Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH3:21])[C:3]=1[CH2:22][CH2:23]Cl.[NH2:25][CH:26]([CH2:30][CH3:31])[CH2:27][O:28][CH3:29]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:29][O:28][CH2:27][CH:26]([N:25]1[C:2]2[C:11]3[N:10]=[CH:9][CH:8]=[C:7]([C:12]4[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=4[CH3:20])[C:6]=3[N:5]=[C:4]([C:21]3[C:13]([CH3:14])=[CH:12][C:7]([CH3:8])=[CH:6][C:11]=3[CH3:2])[C:3]=2[CH:22]=[CH:23]1)[CH2:30][CH3:31]
Reactant: CCC(N)COC
Reactant: Cc1cc(C)c(-c2ccnc3c(Cl)c(CCCl)c(C)nc23)c(C)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCC(COC)n1ccc2c(-c3c(C)cc(C)cc3C)nc3c(-c4c(C)cc(C)cc4C)ccnc3c21

Procedure:
A solution of 4-chloro-3-(2-chloroethyl)-8-mesityl-2-methyl[1,5]naphthyridine (200 mg, 0.557 mmol) in 2-amino-1-methoxybutane (2.0 mL) was stirred at 200° C. for four hours in a sealed tube. After evaporating, the residue was purified by silica gel column chromatography (30-50% ethyl acetate/hexane). Activated manganese dioxide (290 mg, 3.24 mmol) was added to a solution of the resulting product (130 mg, 0.33 mmol) in toluene (20 mL) and the mixture was heated under reflux for one day. After filtering through Celite, the mixture was evaporated. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane), to give the title compound (108 mg) as white crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: Clc1cc(Cc2ccccc2)ncn1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(Cc2ccccc2)ncn1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.06 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.08 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.6 ml of a tetrahydrofuran solution containing 0.2 g of 4-chloro-6-benzylpyrimidine was slowly added dropwise at room temperature, followed by stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.21 g of 4-(2-butynyloxy)-6-benzylpyrimidine (the present compound (91)).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[N:16]1([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][N:28]=2)[CH:24]=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][N:2]([CH:10]1[CH2:11][CH2:12][N:13]([CH2:24][C:23]2[CH:26]=[CH:27][N:28]=[C:21]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:22]=2)[CH2:14][CH2:15]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: O=Cc1ccnc(N2CCCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C(=O)OC(C)(C)C)C1CCN(Cc2ccnc(N3CCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
tert-Butyl methyl(piperidin-4-yl)carbamate (2.333 mmol, 1 eq) and 2-(pyrrolidin-1-yl)-isonicotinaldehyde (2.66 mmol, 1.14 eq) were dissolved in dichloromethane (15 ml), and acetic acid (5.459 mmol, 2.34 eq) and sodium triacetoxyborohydride (3.266 mmol, 1.4 eq) were added. The reaction mixture was stirred for 48 h at RT. When the reaction was complete (TLC monitoring), sat. sodium hydrogen carbonate solution was added to the reaction mixture and the phases were separated. The aqueous phase was extracted with dichloromethane (2×30 ml). The combined organic phases were washed with sat. NaCl solution, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, ethyl acetate:cyclohexane 2:1). Yield: 64%.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]([NH:18][NH2:19])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>C(O)C>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[N:19][NH:18][C:16]([C:8]2[NH:9][C:10]3[C:15]([C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:17])=[CH:23][CH:22]=1
Reactant: NNC(=O)c1[nH]c2ccccc2c1-c1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Solvent: CCO
Product: O=C(NN=Cc1ccc(Br)cc1)c1[nH]c2ccccc2c1-c1ccccc1
Temperature: 25 °C

Procedure:
A solution of Example 1C (1.76 g, 7.0 mmol) and 4-bromobenzaldehyde (1.36 g, 7.35 mmol) in ethanol (120 mL) was refluxed for 18 hours, cooled to room temperature, and filtered. The resulting solid was washed with ethanol and dried under vacuum to provide
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)(O)[CH3:13])[C:6]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)\[CH3:13])[C:6]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:5]=3[C:4]=2[CH:3]=1
Reactant: COc1ccc(C(C)(O)Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1ccc(/C(C)=C/n2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc1
Temperature: 7.5 °C
Yield: 69.2 %

