Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[CH3:10][C:11](C)([O-])[CH3:12].[K+].C(Br)C=C.S([O-])(O)(=O)=O.[K+]>O1CCCC1.CN(C)C=O>[CH2:12]([N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7])[CH:11]=[CH2:10]
Reactant: COC(=O)c1ccc[nH]1
Reactant: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C=CCBr
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCn1cccc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.3 %

Procedure:
To a solution of methyl 1H-pyrrole -2-caboxylate (4.48 g, 35.8 mmol) in tetrahydrofuran (100 ml) were added potassium t-butoxide (4.2 g, 37.4 mmol) and dimethylformamide (20 ml), and the mixture was stirred for 10 minutes at room temperature. To the mixture was added allyl bromide (5.4 g, 44.6 mmol), and the mixture was stirred for 4 hours at room temperature. Thereto was added an aqueous 5% potassium hydrogensulfate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was removed and the residue was purified with silica gel chromatography (hexane:ethyl acetate=5:1→3:1) to give the subject compound (5.46 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[C:23]([C:24]=1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[CH:22][CH:21]=[C:20]([C:31]([O:33][CH3:34])=[O:32])[CH:19]=2.C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:44][CH2:45][C:46](Cl)=[O:47]>O1CCCC1.O>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([C:16]2[NH:17][C:18]3[C:23]([C:24]=2[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:22][CH:21]=[C:20]([C:31]([O:33][CH3:34])=[O:32])[CH:19]=3)=[C:2]([NH:1][C:46](=[O:47])[CH2:45][Cl:44])[CH:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OCc4ccccc4)cc3N)[nH]c2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OCc4ccccc4)cc3NC(=O)CCl)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
To a suspension of methyl 2-(2-amino-4-benzyloxyphenyl)-3-cyclohexyl-1H-indole-6-carboxylate (6.17 g, 13.5 mmol), sodium acetate (1.22 g, 14.9 mmol) and acetic acid (0.86 ml, 14.9 mmol) in tetrahydrofuran (62 ml) was added dropwise chloroacetyl chloride (1.19 ml, 14.9 mmol), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and methanol was added. The precipitated solid was collected by filtration, washed with methanol and dried in vacuo to give methyl 2-[4-benzyloxy-2-(2-chloroacetylamino)phenyl]-3-cyclohexyl-1H-indole-6-carboxylate (3.90 g, yield 54%).
Reaction SMILES: N1C=CN=C1.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].Cl[Si:15]([CH3:18])([CH3:17])[CH3:16].CCOCC>CN(C)C=O.CCCCCC>[CH3:16][Si:15]([CH3:18])([CH3:17])[O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH2:6]
Reactant: C[Si](C)(C)Cl
Reactant: Nc1ccccc1O
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[Si](C)(C)Oc1ccccc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.6 %

Procedure:
Imidazole (3.73 g) was added in one portion to a solution of 2-aminophenol (2.0 g) in dry dimethylformamide (10 ml) stirred at 25° C. under nitrogen. Chlorotrimethylsilane (2.98 g) was added dropwise over 5 minutes and stirring continued for a further 18 hours. The mixture was poured onto water (30 ml) and extracted with diethyl ether (2×60 ml). The organic solution was separated and washed with 2N sodium hydroxide (2×40 ml), brine and dried over magnesium sulphate. Evaporation of the filtrate under reduced pressure gave an oil. Column chromatography on silica eluting with 10% ether:hexane gave 2-trimethylsilyloxyaniline (0.85 g), NMR 1H: 0.2(9H,s), 3.5(2H,s), 6.4(4H,m).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[K].C(C(Cl)(C)[C:10]([O-:12])=[O:11])C.O.[CH:16]1C=C[CH:19]=[CH:18][CH:17]=1>>[CH2:17]([CH2:18][CH2:19][O:12][C:10]([N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)=[O:11])[CH3:16]
Reactant: c1ccccc1
Reactant: CCC(C)(Cl)C(=O)[O-]
Reactant: c1cc[nH]c1
Agent: [K]
Solvent: O
Product: CCCCOC(=O)n1cccc1
Temperature: 80 °C

