Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:35])([C:29]2[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH3:28])[CH:21]=2)=[CH:4][CH:3]=1.Br[CH2:37][CH:38]([CH3:40])[CH3:39]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:35])([C:29]2[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:14](=[O:19])[CH:13]=[C:12]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH3:28])[CH:21]=2)=[CH:4][CH:3]=1
Reactant: CC(C)CBr
Reactant: CCOc1cccc(-c2cc(=O)[nH]c3ccc(C(O)(c4ccc(Cl)nc4)c4cncn4C)cc23)c1
Product: CCOc1cccc(-c2cc(=O)n(CC(C)C)c3ccc(C(O)(c4ccc(Cl)nc4)c4cncn4C)cc23)c1
Yield: 42.9 %

Procedure:
The same procedure described in example 8, 6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethoxy-phenyl)-1H-quinolin-2-one (50 mg, 0.103 mmol) and 1-bromo-2-methylpropane (0.022 ml, 0.206 mmol) generated the title compound as a white solid (24 mg, 40% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]3[CH2:13][N:14]([CH3:16])[CH2:15][C@H:9]23)=[CH:4][CH:3]=1.[C:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:19])[CH3:18].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:16][N:14]1[CH2:13][C@@H:10]2[C@@H:9]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([N:23]4[CH2:24][CH2:25][N:20]([C:17](=[O:19])[CH3:18])[CH2:21][CH2:22]4)=[CH:3][CH:4]=3)[CH2:12][CH2:11]2)[CH2:15]1
Reactant: CC(=O)N1CCNCC1
Reactant: CN1C[C@H]2CCN(c3ccc(Br)cc3)[C@H]2C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N1CCN(c2ccc(N3CC[C@@H]4CN(C)C[C@@H]43)cc2)CC1
Temperature: 150 °C

Procedure:
The product of Example 7C (500 mg, 1.78 mmole), 1-acetylpiperazine (274 mg, 2.13 mmole), tris(dibenzylideneacetone)dipalladium (32.6 mg, 0.036 mmole), (r)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl were (44.3 mg, 0.071 mmole), sodium tert-butoxide (256 mg, 2.67 mmole) and 5 ml of toluene were mixed under N2 in a Emrys process vial. The vial was sealed, then heated in the microwave for 20 minutes at 150° C., using the Emrys Creator microwave reactor. The mixture was diluted with water and extracted with dichloromethane (4×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography (eluting with a mixture of 10% methanol and 1% ammonium hydroxide in dichloromethane) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 6.87-6.91 (m, 2H) 6.53-6.60 (m, 2H) 4.05-4.07 (m, 1H) 3.73-3.79 (m, 2H) 3.57-3.63 (m, 2H) 3.46-3.54 (m, 1H) 3.12-3.20 (m, 1H) 2.96-3.03 (m, 4H) 2.56-2.71 (m, 5H) 2.34 (s, 3H) 2.14-2.18 (m, 1H) 2.13 (s, 3H) 1.87-1.97 (m, 1H). MS: (M+H)+=329.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20](O)=[O:21])=[N:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:24][CH2:25][C:26]([CH3:32])([OH:31])[C:27]([F:30])([F:29])[F:28]>>[F:28][C:27]([F:30])([F:29])[C:26]([OH:31])([CH3:32])[CH2:25][NH:24][C:20]([C:3]1[C:2]([NH2:1])=[CH:7][C:6]([C:8]([F:10])([F:9])[F:11])=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[N:4]=1)=[O:21]
Reactant: CC(O)(CN)C(F)(F)F
Reactant: Nc1cc(C(F)(F)F)c(-c2ccc(Cl)cc2Cl)nc1C(=O)O
Agent: Cl
Product: CC(O)(CNC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(C(F)(F)F)cc1N)C(F)(F)F

