowed to stir for 1 hour and then diluted with THF (50 mL) and filtered. The filter cake was washed with additional THF (50 mL) and the filtrate was concentrated to approximately 50 mL using a rotary evaporator. The concentrated filtrate was then stirred at −20° C. and a solution of NaBH4 in H2O (20 mL) was dropwise added over a period of 15 minutes. The resulting suspension was stirred for 2 hours at 0° C., diluted with water (200 mL), and extracted with ethyl acetate (2×100 mL). The ethyl acetate layers were combined and washed with 1.0 N HCl solution (100 mL) followed by a 5% bicarbonate solution wash (100 mL). The ethyl acetate solution was then concentrated to an oily residue of 2-(2-fluoro-biphenyl-4-yl)propanol (4.47 g, 95% yield).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[O:23])[NH:11][C:12]1[NH:13][N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=1)[CH3:9])(C)(C)C.O1CCOCC1.[ClH:31]>>[ClH:31].[ClH:31].[NH2:7][CH:8]([CH3:9])[C:10]([NH:11][C:12]1[NH:13][N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=1)=[O:23]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(-c2ccccc2)n[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: CC(N)C(=O)Nc1cc(-c2ccccc2)n[nH]1
Reaction time: 3 h

Procedure:
To 100 mg (0.30 mmol) of the product of Step A [1-(5-phenyl-2H-pyrazol-3-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester was added 1 ml of 4N HCl dioxane solution (Aldrich) at ambient temperature. The reaction was allowed to stir for 3 hours. After evaporation to dryness and trituration with ether, 73 mg of amino-N-(5-phenyl-2H-pyrazol-3-yl)-propionamide dihydrochloride was obtained as a white powder (80%) ( MS: 231[P+1]/229 [P−1])(RF=0.2 on silica TLC (9/1 Chloroform/ Methanol).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[NH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13](=[O:20])[CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13](=[O:20])[CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: O=C1CCCNc2ccccc21
Reactant: O=C(Cl)CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCCN(C(=O)CCCCCl)c2ccccc21
Temperature: 10 °C
Reaction time: 1 h

Procedure:
5-Chlorovaleryl chloride (18.61 mmol, 2.89 g) in dimethylformamide (20 ml) was added dropwise at 10° to a suspension of 1,2,3,4-tetrahydro-5H-1-benzazepin-5-one (12.41 mmol, 2.00 g, preparation according to J. Org. Chem 1972, 37, 2849) and potassium carbonate (14.89 mmol, 2.06 g) in dimethylformamide (40 ml). The reaction mixture was stirred first at 10° C. for 1 h and then under reflux for 3 h. The precipitated salts were filtered off and the filtrate was concentrated to dryness. CH2Cl2 was added to the oil obtained in this way and the mixture was washed three times with 50 ml each time of a 5% aqueous sodium hydrogencarbonate solution, neutralized with 0.1N HCl (20 ml) and then washed three times with a saturated sodium chloride solution. The organic phase was dried over Na2SO4 and concentrated under reduced pressure; yield 3.90 g (80% pure).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:19])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH2:15][O:16][CH2:17][CH3:18])[CH3:14])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH2:28][CH:29]=[C:30]1[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]=2[CH2:34][O:33][C:32]2[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:19])[CH2:13][CH2:12][N:11]([CH2:27][CH2:28][CH:29]=[C:30]3[C:36]4[CH:37]=[CH:38][CH:39]=[N:40][C:35]=4[CH2:34][O:33][C:32]4[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]3=4)[CH2:10][C:9]2([CH2:15][O:16][CH2:17][CH3:18])[CH3:14])=[CH:4][CH:3]=1
Reactant: CCOCC1(C)CNCCC1(O)c1ccc(Cl)cc1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOCC1(C)CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-3-ethoxymethyl-3-methyl-piperidin-4-ol (0.038 g, 0.13 mmol) in acetonitrile/water (8:2) (1.3 mL) was added K2CO3 (0.075 g, 0.53 mmol) and 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.050 g, 0.13 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated and partitioned between EtOAc/H2O, extracted with EtOAc (3×). The organics were collected, dried over MgSO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (75% ethyl acetate/25% hexane) to yield the title compound in 65% yield. 1H-NMR (CDCl3): δ 0.81 (s, 3H), 0.98 (t, 3H), 1.58 (s, 6H), 1.84 (s, 1H), 2.31-2.49 (m, 5H), 2.58 (d, 1H), 2.67 (s, 1H), 2.77 (d, 2H), 3.26 (q, 2H), 3.65 (d, 2H), 5.33 (bs, 2H), 6.16 (t, 1H), 6.82 (d, 1H), 7.22-7.36 (m, 7H), 7.45 (d, 1H), 7.60 (d, 1H).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:28])=[C:9]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:10]([CH3:17])=[N:11]2.CO.[OH-].[Na+]>C(O)=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:29])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)(=[O:19])=[O:20])=[C:8]2[CH3:28]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(S(=O)(=O)c3ccc(Cl)cc3)c(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Product: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(C)c1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
A solution of [8-chloro-3-(4-chlorobenzenesulfonyl)-2,4-dimethylquinolin-5-yloxy]acetic acid methyl ester (0.020 g), methanol (3.0 mL) and 1.0 M aqueous sodium hydroxide solution (0.22 mL) was stirred at room temperature for 3 hours. The pH of the solution was adjusted to 5 by the addition of formic acid and the solvent removed under reduced pressure. Purification of the residue by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water gave title compound as a pale yellow solid, 0.0025 g.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:29])=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[NH2:38][N:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1>O1CCCC1>[CH3:45][N:42]1[CH2:43][CH2:44][N:39]([NH:38][CH2:2][C:3]2[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH3:29])=[C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:20]=[CH:19][N:18]=4)[CH:15]=3)=[O:8])=[CH:5][CH:4]=2)[CH2:40][CH2:41]1
Reactant: CN1CCN(N)CC1
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccc(CNN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
N-[5-(4-chloromethylbenzoylamino)-2-methylphenyl]-4-(3-pyridyl)-2-pyrimidine-amine (1 g, 2.33 mmol) was dissolved in tetrahydrofuran (20 ml), pyridine (360 μl, 4.66 mmol) was added thereto, and the mixture was stirred for 30 minutes. 1-Amino-4-methylpiperazine (418 μl, 3.49 mmol) was added, and the mixture was refluxed for 12 hours and filtered. The filtrate was concentrated, subjected to column chromatography (eluent: chloroform:methanol=3:1(v/v)), concentrated again, and then crystallized from dimethylether to give 4-(4-methylpiperazin-1-ylaminomethyl)-N-[4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-yl)aminophenyl]benzamide (880 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:28][O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:28][O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34]([O:8][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:33][CH:32]=1
Reactant: CN1CCC(O)CC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC2CCN(C)CC2)cc1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
To a solution of 1-methyl-piperidin-4-ol (6.8 g, 59 mmoles), PPh3 (triphenylphosphine, 15.5 g, 59 mmoles) and 4-hydroxy-benzoic acid methyl ester (6 g, 39 mmoles) in THF (150 ml) at 0° C., diethyl azodicarboxylate (9.5 ml, 59 mmoles) in THF (30 ml) was slowly added. The reaction mixture was allowed to warm to room temperature over a period of 24 hours. It was then evaporated and the residue redissolved in 5% aqueous citric acid (700 ml). The solution was washed with ethyl acetate (3×250 ml), made alkaline with concentrated NH4OH (pH ˜8) and then extracted with dichloromethane (3×250 ml). The combined dichloromethane extracts were washed with brine, dried and evaporated to give an oil which was purified by flash chromatography on silica gel using dichloromethane-MeOH (90:10) as eluent, to give the title compound as a yellow oil (7.4 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][NH:12][C:13]([CH3:16])([CH3:15])[CH3:14]>>[CH3:11][N:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1
Reactant: CNC(C)(C)C
Reactant: O=C(Cl)c1cccc(F)c1
Product: CN(C(=O)c1cccc(F)c1)C(C)(C)C

