Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([O:24]C4C=CC=CC=4)=O)[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:31])=[N:9]2)=[CH:4][CH:3]=1>C(#N)C>[CH2:8]([NH2:9])[CH2:7][CH3:6].[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([NH:9][CH2:8][CH2:7][CH3:6])=[O:24])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:31])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Solvent: CC#N
Product: CCCN
Product: CCCNC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 178.4 %

Procedure:
Following the procedure of Example 1 but starting with 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (8.6 g.) and a 40% (w/v) aqueous solution of propylamine (8.75 cc.) in acetonitrile (200 cc.), 2-(7-chloro-1,8-naphthyridin-2-yl)-3-propylaminocarbonyloxy-isoindolin-1-one (4.7 g.), melting at 208°-209° C., is obtained.
Reaction SMILES: BrCC[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:26]3[CH:27]=[CH:28][NH:29][C:25]=3[CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1.C([C:49]1[NH:50][CH:51]=[CH:52][N:53]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:54]O>C(#N)C>[N:53]1([CH2:54][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][CH:8]=[C:7]3[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]4[CH:27]=[CH:28][NH:29][C:25]=4[CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)[CH:52]=[CH:51][N:50]=[CH:49]1
Reactant: BrCCc1ccc2[nH]cc(CCN3CCN(c4nccc5[nH]ccc45)CC3)c2c1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)c2ncc[nH]2)cc1
Reactant: CO
Solvent: CC#N
Product: c1cn(Cc2ccc3[nH]cc(CCN4CCN(c5nccc6[nH]ccc56)CC4)c3c2)cn1

Procedure:
A solution of 3.7 mmol of the compound obtained in Step 6 and 4.1 mmol of tritylimidazole in 50 ml of acetonitrile is heated at reflux for 24 hours and then heated at 60° C. for 24 hours in the presence of 50 ml of methanol. The reaction mixture is then concentrated in vacuo. The residue is taken up in a 5/1 biphasic mixture: dichloromethane/20% sodium hydroxide solution. The organic phase is dried, filtered and concentrated under reduced pressure, enabling the expected product to be obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:19]1[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([CH3:28])[C:20]=1[CH3:29].C(O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:19]2[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([CH3:28])[C:20]=2[CH3:29])=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1sc(Br)c(C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1sc(-c2ccc(OC)cc2)c(C)c1C
Temperature: 97.5 °C
Yield: 90.2 %

Procedure:
(4-methoxyphenyl)boronic acid (0.56 g, 3.70 mmol) and potassium carbonate (1.40 g, 10.11 mmol) were added to a solution of methyl 5-bromo-3,4-dimethylthiophene-2-carboxylate (9b, 0.8 g, 3.37 mmol) in a mixture of toluene:ethanol (10:30 ml) in a tube at 25° C. Nitrogen gas was bubbled through reaction mixture for 15 minutes. Tetrakis(triphenylphosphine)(0)palladium (0.19 g, 0.17 mmol) was added to the reaction mixture under nitrogen and the tube was sealed. The reaction mixture was heated at 95-100° C. for 2 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and was filtered through celite. The celite cake was washed with ethyl acetate (30 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was further purified by column chromatography using 5% ethyl acetate in hexanes as an eluent to obtain the title compound 9c (0.84 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH2:10])=[O:4].[N:17]1([CH:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)[CH:21]=[CH:20][N:19]=[N:18]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:10][CH:25]1[CH2:24][CH2:23][CH:22]([N:17]2[CH:21]=[CH:20][N:19]=[N:18]2)[CH2:27][CH2:26]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Reactant: O=C1CCC(n2ccnn2)CC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC(n2ccnn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-amino-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (example 9)(0.387 g, 1.6 mmol) and 4-[1,2,3]triazol-1-yl-cyclohexanone (0.27 g, 1.6 mmol) in dry THF is added dibutyltin dichloride (0.024 g, 0.080 mmol) followed by phenylsilane (0.276 ml, 2.2 mmol). The mixture is stirred overnight at room temperature. Solvent is evaporated under reduced pressure, and the residue is diluted with ethyl acetate. The organic layer is washed with water and brine, dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica get using gradient 50-100% ethyl acetate in hexane to afford 5-(3,3-dimethyl-but-1-ynyl)-3-(4-[1,2,3]triazol-1-yl-cyclohexylamino)-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14](=[O:23])[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH2:16])[C:8]=1[OH:24]>>[CH3:13][C:11]1[CH:12]=[C:7]([CH3:6])[C:8]([OH:24])=[C:9]2[C:10]=1[CH2:16][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]2=[O:23]
Reactant: C=C(C(=O)c1cc(C)cc(C)c1O)c1ccccc1
Agent: O=S(=O)(O)O
Product: Cc1cc(C)c2c(c1O)C(=O)C(c1ccccc1)C2
Temperature: 0 °C
Yield: 70.3 %

