Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][C:17](Cl)=[C:18]([F:23])[CH:19]=2)[N:14]([CH2:25][CH3:26])[CH:13]=1)=[O:11])[CH3:8].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][C:17]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[C:18]([F:23])[CH:19]=2)[N:14]([CH2:25][CH3:26])[CH:13]=1)=[O:11])[CH3:8]
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1cn(CC)c2cc(Cl)c(F)cc2c1=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(CC)c2cc(N3CCNCC3)c(F)cc2c1=O
Reaction time: 5 h
Yield: 81 %

Procedure:
Anhydrous piperazine (10.3 g) and 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester were added to a mixture of pyridine (9 ml) and toluene (18 ml), and the mixture was refluxed with stirring for 5 hrs. The same procedure as described in Example 1 was followed to give 8.4 g (81% yield) of 1-ethyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester. mp: 178.5°-180° C.
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:14](O)=[CH:15][C:16](=[O:18])[CH3:17])=[CH:7]2.C([O-])(=O)C.[Na+].[H][H]>O.[Pd].C(O)(C)C>[CH3:17][C:16]([CH2:15][CH2:14][C:6]1[CH:5]=[CH:4][C:3]2[CH:2]=[C:11]([O:12][CH3:13])[CH:10]=[CH:9][C:8]=2[CH:7]=1)=[O:18]
Reactant: COc1ccc2cc(C(O)=CC(C)=O)ccc2c1Br
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc2cc(CCC(C)=O)ccc2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
49.44 Grams (0.154 moles) of 4-(5-bromo-6-methoxy-2-naphthyl)-4-hydroxybut-3-en-2-one, 12.24 g (0.149 moles) of anhydrous sodium acetate, 4 g of a 50% suspension in water of 5% palladium on carbon, equivalent to 0.00094 moles of palladium and 400 ml of isopropanol are put into a hydrogenator. The hydrogenator is washed with nitrogen in order to eliminate the oxygen and then hydrogen is introduced at the pressure of 2.5 atmospheres. For a period of time of 9 hours the temperature of reaction is kept at 50° C., then the hydrogen is let off, the hydrogenator is washed with nitrogen and the reaction mixture is filtered in order to eliminate the catalyst. The solution is concentrated to 130 ml, diluted with 45 ml of water, heated to 60° C. and added with 18.2 g of sodium metabisulfite. The reaction mixture is kept for one hour at 60° C. and then is cooled to 0° C. The so obtained suspension is kept at 0° C. for two hours and then is filtered; the solid is washed with 60 ml of isopropanol cooled to 0° C. and then is suspended in a mixture made by 70 ml of a 10% aqueous solution of sodium hydroxide and 270 ml of toluene. The reaction mixture is stirred for one hour and half at room temperature, then is heated at 60° C. and the layers are separated. The organic phase is washed with 60 ml of water and is concentrated under vacuum at 60° C. until an oil is obtained which solidifies by cooling. The solid is dissolved at 60° C. in 40 ml of isopropanol and the resulting solution is cooled to 0° C. in two hours. The obtained suspension is kept for one hour at this temperature, filtered, washed with 10 ml of cold isopropanol and dried in oven under vacuum until constant weight. 26.3 Grams of nabumetone are obtained with a yield equal to 74.8%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:26])[CH2:15][CH:16]([CH2:22][CH2:23][O:24][CH3:25])[C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:28]1[S:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.[OH-].[Na+].CO>C(O)CCC>[S:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=[O:26])[CH2:15][CH:16]([CH2:22][CH2:23][O:24][CH3:25])[C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Clc1nc2ccccc2s1
Reactant: CCOC(=O)C(CCOC)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCO
Product: COCCC(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4s3)cc2)cc1)C(=O)O
Temperature: 90 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of ethyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2-(2-methoxyethyl)-4oxobutanoate (75 mg, 0.21 mmol) in butanol (4 mL), 2-chloro-benzothiazole (43 mg, 0.25 mmol) was added and the reaction mixture was heated at 90° C. overnight. The solvent was removed by rotary evaporation, the residue was redissolved in DMF (1 mL), a solution of 1 N aqueous NaOH (0.63 mL, 0.63 mmol) was added, and the mixture was stirred at rt overnight. A solution of 1 N aqueous HC1 (0.3 mL, 0.3 mmol) and methanol (5 mL) were added to the reaction mixture, and the crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2-(2-methoxyethyl)-4-oxobutanoic acid as a white solid (30 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, 2H), 7.95 (d, 2H), 7.70 (m, 5H), 7.60 (d, 1H), 7.30 (t, 1H), 7.15 (t, 2H), 3.35 (m, 2H), 3.25 (s, 3H), 3.20 (m, 2H), 2.90 (m, 1H), 1.95-1.75 (m, 2H); LC-MS ret. time 3.29 min (method 2), m/z 461.15 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.Cl.[CH3:11][NH:12][O:13][CH3:14].N1C=CC=CC=1>ClCCl>[CH3:14][O:13][N:12]([CH3:11])[C:7](=[O:9])[CH2:8][CH:2]([CH3:1])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC1CC(=O)OC(=O)C1
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)CC(C)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
A solution of 3-methylglutaric anhydride (5.0 g) and N,O-dimethylhydroxylamine hydrochloride (4.19 g) in dichloromethane (100 mL) was stirred at 0° C. and treated dropwise with pyridine (6.9 mL). The resulting solution was warmed to rt over 45 min and then stirred overnight. After this time, the mixture was concentrated under vacuum, and the resulting residue was taken up in saturated aqueous sodium chloride and 1:1 ether/dichloromethane. The aqueous and organic layers were separated and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum to provide 5-(methoxy(methyl)amino)-3-methyl-5-oxopentanoic acid as a yellow oil (7.27 g). Mass spectrum m/z 188.10 (M−H−).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([OH:29])[CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.Br[CH2:38][CH2:39][OH:40]>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([OH:29])[CH2:26][N:25]5[CH2:38][CH2:39][OH:40])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1C[C@@H](O)CN1
Reactant: OCCBr
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1C[C@@H](O)CN1CCO

