Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC=CC=1.NCCCCCCC#N.[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=O)[C:26](OCC)=[O:27])#[N:17]>N1C=CC=CC=1>[OH:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:16][NH2:17]
Reactant: CCOC(=O)C(=O)NCCCCCCC#N
Agent: N#CCCCCCCN
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: NCCCCCCCNCCO
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The intermediate N-(2-hydroxyethyl)-1,7-heptanediamine was prepared in two steps as follows: To a stirred and ice-cooled solution containing 650 ml. of benzene and 43.5 g. of pyridine was added dropwise over a period of 30 minutes 75 g. of ethyl oxalyl chloride followed by dropwise addition over a period of 30 minutes 63 g. of 7-amino-heptanonitrile. The reaction mixture was stirred in the ice bath for 3 minutes, next stirred at room temperature for 45 minutes and then allowed to stand overnight at room temperature. The white solid was filtered off and rinsed with fresh benzene. The combined benzene filtrates were washed successively with two 250 ml. portions of 5% aqueous glycine solution containing 25 ml. of 10% aqueous potassium hydroxide solution, a 250 ml. portion of 0.6N hydrochloric acid and two 250 ml. portions of water. The benzene solution was then dried over anhydrous magnesium sulfate and evaporated in vacuo to yield 102.7 g. ethyl N-(6-cyanohexyl)oxamate. A 23.1 g. portion was fractionally distilled at high vacuum for analysis, thereby yielding 14.7 g. of ethyl N-(6-cyanohexyl)oxamate, b.p. 170°-174° C. at 0.05 mm.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]4[CH2:12][N:13]([C:27]([CH2:29][CH2:30][C:31]([O:33]CC5C=CC=CC=5)=[O:32])=[O:28])[C:14](=[O:26])[C:15]=4[CH:16]=[C:17]4[CH:25]=[CH:24][C:23]5[O:22][CH2:21][O:20][C:19]=5[C:18]=34)=[CH:9][C:4]=2[O:3][CH2:2]1>[C].[Pd].C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]4[CH2:12][N:13]([C:27]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[C:14](=[O:26])[C:15]=4[CH:16]=[C:17]4[CH:25]=[CH:24][C:23]5[O:22][CH2:21][O:20][C:19]=5[C:18]=34)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(CCC(=O)N1Cc2c(cc3ccc4c(c3c2-c2ccc3c(c2)OCO3)OCO4)C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CCC(=O)N1Cc2c(cc3ccc4c(c3c2-c2ccc3c(c2)OCO3)OCO4)C1=O
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To an ethyl acetate (2 ml) solution of Benzyl 3-[10-(1,3-benzodioxol-5-yl)-8,9-dihydro-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one-8-yl]carbonyl-propionate (50 mg) was added 10% palladium carbon (10 mg) and stirred overnight under hydrogen atmosphere. The catalysts were filtered off and the filtrate was concentrated under reduced pressure, then recrystallized from ethyl acetate-hexane to give the entitled compound (28 mg) as colorless crystals.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[C:9]=2[OH:11])[C:4](=O)[O:3]1.[NH2:15][NH2:16]>C(O)C>[OH:11][C:9]1[C:8]([O:12][CH3:13])=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:2]=[N:15][NH:16][C:4]2=[O:3]
Reactant: COc1ccc2c(c1O)C(O)OC2=O
Reactant: NN
Solvent: CCO
Product: COc1ccc2c(=O)[nH]ncc2c1O
Yield: 72 %

Procedure:
A solution of 3,4-dihydroxy-5-methoxy-3H-isobenzofuran-1-one (6.63 g, 34 mmoles), prepared as described in example 57, in ethanol (60 ml) was added with 98% hydrazine (8.5 ml). The mixture was heated to clarity and after 5 minutes a precipitate formed and was filtered and treated with 1N HCl. The mother liquors were concentrated more times and the resultant solid fractions joined to give 4.65 g of the title compound (yield: 72%).
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C:4]([C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)=[O:5].C(O)(C)(C)C>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[CH2:3][C:4]1([C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)[OH:5]
Reactant: CC(C)CC(=O)c1cnccn1
Solvent: c1ccccc1
Solvent: CC(C)(C)O
Product: CC1(C)CC1(O)c1cnccn1
Reaction time: 40 h

