Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH2:25])[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1.Br[C:30]1[S:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][N:34]=1.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH:25][C:30]2[S:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][N:34]=2)[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1
Reactant: NCCNc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Reactant: O=[N+]([O-])c1cnc(Br)s1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)s1
Temperature: 130 °C

Procedure:
100 mg (0.238 mmol) of the amine (Example 8A) are introduced into 3 ml of DMSO, 76 mg (0.357 mmol) of 2-bromo-5-nitro-1,3-thiazole and 154 mg (1.19 mmol) of DIEA are added, and the mixture is heated in a microwave at 130° C. for 30 min. Purification by preparative HPLC results in 35 mg (33% of theory) of the product as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[C:13]([CH3:20])([CH3:19])[C:14](OCC)=[O:15].[F-].[K+].O>CN(C=O)C>[CH3:19][C:13]1([CH3:20])[C:14](=[O:15])[NH:1][C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[O:11]1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
At room temperature, a solution of 2-amino-4-nitro-phenol (82.5 g, 0.54 mol) in DMF (660 ml) is treated with ethyl 2-bromoisobutyrate (160 ml, 1.07 mol) and KF (124.7 g, 2.15 mol), stirred at the same temperature for 1 h, warmed to 60° C., and stirred for 48 h. After pouring the mixture into H2O (3500 ml), the resulting precipitate is collected by filtration, and washed with H2O and Et2O for several times respectively to give 2,2-dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one (84.8 g, 71%) as yellow solid. Rf (hexane/EtOAc 2:1) 0.42. 1H-NMR (400 MHz, DMSO-d6) 1.48 (s), 7.16 (d, J=9.0), 6.42 (d, J=0.4), 8.00 (dd, J=9.0, 0.4). 13C-NMR (100 MHz, DMSO-d6) 167.7 (s), 147.5 (s), 142.0 (s), 128.0 (s), 119.2 (d), 117.3 (d), 110.3 (d), 78.9 (s), 23.7 (2q).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:53][C:54]1[CH:55]=[C:56]([C:60]2[N:69]=[C:68]([NH:70][C:71]3[CH:72]=[C:73]4[C:77](=[CH:78][CH:79]=3)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]4)[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[N:61]=2)[CH:57]=[CH:58][CH:59]=1>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][C:8]([NH:53][C:54]2[CH:55]=[C:56]([C:60]3[N:69]=[C:68]([NH:70][C:71]4[CH:72]=[C:73]5[C:77](=[CH:78][CH:79]=4)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]5)[C:67]4[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=4)[N:61]=3)[CH:57]=[CH:58][CH:59]=2)=[O:10])[CH2:5][CH2:6]1
Reactant: O=C(O)CN1CCOCC1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)CN5CCOCC5)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of 2-morpholinoacetic acid (16 mg, 0.11 mmol), PyBOP® (57 mg, 0.11 mmol), DIEA (96 μL, 0.55 mmol) in CH2Cl2 (0.5 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate 0 (100 mg, 0.22 mmol) and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 0.5 equivalent of the acid as described above and it was once again added to the reaction mixture and stirred for 1.5 h. Added two more 0.5 equivalents of activated acid while stirring 1.5 hr between each addition. Diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired oil product tert-butyl 5-(2-(3-(2-morpholinoacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][NH:21][CH2:20][CH2:19]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=4)[CH2:22]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: COc1cc2c(cc1OC)CN(C(=O)c1cc3ncc(Cl)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[C:10](=[O:28])[NH:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][N:11]3[CH2:12][C@H:8]([C:6]([OH:7])=[O:5])[NH:9][C:10]3=[O:28])=[CH:15][CH:16]=2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CN(Cc2ccc(Oc3ccc(F)cc3)cc2)C(=O)N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CN(Cc2ccc(Oc3ccc(F)cc3)cc2)C(=O)N1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of (4R)-1-[4-(4-fluorophenoxy)benzyl]-2-oxo-imidazolidine-4-carboxylic acid tert-butyl ester (810 mg, 1.56 mmol) in CH2Cl2 (8 mL) was treated with trifluoroacetic acid (8 mL). The reaction mixture was stirred at room temperature for 2.5 hours and concentrated to leave an oil. The title compound, a white solid (297 mg, 58%), was collected by filtration, after triturating the oil with a mixture of warm diethyl ether and hexane.
Reaction SMILES: [C:1]([C:9]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:10]=1[NH:11][C:12](=[O:21])[C:13](=[N:19]O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl>[Zn].C(O)(=O)C>[Cl:26][C:24]1[CH:23]=[CH:22][C:10]2[NH:11][C:12](=[O:21])[CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:19]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]=2[CH:25]=1
Reactant: CCOC(=O)C(=NO)C(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O

