Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Cl:3])[Cl:2].C([Li])CCC.C([N:17]1[CH2:22][CH2:21][C@@H:20]([CH2:23][CH:24]=[O:25])[C@@H:19]([CH:26]=[CH2:27])[CH2:18]1)(=O)C1C=CC=CC=1>O1CCCC1.CCCCCC>[ClH:2].[Cl:2][CH:1]([Cl:3])[C@@H:24]([OH:25])[CH2:23][C@@H:20]1[CH2:21][CH2:22][NH:17][CH2:18][C@@H:19]1[CH:26]=[CH2:27]
Reactant: ClCCl
Reactant: C=C[C@H]1CN(C(=O)c2ccccc2)CC[C@H]1CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C[C@H]1CNCC[C@H]1C[C@H](O)C(Cl)Cl
Product: Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution containing 3.07 ml. of methylene chloride in 60 ml. of anhydrous tetrahydrofuran cooled to -70°, there was added over a period of 1 hour 44 mmoles of n-butyllithium in 28 ml. of hexane under an atmosphere of dry nitrogen. Stirring of the mixture at the same temperature was continued for 20 minutes and then followed by the dropwise addition of 5.19 g. (20 mmoles) of 2-[1-benzoyl-3(R)-vinyl-4(S)-piperidinyl]acetaldehyde in 30 ml. of anhydrous tetrahydrofuran. After 30 minutes, the reaction was quenched by the addition of 30 ml. of water. The mixture was allowed to warm up to room temperature and was subsequently extracted three times with ether. The combined ether extracts were washed with water, dried over sodium sulfate and evaporated to dryness. The residue was dissolved in 80 ml. of 3N hydrochloric acid. The acidic solution was washed with ether and neutralized with 3N sodium hydroxide. The solution was washed again with ether, rendered alkaline by the addition of 3N sodium hydroxide and extracted with ether. The ether extract was washed with water, dried over sodium sulfate and evaporated to dryness. The residue (3.8 g.) was dissolved in ethanol and treated with an excess of ethanolic hydrogen chloride. The solvent was evaporated under reduced pressure and the resulting solid residue was crystallized from ethanol to give 2.0 g. of a mixture of epimeric 1,1-dichloro-3-[3(R)-vinyl-4(S)-piperidinyl]propan-2ε-ol hydrochlorides. Fractional crystallization from ethanol followed by recrystallization of the combined fractions from ethanol gave 1,1-dichloro-3-[3(R)-vinyl-4(S)-piperidinyl]propan-2(S)-ol hydrochloride, m.p. 225°-225.5°, [α]D25 -13.3° (c 1.02, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:16][C:17]([F:22])([F:21])[CH2:18][CH2:19][NH2:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[F:16][C:17]([F:22])([F:21])[CH2:18][CH2:19][NH:20][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[C:9]([NH:11][CH3:12])=[CH:10][C:2]=1[Cl:1]
Reactant: NCCC(F)(F)F
Reactant: CNc1cc(Cl)c(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(Cl)c(C(=O)NCCC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to 5c from 2-chloro-4-methylamino-5-nitro-benzoic acid (900 mg, 3.9 mmol), 3,3,3-trifluoro-propylamine (0.58 g, 3.9 mmol), TBTU (1.38 g, 4.2 mmol), DIPEA (2.0 mL, 11.7 mmol) and THF (20 mL).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)S(O[C:25]1[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH:30]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Yield: 71.8 %

Procedure:
A mixture of 4-nitrophenylboronic acid pinacol ester (4.5 g; 18.1 mmol; 1.2 eq.), tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (5.0 g; 15.1 mmol; 1.0 eq.) and sodium carbonate (1.07 g, 10.1 mmol, 5 eq.) were dissolved in DME (50 mL) and water (25 mL). The mixture was degassed for 5 min with nitrogen before the addition of Pd(PPh3)4 (349 mg; 0.30 mmol; 0.02 eq.) and heated at 80° C. O/N. Water (100 mL) was added and aqueous phase was extracted with EtOAc (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (EtOAc:heptane, 10.90) to give the title compound as a yellow solid (3.3 g, 72%). 1H NMR (300 MHz, DMSO-d6) δ 8.24-8.17 (m, 2H), 7.65-7.68 (m, 2H), 6.45 (brs, 1H), 4.06 (m, 2H), 3.56 (t, 2H), 2.55-2.48 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][C:10]([NH:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])=[O:11].O>CN(C)C=O>[CH3:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:20])[C:13]=1[NH:12][C:10](=[O:11])[CH2:9][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C)c1NC(=O)Cn1ccnc1
