Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[NH:4][C:5]1[CH2:6][S:7][CH2:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11].C12CC(CC1)=CC=2.C12CC(CC1)C=C2>[Pd].C1CCCCC=1>[NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[NH:4][C:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][S:7][CH:6]=1
Reactant: COC(=O)C1=C(Nc2ccccc2N)CSC1
Agent: [Pd]
Agent: C1=C2CCC(=C1)C2
Agent: C1=CC2CCC1C2
Solvent: C1=CCCCC1
Product: COC(=O)c1cscc1Nc1ccccc1N
Reaction time: 4 h

Procedure:
Methyl 3-(2-aminoanilino)-2,5-dihydrothiophene-4-carboxylate (2.5 g, 0.001 mol) was added to a flask contining palladium on charcoal catalyst (5%, 200 mg) in cyclohexene (or norbornadiene or norbornylene) (50 ml) and the reaction was heated at reflux with stirring for 4 hours, the reaction being followed by t.l.c.
Reaction SMILES: CS[C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:21][NH2:22]>C(O)C>[CH3:21][NH:22][C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: COc1cccnc1CSCCNC(=C[N+](=O)[O-])SC
Reactant: CN
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCCSCc1ncccc1OC

Procedure:
1-Methylthio-1-[2-((3-methoxy-2-pyridyl)methylthio)ethylamino]-2-nitroethylene (1.4 g) was stirred with a solution of methylamine in ethanol (25 ml, 33% solution) and dissolved within a minute. After a further 3 minutes a crystalline product separated and recrystallisation from ethanol/ether yielded the title product (1.1 g), m.p. 145.5°-147°.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([SH:19])=[N:16][C:15]=2[CH:20]=1)=[O:10])[CH2:5][CH2:6][CH3:7].N[C:22]1C=C(C=CC=1O)C(NC(CCC)CCC)=O>CCO>[CH3:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([S:19][CH3:22])=[N:16][C:15]=2[CH:20]=1)=[O:10])[CH2:3][CH2:2][CH3:1]
Reactant: CCCC(CCC)NC(=O)c1ccc(O)c(N)c1
Reactant: CCCC(CCC)NC(=O)c1ccc2oc(S)nc2c1
Solvent: CCO
Product: CCCC(CCC)NC(=O)c1ccc2oc(SC)nc2c1
Temperature: 80 °C
Yield: 55 %