Procedure:
A solution of 3-methyl-1-(pyrazin-2-yl)butan-1-one (1.0 g, 6.1 mmol) in 120 mL of a 19/1 mixture of tert-butanol and benzene was irradiated using a 6 W 366 nm lamp (TLC lamp) in a pyrex glass tube. The conversion was 50% after 16 h and 80% after 40 h. At this point the volatiles were removed in vacuo and the material was purified by column chromatography (silica, EtOAc/heptanes 1/4) to afford 2,2-dimethyl-1-(pyrazin-2-yl)cyclopropanol as a reddish-brown oil (375 mg; 38%). 1H NMR (CDCl3) 0.90 (3H, s), 1.00 (2H, d), 1.40 (2H, s), 3.20 (1H, s), 8.42 (1H, m), 8.50 (1H, m), 8.76 (1H, m).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].CCN(CC)CC.[Cl:17][C:18](Cl)=[CH2:19]>>[CH2:2]([O:3][C:4]([C:6]1[CH:19]=[C:18]([Cl:17])[O:8][N:7]=1)=[O:5])[CH3:1]
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: C=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(Cl)on1
Temperature: 25 °C
Reaction time: 23 h
Yield: 35 %

Procedure:
To a solution of ethyl chlorooximidoacetate (11.0 g, 72.6 mmol, 1 equiv) in 1,1-dichloroethylene (350 mL) was added Et3N (25.3 mL, 181 mmol, 2.5 equiv) in 1,1-dichloroethylene (100 mL) via addition funnel over 30 min. The reaction mixture was stirred at room temperature for 23 h, then was partitioned between water (150 mL) and CH2Cl2 (2×150 mL). The combined organic layers were dried over Na2SO4 and were concentrated. The residue was purified by flash column chromatography (10% EtOAc in hexanes) to give the title intermediate (4.49 g, 35%) as a pale yellow oil: IR (cm−1) 1735, 1436, 1253; 1H NMR (CDCl3) δ 1.45 (t, 3H, J=7.2), 4.49 (q, 2H, J=7.2), 7.29 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]([CH3:14])[C:12](=[O:15])[N:11]([CH3:16])[C:10](=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:9]=2)=[CH:4][CH:3]=1.[N-:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.[Na+]>CS(C)=O>[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]([CH3:14])[C:12](=[O:15])[N:11]([CH3:16])[C:10](=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(-c2ccc(F)cc2)cc(=Nc2ccccc2)n(C)c1=O
Reactant: c1c[n-]cn1
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1c(-c2ccc(-c3ncc[nH]3)cc2)cc(=Nc2ccccc2)n(C)c1=O

Procedure:
The invention encompasses compounds of Formula I which are prepared by arylating a starting material such as 3,4-dihydro-6-(4-fluorophenyl)-1,3,dimethyl-4-phenylimino-2(1H)-pyrimidinone with excess sodium imidazolide in DMSO in the presence of heat, whereby the fluoro group on the 6-phenyl ring is substituted by the imidazolyl group to produce 3,4-dihydro-6-(4-imidazolylphenyl)-1,3-dimethyl-4-phenylimino-2(1H)-pyrimidinone.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:21])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[CH:10]=[CH:9][C:8]=2[F:20])(=[O:3])[CH3:2].[CH3:22][O:23][CH2:24][CH:25]([NH2:27])[CH3:26]>>[C:1]([C:4]1[C:5](=[O:21])[NH:6][C:7]2[C:12]([C:13]=1[NH:27][CH:25]([CH3:26])[CH2:24][O:23][CH3:22])=[CH:11][CH:10]=[CH:9][C:8]=2[F:20])(=[O:3])[CH3:2]
Reactant: COCC(C)N
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)ccc(F)c2[nH]c1=O
Product: COCC(C)Nc1c(C(C)=O)c(=O)[nH]c2c(F)cccc12
Yield: 86.6 %

