Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]([CH3:14])[CH3:13])[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[CH2:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].C(=O)(O)[O-].[Na+].O1CCOCC1>O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[CH2:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[N:8][C:9]=4[NH2:11])[N:4]([CH:12]([CH3:14])[CH3:13])[N:3]=3)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)=[O:25]
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)c2c(N)ncnc21
Temperature: 120 °C

Procedure:
To a 25 mL pressure tube was charged 3-iodo-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (70.9 mg, 0.234 mmol), 1-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (93 mg, 0.234 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9.55 mg, 0.012 mmol), and sodium bicarbonate (39.3 mg, 0.468 mmol) followed by dioxane (4 mL), and water (1 mL). The reaction was heated at 120° C. for 40 min in microwave reactor. LCMS showed incomplete conversion. The reaction was heated in microwave at 120° C. for another 1 hour. The reaction was cooled to room temperature, the mixture was transferred into a 100 mL erlenmeyer flask, rinsed by EtOAc, with the water layer and black greasy solid stayed in tube (total 100 mL of EtOAc was added to the mixture). The EtOAc solution was evaporated to dryness, and re-dissolved in CH2Cl2/MeOH (8 mL/2 mL). It was purified by flash column 25-100% EtOAc/hexane, then 0-10% MeOH/EtOAc, Analogix Si SF15-24g, to afford a brown solid. The brown solid was further purified by recrystallization from CH3CN to give the title compound as a brown solid. LC/MS (ES) m/z=449.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49 (d, J=6.82 Hz, 6H), 3.27-3.33 (m, 2H), 3.97 (s, 2H), 4.31 (t, J=8.46 Hz, 2H), 5.06 (t, J=6.82 Hz, 1H), 7.18-7.21 (m, 1H), 7.22-7.27 (m, 2H), 7.44 (d, J=8.08 Hz, 1H), 7.54 (s, 1H), 8.15 (d, J=8.34 Hz, 1H), 8.23 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+].C(O)(=O)C>O.C(OCC)(=O)C>[N+:17](/[CH:20]=[CH:13]/[C:12]1[CH:15]=[CH:16][C:9]([CH2:8][O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:10][CH:11]=1)([O-:19])=[O:18]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(COc2ccccn2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(COc2ccccn2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 465.3 %

Procedure:
A mixture of 4-(pyridin-2-yloxymethyl)-benzaldehyde (26.8 g, 26 mmol) described in Manufacturing Example 1-2-2, nitromethane (34 mL, 630 mmol), ammonium acetate (19 g, 252 mmol), and acetic acid (90 mL) was stirred for 1 hour and 30 minutes at 100° C. Ethyl acetate and water were added to separate the reaction mixture. The organic layer was separated, washed with water (five times) and saturated sodium bicarbonate water (once), dried over anhydrous magnesium sulfate, and filtered. This filtrate was concentrated under a reduced pressure, so as to obtain a crude product of the titled compound (31 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[C:11]([NH:15][OH:16])([CH3:14])([CH3:13])[CH3:12]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[N+:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[O-:16])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(C=O)c1
Reactant: CC(C)(C)NO
Product: COc1cccc(C=[N+]([O-])C(C)(C)C)c1

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 3-methoxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 56.5% overall yield as a crystalline solid, m.p. 93.4° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:17]=[C:18]([P:22](Cl)(Cl)=[O:23])[CH:19]=[CH:20][CH:21]=1>>[CH3:15][C:16]1[CH:17]=[C:18]([P:22]2(=[O:23])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: Cc1cccc(P(=O)(Cl)Cl)c1
Product: Cc1cccc(P2(=O)c3ccccc3CN2c2ccccc2)c1
Yield: 26 %