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-hydroxy-1-(2-hydroxyethyl)pyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-hydroxypyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione (Example 182) and 2-bromoethanol following General Procedure S.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:16]4=[O:23])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1.[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>>[OH:43][C:26]([CH3:42])([CH3:25])[CH2:27][N:28]1[CH:32]=[C:31]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[N:12]=[C:13]([N:15]5[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:16]5=[O:23])[S:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:24]=2)[CH:30]=[N:29]1
Reactant: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(N4C(=O)NC(=O)C4(C)C)nc2-3)cn1
Yield: 12 %

Procedure:
1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dione was coupled with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol under Suzuki conditions to give 485. Yield 12% MS (ESI+): 468.2. 1H NMR (400 MHz, DMSO) δ 11.86 (s, 1H), 8.16 (t, J=8.8, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.38 (dd, J=8.2, 1.8, 1H), 7.24 (d, J=1.8, 1H), 4.73 (s, 1H), 4.33 (t, J=4.9, 2H), 4.03 (s, 2H), 3.25 (t, J=5.0, 2H), 1.78 (s, 6H), 1.09 (s, 6H)
Reaction SMILES: ClC(Cl)(Cl)C(=N)OC.F[C:10](F)(F)[C:11]([OH:13])=[O:12].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([NH2:26])[CH:20]=1)([O-:18])=[O:17]>ClCCl.C(OCC)C>[N+:16]([C:19]1[CH:24]=[CH:23][C:22]2[NH:25][C:10]([C:11]([OH:13])=[O:12])=[N:26][C:21]=2[CH:20]=1)([O-:18])=[O:17]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(O)C(F)(F)F
Agent: COC(=N)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)c1nc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.9 %

Procedure:
Methyl 2,2,2-trichloroacetimidate (0.73 g, 4.09 mmol) and trifluoroacetic acid (0.63 mL, 8.17 mmol) were added to a suspension of 4-nitrophenylenediamine (0.50 g, 3.27 mmol) in a 2:3 mixture of dichloromethane/diethyl ether (40 mL). After stirring at RT for 3 h, the reaction mixture was filtered. The residue in the filter was washed with a 1:1 mixture of dichloromethane:ether. The filtrates were combined and shaken with 1.5N aqueous sodium hydroxide (40 mL). The organic layer was removed. A 1:1 mixture of methanol/ether (40 mL) was added, and the mixture was stirred at RT overnight. The precipitated yellow solid was collected by filtration, suspended in water and the mixture acidified with 6N aqueous HCl. The precipitate was collected by filtration and dried under vacuum overnight to give the title compound (0.331 g, 49%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.56 (s, 1H), 8.20 (d, 1H), 7.79 (d, 1H). MS: m/z 208 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]([OH:28])=O)=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.Cl.C([N:43]=C=NCCCN(C)C)C.CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]([NH2:43])=[O:28])=[CH:22][N:21]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(N)=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.5 %

