Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:23]N(C)C=O.IC>O>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][N:11]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH3:23])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CNc2nc3ccccc3s2)CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(=O)N1CCC(CN(C)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 8.7 parts of 1-acetyl-N-(2-benzothiazolyl)-4-piperidinemethanamine, 1.44 parts of a sodium hydride dispersion 60% and 270 parts of N,N-dimethylformamide was stirred for 1 hour at room temperature. 5.48 Parts of iodomethane were added dropwise slowly. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured into water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated in vacuo. The residue was purified by column chromatography (HPLC) over silica gel using a mixture of dichloromethane and methanol (98.75:1.25 by volume) as eluent. The second faction was collected and the eluent was evaporated, yielding 7.6 parts (84%) of 1-acetyl-N-(2-benzothiazolyl)-N-methyl-4-piperidinemethanamine as a residue (intermediate 52).
Reaction SMILES: [NH:1]1[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].[NH:20]([C:36]([CH3:38])=[O:37])[C@H:21]([C:33](O)=[O:34])[CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CC(=O)OCC>[NH:20]([C:36]([CH3:38])=[O:37])[C@H:21]([C:33]([N:1]1[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4])=[O:34])[CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27]
Reactant: O=C(CNC(=O)[C@@H]1CCCN1)OCc1ccccc1
Reactant: CC(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
6.4 g of H-Pro-Gly-OBzl, 4.6 g of Ac-Orn(Boc)-OH, 3.0 ml of NEM and 3.1 g of HOBt are dissolved in 30 ml of EA and then 4.8 g of DCC in 10 ml of EA are added. After the mixture has been stirred at room temperature for 24 hours, it is filtered and the filtrate is evaporated. Chromatography of the residue on silica gel (system 1) results in 4.7 g (yield: 41%) of the desired compound being isolated as a colorless powder. Rf (system 1)=0.3; MS (FAB): 519 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH3:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[N:20][CH:21]=1>>[CH3:15][C:16]1[CH:17]=[C:18]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:7][CH:8]=2)[CH:19]=[N:20][CH:21]=1
Reactant: Cc1cncc(B(O)O)c1
Reactant: BrCc1ccc(-c2ccccc2)nc1
Product: Cc1cncc(Cc2ccc(-c3ccccc3)nc2)c1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 61a (70 mg, 0.28 mmol) and 5-methylpyridine-3-boronic acid (58 mg, 0.42 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel ethyl acetate as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. Light yellow solid. Yield: 56 mg, 77%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=2.30 (d, J=0.6 Hz, 3H), 3.98 (s, 2H), 7.28-7.32 (m, 1H), 7.38-7.44 (m, 1H), 7.44-7.55 (m, 3H), 7.67 (dd, J=8.0, 0.8 Hz, 1H), 7.96-8.01 (m, 2H), 8.36 (d, J=1.6 Hz, 1H), 8.33 (d, J=1.6 Hz, 1H), 8.58 (dd, J=1.6, 0.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=18.3, 35.7, 120.4, 126.7, 128.7, 128.9, 133.1, 133.8, 134.8, 136.8, 137.0, 139.0, 147.2, 148.6, 149.8, 155.8; (ESI): m/z=260.84 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[CH:15]=[CH:14][CH2:13][CH2:12]1.C1C2C=CC(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2)CCC2C=CC(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2)C1.C1OC2C=CC(P(C3C=CC=CC=3)C3C=CC=CC=3)=C(C3C4OCCOC=4C=CC=3P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC1.C1OC2C(C3C4OCOC=4C=CC=3P(C3C=CC=CC=3)C3C=CC=CC=3)=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2O1.C1(P(C2C=CC=CC=2)C(CC(P(C2C=CC=CC=2)C2C=CC=CC=2)C)C)C=CC=CC=1>[Pd]>[O:11]1[CH:12]=[CH:13][CH2:14][CH:15]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: C1=COCC1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Pd]
