Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:22](/[CH:31]=[CH:32]/[C:33]([O:35]CC)=[O:34])=[CH:21]2)=[CH:17][CH:16]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:22](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])=[CH:21]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(/C=C/C(=O)O)c(-c3ccccc3)c2)cc1
Yield: 91.8 %

Procedure:
A mixture of ethyl(E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propenoate (600 mg), a 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at 60° C. for 3 hours and 1N hydrochloric acid (7 ml) was added, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The crystals obtained were collected by filtration to yield (E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propenoic acid (521 mg, yield: 92%). This was recrystallized from ethyl acetate-hexane. Melting point: 154–155° C.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[N:10]=2)=CC=1>CO.[Pd]>[F:18][C:15]([F:16])([F:17])[C:13]1[CH:12]=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:26])([F:28])[F:27])[N:10]=[C:9]([NH2:8])[CH:14]=1
Reactant: COc1ccc(CNc2cc(C(F)(F)F)cc(-c3ccccc3C(F)(F)F)n2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(F)(F)F)cc(-c2ccccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (4-methoxy-benzyl)-[4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amine (1.00 g, 2.34 mmol, prepared as described in STEP B above) in MeOH (20 mL) was added, the flask was flushed well with Ar, Pd/C (500 mg, 0.235 mmol, 5% on carbon) was added, and the flask was flushed with Ar and fitted with an H2 balloon. The resulting mixture stirred at room temperature for 4 h. The balloon was removed, the flask was flushed again with Ar, the mixture was filtered through diatomaceous earth, and the filter cake was washed well with MeOH. The filtrate was concentrated in vacuo to yield 4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine as a tan solid. 1H-NMR (400 MHz, CDCl3) δ: 7.81 (d, J=7.6 Hz, 1H), 7.64-7.76 (m, 2H), 7.59 (d, J=7.1 Hz, 1H), 7.25 (s, 1H), 6.79 (s, 1H), 3.22 (br. s., 4H).
Reaction SMILES: C([O:8][C:9](=[O:35])[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([C:22](=[O:24])[CH3:23])[CH2:14][C@H:13]([NH:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:12]1=[O:34])C1C=CC=CC=1>CO.[Pd]>[O:34]=[C:12]1[N:11]([CH2:10][C:9]([OH:35])=[O:8])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([C:22](=[O:24])[CH3:23])[CH2:14][CH:13]1[NH:25][C:26](=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(=O)N1C[C@H](NC(=O)c2ccccc2)C(=O)N(CC(=O)OCc2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CC(NC(=O)c2ccccc2)C(=O)N(CC(=O)O)c2ccccc21
Reaction time: 0.5 h

