Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH2:24])=[C:14]([O:16]CC3C=CC=CC=3)[CH:15]=2)=[CH:6][CH:5]=1>CCO.O.[Pd]>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH2:24])=[C:14]([OH:16])[CH:15]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2cnc(N)c(OCc3ccccc3)c2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(-c2cnc(N)c(O)c2)cc1
Reaction time: 22 h
Yield: 31 %

Procedure:
To a stirring solution of 4-(6-amino-5-benzyloxy-pyridin-3-yl)-benzoic acid methyl ester (10.0 g, 0.03 mol) in EtOH:H2O (95:5, 600 mL) was added Pd/C (15.9 g, 0.015 mol) (the reaction was de-gassed under vacuum). The solution was allowed to stir under an H2 atmosphere for 22 hr. The solution was filtered through wet celite and the celite washed with EtOH. The filtrate was concentrated under vacuum to yield 4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoic acid methyl ester (2.3 g, 9.3 mmol, 31%). 1H NMR (MeOD, 300 MHz) δ 3.90 (s, 3H), 7.21 (d, 1H, J, 1.9 Hz), 7.62 (d, 2H, J, 8.5 Hz), 7.76 (d, 1H, J, 1.9 Hz), 8.04(d, 2H, J, 8.5 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]([Cl:18])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=O)[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)S(O)(=O)=O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH3:17])=[CH:14][CH:15]=2)[C:5]([Cl:18])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: CCc1ccc(C(=O)c2cc(Br)c(OC)cc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(Cc2cc(Br)c(OC)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a solution of (5-bromo-2-chloro-4-methoxyphenyl)(4-ethylphenyl)methanone (AR) (7.08 g, 20 mmol) in 2,2,2-trifluoroacetic acid (50 mL) was added triethylsilane (4.65 g, 40 mmol) under argon. After stirring for 10 min at room temperature, trifluoromethane-sulfonic acid (0.1 mL) was added. The reaction temperature was raised to reflux. After stirring for 2 h, TLC showed the reaction was complete. The reaction mixture was evaporated and the residue was dissolved in EtOAc (150 mL). The organic layer was washed with H2O, NaHCO3 and brine. After drying over anhydrous Na2SO4, it was filtered and concentrated to give AS as a yellow oil (6.18 g, yield 91%). 1H-NMR (CDCl3, 300 MHz) δ 7.33 (s, 1H), 7.13 (m, 4H), 6.92 (s, 1H), 3.99 (s, 2H), 3.87 (s, 3H), 2.52 (q, J=7.5 Hz, 2H), 1.23 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CS(Cl)(=O)=O.[S:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1=[O:37].[H-].[Na+]>CCN(CC)CC>[CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:33]3[C:34](=[O:36])[CH2:35][S:31][C:32]3=[O:37])=[CH:22][CH:23]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: C=C(c1ccc(CO)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: O=C1CSC(=O)N1
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: C=C(c1ccc(CN2C(=O)CSC2=O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Yield: 38.6 %

Procedure:
Adopting the procedure outlined for example 9 using 40.0 mg (0.12 mmol) of {4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-phenyl}-methanol, 0.05 mL of Methanesulfonyl chloride, 0.10 mL of NEt3, 280 mg of thiazolidine-2,4-dione, and 57 mg of NaH, 20.1 mg of the product was obtained.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][S:15]([NH:18][CH3:19])(=[O:17])=[O:16])[CH:12]=2)[NH:7][CH:6]=1.[CH3:20][O:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:20][O:21][C:22]1[C:27]([N:28]2[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH2:4][C:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][S:15]([NH:18][CH3:19])(=[O:17])=[O:16])[CH:12]=4)[NH:7][CH:6]=3)[CH2:32][CH2:33]2)=[CH:26][CH:25]=[N:24][CH:23]=1
Reactant: COc1cnccc1N1CCNCC1
Reactant: CNS(=O)(=O)Cc1ccc2[nH]cc(CCCI)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNS(=O)(=O)Cc1ccc2[nH]cc(CCCN3CCN(c4ccncc4OC)CC3)c2c1
Yield: 52 %

