Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:14][C:15]([C:17]1[C:18]([CH:26]([CH3:28])[CH3:27])=[N:19][N:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=12)=[O:16]>C(O)C>[CH2:11]([O:10][C:2]([CH:3]([CH2:14][C:15]([C:17]1[C:18]([CH:26]([CH3:28])[CH3:27])=[N:19][N:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=12)=[O:16])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:9])[CH3:12]
Reactant: CC(C)c1nn2ccccc2c1C(=O)CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CC(=O)c1c(C(C)C)nn2ccccc12)C(=O)OCC
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 32.4 %

Procedure:
Sodium (0.10 g) was dissolved into ethanol (4 ml) and diethyl malonate (0.71 g) was added at room temperature. After stirring for 20 minutes at 50° C., a solution of 3-(2-bromoacetyl)-2-isopropylpyrazolo[1,5-a]pyridine (1.06 g) in ethanol (6 ml) was added and the mixture was stirred for 75 minutes at 80° C. The reaction liquor was concentrated, and, water and ethyl acetate were added to the residue to separate the organic layer. After the organic layer was washed with water and with saturated brine and dried over anhydrous sodium sulfate, solvent was distilled off and the residue was purified by means of silica gel column chromatography (developing solvent, ethyl acetate, n-hexane=1:3) to obtain aimed product (0.44 g) as pale yellow powder.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Cl[CH2:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28]>O1CCCC1>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:23][C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=3)[C:27]([O:29][CH3:30])=[O:28])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CCc1ccccc1N2
Reactant: COC(=O)c1cccc(CCl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN2c3ccccc3CCc3ccccc32)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.6 %

Procedure:
To a solution of 10,11-dihydro-5H-dibenz[b,f]azepine (2.44 g) in tetrahydrofuran (25 ml) was added potassium tert-butoxide (2.02 g) at 0° C. The mixture was stirred at 0° C. for 15 minutes, and then a solution of methyl 3-(chloromethyl)benzoate (3.57 g) in tetrahydrofuran (15 ml) was added. The mixture was stirred at 25° C. for 1 hour, and then evaporated. The residue was partitioned between ethyl acetate and 0.1N hydrochloric acid. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (40:1) to give methyl 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-ylmethyl)benzoate (1.10 g) as an oil.
Reaction SMILES: [CH2:1]([P:17](=[O:20])([OH:19])[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+].[Cl-].[Ca+2:24].[Cl-]>CCCCCC>[Ca+2:24].[CH2:1]([P:17](=[O:18])([O-:20])[O-:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCP(=O)(O)O
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCP(=O)([O-])[O-]
Yield: 96 %

Procedure:
306 g (1 mol) of hexadecylphosphonic acid (produced as in example 13) are suspended in 1.5 l of hexane and 200 ml of a 10 molar solution of sodium hydroxide are added and the suspension is refluxed for 2 hours. Then, 500 ml of a 1 molar solution of calcium chloride are added, and the suspension is refluxed for 4 hours and water removed by azeotropic distillation. The reaction solution is filtered and the residue is washed with water and hexane and dried under reduced pressure to obtain 313 g (96% of theory) of hexadecylphosphonic acid calcium salt as colorless solid.
