Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]#[C:25][Si](C)(C)C)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl-].[NH4+].C(OCC)(=O)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:32])([F:31])[F:33])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]#[CH:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C[Si](C)(C)C#Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12

Procedure:
A solution of tetrabutylammonium chloride (1 M in THF, 2.25 ml) is slowly added to a solution of crude 5-(3,5-dichloro-phenyl)-5-trifluoromethyl-3-(4-trimethylsilanylethynyl-naphthalen-1-yl)-4,5-dihydro-isoxazole (step A) in THF (25 ml) at 5° C. After 3 hours at 5° C. a saturated solution of ammonium chloride and ethyl acetate are added. The organic phase is washed with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 5-(3,5-dichloro-phenyl)-3-(4-ethynyl-naphthalen-1-yl)-5-trifluoromethyl-4,5-dihydro-isoxazole as a brown solid.
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)=[O:7])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[C:21]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:24]([O:23][C:21](=[O:22])[NH:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][C:2]2[CH:17]=[CH:16][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=3)=[CH:4][C:3]=2[N+:18]([O-:20])=[O:19])=[CH:33][CH:34]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Cl)cn3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 60.9 %

Procedure:
A solution of the product of Example 199A (300 mg, 0.9612 mmol) in anhydrous N,N-dimethylformamide (5 mL) was treated with N-Boc-4-hydroxyaniline (201 mg, 0.9612 mmol) and potassium carbonate (266 mg, 1.922 mmol) at room temperature, then heated at 80° C. under a nitrogen atmosphere for 5 hours. The reaction was cooled to room temperature and the solvent removed by rotary evaporation in vacuo. The residue was taken up in ethyl acetate (100 mL) and washed with water (4×50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. Trituration with 5% ethyl acetate gave the title compound (284 mg, 61%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O>C(O)C>[OH:1][CH2:2][C:3]1[C:4]2[N:5]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:9]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1ncccc1CO
Solvent: CCO
Product: OCc1cccn2cc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 62.4 %

Procedure:
A mixture of 1.24 g (10 mmole) of 3-hydroxymethyl-2-pyridinamine and 2.0 g (10 mmole) of α-bromoacetophenone in 25 ml of ethanol was stirred at room temperature. After 18 hours the resultant solid was collected, washed with ethano, and dissolved in water. The solution was made basic with aqueous potassium carbonate and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with diethyl ether, collected by filtration, washed with diethyl ether, and air dried to yield 1.4 g of 8-hydroxymethyl-2-phenylimidazo[1,2-a]pyridine, as confirmed by the nmr and infrared spectra and by elemental analysis. [Calcd. for C14H12N2O2 : C, 74.98; H, 5.39; N, 12.49. Found: C, 74.68; H, 5.39; N, 12.40.] A mixture of 871 mg (5.8 mmole) of 2-mercaptobenzimidazole and 1.3 g (5.8 mmole) of 8-hydroxymethyl-2-phenylimidazo[1,2-a]pyridine was dissolved in 10 ml of 47% aqueous hydrobromic acid and 10 ml of acetic acid and heated to reflux. After being cooled to room temperature, the mixture was poured into water, made alkaline with potassium carbonate, and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Trituration of the residue with diethyl ether yielded 1.8 g of the analytically pure title compound. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[C:8]([O:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[C:6]=2[CH:7]=1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:59][C:60]1[CH:61]=[CH:62][C:63]([NH2:66])=[N:64][CH:65]=1>CN(C=O)C.O>[CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([NH:66][C:63]3[CH:62]=[CH:61][C:60]([CH3:59])=[CH:65][N:64]=3)=[O:14])[CH:9]=[C:8]([O:15][C:16]3[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=3)[C:6]=2[CH:7]=1)[CH3:2]
Reactant: CCc1cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)O)cc2o1
Reactant: Cc1ccc(N)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)Nc3ccc(C)cn3)cc2o1
Reaction time: 8 h
Yield: 30.8 %