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-methoxyphenyl)propan-2-ol (500 mg, 1.3 mmol, 1 equiv.) was heated to 55° C. with sulfuric acid (0.375 mL) in water (5 mL) for 2.5 h, cooled to 5-10° C. and neutralized by dropwise addition of saturated aqueous sodium hydrogen carbonate solution followed by extraction with EtOAc (2×15 mL). The combined organic extract was washed with water (10 mL), brine, dried over sodium sulfate and evaporated under reduced pressure to obtain 330 mg of product. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.60 (m, 3H), 7.24 (d, 1H), 7.19 (d, 1H), 7.10 (d, 1H), 7.0 (m, 2H), 4.40 (m, 2H), 3.80 (s, 3H), 3.10 (m, 4H), 2.80 (s, 3H), 1.80 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:14][CH2:13][CH2:12][CH:6]([C:7]([O:9]CC)=[O:8])[CH2:5]1)[CH2:2][CH3:3].O.[OH-].[Li+:17]>C(O)C>[CH2:1]([N:4]1[CH2:14][CH2:13][CH2:12][CH:6]([C:7]([O-:9])=[O:8])[CH2:5]1)[CH2:2][CH3:3].[Li+:17]
Reactant: CCCN1CCCC(C(=O)OCC)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCN1CCCC(C(=O)[O-])C1

Procedure:
Ethyl N-propylnipecotate (73.86 g) was dissolved in 500 ml ethanol, treated with lithium hydroxide monohydrate (15.57 g) at reflux for 24 hours. Upon evaporation and drying in vacuo (100° C., eight hours), lithium N-propylnipecotate was obtained (white powder; 60 g). A solution of 17.7 g of this salt in 200 ml THF was treated dropwise with one equivalent of methyl-lithium, at 0° C. After stirring at room temperature overnight, an aqueous work-up yielded 3-acetyl-N-propylpiperidine (mp of HCl salt 108°-111° C.). When 2.5 of this compound were intimately mixed with 2.28 g of thiourea and 3.81 g of iodine and heated on a steam bath for 24 hours, followed by a column chromatography (Silica; acetone) and salt formation by the procedure of Example 2, 1.75 g of 4-(1-propyl-3-piperidyl)-2-thiazolamine hydrochloride (mp 243°-248° C.) were obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>N1C=CC=CC=1>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:16]1[CH:17]=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:36]([CH:33]4[CH2:35][CH2:34]4)=[O:37])=[N:10][C:9]3=[CH:8][CH:7]=2)[CH:13]=[CH:14][C:15]=1[CH3:32])=[O:31])([CH3:27])[CH3:28])#[N:30]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3n2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (300 mg, 0.676 mmol) in pyridine (6.0 mL) was added cyclopropanecarbonyl chloride (80 μL, 0.879 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate (200 mL), washed with 5% aqueous sodium hydrogen carbonate solution (200 mL), water (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (234 mg, 68%) as a colorless powder.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][C:22]4[S:26][CH:25]=[N:24][C:23]=4[CH3:27])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:28]3[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=3)[S:8][C:7]=2[CH:36]=1.[Al+3].[Cl-].[Cl-].[Cl-].CCS>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][C:22]4[S:26][CH:25]=[N:24][C:23]=4[CH3:27])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:28]3[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=3)[S:8][C:7]=2[CH:36]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCc3scnc3C)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: Cc1ncsc1CCOc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Yield: 95 %

