Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:28]=1[NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:31]3[CH:30]=[CH:29][C:28]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[C:27]([O:26][CH3:25])[CH:32]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C

Procedure:
cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10 g, 22.66 mmol), tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (9.49 g, 27.17 mmol), palladium tetrakistriphenyphosphine (1.57 g, 1.36 mmol) and sodium carbonate (5.76 g, 54.38 mmol) were mixed with ethylene glycol dimethyl ether (180 mL) and water (90 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by preparative thin layer column chromatography using dichloromethane/methanol (80:20) as mobile phase to give cis-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate (10.859 g, 89%). 1H NMR (DMSO-d6) δ 1.49 (s, 9H), 1.58 (m, 2H), 1.71 (m, 2H), 2.08 (m, 2H), 2.17 (s, 3H), 2.45 (m, 4H), 2.38 (m, 4H), 2.45 (m, 3H), 3.87 (s, 3H), 4.80 (m, 1H), 7.22 (m, 2H), 7.91 (d, J=8.14, 1H), 8.04 (s, 1H), 8.22 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2([C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:20].C(N([C:26]1([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35]2([C:50]3[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([Cl:57])[CH:51]=3)[CH2:41][CH2:40][CH2:39][CH2:38][N:37]([C:42](=[O:49])[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:36]2)[CH2:28][CH2:27]1)C)(=O)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C>[OH2:14].[ClH:56].[C:42]([N:37]1[CH2:38][CH2:39][CH2:40][CH2:41][C:35]([C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([Cl:57])[CH:51]=2)([CH2:34][CH2:33][CH2:32][N:10]2[CH2:11][CH2:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[CH2:8][CH2:9]2)[CH2:36]1)(=[O:49])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1.[C:42]([N:37]1[CH2:38][CH2:39][CH2:40][CH2:41][C:35]([CH2:34][CH2:33][CH2:32][N:29]2[CH2:28][CH2:27][C:26]([C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)[CH2:31][CH2:30]2)([C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([Cl:57])[CH:51]=2)[CH2:36]1)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[ClH:20]
Reactant: CC(=O)N(C)C1(c2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCCN(C(=O)c3ccccc3)C2)CC1
Reactant: O=C(N1CCCC1)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O
Product: O=C(c1ccccc1)N1CCCCC(CCCN2CCC(C(=O)N3CCCC3)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Yield: 32.3 %

Procedure:
This compound is prepared by the procedure described in step D of EXAMPLE 13, starting from 0.96 g of 4-phenyl-4-(pyrrolidin-1-ylcarbonyl)-piperidine, 1.5 g of the compound obtained in step C of EXAMPLE 13 and 1.5 g of K2CO3 in 10 ml of a DMF/acetonitrile mixture (50/50; v/v). This gives 0.34 g of the expected product, m.p.=135° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([C:14]#[CH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:2]1([C:15]#[C:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: Ic1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 80 °C
Yield: 15 %

Procedure:
To an ethanol solution (3 ml) containing iodobenzene (102 mg), phenylacetylene (56.1 mg), and potassium carbonate (138 mg) the mesh catalyst precursor (12 mm by 14 mm, wire diameter of 0.1 mm, opening of 0.154 mm) prepared in Example 3 was added to be heated for 12 hours at 80° C. The reaction mixture was cooled to room temperature, and the mesh catalyst precursor was washed with ethanol to be taken off from the mixture. The solvent was distilled away from the reaction mixture under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane) to give an intended product, diphenylacetylene with 15% yield.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[S:12][N:11]=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.O.[NH2:15][NH2:16]>O>[S:12]1[C:13]2[C:5]([C:3]([NH:15][NH2:16])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=2[N:10]=[N:11]1
Reactant: COC(=O)c1cccc2nnsc12
Reactant: NN
Solvent: O
Product: NNC(=O)c1cccc2nnsc12
Reaction time: 6 h