Procedure:
A mixture of (3S)-2-oxo-3-(benzoylamino)-5-acetyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-acetic acid benzyl ester (602d; 510 mg, 1.08 mmol) and 5% Pd/C (250 mg) in MeOH (10 ml) stirred under H2 (1 atm) for 0.5 h. The react was filtered and concentrated in vacuo 410 mg of 603d as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([C:23]3[NH:27][CH:26]=[N:25][CH:24]=3)=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[C:12]=2[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.C(Cl)Cl.[C:37](OC(=O)C)(=[O:39])[CH3:38].CO.C(=O)(O)[O-].[Na+]>O>[C:13]([C:12]1[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[C:10]([C:23]2[NH:27][CH:26]=[N:25][CH:24]=2)[S:9][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:37](=[O:39])[CH3:38])[CH:7]=1)#[N:14]
Reactant: N#Cc1c(-c2ccnc(N)c2)sc(-c2cnc[nH]2)c1-c1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)Nc1cc(-c2sc(-c3cnc[nH]3)c(-c3ccc(Cl)cc3Cl)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of 2-(2-aminopyridin-4-yl)-4-(2,4-dichlorophenyl)-5-(1H-imidazol-5-yl)thiophene-3-carbonitrile (16.3 mg, 0.0395 mmol) in Pyridine (130.5 mg, 1.650 mmol) and DCM (1.0 mL, 16 mmol) was added acetic anhydride (108.2 mg, 1.060 mmol). The mixture was stirred at rt overnight. The solvent was evaporated and the residue was dissolved in MeOH (4 mL, 90 mmol). Sodium bicarbonate (0.5 g, 6 mmol) was added and followed by water. The mixture was stirred for 30 min. The mixture was concentrated and the residue was dissolved in EtOAc. The organic phase was washed with water and the organic layer was separated and dried over sodium sulfate. The crude product was obtained by evaporation and the purified by column chromatography to afford pure title compound as a yellow solid (12.4 mg, 69.4%). LC/MS (AA) ES+ 454, 456; ES− 452, 454. 1H-NMR (DMSO-d6, 300 MHz) δ: 12.63-12.07 (1H, br), 10.79-10.74 (1H, s), 8.57 (1H, s), 8.48 (1H, d, J=5.2 Hz), 7.94 (1H, d, J=1.89 Hz), 7.74 (1H, d, J=0.92 Hz), 7.62 (1H, s), 7.64 (1H, d, J=1.98 Hz), 7.51 (1H, dd, J=5.3, 1.7 Hz), 6.30 (1H, d, J=0.94 Hz), 2.13 (3H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14](Cl)[C:13]([F:17])=[CH:12][C:3]=1[C:4]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5].[F-:18].[K+]>>[Cl:1][C:2]1[CH:15]=[C:14]([F:18])[C:13]([F:17])=[CH:12][C:3]=1[C:4]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5]
Reactant: [F-]
Reactant: O=C(OCC(F)(F)F)c1cc(F)c(Cl)cc1Cl
Agent: [K+]
Product: O=C(OCC(F)(F)F)c1cc(F)c(F)cc1Cl
Yield: 87.2 %

Procedure:
Into a 1 l glass reactor equipped with a condenser, 291 g (1 mol) of 2,2,2-trifluoroethyl 2,4-dichloro-5-fluorobenzoate, 87 g (1.5 mol) of spray dried potassium fluoride and 500 g of sulforane were charged and reacted at 180° C. for 9 hours under vigorous stirring. After cooling, the inorganic salt was removed by filtration, and the filtrate was distilled under reduced pressure to obtain 239.4 g (yield: 87.2%) of 2,2,2-trifluoroethyl 2-chloro-4,5-difluorobenzoate.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([N+:14]([O-])=O)[C:8]=2[N:7]=[C:6]1[C:17]1[C:22](OC)=[CH:21][CH:20]=[CH:19][C:18]=1[F:25].[C:31](O)(=[O:33])C>Cl>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([NH2:14])[C:8]=2[N:7]=[C:6]1[C:17]1[CH:22]=[CH:21][C:20]([O:33][CH3:31])=[CH:19][C:18]=1[F:25]
Reactant: CC(=O)O
Reactant: COc1cccc(F)c1-c1nc2c([N+](=O)[O-])cccc2n1Cc1c(F)cccc1F
Agent: Cl
Product: COc1ccc(-c2nc3c(N)cccc3n2Cc2c(F)cccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To 1-(2,6-difluorobenzyl)-2-(2-fluoro-4-methoxylphenyl)-4-nitrobenzimidazole (Example 50) (2.00 g, 4.98 mmol) dissolved in acetic acid (20 mL) was added SnCl2x2H2O (9.02 g) dissolved in concentrated HCl (8 mL). After stirring for 30 min at room temperature, the mixture was concentrated. The residue was diluted with CH2Cl2 and washed with NaHCO3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (Na2SO4), filtered, and evaporated. The crude product was recrystallized from methanol to give 3.26 g of white crystals, (8.78 mmol, 70% yield). M.p. 200-202° C. 1H-NMR (200 MHz, CD2Cl2) δ7.45 (m, 1H, H4′), 7.22 (m, 1H, H4″), 7.05 (dd, J=7.8, 7.6 Hz, 1H, H6), 6.85-6.72 (m, 5H, H3″,5″), 6.50 (dd, J=7.7, 1.0 Hz, 1H, H5), 5.21 (d, J=5.4 Hz, 2H, CH2PhF2 (rotamers)), 4.34 (br, 2H, NH2), 3.72 (s, 3H, OCH3).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH2:8][CH2:9][CH3:10])[NH:5][C:6]=1I.S([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[I:1][C:2]1[N:3]=[C:4]([CH2:8][CH2:9][CH3:10])[NH:5][CH:6]=1
Reactant: CCCc1nc(I)c(I)[nH]1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1nc(I)c[nH]1
Yield: 88.2 %

