Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH3:13][O:14][C:15](=[O:34])[C@@H:16]1[CH2:20][C@H:19]([OH:21])[CH2:18][N:17]1[C:22](=[O:33])[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:25]>ClCCl.C(Cl)(Cl)Cl>[CH3:13][O:14][C:15](=[O:34])[C@@H:16]1[CH2:20][C@H:19]([O:21][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:18][N:17]1[C:22](=[O:33])[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH3:25]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)CN(C)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Triethylamine (678 μL) and methanesulfonyl chloride (342 L) were added to a solution of 1-(N-tert-butoxycarbonyl-N-methylglycyl)-cis-4-hydroxy-L-proline methyl ester (A, 699 mg) in dichloromethane (15 mL) at 0° C. After stirring at 0° C. for 45 min and at room temperature for 45 min, the reaction mixture was diluted with chloroform. The organic layer was washed with 10% citric acid, saturated sodium hydrogen carbonate, and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to afford the title compound (0.82 g) as a pale yellow oil.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][C:7]([CH3:13])([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22].[Cl-].[Na+]>CN(C=O)C>[C:1]([CH:4]1[CH2:9][CH2:8][C:7]([CH3:13])([C:10]([O:12][CH2:22][CH:21]=[CH2:20])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=CCBr
Reactant: CC(=O)C1CCC(C)(C(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)C1(C)CCC(C(C)=O)CC1

Procedure:
1.4 g of 4-acetyl-1-methyl-1-cyclohexanecarboxylic acid (Example 36) was dissolved in 50 ml of DMF, and 5 g of potassium carbonate and 3 ml of allyl bromide were added to the resultant solution. The solution was reacted for 6 hours at room temperature. After reaction, 100 ml of an aqueous sodium chloride solution was added to the reaction solution. The solution was extracted three times with 30 ml of methylene chloride. The organic layer obtained was washed three times with an aqueous sodium chloride solution and dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The oily substance obtained was subjected to column chromatography using 20 g of silica gel. From the fraction eluted with hexane and ethyl acetate=10:1, the solvent was removed in vacuo, yielding obtaining 1.5 g of allyl 4-acetyl-1-methyl-1-cyclohexanecarboxylate as a colorless oil, which had the following physiochemical properties:
Reaction SMILES: [C:1]12([C:11]([OH:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(Cl)(=O)C(Cl)=O.[NH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH:25]1[O:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[O:27][CH2:26]1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[O:30]1[C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[O:27][CH2:26][CH:25]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20][C:11]([C:1]12[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2)=[O:13]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: NCCNCC1COc2ccccc2O1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCNCC1COc2ccccc2O1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
Adamantane-1-carboxylic acid (1.7 g, 10 mmole) was dissolved in 100 ml of dichloromethane and 3 drops of DMF added. Oxalyl chloride (2.0 ml, 23 mmole) was added and the mixture was stirred at room temperature for 2 hours. An additional 1.0 ml of oxalyl chloride (11.5 mmole) was then added, and stirring continued for 30 minutes. The mixture was concentrated to dryness in vacuum. 2-{N-(2-aminoethyl)]aminomethyl-2,3-dihydrobenzodioxin (2.1 g, 10 mmole) was dissolved in 100 ml of methylene chloride and 1.3 g (10 mmole) of diisopropylethylamine was added. To this mixture was added the acid chloride prepared above as a solution in 50 ml of dichloromethane. The addition was performed at 0° C. over 5 minutes. The mixture was then stirred overnight at room temperature. The reaction was next washed with saturated aqueous sodium bicarbonate, with saturated sodium chloride, dried over sodium sulfate, filtered and evaporated in vacuum. Column chromatography on 100 g of silica gel with chloroform as eluant, followed by crystallization from 100 ml of isopropanol with addition of 5 ml of 4N isopropanolic HCl and 400 ml of diethyl ether gave 1.3 g of the title compound as a monohydrochloride 1/4 hydrate, m.p. 147°-149° C.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li].[CH2:12]([O:19][C:20]([NH:22][CH2:23][C@H:24]([NH:30][C:31](=[O:36])[CH2:32][C:33](O)=[O:34])[C@@H:25]([OH:29])[C:26]#[C:27][CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:12]([O:19][C:20](=[O:21])[NH:22][CH2:23][C@H:24]([NH:30][C:31](=[O:36])[CH2:32][C:33](=[O:34])[NH:10][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][N:7]=1)[C@@H:25]([OH:29])[C:26]#[C:27][CH3:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CC(=O)O
Reactant: CC(C)(C)c1nnc(N)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CC(=O)Nc1nnc(C(C)(C)C)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.9 %

