Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(S)C.[CH:11]([C:13]1[CH:18]=CC=[CH:15][C:14]=1[CH:19]=C)=C.C=CC1C=CC=CC=1.[CH3:29][C:30]([CH3:32])=[O:31]>>[CH3:15][C:14]([C:13]1[CH:18]=[CH:32][C:30]([OH:31])=[CH:29][CH:11]=1)([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)[CH3:19]
Reactant: CC(C)=O
Reactant: C=Cc1ccccc1C=C
Reactant: Oc1ccccc1
Solvent: CCS
Solvent: C=Cc1ccccc1
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
Referring now to the drawing, a stoichiometric excess of phenol, acetone, and a mercaptan reaction promoter such as ethyl mercaptan, are fed to a reactor 12 that is maintained at a temperature of, for instance 55°-80° C, and which contains an acid catalyst such as sulfonated styrene-divinylbenzene ion exchange resin. Alternatively, a mercaptan reaction promoter can be combined with an acid catalyst such as sulfonated styrene-divinylbenzene ion exchange resin in the reactor as disclosed, for example, in McNutt et al., U.S. Pat. No. 3,394,089 and Gammill et al., U.S. Pat. No. 3,634,341 and addition thereof with the phenol and acetone feed can be eliminated. In the reactor 12, the reaction of phenol with acetone to produce 4,4'-bisphenol-A occurs. The product stream flowing from the reactor 12 contains phenol, 4,4'-bisphenol-A, some unreacted acetone, mercaptan promoter, water, and by-products. The product stream flows from the reactor 12 to a dehydrator 14, in which the acetone, mercaptan promoter, water, and some of the phenol are stripped from the product stream. The dehydrated product stream flows from the dehydrator 14 to a crystallizer 16, in which 4,4' -bisphenol-A/phenol adduct crystals are precipitated by cooling. The slurry of mother liquor and adduct crystals flows from the crystallizer to a solid-liquid separator such as a centrifuge 18, in which the mother liquor and adduct crystals are separated. The 4,4'-bisphenol-A product is recovered from the adduct crystals by known techniques (not shown). The mother liquor flows from the centrifuge 18 to a mother liquor storage container 22, prior to being recycled to the reactor 12. At least a portion of the mother liquor flowing from the centrifuge 18 may be introduced into a purge recovery reactor 20, in which it is subjected to elevated temperature (e.g., 100° to 300° C., and preferably 150° to 250° C.) in the presence of a base catalyst, to cleave the bisphenols and other polyphenols present in the mother liquor to phenol and IPP, including IPP dimer. The phenol and IPP products of the cleavage reaction are continuously removed from the purge recovery reactor 20, as by distillation, and the cleavage reaction product stream 21 is returned to the mother liquor recycle stream 19.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.CC[O:13][C:14]([C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O.O>C1(C)C=CC=CC=1.C(OCC)C>[C:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[CH:14]=[O:13])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Temperature: -78 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
At −78° C., a 1.2 M solution of diisobutylaluminum hydride (31.7 ml, 38 mmol) in toluene was added dropwise to a solution of (2S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (4.02 g, 16.5 mmol) in diethyl ether (1.5 ml). The reaction mixture was stirred for 3 h at −78° C. Water (9.9 ml) was added dropwise. The reaction mixture was warmed to room temperature. The mixture was filtered through a plug of celite. The celite was washed with tert-butyl methyl ether (3×100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo, to give 2.34 g of crude N-t-butyloxycarbonyl-(S)-prolinal, which was used for the next step without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.I(O)(=O)(=O)=[O:13].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.[Fe](Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)=[O:13]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CSc1ccc([N+](=O)[O-])cc1
