Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23].[C:27](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[C:19]([C:4]1[C:3]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:2]([NH:1][CH3:27])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CNc1c(C(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoroacetylpyrazole (1 g) in anhydrous N,N-dimethylformamide (5 ml) at room temperature was added potassium carbonate (0.69 g), then iodomethane (97 μl). The mixture was stirred at room temperature for one hour. Water (30 ml) was then added, and the mixture was extracted with ether (50 ml, ×2). The combined organic layers were washed with water (30 ml, ×2), and evaporated. The residue was purified by column chromatography on silica gel (50 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p 160-161° C.
Reaction SMILES: [CH3:1][CH:2]([OH:7])[CH2:3][CH2:4][CH:5]=[CH2:6].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:7][CH:2]([CH2:3][CH2:4][CH:5]=[CH2:6])[CH3:1])(=[O:18])=[O:17]
Reactant: C=CCCC(C)O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCC(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a solution of Hex-5-en-2-ol (50 g crude, 500 mmole) in dichloromethane was added triethylamine (103 mL, 750 mmol) at room temperature. The reaction mass was cooled to 0° C. and to it was added a solution of methane sulfonyl chloride (50.4 mL, 650 mmol) in DCM over a period of 30 min. The reaction mass was allowed to come to room temperature and stirred for 2 h. The solution was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get crude compound Hex-5-en-2-yl methanesulfonate as light brown oily liquid (73 g, 82%). 1H NMR (400 MHz, CDCl3): δ ppm 5.84-5.80 (m, 1H), 5.10-5.0 (m, 2H), 4.99-4.98 (m, 1H), 3.15 (s, 3H), 2.52-2.09 (m, 2H), 1.75-1.66 (m, 2H), 1.36-1.34 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=O)[CH2:11][F:12].N1C=CC=CC=1.Cl.[CH3:21][O:22][NH2:23]>CO>[CH3:21][O:22][N:23]=[C:10]([CH2:11][F:12])[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: O=C(CF)Cc1ccc(Cl)cc1Cl
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C(CF)Cc1ccc(Cl)cc1Cl
Temperature: 23 °C
Reaction time: 16 h
Yield: 106.6 %

Procedure:
To a stirred solution of 1-(2,4-dichloro-phenyl)-3-fluoro-propan-2-one (0.34 g; 1.5 mmol) in methanol (3 ml) was added pyridine (0.4 ml; 4.9 mmol) followed by a portionwise addition of methoxyamine hydrochloride (0.41 g; 4.9 mmol). The reaction mixture was stirred for 16 hours at 23° C. The mixture was washed with water (5 ml), the aqueous layer was extracted with dichloromethane (3×5 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford 0.40 g (100% of theory) of crude 1-(2,4-dichloro-phenyl)-3-fluoro-propan-2-one O-methyl-oxime (isomers E/Z) as a yellow oil.
Reaction SMILES: B(F)(F)F.B(F)(F)F.CC[O:11]CC.B(F)(F)F.CCCCOCCCC.[O:27]1[CH2:32]C[O:30][CH2:29][CH:28]1[C:33]([OH:35])=O.B(F)(F)F.C(OC(=O)C)(=O)C.B(F)(F)F>>[O:27]1[CH2:28][CH2:29][O:30][CH2:32]1.[O:35]1[CH2:33][CH2:28][CH2:29][O:30][O:11]1
Reactant: CCOCC
Reactant: O=C(O)C1COCCO1
Agent: FB(F)F
Solvent: CCCCOCCCC
Solvent: CC(=O)OC(C)=O
Product: C1COCO1
Product: C1COOOC1

