Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C[O-].[Na+].[C:8]1(=[O:14])[NH:12][C:11](=[O:13])[CH2:10][CH2:9]1.[Cl:15][C:16]1[C:17]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[C:18]2[C:26]3[CH2:27][CH2:28][S:29][CH2:30][C:25]=3[S:24][C:19]2=[N:20][C:21]=1[CH2:22]Cl>O.CO>[Cl:15][C:16]1[C:17]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[C:18]2[C:26]3[CH2:27][CH2:28][S:29][CH2:30][C:25]=3[S:24][C:19]2=[N:20][C:21]=1[CH2:22][N:12]1[C:11](=[O:13])[CH2:10][CH2:9][C:8]1=[O:14]
Reactant: O=C1CCC(=O)N1
Reactant: COc1ccc(-c2c(Cl)c(CCl)nc3sc4c(c23)CCSC4)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCSC4)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To dimethyl sulfoxide (2450 ml) was added 28% sodium methoxide (97.4 g), followed by addition of succinimide (178.9 g). The mixture was stirred at about 20° C. for 30 minutes and then 3-chloro-2-chloromethyl-5,8-dihydro-4-(4-methoxyphenyl)-6H-thiopyrano[4′,3′:4,5]thieno-[2,3-b]pyridine (490 g) was added thereto. The mixture was stirred at room temperature for 2.5 hours and then a mixture of methanol (1225 ml) and water (490 g) was added dropwise thereto. The mixture was stirred at 10° C. or lower and crystals deposited were filtered off to the titled compound (546 g, 96.3%).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH2:17])=[O:16].CC(C)([O-])C.[Na+].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1>FC(F)(F)C1C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=1[C:5]1[O:6][C:2]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[C:3]([C:15]([NH2:17])=[O:16])[N:4]=1
Reactant: COc1ccc(N)cc1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: FC(F)(F)c1ccccc1
Product: COc1ccc(Nc2oc(-c3c(F)cccc3F)nc2C(N)=O)cc1
Temperature: 160 °C
Yield: 2.4 %

Procedure:
To a stirred, degassed solution of 5-bromo-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.125 g, 0.41 mmol) in trifluorotoluene (10.5 mL) was added tris(dibenzylideneacetone)dipalladium(0) (0.019 g, 0.02 mmol), (±)-2,2″-bis(diphenylphosphino)-1,1″-binaphthalene (0.026 g, 0.04 mmol), and sodium tert-butoxide (0.059 g, 0.62 mmol). This was followed by addition of p-anisidine (0.076 g, 0.62 mmol) after approximately 3 minutes stirring. The resulting reaction mixture was degassed, placed under an N2 atmosphere and heated in the microwave at 160° C. for 20 minutes. The solution was then washed with 2M aqueous HCl and brine, dried over MgSO4 and then passed through a MP-SH resin cartridge (500 mg). The solvent was removed in vacuo and the residue purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(4-methoxyphenylamino)oxazole-4-carboxamide (0.0037 g, 0.01 mmol, 8%) as a white solid. 1H NMR (DMSO) δ 3.74 (3H, s), 6.93 (2H, d), 7.29 (2H, br. s), 7.32 (2H, t), 7.37 (2H, d), 7.62 (1H, m), 9.17 (1H, br. s). LCMS (2) Rt: 2.80 min; m/z (ES+) 346.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([CH3:11])[N:9]=[CH:8][C:7]=1[C:12]#[N:13].S(=O)(=O)(O)[OH:15].[OH-].[Na+]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([CH3:11])[N:9]=[CH:8][C:7]=1[C:12]([NH2:13])=[O:15]
Reactant: Cn1ncc(C#N)c1-c1ccco1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cn1ncc(C(N)=O)c1-c1ccco1
Yield: 91 %

