Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]=1.C([N-]C(C)C)(C)C.[Li+].CN([CH:30]=[O:31])C.C(=O)=O>O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([CH:30]=[O:31])[O:4][C:3]=1[C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[N:8]=1
Reactant: Clc1ccc(-c2noc(-c3occc3Br)n2)cc1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1cc(Br)c(-c2nc(-c3ccc(Cl)cc3)no2)o1
Reaction time: 1 h
Yield: 60.4 %

Procedure:
A solution of 5-(3-bromo-furan-2-yl)-3-(4-chloro-phenyl)-[1,2,4]-oxadiazole (599 mg, 1.84 mmol) in tetrahydrofuran (10 mL) was added under argon over 20 min to a stirred solution of 1.5 M lithium diisopropylamide (1.3 mL, 1.95 mmol) and tetrahydrofuran (10 mL) in a dry ice/acetone bath, and it was stirred for 1 h. To the solution was then added dry DMF (1.5 mL, 19.4 mmol) dropwise and the solution was stirred for 30 min. The dry ice bath was replaced by an ice bath and the solution was stirred for 20 min. The ice bath was removed and the solution was quenched with methanol (10 mL) and then saturated sodium bicarbonate (3 mL). To the solution was added 1 N hydrochloric acid until the solution reach pH 3. The solution was extracted with dichloromethane (2×100 mL). The extracts were dried over sodium sulfate, filtered, and concentrated. The product was purified twice by column chromatography (dichloromethane) to yield 393 mg (60%) of the title compound as a light yellow solid. 1H NMR (DMSO-d6): 9.79 (s, 1H), 8.11 (dd, J=8.52, 2.13 Hz, 2H), 8.05 (s, 1H), 7.70 (dd, J=8.24, 2.06 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([CH:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[CH2:10][OH:11])[CH:3]=1>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)c1ccc(C(CO)c2cc(Br)ccc2O)cc1
Solvent: CO
Product: CC(C)c1ccc(C2COc3ccc(Br)cc32)cc1
Yield: 62 %

Procedure:
Using 4-bromo-2-(2-hydroxy-1-(4-isopropylphenyl)ethyl)phenol synthesized in Reference Example 11, the title compound was synthesized in the same manner as in Reference Example 13. Yield 62%. Melting point: 90-91° C. (methanol).
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH3:13])C.[Li]CCCC.[CH:22]([O:25][C:26]1[CH:33]=[CH:32]C(C#N)=[CH:28][CH:27]=1)([CH3:24])[CH3:23]>C1COCC1>[CH:22]([O:25][C:26]1[CH:33]=[CH:32][C:16]([C:15]2[NH:3][C:4](=[O:14])[C:5]3[C:6]([CH:13]=2)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=3)=[CH:28][CH:27]=1)([CH3:24])[CH3:23]
Reactant: CC(C)Oc1ccc(C#N)cc1
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2c(=O)[nH]c(-c3ccc(OC(C)C)cc3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a stirred solution of N,N-diethyl-4-methoxy-2-methylbenzamide (3.5 g, 15.82 mmol) in THF (35 ml) was added n-BuLi (2.82 ml, 4.52 mmol, in hexane) at −78° C. and stirred for 1 h. 4-isopropoxy benzonitrile (2.55 g, 15.82 mmol) was added at same temperature and allowed to warm to room temperature and continued the stirring for another 1 h at room temperature. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc (2*100 ml). The organic phase was washed with brine then dried on Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (3.5 g, 71.5%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.21(s, 1H), 8.09-8.07 (d, J=8 Hz, 1H), 7.71-7.69 (d, J=8 Hz, 2H), 7.14 (d, J=8 Hz, 1H), 7.03-7.01 (d, J=8 Hz, 3H), 6.76 (s, 1H), 4.71 (m, 1H), 3.88 (s, 3H), 1.30 (m, 6H); MS: MS m/z 310.7 (M++1).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH:2]1[O:4][CH2:3]1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1>>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:1][CH:2]([OH:4])[CH2:3][N:15]1[CH2:20][CH2:19][CH:18]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)[CH2:17][CH2:16]1)[CH:6]=[CH:7]2
Reactant: Fc1ccc2c(ccn2CC2CO2)c1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Product: OC(CN1CCC(c2c[nH]c3ccccc23)CC1)Cn1ccc2cc(F)ccc21
Yield: 51 %