Reaction SMILES: [Na].CS[C:4]1[N:5]([CH2:14][CH2:15][CH3:16])[C:6](=[O:13])[C:7]2[S:12][CH:11]=[CH:10][C:8]=2[N:9]=1>C(O)CC>[CH2:6]([O:13][C:4]1[N:5]([CH2:14][CH2:15][CH3:16])[C:6](=[O:13])[C:7]2[S:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:7][CH3:8]
Reactant: CCCn1c(SC)nc2ccsc2c1=O
Agent: [Na]
Solvent: CCCO
Product: CCCOc1nc2ccsc2c(=O)n1CCC
Yield: 154.7 %

Procedure:
In a sulfonation flask, 1.66 g (0.02 mol) of sodium propylate and 1.5 g (0.00625 mol) of 2-methylsulfanyl-3-propyl-3H-thieno-[3.2-d]pyrimidin-4-one are stirred in 50 ml of absolute n-propanol for 3 hours under N2 at reflux temperature. The n-propanol is then removed in a water-jet vacuum and the residue is taken up in ethyl acetate/water and extracted three times with water. The organic phase is dried over sodium sulfate and the solvent is removed in the water-jet vacuum, giving the crude product which is then purified by column chromatography over silica gel (eluant: ethyl acetate/hexane 1:3). 1.22 g of 2-propoxy-3-propyl-3H-thieno[3.2-d]pyrimidin-4-one are obtained in the form of a beige powder having a melting point of 42-45° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:18][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[C@H:16]([C:27](OC)=[O:28])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)(C)C.[Cl-].[Na+]>O1CCCC1>[CH2:7]([N:14]1[CH2:18][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[C@H:16]([CH2:27][OH:28])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1OC
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1ccccc1[C@@H]1CN(Cc2ccccc2)C[C@H]1CO
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To 560 mmol of lithium aluminum hydride in 800 ml of tetrahydrofuran (THF), under a nitrogen atmosphere and at 5° C., are added 225 mmol of methyl [trans-1-benzyl-4-(2-methoxyphenyl)pyrrolidin-3-yl]carboxylate (described in Preparation A) dissolved in 500 ml of THF. After stirring for 1 hour at 5° C., 139 ml of isopropyl alcohol are added slowly to the above mixture, followed by 85.2 ml of saturated sodium chloride solution. The mixture is stirred slowly at room temperature. After filtration and evaporation of the solvents, the expected product is obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[O:8]2)[CH2:4][CH2:3]1.[OH:17][C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[CH:26][C:27]([NH:30][C:31](=O)[O:32]C3C=CC=CC=3)=[N:28][CH:29]=2)[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[OH:17][C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[CH:26][C:27]([NH:30][C:31]([N:2]3[CH2:7][CH2:6][C:5]4([C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[C:9](=[O:16])[O:8]4)[CH2:4][CH2:3]3)=[O:32])=[N:28][CH:29]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Nc1cnc(-c2cccc(O)c2)cn1)Oc1ccccc1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1OC2(CCN(C(=O)Nc3cnc(-c4cccc(O)c4)cn3)CC2)c2ccccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
A mixture of spiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (40 mg), phenyl N-[5-(3-hydroxyphenyl)-2-pyrazinyl]carbamate (51 mg) and triethylamine (119 μL) in chloroform (5 mL) was stirred at 80° C. for 2 hours. The reaction mixture was poured into water and extracted with chloroform (20 mL). The organic layer was washed with saturated saline solution (20 mL) and then dried over anhydrous Na2SO4. The concentration of the solvent left a residue, which was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) followed by recrystallization from ethyl ether-hexane to give the subject compound (24 mg) as colorless crystals (melting point 257-259° C.).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[CH2:8][N:7]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5])C.[Li+].[OH-]>C1COCC1.O>[C:17]([O:16][C:14]([N:7]1[CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C@H:6]1[C:4]([OH:5])=[O:3])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)[C@@H]1C2CCCC2CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CCCC2[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2 g of (S)-Hexahydro-cyclopenta[c]pyrrole-1,2-dicarboxylic acid 2-tert-butyl ester 1-ethyl ester and 449 mg of LiOH in 30 ml of THF and 10 ml of H2O is stirred at rt for 16 hours. The reaction is quenched with brine, acidified to pH 2 with aq. 2N HCl solution and extracted with EtOAc. The combined organic phases obtained are washed with brine, dried and solvent is evaporated to afford the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:21](OC)=[O:22])[C:8]=2[C:25](OC)=[O:26])=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([CH2:21][OH:22])[C:8]=2[CH2:25][OH:26])=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccncc2)c1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2cc(CO)c(CO)c(-c3ccncc3)c2cc1OC
Yield: 79.1 %

Procedure:
A solution of 1-(4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene (2.0 g) in tetrahydrofuran (50 ml) is added dropwise to a suspension of lithium aluminum hydride (100 mg) in tetrahydrofuran (20 ml) at -20° C. The mixture is stirred under ice-cooling for one hour, and thereto are added water (0.1 ml) and 15% aqueous sodium hydroxide solution (0.1 ml). Ten minutes thereafter, water (0.3 ml) is added to the reaction mixture, and the mixture is stirred at room temperature for one hour. The insoluble materials are removed by filtration on celite, and the filtrate is concentrated. The residue is recrystallized from a mixture of ethyl acetate and diethyl ether (1:1) to give 1-(4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (1.35 g).
