Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[C:11]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[OH-].[K+]>CC1C=CC(C(C)C)=CC=1>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]([OH:18])=[O:17])=[CH:3]1
Reactant: O=C1CCCCCO1
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccc(C(C)C)cc1
Product: O=C(O)CCCCCc1c[nH]c2ccccc12
Reaction time: 96 h

Procedure:
In a water separator, indole (50 g, 0.43 mol.), ε-caprolactone (oxepan-2-one, 55.9 g, 0.49 mol.), potassium hydroxide (35.9 g, 0.64 mol.) in p-cymene (1-isopropyl-4-methylbenzene, 250 ml) were heated at boiling for 4 d, with stirring. For working up, water (200 ml) was added to the mixture, the phases were separated, and the aqueous phase was adjusted to pH 4 with 2M HCl and stored for 2 d at 4° C. in a refrigerator. The resulting solid was filtered off with suction and washed with water (3×20 ml). Recrystallisation from ether (50 ml) yielded 6-(1H-indol-3-yl)hexanoic acid in the form of a white solid having a melting point of 124–126° C. in a yield of 16.9 g.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[O:11][CH2:12][C:13](=[O:20])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:6][CH2:5]1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.N1CCCCC1>C(O)C>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:12]2[O:11][C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[CH2:9][CH2:8]3)=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:22]1
Reactant: CCOC(=O)C1=C(N2CCN(CCO)CC2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(N2CCN(CCO)CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 10.1 %

Procedure:
To a solution of ethyl 2-[4-(2-hydroxyethyl)piperazinyl]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.35 g, 1.2 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.18 g, 1.2 mmol) in ethanol (6.0 mL), piperidine (0.12 mL, 1.4 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.050 g, y. 10%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=3)[N:18]=[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[OH:32])[N:16]=2)[CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=3)[N:18]=[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[OH:32])[N:16]=2)[CH2:10]1
Reactant: Cc1ccc2c(N3CCC[C@@H](CNC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To tert-Butyl-((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (700 mg, 1.56 mmol) was added 20 mL CH2Cl2 followed by addition of 7 mL of TFA. After the reaction was stirred for 1 hour it was neutralized with a 1.0 M aqueous NaOH solution. The mixture was partitioned between H2O and CH2Cl2, and separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to yield 2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (400 mg, 74%). LC/MS: m/z 349.3 (M+H)+ at 1.52 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl[CH2:2][C:3]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])=[CH2:4].[I-:42].[Na+]>CC(C)=O>[I:42][CH2:2][C:3]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])=[CH2:4]
Reactant: [I-]
Reactant: C=C(CCl)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(CI)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1

Procedure:
To a solution of (3S,4S)-4-(1-chloromethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (2.24 g) in acetone (25 ml) was added sodium iodide (1.2 g), and the resultant mixture was stirred at room temperature for 5 hours and concentrated in vacuo to make a volume of about 10 ml. The concentrated solution was diluted with benzene (50 ml) and diethyl ether (50 ml), washed successively with 5% sodium bicarbonate and water and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave (3S,4S)-4-(1-iodomethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di-(p-anisyl)methyl-2-azetidinone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-].[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>C(Cl)Cl.FC1C(F)=C(F)C=CC=1>[Br:1][C:2]1[N:3]=[C:4]([NH:14][C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)[n+]([O-])c1
Reactant: CC(C)(C)N
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: Fc1cccc(F)c1F
Solvent: ClCCl
Product: Cc1ccc(Br)nc1NC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 19.4 %

