Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH:10]1[OH:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([O:8][C@H:9]([C@@H:14]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C@H:13]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:12]([OH:11])[CH2:31][O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:10][OH:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.6 %

Procedure:
To a stirred solution of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]oxan-2-ol 1 (25 g, 46.24 mmol) in THF (310 mL) was added solid LiAlH4 (6.14 g, 161.84 mmol) portion-wise at 0° C. and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was cooled to 0° C. and carefully quenched with with saturated Na2SO4 solution (35 mL) and the reaction mixture was stirred at room temperature for 30 min. Solid was filtered through a celite pad and the filtrate was diluted with ethyl acetate (250 mL). Organic part was separated and washed with saturated aqueous solution of NH4Cl (3×100 mL). The organic phase was dried over Na2SO4, concentrated under reduced pressure to get crude was purified by column chromatography using 100-200 mesh silica gel and eluting with 12% EtOAc/hexane to get (2S,3R,4R,5R)-2,3,4,6-tetrakis(benzyloxy)hexane-1,5-diol 2 (24 g, 95%) as sticky oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1([C:11]2([C:18]3[CH:27]=[C:26]([O:28][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)[CH:25]=[CH:24][C:19]=3[C:20]([NH:22][NH2:23])=O)[CH2:16][CH:15]3[CH2:17][CH:12]2[CH2:13][CH2:14]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>>[CH3:2][C:1]1[O:3][C:20]([C:19]2[CH:24]=[CH:25][C:26]([O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)=[CH:27][C:18]=2[C:11]2([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:16][CH:15]3[CH2:17][CH:12]2[CH2:13][CH2:14]3)=[N:22][N:23]=1
Reactant: NNC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Cc1nnc(-c2ccc(OCc3ccc4ccccc4n3)cc2C2(c3ccccc3)CC3CCC2C3)o1
Reaction time: 18 h

Procedure:
Acetyl chloride (10.0 μL, 0.14 mmol) was added to a stirred solution of 4d (50.0 mg, 0.11 mmol) and triethylamine (38.0 μL, 0.27 mmol) in THB (900 μL) at room temperature. After approximately 18 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude intermediary acylhydrazide was treated with thionyl chloride (˜1 mL, excess), and the resulting mixture was aged for approximately 18 h. The reaction mixture was poured carefully into cold saturated aqueous sodium bicarbonate and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (gradient elution; 20-100% acetonitrile/water as eluent, 0.1% TFA as modifier). Lyophilization of the purified fractions afforded the title compound 5d, m/z (ES) 488 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:4]=[C:3]1[CH:17]([O:19][C:20]1[N:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23])[CH3:18].[OH-:28].[Na+].O>C(O)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:4]=[C:3]1[CH:17]([O:19][C:20]1[N:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]([NH2:23])=[O:28])[CH3:18]
Reactant: CC(Oc1ncccc1C#N)c1nnc(-c2ccccc2C(F)(F)F)n1C
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(Oc1ncccc1C(N)=O)c1nnc(-c2ccccc2C(F)(F)F)n1C
Temperature: 70 °C
Reaction time: 5 h

Procedure:
2-(1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)nicotinonitrile (270 mg) was dissolved in ethanol (10 ml), a 1M aqueous sodium hydroxide solution (3.7 ml) was added thereto, followed by stirring at 70° C. for 5 hours. The reaction solution was cooled to room temperature, and water was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting solid was washed with ethyl acetate, to obtain, as a colorless solid, 2-(1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)nicotinamide (120 mg).
Reaction SMILES: Br.Cl[C:3]1[C:12]2[N:13]=[C:14]([NH2:20])[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[NH3:21]>CO>[CH3:18][CH:17]([CH3:19])[CH2:16][N:15]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([NH2:21])[C:12]=2[N:13]=[C:14]1[NH2:20]
Reactant: N
Reactant: CC(C)Cn1c(N)nc2c(Cl)nc3ccccc3c21
Agent: Br
Solvent: CO
Product: CC(C)Cn1c(N)nc2c(N)nc3ccccc3c21
Temperature: 150 °C

