Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20]Cl.O>CN(C)C=O>[CH3:18][O:19][CH2:20][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:10])([F:11])[F:1]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccccc1C(F)(F)F
Reaction time: 1 h

Procedure:
2-trifluoromethylphenol (50.00 g) was dissolved in N,N-dimethylformamide (100 mL), and potassium carbonate (85.14 g) and chloromethyl methyl ether (34.7 mL) were added to the solution, and then the mixture was stirred under water cooling for 1 hour. Water was added to the reaction solution, and then the mixture was extracted with n-hexane. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (64.13 g) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:17]1([N:27]=[C:28]=[O:29])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:28]([NH:27][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[O:29])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1cccc2ccccc12
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1ccc(NC(=O)Nc2cccc3ccccc23)cc1-c1c(Cl)cnn1C
Yield: 60 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 1-naphthyl isocyanate in a similar manner as described in Example 1.53, providing 21.1 mg (60%) of Compound 78: LCMS m/z (%)=409 (M+H37Cl, 38), 407 (M+H35Cl, 100). 1H NMR (400 MHz, DMSO-d6) δ: 9.02 (s, 1H), 8.71 (s, 1H), 8.10 (d, J=8 Hz, 1H), 7.96 (d, J=8 Hz, 1H), 7.91 (d, J=8 Hz, 1H), 7.61 (s, 1H), 7.59 (t, J=4 Hz, 1H), 7.58 (s, 1H), 7.56 (t, J=2 Hz, 1H), 7.54 (dd, J1=4 Hz, J2=2 Hz, 1H), 7.45 (d, J=8 Hz, 1H), 7.41 (d, J=4 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 3.75 (s, 3H), 3.60 (s, 3H).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[CH3:13][NH:14][O:15][CH3:16].[Br:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH:21]=[CH:20][C:19]=1[CH2:29][C:30]([OH:32])=O.C1C=CC2N(O)N=NC=2C=1>C(#N)C.C(N(CC)CC)C>[Br:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]2[CH2:27][CH2:28]2)[CH:21]=[CH:20][C:19]=1[CH2:29][C:30]([N:14]([O:15][CH3:16])[CH3:13])=[O:32]
Reactant: CNOC
Reactant: O=C(O)Cc1ccc(OCC2CC2)cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Cc1ccc(OCC2CC2)cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.6 %

Procedure:
WSC (4.89 g) was added to a solution of N,O-dimethylhydroxyamine hydrochloride (2.49 g), [2-bromo-4-(cyclopropylmethoxy)phenyl]acetic acid (4.85 g), HOBt (3.91 g) and triethylamine (3.56 mL) in acetonitrile (100 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with 1M hydrochloric acid, water, saturated sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, passed through an NH silica gel pad, and the solvent was evaporated under reduced pressure to give the title compound (4.78 g). MS (ESI+): [M+H]+ 328.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([CH3:29])[CH:23]=1>>[CH3:29][C:24]1[CH:23]=[C:22]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][C:2]([CH3:20])([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)[CH:27]=[CH:26][C:25]=1[CH3:28]
Reactant: Cc1ccc(Br)cc1C
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Product: Cc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cc1C
Yield: 18.5 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (274 mg, 1.00 mmol) synthesized in Reference example 61 and 4-bromo-1,2-dimethylbenzene (278 mg, 1.50 mmol), the reaction was carried out in the same manner as Example 23 to obtain the title compound 70 mg (yield 18%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8](Cl)=O)=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=C.C(N1CCOCC1)C>C1(C)C(C)=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[C:7]([CH:8]=[CH:16][C:15]([O:19][CH2:20][CH3:21])=[O:18])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14]
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCN1CCOCC1
Solvent: Cc1ccccc1C
Product: CCOC(=O)C=Cc1c(F)c(F)c(F)c(F)c1F

