Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[F:8][C:9]1[CH:10]=[C:11]([C:19]2[C:20]([CH3:34])=[CH:21][C:22]([O:25][CH2:26][C:27]([CH3:33])([CH3:32])[C:28]([O:30][CH3:31])=[O:29])=[N:23][CH:24]=2)[CH:12]=[CH:13][C:14]=1[C:15](=[NH:18])[NH:16]O>C(O)(=O)C>[C:1]([OH:4])(=[O:3])[CH3:2].[C:15]([C:14]1[CH:13]=[CH:12][C:11]([C:19]2[C:20]([CH3:34])=[CH:21][C:22]([O:25][CH2:26][C:27]([CH3:32])([CH3:33])[C:28]([O:30][CH3:31])=[O:29])=[N:23][CH:24]=2)=[CH:10][C:9]=1[F:8])(=[NH:16])[NH2:18]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(C(=N)NO)c(F)c2)cn1
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(C(=N)N)c(F)c2)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Acetic anhydride (1.62 mL) was added to an acetic acid (10 mL) solution containing methyl 3-({5-[3-fluoro-4-(N-hydroxycarbamimidoyl)phenyl]-4-methylpyridin-2-yl}-oxy)-2,2-dimethylpropanoate (3.65 g), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (30 mL), 10% palladium carbon (50%, 365 mg) was added to the resulting solution, and the mixture was stirred under hydrogen atmosphere at room temperature for 13 hours. The catalyst was filtered off by using a membrane filter, and the filtrate was concentrated under reduced pressure. Ether was added to the obtained residue, and the precipitated solid was collected by filtration, washed with ether and dried to obtain methyl 3-{[5-(4-carbamimidoyl-3-fluorophenyl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate acetic acid salt (2.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20]
Reactant: Cc1cc(Cl)c(N2C(=O)C3=CCCCN3C2=O)cc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(Cl)c(N2C(=O)C3=CCCCN3C2=O)cc1OC1CCCC1
Yield: 67.4 %

Procedure:
An acetonitrile (10 mL) solution of 2-(2-chloro-4-methyl-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.34 g, 1.11 mmol), cyclopentylbromide (0.13 mL, 1.22 mmol) and potassium carbonate (0.15 g, 1.11 mmol) was stirred for 4 hours under reflux. A saturated ammonium chloride solution (20 mL) was added to the resulting mixture and the organic layer was separated. The aqueous layer was extracted with diethyl ether (10 mL×2 times), and the organic layer combined was washed with a saturated sodium chloride solution (40 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane=1/2) to obtain a white solid of 2-(2-chloro-5-cyclopentyloxy-4-methylphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.27 g, yield:64.3%).
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.[SH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C[O-].[Na+].O>CO>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][S:13][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1)[CH3:19]
Reactant: CCOC(=O)CS
Reactant: Clc1nc(-c2ccccc2)no1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CSc1nc(-c2ccccc2)no1
Reaction time: 3 h
Yield: 75 %

Procedure:
5-chloro-3-phenyl-1,2,4-oxadiazole (36 parts) was added portionwise to a solution of ethyl mercaptoacetate (24 parts) and sodium methoxide (11 parts) in methanol (500 parts). The temperature rose to about 50° C. and the mixture was allowed to stand for three hours. The product was poured into an excess of cold water, and extracted with benzene, washed with water and the solvent then evaporated off. Recrystallisation gave ethyl(3-phenyl-1,2,4-oxadiazol-5-ylthio)acetate (40 parts, 75% yield), melting point 50-52° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl.[NH2:21]O.[OH-].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[O:18][N:21]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc(-c2cc(-c3ccc(Br)cc3)on2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a 250 ml round bottom flask, 4 g (10.4 mmol) of [2] was dissolved in 100 ml dry dioxane and heated to reflux, then 3.0 g (43.2 mmol) hydroxylamine hydrogen chloride in 10 ml water and 5 ml (25 mmol) 5 N NaOH was then dropped into the refluxing mixture. After 12 hours, the reaction mixture was cooled down to room temperature, and the solvent was removed in vacuo. The product was recrystallized from ethanol. Characterization. Yield: 3.41 g (85%). M.P. 218.5-219.5° C. 1H NMR (300 MHz, CDCl3, 20° C., δ): 7.78 (d, 2H, ArH), 7.74 (d 2H, Ar′H), 7.66 (d, 2H, ArH), 7.62 (d, 2H, Ar′H), 6.82 (s, 1H, isoxazole proton). EI-MS: 379 (M+), 224, 183, 155.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2C(=O)C(F)(F)F)=[CH:4][CH:3]=1.[CH3:18][C:19]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=2)[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].Cl>>[F:35][C:30]1[CH:29]=[C:28]([C:26]2[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH2:7][CH2:8][NH:9]4)=[CH:4][CH:3]=3)=[O:22])=[C:19]([CH3:18])[N:27]=2)[CH:33]=[CH:32][C:31]=1[F:34]
Reactant: Cc1nc(-c2ccc(F)c(F)c2)ccc1C(=O)O
Reactant: Nc1ccc2c(c1)N(C(=O)C(F)(F)F)CCC2
Agent: Cl
Product: Cc1nc(-c2ccc(F)c(F)c2)ccc1C(=O)Nc1ccc2c(c1)NCCC2

