Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:5][C:4]=2[NH:3]1.C1C(=O)N([Br:26])C(=O)C1.O.N>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:26][C:13]1[S:14][C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:5][C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH:12]=1
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1ccsc12
Reactant: O=C1CCC(=O)N1Br
Agent: N
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)c1cc(Br)sc12
Temperature: 70 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
Methyl 4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate (1.0 eq, 17 mg, 0.066 mmol) was suspended in a mixture of chloroform (0.3 ml) and acetic acid (0.1 ml). NBS was added (9.5 eq, 112 mg, 0.63 mmol) and the mixture stirred at 70° C. for 16 hours. Water and aqueous ammonia was added and the material was extracted with CH)Cl2 (2×). The combined extracts were dried over Na2SO4 and the solvent removed in vacuo to provide methyl 2-bromo-4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate (17 mg, 76%). LCMS (ES): >85% pure, m/z 338 [M]+, 340 [M+2]+; 1H NMR (CDCl3/CD3OD, δ: 1, 400 MHz) δ 3.99 (s, 3H), 7.30 (m, 1H), 7.69 (d, J=8.4, 1H), 7.45 (m, 1H), 7.88 (br d, J=8, 1H), 8.05 (br s, 1H) ppm.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:19](OCC)=[O:20])[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:8][CH2:7]1)=O)C>O1CCCC1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH2:10][CH2:11][C:6]([CH2:4][OH:3])([CH2:19][OH:20])[CH2:7][CH:8]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CC=C(c2ccc(Cl)cc2)CC1
Solvent: C1CCOC1
Product: OCC1(CO)CC=C(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
An oven-dried flask under nitrogen was charged with 4-(4-chloro-phenyl)-cyclohex-3-ene-1,1-dicarboxylic acid diethyl ester (6.5 g, 19.30 mmol) in tetrahydrofuran (80 ml), and at −78° C. was added lithium alumina hydride (30.9 ml, 30.9 mmol) in one portion. The mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched with saturated aqueous sodium chloride solution (5 ml) at 0° C. The mixture was filtered and the filtrate was extracted with ethyl acetate (3×100 ml), and the residue solid was washed with acetone (100 ml). The organic solvents were combined, dried over Na2SO4, and concentrated. The residue was purified by chromatography (heptanes/acetone 1/2) to afford [4-(4-chloro-phenyl)-1-hydroxymethyl-cyclohex-3-enyl]-methanol (4.7 g, 96%) as white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.64-1.74 (m, 2H) 2.04 (d, J=3.66 Hz, 2H) 2.37-2.46 (m, 2H) 3.50 (td, J=10.80, 8.80 Hz, 4H) 6.03-6.11 (m, 1H) 7.27 (d, J=8.40 Hz, 2H) 7.36 (d, J=8.40 Hz, 2H).
Reaction SMILES: [N:1]([C@H:4]1[C:9]([F:11])([F:10])[CH2:8][CH2:7][CH2:6][C@H:5]1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C@H:4]1[C:9]([F:11])([F:10])[CH2:8][CH2:7][CH2:6][C@H:5]1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@@H]1N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@@H]1N
Reaction time: 16 h
Yield: 91.7 %

Procedure:
A solution of tert-butyl [(1R,6R)-2-azido-3,3-difluorocyclohexyl]carbamate 28 (0.94 g, 3.40 mmol) in methanol (20 mL) was degassed with nitrogen and treated with 10% Pd/C (72 mg). The resulting heterogenous solution was exposed to a hydrogen atmosphere and stirred vigorously for 16 hours. The reaction was filtered, washing with methanol, and evaporated in vacuo to give 0.78 g (91%) of tert-butyl [(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate 29 as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 6.67 (1H, d, J=8.3 Hz), 3.55 (1H, bs), 3.07 (1H, bs), 2.03 (1H, m), 1.62 (3H, m), 1.45 (1H, m), 1.36 (12H, m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=C(NC)[C:5]([NH2:10])=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:23][N:24]([CH:26]=[O:27])[CH3:25]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[N:7]=[C:23]2[N:24]([CH3:25])[C:26](=[O:27])[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: CNc1nc(Cl)ccc1N
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cn1c(=O)[nH]c2ccc(Cl)nc21
Temperature: 80 °C

