Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:25][C:26]1[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1.O>C1(C)C=CC=CC=1>[Br:25][C:26]1[S:30][C:29]([CH:31]=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[CH:28][CH:27]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)s1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccc(Br)s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
4.2 g (12.5 mmol, 1.2 eq) of methyl triphenylphosphoranylideneacetate are added to a solution of 2.0 g (10.4 mmol, 1.0 eq) of 5-bromothiophene-2-carbaldehyde in 15 mL of toluene. The reaction mixture is stirred for 1 hour at 80° C. The reaction is stopped by adding 20 ml of water and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (80/20 heptane/ethyl acetate). 2.1 g of methyl 3-(5-bromothiophen-2-yl)acrylate are obtained. Yield=82%.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>ClCCl>[Cl:20][C:21]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:22]=1[C:23]([N:7]1[CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]1=2)=[O:24]
Reactant: O=C1CCCNc2ncccc21
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2Cl)c2ncccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-5-one and 0.234 g of triethylamine in 6 ml of dichloromethane is added 0.506 g of 2-chloro-4-nitrobenzoyl chloride in 2 ml of dichloromethane. The mixture is stirred at room temperature overnight under argon. The solution is washed with H2O, 10% NaHCO3 and dried (MgSO4). The solvent is removed to give a brown oil which crystallizes. The mixture is chromatographed on silica with a waters Prep-500 instrument with ethyl acetate-hexane (1:1) as solvent to give 2.4 g of off-white crystals, m.p. 162°-164° C. (identified as O-2-chloro-4-nitrobenzoyl derivative (2-chloro-4-nitrobenzoyl enolate of product) and 0.80 g of product as crystals, m.p. slowly decomposes 160°-220° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C1C=CC=CC=1>O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: O=Cc1cccc(Cl)c1
Reactant: COC(=O)c1ccc(N)cn1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1ccc(N=Cc2cccc(Cl)c2)cn1

Procedure:
The starting material is prepared as follows: the mixture of 30.44 g of 5-aminopyridine-2-carboxylic acid methyl ester, 30.9 g of m-chlorobenzaldehyde, and 400 ml of benzene is refluxed for 3 days on a water-separating trap. The initial suspension eventually becomes a pale yellow solution, which is evaporated. The residual yellow solid is recrystallized from benzene-ethyl acetate-diethyl ether, to yield the 5-(m-chlorobenzylideneamino)-pyridine-2-carboxylic acid methyl ester melting at 139°-142°.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:11][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][N:2]([CH3:1])[S:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CNCC(O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(CC(O)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of α-(methylaminomethyl)benzyl alcohol (1.00 g, 6.61 mmol) in 15 mL of THF was cooled in an ice bath. Benzenesulfonyl chloride (0.886 mL, 1.23 g, 6.94 mmol) and N,N-diisopropylethylamine (2.3 mL, 1.7 g, 13 mmol) were added and mixture was allowed to warm to room temperature. After 30 min, the solvent was evaporated and the residue was partitioned between 50 mL of ethyl acetate and 40 mL of saturated aqueous sodium bicarbonate. The aqueous layer was extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with 50 mL of brine, dried over sodium sulfate, and evaporated. Purification by flash column chromatography on silica gel, eluting with 20-50% ethyl acetate in hexane, gave the title compound in quantitative yield.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:33][CH:32]=1
Reactant: COc1ccc(O)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(O[C@@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.8 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 4-methoxyphenol (6.20 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.2 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.6 mg, 37.9% yield) as a thick oil. 1H NMR (400 MHz, CDCl3) δ 7.38–7.14 (m, 8H), 6.90 (apparent d, 1H, J=7.7 Hz), 6.72–6.46 (m, 4H), 5.09 (apparent dd, 1H, J=4.8, 8.1 Hz), 3.64 (s, 3H), 3.18 (m, 2H), 2.73 (m, 2H), 2.50 (m, 2H), 2.37–1.72 (m, 8H), 1.25 (d, 6H, J=7.4 Hz); ESMS m/e: 487.4 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([NH:36][S:37](Cl)(=[O:39])=[O:38])=[O:35]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][S:37]([NH:36][C:34]([C:30]2[O:29][CH:33]=[CH:32][CH:31]=2)=[O:35])(=[O:38])=[O:39])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C(NS(=O)(=O)Cl)c1ccco1
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(COCCNS(=O)(=O)NC(=O)c2ccco2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.5 g) in chloroform (dried over alumina) and triethylamine (2 ml) was added 2-furoylsulphamoyl chloride in one portion and the mixture stirred at room temperature for 17 hours. After evaporation to dryness, the resultant oil was partitioned between 5% aqueous sodium bicarbonate and methylene chloride. The combined organic liquors were dried (MgSO4), filtered and evaporated to give 0.35 g of solid which was crystallised from diisopropyl ether to give pure title compound (0.2 g), m.p. 138° C. Found: C, 51.30; H, 5.23; N, 7.41. C25H28ClN3O9S requires C, 51.59; H, 4.85; N, 7.22%.
