Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][NH:32]2)=[CH:28][C:27]=1[OH:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][NH:32]2)=[CH:28][C:27]=1[O:35][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Reactant: Oc1cc2cc[nH]c2cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cc[nH]c4cc3F)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 95 °C
Yield: 47.7 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (282 mg, 0.662 mmol), 6-fluoro-5-hydroxyindole (120 mg, 0.794 mmol), (prepared as described for the starting material in Example 242), in DMF (3 ml) containing potassium carbonate (137 mg, 0.994 mmol) was heated at 95° C. for 3 hours. After cooling, the residue was poured in water (12 ml) and the pH was adjusted to 8. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by preparative column chromatography on C18 silica eluting with 60% methanol in aqueous ammonium carbonate (2g ammonium carbonate/liter saturated with CO2). The fractions containing the expected product were combined and evaporated. The residue was triturated with ether and the solid was filtered, dried under vacuum to give 4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (147 mg, 48%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:28][CH2:29][CH:30]([OH:41])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1>>[OH:41][CH:30]([CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[CH2:29][NH:28][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(OCC(O)CN)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: COc1ccc(OCC(O)CNC2CCN(c3ccc(NS(=O)(=O)c4ccc(NC(C)=O)cc4)cc3)CC2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and 1-amino-3-(4-methoxy-phenoxy)-propan-2-ol according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.55-1.75 (m, 2H), 1.95-2.15 (m, 2H), 2.06 (s, 3H), 2.50-3.20 (m, 5H), 3.85-3.95 (m, 2H), 4.10-4.20 (m, 1H), 5.70 (brs, 1H), 6.80 (d, J=9.0 Hz, 2H), 6.80-6.95 (m, 6H), 7.59 (d, J=9.0 Hz, 2H), 7.69 (d, J=9.0 Hz, 2H), 10.38 (s, 1H); MS (ES) m/z: 569.6 (MH+); HRMS Calcd. for C29H37N4O6S(MH+): 569.2434. Found: 569.2418.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:6]([CH3:12])=[N:7]2.[Br:20]N1C(C)(C)C(=O)N(Br)C1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:20][CH2:12][C:6]1[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[N:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cccc(-c2nc3c(Cl)cccc3nc2CBr)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-chloro-3-(3-fluorophenyl)-2-methylquinoxaline (0.3907 g, 1.433 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (0.2458 g, 0.8596 mmol) were suspended in carbon tetrachloride (14.33 mL, 1.433 mmol). To the mixture was added benzoyl peroxide (0.04627 g, 0.1433 mmol) and the mixture was heated at reflux. After 24 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 9% gradient of EtOAc in hexane over 1.3 min, then 9% isocratic of EtOAc for 7.6 min, then 9 to 100% gradient of EtOAc in hexane over 12.7 min, then 100% isocratic of EtOAc for 10 min as eluent to give 2-(bromomethyl)-5-chloro-3-(3-fluorophenyl)quinoxaline as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (1H, dd, J=8.4, 1.2 Hz), 8.12 (1H, dd, J=7.6, 1.4 Hz), 7.92 (1H, dd, J=8.4, 7.8 Hz), 7.64-7.70 (3H, m), 7.43-7.50 (1H, m), 4.91 (2H, s); LC-MS (ESI) m/z 351.0 and 352.9 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9](=[O:38])[CH:10]([O:14][C:15]1[CH:37]=[CH:36][C:18]2[C:19]3[N:23]([CH2:24][CH2:25][O:26][C:17]=2[CH:16]=1)[CH:22]=[C:21]([C:27]1[N:28]([CH:33]([CH3:35])[CH3:34])[N:29]=[C:30]([CH3:32])[N:31]=1)[N:20]=3)[CH2:11][CH2:12]Br>C1COCC1.O>[CH3:7][O:8][C:9]([C:10]1([O:14][C:15]2[CH:37]=[CH:36][C:18]3[C:19]4[N:23]([CH2:24][CH2:25][O:26][C:17]=3[CH:16]=2)[CH:22]=[C:21]([C:27]2[N:28]([CH:33]([CH3:35])[CH3:34])[N:29]=[C:30]([CH3:32])[N:31]=2)[N:20]=4)[CH2:12][CH2:11]1)=[O:38]
Reactant: COC(=O)C(CCBr)Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(Oc2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
Potassium tertbutoxide (611 mg, 5.45 mmol) was added to a solution of 4-bromo-2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]butyric acid methyl ester (2.5 g, 4.96 mmol) in THF (20 mL) and the mixture was stirred at RT for 30 min. The crude reaction mixture was diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with brine, then dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-7% MeOH in DCM) affording 1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]cyclopropanecarboxylic acid methyl ester (1.4 g, 67%). 1H NMR (CDCl3, 400 MHz): δ 8.42 (1H, d, J=8.98 Hz), 7.56 (1H, s), 6.75 (1H, dd, J=8.97, 2.58 Hz), 6.58 (1H, d, J=2.55 Hz), 5.97-5.82 (1H, m), 4.50-4.35 (4H, m), 3.74 (3H, s), 2.40 (3H, s), 1.67-1.60 (2H, m), 1.55 (6H, d, J=6.52 Hz), 1.38-1.31 (2H, m)
Reaction SMILES: C(/[C:5](=[CH:9]\[C:10]([OH:12])=[O:11])/[C:6]([OH:8])=[O:7])(C)(C)C.[CH2:13]([N:15]([CH2:20][CH3:21])[C:16](=[O:19])[CH2:17]Cl)[CH3:14].C(=O)([O-])O.[Cs+]>CN1CCCC1=O>[CH2:13]([N:15]([CH2:20][CH3:21])[C:16]([CH2:17][O:12][C:10](/[CH:9]=[CH:5]/[C:6]([OH:8])=[O:7])=[O:11])=[O:19])[CH3:14]
Reactant: CC(C)(C)/C(=C\C(=O)O)C(=O)O
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCN(CC)C(=O)COC(=O)/C=C/C(=O)O
Yield: 5.5 %

