Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:9][O:10][C:11]1[CH:26]=[CH:25][C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:16])=[CH:13][CH:12]=1>[Zn].C1C=CC=CC=1>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]([C:14]2[CH:25]=[CH:26][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)([OH:16])[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)C(C)C(O)(c1ccc(OC)cc1)c1ccc(OC)cc1
Yield: 50.5 %

Procedure:
A mixture of 8.25 g of ethyl 2-bromopropionate, 11.81 g of 4,4'-dimethoxybenzophenone, 7.16 g of zinc and 70 ml of benzene was heated on an oil bath for 4 hours under reflux. The mixture was then allowed to stand to cool, after which the reaction solution was filtered. The filtrate was washed with 10% w/v aqueous sulfuric acid, with water and with a saturated aqueous solution of sodium chloride, in that order. After that mixture had been dried, the solvent was distilled off under reduced pressure. The residue was subjected to flash column chromatography through silica gel (about 400 mesh, 300 g). 7.92 g of the title compound were obtained as white crystals, melting at 67°-69° C. (after recrystallisation from a mixture of methylene chloride and hexane), from those fractions eluted with a 100:2 by volume mixture of hexane and ethyl acetate.
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:27])[CH2:9][C:10]1[N:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.[C:28]1([Mg]Br)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([C:10]([CH2:9][C:8]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:27])=[C:11]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[N:12]=2)[CH:15]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)Sc2ccccn2)cc1
Reactant: Br[Mg]c1ccccc1
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)c2ccccc2)cc1

