Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15](Cl)=[O:16])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH:18]1[CH2:20][CH2:19]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)Cl>[Cl:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:16])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH:18]1[CH2:19][CH2:20]1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccc2nc(C3CC3)n(Cc3ccccc3Cl)c2c1
Agent: Cl
Solvent: ClCCl
Product: O=C(c1ccc2nc(C3CC3)n(Cc3ccccc3Cl)c2c1)N1CCOCC1
Reaction time: 1 h
Yield: 13.8 %

Procedure:
1-(2-Chlorobenzyl)-6-chlorocarbonyl-2-cyclopropylbenzimidazole hydrochloride (140 mg) was added to a solution prepared by adding 298 mg of morpholine (30% methanol solution) to 10 ml of methylene chloride at room temperature. The reaction mixture was stirred at the same temperature for 1 hour, then washed with water, dried, and concentrated under reduced pressure. The residue was recrystallized with ether to give 20 mg of 1-(2-chlorobenzyl)-2-cyclopropyl-6-morpholinocarbonylbenzimidazole (66).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1)[CH2:25][CH3:26]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([O:27][CH2:24][CH2:25][CH3:26])=[CH:33][CH:32]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCCOc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-propoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (stage 55.1.1) to give the title compound as a white solid. (HPLC: tR 2.87 min (Method A); M+H=429 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.95 (s, 1H), 8.28 (s, 1H), 8.15-8.11 (m, 1H), 8.11-8.05 (m, 1H), 7.92-7.86 (m, 1H), 7.79-7.73 (m, 1H), 7.50-7.45 (m, 1H), 6.95-6.89 (m, 1H), 4.24 (t, 2H), 3.91 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H), 1.78-1.68 (m, 2H), 0.98 (t, 3H))
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:15][NH2:16]>CN(C)C=O>[CH3:15][NH:16][C:2]1[C:3]2[N:4]([CH:12]=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Clc1nc2ccccc2n2cnnc12
Reactant: CN
Solvent: CN(C)C=O
Product: CNc1nc2ccccc2n2cnnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
4-Chloro-[1,2,4]triazolo-[4,3-a]quinoxaline (2.0 g., 0.01 mole), the product of Example 2, in N,N-dimethyl formamide (30 ml.) was saturated with monomethylamine gas and stirred at room temperature for 3 hours. Monomethylamine gas was again bubbled into the solution and the solution was stirred at room temperature for an additional 2 hours. The precipitate was separated by filtration and washed with N,N-dimethylformamide. Recrystallization from N,N-dimethylformamide gave 1.37 g. (69% yield) of 4-methylamino-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. >300° C. Mass spectrum: m/e, 199 (P).
Reaction SMILES: C[N+]1([O-])CCOCC1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][C:14]=1[NH:23][C:24](=[O:43])[CH2:25][CH:26]([C:32]1[CH:37]=[CH:36][C:35]([CH:38]([OH:40])[CH3:39])=[CH:34][C:33]=1[O:41][CH3:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH3:12])([CH3:11])[CH3:10].C(OCC)(=O)C>C(Cl)Cl.CCCCCC.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][C:14]=1[NH:23][C:24](=[O:43])[CH2:25][CH:26]([C:32]1[CH:37]=[CH:36][C:35]([C:38](=[O:40])[CH3:39])=[CH:34][C:33]=1[O:41][CH3:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH3:10])([CH3:11])[CH3:12]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(C(C)O)cc1OC
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.2 %

