Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1I.C[O:11][C:12](=O)[C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:16]=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[CH:18][C:13]=1[C:12](=[O:11])[NH:8]2
Reactant: Nc1nccc(Cl)c1I
Reactant: COC(=O)c1cc(OCCCN2CCOCC2)ccc1B1OC(C)(C)C(C)(C)O1
Product: O=c1[nH]c2nccc(Cl)c2c2ccc(OCCCN3CCOCC3)cc12
Yield: 23.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 1 using 4-chloro-3-iodopyridin-2-amine (350 mg, 1.38 mmol) and 5-(3-morpholin-4-yl-propoxy)-2-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)-benzoic acid methyl ester (697 mg, 1.72 mmol) to provide 226 (120 mg, 23% yield) as a white solid. LC-MS (M+H=374, obsd.=374).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.[C:18]1([Li])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([OH:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:2]3[CH:15]=[CH:14][CH:13]=[CH:4][CH:3]=3)([OH:17])[C:4]=2[CH:3]=1
Reactant: [Li]c1ccccc1
Reactant: O=C1c2ccccc2C(=O)c2cc(Br)ccc21
Solvent: C1CCOC1
Product: OC1(c2ccccc2)c2ccccc2C(O)(c2ccccc2)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4.9 g (17 mmol) of 2-bromo-9,10-anthraquinone was put into a 300 mL three-neck flask. The atmosphere in the flask was substituted with nitrogen. 100 mL of tetrahydrofuran (THF) was added and dissolved well. After that, 18 mL (37 mmol) of phenyl lithium was dripped into the solution, and the mixture was stirred at room temperature for about 12 hours. After the reaction, the solution was washed with water. Then, the aqueous layer was extracted with ethyl acetate. The extracted solution and an organic layer were mixed to be dried with magnesium sulfate. After the drying, this mixture was suction-filtrated and the filtrate was concentrated, so that 2-bromo-9,10-diphenyl-9,10-dihydroanthracene-9,10-diol (about 7.6 g), which was an object, was obtained.
Reaction SMILES: [C:1]1([C:7]2[C:12]([O:13][CH2:14][C:15]3[N:16](COCC[Si](C)(C)C)[N:17]=[CH:18][N:19]=3)=[N:11][N:10]3[C:28]([C:31]4[CH:36]=[N:35][CH:34]=[CH:33][N:32]=4)=[N:29][N:30]=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:1]1([C:7]2[C:12]([O:13][CH2:14][C:15]3[N:19]=[CH:18][NH:17][N:16]=3)=[N:11][N:10]3[C:28]([C:31]4[CH:36]=[N:35][CH:34]=[CH:33][N:32]=4)=[N:29][N:30]=[C:9]3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCn1ncnc1COc1nn2c(-c3cnccn3)nnc2cc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(-c2cc3nnc(-c4cnccn4)n3nc2OCc2nc[nH]n2)cc1
Temperature: 65 °C