Procedure:
[step 1] 2-Propylimidazole (3.0 g, 27.3 mmol) was dissolved in dioxane/water (55 mL/55 mL), sodium hydrogen carbonate (8.67 g, 81.8 mmol) and iodine (15.0 g, 59.9 mmol) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4,5-diiodo-2-propylimidazole (7.09 g, 72%). [step 2] 4,5-Diiodo-2-propylimidazole (3.0 g, 8.31 mmol) obtained in Reference Example A16, step 1 was dissolved in ethanol/water (60 mL/60 mL), sodium sulfite (8.40 g, 66.5 mmol) was added, and the mixture was heated under reflux overnight. After completion of the reaction, the mixture was extracted 3 times with chloroform. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4-iodo-2-propylimidazole (1.73 g, 88%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:18][CH:19]=2)[O:14][CH2:13][C:12]1([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=1)[CH3:25].[F:36][C:37]([F:49])([C:45]([F:48])([F:47])[F:46])[CH2:38][CH2:39][CH2:40]S(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:24][O:23][CH2:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:40][CH2:39][CH2:38][C:37]([F:49])([F:36])[C:45]([F:48])([F:47])[F:46])[C:12]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:30][CH:31]=3)([CH3:25])[CH2:13][O:14]2)=[CH:19][CH:18]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCN)cc1
Reactant: O=S(=O)(Cl)CCCC(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCNCCCC(F)(F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
4-(9-aminononyl)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (82.3 mg, 0.17 mmol) was dissolved in 5 ml of methylenechloride under argon atmosphere, which was then cooled down to 0° C. 4,4,5,5,5-pentafluoropentylsulfonyl chloride (110.4 mg, 0.42 mmol) in 1 ml of methylene chloride and triethylamine (0.07 ml, 0.5 mmol) was added thereto, and the mixture was stirred at the same temperature for 30 minutes. The reaction was quenched with water, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subject to flash chromatography in silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (81 mg, yield: 67%) as a colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C@H:19]([CH3:20])[C:18](=O)[NH:17][C@@H:16]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[CH2:15][C@@H:16]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:17][CH2:18][C@@H:19]1[CH3:20])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[C@@H]1C(=O)N[C@@H](Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CN[C@H](Cc2ccccc2)CN1Cc1ccccc1
Temperature: 0 °C

