Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]([C:21](=O)[CH3:22])=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[O:9])[CH2:4][CH2:3]1.Cl.[C:25]([NH2:33])(=[NH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(O)CCC>[CH3:22][C:21]1[N:33]=[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:32]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]=1[C:8]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:9]
Reactant: N=C(N)c1ccccc1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)N1CCN(C)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-(4-methylpiperazin-1-ylcarbonyl)-1-(3-nitrophenyl)-1-buten-3-one (20 g), benzamidine hydrochloride (9.9 g) and triethylamine (11.4 ml) in n-butanol (200 ml) was refluxed for 2 hours. After evaporating the solvent, the residue was dissolved in a suspension of water (200 ml) and chloroform (200 ml). The separated organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. To this solution was added activated manganese dioxide (120 g) and the mixture was refluxed for 1 hour with stirring vigorously. After cooling to a room temperature, manganese dioxide was filtered off. The filtrate was evaporated in vacuo, and the residue was subjected to column chromatography on alumina (200 g) eluting with chloroform. The fractions containing the object compound were combined and concentrated under reduced pressure. The crystals were recrystallized from diethyl ether to give 6-methyl-5-(4-methylpiperazin-1-ylcarbonyl)-4-(3-nitrophenyl)-2-phenylpyrimidine.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH:12]=O)=[CH:9][O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH3-]C#[N:16].[Na+]>CO>[C:1]1([C:7]2[C:8]([CH2:12][NH2:16])=[CH:9][O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cocc1-c1ccccc1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: NCc1cocc1-c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 20.8 %

Procedure:
Prepare a solution of 4-phenyl-3-formylfuran (1.36 g, 7.91 mmol) in methanol (35 mL). Add NH4OAc (6.1 g, 79.1 mmol) and NaCNBH3 (348 mg, 5.54 mmol). Stir the reaction mixture at room temperature under nitrogen for 2.5 days then concentrate the mixture, dilute with water (50 mL), basify with 1 N sodium hydroxide, and extract with methylene chloride (2×100 mL). Dry the organic phase (Na2SO4), filter, and concentrate. Perform flash chromatography on silica gel eluting with 9:1 ethyl acetate/MeOH followed by 100% MeOH to afford 200 mg of the title compound. 1H NMR (CDCl3) δ 7.52 (s, 1H), 7.30-7.46 (m, 6H), 3.87 (s, 2H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:30])=[CH:23][CH:24]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)NCCCSc2ccncc2)cc1
Yield: 78.9 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 846 mg (4.96 mmol) of 4-anisoyl chloride under ice-cooling with stirring and the mixture was stirred for at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with ether and dried to obtain 990 mg of the desired compound (78.9%, colorless powder), mp: 121.0°-122.0° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH2:13].Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]([N:13]=[C:15]=[O:17])=[C:4]([Cl:12])[C:5]([O:10][CH3:11])=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(OC)c(Cl)c(N)c1Cl
Solvent: C1COCCO1
Product: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Temperature: 130 °C
Yield: 162 %

Procedure:
A mixture of 2,6-dichloro-3,5-dimethoxy-phenylamine (500 g, 2.25 mmol), triphosgene (335 mg, 1.12 mmol) and TEA (342 g, 3.38 mmol) in dioxane (15 mL) was heated to 130° C. for 2 hours under microwave. The reaction was concentrated and the residue was purified by flash chromatography on silica eluting with DCM to obtain the title compound (450 mg, yield: 80%). 1H-NMR (400 MHz, CDCl3) δ 3.92 (s, 6H), 6.42 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([Br:8])[CH:7]=1.C[Si]([C:14]#[N:15])(C)C.CN(C)C(Cl)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:14]([C:3]1[C:2]([Br:1])=[CH:7][C:6]([Br:8])=[CH:5][N:4]=1)#[N:15]
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1cc(Br)cc(Br)c1
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ncc(Br)cc1Br

Procedure:
A mixture of 3,5-dibromopyridine N-oxide (prepared in the above (1)) 2.26 g, trimethylsilylcyanide 1.06 g and dimethylcarbamic acid chloride 1.15 g in methylene chloride 25 ml is refluxed under heating for 1 day. To the mixture are added trimethylsilylcyanide 443 mg and dimethylcarbamic acid chloride 480 mg, and the mixture is refluxed under heating for 20 hours. An aqueous sodium hydrogen carbonate solution is added to the reaction mixture cooled, and the mixture is extracted with methylene chloride. The combined extract is washed, dried and the solvent is removed in vacuo. The residue is purified by silica gel chromatography (solvent; n-hexane:ethyl acetate=1:1) to give 2-cyano-3,5-dibromopyridine 1.38 g. mp 109-112° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2O[C:12](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)=[N:13][N:14]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:35]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[NH:35][C:12](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)=[N:13][N:14]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COc1cc(/C=C/c2nnc(CCc3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2nnc(CCc3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 24.3 %

