Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([P:4](=[O:10])([CH:7]([CH3:9])[CH3:8])[CH:5]=[CH2:6])([CH3:3])[CH3:2].[CH3:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:12]([CH3:11])[CH2:6][CH2:5][P:4]([CH:7]([CH3:9])[CH3:8])([CH:1]([CH3:3])[CH3:2])=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNCc1ccccc1
Reactant: C=CP(=O)(C(C)C)C(C)C
Product: CC(C)P(=O)(CCN(C)Cc1ccccc1)C(C)C
Temperature: 200 °C

Procedure:
Diisopropyl(vinyl)phosphine oxide (1.00 g, 6.24 mmol) was combined with N-methylbenzylamine (1.61 mL, 12.48 mmol) in a microwave vial and heated at 200° C. for 4 h total (reaction progress checked after 2 h). The crude mixture was directly purified by flash chromatography (0-10% MeOH/CH2Cl2). Coelution of the product with minor impurities required a second column (0-10% MeOH (w/2 N NH3)/CH2Cl2) to give clean product as a yellow oil. 1H NMR (CDCl3, 600 MHz) δ 7.30-7.20 (m, 5H), 3.50 (s, 2H), 2.76-2.70 (m, 2H), 2.20 (s, 3H), 2.00-1.92 (m, 2H), 1.90-1.84 (m, 2H), 1.17 (dd, J=14.6, 7.2 Hz, 6H), 1.12 (dd, J=15.1, 7.1 Hz, 6H). MS: cal'd 282 (MH+), exp 282 (MH+).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][OH:11].N1C(C)=CC(C)=CC=1C.[Cl-:21].[Li+].[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>CN(C)C=O>[Cl:21][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][O:11][S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: [Cl-]
Reactant: OCCc1ccccc1CO
Reactant: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CS(=O)(=O)OCCc1ccccc1CCl
Temperature: 0 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
Mix 2-(2-hydroxymethyl-phenyl)-ethanol (12.0 g, 78.8 mmol) and collidine (23 mL, 0.17 mol) and treat with lithium chloride (7.35 g, 0.173 mmol) in dimethylformamide (125 mL). Cool in an ice bath and treat, by dropwise addition, with mesyl chloride (13.4 mL). Stir at 0° C. for 4 hours, partition between ice water (300 mL) and a 1:1 mixture of ether:pentane (2×400 mL). Wash the organic layer with a saturated solution of CuSO4 (2×200 mL), dry (MgSO4) and purify by silica gel chromatography (2.5:1 hexane/ethyl acetate followed by 2:1 hexane/ethyl acetate followed by 3:2 hexane/ethyl acetate) to give methanesulfonic acid 2-(2-chloromethyl-phenyl)-ethyl ester as a pale yellow oil (8.8 g, 45%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C#N)c1
Reaction time: 0.02 h
Yield: 112.1 %

Procedure:
40% Methanolic Triton B (0.06 mL, 0.13 mM) was added to a solution of the 9-[(3-cyanophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (34.1 mg, 0.1 mM) in 5 mL DMF at room temperature. After 1 minute, tert-butyl bromoacetate (40 mg, 0.2 mM) was added and the resultant mixture stirred at room temperature for 24 h. The mixture was diluted with ethyl acetate, washed four times with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was triturated with hexane to afford 51 mg (100%) of the {9-[(3-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (CDCl3) δ 7.55 (d, 1H, J=8 Hz), 7.5-7.2 (m, 7H), 6.95 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.3 (br s, 1H), 6.1 (br s, 1H), 5.5 (s, 2H), 4.8 (s, 2H), and 1.5 (s, 9H). IR (KBr, cm−1) 2228, 1748, and 1669. MS (ES) m/e 455, 456.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([C:19]1[O:23][N:22]=[C:21]([OH:24])[CH:20]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:15]([C:19]1[O:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[C:21](=[O:24])[CH:20]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)c1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(=O)n(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])o1
Yield: 45.5 %

