Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=2[O:13][CH:14]([F:16])[F:15])[CH2:8][OH:9])[CH2:3][CH2:2]1>ClCCl.C(OCC)(=O)C.O=[Mn]=O>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=2[O:13][CH:14]([F:15])[F:16])[CH:8]=[O:9])[CH2:2][CH2:3]1
Reactant: OCc1ccc(OC(F)F)c(OC2CC2)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OC(F)F)c(OC2CC2)c1
Yield: 75.9 %

Procedure:
To a solution of the 3-Cyclopropyloxy-4-difluoromethoxybenzyl alcohol from Step 5 (41 g, 179 mmol) in dichloromethane (1.2 L) was added MnO2 (220 g, 2.15 mol) in four portions over 2 days. When TLC indicated the reaction was complete, the mixture was diluted with ethyl acetate and filtered through Celite® (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.), washing extensively with a succession of ethyl acetate, dichloromethane, EtOH and toluene. The combined filtrates were concentrated. Flash chromatography of the residue (silica gel; hexane/ethyl acetate 3:1 to 7:3) provided the 3-Cyclopropyloxy-4-difluoromethoxybenzaldehyde compound (31 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]=O>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]1[N:12]([CH2:11][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[C:15](=[O:14])[CH2:16][CH2:19][CH2:20]1
Reactant: COc1cccc(OC)c1C=O
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available (4-(methylsulfonyl)phenyl)methanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC the target compound. LC-MS (conditions E): tR=0.65 min.; [M+H]+: 404.07 g/mol.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][O:14][C:15]1[CH:40]=[CH:39][C:18]([NH:19][C:20]2[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:21]=2[C:22]([NH:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:23])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N:19]2[C:20]3[C:21](=[CH:33][C:34]([F:38])=[C:35]([F:37])[CH:36]=3)[C:22](=[O:23])[N:24]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:1]2=[O:2])=[CH:39][CH:40]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(Nc2cc(F)c(F)cc2C(=O)NOCc2ccccc2)cc1
Product: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(F)cc32)cc1
Yield: 45.2 %

Procedure:
Using General Method 3, the reaction of carbonyldiimidazole (6.7 g, 41.6 mmol) and crude 2-(4-methoxy-anilino)-N-benzyloxy-4,5-difluoro-benzamide (Example V, 8.0 g, 20.8 mmol) provided 3.86 g of the title compound as a solid, mp 211-212° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:22])[CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:15]([NH2:21])=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1.[C:23](Cl)(=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>ClCCl>[CH2:39]([C:40]1[N:13]([CH2:12][CH2:11][CH2:10][N:9]([CH3:8])[CH3:22])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[N:21]=1)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23]
Reactant: Cc1ccc(NCCCN(C)C)c(N)c1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCc1nc2cc(C)ccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 31.3 %

Procedure:
Triethylamine (0.557 g) was added to a solution containing N1-[3-(dimethylamino)propyl]4-methyl-1,2-benzenediamine (1.037 g) in dichloromethane (5 ml), and then a solution containing stearoyl chloride (1.515 g) in dichloromethane (5 mnl) was added thereto while being cooled with ice. After being stirred for 4.5 hours at room temperature, the reaction mixture was diluted with dichloromethane, washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (3.5 ml) was added to a solution containing the residue (1.97 g) in ethanol (20 ml). After being stiffed for 5.5 hours at 90° C., the reaction mixture was concentrated. The residue, with chloroform added thereto, was washed with 0.5N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (1.03 g) was purified by silica gel column chromatography (silica gel 30 g, chloroform:methanol=50:1-1:1), thereby yielding the entitled compound (0.714 g) as pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].C([C:22]1[C:27]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)(C)(C)C>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[S:28](=[O:30])(=[O:31])[NH:29][C:3]([CH3:13])([CH3:4])[CH3:2])=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: CC(C)(C)c1c(B(O)O)cccc1S(N)(=O)=O
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1cnc(N)c(C(=O)Nc2ccncc2)c1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 2-tert.-butyl-sulfamoyl-benzeneboronic acid gives “A64”; method 1: HPLC/MS: 1.41 min, [M+H]=426;
