Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:23][C:24]([C:26]2[CH:27]=[N:28][N:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:30]=2[CH3:31])=[O:25])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([O:15][Si](C(C)(C)C)(C)C)[CH2:11][CH2:10]1)#[N:2].[H-].[Na+].Br[CH2:42][C:43]([O:45]CC)=[O:44].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([N:23]([C:24]([C:26]2[CH:27]=[N:28][N:29]([C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)[C:30]=2[CH3:31])=[O:25])[CH2:42][C:43]([OH:45])=[O:44])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:10][CH2:11][CH:12]([OH:15])[CH2:13][CH2:14]1)#[N:2]
Reactant: Cc1c(C(=O)Nc2ccc(N3CCC(O[Si](C)(C)C(C)(C)C)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N(CC(=O)O)c2ccc(N3CCC(O)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Yield: 10.2 %

Procedure:
N-(3-Cyano-4-(4-tert-butyldimethylsilyloxypiperidin-1-yl) phenyl)-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide (3.3 g) and sodium hydride (60% content, 0.3 g) were reacted in dimethylformamide (30 ml) under ice-cooling for 1 h. Dimethylformamide solution (10 ml) containing ethyl bromoacetate (1.4 g) was added and the mixture was stirred under ice-cooling for 1 h and, after allowed to warm to roan temperature, stirred for another 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Tetrabutylammonium fluoride (3.0 g), tetrahydrofuran (20 ml) and acetonitrile (20 ml) were added to the residue and the mixture was stirred at 80° C. for 1 h. The solvent was evaporated under reduced pressure. To the residue was added dilute hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A mixed solvent of toluene-ethyl acetate was added to the residue to allow crystallization. The crystals were recrystallized from hydrous isopropanol to give the title compound (0.3 g), melting point: 155–158° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (10 g, 65.12 mmol, 1.0 eq) in THF (300 mL), NaH (5.30 g, 130.24 mmol, 2 eq) was added at 0° C. After 3 h, benzenesulfonyl chloride (22.53 g, 130.24 mmol, 2 eq) was added. The temperature was warmed to RT and continued for 1 h. The reaction mixture was poured into sat. NH4Cl and extracted with EtOAc. The organic layers were dried, concentrated and purified by column chromatography (eluting with 10% EtOAc in PE) to afford 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine as brown solid (4.5 g, 24% in yield)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[S-:18].[Li+].CCOCC.C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[N+:8]([C:7]1[CH:6]=[CH:5][C:4]([C:11](=[O:13])[CH3:12])=[CH:3][C:2]=1[S:18][C:17]1[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=1[C:15]([F:14])([F:23])[F:24])([O-:10])=[O:9]
Reactant: FC(F)(F)c1ccccc1[S-]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1ccc([N+](=O)[O-])c(Sc2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3'-chloro-4'-nitroacetophenone (2.7 g) in toluene (50 ml) was added to a stirred solution of lithium 2-(trifluoromethyl)thiophenoxide [4.4 g; Aust. J. Chem. 32 2313 (1979)]in ether (142 ml) at 0° C. The mixture was stirred at room temperature for 2 hours and refluxed for 20 minutes. The resulting mixtures were added ethyl acetate and water, and the organic layer was washed with water, dried and evaporated. The oily residue was purified by column chromatography on silica gel (70 g) eluting with toluene to give a yellow oil of 4'-nitro-3'-[2-(trifluoromethyl)phenylthio]acetophenone (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:26])C.ClCCl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:26]
Reactant: CC(=O)O
Reactant: N#Cc1ccc(C(F)(F)F)cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=Cc1ccc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
Dissolve 2-chloro-4-trifluoromethylbenzonitrile (405 mg, 1.97 mmol) in anhydrous toluene (7 mL) and cool in a dry ice/ethanol bath. Add diisobutylaluminum hydride (DIBAL) (3.94 mL, 3.94 mmol, 1.0 M in toluene) slowly. Stir 30 min. Warm to room temperature, add acetic acid (2 mL) and wafer (10 mL) and stir for 2 hours. Extract the aqueous layer with ethyl acetate twice. Wash the organic layer with potassium sodium tartrate solution (Rochelle salt) twice. Dry (magnesium sulfate), filter, and concentrate to give a residue. Chromatograph the residue on silica gel eluting with a gradient of 100:0 to 1:1 hexanes:dichloromethane to give 2-chloro-4-trifluoromethylbenzaldehyde (123 mg, 30%). 1H NMR (400 MHz, CDCl3) δ 10.52 (s, 1H), 8.05 (d, 1H, J=8.0 Hz), 7.75 (s, 1H), 7.66 (d, 1H, J=8.0 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:14]2[C:6]([N:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:5][C:4]2[CH:15]=[C:16]3[C:21]([C:3]1=2)=[CH:20][CH2:19][CH:18]=[CH:17]3.I[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.S(=O)(O)[O-].[Na+].C(C1C=C(C(C)(C)C)C=C(C(O)=O)C=1O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>[Cu].C(C1C=CC=CC=1)CCCCCCCCCCC>[CH3:1][C:2]1([CH3:22])[C:14]2[C:6]([N:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:5][C:4]2[CH:15]=[C:16]3[C:21]([C:3]1=2)=[CH:20][CH:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:18]=[CH:17]3
Reactant: Ic1ccccc1
Reactant: CC1(C)C2=C(C=C3C=CCC=C32)C=C2N=c3ccccc3=C21
Agent: [Cu]
Agent: CC(C)(C)c1cc(C(=O)O)c(O)c(C(C)(C)C)c1
Agent: CCCCCCCCCCCCc1ccccc1
Product: CC1(C)C2=C(C=C3C=CC(c4ccccc4)C=C32)C=C2N=c3ccccc3=C21
Temperature: 170 °C
Reaction time: 10 h
Yield: 88.3 %