Procedure:
After adding 30 ml of benzene to the potassium pyrrole, a solution of 30.0 g (0.22 mole) of ethylchloropropionate in 30 ml benzene is slowly added to the paste over a period of 1 hour with constant stirring. The reaction mixture is heated to 80°C for 30 minutes. Then 100 ml of water is added and the mixture is extracted with diethyl ether. The ether extract is dried over anhydrous magnesium sulfate and the dried extract is evaporated to yield residue which is distilled under vacuum. The pyrrole derivative having the formula given above is obtained as 3 g of a colorless liquid with a boiling point of 108°C at 14 mm Hg pressure. MS shows the m/e peaks: 80, 94, 167, 27, 95.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=CC=1.[O:7](S(C(F)(F)F)(=O)=O)[S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9].CCOC(C)=O.[CH3:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl.[Cl-].[Na+].O>[F:12][C:11]([F:14])([F:13])[S:8]([O:7][C:30]1[CH:31]=[C:32]([CH:4]2[CH2:5][CH2:6]2)[CH:33]=[CH:34][C:29]=1[CH3:28])(=[O:10])=[O:9]
Reactant: c1ccncc1
Reactant: CCCCCCC
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C2CC2)cc1OS(=O)(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of the crude product (1.73 g) and pyridine (1.21 mL, 15.0 mmol) in DCM (15 mL), Tf2O (2.17 mL, 12.8 mmol) was added at 0° C. under nitrogen. The mixture was allowed to stir for 1 h. The reaction was monitored by TLC (25% EtOAc/heptane). The mixture was diluted with brine and DCM. The organic layer was separated and concentrated. The residue was purified by flash column chromatography on 40 g silica gel (with 15 g pre-column of silica gel; eluent: heptane/EtOAc=100:0 to 85:15) to give 5-cyclopropyl-2-methylphenyl trifluoromethanesulfonate. 1H NMR (400 MHz, CDCl3) δ ppm 7.16 (d, J=7.87 Hz, 1 H), 6.96 (dd, J=1.64, 7.87 Hz, 1 H), 6.92 (d, J=1.64 Hz, 1 H), 2.32 (s, 3 H), 1.85-1.92 (m, 1 H), 0.97-1.01 (m, 2 H), 0.65-0.69 (m, 2 H).
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:8]=1[C:9]([O:11][CH3:12])=[O:10].[C:18]([NH:21][C@H:22]([C:67]([OH:69])=O)[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]([C:53](=[O:64])[C:54]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[O:55])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([O:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])=[C:26]([CH2:65][CH3:66])[CH:25]=1)(=[O:20])[CH3:19].F[B-](F)(F)F.[N:75]1(OC(N(C)C)=[N+](C)C)[C:79]2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:18]([NH:21][CH:22]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]([C:53](=[O:64])[C:54]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[O:55])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([O:39][CH:40]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:38])=[C:26]([CH2:65][CH3:66])[CH:25]=1)[C:67]([NH:75][CH2:79][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[O:69])(=[O:20])[CH3:19]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COC(=O)c1c(O)cccc1OCCCCN
Reactant: CCc1cc(C[C@H](NC(C)=O)C(=O)O)ccc1N(C(=O)C(=O)OCc1ccccc1)c1ccccc1C(=O)OC(c1ccccc1)c1ccccc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc(CC(NC(C)=O)C(=O)NCCCCCOc2cccc(O)c2C(=O)OC)ccc1N(C(=O)C(=O)OCc1ccccc1)c1ccccc1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 57.8 %

Procedure:
Methyl 2-(4-aminobutoxy)-6-hydroxybenzoate (42 mg, 0.12 mmol), N-acetyl-4-{2-[(benzhydryloxy)carbonyl][(benzyloxy)(oxo)acetyl]anilino}-3-ethylphenylalanine (70 mg, 0.1 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (32 mg, 0.1 mmol) and diisopropylethylamine (70 μL, 0.4 mmol) in N,N-dimethylformamide (1 mL) was stirred at ambient temperature overnight, diluted with ethyl acetate and washed with aqueous NaHCO3 (1×30 mL), brine (2×30 mL), dried (MgSO4), filtered and concentrate under reduced pressure. The residue was purified on silica gel eluting with ethyl acetate to provide of titled compound 54 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:11])=[C:7]([CH:10]=1)[CH2:8]O.O.[BrH:13]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:11])=[C:7]([CH:10]=1)[CH2:8][Br:13]
Reactant: COc1ccc(Br)c(CO)c1
Reactant: Br
Solvent: O
Product: COc1ccc(Br)c(CBr)c1
Temperature: 25 °C

