Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[N:15]1[CH2:21][C:20]2[CH:22]=[C:23]([C:26]3[CH:27]=[C:28]([NH2:33])[C:29]([NH2:32])=[N:30][CH:31]=3)[CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH2:16]1.[CH3:34][O:35][C:36]([NH:38][C:39](=NC(OC)=O)SC)=[O:37]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[N:15]1[CH2:21][C:20]2[CH:22]=[C:23]([C:26]3[CH:27]=[C:28]4[NH:33][C:39]([NH:38][C:36](=[O:37])[O:35][CH3:34])=[N:32][C:29]4=[N:30][CH:31]=3)[CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: COc1cc2nccc(N3CCOc4ccc(-c5cnc(N)c(N)c5)cc4C3)c2cc1OC
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ncc(-c3ccc4c(c3)CN(c3ccnc5cc(OC)c(OC)cc35)CCO4)cc2[nH]1
Temperature: 65 °C
Yield: 55 %

Procedure:
To a solution of 5-{4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}pyridine-2,3-diamine (85 mg, 0.19 mmol) in acetic acid (3 mL) was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (40 mg, 0.19 mmol). The reaction mixture was heated (65° C.) for 18 h and then concentrated. The resulting residue was dissolved in acetonitrile and purified by preparative reverse phase HPLC to provide methyl (6-{4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1H-imidazo[4,5-b]pyridin-2-yl)carbamate (55 mg, 54% yield) as a white solid. 1H NMR (400 MHz, DMSO-D6): δ 7.93 (br, 2H), 7.93 (br, 1H), 7.78 (br, 1H), 7.59 (dd, 1h), 7.31 (s, 1H), 7.14 (dd, 1H), 7.09 (s, 1H), 6.95 (d, 1H), 4.60 (s, 2H), 4.43 (m, 2H), 3.89 (s, 3H), 3.78 (s, 3H), 3.73 (m, 2H), 3.53 (s, 3H), MS (EI) for C28H26N6O5: 527 (MH+).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:16]1[C:17]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:18]=2[N:19]=[CH:20][N:21]=1>>[CH2:25]([C:23]1[S:22][C:18]2[N:19]=[CH:20][N:21]=[C:16]([N:11]3[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH:10]3[CH3:14])[C:17]=2[CH:24]=1)[CH3:26]
Reactant: CCc1cc2c(Cl)ncnc2s1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Product: CCc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3C)ncnc2s1
Yield: 96 %

Procedure:
1-BOC-3-Methylpiperazine was coupled with 4-chloro-6-ethylthiopheno[2,3-d]pyrimidine according to Example 87. Yield=96%, ES-MS: (M+H)+ 363.
Reaction SMILES: [C:1]12([CH2:11][NH2:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:13][C:14]1[S:18][C:17]([C:19](O)=[O:20])=[CH:16][CH:15]=1.[Cl-].ClC1N(C)CC[NH+]1C>[OH-].[Na+]>[C:1]12([CH2:11][NH:12][C:19]([C:17]3[S:18][C:14]([CH3:13])=[CH:15][CH:16]=3)=[O:20])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(C(=O)O)s1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Agent: [Na+]
Product: Cc1ccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)s1
Temperature: 50 °C

