Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:16][NH2:17]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH:17][CH3:16])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)cc2)C1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2ccc(Cl)cc2)C1
Reaction time: 18 h
Yield: 85.2 %

Procedure:
A stirred solution of 5 g (0.02 mole) of 3-(4-chlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4.7 g (0.06 mole) of 40% aqueous monomethylamine. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water and the solid which separated was collected by filtration, 5.7 g. Recrystallization from benzene-ligroin was accomplished by adding magnesium sulfate to absorb the water which separated from the wet product. After filtering and cooling the hot filtrate, the precipitated solid was collected by filtration to yield 4.1 g (85.2%) of white crystals, m.p. 144°-145° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].CCN(C(C)C)C(C)C.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:21](=[O:23])[CH3:22]
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-Bromo-5-nitroaniline (10 g) was dissolved in 500 mL of CH2Cl2, DIEA (6.6 g) was added to the mixture, followed by DMAP (100 mg). The mixture was cooled to 0° C. in ice bath. Acetyl chloride (4 g in 50 mL CH2Cl2) was added dropwise to the reaction mixture. After the mixture was stirred at RT over 3 h, extracted once with saturated NaHCO3 solution and once with brine, the resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 1:1 EtOAc:Hexane to 100% EtOAc to afford N-(2-bromo-5-nitrophenyl)acetamide as a white solid. MS: 258 (M−1). Calc'd. for C8H7BrN2O3—259.06.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:6]=1.O.[OH-].[Na+]>C(O)(=O)C>[N+:1]([C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=2)[CH:16]=[CH:15][C:14]=1[OH:17])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(-c2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(-c2cccnc2)ccc1O
Temperature: 60 °C
Yield: 43.4 %

Procedure:
Nitric acid (60 μL, 1.0 mmol) was added to a solution of 4-pyridin-3-yl-phenol (164 mg, 0.96 mmol) in acetic acid (2.8 mL). The mixture was heated at 60° C. for 30 min and the solution turned orange/brown in color. Upon cooling, water was added (3 mL) and 6 N NaOH (aq) was added until the solution was basic. The solution was extracted with ethyl acetate (3×) and then the aqueous phase was concentrated. The crude residue was washed with boiling methanol to afford 90 mg (43%) of 2-nitro-4-pyridin-3-yl-phenol as an orange solid: mp>300° C., MS (Cl) m/z 217.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:15]([OH:17])=O)[CH3:2].S(Cl)([Cl:20])=O>>[CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:15]([Cl:20])=[O:17])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOc1nc2c(cnn2CC)nc1C(=O)O
Product: CCOc1nc2c(cnn2CC)nc1C(=O)Cl

Procedure:
40 g. of 6-ethoxy-1-ethyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid (0.17 mol.) and 300 ml. of thionyl chloride are refluxed for 21/2 hours. After removal of the excess thionyl chloride under vacuum, the 6-ethoxy-1-ethyl-1 H- pyrazolo[3,4-b]-pyrazine-5-carbonyl chloride is treated with hexane, filtered off and then dried at 60°, yield 41.5 g. (96%), m.p. 86°-87°.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9]Cl>C(#N)C>[CH3:1][N:2]([CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[C:6]([O:5][CH3:4])[CH:7]=1)[CH3:3]
Reactant: COc1cccc(CCl)c1
Reactant: CNC
Solvent: CC#N
Product: COc1cccc(CN(C)C)c1
Reaction time: 4 h

Procedure:
Four hundred grams of dimethylamine were added to 1.5 liters of acetonitrile previously cooled with an external ice/ethanol bath. To this solution were added 322.7 g. of 3-methoxybenzyl chloride in a dropwise fashion. When the addition was completed, the reaction was stirred for an additional four hours with cooling. The reaction was stirred an additional 20 hours at room temperature, heated to reflux for five hours, and then concentrated under reduced pressure. The residue was taken up in water, the aqueous solution was made strongly basic with aqueous sodium hydroxide, and the solution was then extracted with diethyl ether. The ether layer was first washed with water and then extracted with dilute hydrochloric acid. The acid layer was made basic with an aqueous sodium hydroxide solution and extracted with diethyl ether. The layer was dried over sodium sulfate and evaporated to dryness. The residue was vacuum distilled at 3 torr. The fraction between 88 and 92° C. afforded 257 g. of the desired title intermediate. NMR.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C1(C(O)=O)[C:9]2([CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:8]1>ClCCl.CN(C)C=O>[CH:1]1([C:2]([Cl:4])=[O:3])[C:9]2([CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:8]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CC12CCOCC2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CC12CCOCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
60.0 ml of oxalyl chloride are added to a solution of 98.73 g of 6-oxaspiro[2.5]-octane-1-carboxylic acid in 500 ml of dichloromethane at 0° C. One drop of N,N-dimethylformamide is added, and the reaction solution is stirred at room temperature for 1 hour. The reaction solution is then evaporated, and the crude product is employed directly for the next stage.
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([O:17][CH3:18])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[CH3:18][O:17][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[C:6]([C:5]1[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=1[OH:20])=[O:19]
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(OC)cc1)OC
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Product: COc1ccc(CN(OC)C(=O)C2=C(O)C(=O)N(C)C2)cc1
Yield: 58 %

