Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[NH:7][CH3:8].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=2)[NH:7][CH3:8])[CH:18]=[CH:17][N:16]=1
Reactant: CNc1cc(F)ccc1[N+](=O)[O-]
Reactant: COc1cc(O)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cc(Oc2ccnc(OC)c2)ccc1[N+](=O)[O-]
Yield: 66 %

Procedure:
A solution of 5-fluoro-N-methyl-2-nitroaniline (US2003-675927, 3.30 g, 19.4 mmol), 2-methoxypyridin-4-ol (2.70 g, 21.6 mmol) produced in Example (16b) and cesium carbonate (10.6 g, 32.4 mmol) in DMF (20 mL) was stirred at 80° C. for two hours. After leaving to cool, water (100 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL). The organic layer was washed with water (100 mL) twice and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (hexane/ethyl acetate, 2:1) to obtain the title compound (3.90 g, 66%) as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([CH2:7][NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NCc1ccccc1)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(=O)NCc2ccccc2)c1
Reaction time: 1.5 h

Procedure:
A sample of the product of step (a), 8.8 g, was dissolved in 100 ml of methanol and hydrogenated with 0.4 g of 10% palladium on carbon and 50 PSI hydrogen. After 90 minutes, the mix was filtered and evaporated. The solid residue was slurried in ethyl ether, and filtered to provide crude N-phenylmethyl-3-aminobenzamide, mp 95-100° C, m.s. (M+H)+ =227
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=O.[CH:12](=[O:15])[CH2:13][CH3:14]>>[CH3:14][CH:13]([CH2:3][CH:2]([CH3:1])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:12]=[O:15]
Reactant: CCC=O
Reactant: CC(C=O)Cc1ccccc1
Product: CC(C=O)CC(C)Cc1ccccc1

Procedure:
The 2,4-dimethyl-5-phenylpentan-1-yl derivatives in accordance with the present invention can be prepared by a variety of ways. For example, by an Aldol condensation between 2-methyl-3-phenylpropanal and proprionaldehyde, followed by hydrogenation of the resulting α,β-unsaturated aldehyde to form the saturated aldehyde, 2,4-dimethyl-5-phenylpentanal as described above. This aldehyde is the direct precursor for the alcohol, 2,4-dimethyl-5 -phenylpentan-1-ol via reduction with, e.g. sodium borohydride, as well as the nitrile, 2,4-dimethyl-5-phenyl-pentanitrile via oxidation dehydration chemistry by reaction of hydroxylamine/formic acid as described above.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:12]2[CH2:11][CH2:10][N:9]([C:4]3[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:14][CH2:13]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(OCc2ccccc2)cc1)N1CCN(c2ncccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.9 %

Procedure:
To a stirred solution of 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine (100 mg, 0.39 mmol) in anhydrous dichloromethane (2 mL) was added 4-benzyloxy-benzenesulfonyl chloride (110.27 mg, 0.39 mmol) then diisopropylethylamine (0.17 mL, 0.98 mmol). The mixture was stirred at room temperature for 4 hour. Reaction was complete as determined by TLC. The reaction mixture was purified with flash column chromatography to yield 1-{[4-(benzyloxy)phenyl]sulfonyl}-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine in 78.9% yield (147 mg) as white solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:13]=[C:14]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])=[CH:24][N:23]=3)[C:15]3[N:16]([N:18]=[CH:19][N:20]=3)[CH:17]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:36]1[N:45]=[CH:44][C:43]2[C:38](=[C:39]([F:50])[CH:40]=[C:41]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:42]=2)[C:37]1=[O:51])(=O)C.[OH-].[Na+]>C1COCC1.C([O-])(O)=O.[Na+].C(Cl)Cl>[C:46]([C:41]1[CH:42]=[C:43]2[C:38](=[C:39]([F:50])[CH:40]=1)[C:37](=[O:51])[N:36]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:13]=[C:14]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([N:30]5[CH2:31][CH2:32][O:33][CH2:34][CH2:35]5)=[O:29])=[CH:24][N:23]=4)[C:15]4[N:16]([N:18]=[CH:19][N:20]=4)[CH:17]=3)[C:6]=1[CH2:5][OH:4])[N:45]=[CH:44]2)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c3ncnn3c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-c4cc(Nc5ccc(C(=O)N6CCOCC6)cn5)c5ncnn5c4)c3CO)ncc2c1
Temperature: 60 °C
Yield: 22.5 %

