Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].[I:15]I.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O>[CH2:1]([S:6][C:7]1[CH:12]=[CH:11][C:10]([I:15])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCSc1ccc(Br)cc1
Reactant: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Mg]
Agent: [Na+]
Solvent: O
Product: CCCCCSc1ccc(I)cc1
Reaction time: 16 h

Procedure:
The Grignard reagent from the product of Step 2.1 (15 g) was prepared using magnesium in tetrehydrofuran (60 ml). Iodine (16.2 g) was added over 10 min and the mixture was stirred for 16 hrs. Water was added and then 10% sodium metabisulphite (100 ml). The product was extracted into petroleum ether and distilled. Yield 10.5 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][N:17]3[CH2:25][C:24]4[C:19](=[CH:20][C:21]([O:28][CH3:29])=[C:22]([O:26][CH3:27])[CH:23]=4)[C:18]3=[O:30])[CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>C(Cl)Cl>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][N:17]3[CH2:25][C:24]4[C:19](=[CH:20][C:21]([O:28][CH3:29])=[C:22]([O:26][CH3:27])[CH:23]=4)[C:18]3=[O:30])[CH2:11]2)=[CH:6][CH:7]=1)[C:38]([CH3:39])=[O:40]
Reactant: CC(=O)Cl
Reactant: COc1cc2c(cc1OC)C(=O)N(CC1CCCN(CCc3ccc(N)cc3)C1)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(=O)N(CC1CCCN(CCc3ccc(NC(C)=O)cc3)C1)C2
Temperature: 25 °C

Procedure:
819 mg (2 mmol) of 2-[(N-(2-(4-amino-phenyl)-ethyl)-piperidin-3-yl)-methyl]-5,6-dimethoxy-1-oxo-1,3-dihydro-isoindole are mixed with 10 ml of methylene chloride and after the addition of 0.3 ml (2.2 mmol) of triethylamine, 0.16 ml (2.2 mmol) of acetyl chloride are added dropwise. The reaction temperature rises to 30° C. The mixture is stirred for half an hour at ambient temperature, extracted twice with water, the organic phase is dried over magnesium sulphate and evaporated down in vacuo. The residue is crystallised from acetone.
Reaction SMILES: B.C1C[O:5]CC1.[CH3:7][O:8][CH:9]1[CH2:14][CH2:13][CH:12]=[CH:11][O:10]1>C1COCC1>[CH3:7][O:8][CH:9]1[O:10][CH2:11][CH:12]([OH:5])[CH2:13][CH2:14]1
Reactant: COC1CCC=CO1
Reactant: C1CCOC1
Agent: B
Product: COC1CCC(O)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 217.7 %

Procedure:
Borane-THF 1M (14.6 ml, 14.6 mmol) was added slowly to an ice cooled solution of 3,4-dihydro-2-methoxy-2H-pyran (55.0 g, 44 mmol) in THF (15 ml). The ice bath was removed and the reaction was stirred at room temperature for 1 h, cooled to 0° C. and 3 N sodium hydroxide (14.6 ml) was added followed with 30% hydrogen peroxide (9 ml). This was allowed to stir for 4 hs warming to room temperature. The reaction was extracted with ethyl acetate (2×50 ml). The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 6-methoxytetrahydro-2H-pyran-3-ol (4.2 g, 72%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]([CH3:13])[CH3:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].[O:21]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:11]([CH3:13])[CH3:12])[CH2:9][O:10][CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:29]=2)=[CH:6][CH:7]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(CO)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)C(COCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
2.0 g of 2-(4-chlorophenyl)-3-methylbutanol in 10 ml of a 20% mixture of dimethylformamide and toluene was added over a 5 minute period to sodium hydride (0.8 g, 50% in oil) in 20 ml of toluene at 110°-120° C, and the mixture was stirred for 15 minutes. 3.0 g of 3-phenoxybenzyl bromide in 15 ml of toluene was then added over a 15 minute period and the mixture was gently refluxed for 2 hours, then was cooled and 10 ml of mineral spirits was added. The mixture was poured into ice/hydrochloric acid, extracted with ether, washed with sodium bicarbonate solution and dried (MgSO4). The solvent was removed to give an orange oil, which was chromatographed on silica gel using 1:1 methylene dichloride:hexane as eluent to give 1.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:7][CH:6]=1.[OH-].[K+].O>C(O)C>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:26])=[O:2])=[CH:6][CH:7]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1
Yield: 84.1 %

