Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1Br.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2)C2C=CC(C)=CC=2)=CC=1>C1(C)C=CC=CC=1.CCOCC.[Pd]>[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[NH:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(CCc2ccc(Cl)c(Cl)c2)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: [Pd]
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2cccc3ccccc23)cc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)c1cc([N+](=O)[O-])ccc1Nc1ccc(CCc2ccc(Cl)c(Cl)c2)cc1
Yield: 64.4 %

Procedure:
A mixture of 4-[2-(3,4-dichlorophenyl)-ethyl]benzenamine (600 mg, 2.25 mmol), 2-bromo-5-nitrobenzoic acid methyl ester (489 mg, 1.88 mmol), cesium carbonate (857 mg, 2.62 mmol), tris(dibenzylideneacetone-dipaladium(0) (51 mg, 0.056 mmol) and (S)-(2,2′-bis(di-p-tolylphosphino-1,1′-binaphthyl (98%, (S)-tol-BINAP) (58 mg, 0.085 mmol) (Ligand/Pd=1.5) in anhydrous toluene (16 mL) was heated to 100° C. for 12 hours under N2. After cooling, the reaction mixture was diluted with ether, filtered through celite and rinsed thoroughly with ether. The filtrate was evaporated to dryness to give a brown residue. Purification by flash chromatography (silica gel, 5% EtOAc/hexane) yielded 540 mg (1.21 mmol, 64%) of the desired product. mp 107-108° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][O:30][C:31]2[C:36]([N:37]3[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]3)=[C:35]([CH3:44])[CH:34]=[CH:33][N:32]=2)=[CH:27][CH:26]=1>ClCCl>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][O:30][C:31]2[C:36]([N:37]3[CH2:42][CH2:41][C:40](=[O:43])[CH2:39][CH2:38]3)=[C:35]([CH3:44])[CH:34]=[CH:33][N:32]=2)=[CH:45][CH:46]=1
Reactant: COc1ccc(COc2nccc(C)c2N2CCC(O)CC2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(COc2nccc(C)c2N2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of Dess-Martin periodinane (11.61 g, 27.37 mmol) in dichloromethane (122 ml) at room temperature was treated with a solution of 2′-(4-Methoxybenzyloxy)-4′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-ol (7.49 g, 22.81 mmol) in dichloromethane (81 ml) and the reaction mixture was stirred at room temperature. After 1 hour, the reaction mixture was washed with sat'd Na2S2O3(aq.), sat'd NaHCO3(aq.), and sat'd NaCl(aq.), dried over MgSO4, filtered, and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 3:2 hexanes:EtOAc) gave the title compound as an off-white, crystalline solid (6.40 g, 86%).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[C:6]([F:12])[C:3]=1[CH:4]=O.[N+:13]([CH2:16][CH3:17])([O-:15])=[O:14].C1(N)CCCCC1>C(O)(=O)C>[F:11][C:7]1[CH:8]=[C:9]([F:10])[C:2]([F:1])=[C:3]([CH:4]=[C:16]([N+:13]([O-:15])=[O:14])[CH3:17])[C:6]=1[F:12]
Reactant: O=Cc1c(F)c(F)cc(F)c1F
Reactant: CC[N+](=O)[O-]
Solvent: NC1CCCCC1
Solvent: CC(=O)O
Product: CC(=Cc1c(F)c(F)cc(F)c1F)[N+](=O)[O-]
Temperature: 80 °C
Yield: 91.1 %

