Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([N+:10]([O-])=O)[N:7]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]=1)=[O:4].O.O.Cl[Sn]Cl>O(CCOC)C>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc([N+](=O)[O-])n(C(=O)OCc2ccccc2)n1
Agent: Cl[Sn]Cl
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(N)n(C(=O)OCc2ccccc2)n1
Yield: 95 %

Procedure:
A mixture of 5-nitropyrazole-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester (3.2 g, 10.48 mmol) and SnCl2.2H2O (7.2 g, 31.9 mmol) in 1,2-dimethoxylethane (60 mL) was heated to reflux for 2 hours. The solvent was removed in vacuo. The residue was neutralized with saturated aqueous sodium carbonate. The resulting solution was filtered and the filtrate was extracted with ethyl acetate. The organic layer was separated and dried over anhydrous Na2SO4 and concentrated to give 5-aminopyrazole-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester (2.74 g, 90%). 1H NMR (300 MHz, CDCl3) δ 7.30-7.18 (m, 5H), 6.17 (s, 1H), 3.82 (s, 3H), 3.63 (s, br., 2H).
Reaction SMILES: [CH2:1]([S:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].[I:15]I.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O>[CH2:1]([S:6][C:7]1[CH:12]=[CH:11][C:10]([I:15])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: II
Reactant: CCCCCSc1ccc(Br)cc1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Mg]
Agent: [Na+]
Solvent: O
Product: CCCCCSc1ccc(I)cc1
Reaction time: 16 h

Procedure:
The Grignard reagent from the product of Step 2.1 (15 g) was prepared using magnesium in tetrehydrofuran (60 ml). Iodine (16.2 g) was added over 10 min and the mixture was stirred for 16 hrs. Water was added and then 10% sodium metabisulphite (100 ml). The product was extracted into petroleum ether and distilled. Yield 10.5 g.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].C(O[CH:10]1[NH:13][C:12](=[O:14])[CH:11]1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])=[N:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])(=O)C>C1COCC1>[CH2:3]([S:5][C@@H:10]1[NH:13][C:12](=[O:14])[C@H:11]1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])=[N:20][C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])[CH3:4]
Reactant: CCS
Reactant: CC(=O)OC1NC(=O)C1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS[C@@H]1NC(=O)[C@H]1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a 0° C. suspension of NaH (60% oil dispersion, 200 mg, 498 mmol) in THF (20 ml) was added ethanethiol (0.37 mL, 4.98 mmol). The resultant mixture was stirred for 10 min, cooled to -20° C., and compound 13 (1.9g, 3.83 mmol) was added. The solution was stirred further for 30 min at room temperature and concentrated. The residue was partitioned between ethyl acetate and pH 7.0 aqueous buffer. The organic phase was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (Et2O) to afford 718 mg (36%) of the title product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].Cl[C:14]1[C:19]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[O:12][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Clc1ncccc1-c1ccncn1
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc([N+](=O)[O-])c(C)c1Oc1ncccc1-c1ccncn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dissolved 2,6-dimethyl-3-nitrophenol (1.96 g, 11.7 mmol) and 4-(2-chloropyridin-3-yl)pyrimidine (1.50 g, 7.83 mmol) in dimethylsulfoxide (15.0 ml) and added cesium carbonate (5.10 g, 15.7 mmol). Reaction mixture was heated to 1200C in a sealed tube for 8 hours. Reaction mixture was then allowed to cool to room temperature and then poured into 250 mL of rapidly stirring water in an Erlenmeyer flask. After 10 minutes, the opaque brown aqueous solution was cooled to 0° C. and allowed to stand for 10 minutes, then filtered. The precipitate was collected as the title compound. MS m/z=323 (M+H)+. Calc'd for C17H16N4O3: 324.34.
Reaction SMILES: [C:1]([C:3]12[CH2:9][N:6]3[CH2:7][CH:8]1[CH:4]2[CH2:5]3)#N.[H-].C([Al+]CC(C)C)C(C)C.C1C[O:23]CC1>CCCCCC>[CH:1]([C:3]12[CH2:9][N:6]3[CH2:7][CH:8]1[CH:4]2[CH2:5]3)=[O:23]
Reactant: N#CC12CN3CC1C2C3
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: O=CC12CN3CC1C2C3
Temperature: 25 °C
Yield: 55 %