Procedure:
A solution of 3-(3-iodopropyl)-N-methyl-1H-indole-5-methanesulfonamide (0.556 g, 1.26 mmol), 1-(3-methoxy-4-pyridinyl)piperazine (0.4 g, 2.02 mmol), and K2CO3 (0.5 g, 3.6 mmol) in 30 mL of MeCN was heated to reflux for 12 h. The reaction mixture was cooled, concentrated in vacuo, and the residue dissolved EtOAc. The EtOAc solution was washed with water, dried (MgSO4), filtered and concentrated in vacuo. Silica gel chromatography (100:3:1 CH2Cl2 -MeOH-Et3N) of the residue gave 4-(5-methoxy-4-pyridinyl)-1-[3-[5-[[(methylamino)sulfonyl]methyl]-1-H-indol-3-yl]propyl]piperazine (300 mg, 52%). The hydrochloride salt was prepared by dissolving the free base in 3 equivalents of 1.5 M HCl in EtOH. The solution was concentrated in vacuo and the residue recrystallized from MeOH to yield the title compound (380 mg, 50%): mp 100°-103° C. Anal. Calcd for C23H31N5O3S.3.8 HCl: C, 46.34; H, 5.88; N, 11.78. Found: C, 46.32; H, 6.18; N, 11.67
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][N:3]=1.C([Li])(C)(C)C.CCCCC.CN([CH:29]=[O:30])C>C1COCC1>[Cl:1][C:2]1[C:7]([CH:29]=[O:30])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (2-chloropyridin-4-yl)carbamate (1.14 gm, 5 mmol) in dry THF (20 mL) was cooled to −70° C. under an inert atmosphere and 1.7 M t-butyl lithium/pentane (8 mL, 13.5 mmol) was slowly added. The reaction was stirred for two hours and then dry DMF (1.2 mL, 15.5 mmol) was added. The reaction was allowed to slowly warm to room temperature over a three hour period. The reaction mixture was quenched with 3 N HCl (12 mL) and diluted with diethyl ether. The ether layer was washed with aqueous NaHCO3, dried (over Na2SO4), filtered and evaporated. The residue was triturated with cold diethyl ether to give pure t-butyl (2-chloro-3-formylpyridine-4-yl)carbamate. The mother liquors were chromatographed on silica gel eluting with 15-20% ethyl acetate/hexane to give additional product. 1H-NMR (500 MHz, CDCl3): δ 11.0 (1H, br s), 10.52 (1H, s), 8.38 (1H, d, J=6 Hz), 8.31 (1H, d, J=6 Hz), 1.54 (9H, s); m/e (m+1): 257.2.
Reaction SMILES: C(OC(=O)[O:7][CH2:8][C@@H:9]1[C@H:13]([CH2:14][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:16]([CH3:18])[CH3:17])[CH2:12][N:11]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10]1)(C)(C)C.CC[O-].[Na+]>CCO>[C:22]([O:21][C:19](=[O:20])[N:15]([CH2:14][C@H:13]1[C@@H:9]([CH2:8][OH:7])[CH2:10][N:11]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:12]1)[CH:16]([CH3:17])[CH3:18])([CH3:24])([CH3:25])[CH3:23]
Reactant: CC(C)N(C[C@@H]1CN(Cc2ccccc2)C[C@@H]1COC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)N(C[C@@H]1CN(Cc2ccccc2)C[C@@H]1CO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of carbonic acid (3R*,4S*)-1-benzyl-4-[(tert-butoxycarbonyl-isopropyl-amino)-methyl]-pyrrolidin-3-ylmethyl ester tert-butyl ester (2.02 g, 4.31 mmol) and NaOEt (0.59 g, 8.62 mmol) in EtOH (35 mL) is stirred for 2 h at room temperature. The solvent is concentrated and the residue is diluted by CH2Cl2 and H2O. The layers are separated and the organic extract is washed successively with H2O and brine. The combined organic layers are dried with MgSO4, filtered and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 95:5) to give the title product. TLC, Rf (AcOEt)=0.23. MS (LC-MS): 363.3 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/2.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.06 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[N:13]=2)=[N:6][CH:7]=1.O.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:13]=2)=[N:6][CH:7]=1
Reactant: COC(=O)CCc1csc(Nc2ncc(Br)cc2Sc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1csc(Nc2ncc(Br)cc2Sc2ccccc2)n1
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To a mixture of methyl 3-(2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)propanoate (1.40 g, 3.11 mmol) in 50 mL THF was added 25 mL water followed by sodium hydroxide (0.249 g, 6.22 mmol) and the mixture was stirred overnight. The mixture was concentrated to dryness, water added and acidified with NH4Cl. The mixture was then extracted with THF. The organics were dried over Na2SO4 and concentrated to give the title compound (1.38 g, 102% yield) that was used as the crude material.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:3]=1.Cl[CH2:18][CH2:19][C:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:22])[CH3:21]>>[CH3:22][C:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:21])[CH2:19][CH2:18][N:6]1[C:2]([CH3:1])=[N:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=2)=[N:5]1
Reactant: CC(C)(CCCl)NC(=O)OC(C)(C)C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)n[nH]1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)nn1CCC(C)(C)NC(=O)OC(C)(C)C

