Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[NH:12][N:13]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH:15]=2)=[O:9])=[N:6][CH:7]=1.CN1[C@@H](C)CNC[C@H]1C.[CH3:37][C@H:38]1[CH2:43][NH:42][CH2:41][C@@H:40]([CH3:44])[N:39]1[CH2:45][C:46]#[N:47].C(N(C(C)C)C(C)C)C>CS(C)=O.CO>[C:46]([CH2:45][N:39]1[C@@H:38]([CH3:37])[CH2:43][N:42]([C:2]2[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]3[NH:12][N:13]=[C:14]([O:16][CH2:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=4)[CH:15]=3)=[O:9])=[N:6][CH:7]=2)[CH2:41][C@H:40]1[CH3:44])#[N:47]
Reactant: C[C@@H]1CNC[C@H](C)N1CC#N
Reactant: COc1cc(COc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Agent: C[C@@H]1CNC[C@H](C)N1C
Solvent: CS(C)=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(COc2cc(NC(=O)c3cnc(N4C[C@@H](C)N(CC#N)[C@@H](C)C4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.3 %

Procedure:
5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (273 mg, 0.70 mmol) was added in one portion to a 3:1 mixture of (2R,6S)-1,2,6-trimethylpiperazine and 2-[(2S,6R)-2,6-dimethylpiperazin-1-yl]acetonitrile (180 mg, 1.40 mmol) in anhydrous dimethylsulfoxide (1.40 ml) at 25° C. The resulting solution was stirred at ambient temperature for 2 h. The reaction was incomplete and N-ethyldiisopropylamine (0.24 ml, 1.40 mmol) was added and the solution was stirred at 60° C. for a further 2 h. The reaction mixture was diluted with methanol (20 mL) and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (65 mg, 18%) as a yellow solid.
Reaction SMILES: [Br-:1].[Li+].[CH3:3][O:4][N:5]=[CH:6][C@@H:7]([F:41])[C@H:8]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C@H:9](OC1C=C(Cl)C(Cl)=CC=1Cl)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C(OCC)(=O)C>O1CCCC1.CN1CCN(C)C1=O>[CH3:3][O:4][N:5]=[CH:6][C@H:7]([F:41])[C@H:8]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C@@H:9]([Br:1])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: CON=C[C@@H](F)[C@H](OCc1ccc(OC)cc1)[C@@H](COCc1ccc(OC)cc1)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: [Br-]
Agent: [Li+]
Solvent: CN1CCN(C)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CON=C[C@H](F)[C@H](OCc1ccc(OC)cc1)[C@@H](Br)COCc1ccc(OC)cc1
Temperature: 65 °C
Reaction time: 7 h
Yield: 92.5 %

Procedure:
451 mg of lithium bromide was added to a solution of 1.15 g of (2R,3R,4R)-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)-4-(2,4,5-trichlorophenoxy)pentan al O-methyloxime in 6 mL of tetrahydrofuran and 6 mL of 1,3-dimethyl-2-imidazolidinone, and the obtained mixture was then stirred at 65° C. for 7 hours. Thereafter, ethyl acetate and a 25% lithium bromide aqueous solution were added to the reaction mixture. The organic layer was fractionated, and it was washed with a 12% lithium bromide aqueous solution and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 60/40), so as to obtain 857 mg of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)pentanal O-methyloxime in the form of a colorless oily product.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8]>CO.[Pd]>[CH2:3]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])[CH:2]([CH3:12])[CH3:1]
Reactant: CC(C)=Cc1cccc(C#N)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 3-(2-methyl-1-propenyl)benzonitrile (5.80 g) in methanol (50 ml) was added 10% palladium on activated carbon (1 g), and the mixture was stirred under hydrogen atmosphere (3 atm) at 25° C. for 1 hour. The catalyst was filtered off and the liltrate was evaporated to give 3-isobutylbenzonitrile (5.52 g) as a pale yellow oil.
Reaction SMILES: [CH:1]([O-])([O-])[O:2]C.[CH3:6][O:7][N:8]=[C:9]([C:15](=[O:17])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH3:18]O>>[CH3:6][O:7][N:8]=[C:9]([C:15]([O:2][CH3:1])([O:17][CH3:18])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=NOC)C(C)=O
Reactant: CO
Reactant: COC([O-])[O-]
Product: CCOC(=O)C(=NOC)C(C)(OC)OC
Reaction time: 2.5 h

