Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([C:7]1[CH:25]=[CH:24][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18](C([O-])=O)[CH2:17][CH2:16]2)=[CH:9][CH:8]=1)#[N:6].FC(F)(F)C(O)=O>O>[NH:18]1[CH2:19][CH2:20][CH:15]([CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:7]([C:5]#[N:6])=[CH:25][CH:24]=2)[CH2:16][CH2:17]1
Reactant: N#Cc1ccc(OCCCC2CCN(C(=O)[O-])CC2)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(OCCCC2CCNCC2)cc1
Reaction time: 0.33 h

Procedure:
To a chloroform (100 mL) solution of 14.0 g of tert-butyl=4-[3-(4-cyanophenoxy)propyl]-1-piperidinecarboxylate was dropwise added 40 mL of trifluoroacetic acid under cooling with water over a period of 10 minutes. This mixture was stirred at the same temperature for 20 minutes, and then stirred at room temperature for 35 minutes. After distilling off the solvent under reduced pressure, chloroform and water were added. A sodium hydroxide aqueous solution was added thereto for adjustment to pH 13.0. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, which was then washed with a sodium hydroxide aqueous solution and dried with potassium carbonate, followed by distilling off the solvent under reduced pressure to provide 10.3 g of 4-[3-(4-piperidinyl)propoxy]benzonitrile as pale yellow solid form.
Reaction SMILES: Br[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH2:13]([O:15][CH2:16][CH2:17][N:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[N:20]=[C:19]1[NH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:14].C(=O)([O-])O.[Na+]>C(O)C>[OH2:5].[CH2:13]([O:15][CH2:16][CH2:17][N:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[N:20]=[C:19]1[NH:27][CH:28]1[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][S:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:32][CH2:33]1)[CH3:14].[CH2:13]([O:15][CH2:16][CH2:17][N:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[N:20]=[C:19]1[NH:27][CH:28]1[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][S:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:32][CH2:33]1)[CH3:14]
Reactant: CCOCCn1c(NC2CCNCC2)nc2cccnc21
Reactant: O=S(=O)(CCBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOCCn1c(NC2CCN(CCS(=O)(=O)c3ccccc3)CC2)nc2cccnc21
Product: O
Reaction time: 2 h
Yield: 37.1 %

Procedure:
A mixture of 3.7 parts of [(2-bromoethyl)sulfonyl]benzene, 4.34 parts of 3-(2-ethoxyethyl)-N-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine, 2.5 parts of sodium hydrogen carbonate and 120 parts of ethanol was stirred for 2 hours at reflux temperature. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated. The residue was taken up in water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of tetrahydrofuran and 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.6 parts (37.1%) of 3-(2-ethoxyethyl)-N-[1-[2-(phenylsulfonyl)ethyl]-4-piperidinyl]-3H-imidazo-[4,5-b]pyridin-2-amine hemihydrate; mp. 101.9° C. (compound 99).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[C:25]([C:32]2[C:37](Cl)=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[N:26][O:27][C:28]=1[CH:29]([CH3:31])[CH3:30].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:39][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:25]1[C:24]([CH2:23][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:17]=[C:16]4[C:11]([CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[N:14]=[CH:15]4)=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[C:28]([CH:29]([CH3:31])[CH3:30])[O:27][N:26]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Reactant: COC(=O)c1cc2ccc(-c3ccc(O)cc3)cc2cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(-c3ccc(OCc4c(-c5ccccc5Cl)noc4C(C)C)cc3)cc2cn1
Temperature: 50 °C
Reaction time: 20 h
Yield: 61.6 %