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.CN(C)C=O.O[C:13]1[C:22]2[C:17](=[C:18]([O:25][CH3:26])[N:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(#N)C>[Cl:4][C:13]1[C:22]2[C:17](=[C:18]([O:25][CH3:26])[N:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1cnc2c(OC)nc(OC)cc2c1O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(OC)nc(OC)cc2c1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3.5 g of oxalyl chloride in 5 ml of dry acetonitrile is added dropwise to anhydrous dimethylformamide at -30°. After 20 minutes, 7.0 g of ethyl 4-hydroxy-6,8-dimethoxy-1,7-naphthyridine-3-carboxylate is added at -30°. Reaction temperature is kept between -20° and -30° for 30 minutes, then allowed to warm up to room temperature and evaporated to dryness. Residue is taken up in chloroform, washed with cold sodium bicarbonate aqueous solution, dried over magnesium sulfate, treated with decolorizing charcoal and evaporated to dryness to yield ethyl 4-chloro-6,8-dimethoxy-1,7-naphthyridine-3-carboxylate, m.p. 200°-210°.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=1>>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])=[N:17][CH:18]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Cc1ccc(Br)nc1
Product: Cc1ccc(C#Cc2c(-c3ccccc3)noc2C)nc1
Yield: 55 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-5-methylpyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 75 mg, 55%) which was obtained as a light brown solid. MS: m/e=275.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5](/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:4][CH:3]=1.[CH2:30]([Mg]Br)[CH3:31].[Cl-].[NH4+]>[Cu]I>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:30][CH3:31])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: CCOC(=O)/C=C/c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Product: CCOC(=O)CC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a mixture of ethyl (2E)-3-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]prop-2-enoate (489 mg, 1.08 mmol) and copper (I) iodide (155 mg, 1.08 mmol) was added ethylmagnesium bromide (3.0 M in diethyl ether, 1.44 mL, 4.32 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hr. Aqueous ammonium chloride was added to the reaction mixture at 0° C. and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound (308 mg, 0.641 mmol, 59%) as a colorless amorphous.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[C:6]1([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O+]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)C>[F:1][B-:2]([F:5])([F:4])[F:3].[C:31]1([N+:30]2[C:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:17][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:14]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccccc1
Reactant: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Agent: F[B-](F)(F)F
Solvent: CCO
Product: c1ccc(-c2cc(-c3ccccc3)[n+](-c3ccccc3)c(-c3ccccc3)c2)cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
A 500 mL round-bottomed flask equipped with a condenser was charged with 2,4,6-triphenyl-pyrylium tetrafluoroborate (22.4 g, 0.056 mole), aniline (5.8 g, 0.060 mole) and ethanol (200 mL). The resulting solution was magnetically stirred and refluxed under a nitrogen atmosphere for 6 hours. The solution was cooled to room temperature, and the product 27 precipitated as greenish-yellow, crystalline solid. The product was collected by filtration and dried in a vacuum oven at 100° C. (23 g, 87% yield). Mp=253° C.
Reaction SMILES: CSC.[C:4]1([Mg]Br)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[CH:27]=[CH:28][C:29]([N:31]1[C@H:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:34][O:33][C:32]1=[O:42])=[O:30])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.[Cu]Cl>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[C@H:27]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:28][C:29]([N:31]1[C@H:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:34][O:33][C:32]1=[O:42])=[O:30])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C(C=Cc1cc(Br)ccc1OCc1ccccc1)N1C(=O)OC[C@H]1c1ccccc1
Agent: Cl[Cu]
Solvent: CSC
Solvent: C1CCOC1
Product: O=C(C[C@@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)N1C(=O)OC[C@H]1c1ccccc1
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
To a precooled (−30° C.) mixture of copper-(I) chloride (21.0 g) and dimethylsulfide (45 ml) in dry tetrahydrofuran (150 ml) was added dropwise an ethereal solution of phenylmagnesiumbromide (0.3 mol). The mixture was stirred 20 min at the same temperature and then cooled to −40° C. A solution of 3-[3-(2-Benzyloxy-5-bromophenyl)-acryloyl]-(4R)-4-phenyloxazolidin-2-one (50.0 mmol) in dry tetrahydrofuran (150 ml) was added during 10 min. The cooling bath was removed and stirring was continued for 18 hrs. The mixture was quenched with half-saturated aqueous ammonium chloride solution and the product was isolated by extraction with ethyl acetate.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29](O)=[O:30])[CH:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:13][C@H:12]1[CH3:32])=[O:10])([CH3:7])([CH3:6])[CH3:5]>>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29](=[O:30])[N:2]([CH3:3])[CH3:1])[CH:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:13][C@H:12]1[CH3:32])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CNC