Procedure:
2-Hydroxy-3-[methoxy-(4-methoxybenzyl)-carbamoyl]-acrylic acid methyl ester (Compound 55-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (58% yield); mp 135–137° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.09 (3H, s, NCH3), 3.71 (3H, s, OCH3), 3.80 (3H, s, OCH3), 4.14 (2H, s, NCH2), 4.82 (2H, s, NCH2), 6.88 (2H, m, aromatics), 7.27 (2H, m, aromatics). Anal. calcd for C15H18N2O5: C, 58.81; H, 5.92; N, 9.14. Found: C, 58.62; H, 5.88; N, 9.12.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:10]=1)[C:7]#[N:8].[C:23]([NH:26][C:27]1[CH:37]=[CH:36][CH:35]=[C:29]2[C:30]([O:32][C:33](=O)[C:28]=12)=[O:31])(=[O:25])[CH3:24]>C(O)(=O)C.CCOC(C)=O>[C:7]([CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:10]=1)[N:5]1[C:33](=[O:32])[C:28]2[C:29](=[CH:35][CH:36]=[CH:37][C:27]=2[NH:26][C:23](=[O:25])[CH3:24])[C:30]1=[O:31])#[N:8]
Reactant: COc1ccc(C(N)C#N)cc1OC1CCCC1
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(C(C#N)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1OC1CCCC1
Yield: 65 %

Procedure:
A mixture of 2-amino-2-(3-cyclopentyloxy-4-methoxyphenyl)ethanenitrile acetate (3.5 g, 11.0 mmol) and 3-acetamidophthalic anhydride (2.3 g, 11.0 mmol) in glacial acetic acid (40 mL) was heated to reflux for 17 hours. The mixture was concentrated in vacuo to give an oil. The oil was dissolved in EtOAc and washed with water, brine and dried (MgSO4). Solvent was removed and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 98:2) to give 3.1 g (62%) of N-{2-[cyano(3-cyclopentyloxy-4-methoxyphenyl)methyl]-1,3-dioxoisoindolin-4-yl}acetamide as white solid; mp 124-126° C.; 1H NMR (CDCl3) δ 9.44 (s, 1H), 8.76 (d, J=8.4 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.03-6.99 (m, 2H), 6.84 (d, J=8.0 Hz, 1H), 5.60-5.53 (dd, J=6.2 and 10.4 Hz, 1H), 4.79-4.74 (m, 1H), 3.86-3.75 (m, 1H), 3.82 (s, 3H), 3.29-3.20 (dd, J=6.4 and 17 Hz, 1H), 2.72 (s, 3H0, 1.97-1.56 (m, 8H); 13C NMR (CDCl3) δ 169.58, 169.11, 167.18, 150.61, 147.98, 137.72, 136.28, 130.89, 128.66, 125.09, 119.80, 118.29, 116.78, 114.19, 111.90, 80.68, 56.02, 51.10, 32.73, 24.92, 24.03, 21.07. Analy. Calculated for C25H25N3O5: C, 67.10; H, 5.63; N, 9.39. Found: C, 66.89; H, 5.42; N, 9.26.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][C:2]1[C:3]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccccc3)c(C)cc2c1
Temperature: 70 °C
Yield: 98 %

