Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:49][C:50]#[N:51]>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7](=[O:10])[N:8]([CH2:49][C:50]#[N:51])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: N#CCBr
Product: CCCCc1nn(CC#N)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 58 %

Procedure:
The alkylation of 5-n-butyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Example 2, Step D) with bromoacetonitrile was carried out as described in Example 3, Step A. After work-up, the residue was flash chromatographed over silica gel (30 mL for 0.162 mmole, gradient elution using 0.5-2.0% MeOH/CH2Cl2 to give the desired compound in 58% yield, homogeneous by TLC in 2% MeOH/CH2Cl2, mass spectrum (FAB) m/e 657 (M+1)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][NH:19][C:18]2=[O:22])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[H-].[Na+].[CH3:25][S:26][CH2:27][CH2:28]Cl>CN(C=O)C.C(OCC)C.Cl>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][N:19]([CH2:28][CH2:27][S:26][CH3:25])[C:18]2=[O:22])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CSCCCl
Reactant: CC(C)(C)c1cc(C=C2SCNC2=O)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CSCCN1CSC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 100 °C
Reaction time: 144 h

Procedure:
26.7 g of 5-{[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-4-thiazolidinone (i.e., the compound of Example 2) was dissolved in 418 ml of DMF to which was added 3.34 g of a 60% sodium hydride dispersion. The resultant mixture was stirred at 100° C. under an argon atmosphere. To this was added 8.33 ml of methylthioethyl chloride and the resulting black solution was stirred at 100° C. for 6 days. The material was allowed to cool to 30° C. after which insoluble material was filtered off. The solid was washed with DMF until its color was gone leaving a white solid which was discarded. The pH of the filtrate and washings was adjusted to 1.5 by the addition of 1N hydrochloric acid with stirring. The mixture was then diluted with a mixture of 1000 ml of diethyl ether and 500 ml of 1N hydrochloric acid which was then shaken and separated. The organic layer was washed with two portions of water and one portion of brine and subsequently dried over sodium sulfate, filtered, evaporated and chased with chloroform to give a black foam/oil. This material was triturated with about 75 ml of chloroform and then filtered and the insoluble solid was washed with additional chloroform until its brown color was gone. The filtrate was then loaded onto a silica gel column which was eluted with 8000 ml of a gradient of 10-30% ethyl acetate in hexane. The various fractions containing the desired product were combined and again loaded onto a silica gel column and eluted with 8000 ml of a gradient of 10-35% acetone in hexane. The fractions containing the desired product were recrystalled with hexane/ethyl acetate to give 1.2 g of the title compound as a tan/orange solid, m.p. 165.5°-168° C.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.OC1[C:27]2[N:26]=NN[C:23]=2[CH:22]=[CH:21]C=1.C(N(CC)CC)C.C1(CN)CC1>C(Cl)Cl>[CH:23]1([CH2:27][NH:26][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:6])[CH2:21][CH2:22]1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: NCC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CC1)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
Cyclopropyl carboxylic acid (1.0 g, 11.63 mmol) was added to a 50 mL two neck round bottom flask, along with DCM (25 mL). This mixture was cooled to 0° C., EDCI (4.15 g, 13.95 mmol) was added portionwise to the mixture with stirring under nitrogen atmosphere, and the temperature was maintained for 0.5 h. After this time, hydroxybenzotriazole (1.88 g, 13.95 mmol) was added to the 0° C. mixture which was stirred for 10 min, then triethylamine (1.7 g, 11.63 mmol) was added, and stirring of the mixture was continued at the same temperature for another 0.5 h. Then, cyclopropylmethylamine (0.825 g, 11.63 mmol) was added, and the reaction was allowed to reach RT, and stirring was continued overnight. The solvent was then removed in vacuo, and the crude residue was purified by passing through a column over 60-120 silica gel, eluting with dichloromethane, to afford the title compound (1.6 g), yield: 87%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([C:8]2[C:17](=[O:18])[N:16]([CH3:19])[C:15]3[C:10](=[CH:11][N:12]=[C:13]4[NH:22][CH:21]=[CH:20][C:14]4=3)[CH:9]=2)[CH:7]=1.[CH2:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=2)[C:35](O)=[O:36])[CH2:28][CH2:27]1)[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C>>[CH2:24]([N:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=2)[C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([C:8]3[C:17](=[O:18])[N:16]([CH3:19])[C:15]4[C:10](=[CH:11][N:12]=[C:13]5[NH:22][CH:21]=[CH:20][C:14]5=4)[CH:9]=3)[CH:7]=2)=[O:36])[CH2:30][CH2:31]1)[CH3:25]
Reactant: CCN1CCN(c2cc(C(=O)O)cc(C(F)(F)F)c2)CC1
Reactant: Cc1ccc(N)cc1-c1cc2cnc3[nH]ccc3c2n(C)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCN(c2cc(C(=O)Nc3ccc(C)c(-c4cc5cnc6[nH]ccc6c5n(C)c4=O)c3)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-(5-amino-2-methyl-phenyl)-9-methyl-3,9-dihydro-3,4,9-triaza-cyclopenta[a]naphthalen-8-one (22 mg, 0.07 mmol), 3-(4-Ethyl-piperazin-1-yl)-5-trifluoromethyl-benzoic acid (24 mg, 0.08 mmol), HATU (30 mg, 0.08 mmol) and DIEA (27 mg, 0.21 mmol) in 0.5 mmol DMF is stirred at room temperature for 2 hours. The solvent is removed by rotary evaporation. The crude product is purified by reverse phase HPLC to give the title compound as white solid. 1H NMR 400 MHz (DMSO-d6) δ 12.19 (s, 1H), 10.32 (s, 1H), 9.71 (s, 1H), 8.54 (s, 1H), 8.01 (s, 1H), 7.72 (s, 1H), 7.66 (m, 2H), 7.58 (s, 1H), 7.50 (t, 1H, J=2.8 Hz), 7.45 (s, 1H), 7.23 (d, 1H, J=8.4), 7.04 (s, 1H), 4.06 (m, 2H), 3.99 (s, 3H), 3.55 (b, 2H), 3.15 (m, 2H), 3.06 (m, 4H), 2.09 (s, 3H), 1.20 (t, 3H, J=7.2). MS m/z 589.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[N:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=2[CH3:1])=[CH:13][CH:12]=1
Reactant: Cc1c(N)cccc1Cl
Reactant: O=Cc1ccc(Cl)cc1
Product: Cc1c(Cl)cccc1N=Cc1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
2-methyl-3-chloroaniline (0.25 mole) and 4-chlorobenzaldehyde (0.25 mole) are ground in a mortar. The mixture is heated, with stirring in a water bath for 1.5 hours. Distillation at reduced pressure gives N-(p-chlorobenzylidene)-2-methyl-3-chloroaniline; Bp. 139° C./0/020 mm.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([NH2:20])=[N:16][NH:17]2)=[CH:13][CH:12]=1.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28](Cl)=[O:29]>N1C=CC=CC=1>[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([NH:20][C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)=[O:29])=[N:16][NH:17]2)=[CH:13][CH:12]=1
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2cc(Cl)ccc12)c1ccccn1
Temperature: 8 °C
Reaction time: 18 h