Procedure:
A solution of 2-[2-(4-fluorophenyl)ethyl]-5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole (33 mg) and ammonium acetate (126 mg) in acetic acid (1 mL) was stirred at 150° C. for 10 hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate→ethyl acetate:methanol=5:1) to obtain 8 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>C(Cl)Cl>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:22]2[CH2:23][CH2:24][CH:25]([NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH2:26][CH2:27]2)(=[O:20])=[O:21])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: C=CC(=O)Cl
Reactant: NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
Diisopropylethylamine (6.8 ml, 41.5 mmol) was added in one portion to a stirred solution of 1-(4-nitro-benzenesulfonyl)-piperidin-4-ylamine (2.36 g, 8.3 mmol) in DCM (10 ml) followed by the drop wise addition of acryloyl chloride (0.78 ml, 9.1 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the resulting precipitate was collected by filtration, washed with water and dried under vacuum to give the title compound (2.80 g, 98% yield) as a white solid. δH (500 MHz, DMSO) 8.39-8.51 (m, 2 H) 7.95-8.10 (m, 3 H) 6.11-6.21 (m, 1 H) 6.01-6.10 (m, 1 H) 5.56 (dd, J=10.09, 2.20 Hz, 1 H) 3.61-3.68 (m, 1 H) 3.52-3.60 (m, 2 H) 2.56-2.66 (m, 2 H) 1.83 (dd, J=13.20, 3.30 Hz, 2 H) 1.36-1.47 (m, 2 H). Tr=1.63 min, m/z (ES+) (M+H)+ 340.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>C(=O)([O-])[O-].[K+].[K+]>[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: Nc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1cccc(Nc2nnc(Cc3ccncc3)c3ccccc23)c1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
A mixture of 1.28 g (5 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 2.6 ml (25 mmol) 3-chloroaniline is stirred for 45 min at 90° C. under a nitrogen atmosphere. Excess 3-chloroaniline is then distlled off under HV at 60° C. and the residue distributed between 30 mldichloromethane and 20 ml of 20% aqueous potassium carbonate solution. The organic solution dried over anhydrous sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate and acetate/methanol (20:1). The product-containing fractions are dissolved in 3 ml of methanol, and acidified with 2.3 ml 3N methanolic HCl, then ether is added while stirring until slight turbidity occurs, and the mixture is cooled to 0° C., resulting in the formation of a crystalline precipitate. After filtration, washing of the filter residue with ether, drying under HV (8 h, 110° C.) and equilibration for 65 h at 20° C. and in room atmosphere, the title compound is obtained with a water content of 7.3%; Smp. 233-236° C.; ESI-MS: (M+H)+=347.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=1[NH2:16].C(N(CC)CC)C.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>>[CH3:7][C:4]1[CH2:5][CH:6]=[C:2]([CH3:1])[C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=1[NH:16][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CC1=CCC(C)=C1c1c(C)cc(C)cc1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC1=CCC(C)=C1c1c(C)cc(C)cc1NC(=O)C(C)(C)C
Yield: 69.8 %

Procedure:
0.717 g (3.36 mmol) of 2-(2,5-dimethylcyclopenta-1,4-dienyl)-3,5-dimethylphenylamine, 0.408 g (4.03 mmol) of triethylamine, and 0.486 g (4.03 mmol) of pivaloyl chloride were used in the same manner as in Example 11. The resultant reaction product was purified using a column chromatography using a toluene/MC (v/v, 1:1) solvent, and then the solvent in the purified product was removed in vacuum, thereby obtaining while solid (0.698 g, 70%).
Reaction SMILES: [OH-].[K+].S(O)(O)(=O)=O.[C:8]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)(=[NH:10])[NH2:9].[C:24]([CH:27]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:28](OCC)=[O:29])(=O)[CH3:25]>C(O)C.C1(C)C=CC=CC=1>[CH2:17]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[N:9]=[C:28]([OH:29])[C:27]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:24]([CH3:25])[N:10]=2)[CH2:12][CH2:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)CC(C(C)=O)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)Cc1c(C)nc(N2CCN(Cc3ccccc3)CC2)nc1O
Reaction time: 0.5 h
Yield: 17.6 %