Procedure:
1-Cyano-4-azatricyclo[2.2.1.02,6 ]heptane (WO92/11261) (5.0 g, 42 mmol) in dry THF (150 ml) was treated with diisobutylaluminium hydride (84 ml of a 1M solution in hexane, 84 mmol) at 0° C. under nitrogen. After 3H the reaction mixture was allowed to warm to room temperature and quenched with 4N HCl. The THF was removed by concentrating in vacuo and the residue extracted with ethyl acetate (2×-discarded). The aqueous phase was made basic (pH 10-11) with potassium carbonate and the mixture extracted with dichloromethane (6×). The dichloromethane extracts were dried (MgSO4) and filtered. Evaporation of the solvent gave 2.8 g (55%) of the title compound.
Reaction SMILES: C(O)C.[CH2:4]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][CH3:8].[F:24][C:25]([F:37])([F:36])[C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:27]=1Br.C(=O)([O-])[O-].[Na+].[Na+]>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.CCOCC.O.C1C=CC=CC=1>[CH2:4]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:27]3[CH:28]=[CH:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][C:26]=3[C:25]([F:24])([F:36])[F:37])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(B(O)O)cc2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc([N+](=O)[O-])cc3C(F)(F)F)cc2)CC1

Procedure:
First, 100 ml of ethanol containing 6.57 g of 4-(trans-4-pentylcyclohexyl)phenylboronic acid dissolved therein, 100 ml of benzene containing 10.0 g of 2-trifluoromethyl-4-nitrobromobenzene dissolved therein, 37 ml of a sodium carbonate aqueous solution with a concentration of 2 mol/l, and 1.07 g of tetrakis(triphenylphosphine)palladium(0) were put in an argon-replaced 300 ml flask, and stirred under reflux for 12 hours. After the reaction, water and ether were added to the reaction solution for extraction. The resultant ether layer was washed with a saturated brine and dried with sodium sulfate. The solvent was then distilled off. The residue was purified by silica gel column chromatography (eluent:hexane/toluene=4/1), to obtain 14.2 g (Y: 91.3%) of 4′-(trans-4-pentylcyclohexyl)-2-trifluoromethyl-4-nitrobiphenyl. The purity of the resultant compound was 100.0% as measured by GC.
Reaction SMILES: [NH2:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][C:5]2[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:20]([Cl:35])=[CH:19][N:18]=1.Cl.O1CCOCC1>COCCO>[Cl:35][C:20]1[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[N:22][C:17]([NH:1][C:2]2[C:13]([O:14][CH3:15])=[CH:12][C:5]3[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCNC(=O)C2
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCNC(=O)C2
Temperature: 120 °C
Yield: 46.2 %

Procedure:
7-Amino-8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (50 mg, 0.2 mmol), N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (90.5 mg, 0.27 mmol), and a 4 M solution of hydrogen chloride in dioxane (0.1 mL, 2 eq), were added to 2-methoxyethanol (2 mL), and the reaction mixture was heated for 6 hours at 120° C. The reaction mixture was partitioned between aqueous saturated Na2CO3 and dichloromethane, and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were dried (MgSO4), filtered, and then concentrated on SiO2. Flash chromatography on SiO2 (MeOH/dichloromethane 0-5%) gave N-{(1R,2R)-2-[5-Chloro-2-(8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (47 mg, 30%) as a beige solid. MP: 109-115° C.; 1H-NMR (CDCl3) δ 8.06 (s, 1H), 7.90 (s, 1H), 7.40 (s, 1H), 6.62 (s, 1H), 6.18 (m, 1H), 6.00 (d, J=6.5 Hz, 1H), 5.51 (d, J=7.8 Hz, 1H), 3.94 (m, 1H), 3.86 (s, 3H), 3.75 (m, 2H), 3.53 (m, 2H), 3.25 (m, 1H), 3.04 (t, J=6.1 Hz, 2H), 2.85 (s, 3H), 2.60 (s, 2H), 2.20 (m, 2H), 1.8 (m, 2H), 1.34 (m, 2H); LC/MS (ESI+): 509.28 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[Br:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN.[C:21]([BH3-])#[N:22].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:22][CH3:21])=[CH:11][C:10]=1[Br:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(Br)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNCc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.6 %