Procedure:
9.7 g of 7-methoxycarbonylbenzo-1,2,3-thiadiazole are reacted for 19 hours with 4.8 g of hydrazine hydrate in 30 ml of water at 50° C. and then for a further 6 hours at 80°-90° C. The suspension is cooled slightly, filtered while hot and washed with water to give 8.8 of white crystals having a melting point of 270°-272° C.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][N:7]1[CH2:11][C@H:10]2[C@@H:12]([NH:15][C:16](=[O:23])[C@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18])[CH2:13][CH2:14][C@H:9]2[CH2:8]1.C(N(CC)CC)C.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1>ClCCl>[CH:36]1([S:39]([NH:18][C@H:17]([C:16]([NH:15][C@@H:12]2[C@H:10]3[C@H:9]([CH2:8][N:7]([CH2:6][C:5]4[CH:24]=[CH:25][CH:26]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:4]=4)[CH2:11]3)[CH2:14][CH2:13]2)=[O:23])[CH2:19][CH:20]([CH3:21])[CH3:22])(=[O:41])=[O:40])[CH2:38][CH2:37]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)C[C@H](N)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](NS(=O)(=O)C1CC1)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N1-{(3aS,4S,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide from Step A (80 mg, 0.184 mmol) in dichloromethane (0.5 mL) was added triethylamine (0.064 mL, 0.461 mmol) followed by cyclopropanesulfonyl chloride (38.9 mg, 0.277 mmol) in a solution of 300 μL dichloromethane and the reaction mixture was stirred at room temperature overnight. The reaction was reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-12). The title compound was eluted with a gradient of 20% to 100% ethyl acetate/hexanes over 20 minutes to give N2-(cyclopropylsulfonyl)-N1-{(3aS,4S,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 9.34 (d, J=9.0, 1H), 8.84 (d, J=6.8, 1H), 7.73 (s, 1H), 7.64 (d, J=7.5, 1H), 7.59 (d, J=12.3, 1H), 7.43 (dd, J=6.6, 14.3, 1H), 4.53-4.42 (m, 2H), 3.76 (d, J=13.2, 1H), 3.41 (d, J=13.2, 1H), 2.99 (qd, J=4.2, 8.0, 1H), 2.90 (dd, J=3.6, 9.5, 1H), 2.82-2.74 (m, 1H), 2.57-2.48 (m, 1H), 2.40 (dd, J=8.5, 19.8, 2H), 2.30 (dd, J=3.4, 9.2, 1H), 2.02 (td, J=6.5, 13.7, 1H), 1.94-1.85 (m, 2H), 1.85-1.78 (m, 1H), 1.71 (td, J=6.2, 11.6, 1H), 1.67-1.58 (m, 1H), 1.40-1.28 (m, 2H), 1.22 (dt, J=4.7, 10.8, 1H), 0.93 (ddd, J=6.6, 12.3, 14.0, 2H), 0.87 (d, J=6.5, 3H), 0.84 (d, J=6.7, 3H); MS (ESI+) m/z 502 (M+H)+.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]1(C)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:22]([NH:30][C:31]1[CH:40]=[C:39]([OH:41])[CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(O)CCCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C(OCC)(=O)C.O1CCCC1>[C:22]([NH:30][C:31]1[CH:40]=[C:39]([O:41][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(O)cc1NC(=O)c1ccccc1
Reactant: Cc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: OC1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC2CCCCC2)cc1NC(=O)c1ccccc1
Reaction time: 5 h

