Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[C:5]([C:8]2[CH:13]=[C:12]([S:14][CH3:15])[N:11]=[CH:10][N:9]=2)[CH:4]=[N:3]1.Br[C:17]1[CH:18]=[C:19]([NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[CH:20]=[CH:21][C:22]=1[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1COCC1>[CH3:23][C:22]1[CH:17]=[CH:18][C:19]([NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[CH:20][C:21]=1[NH:7][C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[C:8]1[CH:13]=[C:12]([S:14][CH3:15])[N:11]=[CH:10][N:9]=1
Reactant: CSc1cc(-c2cnn(C)c2N)ncn1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CSc1cc(-c2cnn(C)c2Nc2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2C)ncn1
Temperature: 25 °C

Procedure:
2-Methyl-4-(6-methylsulfanyl-pyrimidin-4-yl)-2H-pyrazol-3-ylamine (120 mg, 0.54 mmol) is mixed with N-(3-Bromo-4-methyl-phenyl)-3-trifluoromethyl-benzamide (290 mg, 0.81 mmol), palladium acetate (25 mg, 0.1 mmol), Xantophos (100 mg, 0.17 mmol) and cesium carbonate (530 mg, 1.63 mmol). 10 mL of anhydrous 1,4-dioxane is added under a nitrogen environment and the mixture is subjected to microwave irradiation to 150° C. for one hour. The reaction mixture is then cooled to room temperature, treated with 100 mL THF, passed through a celite column and concentrated. The crude product is purified by ISCO chromatography eluting with ethyl acetate in hexanes from 10% to 100% to afford N-{4-Methyl-3-[2-methyl-4-(6-methylsulfanyl-pyrimidin-4-yl)-2H-pyrazol-3-ylamino]-phenyl}-3-trifluoromethyl-benzamide: MS m/z 499.1 (M+1).
Reaction SMILES: CN(N=O)C(N[C@H:6]1[CH:11]([OH:12])[O:10][C@H:9]([CH2:13][OH:14])[C@@H:8]([OH:15])[C@@H:7]1[OH:16])=O.CC[O:21]CC>O>[OH:14][CH2:13][C@@H:9]([C@H:8]([C@@H:7]([C@@H:6]([CH2:11][OH:12])[OH:21])[OH:16])[OH:15])[OH:10]
Reactant: CN(N=O)C(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCOCC
Solvent: O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 18 h

Procedure:
Spraque-Dawley rats (male, 5-7-week-old, 5 animals per group) were fasted for 18 hours, and received injection of 70 mg/kg of streptozocin (Cal Biochem Co.) into the caudal vein under anesthesia with ether, so that diabetic rats were obtained. From immediately after the injection of streptozocin these rats were given orally the test compound of 50 mg/kg or 30 mg/kg in the form of 5% gum arabic suspension twice a day (at 10 a.m. and 5 p.m.) for 2 days. During this period the rats were allowed to take CE-2 diet (Clea Japan, Inc.) and water ad libitum. In the morning on the 3rd day (9 a.m.) the rats were killed (decapitation and venesection), and immediately the sciatic nerves were isolated, from which sorbitol was extracted according to the method of M. J. Peterson et al. described in Metabolism, 28, 456 (1979) and the sorbitol level was determined by the enzymatic method of P.S. Clements et al. in Science, 166, 1007 (1969). The results are expressed in percentage (%) taking the value of the untreated control group as 100, and shown in table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C([N:57]([CH:60]([CH3:62])[CH3:61])[CH2:58]C)(C)C.C1(NC)CC1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:57]([CH:60]1[CH2:61][CH2:62]1)[CH3:58])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: CNC1CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N(C)C3CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N-cyclopropyl-methylamine in DMSO at ambient temperature.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:10]1([C:13](=[S:15])[NH2:14])[CH2:12][CH2:11]1>C(O)C>[CH:10]1([C:13]2[S:15][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:14]=2)[CH2:12][CH2:11]1
Reactant: NC(=S)C1CC1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(C2CC2)n1
Yield: 23.1 %