Procedure:
Stir 1.1 g of 5-(2-furyl)-1-methylpyrazole-4-carbonitrile together with 7 ml of concentrated sulfuric acid for 24 hours at room temperature. Pour the resulting mixture onto ice and adjust its pH-value to 4 with caustic soda. Then extract it with methylene chloride and reduce the organic phase to dryness to obtain 5-(2-furyl)-1-methylpyrazole-4-carboxamide [m.p. 115.5° to 116° C (from ethanol)] with a yield of 91%.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[Cl:13][C:14]1[C:15](C(O)=O)=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=1>C1(OC)C=CC=CC=1>[Cl:13][C:14]1[C:15]([CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[O:3][CH:2]([F:12])[F:1])[OH:7])=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=1
Reactant: O=Cc1ccccc1OC(F)F
Reactant: CSc1ncc(Cl)c(C(=O)O)n1
Solvent: COc1ccccc1
Product: CSc1ncc(Cl)c(C(O)c2ccccc2OC(F)F)n1
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 54.9 %

Procedure:
A mixture of 780 mg of 2-(difluoromethoxy)benzaldehyde and 300 mg of 5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylic acid 1 in 15 ml of anisole is microwave-heated at 130° C. for 45 min and then again for 15 min and again at 140° C. for 15 min. 160 mg of 5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylic acid 1 is then added and the mixture is again heated at 130° C. for 30 min. The mixture is concentrated under vacuum and purified on 40 g of silica, elution being carried out with 0-10% of ethyl acetate in heptane, so as to obtain 268 mg of [5-chloro-2-(methylsulfanyl)pyrimidin-4-yl][2-(difluoromethoxy)phenyl]methanol 6 in the form of a colourless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:17][CH3:18])[C:15]=3[CH3:16])[S:10][C:3]=12.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:27]=1[OH:35]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[CH2:17]([N:14]1[C:15]([CH3:16])=[C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:35][C:27]3[CH:28]=[CH:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][C:26]=3[F:25])[CH:8]=2)[N:12]=[CH:13]1)[CH3:18]
Reactant: CCn1cnc(-c2cc3nccc(Cl)c3s2)c1C
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1C
Temperature: 25 °C
Yield: 64.1 %

Procedure:
A suspension of 87 (650 mg, 2.35 mmol), potassium carbonate (970 mg, 7.04 mmol) and 2-fluoro-4-nitrophenol (738 mg, 4.7 mmol) were heated at 190° C. in diphenyl ether (15 ml) for 3 hrs. The mixture was cooled to room temperature, diluted with DCM and filtered. The filtrate was concentrated and the residue was purified by column chromatography (eluents EtOAc, then MeOH:EtOAc, 1:9) to afford title compound 88 (600 mg, 64%) as a yellow solid. MS (m/z) 399.0 (M+H).
Reaction SMILES: C(O)(C(F)(F)F)=O.O[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1.[SH:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>>[N:32]1[CH:33]=[CH:34][C:29]([S:28][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)=[CH:30][CH:31]=1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Reactant: Sc1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(CCSc2ccncc2)cc1)c1ccccc1
Yield: 5 %

Procedure:
The title compound was prepared as its TFA salt in 5% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 4-mercaptopyridine. NMR (400 MHz; CDCl3): δ 3.07 (t, 2H), 3.36 (t, 2H), 3.44 (br s, 3H), 7.06 (br d, 2H), 7.20 (d, 2H), 7.25–7.43 (m, 7H), 8.51 (d, 2H); HPLC-MS: m/z=365.2 (M+1); Rt=2.53 min.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[C:7]1([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)(C(F)(F)F)=O>[C:13]([CH:2]([SH:3])[C:1]([O:5][CH3:6])=[O:4])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CS
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(S)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl thioglycolate (0.50 g, 4.71 mmol) was dissolved in 5 mL anhydrous TFA. Triphenylmethanol (1.23 g, 4.71 mmol, 1 equiv.) was added and the deep-red solution was stirred at room temperature for 2 hours. TFA was evaporated and the residue was dissolved in ether (100 mL), washed with saturated sodium bicarbonate (50 mL×2) and brine (50 mL×1), dried over MgSO4, and concentrated to dryness, yielding a white solid (1.64 g, quantitative). Rf =0.45 (20% ether/petroleum ether). Products were confirmed by 1H NMR (400 MHz, CDCl3).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH2:23][CH2:24][NH:25]4)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].C([O-])([O-])=O.[K+].[K+].I[CH2:39][CH2:40][C:41]([NH2:43])=[O:42].C([O-])(O)=O.[Na+]>C(#N)C>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH2:23][CH2:24][N:25]4[CH2:39][CH2:40][C:41]([NH2:43])=[O:42])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:12])([F:13])[F:14]
Reactant: CC(Oc1ccc(-c2nc(-c3cccc4c3CCN4)no2)cc1C(F)(F)F)C(F)(F)F
Reactant: NC(=O)CCI
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Oc1ccc(-c2nc(-c3cccc4c3CCN4CCC(N)=O)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 80 °C
Reaction time: 15 h
Yield: 20.3 %

