Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[O:8]1[CH:10]([CH2:11][CH3:12])[CH2:9]1.[CH3:13][Si](C)(C)N[Si](C)(C)C>Cl.[I-].[Zn+2].[I-]>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:9][C@@H:10]([OH:8])[CH:11]([CH3:12])[CH3:13])(=[O:7])[OH:6]
Reactant: NCCCP(O)O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCC1CO1
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Product: CC(C)[C@H](O)CP(=O)(O)CCCN
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml of hexamethyldisilazane is heated to reflux under an inert gas for 24 hours after which a clear solution results. The excess hexamethyldisilazane is removed by distillation at atmospheric pressure under a slight positive pressure of inert gas to afford a colourless oil. The oil is cooled to circa 40° and treated with 0.64 g of anhydrous zinc iodide and 25 ml of (S)-(+)-1,2-exoxy-3-methyl-butane. An exothermic reaction occurs and the epoxybutane refluxes. Reflux is continued for 6 hours after which time thin layer chromatography indicates the reaction to be complete. The reaction mixture is filtered and the filtrate evaporated to dryness in vacuo at 40°. The residue is dissolved in water and stirred at room temperature for 1 hour and the water removed in vacuo to give an oily solid. This is dissolved in some 2.0 M aqueous hydrochloric acid and washed with dichloromethane and ether. Removal of the water at 40° in vacuo affords a brown solid which is purified by ion-exchance chromatography on DOWEX® 50 W x 8 (14-40 mesh) to give 3-aminopropyl[2-(S)-hydroxy-3-methyl-butyl]phosphinic acid, m.p. 187-189°, [α]20D =-14.5°.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:15]/[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])/[C:12](O)=[O:13])[N:10]=1)=[O:4].P(Cl)(Cl)(Cl)(Cl)[Cl:23].CCCCCC>C(Cl)Cl>[ClH:1].[Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:15]/[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])/[C:12]([Cl:23])=[O:13])[N:10]=1)=[O:4]
Reactant: COC(=O)CO/N=C(\C(=O)O)c1csc(NC(=O)CCl)n1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: COC(=O)CO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Product: Cl
Temperature: 25 °C
Yield: 193.1 %

Procedure:
In 20 ml of methylene chloride is suspended 810 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxycarbonylmethyloxyiminoacetic acid and under ice-cooling and stirring 602 mg of phosphorus pentachloride is added. The mixture is stirred under ice-cooling for one hour and at room temperature for 30 minutes, after which 30 ml of hexane is added under ice-cooling. The resultant crystals are recovered by filtration and washed with hexane to give 910 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxycarbonylmethyloxyiminoacetyl chloride hydrochloride, m.p. 77°-80° C.
Reaction SMILES: [NH:1]1[C@H:10]2[C@H:5]([NH:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[C:22]([C:28]#[N:29])=[N:23][CH:24]=[C:25](Cl)[N:26]=1.[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33]>CN1C(=O)CCC1.CCOC(C)=O>[Cl:20][C:21]1[N:26]=[C:25]([N:1]2[CH2:2][CH2:3][CH2:4][C@@H:5]3[C@H:10]2[CH2:9][CH2:8][CH2:7][N:6]3[C:32]([N:31]([CH3:35])[CH3:30])=[O:33])[CH:24]=[N:23][C:22]=1[C:28]#[N:29]
Reactant: C1CN[C@@H]2CCCN[C@@H]2C1
Reactant: CN(C)C(=O)Cl
Reactant: N#Cc1ncc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)N1CCC[C@@H]2[C@H]1CCCN2c1cnc(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 18.7 %

