Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:20]=[C:19]([F:21])[C:18]3[O:17][C:16]4[C:11](=[CH:12][C:13]([C:22]5[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=5)=[CH:14][CH:15]=4)[C@:10]4([N:33]=[C:32]([NH2:34])[CH2:31][O:30][CH2:29]4)[C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.[H][H]>CCO.[Pd]>[F:21][C:19]1[C:18]2[O:17][C:16]3[C:11](=[CH:12][C:13]([C:22]4[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:14][CH:15]=3)[C@:10]3([N:33]=[C:32]([NH2:34])[CH2:31][O:30][CH2:29]3)[C:9]=2[CH:8]=[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:20]=1
Reactant: [H][H]
Reactant: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Agent: [Pd]
Solvent: CCO
Product: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(C3CCOCC3)cc12
Reaction time: 48 h
Yield: 71.9 %

Procedure:
In a microwave vial, (S)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (0.040 g, 0.087 mmol) and Pd/C (10%, 0.055 g, 0.052 mmol) were suspended in EtOH (1.5 mL). A balloon full of hydrogen (˜1 L) was emptied into the vessel, venting through a needle, and the vessel was sealed. After 2 days, the mixture was filtered through Celite, rinsing with 5% MeOH-DCM. The filtrate was concentrated, and the residue was purified by chromatography (7.5% MeOH/DCM) to afford 29 mg of (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(tetrahydro-2H-pyran-4-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine
Reaction SMILES: Cl.[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1)#[CH:3].[OH-].[Na+].[CH3:12][C:13]1[S:14][C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:16]([C:18](Cl)=[O:19])[N:17]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:18]([C:16]1[N:17]=[C:13]([CH3:12])[S:14][C:15]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:19])#[CH:3]
Reactant: Cc1nc(C(=O)Cl)c(-c2ccccc2)s1
Reactant: C#CC1CCCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C#CC1CCCCN1C(=O)c1nc(C)sc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a rapidly-stirred mixture of 2-ethynylpiperidine hydrochloride (330 mg, 2.27 mmol), toluene (5 mL), and 1N NaOH (4.7 mL), cooled at 0° C., was added a solution of 2-methyl-5-phenyl-1,3-thiazole-4-carbonyl chloride (539 mg, 2.27 mmol) in toluene (8 mL) dropwise over 20 mins. The mixture was stirred at 0° C. for 20 mins, then allowed to warm to ambient temperature. After 1 h, the solution was diluted with EtOAc and the layers separated. Brine was added to the aqueous layer and it was extracted with EtOAc. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with 0-50% EtOAc in hexanes to provide (2-ethynylpiperidin-1-yl)(2-methyl-5-phenyl-1,3-thiazol-4-yl)methanone as an orange foam. The compound gave a mass ion (ES+) of 311.2 for M+H+. 1H NMR δ (ppm) (CDCl3): 7.44-7.50 (2 H, m), 7.31-7.39 (3H, m), 5.78 (1H, s), 4.58 (1H, d, J=13.6 Hz), 3.33 (1H, d, J=11.2 Hz), 2.99-3.10 (1H, m), 2.73 (3H, s), 2.30 (1H, dd, J=22.0, 3.2 Hz), 1.55-2.04 (4H, m), 1.36-1.42 (1H, m), 1.20-1.28 (1H, m), 0.87-0.97 (1H, m).
Reaction SMILES: [I-].[F:2][C:3]([F:26])([F:25])[CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:37]([O:39][C:40](Cl)=[O:41])[CH3:38]>O1CCCC1>[CH2:37]([O:39][C:40](=[O:41])[C:5](=[P:6]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][C:3]([F:2])([F:25])[F:26])[CH3:38]
Reactant: FC(F)(F)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(F)(F)F)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -5 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A suspension of (3,3,3-trifluoropropyl)triphenylphosphonium iodide (194.5 g, 0.4 moles) in tetrahydrofuran (THF—anhydrous, 800 mL) was cooled to −5° C. in an ice/brine bath under nitrogen. Lithium bis(trimethylsilyl)amide (1.0 M in THF, 800 mL, 0.8 moles) was added to this suspension drop-wise over 2 hours. The temperature was maintained below 5° C. throughout the addition. The reaction mixture was then cooled to −75° C. in a dry ice/acetone bath. To this solution, ethylchloroformate (76.5 mL, 0.8 moles) was added drop-wise over 30 minutes. The reaction was stirred at −75° C. for an additional hour and allowed to warm to 25° C. overnight. The reaction mixture was poured onto brine (1.5 L) and stirred for 30 minutes. The layers were separated and the organic layer was washed with brine (200 mL). The aqueous layer was washed with dichloromethane (CH2Cl2−2×200 mL) and the combined organics were concentrated to a residue. This residue was redissolved in CH2Cl2 (500 mL), dried over MgSO4, and filtered through a plug of magnasol. The solvent was reduced to a minimum (˜100 mL) in vacuo and the product was precipitated with hexanes (250 mL). The solvent was completely removed in vacuo and the solid product was triturated with hexanes (500 mL). The solid was isolated by filtration and dried overnight in vacuo at 25° C. to give a beige powder 152.8 g, 89%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH2:12][CH2:13][NH2:14])[C:9]2[C:4](=[CH:5][C:6]([C:15]([F:18])([F:17])[F:16])=[CH:7][CH:8]=2)[N:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([C:2]2[N:11]=[C:10]([CH2:12][CH2:13][NH2:14])[C:9]3[C:4](=[CH:5][C:6]([C:15]([F:18])([F:17])[F:16])=[CH:7][CH:8]=3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: NCCc1nc(Cl)nc2cc(C(F)(F)F)ccc12
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: COCCOC
Solvent: O
Product: NCCc1nc(-c2ccc(C(F)(F)F)cc2)nc2cc(C(F)(F)F)ccc12