Procedure:
Methyl orthoformate (31.8 g) and "Amberlist 15" (trademark) (1.7 g) were added to a stirred solution of ethyl 2-methoxyimino-3-oxobutyrate (syn isomer, 17.3 g) in dry methanol (50 ml) and stirred at 50° to 60° C. for 2.5 hours. To the resultant solution was added methyl orthoformate (10.6 g) and stirred for 2 hours. The solution was allowed to stand in refrigerator overnight and stirred at 50° to 60° C. for 2 hours. After evaporating methanol in vacuo, diethyl ether (100 ml) and water (50 ml) were added to the residue, and the organic layer was separated. The aqueous layer was extracted with diethyl ether. The organic layer and the extract were combined together and washed with a saturated aqueous solution of sodium chloride. The solution was dried over magnesium sulfate and evaporated under reduced pressure to give ethyl 2-methoxyimino-3,3-dimethoxybutyrate (syn isomer, 18 g). bp 61° to 64° C./0.35 mmHg.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:29]=[CH:28][C:14]3[NH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([N+:25]([O-])=O)[CH:19]=4)=[N:17][C:13]=3[CH:12]=2)[CH2:7][CH2:6]1>[Pd].C(OCC)(=O)C.CO>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:29]=[CH:28][C:14]3[NH:15][C:16]([C:18]4[CH:19]=[C:20]([NH2:25])[C:21]([NH2:24])=[CH:22][CH:23]=4)=[N:17][C:13]=3[CH:12]=2)[CH2:9][CH2:10]1
Reactant: COCCN1CCN(c2ccc3[nH]c(-c4ccc(N)c([N+](=O)[O-])c4)nc3c2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COCCN1CCN(c2ccc3[nH]c(-c4ccc(N)c(N)c4)nc3c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-{5-[4-(2-methoxy-ethyl)-piperazin-1-yl]-1H-benzoimidazol-2-yl}-2-nitro-phenylamine (0.5 g, 1.2 mmol) in 4:1 ethyl acetate/methanol (60 ml) under nitrogen, was added 5% palladium on carbon (100 mg) and the mixture was first evacuated and then stirred at room temperature under an atmosphere of hydrogen for 1 day. The reaction mixture was then filtered through Celite, washed with 1:1 ethyl acetate/methanol (10 mL) and the combined filtrate and washings were concentrated to give the crude 4-{5-[4-(2-methoxy-ethyl)-piperazin-1-yl]-1H-benzoimidazol-2-yl}-benzene-1,2-diamine as a thick oil that was used in the next step without any purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=1.[C:24](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:20]=1
Reactant: Cc1cc(N2CCC(C)C2=O)ccc1-c1ccc(C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(N3CCC(C)C3=O)cc2C)cc1
Reaction time: 3 h
Yield: 98.4 %

Procedure:
A stirred solution of 2'-methyl-4'-(3-methyl-2-oxopyrrolidin-1-yl)biphenyl-4-carboxylic acid (D21, 0.35 g, 0.0011 mole) in DMF (5 ml) at 25° C. was treated with anhydrous potassium carbonate (0.27 g, 0.0020 mole) and iodomethane (0.08 ml, 0.0014 mole). The mixture was stirred for 3 hours, then diluted with water (100 ml) and extracted with ethyl acetate (2×100 ml). The combined extract was washed with water (2×100 ml), then dried (Na2SO4) and concentrated in vacuo to afford the title compound as a beige solid (0.35 g, 99%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](/[CH:27]=[CH:28]/[C:29](O)=[O:30])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1cccc(/C=C/C(=O)O)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: COc1cccc(/C=C/C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)c1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(3-methoxy-phenyl)-acrylic acid.
Reaction SMILES: Br[CH:2]([CH:20]([CH3:22])[CH3:21])[C:3]([O:5]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:4].[CH2:23]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[CH3:24].[CH:32]([C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)([CH3:34])[CH3:33]>>[CH2:23]([C:25]1[CH:31]=[CH:30][C:28]([NH:29][C@H:2]([C:3]([OH:5])=[O:4])[CH:20]([CH3:22])[CH3:21])=[CH:27][CH:26]=1)[CH3:24].[CH:32]([C:35]1[CH:41]=[CH:40][C:38]([NH:39][C@H:2]([C:3]([OH:5])=[O:4])[CH:20]([CH3:22])[CH3:21])=[CH:37][CH:36]=1)([CH3:34])[CH3:33]
Reactant: CCc1ccc(N)cc1
Reactant: CC(C)C(Br)C(=O)OCc1cccc(Oc2ccccc2)c1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(N[C@H](C(=O)O)C(C)C)cc1
Product: CCc1ccc(N[C@H](C(=O)O)C(C)C)cc1

