Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:31])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:30])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25](OC)=[CH:24][CH:23]=2)[CH2:14][CH2:13]1.[F:32][C:33]([F:43])([F:42])C1C=CC(CCl)=CC=1.COC1C=CC(CCl)=CC=1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:31])[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([OH:30])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:33]([F:43])([F:42])[F:32])=[CH:26][CH:27]=2)[CH2:16][CH2:17]1
Reactant: COc1ccc(CCC(O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)cc1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Agent: COc1ccc(CCl)cc1
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)CCc2ccc(C(F)(F)F)cc2)CC1

Procedure:
Compound 21 was prepared in a manner similar to that of compound 16 substituting 4-trifluoromethylbenzyl chloride for 4-methoxybenzyl chloride. (M+1)=464.2
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])[N:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[Cl:8][C:6]1[CH:7]=[C:2]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])[N:5]=1
Reactant: CC1(C)CCCC(C)(C)N1c1nc(Cl)cc(Cl)n1
Reactant: C1CCNC1
Product: CC1(C)CCCC(C)(C)N1c1nc(Cl)cc(N2CCCC2)n1
Yield: 75.08 %

Procedure:
4,6-Dichloro-2-(2,2,6,6-tetramethyl-1-piperidinyl)pyrimidine is reacted with pyrrolidine as described in Example 12 to give the title compound in a yield of 75.08%, m.p.: 130°-135° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:33])[N:25]([CH3:32])[C:26](=[O:31])[N:27]([CH3:30])[C:28]=2[CH3:29])=[C:19]([CH3:34])[CH:18]=1)[NH:5]C(OCC1C=CC=CC=1)=O.C1CCCCC=1>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:33])[N:25]([CH3:32])[C:26](=[O:31])[N:27]([CH3:30])[C:28]=2[CH3:29])=[C:19]([CH3:34])[CH:18]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)c(C)c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)c(C)c1
Yield: 71.9 %

Procedure:
A mixture of N-(benzyloxycarbonyl)-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester (0.145 mmol, 70 mg), cyclohexene (1 mL) and 10% palladium on carbon (100 mg) in ethanol (2 mL) was heated to reflux for 15 h. Then, it was filtered through a pad of celite and the pad was washed with ethanol (10 mL). The combined filtrate was concentrated under reduced pressure. The residue was dried under high vacuum to afford 36 mg (72% yield) of 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester as a light yellow solid. ES-HRMS m/e calcd for C18H23N3O4 (M+Na) 368.1327, found 368.1321.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[OH:13])[C:6]3[CH2:20][CH2:21][NH:22][CH2:23][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH:32]([OH:34])[CH3:33]>C(#N)C.O>[OH:13][CH:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[C:5]2[CH2:23][N:22]([CH2:31][CH:32]([OH:34])[CH3:33])[CH2:21][CH2:20][C:6]1=2
Reactant: CC(O)CBr
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(CC(C)O)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol (200 mg, 0.651 mmol) in acetonitrile (4 mL), potassium carbonate (270 mg, 1.95 mmol) and 1-bromopropan-2-ol (135 mg, 0.977 mmol) were added and stirred the reaction mixture at 100° C. for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 1-[5-(2-hydroxy-2-pyridin-4-yl-ethyl)-8-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-propan-2-ol. 1H NMR, (CDCl3, freebase) δ (ppm): 8.58 (s, 2H), 7.36 (m, 2H), 7.2 (m, 2H), 7.02 (d, 1H), 5.1 (s, 1H), 4.3 (m, 1H), 4.1 (m, 2H), 4.0 (m, 2H), 3.56 (m, 1H), 3.37 (m, 1H), 3.1-3.3 (m, 2H), 2.8 (m, 2H), 2.42 (s, 3H), 1.2 (d, 3H). Separation by chiral HPLC provides diastereomers II-83a-d.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:27][S:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:30])=[O:29].O>CN(C)C(=O)C.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.COC(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:34]3[CH:35]=[CH:36][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:32][CH:33]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (6.92 g, 30.75 mmol), potassium carbonate (7.34 g, 53.09 mmol) and 4-methanesulfonylbenzeneboronic acid (5.31 g, 26.55 mmol) in N,N-dimethylacetamide (90 mL) and purge for 15 min. Add water (35 mL) and the mixture further purged for 15 min. Add tetrakis(triphenylphosphine)palladium(0) (0.130 g, 0.11 mmol) and heat for 2 hr. 10 min. at 110° C. Allow to cool to 65° C., add water (30 mL) and t-butyl methyl ether (70 mL) and stir for 0.5 hr. Filter off the solid and dry in a vacuum oven to give 3′-(4-methanesulfonylphenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (8.3 g, 86%). MS (ES): m/z=419 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([C:22]3[C:30]4[O:29][C:28]([NH:31][C:32]5[CH:37]=[CH:36][C:35]([C:38](=[O:44])[N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[C:34]([CH3:45])[CH:33]=5)=[N:27][C:26]=4[CH:25]=[CH:24][CH:23]=3)=[CH:17][C:16]=2[F:46])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:21][C:20]1[CH:19]=[C:18]([C:22]2[C:30]3[O:29][C:28]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([N:39]([CH2:40][CH3:41])[CH2:42][CH3:43])=[O:44])=[C:34]([CH3:45])[CH:33]=4)=[N:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)[CH:17]=[C:16]([F:46])[C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CCN(CC)C(=O)c1ccc(Nc2nc3cccc(-c4cc(F)c(CN5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)c3o2)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)c1ccc(Nc2nc3cccc(-c4cc(F)c(CN5CCNCC5)c(F)c4)c3o2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.5 %

