Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5](O)=O)O.S(=O)(=O)(O)O.[C:19]1(O)C=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=1>>[OH:25][C:21]1[CH:22]=[C:23]2[C:5]([C:3]([CH2:2][C:1]([OH:13])=[O:12])=[CH:8][C:9](=[O:10])[O:11]2)=[CH:19][CH:20]=1
Reactant: Oc1cccc(O)c1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cc(=O)oc2cc(O)ccc12
Temperature: 70 °C

Procedure:
84 g of citric acid and 112 ml of concentrated sulfuric acid were stirred for one hour at ambient temperature and then heated progressively to 70° C. and maintained there for 35 minutes. The mixture was cooled to 0° C. and 34.56 g of 1,3-benzene diol and 44.8 ml of concentrated sulfuric acid were added. The mixture was maintained for 16 hours at 0° C. and then poured over ice. The crystallized product was separated off and dried under reduced pressure to obtain after crystallization from water, 22.77 g of the expected product melting at 210° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9]Br)=[CH:4][C:3]=1[O:12][CH3:13].[NH2:14][C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1>C(#N)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:14]=[C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]3[CH:9]=2)=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc(C(=O)CBr)ccc1O
Reactant: Nc1ncccn1
Solvent: CC#N
Product: COc1cc(-c2cn3cccnc3n2)ccc1O
Temperature: 65 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
To 30 ml of an acetonitrile solution of 3.9 g (16 mmol) of 4′-hydroxy-3′-methoxy-2-bromoacetophenone was added 3.2 g (34 mmol) of 2-aminopyrimidine, and the mixture was stirred at 65° C. for 2 hours. The precipitated crystals were suction filtered and dissolved in 100 ml of 50% methanol. This solution was mixed with 1.3 g of sodium hydrogencarbonate and stirred at room temperature for 10 minutes. The precipitated crystals were suction filtered, and recrystallized from 50 ml of 50% methanol, thereby giving 2.4 g of 2-(4-hydroxy-3-methoxyphenyl)imidazo[1,2-a]pyrimidine in an yield of 62%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][C:13]=2[Cl:14])=[CH:4][CH:3]=1.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:12][C:13]=2[Cl:14])=[CH:6][C:7]=1[N+:21]([O-:23])=[O:22]
Reactant: Cn1c(C(F)(F)F)cc(Cl)c(-c2ccc(Cl)cc2)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)cc(Cl)c(-c2ccc(Cl)c([N+](=O)[O-])c2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
0.2 g (0.62 mmol) of 3-(4-chlorophenyl)-4-chloro-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 2 ml of concentrated sulfuric acid, and 0.04 g (0.64 mmol) of fuming nitric acid was added thereto under cooling with ice, followed by stirring for 1 hour. After completion of the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium hydrogencarbonate aqueous solution and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained crude crystals were washed with isopropyl ether to obtain 0.21 g (yield: 91%) of the desired product. 1H-NMR (300 MHz, CDCl3) δ value: 3.74(3H,s), 6.66(1H,s), 7.40(1H,dd), 7.61(1H,d), 7.59(1H,s), 7.82(1H,d)ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:4]=1[NH2:5].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22]C)C(O)=O>>[Cl:12][C:13]1[CH:14]=[C:15]([C:1]2[O:2][C:3]3[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:4]=3[N:5]=2)[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: COc1ccc(OC)c(N)c1
Reactant: COc1ccc(C(=O)O)cc1Cl
