Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])(O)=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[NH:14])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17].CN(C)[CH:21]=[CH:22][C:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=O>>[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:15]=[C:23]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:22]=[CH:21][N:14]=2)=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17]
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: N=C(N)Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc(Nc2nccc(-c3cccnc3)n2)ccc1F
Yield: 63 %

Procedure:
4-Fluoro-3-nitrophenyl-guanidine nitrate (40 g, 0.153 mol) and 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (27 g, 0.153 mol) were reacted according to the same procedure as Step 1.3 of Preparation 1 to give N-(4-fluoro-3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine (30 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])=[CH:4][CH:3]=1.[NH2:17][C:18](N)=[O:19].O>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:15][C:18](=[O:19])[N:17]=2)=[CH:4][CH:3]=1
Reactant: NC(N)=O
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1nc(-c2ccc(F)cc2)c2ccccc2[nH]1

Procedure:
4'-Fluoro-2-aminobenzophenone (164.5 g, 1.20 mol) is heated with urea (72.09 g, 0.500 mol) at 195° C. (1 h) in NMP (500 mL). The solution is cooled and poured into water (2 L). The product is collected by filtration and dried. The product is purified by recrystallization.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[CH:15]([Si:18]([C:25]#[CH:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16].ClCCl>C(N(CC)CC)C.[Cu](I)I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:14][C:5]1[CH:4]=[CH:3][C:2]([C:26]#[C:25][Si:18]([CH:15]([CH3:17])[CH3:16])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[CH:7][C:6]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: Fc1ccc(Br)cc1N1CCOCC1
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](C#Cc1ccc(F)c(N2CCOCC2)c1)(C(C)C)C(C)C
Yield: 99.6 %

Procedure:
To a CEM snap top microwave vial (10 ml) equipped with a magnetic stir bar (3×10 mm) was added 4-(5-bromo-2-fluorophenyl)morpholine (390 mg, 1.50 mmol) in triethylamine (1.5 mL). Copper iodide (12 mg, 0.060 mmol), Tetrakis(triphenylphosphine) palladium (35 mg, 0.030 mmol) and triisopropylsilyl-acetylene (0.390 mg, 2.14 mmol) were added at room temperature. The reaction was capped and irradiated in a CEM Explorer microwave at 80° C. for 30 minutes then forced air-cooled. The crude material was loaded onto silica gel and chased with dichloromethane. Purification by chromatography (hexanes) afforded 540 mg of an oil (quant); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.10 (m, 21H) 3.00 (t, J=4.6 Hz, 4H) 3.71 (t, J=4.6 Hz, 4H) 7.01 (dd, J=8.5, 2.0 Hz, 1H) 7.08 (ddd, J=4.9, 2.9, 2.6 Hz, 1H) 7.11-7.18 (m, 1H); MS (ES) m/z 362.2 [M+H]+
Reaction SMILES: [S:1]1([CH2:7][CH:6]=[CH:5][CH2:4]1)(=[O:3])=[O:2].[C:8]1([NH:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[K+]>>[C:8]1([N:14]([CH:5]2[CH2:6][CH2:7][S:1](=[O:3])(=[O:2])[CH2:4]2)[NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NNc1ccccc1
Reactant: O=S1(=O)CC=CC1
Agent: [K+]
Agent: [OH-]
Product: NN(c1ccccc1)C1CCS(=O)(=O)C1
Temperature: 60 °C
Reaction time: 10 h
Yield: 53 %