Procedure:
Reaction of a compound of Example 11 (0.27 g, 0.52 mmol), AlCl3 (0.42 g, 3.12 mmol) and EtSH (0.19 mL, 2.6 mmol) in CH2Cl2 (10 mL) at room temp. for 0.5 h. according to the procedure described in Example 3 provided a 95% of the desired product as a yellow solid: 1H-NMR (300 MHz, CDCl3) δ9.91 (s, 1H), 9.71 (s, 1H), 8.82 (s, 1H), 7.67 (d, J=8.7 Hz, 2H), 7.35 (d, J=2.3 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.18 (d, J=8.9 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 6.86 (dd, J=8.9, 2.3 Hz, 1H), 6.66 (d, J=8.8 hz, 2H), 4.19 (t, J=3.3 Hz, 2H), 3.20 (t, J=3.6 Hz, 2H), 2.32 (s, 3H); IR (thin film) 3299, 1700, 1635 cm-1; MS (FD) 488 (M+) Anal. calcd. for C25H21O4NS2 ; calc'd/found C(66.51/66.88), H (4.34/4.49), N (2.88/2.95).
Reaction SMILES: C(O[C:4]([CH:6](NC1C=CC=CC=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:16])O)=O)C.S(=O)(=O)(O)O.C([O:31][C:32](=O)[NH:33][C:34]1[CH:39]=[CH:38]C=[CH:36][CH:35]=1)C>>[CH:11]1[CH:12]=[C:7]([CH2:6][C:4]2[CH:38]=[CH:39][C:34]([N:33]=[C:32]=[O:31])=[CH:35][CH:36]=2)[C:8]([N:13]=[C:14]=[O:16])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(Nc1ccccc1)c1ccccc1NC(=O)O
Reactant: CCOC(=O)Nc1ccccc1
Agent: O=S(=O)(O)O
Product: O=C=Nc1ccc(Cc2ccccc2N=C=O)cc1
Temperature: 100 °C

Procedure:
0.3 g. of an ethyl ester of 2-[(ethoxycarbonyl)-phenylaminomethyl]phenylcarbamic acid (N-benzyl compound), prepared as in Example 1, along with 1.0 g. of 96.4 weight percent concentrated sulfuric acid was charged to a 300 ml reaction flask. The mixture was heated to 100° C. on a constant temperature bath for 60 minutes. High speed liquid chromatographic analysis showed conversion of the ethyl ester of 2-[(ethoxycarbonyl)phenylaminomethyl]phenylcarbamic acid to the diethyl ester of 2,4'-methylenebis(phenylcarbamic) acid and higher homologs to be 99+ percent with minor amounts of ethylphenylcarbamate. After acid extraction with water, the resulting 2,4'-methylenebis(phenylcarbamic) acid, diethyl ester (diurethane) was subjected to thermal decomposition by the method described in U.S. Pat. No. 3,962,302 to produce the diphenylmethane-2,4'-diisocyanate in good yield.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:12]=1)[CH2:2][CH2:3][CH3:4].CCN(CC)CC.[H][H]>CCO.O=[Pt]=O>[CH2:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCOC(=O)CCC#Cc1cccc(NCc2ccc(OC)cc2)n1
Agent: O=[Pt]=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCOC(=O)CCCCc1cccc(NCc2ccc(OC)cc2)n1
Yield: 94.5 %

Procedure:
A mixture of 6-5 (6.54 g, 17.8 mmol), Et3N (1.85 mL, 13.3 mmol), and PtO2 (0.405 g, 1.78) in EtOH (150 mL) was stirred under a balloon of hydrogen for 6 h. Filtration through celite and evaporative removal of the solvent afforded 6.23 g of 6-6 as a colorless oil. The crude product was used directly in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[C:27]([NH:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)(=[O:29])[CH3:28]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:35][C:34]4[CH:33]=[CH:32][C:31]([NH:30][C:27](=[O:29])[CH3:28])=[CH:38][CH:37]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc(NC(C)=O)cc3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.045 mmol) was reacted with 4-acetamidobenzaldehyde to provide 23 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [BH4-].[Na+].[Cl-].[CH2:4]([N+:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>CCO>[CH2:4]([N:11]1[CH2:12][CH:13]=[C:14]([C:17]([F:20])([F:18])[F:19])[CH2:15][CH2:16]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1cc[n+](Cc2ccccc2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: FC(F)(F)C1=CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
3.00 g (79.36 mmol) of sodium borohydride was added batchwise to a solution of 14.48 g (52.91 mmol) of 1-benzyl-4-trifluoromethylpyridinium chloride in 100 mL of EtOH with strong cooling at 0° C., then the cooling was stopped and the reaction mixture was stirred for 1.5 hours at 14° C. While cooling, 50 mL of water and then 50 mL of EtOH were added within 30 minutes. The reaction mixture was stirred for another 30 minutes, the resulting suspension was filtered and the filtrate was evaporated down in vacuo. Yield: 11.72 g (92% of theoretical); C13H14F3N (M=241.252); calc.: molpeak (M+H)+: 242; found: molpeak (M+H)+: 242; HPLC-MS: 3.60 minutes (method B).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][C:18](=O)[NH:17][C@H:16]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([O:28][CH3:29])[CH:22]=2)[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>O1CCCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][NH:17][C@H:16]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([O:28][CH3:29])[CH:22]=2)[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1cc([C@H]2NC(=O)CN(Cc3ccccc3)C2=O)ccc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc([C@@H]2CN(Cc3ccccc3)CCN2)ccc1C
Temperature: 0 °C

