Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl.[N:10]12[CH2:17][CH2:16][CH:13]([CH2:14][CH2:15]1)[C:12](=O)[CH2:11]2.N12CCN(CC1)CC2.S([O-])([O-])(=O)=O.[Mg+2]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:10]12[CH2:17][CH2:16][CH:13]([C:12]3[NH:4][C:3]4[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=4[C:11]=31)[CH2:14][CH2:15]2
Reactant: Nc1ccccc1I
Reactant: O=C1CN2CCC1CC2
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: c1ccc2c3c([nH]c2c1)C1CCN3CC1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A mixture of 2-iodoaniline (1.00 g, 4.57 mmol; Aldrich), quinuclidin-3-one hydrochloride (1.24 g, 7.67 mmol; Aldrich), palladium(II) acetate (51 mg, 0.23 mmol; Aldrich), 1,4-diazabicyclo[2.2.2]octane (DABCO; 1.79 g, 15.98 mmol; Aldrich) and magnesium sulfate (0.88 g, 7.31 mmol; Aldrich) in dry N,N-dimethylformamide (14 mL) was evacuated and purged with nitrogen (three cycles) and stirred at 110° C. for 18 hours. The reaction mixture was cooled to ambient temperature and filtered through a microfiber frit. The filtrate was concentrated in vacuo, dissolved in methanol (10 mL) and purified by preparative HPLC [Waters XBridge RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 10-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (500 MHz, methanol-d4) δ ppm 1.52-1.66 (m, 2H), 1.97-2.06 (m, 2H), 2.58-2.71 (m, 2H), 3.24-3.31 (m, 2H), 3.40-3.45 (quintet, J=2.9 Hz, 1H), 6.94-7.05 (m, 2H), 7.31-7.35 (m, 1H), 7.52-7.57 (m, 1H); MS (APCI) m/z 199 (M+H)+.
Reaction SMILES: N[C@H](C(NCC(NCC(N[C@H](C([NH:32][C@H:33]([C:38]([OH:40])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=O)CC1C=CC=CC=1)=O)=O)=O)CC1C=CC(O)=CC=1>P([O-])([O-])([O-])=O>[NH2:32][C@H:33]([C:38]([OH:40])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Agent: O=P([O-])([O-])[O-]
Product: CC(C)C[C@H](N)C(=O)O
Reaction time: 0.02 h

Procedure:
The degradation H-Tyr-Gly-Gly-Phe-Leu-OH (SEQ ID NO: 12) (˜1.8×10−4 M) in 50 mM phosphate buffer solutions of pH 7.4 containing carboxypeptidase A (1 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 9.8×10−1 min−1 and the corresponding half-life calculated to 0.7 min as previously described.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1.[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[O:13]>C(#N)C>[CH3:8][C:6]1[N:7]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:12]([O:11][CH3:10])=[O:13])(=[O:22])=[O:21])=[O:25])[N:3]=[N:4][C:5]=1[CH3:9]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1nnc(N)nc1C
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nnc(C)c(C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.8 %

Procedure:
To a stirred suspension of 1.2 g of 3-amino-5,6-dimethyl-1,2,4-triazine in 25 ml of anhydrous acetonitrile was added at ambient temperature 2.4 g of 2-methoxycarbonylbenzenesulfonylisocyanate. After stirring for 24 hours at ambient temperature, the resultant precipitate was filtered off to yield 2.5 g of the desired compound melting at 150°-151°. It showed infrared absorption peaks at 1700, 1680 and 1550 cm-1, consistent for N-[(5,6-dimethyl-1,2,4-triazin-3-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.[CH2:22]([O:24][C:25](=[O:53])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][CH2:36][NH:37][CH2:38][CH2:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:29]=1)[CH3:23].Cl>CN(C=O)C.CCOC(C)=O>[CH2:22]([O:24][C:25](=[O:53])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][CH2:36][N:37]([CH2:38][CH2:39][CH:40]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:9](=[O:11])/[CH:8]=[CH:7]/[C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:29]=1)[CH3:23]
Reactant: O=C(O)/C=C/c1ccncc1
Reactant: CCOC(=O)COc1cccc(CCCNCCC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(CCCN(CCC(c2ccccc2)c2ccccc2)C(=O)/C=C/c2ccncc2)c1
Reaction time: 8 h