Procedure:
The boron trifluoride and the coordination compound of boron trifluoride such as boron trifluoride diethyl etherate, boron trifluoride dibutyl etherate, boron trifluoride dioxanate, boron trifluoride acetic anhydride and boron trifluoride triethylamine complex compounds, which are used either alone or in combination in the present invention, are a cationic polymerization catalyst for producing a polyacetal resin mainly comprising 1,3-dioxolane and trioxane.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.Br[CH2:16][C:17]([NH:19]/[C:20](/[CH3:26])=[CH:21]\[C:22]([O:24][CH3:25])=[O:23])=[O:18]>CC(C)=O>[F:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][CH2:16][C:17]([NH:19]/[C:20](/[CH3:26])=[CH:21]\[C:22]([O:24][CH3:25])=[O:23])=[O:18]
Reactant: COC(=O)/C=C(/C)NC(=O)CBr
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)/C=C(/C)NC(=O)COc1cccc(F)c1
Temperature: 25 °C
Yield: 69.8 %

Procedure:
To a suspension of K2CO3 (0.37 g, 2.68 mmol) in acetone (10 mL) were added 3-fluorophenol (0.30 g, 2.68 mmol) and methyl 3-(2-bromoacetamido)crotonate (0.76 g, 3.22 mmol), the mixture was refluxed for 5 h and cooled to rt. The mixture was concentrated in vacuo and the residue was dissolved in CH2Cl2 (40 mL), washed with brine (40 mL×3). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=10:1) to give the title compound as a yellowish solid (0.50 g, 70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([OH:14])=O)[C:7]1=[O:15].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(Cl)Cl.C(N(CC)C(C)C)(C)C.[NH2:56][C@@H:57]([C:62]1[S:63][CH:64]=[CH:65][CH:66]=1)[CH2:58][C:59]([OH:61])=[O:60]>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:56][C@@H:57]([C:62]2[S:63][CH:64]=[CH:65][CH:66]=2)[CH2:58][C:59]([OH:61])=[O:60])=[O:14])[C:7]1=[O:15]
Reactant: N[C@H](CC(=O)O)c1cccs1
Reactant: O=C(O)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1cccs1

Procedure:
Into a round bottom was added 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (0.400 g, 0.00151 mol;), N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.573 g, 0.00151 mol;), Methylene chloride (14 mL, 0.23 mol;), and N,N-Diisopropylethylamine (1310 uL, 0.00754 mol;). The reaction was stirred until all contents were dissolved and preactivation was complete. (R)-3-Amino-3-thiophen-2-yl-propionic acid (0.28 g, 0.0016 mol;) was added and the reaction was allowed to stir for 1-2 hours then an LC-MS was taken which showed product at 1.47. The reaction was worked up by washing with citric acid and brine then drying with magnesium sulfate. The crude concentrated reaction was taken on directly to the next step. ES (+) MS m/e=419.08
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[NH:15][N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([B:30]3[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]3)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>N1C=CC=CC=1.O>[CH3:39][N:40]([CH3:44])[C:41]([N:15]1[C:12]2[C:13](=[O:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:9]([C:24]3[CH:29]=[CH:28][C:27]([B:30]4[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]4)=[CH:26][CH:25]=3)=[N:10][C:11]=2[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:16]1)=[O:42]
Reactant: CN(C)C(=O)Cl
Reactant: CC1(C)OB(c2ccc(-c3nc4c(-c5ccccc5)n[nH]c4c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Solvent: O
Solvent: c1ccncc1
Product: CN(C)C(=O)n1nc(-c2ccccc2)c2nc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)n(-c3ccc(Cl)cc3)c(=O)c21
Temperature: 80 °C