Procedure:
N-(Heptan-4-yl)-2-(mercapto)benzo[d]oxazole-5-carboxamide: To a solution 3-amino-4-hydroxy-N-(1-propylbutyl)benzamide (example 41a) (250 mg, 1.0 mmol) in EtOH was added KSCSOEt (160 mg, 1.0 mmol). The resulting reaction mixture was heated at 80° C. overnight. The solvent was removed under reduced pressure. And the residue was taken up in water. The resulting mixture was acidified with HOAc to pH ˜5 and then filtered. The residue was washed with water to afford the product as a white solid (160 mg, 55%). MS (M+H, 293.1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13](OCC)([O:19]CC)[C:14](OCC)=O)[CH3:11]>>[CH2:10]([O:12][C:13]([C:14]1[O:9][C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[N:1]=1)=[O:19])[CH3:11]
Reactant: Cc1ccc(O)c(N)c1
Reactant: CCOC(=O)C(OCC)(OCC)OCC
Product: CCOC(=O)c1nc2cc(C)ccc2o1
Temperature: 110 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To 2-amino-4-methylphenol (1 g, 8.1 mmol) was added ethyl triethoxyacetate (5.4 g, 3 eq). The mixture was stirred at 110° C. overnight. The reaction mixture was cooled and triturated with hexane. Filtration gave 850 mg (91%) of 5-methyl-benzooxazole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:20][C:21]([C:23]2[CH:32]=[C:31]([O:33][CH3:34])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[O:22])[CH2:15][CH2:16][C:17](O)=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.[C:36]([O:40][C:41](=[O:44])[CH2:42][NH2:43])([CH3:39])([CH3:38])[CH3:37].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:20][C:21]([C:23]2[CH:32]=[C:31]([O:33][CH3:34])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[O:22])[CH2:15][CH2:16][C:17]([NH:43][CH2:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:44])=[O:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Reactant: CC(C)(C)OC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)NCC(=O)OC(C)(C)C)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-methoxyquinoline (142 mg, 0.30 mmol) in tetrahydrofuran (THF) (5 mL) was added glycine t-butyl ester hydrochloride (44 mg, 0.33 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (64 mg, 0.33 mmol), 1-hydroxybenzotriazole (HOBT) (45 mg, 0.33 mmol) and diisopropylethylamine (DIEA) (0.43 g, 0.33 mmol). The reaction was stirred at ambient temperature overnight. The resultant solution was partitioned between water and ethyl acetate. The organic layer was concentrated in vacuo to afford an oil. The crude product was purified by elution through silica gel with 20:1 methylene chloride-methanol to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(((1,1-dimethylethoxycarbonyl)methyl)aminocarbonyl)propyl]aminocarbonyl-4-methoxyquinoline (62 mg, 35%); NMR (CDCl3) 1.25 (t, 3), 1.50 (s, 9), 2.00 (m, 1), 2.15–2.50 (m, 3), 3.31–3.95 (m, 9), 4.10–4.32 (m, 7), 5.40 (m, 1), 759 (t, 1), 7.63 (s, 1), 7.75 (t, 1), 8.14 (d, 1), 8.22 (d, 1), 9.41 (d, 1) ppm.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]([OH:12])=O)[CH:7]=[CH:6][S:5]2.[N:13]1([CH2:19][C:20]2[CH:34]=[CH:33][C:23]3[NH:24][C:25]([C:27]4[C:31]([NH2:32])=[CH:30][NH:29][N:28]=4)=[N:26][C:22]=3[CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(Cl)CCl>CN(C=O)C>[N:13]1([CH2:19][C:20]2[CH:34]=[CH:33][C:23]3[NH:24][C:25]([C:27]4[C:31]([NH:32][C:10]([C:9]5[N:8]6[C:4]([S:5][CH:6]=[CH:7]6)=[N:3][C:2]=5[CH3:1])=[O:12])=[CH:30][NH:29][N:28]=4)=[N:26][C:22]=3[CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Reactant: Cc1nc2sccn2c1C(=O)O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1nc2sccn2c1C(=O)Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Reaction time: 20 h

Procedure:
A mixture of 6-methyl-imidazo[2.1-b]thiazole-5-carboxylic acid (Bionet) (61 mg, 0.33 mmol), 3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (100 mg, (133 mmol), EDC (77 mg 0.39 mmol) and IIOAt (54 mg, 0.39 mmol) was stirred in DMF (3 ml) at 80° C. for 1 h then at ambient temperature for 20 h. The mixture was reduced in vacuo and the residue was partitioned between EtOAc and saturated NaHCO. The organic portion was washed with brine, dried (MgSO4) and reduced in vacuo. The residue was purified by preparative LC/MS to give 6-methyl-imidazo[2.1-b]thiazole-5-carboxylic acid [3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (29 mg). (LC/MS Basic: Rt 2.56 [M+H]+ 463).
Reaction SMILES: O=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18](N)=[O:19])=[CH:16][C:3]1=2.O.NN.C([OH:26])C.[OH-].[Na+]>O.C(O)COCCO>[N:12]1[C:6]2[O:5][C:4]3[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:19])=[O:26])=[CH:16][C:3]=3[CH2:2][CH2:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CCO
Reactant: NC(=O)Cc1ccc2c(c1)C(=O)Cc1cccnc1O2
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)CCc1cccnc1O2
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 18 %

Procedure:
A mixture of 20 mg of (5,6-dihydro-6-oxo benzo[b]pyrido-[3,2-f]oxepin-8-yl)-acetamide, 0.5 ml of hydrazine hydrate and 1.5 ml of ethanol was refluxed for 1 hour. The solvent and excess hydrazine hydrate were removed by distillation to obtain a residue, to which was added ethanol. Thereafter, the solvent was distilled off to obtain a yellow oil, to which were added 0.1 g of sodium hydroxide and 3 ml of dry diethylene glycol. The mixture was stirred at 100° C. for 20 minutes and then at 120° C. for 2.5 hours. After cooling, to this was added water, and the mixture was washed with ethyl acetate. The aqueous layer was acidified with acetic acid and extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a solid, which was chromatographed over 1 g of silica gel and eluted with chloroform, thereby yielding 3.5 mg (yield: 18%) of (5,6-dihydrobenzo[b]pyrido[3,2-f]oxepin-8-yl)-acetic acid as white needle crystals having a melting point of 203°-204° C.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][C@H:28]1[C:33]([OH:35])=[O:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@H:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C(O)[C@@H]1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 80.2 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.6 g, 3.37 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.44 g, 3.37 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (1.42 g, 80%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1N)([O-:3])=[O:2].C1(N)C=CC=CC=1N.FC1C=CC=CC=1[N+]([O-])=[O:34]>>[OH:34][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccccc1Nc1ccccc1[N+](=O)[O-]
Agent: Nc1ccccc1N
Product: O=[N+]([O-])c1ccccc1Nc1ccccc1O