Procedure:
Potassium hydroxide (3.1 g) was added to 200 ml of ethanol, and the mixture was stirred for 30 minutes. Then, 12.4 g of 1-amidino-4-benzylpiperazine sulfate was added. The mixture was stirred at room temperature for 10 minutes. To the solution was added 12.4 g of diethyl acetylsuccinate. The mixture was refluxed for 2 hours. Then, 200 ml of toluene was added, and the mixture was refluxed for 3 hours. After the reaction, ethanol was evaporated, and the residue was poured into 50 ml of an aqueous solution of hydrochloric acid. NaHCO3 was added to the solution to neutralize it. The precipitated solid was washed with water and dried over P2O5 to give 2.55 g (yield 15%) of 2-(4-benzylpiperazino)-5-ethoxycarbonylmethyl-4-hydroxy-6-methylpyrimidine as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].[CH2:10]([NH2:14])[CH:11]([CH3:13])[CH3:12]>C(OCC)C>[C:11]([N:14]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:2][C:3]([OH:5])=[O:4])([CH3:13])([CH3:12])[CH3:10]
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCOCC
Product: CC(C)CN(CC(=O)O)C(C)(C)C
Reaction time: 1 h
Yield: 82 %

Procedure:
t-Butyl bromoacetate (8.4 ml, 10.1 g) was added under an atmosphere of argon to a solution of isobutylamine (50 ml, 36.8 g) in diethyl ether (100 ml) at −40° C. with stiming over 5 min. The solution was stirred at this temperature for 1 hr and then at ambient temperature for 18 hr. The mixture was filtered and the filtrate distilled at ambient pressure to remove ether and subsequently excess isobutylamine (b.p. 64-66° C.) and then under reduced pressure to give the product Yield 82% b.p. 68° C./3 mm NMR (CDCl3 300 MHz, ppm) 3.28(2H, s), 2.4(2H, d), 1.72(1H, m), 1.48(9H,s), 0.92(6H,d). m/Z 188.3 (M+H).
Reaction SMILES: BrCCCCC[OH:7].CCN(CC)CC.[CH3:15][C:16]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])[CH3:17].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:19]([OH:7])([C:16]([CH3:18])([CH3:17])[CH3:15])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCCCCBr
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](O)(c1ccccc1)c1ccccc1
Yield: 155.3 %

Procedure:
A solution of 5-bromo-pentanol (0.9889 g, 5.9 mmol, 1 eq) in anhydrous CH2Cl2 (20 mL) under N2 at 25° C. was treated with anhydrous Et3N (1.0 mL, 7.2 mmol, 1.2 eq), TBDPSCl (1.7 mL, 6.5 mmol, 1.1 eq) and DMAP (0.23 g, 1.9 mmol, 0.3 eq). The reaction mixture was stirred for 2 h before an aqueous solution of saturated NH4Cl (100 mL) was added. The aqueous layer was extracted with EtOAc (3×100 mL) and the organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was chromatographed (SiO2, 5×20 cm, 0-20% EtOAc/hexanes, gradient elution) to afford TBDPSOH (2.35 g, 98%) as a clear oil; 1H NMR (CDCl3, 400 MHz) δ 7.66-7.60 (m, 4H), 7.44-7.33 (m, 6H), 3.64 (t, 2H, J=6.1 Hz), 3.37 (t, 2H, J=6.9 Hz), 1.82 (p, 2H, J=7.3 Hz), 1.59-1.45 (m, 4H), 1.03 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 135.6, 129.6, 127.6, 127.5, 63.5, 33.9, 32.5, 31.6, 26.8, 24.5, 19.2; IR (film) υmax 3069, 2930, 2856, 2359, 1470, 1427, 1389, 1106, 822, 738, 700 cm−1; FABHRMS (NBA-CsI) m/z 537.0235 (C21)H29OSiBr+Cs+ requires 537.0225).
Reaction SMILES: [CH2:1]([Si:4]([CH3:7])([CH3:6])[CH3:5])[CH:2]=[CH2:3].[C:8]1([PH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:5][Si:4]([CH2:1][CH2:2][CH2:3][P:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6]
Reactant: C=CC[Si](C)(C)C
Reactant: c1ccc(Pc2ccccc2)cc1
Product: C[Si](C)(C)CCCP(c1ccccc1)c1ccccc1
Yield: 50 %

