Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][CH:18]([C:21](=[O:29])[C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[H-].[Na+].[CH3:32]I>C1COCC1>[CH:1]1([CH2:4][CH2:5][N:6]([CH3:32])[C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:16][CH2:17][CH:18]([C:21](=[O:29])[C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:19][CH2:20]3)=[CH:13][CH:14]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: CI
Reactant: O=C(NCCC1CC1)c1ccc(N2CCC(C(=O)c3ccc(F)cc3)CC2)nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCC1CC1)C(=O)c1ccc(N2CCC(C(=O)c3ccc(F)cc3)CC2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a mixture of 6-[4-(4-fluorobenzoyl)piperidin-1-yl]pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.075 g, 0.189 mmol) and sodium hydride (0.009 g, 60% in mineral oil) in THF (15 mL) was added methyl iodide (0.134 g, 0.945 mmol) at 0° C. The reaction mixture was stirred at ambient temperature overnight, then concentrated in vacuo. The residue was diluted with water and then extracted with ethyl acetate. The organic layer was dried, concentrated and purified by column chromatography to yield the title compound in 52% yield (0.040 g). 1H NMR (300 MHz, CDCl3) δ 8.0-7.96 (m, 2H), 7.69-7.6 (m, 1H), 7.18-7.07 (m, 2H), 6.98-6.94 (m, 1H), 5.54-4.45 (m, 2H), 3.8-3.73 (m, 1H), 3.65-3.47 (m, 2H), 3.32-3.07 (m, 4H), 2.06-1.7 (m, 5H), 1.6-1.47 (m, 2H), 0.79-0.67 (m, 1H), 0.52-0.41 (m, 1H), 0.36-0.28 (m, 1H), 0.12-0.07 (m, 1H), 0.1-−0.06 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 200.1, 167.5, 167.2, 166.3, 164.1, 158.8, 148.6, 148.5, 132.1, 132.07, 131.0, 130.9, 129.2, 128.9, 116.1, 115.8, 112.3, 112.2, 51.6, 49.2, 44.5, 43.2, 38.2, 34.4, 33.6, 32.0, 27.9, 8.6, 8.3, 4.3, 4.26. MS (ES+) m/z 411 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:21])[N:4]=1.[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1>CN(C=O)C>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:21])[N:4]=1
Reactant: O=c1c2c(F)cccc2nc(CCl)n1-c1ccccc1Cl
Reactant: Nc1ncnc2nc[nH]c12
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2cccc(F)c2c(=O)n1-c1ccccc1Cl
Yield: 64.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2e (200 mg, 0.619 mmol), adenine (92 mg, 0.681 mmol), L2CO3 (94 mg, 0.680 mmol), and DMF (4 mL). The crude product was chromatographed in MeOH/CH2Cl2 to provide 168 mg of an off-white solid (64%), mp 159-172° C. (gradually decomposes). 1H NMR (DMSO-d6) δ: 8.10 (s, 1H); 8.08 (s, 1H); 7.73-7.89 (m, 3H); 7.57-7.71 (m, 2H); 7.37-7.48 (m, 2H); 7.34 (d, J=11 Hz, 1H); 7.30 (d, J=8.3 Hz, 1H); 5.14 (d, J=17 Hz, 1H); 4.94 (d, J=17 Hz, 1H). 13C NMR (DMSO-d6) ppm: 160.8 (d, J=264 Hz), 157.5 (d, J=4.2 Hz), 155.8, 152.4, 152.4, 150.0, 148.7, 142.1, 136.4 (d, J=11 Hz), 133.0, 132.2, 132.1, 131.2, 130.9, 129.4, 123.8 (d, J=3.6 Hz), 118.4, 114.5 (d, J=20 Hz), 110.2 (d, J=6.0 Hz), 44.9. MS (ES): m/z 422.0 (M+). Anal. calcd. for C20H13ClFN7O: C, 56.95; H, 3.11; Cl, 8.40; N, 23.24. Found: C, 54.62; H, 3.32; Cl, 9.40; N, 21.29.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([CH3:15])[CH:13]=3)[C:8]([C:17](O)=[O:18])=[C:7]2[C:20]2[CH:25]=[CH:24][C:23]([S:26](=[O:35])(=[O:34])[NH:27][C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])=[CH:22][N:21]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:38]>>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([CH3:15])[CH:13]=3)[C:8]([C:17]([Cl:38])=[O:18])=[C:7]2[C:20]2[CH:25]=[CH:24][C:23]([S:26](=[O:35])(=[O:34])[NH:27][C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])=[CH:22][N:21]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc2c(cc1F)c(C(=O)O)c(-c1ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn1)n2C1CCCC1