Procedure:
0.0561 g (0.25 millimol) of palladium acetate, 5.76 g (25 millimols) of pentafluorobenzoyl chloride, 2.50 g (25 millimols) of ethyl acrylate and 2.88 g (25 millimols) of N-ethylmorpholine, in 100 ml of xylene, are stirred for 6.5 hours at 130° C. The crude product is distilled in vacuo. 3.9 g (59% of theory) of a colourless liquid (which distils at 61°-64° C./12 Pa) are obtained. Analysis for C11H7F5O2 : calculated C 49.64%, H 2.65%, F 35.69%; found C 49.76%, H 2.72%, F 35.90%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=2)[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]#[N:19].[OH-:20].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=2)[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]([NH2:19])=[O:20]
Reactant: [OH-]
Reactant: CC(C)c1nn(-c2ncc(Cl)cc2Cl)c(N)c1C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)c1nn(-c2ncc(Cl)cc2Cl)c(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
5-Amino-1-(3,5-dichloropyridyl)-3-isopropyl-1H-pyrazole-4-carbonitrile (56 g, 189 mmole) was taken up in concentrated H2SO4 (160 mL) and stirred at room temp for 16 hours. The reaction was then poured onto 3M aqueous NaOH (2 L) at 0° C. The resulting solid was then filtered and washed with H2O (1 L). The product was then dried under vacuum to yield the desired amide (49 g, 82% yield).
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])S(C1C=CC(C)=CC=1)(=O)=O.[Br:26]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:26][C:3]1[C:22]2[C:17](=[C:18]([F:23])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[N:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(CN(Cc1ccccc1F)S(=O)(=O)c1ccc(C)cc1)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cccc2c(Br)cncc12
Temperature: 80 °C

Procedure:
To a solution of N-(2,2-dimethoxyethyl)-N-(2-fluorobenzyl)-4-methylbenzenesulfonamide (DD; 0.6 g, 0.0041 mol) in carbon tetrachloride (15 mL) was added N-bromosuccinimide (1.08 g, 0.00603 mol) followed by AIBN (0.06 g, 0.00041 mol) and heated for 3 h at 80° C. Then carbon tetrachloride was evaporated and the crude was purified by column chromatography to get the title compound. 1H NMR (400 MHz, CDCl3) δ 9.46 (1H, s), 8.80 (s, 1H), 7.97-7.95 (d, J=8.4 Hz, 1H), 7.79-7.74 (m, 1H), 7.35-7.31 (dd, J=8.0, 9.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]=[N+]=[N-])[O:10][C:9]2=[O:17])[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:22][CH:21]2[CH2:23][C:24]3([CH2:29][CH:20]2[CH2:19]1)[O:28][CH2:27][CH2:26][O:25]3.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(OCC)(=O)C.[Pd]>[C:36]([NH:14][CH2:13][C@@H:11]1[O:10][C:9](=[O:17])[N:8]([C:6]2[CH:5]=[CH:4][C:3]([N:18]3[CH2:22][CH:21]4[CH2:23][C:24]5([CH2:29][CH:20]4[CH2:19]3)[O:28][CH2:27][CH2:26][O:25]5)=[C:2]([F:1])[CH:7]=2)[CH2:12]1)(=[O:38])[CH3:37]
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(N3CC4CC5(CC4C3)OCCO5)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CC4CC5(CC4C3)OCCO5)c(F)c2)C(=O)O1
Reaction time: 5 h
Yield: 51 %

