Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[C:26]([O:30][C:31](=[O:34])[CH2:32]Br)([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>O>[C:26]([O:30][C:31](=[O:34])[CH2:32][N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: c1ccc(Cc2ccc(OC[C@@H]3CCCN3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Temperature: 60 °C
Yield: 64.3 %

Procedure:
(S)-2-(4-Benzyl-phenoxymethyl)-pyrrolidine (200 mg, 0.658 mmol) was taken into DMF (2 mL), and t-butylbromoacetate (141 mg, 0.724 mmol) was added, followed by potassium carbonate (182 mg, 1.317 mmol). The mixture was heated to 60° C. and left to react overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over sodium sulfate, and concentrated to dryness. The compound was then purified by flash chromatography (eluted with 0.5% methanol in dichloromethane with a 40:1 silica ratio) to obtain the title product (161 mg, 0.423 mmol, 64% yield); LCMS; m/z 381.52, found 381 (M); 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 1.66-1.73 (m, 2H), 1.79-1.85 (m, 2H), 1.99-2.06 (m, 1H), 2.63-2.69 (m, 1H), 3.18-3.22 (m, 2H), 3.40 (d, J=17.2, 1H), 3.59 (d, J 16.8, 1H), 3.79-3.83 (m, 1H), 3.91-3.95 (m, 2H), 6.82 (d, J 8.88, 2H), 7.08 (d, J8.8, 2H), 7.15-7.27 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:18].ClCCl>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:10]([O:18]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC2OC2C1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
Stir a mixture of 2,5-dihydropyrrole-1-carboxylic acid tert-butyl ester (2 g, 11.8 mmol), 3-chloroperoxybenzoic acid (77%, 3.1 g, 14.2 mmol) and 3-tert-butyl-4-hydroxy-5-methylsulfide (254 mg, 0.7 mmol) in 1,2-dichloroethane (50 mL) at 85° C. for 4 h under nitrogen. Add extra 3-chloroperoxybenzoic acid (77%, 1.16 g, 4.7 mmol) and stir at 85° C. for 5 h. Allow to cool to room temperature and add dichloromethane (120 mL), wash with 5% aqueous sodium bisulfate, then with saturated aqueous sodium hydrogen carbonate and finally with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and chromatograph on silica gel, eluting with 0:100 to 40:60 ethyl acetate:cyclohexane to give 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.55 g, 71%). 1H NMR (400 MHz, CDCl3) δ 3.82 (1H, d, J=13.20 Hz), 3.74 (1H, d, J=12.72 Hz), 3.67 (2H, d, J=3.42 Hz), 3.31 (2H, dd, J=13.45, 5.14 Hz), 1.44 (9H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]2[N:10]=[C:11](S(C)=O)[N:12]=[CH:13][C:8]=2[C:7]=1[CH3:25])=[O:5])[CH3:2].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(OCC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]2[N:10]=[C:11]([NH:45][C:42]3[CH:43]=[CH:44][C:39]([N:36]4[CH2:37][CH2:38][N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:34][CH2:35]4)=[CH:40][N:41]=3)[N:12]=[CH:13][C:8]=2[C:7]=1[CH3:25])=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CCOC(=O)c1c(C)c2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 28.9 %

Procedure:
A solution of 8-cyclopentyl-2-methanesulfinyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (110 mg, 0.30 mmol) and 4-(6-amino-pyridin-3yl)-piperazine-1-carboxylic acid tert-butyl ester (310 mg, 1.1 mmol) in toluene was heated at 100° C. for 10 hours and then cooled to room temperature. Diethyl ether was added to the reaction mixture and the product precipitated. This precipitate was collected by filtration and dried to provide 2-[5-(4-tert-butoxycarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (50 mg, 29%). M++1: Calc'd. 578.3. Found 578.4.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:41])[CH2:20][C@H:21]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH2:14]1.ClCCl.[C:45](Cl)(=[O:47])[CH3:46].N1C=CC=CC=1>CO>[C:45]([NH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:41])[CH2:20][C@H:21]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])[CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH2:14]1)(=[O:47])[CH3:46]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCC[C@@H](c2nc3ccccc3n2CCN)C1)Cc1ccc2ccccc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)NCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 0 °C
Yield: 36 %