Procedure:
Following the procedure of Example 1, m-phenoxybenzyl α-bromoisovalerate is reacted with each of 4-ethylaniline and 4-isopropylaniline to yield the m-phenoxybenzyl ester of N-(4-ethylphenyl)valine, MS m/e 403.2 (M+), and N-(4-isopropylphenyl)valine, MS m/e 417.2 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[SH:7].[H-].[Na+].Cl[C:11]1[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=1>CN(C=O)C.C1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][C:11]1[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=1
Reactant: N#Cc1nccnc1Cl
Reactant: Cn1ccnc1S
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cn1ccnc1Sc1nccnc1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The title compound was prepared according to Example 1 by using 1-methyl-1H-imidazole-2-thiol (228 mg, 2.00 mmol), NaH (60% dispersion in mineral oil, 88 mg, 2.20 mmol), and 3-chloropyrazine-2-carbonitrile (280 mg, 2.00 mmol) in DMF and benzene (6 ml, 1/1) by stirring at room temperature under nitrogen atmosphere for 4 hr.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.Cl.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCCCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCCCCl
Yield: 72.5 %

Procedure:
A solution of 20.6 g (0.139 mole) of phthalic anhydride, 20 g (0.126 mole) of 5-chloropentylamine hydrochloride and 17.6 ml (0.126 mole) of triethylamine in 250 ml of toluene was heated to 130° C. for 4 hours. The obtained mixture was evaporated to dryness. The residue was taken up into 200 ml of water and extracted with ethyl acetate. The phases were separated and the organic phase was dried over sodium sulfate and evaporated to dryness. From the crude product, 23 g of the title product were obtained as an oil having the following characteristics:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(C1C=CC=C(CC=C)C=1[OH:24])C=C.C1(O)C=CC=CC=1.C(N(CC)CC)C>C(N(CC)CC)C>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:24])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: C=CCc1cccc(CC=C)c1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Oc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
Triethylamine (4 ml) and 4-toluenesulfonyl chloride (3.80 gm, 0.02 mol) were diluted with 1,2-dichloromethane (50 ml) and 2,6-diallylphenol (3.48 gm, 0.02 mol), dissolved in 1,2-dichloromethane (10 ml), was added drop wise to the phenol-triethylamine solution at room temperature and then refluxed for 1 hr. The reaction mixture was cooled, washed with water and dried over MgSO4, filtered and evaporated to give 4-toluenesulfonic acid: 2,6-diallylphenyl ester as an oil. Purification was carried out via filtering a hexane solution of the ester through silica gel. MS m/z 328 (M+ calcd for C19H20O3S=328). H NMR (300 MHz, CDCl3) d 2.50 (s, 3, CH3), 3.25–3.35 (d, 4, CH2), 4.95–5.10 (m, 4, CH2 vinyl), 5.75–5.90 (m, 2, CH, vinyl), 7.10–7.25 (m, 3, aromatic), 7.85–7.95 (m, 2, aromatic). Oxidation of product as described in Example 1 gave 4-toluenesulfonic acid 2,6-di(2,3-epoxypropyl)phenyl ester. MS m/z 360 (M+ calcd for C19H20O5S=360. H NMR (300 MHz, CDCl3) d 2.45–2.55 (m, 2, CH2 epoxypropyl), 2.50 (s, 3, CH3), 2.35–2.95 (m, 6, CH2 epoxypropyl), 3.21–3.35 (m, 2, CH epoxypropyl), 7.25–7.45 (m, 5, aromatic), 7.85–7.95 (d, 2, aromatic).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.I.O.[I-].[Na+]>C(#N)C>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:25][C:24]3[CH:26]=[CH:27][C:21]([C:20]([F:19])([F:28])[F:29])=[CH:22][CH:23]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: I
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1