Procedure:
To a 2 mL reaction vial is added adamantylmethylamine (0.15 mL, 0.2M in toluene), 5-methylthiophene-2-carboxylic acid (0.15 mL, 0.2M in dimethylacetamide), 2-chloro-1,3-dimethylimidazolinium chloride (0.20 mL, 0.2M in ACN), and TEA (0.20 mL, 0.2M in toluene). The mixture is placed on a shaker and heated to 50° C. for 16 h. The mixture is cooled to RT and diluted with 1M aqueous sodium hydroxide (0.5 mL). The resulting mixture is extracted with 50% EtOAc-hexane (3×0.5 mL) and purified over benzenesulfonic acid ion exchange resin (eluted with 50% EtOAc-hexane) to afford the title compound. LC/MS: (M+1)=290.19; RT=1.33 min.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](O)=[O:20])[CH2:13][CH2:12]2)=[O:10])[N:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19]([NH:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)=[O:20])[CH2:15][CH2:16]2)=[O:10])[N:3]=1
Reactant: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3C(=O)O)CC2)n1
Reactant: Nc1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3C(=O)Nc3ccncc3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To 2-{4-[2-(3,5-dimethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-benzoic acid (0.051 g, 0.150 mmol) in 2 mL of CH2Cl2 at 4° C. is added 2 M oxalyl chloride solution (0.100 mL, 0.200 mmol) and 2 drops of dry DMF. The mixture is allowed to warm to room temperature over 1 h. To this is added 4-aminopyridine in one portion and diisopropylethyl amine (0.100 mL, 0.310 mmol). The mixture is stirred for 16 h. The mixture is concentrated and then purified via preparative HPLC (20-80% CH3CN/H2O). The product is further purified using a SiO2 prep-plate, eluting with (10% MeOH/CH2Cl2) to give 0.032 g of the title compound in 63% yield. MS MH+=419.2
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[N:23]([C:26](=[O:48])[CH:27]([NH:34][C:35](=[O:47])[CH:36]([N:38](C(OC(C)(C)C)=O)[CH3:39])[CH3:37])[CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:24][CH2:25][CH:19]12)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[N:23]([C:26](=[O:48])[CH:27]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[NH:34][C:35](=[O:47])[CH:36]([NH:38][CH3:39])[CH3:37])[CH2:24][CH2:25][CH:19]12)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C(=O)NC(C(=O)N1CCC2C1CCN2C(=O)OCc1ccccc1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C(=O)NC(C(=O)N1CCC2C1CCN2C(=O)OCc1ccccc1)C1CCCCC1
Reaction time: 1.5 h

Procedure:
TFA (5 mL) was added to a solution containing crude 116 (0.9 g) in DCM (20 mL) at 0° C. After 90 min, another portion of TFA (2 mL) was added. After 75 min, the reaction mixture was carefully quenched by the addition of saturated aqueous NaHCO3. The mixture was then diluted with EtOAc and water and the layers were separated. The organic phase was washed three times with aqueous NaHCO3 then once with brine. The combined aqueous washes were back-extracted with EtOAc and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by reverse-phase HPLC [2″ Dynamax C18; Method: 10-55% ACN/water containing 0.1% HOAc over 30 min; Flow: 40 mL/min]. The product-containing fractions were pooled, frozen, and lyophilized to afford 410 mg (53% from 115) of 117 as a white-colored solid. 1H NMR (300 MHz, d6-DMSO), mixture of carbamate rotomers: δ7.67 (d, J=8.7 Hz, 1H), 7.34-7.28 (m, 5H), 5.17-5.05 (m, 2H), 4.52 (m, 2H), 4.34 (m, 1H), 4.00 (m, 1H), 3.75 (m, 1H), 3.33 (m, 1H), 3.14-3.01 (m, 2H), 2.35 (br s, 3H), 2.30 (m, 1H), 1.90 (m, 1H), 1.69-1.60 (m, 5H), 1.27 (d, J=6.9 Hz, 3H), 1.18-0.94 (m, 5H) ppm. 13C NMR (75 MHz, d6-DMSO), mixture of carbamate rotomers: δ174.7, 174.4 172.9, 170.1, 170.0, 154.1, 154.0, 137.5, 129.1, 128.5, 128.2, 128.1, 66.7, 66.6, 63.0, 61.9, 61.6, 60.9, 59.5, 55.2, 54.7, 46.7, 46.1, 45.6, 41.5, 34.5, 32.3, 31.2, 30.7, 30.1, 29.6, 29.5, 28.9, 28.7, 26.4, 26.2, 26.1, 26.0, 22.0, 19.5, 19.4 ppm. Mass spectrum, m/z [471.0] (M+H)+.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[C:19]3[CH:34]=[C:35]([Cl:39])[C:36](I)=[CH:37][C:18]=3[N:17]=2)[CH:12]=[CH:11][C:10]=1[CH3:40])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:41][N:42]1[C:50]2[C:45](=[CH:46][C:47](B(O)O)=[CH:48][CH:49]=2)[CH:44]=[CH:43]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.[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>[CH2:1]([O:3][P:4]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[C:19]3[CH:34]=[C:35]([Cl:39])[C:36]([C:47]4[CH:46]=[C:45]5[C:50](=[CH:49][CH:48]=4)[N:42]([CH3:41])[CH:43]=[CH:44]5)=[CH:37][C:18]=3[N:17]=2)[CH:12]=[CH:11][C:10]=1[CH3:40])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: CCOP(=O)(OCC)c1cc(Oc2nc3cc(I)c(Cl)cc3n2Cc2ccc(-c3ccccc3)cc2)ccc1C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1cc(Oc2nc3cc(-c4ccc5c(ccn5C)c4)c(Cl)cc3n2Cc2ccc(-c3ccccc3)cc2)ccc1C
Temperature: 130 °C