Procedure:
4.2 cm3 of diisopropylethylamine are added to 1 g of 6-chloro-1H-indazole-3-amine in 15 cm3 of pyridine. The reaction medium is cooled to about 8° C. to add 1.08 g of picolinoyl chloride hydrochloride, and the temperature is allowed to return to room temperature over 18 hours. The reaction medium is concentrated to dryness under reduced pressure (2 kPa; 40° C.) and the residue is then taken up in 25 cm3 of ethyl acetate and 25 cm3 of distilled water. The organic phase is washed with 25 cm3 of water and then with 25 cm3 of saturated aqueous sodium chloride solution. After drying over magnesium sulphate, filtration and concentration under reduced pressure (2 kPa; 40° C.), the residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a dichloromethane/methanol mixture (99/1 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 2×15 cm of diisopropyl ether. After filtration on a sinter funnel and drying under reduced pressure (90 Pa; 50° C.), 572 mg of N-[6-chloro-1H-indazol-3-yl]-2-pyridinecarboxamide are obtained in the form of a white solid melting at 177° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:34]1[CH:35]=[CH:36][N:37]=[C:38]2[C:43]=1[N:42]=[CH:41][C:40]([O:44][CH3:45])=[CH:39]2>CN(C=O)C.O>[CH3:45][O:44][C:40]1[CH:39]=[C:38]2[C:43]([C:34]([O:26][C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:12]4[C:13]5[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=5)[C:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)=[N:10][N:11]=4)=[CH:25][CH:24]=3)=[CH:35][CH:36]=[N:37]2)=[N:42][CH:41]=1
Reactant: COc1ccc(-c2nnc(Nc3ccc(O)cc3)c3ccccc23)cc1
Reactant: COc1cnc2c(Cl)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnc(Nc3ccc(Oc4ccnc5cc(OC)cnc45)cc3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 5 mL microwave tube was charged with 4-(4-(4-methoxyphenyl)phthalazin-1-ylamino)phenol and 3 equivalents of cesium carbonate (342 mg, 1.048 mmol) in 1.8 mL of DMF. The mixture was stirred at RT for 10 min. Following addition of 8-chloro-3-methoxy-1,5-naphthyridine (88 mg, 0.454 mmol), the vessel was capped and irradiated at 150° C. for 15 min in the microwave, at which time the reaction was determined complete by LC/MS. The mixture was cooled to ambient temperature and diluted with water. The solids were filtered and washed with water. The solids were triturated with methanol, filtered to remove remaining impurities, washed with additional methanol and dried under vacuum to afford N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)-4-(4-methoxyphenyl)phthalazin-1-amine as a light orange solid. MS [M+H]=502; Calc'd 501.54 for C30H25N5O3.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[CH2:9][CH:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:35]([N:37]([CH2:42][CH3:43])[C:38](=[O:41])[CH2:39]Cl)[CH3:36]>C(COC)OC.CCOCC>[CH2:35]([N:37]([CH2:42][CH3:43])[C:38](=[O:41])[CH2:39][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH:10]([OH:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:27][CH:26]=1)[CH3:36]
Reactant: Oc1ccc(CCN(Cc2ccccc2)CC(O)COc2ccccc2)cc1
Reactant: CCN(CC)C(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOC
Product: CCN(CC)C(=O)COc1ccc(CCN(Cc2ccccc2)CC(O)COc2ccccc2)cc1
Reaction time: 2 h
Yield: 99.6 %

