Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.[CH3:8][C:9](OC(C)=O)=[O:10].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[NH:28][C:27]4[N:35]=[CH:36][CH:37]=[CH:38][C:26]=4[N:25]3[C:39]=2[C:40]2[CH:45]=[CH:44][C:43]([C:46]3([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:49][CH2:48][CH2:47]3)=[CH:42][CH:41]=2)=[CH:18][CH:17]=1>C(Cl)Cl>[C:9]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[C:24]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[NH:28][C:27]4[N:35]=[CH:36][CH:37]=[CH:38][C:26]=4[N:25]3[C:39]=2[C:40]2[CH:45]=[CH:44][C:43]([C:46]3([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:54])([CH3:56])[CH3:55])[CH2:47][CH2:48][CH2:49]3)=[CH:42][CH:41]=2)=[CH:20][CH:21]=1)(=[O:10])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(N)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Yield: 59.5 %

Procedure:
Et3N (25.9 μL, 0.186 mmol) and Ac2O (6.45 μL, 0.0682 mmol) were added to a solution of tert-butyl (1-{4-[2-(4-aminophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (35.4 mg, 0.0620 mmol) in DCM (1 mL) at 0° C. After stiffing the mixture for 17.5 hours at room temperature, the mixture was concentrated. The residue was diluted with sat. NaHCO3 aq. and extracted with CHCl3 (3×). The combined organic layers were dried over anhydrous Na2SO4, and concentrated. The residue was purified by PTLC (CHCl3/MeOH=9:1) to afford desired product (22.6 mg, 59.5%) as a white solid. 1HNMR (CDCl3) 400 MHz δ: 8.18-8.13 (m, 1H), 8.03-7.97 (m, 1H), 7.60-7.49 (m, 2H), 7.45-7.25 (m, 8H), 7.19-7.10 (m, 3H), 6.95 (d, J=7.8 Hz, 1H), 6.85-6.73 (m, 1H), 6.59 (dd, J=8.0, 4.8 Hz, 1H), 6.46-6.37 (m, 1H), 5.27-5.17 (m, 1H), 2.64-2.25 (m, 4H), 2.20-2.01 (m, 1H), 2.14 (s, 3H), 1.98-1.83 (m, 1H), 1.38 (br s, 9H); LCMS: 613 [M+H].
Reaction SMILES: [NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@@H:2]([NH:1][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=2)=[O:30])[C:3]1=[O:20]
Reactant: CN1C(=O)[C@H](N)N=C(c2ccccc2)c2ccccc21
Reactant: Cc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(C)C2=O)cc1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-methylphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 233°-235° C.
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].S(O[CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])(O)(=O)=O.[CH2:18]([SH:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(O)C>[CH3:15][C:14]([NH2:17])([CH3:16])[CH2:13][S:26][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCS
Reactant: CC(C)(N)COS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCSCC(C)(C)N
Temperature: 25 °C
Yield: 99.3 %

Procedure:
In a mixed solvent of 10 ml of water and 10 ml of ethanol was suspended 1.38 g (10 mmol) of potassium carbonate. To the suspension were added 0.85 g (5 mmol) of 2-amino-2-methylpropyl hydrogensulfate and 0.73 g (5 mmol) of 1-octanethiol, and the resulting mixture was gently refluxed for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and the desired compound was extracted three times with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby 1.08 g of 2-methyl-1-n-octylthio-2-propylamine was obtained. The purity was measured in terms of area percentage by gas chromatography and found to be 91%.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:37])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34](O)=[O:35])[CH:12]=[CH:13][CH:14]=1.[NH2:38][C:39]([CH3:43])([CH3:42])[CH2:40][OH:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:41][CH2:40][C:39]([NH:38][C:34]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:37])[C:19]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:32])([CH3:31])[CH3:33])[NH:17]1)=[O:35])([CH3:43])[CH3:42]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)NC(C)(C)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Yield: 90.7 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.2 g, 0.36 mmol) was reacted with 2-amino-2-methyl-1-propanol (Fluka) (0.2 g, 2.2 mmol), HATU (0.3 g, 0.78 mmol) and iPr2NEt (0.5 g, 3.8 mmol) in CH2Cl2 (10 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide as a white solid (0.17 g, 91%).
Reaction SMILES: CCC(CO[C:8]([C:21]([N:23](CC[NH+](C)C)C)=O)(C1C=CC=CC=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)CC.[Cl-].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:36].[OH-:51].[Na+]>>[NH2:23][CH2:21][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:36])=[C:11]([OH:51])[CH:10]=1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: [OH-]
Reactant: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: NCCc1ccc(O)c(O)c1
Temperature: 80 °C