Procedure:
To a solution of 6-(4-chloro-phenyl)-3-phenyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one (100.0 mg, 0.191 mmol) in anhydrous pyridine (1.0 mL) is added dimethylcarbamyl chloride (87.4 μL, 0.953 mmol). The reaction mixture is heated at 80° C. overnight before removal of the solvent. The residue is taken in water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layer is washed with brine, concentrated, and purified by silica gel chromatography to provide 6-(4-chloro-phenyl)-7-oxo-3-phenyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-6,7-dihydro-pyrazolo[4,3-d]pyrimidine-1-carboxylic acid dimethylamide as a white solid product; HPLC-MS calculated for C32H31BClN5O4 (M+H+) 596.2, found 596.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:18]1([C:22]([C:24]2[CH:29]=[N:28][C:27](Cl)=[CH:26][N:25]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O.C(OCC)(=O)C>[N:18]1([C:22]([C:24]2[N:25]=[CH:26][C:27]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[N:28][CH:29]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)OC)c1
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added methyl 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoate (1.0 eq), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (1.05 eq), cesium carbonate (1.5 eq) and dimethylsulfoxide (10 vols) under a nitrogen atmosphere. The contents of the flask were heated to 45° C. for 1.5 hours, then cooled to 22° C. Ethyl acetate (6 vols) and water (6 vols) were added to the flask, the mixture was agitated for 15 minutes, then the layers were separated. Water (3 vols) was added to the organic layer, the batch agitated for 15 minutes, then the layers were separated. This process was repeated with water (3 vols) then saturated brine (6 vols), then with water (6 vols). The organic layer was evaporated on the rotary evaporator to yield the title compound as an oil (93% yield corrected for assay). 1H NMR δ (400 MHz) DMSO: 8.62 (s, 1H), 8.50 (s, 1H), 7.34 (s, 1H), 7.30 (s, 1H), 7.17 (s, 1H), 4.68-4.64 (m, 1H), 4.54-4.49 (t, 2H), 4.07-4.03 (t, 2H), 3.81 (s, 3H), 3.49-3.41 (m, 2H), 3.25 (s, 3H), 2.29-2.22 (m, 2H), 1.20-1.18 (d, 3H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:7]2[CH:8]=[CH:9][N+:10]([O-])=[CH:11][C:6]2=[N:5][N:4]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:11]1[C:6]2[N:7]([C:3]([C:2]([F:14])([F:13])[F:1])=[N:4][N:5]=2)[CH:8]=[CH:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccn2c(C(F)(F)F)nnc2c1
Product: FC(F)(F)c1nnc2c(Cl)nccn12

Procedure:
A suspension of 40 mg (0.196 mmol) of 3-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyrazine 7-oxide in 0.9 mL of phosphorus oxychloride was stirred at reflux for 2.5 h. The cooled solution was concentrated to dryness. Purification of the residue by preparative HPLC (C18 reverse phase column, 10-70% acetonitrile in water containing 0.05% trifluoroacetic acid) and then by flash chromatography on silica gel (10-30% ethyl acetate in hexanes) yielded the title compound as a white solid. LC-MS 223 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([N:28]1[C:33](=[O:34])[CH:32]=[CH:31][NH:30][C:29]1=[O:35])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:36]([O:55][CH2:56]/[CH:57]=[CH:58]/[CH2:59]O)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCCCCC.CCOC(C)=O>[C:20]([N:28]1[C:33](=[O:34])[CH:32]=[CH:31][N:30]([CH2:59]/[CH:58]=[CH:57]/[CH2:56][O:55][C:36]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:29]1=[O:35])(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(c1ccccc1)n1c(=O)cc[nH]c1=O
Reactant: OC/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)n1c(=O)ccn(C/C=C/COC(c2ccccc2)(c2ccccc2)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.7 %

