Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=2[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[CH:6][CH:7]=1.[C:22]([O:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[CH2:40][O:41][C:42](=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:35]Br)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:50](=O)([O-])[O-].[K+].[K+]>>[C:23]1([C:22]([O:30][CH2:31][C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=2[CH2:40][O:41][C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:49])[CH2:35][O:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:50])=[O:15])=[CH:10][C:9]=3[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[CH:6][CH:7]=2)=[O:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(-c2cccc(O)c2)c(C(C)(C)C)c1
Reactant: O=C([O-])[O-]
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Agent: [K+]
Product: CCOC(=O)c1ccc(-c2cccc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)c2)c(C(C)(C)C)c1

Procedure:
In a manner similar to that of Example 1(i), by reaction of 5.3 g (17.7 mmol) of methyl 3′-hydroxy-2-tert-butylbiphenyl-4-carboxylate with 8.46 g (19 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide and 2.54 g (18 mmol) of potassium carbonate, the desired product is obtained in the form of a yellow oil (m=11 g; Y=94%).
Reaction SMILES: [N:1]([C@@H:4]([C@H:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH3:20])[C:5](N1[C@@H](C2C=CC=CC=2)COC1=O)=[O:6])=[N+:2]=[N-:3].[OH2:28].OO.[OH-].[Li+]>C1COCC1>[N:1]([C@@H:4]([C@H:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH3:20])[C:5]([OH:6])=[O:28])=[N+:2]=[N-:3]
Reactant: O
Reactant: C[C@@H](c1ccc(F)cc1)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(F)cc1)[C@H](N=[N+]=[N-])C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of the product from Step C (0.88 g, 2.39 mmol) in THF (30 mL) was added water (10 mL). The solution was stirred at 0° C. for 15 min, and then 30% hydrogen peroxide (1.60 mL, 14.3 mmol) was added followed by slow addition of lithium hydroxide (0.17 g, 7.23 mmol). The resultant mixture was stirred at 0° C. for 4 h. The reaction was quenched by addition of saturated aqueous sodium sulfite solution and stirred at room temperature for 30 min. The aqueous phase was separated and extracted with three portions of dichloromethane. The aqueous phase was then acidified to pH 1 with 3N hydrochloric acid and extracted with three portions of ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate, and evaporated in vacuo to give the product, which was used in the next step directly. LC/MS 224.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][S-:13].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:12][S:13][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: C[S-]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccc([N+](=O)[O-])c(N)c1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
5-Chloro-2-nitroaniline (15 g, 87.2 mmol) was dissolved in 250 mL of DMF with stirring. Sodium thiomethoxide (9.8 g, 140 mmol) was added and the reaction stirred at 65° C. for 20 h. The reaction was cooled to rt and diluted with EtOAc. then washed with water (5×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 12.9 g (81%) of 5-(methylthio)-2-nitroaniline as a red-orange solid. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=8.97 Hz, 1H), 7.45 (br s, 2H), 6.78 (d, J=1.83 Hz, 1H), 6.47 (dd, J=1.83 and 9.16 Hz, 1H), 2.47 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:23].[C:24](Cl)(=O)[O:25]C1C=CC([N+]([O-])=O)=CC=1.[CH:37]1([NH2:41])[CH2:40][CH2:39][CH2:38]1>ClCCl>[CH:37]1([NH:41][C:24](=[O:25])[NH:1][C:2]2[CH:22]=[CH:21][C:5]([C:6]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][CH2:9]3)=[O:7])=[CH:4][C:3]=2[F:23])[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)c(F)c2)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC1CCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NC(=O)NC3CCC3)c(F)c2)CC1
Reaction time: 20 h
Yield: 22.6 %

Procedure:
tert-Buty 4-(4-amino-3-fluorobenzoyl)piperazine-1-carboxylate (9.5 g, 29.41 mmol) was dissolved in dichloromethane (100 mL) and 4-nitrophenyl carbonochloridate (5.93 g, 29.41 mmol) was added. The reaction mixture was stirred for 20 hours and cyclobutylamine (7.5 mL, 88.2 mmol) added. After 2 hours, the reaction mixture was chromatographed on silica (eluting with dichloromethane to dichloro-methane/ethyl acetate) to give the title compound (2.8 g). MS (ESI) m/z: 421.0 [M+H]+
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:5]([C:12]([O:14][CH2:15]C)=[O:13])=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[N:7]=1)[CH3:2].O.[OH-].[Li+].[C:57]([O:63]CCl)(=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59]>>[CH2:1]([C:3]1[N:4]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:33]=[N:32][N:31]=3)=[CH:22][CH:23]=2)[C:5]([C:12]([O:14][CH2:15][O:63][C:57](=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59])=[O:13])=[C:6]([C:8]([OH:11])([CH3:9])[CH3:10])[N:7]=1)[CH3:2]
Reactant: CCOC(=O)c1c(C(C)(C)O)nc(CC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 100.2 %