Procedure:
Butadiene sulfone (0.5 mol, obtained from Aldrich chemicals, Milwaukee, Wis.) and phenyl hydrazine (0.55 mol, 1.1 equiv. obtained from Aldrich Chemicals, Milwaukee, Wis.) were stirred for 5-10 minutes, and then 40% aqueous KOH solution (0.005 mol, 0.01 equiv. obtained from Aldrich Chemicals, Milwaukee, Wis.)) was added. The mixture was heated at 60° C. for 2 hours whereupon a solid separated. After 10 hours at room temperature, the solid was filtered, washed with excess of water and recrystallized from methanol to give the product as white crystals; yield 53%; mp 119.9-121.5° C.; 1H-NMR and 13C-NMR spectra in CDCl3 were in full agreement with the structure.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=2)[C:3]=1[CH3:21].[CH3:22][S:23]([C:26]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][C:27]=1[NH2:28])(=[O:25])=[O:24].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C(Cl)Cl>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:28][C:27]1[CH:29]=[C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[CH:31]=[CH:32][C:26]=1[S:23]([CH3:22])(=[O:25])=[O:24])=[C:3]([CH3:21])[C:4]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)=[N:5]2
Reactant: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Reactant: CS(=O)(=O)c1ccc(N2CCOCC2)cc1N
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Nc3cc(N4CCOCC4)ccc3S(C)(=O)=O)c2C)c1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
A screw-cap vial was charged with 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (50 mg, 0.16 mmol), 2-(methylsulfonyl)-5-morpholinoaniline (Matrix Scientific; 50.5 mg, 0.20 mmol), XPhos precatalyst (CAS 1028206-56-5; 24.24 mg, 0.033 mmol), sodium tert-butoxide (39.4 mg, 0.41 mmol), and toluene (1.5 mL). The mixture was stirred at 95° C. under nitrogen gas for 3 h. The reaction was then cond and the resulting residue was dissolved in DCM. This solution was washed with water, dried over magnesium sulfate, and cond. The resulting crude product was purified by flash-chromatography (silica gel, 0-85% EtOAc in hexanes), affording 5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)-N-(2-(methylsulfonyl)-5-morpholinophenyl)quinolin-4-amine as a white solid. Mass Spectrum (ESI) m/e=525.3 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.62 (1H, d, J=6.5 Hz), 8.55 (1H, d, J=5.1 Hz), 7.79 (1H, d, J=9.0 Hz), 7.67-7.70 (1H, m), 7.62-7.67 (1H, m), 7.18-7.25 (1H, m), 6.96-7.04 (1H, m), 6.47-6.52 (1H, m), 5.98-6.01 (1H, m), 3.70-3.80 (4H, m), 3.17 (3H, s), 3.06-3.16 (4H, m), 2.49 (3H, s), 2.28 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]([NH:9][C:10]([CH3:17])([CH3:16])[CH2:11][C:12]([O:14]C)=O)=[O:8])=[O:5])C.[Na]>CO>[CH3:16][C:10]1([CH3:17])[NH:9][C:7](=[O:8])[CH:6]([C:4]([O:3][CH3:1])=[O:5])[C:12](=[O:14])[CH2:11]1
Reactant: CCOC(=O)CC(=O)NC(C)(C)CC(=O)OC
Agent: [Na]
Solvent: CO
Product: COC(=O)C1C(=O)CC(C)(C)NC1=O
Yield: 72 %

Procedure:
A solution of methyl 3-(ethoxycarbonylacetamido)-3-methylbutyrate (45 g) and sodium metal (4.22 g) in anhydrous methanol (450 ml) was heated at a reflux for 3 hours. The cooled mixture was evaporated under reduced pressure and the residue dissolved in water (200 ml). The aqueous solution was washed with ether (3×100 ml), acidified with 2N hydrochloric acid and the acidic mixture extracted with dichloromethane (3×100 ml). The combined extracts were washed with water (2×100 ml), dried over magnesium sulphate and evaporated under reduced pressure to give methyl 6,6-dimethylpiperidine-2,4-dione-3-carboxylate (26.3 g), mp 170°-172° C., as a cream crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>>[F:13][C:14]([F:24])([F:25])[C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([N:8]=[C:4]([O:5][CH2:6][CH3:7])[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1])=[O:18]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CCOC(=N)c1ccccc1Cl
Product: CCOC(=NC(=O)c1ccccc1C(F)(F)F)c1ccccc1Cl

Procedure:
Analogously to the procedure described in Example 2, starting from ethyl o-chlorobenzimidate and o-trifluoromethyl-benzoyl chloride there is obtained ethyl N-(o-trifluoromethyl-benzoyl)-o-chlorobenzimidate, m.p. 64°-65° C., and therefrom by means of 2-hydroxyethylhydrazine there is obtained 3-(o-chlorophenyl)-1-(2-hydroxyethyl)-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, m.p. 115° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH3:18])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:19])[N:7]([CH3:18])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(Cc1ccccc1N)C(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 90.7 %