Procedure:
The target compound is obtained analogously to the method described for intermediate product 1c) from 4.90 g (21.6 mmol) 5-methyl-3-(4-trifluoromethyl-phenyl)-1H-[1,2,4]triazol and 7.17 g (32.4 mmol) tert-butyl (3-chloro-1,1-dimethyl-propyl)-carbamate. White solid. Yield: 5.06 g (57%); mass spectroscopy [M+H]+=413.
Reaction SMILES: C([C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[C:17]3[CH2:26][N:25]4[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]4)[CH2:19][CH2:18]3)[C:5]=2[CH:4]=1)#N.C[Mg]Br.Cl.[CH3:31][CH2:32][O:33]CC>C1C=CC=CC=1>[C:32]([C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[C:17]3[CH2:26][N:25]4[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]4)[CH2:19][CH2:18]3)[C:5]=2[CH:4]=1)(=[O:33])[CH3:31]
Reactant: N#Cc1ccc2c(c1)C(=C1CCC3CCCCN3C1)c1ccccc1S2
Reactant: CCOCC
Agent: C[Mg]Br
Agent: Cl
Solvent: c1ccccc1
Product: CC(=O)c1ccc2c(c1)C(=C1CCC3CCCCN3C1)c1ccccc1S2
Temperature: 10 °C

Procedure:
A solution of 3.42 g. (0.01 mole) of 3-(2-cyanothioxanthen-9-ylidene)quinolizidine in 50 ml. of benzene is added to a stirred solution of 0.013 mole of methyl magnesium bromide in 5 ml. of ether and 50 ml. of benzene. The stirred mixture is heated at reflux temperature for two hours, then it is cooled to 10° C. and added slowly to 250 ml. of vigorously stirred ice-water. Excess 3 N hydrochloric acid is added to the stirred mixture. The aqueous layer is separated and then it is made alkaline with 2.5 N sodium hydroxide. The mixture is extracted with ethyl acetate. After being dried over magnesium sulfate, the extracts are concentrated. The residue is chromatographed on an alumina column using ether as the eluate. Evaporation of the appropriate fractional eluant gives 3-(2-acetylthioxanthen-9-ylidene)quinolizidine which is converted to a fumarate salt by treatment with a molar equivalent of fumaric acid in methanol.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH3:16])=[N:13][CH:14]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>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(O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:9]2[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH3:16])=[N:13][CH:14]=2)=[CH:22][CH:21]=1
Reactant: CC(=O)c1ccc(Br)cn1
Reactant: COc1ccc(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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc(C(C)=O)nc2)cc1
Reaction time: 5 h
Yield: 88 %

Procedure:
To a stirred solution of toluene and ethanol (9 mL, 2:1) of 1-(5-bromopyridin-2-yl)ethanone (200 mg, 1 mmol) was added (4-methoxyphenyl) boronic acid (304 mg, 2 mmol), 2M Na2CO3 (2.84 mL), and Pd(PPh3)4 (11 mg, 0.01 mmol) under argon atmosphere and heating was continued for 5 hours at 70° C. The reaction mixture was concentrated under vacuum and diluted with water (100 mL) and extracted with EtOAc (2×200 mL). The combined extracts were washed with brine solution (20 mL), and organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. This, on purification by flash chromatography (silica gel, 60-120μ) using 10% ethyl acetate in hexane eluent, afforded 1-(5-(4-methoxyphenyl)pyridin-2-yl)ethanone as off-white solid (200 mg, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.99 (d, 1H), 8.20 (dd, 1H), 7.97 (d, 1H), 7.76 (d, 2H), 7.07 (d, 2H), 3.81 (s, 3H), 2.63 (s, 3H); LC-MS m/z calculated for [M+H]+ 228.27. found 228.4.
Reaction SMILES: [CH2:1]([N:4]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)(=[O:22])=[O:21])[C@@H:5]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7])[CH:2]=[CH2:3].B1C2CCCC1CCC2.Br[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CN(C=O)C.C(OCC)(=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.O>[CH2:13]([O:12][C:10](=[O:11])[C@H:5]([N:4]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)(=[O:22])=[O:21])[CH2:1][CH2:2][CH2:3][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[C:6]([CH3:9])([CH3:8])[CH3:7])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=CCN([C@@H](C(=O)OCc1ccccc1)C(C)(C)C)S(=O)(=O)c1cccc(OC)c1
Reactant: Brc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(S(=O)(=O)N(CCCc2cccnc2)[C@@H](C(=O)OCc2ccccc2)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 59 %