Procedure:
A mixture of 0.146 g (0.224 mmol) 4-{4-[2-(4-diethylcarbamoyl-3-methyl-phenylamino)-benzooxazol-7-yl]-2,6-difluoro-benzyl}-piperazine-1-carboxylic acid tert-butyl ester, 2 ml trifluoroacetic acid and 10 ml dichloromethane is stirred at room temperature for 2 h. Then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, 100% EtOAc=>EtOAc:MeOH=1:1+1% triethylamine) to afford 0.04 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:16](Br)=[C:15](Br)[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccccc2)c1O

Procedure:
Prepared in analogy to that of Example 6(a) from 1-benzyl-2,3-dibromo-7-cyano-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, ammonium formate and Pd/C. The title compound, ESI MS (m/z): 322 (M+H)+.
Reaction SMILES: C([O:8][C:9]([CH2:11][CH2:12][C@H:13]1[NH:18][C:17](=[O:19])[C@@H:16]([CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:30])[CH:22]=2)[NH:15][C:14]1=[O:31])=[O:10])C1C=CC=CC=1>C(O)C>[C:9]([CH2:11][CH2:12][C@H:13]1[NH:18][C:17](=[O:19])[C@@H:16]([CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:30])[CH:22]=2)[NH:15][C:14]1=[O:31])([OH:10])=[O:8]
Reactant: Cn1cc(C[C@H]2NC(=O)[C@@H](CCC(=O)OCc3ccccc3)NC2=O)c2ccccc21
Solvent: CCO
Product: Cn1cc(C[C@H]2NC(=O)[C@@H](CCC(=O)O)NC2=O)c2ccccc21
Yield: 49.2 %

Procedure:
A solution of (3R,6R)-3-(2-benzyloxycarbonylethyl)-6-(1-methylindol-3-ylmethyl)piperazine-2,5-dione (1.50 g) in ethanol (300 ml) containing 10% paradium on charcoal (0.75 g) was hydrogenated at ambient temperature and atmospheric pressure. After catalyst was filtered off and solvent was evaporated, crude solid was recrystallized from ethanol and dried in vacuo to give (3R,6R)-3-(2-carboxyethyl)-6-(1-methylindol-3-ylmethyl)piperazine-2,5-dione (0.58 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])=[O:11].[OH-].[Na+:25]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O-:21])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:11])=[O:12].[Na+:25]
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: O=C([O-])C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Temperature: 55 °C
Reaction time: 12 h

