Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](Cl)=[N:8][OH:9].[OH:11][C:12]1[CH:13]=[C:14]([C:18]#[CH:19])[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[OH:11][C:12]1[CH:13]=[C:14]([C:18]2[O:9][N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: ON=C(Cl)c1ccccn1
Reactant: C#Cc1cccc(O)c1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Oc1cccc(-c2cc(-c3ccccn3)no2)c1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
A stirred solution of pyridine-2-carbohydroximoyl chloride (300 mg, 1.9 mmol) and 3-hydroxyphenylacetylene (760 mg, 6.4 mmol) in a 1:1 mixture of THF/CH2Cl2 (10 mL) at 0° C. was treated with triethylamine (2 mL, 1.45 g, 15 mmol). The mixture was allowed to warm to room temperature overnight. The solvent was removed in vacuo. The residue was dissolved in dichloromethane, washed with brine and dried over anhydrous sodium sulphate. Removal of the solvent in vacuo followed by trituation with 10% ethylacetate in hexane afforded 200 mg (44%) of 5-[3-hydroxyphenyl]-3-[pyridin-2-yl]-1,2-oxazole as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].Cl.[OH:13][CH:14]1[CH2:17][NH:16][CH2:15]1.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([N:16]1[CH2:17][CH:14]([OH:13])[CH2:15]1)=[S:11]
Reactant: OC1CNC1
Reactant: S=C=Nc1ccc(Br)cc1Br
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OC1CN(C(=S)Nc2ccc(Br)cc2Br)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2,4-Dibromophenylisothiocyanate (CAS#13037-63-3, 3.02 g, 0.0103 mole), and 3-hydroxyazetidine hydrochloride (CAS#18621-18-6, 1.18 g, 10.8 mmol) were suspended in acetonitrile (35 mL). Triethylamine (1.53 mL, 0.011 mole) was added dropwise to the stirred suspension. After 20 minutes of stirring at room temperature, the reaction mixture had become a light yellow solution. After another 10 minutes of stirring at room temperature, the isothiocyanate was consumed and the intermediate, N-(2,4-dibromophenyl)-3-hydroxyazetidine-1-carbothioamide had formed. Although not necessary, this intermediate thiourea was isolated and purified by partitioning between 1:1 hexane/ethyl acetate (150 mL) and 1 M aqueous KH2PO4 (35 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (10 mL) and dried (Na2SO4). The filtrate was partially concentrated at which point the thiourea crystallized. The crystals were collected by filtration and dried under vacuum to provide N-(2,4-dibromophenyl)-3-hydroxyazetidine-1-carbothioamide.
Reaction SMILES: CO[C:3](=[O:17])[C@@H:4]1[CH2:8][C@H:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[CH2:6][NH:5]1.C([O-])([O-])=O.[K+].[K+].[Cl:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[C:29]([Cl:31])[CH:30]=1.O>CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([N:32]2[C:3](=[O:17])[C@@H:4]3[CH2:8][C@H:7]([O:9][C:10]4[CH:11]=[CH:12][C:13]([Br:16])=[CH:14][CH:15]=4)[CH2:6][N:5]3[C:33]2=[O:34])[CH:28]=[C:29]([Cl:31])[CH:30]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)[C@@H]1C[C@H](Oc2ccc(Br)cc2)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1[C@@H]2C[C@H](Oc3ccc(Br)cc3)CN2C(=O)N1c1cc(Cl)cc(Cl)c1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
The compound of formula (II), wherein R11 is 4-bromo, m is 0, W=O, and the bonds depicted as wavy bonds define the 7aS,6S stereoisomer, was prepared as follows. To a solution of cis-4-(4-bromo-phenoxy)-L-proline methyl ester (0.2 g) (0.66 mmol) (Preparation 4) and K2CO3 (0.09 g) (1 eq.) in 10 mL of DMF at 0° C. was added 3,5-dichlorophenyl isocyanate (0.12 g) (1 eq.). The reaction mixture was allowed to warm to 20° C. and was stirred overnight. After adding water, the mixture was extracted with EtOAc. The combined organic extracts were washed with water, dried over MgSO4, and evaporated under reduced pressure to afford after SiO2 chromatography (eluent: DCM), the above-titled compound (60 mg). Mp=116° C. NMR (DMSO, 200 MHz): 7.75 (1H, m), 7.5-7.4 (4H, d+d), 6.85 (2H, d), 5.1 (1H, m), 4.6 (1H, dd), 3.95 (1H, dd), 3.35 (1H, dd), 2.7-2.5 (1H, m), 2.25 (1H, bd).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[H-].[Na+].CI.[C:15](OCC)(=O)C.CCCCCC>C1COCC1.O>[CH3:15][O:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(CO)cc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COCc1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
