Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C@@H:5]1[OH:17])=[N+]=[N-].[H][H]>CO.[OH-].[Pd+2].[OH-]>[NH2:1][C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:6][C@H:5]1[OH:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N=[N+]=[N-])[C@@H](O)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reaction time: 72 h

Procedure:
(3S*,4S*)-tert-butyl 4-azido-3-hydroxypiperidine-1-carboxylate from example C1 (47 g, 194 mmol) is dissolved in methanol (1200 mL) under nitrogen. Palladium hydroxide (20% on carbon; 4.7 g) is added. The atmosphere is changed to hydrogen and the stirred reaction mixture is hydrogenated at room temperature and 70 psi for 72 hours. The mixture is filtered through celite. The filtrate is evaporated. The residue is recrystallized from CH2Cl2 with a small amount of MeOH to obtain the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([OH:10])=[C:5]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:4]=1[CH2:21][C:22]([O:24]C)=[O:23])[CH3:2].[OH-].[Na+].Cl>CO>[CH2:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([OH:10])=[C:5]([C:11](=[O:20])[C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C:4]=1[CH2:21][C:22]([OH:24])=[O:23])[CH3:2]
Reactant: CCc1c(O)cc(O)c(C(=O)c2ccc(OC)cc2)c1CC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(O)cc(O)c(C(=O)c2ccc(OC)cc2)c1CC(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.1 %

Procedure:
Compound 8 (0.18 g, 0.53 mmol) obtained in Example 8 was dissolved in methanol (1.5 mL), and a 2 mol/L aqueous solution of sodium hydroxide (1.5 mL) was added thereto. The mixture was stirred at room temperature for 6 hours, and then stirred at 50° C. for 1.5 hours. After cooling to room temperature, the reaction mixture was made acidic by addition of 4 mol/L hydrogen chloride (3.0 mL), followed by extraction with chloroform (50 mL×3). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 2-ethyl-3,5-dihydroxy-6-(4-methoxybenzoyl)phenylacetic acid (0.17 g, 0.52 mmol).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:5]=[N:4][CH:3]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17]>>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:15])[CH3:14])[C:6]=3[CH:5]=[N:4][CH:3]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: CC(=O)N[C@@H]1CCCc2c(Br)cncc21
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CC(=O)N[C@@H]1CCCc2c(-c3ccc(C#N)cc3)cncc21
Yield: 87 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (+)-(R)—N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide (intermediate A-12) was reacted with 4-cyanophenylboronic acid to give the title compound as off-white solid in 87% yield. MS: 292.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[CH:9][N:10]=1)[CH:5]=[N:6][OH:7].[I:20]Cl>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8]([C:11]([I:20])=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N+:6]([O-:7])=[CH:5]2)=[CH:9][N:10]=1
Reactant: ClI
Reactant: ON=Cc1cc(Cl)ncc1C#Cc1ccccc1Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: [O-][n+]1cc2cc(Cl)ncc2c(I)c1-c1ccccc1Cl
Temperature: 25 °C

Procedure:
To a slurry of 2-chloro-5-((2-chlorophenyl)ethynyl)isonicotinaldehyde oxime (850 mg, 2.9 mmol) in acetonitrile (8 mL) was added iodine monochloride (1.4 g, 8.8 mmol). The reaction mixture instantly became homogeneous and was stirred at room temperature. After 15 minutes the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford an orange residue that was used in the next step without further purification (1.2 g, 98%).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2([OH:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:14][CH2:13]1)C1C=CC=CC=1>[Pd].CO>[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2([OH:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:14][CH2:13]1
Reactant: O=C(NCC1CCN(CC2(O)CCOCC2)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCC1CCN(CC2(O)CCOCC2)CC1
Reaction time: 20 h
Yield: 93.2 %