Procedure:
10 g (24.8 mmol) of 2-[2-fluoro-4-[(5R)-5-(azidomethyl)-2-oxo-3-oxazolidinyl]phenyl]-hexahydro-1H-spiro[cyclopenta[c]pyrrol-5,2′-[1,3]dioxolane] prepared in the step 9 was dissolved in 100 ml of ethyl acetate, and 1 g of 10% palladium/active carbon, 4.01 ml (45.6 mmol) of pyridine and 3.5 ml (37.2 mmol) of acetic anhydride were added, and then, the mixture was stirred for 5 hours under hydrogen gas balloon. After the reaction was completed, the reaction mixture was filtered to remove solid and concentrated under reduced pressure. The concentrate was separated by column chromatography to obtain 5.30 g (51%) of the title compound, of which NMR data is as follows.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C@H:8]([CH2:12][C@H:13]([CH3:18])[CH2:14][CH2:15][CH2:16][CH3:17])[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].CSC.B>C1COCC1>[C:1]([O:5][C:6](=[O:19])[CH2:7][C@@H:8]([CH2:9][OH:10])[CH2:12][C@H:13]([CH3:18])[CH2:14][CH2:15][CH2:16][CH3:17])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CCCC[C@@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of the crude acid 139 (6.14 mmol) in 30 mL THF at 0° C. was added borane-dimethyl sulfide complex (2.0 M solution in THF, 4.6 mL, 9.2 mmol), and the mixture was allowed to warm slowly to ambient temperature overnight. Additional BH3DMS was added until the acid was completely consumed (ca. 5 mL). The reaction was quenched by addition of MeOH, then partitioned between Et2O and sat. NaHCO3 (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated to provide alcohol 140. LRMS: m/z 226.1; 1H NMR (CDCl3): δ 3.63 (dd, J=11.0, 4.2 Hz, 1H), 3.42 (dd, J=11.0, 6.8 Hz, 1H), 2.30 (dd, J=14.9, 7.6 Hz, 1H), 2.20 (dd, J=14.9, 5.6 Hz, 1H), 2.03 (m, 2H), 1.42 (s, 9H), 1.24 (m, 6H), 1.02 (m, 2H), 0.85 (m, 6H). The crude product was used without purification.
Reaction SMILES: [C:1]1([C:7]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1>C1COCC1>[C:1]1([C:7]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH2:43][C:42]3[CH:45]=[CH:46][C:39]([C:31]4[O:30][C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=5[N:32]=4)=[CH:40][CH:41]=3)[CH2:23][CH2:22]2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: O[C@H]1CC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(C(N[C@H]2CC[C@H](OCc3ccc(-c4nc5ccccc5o4)cc3)CC2)(c2ccccc2)c2ccccc2)cc1

Procedure:
To a mixture of trans-4-triphenylmethylaminocyclohexanol (3.18 g; 8.90 mmol) is 100 ml THF is added sodium hydride (60%; 0.320 g; 13.35 mmol) and this is followed by the addition of 4-(benzoxazol-2-yl)benzyl bromide after about 1 hr. The mixture is heated at reflux for 1 week, cooled, concentrated in vacuo and dissolved in about 40 ml CH2Cl2 ; hexane:ethylacetate (9:1 ). The solid material is filtered off and the residue flash chromatographed using hexane:ethylacetate; 7:1 to obtain trans-4-triphenylmethylamino-[4-(benzoxazol-2-yl)benzyloxy]cyclohexane as a white solid which is used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[N:4]=[C:5]([S:30][CH3:31])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([OH:28])[C:21]=1[F:29])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[Si:33]([O:40][CH2:41][C@H:42](O)[CH3:43])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3](=[O:32])[N:4]=[C:5]([S:30][CH3:31])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][C@@H:42]([CH3:43])[CH2:41][O:40][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:21]=1[F:29])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(O)c1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1F
Temperature: -78 °C
Reaction time: 8 h

Procedure:
[2-(2-Fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (3d), 275 mg), (R)-1-(t-butyldimethylsilanyloxy)propan-2-ol [CAS No. 136918-07-5] (171 mg), and triphenylphosphine (236 mg) were dissolved in 3 ml of THF under a nitrogen atmosphere, and the resulting mixture was cooled to −78° C. After the addition of 0.177 ml of N,N′-diisopropylazodicarboxylate, the mixture was allowed to warm to room temperature with stirring overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give the title compound (343 mg).
Reaction SMILES: [C:1]([C:4]1[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[CH:11][C:5]=1[O:6][CH2:7]C(O)=O)(=O)[CH3:2].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(=O)(O)[O-].[Na+]>[Cl:15][C:14]1[C:4]2[C:1]([CH3:2])=[CH:7][O:6][C:5]=2[CH:11]=[C:12]([Cl:16])[CH:13]=1
Reactant: CC(=O)c1c(Cl)cc(Cl)cc1OCC(=O)O
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1coc2cc(Cl)cc(Cl)c12
Temperature: 155 °C
Yield: 62.8 %