Procedure:
A solution of 2 g. of ethyl 2'-benzoyl-4'-chloro-mesoxalanilate-2-oxime in 40 ml. of methylene chloride is treated with 2 g. of zinc dust. 4 ml. of glacial acetic acid are added dropwise within 5 minutes with stirring. After the addition, the mixture is stirred at room temperature for 1 hour. The reaction mixture is filtered and the filtrate evaporated. The residue is boiled under reflux for 2 hours in 20 ml. of benzene and 2 ml. of glacial acetic acid. The reaction mixture is washed out with 10% soda solution, dried over sodium sulphate and evaporated. Crystallization of the residue from alcohol yields ethyl 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one-3-carboxylate, m.p. 232°-234°. Further material crystallizes from the mother liquor.
Reaction SMILES: [H-].NN.C1(=O)[N:8]([CH2:9][CH2:10][CH2:11][S:12][C:13]2[O:14][CH:15]=[CH:16][N:17]=2)C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[O:14][CH:15]=[CH:16][N:17]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1ncco1
Agent: NN
Agent: [H-]
Solvent: CCO
Product: NCCCSc1ncco1

Procedure:
Hydrazine hydride (5.3 g.) was added carefully to a solution of 2-(3-phthalimidopropylthio)oxazole (10 g.) in ethanol (173 ml.) with stirring. The solution was then heated under reflux for 25 minutes. After cooling, and filtration from phthalhydrazide, the filtrate was concentrated under reduced pressure and the residue was re-evaporated with ethanol to yield crude 2-(3-aminopropylthio)oxazole which was washed twice with ether and dissolved in ethanol (60 ml.). Methyl isothiocyanate (2.54 g.) was added and the solution was heated under reflux for 30 minutes. Following cooling and filtration from insoluble material, the filtrate was concentrated to an oil which was chromatographed on a column of silica gel with ethyl acetate as eluant. The product obtained crystallised from ethanol-ether-n-hexane to give N-methyl-N'-[3-(2-oxazolyl)propyl]thiourea (2.4 g.), m.p. 43°-45°.
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]2[N:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][C:24]=3[O:33][CH3:34])[C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].N1C=CC=CC=1.[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)Cl>[C:43]([N:11]1[C@@H:10]([CH3:12])[C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:8](=[O:21])[N:7]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][C:24]=2[O:33][CH3:34])[C:6]2[CH:35]=[CH:36][C:3]([C:1]#[N:2])=[CH:4][C:5]1=2)(=[O:45])[CH3:44]
Reactant: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)Nc2cc(C#N)ccc21
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a 0° C. solution of tert-butyl(3S,4S)-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (448 mg, 921 μmol) in CH2Cl2 (9.21 ml) was added pyridine (375 μl, 4.6 mmol), followed by acetyl chloride (78.8 μl, 1.1 mmol), dropwise. The reaction was stirred at 0° C. for 1 h, then allowed to warm to rt and stirred for an additional 20 h, then quenched by the addition of H2O and extracted with CH2Cl2. The combined organic layers were washed with sat. aq. NaHCO3 and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(3S,4S)-5-acetyl-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (316 mg, 65%) as a white solid. MS m/z 551 (MNa)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][Br:16])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCCCBr
Reactant: Oc1ccc(OCc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: BrCCCCCOc1ccc(OCc2ccccc2)cc1
Reaction time: 120 h

