Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[C:26](=O)[NH2:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[C:26](=[S:38])[NH2:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](C(N)=O)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](C(N)=S)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl (1R,3R,4S)-4-((benzyloxycarbonyl)amino)-3-carbamoylcyclohexylcarbamate (4.8 g, 0.01 mol) in 50 ml of dry THF was added Lawesson's reagent (2.97 g, 0.007 mol) portionwise under nitrogen. After the completion of addition the reaction mixture was stirred for 5 h at RT. THF was removed and the crude product was dissolved in ethyl acetate. The organic layer was washed with 10% sodium hydroxide, water, brine and concentrated. The crude product was purified by recrystallization from pet-ether and ether mixture to give 3.5 g crude of tert-butyl (1R,3R,4S)-4-((benzyloxycarbonyl)amino)-3-carbamothioylcyclohexylcarbamate as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:19])([F:18])[CH2:13][O:14][CH2:15][CH2:16][OH:17]>>[F:11][C:12]([F:19])([F:18])[CH2:13][O:14][CH2:15][CH2:16][O:17][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: OCCOCC(F)(F)F
Product: CC(=O)c1ccc(OCCOCC(F)(F)F)nc1
Yield: 50 %

Procedure:
The title compound is prepared in 50% yield (1.67 g, colorless oil) from 1-(6-chloropyridin-3-yl)ethanone (2.0 g, 12.9 mmol) and 2-(2,2,2-trifluoroethoxy)ethanol instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:18][CH2:19]OS(C)(=O)=O)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]1=[O:25].[CH2:33]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[NH:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:18][CH2:19][N:51]2[CH2:50][CH2:49][CH:48]([NH:47][C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:33][CH3:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)[CH2:53][CH2:52]2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]1=[O:25]
Reactant: COc1cc(CN2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2=O)cc(OC)c1OC
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 16.7 using 1-(3,4,5-trimethoxybenzyl)-3-(2-methanesulfonyloxyethyl)-3-phenyl-2-oxopyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound: Rf=0.34 (silica gel, 2% triethylamine/5% methanol/ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([O:22][Si](C)(C)C)=[C:19]([CH3:21])[CH3:20]>[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:19]([CH3:21])([CH3:20])[C:18]([O:17][CH3:16])=[O:22])=[CH:4][CH:3]=1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: OC(c1ccccc1)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(Br)cc1
Yield: 98.5 %

Procedure:
In a similar manner to Preparation 14, Step 2, the reaction of (4-bromophenyl)(phenyl)methanol (10 g, 38 mmol), and (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (23.2 g, 133 mmol) in the presence of titanium tetrachloride (1M in DCM, 42 ml. 41.8 mmol) afforded methyl 3-(4-bromophenyl)-2,2-dimethyl-3-phenylpropanoate (13 g, 99% yield). LC/MS (m/z) 347.05, 349 [(M+1)+]; HPLC Rt: 4.18 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[N:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][N:12]=1)[C:5](O)=[O:6].S(Cl)([Cl:27])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[N:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][N:12]=1)[C:5]([Cl:27])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCc1cnc(-c2ccc(C(=O)O)cc2F)nc1
Product: CCCCCCCCc1cnc(-c2ccc(C(=O)Cl)cc2F)nc1

Procedure:
3-Fluoro-4-(5-n-octylpyrimidine-2-yl)benzoic acid (1.66 g) was heated together with excess thionyl chloride for 8 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 3-fluoro-4-(5-n-octylpyrimidine-2-yl)benzoic acid chloride.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]C)=O.[NH2:12][NH2:13]>C(O)C>[NH2:12][NH:13][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: NN
Reactant: COC(=O)CN1CCCC1=O
Solvent: CCO
Product: NNC(=O)CN1CCCC1=O