Procedure:
To a solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(8-(5-(morpholine-4-carbonyl)pyridin-2-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)benzyl acetate (289 mg, 418 μmol, Eq: 1.00) in THF (5.0 ml) was added NaOH (1.0 N, 5.0 ml, 5.00 mmol, Eq: 12.0). The solution was heated to 60° C. for 18 h. The reaction was cooled to room temperature. The reaction was diluted with sat NaHCO3 (aq) and DCM. The layers were separated. The aqueous layer was extracted three times with DCM, and then dried over MgSO4. The solid was removed by filtration. The filtrate was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 10% MeOH/DCM gradient) to give a residue. The residue was triturated with Et2O to give 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{8-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-6-yl}-phenyl)-2H-phthalazin-1-one (61 mg, 23%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.36-1.49 (m, 9H) 3.51-3.95 (m, 8H) 4.40 (s, 2H) 7.20 (dd, J=18.13, 7.18 Hz, 1H) 7.41-7.67 (m, 6H) 7.76 (dd, J=8.31, 2.27 Hz, 1H) 8.31 (d, J=2.64 Hz, 1H) 8.36-8.48 (m, 2H) 8.66 (s, 1H) 8.95 (s, 1H) LC/MS-ESI observed [M+H]+ 649.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13](F)[CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH:5]2[NH2:16].[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH2:28][C:29](O)=[O:30])=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH2:28][C:29]([NH:16][CH:5]3[C:4]4[C:12](=[CH:13][CH:14]=[C:2]([F:1])[CH:3]=4)[O:11][C:7]4([CH2:10][CH2:9][CH2:8]4)[CH2:6]3)=[O:30])=[CH:26][C:21]=2[O:20][CH:19]=[CH:18]1
Reactant: O=C(O)CCc1ccc2c(c1)OCCO2
Reactant: NC1CC2(CCC2)Oc2c(F)cc(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccc2c(c1)OC=CO2)NC1CC2(CCC2)Oc2ccc(F)cc21

Procedure:
The title compound was prepared from Intermediate 6 (200 mg, 0.963 mmol) and 3-(2,3-dihydro-1,4-benzodioxin-6-yl)propanoic acid (187 mg, 0.963 mmol) in presence of EDCI.HCl (276 mg, 1.441 mmol), HOBt (221 mg, 1.441 mmol) and triethylamine (403 μl, 2.891 mmol) in dichloromethane (10 ml) as described in Example 1 to give 16 mg of the product as a white solid; IR (KBr) 3307, 2951, 1869, 1643, 1508, 1257, 1071, 817 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 1.13-1.23 (m, 1H), 1.66-1.78 (m, 3H), 2.04-2.13 (m, 3H), 2.18-2.27 (m, 2H), 2.42-2.49 (m, 1H), 2.72-2.79 (m, 2H), 4.17 (s, 4H), 5.01 (br s, 1H), 6.54 (d, J=11.1 Hz, 1H), 6.38-6.74 (m, 4H), 6.93 (t, J=8.1 Hz, 1H), 8.25 (d, J=8.4 Hz, 1H); ESI-MS (m/z) 396.66 (M−H)−.
Reaction SMILES: [CH3:1][NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[N:39][N:38]3[C:43]=2[CH2:44][N:45]2[C:49]([C:50]([O:52]C)=O)=[N:48][CH:47]=[N:46]2)=[CH:31][CH:30]=1.CN>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[N:39][N:38]3[C:43]=2[CH2:44][N:45]2[C:49]([C:50]([NH:2][CH3:1])=[O:52])=[N:48][CH:47]=[N:46]2)=[CH:33][CH:34]=1
Reactant: COC(=O)c1ncnn1Cc1c(-c2ccc(Cl)cc2)nc2cccnn12
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: CN
Product: CNC(=O)c1ncnn1Cc1c(-c2ccc(Cl)cc2)nc2cccnn12

