Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:30]([C:34]1[CH:39]=[CH:38][C:37]([C:40]#[CH:41])=[CH:36][CH:35]=1)[CH2:31][CH2:32][CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCOCC.[Pd](Cl)Cl.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.[Cu]I>[CH2:30]([C:34]1[CH:35]=[CH:36][C:37]([C:40]#[C:41][C:2]2[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:9])=[O:10])=[CH:6][CH:7]=2)=[CH:38][CH:39]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCN(Cc1ccc(F)c(C(=O)OC)c1)S(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1ccc(CCCC)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCN(Cc1ccc(F)c(C(=O)OC)c1)S(=O)(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1
Temperature: 150 °C
Reaction time: 0.42 h
Yield: 58.5 %

Procedure:
To a solution of methyl 5-{[[(4-bromophenyl)sulfonyl](hexyl)amino]methyl}-2-fluorobenzoate (96 mg; 0.20 mmol) in DMF (5 mL) were added (Aldrich, p-butylphenylacetylene (31 mg; 0.20 mmol), bis(triphenylphosphine) palladium (II) chloride (6.9 mg; 0.01 mmol), copper(I) iodide (1.9 mg; 0.01 mmol), triphenylphosphine (10.4 mg; 0.04 mmol) and TEA (0.08 mL; 0.59 mmol). The mixture was stirred for 1500 s at 150° C. under MW. The mixture was diluted with Et2O (50 mL) and the precipitate obtained filtrated off. Filtrate was washed with HCl 1N and with brine (75 mL). The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification by flash chromatography using silicagel (c-Hex:EtOAc, 9:1 then 1:1) gave 66 mg (63.3%) of the title compound as a white solid. HPLC: Rt=6.12 min (purity=99.6%). LC/MS: M+(ESI): 564.4. 1H NMR (CDCl3) δ: 7.79 (d, J=8.3 Hz, 3H) 7.64 (d, J=8.7 Hz, 2H), 7.56 (m, 1H), 7.46 (d, J=8.3 Hz, 2H), 7.19 (d, J=7.9 Hz, 2H), 7.15 (s, 1H), 4.33 (s, 2H), 3.92 (s, 3H), 3.11 (t, J=7.5 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.61 (t, J=7.7 Hz, 2H), 1.35 (m, 5H), 1.15 (m, 5H), 0.93 (t, J=7.3 Hz, 3H), 0.81 (t, J=6.9 Hz, 3H).
Reaction SMILES: [NH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)[NH2:2].[CH2:11]([CH2:13][CH2:14][CH2:15][C:16](CC([O-])=O)=[O:17])[CH3:12]>>[O:17]=[C:16]1[N:1]([C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)[N:2]=[C:14]([CH2:13][CH2:11][CH3:12])[CH2:15]1
Reactant: N#Cc1ccc(NN)cc1
Reactant: CCCCCC(=O)CC(=O)[O-]
Product: CCCC1=NN(c2ccc(C#N)cc2)C(=O)C1

Procedure:
From the reaction of 4-hydrazinobenzonitril and ethylbutyrylacetate, 4-(4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzonitrile is obtained. Subsequent reaction with 2-ethylaniline yields 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzonitrile, Mp 196.7° C.
Reaction SMILES: [C:1]([NH:9][C:10](SC)=[N:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][CH:25]=1>C(O)(C)C>[NH2:30][C:28]([C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)=[CH:25][CH:26]=1)=[O:29]
Reactant: CSC(=NC(=O)c1cccc(Br)c1)NC(=O)c1ccccc1
Reactant: NC(=O)c1ccc(N)cc1
Solvent: CC(C)O
Product: NC(=O)c1ccc(NC(=NC(=O)c2cccc(Br)c2)NC(=O)c2ccccc2)cc1
Yield: 68.2 %