Procedure:
To a solution of methyl 2-(2-oxopyrrolidinyl)acetate (0.884 mL, 6.36 mmol) in 1 mL of anhydrous ethanol was added anhydrous hydrazine (0.308 mL, 6.36 mmol). The solution was heated to reflux temperature overnight. The solvent was then removed under reduced pressure and the product was isolated as a solid in a quantitative yield and was used without further purification: 1H NMR (CDCl3) δ 8.17 (br s, 1H), 3.94 (s, 2H), 3.55 (t, 2H), 2.43 (t, 2H), 2.10 (quintet, 2H); ES-MS (m/z) 158 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH2:25]([N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH2:37][CH2:38][CH:39]=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[BH4-].[Na+].[OH-].[Na+]>C(O)C.C(#N)C>[CH2:25]([N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH2:37][CH2:38][CH2:39][NH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)(=[O:16])=[O:15])=[CH:7][CH:6]=1)([CH3:3])[CH3:4])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccc(S(=O)(=O)NCCc2ccc(C(C)(C)N)cc2)cc1
Reactant: O=CCCc1nccn1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Product: COc1ccc(S(=O)(=O)NCCc2ccc(C(C)(C)NCCCc3nccn3Cc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-{2-[4-(1-amino-1-methylethyl)phenyl]ethyl}-4-methoxybenzenesulphonamide (0.97 g), 3-(1-benzylimidazol-2-yl)propionaldehyde (0.66 g), 4A molecular sieves (0.7 g) and acetonitrile (15 ml) was stirred at ambient temperature for 18 hours. The mixture was filtered and the filtrate evaporated under reduced pressure to give a residue which was dissolved in absolute ethanol (15 ml). Sodium borohydride (0.18 g) was added to the ethanolic solution and the mixture was boiled under reflux for 3 hours. The solvent was removed under reduced pressure and water was added to the residue followed by dilute hydrochloric acid to give an acidic mixture. After 20 minutes the mixture was basified with dilute sodium hydroxide solution and extracted with ethyl acetate to give an oil which was purified with flash column chromatography on silica to give N-[2-(4-{1-[3-(1-benzylimidazol-2-yl)propylamino]-1-methylethyl}phenyl)ethyl]-4methoxybenzenesulphonamide. A mixture of this product (0.61 g), absolute ethanol (30 ml), ammonium formate (0.42 g) and 10% palladium on carbon (0.91 g) was boiled under reflux for 1 hour. The mixture was filtered and the filtrate was evaporated under reduced pressure to give a residue which was purified by flash column chromatography on silica using ethyl acetate/methanol/triethylamine (18:1:1) as the mobile phase to give N-[2-(4-{1-[3-(imidazol-2-yl)propylamino]-1-methylethyl}phenyl)ethyl]-4-methoxybenzenesulphonamide as an oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]([C:18]2[S:22][C:21]([CH2:23][CH2:24][C:25]([OH:27])=O)=[C:20]([CH3:28])[CH:19]=2)=[O:17])=[CH:13][CH:12]=1)(=[NH:10])[NH2:9].CCN=C=N[CH2:36][CH2:37][CH2:38][N:39]([CH3:41])C.Cl>N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:38]([N:39]([C:25](=[O:27])[CH2:24][CH2:23][C:21]1[S:22][C:18]([C:16]([O:15][C:14]2[CH:13]=[CH:12][C:11]([C:8](=[NH:10])[NH2:9])=[CH:30][CH:29]=2)=[O:17])=[CH:19][C:20]=1[CH3:28])[CH2:41][C:3]([OH:5])=[O:4])[CH:37]=[CH2:36]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(C(=O)Oc2ccc(C(=N)N)cc2)sc1CCC(=O)O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: C=CCN(CC(=O)O)C(=O)CCc1sc(C(=O)Oc2ccc(C(=N)N)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 242.4 %

Procedure:
The compound (100 mg, 0.224 mmol) obtained in step 1, M-5 (49.9 mg, 0.291 mmol), and WSC hydrochloride (64.4 mg, 0.336 mmol) were dissolved in pyridine (0.5 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, trifluoroacetic acid (1.0 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by high performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to give the title compound (98.5 mg, 0.181 mmol, 81%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[F:16][C:17]([F:29])([F:28])[C:18]1[N:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:24]([C:21]2[CH:22]=[N:23][C:18]([C:17]([F:29])([F:16])[F:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)nc1
Reactant: Nc1ccc(C(F)(F)F)c2cccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(C(F)(F)F)c2cccnc12)c1ccc(C(F)(F)F)nc1
Yield: 12.6 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-trifluoromethyl-quinolin-8-ylamine (Intermediate 45) (100 mg, 0.47 mmol), 6-(trifluoromethyl)pyridine-3-sulfonyl chloride (138 mg, 0.56 mmol), pyridine (0.08 ml, 0.94 mmol), DMAP (cat.) and DCM (5 ml) gave the title compound (25 mg, 13%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: CO[C:3](=[O:10])[CH2:4][C:5]([CH:7]1[CH2:9][CH2:8]1)=O.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C>[CH:7]1([C:5]2[CH2:4][C:3](=[O:10])[N:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:18]=2)[CH2:8][CH2:9]1
Reactant: NNc1ccccc1
Reactant: COC(=O)CC(=O)C1CC1
Solvent: CC(=O)O
Product: O=C1CC(C2CC2)=NN1c1ccccc1
Temperature: 120 °C
Yield: 86.9 %