Reaction SMILES: [C:1]1([N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S1(CCCC1)(=O)=O.[I-].[Na+].C[Si](C)(C)Cl>O>[C:1]1([N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(CCc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Oc1ccc(CCc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
A mixture of 38.5 g of the 1-(4-diphenylaminophenyl)-2-(4-methoxyphenyl)ethane prepared in Synthesis Example 1-2, 200 ml of sulfolane, and 45 g of sodium iodide was stirred in a four-neck flask at 120° C. to obtain a solution. The thus obtained solution was cooled to 60° C., and 2 ml of distilled water was added to the solution. 32.6 g of trimethylchlorosilane was then added dropwise to the above solution over a period of 30 minutes. Thus, the reaction was carried out at 60° to 70° C. for three hours. The thus obtained reaction mixture was poured into 500 ml of water, whereby a brown tar was obtained. The thus obtained tar was washed with 200 ml of water several times, and dissolved in 300 ml of toluene, whereby a brown toluene solution was obtained. The thus obtained toluene solution was washed twice with 100 ml of a saturated aqueous solution of sodium sulfite, whereby a transparent toluene solution of light yellow in color was obtained. After the thus obtained transparent toluene solution was dried over anhydrous magnesium sulfate, a solvent was distilled away. The thus obtained product was subjected to chromatography using a silica gel and toluene, whereby 31.4 g of 1-(4-diphenylaminophenyl)-2-(4-hydroxyphenyl)ethane was obtained as an oily material.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[CH2:24]([O:26][C:27](=[O:32])[NH:28][CH2:29][CH2:30]Cl)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:32])[NH:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1)[CH3:25]
Reactant: CCOC(=O)NCCCl
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CCOC(=O)NCCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O

Procedure:
Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and ethyl-2-chloroethylcarbamate.
Reaction SMILES: CC([O:5][C:6](=[O:29])[CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:8]([O:10]C(C)(C)C)=[O:9])(C)C.CC([O-])(C)C.[K+].[C:36]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:39])[CH:37]=[CH2:38].CC(O)=O>CC(O)(C)C>[CH2:41]([O:40][C:36](=[O:39])[CH2:37][CH2:38][C:7]([C:8]([OH:10])=[O:9])([C:6]([OH:5])=[O:29])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCC(CCC(=O)OCc1ccccc1)(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
To a solution of di-(dimethylethyl)-n-tetradecylmalonate 34 (4.12 g, 10.0 mmol) and t-BuOK (244 mg, 2.0 mmol) in t-BuOH (10 mL, dried over 4 Å sieves) was added a solution of benzyl acrylate (1.62 g, 10.0 mmol in 5 mL t-BuOH). The initially colorless solution immediately turned brown. It was stirred (3 h, rt) then additional t-BuOK (112 mg, 1.0 mmol) was added and the reaction continued overnight. The mixture was neutralized with AcOH then evaporated to dryness and treated with neat TFA (20 mL, 1 h). The TFA was removed by rotary evaporation, the residue dissolved in warm hexane, treated with activated charcoal then filtered. The filtrate provided fine white crystals which proved to be pasty when filtered. Drying provided product 36 as a white solid (2.31 g, 50%), mp 47°-49° C. High resolution FAB MS:C27H43O6 (M+H); Theor. 463.307147. Found 463.3059 646. Anal. C27H42O6.1/2H2O:C,H.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:31][N:32]([CH3:39])[CH2:33][C:34]#[C:35][C:36](O)=[O:37]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:36](=[O:37])[C:35]#[C:34][CH2:33][N:32]([CH3:39])[CH3:31])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CN(C)CC#CC(=O)O
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Product: CN(C)CC#CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 12 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and 4-(dimethylamino)but-2-ynoic acid (Intermediate 49), to afford the title compound (5.6 mg, 12%). Data: UPLC (C) Rt: 0.97 min; m/z 509.3 (M+H)+.
