Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:3])=[O:23])=[CH:20][CH:19]=1)[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (2 ml) and dimethylformamide (1 drop) were added to a solution of (R)-4-(1-benzyloxycarbonylaminoethyl)benzoic acid (1.11 g) in dichloromethane (10 ml), and the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was evaporated under reduced pressure to give (R)-4-(1benzyloxycarbonylaminoethyl)benzoyl chloride as crystals. Then, the crystals were dissolved in acetonitrile (10 ml), and the solution was dropwise added to a mixed solution of 4-amino-1h-pyrazolo[3,4-b]pyridine hydrochloride (320 mg) and diisopropylethylamine (880 mg) in acetonitrile (10 ml)-dimethylimidazolidinone (3 ml). The mixture was stirred at room temperature for 5 hours. The precipitated crystals were collected by filtration and dried. The residue was dissolved in methanol (7 ml). Sodium methoxide (80 mg) was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the mixture was concentrated under reduced pressure, and water was added to obtained residue. The mixture was extracted with ethyl acetate and dried. The solvent was evaporated under reduced pressure, and the obtained crystals were washed with ethyl acetate to give 310 mg of (R)-N-(1Hpyrazolo[3,4-b]pyridin-4-yl)-4-(1-benzyloxycarbonylaminoethyl)benzamide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.CI.[C:22](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:22][O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: CCOC(=O)C(C)=NNc1ccc(O)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)=NNc1ccc(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
A mixture of ethyl 2-[(4-hydroxy-2-nitrophenyl)hydrazono]propanoate (30 g), methyl iodide (21.3 g), potassium carbonate (21 g) and N,N-dimethylformamide (300 mL) was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid and saturated brine, dried (MgSO4), and concentrated. The obtained residue was crystallized from diethyl ether to give the title compound (28 g, yield 89%) as orange crystals. MS: 282 (MH+).
Reaction SMILES: NC(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(F)(F)F)CC3)C=2)C=1)(C)CCC(O)=O.C(O)(C(F)(F)F)=O.[N+:37]([C:40]([C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[C:52]([O:61][C@H:62]3[CH2:67][CH2:66][C@@H:65]([C:68]([F:71])([F:70])[F:69])[CH2:64][CH2:63]3)[C:53]=2[C:57]([F:60])([F:59])[F:58])[CH:48]=1)([CH3:46])[CH2:41][CH2:42][C:43]([OH:45])=[O:44])([O-])=O>>[NH2:37][C:40]([C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[C:52]([O:61][C@H:62]3[CH2:63][CH2:64][C@@H:65]([C:68]([F:69])([F:70])[F:71])[CH2:66][CH2:67]3)[C:53]=2[C:57]([F:59])([F:60])[F:58])[CH:48]=1)([CH3:46])[CH2:41][CH2:42][C:43]([OH:45])=[O:44]
Reactant: CC(CCC(=O)O)(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Agent: CC(N)(CCC(=O)O)c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1
Solvent: O=C(O)C(F)(F)F
Product: CC(N)(CCC(=O)O)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@@H](C(F)(F)F)CC3)ccc2c1
Yield: 46 %

Procedure:
4-Amino-4-[5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid was synthesized as per 4-amino-4-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid (Example 282) in 46% yield (as TFA salt), using 4-nitro-4-[5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid as starting material. MS: m/z=500.10 [M+Na]+. 1H NMR (400 MHz, to DMSO-d6) δ ppm: 12.23 (br. s., 8.52 (br. s., 3H), 8.23 (d, J=9.3 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.04 (d, J=1.8 Hz, 1H), 7.77 (dd, J=9.3, 2.0 Hz, 1H), 7.71 (d, J=9.3 Hz, 1H), 5.07-5.13 (br. s., 1H), 2.39-2.59 (m, 2H obscured), 2.21-2.34 (m, 2H), 1.93-2.17 (m, 4H), 1.56-1.78 (m, 9H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Cl[C:25]1[C:32]([F:33])=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1>>[F:33][C:32]1[C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10](=[O:11])[C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[N:26][CH:27]=[C:28]([CH:31]=1)[C:29]#[N:30]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: N#Cc1cnc(Cl)c(F)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C#N)cc2F)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 6-chloro-5-fluoronicotinonitrile. ESI-MS (m/z): 435 [M+1]+.
