Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1[C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1
Reactant: COc1cccc(CC(=O)c2cc(OC)ccc2OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Cc1cccc(O)c1)c1cc(O)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
To a solution of 1-(2,5-dimethoxyphenyl)-2-(3-methoxyphenyl)ethanone (3.35 g, 11.7 mmol) in DCM (50 mL) at −78° C., BBr3 (1M in DCM, 48.0 mL, 48.0 mmol) was added dropwise. The reaction mixture was warmed to 0° C., stirred for 30 min, re-cooled to −78° C., and then quenched with methanol (15 mL). The reaction mixture was warmed to room temperature, concentrated under reduced pressure and purified on a silica gel column to give 1-(2,5-dihydroxyphenyl)-2-(3-hydroxyphenyl)ethanone (1.78 g, 62%) as a yellow solid. 1H NMR (DMSO-d6): δ 11.24 (s, 1H), 9.34 (s, 1H), 9.20 (s, 1H), 7.26 (m, 1H), 7.10 (t, 1H), 6.98 (dd, 1H), 6.83 (d, 1H), 6.70 (m, 3H), 4.24 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1>>[CH3:13][N:14]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1
Reactant: CNc1ccc(C(=O)O)cc1
Reactant: Cc1nc(Cl)c2ccccc2n1
Product: Cc1nc(N(C)c2ccc(C(=O)O)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from 4-chloro-2-methylquinazoline and 4-(methylamino)benzoic acid by a procedure described for example 1b. 1H NMR (CDCl3): 8.42-8.39 (m, 1H), 8.28 (m, 2H), 7.84 (m, 1H), 7.45 (m, 2H), 7.37 (m, 1H), 7.22 (m, 1H), 6.84 (d, J=1H, 8.4), 3.91 (s, 3H), 3.01 (s, 3H).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1.[C:12](#N)[CH2:13][CH3:14].S(=O)(=O)(O)[OH:17]>C(OCC)C.O>[CH3:14][C:13]1[CH:12]=[C:5]([C:6](=[O:17])[CH2:7][CH3:11])[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc(Br)c1
Reactant: O=S(=O)(O)O
Reactant: CCC#N
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: CCC(=O)c1cccc(C)c1
Temperature: 25 °C
Yield: 46.8 %

Procedure:
Magnesium turnings (1.00 g; 41.2 mmol) and iodine (two or three granules) were added to anhydrous diethyl ether (10 ml). While the mixture was stirred and heated under nitrogen atmosphere, m-bromotoluene (7.04 g; 41.2 mmol) in anhydrous diethyl ether (20 ml) was slowly added dropwise. The heating was ceased when spontaneous reflux started. After completion of the reflux, the mixture was brought to room temperature, and propionitrile (1.89 g; 34.3 mmol) in anhydrous diethyl ether (20 ml) was added dropwise. After completion of spontaneous reflux, the mixture was left to cool to room temperature. While the mixture was cooled in an ice bath, water and cooled diluted sulfuric acid were added dropwise in a sequential manner, followed by extraction with diethyl ether (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 2.38 g of the target compound as pale yellow oily matter (yield: 46.8%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][C:43]=1[OH:44])[C:8]([NH:10][C@H:11]([B:28]1[O:36][CH:35]2[C:30]([CH3:40])([CH:31]3[CH2:37][CH:33]([CH2:34]2)[C:32]3([CH3:39])[CH3:38])[O:29]1)[CH2:12][C:13]1[C:14]([O:26][CH3:27])=[C:15]([CH:23]=[CH:24][CH:25]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:9])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:52][CH2:53][NH:54]C(=O)OC(C)(C)C.O>CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][C:43]=1[O:44][CH2:52][CH2:53][NH2:54])[C:8]([NH:10][C@H:11]([B:28]1[O:36][CH:35]2[C:30]([CH3:40])([CH:31]3[CH2:37][CH:33]([CH2:34]2)[C:32]3([CH3:39])[CH3:38])[O:29]1)[CH2:12][C:13]1[C:14]([O:26][CH3:27])=[C:15]([CH:23]=[CH:24][CH:25]=1)[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[O:9])(=[O:3])[CH3:2]
Reactant: COc1c(C[C@H](NC(=O)c2ccc(O)c(OC(C)=O)c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C[C@H](NC(=O)c2ccc(OCCN)c(OC(C)=O)c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 3-((2R)-2-(3-acetoxy-4-hydroxybenzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate (100 mg from step 1) in DMF (3 mL) was added K2CO3 (100 mg) followed by tert-butyl 2-bromoethylcarbamate (100 mg). The resulting reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extracted with EtOAc three times. The combined organic phases were dried and concentrated to afford the product which was carried on to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH3:18][N:19]1[C:23]([CH3:24])=[CH:22][C:21]([C:25](O)=[O:26])=[N:20]1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:21]3[CH:22]=[C:23]([CH3:24])[N:19]([CH3:18])[N:20]=3)=[O:26])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: Cc1cc(C(=O)O)nn1C
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: Cc1cc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OC[C@@H]3F)c2)nn1C

