Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:34]=[CH:33][C:24]2[NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:31])([CH3:30])[C:23]=2[CH:22]=1.Cl>O1CCOCC1.COCCO>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[CH:34]=[CH:33][C:24]3[NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:31])([CH3:30])[C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl
Temperature: 25 °C
Yield: 31.1 %

Procedure:
Combined 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (69 mg, 0.2322 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (73 mg, 0.357 mmol), 4 N HCl in dioxane (70 ul) and 2-methoxyethanol (3 mL). Heated reaction to 120° C. for 1.5 hours. Let reaction cool to room temperature and a solid precipitated out, which was filtered off. Purified solid with normal phase chromatography to yield a white solid (33.6 mg, 31%), 2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide. mp 295° C.; LCMS: m/z=465.41 (M+H+), 1H NMR (400 MHz, MeOD) δ 8.76 (d, 1H, J=8.6 Hz), 8.13 (s, 1H), 7.69 (m, 2H), 7.59 (s, 1H), 7.48 (m, 1H), 7.15 (m, 1H), 6.97 (d, 1H, J=8.3 Hz), 2.95 (s, 3H), 2.34 (m, 2H), 2.12 (m, 2H), 1.38 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[O:14])=[C:11]([Cl:24])[CH:10]=1.[C:25](=O)([O:36]C1C=CC([N+]([O-])=O)=CC=1)[O:26][CH2:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:24][C:11]1[CH:10]=[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:25](=[O:36])[O:26][CH2:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:23]=[CH:22][C:12]=1[C:13](=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2N)cc1Cl
Reactant: CCCCCC(=O)OCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCC(=O)OCOC(=O)Nc1ccccc1Nc1ccc(C(=O)c2ccccc2C)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-(2-aminophenylamino)-2-chloro-2′-methylbenzophenone (305 mg, 1.0 mmol) and hexanoyloxymethyl 4-nitrophenyl carbonate (Compound 207) (3.3 g, 10 mmol) in DMF (50 ml) was added 1-hydroxybenzotriazole (270 mg, 2.0 mmol) followed by N-ethyl di-iso-propylamine (0.18 ml, 1.05 mmol). The reaction mixture was stirred at room temperature. After 72 hours, the reaction mixture was poured into ice/water and extracted with diethylether. The etheral extracts were washed with a saturated sodium carbonate solution, water, and brine and dried over anhydrous sodium sulphate. Filtration and concentration in vacuo afforded the crude product. This was further purified by chromatography using Et2O/hexane 2:1 as eluent.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([CH3:31])([CH3:30])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24]CC)=[O:23])C.[OH-].[K+]>CCO.O>[CH3:30][C:5]([CH3:31])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([OH:24])=[O:23])[C:4]([OH:32])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCCCCCC(=O)CCCCCCCC(C)(C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCCCCCC(=O)CCCCCCCC(C)(C)C(=O)O)C(=O)O
Yield: 74.1 %