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]4[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=4[F:45])[N:32]=3)=[O:30])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.CO.[OH-].[Na+]>C1COCC1>[F:44][C:43]1[CH:42]=[CH:41][CH:40]=[C:39]([F:45])[C:38]=1[C:33]1[N:32]=[C:31]([C:29]([NH:28][C:12]2[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:15]3)=[C:8]3[CH2:7][CH2:6][CH:5]([OH:4])[C:9]3=[N:10][CH:11]=2)=[O:30])[CH:36]=[CH:35][C:34]=1[F:37]
Reactant: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cccc3F)n1)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3O)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.4 %

Procedure:
A mixture of 4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (174 mg, 0.28 mmol), MeOH (0.7 mL), THF (0.7 mL) and 1.0 M aq. NaOH (1.1 mL, 1.1 mmol) was stirred at room temperature for 20 min. The organic solvents were removed under reduced pressure. The aqueous layer was diluted with EtOAc and NH4Cl (aq.), extracted with EtOAc twice. The combined organic layers were dried, filtered and concentrated under reduced pressure to give the sub-title compound (151 mg, 93%). LCMS calc. for C30H33F3N5O4 (M+H)+: m/z=584.2. Found: 584.2.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:19])[CH2:15][C:16]([OH:18])=O)([CH3:3])[CH3:2].[CH2:20]([NH:27][CH:28]([CH3:30])[CH3:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C>C(N(CC)CC)C.CO.C(OCC)(=O)C>[CH2:20]([N:27]([CH:28]([CH3:30])[CH3:29])[C:16](=[O:18])[CH2:15][C:14]([NH:13][C:5]1[C:6]([CH:10]([CH3:11])[CH3:12])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:2])[CH3:3])=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)NCc1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CC(=O)N(Cc1ccccc1)C(C)C
Temperature: -5 °C
Reaction time: 8 h

Procedure:
A 2 liter flask equipped with a stirrer and nitrogen inlet was charged with N-( 2,6-diisopropyl-phenyl)-malonamic acid (100 g, 0.380 moles) and N-benzylisopropylamine (82 mL, 74 g, 0.5 moles). The resulting solution was stirred in an ice-acetone bath until cooled to −5° C., then EDAC (80 g, 0.42 moles) was added, followed by triethylamine (75 mL, 54 g, 0.54 moles). The mixture was stirred and allowed to come to room temperature, then left overnight. TLC (ethyl acetate: methanol, 95:5) showed unreacted acid still present. Another 8 g of EDAC and 15 mL of triethylamine were added, and the mixture was stirred at room temperature 4 h longer. TLC showed no change, and the reaction was worked up by washing, first with 2N HCl (500 mL), then 2N NaOH (acidification of the basic wash precipitated ˜13 g of the unreacted malonamic acid). After the acid and base washes, the organic solution was washed with water (500 mL), then brine (250 mL). It was then dried over magnesium sulfate, filtered and concentrated to a thick oil. The crude product was taken up in a small volume of warm heptane and filtered through ˜500 g of silica gel, which was rinsed with 10% ethyl acetate in heptane until all the desired product had come through. This left a thin layer of polar impurities at the top of the silica gel, and gave a nearly pure solution of the product. Most of the solvent was removed on the Rotavap, to remove the ethyl acetate, and then the oil was dissolved in warm heptane (1 liter). The solution was allowed to cool, seeded with a few crystals of the form A polymorph, and stirred at room temperature until precipitation of product was complete. The suspension was further stirred for 24 h, then chilled to 0° C. and filtered with suction. The collected product was air dried at room temperature to give 98 g of the Form A polymorph of N-benzyl-N′-(2,6-diisopropyl-phenyl)-N-isopropyl-malonamide.Melting point was 102.3° C., as determined by DSC, as described above.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH:19]1([C:25]([C:13](=[CH:12][NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH3:3])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCOC(=O)C=CNc1ccccc1OC
Reactant: O=C(Cl)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=CNc1ccccc1OC)C(=O)C1CCCCC1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
50% Sodium hydride (4.8 g, 0.1 mol) was washed with petroleum ether then stirred in dry tetrahydrofuran (50 ml) under nitrogen at -20° C. Ethyl 3-(2-methoxyphenylamino)acrylate (17.4 g, 0.1 mol) in dry tetrahydrofuran (100 ml) was added dropwise, keeping the temperature to -20° C. Cooling was removed and the mixture was stirred until a dark red colour was achieved. The mixture was recooled to -20° C. and cyclohexylcarbonyl chloride (14.0 ml, 0.1 mol) in dry tetrahydrofuran (50 ml) was added dropwise. The mixture was allowed to warm to room temperature and was stirred for a further 3 hours. The solvent was evaporated and the residue was partitioned between dichloromethane and 2M HCl. The organic layer was washed with water and brine, dried and evaporated to an oil which was chromatographed (silica gel, dichloromethane-hexane) to afford ethyl 2-cyclohexylcarbonyl-3-(2-methoxyphenylamino)acrylate as a yellow oil (23.3 g, 70%).
