Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:16])=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.[Cl:17]N1C(=O)CCC1=O>C(#N)C>[Cl:8][C:9]1[C:10]([F:16])=[C:11]([OH:15])[CH:12]=[CH:13][C:14]=1[Cl:17]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Oc1ccc(Cl)c(Cl)c1F
Reaction time: 24 h
Yield: 47.5 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of 3-chloro-2-fluorophenol (750 mg, 5.12 mmol) and N-chlorosuccinimide (684 mg, 5.12 mmol) in acetonitrile (30 mL) and the reaction mixture stirred for 24 h. The mixture was concentrated in vacuo and purified by chromatography on silica gel with heptane:EtOAc (9:1, v/v) as eluent to afford the title compound (440 mg, 48%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:19](Cl)(=[O:26])[O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23]>C(OCC)(=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:26])[O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a two-phase solution of 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine (5.0 g, 23 mmol) in ethyl acetate (45 mL)/3N aqueous sodium hydroxide (20 mL) was added 2,2,2-trichloroethyl chlorocarbonate (4.5 mL, 33 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The obtained organic layer was washed with 5% aqueous sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure to give the title compound (5.0 g, 55%) as a white powder.
Reaction SMILES: [CH3:1][S:2]([CH3:4])=[O:3].CN(P(N(C)C)(N(C)C)=O)C.[Li]CCCC.Br[CH2:22][C:23]1[C:24]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[N:25][C:26]2[C:31]([C:32]=1[C:33]([NH:35][C@H:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:37][CH3:38])=[O:34])=[CH:30][CH:29]=[CH:28][CH:27]=2>C1COCC1>[CH3:1][S:2]([CH2:4][CH2:22][C:23]1[C:24]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[N:25][C:26]2[C:31]([C:32]=1[C:33]([NH:35][C@H:36]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:37][CH3:38])=[O:34])=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:3]
Reactant: CC[C@H](NC(=O)c1c(CBr)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: CS(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC[C@H](NC(=O)c1c(CCS(C)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
A solution of DMSO (0.075 mL, 1.05 mmol) and HMPA (0.38 mL, 2.2 mmol) in anhydrous THF (3 mL) was prepared under N2 and cooled to −78° C. To this was added a solution of n-BuLi (0.71 mL, 1.6 M in hexanes, 1.13 mmol), the reaction allowed to stir for 10 min., then 3-(bromomethyl)-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (8) (200 mg, 0.44 mmol) was added as a solution in anhydrous THF (1 mL). The reaction was allowed to stir 10 min., additional anhydrous THF (1 mL) added, and reaction allowed stirring another 10 min. The cooling bath was then removed, saturated aqueous NH4CI (1 mL), H2O (1 mL), and Et2O (1 mL) added, the layers shaken together, and then separated. The organics were then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/CH2Cl2) to give the desired product (170 mg, 85% yield) as a solid. 1H NMR (300 MHz, CDCl3, 52° C.) δ 8.10 (d, J=8.0 Hz, 1H), 7.86-7.61 (m, 2H), 7.55-7.25 (m, 12H), 5.29-5.16 (m, 1H), 3.44-3.07 (m, 2H), 2.73-2.37 (m, 2H), 2.27-2.15 (m, 3H), 2.15-1.86 (m, 2H), 1.02 (t, J=7.4 Hz, 3H); LCMS: m/z 457 (MH+). HRMS m/z 457.1927, calcd. 457.1950.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.N[C@H](C([NH:19][CH:20]1[C:26](=[O:27])[N:25]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[N:22]([CH2:36][CH:37]2[CH2:39][CH2:38]2)[C:21]1=[O:40])=O)C>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:19][C@H:20]([C:26]([C:20]2([NH2:19])[C:26](=[O:27])[N:25]([CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]([CH2:36][CH:37]3[CH2:39][CH2:38]3)[C:21]2=[O:40])=[O:27])[CH3:21])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)NC1C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O

Procedure:
Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-U), the title compound was prepared as a white solid (melting point=211-212° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1 gradient to 2:3). Rf=0.44 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[CH2:16]1[O:18][C@H:17]1[CH2:19]Cl>>[CH3:8][C:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C@@H:17]2[CH2:16][O:18]2)=[CH:11][CH:10]=1)([CH3:1])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Reactant: ClC[C@H]1CO1
Product: CC(C)(C)CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1

Procedure:
The title compound was prepared from 4-(1,1,3,3-tetramethyl-butyl)-phenol and R-epichlorohydrin employing the procedures as set forth in Step 1 of Example 1.
Reaction SMILES: Cl[CH:2]([Cl:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)([O-:13])=[O:12].O>O1CCCC1>[Cl:10][C:2]1([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH:18]([C:17]2[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:21][CH:20]=2)[O:19]1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C1(Cl)OC1c1ccc([N+](=O)[O-])cc1
Yield: 71.6 %