Procedure:
Lithium aluminum hydride (0.378 g) was added to an ice-cooled suspension of (3R)-1-benzyl-3-(3-methoxy-4-methylphenyl)-2,5-piperazinedione (1.35 g) in tetrahydrofuran (22 ml) below 5° C. under nitrogen atmosphere. The mixture was stirred under reflux for 3 hours. After the mixture was cooled below 5° C., 2N sodium hydroxide was added to the mixture. After the mixture was stirred for 30 minutes, the insoluble materials were removed by filtration and washed with tetrahydrofuran. The filtrate and the washing were combined and evaporated under reduced pressure to give (3R)-1-benzyl-3-(3-methoxy-4-methylphenyl)piperazine as an oil. A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.80 ml) in dichloromethane (1 ml) was added dropwise over 5 minutes to an ice-cooled solution of (3R)-1-benzyl-3-(3-methoxy-4-methylphenyl)piperazine obtained by above procedure and triethylamine (0.84 ml) in dichloromethane (10 ml) below 5° C. After being stirred for 30 minutes at the same temperature, the reaction mixture was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using mixed solvents of hexane and ethyl acetate (4:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-methoxy-4-methylbenzyl)piperazine (1.92 g) as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C(=O)C.CN(C)CCN(C1C=CC(Cl)=CN=1)C(=O)C>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1
Reactant: CC(=O)N(CCN(C)C)c1ccncc1
Agent: CC(=O)N(CCN(C)C)c1ccc(Cl)cn1
Product: CN(C)CCNc1ccncc1

Procedure:
The title compound is prepared by following the procedure of Example 15, Part B, except substituting N-(2-dimethylaminoethyl)-N-(4-pyridyl)acetamide from Part A above for N-(2-dimethylaminoethyl)-N-(5-chloro-2-pyridyl)acetamide. The product has b.p. 120°-128°/0.7 mm.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][C:21]2([OH:27])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][C:21]2([OH:27])[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][C:5]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=3)=[O:6])[CH2:25][CH2:26]2)=[CH:28][CH:29]=1
Reactant: OC1(Cc2ccc(Cl)cc2)CCNCC1
Reactant: COc1ccc(C(=O)CCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C(=O)CCCN2CCC(O)(Cc3ccc(Cl)cc3)CC2)cc1
Temperature: 105 °C
Yield: 54.4 %