Procedure:
tert-Butyl (R)-4-((R)-3-(1-(2-aminoethyl)-1H-benzo[d]imidazoI-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (129D) was added to a 25 mL round-bottomed flask equipped for stirring under nitrogen. Dichloromethane (5 mL) was added and the solution was cooled to 0° C. with an ice/water bath. Acetyl chloride (0.703 mmoles; 0.050 mL) and pyridine (2.47 mmoles, 0.200 mL) were then added and the resultant solution was stirred at 0° C. for 10 min. Solution was allowed to warm to it and stirred for 1 hr. The reaction solution was subsequently concentrated in-vacuo, re-dissolved in methanol (3 mL), and then directly purified by preparative LC/MS (20-90% CH3CN in H2O) to afford tert-butyl (R)-4-((R)-3-(1-(2-acetamidoethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (129E) as a clear oil (0.038 mmoles, 0.023 g, 36% yield over 2-steps). ESI-MS: m/z 598.5 (M+H)+.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:30])[C:22]([N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([CH3:29])[CH2:24]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:31])C1C=CC=CC=1.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[B+3].O.CO>C(O)(C(F)(F)F)=O>[Br:30][C:21]1[C:22]([N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([CH3:29])[CH2:24]2)=[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]2=[C:17]([CH:20]=1)[C:18](=[O:19])[N:9]([OH:8])[C:10]3=[O:31]
Reactant: CC1CCCN(c2c(Br)cc3c4c(cccc24)C(=O)N(OCc2ccccc2)C3=O)C1
Agent: O=C([O-])C(F)(F)F
Agent: [B+3]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: CC1CCCN(c2c(Br)cc3c4c(cccc24)C(=O)N(O)C3=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of 2-benzyloxy-5-bromo-6-(3-methyl-piperidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.24 g, 0.50 mmol, from Example U1) in TFA (8.0 mL) at 0° C. was added a 1.0 M solution of boron tris(trifluoroacetate) in TFA (5 mL). The reaction was stirred at 0° C. for 2 hours, then poured into a solution of water/methanol (1:1), and extracted with chloroform. The organic layer was dried over MgSO4, filtered, and the solvent removed under vacuum to give 0.19 g of the title compound as the TFA salt, mp >250° C.
Reaction SMILES: BrC1C=NC(I)=NC=1.FC1C=C(OCC2C=CC=CC=2)C=CC=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[F:33][C:34]1[C:39](F)=[C:38]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]C)[CH:37]=[CH:36][C:35]=1[C:50]1[N:55]=[CH:54][C:53]([Br:56])=[CH:52][N:51]=1>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.COCCOC>[F:33][C:34]1[CH:39]=[C:38]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:37]=[CH:36][C:35]=1[C:50]1[N:51]=[CH:52][C:53]([Br:56])=[CH:54][N:55]=1
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Brc1cnc(I)nc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Fc1cc(OCc2ccccc2)ccc1-c1ncc(Br)cn1
Yield: 53 %