Procedure:
25 g (86 mmol) of 4-benzyloxy-3-bromo-benzaldehyde, 500 ml of methanol, 29 g (430 mmol) of methylamine hydrochloride and 8 g (127 mmol) of sodium cyanoborohydride are introduced into a round-bottomed flask under a stream of nitrogen. The reaction medium is stirred for 48 hours at room temperature. The methanol is evaporated off. The residue is taken up in ethyl acetate and water and then acidified. After separation of the phases once settling has taken place, the aqueous phase is returned to basic pH with sodium hydroxide and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then evaporated. The residue is purified by chromatography on a column of silica eluted with a dichloromethane/ethanol mixture (9/1). 9.9 g (38%) of the expected product are obtained in the form of a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:31])[CH:11]=[C:12]([CH2:29][OH:30])[N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:15](=[O:28])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10](=[O:31])[CH:11]=[C:12]([CH:29]=[O:30])[N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:15](=[O:28])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)cc(CO)n2CCN1Cc1ccc(Cl)c(Cl)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: O=Cc1cc(=O)c(OCc2ccccc2)c2n1CCN(Cc1ccc(Cl)c(Cl)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a solution of 9-benzyloxy-2-(3,4-dichlorobenzyl)-6-hydroxymethyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (860 mg) obtained in Example 5, Step 6 in chloroform (80 ml) was added Dess-Martin reagent (843 mg). After stirring at room temperature for 1 hr, the solvent was evaporated and chloroform (50 ml) was added to the obtained residue and a solid product was filtered off. The filtrate was concentrated and purified by silica gel column chromatography (chloroform:acetone=1:2) to give 9-benzyloxy-2-(3,4-dichlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-6-carbaldehyde (621 mg).
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][CH2:5][C:4]=1[CH3:11])#[CH:2].C([Li])CCC.[Cl:17][CH:18]=[CH:19][C:20](=[O:22])[CH3:21].C(OCC)(=O)C>O1CCCC1.CCCCCC>[Cl:17]/[CH:18]=[CH:19]/[C:20]([CH3:21])([OH:22])[C:2]#[C:1][C:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][CH2:5][C:4]=1[CH3:11]
Reactant: CC(=O)C=CCl
Reactant: C#CC1=C(C)CCCC1(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1=C(C#CC(C)(O)/C=C/Cl)C(C)(C)CCC1
Temperature: -65 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
A solution of 1.48 g (10 mmol) of 2-ethynyl-1,3,3-trimethyl-cyclohexene in 90 ml of dry tetrahydrofuran in a 250 ml three-necked reaction flask equipped with a magnetic stirrer, a rubber septum and argon gasification means was cooled under an argon atmosphere in a dry ice bath. It was treated dropwise with 7.5 ml (12 mmol) of a 1.6 M solution of n-butyllithium in hexane as fast as the temperature could be maintained at −70 to −60° C. The addition was completed within 10 minutes. After the reaction mixture had been stirred for an additional 30 minutes at −70° C., a solution of 1.045 g (10 mmol) of 4-chloro-buten-2-one in 10 ml of dry tetrahydrofuran was added slowly. After further stirring for 3 hours at −70° C. the reaction mixture was poured into 250 ml of ice water and extracted with three 70 ml quantities of hexane. The combined organic phases were washed with three 100 ml quantities of water and 50 ml of brine, and dried over anhydrous magnesium sulphate. All the volatile material was removed under a reduced pressure of 100–200 mbar (10–20 kPa), and 2.57 g of crude product were obtained. Chromatography through 60 of silica gel (0.04–0.063 mm) with a 95:5 (v/v) mixture of hexane and ethyl acetate afforded 1.19 g (4.7 mmol, 47% yield) of the pure product.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[C:13]([NH2:14])=[CH:12][CH:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[Cl:17][C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27](Cl)=[O:28])=[C:20]2[N:19]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:17][C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]([NH:14][C:13]3[N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=4)[N:10]=[CH:11][CH:12]=3)=[O:28])=[C:20]2[N:19]=1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Reactant: Nc1ccnn1-c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccnn1-c1cccc(C(F)(F)F)c1)c1cnn2ccc(Cl)nc12
Temperature: 50 °C
Yield: 58.7 %

