Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][C:12](O)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8](O)=[O:9].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[C:2]1([CH2:7][CH2:8][OH:9])[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:11][CH2:12][OH:13]
Reactant: O=C(O)Cc1ccccc1CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1ccccc1CCO
Yield: 93.5 %

Procedure:
To a solution of 2,2′-(1,2-phenylene)diacetic acid (10 g, 51.5 mmol) in THF (100 mL) was added to LAH in THF (90 mL) dropwise, the mixture was refluxed for 18 hours. The mixture was cooled in ice bath and carefully added water (8 mL) dropwise, followed by 1 N NaOH (8 mL), then removed the ice bath added water slowly with stirring until the gray precipitate turns white. The mixture was filtrated and the filtrate was concentrated to give crude 2,2′-(1,2-phenylene)diethanol (8 g, 94%). 1H-NMR (CDCl3): 2.02 (s, 3H), 2.97 (m, 4H), 3.83 (m, 2H), 4.12 (m, 1H), 4.24 (t, 1H), 7.19 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][C:9]2[C:18](=[O:19])[C:17]3[C:12](=[C:13]([C:20]([NH2:22])=[O:21])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:23])[CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:18](=[O:19])[C:17]3[C:12](=[C:13]([C:20]([NH:22][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:21])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:23])[CH:10]=2)=[CH:24][CH:25]=1
Reactant: ClCCN1CCCC1
Reactant: COc1ccc(COc2cn(C)c3c(C(N)=O)cccc3c2=O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(COc2cn(C)c3c(C(=O)NCCN4CCCC4)cccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
To a solution of 3-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-8-carboxamide (1.09 g, 3.22 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (0.193 g, 4.83 mmol) and the mixture was stirred at room temperature for 1 h. Then the mixture of 1-(2-chloroethyl)pyrrolidine, Hydrochloride (0.548 g, 3.22 mmol) and triethylamine (0.494 mL, 3.54 mmol) in N,N-dimethylformamide (30.0 mL) was added in one portion. The resulting mixture was stirred at 50° C. for 3.5 h. Extra NaH (0.15 eq) was added, the mixture was stirred at 50° C. for another 0.5 h. The solvent was removed in vacuo, and the residue was partitioned between water (50 mL) and dichloromethane (50 mL), and extracted with DCM for three times. The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The light yellow residue was purified by automatic silica gel column chromatography (Combiflash RF), eluting with [CH2Cl2/MeOH/NH4OH (80:20:2)]/CH2Cl2 (0-50%) to afford 3-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydroquinoline-8-carboxamide (0.3 g, 0.689 mmol, 21.38% yield) as a light brown oil. LCMS: (M+H)+: 436.3.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[OH:25].O>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2Cl)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 2,4-dichlorophenol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H2O (100 ml), extracted with EtOAc (2×50 mL), washed with H2O (2×50 ml) and brine (50 ml), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(2,4-dichloro-phenoxy)-1-nitrobenzene. The crude product was used for further transformation .
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43](OC)=[O:44])=[N:8]1.O.[OH-].[Li+].[C:53]([NH2:57])([CH3:56])([CH3:55])[CH3:54].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O1CCCC1.O>[NH:17]1[C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([C:43]([NH:57][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:44])[CH:47]=[CH:48][CH:49]=2)=[N:20][CH:19]=[N:18]1
