Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH-].[Na+].Br[CH2:12][CH2:13][Cl:14]>C(O)C.O.C(OCC)(=O)C>[Cl:14][CH2:13][CH2:12][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: ClCCBr
Reactant: Nc1ccccc1S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccccc1SCCCl
Reaction time: 0.33 h
Yield: 97.3 %

Procedure:
To a stirred solution of 2-aminobenzenethiol (0.513 mL, 4.79 mmol) in ethanol (5 mL) was added sodium hydroxide (192 mg, 4.79 mmol) as a solution in water (5.00 mL). To the resulting mixture was added 1-bromo-2-chloroethane (1.197 mL, 14.38 mmol), and the resulting mixture was stirred vigorously for 20 minutes The mixture was then diluted with ethyl acetate and washed with saturated sodium carbonate (3×). The organic phase was dried, filtered, and concentrated, giving a yellow liquid, 2-(2-chloroethylthio)aniline (875 mg, 97%). 1H NMR (DMSO-d6) δ 7.27 (d, J=7.5 Hz, 1H), 7.10-7.04 (m, 1H), 6.73 (d, J=8.1 Hz, 1H), 6.56-6.49 (m, 1H), 5.41 (brs, 2H), 3.62 (t, J=7.4 Hz, 2H), 3.02 (t, J=7.4 Hz, 2H). ESI-MS (m/z, %): 188 (MH+, 100).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]([C:11]([CH2:13]Cl)=[O:12])([CH3:10])[CH3:9].[CH2:15]([C:17]([C:28]1[CH:33]=[CH:32][C:31]([O:34][S:35]([C:38]([F:41])([F:40])[F:39])(=[O:37])=[O:36])=[C:30]([CH3:42])[CH:29]=1)([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:18][CH3:19])[CH3:16]>CC(C)=O>[CH3:7][C:8]([CH3:10])([CH3:9])[C:11](=[O:12])[CH2:13][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]([C:28]2[CH:33]=[CH:32][C:31]([O:34][S:35]([C:38]([F:41])([F:39])[F:40])(=[O:37])=[O:36])=[C:30]([CH3:42])[CH:29]=2)([CH2:18][CH3:19])[CH2:15][CH3:16])=[CH:21][C:22]=1[CH3:27]
Reactant: CC(C)(C)C(=O)CCl
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Yield: 83.8 %

Procedure:
Potassium carbonate (59.7 mg, 0.43 mmol) and 1-chloropinacolin (42.0 mg, 0.31 mmol) were added to a solution of trifluoromethanesulfonic acid 4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl ester (Example 1-(1); 0.1 g, 0.24 mmol) in acetone (1.2 mL), and the mixture was heated under reflux for 17 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (6% ethyl acetate/hexane) to give the title compound (103.5 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24](Cl)=[O:25]>>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:25]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(Cl)Cc1cccs1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)Cc4cccs4)cc3c2C1
Yield: 84.3 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.1 μL (0.051 mMol) 2-thienylacetyl chloride, 13.7 mg (84%) of the title compound were recovered as a dark brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[I:18].[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:19]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH:13]=[C:12]2[I:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1cccc(Cl)c1-c1ccc2[nH]cc(I)c2c1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4c(F)cccc4Cl)ccc32)cc1
Yield: 46.7 %

Procedure:
This title compound was prepared analogously to compound 25d using 5-(2-chloro-6-fluorophenyl)-3-iodo-1H-indole (23 g, 0.07 mol) and tosyl chloride (17.7 g, 0.09 mol) to obtain the title compound (17.2 g, 46%).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.Br[CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1>CN(C=O)C.O>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[O:13][CH2:12][CH2:11][S:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1
Reactant: BrCCOC1CCCCO1
Reactant: Sc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cc(SCCOC2CCCCO2)ccn1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
Sodium hydride (890 mg of a 50% suspension in mineral oil, 19 mmol) was added to a solution of 4-mercaptopyridine (2.34 g, 21 mmol) in DMF (75 ml) and the mixture stirred for 30 minutes. 2-(2-Bromoethoxy)tetrahydropyran (4.0 g, 19 mmol), (J. Am. Chem. Soc. 1948, 70, 4187), was added and the mixture heated at 100° C. for 3 hours and then stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 97/3) to give 4-(2-(tetrahydropyran-2-yloxy)ethylthio)pyridine (2.8 g, 56%). 1H NMR Spectrum: (DMSOd6) 1.35-1.64(m, 6H); 3.35-3.42(m, 1H); 3.58-3.82(m, 3H); 4.60(s, 1H); 7.30(dd, 2H); 8.33(dd, 2H)
Reaction SMILES: C([O:4][C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:22])([CH3:21])[CH2:15][C:16]([O:18]CC)=[O:17])(=O)C.C(=O)([O-])[O-].[Ca+2].BrBr>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl.O>[C:16]([CH2:15][C:14]([CH3:22])([CH3:21])[CH2:13][CH2:12][CH2:11][CH2:10][C:6]1[C:5](=[O:4])[CH2:9][CH2:8][CH:7]=1)([OH:18])=[O:17]
Reactant: CCOC(=O)CC(C)(C)CCCCC1=C(OC(C)=O)CCC1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(CCCCC1=CCCC1=O)CC(=O)O