4-(Hydroxymethyl)benzonitrile (6.0 g, 45.09 mmol) was dissolved in THF (60 mL), cooled to −5° C. to −10° C. and treated with sodium hydride (2.16 g, 90.19 mmol). The resulting mixture was stirred for 30 minutes then treated with methyl iodide (9.6 g, 67.65 mmol) at RT for 2 hours. After completion of the reaction (TLC; ethyl acetate/Hexane, 5:5), the mixture was poured into water (50 mL) and extracted with ethyl acetate (3×25 mL). The separated organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by gradient flash chromatography, eluting with 5% ethyl acetate in hexane to afford 4-(methoxymethyl)benzonitrile (6.7 g, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20][F:21]>CN(C)C=O.C(OCC)(=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11][CH2:19][CH2:20][F:21])[CH:3]=1
Reactant: FCCBr
Reactant: O=[N+]([O-])c1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)cc(OCCF)c1
Temperature: 0 °C

Procedure:
A solution of 3-bromo-5-nitrophenol, as described above in Step C, (1.04 g, 4.77 mmol) in dimethylformamide (30 mL) was cooled to 0° C. and treated with cesium carbonate (7.8 g, 23.8 mmol) giving an opaque red mixture. This mixture was treated with 1-bromo-2-fluoroethane (0.71 mL, 9.54 mmol) and the reaction was stirred overnight as the ice bath warmed to room temperature. The reaction was diluted with ethyl acetate/brine/aqueous saturated NH4Cl, the layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give an orange brown oil. This material was purified by radial, thin layer chromatography (hexane to 10:1 hexane: ethyl acetate) to give 3-bromo-5-fluoroethoxynitrobenzene as a clear yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]([C:21]([F:24])([F:23])[F:22])[CH3:20])[N:3]=1.CO[CH:27]1[CH2:31][CH2:30][CH:29](OC)O1.O.C(=O)([O-])O.[Na+]>C(O)(=O)C>[Cl:13][C:12]1[CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=[C:8]([Cl:18])[C:7]=1[N:6]1[C:2]([N:1]2[CH:27]=[CH:31][CH:30]=[CH:29]2)=[N:3][C:4]([CH:19]([C:21]([F:24])([F:23])[F:22])[CH3:20])=[N:5]1
Reactant: CC(c1nc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1)C(F)(F)F
Reactant: COC1CCC(OC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(c1nc(-n2cccc2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1)C(F)(F)F
Reaction time: 1 h
Yield: 67.7 %

Procedure:
3.9 g (0.01 mol) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-(1-trifluoromethylethyl)-1H-1,2,4-triazole and 1.3 g (0.01 mol) of 2,5-dimethoxytetrahydrofuran were dissolved in 15 ml of acetic acid, and the solution was refluxed under stirring for one hour. After cooling, the reaction solution was poured into water and neutralized with sodium hydrogencarbonate. Then, precipitates were extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain 3 g (yield: 68%) of the desired compound having a melting point of from 73.5° to 75° C. as white powder.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][S:8][CH:7]2[CH2:10][C:11]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12](=[O:13])[N:6]12)=O.[NH3:28].CO>CO>[C:24]([O:23][C:21](=[O:22])[NH:20][C:11]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:12](=[O:13])[N:6]2[CH:7]([S:8][CH2:9][CH:5]2[C:3](=[O:2])[NH2:28])[CH2:10]1)([CH3:25])([CH3:26])[CH3:27]
Reactant: COC(=O)C1CSC2CC(NC(=O)OC(C)(C)C)(c3ccccc3)C(=O)N21
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccccc2)CC2SCC(C(N)=O)N2C1=O
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a solution of compound 16 (500 mg, 1.28 mmol) in methanol (10 mL) was added NH3-MeOH (10 mL) at room temperature and stirred for 2 h. The solvent was removed in vacuo and afford compound 17 (470 mg, 97.4%). 1H NMR (400 MHz, CDCl3) δ1.42 (s, 9 H), 3.05-3.08 (m, 1 H), 3.35-3.37 (m, 1 H), 3.37-3.49 (m, 1 H), 3.75-3.80 (m, 1 H), 4.89 (bs, 1 H), 4.98 (bs, 1 H), 5.43 (bs, 2 H), 6.57 (bs, 1 H), 7.37-7.50 (m, 5 H). MS (M+1): 378.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH2:9][CH2:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[CH3:37][O:38][C:39](Cl)=[O:40]>>[CH3:37][O:38][C:39]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=2)[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([OH:19])=[O:18])=[CH:24][CH:25]=2)=[N:6][CH:7]=1)=[O:40]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(N)cn2)cc1
Product: COC(=O)Nc1ccc(N(CCc2ccc(OC(C)(C)C(=O)O)cc2)Cc2ccc(C(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(5-aminopyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and methylchloroformate.
