Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[C:27]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:26][N:25]=[CH:24][N:23]=4)[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH3:38][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[C:27]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:26][N:25]=[CH:24][N:23]=4)[C:17]([C:32]([F:35])([F:33])[F:34])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: NC(=O)Cc1cncnc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncncc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56.7 %

Procedure:
To a suspension of 2-(4-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyrimidin-5-yl)acetamide (29) (0.029 g, 0.060 mmol) in anhydrous methanol (2 mL) was added a 37% aq. solution of formaldehyde (0.018 mL, 0.24 mmol) under an atmosphere of nitrogen, followed by sodium triacetoxyborohydride (0.063 g, 0.30 mmol). The reaction was stirred at room temperature for 2.5 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (50 mL) and sat. aq. NaHCO3 (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL), the combined organic layers were washed with water (40 mL), brine (40 mL), dried (MgSO4), filtered and concentrated in vacuo to give a solid which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice. The resulting off-white solid was suspended in DCM (5 mL) and cyclohexane was added (˜10 mL). The suspension was sonicated and the product was collected by filtration. The solid was washed with petroleum benzine 40-60° C. (5×10 mL), air-dried and subsequently dried under high-vacuum to give the title compound (30) (0.017 g, 57% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.01 (s, 1H), 8.94 (s, 1H), 8.63 (s, 1H), 8.53 (s, 1H), 7.64 (s, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 7.11 (s, 1H), 3.57 (s, 2H), 3.28-3.22 (m, 4H), 2.87 (d, J=11.2 Hz, 2H), 2.46-2.36 (m, 1H), 2.20 (s, 3H), 1.98 (t, J=10.6 Hz, 2H), 1.76-1.58 (m, 4H). LCMS Method C: it 4.52 min; m/z 500.1 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)=[C:15]([O:25][CH3:26])[CH:14]=2)[N:7]=1)=O)C.[CH2:27]([Mg]Br)[CH3:28].C(=O)([O-])[O-].[Na+].[Na+].O1CC[CH2:39][CH2:38]1>>[CH3:26][O:25][C:15]1[CH:14]=[C:13]([NH:12][C:8]2[N:7]=[C:6]([C:4]([OH:3])([CH2:27][CH3:28])[CH2:38][CH3:39])[CH:11]=[CH:10][N:9]=2)[CH:18]=[CH:17][C:16]=1[N:19]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]1
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCC(O)(CC)c1ccnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 9 %

Procedure:
To a solution of 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidine-4-carboxylic acid ethyl ester (46 mg, 0.13 mmol) in tetrahydrofurane (2.5 mL) was added at 0° C. over 1 min a 1 M solution of ethylmagnesiumbromide in tetrahydrofurane (0.43 mL, 0.43 mmol). The reaction mixture was stirred at 0° C. for 15 min followed by 1 h at 20° C. The mixture was poured on saturated sodium carbonate solution (5 mL) and the mixture was extracted with ethyl acetate (40 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using dichloromethane/0-10% methanol as eluent to give the title compound (4 mg, 9%) as yellow oil. MS ISP (m/e): 368.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.42 (d, 1H), 7.66 (d, 1H), 7.65 (s, 1H), 7.39 (s, 1H), 7.20 (d, 1H), 7.06 (dd, 1H), 6.89 (s, 1H), 6.79 (d, 1H), 4.32 (br s, 1H), 3.88 (s, 3H), 2.31 (s, 3H), 2.35 (m, 4H), 0.76 (t, 6H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[S:7])[NH:5][NH2:6])[CH3:2].[CH2:8]([I:10])C>C(O)C>[IH:10].[CH2:1]([N:3]=[C:4]([S:7][CH3:8])[NH:5][NH2:6])[CH3:2]
Reactant: CCNC(=S)NN
Reactant: CCI
Solvent: CCO
Product: CCN=C(NN)SC
Product: I

Procedure:
A stirred solution of 97.0 g. of 4-ethyl-3-thiosemicarbazide and 127.8 g. of ethyl iodide in 500 ml. of ethanol is heated under reflux for 18 hours. The reaction mixture is concentrated under reduced pressure, diluted with n-hexane and filtered, giving the desired product as a nearly colorless solid, m.p. 73°-74° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2O[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH:17]1[CH2:21][CH2:20][CH2:19][CH:18]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C>ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:18]3[CH2:19][CH2:20][CH2:21][C:17]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Fc1cc(-c2cnco2)ccc1C(F)(F)F
Reactant: C1=CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: Clc1ccccc1Cl
Solvent: CCN(CC)CC
Product: Fc1cc(-c2cncc3c2CCC3)ccc1C(F)(F)F
Yield: 43.8 %