Procedure:
A solution of 2-ethyl-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylic acid (300 mg, 0.83 mmol), HATU (476 mg, 1.3 mmol) and DIPEA (162 mg, 1.3 mmol) in DMF (20 mL) was stirred for 1 h. After which 5-methylpyridin-2-amine (108 mg, 1.0 mmol) was added. The resulting mixture was stirred overnight. The reaction was monitored by TLC (petroleum ether/EtOAc 1:1). The mixture was poured into water (30 mL) and extracted with EtOAc (30 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to afford the desired product (115.0 mg, 31%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.52 (s, 1H), 8.18 (d, 1H), 8.04 (s, 1H), 7.86 (d, 3H), 7.52 (d, 1H), 7.42 (s, 1H), 7.06 (d, 2H), 6.20 (s, 1H), 3.00 (s, 3H), 2.74 (q, 2H), 2.24 (s, 3H), 1.26 (t, 3H); MS (ACPI, pos): 451.2.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH:11]=[CH:12][N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].[CH3:18][N:19]([CH3:23])[C:20](=[S:22])[S-:21].C[NH2+]C>C(=S)=S>[CH3:18][N:19]([CH3:23])[C:20](=[S:21])[S:22][CH:11]([CH2:12][N+:13]([O-:15])=[O:14])[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([O:16][CH3:17])[C:5]=1[O:4][C:1](=[O:3])[CH3:2]
Reactant: CN(C)C(=S)[S-]
Reactant: COc1cccc(C=C[N+](=O)[O-])c1OC(C)=O
Agent: C[NH2+]C
Solvent: S=C=S
Product: COc1cccc(C(C[N+](=O)[O-])SC(=S)N(C)C)c1OC(C)=O

Procedure:
As in Example 17, reaction of 2-methoxy-6-(2-nitrovinyl)phenyl acetate from Example 22 with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave 2-acetoxy-3-methoxy-α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 124° C.-125.5° C. after recrystallization without heating from dimethylformamide-methanol solution.
Reaction SMILES: N1(CCC[O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)CCCC1.Cl[CH2:25][CH2:26][CH2:27][N:28]1[C@@H:32]([CH3:33])[CH2:31][CH2:30][C@@H:29]1[CH3:34].CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[CH3:34][CH:29]1[CH2:30][CH2:31][CH:32]([CH3:33])[N:28]1[CH2:27][CH2:26][CH2:25][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1
Reactant: C[C@H]1CC[C@H](C)N1CCCCl
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CCC(C)N1CCCOc1ccc(C2(C#N)CCOCC2)cc1
Yield: 41.1 %

