Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[CH3:2].[CH3:23][N:24]1[CH:28]([CH2:29][CH2:30]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:27][N:26]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=2)[C:25]1=[O:53].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:30][CH2:29][CH:28]2[CH2:27][N:26]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:51])([F:52])[F:50])=[CH:45][CH:44]=3)[C:25](=[O:53])[N:24]2[CH3:23])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1cccc(O)c1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1cccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)c1)Oc1ccccc1
Temperature: 55 °C

Procedure:
To a solution of 3-(3-Hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (Isomer 2) (43 mg, 0.143 mmol,) and Toluene-4-sulfonic acid 2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (Isomer 2) (72 mg, 0.157 mmol) in DMF (1 ml) at 23° C. is added Cs2CO3 (61 mg, 0.186 mmol) and the suspension heated at 55° C. for 7 hours. The mixture is cooled, filtered, and the filter cake washed with DMF (10 ml). The filtrate is poured into 1N HCl (35 ml) and extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with water (25 ml), brine (20 ml), dried (Na2SO4) and concentrated to an oil. Purification by flash chromatography on a Biotage silica cartridge (gradient elution, 4:1 hexanes:acetone to 1:1 hexanes:acetone) provided an oil, (72 mg, 87%) (diastereomer 4).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C([Li])CCC.C(NCC)C.C([N:21]([CH2:33][CH3:34])[C:22](=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:24]=1[CH3:31])C.C[Si](NC[C:41]1[CH:46]=[CH:45]C=[CH:43][CH:42]=1)(C)C.C[Si](C)(C)N[Si](C)(C)C.C(=O)C1C=CC=CC=1.Cl>CCCCCC.C1COCC1>[CH3:30][O:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]2[C:24]=1[CH:31]=[C:33]([C:34]1[CH:45]=[CH:46][CH:41]=[CH:42][CH:43]=1)[NH:21][C:22]2=[O:32]
Reactant: CCN(CC)C(=O)c1cccc(OC)c1C
Reactant: C[Si](C)(C)NCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O=Cc1ccccc1
Product: COc1cccc2c(=O)[nH]c(-c3ccccc3)cc12
Reaction time: 2 h
Yield: 15 %

Procedure:
To a solution of 4.53 mmol of LDA at -78° (generated by adding a 3 ml of 1.55M n-butyllithium in n-hexane to 0.33 g of diethylamine in 5 ml of THF) was added 1.0 g (4.52 mmol) of N,N-diethyl-3-methoxy-2-methylbenzamide in 10 ml THF. Then a solution of 4.53 mmol of trimethylsilyl benzylamine [generated from 0.81 (4.53 mmol) of hexamethyldisilazane in 2 ml of n-hexane added to 3 ml of 1.55N n-butyllithium followed by the addition of 0.48 g (4.53 mmol) of benzaldehyde in 2 ml of n-hexane] was added and stirring continued at -78° for two hours and then at room temperature for one hour. The reaction was cooled to 0° and 50 ml of 1N HCl was added. The red-purple solution became yellow. The mixture was extracted with ether, the ether extracts were washed with 1N HCl, dried (MgSO4), and concentrated. The residue was triturated with ethanol to give 0.17 g (15%) of product; mp 227°-231°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.[H-].[Na+].C([Li])(CC)C.C1CCCCC1.Cl.[C:28](=O)(O)[O-:29].[Na+]>CN(C)C=O.O1CCCC1>[CH:11]([C:9]1[CH:10]=[C:2]([CH:28]=[O:29])[CH:3]=[C:4]2[C:8]=1[NH:7][N:6]=[CH:5]2)([CH3:13])[CH3:12]
Reactant: CC(C)c1cc(Br)cc2cn[nH]c12
Reactant: O=C([O-])O
Agent: Cl
Agent: [H-]
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)c1cc(C=O)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
5-Bromo-7-isopropyl-1H-indazole (3.1 g, 12.1 mmol) and sodium hydride (0.34 g, 1.1 equiv.) were weighed into a flame-dried round-bottom flask containing a magnetic stir bar. Under a nitrogen atmosphere at room temperature, dry tetrahydrofuran (18 mL) was added. The mixture was stirred at room temperature for 15 min, during which time it became homogeneous. The stirred mixture was cooled to −78° C. and a solution of sec-butyllithium in cyclohexane (1.4M, 20 mL, 2.2 equiv.) was added over several minutes. After 1 h at −78° C., dimethylformamide (3.0 mL) was slowly added and the mixture allowed to warm to room temperature overnight. The solution was cooled to 0° C. and carefully treated with 1 N hydrochloric acid (35 mL). After a few minutes, solid sodium bicarbonate was added until a pH of 9–10 was attained. The two layers were separated and the aqueous phase washed twice with ethyl acetate. The combined organic layers were washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography gave 2.1 g (92%) of pure material. LC/MS: tR=1.15 min, 189.12 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2([CH2:19][CH2:20][CH2:21][C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=3)[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1>C(O)(=O)C.[Fe]>[NH2:30][C:26]1[CH:25]=[C:24]([C:23]#[C:22][CH2:21][CH2:20][CH2:19][C:12]2([S:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)(=[O:11])=[O:10])[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])[CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(S(=O)(=O)C2(CCCC#Cc3cccc([N+](=O)[O-])c3)SC(=O)NC2=O)cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)C2(CCCC#Cc3cccc(N)c3)SC(=O)NC2=O)cc1