Reactant: CC(C)(C)N
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NC(=O)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 149.7 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.400 g, 0.619 mmol) in a tetrahydrofuran/water mixture (2.50 mL/1.00 mL) was added lithium hydroxide monohydrate (0.0780 g, 1.86 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.00 mL), tert-butylamine (0.195 mL, 1.86 mmol), 1-hydroxybenzotriazole hydrate (0.251 g, 1.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.356 g, 1.86 mmol). This mixture was stirred for 18 h at ambient temperature. After the mixture was extracted with ethyl acetate (2×), the combined organic extracts were washed with aqueous saturated sodium bicarbonate, followed by brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 40–100% ethyl acetate/hexanes gave the title compound (0.334 g, 78% yield). ES-MS (m/z) 445 [M+1(−Tr)]+
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O.[N:18]([C:21]1([CH2:38][O:39][C:40](=[O:48])[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=2)[CH:28]2[CH:24]([O:25][CH:26]([CH3:29])[O:27]2)[CH:23]([N:30]2[CH:35]=[CH:34][C:33](=O)[NH:32][C:31]2=[O:37])[O:22]1)=[N+:19]=[N-:20]>C(Cl)Cl.O>[N:18]([C:21]1([CH2:38][O:39][C:40](=[O:48])[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=2)[CH:28]2[CH:24]([O:25][CH:26]([CH3:29])[O:27]2)[CH:23]([N:30]2[CH:35]=[CH:34][C:33]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[N:32][C:31]2=[O:37])[O:22]1)=[N+:19]=[N-:20]
Reactant: CC1OC2C(n3ccc(=O)[nH]c3=O)OC(COC(=O)c3cccc(Cl)c3)(N=[N+]=[N-])C2O1
Reactant: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC1OC2C(n3ccc(-n4ccnc4)nc3=O)OC(COC(=O)c3cccc(Cl)c3)(N=[N+]=[N-])C2O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
To a suspension of 0.69 g (10.11 mmol) imidazole and 1.07 g (10.5 mmol) triethylamine in 9 ml methylene chloride was added dropwise at −5 to 0° C. within 15 minutes 0.49 g (3.22 mmol) phosphorous oxychloride. After 15 minutes at −5° C., the resulting suspension was treated with 1.00 g (2.15 mmol) 3-chloro-benzoic acid 4-azido-6-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-methyl-tetrahydro-furo[3,4-d]-1,3-dioxol-4-ylmethyl ester followed by 1 ml methylene chloride. The suspension was allowed to warm to room temperature within 15 minutes and then stirred at room temperature for 69 hours. The suspension was cooled to 0° C. and treated at this temperature with 10 ml water. The suspension was allowed to warm to room temperature and the layers were separated. The aqueous layer was extracted with methylene chloride (2×5 ml). The combined organic layer was dried over MgSO4, filtered, concentrated in vacuo, and dried in vacuo (<10 mbar) at 25° C. for 22 hours to afford 1.07 g (96%) of 3-chlorobenzoic acid 4-azido-6-(4-imidazol-1-yl-2-oxo-2H-pyrimidin-1-yl)-2-methyl-tetrahydro-furo[3,4-d]-1,3-dioxol-4-ylmethyl ester as a beige foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][C:8]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CCCCCC.C(O)C>[C:1]([O:5][C:6](=[O:27])[CH2:7][C@@:8]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cccc(O)c2)=NO1
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@]1(C(=O)OC(C)(C)C)CC(c2cccc(O)c2)=NO1
Yield: 49.1 %