Procedure:
Into 15 ml of concentrated sulfuric acid, under ice-cooled condition with stirring, 3.0 g of 2,4-dimethyl-6-(2-phenylacryloyl)phenol was added gradually then the whole mixture was stirred at room temperature for 1 hour. The reaction mixture was poured in 100 g of ice and extracted with 200 ml of methylene chloride. The extract was washed with water and dried with anhydrous magnesium sulfate, then was concentrated under a reduced pressure to obtain the residue. The residue was recrystallized from ethanol to obtain 2.11 g of 2,3-dihydro-4,6-dimethyl-2-phenyl-7-hydroxy-1H-inden-1-one.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=[O:6].ClCCl>C(O)(C)C>[BrH:3].[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:5](=[O:6])[CH2:4][NH:2][CH3:1])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: COc1ccc(C(=O)CBr)cc1OC
Reactant: CN
Solvent: ClCCl
Solvent: CC(C)O
Product: Br
Product: CNCC(=O)c1ccc(OC)c(OC)c1
Yield: 67 %

Procedure:
To isopropanol (200 ml), 40% aqueous methylamine solution (133 ml) was added and stirred under ice-cooling. 2-Bromo-1-(3,4-dimethoxyphenyl)ethanone (8.47 g, 33 mmol) was dissolved in isopropanol (10 ml) and dichloromethane (10 ml) and dropwise added to the reaction mixture over 1 hour. After the dropwise addition, the mixture was stirred for 15 minutes under ice-cooling. The solvent in the reaction mixture was distilled out at room temperature under reduced pressure and the precipitated crystal was filtered to yield 1-(3,4-dimethoxyphenyl)-2-(methylamino)ethanone hydrobromide (6.36 g, 67%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[C:12]1(=O)[O:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=C(C)C=C(C)C=1>O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([N:6]2[CH2:12][CH2:13][CH2:14][C:15]2=[O:16])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCCO1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: Cc1cc(C)cc(C)c1
Product: O=C1CCCN1c1cccc(C(F)(F)F)c1
Temperature: 198 °C
Yield: 45.8 %

Procedure:
A reaction flask was charged with 70.0 g (0.434 mole) of m-trifluoromethylaniline and 37.4 g (0.434 mole) of butyrolactone. The mixture was heated to reflux at 198° C for 185 minutes. Then, 1.0 g (0.0058 mole) of ptoluenesulphonic acid was added, and the resulting mixture was refluxed for an additional 100 minutes, during which time the temperature dropped from 164° C to 138° C. The mixture was then cooled, a DEan-Stark trap was installed on the condenser, and 50 ml of mesitylene was added. The mixture was then refluxed at 181-187° C until water was no longer produced. The precipitate formed by the reaction was filtered out of the mixture and dried in vacuo, yielding 45.6 g of 1-(m-trifluoromethylphenyl)-2-pyrrolidone, melting point 65°-66° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[CH2:12][CH:13]1[CH2:15][O:14]1.O>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][CH:13]1[CH2:15][O:14]1
Reactant: BrCC1CO1
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cccc(OCC2CO2)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 113.3 %