Procedure:
A sample of 5-(4-methoxybenzenesulfonyl)-5-[5-(3-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione of Example 118 was reduced with iron in acetic acid to give the title compound as crystals, m.p. 135-138° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7]([NH:16][C:17](=[O:33])[CH:18]([NH:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Cl)=[CH:39][CH:38]=1>>[C:1]([O:5][C:6](=[O:34])[CH:7]([NH:16][C:17](=[O:33])[CH:18]([NH:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:41][C:40]2[CH:43]=[CH:44][C:37]([O:36][CH3:35])=[CH:38][CH:39]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(O)cc1)C(=O)OC(C)(C)C
Product: COc1ccc(COc2ccc(CC(NC(=O)C(CC(C)C)NC(=O)N3CCCCCC3)C(=O)OC(C)(C)C)cc2)cc1
Yield: 135.9 %

Procedure:
In a manner similar to the procedure described in Example 27, the product from Example 24 (0.2 g, 0.42 mmol) and 4-methoxybenzyl chloride (75 mg, 0.42 mmol) were converted to the title compound (0.34 g).
Reaction SMILES: O=[C:2]([CH3:18])[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:4][C:5]([O:7][CH3:8])=[O:6].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:18][C:2]1[O:11][C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][C:3]=1[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(NC(=O)c1cccnc1)C(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)Cc1nc(-c2cccnc2)oc1C
Temperature: 0 °C
Yield: 108.7 %

Procedure:
Intermediate 32 (110 mg) was treated with phosphorous oxychloride (0.51 ml) in toluene (2 ml) and the mixture heated under reflux for 3.5 h. The mixture was poured into ice cold saturated aqueous sodium bicarbonate (30 ml) and extracted with dichloromethane (20 ml). The organic layer was evaporated in vacuo to give a yellow gum (111 mg).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[C:27]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:37]2[CH2:36][CH2:35][N:34]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:39][CH2:38]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(CCCCC2(C(=O)NCC(F)(F)F)c3ccccc3-c3ccccc32)CC1

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and Boc-piperazine.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11](Cl)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[CH3:23][NH:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[Fe+2].C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][C:10]1[C:11]([N:24]([CH3:23])[C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccnc1Cl
Reactant: CNc1cccnc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CN(c1cccnc1)c1ncccc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 82.9 %