Procedure:
N-2-nitrophenyl-o-phenylendiamine, M.p. 95°-98° C. by reaction between o-phenylendiamine and 2-fluoronitrobenzene.
Reaction SMILES: [Li].[CH3:2][N:3]([CH3:7])[CH2:4][C:5]#[CH:6].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1>C(N)CN.O1CCCC1>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])([C:6]#[C:5][CH2:4][N:3]([CH3:7])[CH3:2])[CH3:16])=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: C#CCN(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: NCCN
Product: CN(C)CC#CC(C)(O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
In 500 ml of ethylene diamine there is dissolved 13.88 g of lithium wire. After the disappearance of the blue color, the grey suspension obtained is dropwise treated, at 5° C., with 166.3 g of 3-dimethylamino-1-propyne. After 1 hour at room temperature, a solution of 50 g of p-bromoacetophenone in 250 ml of tetrahydrofuran is added. After 2 hours at room temperature, the mixture is poured onto ice and extracted with chloroform to give 62.9 g of crude, 2-(p-bromophenyl)-5-dimethylamino-3-pentyn-2-ol which is dissolved in 500 ml of acetone and treated with 18 ml of methyl iodide. After 18 hours at 5°, the solution is evaporated to dryness and the residue triturated with chloroform-ether to give 68 g of pure 2-(p-bromophenyl)-5-dimethylamino-3-pentyn-2-ol methiodide, mp 185°-190°.
Reaction SMILES: [C:1]([O:4][CH:5]([C:18]([O-:20])=[O:19])[C@@H:6]([C:15]([O-:17])=[O:16])[NH:7]C(OC(C)(C)C)=O)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[C:1]([O:4][CH:5]([C:18]([OH:20])=[O:19])[C@@H:6]([C:15]([OH:17])=[O:16])[NH2:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C(=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(=O)OC(C(=O)O)[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
To a solution of 202 mg (0.50 mmol) of the compound (4) obtained in Step 2 in chloroform (2 ml) was added 2 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 20 hours. The solvent was distilled off and the residue was purified by C18 silica gel column chromatography (RP-C18, distilled water) to give 43 mg of the title compound (9) (yield 45%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.C([Li])CCC.[O:21]1CCC[CH2:22]1.C=O>C(OCC)C.CCCCCC>[OH:21][CH2:22][CH2:8][C:6]1[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: C1CCOC1
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Agent: C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cc(CCO)nc(-n2c(C)ccc2C)c1
Temperature: -17.5 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A solution of 2.97 mg (14.8 mmol) of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine (from Example 53, Step A) in 15 mL of ethyl ether was added to a -20° C. solution prepared from 30 mL of ethyl ether and 12 mL (17 mmol) of 1.4 M n-butyllithium in hexane. The mixture was stirred for 1 h at -20 to -15° C. with the formation of a precipitate. Tetrahydrofuran (10 mL) was added, giving an orange-red solution of the intermediate anion. Paraformaldehyde in a separate flask was heated to 150-160° C., generating formaldehyde gas. The formaldehyde, diluted with nitrogen, was introduced as a gas stream impinging on the anion solution (kept at -15 to -10° C.) until the anion color had faded (20-30 min). The mixture was stirred an additional 15 min, quenched by the addition of 50 mL of saturated aqueous ammonium chloride, and extracted with 50 mL of ethyl acetate. The organic layer was washed with 30 mL of saturated aqueous sodium choride, dried (sodium sulfate), decanted, and evaporated. The residue was purified by flash column chromatography on 90 g of silica gel eluting with 2 L of 30% ethyl acetate in hexane to give 1.55 g (45% yield) of 6-(2-hydroxyethyl)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)pyridine as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13]C)=[O:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.C(N)(C)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:9])([CH3:10])[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: COC(=O)C1(c2ccc(Cl)cc2)CO1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CC(C)N
Solvent: CCO
Product: CC(O)(C(=O)O)c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
MCPBA (35 g, 77%, 156 mmol) was added to a solution of methyl 2-(4-chlorophenyl)-acrylate (20 g, 102 mmol) in CHCl3 (200 mL). The mixture was refluxed for 24 hours. The reaction was cooled to room temperature, diluted with chloroform (200 mL) and washed with 10% Na2S2O3, 10% NaHCO3 and water. The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by hexane/ethyl acetate (9:1) to give methyl 2-(4-chlorophenyl)oxirane-2-carboxylate. Methyl 2-(4-chlorophenyl)oxirane-2-carboxylate (2 g, 9.4 mmol) and ethanol (10 mL) and isopropylamine (1 mL, 11.7 mmol) were added to a 50 mL high pressure bomb. The mixture was heated to 90° C. for 12 hours in the bomb. After cooling, the solvent was removed, and the residue was dissolved in DCM (20 mL) and TEA (2 mL). (Boc)2O (4 g, 23.0 mmol) was added to it. The mixture was stirred at room temperature for 48 hours. The solvent was removed, and the residue was dissolved in THF (20 mL). LiOH (3M, 14 mL) was added to the mixture. The mixture was stirred at room temperature for 16 hours and refluxed for 2 hours. After cooling, the mixture was quenched with 2N HCl (21 mL). The solvent was removed and the residue was subject to column chromatography, eluted by hexane/ethyl acetate (1:1) to give 3-(tert-butoxycarbonykisopropyl)amino)-2-(4-chlorophenyl)-2-hydroxypropanoic acid. LCMS (APCI+) [M−Boc+H]+ 258.1; Rf: 3.66 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1>CC(O)C.CCCCCC>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)nc3)oc2C)cc1
Solvent: CC(C)O
Solvent: CCCCCC
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C)o2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
Ethyl 3-[{[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (12.0 g) which is a synthetic intermediate in Example 149 was dissolved in 2-propanol-hexane (8:2, volume ratio), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.) and eluted with 2-propanol-hexane (8:2, volume ratio) as mobile phase at 30° C., a flow rate 60 mL/min. The fractions showing a peak with retention time 23.7 min were collected, and concentrated. The obtained amorphous compound (5.58 g) was dissolved in ethanol (20 mL) and tetrahydrofuran (20 mL), 1N lithium hydroxide (20 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (30 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (5.2 g, 99%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Si:11]([O:18][C@@H:19]1[CH2:24][CH2:23][NH:22][CH2:21][C@H:20]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>CN(C=O)C>[Si:11]([O:18][C@@H:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:21][C@H:20]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC[C@H]1O[Si](C)(C)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@H]1O[Si](C)(C)C(C)(C)C
Yield: 98 %