Procedure:
A mixture of ethyl bromopyruvate (3.6 g), cyclopropanethioamide (2.2 g) and ethanol (30 ml) was refluxed for two hours. The reaction mixture was cooled, then ethanol was distilled off under reduced pressure. To the residue was added water (30 ml), which was subjected to extraction with ethyl acetate (50 ml) twice. The extract solution was washed with water (30 ml), followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to a silica gel chromatography (2.5×30 cm), eluting with ethyl acetate-hexane (1:3). The desired fraction was concentrated to give ethyl 2-cyclopropyl-4-thiazolcarboxylate (0.84 g) as pale yellow needles.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[F:33][C:34]1[CH:66]=[CH:65][C:37]([C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([C@@H:57]([CH:62]([CH3:64])[CH3:63])[C:58]([O:60]C)=[O:59])[C:53]4=[O:56])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)=[O:39])=[C:36]([C:67]([F:70])([F:69])[F:68])[CH:35]=1>>[F:33][C:34]1[CH:66]=[CH:65][C:37]([C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([C@@H:57]([CH:62]([CH3:64])[CH3:63])[C:58]([OH:60])=[O:59])[C:53]4=[O:56])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)=[O:39])=[C:36]([C:67]([F:70])([F:68])[F:69])[CH:35]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(F)cc4C(F)(F)F)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(F)cc4C(F)(F)F)cc3)cc2C1=O
Yield: 91 %

Procedure:
The compound of example 198 was prepared analogous to compound of example 98 by hydrolysis of compound of example 197.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:19][CH:20]=[C:21]([F:23])[F:22])([CH2:14][CH:15]=[C:16]([F:18])[F:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1>O1CCCC1.[Pd]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH2:14][CH2:15][CH:16]([F:17])[F:18])([CH2:19][CH2:20][CH:21]([F:22])[F:23])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CC=C(F)F)(CC=C(F)F)c1ccc(N)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC(F)F)(CCC(F)F)c1ccc(N)cc1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
2.4 g of ethyl 2-(4-aminophenyl)-2-(3,3-difluoroallyl)-5,5-difluoropent-4-enoate are dissolved in 30 ml of tetrahydrofuran, 1 g of 5% Pd/C (52.3% of water) is added, and the mixture is stirred at 23° C. under a hydrogen atmosphere for 1 h. After aeration, the solid material is filtered off, and the filtrate is evaporated to dryness in vacuo. Yield: 2.3 g (99%) of ethyl 2-(4-aminophenyl)-2-(3,3-difluoropropyl)-5,5-difluoropentanoate; LC-MS retention time: 2.09 min.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])([O-:21])=[O:20]>C1COCC1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([NH:16][C:25](=[O:26])[C:24]4[CH:28]=[CH:29][CH:30]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(N)cc3CC[C@@H]12
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(NC(=O)c4cccc([N+](=O)[O-])c4)cc3CC[C@@H]12
Reaction time: 4 h

Procedure:
A 620 mg portion of (4aR)-(10bR)-4,10b-dimethyl-8-amino-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was dissolved in 100 ml of THF, and an equivalent amount of 3-nitrobenzoyl chloride (500 mg) was added. The reaction mixture was stirred for 4 h, and was then evaporated to dryness under vacuum. The residue was purified by chromatography on silica gel, eluting with 10% methanol in ethyl acetate, and the product-containing fractions were evaporated and the resulting solid was crystallized from dichloromethane/hexane to obtain 595 mg of the desired product, m.p. 240°-242°. FDMS: m/e=393. α[D]589 =+75.79°.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:15][O:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1.C(N(CC)C(C)C)(C)C.[C:45](Cl)(=[O:47])[CH3:46]>O1CCCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:15]([O:16][CH3:17])[C:45](=[O:47])[CH3:46])([CH2:12][CH2:13][CH3:14])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1
Reactant: CCCC1(NOC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC1(N(OC)C(C)=O)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reaction time: 8 h

Procedure:
To a solution of Example 9 (15 mg, 0.029 mmol) in tetrahydrofuran (200 μL) was added N,N-diisopropylethylamine (11 μL, 0.062 mmol) and acetyl chloride (5 μL, 0.070 mmol) and stirring was continued overnight. The solution was concentrated and taken up in H2O (1 mL) and 1N NaOH (0.5 mL). This solution was stirred at room temperature for 2 hours and 1N HCl was added slowly until the solution became acidic. This aqueous solution was extracted with ethyl acetate (3×2 mL), the organic extracts combined, dried over Na2SO4, the drying agent filtered off, the solvent removed in vacuo, and the crude product was purified by column chromatography on silica gel (5% methanol/chloroform) to give the title compound as a colorless solid: 1H NMR (d6-DMSO) δ 13.81 (s, 1H), 10.18 (s, 1H), 8.10, 8.07 (d, 1H), 7.71-7.45 (m, 7H), 4.07 (s, 3H), 3.06 (s, 3H), 2.03 (br s, 3H), 1.30-1.05 (br s, 1H), 1.24 (br s, 2H), 0.75-0.50 (br s, 1H), 0.74-0.65 (t, 3H); MS (ESI) m/z 563 (M+H+).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([C:18]2[C:19](F)=[N:20][CH:21]=[CH:22][CH:23]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[NH2:17])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:1]([C:5]1[NH:6][C:7]2[C:18]3[CH:23]=[CH:22][CH:21]=[N:20][C:19]=3[NH:17][C:11]3[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=3[C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(-c2ccc(F)cc2N)c(-c2cccnc2F)[nH]1
Solvent: CCO
Product: CC(C)(C)c1nc2c([nH]1)-c1cccnc1Nc1cc(F)ccc1-2
Temperature: 180 °C
Yield: 80.3 %

