Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:31]=[O:32].O>O1CCCC1>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:10]([F:16])=[C:11]([C:12]([F:15])=[CH:13][CH:14]=1)[CH:31]=[O:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To dibenzyl-(2,4-difluoro-phenyl)-amine (52, 4.30 g, 13.9 mmol) in tetrahydrofuran (60 mL), under an atmosphere of nitrogen, cooled in a −78° C. acetone/dry ice bath, was added n-butyllithium (2.50 M in hexane, 6.1 mL, 15.3 mmol) slowly. The reaction was stirred for 1 hour, N,N-dimethylformamide (1.2 mL, 15.3 mmol) was added and the reaction was allowed to warm to room temperature for 1 hour. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to provide the compound (53, 4.0 g, 85%). MS (ESI) [M+H+]+=337.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:15]Cl)[CH:14]=1.[H-].[Na+]>>[Br:8][C:9]1[CH:14]=[C:13]([CH2:15][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:7])[CH:12]=[N:11][CH:10]=1
Reactant: O=C1CCCCN1
Reactant: ClCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Product: O=C1CCCCN1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates A-12 [B], piperidin-2-one was reacted with 3-bromo-5-chloromethyl-pyridine (intermediate A-12 [A]) in the presence of NaH to give the title compound as a colorless oil. MS: 269.2, 271.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:3]=[CH:4][C:5]=1[CH3:15])=[O:14]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(Br)cc1NC(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: Cc1ccc(C#C[Si](C)(C)C)cc1NC(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h
Yield: 67.6 %

Procedure:
To a solution of N-(5-bromo-2-methylphenyl)-2,2,2-trifluoroacetamide (15 g, 54 mmol) in THF (300 mL) was added Pd(PPh3)2Cl2 (3.79 g, 5.4 mmol), CuI (513 mg, 2.7 mmol) and TEA (23 mL, 162 mmol). The solution was heated to 60° C. A solution of trimethylsilylacetylene (11.5 mL, 81 mmol) in THF (200 mL) was added dropwise through an addition funnel over about 60 min. After 16 h, the reaction was concentrated onto silica gel and purified by column chromatography to give the desired product (10.92 g, 67%). 1H NMR (400 MHz, d6-DMSO) δ 10.97 (s, 1H), 7.35-7.30 (m, 3H), 2.18 (S, 3H), 0.21 (s, 9H) ppm.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.[C:18]1([CH2:24]O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[CH2:24]([O:17][C:15]([C@H:12]1[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]1)=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2 g (8.2 mmol) trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (commercially available), 0.978 g (9.0 mmol) phenyl-methanol (commercially available), 3.16 g (9.8 mmol) O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and 1.24 g (12.3 mmol) NEt3 in 10 mL DMF was stirred at room temperature for 1 h. The mixture was evaporated to dryness and extracted with DCM and Na2CO3 aq. The combined organic phases were dried with MgSO4 and evaporated. The residue was treated with 100 mL 4N HCl in dioxane at room temperature for 4 h. The mixture was evaporated to dryness to yield trans-4-amino-cyclohexanecarboxylic acid benzyl ester (MS (m/e): 360.4 (MH+)) which was used without further purification. 150 mL DCM was added, 2.95 g (14 mmol) 4-cyano-benzenesulfonyl chloride (commercially available) and 6.17 g (61 mmol) NEt3 and the mixture was stirred at room temperature for 16 h. The mixture was extracted with DCM and 1N HCl aq. and the combined organic phases were evaporated. The residue was recrystallized from methanol to yield 1.9 g (58%) of the title compound. MS (m/e): 397.0 (MH+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][C:8]=1[O:16][CH3:17])(=O)=O.[Br-].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Zn+]>C1COCC1.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>[CH3:17][O:16][C:8]1[CH:9]=[C:10]([C:13](=[O:15])[CH3:14])[CH:11]=[CH:12][C:7]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=1
Reactant: [Zn+]c1ccccn1
Reactant: COc1cc(C(C)=O)ccc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc(C(C)=O)ccc1-c1ccccn1
Temperature: 25 °C