Procedure:
Using the procedure outlined in Example 38, the title compound was prepared from 7-amino-1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline (D5) (73 mg, 0.30 mmol) and 2-methyl-6-(3,4-difluorophenyl)nicotinic acid (D108) (82 mg, 0.33 mmol) then converted to the HCl salt as a buff solid. 1H NMR (400 MHz, DMSO) δ (ppm): 8.23 (dd, 1H), 8.04 (m, 3H), 7.87 (d, 1H), 7.63 (d, 1H), 7.57 (m, 1H), 7.29 (d, 1H), 3.34 (m, 2H), 2.80 (m, 2H), 2.67 (s, 3H), 2.02 (m, 2H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14](I)[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3].[C:23]1([CH2:29][CH2:30][CH:31]=[CH:32][CH3:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14]([C:31](=[CH:30][CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:32][CH3:33])[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3]
Reactant: CC=CCCc1ccccc1
Reactant: CCCOc1ccccc1-c1nc2c(I)cccc2c(=O)[nH]1
Product: CCCOc1ccccc1-c1nc2c(C(=CCc3ccccc3)CC)cccc2c(=O)[nH]1
Yield: 64.6 %

Procedure:
The title compounds are prepared analogously to the method of Example 1, starting with the compound from Example III and 5-phenyl-2-pentene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:19][C:20]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[CH:21][CH:22]=2)[CH:15]=[C:14]([O:28][C@@H:29]([CH3:33])[CH2:30][O:31][CH3:32])[CH:13]=1)[C:5](O)=[O:6].Cl.CN.[CH3:37][N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:19][C:20]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[CH:21][CH:22]=2)[CH:15]=[C:14]([O:28][C@@H:29]([CH3:33])[CH2:30][O:31][CH3:32])[CH:13]=1)[C:5]([NH:38][CH3:37])=[O:6]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(Oc2cc(O[C@@H](C)COC)cc(-c3ccc(-c4nccs4)[nH]3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.2 %