Procedure:
A mixture of 5.0 g (0.019 mol) of 2-(2-acetyl-3,5-dichlorophenoxy) acetic acid, 10.0 g of anhydrous sodium acetate and 50 ml of acetic anhydride was heated at 155° C. for 0.5 hour. The mixture was poured on to 100 g of ice and 100 ml of a saturated sodium bicarbonate solution. When decomposition of the excess acetic anhydride was complete, the mixture was extracted with three 100 ml portions of diethyl ether. The combined extracts were washed neutral with saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated to give a brown oil which solidified on standing. The crude product was purified by distillation to yield 2.4 g of pure 4,6-dichloro-3-methylbenzofuran of boiling point 85° C./1 mmHg. The distilled product could be crystallized from petrol (boiling point 40°-60° C.) in the form of white needles of melting point 45° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[CH2:21]([O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[OH:33])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.C(OCC)(=O)C>[CH2:21]([O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[O:33][CH2:2][C:3]([N:5]1[CH2:10][CH:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][CH:6]1[CH3:20])=[O:4])[CH3:22]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Reactant: CCOC(=O)Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(Cl)ccc1OCC(=O)N1CC(C)N(Cc2ccc(F)cc2)CC1C
Yield: 97.8 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (3.3 g, 11.0 mmol) in 2-butanone (100 mL) was added (5-chloro-2-hydroxy-phenyl)-acetic acid ethyl ester (2.3 g, 11.0 mmol), potassium carbonate (3.05 g, 22.1 mmol), and potassium iodide (1.83 g, 11.0 mmol). The reaction was heated at reflux for 48 hrs. The solution was cooled, diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by dissolving in dichloromethane and passing through a pad of silica gel. Concentration in vacuo gave the title compound (5.13 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:32])[C@@H:16]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:17][CH2:18]SC)[C@H:10]([CH2:33][CH2:34][CH3:35])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:25]([O:24][C:22](=[O:23])[NH:21][C@H:16]1[CH2:17][CH2:18][N:14]([C@H:11]2[CH2:12][CH2:13][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:36])[CH2:9][C@H:10]2[CH2:33][CH2:34][CH3:35])[C:15]1=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)[C@H](CCSC)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.3 %

Procedure:
The compound (1R,3R,4S)-[4-((2S)-2-benzyloxycarbonylamino-4-methylsulfanyl-butyrylamino)-3-propyl-cyclohexyl]-carbamic acid tert-butyl ester (375 mg) was “wetted” with EtOAc, and then the majority of EtOAc was removed under nitrogen stream. The residue was dissolved in iodomethane (6 mL), and the resulting solution was stirred at RT for 48 h before being concentrated in vacuo. The residue was dissolved in methylene chloride, and the resulting solution was concentrated; this was repeated to afford the salt. MS found: (M+H)+=536.3. This material was dissolved in DMF (12 mL) and the solution was charged with Cs2CO3 (470 mg, 1.4 mmol) and stirred for 12 h at RT before being partitioned between EtOAc and brine. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford {(3S)-1-[(1S,2R,4R)-4-tert-butoxycarbonylamino-2-propyl-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid benzyl ester (185 mg). MS found: (M+H)+=474.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][NH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:11]([OH:13])=O.Cl.[NH:19]1[CH2:22][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:20]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[N:5][NH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:11]([N:19]1[CH2:22][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:20]1)=[O:13]
Reactant: COc1cn[nH]c1-c1cc(C(=O)O)ccc1C
Reactant: N#Cc1ccc(C2CNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cn[nH]c1-c1cc(C(=O)N2CC(c3ccc(C#N)cc3)C2)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of 3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 244.7, 60 mg, 0.26 mmol) in N,N-dimethylformamide (2 mL). 4-(Azetidin-3-yl)benzonitrile hydrochloride (75 mg, 0.39 mmol), EDC.HCl (99 mg, 0.52 mmol), and 4-dimethylaminopyridine (63 mg, 0.52 mmol) were added and the solution was stirred for 2 h at room temperature. The reaction was diluted with EtOAc (30 mL) and washed with brine (3×15 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-010(Waters)): Column, SunFire Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (35.0% CH3CN up to 50.0% in 10 min, up to 100% in 1 min, down to 35.0% in 2 min); Detector, UV 254 & 220 nm. The fractions contained pure product were combined and lyophilized to obtain the title compound as an off-white solid (44.3 mg, 46%). m/z (ES+) 373 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH3:30])[C:11]([CH2:12][OH:13])=[CH:10]2
Reactant: OCc1cc2cc(F)ccc2nc1Cl
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccccc1-c1nc2ccc(F)cc2cc1CO
Temperature: 120 °C
Yield: 22.8 %

