Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](Cl)=[O:8])=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)[C:15]2=[O:20].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C1COCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][N:14]([CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[C:15]3=[O:20])=[O:8])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2Cc3c(N)cccc3C2=O)CC1
Reactant: O=C(Cl)c1ccc(Cl)s1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(CCN2Cc3c(NC(=O)c4ccc(Cl)s4)cccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 0.97 g (5.35 mmol) of 5-chlorothiophene-2-carbonyl chloride is added dropwise to a suspension of 1.48 g (4.12 mmol) of tert-butyl 4-[2-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl) ethyl]-1-piperidinecarboxylate, 1.7 ml (20.6 mmol) of pyridine and 25 mg (0.206 mmol) of 4-DMAP in 21 ml of absolute THF. The mixture is slowly warmed to room temperature and stirred overnight. The reaction mixture is concentrated and then separated by chromatography on silica gel (dichloromethane/methanol 97:3).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1F>>[ClH:13].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[O:9][CH:6]1[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]2[O:12][CH:11]=[CH:10][C:5]1=2
Reactant: Fc1cc(Cl)ccc1Cl
Reactant: CN1CCC(O)c2ccoc2C1
Product: CN1CCC(Oc2cc(Cl)ccc2Cl)c2ccoc2C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,5-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [S:1]1(=[O:12])(=[O:11])[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]([OH:10])[CH2:3][NH:2]1.[H-].[Na+].[CH2:15]([O:17][CH2:18][CH2:19][CH2:20]Br)[CH3:16]>CN(C=O)C.O>[CH2:15]([O:17][CH2:18][CH2:19][CH2:20][N:2]1[CH2:3][CH:4]([OH:10])[C:5]2[CH:9]=[CH:8][S:7][C:6]=2[S:1]1(=[O:12])=[O:11])[CH3:16]
Reactant: CCOCCCBr
Reactant: O=S1(=O)NCC(O)c2ccsc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCCN1CC(O)c2ccsc2S1(=O)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71 %

Procedure:
A solution of the product from Example 1, Step C (13.0 g, 63.3 mmol) in DMF (50 mL) was added to a suspension of sodium hydride (2.5 g of a 60% slurry in mineral oil, washed with hexane, 63.3 mmol) in DMF (300 mL) at 0° C. After stirring for 45 min, the product from Step A (10.6 g, 63.3 mmol) was added and the mixture was stirred for 18 hr, during this time the temperature slowly increased to room temperature. The reaction mixture was diluted with cold water (300 mL) and extracted with ethyl acetate (5×10 mL). The combined extracts were washed with water (3×10 mL), saturated aqueous sodium chloride (20 mL), dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, gradient, 3:1 hexane/ethyl acetate to 7:3 methylene chloride/methanol) to provide a clear oil (13.1 g, 71%) which was used in the next step.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[C:16]1([C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N+]=[N-])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>C(OCC)(=O)C.O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:14]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCCCCCCCCCCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(CCCCCCCCCCCO)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
4.32 g of 12-hydroxydodecanoic acid were dissolved in 200 ml of ethyl acetate and 30 ml of water, and 5.5 g of diphenyldiazomethane were added to the resulting solution, which was then stirred at room temperature overnight. At the end of this time, about 10 ml of acetic acid was added to the resulting mixture to decompose the excess diphenyldiazomethane, after which the mixture was washed with 100 ml of water and the organic layer was separated. The organic layer was then washed twice, each time with 100 ml of a 5% w/v aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride. The washed organic layer was then dried over anhydrous magnesium sulfate and the solvent was removed by evaporation under reduced pressure, to afford 9.2 g of a thickly viscous yellow oily residue. This residue was purified by silica gel column chromatography using cyclohexane containing 10% by volume ethyl acetate as eluent, to afford 5.2 g of benzhydryl 12-hydroxydodecanoate as a thickly viscous pale yellow oily substance.
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.C(N(CC)CC)C.[N+:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[NH2:32])([O-:22])=[O:21].[Cl-].[NH4+]>CN(C1C=CN=CC=1)C.C1COCC1>[N+:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[NH:32][C:1](=[O:12])[O:7][C:8]([CH3:9])([CH3:10])[CH3:11])([O-:22])=[O:21]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Reaction time: 0.33 h
Yield: 79.5 %

