Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:15][S:14][CH2:13][CH2:12][NH:11][C:10]1=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20]>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:15][S:14][CH2:13][CH2:12][N:11]([CH:18]([C:19]([O:21][CH3:22])=[O:20])[CH3:23])[C:10]1=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C)I
Reactant: CC(C)(C)OC(=O)NC1CSCCNC1=O
Product: COC(=O)C(C)N1CCSCC(NC(=O)OC(C)(C)C)C1=O
Yield: 81.5 %

Procedure:
The above-named compound is prepared from 6-t-butoxycarbonylamino-perhydro-1,4-thiazepin-5-one (0.1 g) and methyl iodopropionate (0.11 g) according to the procedure described in Example 4. The product (0.11 g) is obtained after chromatography. The NMR spectrum is consistent with the assigned structure.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@:15](O)([CH2:16][C@@H:17]([O:36][C:37](=[O:39])[CH3:38])[CH2:18][C@@H:19]2[O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7].ClCC(O)=O.[C:46](=[O:51])([O:49]C)[O:47][CH3:48]>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:36][C:37](=[O:39])[CH3:38])[CH2:18][C@@H:19]2[O:27][C:28](=[O:35])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:14][C@H:13]3[O:51][C:46]([O:47][CH3:48])=[O:49])[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC(=O)O[C@H]1C[C@H](OC(=O)c2ccccc2)[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)C5OCCO5)CC[C@H]4[C@@H]3C=C[C@@]2(O)C1
Reactant: COC(=O)OC
Agent: O=C(O)CCl
Product: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)C[C@H](OC(=O)c3ccccc3)[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCCO4)CC[C@H]3[C@H]12
Temperature: 100 °C

Procedure:
In 10 ml of dimethyl carbonate was dissolved 350 mg of 20-(1,3-dioxolan-2-yl)-3β-acetoxy-1α-benzoyloxypregn-6-en-5α-ol, followed by addition of 0.1 ml of monochloroacetic acid. The mixture was stirred in an atmosphere of argon gas under heating at a temperature of 100° C. for 10 hours. The reaction mixture was then worked up in the same manner as Example 132 to give 100 mg of 20-(1,3-dioxolan- 2-yl)-3β-acetoxy-1α-benzoyloxy-7α-(methoxycarbonyl)oxypregn-5-ene showing the following physical properties.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13](/[CH:19]=[CH:20]/[C:21]([O:23]C)=[O:22])=[C:12]([CH3:25])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CC#N.O>[NH:1]([C:8]1[N:9]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]2[N:11]=[C:12]([CH3:25])[C:13](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:14][C:15]=2[C:16](=[O:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/c1cc2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1nc2c(cc1/C=C/C(=O)O)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.4 %