Procedure:
In the first method (Experiment 1; FIG. 26), several milliliters of urine were combined with an alkaline detergent solution (1% Triton X-100, 50 mM EDTA, 10 mM NaOH). This mixture was then filtered through a 0.2 micron syringe filter (typically polyethersulfone), which traps the bacteria. A small volume of alkaline rinse solution (50 mM NaOH) was flushed through the filter, to rinse away any artifactually reactive metabolites. Alkaline extraction solution (75 mM NaOH) was back-flushed through the filter, eluting the bacteria trapped on the surface of the filter. The eluted bacteria were heated at 80° C. for several minutes and then combined with an equal volume of neutralization solution (150 mM MOPS). A small volume (typically 0.3 ml) of this neutralized sample was added directly to an assay tube containing the lyophilized BacTx™ reagents (lyophilized hemolymph from Manduca sexta, dopamine, lysostaphin and a separate lyophilized pellet containing MBTH, trehalose, and Ficoll). The BacTx™ reagents consist of lyophilized hemolymph from Manduca sexta, dopamine, lysostaphin and a separate lyophilized pellet containing MBTH, trehalose, and Ficoll. In the presence of bacterial peptidoglycan, the hemolymph proteolytic enzyme cascade is triggered, resulting in the oxidation of dopamine to quinones which form a bright red adduct with MBTH. An increase in absorbance at approximately 500 nm over time, e.g. in 1-90 minutes, is thus an indication of bacteria in the urine sample. In this experiment, a urine sample which had been spiked with 2E6 CFU/ml of E. coli prior to the assay yielded a readily observed bright red color which intensifed over a 90 minute period, while a normal, unspiked urine sample yielded no color development (see Results below).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][C:64]([P:67](=[O:74])([O:71][CH2:72][CH3:73])[O:68][CH2:69][CH3:70])([F:66])[F:65]>>[CH2:69]([O:68][P:67]([C:64]([F:66])([F:65])[CH2:63][CH2:62][O:61][CH2:60][CH2:59][O:58][CH2:57][CH2:56][NH:55][C:20](=[O:21])[C@@H:19]([NH:18][C:16]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:17])[CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=[O:74])[O:71][CH2:72][CH3:73])[CH3:70]
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCOCCN
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(=O)CCCCCCCCCCC
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCC(F)(F)P(=O)(OCC)OCC)NC(=O)CCCCCCCCCCC

Procedure:
The title compound was prepared from (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-((R)-2-dodecanamido-3-(dodecyloxy)propylthio) propanoic acid (1.0 eq, from example 26, step 8) and diethyl 3-(2-(2-aminoethoxy)ethoxy)-1,1-difluoropropylphosphonate (1.2 eq, from example 22, step 3) by following the procedure described for example 26, step 9.
Reaction SMILES: [CH2:1]([C:3]1(C(O)=O)[CH2:8][CH2:7][CH:6]([O:9][CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5][CH2:4]1)[CH3:2].C1C=CC(P([N:35]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C[C:39]([OH:42])(C)C>>[CH2:1]([C:3]1([N:35]=[C:39]=[O:42])[CH2:4][CH2:5][CH:6]([O:9][CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:15])([CH3:16])[CH3:17])[CH2:7][CH2:8]1)[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCC1(C(=O)O)CCC(OCOCC[Si](C)(C)C)CC1
Reactant: CC(C)(C)O
Product: CCC1(N=C=O)CCC(OCOCC[Si](C)(C)C)CC1
Yield: 73 %