Procedure:
4-Chloro-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-amine hydrobromide (8.61 g) and ammonia (131 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated overnight in an oven at 150° C. The resulting solution was concentrated under reduced pressure to provide 7 g of crude product. A portion of the product was purified by flash chromatography on silica gel (eluting with 3-4% methanol in dichloromethane with 1% ammonium hydroxide added.) The isolated product was washed with methanol, purified again by flash chromatography using the same conditions, and dried under high vacuum to provide 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine as a gray, crystalline solid, mp >250° C. Anal. calcd. for C14H17N5: C, 65.68; H, 6.71; N, 27.43. Found: C, 65.69; H, 6.79; N, 27.42.
Reaction SMILES: [Cl:1][SiH:2]([CH2:4][Si:5]([Cl:8])([Cl:7])[Cl:6])[Cl:3].Cl[Si](C[Si](Cl)(Cl)Cl)(Cl)Cl.[CH2:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl[Si](Cl)(C)[Si](Cl)(Cl)Cl>O1CCCC1.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:6][Si:5]([Cl:8])([Cl:7])[CH2:4][Si:2]([Cl:3])([Cl:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: Cl[SiH](Cl)C[Si](Cl)(Cl)Cl
Reactant: C=CCCCCCCCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: C[Si](Cl)(Cl)[Si](Cl)(Cl)Cl
Agent: Cl[Si](Cl)(Cl)C[Si](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCC[Si](Cl)(Cl)C[Si](Cl)(Cl)Cl
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 59 %

Procedure:
Under a nitrogen atmosphere a 1-liter, 3-necked flask equipped with a heating mantle, magnetic stirrer, pot thermometer, addition funnel and condenser was charged with 276.8 g of a mixture of approximately 46% (dichlorosilylmethyl)trichlorosilane and 54% bis(trichlorosilyl)methane [molar ratio 1:1]. The mixture was heated to 90° C. and 10 g of decene were added to the mixture via addition funnel, followed by 0.5 ml of 5% hexachloroplatinic acid in tetrahydrofuran. An immediate exotherm was observed and the reaction mixture changed from clear to dark brown. An additional 173 g of decene were added at an appropriate rate to maintain the temperature between 90 and 110° C. Upon completion of the addition, an additional 0.25 ml of 5% hexachloroplatinic acid solution was added and the mixture was stirred at 100° C. for 45 minutes. GC analysis of the mixture indicated the presence of some unreacted pentachlorodisilapropane. An additional 10 g of decene were added and the reaction mixture was stirred an additional 45 minutes at 100° C. Distillation provided 242 g (59%) of the title compound, bp 126° C./0.1 mm Hg, density @ 20° C. 1.180.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH2:8]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:9]2[O:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:19]=[CH:20][C:2]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[Cl:21])=[CH:3][CH:4]=3)[CH2:8]2)[CH:14]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Brc1ccc(CN2CCOC(c3cccnc3)C2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Clc1ccccc1-c1ccc(CN2CCOC(c3cccnc3)C2)cc1
Temperature: 120 °C
Yield: 97 %

Procedure:
105 mg of 4-(4-Bromo-benzyl)-2-pyridin-3-yl-morpholine was combined with 74 mg of 2-Chlorophenyl boronic acid, 36 mg of tetrakis(triphenylphosphine)palladium(0), 1.055 mL of 2M sodium carbonate solution, 2.8 mL toluene and 1.4 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by reverse phase HPLC. ES MS (+) m/z 365, 97% yield.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([C:8]([O:10]C)=[O:9])[S:5][C:6]=1[CH3:7].Cl>[OH-].[Na+]>[CH3:13][O:12][C:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5][C:4]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1sc(C)c(C)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1c(C(=O)O)sc(C)c1C

