Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([OH:21])(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:15].CCCCCO.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:15][C:14]2[C:13](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([OH:21])=[O:20])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCO
Product: O=C(O)c1ccccc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
In a 3 liter, three necked round bottom flask, provided with a mechanical stirrer, reflux condenser and thermometer (to 200° C.) was placed 300 g. (1.25 m.) 1-bromo-4-chloronitrobenzene, 140 g. (1.02 m.) anthranilic acid, and 130 ml. n-amyl alcohol. The mixture was heated in an oil bath. After most of the chemicals were dissolved (80°-90° C.) the stirrer was started. Then, 1.3 gm. copper powder and 140 gm. (1.02 m.) potassium carbonate were added all at once. A yellow voluminous froth formed but no heat of reaction. As the reaction temperature rose from 180° to 120°, a red reaction mixture became more solid and hindered further stirring. The reflux condenser was replaced to distill off the formed water and amyl alcohol. Meanwhile, the temperature of the oil bath was steadily increased and finally kept at 200°-210° for 3 hours. The oil bath was replaced by a steam bath and the excess bromochloronitrobenzene was removed by steam distillation. After removal of bromochloronitrobenzene was completed, the solution was filtered and water added making the total volume of dark red solution about 2.5 liters. The solution was cooled to room temperature overnight, and filtered. Dilute HCl (1:1) was carefully added to the filtrate until it was just acid to Congo red litmus paper. The ochre-colored precipitate was removed by filtration and washed with water (750 ml.). The product was dried in vacuo at 70°. The original dark-red filter cake was digested with hot water several times and then treated as described above to extract all the desired product. Obtained: 247 grams (83% yield) of crude N-(4-chloro-2-nitrophenyl)anthranilic acid; orange granular powder; m.p. 235°-247° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].O[CH:28]1[CH2:32][CH2:31][O:30][CH2:29]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([Cl:25])[CH:19]=1)[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:28]2[CH2:32][CH2:31][O:30][CH2:29]2)=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCOC1
Reactant: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(O)cc2)cc1Cl
Product: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(OC3CCOC3)cc2)cc1Cl

Procedure:
The title compound was prepared from rac-[1-(3-chloro-4-methyl-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and rac-3-hydroxy-tetrahydrofuran in analogy to Example 9c): MS (ISN): 444.3 (M−H)−.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:32])/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31])(C)(C)C.Cl.C([O-])([O-])=O.[K+].[K+]>CC(O)C>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:32])/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/CCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: Nc1ccccc1NC(=O)/C=C/CCCN1C(=O)c2ccccc2C1=O
Yield: 38.2 %

Procedure:
To a solution of (E)-tert-butyl 2-(6-(1,3-dioxoisoindolin-2-yl)hex-2-enamido)phenylcarbamate (3) (135 mg, 0.3 mmol) in propan-2-ol (10 mL). The mixture was stirred at 0° C. with HCl gas for 1 hour, To the reaction mixture was added 10% K2CO3 to adjust the pH value to 7-8, then the mixture was extracted with DCM (3×50 mL), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the desired compound of (E)-N-(2-aminophenyl)-6-(1,3-dioxoisoindolin-2-yl)hex-2-enamide (40 mg, yield 37%) as an off-white solid after purification by column chromatography (eluent: DCM:MeOH=50:1). 1H NMR (300 MHz, DMSO): δ 1.759-1.830 (m, 2H), 2.202-2.271 (m, 2H), 3.495-3.646 (m, 2H), 4.783 (s, 2H) 6.143-6.194 (d, J=15.3 1H), 6.519-6.692 (m, 1H) 6.705-6.914 (m, 4H), 7.206-7.229 (d, 1H), 7.813-7.891 (d, 2H), 8.350 (m, 4H), 9.175 (s, 1H); LC-MS found 350 (M+H)+, HPLC (214 nm, 99%, 254 nm, 99%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14](OC)=[O:15])([O-])=O>C(OCC)(=O)C>[NH2:10][C:8]1[CH:9]=[C:4]2[C:5]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14](=[O:15])[NH:1]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(F)(F)F