Procedure:
To a stirred solution of 1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (200 mg, 0.88 mmol) in dichloromethane (30 mL) was added 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (215 mg, 1.0 mmol) and diisopropylethylamine (130 mg, 1.0 mmol). The mixture was heated to 50° C. overnight. After cooling to room temperature, the mixture was concentrated to afford crude 5-chloro-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (210 mg, yield 58%), which was used for the next step without further purification. MS (ESI) m/z: 407.2
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[C:16](Cl)(=[O:20])[CH:17]([CH3:19])[CH3:18]>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:16](=[O:20])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)C(=O)Cl
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Product: CC(C)C(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(2-dimethylamino-ethylamino)-nitrobenzene and isobutyryl chloride
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)c(Cl)c1
Reactant: Nc1n[nH]cc1-c1ccccn1
Product: Fc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4ccccn4)c3n2)cc1Cl
Yield: 71 %

Procedure:
Reaction of 1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (269 mg, 1.0 mmol), prepared from commercially available 3-chloro-4-fluoro-acetophenone according to general procedure A, and 3-amino-4-(2-pyridinyl)-pyrazole [CAS No. 493038-87-2; prepared from 2-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (279 mg, 71%). MS (ISP) 393.1 [(M+H)+]; mp 197° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.[NH2:15][C:16]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:17]=1[C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:28][C:27]1[C:16]([NH:15][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=2)=[C:17]([CH:24]=[CH:25][CH:26]=1)[C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19]
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1cccc(C(=O)NC(C)C)c1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC(C)C)c1NC(=O)c1ccc(OC(F)(F)F)cc1
Reaction time: 1 h
Yield: 82.9 %

Procedure:
4-(trifluoromethoxy)benzoyl chloride (0.29 g, 1.3 mmol) was added dropwise to a mixture of the aniline from Step B (0.25 g, 1.3 mmol) and triethylamine (0.13 g, 1.3 mmol) in 5 mL of methylene chloride at room temperature. After stirring for one hour the reaction was poured into water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated under reduced pressure. The resulting solids were washed with hexane/ether and filtered to afford 0.41 g of the title compound, a compound of the present invention, as a solid melting at 207-209° C.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[ClH:1].[CH2:19]([N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:4][CH2:3]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)CCC1CCNCC1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)CCC1CCN(Cc2ccccc2)CC1

Procedure:
A suspension of (piperidin-4-yl)ethylcarboxylate hydrochloride (8.6 g, 44.4 mmol) and K2CO3 (24.5 g, 0.17 mol) in acetone (200 ml) was added benzylbromide (9.11 g, 53.3 mmol) and heated to reflux for 12 h. The solvent was evaporated in vacuo and the residue added H2O (200 ml). The aqueous layer was extracted with Et2O (3×100 ml) and the organic extracts dried over Na2SO4, filtered and evaporated in vacuo. The residue was dissolved in acetone and HCl bubbled into the solution to give the hydrochloride precipitate. The precipitate was filtered, dried and recrystallized from acetone to give the expected product as a white solid (11.03 g, 87.6%).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:13])[C:7](=O)[C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:14]1([C@@H:20]([NH2:22])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C1(C)C=CC=CC=1>[C:1]([NH:5][C:6](=[O:13])[C:7](=[N:22][C@H:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:21])[C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(C)(C)NC(=O)C(=O)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](N=C(C(=O)NC(C)(C)C)C(C)(C)C)c1ccccc1
Yield: 79.6 %

