Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].COC[C:18]1[CH:23]=[C:22](C(O)=O)[CH:21]=[CH:20][C:19]=1[C:27]1C=CC=C[C:28]=1C.C(C1C=CC=CC=1B(O)O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH2:27]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14])[CH3:28]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: COCc1cc(C(=O)OC)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccccc1-c1ccc(C(=O)OC)cc1COC
Reaction time: 12 h
Yield: 83 %

Procedure:
To a solution of methyl 4-bromo-3-(methoxymethyl)benzoate, (Intermediate 28, step 2) (12 g, 0.0463 mol) in toluene (150 mL) and water (35 mL) under N2, was added 2-ethyl benzene boronic acid (9.02 g, 0.0601 mol) followed by potassium carbonate (19 g, 0.1389 mol) and Pd(PPh3)4 (2.67 g, 023). The reaction mixture was degassed with N2 for 10 min before heating. After 12 hours at 100° C., the reaction mixture was diluted with EtOAc. The organic layer was washed with sodium bicarbonate sat. solution (1×100 mL), water (2×100 mL) and finally with brine (1×100 mL). It was then dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, 60-120 mesh, eluting with pet ether/EtOAc) to afford the title compound as a pale yellow liquid (12 g, 83%). 1H NMR (CDCl3, 400 MHz) δ 8.24-8.26 (1H, s), 7.99-8.01 (1H, d), 7.32-7.38 (2H, m), 7.22-7.27 (2H, m), 7.07-7.09 (1H, d), 4.12-4.21 (2H, d), 3.93-3.95 (3H, s), 3.28-3.30 (3H, s), 2.28-2.43 (2H, m), 1.01-1.05 (3H, t).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4([C:47](=[O:49])[CH3:48])[CH2:24][CH2:23][N:22]([CH2:25][C:26]([N:28]5[CH2:33][CH2:32][N:31]([C:34]6[CH:39]=[CH:38][C:37]([C:40]7[N:45]=[CH:44][CH:43]=[CH:42][N:41]=7)=[CH:36][N:35]=6)[CH2:30][CH:29]5[CH3:46])=[O:27])[CH2:21]4)=[O:19])[CH:15]=3)[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4([C:47](=[O:49])[CH3:48])[CH2:24][CH2:23][N:22]([CH2:25][C:26]([N:28]5[CH2:33][CH2:32][N:31]([C:34]6[CH:39]=[CH:38][C:37]([C:40]7[N:41]=[CH:42][CH:43]=[CH:44][N:45]=7)=[CH:36][N:35]=6)[CH2:30][CH:29]5[CH3:46])=[O:27])[CH2:21]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)C1(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cn3)CC2C)C1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cn3)CC2C)C1

Procedure:
Stirred a solution of 3-Acetyl-1-{2-[2-methyl-4-(5-pyrimidin-2-yl-pyridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1Trityl-indazol-5-yl]-amide (10N) (600 mg, 0.664 mmol) in trifluoroacetic acid (20 ml) at room temperature overnight. The solvent was evaporated, water (100 ml) and 1N NaOH (10 ml) were added. The mixture was extracted with MeCl2 (2×150 ml), dried over MgSO4, filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 10% v/v MeOH/MeCl2 containing 2% NH4OH yielding product as a white solid. (350 mg, 79%) LCMS (MH 662.4). Retention time (minutes) 2.21
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([C:24]#[CH:25])([CH3:23])([CH3:22])[CH3:21].Cl[C:27]1[C:32]([C:33]#[N:34])=[CH:31][CH:30]=[C:29]([C:35]([CH3:38])([CH3:37])[CH3:36])[N:28]=1>CN(C=O)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I>[C:35]([C:29]1[CH:30]=[CH:31][C:32]([C:33]#[N:34])=[C:27]([C:25]#[C:24][C:20]([CH3:23])([CH3:22])[CH3:21])[N:28]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: C#CC(C)(C)C
Reactant: CC(C)(C)c1ccc(C#N)c(Cl)n1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C#Cc1nc(C(C)(C)C)ccc1C#N
Temperature: 65 °C
Reaction time: 4 h