Procedure:
A solution of 4-acetyl-2-methoxyphenyl trifluoromethanesulfonate (5.8 g, 19.5 mmol) in THF (100 mL) was degassed by bubbling argon through the solution for 15 min, then treated with 2-pyridylzinc bromide (39 mL of 0.5M in THF, 19.5 mmol) and Pd(PPh3)4 (1.1 g, 0.97 mmol). The resulting reaction mixture was degassed again and heated to reflux for 12 h under an atmosphere of argon. The reaction mixture was cooled to rt, concentrated and purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:9 to 2:3) to afford 1-(3-methoxy-4-pyridin-2-ylphenyl)ethanone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]2[CH2:23]OS(C)(=O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[SH:29][CH2:30][CH2:31][OH:32].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]2[CH2:23][S:29][CH2:30][CH2:31][OH:32])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Reactant: OCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)(c1ccc(Cl)cc1)C1c2c(F)ccc(F)c2OCC1CSCCO
Temperature: 77 °C

Procedure:
Methanesulfonic acid 4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman-3-ylmethyl ester described in Example 10, Step 6 (230 mg, 0.51 mmol) was dissolved in 7.0 mL of methanol and treated with 992 mg (12.7 mmol) of 2-mercaptoethanol and 2.0 mL of 1 M aqueous NaOH. The mixture was heated with a reflux condenser at 77° C. overnight. The mixture was cooled and partitioned between water and DCM. Aqueous phase was extracted with DCM. Combined organic phase was dried over MgSO4 and concentrated. The product was purified by column chromatography using 20% of EtOAc in hexanes as the eluent (140 mg, 63%)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:13]=2[F:22])[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH3:23][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:23][O:9][C:8]([C:5]1[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si:18]([CH3:19])([CH3:21])[CH3:20])=[CH:14][C:13]=2[F:22])=[N:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C[Si](C)(C)c1ccc(Nc2nc(Cl)cnc2C(=O)O)c(F)c1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc(Cl)nc1Nc1ccc([Si](C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a solution of 5-chloro-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-pyrazine-2-carboxylic acid (2.95 g, 8.68 mmol) in methanol (50 mL) and toluene (100 mL) at 0° C. under N2 was added a solution of 2M trimethylsilyldiazomethane in hexanes (9.55 mL, 19.0 mmol, 2.2 eq.), and the reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 50% ethyl acetate in hexane) to give the desired compound as a yellow solid (2.18 g, 71.1%). 1H NMR (CDCl3, 400 MHz) δ ppm 10.54 (s, 1H), 8.36 (t, J=7.86 Hz, 1H), 8.06 (s, 1H), 7.34-7.26 (m, 2H), 4.05 (s, 3H), 0.28 (s, 9H); LCMS (method D1) RT=1.38 min, [M+H]+=354.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][CH3:3].[CH2:8]1[O:10][CH2:9]1.C(O[Al]([O:20][CH:21]([CH3:23])C)OC(C)C)(C)C>C(N(CC)CC)C>[C:1]([O:5][CH2:6][CH2:7][O:10][CH2:9][CH3:8])(=[O:4])[CH2:2][CH3:3].[C:1]([O:5][CH2:6][CH2:7][O:10][CH2:9][CH2:8][O:20][CH2:21][CH3:23])(=[O:4])[CH2:2][CH3:3]
Reactant: CC(C)O[Al](OC(C)C)OC(C)C
Reactant: C1CO1
Reactant: CCOC(=O)CC
Solvent: CCN(CC)CC
Product: CCOCCOC(=O)CC
Product: CCOCCOCCOC(=O)CC
Yield: 9.4 %
Yield: 35.9 %