Procedure:
A mixture of methyl-(2-nitro-benzyl)-carbamic acid tert-butyl ester (2.0 g, 7.5 mmol) and 10% Pd—C (100 mg) in methanol (150 mL) was stirred for 12 h under a hydrogen atmosphere. The catalyst was removed by filtration and the solvent evaporated to give methyl-(2-amino-benzyl)-carbamic acid tert-butyl ester (1.58 g, 6.8 mmol, 91%).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4](O)[CH:3]=1.[CH2:11]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>>[CH2:11]([N:15]([CH2:16][CH2:17][CH2:18][CH3:19])[C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCNCCCC
Reactant: Cc1cc(O)cc(O)c1
Solvent: O
Product: CCCCN(CCCC)c1cc(C)cc(O)c1
Temperature: 200 °C
Reaction time: 48 h
Yield: 61 %

Procedure:
A 300 milliliter Parr minibomb was charged with orcinol monohydrate, 42 grams, 0.3 mole and di-n-butylamine, 128 milliliters. The bomb was sealed and heated to 200° C. At this temperature the internal pressure of the bomb was 90 pounds per square inch as registered on the gauge. After 48 hours at 200°, the bomb was cooled and the light brown syrup analyzed by thin-layer chromatography. The excess di-n-butylamine was removed by distillation at 20 Torr and the product was further purified by filtration through a silica gel column using ethyl acetate as the eluent. The product 3-dibutylamino-5-methylphenol was isolated in 61% yield: 43 grams. This material was not further characterized but used directly in the subsequent reaction.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:17][C:18]([O:20]C)=O)([CH2:13][N+:14]([O-])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].O.C(O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:13][NH:14][C:18](=[O:20])[CH2:17]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC1(C[N+](=O)[O-])CCN(Cc2ccccc2)C1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: O=C1CC2(CCN(Cc3ccccc3)C2)CN1
Temperature: 30 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
A suspension of methyl [1-benzyl-3-(nitromethyl)pyrrolidin-3-yl]acetate a46 (3.3 g, 1.1 mmol, 1 eq) and Raney nickel (1 g of a 50% slurry in water) in ethanol (200 ml) is shaken in a Parr bottle at 30° C. for 24 h, under a hydrogen pressure of 40 psi. The reaction mixture is then filtered through Celite and the filtrate is concentrated to afford 1.8 g of 7-benzyl-2,7-diazaspiro[4.4]nonan-3-one a47 as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@H:13]([C:14]([O:16]CC)=[O:15])[C@@H:12]([C:19]3[CH:27]=[CH:26][C:22]4[O:23][CH2:24][O:25][C:21]=4[CH:20]=3)[CH2:11][N:10]2[CH2:28][C:29]([N:31]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:32][CH2:33][CH2:34][CH2:35]Br)=[O:30])=[CH:5][CH:4]=1.[CH3:41][NH:42][CH3:43]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@H:13]([C:14]([OH:16])=[O:15])[C@@H:12]([C:19]3[CH:27]=[CH:26][C:22]4[O:23][CH2:24][O:25][C:21]=4[CH:20]=3)[CH2:11][N:10]2[CH2:28][C:29]([N:31]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:32][CH2:33][CH2:34][CH2:35][N:42]([CH3:43])[CH3:41])=[O:30])=[CH:5][CH:4]=1
Reactant: CNC
Reactant: CCCCN(CCCCBr)C(=O)CN1C[C@H](c2ccc3c(c2)OCO3)[C@@H](C(=O)OCC)[C@H]1c1ccc(OC)cc1
Solvent: CCO
Product: CCCCN(CCCCN(C)C)C(=O)CN1C[C@H](c2ccc3c(c2)OCO3)[C@@H](C(=O)O)[C@H]1c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of the compound of Example 547D (0.825 g, 1.34 mmol) in 3 mL of ethanol was added 5 mL of 4.07M dimethylamine in ethanol; the resultant solution was heated at reflux for 75 min. Solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 9:1 dichloromethane/methanol. The resultant material was taken up in 5 mL of 1.4N NaOH in 5:1 ethanol/water and stirred at ambient temperature for 14 hrs. Solvents were removed in vacuo; the residue was taken up in water, then adjusted to pH 6-7 with 1M HCl (˜7 mL required). The mixture was extracted with EtOAc (3×); the aqueous layer was concentrated in vacuo. The residue was washed 3× with acetonitrile; the combined washes were filtered through Celite and concentrated to give 596 mg of a white foam.
Reaction SMILES: [CH2:1]([OH:12])[C:2]([C@@H:4]([OH:11])[C@H:5]([OH:10])[C:6]([CH2:8][OH:9])=[O:7])=O.C([BH3-])#N.[Na+].[CH:17]([NH2:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C>CO>[CH:17]([N:30]1[C@:2]2([CH2:1][OH:12])[O:7][C@:6]1([C@H:5]([C@@H:4]2[OH:11])[OH:10])[CH2:8][OH:9])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CO)[C@@H](O)[C@H](O)C(=O)CO
Reactant: NC(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: OC[C@]12O[C@](CO)([C@@H](O)[C@@H]1O)N2C(c1ccccc1)c1ccccc1
Yield: 62.2 %