Reaction SMILES: [Br:1][O-].[Na+].[C:4]1([C:10]#[CH:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[NH4+]>C1COCC1>[Br:1][C:11]#[C:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C#Cc1ccccc1
Reactant: [O-]Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: BrC#Cc1ccccc1
Reaction time: 5 h
Yield: 1001.3 %

Procedure:
To a solution of sodium hypobromite [prepared by slow addition of bromine (11 ml) to 10M sodium hydroxide solution (50 ml) and crushed ice (100 g)] was added a solution of phenylacetylene (20.4 g, 19.97 mmol) in THF (10 ml). The two phase mixture was stirred vigorously for 5 hours. Saturated aq. ammonium chloride was added and the mixture was extracted with diethyl ether (3×30 ml). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure to provide 1-bromo-2-phenyl-acetylene (36.2 g, 99%) as a yellow oil. 1H-NMR; δ (CDCl3), 7.50 (m). IR: Vmax (neat) 2200 cm-1.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[N:10]([C:14]1[CH:19]=[C:18]([S:20]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1[Cl:33])[C:9](=[O:34])[NH:8]2)(O)=[O:2].C(N1C=CN=C1)([N:37]1C=CN=C1)=O.N>O1CCCC1.C(OCC)(=O)C>[C:1]([C:4]1[S:5][CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[N:10]([C:14]1[CH:19]=[C:18]([S:20]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1[Cl:33])[C:9](=[O:34])[NH:8]2)(=[O:2])[NH2:37]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1scc2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCc5ccccc54)ccc3Cl)c(=O)c12
Agent: N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1scc2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCc5ccccc54)ccc3Cl)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 5-carboxy-3-[2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl]thieno[3,4-d]-pyrimidine-2,4(1H,3H)-dione (14 mg) in tetrahydrofuran (1 mL) was added 1,1′-carbonylbis-1H-imidazole (9 mg), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 28% aqueous ammonia solution (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: methylene chloride/ methanol=10/1) to give the title compound (13 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].C(N(CC)CC)C.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21].[I-].[Na+]>C(#N)C>[CH3:11][S:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([O:3][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH2:1])=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)Cl
Reactant: CSc1ccc(C(C)=O)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(O[Si](C)(C)C)c1ccc(SC)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 101.4 %

Procedure:
Under nitrogen, 11.0 g (66.2 mmol) of 4-(methylthio)acetophenone (prepared in Step 1 of Example 1) and 13.8 mL (99 mmol) of triethylamine in 50 mL of acetonitrile was treated with 12.6 mL (99.3 mmol) of chlorotrimethylsilane at ambient temperature and allowed to stir for 20 minutes prior to the slow addition of a suspension of 14.9 g (99.4 mmol) of sodium iodide in 60 mL of acetonitrile. The reaction was stirred for 3 hours, poured into ice/water, and extracted with hexane. The extracts were combined, dried (K2CO3), and concentrated in vacuo to give 16 g of crude 1-methylthio-4-[1[(trimethylsilyl)oxy]ethenyl]benzene as an oil: NMR (CDCl3) δ0.26 (s, 9H), 2.48 (s, 3H), 4.39 (d, J=2 Hz, 1H), 4.87 (d, J=2 Hz, 1H), 7.20 (d, J=8 Hz, 2H), 7.50 (d, J=8 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].S(Cl)([Cl:15])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([Cl:15])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)Cl)cc1C

