Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([O:5]N1C(=O)CCC1=O)=O.[CH:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH2:31])[CH2:29][OH:30])=[CH:24][CH:23]=1>C1COCC1>[OH:30][CH2:29][C@H:28]([NH:31][C:3](=[O:5])[C@@H:2]([CH3:1])[CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:25]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CC(CCCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Product: C[C@@H](CCCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Temperature: 48 °C
Reaction time: 40 h
Yield: 34 %

Procedure:
To a solution consisting of (±)-2,5-dioxopyrrolidin-1-yl 2-methyl-5-phenyl pentanoate (18mb(i), 85.6 g, 296 mmol) in THF (3000 mL) at 48° C. was added R-(−)-2-phenylglycinol (65.9 g, 480 mmol, Bridge Organics) in portions. The resulting reaction mixture was stirred at 48° C. for 40 hours. A white precipitate formed, which was filtered from the reaction mixture and washed with THF. The filtrate was concentrated under vacuum and the residue, comprising the diastereomeric pair, was chromatographed on silica gel. Elution with ethyl acetate-heptane (50:50 v/v) afforded the pure diastereomer title compound (31.3 g, 34%) as a colorless solid; TLC Rf 0.205 (solvent system: 50:50 v/v ethyl acetate-heptane); HPLC retention time 15.1 minutes, stationary phase: Gemini 5μ C18 250×4.6 mm, ultraviolet detector at 210 nm, mobile phase: 1 mL/min, 60:40:0.1 v/v methanol-water-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]([C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][C:21](Cl)=[O:22])=[CH:17][CH:16]=1)#[N:14].C(N(CC)CC)C>ClCCl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:21](=[O:22])[CH2:20][O:19][C:18]2[CH:24]=[CH:25][C:15]([C:13]#[N:14])=[CH:16][CH:17]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: N#Cc1ccc(OCC(=O)Cl)cc1
Reactant: COC(=O)c1cc(Br)ccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Br)ccc1NC(=O)COc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-amino-5-bromobenzoate (4.0 g, 17.39 mmol) in dichloromethane (60 mL) was added 2-(4-cyanophenoxy)acetyl chloride (3.74 g, 19.13 mmol, Intermediate 2: step a) to form a thick suspension. An additional 30 mL of dichloromethane was added. The reaction was then cooled to 0° C. and triethylamine (5.32 mL, 38.25 mmol) was added dropwise. The cold bath was removed and the reaction was stirred at room temperature for 2 hours, then filtered to give the title compound as a white solid. The filtrate was washed with water, followed by saturated aqueous NH4Cl solution. The organic layer was dried (MgSO4), filtered, concentrated, and the residue was purified by flash column chromatography (silica gel, 20% EtOAc-heptane) to afford more of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:28])[CH3:27])=[CH:4][CH:3]=1.CN(C)[C:31](=[O:33])[CH3:32]>C(OCC)(=O)C.CCCCCC>[C:31]([C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:28])[CH3:27])=[CH:6][CH:7]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)N(C)C
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2c1ccc(Br)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C2c3cc(NC(=O)CC(C)(C)C)c(C)c(C)c3OC2(C)C)cc1
Yield: 20 %

