Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([Br:24])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pt]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([Br:24])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)OCC2C=Cc3cc(F)cc(Br)c3O2)cc1
Agent: [Pt]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OCC2CCc3cc(F)cc(Br)c3O2)cc1
Yield: 48.8 %

Procedure:
A solution of (8-bromo-6-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (300 mg, 0.73 mmol) in absolute ethanol was added to 5% sulfided platinum on carbon (50 mg) and the mixture hydrogenated at 55 psi of hydrogen for 1 hour. The mixture was then filtered through celite and the filtrate concentrated under reduced pressure to afford a white semi-solid. Purification by flash chromatography using a solvent gradient of 5 to 25% ethyl acetate in hexane gave 148 mg (49%) of (8-bromo-6-fluoro-3,4-dihydro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate as a white solid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N[C:6](N)=[O:7].C(O)(=O)C[CH2:11][CH2:12][C:13]([OH:15])=[O:14]>>[NH2:1][C:2]([NH2:4])=[O:3].[C:6]([OH:7])(=[O:3])[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CCCC(=O)O
Agent: NC(N)=O
Product: O=C(O)CCC(=O)O
Reaction time: 5 h

Procedure:
50 g. of urea was further added to the mother liquor with the urea-glutaric acid adduct removed and dissolved at 60° C. The resulting solution was then cooled to and allowed to stand at 15° C. for 5 hours to crystallize a urea-succinic acid adduct out of the solution. By filtration, 52 g. of urea-succinic acid adduct (including 22.0 g. of succinic acid) was obtained. Subsequently, the urea-succinic acid adduct was dissolved in 300 g. of water at 30° C. and the resulting solution was treated with the same strongly acidic ion exchange resin as mentioned above to remove urea. 200 g. of water was then distilled off from the treated solution and the solution was cooled to and allowed to stand at 10° C. to crystallize succinic acid. By filtration, 20 g. of succinic acid having a purity of 98% was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.Cl.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32]>C(O)C.O>[CH:14]1([N:7]2[CH2:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:19][C:6]2=3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Temperature: 90 °C

Procedure:
2-Chloro-9-cyclopentyl-8,9-dihydro-5-methyl-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (150 mg, 0.536 mmol) in ethanol (2.25 ml) and water (9 ml) was treated with conc. HCl (0.088 ml) and 4-amino-3-methoxy benzoic acid (134 mg, 0.804 mmol). The mixture was stirred at 90° C. 24 hours, concentrated and the residue triturated with methanol/ether, filtered and the solid washed with ethanol then ether to give 4-(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxo-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as a buff powder (185.5 mg, 84%). NMR DMSO D6 1.51-1.79 (6H, m), 1.82-1.93 (2H, m), 2.70-2.75 (2H m), 3.18 (3H, s), 3.72-3.78 (2H, m), 3.98 (3H, s), 4.81-4.93 (1H, m), 7.57-7.64 (2H, m), 8.15-8.22 (2H, m), 9.46 (1H, br s); HPLC rt(min): 6.57.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].I[C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:9](=[O:18])[NH:10]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:4][CH2:1][C:2]#[C:3][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:9](=[O:18])[NH:10]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(C#CCO)c21