Procedure:
Example 32 was repeated except that 170 g of ethyl propionate and 18.3 g of ethylene oxide were reacted using catalyst of 1.6 g of triisopropoxy aluminum and 0.51 g of triethylamine at 160° C. for 5 hours. As the result, 20.6 g of ethylene glycol ethylether propionate (yield was 35.9 % to ethylene oxide), 3.5 g of diethyleneglycol ethylether propionate (yield was 9.4 % to ethylene oxide) and 7.9 g of polyethyleneglycol ethylether propionate were obtained.
Reaction SMILES: C(O[C:9](=[O:33])[NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:17][N:18]1[CH2:23][C:22](=[O:24])[NH:21][C@@H:20]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:19]1)C1C=CC=CC=1.C1(OC(=O)[NH:42][C:43]2[S:44][C:45]([C:49](=[O:51])[CH3:50])=[C:46]([CH3:48])[N:47]=2)C=CC=CC=1>C(C#N)(C)=O>[C:49]([C:45]1[S:44][C:43]([NH:42][C:9]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:17][N:18]2[CH2:23][C:22](=[O:24])[NH:21][C@@H:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:19]2)=[O:33])=[N:47][C:46]=1[CH3:48])(=[O:51])[CH3:50]
Reactant: CC(=O)c1sc(NC(=O)Oc2ccccc2)nc1C
Reactant: O=C1CN(C[C@@H]2CCCC[C@H]2NC(=O)OCc2ccccc2)C[C@H](Cc2ccc(F)cc2)N1
Agent: CC(=O)C#N
Product: CC(=O)c1sc(NC(=O)N[C@@H]2CCCC[C@H]2CN2CC(=O)N[C@@H](Cc3ccc(F)cc3)C2)nc1C
Temperature: 25 °C
Yield: 43.3 %

Procedure:
A solution of amine from EXAMPLE 3 (75 mg, 0.23 mmol) and carbamate from EXAMPLE 6 (65 mg, 0.23 mmol) in AcCN (4 ml) was warm to 45° C. for 30 minutes. A solid form and the mixture cooled to room temperature and the solid filtered off to give 50 mg of the desired urea. 1H NMR (300 MHz, CDCl3) δ12.21 (bs, 1H), 8.56 (bs, 1H), 6.99-6.90 (m, 4H), 5.49 (bd, J=8 Hz, 1H), 3.52 (m, 1H), 3.40 (m, 1H), 3.24 (d, J=17 Hz, 1H), 2.96 (d, J=17 Hz, 1H), 2.88 (dd, J=5 Hz, J=14 Hz, 1H), 2.73 (dd, J=9 Hz, J=14 Hz, 1H), 2.54 (m, 2H), 2.47 (s, 6H), 2.20-2.06 (m, 3H), 1.90-1.76 (m, 4H), 1.43-1.00 (m, 4H). ESI MS: (M+H)+=502.2; HRMS: (M+H)+=502.2287.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].[NH3:14]>CO.O>[CH3:1][N:2]([CH3:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([NH2:14])=[O:6]
Reactant: COC(=O)c1ccccc1N(C)C
Reactant: N
Solvent: CO
Solvent: O
Product: CN(C)c1ccccc1C(N)=O
Temperature: 25 °C
Yield: 5 %

Procedure:
A solution of methyl 2-dimethylamino-benzoate (1.79 g, 10 mmol) in 2 M ammonia in methanol (20 mL) was heated at 80° C. in a sealed reaction vessel for 3 d. Upon cooling to room temperature, it was diluted with water. The product was extracted with diethyl ether. The ethereal extracts were washed with brine and dried over anhydrous magnesium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 20% ethyl acetate in hexanes yielded 2-dimethylamino-benzamide (85 m g, 5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:16]O)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:16][N:29]4[C:25](=[O:35])[C:26]5=[CH:34][CH:33]=[CH:32][CH:31]=[C:27]5[C:28]4=[O:30])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:24]=1
Reactant: OCCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1CCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 2, 8-bromo-1-(2-hydroxyethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dioxane is treated with phthalimide, triphenylphosphine and subsequently with diethyl azodicarboxylate to give 8-bromo-1-(2-phthalimidoethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C[Mg]Br.O1CCC[CH2:5]1.[C:9]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH:19]=[O:20])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(OCC)C>[C:9]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH:19]([OH:20])[CH3:5])[CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccnc(C=O)c1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1cc(C(C)(C)C)ccn1
Temperature: 25 °C
Yield: 93 %