Procedure:
5.55 g of tert.-butyl dichloroacetate in 30 ml of tetrahydrofuran and 4.99 g of 4-nitrobenzaldehyde in 30 ml of tetrahydrofuran were cooled to -20° C. and, over 20 minutes, 30 ml of a molar solution of potassium tert.-butylate in tetrahydrofuran were added dropwise at -20° C. The reaction mixture was stirred while the temperature was allowed to rise to 20° C., and it was then poured into 100 ml of water and ice, and was extracted with ether. The organic phase was washed with water saturated with sodium chloride, then with water, dried, and concentrated to dryness under reduced pressure. The residue was chromatographed on silica and eluted with methylene chloride to obtain 6.44 g of 1,1-dimethylethyl 2-chloro-3-(4-nitrophenyl)oxirane carboxylate melting at 60° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C@@H:10]([O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[N:19]=[CH:18]4)[C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[F:31][C:32]([F:37])([CH3:36])[C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl>CN1C(=O)CCC1>[O:1]1[C:5]2[CH:6]=[C:7]([C@@H:10]([O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[N:19]=[CH:18]4)[C@@H:11]([NH:13][C:33](=[O:34])[C:32]([F:37])([F:31])[CH3:36])[CH3:12])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2c(c1)OCC2
Reactant: CC(F)(F)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@H](NC(=O)C(C)(F)F)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2c(c1)OCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a solution of (1R,2S)-1-(2,3-dihydrobenzofuran-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine (306a, 85 mg, 0.21 mmol) in NMP (1 mL) was added a solution of 2,2-difluoropropanoic acid (37 mg, 0.34 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.128 g, 340 nmol), and N-ethyl-N-isopropylpropan-2-amine (140 μL, 840 μmol) in NMP (2 mL). The mixture was stirred at r.t. for 2 h. Then aq. HCl (1N, 30 mL) was added, and the mixture was extracted with ethyl acetate (3×45 ml). The organic phase was dried and purified by flash chromatography on silica gel with ethyl acetane/n-heptane (2:1) to give 65 mg (62%) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5](=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.O>CN(C)C=O>[CH2:2]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[CH2:3][CH2:4][C:5](=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: c1c[nH]cn1
Reactant: CCCCCCCCC(=O)CCCBr
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCC(=O)CCCn1ccnc1

Procedure:
1-Bromo-4-dodecanone 6.45 and imidazole (8.34 g) in dimethylformamide (10 ml) at 0° C. were stirred overnight at ambient temperature, then one day at 80° C. The resulting mixture was poured into water (200 ml), extracted with ether (3×75 ml) and the extracts were dried (magnesium sulfate) and evaporated. Chromatography of the product on silica gel eluting with 7% methanol in methylene chloride gave 1-(dodecan-4-on-1-yl)imidazole.
Reaction SMILES: Br[C:2]1[C:3]([O:17][CH2:18][C:19]2[C:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:21][O:22][C:23]=2[CH3:24])=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:8].[CH3:31]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:31][C:2]1[C:3]([O:17][CH2:18][C:19]2[C:20]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:21][O:22][C:23]=2[CH3:24])=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:8]
Reactant: CB1OB(C)OB(C)O1
Reactant: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)NC2CCOCC2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)NC2CCOCC2)cnc1OCc1c(-c2ccccc2)noc1C
Yield: 50.8 %