Procedure:
4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (318 mg, 1.56 mmol), 1-(3-chloro-propyl)-2,5-trans-dimethyl-pyrrolidine (250 mg, 1.42 mmol), DMF (5 ml) and K2CO3 (785 mg, 5.70 mmol) were reacted together according to general procedure E. The crude was dissolved in ethyl acetate (20 ml), washed with brine (2×10 ml), dried over MgSO4, filtered and concentrated in vacuo to give the title compound (200 mg, 56%) as a light brown solid. 1H NMR (400 MHz, CDCl3), δ 7.37 (d, 2H), 6.93 (d, 2H), 4.13-3.97 (m, 4H), 3.89 (td, 2H), 3.14-2.98 (m, 2H), 2.76 (m, 1H), 2.55 (m, 1H), 2.16-1.88 (m, 8H), 1.46-1.30 (m, 2H), 0.97 (d, 6H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]=[O:10].ClC1C=CC=CC=1.C1(=[O:25])CCCCC1>C(O)(=O)C.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:3]1([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:11])[C:2]=1[C:9]([OH:25])=[O:10]
Reactant: O=C1CCCCC1
Reactant: Cc1cc(C)c(C=O)c(C)c1
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: Clc1ccccc1
Product: Cc1cc(C)c(C(=O)O)c(C)c1
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a flask equipped with a stirrer, condenser and an oxygen inlet were added mesitaldehyde (20.0 g, 0.135 mol), 15 mL of chlorobenzene, 15 mL (0.145 mol) of cyclohexanone and 10 mg of cobalt (II) acetate dissolved in 1 mL of acetic acid. Oxygen ws bubbled in slowly while the solution was stirred overnight. The reaction temperature was raised to 50° and the oxidation was continued for an additional 4 hr. The flask was cooled to 0° and the reaction product was removed by filtration and washed with petroleum ether. A total of 12.0 g (55% yield) of crystalline mesitoic acid was obtained. Additional mesitoic acid (2.4 g) was obtained from the filtrate by evaporation, dissolution of the residue in ether, extraction of the ether solution with aqueous sodium bicarbonate and acidification of the aqueous extract. The total yield of product was 65%. The identity of the product was confirmed by its nmr spectrum (CDCl3).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[N:6]=1.P(Cl)(Cl)([Cl:16])=O.[C:19]([CH:22]1[CH2:27][CH2:26]O[C:23]1=[O:24])(=O)[CH3:20].[OH-].[Na+]>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]3[C:23](=[O:24])[C:22]([CH2:27][CH2:26][Cl:16])=[C:19]([CH3:20])[N:1]=[C:2]3[S:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2csc(N)n2)cc1
Reactant: CC(=O)C1CCOC1=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(-c2csc3nc(C)c(CCCl)c(=O)n23)cc1
Temperature: 0 °C
Yield: 35.5 %

Procedure:
5.7 g (30 mmoles) of 2-amino-4-(4-methylphenyl)-thiazol were dissolved in 11 ml (120 mmoles) of phosphorus oxychloride. To the solution formed, 3.25 ml (30 mmoles) of 2-acetyl-butyrolactone were slowly added. The mixture was refluxed for 2 hours, allowed to cool and poured onto 100 g of ice, then basified to pH 9 by adding sodium hydroxide and extracted twice with 100 ml of methylene chloride each time. The organic phase was washed twice with 50 ml of water each time and dried, and the solvent was removed by reduced pressure distillation. The residue formed was purified on a silica gel column using methylene chloride as eluent. 3.4 g of 3-(4-methylphenyl)-6-(2-chloroethyl)-7-methyl-thiazolo[3,2-a]pyrimidin-5-one were obtained as a yellowish solid, mp 152°-165° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11](Cl)[S:12][CH:13]=1)=[O:8].[C:24]([O-:27])([O-])=O.[K+].[K+].[F:30][C:31]([F:40])([F:39])[C:32]1[CH:33]=[C:34](O)C=[CH:36][CH:37]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]([O:27][C:24]2[CH:34]=[CH:33][C:32]([C:31]([F:40])([F:39])[F:30])=[CH:37][CH:36]=2)[S:12][CH:13]=1)=[O:8]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Nc1c(F)cc(CNC(=O)c2csc(Cl)n2)cc1F
Agent: [K+]
Product: CS(=O)(=O)Nc1c(F)cc(CNC(=O)c2csc(Oc3ccc(C(F)(F)F)cc3)n2)cc1F
Yield: 51.7 %