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)NC(=O)C2(O)C(F)(F)F
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of methyl 2-(2,4-dinitrophenyl)-3,3,3-trifluoro-2-hydroxypropanoate (1.3 g, 4.01 mmol) in ethyl acetate (18 mL) was successively added pH3HCl (5.2 mL), then PdC (350 mg) in ethyl acetate (3 mL). The mixture was vigorously stirred overnight under H2 (1 atm). The catalyst was filtered off through Celite and the filtrate was concentrated to dryness. The crude residue obtained was partitioned between DCM (25 mL) and aqueous saturated NaHCO3 (15 mL). The organic phase was separated and the aqueous phase was extracted DCM (2×25 mL). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The crude residue obtained was purified by silica gel column chromatography using a gradient 50-100% ethyl acetate in hexanes to give 6-amino-3-hydroxy-3-(trifluoromethyl)indolin-2-one (921 mg, 99%)
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].C(=O)([O-])O.[Na+].[CH3:16][C:17]([CH3:19])=O>>[CH3:16][C:17]1([CH3:19])[O:4][C@@H:3]2[C@@H:5]([C@@H:7]([CH2:9][OH:10])[O:8][CH:2]2[OH:1])[O:6]1
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1(C)O[C@@H]2[C@@H](CO)OC(O)[C@@H]2O1
Temperature: 58 °C
Reaction time: 5 h
Yield: 51 %

Procedure:
To 500 ml of acetone were added 20.0 g of D-ribose and 250 mg of anhydrous cupric chloride, and the mixture was stirred for 5 hours under reflux in a warm-water bath at 58° C. The refluxing solvent was continuously dried with 30 g of molecular sieves 3A which was placed between the reaction vessel and the cooling tube. After the conclusion of the reaction, a small amount of aqueous sodium hydrogencarbonate is added to the reaction mixture, and the acetone was distilled off under reduced pressure. The residue was dissolved in benzene, and the solution was washed with aqueous sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The benzene was distilled off under reduced pressure and the residue was subjected to distillation under reduced pressure, producing 13 g (51%) of 2,3-O-isopropylidene-D-ribofuranose as a fraction of 109°-112° C./0.04 mmHg.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH2:17]1[O:30][C:29]2[CH:28]=[CH:27][C:21]([CH:22]=[CH:23][C:24](O)=O)=[CH:20][C:19]=2[O:18]1>>[CH2:17]1[O:30][C:29]2[CH:28]=[CH:27][C:21](/[CH:22]=[CH:23]/[C:24]3[NH:1][C:2]4[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=4[N:8]=3)=[CH:20][C:19]=2[O:18]1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc4c(c3)OCO4)nc2n(CCC)c1=O
Yield: 68.4 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 4.25 g (18.8 mmol) of 5,6-diamino-1,3-dipropyluracil and 4.33 g (22.6 mmol) of 3,4-methylenedioxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 4.92 g (yield 69%) of Compound 18 as a pale yellow powder.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.C1(C)C(S(O[CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])(=O)=O)=CC=CC=1>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: COc1ccccc1CCOCCOS(=O)(=O)c1ccccc1C
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: COc1ccccc1CCOCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1

Procedure:
Analogously to Method I, 0.610 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.808 g of 2-[2-(2-methoxyphenyl)ethoxy]ethyl toluene-sulphonate (Example 45b) are reacted. The title compound is obtained as a slightly yellowish oil. Rt=5.10.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:16]2[CH2:18][CH2:17]2)=[CH:12][N:11]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH3:28])=[CH:21][CH:20]=2)[CH:10]=1)C1C=CC=CC=1.CC(O)=O>[Pd].CO>[CH2:25]([C:22]1[CH:21]=[CH:20][C:19]([N:11]2[CH:10]=[C:9]([OH:8])[C:14](=[O:15])[C:13]([CH:16]3[CH2:18][CH2:17]3)=[CH:12]2)=[CH:24][CH:23]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCc1ccc(-n2cc(OCc3ccccc3)c(=O)c(C3CC3)c2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCc1ccc(-n2cc(O)c(=O)c(C3CC3)c2)cc1

Procedure:
A suspension of 3-(benzyloxy)-1-(4-butylphenyl)-5-cyclopropylpyridin-4(1H)-one (27 mg, 0.07 mmol) and 10% Pd/C (1 mg, 0.001 mmol) in a 1:50 mixture of AcOH:MeOH was stirred under H2 (1 atm) for 18 h. The reaction mixture was filtered (0.5μ), concentrated under reduced pressure and purified by reversed phase HPLC (2 cm×5 cm C18, acetonitrile-water gradient, 0.05% TFA added) to provide 1-(4-butylphenyl)-3-cyclopropyl-5-hydroxypyridin-4(1H)-one. 1H NMR (499 MHz, DMSO): δ 7.73 (s, 1 H); 7.55 (d, J=2.7 Hz, 1 H); 7.48 (d, J=8.1 Hz, 2 H); 7.35 (d, J=8.1 Hz, 2 H); 2.64 (t, J=7.7 Hz, 2 H); 2.04-1.95 (m, 1 H); 1.61-1.52 (m, 2 H); 1.37-1.27 (m, 2 H); 0.94-0.87 (m, 3 H); 0.84-0.75 (m, 4 H). HRMS (ES) Calc (M+H)+=284.1645. Found 284.1643.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:18][N:19]([CH3:27])[CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[CH3:18][N:19]([CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]3[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)[CH2:23][CH2:22]1)[CH3:27]
Reactant: CN(C)CC1CCNCC1
Reactant: Cc1cn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cn(C(C)C)c2cc(N3CCC(CN(C)C)CC3)cc(C(=O)O)c12
Temperature: 98 °C
Yield: 53.8 %

Procedure:
To a 10-mL microwave tube were added 6-bromo-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylic acid (100 mg, 0.338 mmol), 1,4-dioxane (2 mL), N,N-dimethyl-1-(4-piperidinyl)methanamine (52.8 mg, 0.371 mmol) and sodium tert-butoxide (71.4 mg, 0.743 mmol), and the mixture was degassed for 5 min. Chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]Pd(11)Me-t-butylether adduct (13.96 mg, 0.017 mmol) was added and the tube was sealed. The mixture was stirred at 98° C. with stirring for 20 h. The mixture was then concentrated and the residue was purified using reverse-phase HPLC (Gemini 5u C18(2) 100A, AXIA; 30×100 mm 5 micron; (30 mL/min, 7% ACN/H2O, 0.1% formic acid to 37% ACN/H2O, 0.1% formic acid) to give the title compound (65 mg, 54%) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.34 (m, 2H), 1.39 (d, J=6.57 Hz, 6H), 1.58-1.71 (m, 1H), 1.82 (d, J=11.87 Hz, 2H), 2.23-2.31 (m, 10H), 2.66 (td, J=11.94, 1.89 Hz, 2H), 3.57-3.71 (m, 2H), 4.70 (quin, J=6.63 Hz, 1H), 7.09 (d, J=2.02 Hz, 1H), 7.15 (dd, J=9.60, 1.52 Hz, 2H). MS: (M+H)+=358.2.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([O:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1)(=O)C.C1(C)C=CC=CC=1>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:21]2[CH:20]=[CH:19][C:18]([OH:17])=[CH:23][CH:22]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC(=O)Oc1ccc(I)cc1
Reactant: C#Cc1ccc(CCCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: CCCCCc1ccc(C#Cc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Pentylphenylacetylene (10.5 g, 61.4 mmol), 4-acetoxyphenyl iodide (16.1 g, 61.4 mmol), a catalytic amount of Pd(PPh3)2Cl2 and a catalytic amount of copper iodide were stirred in diisopropylamine (100 ml) at 70° C. After 5 minutes, a precipitate was seen and the mixture became unstirrable, toluene (100 ml) was added. The mixture was stirred at room temperature for 24 hours and then evaporated to dryness on a rotary evaporator. The residue was redissolved in aqueous potassium hydroxide ethanolic solution and stirred at 70° C. overnight. The mixture was evaporated to dryness, then partitioned between ethyl acetate and water, the organic phase was removed, dried and evaporated. The residue was purified by flash column chromatography using DCM as eluant. A pink coloured solid was left after evaporation of the appropriate fractions. Yield=10.4 g, 64%. 1H-NMR and IR spectroscopy gave the expected signals.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#N)=[C:7]([F:13])[CH:6]=1)[CH:2]=[CH2:3].[H-].C([Al+]CC(C)C)C(C)C.C1C[O:27]CC1>>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:27])=[C:7]([F:13])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C#N)c(F)c1
