Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.C(N(CC)CC)C.[CH3:19][N:20]=[C:21]=[O:22]>C1C=CC=CC=1>[CH3:19][NH:20][C:21]([NH:11][CH:7]1[C:4]2[CH:5]=[CH:6][S:2][C:3]=2[CH2:10][CH2:9][CH2:8]1)=[O:22]
Reactant: NC1CCCc2sccc21
Reactant: CN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CNC(=O)NC1CCCc2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.89 grams (0.01 mole) of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride in 20 ml. of dry benzene is stirred while 1.05 grams (0.01 mole) of triethylamine and 01.7 ml. (excess) of methyl isocyanate are added successively. Addition of the latter gives rise to an exotherm, and the mixture becomes very pasty. The mixture is kept at 45° C. for one hour, and after cooling to room temperature, the solid is collected, washed thoroughly with benzene and then with water. On drying, this gives 1.7 grams (81%) of product, melting point 183° C. to 186° C. Recrystallization from acetone gives 1.23 grams, melting point 187.5° C. to 189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=O)[C:7](=[CH:18]N(C)C)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.Cl.[C:26]([NH2:29])(=[NH:28])[CH3:27].C[O-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:29]=[C:26]([CH3:27])[N:28]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: CC(=N)N
Reactant: CN(C)C=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2C1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 5.1 g (0.015 mol) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one and 2.1 g (0.0225 mol) of acetamidine hydrochloride in 150 ml of methanol was stirred at room temperature under argon, and treated with 2.4 g (0.045 mol) of sodium methylate in one portion. After stirring for 10 min, 90 ml of methylene chloride was added and stirring was continued. Another 2.4 g (0.045 mol) of sodium methylate and 2.1 g (0.0225 mol) of acetamidine hydrochloride were added after 2 hrs. The addition of 0.045 mol of sodium methylate and 0.0225 mol of acetamidine hydrochloride was repeated after another 2 hr interval and stirring at room temperature was continued overnight. After diluting with 150 ml of methylene chloride, the mixture was washed with water, dried over sodium sulfate and evaporated at reduced pressure. Recrystallization of the residue from hexane (charcoal) gave white crystals: mp 104°- 107° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]#[N:10].[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>N1C=CC=CC=1>[C:9]([C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[F:11])#[N:10]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1nn(C)c(N)c1C#N
Solvent: c1ccncc1
Product: Cc1nn(C)c(NC(=O)c2ccccc2F)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
5-Amino-1,3-dimethyl-1H-pyrazole-4-carbonitrile (10 g, 73.4 mmole) was suspended in pyridine (90 ml) and 2-fluorobenzoyl chloride was added dropwise while cooling the reaction mixture on an ice bath. The mixture reaction was stirred overnight at room temperature. Most of the pyridine was removed and 100 ml of cold water was added to precipitate the product. The product was isolated by filtration, washed with cold water and a small amount of cold ethanol, and dried under vacuum to obtain 9.15 g of product (yield: 50%).