Procedure:
To a solution of 209j (11.63 g, 25.6 mmol) in EtOH and H2O (3:1, 200 mL) was added powdered KOH (85%, 4.31 g, 65.3 mmol). The resulting mixture was refluxed for 19 h and concentrated in vacuo until all of the EtOH was removed. Water (200 mL) was added and the resulting mixture was extracted with Et2O (2×200 mL). The aqueous phase was acidified with aqueous HCl (4 M) to pH˜1 and extracted with Et2O (3×200 mL). The combined Et2O layers of the latter extraction were dried over anhydrous Na2SO4 and evaporated in vacuo. The remaining white solid was recrystallized from heptane/iPr2O to give 210j (7.56 g, 74%) as white crystals. Mp 74.3-77.3° C. 1H NMR (CD3OD): δ (ppm): 2.43 (t, J=7.3, 4H), 1.57-1.50 (m, 8H), 1.33-1.21 (m, 16H), 1.14 (s, 12H). 13C NMR (CD3OD): δ (ppm): 214.5, 182.1, 43.6, 43.2, 42.0, 31.2, 30.4, 30.38, 26.2, 25.9, 25.0. HRMS: Calcd for C23H42O5 (M+): 398.3028, found: 398.3032.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH:19]=[CH2:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH:19]=[CH2:20])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:21])=[O:29]
Reactant: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Yield: 78.9 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-ethenylbenzonitrile (0.109 g, 0.361 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.100 g, 0.361 mmol) and DIPEA (0.126 mL, 0.723 mmol) were combined in THF (3 mL) and treated with HATU (0.151 g, 0.397 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in EtOAc, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 20 to 60% EtOAc/hexanes to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.16 g, 0.285 mmol, 79% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.79 (t, J=5.63 Hz, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.37-7.54 (m, 3H), 7.25 (s, 1H), 6.75 (dd, J=17.67, 11.08 Hz, 1H), 6.05 (d, J=17.67 Hz, 1H), 5.51 (s, 2H), 5.44 (d, J=10.99 Hz, 1H), 4.50 (d, J=5.59 Hz, 2H), 3.40 (t, J=8.10 Hz, 2H), 0.76 (t, J=8.06 Hz, 2H), −0.07 (s, 9H). LC-MS (ES−) m/z 559.13, 561.19 [M−1]. LC-MS (ES+) m/z 561.14, 563.12 [M+H].
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[O:22][CH3:23])=[C:16]([CH3:25])[CH:15]=1.[Cl:26][CH:27]([CH3:31])[C:28](Cl)=[O:29].O>CN(C)C=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([C:21]([O:22][CH3:23])=[O:24])[C:28](=[O:29])[CH:27]([Cl:26])[CH3:31])=[C:16]([CH3:25])[CH:15]=1
Reactant: CC(Cl)C(=O)Cl
Reactant: COC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N(C(=O)C(C)Cl)c1ccc(OCc2nc3ccccc3s2)cc1C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
18 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 100 mg of methyl N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]carbamate (prepared as described in Example 22 above) in 4 ml of dimethylformamide cooled in an ice-water bath. The resulting mixture was stirred for 15 minutes at the same temperature, after which 0.059 mi of 2-chloropropionyl chloride were added. The temperature of the resulting mixture was elevated to room temperature and the mixture was stirred for 3 hours. At the end of this time, water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure. The resulting.; residue was purified by preparative thin layer chromatography using a 1:1 by volume mixture of hexane and ethyl acetate to give 70 mg (yield 54%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[Br:18][C:19]1[N:24]=[C:23]([CH:25]=[O:26])[CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>ClCCl>[Br:18][C:19]1[N:24]=[C:23]([CH:25]([C:7]2[C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:9][C:8]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[OH:26])[CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: COc1ccc2cc(-c3ccccc3)[nH]c2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1ccc2c(C(O)c3cccc(Br)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 87.4 %