Procedure:
0.20 mL of 40% diisopropyl azodicarboxylate /toluene was added dropwise to 1 mL of tetrahydrofuran solution containing 90 mg of methyl 2-(benzamido)-4-hydroxybenzoate, 0.035 mL of cyclohexanol and 0.10 g of triphenylphosphine at room temperature, and stirred at the same temperature for 5 hours. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to obtain 36 mg of methyl 2-(benzamido)-4-(cyclohexyloxy)benzoate as while solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[NH:12][N:13]=[C:14]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH:15]=2)=[O:9])=[N:6][CH:7]=1.CN1[C@@H](C)CNC[C@H]1C.[CH3:37][C@H:38]1[CH2:43][NH:42][CH2:41][C@@H:40]([CH3:44])[N:39]1[CH2:45][C:46]#[N:47].C(N(C(C)C)C(C)C)C>CS(C)=O.CO>[C:46]([CH2:45][N:39]1[C@@H:38]([CH3:37])[CH2:43][N:42]([C:2]2[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]3[NH:12][N:13]=[C:14]([CH2:16][CH2:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=4)[CH:15]=3)=[O:9])=[N:6][CH:7]=2)[CH2:41][C@H:40]1[CH3:44])#[N:47]
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Reactant: C[C@@H]1CNC[C@H](C)N1CC#N
Agent: C[C@@H]1CNC[C@H](C)N1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CO
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4C[C@@H](C)N(CC#N)[C@@H](C)C4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (271 mg, 0.70 mmol) was added in one portion to a 3:1 mixture of (2R,6S)-1,2,6-trimethylpiperazine and 2-[(2S,6R)-2,6-dimethylpiperazin-1-yl]acetonitrile (180 mg, 1.40 mmol) in anhydrous dimethylsulfoxide (1.40 ml) at 25° C. The resulting solution was stirred at ambient temperature for 2 h. The reaction was incomplete and N-ethyl-N-propan-2-ylpropan-2-amine (0.24 ml, 1.40 mmol) was added and the solution was stirred at 60° C. for a further 2 h. The reaction mixture was diluted with methanol (20 mL) and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (77 mg, 22%) as a yellow solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:11][CH:10]=1)=[O:7].[CH3:33][C:34]1[S:38][CH:37]=[N:36][CH:35]=1>C(#N)C>[Br-:1].[CH3:33][C:34]1[S:38][CH:37]=[N+:36]([CH2:2][C:3]2[CH:32]=[CH:31][CH:30]=[C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:11][CH:10]=3)=[O:7])[CH:4]=2)[CH:35]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(NC(=O)c2cccc(CBr)c2)cc1
Reactant: Cc1cncs1
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1ccc(NC(=O)c2cccc(C[n+]3csc(C)c3)c2)cc1
Product: [Br-]
Temperature: 25 °C
Yield: 71.4 %

Procedure:
A mixture of 5.5 g of 3-(bromomethyl)-N-[4-(tetradecyloxy)phenyl]benzamide and 3.26 g of 5-methylthiazole in 60 ml of acetonitrile is refluxed under argon for 3 hours. The mixture is poured into 60 ml of acetonitrile and cooled to room temperature. The solid is collected, washed with ether and crystallized from acetonitrile to give 4.7 g of the desired product as a white solid, m.p. 123°-125° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[N+:6]([O-:9])([OH:8])=[O:7]>CCOC(C)=O.CCCCCC>[N+:6]([O-:9])([O-:8])=[O:7].[CH3:1][NH2+:2][CH2:3][CH2:4][O:5][N+:6]([O-:8])=[O:7]
Reactant: CNCCO
Reactant: O=[N+]([O-])O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[NH2+]CCO[N+](=O)[O-]
Product: O=[N+]([O-])[O-]
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
Methyl(2-(hydroxy)ethyl)amine (1.5 g, 20 mmol) in EtOAc (65 mL) was added drop-wise to a mixture of fuming HNO3 (6.3 g, 4.2 mL, 100 mmol) and Ac20 (16.3 g, 15.1 mL, 160 mmol) at −10° C. The reaction mixture was stirred at −10° C. for 30 minutes and diluted with EtOAc and hexane. The precipitate was collected by filtration and washed with hexane to give the title compound (2.79 g, 82% yield) as an off-white solid. Mp 58-62° C. 1H NMR (300 MHz, d6-DMSO) δ 4.59-4.67 (m, 2H), 4.64-4.73 (m, 2H), 2.61 (bs, 3H). 13C NMR (75 MHz, d6-DMSO) δ 59.8, 38.7, 24.4. Mass spectrum (API-TIS) m/z 121 (MH+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[CH2:6][NH:7][CH2:8][CH2:9][O:10][CH3:11].[C:21](N1C=CN=C1)([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:22]>C1(C)C=CC=CC=1.C(Cl)Cl>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:14]=1)[CH2:6][N:7]([CH2:8][CH2:9][O:10][CH3:11])[C:21]([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:22]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COCCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)n1ccnc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
In a mixed solution of 37 ml of toluene and 4 ml of methylene chloride was dissolved 2.76 g of 3,5-bistrifluoromethylbenzyl-2-methoxyethylamine, added thereto was 1.78 g of 1,1′-carbonyldiimidazole, and the mixture was stirred at 60° C. for 3 hours. To the reaction mixture was added distilled water, and extracted with chloroform. The organic layer was dried over magnesium sulfate, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:acetone=9:1→2:1), to give 3.45 g of imidazole-1-carboxylic acid 3,5-bistrifluoromethylbenzyl-2-methoxyethylamide as shown in Table 133 below.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6](B(O)O)=[CH:5][CH:4]=[C:3]3[CH2:2]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:6]2[C:7]3[C:12]4[C:3]([CH2:2][CH2:1][C:11]=4[CH:10]=[CH:9][CH:8]=3)=[CH:4][CH:5]=2)=[CH:19][CH:18]=1
Reactant: Brc1ccc(I)cc1
Reactant: OB(O)c1ccc2c3c(cccc13)CC2
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: Cc1ccccc1
Product: Brc1ccc(-c2ccc3c4c(cccc24)CC3)cc1
Yield: 82.5 %