Procedure:
Lithium aluminum hydride (1 M in THF, 4.8 ml, 4.8 mmol) was added dropwise over 30 min to a solution of (3S,6R)-1,3-dibenzyl-6-methylpiperazine-2,5-dione (0.39 g, 1.2 mmol) in THF (7.5 ml) stirring at 0° C. After stirring at 65° C. for 1 day, the reaction was allowed to cool to room temperature and was slowly quenched with water (0.34 ml). Sodium hydroxide (1 N, 0.68 ml) and then water (0.51 ml) were added and the gelatinous solid was filtered rinsing with THF. The filtrate was evaporated in vacuo and the residue transferred to a separatory funnel with EtOAc. Washing the organic layer with brine and drying with MgSO4 afforded product (0.40 g) after evaporation of the solvent. This was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18](O)=[O:19])=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[N:3]=1.[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][NH:29]1>>[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][N:29]1[C:18]([C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][CH2:17][N:8]([C:6]3[CH:5]=[C:4]([N:21]4[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]4)[N:3]=[C:2]([NH2:1])[N:7]=3)[CH2:9]2)=[CH:14][CH:13]=1)=[O:19]
Reactant: c1ccc2c(c1)CNC2
Reactant: CN1CCN(c2cc(N3CCc4ccc(C(=O)O)cc4C3)nc(N)n2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(C(=O)N5Cc6ccccc6C5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid and isoindoline (Aldrich Cat. No. 515574). LCMS (M+H)+: m/z=470.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH2:14][CH2:15][F:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[NH2:21][CH2:22][CH:23]1[CH:27]([CH3:28])[CH2:26][NH:25][CH2:24]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:21][CH2:22][CH:23]1[CH:27]([CH3:28])[CH2:26][N:25]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:20])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]3[CH2:14][CH2:15][F:16])=[CH:3][C:2]=2[F:1])[CH2:24]1
Reactant: O=C(O)c1cn(CCF)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC1CNCC1CN
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(CCF)c3c2F)CC1CN
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
A mixture of 6,7,8-trifluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-aminomethyl-4-methylpyrrolidine (0.21 g) and DBU (0.26 g) was refluxed for an hour and then stirred at room temperature for 5 hours. The resulting precipitate was collected by filtration and washed with ether to give the title compound (0.45 g) as pale yellow powder, mp 228°-232° C.
Reaction SMILES: ClC1C=CC2NC(C3C=CC(N)=CC=3)=NC=2C=1.C[O:19][C:20](=[O:49])[CH:21]([CH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)[CH2:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[NH:36][C:35]3[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:34]=3[N:33]=2)=[CH:28][CH:27]=1)=[O:24]>>[Cl:41][C:39]1[CH:38]=[CH:37][C:35]2[NH:36][C:32]([C:29]3[CH:28]=[CH:27][C:26]([NH:25][C:23](=[O:24])[CH2:22][CH:21]([CH2:42][CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[C:20]([OH:49])=[O:19])=[CH:31][CH:30]=3)=[N:33][C:34]=2[CH:40]=1
Reactant: COC(=O)C(CC(=O)Nc1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1)CC1CCCCC1
Agent: Nc1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1
Product: O=C(CC(CC1CCCCC1)C(=O)O)Nc1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1

Procedure:
This compound was prepared by the procedure described in Example 1 part (b) from N-[4-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-2-cyclohexylmethyl-succinamic acid methyl ester, and was isolated as an HCl salt.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH:12]([CH3:24])[CH2:13][CH2:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]1)=[O:16].C(N(CC)CC)C.O>C(#N)C>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]=1[S:1][CH:12]([CH3:24])[CH2:13][CH2:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]1)=[O:16]
Reactant: CC(Br)CCC(=O)N1CCC(C)CC1
Reactant: Sc1nc2ccccc2[nH]1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC1CCN(C(=O)CCC(C)Sc2nc3ccccc3[nH]2)CC1
Yield: 21.3 %