Procedure:
A methanolic solution of 1-N-glycidyl-5-fluoroindole (0.52 g, 3.0 mmole) from example 1 and 3-(4-piperidinyl)indole (0.6 g, 3.0 mmole) was refluxed under nitrogen for 15 hours. The reaction mixture was concentrated in vacuo and the product purified by flash silica gel chromatography (ethyl acetate) to afford the titled compound as an oil (0.599 g, 50% yield). Treatment with a 0.25 M ethanolic solution of fumaric acid (0.5 equivalents) gave the required product as a white solid. The product was recrystallized twice from ethanol.
Reaction SMILES: Br[C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:17][C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH3:19])=[O:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(O)(C)(C)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[N:17]([C@@H:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH3:19])[C:15](=[O:16])[CH:10]3[CH2:11][O:12][CH2:13][CH2:14][N:9]3[C:3]=2[N:4]=1
Reactant: C[C@@H](NC(=O)C1COCCN1c1nc(Cl)ncc1Br)c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](c1ccc(Cl)cc1)N1C(=O)C2COCCN2c2nc(Cl)ncc21
Temperature: 105 °C
Reaction time: 72 h
Yield: 12.3 %

Procedure:
To an oven dried vial were added 4-(5-bromo-2-chloropyrimidin-4-yl)-N—((R)-1-(4-chlorophenyl)ethyl)morpholine-3-carboxamide (PREPARATION x31, 574 mg, 1.247 mmol), Xantphos (54.1 mg, 0.094 mmol), potassium phosphate tribasic (265 mg, 1.247 mmol) and palladium(II)acetate (14.00 mg, 0.062 mmol) in dioxane (5 mL) and tert-butanol (1 mL). The reaction mixture was degassed for 5 minutes with N2. The vial was then sealed and heated to 105° C. and the contents were stirred for 72 hours to give a brown suspension. The reaction mixture was subsequently diluted with ethyl acetate and washed with aqueous saturated NH4Cl (3×5 mL) and brine (3×5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give a crude product which was loaded onto an ISCO® silica gel cartridge (40 g) and eluted using an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a white solid (58 mg, 12%). 1H NMR (400 MHz, DMSO-d6) δ 1.68-1.80 (m, 3H), 2.91-3.02 (m, 1H), 3.46-3.64 (m, 1H), 3.64-3.76 (m, 1H), 3.88-4.01 (m, 1H), 4.13-4.27 (m, 2H), 4.41-4.60 (m, 1H), 5.99-6.24 (m, 1H), 7.27-7.49 (m, 4H), 7.50-7.57 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C17H16Cl2N4O2, 379.07. found 379.3.
Reaction SMILES: C(OC([N:8]1[C:11]2([CH2:15][CH2:14][N:13]([C:16]3[C:17]4[CH:24]=[CH:23][NH:22][C:18]=4[N:19]=[CH:20][N:21]=3)[CH2:12]2)[CH:10]([CH3:25])[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.C(Cl)(Cl)Cl>CO>[CH3:25][CH:10]1[C:11]2([CH2:15][CH2:14][N:13]([C:16]3[C:17]4[CH:24]=[CH:23][NH:22][C:18]=4[N:19]=[CH:20][N:21]=3)[CH2:12]2)[NH:8][CH2:9]1
Reactant: CC1CN(C(=O)OC(C)(C)C)C12CCN(c1ncnc3[nH]ccc13)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1CNC12CCN(c1ncnc3[nH]ccc13)C2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 138.2 %