Procedure:
3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloropyridine (1 g), tris(dibenzylideneacetone)-dipalladium(0) (89 mg), 1,1-bis(diphenylphosphino)ferrocene (108 mg), sodium tert-butoxide (559 mg), and 3-(methylamino)pyridine (629 mg) were combined, and 20 mL toluene was added. The mixture was heated 100 C under Ar for 16 h, then cooled to room temperature and filtered through celite, washing with CH2Cl2. The filtrate was concentrated and purified via flash chromatography to give 1.06 g of 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-N-methyl-N-pyridin-3-ylpyridin-2-amine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[C:4]([CH3:20])=[N:3]1>C(O)C.[Pd]>[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:5]1[C:4]([CH3:20])=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: Cc1nn(C)c(C(N)=O)c1Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1nn(C)c(C(N)=O)c1Nc1ccccc1N
Yield: 92.7 %

Procedure:
8.6 g of 1,3-dimethyl-4-[(2-nitrophenyl)amino]pyrazole-5-carboxamide in 400 ml of ethanol are hydrogenated over 0.8 g of 10% strength palladium-on-charcoal for 1 hour at 50° C. analogously to Experiment 1. The mixture is filtered; the filtrate is concentrated to dryness, and the residue from evaporation is recrystallized from 160 ml of ethyl acetate and 120 ml of cyclohexane to yield 7.1 g of 4-[(2-aminophenyl)amino]-1,3-dimethylpyrazole-5-carboxamide, mp 182° to 184° C. (dec.).
Reaction SMILES: Cl.NO.[CH2:4]([O:6][C:7](=[O:24])[C:8]([C:13](=[O:23])[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[CH:9][N:10](C)C)[CH3:5].C([O-])(=O)C.[Na+].O1CCCC1>CO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[N:10][O:23][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:24])[CH3:5]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cnoc1-c1ccc([N+](=O)[O-])cc1
Yield: 45.8 %

Procedure:
Hydroxylamine hydrochloride (0.69 g.; 0.01 mol.) was added to a mixture of ethyl-2-(4'-nitrobenzoyl)-3-dimethylaminopropenoate (2.93 g.; 0.01 mol.) and anhydrous sodium acetate (0.82 g.; 0.01 mol.) in 50 ml. of tetrahydrofuran and 25 ml. of methanol. The resultant mixture was stirred at 25° C. for 16 hours until the reaction was complete. The reaction mixture was filtered and the solvent removed from the filtrate by concentration in vacuo. The residue was dissolved in chloroform, extracted with water, dried over magnesium sulfate and then concentrated in vacuo. Recrystallization with ethanol yielded ethyl-5-(4'-nitrophenyl)-4-isoxazolecarboxylate as a white solid (1.2 g.; 45.8% yield) having a melting point of 73°-76° C. and the following analysis:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:17]([O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)[CH2:18][CH3:19]>CCOC(C)=O>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH2:17][CH2:18][CH3:19])[CH:26]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: CCCOc1cccc(B(O)O)c1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Solvent: CCOC(C)=O
Product: CCCOc1cccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)c1

Procedure:
2,2-Dimethyl-1-[2-(3-propoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 3-propyloxybenzene boronic acid following general procedures as described in these Examples. Silica gel chromatography using 30-70% EtOAc in hexanes as eluant provided 56 mg (38%) of a yellow solid. MP 179-180° C., M+H=338.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][C:3]=1[OH:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(O)[C:28]#[CH:29])=[CH:23][CH:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1COCC1>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:18][C:3]3[CH:4]=[C:5]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:6]4[C:11]([C:2]=3[CH:29]=[CH:28]2)=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:23][CH:22]=1
Reactant: C#CC(O)(c1ccccc1)c1ccc(OC)cc1
Reactant: Oc1cc(N2CCOCC2)c2ccccc2c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C2(c3ccccc3)C=Cc3c(cc(N4CCOCC4)c4ccccc34)O2)cc1
Yield: 16.1 %