Procedure:
A suspension of 5-keto-D-fructose (Formula X, 50 g, 0.28 mol; obtained from Chemical Dynamics) in 400 mL of MeOH was treated with sodium cyanoborohydride (40 g, 0.476 mol). A slurry of benzhydrylamine (42.0 mL, 0.234 mol) in 120-mL of MEOH was treated with sufficient acetic acid to bring the pH to 6-7 and then added over a 0.5 h period to the 5-keto-D-fructose (Formula X) and sodium cyanoborohydride suspension. An additional portion of sodium cyanoborohydride (20 g. 0.235 mol) was added and the mixture was stirred at reflux for 6 h. The solvent was then removed, and the residue treated with 10% sodium carbonate (ca. 100 mi), and the product was extracted into chloroform. The chloroform layers were dried (MgSO4), filtered and concentrated to give a tacky yellow solid. This was purified on two Waters Prep 500 columns (CHCl3 /MeOH/NH4OH, 88:11:1) to give ca. 50 g of the target compound. Recrystallization from ethyl acetate gave 21.3 g (28%) of white needles, 152.5°-154.5° C. (corrected). Both 1H and 13C NMR in CDCl3 supported the assigned structure.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9](/[N:21]=[CH:22]/[C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)=[C:10]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:21][CH2:22][C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)=[C:10]([NH:12][C:13](=[O:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(/C=N/c2ccc(N3CCCC3)cc2NC(=O)c2ccccc2)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNc2ccc(N3CCCC3)cc2NC(=O)c2ccccc2)cc(OC)c1OC