Procedure:
5-Methoxy-2-bromobenzyl alcohol (79.5 g, 0.37 mol) is dissolved in 48% HBr (400 mL) and heated to reflux temperature for 4 hours. The reaction mixture is cooled to room temperature and poured into water (1500 mL). The solution is extracted with EtOAc (2×500 mL). The combined organic layers are dried (MgSO4) and concentrated by rotary evaporator. The crude material is then purified using flash chromatography (CH2Cl2/hexanes, from 1:1 to 4:1) to give 5-methoxy-2-bromobenzyl bromide.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:14][C@H:11]1[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.C(OCC)(=O)C>[Si:24]([O:13][CH2:12][C@@H:11]1[O:14][C@H:10]1[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@@H]1O[C@H]1COCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1O[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
2.15 g of (2S,3S)-4-benzyloxy-2,3-epoxy-1-butanol was dissolved in 13 ml of dry DMF, and 1.83 g of imidazole and 2 g of tert-butyldimethylchlorosilane were added thereto. The mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed sequentially with cold 1N hydrochloric acid, water and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) to obtain 2.3 g of (2S,3S)-4-benzyloxy-2,3-epoxy-1-butanol tert-butyldimethylsilyl ether as colorless oily substance.
Reaction SMILES: [C:1]([C:3]1C=[C:5]([C:9](OCC)=O)[NH:6][C:7]=1[CH3:8])#[N:2].[C:14](OCC)(=O)[CH2:15][C:16](C)=O.[Na].CC[OH:26]>>[CH2:9]([C:5]1[N:2]=[C:1]([OH:26])[CH:3]=[C:7]([CH3:8])[N:6]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCO
Reactant: CCOC(=O)c1cc(C#N)c(C)[nH]1
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Product: CCCCc1nc(C)cc(O)n1

Procedure:
Pentanimidamide hydrochloride (3.2 g) (prepared according to Garigipati, R. S.; Tetrahedron Lett 1990, 31 (14), 1969) was treated with ethyl acetoacetate (3.05 g) in a modified procedure using sodium (1.62 g) in anhydrous EtOH (50 ml) as base (as described in Salimbeni, Aldo; et al. J. Med. Chem. (1995), 38(24), 4806-20) affording the title compound (4.04 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4](Cl)[C:5](=[O:7])[CH3:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:9])[CH:4]([S:17][C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1)[C:5](=[O:7])[CH3:6]
Reactant: Sc1ccc(Cl)cc1
Reactant: COC(=O)C(Cl)C(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(Sc1ccc(Cl)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-chloro-3-oxobutyric acid methyl ester (3.5 g) and 4-chlorobenzenethiol (4.1 g) in dichloromethane (60 mL) at 0° C. was added triethylamine (4.0 mL). The mixture was warmed to room temperature and then stirred at this temperature for 3 days. The solvent was removed under reduced pressure and the residue diluted with ethyl acetate and this mixture was washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:4 by volume) to afford title compound as a waxy solid, 7.2 g.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=O>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:22]([C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[O:19][C:18]([F:17])([F:29])[F:30])=[N:16][N:15]=1
Reactant: O=C(O)c1ccccc1OC(F)(F)F
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccccc2OC(F)(F)F)o1
Yield: 38 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2-(trifluoromethoxy)-benzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 134 mg, 38%) which was obtained as a white solid. MS: m/e=388.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C.C(OC(=O)C)(=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[OH:9]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(Cl)cc1Br
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cc(Br)c1O
Temperature: 0 °C
Yield: 80.1 %

Procedure:
A solution of 2-bromo-4-chloro-phenol (99.24 g, 480 mmol) in acetic acid (110 ml) and acetic anhydride (125 ml) was cooled to -10 EC. Within 1 hour a solution containing 100% nitric acid (33 ml) and acetic acid (40 ml) was added between -10 E and -5 EC, with stirring. The mixture was stirred for an additional 1.5 hours at 0-5 EC, then the suspension poured onto 300 g of ice in 700 ml of water and stirred for a further 0.5 hour. The solid was collected, washed, and dried to give 97.12 g (80.1%) of the title compound (mp 121-2 EC).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[S:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1)([O-])=O.[Cl-].[Cl-].[Ca+2]>C(O)C.O.[Zn]>[NH2:1][C:4]1[CH:19]=[CH:18][C:7]2[S:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2Sc2ccccc21
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)CC(=O)c1ccccc1S2