Procedure:
To a suspension of 2-anilino-6-[(E)-3-methoxy-3-oxo-1-propenyl]-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (10 mg, 0.025 mmol) in CH3CN (2.0 mL) was added 1N NaOH (2.0 mL). The suspension was stirred at room temperature for 18 h. The mixture was diluted with water (10 mL) and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo to afford (2E)-3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)-2-propenoic acid (6.2 mg, 63%): LCMS RT: 2.37 min, MH+: 398.3, Rf=0.51 (EtOAc).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:23])[NH:7][S:8]([C:11]1[C:16]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:15][CH:14]=[CH:13][N:12]=1)(=[O:10])=[O:9])CCC.C(Cl)(Cl)=O.[CH3:28][O:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[N:33]=[C:32](NC)[N:31]=1>ClC1C=CC=CC=1.ClCCl>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[N:33]=[C:32]([N:5]([CH3:1])[C:6](=[O:23])[NH:7][S:8]([C:11]2[C:16]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:19])=[O:20])=[CH:15][CH:14]=[CH:13][N:12]=2)(=[O:9])=[O:10])[N:31]=1
Reactant: CNc1nc(OC)cc(OC)n1
Reactant: CCCCNC(=O)NS(=O)(=O)c1ncccc1N(C)S(C)(=O)=O
Agent: O=C(Cl)Cl
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: COc1cc(OC)nc(N(C)C(=O)NS(=O)(=O)c2ncccc2N(C)S(C)(=O)=O)n1
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
63.0 g (0.17 mol) of 3-butyl-1-[3-(N-methyl-N-methylsulfonylamino)-2-pyridylsulfonyl]urea are suspended in 1 l of chlorobenzene, and the suspension is heated to 70° C. At this temperature, the experiment starts to pass a gentle stream of phosgene into the suspension, and heating is continued for approx. 20 minutes until an internal temperature of 120° C. is reached. After phosgene has been passed in for a further 20 minutes (approx. 50 g (0.5 mol) in total), the lower-boiling components together with approx. 300 ml of chlorobenzene are removed from the reaction mixture by distillation over a period of 30 minutes. After the mixture has cooled to room temperature, 29.0 g (0.17 mol) of 4,6-dimethoxy-2-methylaminopyrimidine dissolved in 500 ml of dichloromethane are added, and the mixture is heated for 7 hours at 40° C. The mixture is cooled, the organic phase is washed with 1×250 ml each of 1N HCl and water, dried and evaporated. After the crude product has been triturated with diethyl ether, 66.6 g (85% of theory) of 3-(4,6-dimethoxypyrimidin-2-yl)-3-methyl-1-[3-(N-methyl-N-methylsulfonyl-amino)-2-pyridylsulfonyl]-urea of m.p. 167°-168° C. (decomp.) remained.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[N:15]1([CH2:14][CH2:13][N:8]2[C:9]3[C:5](=[C:4]([NH2:1])[CH:12]=[CH:11][CH:10]=3)[CH:6]=[N:7]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1cccc2c1cnn2CCN1CCCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c1cnn2CCN1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-Nitro-1-(2-piperidin-1-yl-ethyl)-1H-indazole (mmol), iron powder (mmol), and ammonium chloride (mmol) in a 4:1 solution of ethanol/H2O was heated to reflux for 2 hours, cooled to room temperature and concentrated under reduced pressure. The residue was stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes and filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.36 (m, 2 H), 1.44 (m, 4 H), 2.37 (m, 4 H), 2.66 (t, J=6.95 Hz, 2 H), 4.33 (t, J=6.95 Hz, 2 H), 5.71 (m, 2 H), 6.12 (m, 1 H), 6.66 (m, 1 H), 6.99 (m, 1 H), 8.02 (m, 1 H); MS (DCI/NH3) m/z 245 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:3]=1.[F:17][C:18]([F:36])([F:35])[C:19]1[CH:20]=[C:21]([C:29]([CH3:34])([CH3:33])[C:30](Cl)=[O:31])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:22]=[C:21]([C:29]([CH3:33])([CH3:34])[C:30]([N:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH3:9])=[O:31])[CH:20]=[C:19]([C:18]([F:17])([F:35])[F:36])[CH:24]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(Cl)cc1-c1ccccc1C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 120 °C
Yield: 83.6 %

Procedure:
To the solution of 6-chloro-N-methyl-4-(o-tolyl)pyridin-3-amine (18.87 g, 81.3 mmol) and DMAP (29.8 g, 243.9 mmol) in 200 mL of anhydrous toluene was added the solution of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (28.5 g, 89.4 mmol) in toluene under N2 atmosphere. The solution was heated at 120° C. for 23 hrs. Cooled to room temperature, poured into 1 L of 5% aq. NaHCO3 solution, and extracted with EtOAc twice. The combined organic phases were washed by water and brine consecutively, dried over Na2SO4, filtered and purified by flash chromatography to afford 35 g 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(o-tolyl)pyridin-3-yl)-N,2-dimethylpropanamide as a white solid (Yield: 83.9%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:12]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]2[CH3:18])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])CCC.[CH3:24][C:25]([CH3:27])=[O:26].[NH4+].[Cl-]>C1COCC1.CCCCCC>[CH3:18][C:13]1[N:12]([C:4]2[CH:3]=[C:2]([C:25]([OH:26])([CH3:27])[CH3:24])[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=2)[C:16]([CH3:17])=[CH:15][CH:14]=1
Reactant: CC(C)=O
Reactant: Cc1ccc(C)n1-c1cc(Br)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(C(C)(C)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a solution of 1-[3-bromo-5-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole (4.98 g, 15.6 mmol) in THF (75 mL) at −78° C., was added a solution of 2.50M n-butyllithium in hexane dropwise. The reaction mixture was allowed to stir for 30 min and then acetone (1.49 mL, 20.4 mmol) was added dropwise. The reaction mixture was allowed to stir at −78° C. for 30 min, and then allowed to warm to rt. Saturated aq. NH4Cl was added and the mixture was extracted with EtOAc (3×). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 2-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(trifluoromethyl)phenyl]propan-2-ol (2.29 g, 49.2%). LCMS: (FA) ES+ 298.2.
Reaction SMILES: O([C:3]([CH3:6])([CH3:5])[CH3:4])[K].BrP(C)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:28]1[C:32]2([CH2:37]CC(=O)C[CH2:33]2)[O:31][CH2:30][CH2:29]1>CCOCC>[CH2:4]=[C:3]1[CH2:6][CH2:37][C:32]2([O:31][CH2:30][CH2:29][O:28]2)[CH2:33][CH2:5]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC(C)(C)O[K]
Agent: CP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: C=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.3 %