Procedure:
7-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (12.0 g, 46.3 mmol) was dissolved in 20 mL of anhydrous acetonitrile and 4-(trifluoromethyl)aniline was added (7.0 mL, 55.6 mmol), followed by 47% HI/H2O (2.0 L) and sodium iodide (10.3 g, 69.5 mmol). The mixture was heated at refluxed overnight and solvents were removed under vacuum. The residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to a yellow solid which was purified by silica gel flash chromatography using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as a brown oil (15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].Cl[C:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12].O>CO>[C:14]1([O:13][C:11]([N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH2:3]2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cccnc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(Oc1ccccc1)N1C=CC=C(Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To a solution of 3-chloro-pyridine (6.0 g, 53 mmol) in methanol (50 mL) was added NaBH4 (2.6 g, 69 mmol) at −78° C., following addition of phenyl chloroformate (8.3 g, 53 mmol) at same temperature. The mixture was stirred at r.t. for 0.5 h. Then water (200 mL) was added slowly into the solution. The precipitate was collected by filtration to give crude product (Yield: 8.2 g, 67%).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:11])[O:9][CH3:10].[NH2:13][CH2:14][C@@H:15]1[C@@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:19][CH2:18][N:17]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:16]1.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:28]([N:17]1[CH2:18][CH2:19][C@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C@@H:15]([CH2:14][NH:13][C:8](=[O:11])[O:9][CH3:10])[CH2:16]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)Cl
Reactant: Cc1ccccc1[C@H]1CCN(Cc2ccccc2)C[C@@H]1CN
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)NC[C@H]1CN(Cc2ccccc2)CC[C@@H]1c1ccccc1C
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
111 μL of triethylamine and 37 μL of methyl chlorocarbonate were added to chloroform (2 mL) solution of 93 mg of (3S*,4S*)-3-aminomethyl-1-benzyl-4-o-tolyl-piperidine obtained in Production Example 37, and stirred at room temperature for 50 minutes. Aqueous 1 M sodium hydroxide solution was added to the reaction liquid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through preparative thin-layer chromatography (chloroform/methanol=20/1) to obtain 78 mg of the entitled compound.
Reaction SMILES: [CH3:1][C:2]1[C:14](N)=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7].[C:16](O)(=O)C.C=O.[C:22]([BH3-])#[N:23].[Na+]>C(#N)C>[CH3:1][C:2]1[C:14]([N:23]([CH3:22])[CH3:16])=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7]
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Reactant: COC(=O)C(C)Oc1cccc(N)c1C
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)C(C)Oc1cccc(N(C)C)c1C

Procedure:
To a mixture of 7.7 g (ca. 37 mmole) of the title product of Example 18, 2.1 ml of acetic acid, 30 ml of 37% formaldehyde, and 50 ml of acetonitrile was added 2.3 g (37 mmole) of sodium cyanoborohydride. After the amino compound had been consumed, aqueous sodium hydroxide was added and the mixture extracted with diethyl ether. The organic phase was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel using ethyl acetate-hexane as eluent, giving the title compound (4.2 g) as an oil. The compound was used in subsequent reeactions without further purification.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.C(OC([NH:26][CH:27]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH:40][CH3:41])=[O:39])=[CH:33][CH:32]=1)[C:28]([OH:30])=O)=O)(C)(C)C.[SH:42][C:43]1[N:44]=[N:45][NH:46][CH:47]=1>>[NH2:26][CH:27]([C:31]1[CH:32]=[CH:33][C:34]([NH:37][C:38]([NH:40][CH3:41])=[O:39])=[CH:35][CH:36]=1)[C:28]([NH:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:42][C:43]3[N:44]=[N:45][NH:46][CH:47]=3)[CH2:15][S:14][C@H:9]12)=[O:30]
Reactant: CNC(=O)Nc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: Sc1c[nH]nn1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Product: CNC(=O)Nc1ccc(C(N)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4c[nH]nn4)CS[C@H]23)cc1