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (CAS 5744-59-2) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=364.3 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:5]=2[N:4]=1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1.O>CN(C)C=O>[O:1]([CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:5]=2[N:4]=1)[Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cccc2[nH]c(CO)nc12
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2[nH]c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Reaction time: 28 h
Yield: 67.2 %

Procedure:
To a solution of methyl 2-hydroxymethyl-1H-benzimidazole-4-carboxylate (1.0 g) in N,N-dimethylformamide (10 ml) were added tert-butylchlorodiphenylsilane (1.87 g) and imidazole (495 mg) at ambient temperature and the mixture was stirred at the same temperature for 28 hours. The reaction mixture was poured into water and the aqueous solution was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (10:1) to give methyl 2-tert-butyldiphenylsiloxymethyl-1H-benzimidazole-4-carboxylate (1.45 g) as an oil.
Reaction SMILES: [CH:1]1([NH:7][N:8]=[C:9]([CH3:11])[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:12]=[O:13]>CCCCCCC>[CH:1]1([N:7]=[N:8][C:9]([O:12][OH:13])([CH3:11])[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)=NNC1CCCCC1
Reactant: O=O
Agent: *CC*
Solvent: CCCCCCC
Product: CC(C)(N=NC1CCCCC1)OO
Reaction time: 0.58 h
Yield: 85 %

Procedure:
A solution of 5.0 grams (0.0324 moles) of acetone cyclohexylhydrazone in 70 grams of heptane was oxidized by passing oxygen through the solution as in Example II. The oxidation was initiated at 35° C. The reaction was followed by gas chromatography, following the disappearance of the cyclohexylhydrazone peak. The reaction was complete in 35 minutes at 35° C. The solution was cooled to 0° and drained into a tared, cooled, polyethylene bottle, weighed and stored at -30° C. The solution weighed 75.1 grams (85% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[O:3]1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:44])=[C:41]([Pb+3])[CH:42]=1>ClCCl.Cl>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:44])=[C:39]([CH:6]2[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[O:3][C:4]([CH3:11])([CH3:10])[C:5]2=[O:9])[CH:38]=1
Reactant: Cc1ccc(Br)cc1[Pb+3]
Reactant: CC1(C)OC(C)(C)C(=O)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(Br)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.3 %

