Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[NH2:12].[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>ClCCCl>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([NH:12][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=2)=[O:18]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1cnc2cccnc2c1Cl
Solvent: ClCCCl
Product: O=C(CCCCl)Nc1cnc2cccnc2c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-chloro[1,5]naphthyridin-3-amine (2.0 g, 11 mmol) and 4-chlorobutyryl chloride (4.7 g, 33 mmol) in 1,2-dichloroethane (75 mL) was heated at reflux for 20 hours. The reaction mixture was then concentrated under reduced pressure and the residue washed with two 25 mL portions of hexane. The solid was then taken up in methanol (35 mL), 1.0 mL of 10% solution of sodium hydroxide in water was added, and the solution was stirred at room temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure to provide 4-chloro-N-(4-chloro[1,5]naphthyridin-3-yl)butanamide which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)[CH:9]=2)[C:4](=O)[CH2:3]1.[CH2:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)[CH:9]=2)[CH:4]([NH:31][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:3]1
Reactant: NCCc1ccccc1
Reactant: CC1(C)CC(=O)c2ccc(Oc3ccc(C(N)=O)cn3)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC1(C)CC(NCCc2ccccc2)c2ccc(Oc3ccc(C(N)=O)cn3)cc21
Yield: 66.5 %

Procedure:
Using a method similar to Example 14, using 6-(3,3-dimethyl-1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 11, 100 mg, 0.337 mmol), phenethylamine (49 mg, 0.405 mmol), Ti(iPrO)4 (192 mg, 0.675 mmol), TiCl4 (1.0M/DCM, 0.675 ml, 0.675 mmol), and NaBH3CN (42 mg, 0.675 mmol) gives the title compound (90 mg) as a white solid. Mass spectrum (ion spray): m/z=402 (M+1); 1HNMR (CDCl3): 8.60 (s, 1H), 8.14 (d, 1H), 7.32-7.19 (m, 6H), 6.95-6.88 (m, 3H), 6.25 (br. s, 2H), 4.31 (t, 1H), 3.02 (m, 2H), 2.86 (m, 2H), 2.33 (m, 1H), 1.68 (m, 3H), 1.31 (s, 3H), 1.17 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:31])[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[Cl:30])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13].[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([NH:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:31])[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][C:21]=2[Cl:30])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1N
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1NC(C)=O

Procedure:
A solution of 100 mg (0.217 mmol) N-[3-amino-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Example 160) in 10 mL acetic anhydride was stirred for 3 h at 100° C. and then evaporated down i. vac. The residue was combined with saturated aqueous sodium bicarbonate and exhaustively extracted with EtOAc. The combined org. phases were dried over sodium sulphate, evaporated down i. vac. and the residue was stirred with ether. The precipitate was filtered off, washed with ether and dried in a HV.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12](I)[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:15][N:16](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:15]([C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([CH2:3][O:2][CH3:1])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:16]
Reactant: CN(C)C=O
Reactant: COCc1cc(I)cc(C(=O)OC)c1
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COCc1cc(C#N)cc(C(=O)OC)c1
Temperature: 80 °C
Yield: 86 %