Procedure:
A mixture of 2,3,5,6-tetrafluorobenzaldehyde (25.0 g, 0.14 mol), nitroethane (21.08 g, 0.28 mol), and cyclohexylamine (13.92 g, 0.14 mol) in 150 mL of acetic acid was heated at 80° C. for 5-6 h under an argon atmosphere. After the end of the reaction was established by TLC, the reaction mixture was cooled to room temperature (rt) and the solvent was removed under vacuum. The residue was diluted with water, extracted with ethyl acetate three times. The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated under vacuum. Product was purified by a silica gel chromatography using ethyl acetate and hexanes (1:6 to 1:4) as eluent to afford 30.0 g (91%) of the designed compound as yellow solid. Mass (ESI, positive) m/z 258.0 [M+Na]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.I[CH3:15].[NH2-].[Na+].O>C1(C)C=CC=CC=1.ClCCl>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([CH:9]([CH3:15])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CI
Reactant: N#CCc1cccc(C(F)(F)F)c1
Agent: [NH2-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C#N)c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
1.0 g (5.4 mmol) of 3-(trifluoromethyl)phenylacetonitrile and 767 mg of iodomethane (5.4 mmol) are placed in 5 ml toluene at 80° C. and slowly treated with a 50% suspension of sodamide in toluene. Next the mixture is stirred 1 hr more at 80° C., then cooled to RT and treated with water, then dichloromethane. The organic phase is separated, washed with water, dried over magnesium sulphate and freed of solvent on the rotary evaporator. The residue (1.7 g, 84% of theory) contains the title compound with a purity of ca. 53% by GC/MS and is used without purification for the next reaction.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]([NH:12][CH:13]([C:20]([C:22]3[CH:26]=[C:25]([Cl:27])[S:24][CH:23]=3)=[O:21])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=O)[CH:8]=[CH:9][C:2]1=2.P(Cl)(Cl)(Cl)=O.O>CN(C)C=O>[O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]3[O:21][C:20]([C:22]4[CH:26]=[C:25]([Cl:27])[S:24][CH:23]=4)=[C:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]=3)[CH:8]=[CH:9][C:2]1=2
Reactant: CCOC(=O)CC(NC(=O)c1ccc2occc2c1)C(=O)c1csc(Cl)c1
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc3occc3c2)oc1-c1csc(Cl)c1
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To a solution of the resulting crude product of ethyl 3-[(5-benzo[b]furoyl)amino]-4-(5-chlorothiophen-3-yl)-4-oxobutyrate (896 mg) in N,N-dimethylformamide (7 ml) was added phosphoryl chloride (0.48 ml) at room temperature, and the mixture was stirred at the same temperature overnight. To the reaction mixture was added water, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane:acetone=7:1), and then, triturated with diethyl ether to obtain ethyl 2-(5-benzo[b]furyl)-5-(5-chloro-thiophen-3-yl)oxazol-4-ylacetate (349 mg) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Cl:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][Cl:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccnc(Cl)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: ClCc1ccnc(Cl)n1
Temperature: 25 °C

Procedure:
The mixture of 2-Chloro-4-methyl-pyrimidine (51) (6.48 g, 50 mmol), N-chloro succinimide (8.0 g, 60 mmol), and benzoyl peroxide (2.42 g, 10 mmol) in carbon tetrachloride (100 ml) was refluxed for 22 hr. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:2)) to afford 3.3 g (40%). 1H NMR (200 MHz, CDCl3) δ: 4.57 (2H, s), 7.50 (1H, d, J=5.2 Hz), 8.65 (1H, d, J=5.2 Hz).
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7]([CH2:9][C@@H:10]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11](=[O:22])[NH:12][C@H:13]([CH2:17][O:18][CH2:19][CH:20]=[CH2:21])[CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]1)C=C>ClCCl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[CH:14]([C@@H:13]1[NH:12][C:11](=[O:22])[C@H:10]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:9][C:7]2=[CH:8][N:4]([CH:5]=[N:6]2)[CH2:1][CH:21]=[CH:20][CH2:19][O:18][CH2:17]1)([CH3:15])[CH3:16]
Reactant: C=CCOC[C@@H](NC(=O)[C@@H](Cc1cn(CC=C)cn1)NC(=O)OCc1ccccc1)C(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2)c(C)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: CC(C)[C@H]1COCC=CCn2cnc(c2)C[C@@H](NC(=O)OCc2ccccc2)C(=O)N1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
A solution of 0.735 g (1.62 mmol) of benzyl [(R)-2-(1-allyl-1H-imidazol-4-yl)-1-((S)-1-allyloxymethyl-2-methylpropylcarbamoyl)ethyl]carbamate in 370 ml of dichloromethane was mixed with 0.210 g (0.24 mmol) of benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium (Grubbs II catalyst) and stirred at RT. The mixture was stirred at RT for several days with repeated addition of Grubbs II catalyst until starting material was no longer present (LC/MS). The mixture was concentrated and the residue was chromatographed on silica gel (dichloromethane/methanol 99:1→9:1). 0.506 g of the title compound was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23])([O-:14])=[O:13]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N+:12]([O-:14])=[O:13])=[O:23]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1[N+](=O)[O-]
Yield: 42.7 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(2-nitro phenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-nitro phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (0.44 g, 44%). EI-MS m/z 319 (M+H)+
Reaction SMILES: N1C2C(=CC(O[CH:12]([CH2:22][CH3:23])[C:13]([NH:15][C:16]([CH3:21])([CH3:20])[C:17]#[C:18][CH3:19])=[O:14])=CC=2)C=CC=1.[Br:24]C(CC)C(Br)=O.C(N(CC)CC)C.O>ClCCl>[Br:24][CH:12]([CH2:22][CH3:23])[C:13]([NH:15][C:16]([CH3:21])([CH3:20])[C:17]#[C:18][CH3:19])=[O:14]
Reactant: CC#CC(C)(C)NC(=O)C(CC)Oc1ccc2ncccc2c1
Reactant: CCC(Br)C(=O)Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CC(C)(C)NC(=O)C(Br)CC
Temperature: 3 °C