Procedure:
To a solution of compound NaH (416.2 mg, 17.34 mmol) in DMF (10 mL) was added 3-bromophenol (1.0 g, 5.78 mmol) at 20° C. After addition the solution was stirred for 5 minutes at this temperature before the addition of 2-(bromomethyl)oxirane (1.2 g, 8.67 mmol). The reaction mixture was stirred for 16 h at 20° C. Once complete the reaction mixture was treated with water (50 mL) and extracted with EA (2×20 mL) and the organic layers combined and washed with NaHCO3, brine (30 mL), dried over Na2SO4 and concentrated to give the compound 2-((3-bromophenoxy)methyl)oxirane (1.5 g, crude) as colorless oil which was used in next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH:8][C:9]1[C:13](OCC)=[N:12][S:11](=[O:18])(=[O:17])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[CH3:31][C:32]1[CH:33]=[C:34]([NH:38][C:39]([NH:41][CH2:42][CH2:43][NH2:44])=[O:40])[CH:35]=[CH:36][CH:37]=1.C(N(CC)CC)C>C(O)C>[C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH:8][C:9]1[C:13]([NH:44][CH2:43][CH2:42][NH:41][C:39]([NH:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([CH3:31])[CH:33]=2)=[O:40])=[N:12][S:11](=[O:17])(=[O:18])[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC1=NS(=O)(=O)N=C1N[C@@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C
Reactant: Cc1cccc(NC(=O)NCCN)c1
Agent: O=C[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)NCCNC2=NS(=O)(=O)N=C2N[C@@H](Cc2ccc(O)cc2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a solution of N—(4-ethoxy- 1,1-dioxo—1,2,5-thiadiazol—3-yl)-L-tyrosine tert-butyl ester from Step A (150 mg, 0.38 mmol) and the formate salt of 2—(3-methylphenylaminocarbonylamino)eth—1-ylamine from Step B (210 mg, 0.89 mmol) in ethanol (10 mL) was added triethylamine (133 mg, 1.44 mmol). The reaction was stirred at room temperature overnight. Solvent was removed under reduced pressure and the residue purified by flash column chromatography (silica, 5% MeOH in EtOAc) to give the title compound (130 mg, 91%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[NH2:26][CH2:27][CH:28]([C:30]1[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=1)[OH:29]>>[CH2:1]([O:3][C:4](=[O:25])[C:5](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][CH:21]([NH:26][CH2:27][CH:28]([OH:29])[C:30]3[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=3)[CH2:22][CH2:23]2)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: CCOC(=O)C(=Cc1ccc(N2CCC(=O)CC2)cc1)C(=O)OCC
Product: CCOC(=O)C(=Cc1ccc(N2CCC(NCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1)C(=O)OCC

Procedure:
The title compound was prepared from 2-[4-(4-oxo-piperidine-1-yl)-benzylidene]-malonic acid diethyl ester (which was obtained in Example 153) and N-[5-(-2-amino-1-hydroxy- ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 180 as a yellowish solid; mp >80° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.21 (t, J=7.0 Hz, 3H), 1.23 (t, J=7.0 Hz, 3H), 1.75-1.95 (m, 2H), 2.50-3.50 (m, 7H), 2.92 (s, 3H), 3.75-3.90 (m, 2H), 4.21 (q, J=7.0 Hz, 2H), 4.31 (q, J=7.0 Hz, 2H), 4.47 (dd, J=8.0, 4.2 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.94 (d, J=9.0 Hz, 2H), 7.00 (dd, J=8.2, 2.0 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.33 (d, J=9.0 Hz, 2H), 7.52 (s, 1H); MS (ES) m/z: 576.1 (MH+); HRMS Calcd. for C28H38N3O8S(MH+): 576.2374. Found: 576.2375.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:22][C@H:23]2[C@@H:27]3[O:28][C:29]([CH3:32])([CH3:31])[O:30][C@@H:26]3[C@@H:25]([CH2:33][OH:34])[CH2:24]2)=[N:12][C:13](S(C)(=O)=O)=[N:14][C:15]=1[O:16][CH3:17].[OH-].[NH4+:36].O>O1CCOCC1>[NH2:36][C:13]1[N:12]=[C:11]([NH:22][C@H:23]2[C@@H:27]3[O:28][C:29]([CH3:32])([CH3:31])[O:30][C@@H:26]3[C@@H:25]([CH2:33][OH:34])[CH2:24]2)[C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[C:15]([O:16][CH3:17])[N:14]=1
Reactant: [NH4+]
Reactant: COc1nc(S(C)(=O)=O)nc(N[C@@H]2C[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c1-c1nc2ccccc2s1
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1nc(N)nc(N[C@@H]2C[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c1-c1nc2ccccc2s1
Temperature: 80 °C