Procedure:
After mixing 15.0 g of 4-chloro-3-nitrobenzotrifluoride, 11.3 g of 5-t-butyl-3-hydroxyisoxazole, 11.0 g of potassium carbonate, and 80 ml of dimethyl sulfoxide, the mixture was reacted for 4 hours at 80° C. After cooling, the reaction mixture obtained was poured into water to deposit crystals which were then recovered by filtration and recrystallized from a mixture of water and methanol to provide 10.0 g of the desired compound with a yield of 45.5%. The melting point thereof was 116° to 117° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16](O)[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](Br)=[CH:9][CH:10]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.C([Sn](CCCC)(CCCC)[C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1)CCC>>[F:20][C:14]1[C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:29]4[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:9][CH:10]=3)[C@@:5]3([CH2:4][S:3][C:2]([NH2:1])=[N:22]3)[C:18]=2[CH:17]=[C:16]([C:38]2[N:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[CH:15]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: NC1=N[C@@]2(CS1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Reactant: OB(O)c1cccnc1F
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(-c3ncccn3)cc12

Procedure:
The titled compound was synthesized by stpes analogous to those described in method AA22 above, but using (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[thiazole-4,9′-xanthen]-2′-ol (prepared as described in Method BB26 and Example 2 but using 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one), 2-fluoropyridin-3-ylboronic acid and 2-(tributylstannyl)pyrimidine. MS m/z=460.0 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:8][CH:7]=2)[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: ClCCN1CCCCC1
Reactant: Oc1ccc(-n2cccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccn(-c2ccc(OCCN3CCCCC3)cc2)c1
Temperature: 85 °C
Reaction time: 72 h
Yield: 39.4 %

Procedure:
To a 50 mL vial which contained a solution of 4-Pyrrol-1-yl-phenol (500 mg, 3.1 mmol) and 1-(2-chloroethyl)piperidine hydrochloride (1.25 g, 6.2 mmol) in DMF (30 mL) was added K2CO3 (1.8 g, 13 mmol) at rt. The reaction mixture was heated to 85° C. and stirred at 85° C. for 72 h. After cooled to rt, the reaction mixture was poured into 30 mL ice-water mixture and then was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (3×50 mL) and brine (30 mL), dried over Na2SO4. After concentrated in vacuo, the residue was purified by a column chromatography on silica gel eluting with ethyl acetate:hexane (1:4-1:1) to yield the title compound (330 mg 40%); 1HNMR (500 MHz, CDCl3) 7.29 (d, J=9.0 Hz, 2H), 6.99 (t, J=2.0 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 6.32 (t, J=2.0 Hz, 2H), 4.12 (t, J=6.0 Hz, 2H), 2.79 (t, J=6.0 Hz, 2H), 2.52 (br, 4H), 1.44-1.63 (m, 6H); LCMS; m/z (ESI+ 271.6, M+1); 98%;
Reaction SMILES: C(OC(NC(C(C)(C)C)C(O)=O)=O)(C)(C)C.[CH:17]1([CH2:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(OC(=O)NC(C(=O)NC1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)CC1O)C(C)(C)C)(C)(C)C.ClNC(=O)[O-].C([O:58][C:59]([C:61]1([NH:66][C:67]([CH:69]2[CH2:73][CH:72]([O:74][C:75]3[C:84]4[C:79](=[CH:80][C:81]([O:85][CH3:86])=[CH:82][CH:83]=4)[N:78]=[C:77]([C:87]4[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=4)[CH:76]=3)[CH2:71][N:70]2[C:93](=[O:113])[NH:94][CH:95]([C:100](=[O:112])NC2C3C(=CC=CC=3)CC2O)[C:96](C)(C)C)=[O:68])[CH2:63][CH:62]1[CH:64]=[CH2:65])=[O:60])C>>[CH:42]1([CH2:96][C@H:95]([NH:94][C:93]([N:70]2[CH2:71][C@H:72]([O:74][C:75]3[C:84]4[C:79](=[CH:80][C:81]([O:85][CH3:86])=[CH:82][CH:83]=4)[N:78]=[C:77]([C:87]4[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=4)[CH:76]=3)[CH2:73][C@H:69]2[C:67]([NH:66][C@:61]2([C:59]([OH:58])=[O:60])[CH2:63][C@H:62]2[CH:64]=[CH2:65])=[O:68])=[O:113])[C:100](=[O:112])[NH:24][CH2:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Reactant: NCC1CCCCC1
Agent: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Agent: O=C([O-])NCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@@H](CC1CCCCC1)C(=O)NCC1CCCCC1)C(=O)O