Procedure:
To a solution of (2E)-3-(4-pyridinyl)acrylic acid (23 mg) in DMF (1 mL) was added HOBt (21 mg), ethyl(3-{3-[(3,3-diphenylpropyl)amino]propyl}phenoxy)acetate (55 mg) and WSCD.HCl (29 mg) at ambient temperature. The reaction mixture was stirred for 8 hours at the same temperature. The resulting mixture was diluted with EtOAc and washed successively with water and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=85:15-70:30) to give a ethyl[3-(3-{(3,3-diphenylpropyl) [(2E)-3-(4-pyridinyl)-2-propenoyl]amino}propyl)phenoxy]acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:11][CH2:10]1.[O:20]=[C:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][C:25]([C:31](O)=[O:32])=[CH:26][CH:27]=2)[NH:22]1>>[O:20]=[C:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][C:25]([C:31]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][N:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:14][CH2:13]3)=[O:32])=[CH:26][CH:27]=2)[NH:22]1
Reactant: O=C1CCc2ccc(C(=O)O)cc2N1
Reactant: COc1ccccc1N1CCN(CCCCO)CC1
Product: COc1ccccc1N1CCN(CCCCOC(=O)c2ccc3c(c2)NC(=O)CC3)CC1

Procedure:
4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl 2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate (23c) (Scheme 4) was synthesized from the compound 21c and the carboxylic acid 22 according to the protocol described for the compound 23a (Example 35). Off-white solid, 0.085 g (13%). 1H NMR (400 MHz, CDCl3): δ 1.66-1.72 (m, 2H); 1.78-1.84 (m, 2H); 2.47 (t, J=7.6 Hz, 2H); 2.63-2.67 (m, 6H); 3.01 (t, J=7.2 Hz, 2H); 3.09 (broad s, 4H); 3.84 (s, 3H); 4.34 (t, J=6.8 Hz, 2H); 6.83-7.00 (m, 4H); 7.21 (d, J=8.0 Hz, 1H); 7.47 (s, 1H); 7.66 (dd, J=1.6, 8.0 Hz, 1H); 8.61 (broad s, 1H). MS (ESI): m/z=438.20 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:13])[C:4]2=[CH:14][S:15][CH:16]=[C:3]12.[H-].[Na+].[CH3:19]I>CN(C)C=O>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH3:19])[C:5](=[O:13])[C:4]2=[CH:14][S:15][CH:16]=[C:3]12
Reactant: CI
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2cscc2N(C)c2ccccc21
Reaction time: 8 h

Procedure:
A mixture of 2.8 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 620 mg. of 50% sodium hydride in mineral oil in 30 ml. of dry dimethylformamide is stirred for 11/4 hours. A 2.1 g. portion of methyl iodide is added and the mixture is stirred overnight. The mixture is poured onto ice water and the solid is collected and dried. The solid changes to a glass which is dissolved in methylene chloride, washed with water, filtered and concentrated to dryness. The crude oily solid is triturated in hexane and ether. The ether hexane mixture is concentrated to a yellow gum, dissolved in 15 ml. of 30% methylene chloride in hexane and chromatographed on an alumina column, eluting with the same solvent. Four 200 ml. fractions are collected. The solvent is changed to methylene chloride:hexane (50:50) for fractions 5-8 (200 ml.). The solvent is changed to 100% methylene chloride for fractions 8-11 (200 ml.). The solvent is changed to 20% ethyl acetate in benzene for fractions 12-19 (200 ml.). Fractions 11-19 are combined and concentrated to a yellow oil which crystallizes with trituration in hexane, giving the desired product, mp. 101°-102° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][N:24]([CH3:38])[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[NH2:32]>>[CH3:38][N:24]([CH3:23])[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([NH:32][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:22])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: COc1ccc(N)cc1OCCCN(C)C
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Product: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1OCCCN(C)C