Procedure:
A mixture of 174 mg (0.62 mmol) of methyl 7-(4-hydroxyphenyl)-3-isoquinolinecarboxylate, 285 mg (0.92 mmol) of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole and 260 mg (1.83 mmol) of K2CO3 in 2 mL of DMF was stirred at 50° C. for 20 hr. EtOAc was added then the mixture washed with three portions of H2O, then brine. The organics were dried over Na2SO4 then evaporated and the residue purified by silica gel chromatography (40 g of silica gel eluting with 0-70% EtOAc in hexanes over 45 minutes) to give 196 mg (58%) of methyl 7-[4-({[3-(2-chlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylate as white solid. 1H NMR (400 MHz, CDCl3): δ 9.35 (s, 1H), 8.60 (s, 1H), 8.14 (s, 1H), 7.99 (m, 2H), 7.60 (d, J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 7.33 (m, 1H), 6.92 (d, J=9 Hz, 2H), 4.80 (s, 2H), 4.06 (s, 3H), 3.36 (septet, 1H, J=7 Hz), 1.44 (d, J=7 Hz, 6H). ESI-LCMS m/z 548 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:24]([F:25])=[CH:23][C:5]2[S:6][CH2:7][CH2:8][N:9]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](=[NH:42])OC>C(O)C.C(OCC)(=O)C>[F:25][C:24]1[C:2]([NH:1][C:39]([C:35]2[S:34][CH:38]=[CH:37][CH:36]=2)=[NH:42])=[CH:3][C:4]2[N:9]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH2:8][CH2:7][S:6][C:5]=2[CH:23]=1
Reactant: COC(=N)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCSc3cc(F)c(N)cc32)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCSc3cc(F)c(NC(=N)c4cccs4)cc32)CC1
Temperature: 65 °C

Procedure:
To a stirred solution of tert-butyl 4-(6-amino-7-fluoro-2H-benzo[b][1,4]thiazin-4(3H)-yl)piperidine-1-carboxylate (168 mg, 0.457 mmol) in ethanol (5 mL) and triethylamine (0.643 mL, 4.57 mmol) was added methyl thiophene-2-carbimidate hydrochloride (325 mg, 1.829 mmol). The resulting mixture was stirred at 65° C. over the weekend. The mixture was then cooled to room temperature, diluted with ethyl acetate, and washed with saturated sodium carbonate (3×). The organic phase was dried, filtered, and concentrated, and chromatographed in 1:9 ethyl acetate:hexanes giving a yellow oil (18 mg, 8.26%); 1H NMR (MeOD-d4) δ 7.65-7.61 (m, 1H), 7.59-7.54 (m, 1H), 7.14-7.08 (m, 1H), 6.79 (d, J=10.5 Hz, 1H), 6.49 (d, J=7.5 Hz, 1H), 4.22-4.12 (m, 2H), 3.80-3.67 (m, 1H), 3.43-3.38 (m, 2H), 3.05-3.01 (m, 2H), 2.96-2.79 (m, 2H), 1.83-1.73 (m, 2H), 1.72-1.57 (m, 2H), 1.46 (s, 9H); ESI-MS (m/z, %): 477 (MH+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[CH:13][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:21]=1
Reactant: CCOC(=O)c1cccc(Br)c1
Reactant: Cc1ccc(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cccc(-c2ccc(C)cc2C)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 104.6 %

Procedure:
(2,4-Dimethylphenyl)boronic acid (3.0 g, 20.0 mmol), ethyl 3-bromobenzoate (4.3 g, 18.8 mmol) and cesium carbonate (9.8 g, 30.0 mmol) were added to a mixture of ethanol (20 mL) and toluene (80 mL), and after argon substitution, tetrakis(triphenylphosphine)palladium(0) (0.30 g, 0.26 mmol) was added. The reaction mixture was stirred under an argon atmosphere at 70° C. for 18 hrs. The reaction mixture was cooled and insoluble material was filtered off through celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10) to give the title compound (5.0 g, yield 100%) as a colorless oil.
Reaction SMILES: C(OC([NH:8][CH:9]([C:11]1[NH:12][C:13]([C:21]2[C:30]([F:31])=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24]([NH:33][CH:34]2[CH2:36][CH2:35]2)[C:25]([CH3:32])=[N:26]3)=[CH:14][C:15]=1[C:16]([O:18]CC)=[O:17])[CH3:10])=O)(C)(C)C.Cl.O1CCOCC1.[OH-].[Na+]>O1CCOCC1.O>[NH2:8][CH:9]([C:11]1[NH:12][C:13]([C:21]2[C:30]([F:31])=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24]([NH:33][CH:34]2[CH2:36][CH2:35]2)[C:25]([CH3:32])=[N:26]3)=[CH:14][C:15]=1[C:16]([OH:18])=[O:17])[CH3:10]
Reactant: CCOC(=O)c1cc(-c2c(F)ccc3nc(C)c(NC4CC4)nc23)[nH]c1C(C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2ccc(F)c(-c3cc(C(=O)O)c(C(C)N)[nH]3)c2nc1NC1CC1
Temperature: 120 °C
Yield: 95.1 %

