Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(O[C:15]([O:17][C:18]1([C:38]([NH2:40])=[O:39])[C:26]2[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=2)[N:20]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[C:19]1=[O:37])=[O:16])C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:36][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[Cl:35])[CH2:28][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[C:18]2([O:17][C:15](=[O:16])[NH:40][C:38]2=[O:39])[C:19]1=[O:37]
Reactant: NC(=O)C1(OC(=O)OCc2ccccc2)C(=O)N(Cc2ccc(Cl)c(Cl)c2)c2c(F)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C2(O1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1c(F)cccc12

Procedure:
Potassium carbonate (6.0 g.) was added to a solution of 3-benzyloxycarbonyloxy-1-(3,4-dichlorobenzyl)-7-fluoro-2-oxoindoline-3-carboxamide (2.0 g.) in toluene (100 ml.). The mixture was stirred and heated under reflux for 1 hour. The toluene was removed by evaporation and the residue partitioned between ether (100 ml.) and water (100 ml.). The aqueous phase was adjusted to pH 5 with 2M hydrochloric acid. The ether phase was then separated, washed with water, brine and then dried (MgSO4) and evaporated to give 1'-(3,4-dichlorobenzyl)-7'-fluorospiro[oxazolidine-5,3'-indoline]-2,2',4-trione, as a solid, m.p. 140°-142° C. (recrystallised from ethyl acetate/petrol 60-80).
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]([C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[C:11](/[N:13]=[C:14](/[N:16](C)C)\[CH3:15])=O)=[N:8][C:4]=2[CH:3]=1.[NH2:29]N>C(O)(=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]([C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[C:11]3[N:13]=[C:14]([CH3:15])[NH:16][N:29]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: NN
Reactant: C/C(=N\C(=O)c1ccccc1-c1nc2cc(Br)ccc2n1C(C)(C)C)N(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a round bottom flask is added 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-N-[1-dimethylamino-eth-(E)-ylidene]-benzamide (237 mg, 0.537 mmol) in glacial acetic acid (3 mL), followed by the addition of hydrazine (35% wt solution in water) (2 mL). The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with EtOAc, is washed with sat. NaHCO3, brine, dried under anhy. Na2SO4, filtered and concentrated. The residue is loaded to a silica gel column. The column is eluted with 0-3% 2M NH3 in MeOH/CH2Cl2. The product fractions are collected and concentrated to afford 5-bromo-1-tert-butyl-2-[2-(5-methyl-1H-1,2,4-triazol-3-yl)-phenyl]-1H-benzimidazole (78 mg, 35%) as a light brown solid. LCMS (ESMS): m/z 410.68, 412.71 (M++1)
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:12]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:11][C:10]([S:17](Cl)(=O)=O)=[C:9]([CH:21]([CH2:23][CH3:24])[CH3:22])[CH:8]=1>[Zn]>[Br:6][C:7]1[C:12]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:11][C:10]([SH:17])=[C:9]([CH:21]([CH2:23][CH3:24])[CH3:22])[CH:8]=1
Reactant: CCC(C)c1cc(S(=O)(=O)Cl)c(C(C)CC)cc1Br
Agent: O=S(=O)(O)O
Agent: [Zn]
Product: CCC(C)c1cc(Br)c(C(C)CC)cc1S
Temperature: 0 °C
Yield: 80.4 %

Procedure:
A 128-ml portion of concentrated sulfuric acid was added to 300 g of ice while keeping the temperature at 0°-10°C. Then 41 g of 4-bromo-2,5-di-sec-butylbenzenesulfonyl chloride was added. While maintaining the temperature at 0°-10°C, 65 g of zinc dust was added with good agitation over a period of 2 hours. The reaction mixture was then heated under reflux on a steam bath for 5 hours. After cooling, the mixture was extracted into methylene dichloride, dried over magnesium sulfate, filtered, and concentrated to an oil which was distilled, to give 27 g of 4-bromo-2,5-di-sec-butylbenzenethiol, bp 106°-107°C/0.22 mm, nD25 1.5599.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:30])[N:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][C@H:13]2[C:31](O)=[O:32])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:61][O:62][C:63]1[CH:74]=[CH:73][CH:72]=[CH:71][C:64]=1[CH2:65][N:66]([CH3:70])[CH2:67][CH2:68][NH2:69]>>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:30])[N:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][C@H:13]2[C:31]([NH:69][CH2:68][CH2:67][N:66]([CH3:70])[CH2:65][C:64]2[CH:71]=[CH:72][CH:73]=[CH:74][C:63]=2[O:62][CH3:61])=[O:32])=[O:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cc(Cl)cc(Cl)c2)[C@H](C(=O)O)C1