Procedure:
The procedure of Example 38 was employed utilizing N-benzylaniline and 3-methylphenyl phosphonic dichloride to yield 1-(3-methylphenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (2.5 g, 26% yield) as a white solid having a melting point of 155°-156° C., and the following analysis:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[C:10](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:11]>ClCCl.C(OCC)(=O)C.CCCCCC>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([N:9]=[C:10]=[S:11])[N:6]=1
Reactant: Nc1ccc(Cl)c(Cl)n1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: S=C=Nc1ccc(Cl)c(Cl)n1
Temperature: 40 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
To 5,6-dichloropyridin-2-amine (0.47 g, 2.88 mmol) in dichloromethane (25 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.68 g, 2.94 mmol). The reaction was stirred at 40° C. for 3 hours, then cooled to room temperature. The crude material was purified by chromatography (Biotage: 25-100% ethyl acetate/hexane) 2,3-dichloro-6-isothiocyanatopyridine (0.48 g, 2.34 mmol, 81% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.26 (d, J=8.55 Hz, 1H), 7.47 (d, J=8.24 Hz, 1H). MS (LC/MS) R.T.=2.83; [M+H]+=204.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][CH2:10][C:11]1([CH2:19][C:20]#[C:21][C:22](=[O:24])[CH3:23])[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13][CH2:12]1.CCOC(C)=O.CCCCCC>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:8]=[C:9]1[CH2:10][C:11]3([CH2:12][O:13][C:14]([CH3:18])([CH3:17])[O:15][CH2:16]3)[CH2:19][C:20]1=[C:21]2[C:22](=[O:24])[CH3:23]
Reactant: CC(=O)C#CCC1(CC=Cc2ccccc2Cl)COC(C)(C)OC1
Solvent: Clc1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)c1c2c(cc3c(Cl)cccc13)CC1(COC(C)(C)OC1)C2
Yield: 85 %

Procedure:
To a 2-5 mL microwave irradiation vial equipped with a stir bar was added compound 4a (0.105 g, 0.30 mmol) in 1,2-dichlorobenzene (5 mL). The reaction was irradiated with stirring at 180° C. for 45 min until complete by TLC (AcOEt/n-hexane 3:7). The solution was directly added to a silica gel column, which was eluted with n-hexane to separate the 1,2-dichlorobenzene and then AcOEt/n-hexane 2:8 to collect the pure product. The title compound was isolated as a light yellow solid in an 85% yield (0.088 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]([OH:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.N1CCOCC1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:24]1([CH:23]2[NH:1][C:2]3[C:15]4[CH:14]([CH2:13][CH2:12][CH2:11][C:10]=4[N:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][CH:6]=[CH:7]4)[O:16]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: c1ccc(C2Nc3c4c(nc5ccccc35)CCCC4O2)cc1

Procedure:
9-Amino-1,2,3,4-tetrahydroacridine-1-ol (15.0 g) was refluxed in 1 liter of toluene that contained 12.28 g of morpholine and 9.29 g of benzaldehyde that had been freshly washed with K2CO3. The reaction mixture was refluxed overnight and allowed to cool. The crude product was then filtered off and purified by flash chromatography (20% isopropanol/ethyl acetate) to give 8.07 g of a 80:20 mixture of diastereomers after recrystallization from methanol/water. Recrystallization from dimethylformamide/water gave a 60:40 mixture of diastereomers, m.p. 225°-235° C.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13]C)=[O:12])[C:5]=2[CH:4]=[N:3][N:2]=1.[OH-].[Li+].C1COCC1>O>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH:4]=[N:3][N:2]=1
Reactant: COC(=O)c1cccc2cnncc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc2cnncc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 50 mL round bottom flask was added methyl phthalazine-5-carboxylate (1.0 g, 5 mmol), lithium hydroxide (0.3 g, 11 mmol), THF (4 mL) and water (4 mL). The resulting solution was stirred for 1 hour at room temperature. After removal of THF, the residue was acidified with 1N HCl until a precipitate was formed. The precipitate was filtered to provide phthalazine-5-carboxylic acid, used directly for next step. LCMS (M+H) 175.1 calc. for C9H7N2O2 175.0. 1H NMR (400 MHz, CDCl3): δ ppm 8.06 (d, J=8.41 Hz, 1H) 8.51-8.56 (d, 1H) 8.71 (d, 1H) 9.64 (s, 2H). Carboxylic acid H not detected.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][NH:12][C:13](=[O:33])[C:14]1[CH:19]=[C:18]([CH:20]=O)[C:17]([F:22])=[C:16]([F:23])[C:15]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=1[F:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:35][OH:36].C(=O)(O)[O-].[Na+].O>C(O)C>[Si:1]([O:8][CH2:9][CH2:10][O:11][NH:12][C:13](=[O:33])[C:14]1[CH:19]=[C:18]([CH:20]=[N:35][OH:36])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=1[F:32])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCONC(=O)c1cc(C=O)c(F)c(F)c1Nc1ccc(I)cc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCONC(=O)c1cc(C=NO)c(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
N-[2-(t-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-formyl-benzamide (10.5 mg, 17.7 μmol) prepared in Process B was dissolved in ethanol (1.5 ml). Hydroxylamine hydrochloride (40 mg, 0.57 mmol) and saturated aqueous solution of sodium bicarbonate (0.3 ml) were added thereto, and the mixture was stirred at room temperature for two hours. Water (5 ml) was added to the reaction solution, which was extracted with ethyl acetate (6 ml×3). The organic layers were combined, washed with saturated brine (8 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel-column chromatography (Presep (r) silica gel, 10 g, Wako Pure Chemical Industries, Ltd., n-hexane/ethyl acetate (4:1)) to give N-[2-(t-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-(hydroxyiminomethyl)-benzamide (5.0 mg, 46%).
Reaction SMILES: Br[C:2]([CH3:16])([CH3:15])[C:3]([NH:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:4].[Na+].[CH2:18]([S:21]([O-:23])=[O:22])[CH2:19][CH3:20].N1C=CC=CC=1.Cl>CN(C=O)C>[C:11]([C:9]1[O:8][N:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:16])([S:21]([CH2:18][CH2:19][CH3:20])(=[O:23])=[O:22])[CH3:15])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)on1
Reactant: CCCS(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)C(C)(C)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 50 °C
Reaction time: 18 h
Yield: 49.4 %