Procedure:
Ethyl (2E)-3-(4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenyl)-2-propenoate (9) (2.20 g, 5.02 mmol) was dissolved in THF and EtOH (1:1, 50 mL). To this mixture was added 1 N NaOH (50 mL, excess) at room temperature and the stirred reaction heated to 70° C. for 0.5 h. After cooling to RT, the reaction mixture was acidified with 20% aqueous HCl, and then extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure to afford the crude product. The product was purified by flash column chromatography with CHCl3:MeOH (9:1 to 4:1) as an eluent to give 2.02 g (98%) of compound (10) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J=8.0 Hz, 1H), 7.64 (d, J=16.0 Hz, 1H), 7.57 (s, 1H), 7.26 (dd, J1=12.0 Hz, J2=12.0 Hz, 4H), 7.22 (d, J=4.0 Hz, 1H), 7.14 (d, J=1.8 Hz, 2H), 7.12 (s, 1H), 7.06 and 7.04 (dd, J=12.0 Hz, J2=6.8 Hz, 1H), 6.60 (d, J=8.0 Hz, 2H), 6.22 (d, J=16.0 Hz, 1H), 3.92 (s, 3H), 2.24 (s, 3H). LCMS (ESI) m/z 439.07 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[C:14]([CH3:15])=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[CH3:16])[N:6]=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:11]([C:10]1[CH:9]=[C:8]([CH3:16])[C:7]([C:5]2[N:6]=[C:2]([NH:1][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[S:3][CH:4]=2)=[C:14]([CH3:15])[CH:13]=1)#[N:12]
Reactant: O=C(Cl)c1ccncc1
Reactant: Cc1cc(C#N)cc(C)c1-c1csc(N)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(C#N)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-Aminothiazol-4-yl)-3,5-dimethylbenzonitrile (84 mg, 0.37 mmol) in DCM (2 mL) was added DMAP (84 mg, 0.74 mmol) followed by isonicotinoyl chloride hydrochloride (85 mg, 0.48 mmol). Then the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated, and the saturated aqueous sodium bicarbonate (30 mL) was added. The aqueous solution was extracted with DCM (3×10 mL). The combined organic layers were dried with anhydrous sodium sulfate. After removal of all the solvent, the residue was purified by silica gel chromatography (hexane/acetone=2:1) to give INH174 (55 mg, 44%) as a white solid; mp 248-250° C. 1H NMR (400 MHz, CD3OD) δ 8.88-8.86 (m, 2H), 7.76-7.74 (m, 2H), 7.38 (s, 2H), 6.91 (s, 1H), 2.16 (s, 6H). 13C NMR (125 MHz, DMSO-d6) δ 150.9, 141.0, 139.7, 139.2, 131.2, 122.2, 119.4, 113.3, 111.0, 20.4. MS (ESI) m/z 335.0 (M+H+). HRMS calculated for C18H14N4SONa (M+Na+), 357.0786. found, 357.0789.
Reaction SMILES: [C:1]1([S:7][C:8]2[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[NH:27][CH:28]([CH:32]([CH3:34])[CH3:33])[C:29](O)=[O:30]>>[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[NH:27][CH:28]([CH:32]([CH3:34])[CH3:33])[C:29]([O:15][CH2:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:13]=1)=[O:30]
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Reactant: OCc1cccc(Sc2ccccc2)n1
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)OCc1cccc(Sc2ccccc2)n1

Procedure:
Using the procedure of Example 11, (6-phenylthio-2-pyridyl)methanol is reacted with 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid to yield (6-phenylthio-2-pyridyl)methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate, MS m/e 494 (M+).
Reaction SMILES: [NH2:1][N:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].O.Cl.[O:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=O)[CH2:12][CH2:11]1>C(O)C>[O:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[N:1][N:2]2[CH2:6][CH2:5][O:4][C:3]2=[O:7])[CH2:12][CH2:11]1
Reactant: NN1CCOC1=O
Reactant: O=C1CCOc2ccccc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C1OCCN1N=C1CCOc2ccccc21

Procedure:
A 62 g (0.61 mole) portion of 3-amino-2-oxazolidinone was charged in a 500 ml, 3-necked flask equipped with a thermometer, stirrer and reflux condenser, and treated successively with 92 ml of H2O, 8 ml of 10% HCl and 42 g (0.28 mole) of 4-chromanone in 200 ml of ethanol. The reaction mixture was refluxed for 36 hrs., stripped in vacuo to one-half volume and cooled in the refrigerator overnight. The slurry was filtered and the white crystalline solid washed with 50 ml of isopropanol then 200 ml of ether and dried; m.p. 105°-108°. Yield: 44 g (68%).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([C:13]([OH:15])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.S(Cl)([Cl:18])=O>>[OH:1][C:2]1[C:11]([CH3:12])=[C:10]([C:13]([Cl:18])=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1c(O)nc2ccccc2c1C(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1c(O)nc2ccccc2c1C(=O)Cl