Procedure:
The product from Step 3 (5.0 g) was dissolved in dry dichloromethane (200 ml), cooled to 3° C. with stirring then 2-bromobutyryl bromide (6.25 g) was added followed by dropwise addition of dry triethylamine (10.93 ml), maintaining the reaction at 5° C. The suspension, which had formed during the reaction, was stirred at ambient temperature for 1 hour then water was added. The organic phase was separated, washed with water, dried over magnesium sulphate then evaporated under reduced pressure. The residue was fractionated by chromatography (silica; hexane/diethyl ether, 3:1 by volume) to give the required product, 5.2 g, as a colourless solid, m.p. 79–81° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[CH2:7]([O:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1Cl)[CH:8]=[CH2:9].[OH-].[K+]>CS(C)=O>[CH2:7]([O:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:5]1[CH:6]=[C:2]([Cl:1])[N:3]=[CH:4]1)[CH:8]=[CH2:9]
Reactant: Clc1c[nH]cn1
Reactant: C=CCOc1cc([N+](=O)[O-])ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=CCOc1cc([N+](=O)[O-])ccc1-n1cnc(Cl)c1
Temperature: 90 °C
Yield: 40.4 %

Procedure:
A mixture of 4-chloro-1H-imidazole (3.31 g, 32.0 mmol), 2-(allyloxy)-1-chloro-4-nitrobenzene (6.50 g, 30.8 mmol), and potassium hydroxide flakes (1.90 g, 33.9 mmol) in anhydrous DMSO (50 mL) was heated at 90° C. for 20 h under nitrogen. The reaction mixture was allowed to cool to rt and ice-cold water was added. The resulting precipitate was collected by vacuum filtration. The product was dried, and purified by column chromatography (5% EtOAc/Hexane) to afford the yellow solid 1-(2-(allyloxy)-4-nitrophenyl)-4-chloro-1H-imidazole (3.48 g, 40% yield). LC-MS (M+H)+280.2. 1H NMR (400 MHz, CDCl3) δ ppm 7.97-7.93 (2H, m), 7.77 (1H, s), 7.44 (1H, d, J=8.8 Hz), 6.05-5.98 (1H, m), 5.45-5.37 (2H, m), 4.70-4.65 (2H, m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][CH:2]=1.[OH-].[Na+].Cl[CH2:11][C:12]([OH:14])=[O:13].Cl>>[O:7]=[C:4]1[N:3]([CH2:11][C:12]([OH:14])=[O:13])[CH:2]=[N:1][CH:6]=[CH:5]1
Reactant: O=C(O)CCl
Reactant: O=c1ccnc[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1cnccc1=O
Temperature: 105 °C

Procedure:
To pyrimidin-4(3H)-one (0.608 g, 6.33 mmol) was added 5 N sodium hydroxide solution (2.5 mL) followed by chloroacetic acid (0.598 g, 6.33 mmol). The reaction mixture was heated at 105° C. for 2 h. After cooled down to ambient temperature, it was neutralized with 2 N hydrochloric acid (3.2 mL) and then directly purified by reverse phase HPLC (TMC Pro-Pac C18; 0-40% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). Removal of the volatiles in vacuo afforded the title compound as a white solid. 1H NMR (DMSO-d6): δ 13.2 (s, 1H), 8.43 (s, 1H), 7.94 (d, J=6.7 Hz, 1H), 6.43 (d, J=6.6 Hz, 1H), 4.63 (s, 2H). LC/MS 155.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[O:14])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[ClH:15].Cl.[Cl:17][C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][SH:32])[CH2:25][CH2:24]2)=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:17].[ClH:15].[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[SH:32][CH2:31][CH2:30][CH2:29][N:26]2[CH2:27][CH2:28][N:23]([CH2:22][C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:34][CH:33]=3)[CH2:24][CH2:25]2)[OH:14])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(O)=[SH]CCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Yield: 55.2 %