Procedure:
To a mixture of 2,2,6,6-tetramethylpyran-3,5-dione (6.00 g, 35.29 mmol) and N,N-dimethylaminopyridine (21.62 g, 177.21 mmol) is added anhydrous chloroform (200 ml), followed by stirring at room temperature until dissolution. To this solution is added anhydrous toluene (55 ml), followed by 5-bromo-2-methylphenyllead triacetate (21.60 g, 38.99 mmol) in one portion and the reaction mixture is heated at 80° C. for 2 hours. The mixture is allowed to cool to room temperature, then diluted with dichloromethane (300 ml) and aqueous hydrochloric acid (300 ml), and the mixture is swirled for 5 minutes and filtered to remove inorganic residues. The filter cake is washed with dichloromethane, and all organic fractions are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated in vacuo to afford a crude solid which is recrystallised from dichloromethane/hexanes. This material is then further purified by flash column chromatography (hexane/ethyl acetate 5:1 ratio). The lead residues are removed by dissolving the resulting solid (approximately 6.50 g) in chloroform (100 ml) and stirring with 3-mercaptopropyl-functionalized silica gel (6.50 g, 1.20 mmol/g loading) overnight. The mixture is filtered and the filtrate concentrated in vacuo to afford 4-(5-bromo-2-methyl-phenyl)-2,2,6,6-tetramethylpyran-3,5-dione (6.50 g) as a cream powder.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20]>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([F:11])([F:23])[F:24])(=[O:21])=[O:20])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
Orcinol monohydrate (2.84 g, 20.0 mmol) and 2-trifluoromethylbenzenesulfonyl chloride (4.90 g, 20.0 mmol) were mixed in saturated aqueous NaHCO3 (70 mL) and diethyl ether (70 mL). The biphasic mixture was stirred vigorously at room temperature overnight. The reaction mixture was diluted with water (100 mL) and extracted into ethyl acetate (3×80 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 2% ethyl acetate in dichloromethane) to give the title compound as a white solid (3.65 g, 55%). 1H-NMR (300 MHz, CDCl3) δ 8.12 (d, J=8.0 Hz, 1 H), 7.98 (d, J=7.9 Hz, 1 H), 7.80 (t, J=8.2 Hz, 1 H), 7.69 (t, J=7.8 Hz, 1 H), 6.55 (s, 1 H), 6.48 (s, 1 H), 6.39 (s, 1 H), 5.11 (s, 1 H), 2.23 (s, 3 H).
Reaction SMILES: [I:1][C:2]1[C:3]2[CH2:9][CH2:8][CH2:7][C:4]=2[NH:5][N:6]=1.[CH3:10]C([O-])(C)C.[K+].CI>C1COCC1>[I:1][C:2]1[C:3]2[CH2:9][CH2:8][CH2:7][C:4]=2[N:5]([CH3:10])[N:6]=1
Reactant: Ic1n[nH]c2c1CCC2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2c1CCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 3-iodo-1,4,5,6-tetrahydrocyclopenta[c]pyrazole (305 mg, 1.3 mmol) in THF (8.51 mL) at 0° C. was added KOtBu 1M in THF (1.82 mL, 1.82 mmol) and the mixture stirred at 0° C. for 30 min where it became a pale yellow solution then added MeI (259 mg, 114 μL, 1.82 mmol). The reaction mixture was stirred at 0° C. for 30 min then warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride in water and extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to a clear oil. Then dissolved in toluene and purified by chromatography (40 g column, 50 μm from Analogix, 0-20% EtOAc in hexanes over 20 min) to afford the more polar desired 3-iodo-1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole (177 mg, 714 μmol, 55%) as a white solid. MS (M+H)+=249; 1H NMR (CDCl3) δ: 3.78 (s, 30H), 2.68-2.79 (m, 20H), 2.51-2.58 (m, 4H). The regisomeric product, 3-iodo-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole, (125 mg, 504 μmol, 39%) was also obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCBr
Reactant: Sc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CCCSc1ccc(Cl)cc1
Yield: 92.7 %

Procedure:
14.5 g (0.1 mol) of p-chlorothiophenol are added at 0° C to a solution of 5.4 g (0.1 mol) of sodium methylate in 50 ml of methanol and thereafter 19.5 g (0.1 mol) of ethyl γ-bromobutyrate dissolved in 40 ml of methanol are added dropwise at 20° C, whilst stirring. The mixture is heated for 2 hours to the reflux temperature and is then evaporated in vacuo, the residue is extracted with ether, the extract is washed with water and dried, and the ether is evaporated. 24 g (93%) of a white oil are obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1.[CH2:19]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:19]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]3)=[CH:10][CH:9]=2)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C1CCc2ccc(OCCCCCBr)cc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCc2ccc(OCCCCCN3CCC(Cc4ccccc4)CC3)cc2N1
Yield: 88 %