Procedure:
Method 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, tert-butyl (3R,4R)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate and triethylamine in DMF yielding tert-butyl(3R,4R)-4-(tert-butyldimethylsilyloxy)-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (98%). LCMS (m/z): 453.3 (MH+); LC Rt=4.01 min.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([N:12]2[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNC(=O)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(C2CNC2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
A mixture of 3-(3-oxopiperazin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (400 mg, 1.57 mmol) and TFA (3 mL) in DCM (6 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 4-Azetidin-3-ylpiperazin-2-one as a white solid (227 mg, 93%). 1H NMR (CDCl3, 300 MHz): δ 6.08 (s, 1H); 3.63-3.56 (m, 3H); 3.42-3.35 (m, 3H); 3.31 (t, J=6.74 Hz, 1H); 3.03 (s, 2H); 2.59-2.51 (m, 2H).
Reaction SMILES: [Si:1]([C:8]1[C:9]([CH:21]=O)=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:23](#[N:27])[CH2:24][C:25]#[N:26].N1CCCCC1>CCO>[CH3:19][N:18]([CH3:20])[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:21]=[C:24]([C:23]#[N:27])[C:25]#[N:26])[C:8]([Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:17]2
Reactant: CN(C)c1ccc2cc(C=O)c([Si](C)(C)C(C)(C)C)cc2c1
Reactant: N#CCC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)c1ccc2cc(C=C(C#N)C#N)c([Si](C)(C)C(C)(C)C)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
415.7 mg (1.2616 mmol) of the compound 14 was dissolved in 9 mL of EtOH, and then added with 83.4 mg (1.2616 mmol) of malononitrile and 1 mL (12.616 mmol) of piperidine, and stirred for 3 hours at room temperature. When the reaction was completed, EtOH was removed by vacuum-distillating, and then the mixture was separated and purified by a column chromatography (eluent: EtOAc/n-hexane(v/v)=¼) without an additional extraction process to obtain 333.4 mg (70%) of an orange solid compound 15. 1H NMR (CDCl3, 300 MHz, 293K): δ 8.70(s, 1H), 8.24(s, 1H), 7.70-7.67(d, 1H), 7.02-6.98(dd, 1H), 6.88(s, 1H), 6.60-6.59(d, 1H), 3.14(s, 6H), 1.05(s, 9H), 0.31(s, 6H). 13C NMR(CDCl3, 75 MHz, 293K): δ 154.13, 152.53, 151.30, 140.20, 131.43, 131.09, 121.46, 119.27, 115.40, 114.88, 114.30, 111.78, 103.41, 40.29, 25.79, 18.38, −4.23. HRMS: m/z calcd. for C22H27N3OSi 377.1923 found 377.1923.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:30])=[CH:5][C:6]=1[C:7]1[CH:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[N:10]2[CH:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:22](=[O:24])[CH:23]=[C:9]2[N:8]=1.C=O.[C:33](O)(=O)[CH3:34]>>[CH3:1][C:2]1[O:3][C:4]([CH3:30])=[CH:5][C:6]=1[CH:7]1[CH:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[N:10]2[CH:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:22](=[O:24])[CH:23]=[C:9]2[N:8]1[CH2:11][N:10]([CH3:21])[CH2:9][CH2:23][C:33]1[CH:34]=[CH:2][CH:6]=[CH:7][N:8]=1
Reactant: CCOC(=O)C1C(=O)C=C2N=C(c3cc(C)oc3C)C=C(Cc3ccccc3F)N21
Reactant: CC(=O)O
Agent: C=O
Product: CCOC(=O)C1C(=O)C=C2N(CN(C)CCc3ccccn3)C(c3cc(C)oc3C)C=C(Cc3ccccc3F)N21
Temperature: 25 °C

