Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH3:10])[CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1)[CH3:2].[CH2:11]([O:13][C:14](=[O:24])[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)=[CH2:16])[CH3:12]>C1COCC1>[CH2:11]([O:13][C:14](=[O:24])[CH:15]([C:17]1[CH:18]=[CH:19][C:20]([Br:23])=[CH:21][CH:22]=1)[CH2:16][N:6]1[CH2:7][CH2:8][CH:4]([N:3]([CH2:9][CH3:10])[CH2:1][CH3:2])[CH2:5]1)[CH3:12]
Reactant: C=C(C(=O)OCC)c1ccc(Br)cc1
Reactant: CCN(CC)C1CCNC1
Solvent: C1CCOC1
Product: CCOC(=O)C(CN1CCC(N(CC)CC)C1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl-pyrrolidin-3-yl-amine (0.685 g, 6 mmol) in THF (10 mL) was added 2-(4-bromo-phenyl)-acrylic acid ethyl ester (1.27 g, 5 mmol) dropwise in THF at 0 degrees Celsius. Then the mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue was dissolved in EtOAc (30 mL), washed with water (20 mL×2), brine, dried over Na2SO4, filtered and evaporated. The obtained oil was used directly without further purification. MS: calc'd 397 (MH+), exp 397 (MH+).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[CH:45]1[CH2:50][CH2:49]C[CH2:47][CH2:46]1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH:15]3[CH2:49][CH2:50][CH2:45][CH2:46][CH2:47]3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCC1CCCCC1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CC3CCCCC3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (bromomethyl)cyclohexane and isolated as white solid (4.2 mg, 27%). MS (m/e): 379.5 (MH+).
Reaction SMILES: [CH:1]1([C:4]#[N:5])[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].C(C1C=CC=CC=1)C.Cl[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1>CCCCCCC.O1CCCC1.CN1CCCN(C)C1=O>[CH:31]1([C:1]2([C:4]#[N:5])[CH2:3][CH2:2]2)[C:32]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:28][CH2:29][CH2:30]1
Reactant: N#CC1CC1
Reactant: ClC1CCCc2ccccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CCCCCCC
Product: N#CC1(C2CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.5 %

Procedure:
Cyclopropanecarbonitrile (17.14 g) was added dropwise to a mixture of lithium diisopropylamide solution (2M in a mixture of heptane, tetrahydrofuran and ethylbenzene; 128 ml), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (30 ml) and tetrahydrofuran (240 ml) stirring at -78° C. under nitrogen. Stirring was continued for 1 hour at this temperature then a solution of 1-chlorotetralin (48.4 g) in tetrahydrofuran (50 ml) was added slowly and after a further hour the solution was allowed to warm to ambient temperature, then was heated under gentle reflux for 2 hours. The solvent was removed in vacuo and the residue acidified with concentrated hydrochloric acid then extracted with ethyl acetate (4×100 ml). The combined extracts were dried over magnesium sulphate and the solvent removed in vacuo to leave a semi-solid which was filtered and washed with acetonitrile, then recrystallised from acetone to give 1-(1,2,3,4-tetrahydronaphth-1-yl)cyclopropanecarbonitrile (8.3 g), mp 91°-93° C.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.[CH2:14]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:15]1[O:17][CH2:16]1.C(N(CC)CC)C.O>CC(N(C)C)=O>[CH2:19]([O:18][CH2:14][C@H:15]([OH:17])[CH2:16][O:12][C:11]1[C:2]([Br:1])=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([CH3:13])[CH:5]=[CH:4]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: Cc1ccc2c(Br)c(O)ccc2n1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc2c(Br)c(OC[C@@H](O)COCc3ccccc3)ccc2n1
Yield: 73 %