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268 A1) and 3-(3-dimethylaminopropoxy)-4-methoxyaniline (D23) using a similar procedure to Example 1 (58%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][N:28]=1>>[CH2:20]([N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:29]=[N:28][C:27]([O:26][CH3:25])=[N:32][CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:24])[C:13]2=[O:23])[C:16]([CH3:22])=[N:17]1)[CH3:21]
Reactant: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Reactant: COc1ncc(B(O)O)cn1
Product: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(-c5cnc(OC)nc5)cc4c32)c(C)n1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 49 mg, 0.126 mmol) and 2-methoxy-5-pyrimidineboronic acid (ABCR, Karlsruhe, Germany, 25 mg, 0.162 mmol) to give the title compound as a white solid. (HPLC: tR 2.47 min (Method A); M+H=416 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.76-8.68 (m, 2H), 8.23-8.16 (m, 1H), 8.16-8.09 (m, 1H), 7.99-7.93 (m, 1H), 7.52-7.45 (m, 1H), 4.19 (q, 2H), 3.96 (s, 3H), 3.59 (s, 3H), 1.97 (s, 3H), 1.42 (t, 3H))
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[C:35]([F:38])([F:37])[F:36].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([F:27])=[C:29]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3I)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3I)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)(F)F)c1
Yield: 15.8 %

Procedure:
The title compound was prepared by following the procedure as described for step-6 of Intermediate-26 by using methyl 4-(3-(2-chloro-6-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-1 of Intermediate-34, 0.100 g, 0.20 mmol), 4-fluoro-3-(trifluoromethyl)aniline (0.044 g, 0.34 mmol), trimethyl aluminium (2M solution in toluene) (1.0 mL) and dry toluene (8.0 mL) to afford 0.020 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.94 (s, 3H), 3.78 (t, 1H), 7.52 (t, 2H), 7.71-7.82 (m, 3H), 8.03 (d, J=6.6 Hz, 2H), 10.38 (s, 1H), 12.69 (br s, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C1(C(C2C=CC=CC=2)=[NH:63])C=CC=CC=1.CC([O-])(C)C.[Na+]>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].CN(C=O)C>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH2:63])=[CH:3][C:4]=1[C:10]([F:13])([F:12])[F:11]
Reactant: COc1ncc(I)cc1C(F)(F)F
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ncc(N)cc1C(F)(F)F
Temperature: 120 °C
Yield: 34 %

Procedure:
To 5-Iodo-2-methoxy-3-(trifluoromethyl)pyridine (0.97 g, 3.20 mmol) (ECA International Product List) was added DMF (8.0 mL), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.093 g, 0.160 mmol), Pd2(dba)3 (0.147 g, 0.160 mmol), diphenylmethanimine (0.806 mL, 4.80 mmol), and sodium 2-methylpropan-2-olate (1.231 g, 12.80 mmol), and the resulting mixture was heated at 120° C. for 30 min. The reaction mixture was then diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with 1 N HCl (aqueous), and washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous). The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 5% (2 M ammonia in MeOH)/DCM) provided the title compound (34% yield). m/z (ESI, +ve ion) 193.2 (M+H)+.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.[C-]#N.[Na+].CN(C)[CH:14]=[O:15]>O>[CH:14]1([O:15][C:4]2[CH:8]=[CH:7][S:6][CH:5]=2)[CH2:7][CH2:8][CH2:4][CH2:5]1
Reactant: CN(C)C=O
Reactant: Brc1ccsc1
Agent: [C-]#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: c1cc(OC2CCCC2)cs1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a solution of cyclocentanol (8.75 ml, 95.8 mmol) in N,N-dimethylformamide (250 mL) was added sodium hydride (60% dispersion in mineral oil, 3.84 g, 95.8 mmol) at 0-5° C. under nitrogen. After 10 minutes, the mixture was allowed to reach room temperature and stirred for 40 minutes. 3-Bromothiophene (3.59 mL, 38.3 mmol) was added followed by cuprous iodide (14.63 g, 76.8 mmol). The mixture was heated at 120° C. for 22 hours. After cooling to about 10° C., a solution of sodium cyanide (12.1 g, 0.25 mol) in water (200 mL) was added under vigorous stirring. The mixture was stirred for additional 10 minutes then filtered. The filtrate was extracted with hexane. The extract was washed with water, dried (Na2SO4) and concentrated to dryness. Distillation (100° C., 8 mm Hg) gave 3-cyclopentyloxythiopene (4.52 g, 70%) as a slightly pale yellow oil; 1H NMR (300 Mz, CDCl3) δ 7.15 (dd, J=5.2, 3.1 Hz, 1H), 6.72 (dd, J=5.2, 15 Hz, 1H) 6.19 (dd, J=3.1, 1.5 Hz, 1H), 4.65 (quintet, J=4.2 Hz), 1H), 1.55-1.95 (m, 8H). MS m/e (%): 168 (M+; 17).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Cl.[OH:6][C:7]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:15][C:14]1[C:7]([O:6][CH2:4][CH2:3][O:2][CH3:1])=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10]
Reactant: COCCCl
Reactant: O=Cc1cccc(O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1c(O)cccc1C=O
Temperature: 70 °C
Reaction time: 48 h
Yield: 31.5 %

