Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[NH:10][C:9]1=[O:19])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:27]=1[O:35][CH3:36])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:22][C:23](=[O:24])[NH:25][C:26]2[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:27]=2[O:35][CH3:36])[C:9]1=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(OC)c(NC(=O)CBr)cc1Cl
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2cccnc2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)OC(C)(C)C)c(=O)c3ncccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 25 ml round bottomed flask charged with (2,4-Dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl)-acetic acid t-butyl ester (14.9 mg, 0.054 mmol), 2-Bromo-N-(5-chloro-2,4-dimethoxy-phenyl)-acetamide (26.5 mg, 0.06 mmol), and Cs2CO3 (50.9 mg, 0.11 mmol) is treated with DMF (3 ml) and the solution stirred at RT. After 2 hours, the reaction mixture is treated with water and stirred for 10 minutes. The product is extracted into EtOAc and washed with water (3×10 ml). The organic portions are dried (MgSO4), filtered and concentrated to give the title compound, [M+H]+ 505
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[NH:16][N:15]=1>>[F:24][C:13]([F:12])([F:23])[C:14]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[N:16]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=2)[N:15]=1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: CCC(=O)c1ccc(Br)cc1
Product: CCC(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 1-(4-bromophenyl)-1-propanone and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 1.
Reaction SMILES: [OH:1][CH:2]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:22][C:23]([O-:25])=[O:24].C(Br)(Br)(Br)Br.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[OH:1][C@@H:2]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:22][C:23]([O-:25])=[O:24]
Reactant: CCCCCCCCCCCCC#CC(O)CCCCC
Agent: BrC(Br)(Br)Br
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCCCCCCC#C[C@H](O)CCCCC

Procedure:
This compound was prepared by reaction of 6(±)-hydroxy-7-eicosyn-methylcarboxylate (preparative example V) with CBr4 /Ph3P reagent in exactly the same manner as described in preparative example VIII. Note: By use of the corresponding 6-R, and 6-S alcohols (preparative example VI) the optically active (+) and (-) 6-bromo-7-yne-eicosanoates were also obtained.
Reaction SMILES: [F:1][C:2]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1>>[F:1][C:2]1[C:13]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)=[O:5]
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1F
Reactant: COc1ccc([Mg]Br)cc1
Product: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2F)cc1

Procedure:
Prepared according to Method A step B from 2-fluoro-N-methoxy-N-methyl-3-(trifluoromethyl)benzamide (2.5 g, 10 mmol) and 4-methoxyphenylmagnesium bromide (20 mL, 0.5 M in THF) to give 2.1 g of the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([O:20][C:21]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCO)OCc1ccccc1
Reaction time: 1 h
Yield: 85.8 %

Procedure:
In 300 ml of methylene chloride was dissolved 50 g of 3-aminopropanol, and thereto were successively added dropwise 33 g of triethylamine and 57 g of benzyloxycarbonyl chloride at -10° C. to -5° C. At the same temperature, the resulting mixture was stirred for 1 hour and then further stirred at room temperature for 1 hour. Subsequently, the reaction mixture was washed successively with 100 ml of diluted hydrochloric acid and 100 ml of water, and thereafter dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure to obtain 60 g (yield 86%) of 3-(benzyloxycarbonylamino)propanol having a melting point of 55°-56° C.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=O)OC(C)(C)C)[CH2:8][CH2:7]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:6]1[CH2:7][CH2:8][CH:9]([NH:12][CH3:13])[CH2:10][CH2:11]1
Reactant: CN(C)CC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNC1CCN(CCN(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 1020.1 %

