Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([CH:40]=1)[CH2:7][C@H:8]1[C:14](=[O:15])[N:13]([C:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[O:17])[CH2:12][C:11](=[O:26])[N:10](CC2C(OC)=CC(OC)=CC=2OC)[CH2:9]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([CH:40]=1)[CH2:7][C@H:8]1[C:14](=[O:15])[N:13]([C:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[O:17])[CH2:12][C:11](=[O:26])[NH:10][CH2:9]1
Reactant: COc1cc(OC)c(CN2C[C@@H](Cc3cc(Cl)ccc3OC)C(=O)N(C(=O)Oc3ccccc3Cl)CC2=O)c(OC)c1
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1C[C@@H]1CNC(=O)CN(C(=O)Oc2ccccc2Cl)C1=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 56.1 %

Procedure:
To the compound S141C described in WO 06-059801A, that is, (6R)-2-chlorophenyl 6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-carboxylate (996 mg), anisole (1.75 ml) and trifluoroacetic acid (10 ml) were added, and the mixture was stirred at room temperature for 4.5 hours. The reaction solution was diluted with toluene and concentrated in vacuo. This operation was repeated two times and excessive anisole was distilled off under reduced pressure of a vacuum pump. To the residue, ethyl acetate was added. The precipitated solid was collected by filtration to obtain the title compound (396 mg). Furthermore, the filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate=2/1 to 1/3) to obtain the title compound (198 mg).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[F:17][C:18]([F:28])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](O)=[O:20]>>[F:17][C:18]([F:28])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:19]([NH:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16])=[O:20]
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: O=C(O)C(F)(F)c1ccccc1
Product: O=C(Nn1nc(C(F)(F)F)c2ccccc2c1=O)C(F)(F)c1ccccc1

Procedure:
The product of Example 11B and 2,2-difluoro-2-phenylacetic acid were treated using a method similar to that described in Example 51 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 13.10 (s, 1H), 8.43-8.47 (m, 1H), 8.16 (td, J=7.6, 1.6 Hz, 1H), 8.03-8.12 (m, 2H), 7.74-7.78 (m, 2H), 7.54-7.66 (m, 3H); MS (ESI+) M/Z 384 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[O:11][C:10](C)(C)O[C:8](=[O:14])[C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:3])[CH3:2].C=[N:22][C:23]([CH3:31])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24]>C1(C)C(C)=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[O:11][CH2:10][N:22]([C:23]([CH3:31])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[C:8](=[O:14])[C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:3])[CH3:2]
Reactant: C=NC(C)(C)c1ccccc1
Reactant: CC(=O)OCC1=C(c2ccccc2)C(=O)OC(C)(C)O1
Solvent: Cc1ccccc1C
Product: CC(=O)OCC1=C(c2ccccc2)C(=O)N(C(C)(C)c2ccccc2)CO1
Yield: 72 %

Procedure:
A mixture of 6-acetyloxymethyl-2,2-dimethyl-5-phenyl-2H,4H-1,3-dioxin-4-one (Compound No. 241, 5.0 g) and N-methylene-1-methyl-1-phenylethylamine (2.9 g) was dissolved in xylene (40 ml) and allowed to react by refluxing for 30 minutes. The reaction mixture was purified by silica gel chromatography to afford the captioned compound (yield 72%).
Reaction SMILES: Br[C:2]1([C:12]([O:14][CH3:15])=[O:13])[C:10](=[O:11])[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Li+].[Li+]>CN(C=O)C>[OH:11][C:10]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[CH:4]=[CH:3][C:2]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C1(Br)CCc2sccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2sccc2c1O
Temperature: 100 °C
Yield: 31.8 %