Procedure:
3-[2-tert-Butyl-4-(4-fluoro-2-aminophenyl)-1H-imidazol-5-yl]-2-fluoropyridine (0.070 g, 0.21 mmol) was dissolved in ethanol (2 mL). The reaction was heated in a microwave reactor at 180° C. for 5 min. The reaction was concentrated and purified by column chromatography on silica gel (50% ethyl acetate 50% hexanes) to give 0.052 g of the desired product. 1H NMR (500 MHz, CD3OD): δ 8.16-8.18 (m, 1H), 7.85-7.87 (m, 1H), 7.48-7.51 (m, 1H), 7.07-7.10 (m, 1H), 6.82-6.90 (m, 2H), 1.58 (s, 9H). MS [M+H]=309.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([Si](C)(C)C)=[CH:11][C:10]=2[F:20])[N:5]=[C:4]([C:21]([O:23][CH3:24])=[O:22])[C:3]=1[Cl:25].[Br:26]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([Br:26])=[CH:11][C:10]=2[F:20])[N:5]=[C:4]([C:21]([O:23][CH3:24])=[O:22])[C:3]=1[Cl:25]
Reactant: BrBr
Reactant: COC(=O)c1nc(-c2cc(F)c([Si](C)(C)C)cc2F)c(F)c(N)c1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1nc(-c2cc(F)c(Br)cc2F)c(F)c(N)c1Cl
Reaction time: 24 h
Yield: 76.7 %

Procedure:
To a solution of methyl 4-amino-3-chloro-6-(2,5-difluoro-4-(trimethylsilyl)phenyl)-5-fluoropicolinate (0.240 g, 0.617 mmol) in CH2Cl2 (2.469 mL) at 20° C. was added bromine (0.127 mL, 2.469 mmol). After 24 h, the reaction mixture was poured into a saturated aqueous solution of Na2S2O3 and was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound as a white solid (0.187 g, 0.473 mmol, 77%).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:10]=[C:11]([S:16][C:17]2[CH:18]=[C:19]3[C:25]([NH:26][C:27](=[O:54])[C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]5)=[CH:30][C:29]=4[N:41]([CH:48]4[CH2:53][CH2:52][O:51][CH2:50][CH2:49]4)C(=O)C(F)(F)F)=[N:24][NH:23][C:20]3=[N:21][CH:22]=2)[CH:12]=[C:13]([F:15])[CH:14]=1>CO>[F:8][C:9]1[CH:10]=[C:11]([S:16][C:17]2[CH:18]=[C:19]3[C:25]([NH:26][C:27](=[O:54])[C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]5)=[CH:30][C:29]=4[NH:41][CH:48]4[CH2:49][CH2:50][O:51][CH2:52][CH2:53]4)=[N:24][NH:23][C:20]3=[N:21][CH:22]=2)[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ncc(Sc5cc(F)cc(F)c5)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ncc(Sc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Temperature: 65 °C