Procedure:
2-Chloroethyl methyl ether (4.63 mL, 50.7 mmol) was added dropwise to a mixture of 2,3-dihydroxybenzaldehyde (7.0 g, 50.7 mmol), potassium iodide (8.41 g, 50.69 mmol) and potassium carbonate (7.71 g, 55.8 mmol) in DMF (80 mL). The resulting mixture was stirred at r.t. under a nitrogen atmosphere for two days and at 70° C. for two days. The reaction mixture was partitioned between saturated ammonium chloride (aq.) and CH2Cl2. The water phase was re-extracted with CH2Cl2 and the combined organic phases were washed with brine, dried (Na2SO4) and evaporated onto silica. Purification by flash column chromatography (heptane/ethyl acetate gradient; 0 to 30% ethyl acetate) yielded a crude oil which was further purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 40% ethyl acetate) to yield the title compound (3.13 g, 31%) as an oil.
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([CH2:10][O:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:19])[C:6]=2[C:20](OCC)=[O:21])[CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(OCC)(=O)C>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([CH2:10][O:11][C:12]3[C:13]([CH3:19])=[CH:14][CH:15]=[CH:16][C:17]=3[CH3:18])[C:6]=2[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)c1c(COc2c(C)cccc2C)noc1C1CCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1OCc1noc(C2CCC2)c1CO
Temperature: 0 °C
Yield: 100 %

Procedure:
To a solution of ethyl 5-cyclobutyl-3-{[(2,6-dimethylphenyl)oxy]methyl}-4-isoxazolecarboxylate (1.08 g, 3.26 mmol) at 0° C. was added a 1.5 M solution of diisobutylaluminum hydride in toluene (7.18 mL, 10.8 mmol) at a slow pace. The solution was allowed to stir while warming slightly for approximately 1.5 hours and then was re-cooled to 0° C. Then approximately 40 mL of Rochelle's salt was slowly added followed by ethyl acetate. The mixture was allowed to warm to ambient temperature and stirred overnight. Then the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to afford (5-cyclobutyl-3-{[(2,6-dimethylphenyl)oxy]methyl}-4-isoxazolyl)methanol (937 mg, 100%). 1H-NMR (400 MHz, DMSO-d6) δ 7.03-6.91 (m, 3H), 4.97 (t, J=5 Hz, 1H), 4.83 (s, 2H), 4.35 (d, J=5 Hz, 2H), 3.85-3.77 (m, 1H), 2.36-2.26 (m, 4H), 2.14 (s, 6H), 2.10-1.98 (m, 1H), 1.94-1.84 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[S:25](Cl)([CH3:28])(=[O:27])=[O:26].[O-]S([O-])(=O)=O.[Na+].[Na+]>ClCCl.O>[CH3:28][S:25]([O:1][CH2:2][C@@H:3]([NH:10][C:11]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1ccccc1
Yield: 98 %