Procedure:
To a solution of 2-bromo-5-methylpyridine 1-oxide (2.0 g, 10.6 mmol) in DCM (40 mL) and trifluorobenzene (17 mL) at 0° C. were added tert-butylamine (8.0 mL, 76.7 mmol) and p-toluenesulfonic anhydride (11.4 g, 35.0 mmol) portion-wise. The reaction mixture was stirred at 0° C. for 1.5 hours and then filtered. The filtrate was concentrated to give a residue that was purified by flash chromatography (Si—PPC, Et2O:pentane, gradient 0:100 to 100:0) to give (6-Bromo-3-methylpyridin-2-yl)-tert-butylamine as a colourless oil (500 mg, 19%). 1H NMR (400 MHz, CHCl3-d): δ 6.98 (d, J=7.5 Hz, 1 H); 6.59 (d, J=7.5 Hz, 1 H); 4.05 (s, 1 H); 1.96 (s, 3 H); 1.47 (s, 9 H).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=4)[C:33]([NH:35][C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38])=[O:34])=[CH:26][C:20]=3[C:21]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:13][CH:12]=1.[S:45]1[CH:49]=[N:48][N:47]=[C:46]1[NH2:50].[H-].[Na+]>CN(C=O)C>[S:45]1[CH:49]=[N:48][N:47]=[C:46]1[NH:50][C:37](=[O:38])[C:36]([NH:35][C:33]([C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][C:19]3[O:18][C:17]([C:14]4[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=4)=[C:21]([C:22]([NH:23][CH3:24])=[O:25])[C:20]=3[CH:26]=2)[CH:44]=[CH:43][CH:42]=1)=[O:34])([CH3:40])[CH3:41]
Reactant: Nc1nncs1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)O)c3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)Nc4nncs4)c3)cc12
Reaction time: 8 h
Yield: 47 %

Procedure:
DIEA (44 μL, 0.253 mmol) was added to a stirring solution of 2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoic acid (40 mg, 0.084 mmol), 1,3,4-thiadiazol-2-amine (17.05 mg, 0.169 mmol) in DMF (843 μL) at rt. NaH (17 mg, 0.422 mmol) was added, and the slurry became a clear solution after 10 min. It was allowed to stir overnight. The reaction was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (22 mg, 45%). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.44 (1H, br. s.), 9.14 (1H, br. s.), 8.78 (1H, br. s.), 8.47-8.57 (1H, m), 8.30 (1H, s), 7.97-8.04 (2H, m), 7.88-7.95 (3H, m), 7.75-7.84 (2H, m), 7.61 (1H, t, J=7.78 Hz), 7.41 (2H, t), 2.86 (3H, d, J=4.88 Hz), 1.57 (6H, s). LC-MS retention time: 1.57 min; m/z (MH+): 488. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=11.23 min, purity=97%; Column: Waters XBridge phenyl column 4.6×150 mm, 3.5 mm, Rt=10.56 min, purity=96%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].CO>CN(C)C=O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[O:11][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(Br)cc1O
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)COc1cc(Br)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
A solution of 1-(4-bromo-2-hydroxyphenyl)ethanone (1.06 g, 5 mmol) in dry N,N-dimethylformamide (10 mL) was charged with sodium hydride (240 mg, 10 mmol) and the mixture was stirred at room temperature for 30 minutes, then methyl 2-bromoacetate (0.84 g, 5.5 mmol) was added and the mixture was stirred at room temperature for 12 hours. After completed (40 mL) of methanol was added followed by concentrating under vacuum to give methyl 2-(2-acetyl-5-bromophenoxy)acetate (1.38 g, 90%) as colorless oil. 1H NMR (300 MHz, CD3OD) δ 8.01 (s, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H), 6.97 (s, 1H), 4.73 (s, 2H), 3.81 (s, 3H), 2.69 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.C(O)C.[C].[Pd].[C].[Rh].[Pt](=O)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:16]3=[N:17][S:18](=[O:21])(=[O:22])[CH2:19][CH2:20][N:15]3[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: O=[Pt]=O
Agent: [Pd]
Agent: [Rh]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Yield: 23 %