Reactant: C[C@@H]1CN(CC(=O)N2CCc3ccc(C(=O)O)cc32)CCN1C(=O)OC(C)(C)C
Product: C[C@@H]1CN(CC(=O)N2CCc3ccc(C(=O)N(C)C)cc32)CCN1C(=O)OC(C)(C)C

Procedure:
Starting with dimethylamine and 1-[2-((R)-4-tert-butoxycarbonyl-3-methyl-piperazin-1-yl)-acetyl]-2,3-dihydro-1H-indole-6-carboxylic acid, the title compound was prepared by using similar methods to those described in General Procedure 1. MS: [M+H]+=431.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[S:10]([OH:12])=[O:11].FC1C(F)=C(F)C=CC=1S(Cl)(=O)=O.C(N(CC)CC)C.[Cl:33][CH2:34][CH2:35][CH2:36]I>CN(C=O)C>[Cl:33][CH2:34][CH2:35][CH2:36][S:10]([C:3]1[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=1[F:1])(=[O:12])=[O:11]
Reactant: ClCCCI
Reactant: O=S(O)c1ccc(F)c(F)c1F
Agent: O=S(=O)(Cl)c1ccc(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S(=O)(CCCCl)c1ccc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 30.6 mmol 2,3,4-trifluoro-benzenesulfinic acid (acid (prepared in analogy to example 2.20(a) from 2,3,4-trifluoro-benzenesulfonyl chloride) and 91.8 mmol triethylamine in 20 ml DMF was added 61.2 mmol 1-chloro-3-iodopropane, and the mixture stirred at room temperature for 1 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed twice with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:4) to afford the title compound. MS (m/e): 275.2 ({37Cl}M+H+, 33%), 273.1({35Cl}M+H+, 100%),
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>C1C=CC=CC=1>[CH:1]1([NH:7][C:11](=[O:12])[CH2:10][C:9](=[O:13])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: C=C1CC(=O)O1
Solvent: c1ccccc1
Product: CC(=O)CC(=O)NC1CCCCC1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A mixture of 500 ml of benzene and 99 g of cyclohexyl amine were introduced over 30 minutes to 84 g of diketene and after stirring for 4 hours at 20° C., the mixture was evaporated to dryness by distillation under reduced pressure. The residue was taken up in isopropyl ether and the solution was cooled and vacuum filtered. The recovered precipitate was dried and crystallized from isopropyl ether to obtain 137 g of N-cyclohexyl-acetylacetamide melting at 74° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24](=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])=[CH:4][CH:3]=1)[CH3:22]
Reactant: CCOC(=O)Cc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: C=CCCC(C)Nc1c(C)noc1-c1ccc(Br)cc1
Product: C=CCCC(C)Nc1c(C)noc1-c1ccc(-c2ccccc2CC(=O)OCC)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1-methyl-pent-4-enyl)-amine and [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)[N:3]=1.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(O)O.ClC1C=CC([N+]([O-])=O)=CC=1O>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)=[CH:9][CH:8]=2)[N:3]=1
Reactant: Cc1nc(-c2ccc(Br)cc2)no1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=[N+]([O-])c1ccc(Cl)c(O)c1
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)cc2)no1

Procedure:
The title compound was prepared from 4-(5-methyl-1,2,4-oxadiazol-3-yl)bromobenzene (0.58 g) and 4-boronobenzoic acid (0.4 g) as described in Description 15 as a white solid (0.64 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:14][C:15]1([CH3:23])[O:22][C:20](=[O:21])[CH2:19][C:17](=[O:18])[O:16]1.N1CCCC1C(O)=O.[CH3:32][S:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]2[C:43]=1[NH:42][CH:41]=[CH:40]2>C(#N)C>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]([C:40]1[C:39]2[C:43](=[C:35]([CH2:34][S:33][CH3:32])[CH:36]=[CH:37][CH:38]=2)[NH:42][CH:41]=1)[CH:19]1[C:20](=[O:21])[O:22][C:15]([CH3:23])([CH3:14])[O:16][C:17]1=[O:18]
Reactant: CSCc1cccc2cc[nH]c12
Reactant: O=Cc1ccc(C(F)(F)F)cc1Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Product: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3Cl)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.50 g (7.19 mmol) of 2-chloro-4-(trifluoromethyl)benzaldehyde, 1.04 g (7.19 mmol) of Meldrum's acid and 39.4 mg (0.34 mmol) of D,L-proline were added to a solution of 1.21 g (6.85 mmol) of the compound from Example 8A in 57 ml of acetonitrile. The reaction mixture was stirred at RT overnight. It was concentrated, and the residue was taken up in diethyl ether and again concentrated. 3.64 g (75% of theory, 72% purity) of the title compound were obtained and were reacted without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.CCCCCC.C([Li])CCC.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]#N)=[CH:32][N:31]=2)=[CH:26][CH:25]=1.[O:38]1CCCC1>CO>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36](=[O:38])[C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=3)=[CH:32][N:31]=2)=[CH:26][CH:25]=1