Procedure:
500 mg of 4A molecular sieves and 185 mg (1.58 mmol) of 4-methylmorpholin-4-oxide were added to a solution of 466 mg (0.964 mmol) of N-(2-t-butyl-5-methoxycarbonylphenyl)-3-[4-(1-hydroxyethyl)-2-methoxyphenyl)-octanamide [prepared as described in step (i) above] in 10 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 10 minutes. At the end of this time, 34 mg (0.097 mmol) of tetrapropylammonium perruthenate were added to the mixture. The reaction mixture was stirred at room temperature for 1 hour, after which it was diluted with hexane and the diluted solution was subjected to column chromatography through 25 g of silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 456 mg (yield 98%) of the title ketone derivative as a foam-like substance.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:28])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[O:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42]([C:44]3[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=3)=[O:43])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[CH3:27][N:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([NH:13][C:6]3[CH:7]=[CH:8][C:9]4[NH:10][C:48]([C:47]5[CH:50]=[CH:51][C:44]([C:42](=[O:43])[NH:41][C:38]6[CH:39]=[CH:40][C:35]([N:32]7[CH2:31][CH2:30][O:29][CH2:34][CH2:33]7)=[CH:36][CH:37]=6)=[CH:45][CH:46]=5)=[N:1][C:4]=4[CH:5]=3)=[O:28])=[CH:16][CH:17]=2)[CH2:22][CH2:23]1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Reactant: CN1CCN(c2ccc(C(=O)Nc3ccc([N+](=O)[O-])c([N+](=O)[O-])c3)cc2)CC1
Product: CN1CCN(c2ccc(C(=O)Nc3ccc4[nH]c(-c5ccc(C(=O)Nc6ccc(N7CCOCC7)cc6)cc5)nc4c3)cc2)CC1

Procedure:
Compound 249 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-(4-methylpiperazinyl)benzamide and 4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C36H37N7O3: 616.30; found: 616.09.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([N:14]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:12][CH:11]2[O:13][CH:8]([CH2:9][CH2:10]2)[CH2:7]1)=[O:5])[CH3:2].[ClH:28]>C(OCC)C>[ClH:28].[CH2:1]([O:3][C:4]([C:6]1([NH2:14])[CH2:12][CH:11]2[O:13][CH:8]([CH2:9][CH2:10]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(N=C(c2ccccc2)c2ccccc2)CC2CCC(C1)O2
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C1(N)CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A two-phase mixture of 3-(benzhydrylideneamino)-8-oxabicyclo[3.2.1]octane-3-carboxylic acid ethyl ester (1.4 grams, 3.9 mmol) in aqueous 1N hydrochloric acid solution (100 mL) and diethyl ether (100 mL) was stirred at room temperature overnight. The aqueous layer was concentrated to provide the title compound (0.70 grams, 78%, a 3:1 mixture of exo/endo diastereomers) as a pale yellow solid.
Reaction SMILES: ClC1C2C=C(C3CCC(C)(C)CC3)SC=2N=C(C)N=1.C([Sn](CCCC)(CCCC)C(OCC)=C)CCC.[NH4+].[Cl-].[CH3:40][C:41]1([CH3:62])[CH2:46][CH2:45][CH:44]([C:47]2[S:61][C:50]3[N:51]=[C:52]([CH3:60])[N:53]=[C:54]([C:55]([O:57]CC)=[CH2:56])[C:49]=3[CH:48]=2)[CH2:43][CH2:42]1.Cl>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.CCO.C1(C)C=CC=CC=1>[CH3:40][C:41]1([CH3:62])[CH2:46][CH2:45][CH:44]([C:47]2[S:61][C:50]3[N:51]=[C:52]([CH3:60])[N:53]=[C:54]([C:55](=[O:57])[CH3:56])[C:49]=3[CH:48]=2)[CH2:43][CH2:42]1
Reactant: C=C(OCC)c1nc(C)nc2sc(C3CCC(C)(C)CC3)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cc1nc(Cl)c2cc(C3CCC(C)(C)CC3)sc2n1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)c1nc(C)nc2sc(C3CCC(C)(C)CC3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-chloro-6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine (1.0 g), tributyl(1-ethoxyvinyl)stannane (1.16 mL), and toluene (10.8 mL) was added Pd(PPh3)4 (392 mg), followed by heating to reflux for 5 hours. The reaction mixture was left to be cooled to room temperature, and to the reaction mixture were added a saturated aqueous NH4Cl solution, followed by extraction with EtOAc. The organic layer was washed sequentially with water and brine, dried over MgSO4, and then concentrated under reduced pressure to obtain a crude product (1.12 g) containing 6-(4,4-dimethylcyclohexyl)-4-(1-ethoxyvinyl)-2-methylthieno[2,3-d]pyrimidine. To this crude product were added EtOH (9.0 mL) and 1 M hydrochloric acid (10.2 mL) at room temperature, followed by stirring at 50° C. overnight. The reaction mixture was left to be cooled and concentrated under reduced pressure. To the residue was added water, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column to obtain 1-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]ethanone (820 mg).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:17]([C:21]#[N:22])=[N:18][NH:19][CH:20]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].C(O)(=O)C>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[C:16]3[C:17](=[N:18][NH:19][CH:20]=3)[CH2:21][N:22]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]=2[CH:14]=1
Reactant: N#Cc1n[nH]cc1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Ni]
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1n[nH]cc1-2
Reaction time: 4 h