Procedure:
9.08 ml (65.1 mmol) of triethylamine is added to 2 g (2.96 mmol) of a solution of N-(5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzamide in 65 ml of methanol. The reaction medium is heated at 65° C. for 2 hours, and then overnight at room temperature. The precipitate formed is filtered, rinsed with pentane, with water and then with diethyl ether, and then is dried under vacuum to yield 0.73 g (43%) of (N-(5-(3,5-difluorophenylthio)-1-H-pyrazolo[3,4-b]pyridine-3-yl)-4-(4-methylpiperazine-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide in the form of a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[N:30]=[C:31]=[O:32].C(N(CC)CC)C.Cl>C(#N)C>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[NH:30][C:31]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2)=[O:32]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4c(Cl)cccc4Cl)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a stirred mixture of 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.423 g, 1.15 mmol) and 2,6-dichlorophenyl isocyanate (0.216 g, 1.15 mmol) in acetonitrile (10 mL), was added triethylamine (0.32 mL, 2.30 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (10 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) and dried overnight in vacuo to give 1-(2,6-dichloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.156 g, 29% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 3.74 min (99.7%); mp: 238-240° C.; 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 1H, CH), 2.31-2.47 (m, 1H, CH), 2.60 (d, J=17.0 Hz, 1H, CH), 2.84-3.01 (m, 1H, CH), 4.24-4.51 (m, 4H, CH2, CH2), 5.11 (dd, J=5.0, 13.3 Hz, 1H, NCH), 6.96 (t, J=5.9 Hz, 1H, NH), 7.23-7.33 (m, 1H, Ar), 7.42-7.57 (m, 4H, Ar), 7.69 (d, J=7.7 Hz, 1H, Ar), 8.19 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.48, 31.20, 43.02, 47.07, 51.56, 121.66, 122.85, 126.73, 128.12, 128.38, 130.23, 133.88, 134.07, 142.30, 144.96, 155.13, 167.96, 171.01, 172.86; LCMS: MH=461, 463; Anal Calcd for C21H18N4O4Cl2+0.1H2O: C, 54.47; H, 3.96; N, 12.10; Cl, 15.31. Found: C, 54.12; H, 3.71; N, 11.85; Cl, 15.31.
Reaction SMILES: [Cl:1][CH:2]([CH:10]=[C:11]([Cl:13])[Cl:12])[C:3]([CH3:9])([CH3:8])[CH2:4][C:5](Cl)=[O:6].[O:14]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][OH:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1>C1C=CC=CC=1.C(OCC)C>[Cl:1][CH:2]([C:3]([CH3:9])([CH3:8])[CH2:4][C:5]([O:25][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:22]=1)=[O:6])[CH:10]=[C:11]([Cl:13])[Cl:12]
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: CC(C)(CC(=O)Cl)C(Cl)C=C(Cl)Cl
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(CC(=O)OCc1cccc(Oc2ccccc2)c1)C(Cl)C=C(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
In 30 g of dry benzene were dissolved 2.6 g of 4,6,6,-trichloro-3,3-dimethyl-5-hexenoyl chloride and 2.0 g of 3-phenoxybenzyl alcohol were added to the solution. This was followed by the dropwise addition of 2.4 g of pyridine and the mixture was stirred at room temperature overnight. The reaction mixture was then diluted with diethyl ether, washed with dilute aqueous hydrogen chloride and water, dried over anhydrous magnesium sulfate and distilled to remove the low-boiling fraction. The residual viscous oil was purified by column chromatography. By the above procedure there were obtained 3.9 g of 3-phenoxybenzyl β-(1,3,3-trichloroallyl)isovalerate (3-phenoxybenzyl 4,6,6-trichloro-3,3-dimethyl-5-hexenoate, Compound [17]) the NMR spectrum and elemental analysis of which are given below [yield: 91%].
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=O)=[CH:7][N:6]=[C:5]2[N:14]([CH2:17][C:18]3[O:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[CH:16][C:4]=12)[NH2:2].[C:23]1(O)C=C[CH:26]=[CH:25][CH:24]=1>C(O)C>[CH2:17]([N:14]1[C:5]2[N:6]=[CH:7][C:8]3[C:9]([O:11][C:12]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:13]=4)=[N:14][C:5]4[N:1]([N:2]=[CH:7][N:6]=4)[C:3]=3[C:4]=2[CH:16]=[N:15]1)[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1NN
Reactant: Oc1ccccc1
Solvent: CCO
Product: c1ccc(Oc2nc3ncnn3c3c2cnc2c3cnn2Cc2ccco2)cc1

Procedure:
By substituting 4-hydrazino-1-furfurylpyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,ethyl ester in Example 1 (a), 8-furfuryl-4H-pyrazolo[4',3'-5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one is obtained. This compound is now processed as in Example 1 (b) and then as in Example 4, substituting phenol for the ethanol to obtain 8-furfuryl- 5-phenyloxy-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine.
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)=[O:7])C.[CH:23]([NH2:26])([CH3:25])[CH3:24]>C1(C)C=CC=C(C)C=1>[CH2:15]([O:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[C:6]([C:5](=[CH:6][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([NH:26][CH:23]([CH3:25])[CH3:24])=[O:22])=[O:7])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)N
Reactant: CCOC(=O)CC(=O)c1cccc(OCc2ccccc2)c1
Solvent: Cc1cccc(C)c1
Product: CC(C)NC(=O)C(=Cc1ccccc1)C(=O)c1cccc(OCc2ccccc2)c1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 108.9 %

