Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:5]([C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:20]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:19][CH:18]=1)[CH:6]([CH2:11][C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:7]([O:9][CH3:10])=[O:8])(=O)C.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH2:30]([C:20]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:17](/[CH:5]=[C:6](\[CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)/[C:7]([O:9][CH3:10])=[O:8])=[CH:18][N:19]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCc1ncc(C(OC(C)=O)C(Cc2cccs2)C(=O)OC)n1Cc1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)OC)n1Cc1ccccc1Cl
Temperature: 80 °C
Yield: 75.5 %

Procedure:
A mixture of methyl 3-acetoxy-3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-2-[(2-thienyl)methyl]propanoate (4.36 g, 8.92 mmol) in dry toluene (80 mL) was treated with 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (3.2 mL, 21.4 mmol), and the resulting solution was heated at 80° C. under argon for 3 hours. The solvent was evaporated, the residue triturated with ether and activated charcoal was added. After filtration, the filtrate was concentrated to 6.29 g of an oil that was chromatographed over silica gel with 65:35 hexane/ethyl acetate to give 2.89 g (76%) of methyl (E)-3-[2-n-butyl-1-[(2-chlorophenyl)methyl]-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate whose NMR and TLC (50% ethyl acetate in hexane on silica gel) were identical to the product prepared by Method A.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:20])[C:11](=[O:19])[CH:12]=[CH:13][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[C:4]([F:21])[CH:3]=1.[Cl:22]N1C(=O)CCC1=O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:20])[C:11](=[O:19])[C:12]([Cl:22])=[CH:13][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[C:4]([F:21])[CH:3]=1
Reactant: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(=O)n(C)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of methyl 2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate in DMF was added N-chlorosuccinimide. The reaction mixture was stirred at room temperature for 25 minutes and then quenched with saturated sodium bisulfite. The reaction mixture was diluted with H2O and partitioned between EtOAc/diethyl ether and saturated NaCl. The layers were separated and the aqueous layer was reextracted with EtOAc (1×). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 15:1) gave the desired product as a white solid. MS ESI (+) m/z 389, 391, 393 (M+, Cl, Br pattern) detected. 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 8.13 (s, 1H), 7.34 (d, 1H), 7.24 (d, 1H), 6.69 (t, 1H), 3.87 (s, 3H), 3.29 (s, 3H).
Reaction SMILES: FC1C(F)=C2C(=CC=1F)N=C(C1C=CC(F)=CC=1)N=C2O.FC(F)(C1C=CC(F)=CC=1)C(NC1C=C(F)C=CC=1C(N)=O)=O.[F:45][C:46]([F:68])([C:61]1[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=1)[C:47]([NH:49][C:50]1[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:51]=1[C:52]([NH2:54])=[O:53])=O>>[F:45][C:46]([F:68])([C:61]1[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=1)[C:47]1[N:54]=[C:52]([OH:53])[C:51]2[C:50](=[CH:58][C:57]([O:59][CH3:60])=[CH:56][CH:55]=2)[N:49]=1
Reactant: COc1ccc(C(N)=O)c(NC(=O)C(F)(F)c2ccc(F)cc2)c1
Agent: NC(=O)c1ccc(F)cc1NC(=O)C(F)(F)c1ccc(F)cc1
Agent: Oc1nc(-c2ccc(F)cc2)nc2cc(F)c(F)c(F)c12
Product: COc1ccc2c(O)nc(C(F)(F)c3ccc(F)cc3)nc2c1

Procedure:
2-(Difluoro(4-fluorophenyl)methyl)-7-methoxyquinazolin-4-ol was prepared according to the procedure described in Example 20 for preparation of 2-(difluoro(4-fluorophenyl)-7-fluoroquinazolin-4-ol, substituting 2-(2,2-difluoro-2-(4-fluorophenyl)acetamido)-4-fluorobenzamide in Example 20 with 2-(2,2-difluoro-2-(4-fluorophenyl)acetamido)-4-methoxybenzamide. The crude product (˜100% yield) was taken directly to the next step. 1H NMR (300 MHz, DMSO-d6) δ 3.89 (s, 3H), 7.16 (m, 2H), 7.39 (t, 2H), 7.75 (m, 2H), 8.04 (d, 1H), 12.96 (s, 1H); LC-MS (ESI) m/z 321 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[CH3:23][N:24](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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.C(Cl)(Cl)Cl.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:23]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1)#[N:24]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(Cl)nncc3c2)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(-c2ccc3c(C#N)nncc3c2)c1
Temperature: 100 °C