Procedure:
Using N-(3-(4-bromophenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 284 and N,N-dimethylacetamide, the title compound was synthesized in the same manner as in Example 292. Yield: 20%. Melting point: 195-196° C. (ethyl acetate-hexane).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][C:2]21[C:10]1[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=[CH:14][C:9]=1[S:8](=[O:19])(=[O:18])[CH2:7][CH2:6]2.C(Cl)(=O)C(Cl)=O.[C:26]1(=O)[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[CH2:27]1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][C:2]21[C:10]1[CH:11]=[C:12]([C:15]([O:17][C:26]3[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[CH:27]=3)=[O:16])[CH:13]=[CH:14][C:9]=1[S:8](=[O:19])(=[O:18])[CH2:7][CH2:6]2
Reactant: O=C1CCCC(=O)C1
Reactant: O=C(O)c1ccc2c(c1)C1(CCS2(=O)=O)OCCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C=C(OC(=O)c2ccc3c(c2)C2(CCS3(=O)=O)OCCO2)CCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
2.0 g (7.0 mmol) of the title compound of Step E, 1.2 mL (0.014 mol) of oxalyl chloride (purchase from Janssen), and 2 drops of N,N-dimethylformamide were added to 50 mL of methylene chloride. The mixture was refluxed under nitrogen for 2 h, and was then evaporated to dryness. 50 mL of methylene chloride was added to the residue and the resulting mixture was evaporated to dryness. Another 50 mL of methylene chloride was added to the residue, and the solution was cooled to about 0° C. 0.86 g (7.7 mmol) of 1,3-cyclohexanedione (purchased from Aldrich Chemical Company) was added followed by 2.7 mL (0.0196 mol) of triethylamine, and the mixture was stirred overnight while warming to room temperature. The mixture was evaporated to dryness, the residue was stirred in 100 mL of water and filtered. The crude product was washed with hexane to yield 2.19 g of the title compound of Step F as a solid melting at 185-186° C. 1H NMR (CDCl3): δ2.2 (m,2H), 2.5 (t,2H), 2.7 (t,4H), 3.7 (m,2H), 4.2 (m,2H), 4.3 (m,2H), 6.0 (s,1H), 8.0-8.25 (3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:22]=[CH2:23])=[CH:5][C:6]2[CH2:7][CH2:8][C@@H:9]3[C@@H:18]([C:19]=2[CH:20]=1)[CH2:17][CH2:16][C@@:14]1([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]1[OH:21].C([Sn-3](CCCC)(CCCC)C=C)CCC.[Cl-].[Li+].C1C=CN=CC=1.F>CN(C=O)C.CCOC(C)=O.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.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH3:1][O:2][C:3]1[C:4]([CH:22]=[CH2:23])=[CH:5][C:6]2[CH2:7][CH2:8][C@@H:9]3[C@@H:18]([C:19]=2[CH:20]=1)[CH2:17][CH2:16][C@@:14]1([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]1=[O:21]
Reactant: C=Cc1cc2c(cc1OC)[C@H]1CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C=Cc1cc2c(cc1OC)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Temperature: 90 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
Alternate synthesis of 2-methoxy-3-(vinyl)estra-1,3,5(10)-triene-17β-ol (Compound #25a): Into a solution of 3-triflate-2-methoxyestra-1,3,5(10)-trien-17β-ol (218 mg, 0.5 mmol, prepared as in Shi J. Am. Chem. Soc. 2002, 124, 6921) in 4 mL DMF (anhydrous), was added tributyl(vinyl)Tin(1) (200 μL, 0.6 mmol), lithium chloride (85 mg, 2 mmol), dichlorobis(triphenylphosphine)palladium (II) (10 mg, 0.05 mmol), 2,6-di-tert-butyl-4-methylphenol (2 mg) at room temperature. The reaction was heated at 90° C. for 24 h and then cooled to room temperature. After adding HF-pyridine (4 mL) the reaction mixture was stirred for 16 h. After diluting with EtOAc (20 mL) the reaction mixture was filtered through Celite filter agent and the combined organics were washed with 1 N HCl (1×100 mL), water (1×100 mL), and brine (1×100 mL), then dried with sodium sulfate, filtered, and concentrated via rotary evaporation to give a semi solid viscous oil. The product was purified on a flash silica gel column eluted with a hexane/EtOAc 2:1 mixture to give a white solid product (140 mg, 60%). 1H NMR (CDCl3 δ 7.20 (s, 1 H), 7.00 (dd, J=14, 11 Hz, vinyl, 1H) 6.80 (s, 1 H), 5.70 (d, J=18 Hz, vinyl, 1H), 5.22 (d, J=11 Hz, vinyl, 1H), 3.85 (s, 3H), 2.72 (t, J=4 Hz, 1H), 2.85 (dd, J=5 Hz, 2H), 2.44-1.88 (m, 6 H), 1.80-1.15 (m, 8H), 0.80 (s, 3 H).
Reaction SMILES: CN(C)C=O.[OH:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=1.FC(F)(F)S(O[CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O.[H-].[Na+]>C(OCC)(=O)C.O>[F:26][C:25]([F:28])([F:27])[CH2:24][O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=1
Reactant: COC(=O)c1ccc(CO)nc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COCC(F)(F)F)nc1
Yield: 23 %