Procedure:
A solution of 1-ethyl-4-[[2-(trimethylsilyl)ethoxy]methoxy]cyclohexane-1-carboxylic acid (1.24 g, 4.10 mmol, 1.00 equiv), DPPA (2.03 g, 7.38 mmol, 1.80 equiv) and TEA (1.24 g, 12.25 mmol, 2.99 equiv) in 2-methylpropan-2-ol (30 mL) was stirred for 14 hr at reflux under nitrogen. The reaction mixture was quenched with water, extracted with 3×50 mL of EtOAc. The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:6) to give (2-[[(4-ethyl-4-isocyanatocyclohexyl)oxy]methoxy]ethyl)trimethylsilane (0.9 g, 73%) as colorless oil. 1H NMR (400 MHz, CD3OD): δ 4.70 (2H, s), 3.89-3.80 (1H, m), 3.67 (2H, t), 1.80-1.73 (6H, m), 1.65-1.58 (4H, m), 1.00 (3H, t), 0.94 (2H, t).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[C:10](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:10])=[CH:4][C:3]=1[F:9]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Br)c(F)c1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a suspension of 4-bromo-3-fluorophenol (2.87 g) and cesium carbonate (12.2 g) in N,N-dimethylformamide (30 mL) was added methyliodide (1.87 mL) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 1-bromo-2-fluoro-4-methoxybenzene (3.02 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:16]([O:18][CH3:19])=[O:17].NCC(O)=O>C1COCC1>[CH3:19][O:18][C:16]([NH:1][C@@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4])=[O:17]
Reactant: COC(=O)Cl
Reactant: CC(C)[C@@H](N)CO
Agent: NCC(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)N[C@@H](CO)C(C)C
Temperature: -20 °C