Procedure:
15.7 g (60 mmol) of triphenylphosphine, 6.7 g (30 mmol) of palladium(II) acetate, 5.7 g (30 mmol) of copper(I) iodide and 155.6 g (1.9 mmol) of tert-butylacetylene are added consecutively to a solution of 194.7 g (1 mol) of 2-chloro-3-cyano-6-tert-butylpyridine, S28, in a mixture of 1800 ml of DMF and 1000 ml of triethylamine, and the mixture is stirred at 65° C. for 4 h. After cooling, the precipitated triethylammonium hydrochloride is filtered off with suction, rinsed with 300 ml of DMF. The filtrate is freed from the solvents in vacuo. The oily residue is taken up in 1000 ml of ethyl acetate, the solution is washed five times with 500 ml of water each time and once with 500 ml of saturated sodium chloride solution, and the organic phase is dried over magnesium sulfate. After removal of the ethyl acetate in vacuo, the black oily residue is subjected to bulb-tube distillation (p about 10−2 mbar, T=120-140° C.). Yield: 190.6 g (793 mmol), 79%. Purity: >97% according to 1H-NMR.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[SH:7].C(O)C.Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]Cl.C[O-].[Na+]>CO.C(O)(C)C>[CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[S:7][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1
Reactant: ClCc1ccccn1
Reactant: Cc1occc1S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Solvent: CCO
Product: Cc1occc1SCc1ccccn1

Procedure:
The 3-furyl sulfides of our invention can also be prepared by reacting 3-furan thiols, e.g. 2-methyl-3-furan thiol with an appropriate aralkyl halide or nitrogen heterocyclic halide, or alkenyl halide or alkylthiolalkyl halide (e.g. bromide or chloride); (i) in the presence of a base such as an alkali metal alkoxide (e.g., sodium methoxide); (ii) at a temperature in the range of 15°-65° C; and (iii) in a suitable solvent, e.g., an anhydrous lower alkanol such as anhydrous methanol, ethanol or isopropanol. Thus, for example, alpha picolyl chloride hydrochloride, when reacted with 2-methyl-3-furan thiol in anhydrous methanol in the presence of sodium methoxide at a temperature of 24° C will yield (2-methyl-3-furyl)(2-pyridylmethyl) sulfide. Thus, as a further example, in a methanol solvent sodium methylate is reacted with 2-methyl-3-furan thiol to form the corresponding mercaptide which is, in turn, reacted with allyl bromide at reflux temperature and 1 atmosphere pressure thereby forming (allyl)(2-methyl-3-furyl) sulfide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.C(=O)(O)[O-].[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccccc1-c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.3 %

Procedure:
To a degassed solution of 2-bromopyridine (1.9 mL, 20 mmol) in ethylene glycol dimethyl ether (60 mL) under argon, tetrakis(triphenylphosphane) palladium (o) (700 mg, 0.6 mmol) was added. After stirring for 10 min, 2-methylphenyl boronic acid (2.9 g, 22 mmol) was added, followed by sodium bicarbonate solution (5.04 g, 60 mmol in 60 mL water). The mixture was heated to reflux (~85° C.) and stirred overnight. After cooling to room temperature, the solvent was evaporated, the residue was partitioned between water and ether, and the aqueous layer was extracted twice with ether. The combined organic layers were dried (Na2SO4), and the solvent was evaporated to give a black oil. This oil was distilled at <1 Torr at ~95° C. to give title compound (2.75 g, 82% yield) as a clear oil. ##STR91##
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C:16]3[C:17]([CH3:24])=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[N:14]=[CH:15][C:8]=12>>[Cl:3][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C:16]3[C:17]([CH3:24])=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[N:14]=[CH:15][C:8]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(C#N)cccc1-n1ncc2c(O)ncnc21
Product: Cc1c(C#N)cccc1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
Phosphoryl trichloride (9.92 ml, 103.49 mmol) was added to 3-(4-hydroxy-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylbenzonitrile (Intermediate AT3) (1.3 g, 5.17 mmol). The resulting solution was stirred at 100° C. for 2 hours. The reaction mixture was evaporated (azeotroping with toluene ×3) giving a brown oil which was triturated with ice/water to give afford the product (1.200 g) which was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[NH:11][CH2:10][CH2:9][N:8]([C:12](OCC)=O)[CH2:7]2)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:12][N:8]1[CH2:9][CH2:10][NH:11][CH:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH2:7]1
Reactant: CCOC(=O)N1CCNC(c2ccsc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN1CCNC(c2ccsc2)C1
Yield: 93.4 %

