Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][CH2:12][CH3:13].[N:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1>C(#N)C>[Br-:1].[CH2:2]([N+:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][CH2:12][CH3:13]
Reactant: Cc1ccncc1
Reactant: CCC#CCCCCCCCCBr
Solvent: CC#N
Product: CCC#CCCCCCCCC[n+]1ccc(C)cc1
Product: [Br-]
Yield: 82 %

Procedure:
12-Bromo-dodec-3-yne (1 mmol) was added to a solution of 4-picoline (3 mmol) in acetonitrile, and the solution was refluxed for 24 hours. The acetonitrile was removed in a vacuum, and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no picoline was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (82%). 1HNMR (300 MHz, CDCl3, ppm), 9.24 (d, 2H), 7.86 (d, 2H), 4.90 (t, 2H), 2.64 (s, 3H), 1.95-2.16 (m, 6H), 1.26-1.34 (br, 10H), 0.88 (t, 3H).
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([OH:5])=O.[NH:32]1[CH:36]=[CH:35][N:34]=[CH:33]1>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([N:32]1[CH:36]=[CH:35][N:34]=[CH:33]1)=[O:5]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: c1c[nH]cn1
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)n1ccnc1

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and imidazole (imidazole/pyridine solution).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C)CCN(C)C.[CH3:32][C:33]([CH3:39])([CH2:36][CH:37]=[CH2:38])[CH:34]=[O:35]>C1COCC1.O>[CH3:32][C:33]([CH3:39])([CH2:36][CH:37]=[CH2:38])[CH:34]([OH:35])[CH:12]([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(Cn2ccnc2)cc1
Reactant: C=CCC(C)(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: C=CCC(C)(C)C(O)C(c1ccccc1)n1ccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.6 %

Procedure:
40 ml of 1.5 molar n-butyllithium/hexane solution were added dropwise to a solution of 4.75 g (30 mmol) of 1-benzylimidazole and 3.49 g (30 mmol) of N,N,N',N'-tetramethylethylenediamine (TMED(A) in 60 ml of absolute THF at -70° C. The mixture was stirred at -70° C. to -78° C. for a further 30 minutes, a solution of 3.74 g of 90% purity (30 mmol) 2,2-dimethyl-4-pentenaldehyde in 38 ml of absolute THF was then added dropwise at about -70° C. over 25 minutes, and the mixture was stirred at about -70° C. for a further 20 minutes and allowed to warm to room temperature over about 2 hours. 350 ml of water were then added at 0°-8° C., the mixture was stirred for a further 30 minutes while cooling in an ice bath, and the phases were subsequently separated and the aqueous solution was extracted repeatedly with ether. The combined organic solutions were further worked up as described in Example 1. The extract residue (8.4 g) was chromatographed, eluting with CH2Cl2 and CH2Cl2 /C2H5OH mixtures with an increasing C2H5OH content (to a maximum of 2% by volume) on a silica gel S/CH2Cl2 column (2.8 cm, height 48 cm). After elution of 4.8 g preliminary fractions, 3.5 g of product were eluted in which the compound desired was contained. This product (3.5 g) was again chromatographed in the same fashion as described above on a silica gel S/CH2Cl2 column (φ 2.0 cm, height 60 cm), during which the composition of the fractions eluted was checked by thinlayer chromatography (TLC). After elution of 0.35 g preliminary fractions, 4 fractions were eluted (with CH2Cl2 /C2H5OH 99.6:0.4- 99.5:0.5 ) which contained the compound desired in virtually pure form. These fractions were combined and evaporated in a high vacuum at a bath temperature of 65° C. until the weight remained constant. 0.62 g (≅7.6% yield) of 3,3-dimethyl-1-(1-imidazolyl)-1-phenyl-5-hexen-2-ol was thus obtained as a viscous, colorless oil; the 1H NMR spectrum confirmed the structure of this compound.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.CCN(C(C)C)C(C)C.[CH3:40][O:41][C:42]1[CH:59]=[C:58]([O:60][CH3:61])[CH:57]=[CH:56][C:43]=1[CH2:44][N:45]([CH2:53]OC)[C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:40][O:41][C:42]1[CH:59]=[C:58]([O:60][CH3:61])[CH:57]=[CH:56][C:43]=1[CH2:44][N:45]([CH2:53][C@H:15]([C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[C:14]([N:9]1[C@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:23])[C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49]
Reactant: O=C(Cc1ccc(Cl)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COCN(Cc1ccc(OC)cc1OC)C(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(C[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(Cl)cc2)C(=O)OC(C)(C)C)c(OC)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 73.4 %