Reactant: COc1ccccc1CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cc(Cl)cc(Cl)c2)[C@H](C(=O)NCCN(C)Cc2ccccc2OC)C1
Yield: 89.5 %

Procedure:
According to the procedure of Example 1, Step E above, 46 mg (0.080 mmole) of (S)-1-[N-(3,5-dichlorophenyl)-N-phenylcarbamoyl]-4-(N,N-di-n-pentylcarbamoyl)piperazine-2-carboxylic acid, 12 mg (0.088 mole) of HOBt, 21 mg (0.112 mmole) of EDAC, and 31 mg (0.16 mmole) of N-(2-methoxybenzyl)-N-methylethylenediamine (from Example 1, Step E b) above) after purification by flash chromatography on 16 g of silica gel eluting with 100:5:CH2Cl2 :methanol: provided 54 mg (90%) of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34]>>[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:38]4[CH:39]=[CH:40][C:35]([C:33]([OH:34])=[O:32])=[CH:36][CH:37]=4)[CH:16]=3)([OH:14])[C:10]([F:11])([F:13])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:37][CH:36]=1)=[O:34]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccnc(-c4ccc(C(=O)O)cc4)c3)C(F)(F)F)c(Cl)c2)cc1

Procedure:
In analogy to Example 49, trifluoromethanesulfonic acid 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl ester) (Example 26, step 1) was reacted with (4-methoxycarbonyl-phenyl) boronic acid 19 h at 70° C. to give the title compound as a white solid. MS (m/e)=584.2 [M+H+].
Reaction SMILES: [OH-].[K+].COCCC[O:8][C:9](=[O:25])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([F:18])[F:17])=[C:12]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH:11]=1>CO>[F:17][CH:16]([F:18])[C:13]1[CH:14]=[CH:15][C:10]([C:9]([OH:25])=[O:8])=[CH:11][C:12]=1[O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24]
Reactant: COCCCOC(=O)c1ccc(C(F)F)c(OCCCOC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COCCCOc1cc(C(=O)O)ccc1C(F)F
Temperature: 25 °C
Reaction time: 60 h

Procedure:
1N aqueous KOH (6.7 mL, 6.7 mmol) is slowly added to a solution of 4-difluoromethyl-3-(3-methoxy-propoxy)-benzoic acid 3-methoxy-propyl ester (1.48 g, 4.45 mmol) in MeOH (5 mL) and the reaction mixture is stirred at RT for 60 h. For workup the mixture is concentrated under reduced pressure, the residue is taken up in 2N HCl (until a pH=1 is obtained) and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4), filtered and the solvent is evaporated to give the title compound. MS (LC-MS): 259.1 [M−H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 4.89 min.
Reaction SMILES: C(OC(N(CCCO[C:18]1[CH:19]=[C:20]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:21]=[CH:22][C:23]=1[CH2:24][NH:25][C:26]1[N:27]([C:37]2[N:38]=[CH:39][N:40]=[C:41]([NH2:44])[C:42]=2[N:43]=1)[C@@H:28]1[O:36][C@H:33]([CH2:34][OH:35])[C@@H:31]([OH:32])[C@H:29]1[OH:30])CC)=O)C1C=CC=CC=1.[CH3:51][OH:52]>[Pd]>[CH2:28]([NH:27][CH2:37][CH2:42][CH2:51][O:52][C:19]1[CH:18]=[C:23]([CH2:24][NH:25][C:26]2[N:27]([C:37]3[N:38]=[CH:39][N:40]=[C:41]([NH2:44])[C:42]=3[N:43]=2)[C@@H:28]2[O:36][C@H:33]([CH2:34][OH:35])[C@@H:31]([OH:32])[C@H:29]2[OH:30])[CH:22]=[CH:21][C:20]=1[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH3:29]
Reactant: CO
Reactant: CCN(CCCOc1cc(-c2ccccc2)ccc1CNc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)C(=O)OCc1ccccc1
Agent: [Pd]
Product: CCNCCCOc1cc(CNc2nc3c(N)ncnc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 8-{3-[3-(N-benzyloxycarbonyl-N-ethyl-amino)propoxy]biphenyl-4-ylmethylamino}adenosine (0.18 g) and 10% palladium on carbon (43.8 wt % H2O, 0.21 g) in methanol (5.3 mL) was stirred at room temperature for 24 hours under a hydrogen atmosphere. The insoluble material was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on amino-propylated silica gel (eluent: dichloromethane/methanol=8/1 to 6/1) to give the title compound (0.12 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=2)[N:5]=[C:4]([CH3:21])[CH:3]=1.[CH2:22]([CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([CH:29]1[CH2:33][CH2:32][N:31]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:10]=3)[N:5]=[C:4]([CH3:21])[CH:3]=2)[CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cc(Cl)c2cc(NC(=O)c3ccccc3)ccc2n1
Reactant: c1ccc(CC2CCNC2)cc1
Product: Cc1cc(N2CCC(Cc3ccccc3)C2)c2cc(NC(=O)c3ccccc3)ccc2n1

Procedure:
The title compound was prepared using procedures analogous to those described in Example 1 above, but using N-(4-chloro-2-methylquinolin-6-yl)benzamide (see Preparation 5 above) in place of 4,6-dichloro-2-methylquinoline and 3-benzylpyrrolidine in place of 3-phenylpyrrolidine.