Procedure:
To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy]phenyl]-1,2,4-oxadiazol-3-yl)indoline (100 mg) in acetonitrile (2.5 ml) was added K2CO3 (46 mg) and 3-iodopropanamide (124 mg) at room temperature, followed by stirring at 80° C. for 15 hours. To the reaction solution was added an NaHCO3 aqueous saturated solution, followed by extraction with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 90:10) to obtain 3-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-2,3-dihydro-1H-indol-1-yl)propanamide (23.6 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)[CH2:15][CH:16]=1)[CH:6]=[CH:5]2.[H][H]>[Pt]=O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)[CH2:15][CH2:16]1)[CH:6]=[CH:5]2
Reactant: Clc1ccc2c(ccn2C2=CCN(CCC3Cc4ccccc4C3)CC2)c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: Clc1ccc2c(ccn2C2CCN(CCC3Cc4ccccc4C3)CC2)c1

Procedure:
A mixture of 5-Chloro-1-[1-[2-(indan-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole. 28a. (1.9 g), acetic acid (50 ml), and platinum oxide (0.1 g) was shaken for 3 h under 3 atm. hydrogen pressure. The mixture was filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate and the organic phase was shaken with dilute ammonium hydroxide and then worked up in a conventional manner. Further purification was done on silica gel eluted with ethyl acetate-heptane (1:1) to give 2.0 g of crude product. The crude product was crystallized (ethyl acetate), and the title compound was collected by filtration (1.1 g, 58%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[CH3:16])[CH2:10][CH2:9]1)(C)(C)C.[ClH:25].O1CCOCC1.Cl.Cl.Cl.CC1CCN(CCN2CCC(N)CC2)CC1>>[ClH:25].[ClH:25].[ClH:25].[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][C@@H:15]([N:17]2[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]2)[CH3:16])[CH2:12][CH2:13]1
Reactant: C[C@@H](CN1CCC(NC(=O)OC(C)(C)C)CC1)N1CCC(O)CC1
Agent: CC1CCN(CCN2CCC(N)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1

Procedure:
It is prepared by BOC-cleavage of tert-butyl ester 55 (0.666 g, 1.95 mmol) with 4M−HCl in dioxane (2.93 ml, 11.72 mmol) as described for amine 7.
Reaction SMILES: [CH:1]1(SC2C=CC(C(C3C=CC(C(F)(F)F)=C(OC)N=3)=O)=CC=2)CC1.[Si]([O:42][CH2:43][C@@H:44]([CH3:60])[CH2:45][S:46]([C:49]1[N:53]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:52]=[N:51][N:50]=1)(=[O:48])=[O:47])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[C:54]1([N:53]2[C:49]([S:46]([CH2:45][CH:44]3[CH2:60][CH2:1][O:42][CH2:43]3)(=[O:47])=[O:48])=[N:50][N:51]=[N:52]2)[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: COc1nc(C(=O)c2ccc(SC3CC3)cc2)ccc1C(F)(F)F
Reactant: C[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CS(=O)(=O)c1nnnn1-c1ccccc1
Product: O=S(=O)(CC1CCOC1)c1nnnn1-c1ccccc1