Procedure:
Following general procedure A, mono tert-butyl fumaric acid (0.70 g, 4.06 mmol) was reacted with N,N-diethyl chloroacetamide (0.55 mL, 0.60 g, 4.06 mmol) and CsHCO3 (0.93 g, 4.87 mmol) at ca. 55° C. in N-methylpyrrolidinone (NMP). After isolation and purification, the crude material was reacted in 50 vol-% trifluoroacetic acid (TFA) in dichloromethane (DCM). The free acid was purified by mass-guided preparative HPLC to afford 0.051 g (6% yield) of the title compound (48) as a white solid. 1H NMR (CD3CN, 400 MHz): δ 6.90-6.82 (m, 2H), 4.88 (s, 2H), 3.40-3.32 (q, J=6.8 Hz, 2H), 3.31-3.27 (q, J=6.8 Hz, 2H), 1.22-1.18 (t, J=7.6 Hz, 3H), 1.11-1.07 (t, J=6.8 Hz, 3H). MS (ESI): m/z=230.03 (M+H)+, 228.07 (M−H)−.
Reaction SMILES: CN1CCCC1=O.Br[C:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[F:34][C:35]([F:40])([F:39])C([O-])=O.[Na+]>O>[C:22]1([N:11]2[C:12]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:13][C:14](=[O:15])[C:9]([C:35]([F:40])([F:39])[F:34])=[C:10]2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=c1cc(-c2ccccc2)n(-c2ccccc2)c(-c2ccccc2)c1Br
Reactant: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1cc(-c2ccccc2)n(-c2ccccc2)c(-c2ccccc2)c1C(F)(F)F
Temperature: 160 °C
Yield: 20.4 %

Procedure:
To 40 ml of 1-methyl-2-pyrrolidinone were added 2.0 g (0.0050 mole) of 3-bromo-1,2,6-triphenyl-4(1H)-pyridinone, 2.7 g (0.020 mole) of sodium trifluoroacetate and 1.9 g (0.010 mole) of cuprous iodide. The reaction mixture was then heated at 160° C. for 5 hours in a nitrogen atmosphere. After allowing the reaction mixture to cool down, it was poured into water, followed by extraction with ethyl ether. The organic layer (the extract) was washed with 50 ml of a saturated aqueous solution of sodium hydrogen carbonate. After washing the organic layer further with water, it was dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off, and the residue was crystallized from a 1:3 mixed solvent of ethyl acetate and hexane to yield 0.4 g of 1,2,6-triphenyl-3-trifluoromethyl-4(1H)-pyridinone having a melting point of 222°-225° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:15][OH:16]>>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:15][O:16][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: OCc1cc(F)cc(F)c1
Reactant: O=[N+]([O-])c1cnccc1Cl
Product: O=[N+]([O-])c1cnccc1OCc1cc(F)cc(F)c1
Yield: 78 %