Procedure:
To a solution of benzyl N-allyl-N-[(3-methoxyphenyl)sulfonyl]-3-methyl-D-valinate (222.6 mg, 0.5 mmol) in THF (1 mL) cooled to 0° C. is slowly added a 0.5M solution of 9-BBN (3.0 mL, 1.50 mmol) in THF. The mixture is slowly warmed to room temperature and stirred for two days. This solution is then added to a separate flask containing 3-bromopyridine, Pd(PPh3)4 (57.7 mg, 0.05 mmol), and potassium carbonate (276.2 mg, 2 mmol) in DMF (3.3 mL). The resulting mixture is heated to 70° C. and stirred overnight. The reaction is diluted with ethyl acetate and poured into water. The aqueous layer is extracted three times with ethyl acetate, and the combined organic extracts are washed with brine, dried with sodium sulfate, and concentrated. The crude residue is purified by column chromatography eluting with a gradient of 15-100% ethyl acetate in heptane to yield the desired product as a clear oil (130 mg, 59%). 1H NMR (CDCl3, 400 MHz); δ 8.48 (d, 1H, J=4), 8.43 (s, 1H), 7.58 (d, 1H, J=8), 7.35-7.33 (m, 3H), 7.29-7.27 (m, 1.5H), 7.25-7.23 (m, 1.5H), 7.19-7.18 (m, 2H), 7.05-7.03 (d, 1H, J=8), 4.87 (d, 1H, J=12), 4.69-4.66 (d, 1H, J=12H), 4.36 (s, 1H), 3.74 (s, 3H), 3.57 (m, 1H), 3.18 (m, 1H), 2.58 (t, 2H, J=4), 2.41 (m, 1H), 2.05 (m, 1H), 1.05 (s, 9H). Mass spectrum (511.5; M+1).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:21]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=1>>[C:21]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:22]=[CH:23][C:24]([CH2:27][N:1]2[CH:2]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]2=[O:9])=[CH:25][CH:26]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccc(-c2ccccc2)cc1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available [1,1′-biphenyl]-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=1.00 min.; [M+H]+: 416.23 g/mol.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][C:11]([NH2:13])=[S:12])=[CH:4][C:3]=2[O:2]1.BrBr.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[NH2:13][C:11]1[S:12][C:6]2[CH:7]=[C:8]3[O:9][CH2:1][O:2][C:3]3=[CH:4][C:5]=2[N:10]=1
Reactant: NC(=S)Nc1ccc2c(c1)OCO2
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1nc2cc3c(cc2s1)OCO3
Reaction time: 1 h

Procedure:
3,4-Methylenedioxyphenylthiourea (1.96 g; Lancaster Chemical Co) in chloroform (6 cm3) was stirred at ambient temperature and a solution of bromine (0.37 cm3) in chloroform (3 cm3) was added in portions. The mixture was cooled using a water bath and after 1 hr. was stored for 64 hr., diluted with water (100 cm3), basified with aqueous 2M sodium hydroxide and extracted with ethyl acetate (2×150 cm3). The combined organic phases were washed with water and dried (magnesium sulphate). The solution was evaporated under reduced pressure to give the required product as a pale pink solid; mp 200° C.; 1H NMR (CDCl3): δ7.06 (1H,s); 7.02(1H,s); 5.98(2H,s); 5.0(broad signal, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]2[C:12]([Br:13])=[CH:11][CH:10]=[CH:9][C:6]=2[C:7]=1[CH3:8]>ClCCl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[O:4][C:5]2[C:12]([Br:13])=[CH:11][CH:10]=[CH:9][C:6]=2[C:7]=1[CH3:8])=[O:1]
Reactant: Cc1c(CO)oc2c(Br)cccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1c(C=O)oc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
0.7 g (7.92 mmol) of manganese dioxide is added to a solution of 0.38 g (1.58 mmol) of 2-hydroxymethyl-3-methyl-7-bromobenzofuran in 10 ml of dichloromethane. The solution is stirred at room temperature for 16 h and 0.7 g (7.92 mmol) of manganese dioxide is again added. After stirring for 24 h at room temperature, the manganous precipitate is filtered off and the filtrate is concentrated under vacuum. The residue is purified by silica column chromatography (elution solvent: 10% ethyl acetate in cyclohexane). 0.25 g (Yield: 66%) of 2-formyl-3-methyl-7-bromobenzofuran is obtained in the form of a yellow wax.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:27](I)=[C:26]([NH:29][C:30](=[O:32])[CH3:31])[N:25]([CH3:33])[N:24]=1>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:27]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:26]([NH:29][C:30](=[O:32])[CH3:31])[N:25]([CH3:33])[N:24]=1
Reactant: C#Cc1ccccc1
Reactant: CC(=O)Nc1c(I)c(-c2ccccc2Cl)nn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(C#Cc2ccccc2)c(-c2ccccc2Cl)nn1C
Temperature: 85 °C
Yield: 47 %