Procedure:
An optically-active compound of 3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylic acid tert-butyl ester (9.5 g) was mixed with 4M hydrochloric acid-1,4-dioxane (50 ml), chloroform (50 ml) and methanol (100 ml), and the mixture was stirred at 60° C. for 30 minutes. The mixture was concentrated under reduced pressure, and azeotroped with toluene to give the titled compound (9.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[NH2:10][CH:11]([CH3:15])[CH2:12][O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:10][CH:11]([CH3:15])[CH2:12][O:13][CH3:14])=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: COCC(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC(C)NCc1ccc(Cl)nc1
Temperature: 80 °C
Yield: 48.3 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (1.0 g, 6.17 mmole) in 11 mL of dry acetonitrile is added 1.30 mL (12.3 mmol) of 2-amino-1-methoxypropane followed by 850 mg (6.17 mmol) of potassium carbonate. The reaction is heated at 80° C. for 5 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 640 mg (48% yield) of (6-Chloro-pyridin-3-ylmethyl)-(2-methoxy-1-methyl-ethyl)-amine. Diagnostic C13 NMR (100 MHz, CDCl3) 17.2, 48.0, 52.3, 59.1, 77.2, 124.1, 135.3, 138.9, 149.5, 150.1 MS (217.2 (M+H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:30][C:31]1[CH:36]=[C:35](O)[CH:34]=[C:33]([F:38])[C:32]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[F:30][C:31]1[CH:36]=[C:35]([O:29][CH2:28][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][N:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=3)=[CH:27][CH:26]=2)[CH:34]=[C:33]([F:38])[C:32]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]
Reactant: CCOC(=O)CCc1c(F)cc(O)cc1F
Reactant: OCc1ccc(CN(CCc2ccccc2)c2nc(-c3ccccc3)cs2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c(F)cc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
That is, to a solution of [4-[[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl]phenyl]methanol (350 mg, 0.87 mmol), ethyl 3-(2,6-difluoro-4-hydroxyphenyl)propanoate (200 mg, 0.87 mmol) and tributylphosphine (0.31 mL, 1.24 mmol) in tetrahydrofuran (30 mL) was added 1,1′-(azodicarbonyl)dipiperidine (320 mg, 1.27 mmol), and the mixture was stirred at room temperature for 18 hr. The insoluble materials were filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (300 mg, yield 56%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH:18]C(=O)OC(C)(C)C)[C:10]2[C:15]([CH:16]=[CH2:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C:10]2[C:15]([CH:16]=[CH2:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[NH2:18])=[CH:5][CH:4]=1
Reactant: C=Cc1cccnc1[C@@H](NC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1cccnc1[C@@H](N)c1ccc(C(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 0.03 h

Procedure:
To a 50 mL round bottom flask containing (S)-tert-butyl ((4-(trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methyl)carbamate (97 mg, 0.256 mmol) was added DCM (3 mL). The resulting mixture was then stirred at 23° C. for 2 min. At this time, TFA was added (3 mL) and the reaction was stirred for 3 h. The solvent was removed, and the material was immediately used with no further purification. MS (ESI pos. ion) m/z: 279.1 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[O:18][CH:17]=[CH:16][C:15]=23)=[O:9])[CH2:2]1.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20]([C:25](O)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1>>[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20]([C:25]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[C:14]4[O:18][CH:17]=[CH:16][C:15]=34)=[O:9])[CH2:2]2)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(N[C@@H]1CCCNC1)c1cccc2occc12
Reactant: O=C(O)c1ccccc1-c1ccccc1
Product: O=C(N[C@@H]1CCCN(C(=O)c2ccccc2-c2ccccc2)C1)c1cccc2occc12

Procedure:
prepared by reaction of (R)-benzofuran-4-carboxylic acid piperidin-3-ylamide with biphenyl-2-carboxylic acid acid.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[N:4]([C:10]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=[O:11])[CH2:5][C:6](=[N:8][OH:9])[CH3:7].S(OC)(O[CH3:26])(=O)=O>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.[OH-].[Na+].C(Cl)Cl>[CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[N:4]([C:10]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=[O:11])[CH2:5][C:6](=[N:8][O:9][CH3:26])[CH3:7]
Reactant: CC(CN(C(=O)c1ccco1)c1c(C)cccc1C)=NO
Reactant: COS(=O)(=O)OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CON=C(C)CN(C(=O)c1ccco1)c1c(C)cccc1C
Yield: 19.4 %