Procedure:
3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoic acid (40.0 mg, 0.163 mmol) synthesized in Example (44a) was dissolved in tetrahydrofuran (5 mL), and methylamine hydrochloride (17.3 mg, 0.256 mmol), HATU (64.5 mg, 0.170 mmol) and N,N-diisopropylethylamine (89 μL, 0.51 mmol) were added, followed by stirring at room temperature for 4 hours under nitrogen atmosphere. To the reaction solution, saturated brine (15 mL) was added, and extraction was carried out twice with ethyl acetate (15 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-55%) to afford the desired compound (41 mg, yield ˜100%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4].[CH2:22](Br)[CH:23]=[CH2:24].C1CCN2C(=NCCC2)CC1>ClCCl.CCOC(C)=O>[F:21][C:2]([F:20])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([O:17][CH2:24][CH:23]=[CH2:22])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4]
Reactant: C=CCBr
Reactant: CC1CN(C(=O)C(F)(F)F)C(C)Cc2cc(O)c(Br)cc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCOc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)C(C)C2
Temperature: 20 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
A solution N-trifluoroacetyl-8-bromo-1,4-dimethyl-7-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.030 g, 0.082 mmol) in dichloromethane (2 mL) was treated with allyl bromide (0.030 g, 0.246 mmol), DBU (0.037 g, 0.246 mmol) and stirred 2 hours at 20° C. The product mixture was diluted with EtOAc (10 mL), washed with 5% aqueous HCl (2 mL), brine (5 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 0.028 g of a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.32 (s, 1H), 6.62 (m, 1H), 6.02 (m, 1H), 5.45 (d, J=17 Hz, 1H), 5.30 (d, J=11 Hz, 1H), 4.58 (s, 2H), 4.36 (m, 1H), 3.62 (m, 1H), 3.23 (m, 1H), 3.11 (m, 1H), 2.81 (d, J=10 Hz, 1H), 2.70 (m, 1H), 1.34 (m, 3H), 1.21 (m, 3H).
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[C@@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([OH:19])[C@H:13]([O:20][C:21](=[O:55])[CH2:22][C:23]2[CH:24]=[C:25]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=3[CH2:41][N:42]([CH2:53][CH3:54])[C:43]([NH:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])[C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[O:12]1)=[O:10])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH2:46]([NH:45][C:43](=[O:44])[N:42]([CH2:41][C:32]1[CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=[CH:36][C:31]=1[C:25]1[C:26]([O:29][CH3:30])=[CH:27][CH:28]=[C:23]([CH2:22][C:21]([O:20][C@@H:13]2[O:12][C@H:11]([C:9]([OH:10])=[O:8])[C@@H:16]([OH:17])[C@H:15]([OH:18])[C@H:14]2[OH:19])=[O:55])[CH:24]=1)[CH2:53][CH3:54])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O[C@@H]2O[C@H](C(=O)OCc3ccccc3)[C@@H](O)[C@H](O)[C@H]2O)ccc1OC)C(=O)NCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O[C@@H]2O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]2O)ccc1OC)C(=O)NCc1ccccc1

Procedure:
(2S,3S,4S,5R,6S)-6-{2-[2′-(3-Benzyl-1-ethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetoxy}-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylic acid benzyl ester (0.2 mmol) in EtOAc was treated with 10% palladium on carbon (catalytic) and hydrogenated under a balloon of H2. The solution was filtered over a pad of Celite, and the filtrate was concentrated and purified by preparative HPLC to give the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH2:16])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(Cl)Cl>CN(C=O)C.C(C1C=C(O)C=CC=1O)(C)(C)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([O:8][C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH2:16])[CH:10]=2)([C:4]([F:6])([F:5])[F:7])[C:2]([F:17])([F:18])[F:1])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: C=Cc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: CC(C)(C)c1cc(O)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=Cc1cccc(C(OS(=O)(=O)c2ccc(Cl)cc2)(C(F)(F)F)C(F)(F)F)c1
Temperature: 5 °C
Yield: 84.3 %

Procedure:
12 g (44.4 mmol) of 1,1,1,3,3,3-hexafluoro-2-(3-vinyl-phenyl)-propan-2-ol were dissolved in 50 ml of anhydrous DMF, and a spatula tip of 2-tert-butyl-hydroquinone (10 mg) was added for stabilization. 1.5 g (50 mmol) of sodium hydride were then added while stirring and cooling with ice at about 5° C. After everything had dissolved, 9.92 g (47mmol) of 4-chlorobenzenesulfonyl chloride were added at the same temperature. The mixture was stirred for 72 hours at room temperature, methylene chloride was then added and the mixture was washed with water, dried, filtered and evaporated down. The residue obtained was chromatographed with hexane/chloroform over a silica gel column. 16.65 g of 2-(4-chlorobenzenesulfonyloxy)-1,1,1,3,3,3-hexafluoro-2-(3-vinylphenyl)-propane (=2,2,2-trifluoro-1-trifluoromethyl-1-(3-vinylphenyl)-ethyl 4-chlorobenzenesulfonate) were isolated (colorless crystals, m.p.: 70° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:18])=[C:5]([CH2:11][CH:12]([CH3:17])[CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:18])=[C:5]2[C:6](=[CH:7][C:8]=1[O:9][CH3:10])[C:14](=[O:16])[CH2:13][CH:12]([CH3:17])[CH2:11]2
Reactant: COc1ccc(CC(C)CC(=O)O)c(C)c1OC
Solvent: ClCCl
Product: COc1cc2c(c(C)c1OC)CC(C)CC2=O
Yield: 83 %