Procedure:
A mixture of Compound 8 (1.36 g, 2.458 mmol) and ammonium hydroxide (25 ml, 180 mmol) in 1,4-dioxane (25 ml) was heated in a sealed tube at 80° C. for a period of 1 hr. The solution was cooled to room temperature, and water was added. The aqueous layer was extracted twice by dichloromethane and the combined organic extracts were dried (Na2SO4), filtered and concentrated under vacuum. The residue was then purified by column chromatrography on silica gel (EtOAc/hexanes) to give the title compound. 1H NMR (CDCl3) δ 10.65-10.64 (m, 1H), 7.89-7.43 (m, 2H), 7.43-7.39 (m, 1H), 7.30-7.26 (m, 1H), 4.99 (s, 2H), 4.71-4.69 (m, 1H), 4.63-4.58 (m, 2H), 4.08 (s, 3H), 3.90-3.86 (m, 2H), 2.59-2.54 (m, 1H), 2.47-2.46 (m, 1H), 2.17 (s, 1H), 1.84-1.76 (m, 2H), 1.54 (s, 3H), 1.27 (s, 3H); LCMS 2.01 min, 444 (M+H)
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[O:13][C:10]3([CH2:12][CH2:11]3)[CH2:9][NH:8][C:7]=2[CH:14]=1.[N:17]([O-])=O.[Na+]>C(O)(=O)C.CO.O>[NH2:17][N:8]1[C:7]2[CH:14]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=[CH:5][C:6]=2[O:13][C:10]2([CH2:11][CH2:12]2)[CH2:9]1
Reactant: FC(F)(F)c1ccc2c(c1)NCC1(CC1)O2
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: NN1CC2(CC2)Oc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
3,4-Dihydro-6-trifluoromethyl-2H-1,4-benzoxazine-2-spiro-cyclopropane (930 mg) was dissolved in 0.6 ml of acetic acid and 10 ml of methanol. Added dropwise to the resulting solution was a solution of 616 mg of sodium nitrite in 2 ml of water. The reaction mixture was stirred for 3 hours at room temperature, poured into water and then extracted with chloroform. The organic layer was washed with saturate saline and then dried over anhydrous magnesium sulfate. The chloroform was distilled off and the residue was dissolved in 1.1 ml of acetic acid and 12 ml of ethanol. Zinc powder (1.13 g) was added little by little, followed by stirring for 2 hours at room temperature. Insoluble substance was filtered off and the filtrate was concentrated. The residue was dissolved in chloroform. The solution so formed was successively washed with a 10% aqueous solution of sodium hydroxide, water and saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel chromatography, whereby 707 mg of the title compound were obtained (yield 71%).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[Br:15][CH2:16][CH2:17]Br.[K+].[Br-]>>[Br-:15].[Br:15][CH2:16][CH2:17][C:1]1[C:14]2[C:5](=[NH+:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1
Reactant: BrCCBr
Reactant: c1ccc2c(c1)cnc1ccccc12
Agent: [Br-]
Agent: [K+]
Product: BrCCc1cccc2[nH+]cc3ccccc3c12
Temperature: 110 °C
Reaction time: 72 h
Yield: 95 %