Procedure:
Prepared from (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-thioacetic acid S-pyridin-2-yl ester 1c and phenylmagnesium bromide using a similar procedure described above. 1H NMR (400 MHz, CDCl3) δ 2.26 (s, 3H), 2.37 (s, 3H), 4.64 (s, 2H), 7.00 (d, J=8.8 Hz, 1H), 7.21 (d, J=8.0 Hz, 2H), 7.41 (t, J=7.7 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.58 (m, 3H), 7.96 (d, J=7.3 Hz, 2H). Mass spectrum m/e 341 (M+).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([C:21]#[N:22])([CH3:20])[CH3:19])[CH:13]=2)[CH:6]=[CH:7][C:8]=1[CH3:9].C[Al](C)C.[Br:28][C:29]1[C:33]2=[N:34][CH:35]=[CH:36][N:37]=[C:32]2[S:31][C:30]=1[C:38](OCC)=[O:39]>C1(C)C=CC=CC=1>[Br:28][C:29]1[C:33]2[C:32](=[N:37][CH:36]=[CH:35][N:34]=2)[S:31][C:30]=1[C:38]([NH:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([C:21]#[N:22])([CH3:20])[CH3:19])[CH:13]=2)[CH:6]=[CH:7][C:8]=1[CH3:9])=[O:39]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Reactant: CCOC(=O)c1sc2nccnc2c1Br
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1sc2nccnc2c1Br
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
To a solution of N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (230 mg, 0.697 mmol) in toluene (4 mL) was added trimethylaluminum (1.393 mL, 2.79 mmol). After stirring for 15 min, ethyl 7-bromothieno[3,2-b]pyrazine-6-carboxylate 41 (200 mg, 0.697 mmol) in toluene (4 mL) was added and stirred overnight at 60° C. Quenched with 0.5N NaOH solution and extracted with EtOAc. Organic layer was washed with brine, dried and evaporated. Purification by chromatography (0-10% EtOAc in CH2Cl2) gave the title compound 7-bromo-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 42 (268 mg, 72.0%). NMR (400 MHz, CDCl3) 1.80 (s, 6H), 2.49 (s, 3H), 7.31 (d, J=8.2 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.74 (m, 1H), 7.80 (d, J=7.8 Hz, 2H), 7.95 (s, 1H), 8.00 (s, 1H), 8.36 (d, J=2.3 Hz, 1H), 8.71 (d, J=2.3 Hz, 1H), 8.84 (d, J=2.3 Hz, 1H), 9.10 (s, 1H). (m/z)=534 and 536 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15](O)=[O:16])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.Cl.Cl.[N:57]1([C:63]2[CH:68]=[CH:67][C:66]([N:69]3[CH2:73][C@H:72]([CH2:74][O:75][C:76]4[CH:80]=[CH:79][O:78][N:77]=4)[O:71][C:70]3=[O:81])=[CH:65][C:64]=2[F:82])[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1.C(N(CC)C(C)C)(C)C>ClCCl>[C:24]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([N:60]3[CH2:59][CH2:58][N:57]([C:63]4[CH:68]=[CH:67][C:66]([N:69]5[CH2:73][C@H:72]([CH2:74][O:75][C:76]6[CH:80]=[CH:79][O:78][N:77]=6)[O:71][C:70]5=[O:81])=[CH:65][C:64]=4[F:82])[CH2:62][CH2:61]3)=[O:16])[N:10]=[CH:9]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Reactant: O=C(O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
3-(1-Triphenylmethyl-4-imidazolyl)propionic acid (420 mg, 1.1 mmol) was suspended in dichloromethane (10 ml) under nitrogen, and treated successively with dicyclohexylcarbodiimide (227 mg, 1.1 mmol) and 1-hydroxybenzotriazole (149 mg, 1.1 mmol), then stirred at ambient temperature for 30 minutes. To it was added a solution of 3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (435 mg, 1 mmol) and N,N-diisopropylethylamine (258 mg, 2 mmol) in dichloromethane (5 ml). The mixture was stirred for 18 hours at the same temperature, solid filtered off, and the organic phase purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 15% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (460 mg).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1F)[CH:13]=[O:14].Cl>CN(C)C=O>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[CH:13]=[O:14]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.844 g) in N,N-dimethylfounamide (30.0 mL), 2,2,2-trifluoroethanol (2.11 g) was added at 0° C. and thereafter the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, a solution of 3,4-difluorobenzaldehyde (2.00 g) in N,N-dimethylformamide (10.0 mL) was added and thereafter the mixture was stirred at room temperature for 30 minutes. After adding 1 mol/L hydrochloric acid at 0° C., three extractions were conducted with ethyl acetate. The combined organic layers were passed through a phase separator and thereafter concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=80:20-30:70) to give the titled compound as a colorless oil (2.50 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][NH:8][S:7]1(=[O:13])=[O:12].[CH2:20]([O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([CH2:35]O)=[CH:31][CH:30]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:20]([O:27][C:28](=[O:37])[C:29]1[CH:30]=[CH:31][C:32]([CH2:35][N:8]2[CH2:9][C:10](=[O:11])[N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=3[O:2][CH3:1])[S:7]2(=[O:13])=[O:12])=[CH:33][CH:34]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(OCc1ccccc1)c1ccc(CO)cc1
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)OCc4ccccc4)cc3)S2(=O)=O)c(OC)c1
Temperature: 0 °C