Procedure:
The compound 5-tert-butyl-[1,3,4]thiadiazol-2-ylamine (67 mg, 0.43 mmol) was dissolved in 6 mL of 1:1 CH2Cl2/DMF. The resultant solution was charged sequentially with the lithium salt of N-[(1S,2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-malonamic acid (151 mg, 0.43 mmol, see procedure 21a), N, N-diisopropylethylamine (0.38 mL, 2.1 mmol) and HATU (194 mg, 0.51 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford {(2S,3S)-2-[2-(5-tert-butyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-acetylamino]-3-hydroxy-hex-4-ynyl}-carbamic acid benzyl ester as a colorless oil (90 mg, 43% yield). MS found: (M+Na)+=510.4.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:14]CCC)[C:10](=[O:18])[C:9]([C:19]([OH:21])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:24])=O>>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH3:14])[C:10](=[O:18])[C:9]([C:19]([Cl:24])=[O:21])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCn1c(=O)c(C(=O)O)nn(-c2ccccc2)c1=O
Reactant: O=S(Cl)Cl
Product: Cn1c(=O)c(C(=O)Cl)nn(-c2ccccc2)c1=O
Yield: 88 %

Procedure:
Intermediate g (3.0 g, 0.01 mol) was added to thionyl chloride (10V/W, 30 mL). The mixture was warmed up under stirring to react under reflux for 6 h. The solvent was evaporated off to produce a clear yellow crystal (3 g) in a yield of 88%.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[C:9](=[O:14])[S:10]2)=[O:6])[CH:2]=[CH2:3].[CH3:15][NH:16][CH3:17]>O1CCCC1>[CH3:15][N:16]([CH3:17])[C:9]([C@@H:8]1[CH2:13][C@H:11]([SH:10])[CH2:12][N:7]1[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[O:14]
Reactant: C=CCOC(=O)N1C[C@@H]2C[C@H]1C(=O)S2
Reactant: CNC
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1S,4S)-5-allyloxycarbonyl-2-thia-5-azabicyclo[2.2.1]heptan-3-one (37.3 mg) in tetrahydrofuran (0.3 ml) was added an aqueous 40% dimethylamine solution (39.2 mg). The mixture was stirred for 2 hours at room temperature. After the reaction was over, the same post-treatment as in Example 5-(1) was conducted, thereby to give oily (2S,4S)-N,N-dimethyl-1-allyloxycarbonyl -4-mercapto-2-pirrolidinecarboxamide.
Reaction SMILES: [O-]CC.[Na+].[NH2:5][C:6]1[S:10][C:9]2[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[C:7]=1[C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)=O.[C:24](OCC)(=[O:32])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl>C(O)C.O>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][C:25]1[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[S:10][C:6]2=[N:5][C:24]=1[OH:32])[CH3:31]
Reactant: Cc1ccc(C(=O)c2c(N)sc3c2CCCC3)cc1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1c(O)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Temperature: 100 °C
Yield: 23.5 %