Procedure:
3-Acetyl-8-fluoro-4-methylsulfoxy-2-quinolinone (2.67g, 0.01 mol) and 1-methoxy-2-propylamine(0.88g, 0.01 mol) were used, but the reaction was carried out as the above process of example 37 to obtain the desired product (2.53g, yield: 87%).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>CCO.C1COCC1.O>[CH:21]1([C:19]([NH:18][CH:15]2[CH2:14][CH2:13][CH:12]([O:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:24])=[O:3])=[CH:6][CH:7]=3)[CH2:17][CH2:16]2)=[O:20])[CH2:23][CH2:22]1
Reactant: CCOC(=O)c1ccc(OC2CCC(NC(=O)C3CC3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OC2CCC(NC(=O)C3CC3)CC2)cc1
Reaction time: 17 h

Procedure:
To a solution of 4-[4-(cyclopropanecarbonylamino)cyclohexyloxy]benzoic acid ethyl ester (4.75 g, 14.3 mmol) in EtOH (30 mL) and THF (10 mL) was added NaOH (2.29 g, 57.3 mmol) in 10 ml of water. Stirring was continued at ambient for 17 hrs. The solvents were removed under vacuum, water (50 mL) was added and the whole extracted with EtOAc. The aqueous layer was acidified to pH ˜2 with 2N HCl and the white precipitate obtained was filtered off and washed with hexane affording 4.0 g (92%) of 4-[4-(cyclopropanecarbonyl-amino)-cyclohexyloxy]-benzoic acid as a solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[O:9][C:8]([CH2:10][S:11][C:12]2[S:16][C:15]([NH:17][C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[O:19])=[N:14][CH:13]=2)=[N:7][CH:6]=1)([CH3:4])[CH3:3].[O:26]=[CH:27][CH:28]([CH2:30]O)[OH:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl>CO>[OH:29][CH:28]([CH2:27][OH:26])[CH2:30][N:23]1[CH2:22][CH2:21][CH:20]([C:18]([NH:17][C:15]2[S:16][C:12]([S:11][CH2:10][C:8]3[O:9][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:6][N:7]=3)=[CH:13][N:14]=2)=[O:19])[CH2:25][CH2:24]1
Reactant: CC(C)(C)c1cnc(CSc2cnc(NC(=O)C3CCNCC3)s2)o1
Reactant: O=CC(O)CO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: CC(C)(C)c1cnc(CSc2cnc(NC(=O)C3CCN(CC(O)CO)CC3)s2)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (66 mg, 0.17 mmol, 1 eq) was combined with glyceraldehyde (69 mg, 0.77 mmol, 4.5 eq), sodium triacetoxyborohydride (163 mg, 0.77 mmol, 4.5 eq) and 1,2-dichloroethane (4 mL). The resulting suspension was stirred at rt for 4 h. Methanol (1 mL) was added and the reaction mixture was stirred at rt overnight, concentrated in vacuo and purified by preparative HPLC to provide 69 mg (59%) of (±)-1-(2,3-dihydroxypropyl)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide as a white solid. MS: 455 [M+H]+; HPLC: 100% at 3.06 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N1CCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2cc(N)ccc21

Procedure:
Palladium on carbon (10%, 1.110 g) is added to a mixture of N-acetyl-5-nitro indoline (II, EXAMPLE 1, 5.00 g) in ethyl acetate (freshly opened bottle, about 500 ml). The mixture is stirred under 1 atm of hydrogen (balloon) for 39 hr then filtered and the palladium on carbon is washed with methanol/ethyl acetate (20/80). The filtrate is concentrated under reduced pressure to give the title compound, mp 183°-185°; NMR (CDCl3, 300 MHz) 8.01, 6.53, 6.50, 3.98, 3.56, 3.04 and 2.17 δ; CMR (CDCl3, 75.47 MHz) 23.86, 28.05, 48.71, 111.55, 113.73, 117.66, 132.8, 135.6, 149.1 and 168.1 δ; IR (CHCl3) 3000, 1640, 1600, 1490, 1410, 1330 and 1300 cm-1.
Reaction SMILES: C([O:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)(=O)C1C=CC=CC=1>CO>[CH2:20]([CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][C:12]#[C:11][CH2:10][OH:9])[CH2:19][CH2:18]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(OCC#CCN1CCC(Cc2ccccc2)CC1)c1ccccc1
Solvent: CO
Product: OCC#CCN1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.9 %