Procedure:
A mixture of 10% palladium-carbon (50% wet, 15 mg) and 9-(4-tert-butylphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (150 mg) in THF (25 mL) and ethanol (25 mL) was stirred under a hydrogen atmosphere at room temperature, and stirred under a hydrogen atmosphere (3.5 atm) for 1 hr. To the reaction mixture was added 5% rhodium-carbon (50% wet, 15 mg), and the mixture was stirred under a hydrogen atmosphere (3.5 atm) for 4 hr. To the reaction mixture was added platinum dioxide (15 mg) and the mixture was stirred under a hydrogen atmosphere for 2 hr. The reaction mixture was filtered, the filtrate was concentrated, and the residue was crystallized from THF and diisopropyl ether to give the title compound (35 mg) as a white solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH:12]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[C:7]2[CH:8]=[N:9][N:10]([S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[C:11]=2[CH:12]=1
Reactant: COC(=O)c1cc(Br)cc2[nH]ncc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc2c1cnn2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
Sodium hydride (1.289 g, 32.2 mmol) was added portion wise to a solution of methyl 6-bromo-1H-indazole-4-carboxylate (4.11 g, 16.11 mmol) in N,N-dimethylformamide (50 ml) at 0° C. The dark orange mixture was stirred at 0° C. for 10 mins, then treated with 4-methylbenzenesulfonyl chloride (3.38 g, 17.72 mmol). The resultant pale cream mixture was stirred for 30 mins at 0° C. then poured into water (1000 ml). The cream precipitate was filtered off under vacuum and dried in the vacuum oven at 50° C. for 18 h to give the title compound as a yellow solid (5.51 g).
Reaction SMILES: C(O)C.O[CH:5]([C:17]1[CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[NH:20][CH:21]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H][H]>[C].[Pd].C(Cl)(Cl)Cl>[CH2:5]([C:17]1[CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[NH:20][CH:21]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [H][H]
Reactant: CCCCCCCCCCCC(O)c1c[nH]c(C(=O)OC)c1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCCCCCCCCCCCc1c[nH]c(C(=O)OC)c1
Reaction time: 5.5 h
Yield: 83.8 %

Procedure:
To an ethanol solution (2.0 liters) of 258.0 g (0.73 mol) of methyl 4-(1-hydroxydodecyl)pyrrole-2-carboxylate prepared in Synthetic Example 11 was added 16 g of 10% palladium-carbon. A catalytic reduction with hydrogen was carried out at 50° C. under hydrogen atmosphere. After the reaction was completed within 5.5 hours, 1.5 liters of chloroform was added to the reaction mixture. The catalyst was filtered off, and the solvent was removed under a reduced pressure to give crystals. Recrystallization from 950 ml of ethanol afforded 179.6 g (83% yield) of methyl 4-dodecylpyrrole-2-carboxylate as white crystals, m.p. 68°-69° C.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[BH4-].[Na+]>CO.O>[O:3]1[C:4]2([CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]2)[O:11][CH2:1][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.1 %

Procedure:
1,4-Cyclohexanedione mono-ethylene ketal (5.0 g, 32 mmol) in 20 mL of MeOH/water (1:1) was added NaBH4 (1.21 g, 32 mmol). The mixture was stirred at room temperature overnight. The MeOH was removed via rotary evaporation. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), and concentrated to give an oil which was stored on a high vacuum line overnight to afford 5.12 g of 1,4-dioxaspiro[4.5]decan-8-ol as as an oil. MS (EI) calcd: (M+H)+=159.1; found: 159.2.
Reaction SMILES: ClCCl.Cl[C:5]1[C:6]2[CH:13]=[CH:12][NH:11][C:7]=2[N:8]=[CH:9][N:10]=1.[CH3:14][Mg]Br>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:14][C:5]1[C:6]2[CH:13]=[CH:12][NH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: C[Mg]Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ncnc2[nH]ccc12
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 15.9 %