Procedure:
The product from Example 3 step b) (0.3 g) was suspended in ethanol (10 ml) with 2 N hydrochloric acid (21 ml) and heated at 65° C. for 5.5 h. Saturated sodium carbonate solution was added dropwise until a solid precipitated and this was collected by filtration and washed several times with water in the sinter funnel. The solid was recrystallised from methanol to give the required product (0.115 g, m.p. 255° C.). 1H NMR (360 MHz, DMSO) δ 5.64 (2H, s), 7.50 (3H, m), 7.62 (2H, m), 8.08 (1H, s), 8.16 (1H, s), 8.84 (1H, s), 8.90 (1H, s), 9.85 (1H, s); MS (ES+) m/e 372 [MH+]. Anal. Found C, 58.21; H, 3.53; N, 33.95. C18H13N9O requires C, 58.16; H, 3.26; N, 33.39%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10](Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH:30][C:31]([NH2:33])=[S:32])[CH:21]=[CH:22][C:23]=1[N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]1.C(N(CC)C(C)C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:33]=[C:31]([NH:30][C:20]3[CH:21]=[CH:22][C:23]([N:24]4[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]4)=[C:18]([O:17][CH3:16])[CH:19]=3)[S:32][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2nc3c(s2)CN(C(=O)OC(C)(C)C)CC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 1 step e) from 92 mg (0.33 mmol) 3-bromo-4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea and 43 mg (0.33 mmol) N,N-diisopropyl ethyl amine. The reaction was poured onto water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and the solvent was evaporated in vacuo. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 99 mg (75%) 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester as a light yellow foam. MS ISP (m/e): 442.3 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.32 (s, 1H), 7.64 (s, 1H), 7.47 (s, 1H), 7.31 (d, 1H), 7.25 (d, 1H), 7.02 (d, 1H), 4.43 (s, 2H), 3.78 (s, 3H), 3.64 (t, 2H), 2.63 (m, 2H), 2.14 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([NH:12][C:13]2[C:14]([C:26]([OH:28])=O)=[N:15][N:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[CH2:33]([N:35](CC)CC)[CH3:34].ClCCN>O1CCCC1.CN(C1C=CC=CN=1)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][C:10]([NH:12][C:13]2[C:14]([C:26]3[O:28][CH2:34][CH2:33][N:35]=3)=[N:15][N:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(CSc1ccc(Br)cc1)Nc1cn(CCc2ccccc2)nc1C(=O)O
Reactant: CCN(CC)CC
Agent: CN(C)c1ccccn1
Agent: NCCCl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: O=C(CSc1ccc(Br)cc1)Nc1cn(CCc2ccccc2)nc1C1=NCCO1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
380 mg (0.83 mM) of the compound obtained in Example 23 was dissolved in 1 ml of tetrahydrofuran to which 356 mg (1.65 mM) of di(2-pyridyl (0.1 equivalent)) carbonate and 10 mg (0.08 mM) of dimethylaminopyridine were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. Subsequently, 0.17 ml (1.20 mM) of triethylamine and 144 mg (1.20 mM) of 2-chloroethylamine were added thereto, and the resulting mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=2:1), to obtain 426 mg (99%) of the title compound.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].N([O-])=O.[Na+].S(=O)(=O)(O)N.C1(C)C=CC=CC=1.[ClH:35]>C(O)(=O)C.O>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([S:8][C:6]2[CH:5]=[CH:4][C:3]([N+:16]([O-:18])=[O:17])=[C:2]([Cl:35])[CH:7]=2)=[CH:10][CH:11]=1
Reactant: Cl
Reactant: Nc1cc(Sc2ccc(Br)cc2)ccc1[N+](=O)[O-]
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Sc2ccc(Br)cc2)cc1Cl

Procedure:
A solution of 2-amino-4-(4-bromophenylthio)nitrobenzene (Method 15) (2.25 g) in warm glacial acetic acid (13 ml) was poured onto ice (20 ml). Concentrated hydrochloric acid (3.95 ml) was added and the mixture was stirred and cooled to <5° C. A solution of sodium nitrite (0.524 g) in water (5 ml) was added over 7 minutes and the mixture was stirred for 2 hours at 0-5° C. Aqueous sulphamic acid solution (10% w/v) was added until a negative starch iodide test was observed. Meanwhile toluene was added to a solution of cuprous chloride (0.745 g) in water (1 ml) and concentrated hydrochloric acid (1.15 ml) and the mixture was cooled to <0° C. The first preparation (diazonium salt) was then added to the cold cuprous chloride mixture over 5 minutes and the resultant mixture was stirred at ambient temperature for 18 hours. The organic layer was separated and the aqueous layer was extracted with toluene (3×10 ml). The organic extracts were combined, washed with water and brine then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-15% ethyl acetate/hexane to give the title compound (0.644 g). MS: 343 (M+).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([NH:6][C:7]([NH:9][C:10]2[CH:31]=[CH:30][C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:28][CH3:29])=[C:22]([C:25]([OH:27])=[O:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:4][CH:3]=1.Cl.C(N=C=N[CH2:40][CH2:41][CH2:42]N(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]([NH:9][C:10]2[CH:31]=[CH:30][C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:28][CH3:29])=[C:22]([C:25]([O:27][CH:41]([CH3:42])[CH3:40])=[O:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:32][CH:33]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C(=O)OC(C)C
Yield: 15.8 %