Procedure:
Phenanthridine (5.44 g; 30.4 mmol) was dissolved in 1,2-Dibromoethane (114.2 g; 52 ml; 608 mmol) and stirred at 110° C. for three days. During that time, a white precipitate was formed and was filtered off every 12 hours. After each filtration, the precipitate was rinsed with an additional 5 ml of 1,2-Dibromoethane and the mother liquor was stirred at 90° C. until the next filtration. The reaction was complete after ca. three days when no more precipitate formed. The filtrates were combined and washed thoroughly with ether and with ethyl acetate to give 2 (7.92 g; 21.6 mmol) as a beige powder in a 95% yield; mp: 234-235° C. (dec.); 1H NMR (D2O, 400 MHz): δ 9.81 (s, 1H), 8.72 (d, 1H, J=7.2 Hz), 8.63 (d, 1H, J=7.2 Hz), 8.37 (d, 1H, J=7.2 Hz), 8.26 (d, 1H, J=7.2 Hz), 8.18 (t, 1H, J=7.2 Hz), 7.98 (t, 1H, J=7.2 Hz), 7.90 (m, 2H), 5.37 (t, 2H, J=5.8 Hz), 4.05 (t, 2H, J=5.8 Hz); 13C NMR (D2O, 100 MHz): δ 155.27 (CH), 139.03 (CH), 135.59 (C), 133.18 (CH), 132.78 (C), 132.58 (CH), 130.85 (CH), 130.72 (CH), 126.57 (C), 125.13 (CH), 123.32 (C), 123.00 (CH), 118.91 (CH), 58.87 (CH2), 29.41 (CH2); IR (KBr, cm−1): 2947(w), 1620(m), 763(s), 717(m); MS (ES): 288.1 (M−Br) (100), 206.2 (8); Anal. Calcd for C15H13NBr2: C, 49.32; H, 3.59; N, 3.84. Found: C, 49.15; H, 3.48; N, 3.76.
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:13][O:14][C:15]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:16]=1[CH2:17][NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)=[O:28]>ClCCl>[C:1]([CH2:3][C:4]([N:18]([CH2:17][C:16]1[CH:36]=[CH:37][C:38]([O:40][CH3:41])=[CH:39][C:15]=1[O:14][CH3:13])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[C:27](=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)=[O:5])#[N:2]
Reactant: N#CCC(=O)O
Reactant: COc1ccc(CNc2ccc(OC)cc2C(=O)c2cccc(F)c2)c(OC)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)CC#N)c2ccc(OC)cc2C(=O)c2cccc(F)c2)c(OC)c1

Procedure:
To a solution of cyanoacetic acid (43.0 mg, 0.511 mmol) in 1 mL of dichloromethane at room temperature was added PCl5 (106 mg, 0.511 mmol). The mixture was heated to reflux for 10 minutes. A solution of {2-[(2,4-dimethoxybenzyl)amino]-5-methoxyphenyl}(3-fluorophenyl)methanone (101 mg, 0.255 mmol) in 1 mL dichloromethane was added, and the reaction was refluxed for an additional 1.5 hours. The reaction was partitioned between EtOAc and saturated NaHCO3 solution, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The titled product was isolated as a yellow foam (117 mg, 99% yield) which was used in the next step without further purification. Proton NMR for the product was consistent with the titled compound. ESI+ MS: 463.2 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.CN(C=O)C>[CH2:22]([NH:29][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Oxalyl chloride (132 μL, 1.5 mmol) was added over a 10 minute period to a mixture of 3-phenylbenzoic acid (200 mg, 1 mmol) dissolved in a mixture THF/DMF (3.5 mL/58 μL). After the addition, the reaction was stirred at room temperature for 2.5 hours. Benzylamine (268 μL, 2.5 mmol) was then added into half of the acid chloride solution at 0° C. The reaction mixture was then stirred at room temperature for 18 hours. The reaction mixture was concentrated and water was added to the residue. The aqueous phase was extracted 3 times with CH2Cl2 and the combined organic layers were washed with 2N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. Diethyl ether was added to the residue and a white solid precipitated which was collected by filtration and rinsed with a small amount of diethyl ether. The white solid was then dried under vacuum (105 mg, 73%). NMR 1H (ppm, CDCl3): 8.01 (s, 1H), 7.72 (t, J3=7.89 Hz, 2H), 7.58 (d, J3=7.14 Hz, 2H), 7.49-7.24 (m, 9H), 6.57 (br. s., 1H), 4.64 (d, J3=5.29 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)=[O:5].[C:18]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])([CH3:21])([CH3:20])[CH3:19].C(OCC)C>CO.C(OCC)(=O)C>[NH:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH:23]=1
Reactant: CC(C)(C)c1cccc(C(=O)Cl)c1
Reactant: Nc1ccccc1C(=O)NCCc1ncc[nH]1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)c1cccc(C(=O)Nc2ccccc2C(=O)NCCc2ncc[nH]2)c1