Procedure:
A mixture of 7.55 g (0.02 mole) of N-benzoyl-N-'-(3-bromobenzoyl)carbamimidothioic acid, methyl ester, 2.72 g (0.02 mole) of 4-aminobenzamide and 250 ml of isopropyl alcohol was heated at reflux for 48 hours resulting in precipitation of a solid. The solid was collected by filtration and washed with two 50 ml portions of hot isopropyl alcohol to give 6.35 g of the desired product as a white solid, mp 282°-283° C.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][N:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[CH2:24][CH2:25]O)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].O.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:2][CH2:25][CH2:24][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:17]1[CH2:16][CH2:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=1
Reactant: COc1ccc(CCN2CCCCCC2CCO)cc1OC
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CCN2CCCCCC2CCBr)cc1OC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4 ml of phosphorus tribromide are added dropwize to 2.9 g (9.4 mmol) of N-[2-(3,4-dimethoxy-phenyl)-ethyl]-2-(2-hydroxyethyl)-hexahydro-azepine in 100 ml of carbon tetrachloride, whilst cooling with ice, and the mixture is stirred for 15 hours at ambient temperature. Then water is added, whilst cooling with ice water is continued, and the mixture is made slightly alkaline with 2 molar sodium hydroxide solution. The aqueous/alkaline solution is separated off and extracted twice with methylene chloride. The combined organic solutions are dried over magnesium sulphate and concentrated by evaporation in vacuo. Yield: 3.6 g (100% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C1CNCCN1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C1CN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CCN1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and piperazin-2-one according to conditions described in general procedure C. Mp: 108-110° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.14-3.35 (m, 8 H), 3.73-3.78 (m, 6 H), 6.37 (d, J=5.5 Hz, 1 H), 7.03-7.06 (m, 2 H), 7.26 (d, J=8.5 Hz, 1 H), 7.44-7.63 (m, 4 H), 7.84-7.86 (m, 1 H), 8.00-8.04 (m, 2H), 8.35 (d, J=5.1Hz, 1 H), 10.51 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:20]([N:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32](=O)[CH2:33]Br)=[CH:29][CH:30]=2)[CH2:25][CH2:24]1)(=[O:22])[CH3:21]>C(#N)C>[C:20]([N:23]1[C:31]2[C:26](=[CH:27][C:28]([CH2:32][CH2:33][N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)=[CH:29][CH:30]=2)[CH2:25][CH2:24]1)(=[O:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)N1CCc2cc(C(=O)CBr)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N1CCc2cc(CCN3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Temperature: 70 °C
Yield: 54.8 %

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (0.750 g, 4.03 mmol) in dry acetonitrile (20 mL) grounded potassium carbonate (0.486 mL, 8.05 mmol) was added followed by the product mixture from Example 38a (1.134 g) and the reaction was heated at 70° C. under argon over night. The acetonitrile was evaporated and DCM and water was added. The layers were separated and the aq phase was extracted with DCM (3×). The combined organic phases were dried (Na2SO4), filtered and evaporated. The crude mixture was purified by flash chromatography (heptane/EtOAc 75/25 to 0/100) to give 0.823 g (55%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])[CH3:2].Cl.[NH2:26][CH2:27][C:28]1[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=1[CH:34]([CH3:36])[CH3:35].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH2:1]([N:3]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:12]=1)[C:7]([NH:26][CH2:27][C:28]1[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=1[CH:34]([CH3:35])[CH3:36])=[O:8])[CH3:2]
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)O)c1C)C1CCN(C)CC1
Reactant: Cc1cc(C(C)C)c(CN)c(=O)[nH]1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.5 %