Procedure:
Polymer bound triphenylphosphine (0.75 g, 2.25 mmol) was shaken in THF (5 ml) for 15 minutes, then 3-benzoyluracil (290 mg, 1.35 mmol), trityl alcohol (11) (300 mg, 0.90 mmol) were added to the suspension of the resin. A solution of DIAD (0.354 ml, 1.80 mmol) in THF (2 ml) was added to the mixture. The reaction was shaken 24 hours at room temperature and monitored by TLC (Hexane/EtOAc 50:50). The resin was filtered and washed twice with THF (5 ml). The filtrate was concentrated under reduced pressure and taken in EtOAc (5 ml), a white solid precipitated. The precipitate was filtered; the filtrate was concentrated again and purified by flash chromatography using Hexane/EtOAc 40:60→60:40 as gradient which gave the title compound as a white foam (222 mg, 48%). Rf: 0.55 in Hexane/EtOAc 50:50 (UV/PMA).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:31]=[C:10]3[CH:11]=[CH:12][C:13]([O:15][C:16]4[CH:17]=[C:18]([NH:23]C(=O)OC(C)(C)C)[CH:19]=[CH:20][C:21]=4[CH3:22])=[CH:14][N:9]3[N:8]=2)=[O:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[NH2:23][C:18]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:16]([CH:17]=1)[O:15][C:13]1[CH:12]=[CH:11][C:10]2[N:9]([N:8]=[C:7]([NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[N:31]=2)[CH:14]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A mixture of tert-butyl [3-({2-[(cyclopropylcarbonyl)amino][1,2,4]triazolo[1,5-a]pyridin-6-yl}oxy)-4-methylphenyl]carbamate (1.50 g, 3.54 mmol) and trifluoroacetic acid (5 mL) was stirred at 0° C. for 30 min. The solvent was evaporated under reduced pressure, and the residue was dissolved in water, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (1.04 g, 91%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.C1C[O:26][CH2:25]C1.C([Li])CCC.CN(C)C=O>CCCCCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:25]=[O:26])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To stirred solution of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (10.0 g, 0.0309 mol;) in THF (400 mL, 5 mol) at −78° C. was added 2.5 M of n-Butyllithium in hexane (18 mL). The solution was stirred at −78° C. for 30 minutes. N,N-Dimethylformamide (5.3 mL, 0.068 mol) was added and stirring continued at −78° C. for 1 hours. The reaction was slowly quenched using 0.1N HCl cold solution. The product was extracted with DCM. The organic extracts were combined, washed with brine, filtered, and concentrated to dryness to give 2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-8-carbaldehyde (10.76 g, 99%) as a yellow solid. The crude was carried on without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.[CH2:32]([N:34](C(C)C)C(C)C)[CH3:33].Cl.C(N)C>CN(C=O)C>[CH2:32]([NH:34][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[N:20][CH:21]=1)[CH3:33]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Agent: CCN
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
(S)-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (75 mg, 0.178 mmol) was taken up in DMF (0.9 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (93 μl, 0.53 mmol), O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (101 mg, 0.266 mmol), and ethanamine hydrochloride (15.9 mg, 0.195 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (10-80 MeCN/H2O, TFA buffered). The fractions were collected and lyophilized to yield 27.4 mg (34%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.84 (s, 1H), 10.03 (br. s., 1H), 8.64 (s, 1H), 8.35 (t, J=5.2 Hz, 1H), 8.04 (d, J=9.1 Hz, 1H), 7.83 (s, 1H), 6.90-7.11 (m, 2H), 4.40-4.71 (m, 3H), 4.26 (s, 2H), 3.98 (d, J=11.1 Hz, 1H), 2.96-3.57 (m, 8H), 2.61-2.74 (m, 1H), 2.08 (d, J=11.9 Hz, 1H), 1.87 (d, J=12.4 Hz, 1H), 1.33-1.73 (m, 4H), 1.11 (t, 3H). [M+H] calc'd for C24H31N7O2, 450. found, 450.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:24](O)=O)=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:27])=[N:6][CH:7]=1.[CH2:28]([CH2:30][NH2:31])[OH:29]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=3[CH2:24][NH:31][CH2:30][CH2:28][OH:29])=[CH:10][C:9]=2[F:27])=[N:6][CH:7]=1
Reactant: NCCO
Reactant: Nc1cnc(-c2ccc(-c3ccc(C(F)(F)F)cc3C(=O)O)cc2F)cn1
Product: Nc1cnc(-c2ccc(-c3ccc(C(F)(F)F)cc3CNCCO)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Intermediate IF using 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carboxylic acid and ethanolamine. MS (ESI): mass calcd. for C20H18F4N4O, 406.39; m/z found, 407.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 8.18 (s, 1H), 8.12-8.01 (m, 2H), 7.86 (dd, J=8.1, 1.7, 1H), 7.65 (d, J=8.1, 1H), 7.34 (dd, J=3.5, 1.6, 1H), 7.33-7.31 (m, 1H), 4.38 (s, 2H), 3.78-3.63 (m, 2H), 3.09-3.00 (m, 2H).
Reaction SMILES: Br[CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[C:8](=O)([O-])[O-].[Na+].[Na+].[C-:14]#[N:15].[K+].Cl>O>[C:14]([CH:2]([CH2:6][CH3:7])[C:3]([O:5][CH3:8])=[O:4])#[N:15]
Reactant: O=C([O-])[O-]
Reactant: CCC(Br)C(=O)O
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CCC(C#N)C(=O)OC
Temperature: 50 °C
Yield: 77 %