Procedure:
To a suspension of 6-methoxy-2-phenyl-1H-indole (893 mg) and 6-bromopyridine-2-carboaldehyde (744 mg) in dichloromethane (13.3 mL) was added 1,8-diazabicyclo[5,4,0]-7-undecene (0.060 mL), and the mixture was stirred at room temperature for 13 hours under an argon atmosphere. The reaction mixture was purified by aminopropylated silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.43 g). 1H-NMR (CDCl3) δ ppm: 3.81 (3H, s), 4.71 (1H, d, J=2.6 Hz), 6.09 (1H, d, J=2.6 Hz), 6.65 (1H, dd, J=2.3, 8.7 Hz), 6.86 (1H, d, J=2.3 Hz), 7.02-7.13 (2H, m), 7.33-7.54 (5H, m), 7.64-7.72 (2H, m), 8.10 (1H, br s).
Reaction SMILES: [O:1]([CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[Li]CCCC.[CH2:23](Br)[CH:24]=[C:25]([CH2:27][CH2:28][CH:29]=[C:30]([CH2:32][CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])[CH3:31])[CH3:26].C([O-])(O)=O.[Na+]>C1COCC1>[O:1]([CH:9]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH2:23]/[CH:24]=[C:25](\[CH3:26])/[CH2:27][CH2:28]/[CH:29]=[C:30](\[CH3:31])/[CH2:32][CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])[Si:2]([C:5]([CH3:7])([CH3:6])[CH3:8])([CH3:3])[CH3:4]
Reactant: CCOP(=O)(CO[Si](C)(C)C(C)(C)C)OCC
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C/C=C(\C)CC/C=C(\C)CCC=C(C)C)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of the diethyl (t-butyldimethylsiloxy)methylphosphonate (562 mg, 2.0 mmol) in THF (5 ml) under argon at -78° C. was added n-BuLi (0.84 ml of a 2.5M solution in hexanes, 2.1 mmol) and the resulting mixture stirred at -78° C. for 15 min. Farnesyl bromide (0.542 ml, 2.0 mmol) was added to the mixture over 5 min and the solution stirred a further 1 hr at -78° C. and then allowed to warm to r.t. The reaction mixture was poured into saturated NaHCO3 solution and the organic solvent evaporated in vacuo, the residue was extracted into ethylacetate and washed with brine, dried (MgSO4) and concentrated in vacuo and the resulting oil chromatographed on silica gel eluted with ethylacetate:hexanes (3:7, v:v). to afford the title compound as an oil.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:23])[C:9]([CH2:21]Cl)=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C-:24]#[N:25].[Na+]>CC#N.C1OCCOCCOCCOCCOCCOC1>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:23])[C:9]([CH2:21][C:24]#[N:25])=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(=O)N1CCc2c(C)c(CCl)c(C)c(NC(=O)C(C)(C)C)c21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)N1CCc2c(C)c(CC#N)c(C)c(NC(=O)C(C)(C)C)c21
Yield: 75.9 %

Procedure:
N-(1-Acetyl-5-chloromethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (21 g) was suspended in CH3CN (150 ml), and NaCN (8.1 g) and 18-crown-6 (870 mg) were added, which was followed by refluxing for 15 hr. CH3CN was evaporated under reduced pressure and CHCl3 (300 ml) was added. The mixture was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The obtained residue was washed with boiling MeOH to give 15.5 g of N-(1-acetyl-5-cyanomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: C([O:8][C@@H:9]1[CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[C@H:11]([CH2:24][O:25]CC2C=CC=CC=2)[C@H:10]1[O:33][C@H:34]1[O:87][C@H:86]([CH2:88][O:89]CC2C=CC=CC=2)[C@@H:53]([O:54][C@@H:55]2[O:84][C@H:83]([CH3:85])[C@@H:74]([O:75]CC3C=CC=CC=3)[C@H:65]([O:66]CC3C=CC=CC=3)[C@H:56]2[O:57]CC2C=CC=CC=2)[C@H:44]([O:45]CC2C=CC=CC=2)[C@H:35]1[O:36]CC1C=CC=CC=1)C1C=CC=CC=1>CO.Cl.[OH-].[Pd+2].[OH-].[C]>[C@@H:55]1([O:54][C@@H:53]2[C@@H:86]([CH2:88][OH:89])[O:87][C@H:34]([O:33][C@H:10]3[C@H:9]([OH:8])[CH2:13][NH:12][C@@H:11]3[CH2:24][OH:25])[C@H:35]([OH:36])[C@H:44]2[OH:45])[O:84][C@H:83]([CH3:85])[C@@H:74]([OH:75])[C@H:65]([OH:66])[C@H:56]1[OH:57]
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H](O[C@@H]3[C@@H](COCc4ccccc4)N(C(=O)OCc4ccccc4)C[C@H]3OCc3ccccc3)O[C@@H]2COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: C[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)CN[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 2 h
Yield: 35.2 %