Procedure:
To methyl 3-(1-chlorophthalazin-6-yl)-4-methylbenzoate (2.49 g, 7.96 mmol) and zinc cyanide (1.87 g, 15.9 mmol) was added DMF (39.8 mL). The mixture was sparged with nitrogen for 15 min, and tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.330 g, 0.318 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (0.177 g, 0.318 mmol) were added. The reaction was heated to 100° C. for 30 min. The reaction mixture was diluted with 100 mL ethyl acetate, partitioned with sodium bicarbonate (saturated, aqueous), and the organics were washed 3×50 mL with sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography to give the title compound. MS (ES+): 304(M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([N+:12]([O-])=O)=[CH:4][C:3]=1[OH:15].[H][H]>C1COCC1.[Ni]>[NH2:12][C:5]1[C:6]([C:8]([F:11])([F:9])[F:10])=[CH:7][C:2]([F:1])=[C:3]([OH:15])[CH:4]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(O)c(F)cc1C(F)(F)F
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(O)c(F)cc1C(F)(F)F

Procedure:
Raney-Ni (0.5 g) was added to a solution of 2-fluoro-5-nitro-4-(trifluoromethyl)phenol obtained in Reference Example 17 (0.5 g) in THF (5 ml), and the mixture was stirred for 2 hours in a hydrogen atmosphere. The catalyst was removed by filtration and the catalyst was washed with THF. The combined filtrate and washings were diluted with THF to obtain a solution of 5-amino-2-fluoro-4-(trifluoromethyl)phenol in THF (50 ml).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:25]=[C:24]4[C:19]([N:20]=[CH:21][C:22](=O)[NH:23]4)=[CH:18][CH:17]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1.C[N:28]([CH:30]=[O:31])C>O=P(Cl)(Cl)Cl.C(Cl)(Cl)Cl.C(O)(C)C.[C-]#N.[C-]#N.[Zn+2].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>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:25]=[C:24]4[C:19]([N:20]=[CH:21][C:22]([C:30]([NH2:28])=[O:31])=[N:23]4)=[CH:18][CH:17]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cccc(-c2nn3c(c2-c2ccc4ncc(=O)[nH]c4c2)CCC3)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: Cc1cccc(-c2nn3c(c2-c2ccc4ncc(C(N)=O)nc4c2)CCC3)n1
Temperature: 25 °C
Yield: 59 %

Procedure:
Reflux 7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-quinoxalin-2-one (Example 55b; 20 mg, 0.055 mmol,) in POCl3 overnight. After removing POCl3, treat the residue with Zn(CN)2 (11.6 mg, 0.11 mmol) and Pd(PPh3)4 (3 mg, 0.003 mmol) in DMF (1 mL) at 100° C. for 20 min in microwave. Cool the solution to room temperature, dilute with chloroform/isopropyl alcohol and wash with brine. Dry the solution over sodium sulfate, filter, and evaporate the solvents to give a viscous mixture. Purify the crude product by column chromatography eluting with a gradient from dichloromethane to 10% methanol in dichloromethane to give the desired compound 12 mg (59%). MS (electrospray, m/z) 371.2 (M+1).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][C:14]([CH:23]([OH:25])[CH3:24])=[CH:15][CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:3].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:25][CH:23]([C:14]1[CH:13]=[C:12]2[C:17]([O:18][CH2:19][CH2:20][N:21]3[C:11]2=[N:10][C:9]([C:8]2[N:4]([CH:2]([CH3:1])[CH3:3])[N:5]=[CH:6][N:7]=2)=[CH:22]3)=[CH:16][CH:15]=1)[CH3:24])(=[O:29])=[O:28]
Reactant: CC(O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethan-1-ol (200 mg, 0.590 mmol) in DCM (20 mL) at 0° C. was added TEA (296 mg, 2.93 mmol) and MsCl (136 mg, 1.19 mmol). The reaction mixture was stirred 0° C. for 2 h and then allowed to warm to room temperature. The reaction was quenched with sat. NaHCO3 (10 mL), the resultant mixture was washed with sat. NaCl (20 mL). The organic phase was dried and concentrated to afford 1-{4-[1-(Propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethyl methanesulfonate (246 mg, 100% yield) as a brown solid, which was directly used in next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:25]([C:26](=[O:29])[CH2:27][CH3:28])=[C:24]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Br:36])[CH:22]=3)[C:17]2=[O:37])=[CH:11][CH:10]=1)(=[O:8])=[O:7].CO.[OH-].[Na+].Cl>C1COCC1>[Br:36][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:37])[N:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]([S:6]([NH:5][CH2:4][C:3]([OH:38])=[O:2])(=[O:8])=[O:7])=[CH:10][CH:11]=1)[C:25]([C:26](=[O:29])[CH2:27][CH3:28])=[C:24]2[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(=O)(=O)NCC(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(=O)(=O)NCC(=O)O)cc1
Yield: 48.3 %