Product: Cc1cc2c(cc1F)c(C(=O)Cl)c(-c1ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn1)n2C1CCCC1
Temperature: 66 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-1-cyclopentyl-5-fluoro-6-methyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carboxylic acid (300 mg, 0.58 mmol) in SOCl2 (4 mL) was stirred at 66° C. for 2 h. Volatiles were removed by a stream of nitrogen followed by vacuum to give (S)-1-cyclopentyl-5-fluoro-6-methyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carbonyl chloride as a solid. The above prepared (S)-1-cyclopentyl-5-fluoro-6-methyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carbonyl chloride (100 mg, 0.188 mmol) was treated with a solution of methylamine in THF (2.0 M, 5 mL, 10 mmol) and stirred at room temperature for 5 min. The mixture was then treated with ethyl acetate, washed with water and brine, dried over Na2SO4 and evaporated to give (S)-1-cyclopentyl-5-fluoro-N,6-dimethyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carboxamide (66 mg, 67%). MS m/z 527.3 M+H+; 1H NMR (500 MHz, CDCl3): δ 9.18 (1H, br s), 8.30 (1H, dd, J=8.0 Hz, J=2.0 Hz), 7.73 (1H, d, J=8.5 Hz), 7.66 (1H, d, J=10.5 Hz), 7.28 (1H, br s), 6.26 (1H, br s), 5.91 (1H, d, J=9.5 Hz), 4.51-4.40 (1H, m), 4.15-4.10 (1H, m), 2.84 (3H, s), 2.43 (3H, d, J=1.5 Hz), 2.30-2.23 (2H, m), 2.10-1.90 (4H, m), 1.68-1.62 (2H, m), 1.42 (3H, d, J=8.5 Hz).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[OH:8][C:9]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:12]2[O:13][C:14]([CH:18]=O)([CH3:17])[CH2:15][CH2:16][C:11]=2[C:10]=1[CH3:24]>CO>[OH:8][C:9]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:12]2[O:13][C:14]([CH:18]3[NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][S:4]3)([CH3:17])[CH2:15][CH2:16][C:11]=2[C:10]=1[CH3:24]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C=O)O2
Reactant: N[C@@H](CS)C(=O)O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C1N[C@H](C(=O)O)CS1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A mixture of cysteine (1.5 g, 12.7 mmol) and the intermediate prepared in Example 2 above, 6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2-yl methanal (3.0 g, 13 mmol), in methanol was warmed at reflux for 2.5 h. The reaction mixture was cooled to ambient temperature and then stirred at ambient temperature overnight. The reaction mixture was filtered and the filtrate was recrystallized from ethanol (3 times) to give 1.2 g (28% yield) of (4R)-2-(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2-yl)-4-thiazolidine carboxylic acid as a white solid, m.p. 184°-186° C.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C@H:17]1[O:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH2:38][C@H:37]([CH2:39][N:40]5[CH:44]=[CH:43][N:42]=[N:41]5)[O:36][C:35]4=[O:45])=[CH:30][C:29]=3[F:46])=[CH:24][N:23]=2)[CH2:18]1)=[O:14])=O)(C)(C)C.C(O)(=O)C.Cl>CO>[CH3:6][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C@H:17]1[O:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH2:38][C@H:37]([CH2:39][N:40]5[CH:44]=[CH:43][N:42]=[N:41]5)[O:36][C:35]4=[O:45])=[CH:30][C:29]=3[F:46])=[CH:24][N:23]=2)[CH2:18]1)=[O:14]