Procedure:
The title compound is prepared by the procedure of Example 32 using 75 g of product from Example 51, 34.8 g of potassium hydroxide, 45 ml of water and 800 ml of ethyl alcohol. The residue is recrystallized from carbon tetrachloride/hexane to give 60.6 g of the desired product as white crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([Br:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][NH:14][CH3:15]>O>[Br:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:14]([CH3:15])[CH3:13])[CH:11]=1
Reactant: Brc1cc(Br)c2ccccc2n1
Reactant: CNC
Solvent: O
Product: CN(C)c1cc(Br)c2ccccc2n1
Reaction time: 8 h
Yield: 40 %

Procedure:
The product from (451a) (2.0 g, 7.0 mmol) was dissolved in 10 mL of 40% dimethylamine solution in H2O. The reaction mixture was allowed to stir overnight. The solution was diluted to 40 mL with H2O and it was extracted with EtOAc for three times. The combined organic layer was dried over MgSO4. After concentration, the residue was purified on silica gel column to provide 4-bromo-2-dimethylaminoquinoline (451b) (0.69 g, 40%). MS (AP+): 251 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[O-]CC.[Na+].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[O:9][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: Cc1ccc(O)cc1C
Reactant: CCOC(=O)CCCBr
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(OCCCC(=O)O)cc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3,4-Dimethylphenol (24.5 g, 0.2 mol) was dissolved in 125 ml of anhydrous ethanol. 75 ml of 21 wt % sodium ethoxide solution in ethanol (0.2 mol) was added to the solution. The mixture was stirred at room temperature for 10 min. Ethyl 4-bromobutyrate (40 g, 0.205 mol) was then added. The reaction mixture was refluxed at 80° C. for 24 h. The precipitate was filtered off. The filtrate was then mixed with a solution of sodium hydroxide (10 g, 0.25 mol) in 150 ml of water. The mixture was stirred at 70° C. for about 2 h, monitored with HPLC. It was diluted with 150 ml of water and acidified to pH 1. Oily precipitate formed immediately. It was collected by decanting the supernatant and washed with water twice (100 ml×2). The oily precipitate solidified after being kept in water at room temperature over night.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH:6]=[O:7].[C:13]([OH:23])(=[O:22])[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)O.[B]>CCOCC>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH:6]1[O:23][C:13](=[O:22])[CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:7]1
Reactant: O=C(O)C(O)c1ccccc1
Reactant: O=CCOc1ccc(Cl)cc1Cl
Agent: [B]
Solvent: CCOCC
Product: O=C1OC(COc2ccc(Cl)cc2Cl)OC1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
A solution containing 5.1g (0.025 mole) of 2,4-dichlorophenoxyacetaldehyde, 4.25g (0.028 mole) of mandelic acid, and 10.0g (0.07 mole) of boron trifluoide etherate in 250 ml of ether was allowed to stir for 2 hours at ambient temperature, washed with aqueous sodium carbonate and water, dried and concentrated. The residual solid was purified by silica chromatography to give 2.7g of 2-(2,4-dichlorophenoxymethyl)-5-phenyl-1,3-dioxolan-4-one, trans isomer, having a melting point of 68°-71°.
Reaction SMILES: C(OC(COC(=O)C)C[NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14](N2[C@H](CO)COC2=O)[C:13]([I:25])=[C:12]([C:26]([NH:28]CC(OC(=O)C)COC(=O)C)=[O:27])[C:11]=1[I:40])=[O:9])(=O)C.C[O-].[Na+]>CO.O>[I:40][C:11]1[C:12]([C:26]([NH2:28])=[O:27])=[C:13]([I:25])[CH:14]=[C:15]([I:16])[C:10]=1[C:8]([NH2:7])=[O:9]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2C(=O)OC[C@H]2CO)c1I)OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)c1c(I)cc(I)c(C(N)=O)c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 115.8 %