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
A mixture of 6.0 g of a 60% oil dispersion of sodium hydride in 90 ml of dimethylformamide was stirred and heated at 50° C. during the portionwise addition of 10.32 g of imidazole. After stirring for 20 minutes, 15.0 g of 2-chloro-N-(2,6-dimethylphenyl)acetamide was added and heating was continued for an additional 30 minutes. Water was added and the reaction mixture was evaporated to dryness. The residue was dissolved in 2N hydrochloric acid, washed with ether, made strongly basic with excess sodium hydroxide and the product was extracted with dichloromethane. The combined organic layers were dried with sodium sulfate and evaporated to give 14 g of N-(2,6-dimethylphenyl)-1H-imidazole-1-acetamide, mp 160°-162° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:12](Cl)(Cl)=[S:13].C(OCC)(=O)C>O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[N:5]=[C:12]=[S:13]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccccc1C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccccc1N=C=S

Procedure:
2-trifluoromethylaniline (4.1 ml, 0.0325 mol) is added dropwise at a temperature close to 20° C. and under an argon atmosphere to a mixture containing thiophosgene (2.5 ml, 0.0326 mol) in 43 ml of water. Agitation is carried out for twelve hours then 30 ml of ethyl acetate is added. The organic phase is extracted with water then with a solution of 10% sodium bicarbonate and finally with a solution of salt water. The organic phase is dried over magnesium sulphate and the solvent is evaporated off with a rotary evaporator. The product obtained (6.85 g, 100%) is in the form of a brown oil which is used immediately for the following reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].O>N1C=CC=CC=1.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH:9][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=1[F:10]
Reactant: O=C(Cl)c1ccccc1F
Reactant: NNc1ccccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=C(NNc1ccccc1F)c1ccccc1F
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a stirred solution, under nitrogen of 35.2 g of 2-fluorophenylhydrazine in 250 ml of dry pyridine, cooled in an ice bath, was added, dropwise, 36.7 ml of 2-fluorobenzoyl chloride. The reaction mixture was stirred at ambient temperature for 21 hours. Upon dilution of the reaction mixture with water a precipitate was formed. Attempts to separate the precipitate by filtration, washing with pyridine, resulted in the formation of an oil. That portion of oil which did not pass into the filtrate was dissolved in dichloromethane and concentrated in vacuo. Upon standing, the filtrate separated into aqueous and organic phases Treatment of the organic phase with toluene resulted in the formation of a precipitate. Recrystallization of the combined product from toluene yielded 49.2 g of 2-fluorobenzoic acid, 2-(2-fluorophenyl)hydrazide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH2:10][CH3:11])[CH:3]=1.II.FC(F)(F)C(O[I:19](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O>ClCCl.CO>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH3:11])[N:5]=[C:6]([CH2:8][CH3:9])[C:7]=1[I:19]
Reactant: CCc1cc(N)cc(CC)n1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Solvent: ClCCl
Solvent: CO
Product: CCc1cc(N)c(I)c(CC)n1
Reaction time: 16 h
Yield: 40.2 %

Procedure:
4-Amino-2,6-diethylpyridine (D) (1.8 g) was added to a solution of iodine (3.1 g) and [bis(trifluoroacetoxy)iodo]benzene (5.7 g) in a mixture of dichloromethane (70 ml) and methanol (20 ml) and the mixture was stirred for 16 hours. Solvent was removed by evaporation and the residue was partitioned between ethyl acetate and a mixture of saturated sodium metabisulphite solution (50 ml) and saturated sodium carbonate solution (150 ml). The organic phase was separated, washed with saturated sodium chloride solution and dried (MgSO4). Solvent was removed by evaporation and the residue was purified by flash chromatography eluting with dichloromethane/methanol (97:3 v/v) to give 4-amino-2,6-diethyl-3-iodopyridine (E) (1.33 g) as a solid, m.p. 72°-74° C.; NMR (CDCl3): 1.25(m,6H), 2.65(q,2H), 2.96(q,2H), 4.59(broad s,2H), 6.30(s,1H); mass spectrum (chemical ionisation, ammonia): 277(M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]([C:17](OCC)=O)=[CH:15][S:14][C:13]1=[N:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:46][NH:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1>O1CCCC1.O>[Cl:55][C:52]1[CH:53]=[CH:54][C:49]([CH2:48][N:47]([CH2:17][C:16]2[N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[C:13](=[N:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:33])[F:32])=[CH:27][CH:28]=3)[S:14][CH:15]=2)[CH3:46])=[CH:50][CH:51]=1
Reactant: CCOC(=O)c1csc(=Nc2ccc(OC(F)(F)F)cc2)n1CCCNC(=O)OC(C)(C)C
Reactant: CNCc1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1ccc(Cl)cc1)Cc1csc(=Nc2ccc(OC(F)(F)F)cc2)n1CCCNC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 23.1 %

Procedure:
The compound (300 mg) obtained in Example 208 (2) and triethylamine (101 mg) were dissolved in tetrahydrofuran (30 ml), and thereto was added dropwise methanesulfonyl chloride (115 mg) under ice-cooling. The mixture was stirred at the same temperature for 1.5 hour, and thereto was further added N-methyl-4-chlorobenzylamine (1.04 g), and the mixture was further stirred for one hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane:ethyl acetate (2:1)] to give the title compound (83 mg) as oil. (2)N-[3-(3-Aminopropyl)-4-{[(4-chlorobenzyl)(methyl)amino]methyl}thiazol-2(3H)-ylidene]-4-(trifluoromethoxy)aniline
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8](C#N)[CH2:9][CH2:10][C:11]([CH2:13]CC(C#N)C2C(C)=NC=CC=2)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(CCC(C1C(C)=NC=CC=1)=O)#[N:28].BrCCCC#N>N.[Ni]>[CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[CH:8]1[NH:28][CH2:13][CH2:11][CH2:10][CH2:9]1
Reactant: Cc1ncccc1C(C#N)CCC(=O)CCC(C#N)c1cccnc1C
Reactant: Cc1ncccc1C(=O)CCC#N
Agent: [Ni]
Agent: N
Agent: N#CCCCBr
Product: Cc1ncccc1C1CCCCN1
Reaction time: 20 h
Yield: 89 %

Procedure:
The preparation of 2-methyl-3-pyridyl-3-cyanopropyl ketone was carried out using the procedure described for the synthesis of 2-methyl-3-pyridyl 2-cyanomethyl ketone (Preparation III) except that 4-bromobutyronitrile was used instead of 3 bromopiopionitrile. A solution of 2.8 g of the ketone in 150 ml ammonia saturated ethanol was prepared and 10 g of freshly prepared Raney nickel was added. The mixture was hydrogenated for 20 hours in a Parr apparatus at 67 psi. The reaction mixture was worked up as in Example 2. The product was isolated by distillation (108°-112°/0.2 mm Hg) to give 2.2 g (89%) of 2-methylanabasine.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([I:24])=[C:12]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=3[S:17][C:13]2=[N:14][C:15]=1[CH3:16])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=C[C:35]=2N=N1.C(N(C(C)C)C(C)C)C.CO>ClCCl>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([I:24])=[C:12]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=3[S:17][C:13]2=[N:14][C:15]=1[CH3:16])[C:7]([O:9][CH3:35])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc2sc3c(c2c(I)c1[C@H](OC(C)(C)C)C(=O)O)CCCC3