Reaction SMILES: [NH2:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])[C:3]1[S:7][C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:22]=[CH:21][C:17]4[O:18][CH2:19][O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])=[N:5][C:4]=1[CH3:23].[Si:31]([O:38][C@H:39]([CH2:43]Cl)[CH2:40][CH:41]=O)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].[BH4-].[Na+].C(Cl)Cl>CO.O>[O:18]1[C:17]2[CH:21]=[CH:22][C:14]([C:11]3([C:9]([NH:8][C:6]4[S:7][C:3]([CH:2]([N:1]5[CH2:41][CH2:40][C@H:39]([O:38][Si:31]([C:34]([CH3:36])([CH3:35])[CH3:37])([CH3:32])[CH3:33])[CH2:43]5)[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[Cl:30])=[C:4]([CH3:23])[N:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20][CH2:19]1
Reactant: Cc1nc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)sc1C(N)c1ccccc1Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CCl)CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)sc1C(c1ccccc1Cl)N1CC[C@H](O[Si](C)(C)C(C)(C)C)C1
Reaction time: 3 h

Procedure:
To a solution of N-(5-(amino(2-chlorophenyl)methyl)-4-methylthiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (Isomer A) (450 mg, 1.02 mmol) in MeOH (5 mL) was added (S)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal (289 mg, 1.22 mmol). The reaction mixture was stirred at room temperature for 20 min before NaBH4 (58 mg, 1.53 mmol) was added. Stirring was continued at room temperature for 3 h. After approximately 1 h some precipitate/gum started to form in the reaction solution so MeOH (5 mL) and CH2Cl2 (2 mL) were added to keep everything in solution. The reaction was diluted with H2O and extracted with EtOAc. The combined organic layers was washed with brine, dried over MgSO4 and concentrated. The residue was adsorbed onto silica gel and purified by column chromatography (0-25% EtOAc/hexanes) to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(((S)-3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)(2-chlorophenyl)methyl)-4-methylthiazol-2-yl)cyclopropanecarboxamide (Isomer A) as a pale yellow solid (470 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.83 (dd, J=8.1, 1.6 Hz, 1H), 7.28-7.25 (m, 2H), 7.13 (m, 1H), 6.88-6.83 (m, 2H), 6.79 (d, J=7.9 Hz, 1H), 6.00 (s, 2H), 5.08 (s, 1H), 4.33 (m, 1H), 2.94 (dd, J=9.9, 6.3 Hz, 1H), 2.67 (td, J=8.3, 3.4 Hz, 1H), 2.53 (q, J=8.4 Hz, 1H), 2.37 (s, 3H), 2.17 (dd, J=9.9, 4.7 Hz, 1H), 2.00 (m, 1H), 1.74-1.61 (m, 3H), 1.17 (m, 2H), 0.86 (m, 9H), 0.01 (s, 3H), −0.01 (s, 3H); HPLC ret. time 3.45 min, 10-99% CH3CN, 5 min run; ESI-MS 626.5 m/z (MH+).