Agent: CC(CC(C)P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2cc3ccc2CCc2ccc(c(P(c4ccccc4)c4ccccc4)c2)CC3)cc1
Product: O=[N+]([O-])c1ccccc1C1CC=CO1

Procedure:
In certain embodiments, the palladium catalyst used in the Heck arylation reaction may be any suitable chiral palladium catalyst known to those skilled in the art. Examples of chiral palladium catalysts suitable for the Heck arylation reaction between bromonitrobenzene (IX) and 2,3-dihydrofuran include Pd(II) and Pd(0) complexes of 2,2′-bis(diphenylphosphino)binaphyl (BINAP), other BINAP-type ligands, JosiPhos, other JosiPhos-type ligands, PhanePhos, SynPhos, DifluoroPhos, SegPhos, P-Phos, TunePhos, 2,4-bis(diphenylphosphino)pentane, and PHox. Heck arylation reactions conducted using chiral palladium catalysts may afford enantiomerically-enriched dihydrofuranyl nitrobenzene(s) (VIIIa) and/or (VIIIb), wherein R is H or F. In some embodiments, the enantiomeric excess of dihydrofuranyl nitrobenzene(s) (VIIIa) and/or (VIIIb) may be between about 5-100%, about 10-100%, about 20-100%, about 30-100%, about 40-100%, about 50-100%, about 60-100%, about 70-100%, about 80-100%, about 85-100%, about 90-100%, about 91-100%, about 92-100%, about 93-100%, about 94-100%, about 95-100%, about 96-100%, about 97-100%, about 98-100%, about 99-100%, or about 100%. Thus, any chiral compound derived from the enantiomerically-enriched compound(s) of formula (VIIIa) and/or (VIIIb) may also contain an excess of one of the two enantiomers of the compound.
Reaction SMILES: Cl[CH:2]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(#N)C>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH:2]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[CH:4]=1
Reactant: ClC(c1cccnc1)c1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C(c2cccnc2)c2cccnc2)CC1
Temperature: 80 °C
Yield: 30.6 %

Procedure:
A round bottom flask was charged with 3,3′-(chloromethylene)-dipyridine (415 mg, 2.03 mmol), tert-butyl piperazine-1-carboxylate (1.20 g, 6.45 mmol), and acetonitrile (50 mL). The reaction was heated to 80° C. for 2 hrs, concentrated under reduced pressure, and purified by silica chromatography (100% CH2Cl2 to 5% 2M NH3 in MeOH) yielding tert-butyl 4-(di(pyridin-3-yl)methyl)piperazine-1-carboxylate (220 mg, 31%). 1H NMR 400 MHz (CDCl3) δ 8.64 (d, J=2.0 Hz, 3H), 8.48 (dd, J=4.8, 1.7 Hz, 3H), 7.70 (dt, J=7.9, 1.9 Hz, 3H), 7.24 (ddd, J=7.9, 4.8, 0.7 Hz, 3H), 5.28 (s, 1H), 4.36 (s, 1H), 3.47-3.39 (m, 6H), 2.34 (s, 6H), 1.42 (s, 9H). LCMS (ESI, m/z): 355 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([N+:27]([O-:29])=[O:28])=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[CH:26]=1)(=O)=O.[C:32]([NH:36][C:37]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[C:43]([N+:45]([O-:47])=[O:46])[CH:44]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[C:32]([NH:36][C:37]([C:39]1[CH:40]=[C:41]([C:7]2[C:8]([N+:27]([O-:29])=[O:28])=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=4)=[C:12]([C:22]([NH:23][CH3:24])=[O:25])[C:11]=3[CH:26]=2)[CH:42]=[C:43]([N+:45]([O-:47])=[O:46])[CH:44]=1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)cc12
Reactant: CC(C)(C)NC(=O)c1cc(B(O)O)cc([N+](=O)[O-])c1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3cc(C(=O)NC(C)(C)C)cc([N+](=O)[O-])c3)cc12
Temperature: 99 °C
Yield: 75.7 %

Procedure:
To a mixture of 2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yl trifluoromethanesulfonate (400 mg), (3-(tert-butylcarbamoyl)-5-nitrophenyl)boronic acid (345 mg) and Cs2CO3 (846 mg) in dioxane (8 mL) and water (1.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (150 mg). The mixture was flushed with nitrogen and then heated at 99° C. for 16 hours. The mixture was diluted with water and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column (hexanes/EtOAc=3:1) to give 5-(3-(tert-butylcarbamoyl)-5-nitrophenyl)-2-(4-fluorophenyl)-N-methyl-6-nitrobenzofuran-3-carboxamide 2 (350 mg).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[C:26]([NH2:27])=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[N:22]=1>>[CH3:19][O:20][C:21]1[C:26]([NH:27][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[N:22]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: COc1ccc(N)c(OC)n1