Reactant: C1CCOC1
Reactant: N#Cc1ccc(-c2ccc(Cl)cc2)nc1
Reactant: COc1ccc(Br)cc1OC
Agent: [Li]CCCC
Solvent: CO
Solvent: CCCCCC
Product: COc1ccc(C(=O)c2ccc(-c3ccc(Cl)cc3)nc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In dry tetrahydrofuran (10 ml) was dissolved 4-bromoveratrol (1.2 g). To the solution was added dropwise slowly an n-hexane solution (3.7 ml) of 15% n-butyllithium, while stirring under cooling at -68° C. to -70° C. under an atmosphere of nitrogen gas. The mixture was stirred for 20 minutes at the same temperature range for 20 minutes. Then there was added dropwise in the course of 30 minutes a solution of 2-(4-chlorophenyl)-5-cyanopyridine (0.8 g) in dry tetrahydrofuran (8 ml). The mixture was stirred at the same temperature range for 30 minutes, followed by addition of methanol (6 ml), and warming to the room temperature, slowly. The reaction mixture was concentrated, and there was added ethyl acetate (100 ml), and the solution was washed with ice-water (30 ml) once, to which was added silica gel (60 g), followed by stirring at room temperatures for 2 hours. The reaction mixture was then left standing overnight, and the silica gel was filtered off. To the filtrate was added anhydrous magnesium sulfate for drying, and the filtrate was subjected to filtration. The filtrate was concentrated, and the concentrate was purified by means of a silica gel chromatography (eluted with chloroform), followed by recrystallization from acetonitrile to obtain 2-(4-chlorophenyl)-5-(3,4-dimethoxybenzoyl)pridine (700 mg) as pale yellow granular crystals, m.p. 168° to 170° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[OH:23][C:24]1[CH:25]=[C:26]([O:33][CH:34]([CH3:36])[CH3:35])[CH:27]=[C:28]([CH:32]=1)[C:29](O)=[O:30].[Cl-].[NH4+]>C(Cl)(Cl)Cl>[OH:23][C:24]1[CH:25]=[C:26]([O:33][CH:34]([CH3:36])[CH3:35])[CH:27]=[C:28]([CH:32]=1)[C:29]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)=[O:30]
Reactant: CC(C)Oc1cc(O)cc(C(=O)O)c1
Reactant: Nc1nccs1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1cc(O)cc(C(=O)Nc2nccs2)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 53.3 %

Procedure:
After adding 2.45 g (24.5 mmol) of 2-aminothiazole, 3.40 ml (24.5 mmol) of triethylamine and 4.14 g (24.5 mmol) of 2-chloro-1,3-dimethylimidazolinium chloride to a solution of 2.40 g (12.2 mmol) of the obtained carboxylic acid in chloroform (50 ml) while cooling on ice, the mixture was stirred at room temperature for 13 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, extraction was performed with chloroform, and the organic layer was dried and then concentrated under reduced pressure. After adding 10 ml of 4N aqueous sodium hydroxide to a solution of the obtained residue in methanol (40 ml), the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then saturated aqueous ammonium chloride was added, extraction was performed with chloroform, and the organic layer was dried and then concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=100:1) to obtain 1.81 g of 5-hydroxy-3-isopropoxy-N-thiazol-2-yl-benzamide (yield: 53%) as a white solid.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]2[CH:25]=[CH:24][C:18]3=[N:19][CH:20]=[C:21](Cl)[CH:22]=[C:17]3[C:16](=[O:26])[C:15]=2[CH:27]=1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C(=O)([O-])[O-].[Na+].[Na+]>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>[Si:1]([O:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]2[CH:25]=[CH:24][C:18]3=[N:19][CH:20]=[C:21]([C:32]4[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=4)[CH:22]=[C:17]3[C:16](=[O:26])[C:15]=2[CH:27]=1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(O[Si](C)(C)C(C)(C)C)c1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A test tube fitted with a teflon septum was charged with 7-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (50 mg, 0.13 mmol), PdCl2(PPh3)2 (9 mg, 0.013 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (78 mg, 0.38 mmol), and sodium carbonate (40 mg, 0.38 mmol). The tube was evacuated and backfilled with argon three times. Fully degassed dioxane (1.2 mL) was added and the mixture was stirred at 100° C. overnight. The solution was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, concentrated in vacuo, and purified via flash chromatography (silica, 20-100% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 8.99 (d, 1H); 8.58 (d, 1H); 8.19 (d, 1H); 7.90 (d, 1H); 7.97 (s, 1H); 7.72 (dd, 1H); 7.56 (d, 1H); 7.32 (d, 1H); 7.22 (d, 1H); 5.01 (q, 1H); 3.97 (s, 3H); 1.44 (d, 3H); 0.90 (s, 9H); 0.06 (s, 3H); −0.02 (s, 3H). LRMS (APCI) calc'd for (C26H32N3O2Si) [M+H]+, 446.2; found, 446.2.