Procedure:
A mixture of 2.11 g of 4-chloro-1-(4-methoxy-phenyl)-butan-1-one (1), 1.60 g of 4-(4-chloro-benzyl)-piperidin-4-ol (5), 1.96 g of K2CO3, and 0.45 g of KI in acetonitrile (50 mL) was stirred and refluxed at 100 to 110° C. for 19 hours under nitrogen atmosphere. After the solvent was removed, ice water was added and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and brine and dried over MgSO4. After the solvent was removed, the obtained oily residue was purified by silica gel chromatography (chloroform:methanol=20/1 to 10/1) and the purified product was recrystallized from AcOEt/Et2O to afford 1.55 g of compound (6).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH2:11]([O:13][C:14](=[O:21])[C:15](=O)[CH2:16][C:17](=O)[CH3:18])[CH3:12]>C(O)(=O)C>[Br:2][C:3]1[CH:4]=[C:5]([N:9]2[C:17]([CH3:18])=[CH:16][C:15]([C:14]([O:13][CH2:11][CH3:12])=[O:21])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: NNc1cccc(Br)c1
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)n(-c2cccc(Br)c2)n1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 3-bromophenylhydrazine hydrochloride (2 g, 8.9 mmol) and ethyl-2,4-dioxovalerate (1.69 g, 10.7 mmol) in acetic acid (44 ml) was refluxed for 16 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated bicarbonate and brine, and then dried over sodium sulfate, filtered and concentrated in vacuo. The crude product, thus obtained, was purified by silica-gel column chromatography (4.8:0.2 hexanes/ethyl acetate) to give the product (2.34 g, 84%) as a syrup.
Reaction SMILES: O1CCCC1.[CH3:6][S:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:13][CH:12]=1)(=[O:9])=[O:8].[Br:21]Br.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CCCCCC>[CH3:6][S:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH:18]([Br:21])[CH3:19])=[CH:13][CH:12]=1)(=[O:9])=[O:8]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(OS(C)(=O)=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(Br)C(=O)c1ccc(OS(C)(=O)=O)cc1
Reaction time: 1 h

Procedure:
A tetrahydrofuran solution (50 mL) of 15.0 g (100 mmol) of p-hydroxypropiophenone and 12.143 g (1.2 equivalents) of triethylamine was cooled to 5° C. To this solution, 12.60 g (1.1 equivalents) of methanesulfonyl chloride was added dropwise over 30 minutes, followed by 1 hour of stirring. To the resulting solution, 40 mL of water and 70 mL of ethyl acetate were added to conduct extraction. The organic layer was washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, and subjected to distillation under a reduced pressure to remove the solvents. A white solid was obtained as a result. This white solid was crystallized from 40 mL of ethyl acetate and 120 mL of hexane to thereby obtain white crystals of p-(methanesulfonyloxy)propiophenone (21.17 g, isolation yield: 93%). To a tetrahydrofuran solution (20 mL) of 4.560 g (20 mmol) of p-(methanesulfonyloxy)propiophenone, a hexane solution (5 mL) of 3.516 g (1.1 equivalent) of bromine was added at 15° C., followed by 1 hour of stirring. To the resulting solution, 30 mL of saturated sodium hydrogen carbonate and 30 mL of ethyl acetate were added to conduct extraction. The organic layer was washed with 20 mL of a saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and subjected to distillation under a reduced pressure to remove the solvent. 1-[4-(Methanesulfonyloxy)phenyl]-2-bromo-1-propanone was obtained as an yellow, oily substance (10.12 g, crude yield: 97%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[S:3]([O:6][C:7]1[CH2:13][CH:12]2[N:14](C(OC(C)(C)C)=O)[CH:9]([CH2:10][CH2:11]2)[CH:8]=1)(=[O:5])=[O:4].[ClH:24]>O1CCOCC1>[ClH:24].[F:23][C:2]([S:3]([O:6][C:7]1[CH2:8][CH:9]2[NH:14][CH:12]([CH2:11][CH2:10]2)[CH:13]=1)(=[O:4])=[O:5])([F:22])[F:1]
Reactant: CC(C)(C)OC(=O)N1C2C=C(OS(=O)(=O)C(F)(F)F)CC1CC2
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(OC1=CC2CCC(C1)N2)C(F)(F)F
Reaction time: 3 h

Procedure:
2.76 g of tert-butyl 3-{[(trifluoromethyl)sulfonyl]oxy}-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate in 13 ml of dioxane are placed in a 100 ml round-bottomed flask. 12.8 ml of a 4N solution of hydrochloric acid in dioxane are then carefully added. The reaction mixture is stirred for 3 h. The dioxane is evaporated off, to give 2.27 g of 8-azabicyclo[3.2.1]oct-2-ene-3-yl trifluoromethylsulfonate hydrochloride.