Procedure:
(R)-4-benzyl-3-(2-(4-chlorophenyl)acetyl)oxazolidin-2-one (3.00 g, 9.10 mmol) was dissolved in DCM (91 mL) and cooled to −78° C. A 1M toluene solution of TiCl4 (11.4 mL, 11.4 mmol) was added to the solution followed by DIEA (1.66 mL, 9.55 mmol) to afford a dark purple reaction. This was allowed to stir for 15 minutes before the tert-butyl 2,4-dimethoxybenzyl(methoxymethyl)carbamate (3.40 g, 10.9 mmol) was added as a solution in DCM (10 mL) dropwise. The reaction was allowed to stir for 15 minutes at −78° C., then allowed to warm to −18° C. in a brine-ice bath for one hour. This reaction was allowed to warm slowly to 0° C. over a 2.5 hour period. The reaction was then quenched with the addition of saturated NH4Cl solution (100 mL). The layers were separated, and the organic layers was extracted once with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford a yellow oil. The residue was purified by chromatography (silica gel eluted with 4:1 hexanes:ethyl acetate) to afford the pure material as a colorless oil tert-butyl 2,4-dimethoxybenzyl((S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl)carbamate (4.07 g, 73.5% yield). This tert-butyl 2,4-dimethoxybenzyl(S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl)carbamate (680 mg, 1.12 mmol) was dissolved in DCM (10.6 mL) and water (560 uL; 19:1 DCM:water) at ambient temperature. The solution was treated with DDQ (380 mg, 1.67 mmol), and the reaction was allowed to stir for one day to afford reaction completion by TLC and LCMS analysis. The reaction was diluted with DCM and washed twice with half saturated NaHCO3 solution. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford a yellow-orange oil. The residue was purified by chromatography (silica gel eluted with 9:1 hexanes:ethyl acetate) to afford a mixture of the aldehyde by-product and tert-butyl(S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropylcarbamate (not separable) as a pale-yellow oil (729 mg combined mass). LC/MS (APCI+) m/z 359.1 [M-BOC+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[CH3:10]C(C)=O.C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: CC(C)=O
Reactant: Oc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COc1cc(F)ccc1F

Procedure:
35.0 g of the product of Step A, 350 ml of acetone, 44.6 g of potassium carbonate and 40.7 g of dimethyl sulfate (neutralized on potassium bicarbonte) and was allowed to return to ambient temperature. Water was added and extraction was carried out with ether. The extracts were washed, dried and concentrated to dryness under reduced pressure to obtain 39.8 g of the desired product.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[N:16]=3)[C:12]([Cl:29])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[F:30][C:31]([F:36])([F:35])[C@@H:32]1[O:34][CH2:33]1>CC(O)C>[Cl:29][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:16]=2)=[CH:14][C:9]([NH:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][CH2:33][C@@H:32]([OH:34])[C:31]([F:36])([F:35])[F:30])[CH2:3][CH2:4]2)=[N:10][CH:11]=1
Reactant: FC(F)(F)[C@H]1CO1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Solvent: CC(C)O
Product: O[C@H](CN[C@H]1CC[C@H](Nc2cc(-c3cccc(NCC4CCOCC4)n3)c(Cl)cn2)CC1)C(F)(F)F
Temperature: 60 °C
Reaction time: 17 h