Procedure:
4-[2-(N-Benzyl-N-(2-hydroxy-3-phenoxypropyl)amino)ethyl]phenol (5.1 g) was added to a stirred solution of potassium t-butoxide (1.57 g) in dimethoxyethane (100 ml). To the resulting solution was added N,N-diethylchloroacetamide (2.1 g) and the mixture was stirred for two hours. The mixture was diluted with ether (300 ml) and washed with brine (2×20 ml). The solution was dried (MgSO4) and evaporated under reduced pressure to yield the crude intermediate (12.5 g). The crude intermediate was purified by chromatography on K60 silica (225 g) using a gradient mixture of methanol and dichloromethane (1% to 3% of methanol) to give N,N-diethyl-4-[2-(N-benzyl-N-(2-hydroxy-3-phenoxypropyl)amino)ethyl]-phenoxyacetamide (6.6 g) as a gum. The gum was dissolved in methanol (400 ml) and treated with 10% palladium on carbon (380 mg). The mixture was stirred under an atmosphere of hydrogen for 4 hours. The catalyst was removed by filtration through Kieselguhr, and the filtrate evaporated to give the product (5.0 g) as a colourless oil, which was dissolved in dichloromethane (300 ml) and acidified to pH3with ethereal hydrogen chloride. The solvent was removed by evaporation and replaced with fresh dichloromethane which also was evaporated. The residual gum was dissolved in methyl acetate from which it crystallised as N,N-diethyl-4-[2-(2-hydroxy-3-phenoxypropylamino)ethyl]phenoxyacetamide hydrochloride (4.49 g) m.p. 113°-5° C.; NMR: 1.05[t,3H, CH3 ]; 1.15[t,3H, CH3 ]; 2.90-3.08[m,2H, CH2C6H4 ]; 3.08-3.45(m,8H, CH2NCH2 +CH2NHCH2 ]; 4.0[m,2H,PhOCH2 ]; 4.25[m,CHOH]; 4.75[s,2H,OCH2CO]; 6.85-7.05[m,5H, aromatic H]; 7.25-7.4[m,4H, aromatic H]: microanalysis: found: C, 62.9; H,7.6; N, 6.1; Cl 8.3%; C23H32N2O4.HCl requires: C, 63.2; H,7.6; N, 6.4; Cl 8.1%.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[C:7]=1[CH3:8].[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[O:15]1>>[CH3:8][C:7]1[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][C:3]=1[CH2:2][O:27][C:24]1[CH:23]=[CH:22][C:21]([B:16]2[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]2)=[CH:26][CH:25]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: Cc1c(CCl)oc2ccccc12
Product: Cc1c(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)oc2ccccc12
Yield: 44 %