Procedure:
The resulting 12,12-dimethyl-10,12-dihydroindeno[2,1-b]carbazole (7.8 g), iodobenzene (3.7 ml), sodium bisulfite (0.43 g), a copper powder (0.17 g), 3,5-di(tert-butyl)salicylic acid (0.69 g), potassium carbonate (5.71 g), and dodecylbenzene (10 ml) were added to a nitrogen-substituted reaction vessel, heated, and stirred at 170° C. for 10 hours. The mixture was cooled to 100° C., extracted by adding toluene (100 ml), concentrated under reduced pressure, and crystallized using n-hexane (30 ml) to obtain a pale yellow powder of 12,12-dimethyl-10-phenyl-10,12-dihydroindeno[2,1-b]carbazole (8.73 g; yield 88.3%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([Mg]Br)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Mg].BrC1C=CC(C(C)C)=CC=1.[CH2:23]([O:26][C:27]1[CH:28]=[CH:29][C:30]([N+:35]([O-:37])=[O:36])=[C:31]([CH:34]=1)[CH:32]=[O:33])[CH:24]=[CH2:25].[Cl-].[NH4+]>C1COCC1>[CH2:23]([O:26][C:27]1[CH:28]=[CH:29][C:30]([N+:35]([O-:37])=[O:36])=[C:31]([CH:32]([C:7]2[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[OH:33])[CH:34]=1)[CH:24]=[CH2:25]
Reactant: CC(C)c1ccc([Mg]Br)cc1
Reactant: C=CCOc1ccc([N+](=O)[O-])c(C=O)c1
Agent: CC(C)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCOc1ccc([N+](=O)[O-])c(C(O)c2ccc(C(C)C)cc2)c1

Procedure:
A solution of 4-isopropylphenylmagnesium bromide prepared from 2.35 g (96.5 mmol) magnesium and 18.15 g (96.5 mmol) 1-bromo-4-isopropylbenzene in 80 ml THF is added slowly at −78° C. to a solution of 20 g (96.5 mmol) 5-allyloxy-2-nitro-benzaldehyde in 200 ml THF. After allowing the reaction mixture to warm up to r.t. saturated aqueous ammonium chloride solution is added. Extraction with ethyl acetate followed by chromatographic purification on silica (hexane/ethyl acetate) yields (5-allyloxy-2-nitro-phenyl)-(4-isopropyl-phenyl)-methanol.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4](O)=[N:3][CH:2]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:4]1[C:5]2[CH:9]=[CH:8][NH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2[nH]ccc12
Product: Clc1ncnc2[nH]ccc12
Temperature: 25 °C
Yield: 42 %