Procedure:
To a solution of N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (50 mg, 0.120 mmol) in 2-propanol (0.8 mL) was added (R)-(+)-3,3,3-trifluoro-1,2-epoxypropane (10.4 uL, 0.120 mmol). The mixture was stirred at 60° C. for 17 hr. The reaction mixture was concentrated. The resulting residue was purified by reverse phase HPLC and lyophilized to give 63 mg of (R)-3-(trans-4-(5′-chloro-6-((tetrahydro-2H-pyran-4-yl)methyl)amino-2,4′-bipyridin-2′-yl-amino)cyclohexylamino)-1,1,1-trifluoropropan-2-ol as its TFA salt. LCMS (m/z): 528.3 (MH+), retention time=0.53 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.34 (m, 4H) 1.36-1.56 (m, 2H) 1.61 (d, J=12.52 Hz, 2H) 1.70-1.90 (m, 1H) 2.04 (d, J=9.39 Hz, 3H) 2.13 (d, J=11.74 Hz, 1H) 2.97-3.19 (m, 4H) 3.24 (t, J=10.76 Hz, 3H) 3.64 (d, J=10.96 Hz, 1H) 3.83 (dd, J=10.96, 2.74 Hz, 2H) 4.36-4.50 (m, 2H) 6.54-6.68 (m, 2H) 6.70 (d, J=7.04 Hz, 0H) 6.94 (br. s., 0H) 7.23 (br. s., 0H) 7.53 (br. s., 0H) 8.04 (s, 0H) 8.76 (br. s., 2H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21](Br)[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[Na+].[CH3:32][S:33]([O-:35])=[O:34].[Na+].N1CCC[C@H]1C([O-])=O>CS(C)=O.O.[Cu]I>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([S:33]([CH3:32])(=[O:35])=[O:34])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: O=C([O-])[C@@H]1CCCN1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Temperature: 150 °C
Yield: 51 %

Procedure:
[(R)-4-(3-Bromo-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (118.0 mg, 0.20 mmol), methanesulfinic acid sodium salt (24.5 mg, 0.24 mmol), copper(I) iodide (4.0 mg, 0.02 mmol) and L-proline sodium salt (3.2 mg, 0.04 mmol) were dissolved in dimethyl sulfoxide (1.5 mL) and water (0.3 mL). The mixture was heated in a microwave oven at 150° C. for 30 minutes. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by column chromatography (gradient elution, 0-5% methanol in dichloromethane) to afford [(R)-4-(3-methanesulfonyl-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (52.0 mg, 51.1%) as a white solid. MS calcd. for C19H22F3N3O6S2 509, obsd. (ESI+) [(M+H)+] 510.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].C(Cl)Cl.[NH2:11][C:12]1[S:13][C:14]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH3:22])[C:15]=2[N:16]=1>O1CCCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:14]2[S:13][C:12]([NH:11][C:6](=[O:7])[NH:5][C:3]([O:2][CH3:1])=[O:4])=[N:16][C:15]=2[C:17]=1[CH3:22]
Reactant: Cc1c(Cl)ccc2sc(N)nc12
Reactant: COC(=O)N=C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)NC(=O)Nc1nc2c(C)c(Cl)ccc2s1
Reaction time: 8 h
Yield: 40 %