Procedure:
A glass microwave reaction vessel (80 mL) was charged with ethyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (284a) (0.41 g, 0.81 mmol) and LiOH monohydrate (Sigma-Aldrich) (342 mg, 8.16 mmol) in 1,4-Dioxane (12 mL) and water (10 mL). The reaction mixture was stirred and heated in a CEM Voyager Microwave (Large-Scale Unit) at 120° C. for 35 min (100 watts, Powermax feature off). This material was transferred to a 150-mL round-bottomed flask for next step in the reaction. m/z (ESI, +ve) 470 (M+H). To the mixture from step 1, was added 4 M HCl/1,4-dioxane (Sigma-Aldrich) until pH 2-3. The mixture was stirred at RT for 4 h. The mixture was neutralized with 5 N NaOH (pH 7). The precipitate was collected by filtration and the solids were washed with hexanes. This gave 2-(1-aminoethyl)-5-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid (284b; 285 mg, 0.77 mmol, 95% yield) as light yellow solid. m/z (ESI, +ve) 353 (M-NH2)′.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Br:11])[CH:9]=2)[NH:4][C:3]1=[O:12]>C(O)(=O)C.[Zn]>[Br:11][C:8]1[CH:9]=[C:10]2[CH2:2][C:3](=[O:12])[NH:4][C:5]2=[N:6][CH:7]=1
Reactant: O=C1Nc2ncc(Br)cc2C1(Br)Br
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1Cc2cc(Br)cnc2N1
Yield: 31.3 %