Procedure:
To a solution of the title B compound in Example 9, 2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2.0 g, 7.0 mmol) and 4-hydroxymethyl-benzoic acid benzyl ester (2.54 g, 10.5 mmol) in THF (50 mL) is added triphenylphosphine (3.67 g, 14 mmol) and the mixture is stirred until dissolved. The reaction is cooled to 0° C. and diethyl azodicarboxylate (2.20 mL, 14 mmol) dissolved in THF (20 mL) is added dropwise. The reaction is stirred for 16 h, while allowing to warm to RT, then concentrated. The residue is taken up in CH2Cl2, and chromatographed in two portions on a 110 g silica gel RediSep column (Isco, Inc.) with a 30 mL/min gradient elution of 0:100 (EtOAc:hexane) to 5:95 over 10 min. Fractions containing product are combined and concentrated to yield 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid benzyl ester as a white solid.
Reaction SMILES: C(O)C.[OH-].[Na+].[CH3:6][N:7]([CH3:33])[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][C:28]([O:30]CC)=[O:29])[N:19]=2)=[CH:14][CH:13]=1.Cl>O>[CH3:33][N:7]([CH3:6])[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][C:28]([OH:30])=[O:29])[N:19]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)Cn1nc(-c2ccc(OCCCN(C)C)cc2)c2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)CCCOc1ccc(-c2nn(CC(=O)O)c3ncccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 90 mg of ethanol, 40 ml of water and 2.0 g of sodium hydroxide was added 13 g of ethyl 3-[4-(3-dimethylaminopropoxy)phenyl]-1H-pyrazolo[3,4-b]pyridin-1-ylacetate. The mixture was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was adjusted to pH 7 by dilute hydrochloric acid. The mixture was purified with ion-exchange resin (Diaion HP-20) and recrystallized from hydrous methanol to give 3-[4-(3-dimethylaminopropoxy)phenyl]-1H-pyrazolo[3,4-b]pyridin-1-ylacetic acid, m.p. 221°-223° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Product: CS(=O)(=O)c1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-methanesulfonylphenol: 1H NMR (300 MHz, CDCl3) δ 7.67 (app. d, J=8.8 Hz, 2H), 7.67 (d, J=8.6 Hz, 1H), 7.19 (d, J=2.5 Hz, 1H), 7.05-6.95 (m, 3H), 4.29 (t, J=5.3 Hz, 2H), 4.20 (q, J=8.6 Hz, 2H), 4.05 (t, J=5.1 Hz, 2H), 3.01 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[CH2:16]3)[CH:13]=[N:14][C:7]=12.[C:26]([O:29]C(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:16]3[O:29][C:26](=[O:28])[CH3:27])[CH:13]=[N:14][C:7]=12
Reactant: CC(=O)O[C@H]1C[C@H](n2cnc3c(-c4cccs4)ccnc32)O[C@@H]1CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](CO)O[C@H]1n1cnc2c(-c3cccs3)ccnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.9 %

Procedure:
Compound 9 (247 mg, 0.4 mmol) was azeotroped with pyridine, followed by addition of pyridine (4 ml) and acetic anhydride (75 μl, 0.8 mmol). After stirring at room temperature for 12 hours, the reaction mixture was partitioned between ethyl acetate and 5% aqueous NaHCO3, and the organic layer was washed with 5% aqueous NaHCO3. This organic layer was dried over anhydrous sodium sulfate, concentrated and azeotroped with toluene. The residue was then dissolved in methylene chloride (40 ml). To this reaction mixture, dichloroacetic acid (400 μl) was added at 0° C. and stirred for 15 minutes at 0° C. The reaction mixture was partitioned with 5% aqueous NaHCO3, and the organic layer was washed with 5% aqueous NaHCO3. After drying over anhydrous sodium sulfate, the organic layer was concentrated and purified on a silica gel column to give Compound 13 (125 mg, 87%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:34]([O:36][CH2:37][CH3:38])=[O:35])([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])/[C:9]1=[O:39])=O)(C)(C)C.[Cl:40][C:41]1[CH:42]=[CH:43][C:44]([CH3:56])=[C:45]([CH:47]=[N:48][C:49]([O:51][Si](C)(C)C)=[CH2:50])[CH:46]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:39])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([C:34]([O:36][CH2:37][CH3:38])=[O:35])([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])[CH2:51][C:49](=[O:50])[NH:48][CH:47]3[C:45]3[CH:46]=[C:41]([Cl:40])[CH:42]=[CH:43][C:44]=3[CH3:56])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(Cl)ccc1C)O[Si](C)(C)C
Reactant: CCCC(CCC)(Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OCC
Yield: 20.1 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-6-chloro-3-[5-chloro-2-(1-ethoxycarbonyl-1-propyl-butoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.3 g, 2.3 mmol) was reacted with 1-(5-chloro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (10 mmol) prepared in Example 13b in toluene to give the title compound as a white solid (310 mg).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH2:24][CH3:25])[N:16]=2)=[N:13][CH:14]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[CH2:24]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[C:15]([C:12]2[N:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[N:16]1)[CH3:25]
Reactant: CCn1nc(-c2ccc(OCc3ccccc3)cn2)c2ncccc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCn1nc(-c2ccc(O)cn2)c2ncccc21
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A mixture of 3-[5-(benzyloxy)pyridin-2-yl]-1-ethyl-1H-pyrazolo[4,3-b]pyridine (224 mg) and 10% Pd—C (50% wet, 78 mg) in MeOH (3 mL) and AcOEt (3 mL) was hydrogenated under balloon pressure at room temperature overnight. The solid was filtrated and washed with MeOH (50 mL×3). The filtrate was concentrated under reduced pressure. The precipitate was collected by filtration and washed with 25% AcOEt in hexane to give the title compound (137 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28](OCC)=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28]([NH:38][CH2:37][CH2:36][O:35][CH3:34])=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 110 and was obtained as a white solid: 1H NMR (CDCl3) δ 10.18 (1H, br t, J=5 Hz), 8.54 (1H, d, J=1 Hz), 7.15 (2H, dd, J=9, 5 Hz), 7.07 (1H, s), 7.02 (2H, t, J=9 Hz), 4.88 (2H, s), 4.11 (2H, s), 3.64 (2H, m), 3.57 (2H, m), 3.51 (2H, m), 3.45 (2H, m), 3.39 (3H, s), 2.03 (2H, m), 1.90 (2H, m); HRMS calcd for C25H27FN4O5+H+: 483.2044. Found: 483.2055.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:15]([O:17]C)=O)=[C:8]([C:12](Cl)=[O:13])[NH:9]2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:30][NH2:31])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:19])[C:7]3[C:15](=[O:17])[N:30]([C:24]4[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=4)[N:31]=[C:12]([OH:13])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COC(=O)c1c(C(=O)Cl)[nH]c2cc(Cl)ccc2c1=O
Reactant: COc1ccc(NN)cc1OC
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)cc1OC
Temperature: 0 °C
Yield: 10.5 %