Procedure:
A solution of 2 parts by weight of methoxycarbonylisocyanate in 15 parts by weight of methylene chloride was added gradually with stirring to a solution, at room temperature, of 4 parts by weight of 2-amino-5-chloro-4-methylbenzothiazole in 75 parts by weight of methylene chloride and 50 parts by weight of tetrahydrofuran. After stirring the reaction mixture at room temprature overnight, a product was isolated by filtration giving a 40% yield of methyl 4-(5-chloro-4-methylbenzothiazol-2-yl)allophanate having a melting point greater than 275° .
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=O.O.[NH2:14][NH2:15]>O>[N+:10]([C:6]1[CH:5]=[C:4]([C:2](=[N:14][NH2:15])[CH3:1])[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: NN
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Solvent: O
Product: CC(=NN)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
To a solution of 3-nitroacetophenone (200 g, 1.12 mol) in Industrial Methylated Spirits (1.2 l) was added hydrazine monohydrate (140 ml, 2.25 mol) and the reaction mixture was heated under reflux for 2 h. Water (1.2 l) was added and the reaction mixture was cooled to room temperature. The resulting precipitate was collected by filtration to afford the title compound as a yellow crystalline solid (180 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13](C3C4C(=CC=C([N+]([O-])=O)C=4)NN=3)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[F:28][C:29]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:29]=3[F:28])=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(F)c1)c1ccc(-c2n[nH]c3ccc([N+](=O)[O-])cc23)[nH]1
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Nc1cccc(F)c1)c1ccc(C(=O)c2ccc(F)cc2F)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
To a mixture of 1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide (930 mg, 4.6 mmol) (Example 47) and 2,4-difluoro-benzoyl chloride (1.3 g, 7.4 mmol) in benzene (10 mL) at room temperature, was added a solution of tin (IV) chloride (1.5 mL). After stirring at room temperature for overnight and the usual work-up, the residue was purified on a silica gel column to give 180 mg of 5-(2,4-difluoro-benzoyl)-1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([C:10]#[N:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#CCc1ccc(F)c(F)c1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(F)c(F)c2)CCCCC1
Reaction time: 0.08 h
Yield: 87.2 %

Procedure:
To a solution of 2-(3,4-difluorophenyl)acetonitrile (2 g, 13.06 mmol) in 20 mL of DMF at 0° C. was added 60% sodium hydride (1.149 g, 28.7 mmol), and the mixture was stirred at the same temperature for 5 mins. Then a solution of 1,5-dibromopentane (1.779 mL, 13.06 mmol) in 20 mL of DMF was added dropwise and the mixture was stirred at a temperature in the range 0° C. to room temperature for 5 hrs. The reaction was quenched with water, and extracted with EtOAc. The mixture was washed with water and brine. The combined aqueous layers were back extracted with EtOAc once and washed with brine. The combined extracts were dried over Na2SO4 and evaporated to give an oily residue. It was purified by Combiflash (120 g silica gel) eluting with 1:9 EtOAc-hexane to give 1-(3,4-difluorophenyl)cyclohexanecarbonitrile (2.52 g, 11.39 mmol, 87% yield). 1H NMR (400 MHz, CCl3D) δ ppm 7.12-7.35 (3H, m), 2.14 (2H, d, J=11.86 Hz), 1.75-1.95 (6H, m), 1.64-1.75 (2H, m).
Reaction SMILES: [CH3:1][C:2]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:10]=1)([CH3:5])[CH2:3][NH2:4].[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[N:24]=1>>[CH3:5][C:2]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)[N:10]=1)([CH3:1])[CH2:3][NH:4][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([C:25]2[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=2)[CH:29]=1
Reactant: CC(C)(CN)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Yield: 24 %

Procedure:
This compound was synthesized from 2-methyl-2-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)propan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (10 mgs, 24% yield). 1H NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 8.25 (d, J=7.4 Hz, 1H), 8.09-7.96 (m, 4H), 7.64-7.53 (m, 3H), 3.82 (bs, 2H), 1.56 (s, 6H). MS (ESI) m/z: Calculated for C24H18F6N4O2S: 540.11. found: 541.1 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][N:17]=[C:16](Cl)[CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[N:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:19][CH:18]=1
Reactant: Clc1cc(N2CCN(Cc3ccccc3)CC2)ncn1
Agent: [Pd]
Solvent: CO
Product: c1cc(N2CCNCC2)ncn1
Reaction time: 8 h
Yield: 76.1 %