Agent: Cl[Fe](Cl)Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CS(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A suspension of 25.00 g (147.8 mmol) 1-methylsulphanyl-4-nitro-benzene and 0.69 g (4.2 mmol) iron(III) chloride (anhydrous) in 120 ml acetonitrile is treated with 36.0 g (158.1 mmol) periodic acid and stirred at room temperature. At the start of heat evolution, the mixture is transiently cooled with an ice-bath, so that the temperature does not rise above 30° C. After the heat evolution has subsided, the mixture is stirred at room temperature for a further 10 mins. The mixture is poured into a solution of 150 g sodium thiosulphate in 1000 ml ice-water and then extracted with DCM. The combined organic phases are washed with saturated NaCl solution, dried (Na2SO4), filtered and concentrated. The remaining residue is recrystallised from toluene. 23.6 g (128.0 mmol, corresponding to 86% of theor.) of the product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][NH:10]1.[CH3:19][C:20]1[CH:46]=[CH:45][C:23]([C:24]([O:26][C@@H:27]([C@H:31]([O:35][C:36](=[O:44])[C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[C:32]([OH:34])=[O:33])[C:28]([OH:30])=[O:29])=[O:25])=[CH:22][CH:21]=1>C(#N)C>[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][C@@H:27]([C@H:31]([O:35][C:36](=[O:44])[C:37]2[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][CH:42]=2)[C:32]([OH:34])=[O:33])[C:28]([OH:30])=[O:29])=[O:25])=[CH:45][CH:46]=1.[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][NH:10]1
Reactant: COc1ccccc1C1NCCc2ccccc21
Agent: Cc1ccc(C(=O)O[C@H](C(=O)O)[C@H](OC(=O)c2ccc(C)cc2)C(=O)O)cc1
Solvent: CC#N
Product: COc1ccccc1[C@H]1NCCc2ccccc21

Procedure:
1-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (8.227 g) and (2S,3S)-2,3-bis[(4-methybenzoyl)oxy]succinic acid (13.282 g) were dissolved with stirring in acetonitrile (246 mL) at 70° C. The mixture was slowly cooled with stirring. The resulting crystal was collected by filtration, washed with acetonitrile, and dried under reduced pressure to obtain (1S)-1-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinate (16.193 g).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:32]=[CH:31][C:23]4[C:24]([C:28]([OH:30])=O)=[C:25]([CH3:27])[O:26][C:22]=4[CH:21]=3)[CH:11]=2)=[O:9])[CH2:4]1.C(Cl)(=O)C(Cl)=O.[NH2:39][CH2:40][CH2:41][OH:42]>>[OH:42][CH2:41][CH2:40][NH:39][C:28]([C:24]1[C:23]2[CH:31]=[CH:32][C:20]([O:19][C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[CH:11]=[C:10]([C:8]([N:5]5[CH2:6][CH2:7][CH:3]([O:2][CH3:1])[CH2:4]5)=[O:9])[S:18][C:17]=34)=[CH:21][C:22]=2[O:26][C:25]=1[CH3:27])=[O:30]
Reactant: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)oc5c4)c3s2)C1
Reactant: NCCO
Agent: O=C(Cl)C(=O)Cl
Product: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NCCO)c(C)oc5c4)c3s2)C1

Procedure:
This material was prepared from 6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-methyl-benzofuran-3-carboxylic acid 89e by treatment with oxalyl chloride and 2-aminoethanol in a manner as previously described for example 16d. 1H NMR (DMSO-d6) δ8.57 (1H, d, J=5.6 Hz), 8.06 (1H, s), 8.00 (1H, t, J=5.3 Hz), 7.82 (1H, d, J=8.6 Hz), 7.66 (1H, d, J=2.3 Hz), 7.26 (1H, dd, J=8.3, 2.3 Hz), 6.72 (1H, d, J=5.3 Hz), 4.76(1H, m), 4.10-3.82 (3H, m), 3.67-3.59 (2H, m), 3.55 (2H, t, J=6.1 Hz), 3.37 (2H, t, J=6.1 Hz), 3.27, 3.24 (3H, 2s), 2.63 (3H, s), 2.06 (2H, m).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].Cl.[CH2:9]([O:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([NH:27][C:28]3C=C(O)[C:31]([Cl:35])=[CH:30][C:29]=3[F:36])=[CH:22][CH:23]=[N:24]2)=[CH:19][C:18]=1[O:37][CH3:38])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C1C=CN=CC=1>[C:5]([O:4][C:1]1[C:31]([Cl:35])=[CH:30][C:29]([F:36])=[C:28]([CH:2]=1)[NH:27][C:21]1[C:20]2[C:25](=[CH:26][C:17]([O:16][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:18]([O:37][CH3:38])[CH:19]=2)[N:24]=[CH:23][CH:22]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(Nc3cc(O)c(Cl)cc3F)ccnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: COc1cc2c(Nc3cc(OC(C)=O)c(Cl)cc3F)ccnc2cc1OCc1ccccc1
Yield: 102.8 %

Procedure:
4-Dimethylaminopyridine (12 mg, 0.1 mmol) and acetic anhydride (122 mg, 1.2 mmol) were added to a suspension of 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxyquinoline hydrochloride (461 mg, 1 mmol), (prepared as described in Example 12). The mixture was heated at reflux for 1 hour and the volatiles were removed by evaporation. The residue was triturated with water and the resulting precipitate was collected by filtration and dried under vacuum to give 4-(5-acetoxy-4-chloro-2-fluoroanilino)-7-benzyloxy-6-methoxyquinoline (480 mg, 95%).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[CH:19][NH:20]3)=[CH:16][CH:15]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:23][C:24]1[C:29](/[CH:30]=[CH:31]/[N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=[CH:26][C:25]=1[NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1>[Si:1]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH:30]([C:29]4[C:24]([CH3:23])=[C:25]([NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=5)[CH:26]=[CH:27][CH:28]=4)[CH2:31][N+:32]([O-:34])=[O:33])=[CH:19][NH:20]3)=[CH:16][CH:15]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(c2ccc3cc[nH]c3c2)C1
Reactant: Cc1c(/C=C/[N+](=O)[O-])cccc1NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(C[N+](=O)[O-])c1c[nH]c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)C3)ccc12
Temperature: 110 °C
Yield: 33.4 %

Procedure:
6-(3-(tert-Butyldimethylsilyloxy)pyrrolidin-1-yl)-1H-indole (1.867 g, 5.90 mmol) and (E)-benzyl 2-methyl-3-(2-nitrovinyl)phenylcarbamate (1.5354 g, 4.92 mmol) were dissolved in THF (40 mL), concentrated in vacuo, and the mixture was heated at 110° C. for 1 hr. The reaction mixture was cooled to room temperature and purified by flash chromatography using an ISCO 220 g column eluting with 25-100% EtOAc/hexanes to give the desired product (1.0324 g, 1.642 mmol, 33.4% yield) as a tan solid.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN([CH:28]([CH3:30])[CH3:29])C(C)C.[NH2:31][C@H:32](CC)[C@@H:33]([OH:35])C>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][CH2:32][CH:33]([OH:35])[CH2:30][CH2:28][CH3:29])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CC[C@@H](N)[C@H](C)O
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Solvent: CCCCO
Solvent: CS(C)=O
Product: CCCC(O)CNc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (2.5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.2 mL, 10.96 eq, 1.14 mmol) followed by (2S,3R)-3-amino-pentan-2-ol (60 mg, 5.5 eq, 0.58 mmol). The reaction mixture was placed in a preheated oil bath at 160° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and water (50 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 22 mg (57%). (80% de 3R,2S: 20% de 3R,2R). 1H-NMR (d-CDCl3, 250 MHz): δ 0.90, 1.05 (2×t, 3H, J=6.95 & 7.42 Hz, —NHCH (CH2CH3)CH(CH3)OH), 1.17 & 1.25 (2×d, 3H, J=6.32 & 6.16 Hz, —NHCH (CH2CH3)CH(CH3)OH) 1.57 (d, 6H, J=6.79 Hz, —CH(CH3)2), 1.77-2.09 (m, 2H, —NHCH(CH2CH3)CH(CH3)OH), 3.91-4.03 (m, 2H, —NHCH(CH2CH3)CH(CH3)OH), 4.58-4.69 (m, 1H, —CH(CH3)2), 4.83-5.00 (m, 3H, —HNCH2-Pyr & OH), 6.16 (m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 7.24-7.33 (m, 3H, 2×Pyr-H & —N═CH—N—), 7.55 (m, 1H, Pyr-H), 7.74 (d, 1H, J=7.42 Hz, Pyr-H), 8.67 (m, 1H, HNCH2-Pyr). FABMS m/z (relative intensity): 370 ([M+H]+, 100), 324 (35), 289 (37), 243 (65), 199 (85). Accurate Mass (M+H): Actual: 370.2355, Measured: 370.2347.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[C:12]2[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=1[O:29][CH3:30])=[O:8].CN(C)C=O>ClCCl>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[C:12]2[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([Cl:3])=[O:25])=[CH:22][C:21]=1[O:29][CH3:30])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)O)cc1OC)cn2C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)Cl)cc1OC)cn2C
Reaction time: 2 h

Procedure:
A solution of thionyl chloride (2.42 ml, 33 mmole) in dichloromethane (10 ml) was added dropwise over 5 minutes to a suspension of the product of step b) (10.59 g, 30 mmole) in dichloromethane (90 ml) containing N,N-dimethylformamide (0.2 ml), stirred at reflux under an atmosphere of nitrogen. After 2 hours, solvent was removed from the resulting yellow solution by distillation, approximately 85 ml distillate being collected. Dilution of the residue with methyl t-butyl ether was followed by stirring at 15° C. for 30 minutes prior to collection of the solid precipitate by filtration. After washing with methyl t-butyl ether (2×20 ml), 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxybenzoyl chloride was obtained as an off-white solid, 10.10 g (90.6%); m.p. 147°-149° C.; NMR (250 MHz, DMSO-d6): 3.76, 3.92, 3.97 (each s, 3H, NCH3 plus OCH3 plus CO2CH3), 4.16 (s, 2H, ArCH2Ar'), 6.87 (s, 1H), 7.20 (d, 1H), 7.29 (d, 1H), 7.54 (d, 1H), 7.66 (dd, 1H), 7.92 (dd, 1H), 8.32 (d, 1H).