Reactant: CN(CCCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CNCCCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}pyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methyl 5-[(tert-butoxycarbonyl)(methyl)amino]pentanoate (Example 34: 0.5 g, 0.77 mmol) was combined with acetic acid (15 ml) and hydrochloric acid (4M solution in dioxane, 1 ml, 4 mmol). The suspension was warmed for 2 minutes at approximately 80° C. to dissolve most of the suspended material. The mixture was stirred at room temperature for an additional 15 minutes then concentrated under reduced pressure. The residual solids were dissolved in water (40 ml) then extracted twice with ethyl acetate (20 ml). Evaporation of the aqueous layer followed by drying under reduced pressure gave a solid that was dissolved in methanol (1 ml) and precipitated by the addition of diethyl ether (10 ml). The solution was decanted off and the precipitation was repeated. The resulting sticky oil was dried in vacuo at 50° C. to give the hydrochloride salt of the title compound as a hygroscopic solid (0.46 g), melting point: 184° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]([Cl:11])=[C:6](Cl)[C:7]=1NN.[OH-].[Na+].C(Cl)Cl.Cl>O>[Cl:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]([Cl:11])=[CH:6][CH:7]=1
Reactant: NNc1c(Cl)c(Cl)nc(C(=O)O)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1nc(Cl)ccc1Cl
Temperature: 25 °C
Yield: 62 %

Procedure:
To a reaction flask containing 400 milliliters of water was added 30 grams (0.11 mole) of 3,5,6-trichloro-4-hydrazinopicolinic acid and 4.5 grams (0.11 mole) of sodium hydroxide dissolved in 25 milliliters of water. The reaction was heated to reflux and maintained under reflux while an additional 4.5 grams of sodium hydroxide dissolved in 25 milliliters of water was added dropwise over 50 minutes. The resulting solution was thereafter heated an additional 45 minutes under reflux and cooled to room temperature. The reaction mixture was mixed with 100 milliliters of methylene chloride and the solution acidified with 35 milliliters of concentrated hydrochloric acid. The two phases which formed were separated and the aqueous layer extracted twice with methylene chloride. The extracts were combined and dried over magnesium sulfate and the solvent evaporated to give 13.1 grams (62 percent of theoretical) of 3,6-dichloropicolinic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11]C(=O)C)=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[CH:20][C:19]2=[C:22]([CH3:35])[N:23]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)[N:18]2[N:17]=1>Cl>[NH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([NH:15][C:16]2[N:21]=[CH:20][C:19]3=[C:22]([CH3:35])[N:23]=[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[N:18]3[N:17]=2)[CH:5]=1
Reactant: COc1ccc(CCNC(C)=O)cc1Nc1ncc2c(C)nc(-c3cccc(C(F)(F)F)c3)n2n1
Agent: Cl
Product: COc1ccc(CCN)cc1Nc1ncc2c(C)nc(-c3cccc(C(F)(F)F)c3)n2n1
Yield: 17.3 %

Procedure:
A solution of N-{2-[4-methoxy-3-({5-methyl-7-[3-(trifluoromethyl)phenyl]-imidazo[5,1-f][1,2,4]triazin-2-yl}amino)phenyl]ethyl}acetamide (Example 52) (0.050 g, 0.17 mmol) in dilute HCl(aq) (1N, 15 mL) was heated to reflux for 5 h. Neutralization with NaOH(aq) (1N) and extraction into EtOAc followed by concentration and preparative HPLC gave N-[5-(2-aminoethyl)-2-methoxyphenyl]-5-methyl-7-[3-(trifluoromethyl)-phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (0.013 g) as a yellow solid. 1H NMR (Acetone-d6): δ9.17 (s, 1H), 9.08 (d, J=8.1 Hz, 1H), 8.64 (s, 1H), 8.33-8.30 (m, 1H), 8.13 (s, 1H), 7.97-7.90 (m, 1H), 7.80-7.77 (m, 1H), 7.02-6.95 (m, 2H), 3.96 (s, 3H), 3.48 (t, J=7.4 Hz, 2H), 2.95 (t, J=7.4 Hz, 2H), 2.60 (s, 3H). MS m/z 443 (M+1).