Procedure:
To a solution of methyl-3-cyclopropyl-3-oxopropionate (17 g) in acetic acid (40 mL) in a round bottom flask under argon was added phenylhydrazine (12.93 g). The mixture was immersed into an oil bath and heated to 120° C. overnight. The reaction vessel was then cooled and the acetic acid was evaporated in vacuo and the remaining solid was dissolved in EtOAc and water. The phases were separated and the aqueous phase was extracted with further EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo and azeotroped with toluene (2×). The crude residue was then purified via trituration with a 1:1 mixture of ether/pentane to afford the desired 5-cyclopropyl-2-phenyl-2,4-dihydro-pyrazol-3-one (20.8 g) as a light brown solid. MS (ESI+): 201.3 ([M+H]+).
Reaction SMILES: C([O:9][C@@H:10]1[CH2:14][N:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C@@H:12]([CH2:25][N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][O:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CCOCC.CO>[OH:9][C@@H:10]1[CH2:14][N:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C@@H:12]([CH2:25][N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][O:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)[CH2:11]1
Reactant: COc1ccc(CCN2C[C@@H](OC(=O)c3ccccc3)C[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(CCN2C[C@@H](O)C[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To 870 mg (1.63 mmol) of (+)-5-[[(2R, 4S)-4-benzoyloxy-1-(4-methoxy phenethyl)pyrrolidin-2-yl]methyl]-5,11-dihydrodibenzo[b,e][1, 4]oxazepine in 15 ml of ether was added 460 mg (11.4 mmol) of NaOH in methanol (60 ml) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, then water was added to the residue and the products were extracted with ether. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography (ethyl acetate) to give 680 mg (97.1%) of (+)-5-[[(2R, 4S)-4-hydroxy-1-(4-methoxyphenethyl) pyrrolidin-2-yl]methyl]-5,11-dihydrodibenzo[b,e][1,4]oxazepine as yellow amorphous.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C(F)=NC(F)=NC=1[F:21].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10]([F:21])=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)F)c1ccccc1
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
To an oven-dried, septaed 25 mL round-bottom flask, cooled under an argon atmosphere, and charged with 24j (124.9 mg, 0.50 mmol) was added 1.25 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15 C and to the flask was added cyanuric fluoride (225 μL, 2.5 mmol). The reaction was stirred at −15 C for 15 minutes then anhydrous pyridine (40 μL, 0.5 mmol) was added. Stirring was maintained at −15 C for 60 minutes. Without warning, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 114.8 mg of a mixture of 24j and 25j as an off-white solid. FTIR (film) 1849.3 cm−1.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:31]=[CH:30][C:13]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[C:12]([O:32][CH3:33])[CH:11]=1)=[O:8])=O.C1(C)C(C)=CC=CC=1.C>C(Cl)(Cl)Cl>[C:3]1(=[O:2])[N:9]([C:10]2[CH:31]=[CH:30][C:13]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:22][CH2:23]3)=[C:12]([O:32][CH3:33])[CH:11]=2)[C:7](=[O:8])[CH2:6][CH2:5]1
Reactant: COC(=O)CCC(=O)Nc1ccc(OCCCN2CCN(c3ccccc3)CC2)c(OC)c1
Solvent: Cc1ccccc1C
Solvent: ClC(Cl)Cl
Product: COc1cc(N2C(=O)CCC2=O)ccc1OCCCN1CCN(c2ccccc2)CC1
Temperature: 150 °C
Reaction time: 20 h
Yield: 4.9 %