Procedure:
The enantiomers of 3-amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide were prepared from 3-Amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate H) and 3-amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride analogously to Example 1 and separated by chiral separation using Supercritical Fluid Chromatography:
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3].C(O)[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO>>[CH3:3][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=[O:11])[CH3:8])[CH3:1]
Reactant: CC(C)=CCCC(C)CC=O
Agent: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Product: CC(C)=CCCC(C)=CC=O
Reaction time: 0.03 h

Procedure:
Determination of enantiomeric excess and absolute configuration: the enantiomeric excess of citronellal was determined using a modified β-cyclodextrin capillary column (hydrodex-β-TBDAc, 25 m, 0.25 mm) temperature program: 40° C. hold 2 min, 4° C./min to 120° C., 1 min. hold, 20° C./min to 180° C., 3 min. hold. Retention times were as follows: (S)- and (R)-citronellal 19.84 and 19.97 min resp. The absolute configuration of citronellal was determined by coinjecting a commercially available reference sample with known absolute configuration.
Reaction SMILES: [C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[NH:14][CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:39][C:40]([CH3:46])([CH2:44][CH3:45])[C:41](Cl)=[O:42].N1C=CC=CC=1.O>ClCCCl.C(OCC)(=O)C>[C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:41](=[O:42])[C:40]([CH3:46])([CH3:39])[CH2:44][CH3:45])[CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC(C)(C)C(=O)Cl
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CNc3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(C)(C)CC)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Yield: 41.7 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (500 mg) was suspended in 1,2-dichloroethane (10 ml), 2,2-dimethylbutyryl chloride (144 mg) and pyridine (86 μl ) were added, and the mixture was refluxed for one hour and 30 minutes. Water (100 ml) and ethyl acetate (100 ml) were added to the reaction mixture, separated, the organic layer was washed with 1N hydrochloric acid, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 248 mg of the titled compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: CCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCCCCOC(=O)Cc1cccc(C(F)(F)F)c1

Procedure:
A mixture of 3-trifluoromethylphenylacetic acid (150.0 g), n-octanol (130.0 g), p-toluenesulphonic acid (9.5 g) and benzene (800 ml) is refluxed for 7 hours with a Dean-Stark separator. The solution is washed with a 10% aqueous solution of sodium carbonate (3×500 ml) and with water (3×500 ml). After drying over magnesium sulphate, the solvent is evaporated in vacuo. The residue is distilled (95°-97°/2·10-2Torr) to yield n-octyl 3-trifluoromethylphenylacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=O)[C:10]([F:13])([F:12])[F:11].[Cl:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](Cl)=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:22](=[O:23])[C:21]([O:20][C:19]1[CH:25]=[CH:26][C:16]([Cl:15])=[CH:17][CH:18]=1)=[C:9]2[C:10]([F:13])([F:12])[F:11]
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: Nc1ccc(Br)cc1C(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]c2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-amino-5-bromophenyl)-2,2,2-trifluoroethanone (2.76 g, 10.3 mmol, Intermediate 7, step b) in dichloromethane (20 mL) was added commercially available 2-(4-chlorophenoxy)acetyl chloride (2.11 g, 10.3 mmol). The resulting white solution was cooled with an ice bath to 0° C. and treated with triethylamine (4.29 mL, 30.9 mmol) dropwise. The reaction mixture was stirred at room temperature for 12 hours and at 60° C. for 2 hours. The mixture was diluted with dichloromethane at room temperature and washed with water. The organic phase was dried (MgSO4), filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 25% EtOAc-Heptane), affording the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([O-])=[O:13])[CH:11]=1)[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][CH2:5]2.CC(C[AlH]CC(C)C)C.[OH-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]=[O:13])[CH:11]=1)[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][CH2:5]2
Reactant: CC1(C)CCc2cc(Cl)cc(C(=O)[O-])c2O1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCc2cc(Cl)cc(C=O)c2O1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
6-Chloro-2,2-dimethyl-3,4-dihydro-2H-chromene-8-carboxylate (350 mg, 1.37 mmol) was dissolved in dichloromethane (6.87 mL) and cooled to −78° C. DIBAL-H (4.12 mL, 4.12 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hour. It was then cooled to 0° C., diluted with dichloromethane (10.0 mL) and water (2.00 mL) was added slowly, followed by a 15% aqueous NaOH solution (5.00 mL). The mixture was warmed to room temperature and stirred for 15 minutes. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum. The crude alcohol was used directly in the next step without further purification. The crude alcohol was dissolved in dichloromethane (7.00 mL), and Dess-Martin periodinane (1.20 g, 2.75 mmol) was added in one portion at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under vacuum on silica gel. It was then purified by silica gel chromatography eluting with 0-15% EtOAc/hexanes to give the desired product as a white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:33])[C@H:21]([CH3:32])[NH:22][C:23](=[O:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[F:34]C1C=C(CC(O)=O)C=CC=1>>[F:34][C:29]1[CH:30]=[C:25]([CH2:24][C:23]([NH:22][C@H:21]([C:20]([NH:19][C@@H:3]2[C:2](=[O:1])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C@@H:4]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:33])[CH3:32])=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Reactant: O=C(O)Cc1cccc(F)c1
Product: C[C@H](NC(=O)Cc1cccc(F)c1)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1