Procedure:
To a stirred solution of 3,3,5-tribromo-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (2.0 g, 5.4 mmole) in acetic acid (50 mL) at RT was added Zn metal. The reaction became exothermic and was cooled by the use of an ice bath during the initial 30 minutes. After 5 hr the reaction was filtered through Celite®, and the filter pad was washed with EtOAc. The filtrate was concentrated under vacuum and neutralized with saturated aqueous NaHCO3 solution. The neutralized aqueous filtrate was then extracted with EtOAc (2×200 mL), and the combined organic extracts were dried over Na2SO4 and concentrated to a solid. The solid was washed with hexanes and dried under high vacuum to give the title compound (0.36 g, 32%): MS (ES) m/e 215 (M+H)+. This was used without further purification.
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)=[O:39])[CH:33]=1>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:38]([C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)([C:40]3[CH:41]=[CH:42][C:43]([C:46]([F:47])([F:48])[F:49])=[CH:44][CH:45]=3)[OH:39])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: O=C(c1ccc(C(F)(F)F)cc1)c1cccnc1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)cc3)c3cccnc3)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.07 mL, 0.175 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (75.9 mg, 0.177 mmol, Intermediate 16) in dry THF (3 mL) in a dry ice-acetone bath. After 1.5 minutes, a solution of pyridin-3-yl(4-(trifluoromethyl)phenyl)methanone (48.0 mg, 0.191 mmol, Intermediate 26: step b) in dry THF (0.2 mL) was added dropwise. The reaction mixture was stirred for 5 minutes in a dry ice-acetone bath, then the reaction flask was placed into an ice-water bath. After 10 minutes, the mixture was warmed to room temperature and the reaction was quenched with methanol and water. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 10-50% EtOAc-Hexanes) to provide the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.51 (d, J=2.2 Hz, 1H), 8.48 (dd, J=4.8, 1.4 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.66-7.63 (m, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 7.49 (dd, J=8.8, 2.2 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.26-7.23 (m, 1H), 6.42 (t, J=2.1 Hz, 1H), 4.29 (s, 2H), 4.08 (s, 3H); MS m/e 602.1 [M+H]+.
Reaction SMILES: F[C:2](F)(F)CC[Mg]Br.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18](=[O:20])[CH3:19])=[CH:17][C:12]=2[O:11][CH2:10]1>O1CCCC1>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])([CH3:2])[CH3:19])=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: CC(=O)c1ccc2c(c1)OCO2
Reactant: FC(F)(F)CC[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
In a 500 milliliter, three-necked oven-dried round bottom flask equipped with a magnetic stirrer and charged with 200 milliliters of 0.50 M (3,3,3-trifluoropropyl)magnesium bromide in tetrahydrofuran was added 16.4 grams (0.1 mole) of 1-(benzo[d][1,3]dioxol-5-yl)ethanone, and the mixture was stirred at room temperature for 4 hours. The reaction was quenched by slowly pouring the mixture into 400 milliliters saturated ammonium chloride solution and extracted into 400 milliliters of ethyl acetate, and washed with brine then water to a neutral pH. The ethyl acetate extracts were then dried over sodium sulfate, filtered and concentrated in the rotary evaporator affording 17.28 grams of 2-(benzo[d][1,3]dioxol-5-yl)propan-2-ol (˜96% yield) as an amber oil which was used without further purification. 17 grams (0.096 mole) 2-(benzo[d][1,3]dioxol-5-yl)propan-2-ol and 11.6 grams (0.11 mole) of triethylamine were dissolved in 40 milliliters of methylene chloride and the resulting solution was slowly added to a flask equipped with magnetic stirrer and containing 11 milliliters (0.105 mole) of methacroyl chloride in 100 milliliters of dichloromethane cooled, which had been cooled to 0° C. The resultant mixture was slowly warmed to room temperature and allowed to stir for 12 hours. Upon completion of the reaction, confirmed by thin layer chromatography (TLC), the mixture was quenched by pouring it into 400 milliliters of deionized water, then extracting the product into methylene chloride. The methylene chloride extracts were then dried over sodium sulfate, filtered, and concentrated in the rotary evaporator affording 22.8 grams (˜72% yield) of 2-(benzo[d][1,3]dioxol-5-yl)-5,5,5-trifluoropentan-2-yl methacrylate as an amber oil. The oil was purified further by passing through a silica gel plug eluting with a 70/30 mixture of hexanes/methylene chloride affording 19 grams of the pure product. 1H NMR (500 MHz, Acetone-d6): δ 6.89-6.81 (m, Ar, 3H), 6.23 (s, 1H), 5.97 (s, 2H), 5.92 (s, 1H), 2.48-2.1 (m/m, 4H), 1.914 (s, 3H), 1.89 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@@H:45]([N:48]3[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]3)[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([C@H:42]3[CH2:47][CH2:46][C@@H:45]([N:48]4[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]4)[CH2:44][CH2:43]3)=[C:35]3[C:39]=2[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CN1CCN([C@H]2CC[C@@H](c3ccc(N)c4c3CN(C)C4=O)CC2)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
This compound was prepared in a manner analogous to Example 87 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-2-methyl-4-[cis-4-(4-methylpiperazin-1-yl)cyclohexyl]-2,3-dihydro-1H-isoindol-1-one.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][CH2:17][CH:16]([C:19](O)=[O:20])[C:15]3=[O:22])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:25][NH2:26]>>[CH3:25][NH:26][C:19]([CH:16]1[CH2:17][CH2:18][N:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]3[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[C:15]1=[O:22])=[O:20]
Reactant: O=C(O)C1CCN(c2ccc(OCc3ccc(F)cc3)cc2)C1=O
Reactant: CN
Product: CNC(=O)C1CCN(c2ccc(OCc3ccc(F)cc3)cc2)C1=O