Procedure:
To a solution of sodium ethoxide 21% in ethanol (1.8 mL; 4.8 mmol) in dry ethanol (30 mL) under a nitrogen atmosphere was added (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(p-tolyl)methanone (1.09 g; 4 mmol) and diethyl succinate (0.929 mL; 5.6 mmol). The mixture was heated to 100° C. for 24 h. The reaction mixture was dissolved with water (8 ml) and acidified with a solution of hydrochloric acid 1N to pH 1 and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over sodium sulphate and concentrated under reduced pressure. The crude was suspended in dry ethanol (30 mL) and a catalytic amount of concentrated sulfuric acid (10 drops) was carefully added. The reaction mixture was heated to reflux for 21 h. The volatiles were removed under reduced pressure and the remaining residue was purified by flash-chromatography on silica gel using a gradient of methanol (1-20%) in ethyl acetate as eluent to furnish 0.358 g (19.6%) of ethyl[2-hydroxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate as an ochre solid. ESI/APCI(+): 382 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:15]([O-:17])=[O:16])[C:9]2=[O:18])=[CH:5][CH:4]=1.[CH2:21]=[O:22].C[O-].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:21][OH:22])=[C:10]([N+:15]([O-:17])=[O:16])[C:9]2=[O:18])=[CH:5][CH:4]=1
Reactant: C=O
Reactant: COc1ccc(Cn2ccc(C)c([N+](=O)[O-])c2=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(Cn2ccc(CCO)c([N+](=O)[O-])c2=O)cc1
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To a stirred mixture of 1-(4-methoxybenzyl)-4-methyl-3-nitro-2-pyridone (1.38 g, 5.0 mmol) and paraformaldehyde (0.152 g) in dimethylsulfoxide (8 mL) was added sodium methoxide (0.018 g). After 2 hours, the mixture was diluted with ethyl acetate and washed with water. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was dried, filtered and evaporated. The residual solid was triturated with chloroform/ethyl acetate (10 mL, 1/1) and 1-(4-methoxybenzyl)-4-hydroxyethyl-3′-nitro-2-pyridone was collected by filtration (0.496 g). Fractionation of the supernatant over silica gel (chloroform/ethyl acetate to ethyl acetate/methanol 99/1) gave additional product (0.404 g) (total yield, 2.96 mmol, 59%).
Reaction SMILES: C([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][C:11]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[N:12][C:13]=2[NH2:17])C1C=CC=CC=1.C(O)(C)C.[H][H]>[OH-].[OH-].[Pd+2].C(O)=O>[CH3:23][O:22][C:20]([CH2:19][CH2:18][C:11]1[N:10]=[C:9]2[C:14]([NH:15][CH:16]=[N:8]2)=[C:13]([NH2:17])[N:12]=1)=[O:21]
Reactant: [H][H]
Reactant: COC(=O)CCc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=CO
Product: COC(=O)CCc1nc(N)c2[nH]cnc2n1
Yield: 92.5 %

Procedure:
9-Benzyl-2-(2-methoxycarbonylethyl)adenine (0.29 g, 0.93 mmol) obtained by Example 61 and 20% Pd(OH)2/C (0.32 g) were added to a mixed solvent of isopropanol (8 ml) and formic acid (8 ml), and the mixture was stirred at a pressure of 2 atmosphere of hydrogen at 70° C. for 40 hours. After filtration, the filtrate was concentrated to give the captioned compound (0.23 g, 0.86 mmol) as a white solid.
Reaction SMILES: [C:1]([O:9][C:10]1[C:11]([OH:44])=[N:12][C:13]([C:20]2([CH3:43])[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:22][N:21]2[C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])=[N:14][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[CH3:47]OS(OC)(=O)=O.C(O)(=O)C>O1CCOCC1.CCOC(C)=O.O>[C:1]([O:9][C:10]1[C:11](=[O:44])[N:12]([CH3:47])[C:13]([C:20]2([CH3:43])[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:23][CH2:22][N:21]2[C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])=[N:14][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(C2(C)CN(C(=O)OC(C)(C)C)CCN2C(=O)OCc2ccccc2)nc(O)c1OC(=O)c1ccccc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C2(C)CN(C(=O)OC(C)(C)C)CCN2C(=O)OCc2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
1-Benzyl 4-tert-butyl 2-[5-(benzoyloxy)-4-hydroxy-6-(methoxycarbonyl)pyrimidin-2-yl]-2-methylpiperazine-1,4-dicarboxylate was added to a suspension of LiH (1.1 eq) in dioxane (7 ml/mmol) at room temperature. The mixture was stirred at 40° C. for 45 min, then dimethylsulfate (1.3 eq) was added and the temperature was raised to 60° C. After 1 h glacial acetic acid (0.1 eq) was added to the reaction mixture, followed by water (7 ml/mmol) and EtOAc (7 ml/mmol). The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated. The crude was purified by flash chromatography on silica gel (AcOEt/petroleum ether, 1:4) to separate the title compound A from B (ratio A/B 1.3/1).
Reaction SMILES: Cl[S:2](O)(=O)=O.[CH3:6][O:7][C:8](=[O:24])[CH:9]([CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:15]1)[C:10]([O:12][CH3:13])=[O:11]>>[CH3:13][O:12][C:10](=[O:11])[CH:9]([CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([SH:2])[CH:20]=2)[O:15]1)[C:8]([O:7][CH3:6])=[O:24]
Reactant: COC(=O)C(C(=O)OC)C1CCc2ccccc2O1
Reactant: O=S(=O)(O)Cl
Product: COC(=O)C(C(=O)OC)C1CCc2cc(S)ccc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
Chlorosulfonic acid (15 mL) was cooled to 0° C. Then compound 5B (5.5 g. 20.8 mmol) was added over 30 min. The mixture was stirred at RT for 3 h and was poured into ice (100 g). The cloudy solution was extracted with ether (2×100 mL). The extracts were dried with magnesium sulfate and concentrated to give the desired product (4.0 g, 53%) as a yellow oil. The crude product was used immediately for the next step without purification.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].CN(C=O)C.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([OH:30])[C:28]=1[I:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([O:30][CH:2]([CH3:4])[CH3:3])[C:28]=1[I:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1cc(O)c(I)c(OCc2ccccc2)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCc2ccccc2)c(I)c(OC(C)C)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-Iodopropane (1.47 mL) was added to a DMF (30 mL) suspension of ethyl 3-(benzyloxy)-5-hydroxy-4-iodobenzoate (2.94 g) and potassium carbonate (1.53 g), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.72 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[NH:5][C:6]1[C:11]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:13]2)=[CH:10][CH:9]=[CH:8][C:7]=1[N+:24]([O-])=O)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:27])[NH:5][C:6]1[C:11]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:23])[C:19]([F:20])([F:22])[F:21])[CH2:13]2)=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:24])[CH3:2]
Reactant: CCOC(=O)Nc1c(C2CCCN(C(=O)C(F)(F)F)C2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Nc1c(N)cccc1C1CCCN(C(=O)C(F)(F)F)C1