Procedure:
A method similar to the one described for (113) was used except that 3-fluorophenylacetic acid (77 mg) was used in place of phenylacetic acid to afford the title compound as a 1:1 mixture with the (2S,3R) diastereomer (140 mg), white solid, m.p.130-140° C. 1H NMR (300 MHz, CDCl3) δ 0.97 (d, 1.5H, J=5 Hz), 1.27 (d, 1.5H, J=5 Hz), 3.45 (two peaks, 2H), 4.52 (m, 0.5H), 4.67 (m, 0.5H), 4.91 (t, 1H, J=6 Hz), 5.12 (t, 1H, J=6 Hz), 5.79 (dd, 1H, J=7 Hz, J=10 Hz), 6.15 (d, 0.5H, J=8 Hz), 6.28 (d, 0.5 Hz, J=8 Hz), 6.63 (d, 0.5 h, J=6 Hz), 6.70 (d, 0.5H, J=7 Hz), 6.86-7.70 (m, 13H), 7.96 (s, 1H). MS APCI, m/z=484 (M+Na). LC/MS: 2.09 min.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:22]=2)[C:10]=1[CH3:35])C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[CH3:35][C:10]1[C:9](=[O:8])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:22]=1
Reactant: Cc1c(COc2cccc(OCC3CCOCC3)c2)nc2ccccc2c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(COc2cccc(OCC3CCOCC3)c2)[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a solution of 4-(benzyloxy)-3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinoline (330 mg) in ethanol-THF (1:1, 10 mL) was added 10% palladium-activated carbon (80 mg), and the mixture was stirred at room temperature under hydrogen atmosphere for 1 hour. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinolin-4(1H)-one (207 mg).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:43]5[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][OH:37])[CH2:41][CH2:42]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Reactant: OCCN1CCNCC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCN(CCO)CC1
Yield: 11.9 %