Procedure:
A solution of tert-butyl [1-(2-dimethylaminoacetyl)piperidin-4-yl]carbamate (702 mg) in tetrahydrofuran (10.5 ml) was stirred while cooling in an ice bath under a nitrogen atmosphere. Lithium aluminum hydride (280 mg) was added thereto, and the mixture was stirred in an ice bath for 15 minutes and at room temperature for 15 minutes. The reaction mixture was heated to reflux for 11 hours at 100° C. under a nitrogen atmosphere. The reaction mixture was then cooled in an ice bath. Water (2.8 ml), 5N aqueous sodium hydroxide (2.8 ml) and water (14.0 ml) were added in that order, and the mixture was stirred for 2 hours. The insoluble portion was filtered. The filtrate was concentrated to provide the title compound (4.65 g, quantitative) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:9][CH2:8][C:7]([C:10]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]3[C:11]=2[CH2:12][N:13]([CH3:23])[C:14]3=[O:22])=[CH:6][CH2:5]1)[CH3:2]>[Pd].C(O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:10]([C@H:7]2[CH2:8][CH2:9][C@H:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6]2)=[C:11]2[C:15]=1[C:14](=[O:22])[N:13]([CH3:23])[CH2:12]2
Reactant: CCOC1CC=C(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Agent: [Pd]
Solvent: CCO
Product: CCO[C@H]1CC[C@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Reaction time: 24 h

Procedure:
Palladium on charcoal (10%) (50 mg) was cautiously added to a hydrogenation flask containing a solution of 4-(4-ethoxycyclohex-1-enyl)-2-methyl-7-nitro-2,3-dihydro-isoindol-1-one (Compound 166C, 300 mg, 0.78 mmol) in ethanol (30 mL) and this mixture was hydrogenated at 40 psi for 24 hrs. The mixture was filtered and concentrated to a residue which was purified by flash column chromatography (MeOH:DCM 0.5:99.5) to separate the cis and trans isomers. Compound 166A, the cis isomer eluted first: 90 mg: 1H NMR (CDCl3, 500 MHz): 1.22 (t, 3H, J=7.5 Hz), 1.41-1.6 (m, 2H), 1.82 (q, 2H), 2.1 (m, 2H) 2.40 (m, 1H) 3.15 (s, 3H), 3.45 (q, 2H, J=7.5 Hz), 3.62 (s, 1H), 4.36 (s, 2H), 5.08 (s, 2H), 6.6 (d, 1H, J=8 Hz), 7.18 (d, 1H, J=8 Hz). Compound 166B, the trans isomer, eluted after: 50 mg: 1H NMR (CDCl3, 500 MHz): 1.22 (t, 3H, J=7.5 Hz), 1.28 (q, 2H), 1.38 (q, 2H), 1.82 (d, 2H) 2.2 (d, 2H) 2.40 (m, 1H) 3.18 (s, 3H), 3.38 (m, 1H), 3.6 (q, 2H, J=7.5 Hz), 4.38 (s, 2H), 5.1 (s, 2H), 6.6 (d, 1H, J=8 Hz), 7.18 (d, 1H, J=8 Hz).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32](O)=[O:33])=[CH:26]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([N:16]1[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])[CH:12]=3)[CH2:17]1)=[O:33])=[CH:26]2
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc2[nH]c(C(=O)N3CCc4cc(C(=O)NOC5CCCCO5)ccc4C3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 152 mg 5-methoxyindol-2-carboxylic acid, 111 mg HOBt, 276 mg EDC, 0.603 ml triethylamine and 7 ml DMF is stirred overnight at ambient temperature. The reaction mixture is evaporated. The residue is then purified by silica gel chromatography. 50 mg of the title compound are obtained as yellowish foam.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH2:1]=[C:14]1[CH2:15][CH2:16][C:11]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCC2(CC1)OCCO2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 112.6 %