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[F-].[Cs+].[N:22]1([CH2:28][CH2:29][O:30][C:31]2[CH:59]=[CH:58][C:34]([O:35][C:36]3[C:45](OS(C(F)(F)F)(=O)=O)=[CH:44][CH:43]=[C:42]4[C:37]=3[CH:38]=[CH:39][C:40]([O:54][C:55](=[O:57])[CH3:56])=[CH:41]4)=[CH:33][CH:32]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.B1(B2OCC(C)(C)CO2)OCC(C)(C)CO1.[CH3:76][S:77]([C:80]1[CH:85]=[CH:84][C:83](OS(C(F)(F)F)(=O)=O)=[CH:82][C:81]=1[O:94][CH3:95])(=[O:79])=[O:78]>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH3:76][S:77]([C:80]1[CH:85]=[CH:84][C:83]([C:45]2[C:36]([O:35][C:34]3[CH:58]=[CH:59][C:31]([O:30][CH2:29][CH2:28][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:32][CH:33]=3)=[C:37]3[C:42](=[CH:43][CH:44]=2)[CH:41]=[C:40]([O:54][C:55](=[O:57])[CH3:56])[CH:39]=[CH:38]3)=[CH:82][C:81]=1[O:94][CH3:95])(=[O:79])=[O:78]
Reactant: CC(=O)Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)ccc1S(C)(=O)=O
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: COc1cc(-c2ccc3cc(OC(C)=O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)ccc1S(C)(=O)=O
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 32.4 %

Procedure:
Combine Pd(OAc)2 (46 mg, 0.20 mmol), tricyclohexylphosphine (95 mg, 0.34 mmol), and CsF (1.85 g, 12.26 mmol) in CH3CN (20 mL) under N2. Stir the reaction mixture for 5 minutes. Add acetic acid 5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-6-trifluoromethanesulfonyloxy-naphthalen-2-yl ester (730 mg, 1.36 mmol) and bis(neopentyl glycolato)diboron (460 mg, 2.04 mmol) to the reaction mixture. Heat to 90° C. and stir for about 5 minutes. Add trifluoro-methanesulfonic acid 4-methanesulfonyl-3-methoxy-phenyl ester (500 mg, 1.5 mmol) and continue to heat the mixture for two hours. Cool to room temperature, add water (100 mL), and extract the aqueous layer with CH2Cl2 (3×100 mL). Combine the organic layers and dry with Na2SO4, filter and concentrate. Purify by flash column chromatography (silica gel, 0 to 5% MeOH/CH2Cl2) to give 260 mg of the title compound (33%): mass spectrum: (ion spray): m/z=590.4 (M+H).
Reaction SMILES: C(N(CC)CC)C.C([O-])(=O)C.[Zn+2:12].C([O-])(=O)C.[C:17]1([CH:23]2[O:27][CH:26]([C:28]([Cl:31])([Cl:30])[Cl:29])[NH:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:32](=[S:34])=[S:33]>>[C:17]1([CH:23]2[O:27][CH:26]([C:28]([Cl:31])([Cl:30])[Cl:29])[N:25]([C:32]([S-:34])=[S:33])[CH2:24]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1.[C:17]1([CH:23]2[O:27][CH:26]([C:28]([Cl:31])([Cl:30])[Cl:29])[N:25]([C:32]([S-:34])=[S:33])[CH2:24]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1.[Zn+2:12]
Reactant: S=C=S
Reactant: ClC(Cl)(Cl)C1NCC(c2ccccc2)O1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Product: S=C([S-])N1CC(c2ccccc2)OC1C(Cl)(Cl)Cl
Temperature: 50 °C
Yield: 58 %

Procedure:
A mixture of 30.3 g (0.3 mole) triethylamine, 12.3 g. (0.1 mole) zinc acetate, 55.0 g. (0.206 mole) 5-phenyl-2-trichloromethyloxazolidine and 15.6 g. (0.206 mole) carbon disulfide was stirred at ambient temperatures for 17 hours and then was heated at 50° C. for three hours. A reddish amber-colored semi-solid was obtained after the volatile materials were distilled off at 50°/25 mm. Hg. The semi-solid was dissolved in methanol and the resulting solution added to water with vigorous stirring. The solids were filtered, air-dried, and redissolved in benzene. After drying the solution with magnesium sulfate, filtering the mixture and evaporating the solvent, 37 g. (58%) of the desired product (m.p. 91°-93° C.) was obtained; its infrared spectrum was consistent with the structure.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:8]([N:10]1[CH2:21][CH2:20][CH2:19][C@H:11]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:9])[CH3:7])=[O:4].[H][H]>CO.[Pd]>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:8]([N:10]1[CH2:21][CH2:20][CH2:19][C@H:11]1[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:9])[CH3:7])=[O:4]
Reactant: C[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)CN)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
2.06 g of Z-Gly-Ala-Pro-OtBu are hydrogenated in 30 ml of methanol in the presence of 300 mg of Pd on charcoal (10 %) at room temperature. The hydrogen uptake has ended after 90 minutes. The catalyst is filtered off and the filtrate is concentrated to about 5 ml. 10 ml of ether are added. The product crystallises out overnight. Melting point 132°-134°C; Rf = 0.3 in the system chloroform-methanol (1:1) on silica gel.
