Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[S:12][C:13]=1[C:14]([NH2:16])=O.COC(OC)[N:26]([CH3:28])C.C(O)(=O)C.O.[NH2:36]N>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[S:12][C:13]=1[C:14]1[NH:26][CH:28]=[N:36][N:16]=1
Reactant: NC(=O)c1sc(N2CCOCC2)nc1-c1ccc(Cl)cc1Cl
Reactant: NN
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(-c2nc(N3CCOCC3)sc2-c2nnc[nH]2)c(Cl)c1
Yield: 43.6 %

Procedure:
A mixture of 4-(2,4-dichlorophenyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxamide (23 mg, 0.06 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.8 mL, 6 mol) was irradiated in the microwave at 160° C. (300 watts) for 30 minutes. The reaction was concentrated in vacuo. The residue dissolved in acetic acid (1.0 mL, 0.18 mol) and hydrazine hydrate (30 mg, 0.7 mmol) and subjected to microwave irradiation at 120° C. (300 watts) for 15 minutes. The solvent was removed in vacuo, the residue was diluted with water (1 mL), the precipitate was collected, washed with water (1 mL) and dried to afford the title compound (10 mg, 40%). LCMS: (FA) ES+, 382. 1H NMR (400 MHz, d6-DMSO) δ: 13.9 (s, 1H), 8.42 (s, 1H), 7.63 (d, 1H), 7.44-7.42 (m, 2H), 3.73-3.70 (m, 4H), 3.44-3.42 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([CH:25]=[O:26])=[CH:10][N:9]=1.C[Li].[C:29](=O)([O-])O.[Na+]>O1CCCC1.CCOCC>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([C@@H:25]([OH:26])[CH3:29])=[CH:10][N:9]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C=O)cc1Cl
Agent: [Li]C
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CCCC3CO)ncc2[C@H](C)O)cc1Cl

Procedure:
To a solution of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-formylpyrimidine (91.0 mg) in tetrahydrofuran (20 ml) is added 1.10 M solution of methyl lithium in ether (1.1 ml) at −78° C., and the mixture is reacted for 10 minutes, and thereto is added aqueous sodium hydrogen carbonate solution. The reaction mixture is extracted with ethyl acetate to give crude (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(1-hydroxyethyl)pyrimidine, MS (m/z): 393 (MH30).
Reaction SMILES: O.NN.Br[C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:8]=[CH:9][CH:10]=1.[CH2:16]([O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([O:23][C:24]1[CH:29]=[C:28]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=2)[CH:27]=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: O=C(O)CCc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1cccc(-c2cccc(OCc3ccccc3)c2)c1

Procedure:
21.5 g (77.2 mmol) of sodium metaborate octahydrate, 0.700 g (977 mmol) of bis(triphenylphosphine)palladium(II) chloride, 0.1 ml (2 mmol) of hydrazine hydrate and 10.0 g (42.3 mmol) of 3-(3-bromophenyl)propionic acid are initially introduced in 10 ml of tetrahydrofuran and 30 ml of water, and a solution of 10.0 g (43.9 mmol) of 3-benzyloxy-benzeneboronic acid in 30 ml of THF is added. The batch is subsequently heated under reflux overnight, added to water and extracted three times with MTB ether. The combined org. phases are filtered through silica gel with heptane/ethyl acetate (1:1), and the crude product is recrystallised from toluene, giving 3-(3′-benzyloxybiphenyl-3-yl)propionic acid as a colourless solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].OS(O)(=O)=O.[CH2:21](O)[CH3:22]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:15])[C:12]([O:14][CH2:21][CH3:22])=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCO
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc(CC(C)C)cc1

