Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26][C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[BrH:39].C(O)(=O)C>ClCCl.C(OCC)(=O)C>[Br:39][C@@:5]1([O:28][C@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26][C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:4]
Reactant: Br
Reactant: CC(=O)O[C@H]1O[C@H](COC(=O)c2ccccc2)C[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(OC[C@@H]1C[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@](O)(Br)O1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 1-O-acetyl-2,3,6-tri-O-benzoyl-4-deoxy-α-D-glucopyranose (0.137 g, 0.29 mmol) in 3.0 mL of dry dichloromethane at 0° C. was added 30% hydrogen bromide in acetic acid (0.07 mL, 0.33 mmol). The solution was stirred under argon at room temperature for 4 hours, diluted with ethyl acetate (100 mL) and extracted with a saturated solution of sodium bicarbonate. The organic layer was washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure to yield the target compound as a colorless oil which solidified upon standing. Crystallization from ether and petroleum ether gave the target compound as white crystals (0.15 g, 100%).
Reaction SMILES: [C:1]([Si:5]([CH3:32])([CH3:31])[O:6][CH:7]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:8][CH2:9][CH2:10][C:11]([N:13]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][O:15][C:14]1=[O:24])=[O:12])([CH3:4])([CH3:3])[CH3:2].[CH3:33][O:34][C:35]1[CH:51]=[CH:50][C:38]([CH:39]=[N:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.C(N(C(C)C)CC)(C)C.C[Si](Cl)(C)C.S([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[C:1]([Si:5]([CH3:32])([CH3:31])[O:6][CH:7]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:8][CH2:9][CH:10]([CH:39]([C:38]1[CH:50]=[CH:51][C:35]([O:34][CH3:33])=[CH:36][CH:37]=1)[NH:40][C:41]1[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=1)[C:11]([N:13]1[CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][O:15][C:14]1=[O:24])=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(CCCC(=O)N1C(=O)OCC1c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=Nc2ccc([N+](=O)[O-])cc2)cc1
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(Nc2ccc([N+](=O)[O-])cc2)C(CCC(O[Si](C)(C)C(C)(C)C)c2ccccc2)C(=O)N2C(=O)OCC2c2ccccc2)cc1
Temperature: -30 °C
Reaction time: 12 h
Yield: 74 %

Procedure:
To 5.4 g (12.0 mmol) of product 1 and 6.2 g (24 mmol) of product 2 in 135 ml of methylenchloride 8 ml of diisopropylethylamin is added at 10° C. and 4.8 ml of trimethylsilylchloride is added dropwise. After 1 h 14 ml of a 1 molar solution of titantetrachloride in methylenchloride is added dropwise at —10° C. It is stirred for 3 h at −10° C. and further 12 h at −30° C. stored without stirring. Afterwards 8 ml of acetic acid and 140 ml of a 7% aqueous solution of tartratic acid is added and it is stirred for further 2 h at room temperature. After addition of 50 ml of a 20% aqueous solution of sodiumhydrogensulfit it is stirred for another 1 h and extracted with methylenchloride. The organic phase is dried by magnesium sulfate, evaporated and purified by chromatography on silica gel/Ethylacetate/heptane=1/3−>1/1. 6.3 g (74%) of product 3 is obtained in form of a light yellow solid compound: C40H47N3O7Si (709.92) MS (ESI+) 710 (M+H+).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.Cl.C(=O)(O)[O-].[Na+]>[N+](C1C=C([N+]([O-])=O)C=CC=1C)([O-])=O.Cl>[C:1]([O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: C1=COCCC1
Agent: Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Product: C=C(C)C(=O)OC1CCCCO1
Temperature: 50 °C
Reaction time: 25 h
Yield: 91 %