Procedure:
To a solution of 160 mg (0.55 mmol) of 2-bromo-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamide in DMF (3 mL) were added 87 mg (0.71 mmol) of 1-propanesulfinic acid sodium salt in one portion. Pyridine (48 μL) was added and the reaction was stirred at 50° C. for 18 h. The mixture was acidified with 1M aqueous HCl solution (1 mL) and extracted with diethyl ether (3×3 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (silica, eluent heptanes, 0-20% ethyl acetate) to afford 86 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(propane-1-sulfonyl)-propionamide.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[C:3]=1[F:13].C([Mg]Cl)(C)C.[Cl-].[Li+].C(O[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)(C)C>O1CCCC1.[NH4+].[Cl-].C(OCC)(=O)C>[CH3:32][C:27]1([CH3:33])[C:28]([CH3:31])([CH3:30])[O:29][B:25]([C:2]2[CH:12]=[CH:11][C:5]3[O:6][C:7]([F:10])([F:9])[O:8][C:4]=3[C:3]=2[F:13])[O:26]1
Reactant: Fc1c(Br)ccc2c1OC(F)(F)O2
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc3c(c2F)OC(F)(F)O3)OC1(C)C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
5-Bromo-2,2,4-trifluorobenzo[d][1,3]dioxole (4.0 g, 16 mmol) was dissolved in 20 mL dry tetrahydrofuran, cooled to −20° C. and treated with isopropylmagnesium chloride-lithium chloride complex (1.3 M in tetrahydrofuran; 13 mL, 17 mmol) in portions over 10 min. After stirring for 30 min at −20 to 0° C., 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.1 g, 17 mmol) was added, and stirring was continued for 1 h at 10-15° C. After treatment with saturated NH4Cl solution (10 mL), the mixture was diluted with ethyl acetate (50 mL). The organic phase was washed with saturated NaCl (15 mL), dried (Na2SO4) and evaporated to give the title compound as a brown solid (3.5 g, 72%): 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=26.5 Hz, 1H), 6.90 (dd, J=18.5, 4.5 Hz, 1H), 1.35 (s, 12H); 19F NMR (376 MHz, CDCl3) δ −49.70 (s), −126.00 (s); EIMS m/z 302.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[C:20]#[N:21])[N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH:4]=[N:3]1.[OH-:26].[Na+].OO>O.C(O)C.CCOC(C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[C:20]([NH2:21])=[O:26])[N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(Nc2ncc3cnn(Cc4ccccc4C#N)c3n2)cn1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cn1cc(Nc2ncc3cnn(Cc4ccccc4C(N)=O)c3n2)cn1
Temperature: 60 °C

Procedure:
A suspension of 2-((6-(1-methyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile (see Example 1) (40 mg, 0.24 mmol), sodium hydroxide (0.5 mL, 1M in H2O) and hydrogen peroxide (0.2 mL of a 33% solution in water) in ethanol (5 mL) was heated at 60° C. for 3 h. After cooling to rt the mixture was diluted with EtOAc and washed with water. The organic phase was collected, dried (MgSO4) and concentrated in vacuo to give the title product. 1H NMR (d6-DMSO) δ 9.95 (s, 1H), 8.99 (s, 1H), 8.10-8.16 (m, 3H), 7.66 (s, 1H), 7.60 (dd, 1H), 7.54 (s, 1H), 7.37-7.40 (m, 2H), 6.95 (br s, 1H), 5.85 (s, 2H), 3.88 (s, 3H); LC-MS method B, (ES+) 349.1, RT=6.46 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[N:15]1([CH2:21][CH:22]([N:26]2[CH:30]=[C:29]([C:31]3[C:32]4[CH:39]=[CH:38][N:37](COCC[Si](C)(C)C)[C:33]=4[N:34]=[CH:35][N:36]=3)[CH:28]=[N:27]2)[CH2:23][C:24]#[N:25])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(#N)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([N:18]3[CH2:17][CH2:16][N:15]([CH2:21][CH:22]([N:26]4[CH:30]=[C:29]([C:31]5[C:32]6[CH:39]=[CH:38][NH:37][C:33]=6[N:34]=[CH:35][N:36]=5)[CH:28]=[N:27]4)[CH2:23][C:24]#[N:25])[CH2:20][CH2:19]3)(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=S(=O)(Cl)c1ccc2[nH]ncc2c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#CCC(CN1CCN(S(=O)(=O)c2ccc3[nH]ncc3c2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 16 h