Procedure:
The titled compound was prepared substantially in accordance with the method detailed in Example 46 using 2.50 g (0.0107 mol) of 2-amino-N-[2-(1H-imidazol-2-yl)ethyl]benzamide and 4.20 g (0.0213 mol) of meta-t-butylbenzoyl chloride with the exception that, after reducing the organic layer to dryness the resulting residue was dissolved in a 1:7 methanol/ethyl acetate solution. The resulting solution was concentrated until crystals began to form and then diethyl ether was added. The resulting solution was cooled and 2.90 g of the desired titled compound were recovered by filtration (m.p. 205°-210° C.).
Reaction SMILES: C(ON=[C:5]([C:14]1[C:23]([CH3:24])=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][S:21]2(=[O:26])=[O:25])=[CH:16][CH:15]=1)[C:6]1[C:7]([CH3:13])=[N:8][N:9]([CH3:12])[C:10]=1[OH:11])C.[OH:27]C1NN=CC=1>>[CH3:12][N:9]1[C:10]([OH:11])=[C:6]([C:5]([C:14]2[C:23]([CH3:24])=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][S:21]3(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:27])[C:7]([CH3:13])=[N:8]1
Reactant: CCON=C(c1ccc2c(c1C)S(=O)(=O)CCC2)c1c(C)nn(C)c1O
Reactant: Oc1ccn[nH]1
Product: Cc1nn(C)c(O)c1C(=O)c1ccc2c(c1C)S(=O)(=O)CCC2

Procedure:
Yield: 0.35 g (89% of theory) of 7-(1,3 dimethyl-5-hydroxypyrazole-4-carbonyl)-8-methyl-1,1-dioxo-thio-chroman O-ethyloxime)-5-hydroxypyrazole; 1H NMR (CDCl3): δ [ppm]=9.90 (1H, bs), 8.12 (1H, d), 7.35 (1H, d), 4.32 (2H, q), 3.65 (3H, s), 3.44 (4H, m), 2.70 (3H, s), 1.73 (3H, s), 1.38 (3H, tr).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.[CH3:27][C:28]([CH3:30])=[O:29].[NH4+].[Cl-]>C1COCC1>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:28]([OH:29])([CH3:30])[CH3:27])[CH:21]=1
Reactant: CC(C)=O
Reactant: Fc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(Br)ccc1F
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropyl amine (57.3 ml, 402 mmol) in THF (500 ml) was added under argon a 1.6 M solution of nBuLi in hexane (260 ml, 416 mmol) below −50° C. After stirring for 30 min at −75° C., 4-bromo-1-fluoro benzene (31.1 ml, 277 mmol) was added while keeping the temperature below −70° C. After stirring for 2 h at −75° C., acetone (41.2 ml, 554 mmol) was added below −65° C. and the reaction mixture was stirred for 1 h at −75° C., warmed up to −50° C. and poured onto 10% aqueous NH4Cl solution. The mixture was extracted with TBME, organic phases were washed with aqueous KHSO4 solution, saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated. The crude product was crystallized from hexane to provide the title compound as white crystals: TLC (hexane-EtOAc 3:1): Rf=0.45; UPLC RtH5=1.045 min; 1H NMR (360 MHz, CDCl3): δ 7.74 (dd, 1H), 7.36 (m, 1H), 6.93 (dd, 1H), 2.04 (d, 1H), 1.63 (s, 6H).