Procedure:
Into a round bottom flask the catalyst [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 1:1 complex with dichloromethane (70.0 mg, 0.09 mmol), is placed under nitrogen with 15 mL of toluene along with a stir bar. A suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 1.47 g, 9.57 mmol) in 15 mL of toluene is added at room temperature. After stirring for 10 minutes, methylmagnesium bromide (17.00 mL, 3.00 M in ether, 51.00 mmol) is added dropwise. The solution is slowly heated to 60° C. and stirred for 3 hrs at 60° C., then overnight at room temperature. The resulting dark orange reaction mixture is quenched with 1 N hydrochloric acid and adjusted to pH ˜5, then extracted with ethyl acetate and water saturated with sodium chloride. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound as a yellow solid (8, 202 mg). 1H-NMR (dmso-d6) is consistent with the desired compound. MS (ESI) [M+H+]+=134.3.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[CH:9]([CH3:12])[C:10]#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:25])C.O>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[CH:9]([CH3:12])[CH:10]=[O:25]
Reactant: CC(=O)O
Reactant: CC(C#N)C1CC(C)(C)CC1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C=O)C1CC(C)(C)CC1C
Temperature: 25 °C

Procedure:
2-(2,4,4-Trimethylcyclopentyl)propanenitrile 6 is placed in toluene at 10° C. under an inert atmosphere. 1.2 eq. of Dibal (diisobutylaluminum hydride) are added thereto dropwise. The reaction medium is stirred at ambient temperature for a few hours and is then poured onto a 20:40:40 mixture of acetic acid, water and ice. The aqueous phase is extracted once with toluene. The combined organic phases are washed with a sodium bicarbonate solution and then with an aqueous sodium chloride solution. After drying over magnesium sulfate, filtering through paper and evaporating the solvent, the crude product, obtained in the form of three diastereomers observed by GC in proportions of 73:16:11, is distilled under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:25])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:21]=[C:20]([C:22](O)=[O:23])[O:19][N:18]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl.[CH3:27][O:28][C:29](=[O:35])[C@@H:30]([NH2:34])[CH:31]([CH3:33])[CH3:32].[K+].[Br-]>>[CH3:27][O:28][C:29](=[O:35])[C@@H:30]([NH:34][C:22]([C:20]1[O:19][N:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:25])=[CH:16][CH:15]=2)[CH:21]=1)=[O:23])[CH:31]([CH3:33])[CH3:32]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(Nc1ccc(F)cc1)Nc1ccc(-c2cc(C(=O)O)on2)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: COC(=O)[C@@H](NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(F)cc3)cc2)no1)C(C)C
Yield: 84.2 %