Procedure:
To a solution of {5-[1-biphenyl-4-ylmethyl-6-chloro-5-Iodo-1H-benzoimidazol-2-yloxy]-2-methyl-phenyl}-phosphonic acid diethyl ester (900 mg, 1.3 mmol) in DMF (6 ml) was added 1-methyl-1H-indole-5-boronic acid (460 mg, 2.6 mmol), tetrakis(triphenylphosphine)-palladium(0) (155 mg, 0.13 mmol), and lastly a solution of potassium carbonate (718 mg, 5.2 mmol) in 3 ml of H2O. The mixture was heated in a microwave oven at 130° C. for 15 min. The reaction was partitioned between EtOAc and half-saturated NH4Cl. The EtOAc layer was washed with H2O and then brine. The organic layer was dried with MgSO4, evaporated to an oil, and then purified by flash chromatography. The flash column was eluted with a solvent gradient up to 65% EtOAc in Hexane to isolate the title compound as a mixture of the two protected regioisomers.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1.[O:35]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36]1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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:35]1[CH:39]=[CH:38][C:37]([C:2]2[C:10]3[C:9]([N:11]4[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:25])[C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:13][CH2:12]4)=[N:8][CH:7]=[N:6][C:5]=3[N:4]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:3]=2)=[CH:36]1
Reactant: CC1(C)OB(c2ccoc2)OC1(C)C
Reactant: O=C(NC1CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC1CCN(c2ncnc3c2c(-c2ccoc2)cn3S(=O)(=O)c2ccccc2)CC1)c1ccccc1
Temperature: 25 °C

Procedure:
N-{1-[5-bromo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide D6 (450 mg), 2-(3-furanyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (240 mg, 1.245 mmol, commercially available from e.g. Maybridge, Sigma-Aldrich or Apollo), potassium phosphate trihydrate (660 mg, 2.5 mmol), palladium tetrakis (30 mg, 0.026 mmol) were dissolved in 1,4-dioxane (20 ml) and water (4 ml) and stirred under nitrogen at 90° C. overnight. Cooled to room temperature, solvent removed in vacuo, water (150 ml) was added extracted with EtOAc (3×150 ml). The combined extracts were washed with brine and dried over MgSO4, concentrated to give crude product which was purified by silica gel column eluting with pet eth/EtOAc 1:1 to give 60 mg of desired product D28. LCMS [MH+] 528.2@1.88 min (5 min run)
Reaction SMILES: C([SiH](CC)CC)C.[Br:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH:19]([C:21]2[S:25][C:24]3[CH:26]=[CH:27][C:28]([CH2:30][CH3:31])=[CH:29][C:23]=3[CH:22]=2)O)[CH:10]=1.CO.O>C(Cl)Cl>[Br:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH2:19][C:21]2[S:25][C:24]3[CH:26]=[CH:27][C:28]([CH2:30][CH3:31])=[CH:29][C:23]=3[CH:22]=2)[CH:10]=1
Reactant: CCc1ccc2sc(C(O)c3cc(Br)c4ccccc4c3)cc2c1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc2sc(Cc3cc(Br)c4ccccc4c3)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
In a nitrogen stream, triethylsilane (0.63 ml, 3.93 mmol) and a boron trifluoride-diethyl ether complex (0.27 ml, 2.16 mmol) were added to a solution of (4-bromo-naphthalen-2-yl)-(5-ethylbenzo[b]-thiophen-2-yl)methanol (780 mg, 1.96 mmol) in methylene chloride (20 ml) at 0° C. and the reaction mixture was stirred at room temperature for three hours. To the obtained solution was added methanol (10 ml) and water (30 ml) and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=n-hexane)] to obtain the title compound (460 mg, 62%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=2)=[N:30][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([N:35]3[CH:36]=[CH:37][C:32]([C:29]4[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:39])[F:40])=[CH:31][N:30]=4)=[CH:33][C:34]3=[O:38])[CH:10]=2)[C:6]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:7]1=2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cn2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCCN(C(=O)OC(C)(C)C)C2
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc31)CCCN(C(=O)OC(C)(C)C)C2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
tert-Butyl 8-bromo-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate (0.15 g, 0.39 mmol), 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (0.13 g, 0.54 mmol), and Cs2CO3 (0.19 g, 0.60 mmol) were suspended in DMSO (3.3 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (23 mg, 0.16 mmol) and copper iodide (0.13 g, 0.59 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5:1 MeOH/NH4OH (15 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH2Cl2 (75 mL). The resulting solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH2Cl2 and washed with brine (3×25 mL). The organic solution was dried over Na2SO4, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 5 column volumes; increased to 0:100 over 20 column volumes and held for 5 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (62 mg, 20%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.00 (s, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.91 (d, J=7.5 Hz, 1H), 7.60-7.57 (m, 2H), 7.35-7.32 (m, 1H), 7.28-7.26 (s, 1H), 7.08-7.02 (m, 2H), 4.68-4.64 (m, 2H), 3.78-3.74 (m, 4H), 3.71-3.69 (m, 1H), 2.95-2.94 (m, 2H), 1.96-1.91 (m, 2H), 1.43 (s, 9H); ESI MS m/z 539 [M+H]+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:46]=[CH:45][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH2:31][O:32][CH3:33])=[CH:27][CH:28]=3)[O:23][CH2:22][C:21]2([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:37][CH:36]=2)[CH3:34])=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.OCCCCCCCCCC1C2C(=CC(OCOC)=CC=2)OCC1(C1C=CC(OCOC)=CC=1)C>>[OH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH2:31][O:32][CH3:33])=[CH:27][CH:28]=3)[O:23][CH2:22][C:21]2([C:35]2[CH:36]=[CH:37][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:39][CH:40]=2)[CH3:34])=[CH:45][CH:46]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCOc2ccc(CCCO[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCO)cc1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCOc2ccc(CCCO)cc2)cc1