Procedure:
A mixture of (2-chloro-6-fluoroquinolin-3-yl)methanol (200 mg, 0.95 mmol), K2CO3 (198 mg, 1.43 mmol) and o-tolylboronic acid (143 mg, 1.05 mmol) in DME (10 mL) and water (1 mL) was degassed by bubbling N2 through it for 5 minutes. Pd(PPh3)4 (55 mg, 0.05 mmol) was added and the mixture heated in the microwave at 120° C. for 1 h. The solvent was removed in vacuo. Purification by column chromatography (SiO2, 0-50% EtOAc in heptane) then by preparative HPLC (Method 1) gave the title compound (58 mg, 23%) as a white solid. δH (CDCl3) 8.32 (s, 1H), 8.10-8.15 (m, 1H), 7.45-7.55 (m, 2H), 7.20-7.35 (m, 4H), 4.58 (s, 2H), 2.09 (s, 3H). LCMS (ES+) 268 (M+H)+, RT 2.89 minutes (Method 3).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[NH:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3]1.[N:29]1[C:36]([Cl:37])=[N:35][C:33]([Cl:34])=[N:32][C:30]=1Cl.[OH-].[Na+]>ClCCCl>[Cl:34][C:33]1[N:35]=[C:36]([Cl:37])[N:29]=[C:30]([N:8]([CH:6]2[CH2:7][C:2]([CH3:28])([CH3:1])[NH:3][C:4]([CH3:27])([CH3:26])[CH2:5]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([C:30]2[N:29]=[C:36]([Cl:37])[N:35]=[C:33]([Cl:34])[N:32]=2)[CH:16]2[CH2:17][C:18]([CH3:25])([CH3:24])[NH:19][C:20]([CH3:23])([CH3:22])[CH2:21]2)[N:32]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC1(C)CC(NCCCCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CC1(C)CC(N(CCCCCCN(c2nc(Cl)nc(Cl)n2)C2CC(C)(C)NC(C)(C)C2)c2nc(Cl)nc(Cl)n2)CC(C)(C)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 118.20 g (0.30 mol) of N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)-1,6-diaminohexane in 150 ml of 1,2-dichloroethane is added slowly in the course of 2 hours to a solution, maintained at 0° C., containing 110.70 g (0.60 mol) of cyanuric chloride in 800 ml of 1,2-dichloroethane. 250 ml of an aqueous solution containing 25.20 g (0.63 mol) of sodium hydroxide are then added in 30 minutes at 0° C., and stirring is continued for 2 hours at 0° C. The aqueous phase is then separated off, the organic phase is washed repeatedly with water and dehydrated by means of anhydrous sodium sulfate, and a white solid of melting point 161°-163° C. is precipitated by evaporation of the solvent.