Procedure:
1H-Indazole-5-sulfonyl chloride (26 mg, 0.12 mmol; from Step 1) was added to a solution of 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (24 mg, 0.041 mmol; from Example 12, Step 2) and triethylamine (57 uL, 0.40 mmol) in acetonitrile (0.30 mL). The mixture was stirred for 16 hours, then solvent was removed in vacuo. The residue was stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, and stirred in a solution of methanol (1 mL) containing ethylenediamine (0.2 mL) for one hour. Purification via preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH afforded product as the free base (5 mg, 24%). 1H NMR (300 MHz, d6-dmso): δ 12.08 (br s, 1H), 8.70 (s, 1H), 8.60 (s, 1H), 8.31-8.30 (m, 2H), 8.26-8.23 (m, 1H), 7.72 (d, 1H), 7.61 (dd, 1H), 7.52 (d, 1H), 6.87 (d, 1H), 4.93-4.81 (m, 1H), 3.39-2.41 (m, 12H); LCMS (M+H)+: 517.1.
Reaction SMILES: ClCC([O:5][C@@H:6]1[CH2:10][CH2:9][C:8]([F:12])([F:11])[C@H:7]1[N:13]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](=[O:17])[CH2:15][Cl:16])=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH2:18]([N:13]([C@H:7]1[C@H:6]([OH:5])[CH2:10][CH2:9][C:8]1([F:11])[F:12])[C:14](=[O:17])[CH2:15][Cl:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(CCl)O[C@@H]1CCC(F)(F)[C@H]1N(Cc1ccccc1)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(CCl)N(Cc1ccccc1)[C@H]1[C@H](O)CCC1(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of trans-2-(N-benzyl-2-chloroacetamido)-3,3-difluorocyclopentyl 2-chloroacetate (480 mg, 1.26 mmol) in CH3OH (15 mL), K2CO3 (175 mg, 1.26 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was dissolved in CH2Cl2, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford trans-N-benzyl-2-chloro-N-(2,2-difluoro-5-hydroxycyclopentyl)acetamide. MS ESI calc'd. for C14H16ClF2NO2 [M+H]+ 304. found 304.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])([CH:15]=[CH2:16])[CH3:14])(=[O:11])[CH3:10].[C:23](Cl)(=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C1COCC1>[C:23]([CH2:10][C:9]([O:12][C:13]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])([CH:15]=[CH2:16])[CH3:14])=[O:11])(=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Reactant: CCCCCCCCC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)CCCCCCCC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide in the amount of 133.7 mL (2.0 M, 0.267 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is cooled -78° C. Linalyl acetate in the amount of 24.73 g (0.126 mol) is dissolved in THF (40 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min before being treated with a solution of nonanoyl chloride in the amount of 21.88 g (0.119 mol) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (60 mL). The mixture is poured into a separatory funnel containing ether (160 mL) and water (275 mL). The aqueous layer is extracted with ether (160 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 2% ethyl acetate dissolved in hexane) to give an oil. Purity of the product is determined by thin layer chromatography and the structure confirmed by 1H and 13C NMR.
Reaction SMILES: C([O:8][C:9]([CH2:11][N:12]1[CH2:25][CH2:24][CH2:23][N:22]2[CH2:26][CH2:27][CH2:28][N:15]([CH2:16][CH2:17][CH2:18][N:19]([CH2:29][C:30]([O:32]CC3C=CC=CC=3)=[O:31])[CH2:20][CH2:21]2)[CH2:14][CH2:13]1)=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:30]([CH2:29][N:19]1[CH2:18][CH2:17][CH2:16][N:15]2[CH2:28][CH2:27][CH2:26][N:22]([CH2:23][CH2:24][CH2:25][N:12]([CH2:11][C:9]([OH:10])=[O:8])[CH2:13][CH2:14]2)[CH2:21][CH2:20]1)([OH:32])=[O:31]
Reactant: O=C(CN1CCCN2CCCN(CCCN(CC(=O)OCc3ccccc3)CC2)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CN1CCCN2CCCN(CCCN(CC(=O)O)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.2 %

