Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.Cl.C[O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[CH:8]=[C:7]([CH3:13])[C:6]=1[C:14](=O)[CH3:15].C(SCCC1(O)C(C)=C(C)C=C(C)C1)C>CN(C)C=O>[CH3:11][C:10]1[C:9]([CH3:12])=[CH:8][C:7]([CH3:13])=[C:6]([CH:14]=[CH2:15])[C:5]=1[OH:4]
Reactant: COc1c(C)c(C)cc(C)c1C(C)=O
Agent: CCSCCC1(O)CC(C)=CC(C)=C1C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1c(C)cc(C)c(C)c1O
Temperature: 25 °C
Yield: 16.2 %

Procedure:
Under nitrogen atmosphere, in dry N,N-dimethylformamide (8 mL) was suspended 270 mg (6.75 mmol) of 60% sodium hydride, and 0.60 mL (8.10 mmol) of ethanethiol was gradually added dropwise to the suspension. After stirring for 15 minutes, 400 mg (2.27 mmol) of 3-methoxy-1,2,5-trimethyl-4-vinylbenzene obtained in (4) and dissolved in dry N,N-dimethylformamide (1.5 mL) was added to the mixture, and the resulting mixture was refluxed for 1 hour. After cooling to room temperature, the reaction mixture was poured into water, made acidic by adding hydrochloric acid, and extracted with hexane. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane:ethyl acetate=20:1) and by preparative thin-layer chromatography (available from MERCK CO., 1.05744, developed by hexane:ethyl acetate=8:1) to obtain 63.0 mg (0.389 mmol, Yield from 1-(2-methoxy-3,4,6-trimethylphenyl)ethanone: 16.2%) of 2,3,5-trimethyl-6-vinylphenol and 330 mg (1.47 mmol, Yield from 1-(2-methoxy-3,4,6-trimethylphenyl)ethanone: 61.4%) of 2-[1-(ethylsulfanylethyl]-3,5,6-trimethylphenol.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].CN([CH:9]=[O:10])C.[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)[CH2:12][CH3:13].C([O-])(=O)C.[Na+]>O>[Cl:3][C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:12]([CH3:13])[CH:9]=[O:10]
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(C=O)=C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.2 mol (110 mL) of POCl3 was added at 0° C. to a 2.8 mol (216 mL) of DMF (excess of DMF used as solvent). At the end of the addition, the mixture was allowed to warm to room temperature and stirred for 1 h. Then it was cooled again to 0° C. and treated with 1 mol (134 g) of propiophenone. The resulting reaction mixture was allowed to reach room temperature and stirred overnight. Then it was poured into a mixture of ice and water, added of sodium acetate and extracted with CHCl3 (3×150 mL). The organic phase was separated, washed with water until neutral pH, dried over MgSO4 and evaporated off to dryness. The residue was distilled in vacuo, b.p. 120° C./10 torr. Yield 163 g (90%).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[C:18]([O:22][C:23](=[O:46])[C:24]([CH3:45])([CH3:44])[CH2:25][C:26]1[CH:43]=[CH:42][C:29]([CH2:30][N:31]([CH2:36][C:37]2[O:38][CH:39]=[CH:40][CH:41]=2)[CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1)([CH3:21])([CH3:20])[CH3:19].[CH3:47][C:48]1[CH:54]=[C:53]([CH3:55])[CH:52]=[CH:51][C:49]=1[NH2:50]>CN(C)C1C=CN=CC=1.CN(C)C=O.O>[CH3:47][C:48]1[CH:54]=[C:53]([CH3:55])[CH:52]=[CH:51][C:49]=1[NH:50][C:33](=[O:34])[CH2:32][N:31]([CH2:30][C:29]1[CH:42]=[CH:43][C:26]([CH2:25][C:24]([CH3:44])([CH3:45])[C:23]([O:22][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:46])=[CH:27][CH:28]=1)[CH2:36][C:37]1[O:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1ccc(N)c(C)c1
Reactant: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(CN(CC(=O)O)Cc2ccco2)cc1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1ccc(NC(=O)CN(Cc2ccc(CC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)c(C)c1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
At 0° C., 88 mg (0.648 mmol) of 1-hydroxy-1H-benzotriazole, 124 mg (0.648 mmol) of 1-ethyl-3-(3-dimethylamino)propylcarbodiimide hydrochloride, 151 mg (1.494 mmol) of N-methylmorpholine and 3 mg (0.025 mmol) of 4-dimethylaminopyridine are added to a solution of 200 mg (0.498 mmol) of N-[4-(3-tert-butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-(2-furylmethyl)glycine (Example I-12) and 91 mg (0.747 mmol) of 2,4-dimethylaniline in 8 ml of dimethylformamide, and the solution is stirred at this temperature for 1 h. The mixture is then stirred at room temperature for 9 h and then admixed with 10 ml of water. The aqueous phase is extracted 2× with ethyl acetate and the combined organic phases are washed with 1 N hydrochloric acid, sat. NaHCO3 solution and sat. NaCl solution, dried over sodium sulphate and freed from the solvent under reduced pressure. Chromatographic purification of the residue on silica gel (cyclohexane/ethyl acetate 10:1→3:1) gives 228 mg (91%) of tert-butyl 3-(4-{[(2-(2,4-dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[CH:9])[CH:5]=[CH:6][CH:7]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:10]([O:1][C:2]1[CH:3]=[C:4]([C:8]#[CH:9])[CH:5]=[CH:6][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#Cc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#Cc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 609 %