Procedure:
To (±)-2-bromobutyric acid(167.01 g) was added water (150 ml). Sodium carbonate (54.05 g) was added slowly over an hour and dissolved therein. A solution of potassium cyanide (68.55 g) dissolved in water (150 ml) was added, and heated to about 50° C. Accordingly as the reaction progressed, the temperature of the reaction solution rose to 80° C. The reaction solution was stirred at 80°~90° C. for an hour, cooled to room temperature, and neutralized with conc. hydrochloric acid (120 ml). Afterwards, the such neutralized solution was concentrated under reduced pressure, and ethyl alcohol (500 ml) was added to the residue. The obtained ethanolic solution was concentrated under reduced pressure again. To the residue was added ethyl alcohol (700 ml), followed by filtration. After conc. sulfuric acid (3 ml) was added to the filtrate, the solution was refluxed for 5 hours and distilled to remove about 300 ml of ethyl alcohol. The solution was concentrated under reduced prrssure, and the residue was added to sodium carbonate saturated solution(400 ml). After extraction with ether (500 ml), the separated organic layer was washed with a 10% saline solution (500 ml) and a saturated saline solution(300 ml), dried over anhydrous magnesium sulfate, filtered and then concentrated. The residue was distilled under reduced pressure to give the colorless above-indicated compound(49.90 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH:20]([CH3:22])[CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].C(N(C(C)C)CC)(C)C.Br[C:33]1[S:34][C:35]2[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:33]3[S:34][C:35]4[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][CH:39]=[CH:38][C:36]=4[N:37]=3)[CH2:15][C@H:14]2[O:19][CH:20]([CH3:21])[CH3:22])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2OC(C)C)nc1Cl
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](OC(C)C)C3)sc12
Yield: 63 %

Procedure:
The same operation as in Example (1h) was performed using cis(±)-4-chloro-N-(3-isopropoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (148a) (0.150 g, 0.427 mmol), diisopropylethylamine (0.186 mL, 1.07 mmol) and ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (0.147 g, 0.514 mmol), to obtain 0.140g of the title compound as a yellow foamy solid (63%).
Reaction SMILES: Br[C:2]1[C:3]([C@@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH:35](B(O)O)=[CH2:36].CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C>O.CCO.CCOC(C)=O>[F:16][C:15]([F:18])([F:17])[C:12]1[CH:13]=[CH:14][C:9]([C@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:3]2[C:2]([CH:35]=[CH2:36])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br
Reactant: C=CB(O)O
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: C=Cc1cccnc1[C@@H](NC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a mixture of (S)-tert-butyl ((3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)carbamate (0.4 g, 0.93 mmol) in water (2 mL) and EtOH (8 mL) were added K3PO4 (0.3 g, 1.3 mmol), vinyl boronic acid (4 mL, 9.3 mmol) and A−taPhos)2PdCl2 (Guram, A. S. et al. Org. Lett. 2006, 8, 1787; 0.13 g, 0.01 mmol). The resulting mixture was stirred at 120° C. for 1 h. Reaction progress was monitored by TLC (20% EtOAc in petroleum ether). After completion of reaction, water (50 mL) was added to the reaction mixture, and the product was extracted with DCM (3×25 mL). The combined organic layers were separated, dried over anhydrous sodium sulfate, and purified by column chromatography using silica (100-200 mesh) and using 15-30% EtOAc in petroleum ether as an eluent. In this manner, (S)-tert-butyl ((4-(trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methyl)carbamate was obtained as an off-white solid. MS (ESI pos. ion) m/z: 378.9 (M+1).