Procedure:
A steam of ammonia gas was bubbled through dry-ice/acetone cooled methanol until the concentration of ammonia was about 20%. To this solution was added a solution of 1-(4-benzoyloxybut-2-yn-1-yl)-4-benzylpiperidine (300 mg, 0.860 mmol) in 2 mL of methanol. The resulting solution was allowed to stir at room temperature for 24 hr. Methanol was evaporated in vacuo to give a residue, which was purified by flash chromatography to give the title compound as a brown oil (140 mg, 67%): 1H NMR (CDCl3) d 1.35 (m, 2 H), 1.50 (m, 1 H), 1.62 (m, 2 H), 2.08 (m, 2 H), 2.51 (d, J=6.9 Hz, 2 H), 2.89 (d, J=11.1 Hz, 2 H), 3.25 (s, 2 H), 4.24 (s, 2 H), 4.50 (bs, 1 H), 7.10-7.26 (m, 5 H). HRMS calcd for C16H21NO 243.1613, found 243.1618.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[CH2:4].[H][H]>[Pd].C(OCC)(=O)C>[F:12][C:2]([F:1])([F:11])[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH3:4]
Reactant: [H][H]
Reactant: C=C(c1ccncc1)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(c1ccncc1)C(F)(F)F
Yield: 85.7 %

Procedure:
To 20 ml of ethyl acetate were added 1.5 g of 4-[1-(trifluoromethyl)ethenyl]pyridine and 0.15 g of 10% Pd/C, and the mixture was stirred under the hydrogen atmosphere for 7 hours. The mixture was filtered, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography to obtain 1.3 g of 4-(2,2,2-trifluoro-1-methyl-ethyl)pyridine.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[CH3:12][N:13]([CH3:16])[CH:14]=O>>[CH3:12][N:13]([CH:16]=[C:9]1[CH2:10][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7][C:8]1=[O:11])[CH3:14]
Reactant: CN(C)C=O
Reactant: CC(=O)NC1CCC(=O)CC1
Product: CC(=O)NC1CCC(=O)C(=CN(C)C)C1

Procedure:
According to Reaction Scheme I, 4-acetamido cyclohexanone, prepared by the procedure of Fraser and Swingle, Can. J. Chem., 48, 2065 (1970) is reacted with the dimethylacetal of dimethylformamide to yield 2-dimethylaminomethylene-4-acetamidocyclohexanone (III). Reacting this compound with sodium glycinate followed by a ring closure reaction in the presence of acetic anhydride yields, when R3 is methyl, dl-2-acetyl-5-acetamido-4,5,6,7-tetrahydro-2H-benzo[c]-pyrrole (IV). Treatment of this latter compound with base gives dl-5-amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole (V). This latter compound can be preferentially alkylated on the amino group at C-5 using a reductive alkylation procedure; i.e., reaction with an aldehyde (formaldehyde, acetaldehyde, acrolein, or propionaldehyde) in the presence of a strong organometallic reducing agent such as sodium cyanoborohydride. The dialkylated compound, for instance, dl-5-di(n-propyl)amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole (VI) can also be alkylated on the pyrrole ring nitrogen under basic conditions using an alkyl halide R2X (methyl iodide, allyl chloride, ethyl bromide, or the like) to yield a dl-2-(C1 -C3 alkyl or allyl)-5 -disubstituted-amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole of Formula VII.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:10])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[C:11](Cl)(Cl)=[O:12]>>[Br:1][C:2]1[C:3]([N:10]=[C:11]=[O:12])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(Br)c(N)n1
Product: COc1ccc(Br)c(N=C=O)n1