Procedure:
A mixture of benzyl({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)carbamate (5.60 g, 15.5 mmol, step 1) and palladium on activated carbon (10 wt. %, 1.20 g) in methanol (250 mL) was hydrogenated at room temperature for 20 h. Then, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give 3.30 g (94%) of the title compound as slightly yellow oil.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].O.Cl[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[Br:13][C:9]1[CH:8]=[C:7]([CH2:6][CH:2]([NH:1][C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:3]([OH:5])=[O:4])[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: NC(Cc1cccc(Br)c1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=O)NC(Cc1cccc(Br)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To a suspension of 2-amino-3-(3-bromophenyl)propanoic acid (11.0 g, 45.5 mmol) and NaHCO3 (11.5 g, 136.5 mmol) in THF (100 mL)/H2O (100 mL), ethyl 2-chloro-2-oxoacetate (18.4 g, 135.2 mmol) was added dropwise at 0° C. The mixture was stirred at RT overnight, acidified with aqueous critic acid (10%), and then extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (100 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by Combiflash reverse phase chromatography (50%˜60% MeCN/H2O containing 0.01% TFA) to afford 3-(3-bromophenyl)-2-(2-ethoxy-2-oxoacetamido)propanoic acid as a colorless oil (5.2 g, 33%). MS (ES+) C13H14BrNO5 requires: 343, 345 found: 344 [M+H]+, 346 [M+2+H]+(1:1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([OH:17])=[O:16])[CH:3]=1.[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[N:5]=[C:4]([C:15]([OH:17])=[O:16])[C:3]=1[Cl:18]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cc(C(=O)O)nc(-c2ccc(Cl)cc2)n1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccc(Cl)cc2)nc(C(=O)O)c1Cl
Temperature: 65 °C

Procedure:
To a solution of 6-amino-2-(4-chlorophenyl)-4-pyrimidinecarboxylic acid (i.e. the product of Step B) (75 g, 300 mmol) in N,N-dimethylformamide (300 mL) at 50° C. was added portionwise N-chlorosuccinimide (44.1 g, 330 mmol). The temperature of the reaction mixture increased exothermically to 65° C. Then the reaction mixture was heated at 55° C. for 3 h. Additional N-chlorosuccinimide (14 g, 90 mmol) was added portionwise, and the reaction mixture was maintained at 55° C. for 30 minutes. After the reaction mixture was cooled water was added. The resulting solid was isolated by filtration, washed with water, dissolved in ethyl acetate, washed with water and dried. The solvent was removed using a rotary evaporator to afford the title product, a compound of the present invention, as a tan solid (73.68 g).
Reaction SMILES: Cl.[N:2]1[CH:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[C:7]([N:11]3[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12]3)[C:6]=12.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[N:27][C:26]([C:29](O)=[O:30])=[N:25]2)=[CH:20][CH:19]=1.C(N(CC)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH:28]=[N:27][C:26]([C:29]([NH:16][C@H:13]3[CH2:14][CH2:15][N:11]([C:7]4[C:6]5[N:5]([CH:4]=[CH:3][N:2]=5)[CH:10]=[CH:9][N:8]=4)[CH2:12]3)=[O:30])=[N:25]2)=[CH:22][CH:23]=1
Reactant: O=C(O)c1ncn(-c2ccc(F)cc2)n1
Reactant: N[C@H]1CCN(c2nccn3ccnc23)C1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CCN(c2nccn3ccnc23)C1)c1ncn(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a suspension of (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine hydrochloride salt (55 mg, 0.2 mmol) and 1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxylic acid (42 mg, 0.2 mmol) in DMF (5 mL) was added diethylisopropyl amine (650 mg, 5 mmol), followed by HATU (76 mg, 0.2 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solutions of KH2PO4 and NaHCO3, followed by brine. The organic layer was concentrated in vacuo and the residue purified by reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) to give 45 mg of the title compound (57% yield) as white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:38])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=3)[C:21](=[O:37])[CH2:20]2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-:39].[Li+].Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:38])[CH2:18][CH:19]([CH2:24][C:23]([OH:25])=[O:39])[CH2:20][C:21]([NH:22][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:35][CH:36]=2)=[O:37])[CH2:13][CH2:12]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: [OH-]
Reactant: COC(=O)c1ccc(CN2C(=O)CC(CC(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)CC2=O)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CC(CC(=O)O)CC(=O)NCc2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
To a stirred solution of methyl 4-[(4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}-2,6-dioxopiperidin-1-yl)methyl]benzoate (Example 74, 0.575 g, 1.11 mmol) in THF (5 mL) stirring at 0° C. was added 1 M lithium hydroxide solution (5 mL, 5 mmol). After 1 h the reaction mixture was warmed to room temperature and kept stirring for 3 h. The mixture was acidified with 1 M hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to provide the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=90:10 to 20:80) to provide 4-[({5-[4-(2-tert-butylphenyl)piperazin-1-yl]-3-(carboxymethyl)-5-oxopentanoyl}amino)methyl]benzoic acid (0.608 g, quant) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH2:5].[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>C(O)(=O)C>[O:17]=[C:16]1[C:15]2[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13](=[O:18])[N:5]1[CH:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:3]([O:2][CH3:1])=[O:12]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Solvent: CC(=O)O
Product: COC(=O)CCC(C(=O)OC)N1C(=O)c2ccccc2C1=O