Procedure:
A solution of (2-chloro-7-trifluoromethyl-quinazolin-4-yl)ethylamine (276 mg, 1.00 mmol), p-trifluoromethylphenylboronic acid (285 mg, 1.50 mmol), tetrakis(triphenylphosphine)palladium (116 mg, 0.10 mmol) and sodium carbonate (0.21 g, 2.0 mmol) in dimethoxyethane/water (3 mL, 2:1) was heated at 80° C. for 16 h. The reaction mixture was then concentrated under reduced pressure, diluted with water (50 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography using cyclohexane:ethyl acetate (4:1) as solvent afforded [2-(4-trifluoromethylphenyl)-7-trifluoromethyl-quinazolin-4-yl]ethylamine. Yield=0.20 g, 52%; LC-MS: 3.2 min, 385 (M+); 1H NMR (DMSO-d6): δ 1.34 (t, 3 H, J=7.2 Hz), 3.68-3-78 (m, 2 H), 7.82 (dd, 1 H, J=8.6, 1.7 Hz), 7.88 (d, 2 H, J=8.1 Hz), 8.07 (s, 1 H), 8.50 (d, 1 H, J=8.6 Hz), 8.67 (d, 2 H, J=8.1 Hz), 8.70-8.76 (m, 1 H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[C:13]([CH3:18])=[N:14][CH:15]=[C:16]([CH3:17])[C:5]=12.Br[N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[C:13]([CH3:18])=[N:14][C:15]([N:20]3[C:24](=[O:25])[CH2:23][CH2:22][C:21]3=[O:26])=[C:16]([CH3:17])[C:5]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(C)n2c1c(CCCl)c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1c(N2C(=O)CCC2=O)nc(C)n2c1c(CCCl)c1ccccc12