Procedure:
A solution containing methyl 5-bromo4-oxo-4,5,6,7-tetrahydro-1-benzothiophene-5-carboxylate (Preparation 12, 1.18 g) and lithium carbonate (1.81 g) in anhydrous DMF (10 mL) is heated at 100° C. overnight. After cooling, the solids are removed by filtration and the filtrate is partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated to give a brown solid. This crude product is chromatographed on a Biotage column eluting with 0-20% ethyl acetate in heptane (250 mL each 10%) to give 270 mg (32%) of the title compound as a white solid. Physical characteristics: Mp 94-95° C.; MS (ESI−) m/z 207.0 (M−H)−. Anal. found: C, 57.26; H, 3.88; N, 0.17.
Reaction SMILES: [CH:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3(O)[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][CH:13]34)=[CH:21][C:20]([CH:25]=[CH2:26])=[CH:19][CH:18]=5)[C:8]=2[C:28]([F:31])([F:30])[F:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1.N1C=CC=CC=1.Cl>[CH:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=[CH2:26])=[CH:19][CH:18]=5)[C:8]=2[C:28]([F:29])([F:30])[F:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=Cc1ccc2c(c1)CCC1C2=NOC1(O)c1noc(C2CCCCC2)c1C(F)(F)F
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(C2CCCCC2)c1C(F)(F)F
Temperature: 110 °C
Yield: 16 %

Procedure:
A stirred mixture of 3-(5-cyclohexyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-3,3a,4,5-tetrahydronaphtho[1,2-c]isoxazol-3-ol and thionyl chloride (0.030 g, 0.252 mmol) in toluene (5.0 mL) and pyridine (1.5 mL) was heated at 110° C. for 10 minutes. The reaction mixture was cooled, diluted with 1 N aqueous hydrochloric acid (5.0 mL), and extracted with ethyl acetate (3×20 mL). The ethyl acetate extracts were combined and concentrated to give 3-(5-cyclohexyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole [0.016 g, 0.039 mmol, 16%] as an orange solid. The product had an HPLC ret. time=4.916 min. (condition B). LC/MS M+1=415.08.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[CH3:2].[CH2:15]1COCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4]([C@@H:5]1[CH2:15][C@H:6]1[C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)=[O:14])[CH3:2]
Reactant: C1CCOC1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1

Procedure:
To a solution of E-3-(4-bromo-phenyl)-acrylic acid ethyl ester and Pd(OAc)2 (0.05 eq.) in THF (0.2M) was added portionwise CH2N2 until the reaction was completed. NMR of aliquots monitored the reaction. The resulting mixture was concentrated and filtered on celite to afford the title compound as an oil.
Reaction SMILES: [Na].[CH3:2][C:3]([CH2:11][CH3:12])([CH2:7][CH2:8][CH2:9][CH3:10])[C:4](Cl)=[O:5].[CH3:13][CH2:14][O-:15].[Na+]>C(O)C>[CH3:2][C:3]([CH2:11][CH3:12])([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([O:15][CH2:14][CH3:13])=[O:5]
Reactant: CC[O-]
Reactant: CCCCC(C)(CC)C(=O)Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCCC(C)(CC)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
11.5 gm (0.5 mole ) of sodium were dissolved in 150 ml of ethanol. 44 gm (0.25 mole) of 2-methyl-2-ethyl-hexanoyl chloride were slowly added under agitation to the solution of sodium ethylate at O° to 5° C. The mixture was subsequently agitated for 3 hours at room temperature, filtered, absorbed in ether, washed neutral with water, dried, reduced, and fractionated in vacuo. The ethyl 2-methyl-2-ethyl-hexanoate was obtained in the form of a colorless oil having a fruity/fresh odor with a fragrance of apple and camomile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[Li][CH2:14][CH2:15][CH2:16]C.ICCC>C1COCC1.CCCCCC>[CH2:14]([C:4]1[C:5]([O:11][CH3:12])=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])[CH2:15][CH3:16]
Reactant: COc1cc(OC)cc(OC)c1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCCI
Product: CCCc1c(OC)cc(OC)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
To the stirred solution of 1,3,5-trimethoxybenzene (10.0 g, 59.4 mmol) in 150 mL of dry THF at 0° C. in nitrogen atmosphere was added 23.7 mL (59.3 mmol) of 2.5 M n-BuLi in hexane dropwise via syringe. The resulting solution was stirred at room temperature for 4 hr. The mixture was cooled to -20° C. and 1-iodopropane (6.09 mL, 62.5 mmol) was added dropwise via syringe in 10 min. After being stirred at room temperature for 14 hr and refluxed for 4 hr, the mixture was quenched with 200 mL of water, concentrated in vacuo to remove THF and extracted with ether. The organic layer was washed with water, dried (MgSO4) and concentrated. The crude product was washed with hexane to give 11.07 g of the title compound: mp 48.5-49.5° C.; 1H NMR (CDCl3): 6.13 (2 H, s), 3.80 (3 H, s), 3.79 (6 H, s), 2.52 (2 h, m), 1.44 (2 H, sex, J=7.5 Hz), 0.91 (3 H, t, J=7.5 Hz).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>O.C(O)C>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14](=[N:2][OH:3])[NH2:15]
Reactant: COc1ccccc1C#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccccc1C(N)=NO
Reaction time: 1.5 h
Yield: 30.9 %