Procedure:
To a solution of methyl triphenylphosphonium bromide (13.7 g) in DMSO (140 ml) was added potassium tert-butoxide (4.31 g) under ice-cooling and the mixture was stirred for 1.5 hours at ambient temperature. After cooling, 1,4-dioxaspiro[4,5]decan-8-one (5.0 g) was dropwise added to the solution under ice-cooling and then stirred for 1 hour at room temperature. The reaction mixture was poured into water (300 ml) and extracted twice with ethyl acetate (150 ml). The extracts were washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give a residue. The residue was washed with a mixture of hexane and ethyl acetate (5:1 v/v) (300 ml). The resulting precipitates were collected and were chromatographed on silica gel (500 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 8-methylene 1,4-dioxaspiro[4,5]decane (5.56 g).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[OH-:24].[K+].C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(CCC)=CC(CCC)=CC=1CCC)(C)(C)C.O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:19]([N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([OH:24])[CH:23]=[CH:22][C:5]=4[C:6]=3[N:7]=2)=[N:18][CH:17]=[N:16]1)([CH3:21])[CH3:20]
Reactant: [OH-]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: [Pd]
Agent: CCCc1cc(CCC)c(-c2c(C)c(C)c(C)c(C)c2P(C(C)(C)C)C(C)(C)C)c(CCC)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(O)ccc1-2
Temperature: 100 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
A mixture of 8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 27, see FIG. 4 (1.06 g, 2.70 mmol), pulverized potassium hydroxide (303 mg, 5.4 mmol), tris(dibenzylideneacetone)di palladium(0) (24.8 mg, 0.027 mmol), 2-di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-1-propylbiphenyl (26.0 mg, 0.054 mmol) were combined in a sealed tube. The mixture was then taken up in 1,4-dioxane (2.4 mL), water (2.4 mL), and sealed. The reaction mixture was placed in a pre-heated bath and stirred at 100° C. overnight. Added an additional 2.0 eq of pulverized potassium hydroxide, 1 mol % tris(dibenzylideneacetone)di palladium(0), 2 mol % 2-di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-1-propylbiphenyl, and 0.2 mL of water and 1,4-dioxane and heated at 100° C. for 2 h. The reaction mixture was filtered through a plug of celite and concentrated in vacuo and the residue purified by flash chromatography (silica, 80 g column, ISCO, 0-100% ethyl acetate in heptane) to afford 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-hydroxyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene as a yellow solid (480 mg, 54%). 1H NMR (400 MHz, DMSO) δ 9.87 (s, 1H), 8.22 (d, J=8.8 Hz, 1H), 7.81 (s, 1H), 6.61 (dd, J=8.8, 2.4 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 5.90 (hept, J=6.6 Hz, 1H), 4.51-4.38 (m, 4H), 1.47 (d, J=6.6 Hz, 6H).
Reaction SMILES: CC(OC([N:8]1[CH2:15][C@H:14]2[C@H:10]([CH2:11][CH:12]([OH:16])[CH2:13]2)[CH2:9]1)=O)(C)C.[ClH:17]>O1CCOCC1.ClCCCl.C(OCC)C>[CH2:11]1[CH:12]([OH:16])[CH2:13][C@@H:14]2[C@H:10]1[CH2:9][NH:8][CH2:15]2.[ClH:17]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC(O)C[C@H]2C1
Agent: Cl
Solvent: ClCCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: OC1C[C@H]2CNC[C@H]2C1

Procedure:
3.00 g (13.20 mmol) of tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (see synthesis: WO 2006/108 059) are dissolved in 150 mL of a 2/1 mixture of dioxane and 1,2-dichloroethane. 30 mL (120 mmol) of a 4N solution of hydrogen chloride in dioxane are poured into the medium with stirring. After stirring for 3 hours at room temperature, the medium is concentrated to dryness and the product obtained in hydrochloride form is taken up in diethyl ether for organization of the salt. After filtering off and drying under reduced pressure, 1.745 g (81%) of the expected product are obtained in the form of a hygroscopic solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[C:7]([CH:10]=1)[C:8]#[N:9])=[O:2].P([O-])(O)(O)=[O:18].[K+].Cl([O-])=O.[Na+].CC(=CC)C.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.O.C(Cl)Cl>[C:8]([C:7]1[CH:10]=[C:3]([CH:4]=[CH:5][C:6]=1[O:11][CH2:12][C:13]([F:15])([F:14])[F:16])[C:1]([OH:18])=[O:2])#[N:9]
Reactant: O=P([O-])(O)O
Reactant: N#Cc1cc(C=O)ccc1OCC(F)(F)F
Agent: CC=C(C)C
Agent: O=S([O-])OS(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: N#Cc1cc(C(=O)O)ccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 417.6 %