Procedure:
After dissolving 4-(4-(((4-fluoroanilino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (84 mg, 0.19 mmol) in dimethylformamide (1 ml), there were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54 mg, 0.28 mmol), 1-hydroxy-1H-benzotriazole monohydrate (38 mg, 0.28 mmol), triethylamine (0.079 ml, 0.56 mmol) and 2-propanol (0.15 ml) while stirring on ice, and the mixture was stirred overnight at room temperature. The reaction solution was directly subjected to silica gel column chromatography (eluent—ethyl acetate), the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (15.0 mg, 0.03 mmol, 16%) as white crystals.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)=[C:7]([C:24]([O:26][CH3:27])=[O:25])[CH:6]=1)(=[O:3])[CH3:2].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[C:20]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=[CH:22][C:17]([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)[C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(OC(C)=O)c2ccc(OC)cc2c1-c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(OC(C)=O)c2ccc(OC)cc2c1-c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
In an oven-dried placed flask under a nitrogen atmosphere, the product of Step 3 (150 g), phenylboronic acid (45 g) and sodium carbonate (85 g) were stirred in 1,2-dimethoxyethane (750 mL) and deionized water (225 mL). A nitrogen purge line was inserted directly into the reaction mixture for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (10 g) was added and the reaction mixture heated to reflux for 4.5 hours. After cooling to room temperature, the reaction mixture was slowly poured into a beaker containing deionized water (1.5 L) and ice while stirring. Concentrated hydrochloric acid was added until the pH reached 3. A separatory funnel was used to perform chloroform extractions (3×600 mL). The recovered organic layers were combined, washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate and concentrated by rotary evaporation. The resulting residue was purified by column chromatography on silica gel (400 g) eluting with a solution of 30% ethyl acetate/70% hexanes. Fractions containing product were combined and concentrated by rotary evaporation yielding methyl 1-([1,1′-biphenyl]-4-yl)-4-acetoxy-7-methoxy-2-naphthoate (149 g).
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Br:17])=[O:6])[CH:2]=[CH2:3].[OH-].[Na+].Cl>>[CH2:1]([N:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Br:17])=[N:8][NH:7][C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCNC(=O)NNC(=O)c1ccc(Cl)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=CCn1c(-c2ccc(Cl)cc2Br)n[nH]c1=O

Procedure:
Of the compound from Example 163A, 11.3 g (33.98 mmol) were taken up in 61 ml (183.47 mmol) of 3M aqueous sodium hydroxide solution and heated under reflux for 36 h. The batch was then cooled, the fine precipitate was removed by filtration, and the filtrate was admixed, with ice cooling, with 28 ml (169.88 mmol) of half-concentrated hydrochloric acid to a pH of 10. The batch was filtered with suction and the product was dissolved out of the precipitate using methanol. The methanol was removed on a rotary evaporator. The residue was dried in an HV. This gave 9.78 g (69% of theory) of the title compound in 75% purity.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=[NH:16].[CH:17]1([N:23]=[C:24]=[N:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)(C)(C)C.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=[N:16][C:24]([NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[N:23][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: N=c1ccccn1CCc1ccccc1Br
Solvent: CCCCCC
Solvent: CC(C)(C)O
Product: Brc1ccccc1CCn1ccccc1=NC(=NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Yield: 12 %

Procedure:
A solution of 1-[2-(2-bromophenyl)ethyl]-2-iminopyridine (2.77 g, 0.01 mole) and dicyclohexylcarbodiimide (2.06 g, 0.01 mole) in 30 ml of t-butanol is heated at reflux for 21.5 hours under a nitrogen blanket. The solution is cooled to room temperature and diluted with 60 ml of hexane. The diluted solution is cooled and scratched in a dry ice bath to induce crystallization. The mixture is allowed to warm to room temperature and is filtered to give 0.58 g of material which sinters at 121°C and melts at 125°-129°C. The filtrate is concentrated in vacuo and the residual oil is cooled in an ice bath and scratched under 40 ml of hexane to give 1.32 g of material which sinters at 100°C and melts at 108°-110°C. The two batches of material are combined and dissolved in a boiling solution of 60 ml of cyclohexane and 60 ml hexane and filtered. The solution is cooled for several hours at -30°C, filtered and washed with cooled hexane to yield 1.33 g of the title compound, melting point 127°-129.5°C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]1([CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Mg]Cl>O1CCCC1>[OH:10][C:8]([C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:19])[CH3:9]
Reactant: Cc1ccccc1[Mg]Cl
Reactant: CC(=O)c1cccc(O)c1
Solvent: C1CCOC1
Product: Cc1ccccc1C(C)(O)c1cccc(O)c1