Procedure:
2-Chloro-thiazole-4-carboxylic acid 3,5-difluoro-4-methanesulfonylamino-benzylamide (62 mg, 0.16 mmol), anhyd. K2CO3 (49 mg, 0.20 mmol) was reacted with 3-trifluoromethylphenol (40 μl, 0.19 mmol) as described above to give the title compound (42 mg, 51%) after purification by column chromatography (Hex/EtOAc=3:2)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5](N)=[O:6].[OH-:22].[Na+]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:22])=[O:6]
Reactant: [OH-]
Reactant: NC(=O)c1cc(N)c(Oc2ccccc2)c(S(N)(=O)=O)c1
Agent: [Na+]
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-amino-4-phenoxy-5-sulphamyl-benzamide (1 g) and 1N sodium hydroxide (20 ml) was refluxed for 1 hour. After cooling, the 3-amino-4-phenoxy-5-sulphamyl-benzoic acid was precipitated from the reaction mixture by addition of 4N hydrochloric acid until pH 2.5. After several recrystallizations from aqueous ethanol and drying, the compound was obtained with a melting point of 252°-253° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>>[CH:29]1([NH:32][C:6]2[C:5]3[C:10](=[CH:11][C:2]([F:1])=[C:3]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:4]=3)[N:9]=[C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)[N:7]=2)[CH2:31][CH2:30]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc(NC3CC3)c3cc(N4CCCCC4)c(F)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropylamine in step E. MS (ESI): predicted mass calcd. for C20H21FN6O2, 396.2
Reaction SMILES: C([Li])CCC.[C:6]1([S:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[CH:17]=[CH:16]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN([CH:27]=[O:28])C.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:6]1([S:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[CH:17]=[C:16]2[CH:27]=[O:28])(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)C=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
n-Butyllithium (11.9 mL, 19.0 mmol, 1.6M in hexanes) was added to a solution of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (3.50 g, 13.6 mmol) in THF (53 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes, and then DMF (4.2 mL, 54.2 mmol) was added. The reaction mixture was warmed up to 0° C. and stirred for 3 hours. It was then treated with saturated aqueous ammonium chloride and ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (2.4 g, 62%) as a solid.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[CH:9][N:8]([CH2:11]Cl)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:2]([C:6]1[CH:10]=[CH:9][N:8]([CH2:11][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21])[N:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CC(C)(C)c1ccn(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccn(CC(C#N)(C#N)CCC(F)(F)F)n1
Yield: 38.1 %

Procedure:
1.16 g of 3-t-butyl-1-(chloromethyl)-1H-pyrazole hydrochloride and 0.98 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 17 ml of N,N-dimethylformamide. 1.54 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.63 g of [(3-t-butyl-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (3), hereinafter) shown by below formula.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3cccc(S(C)(=O)=O)c3)nc12
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(Nc3cccc(S(C)(=O)=O)c3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
To a solution of N-tert-butyl-2-(3-(methylsulfonyl)phenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (61 mg, 118 mol) in dichloromethane (1.8 mL) was added trifluoroacetic acid (269 mg, 182 μL, 2.36 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (1.8 mL), methanol (0.9 mL) and ammonium hydroxide (0.25 mL) and stirred at room temperature for 1 h. The mixture was concentrated and triturated with water. The solid was collected by filtration and washed with water and ether. Purification by chromatography (silica, GRADIENT UNKNOWN dichloromethane/methanol/0.5% ammonium hydroxide) gave N-tert-butyl-2-(3-(methylsulfonyl)phenylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (26 mg, 67.1 mol, 57%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.42 (s, 1H), 9.87 (s, 1H), 8.33 (d, J=8.2, 1 H), 8.05 (d, J=3.4, 1 H), 8.03 (s, 1H), 7.79 (t, J=2.0, 1 H), 7.68 (s, 1H), 7.54 (t, J=8.0, 1 H), 7.47 (d, J=7.7, 1 H), 3.21 (s, 3H), 1.42 (s, 9H); MS (EI/CI) m/z: 388.2 [M+H].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH:24]3[CH2:26][CH2:25]3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[CH:24]1([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:31]4[CH:30]=[N:29][C:28]([NH2:27])=[CH:33][CH:32]=4)[CH:7]=3)[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=2)[CH2:26][CH2:25]1
Reactant: FC(F)(F)c1ccc(-c2cc(-c3ccnc(Cl)c3)nc(C3CC3)c2)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C4CC4)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2′-chloro-6-cyclopropyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example E.29) (0.300 g, 0.80 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.229 g, 1.17 mmol) according to the general procedure VI. Obtained as a white solid (0.060 g, 17%). MS (ISP) 433.1 [(M+H)+]; mp 172-174° C.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7]C=[CH:5][C:4]=1O.C=O.[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[CH2:15][CH2:16][NH2:17].[O:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[CH2:15][CH2:16][N:17]1[CH2:7][C:8]2[CH:3]=[CH:4][CH:5]=[C:27]([O:22][CH3:23])[C:26]=2[O:25][CH2:24]1
Reactant: COc1ccccc1O
Reactant: C1COCCO1
Reactant: NCCc1ccccc1Cl
Agent: C=O
Product: COc1cccc2c1OCN(CCc1ccccc1Cl)C2