Procedure:
Di-tert-butyl carbonate (1.76 g), triethylamine (1.13 ml), and DMAP (10 mg) were added to a THF (8.2 ml) solution containing 5-nitro-1H-indazol-3-amine (1.45 g) under ice cooling, followed by stirring for 20 minutes. A saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were extracted with water and saturated saline and dried over sodium sulfate and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=1:0 to 3:2) and a yellow solid of tert-butyl (5-nitro-1H-indazol-3-yl)carbamate (1.8 g) was thus obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH:21]=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:23]#[N:24].[K+].Cl>O1CCCC1.O>[OH:22][CH:21]([CH:9]1[CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13][N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:23]#[N:24]
Reactant: [C-]#N
Reactant: O=CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
To a solution of 5.2 g of crude 1,4-dibenzyl-2-formylpiperazine in a mixture of 30 ml of tetrahydrofuran and 10 ml of water are added 2.2 g (33.8 mmoles) of potassium cyanide and 3.4 ml of concentrated hydrochloric acid under ice-cooling, and the mixture is stirred for 30 minutes, mixed with water and extracted with chloroform. The extract is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to yield 5.70 g of crude oily 2-hydroxy-2-(1,4-dibenzylpiperazin-2-yl)acetonitrile.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:5](=[O:16])[C:6]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[S:9][C:7]=2[N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:31]>C(Cl)(Cl)Cl>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:4]1[C:5](=[O:16])[C:6]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[S:9][C:7]=2[N:8]=[C:3]1[CH2:2][N:35]1[CH2:36][CH2:37][N:32]([CH2:30][CH3:31])[CH2:33][CH2:34]1
Reactant: O=c1c2c3c(sc2nc(CCl)n1-c1ccccc1Cl)CCCC3
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCN1CCN(Cc2nc3sc4c(c3c(=O)n2-c2ccccc2Cl)CCCC4)CC1
Yield: 68.4 %

Procedure:
In 40 ml of chloroform was dissolved 820 mg of 3,4,5,6,7,8-hexahydro-2-chloromethyl-3-(2-chlorophenyl)-4-oxo(1)-benzothieno[2,3-d]pyrimidine, and 300 mg of potassium carbonate was added. Further, 310 mg of 1-ethylpiperazine was added dropwise. The mixture was heated under reflux for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give an oily substance, which was purified by silica gel chromatography. The obtained white crystals were recrystallized from ethanol to give 680 mg of the title compound, m.p. 140°-142° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:9]2)=[N:4][CH:3]=1.[NH2:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:22]=2[N:23]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[O:15]1[CH2:16][CH2:17][N:12]([C:8]2[N:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[CH:3][C:2]([C:25]2[CH:26]=[CH:27][C:21]4[O:20][C:19]([NH2:18])=[N:23][C:22]=4[CH:24]=2)=[CH:11]3)[CH2:13][CH2:14]1
Reactant: Nc1nc2cc(B(O)O)ccc2o1
Reactant: Brc1cnc2ccc(N3CCOCC3)nc2c1
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: O
Solvent: C1COCCO1
Product: Nc1nc2cc(-c3cnc4ccc(N5CCOCC5)nc4c3)ccc2o1
Yield: 67.2 %

Procedure:
A mixture of 7-bromo-2-morpholino-1,5-naphthyridine (F-32) (180 mg, 0.6 mmol, 1.0 eq), 2-aminobenzo[d]oxazol-5-ylboronic acid (131 mg, 0.73 mmol, 1.2 eq), Pd(PPh3)4 (71 mg, 0.06 mmol, 0.1 eq), and Na2CO3 (195 mg, 1.8 mmol, 3.0 eq) were dissolved in a mixture of 1,4-dioxane (10 mL) and water (10 mL). The resulting mixture was degassed and back-filled with argon three times and heated at reflux under an argon atmosphere for 2 h. The reaction was complete based on TLC analysis. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (3-5% MeOH-DCM) to afford 5-(6-morpholino-1,5-naphthyridin-3-yl)benzo[d]oxazol-2-amine (73) (140 mg, 67.2% yield). 1H NMR (400 MHz, DMSO-d6) δ: 8.93 (s, 1H), 8.10 (m, 2H), 7.66 (s, 1H), 7.53 (s, 2H), 7.45 (m, 3H), 3.74 (m, 8H); ESI-MS m/z: 348.11 [M+H]+.
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.[NH2:30][C:31]1[C:36]([C:37](=[O:40])[CH2:38][CH3:39])=[CH:35][CH:34]=[C:33]([NH:41][CH2:42][CH2:43][NH2:44])[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37](=[O:40])[CH2:38][CH3:39])=[CH:35][CH:34]=[C:33]([NH:41][CH2:42][CH2:43][NH:44][C:3]2[N:8]3[N:9]=[C:10]([CH:12]4[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]4)[N:11]=[C:7]3[CH:6]=[C:5]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:4]=2)[N:32]=1
Reactant: CCC(=O)c1ccc(NCCN)nc1N
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCC(=O)c1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C4CCN(C(C)C)CC4)nn23)nc1N
Temperature: 120 °C