Procedure:
The title compound is prepared in analogy to Example 3d) from (RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid and methylamine. Yield: 17% of a colorless solid. MS: m/e=343.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.[CH:16]([O:19][C:20]1[C:25](B(O)O)=[CH:24][CH:23]=[CH:22][N:21]=1)([CH3:18])[CH3:17].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>>[F:15][C:4]1[CH:3]=[C:2]([C:25]2[C:20]([O:19][CH:16]([CH3:18])[CH3:17])=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: CC(C)Oc1ncccc1B(O)O
Reactant: Nc1ncc(-c2ccc(Cl)cc2F)cn1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: CC(C)Oc1ncccc1-c1ccc(-c2cnc(N)nc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a microwave vial the following were added 5-(4-chloro-2-fluorophenyl)-pyrimidin-2-amine (50 mg, 0.22 mmol), (2-isopropoxypyridin-3-yl)boronic acid (51 mg, 0.28 mmol) and X-Phos precatalyst (4 mg, 0.005 mmol). The vial was flushed with nitrogen and then THF (0.5 mL) and 0.5 M K3PO4 (0.9 mL) were added. Both THF and the K3PO4 solution were sparged separately for 30 min prior to use. The resulting biphasic mixture was stirred at rt overnight. The reaction mixture was then poured into sat. NaHCO3 (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (1×50 mL) and brine (1×50 mL), dried (Na2SO4) and concentrated to dryness. The crude product was purified by HPLC to give the title compound (35 mg, 48%). MS (ESI): mass calcd. for C18H17FN4O, 324.14; m/z found, 325.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J=1.4, 2H), 8.21-8.13 (m, 1H), 7.68-7.60 (m, 1H), 7.50-7.36 (m, 3H), 6.99-6.91 (m, 1H), 5.51-5.37 (m, 1H), 5.15 (s, 2H), 1.38 (d, J=6.2, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(O)ccc1Br
Temperature: -78 °C
Reaction time: 30 h
Yield: 70 %

Procedure:
4-Bromo-3-nitroanisole (2.32g, 10 mmol) was dissolved in 25 mL dichloromethane and cooled in an acetone-dry ice bath at −78° C. under nitrogen. A solution of BBr3 (1.0M in dichloromethane) (25 mL, 25 mmol) was added dropwise. Gradually increased temperature to 20° C., stirred for 30 h. The reaction mixture was cooled to 0° C. and distilled water (30 mL) was added dropwise. The aqueous layer was extracted with ethyl acetate (30 mL×2) . The combined organic layer was washed successively with saturated NaHCO, solution (30 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was chromatographed over 100 g of silica gel using 3:1 mixture respectively of hexanes and ethyl acetate to give the phenol in 70% yield; 1H NMR(CDCl3) δ6.92(1H, dd, J1=2.9, J2=8.8), 7.36(1H, d, J=2.9), 7.56(1H, d, J=8.8); 13C NMR(CDCl3) δ105.2 113.4, 116.4, 121.4, 136.3, 155.9; HRMS calcd for C6H4NO3Br: 216.9374, found: 216.9375.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[SH:14].Br[CH2:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.[CH3:33][N:34]1[C:38]([SH:39])=[N:37][N:36]=[N:35]1.[OH-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[S:14][CH2:16][C:17]1[CH:32]=[CH:31][C:20]([C:21](=[O:22])[C:23]2[CH:28]=[CH:27][C:26]([CH2:29][S:39][C:38]3[N:34]([CH3:33])[N:35]=[N:36][N:37]=3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(CBr)cc1
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Reactant: Cn1nnnc1S
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(CSc5nnnn5C)cc4)cc3)n(C)c(=O)c12
Yield: 24 %

Procedure:
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (1.03 g), 4,4'-bis (bromomethyl)benzophenone (1.75 g), 1-methyl-5-mercapto-1H-tetrazole (700 mg), and 1N-aqeuous sodium hydroxide solution (5.5 ml) in DMF (20 ml) was stirred at room temperature for 30 minutes. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia=50:1:0.1) and crystallized from methanol to provide the title compound as colorless solid (603 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[O:11]=[C:8]1[CH2:7][C:6]2[C:10](=[C:2]([NH:1][S:17]([C:13]3[S:12][CH:16]=[CH:15][CH:14]=3)(=[O:19])=[O:18])[CH:3]=[CH:4][CH:5]=2)[NH:9]1
Reactant: Nc1cccc2c1NC(=O)C2
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: O=C1Cc2cccc(NS(=O)(=O)c3cccs3)c2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a mixture of 7-amino-2-oxo-2,3-dihydro-1H-indole (1.53 g) and pyridine (20 mL) was added thiophene-2-sulfonyl chloride (2.26 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography, and eluted with ethyl acetate. The eluate was treated with activated carbon and concentrated to give the title compound (2.93 g, yield 97%) as colorless crystals. The crystals were recrystallized from tetrahydrofuran-hexane. melting point>230° C. (decomposition)