Procedure:
Commercial (4aR,8aR)-decahydro-1,5-naphthyridine (423, 120 mg, 0.86 mmol) was dissolved in 2 mL NMP. To it were added DIEA (150 μL, 0.86 mmol) and then 3,5-dichloropyrazine-2-carbonitrile (150 mg, 0.86 mmol). The mixture was stirred at RT for 1.5 hour, and to it were added DIEA (450 μL, 2.58 mmol) and dimethylcarbamoyl chloride (240 μL, 2.58 mmol). The mixture was stirred at RT for overnight. It was diluted with 100 mL EtOAc, washed with water ×2, dried, concentrated in vacuo, and subjected to silica flash column using 0 to 3% MeOH in DCM to isolate (4aR,8aR)-5-(6-chloro-5-cyanopyrazin-2-yl)-N,N-dimethyloctahydro-1,5-naphthyridine-1(2H)-carboxamide (424, 56 mg, 19%). It was mixed with 4-(1-cyclopentylpiperidin-4-yl)aniline hydrochloride (304) (90 mg, 0.32 mmol), fine-powder cesium carbonate (210 mg, 0.64 mmol), Pd(OAc)2(11 mg, 0.05 mmol), BINAP (31 mg, 0.05 mmol) in 15 mL dioxane. The mixture was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 1.5 hour. The mixture was cooled to RT, diluted with 100 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 11% MeOH in DCM to isolate (4aR,8aR)-5-(5-cyano-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-N,N-dimethyloctahydro-1,5-naphthyridine-1(2H)-carboxamide (425). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were added one NaOH solid bead (about 100 mg), Et3N (60 μL) and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 30 min, diluted with 10 mL MeCN, stirred for 5 min, and concentrated, acidified with 0.3 mL TFA, and subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (4aR,8aR)-5-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-N,N-dimethyloctahydro-1,5-naphthyridine-1(2H)-carboxamide (426) as HCl salt (23 mg). LC-MS (ESI): m/z (M+1) 575.8. UV: λ=269, 276, 305, 335, 372 nm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[C:11]([O:15][C:16](OC([O-])=O)=[O:17])([CH3:14])([CH3:13])[CH3:12]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:16](=[O:17])[O:15][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: COc1ccccc1CN
Solvent: C1CCOC1
Product: COc1ccccc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
13.0 g of 2-methoxybenzylamine was dissolved in 80 ml of tetrahydrofuran, and tetrahydrofuran solution (20 ml) containing 16 g of t-butyldicarbonate was added, followed by stirring for 1 hour at room temperature. The solvent was evaporated, and the residue was dissolved in ethyl acetate and successively washed with 1 N hydrochloric acid and saturated brine. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated, to give 19.0 g of t-butyl N-(2-methoxybenzyl)carbamate.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH2:13]([B:15]([CH2:18][CH3:19])OC)[CH3:14]>CCOCC.O1CCCC1.C(OC(=O)C)C>[CH2:13]([B:15]([CH2:18][CH3:19])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:14]
Reactant: Brc1cccnc1
Reactant: CCB(CC)OC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCB(CC)c1cccnc1
Temperature: -40 °C
Reaction time: 0.08 h

Procedure:
n-Butyllithium (25.6 ml of a 2.5M solution in hexanes, 64 mmol) was added as a rapid stream of droplets to a solution of 3-bromopyridine (10.04 g, 64 mmol) in ether (200 ml) at -40° C., under nitrogen. The addition was carried out over 5 minutes and the reaction temperature was maintained below -40° C. throughout. The reaction was stirred at -40° C. for 20 minutes and then cooled to -70° C. whereupon diethylmethoxyborane in tetrahydrofuran (64.0 ml of a 1M solution, 64 mmol) was added as a rapid stream of droplets over 5 minutes. The reaction temperature was maintained below -63° C. throughout this addiition. The reaction was then allowed to warm slowly to room temperature whereupon it was diluted with ethylacetate and washed with brine. The organic layer was dried (Na2SO4) and the solvent removed under reduced pressure to give the crude product. This was purified by column chromatography on silica gel, eluting with dichloromethane to afford, after combination and evaporation of the appropriate fractions, the title compound as a yellow crystalline solid (7.3 g). Found: C,73.40; H,9.53; N,8.92; C9H14NB requires: C,73.52; H,9.60; N,9.53%.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[C:7]([I:13])=[C:6]([NH2:14])[CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[NH2:14][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[C:7]=1[I:13]
Reactant: CCOc1cc(C(=O)OC)cc(N)c1I
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCOc1cc(CO)cc(N)c1I
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To a solution of 3-amino-5-ethoxy-4-iodo-benzoic acid methyl ester (0.18 g, 0.56 mmol) in THF (5 mL) at 0° C. under Ar was slowly added diisobutylaluminium hydride (2.8 mL, 2.80 mmol, 1 M solution in THF) over a time period of 30 min, the cooling bath removed on completion of addition and the reaction allowed to reach rt. After 2 h, the excess hydride was quenched by cautious addition of a sat. solution of potassium sodium tartrate (50 mL). The solidified mixture was extracted with hot THF, the combined organic phases concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with hexane/ethyl acetate (2:1) providing 0.056 g (34%) of the title compound.
Reaction SMILES: I[C:2]1[CH:25]=[CH:24][C:5]2[NH:6][C:7]([N:9]3[CH2:14][CH2:13][C:12]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[O:23])[O:15]4)[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[CH3:26][N:27]1C(=O)CCC1>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N>[C:26]([C:2]1[CH:25]=[CH:24][C:5]2[NH:6][C:7]([N:9]3[CH2:14][CH2:13][C:12]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[O:23])[O:15]4)[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1)#[N:27]
Reactant: O=C1OC2(CCN(c3nc4cc(I)ccc4[nH]3)CC2)c2ccccc21
Reactant: CN1CCCC1=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]c(N3CCC4(CC3)OC(=O)c3ccccc34)nc2c1
Temperature: 130 °C