Reaction SMILES: [C:1]([N:4]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)[C:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][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][CH2:29][CH2:30][CH3:31])=[O:6])(=[O:3])[CH3:2].[CH2:39]([I:41])[CH3:40]>C(#N)C>[I-:41].[C:1]([N:4]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N+:34]=1[CH2:39][CH3:40])[C:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][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][CH2:29][CH2:30][CH3:31])=[O:6])(=[O:3])[CH3:2]
Reactant: CCI
Reactant: CCCCCCCCCCCCCCCCCCOCCOCCOC(=O)N(Cc1ccccn1)C(C)=O
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCCOCCOCCOC(=O)N(Cc1cccc[n+]1CC)C(C)=O
Product: [I-]

Procedure:
A solution of the compound obtained in example 2 (692 mg, 1.29 mmol) in acetonitrile (1 mL) and ethyl iodide (1 mL) was heated at 70° C. for three days. The solution was concentrated in vacuo, the residue was dissolved in dichloromethane and precipitated with ether. The solid was filtered and dried to yield the desired compound as a yellowish powder (693 mg, 77%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[C:57]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:56][CH:55]=[CH:54][N:53]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[C:57]([C:58]2[CH:59]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:61]=[CH:62][CH:63]=2)=[CH:56][CH:55]=[CH:54][N:53]=1
Reactant: COc1ncccc1-c1cccc(N)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncccc1-c1cccc(NC(=O)c2cc3cccc(OC)c3oc2=O)c1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-methoxy-pyridin-3-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.024 g of product in 92% yield: LCMS (ESI) m/z 403 (MH+).
Reaction SMILES: [C:1]([C@@:8]([NH2:15])([CH2:12][O:13][CH3:14])[C:9]([OH:11])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][O:28][CH2:27][C:26]1=[O:31])[NH:20][CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[C:1]([C@@:8]([NH2:15])([CH2:12][O:13][CH3:14])[C:9]([N:20]([CH3:21])[C:19]1[CH:22]=[CH:23][C:24]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[C:17]([CH3:16])[CH:18]=1)=[O:11])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CNc1ccc(N2CCOCC2=O)c(C)c1
Reactant: COC[C@@](N)(C(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COC[C@](N)(C(=O)OC(C)(C)C)C(=O)N(C)c1ccc(N2CCOCC2=O)c(C)c1

Procedure:
Prepared analogously to Example 1d from (2R)-2-Boc-amino-3-methoxy-propionic acid and 3,N-dimethyl-4-(3-oxo-morpholin-4-yl)-aniline with TBTU and TEA in DMF.
Reaction SMILES: [CH2:1]1[O:15][C:14]2[C:3](=[CH:4][C:5]3[CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7][C:6]=3[CH:13]=2)[O:2]1.[CH2:16]1[O:37][C:36]2[CH:35]=[CH:34][C:20]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]([CH2:32][Cl:33])[CH2:26]3)=[CH:19][C:18]=2[O:17]1>>[ClH:33].[CH2:16]1[O:37][C:36]2[CH:35]=[CH:34][C:20]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]([CH2:32][N:9]4[C:8](=[O:12])[CH2:7][C:6]5[CH:13]=[C:14]6[O:15][CH2:1][O:2][C:3]6=[CH:4][C:5]=5[CH2:11][CH2:10]4)[CH2:26]3)=[CH:19][C:18]=2[O:17]1
Reactant: O=C1Cc2cc3c(cc2CCN1)OCO3
Reactant: ClCC1CCCCN(CCCOc2ccc3c(c2)OCO3)C1
Product: Cl
Product: O=C1Cc2cc3c(cc2CCN1CC1CCCCN(CCCOc2ccc4c(c2)OCO4)C1)OCO3

Procedure:
Prepared from 7,8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and N-[3-(3,4-methylenedioxy-phenoxy)-propyl]-3-chloromethyl-hexahydro-azepine analogously to Example 2.