Procedure:
A mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoic acid (0.30 g), 1-hydroxybenzotriazole ammonia complex (0.17 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.22 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenamide as colorless crystals (0.25 g, yield 83%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 187-188° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:38]([C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][CH:42]=1)([O-:40])=[O:39].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:17]=[C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:18])[N:8]1[C@H:5]1[CH2:4][CH2:3][C@H:2]([O:1][C:45](=[O:46])[C:44]2[CH:43]=[CH:42][C:41]([N+:38]([O-:40])=[O:39])=[CH:49][CH:48]=2)[CH2:7][CH2:6]1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
To a solution of trans-2-(4-Hydroxy-cyclohexyl)-isoindole-1,3-dione (38 g, 154.9 mmol), triphenylphosphine (65 g, 248 mmol), and 4-nitrobenzoic acid (41.4 g, 248 mmol) in 1500 mL of THF was added dropwise diisopropyl azodicarboxylate (50.1 g, 248 mmol) at room temperature. The reaction mixture was stirred overnight. The solvent was evaporated, and the resulting solid was recrystallized from methanol. Yield: 53 g (86.7% of theory). 1H NMR (300 MHz, CDCl3): δ 8.40-8.36 (m, 4H), 7.79 (ddd, J=0.12, 0.02, and 0.02 Hz, 4H), 5.39 (s, 1H), 4.37-4.22 (m, 1H), 2.82-2.65 (m, 2H), 2.27-2.16 (m, 2H), 1.84-1.65 (m, 4H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[CH:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1>O1CCOCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[C:2]([NH:30][CH:26]4[CH2:29][CH2:28][CH2:27]4)[S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: NC1CCC1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Solvent: C1COCCO1
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(NC4CCC4)nc32)c(=O)[nH]c1=O
Temperature: 60 °C

Procedure:
A mixture of the product from example 44 step (viii) (0.25 g) and cyclobutylamine (0.54 ml) in dry 1,4-dioxane (3 ml) were heated at 60° C. for 34 h. The solvent was removed under reduced pressure and the residue partitioned between water and ethyl acetate. The organic extracts were dried (MgSO4) and evaporated under reduced pressure.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[N:8][CH:9]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][NH:2][CH3:1])[C:26]=2[Cl:27])=[O:21])=[N:8][CH:9]=1
Reactant: CN
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NC(=O)c1scc(CCl)c1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CNCc1csc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)c1Cl
Temperature: 25 °C
Yield: 37.2 %

Procedure:
To methylamine (2.0 M in tetrahydrofuran, 16 mL, 32 mmol) was added a solution of N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (3.0 g, 6.3 mmol) in DMF (10 mL) and the mixture stirred at ambient temperature. After 4 hours the reaction mixture was poured into water (100 mL), concentrated in vacuo to remove the tetrahydrofuran and extracted with ethyl acetate (2×75 mL). The combined organics were washed with brine (75 mL), dried over MgSO4 and concentrated of all volatiles in vacuo. Purification by flash chromatography on silica gel afforded 1.1 g (38% yield) of N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide as a yellow solid; NMR (DMSO-d6/TFA) 11.4 (s, 1), 11.0 (s, 1), 8.9 (br s, 2), 7.6-8.4 (m, 7), 4.2 (m, 2), 2.6 (m, 3) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[N:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][CH2:26][C:16]1([C:19]2[CH:24]=[N:23][C:22]([CH3:25])=[N:21][CH:20]=2)[CH2:17][CH2:18][C:13]([F:12])([F:28])[CH2:14][CH2:15]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C2(CN)CCC(F)(F)CC2)cn1
Product: Cc1ncc(C2(CNC(=O)c3cccc(Cl)c3Cl)CCC(F)(F)CC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and C-[4,4-difluoro-1-(2-methyl-pyrimidin-5-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=414.1, tR (minutes, Method F)=2.57
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:34])[C:26]4[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=4[F:33])[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[F:35][C:36]([F:45])([F:44])[C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40]>C(O)(C)C>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[C:25]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]4[CH:41]=[CH:42][CH:43]=[C:37]([C:36]([F:35])([F:44])[F:45])[CH:38]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[N:11]3[N:10]=2)[CH:19]=1)=[O:34]
Reactant: Cc1cccc2c(-c3ccnc(Cl)n3)c(-c3cccc(NC(=O)c4c(F)cccc4F)c3)nn12
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CC(C)O
Product: Cc1cccc2c(-c3ccnc(Nc4cccc(C(F)(F)F)c4)n3)c(-c3cccc(NC(=O)c4c(F)cccc4F)c3)nn12

Procedure:
The title compound was prepared through standard displacement conditions by microwaving N-{3-[3-(2-chloropyrimidin-4-yl)-7-methylpyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 3-trifluoromethylaniline in isopropanol at 150° C. for 15 min. 1H NMR (400 MHz, DMSO d-6) 2.73 (s, 3H), 3.76 (s, 3H), 6.50 (s, 1H), 7.02 (m, 2H), 7.22 (m, 2H), 7.33 (m, 2H), 7.43 (m, 2H), 7.57 (m, 1H), 7.70 (m, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.95 (s, 1H), 8.23 (d, J=5.6 Hz, 1H), 8.35 (d, J=8.4 Hz, 1H), 9.52 (s, 1H), 10.9 (s, 1H); LCMS (ESI): [M+H]+=581.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:21]=[C:20]([NH:22][C:23]3[CH:28]=[N:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=3)[N:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=[O:34]>>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[N:17]=[CH:18][N:19]=[C:20]([NH:22][C:23]3[N:24]=[CH:25][C:26]([C:29]([NH2:30])=[O:34])=[N:27][CH:28]=3)[CH:21]=2)[CH2:10][CH2:9]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncn2)CC1
Product: NC(=O)c1cnc(Nc2cc(NCC3CCNCC3)ncn2)cn1
Temperature: 82 °C
Yield: 15 %