Procedure:
Using Method C above, propargyl alcohol (0.11 g, 1.95 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (0.32 g, 0.78 mmol) (Starting Material 2 above) using (Ph3P)2PdCl2 (27.4 mg) and CuI (7.4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one. (Yield 0.12 g, 46%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[O:4][N:3]=1.[S:9]1[C:13]([S:14](Cl)(=[O:16])=[O:15])=[CH:12][C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]1=2.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:14]([C:13]2[S:9][C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[CH:12]=2)(=[O:15])=[O:16])[O:4][N:3]=1
Reactant: Cc1noc(N)c1C
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1noc(NS(=O)(=O)c2cc3ccccc3s2)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
3,4-Dimethyl-5-amino-isoxazole (0.224 g, 2.0 mmol) and 50 mg of DMAP were stirred in 5 ml of pyridine at 25° C. The benzo[b]thiophene-2-sulfonyl chloride (0.16 g, 2.6 mmol) was added and the dark brown-yellow reaction mixture was stirred for 18 h at ambient temperature, poured into 100 ml of ethyl acetate and washed with 2% HCl (3×50 ml). The organic phase was dried with MgSO4, filtered and concentrated to collect 0.61 g of a brown oil/solid. The brown oil/solid was subjected to flash chromatography (30% ethyl acetate/hexanes) to provide 0.37 g of a light brown solid. This was stirred in 10 ml of methanol and 0.5 g of NaOH. The methanolic solution was heated for reflux for 1 h, then cooled to 25° C. and the methanol was removed in vacuo. The resulting residue was acidified to pH 1 with 2% HCl (100 ml) and extracted with ethyl acetate (2×50 ml) The organic phase was dried with MgSO4, filtered and concentrated to collect 0.225 g of a yellow-orange solid. This was recrystallized from CHCl3/hexanes to produce a light tan-yellow solid (0.194 g, 31% yield), m.p. 157-160° C.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[C:5]([O:13][C@H:14]1[C@@H:20]2[C@@H:18]([O:19]2)[CH2:17][C@:16]([OH:25])([C:21]([O:23][CH3:24])=[O:22])[CH2:15]1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B(F)(F)F.CCOCC>C1COCC1.[Cu]I>[C:5]([O:13][C@@H:14]1[CH2:15][C@@:16]([OH:25])([C:21]([O:23][CH3:24])=[O:22])[CH2:17][C@@H:18]([CH:1]=[CH2:2])[C@@H:20]1[OH:19])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=C[Mg]Br
Reactant: COC(=O)[C@@]1(O)C[C@@H]2O[C@@H]2[C@H](OC(=O)c2ccccc2)C1
Agent: [Cu]I
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@](O)(C(=O)OC)C[C@@H](OC(=O)c2ccccc2)[C@H]1O
Reaction time: 1 h

Procedure:
Vinylmagnesium bromide can be added to a −78° C. suspension of CuI in THF. After stirring for 1 hour, a solution of Example 17D and BF3.Et2O in THF can be added. After stirring for 2 hours at −78° C., the reaction mixture can be quenched with saturated NH4Cl. The reaction mixture can be extracted several times with dichloromethane and the combined dichloromethane layers are washed with brine, dried (MgSO4), filtered and concentrated. The concentrate can be purified by flash column chromatography to afford the desired product.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[NH:12][C:13](=[O:16])[CH2:14][Cl:15])(=[O:3])[CH3:2].S(=O)(=O)(O)[OH:18]>>[C:1]([C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[NH:12][C:13](=[O:16])[CH2:14][Cl:15])[C:10]([NH2:11])=[O:18])(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(=O)c1cc(C#N)ccc1NC(=O)CCl
Product: CC(=O)c1cc(C(N)=O)ccc1NC(=O)CCl
Reaction time: 8 h
Yield: 61.6 %

Procedure:
15.7 Parts of N-(2-acetyl-4-cyanophenyl)-2-chloroacetamide were added portionwise to 146.4 parts of concentrated sulfuric acid at room temperature. Upon complete addition, stirring was continued overnight at room temperature. The reaction mixture was poured into 500 parts of crushed ice while stirring. The precipitated product was filtered off and suspended in water. The precipitated product was filtered off, washed with water and suspended in 20 parts of acetonitrile. The product was filtered off, boiled in 20 parts of acetonitrile and filtered off, after cooling, yielding 10.4 parts (61.6%) of 3-acetyl-4-[(2-chloroacetyl)amino]benzamide (int. 114).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([F:25])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([OH:24])=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26](Cl)(=O)[CH3:27]>C(O)C.C(OCC)(=O)C>[CH2:26]([O:23][C:22](=[O:24])[CH2:21][C@@H:19]1[CH2:18][S:17][C:16]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([F:25])=[CH:8][C:7]=3[NH:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:20]1)[CH3:27]
Reactant: CC(=O)Cl
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
The compound (80 mg, 0.22 mmol) prepared in Example 37 was dissolved in ethanol (2 ml). Acetyl chloride (0.1 ml) was added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (50 mg, Yield 58%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13]Br)[C:6]([O:8][CH3:9])=[O:7].[Cl:15][C:16]1[C:17]2[CH2:24][C:23](=[O:25])[NH:22][C:18]=2[N:19]=[CH:20][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:15][C:16]1[C:17]2[C@@:24]3([CH2:2][C:3]4[C:12](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=4)[CH2:13]3)[C:23](=[O:25])[NH:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: COC(=O)c1ccc(CBr)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncnc(Cl)c21
Reaction time: 0.17 h