Product: COc1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)c(OC)n1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 2,6-dimethoxypyridine-3-amine as the starting materials.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3]/[CH:4]=[CH:5]/[I:6].O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].O.S(=O)(=O)(O)O>CCOCC>[I:6]/[CH:5]=[CH:4]/[CH2:3][C:2](=[O:1])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCC(O)C/C=C/I
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCCCC(=O)C/C=C/I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6.4 g. of 4-hydroxy-1-iodo-trans-1-octene (U.S. Pat. No. 4,061,671, Ex. 4) in 25 ml. of ether, cooled in an ice-bath under argon, is added dropwise over 15 minutes, 25 ml. of a solution prepared by dissolving 100 g. of sodium dichromate dihydrate in 300 ml. of water, followed by 136 g. of sulfuric acid with ice-bath cooling and subsequent dilution to 500 ml. After addition, the mixture is stirred at room temperature for 2 hours and diluted with ether. The ether phase is separated and saved. The aqueous phase is extracted with ether. The ether solutions are combined, washed with saturated sodium chloride solution, 5% sodium thiosulfate solution, twice with saturated sodium chloride solution, dried over magnesium sulfate and taken to dryness, giving the product as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2.N1CCCCC1>C(O)C>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C=C2C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
A stirred solution of 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (52 mg, 0.15 mmol), 5-fluoro-1,3-dihydro-indol-2-one (25 mg, 0.4 mmol) in 0.4 ml of ethanol was added dropwise with anhydrous piperidine (0.04 ml). The mixture was stirred at room temperature overnight. The precipitate was filtered under reduced pressure. The resulting solid was washed with anhydrous ethanol (0.2 ml×5), purified by silica gel column chromatography with dichloromethane:methanol (10:1) as eluents to give 2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 38%) as a yellow solid.
Reaction SMILES: [CH:1]1([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[Li+].CC([N-]C(C)C)C>C1COCC1>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:1]1([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCCCCCBr
Reactant: CCCCOC(=O)C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCOC(=O)C1(CCCCCBr)CCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
Under a N2 atmosphere at −60° C., a solution of butyl cyclopentanecarboxylate (prepared according to Payne, G. B.; Smith, C. W., J. Org. Chem., 1957, 22, 1680-1682, 40.2 g, 0.236 mol) and 1,5-dibromopentane (64 mL, 0.45 mol) in dry THF (400 mL) was added drop wise to a solution of LDA (2M in THF/heptane/ethylbenzene, 200 mL, 0.40 mol) in 30 min. After 3 h, the reaction mixture was allowed to reach rt in 30 min. Then the reaction mixture was poured out into ice-cold saturated aqueous NH4Cl (1 L). The organic layer was decanted and concentrated in vacuo to a smaller volume. The aqueous layer was extracted with Et2O (3×150 mL). The combined organic layers were washed with saturated aqueous NH4Cl (3×150 mL), brine (150 mL), dried (Na2SO4) and evaporated in vacuo. The remaining residue was purified by fractional distillation to give butyl 1-(5-bromo-pentyl)-cyclopentanecarboxylate (49.1 g, >90% pure by GC, 59%) as a bright yellow liquid. bp: T=123° C. (p=0.001 Torr). 