Procedure:
6-chloro-N2-methylpyridine-2,3-diamine (1-2) (35 g, 222 mmol) and 1,1′-Carbonyldiimidazole (63 g, 389 mmol) were added to a round bottom flask and suspended in DMF (150 mL). The solution was heated to 80° C. in an oil bath overnight. The reaction was then suspended in ethyl acetate and sodium bicarbonate. The suspension was washed with sodium bicarbonate, brine (×5), dried over sodium sulfate, filtered, and concentrated to produce the solid 5-chloro-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1-3). MS (M+H)+: observed=184.2, calculated=184.6.
Reaction SMILES: [Mg].C(OCC)C.[CH2:7](Br)[CH2:8][CH2:9][CH3:10].Br[C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][C:15]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:16]3)[CH2:14]1)[CH2:20]2>ClCCl.O>[CH2:7]([C:19]12[CH2:20][CH:13]3[CH2:22][CH:17]([CH2:16][C:15]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:14]3)[CH2:21]1)[CH2:18]2)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCC12CC3CC(CC(Br)(C3)C1)C2
Reactant: CCCCBr
Agent: [Mg]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCC12CC3CC(C1)CC(CCCC)(C3)C2
Yield: 33 %

Procedure:
Into a 1 liter egg plant-shaped flask, 4.9 g (0.2 moles) of magnesium was weighed and placed. Under the stream of nitrogen gas, 80 ml of diethyl ether was added and stirred. Then, a solution prepared by dissolving 27.4 g (0.2 moles) of n-butyl bromide into 20 ml of diethyl ether was added dropwise. After the addition was completed, the resultant mixture was heated under the refluxing condition for 30 minutes. The temperature was adjusted at the room temperature, and diethyl ether was completely removed using a vacuum pump. Then, a solution prepared by dissolving 27.1 g (0.1 mole) of 1-bromo-3-(n-butyl)adamantane obtained in accordance with the process described above in 1-2) into 300 ml of dichloromethane was added dropwise. After the addition was completed, the resultant mixture was heated under the refluxing condition for 5 hours. The reaction fluid was poured into 200 ml of ion-exchanged water and treated by extraction with dichloromethane using a separation funnel. The solvent was removed using an evaporator. The residue was dissolved into 20 ml of hexane and purified in accordance with the silica gel column chromatography (the solvent of development: hexane). The solvent was removed using an evaporator, and 8.20 g of 1,3-di(n-butyl)adamantane of the object compound was obtained (the yield: 33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](B(O)O)=[CH:5][N:4]=1.I[C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]=2)=[CH:5][N:4]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Ic1cnccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: COc1ncc(-c2cnccn2)c(OC)n1
Yield: 45.4 %

Procedure:
2,4-Dimethoxy-pyrimidine-5-boronic acid (1.33 g, 7.27 mmol) was dissolved in degassed n-PrOH (20 ml) and then 2-iodo-pyrazine (1.0 g, 4.85 mmol), Na2CO3 (1.02 g, 9.70 mmol), PPh3 (127 mg, 0.48 mmol) and Pd(OAc)2 (54 mg) were added. The suspension was stirred at reflux for 4 hours. The solvent was evaporated under vacuum and the crude was partitioned between water and DCM. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (99-1-0.1) to give 481 mg of the title compound (45% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][C:18]3[C:19]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])=[N:20][CH:21]=[CH:22][CH:23]=3)[C:13]([C:30]([F:33])([F:32])[F:31])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[NH2:34][CH:35]([CH2:38][OH:39])[CH2:36][OH:37].[OH-].[Na+].CC(O)C>C(Cl)Cl>[OH:37][CH2:36][CH:35]([NH:34][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][C:18]3[C:19]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])=[N:20][CH:21]=[CH:22][CH:23]=3)[C:13]([C:30]([F:33])([F:32])[F:31])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)[CH2:38][OH:39]
Reactant: CN(c1ncccc1CNc1nc(Nc2ccc(CCl)cc2)ncc1C(F)(F)F)S(C)(=O)=O
Reactant: NC(CO)CO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: ClCCl
Product: CN(c1ncccc1CNc1nc(Nc2ccc(CNC(CO)CO)cc2)ncc1C(F)(F)F)S(C)(=O)=O