Procedure:
A mixture of 20 g of 1-{3-[4-(3-methoxycarbonyl-propionamido)-2-methoxyphenoxy]-n-propyl}-4-phenyl-piperazine and 2 ml of xylene is stirred at 150° C. for 20 hours. Then, chloroform is added to the reaction mixture, and said mixture is treated with activated charcoal and then evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel chromatography (Solvent: 1% methanol/chloroform), and then recrystallized from ethyl acetate. 910 mg of 1-[3-(4-succinimido-2-methoxyphenoxy)-n-propyl]-4-phenyl-piperazine are obtained as colorless needles. Yield: 54%
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1.[CH:14](=[O:18])[CH:15]([CH3:17])[CH3:16]>>[CH3:16][CH:15]([CH3:17])[CH:14]([C:11]1[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:13][CH:12]=2)[N:8]=[CH:9][N:10]=1)[OH:18]
Reactant: Cc1ccc(Cn2cncn2)cc1
Reactant: CC(C)C=O
Product: Cc1ccc(Cn2ncnc2C(O)C(C)C)cc1
Yield: 66 %

Procedure:
2-Methyl-1-[1-(4-methylbenzyl)-1H-1,2,4-triazol-5-yl]propan-1-ol was synthesized in a manner similar to that of procedure 21 B but using 1-(4-methylbenzyl)-1H-1,2,4-triazole and isobutyraldehyde as the starting materials. The product was isolated as a white solid in 66% yield.
Reaction SMILES: C([N:8]1[C@@H:13]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:19])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH3:19][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[NH:8]1
Reactant: CC(C)CC[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-methyl-6-isopentylpiperidine (1.5 g, 5.56 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 90 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-methyl-6-isopentylpiperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occured. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 134.1-134.7° C.; 1H NMR (250 MHz) 67 9.36 (s, 2H), 3.53 (s, 1H), 3.25 (s, 1H), 1.96-1.1 (m, 14H), 0.88-0.82 (d, 6H); 13C NMR (62.7 MHz) δ51.9 (s), 47.8 (s), 34.7 (s), 28.9 (s), 28.4 (s), 27.8 (s), 26.0 (s), 22.7 (s), 22.1 (s), 17.3 (s), 16.9 (s). FT-IR (neat): 3422, 2949, 1636, 1602, 1587, 1500, 1422, 1384, 1230, 1105, 1030, 998, 895. Elemental Analysis for C11H24NCl: C, 64.20%; H, 11.78%; N, 6.80%. Found: C, 64.08%; H, 11.72%; N, 6.78%.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([CH2:12][CH2:13][CH3:14])[N:4]=1)#[N:2].[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].O>CC(C)=O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]([CH2:12][CH2:13][CH3:14])[N:4]=1)#[N:2]
Reactant: CCCc1nc(C#N)c(C#N)nc1Cl
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCc1nc(C#N)c(C#N)nc1Oc1ccccc1
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
2,3-Dicyano-5-chloro-6-n-propylpyrazine (0.207 g; 0.001 mole) was dissolved in 15 ml of acetone, and a solution prepared from 0.094 g (0.001 mole) of phenol, 0.040 g (0.001 mole) of sodium hydroxide, 0.7 ml of water and 5 ml of acetone was added dropwise over the period of 5 minutes. Then, the mixture was stirred at 5° to 10° C. for 10 minutes. The reaction mixture was worked up in the same way as in Example 9, and recrystallized from benzene to afford 0.150 g (yield 57%) of 2,3-dicyano-5-phenoxy-6-propylpyrazine.
Reaction SMILES: [CH2:1]([C:4]1([CH2:7][CH2:8][CH3:9])[CH2:6][O:5]1)[CH2:2]C.[NH2:10][C:11]1[CH:12]=[C:13]([CH:17]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:18][C:19]#[N:20])[CH:14]=[CH:15][CH:16]=1>>[Si:22]([O:21][CH:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][CH2:6][C:4]2([OH:5])[CH2:1][CH2:2][CH2:9][CH2:8][CH2:7]2)[CH:12]=1)[CH2:18][C:19]#[N:20])([C:25]([CH3:27])([CH3:28])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OC(CC#N)c1cccc(N)c1
Reactant: CCCC1(CCC)CO1
Product: CC(C)(C)[Si](C)(C)OC(CC#N)c1cccc(NCC2(O)CCCCC2)c1