Procedure:
To a solution of hydroxylamine hydrochloride (245 g.) and sodium carbonate (170 g.) in water (2.6 l.) was added a solution of 2-methoxybenzonitrile (127.5 g.) in ethanol (1.25 l.), and the mixture refluxed with stirring for 1.5 hours. The solution was concentrated in vacuo to low bulk and the resultant oil crystallised on standing. The solid was filtered off, washed with water to remove inorganic salts, dried at 60° C., and recrystallised from benzene to give 2-methoxybenzamidoxime (49.2 g.), m.p. 117°-119° C. Further material (21.2 g., m.p. 119°-120° C.) was obtained by concentration of the recrystallisation mother liquor.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]([CH3:11])[C:7](=[O:12])[CH:6]=1.[CH3:13][C:14]1([CH3:30])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[O:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:11][N:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][NH:2][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([B:16]3[O:17][C:18]([CH3:19])([CH3:20])[C:14]([CH3:30])([CH3:13])[O:15]3)=[CH:29][CH:28]=2)=[CH:6][C:7]1=[O:12]
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: Cn1ccc(CCN)cc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc(CCNC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 150.4 %

Procedure:
A mixture of 4-(2-aminoethyl)-1-methylpyridin-2(1H)-one hydrochloride (76 mg, 0.4 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (100 mg, 0.4 mmol), HATU (190 mg, 0.5 mmol) and DIEA (260 mg, 2 mmol) in 25 mL of DCM and 5 mL of DMF was stirred at room temperature overnight. The solution was washed with sat NaHCO3 (2×20 mL), brine (2×20 mL), dried over anhydrous sodium sulfate, concentrated under reduce pressure to give crude N-(2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (230 mg) and used for next step without further purification. LC-MS: 383 [M+H]+, tR=1.41 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:36]=1)[O:7][CH2:8][C:9]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C@@H:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][C@H:21]2[OH:27])=[C:15]([N+:28]([O-])=O)[CH:14]=1.C(N(CC)CC)C.N1C=CC=CC=1.C1C=CC(O[C:57](OC2C=CC=CC=2)=[N:58][C:59]#[N:60])=CC=1>O1CCCC1.[Pt]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:36]=1)[O:7][CH2:8][C:9]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]2[N:19]([C@@H:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][C@H:21]3[OH:27])/[C:57](=[N:58]/[C:59]#[N:60])/[NH:28][C:15]=2[CH:14]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: CN1CC[C@@H](Nc2ccc(/C=C3/c4ccc(F)cc4OCc4c(F)cccc43)cc2[N+](=O)[O-])[C@H](O)C1
Agent: [Pt]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN1CC[C@@H](n2/c(=N/C#N)[nH]c3cc(/C=C4/c5ccc(F)cc5OCc5c(F)cccc54)ccc32)[C@H](O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
Dissolve (3R,4R)-4-[4-((E)-3,7-Difluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenylamino]-1-methyl-piperidin-3-ol (0.009 mol, 4.48 g) in tetrahydrofuran (100 mL). Add triethylamine (0.018 mol, 1.83 g) and 10% platinum on carbon (2.2 g) and hydrogenate in a Parr shaker at 50 psi (H2) at room temperature for 4 h. Filter off the catalyst through a plug of diatomaceous earth. Add pyridine (100 mL) and diphenyl N-cyanocarbonimidate (0.009 mol, 2.16 g) to the filtrate. Stir at room temperature for 16 h and then heat at 60-70° C. for 8 h. Remove the solvent under reduced pressure. Dissolve the residue in dichloromethane and wash with water and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify on a silica gel column using 5% methanol in dichloromethane as eluent to obtain the title compound (1.2 g, 26%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.66-1.8 (m, 1H), 1.75-1.78 (m, 1H), 1.87-1.90 (m, 1H), 2.03 (br s, 1H), 2.24 (s, 3H), 2.81 (br s, 1H), 2.96 (br s, 1H), 3.99 (br s, 1H), 4.31 (br s, 1H), 5.09 (s, 1H), 5.36 (br s, 1H), 5.46 (br s, 1H), 6.68 (dd, 1H), 6.82-6.87 (m, 3H), 6.99 (d, 1H), 7.09 (s, 1H), 7.26-7.35 (m, 3H), 7.62 (t, 1H), 12.49 (br s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=S)[CH3:2].Cl.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[CH:25]([OH:38])[CH:26]([NH:29][C:30](=[O:37])[CH:31]([NH2:36])[CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:27][CH3:28].C(N(C(C)C)CC)(C)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[CH2:1]([O:3][C:4](=[O:14])[N:5]=[C:6]([NH:36][C@H:31]([C:30](=[O:37])[NH:29][C@H:26]([C:25]([C:17]1[O:16][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)=[O:38])[CH2:27][CH3:28])[CH2:32][CH:33]([CH3:34])[CH3:35])[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOC(=O)NC(=S)N1CCOCC1
Reactant: CCC(NC(=O)C(N)CC(C)C)C(O)c1nc2ccccc2o1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N=C(N[C@@H](CC(C)C)C(=O)N[C@@H](CC)C(=O)c1nc2ccccc2o1)N1CCOCC1
Temperature: 25 °C

