Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:8])[C:4]([NH2:7])([CH3:6])[CH3:5].C(N(CC)C(C)C)(C)C.[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([NH:26][C:27](=O)[O:28]C)=[CH:21][C:20]=1[CH3:31].O>CC(N(C)C)=O>[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([N:26]2[C:3](=[O:8])[C:4]([CH3:5])([CH3:6])[NH:7][C:27]2=[O:28])=[CH:21][C:20]=1[CH3:31]
Reactant: COC(=O)Nc1cc(C)c(Br)c(C)c1
Reactant: COC(=O)C(C)(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(N2C(=O)NC(C)(C)C2=O)cc(C)c1Br
Yield: 28.1 %

Procedure:
α-Aminoisobutyric acid methyl ester (3.2 g, 20.92 mmol) and N,N-diisopropylethylamine (6.1 ml, 34.86 mmol) were added to a solution of methyl (4-bromo-3,5-dimethylphenyl)carbamate (900 mg, 3.48 mmol) in anhydrous DMA (17.5 ml, 0.2 M). After irradiation with microwaves at 170° C. for 30 minutes, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was sequentially washed with water and saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3-(4-bromo-3,5-dimethylphenyl)-5,5-dimethylimidazolidine-2,4-dione (304 mg, 28%)
Reaction SMILES: Br[C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:31]#[N:32])/[C:10]([NH:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20](OCCN(CC)CC)=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])C=C[CH:3]=1.[NH:33]1C=CN=C1C=O.C(CC(N[C@H](C1C=CC=CC=1)CCC)=O)#N>>[C:31](/[C:9](=[CH:8]\[C:6]1[NH:33][CH:3]=[CH:2][N:7]=1)/[C:10]([NH:12][C@H:13]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:14][CH2:15][CH3:16])=[O:11])#[N:32]
Reactant: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCN(CC)CC)cc1
Reactant: O=Cc1ncc[nH]1
Agent: CCC[C@H](NC(=O)CC#N)c1ccccc1
Product: CCC[C@H](NC(=O)/C(C#N)=C/c1ncc[nH]1)c1ccccc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 33 except that 1H-imidazole-2-carbaldehyde was used instead of 6-bromopicolinaldehyde, and (S)-2-cyano-N-(1-phenylbutyl)acetamide was used instead of 2-cyano-N-(1-(4-(2-(diethylamino)ethoxy)phenyl)butyl)acetamide (29). This produced the crude product which was purified by flash silica gel column chromatography, eluting with 1:1 hexanes/ethyl acetate, to give 42 (92 mg, 94%) as a clear oil: MS (ES+) m/z 295.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:24]([O-])=O.C(N(CC)C(C)C)(C)C.[C:36](Cl)(=[O:40])[CH:37]([CH3:39])[CH3:38]>ClCCl>[CH3:23][O:22][C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:24][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:4]=1)[C:17]([CH3:19])([CH3:18])[CH2:16]2)=[O:21]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c([N+](=O)[O-])c1)N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)C(C)C)c1)N2
Yield: 99.8 %

Procedure:
To a solution of methyl 2-(4-fluoro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (150 mg, 0.46 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.91 mmol) in dichloromethane (10 mL) was added isobutyryl chloride (0.053 mL, 0.50 mmol) via syringe with ice cooling. The resultant mixture was stirred for an additional 20 h. The solvent was removed in vacuo and the residue was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to afford 183 mg of methyl-2-(4-fluoro-3-isobutyramidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate. Yield: 97%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.O.[NH2:24][NH2:25]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:24][NH2:25])=[C:6]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: NN
Reactant: Clc1ccc(-c2c(Cl)nnc(Cl)c2-c2ccc(Cl)cc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: NNc1nnc(Cl)c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a round bottom flask was added 3,6-dichloro-4,5-bis(4-chlorophenyl)pyridazine (1.55 gm, 4.201 mmol), pyridine(10 ml) and hydrazine hydrate (617 mg, 12.602 mmol). The reaction was stirred at 120° C. for 4 hrs. After this time, the reaction mixture was concentrated to near dryness. To the resulting residue was added water (50 ml) and a solid formed. The solid was collected by filtration to give product -chloro-4,5-bis(4-chlorophenyl)-6-hydrazinylpyridazine as a beige solid (1.53 gm, 99% yield). HPLC retention time (method A) 2.740 min; LCMS (M+H)=365.1.
Reaction SMILES: Br[C:2]1C(C=C)=C(C)C=C2[C:3]=1C=CC(C)=N2.FC(F)(F)S(O[C:22]1[C:23]([Br:37])=[C:24]2[C:29](=[CH:30][C:31]=1[CH3:32])[N:28]=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=[CH:25]2)(=O)=O>>[Br:37][C:23]1[C:22]([CH:2]=[CH2:3])=[C:31]([CH3:32])[CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([C:33]([F:36])([F:35])[F:34])=[N:28]2
Reactant: C=Cc1c(C)cc2nc(C)ccc2c1Br
Reactant: Cc1cc2nc(C(F)(F)F)ccc2c(Br)c1OS(=O)(=O)C(F)(F)F
Product: C=Cc1c(C)cc2nc(C(F)(F)F)ccc2c1Br