Procedure:
0.91 g of 1-chloro-4-morpholino-2-naphthol are allowed to react with 0.95 g of 1-(p-methoxyphenyl)-1-phenyl-2-propyn-1-ol in 30 ml of THF under reflux for 4 hours in the presence of 0.72 g of p-toluene sulfonic acid. The solution is then neutralized with 30 ml of 1N sodium hydroxide and then extracted twice with 30 ml of toluene. The organic phases are evaporated and then the photochrome is separated by chromatography on an alumina column in eluting with a mixture of ethyl acetate/diisopropyl ether (10/90). 250 mg of 3-(p-methoxyphenyl)-3-phenyl-6-morpholino-[3H]-naphtho-[2,1-b]pyran (compound II) are thus obtained. Its structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:4]=1O.COC1C=C(SC)C(F)=CC=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:43][CH2:44][CH2:45][OH:46].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[C:4]([O:46][CH2:45][CH2:44][Cl:43])=[CH:5][C:6]=1[F:10]
Reactant: COc1cc(F)c(F)cc1O
Reactant: OCCCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COc1cc(SC)c(F)cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(F)c(F)cc1OCCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of a mixture of 2-methoxy-4,5-difluoro-phenol (Intermediate 55) and 2-methoxy-4-methylthio-5-fluoro-phenol (Intermediate 56) (0.66 g), triphenylphosphine (2.16 g), 2-chloroethanol (0.55 ml) in tetrahydrofuran (15 ml) was slowly added diethyl azodicarboxylate (1.3 ml). The reaction was stirred at room temperature for 2 hours. Tetrahydrofuran was removed under vacuum. Chromatography (10% ethyl acetate-hexanes) afforded 0.31 g of 1,2-difluoro-4-(2-chloroethoxy)-5-methoxy-benzene (Intermediate 57) as a white solid: mp 51-52° C.; MS EI m/e 222 (M+), and 0.1 g of 1-fluoro-2-methylthio-4-(2-chloroethoxy)-5-methoxy-benzene (Intermediate 62) as a white solid: mp 58-60° C.; MS EI m/e 250 (M+).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8]([NH:11][C:12]1[CH:21]=[CH:20][C:15]([S:16](Cl)(=[O:18])=[O:17])=[CH:14][CH:13]=1)(=[O:10])[CH3:9].O>CC(C)=O>[C:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([S:16]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])(=[O:18])=[O:17])=[CH:20][CH:21]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCNCCO
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(S(=O)(=O)N(CCO)CCO)cc1
Temperature: 5 °C

Procedure:
Step 1) Diethanolamine (105 parts) was added dropwise over 10 minutes to a stirred mixture of N-acetyl sulphanilyl chloride (93.5 parts), water (400 parts) and acetone (200 parts) while maintaining the temperature at approximately 5° C. The mixture was allowed to warm to room temperature and stirred over night. The resultant 4-acetylamino-N,N-bis-(2-hydroxyethyl)benzenesulphonamide (103 parts) was isolated by filtration, washed with water and dried.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[C:29]([NH2:31])=[O:30])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.BrC1C=CC=CC=1C(N)=O>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=3[C:29]([NH2:31])=[O:30])=[CH:25][N:26]=2)=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2ccccc2C(N)=O)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: NC(=O)c1ccccc1Br
Product: NC(=O)c1ccccc1-c1cnc(C(=O)CCCCCCc2ccccc2)o1
Yield: 100 %

Procedure:
2-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)benzamide. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (52 mg, 0.083 mmol) and 2-bromobenzamide following General Procedure A. Flash chromatography (20-40% EtOAc/hexanes) yielded the title compound as a white solid (39 mg, 100%): 1H NMR (CDCl3, 600 MHz) δ 7.70 (d, 1H, J=7.8 Hz), 7.60 (s, 1H), 7.51-7.48 (m, 2H), 7.39-7.36 (m, 1H), 7.25-7.23 (m, 2H), 7.16-7.13 (m, 3H), 6.48 (br s, 1H), 6.19 (br s, 1H), 4.88 (t, 1H, J=6.0 Hz), 2.57 (t, 2H, J=7.5 Hz), 1.93-1.87 (m, 2H), 1.59-1.56 (m, 2H), 1.44-1.30 (m, 6H), 0.87 (s, 9H), 0.09 (s, 3H), −0.02 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 170.4, 143.6, 137.6, 134.4, 132.5, 131.3, 130.7, 129.7, 129.2, 129.1, 128.6, 128.5, 126.4, 120.1, 69.3, 37.3, 36.8, 32.2, 30.0, 26.6, 26.6, 25.9, 19.0, −4.0, −4.3.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13](I)[CH:14]=1)=[O:8])[CH3:5].[Li+].[Cl-].CCN(C(C)C)C(C)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C=O)C.CCOC(C)=O.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]>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13]([C:34](=[O:36])[CH3:35])[CH:14]=1)=[O:8])[CH3:5]
Reactant: CC(=O)OC(C)=O
Reactant: COCC(C)NC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCC(C)NC(=O)c1cc(C(C)=O)cc(-c2ccc(C)cc2)c1
Temperature: 150 °C
Yield: 75 %