Procedure:
Following a procedure similar to that described in Example 78(a), but using 2.25 g of ethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(trityltetrazole-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 68(a)] and using 203 mg of lithium hydroxide monohydrate for hydrolysis and 0.90 g of pivaloyloxymethylchloride for esterification, 2.53 g of the title compound wet obtained as a glass (purified by column chromatography through silica gel using a 1:1 by volume mixture o f ethyl acetate and hexane as the eluent).
Reaction SMILES: C(O)CCCCC.[H-].[Na+].[C:10]1([O:16][C:17](=[O:51])[O:18][CH2:19][N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][N:38]([C:41]5[C:49]6[CH:48]=[CH:47][S:46][C:45]=6[CH:44]=[CH:43][CH:42]=5)[CH2:37][CH2:36]4)[CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:50])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>O1CCCC1>[CH2:10]([O:16][C:17](=[O:51])[O:18][CH2:19][N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][N:38]([C:41]4[C:49]5[CH:48]=[CH:47][S:46][C:45]=5[CH:44]=[CH:43][CH:42]=4)[CH2:37][CH2:36]3)[CH:28]=2)[CH:23]=[CH:22][C:21]1=[O:50])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=C(OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCCO
Solvent: C1CCOC1
Product: CCCCCCOC(=O)OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21
Yield: 12.3 %

Procedure:
To a solution of n-hexylalcohol (50.5 mg) in tetrahydrofuran (5 ml) was added with stirring under ice-cooling 60% sodium hydride (18 mg) by small portions, and the mixture was stirred at the same temperature for 0.5 hr, a solution of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester (240 mg) in tetrahydrofuran (1 ml) was added dropwise, and the mixture was stirred under ice-cooling for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester hexyl ester (30 mg).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][CH3:7])[CH2:3][OH:4].[NH2:8][C:9]1[N:14]=[C:13](Cl)[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][C:18]=2[O:26][CH3:27])=[C:11]([CH3:28])[N:10]=1>CN1C(=O)CCC1.CCOC(C)=O>[NH2:8][C:9]1[N:14]=[C:13]([NH:1][C@@H:2]([CH2:5][CH2:6][CH3:7])[CH2:3][OH:4])[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][C:18]=2[O:26][CH3:27])=[C:11]([CH3:28])[N:10]=1
Reactant: CCC[C@H](N)CO
Reactant: COc1cc(CC#N)ccc1Cc1c(C)nc(N)nc1Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1OC
Temperature: 140 °C
Reaction time: 50 h