Procedure:
By using 3′-hydroxyacetophenone (200 mg) and a 1 M solution of o-tolylmagnesium chloride in tetrahydrofuran (4.4 ml) as starting materials, the title compound (119.3 mg) was obtained in the same manner as that of Reference Example 69.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[CH:5]=1)[CH3:2].CN(C)CCN(C)CCN(C)C.[Li]CCCC.[CH2:29]([O:31][C:32](=[O:35])[CH:33]=[O:34])[CH3:30]>C1COCC1.C1(C)C=CC=CC=1>[CH2:29]([O:31][C:32](=[O:35])[CH:33]([C:7]1[C:6]([F:11])=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][C:8]=1[F:10])[OH:34])[CH3:30]
Reactant: CCOc1cc(F)cc(F)c1
Reactant: CCOC(=O)C=O
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1c(F)cc(OCC)cc1F
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a solution of 1-ethoxy-3,5-difluoro-benzene (7.50 g, 47.42 mmol, 1.0 equiv) and N-(2-dimethylamino-ethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine (8.63 g, 10.40 mL, 49.80 mmol, 1.05 equiv) in anhydrous THF (125 mL) was added n-BuLi (31.13 mL, 49.80 mmol, 1.05 equiv; 1.6 M solution in hexane) within 1 h at −100° C. A solution of glyoxylic acid ethyl ester (9.68 g, 94.85 mmol, 2.0 equiv) in toluene (19 mL) was slowly added over a time period of 45 min and stirring continued for 2 h at −100° C. The cooling bath was removed and at −30° C. a solution of 2 M HCl (105 mL) was added. The solution was concentrated by evaporation under reduced pressure and the reaction mixture extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate to give 8.2 g (66%) of the title compound. 1H NMR (300 MHz, CDCl3): δ1.24 (t, J=7.5 Hz, 3H), 1.41 (t, J=7.5 Hz, 3H), 3.47 (d, J=6.0 Hz, 1H), 4.00 (q, J=7.5 Hz, 2H), 4.28 (q, J=7.5 Hz, 2H), 5.38 (d, J=6.0 Hz, 1H), 6.41-6.47 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:20])([CH3:19])[C@@H:11]([O:15][C:16](=[O:18])[CH3:17])[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:20])([CH3:19])[C@@H:11]([O:15][C:16](=[O:18])[CH3:17])[C:12]([O:14][CH2:38][C:34]1[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=1)=[O:13])(=[O:6])=[O:7]
Reactant: CC(=O)O[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl
Reactant: OCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H](C(=O)OCc1cccnc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 55.5 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-acetyloxy-3,3-dimethylbutanoic acid (16) (0.31 g, 0.94 mmol) dissolved in 10 mL of anhydrous dichloromethane (DCM) was reacted with 0.56 mL (1.1 mmol) of oxalyl chloride (2.0 M in DCM) in the presence of a catalytic amount of N,N-dimethylformamide (DMF). After completion of the reaction, a solution of 0.28 mL of 3-pyridylmethanol (0.26 g, 2.3 mmol) in dichloromethane was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=2:1) to provide 0.22 g (54% yield) of the title compound (38a) as a colorless oil. Rf=0.55 (EtOAc). 1H NMR (400 MHz, CDCl3):): δ=1.03 (s, 3H), 1.05 (s, 3H), 2.10 (s, 3H), 2.22-2.30 (m, 2H), 3.24-3.28 (m, 2H), 3.62-3.66 (m, 2H), 3.92 (d, J=9.2 Hz, 1H), 4.12 (d, J=9.6 Hz, 1H), 4.77 (s, 1H), 5.15-5.22 (m, 2H), 7.30-7.34 (m, 1H), 7.70-7.73 (m, 1H), 8.54-8.59 (m, 2H) ppm. MS (ESI) m/z 422.00 (M+H)+. The analytical data was consistent with proposed structure.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[N:4]1.[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][N:3]([CH2:2][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20])[N:4]=1
Reactant: FC(F)(F)c1ccn(CCl)n1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1ccc(C(F)(F)F)n1
Yield: 35.9 %