Procedure:
To a rapidly stirred mixture of 1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-ene (35 g., 0.113 mole) chloroform (95 ml.), water (125 ml.) and calcium carbonate (11.8 g.) cooled in an ice-bath is added dropwise over a period of thirty minutes a solution of bromine (18.8 g.) in carbon tetrachloride (31 ml.). After stirring in the cold for an additional 45 minutes the orange colored chloroform layer is separated and washed with dilute sodium bisulfite and saturated saline solution, dried over magnesium sulfate and taken to dryness in vacuo (bath temperature: 35°-40°) leaving an amber colored oil. A slurry of 100 ml. of N,N-dimethylacetamido and 16.5 g. of CaCO3 is stirred and heated to reflux under nitrogen flow. The above dried oil is added from a dropping funnel rapidly, maintaining reflux and nitrogen flow for thirty minutes. The cooled reaction mixture is filtered, and the precipitate is washed with ether. The filtrate is poured into two liters ice-cold water and is extracted with ether. The combined extracts and washing is washed with water, saturated saline, treated with decolorizing charcoal, filtered. The solvent evaporated in vacuo to give 24 g. (77%) of subject product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:24][CH2:25][OH:26])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][C:16](=[O:23])[C:17](=[CH:21][CH:22]=2)[C:18]([OH:20])=[O:19])=[CH:10][CH:9]=1)(=[O:7])=[O:6].O[N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:1][CH2:2][CH2:3][N:4]([CH2:24][CH2:25][OH:26])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[NH:15][C:16](=[O:23])[C:17](=[CH:21][CH:22]=2)[C:18]([O:20][N:28]2[C:32](=[O:33])[CH2:31][CH2:30][C:29]2=[O:34])=[O:19])=[CH:12][CH:13]=1)(=[O:7])=[O:6]
Reactant: O=C(O)c1ccc(-c2ccc(S(=O)(=O)N(CCO)CCO)cc2)[nH]c1=O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1ccc(-c2ccc(S(=O)(=O)N(CCO)CCO)cc2)[nH]c1=O