Procedure:
(Morpholine-4-carbothioyl)carbamic acid ethyl ester (55 mg, 0.25 mmol), 2-amino-4-methylpentanoic acid [1-(benzoxazol-2-ylhydroxymethyl)propyl]amide hydrochloride (90 mg, 0.25 mmol), and diisopropylethylamine (0.13 mL, 0.76 mmol) were dissolved in dichloromethane (5 mL). 2-Chloro-1-methylpyridinium iodide (84 mg, 0.33 mmol) was added and the reaction mixture was stirred at ambient temperature over night. After dilution with ethyl acetate (100 mL), the solution was washed with sat. aq. NaHCO3, and brine, dried with MgSO4 and evaporated under vacuum. The residue was dissolved in dichloromethane (10 mL) and Dess-Martin periodinane (400 mg) was added. The reaction mixture was stirred at ambient temperature for 1 h. After dilution with ethyl acetate (100 mL), the solution was washed with a 0.26 M solution of Na2S2O3 in sat. aqu. NaHCO3, then with sat. aq. NaHCO3, and brine, dried with MgSO4 and evaporated under vacuum. After purification by flash chromatography on silica gel, the title compound was obtained as yellowish glass (10 mg, 0.020 mmol). MS: (M+H)+ 502.
Reaction SMILES: CI.[Br:3][C:4]1[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=2[CH:23]=1.[C:29]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:3][C:4]1[C:5]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:26])=[O:27])=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=2[CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Reaction time: 8 h
Yield: 93.5 %

Procedure:
CH3I (31.6 g, 223 mmol) was added to a mixture of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (32 g, 74 mmol), K2CO3 (25.6 g, 186 mmol) and KI (246 mg, 1.5 mmol) in DMF (150 mL) under N2 protection. The mixture was stirred at 80˜90° C. overnight. After concentrated in vacuo, the resulting residue was washed with water (200 mL) and EtOAc (200 mL) to provide the product of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (31.5 g, 94%). 1H-NMR (CDCl3, 400 MHz) δ 8.16 (s, 1H), 7.88˜7.92 (m, 2H), 7.70 (s, 1H), 7.18˜7.23 (m, 2H), 5.78 (br s, 1H), 3.34 (s, 3H), 3.09 (s, 3H), 3.00 (d, J=4.8 Hz, 3H). MS (M+H)+: 455/457.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](O)=[C:15]([F:20])[CH:14]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl.CCCCCC>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:26]2([OH:8])[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:15]([F:20])[CH:14]=1.[CH3:23][CH2:22][O:21][CH2:26][CH3:25]
Reactant: C1=COCCC1
Reactant: Oc1ccc(Br)cc1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOCC
Product: OC1(c2ccc(Br)cc2F)CCCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
p-Toluene sulfonic acid (0.40 g) was added to an ice-cooled solution of 4-Bromo-2-fluoro phenol (205.38, 1.075 mol) in dihydro-2H-pyran (452.23 g, 5.376 moles). The ice bath was removed after 30 min. and the mixture was stirred for two hours and then diluted with methylene chloride (500 ml). The methylene chloride solution was extracted with 10% aqueous KOH solution (3×500 ml), rinsed with water (3×500 ml), dried over MgSO4, filtered and rotavaped. The crude product was further dried overnight over a vacuum pump and then vacuum distilled. The first distillation fraction was unreacted phenol, (52.0 g) followed by a fraction of the protected phenol (212.29 g, 71.8%). The purified product was frozen in dry ice/acetone bath and then allowed to sit in the refrigerator over 2-3 days to obtain the Monomer IA2 intermediate as clear needle shaped crystals, mp=25-27° C., mp of the Monomer IA1 intermediate=62-63° C., TLC (1:1 CH2Cl2/hexane), Rf=0.42.
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][CH:37]3[CH2:42][CH2:41][N:40]([C:43]4[S:44][CH:45]=[C:46]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)[N:47]=4)[CH2:39][CH2:38]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:54][C@@H:25]([CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:36][CH:37]2[CH2:42][CH2:41][N:40]([C:43]3[S:44][CH:45]=[C:46]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[N:47]=3)[CH2:39][CH2:38]2)=[CH:34][CH:35]=1)[CH2:24][O:23][C:22]1[CH:55]=[CH:56][C:19]([OH:18])=[CH:20][CH:21]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(c4nc(-c5ccccc5)cs4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(c4nc(-c5ccccc5)cs4)CC3)cc2)cc1