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Temperature: 30 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of (2S)-tert-butoxy(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)acetic acid (Preparation 15, 1.0 g, 2.178 mmol) in dichloromethane (34 mL) was added [(benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium hexafluoro phosphate (1.24 g, 3.266 mmol) and ethyl-di-isopropyl-amine (600 μL, 3.266 mmol) and the resulting reaction mixture was stirred at 30° C. for 2 hours. Methanol (17 mL) was added and the reaction mixture was stirred at 30° C. for 18 hours. The reaction was cooled to room temperature and diluted with dichloromethane (50 mL). The solution was washed with a saturated aqueous solution of sodium hydrogen carbonate (50 mL), water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography eluting with 5% ethyl acetate in heptane to give the title compound as a white solid, 963 mg, in a 93% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.22 (s, 9 H), 1.85-1.88 (m, 4 H), 2.65 (s, 3 H), 2.82-2.66 (m, 2 H), 3.23-3.26 (m, 2 H), 3.68 (s, 3 H), 5.94 (s, 1 H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.C([O-])([O-])=O.[K+].[K+].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>CC#N>[S:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=[C:2]1[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Clc1nc2ncccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(Oc2nc3ncccc3s2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a 1-L, round-bottom, 3-necked flask equipped with overhead mechanical stirring, dynamic nitrogen inlet, and thermocouple probe were added 2-chloro-thiazolo[4,5-b]pyridine (51.41 g, 0.248 mol), K2CO3 (38.0 g, 0.275 mol), and CH3CN (400 mL). The resultant slurry was aged at rt for 1 h. The 4-hydroxy-benzaldehyde (30.4 g, 0.248 mol) was then added to the reaction mixture followed by K2CO3 (38.0 g, 0.275 mol). The resultant slurry was diluted with additional CH3CN (100 mL), heated to reflux, and aged for 3.5 h. The solution was cooled to 50° C. and filtered. The inorganic cake was washed with CH3CN (2×100 mL). The washes were added to the filtrate. The filtrate was concentrated until nucleation was observed (removal of ˜350 mL of CH3CN was required). The resultant slurry was heated to reflux and slowly cooled to rt during an overnight aging. The resultant slurry was cooled to 2° C. and filtered. The cake was transferred to a vacuum oven and dried at 55° C. for 16 h to yield 4-(thiazolo[4,5-b]pyridin-2-yloxy)-benzaldehyde (51.6 grams, 0.201 mol) as an orange/red powder. The mother liquor was concentrated and an additional crop of 4-(thiazolo[4,5-b]pyridin-2-yloxy)-benzaldehyde (6.2 g, 0.024 mol) was obtained from recrystallization from CH3CN. 1H NMR (400 MHz, CDCl3): 10.03 (s, 1H), 8.60 (dd, J=4.8, 1.6 Hz, 1H), 8.09 (dd, J=8.0, 1.6 Hz, 1H), 8.03-7.96 (m, 2H), 7.73-7.65 (m, 2H), 7.32-7.22 (m, 1H). MS (ESI): mass calcd. for C13H8N2O2S, 256.03; m/z found, 257.0[M+H]+.
Reaction SMILES: [OH-].[OH:2][C:3]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5](=[O:19])[C:4]=1[NH+:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33].[OH-].[K+]>C(Cl)Cl.O>[C:32]([O:2][C:3]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5](=[O:19])[C:4]=1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)(=[O:34])[CH3:33]
Reactant: O=c1c([NH+]2CCCC2)c(O)c2cccnc2n1-c1ccccc1
Reactant: CC(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1c(N2CCCC2)c(=O)n(-c2ccccc2)c2ncccc12
Temperature: 25 °C

Procedure:
A mixture of 1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-pyrrolidinium hydroxide, inner salt (3 g) and triethylamine (1.41 g) in CH2Cl2 (50 mL) was stirred at room temperature in an atmosphere of nitrogen. Acetyl chloride (1.09 g) was added dropwise and stirring was continued for a total of about 20-24 hours. The product was poured into water (200 mL) and the pH was adjusted to 7 with 10% KOH solution. The organic layer was separated and dried (Na2SO4). The dry solution was filtered and evaporated to a solid which was recrystallized from isopropanol to yield the desired product, 2.17 g (67%) m.p. 197°-200° C.