Procedure:
The solution of 68.9 g (0.29 mol) of tert-butyl (1S)-2-hydroxy-1-phenylethylcarbamate and triethylamine (40.36 mL, 0.29 mol) in 700 mL of dry dichloromethane under inert atmosphere was cooled to −10° C. and 24.79 mL (0.319 mol) of mesylchloride were added dropwise. After 2 hours at 0° C. the mixture was poured into ice and water and extracted with dichloromethane. The organic phase was washed with diluted HCl, aqueous NaHCO3, brine and dried over Na2SO4 yielding 89.8 g of the product (98% yield).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8])[CH2:2][CH3:3].[Cl:14][S:15](O)(=[O:17])=[O:16]>>[Cl:14][S:15]([C:11]1[CH:12]=[CH:13][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8])(=[O:17])=[O:16]
Reactant: CCCOc1ccccc1C(N)=O
Reactant: O=S(=O)(O)Cl
Product: CCCOc1ccc(S(=O)(=O)Cl)cc1C(N)=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Chlorosulphonic acid (200 ml.), cooled to 10° C., was treated with 2-propoxybenzamide (60 g.) in aliquots with stirring during 45 minutes. When complete solution had occurred, the solution was allowed to stand at room temperature for 24 hours. The resulting yellow-brown solution was then added dropwise, with stirring, to ice (1.5 kg.), keeping the temperature at or below 0° C. The precipitated solid was filtered off, washed with ice-cold water, and sucked dry. The solid was then dissolved in dichloromethane (approximately 2 liters), any water still present was separated off, and the organic layer was dried over calcium chloride and then over magnesium sulphate. Most of the dichloromethane was removed in vacuo, the low volume residue was treated with petroleum ether (b.p. 40° - 60° C.) and the precipitated solid was filtered off, to give crude 5-chlorosulphonyl-2-propoxybenzamide (81 g.), m.p. 122° - 129° C.
Reaction SMILES: [Mg].II.[CH:4]([C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[CH:14]([C:16]1[C:24]2[O:23][CH2:22][CH:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20]=2[C:19]([CH3:31])=[C:18]([NH:32][C:33](=[O:39])[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:17]=1[CH3:40])=[O:15]>C1COCC1>[OH:15][CH:14]([C:10]1[CH:11]=[CH:12][C:7]([CH:4]([CH3:6])[CH3:5])=[CH:8][CH:9]=1)[C:16]1[C:24]2[O:23][CH2:22][CH:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20]=2[C:19]([CH3:31])=[C:18]([NH:32][C:33](=[O:39])[CH2:34][C:35]([CH3:36])([CH3:37])[CH3:38])[C:17]=1[CH3:40]
Reactant: CC(C)c1ccc(Br)cc1
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccccc1)CO2
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(O)c1ccc(C(C)C)cc1)OCC2c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of magnesium (119 mg, 4.91 mmol) and a catalytic amount of iodine was added dropwise under an argon atmosphere a solution of 4-isopropyl-1-bromobenzene (978 mg, 4.91 mmol) in THF (10 mL) and the mixture was stirred at room temperature for 20 minutes. To the reaction solution was added dropwise a solution of N-(7-formyl-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (200 mg, 0.547 mmol) obtained in Example 232 in THF (5 mL) and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to ice and the product was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain N-(7-(hydroxy(4-isopropylphenyl)methyl)-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide. To a mixture of the compound and trifluoroacetic acid (5 mL) was added with ice-cooling triethylsilane (0.161 mL, 1.01 mmol), and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, to the residue was added an aqueous saturated sodium bicarbonate solution and the aqueous layer was made alkaline, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and crystallized from hexane to obtain 70 mg (yield: 28%) of the title compound. Melting point: 137-141° C. (ethyl acetate-hexane).
Reaction SMILES: BrC[C:3]1[CH:13]=[C:12]([CH2:14]Br)[CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8]C)=[O:6].[O:16]1CCOCC1.S(=O)(=O)(O)O>C(Cl)Cl>[OH:16][CH2:14][C:12]1[CH:11]=[C:10]2[C:4](=[CH:3][CH:13]=1)[C:5](=[O:6])[O:7][CH2:8]2
Reactant: C1COCCO1
Reactant: CCOC(=O)c1ccc(CBr)cc1CBr
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=C1OCc2cc(CO)ccc21
Temperature: 25 °C

Procedure:
A suspension of 2 (22.1 g, 65.7 mmol) in 700 mL of a 1:1 mixture of dioxane/sulfuric acid (1M) was heated under reflux for 20 h. After cooling to room temperature, the mixture was poured into 200 mL of DCM. The phases were separated and the aqueous phase was extracted with DCM (5×200 mL). The combined organic layers were washed with saturated NaHCO3 (3×200 mL) and brine (1×200 mL) and were dried over MgSO4. The solvent was removed in vacuo to yield 8.70 g (83%) of pure 3 as a colorless solid: 1H-NMR (400 MHz, DMSO-d6): δ 4.65 (s, 2H), 5.39 (s, 2H), 5.47 (br s, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.60 (s, 1H), 7.78 (d, J=7.7 Hz, 1H); 13C-NMR (100 MHz, DMSO-d6): δ 62.4, 69.7, 120.0, 123.3, 124.5, 126.9, 147.5, 149.7, 170.5; MS (Cl+ (NH3)) m/z=165.0 (M+H+, 100), 182.0 (M+NH4+, 49).