Procedure:
A stirred mixture of L-glutamic acid dimethyl ester (2.0 g, 11.4 mmol) and phthalic anhydride (1.7 g, 11.4 mmol) in acetic acid (30 mL) is heated to refluxed for one hour. The solvent is removed in vacuo to yield dimethyl 2-(1,3-dioxoisoindolin-2-yl)-pentane-1,5-dioate which is further purified through chromatography.
Reaction SMILES: CON(C)[C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:24][Mg]Br>C1COCC1>[C:4]([C@H:6]1[CH2:7][CH2:8][C@H:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11]1)(=[O:5])[CH3:24]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl {trans-4-[methoxy(methyl)carbamoyl]cyclohexyl}carbamate (3.43 g, 10.71 mmol) in THF (107 mL) at 0° C. was added methylmagnesium bromide (3.0 M in diethyl ether, 5.35 mL, 16.06 mmol) and the reaction was stirred for one hour at 0° C. An additional portion of methylmagnesium bromide (3.0 M in diethyl ether, 5.35 mL, 16.06 mmol) was then added and the reaction was allowed to warm to room temperature and then stirred for one hour. The reaction was slowly quenched with aqueous saturated ammonium chloride. Water and ethyl acetate were added and the organic layer was separated, dried over magnesium sulfate, filtered and concentrated to afford benzyl (trans-4-acetylcyclohexyl)carbamate that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[CH:20]=[C:19]([CH3:21])[C:13]3[N:14]([CH3:18])[C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)=[O:9])[CH:3]=1.BrN1C(=O)CCC1=O.[N:30]([C:37]([CH3:41])(C)C#N)=[N:31][C:32](C)(C)C#N.N1C=CC=N1.CCN(C(C)C)C(C)C>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[CH:20]=[C:19]([CH2:21][N:31]3[CH:32]=[CH:41][CH:37]=[N:30]3)[C:13]3[N:14]([CH3:18])[C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)=[O:9])[CH:3]=1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Agent: O=C1CCC(=O)N1Br
Agent: c1cn[nH]c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)oc2cc(C(=O)c3cc(Cl)ncn3)cc(Cn3cccn3)c21

Procedure:
Under a nitrogen atmosphere 0.15 g (0.49 mmol) 6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one, 95 mg (0.53 mmol) N-bromosuccinimide and 5.0 mg (30 mmol) 2,2′-azobis-isobutyronitrile (AIBN) in 15 mL carbon tetrachloride were combined and refluxed for 4 h. The precipitate formed was filtered off and the filtrate was combined with 20 μL isopropanol. After brief stirring 36 mg (0.53 mmol) pyrazole and 0.17 mL (0.99 mmol) DIPEA were added and the mixture was refluxed for 6 h. Then the reaction mixture was filtered through silica gel and washed with DCM/EtOAc (1/1). The filtrate was evaporated down i. vac. and the residue was reacted further as the crude product.
Reaction SMILES: [C:1]([N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS(O)(=O)=O>C1(C)C=CC=CC=1>[C:13]1([NH:12][CH:3]([CH3:4])[CH2:2][C:1]([N:6]2[CH2:10][CH2:9][O:8][C:7]2=[O:11])=[O:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: C/C=C/C(=O)N1CCOC1=O
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(CC(=O)N1CCOC1=O)Nc1ccccc1
Temperature: 0 °C
Yield: 23.4 %