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylate and methylamine. 1H-NMR (CDCl3, 400 MHz, δ) 8.42 (dd, J=1.5, 4.4 Hz, 1H), 8.31 (s, 1H), 8.04 (dd, J=1.5, 9.2 Hz, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 7.20 (dd, J=4.5, 9.2 Hz, 1H), 7.06 (broad, 1H), 5.91 (s, 2H), 3.00 (d, J=5.1 Hz, 3H)ppm; m/e 368 (M+H)+.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=1[C:25]([F:28])([F:27])[F:26].CI.Cl>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:1])[C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=1[C:25]([F:26])([F:27])[F:28]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)Cc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: -75 °C
Reaction time: 0.08 h
Yield: 74.3 %

Procedure:
A solution of diisopropylamine (2.97 mL, 20.85 mmol) in THF (22 mL) was stirred at 0° C. and treated dropwise with n-butyllithium (1.6 M in hexane, 13.03 mL, 20.85 mmol). The resulting solution was stirred for 5 min, and then was cooled to about −75° C. Once at the prescribed temperature, a solution of methyl 2-(4-chloro-3-(trifluoromethyl)phenyl)acetate (4.39 g, 17.38 mmol) in THF (44 mL) was added dropwise over a 15 min period. The resulting solution was stirred at about −75° C. for 30 min, and then warmed to 0° C. Once at the prescribed temperature, the solution was rapidly treated with methyl iodide (1.630 mL, 26.1 mmol). The resulting solution was stirred for 30 min, treated with 1.0 M aqueous HCl and then extracted three times with ethyl acetate. The combined organic phases were washed with 5% aqueous sodium bisulfite (2×25 mL) followed by saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel, eluting with 5-15% ethyl acetate-hexane, to provide racemic methyl 2-(4-chloro-3-(trifluoromethyl)-phenyl)propanoate as a colorless oil (3.444 g, 72%). 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=2.0 Hz, 1 H), 7.47 (d, J=8.4 Hz, 1 H), 7.42 (dd, J=8.4, 2.0 Hz, 1 H), 3.76 (q, J=7.3 Hz, 1 H), 3.68 (s, 3 H), 1.52 (d, J=7.3 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:5]=[C:4]([CH:17]=O)[C:3]=1[N:19]1[CH2:24][C@H:23]([CH3:25])[O:22][C@H:21]([CH3:26])[CH2:20]1.[NH:27]1[C:32](=[O:33])[CH2:31][C:30](=[O:34])[NH:29][C:28]1=[O:35]>C(O)(C)C>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:5]=[C:4]2[C:3]=1[N:19]1[CH2:24][C@@H:23]([CH3:25])[O:22][C@@H:21]([CH3:26])[C@@H:20]1[C:31]1([C:30](=[O:34])[NH:29][C:28](=[O:35])[NH:27][C:32]1=[O:33])[CH2:17]2
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(-c4cnccn4)noc3c2Cl)C[C@H](C)O1
Solvent: CC(C)O
Product: C[C@@H]1CN2c3c(cc4c(-c5cnccn5)noc4c3Cl)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Isopropanol (10 ml) was added to 7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)-3-(pyrazin-2-yl)benzo[d]isoxazole-5-carbaldehyde (Intermediate 472, 198 mg, 0.53 mmol) to give a yellow slurry. The pyrimidine-2,4,6(1H,3H,5H)-trione (barbituric acid) (68.0 mg, 0.53 mmol) was added and the yellow mixture was heated to 80° C. The resulting solution was stirred overnight. The resulting off-white suspension cooled to room temperature, then filtered. The filtercake was washed with MeOH/hexanes to give a white solid, 171 mg (67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][CH2:43][NH2:44])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:45][C:46]([CH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)([CH3:50])[C:47](O)=[O:48]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[C@H:11]([CH2:42][CH2:43][NH:44][C:47](=[O:48])[C:46]([CH:51]3[CH2:52][CH2:53][O:54][CH2:55][CH2:56]3)([CH3:50])[CH3:45])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CCN)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CC(C)(C(=O)O)C1CCOCC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CCNC(=O)C(C)(C)C4CCOCC4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 100 mg of 2-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-ethylamine (from example 44b) are reacted with 2-methyl-2-(tetrahydro-pyran-4-yl)-propionic acid [16386-97-3] to afford the title compound as a yellow oil. Rf=0.40 (dichlormethane-methanol-25% ammonia conc. 200:20:1); Rt=3.87.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH3:10])[NH2:6].[Br-:11].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>ClCCl>[Br:11][C:7]1[CH:8]=[C:9]([CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[NH2:6]
Reactant: COc1cc(N)ccc1C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(N)c(Br)cc1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.6 %