Procedure:
A mixture of 2.2 g (7.2 mmole) of 4-[2-benzoyl-4-chlorophenyl]pyrazole-3-carbonitrile, 2.0 g of Raney nickel, and 150 ml of acetic acid was hydrogenated on a Parr apparatus for 4 hr. The Raney nickel was removed by filtration, and the filtrate diluted with 600 ml of ice water. The acetic acid was neutralized with concentrated ammonium hydroxide and the resulting aqueous solution was extracted with methylene chloride. The methylene chloride solution was washed with water, and was dried with sodium sulfate. Concentration of the methylene chloride solution gave a tan solid. Recrystallization from chloroform/hexane gave a white solid, mp 241°-243°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[CH2:7].[H][H]>[Pd].CO>[CH2:6]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[CH:9][CH:8]=1)[CH3:7]
Reactant: [H][H]
Reactant: C=Cc1ccc(OC)c(OC)c1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(OC)c(OC)c1
Yield: 98.8 %

Procedure:
In an atmospheric pressure hydrogenation equipment 10.0 g (60.9 mM) of 3,4-dimethoxystyrene, 0.5 g of palladium charcoal and 200 ml of methanol were charged and introduced with hydrogen. The reaction was continued until the absorption of hydrogen was terminated. Palladium charcoal was filtered off from the reaction mixture. Methanol was distilled off from the filtrate. The residue was distilled under vacuum to obtain 10.0 g (60.2 mM) of 4-ethylveratrole as a colorless transparent liquid having a boiling point of 84°-85° C./2 mmHg
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[CH3:13].O.[ClH:15]>CN(C)C=O.Cl[Ni]Cl>[Cl:15][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1Br
Reactant: Cl
Agent: Cl[Ni]Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(C)(C)C)cc(C)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 500 mL round bottom flask 4.50 g of 2-bromo-5-tert-butyl-1,3-dimethylbenzene (18.6 mmol) and 9.50 g of NiCl2.6 H2O (40.0 mmol) were added. Then 30 mL of N,N-dimethylformamide was added to the flask, giving a blue-green solution. The flask was fitted with a condenser and was left to reflux with stirring. After 0.5 hours the solution was dark blue. After refluxing for 5 days the mixture was cooled to rt and then diluted with 25 mL of 2 M HCl. The aqueous phase was extracted with 40 mL of ethyl acetate. The volatiles were removed from the extract by evaporation to give a white solid. (91% conversion to the title product) All of the solids were dissolved in 25 mL of N,N-dimethylformamide and the solution was placed in a 125 mL round bottom flask. Then 5.1 g of NiCl2·6 H2O (21.5 mmol) was added to the flask. The flask was fitted with a condenser and was left to reflux with stirring. After 0.5 hours the solution was dark blue. After refluxing for 5 days the mixture was cooled to rt and then diluted with 25 mL of 2 M HCl. The aqueous phase was extracted with 40 mL of ethyl acetate. The volatiles were removed from the extract by evaporation to give a white solid. C12H17Cl, fw=196.72. Yield 3.51 g, 95.6%. Mp: 39° C. (melt). 1H NMR (300 MHz, CDCl3): δ 7.01 (s, 2H), 2.30 (s, 6H), 1.22 (s, 9H). Rf=0.69 (cyclohexane/silica).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([N:27](C(OCC(Cl)(Cl)Cl)=O)[C:28](OCC(Cl)(Cl)Cl)=[O:29])=[N:19]1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([NH:27][C:28]([N:15]2[CH2:16][CH2:17][N:12]([C:9]3[S:10][CH:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)[CH2:13][CH2:14]2)=[O:29])=[N:19]1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1noc2ccccc12
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-Phenyl-1,3-thiazol-2-yl)piperazine (330 mg, 0.673 mmol), bis(2,2,2-trichloroethyl) 1,2-benzisoxazol-3-ylimidodicarbonate (326 mg, 0.673 mmol), diisopropylethylamine (0.117 ml, 0.673 mmol) and dimethylsulfoxide (5 ml) was stirred at 70° C. for 2 hours. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) to give the desired product as a solid. The resulting solid was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to yield 115 mg (42.1%) of the desired product.
Reaction SMILES: CS(N)(=O)=O.[N:6]1([S:10]([NH2:13])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1.C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[Cl:41][C:42]1[C:43]([O:52][CH:53]2[CH2:58][CH2:57][C:56]([F:60])([F:59])[CH2:55][CH2:54]2)=[CH:44][C:45]([F:51])=[C:46]([CH:50]=1)[C:47](O)=[O:48]>>[N:6]1([S:10]([NH:13][C:47](=[O:48])[C:46]2[CH:50]=[C:42]([Cl:41])[C:43]([O:52][CH:53]3[CH2:58][CH2:57][C:56]([F:60])([F:59])[CH2:55][CH2:54]3)=[CH:44][C:45]=2[F:51])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: O=C(O)c1cc(Cl)c(OC2CCC(F)(F)CC2)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with azetidine-1-sulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-chloro-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoic acid, the title compound was obtained as a colorless solid (0.028 g, 19%): 1H NMR (300 MHz, DMSO-d6) δ 11.80 (br s, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.38 (d, J=12.4 Hz, 1H), 4.85 (br s, 1H), 4.00 (t, J=7.7, 7.7 Hz, 4H), 2.18-1.86 (m, 10H); 19F NMR (282 MHz, DMSO-d6) δ −92.2 (d, J=231 Hz, 1F), −98.5 (d, J=231 Hz, 1F), −110.1 (s, 1F); MS (ES−) m/z 425.1, 427.1 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH:24]=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.[OH-].[Na+]>CCO.C(Cl)Cl.CO>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]2[N:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]3=[N:8][N:9]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: NNc1ccc(F)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Cc2nnc3ccc(F)cn23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 105.9 %