Procedure:
In accordance with the same procedures as in Preparation 2, except for using 4-chloro-3-nitropyridine prepared in Step 1 of Preparation 1 and 3,5-difluorobenzyl alcohol, the titled compound was obtained as a yellow solid. (Yield: 78.0%)
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[CH3:12][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([N:13]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])c(N(c2ccccc2)c2ccccc2)c1

Procedure:
A solution of 2 g of 3-fluoro-4-nitroanisole in 16 ml of aniline was stirred for 24 hours at 140° C. After cooling, it was taken up in ethyl acetate and extracted with 2N aqueous hydrochloric acid. The organic phase was dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was chromatographed on silica gel.
Reaction SMILES: [CH:1]([C:3]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[C:5]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:4]=1)=[O:2].S(=O)(=O)([OH:33])N.CC(CC)=C.Cl([O-])=O.[Na+]>O1CCCC1.O.CS(C)=O>[C:25]1([CH2:24][O:23][C:5]2[C:6]([C:7]([O:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:8])=[CH:17][C:18]([C:19]([F:22])([F:20])[F:21])=[C:3]([CH:4]=2)[C:1]([OH:33])=[O:2])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1cc(OCc2ccccc2)c(C(=O)OCc2ccccc2)cc1C(F)(F)F
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)c1cc(C(F)(F)F)c(C(=O)O)cc1OCc1ccccc1
Temperature: 0 °C

Procedure:
To a solution of phenylmethyl 4-formyl-2-[(phenylmethyl)oxy]-5-(trifluoromethyl)benzoate (may be prepared as described in Description 54; 80 mg, 0.19 mmol) in tetrahydrofuran (4 ml), water (2 ml) and dimethyl sulfoxide (0.4 ml) was added sulfamic acid (63.7 mg, 0.66 mmol) and 2-methyl-1-butene (0.04 ml, 0.39 mmol). The solution was cooled to 0° C. and sodium chlorite (52.4 mg, 0.58 mmol) in water (2 ml) was added dropwise. After 60 minutes the mixture was quenched with saturated aqueous sodium thiosulfate solution (20 ml) and extracted with ethyl acetate (3×10 ml). The organic layer was dried (MgSO4) and the solvent removed in vacuo to give the title compound as oil. 71 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:26])[CH2:15][NH:16][C@@H:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18]2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:26])[CH2:15][NH:16][C@@H:17]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:19][CH2:18]4)=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CN[C@H]1CCc2ccccc21
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CN[C@H]4CCc5ccccc54)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-((S)-indan-1-ylamino)-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]=1[OH:19])([CH3:8])([CH3:7])[CH3:6].[CH2:20]1[O:23][CH:21]1[CH3:22]>C1(C)C=CC=CC=1>[C:15]([C:11]1[CH:12]=[C:13]([CH:21]([CH3:22])[CH2:20][OH:23])[CH:14]=[C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:10]=1[OH:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CC1CO1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(CO)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 0.17 h
Yield: 16 %