Procedure:
Separately, 72.02g ethyl 2-(4-isobutylphenyl)-propionate, obtained by the esterification of 2-(4-isobutylphenyl)-propionic acid with ethanol and concentrated H2SO4, are solved with 100ml methanol, this solution is introduced drop by drop into the reaction flask, and stirred and cooled for 5 hours on an ice bath. Thereafter it is suction filtered, the residue is washed with alltogether 50ml methanol, the wash is added to the filtrate, thereafter the whole is evaporated in a water bath with a rotating evaporator at a reduced pressure, until 100-200 ml of a concentrated solution are obtained. This solution is poured into a 200 ml beaker into which are stirred approximately 1000 ml 1,25N acetic acid. This mixture is left standing for 24 hours, thereafter suction filtered. The resulting filtrate is taken up with 100ml. petroleum ether at 40°-60° C, in order to solve any possible residue of unreacted starting ester, and refiltered. Approximately 50g of 2-(4-isobutylphenyl)-propriohydroxamic acid are obtained, having a melting point of 119°-121° C on Kofler's hot stage.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=CC1C=C[C:16](O)=[C:13]([O:14]C)[CH:12]=1>CCCCCC.C(OCC)C>[OH:8][CH2:1][C:2]1[CH:7]=[CH:6][C:5]2[O:14][CH:13]([CH3:16])[CH2:12][C:4]=2[CH:3]=1
Reactant: OCc1ccccc1
Reactant: COc1cc(C=O)ccc1O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1Cc2cc(CO)ccc2O1

Procedure:
To a solution of 853 mg (4.14 mmole) ethyl 2-methyl-2,3-dihydrobenzofuran-5-carboxylate in 9 ml dry tetrahydrafuran under nitrogen was added 157 mg (4.14 mmole) lithium aluminum hydride in portions and the resulting mixture was stirred at room temperature overnight. The mixture was worked up as described in Preparation A, Part (v), to afford 752 mg of product. The NMR spectrum showed the presence of a band at 4.5 ppm, characteristic of a benzyl alcohol CH2 group. TLC with 1:1 hexane/ethyl ether showed one spot at Rf 0.2 (vanillin spray).
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[C:3](=[N:4][O:5][N+:6]=2[O-:10])[CH:2]=1.C1CC[N:19]2[C:14](=[N:15]CCC2)CC1.N#CN.C(O)(=O)C>C(#N)C>[CH:1]1[CH:9]=[CH:8][C:7]2[N+:6]([O-:10])=[N:15][C:14]([NH2:19])=[N+:4]([O-:5])[C:3]=2[CH:2]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: [O-][n+]1onc2ccccc21
Agent: N#CN
Solvent: CC#N
Solvent: CC(=O)O
Product: Nc1n[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 22.5 °C
Reaction time: 48 h
Yield: 38.7 %

Procedure:
To a stirred mixture containing 1.000 kg (7.347 moles) of benzofuroxan and 2.237 kg (14.694 moles) of DBU was added a solution containing 618 g (14.694 moles) of cyanamide in 380 ml of acetonitrile while maintaining the temperature below 25° C. After stirring for 48 hours at 20-25° C. the reaction mixture was dilute with 6.620 liters of acetonitrile and cooled below 15° C. To the cooled mixture was added 882 g (14.694 moles) of acetic acid while maintaining the temperature below 15° C. After stirring overnight at 5-10° C. the precipitated product was collected by filtration and washed with acetonitrile (2×2 liters). The resulting solid was suspended in 2 liters of water, stirred about 30 minutes until a homogeneous suspension was obtained, and then filtered. The collected solid was resuspended in 2 liters of water, stirred for 20-30 minutes and filtered. The solid collected was dried to constant weight under vacuum at 50-55° C. to give 506.6 g of tirapazamine.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13]CC)=[O:12].[OH-].[Na+]>CCO.O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1[nH]c2ccccc2c1Br
Yield: 96.7 %