Procedure:
The procedure described in Example 2 was followed, using 1.1 g of 4-ethoxycarbonylphenyl isocyanate, 2.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.85 g (28% of theory) of N-(4-ethoxycarbonylphenyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 231°-233° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1F)#[N:2].[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CS(C)=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1[NH:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)#[N:2]
Reactant: NCC1CCCCC1
Reactant: COC(=O)c1ccnc(-c2ccc(F)c(C#N)c2)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(-c2ccc(NCC3CCCCC3)c(C#N)c2)c1
Temperature: 40 °C
Reaction time: 17 h

Procedure:
In 3 ml of DMSO was dissolved 247 mg of methyl 2-(3-cyano-4-fluorophenyl)isonicotinate, and 0.31 ml of aminomethylcyclohexane was added thereto. After being stirred at 40° C. for 17 hours, the reaction solution was diluted with ethyl acetate and washed with water and brine, successively. The organic layer was dried and concentrated under reduced pressure and then recrystallization was performed from a mixed solvent of diisopropyl ether and hexane to obtain 266 mg of methyl 2-{3-cyano-4-[(cyclohexylmethyl)amino]phenyl}isonicotinate. (2) Then, 266 mg of the compound was dissolved in a mixed solvent of 5 ml of methanol and 10 ml of THF, and 1.14 ml of a 1M aqueous sodium hydroxide solution was added thereto, followed by heating at 80° C. for 1 hour. After cooling, the reaction solution was diluted with water and washed with diethyl ether. The resulting aqueous layer was neutralized with 1M hydrochloric acid and extracted with ethyl acetate and the organic layer was dried and concentrated under reduced pressure. The resulting residue was recrystallized from a mixed solvent of ethanol and water to obtain 199 mg of 2-{3-cyano-4-[(cyclohexylmethyl)amino]phenyl}isonicotinic acid. Then, 199 mg of the compound was dissolved in 10 ml of ethanol and 0.59 ml of a 1M aqueous sodium hydroxide solution was added thereto. After stirring at room temperature for 15 minutes, the reaction solution was concentrated. The resulting residue was washed with 2-propanol to obtain 181 mg of sodium 2-{3-cyano-4-[(cyclohexylmethyl)amino]phenyl}isonicotinate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>O.C1COCC1>[OH:27][CH:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccncc1C#N
Reactant: O=Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cnccc1CC(O)c1ccccc1
Reaction time: 1 h
Yield: 91.1 %

Procedure:
4-methyl-nicotinonitrile (2.0 g, 16.93 mmol) was dissolved in20 mL of anhydrous THF(20 mL), added with LHMDS (1M solution in THF, 34 mL, 33.86 mmol) at −78° C. under the nitrogen atmosphere and then stirred for about 1 hour at the same temperature. The mixture was dropwisely added with benzaldehyde (2.1 mL, 20.32 mmol) and stirred at −50° C. for about 1 hour. The mixture, while being stirred at 0° C., added with 30 mL of saturated solution of ammonium chloride and 50 ML of distilled water, and then extracted twice with 100 ML of EtOAc. The resulting organic layer was washed with a saturated solution of sodium chloride, dried with anhydrous sodium sulfate, filtered and concentrated. A silica gel column chromatography (2% MeOH/MC) was performed on the resulting residue and obtained 3.46 g (91%) of 4-(2-hydroxy-2-phenyl-ethyl)-nicotinonitrile in pale yellow solid.
Reaction SMILES: C(N(CC)C(C1C=CC=CC=1[S:12]([C:15]1[C@H:16]([CH3:46])[C@@H:17]2[C@@H:34]([C@H:35]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH3:36])[C:33](=[O:45])[N:18]2[C:19]=1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21])(=O)=O)=O)C.[N+:49]([C:52]1[CH:65]=[CH:64][C:55]([CH2:56][O:57][C:58]([NH:60][CH2:61][CH2:62]S)=[O:59])=[CH:54][CH:53]=1)([O-:51])=[O:50]>>[Si:38]([O:37][C@@H:35]([C@H:34]1[C:33](=[O:45])[N:18]2[C:19]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:21])=[C:15]([S:12][CH2:62][CH2:61][NH:60][C:58]([O:57][CH2:56][C:55]3[CH:64]=[CH:65][C:52]([N+:49]([O-:51])=[O:50])=[CH:53][CH:54]=3)=[O:59])[C@H:16]([CH3:46])[C@H:17]12)[CH3:36])([C:41]([CH3:43])([CH3:44])[CH3:42])([CH3:39])[CH3:40]
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2[C@H]1C
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H](C)[C@H]12
Yield: 87 %