Reaction SMILES: Br[C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]([OH:29])[CH2:25][CH:26]([CH3:28])[CH3:27].[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:29][CH:24]([C:3]1[C:4]2[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:7](=[O:21])[N:6]([CH3:22])[C:5]=2[S:23][C:2]=1[C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([O:32][C:31]([F:30])([F:42])[F:43])[CH:34]=1)[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: CC(C)CC(O)c1c(Br)sc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)CC(O)c1c(-c2cccc(OC(F)(F)F)c2)sc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: 85 °C
Yield: 61.3 %

Procedure:
To a solution of 6-bromo-5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (70 mg, 0.143 mmol) in dioxane (2 mL) was added (3-(trifluoromethoxy)phenyl)boronic acid (58.9 mg, 0.286 mmol), Pd(PPh3)4 (10 mg) and aq. 2M K3PO4 (0.4 mL). The reaction was heated at 85° C. for 2 h then cooled to RT and filtered. The filtrate was diluted with DCM (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 5:1) to give 5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (50 mg, 61.2% yield) as a solid. LCMS: [MH+-THP] 487 and TR=2.079 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N-]>C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Rh+3].[Rh+3].ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C(OCc1ccccc1)N1CCC(CO)CC1
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)COCC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
In a similar manner to Example 20, starting material step (a), N-benzyloxycarbonylpiperidine-4-methanol (2 g, preparation described in Turconi, M. et al (1989), European Patent Application No. 309422-A2), dirhodium tetraacetate (40 mg), dichloromethane (15 ml total) and ethyl diazoacetate (1.2 ml) were reacted to give ethyl N-(benzyloxycarbonyl)piperidin-4-ylmethoxyacetate (1.47 g) as a colourless oil: NMR Spectrum (DMSO-d6) 1.10 (2H, m), 1.20 (3H, t), 1.70 (3H, m), 2.80 (2H, m), 3.31 (2H, d), 4.00 (2H, m), 4.06 (2H, s), 4.12 (2H, q), 5.06 (2H, s), 7.35 (5H, m); Mass Spectrum m/Z 336 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][CH:4]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCc1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
To a solution of methyl 4-bromomethylbenzoate (5.73 g, 25 mmol) in dry CH2Cl2 (150 mL) cooled to −78° C. with stirring under nitrogen was added dropwise a solution of DIBAL-H (82.5 mL, 1.0 M solution in THF). Stirring was continued for 1.5 h at −78° C., and the reaction mixture was then allowed to warm to 0° C. and quenched with H2O. The organic layer was separated and the aqueous was extracted with CH2Cl2 (2×100 mL). The combined organic extracts were dried (MgSO4) and evaporated to give the desired alcohol (5.0 g, 100%) as a white solid: 1H NMR (CDCl3) δ 1.84 (br, 1H), 4.49 (s, 2H), 4.67 (s, 2H), 7.33 (d, 2H, J=8.2 Hz), 7.38 (d, 2H, J=8.2 Hz).
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]1([CH:14]=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.C(O)(=O)C>CCOCC>[OH:15][CH:14]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[C:1]#[N:2]
Reactant: [C-]#N
Reactant: O=Cc1cccc2ccccc12
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: N#CC(O)c1cccc2ccccc12
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of potassium cyanide in ether (100 mL) at 0° C. was added dropwise a mixture of 1-naphthalenecarbaldehyde (1.56 g, 10 mmol) and acetic acid (1.41 g, 23.5 mmol) in ether (10 mL). The resulting mixture was warmed to 25° C. for 20 h, where the precipitate was filtered and the filtrate was concentrated affording the title compound as a clear oil (1.67 g, 9.14 mmol, 91%): LCMS (ES) m/z 184 (M+H)+.