Procedure:
A solution of ethyl 6-[N-(2, 4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate obtained in Example 3 (Compound 3, 2.5 g) in acetonitrile (288 ml) was admixed with a 1N aqueous solution of sodium hydroxide (228 ml) and the mixture was stirred at 55° C. for 12 hours. The mixture was concentrated under reduced pressure and the residue was purified by CHP-20P column chromatography (eluent: water→methanol/water=1/1). The eluent was concentrated under reduced pressure and the residue was dissolved in water (10 ml) and lyophilized to yield sodium 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (0.50 g) as white crystals.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=O)=O.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1>CN(C)P(N(C)C)(N(C)C)=O>[O:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)OCCCCCCOc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCOc2ccccc2)cc1

Procedure:
A solution of 13.6 g of 6-(phenoxy)-1-hexanol O-methanesulfonate and 16.5 g of ethyl p-aminobenzoate in 75 ml of hexamethylphosphoramide is heated at 110° C. for 16 hours. The product is isolated as described in Example 3 to give crystals. Recrystallization from ethanol gives crystals, mp 105°-108° C.
Reaction SMILES: [Li+].[OH-].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[C:8]([CH:21]=1)[C:9]([O:11]CC1C=CC(F)=C(F)C=1)=[O:10]>O1CCCC1.O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[C:8]([CH:21]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(OCc1ccc(F)c(F)c1)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Solid LiOH (0.26 g, 10.86 mmol) was added to a stirred solution of (3,4-difluorophenyl)methyl 5-bromo-2-{[(3,4-difluorophenyl)methyl]oxy}benzoate (may be prepared as described in Description 88; 1.2 g, 2.17 mmol) in tetrahydrofuran (30 ml) and water (10 ml) in air at room temperature. The reaction mixture was stirred at 70° C. overnight. After cooling to room temperature, the solvent was removed. The residue was dissolved in water (20 ml) and stirred in ice-water bath. 1N HCl (aq) was added to the mixture to adjust the pH to 4. The solid was filtered, and dried in vacuo to yield the title compound as a white solid. 730 mg.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][O:6][C:7]1[C:12]([NH2:13])=[C:11]([O:14][CH3:15])[N:10]=[C:9]([CH3:16])[N:8]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[N:13]([C:12]1[C:7]([O:6][CH3:5])=[N:8][C:9]([CH3:16])=[N:10][C:11]=1[O:14][CH3:15])=[C:1]=[S:2]
Reactant: COc1nc(C)nc(OC)c1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(C)nc(OC)c1N=C=S
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Thiophosgene (7.7 mL, 101 mmol) was added dropwise to a stirred mixture of 4,6-dimethoxy-2-methylpyrimidin-5-amine (14.2 g, 84.3 mmol) in tetrahydrofuran (110 mL) and saturated aqueous sodium hydrogen carbonate (110 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with n-hexane to give the title compound as a brown powder (12.5 g, 59.0 mmol, 70%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C@@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)[CH:18]=3)[O:13][C:10]2=[CH:11][CH:12]=1)(=O)=O.[F:35][C:36]1[C:41](B(O)O)=[CH:40][CH:39]=[CH:38][N:37]=1.C(=O)([O-])[O-].[K+].[K+]>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>[F:35][C:36]1[C:41]([C:7]2[CH:8]=[C:9]3[C@@:20]4([CH2:24][O:23][C:22]([NH2:25])=[N:21]4)[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:26]5[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=5)[CH:18]=4)[O:13][C:10]3=[CH:11][CH:12]=2)=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: OB(O)c1cccnc1F
Reactant: Cc1ccc(-c2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2O3)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(-c2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)cc1
Yield: 72.8 %