Procedure:
A solution of 5-bromo-2-methyl-6-quinolinol (30.1 g, 126 mmol), (R)-benzyl glycidyl ether (24.9 g, 152 mmol) and triethylamine (17.4 g, 172 mmol) in DMA (200 mL) was heated in a 95–98° C. oil bath for 2 days. The solution was cooled and poured into water (300 mL) while stirring. The tan precipitate formed was filtered, washed with water (100 mL) and dried in a vacuum oven to give 37 g (73%) of the title compound as a tan solid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.Cl[CH2:28][C:29]([NH:31][C:32]([NH:34][CH3:35])=[O:33])=[O:30]>>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:28][C:29]([NH:31][C:32]([NH:34][CH3:35])=[O:33])=[O:30])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:16])([CH3:17])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: CNC(=O)NC(=O)CCl
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(=O)NC)CC1

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with N-chloroacetyl-N'-methylurea according to the method of Example 2; m.p. 145°-147°.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1(O)[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10]1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10]1
Reactant: OC1(c2cccc(F)c2F)CCC=CCC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(C2CCC=CCC2)c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.9 %

Procedure:
In a 100 mL round-bottomed flask (t=g) was added (Z)-1-(2,3-difluorophenyl)cyclohept-4-enol (872 mg, 3.89 mmol) in CH2Cl2 (16 mL) to give a colorless solution. Triethylsilane (3.11 mL, 19.44 mmol) was added, following by TFA (8.00 mL). The mixture was stirred at room temperature for 2.5 hours. TLC showed clean conversion to a less polar compound. It was concentrated down and purification by FCC up to 20% Et2O in hexane afforded the desired product as a colorless oil (769 mg, 95%). The product was quickly eluted out. 1H NMR (the major peaks are the same as these in the later synthesis) confirmed the structure.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([CH3:22])[CH:21]=1>>[CH3:15][C:16]1[CH:17]=[C:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[C:20]([CH3:22])[CH:21]=1
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Cc1cc(C)cc(-c2nnc(N)nc2-c2ccccc2)c1
Yield: 65.4 %

Procedure:
6-(3,5-Dimethylphenyl)-5-phenyl-1,2,4-triazin-3-amine (54 mg, 65%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3,5-dimethylphenylboronic acid (51.5 mg, 0.344 mmol) according to the general procedure of Example 1.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([Cl:17])=[C:8]([Cl:16])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1.[ClH:18]>O>[Cl:18][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([Cl:16])[C:7]=1[Cl:17]
Reactant: Nc1cc(C(F)(F)F)cc(Cl)c1Cl
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1cc(Cl)c(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 55 %

Procedure:
A solution of sodium nitrite (39 g.) in water (85 ml.) is added over 1 hour to a solution of 5-amino-3,4-dichloro-α,α,α-trifluorotoluene (117.5 g., 0.51 mol) in 1700 ml. concentrated hydrochloric acid at -6° C. and the solution stirred for 1 hour then filtered. The filtrate is added to a solution of cuprous chloride (76.5 g.) in concentrated hydrochloric acid (500 ml.) over 5 minutes at 0° to 8° C. and gradually heated to 80° C. over 80 minutes. The reaction mixture is cooled to 35° C. and extracted with hexane (2×300 ml.). The extract is washed with water, 2% sodium hydroxide solution, dried and distilled to give 3,4,5-trichloro-α,α,α-trifluorotoluene (70 g., 55%) b.p. 82°-86° C./10 mm, 95% pure.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1.[Cl-].[NH4+]>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)[N:3]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: COC(=O)c1c[nH]nc1C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2ccc(C(F)(F)F)cn2)nc1C
Reaction time: 0.17 h
Yield: 30.6 %

Procedure:
To a solution of methyl 3-methyl-1H-pyrazole-4-carboxylate (5.3 g) synthesized above in dimethylformamide (70 mL) was added sodium hydride (1.9 g, 60% in oil) at 0° C., and the mixture was stirred for 10 min. 2-Chloro-5-trifluoromethylpyridine (7.5 g) was added, and the mixture was stirred at room temperature overnight. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10, volume ratio) to give the title object compound (3.3 g, 31%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10](N)=[C:9]([OH:14])[CH:8]=1)[CH3:2].N([O-])=O.[Na+].[ClH:20]>O.[Cu]Cl>[CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([Cl:20])=[C:9]([OH:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(N)c(O)c1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(Cl)c(O)c1
Temperature: 25 °C