Procedure:
A mixture of KO-tBu (7.4 g, 65.9 mmol) and bromo(methyl)triphenylphosphorane (21.6 g, 60.5 mmol) in ether (100 mL) was refluxed for 0.5 h. Then a solution of 1,4-dioxaspiro[4.5]decan-8-one (6.24 g, 40.0 mmol) in ether (100 mL) was added dropwise during 1.5 h. The reaction mixture was stirred for 2 h, cooled to rt, filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (EtOAc/hexane) to afford 8-methylene-1,4-dioxaspiro[4.5]decane (1.5 g) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.62-4.74 (2H, m), 3.98 (4H, s), 2.30 (4H, dd, J=7.03, 6.02 Hz), 1.66-1.77 (4H, m).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])[C:4]([OH:6])=[O:5].[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:2][CH:3]([CH2:7][CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])[C:4]([OH:6])=[O:5])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: NC(CC1C(=O)Nc2ccccc21)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.25 Grams of 2-amino-3-(oxindol-3-yl)propionic acid hydrochloride prepared in reference example 1, and 1.3 g of N-hydroxysuccinimide ester of p-chlorobenzoic acid were dissolved in 50 ml of dimethylformamide. To this solution was added 1.2 g of triethylamine, and the whole mixture was stirred at a room temperature for 3 hours. Dimethylformamide was removed by evaporation, then water was added to the resultant residue, the crystals formed were collected by filtration to obtain 0.68 g of 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionic acid 1/4-hydrate. Melting point: 133°-135° C. (decomp.) [α]D25 -50.3° (C=1, methanol)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].N1CCCCC1.[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:34]=[CH:33][C:30](C=O)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>C(O)C>[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:34]=[CH:33][C:30]([CH:11]=[CH:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1
Reactant: O=Cc1ccc(N2CCC(O)CC2)cc1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(N3CCC(O)CC3)cc2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A one liter three necked flask fitted with a dropping funnel, mechanical stirrer and condenser is charged with 34.35 g of 4-nitrophenylacetic acid. Piperidine (16.2 g) is added dropwise over a period of 30 minutes. At the end of the addition, 38.4 g of 4-(4-hydroxypiperidyl)benzaldehyde is added. The reaction mixture is heated at 100° C. for three hours, and at 130° C. for three hours. After cooling, the semi-solid product mass is ground in ethanol in a blender, then filtered, washed, and vacuum dried. The crude product is recrystallized from chlorobenzene, m.p. 248°-250° C.
Reaction SMILES: [C:1]([O:9][CH:10]([CH2:22][O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:11][O:12][C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH:46]1[C:51]([Cl:52])=[CH:50][C:49](O)=[C:48]([O:54][C:55]2[CH:56]=[CH:57][C:58]([Cl:62])=[CH:59][C:60]=2[Cl:61])[CH:47]=1>C1(C)C=CC=CC=1>[C:5]([O:7][C:49]1[CH:50]=[C:51]([Cl:52])[CH:46]=[CH:47][C:48]=1[O:54][C:55]1[CH:56]=[CH:57][C:58]([Cl:62])=[CH:59][C:60]=1[Cl:61])(=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([O:9][CH:10]([CH2:22][O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:11][O:12][C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:8]
Reactant: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)OC(=O)CCCC(=O)O
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)OC(=O)CCCC(=O)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Reaction time: 20 h