Procedure:
To a stirred slurry of 66.7 g (0.5 mole) aluminum chloride in 250 ml toluene, 103.0 g (0.5 mole) 2,6-di-tert-butylphenol dissolved in 250 ml toluene was slowly added through a dropping funnel under a nitrogen atmosphere and under dry ice/acetone bath cooling so as to maintain the temperature of the mixture at -25° C. to -20° C. The addition was complete in 10 minutes. To the resulting orange-yellow slurry, 87.0 g (1.5 mole) propylene oxide dissolved in 250 ml toluene dropwise with stirring was slowly added over a period of 1.5 hours while maintaining the temperature at -35° C. to -30° C. After stirring for an additional 0.5 hours, the mixture was worked up as described in Example 1 to give 21.2 g (16% yield) of the desired product as colorless needles. This product proved identical to that obtained in Example 1 based on IR and NMR analysis.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[N:6][CH:7]=1.[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][S:8]([C:5]1[N:4]=[CH:3][C:2]([C:19]#[C:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][N:6]=1)(=[O:10])=[O:9]
Reactant: C#Cc1ccccc1
Reactant: CS(=O)(=O)c1ncc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Temperature: 65 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (1.48 g, 2.11 mmol, 0.05 equiv.) was dissolved in 200 ml THF. (10 g, 42.2 mmol) 5-Bromo-2-(methylsulfonyl)pyrimidine and phenylacetylene (9.26 ml, 84.4 mmol, 2 equiv.) were added at room temperature. Triethylamine (17.6 ml, 127 mmol, 3 equiv.), triphenylphosphine (330 mg, 1.3 mmol, 0.03 equiv.) and copper(I) iodide (80 mg, 420 μmol, 0.01 equiv.) were added and the mixture was stirred for 4 hours at 65° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with EtOAc. The organic layers were extracted with water, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 2-methanesulfonyl-5-phenylethynyl-pyrimidine (6.2 g, 57% yield) was obtained as a yellow solid, MS: m/e=259.1 (M+H+).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1)([OH:3])=[O:2].Cl[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11].[OH-].[Na+].[Cl-].[Na+]>O.O1CCCC1.C(OCC)(=O)C>[CH2:13]([O:12][C:10]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[C:1]([OH:3])=[O:2])=[O:11])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
To a suspension of (2S)-2-carboxypyrrolidine (40 g) in a mixture of water (200 ml) and tetrahydrofuran (200 ml) was added a solution of allyl chloroformate (44 ml) in tetrahydrofuran (40 ml) at ° C. while adjusting pH to around 9 with 4N aqueous sodium hydroxide. After stirring at ° C. for 1 hour at pH 9, the aqueous layer was saturated with sodium chloride, and the mixture was diluted with ethyl acetate (200 ml). The aqueous layer was separated and washed with ethyl acetate. After adjusting pH to around 2 with 6N hydrochloric acid, the mixture was extracted with two portions of ethyl acetate (200 ml×2). The combined extract was dried over magnesium sulfate and evaporated in vacuo to give (2S)-1-allyloxycarbonyl-2-carboxypyrrolidine (72.49 g).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[BH-](O[C:37]([CH3:39])=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:2][N:1]1[C:10]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]=[C:37]1[CH2:39][N:11]([CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(CN(CCCCN2C(=O)c3ccccc3C2=O)C2CCCc3cccnc32)nc2ccccc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 72 %

Procedure:
To a solution of 2-[4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione (0.2011 g, 0.58 mmol) in dichloromethane (5.8 mL) was added 1-Methyl-1H-benoimidazole-2-carbaldehyde (0.1844 g, 1.15 mmol) and NaBH(OAc)3 (0.2462 g, 1.16 mmol), and was stirred at room temperature for four days. The organic phase was washed with NaHCO3 (2×10 mL), dried over Na2SO4, filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (47:2:1 CH2Cl2-MeOH—NH4OH) provided 103 mg (36%) of 2-{4-[(1-Methyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione. 1H NMR (CDCl3) δ 1.30-1.44 (m, 2H), 1.48-1.63(m, 3H), 1.84-1.96 (m, 2H), 2.03-2.07 (m, 1H), 2.54-2.81 (m, 4H), 3.51 (t, 2H, J=7.2 Hz), 3.95 (s, 3H), 3.99-4.06 (m, 2H), 4.19 (d, 1H, J=13.5 Hz), 6.94-6.98 (m, 1H), 7.13-7.21 (m, 2H), 7.24-7.29 (m, 2H), 7.63-7.68 (m, 3H), 7.74-7.78 (m, 2H), 8.40 (d, 1H, J=3.6 Hz).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(N(CC)CC)C>C(OCC)C>[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9][CH2:8]1
Reactant: CN1CCNCC1
Reactant: C=CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCN(C)CC1
Reaction time: 72 h
Yield: 61.6 %