Procedure:
A dark brown solution of (5-fluoro-pyridin-2-yl)-hydrazine (549 mg, 4.32 mmol) and N-Boc-4-piperidine acetaldehyde (Aldrich, 982 mg, 4.32 mmol) in EtOH (10 mL) was stirred at reflux for 30 min, then cooled to 0° C., diluted with DCM (25 mL) and then (diacetoxyiodo)benzene (1.67 g, 5.18 mmol) was added portionwise over 1 min. The purple solution was stirred at RT for 30 min, then aqueous NaOH (1M, 20 mL) was added and the mixture shaken. The aqueous layer was extracted with DCM (2×20 mL), then the combined organics passed through a hydrophobic frit and concentrated in vacuo to leave an orange solid. FCC, using 3% MeOH in DCM, gave the title compound as a pale orange solid (1.53 g, 90%). LCMS (Method 3): Rt 3.15, m/z 235 [M-CO2C4H9+H+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.C(O)(=O)C.[NH2:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:24]=[N:25][N:26]([CH2:28][C@H:29]([OH:34])[C:30]([O:32][CH3:33])=[O:31])[CH:27]=2)[CH:19]=[C:20]([CH3:22])[CH:21]=1>O1CCOCC1.O>[F:10][CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:15][C:16]2[CH:17]=[C:18]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][C@H:29]([OH:34])[C:30]([O:32][CH3:33])=[O:31])[CH:27]=3)[CH:19]=[C:20]([CH3:22])[CH:21]=2)[N:7]=1)[CH3:9]
Reactant: COC(=O)[C@@H](O)Cn1cc(-c2cc(C)cc(N)c2)cn1
Reactant: CC(F)c1ccnc(Cl)n1
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)[C@@H](O)Cn1cc(-c2cc(C)cc(Nc3nccc(C(C)F)n3)c2)cn1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
2-Chloro-4-(1-fluoroethyl)pyrimidine (58 mg, 0.36 mmol) and acetic acid (0.022 mL, 0.38 mmol) were added to an oven-dried flask containing methyl (2S)-3-[4-(3-amino-5-methylphenyl)-1H-pyrazol-1-yl]-2-hydroxypropanoate (100 mg, 0.36 mmol) in dioxane (1.2 mL). The mixture was stirred for 3 hours at 120° C. then cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (2 to 100% EtOAc/hexanes) to afford methyl (2S)-3-[4-(3-{[4-(1-fluoroethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]-2-hydroxypropanoate. MS ESI calcd. for C20H23FN5O3 [M+H]+ 400. found 400.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:15][C:14]([Cl:27])=[CH:13][N:12]=2)[CH2:7][CH2:6]1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(#N)C>[Cl:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:16]1[C:11]([N:8]2[CH2:9][CH2:10][CH:5]([CH2:4][CH2:3][CH2:2][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:6][CH2:7]2)=[N:12][CH:13]=[C:14]([Cl:27])[CH:15]=1)=[O:26]
Reactant: O=C(Nc1cc(Cl)cnc1N1CCC(CCCBr)CC1)c1cccc(Cl)c1
Reactant: C1CCNCC1
Solvent: CC#N
Product: O=C(Nc1cc(Cl)cnc1N1CCC(CCCN2CCCCC2)CC1)c1cccc(Cl)c1
Temperature: 175 °C
Yield: 92.8 %