Procedure:
Prepared from 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea (200 mg, 0.39 mmol) from Example 16C (200 mg, 0.39 mmol) and 1-(2-hydroxyethyl)piperazine (0.144 mL, 1.17 mmol) according to the procedure described for Example 16D to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea as a colorless solid (28 mg, 12%). 1H NMR (300 MHz, DMSO-d6) δ 9.59 (brs, 1H), 9.01 (brs, 1H), 8.55 (s, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.37-7.42 (m, 2H), 7.26 (m, 1H), 6.96 (m, 1H), 6.47 (s, 1H), 4.26-4.35 (m, 3H), 3.99 (s, 3H), 3.40-3.50 (m, 2H), 2.75-2.79 (m, 2H), 2.30-2.50 (m, 9H), 1.27 (s, 9H); LC-MS (ESI) m/z 606 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)([O-])O.[Na+]>ClCCl>[CH3:21][S:22]([O:1][CH2:2][CH2:3][CH2:4][N:5]([C:6]([O:7][C:8]([CH3:10])([CH3:9])[CH3:11])=[O:12])[CH3:13])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCCO)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCCOS(C)(=O)=O)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
tert-Butyl (3-hydroxypropyl)methylcarbamate (551 mg, 2.92 mmol) was dissolved in dichloromethane (15 mL), triethylamine (0.811 mL, 5.83 mmol) and methanesulfonyl chloride (0.337 mL, 4.38 mmol) were added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, the mixture was extracted with methylene chloride, and the resulting organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was purified by short-path silica gel column chromatography (elution solvents, n-hexane:ethyl acetate=1:1→0:1, v/v) to give crude 3-([tert-butoxycarbonyl)(methyl)amino]propyl methanesulfonate as a colorless oily substance. The resulting crude product was dissolved in ethanol (15 mL), N,N-diisopropylethylamine (5.07 mL, 29.2 mmol) and methoxyamine hydrochloride (2.43 g, 29.2 mmol) were added, and the mixture was stirred at 50° C. for 14 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, the mixture was extracted with methylene chloride, and the resulting organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (elution solvents, n-hexane:ethyl acetate:methanol=9:1:0→0:1:0→0:9:1, v/v/v) to give the title compound (362 mg; yield, 19%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH:23]1([NH:26][C:27](=[O:55])[C:28]2[CH:33]=[C:32]([N:34]3[CH:39]=[CH:38][N:37]=[C:36]([NH:40][C@@H:41]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C@@H:42]([CH3:45])[CH2:43][OH:44])[C:35]3=[O:52])[C:31]([CH3:53])=[C:30]([F:54])[CH:29]=2)[CH2:25][CH2:24]1>C(Cl)Cl>[CH:23]1([NH:26][C:27](=[O:55])[C:28]2[CH:33]=[C:32]([N:34]3[CH:39]=[CH:38][N:37]=[C:36]([NH:40][C@@H:41]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C@@H:42]([CH3:45])[CH:43]=[O:44])[C:35]3=[O:52])[C:31]([CH3:53])=[C:30]([F:54])[CH:29]=2)[CH2:25][CH2:24]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(N[C@@H](c2ccccc2)[C@@H](C)CO)c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(N[C@@H](c2ccccc2)[C@@H](C)C=O)c1=O
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
A solution of Dess-Martin Periodinane (0.911 g) in DCM (8 mL) was added dropwise to a solution of N-cyclopropyl-3-fluoro-5-[3-{[(1R,2R)-3-hydroxy-2-methyl-1-phenylpropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide (Example 328d, 0.64 g) in DCM (8 mL) at 22° C. The resulting mixture was stirred at 22° C. for 30 min. The reaction mixture was quenched with sat. aqueous Na2S2O3 and sat. aqeuous NaHCO3 and stirred for a further 15 min and then extracted into DCM. The organic extracts were combined, dried (MgSO4) and concentrated in vacuo to give the subtitle compound as a solid (0.6 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Li+].[Li+].CS(C)=O.[Cl:22][CH2:23][CH2:24]Cl>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:24][CH2:23][Cl:22])=[CH:6][CH:5]=1
Reactant: ClCCCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OCCCl)cc1
Reaction time: 2 h