Procedure:
N-(tert-butoxycarbonyl)-L-cyclohexylalanine was attached to the resin as described for the preparation of compound 16 followed by reaction with cyclohexanemethylamine as described for the preparation of 17 and removal of the Boc group as described for 18. The afforded compound was then reacted with the chlorocarbamate achieved from 12 as described for the preparation of 13 which gave the title compound. Purity by HPLC>95%. M+H+766.4.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:22]1[CH2:26][O:25][CH2:24][CH2:23]1.CC1C(=O)OC[C:29]1=[O:30]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[C:24]3[CH:23]=[C:22]([O:30][CH3:29])[CH2:26][O:25]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(F)cc2N1
Reactant: CC1C(=O)COC1=O
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COC1=CC(=C2C(=O)Nc3cc(F)ccc32)OC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 6-fluorooxindole (2.6 g, 17.5 mmol) in anhydrous THF (30 mL) under nitrogen was added 1.0 M LiHMDS/THF solution (35 mL, 35 mmol). The mixture was stirred at room temperature for 10 minutes. Methyl tetronate (1.0 g, 8.8 mmol) was added as one portion. After stirring at room temperature for 1 hour, the reaction was cooled to 0° C., and quenched with 2M HCl until pH=3. The mixture was stirred at room temperature for 2 more hours, and poured into 250 mL of water. The resulting precipitates were filtered, rinsed with water and dried in vacuum to give 6-fluoro-3-(4-methoxy-5H-furan-2-ylidene)-1,3-dihydro-indol-2-one as off-white solid. Yield: 840 mg, 38%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:19]([CH2:22]C)CC)C.Cl[C:25](OC(C)(C)C)=[O:26].Cl.[CH3:33][N:34]([CH3:36])[OH:35]>ClCCl>[CH3:33][N:34]([CH3:36])[OH:35].[OH:16][C@H:14]1[CH2:15][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@H:9]([C:10]([N:19]([O:26][CH3:25])[CH3:22])=[O:12])[CH2:13]1
Reactant: CC(C)(C)OC(=O)Cl
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CN(C)O
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.85 g of (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline are dissolved in 80 ml of dichloromethane at 0° C. under N2. 3.72 ml of triethylamine and 1.97 ml of tert-butyl chloroformate are added. The reaction medium is stirred at ambient temperature for 1 h. In parallel, a solution of dimethylhydroxylamine is prepared by adding 1.86 ml of triethylamine to a solution of 1.56 g of dimethyl-hydroxylamine hydrochloride in dichloromethane, and then by filtering off the triethylamine hydrochloride. This second solution is added gently, at 0° C., to the first. The reaction medium is stirred at ambient temperature for 16 h. After hydrolysis with a 0.5N aqueous hydrochloric acid solution, extraction is carried out with dichloromethane until the aqueous phase is completely depleted. The organic phase is dried over MgSO4 and concentrated to dryness. 0.9 g of tert-butyl (2S,4R)-4-hydroxy-2-{[methoxy(methyl)amino]-carbonyl}pyrrolidine-1-carboxylate is obtained, which product is subsequently used as it is.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]3[CH2:47][CH2:46]3)[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]3[CH2:46][CH2:47]3)[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(-c2cccc(C3CC3)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2cccc(C3CC3)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.10 g), sodium hydrogen carbonate (1.64 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(3-cyclopropylphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.95 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.45 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.44 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.49 g, 47%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.CCOCC.O>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: BrCCCCCCCCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)(CCCCCCCCCOCc1ccccc1)C(=O)OCC
Yield: 95.7 %