Procedure:
(S)-2-Aminopentan-1-ol (0.136 g) was added to a solution of the product from step (iii) in NMP (2 mL). The resulting mixture was stirred at 140° C. for 50 h then diluted with EtOAc and washed with saturated NaHCO3 solution and saturated brine. The organic phase was dried, filtered and evaporated. The crude product was purified by column chromatography, elution gradient 5 to 10% MeOH in DCM to give the subtitle compound, 0.095 g.
Reaction SMILES: BrC1C=CC=[C:8]2C=1[CH:4]=[C:5](C)[N+:6]([O-])=[CH:7]2.[Cl:14][C:15]1[C:24]2[C:19](=[C:20]([C:25]3[CH:26]=[N:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([CH3:35])[N:16]=1.C1C(=O)N(Br)C(=[O:39])C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.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>[Cl:14][C:15]1[C:24]2[C:19](=[C:20]([C:25]3[CH:26]=[N:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([CH2:35][N:6]2[CH2:7][CH2:8][O:39][CH2:4][CH2:5]2)[N:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2c(Br)cccc2c[n+]1[O-]
Reactant: Cc1cc2c(-c3cnc4ccccc4c3)cccc2c(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1nc(CN2CCOCC2)cc2c(-c3cnc4ccccc4c3)cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Bromo-3-methylisoquinoline-2-oxide was obtained according to Example 1(1) using 5-bromo-3-methylisoquinoline instead of 5-bromoisoquinoline. 3-(1-Chloro-3-methylisoquinolin-5-yl)quinoline was obtained according to Example 5(1) using the obtained 5-bromo-3-methylisoquinoline-2-oxide instead of compound (3a) and Pd(PPh3)4 instead of PdCl2dppf. A suspension of the obtained 3-(1-chloro-3-methylisoquinolin-5-yl)quinoline (0.151 g), NBS (0.098 g), and AIBN (0.017 g) in carbon tetrachloride (5 ml) was heated to reflux overnight. After cooling, insoluble matter was filtered off using celite. THF (3 ml), morpholine (0.1 ml), and diisopropylethylamine (0.2 ml) were added to the filtrate, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 4-((1-chloro-5-(quinolin-3-yl)isoquinolin-3-yl)methyl)morpholine (25 mg). Compound (31) was obtained as a pale yellow solid (yield based on 7 steps: 1%) according to Example 1(5) using the obtained 4-((1-chloro-5-(quinolin-3-yl)isoquinolin-3-yl)methyl)morpholine instead of compound (1d) and 4-cyano-3-(4-hydroxycyclohexylamino)phenylboronic acid pinacol ester instead of 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester.
Reaction SMILES: C(O)=[O:2].[F:4][C:5]1[CH:6]=[C:7]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][C:10]=1[S:11][CH3:12].OO.C(OCC)(=O)C.CCCCCC.[OH2:33]>>[F:4][C:5]1[CH:6]=[C:7]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:12])(=[O:2])=[O:33]
Reactant: O
Reactant: COC(=O)C(C)c1ccc(SC)c(F)c1
Reactant: O=CO
Agent: OO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C(C)c1ccc(S(C)(=O)=O)c(F)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Formic acid (6.5 mL, 1 eq) was added to methyl 2-(3-fluoro-4-(methylthio)phenyl)propanoate (1 g, crude) and the mixture cooled to 0° C. Hydrogen peroxide (1.4 mL, 3 eq) was added drop wise at 0° C. and the reaction mixture was stirred overnight at room temperature. Progress of the reaction was monitored by TLC (20% ethyl acetate/hexane, Rf˜0.4). On completion of the reaction, the contents were cooled to 0° C., water was added and the mixture was extracted with ethyl acetate (2×25 mL). The combined extract was washed with NaHCO3 solution, dried over sodium sulfate and concentrated under reduced pressure to yield methyl 2-(3-fluoro-4-(methylsulfonyl)phenyl)propanoate as colorless thick liquid (1 g, crude). The crude product obtained was directly used for the next step.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=4)[N:16]=[CH:15][CH:14]=3)[CH2:7][CH2:6]2)[O:4]CC1>CC(O)=O.C1COCC1.O>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[C:13]2[CH2:12][CH2:11][CH:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1
Reactant: COc1ccc2nccc(CCC3CCC4(CC3)OCCO4)c2c1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2nccc(CCC3CCC(=O)CC3)c2c1

Procedure:
A solution of 4-[2-(1,4-dioxa-spiro[4.5]dec-8-yl)-ethyl]-6-methoxy-quinoline (0.77 g, 2.35 mmol) in AcOH/THF/H2O (3/2/2, 10 ml) was stirred at 60° C. for 10 hours. The reaction mixture was concentrated to dryness by rotary evaporation. The residue was diluted with EtOAc (100 ml), washed with NaHCO3 (100 ml), dried over MgSO4, filtered and concentrated to dryness by rotary evaporation.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.ClC(OC(Cl)=O)C>ClCCl>[ClH:26].[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1
Reactant: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: Cl
Product: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 154.2 %