Procedure:
2.7 Grams of 7-(5-bromopentoxy)-3,4-dihydrocarbostyril, 2.0 g of 4-benzylpiperidine and 1.5 g of triethylamine were mixed with 30 ml of dimethylformamide and the mixture was heated at 60°-70° C. for 6 hours. The reaction mixture was then concentrated under a reduced pressure to dryness, and to the residue thus obtained was added a 5%-sodium hydrogencarbonate aqueous solution and stirred. The insoluble matters thus formed were collected by filtration, washed with water and dried. Recrystallization from ligroin to obtain 3.6 g (yield: 88%) of 7-[5-(4-benzyl-1-piperidyl)pentoxy]-3,4-dihydrocarbostyril as in the form of colorless plate-like crystals. Melting point: 100°-102° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22])[CH:14]=1.[CH:25]([O:28][C:29]1[CH:43]=[CH:42][C:32]([C:33]([N:35]2[CH2:40][CH2:39][C:38](=[O:41])[CH2:37][CH2:36]2)=[O:34])=[CH:31][C:30]=1[CH3:44])([CH3:27])[CH3:26]>CCCCCC.C1COCC1>[OH:41][C:38]1([CH2:22][C:21](=[O:23])[CH2:20][C:19]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[O:24])[CH2:39][CH2:40][N:35]([C:33](=[O:34])[C:32]2[CH:42]=[CH:43][C:29]([O:28][CH:25]([CH3:26])[CH3:27])=[C:30]([CH3:44])[CH:31]=2)[CH2:36][CH2:37]1
Reactant: CC(=O)CC(=O)c1cccnc1
Reactant: Cc1cc(C(=O)N2CCC(=O)CC2)ccc1OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2CCC(O)(CC(=O)CC(=O)c3cccnc3)CC2)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To an oven-dried round bottom flask was added diisopropylamine (6.4 mL, 46 mmol) and THF (125 mL). It was cooled to −78° C., and a solution of nBuLi (18 mL of 2.5 M, 46 mmol) in hexane was added. It was stirred at 0° C. for 30 minutes and again cooled to −78° C. 1-(3-pyridyl)butane-1,3-dione (3.40 g, 21.0 mmol) in a solution of THF (25 mL) was added dropwise. After 30 minutes at −78° C., a solution of 1-(4-isopropoxy-3-methyl-benzoyl)piperidin-4-one (5.74 g, 20.8 mmol) in THF (25 mL) was added dropwise. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was quenched with saturated ammonium chloride (100 mL). Volatiles were removed under reduced pressure to one-third volume. It was extracted with ethyl acetate (2×75 mL). Organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude brown oil was purified by column chromatography (100% ethyl acetate) to provide 4-[4-hydroxy-1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidyl]-1-(3-pyridyl)butane-1,3-dione (5.85 g) as a yellow foaming solid. 1H NMR (400 MHz, CDCl3) δ 15.81 (s, 1H), 9.08 (d, J=1.9 Hz, 1H), 8.76 (dd, J=4.8, 1.5 Hz, 1H), 8.19 (dd, J=8.0, 1.6 Hz, 1H), 7.49-7.42 (m, 1H), 7.24-7.17 (m, 2H), 6.80 (d, J=8.2 Hz, 1H), 6.20 (s, 1H), 4.55 (m, 1H), 4.51-4.25 (br s, 1H), 3.52-3.26 (m, 4H), 2.68 (s, 2H), 2.20 (s, 3H), 1.75-1.51 (m, 4H), 1.34 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 438.22, found 439.5 (M+1)+; Retention time: 1.37 minutes (3 min run).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:31][CH2:32]2)[N:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(F)ccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(F)ccc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Temperature: 25 °C
Yield: 63.2 %