Procedure:
Epoxide ring opening of 2,2-dipropyloxirane with 3-(3-aminophenyl)-3-(tert-butyldimethylsilyloxy)propanenitrile following the method used in Example 67 gave 3-(tert-butyldimethylsilyloxy)-3-(3-((1-hydroxycyclohexyl)methylamino)phenyl)propanenitrile as a colorless oil. Yield (1.5 g, 56%); 1H NMR (400 MHz, DMSO-d6) δ 7.01 (t, J=7.6 Hz, 1H), 6.63 (s, 1H), 6.57 (d, J=7.6 Hz, 1H), 6.52 (d, J=7.6 Hz, 1H), 5.22 (t, J=5.2 Hz, 1H), 4.91 (t, J=6.4 Hz, 1H), 4.21 (s, 1H), 2.84 (d, J=5.6 Hz, 2H), 2.78-2.75 (m, 2H), 1.77-1.39 (m, 10H), 0.87 (s, 9H), 0.05 (s, 3H), −0.05 (s, 3H).
Reaction SMILES: C([N:8]1[C:12]([C:13](=O)[CH2:14][CH3:15])=[CH:11][N:10]=[CH:9]1)C1C=CC=CC=1.[CH3:17][O:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][C:25]2=O)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][CH:25]2[CH:13]([C:12]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH2:14][CH3:15])=[CH:21][CH:20]=1
Reactant: CCC(=O)c1cncn1Cc1ccccc1
Reactant: COc1ccc2c(c1)C(=O)CC2
Product: CCC(c1c[nH]cn1)C1CCc2ccc(OC)cc21

Procedure:
The procedure of Example 12 is repeated except that 1-(3-benzyl-3H-imidazol-4-yl)-propan-1-one is used in place of 3-benzyl-3H-imidazole-4-carbaldehyde and 6-methoxyindan-1-one is used in place of 1-indanone. The product is a mixture of two diastereomers (1:1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].[F:14][CH:15]([F:18])[CH2:16][NH2:17].CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(Cl)Cl>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][C:11]([CH3:13])=[CH:12][C:4]2=[N:3][C:2]=1[NH:17][CH2:16][CH:15]([F:18])[F:14]
Reactant: NCC(F)F
Reactant: Cc1cc2nc(Cl)c(Cl)nc2cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2nc(NCC(F)F)c(Cl)nc2cn1
Yield: 94.7 %

Procedure:
A solution of 2,3-dichloro-7-methylpyrido[3,4-b]pyrazine (125 mg, 0.584 mmol), 2,2-difluoroethanamine (53.6 μL, 0.701 mmol), and DIPEA (306 μL, 1.752 mmol) in DCM (1.17 mL) was stirred at room temperature for 48 h, then poured into a saturated aqueous solution of NH4Cl and extracted twice with EtOAc. The extracts were combined, filtered through MgSO4, and concentrated to give 3-chloro-N-(2,2-difluoroethyl)-7-methylpyrido[3,4-b]pyrazin-2-amine (143 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([CH3:11])[CH:3]=1.[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([NH2:30])[CH:29]=3)=[O:23])=[CH:20][N:19]([CH:31]([CH3:33])[CH3:32])[C:15]=2[N:16]=[CH:17][N:18]=1>N1C=CC=CC=1>[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[C:28]([NH:30][C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[CH3:11])=[O:10])[CH:27]=[N:26][CH:25]=3)=[O:23])=[CH:20][N:19]([CH:31]([CH3:33])[CH3:32])[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2c(N)ncnc21
Reactant: Cc1cc(Cl)ccc1N=C=O
Solvent: c1ccncc1
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cncc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)c1
Temperature: 45 °C
Yield: 83.3 %

Procedure:
4-Chloro-1-isocyanato-2-methyl-benzene (93.3 mg, 0.56 mmol) was added to a solution of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-amino-pyridin-3-yl)-methanone (150 mg, 0.51 mmol) in pyridine (5 mL). The mixture was heated to 45° C. for 12 h. The reaction mixture was concentrated in vacuo and the resulting yellow solid was triturated with CH2Cl2, filtered, and washed with CH2Cl2. Purification by flash column chromatography [(10% NH4OH/MeOH)/ethyl acetate 2:98] afforded the title compound as a white solid (197 mg, 83%). MS: 464.1 (MH+); HPLC Rf: 5.55 min. (HPLC method 4).