Procedure:
Methyl 4,5-dimethyl-3-methoxythiophene-2-carboxylate (34 g) was heated under reflux in 1M sodium hydroxide solution (500 ml) for 1 hour. After cooling the mixture was acidified with concentrated hydrochloric acid to pH4. The solid was filtered, washed with water and dried, m.p. 142°-143° C.
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[CH2:13]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)C(O)=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[C:1]([C@@H:3]([NH:5][C:6](=[O:12])[C:28]1[CH:27]=[CH:23][CH:22]=[C:21]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:29]=1)[CH3:4])#[N:2]
Reactant: CCCCCCCCc1cccc(C(=O)O)c1
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Product: CCCCCCCCc1cccc(C(=O)N[C@@H](C)C#N)c1
Yield: 34.8 %

Procedure:
General procedure D was used to deprotect 1.15 mmol of 4 and was then immediately coupled to 1.15 mmol of 35. After flash chromatography 0.115 g (0.4 mmol) of the title product was recovered. 1H NMR (500 MHz, CDCl3) δ 7.68-7.55 (m, 2H), 7.34 (dd, J=2.9, 9.5, 2H), 6.73 (d, J=7.7, 1H), 5.16 (p, J=7.2, 1H), 2.63 (t, J=7.7, 2H), 1.66 (d, J=7.2, 2H), 1.61 (s, 2H), 1.30 (dd, J=21.4, 28.1, 10H), 0.87 (t, J=7.0, 3H). 13C NMR (126 MHz, CDCl3) δ 166.89, 143.81, 143.59, 132.58, 132.52, 128.60, 127.34, 124.32, 119.40, 52.60, 48.47, 36.28, 35.81, 31.86, 31.43, 31.38, 29.42, 29.27, 29.23, 22.66, 19.54, 18.65, 14.11.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH2:23]Br)[CH:18]=2)[NH:13][C:12]=1[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>C(#N)C>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:18]=2)[NH:13][C:12]=1[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2ccc(OCCCBr)cc2c1C(=O)OCc1ccccc1
Reactant: C1CCNC1
Solvent: CC#N
Product: Cc1[nH]c2ccc(OCCCN3CCCC3)cc2c1C(=O)OCc1ccccc1
Yield: 42.1 %

Procedure:
5-(3-Bromo-propoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.244 g, 0.605 mmol, 1 eq) was suspended in dry acetonitrile (10 mL) under Ar. Pyrrolidine (0.100 mL, 1.210 mmol, 2 eq) was added. The reaction mixture was stirred and heated to reflux for 24 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.100 g (42%) of the indole-pyrrolidine was obtained as a white solid. This was converted to the .HCl salt. LC/MS (ESI+) 393 (M+1); Anal. Calcd for C24H28N2O3.HCl.H2O: C, 64.49; H, 6.99; N, 6.27; Found: C, 64.36; H, 6.93; N, 6.15.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:27])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[N:5]2[CH:28]=[CH:29][N:30]=[C:4]2[C:3]=1[CH2:31][C:32]([O:34]C)=[O:33].Cl>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:27])[C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=3)=[CH:11][CH:10]=2)[N:5]2[CH:28]=[CH:29][N:30]=[C:4]2[C:3]=1[CH2:31][C:32]([OH:34])=[O:33]
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)n2ccnc12
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)n2ccnc12
Temperature: 100 °C
Yield: 20.6 %

Procedure:
A solution of methyl [7-Chloro-5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-c]-pyrimidin-8-yl]acetate (0.100 g, 0.199 mmol) in dioxane (1.00 mL) was added 6N HCl aq. (0.5 mL) and heated to 100° C. for 22 hours. After cooling to room temperature, the volatiles was removed under reduced pressure to generate a precipitate which was suspended in water, collected by suction, rinsed with water and diethyl ether, and dried under high vacuum to give [7-chloro-5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-c]pyrimidin-8-yl]acetic acid as a white powder (0.020 g, 20%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-])=O>CO.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.7 %