Procedure:
4-hydroxybenzoic acid methyl ester (1.52 g, 10 mmol), anhydrous lithium carbonate (740 mg, 10 mmol), 15 ml of dimethylsulfoxide, and 15 ml of 1,2-dichloroethane are combined and heated to reflux. HPLC shows the reaction is at equilibrium at about 2 hours with a product to starting material ratio of 22.7:68.7.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][C:10]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])=[O:11])=[C:6]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[N:5]=[C:4]([S:29][CH3:30])[N:3]=1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[N:12]1[C:2]2[N:3]=[C:4]([S:29][CH3:30])[N:5]=[C:6]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[C:7]=2[CH:8]=[CH:9][C:10]1=[O:11]
Reactant: CSc1nc(Cl)c(CCC(=O)Nc2c(Cl)cccc2Cl)c(-c2ccc(F)cc2F)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1nc(-c2ccc(F)cc2F)c2ccc(=O)n(-c3c(Cl)cccc3Cl)c2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a refluxing solution of 3-[4-chloro-6-(2,4-difluorophenyl)-2-(methylthio)pyrimidin-5-yl]-N-(2,6-dichlorophenyl)propanamide (0.06 g) and AIBN (0.005 g) in 8 mL of CCl4 was added recrystallized N-bromosuccinimide (0.026 g). The reaction was refluxed for 1 h, then removed from the heat. DBU (0.02 mL) was added and the solution was stirred at rt for 15 min. The reaction mixture was washed with 20 mL of saturated sodium bicarbonate and back extracted with 20 mL of CH2Cl2. The organic layer was washed with 20 mL of brine, dried with sodium sulfate, and concentrated to give the desired product. Mass spectrum m/z (ESI) 450.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[C@H:11]([CH2:21][N:22]3[N:26]=[N:25][C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[N:23]3)[O:10][C:9]2=[O:33])=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[C@H:11]([CH2:21][N:22]3[N:26]=[N:25][C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[N:23]3)[O:10][C:9]2=[O:33])=[CH:4][CH:3]=1
Reactant: COc1cccc([C@H]2[C@H](Cn3nnc(-c4cccnc4)n3)OC(=O)N2c2ccc(Cl)cc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1O[C@@H](Cn2nnc(-c3cccnc3)n2)[C@H](c2cccc(O)c2)N1c1ccc(Cl)cc1
Temperature: -78 °C

Procedure:
To a 10 mL round bottom flask is charged with (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((5-(pyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one (264 mg, 0.57 mmol) and DCM (6 mL) and is cooled to −78° C. Boron tribromide (1M, 2.3 mL, 2.3 mmol) is then added dropwise, and after 30 min. the cooling bath is removed and the reaction is allowed to warm to room temperature. The reaction is quenched with water (5 mL), basified to pH 10 with 1N NaOH, and extracted with DCM. The combined organics are dried over Na2SO4, filtered, and concentrated. Purified on 40 g Redisep silica gel cartridge with 5% MeOH/DCM to give the title compound. 1H NMR (acetone-d6) δ 9.21 (s, 1H), 8.72 (dd, J=4.8, 1.7 Hz, 1H), 8.60 (br s, 1H), 8.36 (ddd, J=6.1, 1.9, 1.9 Hz, 1H), 7.58 (dd, J=8.0, 5.0, 0.8 Hz, 1H), 7.46-7.42 (m, 2H), 7.27-7.22 (m, 3H), 6.95 (d, J=7.6 Hz, 1H), 6.92 (t, J=2.2 Hz, 1H), 6.82 (ddd, J=8.1, 2.4, 0.9 Hz, 1H), 5.67 (d, J=4.7 Hz, 1H), 5.50 (dd, J=14.7, 5.8 Hz, 1H), 5.42 (dd, J=14.7, 3.9 Hz, 1H), 5.12 (ddd, J=5.8, 4.6, 4.0 Hz, 1H), HPLC-MS calculated C22H17ClN6O3 (M+H+) 449.1, found 449.0.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[CH2:12]([N:19]1[C:23]([CH:24]=[O:25])=[CH:22][N:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[C:23]([CH:24]([OH:25])[CH2:2][CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)=[CH:22][N:21]=[CH:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1cncn1Cc1ccccc1
Reactant: Fc1ccc(CCCBr)cc1
Product: OC(CCCc1ccc(F)cc1)c1cncn1Cc1ccccc1

Procedure:
1-benzyl-5-[4-(4-fluorophenyl)-1-hydroxybutyl]-1H-imidazole is prepared from 1-bromo-3-(4-fluorophenyl)propane and 1-benzyl-5-imidazole carbaldehyde by the same method described in example 7a).