Procedure:
3-(3-Benzyloxyphenyl)-3-oxopropionate ethyl ester (174.42 g, 584.47 mmol) was dissolved in m-xylene and the reaction mixture was refluxed while stirring for 30 min at 150° C. Then, isopropylamine (38 g, 642.92 mmol) was added dropwise to the mixture. After stirring and refluxing for 24 hours at room temperature, the organic layer was extracted with saturated sodium chloride and ethyl acetate, dried over anhydrous magnesium sulfate, concentrated, and resulting residue was purified by column chromatography (ethyl acetate:hexane=1:2) to obtain 2-(3-benzyloxybenzoyl)-N-isopropyl-3-phenylacryl amide (127.13 g, yield 70%) as yellow oil.
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=1[O:26][Si:27]([CH3:30])([CH3:29])[CH3:28])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=1[O:26][Si:27]([CH3:30])([CH3:29])[CH3:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C=CC1(C)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1(C)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Reaction time: 48 h
Yield: 99.5 %

Procedure:
To a solution of 0.27 g of ethyl 3-(4,6-di-t-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-yl)-2-propenoate synthesized in Example 75-1) in 20 ml of ethanol was added a catalytic amount of 10% palladium-carbon, and the mixture was stirred for 48 hours under a hydrogen atmosphere. After the catalyst was filtered off, the filtrate was concentrated and the residue was purified on a short column of silica gel eluting with n-hexane containing 9% ethyl acetate to give 0.27 g of ethyl 3-(4,6-di-t-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-yl)propanoate as a colorless viscous liquid.
Reaction SMILES: [Cl:1][C:2]([O-:4])=[O:3].[CH:5]1([CH3:15])[CH2:10][CH2:9][CH:8]([CH:11]([CH3:13])[CH3:12])[CH:7](O)[CH2:6]1.C1(C)CCC(C(C)C)C(Cl)C1.C(=O)(OC1C(C(C)C)CCC(C)C1)OC1C(C(C)C)CCC(C)C1>>[Cl:1][C:2]([O:4][CH:7]1[CH:8]([CH:11]([CH3:13])[CH3:12])[CH2:9][CH2:10][CH:5]([CH3:15])[CH2:6]1)=[O:3]
Reactant: O=C([O-])Cl
Reactant: CC1CCC(C(C)C)C(O)C1
Agent: CC1CCC(C(C)C)C(Cl)C1
Agent: CC1CCC(C(C)C)C(OC(=O)OC2CC(C)CCC2C(C)C)C1
Product: CC1CCC(C(C)C)C(OC(=O)Cl)C1

Procedure:
The product obtained is analysed by gas chromatography. The purity of the chloroformate is 99%, and less than 0.5% by weight of menthol and 250 ppm of menthyl chloride are found. Bismenthyl carbonate is not detected.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)O.[NH2:9][C:10]1[C:11]([CH3:16])=[CH:12][CH:13]=[CH:14][CH:15]=1.P(OCCCC)(OCCCC)OCCCC>O>[CH3:16][C:11]1[C:10]([NH:9][C:1]2[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=2)=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccccc1N
Reactant: Oc1cccc(O)c1
Agent: CCCCOP(OCCCC)OCCCC
Solvent: O
Product: Cc1ccccc1Nc1cccc(O)c1
Temperature: 120 °C
Yield: 93 %

Procedure:
250 parts of resorcinol, 300 parts of o-toluidine and 10 parts of tributyl phosphite are mixed. On heating to 120° C, a melt is formed. When the internal temperature has reached 190° C, the elimination of water commences. The internal temperature is raised to 230° C in the course of 5 hours. After this time, 41 parts of water have distilled off and the reaction has ended. Excess o-toluidine and resorcinol which may still be present are removed by applying reduced pressure, and the 3-hydroxy-2'-methyl-diphenylamine is then distilled, passing over at 185° C/3 mm Hg. 420 parts of end product of ND25 = 1.6455 are obtained, corresponding to a yield of 93% of theory.