Procedure:
to a solution of 25.8 g (0.3 mol) methacrylic acid and 1.8 g (0.011 mol) 2,4-dinitrotoluene in 25.2 g (0.3 mol) dihydropyran was added 0.05 ml (0.0015 mol) concentrated hydrochloric acid. The reaction mixture was allowed to stir at 50° C. for 25 hr. The hydrochloric acid was neutralized with solid sodium bicarbonate and the mixture was filtered. The filtrate was distilled to give 46.5 g (0.273 mol, 91% yield) tetrahydropyran-2-yl methacrylate, bp 50° C. at 0.15 torr.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][CH2:17][C:18]1[CH:19]=[C:20]([CH2:26][CH:27]([O:33][CH:34]([CH3:36])[CH3:35])[C:28]([O:30]CC)=[O:29])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>>[CH:34]([O:33][CH:27]([CH2:26][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([CH2:17][NH:16][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:15][CH:14]=2)[CH:19]=1)[C:28]([OH:30])=[O:29])([CH3:36])[CH3:35]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Using 4-phenylbenzoic acid and ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 2-isopropoxy-3-(4-methoxy-3-[(4-phenylbenzoyl)amino]methylphenyl)propanoic acid was obtained in the same method as in Example 19d) and then in Example 19e).
Reaction SMILES: [C:1]1([C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:8][CH2:9][CH2:10][C:11](ON2C(=O)CCC2=O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45].[OH-].[NH4+]>ClCCl>[OH:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][NH:33][C:11](=[O:12])[CH2:10][CH2:9][S:8][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)ON1C(=O)CCC1=O
Reactant: NCCOCCOCCOCCO
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)NCCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.7 %

Procedure:
Succinimido 3-(triphenylmethylthio)propanoate (4.06 mg, 9.12 mmol) was added to a 0° C. solution of 2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethanol (C. Bertozzi and M. Bednarski, J. Org. Chem. 1991, 56, 4326-4329) (9.12 mmol) in dichloromethane (20 mL). The solution was stirred at room temperature for 2 days and concentrated ammonium hydroxide (1 mL) was added. After 20 minutes, the mixture was filtered and the filtrate was subjected to an extractive workup. The organic layer were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by HPFC on silica gel (gradient elution with 2-19% CMA in chloroform) to provide 3.95 g of N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)-3-(tritylthio)propanamide as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([C:18]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C1CCCCCC1
Product: O=C(O)c1ccc(NC(=O)C2CCCCCC2)cc1

Procedure:
4-Cycloheptanecarbonylamino-benzoic acid was prepared as described in Example 3 from 5.55 g (0.0405 mol) of p-aminobenzoic acid and 8.7 g (0.0425 mol) of cycloheptanecarboxylic acid chloride.
Reaction SMILES: F[C:2]1[C:14](F)=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6]CC(O)=O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CC(C)C[C@@H](B1O[C@@H]2C[C@@H]3C[C@H]([C@]2(C)O1)C3(C)C)N.FC(F)(F)C([O-])=O.CCN(C(C)C)C(C)C>CN(C)C=O>[C:4]([NH2:6])(=[O:5])[C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:2]=1
Reactant: O=C(O)CNC(=O)c1cccc(F)c1F
Agent: CC(C)C[C@H](N)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of [(2,3-difluorobenzoyl)amino]acetic acid (0.205 g, 0.95 mmol) in dimethylformamide (10 mL) were added TBTU (0.337 g, 1.0 mmol) and (1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butan-1-amine as its trifluoroacetate salt (0.362 g, 0.95 mmol). The mixture was allowed to cool to 0° C. and DIEA (0.498 mL, 2.9 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water (100 mL) and the product partitioned into DCM. The organic layer was dried over sodium sulfate and the solvent removed to give 2,3-difluoro-N-[2-({1R)-3-methyl-1-[(3aR,4R,6R,7aS)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]benzamide.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[CH:32]=[CH:31][C:13]3[N:14]([CH3:30])[C:15]([C:17]4[N:27]([CH2:28][CH3:29])[C:20]5=[N:21][CH:22]=[C:23]([O:25]C)[CH:24]=[C:19]5[CH:18]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:3]1.B(Br)(Br)Br>ClCCl.CS(C)=O>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[CH:32]=[CH:31][C:13]3[N:14]([CH3:30])[C:15]([C:17]4[N:27]([CH2:28][CH3:29])[C:20]5=[N:21][CH:22]=[C:23]([OH:25])[CH:24]=[C:19]5[CH:18]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:3]1
Reactant: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](N)C4)ccc3n2C)cc2cc(OC)cnc21
Agent: BrB(Br)Br
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](N)C4)ccc3n2C)cc2cc(O)cnc21
Reaction time: 4 h
Yield: 114.7 %