Procedure:
After bubbling argon into a solution of methyl 3-(methoxymethyl)-5-iodobenzoate (316 mg, 1.03 mmol) in N,N-dimethylformamide (3 mL) for 5 minutes, zinc cyanide (133 mg, 1.13 mmol) and tetrakis(triphenylphosphine)palladium(O) (119 mg, 0.010 mmol) were added. The reaction mixture was heated at 80° C. for 15 minutes under argon. Following cooling, the reaction mixture was diluted with ethyl acetate and then the precipitate that formed was removed by filtration. The filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel chromatography using 10–30% ethyl acetate/hexanes afforded 184 mg (86%) of methyl 3-cyano-5-(methoxymethyl)benzoate as a colorless oil.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([CH2:18]O)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O.C(OCC)(=O)[CH2:26][C:27]([O:29]CC)=[O:28].[Na].Cl>CN(C)C=O.C(O)(=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:10]([CH2:18][CH2:26][C:27]([OH:29])=[O:28])[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: OCc1cnn(-c2ccccc2)c1-c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)CCc1cnn(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a mixture of (1,5-diphenyl-1H-pyrazol-4-yl)methanol (11.78 g), triethylamine (10 ml) and ethyl acetate (300 ml) was added dropwise methanesulfonyl chloride (4.5 ml) at 0° C. The mixture was stirred at room temperature for 1 hr. and the ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give an oil. This oil was dissolved in N,N-dimethylformamide (100 ml) and the resulting solution was added dropwise to a solution of sodium diethyl malonate in N,N-dimethylformamide (prepared using diethyl malonate 20.33 g, sodium hydride (60% in oil, 4.88 g) and N,N-dimethylformamide 200 ml) at 0° C. The mixture was stirred at room temperature for 5 hrs., and poured into a 1N aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with a 1N aqueous hydrochloric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give an oil. A mixture of this oil, a 6N aqueous hydrochloric acid solution (100 ml) and acetic acid (50 ml) was heated under reflux for 5 hrs. The reaction mixture was cooled, concentrated and poured into water. The precipitated crystals were collected by filtration, washed with water, and dried to give 3-(1,5-diphenyl-1H-pyrazol-4-yl)propionic acid. yield: 68%. colorless needle crystals. melting point: 159-160° C. (recrystallized from acetone-hexane).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]2[C:15]([CH:16]=1)=[CH:14][N:13]=[C:12]1[C:8]=2[CH:9]=[CH:10][NH:11]1)=[O:4].[Li+].[OH-].C(O)(=O)C>C1COCC1.O>[S:6]1[C:7]2[C:15](=[CH:14][N:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH:16]=[C:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc2cnc3[nH]ccc3c2s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc2cnc3[nH]ccc3c2s1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid methyl ester (100 mg, 0.43 mmol), LiOH (25.5 mg, 1.07 mmol) is dissolved in THF (4 ml) and H2O (1 mL). The mixture is stirred at 60° C. for 3 hours. Acidification with acetic acid results in a brown solid which is collected by filtration. It is then dried in vacuo and used for the next step without any further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[NH:6])[NH2:5].[OH-].[Na+].Cl[C:10]([O:12][CH3:13])=[O:11]>O>[NH2:6][C:4]([O:3][CH3:2])=[N:5][C:10](=[O:11])[O:12][CH3:13]
Reactant: COC(=N)N
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N=C(N)OC
Yield: 92.2 %

Procedure:
A solution of 110.5 parts of O-methylisourea hydrochloride in 475 parts of water is adjusted with 8.9 parts of 50% NaOH solution to pH 6. After raising the pH to 9, 114.5 parts of methyl chloroformate is added, while maintaining the pH at 9 by the simultaneous addition of 175.3 parts of 50% NaOH solution. The resulting reaction mass is then extracted 5 times with 134 parts methylene chloride, and the combined extracts are then dried by removing the dissolved water by azeotropic distillation. The resulting methylene chloride solution shows by gas chromatographic analysis the presence of 121.0 parts (92.2% yield) of methyl N-[(amino) (methoxy)methylene]carbamate. One half of the above methylene chloride solution is gradually added to 45 parts of neat phosgene at 0° C within 10 minutes. Initally, gummy solids are formed, which gradually dissolve, as a white crystalline solid precipitates. After holding the temperature to 0° C for 30 minutes, 51.7 parts of solids are isolated by filtration. The filtrate is then evaporated to produce 23.5 parts of residue, which is almost completely soluble in water, and represents (based on equation (I) and the starting 0-methylisourea hydrochloride) a 89.3% yield of crude dimethyl N,N'-{[(2,4-dioxo-1,3-diazetidine)-1,3-diyl]-bis[(methoxy)methylidyne]}biscarbamate.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][N:6](C(OC(C)(C)C)=O)[C@@H:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:4]1)#[N:2].[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[F:21][C:17]1[CH:16]=[C:15]([C@@H:5]2[NH:6][CH2:7][C@@H:3]([C:1]#[N:2])[CH2:4]2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C#N)C[C@@H]1c1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#C[C@@H]1CN[C@@H](c2cccc(F)c2)C1