Reaction SMILES: [C:1]([Si:5]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[O:6][CH2:7][C:8]([C:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:32])[C:18]([S:21]([CH2:24][CH:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)(=[O:23])=[O:22])([CH3:20])[CH3:19])[O:13][N:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.C(OCC)C>[C:1]([Si:5]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[O:6][CH2:7][C:8]([C:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:32])[C:18]([CH3:20])([S:21]([CH2:24][CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)(=[O:23])=[O:22])[CH3:19])[O:13][N:12]=1)([CH3:10])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(NC(=O)C(C)(C)S(=O)(=O)CC2CCC(O)CC2)on1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(NC(=O)C(C)(C)S(=O)(=O)CC2CCC(=O)CC2)on1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.2 %

Procedure:
To a solution of 0.21 g (0.36 mmol) of N-{3-[2-(tert-butyl-diphenyl-silanyloxy)-1,1-dimethyl-ethyl]-isoxazol-5-yl}-2-(4-hydroxy-cyclohexylmethanesulfonyl)-2-methyl-propionamide in DCM (3 mL) is added pyridinium chlorochromate (0.15 g, 0.72 mmol) and the reaction mixture is stirred at room temperature for 18 h. The reaction is diluted with diethyl ether (6 mL) and stirred for 10 min. The mixture is filtered through a plug of silica and the filtrate is concentrated to afford 0.12 g of N-{3-[2-(tert-butyl-diphenyl-silanyloxy)-1,1-dimethyl-ethyl]-isoxazol-5-yl}-2-methyl-2-(4-oxo-cyclohexylmethanesulfonyl)-propionamide, which is used without further purification in the next step. Yield: 54%, ES-MS: 637 [M−H]
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[CH3:34])[CH2:16][C:17]([C:19]2[CH:20]=[CH:21][C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:11][CH:10]=1>ClCCl.N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[CH3:34])[CH2:16][C:17]([C:19]2[CH:20]=[CH:21][C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(NC(=O)CCCCl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 10 mL round-bottomed flask 5-[3-(4-amino-phenyl)-3-(4-chloro-2-methyl-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 353, step 1, 100 mg) was dissolved in dichloromethane (1.3 mL) and pyridine (41 mg). Then the reaction mixture was cooled in an icebath and 4-chlorobutyryl chloride (41.6 mg) was added slowly. The icebath was removed and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate. The organic layer was washed 1× with 1 M HCl and 2× with water. The aqueous layers were extracted 2× with ethyl acetate, the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 10% methanol in dichloromethane) to give the title compound as a light yellow foam, MS (ESI+): m/z=485.3 [M+H]+.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([CH3:21])[C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14](F)=[C:13]([F:18])[C:12]=1F)(C)C.[CH2:24]([N:26]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[C:33]2[CH:38]=[C:37]([O:39][C@@H:40]([CH3:44])[CH2:41][O:42][CH3:43])[CH:36]=[C:35]([OH:45])[CH:34]=2)=[N:27]1)[CH3:25].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH2:24]([N:26]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[C:33]2[CH:38]=[C:37]([O:39][C@@H:40]([CH3:44])[CH2:41][O:42][CH3:43])[CH:36]=[C:35]([O:45][C:14]3[CH:15]=[CH:16][C:11]4[C:10](=[O:20])[N:9]([CH3:21])[CH2:8][CH2:7][O:6][C:12]=4[C:13]=3[F:18])[CH:34]=2)=[N:27]1)[CH3:25]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(F)c1F
Reactant: CCn1ccc(NC(=O)c2cc(O)cc(O[C@@H](C)COC)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCn1ccc(NC(=O)c2cc(Oc3ccc4c(c3F)OCCN(C)C4=O)cc(O[C@@H](C)COC)c2)n1
Temperature: 140 °C
Yield: 68.1 %

Procedure:
A suspension of N-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-2,3,4-trifluoro-N-methylbenzamide (300 mg, 0.86 mmol), N-(1-ethyl-1H-pyrazol-3-yl)-3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide (290 mg, 0.91 mmol) and potassium carbonate (237 mg, 1.73 mmol) in DMA (20 mL) was heated to 140° C. for 4 hours. The reaction was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine (50 mL) and dried (MgSO4), filtered and evaporated to give an orange oil. This was purified by column chromatography on alumina, eluting with 30-100% ethyl acetate in isohexane, to give the desired product as a colourless oil (300 mg).