Procedure:
A solution of 5-(3-fluoro-4-(trifluoromethyl)phenyl)-oxazole (0.50 g, 2.16 mmol), cyclopentene (2.95 g, 43.3 mmol) and trifluoroacetic acid (0.49 g, 4.33 mmol) in o-dichlorobenzene (12 mL) was heated under microwave irradiation to 220° C. for 6 h. To the reaction mixture was added triethylamine (5 mL) and the solvent mixture removed under reduced pressure. Purification by flash chromatography (70 g SiO2, Telos-cartridge) eluting with a 0 to 50% EtOAc/n-heptane gradient provided the title compound (266 mg, 44%) as a slightly brown solid. MS: 282.5 (M+H)+.
Reaction SMILES: C([O:8][C@H:9]1[C@H:16]([O:17]CC2C=CC=CC=2)[C@@H:15]([O:25]CC2C=CC=CC=2)[C@H:14]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([CH2:47][CH3:48])=[CH:43][CH:42]=3)[CH:34]=2)[C:11]2([CH2:13][CH2:12]2)[C@@H:10]1[CH2:49][O:50]CC1C=CC=CC=1)C1C=CC=CC=1.ClC1C=CC=CC=1Cl.[H][H]>C1COCC1.CO.[Pd]>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:14]2[C@H:15]([OH:25])[C@@H:16]([OH:17])[C@H:9]([OH:8])[C@@H:10]([CH2:49][OH:50])[C:11]32[CH2:12][CH2:13]3)=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([CH2:47][CH3:48])=[CH:45][CH:46]=1
Reactant: CCc1ccc(Cc2cc([C@H]3[C@H](OCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@@H](COCc4ccccc4)C34CC4)ccc2Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: CCc1ccc(Cc2cc([C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)C34CC4)ccc2Cl)cc1
Yield: 37.3 %

Procedure:
To a solution of (4R,5R,6R,7S,8S)-5,6,7-tris(benzyloxy)-4-(benzyloxymethyl)-8-(4-chloro-3-(4-ethylbenzyl)phenyl)spiro[2.5]octane (36, 20 mg, 25.7 μmol) in a mixture of THF (0.2 mL) and methanol (0.8 mL) was added 1,2-dichlorobenzene (58 μL, 515 μmol) followed by 14 mg of palladium on charcoal (10%). The mixture was stirred under 1 atmosphere of hydrogen for 40 minutes. The mixture was filtered through a small pad of Celite in a 6 mL syringe and the Celite pad was washed with methanol (1 mL). Solvent was evaporated under reduced pressure and the residue was purified on preparative TLC plate (8:1 DCM:EtOH) to get 4 mg (37%) of compound 37 as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.27-6.85 (m, 7H), 4.01 (s, 2H), 3.80 (m, 2H), 3.63 (m, H), 3.35 (d, J=5.1 Hz, 2H), 3.02 (d, J=11.1 hz, 1H), 2.62 (q, J=7.5 Hz, 2H), 2.06 (m, 1H), 1.21 (t, J=7.5 Hz, 3H), 0.40 (m, 1H), 0.29 (m, 1H), 0.076 (m, 1H), −0.326 (m, 1H). LC-ESI-MS m/z 418 (M+H), 440 (M+Na).
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:8][C:9](=[O:11])[CH3:10])C=CC=CC=1.[CH2:24]([S:26][CH:27]([CH3:31])[CH2:28][CH:29]=O)[CH3:25].CCCCCC.CCOCC>ClCCl>[CH2:24]([S:26][CH:27]([CH3:31])[CH2:28][CH:29]=[CH:8][C:9](=[O:11])[CH3:10])[CH3:25]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCSC(C)CC=O
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOCC
Product: CCSC(C)CC=CC(C)=O
Temperature: 25 °C