Procedure:
2-Octanoyloxy-1-(octanoyloxymethyl)ethyl hydrogen glutarate (4.22 g.) was dissolved in dry toluene (40 ml.) and stirred with trifluoroacetic anhydride (5.2 ml.) for 2.5 hours. Triclosan (2.67 g.) was added and the mixture stirred for a further 20 hours. The solution obtained was washed successively with water (2×40 ml.), saturated sodium bicarbonate solution (2×40 ml.) and saturated brine (40 ml.). The organic phase was dried (MgSO4) and evaporated. The oil obtained was chromatographed on silica gel using methylene chloride as eluant to give 5-chloro-2-(2,4-dichlorophenoxy)phenyl 2-octanoyloxy-1-(octanoyloxymethyl)ethyl glutarate as an oil, having the same NMR and mass spectra as described for the ester in Example 1.
Reaction SMILES: [I:1][CH2:2][CH2:3][OH:4].CN(C1C=CC=CN=1)C.C(N(C(C)C)CC)(C)C.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl>[C:26]([Si:23]([O:4][CH2:3][CH2:2][I:1])([CH3:25])[CH3:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: OCCI
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCI
Reaction time: 8 h

Procedure:
To 2-iodoethanol (20 gm, 116 mmol) suspended in methylene chloride (500 mL) was added dimethylaminopyridine (100 mg) followed by diisopropylethylamine (30 mL, 174 mmol) and tert-butyldimethylsilyl chloride (19 gm, 128 mmol). The reaction was stirred overnight and the solvent was removed in vacuo and the residue was passed through a short column of silica gel and eluted with 95:5 methylene chloride: methanol. The desired fractions were combined and the solvent was removed in vacuo to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[CH2:18][C:17]([C:20]3[C:21]([C:27]([F:30])([F:29])[F:28])=[N+:22]([O-:26])[CH:23]=[CH:24][CH:25]=3)(O)[O:16][N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:18]=[C:17]([C:20]3[C:21]([C:27]([F:29])([F:30])[F:28])=[N+:22]([O-:26])[CH:23]=[CH:24][CH:25]=3)[O:16][N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C2=NOC(O)(c3ccc[n+]([O-])c3C(F)(F)F)C2)cc([N+](=O)[O-])c1OC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1cc(-c2cc(-c3ccc[n+]([O-])c3C(F)(F)F)on2)cc([N+](=O)[O-])c1OC
Reaction time: 0.17 h

Procedure:
3-(3-(3,4-dimethoxy-5-nitrophenyl)-5-hydroxy-4,5-dihydroisoxazol-5-yl)-2-(trifluoromethyl)pyridine 1-oxide (2.14 g, 5 mmol) was heated in 20 mL of ethyl acetate to 70° C. To the resulting slurry was added trifluoroacetic acid (0.74 g, 6.5 mmol) dropwise. After 10 minutes, the reaction was evaporated to dryness and the residue was recrystallised from isopropanol to give 3-(3-(3,4-dimethoxy-5-nitrophenyl)isoxazol-5-yl)-2-(trifluoromethyl)pyridine 1-oxide, 1.27 g (62%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6](C(=O)C)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([CH2:14]Br)[CH:8]=2)=[O:4].C[Si](C)(C)[N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.N>C1(C)C=CC=CC=1.C(O)C>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([CH2:14][C:22]1[NH:21][CH:25]=[CH:24][N:23]=1)[CH:8]=2)=[O:4]
Reactant: C[Si](C)(C)n1ccnc1
Reactant: COC(=O)c1cc2ccc(CBr)cc2n1C(C)=O
Agent: N
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1cc2ccc(Cc3ncc[nH]3)cc2[nH]1
Reaction time: 2 h
Yield: 58.4 %