Procedure:
A mixture of 2-hydroxy-3-methylquinoline-4-carboxylic acid (V, Step II, 5.11 g) and thionyl chloride (35 ml) is stirred at reflux for 3.5 hr. After cooling, the excess thionyl chloride is removed under reduced pressure. The residue is taken up in dichloromethane and taken to dryness again under reduced pressure. The dichloromethane addition/removal under reduced pressure is repeated twice. The residue is then dried under greatly reduced pressure for 1 hr to remove the last traces of thionyl chloride to give 2-hydroxy-3-methylquinolin-4-oyl chloride (V-A), which is taken up in 30 to 40 ml of dichloromethane and cooled at 0°. Triethylamine (3.50 ml) is added, followed by pyrrolidine (4.19 ml). After 5-10 min the ice bath is removed. After stirring for 3 hr, the mixture is partitioned between dichloromethane and aqueous sodium bicarbonate. The mixture is filtered through sodium sulfate and concentrated to a residue. The residue is chromatographed (silica gel; methanol/dichloromethane (4/96)) to give pyrrolidino 2-hydroxy-3-methylquinoline-4-carboxamide (VI), mp 175°-176° which is crystallized from acetone, mp 223°-227°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[C:28](B(O)O)=[C:27]([CH3:32])[O:26][N:25]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[C:16]1(=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[C:24]([CH3:23])=[N:25][O:26][C:27]=3[CH3:32])=[CH:3][CH:4]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1noc(C)c1B(O)O
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Yield: 114.7 %

Procedure:
The procedure described for 202 was followed. A round-bottomed flask was charged with 4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (9) (0.100 g, 0.28 mmol), PdCl2(PPh3)2, (0.020 g, 0.028 mmol), (3,5-dimethyl-4-isoxazolyl)boronic acid (0.079 g, 0.56 mmol), Na2CO3 (0.060 g, 0.56 mmol), and THF/H2O (5 mL, 4:1). The reaction mixture was refluxed for 10 h. Standard workup and purification by flash silica gel chromatography provided 0.120 g (78%) of the title compound 206 as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 9.28 (s, 1H), 7.28 (d, J=6.00 Hz, 2H), 7.18 (d, J=6.0 Hz, 2H), 6.94 (d, J=6.6 Hz, 2H), 6.67 (d, J=6.3 Hz, 2H), 2.37 (s, 3H), 2.23-2.22 (br, m, s, 4H), 1.52 (br s, 8H). LCMS (ESI): m/z 372 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.C([OH:20])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:20])[NH:13]2
Reactant: Fc1cccc(F)c1-c1cccc2[nH]ccc12
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2c(F)cccc2F)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To the suspension of 4-(2,6-difluoro-phenyl)-1H-indole (9.5 g, 41.4 mmol) in t-BuOH:ethanol:acetic acid (262 mL:155 mL:81 mL) was added pyridinium tribromide (40.28 g, 126 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added more acetic acid (200 mL). Zinc dust (14.2 g, 217 mmol) was added to the reaction mixture portionwise. After stirring for one hour, the unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (5×), sat. NaHCO3 (2×), brine (3×), dried over Na2SO4, concentrated, triturated with ether to give 7.1 g (70%) of 4-(2,6-difluoro-phenyl)-1,3-dihydro-indol-2-one as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5](C#N)[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)C.C(O)(=O)C.S(=O)(=O)(O)O>O>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([CH:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[CH2:5][C:4]([OH:23])=[O:3])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(C#N)C(c1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Yield: 49.6 %

Procedure:
A mixture of 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-2-cyano-propionic acid ethyl ester (1.91, 4.87 mmol), acetic acid (10 ml), concentrated sulfuric acid (5 ml) and water (5 ml) were refluxed for 2 hours. Reaction mixture was poured into iced water and extracted with ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated, the crude product was purified over flash silica chromatography eluting with ethyl acetate/petroleum ether (1:1) to afford the desired product (0.82 g, 50% yield). LC/MS: (PS-A2) Rt 3.39 [M+H]+ 338.86.
Reaction SMILES: CC(C)(O[C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])C.[CH3:14][N:15](C)[C:16](Cl)=O.C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[CH3:14][N:15]([CH3:16])[C:5]([N:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)=[O:6]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CCNCC1