Procedure:
7-Chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carbonyl chloride (7.00 g, 23.3 mM) was dissolved in tetrahydrofuran (210 mL) and added dropwise over 20 minutes to a cold (0° C.) solution of 3,4-dimethoxyphenylhydrazine (9.80 g, 58.3 mM) in tetrahydrofuran (420 mL)with stirring. The resulting brown suspension was stirred at 0° C. for 30 minutes and at room temperature for 2 hours. Ice/water slurry (450 mL) was added to the reaction mixture followed by 1N HCl (1.2 L) and the brown suspension was stirred for 1 hour. The solids were separated by filtration and washed with water and then ether to provide7-chloro-3-methoxycarbonyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid N-2-(2,4-dimethoxyphenyl)hydrazide (15 g, wet). The combined filtrateand washes were partially concentrated to remove the THF whereupon a precipitate formed. This precipitate was collected and washed with water and then ether to give the crude title compound (2.00 g). Recrystallization of this crude from refluxing methanol (500 mL) gave the title compound (0.98 g, 10%) as a tan powder, mp=334°-336° C.; HS(CI): 400 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:25])=[N:8][C:9]2[C:14]([C:15]=1[NH2:16])=[C:13]([O:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[C:26](O)(=[O:30])[CH2:27][CH2:28][CH3:29]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:25])=[N:8][C:9]2[C:14]([C:15]=1[NH2:16])=[C:13]([O:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([C:26](=[O:30])[CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24]1)[CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCCC(=O)O
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC3CCNCC3)c2c1N
Product: CCCC(=O)N1CCC(COc2cccc3nc(C)c(C(=O)OCC)c(N)c23)CC1