Procedure:
A racemate of tert-butyl 5-(2-tert-butoxy-2-oxoethyl)-3-(3-hydroxyphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (49.5 g) was fractionated by HPLC (column: CHIRALPAK AD (trade name), 50 mm ID×500 mm L, mobile phase: hexane/ethanol=850/150) to obtain the title compound (24.3 g) eluted at a larger retention time.
Reaction SMILES: [CH:1]1([NH:8][C:9]([NH2:11])=[S:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C@@H:13]([CH3:17])[C:14](O)=[O:15]>>[CH:1]1([NH:8][C:9]2[S:10][C@@H:13]([CH3:17])[C:14](=[O:15])[N:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H](Br)C(=O)O
Reactant: NC(=S)NC1CCCCCC1
Product: C[C@@H]1SC(NC2CCCCCC2)=NC1=O

Procedure:
Synthesis was performed from N-cycloheptylthiourea and (2S)-2-bromopropanoic acid according to Method C.
Reaction SMILES: [N:1]1([C:5](=[O:16])[CH2:6][C:7]2[C:12]([F:13])=[CH:11][C:10]([OH:14])=[CH:9][C:8]=2[F:15])[CH2:4][CH2:3][CH2:2]1.[CH2:17]([C:19]1[CH:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([C@H:31]3[CH2:33][C@H:32]3[CH2:34][CH2:35]O)[CH2:27][CH2:26]2)=[N:23][CH:24]=1)[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[N:1]1([C:5](=[O:16])[CH2:6][C:7]2[C:8]([F:15])=[CH:9][C:10]([O:14][CH2:35][CH2:34][C@@H:32]3[CH2:33][C@@H:31]3[CH:28]3[CH2:27][CH2:26][N:25]([C:22]4[N:21]=[CH:20][C:19]([CH2:17][CH3:18])=[CH:24][N:23]=4)[CH2:30][CH2:29]3)=[CH:11][C:12]=2[F:13])[CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Reactant: O=C(Cc1c(F)cc(O)cc1F)N1CCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)N4CCC4)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(azetidin-1-yl)-2-(2,6-difluoro-4-hydroxyphenyl)ethanone (50.0 mg, 0.128 mmol) in 5 ml anhydrous dichloromethane at RT was added a solution of 2-{(1S,2R)-2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (38.0 mg, 0.182 mmol), triphenylphosphine (polymer-bound, 143 mg, 0.412 mmol), and di-tert-butyl azodicarboxylate (84.0 mg, 0.363 mmol). The reaction mixture was stirred at RT for 3 hours. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 35-100% acetonitrile in 0.1% formic acid in water gradient), to give the title compound. LC/MS (m/z) 485.3 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[C:13](#[N:17])[CH2:14][C:15]#[N:16].C(NCC)C.O>CN(C=O)C>[NH2:17][C:13]1[O:1][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[C:14]=1[C:15]#[N:16]
Reactant: COc1ccc(C(=O)CO)cc1
Reactant: N#CCC#N
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2coc(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a cooled solution of 2-hydroxy-4′-methoxyacetophenone (379 mg, 2.28 mmol) in DMF (0.75 ml) was added malononitrile (166 mg, 2.51 mmol) followed by diethylamine (0.1 ml, 0.97 mmol). The mixture was stirred at room temperature for 2 hours, and then poured into large amount of cold water. The precipitate was filtrated, washed with water, and dried under reduced pressure to give the intermediate of Example 1(A) (424 mg, 87%) as a brown solid. 1H NMR (400 MHz, CDCl3) ppm 3.83 (s, 3H), 4.73 (brs, 2H), 6.93 (m, 2H), 6.94 (s, 1H), 7.49 (m, 2H). LC/MS: m/z 215 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][S:9]1(=[O:18])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[CH:28]=1>>[Br:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=1)[CH2:33][N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[S:9]1(=[O:18])=[O:17]
Reactant: BrCc1cccc(CBr)c1
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S1(=O)N(Cc2cccc(CBr)c2)c2ccccc2N1c1ccccc1F
Yield: 70 %

Procedure:
In an analogous manner to general procedure IV, 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.20 g, 0.75 mmol) was treated with cesium carbonate (0.24 g, 0.75 mmol) and 1,3-bis(bromomethyl)benzene) (0.80 g, 3.00 mmol) to provide 0.23 g (70%) of 1-[3-(bromomethyl)benzyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide. MS (ES) m/z 446.7; HPLC purity 98.5% at 210-370 nm, 10.8 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C)=[O:28])=[CH:22][CH:21]=3)=[CH:14][C:13]=2[CH2:31][CH3:32])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:24][CH:25]=3)=[CH:14][C:13]=2[CH2:31][CH3:32])[CH2:10][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(C#Cc2ccc(CC(=O)OC)cc2)ccc1C1(OCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(C#Cc2ccc(CC(=O)O)cc2)ccc1C1(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure I; a solution of methyl {4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetate (Compound 92, 130.0 mg, 0.31 mmol) in ethanol (3 mL) and tetrahydrofluran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up and purification by HPLC (Partisil 10-pac, 10% H2O/CH3CN) afforded the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[N:4]([C:14](=[O:16])[CH3:15])[CH2:3]1>[Pd].CCO>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:17])([CH3:1])[CH2:3][N:4]2[C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1
Reactant: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CC(C)(C)c2ccc(N)cc21
Reaction time: 3 h
Yield: 99.4 %