Procedure:
A solution of 45 g. of 6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinic acid and 14.0 g. of N-hydroxysuccinimide in 450 ml. of dimethylformamide is cooled to 0°-5° C. and treated dropwise, with stirring, with a solution of 26.8 g. of N,N'-dicyclohexylcarbodiimide in 30 ml. of dimethylformamide. The mixture is stirred for 16 hours at room temperature, then cooled and filtered to remove by-product N,N'-dicyclohexylurea. The filtrate is diluted with 1.5 l. of 2-propanol and the resulting precipitate of 6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinic acid, 2,5-dioxo-1-pyrrolidinyl ester is collected by filtration, washed with cold 2-propanol and dried; m.p. 213°-215.5° C.
Reaction SMILES: BrCCBr.[Cl:5][C:6]([Cl:12])(Cl)[C:7]([O:9][CH3:10])=[O:8].[CH3:13][Si:14](Cl)([CH3:16])[CH3:15]>O1CCCC1.CCCCCC.[Zn]>[Cl:5][C:6]([Cl:12])=[C:7]([O:9][CH3:10])[O:8][Si:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: COC(=O)C(Cl)(Cl)Cl
Reactant: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CCCCCC
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(O[Si](C)(C)C)=C(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a suspension of 5.9 g (0.091 g-atom) of zinc powder (−325 mesh) in 40 mL of tetrahydrofuran was added 0.2 mL of 1,2-dibromoethane. The mixture was heated at gentle reflux for 30 minutes. The mixture was cooled to room temperature and 7.1 mL (0.06 mole) of methyl trichloroacetate was added dropwise, followed by 9.1 mL (0.097 mole) of trimethylsilyl chloride at rate such the internal temperature was below 50 degrees. The mixture was stirred at room temperature for 1 hour and then diluted with hexane. The resulting solid was removed by filtration, and the filtrate concentrated under reduced pressure. Solids were removed by filtration, washing with hexane. The filtrated was concentrated under reduced pressure and the residue was then distilled under vacuum to give 8.0 g of (2,2-dichloro-1-methoxy-vinyloxy)-trimethyl-silane as a colorless oil. Bp 45-48 degrees at 1 mm Hg.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:17]([CH3:19])[CH3:18])=[CH:10][C:11]=2[CH:13]([OH:16])[CH2:14][CH3:15])[C:6]([CH3:21])([CH3:20])[CH2:5][CH2:4]1)[CH3:2].C[N+]1([O-])CCOCC1>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:17]([CH3:19])[CH3:18])=[CH:10][C:11]=2[C:13](=[O:16])[CH2:14][CH3:15])[C:6]([CH3:21])([CH3:20])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC(O)c1cc(C(C)C)cc2c1N(CC)CCC2(C)C
Agent: C[N+]1([O-])CCOCC1
Product: CCC(=O)c1cc(C(C)C)cc2c1N(CC)CCC2(C)C

Procedure:
Following General Procedure D, 1-(1-ethyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-propan-1-ol (Intermediate 10, 5.37 g, 21.3 mmol) and 4-methylmorpholine N-oxide (5.00 g, 42.6 mmol) were reacted to give the title compound as a yellow oil.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([NH2:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Cl.C[CH:19]([NH2:34])[C:20]1C=[CH:24][C:23](CCC2C=CC=CC=2)=[CH:22][CH:21]=1>>[ClH:1].[C:7]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=[CH:9][C:4]([CH:3]([N:16]=[C:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:34]2)[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(N)c1ccc(-c2ccccc2)cc1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Agent: Cl
Product: CC(N=C1CCCCCN1)c1ccc(-c2ccccc2)cc1

Procedure:
Following essentially the same procedure described in Example IV above and substituting α-methyl-ρ-phenylbenzylamine hydrochloride for the α-methyl-ρ-phenethylbenzylamine hydrochloride above, results in the formation of 2-[α-(4-biphenylyl)ethylimino]hexahydroazepine hydrochloride having a M.P. of 245°-7° C.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([Br:19])[CH:8]=[C:9]2[C:14]=1[O:13][C:12]([CH3:16])([CH3:15])[CH2:11][C:10]2([CH3:18])[CH3:17])(=O)C.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CO.CCCCCC>[Br:19][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([OH:4])[CH:6]=1)[O:13][C:12]([CH3:16])([CH3:15])[CH2:11][C:10]2([CH3:18])[CH3:17]
Reactant: CC(=O)Oc1cc(Br)cc2c1OC(C)(C)CC2(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(C)CC(C)(C)c2cc(Br)cc(O)c2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
A solution of 8-acetoxy-6-bromo-2,2,4,4-tetramethyl chroman (Intermediate 16, 1.3 g, 3.98 mmol) in methanol was treated with sodium carbonate (0.8 g, 7.95 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford a residue that on flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent afforded the title product as an oil (0.95 g, 84%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Solvent: c1ccncc1
Product: COc1cc(C(=O)/C=C/c2cn(C(C)=O)c3ccccc23)cc(OC)c1OC
Temperature: 100 °C
Yield: 69.5 %

Procedure:
A mixture of Compound 1 (1.69 g) obtained in Example 1, acetic anhydride (5.04 g) and pyridine (5.6 ml) was heated at 100° C. for 12 hours. The reaction solution was subjected to partitioning between chloroform and a 10% aqueous solution of citric acid. The organic layer was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give Compound 6 (1.32 g).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1>>[CH2:21]([CH:18]([N:13]1[C:12]([C:33]2[CH:34]=[CH:35][S:31][CH:32]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH2:19][CH3:20])[CH3:22]
Reactant: OB(O)c1ccsc1
Reactant: CCC(CC)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCC(CC)n1nc2c(c1-c1ccsc1)CCNCC2
Yield: 99.7 %