Procedure:
To a solution of 21 (3.19 g, 5.94 mmol) in ethanol (120 mL) was added 10% Pd/C (0.96 g). The resulting mixture was stirred under H2 (g) atmosphere at room temperature for 12 hours. The reaction mixture was filtered through a celite pad and washed with ethanol (2×20 mL). The combined filtrate was evaporated under vacuum to give an oily residue which was triturated with Et2O to provide white solid 16 (2.1 g, 99% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[CH:14][N:13]=2)=[O:10])=[CH:4][C:3]=1[CH3:25].C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][N:34]=[N:33][CH:32]=1)CCC>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.CN(C=O)C>[F:24][C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:31]4[CH:36]=[CH:35][N:34]=[N:33][CH:32]=4)=[C:3]([CH3:25])[CH:4]=3)=[N:13][CH:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: Cc1cc(CC(=O)Nc2ccc(-c3cccc(F)c3)cn2)cnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(CC(=O)Nc2ccc(-c3cccc(F)c3)cn2)cnc1-c1ccnnc1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
To a reaction tube containing 2-(6-chloro-5-methylpyridin-3-yl)-N-(5-(3-fluorophenyl)pyridin-2-yl)acetamide 74-5 (54 mg, 0.15 mmol), 4-(tributylstannyl) pyridazine (55 mg, 0.15 mmol) and Pd(PPh3)4 (16 mg, 0.015 mmol) under Argon was added DMF (0.8 mL). The mixture was stirred at 120° C. for 10 hours. The crude product was purified by reverse phase HPLC to give N-(5-(3-fluorophenyl)pyridin-2-yl)-2-(5-methyl-6-(pyridazin-4-yl)pyridin-3-yl)acetamide 74 as white solid. MS m/z 400.1 (M+1); 1H NMR 400 MHz (CDCl3) δ 9.42 (dd, 1H, J1=4.8 Hz, J2=1.2 Hz), 9.29 (dd, 1H, J1=10.4 Hz, J2=1.2 Hz), 8.56 (d, 1H, J=1.6 Hz), 8.46 (d, 1H, J=1.6 Hz), 8.28 (d, 1H, J=8.8 Hz), 7.90 (dd, 1H, J1=17.6 Hz, J2=2.4 Hz), 7.72 (d, 1H, J=1.6 Hz), 7.70 (dd, 1H, J1=10.8 Hz, J2=2.0 Hz), 7.44-7.39 (m, 1H), 7.32-7.30 (m, 1H), 7.25-7.21 (m, 1H), 7.09-7.04 (m, 1H), 3.82 (s, 2H), 2.44 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[NH:6][C:7](=O)[CH3:8])([O-])=O.[OH-].[K+].Br[CH2:17][CH2:18][CH:19](C)C.Cl>[Fe].O.C(O)C.CC(C)=O>[CH2:7]([NH:6][C:5]1[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=1[NH2:1])[CH2:8][CH:18]([CH3:19])[CH3:17]
Reactant: CC(=O)Nc1ccccc1[N+](=O)[O-]
Reactant: CC(C)CCBr
Agent: [Fe]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: CC(C)CCNc1ccccc1N

Procedure:
Under cooling, o-nitroacetoanilide (7.2 g, 40 mmol), acetone (28 ml) and powdered potassium hydroxide (2.2 g, 39 mmol) were mixed, to which 1-bromo-3-methylbutane (6.0 g, 40 mmol) was added. After the mixture was refluxed for 5 hours, the precipitate was removed by filtration. The filtrate was concentrated in vacuo and was extracted with chloroform. The occurred oily substance (9.8 g, 39 mmol) was refluxed for concd. hydrochloric acid (39 ml, 390 mmol) for 3 hours. The resultant was extracted with chloroform and concentrated in vacuo to give oily substance (6.4 g, 30.7 mmol), which was added to a mixture of powdered iron (17.1 g, 306 mmol), ethanol (24.5 ml), water (6.2 ml) and concd. hydrochloric acid (0.3 ml, 300 mmol). After the mixture was refluxed for 1.5 hours, the product was treated as in a usual process to obtain the title intermediate.