Procedure:
A solution of 1.20 g of 3-(3-thienyl)-1-piperazine carboxylic acid, ethyl ester in 100 ml of ether was added to a suspension of 380 mg of lithium aluminum hydride in 50 ml of ether. The mixture was refluxed for 12 hours and the product recovered, giving 850 mg of 4-methyl-2-(3-thienyl)piperazine.
Reaction SMILES: [Cl-].[Sc+3:2].[Cl-].[Cl-].[C:5](=[O:8])([OH:7])[O-:6].[Ca+2].[C:10](=[O:13])([OH:12])[O-:11].[Sc]>>[C:5](=[O:6])([O-:8])[O-:7].[Sc+3:2].[C:10](=[O:11])([O-:13])[O-:12].[C:5](=[O:6])([O-:8])[O-:7].[Sc+3:2]
Reactant: O=C([O-])O
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Sc+3]
Product: O=C([O-])[O-]

Procedure:
Adding 6 m3 of scandium chloride solution (0.5 mol/L) into a reactor containing 18.3 m3 of the above calcium bicarbonate solution to react for 3 hours at 35° C., and controlling the pH value of mother liquor at 8.0, scandium ions are precipitated. And then scandium carbonate is obtained after filtration, washing and drying.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([N:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.[CH2:28]([C:30]1[NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[N:31]=1)[CH3:29].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)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]>[CH2:28]([C:30]1[N:31]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH2:15][CH:16]([N:19]([CH3:21])[CH3:20])[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:3]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29]
Reactant: CN(C)C1CCN(CC2Nc3c(N4CCOCC4)nc(Cl)nc3N2C)CC1
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N(C)C)CC3)n(C)c2n1
Temperature: 145 °C
Yield: 48.2 %

Procedure:
According to General Procedure I for Buchwald coupling, into a vial was added 1-((2-chloro-9-methyl-6-morpholino-8,9-dihydro-7H-purin-8-yl)methyl)-N,N-dimethylpiperidin-4-amine (0.044 g, 0.11 mmol), 2-ethyl-1H-benzo[d]imidazole (0.0171 g, 0.117 mmol), Xphos (0.00692 g, 0.0145 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.00696 g, 7.60E-6 mol), and Cesium Carbonate (0.0728 g, 0.223 mmol). The mixture was dissolved in N,N-Dimethylformamide (0.865 mL, 0.0112 mol). The reaction was heated at 145° C. under pressure for 30 minutes in a microwave reactor. The reaction mixture was filtered and concentrated. The crude was purified by reverse phase HPLC to give 306 (26.7 mg, 47%). [M+H]+=536.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][O:13][C:14]([C:22]([F:25])([F:24])[F:23])([C:18]([F:21])([F:20])[F:19])[C:15](O)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:30])=O.CN(C)C=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]([C:18]([F:19])([F:20])[F:21])([C:22]([F:24])([F:25])[F:23])[C:15]([Cl:30])=[O:16])=[CH:26][CH:27]=2)=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F

Procedure:
A mixture of 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionic acid (3.0 g.), thionyl chloride (3.0 ml.), dimethylformamide (0.16 g.) and benzene (10 ml.) is heated under reflux until the solution becomes turbid (ca. 10 minutes). The mixture is evaporated in vacuo, benzene (10 ml.) is added and the evaporation is repeated. Light petroleum (10 ml., b.p. 40°-60° C.) is added to the residue, and the solution is separated from insoluble oils and evaporated to give 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionyl chloride (3.07 g.), m.p. 30°-35° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:15])[NH:9]2)(=[O:3])[CH3:2].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:15])[NH:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Yield: 46.1 %