Procedure:
To a solution of (2R,4S)-tert-butyl 4-cyano-2-(3-fluorophenyl)-pyrrolidine-1-carboxylate (I-30) (72 mg, 0.25 mmol) in DCM (0.5 mL) was added TFA (0.5 mL) with stirring. After 1 hour the volatile organics were removed under reduced pressure. The residue was triturated with Et2O and the resulting solids collected and dried under vacuum to give (3S,5R)-5-(3-fluorophenyl)pyrrolidine-3-carbonitrile 2,2,2-trifluoroacetate (I-31), which was used without purification. MS m/z 191.1 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:14][O:15][C:16]=2/[CH:17]=C/C2C=CC=CC=2)=[N:6][CH:5]=1.I([O-])(=O)(=O)=[O:33].[Na+].C(OCC)(=O)C.O>C(O)(C)(C)C.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:14][O:15][C:16]=2[CH:17]=[O:33])=[N:6][CH:5]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2/C=C/c2ccccc2)nc1
Agent: O=[Os](=O)(=O)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C=O)nc1
Yield: 51.2 %

Procedure:
A mixture of 6-[3-phenyl-5-((E)-styryl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (0.62 g, 1.5 mmol), osmium(VIII) oxide solution (0.38 mL of a 2.5% solution in tert-butanol, 0.037 mmol), sodium metaperiodate (1.29 g, 6 mmol), benzyltriethylammonium chloride (0.14 g, 0.6 mmol) in dioxane (13 mL) and water (4.5 mL) was irradiated in the microwave for 10 min at 120° C. Extractive workup (ethyl acetate/water) was followed by drying of the organic phase over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetate=100:0 to 60:40) afforded the title compound as a light yellow solid (0.26 g, 51%). MS: m/e=339.3 [M+H]+.
Reaction SMILES: Cl.CS([O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:30])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:18][CH:17]=3)=[C:13]([C:31]3[CH:36]=[CH:35][C:34]([O:37]S(C)(=O)=O)=[CH:33][CH:32]=3)[S:12][C:11]=2[CH:42]=1)(=O)=O.[OH-].[Na+]>C(O)C>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:30])[C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:20][CH:21]=3)=[C:13]([C:31]3[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=3)[S:12][C:11]=2[CH:42]=1
Reactant: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(c1ccc(OCCN2CCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12

Procedure:
A 5 g. portion of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-pyrrolidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride, was dissolved in 125 ml. of denatured ethanol and 15 ml. of 5 N sodium hydroxide, and the mixture was stirred under reflux for one hour. The ethanol was then evaporated away under vacuum, and the residue was dissolved in water. The mixture was then made acid with 1 N hydrochloric acid, and was then made basic with sodium bicarbonate. The basic solution was extracted three times with 100 ml. portions of ethyl acetate, dried over magnesium sulfate, filtered and evaporated to an oil, 3.6 g., under vacuum. The oil was shown by thin layer chromatography to contain the desired product by comparison with authentic samples. It was purified further by chromatography on silica gel by elution with 6% methanol in chloroform. The size of the column was 3.5×2.5 cm., and 20 ml. fractions were collected. Fractions 31 through 150 contained 2.4 g. of partially purified product, which was identified by thin layer chromatographic comparison with an authentic sample of the desired product.
Reaction SMILES: [C:1]([O:5][P:6]([C:13]([F:59])([F:58])[C:14]1[CH:57]=[CH:56][C:17]([CH2:18][C:19]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([P:44]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])([F:43])[F:42])=[CH:37][CH:36]=2)([C:30]([O:32]C)=[O:31])[C:20]([O:22][CH2:23]C2C=CC=CC=2)=[O:21])=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:47]([O:46][P:44]([C:41]([F:42])([F:43])[C:38]1[CH:39]=[CH:40][C:35]([CH2:34][C:19]([CH2:18][C:17]2[CH:16]=[CH:15][C:14]([C:13]([P:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([F:58])[F:59])=[CH:57][CH:56]=2)([C:20]([O:22][CH3:23])=[O:21])[C:30]([OH:32])=[O:31])=[CH:36][CH:37]=1)([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:45])([CH3:48])([CH3:49])[CH3:50]
Reactant: COC(=O)C(Cc1ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)(Cc1ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(Cc1ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)(Cc1ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)C(=O)O
Reaction time: 3 h
Yield: 55.8 %