Procedure:
To a solution of methyl 3,4-bis(bromomethyl)benzoate (5.0 g, 15.5 mmol) and 4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (5.3 g, 31.1 mmol) in N,N-dimethylformamide (150 mL) was added cesium carbonate (10.1 g, 31.1 mmol). After 10 min, water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (1% methanol/dichloromethane→5% methanol/dichloromethane) then a second silica gel purification (100% dichloromethane→>75% dichloromethane/EtOAc gave the title compound as a racemic mixture. Chiral separation of the individual enantiomers was accomplished by use of HPLC using a 10 cm ChiralPak® AD column (60% EtOH/hexanes with 0.1% diethylamine to give the title compound as the 1st eluting enantiomer. MS: m/z=330.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.[NH2:22][CH:23]([CH3:29])[CH2:24][O:25][CH2:26][CH2:27][OH:28]>>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:22][CH:23]([CH3:29])[CH2:24][O:25][CH2:26][CH2:27][OH:28])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: CC(N)COCCO
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Product: CC(COCCO)Nc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12

Procedure:
Prepared by the method of example 2 step a), using the product of example 4, step b) and (+/−)-2-[2-aminopropoxy]ethanol,
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][C:19]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([F:10])([F:21])[F:22])=[CH:17][CH:16]=1)=[O:20])[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: CCOC(CNC(=O)Nc1ccc(C(F)(F)F)cc1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To aminoacetoaldehyde diethylacetal (7.8 ml, 53.6 mmol) was added dropwise 10 g (53.4 mmol) of 4-trifluoromethylphenylisocyanate at 0° C. during five minutes. The reaction solution was stirred for one hour at room temperature. The crystals thus produced was collected by filtration and washed with hexane to give 16.2 g of 1-(2,2-diethoxyethyl)-3-(4-trifluoromethylphenyl)urea (95%) as a colorless powder.
Reaction SMILES: Br[CH2:2][C:3]1([CH2:11]Br)[CH2:8][O:7]C(C)(C)[O:5][CH2:4]1.C(=O)(O)[O-].[Na+].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CS(C)=O>[OH:7][CH2:8][C:3]1([CH2:4][OH:5])[CH2:2][N:25]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11]1
Reactant: CC1(C)OCC(CBr)(CBr)CO1
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: OCC1(CO)CN(Cc2ccccc2)C1
Temperature: 135 °C
Reaction time: 1.5 h