Reaction SMILES: [C:1](/[N:3]=[C:4](\[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1)#[N:2].Br[CH2:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1](/[N:3]=[C:4](\[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[N:5]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1)[CH2:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1)#[N:2]
Reactant: BrCCCOC1CCCCO1
Reactant: N#C/N=C(/Nc1ccc(F)c(F)c1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#C/N=C(\Oc1ccccc1)N(CCCOC1CCCCO1)c1ccc(F)c(F)c1
Temperature: 85 °C

Procedure:
To a solution of (Z)-phenyl N′-cyano-N-(3,4-difluorophenyl)carbamimidate (286 mg, 1.05 mmol) and 2-(3-bromopropoxy)tetrahydro-2H-pyran (369 mg, 277 μL, 1.57 mmol) in DMF (10.5 mL) was added at room temperature under an atmosphere of nitrogen potassium carbonate (289 mg, 2.09 mmol). The suspension was heated to 85° C. over night. Additional 2-(3-bromopropoxy)tetrahydro-2H-pyran (140 μL, 0.8 mmol) and potassium carbonate (145 mg, 1.05 mmol) were added and the reaction was heated for 5 hours to 85° C. Water was added and the reaction was extracted twice with diethyl ether. The combined organic layers were washed with water and with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as a light yellow viscous oil (202 mg, 46%) after column chromatography on silica gel using a gradient of heptane/ethyl acetate 4:1 to 1:1 (v/v) as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24]([OH:26])=O)=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.Cl.[NH2:63][CH2:64][C:65]1[CH:66]=[CH:67][C:68]2[C:72]([CH3:74])([CH3:73])[O:71][B:70]([OH:75])[C:69]=2[CH:76]=1>CN(C=O)C.CC(=O)OCC>[OH:75][B:70]1[C:69]2[CH:76]=[C:65]([CH2:64][NH:63][C:24]([C:21]3[C:20]4[N:16]([CH:17]=[CH:18][CH:19]=4)[C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=5)([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=4)=[CH:23][CH:22]=3)=[O:26])[CH:66]=[CH:67][C:68]=2[C:72]([CH3:74])([CH3:73])[O:71]1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: CC1(C)OB(O)c2cc(CN)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)c(Cl)c(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
To a solution of 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)indolizine-8-carboxylic acid (24 mg, 0.05 mmol), HATU (29 mg, 0.075 mmol) and Et3N (0.03 mL, 0.15 mmol) in DMF (10 mL) was added 6-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (23 mg, 0.1 mmol). The mixture was stirred at rt overnight. EA (30 mL) was added and the mixture was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound N-((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxamide (8 mg; yield 25%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.16 (t, J=6.0 Hz, 1H), 9.05 (s, 1H), 8.54 (s, 1H), 7.90 (s, 2H), 7.67 (s, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.29 (s, 2H), 7.06-7.12 (m, 2H), 4.54-4.68 (m, 4H), 1.44 (s, 6H) ppm; HPLC purity: 100.0% at 220 nm and 100.0% at 254 nm; MS: m/z=649.7 (M+1, ESI+).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:12][C:13]([F:25])([F:24])[C:14]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([F:16])[F:15]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:21][C:20]1[CH:19]=[CH:18][C:17]([C:14]([F:15])([F:16])[C:13]([Cl:12])([F:24])[F:25])=[CH:23][CH:22]=1)=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: Nc1ccc(C(F)(F)C(F)(F)Cl)cc1
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 9.3 using 5-bromo-6-chloronicotinic acid and 4-(2-chloro-1,1,2,2-tetrafluoroethyl)aniline (Stage 31.3) to afford a beige crystalline powder. HPLC (Condition 4) tR=6.77 min, UPLC-MS (Condition 3) tR=1.31 min, m/z=444.8 [M+H]+.
Reaction SMILES: [Cl:1][C:2](=[O:7])[CH2:3][C:4]([O-:6])=O.[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1.CCN(C(C)C)C(C)C.[Li+].[OH-]>O.C(Cl)Cl>[Cl:1][C:2](=[O:7])[CH2:3][C:4]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)=[O:6]
Reactant: O=C([O-])CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)CC(=O)Cl)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
A mixture of 3-chloro-3-oxopropanoate (0.235 mL, 2.2 mmol), tert-butyl 3-aminopyrrolidine-1-carboxylate (410 mg, 2.2 mmol), DCM (4.4 mL) and DIPEA (0.766 mL, 4.4 mmol) was stirred for 2 h at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was re-dissolved in THF (2.2 mL), treated with LiOH×H2O (0.185 g, 4.4 mmol) in water (2.2 mL) for 2 h at room temperature and concentrated under reduced pressure to remove the THF. The remaining aqueous solution was extracted with EtOAc, acidified with 2N HCl (until pH˜5), extracted again with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound 35 (286 mg, 48% yield) as a light brown foam which was used in the next step without further purification. MS (m/z): 273.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC1C=NC(C2C=CC=CC=2)=CC=1[I:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:9]([I:34])=[CH:10][C:11]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[N:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cnc(-c2ccccc2)cc1I
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCCCC2)nc1
Product: CC(C)(C)OC(=O)Nc1cnc(N2CCCCC2)cc1I

Procedure:
The title product was prepared from (3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)carbamic acid tert-butyl ester in the same manner as described in the preparation of (4-iodo-6-phenylpyridin-3-yl)carbamic acid tert-butyl ester.