Procedure:
The title compound was obtained as a white solid (22 mg, 4% (three steps)) by performing substantially the same reaction as in Examples 1-47(1), 1-2 and 1-1(2) sequentially except for using [4-(cyclopropylsulfanyl)phenyl][6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanone obtained in Reference Example 1-68 and using 5-{[(2R)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpropyl]sulfonyl}-1-phenyl-1H-tetrazole obtained in Reference Example 3-14 in place of 1-phenyl-5-[(tetrahydrofuran-3-ylmethyl)sulfonyl]-1H-tetrazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[O:22])[C:16]=2[F:23])[N:12]([S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.O>O1CCCC1>[C:1]([O:5][C:6](=[O:33])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[C:16]=2[F:23])[N:12]([S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:25])=[O:26])[CH:11]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1cc(-c2cccc(C=O)c2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2cccc(CO)c2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
To a solution of tert-butyl{[5-(2-fluoro-3-formylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (388 mg) in tetrahydrofuran (8 mL) were added under ice-cooling, sodium borohydride (41.3 mg) and methanol (3 mL). After stirring at the same temperature for 30 min, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=2:1→1:2) to give the title compound as a colorless oil (yield 238 mg, 61%).
Reaction SMILES: [C:1]([C:9]1[CH:36]=[CH:35][C:12]([O:13][CH2:14][C:15]2[CH:34]=[CH:33][C:18]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[OH:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].Br[CH2:46][C:47]([O:49][CH3:50])=[O:48]>O>[C:1]([C:9]1[CH:36]=[CH:35][C:12]([O:13][CH2:14][C:15]2[CH:34]=[CH:33][C:18]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[O:37][CH2:46][C:47]([O:49][CH3:50])=[O:48])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(C(=O)c3ccccc3)c(O)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)ccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a mixture of 4-[4-(4-benzoyl-3-hydroxyphenoxymethyl)phenoxymethyl]-5-methyl-2-phenyloxazole (1.52 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.14 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Methyl bromoacetate (0.57 g) was added to the mixture and the mixture was stirred at 80° C. for 2 hrs., The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give methyl 2-[2-benzoyl-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenoxy]acetate as an oil (1.65 g, 94%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18]([NH2:23])[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]1[N:17]=[C:18]([NH2:23])[N:19]=[C:20]([NH:29][C:28]2[CH:30]=[CH:31][C:25]([Cl:24])=[CH:26][CH:27]=2)[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Nc1nc(Cl)cc(-c2cc(Cl)ccc2OCc2ccccc2)n1
Product: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2cc(Cl)ccc2OCc2ccccc2)n1
Yield: 98 %

Procedure:
Following the method described in Example 72, 4-(2-benzyloxy-5-chloro-phenyl)-6-chloro-pyrimidin-2-ylamine and 4-chloro-aniline provided the title compound (98% yield). 1H NMR (CD3OD) δ 5.26 (s, 2H, CH2), 6.44 (s, 1H, Ar), 7.21 (d, 1H, J=8.8 Hz, Ar), 7.33-7.36 (m, 2H, Ar), 7.38-7.43 (m, 4H, Ar), 7.45 (d, 1H, J=8.8 Hz, Ar), 7.58-7.61 (m, 2H, Ar), 7.80-7.82 (m, 2H, Ar).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([O:30][CH3:31])=[O:29])=[CH:18][CH:17]=2)[C:13]([CH:32]=O)=[N:12][C:11]=1[Cl:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[CH2:41]1[CH2:45]O[CH2:43][CH2:42]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC>[Si:1]([O:8][CH2:9][C:10]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([O:30][CH3:31])=[O:29])=[CH:20][CH:21]=2)[C:13](/[CH:32]=[CH:45]\[CH2:41][CH2:42][CH3:43])=[N:12][C:11]=1[Cl:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccccc1-c1ccc(Cn2c(C=O)nc(Cl)c2CO[Si](C)(C)C(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCC/C=C\c1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-t-Butyldimethylsilyloxymethyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloroimidazole-2-carboxaldehyde (200 mg) was added all at once to a solution of n-butyltriphenylphosphonium bromide (0.26 g) and potassium t-butoxide (70 mg) in THF at 0° C. The reaction mixture was stirred at room temperature for 15 minutes when it was quenched with saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, the organic layers washed with water, dried (MgSO4) and the solvent removed in vacuo. The residue was flash chromatographed in hexane/ethyl acetate (5:1) to yield 100 mg of an oil. NMR (200 MHz, CDCl3) δ7.85 (d, 1H), 7.54 (t, 1H), 7.42 (t, 1H), 7.35-7.24 (m, 3H), 7.07 (d, 2H), 6.07 (d, 1H), 5.87 (d of t, 1h), 5.28 (s, 2H), 4.59 (s, 2H), 3.64 (s, 3H), 2.69 (quart., 2H), 1.46 (sext., 2H), 0.91 (t, 3H), 0.86 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:6][CH:5]=1.[2H-].[Al+3].[Li+].[2H-].[2H-].[2H-]>C1COCC1>[Si:15]([O:14][CH2:13][CH2:12][O:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][CH:6]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: COC(=O)c1ccc(COCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [2H-]
Agent: [Al+3]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87.5 %