Procedure:
Alkylation of 2-chloromethyl-3-methyl-benzofuran with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol was carried out according to Example 136, Step 3, to give 3-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-benzofuran in 44% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.3 (s, 12 H) 2.3 (s, 3 H) 5.2 (s, 2 H) 7.0 (d, J=8.6 Hz, 2 H) 7.3 (m, 2 H) 7.5 (dd, J=21.6, 7.7 Hz, 2 H) 7.8 (d, J=8.8 Hz, 2 H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][C:13]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].Cl>ClC1C=CC=CC=1Cl.C1(C)C=CC=CC=1>[CH3:22][C:20]1[CH:19]=[CH:18][C:14]([C:15](=[O:16])[C:9]2[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=2)=[C:13]([CH3:12])[CH:21]=1
Reactant: Fc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)c2ccc(F)cc2)c(C)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a suspension of anhydrous aluminum chloride (16.2 g) dispersed in 1,2-dichlorobenzene (150 ml) was added fluorobenzene (13 g), and thereto was added dropwise 2,4-dimethylbenzoyl chloride (17.0 g) at 0–20° C. The mixture was stirred at 10–30° C. for 1 hr and heated to 80° C. The mixture was stirred for 1 hr, cooled again and poured into 6N hydrochloric acid. The reaction mixture was diluted with a great excess toluene and partitioned. The obtained organic layer was washed successively with 5% aqueous sodium hydroxide solution and water, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane-ethyl acetate as eluent to give nearly pure 1,3-dimethyl-4-(4′-fluorobenzoyl)benzene (19.4 g, 85%) as pale-yellow oil. The spectrum data of this oil were the same as those confirmed in Example 7.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:25]1[C:29]2[CH:30]=[C:31]([N:34]=[C:35]=[O:36])[CH:32]=[CH:33][C:28]=2[O:27][CH2:26]1>O1CCCC1>[O:27]1[C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([N:15]3[CH2:16][CH2:17][N:12]([C:10]4[S:9][N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:11]=4)[CH2:13][CH2:14]3)=[O:36])=[CH:30][C:29]=2[CH2:25][CH2:26]1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1ccc2c(c1)CCO2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)CCO2)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2,3-dihydrobenzo[b]furan-5-isocyanate (197 mg, 1.22 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 268 mg (81.0%) of the desired product as a solid.
Reaction SMILES: [O:1]=[C:2]([CH:8]=[CH2:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][NH:11][CH3:12]>CCOCC>[CH3:10][N:11]([CH2:9][CH2:8][C:2](=[O:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:12]
Reactant: CNC
Reactant: C=CC(=O)C(=O)OCC
Solvent: CCOCC
Product: CCOC(=O)C(=O)CCN(C)C
Reaction time: 24 h

Procedure:
To a stirred solution of 12.8 g (0.10 mole) of ethyl 2-oxo-3-butenoate in 200 ml of anhydrous ether under a nitrogen atmosphere (in an ice bath) is added over about 1 hr. a cold solution of 4.5 g (0.10 mole) of dimethylamine in 200 ml of anhydrous ether. The reaction is stirred at 0° for several hours, and then at 20°-25° for one day. The solvent is removed, and the resulting crude product is purified by flash chromatography on silica gel using chloroform/methanol as eluant.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([C:7](Br)([F:9])[F:8])[CH:6]=1.[F-:11].[K+]>C(OC(C)C)(C)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:7]([F:9])([F:11])[F:8])[CH:6]=1
Reactant: FC(F)(Br)n1cc(Br)cn1
Reactant: [F-]
Agent: *CC(*)C
Agent: [K+]
Solvent: CC(C)OC(C)C
Product: FC(F)(F)n1cc(Br)cn1
Yield: 55 %