Procedure:
A mixture of 3-hydroxy-1-ethynylbenzene (4.36 g, 37 mmol), benzylbromide (6.95 g, 4.1 mmol) and K2CO3 (10.2 g, 7.4 mmol) in acetanitrile (50 ml) is stirred at room temperature for 24 hr. The insoluble material is removed by filtration and filtrate is concentrated. The crude material is purified by flash chromatography (silica gel, hexane/EtOAc:95/5) to afford the title compound as a clear oil 5.2 g (68%). 1HNMR (400 MHz, CDCl3): δ (ppm) 3.05 (s, 1H), 5.05 (s, 2H), 6.98 (d, 1H) 7.00-7.50 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[S:15][CH:16]=1)[CH:8]=[C:7]2O.O=P(Cl)(Cl)[Cl:30].CO.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[Cl:30][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[C:3]([O:21][CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]2[N:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[S:15][CH:16]=2)[CH:8]=1
Reactant: COC(COc1ccc2c(O)cc(-c3csc(C(C)C)n3)nc2c1Cl)OC
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: COC(COc1ccc2c(Cl)cc(-c3csc(C(C)C)n3)nc2c1Cl)OC
Temperature: 80 °C
Yield: 49.9 %

Procedure:
8-Chloro-7-(2,2-dimethoxy-ethoxy)-2-(2-isopropyl-thiazol-4-yl)-quinolin-4-ol (502 mg, 1.20 mmol) was dissolved in pyridine (10 mL). POCl3 (2.29 mL, 25.0 mmol) was added slowly. The reaction was heated at 80° C. for 4 hours. The reaction was cooled to 0° C. and methanol (5 mL) was added. The reaction was neutralized with a sat NaHCO3(aq) solution. The product was extracted with EtOAc (3×20 mL). The combined organics were dried with Na2SO4, filtered and was concentrated. 4,8-Dichloro-7-(2,2-dimethoxy-ethoxy)-2-(2-isopropyl-thiazol-4-yl)-quinoline (256 mg, 49%) was isolated by silica gel chromatography as a yellow solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)=[O:19])[C:13]=1[OH:34]>O1CCCC1>[CH:1]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)=[O:19])[C:13]=1[OH:34])=[O:3]
Reactant: Nc1ccnc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1O
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CNc1ccnc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1O
Yield: 78 %

Procedure:
There is heated at reflux 61.2 mg of acetic anhydride and 27.6 mg of formic acid for 4 hours and 46 mg of 4-amino-3-hydroxy-N-para-phenoxyphenylpicolin-amide of Example 2 is added, dissolved in 5 ml of tetrahydrofuran. After 8 hours at reflux, the reaction mixture is concentrated and purified by chromatography to give 39 mg of a yellow solid MP 208° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[C:15]([Cl:21])[CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:7]([C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)=[O:9])=[C:15]([Cl:21])[CH:14]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: COc1ccc(C(=O)O)cn1
Product: COc1ccc(C(=O)Cc2ccc(Br)cc2Cl)cn1