Reaction SMILES: C(OC(=O)NC1(C2C=CC(C3C(=O)C4C(=CC([C:29]5[NH:30][N:31]=[CH:32][CH:33]=5)=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[C:41]([O:45][C:46](=[O:78])[NH:47][C:48]1([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[C:67](=[O:68])[C:66]4[C:61](=[C:62](Br)[C:63]([O:69][CH3:70])=[CH:64][CH:65]=4)[O:60][C:59]=3[C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)=[CH:54][CH:53]=2)[CH2:51][CH2:50][CH2:49]1)([CH3:44])([CH3:43])[CH3:42].CC1(C)C(C)(C)OB(C2C=NNC=2)O1>>[C:41]([O:45][C:46](=[O:78])[NH:47][C:48]1([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[C:67](=[O:68])[C:66]4[C:61](=[C:62]([C:33]5[CH:29]=[N:30][NH:31][CH:32]=5)[C:63]([O:69][CH3:70])=[CH:64][CH:65]=4)[O:60][C:59]=3[C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)=[CH:54][CH:53]=2)[CH2:51][CH2:50][CH2:49]1)([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Reactant: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1Br
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1-c1cn[nH]c1
Yield: 52 %

Procedure:
Following the procedure used to prepare (1-{4-[4-oxo-2-phenyl-7-(2H-pyrazol-3-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester, {1-[4-(8-bromo-7-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (100 mg, 0.173 mmol) was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give the title compound (51 mg, 52%). LCMS (Method H): RT=3.77 min, [M+H]+=564.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[F:13])[C:3]([NH2:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[OH:21][CH2:22][C:23]1([N:26]2[CH2:31][C:30]3([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[O:29][CH2:28][C:27]2=[O:37])[CH2:25][CH2:24]1>CN(C)C=O.O>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH:2]([N:34]2[CH2:35][CH2:36][C:30]3([O:29][CH2:28][C:27](=[O:37])[N:26]([C:23]4([CH2:22][OH:21])[CH2:24][CH2:25]4)[CH2:31]3)[CH2:32][CH2:33]2)[C:3]([NH2:5])=[O:4])=[C:7]([F:13])[CH:8]=1
Reactant: O=C1COC2(CCNCC2)CN1C1(CO)CC1
Reactant: NC(=O)C(Br)c1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1(CO)CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-bromo-2-(4-bromo-2-fluorophenyl)acetamide (1.037 mmol) in N,N-dimethylformamide (5 mL) was treated with potassium carbonate (2.96 mmol) and the crude 4-(1-(hydroxymethyl)cyclopropyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride from Example 29a. The reaction was stirred at room temperature overnight. The reaction solution was then diluted with water (100 mL) and was extracted three times with ethyl acetate. The combined organic layers were washed three times with water, three times with brine, and was then dried over sodium sulfate, filtered and concentrated to dryness in vacuo to afford the crude title compound as a yellow oil (500 mg of 85% pure material as determined by 1H NMR, 91% yield over the two steps). MS(ES)+ m/e 470.1/472.0 [M+H]+ (bromide isotope pattern).