Reaction SMILES: [NH2:1][NH2:2].C([O:5][C:6](=O)[CH:7]([C:21](=O)[C:22]([F:25])([F:24])[F:23])[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)C.CO>C1(C)C=CC=CC=1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:6]([OH:5])=[N:1][NH:2][C:21]=2[C:22]([F:25])([F:24])[F:23])[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)C(C(=O)C(F)(F)F)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NN
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2c(O)n[nH]c2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Anhydrous hydrazine (0.040 mL, 41 mg, 1.27 mmol) was added to a stirred solution of 1-(tert-butoxycarbonyl)-α-(trifluoroacetyl)-4-piperidineacetic acid ethyl ester (275 mg, 0.75 mmol, from Step B) in toluene (2.0 mL) at RT. The mixture was warmed to 60° C. for 4 h, followed by 16 h at 80° C. The mixture was allowed to cool to RT, transferred to another flask with CH3OH, and evaporated to give the title compound as a white solid. For the title compound: 1H NMR (500 MHz, CD3OD) δ 4.15 (bd, J=13, 2H), 2.86–2.70 (m, 3H), 1.88 (bq, J=12, 2H), 1.62 (bd, J=13, 2H), 1.47 (s, 9H); ESI-MS 280.3 (M+H−56) and 236.3 (M+H−100); HPLC A: 3.0 min.
Reaction SMILES: [O:1]=[S:2]1(=[O:39])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[N:24]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]5[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)[CH:27]=3)[CH:22]=[N:21]4)=[CH:11][C:10]=2[F:38])[CH2:4][CH2:3]1.C=O.[BH3-][C:43]#N.[Na+]>CO.C(Cl)Cl>[O:39]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[N:24]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]5[CH2:37][CH2:36][N:35]([CH3:43])[CH2:34][CH2:33]5)[CH:27]=3)[CH:22]=[N:21]4)=[CH:11][C:10]=2[F:38])[CH2:6][CH2:7]1
Reactant: O=S1(=O)CCN(Cc2c(F)cc(-c3cccc4ncc(-c5cccc(N6CCNCC6)c5)nc34)cc2F)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2cccc(-c3cnc4cccc(-c5cc(F)c(CN6CCS(=O)(=O)CC6)c(F)c5)c4n3)c2)CC1

Procedure:
A solution of 8-[4-(1,1-Dioxido-thiomorpholin-4-ylmethyl)-3,5-difluoro-phenyl]-2-(3-piperazin-1-yl-phenyl)-quinoxaline (as obtained in example 169, 79 mg, 0.137 mmol) in MeOH (3 ml) and CH2Cl2 (1.5 ml) is treated with HCHO (41 μl, 0.550 mmol, 37% in H2O/MeOH 9:1) and NaBH3CN (35 mg, 0.546 mmol) at RT for 2 h. The reaction mixture is concentrated under reduced pressure. The residue is purified by reverse phase prep-HPLC (Waters) to afford the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[C:10]([NH:17][C:18]3[CH:19]=[C:20]([NH:25]C(=O)OC(C)(C)C)[C:21]([Cl:24])=[N:22][CH:23]=3)=[N:11][CH:12]=[C:13]([O:15][CH3:16])[CH:14]=2)[N:3]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[C:10]([NH:17][C:18]3[CH:19]=[C:20]([NH2:25])[C:21]([Cl:24])=[N:22][CH:23]=3)=[N:11][CH:12]=[C:13]([O:15][CH3:16])[CH:14]=2)[N:3]=1