Procedure:
7 g (0.024 mol) of 2,6-dimethyl-N-(2-furoyl)-N-(2-hydroxyimino-prop-1-yl)-aniline (Example 3) and 0.5 g of triethylbenzylammonium chloride were dissolved in a two-phase mixture of 30 ml of 50% strength sodium hydroxide solution and 100 ml of methylene chloride, and 3.7 g (0.03 mol) of dimethyl sulphate were added, while stirring vigorously. During this addition, the temperature rose from about 20° C. to about 32° C. After stirring the mixture at room temperature for 12 hours, the phases were separated. The organic phase was washed again with water, dried over sodium sulphate and concentrated. The resulting dark oil was distilled in a bulb tube apparatus (boiling point 170° C./0.1 mm Hg). The product (2.3 g) which had crystallized out was recrystallized from petroleum ether. 1.4 g (20% of theory) of 2,6-dimethyl-N-(2-furoyl)-N-(2-methoxyimino-prop-1-yl)-aniline of melting point 108°-109° C. were obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OCC(F)(F)F)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:44])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[C:40]([CH2:41][CH3:42])=[CH:39][N:38]=[C:37]([CH3:43])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.[C:46](O)([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)Cl>[CH2:41]([C:40]1[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:44])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:12]([O:47][CH2:46][C:48]([F:51])([F:50])[F:49])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)=[CH:36][C:37]([CH3:43])=[N:38][CH:39]=1)[CH3:42]
Reactant: O=C(O)C(F)(F)F
Reactant: CCc1cnc(C)cc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(OCC(F)(F)F)cc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Product: CCc1cnc(C)cc1-c1cccc(C2=Nc3cc(OCC(F)(F)F)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from [2-{3-[3-(5-ethyl-2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M134) (0.29 g, 0.45 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (220 mg, 93%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[Cl:6][C:7]1[C:8]([F:38])=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:36][CH3:37])=[C:21]([CH2:24][N:25]([CH3:35])[C:26]4([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:1]([N:29]1[CH2:30][CH2:31][C:26]([N:25]([CH2:24][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][C:20]=2[O:36][CH3:37])[N:17]=[CH:16][N:15]=[C:14]3[NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[C:8]=2[F:38])[CH3:35])([C:32]([NH2:34])=[O:33])[CH2:27][CH2:28]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Acetyl chloride (7 μl, 0.094 mmol) was added to a stirred solution of 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxamide hydrochloride (0.05 g, 0.085 mmol, prepared as described in Example 64) and triethylamine (53 μl, 0.38 mmol) in dichloromethane (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, concentrated and purified by column chromatography on silica eluting with increasingly polar mixtures of dichloromethane/methanol (100/0-90/10) to give the title product (0.039 g, 91%) as a pale yellow solid; 1H NMR Spectrum: (DMSO-d6) 1.75-1.98 (m, 2H), 2.05 (m, 5H), 2.19 (s, 3H), 3.32-3.75 (m, 6H), 3.94 (s, 3H), 7.20 (s, 1H), 7.26 (m, 2H), 7.34 (t, 1H), 7.51-7.57 (m, 2H), 8.38 (s, 1H), 8.46 (s, 1H), 9.80 (s, 1H); Mass Spectrum: (M+H)+ 515.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(C)=O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:1][C:2]2[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:16][CH:17]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(I)ccc1OCc1ccc(F)cc1

Procedure:
To a solution of methyl 2-hydroxy-5-iodobenzoate (15 g, 53.9 mmol) in acetone (200 ml) was added 1-(bromomethyl)-4-fluorobenzene (9.95 ml, 81 mmol), potassium carbonate (14.91 g, 108 mmol) and the mixture was refluxed overnight. The mixture was allowed to cool and then filtered to remove the potassium carbonate. The solid potassium carbonate was washed with acetone (100 ml). The organics were combined and evaporated under reduced pressure on a buchi to give a solid. The solid was taken up into ethyl acetate (500 ml) and the organic phase was washed with water (2×200 ml), dried (MgSO4) and evaporated under reduced pressure on a buchi. The solid obtained was recrystallised from cyclohexane to yield the title compound as a white solid. 18.2 g.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:16][CH2:15][C:14]3[CH:17]=[C:18]([CH2:21][OH:22])[CH:19]=[CH:20][C:13]=3[CH2:12][O:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[S:32](Cl)([CH3:35])(=[O:34])=[O:33].C(=O)(O)[O-].[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[O:16][CH2:15][C:14]3[CH:17]=[C:18]([CH2:21][O:22][S:32]([CH3:35])(=[O:34])=[O:33])[CH:19]=[CH:20][C:13]=3[CH2:12][O:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C2OCc3ccc(CO)cc3CO2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1ccc2c(c1)COC(c1ccc([N+](=O)[O-])cc1)OC2
Yield: 15.8 %