Procedure:
To a stirring solution of 5-iodo-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (1.0 g, 1 eq) in 3 ml anhydrous DMF were added LiCl (520 mg, 5 eq), Pd2(dba)3 (18.34 mg, 1.3% eq), DIPEA (0.8545 ml, 2 eq) and acetic anhydride (1.1636 ml, 5 eq) at room temperature, and the reaction mixture was heated under microwave irridiation at 150° C. for one hour. The reaction mixture was diluted with EtOAc, and the organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with hexane ethyl acetate (8:1 to 2:1), giving 5-acetyl-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (538 mg, 75%), MS (M+H)=326.
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[N:10]([CH3:11])[C:9](=[O:12])[N:8]([CH3:13])[C:7](=[O:14])[CH:6]=1.[Cl:15]N1C(=O)CCC1=O>O>[Cl:15][C:6]1[C:7](=[O:14])[N:8]([CH3:13])[C:9](=[O:12])[N:10]([CH3:11])[C:5]=1[Cl:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1c(Cl)cc(=O)n(C)c1=O
Solvent: O
Solvent: CC#N
Product: Cn1c(Cl)c(Cl)c(=O)n(C)c1=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To 70 ml of an acetonitrile solution containing 21 g of 6-chloro-1,3-dimethyluracil thus-obtained was added 16 g of N-chlorosuccinimide under cooling with ice (at the solution temperature of 5° C). The temperature was gradually raised to 35° C. After further stirring for 1 hour, 70 ml of water was added to the reaction solution, and the crystals thus-deposited were collected by filtration, washed with a cold solvent mixture of 18 ml of acetonitrile and 18 ml of water and dried to obtain 18 g of 5,6-dichloro-1,3-dimethyluracil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:14]([O:15][CH3:16])=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>ClCCl>[C:24]([N:10]1[CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([O:3][CH3:2])[C:14]([O:15][CH3:16])=[CH:13][C:7]=2[CH2:8][CH2:9]1)(=[O:27])[CH:25]=[CH2:26]
Reactant: C=CC(=O)Cl
Reactant: COc1cc2c(cc1OC)CCNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCc2cc(OC)c(OC)cc2CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At ambient temperature, 70 g (287.2 mmol) of the product obtained in Step 2 are dissolved in 1200 mL of dichloromethane, and then 100 mL (718 mmol/2.5 eq.) of triethylamine are added all at once. The mixture is brought to 0° C. and a solution of 25.8 mL (315.9 mmol/1.1 eq.) of acryloyl chloride in 270 mL of dichloromethane is poured in dropwise, maintaining the temperature at about 0° C. After 2 hours at 0° C., the mixture is stirred at ambient temperature overnight. Washing with 750 mL of water, 750 mL of 1N hydrochloric acid and 750 mL of water and then drying over magnesium sulphate are then carried out. After filtration and evaporation, the residue is chromatographed over 3.2 kg of silica (eluant: dichloromethane/ethanol: 95/5), followed by recrystallisation from isopropanol. After filtration over a frit and drying in vacuo at 50° C., the desired product is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1([C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)[CH3:2].[Br:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:29]3[CH:30]=[CH:31][C:26]([Br:25])=[CH:27][CH:28]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: Brc1ccc(I)cc1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(Br)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester and 1-bromo-4-iodo-benzene.