Procedure:
4-Benzyloxyphenol and 1,5-dibromopentane were reacted under conditions described in Example 15 for 5 days. The crude product isolated by a toluene extraction, was distilled to give 1-benzyloxy-4-(5-bromopentoxy)benzene as an oil (88.9% pure by gas chromatography).
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.[O:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.[Cl-].[NH4+]>C(OCC)C.C1COCC1>[OH:21][C:18]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1
Reactant: O=C1CCOCC1
Reactant: N#Cc1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(O)CCOCC2)cc1
Reaction time: 1.5 h

Procedure:
Under inert conditions, 109 ml (218 mmol) of a 2 M solution of isopropylmagnesium chloride in diethyl ether were added dropwise at −40° C. to a solution of 50.0 g (218 mmol) of 4-iodobenzonitrile in 1000 ml of anhydrous THF. After the mixture had been stirred at the same temperature for 1.5 h, a solution of 32.8 g (327 mmol) of tetrahydro-4H-pyran-4-one in 250 ml of anhydrous THF was added. After the addition had ended, the reaction mixture was stirred first at −40° C. for 10 min, then at 0° C. for 30 min and finally at RT for 60 min. Then approx. 20 ml of saturated aqueous ammonium chloride solution were added at −20° C. Subsequently, the solvent was substantially removed on a rotary evaporator. 1000 ml of water were added to the remaining residue, which was extracted three times with approx. 500 ml each time of dichloromethane. The combined organic extracts were washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, the mixture was filtered and the solvent was removed on a rotary evaporator. The resulting crude product was purified by stirring with 10:1 cyclohexane/ethyl acetate. 19.3 g (43% of theory) of the title compound were obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:14][CH2:15][C:16]([Cl:18])=[O:17]>ClCCl>[ClH:18].[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:16](=[O:17])[CH2:15][Br:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(Cl)CBr
Solvent: ClCCl
Product: Cl
Product: O=C(CBr)N[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
(R)-(−)-1-Benzyl-3-aminopyrrolidine (5 g, 28 mmol) was dissolved in dichloromethane (10 ml). To this solution, a solution of bromoacetyl chloride (4.55 g, 28 mmol) in dichloromethane (5 ml) was added at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was filtered, washed with dichloromethane and dried in vacuo to afford 6.8 g (72%) of (3R)-N-(1-benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride as a solid which was used directly in the next step. 4-Hydroxy-2-methoxybenzaldehyde (2.05 g , 13 mmol) was dissolved in DMF (7 ml) and potassium carbonate (6.2 g, 45 mmol) was added followed by a suspension of the above (3R)-N-(1-Benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride (3.0 g, 9 mmol) in DMF (16 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was then partitioned between water (100 ml) and ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were washed with saturated sodium chloride (3×15 ml), dried (MgSO4) and concentrated in vacuo. The residue was crystallized from diethyl ether to afford 2.11 g (64%) (R)-N-(1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)acetamide as a solid. M.p.: 98-101° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH:11]=O)[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2].[CH:20]([NH2:23])([CH3:22])[CH3:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH2:11][NH:23][CH:20]([CH3:22])[CH3:21])[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C=O
Reactant: CC(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CNC(C)C
Reaction time: 4 h

Procedure:
A solution of (3S*,4S*)-4-formyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2.87 g, 10.56 mmol) and isopropylamine (2.72 mL, 31.68 mmol) in 1,2-dichloroethane (150 mL) is stirred 25 min, before addition of NaBH(OAc)3 (3.12 g, 14.78 mmol) follows. The solution is stirred for 4 h, then diluted with CH2Cl2 and washed with an aqueous saturated solution of NaHCO3. The combined organic extracts are dried over Na2SO4 and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 100:0 to 80:20) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][NH2:11])=[N:5][N:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>CC(C)=O.O>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][NH:11][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[N:5][N:4]=[N:3]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cn1nnnc1SCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C(=O)NCCCSc2nnnn2C)cc1
Reaction time: 2 h
Yield: 43.8 %