Reactant: COc1cnc(Nc2cnc(Cl)c(NC(=O)OC(C)(C)C)c2)c(-c2nc(C)nc(N)n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc(Nc2cnc(Cl)c(N)c2)c(-c2nc(C)nc(N)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a 20 mL scintillation vial which contained tert-butyl 5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-methoxypyridin-2-ylamino)-2-chloropyridin-3-ylcarbamate (0.210 g, 0.458 mmol) in DCM (5 mL) was added trifluoroacetic acid (Aldrich) (0.170 mL, 2.288 mmol). The resulting mixture was capped and stirred at rt in closed system for 1 h. The reaction mixture was first neutralized with sat. NaHCO3 then extracted with CHCl3 (3×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified using the column chromatography (40 g, 3% to 5% MeOH in DCM) to afford the desired product as a yellow solid (135 mg). MS (ESI pos. ion) m/z: 359.0. Calc'd exact mass for C15H15Cl N8O: 358.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (s, 3H) 3.84 (s, 3H) 5.43 (s, 2H) 7.78 (br. s., 1H) 7.86 (br. s., 1H) 7.89 (d, J=2.35 Hz, 1H) 7.94 (d, J=2.15Hz, 1H) 8.16 (d, J=3.13 Hz, 1H) 8.40 (d, J=3.13 Hz, 1H) 11.75 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1
Reactant: Fc1cc(-c2ccc(Cl)cc2)c(Cl)cn1
Reactant: OB(O)c1ccccc1Cl
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Fc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Temperature: 95 °C
Reaction time: 16 h
Yield: 35.4 %

Procedure:
To a flame-dried tube was placed 5-chloro-4-(4-chlorophenyl)-2-fluoropyridine (0.71 g, 2.93 mmol), 2-chlorophenylboronic acid (0.55 g, 3.52 mmol), K3PO4 (1.24 g, 5.86 mmol), Pd2(dba)3 (0.134 g, 0.147 mmol), and S-Phos (0.12 g, 0.29 mmol). The reaction vessel was then purged with argon three times before degassed toluene (15 mL) was added in, and sealed. The reaction mixture was stirred at 95° C. for 16 h. Analysis by HPLC/MS indicated the reaction was complete. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (30 mL×3). The combined organic was washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (80 g) eluting with a gradient of EtOAc (0-10%) in hexanes to afford 0.33 g (35%) of the title compound as a white foam. HPLC/MS: retention time=4.03 min, [M+H]+=318.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[C@H:10]([CH2:23][C:24]([O:26]C(C)(C)C)=O)[N:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[CH2:38]([NH2:40])[CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O.CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[C@H:10]([CH2:23][C:24]([NH:40][CH2:38][CH3:39])=[O:26])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCN
Reactant: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=N[C@H]2CC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2ccccc2-c2c(C)noc21
Reaction time: 1 h
Yield: 37 %

Procedure:
To a round bottomed flask was added tert-butyl 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate (0.019 g, 0.046 mmol), CH2Cl2 (2 mL), and TFA (0.400 mL, 5.19 mmol). The reaction was stirred for 1 h before being concentrated. The crude residue was dissolved in DMF (1 mL) and ethylamine (0.032 mL, 0.064 mmol), HATU (0.026 g, 0.068 mmol), and Hunig's base (0.024 mL, 0.137 mmol) were added. The reaction was stirred at room temperature for 1 h before diluting with water and methanol and purification via preparatory HPLC. The fractions were neutralized and the aqueous extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-N-ethylacetamide (0.0068 g, 0.017 mmol). 1H NMR (400 MHz, DMSO-d6) δ 8.27-8.13 (m, 1H), 7.83 (d, J=7.3 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.49-7.36 (m, 4H), 7.34-7.25 (m, 2H), 4.42-4.23 (m, 1H), 3.14 (dd, J=6.98, 12.7 Hz, 4H), 2.51 (s, 3H), 1.07 (t, J=7.2 Hz, 3H); LC/MS m/z 394 [M+H]+.