Procedure:
Methylmagnesium bromide (9.7 ml, 29 mmole) is added to 20 ml dry tetrahydrofuran in an oven dried 100 ml two neck round bottom flask under nitrogen at 0° C. The solution is treated with 4-t-Butyl-2-pyridine-carboxaldehyde (3.8 g, 23.3 mmole) in 2×5 ml diethyl ether followed by 10 ml diethyl ether. The reaction is warmed to room temperature and then to reflux for 1 h. The mixture is cooled to 0° C., is quenched with 1×20 ml 10% hydrochloric acid, and the pH is adjusted to 9 with 2 N sodium hydroxide. The layers are separated, the aqueous layer is extracted with 4×25 ml dichloromethane, and the combined organics are dried over potassium carbonate. The dried organics are concentrated in vacuo to give 3.9 g (93%) of 4-t-Butyl-2-(1-hydroxyethyl)-pyridine as a tan solid. Analytical material is obtained via recrystallization from hexane.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([N:15]2[CH2:26][CH2:25][C:18]3([C:22](=[O:23])[N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:17][CH2:16]2)=[CH:13][C:12]([C:27]#[N:28])=[CH:11][C:10]=1[NH:29][C:30]1[N:35]=[C:34]([N:36]([CH:46]2[CH2:48][CH2:47]2)CC2C=CC(OC)=CC=2)[C:33]2=[N:49][CH:50]=[C:51]([C:52]#[N:53])[N:32]2[N:31]=1.C1(OC)C=CC=CC=1>ClCCCl>[Cl:8][C:9]1[C:14]([N:15]2[CH2:16][CH2:17][C:18]3([C:22](=[O:23])[N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:25][CH2:26]2)=[CH:13][C:12]([C:27]#[N:28])=[CH:11][C:10]=1[NH:29][C:30]1[N:35]=[C:34]([NH:36][CH:46]2[CH2:47][CH2:48]2)[C:33]2=[N:49][CH:50]=[C:51]([C:52]#[N:53])[N:32]2[N:31]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC5(CCN(C)C5=O)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: COc1ccccc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC2(CCN(c3cc(C#N)cc(Nc4nc(NC5CC5)c5ncc(C#N)n5n4)c3Cl)CC2)C1=O
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 43.1 %

Procedure:
TFA (0.417 mL, 5.41 mmol) was added to a solution of 2-((2-chloro-5-cyano-3-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (50 mg, 0.078 mmol) and anisole (0.034 mL, 0.314 mmol) in DCE (1 mL) and the reaction mixture was heated at 60° C. for 1 hours. The solvent was removed in vacuo and the material azeotroped with toluene 3× to remove the excess TFA. 10 ml of 2N NH3 in MeOH was added, and the solution was stirred for 20 min. The solvent was removed in vacuo and the material was purified by prep-HPLC to give 2-((2-chloro-5-cyano-3-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (17.4 mg).
Reaction SMILES: O1CCCC1.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[N:22][OH:23])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]([C:27]1[C:28]([NH2:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[O:23][N:22]=2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Reactant: C#Cc1ccc(C)nc1N
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)cc3)no2)c(N)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 46.7 %

Procedure:
To a tetrahydrofuran (2 mL) solution of 4-benzyloxy-phenyl-acetohydroximoyl chloride (63 mg, 0.23 mmol) described in Manufacturing Example 1-1-3 and 3-ethynyl-6-methyl-pyridin-2-ylamine (20 mg, 0.15 mmol) described in Manufacturing Example 170-1-5 was added triethylamine (42 μL, 0.30 mmol) at room temperature, which was stirred for 4 hours at 50° C. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1), and then further purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (26 mg, 34%) as a trifluoroacetic acid salt.
Reaction SMILES: [F:1][C:2]1([F:22])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[N:19]4[C:14]([CH:15]=[N:16][C:17](SC)=[N:18]4)=[CH:13][CH:12]=3)[C:4]=2[O:3]1.OO.[S:25]([O-:29])([O-])(=[O:27])=S.[Na+].[Na+].[CH3:32]O>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[F:22][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[N:19]4[C:14]([CH:15]=[N:16][C:17]([S:25]([CH3:32])(=[O:29])=[O:27])=[N:18]4)=[CH:13][CH:12]=3)[C:4]=2[O:3]1
Reactant: CO
Reactant: CSc1ncc2ccc(-c3cccc4c3OC(F)(F)O4)n2n1
Reactant: O=S([O-])([O-])=S
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ncc2ccc(-c3cccc4c3OC(F)(F)O4)n2n1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
7-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.435 g, 1.35 mmol) and Sodium Tungstate Dihydrate (59 mg, 0.18 mmol) were suspended in Methanol (15.0 mL), then 50% Hydrogen Peroxide (0.350 mL, 6.16 mmol) was added. The mixture was then heated at 55° C. overnight. A solution of sodium thiosulfate was added, stirred 10 min, then cooled to rt. The product was collected by filtration, washing the yellow solids with 1:1 MeOH:H2O (10 mL). After drying on the Buchner funnel, 7-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-2-methanesulfonyl-pyrrolo[2,1-f][1,2,4]triazine (0.410 g; Yield=85.7%). LCMS (HPLC): 1.15 min, m/z=354 (M+H); 1H-NMR (DMSO-d6): 9.51 (s, 1H), 8.16 (d, 1H, J=8.1 Hz), 7.73 (d, 1H, J=4.8 Hz), 7.56 (d, 1H, J=7.7 Hz), 7.49 (d, 1H, J=4.8 Hz), 7.45 (m, 1H), 3.45 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[CH2:7]([N:11]1[N:12]([CH3:34])[C:13]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:14]/[C:15]/1=[N:16]\[C:17](=[O:29])[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1F)[CH2:8][CH2:9][CH3:10].CC[O:37]C(C)=O.CO>C1COCC1.CCN(CC)CC>[CH2:7]([N:11]1[N:12]([CH3:34])[C:13]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:14]/[C:15]/1=[N:16]\[C:17](=[O:29])[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[O:37][CH2:1][C:2]([OH:4])([CH3:5])[CH3:3])[CH2:8][CH2:9][CH3:10]
Reactant: CCOC(C)=O
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)cc(C(C)(C)C)n1C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OCC(C)(C)O)cc(C(C)(C)C)n1C
Reaction time: 0.75 h
Yield: 57 %