Reaction SMILES: [C@@H]1(O[C@H](CO)[C@H](O)[C@@H](O)C=O)O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O.[O:22]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41])[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O.O=C[C@@H]([C@H]([C@@H](CO)O)O)O.OP([O-])(O)=O.[K+].OP([O-])([O-])=O.[K+].[K+].[Mg+2].[Cl-].[Cl-].SC(O)C>O>[N+:40]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[OH:22])([O-:42])=[O:41]
Reactant: O=[N+]([O-])c1ccccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CC(O)S
Agent: O=C[C@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Solvent: O
Product: O=[N+]([O-])c1ccccc1O
Temperature: 100 °C
Yield: 19 %

Procedure:
In order to synthesize 4-O-β-D-galactopyranosyl-D-xylose, 5 g of o-nitrophenyl β-D-galactopyranoside (Gal-ONP) and 25 g of D-xylose were dissolved in 330 ml of water buffered to a pH of 7 (0.05 M KH2PO4/K2HPO4, 1 mM MgCl2, 5 mM mercaptoethanol), 2 mg (640 u) of E. coli β-galactosidase enzyme were added and the solution thus obtained was subjected to incubation at 37° C. in an orbital stirrer until the Gal-ONP was practically consumed (approximately 2 hours). Following the methodology put forth in example 3, the reaction was stopped by heating at 100° C. for 10 minutes and the ortho-nitrophenol formed was extracted with ethyl acetate. The aqueous solution was concentrated up to an approximate volume of 50 ml, filtered through glasswool and passed through the active carbon/celite column. First of all, the excess D-xylose was eluted with water and afterwards, using a fractioned gradient of EtOH/H2O (2%-10% of EtOH) the mixture of disaccharides was collected. The enriched fractions in the 4-O-β-D-galactopyranosyl-D-xylose regioisomer were combined and concentrated to a reduced volume, after which acetone was added until turbidity appeared and the mixture thus obtained was left to stand cold. The 4-O-β-D-galactopyranosyl-D-xylose was crystallized in a pure form, obtaining 970 mg, namely, a yield of 19% based on the initial Gal-ONP, whose spectral data coincided with those given for the product obtained in accordance with example 3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26]([NH2:28])=[O:27])[CH:22]=[CH:23][CH:24]=1>CN(C=O)C.CCOC(C)=O.O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:20]=[C:21]([CH2:25][C:26]([NH2:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: NC(=O)Cc1cccc(N)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2,4-Dichloro-1,3,5-triazine (173.7 mg, 1.158 mmol) was dissolved in DMF (1 ml). To the stirring solution, cooled to 0° C., was added DIEA (202 μl, 1.158 mmol). This solution was added dropwise to a 0° C. mix of DMF (1 ml) and 3-aminophenyl acetamide. The reaction was stirred at 0° C. for min and then at RT for 1 h. The reaction mix was diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layer was washed 3 times with brine, dried over Na2SO4, and concentrated under reduced pressure, giving 2-[3-(4-chloro-[1,3,5]triazin-2-ylamino)-phenyl]acetamide.