Procedure:
Five point nine gram of the 5-acenaphthene boronic acid obtained and 10.2 gram of 4-bromo iodobenzene were dissolved into 100 milliliter of toluene. Further adding tetrakistriphenylphosphinepalladium in an amount of 1.7 g and 2M-sodium carbonate aqueous solution in an amount of 45 milliliter, an atmospheric air was replaced with argon gas. The resultant solution was refluxed under heating for 6 hours, cooled by leaving it standing and the organic layer was extracted with the use of toluene. Washing with the use of a saturated sodium chloride solution, the organic layer was dried with anhydrous sodium sulfate, and the organic solvent was distillated by means of an evaporator. After refining the residues by means of silicagel column chromatography (spreading solvent: hexane), 9.2 g of the aimed intermediate product 5-(4-bromophenyl) acenaphthene as a pale yellow solid was obtained (yield: 100%).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1C=O>>[C:1]1([S:7](/[CH:10]=[CH:11]/[C:20]2[CH:19]=[CH:16][C:15]([Cl:14])=[CH:22][C:21]=2[Cl:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: O=C(O)CS(=O)(=O)c1ccccc1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1Cl)c1ccccc1
Yield: 60 %

Procedure:
A solution of phenyl sulfonylacetic acid (0.01 mol) and 2,4-dichlorobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 60-65% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C>O1CCCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:21]([OH:26])[OH:22])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-bromoanisole (2 g) in tetrahydrofuran (THF, 32 ml), which was cooled to -78° C., was added a hexane solution of n-butyllithium (0.83 M, 13.5 ml). The solution was stirred 15 minutes, at which time triisopropyl borate (8.6 ml) was added. The solution was stirred for 15 minutes, at which time the solution was allowed to warm to room temperature. Stirring was continued for 12 hrs. The solution was then washed into a hydrochloric acid solution (1M, 60 ml) with a small amount of THF. This solution was stirred an additional 2 hours, and was then extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate, and the solvent was removed in vacuo to yield a white solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6](CO)=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1.S(Cl)([Cl:27])=O.[CH2:29]([Cl:31])Cl>N1C=CC=CC=1>[Cl:27][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:29][Cl:31])=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1
Reactant: OCc1ccc(CO)c(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Reactant: ClCCl
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Fc1ccc(-c2c(CCl)ccc(CCl)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 26 %

Procedure:
A 250 mL 3 neck round-bottom flask equipped with a condenser was flushed with nitrogen and then loaded with 1,4-bis(hydroxymethyl)-2,3-di-(4-fluorophenyl)-benzene (2.70 g, 8.28 mmol), thionyl chloride (2.20 g, 18.5 mmol), methylene chloride (90 mL) and 3 drops of pyridine. The solution was then refluxed overnight and then cooled to room temperature. Methylene chloride was removed by rotary evaporation and then methanol was added to precipitate out the white product (0.77 g, 26% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][NH:5][C:6]1[C:18]2[C:17](=O)[C:16]3[CH:15]=[N:14][CH:13]=[CH:12][C:11]=3[C:10]=2[C:9]2[CH:20]=[CH:21][C:22]([OH:24])=[CH:23][C:8]=2[N:7]=1.Cl.[OH:27][NH3+:28]>N1C=CC=CC=1.ClCCl.CO>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]1[C:18]2[C:17](=[N:28][OH:27])[C:16]3[CH:15]=[N:14][CH:13]=[CH:12][C:11]=3[C:10]=2[C:9]2[CH:20]=[CH:21][C:22]([OH:24])=[CH:23][C:8]=2[N:7]=1
Reactant: CN(C)CCNc1nc2cc(O)ccc2c2c1C(=O)c1cnccc1-2
Reactant: [NH3+]O
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)CCNc1nc2cc(O)ccc2c2c1C(=NO)c1cnccc1-2
Temperature: 80 °C
Reaction time: 10 h