1H NMR (CDCl3): δ=4.06 (t, J=6.6 Hz, 2H), 3.38 (t, J=6.9 Hz, 2H), 2.15-2.07 (m, 2H), 1.89-1.79 (quintet, J=7.1 Hz, 2H), 1.69-1.56 (m, 8H), 1.49-1.32 (m, 6H), 1.28-1.17 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). 13C NMR (CDCl3): δ=177.7, 64.0, 54.0, 39.0, 36.0 (2×), 33.6, 32.5, 30.7, 28.5, 25.1, 24.8 (2×), 19.1, 13.6. HRMS calcd for C15H27BrO2 (M+): 318.1195, found: 318.1192.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:31]3[CH:32]=[N:33][CH:34]=[C:29]([CH3:28])[CH:30]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: Cc1cncc(B(O)O)c1
Product: Cc1cncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 36 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and (5-methylpyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.87 min, m/z=459.1 [M+H]+, m/z=457.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.79 (m, 1H) 1.85 (d, J=9.05 Hz, 1H) 2.39 (s, 3H) 2.88 (d, J=11.98 Hz, 1H) 3.15-3.30 (m, 2H) 3.37-3.49 (m, 1H) 4.15-4.25 (m, 0H) 4.83 (br. s, 0H) 7.35 (d, J=8.31 Hz, 2H) 7.67 (s, 1H) 7.85 (d, 2H) 8.02 (d, J=2.45 Hz, 1H) 8.39-8.49 (m, 2H) 8.77 (d, J=2.45 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[O:6]=[S:7]1(=[O:22])[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH:16][C:17](=[O:21])/[CH:18]=N/O)[CH:14]=[CH:15][C:8]1=2>C(OCC)(=O)C>[O:6]=[S:7]1(=[O:22])[C:8]2[C:9](=[C:12]3[C:13](=[CH:14][CH:15]=2)[NH:16][C:17](=[O:21])[C:18]3=[O:2])[CH2:10][CH2:11]1
Reactant: O=S(=O)(O)O
Reactant: O=C(/C=N/O)Nc1ccc2c(c1)CCS2(=O)=O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc3c(c2C1=O)CCS3(=O)=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
6.74 ml (126.38 mmol) of conc. sulphuric acid were introduced into a three-neck round-bottom flask with thermometer and high-efficiency condenser and heated to 70° C. 3.06 g (12.04 mmol) of N-(1,1-dioxo-2,3-dihydro-1H-1λ6-benzo[b]thiophen-5-yl)-2-[(E)-hydroxyimino]acetamide were then added in portions over the course of half an hour, during which the mixture became dark reddish brown in colour. After the addition was complete, the reaction mixture was heated to 90° C. and stirred at this temperature for one hour. For working up, the reaction mixture was allowed to cool to RT and was then added to a mixture of ice-water (110 ml) and ethyl acetate (25 ml) and briefly stirred. After separation of the phases, the solid which formed was filtered off with suction, washed with diethyl ether and dried in a drying oven at 50° C. overnight. 1.50 g of the desired compound were obtained.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([F:27])=[C:20]([C:23]([F:26])=[CH:24][CH:25]=4)[CH:21]=[O:22])=[CH:14][N:13]3[CH:28]=2)=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([F:27])=[C:20]([CH2:21][OH:22])[C:23]([F:26])=[CH:24][CH:25]=4)=[CH:14][N:13]3[CH:28]=2)=[CH:8][CH:9]=1
Reactant: O=Cc1c(F)ccc(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1c(F)ccc(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
154 mg of sodium borohydride are added portionwise to 150 mg of 3-[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-6-yl]-2,6-difluorobenzaldehyde dissolved in 20 ml of methanol. The mixture is subsequently stirred at ambient temperature for 3 hours and then the solvent is evaporated under reduced pressure. The residue is taken up between water and dichloromethane and then the organic phase is separated, dried over sodium sulphate and evaporated under reduced pressure. The residue is triturated from pentane, collected by filtration and then dried in an oven under reduced pressure. 67 mg of compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[N:6]=[C:5]2[C:19](O)=[O:20].Cl.[OH:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[N:6]=[C:5]2[C:19]([N:28]1[CH2:27][CH2:26][C:25]2[C:30](=[CH:31][CH:32]=[CH:33][C:24]=2[OH:23])[CH2:29]1)=[O:20]