Procedure:
5-formyl-2-[(2,2,2-trifluoroethyl)oxy]benzonitrile (D29; 155 mg, 0.676 mmol) was dissolved in t-butanol (2 ml). A solution of potassium dihydrogen phosphate (23.01 mg, 0.169 mmol) and sodium chlorite (184 mg, 2.029 mmol) in water (2 ml) was added, followed by 2-methyl-2-butene (1.015 ml, 2.029 mmol). The resulting mixture was stirred at room temperature for 4 hrs. A solution of sodium disulfite (450 mg) in water (10 ml) was added carefully. DCM (15 ml) was then added and the phases were separated. The aqueous layer was then extracted once more with DCM (15 ml). The combined organic extracts were passed through a phase separation cartridge, concentrated under vacuum and dried in a vacuum oven to give the title compound as a white solid (173 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[F:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:14]([C:13]2[CH:19]=[CH:20][C:10]([F:9])=[CH:11][CH:12]=2)=[O:15])[CH:3]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Cc1cc(Cl)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1cc(Cl)ccn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.6 %

Procedure:
To a cold (0° C.) solution of 4-chloro-2-picoline (5.0 g, 39 mmol) and ethyl 4-fluorobenzoate (6.6 g, 39 mmol) in tetrahydrofuran (100 mL) was added lithium bis(trimethylsilyl)amide (80 mL, 1.0 M in tetrahydrofuran, 80 mmol) dropwise via a pressure equalizing funnel over 30 minutes. Upon complete addition, the cold bath was removed and the resulting solution was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and methanol was added to the reaction, resulting in the formation of a white precipitate. The precipitate was collected by filtration and dried to give 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (9.6 g, 99%) as a white solid. 1H-NMR (DMSO-d6): δ 7.90 (m, 3H), 7.11 (t, 2H), 6.56(s, 1H), 5.67 (s, 1H), 4.14(m, 2H); 19F-NMR (DMSO-d6): δ115.67; MS m/z 250 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[CH2:10][O:9][C:8]1=[O:20].[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24].[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:19][C:14]1[CH:13]=[C:12]([CH:11]2[CH2:10][O:9][C:8](=[O:20])[N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: O=C1OCC(c2ccc(F)c(F)c2)N1CCCCCBr
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCN3C(=O)OCC3c3ccc(F)c(F)c3)CC2)c1
Temperature: 50 °C
Yield: 40.9 %

Procedure:
A mixture of 3-(5-bromopentyl)-4-(3,4-difluorophenyl)-1,3-oxazolidin-2-one (38.0 mg, 0.110 mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (26.0 mg, 0.100 mmol), NaI (23.0 mg, 0.150 mmol), and K2CO3 (14.0 mg, 0.100 mmol) in DMF (2 mL) was heated for 1 h at 50° C. The crude product was purified by preparative TLC using CH2Cl2/MeOH/isopropyl amine (19:1:0.2) to give the desired product (21 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.39-7.32 (m, 2H), 7.26-7.20 (m, 2H), 7.18-7.11 (m, 1H), 7.10-7.03 (m, 1H), 6.96 (d, 1H, J=7.6 Hz), 4.80-4.73 (m, 1H), 4.62 (t, 1H, J=7.9 Hz), 4.09-4.04 (m, 1H), 3.51-3.42 (m, 1H), 3.03 (d, 2H, J=11.7 Hz), 2.82-2.72 (m, 1H), 2.51-2.42 (m, 2H), 2.32 (t, 2H, J=7.9 Hz), 2.11 (s, 1H), 2.03-1.97 (m, 2H), 1.85-1.70 (m, 4H), 1.49 (m, 4H), 1.31-1.27 (m, 1H), 1.24 (d, 6H, J=6.9 Hz); ESMS m/e: 514.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH2:7][O:8]C2CCCCO2)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[O:20]1[CH2:21][CH2:22][N:17]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][OH:8])=[CH:15][CH:16]=2)[CH2:18][CH2:19]1
Reactant: Brc1ccc(CCOC2CCCCO2)cc1
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: OCCc1ccc(N2CCOCC2)cc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A solution of 2-(4-bromophenethoxy)tetrahydro-2H-pyran (3.42 g, 12 mmol) in toluene (9.0 ml) and morpholine (1.22 g, 14 mmol) were added to a mixture of dry palladium acetate (32.3 mg, 0.14 mmol), 2-(di-t-butylphosphino)biphenyl (86.0 mg, 0.29 mmol) and sodium t-butoxide (1.73 g, 18 mmol), and they were stirred at 70° C. for 16 hours. Water was added to the reaction mixture. After the extraction with ethyl acetate, the product was extracted from the organic layer with 1 M hydrochloric acid. The aqueous layer was neutralized with an aqueous sodium hydroxide solution and the product was extracted with ethyl acetate. The organic layer was dried to obtain 4-morpholinophenethyl alcohol in the form of a light yellow solid (2.35 g, 95%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:5](F)[CH:4]=1.F[C:15]1C=CC(C=O)=C(C)C=1>>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[CH3:15]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1F
Reactant: Cc1cc(F)ccc1C=O
Product: Cc1cc(S(C)(=O)=O)ccc1CBr