Procedure:
12 g of the product of Step D were hydrogenated for 3 hours in 400 ml of ethanol in the presence of 3 g of palladium at 10% on carbon. After filtering, washing with ethanol and evaporating to dryness under reduced pressure, 10.8 g of ethyl-[2-amino-6-[1-(trifluoroacetyl)-3-piperidinyl]-phenyl]-carbamate melting at about 90° C. after crystallization from isopropyl ether were obtained.
Reaction SMILES: [Mg].II.[CH2:4](Br)[CH2:5][C@H:6]([CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH3:7].[CH2:15]=[O:16].[Cl-].[NH4+]>O1CCCC1>[CH3:7][C@@H:6]([CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH2:5][CH2:4][CH2:15][OH:16]
Reactant: C=O
Reactant: CC(C)=CCC[C@H](C)CCBr
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)=CCC[C@H](C)CCCO
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
This example illustrates a synthesis of 1-(4-(S)-Methyl-7,8-oxido-8-methylnonyl)-3,7-dimethylxanthine (inventive compound no. 2548S). To a suspension of magnesium (2.74 g, 140 mmol) and a crystal of iodine in tetrahydrofuran (15 mL) was added (S)-citronellyl bromide (5.0 g, 22.8 mmol) in tetrahydrofuran (10 mL) over 30 minutes and the reaction stirred for a further 30 minutes after the addition was complete. The solution was added via a canula over 5 minutes to a suspension of paraformaldehyde (1.80 g, 60.0 mmol) in tetrahydrofuran (15 mL) and stirred at 25° C. for 6 hours. Saturated ammonium chloride (40 mL) was added and extracted with diethyl ether (2×30 mL). The combined organic extracts were dried (magnesium sulfate) and evaporated to yield 3.25 g (84% yield) 4-(S)-methyl-8-methylnon-7-enyl alcohol as a clear liquid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:3]1.O[N:30]=[C:31]([NH2:35])[CH2:32][O:33][CH3:34]>>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]3[O:28][N:35]=[C:31]([CH2:32][O:33][CH3:34])[N:30]=3)[CH2:10]2)=[O:8])[CH2:3]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)C2)C1
Reactant: COCC(N)=NO
Product: COCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(O)C3)C2)n1