Procedure:
To a solution of 2-nitro-10-oxo-dibenzo[b,f]thiepine (2.40 g, 9.30 mmol) (Coll. Czech. Chem. Commun. 1977, 42:2231) in 78% ethanol, was added a solution of CaCl2 (0.66 g, 5.90 mmol) in water (1.00 mL) followed by zinc dust (19.9 g, 30.4 mmol). The reaction mixture was refluxed for 2 h, filtered through celite and washed extensively with hot ethanol. The ethanol filtrate was concentrated to 5.00 mL and water was added to precipitate out the product. The product was filtered and dried under vacuum, purification was performed by recrystallization from EtOAc and hexane, yield 1.97 g (92.3%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[NH:19][CH:20]=[CH:21][CH:22]=2)=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1.OC1C=CC(NC(C2C=CC=CN=2)=O)=CC=1>>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]2[NH:19][CH:20]=[CH:21][CH:22]=2)=[O:17])=[CH:13][CH:14]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)c1ccc[nH]1
Agent: O=C(Nc1ccc(O)cc1)c1ccccn1
Product: O=C(Nc1ccc(O)cc1)c1ccc[nH]1

Procedure:
This compound was prepared from 1H-pyrrole-2-carboxylic acid (4-benzyloxy-phenyl)-amide (2.5 g, 8.55 mmol), using the same method used to prepare of pyridine-2-carboxylic acid (4-hydroxyphenyl)amide. The product was purified by flash chromatography, on silica gel, eluted with 5 to 7.5% methanol in DCM, to give the product as a colorless solid, 1.47 g (85%). MS m/z 203 MH+). 1H NMR (DMSO-d6) δ 6.14 (m, 1H), 6.72 (d, 2H), 6.92 (m, 1H), 6.99 (d, 1H), 7.47 (d, 2H), 9.19 (s, 1H). Anal. calcd for C11H10N2O2: C, 65.34; H, 4.98; N, 13.85. Found: C, 65.15; H, 4.83; N, 13.81.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:12])[NH:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=O.N1CCCCC1>N1C=CC=CC=1.O>[OH:10][C:9]1[CH:8]=[C:7]([CH3:11])[NH:6][C:5](=[O:12])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:17][C:16]1[CH:19]=[CH:20][C:21]([O:22][C:23]([F:24])([F:25])[F:26])=[C:14]([Cl:13])[CH:15]=1
Reactant: O=Cc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: CC(=O)c1c(O)cc(C)[nH]c1=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: O
Product: Cc1cc(O)c(C(=O)C=Cc2ccc(OC(F)(F)F)c(Cl)c2)c(=O)[nH]1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
A mixture of 0.50 g of 3-acetyl-4-hydroxy-6-methyl-2(1H)-pyridinone, 0.74 g of 3-chloro-4-(trifluoromethoxy)benzaldehyde, 6 mg of pyridine and 0.1 ml of piperidine was heated under refluxing for 4 hours. After cooled to room temperature, 40 ml of water was added to the reaction mixture, precipitated crystals were filtered, and this was washed with tetrahydrofuran, then with ethyl acetate to obtain 0.41 g of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2(1H)-pyridinone [Compound No. (3a-32)] as a yellow crystal.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].[Br:18][C:19]1[N:24]=[C:23]([CH2:25]Br)[CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[Br:18][C:19]1[N:24]=[C:23]([CH2:25][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])[CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1cccc(Br)n1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1cccc(Br)n1
Yield: 69.3 %