Procedure:
15.23 g of 5-acetyl-8-hydroxycarbostyril and 15.7 g of benzyl chloride are added to a mixture of 200 ml of acetone and 90 ml of water, and 10.35 g of potassium carbonate are added thereto. The mixture is refluxed for 12 hours under stirring. Then, the mixture is evaporated under reduced pressure to remove acetone, and the residue is extracted with chloroform. The extract is washed with water, dried and evaporated under reduced pressure to remove chloroform. The residue is recrystallized from a mixture of ethyl acetate and n-hexane. 10.14 g of 5-acetyl-8-benzyloxycarbostyril are obtained as prisms. 1.58 g of said product are further recovered from the mother liquor.
Reaction SMILES: Cl[Si:2]([Cl:18])(Cl)[C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=1.[CH3:19][C:20]1[CH:21]=[C:22]([Li])[CH:23]=[C:24]([CH3:26])[CH:25]=1>C(OCC)C>[Cl:18][Si:2]([C:3]1[CH:4]=[C:5]([C:13]([CH3:15])([CH3:16])[CH3:14])[CH:6]=[C:7]([C:9]([CH3:10])([CH3:11])[CH3:12])[CH:8]=1)([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:13])[CH:4]=1)[C:22]1[CH:21]=[C:20]([CH3:19])[CH:25]=[C:24]([CH3:26])[CH:23]=1
Reactant: CC(C)(C)c1cc(C(C)(C)C)cc([Si](Cl)(Cl)Cl)c1
Reactant: [Li]c1cc(C)cc(C)c1
Solvent: CCOCC
Product: Cc1cc(C)cc([Si](Cl)(c2cc(C)cc(C)c2)c2cc(C(C)(C)C)cc(C(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, to a diethyl ether solution (74 mL) of trichloro(3,5-di-tert-butylphenyl)silane (12.95 g, 40.00 mmol), a solution of 3,5-dimethylphenyllithium (11.09 g, 98.96 mmol) in diethyl ether (95 mL) was added dropwise at −78° C. After the mixture was gradually warmed to room temperature, stirring was performed at room temperature for 2 hours. After completion of the reaction, the solvent was removed under reduced pressure. Thereafter, hexane was added to the residue, and insoluble materials were removed by filtration. The solvent was removed from the filtrate under reduced pressure to quantitatively obtain chloro(3,5-di-tert-butylphenyl)bis(3,5-dimethylphenyl)silane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16](I)[CH:17]=[CH:18][CH:19]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:13])[CH:19]=2)[CH:7]=1
Reactant: Clc1cccc(I)c1
Reactant: COc1ccc(Br)cc1B(O)O
Product: COc1ccc(Br)cc1-c1cccc(Cl)c1
Reaction time: 16 h
Yield: 99 %

Procedure:
I-208 was synthesized from 5-bromo-2-methoxyphenylboronic acid (2.00 g, 8.66 mmol) and 3-chloroiodobenzene (2.48 g, 10.4 mmol) using the same conditions as for I-207. The reaction time was extended to 16 h. The methanol was removed under vacuum, and the residue dissolved in ethyl acetate (100 mL), washed with water (100 mL), and the aqueous wash extracted with ethyl acetate (100 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (2×200 mL), water (2×200 mL) and brine (150 mL), dried over sodium sulfate, filtered and the solvent removed under vacuum to give I-208 (2.56 g, 99% yield). 1H NMR (400 MHz, CDCl3) 7.49-7.48 (m, 1H), 7.44-7.40 (m, 2H), 7.36-7.31 (m, 3H), 6.85 (d, J=8.4 Hz, 1H), 3.80 (s, 3H) ppm.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].C(N(CC)CC)C>ClCCl.O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[O:40])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26]
Reactant: COc1cc(CCCCCCCO)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cc(CCCCCCC=O)ccc1OCc1nc(-c2ccccc2)oc1C
Reaction time: 0.17 h