Procedure:
To a solution of the product of Example 8B (610 mg, 1.857 mmol) in THF (19 mL) at 0° C. was added a 1M solution (in THF) of lithium aluminum deuteride (1.9 mL, 1.857 mmol) dropwise. After completion of addition the ice bath was removed and the reaction was stirred at room temperature for 3.5 hours under nitrogen atmosphere, monitoring by TLC (3:1 pentane:ethyl acetate). The reaction was then diluted with water and extracted with ethyl acetate (2 times). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a clear oil (482 mg, 86% yield). The material was taken to the next step without further purification. 1H NMR (600 MHz, CDCl3): 7.33 (s, 4H), 4.56 (s, 2H), 0.89 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[C:12]1([NH2:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+].Cl>C(O)C>[C:12]1([NH:18][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,6-dichloro-3-nitropyridine (II-1, 193 mg, 1 mmol), phenylamine (III-2, 93 mg, 1 mmol) and sodium bicarbonate (84 mg, 1 mmol) were added to 10 mL anhydrous ethanol, and reacted at room temperature for 24 h. The reaction solution was poured into ice water, and adjusted with diluted HCl to a pH of 5-6, followed by stirring for 30 min, to precipitate a solid. The solid was filtered out, washed with water until neutral, and then dried to obtain compound IV-2 (219 mg, 88), a red solid, mp 95-98° C. 1H NMR (CDCl3) δ 10.28 (1H, b s, NH), 8.47 (1H, d, J=8.4 Hz, ArH-4), 7.66 (2H, d, J=8.0 Hz, ArH-2′, 6′), 7.42 (2H, t, J=8.0 Hz, ArH-3′, 5′), 7.21 (1H, t, J=7.2 Hz, ArH-4′), 6.81 (1H, d, J=8.4 Hz, ArH-5); MS (m/z): 250 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[I:22]Cl>CO.ClCCl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([I:22])=[C:11]([CH:10]=1)[CH2:12][OH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClI
Reactant: OCc1cccc(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OCc1cc(OCc2ccccc2)ccc1I
Reaction time: 1 h
Yield: 71 %

Procedure:
To a well stirred solution of 3-benzyloxybenzyl alcohol (5.5 g, 25.7 mmol) in methanol (100 mL) and sodium hydrogencarbonate (8.4 g, 100 mmol) was added a 1.0 M solution of iodine monochloride in dichloromethane (30 mL) at 0° C. The reaction mixture was brought to room temperature and stirring continued for additional 1 h. The reaction mixture was concentrated and then diluted with dichloromethane (150 mL), washed with 10% aqueous sodium thiosulfate and dried (Na2SO4). The desired compound was purified by flash chromatography (silica) using 20% ethyl acetate in hexane to give 5-benzyloxy-2-iodobenzyl alcohol (6.2 g, 71% yield). The alcohol (4.2 g, 12.4 mmol) was dissolved in dichloromethane (100 mL) added acetic anhydride (2.52 g, 24.7 mmol) and catalytic amount of 4-dimethylaminopyridine. The reaction mixture was then stirred for 12 h, washed with aqueous sodium hydrogencarbonate and then dried (Na2SO4) to give acetic acid 5-benzyloxy-2-iodo-benzyl ester in quantitative yield. MS (ESI) 405 (M+Na); Rf=2.27.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH2:20][CH:21]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:23]1([N:29]2[CH2:34][CH2:33][N:32]([CH2:21][CH2:20][CH2:19][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccccc4)CC3)nn2-c2ccccc2)cc1

Procedure:
116 mg (89%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80 mg, 0.276 mmol), 1-phenylpiperazine (0.041 mL, 0.276 mmol), DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)3 (175 mg, 0.828 mmol).