Procedure:
--Quantities: 5-bromo-2-iodopyrimidine 2 (5.05 g, 17.7 mmol), 2-fluoro-4-benzyloxyphenylboronic acid 27 (4.84 g, 19.7 mmol), tetrakis(triphenylphosphine)palladium (680 mg, 0.59 mmol), 2M sodium carbonate (50 ml), DME (50 ml). The experimental procedure was as described for compound 4 to yield the benzyloxyfluorophenylpyrimidine 28 (3.34 g, 53%) (from MeOH), m.p. 124.2° C.; νmax /cm-1 (KBr) 3030, 2860, 1615s, 1430, 1420, 1320, 1215, 1020 and 830, δ 5.22 (2H, s, CH2), 6.75-6.89 (2H, m, 3'- and 5'-H), 7.32-7.48 (5H, m, Ph), 8.06 (1H, t, 6'-H) and 8.85 (2H, s, 4-and 6-H); m/z 360 (M+), 358 (M+), 269 (M+ -PhCH2), 267 (M+ -PhCH2), 247, 221 and 91.
Reaction SMILES: Cl[C:2]([N:4]=[C:5]=[O:6])=[O:3].[OH:7][NH:8][CH2:9][C:10]1[CH:40]=[CH:39][C:13]([O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH2:30][C:31]4([OH:37])[CH2:36][CH2:35][S:34][CH2:33][CH2:32]4)=[CH:24][C:23]=3[CH3:38])[CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1.Cl.C[O-].[Na+:44]>O.CO.C1COCC1>[OH:37][C:31]1([CH2:30][O:29][C:25]2[CH:26]=[C:27]([CH3:28])[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][O:14][C:13]4[CH:12]=[CH:11][C:10]([CH2:9][N:8]5[C:5](=[O:6])[N-:4][C:2](=[O:3])[O:7]5)=[CH:40][CH:39]=4)[CH:17]=3)=[C:23]([CH3:38])[CH:24]=2)[CH2:32][CH2:33][S:34][CH2:35][CH2:36]1.[Na+:44]
Reactant: O=C=NC(=O)Cl
Reactant: Cc1cc(OCC2(O)CCSCC2)cc(C)c1-c1cccc(COc2ccc(CNO)cc2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(OCC2(O)CCSCC2)cc(C)c1-c1cccc(COc2ccc(Cn3oc(=O)[n-]c3=O)cc2)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Chlorocarbonyl isocyanate (0.14 ml) was dropwise added, under cooling on an ice-methanol bath, to a THF (15 ml) solution of 4-({[3′-({4-[(hydroxyamino)methyl]phenoxy}methyl)-2,6-dimethylbiphenyl-4-yl]oxy}methyl)tetrahydro-2H-thiopyran-4-ol (792 mg), followed by temperature rising to room temperature and subsequent 1 hour of stirring. A 1 M hydrochloric acid (40 ml) was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated under a reduced pressure. By purifying the resulting residue by silica gel column chromatography (chloroform-methanol), a colorless foamy substance (777 mg) was obtained. Sodium methoxide (50 mg) was added to a methanol (10 ml) solution of the resulting foamy substance (116 mg), followed by stirring at room temperature for 30 minutes. Thereafter, sodium methoxide (200 mg) was added to the reaction mixture, followed by stirring at room temperature for 1 hour. The reaction mixture was warmed up to 60° C., stirred for 2 hours and then spontaneously cooled to room temperature. 1 M Hydrochloric acid (10 ml) and water (20 ml) were added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methanol (5 ml)-THF (10 ml), and a 1 M sodium hydroxide aqueous solution (0.20 ml) was added, followed by concentration under a reduced pressure. By washing the resulting residue with isopropanol-diethyl ether, sodium 2-[4-({4′-[(4-hydroxytetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methoxy)benzyl]-3,5-dioxo-1,2,4-oxadiazolidin-4-ide (80 mg) was obtained as a pale yellow solid.
Reaction SMILES: C([O:3][C:4](=O)[NH:5]/[C:6](/[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])=[CH:7]\[C:8]#[N:9])C.[CH3:19][CH:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]([NH:30][NH2:31])=O)[CH2:24][CH2:23]1)[CH3:21].O>CN1CCCC1=O>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:6]1[NH:5][C:4](=[O:3])[N:31]2[N:30]=[C:28]([CH:25]3[CH2:26][CH2:27][N:22]([CH:20]([CH3:21])[CH3:19])[CH2:23][CH2:24]3)[N:9]=[C:8]2[CH:7]=1
Reactant: CC(C)N1CCC(C(=O)NN)CC1
Reactant: CCOC(=O)N/C(=C\C#N)c1ccc(F)cc1F
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)[nH]c(=O)n3n2)CC1
Temperature: 160 °C
Reaction time: 6 h