Procedure:
1-Triphenylphosphoranylidene-2-propanone (12.77 g, 40.0 mmol) is added to a solution of 3-(ethylthio)butyraldehyde (5.30 g, 40.0 mmol) in dichloromethane (100 ml) and the mixture is heated under reflux for 24 hours. The reaction mixture is cooled to room temperature, and the solvent evaporated in vacuo to give a beige solid. The crude product is taken up in a 1:1 mixture of hexane:ether (the insoluble material is discarded), and then concentrated under reduced pressure to give an orange oil which is further purified by column chromatography on silica gel to give 6-(ethylthio)hept-3-en-2-one as a yellow oil.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1>>[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[N:6]2[C:15](=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:27]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCCCCCCCC(=O)Cl
Reactant: c1ccc2c(c1)cnc1ccccc12
Product: CCCCCCCCC(=O)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
1-[6-(1H-Indol-3-yl)-6H-phenanthridin-5-yl]-nonan-1-one was prepared from phenanthridine, pelargonyl chloride, and indole according to GP 2. Yield, 2%. 1H-NMR (DMSO-d6): δ=0.81 (t, J=7.0 Hz, 3H), 0.99-1.24 (m, 10H), 1.44-1.58 (m, 2H), 2.30-2.75 (m, 2H; overlap with solvent signal), 6.08 (s, br., 1H), 6.98 (td, J=7.4 Hz, 1H), 7.04 (td, J=7.4 Hz, 1H), 7.10-7.19 (m, 2H), 7.20-7.33 (m, 3H), 7.38 (td, J=7.3 Hz, J=1.0 Hz, 1H), 7.43-7.51 (m, 2H), 7.69 (d, J=7.5 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 8.00 (d, J=7.4 Hz, 1H), 10.62 (s, 1H); (+)-ESI-MS: m/z=437 [M+H]+, 320 [M-indole+H]+, 180.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[C:15]2[O:14][CH2:13][C:12]([CH3:17])([CH3:16])[C:11]=2[CH:10]=[C:9]([Br:18])[CH:8]=1)C.O.[OH-].[Li+]>CO.O1CCCC1.O>[Br:18][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([OH:19])=[O:3])[C:15]2[O:14][CH2:13][C:12]([CH3:17])([CH3:16])[C:11]=2[CH:10]=1
Reactant: CCOC(=O)CCc1cc(Br)cc2c1OCC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COc2c(CCC(=O)O)cc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of 3-(5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-propionic acid ethyl ester (Intermediate 76, 0.875 g, 2.67 mmol) in methanol (15 mL), tetrahydrofuran (15 mL) and water (7 mL) was treated with lithium hydroxide monohydrate (0.68 g, 16 mmol) and the resulting reaction mixture was stirred at room temperature for 1 h. The volatiles were evaporated in vacuo and the residue was diluted with water and washed with diethyl ether. The aqueous phase was neutralized with concentrated hydrochloric acid and the solution was extracted with ether (×3). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to afford the title compound as an oily foam (0.64 g, 87%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.O.C(Cl)[Cl:16]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[C:9]([Cl:16])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCl
Reactant: CC(C)(C)c1ccc(O)cc1
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 4-tert-butyl-phenol (40.0 g, 0.27 mol) and SO2Cl2 (37.5 g, 0.28 mol) in CH2Cl2 was added MeOH (9.0 g, 0.28 mol) at 0° C. After addition was complete, the mixture was stirred overnight at room temperature and then water (200 mL) was added. The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (Pet. Ether/EtOAc, 50:1) to give 4-tert-butyl-2-chloro-phenol (47.0 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[O-:12][C:13]#[N:14].[K+].C(O)(=O)C.[OH-].[Na+]>O.O1CCOCC1>[CH3:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:13](=[O:12])[NH:14][C:4]2=[O:5]
Reactant: N#C[O-]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2[nH]c(=O)[nH]c(=O)c2c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
2.00 g of 2-amino-5-methylbenzoic acid was suspended in 20 mL of water, to which 1.18 g of potassium cyanate was added and a mixture of 0.23 mL of acetic acid and 1 mL of water were added dropwise, and this suspension was stirred for 1.5 hours at 50° C. Then, after a solution of 1.42 g of sodium hydroxide in 2 mL of water was added drowise, to which 40 mL of water and 20 mL of 1,4-dioxane were added, and this solution was stirred for 3.5 hours while heating it under reflux. The reaction mixture was ice-cooled, from which precipitated solid was filtered, and then 30 mL of water and 3 mL of 6M of hydrochloric acid were added to the resultant solid, which was then stirred for 1.5 hours while heating it under reflux. The reaction mixture was cooled to room temperature, from which resultant precipitate was filtered and washed with water to yield 1.17 g of 6-methyl-2,4-(1H,3H)-quinazolinedione as white solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([N:55](CC3C=CC(OC)=CC=3)[C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[CH:52][N:51]=[C:50]([F:54])[CH:49]=4)=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.C(OC([NH:87][C@H:88]([CH3:92])[C:89](O)=[O:90])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:87][C@@H:88]([C:89]([NH:28][C@H:29]1[CH2:30][CH2:31][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([NH:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[CH:52][N:51]=[C:50]([F:54])[CH:49]=4)=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:33][CH2:34]1)=[O:90])[CH3:92]
Reactant: COc1ccc(CN(c2ccccn2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)cc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](N)C(=O)N[C@H]1CC[C@H](Nc2cc(Nc3ccccn3)c3ncc(C(=O)Nc4ccnc(F)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
BOP (68.4 mg, 0.155 mmol) was added to a solution of 62B (30.0 mg, 0.052 mmol), DIEA (0.036 mL, 0.206 mmol) and (R)-2-(tert-butoxycarbonylamino)propanoic acid (19.52 mg, 0.103 mmol) in DCM (1 mL). The clear reaction mixture was stirred at room temperature for 30 minutes and then concentrated to dryness. TFA (0.238 mL, 3.09 mmol) was added and the reaction solution was stirred at 70° C. for 1 h. The reaction mixture was then concentrated and diluted with MeOH. The crude product was purified by HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 10% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 90% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to afford 6-((trans-4-(D-alanylamino)cyclohexyl)amino)-N-(2-fluoro-4-pyridinyl)-8-(2-pyridinylamino)imidazo[1,2-b]pyridazine-3-carboxamide (11.5 mg, 0.022 mmol, 41.9% yield) as a white solid. HPLC Rt=1.613 (Phenomenex Luna 5 micron C18 4.6×30 mm: 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). [M+H]=533.17.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:29])[CH3:28])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][C:20]([CH2:23]Cl)=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:30]#[N:31].[K+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:29])[CH3:28])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][C:20]([CH2:23][C:30]#[N:31])=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc(CCl)nc2[nH]1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc(CC#N)nc2[nH]1
Yield: 52.1 %