Procedure:
3-Fluorobenzoyl chloride was reacted with N-methyl-N-tert-butylamine using General Method E1 or E2 to produce N-methyl-N-(tert-butyl)-3-fluorobenzamide. This compound was used in General Method A to prepare the title compound. Kugelrohr distillation afforded 12.07 g of analytically pure desired material. m.p. 32-35° C.
Reaction SMILES: C1O[CH:4]([CH:5]([CH3:17])[CH2:6][C:7](=O)[C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)OC1.[C:19]([NH:22][S:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])(=[O:21])[CH3:20].Cl>O1CCCC1>[C:19]([NH:22][S:23]([C:26]1[CH:32]=[CH:31][C:29]([N:30]2[CH:4]=[C:5]([CH3:17])[CH:6]=[C:7]2[C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)=[CH:28][CH:27]=1)(=[O:25])=[O:24])(=[O:21])[CH3:20]
Reactant: Cc1ccc(C(=O)CC(C)C2OCCO2)cc1C
Reactant: CC(=O)NS(=O)(=O)c1ccc(N)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1ccc(-n2cc(C)cc2-c2ccc(C)c(C)c2)cc1
Temperature: 70 °C
Yield: 25.3 %

Procedure:
3.26 g (13.1 mmol) of 3-(3,4-dimethylbenzoyl)-2-methylpropionaldehyde ethylene acetal [prepared as described in step (ii) above] and 2.81 g (13.1 mmol) of 4-acetylaminosulfonylaniline were dissolved in a mixture of 52 ml (52 mmol) of 1N aqueous hydrochloric acid and 16 ml of tetrahydrofuran, and the mixture was heated at 70° C. for 1 hour. At the end of this time, the mixture was left to stand to allow it to cool. The mixture was then extracted three times with ethyl acetate. The organic extracts were combined and washed with a saturated aqueous solution of sodium chloride. The resulting solution was then dried over anhydrous magnesium sulfate, after which it was concentrated by evaporation under reduced pressure. The residue thus obtained was applied to a silica gel chromatography column and eluted with a 3:2 by volume mixture of hexane and ethyl acetate and crystallised from diisopropyl ether, to give 1.27 g (yield 25%) of the title compound as a white powder, melting at 192-193° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=2[C:27]([F:30])([F:29])[F:28])(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:40](=[O:43])[CH:41]=[CH2:42])=[CH:22][C:21]=2[C:27]([F:30])([F:28])[F:29])(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2)c(C(F)(F)F)c1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 127.9 %

Procedure:
4-(4-Amino-2-trifluoromethyl-benzensulfonyl)-piperazine-1-carboxylic acid benzyl ester (0.44 g, 0.11 mmol) was dissolved in THF (15 ml). To this solution was added diisopropylethylamine (0.52 ml, 0.33 mmol) in one portion followed by the drop wise addition of acryloyl chloride (0.09 ml, 0.11 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The THF was removed under vacuum and the resulting crude material, was purified by preparative HPLC to give the title compound (70 mg, 14% yield) as a white solid.