Procedure:
A solution of (R)-(3-aminopiperidin-1-yl)(2-(1-ethyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone (11 mg, 0.025 mmol) in dichloromethane (DCM) (3 mL) was cooled to 0° C. using an ice-water bath under nitrogen. Boron tribromide (8 μL, 0.085 mmol) was added to the reaction dropwise with vigorous stirring. The reaction mixture was allowed to return to room temperature with stirring, over 4 hours. The reaction mixture was partitioned with water (5 mL), the organic layer was isolated using a hydrophobic frit, and the aqueous layer was re-extracted with DCM (2×10 mL). The combined organic layers were evaporated in vacuo but LCMS showed there was no product. The aqueous layer was neutralised by the dropwise addition of NaHCO3, partitioned with DCM and separated. The aqueous was re-extracted with DCM (2×15 mL) and the combined organic layers were concentrated in vacuo to give the crude product. The residue was dissolved in DMSO 1 mL and purified by MDAP with an ammonium bicarbonate modifier (Method E). The appropriate fraction was evaporated in vacuo to give the title compound as a yellow gum (12 mg).
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH3:26][C:27]([CH3:32])([CH3:31])[CH2:28][CH:29]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].Cl>C(Cl)Cl.C(OCC)C.CCOC(C)=O>[ClH:1].[CH2:19]([O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][C@H:3]([NH:2][CH2:29][CH2:28][C:27]([CH3:32])([CH3:31])[CH3:26])[C:4]([NH:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:5])=[CH:17][CH:16]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)CCN[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
(S)-2-Amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide monohydrochloride (1.74 g, 4.80 mmol, Example 2, Step A) and 3,3-dimethylbutyraldehyde (0.48 g, 4.8 mmol, Aldrich, Milwaukee, Wis.) were mixed in CH2Cl2 (24 mL). After stirring at ambient temperature under a nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (1.53 g, 7.20 mmol). The resulting reaction mixture was stirred for 30 minutes at 0° C., followed by an additional 12 hours at ambient temperature. Saturated aqueous NaHCO3 solution (24 mL) was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×25 mL). The combined organic solution was dried over Na2SO4. TLC (50% EtOAc in Hexanes as the eluant) showed two spots with Rf values 0.87 and 0.39. The solution was concentrated in vacuo affording a viscous oil. The lower spot on the TLC (Rf=0.39) was isolated by flash chromatography (40% EtOAc in hexanes). The free amine was dissolved in 20 mL of ethyl ether and treated with ethereal HCl to afford 1.29 g (60%) of the pure titled compound as a white solid; mp 238-240° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]=[CH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15].[B]=O.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH:27]=[CH:26][C:23]=1[CH:24]=O.B(OC(C)C)(OC(C)C)OC(C)C.N1CCCCC1.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1/[CH:10]=[CH:11]/[C:12](=[O:17])[CH2:13][C:14](=[O:16])/[CH:15]=[CH:24]/[C:23]1[CH:26]=[CH:27][C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=2)=[CH:29][C:22]=1[O:21][CH3:20]
Reactant: CC(=O)CC(=O)C=Cc1cc2ccccc2[nH]1
Reactant: COc1cc(OCc2ccncc2)ccc1C=O
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: COc1cc(OCc2ccncc2)ccc1/C=C/C(=O)CC(=O)/C=C/c1cc2ccccc2[nH]1
Temperature: 70 °C
Yield: 76.9 %

Procedure:
In a 20 mL reaction vessel were placed 31.0 mg (136 μmol) of 6-(1H-indol-2-yl)hex-5-ene-2,4-dione and 13.2 mg (0.190 mmol) of boron oxide and they were dissolved in 0.88 mL of ethyl acetate. To the mixture under stirring at 70° C., 33 mg (0.14 mmol) of 2-methoxy-4-(4-pyridylmethoxy)benzaldehyde and 62 μL (0.27 mmol) of triisopropyl borate were sequentially added. After the mixture was stirred at the same temperature for 1 hour, a solution of 2.7 μL (27 μmol) of piperidine in ethyl acetate (0.135 mL) was added and the mixture was further stirred for 1 hour. To the reaction mixture was added a 1:1 solution (0.4 mL) of 1 N hydrochloric acid and saturated brine at room temperature and the mixture was stirred for 5 minutes to 1 hour (further, the mixture was neutralized with a saturated sodium bicarbonate aqueous solution as needed). The resulting organic phase was directly subjected to purification by silica gel column chromatography (hexane/ethyl acetate or methylene chloride/methanol) to give 47.3 mg (78% yield) of the title compound as an orange powder.
Reaction SMILES: CI.[C:3]1([C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:15](=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCOCC>[C:3]1([C:9]2([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1(c2ccccc2)CC1
Reaction time: 1 h