Procedure:
200 mg (0.497 mmol) of the compound from Example 112A and 77 mg (0.746 mmol) of N′-hydroxy-2-methoxyethanimidamide were reacted according to the General Method 2. Yield: 55 mg (24% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Br[CH2:39][CH:40]([CH3:42])[CH3:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:39][CH:40]([CH3:42])[CH3:41])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: CC(C)CBr
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COc1ccc(CC2c3cc(OCC(C)C)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 1-bromo-2-methyl-propane
Reaction SMILES: CN1C(CCCC(O)=[O:15])=NC2C=C(N(CCCl)CCCl)C=CC1=2.O1CCN(C(O)C)CC1.[CH:33]1([N:39]=[C:40]=[N:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl.CN(C1C=CN=CC=1)C>[CH:42]1([NH:41][C:40]([NH:39][CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]2)=[O:15])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(O)N1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.25 h

Procedure:
Bendamustine free base (1.0 g, 2.79 mmol) in dichloromethane (90 ml), morpholinoethanol (0.44 ml, 3.35 mmol) and DMAP (20 mg) were added with stirring. A solution of N,N′-Dicyclohexylcarbodiimide (0.63 g, 3.05 mmol) in dichloromethane (90 ml) was added dropwise over 50 min. After 15 min, a clear reaction solution was obtained and after 70 min a precipitate of dicyclohexyl urea occurred. The reaction mixture was stirred at ambient temperature for a total time of 24 h. After concentration to half of the volume and cooling to 0° C., the precipitate was removed by filtration. Then the solution was extracted with diluted HCl (1 ml 37% HCl to 60 ml Water, 30 ml+2×15 ml portions). The aqueous phase was treated with 25% NH3 (1.6 ml, pH 7-8) and extracted with dichloromethane (20+2×10 ml). Evaporation of the combined organic solvents resulted in a crude oil (1.38 g) that was purified via column chromatography (40 g silica, 10% MeOH/dichloromethane) to afford a slightly yellowish oil (1.26 g) that crystallized after seeding. Further drying in vacuum resulted in 1.08 g (82%) of product as slightly yellowish crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6](=[O:8])[O:5][C:3]1=O.[CH:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([OH:17])[CH:11]=1>CN(C)C=O>[OH:17][C:12]1[CH:13]=[CH:14][C:15]([N:16]2[C:6](=[O:8])[CH2:7][C:2]([CH3:1])([CH3:9])[C:3]2=[O:5])=[CH:10][CH:11]=1
Reactant: CC1(C)CC(=O)OC1=O
Reactant: Nc1ccc(O)cc1
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)N(c2ccc(O)cc2)C1=O
Yield: 70 %

Procedure:
A solution of 2,2-dimethylsuccinic anhydride (128 g, 1 mol) in dimethylformamide (150 ml) was added slowly for a time of 1 h at a temperature of 25° C. to a stirred solution of p-aminophenol (109 g, 1 mol) in dimethylformamide (150 ml) present in a reactor. By continuing the procedure as described in Example 1, N-(4-hydroxyphenyl)-2,2-dimethylsuccinimide was obtained in a yield of 70% and with a purity of more than 95%.
Reaction SMILES: [N:1]([CH2:4][CH:5]([CH2:24][C:25]#[N:26])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[N+]=[N-].C(OC(C)CC(COC(=O)NCCCCCCCCCCCCCCCCCC)CN)(=O)C1C=CC=CC=1>[Pd].CO>[C:25]([CH2:24][CH:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:4][NH2:1])#[N:26]
Reactant: CCCCCCCCCCCCCCCCOCC(CC#N)CN=[N+]=[N-]
Agent: [Pd]
Agent: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)CC(C)OC(=O)c1ccccc1
Solvent: CO
Product: CCCCCCCCCCCCCCCCOCC(CN)CC#N

Procedure:
A suspension of 3.00 g (23 mM) of 1-azido-2-cyanomethyl-3-hexadecyloxypropane Vn1b and 300 mg of 10% palladium on charcoal in 100 ml of methanol is hydrogenated as described in (129) and the crude product of the titled compound IVn1 is obtained.