Procedure:
The title compound was prepared from (3RS,4RS)-4-{3-[4-(3-t-butyl-dimethylsilyloxypropyl)phenoxy]-1-propyl}-7-methoxymethyloxy-3-(4-methoxymethyloxyphenyl)-3-methylchroman according to the same method for the synthesis of 4-[9-hydroxy-1-nonyl]-7-methoxymethyloxy-3-(4-methoxymethyloxyphenyl)-3-methylchroman described in International Patent Appln. No. PCT/KR97/00265.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([NH:9][C:10]1[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]([S:20]([O-:23])(=O)=[O:21])=[CH:12][CH:11]=1)(=[O:8])[CH3:7].[NH+]1C=CC=CC=1>CN1CCCC1=O>[C:6]([NH:9][C:10]1[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]([S:20]([Cl:3])(=[O:23])=[O:21])=[CH:12][CH:11]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)[O-])c2cccnc12
Reactant: O=P(Cl)(Cl)Cl
Agent: c1cc[nH+]cc1
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(S(=O)(=O)Cl)c2cccnc12
Temperature: 0 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
In a 1 liter 3-neck round bottomed flask, fitted with a mechanical stirrer and a calcium chloride drying tube, phosphorus oxychloride (360 ml) was chilled to less than 10° C. N-methylpyrrolidone (20 ml) was added (slight exotherm). When the temperature returned to <5° C., finely ground pyridinium 8-acetamido-5-quinolinesulfonate (36.0 g, 0.104 mole) was added. The reaction mixture was thoroughly packed in ice and stirred for 20 hours. The resulting brown slurry was slowly added to ca. 2500 ml ice/water (cooled by an external ice-salt bath) with vigorous stirring. After stirring for one hour the product was collected by filtration and yielded 27.9 g (94 percent) of a tan powder, m.p. 203°-204° C. (decomp.).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[CH3:29][CH:30]([CH3:33])[CH2:31][SH:32]>>[CH2:31]([S:32][CH2:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3([C:4]([OH:3])=[O:5])[CH2:8][CH2:7]3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)[CH:30]([CH3:33])[CH3:29]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: CC(C)CS
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CSCC(C)C