Procedure:
To a solution of 1.92 g 1-(1,1-dimethylethyloxycarbonyl)piperazine in 11 mL of dichloromethane and 1.5 mL of triethylamine at room temperature was added dropwise 1 mL of dimethylcarbamylchloride. After 16 hours 5% aqueous sodium hydrogencarbonate and dichloromethane were added, the organic layer separated, dried over magnesium sulfate and concentrated. Column chromatography on silica gel (dichloromethane/methanol=95/5 v/v) yielded 1.34 g 1-1,1-dimethylethyloxycarbonyl)-4-(dimethylaminocarbonyl)piperazine. This compound was dissolved in a 3N hydrogen chloride solution in methanol at 0° C. After 15 min the reaction mixture was allowed to warm to room temperature and After stirring for 3 days at room temperature the reaction mixture was concentrated to give 1.06 g of 1-(dimethylaminocarbonyl)piperazine hydrochloride. rf=0.29, SiO2: dichloromethane/methanol=4/1 v/v.
Reaction SMILES: [Br-].[N:2]1([CH2:7][CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C([Li])CCC.[Br:33][C:34]1[CH:49]=[CH:48][C:37]2[O:38][CH2:39][C:40]3[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=3[C:42](=O)[C:36]=2[CH:35]=1>CCCCCC.O1CCCC1>[Br:33][C:34]1[CH:49]=[CH:48][C:37]2[O:38][CH2:39][C:40]3[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=3/[C:42](=[CH:8]/[CH2:7][N:2]3[CH2:3][CH2:4][CH2:5][CH2:6]3)/[C:36]=2[CH:35]=1
Reactant: c1ccc([P+](CCN2CCCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1c2ccccc2COc2ccc(Br)cc21
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Brc1ccc2c(c1)/C(=C\CN1CCCC1)c1ccccc1CO2

Procedure:
Anhydrous 2-(N-pyrrolidinyl)-ethyltriphenylphosphonium bromide (10 g, 45 mmole), 48 mmole of n-butyl lithium in hexane, and 2-bromo-6,11-dihydrodibenz [b,e1-oxepin-11-one (5 g, 35 mmole) were reacted in 300 mL dry tetrahydrofuran by the procedure in Example 1, Step a. This provided the pure Z-isomer (1.76 g) as a light brown solid, mp 108°-109° C.. pmr (DMSO-d6) δ: 7.28-7.50 (m, 6H, aromatic H); 6.80 (d, J=8.8 Hz, 1H, H4); 5.82 (t, 1H, HC=); 5.20 (s, 2H, ArCH2O); 3.29 (m, 2H, NCH2C=); 2.50 (m, 4H, 2NCH2); 1.70 (m, 4H, 2CH2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:13]2([OH:30])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([CH3:12])([CH3:11])[CH3:10].[N:31]#[C:32]Br>C(O)C>[NH2:31][C:32]1[N:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:7]2[CH:6]=[CH:5][C:4]([C:13]3([OH:30])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[N:14]3[CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:3][C:2]=2[N:1]=1
Reactant: N#CBr
Reactant: CC(C)(C)Nc1ccc(C2(O)c3ccccc3C(=O)N2Cc2ccccc2)cc1N
Solvent: CCO
Product: CC(C)(C)n1c(N)nc2cc(C3(O)c4ccccc4C(=O)N3Cc3ccccc3)ccc21
Temperature: 25 °C
Yield: 0.7 %

Procedure:
A solution of 3-{3-amino-4-[(1,1-dimethylethyl)amino]phenyl}-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one (347 mg, 0.862 mmol) and cyanogen bromide (100 mg, 0.948 mmol) in anhydrous ethanol (10 mL) was heated to reflux for 6 h, at which time it was cooled to room temperature and concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate and brine then dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by reverse phase HPLC to afford 3-[2-amino-1-(1,1-dimethylethyl)-1H-benzimidazol-5-yl]-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one (2.7 mg). 1H NMR (400 MHz, d6-DMSO): 7.76 (d, 1H), 7.61 (d, 1H), 7.56-7.53 (m, 2H), 7.32 (br s, 1H), 7.30 (d, 1H), 7.09-7.07 (m, 5H), 6.92 (d, 1H), 4.41 (d, 1H), 4.22 (d, 1H), 1.73 (s, 9H); MS (EI) for C26H26N4O2: 427 (MH+).