Procedure:
2.0 g (4.12 mmol) of ethyl[(Z)-2-cyano-1-(2,4-difluorophenyl)ethenyl]carbamate (Example 37A) and 916 mg (4.95 mmol) of 1-(propan-2-yl)piperidin-4-carbohydrazide (Example 38A) were dissolved in 24 ml of N-methylpyrrolidone, and the mixture was stirred under argon at an oil bath temperature of 160° C. in a flask with fitted calcium chloride drying tube for 6 h. The reaction mixture was cooled to RT, water (50 ml) was added and the mixture was stirred for 15 min. The mixture was extracted with ethyl acetate (three times 50 ml each) and the combined organic phases were freed from the solvent. The residue was purified by preparative HPLC (Method 11). This gave 660 mg (41% of theory) of the product.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:39]1(=[O:45])[O:44][C:42](=[O:43])[CH2:41][CH2:40]1>C1(C)C=CC=CC=1.CS(C)=O.C(OCC)(=O)C>[O:45]=[C:39]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:23])([F:25])[F:24])=[O:16])=[CH:10][CH:9]=2)[CH2:3][CH2:4]1)[CH2:40][CH2:41][C:42]([OH:44])=[O:43]
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: O=C(O)CCC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Reaction time: 3 h

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide hydrochloride (100 mg, 0.204 mmol), triethylamine (57.5 μL, 0.408 mmol) and succinic anhydride (22.4 mg, 0.224 mmol) in 5 mL toluene and 3 mL dimethylsulfoxide were stirred at room temperature. After 3 hrs, an additional 5.5 mg of succinic anhydride was added and stirred for an additional 1 hr. The reaction mixture was diluted with 50 mL ethyl acetate, washed with 500 mL water, dried over magnesium sulfate, filtered and evaporated to dryness under vacuum. The residue was dissolved in acetonitrile and water and lyophilized to yield 4-oxo-4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazin-1-yl)-butyric acid as an amorphous, light yellow solid (83 mg, 78%). ES-MS calcd for C25H23F3N4O5 (m/e) 516.48, obsd 517 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][CH:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[O:11][N:10]=2)=[CH:5][C:4]=1[OH:26].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[NH:55][C:54](=[O:56])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[NH:47]2)=[CH:42][C:41]=1[O:57][CH3:58]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH3:58][O:57][C:41]1[CH:42]=[C:43]([CH:46]2[NH:55][C:54](=[O:56])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[NH:47]2)[CH:44]=[CH:45][C:40]=1[O:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:26][C:4]1[CH:5]=[C:6]([C:9]2[CH2:13][CH:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[O:11][N:10]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCBr
Reactant: COc1ccc(C2=NOC(c3cc(OC)c(OC)c(OC)c3)C2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCOc1cc(C2=NOC(c3cc(OC)c(OC)c(OC)c3)C2)ccc1OC
Temperature: 30 °C
Reaction time: 30 h
Yield: 79.8 %

Procedure:
2-Methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenol (1a) (359.37 mg, 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.31 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (3d) (557 mg, 80% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:11]=1[C:12](Cl)=[O:13]>O1CCOCC1>[NH2:8][C:4]1[N:3]=[C:2]([NH:1][C:12](=[O:13])[C:11]2[C:10]([F:9])=[CH:18][CH:17]=[CH:16][C:15]=2[F:19])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)c2c(F)cccc2F)n1
Yield: 75.2 %