Procedure:
In analogy to Example 165, step 1, 6-methoxynicotinic acid was converted to the acid chloride and subsequently reacted with 4-bromo-1-bromomethyl-2-chloro-benzene to give the title compound (not completely pure) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[C:12](Cl)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(=O)([O-])O.[Na+].Cl>O.CCOCC>[C:12]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(C(=O)O)ccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 45.3 %

Procedure:
4-Amino-3-methylbenzoic acid (5.0 g) was suspended in water (80 ml) and, thereafter, an ether solution (20 ml) of carbobenzoxychloride (3.7 g) and sodium hydrogen carbonate (3.6 g) were alternately added to the suspension under cooling with ice. Following stirring for 2.5 h at room temperature, an ether solution (95 ml) of carbobenzoxychloride (3.7 g) and sodium hydrogen carbonate (7.2 g) were further added alternately under cooling with ice, and the mixture was stirred for 1.5 h at room temperature. After rendering the reaction solution acidic with 4N HCl, the separating insoluble matter was recovered by filtration. The recovered solids were vacuum-dried to yield the end product (2.8 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[C:19]([NH2:22])[CH:18]=2)=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH:18]=2)=[CH:15][CH:16]=1
Reactant: O=C(Cl)CCCCBr
Reactant: COc1ccc(-c2cc(N)n[nH]2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2cc(NC(=O)CCCCBr)n[nH]2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 5-bromovaleryl chloride (2.1 mL, 15.7 mmol) in dry dimethylacetamide (DMA) (35 mL) was cooled to −10° C. (ice water bath) under N2; a solution of 5-(4-methoxy-phenyl)-1H-pyrazol-3-ylamine (3.0 g, 15.7 mmol) and diisopropylethylamine (2.74 mL, 15.7 mmol) in dry DMA (15 mL) was added over 30 min. After two hours at −10° C., LCMS shows completion of the reaction (acylation on the pyrazole ring was also detected). The reaction was quenched by addition of H2O (ca. 50 mL), and the thick white precipitate formed upon addition of water is recovered by filtration. When the reaction was allowed to reach room temperature before quenching, a putative exchange of Br with Cl caused reactivity problems in subsequent steps. Washing with Et2O (3×10 mL) efficiently removed the byproduct (acylation on pyrazole ring). 4.68 g of the title compound was obtained as a white powder (13.3 mmol, 85% yield). Mp=149.5-151.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[Br-:10].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>O.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([Br:10])[C:5]([CH3:8])=[CH:4][C:3]=1[OH:9]
Reactant: Cc1ccc(C)c(O)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(Br)c(C)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a stirred suspension of 2,5-dimethyl phenol (5.0 g, 40.9 mmol) in H2O (150 mL), at room temperature was added tetrabutylammonium tribromide (19.9 g, 41.39 mmol) in CHCl3 (150 mL). The reaction mixture was stirred for 2 h at rt, the organic layer was separated and dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane-ethyl acetate (1:5) to afford 2,5-dimethyl-4-bromophenol as a brown solid (6.2 g, 76%); 1H NMR (300 MHz, DMSO-d6): δ 9.47 (s, 1 H), 7.24 (s, 1 H), 6.74 (s, 1 H), 2.21 (s, 3 H), 2.07 (s, 3 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-ethyl acetate (9:1); Rf=0.52.
Reaction SMILES: [C:1]1([CH:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][NH:20]N.[S]>>[C:1]1([CH:7]([C:8]2[NH:20][CH2:19][CH2:18][NH:17][N:9]=2)[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC(Cc1ccccc1)c1ccccc1
Reactant: NCCNN
Agent: [S]
Product: c1ccc(CC(C2=NNCCN2)c2ccccc2)cc1