Procedure:
The title compound (95 mg) was prepared as in Example 177, Steps C and D, using 150 mg of 2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 183, Step A) and 126 mg of 3-thiopheneboronic acid. MS (ESI): exact mass calculated for C16H23N3S, 289.16. found, m/z 290.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.68-7.64 (m, 1H), 7.52-7.48 (m, 1H), 7.12-7.07 (m, 1H), 3.93-3.86 (m, 1H), 3.44-3.39 (m, 2H), 3.34-3.28 (m, 2H), 3.22-3.17 (m, 2H), 2.85-2.79 (m, 2H), 1.95-1.84 (m, 2H), 1.79-1.69 (m, 2H), 0.71 (t, J=7.4 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1cnccn1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)c(-c2cnccn2)c1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To a degassed mixture of 2-chloropyrazine (1.01 g, 8 mmol), 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.36 g, 8.84 mmol) and potassium phosphate (6.3 g, 30 mmol) in 1,4-dioxane (30 ml) was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.11 g) and the mixture stirred for 15 h at 90° C. The reaction was cooled to ambient temperature, poured into water (100 ml) and extracted with ethyl acetate (4×50 ml). The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Purification by chromatography on silica gel eluting with 50% dichloromethane in isohexane then ethyl acetate gave 2-(2-fluoro-5-nitrophenyl)pyrazine: m/z (ES+) 220 (M++H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.S(Cl)(Cl)=O.[CH2:19](O)[CH2:20][CH3:21]>>[OH:1][C:2]1[C:3]([C:12]([O:14][CH2:19][CH2:20][CH3:21])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(O)c1cc2ccccc2cc1O
Reactant: CCCO
Solvent: O=S(Cl)Cl
Product: CCCOC(=O)c1cc2ccccc2cc1O
Temperature: 120 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3-Hydroxy-naphthalene-2-carboxylic acid (2 g) was dissolved in 1-propanol (10 ml) to prepare a solution which was then brought to 0° C. Thionyl chloride (1.16 ml) was gradually added dropwise to the solution, and the mixture was stirred at 120° C. for 2 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give propyl 3-hydroxy-naphthalene-2-carboxylate (2.15 g, yield 88%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12]>[Pd].C(O)C>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:11][CH3:12])[CH:4]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
A 500 mL Parr bottle was charged with 2.0 g of 10% palladium on carbon (50% water) and covered with 50 mL ethanol. 2-methyl-5-nitroanisole (10.0 g, 59.8 mmol) was dissolved in 100 mL ethanol and added to the catalyst suspension. The reaction was hydrogenated at 50 psi for 3 h. The catalyst was filtered through a celite plug. The filter cake was washed with 150 mL ethanol and the filtrated concentrated under reduced pressure to yield 8.05 g (98%) of 5-amino-2-methylanisole as a clear oil.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH3:22])[CH:10]2[C:13]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:15][CH2:14]2)=[CH:5][C:4]=1[CH3:23]>Br.C(O)(=O)C>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH3:22])[CH:10]2[C:13]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:14][CH2:15]2)=[CH:5][C:4]=1[CH3:23]
Reactant: COc1cc2c(cc1C)CCN(C)C2C1(c2ccccn2)CC1
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc2c(cc1O)C(C1(c3ccccn3)CC1)N(C)CC2
Temperature: 25 °C
Yield: 44.9 %

Procedure:
A solution of 7-methoxy-2,6-dimethyl-1-[1-(2-pyridyl)cyclopropyl]-1,2,3,4-tetrahydroisoquinoline (0.7 g) in 48% hydrobromic acid (10 ml) and glacial acetic acid (10 ml) was heated under reflux under nitrogen for 5 hours. The mixture was cooled to ambient temperature, and concentrated in vacuo. Water (50 ml) was added and the solution basified with aqueous sodium hydroxide solution (2N) until the solution had pH 8. The product was extracted with ether (100 ml) and ethyl acetate (200 ml), and the combined organic fractions were washed with water (100 ml). The organic layer was dried over sodium sulphate and the solvents removed in vacuo to yield a brown solid which was triturated with ether to yield 7-hydroxy-2,6-dimethyl-1-[1-(2-pyridyl)cyclopropyl]-1,2,3,4-tetrahydroisoquinoline (0.3 g) as a solid, mp 218° C. (Dec).
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[CH:13][C:12]=3[CH:16]=2)[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].[Li]CCCC.CCCCCC.[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:28][C:14]1[O:15][C:11]2[CH:10]=[CH:9][C:8]([C:3]3([CH2:1][CH3:2])[O:4][CH2:5][CH2:6][O:7]3)=[CH:16][C:12]=2[CH:13]=1
Reactant: CCC1(c2ccc3occc3c2)OCCO1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC1(c2ccc3oc(Cl)cc3c2)OCCO1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 64.2 %