Procedure:
39.7 g (0.385 mol) of D-valinol (Aldrich) are dissolved under nitrogen in 500 ml of dry THF. 58.7 ml (0.424 mol) of triethylamine are added, the mixture is cooled to -20° C. and 32.8 ml (0.424 mol) of methyl chloroformate (Aldrich) are added dropwise to the mixture with stirring. The mixture is subsequently stirred at this temperature for 30 minutes and then brought to room temperature. 60 g (0.078 mol) of glycine are added and the mixture is stirred once more for 15 minutes. The precipitate is filtered off with suction, the filtrate is concentrated and the residue is taken up in diethyl ether. The organic phase is washed with 1N HCl, saturated NaHCO3 solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated, and the residue is dried in a high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:31]([O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[C:37]([F:42])[CH:36]=1)[CH3:32]>CN(C1C=CN=CC=1)C>[CH2:31]([O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:18](=[O:19])[CH:17]([C:16]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:37]([F:42])[CH:36]=1)[CH3:32]
Reactant: CCOC(=O)c1ccc(N)c(F)c1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 6, [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (example 5.1) was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with 4-amino-3-fluoro-benzoic acid ethyl ester (CAS Reg. No. 73792-12-8) in the presence of DMAP to give the title compound as yellow oil. MS: m/e=538.4 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].[OH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O:12][CH2:30][CH2:29][O:28][CH2:27][CH2:26][OH:25])=[O:11]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: OCCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: O=C(OCCOCCO)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (5.6 g, 0.015 mole), 2-hydroxyethyl ether (6.4 g, 0.06 mole) and p-toluenesulfonic acid (200 mg) was heated at 135°-142° C. for 26 hrs. The resulting solution was cooled to room temperature, taken into 400 ml of ether. The ethereal solution was washed three times with water, dried over CaSO4 and concentrated to 4.9 g of a yellowish gum. The gum was chromatographed on silica gel and eluted with hexane-ethyl acetate (90:10); yield 3.4 g of pure 5-hydroxy-3-oxapentyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate as a pale yellow gum; nmr (DMSO-d6) δ 3.56 (s, broad 5H), 3.76 (m, 2H), 4.52 (m, 2H), 7.18-8.40 (m, 6H); ir (CHCl3) 3610, 1750 Cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:42][C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:42][C:43]4[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])=[O:24]
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCc1ccncc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N′-(2,4-difluorophenyl)urea (55 mg), potassium carbonate (62 mg), and 4-(chloromethyl)pyridine hydrochloride (22 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 80° C. for one hr. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 35 mg (yield 55%) of the title compound.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:53]([OH:56])([CH3:55])[CH3:54])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([C:53]([OH:56])([CH3:55])[CH3:54])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:51])([F:50])[F:52])=[CH:43][CH:42]=1
Reactant: CC(C)(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)(F)F)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
To a solution of 2-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(2,2,2-trifluoroethoxyl) phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]propan-2-ol 18c (156 mg, 0.20 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 15 mL) were added o-dichlorobenzene (0.11 mL, 0.99 mmol) and 10% Pd/C (21.0 mg, 0.02 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours under H2 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=1/1 to give the title compound 18 as pale yellow oil (62.5 mg, 62.5%, HPLC: 95.60%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 563.3 [M+CHOO]−; and 1H NMR (600 MHz, DMSO-d6) δ(ppm): 7.43 (d, 1H), 7.39 (d, 1H), 7.33 (d, 1H), 7.15 (q, 2H), 6.97 (q, 2H), 4.70 (q, 2H), 4.02 (m, 3H), 3.80 (d, 1H), 3.70 (d, 1H), 3.45 (m, 2H), 1.20 (s, 3H), 1.15 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:49][C:50]([NH2:52])=[O:51]>CN(C)C=O.C(OCC)(=O)C>[NH2:52][C:50](=[O:51])[CH2:49][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]2[C@H:35]3[C@H:31]([O:32][CH2:33][CH2:34]3)[O:30][CH2:29]2)[C@H:15]([OH:37])[CH2:14][N:13]([S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)(=[O:12])=[O:11])[CH2:38][CH:39]([CH3:41])[CH3:40])=[CH:19][CH:20]=1
Reactant: NC(=O)CBr
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCC(N)=O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl) (isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate (47 mg, 0.08 mmol) in anhydrous dimethylformamide (2 mL) was added cesium carbonate (78 mg, 0.24 mmol) and 2-bromoacetamide (22 mg, 0.16 mmol). After 1 h at ambient temperature, the mixture was diluted with ethyl acetate, washed with water (3×), brine, dried (sodium sulfate), and evaporated. The residue was purified by chromatography (silica gel, dichloromethane/methanol, 97:3) to afford the title product as a white solid (45 mg) 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.2 (1H, dd), 1.4 (1H, quintuplet), 1.9-2.0 (1H, m), 2.35 (1H, t), 2.6-2.8 (3H, m), 2.9 (1H, d), 2.95 (1H, dd), 3.25-3.30 (1H, m), 3.45 (1H, br s), 3.5-3.6 (3H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.3 (2H, s), 4.8 (1H, dt), 5.0 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.8 (2H, d), 7.0-7.15 (3H, m), 7.22 (1H, s), 7.24 (1H, d), 7.26 (1H, d), 7.32 (1H, s), 7.42 (1H, s); MS: 650 (MH+)
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[Cl:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:7]=1[C:19]([F:22])([F:21])[F:20]>C1CCCCC1>[C:1]([NH:4][C:10]1[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:7]([C:19]([F:20])([F:21])[F:22])=[C:6]([Cl:5])[C:11]=1[N+:12]([O-:14])=[O:13])#[C:2][CH3:3]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: C#CCN
Solvent: C1CCCCC1
Product: CC#CNc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]

Procedure:
The compound was prepared by reacting propargylamine with 2,4-dichloro-3,5-dinitrobenzotrifluoride in cyclohexane to give the product melting at 86° - 87°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[C:51]1([CH:57]([OH:61])[CH2:58][CH2:59][CH3:60])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:61][CH:57]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:58][CH2:59][CH3:60])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: CCCC(O)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C)c1ccccc1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (90 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (125 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux form 15 min. Subsequently, 1-phenyl-1-butanol (62 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (59 mg, yield 40%).