Reaction SMILES: C(O[C:4](=O)[CH2:5][N:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)C.N1C=CC=CC=1C1C=CC=CN=1.[F-].[K+].C[Si]([C:38]([F:41])([F:40])[F:39])(C)C>CN(C=O)C.[Cu]I.CN1C(=O)CCC1>[CH2:17]([O:16][C:14]([N:6]1[CH2:5][CH2:4][C:13]2[CH:12]=[C:11]([C:38]([F:41])([F:40])[F:39])[S:10][C:9]=2[CH2:8][CH2:7]1)=[O:15])[CH3:18]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)CN(CCc1cccs1)C(=O)OCC
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)N1CCc2cc(C(F)(F)F)sc2CC1
Temperature: 80 °C

Procedure:
A solution of the product from step a.) (75 mg, 0.21 mmol) in DMF (0.5 ml) and NMP (0.5 ml) was treated with bipyridyl (43 mg, 0.27 mmol), CuI (44 mg, 0.23 mmol), KF (13 mg, 0.23 mmol) and trimethylsilyltrifluoromethane (2.1 ml, 1.05 mmol). The reaction mixture was heated to 80° C. for 3 days. The reaction was cooled and filtered through celite washing with EtOAc (20 ml). The eluent was washed with brine (2×3 ml) and dried (MgSO4) providing the subtitle compound as a brown oil that was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N:24]2[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=3)[CH:14]=2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(#N)C.[F:41][C:42]([F:57])([S:53](F)(=[O:55])=[O:54])[C:43]([F:52])([F:51])[C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46]>CN(C)C=O>[F:57][C:42]([F:41])([S:53]([O:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:9]3[CH:8]=[C:7]([N:24]4[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]4=[O:31])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]=3[O:11][CH3:12])[CH:14]=2)[CH:19]=1)(=[O:55])=[O:54])[C:43]([F:51])([F:52])[C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: COc1c(-c2ccc3cc(O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1c(-c2ccc3cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reaction time: 0.33 h

Procedure:
A 250-L, 3-neck round-bottom flask equipped with an overhead stirrer was charged with 10 g of 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (98 wt %, 23.5 mmol, 1.0 equiv) and 6.5 g of milled potassium carbonate (325 mesh, 47.1 mmol, 2.0 equiv). Acetonitrile (MeCN, 60 mL, 6 volumes with respect to naphthol) and dimethylformamide (dimethylformide, 40 mL, 4 volumes with respect to naphthol) was charged to the reactor and the slurry was stirred. Perfluorobutanesulfonyl fluoride (96 wt %, 8.3 g, 26 mmol, 1.1 equiv) was charged to the well-stirred mixture over 60 minutes by syringe pump. A trace (<0.1 area %) of starting material was detected by HPLC analysis of an aliquot at 20 minutes reaction time. The acetonitrile/dimethylformamide solution was filtered over a coarse fritted funnel to separate the inorganic solids, and the flask and filter was rinsed with 15 mL of 3:2 (v/v) acetonitrile/dimethylformamide. The total mass of solvents employed was approximately 92 g.
Reaction SMILES: [F:1][C:2]([CH:5]([C:9]([F:11])=[O:10])[C:6]([F:8])=[O:7])([F:4])[F:3].C(N(CC)CC)C.Cl[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23]>CCOCC>[CH3:23][C:22]([CH3:24])=[CH:21][CH2:20][C:5]([C:2]([F:4])([F:3])[F:1])([C:6]([F:8])=[O:7])[C:9]([F:11])=[O:10]
Reactant: O=C(F)C(C(=O)F)C(F)(F)F
Reactant: CC(C)=CCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)=CCC(C(=O)F)(C(=O)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 16 %

Procedure:
To 17.6 g (0.10 mol) of trifluoromethylmalonyl fluoride and 50 ml of ether stirred at -80°C was added dropwise a solution of 9.2 g (0.09 mol) of triethylamine in 25 ml of ether. Then 12.5 g (0.12 mol) of 1-chloro-3-methyl-2-butene was added, and the mixture was stirred at 25°C until homogeneous. After standing at 25°C for 3 days, the mixture was distilled to give 3.9 g (16%) of (3-methyl-2-butenyl)-trifluoromethylmalonyl fluoride, bp 43°-45°C (20 mm); ir (CCl4): 3.31, 3.37 and 3.42 (CH), 5.36 (C=O) and 7.5-8.5 μ (CF).