Procedure:
To an N,N-dimethylformamide solution (10 mL) of methyl 6-(hydroxymethyl)nicotinate (500 mg, 2.99 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (518 μL, 3.59 mmol), sodium hydride (179 mg, 4.49 mmol) was added at 0° C. and the resultant mixture was stirred at room temperature for 4 hours. After completion of the reaction, water was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain the title compound (171 mg, yield 23%).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]([C:10]1[C:11]([N:23]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2/[CH:42]=[CH:43]\[CH2:44]O)(=[O:34])=[O:33])[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:12][CH:13]=[C:14]2[C:19]=1[O:18][CH2:17][C:16]1[O:20][CH:21]=[CH:22][C:15]2=1)=[O:9].C(N(C(C)C)CC)(C)C.[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>C(Cl)Cl>[F:41][C:38]1[CH:39]=[CH:40][C:35]([S:32]([N:23]([C:11]2[C:10]([C:8]([O:7][CH3:6])=[O:9])=[C:19]3[C:14]([C:15]4[CH:22]=[CH:21][O:20][C:16]=4[CH2:17][O:18]3)=[CH:13][CH:12]=2)[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])(=[O:33])=[O:34])=[C:36](/[CH:42]=[CH:43]\[CH2:44][N:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)[CH:37]=1
Reactant: COC(=O)c1c(N(COCC[Si](C)(C)C)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCc1occc1-2
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1c(N(COCC[Si](C)(C)C)S(=O)(=O)c2ccc(F)cc2/C=C\CN2CCOCC2)ccc2c1OCc1occc1-2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 65.6 %

Procedure:
Methanesulfonyl chloride (0.100 g) was added to an ice-cooled, stirred solution of methyl-7-{N-[4-fluoro-2-((Z)-3-hydroxyprop-1-enyl)benzenesulfonyl]-N-(2-trimethylsilanylethoxymethyl)amino]-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 48, 1.57 g) and diisopropylethylamine (0.859 g) in DCM (25 mL) and the mixture was stirred in an ice bath for 20 minutes. Morpholine (0.689 g) was added and the reaction mixture was stirred at room temperature for 90 minutes. It was washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 10-80% to give methyl 7-{N-[4-fluoro-2((Z)-3-{morpholin-4-yl}prop-1-enyl)benzenesulfonyl]-N-(2-trimethylsilanylethoxy-methyl)amino}-4H-furo[2,3-c]chromene-6-carboxylate (1.15 g) as a yellow gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[CH2:22](Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(N(CC)CC)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([CH2:13][C:14]([O:16][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccco1
Reactant: CCCCCCCBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccco1
Reaction time: 4 h
Yield: 42.8 %