Reaction SMILES: [C-:1]#[N:2].[Na+].[I:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1>CS(C)=O.O>[I:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:1]#[N:2])=[CH:7][CH:6]=1
Reactant: BrCc1ccc(I)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.1 %

Procedure:
A mixture of 4.36 g (20.0 mmol) of p-iodotoluene (purchased from Tokyo Kasei), 3.92 g (22.0 mmol) of N-bromosuccinimide (purchased from Tokyo Kasei) and 60 ml of carbon tetrachloride (purchased from Wako Junyaku Kogyo) was refluxed under irradiation by an incandescent lamp for 4 hours to give 2.67 g (yield: 45.0%) of 4-iodobenzyl bromide (as a white crystalline). Subsequently, to a solution of 0.49 g (10.0 mmol) of sodium cyanide (purchased from Kokusan Kagaku) in 10 ml of dimethyl sulfoxide (purchased from Aldrich) heated at 50° C. was added 1.48 g (5.0 mmol) of the above 4-iodobenzyl bromide, the mixture was stirred at ambient temperature for 3 hours, the resultant reaction mass was dissolved in water and extracted with hexane, and hexane was removed to give 0.84 g (yield: 68.9%) of 4-iodophenylacetonitrile as a white crystalline.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](OC(C)(C)C)=O)[CH2:7][CH2:8][CH3:9])[CH3:2].Cl.O1CCOCC1.[NH:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH2:35][N:36]([CH2:44][C:45]1[CH:52]=[CH:51][C:48](C=O)=[CH:47][CH:46]=1)[CH2:37][C:38]1[N:39]([CH3:43])[CH:40]=[CH:41][N:42]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:48]1[CH:51]=[CH:52][C:45]([CH2:44][N:36]([CH2:35][C:31]2[NH:30][CH:34]=[CH:33][N:32]=2)[CH2:37][C:38]2[N:39]([CH3:43])[CH:40]=[CH:41][N:42]=2)=[CH:46][CH:47]=1)[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCN(CCCCNC(=O)OC(C)(C)C)CC(=O)OCC
Reactant: Cn1ccnc1CN(Cc1ccc(C=O)cc1)Cc1ncc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Solvent: CC(=O)O
Product: CCCN(CCCCNCc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1)CC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
The compound (273.0 mg) obtained in Example 84-2 was dissolved in ethanol (2.7 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (2.7 ml) and the whole was stirred at room temperature for 1 hour. Further, the solution was added with a 4 mol/l hydrogen chloride/dioxane solution (1.0 ml) and the whole was stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off, thereby obtaining a crude product (350.0 mg) of [(4-amino-butyl)-propyl-amino]-acetic acid ethyl ester as a colorless oily substance. The resultant crude product (350.0 mg) was dissolved in ethanol (4.5 ml) and added with an ethanol solution (2.6 ml) containing the compound (258 mg) obtained in Example 84-5, acetic acid (0.10 ml), and sodium triacetoxyborohydride (267.0 mg) and the whole was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (238.0 mg) as a pale-yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1.[Al+3].[Cl-].[Cl-].[Cl-].C[Si]([C:28]#[N:29])(C)C>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:11][CH:12]2[C:28]#[N:29])=[O:7])=[CH:4][CH:3]=1
Reactant: c1ccc2scnc2c1
Reactant: C[Si](C)(C)C#N