Procedure:
To a stirred solution of 5-(2-ethyl-1,3-dioxolan-2-yl)benzofuran (350 mg, 1.0 eq) in 20 mL anhydrous THF was added 2.5 M n-BuLi solution in hexane (1.6 mL, 2.4 eq) dropwise at 0° C., and the mixture was stirred at 0° C. for 50 min under nitrogen. A solution of hexachloroethane (915 mg, 2.4 eq) in 10 mL anhydrous THF was added dropwise. The reaction was stirred at rt for 1 h, quenched with sat NH4Cl (aq), and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product (260 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=0.4 Hz, 1H), 7.37-7.38 (m, 2H), 6.57 (s, 1H), 4.01-4.05 (m, 2H), 3.77-3.80 (m, 2H), 1.94 (q, J=7.6 Hz, 2H), 0.88 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH2:9].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[C:10]1([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[NH2:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(N)c(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(N)c(-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
To a degassed solution of 2-bromo-4-methylbenzenamine (0.301 g, 1.618 mmol), phenyl boronic acid (0.296 g, 2.427 mmol), and tetrakistriphenylphosphine palladium(0) (0.187 g, 0.162 mmol) in DME (8 mL) was added 2M sodium carbonate solution (3 ml, 6 mmol) and the mixture was stirred for 16 h at 80° C. Water (30 ml) was added and the product was extracted with EtOAc (2×30 mL). The combined organics were washed with brine, dried (Na2SO4), concentrated and purified by silica gel chromatography to provide 2-phenyl-4-methylbenzenamine as a thick syrup (0.22 g, 75% yield). 1H NMR (400 MHz, CDCl3): δ 7.47-7.41 (m, 4H), 7.36-7.32 (m, 1H), 6.99-6.96 (m, 2H), 6.71 (d, J=8.0 Hz, 1H), 2.28 (s, 3H); MS (ESI) m/z: 184.2 (M+H+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:13][O:12][CH:11]([CH2:14][NH:15][CH2:16][CH3:17])[O:10][C:9]=2[CH:18]=1)(=[O:4])=[O:3].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOC(C)=O>[CH2:19]([N:15]([CH2:14][CH:11]1[O:10][C:9]2[CH:18]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[CH:7][C:8]=2[CH2:13][O:12]1)[CH2:16][CH3:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CCNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN(Cc1ccccc1)CC1OCc2ccc(S(C)(=O)=O)cc2O1
Yield: 89.5 %

Procedure:
N-{[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methyl}ethanamine (0.93 g, 3.4 mmol), benzylbromide (0.43 ml, 3.6 mmol), potassium carbonate (0.61 g, 4.4 mmol) and ACN (20 ml) were heated at 70° C. for 2 h. EtOAc (50 ml) was added before the reaction mixture was filtered and concentrated. Purification by flash chromatography (isooctane/EtOAc 1:1) afforded the title compound (1.1 g). 1H-NMR (400 MHz, MeOH): δ 7.47 (1H, dd, J1 8 Hz, J2 1.6 Hz), δ 7.31 (7H, m), δ 5.18 (1H, t, J 5.2 Hz), δ 4.97 (2H, dd, J1 41 Hz, J2 15 Hz), δ 3.09 (3H, s), δ 2.90 (2H, m), δ 2.70 (2H, m), δ 1.12 (3H, t, J 7.2 Hz).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]I>>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@@H:15]([C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc(Br)cc1F)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CI
Product: C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Br)cc1F
Yield: 61.5 %

Procedure:
Following the procedure outlined for Example 628, (R)-4-benzyl-3-(2-(4-bromo-2-fluorophenyl)acetyl)oxazolidin-2-one (4.6 g, 12 mmol) was reacted with methyl iodide (1M solution in toluene, 12.3 mL, 12.3 mmol) to obtain the desired product (3.0 g, 60%) as light yellow solid: ESI MS m/z 407 [C19H17BrFNO3+H]+