Procedure:
To a solution of 1.5 g of 2-[2-(4-chlorophenyl)-5-(2-furyl)-4-oxazolyl]acetic acid and 1.0 g of n-heptyl bromide in 25 ml of dimethylformamide is dropwise added 0.92 g of triethylamine at room temperature. The mixture is stirred at 30° to 40° C. for 4 hours. Then, the mixture is poured into water, and the aqueous mixture is extracted with a mixture of diethyl ether and ethyl acetate (1:1). The extract is treated in the same manner as described in Example 27, whereby 0.85 g of n-heptyl 2-[2-(4-chlorophenyl)-5-(2-furyl)-4-oxazolyl]acetate is obtained. Yield: 42.7%
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:31][CH3:32])[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18][NH:19][C:20]2[N:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][S:29][CH3:30])=[CH:22][N:21]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH:36]([C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:39]=1)[CH3:37].O>O1CCCC1.CN(C)C=O>[F:45][C:44]([F:46])([F:47])[C:42]1[CH:43]=[C:38]([CH:36]([N:19]([CH2:18][C:9]2[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=2[N:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:31][CH3:32])[C:20]2[N:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][S:29][CH3:30])=[CH:22][N:21]=2)[CH3:37])[CH:39]=[C:40]([C:48]([F:49])([F:50])[F:51])[CH:41]=1
Reactant: CCN(CC1CCCC1)c1ccc(C(F)(F)F)cc1CNc1ncc(OCCSC)cn1
Reactant: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCN(CC1CCCC1)c1ccc(C(F)(F)F)cc1CN(c1ncc(OCCSC)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a stirred solution of N-({2-[(cyclopentylmethyl)(ethyl)amino]-5-(trifluoromethyl)phenyl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (4.39 g, 9.37 mmol) in tetrahydrofuran (40 mL) under ice cooling was added sodium hydride (50% in oil, 1.80 g, 37.5 mmol), and the mixture was stirred at 50° C. for 1 hour. After cooling to −78° C., to the reaction mixture was added a solution of 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane (6.02 g, 18.7 mmol) obtained in Step 2 in N,N-dimethylformamide (40 mL), and the mixture was stirred for 2.5 hours with warming to room temperature. The reaction mixture was added with water and extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain the target compound, N-{1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-N-({2-[(cyclopentylmethyl)(ethyl)amino]-5-(trifluoromethyl)phenyl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (6.03 g, 91%), as a pale yellow oil.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:17][C:18]1[C:19]2[C:20]3[N:30]=[C:29](Br)[CH:28]=[C:27]([C:32]([O:34][CH3:35])=[O:33])[C:21]=3[NH:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:10]([O:17][C:18]1[C:19]2[C:20]3[N:30]=[C:29]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:28]=[C:27]([C:32]([O:34][CH3:35])=[O:33])[C:21]=3[NH:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cccc(OCc3ccccc3)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: COC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cccc(OCc3ccccc3)c12
Temperature: 80 °C
Yield: 93.7 %

Procedure:
A flask containing a mixture of phenylboronic acid (0.889 g, 7.29 mmol), methyl 9-(benzyloxy)-2-bromo-5H-pyrido[3,2-b]indole-4-carboxylate (1.50 g, 3.65 mmol), powdered potassium phosphate tribasic (2.48 g, 11 7 mmol), 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (0.348 g, 0.729 mmol), and Pd(OAc)2 (0.082 g, 0.365 mmol) was flushed with nitrogen. THF (12 mL) was added and the mixture was heated at 80° C. for 2 hr. The reaction was diluted with EtOAc, washed with water, sat. aq. Na2CO3 solution, brine, and dried with sodium sulfate. The solvent was removed and the residue was suspended in a little EtOAc. Filtration and washing with EtOAc, afforded methyl 9-(benzyloxy)-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxylate (1.47 g, 3.42 mmol, 94%). MS (ESI) m/z 408.9 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.68 (1H, s), 8.33 (1H, s), 8.28 (2H, d, J=7.32 Hz), 7.87 (2H, d J=7.63 Hz), 7.37-7.57 (8H, m), 6.99 (1H, d, J=8.24 Hz), 5.45 (2H, s), 4.09 (3H, s).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][C:5]1[CH:6]=[C:7]([C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)[CH2:8]Cl>O.C(O)C>[CH3:4][C:5]1[CH:6]=[C:7]([CH2:8][C:1]#[N:2])[C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1
Reactant: [C-]#N
Reactant: Cc1ccc(Sc2ccccc2)c(CCl)c1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(Sc2ccccc2)c(CC#N)c1

Procedure:
194 g of potassium cyanide in 250 ml of water are heated under reflux for 17 hours under an argon atmosphere with 616.9 g of 3-methyl-6-(phenylthio)-benzyl chloride in 900 ml of ethanol. Then the ethanol is distilled off under reduced pressure, the residue then diluted with water and extracted with ether. The extracts are washed with water, dried over sodium sulphate and evaporated. There is obtained 3-methyl-6-(phenylthio)-phenylacetonitrile as an oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(=S)=S>[C:17]1([CH2:23][C:24]([C:4]2[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:2][CH:3]=2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)CCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)CCc1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 61.2 %