Procedure:
Compound 7D was prepared following the procedure used to prepare compound 5B of Example 5, except that 5-bromo-7-methyl-2-(trifluoromethyl)quinolin-6-yl trifluoromethanesulfonate (7C) was used instead of compound 5A. LCMS-ESI+ (m/z): 316.1, 318.1 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[CH3:8].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1)[CH3:8]
Reactant: CCc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(OCc2ccccc2)c1
Temperature: 2 °C
Reaction time: 0.83 h
Yield: 92.7 %

Procedure:
To a suspension of potassium carbonate (17 g, 123 mmol) in N,N-dimethylformamide (40 ml) was added a solution of 3-ethyl-phenol (14.8 ml, 123 mmol) in N,N-dimethylformamide (40 ml) at 2° C. under an argon atmosphere. After stirring for 50 min at 2° C., benzyl bromide (14.6 ml, 123 mmol) was added over a period of 15 min at 2° C. The suspension was stirred for additional 30 min at 2° C. and for 12 h at ambient temperature. After adding ice water (250 ml), the solution was extracted two times with diethyl ether. The combined extracts were washed two times with brine and dried over sodium sulfate. Evaporation of the solvent gave a yellow oil which was purified by column chromatography (silica gel, cyclohexane) to yield 24.3 g (114 mmol, 93%) of the title compound as yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1.[Br:7][C:8]1[C:9]([Cl:31])=[CH:10][C:11]([O:29][CH3:30])=[C:12]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([S:24](Cl)(=[O:26])=[O:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][C:15]2=[O:28])[CH:13]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl-].[NH4+]>C1COCC1>[Br:7][C:8]1[C:9]([Cl:31])=[CH:10][C:11]([O:29][CH3:30])=[C:12]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([S:24]([NH:1][C:2]4[CH:6]=[CH:5][O:4][N:3]=4)(=[O:26])=[O:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][C:15]2=[O:28])[CH:13]=1
Reactant: Nc1ccon1
Reactant: COc1cc(Cl)c(Br)cc1-n1c(=O)ccc2cc(S(=O)(=O)Cl)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Cl)c(Br)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 0 °C
Yield: 34.3 %

Procedure:
A solution of 3-aminoisoxazole (0.041 ml, 0.548 mmol) and 1-(5-bromo-4-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonyl chloride (0.254 g, 0.548 mmol) in THF (5.48 ml) was cooled to 0° C., at which point LiHMDS, 1.0M in THF (1.152 ml, 1.152 mmol) was added drop wise. After 40 minutes in the ice bath, the reaction was complete and ammonium chloride (sat aq) was added and the product was extracted with ethyl acetate (×3). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified via MPLC, eluting with 0-100% ethyl acetate in heptane to yield 1-(5-bromo-4-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.096 g, 0.188 mmol, 34.3% yield) as a light-yellow solid. m/z (ESI) 510.0 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:6])=O.[ClH:7].Cl.[O:9]([CH2:11][CH:12]([F:16])[CH2:13][NH:14][CH3:15])[NH2:10]>C(O)C>[ClH:7].[C:4](=[N:10][O:9][CH2:11][CH:12]([F:16])[CH2:13][NH:14][CH3:15])([CH3:6])[CH3:3]
Reactant: CC(C)=O
Reactant: CNCC(F)CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNCC(F)CON=C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.5 ml of 1N sodium hydroxide solution and 0.36 ml (5 mmol) of acetone are added to a solution of 488 mg (2.5 mmol) of N-(3-aminoxy-2-fluropropyl)-methylamine dihydrochloride in 10 ml of ethanol and the mixture is stirred for 24 hours at room temperature. The reaction mixture is then concentrated to dryness by evaporation. The residue is taken up in ethanol, filtered and crystallised by the addition of ether.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1.C([Li])CCC.[OH-].[Na+]>O1CCCC1.CCCCCC>[C:3]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17]2)=[CH:6][CH:5]=1)#[CH:2]
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(C=C(Br)Br)cc2)CC1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#Cc1ccc(CC[C@H]2CC[C@H](CCCCC)CC2)cc1
Reaction time: 1.5 h