Procedure:
The compound of Example 41(18.0 mg) and hydroxylammonium hydrochloride (20.0 mg) (Tokyo Kasei Ltd.) were dissolved in pyridine (0.5 ml) (Wako Pure Chemical Industries Ltd.) and the solution was stirred at 80° C. for 10 hours. The reaction mixture was diluted with dichloromethane and filtered through a glass filter. The solid obtained was dissolved in methanol and passed through a Mega Bond Elut SCX (Varian). The column was washed with methanol and the product was eluted with ammonia water (25%, Wako Pure Chemical Industries Ltd.)—methanol=5:95. The solvent was evaporated to dryness. The desired product was obtained as an orange solid. ESI−MS: m/z 350 (MH+); 1H-NMR (MeOH-d4): δ2.45 (6H, s), 2.74 (2H, t, J=6.3 Hz), 3.63 (2H, t, J=6.3 Hz), 6.81 (1H, dd, J=6.6 Hz, 2.3 Hz), 6.93 (1H, d, J=2.3 Hz), 7.77 (1H, d, J=5.3 Hz), 7.83 (1H, d, J=9.2 Hz), 8.42 (1H, d, J=5.3 Hz), 9.16 (1H, s).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH:18]([CH3:27])[NH:19]CC2C=CC=CC=2)[CH2:14][CH2:13]1.[H][H]>[Pd].CO>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([CH:18]([CH3:27])[NH2:19])[CH2:16][CH2:17]1
Reactant: [H][H]
Reactant: CC(NCc1ccccc1)C1CCN(CC2COc3ccccc3O2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(N)C1CCN(CC2COc3ccccc3O2)CC1
Yield: 80.4 %

Procedure:
A mixture of 13.2 parts of 1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-α-methyl-N-(phenylmethyl)-4-piperidinemethanamine and 160 parts of methanol was hydrogenated at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 8 parts (80.4%) of 1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-α-methyl-4-piperidinemethanamine as an oily residue (intermediate 83).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([CH2:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1)=O)(C)(C)C.[ClH:28].C(P(=O)(OCC)O[CH2:33][CH3:34])#N.C([N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])C>O1CCOCC1.CN(C)C=O>[ClH:28].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([CH2:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1.[N:41]1[CH:42]=[CH:43][CH:34]=[CH:33][C:44]=1[C:45]1[CH:26]=[CH:25][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:15]=1
Reactant: CCOP(=O)(C#N)OCC
Reactant: CCCC(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)C(=O)OCC
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCCC(Cc1ccc(OCCN)cc1)C(=O)OCC
Product: O=C(O)c1ccc(-c2ccccn2)cc1
Reaction time: 0.67 h

Procedure:
A solution of ethyl 3-[4-(2-t-butoxycarbonylaminoethoxy)phenyl]-2-propylpropionate (2.20 g) in dioxane containing hydrogen chloride (4N, 30 ml) was allowed to stand at ambient temperature for 40 minutes. At the end of this time the reaction mixture was concentrated under reduced pressure and the hydrogen chloride was azeotropically distilled off with toluene to give a residue. A solution of diethyl cyanophosphonate (0.97 ml) in N,N-dimethylformamide (4.0 ml) was added to a solution of the residue obtained above (ethyl 3-[4-(2-aminoethoxy)phenyl]-2-propylpropionate hydrochloride), 4-pyridine-2-ylbenzoic acid (1.21 g) and triethylamine (1.80 ml) in N,N-dimethylformamide (8.0 ml) in an ice bath. The mixture was stirred for 1 hour in an ice bath and for 3 hours at ambient temperature. The reaction mixture was partitioned between ethyl acetate and water and the ethyl acetate was separated and washed with saturated aqueous sodium hydrogencarbonate and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on a silica gel column using dichloroethane/ethyl acetate=7/3 as the eluant to give the title compound (2.20 g) as a pale yellow powder.