Procedure:
The compound (13.3 g, 10.3 mmol) synthesized in Example 2 (2g) was dissolved in 1% hydrochloric acid methanol solution (250 mL) and 20% palladium hydroxide-carbon (4 g) was added thereto, followed by stirring of the mixture under a hydrogen atmosphere for 2 hours. After the catalyst was removed by celite filtration, 28% ammonia water (5 mL) was added thereto and the mixture was stirred for 10 minutes. After the solvent was distilled off under reduced pressure and the residue was passed through ion exchange resin (Dowex 50w×8) column with water (200 mL), 1% ammonia water (200 mL) was flowed through. The ammonia water containing the desired compound was concentrated under reduced pressure and was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V) to obtain the desired title compound (1.6 g, 35%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[CH2:12](OC(OCC)(OCC)C)[CH3:13]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:12]([CH3:13])=[N:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNC(=O)c1cccc(Br)c1
Solvent: CC(=O)O
Product: Cc1nnc(-c2cccc(Br)c2)o1
Temperature: 150 °C
Reaction time: 3 h
Yield: 33.5 %

Procedure:
In a pressure vessel was suspended 3-bromobenzohydrazide (1.8 g, 8.37 mmol) in 14 ml acetic acid. 1,1,1-Triethoxyethane (4.6 ml, 25 mmol) was added and the reaction was stirred at 150° C. for 3 h. The solvent was concentrated under reduced pressure and the crude was washed with sodium bicarbonate and brine. The organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was re-dissolved in dichloromethane, concentrated under reduced pressure and a solid was precipitated. This solid was washed with diethylether, filtered and dried in the vacuum oven at 40° C. to obtain 670 mg (35% yield) of the title compound. Purity 100%.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:33]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:32])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:31])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]2)[N:6]=1.[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH3:48])[C:43]=1B(O)O>>[NH2:33][C:4]1[S:3][C:2]([C:43]2[C:44]([CH3:48])=[CH:45][CH:46]=[CH:47][C:42]=2[F:41])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:31])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]1)=[O:32]
Reactant: Cc1cccc(F)c1B(O)O
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(-c4c(C)cccc4F)sc3N)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-6-methylphenyl)boronic acid gave 269. 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 7.88 (s, 1H), 7.48-7.33 (m, 3H), 7.25-7.13 (m, 2H), 5.05 (t, J=5.3 Hz, 1H), 3.77-3.63 (m, 5H), 3.34-3.25 (m, 1H), 3.26-3.17 (m, 1H), 2.83 (s, 3H), 2.44 (s, 3H), 1.68-1.50 (m, 4H). LCMS (ES+) m/z 475 (M+1).
Reaction SMILES: [CH3:1][C:2]1([C:12]([O:14]CC2C=CC=CC=2)=[O:13])[CH2:7][CH2:6][CH:5]([O:8][CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.O1CCCC1.[OH-].[Li+]>O>[CH3:1][C:2]1([C:12]([OH:14])=[O:13])[CH2:7][CH2:6][CH:5]([O:8][CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1
Reactant: CC(C)OC1CCC(C)(C(=O)OCc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OC1CCC(C)(C(=O)O)CC1
Yield: 71.2 %

Procedure:
Phenylmethyl 1-methyl-4-[(1-methylethyl)oxy]cyclohexanecarboxylate (D108) (2.3 g, 7.92 mmol) was suspended in water (30 mL) and tetrahydrofuran (THF) (10 mL) along with lithium hydroxide (0.759 g, 31.7 mmol). The resulting solution was warmed to reflux overnight, TLC (SiO2 10% EtOAc/is-hex) showed some of more polar SM present but none of less polar SM. Reaction cooled and extracted with ether (2×20 mL) to remove unhydrolysed SM. Aqueous layer acidified with 2 N HCl (acid to pH stick) and extracted into DCM (2×15 mL). DCM layers combined and dried over MgSO4, filtered and solvent removed under reduced pressure. NMR confirmed 1-methyl-4-[(1-methylethyl)oxy]cyclohexanecarboxylic acid (1.13 g, 5.64 mmol, 71.2% yield) as a mixture of cis and trans isomers. As suspected from the TLC one of the isomers, suspected to be the trans (ether:carboxylate) had hydrolysed faster. This resulted in a ˜2:1 ratio of the acids.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)([OH:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1>>[NH2:31][C:32]1[N:37]=[CH:36][C:35]([C:2]2[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][C:15]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)([OH:18])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:34][N:33]=1
Reactant: OC1(c2ccccc2)CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Nc1ncc(B(O)O)cn1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCC(O)(c5ccccc5)CC4)cc3n2)cn1