Procedure:
In an analogous manner to Example 5, a solution of β,β-dibromo-p-[2-(trans-4-pentylcyclohexyl)ethyl]styrene in absolute tetrahydrofuran was placed in a sulphonation flask and treated within 5 minutes with a solution of butyl lithium in hexane. After completion of the addition, the mixture was stirred at the same temperature for a further 90 minutes, then poured into 1N sodium hydroxide and extracted with petroleum ether. The organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography of the residue on silica gel with hexane gave pure 1-ethynyl-4-[2-(trans-4-pentylcyclohexyl)ethyl]benzene as colourless crystals; m.p. (C-N) 25.5° C., cl.p. 42.5° C.
Reaction SMILES: [SH:1][CH2:2][CH2:3]O.C(N(C(C)C)CC)(C)C.[C:14]1([C:20]2[CH:27]=[CH:26]C(CBr)=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[C:14]1([C:20]2[CH:27]=[CH:26][C:3]([CH2:2][SH:1])=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: OCCS
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: SCc1ccc(-c2ccccc2)cc1
Reaction time: 0.04 h
Yield: 907.7 %

Procedure:
To a peptide synthesis vessel containing 2.3 grams (0.43 mmole) of NpSSMpact-PEG-PS resin 12 was added 15 mL of DMF, 0.25 mL (3.5 mmole) of β-mercaptoethanol and 0.4 mL (2.3 mmole) of diisopropylethylamine and mixture shaken for 2-3 minutes. The red colored mixture was then filtered and the process repeated two more times using the same quantities of BME and DIEA. The resin was then washed five times with DMF, three times with methanol, four times with CH2Cl2 and then three times with DMF. To the resin was then added 0.3 grams (1.21 mmole) of 4-phenyl benzyl bromide dissolved in 15 mL of DMF and 0.5 mL (2.87 mmole) of DIEA and shaken in the dark for 6.5 hours. After 6.5 hours, the mixture was then filtered and washed five times with DMF, three times with methanol and six times with CH2Cl2 in that order. The resin was then dried under pump vacuum to give 2.2 grams of 14.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=[C:19]([NH2:26])[C:18]=2[N:17]=[CH:16]1.[OH-].[Na+].[Cl-].[Na+]>C(Cl)(Cl)Cl>[NH2:26][C:19]1[C:18]2[N:17]=[CH:16][N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:23]=2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=1
Reactant: Cc1nc(N)c2ncn(CCCCN)c2c1C
Reactant: O=C(Cl)N1CCOCC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)c2ncn(CCCCNC(=O)N3CCOCC3)c2c1C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
4-Morpholinecarbonyl chloride (0.250 mL, 2.14 mmol) was added drop wise to a slurry of 1-(4-aminobutyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (0.500 g, 2.14 mmol) in chloroform (10 mL). After 1 hour, analysis by high performance liquid chromatography showed about 60% completion. 4-Morpholinecarbonyl chloride (0.200 mL) was added and the reaction mixture was stirred overnight. The reaction mixture was poured into 5% sodium hydroxide and stirred for 10 minutes. The layers were separated. The aqueous layer was extracted with chloroform (×2). The combined organics were washed with water and brine then dried over magnesium sulfate and concentrated under reduced pressure to provide a yellow oil. The aqueous layer was saturated with sodium chloride and then extracted with dichloromethane (×3). The extracts were combined, dried and then combined with the yellow oil and concentrated under reduced pressure. The residue was purified by column chromatography (43 g of silica gel eluting with 2% methanol in dichloromethane containing 1% triethylamine and then with 5% methanol in dichloromethane containing 1% triethylamine). The residue was dissolved in dichloromethane and the solution was diluted with hexanes. The resulting precipitate was isolated by filtration and then recrystallized twice from acetonitrile to provide 0.283 g of N-[4-(4-amino-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]morpholine-4-carboxamide as a pale yellow powder, m.p. 163.7-167.0° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[C:15]1(O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl.C1(C)C=CC=CC=1.CCOCC>[O:1]([CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccccc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To an ice-cold solution of the compound from Step 1 (2.60 g, 12.9 mmol), phenol (3.64 g, 38.7 mmol), and triphenylphosphine (6.77 g, 25.8 mmol) in DCM (50 mL) was added a solution of diisopropyl azodicarboxylate (5.22 g, 25.8 mmol) in toluene (30 mL). After stirring at room temperature for 60 hours it was diluted with ether and the solution was extracted with aqueous 3N NaOH. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The intermediate tert-butyl (R)-2-(phenoxymethyl)pyrrolidine-1-carboxylate was obtained from the residue by column chromatography (silica gel, cHex/EtOAc 29:1); yield: 1.82 g (51%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17](OCC)=[O:18].COC1C=CC(C(C(=O)C)C#N)=CC=1>>[O:18]=[CH:17][CH:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)[C:15]#[N:16]
Reactant: CCOC=O
Reactant: N#CCc1cccc(Oc2ccccc2)c1
Agent: COc1ccc(C(C#N)C(C)=O)cc1
Product: N#CC(C=O)c1cccc(Oc2ccccc2)c1