Reaction SMILES: C([SiH2][O:6][C:7](C1C=CC=CC=1)(C1C=CC=CC=1)[C:8]1[CH:13]=[C:12]([F:14])[N:11]=[C:10](F)[CH:9]=1)(C)(C)C.[CH2:28]([OH:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[H-].[Na+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOCC>[CH2:28]([O:35][C:10]1[CH:9]=[C:8]([CH2:7][OH:6])[CH:13]=[C:12]([F:14])[N:11]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1cc(F)nc(F)c1
Reactant: OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1cc(F)nc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
To a stirred solution of 4-(tert-butyl-diphenyl-silanyloxymethyl)-2,6-difluoro-pyridine (1.917 g, 5 mmol) and benzyl alcohol (543 μl, 5.25 mmol) in THF (20 ml) cooled in a dry ice-acetone bath (−50° C.) under nitrogen, was added 60% sodium hydride (240 mg, 6 mmol). The mixture was then slowly warmed up to room temperature during 2 hr. The mixture was diluted with ether, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was then dissolved in THF (5 ml) and stirred with 1M tetrabutylammonium fluoride in THF (5.5 ml, 5.5 mmol) at room temperature for 1 hr. The mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:3)) to afford 856 mg (73% for two steps) of (2-benzyloxy-6-fluoro-pyridin-4-yl)-methanol as a colorless oil. 1H NMR (200 MHz, CDCl3) δ 1.99 (1H, br. s), 4.68 (2H, s), 5.32 (2H, s), 6.48 (1H, s), 6.64 (1H, s), 7.30-7.45 (5H, m).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH:16]([CH3:18])[CH3:17])=[C:9]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[N:8]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[C:42](O)(=[O:45])[CH:43]=[CH2:44].CCCP(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[CH:16]([N:13]1[CH:12]=[N:11][C:10]2[C:14]1=[N:15][C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:42](=[O:45])[CH:43]=[CH2:44])[CH2:3]1)=[N:8][C:9]=2[NH:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1)([CH3:18])[CH3:17]
Reactant: CC(C)n1cnc2c(Nc3ccc(N4CCN(C)CC4)cc3)nc(N3CC[C@H](N)C3)nc21
Reactant: C=CC(=O)O
Agent: CCCP(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CC(=O)N[C@H]1CCN(c2nc(Nc3ccc(N4CCN(C)CC4)cc3)c3ncn(C(C)C)c3n2)C1
Reaction time: 0.25 h
Yield: 34.1 %

Procedure:
(S)-2-(3-Aminopyrrolidin-1-yl)-9-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl) -9H-purin-6-amine (436 mg, 1 mmol) was suspended in DMF (3.3 mL). DIPEA (0.53 mL, 3 mmol, 3 mol eq) and acrylic acid (73 μL, 1.05 mmol, 1.05 mol eq) were added to give a suspension. Propylphosphonic anhydride (CAS 68957-94-8, 50% in DMF, 0.7 mL, 1.2 mmol, 1.2 mol eq) was added in one portion. The reaction mixture warmed up slightly to afford a solution. After 15 min, aqueous Na2CO3 (1 M, 2 mL, 2 mmol) was added and stirred for 30 min. Water (10 mL) and ethyl acetate (50 mL) were added. The organic layer was separated, washed with water (3×10 mL), dried over Na2SO4 and evaporated to give a light yellow foamy solid, which was purified by SFC (Column ZymorSpher HADP 150×21.2 mm I.D., 5 μm particles. Modifier: ethanol. Gradient 21% (hold 2 min) to 24% (hold 1 min) at 1.5% per min. Flow rate (58 mL/min) to give the title product (167 mg, 34% yield, >95% purity). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (s, 1 H) 8.36 (d, J=6.85 Hz, 1 H) 7.91 (s, 1 H) 7.85 (d, J=9.05 Hz, 2 H) 6.87 (d, J=9.05 Hz, 2 H) 6.19-6.32 (m, 1 H) 6.05-6.16 (m, 1 H) 5.59 (dd, J=10.09, 2.38 Hz, 1 H) 4.62 (quin, J=6.72 Hz, 1 H) 4.34-4.48 (m, 1 H) 3.76 (dd, J=11.31, 6.30 Hz, 1 H) 3.54-3.70 (m, 2 H) 3.43 (dd, J=11.19, 3.85 Hz, 1 H) 2.93-3.14 (m, 4 H) 2.39-2.47 (m, 4 H) 2.22 (s, 3 H) 2.12-2.20 (m, 1 H) 1.83-1.95 (m, 1 H) 1.51 (d, J=6.72 Hz, 6 H). m/z (APCI+) for C26H35N9O 490.4 (M+H)+.