Procedure:
Add zinc cyanide (0.016 g, 0.13 mmol) and tetrakistriphenylphosphine palladium(0) (0.018 g, 0.02 mmol) to a solution of 1′-(5-iodo-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one (0.1 g, 0.22 mmol) in NMP (2 mL). Heat the reaction mixture at 130° C. for 19 hours. After cooling to ambient temperature, dilute the mixture with EtOAc (20 mL), and wash with water (20 mL) and saturated aqueous NaCl (20 mL). Dry the organic portion over Na2SO4, filter and concentrate. Purify by preparative TLC (80% EtOAc-hexane) to obtain 1′-(5-cyano-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a white solid.
Reaction SMILES: [H-].[Na+].C(OP([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[C:18]1([CH:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:25]2[CH2:28][C:27](=O)[CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[C:18]1([CH:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:25]2[CH2:28][C:27](=[C:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:26]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)=C1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Sodium hydride (60%, 202 mg, 5.06 mmol) was suspended in anhydrous THF (15 mL) and cooled in an ice bath. Ethyl 2-(diethoxyphosphoryl)propanoate (1.2 g, 5.06 mmol) was added dropwise under nitrogen and the mixture was stirred in an ice bath for 1 h. 1-(Diphenylmethyl)azetidin-3-one (1 g, 4.21 mmol) was added in portions as a solid and the mixture was stirred at room temperature for 1 h, then left to stir at room temperature overnight. Water (50 mL) was added and the mixture was extracted with DCM (3×50 mL). Brine was added, and the aqueous and organic layers were separated. The organic layer was dried over sodium sulfate and concentrated. The resulting crude yellow oil was purified by FCC, eluting with 0-50% EtOAc, to afford a clear oil which crystallised upon standing. The solids were sonicated with heptane and the remaining solid was collected by filtration. The filtrate was concentrated and sonicated with heptane to afford a second crop of solid. The filtrate was concentrated and the residue was sonicated with heptane to afford a further crop of solid material. The resultant solids were collected and combined to afford the title compound (892 mg, 66%) as a white solid. δH (250 MHz, CDCl3) 7.56-7.39 (m, 4H), 7.38-7.15 (m, 6H), 4.63-4.45 (m, 1H), 4.24-4.01 (m, 4H), 3.96-3.76 (m, 2H), 1.72-1.58 (m, 3H), 1.27-1.14 (m, 3H).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([NH2:8])=[CH:6][O:5][N:4]=1.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(Cl)CCl.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:40][C:41]2[CH:49]=[CH:48][C:47]([C:50]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[O:51])=[CH:46][C:42]=2[C:43](O)=[O:44])=[CH:35][CH:34]=1>CN(C)C=O>[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:40][C:41]2[CH:49]=[CH:48][C:47]([C:50]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[O:51])=[CH:46][C:42]=2[C:43]([NH:8][C:7]2[C:3]([CH3:2])=[N:4][O:5][CH:6]=2)=[O:44])=[CH:35][CH:34]=1
Reactant: Cc1nocc1N
Reactant: O=C(O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccc(F)cc1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1nocc1NC(=O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccc(F)cc1
Reaction time: 18 h

Procedure:
3-Methyl-4-isoxazolamine hydrochloride (44.9 mg, 0.33 mmol), 1-hydroxy-7-azabenzotriazole (41.7 mg, 0.31 mmol), diisopropylethylamine (0.10 ml, 0.56 mmol) and EDC (80 mg, 0.42 mmol) were added to a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-(4-morpholinylcarbonyl)benzoic acid (100 mg, 0.28 mmol) in N,N-dimethylformamide (5 ml). The solution was stirred for 18 hours before the solvent was removed in vacuo. The residue purified by column chromatography (silica gel; 10% 7M NH3 in methanol/dichloromethane). Trituration with methanol yielded the title compound as a white solid. 21 mg.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:13]([C:31]3[O:35][N:34]=[C:33]([CH3:36])[N:32]=3)=[CH:12][N:11]=2)=[N:7][CH:8]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[CH3:36][C:33]1[N:32]=[C:31]([C:13]2[C:14]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:15][C:10]([NH:9][C:6]3[N:7]=[CH:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=3)=[N:11][CH:12]=2)[O:35][N:34]=1
Reactant: Cc1noc(-c2cnc(Nc3cnc(C#N)cn3)cc2NCC2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1noc(-c2cnc(Nc3cnc(C#N)cn3)cc2NCC2CCNCC2)n1
Reaction time: 3 h
Yield: 56.8 %