Procedure:
Ethyl 3-(4-nitrophenyl)acrylate (3 g, 13.56 mmol) was dissolved in methanol/tetrahydrofuran (20 ml), added with 10%-palladium (Pd) (300 mg). The resulting mixture was stirred for one day under hydrogen gas at room temperature and filtered using celite to remove 10%-palladium (Pd). The filtrate was then concentrated under reduced pressure. The residue was then purified by flash column chromatography (hexane:ethylacetate=3:1) to obtain the title compound (2.14 g, yield: 82%, colorless liquid).
Reaction SMILES: [OH-].[K+].[N+:3]([CH2:5][C:6]([NH2:8])=[O:7])#[C-:4].[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>CO>[F:9][C:10]([F:19])([F:20])[C:11]1[CH:12]=[CH:13][C:14]([C@H:15]2[O:16][CH:4]=[N:3][CH:5]2[C:6]([NH2:8])=[O:7])=[CH:17][CH:18]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: [C-]#[N+]CC(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)C1N=CO[C@@H]1c1ccc(C(F)(F)F)cc1
Temperature: 12.5 °C
Reaction time: 2 h

Procedure:
To a cooled (˜10° C.) solution of KOH (13.2 g, 235 mmol) in MeOH (50 mL) was added the solution of 2-isocyanoacetamide (LXXIV) in MeOH (60 mL) dropwise while maintaining the temperature at 10-15° C. A solution of 4-(trifluoromethyl)benzaldehyde (40.9 g, 235 mmol) in MeOH (50 mL) was then added and the reaction was stirred for an additional 2 h. The reaction mixture was cooled to −20° C. causing a white solid to precipitate. The solid was filtered and dried to give crude (5R)-5-(4-(trifluoromethyl)phenyl)-4,5-dihydrooxazole-4-carboxamide (LXXV) (62 g). The crude product was used for the next step without purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([C:9]([F:12])([F:11])[F:10])[CH:4]([C:6]([OH:8])=[O:7])[NH2:5].[Si](C=[N+]=[N-])(C)(C)[CH3:16].CO>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[F:1][C:2]([F:13])([F:14])[CH:3]([C:9]([F:11])([F:10])[F:12])[CH:4]([C:6]([O:8][CH3:16])=[O:7])[NH2:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: NC(C(=O)O)C(C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(N)C(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of 4,4,4,4′,4′,4′-hexafluoro-dl-valine (1.1 g, 4.88 mmol) in CH2Cl2-MeOH (4:1, 25 mL) was stirred under nitrogen at 0° C. TMS-diazomethane (2.0 M in hexane, 20 mL, 19.55 mL) was added dropwise and the resulting neon greenish solution stirred for 19 h at 25° C. After this time period, the reaction was complete by TLC (10% MeOH in chloroform). After concentration, the resulting residue of methyl 4,4,4,4′,4′,4′-hexafluoro-dl-valinate (1.1 g) was used directly in the next step without further purification. Mass Spectrum (−ESI): 238 (M−H)−.
Reaction SMILES: O[C@@H:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:4]=2[C@H:3]1[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C:17]1=[O:31].[H-].[Na+].O>O1CCCC1>[C:14]([C:12]1[CH:11]=[CH:10][C:5]2[O:6][C:7]([CH3:9])([CH3:8])[CH:2]=[C:3]([N:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:25])[CH3:26])[C:17]3=[O:31])[C:4]=2[CH:13]=1)#[N:15]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2cccc(CO[Si](C)(C)C(C)(C)C)c2=O)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C=C(n2cccc(CO[Si](C)(C)C(C)(C)C)c2=O)c2cc(C#N)ccc2O1
Yield: 48.2 %