Procedure:
3-Oxo-2-(3-phenoxyphenyl)propanenitrile was prepared on a 2.39 mmol scale from 3-phenoxyphenylethanenitrile and ethyl formate using the procedure described for the preparation of 2-(4-methoxyphenyl)-3-oxobutanenitrile in Example 17. The product was a viscous orange oil (84% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:27]1[C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]2[C:36]([O:38][C:39](=O)[C:29]=2[CH:28]=1)=[O:37]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:36](=[O:37])[C:30]3[C:29](=[CH:28][CH:27]=[C:32]([C:33]([OH:35])=[O:34])[CH:31]=3)[C:39]2=[O:38])=[CH:7][CH:6]=1
Reactant: COc1cccc(-c2ccc3oc(-c4cc(N)ccc4OC)nc3c2)c1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1cccc(-c2ccc3oc(-c4cc(N5C(=O)c6ccc(C(=O)O)cc6C5=O)ccc4OC)nc3c2)c1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-(3-methoxyphenyl)benzoxazole (50 mg, 0.14 mmol) and 1,2,4-benzenetricarboxylic anhydride (28 mg, 0.14 mmol) the title compound was obtained (52 mg, 71%). 1H NMR (DMSO) δ 8.43(d, 1H), 8.33(s, 1H), 8.22(d, 1H), 8.10(m, 2H), 7.87(d, 1H), 7.74(m, 2H), 7.48(d, 1H), 7.41(t, 1H), 7.30(m, 2H), 6.96(dd, 1H), 4.04(s, 3H), 3.85(s, 3H). MS 521.3 m/z (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH:3]=[C:2]([O:1][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (10 g, 48.7 mmol) was dissolved in dry DMF (12.0 mL). Trimethylsilyl chloride (6.35 g, 7.39 mL, 58.4 mmol) and triethylamine (11.8 g, 16.2 mL, 117 mmol) were added under argon and the reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, saturated NaHCO3 solution was added and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography (1 drop Et3N was added during conditioning of the column) (silica gel, 100 g, 0% to 100% pentane in Et2O, 45 minutes). The title compound was obtained as a colorless liquid (13.2 g, 99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@@:9]1([CH3:16])[C:10](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH2:25][C:26]1[CH:30]=[C:29]([Br:31])[S:28][C:27]=1[C:32]([NH2:34])=[O:33].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C>[Br:31][C:29]1[S:28][C:27]2[C:32](=[O:33])[NH:34][C:10]([C:9]3([CH3:16])[CH2:13][CH2:14][CH2:15][N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:25][C:26]=2[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Reactant: NC(=O)c1sc(Br)cc1N
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1(C)c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
To a mixture of 1-(tert-butoxycarbonyl)-2-methylproline (425 mg), triethylamine (0.425 mL) and tetrahydrofuran (10 mL) was added 2-methylpropyl chlorocarbonate (0.2 mL) with stirring at room temperature. After 1 hr, 3-amino-5-bromothiophene-2-carboxamide (337 mg) produced in Example 1, step D, was added, and the mixture was stirred at 60° C. overnight. Thereafter, the mixture was stirred in a microwave reactor at 120° C. for 4 hr. The reaction mixture was allowed to cool to room temperature, and poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (5 mL), 2M aqueous sodium hydroxide solution (2.04 mL) was added, and the mixture was stirred at 60° C. for 1 hr and at 80° C. for 1 hr. Ethanol (4 mL) was added to the reaction mixture, and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was allowed to cool to room temperature, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate/tetrahydrofuran mixture. The extract was dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) to give the title compound (109 mg) as a yellow solid.
Reaction SMILES: Cl.OC[CH:4]1[CH2:12][CH:11]2[CH:7]([CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10]2)[C:6](C2C=CC=CC=2F)([OH:20])[CH2:5]1>O1CCOCC1>[CH2:10]1[CH:11]2[CH:7]([CH:6]([OH:20])[CH2:5][CH2:4][CH2:12]2)[CH2:8][NH:9]1
Reactant: CC(C)(C)OC(=O)N1CC2CC(CO)CC(O)(c3ccccc3F)C2C1
Agent: Cl
Solvent: C1COCCO1
Product: OC1CCCC2CNCC12
Reaction time: 2 h