Procedure:
(E)-3-(4-Amino-3-hydroxy-phenyl)-acrylic acid ethyl ester (2.76 g, 13.3 mmol) was suspended in HCl solution (6N, 4 ml), and sodium nitrite solution in water (960 mg, 14 mmol) was added at 0° C. The resulting suspension was added at 0° C. to a solution of copper (I) chloride (2 g, 16 mmol) in concentrated HCl (4 ml). The mixture was slowly warmed to RT and heated to 60° C. for 30 min., shaking occasionally. Then it was cooled to RT, diluted with water and extracted with DCM, which was dried and evaporated. The residue was purified by silica gel column chromatography, eluant petroleum ether/AcOEt 90:10, to give 1.46 g of (E)-3-(4-chloro-3-hydroxy-phenyl)-acrylic acid ethyl ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1
Reactant: Cc1cccc(-c2c(-c3ccc(Cl)cc3)c(C)n[nH]c2=O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cccc(-c2c(Cl)nnc(C)c2-c2ccc(Cl)cc2)n1
Temperature: 130 °C
Reaction time: 4 h
Yield: 62.9 %

Procedure:
6 mg of 5-(4-chlorophenyl)-6-methyl-4-(6-methyl-2-pyridyl)-2H-pyrida zin-3-one and 2 g of phosphorus oxychloride were mixed. The mixture was stirred for 4 hours on an oil bath of 130° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure, to obtain 4 mg of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(6-methyl-2-pyridyl)pyridazine (hereinafter, described as compound (4) of the present invention.).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([S:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[S:4][C:3]=1[N:16]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1.[Cl:25][C:26]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:27]=1[C:28]([N:30]=[C:31]=[O:32])=[O:29]>C(#N)C>[Cl:25][C:26]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:27]=1[C:28]([NH:30][C:31](=[O:32])[NH:1][C:2]1[CH:6]=[C:5]([S:7]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)(=[O:9])=[O:8])[S:4][C:3]=1[N:16]1[CH2:17][CH2:18][CH:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21]1)=[O:29]
Reactant: Nc1cc(S(=O)(=O)N2CCCCC2)sc1N1CCC(C(=O)O)CC1
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Solvent: CC#N
Product: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1cc(S(=O)(=O)N2CCCCC2)sc1N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-[3-Amino-5-(piperidine-1-sulfonyl)thiophen-2-yl]piperidine-4-carboxylic acid (0.2 g of crude product) is dissolved in 2 ml of acetonitrile and admixed with the equimolar solution of 2-chloro-4,5-difluorobenzoyl isocyanate in acetonitrile, and the mixture is stirred at RT. After 3 hours, the solid is filtered off with suction and dried under reduced pressure.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=[C:11]2[CH2:35][CH3:36])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:37][Li].[Cl-].[NH4+]>O1CCCC1>[CH2:35]([C:11]1[N:10]([C:7]2[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:37])[CH3:2])=[CH:9][CH:8]=2)[C:15](=[O:16])[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=1)[CH3:36]
Reactant: [Li]C
Reactant: CCCc1nc(CC)n(-c2ccc(C(C)=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1nc(CC)n(-c2ccc(C(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of 4′-{[1-(4-acetylphenyl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.78 g) in tetrahydrofuran (20 mL) was added methyllithium (2.4 mL, 1.4 M diethyl ether solution) under ice-cooling, and the mixture was stirred for 1 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.30 g, 37%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21]1[C:22]([N:28](COCC[Si](C)(C)C)[S:29]([C:32]2[C:33]([C:38]3[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[CH:40][CH:39]=3)=[N:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])=[N:23][CH:24]=[C:25]([CH3:27])[N:26]=1>C1COCC1>[CH3:19][O:20][C:21]1[C:22]([NH:28][S:29]([C:32]2[C:33]([C:38]3[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[CH:40][CH:39]=3)=[N:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])=[N:23][CH:24]=[C:25]([CH3:27])[N:26]=1
Reactant: COc1nc(C)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccnc1-c1ccc(SC)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(SC)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
Tetrabutylammonium fluoride (0.7 ml of a 1.1M solution in THF) was added to a solution of N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-methylthiophenyl)-N-[2-(trimethylsilyl)ethoxymethyl]pyridine-3-sulphonamide (0.373 g) in dry THF (4 ml) and the solution was heated to 60° C. for 3 hours. More tetrabutylammonium fluoride solution (0.35 ml) was added and heating was continued for 5 hours. Further aliquots of tetrabutylammonium fluoride solution (a further 2.5 ml in total) were added until reaction was complete as judged by thin layer chromatography (eluting with ethyl acetate/hexane (1:1 v/v)). Volatile material was removed by evaporation and the residue was diluted with water and extracted three times with ethyl acetate. The organic extracts were washed with water and saturated sodium chloride solution and then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 0-40% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-methylthiophenyl)pyridine-3-sulphonamide (0.201 g) as a foam; 1H NMR (CDCl3): 2.3 (s, 3H), 2.5 (s, 3H), 3.8 (s, 3H), 7.15-7.35 (m, 4H), 7.5 (m, 1H), 8.7 (dd, 1H), 8.8 (dd, 1H); mass spectrum (+ve ESP): 403 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C:7]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2OCC[O:23]2)=[C:18]([F:27])[CH:17]=1)([CH3:15])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].NC(N)=S>CCO.O>[F:27][C:18]1[CH:17]=[C:16]([C:7]([CH3:15])([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[CH:21]=[CH:20][C:19]=1[CH:22]=[O:23]
Reactant: CC(C)(C)OC(=O)C(C)(C(=O)OC(C)(C)C)c1ccc(C2OCCO2)c(F)c1
Agent: NC(N)=S
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C(=O)OC(C)(C)C)c1ccc(C=O)c(F)c1