Procedure:
To a mixture of [4-(6-bromo-1-oxo-4-phenyl-3-propionyl-1H-isoquinolin-2-ylmethyl)benzenesulfonylamino]acetic acid methyl ester (70 mg), methanol (2.0 ml) and THF (2.0 ml) was added 1N sodium hydroxide (0.23 ml) at room temperature with stirring, and the mixture was stirred at the same temperature for 18 hrs. The reaction mixture was neutralized with 1N hydrochloric acid and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (33 mg) in beige crystals. 1H NMR (CDCl3) δ: 0.52 (3H, t, J=6.9 Hz), 1.78 (2H, q, J=6.9 Hz), 3.82 (2H, d, J=6.0 Hz), 5.25-5.36 (3H, m), 7.23-7.31 (2H, m), 7.33 (2H, d, J=8.4 Hz), 7.44-7.55 (4H, m), 7.70 (1H, dd, J=1.8, 8.4 Hz), 7.80 (2H, d, J=8.4 Hz), 8.37 (1H, d, J=8.4 Hz). HPLC analysis: purity 95.2% (retention time: 4.38 min). MS (ESI+): 583 (M+H), 585.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@H:13]3[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C@@H:12]3[N:6]3[CH2:7][CH2:8][NH:9][C:10]([CH:11]=1)=[C:5]23.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]2[C@@H:13]3[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17][C@@H:12]3[N:6]3[CH2:7][CH2:8][NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCN3
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CCN3
Yield: 61.8 %

Procedure:
Tert-butyl (6bR, 10aS)-5-(2,4-dichlorophenyl)-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (37 mg, 60%) was prepared via coupling of tert-butyl (6bR, 10aS)-5-bromo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (50 mg, 0.13 mmol) with 2,4-dichlorophenyl boronic acid (74 mg, 0.39 mmol) as illustrated above using the general procedure for Suzuki coupling. 1H NMR (CDCl3, 300 MHz) δ 1.46 (s, 9H), 1.82-1.96 (m, 2H), 2.74-2.82 (m, 1H), 2.99-3.05 (m, 1H), 3.16-3.22 (m, 2H), 3.33-3.39 (m, 1H), 3.43-3.50 (m, 1H), 3.52-3.57 (m, 1H), 3.62-3.69 (m, 1H), 3.43-3.50 (m, 1H), 3.52-3.57 (m, 1H), 3.62-3.69 (m, 1H), 3.71-3.79 (m, 1H), 3.80-3.85 (m, 1H), 3.89-4.14 (m, 1H), 6.44 (s, 1H), 6.59 (s, 1H), 7.22 (s, 2H), 7.42 (s, 1H) ppm.
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:32][C:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31][C:25]=5[N:24]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:33]([N:29]1[CH2:30][CH2:31][C:25]2[N:24]=[C:23]([C:18]3[C:17]4[C:21](=[CH:22][C:14]([C:7]5[C:6]([CH2:4][CH3:5])=[CH:11][C:10]([OH:12])=[C:9]([F:13])[CH:8]=5)=[CH:15][CH:16]=4)[NH:20][N:19]=3)[NH:32][C:26]=2[CH2:27][CH2:28]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNCC4)n[nH]c2c1
Reactant: BrCc1ccccc1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3ccccc3)CC4)n[nH]c2c1
Temperature: 50 °C
Yield: 10.4 %