Procedure:
Compound 15a (7.0 g, 27.7 mmol) was added to 35 g of polyphosphoric ester in 100 mL of methylene chloride and refluxed for 1 h. The reaction mixture was poured onto ice, stirred to hydrolyze the polyphosphoric ester, and the resulting solid was filtered and recrystallized from methanol to give 5.4 g (23.0 mmol, 83% yield) of 16a as white plates: mp 106-108° C. 1H NMR:(ppm) 7.48 (s, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 2.95-2.28 (mult, 5H), 2.22 (s, 3H), 1.18 (d, 3H). Anal. (C14H18O3) C,H.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:22])[O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].FC(F)(F)S(O[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:22])[O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:17][CH2:16]3)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: CC(C)c1ccc(NC(=O)Oc2ccc3c(c2)CCN3)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)c1ccc(NC(=O)Oc2ccc3c(c2)CCN3c2ccccc2)cc1
Reaction time: 8 h
Yield: 8.2 %

Procedure:
To a solution of indolin-5-yl 4-isopropylphenylcarbamate (50 mg, 0.17 mmol) in 3.4 mL of acetonitrile was added 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (41 μL, 0.17 mmol) and caesium fluoride (51 mg, 0.34 mmol) at room temperature, successively. After the reaction mixture was stirred at the same temperature overnight, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain the title compound as a white solid (5.2 mg, 8%).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC(Cl)(Cl)C>[CH2:4]([O:3][C:1]([N:11]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:22])[O:21][C@H:23]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)(Cl)Cl
Product: O=C1O[C@@H](c2ccccc2)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccccc1
Yield: 12.4 %

Procedure:
Following the procedure of Karady, Tett. Lett., 1984, 25:4337. N-Cbz-L-phenylalanine (25 g, 83.5 mmol), benzaldehyde (18 g, 170 mmol), and p-toluenesulfonic acid (11.2 g, 58 mmol) were suspended in 1,1,1-trichloroethane (300 ml). The solution was refluxed for 18 hr and the water was removed by azeotropic distillation using a Dean-Stark trap for liquids heavier than water. After cooling, the reaction was washed with saturated aqueous NaHCO3 (3×50 ml), water (1×50 ml), dried over sodium sulfate and concentrated in vacuo to produce an orange oil. After about 1 h a solid crystallized from the oil and it was collected by vacuum filtration. The orange solid was recrystallized from ethyl acetate/hexane to produce colorless crystals (4.0 g, 12%); mp 120°-122° C. MS (CI): 405 (M+NH4)+, 388 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1>>[Cl:19][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccncc1C
Reactant: Clc1cccc(CCCBr)c1
Product: Cc1cnccc1CCCCc1cccc(Cl)c1
Yield: 45.7 %

Procedure:
1.0 g (9.35 mmol) of 3,4-dimethylpyridine and 2.18 g (9.35 mmol) of 1-bromo-3-(3-chlorophenyl)-propane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 1.11 g of the desired compound (yield: 5.9%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:14]4[NH:15][C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[C:22](=[O:23])[C:13]=4[CH2:12][NH:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:32]([CH3:36])[CH:33]=[N:34][CH:35]=2)=[CH:27][N:26]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CC([O-])(C)C.[Na+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:14]4[NH:15][C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[C:22](=[O:23])[C:13]=4[CH2:12][N:11]3[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[N:32]([CH3:36])[CH:33]=[N:34][CH:35]=4)=[CH:27][N:26]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: Cn1cncc1-c1ccc(Cl)nc1
Reactant: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)CCO3)NC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Cn1cncc1-c1ccc(N2Cc3c([nH]c4ccccc4c3=O)C2c2ccc3c(c2)CCO3)nc1