Procedure:
To a solution of 1.00 g of methyl 3-phenylpropionate in 6 ml of carbon disulfide, 1.62 g of anhydrous aluminium chloride was added under ice-cooling, and then 0.94 g of phenylacetyl chloride was added dropwise and stirring was continued at room temperature for 6 hours. The reaction mixture was poured into ice-water and extracted with methylene chloride. The methylene chloride layer was washed successively with water, aqueous potassium carbonate solution and water, dried, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride:n-hexane=2:1) to afford 1.05 g of colorless crystals. Recrystallization from isopropyl ether gave colorless flakes, mp 77°~78° C.
Reaction SMILES: [NH3:1].[F:2][C:3]([F:13])([F:12])[CH2:4][N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.C(O)CCC>CO.[Pd]>[F:2][C:3]([F:13])([F:12])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([NH2:1])[CH2:7][CH2:6]1
Reactant: N
Reactant: O=C1CCN(CC(F)(F)F)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCCCO
Product: NC1CCN(CC(F)(F)F)CC1
Reaction time: 18 h

Procedure:
A 25% aqueous solution of ammonia (170 mL), 10% Pd/C (7.4 g), and a solution of the above 1-(2,2,2-trifluoroethyl)piperidin-4-one /butanol mixture (72.5 g, 0.344 mol, 86:14 weight ratio) in methanol (420 mL) were placed into a 2 L glass autoclave purged with argon. The reaction mixture was hydrogenated in a Parr apparatus at a hydrogen pressure of 40 psi for 18 h. The catalyst was removed by filtration. The filtrate was concentrated in vacuo to 150 mL. Potash (46 g) and ether (200 mL) were added, and the mixture was vigorously stirred for 20 min. The organic layer was separated, and the aqueous one was extracted with ether (100 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to afford a mixture (74.4 g) of 1-(2,2,2-trifluoroethyl)piperidin-4-amine and 1-(2,2,2-trifluoroethyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]piperidin-4-amine in 72:28 weight ratio (contain butanol). This mixture was fractionated at 7-8 mmHg on a 15 cm Vigreaux column (a fraction with bp 75-95° C. was collected) to afford 1-(2,2,2-trifluoroethyl)piperidin-4-amine (38.5 g) as a colorless liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH:49]([CH:51]=[O:52])[NH2:50]>CN(C=O)C>[CH:51]([NH:49][NH:50][C:13](=[O:15])[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:17])[CH3:16])=[O:52]
Reactant: NNC=O
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)NNC=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-(benzyloxycarbonylamino)-2-methylpropanoic acid (Example 8 a, 1.9 g, 8 mmol), HATU (CAN 148893-10-1, 3.97 g, 10 mmol) and N-methylmorpholine (CAN 109-02-4, 2.43 g, 24 mmol) in DMF (20 mL) was stirred at room temperature for 15 min. Then hydrazinecarboxaldehyde (CAN 624-84-0, 0.53 g, 9 mmol) was added and the reaction mixture was stirred at room temperature overnight. After evaporation of solvents, the residue was diluted with ethyl acetate (30 mL) and water (30 mL). The organic layer was washed with saturated sodium bicarbonate solution (30 mL), hydrochloric acid (30 mL, 1 M), brine (30 mL) and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure left the title compounds as yellow oil (2.1 g, 94%); MS: m/e 280.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[N:14]([C:15](=[O:34])[C@@H:16]([NH:20][C:21](=[O:33])[C@@H:22]([N:24](C)[C:25](=O)OC(C)(C)C)[CH3:23])[CH:17]([CH3:19])[CH3:18])[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([NH:3][C:4]([C@H:6]1[N:14]([C:15](=[O:34])[C@@H:16]([NH:20][C:21](=[O:33])[C@@H:22]([NH:24][CH3:25])[CH3:23])[CH:17]([CH3:19])[CH3:18])[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)C1Cc2cccnc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of tert-butyl (2S)-1-((2S)-1-(2-(ethylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (50 mg, 105 μmol, Eq: 1.00) in DCM (1 mL) was added TFA (0.5 mL, 6.49 mmol, Eq: 61.7) and the resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and the residue was treated with saturated aqueous NaHCO3 (5 mL). The resulting aqueous layer was extracted with DCM (3×5 mL) and the combined organic layers were dried over MgSO4 and then concentrated in vacuo. Treatment of the resulting residue with ethyl ether and hexanes gave (S)-1-[(S)-3-methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethylamide as a white solid (33 mg), m/z=376 (M+H).