Procedure:
To a solution of 5-ethyl-2-fluoro-4-[3-(1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 32, 50 mg, 80 μmol) in DMF (1 mL), was added benzyl bromide (14.4 mg, 10 μL, 85 μmol), and DIPEA (56 μL, 320 μmol). The reaction mixture was heated at 50° C. for 18 hours. The reaction mixture was then cooled to room temperature and partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo to furnish a brown oil. The crude material was purified by reverse phase chromatography (Method C) to afford 4 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:7])[CH3:6].C(N(CC)CC)C.[C:23](Cl)(=[O:27])[C:24]([CH3:26])=[CH2:25]>C(Cl)Cl>[C:23]([O:7][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH2:4][CH2:3][C:2]([F:14])([F:15])[F:1])[CH3:6])(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(O)(CCC(F)(F)F)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC(C)(CCC(F)(F)F)c1ccccc1
Reaction time: 12 h
Yield: 72 %

Procedure:
21 g of 5,5,5-trifluoro-2-phenylpentan-2-ol (5) and 11.6 g of triethylamine dissolved in 40 mL of methylene chloride was slowly charged into flask equipped with magnetic stirrer and 11 ml, of methacryloyl chloride in 100 mL of dichloromethane cooled down to 0° C. The resultant mixture slowly warmed up to room temperature and allowed to stir at this temperature for 12 hours. Upon completion of the reaction as confirmed by thin layer chromatography, the mixture was quenched by pouring into 400 mL of deionized water and extracted further into methylene chloride. The methylene chloride extracts were then dried over sodium sulfate, filtered and concentrated in vacuo affording 20 g of 5,5,5-trifluoro-2-phenylpentan-2-yl methacrylate (LG2) (˜72% yield) of as an amber oil. The oil was purified further by passing through a silica gel plug and eluting with a 70:30 mixture of hexanes/methylene chloride to afford 19 g of pure product. 1H NMR (500 MHz, Acetone-d6): δ 7.32 (s, 3H), 7.24 (s, 2H), 6.11 (s, 1H, vinyl), 5.6 (s, 1H, vinyl), 2.45-2.05 (m/m, 5H), 1.92 (s, 3H), 1.87 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][O-:15].[Na+]>CO>[CH3:14][O:15][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1
Reactant: C[O-]
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(F)(F)F)ccc1C#N
Temperature: 60 °C
Yield: 97 %

Procedure:
To 2-chloro-6-trifluoromethyl-nicotinonitrile (0.5 g, 2.4 mmol) in methanol (30 mL) was added sodium methylate in small portion (2 mol eq, 0.26 g). The reaction mixture was heated at 60° C. overnight. The solvent was distilled under reduced pressure and water was added to the residue. The aqueous solution was extracted with EtOAc (3×25 mL) and the organic phases were evaporated at reduced pressure to give 28c as a pale yellow oil (0.48 g, 2.33 mmol, 97% Yield). 1HNMR (DMSO, 200 MHz) δ 4.04 (s, 3H), 7.71 (d, 1H, J=6), 8.59 (d, 1H, J=6).
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[C:13](Cl)(=O)[CH3:14].C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.O>[CH3:13][C:14]1[O:12][C:11]2[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=2)[N:2]=1
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: CC(=O)Cl
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2c(C(=O)O)cccc2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64 %