Procedure:
To a solution of 3-methoxy-4-methyl-aniline (8.19 g, 59.71 mmol) in dichloromethane (200 mL), was added tetrabutylammonium tribromide (28.79 g, 59.71 mmol) and the reaction mixture was stirred at room temperature for 2.5 hrs. Aqueous NaHCO3 was added and the layers separated. The aqueous layer was further extracted with dichloromethane and the combined organics washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (20% ethyl acetate in hexane) to give 11.05 g of 2-bromo-5-methoxy-4-methyl-aniline (85% yield). 1H NMR (300 MHz; CDCl3): 2.09 (s, 3 H), 3.75 (s, 3 H), 3.95 (br s, 1 H), 6.27 (s, 1 H), 7.13 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH:10](O)([CH3:12])[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]([CH3:12])[CH3:11])=[C:4]([F:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: CC(C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Br)cc1F
Temperature: 45 °C
Yield: 107.4 %

Procedure:
To a solution of 4-bromo-2-fluorophenol (10 g, 52.35 mmol) in THF (100 ml), isopropyl alcohol (4.8 ml, 62.62 mmol) and triphenylphosphine (20.6 g, 78.52 mmol) were added and heated to 45° C. followed by diisopropylazodicarboxylate (15.4 ml, 78.52 mmol). The mixture was refluxed for 1 h, concentrated and the residue was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a colourless liquid (13.1 g, 99%) which was used without purification in the next step.
Reaction SMILES: P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:18][NH:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=1.[C:33]([O:37][C:38]([N:40]([CH2:42][C:43]([OH:45])=O)[CH3:41])=[O:39])([CH3:36])([CH3:35])[CH3:34]>CN(C)C=O>[C:33]([O:37][C:38]([N:40]([CH2:42][C:43]([N:19]([C:20]1[CH:32]=[CH:31][C:23]([O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=1)[CH3:18])=[O:45])[CH3:41])=[O:39])([CH3:34])([CH3:35])[CH3:36]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCOC(=O)COc1ccc(NC)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(N(C)C(=O)CN(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 48.5 %

Procedure:
0.12 ml (0.72 mmol) of diethyl cyanophosphate and 0.20 ml (1.43 mmol) of triethylamine were added, whilst ice-cooling, to a solution of 160 mg (0.65 mmol) of ethyl 4-methylaminophenoxyacetate (prepared as an intermediate in Preparation 18) and 135 mg (0.72 mmol) of t-butoxycarbonylsarcosine in 2 ml of dimethylformamide, and the mixture was stirred at room temperature for 14 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was diluted with ethyl acetate. The resulting organic mixture was washed with a 5% w/v aqueous solution of citric acid, with a 5% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The reaction mixture was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by preparative thin layer chromatography, using a 30:1 by volume mixture of methylene chloride and methanol as the developing solvent, to give 120 mg of ethyl 4-[N-(N-t-butoxycarbonylsarcosyl)-N-methylamino]phenoxyacetate as an oil. In a similar manner to that described in Preparation 15, 200 mg (0.55 mmol) of this compound were hydrolyzed to give 170 mg of the title compound as an amorphous substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6](=O)[N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3]1.[Li].I[CH3:23]>C1COCC1>[CH3:23][C:4]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3][C:2]([CH3:20])([CH3:1])[CH2:6][N:5]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CCOC(=O)[C@@H]1CC(C)(C)C(=O)N1C(=O)OC(C)(C)C
Reactant: CI
Agent: [Li]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CC(C)(C)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a solution of (S)-1-tert-butyl 2-ethyl 4,4-dimethyl-5-oxopyrrolidine-1,2-dicarboxylate (163D) (10 g, 0.035 mol) in dry THF (60 mL) stirred at −78° C. under nitrogen was added a 1 M solution of lithium hexmethyldisilazide in THF (38.5 mL, 0.038 mol). The mixture was stirred at −78° C. for 30 min, iodomethane (5.4 g, 0.038 mol) in THF (5 mL) was added, and the mixture was then stirred 1 h, warmed up to room temperature and continued stirring for additional 3 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by flash chromatography (10-20% EtOAc/hexanxe) to furnish (163E) (8.2 g, 72%).
Reaction SMILES: [CH:1]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:15][CH2:16][CH3:17].[H-].[Na+]>>[CH2:15]([O:13][CH:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:16][CH3:17]
Reactant: OC1CCCCCCCCCCC1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Product: CCCOC1CCCCCCCCCCC1