Procedure:
A solution of dimethyl sulfoxide (DMSO) (4 g) in dichloromethane (10 ml) was added dropwise, at temperatures ranging from -60 to -50° C., to a solution of oxalyl chloride [(COCl2)] (2.9 g) in dichloromethane (100 ml). The mixture was stirred for 10 minutes at the same temperature range, to which was then added dropwise a solution of 7-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]heptanol (4.3 g) in dichloromethane (15 ml). The mixture was stirred for 30 minutes at 0° C., to which was added dropwise at -20° C. triethylamine (10.6 g). The mixture was stirred for further 30 minutes at the same temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), followed by distilling off the solvent under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:3), was obtained 7-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-phenyl]heptanal, which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.64-65° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)=O)(C)(C)C.[ClH:21]>C(Cl)Cl.O1CCOCC1>[ClH:21].[NH2:8][CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(CCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CCN)cc1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of methyl 4-[2-(tert-butoxycarbonylamino)ethyl]benzoate (3.50 g, 12.5 mmol) in methylene chloride (35 ml) was added 4N hydrogen chloride in 1,4-dioxane (35 ml) at 5° C. and the mixture was stirred for 30 min. The solvent was removed in vacuo and the resulting solid was collected, washed with isopropyl ether and dried to give methyl 4-(2-aminoethyl)-benzoate hydrochloride (2.63 g, 97%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=2)=[CH:20][C:19]=1[C:35]1[CH:44]=[CH:43][C:42]2[C:41]([CH3:46])([CH3:45])[CH2:40][CH2:39][C:38]([CH3:48])([CH3:47])[C:37]=2[CH:36]=1.O.NN>C(O)C>[NH2:3][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=2)=[CH:20][C:19]=1[C:35]1[CH:44]=[CH:43][C:42]2[C:41]([CH3:46])([CH3:45])[CH2:40][CH2:39][C:38]([CH3:47])([CH3:48])[C:37]=2[CH:36]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCN3C(=O)c4ccccc4C3=O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCN)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 46.2 %

Procedure:
In a manner similar to that of Example 17b, by reaction of 760 mg (1.18 mmol) of ethyl 4′-[5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentyloxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate with 230 μl (4.72 mmol) of hydrazine monohydrate in 50 ml of ethanol. 280 mg of ethyl 4′-(5-aminopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a whitish solid (yield=46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][C:14]([CH:17]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[OH:18])=[CH:13][C:12]=23)[CH:5]=[CH:6][CH:7]=1>O1CCOCC1.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([C:19]4[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=4)=[O:18])=[CH:13][C:12]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(O)c2ccc3noc(-c4cccc(Cl)c4)c3c2)cc1
Agent: O=[Mn]=O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)c2ccc3noc(-c4cccc(Cl)c4)c3c2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of intermediate 18 (0.071 mol) and MnO2 (0.287 mol) in 1,4-dioxane (250 ml) was stirred at 80° C. for 2 hours, then cooled to room temperature, filtered over celite and washed with DCM. The solvent was evaporated till dryness, yielding 24.7 g (100%) of [3-(3-chlorophenyl)-2,1-benzisoxazol-5-yl](4-methylphenyl)-methanone (intermediate 19).
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][CH2:5][CH2:6][OH:7].Br[C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12]=2[S:11][C:10]=1[C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:26].O>O1CCCC1>[OH:7][CH2:6][CH2:5][CH2:4][S:3][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12]=2[S:11][C:10]=1[C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:26]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(C(=O)c3cccnc3)sc21
Reactant: OCCCS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)c(C(=O)c3cccnc3)sc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
To a suspension of sodium hydride (0.068 g) in dry tetrahydrofuran (25 ml) was added dropwise a solution of 3-mercaptopropanol (0.14 g) in dry tetrahydrofuran (5 ml). After 15 minutes, a solution of 5-bromo-3-methyl-1-(2-methylpropyl)-6-[(pyridin-3-yl)carbonyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.60 g, Example 39 step c) in dry tetrahydrofuran (20 ml) was added dropwise and the reaction was stirred for 3 hours at room temperature. The solution was poured into water and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal-phase HPLC eluting with a gradient of 0-5% ethanol in dichloromethane to give the title compound as a cream solid (0.35 g).