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccc(F)cc12
Reactant: Oc1cccc2c1CCNC2
Agent: Cl
Product: O=C(c1nc(-c2ccc(F)cc2)nc2ccc(F)cc12)N1CCc2c(O)cccc2C1
Yield: 22.8 %

Procedure:
Reaction of 6-fluoro-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 101 (22.8% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.62 and 2.88 (2t, 2H), 3.54 and 4.05 (2t, 2H), 4.49 and 4.95 (2s, 2H), 6.35-6.79 (m, 2H), 6.85-7.07 (m, 1H), 7.42-7.45 (m, 1H), 7.64-7.80 (m, 2H), 8.04-8.10 (m 1H), 8.15-8.39 (m, 3H), 9.49 and 9.53 (2s, 1H); MS (ESI) m/z 418 ([M+H]+).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)[C:7](OCC)=[O:8]>C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[N:14]=1
Reactant: CCOC(=O)c1cc(Cl)nc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(Cl)nc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium tetrahydroborate (74 mg, 2.0 mmol) was added to a solution of ethyl 2-chloro-6-(trifluoromethyl)isonicotinate (0.50 g, 2.0 mmol, Anichem) in ethanol (17 mL) at 0° C. The mixture was stirred at 0° C. for one hour, then was allowed to warm to room temperature and stir for 2 hours. The mixture was recooled in an ice bath and was quenched by the dropwise addition of 4.0 mL 1N HCl. The pH was then adjusted to 7 by the addition of saturated sodium bicarbonate solution. The reaction was further diluted with water, and then was extracted with EtOAc. The extract was washed with brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-40% EtOAc in Hexanes afforded product as an oil (0.33 g, 79%). 1H NMR (300 MHz, CDCl3) δ 7.61 (s, 1H), 7.56 (s, 1H), 4.84 (d, J=5.2 Hz, 2H), 2.20 (t, J=5.6 Hz, 1H); LCMS (M+H)+: 212.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:13]([CH2:22][CH2:23][CH3:24])[C:14](=O)[CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8]2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:13]([CH2:22][CH2:23][CH3:24])[CH2:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8]2
Reactant: CCCN(C(=O)Cc1cccs1)C1CCc2cccc(OC)c2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCN(CCc1cccs1)C1CCc2cccc(OC)c2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 16 mg (0.05 mmol) of N-(8-methoxytetralin-2-yl)-N-propyl-2-(2-thienyl)acetamide (A4-1: R═OMe, Cy=2-thienyl) in 10 mL dry diethyl ether 0.15 mL of a 1 M solution of LiAlH4 (0.15 mmol) in dry diethyl ether were added dropwise and stirred for 20 hrs at room temperature. The reaction was terminated by adding a saturated aqueous solution of sodium hydrogen carbonate, the solution was filtered through a matrix consisting of Celite™ —MgSO4—Celite™ and subsequently washed with methylenchloride and ethyl acetate. After evaporating the organic solvents in vacuo the residue was purified by flash chromatography on silica gel with a mixture of hexane/ethyl acetate 10/1 in the presence of 0.5% (v/v) dimethylethylamine to get compound (N-(8-methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine (A5-1: R═OMe, Cy=2-thienyl)).
Reaction SMILES: C([O:3][C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:12][CH:13]1[CH2:15][O:14]1)=O.[OH-].[K+].[OH-].[Na+].O>O1CCOCC1.CCOC(C)=O>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[O:11][CH2:12][CH:13]([CH2:15][OH:14])[O:3][C:4]=2[CH:9]=1
Reactant: O=COc1cc(Br)ccc1OCC1CO1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: OCC1COc2ccc(Br)cc2O1
Yield: 91.4 %

Procedure:
5-bromo-2-(oxiran-2-ylmethoxy)phenyl formate (12.6 g, 46.0 mmol) was dissolved in dioxane (50 ml) and KOH (10%)/NaOH (20%) was added. Water and EtOAc was added and the phases were separated. The combined organic phases were washed with brine and dried to give the title compound (10.3 g). MS m/z (rel. intensity, 70 eV) 245 (M+, 96) 244 (M+, bp), 213 (29), 189 (46), 188 (49).