Procedure:
A vial was charged with (S)-2′-amino-3-p-tolyl-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (45.0 mg, 0.092 mmol), 2-fluoropyridin-3-ylboronic acid (38.7 mg, 0.275 mmol), potassium carbonate (229 μL, 0.458 mmol), and Pd(PPh3)4 (5.29 mg, 4.58 μmol). The vial was flushed with Ar (g), then dioxane (458 μL) (actual amount as 1 mL) and water (0.5 mL) were added in sequence. The vial was sealed and placed in an 80° C. oil bath for 2 hours. The mixture was diluted with EtOAc, washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 12-g Redi-Sep column with 0-5% MeOH/DCM to give (S)-7-(2-fluoropyridin-3-yl)-3-p-tolyl-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (29.53 mg, 0.067 mmol, 73.6% yield) as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][CH3:14])[C:9]([O:15]C)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].B(Br)(Br)Br.[OH-].[Na+].O>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][CH3:14])[C:9]([OH:15])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCc1cc(F)c(C(=O)OC)cc1OC
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCCc1cc(F)c(C(=O)O)cc1O
Temperature: -70 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
Methyl 2-fluoro-5-methoxy-4-propylbenzoate (1.27 g, 5.63 mmol) was dissolved in CH2Cl2 (20 mL) and cooled to -70° C. Boron tribromide (1.64 mL, 16.9 mmol) was added and the temperature was slowly raised to 0° C. during 4.5 h. Methylene chloride (20 mL) and 2M NaOH (25 mL) were added and the mixture was stirred overnight at room temperature. Water (20 mL) was added, the phases separated and the aqueous phase was extracted with CH2Cl2 (20 mL) and acidified to pH 1 by concentrated HCl thus precipitating the acid. Ethyl acetate (50 mL) was added to the mixture and the phases separated. The aqueous phase was extracted by additional EtOAc (50 mL) and the combined organic phases were washed with brine (20 mL), dried (MgSO4) and evaporated yielding 2-fluoro-5-hydroxy-4-propylbenzoic acid (1.09 g) Mp: 134.5°-135.5° C. 1H NMR (DMSO-d6): δ12.88 (br, 1H), 9.57 (br, 1H), 7.23 (d, J=6.5 Hz, 1H), 6.96 (d, J=11.6 Hz), 2.48 (t, J=7.5 Hz, 2H), 1.53 (m, J=7.5 Hz, 2H), 0.87 (t, J=7.4HZ, 3H). 13C NMR (DMSO-d6): δ164.96 (d, J=3 Hz), 154.38 (d, J=248 Hz), 150.84 (d, J=2 Hz), 135.82 (d, J=7 Hz), 117.44 (d, J=24 Hz), 116.28 (d, J=11 Hz), 116.22, 31.38, 21.79, 13.65. MS (EI, 70 eV): m/z (rel. int) 198 (M+, 38).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][C@H:7]([OH:21])[CH2:8][NH:9][C@@H:10]([CH3:20])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CN(C)[CH:27]=[O:28]>>[Si:13]([O:12][CH2:11][C@@H:10]([N:9]1[CH2:8][C@H:7]([CH2:6][O:5][C:4]2[CH:22]=[CH:23][CH:24]=[C:2]([Cl:1])[CH:3]=2)[O:21][C:27]1=[O:28])[CH3:20])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: CN(C)C=O
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)NC[C@@H](O)COc1cccc(Cl)c1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)N1C[C@H](COc2cccc(Cl)c2)OC1=O

Procedure:
A procedure similar to that described in Preparation 11 was repeated, except that 0.82 g of 1(R)-(3-chlorophenoxymethyl)-2-[2-t-butyldimethylsilyloxy-1(S)-methylethylamino]ethanol (prepared as described in Preparation 34), 0.43 g of N,N'-carbonyldiimidazole and 10 ml of anhydrous dimethylformamide were used, to give 0.85 g of the title compound having an Rf value of 0.25 (on silica gel thin layer chromatography, using a 1:2 by volume mixture of ethyl acetate and hexane as the developing solvent) and having [α]D =-33.4° (methanol, c=1.040).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([C:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[Br:1][C:16]1[NH:17][C:18]2[C:23]([C:15]=1[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)=[CH:22][CH:21]=[C:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:19]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Product: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Temperature: 25 °C
Yield: 57 %