Procedure:
The trifluoroacetic acid salt of [4-amino-2-(piperidin-4-ylamino)pyrimidin-5-yl-(4-fluoro-2-methoxy-phenyl)-methanone (72.18 mg, 0.157 mmol, Example 176) in dichloromethane (5 mL) and triethylamine (0.2188 mL, 1.570 mmol) was chilled and methanesulfonyl chloride (0.017 mL, 0.22 mmol, Aldrich) was added and the mixture was stirred at room temperature for several hours. Chromatography provided 42 mg (63%) of the title compound as a white solid. HR-ES(+), observed: 424.1453; Calcd for (M+H)+: 424.1450.
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[N:25]=1.[CH2:37]([NH:39][C:40](=[O:57])[NH:41][C:42]1[CH:47]=[CH:46][C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][CH:43]=1)[CH3:38]>>[CH2:37]([NH:39][C:40]([NH:41][C:42]1[CH:47]=[CH:46][C:45]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]3[CH3:36])[N:25]=2)=[CH:44][CH:43]=1)=[O:57])[CH3:38]
Reactant: C[C@H]1COCCN1c1nccc(Cl)n1
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: CCNC(=O)Nc1ccc(-c2ccnc(N3CCOC[C@@H]3C)n2)cc1

Procedure:
Method as described for intermediate 5 using (S)-4-(4-chloropyrimidin-2-yl)-3-methylmorpholine (intermediate 15) and 4-(3-ethylureido)phenyl boronic acid pinacol ester. Material was purified by prep HPLC (low pH) to afford a brown solid, (77 mg, 40%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][CH2:45][CH2:46][O:47]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:55]1[CH:61]=[CH:60][CH:59]=[N:58][CH:57]=[CH:56]1>C1COCC1>[CH:46]([OH:47])=[O:55].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:54]=[CH:53][CH:52]=[C:43]([O:44][CH2:45][CH2:46][N:58]3[CH2:59][CH2:60][CH2:61][O:55][CH2:56][CH2:57]3)[CH:42]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1=COC=CN=C1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Solvent: C1CCOC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN5CCCOCC5)c4)c4ccccc43)cn12
Product: O=CO
Yield: 101.3 %

Procedure:
A solution of Intermediate 154a (50.5 mg, 66 μmol) and [1,4]oxazepine (70 mg, 0.68 mmol) in THF (1 mL) was heated at 60° C. for 48 h in a sealed vessel. The reaction mixture was concentrated in vacuo and the residue purified by MDAP (Method 7) to give the title compound as a white solid (27 mg, 53%). LCMS (Method 5): Rt 3.68 min, m/z 762 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.2 Hz), 1.27 (9H, s), 1.46-1.54 (2H, m), 1.62-2.17 (12H, m), 2.67-2.72 (3H, m), 2.86 (2H, t, J=6.0 Hz), 2.88-2.94 (1H, m), 3.12-3.19 (1H, m), 3.28-3.34 (1H, m, obscured by water peak), 3.53-3.58 (2H, m), 3.61 (2H, t, J=6.0 Hz), 4.09 (2H, t, J=6.1 Hz), 4.77-4.86 (1H, m), 5.52 (1H, t, J=4.3 Hz), 6.33 (1H, s), 6.94-6.99 (1H, m), 7.05-7.12 (2H, m), 7.19 (1H, dd, J=8.6 Hz, 2.0 Hz), 7.24-7.42 (5H, m), 7.64 (1H, d, J=9.8 Hz), 7.69 (1H, d, J=2.0 Hz), 8.17 (1H, s), 8.18 (1H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1ccc(Cl)cc1F
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccc(Cl)cc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-fluoro-4-chloroaniline to yield 2-[(2-fluoro-4-chlorophenyl)amino]phenylacetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([OH:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:20]([O:19][C:17]([CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([OH:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)C(C)(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(O)c1ccc(OCC(=O)OC(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
A mixture of methyl 4-hydroxyphenyllactate (18.5 g), t-butyl bromoacetate (14 ml), anhydrous potassium carbonate (26.0 g) and anhydrous dimethylformamide (300 ml) was stirred at 60° C. for 10 hours and then allowed to stand at room temperature overnight The reaction mixture was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using hexane:ethyl acetate=2:1-1:1 as the eluant to afford the title compound (17.5 g, Rf=0.62: thin layer chromatography on a silica gel plate using hexane:ethyl acetate=1:1 as the eluant).