Procedure:
A mixture of 2,2-di{4-[(di-tert-butoxyphosphoryl) (difluoro)methyl]benzyl}malonic acid, benzyl methyl ester (0.2 g) and Pd/C (0.1 g, 10%) in 30 mL of MeOH was shaken under 50 psi of H2 for 3 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography eluted with 3:2:0.1 EtOAc/hexane/AcOH to give 0.1 g of the title compound as a yellow syrup.
Reaction SMILES: [Br-:1].[CH3:2][N+:3]1([CH3:25])[C:12]2[C:7](=[C:8]([N:17]=NC3C=CC=CC=3)[CH:9]=[C:10]([CH2:14][CH2:15][CH3:16])[C:11]=2[OH:13])[CH2:6][CH2:5][CH2:4]1.O.[H][H]>[Pd].CO>[Br-:1].[CH3:25][N+:3]1([CH3:2])[C:12]2[C:7](=[C:8]([NH2:17])[CH:9]=[C:10]([CH2:14][CH2:15][CH3:16])[C:11]=2[OH:13])[CH2:6][CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: CCCc1cc(N=Nc2ccccc2)c2c(c1O)[N+](C)(C)CCC2
Agent: [Pd]
Agent: [Br-]
Solvent: CO
Solvent: O
Product: CCCc1cc(N)c2c(c1O)[N+](C)(C)CCC2

Procedure:
One introduces into a stainless steel autoclave 15.75 g of N,N-dimethyl-1,2,3,4-tetrahydro-5-phenylazo-7-propyl-8-hydroxyquinolinium bromide (i.e. 0.05 mole) with 170 ml of water and 17 ml of methanol, and one adds 3 g of 5% palladium on charcoal. One hydrogenates under a 3 kg/cm2 to 5 kg/cm2 hydrogen pressure. After cooling, one filters off the catalyst, evaporates the filtrate, and redissolves the residue in ether so as to remove the aniline. One recrystallizes in acetonitrile and one washes again with ether.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.Cl[C:13]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)=[CH:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]>O1CCCC1.CN(C)C=O>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:9][C:13]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)=[CH:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[CH:6][CH:5]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: COc1ccc(C(Cl)=CC(=O)N2CCOCC2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=CC(=O)N2CCOCC2)OCc2ccc(Cl)cc2)cc1OC
Temperature: 90 °C
Reaction time: 20 h