Procedure:
A mixture of 1-(3,3-dimethyl-6-nitroindolin-1-yl)ethanone (300 mg), 10% Pd—C (50 mg), and EtOH (50 mL) was stirred under hydrogen atmosphere (1 atm) for 3 h. The catalyst was filtered out and the filtrate was concentrated to give a light yellow solid (260 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[C:12](=O)[NH:11][C:10]3=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[CH2:12][NH:11][C:10]3=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NC(=O)C2(c3ccc(Cl)c(Cl)c3)CC12
Solvent: Cc1ccccc1
Product: O=C1NCC2CC12c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane-2,4-dione and toluene were combined in a 500 mL round-bottomed flask and stirred under Ar (g) for 10 min while cooling in an ice bath. Red-A1® was added via addition funnel drop-wise over several minutes. Upon complete addition, the ice bath was removed and the reaction stirred at ambient temperature overnight. The reaction mixture was cooled in an ice bath and 150 mL of 5N NaOH was carefully added. The phases were separated and the aqueous phase was extracted with toluene (2×100 mL), DCM (3×100 mL), and the organic layers combined. The organic layer was washed with brine (200 mL) and dried over sodium sulfate for 8 h. The mixture was filtered, concentrated in vacuo, and dried to afford 5 g of a dark brown semi-solid. The semi-solid was purified on a silica gel column eluting with 20% EtOAc in hexanes increasing the polarity to 30% EtOAc and finally 50% EtOAc. The desired fractions containing the product were combined, concentrated, and dried to afford a light yellow solid. Yield: 2.0 g 30%; LCMS (+) ESI: m/z=242 [M]+; m/z=264 [M+Na]+; 1H NMR (300 MHz, CDCl3) 7.52 (d, 1H, ArH), 7.39 (d, 1H, ArH), 7.28 (dd, 1H, ArH), 6.02 (bs, 1H, NH), 3.64 (dd, 1H, NHCH2), 3.40 (d, 1H, NHCH2), 2.28 (m, 1H, NHCH2CH), 1.50 (dd, 1H, ArCCH2), 1.26 (m, 1H, ArCCH2).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:11](O)[CH:12]=[CH2:13].Cl[Si](C)(C)C>>[CH2:13]([O:6][C:5](=[O:7])[CH2:4][CH2:3][CH:2]([NH2:1])[C:8]([OH:10])=[O:9])[CH:12]=[CH2:11]
Reactant: C=CCO
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: C[Si](C)(C)Cl
Product: C=CCOC(=O)CCC(N)C(=O)O
Yield: 62 %

Procedure:
L-Glutamic acid (3) was protected in 62% yield as the γ-allyl ester using allyl alcohol and chlorotrimethylsilane to provide 2-amino-pentanedioic acid 5-allyl ester 4 as follows:
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:52])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[C:27]=5[O:34][C@H:35]([CH2:37]C=C)[CH3:36])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[C:14]([CH3:40])=[C:13]([CH3:41])[C:12]=2[C@H:42]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[C:43]([O:45][CH3:46])=[O:44])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:48]([O:47][C@@H:42]([C:12]1[C:13]([CH3:41])=[C:14]([CH3:40])[C:15]2=[N:19][C:18]3=[CH:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:52])([O:4][CH2:1][CH:2]=[CH:3][CH2:36][C@H:35]([CH3:37])[O:34][C:27]2[C:28]([F:33])=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:6][CH2:7]1)[C:43]([O:45][CH3:46])=[O:44])([CH3:50])([CH3:51])[CH3:49]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5cc(F)cc(F)c5O[C@@H](C)CC=C)c4)cn23)CC1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OC/C=C\C[C@H](C)Oc1c(F)cc(F)cc1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1c(F)cc(F)cc1-c1cccc-3c1

Procedure:
Prepared in 41.6% yield from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3′,5′-difluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate. LCMS (ESI, M+1): 688.2.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][Mg]Br>C(OCC)C>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH3:11]
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(F)cc1Cl
Solvent: CCOCC
Product: CC(O)c1ccc(F)cc1Cl
Temperature: 0 °C