Procedure:
To a stirred solution of 1-benzhydryl-3-(2,4′-dichlorobenzhydryloxy)azetidine (8) (38 mmol) in dichloromethane (400 mL) was added 1-chloroethylchloroformate (94 mmol) dropwise at 0° C. and the reaction mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, then dissolved in methanol (400 mL) and stirred at room temperature for 2 hours. The reaction mixture was reduced in vacuo and diluted with isohexane (20 mL), diisopropyl ether (200 mL) and methanol (30 mL). Upon stirring, a precipitate formed. Filtration afforded the desired product as a white solid (10.1 g, 77%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:38][C@@H:37]2[C@:32]([CH3:46])([CH2:33][CH2:34][C@H:35]([O:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[CH2:36]2)[C@@H:31]2[C@@H:10]1[C@H:11]1[C@:28]([CH3:47])([CH2:29][CH2:30]2)[C@@H:14]([C@H:15]([CH3:27])[CH2:16][CH2:17][CH2:18][O:19][Si](C(C)(C)C)(C)C)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:8][C@@H:9]1[CH2:38][C@@H:37]2[C@:32]([CH3:46])([CH2:33][CH2:34][C@H:35]([O:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[CH2:36]2)[C@@H:31]2[C@@H:10]1[C@H:11]1[C@:28]([CH3:47])([CH2:29][CH2:30]2)[C@@H:14]([C@H:15]([CH3:27])[CH2:16][CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 90.4 %

Procedure:
Compound 2007 (0.0527 g, 0.079 mmol) in anhydrous THF (4 ml) under Ar was treated with tetrabutylammonium fluoride (TBAF) (0.237 ml, 1M in THF, 0.237 mmol). The solution was stirred until no starting material remained by TLC. The solvent was removed in vacuo, the residue taken up in 5 ml CH2Cl2, washed with 5 ml aqueous saturated NaHCO3 solution, and the aqueous layer was extracted 2× with 5 ml CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered, and the solvent removed in vacuo. Flash chromatography (SiO2, 8:1 hexanes:EtOAc) gave compound 2008 (0.0395 g, 90%) as a white solid foam. 1H NMR (500 MHz, CDCl3) δ: 7.35-7.34 (m, 5H, benzyl Ar-H), 4.71-4.69 (m, 1H, THP ether methine H), 4.585 (d, J=11.8 Hz, 1/2H, benzyl-CH2), 4.58 (d, J=11.8 Hz, 1/2H, benzyl-CH2), 4.315 (d, J=12.0 Hz, 1/2H, benzyl-CH2), 4.29 (d, J=12.0 Hz, 1/2H, benzyl-CH2), 3.94-3.90 (m, 1H, THP OCH2), 3.62-3.58 (m, 3H, C-24 H & THP OCH2), 3.50-3.48 (m, 1H, C-3 H), 3.45 (s, 1H, 7-H), 0.92 (d, J=6.6 Hz, 3H, C-21 H), 0.81 (s, 3H, C-19 H), 0.63 (s, 3H, C-18 H) (Note: product is a mixture of diastereomers); IR (CHCl3) 3600, 2900 cm-1 ; MS (CI/isobutane) m/z 554 (M+1, 2%), 361 (M+1-THP-HOBn, 42%), 343 (M+1-THP-HPBn, H2O, 100%); m.p. 52-56° C.; Anal. calcd. for C36H56O4 : C=78.21, H=10.21; Found: C=77.93, H=10.39.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:23][O:24][CH2:25][C@@H:26]([O:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:27].CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:32]1[CH2:33][CH2:34][CH:29]([O:28][C@@H:26]([CH3:27])[CH2:25][O:24][CH3:23])[CH2:30][CH2:31]1)=[O:5]
Reactant: COC[C@H](C)OC1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H](C)OC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Reaction time: 1 h
Yield: 70.7 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), (S)-4-(1-methoxypropan-2-yloxy)piperidine (92) (0.151 g, 0.87 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.280 g, 0.87 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.152 mL, 0.87 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL) and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a white foam; (0.215 g, 70.7% yield) 1H NMR (400.132 MHz, CDCl3) δ 1.13 (3H, t), 1.61-1.49 (1H, m), 1.78-1.65 (2H, m), 1.91-1.87 (1H, m), 3.17-3.01 (1H, m), 3.31-3.27 (1H, m), 3.39-3.35 (4H, m), 3.57-3.45 (2H, m), 3.72-3.67 (2H, m), 4.06-3.97 (1H, m), 4.27 (2H, s), 7.01 (1H, t), 7.31-7.26 (2H, m), 7.79-7.70 (3H, m), 8.49-8.45 (1H, m), 10.50 (1H, s); m/z (LC-MS, ESI+), RT=1.81 (M+H 454).
Reaction SMILES: [N+:1]([C:4]1[C:12](F)=[C:11]([F:14])[C:10]([F:15])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[OH-].[NH4+:17]>>[NH2:17][C:12]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH:9]=[C:10]([F:15])[C:11]=1[F:14])[C:6]([OH:8])=[O:7]
Reactant: [NH4+]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1[N+](=O)[O-]
Agent: [OH-]
Product: Nc1c(F)c(F)cc(C(=O)O)c1[N+](=O)[O-]