Procedure:
To a solution of N,N'-Bis[2,3-bis(acetyloxy)propyl]-5-(4)-(R)-(hydroxymethyl)-2-oxo-3-oxazolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide of Example 2b (0.410 g, 0.51 mmol) in anhydrous methanol (7 ml) was added a methanolic solution of sodium methoxide (1.18 ml, 1 M solution) and the mixture was stirred at room temperature for 1 h. The methanol was then removed on the rotary evaporator and water (8 ml) was added to redissolve the white residue. Dowex-50 (H+) was added to this solution portionwise to bring the pH down to approximately 7.0. The Dowex-50 resin was filtered off, water was removed on the rotary evaporator, and the white solid dried in vacuo at 60° over P2O5. The solid thus obtained (0.350 g) was redissolved in water (0.5 ml), seeded with a tiny crystal of the racemate and left overnight. The crystallized product was filtered, washed with cold water and dried overnight over P2O5 to obtain N,N'-Bis[2,3-bis(acetyloxy)propyl]-5-(4)-(R)-(hydroxymethyl)-2-oxo-3-oxazolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as white crystalline needles (0.32 g, 84%).
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH2:2][CH3:3].Br[CH2:14][C:15]1[CH:35]=[CH:34][C:18]2/[C:19](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:20]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[F:28][C:27]1[C:20]2/[C:19](=[C:30](\[CH3:33])/[C:31]#[N:32])/[C:18]3[CH:34]=[CH:35][C:15]([CH2:14][N:8]4[C:7]5[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=5[N:5]=[C:4]4[CH2:1][CH2:2][CH3:3])=[CH:16][C:17]=3[CH2:23][O:22][C:21]=2[CH:24]=[C:25]([F:29])[CH:26]=1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)cc(F)c21
Reactant: CCCc1nc2ccccc2[nH]1
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)COc1cc(F)cc(F)c1/C2=C(\C)C#N
Yield: 96.2 %

Procedure:
Using 2-propyl-1H-benzo[d]imidazole (Synthetic Communication, 2002, vol. 32, p 3703; 67 mg, 0.42 mmol) and (E)-2-[8-(bromomethyl)-1,3-difluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (160 mg, 0.43 mmol) obtained in Reference Example 2, and in the same manner as in Reference Example 1A, the title compound (184 mg, 97%) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4].[C:50]([O:54][C:55]([NH:57][CH2:58][C:59](O)=[O:60])=[O:56])([CH3:53])([CH3:52])[CH3:51]>O1CCCC1>[C:50]([O:54][C:55]([NH:57][CH2:58][C:59]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4])=[O:60])=[O:56])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CNC(=O)OC(C)(C)C
Yield: 68 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-glycine. Yield 68%. [α]D =+14.5° (c=0.92, tetrahydrofuran).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH2:2][C:3]2[O:4][C:5](=[O:9])[O:6][C:7]=2[CH3:8])=[CH:14][CH:13]=1
Reactant: Cc1oc(=O)oc1CCl
Reactant: COc1ccc(S)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(SCc2oc(=O)oc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
In 40 ml of dichloromethane was dissolved 2.0 g of 4-chloromethyl-5-methyl-1,3-dioxol-2-one, and 1.9 g of 4-methoxybenzenethiol was added. Then, 1.4 g of triethylamine was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate. The insoluble materials were separated by filtration, and the solvent was evaporated under reduced pressure. The residue was subjected to medium-pressure silica gel column chromatography as in Example 1. The eluate was evaporated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 2.3 g of the captioned compound as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]3[CH:18]=[N:19][CH:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[ClH:21].[H][H]>C(O)C.[Pd]>[ClH:21].[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[N:17]3[CH:18]=[N:19][CH:20]=[C:16]3[CH2:15][CH2:14][CH2:13]2)=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(-c2cccc3cncn23)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(C2CCCc3cncn32)cc1