Procedure:
A process for preparing 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine which comprises reacting benzyl cyanide with benzyl chloride to produce 2,3-diphenylpropionitrile and cyclizing the 2,3-diphenylpropionitrile with 2-aminoethylhydrazine in the presence of a catalytic amount of elemental sulfur to give 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[CH2:29][OH:30])[CH2:6][NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:25])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:23])[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:24])[CH:13]=1.[CH2:31]([Mg]Br)[CH3:32]>C1COCC1>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:11]([CH3:25])=[CH:10][CH:9]=[C:8]([NH:7][CH2:6][C:5]3[CH:26]=[CH:27][C:28]([CH2:29][OH:30])=[C:3]([CH2:2][OH:1])[CH:4]=3)[CH:13]=2)=[C:15]([CH3:24])[CH:16]=1)([OH:23])[CH2:31][CH3:32])[CH3:22]
Reactant: CC[Mg]Br
Reactant: CCC(=O)c1ccc(-c2cc(NCc3ccc(CO)c(CO)c3)ccc2C)c(C)c1
Solvent: C1CCOC1
Product: CCC(O)(CC)c1ccc(-c2cc(NCc3ccc(CO)c(CO)c3)ccc2C)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
450 mg (1.1 mmol) of 1-{5′-[3,4-bis(hydroxymethyl)benzylamino]-2,2′-dimethylbiphenyl-4-yl}-1-propanone are dissolved in 30 ml of THF. 1.5 ml (4.5 mmol) of ethylmagnesium bromide are added and the medium is stirred at room temperature for 1 hour. After the usual work-up, the residue is purified by chromatography on silica gel (eluent: 1 heptane/1 ethyl acetate). A white solid is obtained (m=130 mg; Y=27%).
Reaction SMILES: Cl.O.[C:3]([NH:7][C:8]([C@@H:10]1[CH2:15][N:14](C=O)[CH2:13][CH2:12][N:11]1[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[O:9])([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C>CC(C)=O>[C:3]([NH:7][C:8]([C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][N:11]1[C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)NC(=O)[C@@H]1CN(C=O)CCN1C(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)NC(=O)[C@@H]1CNCCN1C(=O)C(F)(F)F
Temperature: 20 °C
Yield: 81.1 %

Procedure:
A mixture of 50.5 g (430 mmol) of 32% hydrochloric acid and 50 ml of water was added to 32.0 g (103 mmol) of (S)-4-formyl-1-(trifluoroacetyl) piperazine-2-carboxylic acid tert-butylamide in 200 ml of acetone and the resulting mixture was heated at 60° to 65° C. for 2.5 hours. After cooling to 20° C., neutralization was carried out with triethylamine in such a way that the temperature remained below 30° C. The solvent was evaporated off, and 100 ml of water and 200 ml of methyl isobutyl ketone were added. At 50° C. the phases were separated and the aqueous phase was re-extracted with twice 100 ml of methyl isobutyl ketone. The combined organic extracts were dried over magnesium sulfate and evaporated to dryness to give 23.5 g (80%) of the title compound in the form of a slightly reddish solid. Recrystallization from toluene/diisopropyl ether gave the title compound in the form of a white crystalline powder. The melting point of the title compound was: 143.5° to 144.2° C. Other data concerning the title compound was:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14][NH2:15])=[CH:4][CH:3]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].[CH3:35][C:36]1[NH:40][CH:39]=[N:38][C:37]=1[CH2:41][S:42][CH2:43][CH2:44][NH2:45]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][NH:15][C:23]([NH:45][CH2:44][CH2:43][S:42][CH2:41][C:37]2[N:38]=[CH:39][NH:40][C:36]=2[CH3:35])=[O:24])[CH3:16])=[CH:4][CH:3]=1
Reactant: CN(CCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1[nH]cnc1CSCCNC(=O)NCCCN(C)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.8 g (2.5 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,3-propanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.5 g (2.9 mmol) of 2-[[(5-methylimidazol-4-yl)methyl]thio]ethaneamine as starting materials. Working up by chromatography (eluant: ethyl acetate/methanol 9+1) analogously to Example 63 yields the purified title compound in the form of a crystalline solid; m.p.(ether): 102°-104° C.; MS (+FAB method): m/z (rel. int.[%])=515 ([M+H]+, 10), 95 (75), 230 (100).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br-:22].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl.CO.ClCCl>[Br:22][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)CBr)cc2)CCC1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 150.1 %