Procedure:
Prepared as in Example 24a from ethyl-4-amino-2-methyl-5-(piperidin-4-ylmethoxy)-quinoline-3-carboxylate (Example 35b) and butyric acid as a yellow oil (50%). MS 414 (MH+).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[CH3:27][S:28][C:29]1[N:36]2[C:32]([S:33][C:34]([Sn](CCCC)(CCCC)CCCC)=[CH:35]2)=[C:31]([C:50]([C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)=[O:51])[N:30]=1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:34]3[S:33][C:32]4=[C:31]([C:50]([C:52]5[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=5)=[O:51])[N:30]=[C:29]([S:28][CH3:27])[N:36]4[CH:35]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2c(SC)nc(C(=O)c3cccnc3)c2s1
Product: CSc1nc(C(=O)c2cccnc2)c2sc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Yield: 94.6 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[5-methylthio-7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (1.78 g) was prepared in the same manner as in step a) of Example 1, except that 1.10 g of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.88 g of 5-methylthio-7-(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[OH-].[K+].Cl[C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][N:14]=1>CO.C1(C)C=CC=CC=1>[NH2:19][C:18]1[C:13]([O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(Oc2ncccc2N)cc1
Reaction time: 2 h
Yield: 108.5 %

Procedure:
5.87 g of 4-methoxyphenol were dissolved in 8 ml of methanol; 2.61 g of KOH were added, the whole was stirred for 2 hours, and the solvent was evaporated. The solid obtained was dissolved in 150 ml of anhydrous toluene. With stirring, 5 g of 2-chloro-3-nitropyridine were added at 70°-80° C. in the course of 4 hours under a nitrogen atmosphere. The whole was then stirred at ambient temperature for 2 hours. It was washed with 10% aqueous NaOH and then with plenty of water. The organic phase was treated with active carbon at room temperature for 60 minutes. It was filtered and the filtrate was dried with anhydrous magnesium sulphate. After evaporation of the solvent at low pressure, 7.4 g of 3-amino-2-(4-methoxyphenoxy)pyridine (95% yield) were obtained as a pale yellow solid which melted at 105°-107° C. with decomposition.
Reaction SMILES: [Cl-].[C:2]([CH2:5][O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[NH3+:13])([OH:4])=[O:3].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>[OH-].[Na+].C(OCC)C>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([NH:13][C@@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]2[O:6][CH2:5][C:2]([OH:4])=[O:3])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [NH3+][C@@H]1CCCC[C@H]1OCC(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N[C@@H]2CCCC[C@H]2OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.6 %

Procedure:
To a solution of trans-2-carboxymethoxy-cyclohexyl ammonium chloride (1.048 g, 5 mmoles) in 1N NaOH (15 ml), there was aded a solution of p-toluenesulphonyl chloride (1.048 g, 5.5 mmoles) in diethyl ether (20 ml). The mixture was vigorously stirred for 20 hours at room temperature. The aqueous phase was separated, washed with diethyl ether (20 ml), acidified with HCl 18% to pH 2 and extracted with diethyl ether (5×20 ml). The organic extracts were dried with MgSO4, the drying agent was filtered off and filtrate was evaporated in vacuo. The residue was recrystallized from diisopropyl ether. Thus, there were obtained 1.09 g (67%) of the title compound in the form of white crystals, melting point 56°-58° C.
Reaction SMILES: C(OC([N:8]([C@@H:16]1[CH2:22][CH2:21][C@@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[CH2:19][N:18]([CH2:31][C:32]([OH:35])([CH3:34])[CH3:33])[C:17]1=[O:36])C(OC(C)(C)C)=O)=O)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl>[NH2:8][C@@H:16]1[CH2:22][CH2:21][C@@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[CH2:19][N:18]([CH2:31][C:32]([OH:35])([CH3:33])[CH3:34])[C:17]1=[O:36].[C:39]([OH:41])([C:38]([F:43])([F:42])[F:37])=[O:40]
Reactant: CC(C)(O)CN1C[C@H](c2cccc(F)c2F)CC[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)CN1C[C@H](c2cccc(F)c2F)CC[C@@H](N)C1=O

Procedure:
A solution of di-tert-butyl[(3R,6S)-6-(2,3-difluorophenyl)-1-(2-hydroxy-2-methylpropyl)-2-oxoazepan-3-yl]imidodicarbonate (0.095 g, 0.185 mmol) in DCM (10 mL) was treated with trifluoroacetic acid (3 mL). After 1 h the reaction was concentrated to dryness to afford the title compound as a TFA salt. MS 313.2 (M+1).