Procedure:
A suspension of compound (E)-N-(5-(pyrrolidin-1-yl)-2-(3,4,5-trimethoxybenzylideneamino)phenyl)benzamide (3 mmol) in methanol was cooled with an ice bath. Sodium borohydride was added until the color turned white. Excess sodium borohydride was quenched by the addition of distilled water. The resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organics were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuum to obtain N-(5-(pyrrolidin-1-yl)-2-(3,4,5-trimethoxybenzylamino)phenyl)benzamide as a solid.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:8][C:9](=[O:24])[CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=O)[CH:19]=2)[CH:14]=[CH:13][C:12]=1[Cl:23])[CH3:7].C(N(CC)CC)C.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1.CO>[CH2:6]([O:8][C:9](=[O:24])[CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][NH:5][CH2:4][CH2:3][F:2])[CH:19]=2)[CH:14]=[CH:13][C:12]=1[Cl:23])[CH3:7]
Reactant: CCOC(=O)Cc1c(Cl)ccc2ccc(C=O)cc12
Reactant: NCCF
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1c(Cl)ccc2ccc(CNCCF)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Fluoroethylamine hydrochloride (94 mg, 0.94 mmol) is added under an atmosphere of argon to a solution of (2-chloro-7-formyl-naphthalen-1-yl)-acetic acid ethyl ester (200 mg, 0.72 mmol) in 7.6 ml of THF. Triethylamine (0.13 ml, 0.94 mmol) is added, and the mixture is stirred at RT for 18 h, before a solution of sodium cyanoborohydride (50 mg, 0.80 mmol) in MeOH (2.0 ml) and glacial acetic acid (0.21 ml, 3.61 mmol) are added. After stirring at RT for 1 h, TLC analysis indicates complete consumption of starting material. The reaction mixture is diluted with water and adjusted to pH 8 by the addition of a 1 M aqueous solution of NaHCO3. Extraction with EtOAc, washing with brine, drying over Na2SO4 and removal of solvent yields the crude reaction product. Purification by FCC (EtOAc/MeOH 9:1) affords the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.26 (t, J=8.4 Hz, 3H), 2.92-3.04 (m, 2H), 4.06 (s, 2H), 4.19 (q, J=8.4 Hz, 2H), 4.32 (s, 2H), 4.52-4.68 (m, 2H), 7.48 (d, J=9 Hz, 1H), 7.51-7.53 (m, 1H), 7.73 (d, J=9.4 Hz, 1H), 7.82 (d, J=9 Hz, 1H), 7.88 (s, 1H). ES+-MS: 324.2, 326.1 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[NH:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:27]([CH:32]=O)[CH2:28][CH:29]([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:37]([O:36][C:34](=[O:35])[NH:26][CH:27]([CH2:32][NH:2][CH:3]([C:4](=[O:5])[NH:6][C:7]([CH3:8])([CH3:10])[CH3:9])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)[CH2:28][CH:29]([CH3:30])[CH3:31])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(C)CC(CNC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
(S)-2-Amino-3 -(4-benzyloxy-phenyl)-N-tert-butyl-propionamide monohydrochloride (1.68 g, 4.65 mmol, Example 7, Step A) and BOC-Leu-CHO ((tert-butoxy)-N-[1-(2-methylpropyl)-2-oxoethyl]carboxamide) (1.00 g, 4.65 mmol, Peninsula Laboratories, Belmont, Calif.) were mixed in CH2Cl2 (25 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (1.50 g, 6.98 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty-five milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The 2 layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The reaction gave two diastereomers which were purified twice by column chromatography (eluant used in first column chromatography: 30% EtOAc-4% MeOH-66% hexanes; eluant used in second column chromatography: 100% acetonitrile). When the solvent system, 30% EtOAC-66% benzene-4% MeOH, was used as eluant, The two diastereomers gave different Rf values on TLC (0.68 and 0.53). The compound with a Rf value of 0.53 was isolated by preparative plate as a yellow oil (0.27 g) and used in used step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[C:22]([O:26][C:27](=[O:54])[N:28]([C@@H:42]([C:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46][CH:45]=1)[CH3:43])[CH2:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH:31]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH3:25])([CH3:24])[CH3:23]>C1COCC1.O>[C:5]([C:4]1[CH:7]=[C:8]([F:11])[C:9]([N:33]2[CH2:34][CH2:35][CH:30]([CH2:29][N:28]([C@@H:42]([C:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[CH:47]=[CH:46][CH:45]=3)[CH3:43])[C:27](=[O:54])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])[CH:31]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:32]2)=[C:2]([F:1])[CH:3]=1)#[N:6]
Reactant: N#Cc1cc(F)c(F)c(F)c1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2c(F)cc(C#N)cc2F)CC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
To a mixture of 96 mg of 3,4,5-trifluorobenzonitrile, 113 mg of potassium carbonate, and 3.0 mL of DMSO was added a solution of 181 mg of a crude product of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate in 3.0 mL of THF, the reaction vessel was tightly sealed, and the mixture was heated at 100° C. overnight. The reaction mixture was cooled to room temperature, and water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 232 mg of tert-butyl {[1-(4-cyano-2,6-difluorophenyl)-3-phenylpiperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a crude product. FAB+: 582
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[O:18]1[C:22]2[CH:23]=[CH:24][C:25](B(O)O)=[CH:26][C:21]=2[CH2:20][CH2:19]1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:25]2[CH:24]=[CH:23][C:22]3[O:18][CH2:19][CH2:20][C:21]=3[CH:26]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc5c(c4)CCO5)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, light brown solid (80 mg, 91%), MS (ISP) m/z=353.5 [(M+H)+], mp 261° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 2,3-dihydro-benzofuran-5-ylboronic acid (53.3 mg, 0.325 mmol).
Reaction SMILES: [C:1]([CH2:6][CH:7]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:27]([O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCOC(C)=O>C1COCC1>[CH2:27]([O:34][C:35]1[CH:36]=[C:37](/[CH:38]=[C:6](\[CH3:7])/[C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:40]=[CH:41][CH:42]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (carbethoxyethylidene)triphenylphosphorane (available from Aldrich) (5.50 g, 15.2 mmol) in THF (25 mL) was added 3-(benzyloxy)benzaldehyde (available from Aldrich) (2.93 g, 13.8 mmol) in THF (10 mL) under nitrogen at −78° C. The reaction was allowed to slowly warm to room temperature and stirred for 2 hours. EtOAc (100 mL) was added, and the mixture was washed with brine (30×2 mL). The organic layer was dried over MgSO4. The solvent was removed by evaporation. The crude product was purified by passing through a short silica gel column, eluting with hexane/EtOAc (85/15) to give (E)-ethyl 3-(3-(benzyloxy)phenyl)-2-methylacrylate 62.B.