Procedure:
To a solution of tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (9 mg, 0.018 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.15 mL) at r.t. After 3 hr, the solution was evaporated to dryness and purified by ion exchange on SCX-II acidic resin (500 mg) eluting with methanol, then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo to give the title compound as a yellow solid (4 mg, 56%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].[CH2:32](Br)[CH3:33]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[C:10]3[C:2]([NH:1][CH2:32][CH3:33])=[C:3]([C:26](=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29])[O:4][C:5]3=[N:6][C:7]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:12][CH:13]=1
Reactant: CCBr
Reactant: CC(C)(C)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Product: CCNc1c(C(=O)C(C)(C)C)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12

Procedure:
Using the procedure described in Example 39, the product of Example 17 was reacted with one equivalent of ethyl bromide to afford the title compound. HPLC/MS: 500.9 (M+1), 502.9 (M+3); Rt=4.08 min.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:15]1[CH:16]=[CH:17][N:18]=[CH:19][C:14]=1[C:12]1[S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[N:13]=1
Reactant: N#Cc1cnccn1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cnccn2)sc2ccccc12
Temperature: 120 °C
Yield: 22.4 %

Procedure:
A mixture of methyl thiosalicylate (1.68 g, 10.0 mmol), cyanopyrazine (1.06 g, 10.1 mmol), triethylamine (2.10 ml, 15.1 mmol) and toluene (10.0 ml) was refluxed at 120° C. for 8 hrs. The solvent was evaporated and the residue was recrystallized from dioxane-hexane to give the titled compound (0.54 g, 22%) as crystals.
Reaction SMILES: B(Br)(Br)Br.[I:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:7]=1.O.C(Cl)Cl.CO>C(Cl)Cl>[I:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:7]=1
Reactant: COc1ccc(I)cc1CC(C)C
Agent: BrB(Br)Br
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)Cc1cc(I)ccc1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
2.43 ml (2.43 mmol, 2.98 eq.) of a 1 M solution of BBr3 in CH2Cl2 was added to a solution of 176.0 mg (0.61 mmol) 4-Iodo-2-isobutylanisole in 25 ml dry CH2Cl2 at 0° C. via syringe. After that the solution was stirred for 3 h at 0° C. and then for 12 h at r.t. The reaction mixture was then added to water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (hexanes/EtOAc (3+1)) yielded 84.5 mg (0.31 mmol, 50.17%) 4-Iodo-2-isobutylphenol as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:5]([O:6][CH2:7][C:8]([N:10]([CH3:17])[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:9])=[C:4]([CH3:22])[C:3]=1[CH3:23].[CH2:24](Br)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[NH2:1][C:2]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:5]([O:6][CH2:7][C:8]([N:10]([CH3:17])[CH:11]2[CH2:16][CH2:15][N:14]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:13][CH2:12]2)=[O:9])=[C:4]([CH3:22])[C:3]=1[CH3:23]
Reactant: BrCCc1ccccc1
Reactant: Cc1c(C)c(OCC(=O)N(C)C2CCNCC2)c(C)c(C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C)c(OCC(=O)N(C)C2CCN(CCc3ccccc3)CC2)c(C)c(C)c1N
Temperature: 60 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
To a mixture solution of 99 mg of the compound (1) obtained in the Example 1 and 42.3 μl of phenethyl bromide in 2 ml of acetonitrile was added 65 μl of triethylamine, and the mixture was stirred for 5 hours at 60° C. After the reaction, saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saline, dried and concentrated under reduced pressure to give the residue. The obtained residue was purified by amine-coated silica gel (Fuji Silysia Chemical Ltd.) column chromatography (dichloromethane : ether =1:1) to give 86 mg (65%) of the above-mentioned compound (6).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:22]([O:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([O:9][CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=2)=[CH:27][CH:26]=1)[CH3:23]
Reactant: OCc1ccnc(F)c1
Reactant: CCOc1ccc(O)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOc1ccc(OCc2ccnc(F)c2)cc1
Reaction time: 0.5 h
Yield: 8.4 %