Procedure:
1.4 g (6.3 mmol) of 2-nitro-3,4,5-trifluoro-benzoic acid was treated with ammonium hydroxide to produce 3-amino-4,5-difluoro-2-nitro-benzoic acid. LCMS: 219 (M+1)+. 1.2 g (5.5 mmol) of 3-amino-4,5-difluoro-2-nitro-benzoic acid was heated with excess 21% NaOEt in ethanol at 90° C. for 6 h to yield 3-amino-5-ethoxy-4-fluoro-2-nitro-benzoic acid. LCMS: 245 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH2:13]O)[CH:7]=[N:8]2.O=S(Cl)[Cl:17]>C(Cl)Cl>[ClH:17].[Cl:17][CH2:13][C:6]1[CH:7]=[N:8][C:9]2[C:4]([CH:5]=1)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2
Reactant: COc1cccc2ncc(CO)cc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cccc2ncc(CCl)cc12
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of (5-methoxyquinolin-3-yl)methanol CCH 34144-3 (80 mg, 423 μmol) in dry CH2Cl2 (12 mL) at 0° C. under N2 in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (0.60 mL, 8.27 mmol) and the mixture was stirred for 2 h at RT. The volatiles were then removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give 3-(chloromethyl)-5-methoxyquinoline hydrochloride CCH 341448 as an off-white solid (87 mg, 84% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[C:22]([CH3:29])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:6]=1>[Pd].CCO.C(Cl)Cl>[NH2:26][C:24]1[CH:23]=[C:22]([CH3:29])[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)(=[O:14])=[O:13])[CH:6]=2)=[C:2]([CH3:1])[CH:25]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(N)cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Reaction time: 6 h

Procedure:
A mixture of the title C compound, 4-(2,6-dimethyl-4-nitrophenoxy)-2-(4-fluoro-benzenesulfonyl)phenol (0.69 g, 1.65 mmol) and palladium on activated carbon (10 wt. %; 69 mg) in 10 mL of EtOH and 10 mL of CH2Cl2 is stirred under hydrogen atmosphere (H2, 1 atm) for 6 h. The catalyst is removed by vacuum filtration through celite, washed with a 1/1-mixture of EtOH and CH2Cl2, and the combined filtrate and washings are concentrated and dried under vacuum to give 4-(4-amino-2,6-dimethylphenoxy)-2-(4-fluorobenzenesulfonyl)phenol: NMR (DMSO-d6) 1.93 (s, 6H), 4.92 (s, 2H), 6.34 (s, 2H), 6.85 (d, 1H, J=9), 7.00 (dd,1H, J=9,3), 7.12 (d, 1H, J=3), 7.43 (app t, 2H, J=9), 7.94 (dd, 2H, J=9, 5), 9.41 (s, 1H), 10.4 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:12][C:11](=O)[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1.[CH2:17]([C:20]1[C:28]2[O:27][N:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:24]=2[CH:23]=[CH:22][C:21]=1[O:33][CH2:34][CH2:35][CH2:36]Br)[CH2:18][CH3:19].C([O-])([O-])=[O:39].[Cs+].[Cs+].O>CN(C=O)C>[CH2:17]([C:20]1[C:28]2[O:27][N:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:24]=2[CH:23]=[CH:22][C:21]=1[O:33][CH2:34][CH2:35][CH2:36][N:10]1[CH2:11][C:12](=[O:39])[N:8]([CH2:7][C:6]2[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:14])[CH2:18][CH3:19]
Reactant: COc1ccc(CN2CC(=O)NC2=O)cc1
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCN2CC(=O)N(Cc3ccc(OC)cc3)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
A mixture of 1-(4-methoxybenzyl)-imidazolidine-2,4-dione (57 mg), 7-propyl-3-trifluoromethyl-6-(3-bromopropyloxy)-1,2-benzisoxazole from Example 7 (86 mg), and Cs2CO3 (146 mg) in DMF (4.0 mL) was allowed to react overnight. Water was added and the mixture separated by HPLC to yield 1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-3-(4-methoxybenzyl)-imidazolidine-2,4-dione as a clear oil.