Procedure:
To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (0.35 g, 1.50 mmol) and acetyl chloride (0.11 mL, 1.50 mmol) in dichloromethane (10 mL) was added triethylamine (0.84 mL, 6.0 mmol) dropwise, then the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with dichloromethane, and then washed with 2 N HCl. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in toluene (10 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (263 mg, 1.38 mmol). The reaction mixture was then heated to reflux for 1.5 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was separated then washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, 9:1 to 3:1 ethyl acetate/methanol) to afford 2-methylbenzoxazole-4-carboxylic acid (0.17 g, 64%) as an off-white solid: MS (ESI+) m/z 178 (M+H).
Reaction SMILES: CS(O[CH2:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[C:18]([O:25][C@@H:26]3[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]3[O:28][C:29](=[O:31])[CH3:30])=[N:19][NH:20][C:21]=2[CH:22]([CH3:24])[CH3:23])=[C:12]([CH3:49])[CH:11]=1)(=O)=O.Cl.[CH2:51]1[C:56]2([CH2:61][CH2:60][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:58][CH2:57]2)[CH2:55][CH2:54][CH2:53][NH:52]1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:49][C:12]1[CH:11]=[C:10](/[CH:9]=[CH:8]/[CH2:7][CH2:6][N:52]2[CH2:53][CH2:54][CH2:55][C:56]3([CH2:57][CH2:58][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:60][CH2:61]3)[CH2:51]2)[CH:15]=[CH:14][C:13]=1[CH2:16][C:17]1[C:18]([O:25][C@@H:26]2[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]2[O:28][C:29](=[O:31])[CH3:30])=[N:19][NH:20][C:21]=1[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCOS(C)(=O)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CCCC4(CCN(C(=O)OC(C)(C)C)CC4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
Heat a mixture of (3E)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)oxy]-1H-pyrazol-4-yl}methyl)phenyl]but-3-en-1-yl methanesulfonate (1.0 g, 1.41 mmol), tert-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (451 mg, 1.55 mmol), and diisopropylethylamine (730 mg, 5.64 mmol) in acetonitrile (4 mL) at 80° C. overnight. Remove the solvent under the reduced pressure. Purify the resulting residue by flash chromatography (silica gel, gradient ethyl acetate/dichloromethane from 25-85% over 15 min, then with methanol/dichloromethane from 1-3% over 10 min, 40 g column) to provide the title compound (630 mg, 0.73 mmol). MS (m/z): 867.2, 868.4 (M+1), 865.2, 866.4 (M−1).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[O:10]=[C:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]1.C(OCC)(=O)C>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:11]2([OH:10])[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:13][CH2:12]2)=[CH:3][CH:4]=1)#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: N#Cc1ccc(I)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc(C#N)cc2)CC1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A solution of 4-iodobenzonitrile (510 mg, 2.22 mmol, 1.1 equiv) in THF (3 mL) was added to a 10 mL round-bottom flask and the system purged with nitrogen. The mixture was cooled to −40° C. then isopropylmagnesium chloride (1.16 mL of a 2.0 M soln in THF, 2.32 mmol, 1.15 equiv) was added dropwise over 20 minutes. The resulting mixture was stirred at −40° C. for 2 hours then tert-butyl 4-oxoazepane-1-carboxylate (431 mg, 2.02 mmol, 1.0 equiv) in THF (0.5 mL) was added dropwise over 15 minutes. The resulting mixture was stirred at −40° C. for 1 hour then diluted into ethyl acetate (15 mL) and washed with 0.2 M HCl (10 mL), 0.1 M HCl (5 mL), saturated sodium bicarbonate (5 mL) then brine (5 mL). The organics were dried (Na2SO4), filtered and evaporated. To remove remaining ketone and aldol by-product, the residue was dissolved in acetonitrile (3 mL) then hydrazine (0.2 mL) was added and heated at 60° C. for 4 hours. The mixture was diluted with EtOAc (20 mL) and washed with water (20 mL), followed by 0.5 M phosphoric acid (3×20 mL), saturated sodium bicarbonate (10 mL) and brine (10 mL). The organics were dried (Na2SO4), filtered and evaporated. The residue was purified by silica column chromatography (hexanes/ethyl acetate) to obtain the title compound as a pink oil which solidified upon standing (303 mg, 47%). m/z (ES+) 317 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:18]=3)=[CH:11][N:10]=2)=[CH:7][N:6]=[C:5]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[N:4]=1.Br>C(O)(=O)C>[CH3:15][C:13]1[C:12]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]3[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=3)[CH:18]=2)=[CH:11][N:10]=[C:9]([C:8]2[C:3](=[O:2])[NH:4][C:5]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[N:6][CH:7]=2)[CH:14]=1
Reactant: COc1nc(N2CCCC2)ncc1-c1cc(C)c(Oc2ccnc(-c3cnn(C)c3)c2)cn1
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc(-c2cnc(N3CCCC3)[nH]c2=O)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 90 °C
Yield: 59.6 %

Procedure:
A solution of 4-methoxy-5-(4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(pyrrolidin-1-yl)pyrimidine (0.19 g, 0.43 mmol) in acetic acid (2.5 mL) was treated with HBr (48%, 0.10 mL, 1.8 mmol) and heated at 90° C. for 16 h. The mixture was poured onto ice (10 g), neutralized with satd. NaHCO3, and the resulting solid was collected by filtration, washed with water and MeCN and dried to afford 5-(4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(pyrrolidin-1-yl)pyrimidin-4(3H)-one (0.11 g, 58%). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (bs, 1H), 8.68 (s, 1H), 8.38 (s, 1H), 8.34 (d, J=5.7 Hz, 1H), 8.30 (d, J=1.3 Hz, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.22 (d, J=2.4 Hz, 1H), 6.60-6.58 (m, 1H), 3.84 (s, 3H), 3.50 (bs, 4H), 2.15 (s, 3H), 1.91 (bs, 4H); MS (ESI) m/z: 430.2 (M+H+).