Procedure:
Following a procedure similar to that described in Example 19(c), but using 4-nitrobenzyl (1R, 5S,6S)-2-(2-diethylcarbamoylphenylsulfonyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 42) and 2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 87%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1)[NH2:5].Br[C:19]1[S:23][C:22]([N:24]2[CH2:30][CH2:29][CH2:28][NH:27][C:26](=[O:31])[CH2:25]2)=[N:21][C:20]=1[Cl:32].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:5][C:4]1[CH:6]=[C:7]([C:19]2[S:23][C:22]([N:24]3[CH2:30][CH2:29][CH2:28][NH:27][C:26](=[O:31])[CH2:25]3)=[N:21][C:20]=2[Cl:32])[CH:8]=[C:2]([CH3:1])[CH:3]=1
Reactant: O=C1CN(c2nc(Cl)c(Br)s2)CCCN1
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(N)cc(-c2sc(N3CCCNC(=O)C3)nc2Cl)c1
Temperature: 100 °C
Yield: 55.6 %

Procedure:
To a solution of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (preparation described in Intermediate XIX (1), 59 mg, 0.253 mmol), 4-(5-bromo-4-chloro-1,3-thiazol-2-yl)-1,4-diazepan-2-one (75 mg, 0.241 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (35 mg, 0.048 mmol) in dioxane (0.600 mL) was added 2M aqueous sodium carbonate (0.240 mL, 0.480 mmol). The mixture was heated on a reaction block at 100° C. for 3 hours, and subsequently cooled to room temperature. The dark mixture was filtered through a celite plug, which was rinsed with 10% isopropanol in CHCl3. The eluent was concentrated and purified by preparative HPLC Normal phase, eluting with CH2Cl2/MeOH (0-30%). The 3rd peak was collected and concentrated to give 4-[5-(3-amino-5-methylphenyl)-4-chloro-1,3-thiazol-2-yl]-1,4-diazepan-2-one (45 mg, 0.134 mmol, 29.1% yield) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([CH3:10])=[C:7]([CH:9]=1)N.Cl.N([O-])=O.[Na+].[Cu](C#N)[C:20]#[N:21].[C-]#N.[Na+]>CC(C)=O.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([CH3:10])=[C:7]([CH:9]=1)[C:20]#[N:21]
Reactant: N#C[Cu]C#N
Reactant: COc1cc(N)c(C)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=N[O-]
Agent: [C-]#N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cc(C#N)c(C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To 5-methoxy-2-methyl-4-nitroaniline (4.9 g, 26.8 mmol) in a mixture of acetone (17.5 mL) and water (19 mL) at 0° C. was added conc. HCl (5.6 mL). A solution of sodium nitrite (2.25 g, 32.6 mmol) in water (7.5 mL) was added dropwise and the mixture was allowed to stir at 0° C. for 30 min. The mixture was then added dropwise to a mixture of copper cyanide (3.75 g, 42 mmol) and sodium cyanide (5.5 g, 112 mmol) in water (25 mL) and EtOAc (12.5 mL). The mixture was allowed to stir at RT for 2 h and then water (50 mL) was added. The mixture was extracted with EtOAc (3×100 mL) and the combined organic fractions were washed with 2 M NaOH(aq) (50 mL) and brine (50 mL). The organic fraction was passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was triturated with iso-hexane and dried to give 5-methoxy-2-methyl-4-nitrobenzonitrile (4.62 g, 90%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M]−=192 at 3.19 min. 1H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H), 7.31 (s, 1H), 3.98 (s, 3H), 2.55 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CCN(CC)CC.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(Cl)Cl>[N:21]1([S:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1COCCN1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a suspension of 4-acetylbenzenesulfonyl chloride (5.5 g, 25 mmol) in CH2Cl2 (75 mL) and Et3N (2 equiv, 7.0 mL, 50 mmol) was added morpholine (1.5 equiv, 3.3 mL, 38 mmol) dropwise. The mixture was stirred at room temperature for 30 min. The mixture was then diluted with CH2Cl2 (100 mL) and washed with 5% HCl (2×50 mL), water (50 mL), and then brine (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to afford crude 1-[4-(morpholine-4-sulfonyl)phenyl]ethanone (2) (4.78 g, 18 mmol, 71%): HPLC Retention Time; 5.82 min. (Method B) M+1, 270.0.