Procedure:
30 mg (0.07 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 40A), 21 mg (0.09 mmol) of 1-{2-amino-6-[(2-aminoethyl)amino]pyridin-3-yl}propan-1-one hydrochloride (Example 25A) and 75 μl (0.4 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 120° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 21 mg (50% of theory) of the product as a solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:19][C:20]([F:26])([F:25])[S:21](Cl)(=[O:23])=[O:22].CN1CCOCC1>O.C(#N)C>[F:19][C:20]([F:26])([F:25])[S:21]([NH:2][C@@H:3]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CCOC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
Acetonitrile (100 ml) was added to hydrochloride (4.00 g, 14.6 mmol) of ethyl (S)-2-amino-3-(4-nitrophenyl)propionate and trifluoromethylsulfonyl chloride (2.5 ml, 23.5 mmol) and then N-methylmorpholine (3.2 ml, 29.1 mmol) were added. The mixture was stirred at room temperature for 2 hours. Water (100 ml) was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/n-hexane=2/1) to give 2.25 g of ethyl (S)-2-(trifluoromethylsulfonylamino)-3-(4-nitrophenyl)propionate as a yellow solid (42%). This solid (1.97 g, 5.32 mmol) was dissolved in acetic acid. (100 ml) and 10% palladium-carbon (750 mg) was added. The mixture was stirred at room temperature for 66 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite and acetic acid was distilled away from the filtrate under reduced pressure. The residue was washed with water to quantitatively give 1.81 g of ethyl (S)-3-(4-aminophenyl)-2-(trifluoromethylsulfonylamino)propionate as a yellow solid.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[O:22][CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C1C(=O)N([Br:31])C(=O)C1>C(Cl)Cl>[Br:31][C:19]1[S:18][C:17]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])=[C:21]([O:22][CH3:23])[CH:20]=1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sccc3OC)c(C)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3OC)c(C)nc12
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of 8-(1-ethyl-propyl)-3-(3-methoxy-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.78 g, 2.37 mmol) and CH2Cl2 (10 mL) is added NBS (0.44 g, 2.49 mmol). The solution is stirred for 1 hour, washed with water (3×10 mL), concentrated and purified by ISCO column chromatography (5%-15% EtOAc/hexane gradient) to furnish the title compound (0.87 g, 2.13 mmol, 90%). 1H NMR (CDCl3) δ 0.85 (t, J=7.5 Hz, 6H), 1.71-1.89 (m, 4H), 2.46 (s, 3H), 2.52 (s, 3H), 3.25-3.35 (m, 1H), 3.82 (s, 3H), 6.65 (s, 1H), 6.97 (s, 1H). LC/MS (m/z): calcd. for C18H22BrN3OS (M+H)+: 408.1; found: 408.3.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=[O:9])=[O:2].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[CH3:14][O:9][C:8](=[O:10])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([CH:1]=[O:2])[CH:4]=1
Reactant: O=Cc1cccc(OCC(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(C=O)c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
A mixture of (3-formyl-phenoxy)-acetic acid (3.6 g, 20.0 mmol), potassium carbonate (3.30 g, 23.9 mmol) and methyl iodide (1.86 g, 30.0 mmol) in 25 mL DMF was heated to 110° C. for 2 hours and was stirred at room temperature for 16 h. The mixture was diluted with water and the aqueous solution was extracted with EtOAc. The organic solution was washed with water, dried over MgSO4, filtered and concentrated in vacuo. The product was purified via silica gel chromatography (4:1 hexanes: EtOAc) to afford the title compound as a pale yellow oil (3.4 g). 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 7.48 (m, 2H), 7.33 (s, 1H), 7.23 (m, 1H), 4.68 (s, 2H), 3.79 (s, 3H).
Reaction SMILES: Cl[CH:2](Cl)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][S:12]([NH2:15])(=[O:14])=[O:13].[C:16](=[O:19])([O-])O.[Na+]>C(#N)C>[CH3:11][S:12]([NH:15][CH:2]([O:19][C:16]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:14])=[O:13]
Reactant: CS(N)(=O)=O
Reactant: ClC(Cl)Oc1ccccc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CS(=O)(=O)NC(Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of dichlorophenoxymethane (1 g) in acetonitrile (10 mL) was added methanesulfonamide (0.39 g) under ice-cooling, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 1-(N-methanesulfonylamino)-1,1-diphenoxymethane (0.95 g). To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole (50 mg) in tetrahydrofuran (1 mL) was added 1-(N-methanesulfonylamino)-1,1-diphenoxymethane (26 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2-aminoethanol (49 mg), and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.008 mL), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added acetic acid (0.01 mL). The resulting 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 (38 mg).
Reaction SMILES: [CH3:1][C:2]1[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCO>CO.[Pd]>[CH3:1][C:2]1[C:3]([CH2:4][N:5]2[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]2)=[CH:12][CH:13]=[CH:14][C:15]=1[NH2:16]
Reactant: Cc1c(CN2CCN(C)CC2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Cc1c(N)cccc1CN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(2-Methyl-3-nitrobenzyl)-4-methylpiperazine (1.2 g, 4.8 mmol) was dissolved in 50 ml of MeOH, and to this was added a slurry of 10% Pd/C in a minimal amount of EtOH. The reaction mixture was evacuated and purged with H2, and then stirred at room temperature for 3 hours. The mixture was purged with N2 for 30 minutes and then filtered through a pad of celite. Solvent evaporation afforded 2-methyl-3-((4-methylpiperazin-1-yl)methyl)benzeneamine.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(O[CH2:13][C:14]1[CH:19]([C:20]([OH:22])=[O:21])[N:18]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:17]2[S:16][CH:15]=1)(=O)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[OH:2][C:1]1[CH:8]=[C:7]([CH:6]=[CH:5][C:3]=1[OH:4])[CH2:13][C:14]1[CH:19]([C:20]([OH:22])=[O:21])[N:18]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C@H:17]2[S:16][CH:15]=1
Reactant: Oc1ccccc1O
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(Cc3ccc(O)c(O)c3)=CS[C@H]12
Reaction time: 0.25 h