Procedure:
To a refluxing solution of 5-(2-chloroethyl)-1,4-dimethylpyrimido[1,6-a]indole (13 g, described in Example 12), in chloroform (400 ml) is added N-bromosuccinimide (9.4 g) and anhydrous potassium carbonate (7 g). The reaction mixture is stirred and refluxed for 45 minutes. The resulting slurry is cooled and washed with water, and the organic phase is separated and evaporated. The residue is chromatographed on silica gel using chloroform and the eluates are evaporated. The residue (6.6 g) is crystallized from ethyl acetate to give 1-[5-(2-chloro)ethyl-1,4-dimethylpyrimido[1,6-a]indol-3-yl]pyrrolidine-2,5-dione; mp 232°-234° C.; ir (CHCl3) 1780 (weak) and 1705 cm-1 ; uv (MeOH) λmax 299, 310, and 324 nm; ε=6300, 10180, and 13170, respectively; nmr (CDCl3) δ2.31(s), 2.82(s), 2.91(s), 3.55(m), 7.0(m) and 8.0(m).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:19]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([I:19])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cn2nccc2-c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Ic1cnn(Cc2ccccc2)c1-c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 65E (270 mg) in N,N-dimethylformamide (5 mL) was added N-iodosuccinimide (259 mg). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with aqueous sodium bisulfite, water, and brine. The organic layers were combined, and evaporation of the solvent provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][CH2:12][C:11]2=[C:15]([CH:19]=[CH2:20])[N:16]([CH3:18])[N:17]=[C:10]12.N(C([O-])=O)=NC([O-])=O.[K+].[K+].C(O)(=O)C>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][CH2:12][C:11]2=[C:15]([CH2:19][CH3:20])[N:16]([CH3:18])[N:17]=[C:10]12
Reactant: C=Cc1c2c(nn1C)N(c1ccc(Cl)cc1Cl)CCC2
Agent: O=C([O-])N=NC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1c2c(nn1C)N(c1ccc(Cl)cc1Cl)CCC2
Reaction time: 3 h

Procedure:
To a solution of 7-(2,4-dichloro-phenyl)-2-methyl-3-vinyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine (3-7; 0.046 g, 0.15 mmol) in 2 mL of methanol was added dipotassium azodicarboxylate (0.174 g, 0.90 mmol) [prepared according to D. J. Pasto and R. J. Taylor, Organic Reactions 1991 40:91]. To the yellow suspension was added acetic acid (0.102 mL, 1.80 mmol) in 2 mL of methanol over 40 minutes. The reaction mixture was again treated with dipotassium azodicarboxylate (0.087 g, 0.45 mmol) and then acetic acid (0.051 mL, 0.90 mmol) in 1 mL of methanol over 20 nm. After 3 h at room temperature, the solvent was evaporated, the residue was treated with 10 mL of saturated sodium bicarbonate solution, extracted three times with 25 mL portions of dichloromethane, dried over magnesium sulfate, and evaporated to afford 41 mg of crude product. The crude product was purified by silica gel column chromatography eluting with 0 to 15% ethyl acetate/hexane which afforded 30 mg (65% theory) of 4-6 as a colorless oil: ms (M+H)+=310.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.C([O:14]/[CH:15]=[CH:16]/[C:17](OCC)=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].CC(O)=O>CN(C=O)C>[OH:14][C:15]1[CH:16]=[CH:17][N:3]2[N:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[N:1]=1
Reactant: CCO/C=C/C(=O)OCC
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2ccc(O)nc12
Temperature: 110 °C

Procedure:
Ethyl 3-amino-1H-pyrazole-4-carboxylate (25.0 g, 161 mmol) and (E)-ethyl 3-ethoxyacrylate (35.8 ml, 242 mmol) were mixed in DMF (537 mL). Cesium carbonate (78.7 g, 242 mmol) was added and the mixture heated to 110° C. for 15 hours. The reaction mixture was cooled to ambient temperature and acidified with HOAc to pH 4. The resultant precipitate was filtered and washed with water and EtOAc, yielding the title compound as a fluffy white solid. Additional material was obtained by an aqueous workup. The filtrate was concentrated to remove the DMF, was diluted in EtOAc (500 mL) and washed with H2O. The resultant precipitate in the EtOAc layer was filtered and washed with water and EtOAc to obtain additional product. The solids were pooled and dried in vacuum to afford ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (33.3 g, 100% yield) as a fluffy white solid. MS (apci) m/z=206.2 (M−H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](Cl)=[O:11].[OH:13][C:14]12[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[C:18]1([NH:27][C:28](=[O:30])[CH3:29])[C:17]1[CH:31]=[CH:32][C:33]([CH:35]([CH3:37])[CH3:36])=[CH:34][C:16]=1[O:15]2>C1COCC1>[C:10](=[O:11])([O:9][CH3:8])[O:15][C:16]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[CH:31][C:17]=1[C:18]1([NH:27][C:28](=[O:30])[CH3:29])[C:19](=[O:26])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]1=[O:13]
Reactant: COC(=O)Cl
Reactant: CC(=O)NC12C(=O)c3ccccc3C1(O)Oc1cc(C(C)C)ccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Oc1cc(C(C)C)ccc1C1(NC(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 17.1 %