Procedure:
A solution of 2-[5-(benzyloxy)-2-isopropoxyphenyl]-5-(chloromethyl)-3H-imidazo[4,5-b]pyridine (0.11 g) and potassium cyanide (30 mg) in N,N-dimethylformamide (5 ml) was stirred at 60° C. for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC, and saturated aqueous sodium hydrogencarbonate solution was added to the obtained fraction to neutralize the mixture. The mixture was extracted with dichloromethane, and the extract was concentrated to give the title compound (56 mg, yield 52%) as colorless crystals. purity 90%. M+H: 399.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:25]=C[C:23](F)=[CH:22][CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC([N:34]1CCN(C2N=CC(Br)=CN=2)CC1)=O)(C)(C)C.B1(C2C=CC=NC=2)OCCCO1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]([C:20]3[CH:25]=[N:34][CH:23]=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1
Agent: c1cncc(B2OCCCO2)c1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccnc3)cn2)CC1
Yield: 99 %

Procedure:
Prepared according to the method for the preparation of 4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester, from 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (0.403 g) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (0.211 g), to yield the title compound as an orange solid (0.399 g, 99%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].[Mg].[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.[Cl-].[NH4+]>O1CCCC1>[F:10][C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[C:19]1([OH:22])[CH2:20][CH2:21][C:16]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:17][CH2:18]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1cc(F)c(Br)cc1F
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2cc(F)c(F)cc2F)CCC2(CC1)OCCO2
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A three neck flask (2 L) under an atmosphere of nitrogen with Mg turnings (9.8 g) was stirred for 15 min and tetrahydrofuran (90 mL) was added and stirring continued for an additional 15 min. 1-Bromo-2,4,5-trifluorobenzene (85 g) was dissolved in tetrahydrofuran (340 mL). A portion of this solution (75 mL) was added to the stirred magnesium turnings and then heated to 50° C. The rest of the solution was added and stirring continued at the same temperature for an additional 1 h. The reaction mixture was cooled to 40° C., a solution of 1,4-dioxaspiro[4.5]decan-8-one (57.3 g) in tetrahydrofuran (275 mL) was added, and stirring continued for 10 h. The reaction mixture was poured into saturated aqueous ammonium chloride solution (970 mL) and extracted with toluene (700 mL). The organic layer was washed with water (3×700 mL), dried over anhydrous sodium sulfate, filtered and evaporated to yield the title compound as a red-orange oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH:11]=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[NH:25][C:24]2[C:26]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:27][CH:28]=[CH:29][C:23]=2[N:22]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[NH:25][C:24]2[C:26]([CH:30]3[CH2:35][CH2:34][N:33]([CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH2:32][CH2:31]3)=[CH:27][CH:28]=[CH:29][C:23]=2[N:22]=1
Reactant: COc1ccccc1-c1nc2cccc(C3CCNCC3)c2[nH]1
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccccc1-c1nc2cccc(C3CCN(CCN(C)C(=O)OC(C)(C)C)CC3)c2[nH]1
Temperature: 25 °C
Yield: 25.8 %