Procedure:
The titled compound is prepared analogously to 4-bromomethyl-2-fluoro-1-methanesulfonyl-benzene by replacing 3,4-difluorobenzaldehyde with 4-fluoro-2-methyl-benzaldehyde.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCCOCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCCOCCO)ccc21
Yield: 40.1 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [3-(2-hydroxy-ethoxy)-propyl]-amide (41 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (82 mg), 2-(3-amino-propoxy)-ethanol (49 mg), HBTU (91 mg), and DIEA (52 uL). LC/MS: m/z 509.8.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].C(=O)(O)[O-].[Na+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([O:22][C:23]([NH:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)C[C@@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC(=O)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O

Procedure:
D-Asparagine, 50 g., is dissolved in 500 ml. of water at 60° C., adding 70 g. of sodium bicarbonate and cooling to 20° C. The solution is treated with 68 g. of benzylchloroformate during one hour with stirring and is stirred for an additional two and a half hours. The solution is extracted three times with ether and the aqueous solution is acidified with cold concentrated hydrochloric acid. The white solid product is separated, washed with water and dried; 77 g.; m.p. 165°-166° C.; [α]D23 + 7.4° (c 2.02, DMF).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:6]([CH:18]3[CH2:24][CH:23]4[N:25]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:20]([CH2:21][CH2:22]4)[CH2:19]3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.[Pd](Cl)Cl.C(PC(C)(C)C)(C)(C)C.C(OCC)(=O)C>[F:28][C:27]([F:29])([F:30])[C:26]([N:25]1[CH:20]2[CH2:21][CH2:22][CH:23]1[CH2:24][CH:18]([CH:6]1[C:5]3[CH:4]=[CH:3][C:2]([C:34]4[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=4)=[CH:15][C:14]=3[O:13][C:12]3[C:7]1=[CH:8][CH:9]=[CH:10][C:11]=3[O:16][CH3:17])[CH2:19]2)=[O:31]
Reactant: COc1cccc2c1Oc1cc(Br)ccc1C2C1CC2CCC(C1)N2C(=O)C(F)(F)F
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: CC(C)(C)PC(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc2c1Oc1cc(-c3cccnc3)ccc1C2C1CC2CCC(C1)N2C(=O)C(F)(F)F
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of 1-[3-(3-bromo-5-methoxy-9H-xanthen-9-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone, 5k (0.505 g, 1.02 mmol) in dioxane (15 mL) were added 3-pyridylboronic acid (0.188 g, 1.53 mmol), di-tert-butylphosphine palladium (II) dichloride (35 mg), and a 2 M sodium carbonate solution (1.3 mL, 2.54 mmol), and the mixture was heated at 75° C. for 2 h under an argon atmosphere. The mixture was allowed to cool to rt and water and ethyl acetate were added. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent gradient: 50% to 95% EtOAc in heptane) to yield 0.47 g (93%) of title compound 2,2,2-trifluoro-1-[3-(5-methoxy-3-pyridin-3-yl-9H-xanthen-9-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethanone, 6k. MS m/z (MH+) 495.1.