Procedure:
A solution of 11.5 g. (0.07 mol.) of 3-methyl-4-methoxybenzoic acid and 10.7 g. (0.09 mol.) of thionyl chloride in 60 ml. of methylene chloride is refluxed on a steam bath for two hours. Concentration under reduced pressure and distillation of the residue gives 3-methyl-4-methoxybenzoic acid chloride, m.p. 37°-39°.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][C:14]=2[F:21])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>C1COCC1>[F:3][C:4]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:23]3[CH:24]=[C:25]4[N:32]([CH3:33])[CH2:31][CH2:30][N:26]4[C:27](=[O:29])[N:28]=3)=[CH:15][C:14]=2[F:21])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Oc2ccc(CO)cc2F)cc1F
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)c(F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (5.51 mg, 0.230 mmol) in THF (5 mL), 2-fluoro-4-(2-fluoro-4-(hydroxymethyl)phenoxy)benzonitrile (30 mg, 0.115 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (21.3 mg, 0.115 mmol).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([NH:30][C:31]4[CH:32]=[N:33][C:34]([CH3:38])=[C:35](Br)[CH:36]=4)=[O:29])[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.O1C2C=CC(C3(C(NC4C=NC(C)=C(C5C=CC=CC=5)C=4)=O)CC3)=CC=2OC1>>[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([NH:30][C:31]4[CH:32]=[N:33][C:34]([CH3:38])=[C:35]([C:8]5[CH:9]=[CH:10][CH:11]=[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:15])[CH3:1])[CH:7]=5)[CH:36]=4)=[O:29])[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1
Reactant: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Reactant: CN(C)S(=O)(=O)c1cccc(B(O)O)c1
Agent: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccccc1
Product: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1cccc(S(=O)(=O)N(C)C)c1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-(3-(N,N-dimethylsulfamoyl)phenyl)-6-methylpyridin-3-yl)cyclopropanecarboxamide was prepared from 3-(N,N-dimethylsulfamoyl)phenylboronic acid and 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-6-methylpyridin-3-yl)cyclopropanecarboxamide in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-5-phenylpyridin-3-yl)cyclopropanecarboxamide.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[S:10]([NH2:13])(=[O:12])=[O:11])#[N:2].[CH2:14]([O:16][C:17](OCC)(OCC)[O:18][CH2:19][CH3:20])[CH3:15]>C(O)C>[C:1]([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[S:10]([N:13]=[C:17]([O:18][CH2:19][CH3:20])[O:16][CH2:14][CH3:15])(=[O:12])=[O:11])#[N:2]
Reactant: Cc1cccc(S(N)(=O)=O)c1C#N
Reactant: CCOC(OCC)(OCC)OCC
Solvent: CCO
Product: CCOC(=NS(=O)(=O)c1cccc(C)c1C#N)OCC
Temperature: 25 °C
Yield: 90 %

Procedure:
3.60 g (18.4 mmol) 2-cyano-3-methyl-benzenesulfonamide and 5.29 g tetraethoxymethane (27.5 mmol) were heated to 160° C. slowly with stirring under removal of ethanol from the mixture. The mixture was cooled to room temperature. The residue was digerated with petrol ether, filtered and dried to afford 4.91 g (90% of theory) 2-Cyano-N-diethoxymethylene-3-methyl-benzene-sulfon-amide.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([S:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[S:6][C:5]=1[N:18]1[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]1)([O-])=O.[Sn](Cl)Cl.O>C(OCC)(=O)C>[NH2:1][C:4]1[CH:8]=[C:7]([S:9]([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)(=[O:11])=[O:10])[S:6][C:5]=1[N:18]1[CH2:19][CH2:20][CH:21]([C:24]([OH:26])=[O:25])[CH2:22][CH2:23]1