Reaction SMILES: [N+:1]([C:4]([C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)([CH3:6])[CH3:5])([O-:3])=[O:2].[CH3:13][I:14]>CO>[I-:14].[CH3:13][N+:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:4]([N+:1]([O-:3])=[O:2])([CH3:5])[CH3:6])[CH:12]=1
Reactant: CC(C)(c1cnccn1)[N+](=O)[O-]
Reactant: CI
Solvent: CO
Product: C[n+]1ccnc(C(C)(C)[N+](=O)[O-])c1
Product: [I-]

Procedure:
2.0 g of 2-(1-nitroisopropyl)pyrazine (3600) was dissolved in 10 ml of methanol, 5 ml of methyl iodide added and the solution refluxed for 4 days. The solvent was removed and the residue was taken up in water and washed with chloroform. It was then chromatographed (Biogel P-2/water) and freeze-dried giving 3.2 g of product (3700). It was recrystallized from ethyl acetate/ethanol, m.p. 135°-6°. UV H2O max: 227 (4.18), 281 (3.89).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH:3]=[CH:4][N+:5]([O-:7])=[O:6].C(O)(C(F)(F)F)=O.[CH3:16][S:17]([C:20]1[CH:28]=C2[C:23]([CH:24]=CN2)=[CH:22][CH:21]=1)(=[O:19])=[O:18]>>[N+:5]([CH:4]=[CH:3][N:2]1[C:8]2[C:23](=[CH:22][CH:21]=[C:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:28]=2)[CH:24]=[CH:1]1)([O-:7])=[O:6]
Reactant: CS(=O)(=O)c1ccc2cc[nH]c2c1
Reactant: CN(C)C=C[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc2ccn(C=C[N+](=O)[O-])c2c1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Combine 1-dimethylamino-2-nitroethylene (892.1 mg, 7.68 mmol) and TFA (9.0 ml) and stir until dissolved. Add 6-methanesulfonyl-1H-indole (1.5 g, 7.68 mmol) and stir at ambient temperature. After 24 hours, pour the reaction mixture into ice/water, extract with ethyl acetate, then wash ethyl acetate with brine and saturated sodium bicarbonate. Filter, wash, and dry the precipitate to give the title compound as a yellow powder: mp >250° C. MS (ACPI): m/e 267.0 (M+1). Analysis for C11H10N2O4S: Calcd: C, 49.62; H, 3.79; N, 10.52; found: C, 49.86; H, 3.97; N, 10.25.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][CH:19]([CH2:25]O)[CH2:20]2.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][CH:19]([CH2:25][N:31]1[C:30](=[O:32])[C:29]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]3[C:27]1=[O:37])[CH2:20]2
Reactant: COc1cccc2c1CCC(CO)C2
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc2c1CCC(CN1C(=O)c3ccccc3C1=O)C2
Reaction time: 24 h
Yield: 55.3 %

Procedure:
A solution of diethyl azodicarboxylate (871 mg) in tetrahydrofuran (4 ml) was added slowly to a stirred solution of (1,2,3,4-tetrahydro-5-methoxy-2-naphthyl)methanol (961 mg), phthalimide (736 mg), and triphenyiphosphine (1.31 g) in tetrahydrofuran (10 ml) at room temperature and the resulting mixture was stirred at the same temperature for 24 hours. The reaction mixture was evaporated in vacuo and the residue was chromatographed (toluene) over silica gel. The eluate was evaporated in vacuo and the residue was triturated with n-hexane to afford N-[(1,2,3,4-tetrahydro-5-methoxy-2-naphthyl)methyl]phthalimide (888 mg) as a colorless powder. mp: 143°-144° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C(OC)(OC)OC.[C:36]1(=O)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH:36]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: O=C1CCCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: COC(OC)OC