Procedure:
To a stirred solution of 3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzoic acid (crude material, ˜0.313 mmol) and 3-(aminomethyl)-6-methyl-4-(propan-2-yl)-1,2-dihydropyridin-2-one HCl salt (88.0 mg, 0.407 mmol) in DMSO (2.4 mL) was added PyBOP (244 mg, 0.470 mmol) and hunig base (164 ul, 0.939 mmol). The reaction mixture was stirred at rt for 16 hours. The reaction mixture was quenched with water and diluted with ethylacetate. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (NH—SiO2 ethylacetate/MeOH=20/1+5% triethylamine). The crude compound was dissolved with DMSO, diluted with water. The precipitated solid was collected and triturated with ethylacetate/TBME/hexane to give the titled compound as a white solid (80.0 mg, 51% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.31 (s, 1H), 7.26 (s, 1H), 7.03-7.10 (m, 1H), 6.04 (s, 1H), 4.59 (d, J=6.0 Hz, 2H), 3.49-3.55 (m, 1H), 3.09 (q, J=6.8 Hz, 2H), 2.81-2.84 (m, 2H), 2.70-2.78 (m, 1H), 2.32 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H), 1.86-1.89 (m, 2H), 1.68-1.71 (m, 4H), 1.22 (d, J=6.4 Hz, 6H), 0.84 (t, J=6.8 Hz, 3H); MS (ES) [M+H] 507.2, [M+Na] 529.2; HPLC 97.7% purity.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3]1.C[C:20]1([CH3:60])[C:46]2[C:41](=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=C[CH:45]=2)[O:40]C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=[O:62].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:45][C:46]1[C:41](=[O:62])[O:40][CH2:60][C:20]=1[N:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:2]1=[O:1]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2=O)CC1
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (I-11, 80.0 g, 315 mmol) and 4-methyl-5-oxo-2,5-dihydrofuran-3-yltrifluoromethanesulfonate (I-9, 85.2 g, 346 mmol), Xantphos (13.6 g, 23.6 mmol), Cs2CO3 (153.7 g, 471.8 mmol) in toluene (1200 mL), was added Pd2(dba)3 (7.20 g, 7.86 mmol) under N2. The resulting reaction mixture was heated to 90° C. and stirred under N2 for 18 h. The mixture was filtered through a pad of CELITE® and the filtrate was concentrated. The residue was purified by precipitation to give tert-butyl 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate. 1H NMR (400 MHz, CDCl3) δ 5.23 (s, 2H), 4.02-3.99 (m, 4H), 3.06-3.05 (m, 2H), 2.15-2.11 (m, 2H), 2.02 (s, 3H), 1.87-1.81 (m, 2H), 1.51-1.41 (m, 11H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:33](=[O:35])=[O:34]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]2[CH:26]=[CH:25][C:24]([C:33]([OH:35])=[O:34])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)cc2)(c2ccc(Br)cc2)CC1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)cc2)(c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C

Procedure:
Under nitrogen, a solution of 4-(4-bromo-phenyl)-4-(4-chloro-phenyl)piperidine-1-carboxylic acid tert-butyl ester* (888 mg, 1.97 mmol) in THF (5 mL) was cooled to −78° C. A solution of n-butyllithium (1.5 mL, 1.6M in hexanes) was added dropwise and the mixture maintained at this temperature for 25 minutes. Carbon dioxide gas (generated from dry ice and dried by passage through a column of calcium chloride pellets) was bubbled through the anion solution for 80 minutes then the mixture was allowed to warm to room temperature. The solvents were removed in vacuo then the residue was partitioned between 1N hydrochloric acid and diethyl ether. The organic phase was separated, dried (MgSO4), filtered and concentrated. The combined aqueous phases were further extracted with ethyl acetate, this extract also being dried (MgSO4), filtered, combined with the ethereal extract and concentrated to afford 4-(4-carboxy-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (889 mg); LCMS (PS-A2) Rt 3.52 min [M-tBu+H]+ 360.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:16][CH2:17][C:18](=O)[NH2:19])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)(Cl)(Cl)Cl>[CH2:9]([O:8][C:6]([NH:5][C@@H:4]([CH2:16][CH2:17][C:18]#[N:19])[C:3]([O:2][CH3:1])=[O:21])=[O:7])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@H](CCC#N)NC(=O)OCc1ccccc1
Temperature: 50 °C