Reactant: O=C(O)C1CCN(c2sc(S(=O)(=O)N3CCCCC3)cc2[N+](=O)[O-])CC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(S(=O)(=O)N2CCCCC2)sc1N1CCC(C(=O)O)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
The solution of 300 mg of 1-(3-nitro-5-piperidine-1-sulfonylthiophen-2-yl)piperidine-4-carboxylic acid in 20 ml of ethyl acetate is admixed with 1.0 g of tin(II) chloride and stirred at 65° C. for 8 h. After cooling, it is stirred with 30 ml of water and filtered off with suction through Celite, and the ethyl acetate phase is removed, dried and concentrated under reduced pressure. This crude product is used further without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:12]2.[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH:35]=O.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:23][CH2:24][CH3:25])[CH2:26][CH2:27][CH3:28])[CH2:12]2)[CH2:35][C:31]1[N:30]([CH3:29])[CH:34]=[CH:33][N:32]=1
Reactant: CCCN(CCC)CCCCN1Cc2ccc(CNCc3ncc[nH]3)cc2C1
Reactant: Cn1ccnc1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN1Cc2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
The compound (12.5 mg) obtained in Example 38-1 was dissolved in methanol (2.0 ml) and added with 1-methyl-2-imidazole carboxaldehyde (4.4 mg) and sodium cyanoborohydride (4.2 mg). The solution was adjusted to pH 4 with acetic acid and stirred at room temperature for 8 hours. The residue obtained by concentration of the solution was added with a saturated aqueous sodium hydrogen carbonate solution to neutralize the solution and the whole was subjected to extraction with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (7.7 mg) as a colorless oily substance.
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][OH:25].[CH2:26](Br)[CH:27]=[CH2:28]>O>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH:27]=[CH2:28]
Reactant: COCCOCCOCCOCCO
Reactant: C=CCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOCCOCCOCCOCCOC
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
An oven-dried 100 mL round bottom flask was charged with t-BuOK (13 mmol), dry THF (30 mL), purged with argon and cooled to 0° C. in an ice bath. Tetraethyleneglycol monomethyl ether (10 mmol) was then added dropwise to the solution and the reaction stirred at 0° C. for 1 h under argon. Allyl bromide (13 mmol) was added dropwise, and the solution was warmed to R.T. and allowed to stir for 24 h under argon. Deionized water (2 mL) was then added and the reaction stirred for 10 min. All liquid were then removed in vacuo and the residue redissolved in ethyl acetate (50 mL). The organic was washed three times with water (20 mL), dried over Na2SO4, filtered over Celite and then concentrated in vacuo to yield clear/light yellow oil (47%). 1HNMR (400 MHz, CDCl3): δ=5.90 (m, 1H), 5.23 (dd, 1H, 3JHHtrans=17.3 Hz, 2JHHgem=1.7 Hz), 5.15 (dd, 1H, 3JHH=10.4 Hz, 2JHHgem=1.5 Hz), 4.00 (dd, 2H, 3JHH=5.89 Hz, 4JHH=1.5 Hz), 3.65 (m, 12H), 3.59 (m, 2H), 3.53 (m, 2H), 3.36 (s 3H) ppm. 13CNMR (400 MHz, CDCl3): δ=134.8, 117.0, 72.2, 71.9, 70.6, 70.6, 70.6, 70.5, 69.4, 59.0 ppm. HRMS-ESI: Calculated [M+Na]+: 271.1516. found: 271.1516.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[CH:13]=[C:12](I)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]=2)=[CH:5][C:4]([CH3:19])=[N:3]1.[NH2:20][C:21]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:22]=1[C:23]([NH:25][CH3:26])=[O:24]>>[CH3:1][N:2]1[C:6]([NH:7][C:8]2[CH:13]=[C:12]([NH:20][C:21]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:22]=3[C:23]([NH:25][CH3:26])=[O:24])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]=2)=[CH:5][C:4]([CH3:19])=[N:3]1