Procedure:
Prepared according to the procedure described in Example 48, Step 2, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-methyl-propane-1-thiol.
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH3:13])[C:11](=[O:14])[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:17])C>[O-2].[Cr+6].[O-2].[O-2]>[C:1]([C:8]1[N:12]([CH3:13])[C:11](=[O:14])[O:10][N:9]=1)(=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Cn1c(Cc2ccccc2)noc1=O
Agent: [Cr+6]
Agent: [O-2]
Product: Cn1c(C(=O)c2ccccc2)noc1=O
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 3-benzyl-4-methyl-1,2,4-oxadiazol-5(4H)-one (3.87 g, 20.34 mmol, 1 eq.) in acetic acid (120 ml) was added chromium(VI) oxide (6.10 g, 61.04 mmol, 3 eq.) and stirring was allowed overnight. The reaction was quenched by addition of water and extracted with Et2O (3×50 ml). The organics were combined, washed with aq. sat. NaHCO3, dried over MgSO4 and concentrated to give 3-benzoyl-4-methyl-1,2,4-oxadiazol-5(4H)-one (3.85 g, 88% yield) as a white solid.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C([O:11][C:12](=O)[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])C.Cl>C1COCC1>[O:11]=[C:12]([CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])[CH2:2][C:1]#[N:3]
Reactant: CCOC(=O)Cc1c(C)cc(C)cc1C
Reactant: CC#N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(CC(=O)CC#N)c(C)c1
Temperature: -78 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (0.506 mL) in 25 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then treated in dropwise fashion with 6.0 mL of a 1.6 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 1 h and subsequently treated in dropwise fashion with a solution of 5 gms. of (2,4,6-trimethyl-phenyl)-acetic acid ethyl ester in 25 mL of anhydrous THF. The resulting solution is then stirred 5 h at room temperature. Subsequently, the reaction mixture is acidified (pH 7–8) with dropwise addition of conc. HCl and a 1 M HCl(aq) solution. The quenched reaction mixture is then partitioned between water and ethyl acetate. The organic layer is dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield the desired 3-oxo-4-(2,4,6-trimethyl-phenyl)-butyronitrile as a yellow-white solid in the amount of 1.41 gms. (72% yield).
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[C:9]([OH:13])([CH3:12])([CH3:11])[CH3:10]>C1(C)C=CC=CC=1>[C:1]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 50 %

Procedure:
A mixture of 1 equivalent of methyl acetoacetate, 1 equivalent of tertiary butyl alcohol and 100 mg of sulfated tin oxide catalyst prepared according to example 1, in 20 ml of toluene was heated to 110° C. in a two necked round bottom flask provided with a distillation condenser to remove methanol. The reaction was monitored by thin layer chromatography (TLC). After completion of the reaction (about 6 hours), the catalyst was filtered and the filtrate was concentrated and chromatographed on a silica gel column (95% petroleum ether and 5% ethyl acetate) to afford t-butyl acetoacetate as a viscous colorless liquid in 50% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.O[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cccc(Br)c1
Reactant: OCc1ccc(B(O)O)cc1
Product: OB(O)c1ccc(COCc2cccc(Br)c2)cc1

Procedure:
According to the method of (Example 129) <Step 1>, from (3-bromophenyl)methanol (0.50 g) and (4-(hydroxymethyl)phenyl)boronic acid (0.69), the subject compound (0.25 g) was obtained as a colorless solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH:9]2[C:19]3[CH:25]=[C:24](Br)[CH:23]=[C:22]([Cl:27])[C:20]=3[O:21][CH:8]2[CH2:7]1)(=[O:3])[CH3:2].[C:28]1([S:34]([O-:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Na+]>>[C:1]([O:4][CH2:5][CH:6]1[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][C:9]2[C:19]3[CH:25]=[C:24]([S:34]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:36])=[O:35])[CH:23]=[C:22]([Cl:27])[C:20]=3[O:21][C:8]=2[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CC2Oc3c(Cl)cc(Br)cc3C2CN1C(=O)OC(C)(C)C
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: CC(=O)OCC1Cc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c2CN1C(=O)OC(C)(C)C
Yield: 84 %

Procedure:
The product from step J and sodium benzenesulfinate were coupled following the procedure of Example 29 step C. The crude product was purified by flash column chromatography (SiO2, 9:1 to 7:3, hexanes/ethyl acetate) to give tert-butyl 3-(acetoxymethyl)-6-chloro-8-(phenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (110 mg, 84%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 7.98-7.95 (m, 3H), 7.86 (s, 1H), 7.58-7.49 (m, 3H), 5.10 (br s, 2H), 4.20-4.04 (m, 3H), 3.22-3.14 (m, 1H), 2.81 (d, J=17.4 Hz, 1H), 2.04 (s, 3H), 1.53 (s, 9H).