Procedure:
A mixture of 7 (100 mg, 0.200 mmol), 2-amino-1,3-propanediol (90.9 mg, 0.998 mmol), sodium hydroxide (7.98 mg, 0.200 mmol) and 2-propanol (0.5 mL) was heated to reflux. After 30 minutes the mixture was cooled, treated with DCM, and washed with water. The organic phase was dried over MgSO4, filtered and concentrated. The resultant residue was then purified by column chromatography (silica gel; eluting with 6% MeOH/DCM with NH4OH), and the eluents containing the product were combined and concentrated to provide 8 as a white solid. Yield: 60.9 mg, 55%. MS+ 556.2. 1H NMR (500 MHz, d6-DMSO) δ: 9.48 (s, 1H), 8.41 (s, 1H), 8.21 (s, 1H), 7.59 (m, 2H), 7.34 (m, 3H), 6.99 (d, 2H), 4.75 (d, 2H), 4.35 (t, 2H), 3.58 (s, 2H), 3.34 (m, 4H), 3.12 (s, 3H), 3.09 (s, 3H), 2.45 (m, 1H). FAK IC50: <0.000595 μM (Table 1, Example 389)
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=O)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C(N(CC)CC)C.ClC(OC)=O>O1CCCC1>[CH2:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([CH2:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)c2ccccc2O)cc1
Agent: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCOc1ccc(Cc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.6 %

Procedure:
To a solution of 4-allyloxy-2′-hydoxybenzophenone (0.87 g) in tetrahydrofuran (14 mL) were added triethylamine (0.53 mL) and methyl chloroformate (0.29 mL) at 0° C., and the mixture was stirred at room temperature for 1.5 hours. An insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. To a solution of the residue in tetrahydrofuran (18 mL) and water (9 mL) was added sodium borohydride (0.52 g) at 0° C., and the mixture was stirred at room temperature for 2.5 hours. To the reaction mixture was added 0.5 mol/L aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=8/1) to give 2-(4-allyloxybenzyl)phenol (0.72 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([SH:9])[N:4]=1.Cl[CH2:11][C:12]1[C:17]([CH3:18])=[C:16]([S:19][CH2:20][CH2:21][CH2:22][S:23][C:24]2[CH:25]=[CH:26][C:27]3[N:28]([C:30]([N+:33]([O-:35])=[O:34])=[CH:31][N:32]=3)[N:29]=2)[CH:15]=[CH:14][N:13]=1.[OH-].[Na+]>CC(O)C>[CH3:18][C:17]1[C:12]([CH2:11][S:9][C:5]2[N:4]=[C:3]([CH3:2])[CH:8]=[CH:7][N:6]=2)=[N:13][CH:14]=[CH:15][C:16]=1[S:19][CH2:20][CH2:21][CH2:22][S:23][C:24]1[CH:25]=[CH:26][C:27]2[N:28]([C:30]([N+:33]([O-:35])=[O:34])=[CH:31][N:32]=2)[N:29]=1
Reactant: Cc1ccnc(S)n1
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1ccnc(SCc2nccc(SCCCSc3ccc4ncc([N+](=O)[O-])n4n3)c2C)n1
Temperature: 0 °C

Procedure:
A suspension of 4-methyl-pyrimidine-2-thiol hydrochloride (0.46 g, 2.8 mmol) and 6-[3-(2-chloromethyl-3-methyl-pyridin-4-ylsulfanyl)-propylsulfanyl]-3-nitroimidazo[1,2-b]pyridazine (1.03 g, 2.5 mmol) in 2-propanol (50 ml) is heated under reflux for 4 h under a nitrogen atmosphere. After cooling, the mixture is treated with ice water (100 ml), adjusted to pH 10 with 40% strength sodium hydroxide solution, and extracted with ethyl acetate. The combined extracts are washed with sodium carbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed (silica, toluene/dioxane 2:1) and crystallized from acetonitrile to give the title compound as a colourless solid, 0.49 g (39%). M.p. 136-8° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O:10][CH:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)=[N:2]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O:10][CH:11]2[CH2:16][CH2:15][CH:14]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:13][CH2:12]2)=[N:2]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(Oc2noc3ccccc23)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(Oc3noc4ccccc34)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(benzo[d]isoxazol-3-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]1)=[CH:13][C:12]([C:31]1[CH:36]=[C:35]([Cl:37])[C:34]([OH:38])=[C:33]([Cl:39])[CH:32]=1)=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4].O.Cl>C1COCC1>[NH2:23][C@H:20]1[CH2:21][CH2:22][C@H:17]([NH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:31]4[CH:32]=[C:33]([Cl:39])[C:34]([OH:38])=[C:35]([Cl:37])[CH:36]=4)[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH2:18][CH2:19]1
Reactant: CCCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N)CC1