Procedure:
Using a method similar to Preparation 48, using 2,6-diaminopyridine (2.6 g, 24 mmol), dioxane (75 mL), and 2,6-difluorobenzoyl chloride (1.4 g, 8 mmol)(stir at 25° C. for 16 hr.), gives the title intermediate (1.5 g, 75% yield): mass spectrum (ion spray): m/z=250.1 (M+1).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([O:17][C:18](=[O:34])[N:19]([CH2:23][C:24]1[CH:25]=[C:26]([F:33])[CH:27]=[C:28]2[C:32]=1[NH:31][CH:30]=[CH:29]2)[CH2:20][CH2:21][OH:22])([CH3:16])([CH3:15])[CH3:14]>ClCCl.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:19]([CH2:23][C:24]1[CH:25]=[C:26]([F:33])[CH:27]=[C:28]2[C:32]=1[NH:31][CH:30]=[CH:29]2)[CH2:20][CH2:21][O:22][S:9]([CH3:8])(=[O:11])=[O:10])=[O:34])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1cc(F)cc2cc[nH]c12
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCOS(C)(=O)=O)Cc1cc(F)cc2cc[nH]c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
Add triethylamine (4.64 mL, 33.3 mmol) followed by methanesulfonyl chloride (1.29 mL, 16.65 mmol) to a solution of (5-fluoro-1H-indol-7-ylmethyl)-(2-hydroxyethyl)-carbamic acid tert-butyl ester (4.9 g, assume 15.14 mmol) in dichloromethane (70 mL) at 0° C. Stir the reaction mixture for 30 minutes at 0° C. Dilute with ethyl acetate (200 mL), wash with sequentially with saturated aqueous sodium bicarbonate (200 mL×3) and saturated aqueous sodium chloride (200 mL×2). Dry the organic phase over sodium sulfate and concentrate under reduced pressure to provide the desired compound as a yellow brown oil (5.9 g, >100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.C1COCC1.OS(O)(=O)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CCC3(CC2)OCCO3)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1CCC(c2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
A solution of the intermediate from step B (8.6 g, 36.5 mmol) in toluene (40 mL), THF (20 mL) and 10% H2SO4 in water (25 mL) was stirred at reflux overnight. After cooling to room temperature, the organic layer was separated, washed with brine, dried over MgSO4 and concentrated. Flash chromatography on silica gel eluting with 5% and then 10% EtOAc in hexanes provided the title compound (6.0 g, 86%) as an oil. MS calculated (M+H)+ 193. found 193.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.[CH2:25]([Li])[CH2:26]CC.C(I)C>C1COCC1>[CH2:25]([C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1)[CH3:26]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Reactant: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cc(C)c(Oc2nc(C)cc(NC(CC)CC)c2C)c(C)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butyllithium at −78° C. After stirring at −78° C. for 10 min, ethyl iodide was added and the resulting mixture was stirred at −78° C. for 30 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with brine and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound. 1H NMR(CDCl3) d 6.89(s,2H), 6.07(s,1H), 3.72(d,1H), 3.34(m,1H), 2.58(q,2H), 2.16(s,3H), 2.12(s,3H), 2.09(s,6H), 1.4–1.7(m,4H), 1.25(t,3H), 0.96(t,6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22]Br)=[CH:16][CH:15]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[CH:16][CH:15]=1
Reactant: BrCCOc1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCOc2ccc(Br)cc2)cc1

Procedure:
A mixture of 26.4 g of ethyl p-aminobenzoate, 22.4 g of 2-bromoethyl p-bromophenyl ether and 80 ml of hexamethylphosphoramide is heated at 100°-110° C. for 20 hours. The mixture is chilled, diluted with 25 ml of water, chilled and filtered. The solid is washed with 100 ml of ethanol-water (1:1), with 25 ml of ethanol and with water to give tan crystals, mp 128°-133° C. Recrystallization from ethanol gives yellow crystals, mp 135.5°-137° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[C:6]([Cl:21])[C:7]([Cl:20])=[C:8]([O:18][CH3:19])[CH:9]=2)[C:4]1=[O:22])[CH3:2].[CH3:23]I.C[O-].[Na+].O>CN(C)C=O.C1C=CC=CC=1>[CH2:1]([C:3]1([CH3:23])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[C:6]([Cl:21])[C:7]([Cl:20])=[C:8]([O:18][CH3:19])[CH:9]=2)[C:4]1=[O:22])[CH3:2]
Reactant: CCC1C(=O)c2c(cc(OC)c(Cl)c2Cl)C1c1ccccc1
Reactant: CI
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O
Product: CCC1(C)C(=O)c2c(cc(OC)c(Cl)c2Cl)C1c1ccccc1
Reaction time: 1 h

Procedure:
2-Ethyl-3-phenyl-6,7-dichloro-5-methoxy-1-indanone (10.05 g., 0.03 mole) and methyl iodide (12.5 ml., 0.2 mole) dissolved in dimethylformamide (100 ml.)-benzene (100 ml.) at 0° C. under nitrogen are treated portionwise with sodium methoxide (3.54 g., 0.033 mole) over a 30 minute period. The reaction mixture is stirred in an ice-water bath for one hour, then poured into water (500 ml.), extracted with benzene, the organic layer separated, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to give an oily residue which on trituration with hexane gives 7.64 g. (71%) of 2-ethyl-2-methyl-3-phenyl-6,7-dichloro-5-methoxy-1-indanone which melts at 132° C. on crystallization from cyclohexane.