Procedure:
To a degassed solution of phenylacetylene (157 μl, 1.43 mmol) and Et3N (3.3 mL) in DMF (1.2 mL) were added N-(3-(2-chlorophenyl)-4-iodo-1-methyl-1H-pyrazol-5-yl)acetamide (413 mg, 1.1 mmol), CuI (42 mg, 0.22 mmol) and PdCl2(PPh3)2 (77 mg, 0.11 mmol). The mixture was flushed with N2 and then heated to 85° C. for 3 h. The reaction mixture was concentrated in metro and the residue was purified by column chromatography (silica gel, gradient 0 to 100% ethyl acetate/isohexane) yielding N-(3-(2-chlorophenyl)-1-methyl-4-(phenylethynyl)-1H-pyrazol-5-yl)acetamide as a solid (181 mg).
Reaction SMILES: [CH:1]1([C:4]2[CH:25]=[N:24][C:7]3[O:8][CH2:9][CH2:10][N:11]([C:12]([C:14]4[CH:19]=[C:18]([Br:20])[C:17]([O:21]C)=[C:16]([Br:23])[CH:15]=4)=[O:13])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.B(Br)(Br)Br.[OH-].[Na+]>ClCCl>[CH:1]1([C:4]2[CH:25]=[N:24][C:7]3[O:8][CH2:9][CH2:10][N:11]([C:12]([C:14]4[CH:15]=[C:16]([Br:23])[C:17]([OH:21])=[C:18]([Br:20])[CH:19]=4)=[O:13])[C:6]=3[CH:5]=2)[CH2:2][CH2:3]1
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ncc(C4CC4)cc32)cc1Br
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ncc(C3CC3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.7 %

Procedure:
To a 10 ml flask, (7-cyclopropyl-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl)-(3,5-dibromo-4-methoxy-phenyl)-methanone (9.0 mg, 0.019 mmol) was dissolved in dichloromethane, and then cooled to 0□. 1.0M Boron tribromide dissolved in dichloromethane (0.2 ml*2, 0.203 mmol) was added thereto and then stirred at room temperature for 16 hours. The pH was adjusted to 6 with 1N sodium hydroxide solution and the reaction mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure to obtain solid. The resulting solid was recrystallized from dichloromethane to obtain white solid (6.7 mg, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH:13]([OH:29])[CH2:12]1.[H-].[Na+].[CH3:32]I.O>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH:13]([O:29][CH3:32])[CH2:12]1
Reactant: COc1cccc(OC)c1C1CC(O)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(OC)c1C1CC(OC)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A cooled (0° C.) solution of rac-(3S*,5S*)-5-(2,6-dimethoxyphenyl)-3-hydroxy-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one (53 mg; 0.12 mmol) in anh. THF (3 ml) was treated with NaH (60% dispersion in mineral oil; 6 mg; 0.14 mmol). Stirring was continued at 0° C., under nitrogen, for 5 min., and then at rt for 20 min. The mixture was again cooled to 0° C., and a solution of CH3I (20 mg; 0.14 mmol) in anh. THF (1 ml) was added. The obtained mixture was further stirred at 0° C. for 5 min., and then at rt for 17 h. Water and AcOEt were added, and the separated aq. layer was further extracted with AcOEt. The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=30/1) afforded rac-(3S*,5S*)-5-(2,6-dimethoxyphenyl)-3-methoxy-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one as a yellow oil. LC-MS (conditions A): tR=0.88 min.; [M+H]+: 426.19 g/mol.