Procedure:
To a solution of 3-crotonoyl-1,3-oxazolidin-2-one (155 mg, 1.0 mmol) in toluene (3 ml) in a stream of nitrogen was added Pd((R)-binap)(H2O)2(OTf)2 (26.6 mg, 0.025 mmol), and the resulting mixture was cooled to 0° C. Aniline (0.11 ml, 1.2 mmol) was added to the mixture, and to the solution was added slowly methanesulfonic acid (0.039 ml, 0.6 mmol). Then, the cooling ice-bath was removed and the reaction mixture was reacted at room temperature for 15 hours with stirring. After completion of the reaction, the solvent was evaporated off, and the crude product obtained was purified by a silica gel column chromatography (hexane:ethyl acetate=1:1) to give the objective compound 3-(3-phenylaminobutyryl)-oxazolidin-2-one (58 mg, 23% yield). Enantiomeric excess ratio of this product was determined by a liquid chromatography using a column for separation of optical isomers (column: AD-H) to be 78% e.e.
Reaction SMILES: Cl[Si](C)(C)C.Br[CH2:7][C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].[CH3:14][NH:15][C:16]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]([C:30]3[N:31]=[CH:32][N:33]([C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:34]=3)=[O:29])[CH:24]=2)[CH:19]=1)=[O:17]>C1COCC1.C(OCC)(=O)C.Cl.[Zn]>[OH:29][C@@:28]([C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[CH:26][CH:27]=[C:18]([C:16]([NH:15][CH3:14])=[O:17])[CH:19]=2)[CH:24]=1)([C:30]1[N:31]=[CH:32][N:33]([C:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:34]=1)[CH2:7][C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)OC(=O)CBr
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2cc([C@@](O)(CC(=O)OC(C)C)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
50 mL of 0.1N hydrochloric acid was added to 5 g of zinc powders, the mixture was stirred vigorously for 10 minutes, filtered, and washed successively with 30 mL of water, 30 mL of ethanol, and 30 mL of ether. Zinc was filtered, followed by vacuum drying at 100° C. for 8 hours. Under argon atmosphere, 4 mL of THF and 0.075 mL (0.59 mmol) of chlorotrimethylsilane were added to 0.52 g (8 mmol) of the zinc powders. The mixture was stirred at 25˜28° C. for 2 minutes, and a solution of 1.04 mL (8 mmol) of isopropyl bromoacetate in 10 mL of THF was added over 10 minutes. The mixture was stirred at 45˜50° C. for 45 minutes. A solution of 0.94 g (1.8 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 7.5 mL of THF was added dropwise at −33˜35° C. over 5 minutes. The mixture was stirred at −43˜35° C. for 30 minutes, at 15˜25° C. for 3 hours, and at 45˜50° C. for 50 minutes. 5 mL of 1N hydrochloric acid was added dropwise at 25° C., diluted with 25 mL of ethyl acetate, 5 mL of 1N hydrochloric acid was added, and the layers were separated. The organic layer was washed successively with 5 mL of 1N hydrochloric acid two times, 10 mL of water, 5 mL of an aqueous saturated sodium bicarbonate solution, and 5 mL of an aqueous saturated sodium chloride solution. After concentrated under reduced pressure, 2 mL of ethyl acetate was added to the concentration residue. Crystals were filtered, and washed with 1 mL of ethyl acetate. Vacuum drying (40° C.) to a constant weight afforded 0.78 g of isopropyl(3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 70%).
Reaction SMILES: [C:1]([C:3]1[C:4]([F:19])=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:2]>C1COCC1.Cl[Pd]Cl>[C:1]([C:3]1[C:4]([F:19])=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:2]
Reactant: CCOC(=O)/C=C/c1c[nH]c2c(C#N)c(F)ccc12
Agent: Cl[Pd]Cl
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2c(C#N)c(F)ccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.1 %

Procedure:
To a solution of ethyl (2E)-3-(7-cyano-6-fluoro-1H-indol-3-yl)-2-propenoate (D143) (1.8 g) in THF (50 mL) was added PdCl2 (0.5 g). The reaction was stirred under H2 (15 psi) atmosphere at RT for about 5 hours. TLC showed the starting material was completely consumed. Then PdCl2 was removed by filtration, the filtrate was concentrated and washed with PE to afford ethyl 3-(7-cyano-6-fluoro-1H-indol-3-yl)propanoate (D144) (1.67 g) as a white solid. δH (DMSO-d6, 400 MHz): 1.15 (3H, t), 2.66 (2H, t), 2.93 (2H, t), 4.03 (2H, q), 7.08 (1H, dd), 7.28 (1H, s), 7.93 (1H, dd), 11.90 (1H, s); MS (ES): C14H13FN2O2 requires 260; found 261.2 (M+H+).
Reaction SMILES: Cl.C(OCC)C.[F:7][C:8]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:9]=1[CH2:10][O:11][C:12]1[C:13]2[N:14]([C:18]([C:22]([NH:24][CH:25]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH2:26][NH:27]C(=O)OC(C)(C)C)=[O:23])=[C:19]([CH3:21])[N:20]=2)[CH:15]=[CH:16][CH:17]=1>>[NH2:27][CH2:26][CH:25]([NH:24][C:22]([C:18]1[N:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][C:9]3[C:42]([F:46])=[CH:43][CH:44]=[CH:45][C:8]=3[F:7])[C:13]2=[N:20][C:19]=1[CH3:21])=[O:23])[C:35]1[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CNC(=O)OC(C)(C)C)c1ccc(F)cc1
Agent: Cl
Solvent: CCOCC
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CN)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7 ml of 2M hydrochloric acid in diethyl ether (14 mmol) were added to 363 mg of tert-butyl {2-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-carbonyl)amino]-2-(4-fluorophenyl)ethyl}carbamate (Example 79A, 0.63 mmol), and the mixture was stirred at RT for 3 h. The resulting precipitate was filtered off, washed with diethyl ether, dissolved in dichloromethane and methanol and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulphate and filtered and the filtrate was concentrated and dried under high vacuum. This gave 275 mg of the title compound (96% of theory).
Reaction SMILES: CN(C1C=CC(C(C2C=CC(N(C)C)=CC=2)C2C=CC(N(C)C)=CC=2)=CC=1)C.CN(C)C1C=CC(C)=C(C(C2C=C(N(C)C)C=CC=2C)C2C=C(N(C)C)C=CC=2C)C=1.CN(C)C1C=CC(C)=C(C(C2C=C(N(C)C)C=CC=2C)C2C=CC=CC=2)C=1.CN(C)C1C=CC(C)=C(C(C2C=C(N(C)C)C=CC=2C)C2SC=CC=2)C=1.[C:113]([C:121]1[C:134]2[NH:133][C:132]3[C:127](=[CH:128][C:129](NCC)=[CH:130][CH:131]=3)OC=2C=C(NCC)C=1)(=O)[C:114]1[CH:119]=[CH:118][CH:117]=[CH:116]C=1.C(C1C2C(=NC3C(N=2)=C(C2C=CC=CC=2)C=C(NCC)C=3)C=C(NCC)C1)(=O)C1C=CC=CC=1>>[CH2:134]([NH:133][C:132]1[CH:131]=[CH:130][CH:129]=[CH:128][CH:127]=1)[CH2:121][C:113]1[CH:114]=[CH:119][CH:118]=[CH:117][CH:116]=1
Reactant: CCNc1ccc2c(c1)Oc1cc(NCC)cc(C(=O)c3ccccc3)c1N2
Agent: CCNC1=Cc2nc3cc(NCC)cc(-c4ccccc4)c3nc2C(C(=O)c2ccccc2)C1
Agent: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)cc1
Agent: Cc1ccc(N(C)C)cc1C(c1cc(N(C)C)ccc1C)c1cc(N(C)C)ccc1C
Product: c1ccc(CCNc2ccccc2)cc1