Procedure:
To 7H-pyrrolo[2,3-d]pyrimidin-4-ol (0.425 g, 3.14 mmol) was added phosphorus oxychloride (4 ml). The mixture was heated at reflux for 90 minutes and then cooled to room temperature. The solution was poured onto cracked ice, and extracted with chloroform (3×50 ml) and ethyl acetate (100 ml). The extracts were then dried and concentrated, and the residue obtained triturated with hot ethyl acetate (200 ml) to yield the title compound (0.204 g, 42%).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>C(N(CC)C=O)C.CN(C)C=O>[Si:10]([O:31][C:28]1[CH:29]=[CH:30][C:25]([Br:24])=[CH:26][CH:27]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: CCN(C=O)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc(Br)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
11.06 g (162.5 mmol) of imidazole in 30 ml of diethylformamide are added dropwise at room temperature to 35.24 g (130.0 mol) of tert-butyl-chlorodiphenylsilane and 11.25 g (65.0 mol) of 4-bromophenol in 150 ml of dimethylformamide. After the reaction mixture has been stirred at room temperature for one hour, it is poured into 1000 ml of 5% strength by weight aqueous sodium hydrogencarbonate solution and extracted twice with 400 ml of dichloromethane, and the organic phase is washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. Chromatographic purification (silica gel/hexane: ethyl acetate 8:2) gives 23.40 g of 4-bromophenyl tert-butyldiphenylsilyl ether. ##STR29##
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9]([C:11]2[C:12]([CH3:23])=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=2)S[CH:16]=[CH:15][C:14]3=[O:22])=[O:10])[CH:5]=[N:4]1)[CH3:2].C(OO)(=O)C.C(O)(=O)C.[S:33]([O-:36])([O-])=[O:34].[Na+].[Na+].C(OO)(=O)C>C(Cl)(Cl)Cl.O>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9]([C:11]2[C:12]([CH3:23])=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=2)[S:33](=[O:36])(=[O:34])[CH:16]=[CH:15][C:14]3=[O:22])=[O:10])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(C(=O)c2cc(C)c3sccc(=O)c3c2C)c1O
Reactant: O=S([O-])[O-]
Agent: CC(=O)OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCn1ncc(C(=O)c2cc(C)c3c(c2C)C(=O)C=CS3(=O)=O)c1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 77 %

Procedure:
0.39 Gram (1.2 mmol) of 6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-5,8-dimethylthiochrom-2-en-4-one was dissolved in 4 ml of chloroform, and 0.62 g (2.6 mmol) of a 32 wt % peracetic acid/acetic acid solution was added. The mixture was allowed to react at room temperature for 5 hours, and then allowed to react at 50° C. for 2 hours and further stirred at room temperature for 17 hours. After the reaction, the reaction mixture was diluted with water, and a 1 wt % sodium sulfite aqueous solution was added to decompose excess peracetic acid. An organic substance was extracted with ethyl acetate, washed with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 0.33 g (yield 77%) of the titled compound. Table 24 shows the physical property data of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15]([OH:17])=O)=[C:10]2[CH:9]=[CH:8][CH:7]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:46]([O:50][C:51](=[O:60])[NH:52][C:53]([CH3:59])([CH2:56][CH2:57][CH3:58])[CH2:54][NH2:55])([CH3:49])([CH3:48])[CH3:47].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:46]([O:50][C:51](=[O:60])[NH:52][C:53]([CH3:59])([CH2:56][CH2:57][CH3:58])[CH2:54][NH:55][C:15]([C:14]1[C:13]([CH3:18])=[N:12][N:11]2[C:6]([O:5][CH2:4][C:3]3[C:2]([F:1])=[CH:22][CH:21]=[CH:20][C:19]=3[F:23])=[CH:7][CH:8]=[CH:9][C:10]=12)=[O:17])([CH3:49])([CH3:48])[CH3:47]
Reactant: Cc1nn2c(OCc3c(F)cccc3F)cccc2c1C(=O)O
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 100 mg (0.19 mmol, 61% pure) of 7-[(2,6-difluorobenzyl)oxy]-2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 130A in 4 ml of tetrahydrofuran was admixed with 39.1 mg (0.287 mmol) of 1-hydroxybenzotriazole and 74.3 mg (0.287 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The resulting solution was stirred at room temperature for 15 min, and then 62.2 mg (0.287 mmol) of rac-(1-amino-2-methylpentan-2-yl)carbamic acid tert-butyl ester from Example 152A were added, followed by 0.1 ml (0.575 mmol) of N,N-diisopropylethylamine After the addition, the mixture was stirred at room temperature for a further 15 h. The solvent was drawn off under reduced pressure and the residue was partitioned between dichloromethane (10 ml) and water (10 ml). The organic phase was removed and washed with water and saturated aqueous sodium chloride solution, dried with a phase separation cartridge and concentrated under reduced pressure, which gave 45 mg (24% of theory, 53% pure) of the target compound.
Reaction SMILES: C(N(CC)CCCN1C2C(=C(Cl)C=CC=2)C(N)=N1)C.C1(=O)[N:24]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][N:26]=2)C(=O)C2=CC=CC=C12.Br.[CH3:41][CH:42]([N:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)[CH2:43][CH2:44]Br.C1(=O)N(C2C3C(=CC=CC=3Cl)NN=2)C(=O)C2=CC=CC=C12.Br.BrCCCN(CC)CC>>[N:46]1([CH:42]([CH3:41])[CH2:43][CH2:44][N:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:25]([NH2:24])=[N:26]2)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: CC(CCBr)N1CCCCC1
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccccc12
Agent: Br
Agent: CCN(CC)CCCBr
Agent: CCN(CC)CCCn1nc(N)c2c(Cl)cccc21
Product: CC(CCn1nc(N)c2ccccc21)N1CCCCC1
Yield: 151 %