Procedure:
In 50 ml of anhydrous tetrahydrofuran, is dissolved 1.32 g of trans-3-hydroxy-6-cyano-3,4-dihydro-2,2-dimethyl-4-(1,2-dihydro-2-oxo-3-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran obtained in Example 16. Then, 0.12 g of 60% oily sodium hydride is added to the solution at room temperature and reacted under reflux for 3 hours. After stopping the reaction by adding water, the reaction mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by silica gel column chromatography using 1/25 mixture of methanol/methylene chloride as a developing solvent to obtain 0.61 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-3-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran.
Reaction SMILES: Cl[C:2]1[N:7]2[C:8](=[O:11])[NH:9][N:10]=[C:6]2[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:3]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>C1COCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:4]2[N:3]=[C:2]([NH:29][CH:26]([CH3:28])[CH3:27])[N:7]3[C:8](=[O:11])[NH:9][N:10]=[C:6]3[C:5]=2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:20][CH:21]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)Nc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2n[nH]c(=O)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (39 mg, 0.10 mmol) in 1 mL THF, was added isopropylamine (18 mg, 0.30 mmol). The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The resulting crude title compound was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:11])=[N:8][S:9][CH:10]=1)=[O:5])C.C1COCC1.Cl>>[CH3:11][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:10][S:9][N:8]=1
Reactant: CCOC(=O)c1csnc1C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1nscc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-methyl-isothiazole-4-carboxylic acid ethyl ester (method 53) (23.3 g, 136 mmol) in THF (200 mL) aqueous NaOH (6.5 g, 162 mmol, in 100 ml of water) was added and the mixture was stirred at room temperature for 16 h. The TLC of the reaction mixture showed the complete disappearance of the starting material. The reaction mixture was cooled in an ice bath and acidified to pH 5 using 6M HCl and the resultant mixture was extracted with ether (3×100 mL). The ether layers were combined, washed with water (100 mL), brine (100 mL), dried (Na2SO4) and concentrated to about 10 mL. Addition of hexanes to the above mixture resulted in the precipitation of the product which was filtered off, washed with hexanes and dried to provide the pure product as a tan powder. Yield 15.3 g (79%). 1H NMR (300 MHz) δ 2.39 (s, 3H), 8.98 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3]Br.[OH-].[Na+].C1(C)C=CC=CC=1.[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24])#[N:15]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1([C:23]([O:25][CH3:26])=[O:24])[CH2:3][CH2:2]1)#[N:15]
Reactant: COC(=O)Cc1ccccc1C#N
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1(c2ccccc2C#N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
1.5 g of tetra-n-butylammonium bromide, 6.5 g of 1,2-dibromoethane and 20 mL of aqueous 50% sodium hydroxide solution were added to a toluene (40 mL) solution of 4.0 g of methyl 2-cyanophenylacetate, and stirred at room temperature for 1 hour. Water was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain 3.0 g of the entitled compound as a colorless compound. 1H-NMR (400 MHz, CDCl3) δ: 7.66 (1H, dd, J=7.6, 1.2 Hz), 7.55 (1H, td, J=7.6, 1.2 Hz), 7.43-7.36 (2H, m), 3.66 (3H, s), 1.82 (2H, q, J=3.7 Hz), 1.30 (2H, q, J=3.7 Hz) ESI-MS Found: m/z [M+H] 202.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:23][C:24]=3[CH3:25])[CH:15]=[CH:14][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:32][C:33]1[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][N:35]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:21][C:20]=1[CH2:19][O:18][C:16]1[CH:15]=[CH:14][C:6]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:3]([CH2:2][O:32][C:33]3[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][N:35]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:34]=3)[O:4][C:5]=2[CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2c(-c3ccccc3)c(CCl)oc2c1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccccc2)nc1OCc1oc2cc(OCc3nc(-c4ccccc4)oc3C)ccc2c1-c1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
A mixture of 4-({[2-(chloromethyl)-3-phenyl-1-benzofuran-6-yl]oxy}methyl)-5-methyl-2-phenyl-1,3-oxazole (1.16 g), ethyl 3-hydroxy-1-phenyl-1H-pyrazole-4-carboxylate (0.58 g), potassium carbonate (0.35 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 3 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration, and subjected to silica gel column chromatography to give ethyl 3-({6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-phenyl-1-benzofuran-2-yl}methoxy)-1-phenyl-1H-pyrazole-4-carboxylate as colorless crystals (1.19 g, 76%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 143-144° C.