Reaction SMILES: [N+](C1C=CC(COC([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([C@@H:20]3[CH2:24][C@H:23]([S:25][C:26]4[C@H:27]([CH3:50])[C@@H:28]5[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]5[C:30]=4[C:31]([O:33]CC4C=CC([N+]([O-])=O)=CC=4)=[O:32])[CH2:22][N:21]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:19])[CH2:13]2)=O)=CC=1)([O-])=O.[ClH:66]>O1CCCC1.O>[ClH:66].[NH:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([C@@H:20]2[CH2:24][C@H:23]([S:25][C:26]3[C@H:27]([CH3:50])[C@@H:28]4[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]4[C:30]=3[C:31]([OH:33])=[O:32])[CH2:22][NH:21]2)=[O:19])[CH2:13]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N[C@H]4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N[C@H]4CCNC4)C3)[C@H](C)[C@H]12

Procedure:
475 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(3S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylaminocarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 15 ml of a 2:1 by volume mixture of tetrahydrofuran and water, after which 0.45 ml of 1N aqueous hydrochloric acid was added, and the mixture hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 1 g of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 18(b), to give 46 mg of the title compound as a powder.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:17](C(O)=O)[C:11]=3[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=[O:22].[NH2:25][CH:26]([CH3:36])[CH:27]([C:29]1[CH:34]=[CH:33][C:32](Cl)=[CH:31][CH:30]=1)[OH:28]>O1CCCC1>[N+:1]([C:4]1[S:8][C:7]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:22][CH2:36][CH:26]([NH-:25])[CH:27]([OH:28])[C:29]1[CH:34]=[CH:33][C:32]([N+:1]([O-:3])=[O:2])=[CH:31][CH:30]=1
Reactant: O=S(Cl)Cl
Reactant: CC(N)C(O)c1ccc(Cl)cc1
Reactant: O=C(O)c1cccc2[nH]c(-c3ccc([N+](=O)[O-])s3)nc12
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-c2nc3ccccc3[nH]2)s1
Product: [NH-]C(CO)C(O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
1.0 g of 2-(5-nitro-2-thienyl)-1H-benzimidazole-4-carboxylic acid is added into 15 ml of thionyl chloride; and to heat and reflux it for 60 minutes. After end of the reaction, 2-amino-1-p-chlorophenyl-1-propanol (1.1 eq) is dissolved into tetrahydrofuran, and then drop acyl chloride to the above tetrahydrofuran mixture under stirring at the room temperature and then filter inorganic salt, evaporate the solvent to dry, and then isolate the mixture through column chromatography to obtain 2-(5-nitro-2-thienyl)-1H-benzimidazole-4-(N-(1-hydroxymethyl-2-p-nitrophenylhydroxyethyl)amide. The yield is about 92%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([OH:11])[CH:3]=1.O[CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][CH2:15][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH3:13])[CH:3]=1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cnc(O)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H](COc1cc(Cl)c([N+](=O)[O-])cn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
To a solution of 4-chloro-5-nitropyridin-2-ol (1.00 g), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (1.51 g) and triphenylphosphine (2.25 g) in THF (10 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 4.52 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (860 mg).
Reaction SMILES: [N+:1]([CH:4]([N+:6]([O-:8])=[O:7])[CH3:5])([O-:3])=[O:2].[OH-].[K+].[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:14])[CH:12]=[CH2:13].CO>O>[N+:1]([C:4]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:13][CH2:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])([O-:3])=[O:2]
Reactant: CC([N+](=O)[O-])[N+](=O)[O-]
Reactant: C=CC(=O)OCCCCCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCOC(=O)CCC(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
Dinitroethane (2.4 g, 0.02 mol) and potassium hydroxide (1.2 g, 0.022 mol) were dissolved in 50 mL of water to form a first solution. 50 mL of water was added to the first solution to dissolve a salt remaining in the first solution to form a second solution. Hexyl acrylate (8.8 mL, 0.05 mol) was mixed with 50 mL of methanol, and then the mixture was slowly added to the second solution to form a third solution. The third solution was stirred at room temperature for 4 hours. The reaction product was extracted by diethyl ether, and was then distilled under reduced pressure to obtain yellow liquid hexyl 4,4-dinitropentanoate (4.5 g, yield: 81%).