Procedure:
To 120 ml. of dioxane are added 5 g. of ortho-methoxyphenol, 9 ml. of 37% formalin and 7.56 g. of ortho-chlorophenethylamine. The mixture is heated on reflux for 3 hours and distilled to remove the solvent. The residue is purified by column chromatography on silica gel with a mixture of acetone and benzene (1:4). The resultant oil is cooled to be solidified. Recrystallization from methanol yields 3-(2-chlorophenethyl)-8-methoxy-3,4-dihydro-2H-1,3-benzoxazine as colorless needles melting at 79°-81° C. Yield: 6 g.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl[C:8]1[N:13]=[C:12]([N:14]=CN(C)C)[C:11]([C:19]#[N:20])=[N:10][C:9]=1[C:21]1[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH:28]([CH3:30])[CH3:29])[N:22]=1.[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>O.O1CCOCC1.C(Cl)(Cl)Cl.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>[NH2:14][C:12]1[C:11]([C:19]#[N:20])=[N:10][C:9]([C:21]2[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH:28]([CH3:29])[CH3:30])[N:22]=2)=[C:8]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[Br:31])[N:13]=1
Reactant: OB(O)c1ccccc1Br
Reactant: CC(C)n1nc(-c2nc(C#N)c(N=CN(C)C)nc2Cl)ccc1=O
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: O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)n1nc(-c2nc(C#N)c(N)nc2-c2ccccc2Br)ccc1=O
Temperature: 102.5 °C
Reaction time: 4 h
Yield: 10.2 %

Procedure:
Under nitrogen atmosphere, a solution of Na2CO3 (427 mg) in water (8.8 ml) was added to a suspension of N′-[6-chloro-3-cyano-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinyl]-N,N-dimethylimidoformamide (346 mg), (2-bromophenyl)boronic acid (503 mg) and tetrakis(triphenylphosphine)palladium (35 mg) in dioxane (22 ml) and the mixture was stirred at 100-105° C. for 4 hours. Dioxane was evaporated under reduced pressure to give a residue. The residue was dissolved in CHCl3, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel. By elution with a mixture of n-hexane and EtOAc (70:30 v/v) was obtained 3-amino-5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarbonitrile as a solid (42 mg) and by elution with a mixture of n-hexane and EtOAc (50:50 v/v) was obtained N′-[6-(2-bromophenyl)-3-cyano-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinyl]-N,N-dimethylimidoformamide as a solid (360 mg).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:23]O.C([O-])(=O)C.[Na+].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]#[N:23])=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Stir 5 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehyde together with 1.29 of hydroxylamine hydrochloride and 1.52 g of anhydrous sodium acetate in 15 ml of dimethylformamide for 1.5 hours at room temperature. Then add 2.85 g of phosphorus oxychloride dropwise to the resulting reaction mixture, the temperature of which rises to 40° C. Stir for 1 hour and then confirm that the reaction is complete by a thin layer chromatograph. Allow the solution to stand overnight and then pour onto 90 ml of ice water. Stir for 30 minutes at room temperature and then for 30 minutes at 40° C. Draw off the formed precipitate by vacuum filtration, wash the precipitate well with water and dry to obtain a 98% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carbonitrile [m.p. 190° to 192° C].