Procedure:
1.44 g of 1-(chloromethyl)-3-(trifluoromethyl)-1H-pyrazole and 1.30 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 16 ml of N,N-dimethylformamide. 2.21 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 recrystallized from hexane-ethyl acetate to obtain 0.87 g of {[3-(trifluoromethyl)-1H-pyrazole-1-yl]methyl}(3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (6), hereinafter) shown by below formula.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[IH:28]>C(O)C>[IH:28].[IH:28].[CH:21]1([CH2:20][N:19]2[C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[N:16]=[C:15]2[N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CC2CC2)CC1
Agent: I
Solvent: CCO
Product: c1ccc2c(c1)nc(N1CCCNCC1)n2CC1CC1

Procedure:
Hydrolyze 4-(1-cyclopropylmethyl-1H-benzoimidazol-2-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.70 g, 1.81 mmol) by refluxing an ethanol (10 mL) solution of the compound with hydroiodic acid (57%, 5 mL) for 1 hour as described in Example 111 to provide 1-cyclopropylmethyl-2-[1,4]diazepan-1-yl-1H-benzoimidazole dihydroiodide (0.85 g)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13](COCC[Si](C)(C)C)[CH:12]=2)=[O:10])[CH3:7])=[N:2]1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])[CH3:7])=[N:2]1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccon1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccon1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-isoxazol-3-yl-ethyl)-amide (113 mg, 0.211 mmol) was dissolved in dichloromethane (1.1 ml) and trifluoroacetic acid (0.65 ml, 8.4 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (1.1 ml) and ethylenediamine (0.86 ml, 12.7 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 46 mg (54%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-isoxazol-3-yl-ethyl)-amide as a light yellow powder. MS: (M+H)+=406; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.89 (br. s., 1H), 9.12 (s, 1H), 8.91 (d, J=1.5 Hz, 1H), 8.58 (d, J=8.7 Hz, 1H), 8.50 (s, 1H), 8.44 (dd, J=8.9, 5.5 Hz, 1H), 7.68 (dd, J=9.6, 2.1 Hz, 1H), 7.02 (td, J=9.1, 1.9 Hz, 1H), 6.68 (d, J=1.5 Hz, 1H), 5.53 (quin, J=7.2 Hz, 1H), 4.15 (s, 3H), 1.65 (d, J=6.8 Hz, 3H).
Reaction SMILES: C(OC([NH:8][C:9]1([CH2:20][NH:21][C:22]2([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:17]2[C:12](=[C:13]([F:19])[CH:14]=[C:15]([F:18])[CH:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:31]>CCOC(C)=O>[ClH:31].[NH2:8][C:9]1([CH2:20][NH:21][C:22]2([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:17]2[C:12](=[C:13]([F:19])[CH:14]=[C:15]([F:18])[CH:16]=2)[CH2:11][CH2:10]1
Reactant: COC(=O)C1(NCC2(NC(=O)OC(C)(C)C)CCc3c(F)cc(F)cc32)CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)C1(NCC2(N)CCc3c(F)cc(F)cc32)CCCC1
Reaction time: 0.75 h

Procedure:
A solution of methyl 1-[({1-[(tert-butoxycarbonyl)amino]-4,6-difluoro-2,3-dihydro-1H-inden-1-yl}methyl)amino]cyclopentanecarboxylate from Step G (753 mg, 1.77 mmol) in EtOAc (40 mL) at 0° C. was saturated with HCl (g). The reaction mixture was aged at 0° C. for 45 min then concentrated in vacuo to give the title compound. MS: m/z=325 (M+1).