Procedure:
A solution of 30.0 g (162 mmol) of N-tert-butyl-3,3-dimethyl-2-oxo-butyramide (D. Seyferth, R. C. Hui, Tetrahedron Lett. 1984, 25, 5251) and 50 g (413 mmol) of (S)-1-phenylethylamine in 150 ml of toluene was boiled under reflux on a water separator for 20 hours. Subsequently, the solvent and excess amine were removed in a vacuum. The residue was treated with 200 ml of hexane at 0° C. and stirred. After filtration of the suspension and concentration in a vacuum the residual oil was distilled. There were obtained 37.2 g (80%) of (S)-N-tert-butyl-3,3-dimethyl-2-(1-phenylethylimino)-butyramide of boiling point 140° C. at 0.3 mbar. [α]=-40.7 (c=1.0, CHCl3).
Reaction SMILES: C(=O)([O-])[O-].[Na+:5].[Na+].Br.Br[C:9]1[NH:10][CH:11]([OH:17])[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=1.[CH3:18][C:19]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[CH:21][C:20]=1[NH:34][C:35]([C:37]1[S:41][C:40]2[CH2:42][CH2:43][CH2:44][CH2:45][C:39]=2[CH:38]=1)=[O:36]>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.O1CCOCC1>[CH3:15][N:13]1[CH:14]=[C:9]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:34][C:35]([C:37]3[S:41][C:40]4[CH2:42][CH2:43][CH2:44][CH2:45][C:39]=4[CH:38]=3)=[O:36])[C:19]=2[CH3:18])[N:10]=[C:11]([O-:17])[C:12]1=[O:16].[Na+:5]
Reactant: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1C=C(Br)NC(O)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c([O-])n1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
A 250-mL three-neck round-bottomed flask equipped with a mechanical stirrer, reflux condenser and nitrogen inlet was charged with 1,4-dioxane (100 mL) and aqueous 2.0 M sodium carbonate (15 mL, 29.5 mmol). After bubbling nitrogen through the resulting solution for 15 minutes, 5 (8.44 g, 29.5 mmol), 9 (12.9 g, 32.5 mmol) and tetrakis(triphenylphosphine)palladium (2.38 g, 2.06 mmol) were added and the reaction mixture then heated at reflux for 20 h. After this time the reaction was cooled to room temperature and filtered through a pad of Celite 521. The filter cake was washed with a 1:1 solution of methanol/methylene chloride (350 mL) and the filter cake discarded. On standing a precipitate formed in the filtrate and this solid was filtered. The filter cake was triturated with ethyl acetate (50 mL), filtered and dried under vacuum. The resulting solid was suspended in water (75 mL), filtered and the filter cake washed with water (25 mL). The filter cake was dried to a constant weight to give a 53% yield (6.57 g) of 10 as a light yellow solid: mp 225-230° C. dec, 1H NMR (500 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.66 (s, 1H), 7.21 (m, 1H), 7.16 (m, 2H), 6.37 (s, 1H), 2.75 (m, 2H), 2.61 (m, 2H), 2.20 (s, 3H), 1.77 (m, 4H); MS (ESI+) m/z 418 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18](=[O:37])[CH2:19][CH2:20][N:21]2[CH2:26][CH:25]=[C:24]([C:27]3[C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][CH:28]=3)[CH2:23][CH2:22]2)[CH2:11][CH2:10]1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][C:18](=[O:37])[CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27]3[C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][CH:28]=3)[CH2:25][CH2:26]2)[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCNC(=O)CCN2CC=C(c3c[nH]c4cc(Cl)ccc34)CC2)CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1N1CCN(CCNC(=O)CCN2CCC(c3c[nH]c4cc(Cl)ccc34)CC2)CC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 95.2 %

Procedure:
A mixture of the compound of EXAMPLE 2 (0.383 mmol) and triethylsilane (0.422 mmol) in trifluoroacetic acid (6 ML) was stirred at 0° C. for 2.5 hours. The mixture was diluted with dichloromethane (20 mL) and quenched with sodium hydroxide solution until the pH was 10-13. The mixture was extracted with dichloromethane, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 8% methanol, 0.5% ammonium hydroxide in dichloromethane to give the title compound (191 mg, 95%).