Procedure:
A mixture of tert-butyl-4-((6-(5-cyanopyrazin-2-ylamino)pyrimidin-4-ylamino)methyl)-piperidine-1-carboxylate (0.15 mmol) and trifluoroacetic acid was heated at 82° C. for 4 hours. The solution was evaporated to dryness and the residue was purified by preparative HPLC to give 5-(6-(piperidin-4-ylmethylamino)pyrimidin-4-ylamino)pyrazine-2-carboxamide (7.36 mg, 15%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@@H:10]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:11]([OH:30])[CH2:12][N:13]1[C@H:22]([C:23]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][C@H:20]2[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14]1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[C:38](O)(=[O:49])[C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1.OC1C2N=NNC=2C=CC=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[C:26]([NH:25][C:23]([C@@H:22]1[CH2:21][C@H:20]2[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14][N:13]1[CH2:12][C@@H:11]([OH:30])[C@@H:10]([NH:9][C:7](=[O:8])[C@H:2]([CH2:3][C:4](=[O:6])[NH2:5])[NH:1][C:38]([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1)=[O:49])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:24])([CH3:28])([CH3:29])[CH3:27]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 64 h
Yield: 25 %

Procedure:
A solution of 154 mg of 2-[3(S)-[(L-asparaginyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro(4aS,8aS)-isoquinoline-3(S)-carboxamide and 52 mg of quinaldic acid in 6 ml of dry tetrahydrofuran was cooled in an ice/salt mixture. 41 mg of hydroxybenzotriazole, 35 mg of N-ethylmorpholine and 68 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 64 hours. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and with sodium chloride solution and then evaporated. The residue was chromatographed on silica gel using dichloromethane/methanol (9:1) for the elution to give 50 mg of N-tert.butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid; MS: m/e 671 [M+H]+, NMR: δ (d4CH3OH, 400 MHz):
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH2:4]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:36]>>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH2:4][Cl:36]
Reactant: Cc1ccc(-c2ccccc2)cc1CO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(-c2ccccc2)cc1CCl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
500 mg (2.52 mmol) of 2-methyl-5-phenylbenzyl alcohol (produced in the same manner as in Reference Production Example 1 (4)) was dissolved in 2 ml of carbon tetrachloride, and to this solution was added 1.0 g (3.28 mmol) of triphenylphosphine under nitrogen atmosphere. The reaction mixture was stirred for 1.5 hours under reflux with heating, cooled to room temperature, then, concentrated. The residue was subjected to silica gel column chromatography (eluant: hexane/ethyl acetate=10/1 (v/v)), to obtain 508 mg of 2-methyl-5-phenylbenzyl chloride.
Reaction SMILES: [CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][NH:5]1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:29]1[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[C:32]([C:39](=[O:41])[CH3:40])=[CH:31][N:30]=1>CC(O)C>[CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][N:5]1[C:29]1[N:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[C:32]([C:39](=[O:41])[CH3:40])=[CH:31][N:30]=1)([CH3:3])[CH3:2]
Reactant: CSc1ccc2cc3n(c2c1)CCNC3C(C)C
Reactant: CC(=O)c1cnc(Cl)nc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CSc1ccc2cc3n(c2c1)CCN(c1ncc(C(C)=O)c(C(F)(F)F)n1)C3C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a solution of 1-isopropyl-7-(methylthio)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (100 mg, 0.38 mmol) and DIPEA (246.72 mg, 1.91 mmol) in i-PrOH (2 mL) was added 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (172.50 mg, 0.76 mmol). The reaction mixture was stirred at rt overnight. The mixture was concentrated and purified by preparative TLC on silica gel eluting with PE/EtOAc 1:1 to afford 1-(2-(1-isopropyl-7-(methylthio)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (120 mg, 69.67% yield) as a colorless oil. LC-MS MS (ESI) m/z 449.2 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 8.66 (s, 1H), 7.44-7.40 (m, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.27-6.25 (m, 1H), 5.79-577 (m, 1H), 5.13-5.02 (m, 1H), 4.21-4.16 (m, 1H), 3.97-3.91 (m, 1H), 3.82-3.71 (m, 1H), 2.48 (s, 3H), 2.46 (s, 3H), 2.21-2.15 (m, 1H), 1.12-1.08 (m, 3H), 0.96-0.93 (m, 3H).