Procedure:
Di-tert-butyl[4-(1,3-dioxolan-2-yl)-3-fluorophenyl](methyl)malonate (0.91 g, 2.30 mmol) and thiourea (0.87 g, 11.4 mmol) were stirred in refluxing EtOH/H2O (6.7 mL/6.7 mL) for 7 hours. Room temperature was attained and the solvent removed in vacuo. H2O (100 mL) was added to the residue and the products extracted into EtOAc (2×100 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give the clean product (pale yellow gum). 1H NMR (CDCl3) δ 10.33 (s, 1H), 7.82 (t, J=8.1 Hz, 1H), 7.31 (dd, J=8.1, 1.8 Hz. 1H). 7.27 (dd, J=12.0, 1.8 Hz, 1H), 1.77 (s, 3H), 1.46 (s, 18H).
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([C:14](=[O:29])[NH:15][C@H:16]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:17]([CH3:19])[CH3:18])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:51]2[C@H:52]([CH3:75])[C@H:53]3[C@@H:70]([C@H:71]([OH:73])[CH3:72])[C:69](=[O:74])[N:54]3[C:55]=2[C:56]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][C:63]([N+:66]([O-:68])=[O:67])=[CH:62][CH:61]=2)=[O:57])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[Si:22]([O:21][CH2:20][C@@H:16]([NH:15][C:14]([C:12]1[N:13]=[C:9]([N:7]2[CH2:8][CH:5]([S:4][C:51]3[C@H:52]([CH3:75])[C@@H:53]4[C@@H:70]([C@H:71]([OH:73])[CH3:72])[C:69](=[O:74])[N:54]4[C:55]=3[C:56]([O:58][CH2:59][C:60]3[CH:61]=[CH:62][C:63]([N+:66]([O-:68])=[O:67])=[CH:64][CH:65]=3)=[O:57])[CH2:6]2)[S:10][CH:11]=1)=[O:29])[CH:17]([CH3:19])[CH3:18])([C:25]([CH3:27])([CH3:28])[CH3:26])([CH3:23])[CH3:24]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CC(=O)SC1CN(c2nc(C(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)C(C)C)cs2)C1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a solution of 3-acetylthio-1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-2-methyl-propylcarbamoyl]-1,3-thiazol-2-yl}azetidine (500 mg, 1.09 mmol) (obtained as described in Reference Example 36) in dimethylformamide (25 ml) was added hydrazine acetate (121 mg, 1.31 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (648 mg, 1.09 mmol) in acetonitrile (33 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (759 μl, 4.36 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 10% aqueous sodium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane: ethyl acetate (1:2 and 1:4) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-2-methyl-propylcarbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (649 mg, yield 84%) as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].[C:9]1([CH2:15][CH:16]=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH:8][CH:16]=[CH:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=CCc1ccccc1
Reactant: NNc1ccccn1
Product: C(=Cc1ccccc1)NNc1ccccn1
Yield: 100 %