Procedure:
2-(2,5-Dimethyl-3-furyl)-6-ethoxycarbonyl-4-(2-fluorophenylmethyl)-pyrrolo[1,2-a]pyrimid-7-one (50 mg, 122 umol) was added into a solution of formaldehyde (5 μL, 184 μmol) and a secondary amine (184 μmol) in acetic acid (2 mL). The resulting solution was stirred at room temperature for ten minutes, and then 50° C. for another ten minutes. HOAc was evaporated and the residue was diluted with DCM and purified by prep-TLC (MeOH/DCM−1:9) to yield the desired product, which was characterized by proton NMR and mass spectra.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH3:23])=[O:10])[CH2:2]1.F[C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28].CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[S:15][C:11]([C:9]([NH:8][CH2:7][CH:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:25]4[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=4[C:27]([O:29][CH3:30])=[O:28])[CH2:2]3)=[O:10])=[C:12]([CH3:23])[N:13]=2)=[CH:21][CH:20]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CCCNC1
Reactant: COC(=O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccccc1N1CCCC(CNC(=O)c2sc(-c3ccc(Cl)cc3)nc2C)C1
Temperature: 130 °C
Reaction time: 6 h
Yield: 20.3 %

Procedure:
N-(Piperidin-3-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (105 mg, 0.300 mmol) and methyl 2-fluorobenzoate (0.0382 mL, 0.300 mmol) were added to dimethylsulfoxide (5 mL). To this mixture, potassium carbonate (82.9 mg, 0.600 mmol) was added and the mixture was stirred for 6 hours at 130° C. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract was washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=10:1->2:1) gave 29.5 mg (20%) of the desired compound as a colorless oil.