Procedure:
3 g (10 mmol) of [7-(4-nitrophenyl)-(5H,9H)-6,8-dioxabenzocyclohepten-2-yl]methanol in 50 ml of dichloromethane are introduced into a flask. 1.54 g (12 mmol) of diisopropylethylamine are added and 1.37 g (12 mmol) of mesyl chloride in solution in 10 ml of dichloromethane are added dropwise at −5° C. After 1 hour 30 minutes of reaction at −5° C., 20 ml of a 5% sodium bicarbonate solution are added, the phases are separated by decantation and the organic phase is washed with water. It is dried over sodium sulfate and the solvent is evaporated off. The crude product is purified by silica gel chromatography (heptane/ethyl acetate: 3/2) to give 0.6 g of methanesulfonic acid [7-(4-nitrophenyl)-(5H,9H)-6,8-dioxabenzocyclohepten-2-yl]methyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[CH:8]=3.[CH:26](/B(O)O)=[CH:27]\[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:17]1([C:15]([C:9]2[CH:8]=[C:7]3[C:12]([C:13]4[CH:14]=[C:2](/[CH:26]=[CH:27]/[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]=4[NH:6]3)=[CH:11][CH:10]=2)=[O:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Reactant: OB(O)/C=C/c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: NC(=O)c1cc(/C=C/c2ccccc2)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 130 °C
Yield: 3.3 %

Procedure:
3-Bromo-7-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide (40 mg, 0.10 mmol, Example 144A) and dicyclohexy(2′,6′-dimethoxybiphenyl-2)phosphine (8.2 mg) were dissolved in dioxane (1.5 mL) and added into a 2-ml microwave vial containing (E)-styrylboronic acid (37 mg, 0.25 mmol), followed by addition of potassium phosphate (64 mg in 0.15 mL water) into above vials. Pd(OAc)2 (4.49 mg, 20.00 μmol) was added as solid. The vial was sealed and heated to 130° C. for 10 minutes. The crude reaction mixture was evaporated to dryness, dissolved in DMF+MeOH (1.2 mL+0.4 mL), filtered and purified by preparative HPLC. Product containing fractions were combined and evaporated to dryness to give 1.4 mg (E)-7-(morpholine-4-carbonyl)-3-styryl-9H-carbazole-1-carboxamide. HPLC retention time 4.39 min. (SUPELCO® Ascentis Express 4.5×50 mm 3 um C18, 2 ml/min, 5 to 95% B in 8 minutes, then 95% B for 1 minute. Solvent A: 5% CH3CN—95% H2O—10 mM NH4OAc; Solvent B: 95% CH3CN—5% H2O—10 mM NH4OAc). MS (ESI) m/e+=426 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[NH:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[N:11]([C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.84 g, prepared according to the procedure described in WO 96/31478 Step B page 94) in dry dichloromethane (50 mL) was treated with triethylamine (1.1 mL), then benzoyl chloride (0.91 mL). After stirring at room temperature for a further 5 hours the reaction mixture was treated with further dichloromethane (150 mL) and then washed twice with a saturated aqueous solution of sodium hydrogen carbonate (50 mL) and twice with brine (50 mL). The organic phase was then dried over magnesium sulfate and evaporated to give the title compound (2.58 g) as an orange oil, MS: 363 [MH]+. 1H NMR [(CD3)2SO]: δ 7.50–7.34 (m, 5H), 5.20–5.00 (s, 1H), 4.44–4.36 (m, 1H), 4.21–4.13 (m, 2H), 3.87–3.78 (m, 1H), 3.73–3.69 (bs, 1H), 3.30–3.20 (m, 2H), 2.98–2.90 (m, 1H), 1.45–1.38 (s, 9H) and 1.27–1.20 (m, 3H).