Procedure:
A solution of 1.1 g of pyrocatechol in 6 ml of trifluoroacetic acid is mixed with 0.8 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid and the solution is left to stand for 15 minutes at room temperature. It is diluted with an equal quantity of toluene, the mixture is evaporated to dryness under reduced pressure, and the residue is twice triturated with 30 ml portions of diethyl ether to remove the excess pyrocatechol. The residue is worked up in accordance with the process described in example 6 and yields 3-(3,4-dihydroxybenzyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid which after crystallisation from a mixture of acetic acid ethyl ester and acetone is obtained in the form of colourless crystals, melting point 114°C; thin layer chromatogram (silica gel): Rf = 0.71 (system n-butanol/acetic acid/water, 75:7.5:21), Rf = 0.73 (system n-butanol/acetic acid/water, 67:10:23) and Rf = 0.44 (system n-butanol/ethanol/water, 40:10:50); ultraviolet absorption spectrum (methanol): λmax 222 mμ (ε = 17600), 250 mμ (ε = 6800) and 283 mμ (ε = 3700); infrared absorption spectrum (in mineral oil): characteristic bands at 3.01μ, 5.72μ, 5.87μ and 6.06μ.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][OH:15])[N:10]=[CH:9]2)C=CC=CC=1.ClC(Cl)(Cl)C(=N)O[C:32]([CH3:35])([CH3:34])[CH3:33].B(F)(F)F.CCOCC>C1CCCCC1.ClCCl>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:32]([CH3:35])([CH3:34])[CH3:33])[N:10]=[CH:9]1
Reactant: OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CC(C)(C)OCCc1c[nH]cn1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
2 mmol of 2-(1-triphenylmethyl-1H-imidazol-4-yl)ethanol and 4 mmol of tert-butyl trichloroacetimidate are dissolved in 4 ml of cyclohexane and 2 ml of dichloromethane. After the addition of 120 μl of boron trifluoride etherate, the solution is stirred at 60-70° C. for 18 hours. Filtration of the reaction mixture and evaporation of the solvent are followed by a detritylation in 2 ml of ethanol, 2 ml of acetone and 15 ml of 2N HCl at 70° C. The ethanol and acetone are removed under reduced pressure and triphenylmethanol is extracted with diethyl ether. The aqueous layer is alkalized with ammonia and extracted with diethyl ether. Evaporation of the solvent and final purification by column chromatography (eluent: dichloromethane/methanol, 90:10) yield the product in the form of an oil, which is crystallized in the form of the hydrogen oxalate in ethanol and diethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl.C(OCN1C2N=CN=C(C3C=NN([CH:30]([O:32][CH2:33][CH3:34])[CH3:31])C=3)C=2C=C1)(=O)C(C)(C)C>C(Cl)Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:31][CH2:30][O:32][CH2:33][CH3:34])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: CCOC(C)n1cc(-c2ncnc3c2ccn3COC(=O)C(C)(C)C)cn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOCCn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.4 %

Procedure:
To a solution of 4-bromopyrazole (21, 70.0 g, 0.476 mol) in CH2Cl2 (600 mL) was added a solution of 3.1 M HCl in dioxane (4 mL) and ethyl vinyl ether (18, 41 g, 0.569 mol, 1.2 equiv). The resulting reaction mixture was stirred at room temperature for 3 hrs. The reaction was quenched with aqueous NaHCO3 and the two layers were separated. The organic layer was washed with water, dried over Na2SO4, and concentrated under reduced pressure to dryness to afford 4-bromo-1-(ethoxyethyl)-1H-pyrazole (22, 113 g, 104.3 g theoretical, 97% yield) as an oily (GC purity: 89%), which was directly used in the subsequent reaction without further purification.