Procedure:
A mixture of 30.2 g of 5,5-bis(bromomethyl)-2,2-dimethyl-1,3-dioxane (0.1 mol), 24.0 g of sodium bicarbonate and 50 ml of dimethyl sulfoxide was heated to 135° C. A solution of 10.7 g of benzylamine in 50 ml of DMSO was then added dropwise with stirring over 1.5 hours. After addition was complete, the mixture was stirred for 2.5 hours at 135° C. After cooling, 100 ml of DMSO and 20 ml of water were added and the solution was extracted with pentane. The extract was washed with water and then shaken with 5% (w/w) sulfuric acid in order to extract the basic 3,3-bis(hydroxymethyl)-1-benzylazetidine acetone acetal.
Reaction SMILES: C(Cl)(=O)C.[Si]([O:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([P:20]([CH3:23])([CH3:22])=[O:21])[CH:19]=1)(C(C)(C)C)(C)C>CO>[CH3:23][P:20]([C:18]1[CH:19]=[C:14]([CH2:13][OH:12])[CH:15]=[N:16][CH:17]=1)([CH3:22])=[O:21]
Reactant: CC(C)(C)[Si](C)(C)OCc1cncc(P(C)(C)=O)c1
Solvent: CC(=O)Cl
Solvent: CO
Product: CP(C)(=O)c1cncc(CO)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (0.044 ml, 0.625 mmol) was added to 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-(dimethylphosphoryl)pyridine (170 mg, 0.568 mmol) stirred in MeOH (1 ml) at 0° C. and the mixture was stirred at 0° C. for 1 h. The reaction was concentrated and left on high vac pump to dry. [5-(dimethylphosphoryl)pyridin-3-yl]methanol was taken on to next reaction crude. MS: cal'd 186 (MH+), exp 186 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+].[Cl-].FC(F)(F)[C:16](O)=[O:17]>Cl[Pd]Cl>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]2[C:5](=[C:6]([F:8])[CH:7]=1)[C:16](=[O:17])[O:10][CH2:9]2
Reactant: Cc1c(Br)cc(F)cc1CO
Reactant: O=C(O)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Product: Cc1c(Br)cc(F)c2c1COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-bromo-5-fluoro-2-methyl-phenyl)-methanol (1.7 g, 7.76 mmol) in trifluoroacetic acid (20 mL) was added Tl(CF3COO)3 (4.2 g, 7.76 mmol). The resulting mixture was stirred at room temperature overnight, then concentrated to dryness. The residue was dissolved in MeOH (50 mL). To the mixture was added PdCl2 (137 mg, 0.776 mmol), LiCl (652 mg, 15.5 mmol) and MgO (652 mg, 15.5 mmol). The resulting mixture was reacted under a CO (50 psi) atmosphere at room temperature overnight, and then filtered. The filtrate was concentrated and the residue was purified by column chromatography to give 5-bromo-7-fluoro-4-methyl-3H-isobenzofuran-1-one.
Reaction SMILES: Cl.[C@@H:2]12[NH:9][C@@H:6](C[CH2:8]1)[CH2:5][N:4]([CH2:10][C@@H:11]([C:13]1[C:14]([CH3:23])=[C:15]3[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[O:17][CH2:16]3)[OH:12])[CH2:3]2.[N:24]1([C:29]2[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=2)[CH:28]=[N:27][N:26]=[N:25]1>>[OH:12][C@H:11]([C:13]1[C:14]([CH3:23])=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[O:17][CH2:16]2)[CH2:10][N:4]1[CH2:3][C@@H:2]2[CH2:8][C@H:5]1[CH2:6][N:9]2[S:35]([C:32]1[CH:33]=[CH:34][C:29]([N:24]2[CH:28]=[N:27][N:26]=[N:25]2)=[CH:30][CH:31]=1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1ccc(-n2cnnn2)cc1
Reactant: Cc1c([C@@H](O)CN2C[C@H]3CC[C@@H](C2)N3)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CN2C[C@@H]3C[C@H]2CN3S(=O)(=O)c2ccc(-n3cnnn3)cc2)ccc2c1COC2=O

Procedure:
5-((R)-1-Hydroxy-2-((1S,4S)-5-(4-(1H-tetrazol-1-yl)phenylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)-4-methylisobenzofuran-1 (3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 14 starting from 5-((R)-2-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one hydrochloride (INTERMEDIATE 15) and commercially available 4-(1H-tetrazol-1-yl)benzene-1-sulfonyl chloride.
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1O[C:11](=[O:27])[C@H:12]([CH3:26])[NH:13][C:14](=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1.Cl.[CH3:29][O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH2:33]>>[CH3:29][O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:33][C:11](=[O:27])[C@H:12]([CH3:26])[NH:13][C:14](=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure Z and using N-(3-nitrophenylacetyl)-L-alanine 2,4,5-trichlorophenyl ester (from Example D8 above) and L-phenylalanine methyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp=154-158° C.). The reaction was monitored by tlc (Rf=0.3 in 1:1 EtOAc/hexanes) and the product was purified by silica gel chromatography using 50-100% EtOAc/hexanes as the eluent.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O.O>CCOCC.C([O-])(=O)C>[Br:14][C:3]1[CH:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOCC
Product: Brc1ccc2[nH]c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76989.7 %