Procedure:
0.3 g (10 mmol) of sodium hydride (80%) are stirred in 15 ml of tetrahydrofuran and 1.42 g (10 mmol) of 4-chlorobenzyl alcohol in 10 ml of tetrahydrofuran are added dropwise. The resulting clear solution is evaporated to dryness and a solution of 2.02 g (6.5 mmol) of 3-chloro-3-(3,4-dimethoxyphenyl)-1-morpholin-4-ylprop-2-en-1-one in 25 ml of dimethylformamide is added. The mixture is stirred at 90° C. for 20 hours. The solvent is then evaporated and the residue shaken with toluene/water. The organic phase is separated, washed with water, dried and purified over a flash column with 40 g of silicagel. Elution is carried out with toluene containing 10, 20 and 30% of acetone. The fractions with the TLC Rf-values 0.45 and 0.31 (toluene/acetone 7:3) are collected and evaporated.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:7]2[C:2]3[C:3]([CH3:29])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:5]([CH3:20])=[C:6]([C:33]4[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=4)[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:18])[CH3:19]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: OB(O)c1ccncc1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1ccncc1)OCC2c1ccc(C(C)C)cc1
Yield: 72 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and pyridin-4-ylboronic acid, the title compound was obtained in the same as in Example 107.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=1[O:37][CH3:38])[C:8]1[N:13]=[CH:12][C:11]([C:14](O)=[O:15])=[CH:10][N:9]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[CH2:71]([O:73][C:74](=[O:79])[CH2:75][CH2:76][CH2:77][NH2:78])[CH3:72].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[F:45][C:42]([F:43])([F:44])[C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:46])[F:47])[CH:41]=1)[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:33]=[C:32]([CH:34]([CH3:35])[CH3:36])[CH:31]=[CH:30][C:29]=1[O:37][CH3:38])[C:8]1[N:9]=[CH:10][C:11]([C:14]([NH:78][CH2:77][CH2:76][CH2:75][C:74]([O:73][CH2:71][CH3:72])=[O:79])=[O:15])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCN
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNC(=O)c1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2OC)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
2-[(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidine-5-carboxylic acid (200 mg) is dissolved in N,N-dimethylformamide (5 ml) and thereto are added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg), 1-hydroxy-benzotriazole (60 mg), triethylamine (125 μl) and 4-aminobutyric acid ethyl ester hydrochloride (75 mg), and the mixture is stirred at room temperature overnight. To reaction mixture is added a saturated aqueous sodium bicarbonate solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=5:2) to give ethyl 4-({2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidine-5-carbonyl}-amino)-butyrate (230 mg). MS (m/z): 785 [M+H]+
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][CH2:13][C@@H:14](OS(C)(=O)=O)[C@@H:15]1[CH2:19][C@@H:18]([CH2:20][CH2:21][CH3:22])[C:17](=[O:23])[O:16]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN1C(=O)N(C)CCC1>[N:1]([C@H:14]([C@H:15]1[O:16][C:17](=[O:23])[C@H:18]([CH2:20][CH2:21][CH3:22])[CH2:19]1)[CH2:13][O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC[C@@H]1C[C@@H]([C@@H](COCc2ccccc2)OS(C)(=O)=O)OC1=O
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: CCC[C@@H]1C[C@@H]([C@H](COCc2ccccc2)N=[N+]=[N-])OC1=O
Temperature: 60 °C
Reaction time: 48 h
Yield: 92.8 %

Procedure:
7.49 g of sodium azide (115 mmol) was added to a solution of 29.1 g of methanesulfonic acid (R)-2-benzyloxy-1-[(2S,4R)-5-oxo-4-propyltetrahydrofuran-2-yl]ethyl ester obtained in Example (116d) (81.7 mmol) in N,N′-dimethylpropyleneurea (300 ml) at room temperature, and the mixture was stirred at 60° C. for two days. The reaction mixture was cooled and then poured into ice water, followed by extraction with diethyl ether. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=6/1) to obtain 23.0 g of the title compound (yield: 93%).
Reaction SMILES: COC1C=CC(C[S:8][CH2:9][C@H:10]([NH:19][C:20]([C:22]2[NH:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][C:25]=3[N+:31]([O-:33])=[O:32])=O)[CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCl>[N+:31]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[NH:23][C:22]([C:20]1[S:8][CH2:9][C@@H:10]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[N:19]=1)=[CH:30]2)([O-:33])=[O:32]
Reactant: COc1ccc(CSC[C@@H](COC(=O)C(C)(C)C)NC(=O)c2cc3cccc([N+](=O)[O-])c3[nH]2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cccc([N+](=O)[O-])c3[nH]2)=N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.2 %

Procedure:
2,2-Dimethyl-propionic acid (R)-3-(4-methoxy-benzylsulfanyl)-2-[(7-nitro-1H-indole-2-carbonyl)-amino]-propyl ester (1.6 g, 3.2 mmol) prepared in Step B was dissolved in dichloromethane (50 mL). Phosphorus pentachloride (1.3 g, 6.4 mmol) was added thereto, and the mixture was stirred for 5 h at room temperature. Saturated aqueous sodium bicarbonate solution was added to the mixture to quench the reaction. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The residue was purified by column chromatography to give the title compound (0.8 g, Yield 69%).