Procedure:
A solution of 2.0 g of 5-(p-ethoxycarbonylphenyl)imidazo[1,5-a]pyridine in 120 ml of anhydrous ethanol containing 30 ml of concentrated hydrochloric acid, is hydrogenated with 1.0 g of 10% palladium on charcoal at 40 psi hydrogen and 60° for 4 h. The catalyst is filtered and the solvent is evaporated to yield a solid which is recrystallized from isopropanol and ether to provide the title compound, m.p. 164°-166°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(CC)CC>O.[Cl-].[Na+].O>[C:10]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1cccc(-c2ccccc2)c1
Yield: 92.6 %

Procedure:
3-Bromobenzonitrile (91 mg, 0.5 mmol), phenylboronic acid (91 mg, 0.75 mmol), and Pd(dtbpf)Cl2 (6 mg, 0.01 mmol) were added to a reaction tube equipped with a magnetic stir bar. Under a positive flow of argon while stirring, surfactant solution (1.0 mL, 2 wt % TPGS-M-PEG-750 in water), and Et3N (0.21 mL, 1.5 mmol) were added by syringe and stirred vigorously for 2 h. The reaction mixture was then diluted with brine and extracted with EtOAc. The solution obtained was dried over anhydrous MgSO4 and concentrated by rotary evaporation. The residue was purified by flash column chromatography eluting with 20% CH2Cl2/hexanes to afford the product (83 mg, 93%) as a slightly yellow oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]OS(C)(=O)=O)=[CH:33][CH:32]=2)=[C:28]([CH:46]([CH3:48])[CH3:47])[NH:27][N:26]=1)(=[O:3])[CH3:2].[NH2:49][C:50]([CH3:58])([CH3:57])[C:51]([NH:53][CH2:54][CH2:55][OH:56])=[O:52].[I-].[Na+]>C(#N)C.C(O)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@@H:8]([CH2:9][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:49][C:50]([C:51](=[O:52])[NH:53][CH2:54][CH2:55][OH:56])([CH3:58])[CH3:57])=[CH:33][CH:32]=2)=[C:28]([CH:46]([CH3:47])[CH3:48])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCOS(C)(=O)=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)C(=O)NCCO
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCNC(C)(C)C(=O)NCCO)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 60.7 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole (0.77 g) in dichloromethane (5 mL) were added triethylamine (0.26 mL) and methanesulfonyl chloride (0.12 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)-propoxy]phenyl}methyl)-1H-pyrazole (0.85 g). The obtained 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]phenyl}-methyl)-1H-pyrazole (0.2 g) was dissolved in a mixed solvent of acetonitrile (1.5 mL) and ethanol (1.5 mL). To the solution were added 2-[2-amino-2-(methyl)propionylamino]ethanol (0.25 g) and a catalytic amount of sodium iodide, and the mixture was stirred at 60° C. for 4 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-(2-hydroxyethylcarbamoyl)-1-(methyl)ethylamino]propoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole (0.13 g). This material was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.05 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (93 mg).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:24]([Cl:25])=[C:23]([Cl:26])[N:22]=[C:21]([NH:27][CH3:28])[N:20]=3)[CH2:15][CH2:14]2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[Cl:25][C:24]1[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([NH:4][C:36](=[O:38])[CH3:37])[CH2:6][CH2:7]3)[CH2:18][CH2:17]2)=[N:20][C:21]([NH:27][CH3:28])=[N:22][C:23]=1[Cl:26]
Reactant: CNc1nc(Cl)c(Cl)c(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNc1nc(Cl)c(Cl)c(N2CCN(CC[C@H]3CC[C@H](NC(C)=O)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.28 g (4.6 mmol) trans-(4-{4-[2-(4-amino-cyclohexyl)-ethyl]-piperazin-1-yl}-5,6-dichloro-pyrimidin-2-yl)-methyl-amine trihydrochloride was suspended in dichloromethane (50 ml). Triethylamine (3.5 ml, 25.3 mmol) was added followed by the addition of acetyl chloride (0.49 ml, 6.9 mmol). The reaction mixture was stirred for 24 hours at room temperature. The precipitate was filtered, washed with water and purified using column chromatography to give the title compound (1.39 g, 70%), MS (EI): 430.2 (MH+); 1H NMR (300 MHz, DMSO-d6 (TMS)+1 drop of cc. DCl, □ (ppm)): 0.89-0.96 m (2H); 1.06-1.35 m (3H); 1.55-1.82 m (6H); 1.79 s (3H); 2.76 (3H); 2.98-3.18 m (4H); 3.37-3.58 m (5H); 4.16-4.29 m (2H); 7.90 br (residual NH); 11.35 br (residual NH).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]1([CH3:28])[CH:20]=[CH:19][C:18]([NH:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1.[CH:29]([CH2:31][C:32]1([CH2:38][CH2:39][N:40]2[C:44](=[O:45])[C:43]3=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]3[C:41]2=[O:50])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=O.C(O)(=O)C.C(=O)([O-])O.[Na+]>ClCCCl>[C:15]1([CH3:28])[CH:16]=[CH:17][C:18]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:29][CH2:31][C:32]3([CH2:38][CH2:39][N:40]4[C:44](=[O:45])[C:43]5=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]5[C:41]4=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)[CH2:24][CH2:23]2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(NC2CCNCC2)cc1
Reactant: O=CCC1(CCN2C(=O)c3ccccc3C2=O)CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1ccc(NC2CCN(CCC3(CCN4C(=O)c5ccccc5C4=O)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 108.4 %