Product: O=C(NCCCCNC1CCCCCC1)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound (30.0 mg) obtained in Example 3-2 was dissolved in methanol (0.6 ml). This solution was added with trimethyl orthoformate (30.0 μl), acetic acid (30.0 μl), cycloheptanone (manufactured by Merck, Inc.) (18.7 μl), and sodium cyanoborohydride (14.9 mg), followed by stirring for 3 hours at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. Then, the residue was dissolved in chloroform, washed with a 1 mol/l sodium hydroxide aqueous solution, and added with 1 mol/l hydrochloric acid to transfer the objective substance to the aqueous layer, followed by washing with chloroform. The 1 mol/l sodium hydroxide aqueous solution was added again to alkalinize the solution. The solution was subjected to extraction with chloroform and the extract was then washed with saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Then, the residue was dried under vacuum and treated with hydrochloric acid, thereby obtaining hydrochloride (32.2 mg) of the subject compound as a white solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](#[N:13])[CH2:10][C:11]#[N:12].C(N(CC)CC)C.[C:21]1([N:27]2[C:31](=[O:32])[CH2:30][C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[NH2:12][C:11]1[O:32][C:31]2[N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:28]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:30]=2[CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:10]=1[C:9]#[N:13]
Reactant: O=Cc1ccccc1
Reactant: N#CCC#N
Reactant: O=C1CC(c2ccccc2)=NN1c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#CC1=C(N)Oc2c(c(-c3ccccc3)nn2-c2ccccc2)C1c1ccccc1
Reaction time: 0.02 h
Yield: 29.4 %

Procedure:
A mixture of benzaldehyde (290 μL, 2.87 mmol, 1.0 equ.), malononitrile (190 mg, 2.87 mmol, 1.0 equ.) and triethylamine (400 μL, 2.87 mmol, 1.0 equ.) in ethanol (10 mL) was stirred for 1 min, followed by the addition of 1,3-diphenyl-1H-pyrazol-5(4H)-one (678 mg, 2.87 mmol, 1 equ.). The precipitate was filtered off and washed with ethanol and hexanes, and re-crystallized from ethanol to give 6-amino-1,3,4-triphenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (330 mg, 0.845 mmol, 29%) as a white solid. 1H-NMR (400 MHz) CDCl3: 7.82-7.80 (d, 2H), 7.55-7.50 (m, 4H), 7.41-7.37 (t, 1H), 7.32-7.22 (m, 8H), 4.96 (s, 1H), 4.68 (s, 2H), 13C-NMR (100 MHz) CDCl3: 157.5, 147.7, 144.9, 142.6, 137.5, 132.2, 129.3, 128.8, 128.2, 128.2, 127.5, 127.4, 127.1, 126.9, 121.6, 118.9, 97.5, 64.8, 38.2; LC/MS-MS: 391.1→325.0 m/z; GS1 and GS2 at 30, DP=91, CE=33, CXP=22, tR=4.33 min.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][C:25]([F:48])([F:47])[CH2:26][C@@H:27]([C:42](OCC)=[O:43])[N:28]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[BH4-].[Li+].CO.O>C1COCC1>[NH2:41][C:38]1[CH:37]=[CH:36][C:35]([S:32]([N:28]([CH:29]([CH3:31])[CH3:30])[C@H:27]([CH2:42][OH:43])[CH2:26][C:25]([F:48])([F:47])[CH2:24][CH2:23][NH:22][C:20](=[O:21])[C@H:6]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:5][C:3]([O:2][CH3:1])=[O:4])(=[O:33])=[O:34])=[CH:40][CH:39]=1
Reactant: CCOC(=O)[C@H](CC(F)(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)N(C(C)C)S(=O)(=O)c1ccc(N)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)N[C@H](C(=O)NCCC(F)(F)C[C@@H](CO)N(C(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
To a solution of the material from Step 11 (50 mg, 0.073 mmol) in THF (726 μL) at 0° C. were added a solution of 2 M lithium borohydride in THF (145 μL, 0.290 mmol) and methanol (11.75 μL, 0.290 mmol). The reaction mixture was stirred at room temperature for 2 hours. TLC showed not complete reaction. Additional 2 equiv of lithium borohydride was added, stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine, dried with MgSO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel using ethyl acetate-hexanes (0:100 to 100:0) to afford 26 mg of the title compound as a colorless foam. LCMS (M+1)=647. 1H NMR (Acetone-d6): δ 7.62 (d, J=8.32 Hz, 2H), 7.46-7.36 (m, 4H), 7.34-7.25 (m, 4H), 7.23-7.15 (m, 3H), 6.76 (d, J=8.32 Hz, 2H), 6.40 (d, J=9.02 Hz, 1H), 5.49 (s, 2H), 4.97 (t, J=10.09 Hz, 1H), 4.42 (d, J=11.05 Hz, 1H), 3.93-3.81 (m, 2H), 3.80-3.69 (m, 2H), 3.66-3.59 (m, 1H), 3.50 (s, 3H), 3.34-3.14 (m, 1H), 3.12-2.95 (m, 1H), 2.46-2.29 (m, 2H), 1.81-1.44 (m, 2H), 1.20 (d, J=8.20 Hz, 6).