Reactant: Cc1cc(Nc2cc(I)c(C(F)(F)F)cn2)n(C)n1
Reactant: CNC(=O)c1ccc(F)cc1N
Product: CNC(=O)c1ccc(F)cc1Nc1cc(Nc2cc(C)nn2C)ncc1C(F)(F)F

Procedure:
This compound was prepared from N-(1,3-dimethylpyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine and 2-amino-4-fluoro-N-methylbenzamide. 54 mg, 33%; triturated in tBuOMe; NMR Spectrum: (DMSOd6) 2.08 (s, 3H), 2.76 (d, 3H), 3.55 (s, 3H), 6.04 (s, 1H), 6.76 (s, 1H), 6.95 (ddd, 1H), 7.39 (dd, 1H), 7.79 (dd, 1H), 8.27 (s, 1H), 8.69 (q, 1H), 9.06 (s, 1H), 10.65 (s, 1H); Mass spectrum: MH+ 423.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[C:11]=2[C:19]([OH:21])=O)=[CH:5][CH:4]=1.[O:22]=[C:23]1[CH:28]([N:29]2C(=O)C3C(=CC=CC=3NCCOC)C2=O)[CH2:27][CH2:26][C:25](=[O:45])[NH:24]1>>[O:22]=[C:23]1[CH:28]([N:29]2[C:19](=[O:21])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][CH2:8][C:6]3[O:7][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=3)[C:13]2=[O:15])[CH2:27][CH2:26][C:25](=[O:45])[NH:24]1
Reactant: O=C(O)c1cccc(NCc2ccc(CO)o2)c1C(=O)O
Reactant: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Product: O=C1CCC(N2C(=O)c3cccc(NCc4ccc(CO)o4)c3C2=O)C(=O)N1

Procedure:
3-[(5-Hydroxymethyl-furan-2-ylmethyl)-amino]-phthalic acid (3.04 mmol) was treated in the same manner as described above for the synthesis of 2-(2,6-Dioxo-piperidin-3-yl)-4-(2-methoxy-ethylamino)-isoindole-1,3-dione. The solid yellow residue was purified by chromatography (SiO2, 60% ethyl acetate/hexanes) to give 0.40 g of solid which was dissolved in methylene chloride (70 ml) and washed with saturated NaHCO3 (2×100 ml), brine (1×100 ml), dried (magnesium sulfate), and filtered. The solvent was evaporated leaving 0.32 g (27%) of product as a yellow solid: mp 172–174° C.; 1H NMR (DMSO-d6) δ 11.11 (s, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 7.06 (d, J=7.0 Hz, 1H), 6.99 (t, J=6.0 Hz, 1H), 6.27 (d, J=2.9 Hz, 1H), 6.20 (d, J=2.9 Hz, 1H), 5.18 (t, J=5.7 Hz, 1H), 5.07 (dd, J=5.2 and 12.5 Hz, 1H), 4.54 (d, J=5.9 Hz, 2H), 4.33 (d, J=5.7 Hz, 2H), 2.96–2.82 (m, 1H), 2.63–2.46 (m, 2H), 2.06–1.99 (m, 1H); 13C NMR (DMSO-d6) δ 172.80, 170.07, 168.80, 167.24, 155.00, 151.10, 145.79, 136.08, 132.12, 117.57, 111.04, 109.71, 108.06, 107.60, 55.63, 48.60, 39.05, 30.98, 22.13; Anal. Calcd. For C19H17N3O6: C, 59.53; H, 4.47; N, 10.96. Found: C, 59.30; H, 4.54; N, 10.70.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[OH2:15]>OS(O)(=O)=O>[NH2:1][C:2]1[C:6]([C:7]([NH2:8])=[O:15])=[CH:5][N:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: O
Reactant: N#Cc1cn(-c2ccccc2)nc1N
Agent: O=S(=O)(O)O
Product: NC(=O)c1cn(-c2ccccc2)nc1N

Procedure:
3-amino-1-phenyl-1H-pyrazole-4-carbonitrile (0.34 g, 1.846 mmol) was stirred in 95% H2SO4 (10 mL) at 50° C. for 3 hours. Room temperature was attained, water was added and the products extracted into EtOAc (×3). The aqueous phase was neutralised with 2 N NaOH and the products extracted into DCM (×2) followed by 20% MeOH-DCM (×4). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was triturated in EtOAc to give 3-amino-1-phenyl-1H-pyrazole-4-carboxamide as a pale yellow solid.