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[ClH:20].O1CCOCC1>>[ClH:20].[CH2:17]([O:16][C:14]([C@@H:13]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[NH:8]1)=[O:15])[CH:18]=[CH2:19]
Reactant: C=CCOC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C=CCOC(=O)[C@@H]1C[C@H]2C[C@H]2N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-allyl ester 2-tert-butyl ester (1.69 g, 6.32 mmol) was added HCl 4N in dioxane (15.8 mL, 63.2 mmol). The reaction mixture was stirred for 6 h at RT and subsequently lyophilized. MS: 168.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14]>CCCCCC.C1COCC1>[Br:8][C:4]1[CH:3]=[C:2]([CH:13]([C:12]2[CH:15]=[CH:16][CH:17]=[C:10]([Br:9])[CH:11]=2)[OH:14])[CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: Brc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1cccc(Br)c1)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
n-Bui (26.5 mL, 42.4 mmol, 1.6M in hexane) was added to a solution of 1,3-dibromobenzene (10 g, 42.4 mmol) in THF (50 mL) at −78° C. After stirred for 2 h at −78° C., the 3-bromobenzaldehyde (7.84 g, 42.4 mmol) was added to the reaction mixture. The reaction mixture was allowed to warm up to r.t. and stirred at 30° C. for 12 h. The reaction was quenched with aq NH4Cl (100 mL). The mixture was extracted with dichloromethane (80 mL×5). The combined organic layers were dried and concentrated. The residue was purified by column chromatography (on silica gel, eluent with Petroleum ether ˜Petroleum ether: EtOAc=20:1) to afford 8.4 g of the title compound (24.5 mmol, 58%). LC/MS: [M−18+1]=325. 1HNMR (DMSO-d6), 400 MHz: δ 5.74 (d, 1H, J=4.0 Hz), 6.19 (d, 1H, J=4.4 Hz), 7.26-7.31 (m, 2H), 7.37-7.43 (m, 4H), 7.59 (s, 2 H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH:9]3[CH:7]([CH:8]3[C:11]([O:13]CC)=[O:12])[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.O1CCCC1.O.[OH-].[Li+].Cl>O>[CH:1]1([N:5]2[CH2:10][CH:9]3[CH:7]([CH:8]3[C:11]([OH:13])=[O:12])[CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)C1C2CN(C3CCC3)CC21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1C2CN(C3CCC3)CC21
Temperature: 0 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
To a stirred mixture of ethyl 3-cyclobutyl-3-aza bicyclo[3.1.0]hexane-6-carboxylate (218 mg, 1.04 mmol, obtained in the above step), tetrahydrofuran (2 mL) and water (2.0 mL) cooled at 0° C., lithium hydroxide monohydrate (133 mg, 3.19 mmol) was added in a single lot. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was cooled again to 0° C. and acidified with 2N hydrochloric acid to pH: 2-3. The volatiles were removed under reduced pressure and the traces of water were removed by azeotropic distillation with toluene to obtain 3-cyclobutyl-3-aza bicyclo[3.1.0]hexane-6-carboxylic acid (180 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1.Cl.[CH3:33][O:34][C:35](=[O:40])[C@H:36]([CH2:38][OH:39])[NH2:37]>ClCCl.C(Cl)(Cl)Cl>[CH3:33][O:34][C:35](=[O:40])[C@H:36]([CH2:38][OH:39])[NH:37][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CO)NC(=O)Cc1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
To an ice cooled solution of 3,5-difluorophenylacetic acid (2.16 g) in anhydrous dichloromethane (100 mL) under nitrogen was added HOBt-hydrate (4.23 g), EDAC-HCl (3.6 g), and NMM (2.2 mL). The reaction mixture was stirred at 0° C. under nitrogen for 15 min and L-serine methyl ester-HCl (1.96 g) was added followed by NMM (1.38 mL). The reaction was stirred at 0° C. for 1H and RT for 2H. The reaction mixture was concentrated in vacuo and partitioned between water (100 mL) and ethyl acetate (125 mL). The organic phase was collected and consecutively washed with water, dilute aqueous sodium bicarbonate, brine, dried, filtered and the solvent removed in vacuo to yield a white solid. Trituration with CHCl3 afforded pure title compound (1.8 g). The impure filtrate was subjected to flash chromatography (20% acetone/CHCl3) to afford additional title compound (800 mg, total yield 76%). 1H NMR (300 MHz, d6-DMSO) δ3.57 (d, 2H), 3.62 (s, 3H), 3.7 (m, 1H), 4.35, (m, 1H), 5.1 (bs, 1H), 7.00 (d, 2H), 7.09 (t, 1H), 8.53, (d, 1H). MS APCI m/z=274 (M+1). LC/MS: 1.34 min.
Reaction SMILES: [O:1]=[S:2]1(=[O:38])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([N:30]2[C@H:34]([CH2:35][OH:36])[CH2:33][O:32][C:31]2=[O:37])[CH:10]=[CH:11][C:12]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH2:28][CH3:29])=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=[O:14].[CH3:39]I>>[O:38]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([N:30]2[C@H:34]([CH2:35][O:36][CH3:39])[CH2:33][O:32][C:31]2=[O:37])[CH:10]=[CH:11][C:12]=1[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH2:28][CH3:29])=[CH:23][N:22]=2)[CH2:19][CH2:20]1)=[O:14]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reactant: CI
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4COC)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 73.3 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-3-{3-(1,1-dioxoisothiazolidin-2-yl)-4-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-4-hydroxymethyloxazolidin-2-one (761 mg) described in Example 327 and methyl iodide (238 mg), the title compound (572 mg) was obtained.