Procedure:
A solution of ethyl 3-bromoindole-2-carboxylate (54.40 g, 203 mmol) in EtOH (600 ml) and water (50 ml) with NaOH (20.20 g, 505 mmol) was refluxed for 1 h. The mixture was cooled and the sodium salt of the title compound was removed by filtration. This was acidified (aqueous 3N HCl) and extracted with ethyl acetate. The organic extract was washed with water then brine, dried (sodium sulfate) and concentrated. Crystallization from ethyl acetate afforded the product (47.1 g, 88%). mp 201°-203° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4]2=[CH:7][C:8]3[O:9][CH2:10][C:11]4([C:21]=3[CH:22]=[C:3]12)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:13][C:12]4=[O:20].Br[CH2:25][C:26]1[O:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(=O)CC>[CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4]2=[CH:7][C:8]3[O:9][CH2:10][C:11]4([C:21]=3[CH:22]=[C:3]12)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:25][C:26]1[O:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1)[C:12]4=[O:20]
Reactant: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a solution of 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.09 g, 0.29 mmol) in 2-butanone (10.0 mL) was added 2-bromomethyl-5-(trifloromethyl)furan (0.08 g, 0.35 mmol) followed by cesium carbonate (0.19 g, 0.58 mmol) at 0° C. The mixture was stirred at ambient temperature overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/5) to give the title compound (0.06 g, 45%): mp 155-160° C.; 1H NMR (300 MHz, CDCl3,) δ 7.29 (t, 1H), 7.19 (d, 1H), 7.07 (t, 1H), 6.97 (d, 1H), 6.73 (t, 1H), 6.42-6.37 (m, 2H), 6.30 (s, 1H), 5.08 (d, 1H), 4.94-4.84 (m, 2H), 4.65 (d, 1H), 4.18 (s, 2H), 1.19 (s, 3H), 1.14 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.5, 161.2, 161.0, 152.0, 141.4, 132.5, 130.1, 128.8, 124.2, 123.8, 120.1, 116.4, 112.6, 109.3, 108.7, 93.4, 85.5, 80.6, 57.7, 41.4, 36.9, 27.6, 27.5; MS (ES+) m/z 456.5 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(Cl)Cl.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:34](Cl)=[O:35]>O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH:15]([O:18][C:34](=[O:35])[C:33]3[CH:32]=[C:31]([O:30][CH3:29])[C:39]([O:40][CH3:41])=[C:38]([O:42][CH3:43])[CH:37]=3)[CH2:14]1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: Cc1[nH]c2ccccc2c1CCN1CCC(O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(C(=O)OC2CCN(CCc3c(C)[nH]c4ccccc34)C2)cc(OC)c1OC
Reaction time: 24 h

Procedure:
To a suspension of 5 g. (0.02 mole) of 2-methyl-3-[2-(3-hydroxypyrrolidinyl)ethyl]indole and 8 g. (0.075 mole) of sodium carbonate in 40 ml. of chloroform was added 4.2 g. (0.018 mole) of 3,4,5-trimethoxybenzoyl chloride in 30 ml. of chloroform. The mixture was stirred under anhydrous conditions for 24 hours, then treated with 25 ml. of water and stirred an additional hour. The chloroform layer was separated, dried over magnesium sulfate and evaporated on a rotating evaporator to a viscous oil.
Reaction SMILES: C([C:10]1[NH:11][C:12]2[C:17]([C:18]=1[CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[CH:16][CH:15]=[CH:14][CH:13]=2)C1C=CC(OC)=CC=1.N1(CC2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([O:40]C)[CH:38]=3)NC=2)C=CN=C1>>[OH:40][C:37]1[CH:38]=[CH:39][C:34]([C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:35][CH:36]=1
Reactant: COc1ccc2[nH]cc(Cn3ccnc3)c2c1
Reactant: COc1ccc(Cc2[nH]c3ccccc3c2Cn2ccnc2)cc1
Product: Oc1ccc(-c2[nH]c3ccccc3c2Cn2ccnc2)cc1

Procedure:
The procedure described in Example XLVII was repeated except that 2-(p-anisyl)-3-(imidazol-1-ylmethyl)indole was the starting material employed in place of 3-(imidazol-1-ylmethyl)-5-methoxyindole, using the same molar proportions as before. In this particular case, the solid product obtained was chromatographed on silica gel and then finally eluted with chloroform/methanol (20:1 by volume). Evaporation of the product-containing eluate then gave a solid material which was crystallized from ethanol to afford pure 2-(p-hydroxyphenyl)-3-(imidazol-1-ylmethyl)indole, m.p. 245°-247° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([I:16])[CH2:12][CH2:13][CH2:14][CH3:15]>CCOCC>[I-:16].[CH2:11]([N+:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3][C:2]=1[CH3:1])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCI
Reactant: Cc1nc2ccccc2o1
Solvent: CCOCC
Product: CCCCC[n+]1c(C)oc2ccccc21
Product: [I-]
Yield: 81.7 %