Procedure:
3-(2,3-dihydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one (0.127 g, 0.372 mmol), 2-chloro-5-(3-methyl-3H-imidazol-4-yl)-pyridine (0.06 g, 0.31 mmol), Pd(OAc)2 (3.5 mg, 0.0155 mmol), biphenyl-2-yl-dicyclohexyl-phosphane (5.43 mg, 0.0155 mmol) and NaOtBu (0.104 g, 1.085 mmol) were stirred in 1,4-dioxane (0.6 mL) at 90° C. Purification by preparative TLC (5% MeOH in CH2Cl2) yielded the product as yellow solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:43])[NH:17][CH2:18][C:19]3[N:20]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:21](=[O:38])[C:22]4[C:27]([C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][C:25]([C:35]([NH2:37])=[S:36])=[CH:24][CH:23]=4)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:45][C:46](=O)[CH3:47].O>C(O)C>[CH2:39]([N:20]1[C:19]([CH2:18][NH:17][C:16](=[O:43])[O:15][CH2:14][CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:35]3[S:36][CH:45]=[C:46]([CH3:47])[N:37]=3)[CH:26]=2)[C:21]1=[O:38])[CH:40]([CH3:41])[CH3:42]
Reactant: CC(C)Cn1c(CNC(=O)OCC2c3ccccc3-c3ccccc32)c(-c2ccccc2)c2cc(C(N)=S)ccc2c1=O
Reactant: CC(=O)CBr
Solvent: O
Solvent: CCO
Product: Cc1csc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OCC4c5ccccc5-c5ccccc54)c(-c4ccccc4)c3c2)n1
Yield: 81.9 %

Procedure:
A suspension of 9H-fluoren-9-ylmethyl[6-(aminocarbothioyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.47 g, 0.8 mmol) and bromoacetone (0.22 g, 1.6 mmol) in ethanol (10 ml) was refluxed under heating for 1 h. The reaction mixture was poured into water and extracted with ethyl. acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 9H-fluoren-9-ylmethyl [2-isobutyl-6-(4-methyl-1,3-thiazol-2-yl)-1-oxo-4phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.41 g, 82.0%) as an amorphous.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[C:16]([O:19][CH3:20])[CH:15]=[C:14]([O:21][CH3:22])[C:13]=2[F:23])=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[C:24]([Cu])#[N:25]>CN1C(=O)CCC1.C(Cl)Cl>[F:23][C:13]1[C:14]([O:21][CH3:22])=[CH:15][C:16]([O:19][CH3:20])=[C:17]([F:18])[C:12]=1[C:9]1[C:8]2[N:7]=[CH:6][CH:5]=[N:4][C:3]=2[C:2]([C:24]#[N:25])=[CH:11][CH:10]=1
Reactant: N#C[Cu]
Reactant: COc1cc(OC)c(F)c(-c2ccc(Br)c3nccnc23)c1F
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C#N)c3nccnc23)c1F
Temperature: 150 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
A mixture of 5-bromo-8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline (Step 88.3) (1.1 g, 2.9 mmol) (Step 88.3) and CuCN (312 mg, 3.4 mmol, 1.2 equiv) in NMP (10 mL) was stirred for 4 h at 150° C., under an argon atmosphere. The reaction mixture was allowed to cool to rt, diluted with DCM/(10% aqueous solution of ethylenediamine) (100 mL) and extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was triturated in EtOAc to provide 702 mg of the title compound as a beige solid: ESI-MS: 328.1 [M+H]+; tR=4.48 min (System 1).
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]3[CH3:37])[N:27]=[C:26]([CH3:38])[N:25]=2)=[O:21])[CH2:8][N:9]([O:12]CC2C=CC=CC=2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]3[CH3:37])[N:27]=[C:26]([CH3:38])[N:25]=2)=[O:21])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCOC[C@@H]2C)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CCOC[C@@H]2C)n1
Reaction time: 1 h

Procedure:
To a solution of [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[(3S)-3-methyl-4-morpholinyl]-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (309.1 mg, 0.563 mmol) in methanol (6 mL) was added 20% Pd(OH)2/C (50% water, 62 mg). The suspension was hydrogenated for 1 h and then filtered through a PTFE membrane. The resulting solution was concentrated in vacuo and purified by Gilson RPLC to give [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[(3S)-3-methyl-4-morpholinyl]-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide (94.0 mg, 36%) as a white solid following crystallization from EtOAc-Et2O. LCMS: (M+H)+: 459.1.