Procedure:
3-Bromo-2-isocyanato-6-methoxy-pyridine was prepared by reaction of 3-bromo-6-methoxy-pyridin-2-ylamine with phosgene using the procedure of step 2 of Example 1.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][C:13]([CH3:32])([CH3:31])[C:14]([O:16][CH:17]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[CH2:18][CH3:19])=[O:15]>CC(OC)(C)C.CC(C)=O.O>[CH3:31][C:13]([CH3:12])([CH3:32])[C:14]([O:16][CH:17]([O:20][C:21]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:22])[CH2:18][CH3:19])=[O:15]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCC(OC(=O)ON1C(=O)CCC1=O)OC(=O)C(C)(C)C
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Solvent: O
Product: CCC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)C(C)(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]propyl 2,2-dimethylpropanoate (290 mg, 0.96 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 31 (147 mg, 45% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 5H), 1.12 (s, 9H), 1.16-1.38 (m, 3H), 1.64-1.76 (m, 4H), 1.82-1.91 (br. m, 2H), 2.09 (tt, J=12.0, 3.2 Hz, 1H), 2.72-2.90 (m, 2H), 6.51 (t, J=5.6 Hz, 1H), 7.44 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 366.21 (M+Na)+; 342.16 (M−H)−.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13]C(=O)OC(C)(C)C)[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=1)([OH:3])=[O:2].O.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([OH:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[C:22]1([CH3:32])[CH:23]=[CH:24][C:25]([S:28]([OH:31])(=[O:29])=[O:30])=[CH:26][CH:27]=1.[NH2:13][C:6]1[CH:7]=[C:8]([C:10]([O:12][CH2:1][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:11])[CH:9]=[C:4]([CH:5]=1)[C:1]([O:3][CH2:32][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)O)cc(C(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cc(C(=O)OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Temperature: 80 °C

Procedure:
Carbamate (7.61) (3.75 g, 8 mmol) and p-toluenesulfonic acid monohydrate (1.5 g, 8 mmol) were dissolved in toluene (55 ml) and heated at 80° C. for 45 min. A white precipitate formed during the reaction. This was collected by filtration, washed with hexanes, and dried to give the title compound which recrystallised from toluene as a white crystalline solid (needles) (3.91 g, 96%). M.p. 200°-201° C.; m/z (+ES) 362 (100%, M+H+); δH (250 MHz, d6 -DMSO) 2.5 (3H, s, CH3), 5.35 (4H, s, 2×Ar--CH2), 7.05 (2H, d, J 7.5 Hz 2×Ar--H), 7.25-7.60 (12H, m, 12×Ar--H), 7.75 (2H, d, 2×Ar--H), 8.00 (1H, s, Ar--H); δC (62.5 MHz, δ6-DMSO) 21.24, 67.08, 118.13, 121.94, 122.61, 125.95, 128.63, 128.74, 129.04, 131.52, 136.31, 138.40, 143.88, 145.65, 165.84; RF 0.15 [DCM/methanol (9:1).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:13])[CH2:8][CH2:7]1)C.C(O)C.[OH-].[Na+].Cl>O>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]([CH:9]1[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:20])=[O:3])[CH2:11][CH2:10]1)=[O:13]
Reactant: CCOC(=O)CN1CCC(C(=O)c2ccccn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CN1CCC(C(=O)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.6 %