Procedure:
Triethylamine (0.24 ml, 1.77 mmol) and methylchloroformate (0.11 ml, 1.48 mmol) were added to N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-9b-yl)acetamide (0.50 g, 1.48 mmol) in THF (5 ml). The reaction mixture was stirred at room temperature for 12 hrs, concentrated in a vacuum to remove solvent. The reaction mixture was extracted with water and methylene chloride, and purified through silica gel column chromatography (ethylacetate:hexane=1:2) to afford the title compound (0.10 g, 14%).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[OH-].[K+].[CH3:7][N:8]1[C:12](Cl)=[C:11]([Cl:14])[C:10]([Cl:15])=[N:9]1>C1OCCOCCOCCOCCOCCOC1.CS(C)=O.O>[CH3:7][N:8]1[C:12]([S:1][CH2:2][CH2:3][OH:4])=[C:11]([Cl:14])[C:10]([Cl:15])=[N:9]1
Reactant: Cn1nc(Cl)c(Cl)c1Cl
Reactant: OCCS
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cn1nc(Cl)c(Cl)c1SCCO
Temperature: 140 °C
Yield: 38.1 %

Procedure:
To a mixture of 26.5 g (0.34 moles) 2-mercaptoethanol, 19 g of 85% potassium hydroxide, and a few drops of 18-Crown-6 in 250 ml of DMSO, 60 g (0.32 moles) 1-methyl-3,4,5-trichloro pyrazole (product of Example 1 or 1A) were added in portions. When the addition was complete, the reaction mixture was heated to 140° C. for 1 day. The cooled reaction mixture was diluted with water and extracted with ether. The organic phase was washed four times with 200 ml water per time, dried and stripped. The crude product was chromatographed on a silica gel column. The product, 1-methyl-3,4-dichloro-5-(2-hydroxyethyl)thio pyrazole, was eluted from the column with ethyl acetate, yielding 27.7 g (37.7% yield) of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13](=[O:17])[NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:18]([C:20]1[NH:21][C:22]([CH3:30])=[CH:23][C:24]=1[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([C:12](=[CH:18][C:20]4[NH:21][C:22]([CH3:30])=[CH:23][C:24]=4[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:13](=[O:17])[NH:14]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1Cc2ccc(-c3ccc(F)cc3)cc2N1
Reactant: Cc1cc(CCC(=O)O)c(C=O)[nH]1
Product: Cc1cc(CCC(=O)O)c(C=C2C(=O)Nc3cc(-c4ccc(F)cc4)ccc32)[nH]1

Procedure:
6-(4-Fluorophenyl)-1,3-dihydroindol-2-one (70 mg, 0.31 mmol) was condensed with 3-(2-formyl-5-methyl-1H-pyrrol-3-yl)-propionic acid (56 mg) to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(COc2ccc(Br)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A mixture of 4-(tert-butyl)benzyl bromide (6.252 g, 27.522 mmol), 4-bromo-2-nitrophenol (5.0 g, 22.934 mmol), potassium carbonate (12.679 g, 91.736 mmol) and dimethylformamide (40 ml) was stirred at 50° for 3 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was washed with n-hexane to give the title compound (8.1 g, 97.0%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.OO.C([O-])([O-])=[O:16].[K+].[K+]>CS(C)=O>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([C:7]([NH2:8])=[O:16])=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 182.3 %