Procedure:
To a solution of tert-butyl methyl(2-oxoethyl)carbamate (0.165 g, 0.950 mmol) in DCM (3 ml) was added a solution of 175 (0.292 g, 0.950 mmol) in MeOH (3.00 ml) followed by acetic acid (0.082 ml, 1.425 mmol) and after 1 hour of stirring at room temperature, sodium triacetoxyborohydride (0.242 g, 1.140 mmol) was added according to the procedure described for 59 (scheme 8, example 6, step 7) to give tert-butyl 2-(4-(2-(2-methoxyphenyl)-1H-benzo[d]imidazol-7-yl)piperidin-1-yl)ethyl(methyl)-carbamate (0.114 g, 0.245 mmol, 25.8% yield) as a white crusty solid. LRMS (ESI): (calc.) 464.6 (found) 465.5 (MH)+
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]2[C:12]([CH3:14])([CH3:13])[O:11][B:10]([OH:15])[C:9]=2[CH:16]=1)([CH3:4])[CH3:3].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.[CH3:50][C:51]1[CH:59]=[C:58]([C:60]2[CH2:64][C:63]([C:69]3[CH:74]=[C:73]([Cl:75])[C:72]([Cl:76])=[C:71]([Cl:77])[CH:70]=3)([C:65]([F:68])([F:67])[F:66])[O:62][N:61]=2)[CH:57]=[CH:56][C:52]=1[C:53](O)=[O:54]>C1COCC1.CC(=O)OCC>[OH:15][B:10]1[C:9]2[CH:16]=[C:5]([C:2]([NH:1][C:53](=[O:54])[C:52]3[CH:56]=[CH:57][C:58]([C:60]4[CH2:64][C:63]([C:69]5[CH:74]=[C:73]([Cl:75])[C:72]([Cl:76])=[C:71]([Cl:77])[CH:70]=5)([C:65]([F:68])([F:67])[F:66])[O:62][N:61]=4)=[CH:59][C:51]=3[CH3:50])([CH3:4])[CH3:3])[CH:6]=[CH:7][C:8]=2[C:12]([CH3:14])([CH3:13])[O:11]1
Reactant: CC(C)(N)c1ccc2c(c1)B(O)OC2(C)C
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC(C)(C)c1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a solution of 6-(2-aminopropan-2-yl)-3,3-dimethylbenzo[c][1,2]-oxaborol-1(3H)-ol (100 mg), HATU (277 mg, 0.73 mmol) and DIPEA (0.2 mL, 1.1 mmol) in THF (5 mL) was added 2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzoic acid (80 mg, 0.37 mmol). The reaction mixture was stirred at rt overnight. EA 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 final title compound N-(2-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)propan-2-yl)-2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamide (100 mg; yield 38% over 3 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.99 (s, 1H), 8.64 (s, 1H), 7.85 (s, 2H), 7.74 (s, 1H), 7.47-7.55 (m, 4H), 7.36 (d, J=8.4 Hz, 1H), 4.41 (d, J=18.4 Hz, 1H), 4.34 (d, J=18.4 Hz, 1H), 2.33 (s, 3H), 1.66 (s, 6H), 1.44 (s, 6H) ppm; HPLC purity: 99.29% at 220 nm and 99.63% at 254 nm; MS: m/z=653.8 (M+1, ESI+).