Procedure:
A solution of N-benzyloxycarbonyl-L-glutamine methyl ester (25 g) in THF (500 ml) was added dropwise to a stirred solution of triphenylphosphine (44.5 g) in carbon tetrachloride (1 L). The mixture was heated to 50° C. for 2 hours. The mixture was evaporated. The resultant oil was triturated in ethyl acetate. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatogaphy using a 1:1 mixture of hexane and ethyl acetate as eluant. There was thus obtained methyl (2S)-2-benzyloxycarbonylarnino-4-cyanobutyrate (19.38 g, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([NH:20][CH2:21][CH2:22][OH:23])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(OCC)(=O)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>O>[CH3:30][S:31]([O:23][CH2:22][CH2:21][NH:20][C:19]1[C:15]([C:10]2[N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=3)[C:13](=[O:14])[O:12][N:11]=2)=[N:16][O:17][N:18]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1onc(-c2nonc2NCCO)n1-c1ccc(F)c(Br)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.5 %

Procedure:
4-(3-bromo-4-fluorophenyl)-3-(4-(2-hydroxyethylamino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (72.2 g, 0.188 mol) was mixed with ethyl acetate (600 mL). Methanesulfonyl chloride (19.2 mL, 0.248 mol) was added followed by triethylamine (34.9 mL, 0.250 mol). The reaction was stirred at room temperature for 5 min. When LCMS indicated completion of reaction (M+H=442), 500 mL of water was added into reaction. The reaction was extracted with ethyl acetate (2×500 mL). The combined ethyl acetate solution was washed with brine (500 mL), dried over sodium sulfate and concentrated to give 85.1 g crude brown solid. 1H NMR verified the structure. Crude yield was 97%. LCMS for C13H11BrFN5O6SNa (M+Na)+: m/z=485.9, 487.9. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J=6.2, 2.5 Hz, 1H), 7.72 (m, 1H), 7.58 (t, J=8.7 Hz, 1H), 6.75 (t, J=5.9 Hz, 1H), 4.36 (t, J=5.3 Hz, 2H), 3.58 (dd, J=11.2, 5.6 Hz, 2H), 3.18 (s, 3H).
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6])[CH3:3].[CH3:31]CCCCC.C([Li])CCC.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][C:51]=1[O:52][CH2:53][C:54]1[N:55]=[C:56]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[O:57][C:58]=1[CH3:59])C=O>O1CCCC1.O>[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH2:31][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH:49]=[CH:50][C:51]=1[O:52][CH2:53][C:54]1[N:55]=[C:56]([C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[O:57][C:58]=1[CH3:59]
Reactant: CCCCCC
Reactant: CCOC(=O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a suspension of (5-ethoxycarbonylpentyl)triphenylphosphonium bromide (3.0 g) in tetrahydrofuran (THF) (70 ml) was added dropwise, in nitrogen streams at -30° C., a hexane solution of n-butyl lithium (1.6M, 3.9 ml). The mixture was stirred for 30 minutes at the same temperature, to which was added dropwise at -30° C. a solution of 3-methoxy-4-[5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (1.0 g) in tetrahydrofuran (THF) (10 ml). The mixture was stirred for 4 hours at temperature ranging from 50 to 60° C. The reaction mixture was then poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), followed by distilling off the solvent under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:4), was obtained ethyl 7-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]heptanoate (9.7 g, 85%) as an oily product.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CC1C2C(=CC=CC=2)C=CC=1.[C-]#N.[Na+].[CH2:28]([N:32]1C=CN=C1)CCC>[Cu]I.O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:28]#[N:32])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Reactant: CCCCn1ccnc1
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: Cc1cccc2ccccc12
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C