Procedure:
After adding sodium triacetoxyborohydride (0.82 g, 3.85 mmol) to a solution of 4-(p-toluidino)piperidine (0.73 g, 3.85 mmol), N-[2-[1-(formylmethyl)cyclohexyl]ethyl]phthalimide (0.77 g, 2.57 mmol) and acetic acid (0.30 mL, 5.14 mmol) in 1,2-dichloroethane (10 mL), the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous sodium hydrogencarbonate was then added, and extraction was performed with chloroform-ethanol (10:1). After drying (anhydrous sodium sulfate), the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (25 g Merck Art 9385, chloroform:methanol=20:1) to obtain the title compound as a colorless oil (1.32 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[O:20]C.[Br-].[Br-].[Br-].B.O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[OH:20]
Reactant: COc1ccc(C2(c3ccccc3)CCCCC2)cc1F
Agent: B
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(C2(c3ccccc3)CCCCC2)cc1F
Reaction time: 3 h

Procedure:
A solution of the crude 2-fluoro-1-methoxy-4-(1-phenyl-cyclohexyl)-benzene in dichloromethane (100 mg, 0.25 mmol, 2 mL) was added to a solution of borane tribromide in dichloromethane (1 M, 0.25 ml, 025 mmol) at −78° C. under an argon atmosphere and stirred at r.t for 3 h. Water (10 mL) was added and the mixture was extracted with dichloromethane (2×10 mL). The combined organic phase was dried (Na2SO4) and concentrated to a syrup. Work-up by flash-chromatography (eluent: 30→80% dichloromethane in heptane) gave the title product in a yield of 50 mg.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C(Cl)Cl>[C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH2:21][CH2:22][C:23]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:24])(=[O:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(=O)N1c2ccccc2SC1c1ccccc1OCCCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1c2ccccc2SC1c1ccccc1OCCCC(=O)N1CCOCC1
Temperature: -13 °C

Procedure:
To the solution of 1.79 g of 3-acetyl-2-[2-[3-(carboxy)propoxy]phenyl]benzothiazoline and 0.51 g of triethylamine in 20 ml of anhydrous methylene chloride, 0.68 g of isobutyl chloroformate is added dropwise while stirring at -13° C. and stirred additional 10 minutes at the same temperature. To the solution 0.44 g of morpholine in 5 ml of methylene chloride is added dropwise.