Procedure:
Methyl-malonic acid diethyl ester (0.850 ml, 4.99 mmol) was added to a suspension of sodium hydride (55% oily suspension, 139.5 mg, 3.197 mmol) in THF (0.8 ml) over seven minutes under ice-cooling, and the mixture was stirred until foaming was terminated at room temperature (for about 25 minutes). A solution of (9-bromo-nonyloxymethyl)-benzene (593 mg, 1.89 mmol) in THF (0.12 ml) was added to the reaction solution at room temperature over 15 minutes, and the mixture was then stirred at 90° C. for five hours. The reaction mixture was diluted with ether and water was then added, followed by extraction with ether. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=30/1→20/1) to give 2-(9-benzyloxy-nonyl)-2-methyl-malonic acid diethyl ester (735 mg, 96%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:26])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:10]([CH3:17])[NH:11]2.IC.[CH3:30]N(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:26][CH3:30])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:10]([CH3:17])=[N:11]2
Reactant: CN(C)C=O
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(Cl)cc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(OC)c12
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of [8-chloro-3-(4-chlorobenzyl)-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.13 g), iodomethane (0.20 mL), N,N-dimethylformamide (1.0 mL) and potassium carbonate (0.14 g) were stirred at room temperature for 22 hours. The mixture was diluted with water and extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (1:19 to 19:1 by volume) gave title compound as a gum, 0.059 g.
Reaction SMILES: Cl[C:2]1([Cl:8])[NH:7][CH:6]=[N:5][CH:4]=[CH:3]1.CN(C)C=O.[F:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[OH:24].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[Cl:8][C:2]1[CH:3]=[C:4]([O:24][C:16]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=2[F:14])[N:5]=[CH:6][N:7]=1
Reactant: ClC1(Cl)C=CN=CN1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)c(F)c1
Yield: 85.7 %

Procedure:
6,6-dichloropyrimidine (1.000 g, 7 mmol) was dissolved in N,N-dimethylformamide (5 ml, 7 mmol), then 2-fluoro-4-nitrophenol (1 g, 7 mmol) was added into the mixture. Then Cesium Carbonate (2 g, 10 mmol) was added into the mixture with stirring. The mixture was stirred at ambient temperature under nitrogen overnight. The progress of the reaction was monitored by LC/MS, which had confirmed completion. Then diluted the mixture with water was stirred an additional 3 hours. The precipitate was collected by filtration and washed with hexanes. The solid was dried in a reduced-pressure oven overnight to give the desired product 4-chloro-6-(2-fluoro-4-nitrophenoxy)pyrimidine (1.500 g, 6 mmol, 83% yield) as a yellow solid. MS (ESI pos. ion) m/z: 270 (MH+). Calc'd exact mass for C10H5ClFN3O3: 269. 1HNMR (300 MHz, CDCl3): 7.14 (s, 1H), 7.43 (s, 1H), 8.14 (s, 2H), 8.55 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9](C(OC(C)(C)C)=O)[C:10]2[C:15]([C:16]=1[CH:17]([CH:19]1[C:23](=[O:24])[N:22]([C:25](OC(C)(C)C)=O)N(C3C4CC5CC(CC3C5)C4)[CH2:20]1)O)=[C:14]([Cl:42])[CH:13]=[C:12]([Cl:43])[CH:11]=2)=[O:7])(C)(C)C.Cl>C(O)C>[Cl:42][C:14]1[CH:13]=[C:12]([Cl:43])[CH:11]=[C:10]2[C:15]=1[C:16](/[CH:17]=[C:19]1/[C:23](=[O:24])[N:22]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:25][CH2:20]/1)=[C:8]([C:6]([O:5][CH3:1])=[O:7])[NH:9]2
Reactant: CC(C)(C)OC(=O)c1c(C(O)C2CN(C3C4CC5CC(C4)CC3C5)N(C(=O)OC(C)(C)C)C2=O)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: COC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1/C=C1\CCN(c2ccccc2)C1=O
Temperature: 25 °C
Yield: 215.8 %

Procedure:
INTERMEDIATE 4 (700 mg) was suspended in ethanol (95 %) (10 ml), hydrochloric acid (10 ml, 6M) was added and the heterogeneous mixture refluxed for 10 h. The suspension was cooled to room temperature and the solid filtered, washed with further portions of 6M hydrochloric acid and finally vacuum dried to yield the title compound (427 mg, ) as a white solid.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[F:5][C:6]([F:16])([F:15])[C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[Cl:14])[NH2:10]>O.C(O)(=O)C>[Cl:14][C:13]1[CH:12]=[CH:11][C:9]([NH:10][C:2]([NH2:3])=[O:1])=[CH:8][C:7]=1[C:6]([F:5])([F:15])[F:16]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 121.5 %