Procedure:
To a solution of (2-fluoropyridin-4-yl)methanol (5.06 g, 39.8 mmol) in DMF (100 mL) were added triethylamine (8.30 mL, 59.7 mmol) and methanesulfonyl chloride (3.08 mL, 39.8 mmol) under ice-cooling. After stirring for 30 min, 4-ethoxyphenol (5.77 g, 41.8 mmol) and potassium carbonate (5.50 g, 39.8 mmol) were added thereto and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added ethyl acetate, and the mixture was washed with water, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3). A mixture of the obtained product and 4-ethoxyphenol (starting material) was purified again by basic silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give the title compound (822 mg, yield 8.4%).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C([O:41][C:42]1[N:47]=[CH:46][C:45]([CH2:48][C:49](=O)[CH3:50])=[CH:44][CH:43]=1)C1C=CC=CC=1.S([O-])([O-])(=[O:54])=S.[Na+].[Na+]>C1COCC1>[Br:1][CH:49]([CH3:50])[C:48]([C:45]1[CH:46]=[N:47][C:42]([OH:41])=[CH:43][CH:44]=1)=[O:54]
Reactant: CC(=O)Cc1ccc(OCc2ccccc2)nc1
Reactant: [Br-]
Reactant: O=S([O-])([O-])=S
Agent: C[N+](C)(C)c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(Br)C(=O)c1ccc(O)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
Phenyltrimethylammonium tribromide (9.28 g) was added to a THF solution of the compound (5.67 g, 23.5 mmol) synthesized in the above (2), and stirred at 80° C. for 3 hours. Aqueous saturated sodium thiosulfate solution was added to the reaction liquid, and extracted three times with chloroform. After dried with magnesium sulfate, this was concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate and hexane to obtain the entitled compound (2.3 g, 42%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]([O:13][C:14]3[C:15]4[O:23][CH:22]=[C:21]([C:24]5[CH:25]=[N:26][N:27]([CH:29]6[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]6)[CH:28]=5)[C:16]=4[CH:17]=[N:18][C:19]=3[NH2:20])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[CH3:35][N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[CH3:35][N:36]1[CH:40]=[C:39]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@@H:11]([O:13][C:14]4[C:15]5[O:23][CH:22]=[C:21]([C:24]6[CH:25]=[N:26][N:27]([CH:29]7[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]7)[CH:28]=6)[C:16]=5[CH:17]=[N:18][C:19]=4[NH2:20])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:38]=[N:37]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@H](Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)coc12)c1nnc2ccc(Cl)nn12
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)coc12)c1nnc2ccc(-c3cnn(C)c3)nn12
Temperature: 100 °C

Procedure:
A suspension of 7-[(S)-1-(6-Chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethoxy]-3-(1-piperidin-4-yl-1H-pyrazol-4-yl)furo[3,2-c]pyridin-6-ylamine (0.289 mmol, 1 eq), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.507 mmol, 2.7 eq), Pd(PPh3)4 (66.8 mg, 0.0578 mmol, 20 mol %), and K2CO3 (200 mg, 1.45 mmol, 5.0 eq) in a 4:1 ratio of dioxane (4 mL) to H2O (1 mL) was evacuated and charged with nitrogen several times. The reaction sample was then heated in a microwave reactor at 100° C. for 0.5 h. CH2Cl2 and H2O were added and a standard aqueous workup was performed. The crude material was purified by chromatography on an SCX column and HPLC giving the title compound as a diformate salt. 1H NMR (400 MHz, CD3OD): δ=2.15 (d, J=6.8 Hz, 3H), 2.25-2.40 (m, 4H), 3.18-3.28 (ddd, J=12.9, 11.6, 3.8 Hz, 2H), 3.59 (dt, J=13.3, 3.3 Hz, 2H), 3.85 (s, 3H), 4.60 (dddd, J=10.0, 4.9, 4.8 Hz, 1H), 6.34 (q, J=6.6 Hz, 1H), 7.62 (d, J=9.6 Hz, 1H), 7.81 (s, 1H), 7.84 (s, 2H), 8.03 (s, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.13 (d, J=9.6 Hz, 1H), 8.34 (br s, 4H). MS (ES+): m/z 526.17 (20) [MH+]. HPLC: tR=1.94 min (ZQ3, polar—5 min).