Procedure:
Exemplary compounds include leucocrystal violet, tris(4-dimethylamino-o-tolyl)methane, bis(4-dimethylamino-o-tolyl)phenylmethane, bis(4-dimethylamino-o-tolyl)thienylmethane, 2-(2-chlorophenylamino-6-N,N-dibutylamino-9-(2-methoxycarbonyl)-phenylxanthene, 2-N,N-dibenzylamino-6-N,N-diethylamino-9-(2-methoxycarbonyl) phenylxanthene, benzo[a]-6-N,N-diethylamino-9-(2-methoxycarbonyl)phenylxanthene, benzoylleucomethylene blue, benzoyl-3,7-diethylaminophenoxazine, benzoyl-3,7-diethylamino-9-phenyldihydrophenazine, 6,6'-di-t-butyl-p,p'-bi-o-cresol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]#[C:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:3][CH:2]=1>C(O)C.[OH-].[Pd+2].[OH-]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:3][CH:2]=1
Reactant: OCCCC#Cc1ccncc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: OCCCCCc1ccncc1
Yield: 91.6 %

Procedure:
5-(4-Pyridyl)pent-4-yn-1-ol (3.41 g) prepared according to the procedure described above was dissolved in ethanol (30 ml) and hydrogenated over palladium hydroxide catalyst (0.300 g) at 45 psi for 3 h. The catalyst was filtered and the ethanol evaporated in vacuo to yield the title product as a colourless oil (3.2 g). 1H NMR (250 MHz, CDCl3) δ 1.40-1.45 (2H, m), 1.47-1.80 (4H, m), 2.00 (1H br s), 2.62 (2H, t), 3.64 (2H, t), 7.10 (2H, d), 8.45 (2H, d).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([NH:15][C:16](OC2C(O)=C(C3C=CC=CC=3)S(=O)(=O)C=2C2C=CC=CC=2)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OCC)(=O)C>[CH2:1]([NH:8][C:16]([NH:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1)OC1=C(c2ccccc2)S(=O)(=O)C(c2ccccc2)=C1O
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1)Nc1ccccc1

Procedure:
540 mg of benzylamine are added to 2.1 g of 3-(N-phenylcarbamyloxy)-4-hydroxy-2,5-diphenylthiophene-1,1-dioxide in 20 ml of ethyl acetate. The solution is boiled under reflux for 1 hour and then washed three times with 25 ml of concentrated aqueous NaHCO3 solution and three times with 20% strength aqueous citric acid solution. The wash liquors are extracted with ethyl acetate and the combined organic phases are dried over magnesium sulfate. After evaporating the filtrate, the crystalline residue is recrystallized from dilute ethanol.