Procedure:
The title compound was prepared from 3-{4-[3-(4-fluoro-phenyl)-ureido]-phenyl}-isoxazole-5-carboxylic acid and (S)-2-amino-3-methyl-butyric acid methyl ester hydrochloride using the procedure as set forth in Example 5 and was obtained in 84.2% yield. Mass (ES+): 455 (M++1); IR (KBr): 3310, 1742, 1672, 1553 (br), 1506, 1434; 1H NMR (DMSO-d6) δ: 0.92 (2×d, 6H), 2.18 (m, 1H), 3.65 (s, 3H), 4.29 (t, 1H), 7.11 (t, 2H), 7.59 (d, 2H), 7.66 (s, 1H), 7.82 (d, 2H), 8.77 (s, 1H), 8.94 (s, 1H), 9.16 (d, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:28][C:12]2=[CH:13][C:14]3[C:15](=[O:27])[N:16]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:17](=[O:21])[C:18]=3[C:19]([CH3:20])=[C:11]2[N:10]=1.[F:29][C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[C:32]([F:38])[C:31]=1[CH2:39][CH:40]([NH2:42])[CH3:41].CCN(C(C)C)C(C)C>C(O)CCC>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:16]1[C:15](=[O:27])[C:14]2[CH:13]=[C:12]3[NH:28][C:9]([C:3]4[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=4[NH:42][CH:40]([CH3:41])[CH2:39][C:31]4[C:32]([F:38])=[C:33]([F:37])[CH:34]=[C:35]([F:36])[C:30]=4[F:29])=[N:10][C:11]3=[C:19]([CH3:20])[C:18]=2[C:17]1=[O:21]
Reactant: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Reactant: CC(N)Cc1c(F)c(F)cc(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Yield: 42.8 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)-4-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione, (0.54 g, 1.35 mmol), 1-(2,3,5,6-tetrafluorophenyl)propan-2-amine (0.34 g, 1.62 mmol), Hunig's base (0.87 g, 6.75 mmol), and 12 mL of anhydrous 1-butanol was heated at reflux for 13-14 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 0.33 g of the designed compound as yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.33 (s, 1H, NH), 11.29 (br s, 1H, NH), 11.00 (d, J=5.7 Hz, 1H, NH), 7.97 (s, ArH), 7.73-7.70 (m, 1H, ArH), 7.40 (d, J=7.6 Hz, 1H, ArH), 6.21 (d, J=7.6 Hz, 1H, ArH), 4.32-4.28 (m, 1H, CH), 3.65 (t, J=6.3 Hz, 2H, CH2), 3.08 (d, J=5.1 Hz, 2H, CH2), 2.72 (s, 3H, CH3), 2.19 (S, 6H, 2×CH3); 1.36 (d, J=6.3 Hz, 3H, CH3), 1.11 (t, J=6.3 Hz, 2H, CH2); Mass (ESI, negative) m/z 568.8 [M−H]−.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[C:9]([I:14])=[N:10][CH:11]=[CH:12][CH:13]=1>N1C=CC=CC=1>[CH2:5]([O:4][C:2](=[O:3])[NH:7][C:8]1[C:9]([I:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Nc1cccnc1I
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cccnc1I
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
Ethyl chloroformate (0.91 mL, 9.5 mmol) is added to a solution of 3-amino-2-iodo-pyridine (1.4 g, 6.36 mmol) in 15 mL of pyridine cooled at 0° C. The mixture is stirred at 0° C. for 2 hours and allowed to warm slowly to room temperature. At this time, excess pyridine is removed in vacuo. The residue is diluted with EtOAc and washed with water, 1N HCl and saturated NaHCO3. The organic layer is dried over MgSO4, filtered and concentrated in vacuo. The crude product is purified by column chromatography eluting with 30% EtOAc/hexanes to give the title compound (1.2 g, 4.11 mmol) as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1.[C:45]1([CH3:57])[CH:50]=[C:49]([CH3:51])[CH:48]=[C:47]([CH3:52])[C:46]=1[S:53](Cl)(=[O:55])=[O:54].N1C=CC=CC=1>ClCCCl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[O:26])[C:14](=[O:44])[N:11]2[CH2:12][CH2:13][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][S:53]([C:46]3[C:47]([CH3:52])=[CH:48][C:49]([CH3:51])=[CH:50][C:45]=3[CH3:57])(=[O:55])=[O:54])[CH2:9][CH2:10]2)=[CH:22][CH:21]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N)CC1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1cc(C)c(S(=O)(=O)Nc2ccccc2C2CCN(C(=O)[C@@H](Cc3ccc(Cl)cc3)NC(=O)[C@@H]3Cc4ccccc4CN3C(=O)OC(C)(C)C)CC2)c(C)c1
Yield: 73.1 %

Procedure:
The title compound was prepared according to the procedure described in Example 21 (Step a) by treating tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Example 20) (154 mg, 0.25 mmol) with 2-mesitylenesulfonyl chloride (Aldrich) (55 mg, 0.25 mmol) and pyridine (0.03 mL, 0.375 mmol) in 1,2-dichloroethane (10 mL). Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (146 mg). MS (ESI, pos. ion) m/z: 799 (M+1); MS (ESI, neg. ion) m/z: 797 (M−1) Calc'd for C44H51ClN4O6S: 798.32.