Procedure:
To a suspension of 5-bromo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide (200 mg, 0.42 mmol) in 1,2-dimethoxyethane (1 mL) was added trimethylboroxine (88 μL, 0.64 mmol), aqueous sodium carbonate (1 M, 0.64 mL, 0.64 mmol) and tetrakis(triphenylphosphine)palladium(0) (49 mg, 0.04 mmol). The reaction mixture was then irradiated in the microwave for 20 min at 140° C. under an argon atmosphere. It was diluted with ethyl acetate (10 mL) and washed with water (10 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic layers were dried over sodium sulfate. Trituration from tert-butylmethylether afforded the title compound (87 mg, 50%) which was obtained as a white solid. MS: m/e=408.4 [M+H]+
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:12]=3[C:13]=2[CH3:14])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:22])=O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:22][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[O:10][C:11]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:12]=2[C:13]=1[CH3:14]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2oc(C(O)C3CCCCC3)c(C)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc2oc(C(Cl)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
To a solution (20 mL) of cyclohexyl(3,5-dimethyl-1-benzofuran-2-yl)methanol (1.13 g) synthesized above in toluene pyridine (424 μL) and thionyl chloride (382 μL) were added, and the mixture was stirred at room temperature for 5 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (1.12 g, 93%) as a yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O-:18])=O)=[O:9].Cl.[NH2:20][OH:21].[OH-].[Na+].Cl>CO.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:18])[NH:20][OH:21])=[O:9]
Reactant: O=C([O-])CCCCCNC(=O)/C=C/c1ccco1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(C=Cc1ccco1)NCCCCCC(=O)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
To a solution of 6-{[(E)-3-(2-furyl)-2-propenoyl]amino}hexanoate (0.200 g, 0.75 mmol) in methanol (2 ml) a solution of hydroxylamine hydrochloride (0.210 g, 3.02 mmol) in methanol (3 ml) and NaOH (242 mg, 6.04 mmol) in H2O (1 ml) were added. The mixture was stirred for 30 min at room temperature and acidified with 1N HCl to pH 3 of the reaction medium. The mixture was extracted with ethyl acetate (3×25 ml), the organic phase was washed with brine and dried (Na2SO4). The solvent was evaporated and the residue (0.172 g) was crystallized from acetonitrile (5 ml) to give the title compound (0.117 g, 58%). M.p. 151-152.5° C. 1H-NMR (DMSO-d6, HMDSO), δ: 1.15-1.62 (m, 6H); 1.94 (t, J=7.2 Hz, 2H); 3.14-3.22 (m, 2H); 6.40 (d, J=15.5 Hz, 1H); 6.57 (dd, J=1.6 and 3.2 Hz, 1H); 6.74 (d, J=3.2 Hz, 1H); 7.21 (d, J=15.5 Hz, 1H); 7.75 (s, 1H); 8.11 (t, J=5.6 Hz, 1H); 8.67 (d, J=1.6 Hz, 1H); 10.34 (s, 1H). HPLC analysis on Zorbax SB-C18 column: impurities 1% (column size 4.6×150 mm; mobile phase acetonitrile+0.1% H3PO4, gradient from 25 to 100%; detector UV 270 nm; sample concentration 1.0 mg/ml; flow rate 1.5 ml/min). Anal. Calcd for C13H18N2O4, %: C, 58.64; H, 6.81; N, 10.52. Found, %: C, 58.64; H, 6.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[CH:8]=1)([CH3:6])[CH2:4][F:5].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][N:28]=[C:27]2[O:36][C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40]>CN(C)C1C=CN=CC=1.C1COCC1>[F:5][CH2:4][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[C:37]([O:36][C:27]3[C:26]4[C:31](=[CH:32][C:33]([O:34][CH3:35])=[C:24]([O:23][CH3:22])[CH:25]=4)[N:30]=[CH:29][N:28]=3)[CH:38]=2)=[O:21])[CH:8]=1)([CH3:6])[CH2:2][F:1]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)no1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)on4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
A mixture of phenyl 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate from the previous step (0.089 g, 0.3 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.089 g, 0.3 mmol), and 4-(dimethylamino)pyridine (0.03 g) in THF (6 mL) was stirred at room temperature overnight. The reaction was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluting with 70-95% EtOAc/hexane) to afford 1-[5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl]-3-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]urea as solid (0.055 g, 31%). 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.02 (s, 1H), 8.57 (s, 1H), 7.57 (m, 2H), 7.40 (m, 2H), 7.27 (d, 1H), 6.98 (d, 1H), 6.77 (s, 1H), 4.71 (s, 2H), 4.56 (s, 2H), 4.00 (s, 3H), 3.98 (s, 3H), 1.28 (s, 3H); LC-MS (ESI) m/z 500 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[K+].I[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[Cl:23].CCOC(C)=O>CN1CCCC1=O>[Cl:19][C:18]1[CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=[C:14]([Cl:23])[C:13]=1[O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(I)c(Cl)c1
Reactant: Cc1cc(O)ccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1F
Temperature: 130 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A mixture of 3-methyl-4-fluorophenol (99 mg, 0.79 mmol), potassium hydroxide (53 mg, 0.94 mmol), 4-iodo-3,5-dichloro-nitrobenzene (250 mg, 0.79 mmol) and 4A° molecular sieves (75 mg) in N-methylpyrolidinone (3 mL) was stirred at 130° C. for 2 h. The reaction mixture was poured into ice cold 1 N HCI (20 mL) and EtOAc (25 mL) was added. The EtOAc phase was separated and washed with 1 N HCI (3×25 mL) and brine (25 mL). The EtOAc solution was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (Hexanes: CH2CI2=7:3) to afford 3,5-dichloro-4-(4-fluoro-3-methyl-phenoxy)-nitrobenzene (207 mg). MS Calc.: 315.0 Found: 315.0 (M).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38].CN(C)C=O>O>[O:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=3[O:37][CH3:38])[CH2:7][CH2:6]2)=[N:9]1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3ccccc23)CC1
Reaction time: 16 h
Yield: 47.7 %