Procedure:
A stirred solution of 2-methylbenzoxazole (10 g, 75 mmol) and n-pentyl iodide (14.85 g, 75 mmol) was heated at reflux for 18 h. After cooling, the yellow-brown solid was slurried in ether, filtered off and washed with ether. The resulting solid was air dried to give 3-n-pentyl-2-methylbenzoxazolium iodide (20.3 g, 82%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)=[CH:20][CH:19]=1)[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([O:8][C:9](=[O:32])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([CH2:26][C:27]2[NH:31][CH:30]=[CH:29][N:28]=2)[CH2:39][C:35]2[N:34]([CH3:33])[CH:38]=[CH:37][N:36]=2)=[CH:22][CH:23]=1)[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCCCNC(=O)OCc1ccccc1)Cc1ccc(CNCc2ncc[nH]2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CCCCNC(=O)OCc1ccccc1)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.9 %

Procedure:
The compound (608.7 mg) obtained in Example 103-5 was dissolved in anhydrous methanol (24 ml) and added with 1-methyl-2-imidazole carboxaldehyde (231.3 mg) and sodium cyanoborohydride (176.0 mg). The solution was adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 3 days. After the reaction, the solvent was distilled off. The residue was added with a 1 mol/l sodium hydroxide aqueous solution and subjected to extraction with chloroform. The extract was dried with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (502.6 mg) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:23])(=[O:22])[N:19]([CH3:21])[CH3:20])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH2:32](O)[CH3:33]>>[CH2:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:23])(=[O:22])[N:19]([CH3:20])[CH3:21])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][CH2:32][CH3:33])=[O:6])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCO
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)cc(N)c1Oc1ccccc1
Reactant: BrCc1ccccc1
Product: CCOC(=O)c1cc(NCc2ccccc2)c(Oc2ccccc2)c(S(=O)(=O)N(C)C)c1

Procedure:
A mixture of 3-amino-5-dimethylsulphamyl-4-phenoxy-benzoic acid (1.68 g), benzyl bromide (2 g), and ethanol (15 ml) was refluxed for 5 hours. After cooling, the precipitated ethyl 3-benzylamino-5-dimethylsulphamyl-4-phenoxy-benzoate was isolated and recrystallized from ethanol. After drying in vacuo, the compound was obtained with a melting point of 154-155°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:17]([O:21][C:22](=[O:23])[NH:24][CH:25]([C:26]1[N:9]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)[CH3:29])([CH3:20])([CH3:19])[CH3:18]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1Nc1ncccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CC(NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ncccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
A mixture of 4-fluoro-N2-(3-fluoropyridin-2-yl)benzene-1,2-diamine (81 mg, 0.37 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (76 mg, 0.40 mmol), HOAt (55 mg, 0.40 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (77 mg, 0.40 mmol) in DCM (5 mL) was stirred at 0° C. for 2 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was dried and concentrated in vacuo. The resulting residue was taken up in AcOH (5 mL) and heated at 70° C. for 24 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic fraction was washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting oil was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) to afford the title compound as an orange oil (84 mg, 61%). LCMS (Method C): RT 3.28 min [M+H]+ 375.22
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[S:11])([OH:3])=[O:2].C([O-])(=O)C.[Na+].C(O)(=O)C.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[C:1]([CH2:4][N:5]1[C:9](=[O:10])[C:8](=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:7][C:6]1=[S:11])([OH:3])=[O:2]
Reactant: O=Cc1ccccc1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CN1C(=O)C(=Cc2ccccc2)SC1=S
Yield: 50.1 %