Procedure:
A mixture of 0.032 g (0.068 mmol) of N-[4-(3-bromo-propyl)-5′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-3-chloro-benzamide, 0.029 g (0.34 mmol) of piperdine, and 0.50 mL (2.8 mmol) in acetonitrile (1 mL) is heated at 175° C. in a microwave reactor for 30 minutes. The mixture is cooled to room temperature and purified by preparative reverse phase HPLC to give 0.030 g (93%) of the title compound (36) as a colorless foam. [M+H]+=475.3.
Reaction SMILES: [O:1]=[C:2]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:19]1)[CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.C(N)(=O)C1C=CC=CC=1.O=C(N[C@@H]1CCNC1)CNC(=O)C1C=CC=C(C(F)(F)F)C=1>>[O:1]=[C:2]([NH:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH2:19]1)[CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCOCC2)C1
Agent: NC(=O)c1ccccc1
Agent: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CCN(C2CCOCC2)C1

Procedure:
The title compound was synthesized in a similar fashion to N-(2-oxo-2-{[(3R)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide, substituting (S)—N-(2-oxo-2-(pyrrolidin-3-ylamino)ethyl)-3-trifluoromethyl)benzamide for (R)—N-(2-oxo-2-(pyrrolidin-3-ylamino)ethyl)-3-(trifluoromethyl)benzamide 1H-NMR (CD3OD) δ: 1.69-1.77 (m, 2H), 2.01-2.09 (m, 3H), 2.39-2.46 (m, 1H), 3.24-3.44 (in 5H), 3.51-3.59 (m, 2H), 3.96-4.09 (m, 4H), 4.50-4.53 (m, 1H), 7.70 (t, J=7.9 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 8.15 (d, J=8.4 Hz, 1H), 8.21 (s, 1H), 8.34 (s, 1H). MS m/z: 400 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+]([O-])=O)=[C:5]([CH:12]=[CH:13][N:14](C)C)[N:4]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[NH:14][CH:13]=[CH:12]2
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])c(C=CN(C)C)n1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2[nH]ccc2n1
Yield: 76.1 %

Procedure:
2-Methoxy-5-Nitro-6-(2-Dimethylaminoethen-1-yl)pyridine (38.78 g, 174 mmol) was dissolved in 1.2 L of ethanol, and charged with 10% palladium on carbon (5.0 g). The mixture was hydrogenated at room temperature under 40 p.s.i. of hydrogen pressure for 4 hours. After filtration through celite followed by chromatography on silica gel (50% ethyl acetate/hexane), the material was recrystallized from ethyl acetate/hexane to provide 19.62 g of the title compound. (76%). MS(m/e): 149 (M+). EA calculated for C8H8N2O: C, 64.85; H, 5.44; N, 18.91. Found: C, 64.72; H, 5.33; N, 18.76.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[N:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:10]2=[N:9][CH:8]=1)(C)C.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:6]([C:7]1[N:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:10]2=[N:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cnc2cnccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cnc2cnccn12
Reaction time: 1 h

Procedure:
To a solution of 3-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyrazine (1.39 mol) in 10× volume of Ethyl acetate and 1.5× volume of Methanol is added two and a half equivalents of potassium carbonate at ambient temperature and the solution stirred for 1 hour. Potassium carbonate is filtered off and the organic stream is washed with water and with saturated sodium chloride solution (two or more times).