Procedure:
A mixture of 22.8 g (0.2 mole) allyl trimethyl silane and 37.2 g (0.2 mole) diphenyl phosphine was reacted for 158 hours in the manner described in Example 1. A subsequent fractional distillation, yielded the desired pure adduct as a clear, colorless liquid. The distillation yield was 50%. The product had a boiling point of 150° C. at 0.10 mm.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:45][O:46][CH2:47][CH2:48][CH2:49][NH2:50]>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([NH:50][CH2:49][CH2:48][CH2:47][O:46][CH3:45])[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCN
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2Cl)CN(C(=O)OC(C)(C)C)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
1-tert-Butyl 3-methyl (3R*,5S*)-5-{[(2-tert-butyl-4-chloropyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate (2.46 g) and diisopropylethylamine (1.38 ml) were dissolved in N,N-dimethylformamide (50 ml), 3-methoxypropan-1-amine (990 μl) was added and the mixture was stirred at 80° C. for 30 min. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with hexane to ethyl acetate-hexane (35:65) was concentrated under reduced pressure to give the object compound (2.47 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH:26]=[O:27])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[O-:28][Mn](=O)(=O)=O.[K+].[OH-].[K+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[C:26]([OH:28])=[O:27])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)c[nH]c34)no2)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbaldehyde (D71) (1.1 g) in THF (20 mL) was added KMnO4 (0.9 g) and aqueous KOH (10 mL). The reaction was stirred at 55° C. overnight. After cooled to room temperature, the mixture was diluted with THF (20 mL) and filtered. The filtrate was concentrated and the aqueous suspension was acidified with aqueous HCl (2 M) to pH 5-6. The resulting solid was collected by filtration, washed with water, dried in vacuo to give the crude compound, which was purified by column chromatography (20% ethyl acetate in hexane) to afford 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole-3-carboxylic acid as a white solid (D94) (1.0 g). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 4.90 (1H, m), 7.38 (1H, t), 7.46 (1H, d), 8.02 (2H, m), 8.22 (1H, dd), 8.30 (1H, dd), 8.41 (1H, d), 11.66 (1H, br s). MS (ES): C20H16ClN3O4 requires 397; found 398.1 (M+H+).
Reaction SMILES: O.O.Cl.[F:4][C:5]([F:16])([F:15])[C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[NH:11])=[CH:8][CH:7]=1.C(O[CH:20]=[C:21]([CH3:24])[CH:22]=O)C.C[O-].[Na+]>CO>[CH3:24][C:21]1[CH:20]=[N:11][C:10]([C:9]2[CH:13]=[CH:14][C:6]([C:5]([F:15])([F:16])[F:4])=[CH:7][CH:8]=2)=[N:12][CH:22]=1
Reactant: CCOC=C(C)C=O
Reactant: N=C(N)c1ccc(C(F)(F)F)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A sample of 4-trifluoromethylbenzamidine hydrochloride dihydrate (Maybridge, 15.2 g, 58 mmol) was dissolved in 100 mL of methanol and 3-ethoxy-2-methylacrolein (Janssen, 7.8 g, 64 mmol) was added. Sodium methoxide (25% solution in methanol, 14.7 mL) was added and the mixture was heated at 50° C. for 3 h. The cooled reaction mixture was then dded to 500 ml of ice water and stirred for 30 minutes. The white solid was filtered, air dried, dissolved in 300 mL of dichloromethane and dried over magnesium sulfate. The solvent was removed under reduced pressure to yield, after trituration with hexanes, 12.5 g of the product as a white solid melting at 143-146° C. 1H NMR (CDCl3): δ2.37 (s, 3H), 7.73 (d, 2H), 8.53 (d, 2H), 8.66 (s, 2H).
Reaction SMILES: [F:1][C:2]1([F:46])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[CH:34]([F:45])[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:54][CH:55]([CH3:57])[CH3:56].O>O1CCCC1>[F:46][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:54][CH:55]([CH3:57])[CH3:56])=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]=2[CH:34]([F:45])[C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=2)[CH2:6][CH2:7]1
Reactant: CC(C)CI
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)COc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Temperature: 50 °C
Reaction time: 14 h
Yield: 68.4 %

Procedure:
To a solution of 55 mg (0.085 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, in 1 ml of tetrahydrofuran, 33 mg (0.10 mmol) of cesium carbonate and 11 μl (0.094 mmol) of 1-iodo-2-methyl propane were added, and the reaction solution was stirred at room temperature for 2 hours, at 50° C. for 3 hours and further at room temperature for 14 hours. After stirring at room temperature, 50 (0.43 mmol) of 1-iodo-2-methyl propane and 50 mg (0.15 mmol) of cesium carbonate were added and the reaction solution was stirred at 70° C. for 9 hours. After stirring with heating, 50 μl (0.43 mmol) of 1-iodo-2-methyl propane and 100 mg (0.31 mmol) of cesium carbonate were further added and the reaction solution was stirred at room temperature for 14.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-70/30 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. n-Hexane was added to the obtained residue and the precipitate was obtained by filtration to provide 41 mg of the title compound as a white solid (yield: 68%).