Procedure:
A solution of acryloyl chloride (9 g, 0.10 mole) in ethyl ether (20 ml) was added dropwise to a stirring, cold solution of N-methylpiperazine (10 g, 0.10 mole) and triethylamine (30.6 ml, 0.22 mole) in ethyl ether (150 ml) over a thirty minute period. An additional 75 ml of ethyl ether was added and the reaction stirred for 72 hours. The resulting white solid was filtered and washed well with ethyl ether. The ethyl ether was collected, combined with the filtrate and the solvent evaporated on a rotary evaporator to yield 9.5 g of product as an orange oil. NMR confirmed the structure of the product.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[C:15]([CH3:16])=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[CH3:17])=[CH:6][CH:5]=1.[CH3:22][CH:23]([C:29]([CH3:31])=O)[C:24](OCC)=[O:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]([F:20])([F:21])[O:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[C:10]([CH3:17])=[C:11]3[C:12](=[CH:14][C:15]=2[CH3:16])[N:13]=[C:29]([CH3:31])[C:23]([CH3:22])=[C:24]3[OH:25])=[CH:6][CH:5]=1
Reactant: Cc1cc(N)cc(C)c1Oc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1cc2nc(C)c(C)c(O)c2c(C)c1Oc1ccc(OC(F)(F)F)cc1
Yield: 130.1 %

Procedure:
A solution of 1.78 g of 4-(4-trifluoromethoxyphenoxy)-3,5-dimethylaniline, 1.92 g of ethyl 2-methylacetoacetate, and 1.14 g of p-toluenesulfonic acid dissolved in 61 mL of xylene was heated under reflux for 9 hr. This reaction solution was cooled, and the precipitated crystals were then collected by filtration and were washed with distilled water and n-hexane to give 2.94 g of 6-(4-trifluoromethoxyphenoxy)-4-hydroxy-2,3,5,7-tetramethyl-quinoline 2.26 g (yield 100%). A 1.14 g portion in the crystals thus obtained was stirred in 15 mL of acetic anhydride with heating at 120 to 125° C. for 2 hr. The reaction solution was concentrated, ethyl acetate was then added to the concentrate, the mixture was washed with saturated brine, and the solvent was then concentrated under the reduced pressure. The crude product was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane/ethyl acetate) to give 0.74 g of 4-acetoxy-6-(4-trifluoromethoxyphenoxy)-2,3,5,7-tetramethyl-quinoline (yield 58.4%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1.C([O-])([O-])=O.[K+].[K+].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>[C:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[CH2:10][CH2:9]2)[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(CN1CCN(c2cccc(Br)c2)CC1)N1CCN(C2CCC2)CC1
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: [K+]
Solvent: C1COCCO1
Product: O=C(CN1CCN(c2cccc(-c3ccccc3)c2)CC1)N1CCN(C2CCC2)CC1
Temperature: 85 °C

Procedure:
In a sealed vial, dissolve 1-(3-bromophenyl)-4-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]piperazine (17 mg, 0.04 mmol), phenyl boronic acid (9.8 mg, 0.08 mmol), and Pd(PPh3)4 (2.3 mg, 0.002 mmol) in dioxane (0.7 mL) and 2N K2CO3 (0.1 mL). Degas with N2 and seal the vial. Heat the mixture at 85° C. overnight. Cool and add partition EtOAc (0.5 mL) and 1N NaOH (0.5 mL). Extract the organic phase and place directly on SCX ion exchange resin. Wash the resin with EtOAc/MeOH (9:1). Discard this wash. Wash the resin with EtOAc/MeOH/TEA(9:1:1) and collect. Remove the solvent to yield the title compound. 1H NMR (CDCl3) δ 7.59-7.56 (m, 2H) 7.45-7.40 (m, 2H), 7.36-7.31 (m, 2H), 7.13-7.07 (m, 2H) 6.94-6.90 (m, 1H), 3.64 (t, 4H), 3.29-3.25 (m, 6H), 2.73-2.67 (m, 5H), 2.33-2.27 (m, 4H), 2.06-2.02 (m, 2H), 1.90-1.83 (m, 2H), 1.75-1.69 (m, 2H); LC-MS (M+1) 419.06.