Procedure:
Methyl iodide (2.8 mL, 0.045 mol) was added to a mixture of 1-phenylcyclopropane carboxylic acid (4.9 g, 0.030 mol) and potassium carbonate (8.3 g, 0.060 mol) in N,N-dimethylformamide (40 mL, 0.5 mol) at room temperature and then stirred for 1 hour. The mixture was diluted with ether, washed with water (×2) and brine successively, dried and concentrated to give the desired product.
Reaction SMILES: C[O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[O:5][C:6]1[CH:7]=[C:8]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:9]=[CH:10][C:11]=1[CH:12]2[CH:17]1[CH2:23][CH:22]2[NH:24][CH:19]([CH2:20][CH2:21]2)[CH2:18]1.B(Br)(Br)Br>C(Cl)Cl>[CH:22]12[NH:24][CH:19]([CH2:20][CH2:21]1)[CH2:18][CH:17]([CH:12]1[C:13]3[CH:14]=[CH:15][CH:16]=[C:3]([OH:2])[C:4]=3[O:5][C:6]3[C:11]1=[CH:10][CH:9]=[C:8]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH:7]=3)[CH2:23]2
Reactant: COc1cccc2c1Oc1cc(-c3cccnc3)ccc1C2C1CC2CCC(C1)N2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc2c1Oc1cc(-c3cccnc3)ccc1C2C1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 24 h
Yield: 4.1 %

Procedure:
To a solution of 3-(5-methoxy-3-pyridin-3-yl-9H-xanthen-9-yl)-8-aza-bicyclo[3.2.1]octane, 7k (0.3 g, 0.803 mmol) in CH2Cl2 (20 mL) was added dropwise a 1M BBr3 solution in methylene chloride (3.2 mL, 3.2 mmol) at 0° C. The mixture was stirred at rt for 24 h, and quenched with a saturated NaHCO3 solution (20 mL). The organic layer was dried over MgSO4 and concentrated. The crude product was purified via reverse phase HPLC (eluent: CH3CN in water containing 0.1% TFA) to yield 20 mg (4.1%) of title compound 9-(8-aza-bicyclo[3.2.1]oct-3-yl)-6-pyridin-3-yl-9H-xanthen-4-ol, 8k as a TFA salt. MS m/z (MH+) 385.2.
Reaction SMILES: BrCBr.O1CCC[CH2:5]1.[Si:9]([O:16][CH:17]1[CH2:21][C:20](=O)[C:19]([CH2:23][CH:24]=[CH2:25])=[C:18]1[CH3:26])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(=O)(O)[O-].[Na+]>ClCCl.CCCCC.[Zn].[Ti](Cl)(Cl)(Cl)Cl.O>[CH3:26][C:18]1[CH:17]([O:16][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:21][C:20](=[CH2:5])[C:19]=1[CH2:23][CH:24]=[CH2:25]
Reactant: C1CCOC1
Reactant: C=CCC1=C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCC
Solvent: O
Product: C=CCC1=C(C)C(O[Si](C)(C)C(C)(C)C)CC1=C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
2 Dibromomethane (6.13 g) and zinc dust (6.92 g) were added to dry tetrahydrofuran (100 ml), and the resulting mixture was cooled to 0°~5° C. A dichloromethane solution (25.9 ml) of 1M titanium tetrachloride was added to the tetrahydrofuran solution in about 10 min, and the resulting mixture was allowed to react for 4 days at 0°~5° C. Then a solution of (RS)-4-tert-butyldimethylsilyloxy-3-methyl-2-(2-propenyl)cyclopent-2-ene-1-one (6.27 g) in dichloromethane (30 ml) was added at 0°5° C. in about 10 min. After the mixture was allowed to react for 12 hours at the same temperature, the reaction mixture was diluted with pentane (150 ml), and then a slurry consisting of sodium bicarbonate (150 g) and water (80 ml) was slowly added. After stirring for 2 hours at the same temperature, the reaction mixture was filtered by passing through a celite pad, and the separated layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent; n-hexane: ethyl acetate=50:1) to afford the desired product, (RS)-2-methyl-4-methylidene-3-(2-propenyl)-1-tert-butyldimethylsilyloxycyclopent-2-ene (5.5 g, yield 88.4%) as a pale yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:48]=[C:49]([N:66]1[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]1)[CH2:50][NH:51][C:52]([C:54]1[CH:59]=[CH:58][C:57]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[CH:56][CH:55]=1)=[O:53]>CN(C=O)C.O>[C:10]([O:14][C:15](=[O:16])[NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([N:69]1[CH2:68][CH2:67][N:66]([C:49](=[O:48])[CH2:50][NH:51][C:52]([C:54]2[CH:59]=[CH:58][C:57]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[CH:56][CH:55]=2)=[O:53])[CH2:71][CH2:70]1)=[O:22])([CH3:11])([CH3:12])[CH3:13]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1C(=O)N1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 50.3 %