Procedure:
To a cold solution of 4-(trifluoromethyl)benzonitrile (0.500 g, 2.92 mmol) in DMSO (6.0 mL) was added H2O2 (50%) (5 mL) at 0° C., followed by portion-wise addition of K2CO3 (0.121 g, 0.87 mmol). The reaction mass was allowed to attain RT and stirred for 1 h. The reaction mass was quenched in ice water and extracted with DCM and concentrated to afford 0.300 g of product. 1H NMR (400 MHz, DMSO d6): δ 7.60 (br s, 1H), 7.82 (d, J=7.5 Hz, 2H), 8.05 (d, J=6.6 Hz, 2H), 8.17 (br s, 1H); MS (m/z): 190.11 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([Cl:11])[CH:9]=[CH:10][N:6]2[N:5]=[C:4]([CH:12]2[CH2:14][CH:13]2[C:15]#[N:16])[N:3]=1.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][N:6]2[C:7]=1[C:2]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[N:3][C:4]([CH:12]1[CH2:14][CH:13]1[C:15]#[N:16])=[N:5]2
Reactant: N#CC1CC1c1nc(Cl)c2c(Cl)ccn2n1
Reactant: NCc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#CC1CC1c1nc(NCc2ccccn2)c2c(Cl)ccn2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of (±)-2-(4,5-dichloropyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropanecarbonitrile (60.0 mg, 0.237 mmol) in THF (1 mL) was added 2-(aminomethyl)pyridine (0.0290 mL, 0.284 mmol) followed by DIPEA (0.124 mL, 0.711 mmol). The reaction mixture was stirred at RT for 1 hour. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts was washed with brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by CombiFlash (REDISEP®, silica gel, 4 g, 10% EtOAc/petroleum ether) to afford (±)-2-(5-chloro-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropanecarbonitrile (50.0 mg, 59.1%) as off-white solid. LCMS Condition B-41: retention time 0.67 min, [M+1]=325.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30-1.34 (m, 1H), 1.48-1.51 (m, 1H), 1.92-1.96 (m, 1H), 2.45-2.49 (m, 1H), 4.76 (t, J=4.8 Hz, 2H), 6.72 (d, J=2.8 Hz, 1H), 7.29 (q, J=4.8 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.68 (d, J=2.8 Hz, 1H), 7.77 (q, J=2.0 Hz, 1H), 8.14 (s, 1H), 8.53 (dd, J=1.2 Hz, J=3.2 Hz, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=O)C.[CH:14]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]=[C:28]3[C:34]([NH2:35])=[CH:33][N:32]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:29]3=[N:30][CH:31]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>C(Cl)Cl>[OH:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:35][C:34]1[C:28]2[C:29](=[N:30][CH:31]=[C:26]([C:23]3[CH:24]=[CH:25][C:20]([S:17]([CH:14]([CH3:16])[CH3:15])(=[O:19])=[O:18])=[CH:21][CH:22]=3)[N:27]=2)[N:32]([C:36]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=1)=[O:9]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(NC(=O)c2ccccc2O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 5 mL microwave vial was charged with 2-acetoxybenzoic acid (33.87 mg, 0.1880 mmol) To this was added a solution of 2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-amine (100 mg, 0.1790 mmol), TBTU in DCM (1 mL) followed by PS-NMM. The reaction was shaken for 3 hours at ambient temperature then filtered and the resin washed with DCM (1 mL). This crude mixture was taken onto the next step as is.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:20]=[CH:19][C:14]2[B:15]([OH:18])[O:16][CH2:17][C:13]=2[CH:12]=1)[C:5]#[N:6].[CH:21]1(I)[CH2:25][CH2:24][CH2:23][CH2:22]1.CN(C)C=O.[H-].[Na+]>O>[CH:21]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][C:11]2[CH:20]=[CH:19][C:14]3[B:15]([OH:18])[O:16][CH2:17][C:13]=3[CH:12]=2)[C:5]#[N:6])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: IC1CCCC1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
A solution of 3-hydroxy-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile (0.500 g, 1.87 mmol), cyclopentyl iodide (0.65 mL, 5.61 mmol), and N,N-dimethylformamide (30 mL) under a nitrogen balloon was cooled to 0° C. on an ice water bath. Sodium hydride (0.224 g, 5.61 mmol) was added and then the reaction was stirred for 5 minutes on the ice water bath. The reaction was then stirred at room temperature for 2 hours. More cyclopentyl iodide (0.22 mL, 1.87 mmol) was added and the reaction was cooled to 0° C. on an ice water bath. Sodium hydride was added (0.075 g, 1.87 mmol) and the reaction was stirred at 0° C. for 5 minutes. The reaction was then stirred at room temperature for another 2 hours. Water was added to quench excess sodium hydride and the reaction was then neutralized using 1 M HCl. Water was added and the solution was extracted using ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 3-(cyclopentyloxy)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile (0.396 g, 63% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (m, 2H), 1.38 (m, 2H), 1.50 (m, 2H), 1.73 (m, 2H), 4.86 (m, 2H), 6.84 (s, 1H), 6.87 (d, J=8.2 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.58 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 9.06 (s, 1H).