Procedure:
A mixture of 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.8 g, 20 mmol), K2CO3 (5.2 g, 40 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a few crystals of KI and dimethylformamide (60 ml) was stirred at 90 C. for 16 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The extract was washed (water), dried (MgSO4) and concentrated to afford a brown oil. The oil was chromatographed on a Waters Prep 500 utilizing silica gel columns and ethyl acetate-diethylamine (2%), as eluent. Concentration of the appropriate fractions afforded 3.9 g of product as an off-white solid. Recrystallization from absolute ethyl alcohol afforded 2.6 g (33%) of 1-[4-[3-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxypehenyl]ethanone, m.p.=102°-104° C., as colorless needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH:36]=[C:35]([C:37]2([NH2:40])[CH2:39][CH2:38]2)[N:34]=[CH:33]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:40][C:37]5([C:35]6[N:34]=[CH:33][N:32]([CH3:31])[CH:36]=6)[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: Cn1cnc(C2(N)CC2)c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cn(C)cn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.15 g, 0.37 mmol, 1 eq), 1-(1-methyl-1H-imidazol-4-yl)cyclopropanamine (0.061 g, 0.44 mmol, 1.2 eq), EDCI.HCl (0.078 g, 0.40 mmol, 1.1 eq), HOBT (0.049 g, 0.37 mmol, 1.0 eq) and TEA (0.15 ml, 1.1 mmol, 3 eq) were dissolved in dichloromethane and the above mixture was stirred at room temperature for 18 h. The mixture was then added with water. The organic layer was separated, washed with water, concentrated and the crude product purified by Prep. HPLC. Yield: 24.69 mg (10%). 1HNMR (400 MHz, DMSO-d6): δ1.04-1.07 (m, 2H), 1.17-120 (m, 2H), 2.29 (s, 3H), 2.82 (d, J=4.4 Hz, 3H), 3.54 (s, 3H), 6.7 (s, 1H), 7.37-7.43 (m, 5H), 7.58 (s, 1H), 7.74-7.77 (d, J=8.8 Hz, 1H), 7.81-7.82 (m, 2H), 7.97-8.01 (m, 2H), 8.46-8.47 (m, 1H), 9.06 (s, 1H) LCMS: (ES+) m/z=523.2 (M+H)+
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:16][C:17](=[O:24])[C:18](=[CH:22][CH:23]=3)[C:19](O)=O)=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)[Cl:26].C[Si](Cl)(C)C.S(Cl)(Cl)=O>C(N(CC)CC)C>[N:1]1([S:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:16][C:17](=[O:24])[C:18](=[CH:22][CH:23]=3)[CH2:19][Cl:26])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(-c2ccc(S(=O)(=O)N3CCCC3)cc2)[nH]c1=O
Reactant: ClCCl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=c1[nH]c(-c2ccc(S(=O)(=O)N3CCCC3)cc2)ccc1CCl

Procedure:
From 4.4 g. of 6-[4-(1-pyrrolidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 150 ml. of methylene chloride, 1.6 ml. of triethylamine, 1.45 ml. of trimethylsilyl chloride and 1.7 ml. of thionyl chloride, following the procedure of a) above, there is obtained 6-[4-(1-pyrrolidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]([CH:27](O)[C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)=[C:25]([CH:40]([CH3:42])[CH3:41])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:45])[CH2:20][C:21]([CH3:44])([CH3:43])[O:22]3)=[CH:13][CH:12]=1.O>ClCCl>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]([CH:27]([F:7])[C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]([F:36])([F:38])[F:37])=[CH:32][CH:33]=3)=[C:25]([CH:40]([CH3:41])[CH3:42])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:45])[CH2:20][C:21]([CH3:43])([CH3:44])[O:22]3)=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Solvent: O
Solvent: ClCCl
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 2.5 h

Procedure:
At −78° C., a solution of 45 μl (340 μmol) of diethylaminosulfur trifluoride in 1 ml of dichloromethane is slowly added dropwise to a solution of 157 mg (310 μmol) of rac-5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethoxy)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 24A) in 4 ml of dichloromethane, and the mixture is stirred at this temperature for 2.5 h. The mixture is then allowed to thaw slowly to −15° C. and stirred for a further 1.5 h. Water is then added, and the mixture is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. Column chromatography of the residue on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 10:1→15:1) gives the target compound.