Procedure:
By using (3,3,3-trifluoropropyl)malononitrile (540 mg), N,N-dimethylformamide (4 ml), potassium carbonate (400 mg) and 6-bromo-2-(bromomethyl)pyridine (590 mg) according to the similar method described in Production Example 4 was obtained 541 mg of 2-((6-bromo-2-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (14)).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][C:9]2[N:8]3[CH2:16][CH2:17][N:18]([C:23]4[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[C:26]([C:33](=[O:35])[CH3:34])=[CH:25][N:24]=4)[CH:19]([CH:20]([CH3:22])[CH3:21])[C:7]3=[CH:6][C:5]=2[CH:4]=1.N1C=CC=CC=1.[C:42](Cl)([CH3:44])=[O:43]>C(Cl)Cl>[C:42]([O:1][CH2:2][C:3]1[C:11]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:10][C:9]2[N:8]3[CH2:16][CH2:17][N:18]([C:23]4[N:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[C:26]([C:33](=[O:35])[CH3:34])=[CH:25][N:24]=4)[CH:19]([CH:20]([CH3:22])[CH3:21])[C:7]3=[CH:6][C:5]=2[CH:4]=1)(=[O:43])[CH3:44]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1cnc(N2CCn3c(cc4cc(CO)c(S(C)(=O)=O)cc43)C2C(C)C)nc1C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1cc2cc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(C)=O)c(C(F)(F)F)n1)C3C(C)C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (132 mg, 0.26 mmol) in CH2Cl2 (5 mL) was added pyridine (1 mL) and AcCl (130 μL, 1.3 mmol). The mixture was stirred at rt for 10 h. The reaction was quenched with water (5 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine, and then dried over anhydrous Na2SO4. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (1/1) to give (2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indol-8-yl)methyl acetate. LC-MS m/z 553 [M+H]+.
Reaction SMILES: F[B-](F)(F)F.N1(O[C:16](=[N+](C)C)[N:17](C)[CH3:18])C2C=CC=CC=2N=N1.[OH:23][C:24]([CH3:57])([CH3:56])[CH2:25][C@@:26]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:31][C:30](=[O:32])[N:29]([C@H:33]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[N:46]=[N:45][C:44]([C:47](O)=[O:48])=[CH:43][CH:42]=3)=[CH:37][CH:36]=2)[CH3:34])[CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C.CNC>CN(C)C=O>[CH3:16][N:17]([CH3:18])[C:47]([C:44]1[N:45]=[N:46][C:41]([C:38]2[CH:37]=[CH:36][C:35]([C@@H:33]([N:29]3[CH2:28][CH2:27][C@:26]([CH2:25][C:24]([OH:23])([CH3:56])[CH3:57])([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[O:31][C:30]3=[O:32])[CH3:34])=[CH:40][CH:39]=2)=[CH:42][CH:43]=1)=[O:48]
Reactant: C[C@@H](c1ccc(-c2ccc(C(=O)O)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc(-c2ccc(C(=O)N(C)C)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[(Benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium tetrafluoroborate (TBTU, 110 mg) was added to a solution of 6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazine-3-carboxylic acid (140 mg) and ethyl-diisopropyl-amine (60 μL) in N,N-dimethylformamide (2 mL) at room temperature. The resulting solution was stirred for 20 min, before dimethylamine (2 mol/L in tetrahydrofuran, 300 μL) was added. After stirring the solution at room temperature for another 2 h, the solution was concentrated and the residue was purified by HPLC on reversed phase (methanol/water/NH4OH) to afford the title compound. Yield: 50 mg (34% of theory); Mass spectrum (ESI+): m/z=503 [M+H]+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[C:4]([CH2:3][CH2:2][C:1]([N:24]1[CH2:23][CH2:22][CH:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:20][CH2:19]2)[CH2:26][CH2:25]1)=[O:7])([OH:6])=[O:5]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(C(=O)CCC(=O)O)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4.1 g (40.7 mmol) succinic acid anhydride in 50 mL THF was added dropwise at RT to a solution of 10.0 g (37.3 mmol) tert-butyl[4,4′]bipiperidinyl-1-carboxylate in 100 mL THF and the reaction mixture was stirred overnight at RT. To complete the reaction another 2.0 g (19.9 mmol) succinic acid anhydride were added, the mixture was stirred for 4 h at 50° C. and stirred overnight at RT. 200 mL of 7.5% K2CO3 solution was added and the aqueous phase was washed with 200 mL EtOAc. The organic phase was extracted with 200 mL 7.5% K2CO3 solution and the combined aqueous phases were acidified with citric acid. The mixture was extracted exhaustively with EtOAc and the combined organic phases were evaporated down i. vac.