Procedure:
32 g (0.19 mmol) of 9H-carbazole was put into a 2 L Erlenmeyer flask, and then ether acetate (1.2 L) was added thereto so that the 9H-carbazole was dissolved in the ether acetate. To this solution was added 34 g (0.19 mol) of N-bromosuccinimide (NBS), and the mixture was stirred for about 15 hours in the air at room temperature. After the stirring, water was added to the mixture so that the precipitate was dissolved in the mixture. The organic layer of this mixture was washed with water three times and then with a saturated saline solution once. Magnesium sulfate was added so that the organic layer was dried. After the drying, the mixture was subjected to gravity filtration. The obtained filtrate was condensed to give a white solid. The obtained solid was recrystallized with ether acetate/hexane to give 36 g of a white powdered solid, which was the object of the synthesis, at a yield of 67%. A synthesis scheme of Step 1 is shown in (c-1) given below.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:20]([OH:22])=[O:21])[C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2OC)=[CH:8][CH:9]=1)(=[O:3])[CH3:2].O=S(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[C:1]([C:4]1[CH:9]=[CH:8][C:7]2[C:10]3[C:11](=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[O:22][C:20](=[O:21])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2C(=O)O)c(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc2c(c1)oc(=O)c1cc(C(C)=O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
The compound from Step D was dissolved in 1,2-dichloroethane (60 mL) and SOCl2 (1.7 mL, 23 mmol) was added. The mixture was refluxed for 90 min and then cooled to 0° C. at which point AlCl3 (2.3 g, 17.3 mmol) was added. The resulting reaction mixture was stirred overnight at room temperature. The solvent was removed and the crude product chromatographed on silica gel with hexane/ethyl acetate (1:1) to yield 5.1 g (90%) of the title compound. 1H-NMR (400 MHz, CDCl3) δH 2.74 (3H, s, COCH3), 3.94 (3H, s, OCH3), 6.92 (1H, s, ArH), 6.99 (1H, ArH), 8.02 (1H, d, ArH), 8.11 (1H, d, ArH), 8.41 (1H, d, ArH), 8.91 (1H, s, ArH).
Reaction SMILES: [C:1]([C:4]1([O:17][CH3:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(NC(C)C)(C)C.[Li].[CH:27](=[O:30])[CH2:28][CH3:29].[Cl-].[NH4+]>O1CCCC1>[OH:30][CH:27]([CH2:28][CH3:29])[CH2:2][C:1]([C:4]1([O:17][CH3:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:6][CH2:5]1)=[O:3]
Reactant: CCC=O
Reactant: COC1(C(C)=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC(O)CC(=O)C1(OC)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
To a solution of tert-butyl 4-acetyl-4-methoxypiperidine-1-carboxylate (0.589 g, 2.29 mmol) from Step A in tetrahydrofuran (20 mL) at −78° C. was added lithium diisopropylamine (0.650 mL, 0.974 mmol) followed by propionaldehyde (0.266 g, 0.330 mL, 4.58 mmol). After 5 min, the reaction mixture was poured into saturated ammonium chloride, and extracted three times with diethyl ether. The organic layers were combined, washed with saturated sodium chloride solution, dried over sodium sulfite, filtered, and concentrated. The residue was purified by flash chromatography eluting with 40% ethyl acetate/hexanes to afford the title compound (0.404 g). MS/EI (acetonitrile/water): m/z 216.1 (M+1−BOC) retention time=2.69 min.
Reaction SMILES: NC1C=CC([N:8]2[CH2:13][CH2:12][CH:11]([CH:14](C3C=CC=CC=3)[C:15]([O:17]C)=[O:16])[CH2:10][CH2:9]2)=CC=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]1
Reactant: COC(=O)C(c1ccccc1)C1CCN(c2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 399.1 %

Procedure:
DMF (0.5 ml) was added to a solution of 2-biphenylcarboxylic acid (0.077 mol) in DCM (250 ml). Thionyl chloride (0.154 mol) was added. The mixture was stirred and refluxed for 1 hour. The solvent was evaporated and then co-evaporated twice with DCM (100 ml). The residue was dissolved in DCM (100 ml) to give solution (A). Intermediate (18) (0.077 mol) and DIPEA (0.154 mol) were stirred in DCM (400 ml). Solution (A) was added. The mixture was stirred at room temperature for 3 hours and then washed with water. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 44 g of 4-piperidineacetic acid, 1-[4-[([1,1′-biphenyl]-2-ylcarbonyl)amino]phenyl]-α-phenyl-, methyl ester (intermediate 21).