Procedure:
1-Methyl-5-(3-aminopropylthio)-1,2,3,4-tetrazole (0.9 g) is dissolved in a mixture of acetone (50 ml) and water (10 ml). To the mixture is added potassium carbonate (0.7 g) and thereto is added dropwise with stirring 4-methoxybenzoylchloride (1.1 g) under ice-cooling. Stirring is continued for 2 hours under ice-cooling. After acetone is distilled off, water is added to the resulting residue and the mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over sodium sulfate. Chloroform is distilled off and then the residue is purified by column chloratography (Wakogel C-200), followed by eluting with chloroform to give 1-methyl-5-{3-[N-(4-methoxybenzoyl)amino]propylthio}-1,2,3,4-tetrazole (0.7 g), colorless needles (ethyl acetate-ethanol), m.p. 118°-122° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:37])[C@@H:15]4[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]4[C:17]=3[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])[S:10][C:9]=12.[N:38]12[CH2:45][CH2:44][N:41]([CH2:42][CH2:43]1)[CH2:40][CH2:39]2>C(#N)C>[Br-:1].[N+:38]12([CH2:2][CH2:3][S:4][C:5]3[N:6]=[CH:7][N:8]4[CH:12]=[C:11]([C:13]5[C@H:14]([CH3:37])[C@@H:15]6[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]6[C:17]=5[C:18]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=5)=[O:19])[S:10][C:9]=34)[CH2:45][CH2:44][N:41]([CH2:42][CH2:43]1)[CH2:40][CH2:39]2
Reactant: C1CN2CCN1CC2
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCBr)c4s3)[C@H](C)[C@H]12
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCC[N+]56CCN(CC5)CC6)c4s3)[C@H](C)[C@H]12
Product: [Br-]
Temperature: 50 °C
Reaction time: 12 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[7-(2-bromoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (177 mg) was dissolved in 5 ml of acetonitrile. 1,4-Diazabicylco[2,2,2]octane (43 mg) was added to the solution. The mixture was stirred at 50° C. for 12 hr. The reaction solution was concentrated, and the residue was purified by column chromatography on Sephadex LH-20 (chloroform:methanol=1:1) to prepare 184 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-[2-(1-azonia-4-azabicyclo-[2,2,2]oct-1-yl)ethyl]thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate bromide.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([C:17]([O:19]C)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH3:22]>CCOCC>[C:1]1([C:7]2[CH:16]=[C:15]([C:17](=[O:19])[CH3:22])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(-c2ccccc2)nc2ccccc12
Reactant: [Li]C
Solvent: CCOCC
Product: CC(=O)c1cc(-c2ccccc2)nc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
To methyl 2-phenyl-4-quinolinecarboxylate (1 g, 3.80 mmol) in 10 ml ether, at 0° C. was added MeLi (1.4M, 3.0 ml, 4.1 mmol) dropwise over a five minute period. The reaction mixture was stirred at 0° C. for 30 minutes and quenched by the addition of 10 ml of water. The ether layer was separated, dried over sodium sulfate, filtered, concentrated and purified (hexane:EtOAc; 4.5:0.5) to give 0.233 g (23%) of the product as a syrup which was used as such for the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[N:3]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7](OCC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][C:6]=1[CH2:7][OH:8]
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc(CO)c1Cl
Temperature: -70 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
A solution (30 mL) of ethyl 2-chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (1.27 g) in tetrahydrofuran was cooled to −70° C., a 1.5 mol/L solution (7.6 mL) of diisobutylaluminum hydride in toluene was added dropwise by small portions. The mixture was further stirred at −70° C. for 1 hr, 1 mol/l hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as pale-red crystals (yield 882 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([CH2:51][N:52]=[S:53]([CH3:58])([N:55]([CH3:57])[CH3:56])=[O:54])=[CH:47][CH:46]=1>O1CCOCC1>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[CH:50]=[CH:49][C:48]([CH2:51][N:52]=[S:53]([CH3:58])([N:55]([CH3:57])[CH3:56])=[O:54])=[CH:47][CH:46]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CN(C)S(C)(=O)=NCc1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Solvent: C1COCCO1
Product: CN(C)S(C)(=O)=NCc1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)cc1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N′-[(4-bromophenyl)methyl]-N,N-dimethyl-methanesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3) using 1,4-dioxane as a solvent. LC (method 1): tR=1.04 min; Mass spectrum (ESI+): m/z=714 [M+H]+.