Procedure:
React Pyridin-2-yl-hydrazine and Phenyl-acetaldehyde under literature conditions (Azaindoles. I. Preparation of 7-azaindoles by thermal indolization of 2-pyridylhydrazones. Canadian Journal of Chemistry (1966), 44(21), 2455-9) to give N-Pyridin-2-yl-N′-styryl-hydrazine (10 g, 100% yield crude material) Mass Spectrum (m/e): 211.96 (MH+).
Reaction SMILES: ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)CCCCN)C1C=CC=CC=1.[NH:50]([C:88]([O:90][C:91]([CH3:94])([CH3:93])[CH3:92])=[O:89])[CH2:51][C:52]([NH:54][CH2:55][C:56]([NH:58][CH2:59][C:60]([NH:62][C@H:63]([C:71]([NH:73][CH2:74][CH2:75][CH2:76][CH2:77][C:78]([O:80]CC1C=CC=CC=1)=[O:79])=[O:72])[CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:61])=[O:57])=[O:53]>CN(C=O)C.CO.O.[Pd].C(N(CC)CC)C>[NH:50]([C:88]([O:90][C:91]([CH3:94])([CH3:93])[CH3:92])=[O:89])[CH2:51][C:52]([NH:54][CH2:55][C:56]([NH:58][CH2:59][C:60]([NH:62][C@H:63]([C:71]([NH:73][CH2:74][CH2:75][CH2:76][CH2:77][C:78]([OH:80])=[O:79])=[O:72])[CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:61])=[O:57])=[O:53]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCCCC(=O)OCc1ccccc1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCCCC(=O)O
Reaction time: 0.5 h

Procedure:
Boc-y-Gly-Gly-Phe-OH (575 mg) (SEQ ID NO. 8), HOSu (182 mg), and DCC (326 mg) were dissolved in DMF (20 ml), and the mixture was stirred for 30 minutes. The solution was added with a solution of p-toluenesulfonic acid salt of 5-aminopentanoic acid benzyl ester (500 mg) and triethylamine (0.184 ml) dissolved in DMF (10 ml), and the mixture was stirred for 3 days at room temperature. The reaction mixture was concentrated, and the residue was purified by column chromatography (CH2Cl2:MeOH=20:1) to obtain 380 mg of Boc-Gly-Gly-Gly-Phe-NH—(CH2)4—COOBzl (Bzl represents benzyl group) (SEQ ID NO. 8). The Boc-Gly-Gly-Gly-Phe-NH—(CH2)4—COOBzl (SEQ ID NO. 8) (380 mg) was dissolved in methanol containing 50% of water (20 ml), and the solution was added with 5% Pd—C (water content; 50%, 300 mg) and stirred overnight under hydrogen at ordinary pressure. The catalyst in the reaction mixture was removed by filtration, and the filtrate was concentrated to dryness to obtain Boc-Gly-Gly-Gly-Phe-NH—(CH2)4—COOH (SEQ ID NO. 8) (330 mg).