Procedure:
A solution of 5.25 g (0.033 mole) of 2-chloro-4-fluorobenzaldehyde in 100 ml of diethyl ether was cooled to -10° C., and 11.2 ml (0.033 mole) of a 2.95M solution of methylmagnesium bromide in diethyl ether was added dropwise with stirring. The reaction mixture was warmed to 0° C. and was stirred for several hours. After warming to room temperature, the reaction mixture was poured into an ice/water mixture. The resulting mixture was extracted with methylene chloride. The solvent was evaporated from the extract under reduced pressure, and the residue was passed through a column of silica gel, eluting first with heptane and then with ethyl acetate/heptane (1/9). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure, leaving 1.46 g of 1-(2-chloro-4-fluorophenyl)ethanol as an amber oil. The nmr and ir spectra were consistent with the proposed structure. This reaction was repeated on a larger scale to provide sufficient 1-(2-chloro-4-fluorophenyl)ethanol for Step D.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)=[CH2:22].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:21]=[CH2:22])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: C=Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Yield: 91 %

Procedure:
Methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in WO 2004065367) and (2-vinylphenyl)boronic acid (1.5 eq) were dissolved in dioxane (0.07 M) and 2M aqueous Na2CO3 (6 eq) was added. The solution was degassed by bubbling argon, Pd(PPh3)2Cl2 (0.2 eq) was added, and the reaction mixture was refluxed for 1 h; after cooling, EtOAc was added, and the solution washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The title compound was isolated by chromatography (PE/EtOAc 9:1) in 91% yield; MS (ES+) m/z 360 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:33][CH3:34])=[C:5]([C:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH2:24][CH2:25][CH2:26][CH2:27]OS(C)(=O)=O)(=[O:16])=[O:15])=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:2].[CH3:35][CH:36]1[CH2:40][CH2:39][CH2:38][NH:37]1>CC#N>[CH2:1]([C:3]1[C:4]([O:33][CH3:34])=[C:5]([C:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH2:24][CH2:25][CH2:26][CH2:27][N:37]2[CH2:38][CH2:39][CH2:40][CH:36]2[CH3:35])(=[O:16])=[O:15])=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:2]
Reactant: CCc1ccc(NS(=O)(=O)c2ccc(F)cc2CCCCOS(C)(=O)=O)c(C(=O)OC)c1OC
Reactant: CC1CCCN1
Solvent: CC#N
Product: CCc1ccc(NS(=O)(=O)c2ccc(F)cc2CCCCN2CCCC2C)c(C(=O)OC)c1OC

Procedure:
A solution of Example 615D (0.165 g, 0.31 mmol) and 2-methylpyrrolidine (70 mg, 0.8 mmol) in anhydrous CH3CN (3.0 mL) was heated at 50° C. for 10 hours. The mixture was directly purified on a silica gel column, eluting with ethyl acetate, then 5% methanol in CH2Cl2, giving the desired product. 85 mg, 52.7%. MS (ESI(−)) m/e 505 (M−H)−.
Reaction SMILES: O=C1C2CCCCC=2C(=O)N1CC(C1(C)OCCO1)C(OC)=O.[NH2:24][CH2:25][CH:26]([C:31]1([CH3:36])[O:35][CH2:34][CH2:33][O:32]1)[C:27]([O:29][CH3:30])=[O:28].[F:37][C:38]1[CH:48]=[CH:47][C:46]([F:49])=[C:40]2[C:41]([O:43][C:44](=O)[C:39]=12)=[O:42]>>[F:37][C:38]1[CH:48]=[CH:47][C:46]([F:49])=[C:40]2[C:39]=1[C:44](=[O:43])[N:24]([CH2:25][CH:26]([C:31]1([CH3:36])[O:32][CH2:33][CH2:34][O:35]1)[C:27]([O:29][CH3:30])=[O:28])[C:41]2=[O:42]
Reactant: COC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)c2c(F)ccc(F)c21
Agent: COC(=O)C(CN1C(=O)C2=C(CCCC2)C1=O)C1(C)OCCO1
Product: COC(=O)C(CN1C(=O)c2c(F)ccc(F)c2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.27 g, 31%) in the same manner as described in the above example 5. (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.47 g, 2.47 mmol) and 3,6-difluorophthalic anhydride (0.50 g, 2.72 mmol), and the obtained product was identified with the following NMR data.