Procedure:
HF-pyridine complex (129 mL) was added to a stirred and cooled (ice bath) solution of bromide 5 (72.68 g, 0.263 mol) in diisopropyl ether (196 mL) in a polypropylene reaction vessel. Mercuric oxide red (48.4 g, 0.222 mol) was then added in small portions over a period of 3 h at RT. The mixture was stirred for additional 4 h at RT and was poured onto a 25% aqueous KF (650 mL). The solid was filtered off and washed with ether (100 mL). The filtrate was extracted with ether (3×100 mL). Combined extracts were dried (MgSO4), concentrated under reduced pressure and distilled to afford 6 (31.05 g, 55%) as colourless liquid b.p. 35-37° C./25 mm Hg, which crystallized on standing in a refrigerator, m.p. 4° C. 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.86 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:24][CH2:25][O:26][CH3:27])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[CH2:28][CH2:29][CH3:30])[CH:5]=[CH:4][N:3]=1.O.Cl.O1CCOC[CH2:34]1>CCCCCCC.C[Al](C)C>[F:17][C:16]([F:19])([F:18])[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:34])[CH:7]=2)=[C:10]([CH2:28][CH2:29][CH3:30])[CH:11]=1)([O:24][CH2:25][O:26][CH3:27])[C:20]([F:23])([F:22])[F:21]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(Cl)c1
Reactant: C1COCCO1
Agent: C[Al](C)C
Agent: Cl
Solvent: CCCCCCC
Solvent: O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(C)c1
Yield: 94 %

Procedure:
To a solution of 2-chloro-4-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy) pyridine (867 mg, 559 μmol) in 1,4-dioxane, trimethylaluminum heptane solution (2 mol/L, 1.13 mL) and tetrakis triphenylphosphine palladium complex (218 mg) were added at room temperature under an argon atmosphere, and then the resultant mixture was heated at 80° C. After completion of the reaction, the reaction solution was neutralized by adding water and 2 mol/L of hydrochloric acid, extracted with ethyl acetate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (780 mg, yield 94%) was obtained as a colorless oil.
Reaction SMILES: O(P(O[C:18]1[CH2:19][C@@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[O:42]=[C:43]1[NH:47][C:46](=[O:48])[CH:45]([C@@H:49]2[CH2:53][C@H:52]([S:54]CC3C=CC(OC)=CC=3)[CH2:51][N:50]2[C:64]([O:66][CH2:67][C:68]2[CH:73]=[CH:72][C:71]([N+:74]([O-:76])=[O:75])=[CH:70][CH:69]=2)=[O:65])[NH:44]1>>[O:42]=[C:43]1[NH:47][C:46](=[O:48])[CH:45]([C@@H:49]2[CH2:53][C@H:52]([S:54][C:18]3[CH2:19][C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])[CH2:51][N:50]2[C:64]([O:66][CH2:67][C:68]2[CH:73]=[CH:72][C:71]([N+:74]([O-:76])=[O:75])=[CH:70][CH:69]=2)=[O:65])[NH:44]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C3NC(=O)NC3=O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)C[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4NC(=O)NC4=O)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Yield: 17.6 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (150 mg, 0.258 mmol) and (2S,4S)-2-(2,4-dioxoimidazolidin-5-yl)-4-(p-methoxybenzylthio)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (120 mg, 0.240 mmol, compound of Reference Example 28) to obtain p-nitrobenzyl (5R,6S)-2-[(2S,4S)-2-(2,4-dioxoimidazolidin-5-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (30 mg, yield: 18%).
Reaction SMILES: N[C:2]1[N+:7]([O-:8])=[C:6]([CH2:9][C:10](CC(C)C)([CH3:12])[CH3:11])[C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4][C:3]=1[CH2:25][OH:26].[CH3:27][S:28]SC.N(OCCC(C)C)=O.C(OCC)C>CC#N>[CH2:18]([O:17][C:5]1[C:6]([CH2:9][CH:10]([CH3:12])[CH3:11])=[N+:7]([O-:8])[C:2]([S:28][CH3:27])=[C:3]([CH2:25][OH:26])[N:4]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CSSC
Reactant: CC(C)CC(C)(C)Cc1c(OCc2ccccc2)nc(CO)c(N)[n+]1[O-]
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: CCOCC
Product: CSc1c(CO)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Temperature: 25 °C

Procedure:
4.55 Grams of 6-amino-5-hydroxymethyl-3-benzyloxy-2-isobutyl isobutylpyrazine 1-oxide and 6.75 ml of dimethyl disulfide were dissolved in 50 ml of CH3CN, and thereto was added 3.02 ml of isoamyl nitrite. The mixture was subjected to a reaction for 20 minutes at 70°-80° C., and the reaction mixture was cooled to room temperature, and mixed with 150 ml of diethyl ether. The resulting mixture was washed with water (100 ml×3), and the ether layer was dried over MgSO4. The solvent was removed by evaporation. The residue was purified by a silica gel chromatography (30% EtOAc-hexane), followed by recrystallization from isopropyl ether-n-hexane to obtain 2.17 g of colorless needle-like crystals (Compound E-52c) having a melting point of 88.5°-86.5° C.