Procedure:
0.15 g of 2-mercaptobenzimidazole and 0.26 g of 1-(4-bromovaleroyl)-4-methylpiperidin were suspended in acetonitrile, and the suspension was added with 0.17 ml of triethylamine and refluxed for 7 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:methylene chloride=1:10) to obtain 0.07 g of the title compound as oil (yield: 21%).
Reaction SMILES: C([O:8][C:9](=[O:72])[C@H:10]([CH2:68][CH:69]([CH3:71])[CH3:70])[NH:11]C(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC1C=CC=CC=1C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(OC(C)(C)C)=O)C1C=CC=CC=1>CN(C)C=O.[Pd]>[NH2:11][C@H:10]([C:9]([OH:72])=[O:8])[CH2:68][CH:69]([CH3:71])[CH3:70]
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
A solution of 6.8 g (6.75 mmol) of N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in 200 ml of dimethylformamide was hydrogenated over 600 mg of 10% palladium/carbon for 1 hour. The catalyst was removed by filtration and the filtrate was evaporated to give 15 g of crude product which was chromatographed on silica gel using 10-15% methanol in dichloromethane for the elution to give 6 g of N-N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine as a white solid of melting point 235-236° C.; MS: m/e 918.4 [M+H]+, m/e 940.3 [M+Na]+.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[CH2:11]Br.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:14]([N:21]1[CH2:11][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][C:6]=2[Cl:10])[C:3]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cccc(Cl)c1CBr
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2cccc(Cl)c2CN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
A mixture of 2-bromomethyl-3-chloro-benzoic acid methyl ester (0.132 g, 0.5 mmol), benzylamine (0.065 mL, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-4-chloro-2,3-dihydro-isoindol-1-one (0.129 g, 100%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.24 (s, 2H), 4.70 (s, 2H), 7.27-7.48 (m, 7H), 7.80 (d, 1H). GC-MS: m/z 257 (M)+, 180 (M−77)+.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[CH2:12]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(Cn2cnc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A solution of 4.96 g (42 mmol) of benzimidazole in 250 ml of tetrahydrofuran was cooled under N2 atmosphere to 0° C. and treated sequentially with 2.12 g (44 mmol) of sodium hydride (50% dispersion in oil) and 5.0 ml (42 mmol) of benzyl bromide. The resulting suspension was stirred at ambient temperature for 16 h, washed sequentially with water and saturated brine, dried over MgSO4, and concentrated. The resulting oil was taken up in 75 ml of ethyl acetate, triturated with 300 ml of hexane, and filtered. The mother liquor was concentrated and filtered, and the combined solids were dried in vacuo at 50° C. to give 7.00 g (80%) of the desired compound. 1H NMR (CDCl3) δ 5.38 (s,2H), 7.2 (m,2H), 7.3-7.4 (m,6H), 7.83 (br d,1H), 7.96 (br s,1H).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=3[F:25])=[C:13]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[N:12]=2)[N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([CH:39]=[CH:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])O1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:13]1[N:12]=[C:11]([CH2:10][O:9][C:6]2[N:5]=[CH:4][N:3]=[C:2](/[CH:39]=[CH:40]/[C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:7]=2[F:8])[CH:16]=[CH:15][C:14]=1[C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[F:25]
Reactant: CCOC(=O)C=CB1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(F)c(-c2ccc(COc3ncnc(Cl)c3F)nc2CC(C)(C)C)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ncnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1F
Temperature: 90 °C
Reaction time: 6 h
Yield: 26.7 %

Procedure:
To a solution of 4-chloro-6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-fluoropyrimidine (930 mg) in DMF (10 mL) were added ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (970 mg), tris(dibenzylideneacetone)dipalladium (250 mg), cesium carbonate (1.00 g) and dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (205 mg), and the mixture was stirred at 90° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (285 mg) as a white solid.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1>C(O)(=O)C>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])=[C:15]([F:20])[CH:14]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccc(Br)cc1F
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Br)cc1F
Reaction time: 0.5 h

Procedure:
A solution of 10 parts of 3,4,5,6-tetrahydrophthalic anhydride in 100 parts of glacial acetic acid was treated in one portion with 11 parts of 4-bromo-2-fluoroaniline and was stirred for 30 minutes. The reaction mixture was refluxed for 16 hours and then poured over 200 parts ice. The resulting purple crystals were filtered and recrystallized from 100 parts methanol at -40° C. to yield 13 parts of pink plates of 2-(4-bromo-2-fluorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione melting at 102.0°-102.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[CH:6]=1)[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=3)[C:14]=2[CH3:24])[CH:6]=1)[CH3:2]
Reactant: CCCn1cc(Br)cn1
Reactant: CCOC(=O)c1cc(F)cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Product: CCCn1cc(-n2c(C)c(Sc3cc(F)cc(C(=O)OCC)c3)c3ccc(Cl)c(F)c32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-Chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-5-fluoro-benzoic acid ethyl ester and 4-bromo-1-propyl-1H-pyrazole.