Procedure:
Cyclododecanol (2.6 g, 14.11 mmol), 1-iodopropane (1.74 g, 102.54 mmol), and 60% sodium hydride in mineral oil (750.0 mg, 18.75 mmol) prepared as in Example 1 were strongly refluxed for 3 hours. A 3.0 g sample (94.0%) was isolated as in Example 1. GC showed 99% one component; bp 69°-71° C. at 0.09 mm. IR (neat, cm-1) 2955, 2882, 1485, 1460, 1350, 1105 (C-O-C); 13C NMR (ppm, CDC13) 77.02 (α-ring carbon), 70.32 (α-chain carbon), 29.18, 24.94, 24.49, 23.39, 20.98, 10.82. Anal calcd for C15H30O:C,79.58, H,13.36. Found: C,79.55; H,13.42.
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[Cl:16][C:17]1[N:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Cl:16][C:17]1[N+:22]([O-:6])=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)Cc1ccc(Cl)[n+]([O-])c1
Reaction time: 0.5 h
Yield: 44 %

Procedure:
Hydrogen peroxide (0.409 mL of a 30% aqueous solution, 3.6 mmol) was added slowly to a stirred solution of trifluoroacetic anhydride (0.915 mL, 6.55 mmol) in DCM (5 mL) with heating under reflux. After 30 min, methyl (6-chloropyridin-3-yl)acetate (Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (2004), 43B(4), 864) (608 mg, 3.28 mmol) was added as a solution in DCM (5 mL). The reaction mixture was stirred under reflux for 1 h and then allowed to cool with stirring for 16 h. Solid potassium carbonate was added until there was no more effervescence then the mixture was filtered, concentrated by evaporation and the resultant oil was triturated with Et2O to give the title compound (291 mg, 44%) as a solid; 1H NMR δ 3.64 (s, 3H), 3.79 (s, 2H), 7.30 (d, 1H), 7.75 (d, 1H), 8.45 (s, 1H); MS m/e MH+ 202.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].Br[C:6]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([N+:18]([O-:20])=[O:19])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2.N1C=CC=CC=1>O.C([O-])(O)=O.[Na+]>[CH3:2][N:3]([CH3:4])[C:6]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([N+:18]([O-:20])=[O:19])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2
Reactant: CNC
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc([N+](=O)[O-])c2ncccc2c1N(C)C
Yield: 18 %

Procedure:
A solution of 18 g (0.22 mole) of dimethylamine hydrochloride in 50 ml of warm water was added to a stirred mixture of 30 g (0.11 mole) of 5-bromo-6-methoxy-8-nitroquinoline--Example 13A--30 g of NaHCO3 and 180 ml of pyridine. The mixture was heated under reflux for 30 hr, allowed to cool and filtered. The filtered solid was washed with acetone and the combined filtrate and washings were slowly diluted with water to 4 l. Unreacted 5-bromo compound separated first followed by product. Crystallization from methanol gave 4.9 g of 5-dimethylamino-6-methoxy-8-nitroquinoline (20% yield) as orange crystals which melted 79°-80°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:11][C:10]=1[NH2:26])([CH3:4])([CH3:3])[CH3:2].[CH:28](=O)[CH2:29][CH2:30][CH3:31]>C(O)C.C(O)(=O)C>[C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]1[C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)(=[O:18])=[O:17])=[CH:11][C:10]=2[N:26]=[C:28]1[CH2:29][CH2:30][CH3:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNc1ccc(NS(=O)(=O)c2ccc(F)cc2)cc1N
Reactant: CCCC=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
The product from step c.) (100 mg, 0.25 mmol) was dissolved in ethanol (5 mL) and treated with acetic acid (2 drops) followed by butyraldehyde (35 uL, 0.39 mmol). The reaction was heated to 70° C. for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to give the crude sub-title compound that was used without further purification.