Product: Oc1ccc2oc(-c3ccc(O)c(Cl)c3)nc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,5-dimethoxyaniline, and 3-chloro-4-methoxybenzoic acid and was obtained as a white solid, m.p. 254-256° C.; MS m/e 260 (M−H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].[OH-].[K+]>C(#N)C>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH3:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: Cc1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1ccccc1Oc1ccc2ccc(N)nc2n1
Temperature: 4 °C
Yield: 62.1 %

Procedure:
The procedure is similar to that described in Example 4, but starting with 2-amino-7-chloro-1,8-naphthyridine (17.95 g), 2-methylphenol (43.2 g) and potassium hydroxide pellets (13.2 g; 85% purity). After treatment with caustic soda and washing, the product obtained (21.2 g; m.p. 188° C.) is dissolved in boiling acetonitrile (100 cc). After 4 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). 2-Amino-7-(2-methylphenoxy)-1,8-naphthyridine (15.6 g) is produced, m.p. 192° C.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[NH2:17]>C(O)C>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:17][C:16]2[CH:15]=[C:14]([Cl:13])[CH:20]=[C:19]([Cl:21])[CH:18]=2)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: CCO
Product: COC(=O)c1ccc(C=Nc2cc(Cl)cc(Cl)c2)cc1
Reaction time: 0.25 h

Procedure:
p-Carbomethoxybenzaldehyde (0.20 moles) was treated with 3,5-dichloroaniline (0.20 moles) with vigorous stirring in a 1 liter Erlenmeyer Flask. After 15 mins., 33 cc. of 95% ethanol was added and the reaction mixture was stirred vigorously for an additional 5 minutes. The reaction mixture was left standing at room temperature for 10 min.; then it was placed in an ice bath for 0.5 hours. The crystals which formed were collected, washed with 95% ethanol, and air-dried. Recrystallization from 85% ethanol gave N-(p-carbomethoxybenzylidene)-3,5-dichloroaniline.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].Cl[CH2:9][C:10]1[CH:44]=[CH:43][C:13]([C:14]([NH:16][C:17]2[C:18]3[CH:31]=[C:30]([C:32]([NH:34][N:35]([CH3:42])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[S:29][C:19]=3[N:20](C(OC(C)(C)C)=O)[N:21]=2)=[O:15])=[CH:12][CH:11]=1.ClCC1C=CC(C(NC2C3C=C(C(NN(C4C=CC(Cl)=CC=4)C)=O)SC=3N(C(OC(C)(C)C)=O)N=2)=O)=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][C:17]2[C:18]3[CH:31]=[C:30]([C:32]([NH:34][N:35]([CH3:42])[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[O:33])[S:29][C:19]=3[NH:20][N:21]=2)=[O:15])=[CH:43][CH:44]=1)[CH3:6]
Reactant: CNCCN(C)C
Reactant: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccc(Cl)cc1
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(C)CCN(C)Cc1ccc(C(=O)Nc2n[nH]c3sc(C(=O)NN(C)c4ccccc4)cc23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
27 mg (74 μmol) of tetrabutylammonium iodide and then 144 μL (1.11 mmol) of N,N,N′-trimethylethylenediamine are added to a solution of 200 mg (0.37 mmol) of an approximately 70:30 mixture of tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate in 6 mL of dimethylformamide under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 16 hours and then poured onto ice. It is then extracted twice with a 50/50 mixture of ethyl acetate and heptane. The organic extracts are combined, dried over magnesium sulfate and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is dissolved in 4 mL of methanol and the solution is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for 30 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (conditions B). 40 mg of 4-{[(2-dimethylaminoethyl)methylamino]methyl}-N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]benzamide are thus obtained in the form of a yellow powder. LC-MS-DAD-ELSD: 506(+)=(M+H)(+).