Procedure:
Sodium cyanate (1.7 g, 0.02 mol) was dissolved in water (17 ml) at room temperature to obtain a clear solution. This solution was then charged drop wise to the clear solution of 3-trifluoromethyl-4-chloroaniline (5 g, 0.025 mol) in acetic acid (25 ml) at 40° C.-45° C. within 1-2 hours. The reaction mass was agitated for whole day and cooled gradually to room temperature. The obtained solid was filtered washed with water and vacuum dried at 50° C. to afford the desired product (5.8 g), i.e., 1-(4-chloro-3-(trifluoromethyl)phenyl)urea.
Reaction SMILES: F[C:2](F)(F)S(OC)(=O)=O.[F:10][C:11]([F:24])([C:13]([F:23])([O:18][C:19]([F:22])([F:21])[F:20])[C:14]([F:17])([F:16])[F:15])[O-:12].CN([S+](N(C)C)N(C)C)C>C(#N)C1C=CC=CC=1>[F:10][C:11]([O:12][CH3:2])([F:24])[C:13]([F:23])([O:18][C:19]([F:20])([F:22])[F:21])[C:14]([F:17])([F:16])[F:15]
Reactant: [O-]C(F)(F)C(F)(OC(F)(F)F)C(F)(F)F
Reactant: COS(=O)(=O)C(F)(F)F
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: N#Cc1ccccc1
Product: COC(F)(F)C(F)(OC(F)(F)F)C(F)(F)F
Temperature: 25 °C

Procedure:
Methyl trifluoromethanesulfonate, 8.53 g (0.052 mol), was added dropwise to a stirred solution of 23.0 g (0.055 mol) of tris(dimethylamino)sulfonium 1,1,2,3,3,3-hexafluoro-2-(trifluoromethoxy)propoxide (prepared as in Example 10) in 50 mL of benzonitrile at 25°. The reaction mixture warmed spontaneously to 40°. After stirring for one h at ambient temperature the more volatile portion of the reaction mixture was distilled out at reduced pressure, and then redistilled at atmospheric pressure to give 8.96 g (65%) of the ether as a colorless liquid: bp 64.4°; 1H NMR (CDCl3) δ3.71 ppm (s); 19F NMR (CDCl3) δ-54.1 ppm (m, 3F), -80.8 ppm (m, 3F), δ-88.6 ppm (m, 2F) and -146.1 ppm (m, 1F). Anal. Calcd. for C5H3F9O2 : C, 22.57; H, 1.14; F, 64.27. Found: C, 22.63; H, 1.17; F, 63.67.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>ClCCl.CCOC(C)=O>[CH3:21][O:20][N:19]([CH3:18])[C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
(R)-1-(tert-Butoxycarbonyl)piperidine-3-carboxylic acid (25 g, 0.11 mol, 1.0 equiv), N,O-dimethylhydroxylamine hydrochloride, (10.5 g, 0.14 mol, 1.25 equiv) and EDCI.HCl (26.3 g, 0.14 mol, 1.25 equiv) and diisopropylethylamine (48 mL, 0.28 mol, 2.5 equiv) were dissolved in dichloromethane (400 mL) and stirred overnight at rt. The reaction mixture was diluted with EtOAc, washed with 5% aq HCl (2×150 mL), satd aq NaHCO3 (150 mL), brine (100 mL), and dried over Na2SO4. Concentration afforded (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (24.42 g, 82%) as a clear oil. The crude product was used for next step without further purification. MS ESI+ve m/z 295 (M+Na). 1H NMR (CDCl3) δ 4.19-4.00 (m, 2H), 3.77 (m, 3H), 3.12 (s, 3H), 2.79 (m, 2H), 2.64 (m, 1H), 1.89 (m, 1H), 1.71-1.52 (m, 2H), 1.51-1.33 (m, 10H).