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: C=CCOc1ccc(C=O)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from Example 53A (6.42 g, 36.5 mmoles) in anhydrous THF (50 mL) was treated with diisobutylaluminum hydride (DIBAL) (37.0 mL, 37.0 mmoles, 1.0M in hexanes) dropwise at −78° C. After 30 minutes, an additional portion of DIBAL (37.0 mL) was added dropwise. After an additional 30 minutes, the acetone/dry ice bath was removed, and the reaction mixture was warmed to 0° C. After an additional 30 minutes, the reaction was carefully quenched with saturated NH4Cl. The mixture was diluted with diethyl ether (200 mL) and saturated sodium potassium tartrate (250 mL) and stirred vigorously for 2.0 hours. The two phases were separated, and the organic phase was washed with brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to provide the title compound with no further purification. MS (DCI) m/z 181 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:26])[CH:9]([CH2:13][CH2:14][N:15]1C(=O)C2C(=CC=CC=2)C1=O)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[NH2:15][CH2:14][CH2:13][CH:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:26])[C:10]([OH:12])=[O:11]
Reactant: CN(C(=O)OC(C)(C)C)C(CCN1C(=O)c2ccccc2C1=O)C(=O)O
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C(CCN)C(=O)O

Procedure:
11.8 g (32.6 mmol) of the compound from example 5A was dissolved in approx. 640 ml ethanol and 23.8 ml (488 mmol) hydrazine hydrate was added to the reaction mixture. After stirring over night, the reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The raw product was dissolved in ethanol and approx. 50 g silica gel was added, the solvent was removed under reduced pressure. The resulting solid was added onto a approx. 500 g silica gel column and chromatographed. Solvents used were dichloromethane/methanol 9/1 to dichloromethane/methanol 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 2.98 g (12.8 mmol, 39% of theory) product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2([C:22]#[N:23])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[H][H]>C(O)C.[Pd]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2([C:22]#[N:23])[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(C#N)c2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(CN)c2)CC1
Reaction time: 3 h
Yield: 63.4 %

Procedure:
To a mixture of 0.31 g (1 mmole) of 4-(3-cyanophenyl)-1-tert-butoxycarbonyl-piperidine-4-carbonitrile in 30 ml of absolute ethanol was added 0.08 ml (1 mmole) of conc. hydrochloric acid followed by 30 mg of 5% Pd/C. The mixture was agitated in a Parr shaker for 3 hours at 30 lbs. of pressure of hydrogen. The mixture was filtered through celite and the filtrate was evaporated. The residue was treated with ether and was stirred for 30 minutes and was filtered. The filter cake was treated with aqueous sodium carbonate and was extracted with dichloromethane to give 0.2 g of product: 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.38-1.60(m, 9H), 1.88-2.18(m, 4H), 3.05-3.30(m, 4H), 3.79-4.0(m, 2H), 7.22-7.85(m, 4H); MS (ESI) m/e 316 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23](O)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][C:12]=2[C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[O:9])[NH:6][CH:7]=1)#[N:2].ClC(OC)=O.CC[N:39](C(C)C)C(C)C.[OH-].[NH4+]>C1COCC1.CCOC(C)=O>[C:23]([C:17]1([C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:5]3[NH:6][CH:7]=[C:3]([C:1]#[N:2])[N:4]=3)=[O:9])=[C:12]([C:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=3)[CH:13]=2)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)(=[O:24])[NH2:39]