Reaction SMILES: [NH2:1][C:2]1([CH2:18][CH2:19][OH:20])[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[O:9][C:8]2[C:3]1=[CH:4][C:5]([I:17])=[CH:6][CH:7]=2.[C:21]([N:29]=[C:30]=S)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CCC(N=C=NC2CCCCC2)CC1.O>C1COCC1>[Br:16][C:13]1[CH:14]=[C:15]2[C:2]3([CH2:18][CH2:19][O:20][C:30]([NH:29][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:1]3)[C:3]3[C:8](=[CH:7][CH:6]=[C:5]([I:17])[CH:4]=3)[O:9][C:10]2=[N:11][CH:12]=1
Reactant: NC1(CCO)c2cc(I)ccc2Oc2ncc(Br)cc21
Reactant: O=C(N=C=S)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1=NC2(CCO1)c1cc(I)ccc1Oc1ncc(Br)cc12)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
In a 250-mL flask, the 2-(5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)ethanol (2.24 g, 5.01 mmol) was dissolved in THF (30 mL). Benzoyl isothiocyanate (0.607 mL, 4.51 mmol) was added. After 1 h, the mixture was concentrated. The residue was taken up in ACN (30 mL), and catalytic TEA (0.069 mL, 0.501 mmol) was added, followed by DCC (1.137 g, 5.51 mmol). A water-cooled condenser was affixed, and the solution was stirred in an 80° C. oil bath for 2 h. The reaction was then concentrated. The residue was used directly in the next step without further purification or purified by column chromatography (silica gel, 10-50% EtOAc/hexanes) to obtain N-(3-bromo-7-iodo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-yl)benzamide as a yellow solid. MS (m/z) 575.8/577.7 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][C:16]=2[C:24]([F:27])([F:26])[F:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]3[CH:43]=[C:44]([CH:46]=[CH:47][C:48]=3[CH3:49])[NH2:45])[N:36]=2)[CH:32]=[N:33][CH:34]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:45][C:44]3[CH:46]=[CH:47][C:48]([CH3:49])=[C:42]([NH:41][C:37]4[N:36]=[C:35]([C:31]5[CH:32]=[N:33][CH:34]=[C:29]([Br:28])[CH:30]=5)[CH:40]=[CH:39][N:38]=4)[CH:43]=3)=[O:21])=[CH:17][C:16]=2[C:24]([F:26])([F:25])[F:27])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cncc(Br)c2)n1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)O)cc2C(F)(F)F)CC1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)cc1Nc1nccc(-c2cncc(Br)c2)n1

Procedure:
This compound was prepared in the same manner as in Example 34, except that 4-[4-(t-butoxycarbonyl)piperazin-1-ylmethyl]-3-trifluoromethylbenzoic acid (Reference Example 13) and 3-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline (Reference Example 19) were used.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[CH:15]=[C:14]([NH:16][CH:17]3[CH2:23][CH2:22][CH2:21][CH2:20][NH:19][C:18]3=[O:24])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[S:4][N:3]=1.[OH-].[Na+].OO.CC(O)=[O:31]>CCO.CS(C)=O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[CH:15]=[C:14]([NH:16][CH:17]3[CH2:23][CH2:22][CH2:21][CH2:20][NH:19][C:18]3=[O:24])[CH:13]=[CH:12][C:9]=2[C:10]([NH2:11])=[O:31])[S:4][N:3]=1
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2cc(NC3CCCCNC3=O)ccc2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(Nc2cc(NC3CCCCNC3=O)ccc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2-(3-methylisothiazol-5-ylamino)-4-(2-oxoazepan-3-ylamino)benzonitrile (143 mg, 0.263 mmol) in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1 mL, 1.0 mmol) and aq. H2O2 (50%, 1 mL) were added. The mixture was stirred at room temperature for 3 h. HOAc (1 mL) was added. The mixture was then purified by HPLC to give the titled compound (72 mg). MS 360.3 (M+H); UV 202.1, 300.7 nm.