Procedure:
17 cm3 of a 7N solution of hydrogen chloride in dioxane is added at room temperature to a solution of 3.35 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)-2-tert-butyloxycarbonylperhydroisoindol-4-ol in 35 cm3 of dioxane. The reaction mixture is stirred at this temperature for 2 hours, then concentrated to dryness under reduced pressure (2.7 kPa). Trituration in diisopropyl ether gives 2.77 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(]2-fluorophenyl)perhydroisoindol-4-ol in the form of a thick white foam.
Reaction SMILES: Br[C:2]1[N:7]2[C:8](=[O:25])[N:9]([CH2:11][CH2:12][C:13]3[N:14]([CH3:24])[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:24][N:14]1[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=[C:13]1[CH2:12][CH2:11][N:9]1[C:8](=[O:25])[N:7]2[C:2]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:3][CH:4]=[CH:5][C:6]2=[N:10]1
Reactant: Cn1cc(-c2ccccc2)nc1CCn1nc2cccc(Br)n2c1=O
Reactant: C1COCCN1
Product: Cn1cc(-c2ccccc2)nc1CCn1nc2cccc(N3CCOCC3)n2c1=O
Temperature: 120 °C
Yield: 31.4 %

Procedure:
In a 2 mL microwave vial were placed 11-4 (0.025 g, 0.063 mmol) and morpholine (0.459 g, 0.461 mL, 5.27 mmol). The vial was sealed and heated in an oil bath for 15 min at 120° C. The mixture was concentrated in vacuo and purified by reverse phase HPLC (5-50% MeCN/water with 0.01% TFA additive). Fractions containing pure product were treated with sat. aq. NaHCO3 and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and filtered. The filtrate was dried under reduced pressure to give 8 mg (32%) of 12-1. LC/MS: m/z (M+H)=405.5. 1H NMR (500 MHz, CHCl3-d): δ 7.68 (d, J=7.7 Hz, 2H), 7.31 (d, J=7.6 Hz, 2H), 7.21-7.16 (m, 1H), 7.08 (s, 1H), 6.91 (dd, J=9.3, 7.0 Hz, 1H), 6.68 (d, J=9.3 Hz, 1H), 5.60 (d, J=7.3 Hz, 1H), 4.37 (t, J=7.5 Hz, 2H), 3.90-3.86 (m, 4H), 3.74-3.70 (m, 2H), 3.64 (s, 3H), 3.21 (t, J=7.5 Hz, 2H), 2.96-2.87 (m, 2H). HRMS (ES) 405.2048 found (M+H), 405.2035 required.