Procedure:
N-bromosuccinimide (1.1 eq) was added portionwise over 1 h to tert-butyl 3-cyclohexyl-1H-indole-6-carboxylate in CCl4 (from Step 4, 0.07 M) with vigorous stirring. The reaction was stirred at RT for a further hour following complete addition of NBS. The CCl4 was then removed in vacuo and the residue taken up in EtOAc. The organics were washed with a saturated aqueous solution of sodium thiosulfate (twice), brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification was by flash chromatography (5-20% EtOAc/PE gradient) to yield the title compound (57%); MS (ES+) m/z 380 (M+H)+, 378 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O>[O:7]=[C:4]1[CH2:5][CH2:6][N:1]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCBr
Reactant: O=C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCN1CCC(=O)CC1
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 66.1 %

Procedure:
4-Piperidinone (10.0 g, 73.7 mmol) and potassium carbonate (30.6 g, 221 mmol) were added to N,N-dimethylformamide (100 ml), and ethyl 3-bromopropionate (10.0 ml, 78.0 mmol) was added. The mixture was stirred at 60° C. for 4.5 hours. The reaction mixture was filtrated and the filtrate was added with a saturated aqueous sodium hydrogencarbonate solution (150 ml). The mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=19/1) to give 9.70 g of ethyl 3-(4-oxopiperidino)propionate as a pale-yellow oil (66%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:3]1.[CH3:27][CH2:28][CH:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br)[CH2:30][CH3:31].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[O:1]=[C:2]1[C@H:7]([CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([CH:29]([CH2:30][CH3:31])[CH2:28][CH3:27])[CH:33]=2)[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:3]1
Reactant: CCC(CC)c1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CC(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)c1cccc(C[C@H]2C(=O)O[C@H](c3ccccc3)[C@H](c3ccccc3)N2C(=O)OC(C)(C)C)c1
Yield: 47.6 %

Procedure:
According to example 142, 3.27 g of tert-butyl (2R, 3S)-(−)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate was alkylated with 2.23 g of 3-(3-pentyl)benzyl bromide in 70 mL of anhydrous TBF using 9.71 mL of 1 M sodium bis(trimethylsilyl)amide in THF. The crude product was subjected to flash chromatography on silica gel (9:1 hexane:EtOAc) and then recrystallization from EtOH-water to afford 2.26 g (48%) of tert-butyl (2R,3S,5S)-6-oxo-2,3-diphenyl-5-(3-(3-pentyl)benzyl)4-morpholinecarboxylate as a white crystalline solid, m.p. 143-144° C.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:27])[CH2:6][CH2:7][C:8]1[C:17]([CH3:18])=[C:16]2[C:11]([C:12]([CH3:21])([CH3:20])[CH2:13][C:14](=[O:19])[O:15]2)=[C:10]([CH3:22])[C:9]=1[O:23]COC)[CH:2]=[CH2:3].Br[Si](C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:4][C:5](=[O:27])[CH2:6][CH2:7][C:8]1[C:17]([CH3:18])=[C:16]2[C:11]([C:12]([CH3:20])([CH3:21])[CH2:13][C:14](=[O:19])[O:15]2)=[C:10]([CH3:22])[C:9]=1[OH:23])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)CCc1c(C)c2c(c(C)c1OCOC)C(C)(C)CC(=O)O2
Agent: C[Si](C)(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOC(=O)CCc1c(C)c2c(c(C)c1O)C(C)(C)CC(=O)O2
Temperature: -35 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
The compound G (393 mg, 1.04 mmol) was dissolved in 10 mL of methylene chloride and cooled to −35° C. Bromotrimethylsilane (414 μL, 3.13 mmol) was added dropwise, and the solution was stirred for 1 h. A solution of saturated NaHCO3 (15 mL) was added followed by extraction with methylene chloride (2×30 mL). The organic layers were combined and dried with MgSO4. After filtration and evaporation, the residue was purified using column chromatography with hexanes/ethyl acetate (4:1, v/v) to give 262 mg (76%) of the compound H as a white oily solid. 1H NMR 400 MHz (CDCl3) δ7.80 (s, 1H), 5.87 (m, 1H), 5.25 (m, 2H), 4.58 (d, J=5.6 Hz, 2H ), 2.92 (t, J=5.5 Hz, 2H), 2.72 (t, J=5.6 Hz, 2H), 2.50 (s, 2H), 2.36 (s, 3H), 2.19 (s, 3H), 1.43 (s, 6H).