Reaction SMILES: [NH2:1][CH:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH2:12])=[C:5]2[C:4](=[O:13])[N:3]1[CH2:14][O:15][CH:16]([CH3:18])[CH3:17].[CH:19](=O)[CH2:20][CH3:21].[BH4-].[Na+].C(O)(=O)C>CO>[NH2:1][CH:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH:12][CH2:19][CH2:20][CH3:21])=[C:5]2[C:4](=[O:13])[N:3]1[CH2:14][O:15][CH:16]([CH3:18])[CH3:17]
Reactant: CCC=O
Reactant: CC(C)OCN1C(=O)C2=C(CN)C=NC2=NC1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCNCC1=C2C(=O)N(COC(C)C)C(N)N=C2N=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
In 5.0 ml of dry methanol were dissolved 251 mg of 2-amino-5-aminomethyl-3-isopropyloxymethylpyrrolo[2,3-d]pyrimidin-4-one and 64 mg of propionaldehyde and the solution was allowed to stand under stirring at room temperature for 30 min. Then, 20 mg of sodium borohydride was added and the mixture was reacted at room temperature for an hour. The excess reagent was decomposed with a small amount of acetic acid, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to give 76 mg of 2-amino-5-propylaminomethyl-3-isopropyloxymethylpyrrolo[2,3-d]pyrimidin-4-one. The whole amount of this product was dissolved in 30 ml of 2 N--HCl and, after nitrogen purging, hydrolyzed under heating at 70° C. for 6.5 hours. The solvent was then evaporated off under reduced pressure to give 73 mg of the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[CH:10]=[N:9][N:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:6]=2[N:7]=1.[CH3:30][C:31]1([CH3:48])[CH2:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:33]([CH3:47])([CH3:46])[NH:32]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:27][C:26]1[CH:25]=[C:24]([CH3:28])[NH:23][C:22](=[O:29])[C:21]=1[CH2:20][NH:19][C:17]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:6]=2[N:7]=[C:2]([C:35]2[CH2:34][C:33]([CH3:47])([CH3:46])[NH:32][C:31]([CH3:48])([CH3:30])[CH:36]=2)[CH:3]=1)=[O:18]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C2CCOCC2)c(=O)[nH]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2CCOCC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) solution was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (14%). LCMS: 519.30 (M+1)+; HPLC: 98.464% (@ 254 nm) (Rt; 4.823); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (bs, 1H); 8.87 (s, 1H); 8.30 (s, 1H); 7.82 (s, 1H); 6.81 (s, 1H); 5.90 (s, 1H); 5.06 (m, 1H); 4.38 (s, 2H); 3.01 (d, J=11.2, 2H); 3.59 (t, J=12.0 Hz, 2H); 2.23 (s, 3H); 2.23-2.19 (m, 2H); 2.12 (s, 3H); 1.90 (d, J=12.0 Hz, 2H); 1.27-1.23 (m, 14H).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]([OH:18])[CH2:16]Cl)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[OH-].[Na+]>O1CCOCC1>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]([OH:18])[CH2:16][N:30]3[CH2:29][CH2:28][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])[CH2:32][CH2:31]3)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2cccc(OCC(O)CCl)c2o1
Reactant: COc1ccccc1N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccccc1N1CCN(CC(O)COc2cccc3cc(C(C)=O)oc23)CC1

Procedure:
There was dissolved 1.3 g (0.005 mole) of 2-acetyl-7-(3-chloro-2-hydroxypropoxy)benzofuran and 1.1 g (0.0055 mole) of 1-(2-methoxyphenyl)piperazine in 10 ml of dioxane, and then the mixture was refluxed with heating for 6 hours. After completion of the reaction, 2N-NaOH solution was added to give the free base, which was extracted from chloroform. The extract was dried with magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resultant residue was crystallized from ethyl acetate.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH2:19]([O:26][CH2:27][C:28]1([C:38]#[C:39][C:40]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)=O)[CH2:37][CH2:36][C:31]2([O:35][CH2:34][CH2:33][O:32]2)[CH2:30][CH2:29]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:19]([O:26][CH2:27][C:28]1([C:38]2[CH:39]=[C:40]([C:42]3[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=3)[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=2)[CH2:29][CH2:30][C:31]2([O:32][CH2:33][CH2:34][O:35]2)[CH2:36][CH2:37]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1ccc(C(=O)C#CC2(COCc3ccccc3)CCC3(CC2)OCCO3)cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C3(COCc4ccccc4)CCC4(CC3)OCCO4)cc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
To a solution of 4-methoxyphenylhydrazine hydrochloride (280 mg, 1.60 mmol) in ethanol (2.7 mL), triethylamine (0.447 mL, 3.20 mmol) was added dropwise, and the obtained solution was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 3-(8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-tolyl)propyn-1-one (Reference Example 89) (540 mg, 1.33 mmol) in ethanol (2.7 mL) was added dropwise, and the obtained solution was stirred at room temperature for 14 hours. Thereafter, the reaction solution was concentrated under reduced pressure. Water was added to the residue and the resultant was extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, distilled water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (458 mg, 0.872 mmol, 65%) as a white amorphous product.