Procedure:
To a suspension of tert-butyl (trans-4-((3-butyryl-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-4-yl)amino)cyclohexyl)carbamate (35.2 mg, 0.061 mmol) in THF (3 mL) was added water (2 mL) and 6N aqueous HCl (2 mL). The resultant solution was heated at 65° C. for 4 h. The reaction mixture was cooled and concentrated The resultant residue was purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA). The residue was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to obtain the desired product (3.7 mg, 13%) as a yellow solid. 1H NMR (500 MHz, MeOD+TFA-d) δ 9.15 (s, 1H), 8.46 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.72 (s, 2H), 4.53 (br s, 1H), 3.12 (t, J=7.2 Hz, 2H), 2.52 (s, 2H), 2.28 (d, J=12.3 Hz, 2H), 1.95-1.75 (m, 4H), 1.73-1.64 (m, 2H), 1.06 (t, J=7.4 Hz, 3H). ESI MS m/z 472 [C25H27Cl2N3O2+H]+; HPLC>99% (AUC), tR=11.86 min.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]=[C:6]1[O:10][C:8](=[O:9])[CH2:7]1>O1CCCC1>[OH:2][CH2:1][CH2:3][NH:4][C:8](=[O:9])[CH2:7][C:6](=[O:10])[CH3:5]
Reactant: C=C1CC(=O)O1
Reactant: NCCO
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
23 ml (0.38 mmol) of ethanolamine were added dropwise to a solution of 30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 41.44 g (0.29 mol, 80% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].Cl[CH2:7][C:8]([OH:10])=[O:9].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][C:2](=[N:4][O:5][CH2:7][C:8]([OH:10])=[O:9])[CH3:3]
Reactant: CC(C)=NO
Reactant: O=C(O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)=NOCC(=O)O
Reaction time: 1 h

Procedure:
7.3 g of acetone oxime, 14.2 g of chloroacetic acid and 2% of tetrabutylammonium bromide are placed in 80 ml of toluene. An aqueous sodium hydroxide solution (10 g of sodium hydroxide dissolved in 150 ml of water) is added dropwise. The reaction medium is stirred for 1 h and then the toluene is evaporated under vacuum. The residue is then acidified with concentrated hydrochloric acid to pH 2.5, then washed with water and extracted twice with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is evaporated to give the expected product.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]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][C:22]([Cl:25])=[CH:21][CH:20]=4)([OH:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:32][C:33]1[N:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1>>[NH2:32][C:33]1[N:38]=[CH:37][C:36]([C:2]2[N:3]=[C:4]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]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][C:22]([Cl:25])=[CH:21][CH:20]=5)([OH:18])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:35][N:34]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: OC1(c2ccc(Cl)cc2)CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCC(O)(c5ccc(Cl)cc5)CC4)cc3n2)cn1
Yield: 46.7 %

Procedure:
1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-4-(4-chloro-phenyl)-piperidin-4-ol (146 mg, 0.30 mmol) was reacted with 2-amino-pyrimidine-5-boronic acid pinacol ester (94 mg, 0.45 mmol) in General Procedure A. After extraction into 2M HCl, the mixture was washed with EtOAc then made basic and the precipitate collected by filtration. Purification on silica gave 421 as a pale yellow solid (75 mg, 0.14 mmol). NMR (CD3OD, 400 MHz), 9.19 (s, 2H); 7.52 (m, 2H); 7.39 (s, 1H), 7.35 (m, 2H); 4.08 (t, 4H, J=4.1 Hz); 3.97 (s, 2H); 3.89 (t, 4H, J=4.8 Hz); 2.87 (d, 2H); 2.70 (t, 2H, J=11.2 Hz); 2.18 (m, 2H); 1.77 (d, 2H, J=13.2 Hz) MS: (ESI+): MH+=538.27
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].[CH2:11](Br)[CH:12]=[CH2:13].C([O-])([O-])=O.[K+].[K+].CC(C)=O>O>[CH3:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][CH:12]=[CH2:11])=[CH:6][CH:5]=1)=[CH2:3]
Reactant: C=CCBr
Reactant: C=C(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=C)C)cc1
Yield: 63 %

Procedure:
A 10 g-portion of p-isopropenylphenol, 1.0 equivalent allyl bromide, 1.0 equivalent K2CO3, and 20 ml acetone were mixed and refluxed overnight. The reaction mixture was poured into 60 ml water and extracted with two portions of ether. The combined ether layers were washed with two portions of 10% aqueous NaOH, two portions of saturated aqueous NaCl and dried over K2CO3. Removal of solvent followed by distillation under reduced pressure gave a 63% yield of 1-(1-methylethenyl)-4-(2-propenyloxy)benzene, mp 22°-23° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])=[O:10].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:22][C:23]([OH:25])=[O:24])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:20])([F:21])[F:19])=[O:10]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.6 %