Procedure:
To a solution of tert-butyl (1-(4-acetylphenyl)cyclobutyl)carbamate (0.1 g, 1 eq.) in chloroform (3.5 mL) and methanol (1.5 mL) was added the tetrabutyl ammonium tribromide (0.175 g, 1.05 eq.). The mixture was stirred at 40° C. for 90 minutes. The reaction mixture was diluted with dichloromethane (10 mL), washed with water (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by column chromatography (10% ethyl acetate in dichloromethane), giving tert-butyl (1-(4-(2-bromoacetyl)phenyl)cyclobutyl)carbamate (0.1 g, 78%) as a colorless oil. LCMS: 312 [M−tBu+H], 314 [M−tBu+H].
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[CH:70]=[N:69][N:68]([CH3:71])[N:67]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.Cl.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:64][S:65][C:66]4[CH:70]=[N:69][N:68]([CH3:71])[N:67]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: Cn1ncc(SCC2=C(C(=S)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(=O)OC(C)(C)C)n4)[C@H]3SC2)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Solvent: O
Product: Cn1ncc(SCC2=C(C(O)=S)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(N)n4)[C@H]3SC2)n1
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(2-methyl-1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (1.39 g: 1.34 mMol.) in a mixture anisole (5 ml) and nitromethane (20 ml) is added dropwise a solution of aluminum chloride (1.43 g: 10.8 mMol.) in anisole (5 ml) at -40° C. After stirring at -30° to -40° C. for 1 hour, the mixture is diluted with 1N-hydrochloric acid (11 ml) and water and washed with ethyl acetate. The aqueous layer is concentrated under reduced pressure to remove organic solvents and passed through a column of styrene-divinylbenzene copolymer adsorbent. The product is eluted with methanol-water (4:1) to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(2-methyl-1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid as pale yellow powder (534 mg). Yield: 75%.
Reaction SMILES: [CH2:1]([CH:5]([C:9](O)=O)[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3].C(OCC)(=O)C.C(NCC)C.Cl>CCOCC>[CH2:1]([C:5](=[CH2:9])[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC(C(=O)O)C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: C=C(CC(C)C)C(=O)O
Temperature: 5 °C

Procedure:
To a solution of 72.9 g (0.455 mol) of isobutylmalonic acid in 650 ml of ethyl acetate 54.2 ml (38.3 g, 0.524 mol) of diethylamine was added dropwise at 5° C. To the obtained suspension 19.2 g (0.640 mol) of paraform was added. The resulting mixture was refluxed for 5 h, then cooled to 5° C., and 350 ml of ether and 1000 cm3 of 2M HCl were added. After mixing the organic layer was separated, the aqueous layer was additionally extracted with 2×500 ml of ether. The combined organic extract was dried over Na2SO4 and then evaporated to dryness. Rectification of the residue in vacuum gave the title product, bp 75-77° C./6 mm Hg. Yield 51.5 g (88%) of colorless liquid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH:5]=[C:4]([C@@H:13]([NH:15][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:14])[N:3]=1.[C:34]([Zn]C#N)#[N:35].O>CN(C=O)C.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>[Cl:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([C:34]#[N:35])=[N:3][C:4]([C@@H:13]([NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]3[C:17]=1[N:18]=[CH:19][N:20]3[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH3:14])=[CH:5]2
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(Cl)n4)ncnc32)cc1
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C#N)n4)ncnc32)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ((S)—N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 1 (1.5 g, 3.1 mmol, 1.0 eq) and tetrakis(triphenylphosphine)palladium (181 mg, 0.16 mmol, 0.05 eq) in DMF (50 mL) at RT, dicyanozinc (476 mg, 4.06 mmol, 1.3 eq) was added and the resulting mixture was stirred at 100° C. overnight. The reaction mixture was poured into water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-10% MeOH-DCM) to afford the product (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbonitrile 29.