Procedure:
(2S)-1-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-3-[(4-{[1-(4-phenyl-1,3-thiazol-2-yl)-4-piperidinyl]amino}phenethyl)amino]-2-propanol (0.25 g, 0.319 mmol) was reacted following general Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound as the hydrochloride salt (0.12 g, 0.22 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>C(OCC)(=O)C>[C:17]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: OCc1ccc(O)cc1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(CO)cc1
Yield: 40 %

Procedure:
To a cooled suspension of 4-hydroxybenzyl alcohol (1.95 g, 14 mmol) in ethyl acetate (25 mL) in an ice-bath, triethylamine (2.1 mL, 14.9 mmol) was added in one lot under stirring. A solution of acetyl chloride (1.1 mL, 15.5 mmol) in ethyl acetate (12 mL) was added dropwise from an addition funnel. The reaction mixture was stirred overnight. The solid was filtered, washed with ethyl acetate and the residue, after concentration, was purified by column chromatography using hexanes initially and later gradually to 40% ethyl acetate. Yield 40%. 1H-NMR (CDCl3), δ 2.02 (br. s, 1H), 2.29 (s, 3H), 4.65 (s, 2H), 7.07 (d, 2H), 7.36 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#N.CC(C[AlH]CC(C)C)C.Cl.C1C[O:24]CC1>>[Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:24]
Reactant: C1CCOC1
Reactant: N#Cc1ccc(O)cc1Cl
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Product: O=Cc1ccc(O)cc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
After 2-chloro-4-hydroxy-benzonitrile (2 g, 0.013 mol) was dissolved in anhydrous THF (40 mL), DIBAL-H 1M hexane solution (21.7 mL, 0.032 mol) was added thereto at −78° C., and the mixture was stirred for 1 hour, and then stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was added with 1M HCl at 0° C. and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process.
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10](N3C=C(C4C=CC=CC=4O)N=C3CC(C)C)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].S([O-])(=O)(=O)C>CN(C=O)C.O>[C:7]1([O:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:30][CH:29]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)Cc1nc(-c2ccccc2O)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(Oc2ccccc2)cc1
Temperature: 90 °C

Procedure:
{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol (2 mmol) was added to a solution of Cs2CO3 (10 eq., 20 mmol) in anhydrous DMF (5 ml). This was followed by addition of the mesylate obtained above and the reaction mixture was heated to 90° C. for 2–3 h. The reaction mixture was then cooled to rt, diluted with cold water and the product was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give desired phenyl ether.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[N:24]1[CH:25]=[C:26]([C:33](O)=[O:34])[N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=12>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:33]([C:26]2[N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]3=[N:24][CH:25]=2)=[O:34])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1cnc2ccccn12
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cnc3ccccn23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with Imidazo[1,2-a]pyridine-3-carboxylic acid. LC-MS (basic): tR=0.74 min; [M+H]+=477.3.