Procedure:
To a solution of Example 81D (7.6 g, 84 mmol) in THF (300 mL) at 0° C. was added potassium tert-butoxide (18.9 g, 168 mmol). The ice bath was removed and the mixture was stirred for 45 min then a solution of Example 81C (22.4 g, 56.1 mmol) in THF (100 mL) was added. The mixture was stirred for 2 hours at ambient temperature then partitioned between saturated aqueous NaHCO3 (100 mL) and EtOAc (100 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 50% hexanes/EtOAc then 100% EtOAc then 9:1:0.1 EtOAc:MeOH:Et3N) afforded the title compound (15 g, 31.9 mmol, 57% yield). 1H NMR (300 MHz, CDCl3) δ ppm 0.95 (t, J=7.3 Hz, 3H) 1.28 (s, 6H) 1.32-1.42 (m, 2H) 1.42 (s, 9H) 1.61-1.72 (m, 2H) 3.75 (s, 3H) 4.03 (s, 2H) 4.27 (dd, J=7.8 Hz, 2H) 6.16 (s, 1H) 7.00 (d, J=8.5 Hz, 1H) 6.99 (s, 1H) 7.51 (dd, J=8.6, 1.9 Hz, 1H) 8.13 (d, J=2.4 Hz, 1 H); MS (DCI/NH3) m/z 470 (M+H)+; Anal. calculated for C24H34F3N3O3: Calc: C, 61.39; H, 7.30; N, 8.95. Found: C, 61.33; H, 7.38; N, 8.91.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:11][C:10]=1[C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28].[CH:35]1([C:38](=[O:42])[C:39](O)=[O:40])[CH2:37][CH2:36]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:35]1([C:38](=[O:42])[C:39]([N:32]2[CH2:33][CH2:34][N:29]([C:27](=[O:28])[C:10]3[CH:11]=[C:12]([CH2:13][C:14]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:17](=[O:24])[NH:16][N:15]=4)[CH:25]=[CH:26][C:9]=3[F:8])[CH2:30][CH2:31]2)=[O:40])[CH2:37][CH2:36]1
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCNCC1
Reactant: O=C(O)C(=O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(C(=O)N1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one TFA salt (1.24 g, 2.68 mmol), 2-cyclopropyl-2-oxoacetic acid (2.84 g, 24.84 mmol), DIPEA (6.9 ml, 41.4 mmol), and HATU (4.08 g, 10.8 mmol) were mixed in DMF (100 ml), the resulting reaction mixture was stirred at room temperature for overnight until the reaction finished (monitored by TLC). The reaction mixture was then partitioned between DCM and water (100 ml each, the water phase was extracted with DCM (100 ml). The combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was purified by column chromatography on silica gel (DCM: MeOH=100:1) and re-crystallized from methanol to afford the desired product (610 mg, 49.3%) as a white solid.