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH2:77][N:78]1[CH2:83][CH2:82][O:81][CH2:80][CH2:79]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][C:54]([O:58][CH2:59][CH2:60][CH2:61][S:62]([CH3:65])(=[O:64])=[O:63])=[CH:53][C:52]=2[N:66]([CH3:76])[S:67]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][N:71]=1)(=[O:69])=[O:68])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH3:76][N:66]([C:52]1[CH:53]=[C:54]([O:58][CH2:59][CH2:60][CH2:61][S:62]([CH3:65])(=[O:64])=[O:63])[CH:55]=[C:56]2[C:51]=1[NH:50][C:49]([C:47]1[S:43][CH:44]([CH2:77][N:78]3[CH2:79][CH2:80][O:81][CH2:82][CH2:83]3)[CH2:45][N:46]=1)=[CH:57]2)[S:67]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][N:71]=1)(=[O:69])=[O:68]
Reactant: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C(=O)NCC(CN3CCOCC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CSc1ccccc1
Solvent: ClCCl
Product: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reaction time: 0.5 h
Yield: 23.3 %

Procedure:
To a solution of triphenylphosphine oxide (1.0 g) in dichloromethane (4 mL) was slowly added trifluoromethanesulfonic anhydride (0.46 mL) under ice-cooling, and the mixture was stirred for 30 min. A solution of N-[2-(benzylthio)-3-morpholinopropyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-5-[3-(methylsulfonyl)propoxy]-1H-indole-2-carboxamide (0.88 g) and thioanisole (0.61 mL) in dichloromethane (25 mL) was added dropwise, and the mixture was stirred for 90 min under ice-cooling. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=50:50-85:15), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (174 mg, yield: 23%) as colorless prism crystals. MS:608(MH+). melting point 168-169° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:17])[N:3]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[OH:27].CC(C)([O-])C.[K+]>C1COCC1>[CH2:13]([CH:12]([O:11][C:6]1[CH:5]=[C:4]([CH3:17])[N:3]=[C:2]([O:27][C:20]2[C:21]([CH3:26])=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=2[CH3:18])[C:7]=1[N+:8]([O-:10])=[O:9])[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)Oc1cc(C)nc(Cl)c1[N+](=O)[O-]
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a mixture of 2-chloro-4-(1-ethyl-propoxy)-6-methyl-3-nitro-pyridin (500 mg, 1.93 mmol), and 2,4,6-trimethylphenol (289 mg, 2.13 mmol) in dry THF was added potassium t-butoxide. The resulting mixture was stirred at rt. overnight. The mixture was quenched with water, brine and extracted 3 times with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated to dryness. After silica gel column chromatography purification, the title compound was obtained as a light yellow crystal, mp 106-109° C. Anal. For C20H26N2O4 calc. C, 67.02; H, 7.31; N, 7.82; found, C, 67.34; H, 7.40; N, 7.42.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])[NH2:20]>>[F:24][C:23]1[CH:22]=[CH:21][C:19]([NH:20][C:3]([C:4]2[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=2)=[N:2][OH:1])=[CH:18][C:17]=1[C:16]([F:15])([F:25])[F:26]
Reactant: COCCNc1nonc1C(Cl)=NO
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Product: COCCNc1nonc1C(=NO)Nc1ccc(F)c(C(F)(F)F)c1

Procedure:
The desired compound was prepared according to the procedure of Example 13, step A, using N-hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidoyl chloride [made according to Example 1, steps A through E] and 3-trifluoromethyl-4-fluoroaniline [Aldrich, product #217778] as the starting materials in quantitative yield. LCMS for C13H14F4N5O3 (M+H)+: m/z=364.0. 1H NMR (400 MHz, CD3OD): δ 7.15 (m, 2H), 7.08 (m, 1H), 3.60 (t, J=5.3 Hz, 2H), 3.46 (t, J=5.3 Hz, 2H), 3.38 (s, 3H).
Reaction SMILES: BrC1C=CC(O[CH2:7][C:8]2([CH3:19])[O:12][C:11]3=[N:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][N:10]3[CH2:9]2)=CC=1.[F:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:34][C@H:33]([CH2:35][NH:36][C:37](=[O:39])[CH3:38])[O:32][C:31]2=[O:40])[CH:26]=[CH:27][C:28]=1[OH:29]>>[F:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:34][CH:33]([CH2:35][NH:36][C:37](=[O:39])[CH3:38])[O:32][C:31]2=[O:40])[CH:26]=[CH:27][C:28]=1[O:29][CH2:7][C:8]1([CH3:19])[O:12][C:11]2=[N:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][N:10]2[CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(O)c(F)c2)C(=O)O1
Reactant: CC1(COc2ccc(Br)cc2)Cn2cc([N+](=O)[O-])nc2O1
Product: CC(=O)NCC1CN(c2ccc(OCC3(C)Cn4cc([N+](=O)[O-])nc4O3)c(F)c2)C(=O)O1

Procedure:
The title compound was prepared by following the same procedure as described in the preparation of Example 36, 2-(4-Bromo-phenoxymethyl)-2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazole (prepared similarly as described by Sasaki, H. et al: Journal of Medicinal Chemistry (2006), 49(26), 7854-7860), except N-[3-(3-fluoro-4-hydroxy-phenyl)-2-oxo-oxazolidin-5(S)-ylmethyl]-acetamide was used in the place of 4-bromophenol. The product isolated as a solid. ESI MS m/z 450 (M+H+).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:35])(=[O:34])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:36])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[CH2:27]([NH:26][S:25]([C:22]1[CH:21]=[CH:20][C:19]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:36])[CH:14]=3)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]=2[CH3:18])=[CH:24][CH:23]=1)(=[O:35])=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
Lithium hydroxide monohydrate (0.031 g, 0.70 mmol) was added to a solution of [4-(4-benzylsulfamoyl-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (0.090 g, 0.18 mmol) in a 3:1 mixture of THF—H2O mixture (12 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove the THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane gave [4-(4-benzylsulfamoyl-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid (0.080 g, 92%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.38-12.59 (m, 1 H), 8.34 (t, J=6.40 Hz, 1 H), 7.97 (d, J=8.20 Hz, 1 H), 7.88-7.93 (m, 3 H), 7.50 (dd, J=8.60, 2.40 Hz, 1 H), 7.40 (d, J=8.31 Hz, 2 H), 7.17-7.32 (m, 5 H), 7.03 (d, J=1.47 Hz, 1 H), 4.18 (d, J=5.87 Hz, 2 H), 3.86 (s, 2 H), 2.04 (s, 3 H). MS calcd. for C26H21ClNO4S [(M−H)−] 478, obsd. 478.2.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Br:11])[C:3]1=[O:12].BrC1C=CC=CC=1CBr.C[CH:23](C(OCC)=O)[C:24](OCC)=[O:25].C([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)CO>[CH2:24]1[O:25][C:3]2([C:4]3[C:9](=[C:8]([Br:11])[CH:7]=[CH:6][CH:5]=3)[CH2:10][CH:2]2[CH3:1])[O:12][CH2:23]1
Reactant: CC1Cc2c(Br)cccc2C1=O
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: BrCc1ccccc1Br
Agent: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: O
Product: CC1Cc2c(Br)cccc2C12OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4.88 g of 2-methyl-4-bromo-1-indanone derived from 2-bromobenzyl bromide and diethyl methylmalonate in 12 ml of ethylene glycol was added 5.4 ml of ethyl orthoformate. After a catalytic amount of p-toluenesulfonic acid monohydrate was added, the mixture was stirred overnight at room temperature. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ether. After the organic layer was dried over magnesium sulfate, the solvent was removed by distillation under reduced pressure. The residual concentrate was purified by silica gel column chromatography to give 4.08 g of the title compound.
Reaction SMILES: [CH:1]([C:12](OCC)=O)([C:7](OCC)=[O:8])[C:2](OCC)=[O:3].[F:17][C:18]1[C:28]([NH:29][CH2:30][C:31]2[CH:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=3)[CH:34]=[CH:33][C:32]=2[F:44])=[C:27]([F:45])[CH:26]=[CH:25][C:19]=1[O:20][CH2:21][C:22]([OH:24])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[OH:3][CH2:2][CH:1]([CH2:7][OH:8])[CH2:12][O:23][C:22](=[O:24])[CH2:21][O:20][C:19]1[CH:25]=[CH:26][C:27]([F:45])=[C:28]([NH:29][CH2:30][C:31]2[CH:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=3)[CH:34]=[CH:33][C:32]=2[F:44])[C:18]=1[F:17]
Reactant: O=C(O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O=C(COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F)OCC(CO)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a stirred solution of triethyl methanetricarboxylate (700 mg, 1.73 mmol, 1.0 eq) in DMF (40 mL) was added 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetic acid (I(b)) (367 mg, 3.45 mmol, 2.0 eq), TEA (699 mg, 6.91 mmol, 4.0 eq) and HATU (985 mg, 2.60 mmol, 1.5 eq). The resulting mixture was stirred at room temperature overnight under N2. The reaction was diluted with water then extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (DCM:MeOH=100:1-20:1) to give the title compound as a colourless oil (475 mg, 49%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:28]=[CH:27][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>CO.O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:28]=[CH:27][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CCCCCOc1ccc(OCCCCCn2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCOc1ccc(OCCCCCn2ccnc2)cc1
Yield: 86.2 %

Procedure:
To a solution of 2.5 g ethyl 6-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]hexanoate in 10 ml methanol, was added a solution of 520 mg sodium hydroxide in 5 ml water, and the mixture was heated under reflux for 5 hours. Methanol was distilled off under reduced pressure, and dilute hydrochloric acid was added to the remaining aqueous soluiton to lower its pH down to about 5. The solid which separated out was collected by filtration, washed with water, and recrystallized from methanol, affording 2 g of 6-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]hexanoic acid.