Procedure:
The same procedures for preparing 1-(3-diethylaminopropyl)-3-amino-4-chloroindazole as described in Example 89 were repeated except that 8 g of 3-phthalimidoindazole and 10.5 g of 1-(1-methyl-3-bromopropyl)-piperidine hydrobromide were employed instead of the 3-phthalimido-4-chloroindazole and the 3-bromopropyldiethylamine hydrobromide, respectively. As a result, 12.5 g of 1-(3-piperidinobutyl)-3-aminoindazole was obtained.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:28]1[N:29]=[C:30]([NH:33]C(=O)C(F)(F)F)[S:31][CH:32]=1)[C:5]([NH:7][CH:8]1[C:26](=[O:27])[N:10]2[C:11]([C:23]([OH:25])=[O:24])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6].[OH-].[Na+].O.Cl>C(O)C.C(OCC)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)[C:5]([NH:7][CH:8]1[C:26](=[O:27])[N:10]2[C:11]([C:23]([OH:25])=[O:24])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(N)n1
Yield: 47.5 %

Procedure:
A solution of 7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.3 g.) in a 0.1 N aqueous solution of sodium hyroxide (10.5 ml.) was warmed at 45° C. for 6 hours. Water (15 ml.) and ethyl acetate (30 ml.) were added to the reaction mixture and the resulting mixture was adjusted to pH 3.5 with 10% hydrochloric acid. The aqueous layer was separated, washed with ethyl acetate and adjusted to pH 5.0 with an aqueous solution of sodium bicarbonate. The aqueous solution was subjected to column chromatography on Amberlite XAD-2 (20 ml.) (prepared by Rohm & Haas Co.) using 10% ethanol as developing solvent. The eluate containing object compound was collected and lyophilized to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.12 g.).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)=[O:5])C.[H-].[Na+].I[CH3:21]>CN(C=O)C.CCCCCCC>[CH3:21][N:7]1[C:8]2[C:13](=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:3])=[O:5]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: Cn1c(C(=O)O)cc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-Nitro-1H-indole-2-carboxylic acid ethyl ester (234 mg, 1 mmol) was dissolved in DMF (2 ml). NaH (32 mg, 1.4 mmol) was added as a suspension in heptane (0.5 ml) and the mixture was stirred at room temperature for 10 min. Iodomethane (170 mg, 1.2 mmol) was added drop-wise and the solution was left stirring for 1 h. During this reaction, hydrolysis occurred. The reaction mixture was quenched with H2O (2 ml) and washed with EtOAc (3×1 ml). The aqueous layer was acidified to pH 1 with conc. HCl until a white precipitate formed and extracted with EtOAc (3×1 ml). These organic layer were combined, dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])[O:3][C:2]1=O.[NH:12]([CH2:14]C(O)=O)[CH3:13]>CS(C)=O.C(OCC)(=O)C>[CH3:13][N:12]1[C:4](=[O:10])[C:5]2[S:9][CH:8]=[CH:7][C:6]=2[NH:1][C:2](=[O:3])[CH2:14]1
Reactant: O=c1[nH]c2ccsc2c(=O)o1
Reactant: CNCC(=O)O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN1CC(=O)Nc2ccsc2C1=O