Procedure:
A 100-mL, three-necked flask equipped with a mechanical stirrer, thermometer and condenser was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (99.1% purity, 5.0 g, 0.02 mol) and 1-methylnaphthalene (20 g) while maintaining a flow of nitrogen through a gas inlet line connected to the condenser. The reaction mixture was stirred at room temperature, and sodium cyanide (ground to a powder just prior to use) (1.25 g, 0.024 mol, assuming 95% purity), copper(I) iodide (0.57 g, 0.003 mol, 98% purity) and 1-butyl-1H-imidazole (2.15 g, 0.017 mol, 98% purity) were added. The mixture was heated to between 158 and 167° C. for 5 h and then allowed to cool overnight. Water (20 mL) was added dropwise to the reaction mixture over 5 minutes while stirring. After stirring for an additional 1 h, the reaction mixture was filtered, and the solid collected was washed water (3×10 mL), xylenes (10 mL) and dried to a constant weight in a vacuum-oven at 80° C. to give the title compound as a light brown solid (3.4 g).
Reaction SMILES: [OH-].[Na+].O.[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]=1[OH:18])([CH3:7])([CH3:6])[CH3:5].[CH2:19](Br)[CH:20]=[CH2:21]>C1(C)C=CC=CC=1>[C:14]([C:10]1[CH:11]=[C:12]([CH2:21][CH:20]=[CH2:19])[CH:13]=[C:8]([C:4]([CH3:7])([CH3:6])[CH3:5])[C:9]=1[OH:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: C=CCBr
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A 1 liter, 3 neck flask equipped with a mechanical stirrer, thermometer, nitrogen inlet, dropping funnel and condenser was charged with 40 grams (1.0 mole) of sodium hydroxide and 50 ml. of H2O. The NaOH was dissolved with stirring and the solution was cooled to 25° C. and then 100 ml. of toluene, 2.06 grams (0.01 moles) 2,6-di-t-butyl phenol and 6.25 grams (≈0.006 moles) of S-X1 polystyrene quaternary phosphonium resin catalyst was charged into the reaction vessel. The dropping funnel was charged with a solution prepared from 49.44 grams (0.264 mole) of 2,6-di-t-butyl phenol, 32.0 grams (0.264 mole) of allyl bromide and 100 ml. of toluene. This solution was then added dropwise over a 40 minute period to the reaction vessel which had been heated to 50°-60° C. as stirring took place under a nitrogen blanket. After 3 hours of reaction time at 72° C. gas chromatographic analysis indicated that 50% of the starting materials had reacted to form 2,6-di-t-butyl-4-allyl phenol.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:9])=[O:5].Cl>CO.O1CCOCC1>[NH2:1][C:2]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)=[O:9])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)CNC(=O)c2cc(Cl)ccc2N)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ccc(Cl)cc1C(=O)NCC(=O)NCC1CCNCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.4 %

Procedure:
To a solution of 4-[{(N-(2-amino-5-chlorobenzoyl)glycyl)amino}methyl]-1-(tert-butoxycarbonyl)piperidine (1.63 g, 3.84 mmol) in methanol (20 mL) was added 4 N HCl in dioxane (9.5 mL). The solution was stirred at room temperature for 6 h. The reaction mixture was concentrated and 2 N aqueous NaOH solution (20 mL) was added. The mixture was extracted with dichloromethane (20 mL×3), and the combined extracts were dried over sodium sulfate, filtered and concentrated to give 4-[{(N-(2-amino-5-chlorobenzoyl)glycyl)amino}methyl]piperidine (1.19 g, 95%): 1H NMR (CDCl3, 270 MHz) δ 1.10-1.76 (m, 4 H), 2.55 (td, J=2.4 and 12.2 Hz, 2 H), 3.00-3.10 (m, 2 H), 3.17 (t, J=6.2 Hz, 2 H), 3.48 (s, 2 H), 4.03 (d, J=4.9 Hz, 2 H), 5.50 (br. s, 2 H), 6.11-6.23 (m, 1 H), 6.60 (d, J=8.8 Hz, 1 H), 6.85-7.02 (m, 1 H), 7.15 (dd, J=2.7 and 8.8 Hz, 1 H), 7.38 (d, J=2.4 Hz, 1 H); ESI/MS m/e 325.2 (C15H21ClN4O2).