Reaction SMILES: [CH3:1][C:2]1(C)[CH2:6][CH:5](C)[CH2:4][C:3]1=O.[C:10]([O-:13])(=[O:12])[CH3:11].[Na+].C(OO)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:6])[CH2:3][CH:4]([CH3:5])[O:12][C:10](=[O:13])[CH2:11]1
Reactant: CC1CC(=O)C(C)(C)C1
Reactant: CC(=O)[O-]
Agent: CC(=O)OO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1CC(C)(C)CC(=O)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3.84 gm of 2,2,4-trimethyl-cyclopentanone were dissolved in 50 ml of chloroform and cooled in the ice bath. At 0° C., a solution of 0.2 gm of sodium acetate in 11.4 gm of a 40% aqueous peracetic acid was added. The reaction mixture was stirred for 18 hours at room temperature, then neutralized with a sodium hydrogen carbonate solution. The organic phase was separated, dried and concentrated. By distillation, 3.4 gm of 4,6,6-trimethyl-tetrahydropyran-2 -one (I) were recovered with the following characteristics:
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:16]=[C:15](C(=O)C(C)C)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[OH-:23].[Na+].Cl>CO>[C:3]([C:5]1[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])=[CH:14][CH:15]=[CH:16][C:4]=1[C:3]([OH:2])=[O:22])(=[O:23])[CH:4]([CH3:16])[CH3:5]
Reactant: [OH-]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(=O)C(C)C)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCN(C)C(=O)c1cccc(C(=O)O)c1C(=O)C(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Dissolve 5-isobutyryl-N-methyl-N-propyl-isophthalamic acid methyl ester (50 mg, 0.16 mmol) in methanol (3 mL) and add dropwise 2 N NaOH (0.16 mL). Stir the mixture at room temperature for 6 h, store overnight at 4° C. and acidify to about pH=6 by 5 N HCl. Concentrate to near dryness and dilute the residue with ethyl acetate. Wash with saturated aqueous sodium chloride solution and extract the organic layer, dry (magnesium sulfate) and concentrate to give the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]([C:11]2[CH:15]=[CH:14][O:13][N:12]=2)[C:9]([C:16]2[C:21]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=3)(=[O:25])=[O:24])=[CH:20][C:19]([Cl:37])=[CH:18][N:17]=2)=[N:8][N:7]=1)=O)C.[BH4-].[Li+].CO.Cl>C1COCC1>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([NH:22][C:21]2[C:16]([C:9]3[N:10]([C:11]4[CH:15]=[CH:14][O:13][N:12]=4)[C:6]([CH2:4][OH:3])=[N:7][N:8]=3)=[N:17][CH:18]=[C:19]([Cl:37])[CH:20]=2)(=[O:25])=[O:24])=[CH:27][C:28]=1[C:33]([F:36])([F:35])[F:34]
Reactant: CCOC(=O)c1nnc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)n1-c1ccon1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(Cl)cnc1-c1nnc(CO)n1-c1ccon1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-4-isoxazol-3-yl-4H-[1,2,4]triazole-3-carboxylic acid ethyl ester (28 mg, 0.05 mmol), 0.14 ml (0.28 mmol) of lithium borohydride (2.0M) and 0.020 ml of methanol in 1.5 ml of THF was stirred at room temperature for 2 hours. The mixture was mixed with diluted HCl (1.0M), extracted with ethyl acetate, and the extracts were combined and washed with brine and dried. After concentration the residue was purified by prep TLC to afford title compound as a white solid. MS (ES) [M+H]+ expected 535.0, found 535.0
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[H][H]>[Ni]>[CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@@H:9]([C@H:14]([OH:15])[C@@H:13]([OH:16])[CH2:12][OH:17])[C@H:10]([OH:11])[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: [H][H]
Agent: [Ni]
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@@H](O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)[C@@H](O)CO

Procedure:
A commercially available aqueous solution of high purity maltose (mfd. by NIHON SHOKUHIN KAKO K.K., concentration: 60%, sugar composition in the solid component: maltose: 84.6%, glucose: 7.8%, sugar of equal or more than DP3: 7.6%) was reduced under the existence of Raney nickel catalyst at a hydrogen pressure of 100 kg/cm2 and 130° C. for 60 minutes, to obtain aqueous solution of maltitol.