Procedure:
To a stirred solution of tert-butyl 3-methyl-4-[N′-(2-trifluoromethylphenyl)ureido]phenylacetate (1.06 g, 2.60 mmol) in CH2Cl2 (10 ml) was added TFA (10 ml) and the reaction mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated to a small volume and poured into ice-H2O. The resulting precipitate was collected under a reduced pressure and the crude solid was recrystallized from MeOH—CHCl3—IPE to give 3-methyl-4-[N′-(2-trifluoromethylphenyl)ureido]phenylacetic acid (702 mg, 77%) as a white crystalline powder. mp 262-263° C.; 1H-NMR (DMSO-d6) δ2.24 (s, 3 H), 3.48 (s, 2 H), 7.03 (d, J=8.3 Hz, 1 H), 7.08 (s, 1 H), 7.26-7.30 (m, 1 H), 7.61-7.69 (m, 3 H), 7.88 (d, J=8.3 Hz, 1 H), 8.39 (s, 1 H), 8.55 (s, 1 H), 12.28 (br s, 1 H); Anal. Calcd. for C17H15F3N2O3: C, 57.96; H, 4.29; N, 7.95; F, 16.18. Found: C, 57.73; H, 4.23; N, 7.92; F, 16.05.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:10]([N:11]3[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]3=[O:23])=[C:9]([F:24])[CH:8]=[C:7]([Cl:25])[C:5]=2[N:6]=1.[C:26](Cl)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([NH:1][C:2]1[O:3][C:4]2[C:10]([N:11]3[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[N:13]([CH3:22])[C:12]3=[O:23])=[C:9]([F:24])[CH:8]=[C:7]([Cl:25])[C:5]=2[N:6]=1)(=[O:28])[CH3:27]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(N)oc23)c1=O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1

Procedure:
Additional moieties may also be added to the benzoxazole ring at this point. For example, bromine moieties are added to 3-(2-methyl-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione by reacting it with N-bromosuccinimide under basic conditions, yielding the corresponding 3-(2-dibromomethyl-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (VB). An alkyl group can also be added to 3-(2-thio-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione by reacting it with an alkyl halide in the manner described previously, yielding the appropriate 3-(2-alkylthio-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (VC). In addition, (V), where R in the 2-position is amino may be further reacted to add additional moieties to the amine. For example, an acetyl moiety is added to 3-(2-amino-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione by reacting it with acetyl chloride in the presence of pyridine affording 3-(2-acetylamino-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (VD). The so-prepared pyrimidinedione (VD) is in turn reacted with sodium hydride and methanesulfonyl chloride to form the appropriate 3-[2-(N-acetyl-N-methylsulfonylamino)-disubstituted-benzoxazol-7-yl]-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (VE), which is hydrogenated under acidic conditions affording 3-(2-methylsulfonylamino-disubstituted-benzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (VF). The pyrimidinedione (VF) is in turn alkylated in the manner described previously, affording 3-[2-(N-alkyl-N-methylsulfonyl-amino)-disubstituted-benzoxazol-7-yl]-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (VG). Examples 14, 17, 20, 21, 22, and 23 provide the detailed procedures for this route.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOC(C)=O.O>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[N:12][CH:13]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Yield: 84.1 %

Procedure:
4-hydroxybenzaldehyde (4.094 mmol, 1 eq), 2-bromo-5-(trifluoromethyl)pyridine (4.094 mmol, 1 eq) and potassium carbonate (6.142 mmol, 1.5 eq) were suspended in N,N-dimethylformamide (15 ml). The reaction mixture was irradiated by microwave Biotage Initiator at 130° C. for 30 min. Reaction mixture was diluted with EtOAc (15 ml) and extraction with water followed (3×15 ml). Organic layers were combined, washed with brine, dried over MgSO4, filtered and evaporated giving 4-(5-trifluoromethyl-pyridin-2-yloxy)-benzaldehyde (3.443 mmol, yield=84%, purity=94%). [M+H]+=268.25 1H NMR (300 MHz, DMSO-d6) δ/ppm 7.33-7.38 (m, 1H), 7.43 (d, J=8.5 Hz, 2H), 7.99 (d, J=8.7 Hz, 2H), 8.26-8.33 (m, 1H), 8.57-8.62 (m, 1H)