Procedure:
Acylation of 7-ADCA, 7-amino-3-(5-methyl-1,3,4-thiadiazole-2-ylthiomethyl)-3-cephem-4-carboxylic acid or any of the cephem compounds named in Example 6 with α-t-butoxycarboxyamino-p-(3-methylureido)phenylacetic acid followed be deblocking according to the procedure of Example 2 gives the corresponding 7-[α-amino-p-(3-methylureido)-phenylacetamido]cephem compound. 7-[α-amino-p-(3-methylureido) phenylacetamido]-3-(1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylic acid is prepared by reacting 7-ACA with α-t-butoxycarbonylamino-p-(3-methylureido)phenylacetic acid and then with 4-mercapto-1,2,3-triazole with subsequent deblocking of the amino grouping according to the procedure of Example 5.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH2:25][CH2:26][C:16]=2[N:15]=1)=[CH:23][C:22]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([C:37]1[NH:41][C:40]([C@@H:42]4[CH2:46][CH2:45][CH2:44][N:43]4C(OC(C)(C)C)=O)=[N:39][CH:38]=1)[CH:31]=[CH:30]2)=[CH:21][CH:20]=3)=[O:8])=[O:4].Cl.[CH3:61][O:62][C:63]([NH:65][C@H:66]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:67]([OH:69])=O)=[O:64].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:61][O:62][C:63]([NH:65][C@H:66]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:67]([N:43]1[CH2:44][CH2:45][CH2:46][C@H:42]1[C:40]1[NH:41][C:37]([C:32]2[CH:33]=[C:34]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[C:27]([C:22]2[CH:23]=[C:24]4[C:19](=[CH:20][CH:21]=2)[C:17]2[NH:18][C:14]([C@@H:10]5[CH2:11][CH2:12][CH2:13][N:9]5[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:54]5[CH2:55][CH2:56][O:57][CH2:58][CH2:59]5)=[N:15][C:16]=2[CH2:26][CH2:25]4)[CH:36]=[CH:35]3)=[CH:38][N:39]=1)=[O:69])=[O:64]
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2c([nH]1)-c1ccc(-c3ccc4cc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc1CC2)C1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2c([nH]1)-c1ccc(-c3ccc4cc(-c5cnc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]5)ccc4c3)cc1CC2)C1CCOCC1
Reaction time: 1 h
Yield: 37.6 %

Procedure:
(S)-tert-butyl 2-(5-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (136 mg, 0.17 mmol) was dissolved in DCM (5 mL) and HCl (4M in dioxane, 1 mL) was added. After stirring for 1 h, the reaction mixture was concentrated and the residue was treated with (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (36 mg, 0.170 mmol), COMU (73 mg, 0.170 mmol) and DMF (3 mL). DIPEA (0.12 mL, 0.68 mmol) was added dropwise. After 20 min, the reaction was quenched by addition of H2O and the crude mixture was purified by HPLC to afford the title compound (57 mg, 38%). MS: (ESI) m/z 891 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].C(Cl)(=O)C([Cl:24])=O>ClCCl.CN(C)C=O>[Cl:24][C:16]([C:15]1[CH:19]=[CH:20][C:12]([O:11][C@@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]2)=[CH:13][CH:14]=1)=[O:17]
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)O)cc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)Cl)cc2)CC1
Temperature: 25 °C

Procedure:
0.4 g of cis-4-(4-methoxycarbonylcyclohexyloxy)benzoic acid is placed in 10 mL of dichloromethane with stirring, at room temperature, under a nitrogen atmosphere. 0.18 mL of oxalyl chloride (2.16 mmol, 1.5 eq.) and 2 drops of dimethylformamide are successively added. The reaction medium is stirred for 2 hours and concentrated under vacuum. The methyl cis-4-(4-chlorocarbonylphenoxy)cyclohexanecarboxylate formed is dissolved in 15 mL of acetonitrile and placed under nitrogen. The mixture is cooled in an ice bath and 0.210 g of potassium thiocyanate (2.16 mmol, 1.5 eq.) is added. The reaction mixture is stirred at room temperature for 1 hour 30 minutes. 0.455 g of cyclopentyloxyacetic acid hydrazide (2.87 mmol, 2 eq.) dissolved in 5 mL of acetonitrile is then added to the methyl cis-4-(4-isothiocyanatocarbonylphenoxy)cyclohexanecarboxylate obtained and the mixture is refluxed for 2 hours 30 minutes and then left to stand at room temperature for 36 hours. The precipitate formed is filtered off and washed with acetonitrile. 0.450 g of methyl cis-4-[4-(5-cyclopentyloxymethyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenoxy]cyclohexanecarboxylate is obtained.