Procedure:
A solution of 1-acetyl-6-bromomethylindole-2-carboxylic acid methyl ester (3.1 g.) in toluene (25 ml.) was added dropwise with stirring to a solution of 1-trimethylsilylimidazole (5.60 g.) in toluene (25 ml.) at 80° C. The mixture was stirred at 80° for 2 hours and then evaporated. Water was added and the mixture was extracted several times with ethyl acetate. The combined extracts were washed with water, dried (Na2SO4) and evaporated to give an oil which was dissovled in a concentrated solution of ammonia in ethanol (40 ml.). The solution was allowed to stand at room temperature for 2.5 hours and then evaporated and the residue was chromatographed on silica gel. Elution with chloroform gave a solid which was crystallized from ethyl acetate to give 6-(1-imidazolylmethyl)indole-2-carboxylic acid methyl ester (1.49 g.), m.p. 204°-205° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[C@@H:31]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:32]([O:34]C)=[O:33].[OH-].[Li+].CO>O>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:4][N:3]1[C@@H:31]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:32]([OH:34])=[O:33]
Reactant: COC(=O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.2 %

Procedure:
A solution of (S)-methyl 2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate (295 mg, 0.533 mmol, 1 equiv) and lithium hydroxide (44.77 mg, 1.07 mmol, 2.0 equiv) in a 3:1 mixture of methanol and water (5 ml t/v) was stirred at ambient temperature for 24 hrs. The reaction was concentrated in vacuo and purified using preparatory high performance liquid chromatography. The combined pure fractions were lyophilized to afford the acetate salt of the title compound as a white solid (61 mg, 21%); 1H NMR (400 MHz, DMSO-d6): δ 1.57-1.66 (m, 2H), 1.87-1.91 (m, 2H); 2.79-2.86 (m, 4H); 3.27-3.42 (bs, 4H); 3.85 (t, 2H, J=6.8 and 6.4 Hz); 4.11 (d, 1H, J=4.8 Hz); 4.94 (d, 1H, J=3.2 Hz); 5.68 (s, 1H); 6.74-6.80 (m, 3H); 6.95-6.98 (m, 3H); 7.17-7.21 (m, 3H); 7.33-7.42 (m, 5H); 10.85 (s, 1H); 12.5 (bs, 1H); MS for C31H33ClN5O4 m/z 540.07 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][NH2:41]>C1COCC1.CCOC(C)=O>[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][NH:41][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:21])=[O:22]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: COCCOCCN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOCCNS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Yield: 68.4 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available 2-(2-methoxy-ethoxy)-ethylamine [CAS-no. 31576-51-9] (0.244 mg, 2.04 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.160 g, 68%) as a light yellow oil. MS (ISP) 572.2 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][OH:25]>CN(C=O)C.S([O-])([O-])(=O)=O.[Ag+2]>[OH:25][CH2:24][CH2:23][CH2:22][NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Reactant: OCCCBr
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C1=C1OCc2ccc(NCCCO)cc21
Temperature: 120 °C
Yield: 9.8 %

Procedure:
A mixture of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (25.0 mg, 0.095 mmol), 3-bromo-1-propanol (85.5 μL, 0.946 mmol), and silver sulfate (59.0 mg, 0.189 mmol) in 0.8 mL DMF was heated at 120° C. for 1.5 h. The mixture was partitioned between EtOAc and H2O and the organic layer separated from the silver salts. The solution was washed with H2O, brine and then dried with Na2SO4. Concentrating the solution in vacuo gave a residue which was purified by chromatography (silica gel, CHCl3/MeOH, 96:4) to give the title compound (3 mg, 10%) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([CH:10](O)[CH3:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([Cl:22])(=O)=O)=CC=1.O>N1C=CC=CC=1>[Cl:22][CH:10]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[O:9][N:8]=1)[CH3:11]
Reactant: CC(O)c1cc(C(C)(C)C)on1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(Cl)c1cc(C(C)(C)C)on1
Reaction time: 5 h

Procedure:
1.18 g of 1-(5-t-butyl-isoxazol-3-yl)ethanol was dissolved in 2 ml of pyridine, and 1.36 of 4-toluenesulfonyl chloride was then added under ice-cooling. The mixture was stirred for 5 hours under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.60 g of 3-(1-chloroethyl)-5-t-butylisoxazole.