Procedure:
1-(Benzyl)-4-(4-chloropyrimidin-6-yl)piperazine (58.0 g; 0.20 mol) was dissolved, with some heating, in methanol (700 ml), treated with 10% Pd on activated carbon (11.6 g) and agitated and hydrogenated at s.t.p. for 8 h. After this period the catalyst was removed by filtering through celite. The filtrate thus obtained was then evaporated under reduced pressure to a yellow-brown viscous gum which was chromatographed through 60 μm silica gel, eluting with 5% methanol, 1% ammonium hydroxide and 94% CH2Cl2 to obtain as white solid, 25 g (76% yield based on prehydrogenation substrate) of 4-(4-pyrimidinyl)piperazine;
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl[C:16]1[CH:21]=[C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[N:19]=[CH:18][N:17]=1>>[CH2:23]([O:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:21]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CC(C)COc1cc(Cl)ncn1
Product: CC(C)COc1cc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)ncn1

Procedure:
The title compound was prepared according to the procedure described in Step-1 of Intermediate C using tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and 4-chloro-6-isobutoxypyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:28])[C:15]([NH:17][C@@H:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:19][OH:20])=O.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH2:21]([C@H:18]1[CH2:19][O:20][C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:28])=[N:17]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C(=O)N[C@H](CO)Cc1ccccc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1=N[C@@H](Cc2ccccc2)CO1
Temperature: 80 °C
Reaction time: 20 h
Yield: 4.5 %

Procedure:
A sealed tube containing (S)—N1-(2-(5-chloro-1H-indol-3-yl)ethyl)-N2-(1-hydroxy-3-phenylpropan-2-yl)oxalamide (0.117 g, 0.293 mmol) and Burgess reagent [(methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt (0.115 g; 0.468 mmol)] in dry THF (6 mL) was stirred at 80° C. for 20 hours. The solution was evaporated and the resulting residue was purified by flash chromatography on silica gel (eluent 7 to 60% ethyl acetate in dichloromethane) to give 0.005 g (4%) of (S)-4-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4,5-dihydrooxazole-2-carboxamide as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:40])[CH2:38][CH3:39].[OH-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:37](=[O:40])[CH2:38][CH3:39])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])=[CH:6][CH:7]=1
Reactant: Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)c(F)c2)ccn1
Reactant: CCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)c(F)c2)ccn1
Reaction time: 8 h
Yield: 39 %

Procedure:
N-(4-Fluorophenyl)-N′-[4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]malonamide (20.2 mg) was dissolved in N,N-dimethylformamide (0.5 ml), and then triethylamine (0.042 ml) and propionyl chloride (0.013 ml) were added dropwise thereto under a nitrogen atmosphere at room temperature, followed by stirring overnight. To the reaction mixture was added a 1 N aqueous solution of sodium hydroxide (1.5 ml), followed by stirring and extracting with ethyl acetate. The organic layer was concentrated under a reduced pressure to give a residue, which was purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, which was then dried in vacuum to provide the titled compound (9.0 mg, 39%) as pale yellow powder.
Reaction SMILES: [ClH:1].[CH2:2]([N+:9]1(C)[CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:20][CH3:21])=[C:14]([O:18][CH3:19])[CH:15]=2)[CH2:10]1)C1C=CC=CC=1.Cl.[H][H]>CO.[C].[Pd]>[ClH:1].[CH3:19][O:18][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:20][CH3:21])[CH2:10][N:9]([CH3:2])[CH2:17]2
Reactant: [H][H]
Reactant: COc1cc2c(cc1OC)C[N+](C)(Cc1ccccc1)C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cc2c(cc1OC)CN(C)C2

Procedure:
1.0 g (3.12 mmol) of N-benzyl-5,6-dimethoxy-N-methylisoindolinium hydrochloride was dissolved in 20 ml of methanol, and 0.5 ml of 6N hydrochloric acid and 100 mg of a 10% palladium carbon catalyst were added thereto. The catalytic reduction was conducted at room temperature for 5 hours in a hydrogen gas stream. The catalyst was filtered off, and the solvent was distilled off under reduced pressure. The crystal residue was washed with 10 ml of acetone to obtain 650 mg of the above identified compound.