Procedure:
A mixture of 955 mg of 3-carboxymethylrhodanine, 516 mg of sodium acetate, 10 ml of acetic acid and 637 mg of benzaldehyde was heat-refluxed for 2 hours. To the reaction mixture was added 20 ml of water, and the precipitated crystals were filtered. The resulting crystals were recrystallized from ethanol to obtain 699 mg of the titled compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:22](=[O:23])[N:4]2[C:5]([C:19]([O-:21])=[O:20])=[C:6]([CH2:9][N+:10]3[N:11]([CH3:18])[CH:12]=[C:13]([NH:15][CH:16]=[O:17])[CH:14]=3)[CH2:7][S:8][C@H:3]12.C[Si](C)(C)NC(=O)C.[NH2:32][C:33]1[S:37][N:36]=[C:35](/[C:38](=[N:46]/[O:47][CH2:48][C:49]([OH:51])=[O:50])/[C:39](OS(C)(=O)=O)=[O:40])[N:34]=1.C(OC(C)C)(C)C>O1CCCC1>[NH2:32][C:33]1[S:37][N:36]=[C:35]([C:38](=[N:46][O:47][CH2:48][C:49]([OH:51])=[O:50])[C:39]([NH:1][C@@H:2]2[C:22](=[O:23])[N:4]3[C:5]([C:19]([O-:21])=[O:20])=[C:6]([CH2:9][N+:10]4[N:11]([CH3:18])[CH:12]=[C:13]([NH:15][CH:16]=[O:17])[CH:14]=4)[CH2:7][S:8][C@H:3]23)=[O:40])[N:34]=1
Reactant: Cn1cc(NC=O)c[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CS(=O)(=O)OC(=O)/C(=N\OCC(=O)O)c1nsc(N)n1
Agent: CC(=O)N[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: Cn1cc(NC=O)c[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c3nsc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a solution of di(trifluoroacetic acid) salt of 7β-amino-3-(4-formamido-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (4.0 g) and N-(trimethylsilyl)acetamide (9.29 g) in tetrahydrofuran (60 ml) was added methanesulfonyl (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetate (2.07 g) under ice-cooling. The mixture was stirred for 1 hour at ambient temperature and then the resulting mixture was added dropwise to diisopropyl ether. Thus produced precipitate was collected by filtration, dissolved in water and then subjected to column chromatography on macroporous non-ionic adsorption resin, Diaion HP-20 (Trademark: manufactured by Mitsubishi Chemical Industries). The desired product was eluted with 10% aqueous isopropyl alcohol solution, and then lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3- (4-formamido-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer 0.714 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][C:31]=1[F:39]>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>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)=[CH:32][C:31]=1[F:39]
Reactant: N#Cc1ccc(-c2ccc(Br)cc2)cc1
Reactant: COc1ccc(B(O)O)cc1F
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: c1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc(-c3ccc(C#N)cc3)cc2)cc1F
Yield: 88.6 %

Procedure:
To a mixture of 2.4 g of 4-bromo-4'-cyanobiphenyl, 0.37 g of tetrakis(triphenylphosphine)palladium(0), 15.2 ml of a 2N aqueous sodium carbonate solution, and 19.4 ml of benzene, a solution which was prepared by dissolving 1.9 g of 4-methoxy-3-fluoro-benzene boronic acid synthesized in [1] above in 14.4 ml of ethanol was slowly added dropwise with stirring, and the solution was subjected to reflux for 8 hours. After the reflux was finished, the solution was cooled, and the crystals thus precipitated were separated by filtration and washed with water and methanol in turn, and dried to obtain 2.5 g of 4-methoxy-3-fluoro-4"-cyano-p-terphenyl.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([C:21]3[C:26]([F:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:29](O)=[O:30])[CH2:12]1)(=[O:10])=[O:9].[CH2:32]([NH:36][C:37](=[O:45])[C:38](=[O:44])[C@@H:39]([NH2:43])[CH2:40][CH2:41][CH3:42])[CH2:33][CH2:34][CH3:35]>>[CH2:32]([NH:36][C:37](=[O:45])[C:38](=[O:44])[C@@H:39]([NH:43][C:29]([C@@H:13]1[CH2:12][C@@H:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[CH2:15][N:14]1[C:16]([C:18]1([C:21]2[C:26]([F:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=2)[CH2:20][CH2:19]1)=[O:17])=[O:30])[CH2:40][CH2:41][CH3:42])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCNC(=O)C(=O)[C@@H](N)CCC
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1
Product: CCCCNC(=O)C(=O)[C@H](CCC)NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid and (S)-3-Amino-2-oxo-hexanoic acid butylamide in step 1. MS (m/e)=669.17 [M+H+].