Procedure:
DIPEA (194.78 mg, 0.26 mL, 0.15 mmol) was added to a stirred solution of 2-tert-butoxycarbonylamino-benzoic acid (79.47 mg, 0.33 mmol) in DMF (3 mL). HOBT (49.7 mg, 0.36 mmol) and EDCI (160.5 mg, 0.83 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (130 mg, 0.4 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silicagel of 60-120 mesh and 60% EtOAc in Hexane as eluent) to afford 90 mg (49.5% yield) [2-(4-{2-[(Biphenyl-4-carbonyl)-amino]-acetyl}-piperazine-1-carbonyl)-phenyl]-carbamic acid tert-butyl ester
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH:12]1[C:17](=[O:41])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][C:27]2[C:28]([C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[OH:40])=[N:29][N:30]([CH3:32])[CH:31]=2)=[CH:21][CH:20]=1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:39][C:37]1[CH:36]=[CH:35][C:34]([OH:40])=[C:33]([C:28]2[C:27]([C:26]#[C:25][C:22]3[CH:23]=[CH:24][C:19]([NH:18][C:17]([CH:12]4[CH2:13][O:14][CH2:15][CH2:16][N:11]4[C:9](=[O:10])[CH:8]([NH2:7])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)=[O:41])=[CH:20][CH:21]=3)=[CH:31][N:30]([CH3:32])[N:29]=2)[CH:38]=1
Reactant: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3C(=O)C(NC(=O)OC(C)(C)C)c3ccccc3)cc2)c(-c2cc(Cl)ccc2O)n1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3C(=O)C(N)c3ccccc3)cc2)c(-c2cc(Cl)ccc2O)n1
Yield: 85 %

Procedure:
To a solution of compound 8D was slowly added TFA (20 eq). The reaction mixture was stirred at rt till all the compound 8D was reacted (4-5 h, checked with LCMS). The solvent was removed with rotavapor at 25° C. More dichloromethane was added and the solvent was removed again. The same process repeated two more times. The residua were then transferred to a separatory funnel with EtOAc and washed with saturated aqueous NaHCO3. It was dried over sodium sulfate and filtered. Solvent was removed to give the title compound 9D in >85% yield. It was used for next step without further purification. LCMS (ESI) m/z 592.34 (MNa+), 570.44 (MH+). HPLC: tR=4.27 min.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[N:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:29][O:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[C:34](B(O)O)=[CH:33][N:32]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[CH3:29][O:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[C:34]([C:2]2[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]3[CH:10]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[N:11]([C@H:14]4[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]4)[C:12](=[O:13])[C:4]=3[CH:3]=2)=[CH:33][N:32]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(C#N)cc1)N([C@H]1CC[C@H](O)CC1)C2=O
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(C#N)cc2)N([C@H]2CC[C@H](O)CC2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 4-[2-bromo-5-(trans-4-hydroxy-cyclohexyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl]-benzonitrile (Intermediate AV) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a white solid. tR: 5.54 min (HPLC 2); ESI-MS: tR=0.86 min, [M+H]+ 502 (LC-MS 1); TLC: Rf=0.11 (EtOAc).