Procedure:
1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-4-phenylpiperidin-4-ol was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica gave 289, purity 95%. NMR (400 MHz 1H DMSO): 9.12 (s, 2H); 7.50 (d, 2H, J=7.26); 7.34 (d, 2H, J=11.96); 7.32 (d, 1H, J=15.36); 7.21 (t, 1H, J=7.28); 7.04 (s, 2H); 3.96 (t, 4H, J=4.70); 3.89 (s, 2H); 3.79 (t, 4H, J=4.67); 2.74 (d, 2H, J=10.55); 2.58 (t, 2H, J=10.65); 2.97 (m, 2H); 1.65, (d, 2H, J=12.40). LC-MS (m+1)=503.63
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][OH:27])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1.C(OCC)(=O)C>[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][O:27][CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CO)no1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)OCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
A suspension of sodium hydride 60% suspension in mineral oil (18 mg, 0.45 mmol) in anhydrous tetrahydrofuran (1 ml) was cooled to 0° C. and treated with a solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 85) (142 mg, 0.40 mmol) in anhydrous tetrahydrofuran (1 ml) and stirred under a nitrogen atmosphere for 0.5 hours. Ethyl 2-bromopropionate (37 μl, 0.33 mmol) was added and the mixture was stirred for 2 days, being allowed to warm to room temperature over this time. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of pentane : ethyl acetate (99:1) to pentane:ethyl acetate (0:100) to afford the title compound as a colourless oil (90 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([CH:12]1[CH2:17][CH:16]([OH:18])[C:15](=[O:19])[NH:14][C:13]1=[O:20])[C:6]2=[O:11].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH:27]=O.[BH4-].[Na+]>C(O)(=O)C>[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([CH:12]1[CH2:17][CH:16]([OH:18])[C:15](=[O:19])[NH:14][C:13]1=[O:20])[C:6]2=[O:11]
Reactant: Nc1cccc2c1C(=O)N(C1CC(O)C(=O)NC1=O)C2=O
Reactant: O=Cc1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=O)C(N2C(=O)c3cccc(NCc4ccco4)c3C2=O)CC1O

Procedure:
A solution of 3-(4-amino-1,3-dioxoisoindolin-2-yl)-5-hydroxypiperidine-2,6-dione (0.82 g, 3.0 mmol) and 2-furaldehyde (0.34 g, 3.5 mmol) in acetic acid (10 mL) is heated at reflux for 4 hours. To the mixture is added sodium borohydride (130 mg, 3.5 mmol) at room temperature and this mixture is maintained for 18 hours. The mixture is worked up to give 3-(4-fur-2-ylmethylamino-1,3-dioxoisoindolin-2-yl)-5-hydroxypiperidine-2,6-dione which is further purified by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH2:26][S:27][CH3:28])[CH:6]=[CH:5][C:4]=1[C:29]1[NH:33][C:32](=[O:34])[O:31][N:30]=1.ClC1C=CC=C(C(OO)=[O:43])C=1.O>CN(C)C=O>[CH3:28][S:27]([CH2:26][C:12]1[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=2)[S:15][C:11]=1[CH2:10][O:9][C:7]1[CH:6]=[CH:5][C:4]([C:29]2[NH:33][C:32](=[O:34])[O:31][N:30]=2)=[C:3]([O:2][CH3:1])[CH:8]=1)=[O:43]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CSC)ccc1-c1noc(=O)[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CS(C)=O)ccc1-c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 75.7 %

Procedure:
To a solution of 32 mg of 3-{2-methoxy-4-[4-methylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-1,2,4-oxadiazol-5-one in 4 mL of dimethylformamide was added 15 mg of metachloroperbenzoic acid. The resulting mixture was stirred for 45 min at room temperature, then poured into water and extracted with dichloromethane. The organic extracts were washed with a saturated aqueous solution if sodium bicarbonate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of methanol in dichloromethane) to give 25 mg of 3-{4-[4-methanesulfinylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-1,2,4-oxadiazol-5-one as a white solid which was further purified by trituration with diisopropyl ether.