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3(C(=O)O)CCOCC3)cc2C2=CCCCC2)n1
Reactant: CCN(C(C)C)C(C)C
Agent: COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3(C(N)=O)CCOCC3)cc2C2=CCCCC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a solution of 4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-tetrahydro-pyran-4-carboxylic acid (as prepared in Example 18, step (d), 14.5 mg, 0.0345 mmol) in 1 mL of THF was added ClCO2Me (3.6 mg, 0.038 mmol). The mixture was cooled to 0° C., DIEA (18 μL, 0.10 mmol) was added. After warming to RT and stirring for 1 h, the mixture was cooled back to 0° C. Concentrated ammonium hydroxide (25 μL, 0.37 mmol) was added and the resulting mixture was warmed to RT and stirred for 16 h. The reaction was treated with 30 mL of EtOAc and washed with brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1-5 MeOH/DCM) to afford the title compound (4.7 mg, 32%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 12.00 (s, 1H), 9.53 (s, 1H), 8.33 (d, 1H, J=8.6 Hz), 7.74 (d, 1H, J=2.3 Hz), 7.33 (dd, 1H, J=8.6, 2.3 Hz), 7.20 (d, 1H, J=2.3 Hz), 5.85 (m, 1H), 5.81 (br s, 1H), 5.32 (br s, 1H), 3.82 (m, 4H), 2.38 (m, 2H), 2.19-2.34 (m, 4H), 2.11 (m, 2H), 1.82 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C23H25N5O3, 420.2 (M+H). found 420.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([I:19])=[CH:14][C:13]=2[CH3:20])=[C:6]2[C:10]=1[C@@H:9]([OH:11])[CH2:8][CH2:7]2.O[C:22]1[CH:35]=[CH:34][C:25]2[C@H:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:27][O:28][C:24]=2[CH:23]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[C:13]([CH3:20])=[CH:14][C:15]([I:19])=[CH:16][C:17]=2[CH3:18])=[C:6]2[C:10]=1[C@H:9]([O:11][C:22]1[CH:35]=[CH:34][C:25]3[C@H:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:27][O:28][C:24]=3[CH:23]=1)[CH2:8][CH2:7]2
Reactant: Cc1cc(I)cc(C)c1-c1ccc(F)c2c1CC[C@@H]2O
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(I)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from (S)-7-fluoro-4-(4-iodo-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-ol and (S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 3 of Intermediate 1. LC (method 8): tR=1.08 min; Mass spectrum (ESI+): m/z=595 [M+Na]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[I:63][C:64]1[CH:70]=[CH:69][C:67]([NH2:68])=[CH:66][CH:65]=1>>[I:63][C:64]1[CH:70]=[CH:69][C:67]([NH:68][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:66][CH:65]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: Nc1ccc(I)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(I)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.2 g, 0.36 mmol), was reacted with diisopropylethylamine (0.18 g, 1.4 mmol), diphenylphosphinic chloride (0.25 g, 1.1 mmol), then reacted with 4-iodoaniline (Aldrich) (0.093 g, 0.43 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-iodo-phenyl)-amide as a off white solid (Yield 0.09 g, 38%).
Reaction SMILES: O=[C:2]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)[CH2:3][C@H:4]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].Cl.[NH2:38][OH:39].C(=O)([O-])O.[Na+]>>[OH:39]/[N:38]=[C:2](/[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[CH:28]=1)\[CH2:3][C@H:4]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([OH:26])=[O:25])=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11]
Reactant: NO
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccnc(C(F)(F)F)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccnc(C(F)(F)F)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In analogy to example 132, step 6, from 4′-[(R)-3-oxo-1-o-tolyl-3-(2-trifluoromethyl-pyridin-4-yl)-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a light brown foam, MS (ESI−): m/z=503.0 ([M−H]−).