Reaction SMILES: [Mg].II.[CH3:4][N:5]1[C:9]([S:10][CH2:11][CH2:12][CH2:13]Cl)=[N:8][N:7]=[N:6]1.C(Br)C.C(#N)CC.Cl.[O:23]1C[CH2:26][CH2:25][CH2:24]1>O>[CH3:4][N:5]1[C:9]([S:10][CH2:11][CH2:12][CH2:13][C:24](=[O:23])[CH2:25][CH3:26])=[N:8][N:7]=[N:6]1
Reactant: Cn1nnnc1SCCCCl
Reactant: C1CCOC1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: CCBr
Solvent: CCC#N
Product: CCC(=O)CCCSc1nnnn1C

Procedure:
Magnesium (0.3 g) is suspended in dried tetrahydrofuran (5 ml). To the suspension is added a small piece of iodine with stirring in nitrogen gas flow, and further added 1-methyl-5-(3-chloropropyl)thio-1,2,3,4-tetrazole (0.3 g). To the mixture is added ethyl bromide (0.1 ml), and the reaction is started by heating the mixture from outside. A solution of 1-methyl-5-(3-chloropropyl)thio-1,2,3,4-tetrazole (1.8 g) in dried tetrahydrofuran (15 ml) is additionally added dropwise to the mixture. After the solution is added, the mixture is refluxed for 1 hour. To the obtained Grignard reagent is added dropwise a solution of propionitrile (0.5 g) in dried tetrahydrofuran (5 ml) with stirring under ice-cooling, and the mixture is stirred for 3 hours at room temperature. To the mixture is added 1 N-HCl (20 ml) under ice-cooling and the mixture is stirred for 1 hour. The reaction mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over sodium sulfate. After chloroform is distilled off, the residue is purified by silica gel column chromatography (Kieselgel 60) and eluted with benzene-ether (10:1) to give 1-methyl-5-(3-propionylpropyl)thio-1,2,3,4-tetrazole (0.5 g) as colorless liquid, nD25 =1.5042.
Reaction SMILES: C(O[C:4](=[O:20])[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:7]1)C.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]2=[O:34])=[CH:24][C:23]=1[F:35]>>[F:35][C:23]1[CH:24]=[C:25]([N:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]2=[O:34])[CH:26]=[CH:27][C:22]=1[NH:21][C:4]([CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:7]1)=[O:20]
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: CCOC(=O)CN1CC[C@@H](NC(=O)c2ccc(Cl)s2)C1
Product: O=C(CN1CC[C@@H](NC(=O)c2ccc(Cl)s2)C1)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
1.4 Using general method F, {(R)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidin-1-yl}-acetic acid ethyl ester was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to WO 2003045912) to give 5-chloro-thiophene-2-carboxylic acid ((R)-1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidin-3-yl)-amide. Off-white amorphous solid. Light yellow solid. MS 475.3 ([M+H]+)
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=1.[Cl:21][C:22]1[C:23]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:24][CH:25]=[C:26]([Cl:28])[CH:27]=1>>[Cl:21][C:22]1[C:23]([N:29]2[CH2:34][CH2:33][N:32]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:20])=[CH:8][C:9]=3[S:16]([CH3:19])(=[O:18])=[O:17])=[O:13])[CH2:31][CH2:30]2)=[N:24][CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: Clc1cnc(N2CCNCC2)c(Cl)c1
Reactant: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Product: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(Cl)cc2Cl)CC1
Yield: 12.8 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylbenzoic acid (319 mg) described in Preparation Example 22 and 1-(3,5-dichloropyridin-2-yl)piperazine (232 mg) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (68 mg) was obtained.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([Cl:14])=[N:4][CH:3]=1.C([Li])CCC.B(OC(C)C)(OC(C)C)[O:21]C(C)C.OO.[OH-].[Na+].S([O-])([O-])=O.[Na+].[Na+].O.Cl>C1COCC1>[Cl:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([OH:21])=[CH:3][N:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc2c(Cl)ncc(Br)c2c1
Agent: Cl
Agent: O=S([O-])[O-]
Agent: OO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(Cl)ncc(O)c2c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a solution of 4-bromo-1-chloro-6-methoxyisoquinoline (0.25 g, 0.917 mmol) in THF (30 ml) was added n-Butyl Lithium (1.147 ml, 1.835 mmol) at −78° C. under nitrogen. The reaction mixture was stirred for 30 minutes and Triisopropyl borate (0.426 ml, 1.835 mmol) was added and stirred for another 30 minutes. To this Hydrogen Peroxide (0.273 ml, 8.90 mmol) (30% solution 1.5M) was added followed by the addition of sodium hydroxide (0.917 ml, 0.917 mmol). The resulting mixture was stirred for additional 1 h at room temperature. The reaction mixture was cooled to −40° C. and added sodium sulfite solution in water (1.156 g, 9.17 mmol). The resulting slurry was neutralized with 6N HCl solution and extracted with ethyl acetate. The combine organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (0.13 g, 67.6%) as solid. MS: MS m/z 210.06 (M++1).