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: N#CC1Sc2ccccc2N1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-Fluorobenzoylchloride (6.5 g, 41.0 mmol) was added dropwise to a stirring solution of benzothiazole (5.4 g, 40.0 mmol) in dichloromethane (40 mL) under argon atmosphere. A catalytic amount of AlCl3 and trimethylsilylcyanide (4.1 g, 42.0 mmol) were than added into the reaction mixture. After being stirred for 15 h at room temperature, the reaction mixture was evaporated to dryness in vacuo and the residue was triturated with ether to give 3-(4-fluorobenzoyl)-2,3-dihydrobenzo[d]thiazole-2-carbonitrile, 9.3 g (82%); mp 150-151° C. 1H NMR (DMSO-d6) δ 6.71 (1H, brs, C2-H), 6.85 (1H, s, ArH), 7.04-7.07 (1H, m, ArH), 7.12-7.16 (1H, m, ArH), 7.38-7.40 (2H, m, 2×ArH), 7.52-7.54 (1H, m, ArH), 7.64-7.67 (2H, m, 2×ArH). Anal. Calcd. for (C15H9FN2OS): C, 63.37; H, 3.19; N, 9.85; S, 11.28. Found: C, 63.02; H, 3.27; N, 9.81; S, 11.31.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=O.[CH2:13]([O:20][C:21]1[C:26](=[O:27])[CH:25]=[C:24]([CH3:28])O[C:22]=1[C:29]([OH:31])=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33].CN.CO>CN(C=O)C>[CH2:13]([O:20][C:21]1[C:26](=[O:27])[CH:25]=[C:24]([CH3:28])[N:3]([CH3:1])[C:22]=1[C:29]([N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])=[O:31])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCNCC
Agent: CN
Solvent: CO
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1c(OCc2ccccc2)c(=O)cc(C)n1C
Temperature: 40 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
1,1′-carbonyldiimidazole (1.87 g, 111.53 mmol) was added to a solution of the 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid (2.0 g, 7.69 mmol) in DMF (15 ml) at room temperature. The resulting solution was heated at 40° C. for 3 hrs. A clear yellow solution was observed. Diethylamine (1.08 ml, 9.2 mmol) was added. The reaction mixture was stirred at 40 to 45° C. for 2 hrs. The reaction was cooled to room temperature at which time a solution of methylamine in methanol (11 ml of 2M solution in methanol, 15.4 mmol) was added. The solution was stirred at 65 to 70° C. for 15 hrs under pressure. The solvent was removed under reduced pressure and dichloromethane was added (70 ml). The solution was washed with water and dried over magnesium sulfate (1 g). Solvent evaporation gave light yellow oil as a crude product. The column was eluted with 10% to 25% methanol in ethyl acetate to give the titled compound (1.74 g, yield 67%). H-NMR (CDCl3) σ: 1.09 (t, J=7.11 Hz, 3H, Me), 1.16 (t, J=7.04 Hz 3H, Me), 2.34 (s, 3H, Me), 3.13-3.30 (m, 2H, CH2), 3.47 (s, 3H, NMe), 3.50-3.60 (m, 2H, CH2), 4.91(d, J=10.76 Hz, 1H, CH2), 5.52(d, J=10.74 Hz, 1H, CH2), 6.41 (s, 1H, CH), 7.10-7.33 (m, 5H, Ph), Mass spect. 329 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([CH3:13])[CH:3]=1.Cl.[CH2:15]([O:17][C:18](=[O:29])[CH:19](CC)[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][NH:22]1)[CH3:16].C(N(CC)CC)C>ClCCl>[CH2:15]([O:17][C:18](=[O:29])[CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][N:22]1[S:9]([C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Cl:1])=[CH:3][C:4]=1[CH3:13])(=[O:11])=[O:10])[CH3:16]
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)cc1Cl
Reactant: CCOC(=O)C(CC)CC1CCCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC1CCCCN1S(=O)(=O)c1cc(C)c(Cl)cc1C
Temperature: 0 °C
Yield: 50 %

Procedure:
4-Chloro-2,5-dimethyl-benzenesulfonyl chloride (1 g, 3.8 mmol) was added to a solution of ethyl 3-(piperidin-2-yl)propionic acid ethyl ester hydrochloride (1.1 g, 4.6 mmol) in dichloromethane (15 ml) while stirring, the mixture was cooled to 0° C., and triethylamine (1.6 ml, 11.5 mmol) was added dropwise over 15 min. The mixture was stirred for 4 h at 0° C., then diluted with dichloromethane, washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated to small volume under vacuum. The crude product was purified with ethyl acetate/hexane (9:1) by column chromatography. Yield: 50%