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A mixture of 30.0 g (177 mmol) of 2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione and 17.3 g (195 mmol) of sarcosine in 100 ml of dimethyl sulphoxide is stirred at 110° C. for 1.5 hours. The dark brown coloured solution is poured into ca 600 ml of ice/water. The separated oil is taken up in ca 200 ml of ethyl acetate and the aqueous phase is evaporated in vacuo until crystallisation begins. The mixture is cooled in an ice-bath for ca 3 hours and the separated material is filtered off under suction and washed with a small amount of water. After drying on a rotary evaporator, there is obtained 3,4-dihydro-4-methyl-2H-thieno[3,2-e][1,4]diazepine-2,5(1H)-dione of melting point 270°-272° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:17])=[CH:18][CH:19]=1)([O-:10])=[O:9]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1ccc([N+](=O)[O-])cc1
Yield: 97.5 %

Procedure:
Using aniline (1.50 ml, 16.5 mmol) and 4-nitrobenzoic acid (1.77 g, 10.5 mmol), the procedure of Reference Example 16 was repeated to obtain 2.48 g (97.5%) of the title compound in the form of colorless powder.
Reaction SMILES: C[O-].[Na+].[Na].[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[N+:25]=[N-:26]>CO.O>[N:24](/[C:27](=[CH:17]\[C:16]1[CH:19]=[CH:20][C:13]([O:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=1)/[C:28]([O:30][CH3:31])=[O:29])=[N+:25]=[N-:26]
Reactant: O=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: COC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)/C(=C/c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 5 h
Yield: 58.7 %

Procedure:
Under argon, to a sodium methoxide solution (prepared from 2.5 g (108.7 mmol) of sodium and 70 ml of methanol) a mixture of 6.1 g (23.7 mmol) of 4-benzyloxy-3-nitrobenzaldehyde and 11.2 g (97.3 mmol) of methyl azidoacetate in 100 ml of methanol is added at 0° C. The mixture is stirred at 0° C. for 5 h, then diluted with 350 ml of water, the precipitated crystalls were filtered off, washed with water and dried to yield 4.93 g (59%) of the title compound. Mp.: 95-96° C. (water).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH3:21])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:22][CH2:23][C:24]([OH:26])=O)=[CH:5][C:4]=2[N:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH3:21])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:22][CH2:23][C:24]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[O:26])=[CH:5][C:4]=2[N:3]=1
Reactant: CCc1nc2c(N)nc3cc(CCC(=O)O)ccc3c2n1CC(C)(C)O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3cc(CCC(=O)N4CCOCC4)ccc3c2n1CC(C)(C)O
Reaction time: 0.5 h

Procedure:
3-[4-Amino-2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoic acid (500 mg, 1.4 mmol), chloroform (100 mL) and 1-hydroxybenzotriazole (575 mg, 4.26 mmol) were combined and then stirred for 30 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (1.00 g, 5.2 mmol) was added and the reaction was stirred for 30 minutes. Morpholine (10 mL) was added in one portion. After 4 hours, 1% aqueous sodium carbonate (100 mL) was added and the mixture was stirred. The fractions were separated and the organic fraction was sequentially washed with 1% aqueous sodium carbonate (50 mL), dried (MgSO4), filtered, and concentrated to a white solid. Recrystallization from acetonitrile provided 225 mg of 3-[4-amino-2-ethyl-1-(2-hydroxy-2-methyl-propyl)-1H-imidazo[4,5-c]quinolin-7-yl]-1-(morpholin-4-yl)propan-1-one as a white solid, mp 237-239° C.