Procedure:
To a solution of compound [4-(pyridine-2-carbonyl)-piperidin-1-yl]-acetic acid ethyl ester (198 mg, 0.72 mmol), in water (4 mL) and ethanol (4 mL) and was added 4N sodium hydroxide (0.36 mL, 1.43 mmol). The reaction was stirred at 25° C. for 48 hours and then heated at 40° C. for 3 hours. The reaction mixture was acidified with 1N HCl to pH 3 and the solvent was removed under vacuum. The residue was co-evaporated 3 times with acetonitrile to afford the title compound (178 mg). The crude product was used directly in the next step without subsequent purification. MS m/z ES+=248.8 (M+H), retention time 1.66.
Reaction SMILES: C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[Si]([O:35][CH2:36][CH2:37][S:38][C:39]1[N:40]=[CH:41][N:42]2[CH:46]=[C:45]([C:47]3[C@H:48]([CH3:71])[C@@H:49]4[C@@H:66]([C@H:67]([OH:69])[CH3:68])[C:65](=[O:70])[N:50]4[C:51]=3[C:52]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=3)=[O:53])[S:44][C:43]=12)(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+]>C1COCC1.[Cl-].[Na+].O>[OH:69][C@@H:67]([C@H:66]1[C:65](=[O:70])[N:50]2[C:51]([C:52]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=3)=[O:53])=[C:47]([C:45]3[S:44][C:43]4=[C:39]([S:38][CH2:37][CH2:36][OH:35])[N:40]=[CH:41][N:42]4[CH:46]=3)[C@H:48]([CH3:71])[C@H:49]12)[CH3:68]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCO[Si](C)(C)C(C)(C)C)c4s3)[C@H](C)[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCO)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Acetic acid (0.207 ml) and 1.21 ml of a 1 M tetra-n-butylammonium fluoride/THF solution were added to a solution of 265 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-(2-t-butyldimethylsilyloxyethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 5 ml of THF. The mixture was stirred at room temperature for 6 hr. Brine was added to the reaction solution, and a saturated sodium hydrogencarbonate solution was added thereto. The mixture was adjusted to pH 8.2, and was extracted with ethyl acetate twice. The organic layers were combined, were washed with brine, and were dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to prepare 208 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(2-hydroxyethyl)thioimidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][NH:3][C:2]=1/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9].[CH3:11]O>>[NH:5]1[CH:1]=[C:2]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])[N:3]=[CH:4]1
Reactant: CO
Reactant: O=C(O)/C=C/c1cnc[nH]1
Product: COC(=O)C=Cc1c[nH]cn1
Reaction time: 1 h

Procedure:
Through a suspension of urocanic acid (5.0 g) in methanol at 0° C. was bubbled HCl gas until the solution was saturated. The reaction was stirred for one hour, then concentrated in vacuo to dryness to provide the crude product 2 which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]([C:4]([CH2:11][CH3:12])([CH2:9][CH3:10])[C:5]([O:7][CH3:8])=[O:6])=[O:3].C(N(CC)CC)C.[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][NH:25][CH3:26]>CCOCC>[CH2:9]([C:4]([CH2:11][CH3:12])([C:2](=[O:3])[N:25]([CH3:26])[CH2:24][CH2:23][C:22]([O:21][CH3:20])=[O:27])[C:5]([O:7][CH3:8])=[O:6])[CH3:10]
Reactant: CNCCC(=O)OC
Reactant: CCC(CC)(C(=O)Cl)C(=O)OC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCC(CC)(C(=O)OC)C(=O)N(C)CCC(=O)OC
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of 19.2 g of methyl 2-chloroformyl-2-ethyl-butyrate and 20 g of triethylamine in 100 ml of dry ether, which is mechanically stirred and cooled at -10° C, there is added dropwise 12.8 g of N-methyl-β-alanine methyl ester dissolved in 50 ml of dry ether. After the addition, which takes 30 minutes, the mixture is stirred during 18 hours at room temperature. After filtration of the separated triethylamine hydrochloride, the solvent is evaporated leaving the desired product as an oil, boiling at 118° C (0.2 mm). Yield 93%. nD19 1.4646.
Reaction SMILES: [CH3:1][N:2]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[NH2:3].Cl.[C:12](=[NH:17])(OCC)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:7]([O:6][C:4]([N:2]([CH3:1])[NH:3][C:12](=[NH:17])[CH3:13])=[O:5])([CH3:10])([CH3:9])[CH3:8]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: CCOC(C)=N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=N)NN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A solution of tert-butyl 1-methylhydrazinecarboxylate (10.0 g, 68.4 mmol), ethyl acetimidate hydrochloride (42.1 g, 342 mmol), and potassium carbonate (94.4 g, 684 mmol) in DMF (150 mL) was heated at 105° C. for 5 hours. The contents were cooled to 0° C. before the precipitated material was collected by vacuum filtration and resuspended in H2O (100 mL). After 30 minutes of vigorous stirring, the remaining precipitate was collected and dried in a 45° C. vacuum oven overnight to yield the title compound as a white solid (7.56 g, 59.0%): mp 187-189° C.; 1H NMR (400 MHz, DMSO-d6) δ 6.28 (br s, 1H), 2.77 (s, 3H), 1.64 (s, 3H), 1.36 (s, 9H).